SK145993A3 - Antiretroviral hydrazine derivatives - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R1 and R9, independently of each other, denote hydrogen, acyl or unsubstituted or substituted alkyl; sulpho; or sulphonyl which is substituted by unsubstituted or substituted alkyl, aryl or heterocyclyl, with the proviso that at most one of the radicals R1 and R9 denotes hydrogen; and R2 and R8, in each case independently of each other, denote hydrogen or unsubstituted or substituted alkyl; R3 and R4, independently of each other, denote hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or aryl; R5 denotes acyloxy; R6 denotes hydrogen; and R7 denotes unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or aryl; are described, as are salts of the said compounds, insofar as salt-forming groups are present; these compounds exhibit anti-retroviral activity.

Description

Technical field

The present invention relates to novel antiretroviral active compounds, to a process for the preparation of these compounds, to novel products for the preparation of these compounds, in particular to such compounds having antiretroviral activity, to pharmaceutical compositions containing these compounds, to such compounds for use in a therapeutic method for the human or animal body. for the therapeutic treatment of the human or animal body or for the manufacture of pharmaceutical preparations.

BACKGROUND OF THE INVENTION

There are a number of diseases that are caused by retrovirus as well.

To date, AIDS is a disease that is caused by the HIV (Human Immunodefociency Virus) retrovirus. There are already millions infected. The disease continues to spread and always leads to practically death of the patient.

Heretofore, HIV-1 and HIV-2 retroviruses have been identified as the cause of this disease (HIV means Human Immunodeficiency Virus). For the treatment of this disease, it is desirable to seek for compositions which will adversely affect the multiplication of the virus itself without causing damage to the virus-affected cells and tissues of the patients.

The retroviral protease is a proteolytic enzyme which, due to the aspartate residue present in the active center, counts among aspartate proteases. the enzyme participates in the reproductive cycle of a whole range of retroviruses to mature new infectious virions inside the infected cells.

For example, HIV-1 and HIV-2 retroviruses always have a region in their genome that encodes a gag protease. This gag protease is responsible for the correct proteolytic cleavage of protein precursors that originate from genomic grafts encoding Group Specific Antigens (gag). This releases the structural proteins of the viral core. The gag protease itself is part of a protein precursor that is encoded by HIV-1 and HIV-2 1-genomic grafts, which also contains reverse transcriptase and integrase grafts, and is likely to be cleaved autoproteytically. .

The Gag protease cleaves the major core protein of p24 of HIV-1 and HIV-2 retroviruses, preferably at the N-terminal flanking position of the new residue, for example, to the two-valent radical Phe-Pro, Leu-Pro or Tyr-Pro.

Given the central role of the gag protease in the processing of said core protein, it is believed that effective inhibition of this enzyme in vivo can prevent the formation of mature virions, and that corresponding inhibitors can be therapeutically used for this purpose.

In general, to combat retroviral diseases, such as AIDS, research teams have been working for some time to produce compounds that are effective as inhibitors of in vivo retroviral gag proteases, particularly retrovirus gag protease. HIV-1 (HIV-1 protease), but also against HIV-2 retrovirus protease or other AIDS-virus proteases.

At present, the main task is to provide such compounds which would preferably have the best pharmacokinetic properties.

A prerequisite for in vivo therapeutic efficacy is the good attainability of these inhibitors for the body, for example, good resorbability and / or high levels of these inhibitors in blood plasma, also when administered enterally, particularly orally, to achieve a high concentration of inhibitory active agent in infected cells.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

Rs in which

R (9) and R (9) independently of one another are hydrogen, acyl, unsubstituted or substituted alkyl, sulfo or unsubstituted or substituted alkyl, aryl or heterocyclyl substituted sulfonyl, with the proviso that at most one of R 1 and R 5 is hydrogen, and

R ₂ and R 5 are each independently hydrogen or unsubstituted or substituted alkyl,

R5 and R8, independently of one another, are hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or aryl,

R 5 represents an acyloxy group,

Re represents a hydrogen atom and

R? means unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or aryl, as well as salts of said compounds, when these compounds contain salt-forming groups, wherein the compounds of formula I exclude a compound wherein R 1 and R a are each R 8, R 3, R 4, R _e and R 5 are each hydrogen, R 5 is acetyloxy and R 6 is acetyl; represents 2,2- (N-ethoxycarbonylmethyl-N-methyl) hydrazin-1-ylcarbonylmethyl.

The term below, used in the description of the invention to define groups or moieties, for example the definition of a lower alkyl group, a lower alkoxy group or a lower and 1 kanoyl group, means that groups or moieties as defined herein, unless otherwise stated, contain at most 7 and preferably at most 4 carbon atoms. In the case of a lower and 1 kenyl group or a lower alkynyl group, these groups contain 2 to 7, preferably 3 to 7, in particular 3 or 4, carbon atoms to a.

Unless expressly stated otherwise, the groups R 1, R ₂ , R 5, R 6, Ry, R 5 and / or R 9 represent several substituents, in particular one to example one substituent.

occurs independently of one or three substituents, if one general symbol is defined together with another general symbol and their meanings are given by the specification independently of each other, then this means that the two general symbols need not have the same compound in the same compound however, these specific meanings may be the same.

The carbon atoms substituted in the compounds of formula I by R 3 and R ₄ , optionally R 5 and R 5 and, if they are asymmetric carbon atoms, may have the (R), (S) or (R) configuration as well as any other asymmetric carbon atoms present. ,WITH). Consequently, the compounds of the invention may exist as isomeric mixtures or as pure isomers, in particular diastereomeric mixtures, enantiomeric vapors or pure enantiomers. Preferred compounds of formula I, where they are carbon atoms which are substituted by R ₃ and R, each configuration (S), and in which are further optionally present asymmetric carbon atoms, independently of one another, the (R), (S) or (R ,WITH) .

The general terms and designations used throughout the specification have the following meanings unless otherwise indicated:

The acyl group R 1 or R y contains, for example, up to 25, preferably 19, carbon atoms and this acyl group is in particular an acyl group of a carboxylic acid, a half ester of carbonic acid, unsubstituted or N-substituted carbamic acid or unsubstituted or substituted amino acid.

Preferred acyl groups R, or Ry of the carboxylic acid are unsubstituted or substituted alkanoyl, alkenoyl or alkyinoyl group containing up to 19 carbon atoms, for example n-decanoyl or preferably lower alkanoyl group such as formyl, acetyl, propionyl, butyryl or a pivaloyl group, or in addition or in particular a 3,3-dimethylbutyryl group, or a substituted lower alkyl group in which preferably up to four, in particular (up to three times, halogen, which may be present as a substituent up to three times) may be present, in particular one substituent (except for halogen, which may be present as a substituent up to three times), said substituents being preferably selected from the group consisting of a cycloalkyl group having preferably 3 to 7 carbon atoms, in particular in the cycloalkyl (lower and 1-cyano) groups 1) s a lower alkyl group as defined above, for example in a cycloalkylcarbonyl group having, for example, a total of 4 to 8 carbon atoms, such as in a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylcarbonyl group; a cyclohexyl- or 2-cyclopentylacetyl group, a cycloalkenyl group which preferably contains 3 to 7 carbon atoms, in particular in a cycloalkenyl (lower and 1 kanoyl) group, such as in a cycloalkenylcarbonyl group, for example having 4 to 8 carbon atoms such as 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl or 1-cyclohexenylacetyl or 1,4-cyclohexadienyl acetyl, a bicycloalkyl group having preferably 5 to 10 carbon atoms, in particular 1-cycloalkyl (lower and lower alkyl); In a bicycloalkylcarbonyl group, e.g. having 8 to 11 carbon atoms, such as in a decahydronaphthyl-1-carbonyl group, bicycohexyl-, bicyclooyl, bicyclonoyl, or bicyclooyl or 3-propionyl, bicyclooyl, preferably 8 to 12 carbon atoms, especially bicyclooylcarbonyl, as in bicyclonoyl or bicyclonoyl, 5-norbornene-2-ylcarbonyl or bicyclo [2.2.2] octen-2-ylcarbonyl, a tricycloalkyl group containing, for example, 8 to 10 carbon atoms, especially in a tricycloalkyl (lower alkanoyl) group, e.g. in a tricycloalkylcarbonyl group, for example having 8 to 11 carbon atoms, such as a 1- or 2-adamantylcarbonyl group, an aryl group having preferably 6 to 14 ring carbon atoms such as a phenyl group, an indenyl group, an indanyl rem halogen which it may be present as a substituent up to three times) up to two substituents, in particular one substituent (except for halogen, which may be present as a substituent up to three times), said substituents being in particular while selected from the group consisting of a cycloalkyl group which preferably contains 3 to 7 carbon atoms, in particular in the alkyl group (lower and 1 kanoyl) in which the lower alkyl group is as defined above, for example in cyclic A carbonyl group having, for example, a total of 4 to 8 carbon atoms, such as in the cyclopropyl 1-, cyclobutyl-, cyclopentents 1- or cyclohexylcarbonyl group or 2-cyclohexyls 1- or 2-carboxylic acid groups. a cyclopentyl acetyl group, a cycloalkenyl group which preferably contains 3 to 7 carbon atoms, in particular in a cycloalkenyl (lower alkanoyl) group, such as in a cycloalkenylcarbonyl group, for example having 4 to 8 carbon atoms; as in 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl or 1-cyclohexenylacetyl or 1,4-cyclohexadienyl acetyl, cyclic and alkyl, preferably containing 5 to 10 carbon atoms, especially in bicykloa an alkyl (lower alkanoyl) group, for example in a cycloalkylcarbonyl group, for example of 8 to 11 carbon atoms, such as decahydronaphthyl-1-carbonyl, bicycohexyl, bicyclooctyl, bicyclooctyl, bicyclonoyl, or bicyclonoyl a bicycloalkenyl group or a 3-propionyl group, a bicycloalkenyl group, preferably having 8 to 12 carbon atoms, in particular in a bicycloalkenylcarbonyl group, such as in a 5-norbornene-2-ylcarbonyl group or bicyclo [2.2.2] octene A 2-ylcarbonyl group, a tricycloalkyl group containing, for example, 8 to 10 carbon atoms, in particular in a tricycloalkyl (lower and 1-alkoyl) group, for example in a tricycloalkylcarbonyl group, for example having 8 to 11 carbon atoms such as in the 1- or 2-adamantylcarbonyl group, an aryl group having preferably 6 to 14 ring carbon atoms, such as phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl acenaphthyl or fluorenyl, and which may be unsubstituted or substituted one to three times with substituents selected from the group consisting of lower alkyl, such as methyl, ethyl or propyl, and halo (lower alkyl), such as trifluoromethyl , phenyl, 2- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl (lower alkoxy), N (lower alkyl) carbamoyl (lower alkoxy) or N , N-di- (lower alkyl) carbamoyl (lower and 1-alkoxy) -amino, amino, mono- or di (lower and 1-alkylamino) amino, (lower and 1-alkoyl) -amino, for example pivaloylamino, a halogen atom, for example a fluorine atom, a chlorine atom or a bromine atom, a carboxyl group, a (lower alkoxy) carbonyl group, such as a tert-butoxycarbonyl group, a phenyl, naphthyl or fluorenyl (lower alkoxy) carbonyl group a group such as a tert-butoxycarbonyl, phenyl, naphthyl or fluorenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl group, a lower alkanoyl group, a sulfo group, a (lower and alkyl) sulfonyl group, for example, methylsulfonyl, phosphono, hydroxy (lower alkoxy) phosphoryl or di (lower alkoxy) phosphoryl, carbamoyl, mono- or di (lower alkyl) carbamoyl, sulfamoyl, mono- or a di (lower and 1-cyano) amino group, a nitro group and / or a cyano group, in particular in an aryl (lower and 1-cynoyl) group in which the phenyl group may be present once or also up to three times, for example in a diphenyl, di-benzyl and 1-canoyl group, such as in a diphenyl, nylacetyl group, in which the lower alkanoyl group is unsubstituted or further substituted, for example, by carboxyl, (lower alkoxy) carbonyl, e.g. ad methoxy-, ethoxy-, n-propoxy, isopropoxy-, n-butoxy, isobutoxy-, sec-butoxy-, t-butoxy-, η-pentoxy-, isopentoxy-, neopentoxy-, t -pentoxy-, η-hexoxy isohexoxy- or n-heptoxycarbonyl, aryl (lower and 1-alkoxy) carbonyl or triphenyl (lower diberisyl or triphenyl) in which the aryl radical has 6 to 12 carbon atoms, for example benzyloxycarbonyl, carbamoyl, substituted carbamoyl at a nitrogen atom with one or two substituents selected from the group consisting of lower alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example in N- methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, carboxy (lower alkyl) or (lower alkoxy) carbonyl (lower alkyl), for example carboxymethylcarbamoyl bonyl (glycinylcarbonyl) or tert-butoxycarbonyl methylcarbonyl, alkyl), for example di (lower and 1-alkyl) amino (lower 2-dimethylaminoethyl, hydroxy (lower alkyl)) a hydroxymethyl or hydroxyethyl group, an adi (lower alkoxy) (lower alkyl) group, for example a 2- (2,2-dimethoxyethyl) group, and / or a cyano group, and is unbranched or branched in particular selected from phenyl (lower and 1-alkoyl) such as benzoyl, phenyl acetyl or 3-phenylpropionyl, which may be unsubstituted or mono- or polysubstituted on the phenyl ring, for example lower alkyl, for example methyl, a phenyl group, a halogen atom, for example a fluorine atom or a chlorine atom, a hydroxy group, a lower group and a 1-alkoxy group, for example a methoxy group and / or an anro group such as t o for a 4-chloro-, 4-methoxy- or 4-nitrobenzoyl group, a naphthylcarbonyl group such as an alpha- or beta-naphthylcarbonyl group or a 1,8-naphthalenediocarbonyl group which binds via both carbonyl groups on the amino group, an indenylcarbonyl group such as 1-, 2- or 3-indenylcarbonyl group, indanylcarbonyl group, such as 1- or 2-indanylcarbonyl group, phenanthrenylcarbonyl group, such as 9 -phenanthenylcarbonyl, and 1-phthalicyl-acetyl, beta-naphthyl-acetyl group, (lower alkyl) phenylacetyl, such as 4-methylphenylacetyl, (lower alkoxyphenylacetyl, such as 4-methoxyphenylacetyl), a (p-hydroxyphenyl) propionyl group, a diphenylacetyl group, a di- (4-methoxyphenyl) acetyl group, three phenyl acetyl groups, a 2,2-dibenzyl acetyl group, a 3-alpha-or 3-beta-naphthylpropionyl group, a phenyl (lower and 1-alkoyl) group in which it is lower an alkanoyl radical substituted with a carbamoyl group, for example a 2-carbamoyl-3-phenylpropionyl group such as a 2 (R, S) carbamoyl-3-phenylpropionyl group, 3-alpha-naphthyl-2-carbamoyl propionyl group, 3-phenyl - or 3-a1-naphthyl-1-2-tert-butylcarbamoylpropionyl, 3-phenyl- or 3-alpha-naphthyl-2- (2-dimethylaminoethyl) carbamoylpropionyl, 3-a1-naphthyl-1- ( carboxy- or tert-butoxycarbonyl) methylcarbamoylpropionyl, 3-phenyl- or 3-alpha-naphthyl- (3-hydroxy-2-propyl) carbamoyl, 3-phenyl- or 3alpha-naphthyl-2 - (2,2-dimethoxyethyl) carbamoylpropionyl group and 3-phenyl or 3-aphaphthyl-2 (5-amino-5-carboxypentyl) carbamoyl propionyl group, in particular phenyl (lower and Or a phenyl (lower alkanoyl) group in which the lower alkanoyl radical is substituted by a carbamoyl group such as 2 (R, S) -carbamoyl-3-phenylpropionyl a heterocyclic group, which is preferably a single or double ring system of 3 to 10 ring atoms, which is bonded via a carbon atom or, in particular, a nitrogen atom, and which contains 3 further heteroatoms selected from oxygen, nitrogen, sulfur and sulfur which is bound by one or two oxygen atoms, said ring system may additionally be fused to one or two phenyl or naphthyl radicals, the naphthyl group may also be condensed on both sides or with one or two cyclic radicals wherein the cycloalkyl radical preferably contains 5 to 7 ring atoms and is unsaturated or also partially or fully saturated, for example thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazo 1-yl, pyridyl, pyrazinyl a pyrimidinyl, pyrimidazinyl, indolyl, benzimidazolyl, quinolyl, isoquinoyl, 3,1-benzfuranyl, cyclohexa / b / pyrrolidinyl, cyclohexa / b / pyr idyl, cyclohexa / b / pyrazinyl, cyclohexa / b / pyrimidinyl, pyrrolidinyl, pyrrolidinyl, imidazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, indolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4- tetrahydroquinolyl or 1,2,3,4-tetraisoquinolinyl, wherein the heterocyclyl group, for example one of the latter, is unsubstituted or substituted by a lower alkyl group, for example methyl, phenyl, 1- or 2-naphthyl group, bitches Y 1 (lower alkyl) such as benzyl, hydroxy (lower alkyl) such as hydroxymethyl or 2-hydroxyethyl, (lower alkoxy) (lower alkyl) such as methoxymethyl or 2-methoxyethyl, (lower and 1-alkoyl) oxy (lower alkyl), for example acetyloxymethyl, phenyl or naphthyl lower alkanoyl) oxy (lower alkyl), for example benzoyloxy, phenylacetyloxy or 1- or 2-naphthyloxymethyl, -2-ethyl or -2- (2,2-dimethylethyl), (lower alkoxy) carbonyloxy (lower alkyl), for example tert-butoxycarbonyloxy (lower alkyl), phenyl (ni) (alkoxy) carbonyloxy (lower alkyl), for example 2-benzyloxycarbonyloxyethyl, amino (lower alkyl), for example aminomethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy, amino, (lower alkyl) amino, for example methyl, ethyl or tert-butylamino, di (lower alkyl) amino, for example dimethyl or diethylamino, carboxyl, a lower and 1-alkoxy) carboxy group such as, for example, adoxy isopropoxy, sec-butoxy or tert-butoxycarbonyl, phenyl or naphthyl (lower alkoxy) carboxyl, for example benzyloxycarbonyl, halogen, for example fluorine, a chlorine atom, a bromine atom or an iodine atom, in particular a chlorine atom or a bromine atom, a lower alkanoyl group such as acetyl or pivaloyl group, a carbamoyl group, a mono- or di (lower alkyl) carbamoyl group such as N-methylcarbamoyl group, Nn -butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy- or carboxy (lower and alkyl) carbamoyl, for example hydroxy- or carboxymethyl arbamoyl or hydroxy- or carboxyethyl-carbamoyl, especially in the heterocyclic (lower alkanoyl) group in which the lower alkanoyl radical is unsubstituted or independently substituted by one of the substituents defined above in relation to aryl (lower alkanoyl) with R and R _9, wherein the heterocyclic (lower alkanoyl) group is especially selected from pyrro1 1karbony1ovej yl group, e.g., 2- or 3-pyrrolylcarbonyl, t ieny1 1ovej carbonyl group, such as 2-tieny1 1ovej carbonyl group, furyl 1karbonylove groups such as 2-furylcarbonyl, indonylcarbonyl, such as 2-, 3- or 5-indolylcarbonyl, 4,5,6,7-tetrahydroindol-2-carbonyl a quinolyl-lower alkanoyl group, for example a quinolylcarbonyl group such as a 2-, 3- or 4-quinolylcarbonyl group, such as a quinolylcarbonyl group such as a 2-, 3- or 4-quinolylcarbonyl group; -, 3or 4-i žoch i no 1 y 1 ka p-carbonyl, such as p-piperidinylcarbonyl or 2-, 3- or 4-piperidylcarbonyl, piperazinylcarbonyl as p-pyridazin-1-ylcarbonyl a morpholinyl (lower alkanoyl) group, e.g. morpholino (lower alkanoyl) such as morpholino-inocarbonyl, thiomorpholino (lower alkanoyl) such as thiomorpholino (lower and 1-alkoyl) such as thiomorpholino-inocarbonyl, S, S- dioxothiomorpholinylcarbonyl, such as S, S-dio12 xothiomorphol-1 inocarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, such as 1,2,3,4-tetrahydroquinolyl-1-2, -3 or -4-carbonyl, 1,2,3,4-tetrahydroisoquinolin-1-carbonyl such as 1,2,3,4-tetrahydroisoquinolin-1 -, -3- or - 4-carbonyl, a tetrazolyl (lower alkanoyl) group such as a 3- (tetrazol-1-yl) propionyl group, and a pyridyl (lower and 1-alkanoyl) group such as pyridylcarbonyl a group such as 2-, 3- or 4-pyridylcarbonyl or a pyridyl acetyl group such as 2-, 3- or

4-pyridyl acetyl, and in particular selected from morpholinocarbonyl, thiomorpholinocarbonyl, quinol-2-ylcarbonyl, 3- (tetrazol-1-yl) propionyl, 2-pyridylcarbonyl or 2- or 3-pyridyl acetyl, hydroxy, especially in hydroxy (lower alkanoyl), such as 3-hydroxypropionyl or 2-hydroxy-3-methylpentanoyl, hydroxy (lower alkoxy) -group especially in a hydroxy (lower and 1-alkoxy) (lower and 1-alkoyl) group, such as a hydroxy-n-propylcarbonyl group, a lower alkoxy group, especially in a (lower alkoxy) (lower alkanoyl) group, for example (lower and (Alkoxy) acetyl or (lower alkoxy) propionyl, such as methoxyacetyl, ethoxyacetyl, or 3-methoxypropionyl, (lower and 1-alkoxy) (lower and 1-alkoxy) -supers, especially in the (lower) alkoxy) (lower alkoxy) (lower alkanoyl) group such as

2-methoxymethoxy-3-methylpentanoyl or, more particularly, 2- (methoxy) ethoxyacetyl, (lower and 1kanoyl) oxy, especially in the (lower and 1kanoyl) oxy (lower and 1kanoyl) group, in which (lower alkanoyl) oxy means, for example, an acezoxy, propionoxy, butyroxy, isobutyroxy or pivaloyloxy group such as an acetoxyacetyl group or a 3-acetoxypropionyl group, an amino group not present in the position alpha or beta relative to the carboxyl group of the acyl residue it substitutes, for example, in the amino (lower and 1 -kanoyl) group in which the amino group is not in the alpha or beta position, such as the 5-aminopentanoyl group (lower and 1kanoyl) an amino group which is not in the alpha or beta position relative to the carboxyl group of the acyl radical it substitutes, especially in the (lower alkanoyl) amino (lower and 1 -kanoyl) group in which the amino group is not present in the an alpha or beta (lower and 1-canoyl) residue such as a 5-allyl amine inopentanoyl, (lower alkoxy) carbonylamino group which is not in the alpha or beta position relative to the carboxyl group of the acyl residue it substitutes especially in the (lower and 1-alkoxy) carbonylamino group, in which the amino group is not in the alpha or beta (lower alkanoyl) position, such as a 5- (t-b) an alkoxycarbonylaminoipentanoyl group, a phenyl (lower and 1-alkoxy) carbonyl group and an amino group which is not in the alpha or beta position relative to the carboxyl group of the acyl radical it substitutes, especially in the phenyl (lower alkoxy) carbonylamino (lower alkanoyl) group the amino group is not in the alpha or beta (lower alkanoyl) position, such as a 5-benzyloxycarbonylaminopentanoyl group or a 6-benzyloxycarbonylaminohexanoyl group, an amino group substituted on a nitrogen atom of a heterocyclic (lower alkanoyl) group in which the heterocyclyl radical is independently defined as the above-mentioned heterocyclyl substituent of the lower alkanoyl group R 1 or R ₉ , in particular a substituted N-morpholino- or N-thiomorpholinocarbonyl group, especially in a heterocyclyl (lower alkanoyl) amino (lower alkanoyl) group, for example an N-morpholino- or N-thiomorpholinocarbonyl amine (lower alkanoyl) group such as an N-morpholino or N-1-morpholinocarbonylaminomethyl group, preferably up to three halogen atoms, especially in the halo (lower alkanoyl) group containing up to three halogen atoms, for example an alpha-haloacetyl group such as alpha-fluoro- and 1 fachloro-, alpha-bromo-. alpha-iodo, a 1 fa, a 1 fa, a 1 fa-tri-fluoro- or a 1 fa, a 1 fa, a 1 fa-tri-chloroacetyl group, or 1-halogenpropiones, such as beta-chlorine - or a beta-bromopropionyl group, a carboxyl group, in particular in a carboxy (lower alkanoyl) group, for example a carboxyacetyl group or a beta-carboxypropionyl group, a (lower alkoxy) carbonyl group, particularly in a (lower alkoxy) carbonyl (lower alkanoyl) group a (lower alkoxy) carbonylacetyl group or a (lower alkoxy) carbonylpropionyl group, such as a methoxycarbonyl acetyl group,

A 3-methoxycarbonylpropionyl group, an ethoxycarbonylacetyl group, a 3-ethoxycarbonylpropionyl group or a 3-tert-butoxycarbonylpropionyl group, a sulfonyl group, in particular in a sulfonyl (lower alkanoyl) group, such as a 3-sulfonylpropionyl group, in particular a 3-carbonylpropionyl group; a lower alkanoyl group such as a carbamoyl acetyl group or a 3-carbainoylpropionyl group, a (lower alkyl) carbamoyl group, in particular a (lower alkyl) carbamoyl (lower and 1-alkoyl) group, e.g. to 1 ad (lower alkyl) carbamoyl acetyl; or a methylcarbamoyl (lower and 1 to anoyl) group, such as a methylcarbamoylacetyl group, a di (lower alkyl) carbamoyl group, especially a di (lower alkyl) carbamoyl (lower alkanoyl) group, for example a di (lower alkyl) a carbamoyl acetyl group or a dimethylcarbamoyl (lower alkanoyl) group such as a dimethylcarbamoyl acetyl group, a carbamoyl group substituted on an atom a nitrogen atom with a substituent selected from the group consisting of an ethyl group, a trimethylene group, a tetramethylene group and a pentamethylene group in which the carbon atom may be replaced by a nitrogen atom, an oxygen atom, a sulfur atom or a sulfur atom which is substituted once or twice by an oxygen atom; in the correspondingly N-substituted carbamoyl (lower and 1-cyanoyl)

5

j.

and the residue thus formed may also be wholly or partially unsaturated, for example piperidino, pyrazin-1-yl, piperazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorphol. an amino or S, S-dioxothiomorpholino-inocarbonyl (lower alkanoyl) group, such as a morpholinocarbonyl (lower alkanoyl) group, such as morpholino-inocarbonyl acetyl, 3- (morpholino-carbonyl) propionyl or a 3- (morpholino-carbonyl) -2-isobutylpropionyl group,

N-heterocyclyl (lower and alkyl) carbamoyl or N- (lower alkyl) -N-heterocyclyl (lower alkyl) carbamoyl, especially in N-heterocyclyl (lower alkyl) carbamoyl (lower alkanoyl) or N- (lower alkyl) -N-heterocyclyl (lower alkyl) carbamoyl (lower and 1 kanoyl) in which the heterocyclyl radical is preferably selected from the group consisting of pyrrolyl, furyl, a phenyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidyl group, an indolyl group, a quinolyl group, and even a 1-yl group, which may also be fully or partially saturated, The 1-ynyl group and the isomorpholinyl group as in the N-methyl-2- (Ν-2-pyridylmethyl) carbamoyl acetyl group, 2- (N-morpholino (lower and 1-alkyl) carbamoyl) (lower and 1 canoyl) as 2 (R, S) -N- (2-morphol inoethyl) carbamoyl-3-methylbutyryl or 2- / N- (pyridyl (lower and lower alkyl) carbamoyl) (lower alkanyl) groups such as / 2 (R, S) - ( N- (2-pyridylmethyl) carbamoyl) -3-methyl / butyryl, oxo, especially in oxo (lower alkanoyl) such as acetoacetyl or propionyloacetyl, and cyano, especially in cyano (lower alkanoyl) such as cyanoacetyl, 2- or 3-cyanopropionyl or 2-, 3- or 4-cyanobutyl, lower alkenoyl of 3 to 7 carbon atoms, preferably 3 or 4 carbon atoms, such as acryloyl, vinylation16 or lower alkinoyl having 3 to 7 carbon atoms, preferably 3 or 4 carbon atoms, for example propioloyl or 2- or 3-butinoyl.

Preferred acyl groups R or FU of the half-carbonic ester are (lower alkoxy) carbonyl, for example methoxy, ethoxy, isopropoxy, isobutoxy or tertiary (lower and 1 alkoxy) carbonyl, or in addition or in particular n-propyloxycarbonyl, such as tert-butoxycarbonyl or isobutoxycarbonyl,

2-halo (lower alkoxy) carbonyl, 2-chloro, 2-bromo, 2-iodo or 2,2,2-trichloroethoxycarbonyl, aryl (lower alkoxy) carbonyl, for example arylmethoxycarbonyl, wherein the aryl group contains 6 to 14 carbon atoms and is, for example, phenyl, biphenyl, 1- or 2-naphthyl, fluorenyl or phenyl which is substituted one or more times by lower alkyl, for example methyl or tert-butyl , hydroxy, lower alkoxy, for example methoxy, ethoxy or tert-butoxy, halogen, for example chlorine or bromine, or / an itro, for example phenyl 1 (lower and 1 alkoxy) carboxy a bonyl group such as a benzyloxycarbonyl or 4-methoxybenzyloxycarbonyl group, a heterocyclyl (lower alkoxy) carbonyl group in which the heterocyclyl radical is preferably selected a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group and others; they may be fully or partially saturated, a morpholinyl group and an isomorpholinyl group, and are unsubstituted or substituted in particular by a lower alkyl group such as a methyl group such as a furylmethoxycarbonyl group, a tetrahydrofuryl (lower and 1-alkoxy) carbonyl group, such as 2-tetrahydrofurylmethoxycarbonyl, 2-morpholinoethoxycarbonyl, or 2-, 3- or 4-pyridylmethoxycarbonyl, (lower alkenyl) oxycarbonyl, in which, for example, the (lower alkenyl) radical is bound to the oxygen bonding moiety through a saturated carbon atom such as an allyloxycarbonyl group (lower alkoxy) ( lower alkoxy) carbonyl, such as 2-methoxyethoxycarbonyl, or / (lower and 1-alkoxy) (lower and 1-alkoxy) / (lower and 1-alkoxy) carbonyl, such as 2- (2-methoxyethoxy) ethoxycarbonyl.

Preferred acyl groups R 1 or R _{9 of the} unsubstituted or substituted carbamic acid are carbamoyl or unsubstituted or substituted N-alkyl or alky, dial-dialkylcarbamoyl in which the alkyl radical contains up to 12 carbon atoms, preferably unsubstituted or substituted (lower alkyl) - or a di (lower alkyl) carbamoyl group such as methyl, ethyl, propyl, tert-butyl, dimethyl, diethyl or di-propyl carbamoyl, wherein the substituents are selected from the group consisting of phenyl , for example, in the benzylcarbamoyl group, the N-phenyl (lower alkyl) -N- (lower alkyl) carbamoyl group such as the N-benzyl-N-methylcarbamoyl group, or the dibenzylcarbamoyl group a heterocyclyl group which is independently defined as the aforementioned heterocyclic substituent of a lower alkanoyl group R 1 and R a, preferably a pyridyl group such as 2-, 3- or

4-pyridyl, especially in N-heterocyclic (lower alkyl) -N-lower alkyl (carbamoyl), for example

N-pyridyl (lower alkyl) -N- (lower alkyl) carbamoyl group such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, or N-heterocyclyl (lower alkyl) carbamoyl, for example 2- or 3-pyridyl (lower alkyl) aminocarbonyl; a hydroxy group such as a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, a 2-hydroxypropyl group, and a lower alkoxy group, preferably in a (lower alkoxy) (lower alkyl), for example methoxymethyl or 2-methoxyethyl, or in addition or in particular N (lower alkyl) -N-morpholino (lower alkyl) 1-aminocarbonyl such as N-methyl 1-N- (2-morpholinoethyl) aminocarbonyl or N-morpholino (lower and alkyl) amocarbonyl such as N- (2- morpholinoethyl) aminocarbonyl; on the.

Preferred acyl groups R 1 or R 5 of the unsubstituted or substituted amino acid are the amino acid residues of the alpha- or beta-amino acid residues that bind through the carbonyl group of their carboxyl group, especially the L-configuration natural alpha-amino acid normally found in proteins. , or the epimer of such an amino acid, i. j. having a non-natural D configuration, or a D, L-isomeric mixture thereof, of an acid homologue in which the amine acid side chain is extended or truncated by one or two methylene groups wherein the amine group is in the beta position and / or wherein the methyl group is replaced by a hydrogen atom, a substituted aromatic amino acid, wherein the aromatic moiety contains 6 to 14 carbon atoms, for example substituted phenylalanine or 1 g of 1-phenylene, wherein the phenyl substituent may be a lower alkyl group such as methyl a hydroxy group, a lower group and a 1 alkoxy group, e.g. to 1 ad methoxy group, (lower and 1 kanoyl) oxy group, for example acetoxy group, amino group, (lower and 1 kyl) am ino, for example methylamino, di (lower alkyl) amino, for example dimethylamino, (lower and 1-canoyl) amine, for example acetylamino or beer amine, (lower alkoxy) carbonylamino groups, for example tert. butoxycarbonylamino, arylmethoxycarbonylamino, in which the aryl radical contains 6 to 14 carbon atoms, for example benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, halogen, e.g. fluorine, atom chlorine, bromine or iodine, carboxyl and / or itro, and this substituent is present one or more times, benzanlated phenylalanine or phenylglycine, such as alpha-naphthylalanine, or hydrogenated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycine.

These amino acids may be substituted at the free amino or hydroxy function i, preferably at the free amine function i, by one of the radicals mentioned above in relation to the acyl group R 1 or R a in the function of the acyl group of a carboxylic acid, a half ester of an acid carbonic or unsubstituted or N-substituted carbamic acid, or one of the moieties mentioned below in connection with an unsubstituted or substituted alkyl group R 1, R 2;

R e or R a.

Particularly preferred is an amino acid residue selected from the group consisting of glycine, including glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (acid a 1 fa), via a carbonyl group. -aminoic), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (a-pha-aminohexanoic acid, NNle-OH), serine (H-Ser-OH), homoserine ( alpha-amino-gamma-hydroxybutyric acid), threonine (H-1 H-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H-Tyr-OH), 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, beta-phenylserine (beta-hydroxyphenylalanine), phenylglycine, and 1-anaphthylalanine (H-Nal-OH), cyclohexyl and lane (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indole-2-carboxylic acid, 1,2, 3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asp-OH), amine acid ononic acid, monoamide of aminotonic acid, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys) -OH), de-1-hydroxy-1-yzine, or 20-nitrite (a 1 fa, delta-diaminoic acid), 3-aminopropanoic acid, a 1 fa, gamma-diamine inomas 1 and a?,? -diaminopropionic acid, with an aliphatic amino acid residue selected from valine, aniline, leucine and isoleucine or an amino acid selected from glycine, glutamic acid and asparagine, with (except glycine) each being particularly preferred of said amino acids may be in the form of D, L or (D, L), preferably (except Val, which may also be in the form of D, or (D, L) in the form of L, and a? -amino group on is unsubstituted or N-alkylated once or twice, for example by a lower alkyl group such as a methyl or n-propyl group, or an amine o- (lower alkyl), such as 3-aminopropyl, or N-acylated with one of the acyl radicals mentioned above in relation to the carboxylic acid, half-carbonic acid ester or unsubstituted or N-substituted carbamic acid , preferably lower alkanoyl such as acetyl, aryl (lower and 1-alkoyl) wherein the aryl moiety is selected from the group consisting of phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl, and is unsubstituted or in particular one to three times in particular substituted by lower alkyl, for example methyl, ethyl or propyl, halogen (lower alkyl), phenyl, hydroxy, lower alkoxy , for example, methoxy, carbamo y1 (lower and 1 alkoxy) -button or N, N-di (lower alkyl) carbamoyl (lower alkoxy, amino, mono- or di- (lower alkyl) amino, (lower and 1 kanoyl) an amino group such as a pivaloylamino group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, a carboxyl group, a (lower alkoxy) carbonyl group such as a tert-butoxycarbonyl group, phenyl, naphthyl or fluorenyl ( lower and 1-alkoxy) carbonyl groups such as trifluoromethyl- or 2-naphthyl moieties, carbamoyl and 1-carbamoyl tert-butoxycarbonyl, phenyl, naphthyl or fluorene (lower and 1-alkoxy) carbonyl groups An alkyl group such as a benzyloxycarbonyl group, a lower alkanoyl group, a sulfo group, a ((lower alkyl) sulfonyl group, for example, a methylsulfonyl group, a phosphonium group, a hydroxy ((lower and 1-alkoxy) phosphoryl group or di (lower and 1-alkoxy) phosphorus A mono or di (lower sulfamoyl group, mono or di (lower alkyl) aminosulfonyl group, an nitro group and / or a cyano group, and the lower alkanoyl group may be unsubstituted or in particular substituted by a carboxyl group, ( lower alkoxy) by a carbonyl group, for example methoxy-, ethoxy-, n-propoxy-, isopropoxy-, η-butoxy-, isobutoxy-, sec-butoxy-, t-butoxy-, n-pentoxy-, isopentoxy-, neopentoxy- t-pentoxy-, η-hexoxy-, isohexoxy or n-heptoxycarbonyl, aryl (lower alkoxy) carbonyl, in which the aryl radical contains 6 to 12 carbon atoms, for example benzyloxycarbonyl, aramoyl, carbamoyl , substituted with one or two substituents selected from the group consisting of lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl n-pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, isohexyl or n-heptyl, for example in N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethyl 1 carbamoyl, carboxy (lower alkyl), (lower alkoxy) carbonyl (lower alkyl), for example in the carboxymethylcarbamoyl group (glycinylcarbonyl)) or tert-butoxycarbonyl (1-methylcarbamoyl, di-lower and lower alkyl) an amino (lower alkyl) group such as a 2-dimethylaminoethyl group, a hydroxy (lower alkyl) group such as a hydroxymethyl group, or a hydroxyethyl group and a lower (alkoxy) (lower alkyl) group such as a 2- ( 2,2-dimethoxyethyl, and / or cyano, and is unbranched or branched, with phenyl (lower and 1-alkanoyl) being particularly preferred, such as phenyl and acetyl, but or a phenyl (lower alkanoyl) group in which the lower alkanoyl radical is substituted by a carbamoyl group such as

2-carbamoyl-3-phenyl-propionyl, heterocyclyl (lower and 1-alkanoyl) wherein the heterocyclyl radical is independently defined as the lower alkanoyl heterocyclic substituent R And, in particular, is morpholino-1-amino, thiomorpholino, pyridyl, quinolyl or tetrazolyl, in particular pyridylcarbonyl, such as 2-, 3- or 4- pyrimidylcarbonyl, morpholino-inocarbonyl, thiomorpholino-inocarbonyl, S, S-dioxothiomorpholino-inocarbonyl, indol-2-ylcarbonyl, quinol-2-ylcarbonyl bonyl, pyridyl acetyl such as 2- or 3-pyridyl acetyl, imidazolyl acetyl such as imidazol-1-yl acetyl, morpholinyl acetyl such as morpholinoacetyl, pyridylpropionyl such as 3- (2- or 3-pyridyl) propionyl, a pyrrolidinylpropionyl group such as a 3- (4-pyrrolidinyl) propionyl group, a morpholinopropionyl group such as a 3-morpholinopropionyl group, or a tetrazolylpropionyl group such as

A 3- (tetrazol-1-yl) propionyl group, a halo (lower alkanoyl) group containing up to 3 halogen atoms, for example, and a 1-haloacetyl group, such as alpha-fluoro-, alpha-chloro, alpha-bromo, alpha-iodo, alpha, alpha, alpha-trifluorooral and 1 fa, and 1 fa, and 1 fa-trifluoroacetyl, or a halopropionyl group such as beta-chloro - or beta-bromopropionyl, (lower and 1-alkoxy) (lower alkoxy) - (lower alkanoyl), (lower alkoxy) carbonyl, such as tert-butoxycarbonyl, aryl 1 (lower alkoxy) -carbonyl wherein the aryl radical contains 6 to 14 carbon atoms and is selected, for example, from the group phenyl, naphthyl and fluorenyl, for example phenyl (lower alkoxy) carbonyl, such as benzyloxycarbonyl, or 9-phenyl; uorenylmethoxycarbonyl, heterocyclic (lower and 1-alkoxy) carbonyl, hete a rocyclyl (lower alkoxy) carbonyl group in which the heterocyclyl radical is preferably selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl an indolyl group, a quinolyl group and an isoquinolyl group, which may also be fully or partially saturated and unsubstituted or substituted in particular by a lower alkyl group such as a methyl group, for example 2-furylmethoxycarbonyl testing, tetrahydrofuryl (lower and 1-alkoxy) carbonyl. a 2-tetrahydrofurylmethoxycarbonyl group, or a 2-morpholinoethoxycarbonyl group, a (lower alkenyl) oxycarbonyl group (preferably with a saturated carbon atom on the bonding oxygen atom), such as a 11 yloxycarbonyl group, (lower and 1 alkoxy) (ni) (alkoxy) carbonyl for a group such as 2-methoxyethoxycarbonyl, a (lower alkoxy) (lower alkoxy) / (lower alkoxy) carbonyl group such as a 2- (2-methoxyethoxy) ethoxycarbonyl group, a carboxy (lower alkanoyl) group such as a 3-carboxypropionyl group , (lower alkoxy) carbonyl (lower and 1-canoyl), amino (lower and 1-canoyl) substituted at the amino-nitrogen atom with heterocyclyl (lower and 1-canoyl), wherein the heterocyclyl radical is preferably independently defined as above a lower alkanoyl heterocyclyl substituent R 1 or R ₉ . especially N-morpholino- or N-thiomorpholinocarbonyl, for example N-morpholino- or N-thiomorpholinocarbonylamino (lower alkanoyl) such as N-morpholino- or N-thiomorpholinocarbonyl aminoacetyl, carbamoyl, phenyl (lower alkyl) aminocarbonyl such as benzylaminocarbonyl, N-heterocyclyl (lower alkyl) -N- (lower alkyl) carbamoyl or N-heterocyclyl (lower alkyl) carbamoyl in which the heterocyclyl group is independently defined as above the heterocyclyl substituent of the lower alkanoyl group R 1 or R 10a is especially a pyridyl group such as

A 3- or 4-pyridyl group, in particular a 2- or n, such as 2a or N-2-,

3-pyridyl (lower and alkyl) aminocarbonyl or 3-pyridylmethyl aminocarbonyl, N-3- or N-4-pyridyl (lower alkyl) -N- (lower alkyl) aminocarbonyl such as N- 2-, N-3- or

N-4-pyridylmethyl-N-methylaminocarbonyl, heterocyclyl (lower and alkyl) carbamoyl (lower and 1 kanoyl) wherein the heterocyclyl radical is independently defined as the lower alkyl heterocyclic substituent R, R = , R 5 or R 10, for example a 2- (N-morpholino (lower alkyl) carbamoyl) (lower al kanoyl) group such as a 2 (R, S) - (N- (2-morpholinoethyl) carbamoyl-3-methylbutyryl group) or 2- (N- (pyridyl (lower alkyl) carbamoyl) (lower alkanoyl) group, such as 2- (R, S) - (N- (2-pyridylmethyl) carbamoyl) -3-methyl. a butyryl group, a sulfonyl group, a (lower alkane) sulfonyl group such as a methane or ethanesulfonyl group, an arylsulfonyl group (aryl-SO4 -) in which the aryl radical contains 6 to 10 carbon atoms, for example, is selected from the group consisting of phenyl anates And is unsubstituted or in particular substituted by a lower alkyl group such as a methyl group or a lower alkyl group. and a 1-alkoxy group, such as a methoxy group, such as a p-toluenesulfonyl group, or a heterocyclylsulfonyl group (heterocyclyl-SO 2 -), wherein the heterocyclyl radical is preferably selected from the group consisting of pyrrolyl, furyl, thienyl imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl and isoquinolyl, which may also be fully or partially saturated, and morpholinyl And is an unsubstituted or may be substituted, in particular by a lower alkyl group such as a methyl group such as a morpholinosulfonyl group, a thiomorpholinosulfonyl group, a piperidinosulfonyl group or a piperazinosulfonyl group (wherein the heterocyclylsulfonyl group as a substituent in preferred (N-morpholino-carbonyl-amine acetylvinyl, N-methanesulfonylamino-N-morpholino-1-phenylamino, N-acetyllecin, N- (4-thiomorpholino-inocarine) bony 1) leucine, N- (4- (S, S-dioxothiomorpholino) carbonyl) leucine, N (benzyloxycarbonyl) leucine, N-acetylisoleucine, N-propionylisoleucine, N- (benzyloxycarbonyl) iuucine, N- (tert-butoxycarbones) 1) norucine, N-benzyloxycarbonylgututic acid, aspartic acid, glutamine, N-benzyloxycarbonylasparagine, quinolin-2-ylcarbonylasparagine and N- (morpholinocarbonyl) asparagine and these groups are preferred as well as the corresponding N- (3, 3, 3) di-methyl-butyryl) -valine, N- (n-propyloxycarbonyl) valine, N- (2- (2-methoxyethoxy) ethoxycarbonyl) valine, N- (2- (2-methoxyethoxy) ethoxycarbonyl) valine, N- (2 -methoxyethoxyacetyl) valine, N- (N, N-dimethylaminocarbonyl) valine, N- (N- (2-methoxyethyl) amino) valine, N- (benzylaminocarbonyl) valine, N- (2-morpholinoethylaminocarbonyl) valine, or N- (N-methyl-N- (2-morpholinoethyl) aminocarbonyl) valine, said amino acid residues preferably being in the form of L or (D, L) and, in the case of valine, also in the form of D.

The unsubstituted or substituted alkyl group R @ 1, R @ 2, R @ ₃ or R @ ₃ contains an alkyl radical of 1 to 20 carbon atoms, preferably of at most 10 carbon atoms, branched or unbranched and represents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferred is a lower alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, isohexyl or n-heptyl, which is unsubstituted or substituted.

Substituents of the substituted alkyl group R, R>, _R or R, preferably a substituted lower alkyl group, are, for the group, which was placed on a lower alkanoyl group, R, and R.

Particularly preferred is an unsubstituted lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.

The alkyl-substituted sulfonyl group R 1 or R 10 (alkyl-SO 2 -) preferably contains an unsubstituted or substituted alkyl radical referred to in connection with the alkyl groups R 1, R c, R 5 and R ₉ and in particular represents (lower and 1-alk) sulfonyl a group such as a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group or a tert-butylsulfonyl group, or an aryl (lower and 1-alkyl) substituted sulfonyl group (aryl (lower and 1-alkyl) -SO 4 -) containing, for example, unsubstituted or a substituted aryl radical which is defined as an aryl radical in an aryl group substituted with a lower alkyl group R 1, R 2, R a and R 4, and which is particularly selected from phenylmethane-4-chlorophenylmethane, 4-methoxyphenylmethane or 4-nitrophenylmethane -, naphthylmethane, such as alpha or beta-naphthylmethane, 2-phenylethane, 2-alpha-naphthylethane, 2-beta-naphthylethane, 2- (4-methylphenol) 1-ethane, 2- (4-methoxyphenyl) ethane, 3-phenylpropane, 3- (phydroxyphenyl) propane, 2,2-diphenylethane and 2,2-di- (4-methoxyphenyl) ethanesulfonyl.

The aryl-substituted sulfonyl group R or R a (aryl-SO-2-) preferably contains an unsubstituted or substituted aryl radical mentioned in connection with the definition of an aryl group as a substituent of a lower alkanoyl group R 1 or R 1 and in particular is benzene or 1- or 2- a naphthalenesulfonyl group which is substituted or mono- or double-substituted with a lower alkyl group such as benzenesulfonyl or 1- or 2- or 4-toluenesulfonyl 2-naphthalenesulfonyl.

Preferably, the heterocyclyl substituted sulfonyl group R 1 or FU (heterocyclyl-SO ₂ -) preferably contains a heterocyclyl radical selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl a thiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group, and a quinolyl group which is saturated, and a morpholinyl group which is unsubstituted or substituted, in particular by a lower alkyl group such as methyl the group being, in particular, morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl or piperazinosulfonyl. In particularly preferred embodiments of the invention, the heterocyclylsulfonyl group may be absent as a substituent.

they may be wholly or partially and thiomorpholinyl

The acyloxy group R 2 contains, for example, up to 25 carbon atoms and in particular represents or unsubstituted wherein said acyloxy group acyloxy group of a carboxylic acid or substituted amino acid is bonded via its carbonyl group to an oxygen atom, further amine carbonyloxy group, N-substituted half moiety an aminocarbonyloxy group or an acyl ester of a carbonic acid linked to an oxygen bonding atom through its carbonyl group.

Preferred acyloxy carboxylic acid R 5 is, for example, unsubstituted and 1 to 20 carbon atoms, such as n-decanoyloxy or palmitoyloxy, and 1 to 20 carbon atoms or alkinoyloxy. containing from 3 to 20 carbon atoms or a substituted alkanoyloxy group containing from 1 to 20 carbon atoms, and a 1-alkoyloxy group containing from 3 to 20 carbon atoms, one of the alkoxy group, the mov carbon or an alkyinoyloxy group containing from 3 to 20 carbon atoms, in particular ( lower alkanoyl) -oxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy or in addition or in particular palimoyloxy, and 1 to 7-carbonoyloxy or a C 3 -C 7 alkyinoyloxy group or a substituted (lower and 1-alkoyl) oxy group in which the substituents are, for example, one or more a plurality of residues, preferably up to three residues, in particular a group comprising a hydroxy group, a lower phenoxy group, a naphthoxy group, a (lower alkanoyl) oxy group, a phenyl (lower and 1-alkoyl) oxy group such as a benzoyloxy group or a hairdryer 1-acetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, especially chlorine or fluorine, carboxyl, (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, such as benzyloxycarbonyl, carbamoyl a (lower alkyl) carbamoyl group, a hydroxy (lower and 1 alkyl) carbamoyl group, a di (lower alkyl) carbamoyl group, a bis (hydroxy (lower and 1 alkyl)) carbamoyl group, a cyano- C 3 -C 8 -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C 6 -C 12 bicycloalkyl; alkyl, such as decahydronaphth-2-yl, tricyclic of 9 to 14 carbon atoms, such as 1- or 2-adamantyl, cycloalkenyl of 4 to 8 carbon atoms, such as 1-cyclohexenyl, or 1,4 -cyclohexadienyl, heterocyclyl which preferably represents a saturated, partially saturated or unsaturated single ring containing 3 to 7, preferably 5 to 7 ring atoms and up to four heteroatoms selected from the group consisting of nitrogen, a sulfur atom and an oxygen atom, preferably 1 or 2 of said heteroatoms, wherein said ring exists as such or may be up to twice, preferably simply, benzanated, cyclopenta-, cyclohexa- or cyclohexaneate, and is unsubstituted or substituted, especially by a lower alkyl group , lower alkanoyl, hydroxy, lower and 1-alkoxy, -phenyl (lower alkoxy), such as benzyl a alkoxy group, a hydroxy (lower alkyl) group such as a hydroxymethyl group, a halogen atom, a cyano group and / or a trifluoromethyl group, said heterocyclyl group being, for example, a pyrrolyl group, a 2,5-dihydropyrrole group, furyl, thienyl, tetrahydrofuryl, cyclopenta (b) pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1,3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydrooxazolyl , tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, indolyl, indolyl, quinolyl, quinolyl, benzimidazolyl, benzimidazolyl benzofu a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group, a piperazin-1-yl group, a morpholino-thiomorpholino group, a S, S-dioxothiomorpholino group, 1, 2-dihydro- or 1,2,3,4-tetrahydroquinolinyl or 1,2-dihydro- or 1,2,3,4-tetrahydroquinolyl;

1,2.3.4-tetrahydroisoquinolyl, said radicals being unsubstituted or substituted as described above, in particular by a lower alkyl group, for example in a 4- (lower and 1-alkyl) piperazin-1-yl group such as 4-methyl- or 4- ethylpiperazin-1-yl, lower alkanoyl, for example in 4- (lower and 1-canoyl) piperazin-1-yl, such as 4-acetylpiperazin-1-yl, or hydroxy (lower alkyl) a group, such as a 5-hydroxymethylfuran-2-ylcarbonyl group, wherein aryl is preferably an aryl group having 6 to 14 carbon atoms, for example a phenyl group, a naphthyl group such as 1- or 2-naphthyl group, or a fluorenyl group, as a fluoren-9-yl group, wherein the aryl is unsubstituted or, for example, one or more times, preferably once substituted by a lower alkyl group, for example a methyl group, and a halogen (lower alkyl) group, such as trifluoromethyl or a chlorine or bromomethyl group, a halogen such as fluorine, chlorine, hydroxy, a lower alkoxy group, such as a methoxy group, a (lower and 1 -kanoyl) oxy group, a carboxyl group, (lower alkyl) oxycarbonyl a phenyl (lower alkoxy) carbonyl group, a carbamoyl group, a mono- or di (lower alkyl) carbamoyl group, a mono- or dihydroxy (lower alkyl) carbamoyl group such as a heterocyclyl (lower alkyl) group, in wherein the heterocyclyl group is defined as the aforementioned heterocyclyl group forming a substituent of the (lower and 1 -kanoyl) oxy-ups Rs, in particular a heterocyclyl methyl group, in which the heterocyclyl radical is bonded via a ring nitrogen atom, e.g. buy another, piperazin-1-ylmethyl, 4- (lower alkyl) -piperazin-1-ylmethyl, such as 4-methyl- or 4-ethylpiperazin-1-ylmethyl, 4- (lower alka) noyl) piperazin-1-ylmethyl such as 4-acetylpiperazin-1-ylmethyl, morpholinomethyl or thiomorpholomethyl, cyano and / or nitro, especially phenyl, para substituted with any of the above substituents, preferably a (lower alkanoyl) oxy group such as a formyloxy group, acetyloxy group, propionyloxy group, or a heptanoyloxy group such as n-heptanoyloxy group, hydroxy (lower alkanoylo) oxy group, for example, beta-hydroxypropionones of a loxy group, (lower and 1 alkoxy) (lower alkanoyl) oxy group, for example, (lower alkoxy) acetyloxy or (lower and 1 cox) propionyloxy, such as methoxyacetyloxy or beta-methoxypropionyloxy - (lower alkanoyl) oxy (lower and 1-canoyl) oxy) - for example, (lower alkanoyl) oxyacetyloxy or (lower and 1-alkoyl) oxypropionoxy, such as acetoxyacetyloxy or beta-acetoxypropionyloxy; a halo (lower and 1-canoyl) oxy group such as acetoxyacetyloxy or beta acetoxy-propionyloxy group, halogen (lower and 1-canoyl) oxy group, for example, and 1 phenoxyacetyl oxy group such as alpha-chloro, alpha-bromo-, alpha-iodo, alpha, alpha, alpha-tri-3-fluoro- or alpha, alpha, alpha-trichloro-acetyloxy, or halogeno-propoxyoxy, such as beta-chloro- or a beta-bromopropionoxy group, a carboxy (lower alkanoyl) oxy group, for example a carboxyacetyl oxy group or a 3-carboxypropionoxy group, a (lower alkoxy) carbonyl (lower alkanoyl) oxy group, for example (lower alkoxy) carbonylacetyloxy or (lower alkoxy) carbonylproionyloxy, such as methoxycarbonylacetyloxy, betamethoxycarbonylpropionoxy, ethoxycarbonylacetyloxy, beta-ethoxycarbonylpropionyloxy, tert-butoxycarbonyloxy butoxycarbonylpropionyl oxy, carbamoyl (lower alkanoyl) ox a γ-group, for example a carbamoylacetyloxy group or a beta-carbamoylpropionyl oxy group, (lower alkyl) carbamoyl (lower alkanoyl) oxy group, di (lower alkyl) carbamoyl (lower alkanoyl) oxy group, hydroxycarboxy (lower alkanoyl) oxy, hydroxy (lower alkoxy) carbonyl (lower alkanoyl) oxy, dihydroxycarboxy (lower and 1-alkoyl) oxy, dihydroxy (lower alkoxy) carbonyl (lower alkanoyl) oxy, heterocyclyl (lower alkanoyl) oxy, for example pyrrolylcarbonyloxy, such as 2- or 3-pyrrolylcarbonyloxy, furylcarbonyloxy, for example 2-furylcarbonyloxy, 5-hydroxymethylfuran A 2-thienylcarbonyloxy group, for example a 2-thienylcarbonyloxy group, an imidazolylcarbonyloxy group such as a 4-imidazolylcarbonyloxy group, an imidazolylcarbonyloxy group, such as a 3- (4-imidazolylpropionyl oxy group, pyridylcarbonyloxy group, for example 2-, 3- al. or 4-pyridylcarbonyloxycarbonyl, indolylcarbonyloxy, for example 2-, 3 or 5-indolylcarbonyloxy, 1-methyl-, 5-methyl, 5- methoxy, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindol-2-carbonyloxy, quinolylcarbonyloxy, such as quinol trans-2-carbonyloxy, pyrrolidinylcarbonyloxy, such as pyrrolidinyl-3-carbonyloxy, piperidinylcarbonyloxy, for example 2-, 3- or 4-piperidinylcarbonyloxy, morpholinocarbonyloxy, thiomorpholinocarbonyloxy, thiomorpholinocarbonyloxy a group, a morpholinoacetyloxy group, a thiomorpholinoacetyloxy group, or a 4- (lower alkyl) -1-piperazinoacetyloxy group such as a 4-methylpiperazinoacetyloxy group, (lower alkenoyl) oxy group, for example an acryoyloxy group, in alkynyl acetyl, crotonoyloxy or 3- or 4-pentenoxy-alkoxy, (lower and 1-inoyl) oxy, for example propionyl or 2- or 3-butinoyloxy- a cycloalkylacetoxy group in which the cycloalkylacetoxy radical contains from 3 to 8 carbon atoms, for example cyclopropyl-cyclopropyl, butyl - cyclopentyl or cyclohexylcarbonyloxy, cyclopropylacetyloxy, cyclopentylacetyloxy or cyclohexylacetyloxy, phenyl (lower alkanoyl) oxy, for example benzoyloxy, phenylacetoxy or 3-phenylpropionyloxy, in which the phenyl residue is unsubstituted or mono- or polysubstituted by lower alkyl, for example methyl, halogen (lower alkyl), such as chloro or bromomethyl, halogen, for example fluorine or chlorine, hydroxy, lower and 1-alkoxy, for example methoxy, piperidinomethyl, piperidin-1-ylmethyl, 4- (lower alkyl) piperazin-1-yl methyl, such as 4-methyl- or 4-ethylpiperazin-1-ylmethyl, 4- (lower alkanoyl) piperazin-1-ylmethyl, such as 4-acetylpiperazin-1-ylmethyl a morpholino (lower alkyl) group such as morpholinylmethyl, thiomorpholinylmethyl, cyano, or / anthro, for example 4-chloromethyl-, 4-bromomethyl-, 4-fluoro- 4-chloro-, 4-methoxy-, 4-morpholinylmethyl-, 4-thiomorpholinylmethyl-4-cyano or 4-nitrobenzoyloxy or (lower and alkyl) phenylsacetyloxy such as 4-methylphenylsacetyloxy groups.

A preferred acyloxy group R 5 of the acyl moiety of a half-carbonic acid ester that is bonded through its carbonyl group to an oxygen atom is, for example, unsubstituted or substituted and alkyloxycarbonyloxy, especially unsubstituted or substituted (lower alkoxy) carbonyloxy, e.g. methoxy ethoxy or tertiary (lower alkoxy) carbonyloxy group, such as tert-butoxycarbonyloxy, 2-halogen (lower and 1-alkoxy) carbonyloxy, for example 2-chloro, 2bromo, 2-iodo-2-carboxylic acid, e.g. a d- or 2,2,2-trichloroethoxycarbonyloxy group, an aryl (lower alkoxy) carbonyloxy group, for example an arylmethoxycarbonyloxy group, in which the aryl radical preferably contains 6 to 14 carbon atoms, is unsubstituted or singly or multiply, preferably once, substituted with a lower alkyl group, for example a methyl group, a halo (lower alkyl) group such as a trifluoromethyl group or a chloro- or bromo methyl group halogen, for example fluorine or chlorine, hydroxy, lower alkoxy such as methoxy, (lower alkanoyl) oxy, carbonyloxy, (lower alkyl) oxycarbonyl, phenyl (lower alkanoylloxycarbonyl) , carbamoyl, mono- or di (lower alkyl) carbamoyl, mono- or di hydroxy (lower and lower alkyl) carbamoyl, heterocyclic (lower and lower alkyl) groups wherein the heterocyclyl radical is defined as the aforementioned heterocyclyl substituent for the (lower alkanoyl) oxy group R 5, in particular a heterocyclyl radical, in which the heterocyclyl radical is bonded via a ring nitrogen atom, e.g. 1-ylmethyl, 4- (lower and 1-cyanoyl) -piperazin-1-ylmethyl such as 4-acetylpiperazin-1-ylmethyl, morpholinylmethyl or thiomorpholinylmethyl in the case of a group, cyano and / or nitro group, and in particular represents a phenyl group, 1- or 2-naphthyl group, a fluorenyl group or a phenyl group substituted one or more times with a lower alkyl group, for example methyl or tert-butyl, lower alkoxy a group, for example a methoxy group, an ethoxy group or a tert. butoxy, hydroxy, halogen, for example fluorine, chlorine or bromine and / or nitro, for example phenyl 1 (lower alkoxy) carbonyloxy, such as benzyloxycarbonyloxy, 4-methoxybenzyloxycarbonyloxy .

4-nitrobenzyloxycarbonyloxy, diphenyl (lower alkoxy) carbonyloxy, such as diphenylmethoxycarbonyloxy, di (4-methoxyphenyl) methoxycarbonyloxy, trityloxycarbonyloxy or fluorenes 1 (n) lower and 1-alkoxy) carbonyloxy, such as 9-fluorenylmethoxycarbonyloxy, or further heterocyclyl (lower and 1-alkoxy) carbonyloxy, in which the heterocyclyl radical is defined as the above-mentioned heterocyclyl substituent (lower alkanoyl) oxy groups R 5, for example furan-2-ylmethoxycarbonyloxy or pyridin-2-, -3- or -4-ylmethoxycarbonyl. The definitions falling within the definition of the acyl groups R 5 of the half-carbonate ester can advantageously be omitted in all the preceding and subsequent definitions of the compounds of the formula I.

