EP0858457A1 - 5-membered heterocycles, pharmaceutical agents containing said compounds and the use thereof and methods of producing them - Google Patents

Abstract

Disclosed are five-membered heterocycles of general formula (I) in which X1-X5 have the meanings indicated in claim 1, the tautomers and stereoisomers thereof including mixtures thereof, and the salts thereof especially those salts with physiologically acceptable acids and bases with valuable pharmacological properties, preferably aggregation-inhibiting properties. Also disclosed are pharmaceutical agents containing these compounds and the use of the compounds as well as methods of producing them.

Description

5-PIECE HETEROCYCLES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND THE USE THEREOF AND METHOD FOR THE PRODUCTION THEREOF

WO 95/14683, EP-A-O, 525, 629 and EP-A-O, 608, 858 already describe 5-membered heterocycles which have valuable pharmacological properties, preferably anti-aggregation effects.

It has now been found that the new 5-membered heterocycles of the general formula

also have valuable pharmacological properties.

The present invention thus relates to the above 5-membered heterocycles of the general formula I, which differ from the known 5-membered heterocycles by the radicals D and E, their tautomers, their stereoisomers including their mixtures and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably aggregation-inhibiting effects, medicaments containing these compounds and their use and processes for their preparation.

In the above general formula I means

one of the radicals X _] _ to X5 is a group of the formulas A - B - N

A - B - CH ^ or

A - B - , in which

A is a cycloalkyl group with 5 to 7 carbon atoms, optionally substituted by 1 to 4 alkyl groups, in which an unsubstituted methylene group is replaced by the R _a -N <group, which is additionally substituted by a cyano, ammocarbonyl, carboxy, alkoxycarbonyl - Or phenylalkoxycarbonyl group or, if the substitution is not in the α-position to a nitrogen atom, may be substituted by a hydroxy, alkoxy, phenylalkoxy group, and in the

R _{a is} a hydrogen atom, an alkyl group, a phenylalkyl group, an alkoxycarbonyl group with a total of 2 to 6 carbon atoms, a phenylalkoxycarbonyl group, an alkyleneoxycarbonyl group with a total of 4 to 6 carbon atoms, a cycloalkoxycarbonyl group with a total of 6 to 8 carbon atoms or one R] _- CO-0- (R2CH) -O-CO group in which

Rι_ an alkyl group with 1 to 5 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, a phenylalkyl group, an alkoxy group with 1 to 5 carbon atoms, a cycloalkoxy group with 5 to 7 carbon atoms or a phenyl group and

R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or a phenyl group,

and additionally in the 6- or 7-glιedrιgen azacycloalkyl groups thus formed a> CH unit in the 4-position by a nitrogen atom or in the 5- to 7-glιedrιgen azacycloalkyl groups thus formed a -CH2 "CH <unit by a -CH = C <unit and in the piperazmyl or homopiperazmyl rings thus formed one or two methylene groups which are adjacent to the nitrogen atom in the 4-position, can each be replaced by a carbonyl group, or

a quinuclidinyl group,

B is a straight-chain or branched alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 or 3 carbon atoms, a -0 (CH ₂ ) _n ~ / - ⁽ CH2 ⁾ _n ^0_ _' -S (CH ₂ ) _n -, - ( CH ₂ ) _n S-, -CONR3-, -R3NCO-, -NR3 (CH2) _n - or - (CH2) _n NR3 group, in which

n is the number 1 or 2 and

R3 represents a hydrogen atom, a phenylalkyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by an alkyl, hydroxy or alkoxy group, an alkyl or pyridylalkyl group and an oxygen, sulfur or nitrogen atom of the radical B not directly is connected to a nitrogen atom of the radical A or to a nitrogen atom of the 5-membered heterocycle,

or a bond with the proviso that a nitrogen atom of group A is not bound to a nitrogen atom of the 5-membered heterocycle,

a second of the radicals X] _ to X5 is a group of the formulas

R _b 0 - CO - FE - DN

R _b 0 - CO - F - E - D - CH _\ or

R _b 0 - CO - F - E - D - C ^, in which

D a -CO-, -CO-NR3-, -NR3-CO-, -S0 ₂ -NR ₃ -, -NR ₃ -S0 ₂ -, -W-CO-NR3-, -W; L-NR3-C0 -, -W2-S02NR3-, -W ₁ -NR ₃ S0 ₂ -, -C0-NR3-W! -, -NR3-C0-W! -, -S02NR3-W! -, -NR3SÜ2-W! -, -CO- (CH ₂ ) _n "0-, -CO- (CH ₂ ) _n - ^NR 3- '-0-Wι_-, -Wχ-0-, -S-WT _. -, -W ^ S-, - ^ - W] ^, -W ₁ -NR ₃ -, - (CH ₂ ) _n ^{~ 0} "( ^CH 2 ⁾ n- ' ^{~ (} CH ₂ ⁾ _n -NR ₃ - (CH ₂ ) _n - or-W - Group or also a -W-CO group if the 5-membered X _j _ to X5- Ring is not an isoxazole or isoxazoline ring, with the proviso that the above groups are not bonded via a carbonyl or sulfonyl group to a nitrogen atom of the 5-membered heterocycle in which

R3 and n are defined as mentioned above,

Wi is an alkylene group with 1 to 3 carbon atoms,

W2 is an alkenylene group with 2 or 3 carbon atoms and

W is an alkylene group having 1 to 3 carbon atoms or one

Represent alkenylene group with 2 or 3 carbon atoms,

E is a phenylene group which can be mono- or disubstituted by fluorine, chlorine or bromine atoms, by alkyl, trifluoromethyl, R ₃ O or R ₃ θ-CO-CH 2 ~ 0 groups, the substituents being identical or different can be and R ₃ is defined as mentioned above,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene group, each of which can be substituted in the carbon skeleton by a chlorine atom, by an alkyl or alkoxy group, with one or two -CH = N groups additionally each having a - C0-NR ₃ ~ group, in which R _{3 is} as defined above, can be replaced and one of the nitrogen atoms can be attached to the radical F instead of to the radical R ₃ , provided that this does not represent a bond can,

a cycloalkylene group with 4 to 5 carbon atoms optionally substituted by an alkyl, phenylalkyl or phenyl group, in which a> CH unit can be replaced by a nitrogen atom and additionally a methyl group adjacent to the nitrogen atom by a carbonyl group , or

a cycloalkylene group with 6 or 7 carbon atoms, optionally substituted by an alkyl, phenylalkyl or phenyl group, in which one or two> CH units can each be replaced by a nitrogen atom, with additional a methylene group adjacent to a nitrogen atom can be replaced by a carbonyl group,

F a bond,

one optionally by a phenylalkyl, phenyl, pyridyl, R ₃ 0, R3S, R3R3N, R3O-CO, R3R3N-CO, R4CO-NR3, R5O-CO-NR3, R ₄ S0 ₂ -NR ₃ -, R3R3N-CO-NR3-, R ₃ 0-CO-C ₁ _ ₃ -alkyl or R3R3N-CO-Cι_3-alkyl group substituted straight-chain or branched alkylene or alkenylene group, in each of which the alkylene part 1 can contain up to 5 carbon atoms and the alkenylene part 2 to 5 carbon atoms, or a -Y-Wχ group in which

R3 and Wi are defined as mentioned above, R4 is an alkyl group with 1 to 5 carbon atoms, a phenylalkyl, phenyl or pyridyl group,

R5 is an alkyl group with 1 to 5 carbon atoms, a phenylalkyl, cycloalkyl or cycloalkylalkyl group and Y is an oxygen atom, a -CO-, sulfenyl-, sulfinyl-, sulfonyl-, -NR ₃ -, -N (C0R4) -, -N (S0 ₂ R4) -, -CO-NR3- or -NR3-CO- group, where Y is linked to the radical E with the proviso that a heteroatom of the radical E is not attached to a nitrogen or sulfur atom of the above groups is bound,

and R _{b is} an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 5 to 7 carbon atoms in the cycloalkyl part, it being possible for the above-mentioned groups in the alkyl and cycloalkyl part from position 2 in each case to be substituted by an R3O or R3R3N group , an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl part, which can be substituted in the alkyl part from position 2 by an R3O or R3R3N group, where R3 is in each case as defined above , a Rι_-CO-0- (R2CH) group in which R] _ and R2 are defined as mentioned above, or a hydrogen atom, if the RκO-CO group is not directly bound to a nitrogen atom of the radical E,

wherein the distance between the furthest nitrogen toffatom the group A and the group COORκ compounds is at least 11 Bin¬ as well as the above-mentioned AB and R _j - _j O-CO- FED-groups in 1,3-position to each other stand,

a third of the residues Xi to X5 is a sulfur atom, an HN <,

R ₄ N <, R7C-v ^. or (R7) 2C <group or an N atom, where

R4 is as defined at the beginning and

R7 represents a hydrogen atom, an alkyl, phenylalkyl or phenyl group,

a fourth of the radicals Xi to X _{5 is} an oxygen, sulfur or nitrogen atom or an R ₇ C ^^ group in which R ₇ is defined as mentioned above,

a fifth of the residues Xη_ to X5 eiiji nitrogen atom, an R-7C ^. or (R7) 2C <group, where R7 is defined as mentioned above,

or two adjacent radicals of the radicals X ^ to X5 together form an o-phenylene group, but at least one of the radicals Xl to X5 in the aforementioned X 1 ~ X 5 ring must be a ring hetero atom,

unless otherwise mentioned,

the alkyl, alkylene or alkoxy parts mentioned above can each contain 1 to 3 carbon atoms and the cycloalkyl parts mentioned above can each contain 3 to 7 carbon atoms. The general formula I mentioned above thus includes, for example, the correspondingly substituted furan, tetrahydrofuran, 2,3-dihydro-furan, 2,5-dihydro-furan, thiophene, 2,3-dihydro-thiophene , 2, 5-dihydro-thiophene, tetrahydrothiophene, pyrrole, indole, isoindole, 2,3-dihydro-indole, 2,3-dihydro-isoindole, imidazole, 4,5 -Dιhydro-ιmιdazol-, tetrahydro- imidazole-, benzimidazolm-, pyrazole-, 4, 5-dιhydro-pyrazole-, 2, 3-dιhydro-pyrazole-, indazole, 2, 3-dιhydromdazole-, oxazole-, isoxazole , Oxazoline, oxazolidm, isoxazoline, thiazole, isothiazole, thiazolm, thiazolidine, 1, 3, 4-0xadιazol-, 1,2,4- oxadiazole-, 1, 3, 4-thιadιazol- , 1, 2, 4-thιadιazole, 1,2,3-trιazole, 1, 2, 4-trιazole and tetrazole derivatives.

However, preferred compounds of the general formula I are those in which

one of the residues Xi to X5 is a group of the formulas

A - B - N

A - B - CHC _^ . bleak

A - B - C ^^ in which

A is a cycloalkyl group with 5 to 7 carbon atoms, optionally substituted by 1 to 4 alkyl groups, in which an unsubstituted methylene group is replaced by the R _a -N <group, which is additionally replaced by a cyano, aminocarbonyl, carboxy or alkoxycarbonyl group or also if the substitution is not in the α-position to a nitrogen atom, can be substituted by a hydroxy or alkoxy group, and in which

R _{a is} a hydrogen atom, an alkyl, phenylalkyl, alkoxycarbonyl or phenylalkoxycarbonyl group or an Rl-CO-0- (R2CH) -O-CO group in which Rl is an alkyl, cycloalkyl, phenyl, alkoxy or cycloalkoxy group each having 5 to 7 carbon atoms in the cycloalkyl part and

R2 represents a hydrogen atom or a methyl group,

and additionally in the 6- or 7-membered azacycloalkyl groups thus formed a> CH unit in the 4-position by a nitrogen atom or in the 5- to 7-membered azacycloalkyl groups thus formed a -CH2 ~ CH <unit by a -CH = C <unit can be replaced, or

a quinuclidinyl group,

B is an alkylene group with 1 to 5 carbon atoms, an alkylene group with 2 or 3 carbon atoms, an -OCH2-, -CH ₂ 0-, -SCH ₂ -, -CH ₂ S-, -CONR3-, -R3NCO-, - NR ₃ CH ₂ or -CH2NR3 group in which

R3 represents a hydrogen atom, an alkyl, phenylalkyl or pyridylalkyl group and an oxygen, sulfur or nitrogen atom of the radical B is not directly connected to a nitrogen atom of the radical A or to a nitrogen atom of the 5-membered heterocycle,

or a bond with the proviso that a nitrogen atom of group A is not bound to a nitrogen atom of the 5-membered heterocycle,

a second of the radicals Xi to X5 is a group of the formulas

R _b 0 CO - F - EN

R _b 0 - CO F - ED - CH or

Rl _vb .00 - CCOO - FF - EE - DD -, in which D a -CO-, -CO-NR3-, -NR3-CO-, -SO2-NR3-, -NR ₃ -SO2-, -W-CO-NR ₃ -, -W1-NR3-CO-, -W1 -SO2NR3-, -W1-NR3SO2-, -CO-NR3-W1-, -NR3-CO-W1-, -S0 ₂ NR ₃ -Wι-, -NR3S02-W! -, -CO-CH ₂ -0- , -CO-CH ₂ -NR ₃ -, -O-Wi-, -Wι-0-, -SW! -, -Wi-S-, -NR3-W! -, -W1-NR ₃ -, -CH2 -0-CH ₂ -, -CH2-NR3-CH2 or -Wi group or also a -W-CO group, if the 5-membered Xi to X5 ~ ring is not an isoxazole or isoxazoline ring, with the proviso that that the above groups are not linked via a carbonyl or sulfonyl group to a nitrogen atom of the 5-membered heterocycle in which

R ₃ is defined as mentioned above,

Wi is an alkylene group with 1 to 3 carbon atoms,

W2 is an alkenylene group with 2 or 3 carbon atoms and

W is an alkylene group having 1 to 3 carbon atoms or one

Represent alkenylene group with 2 or 3 carbon atoms,

E is a phenylene group which can be substituted by a fluorine, chlorine or bromine atom, by an alkyl, trifluoromethyl, R ₃ O or R ₃ θ-CO-CH2 ~ 0 group, R ₃ as before ¬ standing is mentioned,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group, each of which can be substituted in the carbon skeleton by an alkyl or alkoxy group,

a 1,4-cyclohexylene group in which one or two> CH units can each be replaced by a nitrogen atom, it being possible for a methylene group adjacent to a nitrogen atom to be replaced by a carbonyl group,

a 1,3-cyclohexylene group in which a> CH unit can be replaced by a nitrogen atom, in which case a methylene group adjacent to the nitrogen atom can then be replaced by a carbo- ¹ -nyl group, a 1,3-pyrrolidinylene, 2-oxo-l, 3-pyrrolidinylene, 5-oxo-l, 3-pyrrolidinylene or 1,4-homopiperazinylene group,

F a bond,

a straight-chain or branched alkylene group with 1 to 5 carbon atoms or one optionally substituted by a phenyl, pyridyl, R3O, R4CO-NR3, R5O-CO-NR3, R4SO2-NR3 or R3R3N-CO-NR ₃ group or one -Y-Wι ~ group in which

R3 and Wi are defined as mentioned above,

R4 is an alkyl group of 1 to 5 carbon atoms, one

Phenylalkyl, phenyl or pyridyl group,

R5 is an alkyl group of 1 to 5 carbon atoms or one

Phenylalkyl group and

Y is an oxygen atom, a sulfenyl, -NR3-, -N (C0R4) - or

-N (Sθ2R4) group, where Y with the rest E with the

Provided that a hetero atom of the radical E is not bound to a nitrogen or sulfur atom from the above groups,

and R _{b is} an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 5 to 7 carbon atoms in the cycloalkyl part, which in the alkyl and cycloalkyl part from position 2 onwards can each be substituted by an R3O or R3R3N group, an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl part, which can be substituted in the alkyl part from position 2 by an R3O or R3R3N group, where R3 is defined as mentioned above, a R1 CO-0- (R2CH) group in which R 1 and R 2 are defined as mentioned above, or also a hydrogen atom if the R _b O-CO group is not bonded directly to a nitrogen atom of the radical E,

the distance between the most distant nitrogen atom of group A and the COORκ group is at least 11 binary fertilize and the above-mentioned AB and R _b O-CO-FED groups are in the 1,3 position to one another,

a third of the radicals Xi to X5 is a sulfur atom, an HN <, R ₄ N <, R ₇ C <^ or (R ₇ ) ₂ C <group or an N atom, where

R4 is as defined at the beginning and

R _{7 represents} a hydrogen atom, an alkyl, phenylalkyl or phenyl group,

a fourth of the radicals X j to X 5 ^'is defined as mentioned above R a R ₇ C ^ C group in which R ₇ is an oxygen, sulfur or nitrogen atom ode,

a fifth of the radicals Xi to X5 is a nitrogen atom, an R ₇ Cx or (R ₇ > 2C <group, where R ₇ is defined as mentioned above,

or two adjacent residues of the residues Xi to X5 together denote an o-phenylene group, but at least one of the residues Xi to X5 in the aforementioned X 1 ~ X 5 ring must be a ring hetero atom,

unless otherwise mentioned,

the alkyl, alkylene or alkoxy parts mentioned above can each contain 1 to 3 carbon atoms,

their tautomers, their stereoisomers including their mixtures and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases.

