CS240970B2 - Process for preparating substituted phenylalkylamides ofphenylacetic acid - Google Patents

Abstract

Die vorliegende Erfindung betrifft neue Phenylessigsäure-Derivate der allgemeinen Formel in der
R₁ bis R₃, A und W wie im Anspruch 1 definiert sind, deren optisch aktive Antipoden und deren Salze, insbesondere deren physiologisch verträgliche Säureadditionssalze, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine blutzuckersenkende Wirkung.

Die Verbindungen der Formel I können nach für analoge Verbindungen üblichen Verfahren hergestellt werden.

Description

A process for the preparation of substituted phenylalkylamides of a substituted phenylacetic acid of the formula I

their optical antipodes and their salts, in particular their physiologically tolerable addition salts with inorganic or organic acids or bases, in which the amine of the formula II or its tautomer or its lithium or magnesium halide complex is reacted in a solvent with the carboxylic acid of the formula III or with its reactive derivative, optionally prepared in the reaction mixture, and the protecting group used, are optionally cleaved, whereupon optionally the individual substituents in the resulting product are exchanged with each other and / or the resulting product is optionally separated into individual enantiomers or converted into a salt.

The compounds produced exhibit valuable pharmacological properties, in particular a metabolic effect and, above all, lower blood sugar levels.

/AND/

240970 '' ·. . 2 / ’., <

The present invention describes novel phenylacetic derivatives. of an acid of formula I

their anantiomers. and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, a process for the preparation of these compounds and - medicaments containing the said compounds as active substances.

These novel compounds exhibit valuable faxological properties, in particular a metabolic effect, but preferably lower blood sugar levels.

In the above general formula - I

A represents the remainder of the formula

R. Rc '-Λ'

I ·

-CH- or -Cwhere

R 4 is C 1 -C 3 alkoxy or phenyl substituted C 1 -C 3 alkyl, n-propyl, C 4 -C 6 alkyl, C 3 -C 5 alkenyl, cyano, aminocarbonyl, aryl of 6 or - 10 carbon atoms, optionally mono- or di-substituted halogen atoms, - alkyl, hydroxyl, alkoxy, phenylalkoxy and / or electrolysthenyl groups, the substituents may be the same or different and their individual alkyl moieties may each contain - from 1 to 3 carbon atoms, or represent a naphthyl, pyridyl, quinolyl or isoquinolyl group, ^{R 5} - and may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; - up to 5 carbon atoms or ^r 5 ^{and R} 6 together with the carbon atom which is between them form a phenylalkylidene group having 1 to 4 carbon atoms in and Alkylidern parts

R 1 is optionally alkyl groups having from 1 to 3 carbon atoms mono- or disubstituted unbranched alkyl groups having from 4 to 9 carbon atoms or a dialkyl amino group containing each. - alkyl of 1 to 5 carbon atoms, in each case 1 to 5 carbon atoms,

R2 represents a hydrogen atom, a fluorine, chlorine or bromine atom, a nitro group, an alkyl or alkoxy group containing from 1 to 3 carbon atoms, or also when R and R6 are as defined above and R4 represents an alkoxy group; C 1 -C 3 or phenyl substituted C 1 -C 3 alkyl, h-propyl, C 4 -C 6 alkyl, C 3 -C 5 alkenyl, nitrio or aminocarbonyl represents R ₂ is an iodine atom, a hydroxyl group or an amino group; R 3 represents an alkyl group having 1 to 3 carbon atoms; a hydrogen atom, or a halogen atom, and

W- represents a methyl group, a hydroxymethyl group, a formyl group, a cyano group, a carboxyl group, a carboxy group, a 2-carboxyethyl group,

A 2-carboxycythenyl group, an alkoxycarbonyl group having a total of 2 to 5 atoms. in which the alkyl moiety is optionally substituted by one or two hydroxyl groups, a C1 -C3 alkoxy group or a pyridine carbonyloxy group from the .beta.-carbon optionally substituted by. it is furthermore an alkoxycarbonylmethyl group, a 2-alkoxycarbonylethyl group or a 2-alkoxycarbonylethenyl group, the alkoxy groups in each case having 1 to 3 carbon atoms.

Possible radicals in the meaning of R3 and Rg and 'W' as defined above are, for example:

for R 1, dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-n-pentylamino, diisobutylamino, N-methylethylamino, N-methyl-n-propylamino, N-methylisopropylamino, n-isopropyl N-isobutyl-n-propylamino, N-methyl-n-butylamino, N-ethyl-n-butylamino, N-ethylisopropylamino, N-ethyl-n-pentylamino, N-propyl-n-butylamino, pyrrolidino, piperidino, hexamethylene, heptamethyleniminoskupina, oktamethyleniminoskupina, nonamethyleniminoskupina, methylpyrrolidinoskupina, dimethylpyrrolidinoskupina, ethylpyrrolidinoskupina, methylpiperidinoskupina, ethylpiperidinoskupina, dimethylpiperidinoskupina, diethylpiperidinoskupina, methylethylpiperidinoskupina, n propylpiperidinoskupina, methyl n-propylpiperidinoskupina, isopropylpiperidinoskupina or di-n-propylpiperidinoskupina for R ₂ is hydrogen, fluorine, chlorine, bromine or iodine, methyl groups pin, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro or amino, for R 3 is hydrogen, fluorine, chlorine or bromine, methyl, ethyl, n-propyl or isopropyl, for n-propyl, n-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3 -methoxypropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenyl-n-propyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl, 3-buten-1-yl a group, 2-buten-1-yl, 4-penten-1-yl, cyano, aminocarbonyl, phenyl, taftyl, fluoro-4-yl, chlorophenyl, bromophenyl group, muthylfetylová group ethylfetynová group isopropylfetynovO group hydroxyfutynolO group mubhoxyfunynolá group ebhoxyfetylolá group, n-propoxyphenyl group, butzyloxyfutynová, 2-fetynebhoxyfutylová group 3efetylpropoxyfenylová group muthylsunfutylfetynolá group ethylsulfunynfenylolá group mebhylnafbynolO group hydroxytafbynová group, muthoxynaftylolá group , dichlorophenyl, chlorobromophenyl, dimethynphetylolO, diisopropylphenyl, chloromethylphenyl, dimubhoxyfutyn, methyl-mubhoxyfutyn, chloromethoxyfunyl, bromomethoxyphenetnol, pyridylol R, isoquinolyl or quinolinyl; , methyl, ethyl, t-propyl, isopropyl, isobubyl, isobubyl, sec-butyl or n-pentyl, for Rg and Rg together with carbon an atom located between these symbols: benzynidetone, 1-fetyluthynidetone, 2-ethylmethynidonol, 1-ethyl-2-propylidiethyl, 1-phenyl-2,2-propylidiethyl or 3-phenyl-n-propylidene and for W, hydroxymethylbenzyl, , carboxymubhynol, 2ecarboxyebhyn, 2-carboxyuthenyl, mutoxycarbonyl, ethoxycarbonyl, t-propoxycarbonyl, isopropoxycarbonyl, or butoxycarbonyl, isobutoxycarbotyl _| (2-hydroxyuthoxy) carbonyl, (2-hydroxy-n-propoxy) carbotyl, (1-hydroxy-2-propoxy) carbotyl, oxyebhoxy / carbotyl, (2-ethoxyebhoxy) carbonyl, (2-n-propoxyethoxy) carbonyl, (2-nicotinoyloxyethoxy) carbonyl, (2-isonicotinoyloxyethoxy) carbonyl, (2,3-dihydroxy-n-propoxycarbonyl, methyl, cyano, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, 2-methoxy -ethoxycarbonylethyl, 2-isopropoxycarbonylethyl, 2-methoxycarbonylethenyl, 2-ethoxycarbonylethenyl or 2-n-propoxycarbonylethenyl.