The preferred N-substituted aminocarbonyloxy group, acyloxy, R5 carries 1 to 2 substituents on the nitrogen atom, each independently of one another being selected from unsubstituted or substituted lower alkyl groups, the substituents being selected from substituents selected from the group consisting of unsubstituted or substituted lower alkyl groups. are given above for the (lower alkanoyl) oxy group R 5 and may be available in the calculation herein, these substituents being preferably selected from the group consisting of hydroxy, lower alkoxy, (lower alkanoyl) oxy, phenyl ( lower and 1-alkoyl) oxy, such as benzoyloxy or phenylacetyloxy, halogen such as fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, carboxyl, (lower alkoxy) carbonyl, phenyl 1 (lower) (alkoxy) carbonyl, such as benzyloxycarbonyl, cyano, oxo and phenyl or naphthyl, which are unsubstituted or, for example, one or more times, preferably once substituted by a lower alkyl group, for example methyl, halo (lower alkyl) ), such as a three-fluoromethyl group or a chloro- or bromomethyl group, and a halogen, for example fluorine or chlorine, a hydroxy group, a lower alk oxy, such as methoxy, (lower and 1-cyano) oxy, carboxyl, (lower and 1-alkyl) oxycarbonyl, phenyl (lower and 1-alkoxy) carbonyl, cyano and / or an itro group, in particular a phenyl group which is substituted in the para position by one of the abovementioned groups, in particular from unsubstituted lower alkyl groups such as methyl or ethyl, and from aryl groups which preferably contain 6 to 14 carbon atoms are unsubstituted or, for example, one or more times, preferably once substituted by a lower alkyl group, for example a methyl group, a halogen (lower alkyl) group such as a chloro- or bromomethyl group, a halogen such as fluorine or chlorine, a hydroxy group, a lower alkoxy- such as methoxy, (lower and 1-alkoyl) oxy, carboxyl, (lower and 1-alkyl) oxycarbonyl, phenyl (lower alkoxy) carbonyl a halogen (lower alkyl) group such as trifluoromethyl, cyano and / or nitro, wherein the carbamoyl nitrogen atom carries no more than one aryl group; in particular the acyloxy group R _{5 of the} N-substituted carbamic acid is a di (lower alkyl) aminocarbonyloxy group such as Ν-methyl-, N-ethyl-, N, N-dimethylamino or N, N-diethylaminocarbonyloxy a group or phenyl (lower and alkyl) aminocarbonyloxy group in which the phenyl radical is unsubstituted or preferably three times, in particular once, independently substituted by a lower alkyl group, for example methyl, halo (lower alkyl) a group such as a chloro- or bromomethyl group or a trifluoromethyl group, a halogen such as fluorine or chlorine, a hydroxy group, a lower alkoxy group such as a methoxy group, a carboxyl group and / or a cyano group such as para, such as in Ν -benzyl-, N (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N- (4-cyanobenzyl) aminocarbonyloxy, with aminocarbonyloxy being particularly preferred substituted on the nitrogen atom with only one substituent, n and, for example, an N- (lower and 1-alkyl) aminocarbonyloxy group, such as an N-methyl or N-ethylaminocarbonyloxy group, or a phenyl (lower alkyl) aminocarbonyloxy group in which the phenyl moiety is not 37

J.

substituted or substituted with a lower alkyl group such as a methyl group, a halo (lower alkyl) group such as a chloro- or bromomethyl group or a trifluoromethyl group, a halogen such as fluorine or chlorine, a hydroxy group, a lower alkoxy group such as methoxy, carboxyl and / or cyano, preferably independently of one another substituted by up to three of said substituents, in particular one of them, for example in the para position, such as Ν-benzyl-, N- (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N- (4-cyanobenzyl) aminocarbonyloxy. The definitions included in the definition of groups R acy1oxy-N-substituted carbamic acid ester and the AM-Anilinocarbonyl 1oxy radical _R may be preferably emitted from all of the foregoing and following above definitions of the compounds of formula I.

The unsubstituted or substituted amino acid in the acyloxy group R 5, which binds through its carbonyl group to the oxygen bonding atom, is preferably formed by amine acid residues and through the carbonyl group of their carboxyl group and the oxygen atom (amineocyloxy), alpha-, beta- or gamma-amino acids, in particular natural and 1-amino acids of L-configuration, as normally found in proteins or epimers of such amino acids, i.e. having a non-natural D configuration, or a D, L-isomeric mixture thereof, of an amino acid homology in which, for example, the amino acid side chain is extended or truncated by one or two methylene groups in which the amino group is at the beta, gamma or delta and / or wherein the methyl group is replaced by a hydrogen atom, a substituted aromatic amino acid, wherein the aromatic residue contains 6 to 14 carbon atoms, for example substituted phenylalanine or phenylglycine, wherein the phenyl substituent may be a lower alkyl group such as methyl, hydroxy - a lower alkoxy group, for example a methoxy group, a (lower and 1-alkoyl) oxy group, for example an acetoxy group, an amino group, (a lower alkyl) amino group, for example a methylamino group, di (lower and alkyl) amino groups, for example dimethylamino, (lower alkanoyl) amino groups, for example acetylamino or beers loylamino, (lower and 1-alkoxy) carbonylamino, for example tert-butoxycarbonylamino, arylmethoxycarbonylamino, in which the aryl radical preferably contains 6 to 12 carbon atoms, for example benzyloxycarbonylamino- or a 9-fluorenymethoxycarbonylamino group, a halogen such as fluorine, chlorine, bromine or iodine, a carboxyl group and / or an itro group, and this substituent occurs one or more times, benzane-phenylalanine or phenylglycine, such as alpha-naphthylalanine, or hydrogenated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexyl g of lycin.

These amino acid residues may be in the free hydroxy function aminoalebo substituted as that described above for the amino acid residues of Ri and R _ninth

Particularly preferred is an amino acid residue that binds through the carbonyl group of the carboxyl group, said amino acid selected from the group consisting of glycine (H-Gly-OH), alanine (H-Ala-OH), 2-aminobutyric acid, 3 -aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid or 5-aminohexanoic acid, valine (H-Val-OH), nor valine (alpha-aminovaleric acid), Leucine (H-Leu-OH), Isoleucine (H-Ile-OH), Norleucine (α-1-aminohexanoic acid and N-Nle-OH), Serine (HSer-OH), Homoserine ( and 1? -amino-gamma-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans- 3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H-Tyr-OH), 4-aminophenyl and n-n, 4-chlorophenyl and n-n, beta-phenyserine (beta-hydroxyphenyl and Nani, phenylglycine, and 1 phane phthalic acid (H-Nal-OH), cyclohexyl and l-methyl (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1,2,3,4- tetrahydroizochinolín39

3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asp-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), delta-hydroxylysine, ornithine (alpha, delta-diaminovaleric acid), 3-aminopropanoic acid, 1 fa , gamma-diamine inomasic acid and 1α, beta-diamine inopropionic acid, with the aliphatic amino acid residue particularly preferably selected from alanine, valine, norvaline, leucine, 3-aminopropionic acid, acid

2- am inomoyl, 4-amomoyl,

4-aminopentane,

3-aminohexane,

5-aminohexanoic acid and acidic acid

3-aminobutyric acid, 3-aminopentanoic acid, 5-aminopentanoic acid, acid

A 4-aminohexanoic or pin or n-butyl group such as 2-, 3-isoleucine or an amino acid selected from the group consisting of glycine, asparagine, glutamine, methionine, lysine, histidine, proline and phenylalanine, each of which may be (except when there is no asymmetric carbon as in the case of glycine) in form D, L or (D, L), preferably in form L, and the amino group is unsubstituted or once or twice N-alkylated, for example lower alkyl such as methyl, n-propyl, pyridyl (lower alkyl) or 4-pyridylmethyl, and / or phenyl (lower alkyl) such as benzyl, and / or N-acylated , for example, unsubstituted or substituted lower alkanoyl, which is defined as the above-mentioned lower alkanoyl group for the (lower and 1-alkoyl) oxy group R 5, in particular acetyl, propi an aryl (lower alkanoyl) group such as a phenyl (lower alkanoyl) group such as a benzoyl group or a phenylacetyl group, a (lower alkoxy) carbonyl group such as a tert-butoxycarbonyl group, or aryl (lower and 1-alkoxy) carbonyl, for example phenyl (lower alkoxy) carbonyl such as benzyloxycarbonyl.

Of the latter residues, preferred are acyloxy groups R 5 of unsubstituted or substituted amino acid selected from the group consisting of aminoacetyloxy (gyloxy), N - (lower and lower) aminoacetyloxy, N, N-di (lower alkyl) aminoacetyloxy, N- (lower alkyl) -N-phenyl (lower and alkyl) aminoacetyl oxy and N-phenyl (lower and 1 alkoxy) carbonyl 1N- ( lower alkyl) aminoacetyloxy, such as N-methylaminoacetyloxy, Ν, Ν-dimethylaminoacetyloxy, N-methyl-N- (n-butyl) aminoacetyloxy, N-methyl-N-benzylaminoacetyloxy, N-methyl-N - [(2-, 3- or 4-) pyridylmethyl] aminoacetyloxy, such as N-methyl-N-3-pyridylmethylaminoacetyloxy, N-methyl-N-tert-butoxycarbonylaminoacetyloxy a group, N-benzyloxycarbonyl 1-N- (lower alkyl) aminoacetyloxy, propyloxy, histoxy, g-butyloxy and asparagyloxy, the amino acid residues being (except where there is no asymmetric carbon atom, such as in the case of glycine), preferably in form L or further in form (D, L).

Unsubstituted or substituted alkyl group R ₃ , R a or R 6; is preferably one of the radicals mentioned in connection with the alkyl group R 1, R ₂ , R e and R ₉ , which group is unsubstituted or substituted, in particular the substituents mentioned for the lower alkanoyl group R 1 or R ₉ , especially one of these substituents, and is especially selected from the group consisting of lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, cycloalkyl (lower alkyl) in which the cycloalkyl radical contains for example 3 to 7 carbon atoms and represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, the cycloalkyl radical being unsubstituted or substituted one to three times by lower alkyl such as isopropyl, halogen (lower alkyl, ako tr fluoromethyl, hydroxy, lower alkoxy, amino, mono or di (lower and alkyl) amine, halogen such as fluorine, chlorine or bromine, nitro and / or cyano and binds to a lower alkyl group, in particular methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl or tert-butyl, preferably terminally, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl (lower) alkyl), with cycloohexyl (lower alkyl) being particularly preferred, such as cyclohexylmethyl, and aryl (lower alkyl) wherein the aryl radical is, for example, independently defined as the aryl substituent of the lower alkanoyl group R 1 or R a, which is unsubstituted or substituted as described therein, in particular phenyl (lower alkyl) such as benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluorobenzene a 4-cyanobenzyl group, a 4-trifluorobenzyl group, a 4-hydroxybenzyl group or a 4-methoxybenzyl group or, moreover, or in particular a 4- (lower alkoxy) benzyl group (in particular having a total carbon atom number in the alkoxy group) higher than in 4-methoxybenzyl), such as 4-isobutyloxybenzyl, 3,4-di (lower alkoxy) benzyl, such as 3,4-dimethyloxybenzyl, phenyl (lower alkoxy) benzyl, such as 4- benzyloxybenzyl, 4 * (3,4-di (lower alkoxy) benzyloxy) benzyl, (lower alkoxy) (lower alkoxy) benzyl, such as 4- (2-methoxyethoxy) benzyl, (lower alkylene) dioxyphenylmethyl a group such as 3,4-methylenedioxyphenylmethyl, or a biphenylylmethyl group, such as a 4-biphenylylmethyl group, with a phenyl (lower alkyl) group particularly preferred as defined above, or (hereinafter or in particular) thi; enylmethyl or tetrahydropyranylmethyl, such as 2-thienylmethyl or 4- (2,3,3,6-tetrahydro) pyranylmethyl.

Cycloalkyl group R ₃ , R _A or R 6; is preferably defined as a cycloalkyl substituent of a lower alkanoyl group

R 1 or R 9a is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, the cycloalkyl being unsubstituted or substituted one to three times by lower alkyl such as isopropyl, halogen (lower alkyl) , such as trifluoromethyl, hydroxy, lower alkoxy, amino, mono- or di (lower and alkyl) amino, halogen such as fluorine, chlorine or bromine, nitro and / or cyano such as cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, with cyclohexyl being particularly preferred.

The aryl group R 3, R ₄ or R 7 is preferably independently defined as the aforementioned aryl substituent of the lower alkanoyl group R 1 or R y and is unsubstituted or substituted as described herein, in particular being a phenyl group which is unsubstituted or once or up to three times substituted by lower alkyl such as isopropyl, halogen (lower alkyl) such as trifluoromethyl, hydroxy, lower alkoxy, halogen such as fluorine, chlorine or bromine, nitro and / or cyano, such as phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl or 4-cyanophenyl.

When in the compounds of formula I nitrogen atoms with free hydrogen and / or hydroxy groups are vicinal to the double or triple bond, then the compounds of the invention also include the corresponding tautomeric imino or oxo compounds.

The salts of the compounds of the formula I are, in particular, acid addition salts, base salts or, optionally, mixed salts or internal salts if more than one is present.

In particular, these salts are the pharmaceutically usable non-toxic salts of the compounds of formula I.

Such salts comprise, for example, compounds of the formula I having an acidic group, for example a carboxyl group, and are, for example, salts of these compounds with suitable bases such as non-toxic metal salts of metals Ia, lb, IIIa and IIb of the Periodic Table of Elements. alkali metals such as lithium salts, sodium or potassium salts, or alkaline earth metal salts such as magnesium or calcium salts, zinc salts or ammonium salts, as well as salts formed with organic amines such as optionally hydroxy substituted mono-, di or trialkylamines, in particular mono-, di- or tri (lower alkyl) amines, or quaternary ammonium compounds, for example with N-methyl-N-ethylamine, diethylamino, triethylethylamine Mono, bis- or tri-2- (2-hydroxy- lower alkyl) amines such as mono-, bis- or tri- (2-hydroxyethyl) amine, 2-hydroxy- tert-butyl mine or three with (hydroxymethyl) methylamine, N, N-di (lower alkyl) -N- / hydroxy (lower alkyl) amines such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri- ( 2-hydroxyethyl) amine, N-methyl-D-glucamine or quaternary ammonium salts such as tetrabutane 1 ammonium salts. Compounds of the general formula with a basic group such as a tertiary amino group can form acid addition salts with, for example, inorganic acids such as hydrohalic acids, for example hydrochloric, sulfuric or phosphoric acids, or organic carboxylic acids, sulfonic acids, sulfo- or phosphoacids, or with N-substituted sulfonic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methyl maleate, fumaric acid, malic acid, tartaric acid, gluconic acid, glucuric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxyb enzoic acid, nicotinic acid or isonicotinic acid, or further with amino acids, for example with the aforementioned α 1 -amino acids, such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, acid benzosulphonic acid, 4-methylbenzenesulphonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, gosozo-6-phosphate, N-cyclohexylsulphamic acid (in the formation of cyclamates) or other organic compounds such as ascorbic acid . Compounds of formula I with acidic and basic groups may also form internal salts.

Pharmaceutically unsuitable salts may also be used for isolation and purification.

The compounds of the formula I have valuable pharmacological properties. These compounds are antiretroviral active, in particular against AIDS, for example against HIV-1 and HIV-2. They serve as metabolic precursors for compounds of formula II

(II) wherein the general symbols have the meanings given for compounds of formula I (analogs of compounds of formula I in which R 5 is hydrogen instead) which are useful as inhibitors of retroviral aspartate proteases, in particular as HIV-1 or HIV-1 retroviral gagprotease inhibitors Compounds of formula (II) (with a hydroxy group instead of R _{with a} formula of formula 2) (and optionally aspartoproteases of other retroviruses which induce symptoms analogous to those of AIDS and thus are useful in the treatment of retroviral diseases such as AIDS or precursors thereof. I) are thereby released from the compounds of formula I in the body of the animal to be treated, preferably a warm-blooded animal, including man.

Compounds of formula I preferably exhibit advantageous pharmacodynamic properties over compounds of formula II, which can be demonstrated, for example, in the following manner.

Compounds of formula I to be tested, or used as control subjects, comparative compounds of formula II are dissolved in dimethylsulfoxide (DMSO) at a concentration of 240 mg / ml. The solutions obtained are diluted with 20% (w / v) hydroxypropyl-beta-cyclodextrin (HPbetaCD) to a concentration of 12 mg / ml. This solution is administered to mice in special formula at 120 mg / ml. 60, 90, and 120 minutes after this administration, the mice are sacrificed and then bled. Three to four experimental animals are used for each of the time intervals. The collected blood is heparinized and processed for analysis as follows. An internal standard at a final concentration of 4 µM is added to the heparinized blood. The blood is then centrifuged. 0.25 ml of plasma is collected and this plasma is deproteinized with an equal volume of acetonitrile. After centrifugation, the supernatant is dried under vacuum and the residue is suspended in 20 µl of 1 M sodium chloride solution and 100 µl of 0.05 M phthalate buffer, pH 3.0. This suspension is extracted first with 2 ml and then with 0.2 ml of isopropyl ether. The resulting diisopropyl ether solution was evaporated to dryness and the residue was dissolved in 50% (w / w) aqueous acetonitrile solution. This solution was subjected to reverse phase HPLC analysis.

This reverse phase HPLC analysis was carried out using a 125 x 4.6 mm C Nucleosil column (reverse phase material from Macherey-Nagel, Duren, Federal Republic of Germany, based on silica derivatized with 18 carbon atoms). is in equilibrium with the mobile phase consisting of a 50% acetonitrile / water solution containing 0,1% tri-fluoroacetic acid. The flow rate is equal to 1 ml / min. Detection is performed at 215 nm. Blood samples were processed analogously to standards and subsequently used to plot standard curves to determine in vivo concentrations.

The following results were obtained when comparing the compounds of the formula I with those of the formula II (active ingredients in which a hydrogen atom is present in place of the acyloxy group R 5). The concentration of the active ingredients of formula II in the blood of mice is markedly higher when administered orally with a compound of formula I, for example a compound of formula I in which R 1 is acetyl, at most of the above times, preferably above. of the formula II in an ester-fed form, for example more than three times as high, in particular more than 10 times as high, and in particular about 20 to 150 times as high. Alternatively or additionally, the absorption of a compound of formula I, for example a compound of formula I in which R 1 is acetyl, is significantly higher than that of a compound of formula II, for example more than four times as high. It is also possible to achieve a higher blood concentration of the active ingredient over a longer period of time with the compound of formula I than with the compound of formula II.

Preferably, the achievable blood concentration of the active compound of formula (II) at the indicated times is significantly higher than the ED 90 determined in the cell assay for the corresponding compound of formula (II) (see below).

The compounds of the formula I as well as the compounds of the formula II can also be used as standards for comparing different test systems in different animal species, which represents an additional commercial utility. By finding comparable blood count values in different animal species, the results obtained in different animal test models can then be compared.

The compounds of the formula II or their salts which are released under physiological conditions from the compounds according to the invention or which serve as starting materials for the preparation of the compounds of the formula I exhibit viral aspartate protease inhibitory activity, in particular a gag protease inhibiting activity. For the following tests, and at 10 ~ ^6-1 0 ^{'1 -9} mol / 1 primarily inhibit the gag-protease retr ovírusov HIV-1 and HIV-2 and are therefore useful as an agent for diseases caused by these or related r etr Russians such as AIDS or its preliminary stages.

Blood images of these compounds of formula II can be determined analogously using the methods outlined above for compounds of formula I.

The ability of the compounds of formula II to inhibit proteolytic activity, e.g.

HIV-1 proteases may be demonstrated by J. Hansen et al. in EMBO Journal 7, 1785-1719 (1988). In this method, inhibition of the effect of gag protease on a substrate, which is a condensation protein from a gag precursor protein and MS-2 expressed in E.Coli, is measured. The substrate and its cleavage products are separated by polyacrylamide gel electrophoresis and determined by immunoblotting with monoclonal antibodies to MS-2.

In an even simpler assay that allows accurate quantitative determination, a synthetic peptide that corresponds to the cleavage site of the gag precursor protein is used as the substrate for the gag protease. This substrate and its cleavage products can be determined by high pressure liquid chromatography (HPLC).

Thus, for example, in a procedure analogous to that described by Richards, A.D. et al. v J. B i o 1. Chem. , 265, (14), 7733-7736 (1990), is used as a substrate for recombinant HIV-1 protease (preparation according to: Bi 11, S. et al.

J.B i 1. Chem., 263 (34), 17905-17790 (1990)) a synthetic chromophore peptide (e.g. HKARVL / NOs / FEANleS (Bachem, Switzerland) or Icosa-peptide such as RRSNQVSQNYPIVQNIQGRR (prepared by peptide synthesis carried out in a known manner): J Schneider et al., Cell, 54, 363-368 (1988)), which corresponds to the cleavage sites of the gag precursor protein, and this substrate and its cleavage products can be determined by high pressure liquid chromatography (HPLC).

For this purpose, the test inhibitor of formula II is dissolved in dimethylsulfoxide. The enzyme assay is performed by adding to the assay mixture 67.2 _of µM the above chromophore peptide in 0.3M sodium acetate, 0.1 M N and Cl, pH 7.4 or 122 µM of the above Icosa-peptide in 20 mM MES buffers, pH 6.0 add appropriate dilutions of inhibitor in 20 mM beta-morpholinoethanesulfonic acid (MES) buffer (pH 6). The handle size is 100 zul. The reaction is started by addition of 2 ZU1 in the first case and 10 in the second case ZU1 HIV-I proeteázy and ends in the first case after 15 min pridadním 100 ul _of 0.3 M HCIC and in the latter of the tube at 37 ° C by addition of 10 perm 0.3M HCl CU. Reaction products are quantitated after centrifugation of the sample for 5 minutes at 10,000 xg in 100 µl (chromophoric peptide feed) or 20 _of µl (Icosapeptide feed), the supernatant obtained and after loading onto a C 18-5zu.HPCL-st1 Nucleosil furnace. with dimensions of 125x4.6 mm (Macherey and Nagel, Duren) and elution by measuring the peaks for the cleavage product of formula II at 280 nm (chroporic peptide feed) or 215 nm (Icosa-peptide feed). Gradient: 100% E1.1 to 50% E1.1 / 50% E1.2 (E1.1: 75% acetonitrile, 90% HcO, 0.1% trifluoroacetic acid (TFA); E1.2; 75 % acetonitrile, 25% K-Ο, 0.08% TFA), time 15 min, flow rate 1 m 1 / m 1.

In the above assay, IC 50 values (IC 50 - concentration that reduces the efficacy of HIV-1 protease over a 50% inhibitor-free control) were preferably determined from about 10 ^e to 10 ⁹ , especially from about 10 ⁷ to about 10 ^8. M.

In another assay, compounds of Formula II that are released from compounds of Formula I may be shown to protect cells that have been normally infected with HIV retroviruses from the infection or are at least capable of retarding the infection. In this assay, the human cell line MT-2 (leukemia T cells, Science, 229, 563 (1985)), which are extremely sensitive to the cytopathogenic effect of HIV, is incubated either with HIV alone or with HIV in the presence of compounds of the invention. the viability of the cells thus treated is determined over several days.

For this purpose, MT-2 cells are maintained in a culture medium of PPMI 1640 (Genco, Switzerland, RPMI 1640 contains a mixture of amino acids without L-Gln) which is supernatured with 10% heat-activated fetal calf serum, L-g 1 utamine. , Hepes (2- / 4- (2-hydroxyethyl) -1-piperazino / ethanesulfonic acid) and standard antibiotics, at 37 ° C and under humidified air with 5% carbon dioxide. To 4x10 ³ exponentially growing MT-2 cells in 50 _z in 1 culture medium contained in each well of a 96 well microtiter plate, 50 _z in 1 test compound in culture medium and 100 _of u1 HIV in culture medium are always added (800 TCID) 50 / ml) (TCID 50 = Tissue Culture Infectious Dose = 50 dose that infects 50% of MT-2 cells). The parallel shaft to the next microwaves Roti t of ratchet plates with the cells and a test compound comprising 100 .mu.l _of culture medium without virus. After 4 days incubation, reverse transcriptase (RT) activity is determined in 10 µl of cell supernatant. RT-activity was determined in 50 mM tris (alpha, alpha, alpha (hydroxymethyl) methylamine (ultra-pure, Merck, Federal Republic of Germany), pH 7.8, 75 mM KCl, 2 mM dithromic to 1 µm, 5 mM M g C 1 .- ·, 0.05% Nonidet P-40 (detergent, Sigma, Switzerland), 50 µg polyadenylic acid (Pharmacia, Sweden), 1.6 zug / ml dT (12-18) (Sigma, Switzerland The mixture is filtered through an Acrodisc filter (0.45 µm, Gellmen Science Inc.Ann Arbor) and stored at -20 ° C. To an aliquot of this solution is added 0.1% (v / v) / a1fa - ³² P / dTTP to achieve a final radioactivity of 10 zCi / ml 10 µl of supernatant above the culture medium is applied to a new 96-well microtiter plate and 30 µl of said RT-mixture is added to this supernatant. 1.5 and 3 hours at 37 [deg.] C. 5 [mu] l of this reaction mixture was transferred to Whatman DE81 paper (Whatman) and the dried filter was washed three times for 5 minutes with 300 mM NaCl / 25 mM citrate. m with trisodium and once with 95% ethanol and air-dried again. Evaluation is performed on a Matrix Packard 96well computer (Packard). ED90 values are calculated and defined as the lowest concentrations of a given test compound that reduce RT-activity by 90% compared to cell seed not treated with the test compound. RT-activity is a measure of HIV-1 retrovirus multiplication.

Compound with hydroxy group in place of R _in this case have ED 90 values of about 10 ^-5 to about 10 ^"3, preferably about 5 x 10 ^-7 to 5x10 ^-8 M.

In the tests of the following general formula I, it may be more convenient, for example, to replace the more general definitions by more specific definitions, by using the definitions of the above general definitions.

that are listed

Preferred is a compound of formula I wherein R a and R a independently of one another represent a hydrogen atom, a lower alkanoyl group such as a formyl group, acetyl group, propionyl group, butyryl group or pivaloyl group, or additionally or 3,3-dimethylbutyryl group an aryl group, especially an acetyl group, an aryl (lower alkanoyl) group in which the aryl radical contains from 6 to 14 carbon atoms, preferably is phenyl, indenyl, indanyl, naphthyl, antyl, phenanthryl acetylphthyl or fluorenyl, and is unsubstituted or mono- or triple-substituted, in particular lower alkyl, for example methyl, ethyl or propyl, halogen (lower alkyl), for example trifluoromethyl, phenyl group, 1- or 2-naphthyl, hydroxy, lower alkoxy a pin, such as a methoxy group, a carbamoyl (lower alkoxy) -group, an N- (lower alkyl) carbamoyl (lower alkoxy) group, or an N, N-di (lower alkyl) carbamoyl (lower alkoxy) -contained, amino, mono- or di (lower alkyl) amino, (lower alkanoyl) amino, e.g. pivaloylamino, halogen, e.g. fluorine, chlorine or bromo, carboxy, (lower alkoxy) carbonyl, such as tert-butoxycarbonyl, phenyl, naphthyl or fluorenyl (lower alkoxy) carbonyl, such as benzyloxycarbonyl, lower alkanoyl, sulfo, (lower and 1 methyl) with a sulfonyl group, for example methylsulfonyl, phosphono, hydroxy (lower alkoxy) phosphoryl or di (lower alkoxy) phosphoryl, carbamoyl, mono- or di (lower alkyl) caramoyl, mono or di (lower amoyl) and (1) amino) nitro, nitro and / or cyano in which the lower alkanoyl radical is unsubstituted or substituted by a carbamoyl or carbamoyl group on the nitrogen atom by one or two radicals selected from the group consisting of lower alkyl, carboxy (lower alkyl), (lower and 1-alkoxy) carbones Lower alkyl), di (lower and alkyl) amino (lower alkyl), heterocyclic (lower) an alkyl (lower and alkoxy) (lower alkyl) group, preferably as described above in the general definitions for an aryl (lower alkanoyl) group, for example 4-chloro, 4-methoxy- A 4-nitrobenzoyl group, a naphthylcarbonyl group such as an alpha or beta-naphthylcarbonyl group or via both carbonyl groups to an amino-linked 1,8-naphthalenediocarbonyl group, a phenyl (lower alkanoyl) group such as a phenylacetyl group u or 3-phenylpropionyl groups, (lower and 1-alkyl) phenyl acetyl, such as 4-methylphenylacetyl, (lower alkoxy) phenylacetyl, such as 4-methoxyphenylacetyl, 3- (p-hydroxyphenyl) propionyl, diphenylacetyl a di- (4-methoxyphenyl) acetyl group, a 2,2-dibenzylacetyl group, a 3-α 1 α- or 3-beta-naphthylpropionyl group, a phenyl (lower alkanoyl) group in which the lower alkanoyl group is a carbamoyl-substituted residue such as a 2-carbamoyl-3-phenylpropionyl group, for example 2- (R, S) -carbamoyl-3-phenylpropionyl, 3-phenyl- or 3- and 1-naphthyl-2-carbamoylpropionyl 3-phenyl- or 3-alpha-naphthyl-2-carbamoylpropionyl, 3-phenyl- or 3-alpha-naphthyl-2-tert-butylcarbamoylpropionyl, 3-phenyl- or 3-alpha-naphthyl-2- ( 2-dimethylaminoethyl) carbamoylpropionyl, especially phenyl (lower and 1-kanoyl), such as phenylacetyl; or a phenyl (lower alkanoyl) group in which the lower alkanoyl radical is substituted by a carbamoyl group, such as a 2-carbamoyl-3-phenylpropionyl group, e.g. S) carbamoyl-3-phenylpropionyl, heterocyclyl (lower al53 kanoyl), wherein the heterocyclyl radical is thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazole 1 y 1 a pyridyl group, a pyrazinyl group, a pyrimimidinyl group, a pyridazinyl group, an ondolyl group, a benzimidazolyl group, a quinolyl group, a quinolyl group, a 3,1-benzfuranyl group, a cyclohexa / b / pyrrolidinyl group, a cyclohexyl group b) pyridyl, cyclohexa / b / pyrazinyl, cyclohexa / b / pyridyl, cycohexa / b / pyrazinyl, cyclohexa / b / pyrimidinyl, pyrrolidinyl, pyrrolidinyl vinyl, imidazolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4- a tetrahydroquinolyl group or a 1,2,3,4-tetrahydroisoquinolyl group which is bonded via a ring carbon atom or a ring nitrogen atom, in the case of a saturated heterocycle preferably via a ring nitrogen atom, in particular an indolycarbonyl group such as 2-, 3- or 5-indolylcarbonyl a quinolyl (lower alkanoyl) group, for example a quinolylcarbonyl group, such as a 2-, 3- or 4-quinolylcarbonyl group, a piperidycarbonyl group, such as a piperidinecarbonyl group, or a 2-, 3- or 4-pi group. peridylcarbonyl, piperazinylcarbonyl, such as piperazin-1-ylcarbonyl, morpholinyl (lower alkanoyl), for example morphol a (lower alkanoyl) group, for example a morpholino-inocarbonyl group, such as a morpholinocarbonyl group, a thiomorpholine (lower and 1-cannoyl) group, e.g. to 1 ad thiomorpholine (lower alkanoyl) such as thiomorpholinocarbonyl, such as thiomorpholino-inocarbonyl, S, S-dioxothiomorpholinylcarbonyl, tetrazolyl (lower alkanoyl), such as 3- (thiazol-1-yl) propionyl, and pyrrolidinyl (lower) a higher alkanoyl group, for example a pyridylcarbonyl group such as a 2-, 3- or 4-pyridylcarbonyl group, or a pyridyl acetyl group such as a 2-, 3- or 4-pyridyl acetyl group, in particular morpholino (n); a lower alkanoyl group such as a morpholino-carbonyl group, a thiomorpholino (lower alkanoyl) group such as a thiomorpholinocarbonyl group, a pyridyl (lower alkanoyl) group such as a 2-, 3- or 4- a pyridinyl acetyl group, and a tetrazolyl (lower alkanoyl) group n, such as a 3-tetrazol-1-yl propionyl group, (lower alkoxy) (lower alkoxy) (lower alkanoyl), heterocyclic (lower alkanoyl group on the amino-nitrogen atom substituted with amino (lower) alkanoyl) in which the heterocyclyl (lower alkanoyl radical is independently defined as the above-mentioned heterocyclyl (lower alkanoyl) radical R @ 1 and R @ 5, in particular an N-morpholino- or N-1-morpholino-carbonyl group per amino group a nitrogen-substituted amino (lower alkanoyl group, in particular N-morpholino or N-thiomorpholino-carbonylamino) (lower alkanoyl) such as N-morpholino- or N-thiomorpholinocarbonylaminoacetyl, halogen (lower alkanoyl) a group containing up to three halogen atoms, in particular an alpha-haloacetyl group, such as alpha-fluoro, and 1fluoro-, alpha-iodo, alpha, alpha, alpha-trifluoro- or alpha, alpha, alpha-trichloroacetyl, or halopropionyls a group such as a beta-chloro- or beta-bromopropionium group, in particular a trifluoroacetyl group, (N-heterocyclyl (lower and 1-carbamoyl)) (lower alkanoyl), wherein the heterocyclyl radical preferably represents a pyrrolyl group, a furyl group, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl and isoquinolyl, which may be wholly or partially saturated, and in particular morpholinyl, thiomorpholinyl and thiomorpholinyl; - (N-morpholino (lower alkyl) carbamoyl) (lower alkanoyl) group, such as 2 (R, S) - (2-2-morpholinoethyl) carbamoyl) -3-methyl-butyryl or a 2- (N- (pyridyl (lower alkyl) carbamoyl)) (lower alkanoyl) group such as 2 (R, S) - (N- (2-pyridyl 1-meth) 1) carbamoyl) -3-methylbutyryl group, (ni a lower alkoxycarbonyl group, in particular a methoxy, ethoxy, isopropoxy, isobutoxy or tertiary (lower and 1 alkoxy) carbonyl group, for example a methoxycarbonyl group, a tert-butoxycarbonyl group or an isobutoxycarbonyl group, an aryl (lower alkoxy) carbonyl group in which the aryl radical is a phenyl group, a biphenyl group, or a 1- or 2-naphthyl group, a fluorenyl group or a phenyl group one or more times, preferably three times, in particular once substituted by a lower alkyl group, e.g. or a tert-butyl group, a hydroxy group, a lower alkoxy group, for example a methoxy group, an ethoxy group or a tert-butoxy group, a halogen such as chlorine or bromine or an anro group. for example a phenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl group or a 4-methoxybenzylcarbonyl group, in particular a phenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl group, a heterocyclyl (lower alkoxy) carbonyl group in which the heterocyclic radical is means pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidyl, indolyl, quinolyl and isoquinolyl groups, which may be wholly or partially saturated, partially or completely saturated a thiomorpholinyl group, and is unsubstituted, for example a 2-furyl methoxycarbonyl group, or a tetr ahydrofuryl (lower alkoxy) carbonyl group, if a 2-tetrahydrofurylmethoxycarbonyl group, in particular a tetr ahydrofuryl (lower alkoxy) carbonyl group such as (R, S) a tetrahydrofurylmethoxycarbonyl group, a (lower alkenyl) oxycarbonyl group in which the lower alkenyl group via a saturated carbon atom, a (lower alkoxy) radical is bonded to an oxygen atom, for example an allyloxycarbonyl (lower alkoxy) carbonyl group such as a 2-methoxyethoxycarbonyl group , ((lower alkoxy) (lower and 1-alkoxy) (lower alkoxy)) carbonyl, such as 2- (2-methoxyethoxy) ethoxycarbonyl, (lower alkane) sulfonyl, for example methane or ethanesulfonyl, especially methanesulfonyl, heterocyclylsulfonyl (heterocyclyl-SO-), wherein the heterocyclyl radical is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl , a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group and any other 1-yl group which may can be wholly or partially saturated, and a morpholinyl group and a thiomorpholinyl group and is unsubstituted or substituted by a lower alkyl group such as a methyl group, such as a morpholinyl group, a thiomorpholinyl group, a p or a piperazinosulfonyl group, a carbamoyl group, an N-heterocyclyl (lower alkyl) -N- (lower and alkyl) carbamoyl group wherein the heterocyclyl radical is independently one of the abovementioned radicals. above for the definition of the heterocyclic yl (lower and 1-alkoyl) of the group R 1 or R a, in particular a pyridyl group such as 2-,

3- or 4-pyridyl, preferably N-pyridyl (lower alkyl) -N- (lower alkyl) carbamoyl, such as N- (2-, 3- or 4-pyridylmethyl) -N-methyl a carbamoyl group or, in addition, or in particular an N- (lower and 1-alkyl) -N- (morpholino (lower alkyl)) aminocarbonyl group, such as an N-methyl-N- (2-morpholinoethyl) aminocarbonyl group, or an acyl group an amino acid residue having an in-function and is free but: the others hitherto mentioned, wherein the amino acid is acylated with one residue for the R and R ₉ residues are selected from radicals that bind through the carbonyl group of their 1-carboxyl group, amino acids, which are selected from the group consisting of glycine, alanine, valine, nor valine, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenyl and 1 and 1-in,

4-chlorophenylalanine, 4-carboxyphenylalanine, beta-phenylserine, phenylglycine, and 1 phtha-naphthalene, cyclohexylglycine, cyclohexylglycine, tryptophan, indole-2-carboxylic acid, 1,2,3,4 acid -tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomonic acid, aminomoniconic acid monoamide, glutamic acid, glucamine, histidine, arginine, lysine, di-hydroxy-yzine, ornithine, acid 3-aminopropanoic acid, 1α, gamma-diaminobutyric acid and alpha, beta-diaminopropionic acid, even more preferably from amino acid residues selected from valine, alanine, leucine, isoleucine, glycine, glutamic acid and asparagine, each of said amino acids (except glycine may be in the form of D or L or (D, L), preferably (except Val, which may also be in the form of D or (D, L) in the form of L, wherein the alpha amino acid is unsubstituted or acylated) of the radicals mentioned above for R 1 and R 5, in particular lower alkanoyl, phenyl (lower alkanoyl) such as phenyl acetyl, phenyl (lower alkanoyl) in which the lower alkanoyl radical is substituted by carbamoyl such as 2 (R, S) -carbamoyl-3-phenylpropionyl, morpholino (lower alkanoyl), morpholino (lower alkanoyl) such as morpholinocarbonyl, thiomorpholino (lower alkanoyl) ) by a group such as thiomorpholinocarbonyl, a pyridyl group (lower and 1-canoyl) by a group such as 2-, 3- or 4-pyridyl acetyl), by quinolyl (lower and 1-canoyl) a group such as quinolin-2-yl-carbonyl, a tetrazole (lower alkanoyl) group such as a 3-tetrazol-1-propionyl group, (lower alkoxy) (lower alkoxy) (lower alkanoyl) group 58, amino (lower and 1-alkoyl group substituted at the amino-ato N-morpholino- or N-morpholinocarbonyl, for example N-morpholino or N-thiomorpholinocarbonylamino (lower and 1-kanoyl), such as N-morpholino- or N-thiomorpholino-carbonyl 1-amine acetyl, a halogen (lower alkanoyl) group containing up to three halogen atoms, for example an alpha-haloacetyl group such as alpha-fluoro-, alpha-chloro-, alpha-bromo-, alpha-iodo-, alpha, alpha, alpha -trifluoro- or α1α, alpha, alpha-trichloroacetyl, or halopropionyl, such as beta-chloro- or beta-bromopropionyl, especially trifluoroacetyl, 2- (N-morpholino (lower alkyl) carbamoyl (lower alkanoyl)) a group such as 2 (R, S) - (N- (2-morpholinoethyl) carbamoyl-3-methylbutyryl), a 2- (N- (pyridyl (lower alkyl)) carbamoyl) (lower alkanoyl) group such as 2 (R, S) - (N (2-pyridylmethyl) carbamoyl) (lower alkanoyl), (lower alkoxy) carbonyl, phenyl (lower) and a 1-alkoxy) carbonyl group, a tetrahydrofuryl (lower alkyl) xcarbonyl group such as a 2 (R, S) tetrahydropyrurylmethoxycarbonyl group, a (lower aikenyl) oxycarbonyl group in which the lower alkenyl moiety binds to the oxygen bonding moiety through saturated carbon atom, (lower and 1-alkoxy) (lower and 1-alkoxy) carbonyl, ((lower alkoxy) (lower-alkoxy) (lower alkoxy) carbonyl, (lower and 1-alkan) sulfones 1-phenyl, morpholino-1-phenyl, thiomorpholinosulfonyl, piperidinyl, 4-methylpiperazinylsulfonyl or piperazinosulfonyl or N-pyridyl (lower and 1-alkyl) -N- ( lower and (1-alkyl) carbamoyl, such as N- (2-, 3- or 4-pyridylmethyl) -N-methyl-carbomoyl, or in addition or in particular N (phenyl (lower alkyl) aminocarbonyl) a group such as Nbenzyl amine carbonyl, N- (lower alkyl) aminocarbonyl, such as t-butylaminocarbonyl, N, Nd 1 (lower alkyl) aminocarbonyl, such as Ν, Ν-dimethylaminocarbonyl, N - ((lower and 1-alkoxy) (lower and 1-alkyl) aminocarbones A group such as an N- (2-methoxyethoxy) am inocarbonyl group or an N- (morpholino (lower alkyl) am inocarbonyl group such as an N- (2-morpholinoethyl) am inocarbonyl group, or an acyl residue of an amino acid defined by above, with the proviso that at most one of the two residues

R1 or Ra may be hydrogen,

R 2, R _4j Re and R 5 represent a hydrogen atom,

R ₃ represents a lower alkyl group such as an isobutyl group or an n-butyl group, a cyclo (lower alkyl) group in which the cycloalkyl radical contains 3 to 7 carbon atoms and is unsubstituted or substituted one or three times by a lower alkyl group , such as isopropyl, halogen (lower alkyl), such as trifluoromethyl, hydroxy, lower alkoxy, amino, mono- or di (lower and alkyl) amino, halogen, such as fluorine, chlorine or bromine, nitro and / or cyano and is bound to a lower alkyl group, in particular methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl or tert-butyl . a butyl group, preferably terminally, such as a cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl (lower alkyl) group, as a methyl or ethyl group, in particular a cyclohexyl (lower alkyl) group, in particular a cyclohexylmethyl group, or an aryl 1 (lower alkyl) group in which the aryl radical is independently defined as in the aryl 1 (lower alkanoyl) group R 1 or R ₉ , or in addition or in particular phenyl (lower alkoxy) benzyl, 4- (3,4-di- (lower alkoxy) benzyloxy) benzyl, (lower alkoxy) (lower alkoxy) benzyl or (lower alkylene) dioxyphenylmethyl, and in particular is phenyl which is unsubstituted or substituted one or three times by a lower alkyl group, for example methyl, ethyl or isopropyl, a halo (lower alkyl) group such as trifluoromethyl, phenyl, 1- or 2-naphthyl alkyl, hydroxy, lower and 1-alkoxy, for example methoxy or in addition or in particular isobutyl, carbamoyl (lower and 1-alkoxy), N- (lower and 1-alkyl) carbamoyl (lower and 1-alkoxy) or N , N-di (lower alkyl) carbamoyl (lower alkoxy), amino, mono- or di (lower alkyl) amino, (lower alkanoyl) amino, e.g. pivaloylamino, halogen, e.g. fluorine or chlorine, carboxyl, (lower alkoxy) carbonyl, benzyl, naphthyl or fluorenyl (lower and 1-alkoxy) carbonyl, lower alkanoyl, sulfo, (lower alkyl) sulfonyl, phosphono -hydroxy (lower and 1-alkoxy) phosphoryl or di-lower alkoxy) phosphoryl, carbamoyl, mono- or di-lower alkyl) carbamoyl, sulfamoyl, mono- or di (lower alkyl) sulfamoyl , n itro and / or cyano, especially phenyl (lower alkyl), which is unsubstituted or substituted by the substituents mentioned, especially benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluoro, 4-trifluoromethyl- , 4-cyano-, 4-methoxy- or 4-hydroxybenzyl or, more particularly, a 4- (lower alkoxy) benzyl group (especially having a total number and 1 carbon atoms higher than in the 4-methoxybenzyl group), such as 4 -isobutyloxybenzyl, 3,4-di (lower alkoxy) benzyl, such as 3,4-dimethyloxybenzyl, phenyl (lower alkoxy) benzyl, such as 4-benzyloxybenzyl, 4- (3,4-dimethyloxybenzyl); di (lower alkoxy) benzyloxy) benzyl, (lower and 1-alkoxy) (lower alkyl) oxybenzyl, such as 4- (2-methoxyethoxy) benzyl, (lower alkylene) dioxyphenylmethyl, such as 3,4-methylenedioxyphenyl, methyl group or

j.

a biphenylylmethyl group such as a 4-biphenylylmethyl group, particularly preferably a phenyl (lower alkyl) group, especially as defined above, or further or particularly a thienylmethyl or tetrahydropyranylmethyl group, such as a 2-thienylmethyl group or 4- (2,3) 5,6-tetrahydro-pyranylmethyl,

R 5 represents (lower alkanoyl) oxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy, hydroxy (lower alkanoyl) oxy, (lower and 1 alkoxy) (lower) a (alkanoyl) oxy group, a (lower alkanoyl) oxy (lower alkanoyl) oxy group, a halo (lower alkanoyl) oxy group, for example an alpha-haloacetyloxy group such as alpha-chloro, alpha-bromo, and 1 f a-j 1 d, a 1 fa, a 1 fa, a 1 fa-tri fluoro- or a 1 fa, a 1 fa, a 1 fa-tri chloroacetyl 1-oxy group, carboxy (lower a 1 kanoyl) oxy, (lower alkoxy) carbonyl (lower alkanoyl) oxy, carbamoyl (lower and 1 kanoyl) oxy, (lower alkyl) carbamoyl (lower alkanoyl) oxy, di (lower and lower) 1) 1) carbamoyl (lower and 1 kanoyl) oxy-upin, hydroxycarboxy (lower and 1 kanoyl) oxy, hydroxycarboxy (lower and 1 kanoyl) oxy, hydroxy (lower and 1) alkoxycarbonyl (lower alkanoyl) oxy, dihydroxy carboxy (lower and 1-kanoyl) oxy, dihydroxy (lower and 1-alkoxy) carbonyl 1 (lower and 1-kanoyl) oxy, pyrrolylcarbonyloxy, such as 2- or 3-pyrrolylcarbonyloxy, furyl (lower alkanoyl) oxy, for example furylcarbonyloxy, such as 2-furylcarbobonyloxy, thienylcarbonyloxy, for example 2-thienylcarbonyloxy, imidazolyl (lower alkanoyloxy), for example imidazolyl a group such as a 4-imidazolylcarbonyloxy group, an imidazolylacetoxy group, such as a 4-imidazolyl acetoxy group, an imidazolylpropionyl alkoxy group, such as a 3- (4-imidazolylpropiononyloxy group, pyridyl 1 (lower) alkanoyl) oxy such as pyridylcarbonyloxy, for example 2-, 3- or 4-pyridylcarbonyloxy, indolylcarbonyloxy, for example 2-, 3- or 5-indolylcarbonyloxy, quinolyl (lower and 1-canoyl) oxy, such as quinolylcarbonyloxy, such as quinolin-2-ylcarbonyloxy, pyrrolidines 1-carboxy, such as pyrrolidinyl-3-carbonyloxy, piperidinyl carbonyloxy, for example 2-, 3- or 4-piperidinylcarbonyloxy, morpholinocarbonyloxy, thiomorpholinocarbonyloxy, morpholinoacetyloxy, thiomorpholinoacetyloxy; or a 4- (lower alkyl) -1-piperazinoacetyloxy group such as a 4-methylpiperazinoacetyloxy group, a (lower alkanoyl) oxy group (in which the lower alkanoyl radical is preferably attached to a bonding oxygen atom through a saturated carbon atom), for example an acryoyloxy group, a vinylacetyloxy group, a crotonoyloxy group or a 3- or 4-pentenoyloxy group, a (lower and 1-kinoyl) oxyl group, for example a propionyloxy group or a 2- or 3-butinoyloxy group, cycloalkyl and cycloalkylacetoxy in which the cycloalkyl radical contains from 3 to 8 carbon atoms and the cycloalkyl radical contains from 3 to 8 carbon atoms. carbon, phenyl (lower and 1-canoyl) oxy, for example benzoyloxy, phenyl acetoxyl or 3-phenylpropionyloxy, which is unsubstituted or mono- or poly-substituted by lower alkyl a methyl group, a halogen (lower alkyl group), such as a chlorine or bromomethyl group, a halogen such as fluorine or chlorine, a hydroxy group, a lower alkoxy group such as a methoxy group, a piperidinepmethyl group, a piperazine group, 1-ylmethyl, 4- (lower alkylpiperazin-1-ylmethyl) such as 4-methyl- or 4-ethylpiperazin-1-ylmethyl, 4- (lower and 1-canoyl) piperazin-1-ylmethyl such as 4- acetylpiperazin-1-ylmethyl, morpholino (lower alkyl) such as morpholinomethyl, thiomorpholino methyl, cyano and / or nitro, especially substituted is one of said substituents, a63

Or an amino acid radical which is linked through a carbonyloxy group which contains a carbonyl group from the carboxyl group of the respective amino acid, wherein said amino acid is selected from the group consisting of glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid , 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine, norvaline, leucine, isoleucine, norleucine, serine, methine, treoserine, treoserine, threine cysteine, proline, phenylalanine, tyrosine, cyclohexylalanine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, lysine, ornithine, 3-aminopropanoic acid, α 1 α, gamma-diaminomas acid and 1α, β-diamine inopropionic, particularly preferably an aliphatic amino acid residue selected from the group consisting of alanine, valine, norvaline, leucine, 3-aminopropionic acid, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid and isoleucine or amino acids selected from the group consisting of glycine, asparagine, glutamine, methionine, lysine, histidine, are fused to phenylalanine, each of said amino acids (except when there is no asymmetric carbon atom such as for example, in the case of glycine) it may exist in the form of D, L or (D, L), preferably in the form of L, wherein the amino group is unsubstituted or N-alkylated once or twice with a lower alkyl group such as methyl, n -propyl or n-butyl, pyridyl (lower alkyl), such as 2-, 3 or 4-pyridylmethyl, and / or phenyl (lower alkyl) with a lower alkanoyl group, in particular an acetyl group, a propenyl group or a pivaloyl group, a phenyl (lower alkanoyl) group such as a benzyl group or a phenylacetyl group, (a lower alkoxy) carbonyl group a group such as a tert-butoxycarbonyl group or a phenyl (lower and 1-alkoxy) carbonyl group such as a benzyloxycarbonyl group, or in addition or in particular a palmitoyloxy group, and

R? independently of R a, any of the radicals defined therein, in particular a lower alkyl group, in particular a butyl or n-butyl group, is a cycloalkyl (lower alkyl) group in which the cycloalkyl radical contains 3-7 carbon atoms, in particular a cyclohexyl (lower alkyl) group such as a cyclohexylmethyl group, or an aryl (lower alkyl) group, as described for aryl (lower alkyl) group R ₃ , especially phenyl (lower alkyl), which is unsubstituted or substituted by the substituents mentioned, such as benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluoro, 4-trifluoromethyl-, 4-cyano- , 4-methoxy- or 4-hydroxybenzyl, or in addition or in particular 4- (lower alkoxy) benzyl (especially higher than 4-methoxybenzyl), such as 4-isobutyloxybenzyl, 3,4 -di (lower alkoxy) benzyl, such as 3,4d imethyloxybenzyl, phenyl (lower and 1-alkoxy) -benzyl, such as 4-benzyloxybenzyl, 4- (3,4-di (lower alkoxy) benzyloxy) benzyl, (lower and 1 alkoxy) ( lower alkyl) oxybenzyl, such as 4- (2-methoxyethoxy) benzyl, (lower and alkyloxydioxyphenylmethyl, such as 3,4-methylenedioxyphenylmethyl, or biphenylylmethyl, such as 4-biphenylylmethyl, particularly preferably a phenyl (lower alkyl) group, in particular as defined by the latter, or in addition or in particular a thienylmethyl group or a tetrahydropyranylmethyl group, such as a 2-thienylmethyl group or 4- (2,3,5,6-tetrahydro) ) a pyranylmethyl group, or a salt thereof, if there is at least one salt forming group.

Particularly preferred is a compound of formula I wherein

R 1 and R 10 independently of one another represent a hydrogen atom, a lower alkanoyl group such as an acetyl group or a propionyl group, a phenyl (lower alkanoyl) group such as a phenylacetyl group, a phenyl- (lower alkanoyl) group in which a lower alkano- yl substituted by carbamoyl, such as 2-carbamoyl-3-phenylpropio, nyl, morpholino (lower alkanoyl), such as morpholinocarbonyl, thiomorpholino (lower alkanoyl), such as thiomorpholinocarbonyl, pyridyl 1 (lower alkanoyl) such as 2-, 3- or 4-pyridylacetyl, quinolyl (lower alkanoyl) such as quinol-2-ylcarbonyl, tetrazolyl (lower alkanoyl) such as 3 a -tetrazol-1-ylpropionyl group, an amino (lower alkanoyl) group substituted on the amino atom of the nitrogen by an N-morpholino- or N-thiomorpholino-carbonyl group, for example N-morpholino- or N-thiomorpholinecarb an onylamino (lower alkanoyl) group such as N-morpholino or N-thiomorpholinecarbonylaminoacetyl, a halogen (lower alkanoyl) group containing up to three halogen atoms such as a trifluoroacetyl group, 2- (N-morpholino (lower alkyl) carbamoyl (lower alkyl) alkanoyl) such as 2 (R, S) - (N- (2-morpholinoethyl) carbamoyl-3-methylbutyl), 2- (N-pyridyl (lower and 1-alkyl) carbamoyl) (lower and 1-cyano) 1) a group such as 2 (R, S) - (N-2-pyridylmethyl) carbamoyl (3-methylbutyryl), a (lower and 1 alkoxy) carbonyl group such as a methoxy, ethoxy, isobutoxy or tert. (lower and 1 alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, such as benzyloxycarbonyl, tetrahydrofury 1 (lower alkoxy) carbonyl, such as 2-tetrahydrofurylmethoxycarbonyl, (lower alkenyl) oxycarbonyl (preferably lower) an alkenyl group bonded to a bonding oxygen atom through a saturated carbon atom) such as allylo a lower alkoxy) (lower alkoxy) carbo

A phenyl group such as a 2-methoxyethoxycarbonyl group, a ((lower alkoxy) (lower alkoxy) carbonyl group such as a 2- (2-methoxyethoxy) ethoxycarbonyl group, a (lower alkane) sulfonyl group, for example a methanesulfonyl group; or an ethanesulfonyl group, morpholinesulfonyl group, thiomorpholinesulfonyl group, N-pyridyl (lower alkyl) -N- (lower alkyl) carbamoyl group such as N- (2-pyridylmethyl) -N-methyl aminocarbonyl group or an acyl residue of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, glutamic acid, and asparagine in the form of D, L or (D, L) (excluding glycine) linked via a carbonyl group of the carboxyl group. the amino group is unsubstituted or acylated by any of the last R1 or Ro residues other than the acyl amino acid residue, most preferably the amino acid acyl residues selected from the group consisting of N-morpholinocarbo nylglycine, N- (N- (2-, 3- or 4-pyridyl) methyl-N-methylaminocarbonyl) glycine, valine, N (trifluoroacetyl) vaine, N-phenylacetylvaline, N-acetylvaline, N- (2-carbamoyl-3-phenylpropionyl) -vinyl, N- (2-, 3- or 4-pyridyl-acetyl) valine, N-2-tetrahydrofuryl- (2H) -methoxycarbonylvaline, N- (2-methoxy) ethoxycarbonylvaline, N- (2-methoxyethoxy) ethoxycarbonylvaline, N-3- (tetrazol-1-yl) propionylvaline, N- (quinol-2-ylcarbonyl) vaine, N-methoxycarbonylbutyl n, Nizobutoxycarbonylvaline, N-tert-butoxycarbonylvaline, N-benzyloxycarbonylvaline, N- (morpholinocarbonyl) valine, N - (N (morpholinocarbonyl) aminoacetyl) valine, N- (thiomorpholinocarbonyl) valine, N- (N-2-pyridylmethyl-N-) methylamino aminocarbonyl) valine, N-morpholinocarbonyl amine acetylvinyl, N-methylsulfonylvaline, morpholoforoforphonylvinyl, N-acetylglycine, Npropionylisoleucine, N- (benzyloxycarbonyl) isole , glutamic acid, N-benzylcarbonyl1 g 1-butyric acid, asparagine, N-benzylcarbonylasparagine The amine acid residues are preferably in the form of L or (D, L) and, in the case of valine, also in the form of D, with the proviso that not more than one (2) -carbonyl-asparagine is present.

J of the radicals R 1 and R 5 represents a hydrogen atom,

R 5, R ₄ , R 6 and R 5 are hydrogen,

R ₃ represents a lower alkyl group such as an n-butyl or isobutyl group, a cyclohexyl (lower alkyl) group such as a cycohexylmethyl group, or a phenyl (lower alkyl) group which is unsubstituted or substituted by halogen, such as fluorine, lower alkoxy, such as methoxy or cyano, especially benzyl, 4-fluorobenzyl or 4-cyanobenzyl,

R 5 represents (lower alkanoyl) oxy, such as acetyloxy, propionoxy, butyryloxy, pentanoyloxy or privoyloxy, octanoyloxy, decanoyloxy, dodecanoyloxy, carboxy (lower alkanoyl) oxy, such as 3-carboxypropionyloxy, furyl (lower alkanoyl) oxy, such as 2-furyl carbonyloxy, imidazolyl (lower alkanoyl) oxy, such as 4-imidazolylcarbonyloxy, 4-imidazolylacetyloxy a group or 3- (4-imidazolyl) propionoxy group, a pyridyl (lower and 1-alkanoyl) oxyl group, such as a 2-, 3- or 4-pyridyl carboxy group, 2-pyridylacetoxy or 3- (2-pyridyl) propionoxy, quinolyl (lower alkanoyl) oxy, such as quinolin-2-ylcarbonyloxy, aminocetyloxy (glycyloxy), N- (lower alkyl) aminoacetyloxy, such as N-methylaminocetyloxy, N, N-di (lower alkyl) aminoacetyloxy, such as Ν, Ν-dimethylaminoacetyloxy, N - (lower alkyl) -N-phenyl 1 (lower alkoxy) carbonylaminoacetyloxy, such as Nbenzyloxycarbonyl-N-methylaminoacetyloxy, phenyl 1 (lower and 1-cyano) oxy, such as benzoyloxy, 4-morpholino a (lower alkyl) benzoyloxy group such as a 4-morpholinomethylbenzoyloxy group, a 4-halomethylbenzoyloxy group, a hididyloxy group or a 1-yloxy group, and

R y has the same meanings as last mentioned for R 5, especially means lower alkyl such as isobutyl or n-butyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) which is unsubstituted or substituted by halogen , such as fluorine, a lower alkoxy group, such as a methoxy group, or a cyano group, as last defined for R ₃ , or a salt thereof, if there is at least one salt-forming group, more preferably those in which R 1 and / or and R ₉ do not represent a morpholylphenyl group or a thiomorpholylphenyl group.

Particularly preferred is a compound of formula (I) wherein:

ri

R ₂ r ₃ r ₄

R 5 represents a (lower alkoxy) carbonyl group, a halogen (lower alkoxy) carbonyl group, a phenyl (lower alkoxy) carbonyl group, a monovalent aliphatic amino acid monovalent group selected from the group consisting of valine, alanine, leucine and isoleucine or via a carbonyl group of the above-defined aliphatic amino acid acylated at the amino-nitrogen atom with a phenyl (lower and 1-koyoyl) group, morpholine (lower alkanoyl), a thiomorpholine (lower and 1 k anoyl) group, a pyridyl (lower and 1-koyoyl) group , (lower alkoxy) carbonyl or phenyl (lower alkoxy) carbonyl, all of which may be in the form of D, L or (D, L), represents a hydrogen atom, represents a phenyl (lower alkyl) group, 4- fluorenes (lower alkyl) or cyclohexyl (lower alkyl), represents a hydrogen atom, represents (lower alkanoyl) oxy a group, octanoyloxy group, decanoyloxy group, dodecanoyloxy group, carboxy (lower and 1 kanoyl) oxy group, furyl (lower and 1kanoyl) oxy group, imidazolyl (lower alkanoyl) oxy group, pyridyl (lower alkanoyl) oxy group, quinolyl (lower alkanoyl) o69 xy group, amine acetyl group (gycyloxy), N- (lower alkenyl) amino group, N, Nd i (lower) (lower alkyl) amino-acetyloxy, N- (lower alkyl) -N-phenyl (lower alkoxy) carbonylaminoacetyloxy, phenyl (lower alkanoyl) oxy, 4-morpholinomethylbenzoyloxy, 4-halomethylbenzoyloxy , histidyloxy or proxy,

R 5 represents a hydrogen atom,

R 7 is lower alkyl, cyclohexyl (lower alkyl), phenyl (lower alkyl), 4-cyanophenyl (lower alkyl) or 4-fluorophenyl (lower alkyl) .

R 5 represents a hydrogen atom,

R a is one of the groups listed for R 1, and R ₃ and R 5 bearing asymmetric carbon atoms have the S configuration, and pharmaceutically acceptable salts thereof.

Very preferred is a compound of formula I in which

R 8 and R 9 are N-methoxycarbonylvalyl,

Ra, R ₄ , R 5 and R 5 are hydrogen,

R3 is benzyl or cyclohexylmethyl,

R 5 represents (lower and 1-canoyl) oxy, in particular acetyloxy, or pyridylcarbonyloxy, in particular 2-pyridylcarbonyloxy, and

R? represents a cyclohexylmethyl group or further a benzyl group, as well as pharmaceutically usable salts thereof, in particular an isomer of the compound in which the R ₃ and R 5 bearing carbon atom are in the S configuration.

Also highly preferred is a compound of formula I, wherein R 1 and R 4 independently of one another are N- (lower alkoxy) carbonylvalyl,

R @ - represents a hydrogen atom,

R ₃ is phenylmethyl or cyclohexylmethyl,

FU means a hydrogen atom,

R 5 represents a palmitoyloxy group, a (lower alkoxy) (lower and 1-canoyl) oxy group,

Re represents a hydrogen atom,

R? is phenylmethyl or cyclohexylmethyl; and

R 5 represents a hydrogen atom, or a pharmaceutically acceptable salt thereof.

Particularly preferred of these compounds are:

1- / 2 (S) -palmitoyloxy-3 (S) - (N- (methoxycarbonyl) ~ (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) - valyl / hydrazine of formula I or a pharmaceutically acceptable salt thereof, or

1- / 2 (S) -metoxyacetoxy) -3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- ( L) vayl / hydrazine of the formula I or a pharmaceutically acceptable salt thereof, or

1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - (tert-butoxycarbonyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) hydrazine of formula I, or a pharmaceutically acceptable salt thereof.