However, particularly preferred compounds of the general formula I are those in which one of the residues Xi to X5 is a group of the formulas

A - B - N - ^ or

A - B - C <- ^., In which

A is a cycloalkyl group with 5 or 6 carbon atoms in which an unsubstituted methylene group in the 3- or 4-position is replaced by the R _a -N <group in which

R _{a represents} a hydrogen atom, a Cι_2-alkyl, Cι_4-alkoxycarbon- yl or benzyloxycarbonyl group,

and in the 4-piperidinyl groups thus formed, a> CH unit in the 4-position can be replaced by a nitrogen atom,

B is a bond, a Cι_2-alkylene, -OCH2 or -CH2θ group,

a second of the radicals Xi to X5 is a group of the formulas

R _b 0 - CO DN or

R _H 0 - CO - F - E - D - CX "" - ^, in which

D is -CO-, -CO-NR3-, -NR3-CO-, -W-CO-NR3-, -CO-NR ₃ -W1-, -NR3-CO-W1-, -CO-CH ₂ -0 -, -O-Wi-, -Wι ~ 0- or -Wι ~ group or also a -W-CO group if the 5-membered Xi to X5 ~ ring is not an isoxazole ring, with the proviso that the vorste¬ groups are not bound via a carbonyl group to a nitrogen atom of the 5-membered heterocycle in which

R3 is a hydrogen atom, a C 4 alkyl, benzyl or pyridylmethyl group, Wi a Cι_2 alkylene group and

W represent a C 2 alkylene or vinylene group,

E is a 1,4-phenylene group, which can be substituted by a hydroxy, methoxy, carboxymethoxy or methoxycarbonylmethoxy group,

a 1, 4-cyclohexylene group in which one or two> CH units can each be replaced by a nitrogen atom,

F a bond,

a straight-chain or branched alkylene group with 1 to 3 carbon atoms, optionally substituted by an R4CO-NR3 or R4Sθ2 ~ NR3 group, or a -Y-Wι ~ group in which

R3 and Wi are defined as mentioned above, R4 represents a methyl, ethyl or phenyl group and Y represents an oxygen atom, an -NR3 or -N (SO2R4) group, Y being linked to the radical E with the proviso that a nitrogen atom of the radical E is not bound to a nitrogen atom of the above groups and R3 and R4 are defined as mentioned above,

and R _{b is} a C 5 alkyl, cyclohexyl or benzyl group or also a hydrogen atom if the R _b O-CO group is not bonded directly to a nitrogen atom of the radical E,

wherein the distance between the most distant nitrogen atom of group A and the COOR _b group is at least 11 bonds and the above-mentioned AB and R _b O-CO-FED groups are in the 1,3 position to one another ,

a third of the radicals Xi to X5 is an HN <, R41NK or R ₇ C group or a nitrogen atom, where R4 is as defined at the beginning and

R _{7 represents} a hydrogen atom, a C 2-2 alkyl or phenyl group,

a fourth of the radicals X] _ to X5 is an oxygen, sulfur or nitrogen atom or an R ₇ C ^^ group in which R _{7 is} defined as mentioned above,

a fifth of the radicals Xi to X _{5 is} a nitrogen atom or an R ₇ C ^ ~

Mean group, where R ₇ is defined as mentioned above and at least one of the radicals Xi to X5 in the above-mentioned X 1 ~ X 5 ring must be a ring hetero atom,

their tautomers, their stereoisomers including their mixtures and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases.

However, very particularly preferred compounds of the general formula I are those in which

one of the residues Xi to X5 is a group of the formulas

A - B - N - _^ or

A - B - C- ^ s. , in which

A is a cyclohexyl group in which an unsubstituted methylene group in the 4-position is replaced by the R _a -N <group in which

R _{a represents} a hydrogen atom, a Cι_4-alkoxycarbonyl or benzyloxycarbonyl group,

B is a bond or a C 2 alkylene group, a second of the radicals Xi to X5 is a group of the formulas

R _b O - CO - F - E - D - N \ or

R _h O - CO - F - E - D - C / ^u -s ^, in which

D a -CH ₂ CH ₂ -, -CO-, -CH ₂ -0-, -CH ₂ CH ₂ -CO-, -CH = CH-CO-, -CO-NR3-, -NR3-CO-, - CH ₂ CH ₂ -CO-NR ₃ -, -CO-NR ₃ -CH ₂ - or -CO-NR3-CH2CH2 ~ group with the proviso that the above groups are not bound via a carbonyl group to a nitrogen atom of the 5-glιederιgen heterocycle smd in which

R3 represents a hydrogen atom or a pyridylmethyl group,

E eme 1, 4-phenylene, 1, 4-cyclohexylene, 1, 4 -Pιperιdιnylen- or 1, 4-Pιperazmylengruppe,

F a bond,

eme -CH ₂ -, -CH ₂ CH ₂ -, -0-CH ₂ -, -0-CH ₂ CH ₂ - or -N (S0 ₂ CH ₃ ) -CH ₂ "group,

and R _b eme Cι_4-alkyl or cyclohexyl group or a hydrogen atom if the R _b O-CO group is not bonded directly to the nitrogen atom of the radical E,

wherein the distance between the most distant nitrogen atom of group A and the COORκ group is at least 11 bonds and the AB and R _b O-CO-FED groups mentioned above are at a 1.3 pitch,

em third of the residues Xi to X5 em nitrogen atom or an ^R 7 ^{C <} _sNs group in which

R _{7 represents} a hydrogen atom or a methyl group, a fourth of the radicals Xi to X5 is a sulfur or nitrogen atom or an R ₇ C ^" ^^ group in which R ₇ is defined as mentioned above,

a fifth of the radicals Xi to X5 is a nitrogen atom or an R ₇ C ^ ~ ^'

Are a group, where R ₇ is defined as mentioned above and at least one of the radicals Xi to X5 in the above-mentioned X _] _-X5 ring must be a ring heteroatom,

their tautomers, their stereoisomers including their mixtures and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

The following may be mentioned as particularly preferred compounds:

(1) 4- [[trans-4- (2-carboxy-ethyl) cyclohexyl] -ammocarbonyl] -

1- (4-pιperιdyl) imidazole,

(2) 5- [[trans-4- (2-carboxy-ethyl) -cyclohexyl] -ammocarbonyl] - 4-methyl-2- (4-pιperιdyl) -1, 3-thιazole,

(3) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -4-methyl- 2- (4-pιperιdyl) -1, 3-thιazole,

(4) 5- [[trans-4- (2-carboxy-ethyl) -cyclohexyl] -ammocarbonyl] - 2- (4-pιperιdyl) -1, 3, 4-thιadιazol,

(5) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-pιperidyl) -1,3,4-thιadιazole,

(6) 5- [[trans-4- (carboxymethyloxy) cyclohexyl ]ammocarbonyl] -

2- (4-pιperιdyl) -1, 3-thιazol, (7) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole,

(8) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole,

(9) 4- [[trans-4-carboxy-cyclohexyl] aminocarbonyl] -1- [2- (4-piperidyl) ethyl] imidazole,

whose Cι_4-alkyl and cyclohexyl esters and their salts.

According to the invention, for example, the new compounds are obtained by the following methods:

a) For the preparation of a compound of general formula I in which R _{a has} a hydrogen atom and R _b, with the exception of the Rl-CO-0- (R2CH) group, has the meanings mentioned at the outset for R _b , R _{a has} the entry at R _a has the meanings mentioned and R _{b represents} a hydrogen atom or R _a and R _b each represent a hydrogen atom:

Conversion of a compound of the general formula

in which one of the residues Xi to X5 is a group of the formulas

A ¹ - B - cζ. , in which

B is as defined at the beginning and A 'has the meanings mentioned for A at the outset and additionally contains a protective radical which can be split off for an imino group,

a second of the radicals Xi to X5 is a group of the formulas

R _b '0 - CO - F - E - D - N ^ ^"

R _b '0 - CO - F - E - D - CH ^ or

R _b "0 - CO - F - E - D - C <v ^, in which

F, E and D are as defined at the beginning and

RK, ^{1 has} the meanings mentioned for R _b and additionally represents a protective radical which can be removed from a hydroxyl group of a carboxyl group, but at least one of the radicals A ¹ or RK, 'must contain or represent a removable protective radical,

and the rest of the residues Xi to X5 are as defined at the outset,

by hydrolysis, treatment with an acid or base, thermal analysis or hydrogenolysis into a compound of general formula I in which R _a em hydrogen atom and R _b, with the exception of the R ~ CO-0- (R 2 CH) group for the R _{b has the} meanings mentioned at the outset, R _{a has} the meanings mentioned for R _a and R _b em is a hydrogen atom or R _a and R _{b are} each a hydrogen atom.

Protective groups for an imino group can be, for example, acyl groups such as the formyl, acetyl, trifluoroacetyl or benzoyl group and carbonic acid ester residues such as the allyloxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl or benzyloxycarbonyl group by means of hydrolysis, Arylmethyl groups such as the benzyl group or arylmethyloxycarbonyl groups such as the benzyloxycarbonyl group by means of hydrogenolysis and

Carbonic acid ester residues with tertiary alcohols such as the tert-butyloxycarbonyl group can be split off by treatment with an acid or thermolysis and

Protective groups for a hydroxyl group of a carboxy group can be, for example, the functional derivatives of a carboxy group such as their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or immoesters by means of hydrolysis in a carboxyl group,

Esters with tertiary alcohols, e.g. the tert. Butyl ester, by means of treatment with an acid or thermolysis in a carboxy group and

Esters with aralkanols, e.g. the benzyl ester can be converted into a carboxyl group by means of hydrogeolysis.

The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as Water, methanol, ethanol, isopropanol, ether, tetrahydrofuran, dioxane, methylene chloride or their mixtures at temperatures between -10 and 120 ° C, for example at temperatures between 0 ° C and the boiling point of the reaction mixture,

the hydrogenolysis expediently with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, glacial acetic acid or trifluoroacetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C. preferably however at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar,

the thermolysis expediently by heating, if appropriate in the presence of an acid such as trifluoroacetic acid and

the treatment with an acid is conveniently carried out in the presence of an acid such as trifluoroacetic acid, hydrogen bromide / glacial acetic acid or hydrogen chloride, optionally using a solvent such as methylene chloride, tetrahydrofuran, dioxane, methanol, ethanol, ether or mixtures thereof.

To prepare a compound of the general formula I in which R _{a represents} a hydrogen atom and R _b with the exception of the Rl-CO-O- (R2CH) group is as defined in the introduction, a corresponding compound of the general formula II is preferably m A 'contains a benzyloxycarbonyl group and R _b ' is defined as mentioned above, using hydrogen bromide / glacial acetic acid at room temperature

or a corresponding compound of the general formula II, in which A 'contains a tert-butyloxycarbonyl group and R _b ' is defined as mentioned above, by means of trifluoroacetic acid / methylene chloride at room temperature

or a corresponding compound of the general formula II, in which A 'contains tert-butyloxycarbonyl group and R _b ' represents an alkyl group, by means of hydrogen chloride in a corresponding alkanol, for example in methanol, methanol / ether or methanol / dioxane / ether Room temperature converted into the desired compound,

or for the preparation of a compound of the general formula I in which R _a em represents a hydrogen atom, a C 1-3 alkyl or phenyl C 3 alkyl group and R _b em represents a hydrogen atom, preferably a corresponding compound of the general formula II in which A ' has the meanings mentioned for A at the outset and R 'is defined as mentioned above, using an acid such as hydrochloric acid or using a base such as sodium hydroxide or lithium hydroxide in a solvent such as methanol, tetrahydrofuran, water or mixtures thereof at temperatures between 0 ° C. and the boiling point of the solution used ¬ medium, but preferably at temperatures between 0 and 40 ° C,

or a corresponding compound of the general formula II, in which A 'contains a benzyloxycarbonyl group and R _b ' represents a tert-butyl group, using an acid such as hydrogen bromide / glacial acetic acid at temperatures between 0 ° C. and the boiling point of the solvent used, but preferably at temperatures between 0 and 40 ° C, converted into the desired compound.

For example, means RK. ' in a compound of formula II the tert. Butyl group and / or R _a the tert. Butyloxycarbonyl¬ group, these groups are particularly advantageous by treatment with an acid such as trifluoroacetic acid, formic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, hydrogen bromide, phosphoric acid or polyphosphoric acid, optionally in a solvent such as methylene chloride, chloroform, Benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol or their mixtures preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or also thermally, if appropriate, in an inert solvent such as methylene chloride, Chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used, for example at temperatures between 40 and 120 ° C.

If, for example in a compound of the general formula II, R _a eme benzyl or benzyloxycarbonyl group and R _b em benzyl group, these protective groups are particularly preferred. partially hydrogenolytically with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C., for example at room temperature, and one Split off hydrogen pressure from 1 to 5 bar.

If a hydrobromide is used as the starting compound in the hydrolysis of ester by means of hydrochloric acid, the corresponding hydrobromide is preferably obtained after evaporation of the hydrochloric acid and after recrystallization after evaporation of the hydrochloric acid.

b) For the preparation of a compound of the general formula I in which four of the radicals Xi to X5 are as defined above and the last radical of the radicals Xi to X5 is an R _b O-CO-FED-CH <,

R _{b represents} -CO-FEDN <or group in which

D a -CO-NR3-, -NR3-CO-, -S0 ₂ -NR ₃ -, -NR ₃ -S0 ₂ -, -W-CO-NR3-, -W1-NR3-CO-, -Wι-S0 ₂ NR ₃ -, -Wι-NR ₃ S0 ₂ -, -CO-NR3-W1-, -NR3-CO-W1-, -SO2NR3-W1- or -NR3Sθ2 ~ Wι group or D together with the hydrogen atom of an im Rest E present imino group means a -CO- or -W-CO group means:

Implementation of a compound of the general formula

with a compound of the general formula

Ui - E - F - CO - 0R _b , (IV)

in which

E, F, R _b with the exception of the Rι-CO-0- (R2CH) -O-CO group and four of the radicals Xi to X5 as defined above, the last of the radicals Xi to X5 is a Zι ~ CO, Z1-SO2, Zι ~ CO-W or Zι-Sθ2 ~ Wι group and

Ui is a hydrogen atom of an imino group of the radical E, an HNR3 or HNR3 ~ W group or the last of the radicals Xi to X5 an HNR3 or HNR3-W1 group and

Ui mean a Z2-CO, Z2-SO2 / Z2-CO-W1 or Z2 ~ S02-W group, in which

R3, W and Wi are as defined in the beginning,

Zi or Z2 denotes a nucleofugic leaving group such as a hydroxycarboxylic group is a halogen atom, eg a chlorine or bromine atom, an imidazolyl, 4-nitrophenyloxy or benzotriazol-1-oxy ^■.

The reaction is conveniently carried out in a solvent such as methylene chloride, dimethylformamide, dimethyl sulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, dioxane or mixtures thereof, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyciohexylcarbodiimide, N, N'-dicyclohexylcarbodiimine / benzotriazole (N-hydroxysulfide), 1-yl) - 1, 1, 3, 3-tetramethyluronium salts such as 2- (1H-benzotriazol-1-yl) - 1,1,3, 3-tetramethyluronium tetrafluoroborate, N, N '-thionyldiimidazole, N, N '-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of 4-dimethylaminopyridine or 1-hydroxy-benzotriazole and / or a base such as triethylamine, N-ethyl-disopropylamine, N-methyl-morpholine or pyridine Temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, carried out.

However, the sulfonic acid amides of the general formula I are obtained particularly advantageously by reacting a corresponding sulfonic acid halo, which is genids, preferably the chloride, with an appropriate amine.

c) For the preparation of a compound of the general formula I in which D represents a -CH2CH2-CO-NR3 or -CH ₂ CH2CH2-CO-NR ₃ group:

Catalytic hydrogenation of a compound of the general formula

in the

Xl to X5 are as defined in the introduction, with the proviso that D in the second of the radicals Xi to X5 contains an alkenylene group with 2 or 3 carbon atoms.

The catalytic hydrogenation is preferably in a medium Lösungs¬ as water, methanol, ethanol, tetrahydrofuran, dioxane or mixtures thereof at temperatures between 0 and 100 ^C C., preferably at temperatures between 20 ° C and the boiling temperature of the solvent used, carried out with hydrogen in the presence of a hydrogenation catalyst, for example in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.

d) for the preparation of a compound of the general formula I in which RK is an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group each having 5 to 7 carbon atoms in the cycloalkyl part, represents a Rl-CO-0- (R2CH) group: Implementation of a compound of the general formula

in the

Xl to X5 smd defined as hereinbefore with the proviso that _RK, em hydrogen atom, with a compound of my corresponding to general formula

HO - R _b , (VII)

or with a compound of the general formula

Z ₃ - R _c , (VIII)

in which

RK, an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group each with 5 to 7 carbon atoms in the cycloalkyl part,

R _c eme alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group each with 5 to 7 carbon atoms in the cycloalkyl part, an Rl-CO-0- (R2CH) - Group in which

Rl and R2 as initially defined smd, and Z3 a leaving group such as a halogen atom, e.g. B. em chlorine or bromine.

The reaction with an alcohol of the general formula VII is advantageously carried out in a solvent such as methylene chloride, benzene, toluene, chlorobenzene, ether, tetrahydrofuran, dioxane or mixtures thereof, but preferably in an alcohol of the general formula VII, if appropriate in the presence of a Acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or in the presence of a dehydrating agent By means, for example, in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyciohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldi Thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine, advantageously at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C.

With a compound of the general formula VIII, the reaction is advantageously carried out in a solvent such as methylene. Chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N -Ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent, or, if appropriate, in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C , carried out.

e) For the preparation of 1, 3,4-oxathiazole, 1, 3, 4-thiadiazole and 1, 3, 4-triazole derivatives of the general formula I:

Cyclization of a compound of the general formula optionally formed in the reaction mixture

N - N. _A - B - CC - E - F - CO - R _b <<I ^χ >

Z ₄ ^Z 5 in the

Z4 and Z5, which may be the same or different, halogen atoms, amino groups optionally substituted by R7, where in R7 as defined at the outset, represent hydroxyl, alkoxy, mercapto or alkyl mercapto groups.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, 1,2-dichlorobenzene or pyridine at temperatures up to the boiling point of the solvent used, e.g. at temperatures between 20 and 180 ° C.

