FI78477B - FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT ANVAENDBARA FENYLAETTIKSYRA-DERIVAT. - Google Patents

Description

78477

The method prepares pharmacologically useful phenylacetic acid derivatives. - Förfarande för framställning av pharmacologiskt användbara fenylättiksvra-derivat.

The present invention relates to a process for the preparation of pharmacologically useful phenylacetic acid derivatives of the formula I - NH - CO - CH 2 HfyW <I} wherein A is a group of the formula R => R «* ^ Re - CH - or - C -. when

R 5 is an alkyl group substituted with 1 to 3 carbon atoms or a phenyl group having 1 to 3 carbon atoms, an n-propyl group A to 7 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cyano or alkyleneiminocarbonyl group having A to 6 carbon atoms, optionally an alkyl or phenylalkyl group having 1 to 3 carbon atoms, a mono- or disubstituted aminocarbonyl group, halogen atoms, alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulfinyl and / or alkylsulfonyl a mono- or disubstituted phenyl group, the substituents may be the same or different and each contain 1 to 3 carbon atoms in the alkyl moiety, a naphthyl group or a pyridyl group, or R 3 may also be a methyl group when R 1 is a piperidine group and R 4 is a fluorine atom and W is a carboxy or alkoxycarbonyl group in which the alkyl moiety 2 73477 contains 1 to 3 carbon atoms, or Ra may also be a phenyl group when R »is in the 2-3 position a methyl-substituted piperidine group, Ra is a hydrogen atom and W is a carboxy or alkoxycarbonyl group in which the alkyl moiety contains 1 to 3 carbon atoms, or when Ra is a piperidine group, R * is a chlorine atom in the 3-, 4- or 6-position or 4 or 6 and W is a carboxy or alkoxycarbonyl group having 1 to 3 carbon atoms in the alkyl moiety, or when Rx is a piperidine group, Ra is a hydrogen atom and W is a formyl group, a 2-carboxyethenyl or 2-alkoxycarbonylethenyl group having an alkyl moiety 1 to 3 carbon atoms, R. * and Ro together with the carbon atom in between are an alkylidene group having 3 to 9 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety,

Rx is an unbranched alkyleneimino group having 4 to 9 carbon atoms, mono- or disubstituted by alkyl groups having 1 to 3 carbon atoms, R1 is a hydrogen, fluorine, chlorine or bromine atom, hydroxy, trifluoromethyl, nitro, amino. , a piperidino, alkyl or alkoxy group, wherein the alkyl moiety each contains 1 to 3 carbon atoms, and W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl moiety may be substituted with a phenyl group and (from 3 carbon atoms with one or two hydroxyphenyl groups, one alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy, each alkyl moiety each containing 1-3 carbon atoms and the alkyleneimino group having 4-6 carbon atoms, an alkenyloxycarbonyl group having a total of 4-6 carbon atoms, 1- 3-carbon alkyl group, hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 78477 3 2-carboxyethyl, 2-carboxyethenyl, 2,2-bis- (carboxy) -e a methyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonyl-ethenyl or 2,2-bis- (alkoxycarbonyl) ethyl group, each alkoxy group each containing 1 to 3 carbon atoms, and their optically active antipodes and their salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids or bases.

In the context of the definitions of the groups R »- Ro and W, the meanings already mentioned are, for example: R» is pyrrolidino, piperidino, hexamethyleneimino, hepta-methyleneimino, octamethyleneimino, methyl-pyrrolidino, dimethyl- pyrrolidino, ethyl pyrrolidino, methyl piperidino, ethyl piperidino, dimethyl piperidino, diethyl piperidino, methylethyl piperidino, n-propyl piperidino, methyl n-propyl piperidino, isopropyl piperidino - or a di-n-propylpiperidino group,

Ra is a hydrogen, fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, n-propoxy, isopropoxy, trifluoro -methyl, nitro, amino, piperidino, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, methylsulfinyl, ethylsulfinyl, methylsulfonyl, n-propylsulfonyl, benzyloxy, 1-phenyloxy , 2-phenyl-ethoxy, 3-phenyl-propoxy, acetoxy, propionyloxy, formylamino, acetylamino, propionylamino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino. a di-n-propylamino or methylethylamino group,

Ra is n-propyl, n-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, iso- 73477 4 propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxy-propyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenyl-n-propyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl, 3-butene 1-yl, 2-buten-1-yl, 4-penten-1-yl, cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, benzylaminocarbonyl, 2-phenylethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, phenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, bromophenyl , hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxyphenyl, 2-phenylethoxyphenyl, 3-phenylpropoxyphenyl, methylsulphenylphenyl -, ethylsulphenyl-phenyl, methylsulphonyl-phenyl- 'n-propylsulphinyl-phenyl-, ethyl-sulphonyl-phenyl-, ethyl-sulphonyl-phenyl-, isopropylsulphonyl-phenyl-, methyl-naphthyl-. hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl, dimethyl-phenyl, diisopropyl-phenyl, chloromethyl-phenyl, dimethoxy-phenyl, methyl-methoxyphenyl, chlorine -methoxy-phenyl, bromo-methoxy-phenyl, pyridyl, pyriraidyl, quinolyl, isoquinolyl or quinazolyl group, R 1 and R 2 represent hydrogen atoms, methyl, ethyl, n-propyl, isopropyl -, n-butyl, isobutyl, see. butyl or n-pentyl groups, wherein R * and Re together with the carbon atom form an alkylidene group having 3 to 9 carbon atoms.

R 1 and R 6 together with the carbon atom in between mean benzylidene, 1-phenylethylidene, 2-phenylethylidene, 1-phenyl-n-propylidene, 1-phenyl-2,2-propylidene or 3- phenyl-n-propylidene group and W is hydroxymethyl, formyl, carboxy, carboxymethyl, 78477 s 2-carboxyethyl, 2-carboxyethenyl, 2,2-bis- (carboxy) ethyl, methoxycarbonyl , ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, allyloxycarbonyl, crothyloxycarbonyl, (2-hydroxyethoxy) carbonyl, (2-hydroxy-n-propoxy) carbonyl , (1-hydroxy-2-propoxy) carbonyl, (2-methoxyethoxy) carbonyl, (2-ethoxyethoxy) carbonyl, (2-n-propoxyethoxy) carbonyl, (2-nicotinoyloxyethoxy) carbonyl -, (2-isonicotinoyloxy-ethoxy) carbonyl-, (2,3-dihydroxy-n-propoxy) carbonyl-, (2-dimethylamino-ethoxy) -carbonyl-, (2-diethylamino-ethoxy) carbonyl-, methyl -, ethyl, n-propyl, isopropyl, m.p. yano, aminocarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, 2-methoxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxycarbonyl-ethyl-, 2-methoxycarbonyl-ethenyl , 2-ethoxycarbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl, 2,2-bis- (methoxycarbonyl) -ethyl, 2,2-bis (ethoxycarbonyl) -ethyl or 2,2-bis (isopropoxycarbonyl) ethyl group.

Preferred compounds of general formula I according to the invention are those in which A is a group of formula R ** Ro

Ro C

I 11 - CH - where - C -, where

Ro is an alkyl group substituted with 1 to 3 carbon atoms or a phenyl group having 1 to 3 carbon atoms, an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cyano or aminocarbonyl group, halogen atoms, alkyl, hydroxy aryl group having 6 or 10 carbon atoms mono- or disubstituted by -, alkoxy, phenylalkoxy and / or alkylsulfinyl groups, the substituents may be the same or different and the alkyl moiety may in each case contain 1 to 3 carbon atoms, naphthyl, pyridyl , a quinolyl or isoquinolyl group, R * and Re together with the carbon atom interposed therein are an alkylidene group having 3 to 9 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety,

R 1 is a straight-chain alkyleneimino group having 4 to 8 carbon atoms or, with alkyl groups each having 1 to 3 carbon atoms, a mono- or disubstituted piperidino group,

Ra is a hydrogen, fluorine, chlorine or bromine group, a nitro, alkyl or alkoxy group having in each case 1 to 3 carbon atoms, or also when R * and Re have the same meaning as above and R1 is an alkoxy group having 1 to 3 carbon atoms or a phenyl group substituted with a phenyl group having 1 to 3 carbon atoms, an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a nitrile or aminocarbonyl group, an iodine atom, a hydroxy or amino group, W is methyl, hydroxymethyl , formyl, cyano, carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and an alkyl moiety (from 3 carbon atoms onwards) may be substituted by one or two hydroxy groups, one alkoxy group having 1 to 3 carbon atoms or one pyridinecarbonyloxy group, an alkoxycarbonylmethyl, 2-alkoxycarbonylethyl or 2-alkoxycarbonylethenyl group, in which case the alkoxy group may in each case contain 1 to 3 carbon atoms.

According to the invention, the novel compounds of the formula I are obtained by the following methods: 73 a) amine A - NH-

,, _ £ J

wherein A, R & a and R 5 are as defined above or, when A represents the vinylidene group already mentioned, its tautomer, its lithium or magnesium halide complex, is reacted with a carboxylic acid of the general formula III HO - CO - CH 2 "\ y - w '\ - / (III) wherein W * represents the same as above or a carboxyl group protected by a protecting group, or any reactive derivatives thereof prepared in the reaction mixture, and, if necessary, the protecting group used is cleaved off.

Suitable reactive derivatives of the compound of the general formula III are, for example, its esters, such as methyl, ethyl or benzyl ester, its thioesters, such as methylthio or ethylthioesters, its halides, such as acid chloride, its anhydrides or imidazoles.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. phosphorus-78477 8 bentoxide, N, N'-dicyclohexylcarbodiimide, N, Ν'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyl di imidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, e.g. phosphorus trichloride, optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously act as a solvent between temperatures between -10 ° C and on Boiling point of the solvent. The reaction can also be carried out without a solvent, and in addition, the water formed during the reaction can be removed by azeotropic distillation, e.g. by heating with toluene in a water separator, or by adding a desiccant such as magnesium sulfate or a molecular sieve.

Subsequent cleavage of the protecting group may be conveniently carried out hydrolytically, conveniently in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol. in water / dioxane, at temperatures between -10 ° C and 120 ° C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

Tert used as a protecting group. the butyl group may also be cleaved by heat in an optionally inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

In addition, the benzyl group used as a protecting group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

b) for the preparation of a compound of general formula I in which W is a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, a compound of general formula IV

CA - NH - CO - CH, "V /" B

2 \ = / <IV>

II

wherein R 1, R a and A have the same meaning as above and B is a group which can be converted into a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group is converted to the corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis.

Suitable hydrolyzable groups are, for example, functional derivatives of a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, such as their unsubstituted or substituted amines, their nitriles, esters, thiol esters, orthoesters, iminoethers, malides, amidines or anhydrides. 1) -yl group, tetrazolyl group, optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group, and as thermolytically cleavable groups, e.g. esters with tertiary alcohols, e.g. butyl ester, and as hydrogenolytically cleavable groups, e.g. esters with aralkanols, e.g. benzyl esters.

The hydrolysis is conveniently carried out in the presence of either an acid such as 73477 hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / isopropanol or water / dioxane, e.g., at temperatures between room temperature and the boiling point of the reaction mixture.

If B in a compound of general formula IV represents a cyano or aminocarbonyl group, these groups can also be converted into carboxy groups between 0 and 50 ° C with nitrite, e.g. sodium nitrite in the presence of an acid such as sulfuric acid, this being suitably used simultaneously as solvent.

If B in a compound of general formula IV means e.g. tert. butyloxycarbonyl group, then tert. the butyl group may also be cleaved off thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and most preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid or polyphosphoric acid mode, e.g., at temperatures between 40oC and 100oC.

If B in a compound of general formula IV is e.g. a benzyloxycarbonyl group, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, dimethylacetate, acetic acid or ethyl acetate, ethyl acetate , preferably at temperatures between 0 ° C and 50 ° C, e.g. at room temperature, and at a hydrogen pressure of 1 to 5 bar. Other groups, e.g. a nitro group to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylidene group or a cinnamic acid group to a corresponding phenylpropionic acid group, may be simultaneously reduced in the hydrogenolysis, or replaced by hydrogen atoms, hydrogen atoms.

c) a compound of general formula I wherein A is a group of formula

R 5 'r - CH - wherein R 5' is the same as R 5 above except for the alkenyl group or the cyano group, for the preparation of a compound of general formula V

^ • vD - CO - CH2 W

- <X, ^ - where

Ri, Ra and W have the same meaning as above and D is a group of formula q »f D * D f t \ 3 K *.

- C. or ^ C

S is N - - C ^

N -I

B

wherein Rs "means the same as Rs above except for the cyano group, and R * 'and Re' together with the carbon atom intervening mean a propylidene group, an alkylidene group having 4 to 6 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety are reduced with hydrogen in the hydrogenation catalyst.

The reduction is best performed with hydrogen in the presence of a hydrogenation catalyst 78477 12 such as palladium / carbon or Raney nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethanol / water on glacial acetic acid, ethyl acetate in benzane, tetrahydrofuran or ethylene, dimethylformamide, dimethylformamide However, OeC and ΙΟΟ'Ό are best at temperatures between 20 ° C and 50 ° C, and at a hydrogen pressure of 1-5 bar. When using a suitable chiral hydrogenation catalyst such as a metal ligand complex, e.g. μ, μ'-dichloro-bis / 1,5-cyclooctadiene-rhodium / - and (+) - or (-) O-isopropylidene-2,3-dihydroxy -1,4-bis (diphenylphosphino) -butane (= DIOP) complex, hydrogen coupling occurs enantioselectively. In addition, in catalytic hydrogenation, other groups may be reduced, e.g. a nitro group to an amino group, a benzyloxy group to a hydroxy group or a cinnamic acid group to a phenylpropionic acid group, or replaced by hydrogen atoms, e.g. a halogen atom to a hydrogen atom.

d) for the preparation of compounds of general formula I in which Ra "has the same meaning as Ra above with the exception of the cyano group, compound r of general formula VI"

- OH

^ \ [(VI) where

Rx, Ra and Ra "have the same meaning as above to react with a compound of general formula VII f ~~ \ _ (VII) N * c-CH2-f V-> where W has the same meaning as above.

78477 13

The reaction is carried out in the presence of a strong acid which can simultaneously act as a solvent, preferably in concentrated sulfuric acid, at temperatures between 0 ° C and 150 ° C, but most preferably at temperatures between 20 ° C and 100 ° C.

e) compounds of general formula I in which R »is a hydrogen atom and A is a group of formula

Rs »t - CH - where

Ra is the same as above, for the preparation of which a halogen atom is removed from a compound of general formula VIII

A - HH - CO - CH2 M

\ = J (viix) “<X, where

Rx, A and H have the same meaning as above and Hal is a fluorine, chlorine, bromine or iodine atom.

The removal of the halogen atom is conveniently carried out in a solvent such as methanol, ethanol, acetic acid ester, glacial acetic acid or dimethylformamide with catalytically activated hydrogen, e.g. hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 ° C and 100 ° C, but preferably at room temperature, but at room temperature, -neessa. Upon removal of the halogen atom, other groups may be simultaneously reduced, e.g. a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylene group or a phenylpropionic acid group corresponding to a cinnamic acid group, or replaced by hydrogen atoms, e.g. a halogen atom to a hydrogen atom.

f) compounds of the general formula I in which A is a group 78477 14 of the formula

Rs r

- CH

where

R 5 is an alkylene iminocarbonyl group having 4 to 6 carbon atoms in the alkylene ring, or optionally an alkyl or phenylalkyl group each having 1 to 3 carbon atoms in the alkyl moiety, to prepare a mono- or disubstituted aminocarbonyl group, oxidizing a compound of general formula XI

? ° 0H

'-a., ^ - where

Rx and Rz have the same meaning as above and W "has the same meaning as W above except for the carboxy, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl or 2,2-bis- (carboxy) ethyl group, is reacted with an amine of general formula X H - R * (X) wherein

Re is an alkyleneimino group having 4 to 6 carbon atoms or, optionally, alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety, a mono- or disubstituted amino group.