Finally, the compounds of the formula I in which

R1 is quinolin-2-ylcarbonyl- (L) -asparaginyl,

R2 represents a hydrogen atom,

R 5 is phenylmethyl, 4- (lower alkoxy) phenylmethyl or 4-benzyloxyphenylmethyl,

R4 represents a hydrogen atom,

R 5 represents (lower and 1-alkoyl) oxy, such as butyryloxy, octanoyloxy, decanoyloxy, dodecanoyloxy, palmitoyloxy, (lower alkoxy) (lower and 1-alkoyl) oxy, such as methoxyacetoxy a group, carboxy (lower and 1-alkoyl) oxy, furyl (lower alkanoyl) oxy, imidazolyl (lower alkanoyl) oxy, pyridyl (lower alkanoyl) oxy such as, in particular, pyridinylcarbonyloxy, for example 2- or 3-pyridinylcarbonyloxy, quinolyl (lower alkanoyl) oxy, aminoacetyloxy, N- (lower and 1-alkylamino) aminoacetyloxy, N, N- (lower alkyl) aminoacetyloxy -group, N (lower alkyl) -N-phenyl (lower alkoxy) carbonylaminoacetyloxy, phenyl (lower alkanoyl) oxy, 4-morpholinomethylbenzoyloxy, 4-halomethylbenzoyloxy, hididyloxy or 1-yloxy .

R 5 represents a hydrogen atom,

R? means phenylmethyl, 4- (lower alkoxy) phenylmethyl or cyclohexylmethyl,

R 5 represents a hydrogen atom,

R 5 is (lower and 1-alkoxy) carbonyl 1- (L) -vinyl, (lower alkoxy) (lower alkoxy) (lower alkoxy) carbonyl-L) valyl, phenyl (lower and 1 alkoxy) carbonyl 1- (L) -vinyl, (lower and 1-canoyl) - (L) -vinyl, benzylaminocarbonyl, and 1-kenyloxycarbonyl in which the alkenyl radical contains 3 to 7 carbon atoms, or ( a lower and 1-alkoxy) carbonyl group, or a pharmaceutically acceptable salt thereof, in particular a compound selected from the group consisting of:

1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - (N-quinoline-2-carbonyl) (L) -asparaginyl) amino-4-phenylbutyl-1 / phenylmethyl / 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) butyryloxy-3 (S) - (N-quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl-1 / phenylmethyl / 2- / N- (methoxycarbonyl (L) -valyl / hydrazine, - / 2 (S) - (2-pyridylcarbonyljoxy-3 (S) - (N-quinoline-2-carbonyl) (L) -asparaginyl) amino-4-phenylbutyl-1- / 4 -methoxyphenylmethyl (1-7) - N - (benzyloxycarbonyl) - (L) -valyl / hydrazine and

1- / 2 (S) - (methoxyacetyl) oxy-3 (S) - (N-quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl-1/4-methoxyphenyl-methyl / -2 (N- (benzyloxycarbonyl)) - (L) -vinyl) is substituted for their pharmaceutically usable salts.

Particularly preferred compounds of formula I are especially those selected from the group consisting of

1- / 2 (S) -propionyloxy-3 (S) - (N (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl)] - (L) -valyl / hydrazine,

1- / 2 (S) -butyryloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -pentanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - ( L) valyl / hydrazine,

1- / 2 (S) -oktanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - ( L) valyl / hydrazine,

1- / 2 (S) -dekanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - ( L) valyl / hydrazine,

1- (2 (S) -dodecanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -pivaloyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (2-Furylcarbonyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (4-Imidazolylcarbonyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (4-Imidazolylacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N) - (methoxycarbonyl) - (L) -valyl / hydrazine,

1- (2 (S) - (3- (4-Imidazolyl) propionyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexyl methyl) 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -benzoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (| _) - valyl / hydrazine,

1- / 2 (S) - (2-Pyridylacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (3- (pyridin-2-yl) -propionyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexyl methyl / 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (quinolin-2-ylcarbonyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (Aminoacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- (N-) (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (N-methylaminoacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (N, N-dimethylaminoacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (N-benzyloxycarbonyl-N-methylaminoacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / -2 - / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -proly1oxy-3 (S) - (N (metoxykarbony1) - (L) valyl) amino-4-phenylbutyl / -L / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - ( L) valyl / hydrazine,

1- / 2 (S) - (4-morfo1ínometylbenzoyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (4-ch1órmetylbenzoy1) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) - (3-carboxypropionyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -vinyl / hydrazine and pharmaceutically acceptable salts thereof.

Particularly particularly preferred compounds of formula I are the compounds and salts thereof set forth in the Examples below.

The compounds of formula I and salts of such compounds with at least one salt-forming group are obtained by known methods, for example by

(a) a hydroxy compound of the formula II

(II) wherein the general symbols have the meanings given for the compounds of formula I, acylates with a carboxylic acid of formula III

R 5 -H (III) or a reactive derivative of such an acid, wherein R 5 has the meanings given for the compounds of formula I, wherein the free functional groups in the starting materials of formulas II and III not to be involved are in protected form, thereafter the protective groups present are cleaved, or

b) for the preparation of compounds of the formula I in which R 5 represents an acyl group, a sulfonyl group or a sulfonyl group substituted by an unsubstituted or substituted alkyl group, an aryl group or a heterocyclyl group and the other general meanings have the meanings indicated, the amino compound is condensed of formula IV

(IV) wherein the general symbols have the same meanings as indicated above, with an acid of formula (V) or a reactive derivative thereof, wherein R ₃ 'has the meanings given for R o except for hydrogen and unsubstituted or substituted alkyl; with the exception of the functional groups involved in the reaction, are protected, if necessary, and then the protecting groups present are cleaved, or

c) for the preparation of compounds of the formula I in which R 1 represents an acyl group, a sulfo group or a sulfonyl group substituted by an unsubstituted or substituted alkyl group, an aryl group or a heterocyclyl group and the other general meanings have the meanings indicated, of formula VI (VI)

in which the general symbols have the meanings given above, with an acid of the general formula VII

R, '- OH (VII) or a reactive derivative thereof, wherein R' 'has the meanings given for R i except for a hydrogen atom and an unsubstituted or substituted alkyl group, with free functionalities other than those involved in the reaction being protected form, and then the protecting groups present are cleaved, or

d) for the preparation of compounds of formula I in which R1 and Re are two identical radicals selected from the group consisting of acyl, sulfo and sulfonyl substituted by unsubstituted or substituted alkyl, aryl or heterocyclyl and other general symbols have the meanings indicated, condenses the di amine compound to the general formula (VIII ₎

R?

N.

(VIII) wherein the general symbols have the meanings just mentioned, with an acid suitable for introducing the same R and R ₉ radicals or a reactive derivative of such an acid, wherein R 1 and R a have the meanings indicated and free functional groups except those involved in the reaction if desired, in protected form and then deprotected or present

(e) for the preparation of compounds of the formula I in which R @ 1 is replaced by R @ 2? R 1, which represents an unsubstituted alkyl group or a cycloalkyl group, introduces in the compound of formula I '

in which R? ' represents a hydrogen atom and the other general symbols have the meanings indicated, the radical R? substitution with a compound of formula XII

R ₇ -X (XII) wherein X is a leaving group and R ₇ is an unsubstituted or substituted alkyl or cycloalkyl group, wherein the free functional groups, except for those involved in the reaction, are in protected form if desired, then optionally protecting groups present are cleaved, or

(f) in a compound of the formula I in which the general symbols have the meanings given above, with the proviso that the compound of the formula I is at least protected by a protecting group, the protective groups present are cleaved, and optionally one of the compounds of the formula I with at least one salt-forming group obtained by any of the aforesaid processes a) to f), is converted into a salt or the resulting salt is converted into a free compound or another salt and / or the optionally obtained isomeric mixture is separated and / or a compound of the invention of formula I is converted to another compound of the invention of formula I.

These methods are described in more detail below. Unless explicitly stated otherwise, have the symbols R 1, R, R _3, R @ _{3, R,} R, R, R and R as defined for a compound of formula I.

Method a) (acylation of the hydroxy group)

For example, the acylation of the hydroxy group is carried out in a manner known per se using an acid of formula III in which R 5 has the meanings indicated in addition to the aminocarbonyloxy group or the N-substituted carbamic acid moiety that binds via its aminocarbonyloxy group or a reactive derivative thereof. . Suitable reactive derivatives are, for example, the carboxylic acid of the formula IX

R 5 '- Z 1 (IX) wherein R 5' is any of the acyl residues defined above in the above defined acyloxy group and Z 1 represents a reactive activated hydroxy group (the compound of formula IX contains a reactive activated carbonyl group reactive to the carbonyl group) an activated hydroxy group, preferably further defined). The free carboxylic acid of the formula III can be activated, in particular also in situ, for example with strong acids such as hydrohalic acid, sulfuric acid, sulfonic acid or carboxylic acid or with acidic ion exchangers, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, alkanoic acid, optionally substituted with, for example, a halogen atom or an acid of formula III, preferably with an excess of an acid of formula III, if necessary by binding the resulting reaction water with a water-binding agent, azeotropically distilling the reaction water or extracting esterified by acid anhydrides, in particular inorganic acid anhydrides; in particular organic acid anhydrides such as carboxylic acid anhydrides such as carboxylic acid anhydrides (lower and alkane) (except formic anhydride) such as acetic anhydride, al or suitable activating or coupling agents of the type described below. A compound of the formula _R '- Z may also be a carboxylic acid azides (which can for example be obtained by reacting the corresponding ester of the corresponding hydrazide and its treatment with nitrous acid), carboxylic acid halide, in particular chloride or bromide, which may be e.g. can be obtained by reaction with organic acid halides, in particular with oxalic acid, such as oxalic acid, or in particular with inorganic acid halides, such as phosphorus or sulfur halides, such as phosphorus trichloride, phosphorus tribromide , phosphorus pentachloride, phosphorus pentachloride, phosphorus pentachloride, phosphorus pentachloride, thionyl chloride or thionyl bromide, or, in particular, under gentle conditions by reaction with tetra (lower and 1-alkyl) -alpha-halo-enamine, such as tetramethyl-alpha-halenenamine, in particular 1-chloro-N, N, 2-trimethyl-1-propenamine (preferably by reaction in an inert solvent col., J C. Chem.Commun et al., Or. Synth., 59, 26 et seq., Especially in a chlorinated hydrocarbon such as methylene chloride or choroform, or an ether such as diethyl ether, dioxane or tetrahydrofuran at a preferred temperature of -78 to 50 ° C, especially at a temperature of -60 to 30 ° C, for example at a temperature between -10 ° C and ambient temperature (see Devos, A

1979, 1180-81, and Haveaux, B.

(1980)), wherein the acid halide obtained, for example the acid chloride of the formula IX in which Z 1 is a chlorine atom, can also be directly processed, for example by reaction with a compound of the formula II in the presence of tertiary nitrogen bases such as pyridine and / dimethylaminopyridine (DMAP, which is preferably added in a catalytic amount), at a preferred temperature between -20 and 50 ° C (in particular at a temperature between 0 ° C and ambient temperature), an activated ester, wherein Z 1 is the alcohol residue electron affinity substituents, in particular a cyanomethoxy or aryloxy group, in which the aryl group preferably represents a phenyl or naphthyl group which is substituted one or more times by halogen, nitro and / or cyano, for example nitrophenoxy, such as A 4-nitrophenoxy group or a 2,4-di-itrophenyloxy group, or a polyhalophenoxy group such as a pentachlorophenoxy group; or symmetrically or preferably asymmetric acid anhydride, which can be obtained, for example, by reacting a salt, for example an alkali metal salt such as a sodium or potassium salt, of an acid of formula III or its reaction partner. an anhydride such as acetic acid, acids, and thus in particular either an acid of formula III with a carboxylic acid halide, for example a carboxylic acid chloride such as acetyl chloride, or a reaction of a carboxylic acid halide of formula IX in which Zi represents a halogen atom, for example a chlorine atom or a bromine atom, with a (lower alkane) carboxylic acid salt, in particular with sodium or potassium acetate.

In particular, carbodiimides, for example, N, N'-di-carbodiimide whose alkyl radical contains 1 to 4 carbon atoms, or Ν, Ν'-dicycloalkyl, may be used as activating and coupling agents for the in situ activation of carboxylic acids of the formula III. a carboxyl iimide whose cycloalkyl radical contains 5 to 7 carbon atoms, such as diisopropylcarbodiimide or N, N'-dicycohexylcarbodiimide, preferably by the addition of an activating catalyst such as hydroxysicinimide or optionally a halogen atom with a C 1-6 alkyl group C1-C7 or C1-C7-alkoxy substituted by N-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, and 1-halo-o-formate, the alkyl radical of which contains 1 to 4 carbon atoms, for example isobutyl chloroformate, suitable carbonyl compounds, for example Ν, Ν-carbonyldiimidazole, suitable 1,2-oxazolium compounds, e.g. d 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methylisoxazolium m-perchlorate, suitable acylamino compounds, for example 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or suitable phosphoryl cyanamides or azides, for example diethylphosphoryl cyanamide, or diphenylphosphoryl azide, triphenylphosphine disulfide or 1-alkyl-2-halopyridinium halide, the alkyl group of which contains 1 to 4 carbon atoms, for example 1-methylpyridine-2 i umjod i d.

When there are two free carboxyl groups in the compound of formula (II), such as in carboxy (lower alkane) acids, such as 3-carboxypropanoic acid, the activated acid derivative may also be an internal anhydride such as succinic anhydride.

Z i is preferably a halogen atom, such as a chlorine atom or a bromine atom, as well as an acyloxy group, for example an ad (lower alkanoyl) oxy group, such as an acetyloxy group.

Especially suitable for the introduction of the acyl moiety of a half-carbonated ester attached to an oxygen atom through its carbonyl group are compounds of formula IX in which Z 1 is a halogen atom, such as a chlorine atom, which can be prepared e.g. unsubstituted or substituted alkyl alcohols, aryl (lower alkyl) alcohols or heterocyclyl (lower alkyl) alcohols in which the radicals are as defined in the definition of unsubstituted or substituted alkoxycarbonyl, aryl (lower alkoxy) carbonyl or heterocyclyl (lower alkoxy) ) carbonyl R _a, with phosgene or its analogues with or, in place of the chlorine containing other halogen atoms, in particular bromine, preferably in the presence of a tertiary nitrogen base, such as pyridine or triethylamine, and in inert solvents such as CH fluorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxane, or carboxylic acid amides, for example in dimethylformamide. Also suitable are the corresponding N-carbonylazolides of the general formula IX (Z, = nitrogen-containing heterocyclyl, such as 1-imidazolide), which can be obtained, for example, by reaction of the corresponding N, N'-carbonyl-diazidides such as is, for example, N, N-carbonyl diimidazole under the conditions described for phosgene and analogues thereof with other halogen atoms. The reaction of the compounds of formula II with the corresponding compounds of formula IX is also carried out under these conditions (see Staab, HA, Angew. Chemie, 74, 407 (1962)).

In the particular case of the introduction of an aminocarbonyloxy group R 5 or an N-substituted aminocarbonyloxy group, the corresponding isocyanate of the general formula IX 'is particularly suitable as an activated acid derivative.

QN = C = O (IX ') wherein Q represents an amino function protecting group, for example, a three-haloacetyl group, such as a trifluoro- or tri-chloroacetyl group, or one of the lower alkyl or aryl groups which are unsubstituted or substituted, and which are mentioned in connection with the definition of the amine inocarbones of the 1-methoxy group R 5 in which the amine group bears 1 to 2 substituents, where, when Q represents an amino function protecting group, the corresponding compound is obtained after reaction with a compound of formula II of the formula I in which R 5 represents a free aminocarbonyloxy group by cleavage of the protecting group Q as described below in the release of the amino group protected by an acyl group, in particular by acid hydrolysis, or when Q represents one of the abovementioned substituted or unsubstituted lower alkyl or aryl groups, corresponding to the compounds and of the general formula I with a monosubstituted aminocarbonyloxy group R 5 at the nitrogen atom. Both the aminocarbonyloxy group and the monosubstituted aminocarbonyloxy group R 5 can be converted to the N-disubstituted aminocarbonyloxy group by alkylation with an additional unsubstituted or substituted lower alkyl radical using suitable starting materials and analogous conditions to those described. below for additional method operations.

These reactions may be carried out under reaction conditions known per se, at conventional temperatures, in the presence of inert solvents or diluents or in the presence of such solvents or diluents, in particular when using (lower and 1-alkan) 1-yl anhydrides to activate the carbonic acid of formula III, wherein said solvents or diluents are, for example, acid amides, for example carboxylic acid amides such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-1,3,4,5,6-tetrahydro-2 (1H) -pyrimidone (DMPU) ) or amides of inorganic acids such as hexamethylphosphoric triamide, ethers such as cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons such as halogen (lower) alkanes, for example methylene chloride or chloroform, ketones such as acetone, nitriles such as acetonitriles acid anhydrides such as acetic anhydrides, esters such as ethyl acetate, bis-alkanesulfines such as dimethylsulfoxide, nitrogen heterocycles such as pyridine, or mixtures of these solvents, especially anhydrous solvents, such solvents as suitable for the above reactions may be selected for each particular reaction, optionally using salts of the compounds used, in particular the metal salts of the carboxylic acids used, such as alkali metal or alkaline earth metal salts, for example sodium or potassium salts, in the absence or presence of catalysts, condensing agents or neutralizing agents, depending on the type of reaction and / or the reactants, at atmospheric pressure or in a closed vessel, at normal pressure, or in a closed tube under reaction conditions, and / or under an atmosphere of argon or nitrogen. The acylating agent itself, for example a carboxylic acid or carboxylic acid anhydride, may also serve as the solvent. The reaction is suitably monitored by conventional analytical methods, in particular by thin layer chromatography.

increased pressure to the reaction mixture under an inert atmosphere used, for example

Among these reaction conditions, those suitable for the reactions described above may be selected, with the preferred conditions being those specifically mentioned.

Said reaction according to the invention is preferably carried out under mild conditions, in particular at temperatures between -10 ° C and 60 ° C, for example at 0 ° C to ambient temperature, or at slightly elevated temperatures up to about 50 ° C, for example at about 0 ° C and ambient temperature. Both in the reaction with a carboxylic acid halide of the formula IX in which Z i is a halogen atom such as a chlorine or bromine atom, and in the reaction with an anhydride, in particular with a symmetrical anhydride (Z i = O-R 5 '), in particular about an equimolar amount or an excess of the corresponding compound of formula IX (halide or R 5 '-O-R 5'), for example 0.95 to 10 times molar amount.

Compounds suitable for the process of formula II '

a) are

wherein the general symbols have the meanings given for formula (I), as well as the salts of said compounds have salt-forming groups.

compounds, if

The functional groups in the starting materials to be prevented, in particular the carboxy, amino, hydroxy, mercapto and sulfo groups, may be protected by suitable conventi on 1 protecting groups, which are usually used in the synthesis of peptide compounds, but also in the synthesis of cephalosporins and penicillins, as well as nucleic acid and sugar derivatives. These protecting groups may already be present in the precursors and are intended to protect the respective functional groups against unwanted side reactions such as acylation, etherification, esterification, oxidation, solvolysis, etc. In certain cases, protective groups may be used.

d.

In addition, the pins influence the selective, for example stereoselective, course of the reaction. Characteristic of the protecting groups is that they are readily cleavable, i. cleavable without the desired side reactions, for example solvolytically, reducing, photolytically, or else enzymatically, for example under physiological conditions, and that they are no longer present in the final substances.

The protection of functional groups with such protecting groups, the protecting groups themselves, and the reactions leading to the cleavage of these protecting groups are described, for example, in standard publications such as: JFW-McOmi, Protective Groups in Organic Chemistry, Plenum Press, London and New York, 1973, Th.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981, The Peptides, Vol. 3 (E. Gross and J. Meinhofer), Academic Press, London and New York, 1981, Methoden der organischen Chemie, Houben-Weyl, 4th ed. 15/1, Georg Thieme Verlag, Stuttgart, 1974, HD Jakubke and H. Jescheit, Am inosäuren, Peptide, Protein, Verlag Chemie, Weinheim, Deerfield Beach and B ase 1, 1982 and Jochen L ehmann, Chemie der Kohlenhydrate: Monosaccharide und Derivatives, Georg Thieme V er 1ag, Stuttgart, 1974.

For example, the carboxyl group is protected as an ester group which is selectively cleavable under gentle conditions. The carboxyl group protected in the esterified form is primarily esterified by a lower alkyl group which is branched at the 1-position of the lower alkyl group or substituted at the 1- or 2-position of the lower alkyl group by suitable substituents.

A protected carboxyl group which is esterified with a lower alkyl group is, for example, a methoxycarbonyl group or an ethoxycarbonyl group.

The protected carboxyl group which is esterified with a lower alkyl group which is branched at the 1-position of the lower alkyl group is primarily a tertiary (lower alkoxy) carbonyl group, for example a tert-butoxycarbonyl group.

A protected carboxyl group which is esterified with a lower alkyl group which is substituted at the 1-position or the 2-position by suitable substituents is, for example, an arylmethoxycarbonyl group having one or two aryl radicals, the aryl group being unsubstituted or substituted by, for example, a lower alkyl group. for example a tert-lower alkyl group such as a tert-butyl group, a lower alkoxy group such as a methoxy group, a hydroxy group, and a halogen atom such as a chlorine atom and / or a nitro group, and in particular a phenyl group such as a benzyloxycarbonyl group, a substituted benzyloxycarbonyl group such as a 4-nitrobenzyloxycarbonyl group, or a 4-ethoxybenzyloxycarbonyl group, a diphenylmethoxycarbonyl group, or a diphenylmethoxycarbonyl group substituted with said substituents a 1- (4-methoxyphenyl) methoxycarbonyl group, further a lower alkyl group esterified with a carboxyl group, wherein the lower alkyl group in the 1 or 2 position is substituted with suitable substituents such as a 1- (lower alkoxy) (lower alkoxy) carbonyl group , for example, methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or i-ethoxyethoxycarbonyl, 1- (lower alkyl) thio (lower alkoxy) carbonyl, for example 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl an aroylmethoxycarbonyl group in which the aroyl group is a benzoyl group optionally substituted, for example, with a bromine atom, for example a phenacyloxycarbonyl group, a 2-halo (lower alkoxy) carbonyl group, for example a 2,2,2-trichloroethoxycarbonyl group, a 2-bromomethoxycarbonyl group 2-iodoethoxycarbonyl as well as 2- (trisubstituted silyl) (lower and 1-alkoxy) ka a bonyl group, wherein said substituents are, independently of one another, aliphatic, aralkyl, cyclic, or fatal or aromatic hydrocarbon radicals which are optionally substituted, for example, by a lower alkyl group, an aryl group, a halogen atom and / or a nitro group , for example optionally substituted lower alkyl, phenyl (lower alkyl), cycloalkyl or phenyl, such as 2-R 1 (lower alkyl), 1 Y 1 (lower alkyl) 1-alkoxy) carbonyl, such as 2-tri (lower alkyl) silyl ethoxycarbonyl, for example 2-trimethylsilyl-ethoxycarbonyl or 2- (dimethylbutyl) methyl 1) an ethoxycarbonyl group or a 2-triarylsulfonyl ethoxycarbonyl group such as triphenylsilyl ethoxycarbonyl group.

The carboxyl group is also protected as an organic silyloxycarbonyl group, for example

Such an organic silyloxycarbonyl tri-lower alkyl Isilyloxycarbonyl group, for example a trimethylsilyloxycarbonyl group. The 1-yloxycarbonyl-silicon atom may also be substituted by two lower alkyl groups, for example methyl groups, and one amino- or carboxy-group of a second molecule of formula I. Compounds with such protecting groups may be prepared, for example, using dimethyl chlorosilane as a silylating agent.

The protected carboxyl group is preferably a tertiary (lower alkoxy) carbonyl group, for example a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 4-nitrobenyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group or a diphenylmethoxycarbonyl group.

The protected amino group is protected with an amino function protecting group, for example in the form of an acylamino group, arylmethylamino group, esterified mercaptoamino group, 2acyl (lower and 1k-1-ene) ylamino group. with a coupon or a 1 y 1 am i no-coupon or as an azido group.

In an acylamino group, an acyl group is, for example, an acyl residue of an organic carboxyl group having, for example, up to 18 carbon atoms, in particular a (lower and 1-can) carboxylic acid, optionally substituted, for example, by halogen or aryl, or benzoic acid. optionally substituted with, for example, a halogen atom, a lower alkoxy group or an nitro group, or preferably a half-carbonate ester. Such acyl groups are preferably (lower alkane) oyl, such as formyl, acetyl, propionyl or pivaloyl, halogen (lower alkane) oyl, for example 2-haloacetyl, such as 2-chloro-2-, 2- bromo, 2-iodo, 2,2,2, -trifluoroor 2,2,2-trichloroacetyl, optionally with, for example, a halogen atom, a lower alkoxy group or a nitro-substituted benzoyl group such as a benzoyl group; a chlorobenzoyl group, a 4-methoxybenzoyl group or a 4-nitrobenzoyl group, a (lower alkoxy) carbonyl group, preferably at the 1-position of the lower alkyl radical branched in the 1- or 2- position of a suitably substituted (lower alkoxy) carbonyl group, e.g. a (lower alkoxy) carbonyl group, such as a tert-butoxycarbonyl group, an arylmethoxycarbonyl group having one, two or three aryl radicals, which may be, for example, a lower alkyl group, in particular a tertiary (lower alkyl) group such as a methoxy group a halogen atom, such as a chlorine atom and / or a nitro group, a mono- or oolysubstituted phenyl group, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, aroy 1 m ethoxycarbonyl group in which the aroyl group preferably represents optionally a halogen atom such as bromine, a substituted benzoyl group such as a phenacyloxycarbonyl group, a 2-halo (lower alkoxy) carbonyl group such as a trichloroethoxycarbonyl group, 2-bromomethoxycarbonyl group or 2-iodoethoxy , 2- ( trisubstituted (1 &apos;) (lower and 1-alkoxy) carbonyl group, e.g. 1 ad 2-tri (lower &lt; 1 &gt; and 1 &apos;) 1 &apos; trimethylsilylmethoxycarbonyl or 2- (di-butylmethylsilyl) ethoxycarbonyl, or triarylsilyl (lower alkoxy) carbonyl, for example 2-triphenylsilyl-ethoxycarbonyl.

In the arylmethyl amino group, for example in the mono-, di- or especially triarylmethylamino group, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are, for example, benzyl, diphenylmethyl or, in particular, tri-yl and mine.

In an etherified mercaptoamino group, the mercapto group is primarily present as a substituted arylthio or aryl (lower alkyl) thio group, for example, an aryl group optionally being, for example, a lower alkyl group such as a methyl group or a tert-butyl group, a lower alkoxy group. a group such as a methoxy group, a halogen atom, such as a chlorine atom, and / or an itro-substituted phenyl group, for example as a 4-nitrophenylthio group.

In a 2-acyl (lower alk-1-ene) moiety that is useful as an amino function protecting group, an acyl group is, for example, the corresponding (lower and 1-alk) carboxylic acid moiety, optionally for example a lower alkyl group such as methyl or tert. butyl, lower and 1 alkoxy, such as methoxy, halogen, such as chlorine, and / or an an-substituted benzoic acid or, in particular, a half-carbonic acid ester, in particular (lower and 1-alkyl) after one carbonic acid ester . Corresponding protecting groups are in particular 1- (lower alkan) oyl (lower alk-1-ene) -2-yl, for example 1- (lower alkane) oylprop-1-en-2-yl such as 1 -acetylprop-1-en-2-yl, or (lower and 1-alkoxy) carbonyl (lower alk-1-ene) -2-yl, for example (lower alkoxy) carbonylprop-1-en-2-yl such as 1 ethoxycarbonylprop-1-en-2-yl group.

For example, with an 11-amino-amino group is a tri (lower alkylsilyl-1-amino group, for example, a three-methylsilyl-1-amino group or a tert-butyldimethylsilyl-1-amino group. The silicon-amino silicon atom may also be substituted by two lower alkyl groups, for example methyl and the amino or carboxyl group of the second molecule of formula I. Compounds with such protecting groups may be prepared, for example, by using silylating agents that form chlorosilanes, for example dimethylsilane.

The amino group may also be protected by protonation. Suitable anions are, in particular, anions of inorganic acids, such as sulfuric acid, phosphoric acid, or h and hydroxylic acids, for example chlorine or bromine anion, or organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino-protecting groups are (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl acid, fluorenes (lower and 1 alkoxy) carbonyl, 2 (lower and 1-alk) oyl (lower) 1- and 1-k-1-ene-2-yl or (lower alkoxy) carbonyl (lower alk-1-en-2-yl), with tert-butoxycarbonyl or benzyl oxycarbonyl being particularly preferred.

For example, a hydroxy group may be protected by an acyl group, for example unsubstituted or a halogen atom, in particular a chlorine atom, substituted by a lower alkanoyl group such as an acetyl group or a 2,2-dichloroacetyl group, or in particular an acyl residue of the for protected amino groups. A preferred hydroxy-protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or triphenylmethoxycarbonyl. The hydroxy group may further be protected by a tri (lower alkyl) silyl group, for example trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, readily cleavable by an etherified group, for example an alkyl group, if tert. ) a tert-butyl group, for example an oxa- or thiaaliphatic or cycloaliphatic, especially a 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon radical, for example 1- (lower and 1-alkoxy) ( lower alkyl or 1 (lower alkyl) thio (lower alkyl) such as methoxymethyl, i-methoxyethyl, i-ethoxyethyl, methyl 11-methyl, 1-methyl-11-ethyl, or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl having 5 to 7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or the corresponding thia as well as 1-phenyl (lower alkyl), such as benzyl, diphenylmethyl or trityl, the phenyl being substituted by, for example, a halogen atom, a chlorine atom, a lower and a 1-alkoxy group, e.g. exemplified by methoxy and / or nitro.

Two, in particular adjacent, hydroxy or adjacent hydroxy and amino groups present in one molecule may be protected, for example, with bivalent protecting groups such as preferably a methylene group substituted with one or two lower alkyl groups or an oxo group, for example unsubstituted or substituted alkynyl group, for example lower alkynyl group such as isopropylidene, cycloidene group, especially cyclohexylidene group, carbonyl group or benzylidene group.

The mercapto group, as in cysteine, for example, may be protected, in particular, by S-alkylation with optionally substituted alkyl residues, silylation, thioacetal formation, S-acylation or formation of asymmetric di-grouping. Preferred mercapto-protecting groups are, for example, benzyl optionally substituted on the phenyl moiety with a methoxy or nitro group such as 4-methoxybenzyl, diphenylmethyl optionally substituted on the phenyl moiety such as methoxy, such as di 1- (4- methoxyphenyl) methyl, triphenylmethyl, pyridylphenylmethyl, three methylsilyl, benzylmethyl, tetrahydropyranyl, acylaminomethyl, such as acetamethyl. isocarbonyl, 2-chloroacetamidomethyl, 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkyl, in particular (lower and 1-alkyl) am inocarbonyl, such as ethyl and inocarbonyl, and i (lower) and 1-alkylthio, such as S-ethylthio or S-tert-butyl, or S-sulfo.

For example, the sulfonyl group may be protected by a lower alkyl group, for example a methyl group or an ethyl group, a phenyl group, or as a sulfonamide, for example, as an imidazole.

For the purpose of this patent application, a polymeric carrier which is bound in an easily cleavable manner to a functional group to be protected, for example a carboxyl group such as is suitable for a Merrifield, is to be expressly understood as a protecting group, for example a carboxyl function protecting group. synthesis. Such a suitable polymeric carrier is, for example, a polystyrene resin weakly crosslinked by di-vinyl benzene copolymerization, which carries suitable bridging members to form the reverse bonds.

Optionally, the release of the protected groups is carried out according to the procedures described below under method f) (cleavage of the protecting groups).

Method b) (condensation to prepare a compound)

In the starting materials of formula IV and formula V, functional groups other than those which are to be present in the reaction or which do not react independently of each other under the reaction conditions are protected by the protecting groups mentioned under process a).

The acids of formula V contain a free carboxylic or free sulfonic group or reactive derivatives thereof, so that there can also be reactive derivatives of acids of formula V, for example derived activated esters or reactive anhydrides, further reactive cyclic amides. Said reactive acid derivatives may also be formed in situ.

Active esters of a compound of formula V with a carboxy group, in particular esters unsaturated on a carbon atom, which attaches an ester and a pertinent residue, for example of the vinyl ester type, such as vinyl ester (obtainable for example by reesterification of the corresponding ester with vinyl acetate; activated inyl ester method); carbamoyl ester for example by reaction of the corresponding acid with an isoxazolium reagent; 1,2-oxazoline or Woodward method), or 1- (lower alkoxy) vinyl ester (obtainable, for example, by reaction of the corresponding acid with (lower alkoxy) acetylene; ethoxyacetylene method) or novel amide esters , such as Ν, Ν'-disubstituted amidinoesters (prepared, for example, by reaction of the corresponding acid with a suitable Ν, Ν'-disubstituted carbodiimide, for example N, N'-dicyclohexylcarbonyl, carboximide method) or Ν, Ν ' -disubstituted amidinoesters (obtainable, for example, by rea by reaction of the corresponding acid with N, N-disubstituted cyanamide; cyanamide method), suitable aryesters, in particular phenyl substituted substituents (obtainable, for example, by reaction with phenol, with an electron affinity of the corresponding acid, for example 4-nitrophenol, with suitably substituted)

4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pen96 tachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide; activated aryl ester method), cyanomethyl ester (obtainable, for example, by reaction of the corresponding acid with chloroetonitrile in the presence of a base; cyanomethyl ester method), thioesters, especially phenyl ioesters optionally substituted with, for example, nitro group (prepared for example by reaction of the corresponding acid with substituted thiophenols a group, inter alia by means of the anhydride or carbodiimide method; activated thiolester method) or, in particular, amino or amidoesters (if appropriate, for example, by reacting the corresponding acid with an N-hydroxyamino or N-hydroxyamino compound such as N-hydroxysuccinimide, Nh droxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-benztriazin-4-one, for example anhydride or the carbodiimide method, the active N-hydroxyester method also internal esters, for example gamma-1actone.

The acid anhydrides of the formula V can be symmetrical or preferably mixed anhydrides of this acid, for example anhydrides with inorganic acids such as acid halides, in particular acid chlorides (obtainable by reaction of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxaldehyde; acids), azides (if appropriate, for example, from the corresponding ester via the corresponding hydrazide and its treatment with nitrous acid; azide method), anhydrides with half acid esters, for example by reaction of the corresponding alkyl) chloroformic or carbonic esters (obtainable acids with (lower alkoxy) carbonyl-2- (lower and 1-alkoxy) -1,2-dihydroquinoline: mixed anhydride hydrides with dihalogenated, 0-alkylcarbonic acid or, in particular, dichlorophosphoric acid (obtainable, for example, by reaction of the corresponding acid with phosphorous pentachloride); phosphoric acid (A) -oxides with other phosphoric acid derivatives (for example, derivatives that can be obtained with phenyl-N-phenylphosphoric amidochlorides or by reaction of alkylphosphoric amides in the presence of sulfonic acids and / or racemization reducing additions, for example N-hydroxybenzotriazole, or in the presence of a child of cyanophosphonic acid ether) or phosphorous acid derivatives or anhydrides with organic acids such as mixed anhydrides with organic carboxylic acids (prepared, for example, by reaction of the corresponding acids with an optionally substituted acid halide (lower and 1 k) and n) - or phenyl (lower alkane) carboxylic acid, such as, for example, phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; a method of mixing anhydrides k and rb o with organic sulfonic acids by reacting a salt, for example an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide such as lower alkane- or α-γ-1 chloride such as methane or p-toluenesulfonic acid; mixed sulfonic anhydride method) as well as symmetric anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of carbodiimide or 1-diethylamidopropin; symmetric anhydride method).

Suitable cyclic acid amides V are in particular amides with five-membered aromatic diazacyclides, such as amides with imidazoles, for example imidazole (obtainable, for example, by reaction of the corresponding acid with s, Ν'-carbonyldiimidazole; imidazole method) or pyrazole, for example 3,5- dimethylpyrazole (obtainable, for example, via an acid hydrazide by reaction with acetyl acetone; pyrazolidide method).

xylic acids) or (prepared for example

As mentioned above, the carboxylic acid derivatives V used as acylating agents can also be prepared in situ. Thus, for example, an N, N'-disubstituted amidinoester can be prepared in situ by reacting a mixture of a starting material of formula (V) and an acid of formula (V) which has been used as an acylating agent in the presence of a suitable N, N'-d isubstituted carbodiimide. in the presence of a suitable base such as triethylamine.

Further, it is possible to form the amino or amido ester of an acid which has been used as an acylating agent in the presence of a starting material of formula IV for acylation by reacting a mixture of the corresponding starting acid and amino compound in the presence of Ν, Ν'-disubstituted carbodiimide. N, N'-dicyclohexylcarbonylimide, and N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base such as 4-dimethylaminopyridine.

Further, in situ activation can be achieved by reaction with N, N, N ', N' -tetraalkyl compounds such as O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate.

Finally, the phosphoric anhydrides and carboxylic acids of the formula V can be prepared in situ by reacting a phosphoric acid amide such as hexamethylphosphoric acid amide in the presence of a sulfonic anhydride such as 4-toluenesulfonic anhydride, with a salt such as tetrafluoroborate, for example, sodium tetrafluoroborate, or with another hexamethyl 1-amide derivative, such as benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexyl fluoride, preferably in the presence of a racemization-limiting agent such as N-hydroxybenztriazole.

Analogously, many of the reaction types mentioned for the carboxylic acids of the formula V can also be used, also for the compounds of the formula V with a terminal sulfonyl group when condensed with the compounds of the formula IV into sulfonamides.

Thus, for example, activated sulfonic acid esters, for example the corresponding, especially nitro-substituted aryl esters, such as the phenyl ester, can be used, the amine component of formula IV can also be used as an alkali metal amide such as an alkali metal arylamide or alkali metal salt nitrogen-containing heterocycles such as potassium pyrrolidide.

In addition, reactive anhydrides such as the corresponding symmetric (obtainable by reaction of, for example, silver salts and alkylsulphonic acids with 1sulphonic acid chloride) may be used, or preferably asymmetric acid anhydrides, for example anhydrides with inorganic acids such as sulphonates. halides, in particular sulfonyl chlorides (obtainable, for example, by reaction of the corresponding sulfonic acids with inorganic acid chlorides such as thionyl chloride or phosphorus pentachloride), with organic carboxylic acids (preferably by reaction of a sulfonic acid halide with a carboxylic acid salt, such as an alkali salt) metal, carried out in a manner analogous to the above-mentioned mixed sulfonic anhydride method) or azides (obtainable, for example, from the corresponding sulfonic acid chloride and sodium azide via the corresponding hydrazide by reaction with the cyanide by nitrous nitride, carried out in a manner analogous to the above azide method).

The amino group of the compounds of formula (IV) involved in the reaction preferably carries at least one reactive hydrogen atom, especially when the carbol or sulfonyl reacting group is present in reactive form. However, this group may itself also be derivatized, for example by reaction with a phosphite such as diethyl chlorophosphite,

1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylene chlorophosphite or tetraethylpyrophosphite. For example, a derivative of such an amino compound is also a carbamic acid halide or isocyanate, wherein the amino group involved in the reaction is substituted with a halocarbonyl group, e.g. chloro100 carbonyl, optionally converted to an isocyanate group; which carries a hydrogen atom (R 5 -H) on the nitrogen atom formed by the reaction of the formed amide group.

The condensation to prepare the amide compound can be carried out in a manner known per se, for example by the methods described in standard publications, including Houben-Weyl, Methoden der organischen Chemie, 4th ed. 15/11 (1974), Vol. IX (1955), Vol. E 11 (1985) by Georg Thieme

Verlag, Stuttgart, The Peptides (E. Gross and J. Meienhofer, Hg.), Vol. 1 and 2, Academic Press, London and New York, 1979/1980 or M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, Berlin, 1984.

The condensation of the free carboxylic acid of the formula V with the corresponding amine of the formula IV can be carried out in the presence of any of the usual coupling agents or by using carboxylic acid anhydrides or carboxylic acid halides such as carboxylic acid chlorides or activated carboxylic acid esters such as p-nitrophenes 1 esters. Conventional condensing agents are, for example, carbodiimides, for example diethyl, dipropyl-, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or, in particular, dicyclohexylcarbodiimide, further suitable carbonyl compounds, for example carbonylimidazole, 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methyl-isoxazole-bromo-chlorate, and / or suitable acylamino compounds for example 2-ethoxy-1-ethoxycarbonyl - 1,2-dihydroquinoline, N, N, N ', N'-tetraalkyluronium compounds such as O-benzotriazol-1-yl-N, N, N'N''-tetramethyluronium hexafluorophosphate, further activated phosphoric acid derivatives, for example diphenylphosphine or y azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphorylamide ori data, bis- (2-oxo-3-oxazolidinyl) phosphinic acid chloride or 1-benztriazolyloxy-tris- (dimethylamino) phosphonium hexafluorophosphate.

101

If desired, an organic base, preferably a tertiary amine, for example a tri (lower alkyl) amine with voluminous residues, such as ethyl diisopropylamine or triethylamine, and / or a heterocyclic base, for example 4-dimethylaminopyridine, is added. or preferably N-methylmorpholine or pyridine.

The condensation of the activated ester, reactive anhydride or reactive amide with the corresponding amine is usually carried out in the presence of an organic base, for example a simple tri (lower alkyl) amine, for example triethylamine or tributyl amine, or one of the abovementioned bases. If desired, a condensing agent as described for free carboxylic acids is also used.

For example, the condensation of an amine acid anhydride may be carried out in the presence of inorganic carbonates, for example in the presence of ammonium carbonate or alkali metal carbonates, or ammonium or alkali metal bicarbonates, for example in the presence of sodium or potassium hydrogen carbonate or carbonate ).

Carboxylic acid chlorides, such as those derived from the acid of formula V, or chloronic acid derivatives, or sulfonic acid chlorides are condensed with the corresponding amines, preferably in the presence of an organic amine, for example the above tri (lower alkyl) amine, or heterocyclic bases, optionally presence of hydrogen sulphate.

This condensation is preferably carried out in an inert, aprotic, preferably anhydrous solvent or in a mixture of such solvents, for example in a carboxylic acid amide such as formamide or dimethylformamide, a halogenated hydrocarbon such as methylene chloride, carbon tetrachloride or chlorobenzene, for example acetone, a cyclic ether such as tetrahydrofuran, an ester such as ethyl acetate, or nitrile such as acetonitrile, or in a mixture of these solvents, optionally at a reduced or elevated temperature, for example at a temperature of about -40 to about 100 ° C, preferably at a temperature of from about -10 ° C to about 50 ° C, in the case of the use of arylsulfonyl ester also at about 100 ° C to 200 ° C, and optionally under an inert gas atmosphere such as nitrogen or argon.

Aqueous, for example alcoholic (for example ethanol) or aromatic solvents or solvent mixtures, for example benzene or toluene, may also be used. Acetone can also be added in the presence of alkali and alkali metal bases.

Said condensation may also be carried out according to a method known as solid phase synthesis, which is ascribed to

R. Merrifide, described for example

A n g e w. C h e m. 3 7,

1-8 1 2 (1 985), Nat u r s s n s chaf11e n, 7 1, 252 -2 58 (1 984) or in R. And. (1985).

Houghten, Proc. Natl. Acad. Soi. USA, 82, 5131-5135

For the specific carbonic acids of the formula V ', the introduction of the radical R9 is particularly suitable for the half ester of a compound generally Rx-O- (C = O) -Z + (ν') in which Rx is especially lower alkyl, halogen (lower and lower). Alkyl (1-alkyl), aryl (lower alkyl), heterocyclyl (lower and alkyl), lower alkenyl, (lower alkoxy) (lower and alkyl) or (lower alkoxy) (lower alkoxy) (lower alkyl) as defined in connection with the definition of the acyl groups R »of a half-carbonated ester in which Z- represents a halogen atom in the presence of a tertiary or triethylamine, and in it, such as a chlorine atom, can be prepared, for example, by the reaction of complementary alcohols such as (lower alkyl) -, halogen (lower alkyl) -, aryl 1 (lower alkyl) -, heterocyclyl (lower alkyl) -, (lower aikenyl) -, (lower and 1-alkoxy) (lower alkyl) - or (( lower alkoxy) (lower alkoxy)) (lower alkyl) alcohols, with phosgene or analogues thereof containing other halogen atoms in place of the chlorine atom, in particular a bromine atom, preferably nitrogen bases such as pyridine inert solvents such as chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxane, or carboxylic acid amides such as dimethylformamide. Also suitable are the corresponding N-carbonylazolides of formula V '(Zs-nitrogen-containing heterocycle, such as 1-imidazolide heterocycle), which can be obtained, for example, by reaction with the corresponding Ν, Ν'-carbonyldiazolides such as Ν, Ν 1'-carbonyldiimidazole, under the conditions just described for phosgene and analogs with other halogen atoms. The reaction of the compounds of formula IV with the corresponding compounds of these (1962)) under the conditions ((Staab, then also takes place at H.A. Angew. Chemie, 74, 407)

For the particular case of the introduction of unsubstituted or substituted carbamic acid residues such as a carbamoyl residue or an unsubstituted or substituted N-alkylcarbamoyl residue, the corresponding isocyanate of the general formula V is particularly suitable as the activated acid derivative.

WN = C = O (V) wherein W represents an amino function protecting group, for example a trihaloacetyl group such as a three fluoro- or trichloro-10-racetyl group, or any of the unsubstituted or substituted alkyl radicals mentioned above in connection with the definition of the acyl groups R □ substituted carbamic acid, wherein when W is an amino function protecting group, the corresponding compound of formula I in which R ₉ is a carbamoyl group is obtained after reaction with a compound of formula IV by cleavage of the protecting group W as described below to release the protected amine groups, in particular by hydrolysis, or when W represents one of the abovementioned substituted or unsubstituted lower alkyl radicals, the corresponding compound of the general formula I with an N-monosubstituted aminocarbonyl group Ra. Both the aminocarbonyl group and the N-monosubstituted aminocarbonyl group R ₉ can be converted to the N-disubstituted aminocarbonyl group by alkylating further unsubstituted or substituted lower alkyl radicals using suitable starting materials and under conditions analogous to those described above. with the conditions described below under the additional modalities.

The reaction with compounds of formulas V 'and V is carried out under conditions analogous to those described in process a) for the reaction of compounds of formulas IX and IX' with compounds of formula II.

Depending on the starting compounds used, the radicals R 1 and R a in the compounds of formula I prepared may be the same or different from each other.

The release of the protected groups is also carried out according to the methods described below under method f) (cleavage of the protecting groups).

Method c) (Preparation of amide compound)

105

In the starting materials of formulas (VI) and (VII), functional groups, with the exception of those which are to be present in the reaction or which do not react under the reaction conditions, are independently protected from one another by one of the protecting groups mentioned in connection with process (a).

This method is completely analogous to that described in Method b), wherein compounds of formula IV are used instead of compounds of formula IV and compounds of formula VII are used instead of compounds of formula V.

Depending on the starting materials used, the radicals R @ 1 and R @ 5 in the compounds of the formula I prepared may be the same or different from each other.

In the reactions carried out in process b) but also c) and d), the acyl rearrangement of the acyl radical in the acyloxy group R 5 to the nitrogen atom to which the group R ₉ is to be coupled can occur in individual cases. Analogous side reactions are also possible in processes c) or d).

The release of the protected groups is also carried out according to the methods described in process f) (deprotection).

Method d) (Preparation of amide compound)

In the starting materials of formula (VIII) and in an acid suitable for introducing the same radicals R and R ₉ 'or in its reactive derivatives, the functional groups which are not to be reacted independently of one another are protected by the protecting groups mentioned under process a).

The acid suitable for introducing the same residues R 1 and R a has

106 is preferably one of formulas V or VII, or is in the form of a reactive derivative described above.

Preferred compounds of the general formula (VIII) which are optionally protected by protecting groups are those which are described as preferred in the paragraph relating to the starting compounds.

The reaction conditions of this process are analogous to those of process b), wherein compounds of formula IV are used instead of compounds of formula IV and compounds of formula V or VII are used instead of compounds of formula V.

The release of the protected groups is optionally carried out by the methods described below under method f) (cleavage of the protecting groups).

Method e) (alkylation of a secondary nitrogen atom)

In the starting materials of the formula I 'and in the compounds of the formula XII suitable for the introduction of the radical R @ 1, R @ 1 is substituted. or in its reactive derivatives, the functional groups that are not to be involved in the reaction, independently of each other, are protected by the protecting groups mentioned under process a).

Especially, the leaving group X is a nucleofusible leaving group selected from hydroxy groups esterified with a strong inorganic or organic acid, such as a mineral acid, for example a hydrohalic acid such as hydrochloric acid, hydrobromic or hydroiodic acid, or a strong organic sulfonic acid such as (lower and 1-alkan) sulfonic acid, an acid optionally substituted, for example, by a halogen atom, such as a fluorine atom, or an aromatic acid, such as benzenesulfonic acid, optionally substituted by a lower

107 with an alkyl group such as a methyl group, a halogen atom such as a bromine atom, and / or a nitro group such as a hydroxy group esterified with, for example, methanesulfonic acid, p-bromo-toluenesulfonic acid or p-toluenesulfonic acid, forged with hydrochloric acid.

This substitution may take place under the conditions of a first- or second-order nucloefficient substitution.

For example, a compound of formula XII can be used, in particular a compound in which X represents a leaving group having a high polarizability of the electron shell, for example iodine, in a polar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamine. This reaction can also be carried out in water in which an organic solvent, for example ethanol, tetrahydrofuran or acetone, is added as the solubilizing agent. This substitution reaction is carried out at ambient temperature or at a reduced or elevated temperature, for example at a temperature of about -40 to about 100 ° C, preferably at a temperature of about -10 ° C to about 50 ° C, and optionally under an inert gas atmosphere, e.g. nitrogen or argon.

The release of the protected groups is optionally carried out by the methods described below under method f) (cleavage of the protecting groups).

Method f) (cleavage of protecting groups)

The cleavage of the protecting groups which are not part of the desired end product of the general formula I, for example the carboxyl, amine, hydroxy and / or mercapto function, is carried out in a manner known per se, for example by solvolysis, in particular hydrolysis, alcoholysis or acidolysis or using other reducing agents

By means of photolysis, optionally sequentially or simultaneously, enzymatic methods can also be used. For example, cleavage of protecting groups is described in standard publications mentioned in the previous section on protecting groups.

Thus, for example, a protected carboxyl group, for example a tertiary (lower alkoxy) carbonyl group, (lower and 1-alkoxy) carbonyl group, may be substituted at the 2-position by a trisubstituted silyl group or at the 1-position by a lower alkoxy group or or an optionally substituted diphenylmethoxycarbonyl group converted to a free carboxyl group with a suitable acid such as formic acid, hydrochloric acid or trifluoroacetic acid, optionally by addition of a nucleophilic compound such as phenol or anisole. From the (lower alkoxy) carbonyl compound, the carboxyl group can also be released by bases such as hydroxides, for example alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. An optionally substituted benzyloxycarbonyl group can be released, for example, by hydrogenolysis, i. by hydrogen in the presence of a metal hydrogenation catalyst such as a palladium catalyst.

Furthermore, a suitably substituted benzyloxycarbonyl group, such as a 4-nitrobenzyloxycarbonyl group, can also be converted to the free carboxyl group by reduction, for example by treatment with an alkali metal dithionite, for example sodium reading, or using a reducing metal such as zinc or a reducing metal salt, e.g. of an ocular chromium, for example chromium chloride, usually in the presence of a hydrogen-releasing agent which, together with the metal, produces hydrogen at birth, such as an acid, in particular a suitable carboxylic acid such as acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid mandelic acid, 4-chloro-mandelic acid or tartaric acid, or alcohol or thiol, preferably water is added.

109

The 2-halo (lower alkoxy) carbonyl group (optionally after converting the 2-bromo (lower alkoxy) carbonyl group to the corresponding 2-iodo (lower alkoxy) carbonyl group) may also be treated by the reducing metal or reducing metal salt described above. (alkoxy) carbonyl) or aroylmethoxycarbonyl group can be converted to the free carboxyl group.

The aroylmethoxycarbonyl group can also be cleaved by treatment with a nucleophilic, preferably salt-forming agent, such as sodium thiophenoxide or sodium iodide.

A 2- (trisubstituted 1 y 1) (lower alkoxy) carbonyl group, such as a 2-tri (lower and 1 alkyl) 1 y 1 (lower alkoxy) carbonyl group, can also be converted to the free carboxyl group also by treating with a hydrofluoric acid salt which provides a fluoride anion such as an alkali metal fluoride such as sodium fluoride or potassium fluoride, optionally in the presence of a macrocyclic polyether (crown ether) or an organic quaternary base fluoride such as tetra (lower alkyl) ammonium chloride or tri-alkylalryl (lower alkyl) ammonium fluoride, for example, tetraethylammonium fluoride or tetra-butyl ammonium fluoride, in the presence of an aprotic, polar solvent such as dimethylsulfoxide or N, N-dimethylacetamide.

A carboxyl group protected as an organic silyloxycarbonyl group, such as a tri (lower and 1-6 alkyl) oxycarbonyl group, for example a trimethylsilyloxycarbonyl group, can usually be liberated solvolytically, for example by treatment with water, alcohol or acid, or else with fluoride, as described above .

The esterified carboxyl group can also be released enzymatically, for example by esterases or suitable peptidases. For example, esterified arginine or lysine, such as lysine methyl ester, can be treated with trypsin.

A (lower alkoxy) carbonylamino group, such as a tert-butoxycarbonylamino group, can be cleaved in the presence of acids, for example mineral acids, for example hydrogen halides such as hydrochloric or hydrobromic acid, in particular hydrobromic acid or sulfuric acid or phosphoric acid, preferably hydrochloric acid, in polar solvents such as water or carboxylic acid, such as acetic acid, or ethers, preferably cyclic ethers, such as dioxane, and 2-halogeno (lower alkoxy) carbonylamino (optionally after conversion 2-bromo) (lower and 1-alkoxy) carbonylamino groups to 2-iodo (lower and 1-alkoxy) carbonyl amino groups), aroylmethoxycarbonylamino or 4-nitrobenzoylcarbonylamino groups can be cleaved by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as acetic acid.

The aroylmethoxycarbonylamino group can also be cleaved by treatment with a nucleophilic, preferably salt-forming agent, such as sodium thiophenoxide, while the 4-nitrobenzyloxycarbonylamino group can also be cleaved by treatment with an alkali metal di-thiotinated metal, for example di-thiotinated sodium.

Optionally substituted diphenylmethoxycarbonylamino amine, tertiary (lower and 1-alkoxy) carbonyl amine or 2- (trisubstituted silyl) (lower and 1-alkoxy) carbonyl 1 amine, such as 2-tri (lower alkyl) silyl (lower alkoxy) carbonylamino, can be liberated by treatment with a suitable acid, for example formic acid or trifluoroacetic acid.

The optionally substituted benzyloxycarbonylamino group can be cleaved, for example, by hydrogenolysis, i. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst such as a palladium catalyst, preferably in polar solvents such as di (lower alkyl) (lower alkane) oylamides, for example dimethylformamide, ethers such as cyclic ethers, for example dioxane, or alcohols such as ethanol, methanol or propanol, particularly preferably methanol.

Optionally substituted three aryliminoamino or form 1 amino groups can be cleaved by treatment with, for example, an acid such as a mineral acid such as hydrochloric acid or an organic acid such as formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water.

The amino group protected as a silyl amine group can be liberated, for example, by hydrolysis or alcoholysis.

The 2-haloacetyl-protected amino group, for example the 2-chloroacetyl group, can be liberated by treatment with thiourea in the presence of a base or a thiolate salt such as an thiourea-derived alkali metal thiolate and subsequent solvolysis, in particular alcoholysis or hydrolysis of the resulting substitution product.

Amino group protected with 2- (tri substituted silyl) (lower and 1-alkoxy) carbonyl, such as 2-tri (lower and 1-alkyl) silyl (lower and 1-alkoxy) carbonyl groups , can also be converted to the free amino group by treatment with a fluoride anion-providing salt of hydrofluoric acid, as discussed above in connection with the release of a similarly protected carboxyl group. It is also possible to cleave a silyl group directly with fluoride ions, such as a trimethylsilyl group that binds to a heteroatom such as a nitrogen atom.

The azido-protected amino group can be converted to the free amino acid by, for example, reduction, for example, catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, by reduction using mercapto-zen sausages such as are dithiothreitol or mercaptoethanol, or so

12 by treatment with zinc in the presence of an acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, for example methylene chloride, or also in water or in a mixture of water and an organic solvent such as alcohol or dioxane, at a temperature of about 20-25 ° C, or also with cooling or heating. .

A hydroxyl or mercapto group protected with a suitable acyl group, a tri (lower and 1 alkyl) 1-yl group, or an optionally substituted 1-phenyl (lower and 1 alkyl) group, is released analogously to the correspondingly protected amino.

For example, the hydroxy or mercapto group protected with 2,2-dichloroacetyl is liberated by basic hydrolysis.

The hydroxyl group at which the mercapto group is protected by a tertiary lower alkyl group or the 2-ox α- or 2-thiaaliphatic or cycloaliphatic residue is released, for example by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid such as trifluoroacetic acid .

The mercapto group protected by a pyridyl diphenylmethyl group can be released by mercuric salts at pH 2-6 or by a zinc / acetic acid system or by electrolytic reduction.

The mercapto group protected with acetamidomethyl group or isobutyl amide methyl group may be liberated by reaction with mercury salts at pH 2-6.

The 2-chloroacetamidomethyl-protected mercapto group can be released, for example, by treatment with 1-piperidinothiocarboxoles du.

The mercapto group protected with S-ethylthio, S-tert-butylthio and S-sulfo may be liberated by thiolysis by treatment with thiophenol, thioglycolic acid, sodium thiophene oxide or 1,4-diotriol.

Two hydroxy groups or an amino group and an adjacent hydroxy group which are jointly protected by a two-valence protecting group, preferably a methylene group, which is preferably substituted once or twice by, for example, a lower alkyl group such as a (lower and 1-yl) idene group , for example, isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be liberated by acid solvolysis, particularly in the presence of a mineral acid or a strong organic acid.

The tri (lower and alkyl) sulfonyl group can also be cleaved by acidolysis, for example with a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid.

The 2-halo (lower alkoxy) carbonyl group is cleaved by the abovementioned reducing agents, for example a reducing metal, such as zinc, or a reducing agent with divalent chromium, or sulfur compounds, for example sodium di-nitrate or preferably sodium sulfide and carbon disulfide.

For example, a sulfo group protected in the form of a sulfonic acid ester or sulfonamide is liberated by acid hydrolysis, for example in the presence of a mineral acid, or preferably by basic hydrolysis, for example by treatment with an alkali metal hydroxide or an alkali metal carbonate such as sodium carbonate.

In the case of the presence of a plurality of protected functional groups, the protective groups may, if desired, be chosen by simultaneously removing at least two protecting groups, for example by acidolytic removal, in particular by treatment with trifluoroacetic acid or hydrogen in the presence of a hydrogenation catalyst,

14 such as palladium on coal. Protecting groups, on the other hand, can be chosen so that they are not simultaneously cleaved, but in the desired order, whereby the corresponding intermediates are obtained.

Additional modalities

In the additional process steps which may optionally be carried out, the functional groups of the starting materials which are not to be involved in the reaction may be unprotected or protected, for example, by one or more of the protective groups mentioned above under process a). These protecting groups can either remain in the final products or can be totally or partially cleaved by the methods described in process f),

Salts of compounds of formula I with at least one salt-forming group can be prepared in a manner known per se. Thus, salts of the compounds of formula I with acidic groups can be formed, for example, by reaction with metal compounds such as alkali metal salts derived from suitable organic acids such as sodium 2-ethylhexanoic acid with inorganic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates. such as sodium or potassium hydroxide, carbonate or bicarbonate, with the corresponding calcium compounds or with ammonia or a suitable organic amine, preferably using a stoichiometric amount or only a small excess of the forming agent. The acid addition salts of the compounds of the formula I are obtained in a customary manner, for example by reaction with an acid or by contact with a suitable anion exchanger. The internal salts of the compounds of formula I which contain acidic and basic salt-forming acids, such as free carboxylic acid and free amino, can be formed, for example, by neutralizing salts, such as acid addition salts, to an isoelectric point, e.g. ion exchangers.

Salts can be converted to the free compounds in a conventional manner. Metal salts and ammonium salts can be converted, for example, by reaction with suitable acids, while acid addition salts can be converted, for example, by reaction with a suitable basic reagent.

Mixtures of stereoisomers, as well as mixtures of diastereomers and / or enantiomers, such as racemic mixtures, can be separated into the corresponding isomers in a manner known per se by suitable resolution procedures. Thus, the di-stereoisomeric mixtures can be separated into the individual di-stereoisomers by traction crystallization, chromatography, separator methods using solvents and the like. The racemates, after conversion of the optical antipodes into diastereomers, for example by reaction with optically active compounds, for example optically active acids or bases, can be separated by chromatography on a column of material coated with optically active compounds or by enzymes, for example by selective reaction of one of the two enantiomers. This separation can be carried out both in the step of one of the starting materials and in the compounds of the general formula I itself.

At the individual chirality centers in the compound of formula I, the configuration can be targeted. Thus, for example, it is possible to reverse the configuration of asymmetric carbon atoms that carry nucleophilic substituents such as ammonium or hydroxy substituents by second-order nucleophilic substitution, optionally after converting the bound nucleophilic substituents to appropriate nucleophagic leaving groups and reacting with the reagent introducing the original. substituent.

In the compound of formula (I), the aryl radical may be present in R? and / or R ₃ , in particular a phenyl moiety, hydrogenated, for example by catalytic hydrogenation, in particular in the presence of heavy metal oxides such as mixed oxides of rod and platinum, for example using Nishimura catalyst, preferably in a polar solvent such as alcohol or methanol; ethanol, at a temperature between 0 and 80 ° C, in particular between 10 and 40 ° C, and at a hydrogen pressure of 1 to 10 bar, preferably at about normal pressure.

In the compounds of formula I may be alkenyl radical with 3 to 7 carbon atoms or an alkynyl radical of 3-7 carbon atoms, in particular the allyl radical, e.g., in and 11 yl 1 carbonyl 1ovej group contained in the R and / or R _9, hydrogenated , for example, by catalytic hydrogenation in the presence of a metal, such as platinum or especially palladium catalyst, which is as such or on a support such as coal or silica, especially in the presence of palladium on activated carbon, preferably in a polar solvent such as lower and 1 canol. , for example methanol or ethanol, at a temperature between 0 and 80 ° C, in particular between 10 and 40 ° C, and at a hydrogen pressure of at most 10 bar, preferably at about normal pressure.

In the compound of formula I obtained, the amino or carboxamido group may be substituted or the carboxy group present in free or reactive form, may be esterified or amidated.

Substitution of a carboxamide group or other primary or secondary amino group, for example, to introduce radicals such as unsubstituted or substituted alkyl radicals R 1, R ₂ , R 3 _and / or R ₉ in compounds of formula I wherein at least one of these radicals is a hydrogen atom, to introduce an unsubstituted or substituted alkyl radical as defined for an N-substituted aminocarbonyloxy group R 5 as a substituent on a nitrogen atom and an inocarbonyloxy group R 5. or in order to introduce an unsubstituted or substituted alkyl radical as a sub-17 substituent in the unsubstituted or substituted N-alkyl or N, N-di and alkylcarbamoyl group R ₉ or R 1, is carried out, for example, by alkylation using suitable starting materials.