If in a tautomeric compound of the general formula VI Z4 and Z5 each represents a hydroxyl group, the reaction is preferably carried out in the presence of a dehydrating agent such as thionyl chloride for the preparation of a 1, 3, 4-olderxadiazole derivative,

to prepare a 1, 3, 4-thiadiazole derivative, the reaction preferably in the presence of a sulfur-introducing reagent such as, for example, 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane-2, 4-disulfide and

to prepare a 1, 3, 4-triazole derivative, the reaction is preferably carried out in the presence of a halogen-introducing agent such as phosphorus trichloride and in the presence of aniline.

In the reactions described above, any reactive groups present, such as carboxy, amino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.

For example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and comes as a protective radical for a carboxyl group as a protective radical for an amino or imino group, the formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl group and for the amino group ¬ additionally the phthalyl group into consideration.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or lithium hydroxide or by means of ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or ether.

A trifluoroacetyl radical is preferably cleaved off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at structures between 50 and 120 ° C or by treatment with sodium hydroxide solution or aqueous lithium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.

An allyloxycarbonyl radical is cleaved off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an allyl group acceptor such as morpholine or 1,3-dmedon at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1.4 -Dιazabιcyclo [2.2.2] octane at temperatures between 20 and 70 ° C.

A phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

For example, the cis / trans mixtures obtained can be chromatographed in their ice and trans isomers, the compounds of general formula I obtained which occur in racemates, by methods known per se (see Allmger NL and Eliel EL m "Topics m Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 Separate reogenic centers into their diastereomers on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, which, if they occur in racemic form, subsequently as mentioned above in the enantiomers can be separated.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative, such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to various solubilities, the free antipodes being able to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Suitable optically active alcohols are, for example, (+) - or (-) menthol, and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, if the new compounds of the formula I obtained in this way contain a carboxyl group, they can, if desired, be subsequently converted into their salts with inorganic or organic convert ganic bases, in particular for pharmaceutical use, into their physiologically tolerable salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Some of the compounds used as starting materials are known from the literature or can be obtained by processes known from the literature (see Examples I to XXXVIII).

As already mentioned at the beginning, the new 5-membered heterocycles of the general formula I and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, have valuable pharmacological properties, in addition to anti-inflammatory and bone-degrading Effect in particular antithrombotic, antiaggregatory and tumor or metastasis-inhibiting effects.

For example, the compounds of general formula I were examined for their biological effects as follows:

1. Inhibition of ³ H-BIBU 52 binding to human platelets:

A suspension of human platelets in plasma is mixed with ³ H-BIBU 52 [= (3S, 5S) -5- [(4'-amidino-4-biphenylyl) oxymethyl] - 3- [(carboxyl) methyl] -2-pyrrolidinone [ 3- ³ H-4-biphenylyl]], which replaces the ligand ¹² 5j_fibrinogen known from the literature (see DE-A-4,214,245) and incubates various concentrations of the substance to be tested. The free and bound ligand is separated by centrifugation and quantified by scintillation counting. The inhibition of the ³ H-BIBU 52 binding by the test substance is determined from the measured values.

For this purpose, donor blood is drawn from an anti-cubital vein and anticoagulated with trisodium citrate (final concentration 13 mM). The blood is centrifuged at 170 xg for 10 minutes and that protruding platelet-rich plasma (PRP) removed. The remaining blood is again centrifuged sharply to obtain plasma. The PRP is diluted 1:10 with autologous plasma. 750 ml are incubated with 50 ml of physiological saline, 100 ml of test substance solution, 50 ml of ¹⁴ C sucrose (3,700 Bq) and 50 ml of ³ H-BIBU 52 (final concentration: 5 nM) at room temperature for 20 minutes. To measure the non-specific binding, 5 ml BIBU 52 (final concentration: 30 mM) is used instead of the test substance. The samples are centrifuged at 10,000 xg for 20 seconds and the supernatant is removed. 100 ml of this are measured to determine the free ligand. The pellet is dissolved in 500 ml of 0.2N NaOH, 450 ml are mixed with 2 ml of scintillator and 25 ml of 5N HCl and measured. The residual plasma remaining in the pellet is determined from the ¹⁴ C content, the bound ligand from the ³ H measurement. After subtracting the non-specific binding, the pellet activity is plotted against the concentration of the test substance and the concentration for 50% inhibition of binding is determined.

2. Antithrombotic effect:

methodology

Platelet aggregation is measured using the method of Born and Cross (J. Physiol. 1/70, 397 (1964)) in platelet-rich plasma from healthy subjects. In order to inhibit coagulation, sodium citrate 3.14% in a volume ratio of 1:10 is added to the blood.

Collagen-induced aggregation

The course of the decrease in the optical density of the plate suspension is measured and recorded photometrically after the addition of the aggregation-triggering substance. The rate of aggregation is inferred from the angle of inclination of the density curve. The point of the curve at which the greatest light transmission Reliability is used to calculate the "optical density".

The amount of collagen is chosen to be as small as possible, but in such a way that an irreversible reaction curve results. The commercial collagen from Hormonchemie, Munich, is used.

Before the collagen addition, the plasma is incubated with the substance at 37 ° C. for 10 minutes.

An EC5 ₀ , which relates to a 50% change in the "optical density" in the sense of an inhibition of aggregation, is determined graphically from the measurement numbers obtained.

The following table contains the results found:

Because of their inhibitory effect on cell-cell or cell-matrix interactions, the new 5-membered heterocycles of the general formula I and their physiologically tolerable salts are suitable for combating or preventing diseases which have smaller or larger cell aggregates or cell-matrix interactions play a role, for example in combating or preventing venous and arterial thrombosis, cerebrovascular diseases, pulmonary embolism, myocardial infarction, arteriosclerosis, osteoporosis and meta staging of tumors and the therapy of genetically determined or acquired disorders in the interactions of cells with one another or with solid structures. These are also suitable for accompanying therapy in the case of thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or also in the therapy of shock conditions, psoriasis, diabetes and inflammation.

For the control or prevention of the abovementioned diseases, the dose is between 0.1 mg and 30 mg / kg body weight, preferably 1 mg to 15 mg / kg body weight, with up to 4 doses per day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or their i combinations, serotonin antagonists, α-receptor antagonists,

Alkyl nitrates such as glycerol trinitrate, phosphodiesterase inhibitors, prostacyclin and their analogs, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatan sulfate, activated protein C, vitamin K antagonists or other hirudin inhibitors, hirudin, inhibitors Akti¬ fourth coagulation factors, together with one or more inert conventional carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, what ¬ ser / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories. The following examples are intended to explain the invention in more detail:

Preparation of the starting compounds:

Example I

1- (tert-butyloxycarbonyl) -4-piperidylcarboxylic acid hydrazide

A solution of 19.1 g of 1- (tert-butyloxycarbonyl) -4-piperidylcarboxylic acid, 32.1 g of 2- [(IH) -benzotriazol-1-yl] -1, 1, 3, 3-tetra-methyluronium tetrafluoroborate, 30.4 g of triethylamine and 90 g of hydrazine hydrate in 300 ml of dimethylformamide are stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure and the residue with methylene chloride / methanol / conc. Ammonia (9: 1: 0.1) chromatographed over silica gel.

Yield: 11.0 g (55% of theory), melting point: 106-108 ° C

Rf value: 0.47 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example II

N- [1- (tert-Butyloxycarbonyl) -4-piperidylcarbonyl] -N'- [(methoxycarbonyl) carbonyl] hydrazine

A solution of 1.22 g of freshly distilled monomethyl ester chloride in 15 ml of tetrahydrofuran is added dropwise at 0 ° C. to a solution of 2.43 g of 1- (tert-butyloxycarbonyl) -4-piperidylcarboxylic acid hydrazide in 25 ml of tetrahydrofuran. The mixture is stirred at room temperature for 16 hours and the precipitate is filtered off with suction. The filtrate is evaporated under reduced pressure and the crude product is reacted without further purification. Yield: 3.5 g (quantitative) Example III

2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5-methoxycarbonyl-1,3,4-thiadiazole

A suspension of 3.27 g of N- [1- (tert-butyloxycarbonyl) -4-piperidylcarbonyl] -N'- [(methoxycarbonyl) carbonyl] hydrazine and 4.05 g of 2,4-bis (4-methoxyphenyl) - 1,3-dithia-2,4-diphosphetane-2,4-disulfide in 30 mL tetrahydrofuran is heated to reflux for 30 minutes. The solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel using ethyl acetate / cyclohexane (4: 1). Yield: 2.5 g (76% of theory), melting point: 107-110 ° C Rf value: 0.60 (silica gel; ethyl acetate / cyclohexane = 4: 1)

Example IV

2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5-carboxy-1,3,4-thiadiazole

A solution of 5.2 g of 2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5-methoxycarbonyl-1,3,4-thiadiazole in 24 ml of 1M sodium hydroxide solution and 100 ml of methanol is stirred for 10 minutes at room temperature. The solution is neutralized by dropping 0.1 M hydrochloric acid and the methanol is largely evaporated under reduced pressure on a rotary evaporator at a bath temperature below 35 ° C. The precipitate is filtered off, washed with a little water and dried.

Yield: 3.0 g (60% of theory), melting point: 298-302 ° C (dec.)

Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2) Example V

1- (phenylmethyloxycarbonyl) -4-piperidyl-carboxamide

39.9 g of benzyl chloroformate and 234 ml of 1M sodium hydroxide solution are added dropwise to a solution of 30.0 g of 4-piperidylcarboxamide in methylene chloride, so that a pH = 9 is maintained. The mixture is stirred at room temperature for 1 hour. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. Yield: 61.4 g (quantitative),

Rf value: 0.49 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

The following connection is obtained analogously to Example V:

(1) 4- (2-carboxy-ethyl) -1-benzyloxycarbonyl-piperidine 4- (2-carboxy-ethyl) -piperidine hydrochloride (melting point: 240-250 ° C., prepared by hydrogenation of 3- (4-pyridyl) acrylic acid with hydrogen in glacial acetic acid in the presence of platinum oxide and subsequent treatment with hydrochloric acid). After stirring for 2 hours, the reaction solution is brought to pH = 5 by adding 1N hydrochloric acid. The aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried and the solvent is evaporated off under reduced pressure. The red product is mixed with methylene chloride / methanol / conc. Ammonia (4: 1: 0.2) chromatographed on silica gel.

Rf value: 0.29 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25) Example VI

1- (phenylmethyloxycarbonyl) -4-piperidyl-thiocarboxamide

A solution of 20.0 g of 1- (phenylmethyloxycarbonyl) -4-piperidylcarboxamide and 15.4 g of 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4,4-diphosphetane-2,4-disulfide in 500 mL tetrahydrofuran is heated to reflux for 6 hours. The solvent is evaporated off under reduced pressure and the residue is distributed between saturated sodium bicarbonate solution and ethyl acetate. The organic phase is dried, the solvent is evaporated off and the residue is chromatographed on silica gel using ethyl acetate / cyclohexane (1: 1). Yield: 8.47 g (41% of theory), mass spectrum: M ⁺ = 278 Rf value: 0.26 (silica gel; ethyl acetate / cyclohexane = 1: 2)

The following compound is obtained analogously to Example VI:

(1) 4- (2-aminothiocarbonyl-ethyl) -1-phenylmethyloxycarbonyl-piperidine

The mixture is heated to reflux for 2 hours. After shaking, the residue is triturated with ether and suction filtered. Melting point: 148-154 ° C Mass spectrum: (M + H) ⁺ = 307

Rf value: 0.52 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example VII

2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -4-ethoxycarbonyl-1,3-thiazole

A solution of 4.0 g of 1- (phenylmethyloxycarbonyl) -4-piperidyl-thiocarboxamide and 3.36 g of ethyl bromopyruvate in 50 ml of ethanol is stirred for 6 hours at room temperature. The The solvent is evaporated off and the residue is mixed with ethyl acetate /

Cyclohexane (1: 2) chromatographed on silica gel.

Yield: 3.1 g (59% of theory),

Mass spectrum: M ⁺ = 374

Rf value: 0.26 (silica gel; ethyl acetate / cyclohexane = 1: 2)

Example VIII

2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -4-carboxy-1,3-thiazole

Sufficient methanol is added to the suspension of 2.43 g of 2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -4-ethoxycarbonyl-1,3-thiazole in 33 ml of 1N sodium hydroxide solution and 50 ml of tetrahydrofuran to give a clear solution. The mixture is stirred for 10 minutes at room temperature and neutralized with 1M hydrochloric acid. The organic solvents are evaporated off under reduced pressure and the aqueous phase is extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated off under reduced pressure.

Yield: 2.25 g (quantitative) yellowish oil, mass spectrum: M ⁺ = 346

Rf value: 0.20 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

The following compounds are obtained analogously to Example VIII:

(1) 5-Carboxy-4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole

Instead of IM sodium hydroxide solution, IM lithium hydroxide solution is used.

Melting point: 126-128 ° C Rf value: 0.14 (silica gel; methylene chloride / methanol = 15: 1) (2) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4-carboxy-imi¬ dazol

Melting point: 206-208 ° C (dec.)

Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(3) trans-3- [1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-imidazolyl] acrylic acid

The mixture is stirred for 2 hours at room temperature. After neutralization with 1M hydrochloric acid, the organic solvent is evaporated off under reduced pressure and the aqueous phase is cooled in an ice bath. The precipitate is filtered off. Melting point: 305-306 ° C (decomp.)

Rf value: 0.39 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(4) 1- [2- [1- (tert-butyloxycarbonyl) -4-piperidyl] ethyl] - 4-carboxy-imidazole

The mixture is stirred at room temperature for 16 hours. After neutralization with IM hydrochloric acid, the product crystallizes out. Melting point: 243 ° C (decomp.)

Rf value: 0.51 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(5) 2- [2- (l-Benzyloxycarbonyl-4-piperidyl) ethyl] -5-carboxy-4-methyl-1,3-thiazole

The hydrolysis is carried out with lithium hydroxide in tetrahydrofuran / water (4: 5). The red product is mixed with methylene chloride / methanol / conc. Ammonia (4: 1: 0.2) chromatographed over silica gel.

Melting point: 132-136 ° C. Mass spectrum: M ⁺ = 388

Rf value: 0.38 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2) (6) 5-carboxy-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] - 1,3-thiazole

Instead of IM sodium hydroxide solution, IM lithium hydroxide solution is used. Rf value: 0.16 (silica gel; methylene chloride / methanol = 10: 1)

Example IX

2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -4-methyl-5-eth-oxycarbonyl-1,3-thiazole

A solution of 4.0 g of 1- (phenylmethyloxycarbonyl) -4-piperidyl-thiocarboxamide and 2.2 ml of 2-chloroacetoacetic acid ethyl ester in 15 ml of absolute ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel using ethyl acetate / cyclohexane (1: 2 to 1: 1). Yield: 3.35 g (60% of theory), mass spectrum: M ⁺ = 388 Rf value: 0.46 (silica gel; ethyl acetate / cyclohexane = 1: 2)

The following compounds are obtained analogously to Example IX:

(1) 5-Ethoxycarbonyl-4-methyl-2- [2- (1-phenylmethyloxycarbonyl-4-piperidyl) ethyl] -1, 3-thiazole

4- (2-aminothiocarbonyl-ethyl) -1-phenylmethyloxycarbonyl-piperidine is used. The reaction solution is heated to reflux for 6 hours. After 2 and 4 hours, 0.2 equivalents of ethyl 2-chloroacetoacetate are added. The residue is dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried and evaporated. The residue is chromatographed on silica gel using cyclohexane / ethyl acetate (2: 1). Mass spectrum: M ⁺ = 416 Rf value: 0.39 (silica gel; cyclohexane / ethyl acetate = 2: 1) (2) 2- [1- (Phenylmethyloxycarbonyl) -4-piperidyl] -5-ethoxycarbonyl-1,3-thiazole

Ethyl 2-chloro-3-hydroxyacrylic acid is used. The reaction solution is heated to reflux for 2.5 days. After 2 days, a further 0.5 equivalent of 2-chloro-3-hydroxyacrylic acid ethyl ester is added. The reaction solution is evaporated and the residue is chromatographed on silica gel using cyclohexane / ethyl acetate (2: 1). Rf value: 0.26 (silica gel; cyclohexane / ethyl acetate = 2: 1)

(3) 5-Ethoxycarbonyl-2- [2- (l-phenylmethyloxycarbonyl-4-piperidyl) ethyl] -1, 3-thiazole

4- (2-Aminothiocarbonyl-ethyl) -1-phenylmethyloxycarbonyl-piperidine and 2-chloro-3-hydroxyacrylic acid ethyl ester are used. The reaction solution is refluxed for 7 hours. The residue is chromatographed on silica gel using cyclohexane / ethyl acetate (2: 1). Mass spectrum: M ⁺ = 402 Rf value: 0.23 (silica gel; cyclohexane / ethyl acetate = 2: 1)

Example X

1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-methoxycarbonylimidazole

1.5 g of sodium hydride (60% dispersion in mineral oil) are added to a solution of 4.3 g of methyl 4 (5) -imidazole carboxylate in 100 ml of dimethylformamide and the mixture is stirred for 1 hour at room temperature. 9.5 g of methanesulfonic acid [1- (tert-butyloxycarbonyl) -4-piperidyl] ester are added and the mixture is stirred at 60 ° C. for 5 days. The solvent is evaporated off under reduced pressure and the residue is taken up in ethyl acetate. The organic phase is washed with water, dried, the solvent is evaporated and the residue is washed with methylene chloride / methanol / conc. Ammonia (39: 1: 0.1 to 19: 1: 0.1) chromatographed on silica gel. Yield: 2.54 g (24% of theory), Mass spectrum: M ⁺ = 309

Rf value: 0.52 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

The following compounds are obtained analogously to Example X:

(1) Trans-3- [1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-imidazolyl] acrylic acid methyl ester

3- [4 (5) -Imidazolyl] acrylic acid methyl ester is used. Rf value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(2) 1- [2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] ethyl] - 4-methoxycarbonyl-imidazole

It is methanesulfonic acid [2- [1- (tert.butyloxycarbonyl) -4-piperidyl] ethyl] ester (prepared by reduction of [1- (tert.butyloxycarbonyl) -4-piperidyl] acetic acid methyl ester with lithium borohydride in tetrahydrofuran and subsequent esterification with methanesulfonyl chloride Ver¬ in methylene chloride in Ge genwart of triethylamine, melting point: 85.5-87.5 ^c sets einge¬ C). The mixture is stirred for 4 days at room temperature.