Preferred compounds of the invention are those compounds of formula (I) above wherein:

A, R ₂ and W are as defined above,

R ^ represents a straight-chained (C až-C 8 alky) alkyleneimino group or a C alkyl alkyl-C alkyl alkyl alkyl group having a mono- or di-substituted piperidino group, and

R ₃ represents a hydrogen or chlorine atom;

4- [N- (6-chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid and its alkyl esters of 1 to 3 carbon atoms,

3- [4- [ _N - [alpha] -phenyl-2-piperidinobenzyl] aminocarbonylmethyl] phenyl] propionic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (4-chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (3-chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (6-methyl-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (4-methyl-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (2- (2-methylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N- (2- (3-methylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [N - (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde,

4- [1- (4-fluoro-2-piperidinophenyl) ethyl / aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms,

4- [1- (3-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid and its alkyl esters of 1 to 3 carbon atoms; and

4- [1- (3-methyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid and its C1-C3 alkyl esters, in particular those compounds of formula I in which:

A represents the remainder of the formula

- OR where

R @ 1 represents methoxy or phenyl substituted C1-C3 alkyl, n-propyl, cyano, aminocarbonyl, C4-C6 alkyl, C3-C5 alkenyl, fluorine, chlorine or chlorine; bromine, methyl, hydroxy, methoxy, benzyloxy or methylsulfenylovou substituted phenyl or pyridyl, and? 5 ^and? 6 ^P ° ^{gether with the} carbon atom located between the two symbols form an alkylidene group having 3-9 carbon atoms or fenylaikylidenovou group 1 to 3 carbon atoms in the alkyl moiety,

R ₁ is an unbranched alkylene- with 4-8 carbon atoms, piperidino or phenyl mono- or disubstituted by methyl, represents hydrogen, fluorine, chlorine, bromine, methyl or methoxy, or else, if they have R and R defined above and is methoxy or phenyl substituted alkyl of 1-3 carbon atoms, n-propyl, a nitrile group or an aminocarbonyl group, an alkyl group with 4-6 carbon atoms or alkenyl of 3 to 5 carbon atoms, R represents ₂ an iodine atom, hydroxy or amino, represents a hydrogen atom or a chlorine atom;

W represents methyl, hydroxymethyl, formyl, cyano, carboxyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonyl having a total of 2 to 5 carbon atoms in which the alkyl moiety may be substituted by the beta-carbon one or two hydroxy, C 1 -C 3 alkoxy or pyridinecarbonyloxy, alkoxycarbonylmethyl, 2-alkoxycarbonylethyl or 2-alkoxycarbonylethenyl, the alkoxy groups may each contain 1 to 3 carbon atoms and

4- [N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid and its alkyl esters of 1 to 3 carbon atoms,

240970., 6

4- [N / 3 "chloro-.alpha.-phenyl-2-piperidinobenzyl / ^{aminocarbonylmethyl]} benzoic acid and its alkyl esters having 1-3 carbon atoms, ^{4- [N} / methyl ^{methyl 6- alpha-LF} and phen ^yl - ² - ^p iperidinobenz ^yl / ^b aminocarbonyl he ^hylJ meth ^{yl benzoic Lin kY} aa its alkyl esters having 1-3 carbon atoms;

4- (N / 4-methyl "alpha-phenyl-2-piperidin Benzyl ^b / miinokarbonylmethylJ benzoic acid and its alkyl esters having 1-3 carbon atoms, ^4- [N ^- / ² - / 2-meth ^{YIp p} i eri ^d amino / -al ^f a- ^f en ^b enz ^y l ^y l / <Mnino ^to he ar ^{b y} hnethy; l ^b enzoová acid and its alkyl esters having 1 to 3 carbon atoms, ⁴ - [Nal2- / ^{3-methylthiophenyl} l ^{piperidino and} amino / -al ^f a- ^{f? lb} en enz ^y l / ^b ar ^to amino on meth ^yl enzoov ^y ^ ^{b and k y} are ^L INA and its alkyl esters having 1-3 carbon atoms, ^4- [N ^{- /} a ^LF and ^{-f en-2-yl p} i ^p er ^id ino ^b enz ^yl / ^{amino for} r ^b on ^y lmet.h ^yj enzal ^{b d} e ^{hyd, 4} - [/ l- / 4- ^fluoro-2 - ^p i ^{p d} eri inofen ^yl / eth ^yl / Arbon ^yl amine ^to meth ^{yl] b} enzoov Selina ^{s ky} and its alkyl esters having 1-3 carbon atoms;

4 - [/ L- / 3-chloro-2 and ^{IP p} eridinofenyl / ethyl / ^{amino to} Arbon ^pyran-y l] ^b enzoov ^{sic y} ina ^l and its alkyl esters having 1-3 carbon atoms and

4 - [/ L- / 3-meth ^{yl-2- p} i ^p l ^y eridinofen / et ^hy l / ^b ar ^to amino they ^{methylthiophenyl l} l] enzoov ^{b and k y} ^ is on and its ^lower alkyl esters having 1 to And their salts, in particular their physiologically tolerable salts with inorganic or organic acids, or bases.

Another preferred group of compounds of the invention are those compounds wherein A, R ₁ to R 3 and W are as defined above, especially those in which:

W represents a carboxyl group or an alkoxycarbonyl group containing up to 5 carbon atoms in total, wherein the alkyl moiety may be substituted by one or two hydroxy groups as well as their optically active antipodes and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases.

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

A represents the remainder of the formula

C _H. -ch where ^; R R represents n-propyl, alkyl of 4 or 5 carbon atoms, methyl, fluoro or chloro substituted phenyl or pyridyl and

R ₅ and R 8 together with the carbon atom between these symbols form an alkylidene group of 3 to 5 carbon atoms or a phenylalkylidene group of 1 to 3 carbon atoms in the alkylidene moiety.

R2 denotes an optionally by one or two methyl groups substituted piperidino, ^R5 \ _c / ⁶ * i ', or

R 6 represents a hydrogen atom and

W 'represents a carboxyl group or an alkoxycarbonyl group having a total of at least 4 carbon atoms, and in particular those of the formula I in which:

A represents the remainder of the formula

- OR

where

R ₄ represents n-propyl or alkyl having 4 or 5 carbon atoms and

R ₅ and R 8 together with the carbon atom between them represent an alkylidene group having from 3 to 5 carbon atoms or a phenylalkylidene group having from 1 to 3 carbon atoms in the alkylidene moiety, their optically active antipodes and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases.