The amidation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide. pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohe- phosphine / carbon tetrachloride, or in the presence of an amino group activating agent, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine which can simultaneously act as a solvent at temperatures between -25eC and 250 ° C. between -10 ° C and the boiling point of the solvent used.

g) for the preparation of compounds of general formula I in which u is a carboxy group, oxidizing a compound of general formula XI

C CH - NH - CO - CH, -f \ B

where

Rx, Ra and R5 have the same meaning as above and E is a group which can be converted to a carboxy group by oxidation.

Examples of suitable oxidizing groups are the formyl group and its acetals, the hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group such as an acetyl, chloroacetyl, propionyl, malonic acid (1) -yl group or a malonic ester (1) -yl group.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether at temperatures between 0 ° C and 200 ° C, most preferably at temperatures between 20 ° C and 50 ° C. However, the reaction is best carried out with silver oxide / sodium hydroxide, manganese dioxide / acetone or methylene chloride, hydrogen 73477 16 peroxide / sodium hydroxide, bromine or chlorine / sodium or potassium hydroxide, chromium oxide / pyridine or pyridinium chlorochromate.

h) for the preparation of compounds of general formula I in which W is an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the alkyl moiety may be substituted from 1 to 3 carbon atoms by one or two hydroxy groups or one alkoxy group of 1 to 3 carbon atoms, a carboxylic acid of general formula XII

A - NH - CO - CH2 - \ y-COOH

> = / (xii) where

R 1, R a and A have the same meaning as above, or a derivative thereof optionally prepared in the reaction mixture is esterified with an alcohol of general formula XIII HO - R-p- (XIII) wherein R? is an alkyl group having 1 to 4 carbon atoms which, from 3 carbon atoms, may be substituted by one or two hydroxy groups or one alkoxy group having 1 to 3 carbon atoms.

Suitable reactive derivatives of the compound of the general formula XII are, for example, its halides, such as the acid chloride, its anhydride or imidazole.

The reaction is conveniently carried out using a corresponding alcohol or a suitable solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, dioxane, benzene or toluene, optionally in the presence of an acid activator or dehydrating agent, e.g. in the presence of hydrogen chloride, thionyl chloride, carbon tetrachloride / triphenylphosphine, carbonyldiimidazole or Ν, Ν'-dicyclohexylcarbodiimide or its isourea ethers, optionally in the presence of a reaction accelerator such as an organic base such as copper chloride, and optionally in the presence of a sodium base such as an organic base or pyridine, or by esterification, e.g. with the corresponding carbonic acid diester, at temperatures between -20 ° C and 100 ° C, most preferably at temperatures between -10 ° C and the boiling temperature of the solvent used.

i) a compound of general formula I wherein W is an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group and A is a group of the formula R

Re "means the same as R» above except for the cyano group, for the preparation of a compound of general formula XIV R3 · / -v * - NH - CO - CH2 -f Vw- --CX, where R », Ra and Ra" have the same meaning as above and W '' is a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethenyl group, converted to the corresponding ester by alcoholysis.

The alcoholysis is conveniently carried out in the corresponding alcohol used as a solvent such as methanol, ethanol or propanol, preferably in the presence of an acid such as hydrochloric acid or sulfuric acid, at temperatures between 20 ° C and the boiling point of the solvent used, preferably between 50 ° C and 100 ° C.

If according to the invention a compound of general formula I in which W is a carboxy or alkoxycarbonyl group is obtained, this can be reduced by reduction to the corresponding compound of general formula I in which W is a formyl or hydroxymethyl group and / or a compound of general formula I in which W is a carboxy group , this can be converted to the corresponding compound of general formula I in which W is a formyl group by first conversion to a sulfonic acid hydrazide and then by disproportionation, and / or a compound of general formula I in which W is a formyl group, this can be condensed and optionally followed by hydrolysis and / or by decarboxylation to the corresponding compound of general formula I in which W is a 2-alkoxycarbonyl-ethenyl or 2-carboxy-ethenyl group and / or a compound of general formula I in which W is 2-carboxy-ethenyl or 2-alkoxycarbonyl -ethenyl group, so this can be your catalytic! by hydrogenation to the corresponding compound of general formula I in which W is a 2-carboxyethyl or 2-alkoxycarbonylethyl group and / or a compound of general formula I in which W is an alkoxycarbonyl group which may be substituted from the β-carbon atom by a hydroxy group , this can be converted to the corresponding (pyridinecarbonyloxyalkoxy) carbonyl compound by acylation with pyridine carboxylic acid, and / or

a compound of general formula I wherein W is a hydroxymethyl group, this can be converted to the corresponding compound of general formula I

A compound of formula I wherein W is an ethyl group substituted by two alkoxycarbonyl groups after first conversion to the corresponding halomethyl compound by reaction with a malonic acid diester, and / or a compound of general formula I wherein M is an ethyl group substituted by two alkoxycarbonyl groups, this can be converted by hydrolysis to the corresponding compound of general formula I wherein W is an ethyl group substituted by two carboxy groups, and / or a compound of general formula I wherein W is an ethyl group substituted by two alkoxycarbonyl groups, then this can be converted by hydrolysis and decarboxylation to the corresponding compound of general formula I is a 2-carboxyethyl group, and / or a compound of general formula I in which R 5 is a nitro group, this can be reduced by reduction to the corresponding compound of general formula I in which R 5 is an amino group and / or a compound of general formula I in which R 5 is amino this can be converted via the corresponding diazonium salt to the corresponding compound of general formula I in which R 5 is a hydrogen, fluorine, chlorine or bromine atom, a hydroxy, alkoxy or alkylsulphenyl group, and / or a compound of general formula 1 in which R 5 is the benzyloxy group and / or R 5 is an aryl group substituted by a benzyloxy group, which can be converted by debenzylation to the corresponding compound of the general formula I in which R 5 is a hydroxy group and / or Ra is a hydroxy-substituted aryl group, and / or a compound of the general formula I in which Ra is aminocarbonyl group, which can be converted by dehydration to the corresponding compound of general formula I in which Ra is a cyano group.

The post-reduction is best performed with a metal hydride, e.g. a complex metal hydride such as lithium aluminum hydride, in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane, at temperatures between 0 ° C and 100 ° C, but most preferably at temperatures between 20 ° C and 60 ° C.

The subsequent disproportionation of the sulfonic acid hydrazide obtained by reacting the corresponding hydratin with the corresponding reactive carboxylic acid derivative is carried out in the presence of a base such as sodium carbonate in a solvent such as ethylene glycol at temperatures between 100 ° C and 200 ° C, preferably 160 ° C to 170 ° C.

Subsequent condensation of the formyl compound is conveniently carried out in a solvent such as pyridine or tetrahydrofuran with malonic acid, malonic acid ester, dialkylphosphonoacetic acid ester or in the presence of alkoxycarbonylmethylenehydridide piperine, e.g. 0 * Ό and 100eC; the desired compound is obtained by subsequent acidification, e.g. with hydrochloric acid or sulfuric acid, or by subsequent alkaline hydrolysis.

The post-catalytic hydrogenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium / carbon at temperatures between 0 ° C and 75 ° C, preferably at room temperature, but preferably at 1-5 ° C. at hydrogen pressure in the bar.

The subsequent O-acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, imidazide and acetyl halide, optionally with an acid such as a reactive derivative of an acididone or dimethylformamide. in the presence of a base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine which can simultaneously act as a solvent at temperatures between -25 ° C and 250 ° C, but preferably at temperatures between -10 ° C and the boiling point of the solvent used.

The subsequent conversion of the hydroxymethyl group to the halogenomethyl group is carried out with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, in a solvent such as methylene chloride, in the following, * C, however, best at temperatures between 50 * »C and 80eC.

The subsequent hydrolysis or hydrolysis and decarboxylation are conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid in a suitable solvent such as water, ethanol, water / ethanol, water / diopropene or water / diopropanol or at the boiling point of the reaction mixture.

The subsequent reduction of the nitro compound is best carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or diraethylformamide, conveniently with hydrogen in the presence of a hydrogenation catalyst 78477 22 such as Raney nickel, platinum or palladium / carbon in the presence of , with salts such as ferrous sulphate, stannous chloride or sodium dithionite or hydrazine in the presence of Raney nickel, at temperatures between 0 ° C and SOeC, but preferably at room temperature.

Subsequent reaction of a diazonium salt, e.g. fluoroborate, fluoride in 40% hydrofluoric acid, hydrosulphate sulfuric acid or hydrochloride, optionally copper or a copper (I) salt such as copper (I) chloride / hydrochloric acid or copper (I) bromide / hydrobromic acid, the reaction is carried out at slightly elevated temperatures, e.g. between 15 ° C and 100 ° C; the subsequent reaction with an aliphosphoric acid is best performed at -5 ° C-OeC. The required diazonium salt is conveniently prepared in a suitable solvent, e.g. water / hydrochloric acid, methanol / hydrochloric acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid, by diazotization of the corresponding amino compound with nitrite, e.g. sodium nitrite or nitric acid at low temperature, e.g. ° C and 5 ^ 0.

The subsequent removal of the benzyl group is conveniently carried out in a solvent such as methanol, ethanol, acetic acid ester, glacial acetic acid or dimethylformamide with catalytically activated hydrogen, e.g. hydrogen in the presence of platinum or palladium / carbon, at temperatures between 1 ° C and 7 ° C, preferably at 1 ° C, preferably at room temperature. at the hydrogen pressure of the bar.

The subsequent dehydration is performed with a dehydrating agent such as phosphorus pentoxide, sulfuric acid or p-toluenesulfonic acid chloride, optionally in a solvent such as methylene chloride or pyridine, at temperatures between 0 ° C and 100 ° C, preferably at temperatures between 20 ° C and ΘΟ'ΘΟ.

78477 23

The obtained compounds of the general formula I, if they contain a chiral center, can furthermore be separated into their enantiomers by conventional methods. This separation takes place by column chromatography in the chiral phase.

The compounds of the general formula I obtained can be further converted into their acid addition salts, in particular their physiologically acceptable salts with inorganic or organic acids or also with bases. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid.

The compounds of the general formulas II-XIV used as starting materials are obtained by methods known in the literature or are known from the literature.

Thus, for example, a compound of general formula II wherein A represents a group of formula R <* R 5

II

- c - or its tautomeric ketimine is obtained by reacting the corresponding nitrile with the corresponding grignard or lithium compound and then hydrolysing or reacting the corresponding ketone with ammonia in the presence of titanium tetrachloride. A further reaction with a compound of general formula III or a reactive derivative thereof, in particular with its acid chloride, an organometallic ketine complex can also be used.

78477 24

A compound of general formula II wherein A is a group of formula Ra CH -, wherein R * is as defined above except for the cyano and aminocarbonyl group, is obtained, e.g., by reacting the corresponding nitrile with the corresponding grignard or lithium compound, and optionally by reduction with lithium aluminum hydride or subsequent hydrolysis to ketimine, which is then reduced with catalytically activated hydrogen, complex metal hydride or evolving hydrogen, hydrolysis or hydrazinolysis with the corresponding thalimido compound in the presence of ammonium with lithium aluminum hydride or catalytically activated or evolving hydrogen, by reduction of the corresponding N-benzyl or N (1-phenylethyl) ketimine, e.g. with catalytically activated hydrogen or complex with a metal hydride in ether or tetrahydrofuran at temperatures between -78 ° C and the boiling point of the solvent used, followed by cleavage of the benzyl or 1-phenylethyl group by catalytic hydrogenation, reaction of the corresponding alcohol with Ritter reaction with potassium cyanide in sulfuric acid or , Lossen or Schmidth decomposition reaction.

A compound of general formula II wherein A is a group

CN

- CH - is obtained by reacting the corresponding aldehyde with ammonium 78477 cyanide or by reacting the corresponding cyanohydrin with ammonium.

The amine of general formula II thus obtained having a chiral center and wherein A is a group of formula R 3 - CH -, wherein

Ra means the same as already defined above, except for the cyano group, can be separated into enantiomers by racemate cleavage, e.g. fractional crystallization of diastereomeric salts with optically active acids followed by resolution of the salts or column chromatography in chiral phase or formation of diastereomeric compounds, followed by resolution.

Furthermore, the optically active amine of general formula II can also be prepared by enantioselectively reducing the corresponding ketimine with complex boron or aluminum hydrides in which part of the hydride hydrogen atoms have been replaced by optically active alcoholate groups, or by hydrogen in the presence of a suitable chiral hydrogenation catalyst or analog. - (1-phenethyl) ketamine or the corresponding N-acylketimine or enamide and then cleaving off the benzyl, 1-phenylethyl or acyl group.

Furthermore, the optically active amine of the general formula II can also be prepared by diastereoselectively reducing the corresponding nitrogen-chirally substituted ketimine or hydrazone on a nitrogen atom with complex or also non-complex boron or alurain hydrides in which some of the hydrogen hydride atoms have optionally been replaced by corresponding alcohol, phenolate or phenolate groups, or by hydrogen in the presence of a suitable hydrogenation catalyst and then optionally by cleavage of the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

Furthermore, an optically active amine of general formula II can also be prepared by adding the corresponding organometallic compound, preferably a grignard or lithium compound, diastereoselectively to the corresponding nitrogen-chirally substituted aldimine, followed by hydrolysis and optionally hydrogenation or cleavage of the chiral auxiliary group.

The compounds of the general formulas IV, VIII, IX, XI, XII and XIV used as starting materials are obtained by replacing the corresponding amine with the corresponding compound of the general formula III or a reactive derivative thereof and optionally followed by hydrolysis.

The compound of general formula V used as starting material is best obtained by acylation of the corresponding ketimine or its organometallic complex with the corresponding carboxylic acid or its reactive derivative.

As already mentioned, the new compounds of the general formula I have valuable pharmacological properties, namely an effect on the metabolism of intermediates, in particular, however, a hypoglycemic effect, in part also an effect on the cardiovascular system.