Rf value: 0.51 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(3) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4-nitro-imidazole 4 (5) -nitroimidazole is used. The reaction solution is stirred at 55 ° C for 14 days. After adding 2.0 g of potassium carbonate, the mixture is stirred at 70 ° C. for 4 days.

Melting point: 153-154 ° C

Rf value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1) Example XI

trans-3- (4-Imιdazolyl) acrylic acid methyl ester

A solution of 6.0 g of trans-3- (4-imidazolyl) acrylic acid in 100 ml of methanol and 20 ml of ethereal hydrochloric acid is heated under reflux for 8 hours. The solvent is evaporated off under reduced pressure and the residue is triturated with acetone, suction filtered and dried. Yield: 8.1 g (99% of theory),

Rf value: 0.91 (silica gel; methylene chloride / methanol / concentrated ammo

Example XII

[4- (Aminocarbonyl) piperidin-1-yl] acetic acid tert-butyl ester

9.0 g Pιperιdm-4-carbonsaureamιd, 11.3 g tert-butyl bromoacetic acid and 10.4 g potassium carbonate in 100 mL acetone are stirred for 4 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is dissolved in water. The aqueous phase is extracted with ethyl acetate, the organic phase is dried and the solvent is evaporated off under reduced pressure. The crude product is mixed with methylene chloride / methanol / conc. Ammonia (9: 1: 0.1) chromatographed over silica gel.

Yield: 15.0 g (88% of theory),

Rf value: 0.47 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XIII

[4- (Aminomethyl) -pιperιdιn-1-yl] -acetic acid tert-butyl ester

To 20 mL of an IM solution of diborane in tetrahydrofuran is added a solution of 2.42 g of [4- (aminocarbonyl) -pιperιdιn-1-yl] - acetic acid tert-butyl ester in 30 mL tetrahydrofuran and heated 4 hours to reflux. 10 ml of an 1M solution of diborane in tetrahydrofuran are added and the mixture is heated under reflux for a further 5 hours. Water is added and the mixture is extracted with ethyl acetate. The aqueous phase is evaporated under reduced pressure and the residue with methylene chloride / methanol / conc. ammonia

(4: 1: 0.25) chromatographed on silica gel. Yield: 0.95 g (42% of theory),

Rf value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XIV

1- (2-Dibenzylamino-ethyl) -4-piperidinecarboxylic acid ethyl ester

A solution of 9.07 g of N- (2-chloroethyl) dibenzylamine hydrochloride, 4.6 ml of 4-piperidinecarboxylic acid ethyl ester and 10.3 ml of ethyldiisopropylamine in 20 ml of methanol is refluxed for 5 hours. The solvent is evaporated under reduced pressure and the residue with methylene chloride / methanol / - conc. Ammonia (30: 1: 0.25) chromatographed on silica gel. Yield: 7.90 g (69% of theory),

Rf value: 0.64 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XV

1- (2-Amino-ethyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride

A solution of 7.9 g of ethyl 1- (2-dibenzylamino-ethyl) -4-piperidinecarboxylate in 21 mL IN hydrochloric acid and 100 mL ethanol is mixed with hydrogen in the presence of 1.0 g 10% palladium on carbon at a hydrogen pressure of 3 bar and hydrogenated at a temperature of 50 ° C. The catalyst is filtered off and the solvent is evaporated off under reduced pressure. The residue is triturated with acetone, suction filtered and dried. Yield: 3.5 g (71% of theory), melting point: 128-130 ° C

Rf value: 0.12 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XVI

1- (tert-butyloxycarbonyl) -4-hydroxy-piperidine

A solution of 31.7 g of di-tert-butyl pyrocarbonate in 100 ml of tetrahydrofuran and then 100 ml of 1N sodium hydroxide solution are added to 15.0 g of 4-hydroxypiperidine. The mixture is stirred at room temperature for 16 hours. The suspension is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off under reduced pressure. Yield: 28.5 g (98% of theory), Rf value: 0.23 (silica gel; methylene chloride / methanol = 15: 1)

Example XVII

1- (tert-butyloxycarbonyl) -4- [(2-cyano-ethyl) oxy] piperidine

30 mg of potassium tert-butoxide are added to a solution of 6.04 g of 1- (tert-butyloxycarbonyl) -4-hydroxy-piperidine in 6.6 ml of acrylonitrile and 10 ml of dioxane and the mixture is heated under reflux under a nitrogen atmosphere for 4 hours. A further 3 ml of acrylonitrile and 30 mg of potassium tert-butoxide are added and the mixture is heated for a further 2 hours. The reaction solution is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is dried and evaporated. The crude product is chromatographed on silica gel using cyclohexane / ethyl acetate (2: 1). Yield: 4.49 g (59% of theory) of an oil. R _f value: 0.60 (silica gel; cyclohexane / ethyl acetate = 1: 1) Example XVIII

4- [(2-methoxycarbonyl-ethyl) oxy] piperidine hydrochloride

A solution of 4.47 g of 1- (tert-butyloxycarbonyl) -4- [(2-cyano-ethyl) oxy] piperidine in 20 ml of absolute methanol and 20 ml of ethereal hydrochloric acid is heated under reflux with the exclusion of water. The solvent is evaporated off under reduced pressure and the residue is partitioned between 20 ml of saturated potassium carbonate solution and ether. The organic phase is dried and evaporated. 5 mL water and 5 mL conc. Hydrochloric acid and stirred for 16 hours at room temperature. The solvent is evaporated off. 20 mL of absolute methanol and 20 mL of ethereal hydrochloric acid are added and the mixture is stirred at room temperature for 16 hours. The solvent is evaporated and the crude product with methylene chloride / methanol / conc. Ammonia (9: 1: 0.1) chromatographed over silica gel.

Yield: 1.7 g (43% of theory),

Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XIX

4- (2-aminocarbonyl-ethyl) -1-benzyloxycarbonyl-piperidine

A suspension of 18.5 g of 4- (2-carboxyethyl) -1-benzyloxycarbonyl piperidine, 10.1 g of triethylamine and 25.7 g of 2- [(IH) -benzotriazol-1-yl] -1, 1.3 , 3-tetramethyluronium tetrafluoroborate in 300 mL tetrahydrofuran is stirred for 2 hours at room temperature. The suspension is added dropwise to 250 mL concentrated ammonia with thorough stirring. The mixture is stirred for 3 days at room temperature, the organic phase is separated off and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent removed under reduced pressure. steams. The solid is triturated with ethyl acetate and suction filtered.

Yield: 12.0 g (65% of theory), melting point: 104-107 ° C

Rf value: 0.72 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example XX

4-Amino-l- [1- (tert-butyloxycarbonyl) -4-piperidyl] imidazole

A solution of 480 mg of 1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-nitro-imidazole in 20 ml of ethanol is washed with hydrogen in the presence of 0.2 g of 10% palladium on carbon in a was Hydrogen pressure of 3 bar hydrogenated at room temperature. The catalyst is filtered off and the solvent is evaporated off under reduced pressure. The residue is dissolved in tetrahydrofuran and evaporated. The product is used without further cleaning.

Yield: 450 mg (quantitative),

Rf value: 0.36 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XXI

Trans-4- (N-methanesulfonylamino) cyclohexane carboxylic acid methyl ester

A solution of 5.2 g of trans-4-amino-cyclohexane carboxylic acid methyl ester hydrochloride, 2.32 ml of methanesulfonyl chloride in 100 ml of methylene chloride and 35 ml of pyridine is stirred for 2 days at room temperature. The reaction solution is evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The organic phase is washed with water, 1M hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated saline solution, dried and evaporated. The crude product is triturated with ether and suction filtered. Yield: 3.8 g (60% of theory),

Rf value: 0.62 (silica gel; methylene chloride / methanol = 15: 1)

Example XXII

methyl trans-4- (N-tert-butyloxycarbonylmethyl-N-methanesulfonylamino) -cyclohexanecarboxylic acid

A suspension of 3.8 g of trans-4- (N-methanesulfonylamino) cyclohexanecarboxylic acid methyl ester, 4.7 ml of tert-butyl bromoacetate and 6.0 g of potassium carbonate in 50 ml of acetone is heated to reflux for 10 hours. The reaction solution is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The crude product is triturated with ether and suction filtered. Yield: 4.6 g (82% of theory), melting point: 116-118 ° C

Rf value: 0.69 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XXIII

trans-4- (N-tert-butyloxycarbonylmethyl-N-methanesulfonylamino) cyclohexane carboxylic acid

Manufactured analogously to Example VIII. The mixture is stirred for 4 hours at room temperature. After neutralization, the organic solvent is evaporated off and the solution is cooled. The precipitate is filtered off and dried. Yield: 2.58 g (88% of theory), melting point: 143-144 ° C. Rf value: 0.35 (silica gel; methylene chloride / methanol = 15: 1) Example XXIV

α- (4-Benzyloxycarbonyl-phenyloxy) acetic acid methyl ester

5.53 g of potassium carbonate are added to a solution of 8.0 g of benzyl 4-hydroxybenzoate in 50 ml of dimethylformamide and the mixture is stirred at room temperature for 30 minutes. 3.3 mL of methyl bromoacetate are added and the mixture is stirred at room temperature for 16 hours. The reaction solution is evaporated and the residue is distributed between water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. Yield: 10.5 g (quantitative), melting point: 60-62 ° .C Rf value: 0.55 (silica gel; cyclohexane / ethyl acetate = 2: 1)

Example XXV

α- (4-Carboxy-phenyloxy) acetic acid methyl ester

A solution of 10.5 g of α- (4-benzyloxycarbonyl-phenyloxy) acetic acid methyl ester in 100 ml of methanol is hydrogenated with hydrogen in the presence of 2 g of 10% palladium on carbon at a hydrogen pressure of 3 bar at room temperature. The catalyst is filtered off, washed with methylene chloride and the solvent is evaporated off under reduced pressure. Yield: 6.9 g (94% of theory), melting point: 172-176 ° C Rf value: 0.36 (silica gel; methylene chloride / methanol = 15: 1)

Example XXVI

5-carboxy-2- [2- (4-piperidyl) ethyl] -1, 3-thiazole hydrochloride

Sufficient methanol is added to a suspension of 1.5 g of 5-ethoxycarbonyl-2- [2- (1-phenylmethyloxycarbonyl-4-piperidyl) ethyl] -1, 3-thiazole in 40 mL 6N hydrochloric acid to dissolve a solution. stands. The mixture is stirred for 24 hours at room temperature and for a further 4 hours at 60 ° C. The solvent is evaporated off under reduced pressure and the residue (Z-deprotected amine) is dissolved in 50 ml of 6N hydrochloric acid and heated to reflux for 6 hours. The solvent is evaporated off. Yield: 0.84 g (94% of theory),

Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

Example XXVII

2- [2- (1-tert.butioxycarbonyl-4-piperidyl) ethyl] -5-carboxy-1,3-thiazole

A solution of 0.74 g is added to a solution of 0.82 g of 5-carboxy-2- [2- (4-piperidyl) ethyl] -1,3-thiazole hydrochloride in 7 mL IN hydrochloric acid while cooling in an ice / water bath Pyrocarbonate di-tert-butyl ester in 15 mL tetrahydrofuran. The cooling bath is removed and the reaction solution is stirred for 24 hours at room temperature. It is acidified with 1N hydrochloric acid and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried and the solvent is evaporated off. The product crystallizes out of the oil obtained (0.9 g). It is filtered off and washed with a little ether. Yield: 0.28 g (27% of theory), mass spectrum: M ⁺ = 340

Rf value: 0.22 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example XXVIII

α- (4-Nitrophenyloxy) acetic acid ethyl ester

125.4 g of 4-nitrophenol are dissolved in 1000 ml of absolute dimethylformamide and, after addition of 150.6 g of dried potassium carbonate, stirred for 45 minutes at room temperature. 150.6 g of ethyl bromoacetate are added dropwise with stirring and the mixture is heated 5 hours at 80 ° C. The heating is switched off and the suspension is stirred for 15 hours. The unsolved anorg. Salts are filtered off and the filtrate is evaporated under reduced pressure. The residue is distributed between ethyl acetate and water. The organic phase is extracted twice with water, dried over sodium sulfate, filtered and evaporated. The residue is triturated with petroleum ether and suction filtered.

Yield: 192.0 g (95% of theory), Rf value: 0.7 (silica gel; methylene chloride)

Example XXIX

cx- (4-nitrophenyloxy) acetic acid

192.0 g of ethyl α- (4-nitrophenyloxy) acetic acid are added to a solution of 68.2 g of sodium hydroxide in 2 L of water. After about 4 hours everything is solved. With good stirring and cooling, the solution is concentrated with. Hydrochloric acid brought to pH = 3. The precipitated product is filtered off, washed with water and dried.

Yield: 149.6 g (89% of theory), Rf value: 0.1 (silica gel; methylene chloride)

Example XXX

α- (4-Nitrophenyloxy) acetic acid cyclohexyl ester

36.2 g of thionyl chloride are added dropwise to 200 ml of cyclohexanol in 500 ml of absolute methylene chloride at -10 ° C. to -20 ° C. while stirring well. After the addition has ended, the mixture is stirred at low temperature for 30 minutes. 50.0 g of α- (4-nitrophenyloxy) acetic acid are added in portions. The suspension is stirred at -10 ° C to -20 ° C for 2 hours. The mixture is then slowly warmed to room temperature and stirred for a further 16 hours. The clear solution is evaporated under reduced pressure and the oily residue is crystallized with petroleum ether. Yield: 66.7 g (94% of theory), Rf value: 0.6 (silica gel; methylene chloride)

Example XXXI

α- (4-Aminophenyloxy) acetic acid cyclohexyl ester

A solution of 66.7 g of α- (4-nitrophenyloxy) acetic acid cyclohexyl ester in 600 ml of ethyl acetate is mixed with hydrogen in the presence of 7.0 g of 10 percent palladium on carbon at room temperature and a hydrogen pressure of 5 bar hydrogenated. After about 2 hours the hydrogen absorption ^is' finished. The catalyst is suction filtered and the filtrate is evaporated. The oil obtained is reacted without further purification. Yield: 59.0 g (99% of theory), R _f value: 0.1 (silica gel; methylene chloride)

Example XXXII

4-dibenzylamino-l- (2-methoxycarbonyl-ethyl) piperidine

A solution of 2.9 g of 1- (1-methoxycarbonyl-ethyl) -piperid-4-one (prepared by reacting piperidin-4-one with methyl acrylate in methanol in the presence of potassium carbonate; oil), 3.15 g of dibenzylamine and 4.66 g of sodium triacetoxyborohydride in 60 ml of tetrahydrofuran and 0.96 ml of acetic acid are stirred for 6 hours at 0 ° C. and then for 16 hours at room temperature. The reaction solution is diluted with ethyl acetate and the organic phase is washed with 1M sodium hydroxide solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. Yield: 5.2 g (91% of theory),

Rf value: 0.33 (silica gel; methylene chloride / methanol / concentrated ammonia = 20: 1: 0.1) Example XXXIII

4-amino-1- (2-methoxycarbonyl-ethyl) piperidine

5.0 g of 4-dibenzylamino-l- (2-methoxycarbonyl-ethyl) piperidine and 4.3 g of ammonium formate in 150 ml of methanol are heated under reflux for 2 hours in the presence of 0.4 g of 10% palladium on carbon. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is mixed with methylene chloride / methanol / conc. Ammonia (9: 1: 0.1) chromatographed on silica gel.

Yield: 1.4 g (56% of theory) of an oil,

Rf value: 0.20 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XXXIV

[4- (Ethoxycarbonyl-methyloxy) phenyloxy] acetic acid benzyl ester

A suspension of 9.0 g of (4-hydroxyphenyloxy) acetic acid benzyl ester [prepared by esterifying (4-hydroxyphenyloxy) acetic acid with benzyl alcohol analogously to Example 8; Melting point: 69-71 ° C.] and 9.7 g of potassium carbonate in 100 ml of dimethylformamide are stirred at room temperature for 30 minutes. 6.7 g of ethyl bromoacetate are added dropwise and the mixture is stirred at room temperature for 16 hours and at 70 ° C. for 1 hour. The reaction solution is evaporated and the residue is partitioned between ethyl acetate / water. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. Yield: 11.5 g (96% of theory), melting point: 66-68 ° C Rf value: 0.52 (silica gel; cyclohexane / ethyl acetate = 2: 1) The following compound is obtained analogously to Example XXXIV:

(1) 3- [4- (Ethoxycarbonyl-methyloxy) phenyl] propionic acid benzyl ester It becomes 3- (4-hydroxyphenyl) propionic acid benzyl ester

[prepared by esterification of 3- (4-hydroxyphenyl) propionic acid with benzyl alcohol analogously to Example 8; Oil, Rf value: 0.28 (silica gel; cyclohexane / ethyl acetate = 2: 1)] was used. The crude product is chromatographed on silica gel using cyclohexane / ethyl acetate (2: 1). Rf value: 0.58 (silica gel; cyclohexane / ethyl acetate = 2: 1)

Example XXXV

[4- (ethoxycarbonylmethyloxy) phenyloxy] acetic acid

Preparation from benzyl [4- (ethoxycarbonyl-methyloxy) phenyloxy] acetic acid by catalytic hydrogenation analogously to Example 7 in ethyl acetate as solvent. Melting point: 90-92 ° C Rf value: 0.05 (silica gel; cyclohexane / ethyl acetate = 2: 1)

Example XXXVI

1- [[[4- (ethoxycarbonyl-methyloxy) phenyl] oxymethyl] carbonyl] -2- [(1-benzyloxycarbonyl-4-piperidyl) carbonyl] hydrazine

Preparation from [4- (ethoxycarbonylmethyloxy) phenyloxy] esacetic acid and (l-benzyloxycarbonyl-4-piperidyl) carboxylic acid hydrazide (prepared analogously to Example I; melting point: 134-136 ° C.) analogously to Example 1. Melting point : 169 ° C

Rf value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1) Example XXXVII

3- [4- (ethoxycarbonylmethyloxy) phenyl] propionic acid

Preparation from benzyl 3- [4- (ethoxycarbonyl-methyloxy) phenyl] propionate by catalytic hydrogenation analogously to Example 7 in ethyl acetate as solvent. Melting point: 75-80 ° C

Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XXXVIII

1- [[2- [4- (Ethoxycarbonyl-methyloxy) phenyl] ethyl] carbonyl] - 2- [(l-benzyloxycarbonyl-4-piperidyl) carbonyl] hydrazine

Preparation from 3- [4- (ethoxycarbonyl-methyloxy) phenyl] propionic acid and (l-benzyloxycarbonyl-4-piperidyl) carboxylic acid hydrazide analogously to Example 1.