In accordance with the invention, the aforementioned novel compounds are prepared by producing an amine of formula (II) in which:

(II), ^R1

A, and R ₂ are as defined above, or, if the aforementioned vinylidene group is also mentioned, its tautomer or its lithium or magnesium halide complex is reacted with a carboxylic acid of formula III

(III), in which

R ₃ is as defined above and

W 'is as defined above for W, or represents a carboxyl group protected by a protecting group or a reactive derivative thereof prepared in a reaction mixture, optionally followed by cleavage of the protecting group used.

Suitable reactive derivatives of the compound of the formula (III) are, for example, its esters, such as methyl, ethyl or benzyl ester, its thioesters, such as methylthio or ethylthioester, its halides, such as the corresponding acid chloride, its anhydrides or imidazolides.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or climethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, for example ethyl chloroformate, thionyl chloride, phosphorus trioxide, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N-dicyclohexylcarbodiimide with N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N-thionyldiimidazole, or a combination of triphenylphosphine-carbon tetrachloride, or an amine activating agent and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which base may also serve as a solvent at a temperature of -25 to 250 ° C, preferably at a temperature of -10 ° C to boiling point. used solvents.

However, the reaction may also be carried out without solvent, and water formed during the reaction may be removed by azeotropic distillation, for example by heating with toluene under a reflux condenser equipped with a water separator, or by the addition of a drying agent such as magnesium sulfate or molecular sieves.

The optional deprotection is preferably carried out hydrolytically, preferably 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, aqueous ethanol, aqueous isopropanol or aqueous dioxane, at -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture.

The tert-butyl residue, optionally used as a protecting residue, can also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

In addition, the benzyl residue used as a protecting group can also be removed by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium on activated carbon in a suitable solvent such as methanol, ethanol, aqueous ethanol, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

In the compound of formula (I) in which W represents a carboxyl group or an alkoxycarbonyl group, it may be reduced to give the corresponding compound of formula (I) in which W is a formyl or hydroxymethyl group and / or a compound of formula (I), wherein W is a carboxyl group, optionally by conversion to an acid hydrazide followed by disproportionation, is converted to the corresponding compound of formula I wherein W is a formyl group and / or optionally a compound of formula I wherein W is a formyl group by condensation and optionally by subsequent hydrolysis and / or decarboxylation to convert to the corresponding compound of formula I wherein W is 2-alkoxycarbonylethenyl or 2-carboxyethenyl and / or optionally a compound of formula I wherein W is 2-carboxyethenyl or 2-a converted by a catalytic hydrogenation to the corresponding compound of formula I in which W represents a 2-carboxyethyl or 2-alkoxycarbonylethyl group and / or optionally a compound of formula I in which W represents an alkoxycarbonyl group substituted by a beta-carbon hydroxy group acylation pyridine carboxylic acid to the corresponding / ругidinkarbonyloxyalkoxy / carbonyl compound of the formula I and / or optionally a compound of formula I wherein R ₂ is a nitro group by reduction into the corresponding compound of formula I in which R ₂ is amino, and / or optionally converting a compound of formula I wherein R ₂ is amino via an appropriate diazonium salt to the corresponding compound of formula I wherein R ₂ is hydrogen or halogen, hydroxy, alkoxy or alkylsulfenyl and / or optionally converting a compound of formula I wherein r ₂ is hydroxy by alkylation to the corresponding compound of formula I wherein R ₂ is alkoxy, and / or optionally a compound of formula I wherein R 1 is aminocarbonyl by dehydration converts to the corresponding compound of formula I wherein R ₄ is cyano.

The additional reduction is preferably carried out by treatment with a metal hydride, for example a complex metal hydride such as lithium aluminum hydride, in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane at a temperature of 0 to 100 ° C, preferably at 20 to 60 ° C.

The disproportionation of the sulfonic acid hydrazide obtained by reacting the corresponding hydrazine 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 a temperature of 100-200 ° C, preferably 160-170 ° C.

The additional condensation of the formyl derivative is conveniently carried out in a solvent such as pyridine or tetrahydrofuran, by reaction with malonic acid, malonic ester, dialkylphosphonoacetic acid ester or alkoxycarbonylmethylene-triphenylphosphorane, optionally in the presence of a base as a condensing agent, for example piperidine, potassium tert-butoxide; sodium hydride, at a temperature of 0 to 100 ° C, followed by acidification, for example with hydrochloric acid or sulfuric acid, or subsequent alkaline hydrolysis, to obtain the desired compound.

The additional 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 on activated carbon at a temperature of 0 to 75 ° C, preferably at room temperature. and under a hydrogen pressure of 1 to 5 bar.

The additional O-acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, preferably by treatment with a reactive acid derivative such as a halide such as acid chloride, anhydride or imidazolide; 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 serve as a solvent, at a temperature of -25 to 250 ° C, preferably at a temperature of -10 ° C to the boiling point of the solvent used.

The additional reduction of the nitro compound is preferably carried out in a solvent such as water, aqueous ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, suitably with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium on activated carbon. iron, tin or zinc in the presence of an acid, by treatment with salts such as ferrous sulfate, stannous chloride or sodium dithionite, or hydrazine in the presence of Raney-nickel at a temperature of 0 to 50 ° C, preferably at room temperature.

The additional reaction of a diazonium salt, for example fluoroborate, fluoride in 40% hydrofluoric acid, hydrogen sulphate in sulfuric acid or hydrochloride, if necessary in the presence of copper or a corresponding copper salt such as cuprous chloride in hydrochloric acid or cuprous bromide in hydrobromic acid at an elevated temperature, for example at a temperature of 15 to 100 ° C, and the additional reaction with phosphoric acid is preferably carried out at a temperature of -5 to 0 ° C.

The desired diazonium salt is conveniently prepared in a suitable solvent, for example aqueous hydrochloric acid, methanolic hydrochloric acid, ethanolic hydrochloric acid or hydrochloric acid in dioxane, diazotizing the corresponding amino compound with a nitrite such as sodium nitrite or nitrous ester at a lower temperature, e.g. at -10 to 5 ° C.

The additional O-alkylation is expediently carried out with the corresponding halide, sulfonic acid ester or diazoalkane, for example methyl iodide, dimethyl sulfate, ethyl bromide, ethyl ester of p-toluenesulfonic acid, isopropyl ester of methanesulfonic acid or diazomethane, optionally in the presence of a base such as sodium hydride, potassium hydroxide or tert -butoxide. , and preferably in a solvent such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, pyridine or dimethylformamide, at a temperature of 0 to 75 ° C, preferably at room temperature.

Subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, sulfuric acid or p-toluenesulphonyl chloride, optionally in a solvent such as ^{methylcarbazole} ENC ^hl chloride or р п ^ ^^^ ^p s ^p te lot ^of from 0 to 100 ° with the above ^ ode ^h s ^{p p} te Lot ^{2 of} 0 to 80 ° C.

The compounds of formula I obtained, when they contain a chiral center, can be separated into enantiomers by conventional methods. This separation is carried out by column chromatography on a chiral phase.

The compounds of the formula I obtained can be further converted into their addition salts, in particular into the salts thereof. their physiologically. tolerable salts with inorganic or organic acids or with bases.

Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, acid. succinic acid, maleic acid or fumaric acid, and as the base sodium hydroxide, potassium hydroxide,. cyclohexyleunine, ethanolamine, diethanolamine, - triethanolamine or ethylenediamine.

The compounds of formulas (II) and (III) used as starting materials are obtained by methods known from the literature or are known per se from the literature.