For example, the properties of the following compounds were studied as follows:-A = (Z) -4 - [(1- (2-piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid, B = (Z ) -4 - [(1- (2-Piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester, 27 78477 C = (E) -4 - [(1- (2- piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid, D = 4 - [(2-methyl-1- (2-piperidinophenyl) -1-propen-1-yl) - aminocarbonylmethyl / benzoic acid, E = (Z) -4 - [(1- (2-piperidinophenyl) -1-hexen-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester, F = (Z) -4 - / (3-phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl] benzoic acid, G = (Z) -4 - [(1- (2- (3.3 (dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid, H = 4 - [(1- (2-pyrrolidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid , J = (±) -4 - [(1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid, K = (+) - 4 - / (- (2- Piperidinophenyl) -1-butyl) aminocarbonylmethyl / benzoic acid, L = (+) - 4 - [(1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester , M * 4 - [(1- (2-Hexahydroazepino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid, N = 4 - [(1- (2-piperidino-phenyl) -1-hexyl) - aminocarbonylmethyl / benzoic acid, O = 4 - [(3-phenyl-1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl] benzoic acid, 28 78477 P s 4 - / (2-methoxy -1- (2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid, qs 4 - [(α-cyano-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid, r = 4- [(-1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzyl alcohol, S = 4 - [(1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] - phenylacetic acid, T = 4 - [(1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] cinnamic acid, U = 4 - [(1- (2-piperidinophenyl) -1-butyl) aminocarbonyl-methyl / -benzoic acid (2,3-dihydroxy-propyl) est different, V = 4 - [(1- (4-fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid, W - 4 - [(1- (4-methoxy-2-piperidino) -phenyl) -1-butyl) aminocarbonylmethyl / benzoic acid, X = 4 - [(α- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, Y = 4- / (α- (3-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid, Z = 4 - [(α- (4-fluoro-phenyl) -2-piperidinobenzyl) -amino] carbonylmethyl / benzoic acid, AA® 4 - [(α- (2-fluorophenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, 29 78477 AB® 4 - / (α- (4-chloro -phenyl) -2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid, AC® 4 - [(α- (3-chlorophenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, AD® 4 - [(2-Piperidino-α- (2-pyridyl) -benzyl) -aminocarbonylmethyl] -benzoic acid, AE = 4 - [(2-piperidino-α- (4-pyridyl) -benzyl) -aminocarbonylmethyl] N-benzoic acid, AF® 4 - [(6-chloro-α-phenyl-2-piperidinobenzyl) aminocarbo -nylmethyl / benzoic acid, AG® 4 - [(α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid, AH® 4 - [(4-chloro-α-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl / benzoic acid, AJ = 4 - [(6-methyl-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid, AK = 4 - [(4-roethyl-α-phenyl) 2-Piperidinobenzyl) aminocarbonyliroethyl / benzoic acid, AL® 4 - [(α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde, AM® 4 - [(2- (2-methyl) (piperidino) -α-phenyl-benzyl) -aminocarbonylmethyl] -benzoic acid, AN = 4 - [(2- (3-methyl-piperidino) -α-phenyl-benzyl) -aminocarbonylmethyl] -benzoic acid, and 73477 AO = 4 - [(3-Chloro-α-phenyl-2-piperidino-benzyl) -aminocarbonyl-ethyl] -benzoic acid.

1. Blood glucose lowering effect

The hypoglycemic effect of the test substances was determined in self-reared female rats weighing 180-220 g and fasted for 24 hours before the start of the experiment. Test compounds were applied immediately prior to the start of the experiment suspended in 1.5% methylcellulose and via gastric tube.

Blood was drawn immediately before compound application and after 1, 2, 3, and 4 hours, respectively, from retro-orbital venous plexus. Proteins were removed from 0.5 microliters each with 0.5 liters of 0.33 N perchloric acid and centrifuged. Glucose was determined from the supernatant by the hexo kinase method using an analytical photometer. Statistical evaluation was performed by t-test (nach student) with a significance of p = 0.05.

The following table shows the values obtained as a percentage of the control:

Compound 5 mg / kg 1 mg / kg __1_2_3_4__1_2__3_4 A -43 -40 -33 -35 B -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 D -36 -32 -27 -25 E -46 -40 -38 -26 -23 -23 -12 -18 F -43 -42 -39 -32 78477 31

Compound 5 mg / kg 1 mg / kg __1_2_3_4__1_2_3_4 G -44 -42 -37 -31 H -50 -46 -44 -45 J -44 -37 -42 -42 -38 -32 -34 -29 K -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 ns

M -46 -43 -40 -36 -33 -30 -21 n.s.

N -42 -42 -37 -33 0 -38 * -31 * n.s. * n.s. * p -49 -43 -34 -22 -37 -19 n.s. socalled

Q -28 -13 n.s. socalled

R -38 -40 -35 -29 -39 -34 -29 -24 S -49 -42 -30 -17 -29 -20 -10 n.s.

T _48 -46 -42 -40 -42 -42 -40 -32 U -43 -43 -49 -45 -39 -35 -29 -24 V -45 -41 -46 -40 -37 -23 -30 -18 W -46 -45 -39 -37 -36 -25 -16 ns

X -30 -33 -14 n.S. -15 -15 -13 n.S.

Y -43 -38 -36 -27 -26 -15 n.S. N. S.

Z -36 -37 -36 -33 AA -28 -32 -27 -28 -16 -20 -17 -14 AB -30 -28 -39 -36 -21 -20 -22 n.s.

AC -43 -39 -30 -26 -17 -19 n.s. socalled

AD -49 * -50 * -36 * -31 * -18 n.s. socalled socalled

AE -41 -37 -20 n.s. -26 -14 n.s. socalled

AF -44 -40 -39 -40 -35 -34 -28 -20 AG -48 * -47 * -40 * -45 * -32 -19 -10 -17 AH -34 -35 -32 -29 -11 - 13 ns socalled

AJ -39 -35 -27 -26 -27 -24 n.s. socalled

AK -37 -34 -32 -31 -21 -17 -15 -11 AL -26 -28 -22 -17 AM -32 -31 -24 -19 -16 -11 n.s. socalled

AN -35 -30 -29 -31 -13 - 9 n.s. socalled

AO -45 -44 -42 -32 -21 -13 n.s. socalled

78477 32 + = dose of 10 mg / kg n.s. = not statistically significant 2. Acute toxicity:

Self-raised female and male mice weighing 20-26 g were tested for toxicity at a 14-day observation period after a single dose (as a suspension in 1% methylcellulose):

Compound__Indirectional acute toxicity__ A> 1000 mg / kg p.o. (6 animals died 0) C> 2000 "" (") D> 500" "(") J> 2000 "" (10 animals died 0) X> 1000 "" (") Y> 1000" "(”) Z > 1000 "" (") AA> 1000" "(") AB> 1000 "" (") AD> 1000" "(")

Based on their pharmacological properties, the compounds of the general formula I prepared according to the invention and their physiologically acceptable salts are suitable for the treatment of diabetes mellitus. For this purpose, it is possible, possibly in combination with other active ingredients, to be processed into customary kalenic formulations, such as tablets, granules, capsules, powders or suspensions. Adults will then have a single dose of 1-50 mg, but preferably 2.5-20 mg, 1 or 2 times a day.

i

The following examples further illustrate the invention: 78477 33

Example 1 4- [N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

To a mixture of 4.2 g (15 mmol) of α- (4-methylphenyl) -2-piperidinobenzylamine and 3.4 g (16.5 mmol) of 4-ethoxycarbonylphenylacetic acid dissolved in 40 ml of acetonitrile, 4.7 g (18 mmol) of triphenylphosphine, 3 g (30 mmol) of triethylamine and 1.5 ml (15 mmol) of carbon tetrachloride are added successively. The reaction mixture is stirred for 2 hours in SO 2, then evaporated, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The evaporation residue is triturated with ethanol and filtered off with suction.

Yield: 4.55 g (65 7 »theoretical),

Melting point: 177-178 ° C

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.19 7.16 5.82

In analogy to Example 1, the following were prepared: (a) 4- [N- [α- (3-methyl-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 48% of theory Melting point: 159-160 ** C Calculated: C 76.57 H 7.28 N 5.95

Found: 76.80 7.35 5.76 (b) 4- [N- [α- (2-methyl-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 35.4% of theory,

Melting point: 196-198 ° C

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.65 7.35 5.90 34 78477 (c) 4- [n- [α- (4-Methoxy-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 45 7 »theoretical,

Melting point: 167-168 ° C

Calculated: C 74.05 H 7.04 N 5.76

Found: 73.72 6.99 5.62 (d) 4- [N- [α- (4-Benzyloxy-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 96 7. Theoretical,

Melting point: 154-155 ° C Calculated: C 76.84 6.81 N 4.98

Found: 76.82 6.68 5.03 (e) 4- [N- [α- (4-Fluoro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 58 7> theoretical Melting point: 174-176 ° C Calculated: C 73.40 H 6.58 N 5.90

Found: 73.55 6.72 5.91 (f) 4- (N- [O- (2-Fluoro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 83% of theory Melting point: 173-175 ° C Calculated: C 73.40 H 6.58 N 5.90

Found: 73.61 6.62 5.85 (g) 4- [N- (O- (4-Chloro-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 57 7, from theoretical

Melting point: 178-181 ° C

Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22

Found: 71.10 6.56 5.26 7.11 78477

3S

(h) 4- (N- [α- (3-Chloro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 71 7, theoretical Melting point: 153-156 ^ 0

Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22

Found: 70.86 6.26 5.65 7.25 (i) 4- (N- [O- (2-Chloro-phenyl) -2-piperidinobenzyl] -aminocarbonyl-ethyl] -benzoic acid ethyl ester

Yield: 66 7% of theory

Melting point: 196-198 ° C

Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22

Found: 70.90 6.30 5.61 7.10 (k) 4- [N- [α- (4-methylmercapto-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 84 7, from theoretical

Melting point: 173-175 * »C

Calculated: C 71.68 H 6.82 N 5.57 S 6.38

Found: 71.92 6.97 5.45 6.21 (1) 4- (N- / 5-chloro-α- (2-chlorophenyl) -2-piperidinobenzyl-1 H (aminocarbonylmethyl) benzoic acid etyy1iesteri

Yield: 92 7, from theoretical

Melting point: 213-215 ** C

Calculated: C 66.28 H 5.75 N 5.33 Cl 13.49

Found: 66.45 5.86 5.25 13.51 (m) 4- (N- (2-Piperidino-α- (2-pyridyl) -benzyl) -aminocarbonylmethyl) -benzoic acid ethyl ester

Yield: 51% of theory

Melting point: 158-159eC

Calculated: C 73.50 H 6.83 N 9.18

Found: 73.40 6.95 9.10 36 78477 (n) 4- (N- (2-Piperidino-α- (3-pyridyl) -benzyl) -aminocarbonylmethyl) -benzoic acid ethyl ester

Yield: 85 7 »theoretically Melting point: 172 ^ 0

Calculated: C 73.50 H 6.83 N 9.18

Found: 73.42 6.76 9.25 (o) 4- [N- (2-Piperidino-α- (4-pyridyl) -benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 20 7, from theoretical

Melting point: 150-152 ° C

Calculated: C 73.50 H 6.83 N 9.18

Found: 73.61 6.91 9.15 (p) 4- [N- (6-chloro-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 12 7 »theoretical

Melting point: Oil

Calculated: molar peak m / e = 490/492

Found: molar peak m / e = 490/492 (q) 4- [n- (4-Chloro-α-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 37 7, from theoretical

Melting point: 148-150eC

Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22

Found: 70.81 6.25 5.61 7.12 (r) 4- [N- (3-chloro-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester Yield: 74 7, theoretical

Melting point: 176-178 ° C

Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22

Found: 70.59 6.25 5.68 7.16 78477 (s) 4- [N- (6-Methyl-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 65% of theory

Melting point: oil

Calculated: molar peak m / e = 470

Found: molar peak m / e = 470 (t) 4- [N- (4-methyl-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 76% of theory

Melting point: 133-135 ° C

Calculated: C 76.57 H 7.28 N 5.95 Found: 76.51 7.16 5.83 (u) 4- / N- (5-chloro-2- (2-methylpiperidin) -a- Phenylbenzyl / aminocarbonylmethyl / benzoic acid ethyl ester Yield: 36.5% of theory

Melting point: 171-173 ° C

Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01

Found: 71.45 6.68 5.59 7.20

Example 2 4- (N- [α- (4-Chloro-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

To a solution of 6.02 g (20 mmol) of (4-chlorophenyl) -2-piperidinobenzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform is added dropwise and, under ice-cooling, the solution. containing 5 g (22.1 mmol) of 4-ethoxycarbonylphenylacetyl chloride in 78 ml of 38 ml of chloroform. Stir for two hours at room temperature, then add to water and extract with chloroform. The extracts are dried and evaporated. The evaporation residue is chromatographed on silica gel using toluene / acetic acid ethyl ester 5: 1 as eluent.

Yield: 5.6 g, 57% of theory Melting point: 178-181 ° C

Calculated: C 70.94 6.36 N 5.71 Cl 7.22

Found: 71.09 6.47 5.61 7.10

In analogy to Example 2, the following were prepared:

(a) 4- [N- (5-Chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 54% of theory Melting point: 178-180 ° C

Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01

Found: 70.91 6.64 5.75 7.01

Example 3 4- [N- (CC- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid 4.4 g (9.35 mmol) of 4- (N -) - (4 -methyl-phenyl) -2-piperidino-benzyl-aminocarbonylmethyl-benzoic acid ethyl ester is dissolved in 150 ml of ethanol with heating. 20 ml of 1N sodium hydroxide are then added and the mixture is stirred for 3 hours at 50 ° C. 20 ml of 1N hydrochloric acid are then added to the reaction mixture and the excess ethanol is removed by evaporation on a rotary evaporator. The remaining aqueous suspension is filtered and the precipitate is washed well with water. It is then recrystallized from acetonitrile.

Yield: 2.45 g (59.3 of the 7th theoretical).

Melting point: 226-228eC

78477 39

Calculated: C 75.99 H 6.83 N 6.33 Found: 75.60 6.75 6.29

In analogy to Example 3, the following were prepared: (a) 4- [N- [α- (3-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid

Yield: 72% of theory,

Melting point: 202-203 ° C

Calculated: C 75.99 H 6.83 N 6.33

Found: 75.64 6.91 6.37 (b) 4- [N- [α- (2-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid

Yield: 42.6% of theory Melting point: 285-290 ** C

Calculated: C 75.99 H 6.83 N 6.33

Found: 76.05 6.98 6.25 (c) 4- (N- [α- (4-methoxy-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid

Yield: 72.4% of theory,

Melting point: 228-230 ° C

Calculated: C 73.34 H 6.59 N 6.11

Found: 73.22 6.61 6.13 (d) 4- (N- (α-Benzyloxy-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl / -benzoic acid

Yield: 57 7, in theory

Melting point: 219-221 ° C Calculated: C 76.38 H 6.41 N 5.24

Found: 76.05 6.44 5.24 e) 4- (N- [α- (4-Fluoro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid 78477 m.p.

Yield: 75% of theory,

Melting point: 238-240 ° C

Calculated: C 72.63 H 6.09 N 6.27

Found: 72.98 6.29 6.32 (f) 4- (N- [α- (2-fluorophenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid

Yield: 87% of theory,

Melting point: 280-283eC

Calculated: C 72.63 H 6.09 N 6.27

Found: 72.70 6.10 6.37 (g) 4n / N- [α- (4-chloro-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid

Yield: 89% of theory

Melting point: 241-242e> C

Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Found: 69.74 6.05 6.01 7.64 (h) 4- (N- [α- (3-chloro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid

Yield: 53% of theory,

Melting point: 223-225 ° C

Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Found: 70.28 5.98 5.78 7.84 (i) 4- (N- [α- (2-chlorophenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid

Yield: 98% of theory,

Melting point: 303-305oC

Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Found: 69.88 6.05 5.87 7.74 (k) 4- [N- [O- (4-methylmercapto-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid 78477 41

Yield: 84.6 7. Theoretical,

Melting point; 225-227 = -0

Calculated: C 70.86 H 6.37 N 5.90 S 6.75

Found: 70.34 6.37 5.68 6.82 (1) 4- [N- [5-chloro-α- (2-chloro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid Yield: 90 7 »theoretical,

Melting point: 317-320 ° C

Calculated: C 65.19 H 5.27 N 5.63 Cl 14.25

Found: 64.87 5.34 5.69 14.22 (m) 4- (2-Piperidino-α- (2-pyridyl) -benzyl) -aminocarbonylmethyl / -benzoic acid

Yield: 91 7, theoretical,

Melting point: 160-161eC

Calculated: C 71.71 H 6.34 N 9.78

Found: 72.43 6.39 10.00 (n) 4- (N- (2-Piperidino-α- (3-pyridyl) -benzyl) -aminocarbonylmethyl) -benzoic acid

Yield: 72% of theory

Melting point: 252-253eC

Calculated: C 72.71 H 6.34 N 9.78

Found: 72.56 6.53 9.60 (o) 4- (N- (2-Piperidino-α- (4-pyridyl) -benzyl) -aminocarbonylmethyl) -benzoic acid

Yield: 68.5% of theory,

Melting point: 260eC (decomposes),

Calculated: C 72.71 H 6.34 N 9.78

Found: 72.31 6.29 9.63 (p) 4- [N- (6-chloro-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid 78477 42

Yield: 82% of theory.