Rf value: 0.43 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Production of the end products:

example 1

5- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1,3-thiazole

To a solution of 720 mg of 5-carboxy-4-methyl-2- [1- (phenyl¬ methyloxycarbonyl) -4-piperidyl] -1, 3-thiazole, 443 mg of 3- (trans-4-aminocyclohexyl) propionic acid. methyl ester hydrochloride and 1.0 ml triethylamine in 20 ml dimethylformamide are added 800 mg 2- [(IH) -benzotriazol-1-yl] -1,1,3,3-tetramethyluronium tetrafluoroborate and stirred for 16 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is taken up in ethyl acetate. The organic phase is washed with water, 1M sodium hydroxide solution and saturated sodium chloride solution, dried and the solvent is evaporated off. The residue is chromatographed on silica gel using methylene chloride / methanol (50: 1 to 30: 1). Yield: 980 mg (93% of theory), mass spectrum: M ⁺ = 527 Rf value: 0.45 (silica gel; methylene chloride / methanol = 15: 1)

The following compounds are obtained analogously to Example 1:

(1) Trans-3- [1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4-imidazolyl] acrylic acid methyl ester

4 (5) -Imidazolyl-acrylic acid methyl ester is used. Rf value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(2) 2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5- [N- [trans- 4- (2-methoxycarbonyl-ethyl) cyclohexyl] -N- (3-pyridylmethyl) aminocarbonyl] -1,3,4-thiadiazole

Mass spectrum: M ⁺ = 571 Rf value: 0.56 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(3) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[trans- 4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] - 1, 3, 4-thiadiazole

Mass spectrum: M ⁺ = 480

Rf value: 0.80 (silica gel; ethyl acetate / cyclohexane = 4: 1)

(4) 4- [[trans-4- (2-methoxycarbonylethyl) cyclohexyl] aminocarbonyl] -2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole

Mass spectrum: M ⁺ = 346

Rf value: 0.82 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(5) 4- [[4- (methoxycarbonyl-methyloxy) phenyl] aminocarbonyl] - 2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1,3-thiazole Rf value: 0.80 (silica gel; methylene chloride / Methanol / concentrated ammonia = 4: 1: 0.25)

(6) 5- [[4- (Methoxycarbonylmethyloxy) phenyl] aminocarbonyl] - 4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole

Rf value: 0.41 (silica gel; methylene chloride / methanol = 15: 1).

(7) 1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4- [[trans-

4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] imidazole Rf value: 0.39 (silica gel; methylene chloride / methanol = 15: 1)

(8) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4- [[4- (methoxycarbonyl-methyloxy) phenyl] aminocarbonyl] imidazole mass spectrum: M ⁺ = 458

Rf value: 0.41 (silica gel; methylene chloride / methanol = 15: 1) (9) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4- [trans- 2- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] ethenyl] imidazole

Melting point: 223-224 ° C (decomp.)

Mass spectrum: M ⁺ = 460

Rf value: 0.39 (silica gel; methylene chloride / methanol = 15: 1)

(10) 1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4- [trans-

2- [[4- (methoxycarbonylmethyl) -1-piperidyl] carbonyl] ethenyl] imidazole

Melting point: 159-160 ° C (decomp.)

Rf value: 0.47 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1:01)

(11) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [N- [trans- 4- (2-methoxycarbonyl-ethyl) -cyclohexyl] -N-methylaminocarbonyl] -1 , 3, 4-thiadiazole

(12) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] aminocarbonyl] -1,3,4-thiadiazole

(13) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[trans- 4- [(methoxycarbonylmethyl) -oxy] cyclohexyl] aminocarbonyl] - 1, 3, 4-thiadiazole

(14) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[1- (methoxycarbonylmethyl) -4-piperidyl] aminocarbonyl] -1, 3,4-thiadiazole

(15) 2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5- [[[1- (methoxycarbonylmethyl) -4-piperidyl] methyl] aminocarbonyl] -1, 3,4-thiadiazole

(16) 2- [4- (tert-butyloxycarbonyl) -1-piperazinyl] -5- [N- [4- (methoxycarbonylmethyloxy) phenyl] -N-methylaminocarbonyl] -1, 3, 4 - thiadiazole (17) 2- [4- (tert-butyloxycarbonyl) -1-piperazinyl] -5- [[trans- 4- (methoxycarbonyl-methyloxy) cyclohexyl] aminocarbonyl] -

1, 3, 4-thiadiazole

(18) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[4- [(2-methoxycarbonyl-ethyl) -oxy] -1-piperidyl] carbonyl] -1.3 , 4-thiadiazole

(19) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[2- (4-methoxycarbonyl-1-piperidyl) ethyl] aminocarbonyl] -1,3,4-thiadiazole

(20) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[4- (methoxycarbonylmethyloxy) phenyl] carbonylamino] -1,3,4-thiadiazole

(21) 2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -5- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] carbonylamino] -1,3,4-thiadiazole

(22) 5- [[4- [(2-methoxycarbonyl-ethyl) -oxy] -1-piperidyl] -carbonyl] -4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -

1,3-thiazole

(23) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] carbonylamino] imidazole

(24) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4- [[[1- (methoxycarbonyl-methyl) -4-piperidyl] methyl] carbonylamino] imidazole

(25) 5- [[4- (methoxycarbonylmethyloxy) phenyl] aminocarbonyl] -4-phenyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole

(26) 5- [[4- (methoxycarbonylmethyloxy) phenyl] aminocarbonyl] - 4-methyl-2- [4- (phenylmethyloxycarbonyl) -1-piperazinyl] -

1,3-thiazole

(27) 5- [[4- (Methoxycarbonylmethyloxy) phenyl] aminocarbonyl] - 2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole (28) 2- [2- [1- (tert-butyloxycarbonyl) -4-piperidyl] ethyl] - 4-methyl-5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] -1 , 3-thiazole

(29) 2- [[1- (tert-butyloxycarbonyl) -4-piperidyl] oxymethyl] - 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] -

1,3-thiazole

(30) 2- [2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] ethyl] - 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] tetrazole

(31) 1- [2- [1- (tert-Butyloxycarbonyl) -4-piperidyl] ethyl] - 4- [N- [trans-4- (methoxycarbonyl) cyclohexyl] -N-phenylmethylaminocarbonyl] pyrazole

(32) 2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5- [[4- [2- (methoxycarbonyl) -2- (methanesulfonylamino) ethyl] phenyl] aminocarbonyl] -1, 3,4-oxadiazole

(33) 5- [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] - 4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1,3-thiazole

Melting point: 101-104 ° C

Rf value: 0.20 (silica gel; methylene chloride / methanol / concentrated ammonia = 20: 1: 0.1)

(34) 5- [[[1- (tert-butyloxycarbonyl-methyl) -4-piperidyl] methyl] aminocarbonyl] -4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1 , 3-thiazole

Mass spectrum: M ⁺ = 570

Rf value: 0.15 (silica gel; methylene chloride / methanol / concentrated ammonia = 20: 1: 0.1) (35) 1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4- [[2- (4-ethoxycarbonyl-1-piperidyl) ethyl] aminocarbonyl] imidazole Melting point: 166-169 ° C.

Mass spectrum: M ⁺ = 477

Rf value: 0.44 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(36) 1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4- [4- [(2-methoxycarbonyl-ethyl) -oxy] -piperidinocarbonyl] imidazole Melting point: 184-185 ° C

Mass spectrum: M ⁺ = 464

Rf value: 0.52 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(37) 1- [2- [1- (tert-butyloxycarbonyl) -4-piperidyl] ethyl] - 4- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] imidazole

Trans-4-amino-cyclohexanecarboxylic acid methyl ester hydrochloride is used. Melting point: 186 ° C

Rf value: 0.38 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(38) 1- [2- [1- (tert-butyloxycarbonyl) -4-piperidyl] ethyl] -

4- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] imidazole Piperazin-1-yl-acetic acid methyl ester dihydrochloride is used.

Melting point: 142-143 ° C

Rf value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(39) 2- [2- [1- (benzyloxycarbonyl) -4-piperidyl] ethyl] -4-methyl- 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] -

1,3-thiazole

Trans-4-amino-cyclohexane carboxylic acid methyl ester is used. Melting point: 148-151 ° C

Rf value: 0.53 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(40) 2- [2- [1- (benzyloxycarbonyl) -4-piperidyl] ethyl] -4-methyl- 5- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] -

1,3-thiazole

Piperazin-1-yl-methyl acetate dihydrochloride is used.

Mass spectrum: M ⁺ = 528

Rf value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(41) 4- [[trans-4- (N-tert.butyloxycarbonylmethyl-N-methanesulfonylamino) cyclohexyl] carbonylamino] -1- (1-tert.butyloxycarbonyl-4-piperidyl) imidazole

Trans-4- (N-tert-butyloxycarbonylmethyl-N-methanesulfonylamino) cyclohexane carboxylic acid and 4-amino-1- [1- (tert-butyloxycarbonyl) -4-piperidyl] imidazole are used. Mass spectrum: M ⁺ = 583

Rf value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(42) 5- [[trans-4- (2-methoxycarbonylethyl) cyclohexyl] aminocarbonyl] -2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole

The residue is triturated with ether and suction filtered.

Mass spectrum: M ⁺ = 513

Rf value: 0.36 (silica gel; methylene chloride / methanol = 15: 1)

(43) 5- [[4- (Cyclohexyloxycarbonyl-methyloxy) phenyl] aminocarbonyl] -2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1,3-thiazole The amine component used is α- (4- Aminophenyloxy) acetic acid cyclo-hexyl ester used.

The residue is triturated with ether and suction filtered.

Mass spectrum: M ⁺ = 577

Rf value: 0.51 (silica gel; methylene chloride / methanol = 15: 1) (44) 5- [[trans-4- (tert-butyloxycarbonylmethyloxy) cyclohexyl] aminocarbonyl] -2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -

1,3-thiazole

The residue is triturated with ether and suction filtered.

Mass spectrum: M ⁺ = 557

Rf value: 0.36 (silica gel; methylene chloride / methanol = 15: 1)

(45) 2- [2- (l-tert-butyloxycarbonyl-4-piperidyl) ethyl] - 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] - 1,3-thiazole

Trans-4-amino-cyclohexane carboxylic acid methyl ester is used.

Rf value: 0.48 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(46) 5- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] aminocarbonyl] -2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole The residue is mixed with Methanol triturated and suction filtered. Mass spectrum: M ⁺ = 514

Rf value: 0.33 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example 2

5- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide

A solution of 960 mg of 5- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1,3 -thiazole in 5 mL glacial acetic acid and 5 mL 33% hydrogen bromide in glacial acetic acid is stirred for 2 hours at room temperature. 50 mL ether are added, the precipitate is filtered off, the residue is triturated with acetone, filtered off again and dried in vacuo. Yield: 900 mg (quantitative), mass spectrum: M ⁺ = 393 Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

The following compounds are obtained analogously to Example 2:

(1) 4- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole hydrobromide mass spectrum: M ⁺ = 379

Rf value: 0.48 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(2) 4- [[4- (Methoxycarbonyl-methyloxy) phenyl] aminocarbonyl] - 2- (4-piperidyl) -1,3- ^J thiazole hydrobromide mass spectrum: (M + H) ⁺ = 376

Rf value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(3) 5- [[4- (methoxycarbonylmethyloxy) phenyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide mass spectrum: M ⁺ = 389

Rf value: 0.41 (silica gel; methylene chloride / methanol = 15: 1)

(4) 5- [[4- [(2-methoxycarbonyl-ethyl) -oxy] -1-piperidyl] carbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide

(5) 5- [[4- (methoxycarbonylmethyloxy) phenyl] aminocarbonyl] -4-phenyl-2- (4-piperidyl) -1,3-thiazole hydrobromide

(6) 5- [[4- (Methoxycarbonylmethyloxy) phenyl] aminocarbonyl] -4-methyl-2- (1-piperazinyl) -1,3-thiazole hydrobromide

(7) 5- [[4- (Methoxycarbonylmethyloxy) phenyl] aminocarbonyl] - 2- (4-piperidyl) -1,3-thiazole hydrobromide

(8) 5- [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] - 4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide Mass spectrum: M ⁺ = 387 Rf value: 0.69 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(9) 5- [[[1- (carboxymethyl) -4-piperidyl] methyl] aminocarbonyl] • 4-methyl-2- (4-piperidyl) -1,3-thiazole dihydrobromide

The starting material is 5 - [[[1- (tert-butyloxycarbonyl-methyl) -4-piperidyl] methyl] aminocarbonyl] -4-methyl-2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole used. Mass spectrum: M ⁺ = 380

Rf value: 0.13 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(10) 5- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1,3-thiazole hydrobromide mass spectrum: M ⁺ = 379

Rf value: 0.66 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(11) 5- [[4- (Cyclohexyloxycarbonylmethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3-thiazole hydrobromide

The residue is triturated with ether and suction filtered. Mass spectrum: M ⁺ = 443

Rf value: 0.64 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(12) 5- [[trans-4- (carboxymethyloxy) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole hydrobromide

5- [[trans-4- (tert-butyloxycarbonyl-methyloxy) cyclohexyl] aminocarbonyl] -2- [1- (phenylmethyloxycarbonyl) -4-piperidyl] -1, 3-thiazole is used. Melting point: 197 ° C (sintering) Mass spectrum: (M + H) ⁺ = 368

Rf value: 0.38 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25) (13) 5- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole dihydrobromide Melting point: from 240 ° C. (sintering )

Mass spectrum: (M + H) ⁺ = 381

Rf value: 0.42 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(14) 5- [[4- (Ethoxycarbonyl-methyloxy) phenyl] oxymethyl] - 2- [4-piperidyl] -1,3,4-thiadiazole hydrobromide Melting point: 168-179 ° C

Mass spectrum: M ⁺ = 377

Rf value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(15) 5- [2- [4- (Ethoxycarbonyl-methyloxy) phenyl] ethyl] - 2- [4-piperidyl] -1,3,4-thiadiazole hydrobromide Melting point: 183-184 ° C

Mass spectrum: M ⁺ = 375

Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example 3

4- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -1- (4-piperidyl) imidazole dihydrochloride

A solution of 420 mg of 1- [1- (tert-butyloxycarbonyl) -4-piperidyl] -4- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] imidazole in 10 mL methanol and 10 mL ethereal hydrochloric acid are stirred for 16 hours at room temperature. The solvent is evaporated under reduced pressure, the residue is triturated with ether and suction filtered. Yield: 390 mg (quantitative), mass spectrum: M ⁺ = 362

Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1) The following compounds are obtained analogously to Example 3:

(1) 4- [[4- (Methoxycarbonyl-methyloxy) phenyl] aminocarbonyl] - 1- (4-piperidyl) imidazole dihydrochloride mass spectrum: M ⁺ = 358

Rf value: 0.15 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(2) 5- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

The reaction is carried out in a solvent mixture of dioxane / methanol / ethereal hydrochloric acid (1: 1: 1). The mixture is stirred for 30 minutes at room temperature. Melting point: 211-215 ° C. Mass spectrum: M ⁺ = 380

Rf value: 0.14 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(3) 4- [trans-2- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] ethenyl] -1- (4-piperidyl) imidazole dihydrochloride mass spectrum: M ⁺ = 360

Rf value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(4) 4- [trans-2- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] ethenyl] -1- (4-piperidyl) imidazole trihydrochloride Melting point: 159-160 ° C ( Dec.)

