SK128193A3 - Carboxylic acids derivatives, medicaments containing these compounds and method of their production - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of the general formula A - B - C - D - E - COORa, (I> in which A to E and Ra are defined as in Claim 1, in particular compounds of the formula (II), <IMAGE> to their tautomers, their stereoisomers, including their mixtures, and to their salts, in particular to their physiologically tolerated salts with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably aggregation-inhibiting effects, to drugs (medicaments, pharmaceuticals) containing these compounds, and to processes for their preparation.

Description

Technical field

The present invention relates to carboxylic acid derivatives, to medicaments containing them, and to processes for their preparation.

BACKGROUND OF THE INVENTION

In European published publications 0478328 and 0478363, phenylalanyl derivatives have been described as antagonists of fibrinogen receptors.

SUMMARY OF THE INVENTION

It has now been found that the novel carboxylic acid derivatives of formula (I)

A-B-C-D-E-COOR _and (I) also exhibit valuable pharmacological properties, in particular aggregation suppression efficiency, wherein the novel compounds differ from the compounds described in the above-mentioned published publication in particular in the remainder of B.

The present invention, together with the novel carboxylic acid derivatives of the above general formula I, their tautomers, their stereoisomers, including mixtures thereof and their salts, in particular the physiologically acceptable salts with inorganic or organic acids or bases, medicaments containing these compounds and their use as well as production methods.

In the above general formula I means

- R 2 is hydrogen, C 1 -C 5 alkyl, C 3 -C 5 alkenyl, C 1 -C 3 phenylalkyl, C 5 -C 7 cycloalkyl or R 1 -CO- O- (R ₂ CH) -C 1 -C 5 -alkyl, C 5 -C 7 -cycloalkyl, C 1 -C 3 -phenylalkyl, C 1 -C 5 -alkoxy, (C 5 -C 7) cycloalkoxy or phenyl; and

R ₂ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 5 -C 7 cycloalkyl group or a phenyl group,

A represents a C 1 -C 5 aminoalkyl or a 5-, 6 or 7-membered azacycloalkyl radical via the carbon atom of radical A with the radical B, wherein the coupling of the azacycloalkyl radical with the radical B is effected via the carbon atom of the azacycloalkyl group and the hydrogen atom of the amino group the aminoalkyl groups and the hydrogen atom on the nitrogen atom of said azacycloalkyl groups may be replaced by a residue and furthermore, the carbon atoms of the azacycloalkyl group may be substituted by one to three alkyl groups of 1 to 3 carbon atoms, alkylamino, cyano, R RO- or R R3O- CO-C 1 -C 3 -alkyl, C 1 -C 3 -phenylalkyl, C 1 -C 3 -alkanoyl, trifluoroacetyl, C 2 -C 6 -alkoxycarbonyl, C 1 -C 3 phenylalkoxycarbonyl; an alkoxy moiety, an alkenyloxycarbonyl group having a total of 4 to 6 carbon atoms, or an R 1 -CO-O- (R ₂ CH) -O-CO-group, where R 1 and R ₂ have already

- 3 as defined above, and

Rg represents a hydrogen atom, an alkyl or phenylalkyl group having from 1 to 3 carbon atoms in the alkyl moiety, as well as in the 6- or 7-membered azacycloalkyl group thus formed, one unit> CH- in the 4-position relative to the ring nitrogen atom the N atom or the 5- to 7-membered azacycloalkyl group -CH2-CH <unit thus formed may be replaced by a -CH = C <unit and the thus formed piperazinyl- or homopiperazinyl ring may be a methylene group adjacent to the nitrogen atom in the 4-position. replaced by carbonyl, quinuclidinyl or pyridyl,

B is optionally a fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl group each having 1 to 3 carbon atoms in the alkyl or alkoxy moiety of a mono- or disubstituted phenylene group wherein the substituents are the same or different and furthermore, 1 or 2 unsubstituted meth groups may in each case be replaced by an N-atom or a piperidinylene group,

C is carbonyl-, -CH 2 CH 2 -, -CH = CH-, -CH 2 -, -CH 2 O-,

-och ₂ -, -con ₄ -, -con ₄ -ch ₂ -, -nr ₄ co-, -nr ₄ co-nr ₄ -,

-CH ₂ NR ₄ -, -NR ₄ CH ₂ -, -SO ₂ NR ₄ -, -SO ₂ NR ₄ -CH ₂ - or

-NR ₄ SO ₂ -group where

R ₄ represents a hydrogen atom, an alkyl or phenylalkyl group having from 1 to 3 carbon atoms in the alkyl part, or also if C represents a -CONR ₄ - group attached via a carbonyl group to the radical B, R ₄ represents a methylene or 1,2-ethylene group, which are always attached to a carbon atom in the ortho position of the carbon atom of residue B to the position of attachment of the residue -conr ₄ 4

D is optionally fluorine, chlorine or bromine, trifluoromethyl, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl having from 1 to 3 carbon atoms in the alkyl and alkoxy moiety of a mono or disubstituted phenylene group, wherein the substituents are the same or different and where or 2 unsubstituted meth groups may in each case be replaced by an N-atom, a cycloalkylene group of 5 to 7 carbon atoms, in which one or two CH- units may be replaced by an N-atom, and in addition the aza- or diazacyclohexylene ring thus formed the methylene group adjacent to the nitrogen atom replaced by a carbonyl group and the bond to the C and E radicals can also be carried out via the nitrogen atom and the diazacyclohexylene ring; and

E represents a bond, an alkyleneoxy group having 1 to 3 carbon atoms in the alkyl moiety, wherein the oxygen atom is attached to the radical D, a direct alkylene group having 1 to 5 carbon atoms which may be substituted by 1 or 2 alkyl groups, hydroxyl, alkoxy, R R; NH-, R ^N (alkyl) - or R ^N (phenylalkyl) - or an alkenylene group having 2 to 5 carbon atoms, which may be substituted by one or two alkyl groups, the alkyl portion of the phenylalkyl group may contain 1 to 3 atoms carbon and other alkyl, alkylene and alkoxy moieties each having from 1 to 8 carbon atoms, wherein

R 8 is hydrogen, C 1 -C 8 alkyl, C 2 -C 5 alkoxycarbonyl, phenylalkoxycarbonyl or C 1 -C 8 alkyl, cycloalkyl, phenylalkyl or phenyl-substituted carbonyl or sulfonyl; wherein the alkyl and alkoxy moieties in said phenylalkyl and phenylalkoxy groups may each contain 1 to 3 carbon atoms and a cycloalkyl moiety of 3 to 7 carbon atoms, wherein in the definition of the radical R 8 the phenyl rings mentioned above may additionally be mono- or disubstituted with fluorine, chlorine or bromine , trifluoromethyl, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl each having 1 to 3 carbon atoms in the alkyl and alkoxy moiety and the substituents may be the same or different, provided that when

i) AB-group represents at the 4-position an Rf-NH-CH 3 -substituted phenyl group in which R 1 represents a benzyloxycarbonyl group, R _and OOC-EDC group cannot represent a 3-carboxy-phenylaminocarbonyl group (see EP- A-0372486 and J. Med. Chem., 35, 4393-4407 (1992)), or when (ii) the AB-group represents in the 4-position an R 1 -N 1 -C 1 -group substituted phenyl group wherein R 1 is a hydrogen atom or an acetyl group, the R _and -OOC-ED-C 1 - group cannot be in the 4-position by carbomethyl, methoxycarbonylmethyl, 2-carboxyethyl, 2-methoxycarbonylethyl or

A phenylcarbonyl substituted 2-ethoxycarbonylethyl group (see EP-A-0044541, JP-A-5813553, JP-A5939866, JP-A-5846051 and Chem. Pharm. Bull. 33, 5059-5061 (1985)), or, when iii) the AB group represents a 4-substituted phenyl group at the 4-position of the NH 2 -CH 2 -CH 2 -group, the R _and OOC-EDC group cannot be a 4-ethoxycarbonylphenylcarbonyl group (see DE-A-3718638) or means 4-aminophenyl, 3-aminomethylphenyl, 4-aminomethyl-3-methoxyphenyl or 3-aminomethyl-4-methoxy-6-xyphenyl, R _and OOC-EDC cannot be 4-ethoxycarbonylmethoxy-2,3-dichlorophenylcarbonyl (see J) Chem., 27, 1579-1587 (1984) and Diuretics: Chem Pharmacol., Clin. Appl., Proc. Int. Conf. Diuretics, 1, 21-29 (1984), or when

v) the AB-group is at the 4-position of NH 2 -CH 2 - or (CH 2) 4 CO-CO-NH-CH 3 -substituted phenyl, the R _and OOC-EDC group cannot be 4-carboxyphenylmethoxy (cf. Int. J. Pept. Protein Res., 18, 451-458 (1981)), or when vi) the AB group represents a 4-substituted phenyl group at the 4-position of the NH 2 -CH 2 group, the R _and OOC-EDC group cannot be 4 -carboxy-phenylaminosulfonyl (see Chem. Pharm.-Bull (Tokyo) 7, 734-739 (1959) and J. Chem. Phys. 32, 691-697 (1960)), or when vii) the AB-group is 4- (2-pyridyl) phenyl or

4- (3-pyridyl) phenyl, R _and OOC-EDC cannot be 4-carboxyphenylcarbonylamino, 4-benzyloxycarbonylphenylcarbonylamino or 2- (4-carboxyphenyl) ethyl (see J. Med. Chem. Chem. 11, 295 (1968) and US-A-2837522) or, when viii) the AB group represents a 3- (4-pyridyl) phenyl group, the R _and OOC-EDC group cannot represent a 2- (carboxymethyl) phenylcarbonylamino group (see Farmaco 44, 721-729 (1989)).

However, preferred compounds of formula (I) above are those in which:

R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety or a cycloalkyl group having 5 to 7 carbon atoms,

A represents a C5-C5 aminoalkyl or piperidinyl group linked via the carbon atom of the A residue of the residue B, wherein the coupling of the piperidinyl group to the B group is carried out via the carbon atom of the piperidinyl group and the hydrogen atom of the amino group in the above aminoalkyl groups; the nitrogen atom of said piperidinyl groups may be replaced by the radical R @ 1 and furthermore, the carbon atoms of the piperidinyl group may be substituted by a methyl, cyano, carboxyl, methoxycarbonyl or aminocarbonyl group wherein C1-3 alkyl, benzyl, alkoxycarbonyl having a total of 2 up to 6 carbon atoms, benzyloxycarbonyl or CH 2 -CO-O- (CH ₂ ) -O-CO-group, as well as in the piperidinyl group> CH- thus formed in the 4-position may be replaced by a nitrogen atom or in the thus formed piperidinyl -CH ₂ -CH? and may be replaced by a -CH = CH unit, a quinuclidinyl or a pyridyl group,

B is optionally a fluorine, chlorine or bromine atom, an alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl group having from 1 to 2 carbon atoms in the alkyl and alkoxy moiety substituted by a phenylene, pyridinylene or piperidinylene group,

C is -CO-, -CH ₂ CH ₂ -, -CH = CH-, -CH ₂ -, -CH ₂ O-, -OCH ₂ -,

- 8 -conr ₄ -, -nr ₄ co-, -nr ₄ co-nr ₄ -, -ch ₂ nr ₄ -, -nr ₄ ch ₂ -, -so ₂ nr ₄ or -NR ₄ S0 ₂ -group, where

R ₄ represents a hydrogen atom, an alkyl or phenylalkyl radical having from 1 to 2 carbon atoms in the alkyl moiety or also when C represents a -CONR ₄ - bonded via the carbonyl group to the radical B, R ₄ represents a methylene or 1,2-ethylene group, which are each attached to a carbon atom of B in the ortho position to the point of attachment of the moiety CONR ₄ where D is chlorine, bromine, alkyl or alkoxy having 1 or 2 carbon atoms substituted phenylene or cyclohexylene, in which one or cyclohexylene two> CH- units may be replaced by an N-atom, and in addition to the piperidinylene or piperazinylene ring thus formed, the methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group and the bond to residues C and E may also be via the piperidinylene or piperazinylene circle and

E represents a bond, a methyleneoxy group wherein the oxygen atom is bonded to the radical D, a 1,2-ethenyl group or a straight alkylene group having 1 to 5 carbon atoms which may be substituted by an alkyl group having 1 to 7 carbon atoms or an R ^NH group wherein is hydrogen, alkyl having 1 to 7 carbon atoms or a benzyl group, a substituted carbonyl group, or an alkyl having 1 to 5 carbon atoms or a benzyl group, a substituted sulfonyl group, wherein, if iii) the AB-group is in the 4-NH _{2 --CH2 CH2} group joining substituted phenyl, R _a OOC-EDC-group can not represent 4-etoxykarbonylfenylkarbonylovú group, or, when vii) the AB-group is 4- (2-pyridyl) -phenyl, or

4- (3-pyridyl) -phenyl, R _and OOC-EDC cannot be 4-carboxyphenylcarbonylamino, 4-benzyloxycarbonylphenylcarbonylamino or 2- (4-carboxyphenyl) ethyl or when viii) AB-group R 3 _and OOC-EDC cannot represent 2- (carboxymethyl) phenylcarbonylamino, their tautomers, their stereoisomers, including mixtures thereof, and their salts.

Particularly preferred are those compounds of formula (I) above wherein

_And R is H, alkyl of 1 to 4 carbon atoms, 2-phenylethyl or cyclohexyl,

A is a C 3 -C 5 aminoalkyl group or a piperidinyl group linked via the carbon atom of the residue A of the residue B, wherein the coupling of the piperidinyl group to the B group is carried out via the carbon atom of the piperidinyl group and the hydrogen atom of the amino group in the above aminoalkyl groups; the nitrogen atom of said piperidinyl groups may be replaced by the radical R @ 1 and furthermore, the carbon atoms of the piperidinyl group may be substituted by a methyl, cyano, carboxyl, methoxycarbonyl or aminocarbonyl group wherein C1-3 alkyl, benzyl, alkoxycarbonyl having a total of 2 up to 5 carbon atoms or a CH 2 -CO-O- (CH ₂ ) -O-CO-group, and in the piperidinyl group> CH- thus formed, the unit at the 4-position may be replaced by a nitrogen atom or in the piperidinyl -CH ₂ - thus formed CH <unit may be replaced by -CH = C <unit, c a hinuclidinyl or 4-pyridyl group,

B represents an optionally methyl or methoxy substituted phenylene, 2,5-pyridinylene or 1,4-piperidinylene group,

C is -CO-, -CH ₂ CH ₂ -, -CH = CH-, -CH ₂ -, -CH ₂ O-, -OCH ₂ -, -CONR ₄ -, -NR 4 CO-, -NR 4 CO-NR 4 - or - A CH 2 NR 4 - group or -SO ₂ NR 4 -, wherein the SO ₂ group is linked to the residue B and wherein

R 4 - represents a hydrogen atom, a methyl atom or a methyl group;

2-phenylethyl or, if C is -CONR4-linked to residue B via a carbonyl group, R4 is methylene or 1,2-ethylene, which are in each case attached to the carbon atom of residue B in the ortho position to the point of attachment of -CONR4 -.

D represents a phenylene group or a group wherein in the cyclohexylene group> CH- units can be replaced by an N-atom, the C and E radicals can also be carried out via the nitrogen atom of the piperidinylene or piperazinylene ring and the cyclohexylene one or two;

E represents a bond, a methyleneoxy group where the oxygen atom is bonded to the radical D, a straight chain alkylene group having 1 to 5 carbon atoms, which may be substituted by a R ^NH group wherein hydrogen atom is an alkyl group having 1 to 5 carbon atoms, substituted carbonyl or C 1 -C 4 alkyl or benzyl substituted sulfonyl, tautomers, stereoisomers thereof, including mixtures thereof, and salts thereof.

Most preferred are those compounds of formula I wherein

R _a represents a hydrogen atom, a C 1 -C 4 alkyl group or a cyclohexyl group,

A represents a piperidinyl group or a 3,4-dehydropiperidinyl group linked via the carbon atom of the radical A to the radical B, in which the hydrogen atom on the nitrogen atom can in each case be replaced by the radical R @ a;

R 1 represents an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, optionally in the 1-position of R 1 substituted by a 4-piperazinyl group, wherein R 1 has the previously defined meaning or a quinuclidinyl group,

B represents a phenylene group,

C is -CONR 4 -, wherein

R4 represents a hydrogen atom, a methyl atom or also, if C represents a CONR4-linked radical through the carbonyl group to the B radical, R6 represents a methylene or 1,2-ethylene radical, which are always attached to the carbon atom of the B radical ortho to the point of attachment residue -CONR ^ -,

D is 1,4-phenylene or 1,4-cyclohexylene; and

E represents a bond, a 1,2-ethylene group which may be substituted with an R 1 NH-group, wherein

R 8 represents a C 1 -C 5 alkyl group, a substituted carbonyl group or a C 1 -C 4 alkyl group substituted a sulfonyl group, their tautomers, their stereoisomers, including mixtures thereof, and salts thereof, in particular the following compounds

4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine,

4- [4 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine,

4- [4 - [[trans-4- (2-carboxy-ethyl) -cyclohexyl] aminocarbonyl] phenyl] piperidine,

4- [4 - [[4- [2- (n-butanesulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] phenyl] piperidine,

4- [3 - [[4- [2- (n-butanesulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] phenyl] piperidine and

4- [3 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine, their tautomers, their stereoisomers, including mixtures thereof, and their salts.