Melting point: 91.94 ° C

Calculated: C 70.04 H 5.88 N 6.05 Cl 7.66

Found: 69.61 5.77 5.96 7.78 (q) 4- [N- (4-chloro-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 61% of theory,

Melting point: 221-223 ^ 0

Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Found: 69.73 5.89 5.87 7.52 (r) 4- [N- (3-chloro-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 83% of theory,

Melting point: 210-213 ° C

Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Found: 70.31 6.03 5.90 7.79 (s) 4- [N- (6-methyl-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 64% of theory,

Melting point.- 165-170 * ^

Calculated: C 75.99 H 6.83 N 6.33

Found: 75.73 6.96 6.14 (t) 4- [N- (4-methyl-α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 96 7, theoretical,

Melting point: 202-203'eC

Calculated: C 75.99 H 6.83 N 6.33

Found: 76.04 6.78 6.23 (u) 4- [N- (5-chloro-2- (2-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid 78477 43

Yield: 52 7, theoretical,

Melting point: 280-282eC

Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: 70.14 6.10 5.75 7.45

(v) 4- [N- (5-Chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Yield · 66% of theory Melting point: 246-248 ° C

Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43

Found: 70.16 6.07 5.87 7.30

Example 4 4- [N- [α- (4-Hydroxy-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid 1.1 g (2 mmol) of 4- (N- [α- (4-benzyloxy) phenyl) -2-piperidinobenzyl (aminocarbonylmethyl) -benzoic acid is suspended in 200 ml of ethanol and the benzyl group is catalytically removed at 50 ° C and 5 bar of hydrogen in the presence of 0.4 g of 10% palladium / carbon. The catalyst is then filtered off, evaporated and recrystallized from acetonitrile.

Yield: 720 mg (66.7% of theory)

Melting point: 202-204 ° C

Calculated: C 72.95 H 6.35 N 6.30

Found: 72.65 6.17 6.20

Example 5 4- [N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzyl alcohol 2.5 g (5.3 mmol) of 4- (N- [α- (4-methyl) -phenyl) -2-78477 44 Piperidinobenzyl / aminocarbonylmethyl / benzoic acid ethyl ester is added portionwise to a suspension of 0.5 g (13.2 mmol) of lithium aluroine hydride in 50 ml of absolute tetrahydrofuran. Stir for a further 30 minutes at room temperature, decompose by dropwise addition of 4 N sodium hydroxide and filter off the sodium aluminate formed. The filtrate is evaporated and the residue is recrystallized from a small amount of toluene.

Yield: 0.98 g (43% of theory),

Melting point: 144-146 ° C

Calculated: C 78.47 H 7.53 N 6.54

Found: 78.20 7.39 6.58

Example 6 4- [N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzaldehyde 8.85 g (20 mmol) of 4- (N- [α- ( 4-Methyl-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzoic acid and 3.25 g (20 mmol) of N, N'-carbonyldiimidazole in 100 ml of absolute tetrahydrofuran are heated at reflux for 2 hours. It is then evaporated, 50 ml of pyridine and 3.7 g (20 mmol) of 4-toluenesulphonic acid hydrazide are added and the mixture is then refluxed for a further 2 hours. It is then poured into ice water, filtered off with suction and the precipitate is dried. To the crude toluenesulfonic acid hydrazide thus obtained is added 20 g of anhydrous sodium carbonate and heated in 50 ml of ethylene glycol for 2 hours at 170 ° C. It is then added to water and extracted with chloroform. The combined extracts are purified by column chromatography on silica gel using toluene / acetic acid ethyl ester 5: 1 as eluent.

Yield: 1.73 g (21 7 »theoretical)

Melting point: 144-146eC

78477 45

Calculated: C 78.84 H 7.09 N 6.57

Found: 78.95 7.19 6.50

Prepared according to Example 6. · (a) 4 (N - [(α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde

Yield: 29% of theory,

Melting point: 168-170 * Ό

Calculated: C 78.61 H 6.84 N 6.79

Found: 78.60 7.00 6.72

Example 7 4- (N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzaldehyde 0.5 g (1.2 mmol) of 4- (N- [α- ( 4-Methyl-phenyl) -2-piperidino-benzyl-aminocarbonylmethyl-benzyl alcohol is added to a suspension of 0.4 g (1.5 mmol) of pyridinium chlorochromate in 2 ml of chloroform. After 12 hours at room temperature, ether is added, filtered and the evaporated filtrate is purified by column chromatography on silica gel (vehicle: toluene / ethyl acetate = 5: 1).

Yield 0.3 g (60% of theory),

Melting point: 145-146 ^

Calculated: C 78.84 H 7.09 N 6.57

Found: 78.97 7.12 6.57

According to Example 7, the following were prepared: (a) 4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde

Yield: 40% of theory.

78477 46

Melting point: 170 ° C

Calculated · C 78.61 H 6.84 N 6.79

Found: 78.59 6.87 6.61

Example 8 4- [N- [α- (4-Methyl-phenyl) -2-piperidin-benzyl] -aminocarbonylmethyl] -cinnamic acid ethyl ester 427 mg (1 mmol) of 4- (N- [α- (4- Methylphenyl) -2-piperidinobenzyl / aminocarbonylmethyl / benzaldehyde is added to an ethereal solution containing 450 mg (2 mmol) of diethylphosphonoacetic acid ethyl ester and 100 mg (2 mmol) of 50% sodium hydride. Stir overnight and add water. It is then extracted with chloroform and purified by column chromatography on silica gel using toluene / acetic acid ethyl ester 5: 1 as eluent.

Yield: 0.18 g (36% of theory)

Melting point: 176-180 ° ¾

Calculated: C 77.39 H 7.31 N 5.64

Found: 77.64 7.25 5.71

According to Example 8, the following were prepared: (a) 4- [N- (α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -cinnamic acid ethyl ester

Yield: 28.6% of theory

Melting point: 159-161 ° C

Calculated: C 77.14 H 7.10 N 5.80

Found: 77.28 7.21 5.65

Example 9 4- (N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -cinnamic acid 78 4 77 47

Prepared according to Example 3 by alkaline saponification of 4- (N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -cinnamic acid ethyl ester.

Yield: 84 7 · theoretical,

Melting point: 173-176 ° C

Calculated: C 76.90 H 6.88 N 5.98

Found: 77.24 7.01 5.64

According to Example 9, the following were prepared: (a) 4- [N- (α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -cinnamic acid

Yield: 75 7, from theoretical

Melting point: 177-180eC

Calculated: C 76.62 H 6.65 N 6.16

Found: 76.75 6.57 6.07

Example 10 4- [N- [α- (3-Methyl-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

To a mixture of 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated sulfuric acid at room temperature is added dropwise a mixture of 0.22 g (0.8 mmol) of α- (3-methylphenyl) -2-piperidino- benzyl alcohol and 0.15 g (0.8 mmol) of 4-cyanomethylbenzoic acid ethyl ester in 2 ml of o-dichlorobenzene. Stir for 2 hours and then add to ice-water, extract once with ether, make alkaline with dilute sodium hydroxide and extract with chloroform. The chloroform extracts are evaporated and the residue is recrystallized from ethanol.

Yield: 0.22 g (607, theoretical).

Melting point: 158-159 ° 0 78477 48

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.41 7.39 5.76

Example 11 4- [N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzoic acid 240 mg (5 mmol) of 4- (N- [5-chloro-α- ( 4-Methyl-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzoic acid is catalytically halogenated in 80 ml of a 1/1 mixture of ethanol and dioxane in the presence of 0.1 g of palladium / carbon (10%), 50 ° At C and a hydrogen pressure of 5 bar. After cooling, the catalyst is filtered off. The filtrate is evaporated and the residue is recrystallized from ethanol.

Yield: 0.16 g (71 7 »theoretical)

Melting point: 226-228eC

Calculated: C 75.99 H 6.83 N 6.33

Found: 75.81 6.73 6.10

In analogy to Example 11, the following were prepared: (a) 4- (N- (2-Methyl-piperidino) -α-phenyl-benzyl) -aminocarbonylmethyl] -benzoic acid 4- (N- (5-chloro-2- (2- methyl-piperidino) -α-phenylbenzyl / aminocarbonylmethyl / benzoic acid

Yield: 68 7, theoretical,

Melting point: 246-248 ° C

Calculated: C 75.99 H 6.83 N 6.33

Found: 75.57 7.10 6.44 (b) 4- [N- [2- (3-Methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid 4- (N- / 5 -Chloro-2- (3-methyl-piperidino) α-phenyl-benzyl / aminocarbonylmethyl / benzoic acid 78477 49

Yield: 43% of theory Melting point: 228-230®C Calculated: C 75.99 H 6.83 N 6.33

Found: 75.91 6.82 6.33

Example 12 4- [N- [α- (4-Methyl-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

To a solution of 2.78 g (10 mmol) of freshly prepared (4-methylphenyl) - (2-piperidinophenyl) ketimine in 50 ml of methylene chloride is added 1.5 ml (11 mmol) of triethylamine and its followed by a solution of 2.5 g (11 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 20 ml of methylene chloride under ice-cooling. Keep for 1 hour at room temperature and then add to ice-water and extract with methylene chloride. The extracts are dried and evaporated and the residue is purified by column chromatography over silica gel (vehicle: toluene / ethyl acetate 10: 1). The crude acylamine is dissolved in dimethylformamide, 0.5 g of palladium (10% on carbon) is added and the mixture is hydrogenated under a hydrogen pressure of 5 bar at room temperature. After the calculated amount of hydrogen has elapsed, the catalyst is filtered off, evaporated and the residue is recrystallized from a small amount of alcohol.

Yield: 2.8 g (60% of theory)

Melting point: 175-177 ° C

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.41 7.19 5.76

Example 13 4- [N- [α- (4-Methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzenitrile 78477 50

Prepared according to Example 1 from α- (4-Methyl-phenyl) -2-piperidinobenzylamine and 4-cyano-phenylacetic acid. Yield: 64% of theory,

Melting point: 144-146 ° C

Calculated: C 79.40 H 6.90 N 9.92

Found: 79.10 6.90 9.78

Example 14 4- (N- (CC- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl) -benzoic acid ethyl ester 4.2 g (10 mmol) of 4- (N- (ct) ( 4-Methyl-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzonitrile and 50 ml of ethanolic hydrochloric acid are refluxed for 24 hours. It is then evaporated, aqueous sodium bicarbonate solution is added to the evaporation residue and extracted with chloroform. The chloroform extract is evaporated and the residue is triturated with ethanol and filtered off with suction.

Yield: 2.9 g (61.6% of theory)

Melting point: 177-179 ° C

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.41 7.35 5.76

Example 15 4- [N- (5-Chloro-α- (2-chloro-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester 10 millimoles of 4- (N- [α- (2-chloro-phenyl) Phenyl) -5-nitro-2-piperidinobenzyl (aminocarbonylmethyl) -benzoic acid ethyl ester is dissolved in 50 ml of dimethylformamide, 1 g of Raney nickel is added and the mixture is hydrogenated at 60 [deg.] C. and 6 bar of hydrogen. The catalyst is then filtered off, the filtrate is evaporated and the residue formed from 4- [N- (5-amino-α- (2-chloro-78477,5-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester is dissolved. To 100 ml of concentrated hydrochloric acid. A solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water is then added dropwise under ice-cooling and the mixture is stirred for a further 1 hour at 0-5 ° C. The reaction mixture is then added dropwise to a solution of 3 g of copper-1-chloride in 25 ml of concentrated hydrochloric acid. Stir for an additional 1 hour, then make alkaline with sodium hydroxide and extract with chloroform. The evaporated chloroform extracts are purified by column chromatography on silica gel using toluene / ethyl acetate 5: 1 as eluent.

Yield 1.5 g (28.6 of the 7th theoretical),

Melting point: 213-215eC

Calculated: C 66.28 H 5.75 N 5.33 Cl 13.49

Found: 66.40 5.91 5.41 13.40

Example 16 3- [4- [N- (α- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -phenyl] -propionic acid 0.91 g (2 mmol) of 4- (N- (α- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl / -cinnamic acid is dissolved in 50 ml of methanol, 0.5 g of palladium (10% on carbon) is added at room temperature and the mixture is catalytically hydrogenated under a hydrogen pressure of 3 bar. After uptake of hydrogen, the catalyst is filtered off and recrystallized from a small amount of acetonitrile.

Yield: 0.68 g (74% of theory)

Melting point: 14-14 ° C

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.41 7.19 5.61 78477 52

Example 17 4- [N- (α- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid sodium salt 442 mg (1 mmol) of 4- [N- (α- (4-methyl) (phenyl) -2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid is dissolved in 25 ml of ethanol and 1 ml of 1N sodium hydroxide is added. It is then evaporated in vacuo, 20 ml of acetone are added, the precipitate formed is filtered off with suction and washed with ethyl acetate.

Yield: 410 mg (85 7 »of theory),

Melting point: 295-300eC

Calculated: C 72.40 H 6.29 N 6.03

Found: 72.15 6.46 5.93

In analogy to Example 17, the following were prepared: (a) 4- [N- (α- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid-ethanolamine salt

Yield: 75 7. Theoretical,

Melting point: 1.88-191 ° C

Calculated: C 71.55 H 7.41 N 8.34

Found: 71.16 7.48 8.52 ib) 4- [N- (α- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid-diethanolamine salt

Yield: 81 7, from theoretical

Melting point: 178-180 ° C

Calculated: C 70.70 H 6.86 N 7.73

Found: 70.25 6.75 7.58 (c) 4- [N- (α- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid-triethanolamine salt Yield: 76% of theory , 78477 53

Melting point: 160-165 ° C

Calculated: C 69.01 H 7.67 N 7.10

Found: 68.91 7.64 7.45 (d) 4- [N- (α- (4-Methyl-phenyl) -2-piperino-benzyl) -aminocarbonylmethyl] -benzoic acid-ethylenediamine salt

Yield: 65% of theory,

Melting point: 160-163 ° C

Calculated: C 71.69 H 7.62 N 11.15

Found: 72.04 7.80 10.96

Example 18 4 - [(2-Methoxy-1- (2-piperidino-phenyl) -ethyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

To a solution of 0.55 g (2.34 mmol) of 2-methoxy-1- (2-piperidinophenyl) ethylamine in 5 ml of acetonitrile is added successively 0.49 g (2.34 mmol) of 4-ethoxycarboxylate. -ylphenylacetic acid, 0.73 g (2.78 mmol) of triphenylphosphine, 0.50 ml (3.66 mmol) of triethylamine and 0.23 ml (2.34 mmol) of carbon tetrachloride and then stirred for 20 hours at room temperature. It is then evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 10/2).