Mass spectrum: M ⁺ = 361

Rf value: 0.44 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(5) 5- [N- [trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] - N-methylaminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole hydrochloride

(6) 5- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole dihydrochloride (7) 5- [[trans-4- [(methoxycarbonylmethyl) oxy] cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

(8) 5- [[1- (methoxycarbonylmethyl) -4-piperidyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole dihydrochloride

(9) 5- [[[1- (methoxycarbonylmethyl) -4-piperidyl] methyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole dihydrochloride

(10) 5- [N- [4- (Methoxycarbonylmethyloxy) phenyl] -N-methylaminocarbonyl] -2- (1-piperazinyl) -1,3,4-thiadiazole dihydrochloride

(11) 5- [[trans-4- (methoxycarbonylmethyloxy) cyclohexyl] aminocarbonyl] -2- (1-piperazinyl) -1, 3,4-thiadiazole dihydrochloride

(12) 5- [[4- [(2-methoxycarbonyl-ethyl) -oxy] -1-piperidyl] carbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

(13) 5- [[2- (4-methoxycarbonyl-l-piperidyl) ethyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole dihydrochloride

(14) 5- [[4- (Methoxycarbonylmethyloxy) phenyl] carbonylamino] - 2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

(15) 5- [[1- (2-methoxycarbonyl-ethyl) -4-piperidyl] carbonylamino] -2- (4-piperidyl) -1,3,4-thiadiazole dihydrochloride

(16) 4- [[1- (2-Methoxyarbonyl-ethyl) -4-piperidyl] carbonylamino] -1- (4-piperidyl) imidazole trihydrochloride

(17) 4- [[[1- (methoxycarbonylmethyl) -4-piperidyl] methyl] carbonylamino] -1- (4-piperidyl) imidazole trihydrochloride

(18) 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] -4-methyl-2- [2- (4-piperidyl) ethyl] -1, 3-thiazole hydrochloride (19) 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] - 2- [(4-piperidyl) oxymethyl] -1,3-thiazole hydrochloride

(20 ⁾ 5- [[trans-4- ⁽ methoxycarbonyl) cyclohexyl] aminocarbonyl] - 2- [2- (4-piperidyl) ethyl] tetrazole hydrochloride

(21) 4- [N- [trans-4- (methoxycarbonyl) cyclohexyl] -N-phenylmethylaminocarbonyl] -l- [2- (4-piperidyl) ethyl] pyrazole hydrochloride

(22) 5- [[4- [2- (methoxycarbonyl) -2- (methanesulfonylamino) ethyl] phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-oxadiazole hydrochloride

(23) 4- [[2- (4-methoxycarbonyl-l-piperidyl) ethyl] aminocarbonyl] -1- (4-piperidyl) imidazole trihydrochloride

Compound 35 of Example 1 is used as starting material. Transesterification takes place under the reaction conditions. Mass spectrum: M ⁺ = 363

Rf value: 0.60 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(24) 4- [4- [(2-methoxycarbonyl-ethyl) -oxy] -piperidinocarbonyl] - 1- (4-piperidyl) -imidazole dihydrochloride

Mass spectrum: M ⁺ = 364

Rf value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(25) 1- [2- (4-piperidyl) ethyl] -4- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] imidazole dihydrochloride

The mixture is stirred at room temperature for 2 hours. Mass spectrum: M ⁺ = 362

Rf value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25) (26) 1- [2- (4-piperidyl) ethyl] -4- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] imidazole trihydrochloride

The mixture is stirred at room temperature for 2 hours. Mass spectrum: M ⁺ = 363

Rf value: 0.33 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(27) 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] - 2- [2- (4-piperidyl) ethyl] -1,3-thiazole

The reaction is carried out in a solvent mixture of dioxane / methanol / methanolic hydrochloric acid (1: 1: 1). Melting point: 219-225 ° C (sintering) Mass spectrum: M ⁺ = 379

Rf value: 0.61 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

Example 4

4- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] - 1- (4-piperidyl) imidazole dihydrochloride

A solution of 225 mg of 4- [[trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] aminocarbonyl] -1- (4-piperidyl) imidazole dihydrochloride in 10 ml of 6M hydrochloric acid is kept at room temperature for 16 hours ¬ door stirred. The solvent is evaporated under reduced pressure, the residue is triturated with acetone and suction filtered.

Yield: 200 mg (92% of theory), mass spectrum: M ⁺ = 348

Rf value: 0.39 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

The following compounds are obtained analogously to Example 4:

(1) 4- [[4- (Carboxymethyloxy) phenyl] aminocarbonyl] -1- (4-piperidyl) imidazole dihydrochloride mass spectrum: M ⁺ = 344 Rf value: 0.18 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(2) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide

The compound of Example 2 is used as starting material. Mass spectrum: M ⁺ = 348

Rf value: 0.39 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(3) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide

Compound 3 of Example 2 is used as starting material. It is recrystallized from water / ethanol. Melting point: 235 ° C (decomposition) Mass spectrum: M ⁺ = 379

Rf value: 0.33 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(4) 4- [[4- (Carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3-thiazole hydrobromide

Compound 2 of Example 2 is used as starting material. The residue is triturated with ether. Mass spectrum: (M + H) ⁺ = 362

Rf value: 0.51 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(5) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole hydrochloride

The mixture is stirred at room temperature for 3 hours. The residue is triturated with ether. Mass spectrum: M ⁺ = 366

Rf value: 0.42 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2) (6) 5- [[4- (Carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole hydrochloride

Melting point: 310-315 ° C (decomp.) Mass spectrum: (M + H) ⁺ = 363

Rf value: 0.14 (silica gel; methylene chloride / methanol concentrated ammonia = 2: 1: 0.2)

(7) 5- [N- [trans-4- (2-carboxyethyl) cyclohexyl] -N- (3-pyridylmethyl) aminocarbonyl] -2- (4-piperidyl) -1, 3, 4 thiadiazole dihydrochloride

The mixture is stirred for 3 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is dried in vacuo. Mass spectrum: M ⁺ = 457

Rf value: 0.28 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(8) 4- [trans-2- [(trans-4-carboxy-cyclohexyl) aminocarbonyl] ethenyl] -1- (4-piperidyl) imidazole dihydrochloride mass spectrum: M ⁺ = 346

Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(9) 4- [2- [(trans-4-carboxy-cyclohexyl) aminocarbonyl] ethyl] - 1- (4-piperidyl) imidazole dihydrochloride mass spectrum: M ⁺ = 348

Rf value: 0.23 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(10) 5- [N- [trans-4- (2-carboxyethyl) cyclohexyl] -N-methylaminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

(11) 5- [[trans-4- (carboxymethyloxy) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

(12) 5- [N- [4- (Carboxymethyloxy) phenyl] -N-methylaminocarbonyl] -2- (1-piperazinyl) -1, 3,4-thiadiazole dihydrochloride (13) 5- [[trans-4- (carboxymethyloxy) cyclohexyl] aminocarbonyl] -2- (1-piperazinyl) -1, 3,4-thiadiazole dihydrochloride

(14) 5- [[4- [(2-carboxyethyl) oxy] -1-piperidyl] carbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole hydrochloride

(15) 5- [[4- (Carboxymethyloxy) phenyl] carbonylamino] -2- (4-piperidyl) -1,3,4-thiadiazole hydrochloride

(16) 5- [[4- [(2-carboxyethyl) oxy] -1-piperidyl] carbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrobromide

The compound of Example 2 (4) is used as starting material.

(17) 5- [[4- (Carboxymethyloxy) phenyl] aminocarbonyl] -4-phenyl- 2- (4-piperidyl) -1,3-thiazole hydrobromide

The compound of Example 2 (5) is used as starting material.

(18) 5- [[4- (Carboxymethyloxy) phenyl] aminocarbonyl] -4-methyl- 2- (1-piperazinyl) -1, 3-thiazole dihydrobromide

The compound of Example 2 (6) is used as starting material.

(19) 5- [[4- (Carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3-thiazole hydrate

5- [[4- (Cyclohexyloxycarbonyl-methyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole hydrobromide is used as starting material. The product is recrystallized from dilute saline.

Melting point: 365 ° C (decomp.) Mass spectrum: (M + H) ⁺ = 362

Rf value: 0.28 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(20) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] - 2- (4-piperidyl) -1,3-thiazole hydrobromide

The compound of Example 2 (10) is used as starting material. Melting point: 245-247 ° C (sintering) Mass spectrum: M ⁺ = 365

Rf value: 0.44 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(21) 5- [[trans-4- (carboxy) cyclohexyl] aminocarbonyl] -2- [(4-piperidyl) oxymethyl] -1, 3-thiazole hydrochloride

(22) 5- [[trans-4- (carboxy) cyclohexyl] aminocarbonyl] - 2- [2- (4-piperidyl) ethyl] tetrazole hydrochloride

(23) 4- [N- [trans-4- (carboxy) cyclohexyl] -N-phenylmethylaminocarbonyl] -1- [2- (4-piperidyl) ethyl] pyrazole hydrochloride

(24) 5- [[4- [2- (Carboxy) -2- (methanesulfonylamino) ethyl] phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-oxadiazole hydrochloride

(25) 4- [[2- (4-Carboxy-l-piperidyl) ethyl] aminocarbonyl] -1- (4-piperidyl) imidazole trihydrochloride

Mass spectrum: (M + H) ⁺ = 350

Rf value: 0.12 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(26) 4- [4- [(2-carboxyethyl) oxy] piperidinocarbonyl] -1- (4-piperidyl) imidazole dihydrochloride

Mass spectrum: M ⁺ = 350

Rf value: 0.21 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(27) 4- [[trans-4-carboxy-cyclohexyl] aminocarbonyl] -1- [2- (4-piperidyl) ethyl] imidazole dihydrochloride

Mass spectrum: M ⁺ = 348

Rf value: 0.13 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25) (28) 5- [[4- (Carboxymethyloxy) phenyl] oxymethyl] -2- [4-piperidyl] -1,3,4-thiadiazole hydrochloride

The compound 14 of Example 2 is used as the starting material. It is stirred for 4 hours at room temperature. The crystalline precipitate is filtered off and dried. The compound crystallizes in the form of the hydrochloride. Melting point: 275-277 ° C Mass spectrum: (M + H) ⁺ = 350

Rf value: 0.06 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(29) 5- [2- [4- (Carboxymethyloxy) phenyl] ethyl] -2- [4-piperidyl] -1,3,4-thiadiazole hydrobromide

The compound 15 of Example 2 is used as the starting material. It is stirred for 4 hours at room temperature. Melting point: 261-264 ° C Mass spectrum: (M + H) ⁺ = 348

Rf value: 0.14 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example 5

5- [[4- (Methoxycarbonylmethyloxy) phenyl] aminocarbonyl] - 2- (4-piperidyl) -1,3,4-thiadiazole trifluoroacetate

To a solution of 390 mg of 2- [1- (tert-butyloxycarbonyl) -4-piperidyl] -5- [[4- (methoxycarbonyl-methyloxy) phenyl] aminocarbonyl] -1, 3, 4- thiadiazole in 20 mL anhydrous methylene chloride is added to 5 mL trifluoroacetic acid at 0 ° C. The mixture is stirred for 1.5 hours at room temperature and evaporated under reduced pressure. The residue is triturated with a little anhydrous methanol and suction filtered.

Yield: 120 mg (44% of theory), mass spectrum: (M + H) ⁺ = 377

Rf value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1) The following compounds are obtained analogously to Example 5:

(1) 5- [N- [trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] -

N- (3-pyridylmethyl) aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thia-diazole dihydrochloride

The residue is dissolved in ethyl acetate and extracted with 0.5M sodium hydroxide solution. The organic phase is dried and evaporated. The residue is dissolved in anhydrous methanol, acidified with ethereal hydrochloric acid and the solvent is evaporated off under reduced pressure. Mass spectrum: (M + H) ⁺ = 472

Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(2) 4- [[trans-4- (N-carboxymethyl-N-methanesulfonylamino) cyclohexyl] carbonylamino] -1- (4-piperidyl) imidazole dihydrochloride 4- [[trans- 4- (N-tert.butyloxycarbonylmethyl-N-methanesulfonylamino) cyclohexyl] carbonylamino] -1- (1-tert.butyloxycarbonyl-4-piperidyl) imidazole. The hydrochloride is prepared by dissolving it in 1N hydrochloric acid and evaporating the solvent.

Mass spectrum: (M + H) ⁺ = 428

Rf value: 0.34 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(3) 4- [[4- (methoxycarbonylmethyloxy) phenyl] carbonylamino] - 1- (4-piperidyl) imidazole dihydrochloride

The residue is dissolved in methanol. Ethereal hydrochloric acid is added and the mixture is evaporated. The product is triturated with acetone and suction filtered. Mass spectrum: M ⁺ = 358

Rf value: 0.18 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1) Example 6

4- [[trans-4- (2-carboxy-ethyl) cyclohexyl] aminocarbonyl] - 2- (4-piperidyl) -1,3-thiazole

So much is added to a suspension of 180 mg of 4- [[trans-4- (2-methoxycarbonylethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1,3-thiazole hydrobromide in 10 mL tetrahydrofuran Methanol that a clear solution is created. 2 mL of sodium hydroxide solution are added, the mixture is stirred at room temperature for 6 hours and neutralized with 1M hydrochloric acid. The solvents are evaporated under reduced pressure and the residue with methylene chloride / methanol / conc. Ammonia = 2: 1: 0.25 chromatographed on silica gel. Yield: 200 mg (product contains inorganic salts), mass spectrum: M ⁺ = 365

Rf value: 0.54 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

The following compounds are obtained analogously to Example 6:

(1) 4- [trans-2- [[4- (carboxymethyl) -1-piperazinyl] carbonyl] ethenyl] -1- (4-piperidyl) imidazole

Mass spectrum: M ⁺ = 347

Rf value: 0.27 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(2) 4- [2- [[4- (carboxymethyl) -1-piperazinyl] carbonyl] ethyl] - 1- (4-piperidyl) imidazole

Mass spectrum: (M + H) ⁺ = 350

Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(3) 5- [[1- (2-carboxyethyl) -4-piperidyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole

(4) 5- [[1- (carboxymethyl) -4-piperidyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole (5) 5- [[1- (carboxymethyl) -4-piperidyl] methylaminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole

(6) 5- [[2- (4-carboxy-l-piperidyl) ethyl] aminocarbonyl] - 2- (4-piperidyl) -1,3,4-thiadiazole

(7) 5- [[1- (2-carboxyethyl) -4-piperidyl] carbonylamino] - 2- (4-piperidyl) -1,3,4-thiadiazole

(8) 4- [[1- (2-carboxyethyl) -4-piperidyl] carbonylamino] - 1- (4-piperidyl) imidazole

(9) 4- [[[1- (carboxymethyl) -4-piperidyl] methyl] carbonylamino] -1- (4-piperidyl) imidazole

(10) 5- [[4- (2-carboxy-ethyl) phenyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole

The hydrolysis is carried out with lithium hydroxide in tetrahydrofuran / water (5: 4). Melting point: 286-289 ° C. Mass spectrum: M ⁺ = 373

Rf value: 0.27 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(11) 1- [2- (4-piperidyl) ethyl] -4- [[4- (carboxymethyl) -1-pipazinyl] carbonyl] imidazole

The residue is stirred with methylene chloride / absolute methanol (1: 1) and suction filtered. The filtrate is evaporated. Mass spectrum: (M + H) ⁺ = 350

Rf value: 0.09 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(12) 5- [(trans-4-carboxy-cyclohexyl) aminocarbonyl] -4-methyl- 2- [2- (4-piperidyl) ethyl] -1, 3-thiazole hydrochloride

The hydrolysis is carried out with lithium hydroxide in tetrahydrofuran / water (5: 4). After 4 hours with IN hydrochloric acid acidified and excess tetrahydrofuran evaporated. The precipitate is filtered off and washed with a little water. Melting point: 285-295 ° C (decomp.) Mass spectrum: M ⁺ = 379

Rf value: 0.16 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(13) 5- [[4- (carboxymethyl) -1-piperazinyl] carbonyl] -4-methyl- 2- [2- (4-piperidyl) ethyl] -1, 3-thiazole

The hydrolysis is carried out with lithium hydroxide in tetrahydrofuran / water (5: 4). After 4 hours the solvent is evaporated under reduced pressure and the crude product with methylene chloride / methanol / conc. Ammonia (2: 1: 0.2) chromatographed on silica gel. Mass spectrum: M ⁺ = 381

Rf value: 0.16 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(14) 4- [[4- (Carboxymethyloxy) phenyl] carbonylamino] -1- (4-pipeidyl) imidazole

The organic solvent is evaporated and the aqueous solution is cooled. The precipitate is filtered off. Mass spectrum: M ⁺ = 344

Rf value: 0.21 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(15) 5- [(trans-4-carboxy-cyclohexyl) aminocarbonyl] -2- [2- (4-piperidyl) ethyl] -1,3-thiazole hydrochloride

The hydrolysis is carried out with lithium hydroxide in tetrahydrofuran / water (5: 4). After 5 hours, acidify with IN hydrochloric acid.

Melting point: 279-284 ° C Mass spectrum: M ⁺ = 365

Rf value: 0.17 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2) (16) 5- [[1- (2-Carboxyethyl) -4-piperidyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole

The hydrolysis is carried out with lithium hydroxide in tetrahydrofuran / water (5: 4). The crude product is mixed with methylene chloride / methanol / conc. Ammonia (2: 1: 0.2) chromatographed over silica gel.

Melting point: 280-285 ° C Mass spectrum: M ⁺ = 366

Rf value: 0.15 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

Example 7

4- [2- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] ethyl] -1- (4-piperidyl) imidazole dihydrochloride

A solution of 770 mg of 4- [trans-2- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] ethenyl] -1- (4-piperidyl) imidazole dihydrochloride in 25 mL methanol is in the presence of Hydrogenated 0.2 g of 10% palladium on carbon at a hydrogen pressure of 3 bar and at a temperature of 40 ° C. The catalyst is filtered off and the solvent is evaporated off under reduced pressure.