According to the invention, new compounds of general formula are obtained

- 13 of formula I, for example, as follows:

(a) for the preparation of compounds of the formula I in which R _a represents a hydrogen atom:

Hydrolysis, pyrolysis or hydrogenolysis of a compound of formula II

ABCDE-COOR _and (II) wherein

A to E are as defined above and R &apos; except for the hydrogen atom has the meanings already given for R _& apos _; .

The hydrogenolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, acetic acid / hydrochloric acid, trichloroacetic acid or trifluoroacetic acid or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, water / methanol, ethanol, water / ethanol, water / isopropanol, water / terahydrofuran or water / dioxane at temperatures between -10 ° C and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture . When treated with an organic acid such as trichloroacetic acid or trifluoroacetic acid, the optionally present alcoholic hydroxy groups may be simultaneously converted to the corresponding acyloxy group, such as trifluoroacetoxy.

In acid hydrolysis, hydrolytically cleavable groups such as acetyl, trifluoroacetyl, benzoyl, tert-butyloxycarbonyl or benzyloxycarbonyl groups can optionally also be present simultaneously in the compound of formula I.

For example, if the compound of formula II contains a tert-butyloxycarbonyl group, the tert-butyl group may also be cleaved by treatment with an acid such as trifluoroacetic acid, hydrochloric acid, formic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, optionally a solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably at temperatures between -10 ° C and 120 ° C, for example at temperatures between 0 ° C and 60 ° C or also thermally or in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and optionally 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 ° C and 100 ° C .

For example, if the compound of formula II contains a benzyloxycarbonyl group, the benzyloxy group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide. at temperatures between 0 ° C and 50 ° C, for example at room temperature and at a hydrogen pressure of from 1 to 10 bar. In the case of hydrogenolysis, other radicals can also be reduced at the same time, for example nitro to amino or benzyloxy to hydroxy and benzylamino to amino. In addition, C = C-double bonds to the bonds can be hydrogenated simultaneously.

(b) For the preparation of compounds of formula I wherein A is substituted with the radical R @ 1:

A ₁ - B - C - D - E - COOR _and (III) where

B to E and R _a are as previously defined and

Also, via a carbon atom having a B moiety linked to an aminoalkyl group 15, a 1 to 5 carbon atom or via a carbon atom having a B moiety attached to a 5-, 6- or 7-membered azacycloalkyl group, wherein the carbon atoms of the azacycloalkyl group may be substituted with one to three alkyl groups. groups of 1 to 3 carbon atoms, aminocarbonyl, cyano, R ^O or R ^O-CO-, in which R má is as defined above, this compound is reacted with a compound of the formula IV

R _b - z ₁ (iv) wherein it is as previously defined and Z -? Represents a nucleophilic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom or also when Z 2 is attached to a carbonyl, hydroxy, alkanoyloxy or alkoxycarbonyloxy group or Z-? together with the adjacent hydrogen atom of R _b represents an oxygen atom.

The reaction is preferably carried out in a suitable solvent, optionally in the presence of a base or optionally in the presence of an acid activating agent or in the presence of a reducing agent at temperatures between -30 ° C and 150 ° C.

When Z = 6 is a nucleophilic leaving group, the reaction may preferably be carried out in a solvent or solvent mixture such as water, tetrahydrofuran, tetrahydrofuran / water, dioxane, dioxane / water, methylene chloride, chloroform, ethyl acetate or dimethylformamide, preferably in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide, or in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methylmorpholine or pyridine, which may simultaneously serve as a solvent, optionally in the presence of a reaction accelerator such as potassium iodide at temperatures between -10 ° C and 80 ° C.

When Z = 6 is hydroxy, the reaction is preferably carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of an acid such as hydrochloric acid or in the presence of a water-removing agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, dicyclohexylcarbodiimide / N-hydroxysuccinimide, 2- (1H-benzotriazolyl) -1,1,3,3-tetramethyluronium salts, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of dimethylaminopyridine or 1- hydroxybenzotriazole, preferably at temperatures between 0 C and ^Q 150, preferably but ä at temperatures between 0 ° C and 50 ° C.

When Z- £ together with the adjacent hydrogen atom of the residue is an oxygen atom, the reductive alkylation is preferably carried out in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile or mixtures thereof with water in the presence of a suitable reducing agent such as formic acid or a suitable complex metal hydride, preferably in the presence of sodium cyanoborohydride or hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon at temperatures between 0 ° C and 50 ° C, preferably at room temperature.

(c) For the preparation of compounds of the formula I, in which R _and with the exception of hydrogen have the meaning defined above:

the compound of formula V is reacted

A - B - C - D - E - COOH (V) where

A to E are as defined above, with a compound of formula VI wherein

R 1 except hydrogen has the meanings given above for R 1 _and Z 2 is a nucleophilic leaving group such as a halogen atom, for example a chlorine or bromine atom, or a sulfonyloxy substituted on a sulfonyl group, for example a methanesulfonyloxy group, methoxysulfonyloxy group, toluenesulfonyloxy or hydroxy group.

The reaction, when Z 2 represents a halogen atom or a sulphonyl group substituted by a sulphonyloxy group, is preferably carried out in a solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate, dimethylsulfoxide or dimethylformamide, preferably in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide; in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methylmorpholine, which may simultaneously serve as a solvent, optionally in the presence of a reaction accelerator such as potassium iodide at temperatures; between -30 ° C and 100 ° C, but preferably at temperatures between -10 ° C and 80 ° C. '

When Z2 is hydroxy, the reaction is preferably carried out using a compound VI as a solvent in the presence of thionyl chloride or an acid such as hydrochloric acid or sulfuric acid at temperatures between -10 ° C and 100 ° C, preferably at temperatures between 0 ° C and 50 ° C.

d) For the preparation of compounds of formula I wherein C is

-CH2-NH-group:

reducing the compound of formula VII

A-B-CH = N-D-E-COOR

G.

where

A, B, D, E and R _and are as previously defined.

(VII)

The reduction is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / ammonia, methanol / water / ammonia, methanol / hydrochloric acid, methanol / ethereal hydrochloric acid, ethanol, ethyl acetate, ether, tetrahydrofuran, dioxane, dimethylformamide or ice. acetic acid in the presence of catalytically activated hydrogen, for example hydrogen in the presence of Raney nickel, platinum or palladium / charcoal, or in the presence of a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium borohydride at temperatures between -20 C and ^e 100 "C, preferably at temperatures between 0 ° C and 60 ° C.

e) For the preparation of compounds of the formula I in which C represents an -CO-NR4-group:

reacting a compound of formula VIII

A ₂ - B - COOH (VIII) where

B has the previously defined meaning of a

A ₂ represents an alkyl-, aralkyl-, alkanoyl-, trifluoroacetyl- or alkoxycarbonyl-substituted A group with an amine of the general formula IX on the nitrogen atom

R ₄ - NH - D - E - COOR _a '(IX) where

D, E and R ₄ are as previously defined and

R ', except for a hydrogen atom, has the meanings previously given for

The reaction is preferably carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a water scavenger, for example in the presence of isobutyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, 2- (1H) -benzol 1,3,3-tetramethyluronium salts,

N, N'-carbonyldiimidazole, N, N'-thionylldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of dimethylaminopyridine or 1-hydroxybenzotriazole and / or a base such as triethylamine, N-ethyl-diisopropylamine or N-methylmorpholine, preferably at temperatures between -10 ° C and 150 ° C, more preferably at temperatures between 0 ° C and 50 ° C.

f) For the preparation of compounds of formula I wherein C represents an -NR 4 CO group:

The compound of formula X is reacted

A ₂ - B - NH - R ₄ (X) wherein

R4 and B are as defined above and

A ₂ represents an alkyl-, α-alkyl-, alkanoyl-, trifluoroacetyl- or alkoxycarbonyl-substituted A group with a carboxylic acid of the general formula XI on the nitrogen atom

HOOC - D - E - COOR _and (XI) where

D and E are as defined above and

R _a ', with the exception of the hydrogen atom, has the meanings given above for ^R a';

The reaction is preferably carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a water scavenger, for example, isobutyl chloroformate hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, 2- (1H-benztriazolyl) -1,1, 3,3-tetramethyluronium salts,

N, N'-carbonyldiimidazole, N, N'-thionylldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of dimethylaminopyridine or 1-hydroxybenzotriazole and / or a base such as triethylamine, N-ethyl-diisopropylamine or N-methylmorpholine, preferably at temperatures between -10 ° C and 150 ° C, more preferably at temperatures between 0 ° C and 50 ° C.

(g) For the preparation of compounds of the formula I in which A represents a C 1 -C 5 aminoalkyl group linked via a carbon atom of the radical B:

The compound of formula XII is reduced

A ₃ - B - C - D - E - COOR _and (XII) where

B to E and R _& apos _;

A ₃ represents cyano or C 1 -C 4 -alkyl cyanoalkyl.

The reduction is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally by addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. - nickel, platinum or palladium / coal or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminum hydride at temperatures between 0 ° C and 100 ° C, preferably at temperatures between 20 ° C and 80 ° C.

When a compound of formula (I) wherein a hydrogen atom is obtained, it may be converted by alkylation to the corresponding compound of formula (I) wherein R4 represents an optionally substituted alkyl group having 1 or 2 carbon atoms.

The subsequent alkylation is preferably carried out with a corresponding halide such as methyl iodide, ethyl bromide, benzyl chloride or phenylethyl bromide, preferably in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of a base such as sodium carbonate, potassium carbonate or a tertiary organic base, such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent at temperatures between -30 ° C and 100 ° C, preferably at temperatures between -10 ° C and 80 ° C .

In the above reactions, reactive groups such as hydroxyl, carboxyl, amino, alkylamine or imino groups may optionally be present during the reaction, protected by conventional protecting groups, which may be cleaved again after the reaction.

For example, trimethylsilyl, acetyl, benzoyl, tert-butyltrityl, benzyl or tetrahydropyranyl protecting groups as hydroxyl protecting groups, trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl or imidinyl amino protecting groups, and as protecting groups for imino, an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and, in addition to the amino group, a phthalyl group.

The optional deprotection subsequently carried out is carried out, for example, hydrolytically in an aqueous solvent, for example water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or alkali metal base. such as lithium hydroxide, sodium hydroxide or potassium hydroxide or via ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 ° C and 100 ° C, preferably at temperatures between 10 ° C and 50 ° C.

The cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid. at temperatures between 0 ° C and 50 ° C, preferably at temperatures between 0 ° C and 50 ° C, preferably at room temperature and at a hydrogen pressure of 0.1 to 0.7 MPa, preferably 0.3 to 0, 5 MPa. In the hydrogenolytic cleavage of the benzyl groups, the C = C-double bonds optionally present in the compound of the formula II can be hydrogenated simultaneously. For example, an N-benzyldehydropiperidyl group can be converted to a piperidyl group in this manner.

Cleavage of the methoxybenzyl group can also be carried out in the presence of an oxidizing agent such as cerium ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 ° C and 50 ° C, preferably at room temperature.

The cleavage of the 2,4-dimethoxybenzyl residue is carried out, for example, in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl residue is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ether or dioxane / ether.

The cleavage of the phthalyl residue is preferably carried out 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 ° C and 50 ° C.

Cleavage of the allyloxycarbonyl moiety is accomplished by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0) preferably in a solvent such as tetrahydrofuran and in the presence of an excess of allyl acceptor such as morpholine or 1,3-dimedone at temperatures between 0 ° C and 100 ° C. preferably at room temperature and under an inert gas or 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-diazabicyclo [2.2.2] octane at temperatures between 20 ° C and 70 ° C.

Furthermore, the compounds of the formula I can be obtained, as mentioned above, separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their cis and trans isomers and chiral compounds into their enantiomers.

Thus, for example, the cis / trans mixtures obtained can be separated into their cis and trans isomers, the obtained compounds of the formula I which are in the form of racemates can be resolved by methods known per se (see Allinger NL and Eliel EL in Topics in Stereochemistry, Vol. 6, Viley Interscience, 1971), to their optical antipodes and compounds of formula I with at least 2 stereogenic centers due to their physicochemical differences, be separated into their diastereomers by known methods, for example chromatography and / or fractional crystallization, which, when present in racemic form, can then be resolved, as mentioned above, into their enantiomers.

The separation of the enantiomers is preferably carried out on a column on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance, forming salts or derivatives such as esters or amides, in particular with acids and their active derivatives or alcohols, with the racemic compound. diastereomeric salts in the form of mixtures or derivatives, for example due to different solubilities, whereby antipodes can be released from the pure racemic salts or derivatives by treatment with a suitable agent. Particularly useful optically active acids are, for example, 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 alcohol is, for example, (+) - or (-) - menthol and, as optically active acyl residue in amides, for example, (+) - or (-) - methyloxycarbonyl.

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

In addition, the novel compounds of the formula I thus obtained, if they contain a carboxyl group, can optionally be converted into their addition salts with inorganic or organic bases, in particular for pharmaceutical use, into their physiologically acceptable addition salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds used as starting materials are partly known from the literature or can be obtained by methods known in the literature (see, for example, I to XXIV).

As already mentioned, these novel carboxylic acid derivatives of the formula I and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, have valuable properties. Novel compounds of formula I wherein A represents an optionally substituted aminoalkyl aza- or diazacycloalkyl group or a pyridyl or quinuclidinyl group or, optionally, in vivo, a convertible group, for example a nitrogen atom, alkoxycarbonyl, alkenyloxycarbonyl, alkenyloxycarbonyl, alkenyloxycarbonyl, trifluormethylcarbonyl, alkanoyloxymetoxykarbonylovou, cykloalkanoyloxymetoxykarbonylovou aralkanoyloxymetoxykarbonylskupinou or substituted amino, aza, or -COOR comprising -diazacycloalkyl _and carboxyl, convertible in vivo into a carboxy group, e.g. alkoxy, alkenyloxy, phenylalkoxy, cycloalkyloxy, alkanoyloxyalkoxylovú, cykloalkanoyloxyalkoxylovú, fenylalkanoyloxyalkoxylovú, benzoyloxýalkoxylovú, alkoxykarbonyloxyalkoxylovú group or cykloalkyloxykarbonylalkoxykarbonylovú show valuable the pharmacological properties are known to be effective in suppressing inflammation and bone breakdown, in particular antithrombotic, antiplatelet and tumor-suppressing metastases.

The compounds of formula I have been investigated for their biological activity, for example, as follows:

about

Competitive binding of H-BIBU 52 / test substance to human platelets

ABOUT

Plasma suspension of human platelets is mixed with H BIBU 52 / = (3S, 5S) -5 - [(4'-amidino-4-biphenylyl) oxymethyl] -3-26 [(carboxyl) methyl] -2-pyrrolidinone- [ 3- (4-biphenylyl)], which replaces the known ligands-fibrinogen (cf.

German patent application P 42 14 245.8 of the same applicant from April 30, 1992, internal reference: Time 5/1093-FL) and incubated with different concentrations of the test substance. Free and bound ligand is collected by centrifugation and quantitated by scintillation counting. Suppression of H-BIBU 52-binding by the test substance is determined from the measured values.

To this end, blood is drawn from the donor anticubital vein and anticoagulated with sodium citrate (final concentration 13 mM). The blood is centrifuged at 170 xg for 10 minutes and platelet-rich plasma (PRP) supernatant is collected. The remaining blood is rapidly centrifuged once more to obtain plasma. PRP is diluted 1:10 with autologous plasma. Incubate 750 μΐ with 50 μΐ physiological sodium chloride, 100 μΐ test substance solution, 50 μΐ ⁴ C-sucrose (3,700 Bq) and 50 μΐ ^ H-BIBU 52 (final concentration: 5 nM) for 20 minutes at room temperature. 5 μΐ BIBU 52 (final concentration: 30μΜ) is used instead of the test substance to measure non-specific binding. The samples are centrifuged for 20 seconds at 10,000 xg and the supernatant is collected. 100 μΐ of the supernatant is used to measure the free ligand. Dissolve the pellet in 500 μΐ 0,2 N NaOH, mix 450 μΐ with 2 ml scintillator and 25 μΐ 5 N HCl and measure. The residual plasma in the pellet is determined from a ⁴⁴ C content, bound ligand from a HH-measurement. After subtraction of non-specific binding, the concentration of test substance against the pellet activity is plotted and the concentration for 50% binding suppression is determined.

2. Antithrombotic efficacy

methodics

Platelet aggregation is measured according to the method of von Born and Cross (J. Physiol. 170, 397 (1964)) in platelet-rich plasma obtained from healthy test subjects. To suppress clotting, blood is diluted 1:10 with sodium citrate 3.14% (v / v)

I

- 27 ratio).

Collagen-induced aggregation

It records and measures photometric the decrease in optical density after the addition of the aggregation-inducing substance. The aggregation rate is determined from the angle of inclination of the density curve. The point on the curve at which the greatest light transmission occurs is to calculate the optical density.

