DD290894A5 - RETROVIRAL PROTEASE INHIBITOR - Google Patents

Abstract

The invention relates to a process for the preparation of peptidic 5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid derivatives of the formula wherein AAN is a bivalent radical consisting of one to five bivalent α-amino acid residues which is N-terminal A is a bivalent radical consisting of one or two bivalent a-amino acid residues which is N-terminally connected to the group CO and C-terminal to the radical R 1, R 1 is hydroxy, etherified hydroxy, amino or substituted amino except for an amino radical derived from an α-amino acid, and R 2 is hydrogen or an acyl radical except for an optionally N-substituted acyl radical of a natural amino acid, furthermore salts of such compounds having salt-forming groups , The compounds are useful as gag protease inhibitors. {5-Amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid derivatives; peptides; a-Aminosaeurereste; Peptide condensation; Retroviruses; AIDS, HIV (human immunodeficiency virus); gag (group specific antigens); gag-protease; Protease inhibitors}

Description

Field of application of the invention

The invention relates to a process for the preparation of compounds which are suitable as inhibitors of the gag protease of HIV (human immunodeficiency virus) and for combating retroviral diseases, for. AIDS, are suitable. The method of the invention is used in the pharmaceutical industry in the field of drug synthesis.

Characteristics of the known prior art

HIV (human immunodeficiency virus) is a retrovirus that causes the generally fatal disease AIDS in humans. While today it is possible to alleviate the effects of AIDS and extend the lives of patients, so far there are no pharmaceutical preparations that effectively combat the cause of AIDS. One possible goal in the treatment of AIDS is to prevent HIV from multiplying without at the same time damaging the patient's intact cell aggregates.

The genome of the hitherto known two types of HIV, HIV-1 and HIV-2, each has a region that encodes a "gag protease." In addition, both viruses contain a region that is responsible for the group-specific antigens Group specific antigen (gag). The corresponding genes are expressed as a precursor protein and released proteolytically from the above-mentioned gag protease the actual gag proteins. The gag protease itself is also excised from a precursor protein, from which other viral proteins, such as the reverse transcriptase and the integrase, arise. This process presumably proceeds autoproteolytically. It is further known that the gag protease preferentially cleaves the major core protein (p24) of HIV-1 and HIV-2, respectively, at N-terminal proline, eg, bai Phe-Pro, Leu-Pro, or Tyr A truncated, pro-terminal ρ24, along with other viral structural proteins, then serves to construct the nucleocapsid and viral envelope of HIV-1 and HIV-2. It is also known that the HIV-1 gag protease Leu-Phe, Leu-Ala, Met-Met, and Phe-Leu sequences cleave with different efficiency, and it is certain that in addition to the amino acid sequence, the conformation contributes to the specificity of the gag protease.

If the effect of the gag protease could be suppressed, the virus would have neither functional structural proteins nor the necessary viral enzymes available, and its proliferation would be hindered, if not interrupted. There is therefore a need for inhibitors or at least inhibitors of the gag protease. Such compounds play an important role as antiviral agents against AIDS or other retroviral diseases.

Compounds similar to the compounds of the present invention have been described in European Patent Applications EP 184550 and EP 236734 and in P. Bühlmayer et al., J. Med. Chem. 31, 1839 (1988). These compounds inhibit the action of the enzyme renin and have hypotensive properties.

Aim of the invention

The object of the invention is to provide a process for the preparation of compounds which are suitable as HIV gag protease inhibitors.

Explanation of the essence of the invention

The object of the invention is to provide a process for the preparation of compounds having the desired properties. According to the invention the object is achieved by a process for the preparation of compounds of the formula

H OH ^ j ⁷

R ² -AAN-N · ·

I'j- ^MC - ^RI (I),

j j

wherein AAN is a bivalent radical consisting of one to five bivalent a-amino acid residues which is N-terminally linked to the radical R ² and C-terminal to the group NH-, AAC is a bivalent radical consisting of one or two bivalent a-amino acid residues which is N-terminally linked to the group C = O and C-terminal to the radical R ¹ , R 'is hydroxy, etherified hydroxy, amino or substituted amino except for an amino group derived from an α-amino acid, and R ^{2 is} hydrogen or an acyl radical, with the exception of an optionally N-substituted acyl radical of a natural amino acid, furthermore salts of such compounds having salt-forming groups, characterized in that

a) a fragment of a compound of formula I having a terminal carboxy group or a reactive acid derivative of this fragment with a compound of the formula I complementary fragment having a free amino group or a reactive derivative thereof with activated amino group, wherein functional components present in the reaction components with the exception optionally in protected form, condensing to form an amide bond, or

b) the keto group in a compound of the formula

CH (CH ₂ ) _{2 2} -H ₂ -C ₆ H ₁₁

H Ο R ² -AAN -N-CH-C-CH ₂ -CHti-AAC-R ¹

CH-CCH ₂ -C ₆

wherein the symbols have the meanings mentioned and functional groups other than the keto group participating in the reaction are optionally in protected form, reduced to a hydroxy group by reaction with a suitable reducing agent, or c) an aldehyde compound of the formula

H Ο

R ² -AAN -N-CH-CH ( _V |),

CH-

wherein the symbols have the meanings mentioned and functional groups, with the exception of the aldehyde group, optionally in protected form, with an organometallic compound of the formula

5 ^{H (CH 3) 2} β (VH

M-CH ₂ -CHti-AAC-R ^{1 l} '''

wherein the symbols have the meanings given and M is a metal radical, reacting and hydrolyzing the resulting addition product, or

-13- 290 894 d) in a compound of the formula

1ίX CH (CHj) ₂ O

- N - CH - CK - CH ₂ --CH - C - AAC - R ¹

CH ₂ - C ₆ Hn

R ² - AAN - N - CH - CK - CH ₂ - CH: - C - AAC - R ^{1 (ν || 1>} '

wherein X is a nucleofugic leaving group, the remaining symbols have the abovementioned meanings and functional groups are optionally present in protected form, the substituent X is replaced by a hydroxy group, or e) in a compound of the formula

H OH CH (CHj) ₂ O

R ² - AAN - N - CH - CH - CH ₂ - CH C - AAC ¹ - CN

CH ₂ - C ₆ Hn

wherein the symbols have the meanings given and AAC has the meaning of AAC minus the terminal C irbonylgruppe and existing functional groups optionally present in protected form, the group AAC-CN converted into a group AAC-R ', or

f) in a compound of the formula

-N-CH- cfi-CiH - CH C

CH ₂ - C ₆ Hn

R ² - AAN --N - CH - CH - CH - CH C - AAC - R ¹ (X),

wherein the symbols have the meanings mentioned and functional groups are optionally present in protected form, with a regioselective reducing agent reduces the epoxy group to a hydroxy group, or g) for preparing a compound de; Formula I, wherein R ^{2 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C-

- 5 - (CH ₂ ) - CH - (CH ₂ ) - C

(X) _ ⁿ ι ^p ti

(CH ₂ )

R ^b and m are 0 or 2, η 1 and ρ 0, a compound of the formula R'-S (O) _m H or a salt thereof to a compound of the formula

b ft ^H ? ^H CH (CHj) ₂ O

R - (CH ₂ ) -CC-AAN-N-CH-CH-CH ₂ -CH C-AAC-R ¹ IXI),

OH ₂ CH ₂ - C ₆ H ₁₁

in which the symbols have the meanings mentioned and functional groups, if appropriate, in protected form, are added together, or

h) for the preparation of a compound of the formula I, wherein R ^{2 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C- (X) ⁿ I ^P 8

(CH ₂ ) < ^la >

and ρ O means a compound of the formula

CH (CHj) ₂

_a H OH CH (CHj) ₂ 0

RS- (CH ₂ ) -CH ₂ -C-AAN-N-CH-CH-CH ₂ -CH C-AAC-R ¹

ti u ₂ - C ₆ H ₁₁

₂ AANNCH-CH-CH ₂ ti tu ₂ -

where did symbols have the meanings mentioned and functional groups are optionally present in protected form, with a compound introducing the radical R ^b - (CH ₂ ) _q - alkylated, and if desired

i) splitting off any protecting groups present in an available compound and / or, if desired, after carrying out one of the abovementioned processes a) -h) or any other process for the preparation of a compound of the formula I, an obtainable compound of the formula I having a salt-forming group in its salt or converting an available salt into the free compound or into another salt and / or separating off any isomer mixtures obtainable and / or reversing the configuration of a chiral carbon atom in an available compound of the formula I and / or converting a compound of the formula I into another inventive compound Compound of formula I converts.

The abbreviation AAN stands for the amino acid part that is truncated with the N-terminus of the central (2S, 4S, 5S) -5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoyl residue (amino acid (s N-terminal), The abbreviation AAC stands for the amino acid part which is linked to the C-terminus of the same central residue (amino acid (s) C-terminal).

In the description of the present invention, in the definition of groups or radicals, e.g. Lower alkyl, lower alkoxy, lower alkanoyl, etc., used the term "lower" to indicate that the groups or groups so defined, unless expressly otherwise defined, contain up to and including 7 and preferably up to 4 carbon atoms.

The substituted α-C atoms of the amino acid residues constituting AAN and AAC may have the R, S or R, S configuration. Preference is given to compounds of the formula I in which these C atoms have the S configuration. The α-amino acid residues of the radical AAN may be N-terminal to increase the stability of the compound of formula I against enzymatic degradation by lower alkyl, e.g. Methyl or ethyl.

A bivalent a-amino acid residue constituting AAN and AAC is, for example, a residue of a natural α-amino acid of the L-configuration as normally found in proteins, a homolog of such an amino acid, e.g. Wherein the amino acid side chain is extended or shortened by one or two methylene groups and / or a methyl group is replaced by hydrogen, a substituted aromatic α-amino acid, eg. A substituted phenylalanine or phenylglycine, wherein the substituent is lower alkyl, e.g. Methyl, halogen, e.g. As fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, ζ. Methoxy, lower alkanoyloxy, e.g. Acetoxy, amino, lower alkylamino, e.g. Methylamino, di-lower alkylamino, e.g. Dimethylamino, lower alkanoylamino, e.g. Acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. B. tert-Butoxycarbonylamino, Arylmethoxycarbonylamino, z. B. benzyloxycarbonylamino, and / or nitro can be and is one or more times, a benzanellierten phenylalanines or phenylglycine, such as a-naphthylalanine, or a hydrogenated phenylalanines or phenylglycine, such as cyclohexylalanine or cyclohexylglycine, a five- or six-membered cyclic, benzanellierten α- Amino acid, ζ. B. indoline-2-carboxylic acid or 1 ^, S ^ -Tetrahydroisochinolin-scarboxylic acid, a natural or homologous α-amino acid in which a carboxy group of the side chain is present in esterified or amidated form, for. As a lower alkyl ester group such as methoxycarbonyl or tert-butoxycarbonyl, or as carbamoyl, lower alkylcarbamoyl such as methylcarbamoyl, or as a di-lower alkylcarbamoyl group such as dimethylcarbamoyl in which an amino group of the side chain is in acylated form, e.g. B. as Niederalkanoylamino-, such as acetylamino or pivaloylamino, as Niederalkoxycarbonylamino-, such as tert-butoxycarbonylamino, or as Arylmethoxycarbonylaminogruppe, such as Benzyloxycarbonylamino, or in which a hydroxy group of the side chain in etherified or esterified form, for. As a lower alkoxy group, such as methoxy, as an aryl-lower alkoxy group, such as benzyloxy, or as a lower alkanoyloxy group, such as acetoxy, or an epimer of such an amino acid, d. H. with the unnatural D configuration.

Such amino acids are, for example, glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-VaI-OH), norvaline (α-aminovaleric acid), leucine, (H-Leu-OH), isoleucine ( H-IIe-OH), norleucine (α-aminohexanoic acid, H-NIe-OH), serine (H-Ser-OH), homoserine (α-amino-Y-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-nitrophenylalanine, 4-amiriophenylalanine, 4-chlorophenylalanine, β-phenylserine (β-hydroxyphenylalanine), phenylglycine, α-naphthylalanine (H-NaI-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, Tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), mono-tert-butyl glutamate, glutamine (H-GIn-OH), N ⁵ -dimethylglutamine, histidine (H-His-OH), arginine (H-Arg-OH ), Lysine (H-Lys-OH), N ^? tert-butoxycarbonyl-lysine, δ-hydroxylysine, ornithine (α, δ-diaminovaleric acid), N ^e -pivaloyl-ornithine, α, γ-diaminobutyric acid or α, β-diaminopropionic acid. The general terms and terms used in the description of the present invention preferably have the following meanings:

An etherified hydroxy group R * is preferably ethereal by such organic radicals which are cleavable under physiological conditions and after cleavage at the concentration in question provide pharmacologically acceptable cleavage products.

Etherified hydroxy R ¹ is z. B. Acyloxyniederalkoxy, wherein acyl represents the acyl group of an optionally branched lower alkanecarboxylic acid or the monoesterified by optionally branched lower alkyl carbonic acid, for. Lower alkanoyloxy lower alkoxy such as acetoxymethoxy, 1-acetoxyethoxy, pivaloyloxymethoxy or 1-pivaloyloxyethoxy, or lower alkoxycarbonyloxy-lower alkoxy such as ethoxycarbonyloxymethoxy, 1-ethoxycarbonyloxyethoxy, tert-butoxycarbonyloxymethoxy or 1-tert-butoxycarbonyloxyethoxy.

Etherified hydroxy R 'is also preferably lower alkoxy, e.g. Methoxy or ethoxy, aryloxy, e.g. Phenoxy, or aryl-lower alkoxy, e.g. Benzyloxy.

Substituted amino R ¹ is, for example, an amino group which is represented by one or optionally two organic radicals, for. As unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals having up to 18, preferably up to and including 10, carbon atoms or unsubstituted or substituted, aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic radicals having up to 18, preferably up to and including 10, C atoms, is substituted.

Excluded as substituted amino R ¹ are the residue of an α-amino acid or its N-substituted, esterified or amidated derivatives.

An unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radical which substitutes the amino group R ¹ is, for example, unsubstituted or substituted alkyl having up to 10 carbon atoms, lower alkenyl or lower alkynyl having up to once 7 carbon atoms, or cycloalkyl or cycloalkyl-lower alkyl having 4 -10 carbon atoms. These radicals may be substituted by one or more of the functional groups mentioned below in connection with lower alkyl R 'and by sulfo.

As substituents, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. Acetoxy, substituted or unsubstituted phenyloxy, e.g. Carbamoylphenyloxy or carbamoylhydroxy-phenyloxy, carboxy, esterified carboxy, ζ. Β. Lower alkoxycarbonyl, such as methoxycarbonyl or tert-butoxycarbonyl, or a physiologically cleavable esterified carboxy, ζ. B. 1- (lower alkanoyloxy) lower alkoxycarbonyl such as acetoxymcthox / carbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, i-lower alkoxycarbonyloxyJ-lower alkoxycarbonyl, such as -fethoxycarbonyloxy) -ethoxycarbonyl, or alpha-amino-lower alkanoyloxymethoxycarbonyl such as alpha-aminoacetoxymethoxycarbonyl or (S) -a- Amino-.beta.-methylbutyryloxymethoxycarbonyl, carbamoyl, substituted or unsubstituted lower alkylcarbamoyl, e.g. B. hydroxy lower alkylcarbamoyl such as 2-hydroxyethylcarbamoyl or tris {hydroxymethyl) methylcarbamoyl, amino, lower alkylamine. 7 B. methylamino, di-lower alkylamino, z. 3. dimethylamino, lower alkoxycarbonylamino, e.g. tert-butoxycarbonylamino, guanidino, nitrogen-atom-bonded, saturated five- or six-membered, optionally oxo-substituted heterocyclyl, e.g. 1-piperidinyl, 4-morpholinyl or 2-oxo-1-pyrrolidinyl, or sulfo preferred.

An aromatic or aromatic-aliphatic radical in a group R ¹ preferably has the same meanings as defined under aryl R "or R" or arylnuclear alkyl R ¹ and is, for example, phenyl or phenyl-lower alkyl. These radicals can be in the aromatic B. B. by lower alkyl, z. As methyl or ethyl, hydroxy, etherified hydroxy, ζ. Β. Lower alkoxy, such as methoxy or tert-butoxy, esterified hydroxy, ζ. B. lower alkanoyloxy, such as acetoxy, or halogen, for. For example, fluorine or chlorine, carboxy, esterified carboxy, for example, lower alkoxycarbonyl, such as tert-butoxycarbonyl, carbamoyl, amino, lower alkylamino, z. For example, methylamines, Diniederalkylamino, z. Dimethylamine), acylated amino, ζ. Β. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, and be substituted by nitro.

Lower alkyl in a radical phenyl-lower alkyl may be substituted by the same substituents as alkyl in a radical R ¹ . A heteroaromatic or heteroaromatic-aliphatic radical in a group R ¹ preferably has the same meanings as defined below under heteroaryl R 'and R ^b or heteroaryl-lower alkyl R ¹ and is, for example, pyridyl-lower alkyl, eg. 2-, 3- or 4-pyridylmethyl, imidazolyl-lower alkyl, e.g. B. 2- (4-imidazolyl) -ethyl or 2- (2- [4-imidazolyll-ethylamino) -ethyl, or indolyl-lower alkyl, e.g. 3-indolylmethyl or 2- {3-indolyl) -ethyl.

Substituted amino R 'is preferably alkylamino, e.g. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl or n-decylamino , Diniodoralkylamino, z. Dimethylamine or diethylamino, hydroxy-lower alkylamino, e.g. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamino or tris (hydroxymethyl) -methylamino, di- (hydroxy-lower alkyl) -amino, e.g. Di- (2-hydroxyethyl) -arrino, lower alkoxy-lower alkylamino, e.g. 2-methoxyethylamino, lower alkanoyl-aoxynol-alkylamino, e.g. 2-acetoxyethylamino, phenoxy-lower alkylamino or phenoxy-hydroxy-lower alkylamino wherein phenoxy is optionally substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or carbamoyl, e.g. 2-Phenoxyethylamino, 2- (3-carbamoyl-4-hydroxyphenoxy) -ethylamin or 3- (3-carbamoylphenoxy) -2-hydroxy-propylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical is, for. 4-carboxy-n-butylamino, 5-carboxy-n-pentylamino, ö-amino-S-carboxy-n-pentylamino, β-carboxy-n-hexylamino, 7-carboxy-n-heptylamino or e-carboxy n-octylamino, furthermore dicarboxymethylamino, lower alkoxycarbonylalkylamino or acylaminoloweralkoxycarbonyl-slkylamino, wherein the carbonyl radical is not in the 1-position of the alkyl radical 3, e.g. 4-tert-butoxycarbonyl-n-butylamino, S-tert-butoxycarbonyl-amino-o-methoxycarbonyl-n-pentyl-amino, 7-tert-butoxycarbonyl-n-heptyl-amine or 8-tert-butoxycarbonyl-n-octylamino, also di-lower alkoxy carbonylmethylamino, e.g. B. Di-methoxycarbonyl-methylamino, physiologically cleavable esterified carboxyalkylamino, wherein the ester function is not in the 1-position of the AlkyIrestes, e.g. 4-Pivaloyloxymethoxycarbonyl-n-butylamino, 7- (1-ethoxycarbonyloxyethoxycarbonyl-n-heptylamino or 7-pivaloyloxy-n-heptylamino, carbamoylalkylamino or hydroxy-lower alkylcarbamoylalkylamino wherein the carbamoyl radical is not in the 1-position of the alkyl radical, for example 4-carbamoyl-n -butylamino, 7-carbamoyl-n-heptylamino or 4- (tris (hydroxymethyl) methyl) -carbamoyl-n-butylamino, furthermore dicarbamoyl-methylamino, di (lower alkylcarbamoyl) -methylamino, eg di (methylcarbamoyl) - methylamino, di- (hydroxy-lower alkylcarbamoyl) -methylamino, 2.B. di- (2-hydroxyethylcarbamoyl) -methylamino, or bis- (di-lower alkylcarbamoyl) -methylamino, e.g., bis (dimethylcarbamoyl) -methylamino, aminoloweralkylamino, e.g. 2-aminoethylamino or 4-aminobutylamino, lower alkylaminoloweralkylamino, e.g., 2-methylaminoethylamino, di-lower alkylaminoloweralkylamino, e.g., 2-oimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylaminoloweralkylamino, e.g., 2- (tert-butoxycarbonyiamino) -ethylamino, Guanidinone-lower alkylamino, e.g. 2-guanidinoethylamino, via a nitrogen atom bonded, saturated five- or six-membered heterocyclyl-lower alkylamino, z. 2- (4-morpholinyl) -ethylamino, 3- (4-morpholinyl) -propylamino or 3- {2-oxo-1-pyrrolidinyl-1-propylamino, lower alkenylamino, e.g. B. allylamines or 2- or 3-butenylamino, lower alkynylamino, z. B. propargylamino, cycloalkylamino, z. Cyclohexylamino or decahydronaphthylamino, cycloalkyl-lower alkylamino, e.g. Cyclopropylmethylamino or cyclohexylmethylamino, naphthylamino, phenylamino or phenyl-lower alkylamino wherein phenyl or naphthyl is optionally substituted by lower alkyl, e.g. As methyl, phenyl, hydroxy, lower alkoxy, ζ. Methoxy or tert-butoxy, lower alkanoyloxy, e.g. For example, acetoxy, halogen, z. For example, fluorine or chlorine, carboxy, lower alkoxycarbonyl, z. B. tdrt-butoxycarbonyl, carbamoyl, amino, lower alkylamino, z. Methylamino, di-lower alkylamino, e.g. Dimethylamino, acylamino, ζ. Β. tert-Butoxycarbo nylamino and / or mono- or polysubstituted by nitro, z. Phenylamino, 2-, 3- or 4-methylphenyi-amino, 4-biphenylylamino, 4-hydroxyphenylamino, 4-methoxyphenylamino, 2,3-, 2,4- or 2,5-dimethoxyphenylamino, 4-chlorophenylamino, 2, 3 or 4-carboxyphenylamino, 2-, 3- or 4-methoxy or tert-butoxycarbonylphenylamino, 2-, 3- or 4-carbamoylphenylamino, 4-aminophenylamino, 4-tert-butoxycarbonylamino-phenylamino or 4-nitrophenylamino, furthermore Benzylamino, 4-methylbonzylamino, 4-biphenylylmethylamino, 4-methoxybenzylamino, 2-, 3- or 4-carboxybenzylamino, 2-, 3- or 4-tert-butoxycarbonylbenzylamino, 2-, 3- or 4-carbamoylbenzylamino, 2-phenylethylamino, 3-phenylpropylamino or 5-phenylpentylamino, pyridyl-lower alkylamino, e.g. 2-, 3- or 4-pyridylmethylamino, 2- (2-, 3- or 4-pyridyl) -ethylamino or 3- (2-, 3- or 4-pyridyl) -propylamino, imidazolyl-lower alkylamino, e.g. 4-imidazolylmethylamino, 2- (4-imidazolyl) -ethylamino or 2- (2- [4-imidazolyl] -ethylamino) -ethylamino, indolyl-lower alkylamino, e.g. 3-indolylmethylamino or 2- (3-indolyl) -ethylamino, or sulfo-lower alkylamino, e.g. 2-sulfoethylamino.

Acyl R ² has z. Up to 25, preferably up to 19, carbon atoms and is primarily the acyl group of a carboxylic acid, a haloester of carbonic acid, an optionally N-substituted carbamic or thiocarbamic acid, an optionally N-substituted oxalamide, a phosphoric acid, a sulfonic acid or an optionally N-substituted sulfamic acid.