Suitable agents for the alkylation of the carboxamide group of formula I are, for example, diazo compounds such as diazomethane. The diazomethane may be decomposed in an inert solvent, whereby the free methylene formed reacts with the carboxamido group of the compound of formula I. The decomposition of the diazomethane is preferably carried out catalytic, for example in the presence of a noble metal in finely divided form such as copper or a noble metal salt. such as copper (II) chloride or copper (II) sulfate.

Other alkylating agents are selected from the group consisting of compounds of formulas:

R-, -X

R :; '-X R 9 -X R 8' - X (Xa),

(Xb), (XIa) and (Xlb), wherein X is a leaving group and R 1 and R 8 have the meanings given for R or R ₃ except for a hydrogen atom, an acyl group or an unsubstituted or higher substituted sulfo group and R'c and R'e except hydrogen. In particular, the leaving group X is a nucleophagic leaving group selected from hydroxy groups esterified with a strong inorganic or organic acid such as a mineral acid, for example a hydrohalic acid such as hydrochloric acid, hydrochloric acid or hydroiodic acid, or a strong organic sulfonic acid, as optionally halogen, such as fluorine, substituted (lower and 1 can) sulfonic acid or aromatic sulfonic acid, for example optionally lower alkyl, such as methyl,

A halogen such as bromine and / or a nitro substituted benzenesulfonic acid, such as a hydroxy group substituted with methanesulfonic acid, trimethanesulfonic acid or p-toluenesulfonic acid, or a hydroxy group esterified with hydrochloric acid.

This reaction may take place under nucleophile conditions of another first or second order substitution.

Thus, for example, compounds of formulas Xa, Xb, Xla or Xlb may be used, especially when X is a leaving group having a high polarizability of an electron shell, for example an iodine atom, in a polar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide. . This reaction can also be carried out in water, optionally mixed with an organic solvent, such as ethanol, tetrahydrofuran or acetone, in the function of a bi-reagent. This substitution reaction is optionally conducted at a reduced or elevated temperature, for example in a temperature range of about -40 ° C to about 100 ° C, preferably about -10 ° C to about 50 ° C, and optionally under an inert gas atmosphere, e.g. nitrogen or argon.

In order to esterify or amidate a carboxyl group in a compound of formula (T), the free acid or, if desired, can be converted into one of the above-mentioned reactive derivatives and reacted with an alcohol, ammonia or primary or or a free acid or a reactive salt thereof, for example a cesium salt, can be reacted with a reactive alcohol derivative for esterification. Thus, for example, the cesium carboxylic acid salt may be reacted with a halide or sulfonic acid ester corresponding to the alcohol. Esterification of the carboxyl group can also be accomplished using other conventional alkylating agents, such as diazomethane, and alkyl halides, sulfonic acid esters, Meerwein salts, or 1-substituted 3-aryltriazines.

An amino group may also be present in the compound of formula (I) to be acylated, for example to introduce one of the acyl residues, the sulfo residue or the substituted sulfonyl residues mentioned for R 1 or R ₉ . This acylation is carried out according to one of the methods mentioned above under methods (b), (c) or (d) for condensation, or according to one of the methods mentioned for protecting groups or, for example, by the procedures outlined in Organization 17th Edition, VEB Deutscher Verlag der Wissenschaften, Berlin (Os t) 1 9 88.

In the compound of formula (I) in which the substituents have the above-mentioned meanings in which at least one free hydroxy group exists and in which the other functional groups are in protected form, the free hydroxy group may be acylated or esterified.

This acylation may be carried out using suitable acylating agents by any of the methods described in methods a) to d) or by the method indicated for protecting groups.

The esterification can be carried out using the above alkylating agents and under the same reaction conditions, for example using diazomethane, alkyl halides, sulfonic acid esters, Meerwein salts, 1-substituted 3-aryltriazines and the like.

In the compound of formula I obtained, the thio group can be converted by oxidation to a sulfinyl or sulfonyl group, i.e. the corresponding sulfoxide or sulfone can be prepared from the sulfide.

Oxidation of the thio group to the sulfonyl group and hence the oxidation of the sulfide to the sulfone can be accomplished using most ob120 sticky oxidizing agents. Particularly preferred are those oxidizing agents which oxidize thio or sulphide sulfur selectively in the presence of other functional groups of a given compound of formula I, for example amino or hydroxy, for example aromatic or aliphatic percarboxylic acid, for example peroxybenzoic acid , monoperoxyphthalic acid, m-chloroperoxybenzoic acid, peroxyacetic acid, peroxy formic acid or trifluoroperoxyacetic acid. This oxidation with peroxycarboxylic acids is carried out in conventional solvents suitable for this purpose, such as, for example, chlorinated hydrocarbons, such as methylene chloride or chloroform, ethers, such as diethyl ether, esters such as ethyl acetate, at temperatures between -78 ° C and ambient temperature, e.g. C and 10 ° C, preferably at about 0 ° C. The peroxyacid may also be prepared in situ, for example by using hydrogen peroxide in acetic acid or formic acid, which optionally contains acetic anhydride, for example by using 30% or 90% hydrogen peroxide in a mixture of acetic acid and acetic anhydride. Other peroxy compounds, for example potassium peroxymonosulphate in mixtures of lower and lower alkanes and water, for example in mixtures of methanol and water or ethanol and water, are also suitable. or in aqueous sulfuric acid, at a temperature between 70 ° C and 30 ° C, for example between -20 ° C and ambient temperature, further sodium metaperiodate in methanol or methanol-water mixtures at temperatures between 0 ° C and 50 ° C, e.g. temperature around ambient temperature. By using stoichiometric amounts of the oxidizing agents mentioned, the corresponding sulfonic acids or sulfoxides can also be obtained. Sodium metaperiodate in methanol or methanol-water mixtures at temperatures between -15 ° C and ambient temperature, for example at about 0 ° C, m-chloroperoxybenzoic acid in methylene chloride, chloroform or ethyl acetate at temperatures between -73 ° C are suitable for this purpose. C and 10 ° C, preferably between -30 ° C and 0 ° C, furthermore tert-butyl hypochlorite in lower alkanols, for example methanol, or hydrogen peroxide in acetone or acetic acid at temperatures around 0 ° C, or the aforementioned potassium peroxymonosulfate at low temperatures.

Reduction of the sulfonyl group or sulfone moiety in the compound of formula (I) obtained may optionally give the corresponding thio compound to or the corresponding sulfide, for example, by using diisobutyaluminium hydride in ether or tetrahydrofuran.

In the compound of formula I obtained with a sulfinyl group, this group can be reduced to a thio group. Preferred are selective reducing agents which leave the other functional groups of formula I unchanged, for example, the amide function. Examples of such selective reducing agents are dichloroborane, which is preferably used in tetrahydrofuran or dimethoxyethane at temperatures between -30 ° C and 10 ° C, triphenylphosphine in boiling carbon tetrachloride, trichlorosilane or hexachlorosilane, iron pentacarbonyl, sodium hydrogen sulfite, mixtures of water and methanol, water and ethanol, or else in a mixture of water and tetrahydrofuran, at temperatures between -10 ° C and 50 ° C, sodium borohydride in the presence of cobalt chloride or water in the presence of catalytic amounts of palladium, for example palladium on charcoal, in boiling ethanol .

Preserved protecting groups or suitable R 1 or R 5 radicals can be cleaved in the compound of formula (I). i in particular those which represent an acyl group, the cleavage being carried out by one of the methods mentioned in process f), in particular by hydrolysis, for example in the presence of a base such as alkali or alkaline earth metal hydroxides, for example sodium hydroxide or acids such as organic or mineral acids, for example hydrohalic acid such as hydrochloric acid. This hydrolysis is carried out under conventional conditions, for example in aqueous solution or anhydrous solvent, in particular in ethers, for example di122 oxane, at temperatures between 50 ° C and reflux temperature of the corresponding reaction mixture, for example between 0 ° C and 50 ° C, preferably in the presence of a shielding gas such as argon or nitrogen.

East and metal fabrics

The novel starting materials and / or intermediates as well as processes for their preparation are also an object of the invention. Preferably, such starting materials are used and the reaction conditions are chosen such that the compounds are said to be preferred.

It should be noted that in the compounds of formulas IV, VI and VIII, the acyl residue of the acyloxy group R 5 may be rearranged to a nitrogen atom, and the above processes (b), (c) and (d) should be considered with this reservation. Methods a), e) and f) and their starting materials are preferred, processes a) and f) being particularly preferred.

In the production of all starting materials, the free functional groups which are not to be involved in the respective reactions may be in an unprotected or protected form, for example protected by the protecting groups mentioned above under process f). The protected groups can then be liberated at the appropriate time by the reactions described in process f). The deprotection is carried out, for example, by the methods described above under process a).

The hydroxy compounds of the formula II which have been used as starting compounds and other starting compounds are obtained by processes analogous to those described in the European patent application published (07.01.1993) under EP 0521827, preferably when used accordingly. a substituted compound, for example, such that

123 is a hydrazine derivative of the general Formula XIII

R?

HN

* 3 (XIII), wherein the general symbols have the meanings given above, adds to the epoxide of formula XIV

(XIV) preferably of formula XIV A

(XIV A)

124 wherein the general symbols have the meanings given above, wherein the free functional groups, with the exception of the functional groups involved in the reaction, are optionally in protected form, and then the protective groups are cleaved off. When compounds of formula XIV A are used, the preferred starting materials of formula II 'mentioned in process a) are obtained. The amino group of the hydrazines of the novel derivative of the general formula (XIII) involved in the reaction has the meaning of R? preferably at least one free hydrogen atom. This group can be derivatized in order to increase the reactivity of the hydrazines of the new derivative.

Said addition of compounds of formula (XIII) to epoxides (oxiranes) of formula (XIV) is preferably carried out under reaction conditions which are customary for addition of nucleophiles to epoxides.

blowing agents, such as benzene / water, optionally

In particular, this addition is carried out in aqueous solution and / or in the presence of polar solvents such as alcohols such as methanol or ethylene glycol, ethers such as dioxane, amides such as dimethylformamide, or phenols such as phenol, also under anhydrous conditions. apolar solutions are benzene or toluene, or in emulsions in the presence of acidic or basic catalysts, for example lyes such as sodium hydroxide, or in the presence of hydrazine-subsidized solid phase catalysts such as alumina, in ethers such as diethyl ether, usually at temperatures of about 0 ° C to reflux temperatures, preferably at a temperature between 20 ° C and 130 ° C, optionally at reflux, at elevated pressure, for example in a pressure tube, and the boiling point of the reaction and / or under inert gas such as is nitrogen or argon, each of the compounds of formulas XIII and XIV may be in excess These compounds are used, for example, in a 1: 1 to 1: 100 molar ratio, preferably in a 1: 1 to 1:10 molar ratio, especially 1: 1 to 1: 3 molar ratio.

mixtures, wherein

125

The starting materials of the formulas XIII and XIV are known and, if new, can be prepared by known methods, for example from hydrazine or its suitable derivatives, to prepare compounds of the formula XIII and from the appropriate amino acids or analogues thereof, for example with any of the foregoing. side chains R _3, to produce compounds of formula XIV.

For example, compounds of formula XIII are available from hydrazine or a suitable derivative thereof of formula XV

(XV) in which R 11 is an amine function e, such as the hydrogen atom or the protecting group described above under process a), in particular tert. a (lower alkoxy) carbonyl group, such as a tert-butoxycarbonyl group, an aryl (lower alkoxy) carbonyl group, such as a benzyloxycarbonyl group, or a 9-fluorenylmethoxycarbone of the above acyl groups, such that these are, for the purpose of Formula I, -functional preparation of the compound of the general following steps, where instead of the radical R? a radical (T-r, which represents an unsubstituted or substituted alkyl or cycloalkyl group) present when the radical R @ 8 is introduced. as defined in process e) are alkylated with a compound of formula XII under the conditions described in process e) or the radical R @ 2 is introduced. by reacting a suitable carbonyl compound with a free amino group of a compound of formula XV or an acylated derivative thereof and then reducing the hydrazone obtained to form a hydrazinated derivative of formula XVI

Rt-NH-NH-R · n (xvi)

126 wherein the general symbols in all the above compounds have the meanings given above and the functional groups in the reactants which are not to be involved are optionally protected, and the protecting group R11, if it does not correspond to any of the radicals R9 in the compounds of formula I, is cleaved. and thereafter introducing a residue R ₉ with hydrogen, optionally by condensation under the conditions given above for process b) with acids of the formula V or by alkylation with a compound of the formula XIa as defined above, and / or a residue Rs other than hydrogen by alkylation with a compound of the formula X 1b, as defined above, under conditions analogous to those set forth above for alkylations in additional process measures.

The carbonyl compounds used to prepare the compounds of formula XVI and suitable for the introduction of R 7 are known or known methods in the legally or commercially available aldehydes or ketones of which the reactive carbonyl groups are part of the reaction with compounds of formula XV and subsequent reduction any of said R 7 radicals, for example (lower alkane) aldehydes, cyclohexyl (lower alkane) aldehydes or phenyl (lower alkane) aldehydes.

The reaction of these carbonyl compounds with compounds of formula XVI to the corresponding hydrazones is carried out under conditions customary for the reaction of carbonyl compounds with amines, preferably in polar organic solvents, for example ethers such as tetrahydrofuran or diethyl ether, alcohols such as methanol or ethanol, carboxylic acid arides acids, such as dimethylformamide, or esters, such as ethyl acetate, or in aqueous solution, preferably methanol, further in the presence or absence of acidic catalysts, for example carboxylic acids, in particular formic acid or acetic or sulfonic acids, for example p-toluenesulfonic acid, at temperatures between 0 ° C and temperature

127, preferably at temperatures from 20 ° C to the reflux temperature of the reaction mixture.

The reduction of the hydrazones obtained is preferably carried out by hydrogenation in the presence of a suitable catalyst. Suitable catalysts for this hydrogenation are metals such as nickel, iron, cobalt or ruthenium, or noble metals or their oxides, such as palladium or rhodium, or their oxides, optionally on a suitable support material such as barium sulfate, aluminum oxide, or activated carbon, or skeletal catalysts such as Raney nickel. Solvents which can be used for this hydrogenation are, for example, water, alcohols such as methanol or ethanol, esters such as ethyl acetate, ethers such as dioxane, chlorinated hydrocarbons such as dichloromethane, carboxylic acid amides such as dimethylformamide, or carboxylic acids , such as acetic acid, or mixtures of these solvents. The hydrogenation is carried out at a temperature of 10 to 250 ° C, preferably at a temperature from ambient temperature to 100 ° C, and at a hydrogen pressure of 0.1 to 20 MPa, preferably 0.1 to 1 MPa, in conventional apparatuses.

Particularly preferred for the preparation of compounds of formula XV are reaction conditions analogous to those described in J. Chem. Soc.Per. 1.1 7 1 2 (1 9 7 5).

Compounds of formula XIV are available, for example, by reduction by known or commercially available, or by known methods of a body of rights and amino acids or analogs of formula XVII, ^R l ₀ - NH COOH (XVIII)

128 wherein Rw represents a hydrogen atom or one of the amino protecting groups mentioned in process a), in particular a tertiary (lower alkoxy) carbonyl group, such as a tert-butoxycarbonyl group, aryl (lower and 1 alkoxy) groups carbonyl groups such as a benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl group or any of the above acyl protecting groups and amino functionalities, and Ra and Ra have the meanings given for compounds of formula I, preferably amino acids of formula XVII A

R _t0 - **

COOH (XVII A) wherein the general formulas have the aforementioned formula (XVIII) as defined for aldehydes

CHO

R;

r ₄ (XVIII) wherein the general symbols have the meanings indicated, preferably to the aldehydes of the general formula XVIII A (XVIII A)

^ 3

129 wherein the general symbols have the meanings indicated (obtainable, for example, from compounds of formula XVII A), by reacting these aldehydes with an ylide compound, preferably a sulfuryl compound, to an epoxide of formula XIX)

wherein the general symbols of the compound of the formula have the meanings indicated, preferably on XIX A)

H

(XIX A) (obtainable, for example, from compounds of formula XVIII A), in which the symbols have the meanings indicated, by cleavage of the protecting group R @ 1 unless it corresponds to the radical R in compounds of formula I, and (for introducing R 1 except hydrogen) by acylation a group of the resulting compound with an acid of formula VII, wherein R 1 'is as defined under the conditions outlined in method b), or by alkylating the amino group of the resulting compound with a nucleogenic cleavage group X of the above group; ) alkylation with a compound of formula Xa, (for the purpose of R 1 introducing R:

wherein R _; of formula (Xb) has the meanings given, under the conditions outlined in the additional process steps, wherein the compounds of formula (XIV) A are preferably obtained from the starting material of formula (XIX).

The reduction of the amino acids XVII or XVII A to the corresponding aldehydes XVIII and XVIII A is carried out, for example, by reduction to the corresponding alcohols and subsequent oxidation to the said aldehydes.

Said reduction to alcohols is effected, for example, by hydrogenation of amino acid halides or other activated carboxylic acid derivatives (e.g., an activated hydroxy group analogous to compounds of formula IX as defined in method a)) under the conditions given for hydrogenation of hydrazones obtained from compounds of formula XVI, or using complex hydrides such as sodium borohydride. The subsequent oxidation of the alcohols obtained is preferably carried out with oxidizing agents which make it possible to selectively (i.e. without further oxidation of the aldehydes to carboxylic acids) the aldehydes of the general formula XVIII or XVIII A, for example using K 2 F e O _Λ in aqueous solution as well as burel in organic solvents, or organic chromic acid derivatives, such as pyridinium dichromate or tert-butylidochromate, in organic solvents such as chlorinated hydrocarbons such as methylene chloride or chloroform in the presence or absence of basic amines such as three (lower alkyl) amines such as triethylamine, at temperatures of -50 to 100 ° C, preferably -10 to 50 ° C, for example under the conditions described in European patent application EP-A-O236734, or in particular by oxidation of a hydroxy group with a sulfoxide such as dimethylsulfoxide in the presence of carboxylic acid chloride; such as oxalyl chloride, in an inert solvent such as a chlorinated hydrocarbon such as dichloromethane and / or an acyclic or cyclic ether such as tetrahydrofuran at -80 to 0 ° C, for example -78 to -50 ° C.

131

Direct reduction of amino acids to aldehydes is also possible, for example by hydrogenation in the presence of a partially deactivated palladium catalyst or reduction of the corresponding amino acid ester, for example (lower and lower), such as ethyl ester, with complex hydrides such as borohydrides such as sodium borohydride, or preferably aluminium hydrides, such as lithium aluminum hydride, lithium tri (tert-butoxy) aluminum hydride or, in particular, diisobutyl and luminium hydride, in apolar solvents, for example in hydrocarbons or aromatic solvents such as toluene, at a temperature of -100 to 0 ° C, preferably -70 to -30 ° C, followed by reaction to the corresponding semicarbazones, for example with the corresponding salts of semicarbazides, such as semicarbazide hydrochloride, in aqueous solvent systems such as 1 and water, e.g. ethanol -water, at temperatures between -20 and 60 ° C, preferably between 10 and 30 ° C, ar reacting the obtained semicarbazone with an aldehyde, for example formaldehyde, in an inert, for example, a polar organic solvent, for example a carboxylic acid amide such as dimethylformamide, at temperatures between -30 and 60 ° C, preferably 0-30 ° C, and then with an acid, for example, a strong mineral acid, such as hydrohalic acid, in aqueous solution, optionally in the presence of the solvents previously used, at temperatures between -40 and 50 ° C, preferably between -10 and 30 ° C. Appropriate esters are obtained by reacting amino acids with the appropriate alcohols, for example ethanol, under conditions analogous to those used in the acylation of process a), for example by reaction with inorganic acid halides such as thionyl chloride in mixtures of organic solvents such as mixtures of aromatic and alcoholic solvents, for example toluene and ethanol, at temperatures between -50 and 50 ° C, preferably between -10 and 20 ° C (optionally using protecting groups).

with a relative solvent,

The preparation of compounds of formulas XVIII or XVIII A is particularly preferably carried out under conditions analogous to those described in J. Org.Chem. 47,3016 (1 982) and 1 e132 or in J.Or g.Chem. 43,3624. (1,978).

The sulfylide suitable for converting compounds of formulas XVIII or XVIII A into epoxides of formulas XIX or XIX A is, for example, diaphosphorylmethyllidyl, e.g. dimethylsulphonomethylthylidyl, alkyl or phenyldialkylalkyl. methyl or phenyldimethyl amide or 1-oxo-methylmethylamide, or dimethylsulfonomethyl-1-ylide, or dimethylsulfonomethyl-amide, e.g. dimethyl or diethylsulfoxonium methylide.

The corresponding sulfur-ylide compound may preferably be prepared in situ from the corresponding sulfonium or sulfoxonium salt and base, such as sodium hydride, in a dipolar aprotic solvent, for example dimethylsulfoxide, or in an ether, for example tetrahydrofuran or 1,2-dimethoxyethane, it may then be reacted with compounds of formula XVIII or XVIII A. This reaction is normally carried out at room temperature, with cooling, for example -20 ° C, or with moderate heating, for example up to 40 ° C. The co-formed sulfide, sulfinamide or sulfoxide may be separated during the subsequent aqueous treatment.

The reaction with sulfur-ylide is particularly preferably carried out under reaction conditions analogous to those described in J. Org.Chem.50,46 15 (1 985).

Compounds of formula XIX (preferably of formula XIXA) can be obtained from a compound of formula XVIIII (preferably of formula XVIIIA) as defined above by reacting it with a three (lower and 1-yl) 1-ylmethyl-Grignard compound, e.g. of an appropriate halogenomethylsilane, such as chloromethylsilane, in an inert solvent, for example ether, such as dioxane or diethyl ether, at temperatures between 0 and 50 ° C, for example at room temperature to about 40 ° C, followed by elimination when removing the silyl residue

133 and the formation of a double bond, for example using a Lewis acid such as BF ₃ , wherein preferably also the present protective function of the amino function R 10 is cleaved in an inert solvent such as an ether such as diethyl ether or a halogenated hydrocarbon such as dichloromethane or in a mixture thereof, at a temperature between -50 ° C and a reflux temperature, in particular between 0 and 30 ° C, optionally by new acylation upon introduction of the amine function as defined above, and oxidation of the resulting double bond to oxirane, preferably peroxycarboxylic acid. 1%, for example m-chloroperoxybenzoic acid, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, at temperatures between -20 ° C and the reflux temperature of the reaction mixture, for example at 10 to 30 ° C.

For example, a preferred starting material of formula (II) of process (a) or a salt thereof is prepared by adding the hydrazine derivative of formula (XVI) to an epoxide of formula (XVI) as defined above and the compound of formula (II ') with at least one salt-forming group. converted to a salt thereof, or the obtained salt is converted to a free compound or to another salt, and / or optionally the mixture of isomers obtained is separated and / or the protecting groups are cleaved in a compound of formula II; a compound of the invention of formula II.

The preparation and conversion of the salts, the separation of the isomeric mixtures, the cleavage of the protecting groups and the conversion of the compounds of the formula II 'are carried out according to procedures analogous to those described for the compounds of the formula I.

The starting materials of process (b), (c) and (d) can be prepared by known methods, for example compounds of formula IV can be prepared from hydrazines of novel derivatives of formula XIII in which R 0 is hydrogen and the other general symbols have the meanings given for compounds IV, 135

134 and epoxides of formula XIV, wherein the general symbols have the meanings given for the compounds of formula IV, followed by acylation of the obtained compounds of formula IV '.

in particular of formula IV

wherein the radicals have the meanings given for the compounds of formula (I) and wherein, instead of the radical Rs present in the compound of formula (IV), it is a free hydroxy group, carboxylic acid of formula (III) or an activated derivative thereof according to method (a) of formula IV for process b)). Compounds of formula (VI) may be obtained from hydrazines of novel derivatives of formula (XIII), wherein the formulas are as defined for compounds of formula (VI) and epoxides of formula (XIV) wherein R 1 is hydrogen and other formulas are as defined for of formula VI, followed by acylation of the compound of formula VI '

135 (70)

in particular of formula VI

wherein the radicals have the meanings given for the compounds of the formula I and in which, instead of the radical R s present in the compound of the formula VI, the free hydroxy group is a carboxylic acid of the formula III or an activated derivative thereof according to the method described in process a) of formula VI for process c)). Compounds of formula (VIII) may be obtained from hydrazines of novel derivatives of formula (XIII) in which Ra represents a hydrogen atom and other general symbols have the meanings given for compounds of formula (VIII) and epoxides of formula XIV in which R1 represents a hydrogen atom and other the symbols have the meanings given for compounds of the general formula IX and subsequent acylation of the compounds of the general formula VIII '

136 of formula VIII in particular

H

H (VIII) wherein the radicals have the meanings given for the compounds of formula I and in which, instead of the radical Rs present in the compound of formula IV, it is a free hydroxy group, carboxylic acid of formula III or another activated derivative thereof. a starting material of the formula VIIa for process d)) is obtained, whereby in the above-mentioned process, optionally protecting groups are introduced and then cleaved off. Preferably, the above methods employ both the S configuration of R ₃ and R ₅ , respectively, for the preparation of preferred compounds of formulas IV (via IV, VI (via VI) and VIII (via VIII) in which the carbon atoms bearing R ₃ and R 5 respectively). , epoxides of formula XIV A.

Compounds of formula I 'in which the substituents have the meanings given above may be prepared, for example, from a compound of formula XIII' 'N (XIII')

137 wherein the general symbols have the meanings given for the compounds of formula I by reaction with a compound of formula XIV, in particular XIV A (resulting in preferred compounds of formula I 'in which both the carbon atoms bearing R ₃ and R 5 are present in configuration S) by the procedure described for the reaction of compounds of formula XIII with compounds of formula XIV or XIV A, followed by acylation of the obtained compound of formula I

wherein the symbols have the meanings given for the compounds of formula (I '), a compound of formula (III) or an activated derivative thereof (preparation of acyloxy radical R 5) under reaction conditions analogous to those described under formula (II). which instead of the rest R? is a) of method a) (the analogue compound, the radical R '' is used instead of the compound), wherein the functional groups present not to be involved in the reaction are case protected and released after the reaction.

Of the starting compounds of formula II or II ', a compound of formula II is particularly preferred

On the one hand, it is a preferred intermediate in process (a) and, on the other hand, it is itself a preferred compound of the invention because it exhibits good pharmacological activity, in particular unexpectedly good activity in the cellular assay described above, indicating high activity in vivo.

Further compounds of formula (II) which possess advantageous pharmacological properties (especially those described in the introduction) and which therefore constitute preferred objects of the invention (also corresponding methods of these compounds, pharmaceutical preparations with these compounds, these compounds for use in therapeutic use) methods of treating the human or animal body and the use of these compounds for the therapeutic treatment of the human or animal body or for the manufacture of pharmaceutical preparations analogous to the corresponding subject-matter of the invention relating to the compounds of formula I are equally as in the case of compounds of formula II to the objects of the invention).

139

Preferred are compounds of formula II wherein R 1 is quinolin-2-ylcarbonyl- (L) -asparaginyl, R ₃ is hydrogen, R ₃ is phenylmethyl, 4- (lower alkoxy) phenylmethyl or 4-benzyloxyphenylmethyl R @ 1 is hydrogen, R @ 5 is hydrogen, R @ 5 is hydrogen; is phenylmethyl, 4- (lower alkoxy) phenylmethyl or cyclohexylmethyl, R 5 is hydrogen and R 10 is (lower alkoxy) carbonyl- (L) -valyl, (lower and 1 alkoxy) (lower alkoxy) (lower alkoxy) - (L) -valyl, phenyl (lower alkoxy) carbonyl- (L) -valyl, (lower alkanoyl) - (L) -valyl, benzylaminocarbonyl or a 1-kenyloxycarbonyl group in which the alkenyl the residue having 3 to 7 carbon atoms, or further a (lower alkoxy) carbonyl group, or a pharmaceutically acceptable salt thereof, in particular some of the following compounds of formula II selected from the group consisting of:

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) -amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- (N) -benzyloxycarbonyl) - (L) -vinyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) ~ (L) -asparaginyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / -2 / t. -butoxycarbonyl /

hydrazine,

3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl) - (L) -valyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / -2- / 2, 3-dimethyl-butyryl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (tert-butyl) .butylaminokarbonyl / hydrazine,

140

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / -2 / ethylaminocarbonyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / benzyl / 2- / N methyloxycarbonyl) - (L) -valy 1 / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / benzyl / 2- / N ethyloxycarbonyl) - (L) -valyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (benzyl) -2- (N-) benzyloxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / benzyl / 2- / N allyloxycarbonyl) - (L) -valyl /

hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (chinolír, 2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 (N-methyloxycarbonyl) - (L) vayl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 / N-benzyloxycarbonyl) - (L) -vinyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (quinolin-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 / N-allyloxycarbonyl) - (L) -vinyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (chinoli'n-2-carbonyl) - (L) -asparaginyl) amino-4- (4-methoxyphenyl) butyl / -1- / benzyl / 2- / N-methoxycarbonyl) - (L) -valyl / hydrazine,

1

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4- (4-methoxyphenyl) butyl / -1- / benzyl / - 2- / N-benzyloxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4- (4-benzyloxyphenyl) butyl / -1- / benzyl / - 2- / N-methoxycarbonyl) - (L) -valyl / hydrazine,

~ 1/2 (S) -hydroxy-3 (S) - (N- (chino1ín-2-carbonyl) - (L) -asparaginyl) amino-4- (4-benzyloxyphenyl) butyl / -1- / benzyl / - 2- / N-alyloxykarbony1) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 / N-methyloxycarbonyl) - (L) -vinyl / hydrazine, 1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4 -phenylbutyl [-1- (4-methoxyphenylmethyl) -2- (N-methyloxycarbonyl) - (L) -vinyl] hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 / N-allyloxycarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-benzy1oxyfenylmetyl / -2- / N-methyloxycarbonyl) - (L) -vinyl-hydrazine, 1- [2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino- 4-phenyl-butyl / -1- / 4-benzyloxyfenylmetyl / 2- / N-allyloxycarbonyl) - (L) -va1y1 / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / fenylmety1 / -2 / t. butoxycarbonyl / hydrazin,

142

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / phenylmethyl / 2- / N (2- (2-methoxyethoxy) -ethoxycarbonyl) - (L) -valyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 / t-butoxycarbonyl / hydrazine a

1- / 2 (S) -hydro.xy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 - (N-ethoxycarbonyl) (L) -valyl / hydrazine, and pharmaceutically acceptable salts thereof.

Also preferred are compounds of formula (II) wherein R 1 is (lower alkenyl) oxycarbonyl- (L) -valyl, each of R ₂ , R ₄ , R 6 and R 8 is hydrogen, R 5 is phenylmethyl, R 6 is phenyl; is cyclohexylmethyl and Ra is N- (lower alkenyl) oxycarbonyl- (L) -valyl, or pharmaceutically acceptable salts thereof, especially 1/2 (S) -hydroxy-3 (S) - (N-allyloxycarbones) 1- (L) -vinyl-amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- (N-allyloxycarbonyl) - (L) -valyl] hydrazine or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula II wherein R 1 is (lower alkoxy) (lower alkoxy) (lower alkoxy) carbonyl, each of R 6, R 6, R 5 and R 5 is hydrogen, R 5 is phenylmethyl, R 5 is phenyl; ? is cyclohexylmethyl and R5 is (lower and 1 alkoxy) (lower alkoxy) (lower alkoxy) carbonyl- (L) -valyl, or a pharmaceutically acceptable salt thereof, especially 1/2 (S) ) -hydroxy-3 (S) - (N (2- (2-methoxyethoxy) ethoxy) carbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (2 - (2-methoxyethoxy) ethoxy) carbonyl) - (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof.

143

Compounds of formula II, wherein R is (lower 1koxy a) (f add Si and 1koxy) (n A d d alkanoyl) (L) -valylovú group, each of the radicals R, R ', R _e, and R @ ₈ is hydrogen, R @ ₃ is phenylmethyl, R @ ₈ is hydrogen; represents cyclohexylmethyl and R 5. means (lower alkoxy) (lower and 1 alkoxy) (lower alkoxy) carbonyl- (L) -valyl group, or pharmaceutically acceptable salts thereof, especially 1- / 2 (S) -hydroxy-3 (S) (N-) (2-methoxyethoxy) acetyl- (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (2-methoxyethoxy) acetyl- (L) -valyl] hydrazine (highly preferred) or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula II wherein R 1 and R ₉ independently of one another are acetyl- (L) -vinyl, methoxycarbonyl- (L) -valyl, ethoxycarbonyl- (L) -valyl, dimethylaminocarbonyl- (L) -vinyl group, (2-methoxyethyl) aminocarbonyl- (L) -valyl group, N (2-morpholin-4-ylmethyl) aminocarbonyl- (L) -valyl group, or N- (2-morpholinyl-4-ylethyl) -N-methylaminocarbonyl- (L) -vinyl, each of R ₂ , R ₄ , R 5 and R 5 is hydrogen, R 5 is phenylmethyl and R ₇ is thiene- A 2-ylmethyl group or a 2,3,5,6-tetrahydropyran-4-ylmethyl group, or a pharmaceutically acceptable salt thereof, in particular one or more compounds selected from the group consisting of:

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / thien-2-ylmethyl / 2- / N-acetyl ) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / thien-2-ylmethyl / 2- / N-methoxycarbonyl - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / thien-2-ylmethyl / 2- / N-ethoxycarbonyl - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) -valyl) amino-4-phenylbutyl [-1- (thien-2-ylmethyl)] - 2- / N- (N, N-dimethylamino-144 carbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N-2-metoxyety'i) aminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 2-thien ylmety1 / 2- / N- (N- (2-methoxyethyl) aminocarbonyl (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vinyl) amino-4-phenylbutyl) -1- (Thien-2-ylmethyl) -2- [N (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl] hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino-4-phenylbutyl (-1-) Thien-2-ylmethyl) -2- N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -vinyl) hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acety1- (L) -valy1) amino-4-fenylbuty1 / of 1- / 2,3,5,6-tetrahydro-4-y1metyl / - 2- / N-acety1) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-fenylbuty1 / -1 / 2,3,5,6-tetrahydropyran-4-ylmethyl ' l / 2- / N-methoxycarbonyl- (L) -va1yl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-etoxykarbony1- (L) -va1y1) amino-4-phenyl-butyl / -1- / 2,3,5,6-tetrahydro-4-ylmety1 / 2- / N-ethoxycarbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimetylaminokarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 2,3,5,6-tetrahydropyrari 4-y1metyl / -2 / N (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- / 2,3,5 6-tetrahydropyran-4-ylmethyl / 2- [N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl] -hydrazine,

145

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) valyl) amino-4-phenylbutyl / -1 - (2,3,5,6-tetrahydropyran-4-ylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) valyl] -hydrazine and

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl-N-methylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl / -1 / 2,3,5,6-tetrahydropyran-4-ylmethyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl N -hydrazine and pharmaceutically acceptable salts thereof.

Also preferred are compounds of formula II wherein R 1 and R 2 and independently of one another are acetyl- (L) -valyl, methoxycarbonyl- (L) -valyl, ethoxycarbonyl (L) -valyl, dimethylaminocarbonyl- (L) -valyl, (2-methoxyethyllaminocarbonyl) aminocarbonyl- (L) -valyl, N- (2-morpholin-4-ylethyl) aminocarbonyl- (L) -valyl or N- (2-morpholin-4-ylethyl) - N-methylaminocarbonyl- (L) -valyl, each of R ₌ , _RΛ , R ₆ and R s is hydrogen, R a is phenylmethyl, and R?? Is hydrogen; means 4 hydroxyphenylmethyl, 4-methoxyphenylmethyl, 4-isobutoxyphenylmethyl, 4-benzyloxyphenylmethyl, 3,4-dimethoxyphenylmethyl, methylene-4,5-dioxyphenylmethyl, 4- (2-methoxyethoxy) phenylmethyl or phenylmethyl; a group, or a pharmaceutically acceptable salt thereof, in particular one or more compounds selected from the group consisting of:

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl) - (L) -valyl) amino-4-phenyl butyl / -1- (4-hydroxyphenylmethyl) -2- (N-ethoxycarbonyl) - (L) - va 1 y 1 / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 4-hydroxyphenylmethyl / 2- / N-methyl / -2 / N (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

146

1- / 2 (S) -hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 4-hydroxyphenylmethyl / -2 - / N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) 1- / 4-hydroxyphenylmethyl / -2 / N (N (2-morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl-N-methylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl / -1- (4-hydroxyphenylmethyl) -2- [N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl] -hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acety1- (L) valyl) amino-4-phenylbutyl / of 1- / 4-methoxyphenyl-methyl / 2- / N-acetyl- (L) -valyl / -hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenyl butyl / -1- (4-methoxyphenylmethyl) -2- (N-methoxycarbonyl) - (L) -valyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / 2- / N-ethoxycarbonyl- (L ) -valyl / hydrazine (particularly preferred),

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 / N- (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 4-methoxyphenyl-methyl / -2 - / N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2) morpholin-4-yl-ethyl) aminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 4-Methoxyphenylmethyl] -2- N - (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl] -hydrazine

147

1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-ylethyl) -N-methylamino carbonyl) - (L) -valyl) amino-4-phenylbutyl) 1- / 4-methoxyphenyl-methyl /

2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) valyl) amino-4-phenylbutyl / of 1- / 4-benzyloxyfenylmetyl / 2- / N-acety1- (L) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4-benzyloxyfenylmetyl / 2- / N-methoxycarbonyl- (L ) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valy1) amino-4-phenyl-butyl / -1- / 4-benzyloxyfenylmetyl / 2- / N-ethoxycarbonyl- (L ) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 4-benzyloxyfenylmetyl / -2- / N- (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl (L) valyl) amino-4-phenyl-butyl / -1- / 4-benzyloxyfenylmetyl / 2- / N (N (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1 - (4-Benzyloxyphenylmethyl) -2- N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl] -hydrin,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholino-4-yl) ethyl) methylaminocarbonyl)) - (L) -vinyl) amino -4-phenylbutyl] -1- (4-benzyloxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) (L) -valyl] -hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4- (3,4-dimethoxybenzyl) oxyfenylmetyl / -2 / N-acetyl- (L) -v148 lyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4- (3,4-dimetoxybenzylloxyfenylmetyl / 2- / N - methoxy carbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl butyl / -1- [4- (3,4-dimethoxybenzyl) oxyphenylmethyl] -2 - / N-ethoxycarbonyl- (L) -va1yl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) -valyl) mino-4-phenylbutyl) -1- / 4- (3,4) dimethoxybenzyl) oxyfenylmetyl / -2 / N (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- / 4- (3, 2-methylbenzyl) 4-dimethoxybenzyl) oxyphenylmethyl] -2- [N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl] hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) valyl) amino-4-phenylbutyl / -1 - [4- (3,4-Dimethoxybenzyl) oxyphenylmethyl] -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino-4- phenylbutyl] -1- [4- (3,4-dimethoxybenzyl) oxyphenylmethyl] -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) - valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) valyl) amino-4-phenylbutyl / of 1- / 4-izobutyloxyfenylmetyl / 2- / N-acetyl- (L) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4-izobutyloxyfenylmetyl / 2- / N-methoxycarbonyl- (L ) -valyl / hydrazine

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- (4-isobutyloxyphenylmethyl) -2- [N-ethoxycarbonyl- ( L) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) -valyl) and mino-4-phenylbutyl / -1- (4-isobutyloxyphenylmethyl) -2- N- (N, Ndimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl (L) valyl) amino-4-phenyl-butyl / -1- / 4-izobutyloxyfenylmetyl / -2 - / N (N (2-methoxyethyl) aminokarbony1) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl (-1- (4-isobutyloxyphenylmethyl) -2-) N- (N- (2-morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vinyl) hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morfo1ín-4-yl) ety1) -N-methylaminocarbonyl) - (L) valyl) amino-4-phenyl-butyl (-1- (4-isobutyloxyphenylmethyl) -2-) N- (N- (2-morpholin-4-yl) ethyl) -N-methylaminocarbonyl) (L) -valyl) hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4- (2-methoxyethoxy) phenylmethyl / 2- / N acetyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) am1no-4-phenyl-butyl / -1- / 4- (2-methoxyethoxy) phenylmethyl / -2 / M -metoxykarbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- / 4- (2-methoxyethoxy) phenylmethyl / -2 / N -ethoxycarbonyl (L) -vinyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dímetylaminokarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4- (2-methoxyethoxy) phenylmethyl / 2- / N- (N, Ndimetylaminokarbonyl) - (L) -valyl / hydrazine,

150

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-metoxyety1) aminokarbony1- (L) valyl) amino-4-phenyl-butyl / -1- / 4- (2-methoxyethoxy ) phenylmethyl / -2 / N (N (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (4-morfo1ín-yl) ethyl) aminocarbonyl) - (L) valyl) amino-4-phenylbutyl / -1 - [4- (2-methoxyethoxy) phenylmethyl] -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vinyl] hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-metylaminokarbonyl- (L) valyl) amino-4-phenylbutyl / -1- [4- (2-methoxyethoxy) phenylmethyl] -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) valyl) amino-4-phenyl-butyl / -1- / methylene-3,4-dioxyfenylmetyl / 2- / N-acetyl ) - (L) -valy 1 / hydrazine,

1- (2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenyl butyl) -1- (methylene-3,4-dioxyphenylmethyl) -2- / N-methoxycarbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- / methylene-3,4-dioxyfenylmetyl / 2- / N ethoxycarbonyl (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) -valyl) and mino-4-phenylbutyl] -1- (methylene-3,4-dioxyphenylmethyl) N- (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl (L) valyl) amino-4-phenyl-butyl / -1- / methylene-3,4- dioxyfenylmetyl / -2 / N (N (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl-ethyl) aminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / methylene-3,4-dioxyphenylmethyl / -2- / N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vertiaryl / hydrazine η 1,1- (S) -hydroxy-3 (S) - (N- (N- (N- (2- (morpholin-4-yl) ethyl) -N-aminocarbonyl) - (L) -vinyl) amino-4-phenylbutyl)) -1- (methylene-3,4-dioxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) methylaminocarbonyl) - (L) vayl] hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) -valyl) aiľiino-4-phenylbutyl / of 1- / 3,4-dimethoxyphenylmethyl / 2- / N-acetyl- ( L) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 3,4-dimethoxyphenylmethyl / 2- / N-methoxycarbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- / 3,4-dimethoxyphenylmethyl / 2- / N-ethoxycarbonyl- (L) -vinyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / 3,4-dimethoxyphenylmethyl / -2 - / N- (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -v and 1 yl)

-amino-4-phenylbutyl / -1- (3,4-dimethoxyphenylmethyl) -2- [N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl] hydrazine, 1- / 2 (S) - hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- / 3,4- dimethoxyphenylmethyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino-4-phenylbutyl] - 1- (3,4-dimethoxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) (L) -valyl] -hydrazine,

152

1- / 2 (S) -hydroxy-3 (S) - (N-acetyl- (L) -valyl) - amino-4-phenylbutyl / 1- (4-biphenylmethyl) -2- (N-) acetyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / 4-biphenylylmethyl / 2- / N-methoxycarbonyl- (L ) -valyl / hydrazin,

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- / 4-biphenylylmethyl / 2- / N-ethoxycarbonyl- (L ) -valyl / hydrazin;

1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-fenylbuty1 / 1- / 4-biphenylmethyl / 2- / N- (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N-ethyl) aminocarbonyl) - (L) -valyl)

amino-4-phenyl-butyl / -1- / 4-biphenylmethyl / 2- / N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-aminocarbonyl) - (L) valyl) amino-4-phenyl-butyl [1- (3,4-Biphenylmethyl) -2-] N (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl / hydrazine and

1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino -4-phenylbutyl] -1- (4-phenylmethyl) 2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl] hydrazine, and pharmaceutically acceptable salts thereof.

Compounds of formula II in which R, and R ₉ represent methoxycarbonyl- (L) -valylovú group, each of the radicals R _z, R ₄₎ R _e, and R is H, R ₃ is phenylmethyl and R ₇ is 4- (lower alkoxy) phenylmethyl or 4-benzyloxyphenylmethyl, or a pharmaceutically acceptable salt thereof.

153

Finally, the following compounds of formula II are preferred:

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-ethoxycarbonyl- (L) - valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-trifluoroacetyl- (L) -valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-trifluoroacetyl- (L) - valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) -vinyl / hydrazine, 1- (2 (S) -hydroxy-3 (S) - (N- (n-propyloxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- / N - (n-propyl) oxycarbonyl (L) -vinyl / hydrazine, 1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1 / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) -valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) -valyl / hydrazine, 1- (2 (S) -hydroxy-3 (S) - (N- (benzyloxycarbonylamino) -4-phenylbutyl))

-1 / phenylmethyl / 2- / N-methoxycarbonyl- (L) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-cyclohexylbutyl / -1 / phenylmethyl / 2- / N-methoxycarbonyl) - (L) -valyl / -hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) valyl) amino-4-cyclohexylbutyl / 1- / 4-methoxyphenyl-methyl / 2- / N-methoxycarbonyl) - ( (L) 1 54 valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-cyclohexylbutyl] -1- (4-isobutyloxyphenylmethyl) -2- (N-methyloxycarbonyl) (L) -v 1-yl-hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-cyclohexylbutyl) -1- (4-ethoxyphenylmethyl) -2- (N-methyloxycarbonyl) - (L) valyl / hydrazine,

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-cyclohexylbutyl) -1- (4-benzyloxyphenylmethyl) -2- (N-methyloxycarbonyl) ( L) - 1-yl / - hydrazine, and / or

1- (2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenyl butyl) -1- (cyclohexylmethyl) -2- (2-pyridylcarbonyl)) hydrazine or their pharmaceutically usable salts.

The preparation of the compounds of the formula II, in particular the preparation according to the invention of the compounds of the formula II, is carried out for example

i) analogously to the reaction of the starting materials of the formula XIII with the compounds of the formula. XIV A according to the procedure described for the preparation of compounds of formula II, wherein in the case of compounds of formula II ', the symbols in the starting compounds have the meanings given for the compounds of formula I, whereas in the case of compounds of formula II .? R is hydrogen, R is benzyl, and Ry is cyclohexylmethyl; or R @ ₃ is N-methoxycarbonyl- (L) -valyl, R @ 2, R @ ₄ , R @ 6 and R @ 6 are hydrogen;

Ii) analogously to process b), in which the compounds of the formula IV 'as defined above are used instead of the starting materials of the formula IV', in particular of the formula IV, wherein in the preparation of the compounds of the formula II ' IV ', while in the preparation of the compounds of formula II, R 1 and R ₉ ' in the starting materials are N-methoxycarbonyl- (L) -buttons, R =, R ₄ , R 6 and R 5 are hydrogen, R 3 is benzyl and R? or (iii) analogously to process (c), in which compounds of formula (VI '), in particular formula (VI), as defined above, are used in place of the starting materials of formula (VI), wherein in the preparation of compounds of formula (II) 'have the general symbols given for the compounds of the formula VI', while in the preparation of the compounds of the formula II R 1 'and R 0' in the case of large-scale disks are N-methoxycarbonyl- (L) -valyl , R ₂ , R ₄ , R e and R a represent a hydrogen atom, R ₃ represents a benzyl group and R represents a cyclohexylmethyl group, or iv) by analogy to the method of using compounds of formula VIII 'instead of starting materials of formula VIII', in particular of formula (VIII) as defined above; the general symbols have the meanings given for the compounds of the general formula (VIII '), while in the case of the preparation of the compounds of the general formula (II), R''andR''' R ₁ , R ₂ , R ₄ , R 6 and R 6 are hydrogen in the starting materials, R ₃ is benzyl, are cyclohexylmethyl, or

(v) analogously to process (e), in which compounds of the formula IV ', in particular of the formula IV, as defined above, are used instead of the starting materials of the formula IV, wherein in the preparation of the compounds of the formula II' for compounds of formula (I), while in the preparation of compounds of formula (II), R 1 and R 2 _and in the starting compounds are N-methoxycarbones 1- (L) -valyl, R ₂₎ R a, R e and R e are hydrogen R ₃ represents a benzyl group and R 7 represents a cyclohexylmethyl group, or vi) in the case of the use of protected starting materials, for example in any of the above processes, by cleavage of the protecting groups by a procedure analogous to method f).

The compound of formula II ', in particular of formula II, obtained by any of the processes i) to vi) above may optionally be converted to a salt, or the obtained salt of this compound may be converted to a free compound or to another salt and / or the resulting isomeric mixtures are separated and / or one compound of the invention of formula II ', in particular of formula II, is converted into another compound of the invention of formula II', in particular of formula II. The conditions of these reactions correspond to the conditions set out in the dodotion procedure for the compounds of formula I.

The preparation of the compounds of the formula II according to the invention is particularly preferably carried out using compounds of the formula VIII, in which R ₂ , R, R 6 and R 8 are hydrogen, R 5 is benzyl and R 6 is hydrogen; represents a cyclohexylmethyl group, and N-methoxycarbonyl- (L) -vinyl or a reactive derivative thereof (corresponding to a compound of formula V and VII, wherein R8 and R8 are N-methoxycarbonyl- (L) -vinyl) in a manner analogous to that described above.

Acids of formulas III, V, VII and IX, derivatives thereof, for example of formulas V ', V or IX', as well as compounds with nucleophagous groups of formula Xa,

157

X b, X 1a, X 1b and XII are commercially available and known or, when new, are known to be known by the art, for example analogous to those of the Examples using appropriate starting materials. The same applies to all other starting substances.

By way of example, the preparation of an aryl 1 (lower alkane) acid substituted with a heterocyclylmethyl group, which is bonded via a ring nitrogen atom (compound of formula III), is preferably carried out by reacting an aryl 1 (lower alkanoyl) radical substituted with a halomethyl group. as a chlorine or bromomethyl group such as a chloromethylbenzoyl residue or a bromomethylbenzoyl residue with an appropriate heterocyclic nitrogen base such as piperidine, piperazine, 1- (lower alkyl) piperazine, 1- (lower alkanoyl) piperazine or especially morpholine or thiomorpholine, at the nucleotide of another halogen atom substitution.

The preparation of an amino acid derivative of the formulas III, V or VII in which α 1 -amino group is alkylated with a radical selected from the group consisting of phenyl (lower and alkyl) or heterocyclyl (lower alkyl) residues, for example is carried out by reductive amination of an amino acid (optionally protected on other groups not to be involved in the reaction) having a primary or secondary α-amino group, using a phenyl (lower and lower alkyl) -ketone or -aldehyde such as benzaldehyde or heterocycle 1 Y 1 (lower and 1 alkyl) ketone or -aldehyde, for example heterocyclylaldehyde, such as furanaldehyde, such as furan-2-aldehyde, or pyridinaldehyde, such as pyridine-3-aldehyde, for example in catalytic hydrogenation, for example in the presence of catalyst heavy metal, such as Raney nickel, at normal pressure or at a pressure of from 0.1 to 10 MPa, preferably at a pressure of about 10 MPa, or by reduction with complex b hydrides such as sodium cyanoborohydride d.

58

For example, isocyanates of formulas IX 'and V can be prepared from the corresponding amine prodrugs by converting the amino group to an isocyanate group, for example by reacting with phosgene hot, for example by heating the reaction mixture to reflux, or dropwise. of a liquid or solvent-dissolved primary, secondary or tertiary amine to an excess of phosgene in a suitable solvent (toluene, xylene, ligroin, chlorobenzene, alpha-chloronaphthalene and the like) under cooling (e.g. to -50 to 0 ° C), to form a mixture of carbamoyl chloride and aminohydrochloride, which is then further phosgenised at elevated temperature (e.g., 50 ° C to reflux) until complete dissolution while eliminating HCl.

For all of the above and below, the following generally applies:

In view of the close relationship between the compounds of the formula I and their salts and starting materials (starting materials intermediates) in free form and in the form of their salts, in the preceding and following text the free compounds or their salts are also understood to be corresponding salts or salts. free compounds.

All of the above process steps may be carried out under known, preferably specific, reaction conditions, in the absence or usually in the presence of solvents or redid 1, preferably those solvents or diluents which are inert to the reactants used and which dissolve the reactants. the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, such as cation exchangers, for example in the form of H, depending on the type of reaction and / or reactants at reduced, normal or elevated temperature, for example at about -100 ° C to about 190 ° C, preferably at a temperature from about -80 ° C to about 150 ° C, for example at -80 to -60 ° C, at room temperature, at -20 to 40 ° C or at reflux temperature, at atmospheric pressure or in a closed vessel, optionally at pressure and / or inert under an argon or nitrogen atmosphere.

In all the reaction steps, the isomeric mixtures occurring can be separated into individual isomers, for example the diastereomers or enantiomers, or to any mixture of isomers, for example racemates or di-stereoisomeric mixtures, for example by procedures analogous to those described in the additional process steps.

In certain cases, for example hydrogenation, stereoselective reactions can be achieved so that, for example, individual isomers are easier to obtain.

Solvents suitable for this type of reaction include, for example, water, esters such as (lower alkyl) (lower and 1 k) oxides, such as ethyl acetate, ethers such as aliphatic ethers, such as diethyl ether, or cyclic esters, such as tetrahydrofuran , liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, acid amides such as dimethylformates d, bases such as heterocyclic nitrogen bases such as pyridine, carboxylic acid anhydrides such as lower alkane anhydrides, such as acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentene, or mixtures of these solvents, such as aqueous solutions, if not specified otherwise. such solvent mixtures may also find use in processing operations, for example in chromatography or separation of substances.

Said compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may contain, for example

160 solvent used in the crystallization.

The invention also relates to those embodiments of the process starting from a compound which is obtained in any reaction step as an intermediate, carrying out the remaining reaction steps or using a starting material formed under the reaction conditions or in the form of derivatives, for example in protected form or as a salt, or under the process conditions a compound is prepared by the process of the invention which is further processed in situ. In the process according to the invention, preference is given to starting materials which lead to the compounds which have been described as particularly valuable at the outset (compounds of the formula I or II). Particularly preferred are reaction conditions analogous to those set forth in the examples.

If desired, protected starting materials can be used in all process steps, with the protective groups removed in suitable reaction steps.

Protecting groups, their introduction and cleavage are described under methods a) and f).

Pharmaceutical preparations

The invention also relates to pharmaceutical compositions comprising compounds of formula I (in particular compounds mentioned as preferred) or compounds of formula II.

The pharmacologically usable compounds of the invention may be used, for example, for the manufacture of pharmaceutical compositions comprising an effective amount of the active ingredient together or in admixture with a significant amount of an inorganic or inorganic, solid or liquid, pharmaceutically acceptable carrier.

The invention also includes a pharmaceutical composition (preparation) suitable for administration to a warm-blooded animal,

161 in particular for the treatment or prevention of a disease which is influenced by the inhibition of a retroviral protease, in particular a retroviral aspartate protease such as HIV-I- or HIVII-gag protease, for example a retroviral disease such as AIDS and which contains a protease effective amount of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention are those for enteral, such as nasal, buccal, rectal or oral, or parenteral, such as intramuscular or intravenous administration to warm-blooded animals (humans and animals), which contain an effective dose of the pharmacologically active agent alone or together with a significant amount. a pharmaceutically usable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, its body weight, age and individual condition, the individual pharmacokinetic properties, the disease to be treated and the route of administration.

The invention also relates to a method of treating diseases caused by viruses, in particular retroviruses, for example AIDS, which comprises administering to a warm-blooded animal, for example a human, in need of such treatment, of the compounds of the formula I or II. Dosages for administration to a warm-blooded animal, such as a human having a body weight of about 70 kg, are between about 3 mg and about 3 g, preferably between about 10 mg and about 1.5 g, for example about 100 mg to about 1000 mg, per person; The dose is preferably subdivided into 1 to 3 parts e of the dose, which may, for example, be of equal size. A child usually receives half the adult dose.

Said pharmaceutical preparations contain about 1 to 95%, preferably about 20 to about 90% of the active ingredient. The pharmaceutical compositions of the invention may be presented, for example, in unit dosage form such as ampoules, vials, lace, dragees, tablets or capsules.

The pharmaceutical preparations according to the invention are prepared in a known manner, for example by means of conventional solution, lyophilization, mixing, granulation or coating processes.

Preferably, solutions of the active substance and, in addition, suspensions or dispersions, in particular isotonic aqueous solutions, dispersions or suspensions, are used, these formulations being, for example, in the case of hydrophilic formulations containing the active substance alone or together with a carrier. , such as mannitol, prepared immediately prior to use. These pharmaceutical preparations may be sterilized and / or contain adjuvants, for example preservatives, stabilizers, wetters, and / or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and / or buffers, and may be prepared in a known manner, for example by conventional dissolving or The isolation procedures. Said solutions, dispersions or suspensions may contain viscosity enhancers such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain the vegetable, synthetic or semi-synthetic oils conventionally used as the oil component for injection purposes. Examples of such oils are, in particular, liquid fatty acid esters which contain, as the acid component, a long chain fatty acid containing 8 to 22, in particular 12 to 22 carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids such as oleic acid,

Elaidic acid, erucic acid, brasidic acid or linoleic acid, optionally with the addition of antioxidants such as vitamin E, beta-carotine or 3,5-di-tert-butyl-4-hydroxy-toluene. The alcohol component of these fatty acid esters has at most 6 carbon atoms and is composed of a mono- or polyvalent, for example mono-, di- or trivalent alcohol, for example methanol, ethanol, propanol, butanol or pentanol or pentanol or isomers thereof, in particular glycol and glycerin. . The fatty acid esters mentioned include, for example, ethyl oleate, isopropyl myristate, isopropyl palmitate, Labrafil M 2375 (polyoxyethylene glycerin trioleate from Gattefossé, Paris), Myglyol 312 (a triglyceride of saturated fatty acids having a chain length of 8 to 12 carbon atoms, Germany) ), but in particular vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and, in particular, ground oil.

The preparation of injectables is carried out in a conventional manner under sterile conditions, as well as filling ampoules or vials and sealing them.

Pharmaceutical preparations for oral use can be obtained by mixing the active ingredient with solid carriers, the resulting mixture optionally being granulated, and after adding suitable excipients, if desired or necessary, to form tablets, dragees or capsules. It is also possible to incorporate the active substances into plastic carriers, which then release the active substance in a controlled manner or let it diffuse in a controlled manner into the physiological environment.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, for example tricalcium phosphate or dibasic calcium phosphate, and binders, such as starch oils based on, for example, corn, wheat. 64 starch, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or, if desired, swelling agents such as the aforementioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, for example sodium alginate. The auxiliaries are, in particular, lubricants and glidants which are used, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings which are resistant to gastric juices, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable formulations. organic solvents or, in the preparation of gastric juice-resistant coatings, also solutions of suitable cellulosic preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The capsules are gelatin insertion capsules as well as soft sealed capsules of gelatin and plasticizers such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, in which case stabilizers and / or antibacterial agents may also be added. Dyestuffs or pigments may be added to the tablets, dragee coatings and capsule shells, for example to identify and distinguish different doses of the active ingredient.

In the following, the invention will be further elucidated by means of examples of specific embodiment thereof, which are illustrative only and not in any way limit the scope of the invention, which is clearly defined by the terms of the claims.

Temperatures are given in degrees Celsius (° C). If no temperature is indicated, the reaction is carried out at room temperature. The R + - values, which give the ratio of start-to-start distances of a given substance, are determined by thin layer chromatography using silica gel thin-layer plates and the following elution systems:

And chloroform / methanol / water / acetic acid

B chloroform / methanol / water / acetic acid

C chloroform / methanol / water / acetic acid

D chloroform / methanol

E chloroform / methanol

F hexane / ethyl acetate

G methylene chloride / diethyl ether / methanol

Methylene or diethyl ether

Toluene / ethyl acetate

K chloroform / methanol

J Methylene or id / diethyl ether

L hexane / ethyl acetate

M hexane / ethyl acetate

N hexane / ethyl acetate ethyl acetate

Methylene chloride / ethanol / aqueous NH 3

Q methylene chloride / diethyl ether

R hexane / ethyl acetate

Methylene or diethyl ether

T chloroform / methanol

U chloroform / methanol

In methylene chloride / diethylether r / h exane

75: 27: 5: 0.5

90: 10: 1: 0.5

85: 13: 1.5: 0.5 8: 1 95: 5 2: 1

20: 20: 1: 1: 1: 1: 1: 1: 1: 1

90: 10: 1 10: 1 3: 1

20: 1: 1

15: 1

1: 1: 3

166

W methylene chloride / diethyl ether 20: 1 x methylene chloride / methanol 40: 1 Y toluene / ethyl acetate That made the score 4 - 1 from methylene chloride / methanol 30: 1 A ' methylene chloride / methanol 15: 1 B ' methylene chloride / methanol 10: 1 C ' hexane / ethyl acetate 1: 3 D ' ethyl acetate / ethanol 100: 3 E ' ethyl acetate / ethanol 20: 1 F ' ethyl acetate / ethanol 10: 1 G ' methylene chloride / methanol 9: 1 H ' ethyl acetate / hexane 3 - 2 I ' methylene chloride / methanol 12: 1 J ' methylene chloride / methanol 19: 1 K ' methylene chloride / diethyl ether / methanol 10:10

For example, R ŕ (A) means that the R τ value was determined in the elution system A. The ratios of the individual solvents are given in parts by volume.

Gradients used in high pressure liquid chromatography:

20% to 100% a) in b) within 35 minutes,

II 0% to 40% a) in b) within 30 minutes,

III 20 to 60% a) in b) within 60m minutes,

10% to 50% a) in b) within 60 minutes and

20% to 1000% a) in b) within 20 minutes.

E1 learning agent (a): acetonitrile + 0.05% TFA; eluent b): water + 0.05% TFA. The column with a size of 250 x 4.6 mm is filled with reversed phase material formed _with a C 1 -Nuc1eosi om (5 / um average particle size, silica gel covalently derivatized with a oktadecy1 1anmi, and Machery Nagel, Düren, Federal Republic of Germany). Detection is by absorption in UV light with a wavelength of 21 nm. The retention time (t rt) is given in minutes. The liquid flow rate is 1 ml / ml n.

167

The following abbreviations have the following meanings:

Boe Boc! BOP benzotriazol-1-yloxy-tris (dimethylamino) fosfóniumhexa- f 1 fluorophosphate DCC dicyclohexylcarbodiimide d DMAP dimethylaminopyridine DIPE diisopropyl ether DMF dimethylformam i d DMSO d i met 1 s u 1 fox i d EDC N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride r id ether d i ethyl ether HBTU 0-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium-hexa- f 1 fluorophosphate HOBt 1-hydroxybenzotriazole NMM N-methylmorpholine s o l a n k a . saturated sodium chloride solution THF tetrahydrofuran TFA trifluoroacetic acid FROM benzyloxycarbonyl.

Mass spectra values were determined either by covalent mass spectroscopy or by using fast atom ionization (Fast Atom Bömbardment-FAB-MS). Mass data refer primarily to unprotonated molecular ion (M) * or to protonated molecular ion (M + H) *.