The collagen concentration is chosen to be as small as possible, but such that an irreversibly running reaction curve is obtained. Commercially available collagen from Hormonchemie, Munich is used. Prior to the addition of collagen, the plasma is incubated with the substance at 37 ° C for 10 minutes.

From the concentration-efficiency curves, EC 50 is calculated, which describes the concentration at which the change in optical density is suppressed by half the maximum.

The following table shows the results found.

substance (example #) ú »V. competitive binding of H-BIBU 52 / suppression 1 test substance on human platelets IC ₅₀ [nM] platelet aggregation EC ^ q [nM] 2 1100 840 2.1 > 100000 3300 2.2 4500 3300 3 190 260 3.1 1400 2400 3.3 17 260 3.4 2000 5800 3.6 14 120 5 2900 5600

Suppression of platelet aggregation following oral administration of test substance is performed ex vivo in Rhesus monkeys.

A blood sample is taken from the cubital vein directly after oral administration in the Natrosol suspended suspension substance. At defined times after administration of the substance, new blood samples are taken and tested as described below.

Blood diluted with 3.14% sodium citrate 1:10 is centrifuged at 200 g for 15 minutes. The plasma-rich platelet supernatant is carefully collected. From the erythrocyte-rich sediment, centrifugation at 4000 g for 10 minutes yields platelet-poor plasma as a supernatant.

Collagen (Hormonchemie, Munich, 2 µg / ml final platelet-poor plasma concentration) induced platelet aggregation is measured photometrically according to the method of von Born and Cross (J. Physiol. 170, 397 (1964) in these samples. After collagen stimulation, the largest measured The light transmittance of the platelet-poor plasma is compared to a reference value to determine aggregation suppression at different times of blood collection after substance administration relative to the reference value.

The compounds of Examples 2 and 5 (2) suppress collagen-induced platelet aggregation ex vivo after oral administration of 1 mg / kg for more than 2 hours.

The compounds of the invention are well tolerated because, for example, when the intravenous administration of 30 mg / kg of each of the 3 mice to the compounds of Examples 2 and 3, no animal died.

Because of their suppressing effect on cell-cell or cell-matrix interactions, the novel carboxylic acid derivatives of formula I and their physiologically acceptable salts are suitable for the treatment or alleviation of diseases in which larger or smaller cell aggregates are formed or play a role in cell interaction. - matrix, optionally in the treatment or prevention of venous or cerebrovascular diseases, pulmonary embolism, heart attack, arteriosclerosis, osteoporosis, tumor metastasis and therapy of genetically-related or also acquired cell interaction disorders with one another or with solid structures. Furthermore, the compounds are also useful in supportive therapy in thrombolysis of fibrinolytics or in vascular interventions such as transluminal angioplasty or in the treatment of shock conditions, psoriasis, diabetes and inflammation.

Dosages between 0.1 gg and 30 mg / kg body weight, preferably 1 gg to 15 mg / kg body weight, are used for the treatment or prevention of said diseases, for up to 4 administrations per day. For this purpose, the compounds of the formula I prepared according to the invention can be processed, optionally in combination with other active substances such as troraboxane receptor antagonists and thromboxane synthesis inhibiting agents or combinations thereof, serotonin antagonists, receptor antagonists, alkyl nitrates such as glycerinnitrate , prostacyclin and an analogue thereof, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase or anticoagulants such as heparin, dermatan sulfate, activated protein C, vitamin A antagonists, hirudin, thrombin inhibitors or other activated clotting factors, together with one or more inert excipients and usually / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / with rbitus, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fat containing substances such as hardened fat or suitable mixtures thereof, for conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or lace.

The following examples serve to explain the invention in more detail.

DETAILED DESCRIPTION OF THE INVENTION

Production of starting compounds

example

4- (4-carboxyphenyl) piperidine hydrochloride

To a solution of 63.0 g of 1-acetyl-4-phenyl-piperidine in 1000 ml of methylene chloride, 157.4 g of oxalyl chloride is added dropwise at -10 ° C to -20 ° C with good stirring. 46.7 g of aluminum chloride are then added. Stir 1 hour at -10 ° C and add another 82.7 g of aluminum chloride. After another 2 hours the cooling bath! is removed and stirred at room temperature for 24 hours. The reaction solution is carefully mixed into about 4 L of ice / water and the aqueous phase is extracted twice with methylene chloride. The combined organic phases were washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved with vigorous stirring in 2.5 L of 2 N sodium hydroxide. Ice was added to the dark aqueous solution and acidified with concentrated hydrochloric acid. The precipitate is suction filtered, washed with water and heated in refluxing 2 L of 6 N hydrochloric acid for 5 hours. The solvent was removed under reduced pressure. The residual solid is triturated with a small amount of water and suction filtered.

Yield: 40.5 g (54% of theory)

Melting point: 300 ° C

Rf value: 0.07 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Example II

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

To 16.4 g of sodium hydroxide in 300 ml of water was carefully added 47.5 g of 4- (4-carboxyphenyl) piperidine hydrochloride. The suspension is diluted with 500 ml dioxane and 250 ml water. Then 54.6 g of di-tert-butyl pyrocarbonate are added portionwise. Stir for 16 hours at room temperature. The precipitate is suction filtered and the filtrate is partially evaporated under reduced pressure. The precipitate and the remaining aqueous filtrate were combined and diluted with 1 L of water. The aqueous phase is adjusted to pH 2 with saturated potassium hydrogen sulphate solution and extracted twice with ethyl acetate. The combined ethyl acetate phases are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is removed under reduced pressure. The crystalline crude product is triturated with a small amount of ethyl acetate, suction filtered and dried.

Yield: 54.0 g (90% of theory)

Melting point: 172-174 ° C

Rj: -value: 0.73 silica gel, ethyl acetate / cyclohexane = 4: 1)

Example III

3- (4-aminophenyl) -2- (n-butanesulfonylamino) propionic acid as methyl ester g of 2- (n-butanesulfonylamino) -3 (4-nitrophenyl) propionic acid methyl ester is treated in 200 ml of ethyl acetate in the presence of 2 g of 10% palladium on carbon for 1.5 hours at room temperature with hydrogen at 0.5 MPa. The catalyst was filtered off, evaporated and the residue was used without further purification. Yield: 17.8 g (100% of theory)

Rf value: 0.43 (silica gel, cyclohexane / ethyl acetate = 1: 1)

The following compound is obtained analogously:

1) 3- (4-aminophenyl) propionic acid methyl ester

Starting from methyl 4-nitro-cinnamate and hydrogenating at 50 ° C.

Rf value: 0.76 (silica gel, cyclohexane / ethyl acetate = 1: 3)

Example IV 2- (n-Butanesulfonylamino) -3- (4-nitrophenyl) propionic acid methyl ester

25.9 g of 2-amino-3- (4-nitrophenyl) propionic acid methyl ester hydrochloride are suspended in 100 ml of methylene chloride and mixed with 32 g of N-ethyl-diisopropylamine to dissolve the precipitate. 17.1 g of n-butanesulfonyl chloride in 20 ml of methylene chloride are added to the solution at 8 to 15 ° C. After stirring at room temperature for 16 hours, 10 g of N-ethyl-diisopropylamine was added under ice-cooling, and 8 g of n-butanesulfonyl chloride was added dropwise again and stirred for another two hours at room temperature. It is mixed with ice water, the organic phase is washed successively with water, 1 N hydrochloric acid and water and evaporated. The residue was purified over silica gel (eluent-methylene chloride).

Yield: 19.4 g (57% of theory)

Melting point: 100-102 ° C

Rf value: 0.38 (silica gel, cyclohexane / ethyl acetate = 6: 4)

Example V

2-Amino-3- (4-nitrophenyl) propionic acid methyl ester hydrochloride g 4-Nitrophenylamine is suspended in 250 ml of methanol and mixed with 10 ml of methanolic hydrochloric acid to dissolve the solid product. It was allowed to stand at room temperature for 60 hours and evaporated in vacuo. The product was used without further purification.

Yield: 25.9 g (99% of theory)

Melting point: 206 to 208 ° C (decomposition)

Rf value: 0.67 (reverse phase-plate RP8, methanol / 5% sodium chloride solution - 6: 4)

The following compound is obtained analogously:

3- (trans-4-Amino-cyclohexyl) -propionic acid methyl ester hydrochloride

Melting point: above 200 ° C

Example VI

3- (trans-4-aminocyclohexyl) propionic acid hydrochloride g of 3- (trans-4-acetaminocyclohexyl) propionic acid is heated in 200 ml of 6 N hydrochloric acid under reflux for 16 hours. It is evaporated to dryness in vacuo and evaporated several times after addition of toluene and methanol. The residue is used directly.

Yield: 26 g (100% of theory)

Example VII

3- (trans-4-acetaminocyclohexyl) propionic acid

112.7 g of 3- (4-acetaminophenyl) propionic acid and 10 g of platinum oxide are treated with hydrogen at 0.5 MPa in 350 ml of glacial acetic acid at 60 ° C. After 1.5 hours and 7 hours, the platinum oxide is always replaced with a new one. The total reaction time is 10 hours. It is evaporated to dryness in vacuo and the residue is crystallized from 1800 ml of acetone. The primary crystallizate is still recrystallized from 50 ml of 80% acetic acid.

Yield: 26 g (22.4% of theory)

Melting point: 200 to 201 ° C

Rf value: 0.30 (silica gel, methylene chloride / ethyl acetate / glacial acetic acid = 4: 1: 0.4)

53.6 g (46% of theory) of cis-3- (4-acetaminocyclohexyl) propionic acid are obtained from the acetone mother liquors after evaporation and after recrystallization from 100 ml of water.

Example VIII

- 34 1-Benzyl-4- (3-carboxy-phenyl) -3,4-dehydro-piperidine hydrochloride g 1-Benzyl-4- (3-bromophenyl) -3,4-dehydro-piperidine is dissolved in 300 ml of tetrahydrofuran . It is cooled to below -65 ° C and 47.6 ml of a 1.6 molar solution of n-butyllithium in hexane is added dropwise over 30 minutes. Stirring is continued for an additional hour and then carbon dioxide dried through concentrated sulfuric acid is introduced in a slow stream. The temperature is kept below -65 ° C for 1 hour, then slowly raised to room temperature and the reaction mixture is allowed to stand at this temperature for 60 hours. It is evaporated to dryness and the residue is taken up in 500 ml of ethyl acetate and extracted with water. The aqueous phases are evaporated in vacuo, cooled in an ice bath, and the pH is adjusted to 1 with 2N hydrochloric acid. The precipitated crystals are filtered off and washed with water.

Yield: 9 g (40% of theory)

Melting point: 185 DEG C. (decomposition).

R.f-value: 0.50 (reversed phase RP8 plate, methanol /

5% sodium chloride solution = 6: 4)

Example IX 1-Benzyl-4- (3-bromophenyl) -3,4-dehydro-piperidine

29.6 g of 1-benzyl-4- (3-bromophenyl) -4-hydroxy-piperidine,

32.5 g of p-toluenesulfonic acid hydrate and 300 ml of toluene were heated in a water separator for 2 hours. After cooling, dilute with methylene chloride, add ice water and basify with 30% sodium hydroxide. The aqueous phase is extracted once more with methylene chloride and the combined organic phases are evaporated. Yield: 25.2 g (90% of theory)

Rf value: 0.69 (silica gel, methylene chloride / methanol = 100: 2)

Example X 1-Benzyl-4- (3-bromophenyl) -4-hydroxy-piperidine

- 35 To a solution of 35.7 g of 1,3-dibromobenzene in 200 ml of ether is added dropwise over 25 minutes at a temperature below 0 ° C 93.1 ml of a 1.6 molar solution of n-butyllithium in hexane. After stirring for 40 minutes, a solution of 28.2 g of freshly distilled 1-benzyl-4-piperidone in 40 ml of ether is added dropwise at a temperature below 10. It was stirred at this temperature for 30 minutes and then at room temperature for 1 hour. It is mixed with 500 ml of saturated sodium chloride solution, the aqueous phase is extracted twice more with ethyl acetate, the organic phases are evaporated in vacuo and the residue is purified by silica gel column chromatography (eluent: methylene chloride / methanol = 100: 2).

Yield: 29.6 g (56% of theory)

Rf value: 0.34 (silica gel, methylene chloride / methanol = 100: 2)

Example XI

3- (4-Acetaminophenyl) propionic acid

155 g of 3- (4-acetaminophenyl) propionic acid methyl ester are dissolved in 1000 ml of methanol, heated to 50 ° C and mixed with 700 ml of sodium hydroxide. It was allowed to cool to room temperature and stirred for 3 hours. Cool in an ice bath, add 750 ml of 2 N hydrochloric acid and stir for one hour with ice cooling. The precipitate was filtered off and washed with a little ice water.

Yield: 112.7 g (77.6% of theory)

Melting point: 144-147 ° C

Rf value: 0.25 (silica gel, methylene chloride / ethyl acetate / glacial acetic acid = 8: 1: 0.4)

Example XII

3- (4-Acetaminophenyl) propionic acid methyl ester

138.4 g of methyl 3- (4-aminophenyl) propionate are dissolved in 100 ml of methylene chloride and 119 ml of triethylamine are added. The mixture is cooled to below 0 ° C and treated dropwise with 58 ml of acetyl chloride in 200 ml of methylene chloride over 35 minutes at 0 ° C to 10 ° C. Stirring is continued for one hour at 0 [deg.] C., 300 ml of water are added, the organic phase is extracted twice more with water and evaporated in vacuo.

Yield: 155.5 g (91% of theory)

Melting point: 118-120 ° C

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 1: 3)

Example XIII

4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminomethyl] phenyl] piperidin--1trifluóracetyl

6.9 g of 4- (4-formylphenyl) -1-trifluoroacetyl-piperidine and 4.33 g of 3- (4-aminophenyl) propionic acid methyl ester were heated in 5 ml of toluene under reflux on a water separator for 5 hours. Evaporate in vacuo and use the product without further purification.

Yield: 10.8 g (100% of theory)

Rf value: 0.43 (silica gel, cyclohexane / ethyl acetate = 2: 1)

Example XIV

4- (4-formylphenyl) -L-trifluoroacetyl-piperidine

To a solution of 8.3 g of (4-phenyl-1-trifluoroacetyl-piperidine in 30 ml of methylene chloride) was added dropwise 7.8 ml of titanium tetrachloride at a temperature below 0 DEG C. After 10 minutes, 3.5 ml of dichloromethyl methyl ether was added dropwise over 40 minutes. while keeping the temperature below 0 ° C, allowed to stand at room temperature for 16 hours, poured onto ice water and the aqueous phase extracted several times with methylene chloride. (ethyl acetate = 2: 1) Yield: 6.9 g (75% of theory).

Mp 76-77 ° C

- 37 Rf value: 0.42 (silica gel, cyclohexane / ethyl acetate = 2: 1)

Example XV

4-Phenyl-1-trifluoroacetyl-piperidine 4-Phenyl-piperidine (g) is dissolved in 250 ml of methylene chloride, treated with 29.8 ml of N-ethyl-diisopropylamine and cooled to 0 ° C. 24.1 ml of trifluoroacetic anhydride are added dropwise such that the temperature does not exceed 10 ° C. Stirring is continued for 30 minutes at 0 ° C, allowed to come to room temperature, 100 ml of water are added and the organic phase is washed twice more with water. The methylene chloride phase was evaporated and the residue was used without further purification.

Yield: 40 g (100% of theory)

Rf value: 0.90 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example XVI

4- (4-aminophenyl) piperidin-trifluoroacetyl

(a) 4-phenyl-1-trifluoroacetyl-piperidine

To a solution of 125 g (0.775 mol) of 4-phenyl-piperidine and 149 ml (0.775 mol) of Ν, Ν-diisopropylethylamine in 1300 ml of dichloromethane is added dropwise at -5 ° C with stirring for 2 hours

120.5 ml (0.775 mol) of trifluoroacetic anhydride. It is then stirred for an additional hour under ice-cooling, allowed to stand overnight at room temperature and then diluted with 400 ml of water. The dichloromethane phase is separated, washed twice with 400 ml of water each time, dried over sodium sulphate and evaporated to dryness in vacuo. Yield: 193 g (97% of theory) of yellow crystals

Rf value: 0.88 (silica gel, cyclohexane / ethyl acetate = 1: 1)

b) 4- (4-nitrophenyl) -1-trifluoroacetyl-piperidine g (0.311 mol) under a) of the obtained crude 4-phenyl-1-trifluoroacetyl-piperidine was dissolved in a mixture of 400 ml of glacial acetic acid and 200 ml of acetic anhydride. This solution is cooled to 10 ° C in an ice bath and treated with stirring with 1.6 g of sodium nitrite and then dropwise with 51.9 ml (0.311 mol) of fuming nitric acid. It is allowed to stand overnight at room temperature and then poured onto 100 ml of water containing 200 g of ice. Use 8 N sodium hydroxide for a period of 2 hours

The pH is adjusted to 8 with cooling so that the temperature does not exceed 20 ° C with cooling for 4.5 hours. It is extracted with a total of 2000 ml of dichloromethane, washed with dichloromethane extracts with 100 ml of 0.1 N sodium hydroxide and then twice with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate / cyclohexane.