Preferred acyl groups R ³ are, for example, alkanoyl, e.g. B. n-decanoyl or lower alkanoyl, for example formyl, acetyl, propionyl or pivaloyl, Hydroxyniederalkanoyl, z. B. β-hydroxypropionyl, Niederalkoxyniederalkanoyl, for example, lower alkoxyacetyl or lower alkoxypropionyl such as methoxyacetyl or ß-methoxypropionyl, Phenoxyniederalkanoyl, z. Phenoxyacetyl, naphthoxy-lower alkanoyl, e.g. For example, α- or β-naphthoxyacetyl, lower alkanoyloxy-lower alkanoyl, e.g. Lower alkanoyloxyacetyl or lower alkanoyloxypropionyl such as acetoxyacetyl or β-acetoxypropionyl, halo-lower alkanoyl, e.g. B. a-haloacetyl, such as α-chloro, α-bromo, α-iodo or α, α, α-trichloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, Carboxyniederalkanoyl, for example carboxyacetyl or ß- Carboxypropionyl, lower alkoxycarbonyl lower alkanoyl, e.g. lower alkoxycarbonylacetyl or lower alkoxycarbonylpropionyl such as methoxycarbonylacetyl, .beta.-methoxycarbonylpropionyl, ethoxycarbonylacetyl or .beta.-ethoxycarbonylpropionyl, carbamoyl-lower alkanoyl, e.g. Carbamoylacetyl or

β-carbamoyl-propionyl, lower-alkylcarbamoyl-lower-alkanoyl, for example, methylcarbamoyl-acetyl, di-lower alkylcerbamoyl-lower-alkanoyl, e.g. Dimethylcarbamoylacetyl, oxo-loweralkanoyl, e.g. Acetoacetyl or propionylacetyl, hydroxy-carboxy-lower alkanoyl, e.g. B. a-hydroxy-a-carboxy-acetyl or a-hydroxy-.beta.-carboxypropionyl, hydroxy-lower alkoxycarbonyl-lower alkanoyl, z. For example, α-hydroxy-α-ethoxy or -methoxycarbonylacetyl or α-hydroxy-β-ethoxy or -methoxycarbonyl-propionyl, esterified hydroxy-lower alkoxycarbonyl-lower alkanoyl, e.g. B. a-acetoxy-amethoxycarbonyl-acetyl, dihydroxy-carboxy-lower alkanoyl, for example, α, β-dihydroxy-β-carboxy-propionyl, Dihydroxyniederalkoxycarbonyl-lower alkanoyl, z. For example, α, β-dihydroxy-β-ethoxy or -methoxycarbonyl-propionyl, esterified dihydroxy-lower alkoxycarbonyl-lower alkanoyl, e.g. For example, α, β-diacetoxy-β-methoxycarbonyl-propionyl, α-naphthoxy-carboxy-lower alkanoyl, e.g. For example, 2-a-naphthoxy-4-carboxy-butyryl, a-naphthoxy-lower alkoxycarbonyl-lower alkanoyl, e.g. A-naphthoxy-ethoxycarbonyl-acetyl, Sa-naphthoxy-S-ethoxycarbonyl-propionyl or 2-a-naphthoxy-4-tert-butoxycarbonyl-butyryl, a-naphthoxybenzyloxycarbonyl-lower-alkanoyl, e.g. 2-α-naphthoxy-3-benzyloxycarbonyl-propionyl, α-naphthoxy-carbamoyl-lower-alkanoyl, e.g. B. 2-α - ^! Aphthoxy-4 · carbamoyl-butyryl, a-naphthoxy-cyano-lower alkanoyl, e.g. A-naphthoxy-cyano-acetyl or 2-a-naphthoxy-4-cyand-butyryl, a-naphthoxy-lower alkylamino-lower alkanoyl, eg 2-a-naphthoxy-5-dimethylaminopentanoyl, a-naphthoxy-oxo-lower alkanoyl, e.g. , B. 2-a-naphtho-4-oxo-pentanoyl _> heterocyclyl-lower alkanoyl, e.g. Indolylacetyl or benzofuranylacetyl, lower alkenoyl, e.g. Acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, lower alkynyl, e.g. B. propioloyl or 2- or 3-butynoyl, Cyrloalkylcarbonyl, z. Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylcarbonyl, bicycloalkylcarbonyl, eg decahydronaphthyl-2-carbonyl, endo- or exo-norbornyl-2-carbonyl, bicyclic (2.2.2) oct-2-ylcarbonyl or bicyclo [3.3.1 ] -non-9-ylcarbonyl, tricycloalkylcarbonyl, for example 1- or 2-adamantylcarbonyl, cycloalkenylcarbonyl, for example 1-cyclohexenylcarbonyi or 1/1-cyclohexadienylcarbonyl, bicycloalkenylcarbonyl, for example 5-norbornene-2-ylcarbonyl or Bicyclo [2.2.2] octene-2-ylcarbonyl, cycloalkyl-lower alkanoyl, for example cyclopropylacetyl, cyclopentylacetyl, cyclohexylacetyl or S-cyclohexylpropionyl, cycloalkyl-lower alkenoyl, for example cyclohexylacryloyl, cycloalkenyl-loweralkanoyl, for example 1-cyclohexenylacotyl or 1-cyclohexadienylacetyl, benzoyl, unsubstituted, mono for example, methyl, phenyl, halogen, ζ, B, chlorine, hydroxy, lower alkoxy, ζ, Meth, methoxy, and / or nitro, ζ, for example, 4-chloro, 4-methoxy, or 4-hydroxy. Nitrobenzoyl, furthermore phenyl, α-naphthyl or β-naphthyl-lower alkanoyl, w orin phenyl unsubstituted, mono- or multiply substituted by lower alkyl, e.g. For example, methyl, phenyl, halogen, for example, chlorine, hydroxy, lower alkoxy, z. For example, methoxy, and / or nitro and lower alkanoyl unsubstituted or substituted z. B. by hydroxy, lower alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and / or oxo be kenn and optionally branched, for example phenylacetyl, a-Naphthylacetyl, ß-naphthylacetyl, Niederalkylphenylacotyl such as 4-methylphenylacetyl, lower alkoxyphenylacetyl such as 4-methoxyphenylacetyl, 3-phenylpropionyl, 3- (p-hydroxyphenyl) -propionyl, diphenylacetyl, di- (4-methoxyphenyl) -acetyl, triphenylacetyl, substituted anilinophenylacetyl such as 2- (o, o-dichloroanilino) -phenylacetyl or 2- (o, o -dichloro-N-benzylanilino) -phenylacetyl, 3-a- or β-naphthylpropionyl, 3-phenyl- or 3-a-naphthyl-2-hydroxy-propionyl, 3 Phenyl or 3-a-naphthyl-2-lower alkoxypropionyl, such as 3-phenyl- or 3-a-naphthyl-2-neopentyloxy-propionyl, 3-phenyl- or 3-a-naphthyl-2-acyloxy-propionyl, as described in U.S. Pat 3-phenyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2-acetoacetoxy-propio nyl, 3-a-naphthyl-2-eth- _T laminocarbonyloxy-propionyl or 3-a-naphthyl-2- (2-amino- or 2-benzyloxycarbonylamino-2-methyl-propionyloxy) -propionyl, 3-phenyl-or 3-a-naphthyl-2-carboxymethyl-propionyl, 3-phenyl or 3-a-naphthyl-2-lower alkoxycarbonyl-propionyl, such as 3-a-naphthyl-2-ethoxycarbonyl-propionyl, 3-phenyl or 3-naphthyl-2-ethoxycarbonyl-propionyl a-Naphthyl-2-benzyloxycarbonylmethyl-propionyl, 3-phenyl or 3-a-naphthyl-2-carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2-tert-butylcarbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2- (2-dimethylaminoethyl) carbamoyl-propionyl, 3-a-naphthyl-2- (carboxy or tert-butoxycarbonyO-methylcarbamoyl-propionyl, 3-phenyl or 3-a-naphthyl) 2- (3-hydroxy-2-propyl-carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2- (2,2-dimethoxyethyl) -carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl -2- (5-amino-5-carboxypentyl) -carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2-cyano-propionyl, 3-phenyl-ode, 3-a-naphthyl-2-cyanomethyl propionyl, 3-phenyl-2-phosphono or phosphonometh yl-propionyl, 3-phenyl-2-dimethoxyphosphoryl or din, ethoxyphosphorylmethyl-propionyl, 3-phenyl-2-diethoxyphosphoryl or diethoxyphosphorylmethyl-propionyl, 3-phenyl-2-ethoxy- or methoxy-hydroxy-phosphoryl-propionyl, 3-phenyl - or 3-a-naphthyl-2-acetonyl-propionyl, 3-phenyl or Sa-naphthyl ^ -dimethylaminomethyl-propionyl, 2-benzyl- or 2-a-naphthylmethyl-4-cyano-butyryl, 4-phenyl or 4 α-naphthyl-3-carboxy-butyryl, 4-phenyl or 4-α-naphthyl-3-benzyloxycarbonyl-butyryl, 2-benzyl-4- (2-benzofuranyl) -4-oxo-butyryl, 2-benzyl or 2-a-naphthylmethyl-4-oxopentanoyl, 2-benzyl or 2-a-naphthylmethyi-4,4-dimethyl-3-oxopentanoyl, 2-benzyl or 2-a-naphthylmethyl-5-dimethylaminopentanoyl , 2-benzyl- or 2-a-naphthylmethyl-5-dimethylamino-4-oxopentanoyl, 2-benzyl- or 2-a-naphthylmethyl-5,5-dimethyl-4-oxo-hexanoyl, α, ρ-diamino -phenylacetyl, α, ρ-diacylamino-phenylacetyl, such as α, ρ-dibenzyloxycarbonylaminophenylacetyl or a-pivaloylamino-p-benzyloxycarbonylamino-phenylacet / I, P henylniederalkenoyl, for example, ß-phenylacryloyl or ß-phenylvinylacetyl, naphthylcarbonyl, for example α- or ß-naphthylcarbonyl or ί, B-naphthalenedicarbonyl, indenylcarbonyl, z. 1-, 2-, or 5-indenylcarbonyl, indanylcarbonyl, eg, 1- or 2-indanylcarbonyl, phei.anthrenylcarbonyl, eg, 9-phenanthrenylcarbonyl, optionally substituted pyrrolylcarbonyl, e.g. 2-or 3-pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-arbonyl, furylcarbonyl, for example 2-furylcarbonyl, thienylcarbonyl, eg 2-thienylcarbonyl, pyridylcarbonyl, for example 2-, 3- or 4-pyridylcarbonyl, optionally substituted indolylcarbonyl, e.g. B. 2-, 3- or 5-indolylcarbonyl, 1-methyl, 5-methyl-1, 5-methoxy, 5-Benzy loxy-, 5-chloro- or 4,5-dimethylindolyl-2-carbonyl, 1 Benzyl indolyl-2- or 3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, cycloheptalbipyrrolyl-S-carbonyl, optionally substituted quinolylcarbonyl, i. 2, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally substituted isoquinolylcarbonyl, e.g. B. 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-i, 2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, 3-chromanecarbonyl, 3-thiochromanecarbonyl, benz [e] indolyl-2- carbonyl, β-carbolinyl-3-carbonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinylcarbonyl, e.g. B. 3- or 4-Hydroxypyrrolidiny! -2-carbonyl, Oxopyrrolidinylcarbonyl, for example, 5-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl.zB 2-, 3- or 4-Piperidinylcarbonyl, indolinylcarbonyl, for example 2- or 3-indolinylcarbonyl, 1,2, 3,4-tetrahydroquinolylcarbonyl, eg, I,..., ^ -Tetrahydroquinolyl, .sup.-, S-, or ^ -carbonyl, I,..., ^, - tetrahydroisoquinolylcarbonyl, for example, 1,2,3,4-tetrahydroisoquinolyl-i, -3- or 4-carbonyl or 1-oxo-1 ^, S ^ -tetrahydroisochi.iolyl-S-carbonyl, lower alkoxycarbonyl, e.g. B. methoxy. Ethoxy or tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2-chloro, 2-bromo, 2-iodo or 2,2,2-trichloroethoxycarbonyl, aryl-lower alkoxycarbonyl, for example

Arylmethoxycarbonyl, wherein aryl is phenyl, Blphenylyl, 1- or 2-naphthyl, fluorenyl or by lower alkyl, for example methyl or tert-butyl, Niederfilkoxy, z. For example, methoxy, ethoxy or tert-butoxy, hydroxy, halogen, z. B. chlorine or bromine, and / or nitro mono- or Mehrfachjjbstituiertes phenyl, ζ. Phenyl-lower alkoxycarbonyl such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenyl-lower alkoxycarbonyl such as diphenylmethoxycarbonyl, di (4-methoxyphenyl) methoxycarbonyl or trityloxycarbonyl, fluorenyl-lower alkoxycarbonyl such as 9-fluorenylmothoxycarbonyl, further oxamoyl or loweralkyloxamoyl, e.g. For example, methyl or Ethyloxamoyl. Acyl R ² is also primarily a substituted by a thio, sulfinyl or sulfonyl group and optionally by further heteroatom-containing groups acyl group of a saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heteroaromatic or he eroaromatic-aliphatic carboxylic acid with the exception of the optionally N-substituted natural amino acid Mulhionin

Preferred substituents R ² are acyl groups of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C-

wherein R 'is unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tricycloalkyl, cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, aryl-lower alkenyl, unsubstituted or substituted heteroaryl, heteroaryl-lower alkyl, unsubstituted or substituted hydroxy or unsubstituted or substituted amino, R ^b Hydrogen, mono-, bi- or tricycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, m is 0.1 or 2, η is 0.1 or 2, ρ is 0.1 or 2 and q is 0.1, 2.3 or 4 represents. The methine carbon atom in the partial formula Ia and, if m is 1, also the sulfur atom may be in the R, S or R ₁ S configuration.

Lower alkyl R * preferably has 1-7 C atoms and is z. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl or tert-butyl, which by one or more functional groups, for example hydroxy, etherified hydroxy, ζ. As lower alkoxy, such as methoxy or ethoxy, or phenoxy, esterified hydroxy, ζ. B. Niedaralkanoyloxy such as acetoxy, halogen, z. As chlorine or bromine, hydroxysulfonyloxy, carboxy, esterified carboxy, ζ. B. lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl, amidated carboxy, ζ. Carbamoyl or mono- or di-lower alkylcarbamoyl, such as methyl or dimethylcarbamoyl, cyano, amino, substituted amino, ζ. B. Mono-lower alkylamino, di-lower alkylamino, acylamino or substituted amino, wherein the amino group may be part of a five- or six-membered heterocycle containing a bi «· two nitrogen atoms and, if desired, an oxygen or sulfur atom, or may be substituted by oxo.

Substituted lower alkyl R 'is, for example, hydroxy-lower alkyl, eg 2-hydroxyethyl, lower alkoxy-lower alkyl, e.g. B. lower alkoxyethyl such as 2-methoxyethyl, Phenoxyniederalkyl, z. 2-phenoxyethyl, lower alkanoyloxy-lower alkyl, e.g. Lower alkanoyloxyethyl, such as 2-acetoxyethyl, halo-lower alkyl, e.g. B. haloethyl, such as 2-chloro or 2-bromoethyl, Hydroxysulfonyloxyniederalkyl, z. 2-hydroxysulfonyloxyethyl, carboxy-lower alkyl, eg carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl, e.g. Lower alkoxycarbonylmethyl or lower alkoxycarbonylethyl, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl-lower alkyl, eg carbamoylmethyl or 2-carbamoylethyl, lower alkylcarbamoyl-lower alkyl, eg methylcarbamoylmethyl, lower alkylcarbamoyl -lower alkyl, eg dimethylcarbamoylmethyl, cyano-lower alkyl, eg 2-cyanoethyl, amino-lower alkyl, e.g. 2-aminoethyl, lower alkylamino-lower alkyl, e.g. 2-methylaminoethyl, lower alkylamino, lower alkyl, e.g. For example, 2-dimethylaminoethyl, morpholinoloweralkyl, e.g. 2-morpholinoethyl, piperidinoloweralkyl, e.g. For example, 2-piperidinoethyl, acyl / amino-lower alkyl / ky /, e.g. Lower alkynylamino lower alkyl such as 2-acetylaminoethyl, benzyloxycarbonylamino lower alkyl such as 2-benzyloxycarbonylaminoethyl, lower Ikoxycarbonylaminoniederalkyl such as 2-tert-Butoxycarbony (aminoethyl, or Oxoniederalkyl, eg 2-oxopropyl or 2-) xobutyl.

Lower alkenyl R 'contains e.g. 2-7, in particular Indere 2-4, C atoms and z. As vinyl, allyl or 2- or 3-butenyl. Lower alkenyl R * may be substituted by the same substituents as lower alkyl, e.g. Hydroxy, etherified hydroxy, e.g. Methoxy, esterified hydroxy, ζ. B. acetoxy, halo | en, ζ. Chlorine or bromine, carboxy, esterified carboxy, ζ.B. Methoxycarbonyl or ethoxycarbonyl, or amidated carboyl, e.g. Carbamoyl.

Lower alkynyl R * contains z. B. 2-7, in particular 2-4, C atoms and is beispielswuise ethynyl, 1-propynyl or 2-propynyl. Cycloalkyl R 'or R ^b contains z. B. 3-8, in particular 3-6, C atoms and z. As cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Bicycloalkyl R 'or R ^b contains e.g. & -10, in particular & -9, C atoms and is e.g. Bicyclohexyl, -heptyl, -octyl, -nonyloder-decy /, z. B. bicyc / o / 3. 1.0] hex-1-, -2- or -3-yl, bicyclo [4.1.0] hept-1- or -7-yl, bicyclo [2.2.1] hept-2-yl, e.g. Endo or exo-norbornyl, bicyclol3.2.1] oct-2-yl, bicyclo (3.3.0) oct-3-yl or bicyc (oi3.3.1-non-9-y /, also α- or β-decahydronaphthyl Tricycloalkyl R * or R ^b contains, for example, & -10 C atoms and is, for example, tricyclol-1, 0'- ^e- dec-vJ-yl or adamantyl, such as 1-adamantyl, C 1-10 -alkoxy-lower alkyl R 'contains, for example, 4-10, in particular 4-7, C atoms and is, for example, CYclopropvlmethyl, cyclobutylmethyl, cycloperrylmethyl or cyclohexylmethyl.

The stated cycloaliphatic or cycloaliphatic-aliphatic radicals may be substituted by the same substituents as lower alkyl R *.

Aryl R * or R ^b contains z. B. 6 to 14 carbon atoms and is, for example, phenyl, indenyl, z. 2- or 4-indenyl, 1- or 2-naphthyl, anthryl, e.g. B. 1- or 2-anthryl, phenanthryl, e.g. 9-phunanthryl, or acenaphthenyl, e.g. 1-acenaphthenyl. Aryl R 'or R ^b is exemplified by lower alkyl, e.g. As methyl, phenyl, hydroxy, lower alkoxy, ζ. For example, methoxy, acyloxy, z. Lower alkanoyloxy such as acetoxy, amino, lower alkylamino, e.g. B. methyl (amino, Diniederalkyfamino, eg., Dimethy / amino, acylamino, ζ B. tert-Butoxycdarbony / amino, or halo, ζ B. chlorine, bromine or iodine, substituted, wherein the substituent in any position of the Arylrestes, for example in the o-, m- or p-position of the pheny / radical, can stand and the aryl radical can also be repeatedly substituted with identical or different substituents.

Aryl-lower alkyl R 'has ζ. B, 7 to 15 carbon atoms and contains, for example, an unsubstituted or substituted, optionally branched radical mentioned under lower alkyl R ¹ and an unsubstituted or substituted radical mentioned under aryl R * or R ^b . Such an aryl-lower alkyl is, for example, benzyl, lower alkylbenzyl, such as 4 Methylbenzyl, biphenylylmethyl, such as 4-biphenylylmethyl, lower alkoxybenzyl, such as 4-methoxybenzyl, 2-phenylethyl, 2- (p-hydroxyphenyl) ethyl, diphenylmethyl, di (4-methoxyphenyl) methyl, trityl or α- or β- naphthylmethyl. Aryl-lower alkenyl R * has z. B. 8 to 16 carbon atoms and contains, for example, a lower alkenyl R 'mentioned unsubstituted or substituted radical and a named aryl R ¹ or R ^b unsubstituted or substituted radical. Such Arylniederalkenyl is, for example, styryl, 3-Phenylallyl, 2- ( a-naphthyl) -viny • or 2- (β-naphthyl) -vinyl. Unsubstituted or substituted heteroaryl R * or R ^b is mono-, bi- or tricyclo-and contains one to two nitrogen atoms and / or one oxygen or sulfur atom. R 'or R ^b is, for example, pyrrolyl, fiyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, ω-sochinolyl, quinoxalinyl, β-carbolinyl or a benzanelated, cyclopenta, cyclohexa or cyclohepta-fused derivative of these radicals. This heterocycle may be attached to a nitrogen atom by oxido, lower alkyl, e.g. Methyl or ethyl, phenyl or phenyl-lower alkyl, e.g. Benzyl, and / or at one or more carbon atoms by lower alkyl, e.g. As methyl, phenyl, phenyl, eg benzyl, halogen, for example, chlorine, hydroxy, lower alkoxy, z. For example, methoxy, phenyl-lower alkoxy, e.g. B. benzyloxy, or oxo substituted and partially saturated and is for example 2- or 3-pyrrolyl, phenyl-pyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl , z. For example, 1-methyl-2-, 4- or 5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl 1,1-oxido-2-, 3- or 4-pyridinio , 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, e.g. 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or 3-indolyl, 4, 5,6,7-tetrahydro-2-indidyl, cyclohepta (b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo 1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzthiazolyl, benz [e] indol-2-yl or β-carbolin-3-yl.

Heteroaryl-lower alkyl R * contains z. For example, a unsubstituted or substituted radical mentioned under lower alkyl R * and an unsubstituted or substituted radical mentioned under heteroaryl R 'or R ^b is, for example, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylmethyl, 2- (2 -, 3- or 4-pyridyl) -ethyl, 4-imidazolylmethyl, 2- (4-imidazolyl) -ethyl, 2- or 3-indolylmethyl, 2- (3-indolyl) -ethyl or 2-quinolylmethyl.

Hydroxy R 'is unsubstituted or substituted for example by lower alkyl or aryl and is z. Hydroxy, methoxy, ethoxy, n-butoxy, phenoxy, 4-hydroxyphenoxy or 3,4-methylenedioxyphenoxy.

Amino R 'is unsubstituted, substituted by one or two Neraleralkylgruppen or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl or part of a five- or six-membered heterocycle containing one to two nitrogen atoms and, if desired, an oxygen or sulfur atom and z. Amino, methylamines), ethylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, benzylamino, acetylamino, pivaloylamino, methoxy, ethoxy or tert-butoxycarbonylamino, benzyloxycarbonylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-methyl-4 -rjyridazinyl, 4-morpholinyl or 4-thiomorpholinyl.

Salts are primarily the pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are exemplified by compounds of formula I having an acidic group, e.g. A carboxy group, and are primarily suitable alkali metal, e.g. Sodium or potassium or alkaline earth metal salts, e.g. As magnesium or calcium salts, also zinc salts or ammonium salts, and those salts which are formed with organic amines, such as optionally substituted by hydroxy mono-, di- or trialkylamines, z. Example, with diethylamine, di- (2-hydroxyethyl) amine, triethylamine, N, N-dimethyl-N- (2-hydroxyethyl) amine, tri- (2-hydroxyethyl) amine or N-methyl-D-glucamine , The compounds of formula I with a basic group, for. As an amino group, can form acid addition salts, eg. As with inorganic acids, eg. As hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic or sulfonic acids, eg. Acetic, propionic, glycolic, succinic, maleic, hydroxymaleic, methylmaleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic or isonicotinic acids, further with amino acids, such as. As the above-mentioned α-amino acids, and with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid, or with other acidic organic compounds such as ascorbic acid. Compounds of the formula I with acidic and basic groups can also form internal salts.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. The compounds of the present invention have gag protease inhibitory effects. In particular, at concentrations down to the nanomolar range, they inhibit the action of the gag protease of HIV-1 and HIV-2 and are therefore useful as agents against diseases caused by these or related retroviruses, such as e.g. Against AIDS. The ability of the compounds of formula I, the proteolytic activity of z. For example, to inhibit HIV-1 protease can be demonstrated according to the method described by J. Hansen et al., The EMBO Journal 7, 1785-1791 (1988). The inhibition of the effect of the gag protease on a substrate is measured, which is expressed in E. coli fusion protein from the gag precursor piotein and MS-2. The substrate and its cleavage products are separated by polyacrylamide gel electrophoresis and visualized by immunoblotting with monoclonal antibodies to MS-2. In an even easier-to-use test, which allows accurate quantitative statements, the substrate used for the gag protease is a synthetic lcosapeptide that corresponds to the cleavage site of the gag precursor protein. This substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC). Compounds of the present invention exhibit inhibitory effects in concentrations of 10 ~ ^e mol / l in this assay.