Yield: 730 mg (94% of theory), mass spectrum: M ⁺ = 362

Rf value: 0.51 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

The following compounds are obtained analogously to Example 7:

(1) 4- [2- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] ethyl] -1- (4-piperidyl) imidazole trihydrochloride mass spectrum: M ⁺ = 363

Rf value: 0.44 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25) (2) 5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] -4-methyl-2- [2- (4-piperidyl) ethyl] -1,3-thiazole

The hydrogenation of 2- [2- [1- (benzyloxycarbonyl) -4-piperidyl] ethyl] -4-methyl-5- [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] -1,3-thiazole takes place at room temperature. The crude product is mixed with methylene chloride / methanol / conc. Ammonia (4: 1: 0.2) chromatographed on silica gel. Melting point: 168-170 ° C. Mass spectrum: M ⁺ = 393

Rf value: 0.19 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(3) 5- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] - 4-methyl-2- [2- (4-piperidyl) ethyl] -1,3-thiazole

The hydrogenation of 2- [2- [1- (benzyloxycarbonyl) -4-piperidyl] ethyl] -4-methyl-5- [[4- (methoxycarbonylmethyl) -1-piperazinyl] carbonyl] -1, 3-thiazole takes place at room temperature. The crude product is mixed with methylene chloride / methanol / conc. Ammonia (4: 1: 0.2) chromatographed on silica gel. Mass spectrum: M ⁺ = 394

Rf value: 0.22 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example 8

5- [[4- (Cyclohexyloxycarbonyl-methyloxy) phenyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1, 3-thiazole hydrochloride

A solution of 150 mg of 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1, 3-thiazole hydrochloride in 15 g of cyclohexanol and 10 mL of ethereal hydrochloric acid is heated to reflux for 1 hour. The ether is distilled off and the reaction solution is stirred at 60 ° C. for 4 hours. The cyclohexanol is evaporated off under reduced pressure, the residue is triturated with ether and suction filtered. Yield: 135 mg (75% of theory), Mass spectrum: M ⁺ = 457

Rf value: 0.80 (silica gel; methylene chloride / methanol = 2: 1: 0.25)

The following compounds are obtained analogously to Example 8:

(1) 5- [[[1- (methoxycarbonylmethyl) -4-piperidyl] methyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1,3-thiazole hydrochloride

The reaction takes place in methanol / ethereal hydrochloric acid (3: 1). The mixture is stirred at room temperature for 16 hours. Mass spectrum: (M + H) ⁺ = 395

Rf value: 0.77 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(2) 5- [[trans-4- (ethoxycarbonylmethyloxy) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole hydrochloride

The reaction takes place in ethanol / ethereal hydrochloric acid (2: 1). The mixture is stirred at room temperature for 16 hours. Mass spectrum: M ⁺ = 395

Rf value: 0.82 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(3) 5- [[4- (Ethoxycarbonylmethyloxy) phenyl] aminocarbonyl] - 2- (4-piperidyl) -1, 3-thiazole hydrochloride

The reaction takes place in ethanol / ethereal hydrochloric acid (2: 1). The mixture is stirred at room temperature for 16 hours. The mixture is then heated under reflux for 5 hours. Mass spectrum: M ⁺ = 389

Rf value: 0.70 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(4) 5- [[4- (iso-propyloxycarbonylmethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride The reaction is carried out in isopropanol / ethereal hydrochloric acid

(6: 1). After the ether has been evaporated, the mixture is heated to 80 ° C. for 5 hours. The precipitate is filtered off. Melting point: 275-278 ° C Mass spectrum: M ⁺ = 404

Rf value: 0.81 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(5) 5- [[4- (iso-butyloxycarbonylmethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

The reaction takes place in isobutanol / ethereal hydrochloric acid (8: 1). After the ether has been evaporated, the mixture is heated to 80 ° C. for 5 hours. The residue is triturated with isobutanol and dried.

Melting point: 284-286 ° C. Mass spectrum: M ⁺ - 418

Rf value: 0.83 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(6) 5- ([4- (Ethoxycarbonylmethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3,4-thiadiazole hydrochloride

The reaction takes place in ethanol / ethereal hydrochloric acid (7: 1). After the ether has been evaporated off, the mixture is heated under reflux for 6 seconds. The residue is triturated with ethanol and dried. Melting point: 265-267 ° C. Mass spectrum: M ⁺ = 390

Rf value: 0.74 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example 9

1- [1- (tert-Butyloxycarbonyl) -4-piperidyl] -4- [[4- (methoxycarbonyl-methyloxy) phenyl] carbonylamino] imidazole

Sufficient methylene chloride is added to a suspension of 340 mg methyl α- (4-carboxyphenyloxy) acetic acid in 10 ml thionyl chloride to give a solution. The mixture is stirred at room temperature for 2 hours and the solvent is evaporated. 430 mg of crude 4-amino-1- [1- (tert-butyloxycarbonyl) -4-piperidyl] imidazole in 40 ml of ethyl acetate and 1.0 ml are added to this solid Triethylamine in 20 mL tetrahydrofuran and stirred for 16 hours at room temperature. The reaction solution is extracted with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is evaporated and the crude product with methylene chloride / methanol / conc. Ammonia (18: 1: 0.1) chromatographed on silica gel. Yield: 310 mg (42% of theory), mass spectrum: M ⁺ = 458

Rf value: 0.52 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example 10

2- [1- (Benzyloxycarbonyl) -4-piperidyl] -5- [[4- (ethoxycarbonylmethyloxy) phenyl] oxymethyl] -1, 3,4-thiadiazole

A suspension of 3.0 g of 1 - [[[4- (ethoxycarbonylmethyloxy) phenyl] oxymethyl] carbonyl] -2- [(l-benzyloxycarbonyl-4-piperidyl) carbonyl] hydrazine and 2.4 g of 2 , 4-Bis- (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane-2j, 4-disulfide in 500 mL tetrahydrofuran is heated to reflux for 30 minutes. The solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel using ethyl acetate / cyclohexane (2: 1).

Yield: 2.1 g (70% of theory), melting point: 96-98 ° C

Rf value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

The following connection is established analogously to Example 10:

(1) 2- [1- (Benzyloxycarbonyl) -4-piperidyl] -5- [2- [4- (ethoxycarbonylmethyloxy) phenyl] ethyl] -1,3,4-thiadiazole mass spectrum: M ⁺ = 509 Rf value: 0.38 (silica gel; cyclohexane / ethyl acetate = 1: 2) Example 11

Dry ampoule with 2.5 mg active ingredient per 1 ml

Composition:

Active ingredient 2.5 mg

Mannitol 50.0 mg

Water for injections ad 1.0 ml

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The dissolution for the ready-to-use solution takes place with water for injection purposes.

Example 12

Dry ampoule with 35 mg of active ingredient per 2 ml

Composition:

Active ingredient 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.

The ready-to-use solution is dissolved with water for injections. Example 13

Tablet with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) milk sugar 98.0 mg

(3) corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215.0 mg

Manufacturing:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side. Tablet diameter: 9 mm.

Example 14

Tablet with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) polyvinyl pyrrolidone 30.0 mg

(5) Magnesium stearate 4.0 mg

600.0 mg Manufacturing:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side. Tablet diameter: 12 mm.

Example 15

Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg

(3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate 2.0 mg

160.0 mg

Manufacturing:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

Example 16

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) Corn starch dried 46.0 mg (3) Milk sugar powdered 30.0 mg

(4) Magnesium stearate 4.0 mg

430.0 mg

Manufacturing:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.