Yield: 54.5 g (58% of theory) of yellow crystals

Melting point: 100-102 ° C

c) 4- (4-aminophenyl) -1-trifluoroacetyl-piperidine

The compound prepared under b) is dissolved in 700 ml of ethyl acetate and, after addition of 7 g of palladium on carbon (10%), hydrogenated at room temperature and a hydrogen pressure of 0.3 MPa. The catalyst was filtered off and the ethyl acetate solution was evaporated to dryness in vacuo.

Yield: 39.7 g (quantitative)

Rf value: 0.25 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example XVII

1-tert-butyloxycarbonyl-4- [4 - [[4- [2- (methoxycarbonyl) ethyl] piperidino] methyl] phenyl] piperidine

a) 1-tert-Butyloxycarbonyl-4- (4-hydroxymethylphenyl) piperidine

To a solution of 5 g (0.0164 mol) of 1-tert-butyloxycarbonyl-4- (4-carbonylphenyl) piperidine and 1.66 g (0.0164 mol) = 2.28 ml of triethylamine in 100 ml of tetrahydrofuran is added dropwise with stirring at 5 ml. ° C solution of 1.78 g (0.0164 mol) = 1.57 ml of ethyl chloroformate in 10 ml of tetrahydrofuran and stirred at this temperature for an additional hour. The resulting triethylamine hydrochloride is filtered off with suction and washed with tetrahydrofuran. The combined tetrahydrofuran phases were added dropwise with stirring and at 10-15 ° C to a solution of 1.55 g (0.0141 mol) of sodium borohydride. After stirring overnight at room temperature, it is evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and 1N sodium hydroxide solution. The ethyl acetate phases are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was crystallized from petroleum ether.

Yield: 4.05 g (84.7% of theory)

Melting point: 78 to 80 ° C.

b) 1-tert-butyloxycarbonyl-4- (4-chloromethylphenyl) piperidine

A solution of 3.95 g (0.0136 mol) of (a) and 2.74 g (0.0271 mol) = 3.8 ml of triethylamine in 80 ml of dichloromethane is slowly mixed with 3.1 g (0.0271) with stirring. mol) = 2.1 ml mesyl chloride. After completion of the addition, it is allowed to stand overnight and then the clear solution is evaporated to dryness. The residue is chromatographed over silica gel, eluting with dichloromethane.

Yield: 3.75 g (89% of theory)

Melting point: 56-58 ° C

Rf value: 0.47 (silica gel, dichloromethane)

c) 1-tert-butyloxycarbonyl-4- [4 - [[4- [2- (methoxycarbonyl) ethyl] piperidino] methyl] phenyl] piperidine

A mixture of 1.8 g (0.0058 mol) of the compound produced under b) 1.44 g (0.007 mol) of methyl piperidinopropionate hydrochloride, 1.42 g = 1.95 ml (0.014 mol) of triethylamine and 3 g of sodium iodide in 150 ml. ml of chloroform are heated at reflux temperature for 36 hours. The insoluble matter is then aspirated. The filtrate was washed twice with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with methylene chloride / methanol (35: 1).

Yield: 2.05 g (79.8% of theory) of resin

Rf value: 0.41 (silica gel, dichloromethane / methanol = 9.5: 0.5)

The following compound is obtained analogously:

1) 1-tert-butyloxycarbonyl-4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminomethyl] phenyl] piperidine

Prepared from 1-tert-butyloxycarbonyl-4- (4-chloromethylphenyl) piperidine and trans -3- [4-aminocyclohexane] propionic acid methyl ester.

resin

Example XVIII

1- [tert-butyloxycarbonyl] -4- [4 - [[trans-4-metoxykarbonylcyklohexyl] aminocarbonyl amino] phenyl] piperidine

A solution of 1.2 g (0.0044 mol) of 1-tert-butyloxycarbonyl-4- [4-aminophenyl] piperidine and 0.8 g (0.0044 mol) of trans- [4-methoxycarbonyl-cyclohexyl] isocyanate in 20 ml of dioxane was added during It is heated to 50 DEG C. for 2 hours. It is then evaporated to dryness under reduced pressure and the solid residue is stirred with tert-butyl methyl ether. The residual solids are aspirated, washed with tert-butyl methyl ether and dried.

Rf value: 0.30 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example XIX

1-tert-butyloxycarbonyl [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] piperidine

a) 1- tert -Butyloxycarbonyl-4- [4 - [(4-ethoxycarbonyl) piperidino] piperidine

A mixture of 24.9 g (0.1249 mol) of N-tert-butyloxycarbonyl-4-pi41 peridone, 19.3 ml (0.1249 mol) of piperidino-4-carboxylic acid ethyl ester and 46.5 ml (0.1562 mol) the titanium (IV) -isopropylate was stirred at room temperature for one hour. 170 ml of anhydrous ethanol are added and then

5.3 g of 0.0837 mol) of sodium cyanoborohydride and stirred for a further 20 hours. It is then mixed with 34 ml of water, the precipitated solid is filtered off with suction and washed with ethanol. The combined filtrates were evaporated to dryness. The residue was dissolved in ethyl acetate. The inorganic insoluble matter was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / cyclohexane = 3: 2 as eluent.

Yield: 32.9 g of oily substance (77.3% of theory) Rf value: 0.36 (silica gel, ethyl acetate)

b) 1- tert -Butyloxycarbonyl-4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] piperidine

3.4 g (0.01 mol) of (a) of the compound obtained are stirred overnight in 20 ml of 1 N sodium hydroxide. After this time, the ethyl ester was saponified completely. 20 ml of 1N hydrochloric acid are added and washed with ethyl acetate. The aqueous phase is evaporated to dryness in vacuo, the residue is taken up twice in ethanol, then evaporated to dryness and then dried under vacuum at 80 ° C. The residue is dissolved in 100 ml of dimethylformamide. This solution was mixed with 2 ml (0.0102 mol) of diphenylphosphoryl chloride, cooled to -5 ° C, 1.4 ml (0.0102 mol) of triethylamine was added with stirring and stirred at -5 ° C for one hour. Then, 2.26 g (0.0102 mol) of trans-3- [4-aminocyclohexyl] propionic acid in is added. methyl ester hydrochloride and 1.4 ml (0.0102 mol) triethylamine and stirred for an additional 4 hours at room temperature and then 1 hour at 60 ° C. To complete the reaction, 1 ml of diphenylphosphoryl chloride and 1.4 ml of triethylamine are added again and stirred overnight at room temperature. It is then evaporated to dryness in vacuo, the residue is taken up in ethyl acetate, the ethyl acetate solution is washed twice with saturated sodium bicarbonate solution and once with water and dried over sodium sulfate. After evaporation in vacuo, 4 g of residue remained, which was purified by column chromatography on silica gel using dichloromethane / methanol = 20: 1 and 10: 1 as eluent.

The residue was triturated with ether / petroleum ether, filtered off with suction and dried. Yield: 2.98 g (62.1% of theory)

Melting point: 182-184 ° C.

PríkladXX

4- [4 - [[of trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminokarbony1] phenyl] -1-piperazine-benzy1

a) 1-benzyl-4- (4-cyanophenyl) piperazine

A mixture of 26 g (0.2147 mol) of 4-fluorobenzonitrile, 37.3 ml (0.2147 mol) of N-benzylpiperazine and 36.7 ml (0.2147 mol) of N-ethyl-diisopropylamine is heated to 140 ° for 8 hours. C. After cooling, it is stirred in water and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ether / petroleum ether.

Yield: 29.8 g (50.1% of theory)

Melting point: 106 to 108 ° C.

b) 1-benzyl-4- (4-carboxyphenyl) piperazine

29.8 g (0.1074 mol) of 1-benzyl-4- (4-cyanophenyl) piperazine are dissolved in 200 ml of ethylene glycol. After the addition of 48 g (0.8592 mol) of potassium hydroxide, it is heated at reflux temperature for 8 hours. The ethylene glycol is then further distilled off under vacuum and the residual oil is diluted with water. After acidification with acetic acid, the precipitated solids are filtered off with suction, washed with water and then with a small amount of acetone and dried.

Yield: 31.4 g (98.7% of theory)

Melting point: 225-227 ° C (decomposition).

c) 4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -1-benzylpiperazine

To a solution of 1.5 g (0.051 mol) of 1-benzyl-4- (4-carboxyphenyl) piperazine in 80 ml of dimethylformamide was added at -5 ° C and stirred with 1 ml (0.0051 mol) of diphenylphosphinic chloride and 0, 7 ml (0.051 mol) triethylamine and stirred for an additional hour at -5 ° C. Then, 1.13 g (0.051 mol) of methyl 3- (4-trans-aminocyclohexyl) propionic acid hydrochloride hydrochloride and 0.7 ml (0.051 mol) of triethylamine are added and stirred overnight at room temperature. It is then evaporated to dryness in vacuo and the residue is purified by silica gel column chromatography using dichloromethane containing 2.5% methanol as eluent. After evaporation of the eluent, the residue obtained is triturated with petroleum ether and filtered off with suction.

Yield: 1.04 g (44% of theory)

Melting point: 188-189 ° C.

Example XXI

4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydroisoindol-6-yl] pyridine

(a) 2-methyl-5-trifluoromethylsulfonyloxybenzoic acid methyl ester

To a solution of 10 g (60 mol) of 3-hydroxy-5-methyl-benzoic acid methyl ester in 40 mL of dried pyridine was added dropwise 18.2 mL (66 mmol) of trifluoromethanesulfonic anhydride over 35 minutes with stirring at -8 to 4 ° C. After addition was complete, stir overnight in an ice bath and then pour into water. It is extracted with tert-butyl methyl ether, the combined extracts are washed with dilute hydrochloric acid and then with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residual orange-red oil was purified by column chromatography on silica gel using cyclohexane / ethyl acetate = 9: 1 as the solvent.

colorless oil

Yield: 15.3 g (85.5% of theory)

Rf value: 0.60 (silica gel, ethyl acetate / cyclohexane = 9: 1)

b) 2-bromomethyl-5-trifluoromethylsulfonyloxy-benzoic acid methyl ester

A mixture of 8.3 g (27.8 mmol) of the compound produced under a), 5.3 g (30 mmol) of N-bromosuccinimide and 20 mg of 2,2'-azaisobutyronitrile in 100 ml of carbon tetrachloride is irradiated with 300 V of UV for 1 hour. - by submersible lamp. It is cooled, the insoluble succinimide is filtered off and the filtrate is evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using cyclohexane / ethyl acetate = 9: 1 as eluent.

Colorless oil.

Yield: 7.7 g (73.3% of theory).

Rf value: 0.55 (silica gel, ethyl acetate / cyclohexane = 9: 1)

c) 2- [trans-4- (2-methoxycarbonyl-ethyl) cyclohexyl] -1-oxo-2,3-dihydro-6-trifluoromethylsulfonyloxy-isoindole

To a solution of 2.2 g (10 mmol) of methyl trans-4-aminocyclohexylpropionate hydrochloride and 3.9 g = 5.1 ml (30 mmol) of N, N-diisopropylethylamine in 100 ml of dried dimethylformamide is added under stirring at temperature A solution of 3.8 g (10 mmol) of the compound obtained under b) in 10 ml of dimethylformamide was stirred at room temperature for 16 hours. It was then evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic phase is separated, dried over sodium sulphate in vacuo and evaporated to dryness. The solid residue is triturated with petroleum ether and filtered off with suction.

Yield: 1.9 g (42.2% of theory)

Melting point: 104-105 ° C

d) 4-2- [trans-4- (2-methoxycarbonylethyl) cyclohexyl] -1-oxo-2,3-dihydro-isoindol-6-yl] pyridine

- 45 A solution of 2.3 g (5.1 mmol) of the compound obtained under c), 1 g (8 mmol) of 4-pyridylboronic acid, 0.58 g (0.5 mmol) of tetrakis-triphenylphosphine-palladium (0) and 3 Triethylamine (3 mL, 24 mmol) in DMF (35 mL) was heated at 100 ° C for 8 h. After cooling, it is poured into 150 ml of water and the precipitate is filtered off with suction and washed with water. After vacuum drying at 40 ° C, it is purified by column chromatography on silica gel, eluting with dichloromethane / methanol = 19: 1. Yield: 1.2 g (62.2% of theory)

Melting point: 210-211 ° C.

Example XXII 1-benzyl-4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] 1-oxo-2,3-dihydroisoindol-6-yl] -3,4-dehydro-piperidine

a) 1-Benzyl-4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydroisoindol-6-yl] pyridinium bromide

A mixture of 0.32 g (0.84 mmol) of 4- [2- [trans-4- (2-methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydroisoindole-pyridine, 0.2 mL (1, 68 mmol) of benzyl bromide and 3 ml of acetonitrile are heated to reflux for half an hour, solids are formed. After cooling and diluting with tert-butyl methyl ether, it is aspirated and the solids are dried at 40 ° C under vacuum. Yield: 0.4 g (86.7% of theory)

Melting point: 252-255 ° C

b) 4-methoxycarbonyl-trans-cinnamic acid methyl ester

A mixture of 184.8 g (0.896 mol) of 4-methoxycarbonyltrans cinnamic acid, 10 ml of sulfuric acid and 3 l of methanol is heated under reflux for 18 hours. After cooling in an ice bath, the crystals obtained are filtered off with suction, washed with methanol and dried. Yield: 175.9 g (89.2% of theory)

Melting point: 121-123 ° C.

(C) 3- (4-methoxycarbonylphenyl) -3- (nitromethyl) propionic acid methyl ester (0.1 mol) methyl 4-methoxycarbonyltrans cinnamate is suspended in 59 g (0.966 mol) = 52 ml of nitromethane and added 2.4 g (0.021 mol) = 2.6 ml 1,1,3,3-tetramethylguanidine. The suspension obtained is heated at 70 ° C for 5 hours, then cooled and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and 2 N hydrochloric acid. The organic phase obtained is washed with water, dried and evaporated to dryness in vacuo. The brown oily residue obtained is chromatographed over silica gel with cyclohexane / ethyl acetate (7: 3 to 3: 2).

Yield: 20.8 g of a yellowish oil (74% of theory)

Rf value: 0.52 (silica, cyclohexane / ethyl acetate = 3: 2)

d) 3- (4-methoxycarbonylphenyl) pyrrolidin-5-one

20.3 g (0.72 mol) of 3- (4-methoxycarbonylphenyl) 3- (nitromethyl) propionic acid are hydrogenated in 200 ml of methanol in the presence of 2 g of Raney-nickel at 60 ° C for 7 hours at pressure 0.3 MPa. The catalyst was then filtered off and the filtrate was evaporated in vacuo. A yellow residue is obtained, which is triturated in dichloromethane, the precipitate thus obtained is filtered off, washed with dichloromethane and dried.

Yield: 11.2 g (70.9% of theory)

Melting point: 154-156 ° C.

e) 3- (4-methoxycarbonyl-phenyl) -pyrrolidinone hydrochloride

16.5 g (274 mmol) = 15.7 ml of glacial acetic acid are slowly added to a solution of 6 g (27 mmol) of 3- (4-methoxycarbonylphenyl) pyrrolidin-5-one and 10.4 g (274 mmol) of sodium borohydride in 120 ml of dioxane with stirring at 10 to 15 ° C. The resulting reaction mixture was heated at reflux for 7 hours. After stirring overnight at room temperature, 5.2 g of sodium borohydride and 7.9 ml of glacial acetic acid in 30 ml of dioxane were added again. The solution obtained is heated at reflux for 6 hours, then evaporated to a small volume, treated with 500 ml of water and extracted with dichloromethane. The organic phase obtained is washed with water, dried and evaporated to a small volume. The solution obtained is treated with hydrogen chloride and evaporated to dryness.

Yield: 6.2 g of anhydrous oil (93.9% of theory)

Rf value: 0.63 (reverse phase RP8 plate, methanol / 5% sodium chloride solution = 6: 4)

f) 1- tert -Butyloxycarbonyl-3- (4-methoxycarbonylphenyl) pyrrolidine

A mixture of 6.2 g (25.6 mmol) of 3- (4-methoxycarbonylphenyl) pyrrolidine hydrochloride, dissolved in a mixture of 40 ml of dioxane, is added with 9.0 g (41.17 mmol) of di-tert-butyl dicarbonate under ice-cooling, 20 ml of water and 14.3 ml of triethylamine. After stirring overnight, the mixture was evaporated to dryness. The oil obtained is partitioned between dichloromethane and water. The organic phase is washed with water, dried and evaporated to dryness. The oily substance thus obtained is chromatographed over silica gel with cyclohexane / ethyl acetate (4: 1).

Yield: 4.8 g (yellowish oil, 61.5% of theory)

Rf value: 0.62 (silica gel, cyclohexane / ethyl acetate = 3: 2)

g) 1- tert -butyloxycarbonyl-3- (4-carboxyphenyl) pyrrolidine

A mixture of 4.7 g (15.4 mmol) of 1-tert-butylcarbonyl-3- (4-methoxycarbonylphenyl) pyrrolidine, 15.4 ml of 2 N sodium hydroxide, 100 ml of tetrahydrofuran and 3.3 ml of water was stirred for 24 hours. Stir at room temperature. 15.4 ml of 2 N sodium hydroxide are then added again and the solution is heated at 50 ° C for 7 hours. After cooling to room temperature, 31 ml of 2 N hydrochloric acid and aqueous citric acid are added to pH 3. The solution obtained is evaporated to a small volume, the crystals obtained are filtered off with suction, washed with water and dried.