In a further test it can be shown that the compounds of the present invention protect, or at least slow down, such an infection from cells normally infected by HIV. Here, the human T-cell leukemia 7-cell line MT-2 (Science 229,563 [1985]), which is extremely sensitive to the cytopathogenic effect of HIV, is incubated with HIV alone or with HIV in the presence of the compound of the present invention and viability after a few days evaluated the so treated cells. Compounds of the invention show infection-inhibiting effects in concentrations of 1tT ⁶ mol / l.

In particular, the invention relates to methods by which the preferred compounds mentioned below can be prepared.

Preferred compounds of the formula I are characterized in that they have two or more α-amino acid residues in the radical AAN or that the radical AAN consists of only one α-amino acid residue and at the same time the radical R ^{2 is} an analog to phenylalanyl (H-Phe) and or that they have two α-amino acid residues in the radical AAC or that the radical AAC consists of only one α-amino acid residue and at the same time the residue R ^{1 is} an analogue to the nitrogen-bonded residue of the amino acid tyrosine (-Tyr-OH)

 A radical R ', which can be regarded as analogous to phenylalanyl, has the structural element of the formula

, 'S, jP i

in which the carbocyclic ring may also be wholly or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked to C ₂ or C ₃ to form a preferably five- or six-membered ring, one of the carbon atoms C ₂ or C ₃ by a heteroatom such as NH, O or S may be substituted, the carbonyl group may be a heterocarbonyl group such as P = O and free valencies bear hydrogen or substituents, for example lower alkyl, lower alkylthione, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl, lower alkyl, lower alkoxy, phenyl lower alkoxy, lower aminoalkyl, lower alkylamino, lower alkanoylamino, lower alkyl , Niedoralkanoyl, Niederalkanoylniederalkyl or lower alkylcarbamoyl, where these substituents preferably occur at C ₂ .

A completely or partially saturated carbocyclic ring is for example cyclohexyl or cyclohexenyl in this context. Five- or six-membered rings within the meaning of the preceding paragraph are, for example, phenyl, cyclohexyl, pyrrolyl, pyranyl, dihydropyranyl or thio analogs of said heterocyclyl radicals. These definitions also apply to the tyrosine analogous radicals R ¹ described below.

Such analogs R ² are, for example, 3-phenyl- or 3-cyclohexylpropionyl which are especially in the 2-position by substituents of the type lower alkyl, such as methyl, ethyl or tert-butyl, lower alkylthio-lower alkyl, such as tert-butylthiomethyl, lower alkylsulfinyl-lower alkyl, such as tert-butylsulfinylmethyl, Lower alkylsulfonyl-lower alkyl such as tert-butylsulfonylmethyl, phenyl-lower alkyl such as benzyl, hydroxy, lower alkoxy such as methoxy, phenyl-lower alkoxy such as benzyloxy, amino-lower alkyl such as aminomethyl or 2-amino-2-propyl, lower alkylamino-lower alkyl such as methylar.iinomethyl, lower alkanoylamino-lower alkyl such as acetylaminomethyl, lower alkanoyl such as acetyl, lower alkanoyl-lower alkyl such as acetylmethyl, isobutyrylmethyl or pivaloylmethyl, or lower alkylcarbamoyl such as methylcarbamoyl, 2-naphthylcarbonyl or hydrogenated forms thereof, e.g. 2-decalydronaphthylcarbonyl, 2- (3-indolyl) -acetyl or 2- (3-benzofuranyl) -acetyl, 3-chromano- or 3-thiochromanecarbonyl, or dibenzyloxyphosphoryl.

A radical R ¹ , which may be considered as an analogue to the nitrogen-bonded radical of the amino acid tyrosine, has the structural element of the formula

(C)

ν \ / de)

in which the carbocyclic ring may contain a heteroatom such as nitrogen and may also be wholly or partially saturated and / or substituted, for example by hydroxy or by phenyl, the index ν is zero to five, for example zero to three, one of the carbon atoms of the carbocyclic ring may be joined to one of the atoms - (C) _v - to form a preferably five- or six-membered ring and free valencies bear hydrogen or substituents, for example lower alkyl or hydroxy-lower alkyl. Furthermore, such a radical R ¹ , which may be considered as an analogue to the rest of the amino acid tyrosine, also be lower alkylamino.

Such analogs R ¹ are, for example, butylamino, cyclohexylamines), 2-decahydronaphthylamino, 6-hydroxy-2-tetrahydronaphthylamino or 2-tetrahydronaph'hylamino, 6-hydroxy-2-naphthylamino or 2-naphthylamino, pyridylmethylamino, phenyl- or hydroxyphenyl-lower alkylamino such as 2-phenyl- or hydroxyphenylethylamino or 5-phenyl- or hydroxyphenylpentylamino, 1-hydroxymethyl-2-hydroxyphenylethylamino or biphenylyl-lower alkylamino, such as 4-biphenylylmethylamino

 Before jte compounds of the invention are compounds of formula II

• ·

R² - A5 - A4 - A3 - N- ·

I · · - A2 - Al - R ¹ <">

• s η

• I I

• t N /

wherein the radicals A1, A2, Λ3 and A4 each denote a bivalent α-amino acid residue which is N-terminal with the radical in formula II to the left thereof and C-terminal with the radical to the right thereof or with the radical R ¹ , A5 is a single bond or a bivalent radical consisting of up to three peptidically linked

α-amino acids, which is N-terminally connected to R ² and C-terminal to A4, and the other symbols have the meanings given for formula I.

Preferred are compounds of formula II wherein A1 is selected from the bivalent residues of tyrosine (Tyr), phenylalanine (Phe), naphthylalanine (NaI), tryptophan (Trp), lysine (Lys) and aspartic acid (Asp), A2 being selected from the bivalent residues of valine (VaI), isoleucine (He), leucine (Leu), norleucine (Never), phenylalanine (Phe), alanine (Ala) and glycine (Gly), A3 is selected from bivalent valine residues (VaI ), Alanine (AIa), leucine (Leu), isoleucine (l'e), asparagine (Asn), glutamine (Gl.i), norleucine (Nie), phenylalanine (Phe), serine (Ser) and histidine (His) A4 is selected from the bivalent residues of phenylalanine (PIkj), tyrosine (Tyr) (including etherified by lower alkyl, mtrosine), tryptophan (Trp), cyclohexylalanine (Cha), leucine (Leu), naphthylalanine (NaI) , Histidine (His), Asparaginsäuie (Asp) and lysine (Lys), and the other symbols call the meanings given for formula II.

Preference is further given to compounds of the formula II in which A1, A2, A3 and A4 have the meanings given immediately above, A5 is a simple bond or a bivalent radical consisting of up to three identical or different peptide-linked α-amino acids selected from arginine , Proline, histidine, lysine, ornithine or tryptophan, R ^{1 is} hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C- (O) ⁿ I ^P ö

(CH ₂ ) ^(la) '

wherein R 'is unsubstituted or hydroxy or lower alkoxy substituted lower alkyl, e.g. For example, methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl or 2-methoxyethyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms, for. 2- or 4-imidazolyl, 1-metbyl-2-imidazolyl, 2-, 3- or 4-pyridyl, 1 -Oxido-2-, 3- or 4-pyridinio or 2-pyrimidinyl, R ^b cyclohexyl or phenyl , m is 0.1 or 2, η is 1, ρ is 0 and q is 1 or 2, and salts thereof.

Among these, preferred are those compounds in which A5 is a single bond or the bivalent radical Arg-Arg-Pro.

Particular preference is given to compounds of the formula II in which A1 is selected from Tyr, Phe, Trp, NaI, Lys and Asp, A2 and A3 are selected from VaI, He, Leu, Nie and Ala, A4 is Phe, Tyr or NaI, A5 a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, Niederaikanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniideralkoxycarbonyl, Diphenylniederalkoxycarbonyl or Fluorenylniederalkoxycarbonyl, and salts thereof.

Particular preference is likewise given to compounds of the formula II in which A1 is Tyr, A2 is selected from VaI, He, Nie, Leu, Phe, Ala and Gly, A3 means Vala, A4 is Phe, Tyr or NaI, A5 is a bond, R 'represents hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniederalkoxycarbonyl, Diphenylniederalkoxycarbonyl or Fluorenylniederalkoxycarbonyl, and salts thereof.

Particular preference is also given to compounds of the formula II in which A1 is Tyr, A2 is VaI or Leu, A3 is selected from VaI, Leu, He, Nie, Ala, Asn, GIn, Phe, Ser and His, A4 is Phe, A5 a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniederalkoxycarbonyl, Diphenylniedornikoxycarbonyl or Fluorenylniederalkoxycarbonyl, and salts thereof.

Also particularly preferred are compounds of formula II, wherein A1 is Tyr, A2 is VaI or Leu, A3 is VaI, A4 is selected from Pns, Tyr, methyletherified Tyr, Trp, Cha, Leu, NaI and Lys, A5 a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniederalkoxycarbonyl, Diphenylniederalkoxycarbonyl or Fluorenylniederalkoxycarbonyl, and salts thereof.

Preference is also given to the compounds of the formula I falling compounds of formula III

• V · jj - A2 - Al - R ¹ HID

i i "w"

wherein all symbols have the meanings given for formula II.

Preference is given to compounds of the formula III in which A1 is selected from the bivalent radicals of tyrosine (Tyr), phenylalanine (Phe). Tryptophan (Trp), a-naphthylalanine (NaI), lysine (Lys) and aspartic acid (Asp), A2 is selected from bivalent residues of valine (VaI), isoleucine (He), leucine (Leu), norleucine (Nie), Phenylalanine (Phe), alanine (Ala) and glycine (Gly), A3 is selected from bivalent residues of valine (VaI), alanine (Ala), leucine (Leu), isoleucine (lie), asparagine (Asn), glutamine ( GIn), norleucine (Never), phenylalanine (Phe), serine (Ser) and histidine (His), and the other symbols have the meanings given for formula I.

Equally preferred are compounds of the formula II in which A 1, A 2, R 'and R ^{2 have} the meanings mentioned and A3 is the bivalent radical of tyrosine (Tyr) or of tyrosine etherified with lower alkyl.

Preference is further given to compounds of the formula III in which A 1, A 2 and A 3 have the meanings given immediately above, R 'is hydroxyl, lower alkoxy, amino or mono- or diniodoalkylamino, and R ^{2 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C-

wherein R ^{1 is} unsubstituted or substituted by hydroxy or lower alkoxy lower alkyl, for example methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl or 2-methoxyethyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms , z. 2-or 4-imidazolyl, 1-methyl-2-imidazolyl, 2-, 3- or 4-pyridyl, 1 -Oxido-2-, 3- or 4-pyridinio or 2-pyrimidinyl, R ^b cyclohexyl or phenyl , m is 0.1 or 2, η is 1, ρ is 0 and q is 1 or 2.

Likewise preferred are compounds of formula III wherein A 1, A2, A3 and R ^{1 have} the meanings given immediately above and R ^{2 is} a radical having the structural element I b, which can be considered as analogous to phenylalanyl, as described further above is defined.

Particular preference is given to compounds of the formula IH in which A1 is selected from Tyr, Phe, Trp, NaI, Lys and Asp, A2 and A3 mean VaI or Leu, R 'represents hydroxyl. N-oralkoxy, Niedtnalkylamino or amino, and R ^{2 is} a radical of the formula la, wherein R ^{a is} lower alkyl, R ^{b is} phenyl and m is two, η one, ρ is zero and q is one, and salts thereof.

Particular preference is likewise given to compounds of the formula III in which A1 is Tyr, A2 is selected from VaI, He, Leu, Nie, Phe, Ala and Gly, A3 is VaI or Leu, R ^{1 is} hydroxyl, lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of formula Ia wherein R 'is lower alkyl, R ^{b is} phenyl and m is two, η is one, ρ is zero and q is one, and salts thereof.

Particular preference is likewise given to compounds of the formula III in which A1 is Tyr, A2 is VaI or Leu, A3 is selected from VaI, Ala, Leu, He, Asn, GIn, Nie, Phe, Ser and His, R 'is hydroxyl, Lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of the formula Ia, wherein R "is lower alkyl, R ^{b is} phenyl and m is two, η one, ρ is zero and q is one, and salts thereof.

Particular preference is likewise given to compounds of the formula III in which A1 is Tyr, A2 is VaI, A3 is selected from VaI, Leu, Nie, Phe, Ala, Ser, Tyr and lower alkyl etherified Tyr, R ¹ for hydroxy, lower alkoxy, lower alkylamino or Amino and R ^{2 is} 3-phenyl- or 3-cyclohexyl-propionyl substituted at the 2-position by lower alkylsulfonyl-alkyl or lower alkanoyl-lower alkyl, and salts thereof.

Preference is likewise given to the compounds of the formula covered by the compounds of the formula I

• ·

H OH V

R ² - A3 -5 I!

I · - A2 - R ¹ (IV),

I i

• ·

wherein A2 and A3 have the meanings given under formula I, R ^{1 is} a radical which can be regarded as analogous to the nitrogen-bonded radical of the amino acid tyrosine and R ^{2 is} a radical which can be regarded as analogous to phenylalanyl, and salts from that.

Among the compounds de. Formula IV is preferred for those in which A2 is selected from the bivalent residues of valine (VaI), isoleucine (He), norleuclene (Never), leucine (Leu), phenylalanine (Phe), alanine (Ala) and glycine (Gly) and A3 is selected from bivalent residues of valine (VaI), alanine (Ala), leucine (Leu), asparagine (Asn), glutamine (GIn), norleucine (Nie), phenylalanine (Phe), serine (Ser) and Histidine (His), especially those in which A2 and A3 are each VaI or Leu. Particular preference is given to compounds of the formula IV in which A2 is valine, A3 is selected from VaI, Leu, Nie, Phe, Ala, Ser, Tyr and lower alkyl etherified Tyr, R ^{1 is} lower alkylamino or a radical having the structural element of the formula Ic, wherein the carbocyclic ring may be unsubstituted or substituted by hydroxy or by ienyl, the subscript ν is zero to five, and free valencies bear hydrogen, and R ^{2 is} 3-phenyl- [not] 2-propyl The invention relates first and foremost to processes for the preparation of the compounds mentioned in the examples and their salts, process a) (preparation of an amide bond):

Fragments of a compound of formula I having a terminal carboxy group which can be condensed with a fragment complementary to the compound of formula I to form an amide bond are e.g. B. Compounds of Foimeln R ² -OH, R ² -A5-OH, R ² -A5-A4-OH, R ² -AAN-OH,

H OH CH (CH ₃ ) ₂ O

R ² - AAN - N - CH - CH - CH ₂ - CH C -

CH ₂ - C ₆ H ₁₁

CH ₂ - CH C-OH,

CH (CH ₃ );

H OH CH (CH ₃ ) ₂ O

R ² - AAN - N - Ch - CH - CH ₂ - CH C - A2 - OH or

CH ₂ - C ₆ H ₁₁

H OH CH (CH ₃ ) ZQ

R ² - AAN - N - CH - CH - CH ₂ - CH • C -

CH ₂ - C ₆ Hi ₁

CH ₂ - CH; C - AAC - OH,

the activated esters or reactive anhydrides derived from these compounds, further reactive cyclic amides. The reactive acid derivatives can also be formed in situ.

Activated esters are especially at the linking carbon atom of the esterifying radical unsaturated esters, eg. Vinyl ester type such as vinyl ester (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl ester (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method) or 1-lower alkoxyvinyl ester (obtainable, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method) or amidino-type esters such as N, N'-disubstituted amidinoesters (obtainable, for example, by treating the corresponding acid with a N, N'-disubstituted carbodiimide, BNN'-dicyclohexylcarbodiimide, carbodiimide method) or Ν, Ν-disubstituted amidinoesters (obtainable, for example, by brightening the corresponding acid with N, N disubstituted cyanamide, cyanamide method), suitable aryl esters, iroOptionally substituted by electron-withdrawing substituents substituted phenyl esters (available, for example, by treating the corre sponding acid with a suitably substituted phenol, eg. 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as Ν, Ν'-dicyclohexylcarbodiimide; Activated aryl ester method), cyanomethyl esters (obtainable, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioesters, especially optionally, e.g. B. by nitro, substituted phenylthio esters (obtainable, for example, by treating the corresponding acid with optionally, for example by nitro, substituted thiophenols, including using the anhydride or carbodiimide method, activated thiolester method) or especially amino or amido esters (obtainable, for example, by treating the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound and their activated derivatives, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxypiperidine Hydroxy-5-norbornene or norbornane-2,3-dicarboximide, 1-hydroxybenzotriazole and benzotriazol-1-yloxy-phosphonium salts or O-benzotriazol-1-yluronium salts, or 3-hydroxy-3,4-dihydro-1,2 , 3-benzotriazin-4-one, for example by the anhydride or carbodiimide method, activated N-hydroxy ester method).

Anhydrides of acids may be symmetrical or preferably mixed anhydrides of these acids, e.g. Example, anhydrides with inorganic acids, such as acid halides, in particular acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, Phorphorpentachlorid or oxalyl chloride, acid chloride method), azides (available, for example, from a corresponding acid ester on the corresponding hydrazide and its Treatment with nitrous acid, azide method), anhydrides with carbonic monoesters, eg. B. Kohlensiederiederalkylhalbestern (available, for example, by treating the corresponding acid with Chlorameisensäureniedenlkylestern or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example i-ethoxycarbonyl ^ -ethoxy-i ^ -dihydroquinoline; method of mixed O-Alkylkohleosäureanhydride) , Anhydrides of dihalogenated, in particular dichlorinated, phosphoric acid (obtainable, for example, by treating the corresponding acid with phosphorus oxychloride, phosphorus oxychloride method), anhydrides with other phosphoric acid brivates (for example those which can be obtained with phenyl-N-phenylphosphoramidochloridate) or with phosphorous acid derivatives, or anhydrides with organic acids, wio mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenyl-lower alkane carboxylic acid halide, eg phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides) or with organic sulfonic acids (available for. By treating a salt such as an alkali metal salt, the corresponding acid with a suitable organic sulfonic acid halide such as lower alkane or aryl, ζ. For example, methane or p-toluenesulfonyl chloride; Mixed sulfonic acid anhydride method) and symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; symmetrical anhydride method).

Suitable cyclic amides are in particular amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, t. Imidazole (obtainable, for example, by treating the corresponding acid with Ν, Ν'-carbonyldiimidazole, imidazole method), or pyrazoles, e.g. B. 3,5-Dimethyipyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

For the compound of formula I complementary fragments with a free amino group z. B. depending on the meaning of R ^{1 is} a primary or secondary amine, further compounds of the formulas

H OH CH (CHj) ₂

H - AAN - Ä - CH - CH - CH ₂ - CH C - AAC - R ¹ ,

CH ₂ - C ₆ Hi ₁

H OH CH (CH ₃ ); - N - CH - CH -

CH ₂ - C ₆ Hn

H - A4 - A3 - N - CH - CH - CH ₂ - CH C - AAC - R ¹ ,

H OH CH (CH ₃ ) ₂ O

H - A3 - N - CH - OH - CH ₂ - CH C - AAC - R ¹ ,

CH ₂ - C ₆ Hn

V Q "QH (CHa) ₂ Ο

H - N - CH - OH - CH ₂ --OH C - AAC - R ¹ ,

CH ₂ - C ₆ H ₁₁

H - AAC - R ¹ or H - Al - R ¹ .

The amino group participating in the reaction in a fragment complementary to a compound of the formula I is preferably present in free form, in particular if the carboxy group reacting therewith is present in a reactive form; but it can also be derivatized itself, z. By reaction with a phosphite such as diethyl chlorophosphite, 1.2 x phenyl chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite. A derivative of such a complementary fragment with an amino group is z. Example, a carbamic acid halide or an isocyanate, wherein the participating in the reaction amino group by halogencarbonyl, z. As chlorocarbonyl, substituted or modified as an isocyanate group, in the latter case, only compounds of formula I are accessible, which carry a hydrogen atom on the nitrogen atom of the amide group formed by the reaction. If the complementary fragment containing an amino group is mono- or di-substituted by lower alkyl or aryl-lower alkyl, a corresponding urea compound is also a reactive derivative. For example, equimolar amounts of this urea compound and the free carboxy group component are used to produce corresponding compounds of the formula I. If the complementary fragment is dimethylamine, dimethylformamide is also a reactive derivative. Functional groups in starting materials whose reaction is to be avoided, in particular carboxy, amino, hydroxyl, mercapto and sulfo groups, may be protected by suitable protective groups, as commonly used in the synthesis of peptide compounds, but also of Cephalosporins and penicillins are used. These protective groups may already be present in the precursors and are intended to protect the relevant functional groups against undesirable side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis, etc. However, protecting groups can also be present in the end products. Compounds of formula I having protected functional groups may have higher metabolic stability than the corresponding compounds having free functional groups. The protection of functional groups by such protecting groups, the protecting groups themselves, as well as their cleavage reactions, are described, for example, in standard works such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, Th. W. Greene, "Protective Groups in Orgsnic Synthesis", Wiley, New York 1981, "The Peptides", Volume 3 (Ed E. Gross and J. Meienhofer), Academic Press, London and New York 1981, as well as in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974 described , A carboxy group is z. B. protected as an ester group, which is selectively cleavable under mild conditions. A carboxy group protected in esterified form is esterified primarily by a lower alkyl group which is branched in the 1-position of the lower alkyl group or substituted in the 1- or 2-position of the lower alkyl group by suitable substituents. A protected carboxy group esterified by a lower alkane group branched at the 1-position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, e.g. B. tert-butoxycarbonyl, or arylmethoxycarbonyl having one or two aryl radicals, wherein aryl is unsubstituted or z. B. by lower alkyl, z. Tert-lower alkyl such as tert-butyl, lower alkoxy, e.g. Methoxy, hydroxy, halogen, e.g. As chlorine, and / or nitro mono-, di- or trisubstituted phenyl, for example benzyloxycarbonyl, substituted by said substituents benzyloxycarbonyl, z. 4-nitrobenzyloxycarbonyl or 4-methoxybenzylxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by said substituents, e.g. Di (4-methoxyphenyl) -methoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group which is substituted at one or two stages of the lower alkyl group by suitable substituents is, for example, 1-lower alkoxy-dimercoxycarbonyl, e.g. Methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, I-lower alkylthio-lower alkoxycarbonyl, e.g. For example, 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. B. 2,2,2-Tricnlorethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, and 2-Triniederalkylsilylniederalkoxycarbonyl, z. B. 2-trimethylsilylethoxycarbonyl.

A carboxy group may also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, e.g. B. trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be represented by two lower alkyl groups, e.g. As methyl groups, and the amino group or the carboxy group of a second molecule of the formula I be substituted.

Compounds with such protective groups can be z. B. with Dimethy'nhlorsilan as silylating agent. A protected carboxy group is preferably tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.

An amino group may, for. B. in the form of an acylamino, arylmethylamino, etherified mercaptoamino or Silylaminogruppe or be protected as azido group.

In a corresponding acylamino group acyl, for example, the acyl radical of an organic carboxylic acid with z. B. up to 18 carbon atoms, in particular an optionally, for. B. by halogen or aryl, substituted lower alkanecarboxylic acid or optionally, for. B. by halogen, lower alkoxy or nitro, substituted benzoic acid, or preferably a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, e.g. B. 2-haloacetyl, such as 2-chloro, 2-bromo, 2-iodo, 2,2,2-Trifluoro- or 2,2,2-trichloroacetyl, optionally z. B. substituted by halogen, lower alkoxy or nitro substituted benzoyl, z. B. benzoyl, 4-chlorobenzoyl, 4-Metnoxybenzoyloder4-nitrobenzoyl, or in the 1-position of the lower alkyl branched or in the 1- or 2-position suitably substituted lower alkoxycarbonyl, z. B. tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, optionally, z. B. by Niederalkyl.z. B. tert-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy,

Hydroxy, halogen, such as chlorine, and / or nitro, mono- or polysubstituted phenyl, ζ. Β. Benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or di- (4-methoxyphenyl) -methoxycarbonyl, aroylmethoxycarbonyl, e.g. B.

Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyi, e.g. For example, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-tr in-lower alkylsilyl-lower alkoxycarbonyl, e.g. P. 2-trimethylsilylethoxycarbonyl, or 2-triarylsilyl-lower alkoxycarbonyl, e.g. B. 2-Triphenylsilylethoxycarbonyl.

An arylmethylamino group is ζ. As mono-, di- or in particular triphenylmethylamino, z. B. benzyl, diphenylmethyl or tritylamino.

In an etherified mercaptoamino group, the etherified mercapto group is primarily substituted arylthio, ζ. Β. 4-nitrophenylthio.

A silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. B. trimethylsilylamino. The silicon atom of the silylamino group may also be represented only by two lower alkyl groups, e.g. Methyl groups, and the amino group or carboxy group of a second molecule of the formula I be substituted. Compounds with such protective groups can be z. B.

with dimethylchlorosilane as securing agent.

Preferred amino protecting groups are acyl radicals of carbonic monoesters, especially tert-butoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-halo-lower alkoxycarbunyl, e.g. 2,2,2-trichloroethoxycarbonyl, further trityl and formyl.

A hydroxy group may be exemplified by a halogen, e.g. Chlorine, substituted lower alkanoyl group, e.g. 2,2-dichloroacetyl, or in particular be protected by an acyl radical of a carbonic monoester mentioned for protected amino groups. A preferred hydroxy-protecting group is, for example, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl. A hydroxy group may also be represented by tri-lower alkylsilyl, e.g. B.

Trimethylsilyl or preferably dimethyl-tert-butylsilyl, an easily cleavable alkyl group, such as tert-lower alkyl, z. Tert-butyl, an oxa or thiaaliphatic or cycloaliphatic hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. Methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiacycloalkyl of 5-7 Rinrj atoms, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analog, and by 1-phenyl-lower alkyl, e.g. B.

Benzyl, diphenylmethyl or trityl, wherein the phenyl radicals, for example by halogen, z. As chlorine, Niedoralkoxy, z. As methoxy, and / or nitro may be protected.

Two adjacent hydroxyl groups may be protected, for example, by a preferably substituted methylene group, e.g. By lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. As cyclohexylidene, or benzylidene.

A mercapto group, such as. As in cysteine, can be in particular by S-alkylation with optionally substituted alkyl radicals, silylation, thioacetal, S-acylation or by the formation of asymmetric disulfide groups goschützt.

Preferred mercapto protecting groups are, for. B. optionally in the phenyl radical, for. B. by methoxy or nitro, substituted benzyl, such as 4-methoxybenzyl, optionally on the phenyl radical, for. Substituted by methoxy, substituted diphenylmethyl, such as di (4-methoxyphenvl) methyl, triphenylmethyl, trimethylsilyl, benzylthiomethyl, 2-tetrahydropyranyl, acylaminomethyl, benzoyl, benzyloxycarbonyl or lower alkylaminocarbonyl, such as ethylaminocarbonyl, further lower alkylthio, e.g. B. methylthio.

A sulfo group may be exemplified by lower alkyl, e.g. As methyl or ethyl, be protected by phenyl or sulfonamide, for example as imidazolide.

The condensation for the preparation of the amide bond can be carried out in a conventional manner, for example as in standard works, such as "Houben-Weyl, Methods of Organic Chemistry", 4th Edition, Volume 15/11, Georg Thieme Verlag, Stuttgart 1974, "The Peptides "(Ed. E. Gross and J. Meienhofer), Ba id 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodanszky," Principles of Peptide Synthesis ", Springor Publishers, Berlin 1984 , described.

The condensation can be carried out in the presence of one of the conventional condensing agents. Conventional condensing agents are e.g. Carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide or, in particular, dicyclohexylcarbodiimide, furthermore suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, eg. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, further activated phosphoric acid derivatives, e.g. Diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phonylphosphoramidochloridate, bis (2-oxo-3-oxazolidinyl) -phosphinic acid chloride or 1-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate.

If desired, an organic base is added, e.g. a tri-lower alkylamine with bulky radicals, e.g. B.

Ethyldiisopropylamine, or a heterocyclic base, e.g. For example, pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.

The condensation of acid anhydrides with amines can, for. B. in the presence of inorganic carbonates, eg. B.

Alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate).

The condensation is preferably in an inert, polar, aprotic, preferably anhydrous. Solvent or solvent mixture carried out, for example in a carboxylic acid amide, for. As formamide or dimethylformamide, a halogenated hydrocarbon, eg. As methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, z. B.

Acetone, cyclic ethers, e.g. For example, tetrahydrofuran, an ester, for. Ethyl acetate, or a nitrile, e.g. For example, acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, for. B. in a temperature range from about -4O ⁰ C to about +100 ⁰ C, preferably from about -10 ⁰ C to about +50 ⁰ C, and optionally under inert gas, for example

Nitrogen atmosphere.

Reactive acid derivatives can also be formed in situ. So you can, for example Form Ν, Ν'-disubstituted amidinoesters in situ by reacting the mixture of the free carboxy group-containing fragment and the complementary fragment with an amino group in the presence of a suitable disubstituted carbodiimide, e.g. B. dicyclohexylcarbodiimide reacted. Further, one may form amino or amido esters of such acids in the presence of the amino component to be acylated by reacting the mixture of the corresponding acid and amino precursors in the presence of a disubstituted carbodiimide, e.g. Dicyclohexylcarbodiimide, and an N-hydroxylamine or N-hydroxyamide, e.g. B. N-hydroxybenzotriazole, N-

Hydroxysuccinimide or N-hydroxy-norbornane ^, S-dicarboximide, optionally in the presence of a suitable base,

z. As 4-dimethylaminopyridine, N-methylmorpholine or ethyldiisop-opylamine reacted.

The condensation of a carboxylic acid with the corresponding, complementary to the compound of formula I fragment with a free amino group can also be achieved in a conventional manner with the aid of enzymes, for. As described by H.-D. Jakubke et al. in Angewandte Chemie 97, (1985). As enzymes, for example, thermolysin, carboxypeptidase Y, papain, chymotrypsin, trypsin or pepsin are suitable. The reaction is preferably carried out in water or in mixtures of water with organic solvents, e.g. B. with lower alkanols, such as ethanol, dimethylformamide, dimethyl sulfoxide, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, acetone, acetonitrile or polyalcohols, for. B.

Ethylene glycol, di-, tri- or poly-ethylene glycol, but also with immiscible organic solvents, eg. B.

Methylene chloride or ethyl acetate, at a pH of 5 to 8, preferably at the neutral point, carried out at temperatures between ^{0 0} C and 5O ⁰ C. The solvents and the reaction conditions are preferably chosen so that the desired compound precipitates or is extracted into the immiscible organic phase and thus removed from the reaction equilibrium. It is also possible to carry out the condensation with enzymes immobilized on a suitable support, as mentioned above, in the known organic solvents mixed with a little water.

The method a) can be carried out in a manner known per se in automated Forin, z. For example, according to the technique known as solid-phase synthesis, which is based on R. Merifield and, for example, in Angew. Cham. 97.801-812

(1985), Science 71, 252-258 (1984) or R.A.Honghten, Proc. Nat'l. Acad. Sci., 82, 5113-5135 (1985)

The fragments of the compound of formula I, which are condensed together according to process a), can also be used as racemates or as mixtures of diastereomers. This produces diastereomer mixtures which contain compounds of the formula I and still have to be subjected to a separation of the diastereomers according to process i).

Process b) (reduction of a keto group):

In a starting material of the formula V, functional groups, with the exception of the keto group to be reduced, are optionally protected by one of the protective groups mentioned under process a).

For the reduction of the keto group in a compound of the formula V, those reducing agents are suitable which, under the reaction conditions of the process, reduce an isolated keto group selectively or faster than the amide groups present in compounds of the formula I.

First of all suitable borohydrides, such as alkali metal borohydrides, in particular sodium borohydride, lithium borohydride or sodium cyanoborohydride, furthermore zinc borohydride, or suitable aluminum hydrides, such as bulky alkali metal lower alkoxyaluminium hydrides, for example lithium tris-tert-butoxyaluminum hydride. The reduction may also be carried out with hydrogen in the presence of suitable heavy-metal catalaors, e.g. B. Raney nickel or platinum or palladium catalysts, for. As platinum or palladium activated carbon, or after Meerwein-Ponndorf-Verley with the help of Aluminiumalkanolaten, preferably aluminum 2-propanolate or -ethanolat be performed. The reduction may preferably be carried out with stoichiometric amounts or a sensibly measured excess of the reducing agent in an inert solvent at temperatures between -8O ⁰ C and the boiling point of the solvent, preferably between -2O ⁰ C and + 100 ⁰ C, if necessary under inert gas, for example nitrogen or argon. An excess of the reducing agent is necessary in particular if it also reacts with the solvent, for example the protons of a protic solvent.

When sodium borohydride is used, polar protic solvents, e.g. Methanol, ethanol or isopropanol; when using the other reducing agents mentioned under process a) polar, aprotic solvent, eg. B. tetrahydrofuran.

Process c) (addition of an organometallic compound):

In a starting material of the formula VI, functional groups, with the exception of the aldehyde group, are optionally protected by the protective groups mentioned under process a). Likewise, existing functional groups are protected in a compound of formula VII.

In a compound of formula VII is a metal radical -M, for example -Li or -MgHaI, z. B. -MgCI, -MgBr or Mgl.

The reaction of a compound of formula VI with a compound of formula VII is carried out in the usual manner in an anhydrous, inert, aprotic solvent, for. Example, in an ether such as diethyl ether or tetrahydrofuran, or a hydrocarbon such as benzene or toluene, or mixtures thereof, optionally with cooling, in particular after the beginning of the reaction, for. B. to about -3O ⁰ C, or under heating, for. B. up to the boiling point of the reaction mixture, optionally in an inert gas, for. B. nitrogen atmosphere. A preferred embodiment of the process is the reaction of the aldehyde of the formula VI with an excess of the lithium compound of the formula VII.

The hydrolysis of the addition product is carried out with solvents which yield H ⁺ ions, for example water (ice-water-Gerr ^: sch) or dilute, aqueous acids, for. As dilute mineral acids, such as dilute, aqueous sulfuric acid, or dilute organic acids, eg. B. dilute, aqueous acetic acid.

The reaction of a compound of formula VI can also be carried out with a compound of formula VII prepared in situ, which z. B. from the corresponding halide, for. As chloride, by reaction with a metallating agent, for. B.

Magnesium, lithium or tert-butyllithium, receives.

Method d) (nucleophilic substitution):

Functional groups are protected in a starting material of the formula VIII> if appropriate protected by the protective groups mentioned under process a).

In a compound of formula VIII, the nucleofugic leaving group X, in particular with a strong inorganic or organic acid esterified hydroxy, such as with a mineral acid, eg. As hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid. Sulfuric acid or halogenated sulfuric acid, e.g. As fluorosulfuric acid, with a strong organic

Sulfonic acid, such as an optionally, for. Example by halogen, such as fluorine, substituted lower alkanesulfonic acid or an aromatic sulfonic acid, eg. B. one optionally substituted by lower alkyl, such as methyl. Halogen, such as bromine and / or nitro substituted benzenesulfonic acid, eg. A methanesulfonic, trifluoromethanesulfonic, or p-toluenesulfonic acid or hydroxy esterified with hydrazoic acid.

A hydroxy group-introducing reagent is e.g. B. a hydroxide-containing base, for. For example, sodium or potassium hydroxide. Preferably, the reaction conditions are chosen so that the reaction proceeds essentially as second order nucleophilic substitution (S _N 2). The reaction with a hydroxide-containing base is preferably in water, optionally as a solubilizer, an organic solvent, for. As ethanol, tetrahydrofuran or acetone, is carried out. The substitution reaction is optionally carried out at reduced or elevated temperature, for example in a temperature range from about -4O ⁰ C to about +100 ⁰ C, preferably from about -10 ⁰ C to about + 5O ⁰ C, and optionally under an inert gas, eg nitrogen atmosphere, carried out.

Process e) (conversion of a cyano group into a group COR ¹ ):

In a starting material of the formula IX, functional groups are optionally protected by the protective groups mentioned under a).

The conversion of a compound of formula IX into a compound of formula I may, for. B. by a Ritter reaction or via carboxylic acid ester imide salts.

In the Ritter reaction, the nitriles are reacted in the presence of a strong acid, for example 85-90% sulfuric acid, or else polyphosphoric acid, hydrogen fluoride, formic acid, boron trifluoride or other Lewis acids, but not aluminum chloride, with compounds which are acidic Can form medium carbenium ions, so z. With olefins, such as propylene, or alcohols, such as benzyl alcohol, .No solvent or, for example, in glacial acetic acid.

In a variant of the Ritter reaction, a nitrile of the formula IX is reacted with an olefin and mercury (II) nitrate and the organomercury compound is subsequently reduced with sodium borohydride to give an N-substituted compound of the formula I.

Acid-catalyzed, preferably hydrogen chloride-catalyzed, addition of alcohols onto the nitriles of the formula IX affords carboxylic acid ester imides which give amides of the formula I by thermal rearrangement at temperatures above about 8O ⁰ C.

For the conversion of a nitrile into a free acid, the hydrolysis with water is advantageously carried out in an inert organic solvent which is at least partially miscible with water, such as ethers (eg diethyl and diisopropyl ether, 1,2-dimethoxyethane or especially dioxane or Tetrahydrofuran), or lower alkanols (eg, methanol, ethanol, isopropyl alcohol, butylalkuliols, especially tort-butyl alcohol), with a larger amount of water being required in the latter cases to prevent alcoholysis. The hydrolysis can be effected both by strong acids, in particular inorganic acids, such as sulfuric acid, or, preferably, hydrohalic acids (eg.

Hydrobromic acid or as a first choice hydrochloric acid), as well as by bases, especially inorganic bases such as hydroxides and carbonates of the alkali metals, e.g. Sodium and potassium hydroxide, are catalyzed. The bases are usually used in at least stoichiometric proportions that give rise to carboxylic acid salts as primary products.

The acidic catalysts are advantageously used in the form of a dilute aqueous solution to obtain the best result.

End products of formula I wherein R 'is etherified hydroxy may be obtained by carrying out the solvolysis of the nitrile with the appropriate alcohol (alcoholysis) in the presence of a catalytic amount of anhydrous strong acid, benefiting from gaseous hydrogen chloride. Usually, an excess of alcohol is used as the solvent, but inert organic solvents such as acyclic and cyclic ethers (especially those mentioned above) and / or halogenated lower alkanes (especially chloroform and dichloromethane) may be added. If the alcoholysis is carried out under strictly anhydrous conditions, the primary product (imidoester) must advantageously be hydrolysed by adding water to the reaction mixture. On the other hand, when the alcoholysis is carried out in the presence of an approximately stoichiometric equivalent of water, the desired ester is obtained directly.

Method f) (reduction of the epoxide):

In a starting material of the formula X, functional groups are optionally protected by the protective groups mentioned under process a).

It is possible to use those reducing agents which, under the reaction conditions of the process, reduce the epoxy group selectively or faster than the amide groups present and open the epoxide so that a sufficiently large and as large proportion of the reaction products as possible correspond to the newly formed hydroxy group in the position corresponding to formula I. wearing. Examples of such selective reducing agents are lithium borohydride or sodium cyanoborohydride / boron trifluoride etherate. With the latter reagent, the reaction z. B. so that one to 1 mole of the compound of formula X and an excess, for. B. 1.4-3 mol, sodium cyanoborohydride in tetrahydrofuran at elevated temperature, eg. B. under reflux, a solution of boron trifluoride etherate, BF ₃ 0 (C ₂ H ₆ )], in tetrahydrofuran so admits that the pH of the reaction solution is maintained in the vicinity of the turnover point of the also added indicator bromocresol green. The reduction with lithium borohydride is preferably carried out in an ether, e.g. As tetrahydrofuran, 1,2-dimethoxyethane or diethylene glycol dimethyl ether, carried out at temperatures between room temperature and reflux temperature.

Method g) (addition to an acrylamide)

A compound of the formula R'-S (O) _m H is either a thiol of the formula R * -SH or a sulfinic acid of the formula R'-SO ₂ H.

In a starting material of the formula XI, functional groups are optionally protected by the protective groups mentioned under process a). Likewise, existing functional groups in the Verbindun j of the formula R "-S (O) _m H are optionally protected.

Suitable salts of the compound of the formula R * -S (O) _m H are, for example, alkali metal salts, eg. For example, sodium or potassium salts.

-27- 290 094

The addition of a compound of the formula R ^a -S (O) _m or a suitable salt thereof to a compound of the formula XI is usually carried out in an inert, polar solvent, for example in a * polar ether, for example tetrahydrofuran, dioxane or dimethoxyethane, a lower alkanol, e.g. As methanol, ethanol or isopropanol, or a dipolar aprotic solvent, for. As dimethylformamide, dimethylacetamide, Oimethylsulfoxid, Hexamethylphosphorsäuretriamid, N-meth>'! Nvrrolidon or acetonitrile, optionally also in mixtures of said solvents with each other or with water, at temperatures between about -30 ⁹ C and the boiling point of the respective solvent, eg between O ⁰ C and + 8OX, for example around 50 ° C. Instead of a sulfinic acid Ff-SO ₂ H, its salts are preferably used, for example the sodium or potassium salt.

A salt of a thiol of the formula R'-SH can also be formed in situ, for example by addition of a suitable base, e.g. Example, alkali metal hydroxide, such as sodium or potassium hydroxide, or alkali metal hydride, for. As sodium hydride, although only anhydrous solvents can be used. It is also possible to carry out the addition reaction with a free thiol of the formula R'-SH in the presence of an organic base, e.g. B. a tertiary amine, z. Triethylamine, N-methylmorpholine, dimethylaniline, diazabicyclo [5.4.0] undec-7-ene or diazabicyclo (4.3.0) -non-5-ene.

Process h) (alkylation in the acyl radical of subformula Ia)

In a starting material of the formula XII, functional groups are optionally protected by the protective groups mentioned under process a).

An example of the radical R ^b - (CHj) q- introducing compound is the corresponding halide, for. As chloride, bromide or iodide, or a reactive ester of the corresponding alcohol, for. For example, a sulfonic acid ester, such as the methanesulfonic or p-toluenesulfonic.

For alkylation, the compound of formula XII is preferably converted by the usual methods with a strong, non-nucleophilic base in the corresponding anion, for example with the lithium or potassium salt of a sterically hindered secondary amine, eg. With lithium diisopropylamide, lithium cyclohexyl isopropylamide, lithium 2,2,6,6-tetramethylpiperidide, lithium or potassium bis (trimethylsilyl) amide or the like. Deprotonation with the base is preferably carried out at low temperatures, e.g. between -100 ° C and -50 ° C in an inert polar solvent, e.g. in a polar ether, e.g. Tetrahydrofuran, dioxane or dimethoxyethane optionally mixed with a hydrocarbon, e.g.

Hexane or toluene, and / or hexamethylphosphoric triamide or N, N'-dimethyl-N, N'-propyleneurea.

Contains the compound of formula XII even more, more easily deprotoniarbare methylene or methine groups, eg. B. solc'ie addition to the sulfinyl or sulfonyl group, so preferably two or more equivalents of the base are used to obtain the corresponding di- or polyanion.

The thus deprotonated compound of formula XII is preferred with the radical R ^b - (CH ₂ ) q- introducing alkylating agent fn situ at low temperatures, for. B. at -78 ° C to -3O ⁰ C, and then warming to room temperature or slightly elevated temperature, for. B. at 50 ⁰ C, reacted in the same solvent or solvent mixture.

If η = 0 in a compound of the formula XII, the alkylation may be carried out under much milder conditions, for example in one of the abovementioned solvents or other polar solvents, eg. B.

Dimethylsulfoxide, dimethylformamide or acetonitrile, with the radical R ^b - (CH ₂ ) q- introducing alkylating agent at temperatures between -30 ⁰ C and about room temperature and a tertiary amine, for. Triethylamine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or diazabicyclo [4.3.0] non-5-ene, or an insoluble inorganic base, e.g. B.

Potassium carbonate or sodium hydride, or an alkoxide, e.g. For example, potassium tert-butoxide. Also suitable is the alkylation under phase transfer conditions, d. H. in a biphasic aqueous base mixture, e.g. Sodium hydroxide, and a non-miscible organic solvent, e.g. Methylene chloride or toluene, and a phase transfer catalyst, e.g. As an ammonium or phosphonium salt.

Procedure I) (postoperations):

The group R ¹ together with the terminal carbonyl group of the radical AAC of the compounds of formula I forms a carboxy group, an esterified carboxy group, a carboxamide group or a substituted carboxamide group. When such groups are mentioned in the context of reoperations, in addition to corresponding groups which may be present as substituents, for. B. in the amino acid residues A1, A2, A3, A4 and A5, each also comprises the C-terminal groups which are formed by R ¹ and the carbonyl group directly attached thereto.

In an available version! ^In order to substitute the formula I, it is possible to substitute a carboxamide group, to esterify a carboxy group present in free or reactive form, or to convert an esterified carboxy group into a free carboxy or a carboxamide group.

The substitution of a carboxamide group or another amino group takes place for. B. by alkylation.

Suitable means for alkylating a carboxamide group in a compound of formula I are, for. B. diazo compounds, for. B.

Diazomethane. Diazomethane can be decomposed in an inert solvent, the free methylene formed reacting with the carboxamide group in the compound of formula I. The decomposition of diazomethane is preferably carried out catalytically,

z. B. in the presence of a noble metal in finely divided form, for. As copper, or a noble metal salt, for. As copper (l) chloride or copper dD sulfate.

Further alkylating agents are the alkylating agents mentioned in German Offenlegungsschrift 2331133, eg. B.

Alkyl halides, sulfonic acid esters, sea wine salts or 1-substituted 3-Aryltriazene, which can be reacted under the reaction conditions mentioned there with a compound of formula I with a carboxamide group.

For the esterification of a carboxy group in a compound of formula I, one can use the free acid or convert the free acid into one of the reactive derivatives mentioned under process a) and react with an alcohol, or the free acid or a reactive salt, for. As the cesium salt, react with a reactive derivative of an alcohol. For example, the cesium salt of a carboxylic acid can be reacted with the halide corresponding to the alcohol.

The esterification of a carboxy group can be carried out with the above for the substitution of the carboxamide group alkylating agents and under the same reaction conditions, for. With diazomethane, alkyl halides, sulfonic acid esters, seaweed salts, 1-substituted 3-aryl triazenes, etc.

For converting an esterified carboxy group in a compound of formula I into a free carboxy group, one of the methods described under process a), cleavage of the carboxy groups, or optionally an alkaline saponification according to the Organikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1976, mentioned reaction conditions.

In a compound of the formula I, an esterified carboxy group can be converted by aminolysis with ammonia or a primary or secondary amine into an optionally substituted carboxamide group. The aminolysis can be carried out according to the reaction conditions mentioned in Organikum, 15th edition, VEB Deutscher Verlag der Wissenschaft, Berlin (East) 1976, for such reactions.

In an available compound of the formula I in which the substituents have the meanings and at least one free hydroxy group is present and the remaining functional groups are optionally present in protected form, the free hydroxy group can be etherified or esterified.

The etherification of this hydroxy group can be carried out in the abovementioned Alkylierungsmitleln and under the same reaction conditions, for. With diazomethane, alkyl halides, sulfonic acid esters, seaweed salts, 1-substituted 3-aryl triazenes, etc.

The esterification of the free hydroxy group can be carried out with the usual acylating agents and the usual reaction conditions specified in the organic compound, e.g. with acetic anhydride.