For example, a compound of formula (II) wherein A - is a radical of formula

Optionally, its tautomeric ketimine is obtained, for example, by reacting the corresponding nitrile with the corresponding Grignard compound or lithium derivative followed by hydrolysis, or by reacting the corresponding ketone with ammonia in the presence. titanium tetrachloride.

To further react with a compound of formula. III, optionally with its reactive derivative, in particular with the corresponding acid chloride, organometallic may also be used. ketimine complex.

A compound of formula II wherein A is a radical of formula

-CH- in which R ₄ is as defined above except for cyano. The compound is obtained, for example, by reacting the corresponding nitrile with the corresponding Grignard compound or lithium derivative, and optionally subsequent reduction with lithium and aluminum hydride or subsequent hydrolysis to ketimine, which is then reduced by catalytically activated hydrogen, a complex metal hydride or hydrogen. in a state of birth,. hydrolysis or hydrazinolysis of the corresponding phthalimide derivative, reaction of the corresponding ketone with an ammonium formate followed by hydrolysis, optionally with an ammonium salt in the presence of sodium cyanoborohydride, by reaction of the corresponding oxime with lithium aluminum hydride or catalytically activated with hydrogen or benzyl, N- (1-phenylethyl) ketamine, for example by catalytically activated hydrogen or a complex hydride. metal in ether or tetrahydrofuran at temperatures ranging from - ⁷ to 8 ° C and ^from there ^pl Ota reflux ^{fo p} ou t he ^s maiden ^ u ^ ed ^ and us eduj ^{l s l} The more odštópenírn benzyl memory. ^eb n ° 1-phenylethyl group by catalytic hydrpgenací, or corresponding alcohol to a Ritter reaction with potassium cyanide in sulfuric acid .or Hofuiannovým, Curtiovýrn / .Lossenovým Schmidt or degradation of the respective compounds. ·

A compound of formula (II) wherein A is a zoyl of formula

CN is obtained by reacting the corresponding aldehyde with ammonium cyanide or by reacting the corresponding cyanohydrin with ammonia.

The amine of formula (II) thus obtained with a chiral center in which A is a radical of formula (I)

for example, by fractional crystallization of diastereomeric salts with optically active acids followed by decomposition of the corresponding salts or by column chromatography on a chiral phase or by preparation of diastereomeric compounds, their resolution and subsequent resolution into the individual enantiomers.

In addition, the optically active amine of formula II can also be obtained by enantio-selective reduction of the corresponding ketimine with complex boron or aluminum hydrides in which part of the hydrogen hydrogens are replaced by optically active alkoxide residues or hydrogen in the presence of a suitable chiral hydrogenation catalyst, N-benzyl or N- (1-phenethyl) ketimine or the corresponding N-acylketimine or enamide, optionally followed by cleavage of the benzyl, 1-phenethyl or acyl residue.

Further, the optically active amine of formula II can also be obtained by diastereo-selective reduction of the corresponding nitrogen-substituted chiral-substituted ketimine or hydrazone by treatment with a complex or also incomplete boron or aluminum hydride, optionally replacing some of the hydride hydrogens with the corresponding alkoxide, phenoxide or alkyl groups. or by treatment with hydrogen in the presence of a suitable hydrogenation catalyst and optionally subsequent cleavage of the chiral auxiliary by catalytic hydrogenolysis or hydrolysis.

Furthermore, an optically active amine of formula (I) may also be prepared by diastereo-selective addition of the appropriate organometallic compound, preferably a Grignard compound or lithium derivative, to the corresponding chiral-substituted aldimine on the nitrogen atom, followed by hydrolysis and optionally subsequent cleavage of the chiral auxiliary by catalytic hydrogenolysis; hydrolysis.

As mentioned above, the novel compounds of the formula I exhibit valuable pharmacological properties, namely the metabolism effect and, in particular, the blood sugar lowering effect, and partly also the heart and circulatory effects.

For example, the properties of the following compounds were tested as follows:

A = [Z] -4- [[1- (2-piperidinophenyl) -1-buten-1-yl] aminocarbonylmethyl] benzoic acid,

С = (E) -4 - [[1- (2-Piperidinophenyl) -1-buten-1-yl] aminocarbonylmethyl] benzoic acid,

D - 4 - [[2-Methyl-1- (2-piperidinophenyl) -1-propen-1-yl] aminocarbonylmethyl] benzoic acid,

AA

AB

AC

AD

AF / Z / -4- [/ 3-phenoxy-1- ^y1 / ^yn 2epipuridinofun / ^El-P for ute1ey ⁿ / ^{amino to} Arbon ^yl ubhy л ^ ^{lj O} butzoov acid / Z / -4- [ / 1- / 2- / 3,3elimebhy ^{np p} er i ^{i i} d a ^/ bitches ^Y1 / ^- 1 ^e-bubun Ley ⁿ / am ^{i n} tokarboty him ^{b y} h njbetzoovO acid,

4- [1- (2-pyrrolidinofut)^yl/ -lebub^{yn /}amito^toar^bhe^ylлιeth^yjbunzoov^O. to^ysuⁿita^,/ ± / -4 ·^{e [f}l- / 2-^pand^peridinophenes^l/^El^ebub^yl/ aminokarЬon^yMethyl] benzo⁰ acid, /+/e.4^E[/ 1 - / 2e^pipuriditofun^y1 H -1-bub^yl/ am^andnokarbon^ylmubh^yn^Jbunzcì:> v^O acid, ubh^ylusbur / + / - 4-⁽/ l- / 2-^pand^peridinophenyl / -1^-bubyl / an^andno^toarЬonyⁿnubh^ynJbut «oov^{é k}yseП ^ у,^4e[/^le/^2ehuxa^hydroazepito^Fethy^l/^-lbat^tyn/ amito^toar^botyⁿme^thylJ benzoov⁰ to^ysuⁿita,

4- ^ ly ^ -piperiťiinoíf ^enyl / ^- lehex ^yl / ^b ar ^to amino online ^yl Muth ^yl] benzoic sour ^0,

4- [/ 3-phenyl / L / ^{2 f} epiper ^id ino Una ^{l / -le} prop ^{yl / -} amino ^for R ^b onylmebh ^y,] benzoic YSU ^{0 to n,} and ^{L i,}

4- [/ ² -mebhoxy-L-7 -piperldinofenyl ² / - ^{l l} -ebhy / ίмnino ^b ar ^to those not ^{b n} hyl] ^{b O} utzoov ^the YSU ⁿⁱ t ^and,

4- [/ a · k ^{y LFA-dioxaborolan-2-yl,} piperidin inobenz ^d L / L · ^y шninokarbon tebh ^yl bei ^ OOV ^{0th k} ysu ⁿ ita ^,

4- ^[/ ι- / 2 ^p er driver -piperazin-l Noten / -1 -but ^y l / amiinokarbony heehhyl] Betz ^yne and ¹ co ^{h 1,} 4 - [/ 1e / ^2-piperid inofen ^yn / ^e . ¹ ebu ^{by1 /} гødLno ^k ar ^b on ^y lmebhy] fet ^y1 ocbov ^O tyseHna,

^J 4- 1- / 2-piperidinyl inofen ^{d y} 1 / e1 ^bub-y1 / ^y1 amino ^to Arbon meth ^y l S ^{k s WWTP} to ^y and ^{n ita,}