Yield: 3.8 g (84.4% of theory)

Melting point: 145-147 ° C.

h) 1- tert -Butyloxycarbonyl-3- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] pyrrolidine

A mixture of 3.75 g (12.87 mmol) of 1-tert-butyloxycarbonyl-3- (4-carboxyphenyl) pyrrolidine, 3.1 g (13.86 mmol) of methyl trans- (4-aminocyclohexyl) propionate, 7 9 g (77.67 mmol) = 10.8 ml triethylamine and 4.45 g (13.86 mmol)

2 - [(1H) -benzotriazol-1-yl] -1,1,3,3-tetra-methyl-uronium tetrafluoroborate in 100 ml of absolute dimethylformamide was stirred at room temperature for 2 hours. After diluting the obtained suspension with 250 ml of water, the colorless precipitate obtained is filtered off, washed with water and dried.

Yield: 5.75 g (100% of theory)

Melting point: 99-103 ° C.

Example XXIV

1-tert-butyloxycarbonyl-3- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -3-methyl-pyrrolidine

(a) 2- (4-methoxycarbonylphenyl) propionic acid nitrile

1.3 g of sodium hydride (55 to 62% in oil) was added to a solution of 5.3 g (30.25 mmol) of 4-methoxycarbonyl-phenylacetonitrile in 50 ml of dimethylformamide under ice-cooling. After 10 minutes, 4.3 g (30.25 mmol) = 1.9 methyl iodide was added dropwise under ice-cooling. The resulting suspension was stirred for 1.5 hours, diluted with water and evaporated to a small volume. The resulting solution was diluted with water again, acidified with citric acid and extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated to dryness in vacuo. The oily substance obtained is chromatographed on silica gel with cyclohexane / ethyl acetate (17: 3).

Yield: 32 g of a yellowish oil (47.1% of theory)

Rf value: 0.5 (silica gel, cyclohexane / ethyl acetate = 7: 3)

b) 3-Cyano-3- (4-methoxycarbonyl-phenyl) -49-butyric acid methyl ester

0.72 g of sodium hydride (55-65% in oil) was added to a solution of 3.1 g (16.38 mmol) of 2- (4-methoxycarbonylphenyl) propionic acid in 50 ml of dimethylformamide under ice-cooling. After 15 minutes with optional ice-cooling, it is added dropwise

2.5 g (16.4 mmol) = 1.55 ml of methyl bromoacetate. The suspension was stirred for 2.5 hours, diluted with water and evaporated to a small volume. The solution obtained is diluted with water again, acidified with citric acid and extracted with ethyl acetate.

The combined organic phases are washed with water, dried and evaporated to dryness in vacuo. The oily substance obtained is chromatographed on silica gel with cyclohexane / ethyl acetate (7: 3).

Yield: 3.6 g (83.7% of theory)

Melting point: 75 to 77 ° C.

c) 3- (4-methoxycarbonyl-phenyl) -3-methyl-pyrrolidin-5-one

A solution of 3-cyano-3- (4-methoxycarbonylphenyl) butyric acid methyl ester (3.3 g of 12.6 ml of methanol is acidified with 12 ml of methanolic hydrochloric acid and hydrogenated at 0 pressure in the presence of 1 g of palladium on charcoal (10%). The filtrate is evaporated to dryness in vacuo, the solid residue is dissolved in ethyl acetate and the organic phase is extracted with water, the aqueous phase is made alkaline by the addition of aqueous potassium carbonate solution and extracted with ethyl acetate. The residue obtained is triturated with ethyl acetate, filtered, washed with ethyl acetate and dried.

Yield: 2.2 g (75.9% of theory)

Melting point: 188-189 ° C.

d) 3- (4-methoxycarbonyl-phenyl) -3-methyl-pyrrolidine hydrochloride

5.6 g (92.5 mmol) = 5.3 ml of ethyl acetate are added slowly

- 50 to a solution of 3- (4-methoxycarbonyl-phenyl) -3-methyl-pyrrolidin-5-one (2.15 g, 9.22 mmol) and sodium borohydride (3.5 g, 92.5 mmol) in dioxane (60 ml) with stirring and at temperatures between 10 and 15 ° C. The mixture thus obtained was heated under reflux for 6 hours. After stirring overnight at room temperature, 1.8 g of sodium borohydride is added again, followed by 2.7 ml of glacial acetic acid in 10 ml of dioxane. After heating at reflux for 7 hours, the solution obtained is evaporated to a small volume, mixed with 300 ml of water and extracted with dichloromethane. The organic phase is washed with water, dried and evaporated to a small volume. The solution thus obtained is treated with hydrogen chloride and evaporated to dryness.

Yield: 1.14 g of anhydrous oil (48.6% of theory)

Rf value: 0.5 (reverse phase RP8 plate, methanol / 5% sodium chloride solution = 6: 7)

e) 1- tert -Butyloxycarbonyl-3- (4-methoxycarbonylphenyl) -3-methylpyrrolidine

1.6 g (7.15 mmol) of di-tert-butyl carbonate are added to a solution of 1.14 g (4.46 mmol) of hydrochloride under ice-cooling.

3- (4-methoxycarbonyl-phenyl) -3-methyl-pyrrolidine in a mixture of 4 ml of water, 8 ml of dioxane and 2.5 ml of triethylamine under ice-cooling. After stirring for 2 hours, the solution was evaporated to dryness and the resulting oily residue was partitioned between dichloromethane and water. The organic phase is washed with water, dried and evaporated to dryness. Yield: 1.18 g of a colorless oil (83.12% of theory)

Rf value: 0.62 (silica gel, cyclohexane / ethyl acetate = 3: 2)

f) 1- tert -Butyloxycarbonyl-3- (4-carboxyphenyl) -3-methylpyrrolidine

A mixture of 1.1 g (3.44 mmol) of 1-tert-butyloxycarbonyl-3- (4-methoxycarbonylphenyl) -3-methylpyrrolidine, 7 ml of 2 N sodium hydroxide, 20 ml of tetrahydrofuran and 1 ml of water was added for 3 days. stirred. Then 7 ml of 2 N hydrochloric acid and citric acid are adjusted to pH 2. The solution obtained is evaporated to a small volume and extracted with dichloromethane. The organic phase is washed with water, dried and evaporated to dryness. The oily substance obtained is chromatographed on silica gel with cyclohexane / ethyl acetate (4: 1 to 1: 1).

Yield: 600 mg of yellowish oil (51.1% of theory)

Rf value: 0.5 (silica gel, cyclohexane / ethyl acetate = 3: 2).

g) 1-tert-butylcarbonyl-3- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -1-methylpyrrolidine

A mixture of 0.57 g (1.87 mmol) of 1-tert-butyloxycarbonyl-3- (4-carboxyphenyl) -3-methylpyrrolidine, 0.445 g (2.01 mmol) of trans- (4-amino-cyclohexyl) methyl ester propionic acid, 1.14 g (0.113 mmol) = 1.56 ml triethylamine and 0.645 g (2 mmol) 2 - [(1H) -benzotriazol-1-yl] -1,1,3,3-tetramethyluronium tetrafluoroborate in 15 ml of absolute dimethylformamide was stirred at room temperature for 2 hours. The suspension obtained is diluted with water and evaporated to dryness. The residue is partitioned between ethyl acetate and dilute potassium carbonate solution. The resulting organic phase was washed with water, dried and evaporated to dryness. The remaining oil was chromatographed over silica gel with cyclohexane / ethyl acetate (4: 1).

Yield: 300 mg of a colorless oil (37.5% of theory)

Rf value: 0.31 (silica gel, cyclohexane / ethyl acetate = 3: 2).

Production of final compounds:

Example 1 1- tert -Butyloxycarbonyl-4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine

A solution of 0.76 g of 1-tert-butyloxycarbonyl-4- (4-carboxyphenyl) piperidine, 0.90 g of 2 - [(1H) -benzotriazol-1-yl] -1,1,3,3-tetramethyluronium tetrafluoroborate, 0.55 g of 3- (trans-4-aminocyclohexyl) -propionic acid methyl ester hydrochloride, 0.38 g of 1-hydroxy- (1H) -benzotriazole and 0.67 g of N-methylmorpholine in 50 ml of dimethylformamide are stirred for 16 hours at a temperature of rooms. The solvent was removed under reduced pressure. Water (200 mL) was added to the residue and the aqueous phase was extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. 1.8 g of solids are obtained, which are chromatographed over silica gel with methylene chloride / methanol (9: 1).

Yield: 1.15 g (98% of theory)

Melting point: sintered at 169 ° C

Rf value: 0.60 (silica gel, methylene chloride / methanol = 9: 1).

The following compounds are obtained analogously:

1) 1-tert-butyloxycarbonyl-4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine

Mp .: 157-162 ° C

Rf value: 0.53 (silica gel, cyclohexane / ethyl acetate = 1: 1)

2) 4- [4 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] -1-tert-butyloxycarbonylpiperidine

Rf value: 0.41 (silica gel, cyclohexane / ethyl acetate = 1: 1) mass spectrum: (M + Na) ⁺ = 624

3) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] quinuclidine

4) 4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] pyridine

5) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] piperidino] pyridine

6) 4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] pyridine

7) 4- [4 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] piperidino] pyridine

8) 4- [4 - [[4- [2- (n-hexanoylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] piperidino] pyridine

9) 4- [4 - [[trans -4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] pyridine

10) 4- [4 - [[trans -4- [2- (n-hexanoylamino) -2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] pyridine

11) 1-tert-butyloxycarbonyl-4- [4 - [[trans -4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] phenyl] piperidine

Melting point: 197-200 ° C

Rf value: 0.20 (silica gel, methylene chloride / methanol = 20: 1)

12) 4- [4 - [[4- (tert-butyloxycarbonylmethoxy) phenyl] carbonylamino] phenyl] -1-trifluoroacetylpiperidine

Prepared from 4- [4-aminophenyl] -1-trifluoroacetylpiperidine and 4- [tert-butyloxycarbonylmethyloxy] benzoic acid.

Melting point: 177-178 ° C.

4) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] oxymethyl] phenyl] piperidine hydrochloride

5) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] methyloxy] phenyl] piperidine hydrochloride

6) 4- [4 - [[trans-4- [2- (n-butanesulfonylamino) -2 (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

7) 4- [4 - [[trans-4- [2- (methanesulfonylamino) -2 (methoxycarbonyl) ethyl] -cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

8) 4- [4 - [[trans-4- [2- (n-hexanoylamino) -2 (methoxycarbonyl) ethyl] -cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

9) 4- [4 - [[trans-4- [2- (methoxycarbonyl) propyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

10) 4- [4- [N- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -N-methylaminocarbonyl] phenyl] piperidine hydrochloride

11) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] carbonylamino] phenyl] piperidine hydrochloride

12) 4- [4 - [[trans-4- [3- (methoxycarbonyl) propyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

13) 4- [4 - [[trans-4- (methoxycarbonylmethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: > 250 ° C

R. £ -value: 0.4 (reverse phase RP8 plate, methanol / 50 sodium chloride solution = 6: 4)

14) 4- [4 - [[4- [3- (methoxycarbonyl) -propyl] piperidino] carbonyl] phenyl] piperidine hydrochloride

15) 4- [4 - [[4- [4- (methoxycarbonyl) butyl] piperidino] carbonyl] phenyl] piperidine hydrochloride

16) 4- [4 - [[4- [3- (methoxycarbonyl) -propyl] piperazino] carbonyl] phenyl] piperidine dihydrochloride

17) 4- [4 - [[1- [2- (methoxycarbonyl) ethyl] 4-piperidinyl] aminocarbonyl] phenyl] piperidine dihydrochloride

18) 4- [4 - [[4- [3- (methoxycarbonyl) propyl] -3-oxo-piperazino] carbonyl] phenyl] piperidine hydrochloride

19) 1- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperazine hydrochloride

Melting point: 190-192 ° C

20) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -3,4-dehydro-piperidine hydrochloride

21) 4- [4 - [[trans-4- [2- (methoxycarbonyl) -octyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

22) 4- [4 - [[trans-4- [2- (benzylsulfonylamino) -2 (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

23) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -4-methylpiperidine hydrochloride

24) 4-Cyano-4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

25) 4-Aminocarbonyl-4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

26) 4- (Methoxycarbonyl) -4- [4 - [[trans-4- [2 (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

27) 3- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -n-propylamine hydrochloride

28) 5- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -n-pentylamine hydrochloride

29) 5- [4 - [[trans-4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] n-pentylamine hydrochloride

56) 5- [4 - [[trans-4- [2- (n-hexanoylamino) -2 (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] n-pentylamine hydrochloride

31) 1- [5 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] pyridin-2-yl] piperazine dihydrochloride

32) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] -3-methylphenyl] piperidine hydrochloride

33) 4- [3-Methoxy-4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

34) 4- [4 - [[trans-4- [2-amino-2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine dihydrochloride

35) 4- [4 - [[cis-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

36) 4- [4 - [[cis-4- [2- (n-butanesulfonylamino) -2 (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

37) 4- [4 - [[4- [2- (n-hexanoylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

38) 4- [4 - [[trans -4- (methoxycarbonylmethoxy) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

39) 4- [3 - [[4- [2- (benzylsulfonylamino) -2 (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

40) 4- [3 - [[4- [2- (n-hexanoylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

41) 4- [4 - [[4- [2- (Benzylsulfonylamino) -2 (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

42) 4- [3-Fluoro-4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

43) 4- [3-ethoxy-4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

44) 4- [2-Bromo-4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperazine hydrochloride

45) 4- [3-chloro-4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

46) 4- [4 - [[2-Bromo-4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

47) 4- [4 - [[2-methoxy-4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

48) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] -2-methylthiophenyl] piperazine hydrochloride

49) 1- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] -2-methylsulfonylphenyl] piperazine hydrochloride

50) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] -2-methylphenyl] aminocarbonyl] phenyl] piperidine hydrochloride

51) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] sulfonylamino] phenyl] piperidine hydrochloride

52) 4- [4 - [[4- [2- (methoxycarbonyl) ethenyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

53) 4- [4 - [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: 260-265 ° C

Rf value: 0.39 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25

54) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] piperidino] methyl] phenyl] piperidine dihydrochloride

Yield: 0.44 g (88% of theory, resin)

Rf value: 0.65 (RP8 plate, reverse phase, methanol /

5% sodium chloride solution = 6: 4) 1 H-NMR spectrum (200 MHz, DMSO-D 6), signals at ppm: 1.2-1.6 (m, 4H), 1.6-2.05 (m 6 + 1H, 2.25-2.4 (t, 2H), 2.8-3.1 (m, 4 + 1H), 3.3-3.55 (t, 4H), 3.6 (s, 3H), 4.2 (d, 2H), 7.3 (d, 2H), 7.5 (d, 2H), 8.4-8.9 (m, 2H), 9.9 ( s, 1H)

55) 1- [4 - [[4- (methoxycarbonylmethoxy) phenyl] carbonylamino] phenyl] piperazine hydrochloride

56) 4- [4 - [[4- [2- (methoxycarbonyl) ethenyl] phenyl] carbonylamino] phenyl] piperazine hydrochloride

57) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] carbonylamino] phenyl] piperidine hydrochloride

58) 4- [4 - [[trans-4- (methoxycarbonyl) cyclohexyl] methylaminocarbonyl] phenyl] piperidine hydrochloride

Melting point: > 250 ° C

Rf value: 0.43 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

59) 4- [4 - [[trans-4- (methoxycarbonyl) cyclohexyl] methylaminocarbonyl] phenyl] piperidine hydrochloride

Rf value: 0.43 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

60) 4- [4 - [[trans-4- (methoxycarbonyl) cyclohexyl] aminocarbonylamino] phenyl] piperidine hydrochloride

61) 4- [4 - [[trans-4- (methoxycarbonylmethoxy) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Rf value: 0.6 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

62) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] piperidinyl] carbonyl] phenyl] piperidine hydrochloride

Trifluoroacetic acid is used instead of hydrochloric acid.

Melting point: 177-179 ° C (decomposition)

63) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] piperidine dihydrochloride Trifluoroacetic acid is used in place of hydrochloric acid.

Yield: 1.98 g (75.4% of theory)

Melting point: 302 DEG-303 DEG C. (decomposition).

Example 3

4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

0.41 g of 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride was stirred with 80 ml of 6 N hydrochloric acid for 4 hours at room temperature. The precipitate formed is filtered off and washed with water.

Yield: 0.33 g (84% of theory)

Melting point: 280-285 ° C

R.f-value: 0.07 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Mass Spectrum: M ⁺ = 358.