The abovementioned alkylation reactions, etherifications, esterifications etc. can be carried out correspondingly also in a starting material instead of in the end product.

In an available compound of formula I, one can oxidize a thio group to a sulfinyl or sulfonyl group or a sulfinyl group to a sulfonyl group.

O Kidation to the sulfonyl group can be carried out with most of the usual oxidizing agents. Preference is given to such oxidizing agents, the thio group or sulfinyl group selectively in the presence of other functional groups of the compound of formula I, z. As the amide function and the hydroxy group, oxidize, for example, aromatic or aliphatic peroxycarboxylic acids, eg. As perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid, performic acid or trifluoroperacetic acid. The oxidation with peroxycarboxylic acids takes place in the usual suitable solvents for example chlorinated hydrocarbons, eg. For example, methylene chloride or chloroform, ether, ethyl acetate or the like, at temperatures between -78 ⁰ C and room temperature, for example between -20 ⁰ C and + 10 ° C, preferably O ⁰ C. The peroxycarboxylic acid can also be formed in situ, for , B. with hydrogen peroxide in acetic acid or formic acid, which optionally contains acetic anhydride, for example with 30% or 90% hydrogen peroxide in acetic acid / acetic anhydride. Also suitable are other peroxo compounds, for example potassium peroxomonosulfate in lower alkanol / water mixtures, eg. As methanol-water or ethanol-water, or in aqueous acetic acid at temperatures between -70 ⁰ C and + 3O ⁰ C, z. B. between -20 ⁰ C and room temperature, further sodium metaperiodate in methanol or methanol-water mixtures at temperatures between ^{0 0} C and 50 ⁰ C, z. B. at room temperature. '

For the oxidation of the thio group to the sulfinyl group, selective oxidants are used in equimolar amounts or only slight excess under controlled reaction conditions to avoid overoxidation to the sulfonyl group. Suitable examples are sodium metaperiodate in methanol or methanol-water mixtures at temperatures between -15 ⁰ C and room temperature, eg. B. to O ⁰ C, m-chloroperbenzoic acid in methylene chloride, chloroform or ethyl acetate at temperatures between -78 ⁰ C and 10 ⁰ C, preferably between -3O ⁰ C and ^{0 0} C, further tert-butyl hypochlorite in lower alkanols, eg. As methanol, or hydrogen peroxide in acetone or acetic acid at temperatures around 0 ° C, or the above-mentioned potassium peroxomonosulfate at low temperatures.

In an available compound of the formula I having a sulfinyl group, this group can be reduced to a thio group. Preference is given to selective reducing agents, the other functional group of the compound of formula I, z. As the amide function, leave unchanged. 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 hexachlorodisilane, iron pentacarbonyl, further sodium bisulfite in aqueous alcoholic solvents, eg. As water-methanol, water-ethanol or water-tetrahydrofuran, at temperatures between -10 ° C and + 5O ⁰ C, further sodium borohydride in the presence of cobalt (II) chloride or hydrogen in the presence of catalytic amounts of palladium, eg. B. palladium / carbon in boiling ethanol.

If desired, in an available compound of Formet I, a sulfonyl group can be reduced to a thio group, for example with diisobutylaluminum hydride in ethric or tetrahydrofuran.

In an available compound of the formula I having a sulfonamide group, this can be alkylated in the manner described for carboxamide groups or hydrolyzed with acid or alkali to a sulfo group. A sulfenamide group may be reacted with any of the reagents mentioned under the oxidation of thio groups to sulfonyl groups, e.g. As potassium peroxomonosulfate, oxidized to the sulfonamide and be hydrolyzed equal in situ. A sulfonic acid ester group can also be converted to a sulfo group by acid or base, for example as described above for the hydrolysis of a carboxylic acid ester group.

In an available compound of the formula I having a sulfo group, these can be converted in a known manner into a sulfonic acid ester or sulfonamide group, for example by conversion into a sulfonic acid halogtinide group and reaction with an alcohol, phenol or amine. A sulfonic acid ester group is converted analogously to the carboxylic acid ester group with an amine into the corresponding sulfonamide group.

In an available compound of formula I wherein one or more functional groups are protected, these groups, e.g. As carboxy, amino, hydroxy, mercapto and / or sulfo groups, in a conventional manner, by solvolysis, in particular hydrolysis, optionally enzymatic hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis, or chemical reduction, optionally gradually or simultaneously released. The deprotection is described in the standard works referred to earlier in the "protecting groups" section.

For example, one can use protected carboxy, ζ. B. tert-Niederalkoxycarbonyl, in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl, by treatment with a suitable acid, for. For example, formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, for. As phenol or anisole, convert into free carboxy.

Optionally substituted benzyloxycarbonyl may e.g. B. by means of hydrogenolysis, d. H. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobicycloxycarbonyl, may also be obtained by reduction, e.g. B. by treatment with an alkali metal dithionite, z. Sodium dithionite, with a reducing metal, e.g. Zinc, or a reducing metal salt, such as a chromium (II) salt, z. ChromoDO chloride, usually in the presence of a hydrogen donating agent which is capable of producing nascent hydrogen together with the metal, such as an acid, primarily a suitable carboxylic acid such as an optional, e.g. B. substituted by hydroxy, lower alkanecarboxylic, z. For example, acetic acid, formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, Mandelsäiiie, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, preferably adding water, transfer in free »carboxy. By treating with a reducing metal or metal salt as described above, one can also convert 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl to free carboxy. Aroylmethoxycarbonyl may also be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. 2-tri-lower alkylsilyl-lower alkoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium or potassium fluoride, optionally in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetranyllalkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, eg tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethyl sulfoxide or N, N-dimethylacetamide can be converted into free carboxy With an organic silyl group, such as tri-lower alkylsilyl, eg trimethylsilyl, esterified carboxy can be solvolytically, for example by treatment with water, an alcohol or acid, or in the usual way esterified carboxy may also be cleaved enzymatically, eg, esterified arginine or lysine, such as lysine methyl ester, by trypsin.

A protected amino group is set free in known per se and depending on the nature of the protective groups in various ways, preferably by solvolysis or reduction. 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino may be e.g. By cleavage with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonylamino may also be obtained by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. Sodium dithionite, are split. Optionally substituted diphenylmethoxycarbonylamino, tert-loweralkoxycarbonylamino or 2-tri-lower alkylsilyl-loweralkoxycarbonylamino may be prepared by treatment with a suitable acid, e.g. For example, formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino e.g. by means of hydrogenolysis, d. H. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino or formylamino z. B. by treatment with an acid such as mineral acid, eg. Hydrochloric acid, or an organic acid, e.g. Example, formic, acetic or trifluoroacetic acid, optionally in the presence of water, and a protected with an organic silyl group amino group z. B. be released by hydrolysis or alcoholysis. A by 2-haloacetyl, z. For example, 2-chloroacetyl, protected amino group may be released by treatment with thiourea in the presence of a base, or with a thiolate salt such as an alkali metal dihydrogenated thiourea, followed by solvolysis such as alcoholysis or hydrolysis of the resulting substitution product. An amino group protected by 2-tri-lower alkylsilyl-lower alkoxycarbonyl may also be converted to the free amino group by treatment with a hydrofluoric acid salt yielding fluoride anions as indicated above in connection with the release of a suitably protected carboxy group. It is likewise possible to cleave SiIyI bound directly to a heteroatom, such as nitrogen, such as trimethylsilyl, by means of fluoride ions.

In the form of an azido protected amino is z. B. converted by reduction in free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or 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, e.g. As methylene chloride, or in water or a mixture of water and an organic solvent such as an alcohol or dioxane, at about 20 ° C to 3O ⁰ C, or under cooling or heating performed.

A hydroxy or mercapto group protected by a suitable acyl group, an organic silyl group or by optionally substituted 1-phenyl-lower alkyl is liberated analogously to a correspondingly protected amino group. A 2,2-dichloroacetyl protected hydroxy or mercapto group is e.g. by basic hydrolysis, a group protected by tert-lower alkyl or by a 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical by acidolysis, e.g. B. by treatment with a mineral acid rder a strong carboxylic acid, eg. As trifluoroacetic acid, released. A silyl group, e.g. Example, a trimethylsilyl or tert-butyldimethylsilyl group is also by acidolysis, for. B. by mineral acid, preferably hydrofluoric acid, or split off a strong carboxylic acid. 2-halo-lower alkoxycarbonyl is replaced by the abovementioned reducing agents, e.g. For example, reducing metal, such as zinc, reducing metal salts, such as chromium (II) salts, or by sulfur compounds, such as sodium dithionite or preferably sodium sulfide and carbon disulfide removed.

Two hydroxy groups which together through a preferably substituted methylene group, such as by lower alkylidene, z. B. isopropylidene, cycloalkylidene, z. As cyclohexylidene, or benzylidene, can be protected by acid hydrolysis, for. In the presence of a mineral acid or a strong organic acid.

A sulfo group protected as sulfonic acid ester or sulfonamide is obtained, for example, by acid hydrolysis, e.g. In the presence of mineral acid, or preferably by basic hydrolysis, e.g. with alkali metal hydroxide or alkali metal carbonate, for example, sodium carbonate.

Salts of compounds of the formula I having salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula I with acidic groups z. By treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. The sodium salt of 2-ethylhexanoic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Sodium bicarbonate, or with ammonia or a suitable

form organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I, which z. B. contain a free carboxy group and a free amino group, z. By neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. B. with weak bases, or by treatment with ion exchangers are formed.

Salts can usually be converted to the free compounds: metal and ammonium salts e.g. by treatment with suitable acids, acid addition salts e.g. by treating with a suitable basic agent.

Stereoisomer mixtures, in particular diastereomer mixtures, in a conventional manner, for. B. by fractional crystallization, chromatography, etc., are separated into the individual isomers.

Racemates can in a conventional manner, for. B. after conversion of the optical) antipodes into diastereomers, beis; ^ to be cleaved by reaction with optically active acids or bases.

At individual chiral centers in a compound of formula I, z. B. the C4 atom in the central 5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoyl radical, the configuration can be specifically reversed.

For example, the configuration at the C4 atom can be reversed by nucleophilic second order substitution according to method d) after conversion of the hydroxy group to a nucleofuge leaving group X and reaction with a hydroxy group introducing reagent.

The invention also relates to those embodiments of the process starting from a compound obtainable as an intermediate at any stage and carrying out the missing steps or stopping the process at any stage or producing a compound obtainable by the process according to the invention under the process conditions and further processed in situ.

Pharmaceutical preparations:

The pharmacologically useful compounds of the present invention may e.g. Example, be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable excipients.

Suitable pharmaceutical preparations are those for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals) containing an effective dose of the pharmacological agent alone or together with a significant amount of a pharmaceutically acceptable carrier contain. The dosage of the active substance depends on the species of warm-blooded animals, body weight, age and individual condition, the disease to be treated and the mode of administration.

For the treatment of diseases caused by retroviruses, e.g. As AIDS, a therapeutically effective amount of the compounds of formula I prepared according to the invention can be administered. The on warm-blooded animals, z. For example, humans of about 70 kg body weight, dosages to be administered are between about 3 mg and about 3 g, preferably between about 10 mg and about 1.5 g, e.g. At about 300 mg to 1000 mg per person per day, preferably divided into 1 to 3 individual doses

z. B. can be the same size. Usually, children receive half the dose of adults.

New pharmaceutical preparations contain from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical preparations may be e.g. in unit dosage form, vials, vials, suppositories, dragoes, tablets or capsules.

The pharmaceutical preparations are prepared in a conventional manner, for. Example by means of conventional solution, lyophilization, mixing, granulation or coating process.

It is preferable to use solutions of the active substance, as well as suspensions, in particular isotonic aqueous solutions or suspensions, these z. 8. in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffer and are in a conventional manner, for. Example by means of conventional solution or lyophilization process. The solutions or suspensions mentioned may contain viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain, as an oily component, the vegetable, synthetic or vegetable injections

semisynthetic oils. As such, particular mention may be made of liquid fatty acid esters containing as acid component a langket'.ige fatty acid having 8-22, especially 12-22, carbon atoms, such as. 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. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, z. B. mono-, di- or trihydric alcohol,

z. As methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol or glycerol. Examples of fatty acid esters include ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2735" (polyoxyethylene glycerol trioleate from Gattefosso, Paris), "myglyol 812" (triglyceride of saturated fatty acids of chain length C ₈ to C ₁₂ from Chemische Werke Witten / Ruhr , Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and especially peanut oil.

The preparation of the injection preparations is carried out in the usual way under sterile conditions, as well as the filling in ampoules or vials and the closing of the container.

Pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained and processing the mixture or granules, if desired or necessary after addition of suitable auxiliaries, into tablets or dragee cores. They can also be incorporated in plastic carriers, which deliver the active ingredients dosed or diffundieien. Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, eg. For example, tricalcium phosphate or Calciumhydrogtnnhosphat, further binders such as starch pastes using z. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrating agents such as the abovementioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, Alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulating lubricants, eg. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragoe cores are provided with suitable, optionally enteric coatings, where u. a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. As for the identification or labeling of different doses of active ingredients, be attached.

Starting materials:

The starting materials for carrying out the process a) can be prepared by processes known per se, for. B. from the relevant amino acids by condensation analogous to the method described above a). For example, one can use a compound of the formula

H OH CH (CH ₃ ) Z 0

HN-CH-CH-CH ₂ -CH C - AAC - R ¹

CH 2 -

CH ₂ - CH C - AAC - R ¹ _(Χ Ι, Ι)

analogous to the method described in European Patent Applications EP 143746 or EP 258183. Compounds of the formula V are prepared, for example, by reacting a carboxylic acid of the formula

R ² -AAN-N-CH-C-OH

CH-CH ₂ -

H ₂ - C ₆ Hn

or a suitable functional derivative thereof, wherein the symbols have the meanings given and functional groups, except for the optionally modified carboxy group, optionally in protected form, with an organometallic compound of the formula VII, wherein M is a metal radical, for. B. -Li or MgHaI, such as -MgCI, -MgBr or -MgI means, and solvolyzing the formed addition product.

Suitable functional derivatives of a carboxylic acid of the formula XIV are, for example, the corresponding lithium salt of the carboxylic acid, a carboxylic acid halide, eg. As carboxylic acid chloride, an anhydride, for. B. the symmetrical carboxylic anhydride or a mixed carboxylic acid anhydride with a sterically hindered carboxylic acid, ζ. With pivalic acid, or a thioester, e.g. 2-pyridylthio.

The reaction of a carboxylic acid of the Fiel iel XIV or a suitable functional derivative thereof with a compound of formula VII is carried out in the usual manner, ι. Example, according to the reaction conditions specified in process c), but optionally with cooling, for example at temperatures of about -50 ⁰ C to about O ⁰ C. In a preferred embodiment of the method, a 2-Pyridy! Thioester dor carboxylic acid of the formula XIV reacted with a bromine magnesium compound of the formula VII. Compounds of formula VI can be prepared by methods known per se, for example by reacting in a compound of formula XIV, wherein the symbols have the meanings mentioned and functional groups optionally in protected form, the carboxy group according to known methods, for example via the corresponding methyl or ethyl ester, via an imidazolide or via an N-methoxy-N-methylamide, reduced to the aldehyde function. Compounds of the formula VII can be synthesized, for example, by reacting a halide of the formula ## STR1 ## which can be prepared by known methods or methods known per se

CH (CHa) ₂ p Hal - CH ₂ - CH C-AAC-R ¹ (XV),

ζ. As the chloride, with a metalating agent, for. As magnesium, lithium or tert-butyllithium, are produced. Compounds of formula VIII are prepared, for example, by reacting an aldehyde of formula VI with an organometallic compound of the formula VII according to process c) and the resulting hydroxy compound of formula I, optionally after separation of the isomers, with a definition corresponding to X strong esterified organic or inorganic acid

 Nitriles of the formula IX are prepared, for example, by reacting a compound of the formula

H OH CH (CH ₃ ) 2 O

R ² - AAN - N - CH - CH - CH ₂ - CH C - AAC '- shark

CH ₂ - C ₆ Hn

wherein the symbols have the meanings mentioned, with a salt of hydrocyanic acid. Suitable salts of hydrocyanic acid should be sufficiently soluble in the chosen inert solvent for reaction to occur. Such salts are e.g. Ammonium cyanide, alkali metal or alkaline earth metal cyanides, e.g. Sodium or potassium cyanide, or transition metal cyanides, e.g. Copper cyanide. The latter are suitable because of their lower basicity compared to the alkali metal cyanides.

Depending on the nature of the cyanide used and the solvent, a balance between the isomeric nitrile and isonitrile forms. The nitrile form is preferably formed when z. B. the reaction is carried out with such metal cyanides whose metal cations have a lower atomic weight uis that of copper.

Suitable inert solvents are, in particular, polar, aprotic solvents, for example carboxylic acid amides, eg. For example, dimethylformamide or dimethylacetamide, nitriles, z. For example, acetonitrile or propionitrile, or Diniederalkylsulfoxide, z. For example, dimethyl sulfoxide.

The reaction takes place at room temperature, at reduced or elevated temperature, for. Example in a temperature range of about ⁰ C to about +100 -4o ⁰ C, preferably from about -10 ° C to about +50 ⁰ C and optionally in an inert gas, such. B. nitrogen atmosphere

 Epoxides of the formula X are z. B. prepared by reacting a compound of formula

-N-CH-

Z ¹ -N-CH-CHO (XVII),

CH ₂ - C ₆ Hn

wherein Z 'is an amino protecting group, with a phosphoranylidyl compound of the formula

CH (CHa) ₂ - ^ P = CH - CH CZ ²

wherein R ^{c represents} an optionally substituted hydrocarbon radical and Z ^{2 is} a carboxy protecting group, and an obtainable compound of the formula

CH (CHj) ₂ Ο

Z ¹ HN - CH - CH = CH - CH CZ ² (XIX)

CH ₂ -

with an oxidant containing the peroxy group converted into an epoxide and in an available compound in any order of the reaction steps, the protective groups Z ¹ and Z ² split off and replaced by the groups R ² -AAN- and -AAC-R ¹ .

R ⁰ is preferably phenyl. The reaction of a compound of the formula XVII with a phosphoranylidene compound of the formula XVIII is carried out under the conditions known for Wittig reactions and z. B. in the organic reaction conditions described.

The dabsi available olefin of formula XIX is optionally in situ with the oxidizing agent, for. As peracetic acid or m-chloroperbenzoic acid reacted. The cleavage of the protective groups Z ¹ and Z ² and the introduction of the groups R ² -AAN- or -AAC-R ¹ is described further above under process a).

Compounds of the formula XI are prepared, for example, by reacting an acrylic acid of the formula

R ^b - (CH ₂₎ - C ₁ - COOH ^(XX)

^q Sh ₂

or a suitable functional derivative thereof with a compound of the formula

tf OH 9H (CH ₃ ); - N - CH - CH -

C ₆ Hn

H - AAN - Ii - CH - CH - CH ₂ - OH C - AAC - R ¹ (XX »

CH-CH ₂ -

according to method a). The compound of formula XXI is also prepared according to process a), for example E'is a protected at the amino group compound of formula Z'-AAN-OH and a compound of formula XIII and subsequent cleavage of the protective group Z ¹ .

Compounds of formula XII are likewise obtained by condensation of a compound of formula XXI with the corresponding carboxylic acid or a suitable functional derivative thereof according to process a). The following examples serve to illustrate the invention, but do not limit its scope in any way. Temperatures are given in degrees centigrade. The Rf values are determined on silica gel thin-layer plates in the following solvent systems:

A Essigester-n-hexane 1: 1 B Essigester-n-hexane 1: 2 C Essigester-n-hexane 1: 4 D Essigester-n-hexane 1: 6 e Essigester-n-hexane 1: 9 F Methylene chloride-methanol 19: 1 G Methylene chloride-methanol 9: 1 H Methylene chloride-methanol 4: 1 I Methylene chloride-methanol-water 300: 10: 1 J Methylene chloride-ether 4: 1 K Methylene chloride-methanol-ammonia conc. 40: 10: 1 L Methylene chloride-methanol-ammonia conc. 350: 50: 1 M Methylene chloride-methanol-water-glacial acetic acid 150: 54: 10: 1 N Methylene chloride-methanol-water 14: 6: 1 O Chloroform-methanol-water-glacial acetic acid 150: 54: 10: 1 P Chloroform-methanol-water-glacial acetic acid 180: 20: 2: 1 Q Chloroform-methanol-water-glacial acetic acid 170: 26: 3: 1 R Essigester S Methylene chloride-methanol-ammonia conc. 800: 50: 1 T Methylene chloride-methanol-ammonia conc. 90: 10: 1 U Toluene Essigester 4: 1

For example, the abbreviation "Ri (A)" means that the Rf value was determined in the system A. The proportions of the solvents to each other are given in parts by volume.

The same abbreviations are used for the designation of the flux systems in flash chromatography and medium pressure chromatography.

The retention times (t _R ") in high pressure liquid chromatography (HPLC) are determined on a 250 χ 4.6 mm reversed phase C ₁₈ Nucleosil® 5μ column at a flow rate of 1 ml / min.

Gradient A: 0% -> 100% acetonitrile in water containing 0.05% trifluoroacetic acid in 60 min .; Gradient B: 10% -> 100% acetonitrile in water containing 0.00% trifluoroacetic acid in 40 min. For example, the abbreviation "t _R " (A) "means that the retention time was determined to be gradient A.

The values for proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) are given in ppm (parts per million) based on tetramethylsilane as internal standard, s = singlet, d = doublet, t = triplet, q = quartet, m = multiply, dd = Double doublet, br = wide. In "fast atom bombardment" mass spectrometry (FAB-MS), the values for the protonated mass (M + H) ⁺ are given.

The residue -Cha-Val- represents the divalent radical of (2S, 4S, 5S) -5-amino-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid and has the formula

H _? H

/ \ / ⁶ k

• ·

I i

• ·

The residue -Cha-VaI- is derived from the residue Cha-Val- by bridging NH and OH by an isopropylidene group and has the formula

A.A λ

, J Ä

ι ι

• ·

To denote divalent radicals of natural α-amino acids, the abbreviations customary in peptide chemistry are used. Tyrosine radicals etherified with the radical R on the phenolic hydroxyl group are designated Tyr (OR). Never the radical of norleucine, Cha, means the radical of cyclohexylalanine.

Next 3 abbreviations:

Section. - absolutely (anhydrous)

BBSP = 2 (S) -benzyl-3-tert-butylsulfonyl-propionyl

BOC = tert-butoxycarbonyl

BOP = benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

DCCI = dicyclohexylcarbodiimide

DCH = dicyclohexylurea

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

Fmoc · = 9-fluorenylmethoxycarbonyl

ges. = saturated

HBTU = O-benzotriazole-1-yl-N, N'N'-N'-tetramethyluronium hexafluorophosphate

HOBH = N-hydroxy-endo-norbornane ^ .S-dicarboxylic acid imide

HOBt = 1-hydroxybenzotriazole

conc. = concentrated

Min. - Minute (s)

Bp = boiling point

M.p. = melting point

Hour = hour (s)

Tcp = trichlorophenyl

THF = tetrahydrofuran

Z = benzyloxycarbonyl

Bolsplel 1

Z-Arg-Arg-Pro-Phe-Val-ChaS · Val-Val-Tyr-OMe

A mixture of 160mg H-Phe-Val-Cha ^ Val-Val-Tyr-OMe, 180mg Z-Arg-Arg-Pro-OH · HCl, 42mg triethylamine hydrochloride, 62mg DCCI, 42mg HOBt and 10ml DMF is charged for 48h. stirred at room temperature. The crystallized DCH is filtered off and the filtrate is evaporated. The residue is dissolved in methanol and precipitated with diisopropyl ether. The crude product is then purified by flash chromatography on 20 g silica gel (mobile phase M). R ₍ (M) = 0.25; FAB-MS: (M + H) ⁺ = 1337; t _R "(A) = 35.2 min.