^2,3-d ih ^y dro ^χyp ro ^py 1uster 4 J / L - / 2 ^p i ^p er ⁱ dito ^f ut ^y1 / ^b u e1e ^Byn / ^{amino b} ar ^to those iehhyr J ^ ^J ^ 1 nzoové acids,

4- ^[/ 1- / 4-ί 1uor-2e ^p i ^{p d} inofety1 URI / ^e e1 Y1 bu ^b / ^b ar ^to ALMINI onyhne hylj benzoic ^b ^ ⁰ tyse to 4e ^{/ 1 / ^y 4emethox E2- ^pip uri ^d ito ^{phenyl 1} / ^e 1ebuty1 / ^{amino for} r ^b on ^Y1 MEB ^Hy1 j tenzoov ^{kY 0} to ^1i,

4- [/ l- / 2-octahydro ^d roazonino ety1 ^f / e1eeb ^h en ^y 1 ^/ amine nokarboty ¹ mU! BH ^y1j enzoov ^b ^ ^O tyse on,

4- (/ L- / ^3-P ch1ore2e Iper inofet ^{d y1} / EB ^{e1e Hy1} ./aIn but ^{also to} he ar ^{b y} L · nebh ^{yl lb} enzoov ^O ^ alkyl Shoots

4- [/ L- / ^3-y MEBH 1e2epi ^p erid ^{Topheth yn} / E1-eth ^y l / aIninokarЬon ^y1 mubh ^yl nzoov ^l ^ ^{0 for} y ^{e 1i those}

4-j / alpha- / 4-Iπeth 1fen ^y 1 ^y / e2e ^p i ^{p d} eri itobenz ^Y1 / ^{1 Amit} carbonyloxy methyl benzoic ^{Y1L b} h ^ ⁰ slashes 4- ^[/ alpha / -3 -m th ^{e ylphenyl} / ^P 2- and ^P eridiňobenz ^yl / n ^{and b} nokar onyhne ^b HYL benzoic ^{l 0} KYSE-on, 4- ^{[/ f} a1 / E4-fnuorfut ^y 1 / e2e ^p i ^{p d} eri ito ^b UNZ ^{y1 / amino} Arbon ^{y1 to} him ^bh benzoic ^nJ y ⁰ 4e ^[/ a1fa / e2ef1 Orfen ^{u y} 1 / ^P e2e IPUR ^d ino ^b enz ^Y1 / ^{amino b} ar ^to those Me ^{n th y1]} benzoic acid ^{4- 0} β / ¹ and f / ^-4e ch ^{1 phenyl} or ^{1 /} - ² INOB piperidino ^{d t} n ^l n ^/ / ^t am nkkarbtУ tmethy ^n: J b ^{enz vO} 4e oo [/ a1fa / e3ech1orf ^e n ^y l / - 2-amino piperidine ^{d b} TNL ^{n /} / tm ⁱ Tokar Ota ^{b 1 b} MLE hy ^{ll be} nfrom ^{o O} acid acid acid,

AE acid,

AG = 4 - {(2-piperidino-alpha- / 2-pyridyl) benzyl] chinocarbonylmethyl] benzoic acid,

N = 4 - {[2-piperidino-alpha- (4-pyridyl) benzyl] aminocarbonylmethyl} benzoic acid,

AJ = 4 - [(chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid,

AK = 4- (alpha-phenyl-1-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid,

AL

AM

AN

АО

AP

AQ

AR

AS

- 3- / 4 - [(alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] phenyl / propionic acid,

- 4- (4-chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid;

4- [[4-Methyl-alpha-phenyl-2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid; alpha-phenylbenzyl / aminocarbonylmethyl] benzoic acid, = 4- ([2- (3-methylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid and = 4 - [(3-chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid.

1. Blood glucose lowering effect

The blood glucose lowering effect of the test compounds was tested in female rats weighing 180-220 g, which were fasted 24 hours prior to the start of the experiment.

Test compounds are suspended in 1.5% methylcellulose immediately prior to the start of the experiment and administered by a swallowing probe.

Blood is collected immediately prior to administration of the test substance and at 1, 2, 3 and 4 hours thereafter, from a retro-orbital venous plexus. From each sample, 50 µl of each protein was added by adding 0.5 ml of 0.33 N perchloric acid and centrifuged.

Glucose is determined in the supernatant by the hexokinase method using an analytical photometer. Statistical evaluation is performed using the Student's t-test with p = 0.05.

Detected values of the lump: expressed in % versus control attempt are listed in the following tested 5 mg / kg 1 mg / kg substance 1 2 3 4 1 2 3 4 AND -43 -40 -33 -35 В -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 D -36 -32 -27 -25 E -46 -40 -38 -26 -23 -2 3 -12 -18 F -43 -42 -39 -32 G -44 -42 -37 -31 H -50 -46 -44 -45 J -44 -37 -42 -42 -38 -32 -34 -29 К -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 n .s. M -46 -43 -40 -36 -33 -30 -21 n.s.

continued table

N -42 -42 -37 -33 0 -38 ⁺ / -31 ^{+ /} n.s // n.s // P -49 -43 -34 -22 -37 -19 n.s. n.s. Q -28 -13 n.s. n.s. R -38 -40 -35 -29 -39 -34 -29 -24 WITH -49 -42 -30 -17 -29 -20 -10 n.s. T -48 -46 -42 -40 -42 -42 -40 -32 AT -43 -43 -49 -45 -39 -35 -29 -24 IN -45 -41 -46 -40 -37 -2 3 -30 -18 W -46 -45 -39 -37 -36 -25 -16 n.s. X -34 + / -21 ^{+ /} -17 ^{+ /} -14 ^{+ /} Y -32 -24 -16 -18 of -22 -33 -28 -26 AA -30 -33 -14 n.s. -15 -15 -13 n.s. AB -43 -38 -36 -27 -26 -15 n.s. n.s. AC -36 -37 -36 -33 AD -2 8 -32 -27 -28 -16 -20 -17 -14 AE -30 -28 -39 -36 -21 -20 -22 n.s. AF -43 · -39 -30 -26 -17 -19 n.s. n.s. AG -49 * / -50 ^{+ /} -36 ^{+ /} -3! ^{+ /} -18 n.s. П.8. n.s. АН -41 -37 -20 n.s. -26 -14 n.s. n.s. AJ -44 -40 -39 -40 -35 -34 -28 -20 AK -48 ^V -47 ^{+ /} -40 ^{+ /} -45 ^{+ /} -32 -19 -10 -17 AL -43 / -41 ^{+ /} -38 ^{+ /} -34 ^{+ /} -40 -31 -23 -12 AM -34 -35 -32 -29 -11 -13 П.8. n.s. AN -39 -35 -27 -26 -27 -24 n.s. n.s. АО -37 -34 -32 -31 -21 -17 -15 -11 AP -26 -28 -22 -17 AQ -32 -31 -24 -19 -16 -11 n.s. n.s. AR -35 -30 -29 -31 -13 - 9 n.s. n.s. AS -45 -44 -42 -32 -21 -13 n.s. n.s.

Legend:

⁺ / at a dose of 10 mg / kg ns - not statistically significant

2. Acute toxicity

Toxic effect after oral administration of test substances as a suspension in 1% methylcellulose is tested in female and male female mice. Test substance is administered once, observation period is 14 days.