The values of proton nuclear magnetic resonance spectroscopy are given in parts per million (ppm) and refer to tetrametes 1 sec / l as an internal standard. In these spectra, the abbreviations have the following meanings:

s = s i ng1et, d = dub 1et, t = tr i p 1 et,

168 q = quartet, m = m at 11 i p 1 e t, dd - double doublet.

Infrared spectral data are given in cm ^-1 , with the solvent used in parentheses. As mentioned, it means s strong, m moderate and w weak intensity of the respective bands.

The residue - - (Phe ^NN Phe) represents the divalent radical 3 (S) -amino-4-phenyl-1- (N-benzylhydrazino) butan-2 (S) -ole and has the formula

CK

The residue - (Phe ^NN Cha) represents the divalent radical 3 (S) amino-4-phenyl-1- (N-cyclohexylmethylhydrazino) butan-2 (S) -ole and has the formula

OH

NH169

The residue - - (Phe ^NN Leu) represents the divalent radical 3 (S) amino-4-phenyl-1- (N-isobutylhydrazino) butan-2 (S) -ole and has a pattern of

The residue - - (Phe ^NN N1e) represents the 3 (S) -amino-4-phenyl-1- (Nn-butylhydrazino) butan-2 (S) -ole radical and has the formula

The residue - (Phe ^NN (pF) Phe) denotes the bivalent radical 3 (S) -amino-4-phenyl-1- (N- (p-fluorophenylmethyl) hydrazino) butane-2 (S) -ole and has the formula

170

The residue - - (pF) Phe ^NN (pF) Phe] represents the divalent radical 3 (S) -amino-4- (p-fluorophenyl-1- (N- (p-fluorophenylmethyl) hydrazino) butane-2 (S)) -ol and has the formula

The residue - - (Phe ^NN (p-CN) Phe) represents a divalent radical

3 (S) -amino-4-phenyl-1- (N- (p-cyanophenylmethyl) hydrazino) butane 2 (S) -one and has the formula

The remainder - (Cha ^NN Leu) denotes a bivalent radical

3 (S) -amino-4-cyclohexyl-1- (N-isobutylhydrazino) butan-2 (S) -ole and has the formula

The 1- (2) (S) -acetoxy-3 (S) -amino-4-phenylbutyl] - (1 cyclohexylmethyl) hydrazine bivalent radical has the formula

Abbreviations common in peptide chemistry are used to denote the divalent radicals of natural alpha-amino acids. However, this occurs for amino acids that stand in the compound names to the right of - (Phe ^NN Leu), - (Phe ^NN Nle), Phe (), - / Phe ^NN (p-CN) Phe (radicals ~ (Phe ^NIM Phe), - / Phe ^NN Cha /,

- (Phe ^NN (pF) Phe), (pF) P he ^NN (pF) deviation from the or - (Cha ^NN Leu), an arched peptide nomenclature, with an amino terminus on the left and a carboxy terminus on the right, when at the indicated

The 172 compounds stand for the carboxy-linking group on the left, which is indicated by an arrow (<-), which symbolizes the reverse direction of the bond.

The configuration on the alpha-carbon atom, if known, is indicated by the prefixes (L) - or (D) -. The tyrosine radical, etherified at the hydroxy group R, is designated Tyr (OR). No means norleucine radical.

Reference example 1

Boc / Phe ^NIM Ph / Boc

A solution of 300 mg (1.14 mmol) of (2R) - / 1 '(S) -8C-amino-2'-phenylethyl / oxirane (J. Org. Chem. 50, 4615 (1985) and 253 mg (1.14 mmol) of tert-butyl-3-benzylcarbazate (J. Chem. Soc., Perkin I, 1712 (1975)) in 4 ml of methanol are heated at reflux for 12 hours. After cooling the reaction mixture to 0 ° C, a substantial portion of the desired compound precipitated, the mother liquor was concentrated and the residue was dissolved in a small amount of methanol, followed by the dropwise addition of hexane as a white precipitate.

Mass spectrum (F-ionization): (M + H) + = 26.8, t Ret (I) - 26.3 min,

Rf (E) = 0.70.

Reference example 2

Z- (L) -Va1- / Phe ^NN Phe / <- ((L) -Val-Z)

191 mg (0.76 mmol) of Z- (L) -vinyl, 336 mg (0.76 mmol) of BOP and 103 mg (0.76 mmol) of HOBt are dissolved in 5 ml of a 0.3M solution of NMM in DMF, then, after 10 minutes, 100 mg (0.25 mmol) of H- / Peh ^NN Phe / -H 3 HCl was added to the obtained solution, and the resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was evaporated, the residue was dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool and concentrated, then the residue is

173 purified by chromatography on a silica gel using a 1: 1 by volume mixture of methylene chloride and ether. After freeze drying of the fractions containing the desired product from dioxane, the title compound is obtained in the form of a white solid. here .

MS (FAB): (M + H) + = 752, t ® _T (I) - 27.8 min;

Rf (E) - 0.45.

The starting material was prepared as follows.

a) H- / Phe- ^MIM Phe / -H. 3HC 1

A solution of 280 mg (0.58 mmol) of Boc- (Phe ^NN Phe) -Boc from Reference Example 1 in 10 ml of N chlorine-blowing dioxane was stirred at room temperature for 2 hours at room temperature. the solution is then filtered. After re-lyophilization from a mixture of dioxane and tert-butanol, the title compound is obtained in the form of a solid inoculum.

Mass spectrum (F-ionization): (M + H) + = 286, t rt (II) = 23.1 min,

Rt - (C) - 0.17.

Reference example 3

Bo c- (L) -Va 1 - / phe ^NIM Phe / <- ((L) -Va 1-Boe)

In a manner analogous to that described in Reference Example 2, from 50 mg (0.13 mmol) of H- / Phe ^NN Phe / -H. 3HCl, 83 mg / 0.83 mmol) Boe- (L) -valine, 168 mg (0.38 mmol)

BOP, 51 mg (0.38 mmol) of HOBt and 2.5 ml of 0.3M MMM in DMF after chromatography on silica gel using a 95% chloroform / ethanol mixture 5) and lyophilization from dioxane affords the title compound. Mass spectrum (F-ionization): (M + H) + = 684, t, -. _; = 27.4 min,

174

Rf (E) = 0.38.

Reference example 4

Boc- (Phe ^MM Cha) -Boc

In a manner analogous to that described in Reference Example 1, 231 mg (0.88 mmol) of (2R, 3S) -1- / 3-Bocamido-2-phenylethyl / oxirane and 200 mg (0.88 mmol) were used. tert -butyl-3-cyclohexylmethylcarbazate gives the title compound as a white precipitate separated from hexane.

Mass spectrum (F-ionization): (M + H) + = 492, t rc (I) - 30.4 min,

_Rf (E) = 0.78.

The starting material is obtained as follows.

a) tert -Butyl 3-cyclohexylmethylcarbazate

10.2 g (45.1 mmol) of cyclohexylcarbiddehyde-t-butoxycarbonylhydrazone, dissolved in 400 ml of methanol, are hydrogenated in the presence of 5.1 g of 5% platinum on carbon at room temperature and a hydrogen pressure of 0.4 MPa. After completion of the reaction, the hydrotreating catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in methylene chloride and the solution was washed with water. Evaporation of the organic phase yields the title compound as a colorless resin.

Ή-Nuclear magnetic resonance spectrum:

(200 MHZ, CDCl 3) δ s, broad. 1 H), 9 (s, broad, 1 H), 6.5 (d, 2H), 8-0.75 (m, 11H), 4.5 (S, 9 H) , t &lt; c (I) = 32.0 min,

Rf = (E) = 0.75.

b) Cyclohexylcarbaldehyde-tert-butoxycarbonylhydrazone.

A solution of 10.8 g (81.2 mmol) of tert. butyl carbazate and 10.1 g (90 mmol) of cyclohexylcarbaldehyde in 400 ml of ethanol are heated at reflux for 2 hours. Then half the solvent is distilled off and the desired compound precipitates after the addition of water. This compound is then directly used in reaction step a).

Reference example 5

H- (L) -Va1 - / Phe ^NM Phe / - ((L) Val) -H.3HCl

A solution of 40 mg (0.06 mmol) of 8oc- (L) -V and 1 (Phe ^NN Phe) - Val-Boc from Reference Example 3 in 4 ml of 4N hydrogen chloride in dioxane was stirred at room temperature for one hour. temperature. The solution is then diluted with dioxane, followed by lyophilization to give the title compound as the hydrochloride salt.

Mass Spec m (fast atom ionization): (M + H) + = 484, t B e f (11) = 25.8 min,

R @ 1 - (A) - 0.45.

Reference example 6

N-Thiomorpholinecarbonyl- (L) -Val- (Phe) ^NN Phe / - (N-thiomorpholine arbonyl 1- (L) -V and 1) solution of 20 mg (0.03 mmol) of H- (L) -Va 1- (Phe ^NIS, Phe) - ((L) -Val) -H 3 HCl! of Reference Example 5 in 0.5 ml of DMF, 35 µl of 1 (0.25 mmol) triethylamine and 16 mg (0.1 mmol) of (4-thiomorpholinylcarbonyl) chlorine are successively added at room temperature. , then the resulting mixture is stirred at room temperature for one hour. The reaction mixture was diluted with chloroform and washed with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool and evaporated. The residue is then chromatographed on silica gel, eluting with a mixture of chloroform and methanol.

176 with a gradient from 15: 1 to 8: 1. The fraction containing the desired compound was evaporated and precipitated in a mixture of methylene chloride and DIPE. After freeze-drying in dioxane, the title compound is obtained as a solid flake product.

Mass spectrum (F-ionization): (M + H) + - 742, t _rt (I) = 21.6 min,

R _f (D) - 0.54.

The starting material is obtained as follows.

a) (4-Thiomorpholinylcarbonyl) chlorides d

To a solution of 35 ml (165 mmol) of 20% phosgene in toluene at 0 ° C was added dropwise a solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene, and the resulting white suspension was stirred at room temperature for one hour. Excess phosgene is removed by introducing nitrogen, the suspension is filtered and the filtrate is evaporated. The title compound is obtained as a yellow oil.

Infrared spectrum:

(CH 3 Cl 2, Cm ^-1 ) 1735, 1450, 1440, 1405, 1370, 1290, 1180.

Reference example 7

N-Morpholinocarbonyl 1 - (-L) -Va 1 - / Phe ^NN Phe / - - (N-morpholinocarbonyl 1 - (L) - V and 1)

To a solution of 100 mg (0.25 mmol) of H- / Phe ^NN Phe / -H.3HCl from Reference Example 2a, 163 mg ((0.76 mmol) of N-morpholinocarbonyl (L) -valine and 288 mg (0.76 mmol) of mmol) of HBTU in 2 mL of DMF was added 210 of 1 (1.52 mmol) of triethylamine and the mixture was stirred at room temperature for 16 hours under nitrogen, then the reaction mixture was completely evaporated, the residue was dissolved in methylene chloride and washed with saturated solution. The organic phase is filtered through cotton wool, evaporated and the residue is chromatographed on silica gel, eluting with a mixture of methanol and methylene chloride (v / v).

177 ratio 1:15. The title compound is precipitated from a mixture of methylene chloride and hexane, after freeze-drying from a mixture of dioxane and tert-butanol as a solid flocculent product. Mass spectrum (F-ionization): (M + H) + = 170, tr _e c (I) = 16.3 min,

R f (E) = 0.1.

The starting material is obtained as follows.

a) N-Morpholinocarbones 1- (L) -vinyl ¹ H-Nuclear Magnetic Resonance Spectrum:

(300 MHy, CD 3 OD) 4.15 (m, 1H),

3.65 (m, 4H);

3.40 (m, 4H);

2.12 (m, 1H),

0.9 δ (2d, 6H).

b) N-Morpholinocarbonyl- (L) -valine benzyl ester

To a solution of 4 g (10.5 mmol) of (L) -vinylbenzyl-sterol-4-olenesulfonate in 56 ml of methylene chloride is added 0.8 ml (8.1 mmol) (morpholinocarbonyl 1). Chloride (prepared as described in J. Med. Chem. 31, 2277 (1933)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine and the resulting mixture is then stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, then 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine were added successively to wash. The organic phase is dried over sodium sulphate and evaporated. After chromatography of the residue on silica gel with ethyl acetate, the N-morpholinocarbonyl- (L) -valin-benzyl ester is obtained as a colorless oil. The ester obtained is used immediately in reaction step a).

Reference example 8

178

Foam Acety1 - (L) -Va1 - / Phe ^NN Phe / <- (N-Phenylacety1- (L) -Va1)

In a manner analogous to that described in Reference Example 7, from 100 mg (0.25 mmol) of H- / Phe ^NN Phe / H.3HCl from Reference Example 2a, 143 mg (0.61 mmol) of Phase 1 Acetyl 1 was obtained. - (L) -vinyl (prepared as described in Mem. Tokyo Univ. Agric. 20, 5 1 (1978)), 230 mg (0.61 mmol) H BTU and 200 µl (1.42 mmol) triethylamine after chromatographic purification using a methylene-

chloride, of ether and methanol in volume ratio 20: 20: 1 and lyofi- 1 i z i i i from the mixture d i o x a n a t-butanol is obtained required from 1 valuables. mass WITH p e k t r u m (ionization fast atoms): (M + H) + = 720, t R θ t (I) - 23.7 mi n, R @ + - (G) = 0 O H .dl.

Reference example 9

N- (3-Pyridyl acetyl) - (L) -Va1- (Phe ^NN Phe) - (N- (3-pyridylacetyl- (L) -Val))

In a manner analogous to that described in Reference Example 7, from 100 mg (0.25 mmol) of H- / Phe ^NN Phe / H.3HCl from Reference Example 2a, 576 mg (1.52 mmol) of HBTIJ,

358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) -vinyl and 316 _of triethylamine (2.3 mmol) after chromatographic purification using a chloroform / methanol mixture (v / v) 5: 1 and lyophilization from dioxane / t-butanol gave the title compound as a white solid.

MS (FAB): (M + H) + - 722, TR _et (11) = 27.9 min;

Rf - (A) = 0.71.

The starting material was prepared as follows.

179

a) N- (3-Pyridyl acetyl) - (L) -vinyl

3.4 g of N- (3-pyridylacetyl) - (L) -valine-tert-butyl ester are dissolved in 20 ml of a 1: 1 by volume mixture of trifluoroacetic acid and methylene chloride and the resulting solution is stirred at room temperature. hours. The reaction solution was completely evaporated and the residue was dogged with DIPE. In this way the title compound is obtained in the form of a white solid amorphous product.

¹ Η-Nu k linear magnetic resonance spectrum:

(200 MHz, CH 3 OD) 8.9 (m, broad, 1H), 9.5 (m, 1H), 3.3 (m, 1H), 9.3 (s, 2H) .

2.2 (m, 1 H),

0.98 (2 d, 6H).

b) N- (3- (Pyridylacetyl) - (L) -valine-tert-butyl ester)

To a solution of 3.36 g (16 mmol) of (1 ') -vinyl-tert-butyl ester, HCl, g (14.5 mmol) of 3-pyridylacetic acid and 2.17 ml (14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml of DMF, 4.2 ml of triethylamine is added dropwise at 0 ° C. The reaction mixture is then stirred for 48 hours at room temperature, then diluted with methylene chloride and washed with 10 .mu.l citric acid solution and saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool and the solvent is evaporated off from the filtrate to give N- (3-pyridylacetyl) - (L) -vinyl-tert-butyl ester which is used immediately in reaction step a).

Reference example 10

Boe- (L) -Va 1 - / Phe ^NM Cha / <- ((L) -Va 1) -Boe

In a manner analogous to that described in Reference Example 7, from 500 mg (1.25 mmol) of H- / Phe ^NN Cha / -H was obtained.

180

3HCl, 1.08 g (4.98 mmol) Boe- (L) -vinyl, 1.39 g (4.98 mmol)

HBTU and 1.39 ml (9.96 mmol) of triethylamine after chromatography on silica gel using a 1: 1 mixture of methylene chloride and ether and lyophilization from dioxane gave the title compound as a solid flake product.

MS (FAB): (M + H) + = 690, t r _e t (I) = 29.3 min;

Rf (H) = 0.48.

The starting material was prepared as follows.

a) H - / Phe ^NN Cha / -H 3 HC1

1.10 g (2.2 mmol) of Boc- (Phe ^NN Cha) -Boc from Reference Example 4 was dissolved in 20 ml of 4M hydrochloric acid in oxane and the resulting solution was then stirred at room temperature for 3 hours. After lyophilization of the reaction mixture, the title compound is obtained in the form of the hydrochloride.

Mass spectrum (F-ionization): (M + H) + = 292, t r (t 1) - 2 7.3 min.

R eferent in Example 11 (L) -Va1 - / Phe ^NN Cha / ((L) -Val) -Z

Using a procedure analogous to that of the Reference Example from Reference 165 mg (0.37

2, from 50 mg (0.12 mmol) of H- (Phe ^NN Cha) -H.3HCl Example 10a, 94 mg (0.37 mmol) of Z - (L) -valine, mmol) BOP, 51 mg (0.37 mmol) HOBt and 2.5 mL 0.3M

Purification by chromatography on silica gel, eluting with methylene chloride / ether (1: 1 by volume) and lyophilization from dioxane, afforded the title compound.

F-MS: (M + H) @ + = 758, t _Re t (I) = 29.1 min;

1

R t (H) = 0.55.

Reference example 12

Boc- / Phe ^NN Leu / -Boc

In a manner analogous to that described in Reference Example 1, from 1.0 g (3.8 mmol) of (2R) - / 1 '(S) -Bocamino-2'-phenylethyl / oxirane and 715 mg (3.8 mmol) of tert. Butyl 1-3-isobutylcarbazate (prepared according to the procedure described in J. Chem. Soc., Perkin I, 1712 (1975)) affords the title compound as a compound excluded from hexane.

Mass spectrum (F-ionization): (M + H) ⁺ - 452, tr ® t (I) - 27.2 min,

Rf = 0.55.

Reference example 13

Z- (L) -Va1 - / Phe ^NN Leu / - Val) -Z

In a manner analogous to that described in Reference Example 2, from 60 mg (0.17 mmol) of H- (Phe ^NN Leu) -H was obtained. 3HCl, 125 mg (0.50 mmol) of Z- (L) -vinyl, 221 mg (0.50 mmol) of BOP, (0.50 mmol) of HOBt and 3.3 mL of 0.3M NMM in DMF after chromatography using Toluene ether (1: 1 by volume) and purification on silica gel with methylene chloride by freeze-drying from dioxane gave the title compound. Mass spectrum (F-ionization): (M + H) = 728, t R, (I) = 26.8 min,

R @ + - (H) = 0.38.

The starting material was prepared as follows.

a) H- / P h ^NN L eu / -H. 3 HC 1

In a manner analogous to that described in re182 of Ferenc Example 10a, from 1.21 g (2.48 mmol) of Boc / Phe ^NN Leu / -Boc was obtained. from Reference Example 12, the title compound is obtained in the form of 1 &apos;

Mass spectrum (F-ionization): (M + H) + = 252, t R _e (II) = 20.9 min,

Rf (K) = 0.23.

Reference example 14

H- (L) -Va1 - / Ph e ^NN C ha / <- ((L) -Va1) -H.3HCl

In a manner analogous to that described in Reference Example 10a, from 632 mg (0.91 mmol) of Boc- (L)-Val / P h ^NN C ha / - ((L) -V and 1) -B ocz of Reference Example 10 after lyophilization affords the title compound as the hydrochloride salt. Mass spectrum (F-ionization): (M + H) + - 490, tr _e c (11) = 29.4 min,

R @ + - (K) = 0.23.

Reference example 15

N- (3-Pyridyl acetyl) - (L) -Val- (Phe ^NN Leu) - (N- (3-pyridylacetyl) - (L) -Val)

In a manner analogous to that described in Reference Example 9, from 90 mg (0.25 mmol) of H- (Phe ^NN Leu) -H-3HCl from Reference Example 3a, 358 mg (1.52 mmol) of N- (3-Pyridyl acetyl) - (L) -vinyl, 5 7 6 mg (1.52 mmol)

Chromatography of the triethylamine (316 mmol) (2.5 mmol) after chromatographic purification using a 15: 1 mixture of methylene chloride and methanol and lyophilization from dioxane, tert. butanol and water yield the title compound.

Mass spectrum (F-ionization): (M + H) + = 688,

183

IRET (IV) - 15.5 min,

Rf (D) = 0.37.

Reference example 16

N-Trifluoroacetyl- / Phe ^NN (pF) Phe / -Boc

A solution of 4.0 g (15.4 mmol) of 2 (R) - / 1 '(S) - (trifluoromethylamino) -2'-phenylethyl / oxirane and 3.89 g (16.2 mmol) of mmol) of tert-butyl-3- (p-tube at 80 ° C) is evaporated, the residue is dissolved in this solution as desired (in the refrigerator). Another portion of flu = orphenylmethyl) carbazate in 35 ml of methanol is heated for 11 and 20 hours. . The reaction mixture was treated with a small amount of dichloromethane and the product precipitated by the addition of hexane product was obtained by silica gel column chromatography using a 95: 7 mixture of methylene chloride and ether as the eluent. Thin layer chromatography: R-r (J) = 0.57, t r t (I) = 23.3 min,

Mass spectrum (F-ionization): (M + H) + = 500.

The starting material was prepared as follows.

a) N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilylbutane

24.7 g (1.02 mol) of magnesium are introduced into 100 ml of absolute ether and a small amount of iodine is added over 35 minutes to the mixture, while 132.5 ml (0.95 mol) of chloromethyltrimethylsilane and 300 ml of ether are added over 35 minutes. the temperature is maintained at 38 ° C using an ice bath. The resulting reaction mixture was then stirred at room temperature for 1.5 hours. After cooling to -60 ° C, a suspension of 48.6 g (0.195 mol) of N-Boc-phenylalaninal (prepared according to the procedure described by DJKempf in J. Org. Chem. 51, 3921 (1986)) is added to the reaction mixture. 1.1 liters of ether are added over 40 minutes. The reaction mixture is warmed to room temperature over 90 minutes

184 and stirred at this temperature for 90 minutes. It is then poured into 2 liters of ice water and 1.5 liters of a 10% aqueous citric acid solution. The separated aqueous phase is extracted twice with 500 ml of ether. All ether extracts are washed with 500 ml of 10% citric acid and twice with brine. After drying over sodium sulfate, it is concentrated in vacuo and the title compound is used in the next step without any further purification.

TLC: Rf - (L) - 0.6, MS (FAB): (M + H) @ - = 338.

b) 1-Phenylene-3-benzene-2 (S) -amine

To a solution of 18.8 g (0.055 mol) of 3 (S) - (Boc-amino) -2 (R, S) -orhoxy-4-phenyl-1-1-trimethylsilane butane 420 ml of methylene chloride was added at 5 [deg.] C. and 35.6 ml (0.28 mol) of about 48% boron trifluoride fluoride solution were added over 10 minutes. The mixture is stirred at room temperature for 16 hours, then cooled to 10 ° C and 276 ml of 4 N sodium hydroxide solution are added over 20 minutes. The aqueous phase is separated and extracted twice with 400 ml of methylene chloride. The combined organic extracts were washed with brine and dried over sodium sulfate. The desired product is used in the next step without any further purification.

TLC: R H (C) = 0.15,

Infrared spectrum:

(methylene chloride, cm ^-1 ) 3370, 3020, 2920, 1640, 160 5.

c) N-Trifluoroacetyl-1-phenyl-3-butene-2 (S) -amine

To a solution of 11.9 g (81 mol) of 1-phenyl-3-buten-2 (S) -amine in 210 ml of methylene chloride and 70 ml of pyridine is added dropwise 17.0 (121 mmol) of acid anhydride at 0 ° C. TFA. After stirring at 0 ° C for 30 min, the reaction mixture was extracted twice with dilute hydrochloric acid,

185 water and brine. The aqueous phases are washed twice more with methylene chloride, dried over sodium sulphate and evaporated.

TLC: Rf (M) = 0.4.

d) 2 (R) - / 1 '(S) - (Trifluoroacetylamino) -2'-phenylethyl / oxirane

To a solution of 14.5 g (60 mmol)

N-Trifluoroacetyl-1-phenyl-3-buten- (2 (S) amine) in 600 ml of chloroform was added 54.28 g (314 mmol) of n-chloroperbenzoic acid and the resulting mixture was stirred at room temperature. The reaction mixture was then washed twice with 10% sodium sulfite solution, twice with saturated aqueous sodium bicarbonate solution, with water and brine, and the aqueous phase was extracted twice more with methylene chloride, then the combined organic phases were dried over sodium sulfate. This gives the title compound which is used in the next step without any further purification.

Thin layer chromatography: R 1 - (N) - 0.6.

e) p-Fluorophenylcarbaldehyde-tert-butoxycarbonylhydrazone

In a manner analogous to that described in Reference Example 4b, a mixture of 32 g (242 mmol) of tert. Butyl carbazate and 30 g (242 mmol) of p-fluorobenzaldehyde are heated in 300 ml of ethanol at 80 DEG C. for 3 hours to give the title compound which crystallizes after cooling and dilution with water. TLC: R 1 - (N) = 0.48, tr _e r. (I) = 19.4 min.

f) tert -Butyl-3- (p-fluorophenylmethyl) k a r b and z

In a manner analogous to that described in Reference Example 4a, 55 g (231 mmol) of p-fluorophenylcarbaldehyde-tert-butoxycarbonylhydrazone are hydrogenated in 500 ml of THF. in the presence of 5.5 g of palladium (5%) on carbon to give the title compound.

186

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 7.35 (dd, 8 and 6 Hz, 2H),

7.05 (t, 8 Hz, 2H), 3.9 (S, 3H), 4.5 (s, 9H).

Reference example 17

N-morpholinocarbonyl (L) -Va1- / Phe ^NN (p ^_ F) Phe / -Boc

A mixture of 185 mg (0.80 mmol) of N-morpholinocarbonyl-1- (L) -vinyl (prepared as described in Reference Example 7a), 270 mg (0.67 mmol) of H- / Phe ^NN (pF) Phe I -Boe, 311 mg (0.70 mmol) of SOP and 95 mg (0.70 mmol) of HOBT are dissolved at room temperature in 6.8 ml of NMM / DMF 0.3M and the solution is then stirred at room temperature. The reaction mixture is concentrated under high vacuum and the residue te for 5 hours, partitioned between 4 sodium carbonate, dried over sulfate by chromatography on ethyl acetate. Thin layer chromatography parts of methylene chloride, 2 parts of IM solution of water and brine. The combined organic phases were evaporated in a day and the residue was purified using silica gel as eluent.

R-e (0) - 0.38, tr _e c (I) = 21.1 min, mass spectrum (fast atom ionization): (M + H)

The starting material was prepared as follows.

a) H- / Phe ^NM (pF) Phe / -3oc

To a solution of 0.3 g (0.6 mmol) of N-trifluoroacetyl- / Phe ^NN (pF) Phe / -Boc (prepared according to Reference Example 16) in 50 ml of methanol under nitrogen atmosphere at 70 ° C. 15 ml of 1M aqueous potassium carbonate solution are added thereto, and the mixture is stirred at that temperature for 25 hours. The reaction mixture is then evaporated under high vacuum, methylene chloride is added to the residue, and the organic phase is washed twice with water and brine. The aqueous phase was extracted twice with methylene chloride twice and the combined organic phases were dried over sodium sulfate and evaporated. The crude product obtained is used in the next step without any further purification.

tr t _e (I) - 16.2 min.

Reference example 18

N-Morpholinocarbonyl 1- (L) -Va1 - / Phe ^NN (pF) Phe / - ((L) -Val) -Z

To a solution of 86 mg (0.34 mmol) of Z- (L) -Val and 160 mg (0.31 mmol) and 160 mg (0.31 mmol) of N-morpholinocarbonyl- (L) -Va1- (Phe) ^NN (pF) Phe / -H

0.25M (0.25M NMM in CH 3 CN) After 4 hours at room temperature in 27 mL of NMMCCH 3 CN, 129 mg (0.34 mmol) of HBr 1 was added. The mixture was evaporated and the residue was partitioned between 3 parts of methylene chloride, 2 parts of saturated sodium bicarbonate solution and brine. After drying the organic phases over sodium sulfate and evaporation, the title compound is obtained, which is purified by digestion using a 1: 1 by volume mixture of methylene chloride and ether.

TLC: Rf (L) = 0.4, t ® _T (I) - 22.4 min MS (FAB): (M + H) + = 749th

The starting material was prepared as follows

a) N-Morpholinocarbonyl- (L) -Val / Phe ^NN (pF) Phe / - H

A solution of 210 mg (0.34 mmol) of M-morpholinocarbonyl-1- (L) -Val / Phe- ^MIM (pF) Phe / -Boc (prepared according to Reference Example 17) in 105 ml of acid The form was stirred at room temperature for 4 hours. The solution was then evaporated, the residue taken up in methylene chloride and the solution was washed with saturated aqueous sodium bicarbonate solution and brine. Extraction of the aqueous phases with 2 parts of methylene chloride, drying of the organic phases over sodium sulphate and evaporation affords the title compound which:

188 was used in the next reaction step i without further purification.

t _R ef (I) = 12.9.

Reference example 19

N-Morpholinocarboxy-1- (L) -Va1 - / Phe ^NN (pF) Phe / - ((L) -Val) -H

160 mg (0.21 mmol) of N-morpholinocarbonyl 1- (L) -Va1- / Phe ^NN (pF) Phe / - ((L) -Va1) -Z (prepared according to reference of Example 18) is hydrogenated in 6 ml of ethanol in the presence of 40 mg of 1% palladium on carbon. Filtration through Celite (kieselguhr from Fluka, Buchs, Switzerland), concentration and lyophilization from dioxane gave the title compound. Ret. (hydrochloride, I) = 13.4 min, MS (F-ionization): (M + H) + = 6.55.

Reference Example 20

N-Morpholinocarbonyl- (L) - .alpha .- / Phe ^NN (pF) Phe / - ((L) -Val) &lt; - &gt; - (N-morpholinocarbonyl 1-G 1 y)

To a solution of 26.9 mg (0.143 mmol) of N-morpholinocarbonyl-1-tin and 80 mg (0.130 mmol) of N-morpholinocarbonyl-1- (L) -Valcino- ^NIM (pF) Phe / - ((L) -Val) -H in 1.1 ml NMM / CH 3 CN 0.25 M was added 54 mg (0.143 mmol) of HBTU and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then evaporated and the residue partitioned between three parts of ethyl acetate, water, 2 parts of saturated aqueous sodium bicarbonate, water and brine. After drying. The reaction mixture was concentrated in sodium sulfate and concentrated to give the title compound which was obtained after purification in a small amount of DMF and precipitated by DIPE in the pure state, tr _θ χ (I) - 15.1 min, mass spectrum (fast atomization): ( M + H + - 785.

189

The starting material is obtained as follows.

a) N-Morpholinocarbonylglycine benzyl ester

In a manner analogous to that described in Reference Example 7b, 7.69 g (22.8 mmol) of sterile 4-toluene-sulfonate are reacted for 18 hours. 8 g (19 mmol) of (morpholinocarbonyl) chloride in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyl diisopropylamine. After extraction with methylene chloride and digestion with hexane, the title compound is obtained in pure form.

t Ret (I) - 11.6 min.

b) N-M-morpholinocarbonylglycine

In a manner analogous to that described in Reference Example 7a, 4.8 g (18.3 mmol) of N-morpholinocarbonyl 1 g of trifluoromethylbenzene are hydrogenated in 100 ml of ethyl acetate in the presence of 1 g of 10 g. % palladium on carbon to give the title compound.

'H-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CDCl 3) 3.88 (s, 2H),

3.64 (s, 4H);

3.50 (s, 2H).

3.35 (s, 4H).

Reference case 21

Z- (L) -Val- / Phe ^NN (pF) Phe / -Boc

To a solution of 335 mg (1.33 mmol) of Z- (L) -Val and 448 mg (1.11 mmol) of H- / Phe ^NN (pF) Phe / -Boc (prepared according to Reference Example 17a) at 9.4. ml NMM / CH 3 CN 0.25M (0.25M NMM

190 (CH 3 CN) 463 mg (1.22 mmol) of HBTU is added. After stirring at room temperature for 16 hours, the reaction mixture was evaporated and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated aqueous sodium bicarbonate and Tank. After drying the organic phases over sodium sulfate and evaporation, the title compound is obtained, which is purified by chromatography on a silica gel column, eluting with a hexane / ethyl acetate gradient of 4: 1 to 1: 1.

t R t t (I) = 26.6 min, mass spectrum (fast atom ionization): (M + H) + = 637.

Reference example 22

Z- (L) -Val- / Phe ^NN (pF) Phe / - ((L) -Va1) -Boe

In a manner analogous to that described in Reference Example 18, 165 mg (0.76 mmol) of Boc- (L) -Val and 371 mg (0.69 mmol) of Z- (L) -Va1 - were reacted. Phe ^NN (pF) Phe / -H in 6 ml NMMCH 2 CN 0.25 with 289 mg (0.76 mmol) of HBTU to give the desired compound, which can be crystallized directly from the reaction solution and filtered off.

t _R t (I) = 27.2 min, mass spectrum (F-ionization): (M + H) + = 736.

The starting material was prepared as follows.

a) Z- (L) -Val- / Phe ^NN (pF) Phe / -H

In a manner analogous to that described in Reference Example 18a, Z- (L) -Va1 - / Phe ^NN (pF) Phe / -Boc was deprotected using 212 ml formic acid to give the title compound.

t _Rt (I) = 17.8 min.

Reference example 23

Z- (L) -Va1 - / Phe ^NN (pF) Phe / - ((L) -Val) -H

In a manner analogous to that described in Reference Example 18a, 250 mg (0.34 mmol) of Z- (L) -Val / Phe ^NN (pF) Phe / <- ((L) -Val) -Boc (Reference Example 22) deprotected using 50 ml formic acid to give the title compound.

tr _e t (I) = 13.0 min; MS (FAB): (M + H) + = 636th

Reference example 24

Z- (L) -Va1 - / Phe ^NN (pF) Phe / <- ((L) -Val) <- (N-morpholinecarbon y 1 - G 1 y)

Following a procedure analogous to that described in Reference Example 20, 32 mg (0.17 mmol) of N-orpholinocarbonyl (1 g) ycin (Reference Example 20b) and 99 mg were reacted. (0.16 mmol) Z- (L) -Val - / Phe ^NN (pF) P h / - ((L) -Val) -H in 1.3 ml NMM / CH with CM 0.25 with 65 mg (0.17 mmol) of HBTiJ to give the title compound, which crystallizes directly in the reaction mixture, tren (I) -2.1 min, mass spectrum (F-ionization): (M + H) + - 806.

Reference example 25

Z- (L) -Asn- / Phe ^NN (pF) Phe / -Boc

To a solution of 2.09 g (5.2 mmol) of H- / Phe ^NN (pF) Phe / -8oc (prepared according to Reference Example 17a) in 68 mL of DMF and 2.7 mL (16 mmol) of N-ethyldiisopropylamine; (L) -asparagine-p-nitrophenyl estary). After 16 hours, the stirring was concentrated under high vacuum to leave methylene chloride (the residue was

nu shall be added 3 0 g (7, 8 mmol) er u (B a c h e m, B u - bendorf, Š v a j - Ί d pri izbovej temperature s and a mixture SOK is removed in bulk m n o ž s -

slightly soluble) and washed

192 parts of 5% aqueous potassium carbonate solution. 192

The aqueous phase is extracted with chloride and extracted twice with a large portion of the methylene-combined organic phases, dried over sodium sulphate and evaporated. Dissolution of the crude product in a small amount of methanol and precipitation by addition of toluene at -20 ° C affords the title compound.

_e t tr (L) - 1.2 2 min.

Reference case 26

H- (L) -Asn- / Phe ^NN (pF) Phe / -Boc

In a manner analogous to that described in Reference Example 19, 0.40 g (0.61 mmol) of Z- (L) -Asn- / Phe ^NN (pF) Phe / -Boc is hydrogenated in 20 ml of methanol to give the desired compound.

tr t _e (I) - 14.9 min.

Reference example 27

Quinoline-2-carbonyl- (L) -Asn- / ^r Phe (pF) Phe / -Boc

In a manner analogous to that described in Reference Example 17, 134 mg (0.78 mmol) of quinoline carboxylic acid (Fluka, B uchs, Switzerland) were reacted in 4 ml of NMM / DMF 0, 3 M with 344 ma (0.78 mmol) BOP, 105 mg (0.78 mmol) HOBT and 268 mg (0.52 mmol) H- (L) -Asn- / Phe ^NN - (pF) Phe / -Boc . Since H- (L) -Asn- / Phe ^NN - (pF) Phe / -Boe was still present in the reaction mixture after stirring for 16 hours at room temperature, according to the result of the high-pressure liquid chromatography, it was added again to the reaction mixture. 299 mg of BOP, 70 mg of HOBT, 89 mg of quinaldinic acid and 113 _of µM NMM. After a further 16 hours, the reaction mixture was evaporated and the residue was partitioned between 3 parts of methylene chloride, 2 parts of a saturated aqueous solution of sodium bicarbonate and Tank. The combined organic phases are dried over sodium sulphate and evaporated. After dissolution of the crude product in a small amount of DMF, precipitation by addition of DIPE and cooling to -20 ° C. to give the title compound.

tr _e t (I) = 22.8 min; MS (FAB): (M + H) + = 673rd

Reference example 28

Z- (L) -Asn- (Phe ^NN - (pF) Phe) - ((L) -Val) -Z with mg (0.35 mmol) of Z- (L) -Val in 3.8 ml NMM / DMF 0.3 N is activated with 153 mg (0.35 mmol) of BOP and 47 mg (0.35 mmol) of HOBT, then 144 mg (0.23 mmol) of Z- (L) -A.snpo 15 / Phe is added in minutes. ^NIM - (pF) Phe / -H. 2HC 1. After stirring at room temperature for 14 hours, the reaction mixture is evaporated, the residue is dissolved in 2 ml of methanol and partitioned between 3 parts of methylene chloride and 2 parts of 1M aqueous sodium carbonate solution and the organic phases are dried over sodium sulfate and evaporated. Redissolution of the crude product in a small amount of DMF and precipitation by addition of DIPE yields the title compound.

t _Ret (I) - 22.2 min, mass spectrum (F-ionization): (M + H) + = 785.

The starting material was prepared as follows

a) Z- (L) -Asn- / Phe ^NN (pF) Phe / -H 2 HCl.

To a solution of 150 mg (0.23 mmol) of Z- (L) -Asn- / Phe ^NN (pF) Phe / Boe (Reference Example 25) in 1 ml of dioxane was added 2 ml of 4N hydrochloric acid in dioxane (Fluka, B uchs, Switzerland). After stirring at room temperature for 1.5 hours, the reaction mixture is lyophilized and the lyophilisate obtained is used immediately in the next step.

Reference example

194

Trifluoroacetyl- / Phe ^NN (pF) Phe / <- ((L) -V and 1) - Z

In a manner analogous to that described in Reference Example 17, 239 mg (0.95 mmol) of Z- (L) -Val in 10.5 ml of 0.3M NMM in DMF with 421 mg were reacted over 15 hours. (0.95 mmol) of BOP, 129 mg (0.95 mmol) of HOBT and 0.3 g (0.63 mmol) of N-trifluoromethyl- / Phe ^NN (pF) Phe / -H. Chromatography on a silica gel column using a 10: 1 mixture of methylene chloride and ether and precipitation of the dimethylformamide solution by addition of DIPE affords the title compound.

TLC: R 1 - (Q) = 0.15, t -c (I) - 25.9 min, mass spectrum (fast atom ionization): (M + H) + - 633.

The starting material is obtained as follows.

a) N-Trifluoroacetyl- / Phe ^NN (pF) Phe / -H

To 0.20 g (0.40 mmol) of N-1-difluoro-acetyl-P h e ' ⁴ ' ^-1 (pF) P h / Boe (prepared according to Reference Example 16) in 5 µL of methylene chloride was added. 5 ml of trifluoroacetic acid are added at 0 ° C. After stirring at 0 ° C for 4 hours and at room temperature for 2 hours, the reaction mixture was evaporated. After lyophilization of the residue from dioxane, the title compound is obtained, which compound is used as is in the following stage.

tr _e t (I) = 14.7 min.

Reference example 30

In a manner analogous to that described in Reference Example 25, 157 mg (0.34 mmol) of H- / Phe ^NN Phe / -Boc in 3.6 ml of DMF and 0.18 ml (1 mmol) of N are reacted. -ethyl 1-isopropylamine with 0.20 g (0.52 mmol)

From (L) -asparagine-p-nitrophenyl ester to give the desired compound, which was purified by silica gel column chromatography using ethyl acetate as eluent. TLC: R + - (O) = 0.19, t _Ret (I) = 20.9 min.

The starting material was prepared as follows.

a) N-Trifluoroacetyl / Phe ^NN Phe / -Boe

In a manner analogous to that described in Reference Example 16, 1.82 g (7.0 mmol) of 2 (R) - / 1 '(S) - (tri fluoromethyl amine) was reacted in a pressure tube. -2'-phenylethyl / oxirane (Reference Example 16d) and 1.58 g (7.1 mmol) of tert. Butyl-3-benzylcarbazate (J.Chem., Per kin I, 1 7 1 2 (1 9 7 5)) in 15 ml of methanol to give the title compound which is purified by chromatography on a silica gel column using a methylene chloride mixture; of ether in a 50: 1 by volume ratio.

Thin layer chromatography: Rt (J) = 0.38, t _R and (I) - 24.5 min.

b) H- / P he ^NN (p-F) P he / -B oc

Following a procedure analogous to that described in Reference Example 17a, 258 mg (0.53 mmol) of N-trifluoromethyl / Phe ^NN Phe / -Boc in 60 ml of methanol are reacted with 10.7 ml of 1M potassium carbonate solution. to give the desired compound.

Reference example 31

Z- (L) - Va1 - / (pF) Phe ^NN (pF) Phe / Boc

In a manner analogous to that described in Reference Example 21, 18 mg (0.070 mmol) was reacted.

196

Z- (L) -Val and 27 mg (0.064 mmol) of H- (pF) Phe ^NN (pF) Phe / -Boe in 0.6 ml of 0.25M NMM in CHaCN with 26.6 mg (0.070 mmol) of HBTU at formation of the desired compound which is purified by solvent in a small amount of methylene chloride and precipitated three times by addition of DIPE. Mass spectrum (F-ionization): (M + H) ^4- = 655.

The starting material was prepared as follows.

a) N-Boc- (p-fluoro-phenylalanine)

To 20 g (109 mmol) of p-fluorophenylalanine (F1 u k a, Buchs, Switzerland) in 0.4 L of dioxane / water (v / v)

1: 1 35.5 g (163 mmol) of Boc-anhydride and 150 g (1.09 mol) of potassium carbonate are added. After 4 hours, the reaction mixture was acidified with aqueous citric acid solution and extracted with 3 portions of ethyl acetate. The organic phases are washed with 10% citric acid, water and brine, dried over sodium sulphate and evaporated. Dissolution of the residue in a small amount of methylene chloride and crystallization after addition of hexane gave the title compound, t rt (I) = 16.9 min.

b) N-Boc- (p-fluorophenylalaninol)

To a solution of 17.9 g (63 mmol) of N-Boc- (p-fluorophenyl and 1 n a) in 73 ml of absolute THF at -5 to -10 ° C was added 9.66 ml (69 mmol) of triethylamine, then a solution of 9.05 mL (69 mmol) of isobutyl chloroformate in 44 mL of absolute ZHF was added dropwise. After stirring for 30 minutes at room temperature, the precipitate formed is suction filtered. The filtrate was added dropwise to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water while cooling. After stirring at room temperature for 4 hours, the mixture was acidified with 10% citric acid solution, THF was concentrated in a rotary evaporator (partially) and the residue was partitioned between 3 parts ethyl acetate, 2 parts 2N aqueous sodium hydroxide solution, water, saturated sodium bicarbonate solution. and with the Tank. After the organic phases are combined, dried over sodium sulphate and evaporated, the residue is dissolved in a small amount of methylene chloride and the desired compound is obtained by crystallization after addition of hexane.

Thin layer chromatography: R (N) = 0.36, t Rt (I) = 16.8 min, ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 7.24 (dd, 6 and 5 Hz, 2H),

6.98 (t, 8 Hz, 2H),

3.73 (m, IH);

3.47 (d, 5Hz, 2H).

2.88 (dd, 13 and 6 Hz, 1H),

2.62 (dd, 13 and 8 Hz, 1H),

1.36 (s, 9H).

c) N-Boc- (p-fluorophenylalaninal)

To a cooled solution (-60 ° C) of 4.0 mL (46.8 mmol) of oxalyl chloride in 4.44 mL (62.4 mmol) of methylene chloride was added dropwise a solution of 4.44 mL (62.4 mmol) under nitrogen. DMSO in 76 mL of methylene chloride. After stirring for 15 minutes, 8.4 g (31.2 mmol) of N-Boc- (p-fluorophenyl 1 and 1-ananol) were added to the clear reaction mixture as a solution in 185 mL of a 1: 1 mixture of methylene chloride and THF ( -> precipitation e) and the mixture is stirred for 25 minutes. 17.3 ml (124.8 mmol) of triethylamine dissolved in 38 ml of methylene chloride are then added. After stirring for 30 minutes, 278 ml of 20% potassium hydrogen sulphate solution was added dropwise followed by 220 ml of hexane. The reaction mixture was allowed to warm to room temperature. The aqueous phase was separated and extracted with 2 portions of ether. Washing the organic phases with saturated sodium bicarbonate solution, water and brine, drying them over sodium sulfate and evaporation affords the title compound which is used in the next step without further purification.

Η-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3) 9.63 (s, 1H),

6.9-7.2 (2m, 4H);

5.04 (m, 1 H);

198

4.42 (m, 1 H);

3.1 Ο (m, 2Η), .43 (S, 9Η).

d) N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4- (p-fluorophenyl) -1-trimethylsilyl 1-butane

In a manner analogous to that described in Reference Example 16a, 1.63 g (67 mmol) of magnesium in 33 ml of absolute ether was reacted with 8.3 ml (60 mmol) of chloromethyltrimethylsilane to give the Grignard compound, which, after treatment with 13 mmol of N-Boc- (pf 1-fluorophenyl and 1-on-1), extraction and chromatography on a silica gel column, eluting with a hexane / ethyl acetate (5: 1 -> 4: 1 by volume) mixture yields the diastereomeric a mixture of the desired compounds. Thin layer chromatography: R + - (L) - 0.32, t Ret (I) 24.9 min (22)) / 25.5 min (78%), mass spectrum (fast atom ionization): (M + H) ) * = 356

e) 1- (p-Fluorophenyl) -3-butene-2 (S) -amine

In a manner analogous to that described in Reference Example 16b, 1.1 g (3.1 mmol) of N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4 are reacted. - (p-fluorophenyl) -1-trimethylsilylbutane in 22 ml of methylene chloride with 1.9 ml (15.5 mmol) of an approximately 48% solution of boron trifluoride in ether to give the title compound.

H-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CDCl ₃ ), 7.2-7.10, and 7, O5-e, S (2m, for 2H),

5.9-5 _: 3 (m, IH),

5.2-5.0 (m, 2H), 57 (m, 1H), 7.9 (dd, 12 and 6 Hz, 1H), 6.22 (dd, 12 and 8 Hz, 1H), 7 (s, broad, 2H).

199

f) N-Trifluoroacetyl-1- (p-fluorophenyl) -3-butene-2 (S) -amine

In a manner analogous to that described in Reference Example 16c, 364 mg (2.2 mmol) of 1- (p-fluorophenyl) -3-buten-2 (S) -amine in 1.8 ml of methylene chloride are reacted. and 5.4 ml of pyridine 460 µl (3.3 mmol) of trifluoroacetic anhydride to give the title compound which is pure after digestion with hexane.

Thin-layer chromatography; Rf (F) = 0.58, Mass Spectrum: (M) &lt; ^{+ &gt;} - 261.

g) 2 (R) - / 1 '- (S) - (Trifluoroacetylamino) -2' - (p-fluorophenyl) ethyl / oxirane

In a manner analogous to that described in Reference Example 16d, 359 mg (1.37 mmol) of N-trifluoroacetyl-1- (p-fluorophenyl) -3-buten-2 (S) -amine was oxidized in 9 ml of chloroform using 1.18 g (6.87 mmol) of m-chloroperbenzoic acid to give the title compound.

TLC: Rf (R) = 0.45.

(h) N-Trifluoroacetyl - / (pF) Phe ^IMN (pF) Phe / -Boc

In a manner analogous to that described in Reference Example 16, 415 mg (1.49 mmol) of 2 (R) - / 1 '- (S) - (trifluoroacetylamino) -2' - (p-fluorophenyl) are reacted. ethyl 7-oxirane and 37 mg (1.57 mmol) of tert-butyl 3- (p-fluorophenylmethyl) carbazate in 9 ml of methanol to give the title compound. Thin layer chromatography: Rt (S) - 0.53, mass spectrum (fast atom ionization): (M + H) - '= 518. ¹ H-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CDOD) 7.4-7.3 and 7.3-7.2 (2m, for 2H),

7.05 to 6.9 (m, 4H);

4.23 (m, 1H),

3.90-3.65 (m, 3H);

3.03-2.78 and 2.74-2.60 (2m for 2H),

200-130 (s, 9H). 199

i) H - / (pF) Phe ^{N N} (pF) Phe / -Boe

In a manner analogous to that described in Reference Example 17a, 285 mg (0.55 mmol) of N-1-trifluoroacetyl-1 (pF) Phe ^NN (pF) P h / -Boc are reacted. 45 ml of methanol with 14 ml of 1M aqueous potassium carbonate solution to give the title compound.

IR (I) - 16.4 min.

Reference example 32

Z- (L) -Val - / (pF) Phe ^NN (pF) Phe / -H

In a manner analogous to that described in Reference Example 18a, 215 mg (0.33 mmol) of Z- (L) -Va1 / (pF) Phe ^NN (pF) Phe / -Boe were deprotected by treatment with 100 ml of formic acid in formation of the desired compound.

Mass spectrum (F-ionization): (M + H) + = 555.

Reference example 33

Z- (L) - / (pF) Phe ^NN (pF) Phe N - (N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -Val)

In a manner analogous to that described in Reference Example 18, 23.6 mg (0.089 mmol) of N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -valine (prepared according to EP) is reacted. 402646) and 45 mg (0.081 mmol) of Z- (L) -Val / (pF) Phe ^NN (pF) Phe / -H with 33.8 mg (0.089 mmol) of HBTU in 0.76 ml of 0.25M NMM / CH 3 CN to give the desired compound which is recrystallized from a mixture of DMP and DIPE.

Thin layer chromatography: Rt (0) = 0.39,

1 mass spectrum (fast atom ionization): (M + H) - 802

Reference example 34

Z- (L) -Val - / (pF) Phe ^NN (pF) Phe / - (N- (2 (R, S) -carbamoyl-3-phenylpropionyl) (L) -Val)

In a manner analogous to that described in Reference Example 18, 26.0 mg (0.089 mmol) of (N- (2 (R, S) -carbamoyl-3-phenylnylpropionyl) (L) -valine) (prepared according to Synth.Struct., Funct., Proc.Am.Pept.Symp., 7 ^th 85 (1 98 L) and 45 mg (0.081 mmol) Z- (L) -Va1 - / (pF) Phe ^NN (pF) Phe-H (Reference Example 32) with 33.8 mg (0.089 mmol) of HBTU in 0.76 mL of 0.25M NMM in CHaCN to give the desired compound which was recrystallized from a mixture of DMP and DIPE.

Rp (P) -0.64

Mass spectrum (F-ionization): (M + H) + = 829.

Reference example 35

Acetyl-Val- (Phe ^NN Phe) - (N-acetyl-Val)

In a manner analogous to that described in the Reference Example, H- / Phe ^NN Phe / -H was obtained from 100 mg (0.25 mmol). 3HCl from Ref. Example 2a, 121 mg (0.76 mmol) of N-acetyl (L) -valine, 288 mg (0.76 mmol) of HBTU and 0.211 mL (1.52 mmol) of triethylamine in DMF were obtained after lyophilization from dioxane the desired compound.

MS (F-ionization): (M + H) + = 563, t Ret (I) = 15.0 min,

Rt - (B) - 0.46.

Reference example 36

Z- (D) -Val- / Phe ^NN Phe / <- ((D) -Val) -Z

In a manner analogous to that described in Example 210 of Example 2, from 50 mg (0.123 mmol) of H- (Phe) ^NN Phe / -H was obtained. Reference Example 2a 3HCl, 95 mg (0.38 mmol)

Z- (D) -valine, 168 mg (0.38 mmol) of BOP, 51 mg (0.38 mmol) of HOBt and 2.53 ml of 0.3M NMM in DMF upon lyophilization from dioxane gave the title compound.

Mass Spectrum (F-Ionization): (M + H) + - 752 t Ret (I) = 26.4 min,

Rf (H) - 0.21.

Reference example 37

Quinoline-2-carbonyl-Val / L ^NN P he he / <- (N-quinolin-2-karbonylVal)

145 mg (0.53 mmol) of N- (quinol-2-carbonyl) -L) -vinyl, 235 mg (0.53 mmol) of BOP and 72 mg (0.53 mmol) of HOBt are dissolved in 3.5 ml of a 0.3M solution of NMM in DMF, then after 70 minutes 70 mg (0.13 mmol) of H- / Phe ^NIM Phe / -H was added. HCl (Reference Example 2a) and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction mixture is evaporated, the residue is dissolved in methylene chloride and the solution is washed twice with saturated aqueous sodium bicarbonate solution, once with 10% in (another citric acid solution and once with saturated aqueous sodium bicarbonate solution). The organic phases are filtered through cotton wool and evaporated and the residue twice After freeze drying from dioxane, the title compound is obtained as a white solid (a mixture of two diastereomers distinguishable by HPLC).

Mass Spectrum (F-ionization): (M + H) ⁺ - 794, t _Ret (A) = 29.1 and 29.3 min,

Rf (B) = 0.81.

a) N-quinoline-2-carbonyl) - (L) -valine

To a solution of 2.5 g (14.5 mmol) of (L) -vinyl-tert-butyl ester

203

Quinoline-2-carboxylic acid (2.5 g, 14.5 mmol) in 10: 1 methylene chloride / THF (100 ml) was added 3,2, d-dicyclohexylcarbodiimide (3.28 g, 15.9 mmol) and 2.0 ml (3.2 ml). Triethylamine (14.5 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to -18 ° C and the urea was removed by filtration. The filtrate was evaporated, the residue was dissolved in methylene chloride and washed once with saturated aqueous sodium bicarbonate solution and water. The organic phase is filtered through cotton wool, evaporated and the residue is chromatographed on silica gel, eluting with a 2: 1 mixture of hexane and ethyl acetate, then N (quinoline-2-carbonyl) - (L) is obtained from the appropriate eluate fractions. valyl-t. Fnd. 2.59 g (12.2 mmol) of this product was left at room temperature for 4.5 hours in a mixture of methylene chloride and TFA. After evaporation, the residue is purified by chromatography on a column of silica gel, eluting with a hexane / ethyl acetate (2: 1) mixture. The eluate fractions containing the desired product are evaporated, redissolved in methylene chloride, then converted to the hydrochloride of the title compound by washing with 1N sodium hydroxide solution and 1N hydrochloric acid.

¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 1.05 and 1.07 (2d, J = 6Hz, 6H),

2.40 (m, IH),

4.65 (m, 1H), 70 (m, 1H),

7.85 (m. 1H);

8.00 (dd, 1H), 20 (m, 2H),

8.48 (d, IH).

Reference example

Acetyl- (L) -Val- / Phe ^NN Cha / - (N-acetyl- (L) -Val)

204

In a manner analogous to that described in Example 37, H- / Phe ^NN Cha / -H was obtained from 160 mg (0.40 mmol). 3HCl of Reference Example 10a, 190 mg (1.19 mmol) of N-acetyl- (L) -valine, 525 mg (1.19 mmol) of BOP, 160 mg (1.19 mmol) of HOBt and 7.9 mL of 0, 3M NMM in DMF upon precipitation from chloroform / methanol by addition of DIPE and lyophilization from dioxane yields the title compound.

Mass Spectrum (F-Ionization): (M + H) = 754, t Ret (I) - 18.1 min,

Rf (B) = 0.30.

Reference example

N- (3-Pyridylacetyl) - (L) -Val- (Phe ^NIM Cha) - (N- (3-pyridylacetyl- (L) Val)).

In a manner analogous to that described in Reference Example 7, from 100 mg (0.25 mmol) of H- / Phe ^NN Cha / H.3HCl from Reference Example 10a, 358 mg (1.52 mmol) was obtained.

N- (3-pyridyl-acetyl) - (L) -vinyl from Reference Example 9a, 576 mg (1.52 mmol) of HBTU and 0.316 ml (2.28 mmol) of triethylamine in DMF gave the title compound which was chromatographed Purification on silica gel, eluting with methylene chloride / methanol (15: 1, v / v), afforded by isolating the eluate fractions containing this compound from dioxane.

Mass spectrum (F-ionization): (M + H) = 728, t Ret = 11.3 min,

Rf (U) = 0.21.

Reference example

Acety1-1le- / Phe ^NN Cha / <- (N-acetyl 1 -11 e)

In a manner analogous to that described in Reference Example ^37, H- / Phe ^IMN Cha / -H was obtained from 160 mg (0.40 mmol).

205

3HCl from Reference Example 10a, 206 mg (1.19 mmol)

N-acetyl- (L) -i from 1eucine, 52 mg (1.19 mmol) of BOP, 160 mg (1.19 mmol) of HOBt and 7.9 ml of 0.3M NMM in DMF after precipitation from a mixture of methylene chloride and methanol by addition of DIPE and lyophilization from dioxane / butanol gave the title compound (a mixture of two diastereomers distinguishable by high pressure liquid chromatometry).

Mass Spectrum (F-Ionization): (M + H) + = 602, t Ret (I) = 20.4 and 20.7 min,

R t (D) = 0.33.

Reference example

T i omor fo l i nokarbony 1 - (L) -Va 1 - / Phe ^Nrj Cha / <- (Nt i omor fo l i nocarbony 1 - (L) - V a 1

Using a procedure analogous to that described in Example 6, from 70 mg (0.12 mmol) of H- (L-Val) (Phe ^NN Cha / - (N- (L) -Val) -H 3 HCl) from Reference Example 14, mg (0.35 mmol) of (4-thiomorpholinylcarbonyl) chloride from Reference Example 6a and 0.127 ml of triethylamine in 2 ml of DMF after chromatography on silica gel using a 95: 5 mixture of methylene chloride and methanol; lyophilization of the appropriate fractions from dioxane affords the title compound.

MS (FAB): (M + H) + = 748, t R _e, (I) - 24.0 min;

R f (B) = 0.70.

Reference example 42

Z- (L) -Glu- / Phe ^NN (pF) Phe / - ((L) -Glu) -Z

A solution of 130 mg (0.14 mmol) of Z- (L) -G 1 u (0-tert-butyl) -Phe ^NN (pF) Phe / - ((L) -G 1 u (0-tert)). Butyl 1) - from (Glu(0- tert-butyl) here means the glutamic acid radical ester esterified on the gamma206 carboxyl group with a tert-butyl residue / in 8 ml of a 1: 1 mixture of methylene chloride and TFA is stirred 3 The solvent was evaporated under reduced pressure, the residue was dissolved in methylene chloride, and the product was precipitated by the addition of DIPE to give the title compound after lyophilization from a mixture of dioxane and tert-butanol.

Mass spectrum (F-ionization): (M + H) + = 830, t _R and (I) = 19.6 min, rt (B) = 0.32.

a) Z- (L) -G 1 u (O-t-butyl) - / Phe ^NN (pF) Phe / - ((L) -G 1 u (O-t-butyl)) - Z

Following a procedure analogous to that described in Reference Example 37, from 100 mg (0.24 mmol) of H- / Phe ^NN (pF) Phe / -H 3 HCl, 245 mg (0.73 mmol) of tert. Z (L) -glutamic acid butyl ester, 321 mg (0.73 mmol) of BOP, 98 mg (0.73 mmol) of HOBt and 4.8 mL of 0.3M NMM in DMF after chromatography on silica gel using a mixture of eluents methylene chloride / ether (1: 1 by volume) gave the title compound.

t Ret (I) = 30.2 min,

Rf (H) = 0.17.

b) H- / Phe ^NN (pF) Phe / -H 3 HCl

Following a procedure analogous to that described in Reference Example 2a, the title compound is obtained from 1.77 g (3.51 mmol) &lt; 3 &gt; / ^phe / Phe / Boc after lyophilization. Mass Spectrum (F-ionization): (M + H) + = 304, Rf (K) - 0.19.

c) Boe- / Phe ^NN (pF) Phe / -Boe

In a manner analogous to that described in Reference Example 1, 2.0 g (7.60 mmol) of (2 R) - / 1 '- (S) -Boe 2 O-amide-2'-phenyl-ethyl / oxirane are obtained and 2.17 g (9.04 mmol) of tert-butyl-3- (4-fluorophenylmethyl) carbamate from Reference Example 16f after chromatography on silica gel using hexane / ethyl acetate (2: 1) to give the desired product compound.

Mass Spectrum (F-ionization): (M + H) ⁺ = 504, t Ret (I) = 26.2 min,

Rf (F) = 0.26.

Reference example

N- (2-Pyridylmethyl) -N-methylaminocarbonyl- (L) -Val- / Phe ^NN (pF) P h - (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -Val)

In a manner analogous to that described in Reference Example 37, from 70 mg (0.17 mmol) of H- / Phe ^NN (pF) Phe / -H.3HCl from Reference Example 42b, 135 mg (0.51 mmol) was obtained.

N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl- (L) -valine (prepared according to EP 0 402 646 A1), 225 mg (0.51 mmol) of BOP, 69 mg (0.51 mmol) of HOBt and 3.4 ml of 0.3M NMM in DMF, after chromatography on silica gel, eluting with methylene chloride / methanol (15: 1 by volume) and lyophilized fractions containing the product from dioxane, gave the title compound.

MS (F-ionization): (M + H) + = 798, t r e. (IV) = 35min

Rf - (U) = 0.21.

Reference example

N- (3-Tetrazol-1-yl) propionyl) -Val - [(pF) Phe ^NN (pF) Phe] - (N (3- (tetrazol-1-yl) propionyl) - V and 1)

In a manner analogous to that described in Reference Example 37, from 100 mg (0.24 nm) of H- / Phe ^NN (pF) Phe / -H.3HCl (from Reference Example 42b), 146 mg (0, N- (3-tetrazol-1-yl) -propionyl) - (L) -valine, 268 mg (0.61 mmol) BOP, 82 mg (0.61 mmol) HOBt and 4 mL 0.3M NMM in DMF, after precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane, the title compound is obtained (4 diastereomers distinguishable by high pressure liquid chromatography).