The starting materials are prepared as follows:

a) 2 (S) -Benzyloxycarbonylamino-3-cyclohexyl-propionic acid ethyl ester: 243 g of (S) -benzyloxycarbonylamino-3-cyclohexylpropionic acid (preparation: Helvetica Chimica Acta 57, 21131 [1974] are initially charged in 600 ml of toluene and 900 ml of ethanol cooled ⁰ C and added dropwise 88,3g thionyl chloride within 30 min.. the cooling is removed and the mixture was stirred 18Std.. the reaction mixture is filtered and the filtrate was concentrated. the residue is (by flash chromatography 2 kg silica gel 60,40- 63 μm, eluent E.) The product-containing fractions are combined, evaporated and dried under high vacuum to give the title compound as a slightly yellowish oil: R ₁ (E) = 0.2, Ri (B) = 0.52.

b) 2 (S) -Benzyloxycarbonylamino-3-cyclohexylpropanol: 116.1 g of 2 (S) -benzyloxycarbonylamino-3-cyclohexylpropionic acid ethyl ester are initially charged in 2.21 toluene and cooled to -65 ° C. 836 ml of diisobutylaluminum hydride are added 30min. was added dropwise at -65 ⁰ C and the mixture 20 min. stirred. Then, at -65 ° C are added dropwise within 10 min methanol 84,2ml., then 825ml aqueous potassium sodium tartrate solution without cooling. the reaction mixture is heated to 31 Dissolved potassium-sodium-tartrate solution / ice and extracted with ether 51. The ether phase is washed with 21% water then immediately poured into a solution consisting of 106g semicarbazide hydrochloride and 156.5g sodium acetate in 620ml water and 620ml ethanol The reaction mixture is stirred for a further hour at room temperature, then separated off in a separating funnel and the aqueous phase is extracted with 2 × 1.51 ether The organic phase is dried over magnesium sulfate and concentrated by evaporation d purified by flash chromatography (2 kg of silica gel 60,40-63 \ im, eluent A). By evaporation of the combined product-containing fractions gives the semicarbazone of the title compound, R ₁ (G) = 0,51130g this semicarbazone are dissolved in 11THF with 282ml of 37% formaldehyde solution and then at 1O ⁰ C with 143 ml of 0.5 N HCl are added , The reaction mixture is stirred for 2 hrs. At room temperature, filtered and the filtrate washed with 0.51 water, 0.51 NaHCO ₃ and 0.51 water. The water phases are extracted with 600 ml of ether. The ether phases are dried over magnesium sulfate and evaporated. The residue is rr ^{; t} . 100 ml of toluene are added and evaporated, whereby the title compound is obtained. This will be processed immediately.

c) (1 (S) -Benzyloxycarbo, nylaminC "2-cyclohexyl-ethyl) -oxlran: 18.9 g of sodium hydride dispersion (55% in oil) are dissolved in DOmI petroleum ether (bp 40-60) in a dry sulfonating flask under argon by stirring three times ⁰ C) followed by decantation of the solvent freed from oil. After drying in a high vacuum, a gray powder is obtained, which is submitted in 500ml THF and 55,6g of trimethylsulfoxonium iodide, and the temperature rises to about 40 ° C. the gray suspension is boiled for 1 h at reflux and then admixed with a solution of 108.6 g of 2 (S) -benzyloxycarbonyl-amino-3-cyclohexyl-propanol in 250 ml of THF within 50 min at -70 ° C. The yellow suspension is distilled for 2 h. stirred at ⁰ ° C. The yellowish cloudy solution is poured onto 500 g of ice, the aqueous solution is extracted with 2.51 of ether, the organic phase is washed with water and, after drying over sodium sulphate, evaporated The oily residue is purified by flash chromatography ( 2.5 kg silica gel 60.40-63μητι, mobile phase C) separated. The product-containing fractions are combined, evaporated and dried under high vacuum. The title pre-binding (diastereomer mixture, about 4: 1) is obtained as a slightly yellowish oil. R, (I) = 0.71; R, (C) = 0.16.

d) SISI-Benzyloxycarbonylamino ^ -cyclohexyl-i-iodo-butane ^ IR.SJ-ol: 42.3 g (ifSIBenzyloxycarbonylamino ^ -cyclohexyl-ethyl) -oxirane are taken up in 200 ml of acetonitrile and the resulting solution is cooled to ⁰ ° C. After the addition of 20.9 g of sodium iodide, 30.7 ml of trimethylchlorosilane are added dropwise at ⁰ ° C. over a period of 30 minutes. The mixture is stirred for 40 min. At 0-3 ° C and then poured onto 700 ml of ice-cold water.

The aqueous mixture is extracted with ether and the organic phase washed with 750 ml of 5% aqueous sodium thiosulfate solution and 750 ml of saturated aqueous Natriumchloridlösuori. After drying over sodium sulfate and evaporation, an oily mixture of the title compound is obtained, which is further processed directly.

e) S-Benzyloxycarbonyl-LSI-cyclohexylmethyl ^^ -dlmethyl-BIRI-iodo-ethyl-IS-oxyzolldine: 49.3 g of the compound Example 1d) and 1.07y p-toluenesulfonic acid monohydrate are dissolved in 140 ml of 2,2-dimethoxypropane and 450 ml of methylene chloride 3 hours. stirred long at room temperature. The mixture is partitioned between 11% methylene chloride and 500 ml of saturated, aqueous sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product is purified by flash chromatography (3 kg silica gel 60.40-63 μιη, eluent D). Evaporation of the combined, product-containing fractions gives the title compound as a slightly yellowish oil. R, (C) = 0.55; R, (D) = 0.46.

f) P'R ^ J-ia-Benzyloxycarbonyl ^ lSl-cyclohexylmethyl ^ .a-dimethyl-ia-oxazolidinyl-SlSl-methyl-S-methyl butyric acid methyl ester: 14.3 ml of diisopropylamine are dissolved in 200 ml of absolute tetrahydrofuran under argon and brought to 0 ° C cooled. The mixture wid 20 min at 0-5 ⁰ C. Long dropwise with 65,8ml of a 1.6 M solution of n-butyllithium in hexane and 20min. touched. Then 13.3 ml Isovalerieansäuremethylester are added dropwise at -70 ° C to -75 ° C and the mixture 1.5 hr. at -75 ⁰ C stirred. At -60 ⁰ C to -75 ⁰ C werdon added dropwise with stirring 320 ml of hexamethylphosphoric triamide. The resulting suspension is stirred for 10 min. And finally treated at -7O ⁰ C to -75 ° C in 5 min. Dropwise with a solution of 43.4 g of the compound Example 1e) in 110 ml of tetrahydrofuran. The reaction mixture is allowed to stand at room temperature for 2.5h. and then poured onto a mixture of 11% saturated aqueous ammonium chloride solution and 500 g of ice. The aqueous phase is extracted with 21 ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. After evaporation, the diastereomeric mixture of the title compound is taken as a yellow oil. Ri (C) = 0.36; R ₁ (E) = 0.21 (values for the less polar component).

g) 2 (R, S). (3-Benzyloxycarbonyl. 4 (S) .cyclohexylmethyl-2,2-dimethyl-1,3-oxa-ol-nyl-5 (S) -methyl) -3-methyl-butyric acid:

16.5 g of potassium tert-butylate are in 250 ml of ether at about 5 ⁰ C with 1.77 ml of water ν irsetzt. The white suspension is stirred for 10 min. In an ice bath and then treated with 35.8 g of the compound Example 1 f) (Diastereomtrengemisch) in 250 ml of ether, the temperature is kept below 10 ° C. The reaction mixture is then kept for 18h. stirred at room temperature and finally poured onto 500 ml of saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate and the organic phase washed with saturated aqueous sodium chloride solution, dried over sodium sulfate ι, d evaporated. The oily crude product is separated by flash chromatography (2.5 kg of silica gel 60.40-63. M., medium C).

Z-Cha -VaI-OH, the less polar component of the title compound having the desired configuration of the isopropyl-bonded C atom (S configuration), is obtained as a yellow oil. R ₍ (I) = 0.20; R ₍ (J) = 0.35.

h) HCl · H-Val-Tyr-OMe: 10.0 g of Z-Val-Tyr-OMe are dissolved in 200 ml of methanol and 24 ml of 1 N HCl in the presence of 1.0 g of palladium-carbon (10% Pd) at normal pressure and room temperature hydrogenated to saturation. The reaction mixture is filtered, and the filtrate is evaporated and dried. Rf (N) = 0.64.

i) Z-Cha-Val-Val-Tyr-OMe: A mixture of 2.06 g of HCl · H-Val-Tyr-OM. , 12 g of Z-Cha-Val-OH, 1.74 g of DCCI, 1.22 g of HOBt, 0.75 g of N-methylmorpholine and 50 ml of DMF is heated for 16 h. stirred at room temperature. The DCH is filtered off, the filtrate is concentrated and dried under high vacuum. The residue is purified by flash chromatography (100 g silica gel 60, eluent B). R, (A) = 0.36.

CX

j) H-Cha ^s Val-Val-Tyr-OMe: 3.6 g of Z-Cha-Val-Val-Tyr-OMe are dissolved in 80 m of methanol-water 9: 1 in the presence of 360 mg of palladium-carbon (10% Pd). hydrogenated at atmospheric pressure and room temperature to saturation. The reaction mixture is filtered and the filtrate is diluted with 30 mL of water and heated for 5h. stirred at room temperature. After evaporation of the solvent, the title compound is lyophilized from dioxane / water 9: 1. R ₁ (H) = 0.10.

k) BOC-Val-ChaSVal-Val-Tyr-OMe is obtained starting from 1.45 g H-Cha ^s Val-Val-Tyr-OMe, 630 mg BOC-VaI-OH, 530 mg HOBH and 660 mg DCCI analogously to Example 1 i) and purified by reprecipitation from methanol-NaHCO ₃ solution. R ₁ (G) = 0.75.

I) KCl H-Val-ChaSVal-Val-Tyr-OMe: 2.16g BOC-Val-ChaiVal-Val-Tyr-OMe are dissolved in 20ml 4.3N HC! Dissolved dioxane and stirred for 30 min. At room temperature. The reaction mixture is evaporated and the residue is purified by flash chromatography (60g Kieselgel 60, eluent G). R ₍ (G) = 0.18.

m) Fmoc-Phe-Val-ChaSVal-Val-Tyr-OMe: A mixture of 240mg HCl · H-Val-ChaSVal-Val-Tyr-OMe, 170mg Fmoc-Phe-OTcp, 0.15ml N-ethyldiisopropylamine and 10ml DMF will be 20h. stirred at the residue. The reaction mixture is evaporated and the residue is precipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyophilised from dioxane / water 9: 1.

η) H-Phe-Val-ChaSVal-Val-Tvr-OMe; A solution of 305 mg of Fmoc-Phe-Val-ChaSVal-Val-Tyr-OMe, 5 ml of DMF is stirred for 60 min at room temperature and then evaporated. The residue is dissolved in a little methylene chloride and precipitated with diisopropyl ether. Dor precipitate is filtered off at ⁰ ° C. and then lyophilised from dioxane / water 9: 1. Ri (M) = 0.7.

Example 2 BBSP-Val-Val-Tyr-ChaSVal-OMe Analogously to Example 1, the title compound starting from 760 mg of HCl · H-Val-Cha ⁵ Val-Val-Tyr-OMe (Example 11), 350 mg

2 (S) -benzyl-3-tert-butylsulfonylpropionic acid (BBSP-OH), 190mg HOBt and 280mg DCCI prepared and flashed

Purified chromium tomography. R ₍ (G) = 0.50; FAB-MS (M + H) ⁺ = 913; t _R "(A) = 42.1 min. The starting material is prepared as follows:

a) 2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid (BBSP-OH): 142 g of 2 (R, S) -benzyl-3-tert-butylsulfonyl-propionic acid are mixed with 85.7 g (+) - Dehydroabietylamine and 27.8 ml of triethylamine in 21 isopropanol. After four times the crystallization of the salt from hot isopropanol, the acid is liberated again by extraction with dilute sodium carbonate solution and subsequent acidification with dilute hydrochloric acid. By recrystallization from ethyl acetate / hexane, the title compound is obtained in high optical purity (over 98% ee): [a) g ° = -10.9 ⁰ C (c = 0.91 InCH ₂ Cl ₂ ); Ömp. 99-101 ⁰ C; R ₁ (A) = 0.16; R, (B) = 0.4.

b) 2- (R, S) -benzyl-3-tert-butylsulfonyl-propionic acid: 91.9 g of ethyl 2-benzyl-3-tert-butylsulfonyl-propionate are dissolved in 500 ml of 6N hydrochloric acid and 100 ml of acetic acid for 15 h. cooked at reflux. On cooling, the title compound crystallizes directly from the reaction mixture. Mp 147-8 ⁰ C; R, (B) = 0.4; 'H-NMR (CDCl ₃ ): 1.35 (s, 9H); 2.97 (m, 1H); 3.05 (dd, 1H); 3.22 (dd, 1H); 3.45 (m, 2H); 7.25 (m, 5H); 8.5 (br, s, 1 H).

c) 2-Benzyl-3-tert-butylsulfonyl-propionic acid ethyl ester: 60 g of ethyl a-benzylacrylate are dissolved in 600 ml of ethanol and reacted with 0.83 g of sodium methylate and 37 ml of tert-butyl mercaptan. The mixture is 24h. Stirred at room temperature, diluted with 500ml 0.04 N aqueous sulfuric acid and with ice cooling with 260g Oxone * (potassium peroxomonosulfate, 50% KHSO ₆ , ventron). The reaction mixture is stirred at room temperature overnight, then filtered and concentrated. The aqueous solution is extracted with methylene chloride, the extracts dried over sodium sulfate and evaporated. Mp. 47-48 ° C; ¹ H-NMR (CDCl ₃ ): 1.13 ppm (t, 3H); 1.38 (s, 9H); 2.95 (dd, 1H); 3.01 (dd, 1H); 3.10 (dd, 1H); 3.42 (dd, 1H); 3.46 (dd, 1H); 4,12 (q, 2H); 7.25 (m, 5H).

d) a-Benzylacrylsäure-ethylester: 20g Benzylmalonsäurediethylester in 40ml ethanol are added at room temperature with 4.0g KOH in 50ml ethanol, stirred overnight at room temperature, evaporated, treated with 7.1 ml of water and concentrated in an ice bath with 6.3 ml , Hydrochloric acid acidified. It is partitioned between water and ether, the organic phase is dried and the ether distilled off. The residue is treated with 12.9 ml of pyridine 0.61 g of piperidine and 1.78 g of paraformaldehyde. The mixture is in Öibad (13O ⁰ C) for 90 min. heated, cooled, mixed with 22OmI water and extracted three times with 75ml η-hexane. The combined organic phases are washed with water, 1N HCl, water, sat. NaHCO ₃ solution and brine. The title compound is recovered by distillation. ¹ H-NMR (DMSO-d _e ): 1.2 ppm (t, 3 H); 3.6 (d, 2H); 4.1 (q, 2H); 5.6 (m, 1H); 6.15 (m, 1H); 7.25 (m, 5H).

Example 3 BBSP-Val-Val-Tyr-ChaiVal-OH A mixture of 65mg BBSP-Val-ChaSVal-Val-Tyr-OMe (Example 2), 2ml 2N NaOH and 3ml dioxane becomes 20min. at Room temperature stirred. The reaction mixture is then diluted with 2 ml of 2N HCl and lyophilized. The residue

is purified by flash chromatography (8 g silica gel, eluent H). Rf (N) = 0.53).

Example 4 BBSP Val-ChaSVal-Val-Tyr-NH: The title compound is prepared analogously to Example 2 starting from 30 mg of HCl · H-Val-ChaSVal-Val-Tyr-NH ₂ , 15 mg (2 (S) -benzyl-3-tert-butyl).

butylsulfonylpropionic acid (BBSP-OH) ₁ 8 mg HOBt and 12 mg DCCI and purified by flash chromatography on 7 g silica gel 60 (eluent F). R ₁ (G) = 0.32; FAB-MS: (M + H) ⁺ = 898; t _B "(A) = 41,7min.

The starting materials are prepared as follows:

a) HCl · H-Val-ChaiVal-Val-Tyr-N ^ is prepared starting from 360 mg of BOC-Va! -Cha * Val-Val-Tyr-NH ₂ and 5.0 ml of 4.3 N HCl in dioxane analogously to Example 11) , R, (L) = 0.3.

b) BOC-Val-ChaSVal-Val-Tyr-NHz is obtained starting from 300 mg of H-Cha * Val-Val-Tyr-NH ₂ , 147 mg of BOC-VaI-OH, 122 g of HOBH and 268 mg of DCCI analogously to Example 1 k). R, (G) = 0.33.

CX

c) H-ChaSVal-Val-Tyr-NH ₂ is obtained by hydrogenating 600 mg of Z-Cha-Val-Val-Tyr-NH ₂ in the presence of 60 mg of palladium-carbon (10% Pd) analogously to Example 1 j). R, (L) = 0.06.

au ry

d) Z-Cha -VaI-VaI-TVr-NH ₁ : A mixture of 772 mg Z-Cha-Val-Val-Tyr-OH, 590 mg NH ₄ Cl, 315 mg DCCI, 217 mg HOBt and 10 ml DMF is mixed with NaHCO ₃ adjusted to pH6.5-6.0 and then for 16h. touched. The DCH is filtered off and the filtrate is evaporated. The residue is purified by flash chromatography on 40 g of silica gel 60 (Run F). Ri (G) = 0.40.

e) Z-Cha-Val-Val-Tyr-OH is prepared starting from 790 mg of Z-Cha-Val-Val-Tyr-OMe (Example 1 i), 4 ml of 4 N NaOH and 16 ml of dioxane analogously to Example 3. R ₁ (G) = 0.07.

Example 5

N- (3-amino-3,3-dlmethylpropunuyl) -Tyr (OMe) -Val - ': ha Val-Val-Tyr-NH2!

A solution of 120 mg of N- (3-tert-butoxycarbonylanino-3,3-dimethyl-propanoyl) -tyr (OMe) -val-Cha ^; Val-Val-Tyr-NH 2 in 1.0 mL of 95% aqueous trifluoroacetic acid is added for 20 min. touched. The reaction mixture is evaporated and the residue is purified by flash chromatography on 10 g silica gel 60 (eluent 60). R ₁ (L) = 0.06, R ₁ (K) = 0.46; FAB-MS: (M + H) ⁺ = 908; t _Ret (A) = 35.6 min.

The starting materials are prepared as follows:

a) N- (3-tert-Butoxycarbonylamino-3,3-dimethylpropanoyl) -tyr (OMe) -Val-Cha ⁵ Val-Val-Tyr-NH ₂ is prepared from 90 mg of H-Tyr (OMe) -Val-ChaSVal -Val-Tyr-NH ₂ , 31 mg S-tert-butoxycarbonylamino-SS-dimethylpropionic acid, 26 mg HOBt around ¹ 34 mg DCCI analogously to Example 1 i) and purified by flash chromatography on 8 g of silica gel 60 (Laufrr.ittel G). R | (G) = 0.30.

b) H-Tyr (OMe) -Val-ChaSVal-Val-Tyr-NH ₂ is prepared starting from 260 mg of HCl H-Val-ChaSVal-Val-Tyr-NH, (Example 4a), 320 mg of Fmoc-Tyr (OMe) -OTcp and 0.15 ml of N Cthyldiisopropylamin prepared analogously to Example 1 m) and 1 n).

c) Fmoc-Tyr (OMe) -OTcp: 7, a solution of 1.45 g Fmoc-Tyr (OMe) -OH in 30 ml abs. THF at 0 ι ⁰ C 0.76 g trichlorophenol and 0.82 g DCCI gegebe ·, jnd the reaction mixture for 1 / 2h. at ⁰ ° C and then for 2h. stirred at room temperature. The DCH is filtered off from O ⁰ C, the filtrate is evaporated and the residue is crystallized from THF / hexane.

Examples

Z-Arg-Arg-Pro-Tyr (OMe) -Val-ChaSVal-Val-Tyr-NHJ

Analogously to Example 1, the title compound is obtained starting from 150 mg of H-Tyr (OMe) is -Val-Cha ^s Val-Val-Tyr-NH _2, 150 mg of Z-Arg-Arg-Pro-OH · HCl, 35mg triethylammonium, 50mg of HOBt and 68 mg DCCI manufactured. R ₍ (M) = 0.24; t _Rs , (A) = 36.3 min.

Example 7

N-UtR.SI-Benzyl-S-pivaloyl-propionyD-Nle-ChaSVal-Val-Tyr-OMD

A solution of 20 mg of HCI · H-Nle-ChaSVal-Val-Tyr-OMe, 22 mg of (R, S) -2-benzyl-3-pivaloylpropionic acid (J. Med. Chem. 31, 1839 [1988]), 33 mg of HBTU and 24μΙ triethylamine in 2ml DMF is added 2h. stirred at room temperature. The mixture is completely evaporated, the residue with sat. Sodium carbonate solution and diisopropyl ether and finally dissolved in DMF. The product is precipitated with diisopropyl ether and, after lyophilization from dioxane / tert-butanol / water, gives the title compound as a mixture of diastereomers. FAB-MS: (M + H) ⁺ = 891; R, (P) = 0.55; HPLC: 2 diastereomers in the ratio 1.8: 1, tu ,, (B) = 30.0 and 30.4 min.

The starting material is prepared as follows:

a) HCl · H-Nle-ChaiVal-Val-Tyr-OM is prepared starting from 50 mg of BOC-NI e-Cha-Val-Val-Tyr-OMe and 5 ml of 4N HCl in dioxane analogously to Example 11). The product is lyophilized from dioxane. R ₁ (P) = 0.15; t _Rl , (B) = 19.9 min.

b) BOC-Nle-ChaSVal-Val-Tyr-OMe: A solution of 60mg H-ChaSVal-Val-Tyr-OMe (Example 1j), 28mg BOC-NIe-OH, 46mg HBTU and 35μΙ triethylamine in 2ml DMF is added 3h , stirred at room temperature. The mixture is evaporated, the residue with sat. Sodium carbonate solution and diisopropyl ether and finally dissolved in DMF. The product is precipitated with diisopropyl ether and lyophilized from dioxane / tert-butanol / water. FAB-MS: (M + H) ⁺ = 761; R ₍ (P) = 0.50; t _fl "(B) = 27.9 min.

Examples

BBSP Nle-ChaSVal-Val-Tyr-OMe

Is obtained analogously to Example 7, the title compound is obtained starting from 20 mg HCI H-Nle-Cha ^£ Val-Val-Tyr-OMe (Example 7 a), 25 mg of 2 (S) -benzyl-3-tert-butyl-sulfonylpropionsäure (BBSP-OH) , 33mg HBTU and 24μΙ triethylamine, purified by flash chromatography on 10g silica gel (eluent P) and lyophilized from dioxane / tert-butanol / water. FAB-MS: (M + H) ⁺ = 927; R, (P) = 0.46; t _R "(B) = 28.0 min.

Examples

BBSP-Tyr-ChaSVal-Val-Tyr-OMe

A solution of 17 mg BBSP-Tyr (OtBu) -Cha ^s Val-Val-Tyr-OMe in 2 ml of 95% aqueous Trifluoressigsäuro is 2h. stirred at room temperature. The mixture is evaporated and the residue is purified by chromatography on 10 g of silica gel (mobile phase P). The product-containing fractions are evaporated, the residue dissolved in DMF and precipitated with diisopropyl ether. The title compound is lyophilized from dioxane / tert-butanol / water. FAB-MS: (M + H) ⁺ = 977; R ₁ (P) = 0.40; t _Re , (B) = 25.5min.