The results are shown in the following overview, where p.o. means oral administration.

test substance indicative acute toxicity

AND > 1 000 mg / kg after. / none that í 6 of animals neuhynulo / C > 2 ООО mg / kg after. / none that ! 6 of animals neuhynulo / D > 500 mg / kg after. / none that _: 6 of animals neuhynulo / J > 2 ООО mg / kg after. / none of 10 of animals neuhynulo / AA > 1 ООО mg / kg after. / none of 10 of animals neuhynulo / AB > 1 ООО mg / kg after. / none of 10 of animals neuhynulo / AC > 1 ООО mg / kg after. / none of 10 of animals neuhynulo / ^AD > 1 ООО mg / kg after. / none of 10 of animals neuhynulo / AE > 1 ООО mg / kg after. / none of 10 of animals neuhynulo / AG 71 ООО mg / kg after. / none of 10 of animals neuhynulo /

Because of their pharmacological properties, the compounds of the formula I according to the invention and their physiologically tolerable salts are suitable for the treatment of diabetes mellitus.

For this purpose, they can be formulated, if desired in combination with other active substances, into conventional galenic preparations, such as tablets, dragees, capsules, powders or suspensions. The unit dose for adults is 1 to 50 mg, preferably 2.5 to 20 mg, and is administered once or twice daily.

The invention is illustrated by the following non-limiting examples.

Example 1 Ethyl ester of the acid 4- (N- [alpha] - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid

To 4/2 g (15 mmol) of alpha- (4-methylphenyl) -2-piperidinobenzylamine and 3.4 g (16.5 mmol) of 4-ethoxycarbonylphenylacetic acid, dissolved in 40 ml of acetonitrile, was added 4.7 g in turn. 18 mmol (triphenylphosphine), 3 g (30 mmol) triethylamine and 1.5 ml (15 mmol) carbon tetrachloride.

The reaction mixture was stirred at 50 ° C for 2 hours, evaporated and acidified with 6N hydrochloric acid and extracted with ethyl acetate. The acidic aqueous phase is extracted several times with methylene chloride, the methylene chloride extracts are washed with sodium bicarbonate solution and, after drying over magnesium sulphate, evaporated. The residue was triturated with ethanol and the solid product was evaporated.

It is obtained. 4.55 g (65% of theory) of product, m.p. 177-178 ° C.

Analysis:

C, 76.57; H, 28.28; N, 5.95.

Found: C, 76.19; H, 7.16; N, 5.82.

The following compounds were prepared in an analogous manner to Example 1:

and [4- (N- [alpha] - (3-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl) benzoic acid ethyl ester.

The product, m.p. 159 DEG-160 DEG C., yields 48% of theory.

Analysis:

C, 76.57; H, 7.28; N, 5.95. Found: C, 76.80; H, 7.35; N, 5.76.

b) 4- [N- [alpha / 2-Methylphenyl] -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester.

M.p. 196 DEG-198 DEG C., yielding 35.4% of theory.

Analysis: Calculated: C, 76.57; H, 7.28; N, 5.95. Found:% C, 76.65;% H, 7.35;% N, 5.90.

(4-) N- [alpha- (4-Methoxyphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester.

Melting point 167 DEG-168 DEG C. yields 45% of theory.

Analysis:

calculated: C, 74.05; H, 7.04; H, 5.76. Found: C, 73.72; H, 6.99; N, 5.62.

d) 4- [N- [alpha- (4-Benzyloxyphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester.

M.p. 154-155 ° C, yielding 96% of theory.

Analysis:

H, 6.81; N, 4.98. Found: C, 76.82; H, 6.68; N, 5.03.

e) 4- [N- [alpha / 4-Fluorophenyl] -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester.

174 DEG-176 DEG C., yielding 58% of theory.

Analysis:

H, 6.58; N, 5.90. Found: C, 73.55; H, 6.72; N, 5.91.

f) 4- (N- [alpha] - (2-Fluorophenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzoic acid ethyl ester.

The product, m.p. 173 DEG-175 DEG C., yields 83% of theory.

Analysis:

C, 73.40; H, 6.58; N, 5.90.

Found: C, 73.61; H, 6.62; N, 5.85.

g / Ethyl ethyl ester.

Analysis:

C, 70.94; H, 6.36; N, 5.71; Cl, 7.22; Found: C, 71.10; H, 6.56; N, 5.26; Cl, 7.11.

4- (N- [alpha] - (4-chlorophenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzoic acid

178 DEG-181 DEG C. yields 57% of theory.

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

153 DEG-156 DEG C., 71% of theory.

Analysis:

C, 70.94; H, 6.36; N, 5.71; Cl, 7.22;

Found: C, 70.86; H, 6.26; N, 5.65; Cl, 7.25.

i) 4-N - [(alpha) - (2-Chloro-phenyl) -2-piperidinobenzyl] aminocarbonylmethyl] -benzoic acid ethyl ester.

»

196 DEG-198 DEG C., 66% of theory.

Analysis:

C, 70.94; H, 6.36; N, 5.71; Cl, 7.22; Found: C, 70.90, H, 6.30, N, 5.61, Cl, 7.10.

к) 4- [N- [alpha] - [4-Methyl-mercaptophenyl] -2-piperidinobenzyl] amino-carbonyl-ethyl] -benzoic acid ethyl ester.

The product, m.p. 173 DEG-175 DEG C., yields 84% of theory.

Analysis:

C, 71.68; H, 6.82; N, 5.57; S, 6.38; Found: C, 71.82; H, 6.97; N, 5.45; S, 6.21.

1) 4- [N- (5-Chloro-alpha- / 2-chloro-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester.

M.p. 213 DEG-215 DEG C. yields 92% of theory.

Analysis:

C, 66.28; H, 5.75; N, 5.33; Cl, 13.49;

Found: C, 66.45; H, 5.86; N, 5.25; Cl, 13.51.

m / 4- [N- (2-Piperidino-alpha- [2-pyridyl] benzyl) aninocarbonylmethyl] benzoic acid ethyl ester.

M.p. 158 DEG-159 DEG C., yielding 51% of theory.

Analysis:

C, 73.50; H, 6.83; N, 9.18. found: C, 73.40; H, 6.95; N, 9.10.

n) 4-N- (2-Piperidino-alpha- [3-pyridyl] benzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

The product, m.p. 172 DEG C., yields 85% of theory.

Analysis:

C, 73.50; H, 6.83; N, 9.18. Found: C, 73.42; H, 6.76; N, 9.25.

o) 4- [N- (2-Piperidino-alpha- [4-pyridyl] benzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

and

240970 “18

The product, m.p. 150 DEG-152 DEG C., yields 20% of theory.

Analysis:

calculated: C, 73.50; H, 6.83; N, 9.18. Found: C, 73.61; H, 6.91; N, 9.15.

p) 4- [N- (6-Chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

The product as an oil resulted in a yield of 12% of theory.

Analysis: calculated: molecular ion m / e - 490/492 found: molecular ion m / e - 490/492.

q) 4- [N- (4-Chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

M.p. 148-150 ° C, yielding 37% of theory.