Yield: 0.45 g (45% of theory),

Melting point: 122-123 ° C

Calculated: C 70.73 H 7.60 N 6.60

Found: 71.04 7.48 6.39

In analogy to Example 19, the following compounds were prepared: 78477 54 (a) 4 - [(1- (3-Chloro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester

Yield: 55% of theory,

Melting point: 141-143® ^:

Calculated: C 68.33 H 7.28 Cl 7.76 N 6.13 Found: 68.30 7.16 8.03 6.20 (b) (4 - / (1- (6-Chloro-2-piperidino) phenyl) -l-butyl) -amino-carbonylmethyl / -benzoic acid ethyl ester

Yield: 73.9 7. Theoretical,

Melting point: 79-83 ^ 0

Calculated: C 68.33 H 7.28 Cl 7.76 N 6.13

Found: 68.45 7.24 7.80 6.09 (c) 4 - [(1- (4-Bromo-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 62.1% of theory,

Melting point: 116-118®C

Calculated: C 62.27 H 6.63 Br 15.93 N 5.58

Found: 62.53 6.48 15.98 5.66 (d) 4 - [(1- (4-Nitro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 74.6% of theory,

Melting point: 127-130®C

Calculated: C 66.79 H 7.11 N 8.99

Found: 66.88 7.08 9.15 (e) 4 - [(1- (3-Methyl-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester

Yield: 68% of theory,

Melting point: 145-147®C

Calculated: C 74.28 H 8.31 N 6.42

Found: 74.40 8.30 6.41 78477 55 (f) 4 - [(1- (4-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 54.7% of theory,

Melting point: 113-114 ° C

Calculated: C 74.28 H 8.31 N 6.42

Found: 74.23 8.30 6.55 (g) 4 - [(1- (5-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 67.9% of theory,

Melting point: 149-150 ^ 0

Calculated: C 74.28 H 8.31 N 6.42

Found: 74.38 8.21 6.49 (h) 4 - [(1- (6-Methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 47 7. Theoretical,

Melting point: 92.93eC

Calculated: C 74.28 H 8.31 N 6.42

Found: 74.50 8.46 6.48 (i) 4 - [(1- (2-Pyrrolidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester

Yield: 57.3% of theory,

Melting point: 122-125eC

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.63 8.07 7.01 (k) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 71.5% of theory,

Melting point: 127-128 ° C

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.90 8.06 6.72 78477 56 (1) 4 - [(1- (2- (4-Methyl-piperidino) -phenyl) -1-butyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 51.1 7, theoretical,

Melting point: 153-155 ° C Calculated: C 74.28 H 8.31 N 6.42

Found: 74.55 8.33 6.45 (m) 4 - [(1- (2-Hexahydro-azepino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 42.7 7, theoretical,

Melting point: 145-Ι47βα

Calculated: C 74.28 H 8.31 N 6.42

Found: 73.98 8.26 6.58 (n) 4 - [(1- (5-Fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield · 55 7. theoretical,

Melting point: 128-130 ° C,

Calculated: C 70.88 H 7.55 N 6.36

Found: 71.14 7.57 6.49 (o) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid methyl ester

Yield: 63.2 7 »from theoretical,

Melting point: 147-148eC

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.66 7.88 6.80 (p) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid n-butyl ester

Yield: 50.9% of theory,

Melting point: 117-119 ° C (ether)

Calculated: C 74.63 H 8.50 N 6.22

Found: 74.49 8.46 6.14 78477 57 (q) 4 - [(1- (2-Piperidinophenyl) -4-penten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester Yield: 18 , 9% of theory,

Melting point: 103-105eC

Calculated: C 74.62 H 7.89 N 6.45

Found: 75.01 8.10 6.26

Example 19 4 - / (1- (5-Nitro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

To a stirred solution of 15.1 g (54.4 mmol) of 1- (5-Nitro-2-piperidinophenyl) -1-butylamine and 8.46 ml (61.4 mmol) of triethylamine in 55 ml of dry raethylene chloride, a solution of 14.6 g (64.6 mmol) of 4-ethoxycarbonylphenylacetic acid in 20 ml of methylene chloride is added dropwise over 30 minutes so that the temperature does not exceed 30 ° C. Stir for two hours at room temperature, add 300 ml of methylene chloride and shake twice with 50 ml of water. The organic phases are dried over sodium sulfate, filtered and evaporated in vacuo. The red-brown oily evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1). Yield: 17.7 g (69.7% of theory),

Melting point: 135-137 ° C »ether

Calculated: C 66.79 H 7.11 N 8.99

Found: 66.73 6.99 9.09

In analogy to Example 19, the following compounds were prepared: (a) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 80.2% of theory, 78477 58

Melting point: 127-129®C

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.98 8.26 6.89 (b) 4 - [(1- (4-Hydroxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 13.5% of theory,

Melting point: 178-180 ° C

Calculated: C 71.21 H 7.81 N 6.39

Found: 71.27 7.82 6.40 (c) 4 - [(1- (5-Hydroxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 37.4% of theory,

Melting point: 188-190eC

Calculated: C 71.21 H 7.81 N 6.39

Found: 71.34 7.89 6.38

Example 20 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] phenylacetic acid

Heat together 3.0 g (15.45 mmol) of p-phenylenediacetic acid and 10 ml of thionyl chloride at reflux for 90 minutes and then evaporate in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride. To this solution, a solution of 3.6 g (15.45 mmol) of 1- (2-Piperidinophenyl) -1-butylamine is slowly added dropwise with stirring at an internal temperature of 10-15 ° C. After 2 hours at room temperature, the mixture is evaporated in vacuo and the residue is partitioned between ice-cold 5% sodium hydroxide (100 ml) and ethyl acetate. Filter the diatomaceous earth and separate the organic phase. The alkaline aqueous phase is adjusted to pH 5.5 with semi-concentrated hydrochloric acid and extracted with 78477 59 ethyl acetate. Dry over sodium sulfate, filter and evaporate the filtrate in vacuo. The residue is purified by column chromatography over silica gel (chloroform / methanol = 20/1).

Yield: 0.10 g (1.6 7% of theory),

Melting point: 136-140 ° C (acetonitrile / ether)

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.17 8.10 6.85

Example 21 4 - [(2-Methyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester

To a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl- (2-piperidinophenyl) ketimine in 62 ml of acetonitrile is added successively 5.58 g (26.8 mmol) of 4-ethoxycarbonylphenylacetic acid, 8 , 43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 mol) of carbon tetrachloride and stirred for 20 hours at room temperature. It is then evaporated in vacuo and partitioned between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 5/1). Yield: 3.0 g (26.6% of theory),

Melting point: 82-84 ^ 0 (ether),

Calculated: C 74.26 H 7.67 N 6.66

Found: 74.20 7.49 6.56

In analogy to Example 21, the following compounds were obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-penten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester Yield: 16% of theory.

78477 60

Melting point: 94-97eC (ethanol)

Calculated: C 74.62 H 7.89 N 6.45

Found: 74.75 7.71 6.24 (b) 4 - [(1- (2-Piperidino-phenyl) -1-hexen-1-yl) -amino] -amino} -benzoic acid ethyl ester

Yield: 27.4% of theory,

Melting point: 83-85 ° C (ethanol),

Calculated: C 74.97 H 8.09 N 6.24

Found: 75.42 7.95 6.00 {c) 4 - [(1- (2-Piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: (lipophilic isomer; probably Form E) 4.1% of theory,

Melting point: <20 ° C

Calculated: m / e = 420

Found: m / e = 420

Yield: (less lipophilic isomer; probably Z-form) 51.9% of theory,

Melting point: 115-117 ° C (ethanol)

Calculated: C 74.26 H 7.67 N 6.66

Found: 73.85 7.59 6.44 (d) 4 - [(2-Phenyl-1- (2-piperidino-phenyl) -ethen-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: (lipophilic isomer; probably Form E): 4% of theory,

Melting point: 74.77 ° C (ether / petroleum ether)

Calculated: C 76.90 H 6.88 N 5.98

Found: 77.31 7.20 5.93

Yield: (less lipophilic isomer; probably Z-form): 42.7% of theory,

Melting point: 157-160 ° C (ethanol)

Found: C 77.19 H 6.95 N 6.02 78477 61 (e) 4 - [(3-Phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 62.6% of theory,

Melting point: <20 ° C Calculated: m / e = 482

Found: m / e = 482 (f) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 33% theoretical,

Melting point: 113-116 ^ 0

Calculated: C 74.97 H 8.09 N 6.24

Found: 75.37 7.93 6.03 (g) 4 - [(1- (6-Methyl-2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 60.4 7. Theoretical (probably Z-shape), Melting point: 95-96eC

Calculated: C 74.62 H 7.89 N 6.45 m / e = 434

Found: 74.44 8.00 δ, S9 m / e * 434

Example 22 4 - [(1- (2-Piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester

A stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-Piperidinophenyl) propyl ketamine and 11.5 ml (82.46 mmol) of triethylamine in 190 ml of anhydrous toluene at 85 ° C. A solution of 18.7 g (82.46 mmol) of 4-ethoxycarbonylphenylacetic acid in 95 ml of anhydrous toluene is added dropwise over 10 minutes and the mixture is stirred for 30 minutes at 95 ° C. Cool to 20 ° C and shake twice with water. The organic phase 78477 62 is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography (toluene / acetone = 20: 1 and 50: 1) several times.

Yield · (lipophilic isomer; probably Form E), 11.2 g (23.6 7 »theoretical),

Melting point: <20 ° C (honey yellow, viscous oil)

Calculated: C 74.26 H 7.67 N 6.66

Found: 73.90 7.92 6.91

Yield: (less lipophilic isomer; probably Z-form), 15.9 g (33.5 from 7th theoretical)

Melting point: 114-116 ° C

Found: C 74.02 H 7.69 N 6.85

Example 23 (E) - and (Z) -4 - [(1- (2-Piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester 1.0 g of the Z ester (see Example 21c) is heated for 30 minutes in a preheated oil bath at 230 ° C. After cooling, the product obtained is purified by column chromatography on silica gel (toluene / acetone = 20/1).

Yield: (E-ester): 0.365 g (36.5 ° C theoretical), Melting point: 115-117 ° C

When the (E) -ester is heated for 3.5 hours together with a catalytic amount of iodine in benzene, a 1/1 mixture of (E )- and (Z) -esters is obtained on the basis of thin-layer chromatography (toluene / acetone = 10/1).

According to Example 23, the following compounds were obtained: (a) (E) - and (Z) -4 - [(1- (6-Methyl-2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester 78477 63 (Z) The ester (see Example 21g) gives a 1/1 mixture of (E) and (Z) esters on the basis of a thin layer chromatogram.

Upper spot (E): Calculated: m / e = 434

Found: m / e * 434

Lower spot (Z): Found: m / e = 434

Example 24 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester 2.9 g (6.90 mmol) 4 - [(1- (2-Piperidinophenyl) ) -1-Buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 100 ml of ethanol is hydrogenated at 50 [deg.] C. and 1 bar of hydrogen under 0.77 g of palladium-on-carbon (10%) catalyst. After two hours, the catalyst is filtered through diatomaceous earth and evaporated in vacuo. The evaporation residue is crystallized from ethanol.

Yield: 1.5 g (51.5 of the 7th theoretical),

Melting point: 126-128 ** C

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.97 8.22 6.57

According to Example 24, the following compounds were obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-pentyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 45 7, theoretical,

Melting point: 117-120 ** C (ether)

Calculated: C 74.28 H 8.31 N 6.42

Found: 74.60 8.13 6.27 (b) 4 - [(1- (2-Piperidinophenyl) -1-hexyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 50 7 »theoretical,

Melting point: 108-110 ° C (ether)

Calculated: C 74.63 H 8.50 N 6.22

Found: 74.85 8.33 6.01 64 78477 (c) 4 - [(2-Phenyl-1- (2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 87.6% of theory,

Melting point: 161-162 ° C (ethanol)

Calculated: C 76.57 H 7.28 N 5.95

Found: 76.71 7.19 5.99 (d) 4 - [- / (3-Phenyl-1- (2-piperidino-phenyl) -1-propyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 57.6 % of theoretical,

Melting point: 118-119 ° C (ethanol)

Calculated: C 76.83 H 7.49 N 5.78

Found: 76.70 7.49 5.90 (e) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 36.5% of theory,

Melting point: 140-141 ° C (ethanol)

Calculated: C 74.63 H 8.50 N 6.22 Found: 74.30 8.23 6.12

Example 25 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

A mixture of 1.2 g (2.84 mmol) of 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester and 4.26 ml of 1N sodium hydroxide in 12 ml in ethanol, stirred for one hour at 60 [deg.] C., then neutralized with 4.26 ml of 1N hydrochloric acid and the ethanol is evaporated off under vacuum. Partition between ethyl acetate and water; The organic extracts are dried and filtered and evaporated in vacuo. The evaporation residue is crystallized from ethanol.

Yield: 0.50 g (44.6% of theory),

Melting point: 213-215eC

Calculated: C 73.07 H 7.66 N 7.10

Found: 73.18 7.51 7.10

According to Example 25, the following compounds were obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-pentyl) aminocarbonylmethyl] benzoic acid

Yield: 70.2 7, theoretical,

Melting point: 213-215eC (acetone)

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.71 7.70 6.90 (b) 4 - [(1- (2-Piperidinophenyl) -1-hexyl) aminocarbonylmethyl] benzoic acid

Yield: 72.6 7. theoretical,

Melting point: 197-200eC (acetone)

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.83 7.93 6.77 (c) 4 - [(2-Phenyl-1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid

Yield · 68.7 7, theoretical,

Melting point: 214-215eC

Calculated: C 75.99 H 6.83 N 6.33

Found: 75.70 6.60 6.32 (d) 4 - [(3-Phenyl-1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl] benzoic acid

Yield: 67.7 7 »from theoretical,

Melting point: 167-170eC (ethyl acetate)

Calculated: C 76.29 H 7.06 N 6, IA

Found: 76.56 7.06 6.23 66 78477 (e) N- (2-Methoxy-1- (2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid

Yield: 60.8 7. of theoretical,

Melting point: 196-198 ° C (ether)

Calculated: C 69.68 H 7.12 N 7.07

Found: 69.72 6.52 6.71 (f) N - [(1- (2-Piperidinophenyl) -A-penten-1-yl) aminocarbonylmethyl] benzoic acid x 0.67 H * 0

Yield: 30.7% of theory,

Melting point: 193-197 ° C (ether / petroleum ether)

Calculated: C 71.7A H 7.38 N 6.69

Found: 71.63 7.21 6.3A

(g) N - ((1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl) -benzoic acid

Yield: A8.2 from the 7th theoretical,

Melting point: 168-170 ° C (petroleum ether)

Calculated: C 73.91 H 8.11 N 6.63

Found: 73.51 7.89 6.32 (h) N - [(1- (3-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 53% of theory,

Melting point: 179-182eC

Calculated: C 73, SO H 7.90 N 6.86

Found: 73.50 7.82 7.01 (i) N- {1- (N-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 85.6% of theory,

Melting point: 170-172 ° C

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.25 7.64 6.89 67 73477 (k) 4 - [(1- (4-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 62.1% of theory,

Melting point: 219-221eC

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.20 7.74 6.89 (1) 4 - [(1- (6-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid x 0.3 Ha0

Yield: 89 7, theoretical,

Melting point: 158-160eC

Calculated: C 72.53 H 7.93 N 6.77

Found: 72.40 7.91 6.92 (m) 4 - [(1- (3-Chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 70 7. Theoretical,

Melting point: 189-191 ° C

Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53

Found: 67.30 6.85 8.36 6.58 (n) 4 - [(1- (4-Chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 57.8 7. from theoretical,

Melting point: 188-189eC

Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 66.90 7.00 8.22 6.53 (o) 4 - / (1- (5-Chloro-2-piperidino- phenyl) -2-butyl) -amino-carbonylmethyl / benzoic acid

Yield: 81.6% of theory,

Melting point: 226-229 ° C

Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53

Found: 67.17 6.59 8.51 6.60 68 78477 (p) 4 - [(1- (6-Chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 69.4 7. of theoretical,

Melting point: 150-153 ° C

Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53

Found: 67.18 6.91 8.42 6.77 (q) 4 - [(4-Bromo-2-piperidinophenyl) -1-butyl) -1-butyl) aminocarbonylmethyl) benzoic acid

Yield: 84.4 7, theoretical,

Melting point: 198-201eC

Calculated: C 60.89 H 6.17 Br 16.88 N 5.92

Found: 60.88 5.98 17.20 5.98 (r) 4 - [(1- (5-Bromo-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 90.7% of theory,

Melting point: 232-235 ° C

Calculated: C 60.89 H 6.17 Br 16.88 N 5.92

Found: 60.96 6.13 16.85 5.90 (s) 4 - [(1- (4-Nitro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 70.9 7, theoretical,

Melting point: 188-190 ^

Calculated: C 65.59 H 6.65 N 9.56

Found: 65.30 6.44 9.53 (t) 4 - [(1- (5-Nitro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 90.7 7. Theoretical.