The starting material is prepared as follows:

a) BBSP-Tyr (OtBu) -ChaSVal-Val-TyrOMe is prepared analogously to Example 7 from 20 mg of H-Tyr (OtBu) -Cha ^s Val-Tyr-OMe, 22mg 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid (BBSP -OH), 30 mg HBTU and 22 μΙ triethylamine. The crude product is purified by flash chromatography on 10 g silica gel (mobile phase P) and lyophilized from dioxane / tert-butanol / water. R | (P) = 0.55.

b) H-TyrlOtBul-ChaSVal-Val-Tyr-OMe: A solution of 70mg Fmoc-TyrfOtBul-Cha ^ al-Val-Tyr-OMe in 2 ml dimethylacetamide / piperidine 30:20 (v / v) is added for 30 min Room temperature stirred. The mixture is evaporated, the residue dissolved in DMF and precipitated with diisopropyl ether. The oily residue is washed with methylene chloride, reprecipitated in DMFgelöst and at 0 ⁰ C with diisopropyl ether to give the title compound as an amorphous solid. R ₍ (P) = 0.30; t _net (B) = 22.3 min.

c) Fmo'c-TyrlOtBuJ-ChaSVal-Val-Tyr-OMe is prepared analogously to Example 7 starting from 60 mg H-Cha ^£ Val-Val-Tyr-OMe, 55 mg Fmoc-Tyr (OtBu) -OH, 46 mg HBTU and 35 μM triethylamine manufactured. The crude product is purified by flash chromatography on 20 g of silica gel (mobile phase P). The product-containing fractions are evaporated and the residue from DMF / diisopropyl ether like. R ₁ (P) = 0.60; t _Rcl (B) = 32.4 min.

Example 10

N-IZlR.Sl-Benzyl-S-pivaloyl-proplonyD-Ala-Val-ChaSVal-Tyr-OMe

A mixture of 185mg crude H-Ala-Cha-Val-Val-Tyr-OMe, 17.5mg 2 (R, S) -benzyl-3-pivaloylpropionic acid, 12.8mg HOBH, 15.6mg DCCI and 0.64ml DMF Stirred for 16 hrs. At room temperature. Analog'Example 1 is worked up, after chromatography (silica gel 60, mobile phase ethyl acetate) a Dib itereomerengemisch the title compound is obtained. FAB-MS:

(M + H) ⁺ = 849.7; R, (R) = 0.7; t _R "(B) = 27.5 and 27.9 min.

The starting material is prepared as follows:

a) H-Ala-ChaSVal-Val-Tyr-OMe: A solution of 90 mg BOC-Ala-ChaSVal-Val-Tyr-OMe in 2.3 ml of 95% aqueous trifluoroacetic acid is stirred for 1.5 hours at 0 ° C. The reaction mixture is added to the ice bath with little Wassor and neutralized the trifluoroacetic acid with solid NaHCO ₃ . The residue is washed several times with ethyl acetate, the organic phases combined and dried over sodium sulfate. After evaporation, the crude title compound is obtained. Ri (R) = 0.

b) BOC-Ala-ChaiVal-Val-Tyr-OMe: A mixture of 109.5 mg H-ChaSVal-Val-Tyr-OMe (Example 1 j), 41.6 mg BOC-Ala-OH, 59.6 mg DCCI, 39 , 8 mg of HOBH and 2 ml of DMF is stirred for 5 hours at room temperature. After cooling to ^{0 0} C and filtration is in a high vacuum at max. 6O ⁰ C distilled off the DMF. The residue is dissolved in 5 ml of methylene chloride, washed with 1 ml of aqueous sodium carbonate solution, the organic phase and dried over sodium sulfate. After evaporation, the crude title compound is purified by chromatography (38 g silica gel 60, mobile phase ethyl acetate). FAB-MS: (M + H) ⁺ = 719; Ri (R) = 0.7.

Example 11

N-UiR.Sl-benzyl-a-plvaloyl-peopionyll-Ser-ChaSVal-Val-Tyr-OMe

Analogously to Example 10, a diastereomeric mixture of the title compound is prepared starting from 80 mg of H-Ser-ChaSVal-Val-Tyr-OMe (crude product), 17.5 mg of (R, S) -benzyl-3-pivaloylpropionic acid, 12.8 mg of HOBH and 15, 8mg DCCI prepared in 0.64ml DMF.

FAB-MS: (M + H) ⁺ = 865; R ₍ (R) = 0.7; t _R "(B) = 26.68 and 26.71 min.

The starting material is prepared as follows:

a) H-Ser-ChaSVal-Val-Tyr-OMe: Analogously to Example 10a), the title compound is prepared from 95 mg of BOC-Ser-Cha ^ Val-Val-Tyr-OMe in 2.3 ml of 95% trifluoroacetic acid. R ₁ (R) = 0.

b) BOC-Ser-Cha-Val-Val-Tyr-OMe: Analogously to Example 10b), the title compound is prepared starting from 109.5 mg of H-Cha-Val-Val-Tyr-OMe, 45.1 mg of BOC-Ser-OH, 39.8 mg HOBH and 49.6 mg DCCI and purified by chromatography. FAB-MS:

(M + H) ⁺ = 735; R ₁ (R) = 0.65.

Example 12

N- (2 (R, S) -benzyl-3-pivaloyl-propionyl) -Phe-ChaSVal-Val-Tyr-OMe

48,5mg H-Phe-Cha ^£ Val-Val-Tyr-OMe and 20,8mg 2 (R, S) -benzyl-3-pivaloylpropionsäure are dissolved in 2 ml of DMF and treated with BOP and 31,7g 14,6μΙ triethylamine. The solution is stirred at room temperature for 15 h and then evaporated.

The residue is digested in a little diisopropyl ether. FAB-MS: (M + H) ⁺ = 925; Rf (S) = 0.5; Tuet (B) = 30.7 and 31.1 min.

The starting material is prepared as follows:

a) H-Phe-ChaSVal-Val-Tyr-OMe: A solution of 83 mg of Fmoc-Phe-Cha ^E Val-Val-Tyr-OMe, 2.4 ml of piperidine and 2.4 ml of DMF is stirred for 90 min. at room temperature and then evaporated. The residue is dissolved in a little methylene chloride and precipitated with diisopropyl ether. The precipitate is filtered off at 0 ^° C. and then lyophilised from dioxane / water 9: 1. FAB-MS: (M + H) ⁺ = 695; R, (Q) = 0.36.

b) Fmoc-Phe-ChaSVal-Val-Tyr-OMe: A mixture of 50mg H-Cha ⁵ Val-Val-Tyr-OMe, 67.3mg Fmoc-Phe-OTcp, 17μΙ N-ethyldiisopropylamine and 1.2ml DMF becomes 75 Min. Stirred at room temperature. The reaction mixture is evaporated and the residue is precipitated with 5 ml of diisopropyl ether. The precipitate is filtered off and precipitated a second time from DMF / diisopropyl ether. R ₁ (Q) = 0.37.

Example 13

N- (2 (R, S) -benzyl-3-pivaloyl-proplonyl) -Leu-ChaSVal-Val-Tyr-OMe

35.5 mg of H-Leu-Cha ^ al-Val-Tyr-OMe and 16 mg of (R, S) -benzyl-3-pivaloylpropionic acid are dissolved in 2 ml of DMF and admixed with 28.5 mg BOP and 11.2 μM triethylamine. After stirring at room temperature for 150 min, the mixture is concentrated and the residue is digested in 20 ml of diisopropyl ether. FAB-MS: (M + H) ⁺ = 891; R ₁ (Q) = 0.57; t _R "(B) = 30.1 and 30.4 min.

The starting material is prepared as follows:

a) H-Leu-ChaSVal-Val-Tyr-OMe: A solution of 108 mg of Fmoc-Leu-ChaSVal-Val-Tyr-OMe, 3.2 ml of piperidine and 3.2 ml of DMF is stirred for 60 min at room temperature and then evaporated , The residue is dissolved in a little DMF and precipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at ⁰ ° C. and then lyophilised from dioxane / water 9: 1. FAB-MS: (M + H) ⁺ = 661; R ₁ (Q) = 0.64.

b) Fmoc-Leu-ChaiVal-Val-Tyr-OMe: A mixture of 80mg H-Cha-Val-Val-Tyr-OMe, 101mg Fmoc-Leu-OTcp, 27.5μΙ N-ethyldiisopropylamine and 1.4ml DMF Stirred for 90 min. At room temperature. The reaction mixture is evaporated and the residue is precipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyophilised from dioxane / water 9: 1. R ₍ (Q) = 0.375.

Example 14

BBSP-Leu-Val-Tyr-ChaSVal-OMe

35.5 mg of HLeu-Cha ^ Val-Val-Tyr-OMe and 18.4 mg of (S) -benzyl-3-tert-butylsulfonylpropionic acid (BBSP-OH) are dissolved in 1 ml of DMF and treated with 28.5 mg BOP and 11, 2 μΙ triethylamine added. After 5 hours of stirring at room temperature, the mixture is concentrated and the residue is digested in diisopropyl ether. FAB-MS: (M + H) ⁺ = 927.5; Ri (Q) = 0.54; t _R "(B) = 28.0 min.

Example 15

BBSP-Leu-ChaiVal-Val-p-blphenylylmethylamid

40mg H-Leu-Val-Val-Cha ^£ p-biphenylylmethylamid and 18,4mg BBSP-OH are dissolved in 1 ml of DMF, and 28.5 mg of BOP and 11 ul of triethylamine. After 5 hours of stirring at room temperature, the mixture is concentrated and the residue is digested in diisopropyl ether. FAB-MS: (M + H) ⁺ = 916; R, (Q) = 0.58.

The starting material is prepared as follows:

a) H-Leu-Cha-Val-Val-p-Blyphenylylmethylamide: A solution of 108 mg of Fmoc-Leu-ChaSVal-Val-p-biphenylylmethylamide, 3 ml of piperidine and 3 ml of DMF is stirred for 60 min. at room temperature and then evaporated. The residue is dissolved in a little DMF and precipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at 0 ° C and then lyophilized from dioxane / water 9: 1. FAB-MS: (M + H) ⁺ = 649; R ₁ (Q) = 0.72.

b) Fmoc-Len-Cha-Val-Val-p-biphenylylmethylamide: A mixture of 100mg H-ChaSVal-Val-p-biphenylylmethylamide, 120mg Fmoc-Leu-OTcp, 35μΙ N-ethyldiisopropylamine and 2ml DMF is added 90 min - »stirred around temperature. The reaction mixture is evaporated and the residue is precipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyophilised from dioxane / water 9: 1. Ri (Q) = 0.41.

c) H-Cha ^s Val-Val-p-Blyphenylylmethylamld: 290mg of N- (5 (S) -azido-6-cyclohexyl-4 (S) -hydroxy-2 (S) -sopropylhexanoyl) -val-p-biphenylylmethyl-amide are reported in US Pat Dissolved 40 ml of methanol, mixed with 70 mg palladium carbon (5% Pd) and reduced with hydrogen. After 2 hours at room temperature, the catalyst is filtered off from the Ka Mysator, the solution is concentrated and the residue is precipitated. FAB-MS: (M + H) ⁺ = 536; R, (T) = 0.23.

d) N- (5 (S) -azido-6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopihexanoyl) val-p-bfphenylylmethylam! d: 386 mg N- (5 (S) -azido 6-cyclohexyl-1- (1-tert-butyldimethylsilyloxy) -tSHsopro, (1-hexanoyl) -Val-p-biphenylylmethylamide in 5 ml of DMF are mixed with 360 mg of tetrabutylammonium fluoride. After 4 hours, the solution is concentrated and the residue taken up in about 100 ml of ethyl acetate and gowaschen with sodium carbonate solution. After concentrating the solution, the residue is crystallized from methylene chloride / hexane. FAB-MS: (M + H) ⁺ = 562; R, (U) = 0.12.

e) N-ISIS-azido-e-cyclohexyMISl-tert-butyldimethylsilyloxy-isl-isopropyl-hexanoyl-Val-p-biphenylylmethylamide: 376 mg 5 (S) -azido-6-cyclohexyl-4 (S) -tert-butyldimethylsilyloxy-2 (S) -isopropylhexanoic acid (J. Org. Chem. 54, 117 [1989]) and 250 mg of valine-p-biphenylylmethylamide are dissolved in 100 ml DMF and treated with 404 mg BOP and 0.16 ml triethylamine. After 16 h at room temperature, it is concentrated and the residue is digested with diisopropyl ether. FAB-MS: (M + H) ⁺ - 676; R | (U) = 0.45.

f) valine p-biphenylylmethylamide; 98 μg of BOC-Val-p-biphenylylmethylamide are allowed to stand in 10 ml of dioxane / 4N HCl for 30 min at room temperature. It is then concentrated and partitioned between ethyl acetate and 1 N NaOH. The organic phase is concentrated and the residue is chromatographed on silica gel. Rf (F) = 0.4.

g) BOC-Val-p-Blyphenylylamide: 3.9 g of N-tert-butoxycarbonyl-L-valine hydroxysuccinimide ester and 2.7 g of biphenylylmethylamine are stirred in 150 ml of methylene chloride at room temperature for 1 h. The mixture is filtered through silica gel and evaporated, and the residue is crystallized from hexane. FAB-MS: (M + H) ⁺ = 383; R ₁ (U) = 0.28.

Example 16

Gelatin solution

A sterile filtered aqueous solution of Z-Arg-Arg-Pro-Phe-Val-Cha ^ al-Val-Tyr-OMe is mixed under aseptic conditions with a sterile gelatin solution containing phenol as a preservative so that 1.0 ml Solution has the following composition:

Z-Arg-Arg-Pro-Phe-Val-Val-Tyr-ChaSVal-OMe 3 mg gelatin 150.0 mg phenol 4.7 mg least. Water up to 1.0 ml

The mixture is filled under aseptic conditions in vials to 1.0 ml.

Example 17 Sterile dry substance for injection

5 mg of Z-Arg-Arg-Pro-Phe-Val-Cha-Val-Val-Tyr-OMe are dissolved in 1 ml of an aqueous solution containing 20 mg of mannitol. The solution is sterilized and filled under aseptic conditions into a 2 ml ampoule, frozen and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological saline. The solution is used intramuscularly or intravenously. This formulation can also be filled in Doppelk'ammerspritzampullen.

Example 18 Nasal Spray

In a mixture of 3.5 ml of Myglyol 812® and 0.08 g of benzyl alcohol are suspended 500 mg of finely ground (<5.0 μM ) BBSP-VaI-Chatyal-Val-Tyr-OMe. This suspension is filled into a container with metering valve. 5.0 g of Freon® are filled under pressure through the valve into the container. By shaking, the Froon® is dissolved in the myglyol benzyl alcohol mixture. This spray container contains about 100 individual doses, which can be applied individually.

Example 19 Lacquered tablets

For the production of 10000 tablets containing per 100 mg of active ingredient, the following ingredients are processed:

BBSP-Val-Chatyal-Val-Tyr-OMe 1000 g

Corn starch 680 g

Colloidal silica 200 g

Magnesium stearate 20 g

Stearic acid 50 g

Sodium carboxymethyl starch 250 g

Water q.s.

A mixture of the BBSP-Val-Val Cha ^{s-Val-Tyr-OMe,} 50g of corn starch and the colloidal silicic acid is processed with starch paste from 250g of corn starch and 2.2 kg of entmineralisiortem water to a wet mass. This is driven through a sieve of 3 mm mesh size and dried at 45 ° C for 30 min. In the fluidized bed dryer. The dry granules are forced through a 1 mm mesh screen, mixed with a previously sieved mixture (1 mm sieve) of 330 g cornstarch, magnesium stearate, stearic acid and sodium carboxymethyl starch and pressed into weakly arched tablets.

The compacts are coated in a coating pan of 45 cm diameter with a solution of 20 g shellac and 40 g hydroxypropyl methylcellulose (low viscosity) in 110 g methanol and 1350 g methylene chloride by uniform spraying for 30 min; it is dried by simultaneous injection of air at 60 ° C.

Instead of the active ingredients mentioned in Examples 16-19, it is also possible in these examples to use this amount of another active substance of the preceding examples.

Example 20 Inhibition of Isolated HIV-1 gag Protease

10μΙ of a solution of HIV-1 gag protease (acetone extract of an expressed in E. coli gag protease according to J. Hansen et al., The EMBO Journal 7,1785 [1988]) and 190μΙ ß-Morpholinoethansulfonsäure buffer solution pH 6 containing 0.01% of 2-amino-4-nitrophenol as an internal standard are preincubated at 37 ° C. Then 10μΙ of a 0.24mM DMSO solution of the substrate H-Arg-Arg-Ser-Asn-Gln-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Asn-Ile-Gln-Gly -Arg-Arg-OH (lcosapeptide according to J. Schneider et al., Cell 54,363 [1988], prepared on an automated peptide synthesizer with Fmoc-protected amino acid building holes) and 10μΙ of a DMSO solution of the compound to be tested for inhibitory activity in a concentration of 22 "10" ⁴ M or 22 χ 10 ~ ^β Μ After one hour, 50 μΙ of reaction solution are removed, mixed with 5 μΙ 0.3 M perchloric acid and centrifuged The amount of unconsumed substrate and the cleavage products in the supernatant solution are determined by HPLC and from this the percentage inhibition is calculated at 10 " ⁴ M and 10" ⁶ M. For the HPLC analysis, a 125 χ 4,6 mm reversed phase C) ₈ Nucleosil® 5 μ acid is used; gradient 10% acetonitrile / 0.1% Trifluoroacetic acid in water -> 25% acetonitrile / 0.08% trifluoroacetic acid in water in 30 min., Flow rate 1.5 ml / min. The compounds of the above Examples exhibit at concentrations of 10 ~ ⁴ M inhibitory activity of over 80% and at 10 ^"e M inhibitory activity of over 20%, usually in excess of 50%.

Example 21 Protection against HIV infection in the 7-test

The cell line MT-2 used is a human T-cell leukemia that is transformed with HTLV-1 and produces HTLV-1 continuously, making the cells extremely sensitive to the cytopathogenic effect of HIV (Science 229,563 [1985]). The MT-2 cells are cultured in RPM11640 medium containing 12% heat-inactivated fetal calf serum (Seromed Biochrom KG, Berlin, Germany), glutamine and standard antibiotics. The cells are kept in air at 37 ^° C. in a humidified atmosphere of 5% CO ₂ and used in the logarithmic growth phase for the cell assay.

HIV LAV-03 (AIDS Research and Reference Reagent Program, NIH, Bethesda, Md., USA) is cultured in A 3.01 cells. The titer is determined in the reverse transcriptase assay. For the batch used, it is 2 × 10 ⁷ IU / ml. 40,000 exponentially growing MT-2 cells in 50 μM culture medium are placed in each of the wells of a 96 round bottom titer plate. The compounds to be tested are added in a predetermined concentration in 50μΙ culture medium, and immediately after HIV in 100μΙ culture medium added. For comparison samples 100 μΙ culture medium without HIV is added. The titer plates are incubated for six days. Thereafter, the viability of the HIV-intiated and control cells is tested in the MTT assay: The MTT assay is based on the reduction of yellow-stained 3- (4,5-dimethylthiazol-2-yl) -2,5- diphenyltetrazolium-bromo: d (MTT, Sigma, St. Louis, USA) by mytochondrial dehydrogenases from metabolically active cells to a blue formazan which can be measured spectrophotometrically at 540nm (J. Virological Methods 20,309 [1988]). The viability of control cells and HIV-infected cells is also determined microscopically in a haemocytometer by the trypan blue exclusion method.

The tested compounds of the above Examples exhibit at concentrations of 10 ^"5 mol / l protective effect against HIV infection on.

Claims (50)