The following compounds are obtained analogously:

1) 4- [4 - [[4- (2-carboxyethyl) phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: 290-293 ° C

R-p value: 0.11 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Mass Spectrum: M ⁺ = 352

2) 4- [4 - [[4- (2-carboxyethyl) phenyl] aminocarbonyl] phenyl] -1-methylpiperidine hydrochloride

It is saponified with lithium hydroxide in a 5: 4 mixture of tetrahydrofuran and water, treated with 1 N hydrochloric acid and the tetrahydrofuran evaporated in vacuo.

Melting point: above 300 ° C

Rf value: 0.13 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Mass Spectrum: M ⁺ = 366

3) 4- [4 - [[4- [2- (n-butanesulfonylamino) -2-carboxyethyl) phenyl] aminocarbonyl] phenyl] piperidine hydrochloride Melting point: 130 ° C (sintered at 120 ° C)

Rf value: 0.15 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Mass spectrum: (M-H) - = 486

4) 4- [3 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

A 1: 1: 0.5 mixture of water is used. hydrochloric acid and glacial acetic acid.

Rj value: 0.60 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Mass Spectrum: M ⁺ = 358

5) 4- [3 - [[4- (2-carboxyethyl) phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

Use 1: 1: 1 water, horse. hydrochloric acid and glacial acetic acid.

- 6l Rf -value: 0.43 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Elemental Analysis Found: C, 60.25%; H, 6.77%; H, 6.65%. Found: C, 60.47; H, 6.77;

6) 4- [3 - [[4- [2- (n-butanesulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride Carried out as in 4).

Melting point: above 200 ° C

Rf value: 0.60 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Mass spectrum. (M + H) &lt; ^{+ &gt}; = 488

7) 4- [4 - [[trans-4- (2-acetamino-2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

8) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -1-isopropylpiperidine hydrochloride

9) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] oxymethyl] phenyl] piperidine hydrochloride

10) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] methyloxy] phenyl] piperidine hydrochloride

11) 4- [4 - [[trans-4- [2- (n-butanesulfonylamino) -2-carboxyethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

12) 4- [4 - [[trans-4- [2-carboxy-2- (methanesulfonyl amino) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

13) 4- [4 - [[trans-4- [2-carboxy-2- (n-hexanoylamino) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

14) 4- [4 - [[trans-4- (2-carboxypropyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

15) 4- [4- [N- [trans-4- (2-carboxyethyl) cyclohexyl] -N-methylaminocarbonyl] phenyl] piperidine hydrochloride Melting point: 245-247 ° C

16) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] carbonylamino] phenyl] piperidine hydrochloride

17) 4- [4 - [[trans-4- (3-carboxy-propyl) -cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

18) 4- [4 - [(trans-4-carboxymethyl-cyclohexyl) aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: > 250 ° C

Rf value: 0.5 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

19) 4- [4 - [[4- (3-Carboxy-propyl) -piperidino] carbonyl] phenyl] piperidine hydrochloride

20) 4- [4 - [[4- (4-Carboxy-butyl) -piperidino] carbonyl] phenyl] piperidine hydrochloride

21) 4- [4 - [[4- (3-Carboxypropyl) -piperazino] carbonyl] phenyl] piperidine dihydrochloride

22) 4- [4 - [[1- (2-Carboxyethyl) -4-piperidinyl] aminocarbonyl] phenyl] piperidine dihydrochloride

23) 4- [4 - [[4- (3-carboxypropyl) -3-oxo-piperazino] carbonyl] phenyl] piperidine hydrochloride

24) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperazine hydrochloride

Melting point: 300 to 302 ° C (decomposition)

25) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] quinuclidine hydrochloride

26) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] pyridine hydrochloride

27) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -3,4-dehydro-piperidine hydrochloride

28) 4- [4 - [[trans-4- (2-carboxy-n-octyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

29) 4- [4 - [[trans-4- [2- (benzylsulfonylamino) -2-carboxyethyl] cyclohexyl] aminocarbonyl] phenyl] -piperidine hydrochloride

30) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -4-methylpiperidine hydrochloride

31) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -4-cyano-piperidine hydrochloride

32) 4-Aminocarbonyl-4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

33) 4-carboxy-4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

34) 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -n-propylamine hydrochloride

35) 5- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -n-pentylamine hydrochloride

36) 5- [4 - [[trans-4- [2- (n-butanesulfonylamino) -2-carboxyethyl] cyclohexyl] aminocarbonyl] phenyl] -n-pentylamine hydrochloride

37) 5- [4 - [[trans-4- [2-carboxy-2- (n-hexanoylamino) ethyl] cyclohexyl] aminocarbonyl] phenyl] -n-pentylamine hydrochloride

38) 1- [5 - [[trans -4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] pyridin-2-yl] piperazine dihydrochloride

39) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -3-methylphenyl] piperidine hydrochloride

40) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -3-methoxyphenyl] piperidine hydrochloride Proceed as in 2).

41) 4- [4 - [[trans-4- (2-amino-2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine dihydrochloride

42) 4- [4 - [[cis-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

43) 4- [4 - [[cis-4- [2- (n-butanesulfonylamino-2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

44) 4- [4 - [[4- [2-Carboxy-2- (hexanoylamino) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

45) 4- [4 - [[trans-4- (carboxymethoxy) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

46) 4- [4 - [[4- (2-Carboxyethyl) phenyl] aminocarbonyl] piperidino] pyridine hydrochloride

47) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] piperidino] pyridine hydrochloride

48) 4- [4 - [[4- [2- (n-Butanesulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] piperidino] piperidine hydrochloride

49) 4- [4 - [[4- [2-Carboxy-2- (n-hexanoylamino) ethyl] phenyl] aminocarbonyl] piperidino] piperidine hydrochloride

50) 4- [4 - [[trans-4- [2- (n-butanesulfonylamino) -2-carboxyethyl] cyclohexyl] aminocarbonyl] piperidino] pyridine hydrochloride

51) 4- [4 - [[trans-4- [2-carboxy-2- (n-hexanoylamino) ethyl] cyclohexyl] aminocarbonyl] piperidino] pyridine hydrochloride

52) 4- [3 - [[4- [2- (Benzylsulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

53) 4- [3 - [[4- [2-Carboxy-2- (n-hexanoylamino) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

54) 4- [4 - [[4- [2- (Benzylsulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

55) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -3-fluorophenyl] piperidine hydrochloride

56) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -3-ethoxyphenyl] piperidine hydrochloride

Proceed as in 2).

57) 1- [2-Bromo-4 - [[trans -4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] piperazine hydrochloride

58) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -3-chlorophenyl] piperidine hydrochloride

59) 4- [4 - [[2-Bromo-4- (2-carboxyethyl) phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

60) 4- [4 - [[4- (2-Carboxyethyl) -2-methoxyphenyl] aminocarbonyl] phenyl] piperidine hydrochloride

61) 1- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -2-methylthiophenyl] piperazine hydrochloride

62) 1- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] -2-methylsulfonylphenyl] piperazine hydrochloride

63) 4- [4 - [[4- (2-Carboxyethyl-2-methylphenyl) aminocarbonyl] phenyl] piperidine hydrochloride

64) 4- [4 - [[4- (2-Carboxy-ethyl-phenyl] -sulfonylamino] -phenyl] -piperidine hydrochloride

65) 4- [4 - [[4- (2-Carboxy-ethenylphenyl] aminocarbonyl] phenyl] piperidine hydrochloride

66) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -1-methylpiperidine hydrochloride

Melting point:> 300 ° C Mass spectrum: M ⁺ = 372

67) 4- [1 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] piperidino] piperidine hydrochloride

68) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] piperidino] piperidine dihydrochloride Yield: 0.77 g (79.5% of theory)

Melting point: .297-300 ° C (decomposition)

69) 1- [4 - [[4- (carboxymethoxy) phenyl] carbonylamino] phenyl] piperazine hydrochloride

70) 4- [4 - [[4- (2-Carboxy-ethenyl) phenyl] carbonylamino] phenyl] piperidine hydrochloride

71) 4- [4 - [[4- (2-Carboxyethyl) phenyl] carbonylamino] phenyl] piperidine hydrochloride

72) 4- [4 - [[trans-4- (carboxy) cyclohexyl] methylaminocarbonyl] phenyl] piperidine hydrochloride

Melting point: 109-110 ° C

73) 4- [2- [4- (2-Carboxy-ethyl) -phenyl] -1-oxo-2,3-dihydro-isoindol-6-yl] -piperidine hydrochloride

Mp .: 291-293 ° C

Rf value: 0.52 (RP8 plate reverse phase, methanol / 5% sodium chloride solution - 6: 4)

74) 2- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] ethylamine hydrochloride

Melting point: 250 ° C

Rf value: 0.65 (RP8 plate reversed phase, methanol / 5% sodium chloride solution - 6: 4)

75) 4- [4 - [[trans-4- (2-carboxymethoxy) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: > 250 ° C

Rf value: 0.65 (RP8 plate reversed phase, methanol / 5% sodium chloride solution - 6: 4)

76) 4- [4 - [[trans-4-carboxy-cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: > 200 ° C

Rf value: 0.70 (RP8 plate reverse phase, methanol / 5% sodium chloride solution - 6: 4)

77) 4- [4 - [[4- (2-Carboxyethyl) phenyl] aminocarbonyl] phenyl] piperidine hydrochloride

78) 4- [4 - [[4- (2-Carboxyethyl) piperidinyl] carbonyl] phenyl] piperidine hydrochloride

Melting point: 207 to 208 ° C (decomposition)

79) 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] 1-oxo-2,3-dihydro-isoindol-6-yl] piperidine hydrochloride R 6 -value: 0.50 (RP8 plate) reverse phase, methanol / 5% sodium chloride solution - 6: 4)

80) 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] 1-oxo-2,3-dihydro-isoindol-5-yl] piperidine R hydrochloride. (RP8 plate reverse phase, methanol / 5% sodium chloride solution - 6: 4)

Melting point: > 300 ° C

81) 4- [2- [4- (2-Carboxy-ethyl) -phenyl] -1-oxo-2,3-dihydro-isoindol-5-yl] -piperidine hydrochloride

Melting point: 303-306 ° C

82) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -1-aza-bicyclo [2.2.1] heptane hydrochloride Rf -value: 0 (plate RP8 reverse phase) , methanol / 5% sodium chloride solution - 6: 4)

83) 4- [4 - [[trans-4- (carboxy) cyclohexyl] methylaminocarbonyl] piperidine hydrochloride

Rf value: 0.56 (RP8 plate reverse phase, methanol / 5% sodium chloride solution - 6: 4) i

Example4 '

4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] -1-methylpiperidine hydrochloride

0.8 g of 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride is dissolved in 35 ml of methanol, mixed with 0.42 g of paraformaldehyde and 0.45 g of sodium cyanoborohydride and Stir for 3 hours at room temperature, maintaining the pH by adding 1 N hydrochloric acid between 3 and 6. An additional 0.5 g of paraformaldehyde and 0.5 g of sodium cyanoborohydride are added and stirred for 16 hours at room temperature while maintaining the above. acidity of the solution. Basify with 10 N sodium hydroxide, extract with ethyl acetate, evaporate the organic phase and purify by silica gel chromatography (eluent: methylene chloride / methanol 9: 1).

Yield: 0.58 g (76% of theory)

Melting point: 161-164 ° C

Rf value: 0.17 (silica, methylene chloride / methanol = 9: 1). Mass Spectrum: M ⁺ = 380

The following compounds are obtained analogously:

1) 1-isopropyl-4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine

2) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -1-methylpiperidine

Melting point: 202-204 ° C

3) 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] 1-oxo-2,3-dihydro-isoindol-5-yl] -1-methylpiperidine hydrochloride Melting point: 301 to 303 ° C

Made from 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine with paraformaldehyde and formic acid.

4) 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -1-methylpyrrolidine hydrochloride

Melting point: 246-250 ° C

Made from 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] pyrrolidine hydrochloride with paraformaldehyde and formic acid.

Example 5

4- [3 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Dissolve 1.7 g of 1-benzyl-4- [3 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -3,4-dehydro-piperidine in 40 ml of methanol, mix 2 ml of methanolic hydrochloric acid and 0.5 g of palladium hydroxide on carbon are hydrogenated at 50 DEG C. and a hydrogen pressure of 0.5 MPa. The catalyst was then filtered off and the mixture was evaporated in vacuo.

Yield: 1.30 g (87% of theory)

Rf value: 0.25 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Mass Spectrum = M ⁺ = 372

The following compounds are obtained analogously:

1) 4- [3 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine

It is operated without the addition of hydrochloric acid with 10% palladium on carbon.

Rf value: 0.27 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

2) 4- [3 - [[4- [2- (n-butylsulfonylamino) -2 (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine hydrochloride The procedure is as in 1) but at 60 ° C.

Rf value: 0.28 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Mass Spectrum: (M + H) ⁺ = 502.

3) 1- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperazine hydrochloride

It is produced by debenzylation of 4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -1-benzylpiperazine in the presence of 10% palladium on carbon.

Melting point: 190-192 ° C.

4) 4- [2- [4- [2- (methoxycarbonyl) ethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-6-yl] piperidine hydrochloride

5) 4- [2- [trans-4- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydro-isoindol-6-yl] piperidine hydrochloride Melting point: 175-178 ° C

Made from 1-benzyl-4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] -cyclohexyl] -1-oxo-2,3-dihydro-isoindol-6-yl] -3,4-dehydro-piperidine and palladium hydroxide on carbon as the catalyst of the lysator.

6) 4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride Melting point: 260-262 ° C

7) 4- [2- [4- [2- (methoxycarbonyl) ethyl] cyclohexyl] 1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

Mp .: 232-235 ° C

Example 6 1-Benzyl-4- [3 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] -3,4-dehydro-piperidine g 1-benzyl-4- (3- of carboxy-phenyl) -3,4-dehydro-piperidine was heated in refluxing thionyl chloride (3.5 ml) for 45 minutes and then evaporated to dryness in vacuo. The acid chloride thus obtained is added in portions to a cooled solution of 1.3 g of 3- (trans-4-amino-cyclohexyl) -propionic acid methyl ester hydrochloride and 3.3 ml of N-ethyl-diisopropylamine in 50 ml of methylene chloride. After 2 hours 300 ml of methylene chloride and 15 ml of methanol are added, washed successively with water, 0.1 N sodium hydroxide, water, 0.1 N hydrochloric acid and water and the organic phase is evaporated. The product was purified by column chromatography over silica gel (eluent: methylene chloride / methanol = 9: 1).

Yield: 1.8 g (64% of theory)

Rf value: 0.42 (silica gel, methylene chloride / methanol = 9: 1)

The following compounds are obtained analogously:

1) 1-Benzyl-4- [3 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] -3,4-dehydro-piperidine M.p .: 194-196 ° C

Rf value: 0.66 (silica gel, methylene chloride / methanol =

9: 1)

2) 1-benzyl-4- [3 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] -3,4-dehydro-piperidine hydrochloride

Rf value: 0.25 (silica gel, methylene chloride / methanol = 20: 1)

Example 7

4- [4 - [[4- (2-Carboxyethyl) phenyl] aminomethyl] phenyl] piperidine hydrochloride

0.7 g of 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminomethyl] phenyl] -1-trifluoroacetylpiperidine, 10 ml of glacial acetic acid and 1 ml of horse. hydrochloric acid was stirred at 80 ° C for 4 hours and at room temperature for 16 hours. It is evaporated to dryness in vacuo, evaporated several times with toluene and the residue is stirred with 50 ml of acetone.

Yield: 0.39 g (66% of theory)

Rf value: 0.76 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 9: 1)

Mass Spectrum: M ⁺ = 338

The following compounds are obtained analogously:

1) 4- [2- [trans-4- (2-carboxy-ethyl) cyclohexyl] 1-oxo-2,3-dihydro-isoindol-6-yl] -piperidine hydrochloride

2) 4- [2- [4- [2- (n-Butanesulfonylamino) -2-carboxyethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-6-yl] -piperidine hydrochloride

3) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminomethyl] phenyl] piperidine dihydrochloride

Melting point: 308-311 ° C (decomposition)

4) 4- [4- [N- [trans-4- (2-carboxyethyl) cyclohexyl] -N-methylaminomethyl] phenyl] piperidine dihydrochloride

5) 4- [4- [N- [trans-4- (2-carboxyethyl) cyclo73 hexyl] -N- (2-phenylethyl) aminomethyl] phenyl] piperidine dihydrochloride

6) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminosulfonyl] phenyl] piperidine hydrochloride

7) 4- [4- [2- [4- (2-carboxyethyl) phenyl] ethenyl] phenyl] piperidine hydrochloride

8) 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] 1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

9) 4- [2- [4- (2-carboxyethyl) phenyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

10) 4- [2- [4- [2- (n-Butanesulfonylamino) -2-carboxyethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

11) 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] 1-oxo-2,3-dihydroisoquinolin-7-yl] piperidine hydrochloride

12) 4- [2- [4- (2-Carboxyethyl) phenyl] -1-oxo-2,3-dihydro-isoquinolin-7-yl] piperidine hydrochloride

13) 4- [2- [4- (2-Carboxyethyl) phenyl] -1-oxo-2,3-dihydro-isoindol-6-yl] piperidine hydrochloride

14) 4- [4- [2- [4- (2-Carboxyethyl) -phenyl] -ethyl] -phenyl] -piperidine hydrochloride

15) 4- [4 - [[4- (2-carboxyethyl) phenyl] methyl] amino] phenyl] piperidine hydrochloride

16) 4- [4 - [(trans-4-carboxy-cyclohexyl) aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: above 310 ° C

Rf value: 0.13 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

17) 4- [4 - [[4- (carboxymethyloxy) phenyl] carbonylamino] phenyl] piperidine hydrochloride

Made from 4- [4 - [[4- (tert-butyloxycarbonylmethyloxy) phenyl] carbonylamino] phenyl] -1-trifluoroacetylpiperidine Rf value: 0.10 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum: (M + H) ⁺ = 355

Example 8

4- [4 - [[4- [2- (metoxykarboxy) ethyl] phenyl] aminomethyl] phenyl] -1-trifluoroacetyl-piperidine

8.6 g of 4- [4 - [[4- [2- (methoxycarboxy) ethyl] phenyl] iminomethyl] phenyl] -1-trifluoroacetyl-piperidine are dissolved in 100 ml of ethyl acetate and hydrogenated in the presence of 0.5 g of platinum oxide. at least 1.5 hours at room temperature with hydrogen at 0.5 MPa. An additional 0.5 g of platinum oxide was added and the temperature rose to 50 ° C. After 3 hours, 0.5 g of platinum oxide was added and hydrogenated for a further 4 hours. After the catalyst was filtered off, the solvent was removed and the residue was purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 3: 1).