Analysis:

C, 70.94; H, 6.36; N, 5.71; Cl, 7.22. Found: C, 70.81; H, 6.25; N, 5.61; Cl, 7.12.

r) 4- [N- (3-Chloro-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

M.p. 176-178 ° C, 74% yield.

Analysis:

H, 6.36; N, 5.71; Cl, 7.22. Found: C, 70.59; H, 6.25; N, 5.68; Cl, 7.16.

s) 4- [N- (6-Methyl-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

The product in the form of an oil resulted in a yield of 65% of theory.

Analysis: -, calculated: molecular ion m / e · 470 found: molecular ion m / e · 470.

t / Ethyl ethyl ester.

4- [N- (5-methyl-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

171 DEG-173 DEG C., 48% of theory.

Analysis:

C, 76.57; H, 7.28; N, 5.95. Found C, 76.75% _F 7.35% H 5.72% N

u) 4-N- [4-Methyl-alpha-phenyl-2-piperidinobenzyl] aminocarbonylmethybenzoic acid ethyl ester.

M.p. 133 DEG-135 DEG C. yields 76% of theory.

24O97Q

Analysis:

C, 76.57; H, 7.28; H, 5.95. Found: C, 76.51; H, 7.16; N, 5.83.

in? 4- [4- (5-Methoxy-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester *

M.p. 122-125 ° C. IQ Λ theory.

Analysis:

calculated: molecular ion m / e = 486 found: molecular ion m / e = 486.

w) 4-N - [(6-Methoxy-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoate ethyl ester.

The product as an oil resulted in 97% of theory.

Analysis:

calculated: molecular ion m / e - 486 found: molecular ion m / e - 486.

x / 3-Chloro-4- [N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

The product, m.p. 175 DEG-176 DEG C., yields 42% of theory.

Analysis:

calculated: C, 70.93; H, 6.36; N, 5.71; Cl, 7.22. Found: C, 70.65; H, 6.36; N, 5.50; Cl, 7.29.

(4-N - [(2-Dimethylamino-alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid ethyl ester).

M.p. 116 DEG-118 DEG C. yields 67% of theory.

Analysis:

H, 6.77; N, 6.73. Found: C, 75.13; H, 6.60; N, 6.78.

z) 4- [N- [2-Di-n-propylamino-alpha-.alpha.-phenylbenzyl] aminocarbonylraethyl] benzoic acid ethyl ester.

M.p. 138-139 ° C, yielding 76% of theory.

Analysis;

calculated: C, 76.24; H, 7.68; N, 5.93. Found: C, 76.41; H, 7.79; N, 5.81.

acids.

Analysis:

calculated: molecular ion m / e = 498 found: molecular ion m / e = 498.

aa) 4- (N- (2-) octahydro-1H-azonino) -alpha-phenylbenzyl) aminocarbonylmethyl benzyl ethyl ester The product was obtained as an oil in 71% yield.

: 24: 0970 ab) 4- [N- (5-Chloro-2- (2-methylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

171 DEG-173 DEG C., 36.5% of theory.

Analysis:

calculated: C, 71.24; H, 6.58; N, 5.54; Cl, 7.01. Found: C, 71.45; H, 6.68; N, 5.59; Cl, 7.20.

αс] 4- [N- (2- (3,3-Dimethylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl benzoic acid ethyl ester.

146 DEG-148 DEG C., yielding 91% of theory.

Analysis:

C, 76.82; H, 7.49; N, 5.78.

Found:% C, 76.91;% H, 7.55;% N, 5.61.

Example 2

4- (N- [alpha] - (4-Chlorophenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

To a solution of 6.02 g (20 mmol) of alpha- (4-chlorophenyl) -2-piperidinobenzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform, a 5 g (22.1 mmol) solution is added dropwise under ice-cooling. -ethoxycarbonylphenylacetyl chloride in 20 ml of chloroform.

The reaction mixture was stirred at room temperature for 2 hours, then poured into water and extracted with chloroform. The extract was dried, evaporated and the residue chromatographed on silica gel using toluene / ethyl acetate (5: 1) as eluent.

178 DEG-181 DEG C., yielding 5.6 g (57% of theory).

Analysis:

C, 70.94; H, 6.36; N, 5.71; Cl, 7.22;

Found: C, 71.09; H, 6.47; N, 5.61; Cl, 7.10.

In an analogous manner to Example 2, the following were prepared:

4- [N- (5-chloro-2- (3-methylpiperidino) -. Alpha .- (phenylbenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

178 DEG-180 DEG C. yields 54% of theory.

Analysis:

C, 71.2-4; H, 6.58; N, 5.54; Cl, 7.01; Found: C, 70.91; H, 6.64; N, 5.75; Cl, 7.01.

Example 3

4- [N- (alpha- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

4.4 g of 4- [N- (alpha- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester (9.35 mmol) are dissolved in 150 ml of ethanol under heating, ml of 1 N sodium hydroxide solution are added and the mixture was stirred at 50 ° C for 3 hours.

20 ml of 1 N hydrochloric acid are added to the reaction mixture, and the excess ethanol is evaporated on a rotary evaporator. The residual aqueous suspension is filtered and the precipitate is washed thoroughly with water and then recrystallized from acetonitrile.

Melting point 226-228 ° C, yields 2.45 g (59.3% of theory).

Analysis: Calculated: C, 75.99; H, 6.83; N, 6.33. Found: C, 75.60; H, 6.75; N, 6.29.

In an analogous manner to Example 3, the following were prepared:

M.p. 202 DEG-203 DEG C. yields 72% of theory.

Analysis:

C, 75.99; H, 6.83; N, 6.33.

Found: C, 75.64; H, 6.91; N, 6.37.

b) 4- [N- (alpha- (2-Methylphenyl) -2-piperidinobenzyl) aminocarbonylmethylethyl] benzoic acid.

Melting point: 285 DEG-290 DEG C. yields 42.6% of theory.

Analysis:

C, 75.99; H, 6.83; N, 6.33.

Found: C, 76.05; H, 6.98; N, 6.25.

M.p. 228 DEG-230 DEG C., 72.4% of theory.

Analysis:

C, 73.34; H, 6.59; N, 6.11. Found: C, 73.22; H, 6.61; N, 6.13.

d) 4-N - [alpha] - (4-Benzyloxyphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid The product, m.p.

Analysis:

C, 76.38; H, 6.41; N, 5.24. Found: C, 76.05; H, 6.44; N, 5.24.

M.p. 238 DEG-240 DEG C. yields 75% of theory.

Analysis:

C, 72.63; H, 6.09; N, 6.27. Found: C, 72.98; H, 6.29; N, 6.32.

f (4-1 N- (alpha) - (2-fluorophenyl) -2-piperidinobenzyl) amino

M.p. 280 DEG-283 DEG C. yields 87% of theory.

H, 6.09; N, 6.27. found 72.70 -% C, - 6.10 -% H, 6.37% - N.

The product of ' ^- - melting point' - 241-242 ° C resulted in a yield of 89. % theory

H, 5.88; N, 6.05; N, 7.66. Cl; Found: C, 69.74; H, 6.05; N, 6.01; Cl, 7.64.

Produkt 'o. temperature, melting. 223 DEG-225 DEG C. yields 53% of theory.