Melting point: 225-227 ° C

Calculated: C 65.59 H 6.65 N 9.56

Found: 65.80 6.61 9.72 73477 69 (u) 4 - [(1- (4-Hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonyl-ethyl] -benzoic acid x 0.5 H * 0

Yield: 85.7% of theory,

Melting point: softens from 70 ° C (foam),

Calculated: (X 0.5 H * O) C 68.71 H 7.45 N 6.68

Found: 68.63 7.55 6.26 (v) 4 - [(1- (5-Hydroxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 89.3% of theory,

Melting point: 186-190 ^

Calculated: C 70.22 H 7.37 N 6.82

Found: 70.31 7.58 6.51 (w) 4 - [(1- (4-Methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

Yield: 78.6% of theory,

Melting point: 185-187 ° C

Calculated: C 70.73 H 7.60 H 6.60

Found: 70.46 7.77 6.56 (x) 4 - [(1- (5-Methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

Yield: 75% of theory,

Melting point: 182-185eC (decomposes)

Calculated: C 70.73 H 7.60 N 6.60

Found: 70.52 7.50 6.70 (y) 4 - [(1- (2-Pyrrolidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid

Yield: 64.5% of theory,

Melting point: 200-203 * »C

t

Calculated: C 72.61 H 7.42 N 7.36

Found: 72.64 7.50 7.38 70 78477 (z) 4 - [(1- (2- (4-Methyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

Yield: 81.4% of theory,

Melting point: 197-201 ** C

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.90 8.06 7.00 (aa) 4 - [(1- (2-Hexahydroazepino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

Yield: 65.6 7 »from theoretical,

Melting point: 199-202 ° C

Calculated: C 73.50 H 7.90 N 6.86

Found: 73.50 7.90 6.76 (ab) 4 - [(1- (4-Fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Rule; 87.1% of theory,

Melting point: 204-207eC

Calculated: C 69.88 H 7.09 N 6.79

Found: 70.25 7.02 7.12 (ac) 4 - [(1- (5-Fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 53.9 7. Theoretical,

Melting point: 200-202eC

Calculated: C 69.88 H 7.09 N 6.79

Found: 69.67 7.24 6.90

Example 26 4 - [(2-Methyl-2- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl] benzoic acid 78477 71

A mixture of 3.5 g (8.3 mmol) of 4 - [(2-Methyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl] benzoic acid / ethyl ester and 12 g of , 5 ml of 1N sodium hydroxide in 35 ml of ethanol, stirred for 2 hours at 60 ° C. Neutralize with 12.4 ml of 1N hydrochloric acid, evaporate in vacuo and partition between ethyl acetate and water. The dried filtered organic extract is evaporated in vacuo. The evaporation residue is crystallized from ethanol.

Yield: 2.4 g (73.6 7, theoretical),

Melting point: 188-191eC

Calculated: C 73.44 H 7.19 N 7.14 Found: 73.60 7.19 7.02

In analogy to Example 26, the following compounds were obtained: (a) (E) -4 - [(1- (2-Piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid

Yield: 71.5 from the 7th theoretical,

Melting point: 188-190 ° C Calculated: C 73.44 H 7.19 N 7.14 Found: 73.15 7.13 7.10

Olefinic proton: 1 H-NMR (CDCl 3): δ = 6.42 ppm (b) (Z) -4 - / (1- (2-Piperidinophenyl) -1-buten-1-yl) amino carbonylmethyl / benzoic acid

Yield: 57.8 7 »from theoretical,

Melting point: 174-175 ° C (ethanol)

Calculated: C 73.44 H 7.19 N 7.14 Found: 73.54 6.97 7.17

Olefinic proton: 1 H-NMR (CDCl 3): δ 5.60 ppm (c) (E) -4 - [(2-Phenyl-1- (2-piperidinophenyl) ethen-1-yl) - aminocarbonylmethyl / benzoic acid x 0.4 Ha0

Yield: 33.2 7, theoretical,

Melting point: 165-167 ° α (ether / petroleum ether) 72 73477

Calculated: (x 0.4 HA): C 75.11 H 6.48 N 6.26

Found: 75.22 6.39 6.26

Olefinic proton: 1 H-NMR (CDCl 3): δ> 6.9 ppm (d) (Z) -4 - [(2-Phenyl-1- (2-piperidinophenyl) ethen-1-yl) aminocarbonylmethyl] -benzoic acid x 1 H * 0

Yield: 72 7 »theoretical,

Melting point: 182-185βΟ (methanol)

Calculated: (x 1 H 2 O): C 73.34 H 6.60 N 6.11

Found: 73.55 6.45 6.00

Olefinic proton: 1 H-NMR (CDCl 3): δ = 6.50 ppm (e) 4 - [(3-Phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl] benzoic acid

Yield: 48.3 7 »from theoretical,

Melting point: 162-164 ° C (ether); probably the (Z) form

Calculated: C 76.63 H 6.65 N 6.16

Found: 76.30 6.47 6.31

Olefinic proton: 1 H-NMR (CDCl 3): δ = 5.80 ppm (f) 4 - / (1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethyl / benzoic acid

Yield: 64.1 7, theoretical,

Melting point: 152-153 ° C (ethyl acetate); probably the (Z) form

Calculated: C 74.26 H 7.67 N 6.67

Found: 73.93 7.57 6.50

Olefinic proton: 1 H-NMR (CDCl 3): δ = 5.55 ppm (g) (Z) -4 - / (1- (6-Methyl-2-piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl / benzoic acid

Yield: 53.3 7 »from theoretical,

Melting point: 142-145 ° C

Calculated: C 73.66 H 7.44 N 6.89

Found: 73.56 7.73 7.15 78477 73

Olefinic proton: 1 H-NMR (CDCl 3): δ = 5.38 ppm Example 27 4 - / (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl / benzoic acid 200 mg (0.51 mmol) ) 4 - [(1- (2-Piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl] benzoic acid is hydrogenated in 10 ml of absolute ethanol at 50 ° C with shaking under 1 bar of hydrogen. The catalyst was 100 mg palladium / carbon (10%). After 1.5 hours, filter and evaporate in vacuo.

Yield: 68 7 »theoretical,

Melting point: 213-214 ^ 0

Calculated: C 73.07 H 7.66 N 7.10

Found: 73.21 7.82 7.02

The yield is 56 7> theoretical when hydrogenated at 50 ° C and 1 bar hydrogen pressure using Raney nickel.

Example 28

4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid sodium salt x 0.5 HeO

10.0 g (25.35 mmol) of 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid are dissolved in 200 ml of ethanol at 50 ° C and 25.35 ml of 1 N sodium are added. hydroxide. Evaporate to dryness in vacuo and dissolve the residue on as little ethanol as possible by heating on a steam bath. Cool in an ice bath, filter off the precipitated crystals, wash with ether and dry at 140 ° C / 15 Torr.

Yield: 9 g (85.3 7% of theory), 78477 74

Melting point: 280-285β0 (decomposes); softens from 255e Calculated: (x 0.5 H0): C 67.74 H 6.87 N 6.58

Found: 67.86 7.13 6.49

Example 29 (+) - 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

To a stirred solution of 2.58 g (11.1 mmol) of (+) - 1- (2-Piperidinophenyl) -1-butylamine / bp 0.03: 87 ° C; ee = 86 (after HPLC, (+) - 1-phenethyl isocyanate derivatization) / in 26 ml of acetonitrile, 2.31 g (11.1 mmol) of 4-ethoxycarbonylphenylacetic acid are added successively at 20 ° C, 3 , 50 g (13.3 mmol) of triphenylphosphine, 4.60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of carbon tetrachloride. Hold for 14 hours at 20 ° C and 1.5 hours at 40 ° C, then evaporate in vacuo and partition between water and ether. The organic phases are dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 6: 1).

Yield: 2.63 g (56% of theory),

Melting point: 118-120 ° C Calculated: C 73.90 H 8.11 N 6.63

Found: 74.02 7.97 6.51 / a> t> 2 ° = 9.2 ° (c = 1; methanol)

In analogy to Example 29, the following compound was obtained: · (a) (-) - 4- (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester

Starting material (-) - 1- (2-Piperidinophenyl) -1-butylamine x 1.4 HCl [α] D 20 -20.0 ° (c = 1, methanol), 78477 75

Melting range: 90-100 °; ee = 80 (HPLC, after derivatization of the base with (+) - 1-Phenethyl isocyanate) /

Yield: 52.6% of theory,

Melting point: 115-120 ° C Calculated: C 73.90 H 8.11 N 6.63

Found: 73.83 8.01 6.47 [α] 20 D -9.0 ° (c = 1, methanol).

Example 30 (+) - 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester 1.0 g (3.27 mmol) (+) - 1- (2- Piperidinophenyl) -1-butylamine dihydrochloride [α] D 20 = + 18.7 ** (c * 1, methanol); Melting point: decomposes from 115eC; ee * 91.6 (HPLC, after derivatization of the base with (+) - 1-Phenethyl isocyanate) / suspended in 6 ml of methylene chloride, 1.4 ml (10 mmol) of triethylamine are added with stirring and a solution containing 0.82 g (3.64 mmol) of 4-ethoxycarbonyl-acetic acid chloride in 2.4 ml of methylene chloride, increasing the reaction temperature from 22 ° C to 38 ° C. Stir for 6 hours at room temperature and shake successively with twice 10 ml of water, once with 10 ml of 2N hydrochloric acid and once with 10 ml of water.

The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 6/1). Yield: 0.53 g (38.2% of theory),

Melting point: 120-122 ^ 0

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.96 7.98 6.61 78477 76 (a) + 9.0 ° (c = 1, methanol).

Example 31 (+) - 4 - [(1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid

2.0 g (4.73 mmol) of (+) - 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester are stirred // ao = + 9 , 2 ° (c = 1, methanol) / in 20 ml of ethanol and 7.0 ml of 1N sodium hydroxide for 2.5 hours in a 65c bath, are cooled and 7.0 ml of 1N hydrochloric acid are added. The slowly separating crystals are filtered off, washed with water and dried at 100 ° C / 5 Torr.

Yield: 1.65 g (88.2% of theory),

Melting point: 185-187 ** C Calculated: C 73.07 H 7.66 N 7.10

Found: 72.90 7.80 7.17 (a) »520 = + 7.9 ° (c = 1, methanol)

In analogy to Example 31, the following compound was obtained: - (a) (-) - 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 80 7, theoretical,

Melting point: 187-190 C Calculated: C 73.07 H 7.66 N 7.10

Found: 72.98 7.44 7.22 / a> t> 3 ° = -7.9 ** (c = 1, methanol).

Example 32 4 - / (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl / benzonitrile 78477 77

Prepared according to Example 19 from 1- (2-Piperidinophenyl) -1-butylamine and 4-cyanophenylacetic acid.

Yield: 57.3% of theory,

Melting point: 147-148eC

Calculated: C 76.76 H 7.78 N 11.19

Found: 76.46 7.81 11.10

In analogy to Example 32, the following compound was obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] toluene

Prepared using 4-tolyl-acetic acid.

Yield: 60.4 7 »from theoretical,

Melting point: 150-153eC

Calculated: C 79.08 H 8.85 N 7.68

Found: 78.97 8.58 7.77

Example 33 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared according to Example 14 from 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzonitrile using ethanolic hydrochloric acid.

Yield: 58% of theory,

Melting point: 127-128 ° C

Calculated: C 73.90 H 8.11 N 6.63

Found: 74.07 8.23 6.87

Example 34 4 - / (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl / benzoic acid ethyl ester 78477 78

Prepared according to Example 10 from 1- (2-Piperidino-phenyl) -1-butanol and 4-cyanomethyl-benzoic acid ethyl ester using concentrated sulfuric acid in O-dichlorobenzene at room temperature.

Yield: 21% of theory,

Melting point: 126-128 ° C

Calculated: C 73.90 H 8.11 N 6.63 Found: 74.12 8.20 6.45

In analogy to Example 35, the following compound was obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Prepared from 1- (2-Piperidinophenyl) -1-butanol and 4-cyanomethylbenzoic acid. Extraction at pH 5.5.

Yield: 29% of theory,

Melting point: 215-217eC

Calculated: C 73.07 H 7.66 N 7.10

Found: 72.82 7.69 6.95

Example 35 4 - [(1- (4-Amino-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid x 0.5 H = 0

Hydrogenate 0.60 g (1.365 mmol) of 4 - [(1- (4-Nitro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid in 10 ml of dimethylformamide for 3 hours at 25 ° C and 1 bar. hydrogen pressure. The catalyst is 0.1 g of palladium / carbon (107 °). The catalyst is filtered off through diatomaceous earth and evaporated in vacuo. The evaporation residue is crystallized from ether. Yield: 0.41 g (73.2% of theory),

Melting point: 118-120 ° C

78477 79

Calculated: (x 0.5 HeO): C 68.87 H 7.71 N 10.04

Found: 68.62 7.64 10.08

According to Example 35, the following compounds were obtained: (a) 4 - [(1- (4-Amino-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 81.7% of theory,

Melting point: 145-146 ° C (ether / petroleum ether)

Calculated: C 71.37 H 8.06 N 9.60

Found: 71.50 8.08 9.68 (b) 4 - [(1- (5-Amino-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

Yield: 64% of theory,

Melting point: 227-230 ° C

Calculated: C 70.39 H 7.63 N 10.26

Found: 70.54 7.54 10.36 (c) 4 - [(1- (5-Amino-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 84.3 7 * of theory,

Melting point: 162-165eC

Calculated: C 71.37 H 8.06 N 9.60

Found: 71.58 7.83 9.65

Example 36 4 - [(1- (5-Chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

A cold diazonium salt solution is prepared at 0 ° C from a mixture of 2.0 g (4.57 mmol) of 4 - [(1- (5-Amino-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester. In 4.8 ml of semi-concentrated hydrochloric acid and 0.315 g (4.57 73477 80 mmol) of sodium nitrite in 1.66 ml of water. This is added dropwise at 0 DEG C. to a stirred mixture of 0.59 g (5.94 mmol) of copper (I) chloride and 2.4 ml of concentrated hydrochloric acid, which is then heated in a 50 DEG C. bath. After gas evolution has ceased (about 15 minutes), the reaction mixture is poured into a mixture of ice and concentrated ammonia and extracted four times with 100 ml of ethyl acetate. The combined organic extracts are shaken with water, dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 10 /).

Yield: 0.80 g (40% of theory),

Melting point: 137-140 ° C (ether)

Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13

Found: 68.42 7.09 8.06 6.05

In analogy to Example 36, the following compounds were obtained: (a) 4 - [(1- (4-Chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 21.9% of theory,

Melting point: 123-125 ° C

Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13

Found: 68.70 7.18 7.77 6.08 (b) 4 - [(1- (5-Bromo-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 53.8% of theory,

Melting point: 140-142 ° C

Calculated: C 62.27 H 6.63 Br 15.93 N 5.58

Found: 62.39 6.78 15.85 5.59 (c) 4 - [(1- (4-Fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 21.6% of theory, 78477 81

Melting point · 110-112 ° C

Calculated: C 70.88 H 7.55 N 6.36

Found: 71.01 7.53 6.21

In addition, a further 40% of 4 - [(1- (4-Hydroxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester (solid foam) is isolated.