MS (F-ionization): (M + H) + = 750, t Ret (III) - 30.8, 31.4, 32.4 and 32.8 min,

R t (K) = 0.5.

(a) N- (3- (tetrazol-1-yl) propionyl) -L) -vinyl

In a manner analogous to that described in Reference Example 9b, from 4 g (16.4 mmol) of (L) -valine-benzyl ester.HCl, 2.1 g (14.9 mmol) of 3- (tetrazole-1) acid are obtained. 1-propionic acid (prepared according to US 4,794,109 A), 2.4 ml of cyanophosphonic acid diethyl ester and 4.4 ml of triethylamine in DMF after chromatographic purification on silica gel using methylene chloride / methanol (30: 1 by volume) gives N- ( 3- (tetrazol-1-yl) -propionyl) - (L) -valine benzyl ester. 2.66 g (8.03 mmol) of this product is hydrogenated in 9: 1 methanol / water in the presence of 530 mg of 10% palladium on carbon at 50 psi hydrogen, then precipitated from methanol by addition of DIPE. to give the title compound.

Ή-Nuclear Magnetic Resonance Spectrum:

(2200 MHz, CDOD) 0.9 (d, J = 7HZ, 6H), 1 (m, 1H), 9.5 (m, 2H),

4.29 (d, J = 6 Hz, 1H), 7.88 (m, 2H), 1.5 (s, 1H).

Reference example

Z- (L) -Va1 - / Phe ^NN (pF) Phe / - ((L) -Val) -Z

In a manner analogous to that described in Reference Example 37, from 100 mg (0.24 mmol),

H- / Phe ^ΝΝ (pF) P h / Η3 HCl 1 (from Reference Example 42b), 182 mg (0.38 mmol) Z- (L) -valine, 321 mg (0.73 mmol) BOP, 98 mg (0.73 mmol) of HOBt and 4.8 mL of 0.3M NMM in DMF upon precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane gave the title compound.

Mass Spectrum (F-ionization): (M + H) + = 770, t _Re t (I) = 26.3 min,

Rf - (H) = 0.25.

Reference example 46

Acetyl-Val- / Phe ^NN (pF) Phe- (N-acetyl-Val)

In a manner analogous to that described in Reference Example 37, from 80 mg (0.19 mmol) of H- / Phe ^NN (pF) Phe / -H.3HCl from Reference Example 42b, 124 mg (0.78 mmol) was obtained. Macethyl- (L) -valine, 344 mg (0.78 mmol) of BOP, 105 mg (0.76 mmol) of HOBt and 4.5 mL of 0.3M NMM in DMF after precipitating twice from methylene chloride / methanol by addition of DIPE and lyophilization from the mixture of dioxane and tert-butanol, the title compound is obtained. Mass spectrum (F-ionization): (M + H) + = 586, t _Re t (I) - 15.8 min,

Rf - (E) = 0.32.

Reference example

Acetyl-Val- / Phe ^NN (p-CN) Phe- (N-acetyl-Val)

In a manner analogous to that described in Reference Example 37, from 80 mg (0.19 mmol) of H- / Phe ^NN (pF) Phe / -H.3HCl, 124 mg (0.78 mmol) of N-acetyl- (L) -will, 344 mg (0.78 mmol) of BOP, 105 mg (0.73 mmol) of HOBt and 4.5 mL of 0.3M NMM in DMF after precipitation from methylene chloride / methanol by addition of DIPE and lyophilization from dioxane gave the title compound as a mixture of 2 diastereomers resolvable by high pressure liquid chromatography.

10

Mass Spectrum (F-Ionization): (M + H) + = 593, t r e (I) - 14.4 and 14.6 min,

Re (D) = 0.39.

a) H- / Phe ^NN (p-CN) Phe / -H 3 HCl

Following a procedure analogous to that described in Reference Example 2a, the title compound was obtained from 2.69 g (5.27 mmol) of Boe- / Phe ^NN (pCN) Phe / -Boc after lyophilization. Mass spectrum (F-ionization): (M + H) + = 311, R + - (K) = 0.16.

b) Boe- / Phe ^NN (p-CN) Phe / -Boe

In a manner analogous to that described in Reference Example 1, 2.0 g (7.60 mmol) of (2R) - / 1 '(S) -Bocamino-2'-phenylethyl / oxirane and 1.87 g are obtained. (7.6 mmol) of tert-butyl 3- (4-cyanophenylmethyl) carbazate after crystallization from methanol / DIPE gave the title compound.

MS (F-ionization): (M + H) + = 511, t _Rt (I) = 25 min,

R f - (Y) - 0.19.

c) tert -Butyl 3- (4-cyanophenylmethylcarbazate)

In a manner analogous to that described in Reference Example 4b, 10 g (76.3 mmol) of 4-cyanobenzaldehyde and 10 g (76.3 mmol) of tert-butylcarbazate in ethanol are reacted to give 4-cyanophenylcarbaldehyde-tert. butoxykarbonylhyarazónu. 11.1 g of this product are hydrogenated in 10 ml of THF in the presence of 2 g of palladium (10%) on carbon at 50 psi hydrogen to give the title compound.

¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3) 7.75 (d, J = 8 H 2, 2 H),

7.45 (d, J = 8Hz, 2H).

6.0 8 (s, broad, 1H),

4.3 (s, broad, 1 H),

4. O2 (s, 2H) .45 (s, 9H).

Reference example

Z- (L) -Val- / Phe ^NN (pF) Phe / - ((L) -Val) -Z

In a manner analogous to that described in Reference Example 37, from 70 mg (0.17 mmol) of H- / Phe ^NN (pCN) Phe / -H.3 HCl (from Reference Example 47a), 125 mg (0, 5 mmol) of Z- (L) -valine, 221 mg (0.5 mmol) of BOP, 68 mg (0.5 mmol) of HOBt and 3.33 ml of 0.3M NMM in DMF after precipitation from methylene chloride by addition of hexane and lyophilization from dioxane gives the title compound.

MS (FAB): (M + H) + = 777, t r _e t (I) - 25.3 min;

Rf (D) - 0.69.

Reference example 49

Z- (L) -11e- / Phe ^NN Leu / <- ((L) -Ile) -Z

In a manner analogous to that described in Reference Example 37, from 70 (0.19 mmol) H- (Phe ^NN Leu) -H was obtained. 3HCl (from Reference Example 13a), 154 mg (0.58 mmol) Z- (L) -isoleucine, 257 mg (0.58 mmol) BOP, 79 mg (0.58 mmol) HOBt and 3.88 mL 0, 3M NMM in DMF after chromatography on silica gel using a 3: 1 mixture of methylene chloride and ether and precipitation of the product containing fractions from methylene chloride by addition of DIPE and lyophilization from dioxane gave the title compound.

Mass spectrum (F-ionization): (M + H) + = 746, t R.t (I) = 28.2 min,

Rf (H) - 0.39.

12

Reference example 50

Isobutoxycarbonyl- (L) -Val- (Phe ^NN Leu) <- (N-isobutoxycarbonyl (L) -Val

In a manner analogous to that described in Reference Example 37, from 70 mg (0.19 mmol) of H- / Phe ^NN Leu / H.3HCl (from Reference Example 13a), 130 mg (0.58 mmol)

N- (1-isobutoxycarbonyl) - (L) -valine, 256 mg (0.58 mmol) BOP, 78 mg (0.58 mmol) HOBt and 3.9 mL 0.3M NMM in DMF after chromatography on silica gel at using a 1: 1 mixture of methylene chloride and ether in a 1: 1 by volume ratio and a 1: 1 fraction of product containing dioxane yields the title compound.

Mass Spectrum (F-Ionization): (M + H) + = 650 t Ret (I) = 26.4 min,

Rf (H) = 0.38.

a) N- (Isobutoxycarbonyl) - (L) -vinyl;

To a solution of (L) -valine (10 g, 85.3 mmol) in 2N sodium hydroxide solution (100 mL) was added isobutyl chloroformate (11.2 mL, 85.3 mmol) and then stirred at room temperature for 18 hours. The reaction solution was washed with methylene chloride, acidified with 4N hydrochloric acid, and extracted with methylene chloride. The organic extracts were washed with brine, filtered through cotton wool and evaporated to give the title compound as a colorless resin.

H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) O, 95 (m, 12h), 9 (m, 1H),

2.15 (m, IH);

3.85 (d, J = 7 Hz, 2H);

4.0 5 (d, broad, 1H).

Reference example 51

13 '

N- (3-Tetrazol-1-yl) propionyl) - (L) -Val- (Phe ^NN Leu) - (N-3- (tetrazol-1-yl) -propionyl- (L) -Val) )

In a manner analogous to that described in Reference Example 37, 150 mg (0.42 mmol) was obtained from 150 mg (0.42 mmol).

H- (Phe ^NM Leu) -H. 3 HCl (from Reference Example 13a), 251 mg (1.04 mmol) of N-3- (tetrazol-1-ylpropionyl) - (L) -valine from Reference Example 44a, 460 mg (1.04 mmol) of BOP, 140 mg (1.04 mmol) of HOBt and 6.9 ml of 0.3M N-methylmorpholine in DMF after precipitation from methylene chloride by addition of DIPE and lyophilization from a mixture of dioxane, tert-butanol and water gave the title compound.

MS (FAB): (M + H) + - 689, t r _e t (I) = 14.7 min;

Rf (K) = 0.36.

Reference example

Acetyl-Val- (Phe ^NN teu) - (N-acetyl-Val)

In a manner analogous to that described in Reference Example 37, 70 mg (0.19 mmol) of H- / Phe ^NN L eu / -H was obtained. 3HCl (from Reference Example 13a), 184 mg (1.16 mmol) N-acemmol) BOP, 156 mg (1.1 mmol) HOBt precipitated from methylene chloride and lyophilized from dioxane, desired compound (2 diastereomers resolvable by high pressure) liquid chromatography).

Mass Spectrum (F-Ionization): (M + H) + = 534, IR (I) = 14.7 and 15.1 min,

Rf - (D) = 0.35.

Reference Example 53 1- (L) -valine, 512 mg (1.1 and 7.8 mL of 0.3M NMM in DMF after methanol) by adding DIPE tert-butanol

Boc- (L) -Val- / Phe ^IMrj Leu / <- ((L) -Val) -Boe

14

In a manner analogous to that described in Reference Example 7, from 300 mg (0.83 mmol) of H- (Phe ^NN Leu) -H was obtained.

3H Cl (from Reference Example 13a), 7 2 2 mg (3.33 mmol) of Boe- (L) -vinyl, 1.262 (3.33 mmol) of HBTU and 0.927 ml (6.66 mmol) of triethylamine in DMF after chromatography Purification on silica gel using a 1: 1 v / v mixture of methylene chloride and ether to precipitate the product fractions and freeze-drying from dioxane gave the title compound.

MS (F-ionization): (M + H) + = 650, t r e (I) = 26.3 min;

Rf - (H) - 0.64.

Reference example

H- (L) -Va1- (Phe ^NN Leu) <- ((L) -Val) -H3 HCl

In a manner analogous to that described in Reference Example 5, from 396 mg (0.61 mmol) of Boe- (L) -Va1 / Phe ^NN Leu / <- ((L) -Va1) -Boe 'from the Reference Example 53 and 10 ml of 4N hydrochloric acid in dioxane gave the title compound after lyophilization of the reaction solution.

Mass Spectrum (F-ionization): (M + H) + = 450, t _Ret (II) = 24.1 min,

Rf (K) - 0.25.

Reference example 55

N-thiomorpholinocarbonyl- (L) -Val- (Phe ^NN Leu) <- (N-thiomorpholino-carbonyl- (L) -Val)

In a manner analogous to that of Example 6, from 100 mg / Phe ^NN Leu / - (L) -Va1-H3HCl, 78.5 mg of inocarbonyl 1) chloride from reference triethylamine in DMF after eye chromatography Purification on silica by the procedure described in (0.16 mmol) of H- (L) -Va1 (0.47 mmol) (4-thiomorphophase 6a and 0.172 ml)

215 gel using a 95: 5 mixture of methylene chloride and methanol, precipitation of product containing fractions from methylene chloride by addition of hexane and lyophilization from dioxane gave the title compound as a solid amorphous product.

MS (F-ionization): (M + H) - 708, t _Ret (I) - 21.4 min,

Rt - (E) - 0.45.

Reference example

2 (R, S) -Tetrahydrofurylmethoxycarbonyl- (L) -Val- (Cha ^NIM Leu) <- (N2 (R, S) tetrahydrofurylmethoxycarbonyl- (L) -Val)

In a manner analogous to that described in Reference Example 37, from 80 mg (0.22 mmol) of H- (Cha ^NN Leu / -H.3HCl, 160 mg (0.65 mmol) of N- / 2 (R, S) tetrofluoromethylmethoxycarbonyl) - (L) -vinyl, 289 mg (0.65 mmol) BOP, 88 mg (0.65 mmol)

HOBt and 4.35 mL of 0.3M NMM in DMF after chromatographic purification on silica gel using ethyl acetate and lyophilization of product containing fractions from dioxane gave the title compound.

MS (F-ionization): (M + H) -712, t Ret (I) = 22.4 min,

Rf (E) = 0.21.

a) H- (Cha ^NN- Leu) -H.3HCl

In a manner analogous to that described in Reference Example 5, 100 mg (83%) of 150 mg (0.33 mmol) of Boe- / Cha ^NN Leu / Boe and 10 ml of 4N hydrochloric acid in dioxane were obtained after lyophilization of the reaction solution. of the desired compound.

Rf (K) = 0.26.

b) Boc / Cha ^NN Leu / Boc

A solution of 200 mg (0.24 mmol) of Boc- (Phe ^NN Leu) -Boc (Reference Example 12) in 15 ml of methanol was hydrogenated in the presence of 10 mg of Nishimura catalyst (rodite platinum dioxide monohydrate, D egussa) at hydrogen pressure of 0, 1 MPa 4 hours. The hydrogenation catalyst is filtered off, the filtrate is evaporated completely and crystallized from methylene chloride with hexane added to give the title compound.

t Ret (I) = 26.7 min,

Rf (V) = 0.21.

c) N- (2 (R, S) -tetrahydrofurylmethoxycarbonyl) - (L) -valine

In a manner analogous to that described in Reference Example 50a, from 7 g (60 mmol) of 2 (R, S) -tetrahydrofurylmethyl chloroformate (prepared according to: Heterocycles 27, 1155 (1988)) in 100 ml of 2 N sodium hydroxide solution and 30 ml. ml of dioxane gives the title compound as a mixture of 2 diastereomers.

t r ® c (11) - 23.5 and 23.8 min.

Reference example

Z-Val- (Phe ^NN Leu) - (N- (3-tetrazol-1-yl) propionyl) -Val

Using a procedure analogous to that described in Reference Example 37, from 100 mg (0.21 mmol) of Z- (L) -Val / Phe ^NN Leu / -H, 75 mg (0.31 mmol) of N- (3) is obtained. -tetrazol-1-yl 1-propionyl 1) (L) -n-n-reference Example 44a, 13 7 mg (0.31 mmol)

BOP, 42 mg (0.31 mmol) of HOBt and 2 ml of 0.3M NMM in DMF after precipitation from methylene chloride by addition of hexane and lyophilization from dioxane / tert-butanol gave the title compound (2 diastereomers distinguishable by high pressure liquid chromatography).

MS (F-ionization): (M + H) + = 708, t Ret (I) = 21.1 and 21.1 min,

Rf (D) = 0.45.

a) Z- (L) -Va1- (Phe ^NN Leu) -H

A solution of 250 mg (0.43 mmol) of Z- (L) - Va1 - (Phe ^NN Leu) -Boe in 5 ml of formic acid was stirred for 7.5 h at room temperature. After this time, starting material was found to be no longer in the reaction mixture by tlc (t _R er (I) = 27.5 min) and the reaction solution was evaporated. The residue was dissolved in chloroform and washed with saturated sodium bicarbonate solution. The chloroform phase is filtered through cotton wool and the crude title compound is obtained after evaporation of the solvents.

t r et (I) = 16.7 min;

Rf (K) = 0.21.

b) Z- (L) -Va1- (Phe ^NN Leu) -Boe

Following a procedure analogous to that described in Reference Example 37, from 230 mg (0.653 mmol) of H- / Phe ^NN Leu / Boc, 247 mg (0.98 mmol) of Z- (L) -valine, 434 mg (0). (98 mmol) of BOP, 133 mg (0.98 mmol) of HOBt and 6.5 mL of 0.3M NMM in DMF upon precipitation from methylene chloride / methanol by addition of DIPE gave the title compound.

Mass Spectrum (F-Ionization): (M + H) ¹ - 585 t Ret (I) - 27.5 min,

Rf - (C) - 0.71.

c) H- (Phe ^NN Leu) -Boe

In a manner analogous to that described in Reference Example 17a, from 1.27 g (2.84 mmol) of N-trifluoromethyl 1- (P h ^NN L eu) -Boe and 24 mL of 1 N aqueous sodium carbonate In 90 ml of methanol, the title compound is obtained, which is precipitated from methylene chloride by addition of DIPE. t _Re t (I) - 14.9 min;

Rf = (K) = 0.38.

d) N-Trifluoroacetyl- (Phe ^NN Leu) -Boc

In a manner analogous to that described in Reference Example 16, 3 g (11.57 mmol) of 2 (R) - / 1 '(S) - (tri-fluoroacetyl-amino) -2'-phenylethyl-oxirane were obtained from 3 g (11.57 mmol). of Reference Example 16d and 2.3 g (12.15 mmol) of tert. Perbutyl carbamate (prepared according to J. Chem. Soc. Perkin I, 1712 (1975)) after chromatographic purification on silica gel using a mixture of methylene chloride and ether in methylene chloride. 20: 1 v / v to give the title compound.

t r e t (I) = 24.7 min;

Rt (W) = 0.36.

Reference example

Acetyl-Val- (Phe ^NN Leu) - (N- (2- (R, S) carbamoyl-3-phenylpropionyl) -Val)

In a manner analogous to that described in Reference Example 37, from 140 mg (0.3 mmol) of acetyl- (L) -Val / Phe ^NN Leu / -H.2HCl, 132 mg (0.45 mmol) of N- (2 (R, S) -carbamoyl-3-phenylpropionyl) - (L) -valine (prepared according to Synth., Struct., Funct., Proc.Am.Pept.Symp. 7 ^r - ^h , 85 (1,980)) BOP, 61 mg (0.45 mmol) of HOBt and 3.5 ml of 0.3M NMM in DMF after precipitation from methylene chloride by addition of DIPE and freeze-drying from dioxane yield the title compound (2). diastereomers distinguishable by high pressure liquid chromatography).

Mass Spectrum (F-ionization): (M + H) ⁺ = 667, t Ret (I) = 17.9 and 18.4 min,

Rf (D) = 0.33.

a) A cets 1 - Va 1 - / P he ^NN L eu / -H. 2 HC 1

Following a procedure analogous to that described in Reference Example 2a, 230 mg (0.46 mmol) of acetyl - (L) - Va1 - (Phe ^NN Leu) -Boe was obtained after lyophilization to give the title compound.

t _Re t (I) = 10.5 min,

Rf (D) = 0.38.

b) Acetyl-N? - (Phe ^NN Leu) -Boe

In a manner analogous to that described in Reference Example 37, from 250 mg (0.71 mmol) of H- / Phe ^NN Leu / Boc from Reference Example 57c, 170 mg (1.07 mmol) of N-azoethyl (L) was obtained. valine, 471 mg (1.07 mmol) of BOP, 144 mg (1.07 mmol) of HOBt and 7.1 mL of 0.3M NMM in DMF after precipitation from methylene chloride by addition of DIPE and freeze-drying of dioxane.

Mass spectrum (F-ionization): (M + H) + = 493 t _R and (I) = 20.5 min;

Rf (D) = 0.59.

Reference example

N-Morpholinocarbonyl- (L) -Val- (Phe ^NN Leu) <- (N- (3- (tetrazol-1-yl) -propionyl) -Val)

In a manner analogous to that described in Reference Example 37, 67 mg (0.38) of 100 mg (0.19 mmol) of N-morpholinocarbonyl-1- (L) -Va1- / Phe ^NN Leu / -H.2HCl. mmol) of N- (3-tetrazol-1-yl) -propionyl) - (L) -valine from Reference Example 44a, 124 mg (0.28 mmol) BOP, 38 mg (0.28 mmol) HOBt and 2.1 mL 0 3M NMM in DMF after precipitation with methylene chloride by addition of DIPE

220 and lyophilization from dioxane gave the title compound (2 diastereomers by high pressure chromatography). MS (F-ionization): (M + H) + = 687, t R t (I) = 15.2 and 15.4 min,

R t (D) = 0.25.

a) N-Morphol inocarbonyl- (L) -Val- (Phe ^NN Leu) -H.2HCl

Following a procedure analogous to that described in Reference Example 2a, the title compound was obtained after lyophilization from 279 mg (0.49 mmol) of N-morpholino-carbonyl-1- (L) -Va1- (Phe ^NN Leu) -Boe.

MS (FAB): (M + H) + = 464 tr θ _t (11) - 30.3 min;

FMD) - 0.46.

b) N-Morphol inocarbonyl- (L) -Val- (Phe ^NN Leu) -Boc

In a manner analogous to that described in Reference Example 37, from 250 mg (0.71 mmol) of H- / Phe ^NN Leu / Boe (from Reference Example 57c), 265 mg (1.07 mmol) of N-morpholino-carbones 1- (L) -vinyl from Reference Example 7a, 471 mg (1.07 mmol) of BOP, 144 mg (1.07 mmol) of HOBt and 7.1 mL of 0.3M NMM in DMF after precipitation from methylene chloride by addition of hexane and lyophilization from dioxane gave the title compound.

MS (F-ionization): (M + H) + = 564, t Ret (I) = 21.5 min,

Rf (K) = 0.69.

Reference example

N-Trifluoroacetyl- (Phe ^NN leu) - (N- (2- (R, S) -carbamoyl-3-phenylpropionyl) - (L) -Va1)

Following a procedure analogous to that described in Reference Example 37, from 136 mg (0.32 mmol) of N-trifluoroacetyl 1- (Phe ^NN L eu) -H.2 HCl 1, 142 mg (0.49 mmol) of N were added. - (2- (R, S) -carbamoyl-1-yl-3-phenylpropionyl) - (L) -valine (prepared according to: Synth., Struct., Funct., Proc. Am.Pept.Symp., 7 ^th , 35 , (1 98 L)), 2 1 5 mg (0.49 mmol) BOP, 66 mg (0.49 mmol) and 3.5 0.3M NMM in DMF after chromatographic purification on silica gel using a mixture of eluents chloroform / methanol (15: 1 by volume), precipitating the product containing fractions from methylene chloride by addition of DIPE and lyophilizing from tert-butanol afforded the title compound (2 distinguishable by high pressure liquid chromatography). Mass Spectrum (F-Ionization): (M + H) + = 622 t Ret (I) - 21.6 and 22.0 min,

Rf (K) = 0.26.

mixtures of dioxane and astereomers

a) N-Trifluoroacetyl- (Phe ^NN Leu) -H.2HCl

Following a procedure analogous to that described in Reference Example 2a, from 300 mg (0.67 mmol) of N-trifluoroacetyl- (Phe ^NN Leu) -Boe from Reference Example 57d after freeze-drying, the title compound is obtained.

R f (W) less than 0.1.

Reference example 61

Z- (L) -Val- / Phe ^{N '} Nl e / - (N- (2- (R, S) - (N- (2-morpholinoethyl) carbamoyl-3-methyl) -butyryl))

In a manner analogous to that described in Reference Example 37, from 100 mg (0.17 mmol) of Z- (L) -Val / Phe ^NM N1e / -H.2HCl, 69 mg (0.27 mmol) of acid 2 was obtained. (R, S) - (N- (2-Morpholinoethyl) carbamoyl-3-methylbutyric acid (N- (2-morpholinoethyl) monoamide) isopropylamino), 119 mg (0.27 mmol) BOP, mg (0.27 mmol) HOBt and 2 1 ml of 0.3M NMM in DMF, precipitated from methylene chloride after addition of DIPE and lyophilized from dioxane, affords the title compound (2 diastereomers distinguishable by high pressure liquid chromatography).

Mass Spectrum (F-Ionization): (M + H) + - 725,

222 t Ret (I) = 17.2a17.6min,

Rf (D) = 0.56.

a) Z- (L) -Va 1 - (Phe ^NN N 1 e) -H. 2HCl. 1

Following a procedure analogous to that described in Reference Example 2a, from 310 mg (0.53 mmol) of Z- (L) -Val / Phe ^NN N1e / -Boc the title compound was obtained after lyophilization. t _Ret (I) = 16.4 min;

Rf @ - (U) = 0.25.

b) Z- (L) -Va 1 - / Phe ^NN N 1 e -Boe

In a manner analogous to that described in Reference Example 37, from 250 mg (0.71 mmol) of H- / Phe ^@ 1 M 1 e / Soc, 268 mg (1.07 mmol) of Z- (L) -valine 4.72 mg (1.07 mmol) of BOP, 144 mg (1.07 mmol) of HOBt and 7.1 mL of 0.3M NMM in DMF after chromatography on silica gel using a 40: 40 mixture of methylene chloride and methanol as eluent. : 1, and precipitation of product containing fractions from methylene chloride by addition of DIPE affords the title compound.

tr _e t (I) = 5.6 min 2,

Rf - (X) = 0.17.

c) H- (Phe ^NN N1e) -Boc

By proceeding in a similar manner as described in Reference Example 17, from 830 mg (1.85 mmol) of N-tri f 1uóracetyl- / L ^NN Nle he / -Boe after precipitation from methylene chloride by addition of DIPE gives the title compound.

t Rt (I) = 15.4 min,

R t (K) = 0.54.

d) N-trifluoroacetyl- (Phe ^NN Nle) -Boc

In a manner analogous to that described in Reference Example 16, from 1 g (3.86 mmol) of 2 (R) - / 1 '- (S) - (trifluoromethylamino) -2'-phenylethyl / oxi Reference Example 16d wound and 720 mg (3.86 mmol) tert. Purification by chromatography on silica gel using a 20: 1 mixture of methylene chloride and ether yields the title compound.

tr _e -t (I) = 25.3 min;

Rf (Q) = 0.43.

e) tert. Butyl-3-butylcarbazate

In a manner analogous to that described in Reference Example 4b, the corresponding tert-butoxycarbonylhydrazone is obtained from 18.0 g (136.2 mmol) of t-butyl, arbazate and 12.3 ml (136.2 mmol) of n-butanol. (25 g, 99%) as a crude product, which was hydrogenated according to Reference Example 4a in the presence of 10 g of 5% platinum on carbon under a hydrogen pressure of 0.4 MPa. Chromatography of the crude product on silica gel (hexane / ethyl acetate 1: 1) gave the title compound.

Rf (N) = 0.44, ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 0.9 2 (t, J = 7 H of, 3 H),

1.43 (s, 9H);

1.30-1.50 (m, 4H); 2.75 (t, J = 7 Hz, 2H).

f) 2 (R, S) - (N- (2-Morpholinoethyl)) carbamoyl-3-methylbutyric acid

In a manner analogous to that described in Reference Example 9b, from 7 g (43.7 mmol) of racemic isopropyl-isopropyl-1-methyl-1-methyl ester ishem. 11, 1196 (1 986)), 6.3 ml (48.1 mmol) of aminoethylmorpholine, 6.6 ml (43.7 mmol) of cyanophosphonic acid diethyl ester and 12.8 ml (91.8 mmol)

224 mmol) of triethylamine in DMF gives 2 (R, S) (Ν-2-morpholinoethyl) -carbamoyl-3-methylbutyric acid methyl ester (Nmorpholinoethyl 1-amide for isopropyl malonic acid). The product is stirred at room temperature for 5 hours in a mixture of 28 ml of 2N sodium hydroxide solution and 28 ml of dioxane, then the mixture is acidified with 2N hydrochloric acid and evaporated completely. The residue is digested with ethanol, filtered and the filtrate is evaporated to give the title compound.

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 0.95 and 1.00 (2d, J = 7H, 6H), 25 (m, 4H),

2.70 (m, 6H), 7.5 (d, J = 8HZ, 1H),

3.45 (m, 2H).

3.75 (m, 4 H).

Reference example

Z- (L) -Val- / Phe ^NN Nle / N - (N- (3- (tetrazol-1-yl) propionyl) -Va1

In a manner analogous to that described in Reference Example 37, from 100 mg (0.18 mmol) of Z- (L) -Val / Phe ^NN -N1e / -H.2HCl (from Reference Example 61a), 65 mg ( 0.27 mmol) of N- (3- (tetrazol-1-yl) propionyl) - (L) -valine from Reference Example 44a, 119 mg (0.27 mmol) of BOP, 36 mg (mmol) of HOBt and 2.1 ml of 0.3M N-methylmorpholine in DMF after precipitation from methylene chloride by addition of DIPE and lyophilization from a mixture of dioxane and tert-butanol gives the title compound (2 diastereomers distinguishable by high pressure liquid chromatography).

Mass Spectrum (F-Ionization): (M + H) + = 708 t _R et (I) - 20.3 and 20.6 min,

Rf (D) = 0.43.

Reference example

Z- (L) -Val- / Phe ^NN Nle / N - (N- (2 (R, S) - (N-pyridylmethyl) carbamoyl) -3-methyl) butyryl) (dibenzenesulfonate)

225

In a manner analogous to that described in Reference Example 37, from 95 mg (0.17 mmol) of Z- (L) -Val / Phe ^{NIM N1e} / -H. 2HCl from Reference Example 61a, 60 mg (0.26 mmol) of N- (2-piperidyl) monoamido (R, S) -isopropylamine, 113 mg (0.26 mmol) of BOP, 35 mg (0, 26 mmol) of HOBt and 2.0 mL of 0.3M NMM in DMF after chromatographic purification on silica gel, eluting with methylene chloride: methanol (15: 1, v / v), afforded the title compound as a free amine. This product is dissolved in methylene chloride, then 2 equivalents of benzenesulfonic acid are added to the solution obtained, followed by precipitation by addition of DIPE. After freeze-drying from t-butanol, the dibenzenesulfonate salt (2 diastereomers expanded by high pressure liquid chromatography) is obtained.

Mass Spectrum (F-Ionization): (M + H) + = 703 trt (I) - 17.7 and 18.0 min,

Rf - (D) = 0.54.

(a) N- (2-Piperoyl) mono-isopropyl-1-ammonium acid

To a solution of 15 g (93.6 mmol) of isopropylmalonic acid monomethyl ester (prepared according to: Chem.Ber, 119,1196 (1986) in 150 mL of THF) was added 10.6 mL (103 mmol) of N-methylmorpholine, followed by a dropwise addition of 13 N-methylmorpholine. 5 ml (103 mmol) of isobutyl chloroformate After 30 minutes, 15.3 ml (150 mmol) of 2-picolyamine are added and the suspension is stirred for 2 hours, then the reaction mixture is diluted with 1N sodium hydroxide solution and water and washed with methylene chloride. The organic phase is filtered through cotton wool and evaporated to crystallize the residue to give N- (2-picolyamide) methyl isopropylmalonate which is hydrolyzed as described in Reference Example 61T with 2N sodium hydroxide and dioxane to give the title compound.

t Ret (II) = 16.0 min.

Reference example

226

Z- (L) -Val- / Phe ^NN (pF) Phe- (N- (3- (tetrazol-1-yl) propionyl) (L) -Val (benzenesulfonate)

In a manner analogous to that described in Reference Example 37, from 100 mg (0.16 mmol) of Z- (L) -Val (Phe ^NN (pF) Phe / -H from Reference Example 22a, 59 mg (0, 25 mmol) of N- (3- (tetrazol-1-yl) propionyl) - (L) -valine from Reference Example 44a, 109 mg (0.25 mmol) of BOP, 33 mg (0.25 mmol) of HOBt and 1, 19 ml of 0.3M N-methylmorpholine in DMP after precipitation from methylene chloride by addition of DIPE gives the title compound as the free amine, the product is dissolved in a mixture of methylene chloride and methanol, and one equivalent of benzenesulfonic acid is added thereto, followed by precipitation After freeze drying from t-butanol, the title compound is obtained as the benzenesulfonate salt.

MS (FAB): (M + H) ⁺ = 760, t r _e t (I) = 21.6 min;

Rf (B) = 0.49.

Reference example

Methylsulfonyl- (Phe ^NN Phe) - (N-phenylacetyl) - (L) -Val)

In a manner analogous to that described in Reference Example 7, 132 mg (0.28 mmol) of methylsulfonyl- (Phe ^NN Phe / -H. 2 HC1 with 197 rng (0) were reacted. , 84 mmol)

N-phenyl-acetyl- (L) -valine (prepared according to: Memokyo Ini v. Agric. 20, 51 (1978)), 317 mg (0.84 mmol) of HBlU and 0.23 ml (1.67) mmol) triethylamine in DMF. Precipitation from methanol by addition of ether gives the title compound.

Mass spectrum (F-ionization): (M + H) + = 581, t Ret (I) = 20.2 min,

Rf (B) = 0.64.

a) Methylsulfonyl- (Phe ^NN Phe / -H.2NCl

227

Following a procedure analogous to that described in Reference Example 2a, the title compound was obtained from 130 mg (0.28 mmol) of methylsulfonyl 1 (Phe ^NN Phe / -Boc after lyophilization). (M + H) + = 364, _tt (II) = 28.5 min,

R f (K) = 0.56.

b) Methyl sulfonyl 1- (Phe ^NN Phe / -Boe

In a manner analogous to that described in Reference Example 16a, from 1.1 g (4.56 mmol),

2 (R) - / 1 '(S) - (methylsulfonyl) -2'-phenylethyl / oxirane and 1.11 g (5.02 mmol) of tert-butyl-3-benzyl carbazate (prepared according to J. Chem. Soc.Perkin I, 1712 (1975)) yields the title compound as a diastereomeric mixture in which the individual diastereomers are represented 4: 1. After crystallization from methylene chloride / hexane, the ratio is changed to 10: 1 in favor of 2 S-d 1 and stereomers.

Mass Spectrum (F-Ionization): (M + H) + = 464, t _rt (I) = 21.3 min,

R @ + - (N) - 0.26.

c) 2 (R) - / 1 '(S) - (Methylsulfonamino) -2'-phenylethyl / oxirane

To a solution of 1-phenyl-3-buten-2 (S) -amine (1 g, 6.8 mmol) from Reference Example 16b in 10 mL of methylene chloride was added 2.36 g (13.6 mmol) of anhydride at 0 ° C. methanesulfonic acid and 1.88 mL (13.6 mmol) of triethylamine and the mixture was stirred for one hour. The reaction mixture is then washed with water and saturated sodium bicarbonate solution, the organic phase is filtered through cotton wool and evaporated to give 2 (S) -methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of this crude product was dissolved in 30 ml of methylene chloride and 3.05 g (17.7 mmol) of 4-chloroperbenzoic acid was added at room temperature, then the mixture was stirred for 18 hours. The reaction mixture was washed five times with a 10% aqueous sulfite solution

228 sodium, filtered through cotton wool and evaporated completely. The crude product obtained contains po

Ez-Nuclear Magnetic Resonance Spectroscopy and both (2R) and (2S) -epimers in a 4: 1 ratio.

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 2.30 and 2.52 (2 s, s at 1 each 3H),

2.6-3.2 (m, 5H),

3.55 (m, 1H), 32 (m, 5H).

Reference example

Methoxycarbonyl- (L) -Val- (Phe ^NN Leu) <- (N-methoxycarbonyl- (L) -Va1

In a manner analogous to that described in Reference Example 37, from 200 µg (0.55 mmol) of H- / Phe ^NN Leu / H 3 HCl (from Reference Example 13a), 291 mg (1.66 mmol) of N- 1- (L) -vinyl (prepared according to: Chem.Lett. 705, (1980), 735 mg (1.66 mmol) BOP, 225 mg (1.66 mmol) HOBt and 11 ml 0, 3M NMM in DMF upon precipitation from methylene chloride by addition of DIPE and isolation from dioxane gave the title compound.

MS (F-ionization): (M + H) + = 566, t Ret (I) = 18.6 min,

R @ + - (U) = 0.33.

Reference example

Methoxycarbonyl- (L) -Val- / Phe ^IMN (pF) Phe / - (N-methoxycarbonyl- (L) -Va 1

In a manner analogous to that described in Reference Example 37, 255 mg (1.45) of 200 mg (0.48 mmol) of H- / Phe ^NN (pF) Phe / -H.3HCl (from Reference Example 42b) were obtained. mmol) of N-methoxycarbonyl- (L) -valine (prepared according to: Chem. Lett. 705, (1980)), 643 mg (1.45 mmol) of BOP, 196 mg (1.45 mmol) of HOBt and 9.7 ml 0.3M NMM in DMF after precipitation from methylene chloride

229 DIPE and freeze-drying from dioxane gave the title compound.

MS (F-ionization): (M + H) + = 618, t _R and (I) - 19.5 min,

Rf (U) = 0.22.

Reference example

Methoxycarbonyl- (L) -Val- / Phe ^NN (p-CN) Phe / - (N-methoxycarbonyl (L) -Val

In a manner analogous to that described in Reference Example 37, from 200 mg (0.48 mmol) of H- / Phe ^NN (p-CN) Phe / methoxycarbonyl- (L) valine (prepared according to: Chem. Lett. 705) , (1980)), 631 mg (1.43 mmol) of BOP, 193 mg (1.43 mmol)

HOBt and 9.5 mL of 0.3M NMM in DMF after chromatography on silica gel using a 15: 1 mixture of methylene chloride and methanol and lyophilization of the fractions containing the product from dioxane gave the title compound.

Mass Spectrum (F-ionization): (M + H) + = S25 t R (I) = 18 min,

Rf (U) = 0.31.

Reference example

Z- (L) -Val - / (pF) Phe ^NN (pF) Phe N - (N- (2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methyl) butyryl )

In a manner analogous to that described in Reference Example 18, 23.0 mg (0.089 mmol) of 2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methyl is reacted. 1butyl (Reference Example 61f) and 45 mg (0.081 mmol) of Z (L) -Va1 - / (pF) Phe ^NN (pF) Phe / -H (Reference Example 32) with 33.8 mg (0.089 mmol) of HBTU at 0 , 76 ml of 0.25M NMM in CHaCN to give the title compound, which is precipitated by dissolution in DMF

230 and adding DIPE.

TLC: Rf (P) = 0.42, MS (FAB): (M + H) @ + = 795.

Reference case 70

Z- (L) -Val - / (pF) Phe ^NN (pF) Phe N - (N- (2 (R, S) - (N- (2-pyridylmethyl) carbamoyl) -3-methyl)) butyryl)

In a manner analogous to that described in Reference Example 18, 21.0 mg (0.089 mmol) of racemic 1-propyl-1-methanoic acid racemic N- (2-picolyl) -amide (Reference Example 63a) was reacted and 45 mg (0.081 mmol) Z- (L) -Val / (pF) (pF) Phe / -H (Reference Example 32) with 33.8 mg (0.089 mmol) HBTU in 0.76 0.25M NMM in CH 3 CN at formation of the desired compound which is precipitated by dissolution in DMF and addition of DIPE.

TLC: Rf = (P) = 0.52; MS (F-ionization): (M + H) @ + = 773.

Reference example 71

The following compounds can be prepared in a manner analogous to those described above.

(a) Z- (L) -Val - / (pF) Phe ^NN (pF) Phe / - ((L) -Val) <- (N-morpholinocarbonyl-G 1y),

(b) N-morpholinocarbonyl- (L) -Val - / (pF) Phe ^NIM (pF) Phe / - ((L) - Val) - (N-morpholino-carbonyl-Gly),

(c) N-quinoline-2-carbonyl- (L) -Asn- / Phe ^NN (pF) Phe / - ((L) -Val) -z,

(d) N- (morpholinylphenyl) - (L) -Valpha (Phe ^NN Leu) - (N-morpholinylphenyl) - (L) -Valpha),

1

e) N- (quinoline-2-carbonyl- (L) -Asn- (Phe ^NN Cha)) - ((L) -Va1) -Z (= 1- / 2 (S) -hydroxy-3 (S)) - (N- (quinoline-2-carbonyl- (L) -asparagyl) amino) 4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (benzyloxycarbonyl) - (L) -vinyl] hydrazine (n) mg (0.107 mmol) of Z-valine in 0.59 ml of a 0.3M solution of NMM in DMF was activated under nitrogen with 47 mg (0.107 mmol) of BOP and 14 mg (0.107 mmol) of HOBT, then added after 15 minutes 50 mg (0.089 mmol) of 1- (2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl- (L) -asparagyl) amino-4-phenylbutyl)) - The mixture was stirred for 18 hours at room temperature, then evaporated under high vacuum, the residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate solution, water and brine, then the aqueous phase was extracted twice with methylene chloride. The organic phases are dried over sodium sulphate and evaporated and chromatographed on a silica gel column, eluting with a mixture of ethyl acetate and ethanol, to give pure compound.

TLC R f (D) = 0.21, t _'et (A) - 1.7 MS (FAB): (M + H) + = 794

The starting material was prepared as follows.

i) 1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl- (L) -asparagyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -hydrazine

In a manner analogous to that described in Example 27 below, 921 mg (1.39 mmol) was reacted.

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl- (L) aspartyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / t-butoxycarbonylamino N -hydrazine (Example 29 below) with 37 ml of formic acid to give the title compound which was used directly in the next step.

232

f) N- (Chloro-2-carbonyl- (L) -Asn- / Phe ^NN (pF) Phe - (N- (methoxycarbonyl) - (L) -Val)).

Example 1

1- / 2 (S) -Acetoxy-3 (S) - (N- (2-methoxyethoxycarbonyl) - (L) -vinyl) -aminophenylbutyl / -1- (cyclohexylmethyl) -2- / N- (2- methoxyethoxycarbonyl) - (L) -valyl / hydrazine

200 mg (0.29 mmol) of N- (2-methoxyethoxycarbonyl- (L) -Val / Phe ^NN Cha) - (N- (2-methoxyethoxycarbonyl)) - (-) are acylated under nitrogen at room temperature for 3 hours. L) -Va1) in 4 mL of THF and 60 µL (0.43 mmol) triethylamine in the presence of 0.5 mg (0.003 mmol) DMAP by treatment with 40 µL (0.43 mmol) acetic anhydride. Between 3 parts methylene chloride, water, saturated sodium bicarbonate solution and Tank, dried over sodium sulfate, concentrated, and silica gel column chromatography eluting with methylene chloride: methanol 30: 1 to give the title compound.

Chromatogr f i TLC: RR- (Z) - 0.17, t r _e t (I) = 22.5 min MS (FAB): (M + H) - 736th

The starting material was prepared as follows.

a) N- (2-Methoxyethoxycarbonyl 1- (L) -Va1- / Phe ^NN Cha) - (N- (2-methoxyethoxycarbonyl) - (L) -Val)

In a manner analogous to that described in Reference Example 2, 820 mg (3.74 mmol) of N- (2-methoxyethoxycarbonyl) - (L) -vilane is activated with 1.65 g (3.74 mmol). BOP and 505 mg (3.74 mmol) of HOBT in 25 ml of a 0.3M solution of NMM in DMF, then after 10 minutes 500 mg (1.25 mmol) of H- / Phe ^NN Cha / -H (hydrochloride salt) ( see Reference Example 10a) and allowed to react for 18 hours. The reaction mixture was then evaporated in a high vacuum, the residue was dissolved in CHCl 3 and the solution was washed with a 10% aqueous citric acid solution, saturated sodium bicarbonate solution and brine. The aqueous phases are extracted with 2 parts of CHCl3 and the organic phases are dried over sodium sulphate and evaporated. The residue is chromatographed on a silica gel column, eluting with a mixture of CHCl3 and MeOH (30: 1 by volume). After precipitation from the methylene chloride solution with hexane, the title compound is obtained.

Thin layer chromatography: Rr - (T) - 0.37, t R e t (I) - 21.5 min, mass spectrum (fast atom ionization): (M + H) * - 694

b) chloroformic acid (2-methoxyethyl) ester

To 100 ml (202 mmol) of a 20% solution of phosgene in toluene was added dropwise 13.3 ml (168 mmol) of 2-methoxyethanol under a nitrogen atmosphere at 0-5 ° C and the resulting mixture was stirred at 0 ° C for 90 minutes. and then for 18 hours at room temperature. The reaction mixture is extracted with water and the organic phase is filtered through cotton wool and evaporated.

Infrared spectrum:

(CH.2C12) among others 3O55w, 2 9 9 5w, 2 9 3 5w, 28 9 5w, 2825w, 1 7 7 5 w,

1 27s, ^ Nuclear Magnetic Resonance Spectrum:

(200 NHz, CDCl 3) 3.38 (s, 3H),

3.64 and 4.44 (21, J = H of, for 2H).

c) N- (2-Methoxyethoxycarbonyl) - (L) -valine

To 2.59 g (22.1 mmol) of L-valine in 26.4 ml of 2N NaOH was added a solution of 3.06 g (22.1 mmol) of chloroformic acid (2-methoxyethyl) ester in a lot of 18 hours organic phase ml. The reaction mixture was stirred at room temperature and extracted with chloroform, acidified with 4N HCl and extracted again with chloroform. After drying and evaporation of the last chloroform phase obtained, the title compound is obtained.

234 ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3) 0.92 and 0.99 (2d, J = 7 Hz, 6H),

2.2 (m, 1 H),

3.38 (s, 3H);

3.59 and 4.24 (2m, for 2H),

4.3 (m, 1 H),

5.4 (d, J = 9 Ηζ, ΗΝ),

8.5 (s broad, 1H).

Example 2

1- / 2 (S) acetoxy-3 (S) - (N- (2-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1 / cyclohexylmethyl / 2- / N- (2- methoxycarbonyl) - (L) valyl / hydrazine

In a manner analogous to that described in Example 1, 200 mg (0.33 mmol) of N- (methoxycarbonyl- (L) -Val- / Phe ^NN Cha) - (N- (methoxycarbonyl) -) are reacted. L) -Val) in 4 mL of THF and 68 _of µl (0.50 mmol) of triethylamine in the presence of 1.2 mg · (0.01 mmol) of DMAP with 46 _of µl (0.50 mmol) of acetic anhydride. TLC: Rt (A ') 0.42 t Ret (I) = 22.6 min, MS (F-ionization): (M + H) &lt; + &gt; - 684

The starting material was prepared as follows.

a) N- (Methoxycarbonyl) - (L) -Val- (Phe ^NN Cha) / <- (N) - (methoxycarbonyl) - (L) -Va1) (= 1- / 2 (S) -hydroxy-3 (S) - (N- (methoxycarbonyl- (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine)

In a manner analogous to that described in Reference Example 2, 1.47 g (8.4 mmol) of N- (methoxycarbonyl) (L) -valine was activated with 3.71 g (8.4 mmol) of BOP and 1.13 g. g (8.4 mmol)

235

HOBT in 54 ml of a 0.3M solution of NMM in DMF, then after 15 minutes add 1.12 g (2.8 mmol) of H- / Phe ^NN Cha / -H (hydrochloride salt) (see Reference Example 10a) and the mixture was allowed to react for 18 hours. The reaction mixture was then evaporated in a rotary evaporator at 50 ° C (→ brown residue), dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution and brine. The aqueous phases are extracted with 2 parts of methylene chloride and the organic phases are dried over sodium sulphate and evaporated. Chromatography on silica gel, eluting with methylene chloride / methanol (15: 1 by volume) and precipitating twice by adding DIPE to a concentrated solution of the product in methylene chloride, afforded the title compound.

Thin layer chromatography: R-f (U) - 0.33, t Ret (I) = 21.5 min, mass spectrum (fast atomization): (M + H) * - 606

The starting material was prepared as follows.

b) N- (Methoxycarbonyl) - (L) -valine

To 7.0 g (60 mmol) of L-valine in 100 ml of 2N NaOH and 30 ml of dioxane was added 5.67 g (60 mmol) of methyl chloroformate (→ exothermic reaction) and the mixture was stirred at room temperature for 18 hours. The reaction mixture is extracted with methylene chloride, the aqueous phase is acidified with 27 ml of 4N HCl and extracted again with methylene chloride. After drying and evaporating the latter methylene chloride phase, the title compound is obtained.

t _R et (I) = 7.2 min, ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 0.66 (t, J = 7 Hz, 6H), 16 (m, 1H),

3.67 (s, 3H);

4.0, 6 (m, 1H),

7, O7 (d, J = 8 Ηζ, ΝΗ or a with the exchange a).

36

Example 3

1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- (cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine

To 81 mg (0.66 mmol) of 2-picolinic acid in 4 ml of methylene chloride was added 56 of 1 (0.4 mol) of 1-chloro-N, N, 2 -, under nitrogen at 0 ° C. 1-Methyl-1-opaine (B. Haveaux, A.Dekoker, M.Rens, ARSidani, J.Toye, L.Murukami, M. Yoshioka and W.Nagata, Organic Syntheses 59,26 ( 1980)). After 45 minutes at room temperature, 1.3 ml of pyridane, 100 mg (0.165 mmol) of N- (methoxycarbonyl) - (L) -Va1 - / Phe ^NN Cha) - (N) - (methoxycarbonyl) - (L) are added. (Val 2a) (Example 2a) and a DMPA spatula tip and the resulting mixture was stirred at room temperature for 18 hours. The dark reaction mixture was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate, water and Tank. Chromatography of the residue on a silica gel column using ethyl acetate as eluent gives pure title compound. The evaporation residue was obtained by evaporation of the methylene chloride phase which had previously been dried over sodium sulfate.

Thin layer chromatography: Rt- (O) - 0.23, _teth (I) = 22.5, mass spectrum (fast atom ionization): (M + H) * = 711

Example 4

Some of the above procedures are prepared:

a) 1- / 2 (S) -propionyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- (N-) (methoxycarbonyl) (L) -vinyl / hydrazine,

b) 1- / 2 (S) -Butyryloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N-) (methoxycarbonyl) 37 (L) -valyl / hydrazine,

c) 1- / 2 (S) -pentanoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) ) (L) -valyl / hydrazine,

d) 1- (2 (S) -octanoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) - N- (methoxycarbonyl) ) (L) -valyl / hydrazine,

e) 1- / 2 (S) -decanoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) ) (L) -valyl / hydrazine,

f) 1- (2 (S) -dodecanoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) N- (methoxycarbonyl) (L) -vinyl / hydrazine,

g) 1- / 2 (S) -pivaloyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) (L) -valyl / hydrazine,

h) 1- (2 (S) - (2-furylcarbonyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) N- (methoxycarbonyl) - (L) -valyl / hydrazine,

(i) 1- / 2 (S) - (4-imidazolylcarbonyl) oxy-3 (S) - (N- (methoxycarbonyl))

- (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl] hydrazine,

j) 1- / 2 (S) - (4-Imidazolylacetyl) oxy-3 (S) - (N- (methoxycarbonyl))

- (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine,

k) 1- / 2 (S) - (3- (4-Imidazolyl) propionyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N238 (methoxycarbonyl) - (L) -valyl) hydrazine,

l) 1- / 2 (S) -benzoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) ) - (L) - y 1 y 1 / hydrazine,

m) 1- (2 (S) - (2-Pyridylacetyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) anrino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) N- (methoxycarbonyl) - (L) -valyl / hydrazine,

n) 1- / 2 (S) - (3- (pyridin-2-yl) propionyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1 - / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine,

o) 1- / 2 (S) - (Quinolin-2-ylcarbonyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine,

p) 1- (2 (S) - (aminoacetyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N) - (methoxycarbonyl) - (L) -valyl / hydrazine,

q) 1- (2 (S) - (N-methylaminoacetyl) oxy-3 (S) - (N- (methoxycarbonyl) (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) N- (methoxycarbonyl) - (L) -valyl / hydrazine,

r) 1- (2 (S) - (N, Nd-Imethylaminoacetyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) - 2 / N (methoxycarbonyl) - (L) -valyl / hydrazine,

s) 1- / 2 (S) - (N-Benzyloxycarbonyl-N-methyl / aminoacetyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1 - / cyclohexylmethyl / 2- / N- (methoxycarbonyl) - (l _) - valyl / hydrazine,

t) 1- (2 (S) -propyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) N- (methoxycarbonyl) ) - (L)

239

Val! / hydrazine,

u) 1- (2 (S) - (4-Morpholinomethylbenzoyl) oxy-3 (S) - (N- (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) - 2 / N (methoxycarbonyl) - (L) -valyl / hydrazine,

(v) 1- (2 (S) - (4-chloromethylbenzoyl) oxy-3 (S) - (N- (methoxycarbonyl) (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) N- (methoxycarbonyl) - (L) -valyl / hydrazine,

w) 1- (2 (S) - (3-carboxypropionyl) oxy-3 (S) - (N- (methoxycarbonyl) (L) -vinyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) - 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine.

Example 5

In one of the above processes, the monoacetylated derivatives are prepared from the compounds of Reference Examples 1 to 70, each of which is in the respective central two-valent radical derivatized with butane-2 (S) -ol with the designation - (Phe ^NM Phe), - (Phe ^NN Cha). , - / Phe ^NN Leu /, - / Phe ^NN Nle /, - / Phe ^NN (pF) Phe /, - / (pF) Phe ^NN (pF) Phe /, - / Phe ^NN (p-CN) Phe / or - (Cha ^NN Leu) contain 2 (S) -acetoxy instead of the free 2 (S) -hydroxy group.

Example 6

The following compounds are prepared by some of the above procedures (the starting materials are shown in square brackets (//) (for example, as an appropriate reference example whose title compound was used as starting material):

a) 1- [2 (S) - (2-Furylcarbonyl) oxy-3 (S) - (N- (benzyloxycarbonyl) (L) -valyl) amino-4-phenylbutyl] -1- (benzyl) -2-] N- (benzyloxycarbonyl) - (L) -valyl (hydrazine) (from the compound of reference example 2 and furan-2-carboxylic acid chloride),

b) 1- / 2 (S) -pivaloyloxy-3 (S) - (N- (benzyloxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- [N- (benzyloxycarbonyl) - (L) -valyl (hydrazine) (from the compound of Reference Example 11 and pivalic anhydride),

c) 1- (2 (S) - (N-methylaminoacetyl) oxy-3 (S) - (N- (morpholinocarbonyl) - (L) -vinyl) amino-4-phenylbutyl) -1- (2-N- (benzyloxycarbonyl) - (L) -valyl) hydrazine, from the compound of Reference Example 18 and N-benzyloxycarbonyl-1-N-methylaminoacetic acid followed by hydrogenolysis obtained 2 ( S) - (N-benzyloxycarbonyl-N-methylaminoacetyl-1-compound in Pd (coal) catalysis,

d) 1- (2 (S) - (N-benzyloxycarbonyl-N-methylaminoacetyl) oxy-3 (S) - (N- (benzyloxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (p) -fluorophenylmethyl [-2-] N- (N- (morpholinocarbonyl) glycyl) - (L) -vinyl] hydrazine (from the compound of Reference Example 24 and N-benzyloxycarbonyl-N-methylaminoacetic acid chloride),

e) 1- / 2 (S) - (N, N-dimethylaminoacetyl) oxy-3 (S) - (N- (quinolin-2-ylcarbonyl) - (L) -aspartoyl) amino-4-phenylbutyl / -1- (fluorophenylmethyl) (2-tert-butoxycarbonyl) hydrazino (from the compound of Reference Example 27 and dimethylaminoacetic acid chloride),

f) 1- / 2 (S) - (pyridylcarbonyl) oxy-3 (S) - (N- (benzyloxycarbonyl) oxy-3 (S) - (N- (benzyloxycarbonyl) - (L) -aspartoyl) amino-4- phenylbutyl (-1- (p-fluorophenylmethyl) -2- (benzyloxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 28 and 2-pyridinecarboxylic acid chloride),

241

g) 1- [2 (S) - (4- (morpholinomethyl) benzoyl) oxy-3 (S) - (N- (benzyloxycarbonyl) - (1 ') -valyl) amino-4- (p-fluorophenyl) butyl] - 1 (p-fluorophenylmethyl (-2- (tert-butoxycarbonyl) hydrazine) from the compound of Reference Example 31 and 4-morpholinomethylbenzoic acid via acid chloride in the presence of N, N, 2-trimethyl-1-chloropropene- (1) -amine) .

h) 1- (2 (S) -benzoyloxy-3 (S) - (N- (benzyloxycarbonyl) - (L) -valyl) amino-4- (p-fluorophenyl) butyl) -1- (p-fluorophenylmethyl) 2 - (N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 33 and benzoyl chloride),

i) 1- (2 (S) - (4-chloromethylbenzyloyl) oxy-3 (S) - (N- (benzyloxycarbonyl) - (L) -valyl) amino-4- (p-fluorophenyl) butyl) -1- Fluorophenylmethyl [-2-] N- (2- (R, S) -carbamoyl-3-phenylpropionyl) - (L) -valyl (hydrazine) from Reference Example 34 and 4-chloromethylbenzoic acid in the presence of N, N, 2 - tri-methyl-1-chloroprene- (l) -amine /,

j) 1- / 2 (S) - (imidazol-4-ylacetyl) oxy-3 (S) - (N- (acetylvalyl) amino-4-phenylbutyl) -1- (benzyl) -2- (N-acetylvalyl) (hydrazine) from the compound of Reference Example 35 and 1-tri-imidazolyl-4-acetic acid (prepared from trityl chloride and 4-imidazolyl-acetic acid in the presence of pyridine) in the presence of N, N, 2-trimethyl -1-chloropropene- (1) -amine (via an intermediate protected with a trityl group and subsequent treatment with a cleavage of the trityl protecting group, for example, with trifluoroacetic acid),

k) 1- (2 (S) - (2-Pyridylacetyl) oxy-3 (S) - (N- (quinolin-2-ylcarbonyl) valyl) amino-4-phenylbutyl) -1- (benzyl) -2-) N-quinolin-2-ylcarbonylvinyl (hydrazine) from the compound of Reference Example 37 and the acid

242 pyridine acetic acid in the presence of N, N, 2-trimethyl-1-chloropropene- (1) -amino],

l) 1- (2 (S) - (3-Pyridylacetyl) oxy-3 (S) - (N- (acetyl- (L) -valyl) -amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- / N-acetyl- (L)

valyl (hydrazine) of the compound of Reference Example 38 and an acid

3-pyridine acetic acid in the presence of N, N, 2-trimethyl-1-chloropropene- (1) -amino;

m) 1- (2 (S) - (4-Pyridylacetyl) oxy-3 (S) - (N- (3-pyridylacetyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) - 2 (N- (3-pyridylacetyl) - (L) -valyl (hydrazine) from the compound of Reference Example 39 and 4-pyridineacetic acid in the presence of N, N, 2-trimethyl-1-chloropropene- (1) -amine),

n) 1- / 2 (S) - (quinolin-2-ylcarbonyl) oxy-3 (S) - (N- (N-2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -valyl / amino-4- phenylbutyl / -1- (p-fluorophenylmethyl) -2- [N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -valyl] hydrazine] from the compound of Reference Example 43 and quinoline-2-carboxylic acid in presence of MM, 2-trimethyl-1-chloropropene- (1) -amine],

o) 1- / 2 (S) - (2-pyrrolidinylcarbonyl) oxy-3 (S) - (N-benzyloxycarbonyl) - (L) -valyl / amino-4-phenylbutyl] -1- (p-fluorophenylmethyl) -2 - (N-benzyloxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 45 and proline in the presence of N, N, 2-trimethyl-1-chloropropene- (i) -amine),

p) 1- / 2 (S) -propionyl) oxy-3 (S) - (N-benzyloxycarbonyl) - (L) -. valyl (amino-4-phenylbutyl) -1- (cyanophenylmethyl) -2- (N-benzyloxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 43 and propanoic anhydride],

q) 1- / 2 (S) -Butyryloxy-3 (S) - (N- (benzyloxycarbonyl) - (1H) -isoindole-4-phenylbutyl) -1- (isobutyl) (-2- (N-benzyloxycarbonyl) - (1 ') - isoucyl (hydrazine) from the compound of Reference Example 49 and from butyric anhydride],

r) 1- / 2 (S) -pentanoyloxy-3 (S) - (N- (isobutoxycarbonyl) - (L) valyl) amino-4-phenylbutyl] -1- (isobutyl) -2- (N-isobutoxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 50 and pentanoic chloride),

s) 1- (2 (S) -Decanoyloxy-3 (S) - (N-acetylvalyl) amino-4-phenylbutyl) -1- (isobutyl) -2- (N-acetylvalyl) hydrazine) from the compound of the Reference Example 52 and decanoic acid in the presence of N, N, 2-trimethyl-1-chloropropene- (1) amine],

t) 1- / 2 (S) -dodecanoyloxy-3 (S) - (N-valylamino-4-phenylbutyl-1- (isobutyl) -2- (N-valyl) hydrazine) from the compound of Reference Example 54 protected on both free valyl-amino groups with a benzyloxycarbonyl protecting group in the presence of N, N, 2-trimethyl-1-chloropropen- (1) -amine and subsequent hydrogenation of the benzyloxycarbonyl protecting groups from the intermediate obtained,

u) 1- / 2 (S) - (3-Carboxypropionyl) oxy-3 (S) - (N- (thiomorpholinocarbonyl- (L) -valyl) amino-4-phenylbutyl-1- (isobutyl) -2-) N - (N- (thiomorpholinocarbonyl) - (L) -vinyl) hydrazine (prepared from the compound of Reference Example 55 and succinic anhydride in the presence of pyridine),

v) 1- / 2 (S) - (4-Imidazolylacetyl) oxy-3 (S) - (N- (benzyloxycarbonyl- (L) -valyl) amino-4-phenylbutyl-1- (isobutyl) -2-) N 3-Tetrazol-1-yl) -propionyl- (L) -valyl (hydrazine) prepared from the compound of Reference Example 57 and 1-triethyl-4-imidazolyl-1-acetic acid by the procedure of

244 is analogous to the procedure of Example 6j),

w) 1- (2 (S) - (Furan-2-ylcarbonyl) oxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl-1- (isobutyl) -2-) N- (2 (R, S) -carbamoyl-3-phenylpropionyl- (L) -valyl (hydrazine) prepared from the compound of Reference Example 58 and furan-2-carboxylic acid chloride),

x) 1- / 2 (S) -pivaloyloxy-3 (S) - (N-benzyloxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl-1- (n-butyl) -2- (2 ( R, S) - (N- (2-morpholinoethyl) carbamoyl-3-methylbutyryl (hydrazine) prepared from Reference Example 61 and pivalic anhydride),

y) 1- / 2 (S) - (N-Benzyloxycarbonyl-N-methylaminoacetyl) oxy-3 (S) - (N-benzyloxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl-1H-butyl (-2-) N- (3- (tetrazol-1-yl) propionyl) butyl (hydrazine) from the compound of Reference Example 62 by a procedure analogous to that of Example 6d),

z) 1- / 2 (S) - (N-methylaminoacetyl) oxy-3 (S) - (N-benzyloxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (n-butyl) -2 - / N- (2 (R, S) - (N- (2-pyridylmethyl) carbamoyl) -3-methyl) butyryl (hydrazine) from the compound of Reference Example 63 via 2 (S) -N-benzyloxycarbonyl-N- methylaminoacetyloxy analog by hydrogenolysis according to Example 6c).