1. A process for the preparation of compounds of the formula • · H fH y R ΑΑΝΝ _{χ / χ / χ} • · I i • · wherein AAN is a bivalent radical consisting of one to five bivalent a-amino acid residues which is N-terminally linked to the radical R ² and C-terminal to the group NH-, AAC is a bivalent radical consisting of one or two bivalent a-amino acid residues which is N-terminally attached to the group C = O and C-terminal to the radical R ¹ , R ^{1 is} hydroxy, etherified hydroxy, amino or substituted amino except for an amino group derived from an α-amino acid, and R ^{2 is} hydrogen or an acyl radical, with the exception of an optionally N-substituted acyl radical of a natural amino acid, furthermore salts of such compounds having salt-forming groups, characterized in that a) a fragment of a compound of formula I having a terminal carboxy group or a reactive acid derivative of this fragment with a compound of the formula I complementary fragment having a free amino group or a reactive derivative thereof with activated amino group, wherein functional components present in the reaction components with the exception optionally in protected form, condensing to form an amide bond, or b) the keto group in a compound of the formula Η 0 CH (CHj) ₂ 0 -N-CH-C-CH ₂ - CH C - CH ₂ - R ² -AAN -N-CH-C-CH ₂ -CH C-AAC-R ¹ (V), in which the symbols have the abovementioned meanings and functional groups, with the exception of the keto group participating in the reaction, are optionally present in protected form, reduced to a hydroxy group by reaction with a suitable reducing agent, or c) an aldehyde compound of the formula R ² -AAN-N-CH-CH (VI), CH ₂ - C ₆ Hn wherein the symbols have the meanings mentioned and are functional groups with the exception of the aldehyde group, optionally in protected form, with an organometallic compound of the formula CH (CHj) ₂
M - CH ₂ - CH wherein the symbols have the meanings given and M is a metal radical, reacting and hydrolyzing the resulting addition product, or d) in a compound of the formula HX CH (CHa) ₂ O - AAN - N - CH - CH - CH ₂ - CH C - AAC - R ¹ CH ₂ - C ₆ Hn in which X is a nucleofugic leaving group, the other symbols have the abovementioned meanings and functional groups are optionally present in protected form, the substituent X is replaced by a hydroxy group, or e) in a compound of the f-ormel CH OH CH (CH ₃ ) 2 O R ² -AAN -N-CH-CH-CH ₂ -CH C-AAC ¹ -CN (IX), CH ₂ - C ₆ H ₁₁ wherein the symbols have the meanings mentioned and AAC has the meaning of AAC minus the terminal carbonyl group and existing functional groups optionally present in protected form, the group AAC-CN in a group AAC-R ¹ transferred, or f) in a compound of the formula IJ .0 CH (CH ₃ ) Z 0 R ² - AAN - N - CH - CH - CH - CH C - AAC - R ¹ W> CH ₂ - C ₆ H ₁₁ wherein the symbols have the meanings mentioned and functional groups are optionally present in protected form, with a regioselective reducing agent reduces the epoxy group to a hydroxy group, or g) for the preparation of a compound of formula I, wherein R ^{2 is} a radical of formula R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C- (ό) ^η > ^p ö (CH ₂ ) and m is 0 or 2, η 1 and ρ 0, a compound of the formula R ^a - (S (O) _m H or a salt thereof to a compound of the formula b fl ^l r? ^H CH (CH ₃ ) 2 o R - (CH ₂ ) -CC-AAN-N-CH-CH-CH ₂ -CH C-AAC-R ¹ (XI), ^q Ch ₂ Ch ₂ - C ₆ H ₁₁ wherein the symbols have the meanings mentioned and functional groups are optionally present in protected form, added, or h) for the preparation of a compound of the formula I, wherein R ^{2 is} a radical of the formula R ^a - 5 - (CH ₂ ) - CH - (CH ₂ ) - C, - Π. P (CH ₂ ) ^(la) and ρ 0 means a compound of the formula H OH CH (CH ₃ ) ₂ O R ^a - S - (CH ₂ ) - CH ₂ --C - AAN - N - CH - OH - CH ₂ - CH C - AAC - R ¹ IXN), (O) ⁿ 0 OH ₂ - C ₆ Hi ₁ wherein the symbols have the meanings mentioned and functional groups are optionally present in protected form, with a compound introducing the radical R ^b - (CH ₂ ) _q - alkylated, and if desired i) splitting off any protecting groups present in an available compound and / or, if desired, after carrying out one of the abovementioned processes a) -h) or any other process for the preparation of a compound of the formula I, an obtainable compound of the formula I having a salt-forming group in its salt or converting an available salt into the free compound or into another salt and / or separating off any isomer mixtures obtainable and / or reversing the configuration of a chiral carbon atom in an available compound of the formula I and / or converting a compound of the formula I into another inventive compound Converted compound of formula I. 2. The method according to claim 1, characterized in that compounds of the formula I, which have two or more α-amino acid residues in the radical AAN or wherein the radical AAN consists of only one α-amino acid residue and at the same time the radical R ^{2 is} an analog to Ph ^ nylalanyl (H-Phe) and / or have two α-amino acid residues in the radical AAC or wherein the radical AAC consists of only one α-amino acid residue and at the same time the residue R ^{1 is} an analogue to the nitrogen-bonded residue of the amino acid tyrosine (-Tyr -OH), as well as salts thereof. 3. The method according to claim 1, characterized in that compounds of the formula R ² - A5 - A4 - A3 I ···, - A2 - Al - R ¹ (H), • · O • · I i • · wherein the radial A1, A2, A3 and A4 are each a bivalent a-amino acid residue, the N-terminal with the radical in formula II in each case to the left thereof radical and C-terminal with each radical to the right thereof or with the radical R ¹ A5 is a single bond or a bivalent radical consisting of up to three peptidically linked a-amino acids, which is N-terminally connected to R ² and C-terminal to A4, and R ¹ and R ² to claim Have 1 meanings given for formula I, and salts thereof are prepared. 4. The method according to claim 3, characterized in that compounds of the formula II, wherein AI is selected from among the bivalent radicals of tyrosine, phenylalanine, naphthylalanine, tryptophan, lysine and aspartic acid, A2 is selected from the bivalent radicals of valine, isoleucine, Leucine, norleucine, phenylalanine, alanine and glycine, A3 is selected from the bivalent residues of valine, alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine. A4 is selected from the bivalent residues of phenylalanine, tyrosine, tyrosine etherified with lower alkyl, tryptophan, cyclohexylalanine, leucine, naphthylalanine, histidine, aspartic acid and lysine, and A5, R ¹ and R ^{2 have} the meanings given in claim 3, as well as salts thereof. 5. The method according to claim 4, characterized in that compounds of formula II, wherein A5 is a single bond or a bivalent radical consisting of up to three identical or different, peptide-linked α-amino acids selected from the bivalent radicals of arginine, proline , Histidine, lysine, ornithine or tryptophan, R ^{1 is} hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or a radical of the formula R ^a - s - (CH ₂ ) - CH - (CH ₂ ) -C- (i) ⁿ ι ^p δ (CH ₂ ) wherein R ^{a is} unsubstituted or substituted by hydroxy or lower alkoxy lower alkyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms, R ^b cyclohexyl or phenyl, m is 0.1 or 2, η 1, ρ 0 and q Represent 1 or 2, and salts thereof are prepared. 6. The method according to claim 5, characterized in that compounds of the formula II, wherein A5 is a single bond or the bivalent radical arginine-arginine-proline, and salts thereof are prepared. A process according to claim 3, characterized in that compounds of formula II wherein A1 is selected from the bivalent residues of tyrosine, phenylalanine, tryptophan, naphthylalanine, lysine and aspartic acid, A2 and A3 are selected from bivalent valine residues, isoleucine , Leucine, norleucine and alanine, A4 is the bivalent radical of phenylalanine, typrosine or naphthylalanine, A5 is a bond, R ^{1 is} hydroxy, Lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniederalkoxycarbonyl, Diphenylniederalkoxycarbonyl or Fluorenylniederalkoxycarbonyl, and salts thereof are prepared. 8. The method according to claim 3, characterized in that compounds of the formula II, wherein A1 is the bivalent radical of tyrosine, A2 is selected from the bivalent radicals of valine, isoleucine, norleucine, leucine, phenylalanine, alanine and glycine, A3 the bivalent A4 is the bivalent radical of phenylalanine, tyrosine or naphthylalanine, A5 is a bond, R ^{1 is} hydroxyl, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, Diphenylniederalkoxycarbünyl or Fluorenylniederalkoxycarbori, Ί, and salts thereof are prepared. 9. Verfahron according to claim 3, characterized in that compounds of the formula II, wherein A1 is the bivalent radical of tyrosine, A2 is the bivalent radical of valine or leucine, A3 is selected from the bivalent radicals of valine, leucine, isoleucine, Norleucine, alanine, asparagine, glutamine, phenylalanine, serine and histidine, A4 is the bivalent radical of phenylalanine, A5 is a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, and salts thereof are prepared. 10. The method according to claim 3, characterized in that compounds of formula II, wherein A1 is the bivalent radical of tyrosine, A2 is the bivalent radical of valine or leucine, A3 is the bivalent Resi of valine, A4 is selected from among bivalent residues of phenylalanine, tyrosine, methyletherified tyrosine, tryptophan, cyclohexylalanine, naphthylalanine and lysine, A5 is a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or lower alkoxy substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, as well as salts thereof. 11. The method according to claim 1, characterized in that compounds of the formula • « H OH ^N · ^{7 R2} " ^A3 \ / \ / \ V · V A2 - Al - R ¹ (HI), in which the radicals A1, A2 and A3 are each a bivalent α-amino acid residue which is N-terminal with the radical in formula III to the left thereof or with the radical R ² and C-terminal with the respective radical to the right thereof or is connected to the radical R ¹ , and R ¹ and R ^{2 have} the meanings given in claim 1 for formula I, and salts thereof are prepared. 12. The method according to claim 11, characterized in that compounds of formula III, wherein A1 is selected from the bivalent residues of tyrosine, phenylalanine, tryptophan, a-naphthylalanine, lysine and aspartic acid, A2 is selected from the bivalent residues of valine, isoleucine , Leucine, norleucine, phenylalanine, alanine and glycine, A3 is selected from the bivalent residues of valine, alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, and R ¹ and R ² are as defined in claim 11 Have meanings, and salts thereof are produced. 13. The method according to claim 11, characterized in that compounds of the formula III wherein A1 is selected from the bivalent radicals of tyrosine, phenylalanine, tryptophan, a-naphthylalanine, lysine and aspartic acid, A2 is selected from the bivalent radicals of valine, isoleucine, Leucine, norleucine, phenylalanine, alanine and glycine, A3 is the bivalent residue of tyrosine or lower alkyletherified tyrosine, and R ¹ and R ² are as defined in claim 11, as well as salts thereof. 14. The method according to claim 12 or 13, characterized in that compounds of the formula III, wherein R ^{1 is} hydroxy, lower-alkoxy, amino or mono- or di-lower alkylamino, and R ^{2 is} a radical of the formula R ^a - s - (CiI ₂ ) - CH - (CH ₂ ) -C- (5) ⁿ ι ^p 8 ^m (CH ₂ ) ^v da) wherein R ^{a is} unsubstituted or substituted by hydroxy or lower alkoxy Niederaikyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms, R ^b cyclohexyl or phenyl, m is 0.1 or 2, η 1, ρ 0 and q represent 1 or 2, as well as salts thereof. 15. The method according to claim 12 or 13, characterized in that compounds of the formula III, wherein R ^{1 is} hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R ^{2 is} a radical having the structural element of the formula wherein the carbocyclic ring may also be wholly or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked with C ₂ or C ₃ to form a five- or six-membered ring, one of the carbon atoms C ₂ or C ₃ by a heteroatom NH, 0 or S may be substituted, the carbonyl group may be a heterocarbonyl group P = O, and free valencies may be hydrogen or a substituent lower alkyl, lower alkylthione, lower alkylsulfinyl, lower, lower alkyl, lower alkyl, lower alkyl, lower alkanoyl lower alkyl, lower alkanoyl, lower alkanoyl lower alkyl or lower alkylcarbamoyl, as well as salts thereof. 16. The method according to claim 14, characterized in that compounds of formula III, wherein A1 is selected from the bivalent residues of tyrosine, phenylalanine, tryptophan, naphthylalanine, lysine and aspartic acid, A2 and A3 represent the bivalent radical of valine or leucine, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of the formula Ia wherein R ^{a is} lower alkyl, R ^{b is} phenyl and m is two, η is one, ρ is zero and q is one, and salts thereof getting produced. 17. The method according to claim 14, characterized in that Vorbindungen of formula III wherein A1 is the bivalent radical of tyrosine, A2 selected \? I by the bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine, alanine and Giycin, A3 the bivalent radical of valine or leucine, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of the formula Ia wherein R ^{a is} lower alkyl, R ^{b is} phenyl and m is two, η one, ρ is zero and q is one, and salts thereof are prepared. 18. The method according to claim 14, characterized in that compounds of the formula III, wherein A1 is the bivalent radical of tyrosine, A2 is the bivalent riding of valine or leucine, A3 is selected from the bivalent radicals of valine, alanine, leucine, Isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of formula Ia wherein R ^{a is} lower alkyl, R ^{b is} phenyl and m is two , η is one, ρ is zero and q is one, and salts thereof are prepared. 19. The method according to claim 15, characterized in that compounds of formula III, wherein A1 is the bivalent radical of tyrosine, A2 is the bivalent radical of valine, A3 is selected from the bivalent radicals of valine, leucine, norleucine, phenylalanine, alanine , Serine, tyrosine and lower alkyletherified tyrosine, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} 3-phenyl- or 3-cyclohexyl-propionyl; substituted in the 2-position by Niederalkylsulfonylniedoralkyl or by Niederalkanoylniederalkyl, and salts thereof are prepared.
20. The method according to claim 1, characterized in that compounds dor formula IV, u OH -N - A2 - Ri _{{| V)} where A3 is a bivalent a-amino acid residue N-terminally attached to the R ^{2 group} and C-terminal to the NH- group, A2 is a bivalent α-amino acid residue N-terminal to the group-C = O and C-terminal connected to the radical R ¹ , R ¹ N'ederalkylamino or a radical having the structural element of the formula in which the carbocyclic ring may contain a nitrogen atom and may also be wholly or partially saturated and / or subsituted by hydroxyl or by phenyl, the index ν is from zero to five, one of the carbon atoms of the carbocyclic ring having one of the atoms - ( C) _v - may be connected to a five- or six-membered ring and carry free valencies hydrogen or a substituent lower alkyl or hydroxy lower alkyl, and R ^{2 is} a solid having the structural element of the formula in which the carbocyclic ring may also be completely or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked to C ₂ or C _{3 to} a five- or six-membered ring, one of the carbon atoms C ₂ or C ₃ by a heteroatom NH, O or S may be substituted, the carbonyl group may be a heterocarbonyl group P = U, and free valencies may be hydrogen or a lower alkyl, lower alkylthione, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkanoyl, lower alkyl, Lower alkanoyl, lower alkanoyl-lower alkyl or lower alkylcarbamoyl, and salts thereof. 21. The method according to claim 20, characterized in that compounds of formula IV, wherein A2 is selected from the bivalent radicals of valine, isoleucine, norleucine, leucine, phenylalanine, alanine and glycine and A3 is selected from the bivalent radicals of valine, alanine , Leucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, as well as salts thereof. 22. The method according to claim 20, characterized in that compounds of formula IV, worm A2und A3 independently of one another in each case denote the bivalent radical of valine or leucine, and salts thereof are prepared. 23. The method according to claim 20, characterized in that compounds of formula IV, wherein A2 is the bivalent radical of valine, A3 is selected from the bivalent radicals of valine, leucine, norleucine, phenylalanine, alanine, serine, tyrosine and etherified with lower alkyl Tyrosine, R ^{1 is} lower alkylamino or a radical having the structural element of the formula Ic, in which the carbocyclic ring may be unsubstituted or substituted by hydroxyl or by phenyl, the index ν is zero to five and free valencies bear hydrogen, and R ² 3- Phenyl or S-cyclohexyl-propionyl which is substituted in the 2-position by lower alkylsulfonyl-lower alkyl or by lower alkanoyl-lower alkyl, and salts thereof are prepared. 24. The method according to claim 11, characterized in that the compound of formula III, wherein A1 is the bivalent radical of tyrosine, A2 and A3 are each the bivalent radical of valine, R ¹ methoxy and R ² 2 {S) -Benzyl-3 tert-butylsulfonylpropionyl is prepared. 25. A process for the preparation of pharmaceutical preparations, characterized in that compounds of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically suitable carrier material. 26. Compounds of the formula • · R'-AAN-A - · V · YaAC-RI (", • · 1 1 • · wherein AAN is a bivalent radical consisting of one to five bivalent a-amionic acid residues which is N-terminally linked to the radical R ² and C-terminal to the group NH-, AAC is a bivalent radical consisting of one or two bivalent a-amino acid residues which is N-terminally linked to the group CO and C-terminal to the radical R ¹ , R ^{1 is} hydroxy, etherified hydroxy, amino or substituted amino except for an amino group derived from an α-amino acid, and R ² Hydrogen or an acyl radical of a natural amino acid, furthermore salts of such compounds with salt-forming groups. 27. A compound according to claim 26, characterized in that they have in the radical AAN two or more a-Aminosäi'rereste or that the radical AAN consists of only one a-amino acid residue and at the same time the radical R ^{2 is} an analog to phenylalanyl (H-Phe ) and / or that they have two α-amino acid residues in the radical AAC or that the radical AAC consists of only one α-amino acid residue and at the same time the residue R ^{1 is} an analogue to the nitrogen-bonded residue of the amino acid tyrosine (-Tyr-OH) , as well as salts thereof. 28. Compounds according to claim 26 of the formula Y Y R ² - A5 - A4 - A3 - N · · · / · · · A2 - Al - R ¹ (H), t · I i wherein the radicals A1, A2, A3 and A4 each denote a bivalent a-amino acid residue which is N-terminal with the radical in formula II to the left thereof and C-terminal with the radical to the right thereof or with the radical R ¹ A5 is a single bond or a bivalent radical consisting of up to three peptide-linked α-amino acids, which is N-terminally connected to R ² and C-terminal to A4, and R ¹ and R ² to claim Have 1 meanings given for formula I, and salts thereof. 29. Compounds according to claim 28 of formula II, wherein A1 is selected from the bivalent residues of tyrosine, phenylalanine, naphthylalanine, tryptophan, lysine and aspartic acid, A2 is selected from bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine, alanine and glycine, A3 is selected from the bivalent residues of valine, alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, A4 is selected from the bivalent residues of phenylalanine, tyrosine, lower alkyletherified tyrosine, tryptophan, Cyclohexylalanine, leucine, naphthylalanine, histidine, aspartic acid and lysine, and A5, R ¹ and R ^{2 have} the meanings given in claim 3, and salts thereof. 30. A compound according to claim 29, wherein A5 is a single bond or a bivalent radical consisting of up to three identical or different, peptidisch linked α-amino acids selected from the bivalent Reston of arginine, proline, histidine, lysine, ornithine or tryptophan , R ^{1 is} hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, aryl-norborno-alkoxycarbonyl! or a remainder of the formula , ^Ra "(Sr ^{(CH 2)} "" T " ^{(CH:) p} ~ (CH ₂ ) wherein R ^{a is} unsubstituted or substituted by hydroxy or lower alkoxy lower alkyl, phenyl, benzyl or unsubstituieites or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms, R ^b cyclohexyl or phenyl, m is 0.1 or 2, η 1, ρ 0 and q 1 or 2, and salts thereof. 31. Compounds according to claim 30, in which A5 represents a single bond or the bivalent radical arginine-arginine-proline and salts thereof. 32. Compounds according to claim 28 of formula II, wherein A1 is selected from the bivalent residues of tyrosine, phenylalanine, tryptophan, naphthylalanine, lysine and aspartic acid, A2 and A3 are selected from the bivalent residues of valine, isoleucine, leucine, norleucine and alanine A4 is the bivalent radical of phenylalanine, tyrosine or naphthylalanine, A5 is a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^? Is hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniederalkoxycarbonyl, Diphenylnied 'alkoxycarbonyl or Fluorenylniederalkoxycarbonyl, and salts thereof. 33. Compounds according to claim 28 of formula II, wherein A1 is the bivalent residue of tyrosine, A2 is selected from the bivalent residues of valine, isoleucine, norleucine, leucine, phenylalanine, alanine and glycine, A3 is the bivalent residue of valine, A4 the bivalent radical of phenylalanine, tyrosine or naphthylalanine, A5 is a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or substituted by lower alkoxy Phenylniederalkoxycarbonyl, Diphenylniederalkoxycarbonyl or Fluorenylniederalkoxycarbonyl, and Salts thereof. 34. Compounds according to claim 28 of the formula II, in which A1 is the bivalent radical of tyrosine, A2 is the bivalent radical of valine or leucine, A3 is selected from the bivalent radical of valine, leucine, isoleucine, norleucine, alanine, asparagine, A4 is the bivalent radical of phenylalanine, A5 is a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, as well as salts thereof. 35. Compounds according to claim 28 of formula II, wherein A1 is the bivalent residue of tyrosine, A2 is the bivalent residue of valine or leucine, A3 is the bivalent residue of valine, A4 is selected from the bivalent residues of phenylalanine, tyrosine , methyl-etherified tyrosine, tryptophan, cyclohexylalanine, naphthylalanine and lysine, A5 is a bond, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} hydrogen, lower alkanoyl, lower alkoxycarbonyl, unsubstituted or lower alkoxy substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl means, as well as salts thereof. 36. Compounds according to claim 26 of the formula • · U OH ^; ^{7 R2} " ^A3 ~ \ / \ / \ i i wherein the radicals A 1, A 2 and A 3 each denote a bivalent α-amino acid residue which is N-terminal with the radical in formula III to the left thereof or with the radical R ² and C-terminal with the respective radical to the right thereof is connected to the radical R ¹ , and R ¹ and R ^{2 have} the meanings given in claim 1 for formula I, and salts thereof. 37. Compounds according to claim 36 of formula III, wherein A1 is selected from the bivalent residues of tyrosine, phenylalanine, tryptophan, α-naphthylalanine, lysine and aspartic acid, A2 is selected from the bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine Alanine and glycine, A3 is selected from the bivalent residues of valine, alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, and R ¹ and R ^{2 have} the meanings given in claim 11, and S. Use it. 38. Compounds according to claim 36 of the formula III in which A1 is selected from the bivalent radicals of tyrosine, phenylalanine, tryptophan, α-naphthylalanine, lysine and aspartic acid, A2 is selected from the bivalent radicals of valine, isoleucine, leucine, norleucine, phenylalanine, Alanine and glycine, A3 is the bivalent residue of tyrosine or lower alkyletherified tyrosine, and R ¹ and R ² are as defined in Example 11, as well as salts thereof. 39. Compounds according to claim 37 or 38, wherein R ^{1 is} hydroxy, lower alkoxy, amino or mono- or di-lower alkyla.nino, and R ^{2 is} a radical of the formula R ³ - S - (CH ₂ ) - OH - (CH ₂ ) -C- (O) ⁿ ι ^p ft (CH ₂ ) there) wherein R ^{a is} unsubstituted or hydroxy or lower alkoxy-substituted lower alkyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms, R ^{b is} cyclohexyl or phenyl, m is 0.1 or 2, η 1, ρ 0 and q represents 1 or 2, as well as salts thereof. 40. Compounds according to claim 37 or 38, wherein R ^{1 is} hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R ^{2 is} a radical with the structural element of the formula .a I i \ y is wherein the carbocyclic ring and may be fully or partially saturated, one of the carbon atoms of the carbocyclic ring by C2 or _C3 may be linked to form a five- or six-membered ring one of the carbon atoms C ₂ or C3 by a heteroatom NH, O, or S can be replaced, the carbonyl group can be a heterocarbonyl group P = O and free valencies bear hydrogen or a substituent lower alkyl, lower alkylthione, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, lower alkyl, lower alkanoyl, lower alkanoyl, lower alkanoyl lower alkyl or lower alkyl carbamoyl, represents, and salts thereof. 41. Compounds according to claim 39 of formula III, wherein A1 is selected from the bivalent radicals of tyrosine, phenylalanine, tryptophan, naphthylalanine, lysine and aspartic acid, A2 and A3 are the bivalent radical of valine or leucine, R ^{1 is} hydroxy, lower alkoxy, Lower alkylamino or amino, and R ^{2 is} a radical of the formula Ia, wherein R ^{8 is} lower alkyl, R ^{b is} phenyl and m is two, η one, ρ is zero and q is one, and salts thereof. 42. Compounds according to claim 39, of formula III, wherein A1 is the bivalent residue of tyrosine, A2 is selected from the bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine, alanine and glycine, A3 the bivalent residue of valine or leucine R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of the formula Ia in which R ^{a is} lower alkyl, R ^{b is} phenyl and m is two, η is one, ρ is zero and q is one, and salts thereof. 43. Compounds according to claim 39 of the formula III, in which A1 is the bivalent radical of tyrosine, A2 is the bivalent radical of valine or leucine, A3 is selected from the bivalent radicals of valine, alanine, leucine, isoleucine, asparagine, glutamine, Norleucine, phenylalanine, serine and histidine, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} a radical of formula Ia wherein R "is niudenealkyl, R ^{b is} phenyl and m is two, η 1 , ρ is zero and q is one, and salts thereof. 44. Compounds according to claim 40 of formula III, wherein A1 is the bivalent radical of tyrosine, A2 is the b'valent radical of valine, A3 is selected from the bivalent radicals of valine, leucine, norleucine, phenylalanine, alanine, serine, tyrosine and lower alkyl etherified tyrosine, R ^{1 is} hydroxy, lower alkoxy, lower alkylamino or amino, and R ^{2 is} 3-phenyl- or 3-cyclohexyl-propionyl substituted at the 2-position by lower alkylsulfonyl lower alkyl or lower alkanoyl lower alkyl, and salts thereof. * 45. Compounds according to claim 26 of formula IV, • · ¹ I ? ^H Y V ^X - ^XX _r A2-R ' • * I i • · wherein A3 is a bivalent a-amino acid residue N-terminally attached to the group R ² and C-terminal to the group NH-, A2 is a bivalent a-amino acid residue N-terminal to the group -C = O and C-terminal connected to the radical R ¹ , R ^{1 is} lower alkylamino or a radical having the structural element of the formula ic) - ^v \ ₌ / (Ic) wherein the carbocyclic ring may contain a nitrogen atom and may also be wholly or partially saturated and / or substituted by hydroxy or by phenyl, the index ν is zero to five, one of the carbon atoms of the carbocyclic ring with one of the atoms - (C ) _v - may be joined to a five- or six-membered ring and free valencies bear hydrogen or a substituent lower alkyl or hydroxy lower alkyl, and R ^{2 is} a radical with the structural element of the formula wherein the carbocyclic ring may also be wholly or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked with C ₂ or C ₃ to form a five- or six-membered ring, one of the carbon atoms C ₂ or C ₃ by a heteroatom NH, O or S may be substituted, the carbonyl group may be a heterocarbonyl group P = O, and free valencies may be hydrogen or a substituent lower alkyl, lower alkylthione, lower alkylsulfinyl, lower, lower alkyl, lower, lower carry, as well as salts thereof. 46. Compounds according to claim 45, wherein A2 is selected from the bivalent residues of valine, isoleucine, norleucine, laucine, phenylalanine, alanine and glycine and A3 is selected from the bivalent residues of \ alin, alanine, leucine, asparagine, glutamine, norleucine , Phenylalanine, serine and histidine, as well as salts thereof. 47. Compounds according to claim 45, wherein A2 and A3 independently of one another are each the bivalent radical of valine or leucine, and salts thereof. 48. Compounds according to claim 45, wherein A2 is the bivalent radical of valine, A3 is selected from the bivalent radicals of valine, leucine, norleucine, phenylalanine, alanine, serine, tyrosine and lower alkyletherified tyrosine, R ¹ lower alkylamino or a radical with the structural element of the formula Ic, wherein the carbocyclic ring may be unsubstituted or substituted by hydroxy or by phenyl, the index ν is zero to five and free valencies bear hydrogen, and R ^{2 is} 3-phenyl or 3-cyclohexyl-propionyl which is substituted at the 2-position by lower alkylsulfonyl-lower alkyl or lower alkanoyl-lower alkyl, and salts thereof. 49. The compound according to claim 36, wherein A1 is the bivalent radical of tyrosine, A2 and A3 are each the bivalent radical of valine, R ^{1 is} methoxy and R ^{2 is} 2 (S) -benzyl-3-tert-butylsulfonylpropionyl. 50. Pharmaceutical preparations containing compounds of claims 26 to 49 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier material. 51. Use of the compounds mentioned in claims 26 to 49 as retroviral protease inhibitors. 52. Use of the compounds mentioned in claims 26 to 49 for the preparation of pharmaceutical preparations for the control of diseases caused by retroviruses.