(d) 4 - [(1- (5-Fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 2% of theory Melting point: 127-129 ° C Calculated: m / e = 440

Found: m / e = 440 (e) 4 - [(1- (4-Fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl] -benzoic acid

Yield: 16.9% of theory,

Melting point: 172-175 ° C

Calculated: C 68.73 H 6.55 N 7.29

Found: 68.78 6.62 7.31

Example 37 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbohylmethyl] benzoic acid

Hydrogenate 1.0 g (2.33 mmol) of 4 - [(1- (5-Chloro-2-piperidinophenyl) -1-butyl (aminocarbonylmethyl) -benzoic acid in 40 ml of absolute ethanol at 50 ° C and Under a hydrogen pressure of 5 bar using 0.5 g of palladium / carbon (10%) as catalyst, after 2 hours the catalyst is filtered off through diatomaceous earth and evaporated in vacuo. and evaporated 78477 82 in vacuo.

Rule; 0.61 g {66% of theory),

Melting point: 213-215 · ° 0

calculated; C 73.07 H 7.66 N 7.10

Found: 73.18 7.42 7.27

The same compound is also obtained from the corresponding 4-chloro, 3-chloro or 6-chloro-substituted starting materials.

Example 38 4 - [(1- (4-Methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

To a mixture of 548 mg (11.4 mmol) of sodium hydride (50 in oil) in 10 ml of absolute dimethylformamide is added dropwise, with stirring at room temperature, a solution containing 5.0 g (11.4 mmol) of 4- / (1- (4-Hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 45 ml of absolute dimethylformamide. Stir for a further 15 minutes and then add dropwise a solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of absolute dimethylformamide. Stir for an additional 2.5 hours at room temperature, evaporate in vacuo and partition between water and ether. The ether phase is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 20/1).

Yield: 1.8 g (34.9% of theory),

Melting point: 115-117 ° C

Calculated: C 71.65 H 8.02 N 6.19

Found: 71.47 7.86 6.19

According to Example 38, the following compound was obtained: 78477 83 (a) 4 - [(1- (5-Methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 68.4% of theory ,

Melting point: 142-145 ° C

Calculated: C 71.65 H 8.02 N 6.19

Found: 71.87 8.06 6.38

Example 39 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid (2,3-dihydroxypropyl) ester

A solution containing 2.0 g (5.07 mmol) of 4 - [(1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid and 0.85 g (5.27 mmol) of N, N'-carbonyldiimidazole in 20 ml of absolute tetrahydrofuran is heated at reflux for 1 hour, 3.7 ml (50.7 mmol) of glycerol are added and the mixture is further heated at reflux for 15 hours. Evaporate in vacuo, partition between water and ethyl acetate, dry and filter the organic solution and evaporate in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 1/1).

Yield: 1.1 g (46.2 7, theoretical),

Melting point: 120-122®C

Calculated: C 68.21 H 7.74 N 5.98

Found: 69.23 7.78 5.93

In analogy to Example 39, the following compounds were obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid (2-hydroxyethyl) ester Yield: 40% of theory .

Melting point: 125-127 ° C

78477 84

Calculated: C 71.21 H 7.81 N 6.39

Found: 71.35 7.54 6.33 (b) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid (2-methoxyethyl) ester Yield: 55.9% of theory,

Melting point: 120-123 ^ 0

Calculated: C 71.65 H 8.02 N 6.19

Found: 72.03 8.03 6.24

Example 40 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid (2-nicotinoyloxyethyl) ester

To a stirred solution of 2.0 g (4.56 mmol) of 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid (2-hydroxyethyl) ester in 40 ml in methylene chloride and 0.7 ml (4.81 mmol) of triethylamine, a solution of 0.7 g (4.68 mmol) of nicotinic acid chloride in 20 ml of methylene chloride is added dropwise rapidly. Stir for 2.5 hours at 20 ° C, shake with water, dry and filter and evaporate the organic phase. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 5/1).

Yield: 1.1 g (44% of theory),

Melting point: 132-135ο0

Calculated: C 70.70 H 6.86 N 7.73

Found: 70.82 6.82 7.91

Example 41 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzyl alcohol 78477 85

To a stirred suspension of 0.68 g (17.95 mmol) of lithium aluminum hydride in 25 ml of absolute tetrahydrofuran is added dropwise to OeC at internal temperature a solution containing 5.0 g (11.83 mmol) of 4 - / (1- ( 2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 75 ml of absolute tetrahydrofuran. Stir for 20 hours at room temperature, cool to 0 ° C and slowly add dropwise enough 4 N sodium hydroxide to form a filterable precipitate. Filter and boil the precipitate several times with ether. The combined organic solutions are evaporated in vacuo. The evaporation residue is partitioned between water and ether. The ether phase is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 5/1). Yield: 1.0 g (22% of theory),

Melting point: 152-154 ° C

Calculated: C 75.75 H 8.48 N 7.36

Found: 75.90 8.45 7.28

Example 42 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzaldehyde 6.6 g (62 mmol) of sodium carbonate and 62 ml of ethylene glycol are heated at 170 ° C in a bath and 6.2 g (11 mmol) of N * - / 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoyl] -N3-tosylhydrazine, melting point, are added over 1 minute with vigorous stirring. 195eC (decomposes), where violent gas evolution is observed.

It is then heated for a further 2.5 minutes at 170 ° C and then immediately poured onto ice. Extract with ether, dry, filter and evaporate the ether solution in vacuo. The evaporation residue is purified by column chromatography over silica gel (chloroform / acetone = 20/1).

73477 86

Yield: 2.2 g (52.9% of theory),

Melting point: 1A2-145 ° C

Calculated: C 76.16 H 7.99 N 7, AO

Found: 76.26 7.96 7.37

Example A3 N- (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl) cinnamic acid ethyl ester

To a mixture of 0.60 g (12.5 mmol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide is added dropwise at room temperature a solution containing 2.80 g (12.5 mmol) of diethylphosphonoacetic acid ethyl ester. in ml of absolute dimethylformamide. Stir for 15 minutes (until gas evolution ceases) and then add dropwise a solution containing 2.4 g (6.34 mmol) of 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl]. / -benzaldehyde in 10 ml of absolute dimethylformamide. Stir for 2 hours at room temperature, evaporate in vacuo and partition between water and ether. The ether phase is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 10/1).

Yield: 0.85 g (29.9% of theory),

Melting point: 135-137 ° C (ether / petroleum ether)

Calculated: C 74.97 H 8.09 N 6.2A

Found: 74.91 7.89 6.29

Example AA

A - / (1- (2-piperidino-phenyl) -1-butyl) -aminokarbonyylimetyy-li / cinnamic acid,

Prepared by alkaline saponification according to Example 25 78477 87 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] cinnamic acid ethyl ester.

Yield: 64% of theory,

Melting point: 180-183 ° C,

Calculated: C 74.26 H 7.67 N 6.66

Found: 74.03 7.47 6.80

Example 45 3 - [(4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] phenyl] propionic acid ethyl ester 0.60 g (1.34 mmol) 4 - / ( 1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl / cinnamic acid ethyl ester in 10 ml of ethanol is hydrogenated at room temperature and 5 bar of hydrogen using 0.20 g of palladium / carbon (10%), filtered and evaporated in vacuo.

Yield: 0.53 g (88% of theory),

Melting point: 98-99eC (petroleum ether)

Calculated: C 74.63 H 8.50 N 6.22

Found: 74.64 8.58 6.23

In analogy to Example 45, the following compound was obtained: (a) 3- [4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] phenyl] propionic acid

Yield: 63% of theory,

Melting point: 131-133 ° C

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.96 8.30 6.56

Example 46 3- [4 - / (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] phenyl] propionic acid 78477 88

Prepared according to Example 25 by alkaline saponification of 3/4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] phenyl] propionic acid ethyl ester.

Yield: 50% of theory,

Melting point: I31-133ec

Calculated: C 73.90 H 8.11 N 6.63

Found: 73.82 8.07 6.41

Example 47 4 - [(α-Aminocarbonyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid ethyl ester

To a stirred solution of 2.0 g (4.7 mmol) of 4 - [(α-Carboxy-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid ethyl ester x 0.167 H * 0 mp 156-159 ° C In 20 ml of anhydrous tetrahydrofuran, 0.90 g (5.5 mmol) of N, N'-carbonyldiimidazole are added at 20 ° C and then heated for half an hour in a bath at 80 ° C. It is then cooled oO ^ C-C and supplied at this temperature for half an hour strong stream of dry ammonia. It is then evaporated in vacuo, partitioned between water and chloroform, the combined chloroform extracts are shaken with a small amount of water, dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 5/1).

Rule; 1.0 g (50.2% of theory),

Melting point: 160-162 ° C (acetone)

Calculated: C 68.07 H 6.90 N 9.92

Found: 68.40 6.92 9.84

Example 48 4 - [(α-Cyano-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester 78477 89

To a mixture of 520 mg (1.22 mmol) of 4 - [(α-aminocarbonyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid ethyl ester in 0.22 ml of pyridine is added in two portions 234 mg (1 , 22 mmol) of 4-toluenesulfochloride and heated to 50 ° C. After two hours and an additional hour, equal amounts of pyridine and 4-toluenesulfochloride are added and heated for a further hour at 50 ° C. Allow to stand for 2 days at 20 ° C and then add 2 N ammonia and extract with chloroform. The chloroform solution is shaken twice with water. After drying and filtration, it is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 10/1).

Yield: 325 mg (65.7% of theory),

Melting point: 114-117 ^ 0 (ether / petroleum ether)

Calculated: C 71.09 H 6.71 N 10.36

Found: 70.79 6.56 10.10

Example 49 4 - [(α-Cyano-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid 1.5 g (3.7 mmol) 4 - [(α-Cyano-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester in 15 ml of dioxane and 3.7 ml of 1 N sodium hydroxide are mixed for 45 minutes in a 60 ° C bath and for a further 45 minutes in an 80 ° C bath. After cooling with ice, 3.7 ml of 1N hydrochloric acid are added, the dioxane is evaporated off under vacuum and partitioned between water and chloroform. The organic solution is shaken with a small amount of water, dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (chloroform / ethanol = 5/1). Yield: 0.50 g (£ 35.7 of theory),

Melting point: 176-180 ° C (decomposes) 73477 90

Calculated: C 70.01 H 6.14 N 11.13

Found: 70.02 6.19 11.05

Example 50

4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid x H * SCU

To a solution of 1.0 g (2.53 mmol) of (4 - [(1- (Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid in 50 ml of ethanol is added 5 ml (2.50 mmol) of ) 1 N sulfuric acid, evaporated to dryness in vacuo and triturated with acetone.

Yield: 0.80 g (65% of theory),

Melting point: 192-197eC (decomposes)

Calculated: C 58.53 H 6.55 N 5.69 S 6.49

Found: 58.05 6.54 5.49 6.35

According to Example 50, the following addition salts were obtained: (a) 4 - [(1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid x 0.5 H »SO- * x 1.5 H» 0

Prepared according to Example 50 using half the amount of sulfuric acid.

Yield: 59.3% of theory,

Melting point: 180-185 ° C; decomposes at 207-210 ° C.

Calculated: C 61.26 H 7.28 N 5.95 S 3.40

Found: 61.28 6.99 6.10 3.23

Claims (2)