Claims

claims 1. 5-membered heterocycles of the general formula I in the one of the residues Xi to X5 is a group of the formulas A - B - N A - B - CHC _^ or A - B - C ^* * ^ in which A is a cycloalkyl group with 5 to 7 carbon atoms, optionally substituted by 1 to 4 alkyl groups, in which an unsubstituted methylene group is replaced by the R _a -N <group, which is additionally substituted by a cyano, aminocarbonyl, carboxy, alkoxycarbonyl - Or phenylalkoxycarbonyl group or, if the substitution is not in the α-position to a nitrogen atom, may be substituted by a hydroxy, alkoxy, phenylalkoxy group, and in the R _{a is} a hydrogen atom, an alkyl group, a phenylalkyl group, an alkoxycarbonyl group with a total of 2 to 6 carbon atoms, a phenylalkoxycarbonyl group, an alkyleneoxycarbonyl group with a total of 4 to 6 carbon atoms, a cycloalkoxycarbonyl group with a total of 6 to 8 carbon atoms or one Rχ-CO-0- (R2CH) -O-CO group in which R1 is an alkyl group with 1 to 5 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, a phenylalkyl group, an alkoxy group with 1 to 5 carbon atoms men, a cycloalkoxy group having 5 to 7 carbon atoms or a phenyl group and R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or a phenyl group, and additionally in the 6- or 7-membered azacycloalkyl groups thus formed a> CH unit in the 4-position by a nitrogen atom or in the 5- to 7-membered azacycloalkyl groups thus formed a -CH2 ~ CH <unit by a -CH = C <unit and in the piperazinyl or homopiperazinyl rings thus formed one or two methylene groups, which are adjacent to the nitrogen atom in 4-division, can each be replaced by a carbonyl group, or a quinuclidinyl group, B is a straight-chain or branched alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 or 3 carbon atoms, a -0 (CH ₂ ) _n ~ / - (CH ₂ ) _n O-, -S (CH ₂ ) _n -, - (CH ₂ ) _n S-, -CONR3-, -R3NCO-, -NR3 (CH ₂ ) _n " ^or - (CH ₂ ) _n NR3 ~ group in which n is the number 1 or 2 and R _{3 represents} a hydrogen atom, a phenylalkyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by an alkyl, hydroxyl or alkoxy group, an alkyl or pyridylalkyl group and an oxygen, sulfur or nitrogen atom of the radical B not is directly connected to a nitrogen atom of radical A or to a nitrogen atom of the 5-membered heterocycle, or a bond with the proviso that a nitrogen atom of group A is not bound to a nitrogen atom of the 5-membered heterocycle, a second of the radicals X ^ to X5 is a group of the formulas R _b 0 CO - FE - D - N R _b 0 - CO - F - E - D - CH \ or R _b 0 - CO - F - E - D - C ^* ^. , in which D a -CO-, -CO-NR3-, -NR3-CO-, -SO2-NR3-, -NR3-SO2-, -W-CO-NR3-, -WX-NR3-C0-, -WX-S02NR3 -, -W ₁ -NR ₃ S0 ₂ -, -CO-NR3-WX-, -NR3-C0-WX-, -S02NR3-W! -, -NR3S02-W! -, -CO- (CH ₂ ) _n -0-, -CO- (CH2) n ^_NR 3- / -0-Wχ-, -Wχ-0-, -3-Wχ-, -Wx-S-, -NR3-Wχ-, -W! -NR ₃ -, - (CH2) n "- ⁰ - (CH ₂ ⁾ n- '" (CH ₂ ) _n -NR ₃ - (CH ₂ ) _n - or -W group or also a -W-CO group, if the 5-membered X ^ to X5 ring is not an isoxazole or isoxazoline ring, with the proviso that the above groups are not bonded via a carbonyl or sulfonyl group to a nitrogen atom of the 5-membered heterocycle in which R3 and n are defined as mentioned above, Wi is an alkylene group with 1 to 3 carbon atoms, W2 is an alkenylene group with 2 or 3 carbon atoms and W is an alkylene group having 1 to 3 carbon atoms or one Represent alkenylene group with 2 or 3 carbon atoms, E is a phenylene group which can be mono- or disubstituted by fluorine, chlorine or bromine atoms, by alkyl, trifluoromethyl, R3O or R3θ-CO-CH2 ~ 0 groups, where the substituents can be identical or different and R3 as defined above, a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene group, each of which can be substituted in the carbon skeleton by a chlorine atom, by an alkyl or alkoxy group, with one or two -CH = N groups additionally each having a - C0-NR3 ~ group, in which R3 is as defined above, can be replaced and one of the stick Substance atoms can also be bound to the radical F instead of to the radical R3, provided that this does not represent a bond, a cycloalkylene group with 4 to 5 carbon atoms optionally substituted by an alkyl, phenylalkyl or phenyl group, in which a> CH unit can be replaced by a nitrogen atom and additionally a methyl group adjacent to the nitrogen atom by a carbonyl group , or a cycloalkylene group with 6 or 7 carbon atoms, optionally substituted by an alkyl, phenylalkyl or phenyl group, in which one or two CH units can each be replaced by a nitrogen atom, with a methylene group adjacent to a nitrogen atom being additionally replaced by a Carbonyl group can be replaced F a bond, one optionally by a phenylalkyl, phenyl, pyridyl, R ₃ 0-, R ₃ S-, R3R ₃ N-, R3O-CO-, R ₃ R3 ^ -CO-, R4CO-NR3-, R5O-CO- NR3, R4SO2-NR3, R3R3N-CO-NR3, R3θ-CO-Cχ_3-alkyl or R3R3N-CO-C1_3 ~ alkyl group substituted straight-chain or branched alkylene or alkenylene group, in each of which the alkylene part 1 to 5 Carbon atoms and the alkenylene part can contain 2 to 5 carbon atoms, or a -Y-Wχ group in which R ₃ and Wi are defined as mentioned above, R4 is an alkyl group with 1 to 5 carbon atoms, a phenylalkyl, phenyl or pyridyl group, R5 is an alkyl group with 1 to 5 carbon atoms, a phenylalkyl, cycloalkyl or cycloalkylalkyl group and Y is an oxygen atom, a -CO-, sulfenyl-, sulfinyl-, sulfonyl-, -NR3-, -N (COR ₄ ) -, -N (S0 ₂ R4) -, -CO-NR3- or -NR3-CO- group, where Y is linked to the radical E with the proviso that a heteroatom of the radical E is not attached to a Nitrogen or sulfur atom of the above groups is bound, and R _{D is} an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 5 to 7 carbon atoms in the cycloalkyl part, it being possible for the above-mentioned groups in the alkyl and cycloalkyl part from position 2 to be substituted by an R3O or R3R3N group , an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl part, which can be substituted in the alkyl part from position 2 by an R3O or R3R3N group, where R3 is in each case defined as mentioned above , an Rχ-CO-0- (R2CH) group in which R ^ and R ₂ are defined as mentioned above, or a hydrogen atom if the R _b O-CO group is not directly attached to a nitrogen atom of the rest E is bound the distance between the most distant nitrogen atom of group A and the COORj- _> group is at least 11 bonds and the above-mentioned AB and R _b O-CO-FED groups in the 1,3 position to one another stand, a third of the residues Xi to X5 is a sulfur atom, an HN <, R ₄ N <, R7C - ^ or (R7) 2C <group or an N atom, where R4 is as defined at the beginning and R7 represents a hydrogen atom, an alkyl, phenylalkyl or phenyl group, a fourth of the radicals X ^ to X5 is an oxygen, sulfur or nitrogen atom or an R ₇ C ^^ group in which R ₇ is defined as mentioned above, a fifth of the radicals X _] _ to X _{5 is} a nitrogen atom, one or (R7) 2C <group, where R7 is defined as mentioned above, or two adjacent radicals of the radicals X to X5 together denote an o-phenylene group, but at least one of the radicals X ^ to X5 in the aforementioned Xχ-X5 ~ ring must be a ring heteroatom, unless otherwise mentioned, the alkyl, alkylene and alkoxy parts mentioned above can each contain 1 to 3 carbon atoms and the cycloalkyl parts mentioned above can each contain 3 to 7 carbon atoms, their tautomers, their stereoisomers including their mixtures and their salts. 2. 5-membered heterocycles of the general formula I according to claim 1, in which the heterocycle contains a furan, tetrahydrofuran, 2,3-dihydro-furan, 2,5-dihydro-furan, thiophene, 2,3-dihydro-thiophene, 2,5-dihydrα-thiophene, tetrahydrothiophene, pyrrole, indole, isoindole, 2,3-dihydro-indole, 2,3-di-hydro-isoindole -, imidazole, 4, 5-dihydro-imidazole, tetrahydro-imidazole, benzimidazoline, pyrazole, 4, 5-dihydro-pyrazole, 2, 3-dihydro-pyrazole, indazole, 2, 3- Dihydroindazole, oxazole, isoxazole, oxazoline, oxazolidine, isoxazoline, thiazole, isothiazole, thiazoline, thiazolidine, 1,3, 4-0xadiazole, 1,2,4-oxadiazole, 1,3, 4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, 1,2, 4-triazole and tetrazole ring, their tautomers, their stereoisomers including their mixtures and their salts. 3. 5-membered heterocycles of the general formula I according to claim 1, in which one of the residues Xi to X5 is a group of the formulas A - B - N A - B - CHC _^ or A - B - ^c * ^ s. • i ⁿ which A is a cycloalkyl group with 5 to 7 carbon atoms, optionally substituted by 1 to 4 alkyl groups, in which an unsubstituted methylene group is replaced by the R _a -N <group, which is additionally replaced by a cyano, aminocarbonyl, carboxy or alkoxycarbonyl group or also if the substitution is not in the α-position to a nitrogen atom, may be substituted by a hydroxyl or alkoxy group, and in which R _{a is} a hydrogen atom, an alkyl, phenylalkyl, alkoxycarbonyl or phenylalkoxycarbonyl group or an Rχ-CO-0- (R2CH) -O-CO group in which Rl is an alkyl, cycloalkyl, phenyl, alkoxy or cycloalkoxy group each having 5 to 7 carbon atoms in the cycloalkyl part and R2 represents a hydrogen atom or a methyl group, and additionally in the 6- or 7-membered azacycloalkyl groups thus formed a> CH unit in the 4-position by a nitrogen atom or in the 5- to 7-membered azacycloalkyl groups thus formed a -CH2 ~ CH <unit by a -CH = C <unit can be replaced, or a quinuclidinyl group, B is an alkylene group with 1 to 5 carbon atoms, an alkylene group with 2 or 3 carbon atoms, an -OCH2-, -CH ₂ 0-, -SCH ₂ -, -CH ₂ S-, -CONR3-, -R3NCO-, - NR ₃ CH ₂ - or -CH2NR3 ~ group in which R3 represents a hydrogen atom, an alkyl, phenylalkyl or pyridylalkyl group and an oxygen, sulfur or nitrogen atom of the radical B is not directly connected to a nitrogen atom of the radical A or to a nitrogen atom of the 5-membered heterocycle, or a bond with the proviso that a nitrogen atom of group A is not bound to a nitrogen atom of the 5-membered heterocycle, a second of the radicals Xi to X5 is a group of the formulas R _b 0 - - CO - FE - D - N- R _b 0 - - CO - FE - D - CH _\ or R _b 0 - - co - F in which ^ D a -CO-, -CO-NR ₃ -, -NR3-CO-, -S02-NR3-, -NR3-SO2-, -W-CO-NR3-, -Wι-NR ₃ -CO-, -W ! -S0 ₂ NR ₃ -, -W! -NR ₃ Sθ2-, -CO-NR3-W1-, -NR3-CO-W1-, -S0 ₂ NR ₃ -Wι-, -NR ₃ S02-W! - , -CO-CH ₂ -0-, -CO-CH ₂ -NR ₃ -, -O-Wi-, -Wι-0-, -S-Wi-, -Wi-S-, -NR ₃ -W! -, -W ₁ -NR ₃ -, -CH2-O-CH2-, -CH2-NR ₃ -CH2- or -Wi group or also a -W-CO group, if the 5-membered Xi to X5 ~ Ring is not an isoxazole or isoxazoline ring, with the proviso that the above groups are not bonded via a carbonyl or sulfonyl group to a nitrogen atom of the 5-membered heterocycle in which R ₃ is defined as mentioned above, Wi is an alkylene group with 1 to 3 carbon atoms, W2 is an alkenylene group with 2 or 3 carbon atoms and W is an alkylene group having 1 to 3 carbon atoms or one Represent alkenylene group with 2 or 3 carbon atoms, E is a phenylene group formed by a fluorine, chlorine or bromine atom, by an alkyl, trifluoromethyl, R3O or R3θ-CO-CH2 ~ 0 group can be substituted, where R3 is defined as mentioned above, a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group, each of which can be substituted in the carbon skeleton by an alkyl or alkoxy group, a 1,4-cyclohexylene group in which one or two> CH units can each be replaced by a nitrogen atom, it also being possible for a methylene group adjacent to a nitrogen atom to be replaced by a carbonyl group, a 1,3-cyclohexylene group in which a> CH unit can be replaced by a nitrogen atom, in which case a methylene group adjacent to the nitrogen atom can then be replaced by a carbonyl group, a 1,3-pyrrolidinylene, 2-0xo-l, 3-pyrrolidinylene, 5-oxo-l, 3-pyrrolidinylene or 1,4-homopiperazinylene group, F a bond, a straight-chain or branched alkylene group with 1 to 5 carbon atoms, which is optionally substituted by a phenyl, pyridyl, R3O, R4CO-NR3, R5O-CO-NR3, R4SO2-NR3 or R3R3N-CO-NR3 group, or a - Y-Wι ~ group in which R3 and Wi are defined as mentioned above, R4 is an alkyl group of 1 to 5 carbon atoms, one Phenylalkyl, phenyl or pyridyl group, R5 is an alkyl group of 1 to 5 carbon atoms or one Phenylalkyl group and Y is an oxygen atom, a sulfenyl, -NR3-, -N (C0R4) - or -N (Sθ2R4) group, where Y with the rest E with the Provided that a hetero atom of the radical E is not bound to a nitrogen or sulfur atom from the above groups, and R _{b is} an alkyl group with 1 to 5 carbon atoms or a cycloalkyl group with 5 to 7 carbon atoms in the cycloalkyl part, which in the alkyl and cycloalkyl part from position 2 onwards can each be substituted by an R3O or R3R3N group, an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl part, which can be substituted in the alkyl part from position 2 by an R3O or R3R3N group, where R ₃ is defined as mentioned above, a Rl ~ CO-0- (R2CH) group in which Ri and R2 are defined as mentioned above, or also a hydrogen atom if the R _b O-CO group is not bonded directly to a nitrogen atom of the radical E, wherein the distance between the most distant nitrogen atom of group A and the COOR _b group is at least 11 bonds and the above-mentioned AB and R _D 0-CO-FED groups are in the 1,3 position to one another , a third of the radicals Xi to X5 is a sulfur atom, an HN <, R ₄ N <, R ₇ C ^** ^ or (R ₇ ) ₂ C <group or an N atom, where R4 is as defined at the beginning and R _{7 represents} a hydrogen atom, an alkyl, phenylalkyl or phenyl group, a fourth of the radicals Xi to X5 is an oxygen, sulfur or nitrogen atom or an R ₇ C ^ ^" C group in which R ₇ is defined as mentioned above, a fifth of the radicals Xi to X _{5 is} a nitrogen atom, an R ₇ C! "C ~ or (R ₇ > 2C <group, where R ₇ is defined as mentioned above, or two adjacent residues of the residues Xi to X5 together denote an o-phenylene group, but at least one of the residues Xi to X5 in the aforementioned X 1 ~ X 5 ring must be a ring hetero atom, unless otherwise mentioned, the alkyl, alkylene or alkoxy parts mentioned above can each contain 1 to 3 carbon atoms, their tautomers, their stereoisomers including their mixtures and their salts. 4. 5-membered heterocycles of the general formula I according to claim 1, in which one of the residues Xi to X5 is a group of the formulas A - B - N - »» or A - B - C <* - ^., In which A is a cycloalkyl group with 5 or 6 carbon atoms in which an unsubstituted methylene group in the 3- or 4-position is replaced by the R _a -N <group in which R _{a represents} a hydrogen atom, a C 2-2 alkyl, C 4 alkoxycarbonyll or benzyloxycarbonyl group, and in the 4-piperidinyl groups thus formed, a> CH unit in the 4-position can be replaced by a nitrogen atom, B is a bond, a Cι_2 ~ alkylene, -OCH2 or -CH2θ group, a second of the radicals Xi to X5 is a group of the formulas Rv-0 - CO - F - E - D - C / ^D <^, where D a -CO-, -CO-NR3-, -NR3-CO-, -W-CO-NR3-, -CO-NR3-W1-, -NR3-CO-W1-, -CO-CH ₂ -0- , -O-Wi-, -Wi-O- or -Wι ~ group or also a -W-CO group, if the 5-membered Xi to Xs ring is not an isoxazole ring, with the proviso that the above Groups are not bound via a carbonyl group to a nitrogen atom of the 5-membered heterocycle in which R3 is a hydrogen atom, a Cι_4-alkyl, benzyl or pyridylmethyl group, Wi a Cι_ ₂ alkylene group and W represents a C ₂ alkylene or vinylene group, E is a 1,4-phenylene group which may be substituted by a hydroxy, methoxy, carboxymethoxy or methoxycarboriylmethoxy group, a 1, 4-cyclohexylene group in which one or two> CH units can each be replaced by a nitrogen atom, F a bond, a straight-chain or branched alkylene group with 1 to 3 carbon atoms optionally substituted by an R4CO-NR3 or R4S0 ₂ -NR3 ~ group or a -Y-Wι ~ group in which R3 and Wi are defined as mentioned above, R4 represents a methyl, ethyl or phenyl group and Y represents an oxygen atom, an -NR3 or -N (S0 ₂ R4) group, Y with the radical E with the proviso is linked that a nitrogen atom of the radical E is not attached to an Is atom of the above groups and R3 and R4 are as defined above, and R _{b is} a C 5 alkyl, cyclohexyl or benzyl group or also a hydrogen atom if the R _b 0-C0 group is not bonded directly to a nitrogen atom of the radical E, wherein the distance between the most distant nitrogen atom of group A and the C00R _b group is at least 11 bonds and the above-mentioned AB and R _b O-CO-FED groups are in the 1,3 position to one another , a third of the radicals X ^ to X5 is an HN <, R ₄ N <or R7C group or a nitrogen atom, where R4 is as defined at the beginning and R7 represents a hydrogen atom, a C ₂ alkyl or phenyl group, a fourth of the radicals Xi to X5 is an oxygen, sulfur or nitrogen atom or an R ₇ C ^ ^* C group in which R ₇ is defined as mentioned above, a fifth of the radicals X ₁ to X _{5 is} a nitrogen atom or an R ₇ C- ^ Group, where R7 is defined as mentioned above and at least one of the radicals Xi to X5 in the above-mentioned X 1 ~ X 5 ring must be a ring hetero atom, their tautomers, their stereoisomers including their mixtures and their salts. 5. 5-membered heterocycles of the general formula I according to claim 1, in which one of the residues Xi to X5 is a group of the formulas A - B - N - «-. or A - B - C- ^ s. , in which A is a cyclohexyl group in which an unsubstituted methylene group in the 4-position is replaced by the R _a -N <group in which R _{a represents} a hydrogen atom, a C 4 alkoxycarbonyl or benzyloxycarbonyl group, B is a bond or a C ₂ alkylene group, a second of the radicals Xi to X5 is a group of the formulas R _b O - C0 - F - E - D - N \ or Ry ^D -0 - CO - F - E - D - C / <^, in which D a -CH ₂ CH ₂ -, -CO-, -CH ₂ -0-, -CH ₂ CH ₂ -CO-, -CH = CH-C0-, -CO-NR3-, -NR3-CO-, - CH ₂ CH ₂ -CO-NR3-, -CO-NR ₃ -CH ₂ - or -CO-NR3-CH ₂ CH2 ^_ group with the proviso that the above groups do not have a carbonyl group on a nitrogen atom of the 5-membered heterocycle are bound in R3 represents a hydrogen atom or a pyridylmethyl group, E is a 1,4-phenylene, 1,4-cyclohexylene, 1,4-piperidinylene or 1,4-piperazinylene group, F a bond, a -CH ₂ -, -CH ₂ CH ₂ -, -0-CH ₂ -, -0-CH ₂ CH ₂ - or -N (S0 ₂ CH ₃ ) -CH ₂ - group, and R _{b is} a C4-alkyl or cyclohexyl group or also a hydrogen atom if the R _b 0-C0 group is not bonded directly to a nitrogen atom of the radical E, wherein the distance between the most distant nitrogen atom of group A and the C00R _b group is at least 11 bonds and the above-mentioned AB and R _b 0-C0-FED groups are in the 1,3 position to one another , a third of the radicals Xi to X5 is a nitrogen atom or an R ₇ C < _ζ . Group in which R _{7 represents} a hydrogen atom or a methyl group, a fourth of the radicals Xi to X5 is a sulfur or nitrogen atom or an R ₇ CΞ ^" _ ^ group in which R ₇ is defined as mentioned above, a fifth of the radicals Xi to X5 is a nitrogen atom or an R ₇ C * ^ Group, where R7 is defined as mentioned above and at least one of the radicals Xi to X5 in the above-mentioned X 1 ~ X 5 ring must be a ring hetero atom, their tautomers, their stereoisomers including their mixtures and their salts. 6. The following 5-membered heterocycles of the general formula I according to claim 1: (1) 4- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] - 1- (4-piperidyl) imidazole, (2) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -4-methyl-2- (4-piperidyl) -1, 3-thiazole, (3) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -4-methyl- 2- (4-piperidyl) -1, 3-thiazole, (4) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole, (5) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole, (6) 5- [[trans-4- (carboxymethyloxy) cyclohexyl] aminocarbonyl] 2- (4-piperidyl) -1, 3-thiazole, (7) 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole, (8) 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -2- (4-piperidyl) -1, 3-thiazole, (9) 4- [[trans-4-carboxy-cyclohexyl] aminocarbonyl] -1- [2- (4-piperidyl) ethyl] imidazole, whose Cι_4 ~ alkyl and cyclohexyl esters and their salts. 7. The following 5-membered heterocycles of the general formula I according to claim 1: 5- [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] - 2- (4-piperidyl) -1,3,4-thiadiazole, 5- [[4- (carboxymethyloxy) phenyl] aminocarbonyl] -2- (4-piperidyl) -1,3,4-thiadiazole, whose Cι_4-alkyl and cyclohexyl esters and their salts. 8. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 7 with inorganic or organic acids or bases. 9. Medicament containing a compound according to at least one of claims 1 to 7 or a physiologically tolerable salt according to claim 8 in addition to optionally one or more inert carriers and / or diluents. 10. Use of a compound according to at least one of claims 1 to 8 for the manufacture of a medicament which is suitable for combating or preventing diseases in which smaller or larger cell aggregates occur or cell-matrix interactions play a role . 11. A method for producing a medicament according to claim 9, characterized in that a compound according to at least one of claims 1 to 8 is incorporated into one or more inert carriers and / or diluents by a non-chemical route. 12. A process for the preparation of the compounds of general formula I according to claims 1 to 8, characterized in that a) for the preparation of a compound of the general formula I in which R _{a is} a hydrogen atom and R _b, with the exception of the R ₁ -CO-O- (R ₂ CH) group, has the meanings mentioned for R _b in claims 1 to 7, R _{a has} the meanings mentioned for R _a in claims 1 to 7 and R _{b represents} a hydrogen atom or R _a and R _b each represent a hydrogen atom, a compound of the general formula 3 ^X 4 , (ID * 2. - * ι in which one of the residues Xi to X5 is a group of the formulas A '- B - l £, A '- B - CIL ^ or A '- B - Cv ^ in which B is as defined in claims 1 to 7 and A ^{1 has} the meanings mentioned for A in claims 1 to 7 and additionally contains a protective radical which can be split off for an imino group, a second of the radicals Xi to X5 is a group of the formulas R _b '0 - CO - F - < ^• R _b '0 - CO - F - E - D - CH- ^ or R _b ^» 0 - CO - F - E - D - C ^>. , in which F, E and D are as defined in claims 1 to 7 and R _b 'has the meanings mentioned for R _b in claims 1 to 7 and additionally represents a protective radical which can be split off for a hydroxyl group of a carboxyl group, but at least one of the Radicals A 'or R _b ' must contain or represent a removable protective radical, and the rest of the radicals Xi to X5 are as defined in claims 1 to 7, by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of the general formula I in which R _{a is} a hydrogen atom and R _b with the exception of the R 1 ~ CO-0- (R ₂ CH) group which has the meanings mentioned for R _b in claims 1 to 7, R _{a has} the meanings mentioned for R _a in claims 1 to 7 and R _{b represents} a hydrogen atom or R _a and R _D each represent a hydrogen atom, is transferred or b) for the preparation of a compound of the general formula I in which four of the radicals Xi to X5 are defined as in claims 1 to 7 and the last radical of the radicals Xi to X5 is one R _b O-CO-FED-CH <, R _b -CO-FEDN <or R _b -CO-FEDC <_> . Represents group in which D a -CO-NR3-, -NR3-C0-, -SO2-NR3-, -NR ₃ -S0 ₂ -, -W-CO-NR3-, -W1-NR3-CO-, -Wι-S0 ₂ NR ₃ -, -W1-NR3SO2-, -CO-NR3-W! -, -NR ₃ -CO-W1-, -S0 ₂ NR3 ~ Wι- or -NR3S0 ₂ -Wι group or D together with the hydrogen atom of an im Rest E present imino group means a -CO- or -W-CO group, a compound of the general formula with a compound of the general formula Ui - E - F - CO - 0R _b , (IV) in which E, F, R _b with the exception of the Rι ~ CO-0- (R ₂ CH) -O-CO group and four of the radicals Xi to X5 as defined in claims 1 to 7, the last of the radicals Xi to X5 a Zi-CO, Zι-S0 ₂ - / Z] _- C0-W or Zι ~ Sθ2-Wι group and Ui is a hydrogen atom of an imino group of the radical E, an HNR3 or HNR3-Wι ~ group or the last of the radicals Xi to X5 an HNR3 or HNR3-W1 group and Ui a Z2-CO-, Z2 ~ S0 ₂ - / Z ₂ -CO-Wι ~ or Z ₂ -S0 ₂ -Wι ~ mean in which R3, W and Wi are as defined in claims 1 to 7, Zi or Z2 denotes a nucleofugal leaving group, is implemented or c) for the preparation of a compound of general formula I, in which D represents a -CH2CH2-CO-NR3- or -CH ₂ CH ₂ CH ₂ -CO-NR3 group, a compound of general formula ^v 3 ^X Ϊ4 * , (V) in the Xl to X5 are as defined in claims 1 to 7, with the proviso that D in the second of the radicals Xi to X5 contains an alkenylene group with 2 or 3 carbon atoms, is catalytically hydrogenated or d) for the preparation of a compound of the general formula I in which R _{b is} an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycljoalkylalkyl group with 5 to 7 carbon atoms in each case Cycloalkyl part, an R 1 ~ CO-0- (R2CH) group, a compound of the general formula in the Xl to X5 with the proviso as defined in claims 1 to 7 that R _{b represents} a hydrogen atom, with a compound of the general formula HO - R _b , (VII) or with a compound of the general formula Z ₃ - R _c , (VIII) in which R _{b is} an alkyl group with 1 to 5 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group each with 5 to 7 carbon atoms in the cycloalkyl part, R _{c is} an alkyl group with 1 to 5 carbon atoms _/ an alkenyl group with 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group each with 5 to 7 carbon atoms in the cycloalkyl part, an R ₁ -CO-O- (R ₂ CH ) Group in the Rl and R _{2 are} as defined in claims 1 to 7 and Z _{3 represent} a leaving group, is implemented or e) for the preparation of 1,3,4-oxathiazole, 1,3,4-thiadiazole and 1,3, 4-triazole derivatives of the general formula I, a compound of the general formula optionally formed in the reaction mixture N - N. A - B - / C - E - F - CO - R _b • < ^IX > Z ₄ ^Z 5 in the Z4 and Z5, which may be the same or different, halogen atoms, optionally substituted by R ₇ amino groups _/ where R ₇ as defined in claims 1 to 7, represent hydroxyl, alkoxy, mercapto or alkyl mercapto groups, is cyclized and if necessary, a protective residue used in the reactions described above is split off again and / or if desired, a compound of the general formula I thus obtained is separated into its stereoisomers and / or a compound of the general formula I thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.