Yield: 3.6 g (42% of theory)

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 2: 1)

Example 9

4- [4 - [[trans-4- [2- (isopropylcarbonyl) ethyl] cyclohexyl] aminomethyl] phenyl] -piperidine hydrochloride

0.15 g of 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminomethyl] phenyl] piperidine hydrochloride is suspended in a mixture of 100 ml of isopropanol and 50 ml of ethereal hydrochloric acid and stirred for 16 hours at room temperature. The product is obtained by evaporating the solution in vacuo.

Yield: 0.135 g (81% of theory)

Melting point: 255-260 ° C

Rf value: 0.31 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

Mass Spectrum: M ⁺ = 400.

_Sl > Analogously the following compounds are obtained:

1) 4- [4 - [[trans-4- [2- (sec-butyloxycarbonyl) * ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

2) 4- [4 - [[trans -4- [2- (cyclohexyloxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride Melting point: 238-240 ° C

3) 4- [4 - [[trans -4- [2- (isobutyloxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride Melting point: 238-240 ° C

4) 4- [4 - [[trans-4- [2 - [(2-phenyl-ethyl) oxycarbonyl] ethyl] cyclohexyl] aminocarbonyl] phenyl] -piperidine hydrochloride

5) 4- [2- [4- [2- (methoxycarbonyl) ethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-6-yl] -piperidine hydrochloride; and

6) 4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydro-isoindol-6-yl] -piperidine hydrochloride

7) 4- [2- [4- [2- (n-Butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-6-yl] piperidine hydrochloride

8) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminomethyl] phenyl] piperidine ditrifluoroacetate

Melting point: 77 to 79 ° C (decomposition)

9) 4- [4- [N- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -N-methyl-aminomethyl] phenyl] piperidine dihydrochloride

10) 4- [4- [N- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -N- (2-phenyl-ethyl) -aminomethyl] phenyl] piperidine dihydrochloride

11) 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminosulfonyl] phenyl] piperidine hydrochloride

12) 4- [4- [2- [4- [2- (methoxycarbonyl) ethyl] phenyl] ethenyl] phenyl] piperidine hydrochloride

13) 4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

14) 4- [2- [4- [2- (methoxycarbonyl) ethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

15) 4- [2- [4- [2- (n-Butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride

16) 4- [2- [trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] -1-oxo-3,4-dihydro-isoquinolin-7-yl] piperidine hydrochloride

17) 4- [2- [4- [2- (methoxycarbonyl) ethyl] phenyl] -1-oxo-3,4-dihydroisoquinolin-7-yl] piperidine hydrochloride

18) 4- [4- [2- [4- [2- (methoxycarbonyl) ethyl] phenyl] ethyl] phenyl] piperidine hydrochloride

19) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] methylamino] phenyl] piperidine hydrochloride

20) 4- [4 - [[4- [2- (methoxycarbonyl) ethyl] phenyl] aminomethyl] phenyl] piperidine hydrochloride

21) 4- [4 - [[trans-4- (isopropylcarbonyl) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: 270 ° C (sintered at 250 ° C)

Rf value: 0.38 (silica gel, methylene chloride / methanol / conc. Ammonia = 4: 1: 0.25)

22) 4- [4 - [[trans-4- [2- (ethoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride

Melting point: 246-248 ° C

23) 4- [4 - [[trans -4- (ethoxycarbonylmethyloxy) cyclohexyl] aminocarbonyl] phenyl] piperidine hydrochloride Rf value: 0.60 (RP8 plate, reverse phase, methanol / 5% sodium chloride solution = 6: 4) )

24) 4- [4 - [[4- (methoxycarbonylmethyloxy) phenyl] carbonylamino] phenyl] piperidine

25) 4- [2- [trans-4- [2- (ethoxycarbonyl) ethyl] cyclohexyl] -1-oxo-2,3-dihydro-isoindol-5-yl] piperidine hydrochloride Melting point: 260-264 ° C.

Example 10

1- (methoxycarbonyl) -4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] -cyclohexyl] -aminocarbonyl] -phenyl] -piperidine

Prepared from 4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminomethyl] phenyl] -piperidine and methyl chloroformate in methylene chloride in the presence of 0.2 N sodium hydroxide.

The following compound is obtained analogously:

1) 1- (acetoxymethoxycarbonyl) -4- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine

Example 11

2- [4 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] ethylamine hydrochloride

A solution of 1.6 g (4.87 mmol) of 2- [4 - [[trans-4- [2- (methoxycarbonyl) -ethyl] -cyclohexyl] -aminocarbonyl] -phenyl] -acetonitrile in 400 ml of methanol was acidified with methanolic acid. hydrochloric acid was hydrogenated in the presence of 0.5 g palladium on carbon (10%) at room temperature and 50 psi pressure until hydrogen consumption was complete. The catalyst is then filtered off with suction and evaporated to dryness under reduced pressure. The residue was triturated with a 1: 1 mixture of tert-butyl methyl ether and ethyl acetate, heated, re-cooled to room temperature and suction filtered. After boiling with acetone and re-standing, 1.2 g = 66.7% of a yellowish crystalline compound is obtained.

Melting point: > 250 ° C

Rf value: 0.45 (silica gel, dichloromethane / methanol = 4: 1)

Example 12

4- [1 - [[trans-4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] piperidino] -piperidine

To an equimolar solution of trans-4- [2- (methoxycarbonyl) ethyl] cyclohexylamine and p-nitrophenyl chloroformate in dry tetrahydrofuran was added dropwise with stirring at 0 ° C a solution of 2 equivalents of triethylamine in tetrahydrofuran and stirred for an additional 2.5 hours at 0 Then, the equivalent of 4,4'-bipiperidyl is added dropwise with further stirring, stirred for a further 16 hours at room temperature and a further 4 hours at 50 ° C. It is evaporated to dryness under reduced pressure, the residue is taken up in ethyl acetate and this ethyl acetate solution is washed with 1 N sodium hydroxide and then with water, dried over sodium sulphate and evaporated to dryness under reduced pressure. The remaining crude product is chromatographed on silica gel using ethyl acetate as the eluent.

Example 13

4- [4 - [[4- (2-Carboxyethyl) -piperidino] methyl] phenyl] piperidine dihydrochloride

1.3 g (0.0029 mol) of 1-tert-butyloxycarbonyl-4- [4 - [[2 (methoxycarbonyl) ethyl] -piperidino] -methyl] phenyl] piperidine are stirred in 80 ml of semi-concentrated hydrochloric acid for 15 minutes at a temperature of rooms. It is then evaporated under vacuum and the residue is digested three times with acetone and the residual resin residue is dried under vacuum.

Yield: 0.82 · g (77.1% of theory)

R-value: 0.54 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

1 H-NMR spectrum (200 MHz, DMSO-d 6), signals at ppm: 1.3-1.7 (m, 5H), 1.7-2.0 (m, 6H), 2.15-2 3 (t, 2H), 2.7-3.1 (m, 4 + 1H), 3.2-3.55 (m, 4H), 4.15-4.2 (d, 2H), 7 3 (d, 2H), 7.6 (d, 2H), 9.1 (s, 2H); 10.7 (s, 1 H),

12.05 (s, 1 H)

The following compounds are prepared analogously:

1) 4- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminomethyl] phenyl] piperidine dihydrochloride

Mp: 308-311 ° C

Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[trans -4- (2-methoxycarbonylethyl) cyclohexyl] aminomethyl] phenyl] piperidine and semi-concentrated hydrochloric acid.

2) 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] pyrrolidine hydrochloride

Rf value: 0 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

3) 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -3-methylpyrrolidine hydrochloride

Rf value: 0 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

4) 4- [2- [trans-4- (2-carboxyethyl) cyclohexyl] -1-oxo-2,3-dihydro-isoindol-6-yl] piridine

Rf value: 0.39 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

5) 1- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminomethyl] phenyl] piperazine dihydrochloride

Melting point: 245 to 248 ° C (decomposition)

Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[trans -4- (2-methoxycarbonylethyl) cyclohexyl] aminomethyl] phenyl] piperazine and semi-concentrated hydrochloric acid.

6) 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] pyrrolidine hydrochloride

Melting point: > 250 ° C

Rf value: 0.55 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Prepared from 1-tert-butyloxycarbonyl-3- [4 - [[trans -4- [2 (methoxycarbonyl) ethyl) cyclohexyl] aminocarbonyl] phenyl] pyrrolidine and semi-concentrated hydrochloric acid.

7) 3- [4 - [[trans-4- (2-carboxyethyl) cyclohexyl] aminocarbonyl] phenyl] -3-methylpyrrolidine hydrochloride

Melting point: 250 ° C

Rf value: 0.5 (RP8 plate reverse phase, methanol / 5% sodium chloride solution = 6: 4)

Prepared from 1-tert-butyloxycarbonyl-3- [4 - [[trans -4- [2 (methoxycarbonyl) ethyl) cyclohexyl] aminocarbonyl] phenyl] -3-methylpyrrolidine and semi-concentrated hydrochloric acid.

Example 14

Dry ampoules with 2.5 mg of active substance per ml

Ingredients:

active substance 2.5 mg mannitol 50.0 mg water for injections ad

1.0 ml

Production:

The active substance and mannitol are dissolved in water. After filling, freeze-dried.

A solution for injection is prepared by dissolving in water.

Example 15

Dry ampoules with 35 mg of active substance per 2 ml

Ingredients:

active substance 35.0 mg mannitol 100.0 mg water for injections ad 2.0 ml

Production:

The active substance and mannitol are dissolved in water. After filling, freeze-dried.

The solution for injection is prepared with water.

P 16 and 16 Tablet with 50 mg of the active substance Ingredients: 1) active substance 50.0 mg 2) milk sugar 98.0 mg 3) maize starch 50.0 mg 4) polyvinylpyrrolidone 15.0 mg 5) magnesium stearate 2.0 mg 215.0 mg

Production:

1), 2) and 3) are mixed and granulated with an aqueous solution 4). They are admixed with the dried granulate 5). Tablets are compressed from this mixture, biplanar with a double-faced facet and a single-sided scoring line. Tablet diameter: 9 mm.

Example

Tablet with 350 mg of the active substance

Ingredients: (1) the active substance 350.0 mg 2) milk sugar 136.0 mg 3) corn starch 80.0 mg 4) polyvinylpyrrolidone 30.0 mg 5) magnesium stearate 4.0 mg 600.0 mg Production: 1), 2) and 3) are mixed and granulated with com 4). They are admixed with the dried granulate 5). tablets are compressed, biplanar with double sided side-sided groove. Diameter of tablets: 12 Example 18 Capsules containing 50 mg of the active substance • Ingredients: (1) the active substance 50.0 mg 2) dried corn starch 58.0 mg 3) powdered milk sugar 50.0 mg 5) magnesium stearate 2.0 mg

160.0 mg

Production:

1) is spread with 3). This mixture is added to mixtures 2) and 4) with vigorous stirring.

This powder mixture is filled on a capsule device into size 3 hard gelatin push-fit capsules.

Example

Capsules with 350 mg of the active substance

1) active substance 350.0 mg 2) dried corn starch 46.0 mg 3) powdered milk sugar 30.0 mg 5) magnesium stearate 4.0 mg 430.0 mg

Production:

1) is spread with 3). This mixture is added to mixtures 2) and 4) with vigorous stirring.

This powder mixture is filled on a capsule device into hard gelatin push-fit capsules of size 0.

Claims (10)