Example 7

The following compounds are prepared by some of the above procedures (the starting materials are shown in square brackets (II) (for example, the corresponding reference example whose title compound was used as starting material):

245

a) 1- / 2 (S) - (N, N-dimethylaminoacetyl) oxy-3 (S) - ((N-benzyloxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (p-fluorophenyl) methyl (2 -) - N- (3- (tetrazol-1-yl) propionyl) valyl (hydrazine) from the compound of Reference Example 64 and dimethylaminoacetic acid chloride],

b) 1- (2 (S) - (pyridin-2-ylcarbonyl) oxy-3 (S) - ((N-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (isobutyl) - 2- (N (methoxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 66 and 2-pyridinecarboxylic acid chloride),

c) 1- / 2 (S) - (4-Morpholinomethylbenzoyl) oxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl [-1- (p-fluorophenylmethyl) -2] - (N- (methoxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 67 and 4-morpholinomethylbenzoic acid) via an acid chloride in the presence of N, N, 2-methyl-1-chloropropene- (1) -amino Nu /,

d) 1- / 2 (S) -benzoyloxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (p-cyanophenylmethyl) -2- [N- ( methoxycarbonyl) - (L) -valyl (hydrazine) from the compound of Reference Example 68 and benzoic anhydride]

Example 8

1- / 2 (S) -Hydroxy-3 (S) - (N-allyloxycarbonyl) - (1) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2-naphthyl yloxycarbonyl) - (L) -vinyl-1H-hydrazine

In a manner analogous to that described in Comparative Example 2, from 500 mg (1.25 mmol) of H- (Phe ^NM Cha / -H.3HCl) from Reference Example 10a, 753 mg (3.74 mmol) of N-allyloxycarb 1- (L) -vinyl, 1.65 g (3.74 mmol) of BOP, 505 mg (3.74 mmol) of HOBt, and 24.7 mL of 0.3M N-methylmorpholine in DMF after double -246 min precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane yields the title compound.

Mass Spectrum (F-ionization): (M + H) + = 658 t _Ret = 25.5 min,

Rf (H) = 0.44.

The starting material was prepared as follows.

a) Allyloxycarbonyl- (L) -valine

In a manner analogous to that described in Reference Example 1c), 10 g (85.3 mmol) of (L) -valine and

10.3 g (85.3 mmol) and 1-chloroformate gave the title compound as a colorless oil.

^1H TLC analysis:

(200 MHz, CDCl 3) 6.05-5.3 (m, 1H),

5.35 (s, 1H), 2.0 (m, 2H),

4.60 (d broad, J = 6 Hz, 2H),

4.33 (m, 1H), 25 (m, 1H), 00 (d, J = 7Hz, 3H),

0.93 (d, J = 7Hz, 3H).

Example 9

1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl) - (L-valyl) amino-4-fenylbuty1 / -1 / cyclohexylmethyl / 2- / N-ethoxycarbonyl) - (L) -valyl / hydrazin

In a manner analogous to that described in Reference Example 2, from 500 mg (1.25 mmol) of H- / Phe ^NN Cha / -H was obtained. 3HCl of Reference Example 10a, 708 mg (3.74 mmol) of N-ethoxycarbonyl - (L) -vinyl, 1.65 g (3.74 mmol) of BOP, 505 mg (3.74 mmol) of HOBt and 24 0.73M of N-methylmorpholine in DMF after chromatographic purification on silica gel, eluting with a mixture of methylene chloride and diethyl ether in a volume ratio

247

1: 1 and precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane yields the title compound.

Mass spectrum (F-ionization): (M + H) + = 634 t _Re t (I) - 24.2 min,

MH + = 0.3.

The starting material was prepared as follows.

a) N-Ethoxycarbonyl- (L) -valine

In a manner analogous to that described in Reference Example 1c, the title compound is obtained as a colorless oil from 10 g (85.3 mmol) of (L) -valine and 9.3 g (85.3 mmol) of ethyl chloroformate. .

¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDCl 3) 5.15 (d broad, 1H),

4.3 2 (m, 1H),

4.15 (q, J = 7Hz, 2H),

2.25 (m, 1H); 25 (t, J = 7Hz, 3H);

Q.98 (d, J = 7Hz),

0.92 (d, J = 7H z, 3H),

Example 10

1- / 2 (S) -hydroxy-3 (S) - (N-trifluoroacetyl- (1) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-trifluoroacetyl- (L) - valyl / hydrazine

In a manner analogous to that described in Reference Example 2, from 500 mg (1.25 mmol) of H- / Phe ^NN Cha / -H was obtained. 3HCl from Reference Example 10a, 798 mg (3.74 mmol) of N-trifluoroacetyl- (1) -valine, 1.65 g (3.74 mmol) of BOP, 505 mg (3.74 mmol) of HOBt and 24.7 mL Purification by chromatography on silica gel using a 1: 1 mixture of methylene chloride and diethyl ether and precipitation from methylene chloride by addition of hexane and freeze-dried dioxane affords the title compound (0.3M) in DMF.

MS (F-ionization): (M + H) ⁺ = 682, t _Rt (I) - 26.1 min,

Rf (H) = 0.65.

The starting material was prepared as follows.

a) N-Trifluoroacetyl- (L) -valine

To a solution of 8.16 g (38.9 mmol) of (L) - tert -butyl ester a

Triethylamine (17.3 mL, 124.5 mmol) in methylene chloride (100 mL) was added dropwise at 0 ° C with trifluoroacetic anhydride (6 mL, 42.8 mmol) and the reaction stirred overnight at room temperature. After washing with 10% citric acid and saturated sodium chloride solution, the organic phase is evaporated to give the N-trifluoroacetyl- (L) -valine-tert-butyl ester as a yellow oil which is dissolved in 40 ml of a 1: 1 mixture of methylene chloride and TFA. The solution was stirred at room temperature for 5 hours. Evaporation of the reaction solution and digestion of the residue with hexane gave the title compound as a white solid.

¹ H-Nuclear magnetic resonance spectrum:

(200 MHz, CDaOD) 4.32 (d, J = 6 H of 1 H),

2.23 (m, 1 H);

0.93 (d, J = 7 Hz, 3H)

0.96 (d, J = 7 Hz, 3H).

Example 11

1- / 2 (S) -Hydroxy-3 (S) - (N- (2- (2-methoxyethoxy) ethoxy) carbonyl- (L) valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2 - / N- (2- (2-methoxy) ethoxy) carbonyl- (L) -valyl / hydrazine

In a manner analogous to that described in Reference Example 2, from 500 mg (1.25 mmol) of H- / Phe ^NN Cha / -H was obtained. 3HCl from Reference Example 10a, 985 mg (3.74 mmol) of N-methoxyethoxycarbonyl-1- (L) -valin, 1.65 g (3.74 mmol) of BOP, 505 mg (3.74 mmol)

249 mmol) of HOBt and 24.7 ml of 0.3M N-methylmorpholine in DMF after chromatography on a silica gel column using a 30: 1 mixture of chloroform and methanol and precipitation from methylene chloride by addition of hexane and freeze drying from dioxane gave the title compound .

Mass Spectrum (F-Ionization): (M + H) + -7 8.2 t R et (I) = 21.2 min,

Rf (T) = 0.26.

The starting material was prepared as follows.

a) N- (2- (2-Methoxyethoxy) ethoxy) carbonyl- (L) -valine

To 100 ml of a 20% phosgene solution in toluene, 19.8 ml (168 mmol) of diethylene glycol monomethyl ether are added dropwise at 0 ° C, and the mixture is stirred at room temperature overnight. The excess phosphate was stripped with nitrogen, the reaction solution was washed with water and evaporated. To crude 2- (2-methoxyethoxy) ethyl chloroformate 15.6 g (85.4 mmol) was added 10 g (85.4 mmol) of (L-valine) according to Reference Example 1c to give the title compound as a colorless resin.

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 4.18 (m, 2H),

4.05 (d, J = 6HZ, 1H),

3.72 to 3.40 (m, 8H);

3.35 (s, 3H), 18 (m, 1H),

0.95 (t, J = 7H, 6H).

Example 12

1- / 2 (S) -Hydroxy-3 (S) - (N- (2-methoxyethoxy) ethoxy) acetyl- (L) -valyl) amino-4-phenylbutyl [-1- (cyclohexylmethyl) -2-] N- (2-methoxyethoxy) acetyl- (L) -valyl / hydrazine

In a manner analogous to that described in re250 of Ferment Example 2, from 500 mg (1.25 mmol) of H- / Phe ^NN Cha / -H was obtained. 3HCl from Reference Example 10a, 873 mg (3.74 mmol)

N- (2) -methoxyethoxyacetyl- (L) -vinyl, 1.65 g (3.74 mmol) of BOP,

505 mg (3.74 mmol) of HOBt and 24.7 ml of 0.3M N-methylmorpholine in DMF after chromatographic purification on silica gel using a 30: 1 mixture of chloroform and methanol and precipitation from methylene chloride by addition of hexane and lyophilization from dioxane gives the title compound.

Mass Spectrum (F-Ionization): (M + H) ⁺ - 722 t Ret (I) = 21.3 min,

Rf (T) - 0.23.

The starting material was prepared as follows.

a) N- (2-Methoxyethoxy) acetyl- (L) -valine

To a solution of 5 g (23.9 mmol) of (L) -valine-tert-butyl ester,

2.91 g (21.7 mmol) of 2- (methoxyethoxy) acetic acid and 3.55 g (21.7 mmol) of cyanophosphonic acid diethyl ester in 30 ml of DMF are added, at 0 ° C, 6.4 ml (45.7 mmol). mmol) of triethylamine and the mixture is then stirred overnight at room temperature. The reaction mixture is diluted with methylene chloride, washed with 10% citric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, then, after evaporation of the organic phase, 5.1 g of N-methoxyethoxyacetyl- (L) -valine-tert-butyl ester is stirred. One hour at room temperature in 22 ml of a 1: 1 mixture of methylene chloride and TFA. Evaporation of the reaction solution gave the title compound as a colorless oil.

¹ H-Nuclear magnetic resonance spectrum:

(200 MHz, CDCl 3) 10.0 (s broad, 1H), δ 2 (broad, 1H),

4.55 (m, 1H), 10 (s, 2H), 70 (m, 2H),

251.58 (m, 2Η),

3.40 (s, 3Η),

2.2 8 (m, 1Η),

0.98 (d, J = 7Hz, 3Η), 0.95 (d, J = 7Hz, 3Η).

Example 13

In a manner analogous to that described in the previous and following examples, the following compounds were prepared:

A) 1- [2 (S) -hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl] -1- (thien-2-ylmethyl) -2- [N-] N- acetyl- (L) -valyl / hydrazine,

B) 1- [2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- (thien-2-ylmethyl) -2- [N-methoxycarbonyl- (L) valyl / hydrazine,

C) 1- [2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- (thien-2-ylmethyl) -2- [N-ethoxycarbonyl- (L) -valyl / hydrazine,

D) 1- (2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl) -1- (thien-2-ylmethyl) - 2 / N (N, N-dimetylaminokarbonyl- (L) -valyl / hydrazine,

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl) - (L) valyl) amino-4-phenylbutyl / -1- (thien-2-ylmethyl) / 2- / N- / N- (2-methoxyethyl) aminocarbonyl (L) -valyl / hydrazine,

F) 1- (2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1 / thien-2-ylmethyl / 2- / N- (N- (2-morpholin-4-yl) ethyl) aminok.arbonyl- (L) -valyl / hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl)) -N-me52

Q

L-Thylaminocarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (thien-2-ylmethyl) -2- [N- (2-morpholin-4-yl) ethyl] -N-methylaminocarbonyl- (L) -valyl / hydrazine.

Example 14

In a manner analogous to that described in the previous and following examples, the following compounds were prepared:

A) 1- [2 (S) -hydroxy-3 (S) - (N-acetyl- (L) -valylamino-4-phenylbutyl) -1- (2,3,5,6-tetrahydropyran-4-ylmethyl)] 2- / N-acetyl) (L) -valyl / hydrazine,

B) 1- (2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (2,3,5,6-tetrahydropyran-4-ylmethyl) 2- / N-methoxycarbonyl- (L) -valyl / hydrazine,

C) 1- (2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (2,3,5,6-tetrahydropyran-4-ylmethyl) -2-ethoxycarbonyl- (L) -valyl / hydrazine,

D) 1- / 2 (S) -hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl] -1- / 2,3,5, 6-tetrahydropyran-4-ylmethyl / -2- [N- (N, N-dimethylaminocarbonyl) - (L) -valyl] hydrazine,

E) 1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl) (L) -valyl) amino-4-phenylbutyl) -1- / 2,3, 5,6-tetrahydropyran-4-ylmethyl- [2- (N-) - (2-methoxyethyl) amino, carbonyl) - (L) -valyl / hydrazine,

F) 1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl)) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl (-1-) 2,3,5,6-tetrahydropyran-4-ylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) - valyl / hydrazine,

G) 1- / 2 (S) -hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methyl-2,3-tylaminocarbonyl) - (L) -vinyl) amino- 4-phenylbutyl] -1- (2,3,5,6-tetrahydropyran-4-ylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -vinyl / hydrazine.

Example 15

In a manner analogous to that described in the previous and following examples, the following compounds were prepared.

A) 1- [2 (S) -hydroxy-3 (S) - (N-acetyl) - (L) -valyl) amino-4-phenylbutyl] -1- (4-hydroxyphenylmethyl) -2- [N-] N- acetyl- (L) -valyl / hydrazine

In a manner analogous to that described in Reference Example 37, from 200 mg (0.48 mmol) of 1- [2 (S) -hydroxy-3 (S) -amino-4-phenylbutyl] -1- / 4- -hydroxyphenylmethyl / hydrazine. 3HCl, 175 mg (1.07 mmol) of N-methoxycarbonyl 1- (L) -t-ex-2b, 473 mg (1.07 mmol) of BOP, 145 mg (1.07 mmol) of HOBt and 8, 4 ml of 0.3M N-methylmorpholine in DMF after chromatography on silica gel using methylene chloride / diethyl ether / methanol (10:10: 1) as eluent, precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane gave the title compound.

MS (FAB): (M + H) + - 616 tr _E t (A) - 11.6 min;

Rf - (K ') - 0.56.

The starting material was prepared as follows.

a) 1- (2 (S) -Hydroxy-3 (S) -amino-4-phenylbutyl) -1- (4-hydroxyphenylmethyl) hydrazine.3HCl

In a manner analogous to that described in Reference Example 2a, from 470 mg (0.94 mmol) of 1- [2 (S) -hydroxy-3 (S) -tert-butoxycarbonylamino-4-phenylbutyl] -1- 4-HydroxyphenylImethyl / -2- (tert-butoxycarbonyl) hydrazine after complete evaporation

254 and digesting the residue with methylene chloride afforded the title compound ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 7.42-7.5 (m, 7H), 9.22 (d, J = 8H2, 2H),

4.3-3.85 (m, 3H);

3.55 (m, 1 H);

3.1 (m, 2H).

2.8 (m. 2H).

b) 1- (2 (S) -Hydroxy-3 (S) -tert-butoxycarbonylamino-4-phenylbutyl) -1- (4-hydroxyphenylmethyl) -2- (tert-butoxycarbonyl) hydrazine

In a manner analogous to that described in Reference Example 1, from 26.2 g (23.6 mmol) of (2R, 3S) -1- (3-Boc-amino-2-phenylethyl) oxirane and 5, 63 g (23.6 mmol) of tert-butyl 3- (4-hydroxyphenylmethyl) carbazate after crystallization from ethyl acetate solution after addition of DIPE gave the title compound.

H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 7.28-7.10 (m, 7H), 70 (d, J = 8 Hz, 2H),

4.7 (m, 4H);

2.95 (m, 4H), 31 (s, 9H), 28 (s, 9H), t Ret (V) - 15.0 min.

c) tert-Butyl-3- (4-hydroxyphenylmethyl) carbazate

In a manner analogous to that described in Reference Example 4a, 14 g (106 mmol) of 4-hydroxybenzaldehyde and 14 g (117 mmol) of tert-butylcarbazate in 125 ml of ethanol are reacted to give 4-hydroxybenzaldehyde-tert-butoxycarbonyl. hydrazone (19.8 g, 80%). 9.73 g of this product are hydrogenated in 200 ml of THF in the presence of 0.6 g of 5% palladium on carbon at 50 psi hydrogen to give the title compound,

255, which was crystallized in hot methanol.

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 7.18 (d, J = 8H2, 2H), 7.3 (d, J = 8H2, 2H),

3.80 (s, 2H);

1.45 (s, 9H).

B) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (1) -valyl) amino-4-phenylbutyl) -1- (4-hydroxyphenylmethyl) -2- N -methoxycarbonyl (L) -v 1 y 1 / hydrazine

C) 1- / 2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (1) -valyl) amino-4-phenylbutyl) -1- (4-hydroxyphenylmethyl) -2- N -ethoxycarbonyl (L) valyl / hydrazine

A solution of 2.0 g (4.86 mmol) of 1- [2 (S) -hyloxy-3 (S) -amino-4-phenylbutyl] -1- (4-methoxyphenylmethyl) hydrazine-3-HCl (Example 15A, and 2.54 g (13.8 mmol) of N-ethoxycarbonyl- (L) -valine from Reference Example 9a and 2.13 ml (13.8 mmol) of cyanophosphonic acid diethyl ester in 45 ml of DMF are cooled to 0 ° C. to this cooled solution was added 4.0 mL (29.2 mmol) of triethylamine. The reaction mixture was then stirred at room temperature and under a nitrogen atmosphere for 6 hours, then completely evaporated in vacuo. The residue was dissolved in methylene chloride, washed with saturated sodium carbonate solution, 10% aqueous citric acid solution and saturated sodium chloride solution, filtered through cotton wool and evaporated. Purification by silica gel chromatography using 10: 10: 1 methylene chloride / diethyl ether / methanol as the eluent, and precipitation twice from methanol / methylene chloride by addition of DIPE affords the title compound.

Mass Spectrum (F-ionization): (M + H) + = 644, IR (V) = 12.8 min,

Rf (B) = 0.41.

5 &

D) 1- (2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (4-hydroxyphenylmethyl) -2 - / N (N, Ndimetylaminokarbonyl) - (L) -valyl / hydrazine

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (4-hydroxyphenylmethyl) (-2-) N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -vinyl / hydrazine

F) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino- 4-phenylbutyl / -1- (4-hydroxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vinyl] hydrazine

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino -4-phenylbutyl] -1- (4-hydroxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -vinyl] / hydrazine.

Example 16

By procedures analogous to those described in the preceding and following examples, the following compounds were prepared.

A) 1- (2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) -2- (N-acetyl-) (L) -valyl / hydrazine

In a manner analogous to that described in Reference Example 37, from 200 mg (0.47 mmol) of 1- [2 (S) -hydroxy-3 (S) -amino-4-phenylbutyl] -1- / 4- mETHOXYPHENYLMETHYL / hydrazine.

HC1, 225 mg (1.41 mmol) N-acetyl- (L) -valine, 624 mg (1.41 mmol) BOP, 191 mg (1.41 mmol) HOBt and 9.4 mL 0.3M N- After purification by chromatography on silica gel using a 12: 1 mixture of methylene chloride and methanol and lyophilization from a mixture of dioxane, water and tert-butanol, the title compound is obtained.

257

MS (F-ionization): (M + H) + = 598, t r e (V) - 11.2 min,

Rf = (0.25).

The starting material is obtained as follows.

a) 1- (2 (S) -Hydroxy-3 (S) -amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) hydrazine. 3HC1

In a manner analogous to that described in Reference Example 2a, from 2.65 g (5.14 mmol) of 1- / 2 (S) hydroxy-3 (S) -tert-butoxycarbonylamino-4-phenylbutyl / -1- / 4 Methoxyphenylmethyl [-2- (tert-butoxycarbonyl) hydrazine] after isolating the title compound gives the title compound.

¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 7.42-7.15 (m, 7 H),

6.92 (d, J = 8 Hz, 2H);

4.1-3.8 (m, 3H),

3.75 (s, 3H);

3.55 (m, 1H), 1 (broad s, 2H),

2.75 (broad m, 2H).

b) 1- (2 (S) -Hydroxy-3 (S) -tert-butoxycarbonylamino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) -2- (tert-butoxycarbonyl) hydrazine

In a manner analogous to that described in Reference Example 1, from 3.13 g (11.9 mmol) of (2R, 3S) -1- (Bocamido-2-phenylethyl) oxirane and 3.0 g (11 g, 9 mmol) of tert-butyl 1-3- (4-methoxyphenylmethyl) carbazate from Reference Example 29c (see below) after crystallization from methanol and DIPE gave the title compound.

¹ H-Nuclear magnetic resonance spectrum:

(200 MHz, CD 3 OD) 7, 3-7, 1 (m, 7 H), 8.5 (d, J = 8 H z),

3.78 (s, 3H);

258.65 (m, 4Η),

2.9-2.5 (m, 4Η),

1.25 (s, 9Η),

1.20 (s, 9Η), tr _β t (V) = 16.6 min.

B) 1- (2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) -2- (N-methoxycarbonyl) (L) 1-yl / hydrazine

In a manner analogous to that described in Reference Example 37, from 200 mg (0.47 mmol) of Example 16A, α, 247 mg (1.41 mmol) of N-methoxycarbonyl- (L) -valine from Example 2b , 624 mg (1.41 mmol) of BOP, 191 mg (1.41 mmol) of HOBt and 9.4 mL (0.3 M of N-methylmorpholine in DMF after chromatographic purification on silica gel, eluting with a mixture of methylene chloride and methanol in a volume ratio) 19: 1 and lyophilization from dioxane affords the title compound.

Mass Spectrum (F-Ionization): (M + H) + - 630 tR _et (V) - 13.5 min,

R _f (A) = 0.27.

C) 1- (2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) -2- (N-ethoxycarbonyl) (L) ) valyl / hydrazine

Following a procedure analogous to that described in Reference Example 37, from 200 mg (0.47 mmol) of the compound of Example 16A, α, 267 mg (1.41 mmol) of N-ethoxycarbonyl- (L) -varyl. from Example 9a, 624 mg (1.41 mmol) of BOP, 191 mg (1.41 mmol) of HOBt and 9.4 ml of 0.3 M N-methylmorpholine in DMP after chromatography on silica gel using a methylene chloride / methanol mixture 12: 1 v / v, precipitated from methylene chloride by addition of DIPE and lyophilization from dioxane gave the title compound.

259

MS (FAB): (M + H) + - 658, t r _e t (A) = 15.0 min;

Rf (I ') = 0.55.

D) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) -2- / N / N, Ndimetylaminokarbonyl / - (L) -valyl / hydrazine

E) 1- (2 (S) -Hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl- (L) valyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) - 2 / N (N (2-methoxyethyl) aminocarbonyl / - (L) -valyl / hydrazine

F) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-morpholin-4-yl) ethyl) aminocarbonyl- (L) -valyl) amino-4-phenylbutyl) -1 - (4-Methoxyphenylmethyl) 2- [N- (N- (2-morpholin-4-yl) ethyl) aminocarbonyl] - (L) -valyl] hydrazin

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino-4- phenylbutyl [1- (4-methoxyphenylmethyl) -2 - [(N-2-morpholin-4-yl) ethyl] -N-methylaminocarbonyl] - (L) -valyl] hydrazine.

Example 17

By procedures analogous to those described in the previous and following examples, the following compounds were prepared:

A) 1- [2 (S) -Hydroxy-3 (S) - (N-acetyl) - (L) -valyl) amino-4-phenylbutyl] -1- (4-benzyloxyphenylmethyl) -2- [(N) acetyl- (L) -valyl /

hydrazine,

B) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -vinyl) amino-4-phenylbutyl] -1- (4-benzyloxyphenylmethyl) -2 - / - ( N-methoxycarbonyl- (L) -valyl / hydrazine,

260

C) 1- (2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4'-benzyloxyphenylmethyl) -2- / - (^ l-ethoxycarbonyl- (L) -valyl / hydrazine,

D) 1- (2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl) -1- (4-benzyloxyphenylmethyl) -2- // N - (N, Nd) methylaminocarbonyl- (L) -valyl / hydrazine,

E) 1- (2 (S) -Hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl) (L) -valyl) amino-4-phenylbutyl) -1- (4-benzyloxyphenylmethyl) 2 / N (N (2-methoxyethyl) aminocarbonyl- (L) -valyl / hydrazine,

F) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl] - 1- (4-benzyloxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl- (L) valyl] hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-morpholin-4-yl) ethyl) -N-methyl aminocarbonyl) - (L) -valyl) amino-4 phenylbutyl / 1- / 4-benzyloxyfenylmetyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-metylaminokarbonyl- (L) -valyl / hydrazine.

Example 18

By procedures analogous to those described in the preceding and following examples, the following compounds were prepared:

A) 1- [2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl] -1- [4- (3,4-dimethoxybenzylloxyphenylmethyl)] - 2- (N-acetyl) - (L) -valyl / hydrazine,

B) 1- [2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- [4- (3,4-dimethoxybenzyl) oxyphenylmethyl] -2- / N-methoxycarbonyl- (L) -valyl / hydrazine,

1

C) 1- [2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- [4- (3,4-dimethoxybenzyl) oxyphenylmethyl] -2- / N-ethoxycarbonyl- (L) -valyl / hydrazine,

D) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- / 4- (3,4- dimethoxybenzyl) oxyfenylmetyl / -2 / N, N-dimetylaminokarbonyl- (L) -valyl / hydrazine,

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl- (L) valyl) amino-4-phenylbutyl) -1- / 4- (3, 2-methylbenzyl) 4-Dimethoxybenzyl) oxyphenylmethyl] -2- [N- (2-methoxyethyl) aminocarbonyl- (L) -valyl] hydrazine,

F) 1- (2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl- (L) -valyl) amino-4-phenylbutyl) -) 1- [4- (3,4-dimethoxybenzyl) oxyphenylmethyl] -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl- (L) -valyl] hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl- (L) -valyl) amino-4- feny1butyl / 1- / 4- (3,4-dimethoxybenzyl) oxyfenylmetyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-metylaminokarbonyl- (L) -valyl / hydrazine .

Example 19

By procedures analogous to those described in the preceding and following examples, the following compounds were prepared:

A) 1- (2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-isobutyloxyphenylmethyl-2- / N-acetyl- ( L) -valyl / hydrazi'n.

B) 1- (2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-isobutyloxyphenylmethyl) -2- (N-methoxycarbonyl- (L) ) -valyl / hydrazine,

262

C) 1- (2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-isobutyloxyphenylmethyl) -2- (N-ethoxycarbonyl- (L) ) valyl / hydrazine,

D) 1- (2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylmethylaminocarbonyl (L) -valyl) amino-4-phenylbutyl) -1- (4-isobutyloxyphenylmethyl) -2-) N- (N, N-dimetylaminokarbonyl- (L) -valyl / hydrazine,

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl (L) -valyl) amino-4-phenylbutyl) -1- (4-isobutyloxyphenylmethyl) - 2- / N- (N- (2- (methoxyethyl) aminocarbonyl- (L) -valyl) hydrazine),

F) 1- (2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl- (L) -valyl) amino-4-phenylbutyl)) -1- (4-isobutyloxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl- (L) -vinyl] hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methyl aminocarbonyl- (L) -valyl) amino) - 4-phenylbutyl] -1- (4-isobutyloxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl- (L) -valyl] hydrazine.

Example 20

By procedures analogous to those described in the preceding and following examples, the following compounds were prepared:

A) 1- (2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl) -1- [4- (2-methoxyethoxy) phenylmethyl-2-] N-acetyl- (L) -valyl / hydrazine,

B) 1- [2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- [4- (2-methoxyethoxy) phenylmethyl] -2- [N] -metoxykarbonyl- (L) -valyl / hydrazine,

263

C) 1- [2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- [4- (2-methoxyethoxy) phenylmethyl] -2- [N] -etoxykarbonyl- (L) -valyl / hydrazine,

D) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- / 4- (2-methoxyethoxy) phenylmethyl] -2- [N- (N, N-dimethylaminocarbonyl- (L) -valyl) hydrazine,

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl- (L) valyl) amino-4-phenylbutyl] -1- / 4- ( 2-methoxyethoxy) phenylmethyl] -2- [N- (2-methoxyethyl) aminocarbonyl- (L) -vinyl] hydrazine,

F) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl- (L) -valyl) amino-4-phenylbutyl) -) of 1- / 4- (2-methoxyethoxy) phenylmethyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl (L) -valyl / hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl)) -N-methylaminocarbonyl- (L) -valyl) amino- 4-phenylbutyl] -1- [4- (2-methoxyethoxy) phenylmethyl] -2- [N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) - valyl / hydrazine.

Example 21

By procedures analogous to those described in the preceding and following examples, the following compounds were prepared:

A) 1- (2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl) -1- (methylene-3,4-dioxyphenylmethyl) -2-) N-acetyl- (L) -valyl / hydrazine,

B) 1- (2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (methylene-3,4-dioxyphenylmethyl) - 2- / N-methoxycarbonyl- (L) -valyl / hydrazine,

264

C) 1- (2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (methylene-3,4-dioxyphenylmethyl) -2- (N-) ethoxycarbonyl- (L) -valyl / hydrazine,

D) 1- (2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl) -1- (methylene-3,4-dioxyphenylmethyl) N- (N, N-dimethylaminocarbonyl) - (L) -valyl / hydrazine,

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (methylene-3) 4-dioxyphenylmethyl] -2- [N- (2-methoxyethyl) aminocarbonyl) - (L) -vinyl] hydrazine,

F) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl)) - (L) -vinyl) amino- 4-phenylbutyl] -1- (methylene-3,4-dioxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethylaminocarbonyl) - (L) valyl / hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino-4 phenylbutyl / -1 / metylén3,4-dioxyfenylmetyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) -L-valyl / hydrazine,

H) 1- (2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl) -1- (3,4-dimethoxyphenylmethyl) -2- [N-] acetyl) - (L) -valyl / hydrazine

I) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (3,4-dimethoxyphenylmethyl) -2- (N) (methoxycarbonyl) - (L) -valyl / hydrazine,

J) 1- / 2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (3,4-dimethoxyphenylmethyl) -2- (N) -ethoxycarbonyl - (L) —valyl / hydrazine,

K) 1- (2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) valyl) amino-4-phenylbutyl) -1- (3,4-dimethoxyphenylmethyl) 2- / N

265

- (N, N-dimethylaminocarbonyl) - (L) -vinyl / hydrazine,

L) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl) - (L) valyl) amino-4-phenylbutyl] -1- (3,4-dimethoxyphenylmethyl) N - (N- (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

M) 1- / 2 (S) -Hydroxy-3 (S) - (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vinyl) amino-4 -phenylbutyl-1- (3,4-dimethoxyphenylmethyl) -2- [N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl / hydrazine,

N) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -vinyl) amino) 4-phenyl-butyl / -1- / 3,4dimetoxyfenylmetyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl / hydrazine.

Example 22

By procedures analogous to those described in the preceding and following examples, the following compounds were prepared:

A) 1- (2 (S) -Hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-biphenylylmethyl) -2- [N-acetyl- (L) -valyl / hydrazine,

B) 1- (2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-biphenylylmethyl) -2- (N-methoxycarbonyl- (L) ) valyl / hydrazine,

C) 1- / 2 (S) -Hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- (4-biphenylylmethyl) -2- N -ethoxycarbonyl- (L) ) valyl / hydrazine,

D) 1- (2 (S) -Hydroxy-3 (S) - (N- (N, N-dimethylaminocarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (4-biphenylylmethyl) -2 - / N (N Ndimetylaminokarbonyl- (L) -valyl / hydrazine.

E) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N-2-methoxyethyl) aminocarbonyl) - (L)

valyl) amino-4-phenyl-butyl / -1- / 4-biphenylyl-methyl / -2 / N (N (2-methoxyethyl) aminocarbonyl) - (L) -valyl / hydrazine,

F) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) aminocarbonyl) - (L) -vinyl) amino- 4-phenyl-butyl / -1- / 4-biphenylylmethyl / 2- / N- (N- (2-morpholin-4-yl) ethyl) aminocarbonyl) - (L) -valyl / hydrazine,

G) 1- / 2 (S) -Hydroxy-3 (S) - (N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl) amino-4 phenylbutyl / 1- / 4-biphenylylmethyl / 2- / N- (N- (2- (morpholin-4-yl) ethyl) -N-methylaminocarbonyl) - (L) -valyl / hydrazine.

Example 23

1- / 2 (S) -hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4cyklohexylbutyl / 1- (cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) valyl / hydrazine

100 mg (0.165 mmol) 1- / 2 (S) -Hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) (-2-) N-methoxycarbonyl-1- (L) -vinyl-hydrazine (Example 2a) in a solution of 8 ml of methanol is hydrogenated at low pressure and at room temperature in the presence of 20 mg of Nishimura catalyst (rhodito-platinum oxide monohydrate) After filtration of the hydrogenation catalyst through Celite and evaporation of the filtrate, the title compound is obtained.

Mass spectrum (F-ionization): (M + H) + = 612.

Example 24

1- / 2 (S) -hydroxy-3 (S) - (N- (n-propyloxy carbonyl) - (L) -valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N- (n-propyl ) oxycarbonyl (L) -valyl / hydrazine

267

100 mg (0.152 mmol) of 1- (2 (S) -Hydroxy-3 (S) - (N- (allyloxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) The 1-yloxycarbones of 1- (L) -vinyl / hydrazine (Example S) in 4 ml of methanol are hydrogenated at low pressure and room temperature in the presence of 50 mg of 5% palladium on carbon as a hydrogenation catalyst. Evaporation of the filtrate and digestion from DIPE yields pure desired compound.

Mass spectrum (F-ionization): (M + H) + - 662

Example 25

1- / 2 (R) -hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L ) -valyl / hydrazine mg (0.186 mmol) of N-methoxycarbonyl-1- (L) -vinyl (Example 2b) is activated under protective atmosphere with 82 mg (0.186 mmol) of BOP and 25 mg (0.186 mmol) of HOBT in 1.24 ml of a 0.3M solution of NMM in DMF, then 25 mg (0.062 mmol) of 1/2 (R) -Hydroxy-3 (S) -amino-4-phenylbutyl] -1- (cyclohexylmethyl) hydrazine (in hexane) are added after 15 min. hydrochloride salt) and allowed to react for 18 hours. The reaction mixture was then evaporated under high vacuum and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and a tank. Chromatography on a silica gel column, eluting with methylene chloride / methanol with a gradient of 99: 1 to 15: 1 and precipitation from a concentrated solution in DMF by addition of DIPE, affords the pure title compound.

tpet (V) = 14.7 min, mass spectrum (F-ionization): (M + H) + = 606.

The starting material was prepared as follows.

(a) 2 (R) - / 1 '(S) - (Trifluoroacetylamino) -2'-phenylethyl / oxirane (alternative procedure to Reference Example)

268

6d)

To a solution of 14.5 g (60 mmol) of N-trifluoroacetyl-1-phenyl-3-buten-2 (S) -amine (Reference Example 16c) in 600 mL of chloroform was added 54.28 g (314 mmol) of m- The mixture was stirred at room temperature for 16 hours. The reaction mixture was washed twice with 10% sodium sulfite solution, twice with saturated sodium carbonate solution, with water and finally with brine. The aqueous phases are extracted twice more with methylene chloride and the combined organic phases are dried over sodium sulphate and evaporated. Chromatography on silica gel using hexane / ethyl acetate (2: 1) gives the title compound as a 6: 1 (2R) - and (2S) -epimer.

TLC: RT (F) - 0.41, TLC: RT (N) = 0.6, T et _R (V) = 12.6 min; ¹ H-1 Nuk Earn Spectrum :

(200 MHz, CDCl 4) among others 4.08 (m, 1/7 H, H-C (2 (S))),

4.47 (m, 6/7 H, H-C (2 (R))).

b) 1- / 2 (S) -Hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl] -1-cyclohexylmethyl] -2- (tert-butoxycarbonyl) hydrazide to 1 - / 2 (R) ) - hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl / -1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) hydrazine

2.5 g (9.65 mmol) of 2 (R) - / 1 '(S) - (trifluoroacetylamino) -2'-phenylethyl / oxirane (containing 14% (2S) -epimer) and 2.2 g (9.65 mmol) mmol) of tert-butyl-3-cyclohexylmethylcarbazate (Reference Example 4a) was dissolved in 31 ml of methanol under a nitrogen atmosphere and the solution was then kept at 75 ° C for 18 hours. The reaction mixture is evaporated and the residue is chromatographed. silica gel, eluting with a toluene / ethyl acetate (10: 1) mixture. As the main product is. in elution, it first obtains the (2S) -epimer, followed by the (2R) -epimer. (2 S) epimer:

263

TLC R f (I), _R t © _t (A) = 18.5 min; Elemental Analysis: = 0,7, C (%) H (%) N (%) calculated tané 59,12 7, 44 8.62 obtained 59.10 7.09 8.81. (2 R) epimer: thin - layer chromatography layer: R r (I) = 0,6, t Ret (V) = 18.5 min, mass spectrum (fast ionization) alkyl) (M + H)

c) 1- (2 (R) -Hydroxy-3 (S) -amino-4-phenylbutyl-1- (cyclohexylmethyl))

2- / tertbutoxycarbonyl / hydrazine

326 mg (0.669 mmol) of 1- (2) (R) -hydroxy-3 (S) - (trifluoromethylamino) -4-phenylbutyl-1- (cyclohexylmethyl) -2- (tert.). The butoxycarbonyl / hydrazine was dissolved in 52 ml of MeOH under nitrogen, the solution was heated to 70 ° C, then 17 ml of 1M aqueous sodium carbonate solution was added thereto, and the resulting mixture was stirred at 17 ° C for 16 hours. The reaction mixture was evaporated and the residue was partitioned between 3 parts methylene chloride, 2 parts water and brine. Evaporation of the organic phase, which was previously dried over sodium sulfate, yields the title compound which is used directly in the next step. ¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CO 3 OD) 1.42 (s, 9H, Boc), S-2.1 (m, 11H), C y C H O x Y 1),

2.4-3.0 (m, 6H);

3.1 (m, 1H), .delta.4 (m, 1H),

7.28 (m, 5H).

d) 1- / 2 (R) -Hydroxy-3 (S) -amino-4-phenylbutyl-1- (cyclohexylmethyl) hydrazine (hydrochloride salt)

To a solution of 80 mg (0.204 mmol) of 1- [2 (R) -hydroxy-3 (S) -amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) hydrazine in 2 ml dioxane was added 2 ml Of 4N hydrochloric acid in dioxane and the mixture was stirred at room temperature for 7 hours, then lyophilized. It is operated under a nitrogen atmosphere. The crude product obtained is then used immediately in the above reaction.

Example 26

1- / 2 (R) -hydroxy-3 (R) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenylbutyl-1 / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) -valyl / hydrazin

315 mg (1.80 mmol) of N-methylcarbonyl- (L) -valine (Example 2b) was activated under a nitrogen atmosphere with 795 mg (1.80 mmol) of BOP and 26 mg (I, 80 mmol) of HOBT in 12 ml of a 0.3M solution of NMM in DMF, then 240 mg (0.60 mmol) of 1- (2) (R) -hydroxy-3 (R) -amino-4-phenylbutyl] -1- (cyclohexylethyl) hydrazine (in the form of the hydrochloride salt) (may be prepared analogously to 1/2 (S) -hydroxy-3 (S) -amino-4-phenylbutyl) -1- (cyclohexylethyl) hydrazine hydrochloride (Reference Example 10a - H- (Phe ^NN Cha) -H (3HCl) from (D) -N-Boc-phenyl and 1-aniline) and allowed to react for 48 hours. The reaction mixture was then evaporated under high vacuum and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and a tank. Chromatography on a silica gel column using a 19: 1 mixture of methylene chloride and methanol and digestion in methylene chloride / DIPE gave the pure title compound.

TLC: Rt = (B ') = 0.60, t Ret (V) - 14.7 min, mass spectrum (fast atom ionization): (M + H) &lt; + &gt; - 606.

Example 27

1

1- / 2 (S) -hydroxy-3 (S) - (benzyloxycarbonylamino) -4-phenyl-butyl / -1- / phenylmethyl / 2- (methoxycarbonyl- (L) -valyl / hydrazine

0.28 mmol of 1- [2 (S) - (benzyloxycarbonylamino) -4-phenylbutyl] -1-phenylmethyl-hydrazine and 54.3 mg (0.31 mmol) of N-methoxycarbonyl- (L) -valine (Example 2b) ) was dissolved in 3.36 mL of 0.25M NMM in CH ₃ CN, and 117.6 mg (0.31 mmol) of HBTU was added to this solution under nitrogen atmosphere and the mixture was stirred at room temperature for 3 hours. During this time, a precipitate of pure desired compound is separated from the initially clear solution. The precipitate was filtered off and washed with 3 ml of a 1: 2 mixture of CHaCN and DIPE.

Thin layer chromatography: Rf (I) = 0.22, t Ret (V) = 15.4 min, mass spectrum (fast atom ionization): (M + H) - 577

Further product can be obtained by evaporating the filtrate, partitioning the residue between 3 parts ethyl acetate, 2 parts saturated sodium bicarbonate solution, water and a tank, drying the organic phases over sodium sulfate, evaporating and digesting from DIPE.

The starting material was prepared as follows.

a) 1- / 2 (S) -Hydroxy-3 (S) - (benzyloxycarbonylamino) -4-phenylbutyl / -1- (phenylmethyl) -2- (tert-butoxycarbonyl) hydrazine

220 mg (0.57 mmol) of 1- (2 (S) -hydroxy-3 (S) -amino-4-phenylbutyl) -1- (phenylimethyl) was reacted at room temperature for 16 hours under a nitrogen atmosphere. -2- (tert-butoxycarbonyl) hydrazine (= H- (Phe ^NN Phe) -Boc, Reference Example 30b) in 15 mL of 1: 1 dioxane / water and 408 mg (2.9 mmol) of potassium carbonate 120 mg (0.69 mmol) of chloroformic acid benzyl ester. Sodium hydrogensulfate solution was then added and the mixture was extracted with 3 portions of ethyl acetate. The organic phase is washed with water and brine, dried over sodium sulphate and evaporated.

272

Digestion with hexane gave the pure title compound. TLC: R f (I) = 0.52, t _Ret (V) = 17.1 min, mass spectrum (F-ionization): (M + H) + = 520.

b) 1- / 2 (S) -Hydroxy-3 (S) - (benzyloxycarbonylamino) -4-phenylbutyl / 1- (phenylmethyl) hydrazine

A solution of 148 mg (0.28 mmol) of 1- [2 (S) -Hydroxy-3 (S) - (benzyloxycarbonylamino) -4-phenylbutyl] -1 - [(phenylmethyl) -2- (tert-butoxycarbonyl) hydrazine] in 7 The reaction mixture was evaporated under high vacuum and the residue was partitioned between 3 parts of ethyl acetate, 2 parts of sodium bicarbonate solution, and the organic phases were dried over sodium sulfate and evaporated.

TLC: Rt- (I) = 0.50, t rt (V) = 11.8 min.

Example 28

1- / 2 (S) -hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-cyclohexylbutyl / -1 / phenylbutyl / 2- / N-methoxycarbonyl) -L valyl / hydrazine

In a manner analogous to that described in Example 16B, 91.7 mg (0.52 mmol) of N-methoxycarbonyl-1- (L) -vinyl (Example 2b), 232 mg (0.52 mmol) of BOP was reacted for 18 hours. and 70.7 mg (0.53 mmol) of HOBt in 3.5 mL of a 0.3 M solution of NMM in DMF with 70 mg (0.174 mmol) of 1- / 2 (S) -Hydroxy-3 (S) -amino- 4-cyclohexylbutyl / hydrazine (in the form of the hydrochloride salt). The reaction mixture was evaporated under high vacuum and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and a tank. Upon precipitation of the concentrated solution in DMF by addition of DIPE, the pure title compound is obtained. Thin layer chromatography: R-t - (G ') = 0.61,

273 t _R et (V) = 14.7 min, mass spectrum (F-ionization): (M + H) + = 606.

The starting material was prepared as follows.

a) N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-cyclohexyl-1-trimethylsilyl butane g (81.3 mmol) N-3 (S) - (Boc-amino) -2 (R, S) -hyloxy-4-phenyl-1-trimethylsilylbutane (prepared according to EP 532466-A2, page 42) is hydrogenated in 882 ml of methanol at low pressure and at room temperature in the presence of 2.94 g of N ishimura catalyst (rhod ito-p-tin oxide in the form of monohydrate, Degussa, Germany). Filtration of the hydrogenation catalyst through Celite and evaporation of the filtrate gave the title compound.

TLC: Rf - (I) - 0.7, MS (FAB): (M + H) @ + - 344.

b) 1-Cyclohexyl-3-butene-2 (S) -amine

To a solution of 23.1 g (67.2 mmol) of 3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-cyclohexyl-1-trimethylsilyl butane in 460 ml of methylene chloride was added at 5 ° C to 42.2 ml (336 mmol) of an approximately 48% solution of boron trifluoride in ether. The reaction mixture was then stirred at room temperature for 6 hours, followed by the addition of 3M sodium carbonate solution. The aqueous phase was separated and extracted twice with methylene chloride. The organic extracts were washed with brine, dried over sodium sulfate and evaporated. The desired product was used in the next reaction step without further purification.

c) N-Boc-1-cyclohexyl-3-butene-2 (S) -amine

To a solution of 8.2 g (53.5 mmol) of 1-cyclohexyl-3-buten-2 (S) -amine in 110 ml of methylene chloride is added 15.2 g (69.5 mmol) of Boc-anhydride at room temperature. . After stirring at rt for 17 h

At room temperature, the mixture was extracted twice with 10% citric acid, water, and brine. The aqueous phases are washed twice more with methylene chloride, dried over sodium sulphate and evaporated. Chromatography of the residue on a silica gel column using a 4: 1 mixture of hexane and ethyl acetate gives the title compound.

TLC: Rf = 0.8.

d) 2 (R) - / 1 '(S) - (Boc-amino) -2'-cyclohexylethyl / oxirane

To a solution of 2.5 g (9.86 mmol) of N-Boc-1-cyclohexyl-3-butene-2 (S) -amine in 65 ml of chloroform was added 8.5 g (172 mmol) of m-chlorobenzoic acid and the mixture was stirred 18 hours at room temperature. The reaction mixture was washed with 10% sodium sulfite solution, saturated sodium carbonate solution, water and brine. The aqueous phases are extracted twice more with methylene chloride and the combined organic phases are dried over sodium sulphate and evaporated. After chromatography on a silica gel column, eluting with a mixture of hexane and ethyl acetate in volume ratio, the pure title compound is finally obtained.

TLC: Rf (L) = 0.22.

e) 1- / 2 (R) -Hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-cyclohexylbutyl / -1- (phenylmethyl) -2- (tert-butoxycarbonyl) hydrazine

A mixture of 200 mg (0.745 mmol) of 2 (R) - / 1 '(S) - (Boc-amino) -2'-cyclohexylethyl / oxirane and 165 mg (0.745 mmol) of tert-butyl-3-benzyl carbazate (J). Chem. Soc., Per Kin I, 1 7 1 2 (1 9 7 5)) in 6 ml of methanol is stirred for 2 days at 75 ° C and under a nitrogen atmosphere. Evaporation of the reaction mixture and precipitation from a concentrated solution in methylene chloride by addition of hexane gave the title compound.

Thin Layer Chromatography: R-p (I) = 0.54.

f) 1- / 2 (R) -Hydroxy-3 (S) -amino) -4-cyclohexylbutyl / -1- (phenylmethyl) hydrazine (Hydrochloride salt)

275

To a solution of 90 mg (0.183 mmol) of 1- (2) (R) -Hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-cyclohexylbutyl] -1- (phenylmethyl) -2 (tert-butoxycarbonyl) hydrazine at 0, In the absence of moisture, 5 ml of dioxane is added 0.5 ml of 4N hydrochloric acid in dioxane. After 5 hours at room temperature, the mixture is lyophilized and the lyophilisate used directly in the next step.

Example 29

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / -2 / t. butoxycarbonyl / hydrazine

940 mg (3.27 mmol) of quinoline-2-carbonyl- (L) -asparagine (as the hydrochloride salt) was dissolved in 35 mL of THF at 5 ° C and 736 mg (3.57 mmol) of DCC was added to the obtained solution. . After 10 minutes, 482 mg (3.57 mmol) of HOBt, 0.82 mL (744 mmol) of NMM and 1.165 g (2.98 mmol) of 1- / 2 (S) -Hydroxy-3 (S) -amino) are added. -4-Phenylbutyl [-1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) -hydrazine, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated. Separation of the residue between 3 parts of ethyl acetate, saturated sodium bicarbonate solution, water and a tank, drying of the organic phases over sodium sulfate and evaporation and chromatography of the residue on silica gel with ethyl acetate gave the title compound.

TLC R f (0) = 0.16; t _Re (V) - 16.5 minutes, neat s MS (FAB): (M + H) + = 661st

The starting material was prepared as follows.

a) Quinoline-2-carbonyl- (L) -asparagine-tert-butyl ester

In a manner analogous to that described in Example 29), 5.45 g (31.4 mmol) of acid are reacted.

276 chlorine per day in 161 ml THF with 7.08 g (34.3 mmol) DCC, 4.63 g (34.3 mmol) HOBT and 5.38 g (28.6 mmol) (L) - asparagine-tert-butyl ester (Bachem, Bubendorf, Switzerland). Filtration, extraction and silica gel column chromatography using a 3: 1 mixture of ethyl acetate and hexane gave pure title compound.

TLC: Rf (C &apos;) = 0.15, _tt (V) = 12.2 min, mass spectrum (F-ionization): (M + H) &lt; + &gt; = 344.

b) Quinoline-2-carbonyl- (L) -asparagine (hydrochloride salt)

4.0 g (11.6 mmol) of quinoline-2-carbonyl- (L) -asparagine-tert. The butyl ester is dissolved in 40 ml of dioxane under a nitrogen atmosphere and 40 ml of 4 N hydrochloric acid in dioxane are added. After stirring at room temperature for 17 hours, the product precipitated as a solid. Filtration and washing with DIPE gave pure desired compound.

^ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 3.02 (d, J = 6 H 2, 2H),

5, O9 (t, J = 6 Hz, 1 H);

7.92 (m, 1H); 12 (m, 1H);

3.26 (m, IH),

8.4 (m, 2H).

9.03 (m, IH).

c) 1- (2 (S) -Hydroxy-3 (S) -amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) hydrazine

Under a nitrogen atmosphere with 2.0 g (4.10 mol) of 1- (2 (S) -hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl) -1- (cyclohexylmethyl) -2- (tert-butoxycarb) of bony 1 / hydrazine (Example 25b) is dissolved in 316 ml of methanol, the solution is heated to 70 ° C and then

277 ml of 1M aqueous potassium carbonate solution was added dropwise thereto, followed by stirring at 70 ° C for 18 hours. The reaction mixture was then evaporated under high vacuum and the residue was partitioned between 3 parts methylene chloride, 2 parts water and a tank. After drying the organic phases over sodium sulfate and evaporating them, the title compound is obtained.

Nukle-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 1.42 (S, 9H, Boe),

0.8-2.1 (m, 11H, cyclohexyl), 35-3.0 (m, 7H),

3.51 (m, 1H); 25 (m, 5H).

B) 1- (2 (S) -Hydroxy-3 (S) - (N-quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl [-1- (phenylmethyl) -2-] tert-butoxycarbonyl / hydrazine

To 4.69 g (12.2 mmol) of 1- (2) (S) -hydroxy-3 (S) -amino-4-phenylbutyl] -1- (phenylmethyl) -2- (tert.). butoxycarbonyl 1 / hydrazine in 250 mL of THF at 0 ° C was added 3.84 g (13.4 mmol) of quinoline-2-carbonyl- (L) -asparagine (hydrochloride salt) (Example 29 A, b). To the obtained suspension was added 2.18 g (13.4 mmol) of HOBT, 2.76 g (13.4 mmol) of DCC and 2.14 ml (19.5 mmol) of NMM and the mixture was stirred at 0 ° for 30 minutes. C and then at room temperature for 17 hours. The reaction mixture is filtered and the filtrate is evaporated to a residual volume of about 50 ml. The fine suspension is taken up in methylene chloride, washed with sodium bicarbonate solution and brine, and the aqueous phases are extracted with 2 parts of methylene chloride. Filtration of the combined organic phases through cotton wool, evaporation and precipitation from a concentrated solution in a mixture of methanol and methylene chloride by addition of DIPE and finally hexane yields the title compound.

TLC: R f (P) = 0.41, t Ret (V) = 14.8 min, mass spectrum (F-ionization): (M + H) + = 655.

278

The starting material was prepared as follows.

a) 1- / 2 (S) -Hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl / -1 (phenylmethyl) 2- (tert-butoxycarbonyl) hydrazine (improved version of Reference Example 30a)

20.49 g (79 mmol) of 2 (R) - / 1 '(S) - (trifluoromethyl-amino) -2' phenylethyl / oxirane (Example 25a) and 17.56 g (79 mmol) of tert-butyl 1-3 -benzyl carbazate (J. Chem. Per Jin I, 1 7 1 2 (1 97 5)) in 300 ml of ethanol is heated at 80 ° C for 20 hours under a nitrogen atmosphere. After cooling, partial evaporation to the beginning of crystallization, filtration and washing with a small amount of ethanol, the pure title compound is obtained.

t _Ret (V) = 16.1 min, mass spectrum (F-ionization): (M + H) * = 482, Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 1.30 (s, 9H),

2.70 (m, 2H).

2.83-3.08 (m, 2H);

3.76 (m, IH);

3.85 (s, 2H).

4.21 (m, IH),

7.2-7.4 (m, 10 H).

b) 1- / 2 (S) -Hydroxy-3 (S) -amino-4-phenylbutyl / -1- (phenylmethyl) -2- tert -butoxycarbonyl / hydrazine (improved version of Reference Example 30b)

Under a nitrogen atmosphere, 6.0 g (12.5 mmol) of 1- (2 (S) -hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl) -1- (phenylmethyl) -2- (tert-butoxycarbony) 1) hydrazine was dissolved in 420 ml of methanol, the solution was heated to 80 ° C and then 125 ml of 1M aqueous potassium carbonate solution (15 minutes) was added dropwise thereto (15 minutes) and the mixture was stirred at 80 ° C for 18 hours. . The reaction mixture was evaporated and the residue was partitioned between 3 parts of methylene chloride, water and brine. Filtration of the organic phases through cotton wool and evaporation of the filtrate gave the title compound, t r e (V) = 11.5 min,

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 1.29 (s, 9H),

2.5-3, O5 (m, 5H), δ6 (m, 1H),

3.8-3.95 (AB, 2H);

7.1-7.4 (m, 10H).

C) 1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- [beta] (methoxyphenyl) methyl Tert-butoxycarbonyl / hydrazine

In a manner analogous to that described in Example 29B, 7.00 g (16.8 mmol) of 1- [2 (S) hydroxy-3 (S) -amino-4-phenylbutyl] -1- tert-butoxycarbonyl / hydrazine in 420 mL of THF with 5.3 g (18.5 mmol) of quinoline-2-carbonyl- (L) -asparagine (hydrochloride salt) (example) 29 A, b), 3.0 g (18.5 mmol) of HOBT, 3.8 g (18.5 mmol) of DCC and 5 ml of NMM. The reaction mixture is then filtered, and the filtrate is evaporated. The evaporation residue is taken up in ethyl acetate and washed twice with sodium bicarbonate solution and brine. The aqueous phases are extracted with 2 parts of ethyl acetate and the organic phases are dried over sodium sulphate and evaporated. Chromatography on a silica gel column eluting with ethyl acetate yields the pure title compound. TLC: Rt = (O) = 0.59, _Rt (V) = 14.5 min, Mass Spectrum (F-ionization): (M + H) - = 685.

280

The starting material is obtained as follows.

a) p- (Methoxyphenyl) carbaldehyde-tert-butoxycarbonylhydrazone

Under protective atmosphere, 65 ml (534 mmol) of freshly distilled anisaldehyde was dissolved in 850 ml of ethanol, 70.6 g (534 mmol) of tert-butylcarbazate were added thereto, and the mixture was heated at 80 ° C for 3 hours. Evaporation of the reaction mixture gave the title compound.

¹ H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 1.53 (s, 9H),

3.82 (s, 3H);

6.94 and 7.64 (2 d, J = 9 Hz of 2H),

7.86 (s, 1 H).

b) tert -Butyl-3- (p-methoxyphenylmethyl) k a r b and z

130 g (520 mmol) of p- (methoxyphenyl) carbonyl and 1-dehydro-1-tert-butoxycarbonylhydrazone are hydrogenated in 1.3 L of THF in the presence of 11.5 g of 5% palladium on carbon. Filtration of the hydrogenation catalyst through Celite and evaporation of the filtrate gave the title compound.

Thin Layer Chromatography: Rt (F) - 0.3, tRet (V) = 8.9 min, H-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDaOD) 1.44 (s, 9H), 7.77 (s, 3H),

3.83 (s, 2H);

6.87 and 7.26 (2d, J = 3 Hz, for 2H).

c) 1- / 2 (S) -Hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl / 1- [p- (methoxyphenyl) methyl] -2- (tert-butoxycarbonyl) hydrazine (57.9 mmol) (R) - / 1 '(S) - (Trifluoroacetyl amine) -2,228 phenylethyl / oxirane (Example 25a) and 14.6 g (57.9 mmol) of tert-butyl 3- (p-Methoxyphenylmethyl) carbazate in 220 ml of ethanol was heated at 80 ° C under protective atmosphere for 18 hours. After cooling, evaporation and digestion in DIPE, the title compound is obtained.

TLC: RR- (F) = 0.42; _Re t (A) = 15.8 min.

d) 1- (2 (S) -Hydroxy-3 (S) -amino-4-phenylbutyl) -1- [p- (methoxyphenyl) methyl] -2- (tert-butoxycarbonyl) hydrazine

In a manner analogous to that described in Example 29B, b, 19.7 g (38.4 mmol) of 1- (2) (S) -hydroxy-3 (S) - (trifluoroacetylamino) -4-phenylbutyl [-1-] p- (methoxyphenyl) methyl [2- (tert-butoxycarbonyl) hydrazine in 1 liter of methanol is hydrolyzed with 384 ml of 1M potassium carbonate solution to give the title compound.

Thin Layer Chromatography: Rt- (G ') - 0.4.

Example 30

1- / 2 (S) -hydroxy-3 (S) - (N-chino1ín-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl (L) -v-yl / hydrazine

Under a nitrogen atmosphere, 100 mg (0.178 mmol) of 1- [2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl] -1- cyclohexylmethyl / hydrazine (Reference Example 71e, i) and 34 mg (0.196 mmol) of N-methoxycarbonyl-1- (L) -vinyl (Example 2b) are dissolved in 1.75 ml of a 0.3M solution of NMM in DMF, 74 mg (0.196 mmol) of HBTU was added to the solution, and the mixture was stirred at room temperature. After three days, unreacted hydrazine is still present in the reaction mixture and 0.3 equivalents of N-methoxycarbonyl- (L) -valine and 0.3 equivalents of HBTU in 0.48 mL of 0.3M NMM in DMF are added once more. After 18 hours, the reaction mixture is concentrated under high vacuum, the residue is dissolved in methylene chloride,

282 was washed with saturated sodium bicarbonate solution, water, and brine. The aqueous phases are extracted twice with methylene chloride and the organic phases are dried over sodium sulphate and evaporated. Chromatography on a silica gel column, eluting with methylene chloride / methanol (15: 1, v / v) and digesting with DIPE, gave the title compound. Thin layer chromatography: Rt- (A ') = 0.17,

IR (V) = 14.5 min, MS (F-ionization): (M + H) + = 718.

Example 31

1- / 2 (S) -hydroxy-3 (S) - (N- (quinolin-2-l <arbonyl) - (L) aspartyl)

amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / 3,3-dimety1butyryl / hydrazine

Under protective atmosphere, 100 mg (0.178 mmol) of 1- (2) (S) hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl / -1- / cyclohexyl of methyl 1 / hydrazine (Reference Example 71e, i) and 25 _of µl (0.196 mmol) of 3,3-dimethylbutyric acid are dissolved in 1.75 ml of a 0.3M solution of NMM in DMF, 74 mg (0.196 mmol) are added. 1) HBTU and the mixture is stirred at room temperature. Since unreacted hydrazine was still present in the reaction mixture after 18 hours, 0.3 equivalents of 3,3-dimethylbutyric acid and HBTU in 0.5 ml of 0.3N NMM in DMF were added to the mixture. After the same treatment as in Example 30, chromatography on a silica gel column using a 20: 1 mixture of ethyl acetate and ethanol and digestion with DIPE gave the title compound.

TLC: R @ + - (E ') = 0.23, t Ret (V) = 15.6 min, mass spectrum (fast atom ionization): (M + H) @ + = 659.

Example 32

283

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) tert. buty1aminokarbonyl / hydrazine

Under a protective atmosphere, 100 mg (0.178 mmol) of 1- / 2 (S) hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl / -1- / cyclohexyl of methyl 1 / hydrazine (Reference Example 71c, i) is dissolved in 0.7 mL of THF and this solution is left with 19 µl of tert. butyl isocyanate for 17 hours at room temperature. The reaction mixture is then evaporated, the residue is dissolved in ethyl acetate, the solution is washed with 5% citric acid solution, water and brine and the inorganic phases are extracted twice with ethyl acetate, dried over sodium sulphate and evaporated. Chromatography on a silica gel column eluting with a 10: 1 mixture of ethyl acetate and ethanol gave the title compound.

Thin layer chromatography: R-r- (F ') = 0.1, t r e. (V) = 15.3 min, MS (F-ionization): (M + H) = 660.

Example 33

1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (benzylaminocarbonyl) hydrazine

In a manner analogous to that described in Example 32, 100 mg (0.178 mmol) of 1/2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L)) were reacted. aspartyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / s not hydrazino (reference example 71e, i) in 0.7 ml THF _from 21 u 1 (0.169 mmol) benzylkyanátu. Silica gel column chromatography eluting with methylene chloride / methanol (15: 1, v / v) and digesting with DIPE gave the title compound. TLC: Rf (A &apos;) = 0.12, _tt (V) = 15.5 min, MS (F-ionization): (M + H) &lt; + &gt; = 694.

Example 34

1- / 2 (S) butyryloxy-3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenylbutyl / -1 / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) - valyl / hydrazine

To an ice cold mixture of 200 mg (0.33 mmol) of 1- / 2 (S) -Hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl / -ΙΑ yclohexylmethyl / -2- (N-methoxycarbonyl- (L) -valyl) hydrazine in 2.6 ml dioxane and 0.4 ml pyridine was added 50 _of µl (0.495 mmol) butyric chloride and 2 mg (0.017 mmol) DMAP. After 18 hours at room temperature, 1- / 2 (S) -Hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino) is still present in the reaction mixture as determined by HPLC analysis. -4-phenylbutyl] -1- (cyclohexylmethyl) -2 (N-methoxycarbonyl- (L) -vinyl) hydrazine; Therefore, 0.75 equivalents of butyric acid chloride and a DMAP grain are added to the reaction mixture. After a further 18 hours, a third portion of 1.5 equivalents of butyric acid chloride is added and the mixture is stirred overnight at room temperature (by HPLC). The reaction mixture is diluted with ethyl acetate, washed with 2 parts saturated sodium bicarbonate solution, water and brine, the aqueous phases are extracted twice with ethyl acetate and the organic phases are dried over sodium sulphate and evaporated. After digesting the oily residue from hexane in an ultrasonic chamber, the pure title compound is obtained.