73477 Claim A process for the preparation of pharmacologically useful phenylacetic acid derivatives of the formula I is - NH - CO - CH, - ^ 'Vw <I) "<X ·, ^ wherein A is a group of the formula Rs R« * .Ro 1 H -CH- or | -C-, wherein R 5 is an alkyl group having 1 to 3 carbon atoms substituted by an alkoxy group having 1 to 3 carbon atoms or a phenyl group, an n-propyl group having an alkyl group having 4 to 7 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, cyano - or an alkyleneiminocarbonyl group having 4 to 6 carbon atoms, optionally an alkyl or phenylalkyl group having 1 to 3 carbon atoms, a mono- or disubstituted aminocarbonyl group, halogen atoms, alkyl, hydroxy, alkoxy, phenylalkoxy- , alkylsulphenyl, alkylsulfinyl and / or alkylsulphonyl groups mono- or disubstituted phenyl group, the substituents may be the same or different and each contains 1 to 3 carbon atoms in the alkyl moiety, a naphthyl group or a pyridyl group, and a R3 may also be a methyl group when R1 is a piperidine group and Ra is a fluorine atom in the 4-position and W is a carboxy or alkoxycarbonyl group in which the alkyl moiety contains 1 to 3 carbon atoms, or R9 may also be a phenyl group when Rt is substituted in the 2-3 position by a methyl group a piperidine group, Ra is a hydrogen atom and W is a carboxy or alkoxycarbonyl group in which the alkyl moiety contains 1 to 3 carbon atoms or, when R1 is a piperidine group, RA is a chlorine atom in the 3-, 4- or 6-position or a 4- or 6-position and W is a carboxy or alkoxycarbonyl group having 1 to 3 carbon atoms in the alkyl moiety, or when R 1 is a piperidine group, R 6 is a hydrogen atom and W is a formyl group, a 2-carboxyethenyl or 2-alkoxycarbonylethenyl group having 1 to 3 alkyl moieties. 3 carbon atoms, R * and R 5 together with the carbon atom between them is an alkylidene group having 3 to 9 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety, R 1 is optionally 1 to 3 carbon atoms a mono- or disubstituted unbranched alkyleneimino group having 4 to 9 carbon atoms, Ra being a hydrogen, fluorine, chlorine or bromine atom, hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl or an alkoxy group, wherein the alkyl moiety each contains 1 to 3 carbon atoms, and W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, and the alkyl moiety may be substituted with a phenyl group and (from 3 carbon atoms with one or two hydroxyphenyl groups, one alkoxy, alkanoyloxy, a dialkylamino, alkyleneimino or pyridinecarbonyloxy group, each alkyl moiety each containing 1 to 3 carbon atoms and an alkyleneimino group having 4 to 6 carbon atoms, an alkenyloxycarbonyl group having a total of 4 to 6 carbon atoms, an alkyl group having 1 to 3 carbon atoms, hydroxymethyl , formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, 2,2-bis- (carboxy) ethyl, alkoxycarbonylmethyl a yl, 2-alkoxycarbonyl-ethyl-, 2-alkoxycarbonyl-ethenyl or 2,2-bis- (alkoxycarbonyl-73477-yl) ethyl group, the alkoxy group in each case containing 1 to 3 carbon atoms, and their optically active antipodes and their salts , in particular their physiologically acceptable acid addition salts with inorganic or organic acids or bases, characterized in that a) the amine of the general formula II is A - NHO 2 (II) R! wherein A, R 1 and Ra have the same meaning as above or, when A represents the vinylidene group already mentioned, its tautomer, its lithium or magnesium halide complex, is reacted with a carboxylic acid of the general formula IIi HO - CO - CH 2 - <f V "· \ == / (III) wherein W 'is the same as above or a carboxyl group protected by a protecting group, or with reactive derivatives thereof optionally prepared in the reaction mixture and, if necessary, the protecting group used is cleaved, or b) a compound of general formula I wherein W is carboxy, carboxymethyl, 2- carboxyethyl or 2-carboxyethenyl group, for the preparation of a compound of general formula IV ^ A - NH - CO - CH0 ”“ \ B -O, ^ ”78477 wherein R1, Ra and A have the same meaning as above and B is a group which can be converted carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, converted to the corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis, or c) the general formula for the preparation of a compound of formula I wherein A is a group of formula R »'- <?: H - wherein R3' is the same as Ra above except for an alkenyl group or a cyano group - a compound of general formula V - CO - CH2 J ~ \ w wherein Ra , Ra and W have the same meaning as above and D is a group of formula Ra "FU 'R«' - ^ tal N - - C ^ N - i H wherein Ra "has the same meaning as Ra above except for the cyano group and R * 'and Re 'together with the intervening carbon atom denotes a propylidene group, an alkylidene group having 4 to 6 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety, reduced by 78477 hydrogen in the presence of a hydrogenation catalyst, or d) for compounds of general formula I cyano group, for the preparation of a compound of general formula VI - V - OH - CX, in which R1, Ra and Ra "have the same meaning as above to react in (\) (VII) N = C - CH 2 --y — w where M is as defined above, or e) compounds of general formula I in which Ra is a hydrogen atom and A is a group of the formula Ra - CH - in which Ra is the same as above, the halogen atom is removed from the compound of general formula VIII ^ A - NH - CO - CH ~ -M \ S- W Hal_ | 0 £ 2 \ = / wherein R 1, A and U have the same meaning as above and Hal is fluorine- , 78477 chlorine, bromine or iodine atoms, or f) compounds of the general formula I in which A is a group of the formula R®-CH in which Eta is an alkylene-aminocarbonyl group having 4 to 6 carbon atoms in the alkylene ring, or optionally alkyl - or with phenylalkyl groups in each case having 1 to 3 carbon atoms in the alkyl moiety, a mono- or disubstituted aminocarbonyl group is prepared by oxidizing a compound of the general formula XI COOK * · <E 2 "- wherein R 1 and R 2 have the same meaning as above and W" has the same meaning as W except carboxy, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl or 2,2-bis- (carboxy) ethyl group, is reacted with an amine of general formula X H - Re (X) wherein EU is an alkyleneimino group having 4 to 6 carbon atoms or optionally alkyl - or phenylalkyl groups in each case having 1 to 3 carbon atoms in the alkyl moiety, a mono- or disubstituted amino group, or g) for the preparation of compounds of general formula I in which W is a carboxy group, a compound of general formula XI is oxidized 73477 h 'Wherein R 1, R a and R a are as defined above and E is a group which can be converted to a carboxy group by oxidation, or h) compounds of general formula I in which W is an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the alkyl moiety can | - from a carbon atom to be substituted by one or two hydroxy groups or one alkoxy group having 1 to 3 carbon atoms, for the preparation of a carboxylic acid XV A - NH - CO - CH2 y-COOH -.- a ,, w wherein R 1, R 2 and A have the same meaning as above, or a derivative thereof optionally prepared in the reaction mixture is esterified with an alcohol of general formula XIII HO - RT- (XIII) wherein R 1 is an alkyl group of 1 to A carbon atoms which may be substituted from 1 to 2 by one or two hydroxy groups or one An alkoxy group having 1 to 3 carbon atoms, or i) a compound of general formula I in which W is an alkoxycarbonyl, alkoxycarbonylacetyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group and A is a group of the formula R CH - 78477 wherein Ra "has the same meaning as Ra above except for the cyano group, for the preparation of a compound of general formula XIV - NH - CO - ch2-v y-W'm --CX, wherein R", R2 and Ra "have the same meaning as above and W "'is a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethenyl group, is converted by alcoholysis to the corresponding ester, and then, if desired, a compound of general formula I obtained according to the invention, wherein W is a carboxy or alkoxycarbonyl group is converted by reduction to the corresponding compound of general formula I wherein W is a formyl or hydroxymethyl group and / or a compound of general formula I according to the invention wherein W is a carboxy group is first converted to sulfonic acid hydrazine and then by disproportionation to the corresponding compound of general formula I in which W is a formyl group and / or the compound of general formula I in which W is a formyl group obtained according to the invention is converted by condensation and optionally followed by hydrolysis and / or decarboxylation to the corresponding compound of general formula I in which W is 2- an alkoxycarbonyl-ethenyl or 2-carboxy-ethenyl group, and / or a compound of general formula I obtained according to the invention in which W is a 2-carboxy-ethenyl or 2-alkoxycarbonyl-ethenyl group is catalytically converted by hydrogenation to the corresponding compound of general formula I, wherein W is 2-carboxyethyl- or a 2-alkoxycarbonyl-ethyl group, and / or a compound of the general formula I obtained according to the invention in which W is an alkoxycarbonyl group substituted by a hydroxy group from the β-carbon atom, converted by acylation with a pyridinecarboxylic acid to the corresponding (pyridinecarboxy) oxy / or a compound of general formula I according to the invention in which W is a hydroxymethyl group is first converted into the corresponding halomethyl compound and then reacted with a malonic acid diester to give the corresponding compound of general formula I wherein W is an ethyl group substituted by two alkoxycarbonyl groups, and / or wherein W is an ethyl group substituted by two alkoxycarbonyl groups is converted by hydrolysis to the corresponding compound of general formula I in which W is an ethyl group substituted by two carboxy groups, and / or according to the invention the obtained compound of general formula I in which W is an ethyl group substituted by two alkoxycarbonyl groups is converted by hydrolysis and decarboxylation into the corresponding compound of general formula I in which W is a 2-carboxyethyl group. and / or the compound of the general formula I in which R2 is an amino group obtained according to the invention is converted via the corresponding diazonium salt into the corresponding compound of the general formula I in which R2 is a hydrogen, fluorine, chlorine or bromine atom, a hydroxy, alkoxy or alkylsulphenyl group, and / or a compound of the general formula I obtained according to the invention, wherein R 2 is a benzyloxy group and / or R 3 is a benzyloxy-substituted aryl group, is converted by removing the benzyl group into the corresponding compound of the general formula I in which R 2 is a hydroxy group and / or R 3 is a hydroxy-substituted aryl group, and / or the compound of general formula I according to the invention in which R3 is an aminocarbonyl group is converted by dehydration into the corresponding compound of general formula I in which R3 is a cyano group and / or the compound of general formula I according to the invention if it contains a chiral center is separated by chiral chromatography enantiomers and / or a compound of the general formula I obtained according to the invention is converted into its salts, in particular its physiologically acceptable salts with inorganic or organic acids or bases. 78477 A compound for the preparation of a pharmacologically active compound with a phenylplate derivative having the formula A - NH - CO - CH, - ^ \ VW (I> *> <x, which is a group A with the formula r3 V / * · - CH - or J 1 - C - colors R 1 is en with 1 to 3 cholera alkoxy groups or phenyl groups substituted with alkyl groups 1 to 3 cholera atom n-propyl groups 4 to 7 cholata alkyl groups * 3 to 5 cholate alkenyl groups; - with alkyleniminocarbonyl group having 4-6 cholatomers, optionally with alkyl- or phenylalkyl group, with alkyl group having 1-3 cholatomers, mono- or disubstituted aminocarbonyl group, with halogen atom, alkyl-, hydroxy-, alkoxy-, phenylalkoxy -, alkylsulphenyl-, alkylsulphinyl- and / or alkyl-sulphonyl groups mono- or disubstituted phenyl groups, colors substituted with residues or ola ooh i alkyldelen i respektive fall inneh &lla 1-3 cholatomers, en naphthyl groups or pyridyl groups, or R3 methyl group, dd R ^ är en piperidingrupp och R ^ är in fluorine and 4-ethyl and carboxy-alkoxycarbonyl groups, in which 1-3 cholaters, or in the case of R 2 -alkyl, in the case of 2 to 3-methyl groups in the same group -produced piperidino group, which Rg en väteatom och V V en en carboxy- or alkoxycarbonylgroup, i vilken alkyldelen innehäller 1-3 78477 cholatomer or d & R1 is piperidinogroup, är Rg en i 3-, 4-eller 6-ställning belägen methylylupp och W a carboxy or alkoxycarbonyl group having 1-3 cholaters of an alkyl group, or a R1 group having a piperidino group, a R8 en a hydrogen atom and a formyl group, a 2-carboxyethenyl or a 2-alkoxycarbonylethyl group having 1 to 3 cholatomic alkyl groups, R and R is preferably an alkylidene group having an alkylidene group of 4 5 to 3-9 colatomers or a phenylalkylidene group having 1-3 colaters, R is an optionally alkyl group having 1-3 colaters mono- or disubstituted with an alkyleneimino group of 4-9 colaters, Rg is en fertilizer, fluorine, chlorine or bromide, en hydroxy-, trifluoromethyl-, nitro-, amino-, piperidino-, alkyl- or alkoxy groups, varvid alkyldelen i respektive fall inneh & ller 1-3 cholatomers, och W är en carboxygroup or en alkoxycarbonylgroup with the same 2-5 cholatomers and wherein the alkyl group may be substituted with a phenyl group and a hydrogen group with a ft atom having a TV & hydroxy phenyl group, an alkoxy, alkanoyloxy, dialkylamino, alkylene imino or pyridinecarbonyloxy group, varvid varje alkyldel i respektive fall innehäller 1- 3 cholatomers and alkylenimino groups 4-6 cholatomers, and alkenyloxycarbonyl groups with the same 4-6 cholatomers, en 1-3 cholate alkyl groups, en hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl -, 2-carboxyethenyl, 2 ', 2-bis- (carboxy) ethyl, alkoxycarbonylmethyl, 2-alkoxycarbonylethyl, 2-alkoxycarbonylethenyl (or 2,2-bis-Calcoxycarbonyl) ethyl, color alkoxy groups and respectable fall inneh & ller 1 - 3 cholaters, as well as optically active antipoders and salts sa, speciellt deras 78477 physiologically heated by the addition of an organic or organic syrup or a base, which is shown in Figure a) Amin med den allmänna formeIn II h2'm2 (n> 2 \ ARi där A, R och R avser samma som ovan eller, d A reddish such vinyl group, a tautomer, a lithium or a magnesium halide complex, a ring-reactant with a carboxylic acid in the form of all forms III HO - CO - CH2 i \ r \ === / (III) där If the same group is used in the case of a reaction group with a carboxyl group, or if the reaction group is optionally used as a reaction group, the reaction group is derived from the reaction group, or (b) for the purpose of the reaction group, en carboxy-, carboxymethyl-, 2-carboxyethyl- or 2-carboxyethenyl groups, which are used for the preparation of all forms IV- - NH - CO - CH, "V y- B 2 \ = / iiv) 104 78477 for R1, R2 and A are selected from the group consisting of the same group as in the case of for the purposes of carboxy-, carboxymethyl-, 2-carboxyethyl- or 2-carboxyethenyl groups, for which the carboxy-derived genomic hydrolyses, thermolyses or hydrogenolyses, or c) are used for the preparation of the compounds of formula I, K - CH - varv R3 * of the same group as R is an alkenyl group or a cyano group, reducers and derivatives of the lower form VD - CO - CH- -MW * · <χ „^» for Bj * Rg and W of the same group The group consisting of R "RV ^, RV - \ tai - - C ^ N - i H varvid Ry * avser samma som R ^ ovan fr & nsett cyanogroupen and Ry och R ^ tillsammans med den mellanliggande kolatomen avser en -.propyldengrupp, en 4 - 6 alkyl groups having 1 to 3 alkyl atoms with 1 to 3 carbon atoms, having a mixture of 78477 hydrogensation catalysts, or d) forming a compound of the same form as the first of the formula I, wherein R is the same as the cyano group, bringas en förening med den allmänna formeln VI r *, 3 - OH - <χ där R ^, R2 och Ry is the same as in the case of a reactant having the same formula VII (VII) n sr c - ch2 — vy— w d a W avser samma som ovan , or (e) for the preparation of a compound of formula I, for which R is a compound of formula A and A for a group of formulas b - CH - for a mixture of a compound of formula VIII - NH - CO - CH2 W Hal (VIII) -där, A och W avser samma som ovan och Hal är en fluor-, Lei or-, 73477 bromo- or iodatom, eller f) förställning av föreningar med den allmänna formuleln I, h - CH - , Wherein R 1 is an alkyleniminocarbonyl group having 4-6 cholaters in an alkylene ring, or an alkylenyl or phenylalkyl group optionally having 1-3 cholatomic mono- or disubstituted aminocarbonyl groups in the form of a compound having the formula IX • 00H »> <X, ^ ™ där och R2 avser samma som ovan ooh W ”avser samma som W ovan fr & n-set carboxy-, carboxymethyl-, 2-carboxyethyl-, 2-carboxy-et enyl or 2,2-bis-carboxy) ethyl group, a ring or a reagent with an amine having the formula XH - Rg (X) to Rg is an alkyleneimino group having 4 to 6 carbon atoms or an optional alkyl or phenylalkyl group with a reactive fall of 1-3 a chelate atom having a mono- or amino-disubstituted amino group, or (g) a compound having a compound of formula I, wherein W is a carboxy group, an oxide having a compound of formula XI '* 3 - NH - CO - CH2 -v yE' ' CX, wherein R1, Rg and the group consisting of an oxy group or an E group, wherein the genomic oxidation can be carried out on a carboxy group, or h) for the preparation of a compound having the same form in Form I, a group having an alkoxycarbonyl group in the same group 2 -5 carbon atoms and one week alkylated at the end of the reaction group with a hydroxyl group or an alkyl group of 1 to 3 carbon atoms, for the carboxyl group with all of the compounds of formula III in which R2 and A are further formed, or dess eventually in response to blandninge N-derivatives of the formula XIII HO - R7 (XIII) are substituted with 1 to 4 alkyl groups, which may be substituted with hydroxyl groups or with 1 to 3 alkyl groups, or i) for the preparation of a compound of formula I, wherein W is an alkoxycarbonyl, a-alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or a 2-alkoxycarbonyl-ethenyl group and a group of the formula "3-CH - 78 ^ 77 108 'ϋ' 'for R3 is selected from the group consisting of R cyano groups, which are present in the form of all forms XIV ^ - NH - CO - CH2- ^ W "-oc, ^ - for R ^» R2 and Ry the same is used for the preparation of cyano-, cyano-methyl-, 2-cyanoethyl- or 2-cyanoethenyl groups, genomic alcohols which are present within the meaning of the present invention, for example in the form of VT is a carboxy- or alkoxycarbonyl group, genomic reduction to a maximum of in which all of the compounds of formula X, in which W is a formyl or hydroxymethyl group, and / or in which all the compounds of formula I, in the case of a carboxy group, are used in the form of a sulfone-cyano-hydrazine and other genome disproportion For a compound of formula I, which is a formyl group, and / or a mixture of compounds of formula I, is used for the formulation of a group, the genomic condensation and eventual addition of a genome of hydrogenation and / or hydrogen for the purposes of formula I, for which 2 are alkoxycarbonyl-ethenyl- or 2-carboxy-ethenyl groups, and for the further addition of compounds of formula I, for which 2-carboxy-ethenyl- or 2-carboxy-ethenyl- -alkoxycarbonyl-ethenyl group, having a genomic catalytic hydrogenation of a compound of formula I, which is 2-carboxy-ethyl- or 2-alkoxycarbonyl-ethyl group, och / el In particular, the addition of compounds of formula I, such as the alkoxycarbonyl group, which results in the substitution of an A-group by a hydroxyl group, the addition of a genomic acylating agent with the form of pyridinecarboxylic acid, the addition of Cypyridicarboxylic acid or in the case of the addition of compounds having the formula I, which in the case of a hydroxymethyl group, for which halogenated methylation and a further ring are used to react with a malonuclear ester in the form of a mixture of the formulation I, an ethyl group, and / or an enrichment in the form of a compound of formula I, in which the alkoxycarbonyl group is substituted by an ethyl group, the evolution of the genomic hydrolysis account in the case of a group of compounds of formula I, in which case substituents on the ethyl group and / or the enriched compound The compound of formula 1, wherein W is an alkoxycarbonyl group substituted with ethyl, is converted to a genomic hydrolysis and decarboxylation account for the preparation of a compound of formula I, which is a 2-carboxy-ethyl group, and / or For the purposes of all forms of formula I, wherein R 1 is an amino group, the intermediate genome and the diazonium salt form are used for the form of form I, for which Kg is selected from the group consisting of v -, alkoxy- or alkylsulphenyl groups, and / or the enriched compounds of the same group