CLAIMS 1. Carboxylic acid derivatives of the general formula I ABCDE-COOR _and (I) where _And R is H, alkyl of 1-5 carbon atoms, alkenyl having 3 to 5 carbon atoms, phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, cycloalkyl having 5 to 7 carbon atoms, or R - ^ - CO O- (R 2 CH) -group wherein R- £ is C až-C alky alkyl, C až-C cyk cycloalkyl, C až-Ceny phenylalkyl, C až-C alko alkoxy, C až-C 7 cycloalkoxy, or a phenyl group; and R 2 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 5 -C 7 cycloalkyl group or a phenyl group, A represents via a carbon atom of the radical A to the radical B an aminoalkyl group having 1 to 5 carbon atoms or 5-, A 6- or 7-membered azacycloalkyl group, wherein the coupling of the azacycloalkyl group to the B moiety is via a carbon atom of the azacycloalkyl group as well as the hydrogen atom of the amino group in said aminoalkyl groups and the hydrogen atom on the nitrogen atom of said azacycloalkyl groups may be replaced by R _b carbon atoms of an azacycloalkyl group substituted by one to three alkyl groups having from 1 to 3 carbon atoms each, alkylamino-, cyano-, R RO- or R OO-CO-, where it represents an alkyl group having 1 to 3 carbon atoms, a phenylalkyl group (C 1 -C 3) alkyl, (C 1 -C 3) alkanoyl, trifluoroacetyl, (C 2 -C 6) alkoxycarbonyl, (C 1 -C 3) phenylalkoxycarbonyl, (C 4 -C 3) alkenyloxycarbonyl up to 6 carbon atoms or an R 1 -CO-O- (R 2 CH) -O-CO-group, where and R2 are as previously defined and Rg represents a hydrogen atom, an alkyl or phenylalkyl group having from 1 to 3 carbon atoms in the alkyl part, as well as in the 6- or 7-membered azacycloalkyl group thus formed, one unit> CH- in the 4-position relative to the ring nitrogen atom the N atom or the 5- to 7-membered azacycloalkyl group -CH2-CH <thus formed may be replaced by a -CH = C unit and the piperazinyl- or homopiperazinyl ring thus formed may be a methylene group adjacent to the nitrogen atom in the 4-position to be replaced by carbonyl , quinuclidinyl or pyridyl, B is optionally fluorine, chlorine or bromine, trifluoromethyl, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl having from 1 to 3 carbon atoms in the alkyl or alkoxy moiety of a mono- or disubstituted phenylene group wherein the substituents are the same or different and furthermore, 1 or 2 unsubstituted meth groups may in each case be replaced by an N-atom or a piperidinylene group, C is carbonyl-, -CH 2 CH 2 -, -CH = CH-, -CH ₂ -, -CH ₂ O-, -och ₂ -, -con ₄ -, -con ₄ -ch ₂ -, -nr ₄ co-, -nr ₄ co-nr ₄ -, -CH ₂ NR ₄ -, -NR ₄ CH ₂ -, -SO ₂ NR ₄ -, -SO ₂ NR ₄ -CH ₂ - or -NR ₄ SO ₂ - wherein R ₄ is H, an alkyl or phenylalkyl group each having 1 to 3 carbon atoms in the alkyl moiety, or alternatively, where C is through a carbonyl group bonded to the rest of the B group -C0NR ₄ -, R ₄ is methylene or 1, 2-ethylene, which are in each case bonded to a carbon atom in the ortho position of the carbon of residue B to the position of attachment of the -conr ₄ D radical, optionally with fluorine, chlorine or bromine, trifluoromethyl, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl of 1 to 3 atoms carbon in the alkyl and alkoxy moiety of a mono or disubstituted phenylene group, wherein the substituents are the same or different and wherein further 1 or 2 unsubstituted meth groups may each be replaced by an N-atom, a C 5 -C 7 cycloalkylene group in which one or two> CH- units can be replaced by an N-atom, in addition in the aza so formed - or the diazacyclohexylene ring, the methylene group adjacent to the nitrogen atom can be replaced by a carbonyl group and the bond to the C and E residues can also be carried out via the nitrogen atom of the aza- or diazacyclohexylene ring, and E represents a bond, an alkyleneoxy group having 1 to 3 carbon atoms in the alkyl moiety, wherein the oxygen atom is attached to the radical D, a direct alkylene group having 1 to 5 carbon atoms which may be substituted by 1 or 2 alkyl groups, hydroxyl, alkoxy, R R; NH- R (N (alkyl)) - or R (N) (phenylalkyl) - or a C 2 -C 5 alkenylene group which may be substituted by one or two alkyl groups, the alkyl portion of the phenylalkyl group may contain 1 to 3 carbon atoms and other alkyl, alkylene and alkoxy moieties of from 1 to 8 carbon atoms in each case denoting a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, a phenylalkoxycarbonyl group or an alkyl group having 1 to 8 carbon atoms; phenylalkyl or phenyl-substituted carbonyl or sulfonyl, in which the alkyl and alkoxy moieties in said phenylalkyl and phenylalkoxy groups may each contain 1 to 3 carbon atoms and the cycloalkyl moiety 3 to 7 carbon atoms, wherein the phenyl radicals mentioned above may be phenyl groups in addition mono- or disubstituted by fluorine, chlorine u or bromo, trifluoromethyl, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl having in each case 1 to 3 carbon atoms in the alkyl and alkoxy moiety and the substituents may be the same or different, wherein, when i) AB-group in the 4-position is R 1 -NH-CH ₂ -substituted phenyl in which R 1 is benzyloxycarbonyl, R _and OOC-EDC cannot be 3-carboxy-phenylaminocarbonyl (see EP- A-0372486 and J. Med. Chem., 35, 4393-4407 (1992)), or when (ii) the AB-group represents in the 4-position the R ₅ -NH-CH ₂ -substituted phenyl group in which it represents a hydrogen atom or an acetyl group, The R _and -OOC-EDC group cannot represent at the 4-position a carbomethyl, methoxycarbonylmethyl, 2-carboxyethyl, 2-methoxycarbonylethyl or 2-ethoxycarbonylethyl substituted phenylcarbonyl group (see EP-A-0044541, JP-A-5813553, JP-A -5939866, JP-A-5846051 and Chem Pharm. Bull., 33, 5059-5061 (1985)), or when (iii) the AB group represents a 4-substituted phenyl group at the 4-position of the NH2-CH2-CH2-group, R _and The OOC-EDC group cannot be a 4-ethoxycarbonylphenylcarbonyl group (see DE-A-3718638) or when iv) the AB group is a 4-aminophenyl, 3-aminomethylphenyl, 4-aminomethyl-3-methoxyphenyl or 3-aminomethyl-4-methoxyphenyl group The RgOOC-EDC group cannot be 4-ethoxycarbonylmethoxy-2,3-dichlorophenylcarbonyl (see J. Med. Chem. 27, 1579-1587 (1984)) and Diuretics: Chem. Pharmacol., Clin. Appl., Proc. Int. Conf. Diuretics, 1, 21-29 (1984) or when v) AB group is at the 4-NH 2 CH 2 or (CH) 3 CO-CO-NH-CH ₂ group joining substituted phenyl, R _a OOC-EDC-group can not be a 4-karboxyfenylmetoxyskupinu (see., Int. J Pept. Protein Res., 18, 451-458 (1981)), or when vi) the AB group represents a phenyl group substituted at the 4-position of the NH 2 -CH 2 -group, the R _and OOC-EDC group cannot represent a 4-carboxy- phenylaminosulfonyl (see Chem. Pharm. Bull (Tokyo) 7, 734-739 (1959) and J. Chem. Phys. 32, 691-697 (1960)) or when vii) the AB group represents a 4- (2-pyridyl) phenyl or 4- (3-pyridyl) phenyl group, the R _and 00C-EDC groups cannot represent 4-carboxyphenylcarbonylamino- 4-benzyloxycarbonylphenylcarbonylamino or 2- (4-carboxyphenyl) ethyl (see J. Med. Chem. 11, 295 (1968) and US-A-2837522) or when viii) AB is 3- (4- pyridyl) phenyl, R _and OOC-EDC cannot be 2- (carboxymethyl) phenylcarbonylamino (see Farmaco 44, 721-729 (1989)). their tautomers, their stereoisomers, including mixtures thereof, and their salts. 2. Carboxylic acid derivatives of the general formula I according to claim 1, wherein R _a represents a hydrogen atom, a C 1 -C 5 alkyl group, a C 1 -C 3 phenylalkyl group or a C 5 -C 7 cycloalkyl group, A represents a C 2-5 aminoalkyl group or a piperidinyl group linked via the carbon atom of the residue A of the residue B, wherein the coupling of the piperidinyl group to the B group is carried out via the carbon atom of the piperidinyl group and the hydrogen atom of the amino group in the above aminoalkyl groups; the nitrogen atom of said piperidinyl groups may be replaced by a residue and furthermore, the carbon atoms of the piperidinyl group may be substituted by a methyl, cyano, carboxyl, methoxycarbonyl or aminocarbonyl group, wherein R 1 represents a C 1 -C 3 alkyl, benzyl, C 2 -C 6 alkoxycarbonyl, benzyloxycarbonyl or CH 2 -CO-O- (CH ₂ ) -O-CO-group as well as in one the piperidinyl> CH- unit thus formed in the 4-position may be replaced by a nitrogen atom or in the piperidinyl -CH ₂ -CH <unit formed by the -CH = CH unit, a quinuclidinyl or pyridyl group thus formed, B is optionally a fluorine, chlorine or bromine atom, an alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl or alkylsulfonyl group having from 1 to 2 carbon atoms in the alkyl and alkoxy moiety substituted by a phenylene, pyridinylene or piperidinylene group, C is -CO-, -CH ₂ CH ₂ -, -CH = CH-, -CH ₂ -, -CH ₂ O-, -OCH ₂ -, -conr ₄ -, -nr ₄ co-, -nr ₄ co-nr ₄ -, -ch ₂ nr ₄ -, -nr ₄ ch ₂ -, -SO ₂ NR ₄ - or -NR ₄ SO ₂ - group wherein R ₄ represents a hydrogen atom, an alkyl or phenylalkyl radical having from 1 to 2 carbon atoms in the alkyl part, or also when C represents a -CONR ₄ - group attached via a carbonyl group to the radical B, R ₄ represents a methylene or 1,2-ethylene group, which are each attached to a carbon atom of B in the ortho position to the point of attachment of -C0NR ₄ D is chlorine or bromine, alkyl or alkoxy having 1 or 2 carbon atoms substituted phenylene or cyclohexylene, in which one or cyclohexylene two> CH- units may be replaced by an N-atom, and in addition to the piperidinylene or piperazinylene ring thus formed, the methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group and the bond to residues C and E may also be via the piperidinylene or piperazinylene circle and E represents a bond, a methyleneoxy group wherein the oxygen atom is bonded to the radical D, a 1,2-ethenyl group or a straight alkylene group having 1 to 5 carbon atoms which may be substituted by an alkyl group having 1 to 7 carbon atoms or an R ^NH group wherein the hydrogen atom is an alkyl group having 1 to 7 carbon atoms or a benzyl group substituted by a carbonyl group or an alkyl group having 1 to 5 carbon atoms or a benzyl group substituted by a sulfonyl group, wherein when iii) the AB group is NH4- CH2-CH2-substituted phenyl, R _and OOC-EDC I cannot be a 4-ethoxycarbonylphenylcarbonyl group, j or, when vii) the AB group is a 4- (2-pyridyl) phenyl or 4- (3-pyridyl) phenyl group, the R _and OOC-EDC group cannot be 4-carboxyphenylcarbonylamino- 4-benzyloxycarbonylphenylcarbonylamino or 2- (4-carboxyphenyl) ethyl 1 or, when viii) AB-group is 3- (4-pyridyl) phenyl, R _and OOC-EDC cannot be 2- (carboxymethyl) phenylcarbonylamino, their tautomers, their stereoisomers, including mixtures thereof, and their salts. 3. Carboxylic acid derivatives of the general formula I according to claim 1, wherein _And R is H, alkyl of 1 to 4 carbon atoms, 2-phenylethyl or cyclohexyl, A is a C 3 -C 5 aminoalkyl group or a piperidinyl group linked via the carbon atom of the residue A of the residue B, wherein the coupling of the piperidinyl group to the B group is carried out via the carbon atom of the piperidinyl group and the hydrogen atom of the amino group in the above aminoalkyl groups; the nitrogen atom of said piperidinyl groups may be replaced by the radical R @ 1 and furthermore, the carbon atoms of the piperidinyl group may be substituted by a methyl, cyano, carboxyl, methoxycarbonyl or aminocarbonyl group wherein C1-3 alkyl, benzyl, alkoxycarbonyl having a total of 2 up to 5 carbon atoms or a CH 3 -CO-O- (CH ₂ ) -O-CO-group, and in the piperidinyl group> CH- thus formed, the unit at the 4-position can be replaced by a nitrogen atom or in the piperidinyl group -CH ₂ -CH <unit may be replaced by -CH = C <unit, c hinuclidinyl or - 93 4-pyridyl, B represents an optionally methyl or methoxy substituted phenylene, 2,5-pyridinylene or 1,4-piperidinylene group, C is -CO-, -CH ₂ CH ₂ -, -CH = CH-, -CH ₂ -, -CH ₂ O-, -OCH ₂ -, -CONR ₄ -, -NR 4 CO-, -NR 4 CO-NR 4 - or - CH ₂ NR 4 - or -SO ₂ NR ₄ -, wherein the SO ₂ group is linked to the residue B and wherein R 4 represents a hydrogen atom, a methyl atom or a methyl group; 2-phenylethyl or, if C is -CONR4-linked to residue B via a carbonyl group, R4 is methylene or 1,2-ethylene, which are in each case attached to the carbon atom of residue B in the ortho position to the point of attachment of -CONR4 -. D represents a phenylene group or a cyclohexylene group, wherein in the cyclohexylene group one or two> CH- units can be replaced by an N-atom, wherein the bond to the C and E residues can also be carried out via the nitrogen atom of the piperidinyl or piperazinylene ring; E represents a bond, a methyleneoxy group where the oxygen atom is bonded to the radical D, a direct alkylene group having 1 to 5 carbon atoms, which may be substituted by an R 4 NH group, wherein R @ 1 represents a hydrogen atom, a C1 -C5 alkyl group, a substituted carbonyl or C1 -C4 alkyl group or a benzyl substituted sulfonyl group, their tautomers, their stereoisomers, including mixtures thereof, and their salts. The carboxylic acid derivatives of formula I according to claim 1, wherein R _a represents a hydrogen atom, a C 1 -C 4 alkyl group or a cyclohexyl group, A represents a piperidinyl group or a 3,4-dehydropiperidinyl group linked via the carbon atom of the radical A to the radical B, in which the hydrogen atom on the nitrogen atom can in each case be replaced by the radical R @ a; R 1 is an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, optionally substituted at the 1-position by R 1 with a substituted 4-piperazinyl group, wherein R 1 is as defined above or a quinuclidinyl group, B represents a phenylene group, C represents a -CONR 4 -group wherein R 4 represents a hydrogen atom, a methyl atom or also, when C represents a CONR 4 group attached via a carbonyl group to a residue B, R 4 represents a methylene or 1,2-ethylene group, which are always bonded to the carbon atom of residue B ortho to the attachment point -CONR4-. D is 1,4-phenylene or 1,4-cyclohexylene; and E represents a bond, a 1,2-ethylene group which may be substituted with an R 1 NH-group, wherein R 8 represents a C 1 -C 5 alkyl group, a substituted carbonyl group or a C 1 -C 4 alkyl group substituted with a sulfonyl group, their tautomers, their stereoisomers, including mixtures thereof, and their salts, The carboxylic acid derivatives of the formula I according to claim 1 which are 4- [4 - [[trans -4- [2- (methoxycarbonyl) ethyl] cyclohexyl] aminocarbonyl] phenyl] piperidine, 4- [4 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine, 4- [4 - [[trans-4- (2-carboxy-ethyl) -cyclohexyl] aminocarbonyl] phenyl] piperidine, 4- [4 - [[4- [2- (n-butanesulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] -phenyl] -piperidine, 4- [3 - [[4- [2- (n-butanesulfonylamino) -2-carboxyethyl] phenyl] aminocarbonyl] phenyl] piperidine and 4- [3 - [[4- [2- (n-butanesulfonylamino) -2- (methoxycarbonyl) ethyl] phenyl] aminocarbonyl] phenyl] piperidine, their tautomers, their stereoisomers, including mixtures thereof, and their salts. Physiologically acceptable addition salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases. A medicament comprising a compound according to at least one of claims 1 to 5 or a physiologically acceptable addition salt according to claims 6, optionally containing one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 2 to 6 for the manufacture of a medicament which is suitable for the treatment or prevention of diseases in which smaller or larger cell aggregates arise or play a role of cell-matrix interaction. A method for producing a medicament according to claim 7, characterized in that the compound according to at least one of claims 1 to 6 is incorporated in a non-chemical manner into one or more inert carriers and / or diluents. A process for the production of carboxylic acid derivatives according to claims 1 to 6, characterized in that (a) for the preparation of compounds of the formula I, in which R _a represents a hydrogen atom, a compound of the formula II A - B - C - D - E - COOR _and (II) where A-E are as defined as in claims 1 to 5, and R _a 'with the exception of hydrogen has the meaning given in claims 1 to 5 for R _&. converted by hydrolysis, pyrolysis or hydrogenolysis to a compound of formula 1 wherein R _& lt _; 6 _&gt; is hydrogen or b) For the preparation of compounds of formula I, wherein A is substituted with R ^, a compound of formula III is used Α _χ - B - C - D - E - COOR _and (III) where B to E and R _a are as defined in claims 1 to 5 a A-? Represents a C 1-5 aminoalkyl linked via a carbon atom of the B moiety or a 5-, 6- or 7-membered azacycloalkyl group attached to the B-linked carbon moiety, wherein the azacycloalkyl carbon atoms may be substituted with one to three alkyl. In each case, the radicals are each of 1 to 3 carbon atoms, aminocarbonyl, cyano, R (O) O or R (O) O-CO, in which R (R) is as defined above, and reacted with a compound of formula (IV). R _b - Z 1 (IV) where R 1 is as defined in claims 1 to 5 and Z 2 is a nucleophilic leaving group or, when Z 2 is attached to a carbonyl group, is hydroxy, alkanoyloxy or alkoxycarbonyloxy, or else in the presence of a reducing agent, if Together with the adjacent hydrogen atom of the radical R @ 1 represents an oxygen atom or k c) For the preparation of the compounds of the formula I wherein R _and with the exception of hydrogen as defined in claims 1 to 5, a compound of the formula V is reacted A - B - C - D - E - COOH (V) where A to E are as previously defined in claims 1 to 5, with a compound of formula VI (VI) wherein R _a 'with the exception of hydrogen have the meanings given above for R _a in claims 1 to 5 a Z 2 represents a nucleophilic leaving group or d) For the preparation of compounds of formula I wherein C is -CH2-NH-, a compound of formula VII * A - B - CH = N - D - E - COOR _and (VII) e where A, B, D, E and R _and are as previously defined in claims 1 to 5, reduce or e) For the preparation of compounds of formula I wherein C represents a -CO-NR4-group, a compound of formula VIII is prepared A ₂ - B - COOH (VIII) where B is as defined in claims 1 to 5 and A ₂ is an alkyl, aralkyl, alkanoyl, trifluoroacetyl or alkoxycarbonyl radical substituted with A, reacted with an amine of formula IX X R ₄ - NH - D - E - COOR _a '(IX) where D, E and R ₄ are as defined in claims 1 to 5 and R 1, with the exception of a hydrogen atom, has the meanings already indicated for R _& apos _; in claims 1 to 5, or f) To produce compounds of formula I wherein C is -NR 4 CO-, a compound of formula X is prepared A ₂ - B - NH - R ₄ (X) wherein R ₄ and B are as defined in claims 1 to 5 a A2 represents an alkyl-, aralkyl-, alkanoyl-, trifluoroacetyl- or alkoxycarbonyl-substituted group A on the nitrogen atom, reacted with a carboxylic acid of the formula XI HOOC - D - E - COOR '(XI) cL where D and E are as defined in claims 1 to 5 and R _a ', with the exception of a hydrogen atom, has the meanings given in claims 1 to 5 for R _a or (g) For the preparation of compounds of the formula I in which A represents a C 1 -C 5 aminoalkyl group linked via a carbon atom of the radical B, a compound of the formula XII Ag-BCDE-COOR _and (XII) wherein B and E, and R _a is as defined in claims 1 to 5, and Ag is cyano or cyanoalkyl group having 1 to 4 carbon atoms in the alkyl moiety and, if necessary, during the reaction for the protection of reactive groups may use protecting moieties are cleaved and / or optionally the following the resulting compound of formula I wherein R 4 is hydrogen is converted to the corresponding compound of formula I wherein R ₄ is an optionally substituted phenyl group having 1 or 2 carbon atoms by alkylation and / or the compound of formula I thus obtained is separated into its enantiomers and / or diastereomers and / or 100, the compound of the formula I thus obtained is converted into its salts, in particular for pharmaceutical use, into its physiologically acceptable salts with inorganic or organic acids and / or the compound of the formula I thus obtained, if it contains a carboxyl group, inorganic or organic bases, in particular for pharmaceutical use for their physiologically acceptable addition salts.