TLC: Rf (O) = 0.67, _Rf (V) = 17.2 min, Mass Spectrum (F-ionization): (M + H) + = 676.

Example 35

285

1- / 2 (S) -palmitoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) - valyl / hydrazine

In a manner analogous to that described in Example 34, 200 mg (0.33 mmol) of 1- / 2 (S) hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -va1) are reacted. y 1) amino-4-phenylbutyl [-1- (cyclohexylmethyl) -2- [N-methoxycarbonyl- (L) -valyl] hydrazine (Example 2a) in 2.6 ml dioxane and 0.4 ml pyridine with 0.15 ml (0.495 mol) of palmitic acid chloride and 2 mg (0.017 mmol) of DMAP. An additional portion of 0.3 mL of palmitic acid chloride and a small amount of DMAP was added to complete the reaction, stirred and extracted. Chromatography on a silica gel column, eluting with a 3: 2 mixture of ethyl acetate and hexane, affords the pure title compound.

TLC: R R (H) = 0.47, t _Re t (A) = 25.2 min; MS (FAB): (M + H) + - 844th

Example 36

1- / 2 (S) - (methoxyacetoxy) -3 (S) - (N- (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) -valyl / hydrazine

In a manner analogous to that described in Example 34, 200 mg (0.33 mmol) of 1- / 2 (S) hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) were reacted. ) amino-4-phenylbutyl / -1 / cyclohexylmethyl / 2- / N-methoxycarbonyl- (L) valyl / hydrazine (example 2a) in 2.6 ml of dioxane and 0.4 ml of pyridine in 50 _of 1 (0.495 mmol) of methoxyacetic acid chloride and 2 mg (0.017 mmol) of DMAP. 0.5 equivalents of methoxyacetic acid chloride and a few grains of DMAP were added to complete the reaction, and the mixture was stirred. Extraction and digestion from a mixture of DIPE and hexane in an ultrasonic chamber yields the pure title compound.

286

TLC R f (0) = 0.48, t θ _t (A) = 15.6 min; MS (FAB): (M + H) + = 678th

Example 37

1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - (tert-butoxycarbonyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / -2 / tert / hydrazine

500 mg (4.07 mmol) of picolinic acid (Fluka, Buchs, Switzerland) in 25 ml of methylene chloride are treated with 0.57 ml (4.07 mmol) of 1-chloro-N, N, 2 at 0 ° C and under nitrogen. trimethyl-1-propenamine (B. Haveaux, A. Decoker, M. Rens, ARSidani, J. Toye, L. Ghosez, M. Murakami, M. Yoshioka and W. Nagata, Organic Syntheses 59, 26 (1980)) After 45 minutes, 10 mL of THF, 8.3 mL of pyridine, 10 mg of DMAP and 1.00 g (2.03 mmol) of 1- (2) -Hydroxy-3 (S) - (tert-butyl) were added. butoxycarbonyl) amino-4-phenylbutyl [1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) hydrazinone (= Boc- (Phe ^NN Cha) -Boc, Reference Example 4) and the mixture was stirred at room temperature for 16 hours. Because, according to the results of the HPLC analysis, the reaction mixture still contains

1- [2 (S) -Hydroxy-3 (S) (tert-butoxycarbonyl) amino-N-phenylbutyl] -1-cyclohexylimethyl / 2-tert-butoxycarbonyl / hydrazine, two more equivalents are added picolinic acid chloride (prepared as described above) as a solution in 20 ml of methylene chloride. After 18 hours at room temperature, the mixture is diluted with methylene chloride, washed twice with saturated sodium bicarbonate solution, water and brine, the organic phases are extracted with 2 parts methylene chloride, dried over sodium sulfate and evaporated. The brown residue is dissolved in a mixture of methylene chloride and ethyl acetate, 10 g of silica gel are added and the mixture is evaporated. The powder obtained is applied to a silica gel column and eluted with a 1: 1 by volume mixture of hexane and ethyl287 acetate to give the title compound.

TLC R f (N) = 0.17, t r _e t (A) = 19.9 min;

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD 3 OD) 0.6-1.85 (m, 11 H, cyclohexyl),

1.36 and 1.40 (2s, 18H, 2 Boe),

2.4-3.1 (m, 6H);

4.28 (m, 1 H);

5.28 (m, 2H).

7.1-7.3 (m, 5H), 72 (m, .delta.),

8.08 (m, 1H); 28 (d, J = 7Hz, 1H);

8.7 δ (d, J = 5 Hz, 1H).

a) 1- (2 (S) -Hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (pyridin-2-ylcarbonyl)) hydrazine n

i) 200 mg (0.335 mmol) of 1- [2 (S) - (pyridin-2-ylcarbonyl) oxy3 (S) - (tert-butoxycarbonyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2-] The butoxycarbonyl / hydrazine is dissolved in 200 ml of formic acid under a nitrogen atmosphere, the solution is stirred at room temperature for 16 hours and then evaporated under high vacuum. The residue was partitioned between 3 parts of methylene chloride, saturated sodium bicarbonate solution and a tank, and the organic phases were dried over sodium sulfate and evaporated.

_e t tr (A) = 11.9 min.

(ii) Dissolve the above residue in 5.3 mL of 0.25M NMM in acetonitrile and add 134 mg (0.763 mmol) of N- (methoxycarbonyl) - (L) -vinyl (Example 2b) and 313 mg ( 0.826 mmol HBTU During 18 h stirring at room temperature, a precipitate of the desired compound precipitates, which is filtered off by filtration and washed with a small amount of acetonitrile.

t r e t (V) = 15.9 min, mass spectrum (fast atom ionization): (M + H) * = 554, Ή-Nuclear Magnetic Resonance Spectrum:

(500 MHz, DMSO-d6) 0.64 and 0.70 (2s, J = 7Hz, (HaC) -C),

0.81 (m, 2Hax-Cg H);

1.0 8 (m, 3 H and x - C e H 1),

1.30 (m, H i -ax ^- C & H i 1),

1.57 (m, 3Heo-CeHi),

1.74 (m, 1 Hoc-C6H4),

1.79 (octet, J = 7 Hz, HC _{(CH3) 2),}

1.88 (m, 1Heq-CeHi), 2.47-2.6O (m, H-C, HCH-CeHi),

2,66-2.84 (m, HC and, HCH-CEH-ii, HCC-phenyl-1), 3.44 (m, ₂ HC),

3.50 (s, H s C-O),

3.73 (m, HC '-iľa-Val).

3.94 (m, HC _3),

4.94 (s, H0).

6.97 (d, J = 9H2, NH-Val),

7, O5 (m, HCphenyl), 1,2 (m, 4 HC phenyl),

7.5 1 (d, J = 9 Ηζ, ΗΝ-Οβ)

7.61 (m, H-Py),

8.00 (m, H 3 -Py, Hx, -Py),

8.51 (d, J = 5Hz, Hs-Py);

9.70 (s, H N-N).

Example 38

1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (benzyl) -2- (N-) methoxycarbonyl / - (L) -valyl / hydrazine

In a manner analogous to that described in Example 40, 157.4 mg (0.898 mmol) of N- (methoxycarbonyl) - (L) -valine (Example 2b) and 453 mg (0.817 mmol) were reacted 1/2. (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (phenylmethyl) hydrazine in 8 ml of 0.3M NMM in DMF with 340 mg (0.898 mmol) of HBTU. Chromatography on silica gel, eluting initially with methylene chloride and then with a 50: 1 to 25: 1 mixture of methylene chloride and methanol, gave the title compound. TLC: Rf @ - (J @ +) = 0.16, t R @ + (V) = 13.6 min, MS (F-ionization): (M + H) @ + - 712.

Example 39

1- / 2 (S) -hydroxy-3 (S) - (N- (chinol.ín-2-carbonyl) - (L) aspartyl)

amino-4-phenylbutyl / -1- (benzyl) -2- (N-ethyloxycarbonyl) - (L) -vinyl / hydrazine mg (0.189 mmol) of N- (ethoxycarbonyl) (L) -valine (example) 9a), 35 mg (0.259 mmol) of HOBT and 38 mg (0.198 mmol) of EDC were dissolved under protective atmosphere in 0.7 ml of 0.3M NMM in DMF and the resulting solution was stirred at room temperature for 10 minutes. Add 100 mg (0.180 mmol) of 1- (2) (S) -Hydroxy-3 (S) - (N- (quinolin-2-carbobonyl) - (L) -asparaginyl) amino- Of 4-phenylbutyl [-1- (phenylmethyl) hydrazine (Example 40a) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under high vacuum, the residue was taken up in ethyl acetate, washed with 2 portions of 10% citric acid, water, saturated sodium bicarbonate solution and brine. The aqueous phases are extracted twice more with ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated. Chromatography on a silica gel column, eluting with methylene chloride / methanol (12: 1, v / v), gave the title compound.

TLC: Rf - (I ') - 0.25, trt (V) - 14.3 min.

Example 40

1- / 2 (8) Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / benzyl / 2- / N benzyloxycarbonyl) - (L) valyl / hydrazine 50 mg (0.198 mmol) Z- (L) -valine and 100 mg (0.18 mmol) 1/2 (S) -Hydroxy-3 (S) - (N) - (quinoline-2-carbobonyl) - (L) -asparaginyl) -amino-4-phenylbutyl] -1-phenylmethyl-hydrazine in 1.8 ml of a 0.3M solution of NMM in DMF is added under a nitrogen atmosphere 75.1 mg (0.198 mmol) of HBTU and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under high vacuum, the residue taken up in ethyl acetate, washed with 2 parts of a 10% citric acid solution, water, saturated sodium bicarbonate solution and brine. The aqueous phases are extracted twice more with ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated. Chromatography on a silica gel column using a 19: 1 mixture of methylene chloride and methanol yields the title compound.

TLC: Rf (J ') = 0.27, tt (V) - 15.7 min, mass spectrum (ionization and fast atoms): (M + H) &lt; + &gt; = 788.

The starting material is obtained as follows.

a) 1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (phenylmethyl) hydrazine

1.0 g (1.53 mmol) of 1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbobonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1-) Phenylmethyl / -2- (tert-butoxycarbonyl) hydrazine (Example 29B) was dissolved in 10 ml formic acid under protective atmosphere and the resulting solution was stirred at room temperature for 16 hours After evaporating the formic acid under high vacuum, separating the residue between 3 parts ethyl acetate, saturated sodium bicarbonate solution and Tank, drying the organic phases over sodium sulfate and

Evaporation gave the title compound, m.p. (V) = 10.7 min.

Example 41

By one of the above methods, 1- (2) (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbobonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (benzyl) is prepared. (-2- (N-allyloxycarbonyl) - (L) -valyl) hydrazin.

Example 42

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) asparaginyl) amino-4-phenylbutyl) -1- (1) is prepared by any of the above or below methods. 4-methoxyphenyl-methyl / -2 / Nmetyloxykarbonyl) - (L) -valyl / hydrazine.

Example 43

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenyl-butyl / -1- / p- (methoxyphenyl) methyl / - 2- (N-benzyloxycarbonyl) - (L) -valyl / hydrazine

330 mg (1.32 mmol) of Z- (L) -valine and 700 mg (1.197 mmol) of 1/2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl] -1- [p- (methoxyphenyl) methyl] hydrazine (Example 49 B) was dissolved in 11.6 ml of a 0.3M solution of NMM in DMF under nitrogen, to which was added 0. 50 g (1.32 mmol) of HBTU are added and the mixture is stirred at room temperature for 18 hours. The reaction mixture was evaporated under high vacuum, the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The aqueous phases are further extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated. After chromatography on a silica gel column using ethyl acetate and crystallization from DIPE, the title compound is obtained.

TLC: R f (G) = 0.50, t _Re t (A) - 15.4 min.

Example 44

1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- [4- (methoxyphenylmethyl) -2- (N-allyloxycarbonyl) - (L) -valyl] hydrazine.

Example 45

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) -amino-4- (4-methoxyphenyl) butyl) -1- (benzyl) The 2- (N-methyloxycarbonyl) - (L) -vinyl / hydrazine is prepared by any of the methods described above or below.

Example 46

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) -amino-4- (4-methoxyphenyl) butyl) -1- (benzyl) The 2- (N-benzyloxycarbonyl) - (L) -vinyl] hydrazine is prepared by any of the methods described above.

Example 47

1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4- (4-benzyloxyphenyl) butyl [-1- (benzyl)] The 2- (N-methyloxycarbonyl) - (L) -vinyl / hydrazine is prepared by any of the methods described above or below.

Example 48

1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4- (4-benzyloxyphenyl) butyl / -1- (benzyl) The 2- (N-allyloxycarbonyl) - (L) -vinyl] hydrazine is prepared by any of the methods described above.

Example 49

1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1-p-methoxyphenyl / methyl-2- (N-ethoxycarbonyl) (L) -vinyl] hydrazine

In a manner analogous to that described in Example 39, 71.2 mg (0.376 mmol) of N- (ethoxycarbonyl) - (L) -vinyl (Example 9a), 66 mg (0.487 mmol) of HOBT were reacted,

72.1 mg (0.376 mmol) of EDC and 200 mg (0.34 mmol) of 1- (2) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - ( L) -asparaginyl) amino-4-phenylbutyl [1- (p- (methoxyphenyl) methyl) hydrazine in 1.33 mL of 0.3M MMM in DMF. Chromatography on a silica gel column, eluting first with methylene chloride and then with a 50: 1 to 20: 1 mixture of methylene chloride and methanol, gave the title compound.

t-e t (V) = 13.9 min.

The starting material is obtained as follows.

a) 1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- [beta] (methoxyphenyl) methyl 1 / hydrazine

In a manner analogous to that described in Example 40a, 4.6 g (6.71 mmol) of 1- (2) Hydroxy-3 (S) - (N- (quinoline-2-carbonyl)) are reacted. (L) -asparaginyl) amino-4-phenylbutyl] -1- [p- (methoxyphenyl) methyl] -2- (tert-butoxycarbonyl) hydrazine (Example 29 C) with 168 ml of formic acid to give the title compound.

t _R <= t (V) - 10.8 min.

Example 50

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) -2-) N- (allyloxycarbonyl) - (L) -vinyl / hydrazine is prepared by any of the methods described above or below.

Example 51

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (4-benzyloxyphenylmethyl) -2-) N- (methyloxycarbonyl) - (L) -valyl / hydrazine is prepared by any of the methods described above or below.

Example 52

1- (2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (4-benzyloxyphenylmethyl) -2-) N- (allyloxycarbonyl) - (L) -vinyl / hydrazine is prepared by any of the methods described above.

Example 53

The following compounds were prepared in a manner analogous to any of the above:

A) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-cyclohexylbutyl] -1- (4-methoxyphenylmethyl) -2- [N- ( methyloxycarbonyl / - (L) -valyl / hydrazine,

295

B) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-cyclohexylbutyl] -1- (4-isobutyloxyphenylmethyl) -2- [N- ( methoxycarbonyl / - (L) -valyl / hydrazine,

C) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-cyclohexylbutyl] -1- (4-ethoxyphenylmethyl) -2- [N- ( methyloxycarbonyl / - (L) -valyl / hydrazine,

D) 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4

-cyklohexylbutyl / 1- / 4-benzyloxyfenylmetyl / 2- / N- (methoxycarbonyl / - (L) -valyl / hydrazine.

Example 54

By a procedure analogous to any of the above, the following are prepared:

1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl) - (L) -valyl) amino-4-phenyl-butyl / -1- / 4-cyclohexylmethyl / -2- / 2-pyridylcarbonyl / hydrazine .

Example 55

1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) aspartyl)

amino-4-phenyl-butyl / -1- / phenylmethyl / 2- / N- (2- (2-methoxyethoxy) ethoxycarbonyl) - (L) -valyl / hydrazine

In a manner analogous to that described in Example 40, 52 mg (0.198 mmol) of N- (2- (2-methoxyethoxy) ethoxy) carbonyl- (L) valine (Example 11a) and 100 mg (0.180 mmol) were reacted. ) 1- / 2 (S) -Hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl-1-yl-phenylmethyl) Hydrochloride 1.8 ml of 0.3M NMM in DMF with 75.1 mg (0.198 mmol) of HBT U. The evaporation residue is taken up in methylene chloride and washed with 2 parts of a 10% citric acid solution, water, saturated sodium bicarbonate solution and brine. . The aqueous phases are extracted twice more with methylene chloride and the combined organic phases are dried over sodium sulphate and evaporated. Chromatography on silica gel, eluting with methylene chloride / methanol (19: 1, v / v), gave the title compound.

TLC: Rf (J &apos;) = 0.08, t _R and V (V) = 13.5 min, mass spectrum (F-ionization): (M + H) &lt; + &gt; = 800.

Example 56

1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - / N (quinolin-2-carbonyl) (L) -asparaginyl) amino-4-phenyl-butyl / -1- / phenylmethyl / -2 - / N- (methoxycarbonyl) - (L) -valyl / hydrazine

In a manner analogous to that described in Example 37, 51 mg (0.416 mmol) of 2-picolinic acid in 0.8 ml are treated with 59 _of 1 (0.416 mmol) of 1-chloro-N, N, 2-trimethyl- 1-propenamine to the acid chloride, the chloride being reacted with 148 mg (0.208 mmol) of 1- / 2 (S) -Hydroxy-3 (S) - (N) after addition of 0.5 ml dioxane and 0.4 ml pyridine. - (quinoline-2-carbonyl) - (L) -asparaginyl) -amino-4-phenylbutyl] -1- (phenylmethyl) -2- (N-methoxycarbonyl) - (L) -vinyl-hydrazine (Example 38) in 5 ml dioxane in the presence of 0.5 mg DMAP. Since all the starting material is not acylated after 18 hours according to HPLC analysis, the acid chloride is added again. Chromatography on a silica gel column, eluting first with methylene chloride and then with a 15: 1 mixture of methylene chloride and methanol, affords the title compound.

Mass spectrum (F-ionization): (M + H) + - 817.

Example 57 1- (2 (S) -Butyroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1- (phenylmethyl) -2- (N- (methoxycarbonyl) (L) -vinyl) hydrazine

To a solution of 121 mg (0.17 mmol) of 1- (2 (S) -Hydroxy-3 (S) - (N (quinoline-2-carbonyl) - (L) -asparaginyl) amino-4-phenylbutyl) -1) phenylmethyl / -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine (translation 38) in 3.5 ml dioxane was added 2 ml methylene chloride, 0.4 ml pyridine, a small amount of DMAP and 0.2 ml chloride Butyric acid After diluting the reaction mixture with methylene chloride, washing with 2 parts of saturated sodium bicarbonate solution, water and brine, extracting the aqueous phases with 2 parts of methylene chloride, drying the organic phases over sodium sulfate, evaporating and chromatography on a silica gel column using methylene chloride / eluent gradient of 50: 1 to 19: 1 gave the title compound.

TLC: Rf - (I ') = 0.5, tRc (V) - 15.6 min.

Example 58

1- / 2 (S) - (2-Pyridylcarbonyl) oxy-3 (S) - (N- (quinoline-2-carbonyl) (L) -asparaginyl) amino-4-phenylbutyl) -1- [beta] (methoxyphenyl) (methyl) 2- [N- (benzyloxycarbonyl) - (L) -valyl] hydrazine

By proceeding in a similar manner as described in Example 37, the 7 2 7 mg (0.591 mmol) of 2-piko1 the new in 2 ml of methylene chloride _of 87 ul (0.614 mmol) 1-chloro-1or N, N, 2- Three methyl 1-1-propenamine are converted to the acid chloride. The latter is treated with 100 mg (0.118 mmol) of 1- / 2 (S) -hydroxy-3 (S) - (N- (quinoline-2-carbonyl) - (L) -asparaginyl) after adding 1.36 mg of pyridine. amino-4-phenylbutyl] -1- [p- (methoxyphenyl) methyl] -2- [N- (benzyloxycarbonyl) - (L) -valyl] hydrazine in the presence of 1 mg of DMAP. Additional acid chloride is then added in portions until all the starting material is found to be by high pressure liquid chromatography.

299

The sterile dry substance for injection (mg) of one of the compounds of the formula (I) prepared in the examples is dissolved in 1 ml of an aqueous solution containing 20 mg of mannitol and 20% cyclodextrin as a 1 µl reagent. This solution is then sterilized and, under septic conditions, filled into 2 ml ampoules in which it is deeply cooled and lyophilized. Immediately before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. This solution is administered intramuscularly or intravenously. This formulation can also be filled into two-chamber injection ampoules.

Example 62

Nasal spray

500 mg of finely divided powder (particle size less than 5.0 µm) of one of the compounds of formula (I) prepared in the examples are suspended in a mixture of 3.5 ml of yg / ml and 0.08 g of benzyl alcohol. The suspension is then filled into a metering valve reservoir. 5.0 g of Freon 12 are then introduced under pressure through the metering valve. ^Tr bed is achieved by dissolving in a mixture of Freon F 1 -y 1 yo ua benzyl alcohol. The reservoir contains about 100 sub-doses which can be administered individually.

Example 63 Tablets

For the manufacture of 10 000 tablets containing 100 mg of active substance, the following ingredients are used:

300 active substance maize starch colloidal silicic acid magnesium stearate stearic acid sodium carboxymethyl starch water

1000 g 680 g 200 g 50 g

250 g sufficient quantity.

A mixture of one of the compounds of the formula I prepared in the examples, 50 g of corn starch and colloidal silicic acid together with corn starch with a starch sebum prepared from 250 g. 2.2 kg of demineralized water, processed into moist meat. This wet mass is then passed through a 3 mm mesh screen, a whirl dryer, a 1 mm mesh bone, a 1 mm mesh bone) and then dried at 45 ° C for 30 minutes in a

The dried granulate is passed through a sieve and mixed with a pre-screened sieve (sieve with a mixture of 330 g of corn starch, magnesium stearate, stearic acid, and a mixture of tablets and sieved into tablets.

Claims (33)

PATENT CLAIMS 1- / 2 (S) - (3-carboxypropionyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. 1- / 2 (S) - (4-chloromethyl-benzoyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) - (4-morfolinometylbenzoyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N (methoxycarbonyl) - (L) -valyl / hydrazine, 1- [2 (S) -Polyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (N-methoxyphenyl) butyl] methoxycarbonyl) - (L) -valyl / hydrazine, 1- (2S) - (N, N-dimethylaminoacetyl) oxy-3 (S) - (N-methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexyl methyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine] - [2 (S) - (N-benzyloxycarbonyl-1-N-methylaminoacetyl) oxy-3 (S) - (N ( methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -vinyl] hydrazine, 320 1- / 2 (S) - (N-methylaminoacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -vinyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine, 1- [2 (S) - (aminoacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- ( methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) - (Quinolin-2-ylcarbonyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) - (3- (pyridin-2-yl) -propionyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) valyl) amino-4-phenyl-butyl / -1- / cyclohexyl methyl / 2- / N- (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) - (2-Pyridylacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N) - (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) -benzoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) - (3- (4-Imidazolyl) propionyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- / cyclohexyl methyl (-2-) N- (methoxycarbonyl) - (L) -valyl) hydrazine, 1- / 2 (S) - (4-Imidazolylacetyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2-, N - (methoxycarbonyl) - (L) - in 1y1 / hy and n, 1- / 2 (S) - (4-imidazolyl carbonyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl.) Amino-4-phenyl-butyl / -1- / cyclohexylmethyl / 2- / N - (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) - (2-furylcarbonyl) oxy-3 (S) - (N (methoxycarbonyl) - (L) -valy1) amino-4-phenyl-butyl / -1- / cyk1ohexylmety1 / 2- / N (methoxycarbonyl) - (L) -vinyl / hydrazine, 1- / 2 (S) -pivaloyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- [N - (methoxycarbonyl) - ( L) -valyl / hydrazine, 1- / 2 (S) -dodecanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine, 1- (2 (S) -decanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) - N- (methoxycarbonyl) - ( L) valyl / hydrazine, 1- / 2 (S) -octanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - ( L) -valyl / hydrazine, 1- / 2 (S) -pentanoyloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl / hydrazine, 1- / 2 (S) -Butylryloxy-3 (S) - (N (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) -2- [N- (methoxycarbonyl) - ( L) -valy1 / hydrazine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, di-hydroxy-yzine , or nitin, 3-aminopropanoic acid, alpha, gamma-diamine inbutyric acid and 1α, beta-diamine inopropionic acid, each of which may, in addition to glycine, be in the form of D, L or (D, L), and the alpha-amino acid is unsubstituted or N-acylated by any of the groups listed above for R 1 and R 2. except for one of the abovementioned acyl residues, with the proviso that not more than one of R 1 or R 6,. can be hydrogen, R ₄ , R e and R e are hydrogen, lower alkyl, cycloalkyl (lower alkyl) in which the cycloalkyl radical contains 3 to 7 carbon atoms and is unsubstituted or substituted one or three times by lower alkyl, halogen (lower) alkyl, hydroxy, lower and 1 alkoxy, amino, mono- or di (lower alkyl) amino, with a halogen atom, nitro and / or cyano , an aryl (lower alkyl) group in which an aryl radical is independently defined as an aryl radical in the aryl (lower and 1 -anoyl) radical of the general substituents R or R ₉ , _R is (a lower 1kanoy1) oxy group, oktanoy1oxy group, a nonanoyl group, a decanoyloxy group, undekanoy1oxyskupinu, dodekanoy1oxy group, a hydroxy (n ižší alkanoyl) oxy group, a (lower alkoxy) (lower alkanoyl) oxy a (lower alkanoyl) oxy (lower alkanoyl) oxy group, a halogen (lower alkanoyl) oxy group, a carboxy (lower and 1kanoyl) oxy group, a (lower alkoxy) carbonyl (lower and 1kanoyl) oxy group , carbamoyl (lower and 1-alkoyl) oxy, (lower all) ylcarbamoyl (lower alkanoyl) oxy, di (lower alkyl) carbamoyl (lower alkanoyl) oxy, hydroxycarboxy (lower alkanoyl) oxy -hydroxy (lower and 1 alkoxy) carbonyl (lower alkanoyl) oxy group, dihydroxycarboxy (lower alkanoyl) oxy group, dihydroxy (lower alkoxy) carbonyl (lower alkanoyl) oxy group, pyrrolylcarbonyloxy group, fury 1 (lower alkanoyl) oxy, thienylcarbonyloxy, imidazolyl (lower alkanoyl) oxyl, pyridyl (lower alkanoyl) anoyl) oxy group, indolylcarbonyloxy group, quinolyl (lower alkanoyl) oxy group, pyrrolidinylcarbonyloxy group, piperidinylcarbonyloxy group, morpholinocarbonyloxy group, thiomorpholinocarbonyloxy group, morpholinoacetyloxy group, thiomorpholino group and thiomorpholino group L) -1-piperazinoacetyl-lupine, (lower alkenoyl) oxy, (lower alkyinoyl loxy), cycloalkylcarbonyloxy, wherein the cycloalkyl radical contains 3 to 8 carbon atoms, cycloalkylacetoxy wherein the cycloalkyl radical contains 3 to 3 carbon atoms, a phenyl- (lower alkanoyl) oxy group which is unsubstituted on the phenyl radical or substituted one or more times with a lower alkyl group, and a halogen (lower alkyl) group , halogen, hydroxy, lower alkoxy, piperidinomethyl, piperazin-1-ylmethyl, 4- (lower alkyl) piperazin-1-ylmethyl, 4 - ( n lower and 1-alkoyl) in the n-1-ylmethyl group, morpholino (lower alkyl) group, thiomorpholinomethyl group, cyano and / or nitro group, or an amino acid group that binds via a carbonyloxy group which contains a carbonyl group from the carboxy group of the amino acid in question, selected from the group consisting of glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-Amino-pentanoic acid, 5-Amino-pentanoic acid, 3-Amino-hexanoic acid, 4-Amino-hexanoic acid, 5-Amino-hexanoic acid, valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine and proline 1 a n, tyrosine, cyclohexylalanine, tryptophan, aspartic acid, aspartic acid, glutamic acid, glutamine, histidin, arginine, lysine, ornithine n, 3-aminopropanoic acid, α 1 fa, gamma-di am i nomas 1 auric acid and 1α, β-diaminopropionic acid, each of which may, except where there is no asymmetric carbon atom, appear in the form of D, L or (D, L) and in these amino acids is an amino acid unsubstituted or once or twice N-alkylated with a lower alkyl group, a pyridyl (lower alkyl) group and / or a phenyl (lower alkyl) group or an N-acylated lower alkanoyl group, phenyl (lower) alkanyl, (lower alkoxy) carbonyl or phenyl (lower and 1-alkoxy) carbonyl, and R? independently of R a, is one of the groups listed for Ro, or a salt thereof, as long as there is at least one 314 in the salt-forming group. Compounds of general formula I in which: R 1 and R 2 and independently of one another represent a hydrogen atom, an acyl group, an unsubstituted or substituted alkyl group, a sulfo group or an unsubstituted or substituted alkyl group, an aryl group or a heterocyclyl substituted sulfonyl group, with the proviso that at most one of R 10 and R 10 are hydrogen, and rc; and R a is, independently of one another, a hydrogen atom or an unsubstituted or substituted alkyl group, R ₃ and R ₄ independently of one another represent a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted cycloalkyl group or an aryl group, R 5 represents an acyloxy group, Re represents a hydrogen atom and R y represents an unsubstituted or substituted alkyl group, an unsubstituted or substituted cycloalkyl group or an aryl group, The compounds of formula (I) exclude a compound wherein R 1 and R _{9 are} each acetyl, R ₂ , R ₃ , R a, R e and R 5 are each a salt thereof. a hydrogen atom, R 5 represents an acetoxy group and R ₇ represents 2,2- (N-ethoxycarbonylmethyl) -N-methyl] hydrazin-1-ylcarbonylmethyl. A compound according to claim 1, wherein R a independently of one another is hydrogen, lower alkanoyl, aryl (lower alkanoyl, wherein the aryl group contains 6 to 14 carbon atoms and is unsubstituted or may be mono- or triple-substituted by lower alkyl, halogen (lower alkyl), phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl (lower and 1 alkoxy) -group, N- ( lower alkyl) carbamoyl (lower alkoxy) -, N, N-di- (lower alkyl) carbamoyl (lower alkoxy) -, amino, mono- or di (lower alkyl) amino, (lower alkanoyl) amino -halo, halogen, carboxyl, (lower alkoxy) carbonyl, phenyl, naphthyl or fluorenyl (lower alkoxy) carbonyl, lower alkanoyl, sulfo, (lower alkyl) sulfonyl, phosphono hydroxy (lower and 1-alkoxy) phosphoryl or di (lower alkoxy) phosphoryl, carbamoyl, mono- or di (lower alkyl) carbamoyl, with 1 famoyl, mono- or di (lower alkyl) aminosulfonyl, nitro and / or cyano, in which the lower alkanoyl group is unsubstituted or substituted by a carbamoyl group, or a carbamoyl group which is substituted on the nitrogen atom by one or two substituents selected from the group consisting of lower alkyl, carboxy (lower 303 alkyl), (lower and 1-alkoxy) carbonyl (lower alkyl), di (lower and 1 alkyl) and amino (lower) hydroxy (lower alkyl) and di (lower alkoxy) (lower alkyl), heterocyclyl (lower and 1 kanoyl) wherein the heterocyclyl group is thienyl furyl, pyrrolylo imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazolyl, pyridyl, pirazinyl, pyrimidinyl, pyridazinyl, iridolyl, benzimidalolyl, quinolyl, isoquinolyl, isoquinolyl, isoquinolyl cyclohexa / b / pyrrolyl, cyclohexa / b / pyridyl, cyclohexa / b / pyrazinyl, cyclohexa / b / pyrimidinyl, pyrrolidinyl, pyrrolinyl, imidazolidyl, piperidyl, pi perazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, and indolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4- a tetrahydroquinoline group or a 1,2,3,4-tetrahydroquinonyl group bonded via a ring carbon atom or a ring nitrogen atom to the amino nitrogen a terocyclyl (lower alkanoyl) substituted with. an amino (lower and 1-alkanoyl) group in which the heterocyclic (lower alkanoyl) group has the meanings given above for heterocycles. 1y1 (lower alkanoyl) group of the general substituents R @ 1 or R @ ₉ , halogen (lower alkanoyl) which contains in addition three halogen atoms, N-heterocyclyl (lower alkyl) to ar bamoyl (ni) The alkanoyl group wherein the heterocyclyl group is preferably selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl a group, a pyrimidinyl group, an indyl group, a quinolyl group and an isoquinolyl group, which may be 304 also fully or partially saturated, morpholinyl and thiomorpholinyl, (lower and 1-alkoxy) carbonyl, aryl (lower alkoxy) carbonyl, in which aryl is phenyl, bi-phenylyl, 1- or 2-naphthyl a fluorenyl group or a phenyl group which is substituted one or more times _{with a} lower alkyl group, a hydroxy group, a lower alkoxy group, a halogen atom and / or a nitro group, a heterocyclyl (lower alkoxy) carbonyl group in which heterocyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoquinolyl, quinolyl, quinolyl be fully or partially saturated, a morpholinyl group; and thiomorpholinyl, and is unsubstituted or substituted in particular by a lower alkyl group, a (lower alkenyl) oxycarbonyl group in which it is substituted. a lower alkenyl group on the oxygen atom binds through a saturated carbon atom, (lower alkoxy) (lower alkoxy) carbonyl, (lower and 1 alkoxy) (lower alkoxy) (lower alkoxy) carbonyl, (lower alkane) sulfonyl, a heterocyclylsulfonyl group in which the heterocyclyl group is selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, indimidinyl and an isoquinolyl group which may be completely or morpholinyl and thiomorpholinesubstituted or substituted by a lower alkyl group, a carbamoyl group, an N-heterocyclyl (lower alkyl) - N - (lower alkyl) carbamoyl group in which the heterocyclyl group is independently partially saturated, now 1 o úku pin, and is 305 represents one of the groups mentioned above for the definition of heterocyclyl (lower alkanoyl group of the general substituents R 1 or R ₉₎ , an acyl residue of an amino acid bonded via a carbonyl group of a 1-carboxy function whose amino function is free or acylated by one of other groups which have heretofore been mentioned for R 1 and R ₃ , wherein the amino acid residues are selected from the groups of amino acids linked through the carbonyl group of their 1-carboxy function from the group consisting of glycine, alanine, valine, norvaline, leucine , isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenyl and 1 &apos; nine, 4-chlorophenylalanine, 4- carboxyphenylalanine, beta-phenylserine, phenylglycine, alpha-naphthylamine, cyclohexylalanine, cyclohexylglycine, tryptophan, indole-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, am inomonic acid, am inomonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, delta-hydroxylysine, ornithine, 3-aminopropanoic acid, aa fa, gamma-diaminobutyric acid and 1 fa, beta-diamonopropionic, wherein each of said amino acids except glycine may exist in the form of D, L or (DL) and alpha-amino acid or N-acylated with any of R 1 and R 9 except some amino acid residues, or N- (morpholino (lower alkyl)) aminocarbonyl, N- (phenyl and lower alkyl) aminocarbonyl, N- (lower and lower alkyl) amocarbonyl, N, Md 1 (lower alkyl) and amino are unsubstituted of the aforementioned acyl carbonyl (alkyl) amino aminocarboxylic acid which was or N - / (lower alkoxy) (the lower group or acyl radical am i defined above and wherein the α 1 -amino group is acylated by one of these residues, with the proviso that not more than one of R 1 or R 4 can be hydrogen, 306 R =, Rd, Re and R 5 are hydrogen, R 5 represents a lower alkyl group, a cycloalkyl (lower alkyl) group in which the cycloalkyl residue contains 3 to 7 carbon atoms and is unsubstituted or substituted one or three times by a lower alkyl group, halogen (lower alkyl) a hydroxy group, a hydroxy group, a lower and a 1 alkoxy group, an amino group, a mono- or di (lower alkyl) amino group, a halogen atom, a nitro group and / or a cyano group, aryl (lower alkyl) group a group in which an aryl radical is independently defined as an aryl radical in the aryl (lower and 1-canoyl) group of the general substituents R or R ₉ , or a phenyl (lower alkoxy) benzyl group, 4- / 3,4-di- ( lower alkoxy) benzyloxy / benzyl, (lower alkoxy) (lower alkoxy) benzyl, (lower alkylene) dioxyphenylmethyl, thienylmethyl or ropranan-4-ylmethyl tetrahydride, _R is (lower and 1kanoy1) oxy group, oktanoy1oxy group, a nonanoyl group, a decanoyloxy group, undekanoyloxyskupinu, dodekanovloxy group, a hydroxy (lower or one alkanoyl 1) oxy - group, a (lower and one alkoxy) (add and 1-kanoyl) oxy group, (lower alkanoylloxy (lower alkanoyl) oxy group, halogen (lower alkanoyl) oxy group, carboxy (lower and 1ka noyl) oxy group, (lower and 1 alkoxy) carbonyl (lower alkanoyl) oxy group, carbamoyl (lower alkanoyl) oxy group, (lower and alkyl) carbamoyl (lower alkanoyl) oxy group, di (lower alkyl) carbamoyl lower alkanoyl) oxy group , hydroxycarboxy (lower alkanoyl) oxy, hydroxy (lower alkoxy) carbonyl (lower and 1-canoyl) -oxy, dihydroxycarboxy (lower alkanoyl) oxy, dihydroxy (lower alkoxy) carbonyl (lower alkanoyl) oxy, pyrrolylcarbonyloxy, fury 1 (lower and 1 kanoyl) oxy, thienylcarbonyloxy, midazo 1 (lower) ia 1-kanoyl) oxy, pyridyl (lower alkanoyl) oxy, indolylcarbonyloxy, quinolyl lower alkanoyl) oxy, pyrrolidinylcarbonyloxy, piperidinylcarbonyloxy, 307 morpholinocarbonyloxy, thiomorpholinocarbonyloxy, morpholinoacetyloxy, thiomorpholinoacetyl oxy or 4- (lower and alkyl) -1-piperazinoacetyl, (lower alkenoyl) oxy lower alkyinoyl) oxy, a cycloalkylcarbonyloxy group in which the cycloalkyl radical contains 3 to 8 carbon atoms, a cycloalkylacetoxy group in which the cycloalkyl radical contains 3 to 8 carbon atoms, a phenyl (lower and 1-alkoyl) oxy group which is unsubstituted or multiply substituted on the phenyl moiety by lower alkyl, halogen (lower alkyl), halogen, hydroxy, lower and 1-alkoxy, piperidinyl, piperazin-1-ylmethyl, 4- ( lower and alkyl) piperazin-1-ylmethyl, 4- (lower alkanoyl) -piperazin-1-ylmethyl, morpholino (lower alkyl), thiomorpholomethyl, cyano or / an an itro group, or an amino acid group that binds through a carbonyloxy group, which contains a carbonyl group from the carboxy group of the respective amino acid selected from the group consisting of glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4 aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine, norvaline, leucine, isoleucine, norleucine, serine, 'homoserine'; threonine, methionine, cysteine, proline, phenylalanine, tyrosine, cyclohexylalanine, tryptophan, aspartic acid, asparagine, glutamic acid, glutamine, histidine, arginine, lysine, ornithine, 3-aminopropanoic acid, acid, and 1 fa, diaminobutyric acid and 1α, β-diam inopropionic acid, each of which may, except where there is no asymmetric atom carbon, occurring in the form of D, L or (D, L), and in these amino acids, the amino group is unsubstituted or once or twice N-alkylated with a lower alkyl group, Pyrid 1 (lower alkyl try308). R _{7 is} phenyl (lower alkyl) and / or N-acyloalkanoyl, phenyl (lower and 1-alkanoyl) (lower alkoxy) carbonyl, or 1-alkoxycarbonyl, or palmitoyl R ₃ denotes one of the groups given for it and / or in the lower group, phenyl (lower 1-group independently of R 3, or a salt thereof, if there is at least one salt-forming group in said compound. A compound according to claim 1, wherein R 1 and R 2 and independently of one another are hydrogen, lower alkanoyl, aryl (lower alkanoyl) in which the aryl radical contains 6 to 14 carbon atoms and is unsubstituted or it may be substituted one or three times by lower alkyl, halogen (lower alkyl), phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl (lower alkoxy), N - (lower alkyl) -carbamoyl (lower alkoxy) -group, NN-di (lower alkyl) carbamoyl (lower and 1 alkoxy) -group, amino, monoalkyl) amino, (lower alkanoyl) halogen, carboxyl, (lower alkoxy) carbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxy) carbonyl, lower alkanoyl, sulfo, (lower alkyl) sulfonyl, phosphono, hydroxy a lower alkoxy) phosphoryl group or a di (lower alkoxy) phosphoryl group, a carbamoyl group, a mono- or alkyl (1) carbamoyl group, a famoyl mono- or di (lower alkyl) aminosulfonyl nitro group, or and a cyano group, wherein the lower alkanoyl radical is unsubstituted or substituted by a carbamoyl group or a carbamoyl group which is substituted on the nitrogen atom by one or two substituents selected from the group consisting of or a di (lower amino) group, di (lower) group, group, 309 lower alkyl, carboxy (lower alkyl), (lower alkoxy) carbonyl (lower alkyl), di (lower and alkyl) amino (lower alkyl), hydroxy (lower alkyl) and di (lower and 1-alkoxy) (lower alkyl), heterocyclyl (lower alkanoyl) in which the heterocyclyl radical is thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl. , thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, quinolyl, a quinolyl, 3,1-benzfurane, cyclohexa / b / pyrrolyl, cyclohexa / b / pyridyl, cycohexa / b / pyrazinyl, cycohexa / b / pyrimidinyl, cycohexa / b / pyrazinyl, cyclohexa / b / pyrimidinyl , py pyrrolidinyl, pyrrolinyl, imidazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6, 7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinoline or 1,2,3,4-tetrahydroisoinyl, and is attached via a ring carbon atom or a ring nitrogen atom , / (loweralkoxy) (lower alkoxy) / (lower alkanoyl), an amino (lower alkanoyl group substituted on the amino nitrogen of a heterocyclyl (lower and 1-alkoyl) group in which the heterocyclyl is 1 y 1 (ni a higher alkanoyl group independently defined as the above-mentioned heterocyclic (lower alkanoyl) group of the general substituents R 1 or R ₉ , a halogen (lower alkanoyl) group containing up to three halogen atoms, N heterocycles; the lowest group, in kt is a heterocyclyl radical selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl , a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group and an isoquinolyl group, which may also be fully or partially saturated, and a morpholinyl group and an isomorpholinyl group, (lower alkoxy) carbonyl group , aryl (lower and 1-alkoxy) carbonyl, in which the aryl radical is phenyl, biphenylyl, 1 or 2-naphthyl, fluorenyl or phenyl one or more times, substituted by lower alkyl, hydroxy, lower and 1-alkoxy a group, a halogen atom, and / or a nitro group, a heterocyclyl (lower alkoxy) carbonyl group in which the hetero a cyclyl radical selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, a quinolyl group and an isoquinolyl assay, which may be wholly or partially saturated, a morpholinyl group and an isomorpholinyl group, and is unsubstituted or substituted by a lower alkyl group, a (lower alkenyl) oxycarbonyl group in which the lower alkenyl radical is attached to an atom oxygen through a saturated carbon atom, (lower alkoxy) (lower alkoxy) carbonyl, / (lower alkoxy) (lower alkoxy) / (lower alkoxy) carbonyl, (lower alkane) sulfonyl, heterocyclylsulfonyl, in which the heterocyclyl radical is selected from the group consisting of pyrrolyl, furyl, and shadows an amidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group and an isoquinolyl group which may be wholly or partially saturated, a morpholinyl group, and thiomorpholinyl, and is unsubstituted or substituted by lower alkyl, carbamoyl, N-heterocyclyl (lower alkyl) -N- (lower alkyl) carbamoyl, wherein the heterocyclyl radical is independently one of the groups listed above for the definition of heterocyclyl ( a lower and 1-alkanoyl radical of the general substituents R 1 or R y, or an acyl radical of an amino acid bonded via a carbonyl group of a 1-carboxy function whose amino function is free or acylated by one of the other groups previously mentioned for R, and R a, wherein the amino acid residues are selected from the group consisting of: the tin carbonyl group of their including glycine, alanine, amino acids linked via 1-carboxy functions from the group of valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3a trans-4-hydroxypropyl n, phenylalanine, tyrosine, A compound according to claim 1, wherein: R10 independently of one another are hydrogen, lower alkanoyl, phenyl (lower alkanoyl), in which carbamoyl is the test, movable and asparagine group or (D, L) wherein the alkanoyl radical is substituted by morpholino (lower alkanoyl) thiomorpholino (lower alkanoyl), pyridyl (lower alkanoyl), quinolyl (lower alkanoyl), tetrazolyl (lower alkanoyl), amino (lower alkanoyl) substituted on the amino amino atom of N-morpholino- or N-thiomorpholino-inocarbonyl, a halogen-lower alkanoyl group containing up to three halogen atoms, 2- / N-morpholino (lower alkyl) carbamoyl ((lower alkanoyl), 2 (N-pyridyl (lower and alkyl) carbamoyl)) ((lower alkanoyl), (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, tetrahydrofuryl lower and 1 coxyl) ) a carbonyl group, ( lower alkenyl) oxycarbonyl, (lower and 1 alkoxy) (lower alkoxy) carbonyl, / (lower and 1 alkoxy) (lower and 1 alkoxy) / (lower alkoxy) carbonyl, (lower alkanone) a sulfonyl group, a plague folinosulfonyl group, a thiomorpholinesulfonyl group, an N-pyridyl / (lower alkyl) -N- (lower alkyl) carbamoyl group, or an acyl residue of an amino acid linked through the carbonyl group of its carboxyl group, said amino acid being selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, glycine acid g 1, it exists in the form of D, L the alpha-amino group is unsubstituted or acylated by one of the other R-groups so far mentioned, or Except for the acyl residue of an amino acid, with the proviso that at most one of R 1 and R 4 is hydrogen, R _2, R <, R and R are H, Ro represents a lower alkyl group, a cyclohexyl (lower alkyl) group or a phenyl (lower alkyl group) which is unsubstituted or substituted by a halogen atom, a lower alkoxy group or a cyano group, R ₅ represents (lower alkanoyl) oxy, octanoyloxy, decanoyloxy, dodecanoyloxy, carboxy (lower alkanoyl) oxy, furyl (lower alkanoyl) oxy, imidazolyl (lower alkanoyl) oxy, pyridyl (lower alkanoyl) oxy, quinolyl (lower and 1-kanoyl) oxy, aminoacetyloxy, N- (lower and 1-alkyl) aminoacetyloxy, N, Nd (lower and 1-alkyl) amino-acetyloxy, N - (lower and alkyl) -N-phenyl (lower and 1-alkoxy) carbonyl aminoacetyloxy, phenyl (lower alkanoyl) oxy, 4-morpholino (lower alkyl) benzoyloxy, 4 a-halomethylbenzoyloxy group, a histidyloxy group or a 1-yloxy group, and R? It has the same meaning as R _3, or a pharmaceutically acceptable salt thereof, as guided vu compound there is at least one salt former group. 4-aminophenyl and 1,4-chlorophenyl and 1,4-carboxyphenylalanine, beta-phenylserine, phenylglycine, and 1 phanaphthylamine, cyclohexylalanine, cyclohexylglycine, tryptophan, indoline-2-carboxylic acid A compound according to claim 1, wherein: R 1 represents a (lower alkoxy) carbonyl group, a halogen (lower alkoxy) carbonyl group, a phenyl (lower alkoxy) carbonyl group, through a carbonyl group bonded by a monovalent group to an aliphatic amino acid selected from valine, alanine, leucine and isoleucine or a carbonyl-linked group of the above defined aliphatic amino acid acylated at the amino-nitrogen atom with a phenyl (lower alkanoyl) group, morpholino316 rc R ₃ R ₄ r ₅ «p R ₇ R _s R o a (lower alkanoyl), thiomorpholino (lower and 1 kanoyl), pyridyl (lower alkanoyl), (lower alkoxy) carbonyl or phenyl (lower alkoxy) -carbonyl, all of which may be present in the form D, L or (D, L), represents a hydrogen atom, represents a phenyl (lower alkyl) group, 4-fluorenyl (lower alkyl) group, or a cyclohexyl (lower and alkyl) group, represents a hydrogen atom, (lower and 1 kanoyl) oxy, octanoyloxy, decanoyloxy, dodecanoyloxy, carboxy (lower alkanoyl) oxy, furyl (lower alkanoyl) oxy, imidazolyl 1 (lower) alkanoyl) oxy, pyridyl (lower alkanoyl) oxy, quinolylflower alkanoyl) oxy, aminoacetyloxy (glycyloxy), N- (lower alkyl) aminoacetyloxy, N, Nd i ( lower alkyl) amino-acetyloxy, N- (lower alkyl) -N-phenyl (lower alkyl) oxy) carbaminoaminoacetyloxy, phenyl (lower alkanoyl) oxy, 4-morpholinomethylbenzoyloxy, 4-halomethylbenzoyloxy, hididyloxy or prolyloxy means hydrogen, lower alkyl a group, a cyclohexyl (lower alkyl) group, a phenyl (lower alkyl) group, a 4-cyanophenyl (lower alkyl) group or a 4-fluorophenyl (lower alkyl group) means a hydrogen atom, is one of the groups listed for R 1, and R 2 bearing asymmetric carbon atoms having the S configuration, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R 1 and R a are N-methoxycarbonylamino, R ₃ , R ₄ , 317 R ₆ and R are hydrogen, R a is benzyl or cyk1ohexylmetylovú group, R is _a (n A d d alkanoyl) oxy, or pyridy1karboxy1oxy and R? represents a cyclohexylmethyl group or further a benzyl group as well as pharmaceutically acceptable salts thereof. An isomer of a compound according to claim 6, wherein R ₃ and R 5 bearing asymmetric carbon atoms have the S configuration and these residues have the meanings given in claim 5, or pharmaceutically acceptable salts thereof. 8. 1- / 2- (S) -Acetoxy-3 (S) - (N- (2-methoxyethoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N) - (2-methoxyethoxycarbonyl) - (L) -valyl / hydrazine according to claim 1 or a pharmaceutically acceptable salt thereof. 9. 1- / 2- (S) -Acetoxy-3 (S) - (N- (2-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (N) - (2-methoxycarbonyl) (L) -valyl / hydrazine according to claim 1 or a pharmaceutically acceptable salt thereof. 10. 1- (2 (S) - (2-Pyridylcarbonyl) oxy-3 (S) - (N-methoxycarbonyl) (CL) -valyl) amino-4-phenylbutyl [-1- (cyclohexylmethyl) -2-] N- (methoxycarbonyl) - (L) -vinyl / hydrazine or pharmaceutically acceptable salts thereof. A compound according to claim 1 selected from 1- (2) (S) -propionyloxy-3 (S) - (N'-methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl ^[ 1- (cyclohexylmethyl) -2] - [N- (methoxycarbonyl) - (L) -vinyl] hydrazine, 318 12. 1- / 2 (S) -Hydroxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) -amino-4-phenylbutyl [-1- (cyclohexylmethyl) -2-] N- ( methoxycarbonyl) (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. 13. 1- / 2 (S) -Butyryloxy-3 (S) -N'- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl [-1- (cyclohexylmethyl) -2-] N- (methoxycarbonyl) (L) -valyl / hydrazine of formula (I ') according to claim 1 or a pharmaceutically acceptable salt thereof. A compound of formula (I) wherein R 1 is R 2. and R c is, independently of one another, an N- (lower alkoxy) carbonylvalyl group, R 5 is a hydrogen atom, R 5 is a phenylmethyl group or a cyclohexyl methyl group, R is a hydrogen atom, R 5 is a palmitoyloxy group, (lower alkoxy) ( lower, 1 alkanoyl 1) oxy, or pyridylamino 1 card will ny 1 by x y with purchase, Re is H, R is driers IMET hunting group or cyklohe32 1 xylmetylovú and R _a is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 15. 1- / 2 (S) -Palmitoyloxy-3 (S) - (N- (methoxycarbonyl) - (L) -valyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- N - (methoxycarbonyl) (L) -valyl / hydrazine of formula I according to claim 14 or a pharmaceutically acceptable salt thereof. 16. 1- / 2 (S) - (Methoxyacetoxy-3 (S) - (N- (methoxycarbonyl) - (L) -amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2-) - N- (methoxycarbonyl) (L) -valyl / hydrazine of the formula I according to claim 14 or a pharmaceutically acceptable salt thereof. 17. 1- (2 (S) - (2-Pyridylcarbonyl) oxy-3 (S) - (tert-butoxycarbonyl) amino-4-phenylbutyl) -1- (cyclohexylmethyl) -2- (tert-butoxycarbonyl) hydrazine or a pharmaceutically acceptable salt thereof. A compound according to claim I of the general formula I, in which R is CH, and no íη l-2-ylcarbonyl- (L) -asparaginylovú, R ₂ is H, R3 is phenylmethyl, 4- (lower alkoxy) phenylmethyl or 4-benzyloxyphenylmethyl, Rd represents a hydrogen atom, R 5 represents (lower and 1-alkoyl) oxy, such as butyryloxy, octanoyloxy, decanoyloxy, dodecanoyloxy, palmitoyloxy, (lower alkoxy) (lower alkanoyl) oxy, such as methoxyacetoxy, carboxy (lower alkanoylioxy), fury 1 (lower and 1 kanoyl) oxy, imidazolyl (lower and 1 kanoyl) oxy, pyridyl (lower alkanoyl) oxy, such as in particular pyridinylcarbonyloxy, for example 2- or 3-pyridinylcarbonyl carboxy, quinolyl (lower and 1-alkoyl) oxy, aminoacetyloxy, N- (lower alkyl) amino amino, N, N —Di (lower alkyl) aminoacetyloxy, N (lower alkyl) -N-phenyl (lower alkoxy) carbonylaminoacetyl oxy, phenyl 1 (lower and 1 kanoyl) (1) oxy-group, 4-morpholinomethylbenzoyloxy, 4-halomethylbenzoyloxy, histidyloxy or prolyloxy; R _e represents a hydrogen atom, R? phenyl is a methyl group, 4- (lower and 1-alkoxy) phenyl is a methyl or cyclohexylmethyl group, Re represents a hydrogen atom, R a represents (lower alkoxy) carbonyl- (L) -valyl, (lower alkoxy) (lower alkoxy) (lower alkoxy) carbonyl-L) valyl, phenyl 1 (lower alkoxy) carbonyl- (L) - valyl, (lower alkanoyl) - (L) -valyl, benzylaminocarbonyl, alkenyloxycarbonyl in which the alkenyl moiety contains 3 to 7 carbon atoms, or (lower alkoxy) carbonyl, or pharmaceutically acceptable salts thereof. A compound of the formula I as claimed in claim 18, entitled 1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - (N-quinoline-2-carbonyl (L) -asparaginyl) amino-4-phenylbutyl -1- (phenylmethyl) -2- [N- (methoxycarbonyl) - (L) -valyl] hydrazine or a pharmaceutically acceptable salt thereof. A compound of the formula I as claimed in claim 13 having the name 1- [2 (S) -butyryloxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1-]. phenylmethyl] -2- [N- (methoxycarbonyl) (L) -vinyl] hydrazine or a pharmaceutically acceptable salt thereof. Compound of formula (I) according to claim 18, named 1- / 2 (S) - (2-pyridylcarbonyl) oxy-3 (S) - (N-quinoline-2-carbonyl (L) -asparaginyl) amine -4-phenylbutyl-1- (methoxyphenylmethyl) -2- (N323 (benzyloxycarbonyl) - (L) -vinyl) hydrazine or a pharmaceutically acceptable salt thereof. A compound of formula I according to claim 18, entitled 1- / 2 (S) - (methoxyacetyl) oxy-3 (S) - (N-quinoline-2-carbonyl- (L) asparaginyl) amino-4-phenylbutyl- 1- (4-Methoxyphenylmethyl) -2- [N (benzyloxycarbonyl) - (L) -vinyl] hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1- (cyclohexylmethyl) -2- N- (benzyloxycarbonyl) - (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1- (cyclohexylmethyl) -2- (N) (methoxy) carbonyl) - (L) -vinyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1- (benzyl) -2- (N-methoxycarbonyl) - (L) -vinyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenyibutyl-1- (4-methoxyphenyl methyl) -2- (N-methyloxycarbonyl) - (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1- (4-methoxyphenylmethyl) -2- (N-benzyloxycarbonyl) - (L) -vinyl] hydrazine or a pharmaceutically acceptable salt thereof. 324 A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1- (4-methoxyphenylmethyl) -2- - (N-allyloxycarbonyl) - (L) -valyl] hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-quinoline-2-carbonyl- (L) -asparaginyl) amino-4-phenylbutyl-1- (phenylmethyl) 2- / N- ( 2- (2-methoxyethoxy) ethoxycarbonyl) - (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N- (2-methoxyethoxy) acetyl- (L) -valyl) amino-4-phenylbutyl / -1- (cyclohexylmethyl) 2- (N- (2-methoxyethoxy) acetyl- (L) -vinyl) hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hyaroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-phenylbutyl / -1- (4-hydroxyphenylmethyl) -2- N- methoxycarbonyl- (L) -vinyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- [2 (S) -hydroxy-3 (S) - (N-acetyl- (L) -valyl) amino-4-phenylbutyl] -1- (4-methoxyphenylmethyl) -2- [N]. -acetyl- (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-methoxycarbonyl- (L) -vinyl) amino-4-phenyibutyl] -1- (4-methoxyphenylmethyl) 2- / N- methoxycarbonyl- (L) -valyl / hydrazine or a pharmaceutically acceptable salt thereof. 325 A compound named 1- / 2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl) -1- (4-methoxyphenylmethyl) 2- / N- ethoxycarbonyl 1- (L) -vinyl / hydrazine or a pharmaceutically acceptable salt thereof. A compound named 1- [2 (S) -hydroxy-3 (S) - (N-ethoxycarbonyl- (L) -valyl) amino-4-phenylbutyl] -1- (cyclohexylmethyl) -2- N -ethoxycarbonyl- (L) -valy1 / hydrazine or a pharmaceutically acceptable salt thereof. 36. 1- / 2 (S) -Hydroxy-3 (S) - (N-methoxycarbonyl- (L) -valyl) amino-4-cyclohexylbutyl] -1- (phenylmethyl) -2- (N-methoxycarbonyl) -L-valyl Hydrazine or a pharmaceutically acceptable salt thereof. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for use in a method of diagnostic examination or therapeutic treatment of the human or animal body. The compound of claim 12, or a pharmaceutically acceptable salt thereof, for use in a method of diagnostic examination or therapeutic treatment of the human or animal body. A compound according to any one of claims 13 to 36, or a pharmaceutically acceptable salt thereof, for use in a method of diagnostic examination or therapeutic treatment of the human or animal body. Use of a compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of AIDS. 326 Use of a compound of a useful salt for the treatment of AIDS. according to claim 12 or a pharmaceutical preparation thereof Use of a compound according to any one of claims 13 to 36 and a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of AIDS. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group together with a pharmaceutically acceptable carrier. 44. Pharmaceutical formulations comprising a compound according to claim 12 or a pharmaceutically acceptable salt of such a compound with a pharmaceutically useful compound. 45. Pharmaceutical formulations comprising a compound according to any one of claims 13 to 36 or a pharmaceutically acceptable salt of such a compound with a pharmaceutically acceptable carrier. 46. A process for the preparation of compounds of the formula I as claimed in claim 1, characterized in that it is: a) acylates the hydroxy compound of formula II 327 (II) wherein the general symbols have the meanings given for a compound of formula I by treatment with a carboxylic acid of formula III _R - H (III) or a reactive derivative of this acid, wherein R is as defined for compounds of formula I, a free functional groups in starting materials of formulas II and III that are not to take part in the reaction, if necessary, is in protected form , and the protecting groups present are cleaved off or (b) in the case of the preparation of compounds of general formula a. I, in which R8 represents an acyl group, a sulfo group or a sulfonyl group substituted by an unsubstituted or substituted alkyl, aryl or heterocyclyl group and the other general meanings have the meanings given above, condenses the amine of the formula to the formula IV ( IV) Rs 328 wherein the symbols have the same meanings as indicated above, with an acid of formula V Ro '- OH (V) or a reactive derivative thereof, wherein R ₉ ' has the meanings given for R ₉ except for a hydrogen atom and an unsubstituted or substituted alkyl group and the free functional groups, except for those involved in the reaction, are protected if necessary , and the protecting groups present are cleaved or removed c) in the preparation of a compound of formula I wherein R 1 is an acyl group, a sulfo group or a sulfonyl group substituted with an unsubstituted or substituted alkyl, aryl or heterocyclyl group and the other general symbols have the meanings given above, condenses amine to compounds of formula VI (VI) in which the symbols have the meanings given above, with an acid of formula V II I 329 R @ 1 --OH (VII) or a reactive derivative thereof, wherein R @ 1 has the meanings given for R, except for a hydrogen atom and an unsubstituted or substituted alkyl group, and the free functional groups are protected, if necessary, , and the protecting groups present are cleaved off or d) for the preparation of compounds of formula I in which R1 and Ro are two identical groups selected from the group consisting of acyl, sulfo and sulfonyl substituted by unsubstituted or substituted alkyl, aryl or heterocyclyl and the other general meanings have the meanings given above condenses the diamino-compound to formula VIII (VIII) wherein the general symbols have the meanings indicated above, with an acid suitable for introducing the same R 1 and R ₉ groups or with a reactive derivative of such an acid, wherein R 1 and R 2 have the meanings indicated and free functional groups are those other than those involved in the reaction if necessary in protected form, and the protecting groups present are cleaved, 330 or sa (e) for the preparation of a compound of formula I in which Ry, which is an unsubstituted or substituted alkyl or cycloalkyl group, is present in place of Ry, introduces a Ry group into a compound of formula I 'in which Ry has the above hydrogen atom and other meanings; by substituting X11 thereof (d) the general symbols (1) by the general formula R y - X (XII) wherein X represents a leaving group and Ry represents an unsubstituted or substituted alkyl or cycloalkyl group, with free functional groups, except for those involved in the reaction, if necessary in protected form. , and the protecting groups present are split off, if necessary, or f) in a compound of formula I in which the general substituents have the meanings given above, with the proviso that in said compound of formula I at least one functional group is protected by a protecting group, it cleaves off the protecting groups present; And thereafter optionally the compound of formula I which is obtained according to one of the above processes and which contains at least one salt-forming group is converted to another salt or the obtained salt is converted to a free compound or another salt and / or isomerically obtained isomerically the mixture is separated and / or the compound of the formula I according to the invention is converted into another compound of the formula I according to the invention