Analysis:

C, 70.05; H, 5.88; 6.05. N, 7.66 (% Cl) found: C, 70.28;% C, 98.98; H, 78%; N, 7.84.

i) 4-N- (alpha - / Chlorophenyl .-- / piperidinobenzamide ^-2-yl) aminocarbonylmethyl benzoic acid.

Product o. 'Te ^{p s} lot ^of counting ^and 3 303 ⁰ 5 ° C results in a 98% effluent.

Analysis:

calculated: 70.05% C, 5.88% H, 6.05% N, 7.66% Cl;

found. C 69.88% H 6.05% 5.87% N 7.74. % Cl.

k) 4- N- (alpha- (4-methylmercaptophenyl) -2-piperidinobenzyl) aminocarbonylmethyl benzoic acid.

Te The product of Lot ^E t ^{p ck} 225 and ^z. . ²²⁷ ° C was obtained in the outlet ^84, 6% of theory.

Analysis:

C, 70.86; H, 6.37; N, 5.90; S, 6.75.

Found: C, 70.34; H, 6.37; N, 5.68; S, 6.82.

N- (5-chloro-alpha- (2-chlorophenyl) -2-benzoic)

acid.

For ^{d t} uk melting counting ^s 317 and ³²⁰ ° C · rezultuje in underflow 90% of that ^of RIE.

Analysis:

C, 65.19; H, 5.27; N, 5.63; Cl, 14.25. Found: C, 64.87; H, 5.34; N, 5.69; Cl, 14.22.

^P r at ^{the knots} of ^T emperature ^{of th} n ^{e of} 161 and 160 ° C results in a projection of 81% t ^EOR i ^e.

Analysis:

C, 72.71; H, 6.34; N, 9.78.

Found:% C, 72.43;% H, 6.39;% O, 10.10.

^{n /} 4- [N ^/ 2 ^p i ^{p d} eri amino ^{/ LF} and a- ^{/ 3} - ^{d p} yri yl ^/ benzyl / benzoic aminokarbonylmethylj to ^{YS ELI.}

For a ^d u ^{k t l} ep ^{I th} of the 2 ^52, and ^{a 253} ° C cut-U is in the underflow 72%.

Aialysis:

C, 72.71; H, 6.34; N, 9.78.

Found: C, 72.56; H, 6.53; N, 9.60.

o / ⁴ - [N- / ^2-P and ^P-piperidine "" alpha / ^4-py chlorides] benzyl ./ ^l / aminocarbonyl] miethyl | benzoic acid.

Produ ^kt and ^{t i} c ⁱ for ^{dec] d} and ^d uo .260 ° C results in a chop in ^{the 68,} 5% 'of theory.

Analysis:

calculated: C, 72.71; H, 6.34; N, 9.78. Found: C, 72.31; H, 6.29; N, 9.63.

p / .. 4- N ^ / ^{6 CH]} or a ^{LF-a- phenyl-l-} 2- ^{piperidino d} amino Benzyl ^b / aininokarbon ^{ylmethyl y n} lJbe ^Zoo and acids.

^Trodat uct of pulse ^l th OTE ^{her 91 to 94} ° C in U is cut ^{LT characterized} in yields against 82% ^Tecra i ^e.

Analysis:

calculated: 70.04% C, 5.88% H, 6.05% N, 7.66% CEL ·, found 69.61% C, 5.77% H, 5.96% N, 7.78% Cl .

^q / 4-1N- / ^{4-chloro-phenyl} @ .alpha 2- ^p i ^p eridinobenzyl / amino ^for R ^b on ^y l ^b lmet ^hy enzoová acid.

The product, ^p te ture counting ^and '221-2 ² 3 ° C results in a yield of ^6% Teona 1.

Analysis:

C, 70.05; H, 5.88; N, 6.05; Cl, 7.66; Found: C, 69.73; H, 5.89; N, 5.87; Cl, 7.52.

r /. 4- [N / 3 chCor - alla ^feenll2-pi-p eri inobenz ^d l ^y / ^y lj éuninokarbonylmeth benzoic acid,

Product of melting ^and counting ^{from 213} and ²¹⁰ ° C was obtained in the above-OCT 8% ^3-e theorem.

Analysis:

C, 70.05; H, 5.88; N, 6.05; Cl, 7.66; Found: C, 70.31; H, 6.03; N, 5.90; Cl, 7.79.

with [4- (N) - (6-methyl) alpha] phenyl (2-piperedenobenzyl) aminocarbonylmethyl] benzoic acid.

For ^{kt d} u ^{t i} c ⁱ and ^at 1 and ^{65 out of 17} 0 C / shnuje on ^d 0 1 ⁵ ° C / ^l Herein cut in a yield of ^64%.

Analysis:

C, 75.99; H, 6.83; N, 6.33. Found: C, 75.73; H, 6.96; N, 6.14%.

t / 4/5 // jN ^h meth ^y l / alpha / phen ^l l / ² / ^p i ^p l ^y eridinobenz / ^e aίn nokarbonylInethyl | benzoic ^y to get.

Prod ^u kt of te ture ^p t ^{i o} n 2 ⁴ 3-2 5 ⁴ DEG C. It was obtained in the EZ ^yl near ^{to 97%.}

Analysis:

C, 75.99; H, 6.83; N, 6.33. Found: C, 75.60; H, 7.01; N, 6.31.

u / N ^^ / ^ / ^ meth / alpha / phen ^^ / ^ p ^ er ^ inobenz / ai ^ he ^ no ^^ methyl-t ^^ ^y fcienzoov.á to Selina.

P ^{r at} the knots of te ture ^p t ^{i o} n 202, and ^from 203 ° C cut in the above-U is ^heavy at 96%.

Analysis: Calculated: C, 75.99; H, 6.83; N, 6.33. Found: C, 76.04; H, 6.78; N, 6.23.

I / N ^ 4/5-methoxy-.alpha.-phen ^yl-2-pi eridinobenz ^{p s} l / ^{l -Methyl} aminocarbonyl] benzoic acid.

Produkttající ^p s '217 to 220' C / sanitates ² 0 ³ ° C / in in rezul.tuje ^ýtěžku · ²⁷ and the TE ^or IE.

Aialysis calculated. 73.34% C, 6.59% H, 6.11% found. % C, 72.92;% H, 6.68;

w / 4- [N / 6-m ^e th ^y ° x - ^and LF ^and phen ^{yl-2- p} i ^p eridinobenzy ^l / ^{m, and even to} a R ^b amino he me ^{th yl yl} tenzoová J acid.

P ^{u r} from ^p kt of te ture mp 90-95 ° C rezuRuje mined in 51.5% yield.

Analysis:

C, 73.34; H, 6.59; C, 6.11; Found: C, 73.03; H, 6.42; N, 5.86.

^{x / 4} - ^ N ^{/ hl 5} c of ^r - ² - ^{/ 3,} 5-ci ^s - ^d ^ in E ^ t ^ y ^ ^h ^] ^ i ^ l ^ i ^ c ^ i ^ j ^ c ^ j ^ r ^ <^ / ^ - ^ and ^ J ^ i ^ i ^ - ^ i ^ (^ and ^ ⁴ ^: ^] ^ i ^ izzyl ^and / MIOK ^and rronyyimeth ^y ljbenzoová acid, ^p genus ^kt of ^{t pl} e of th ^{e I t 253} and ²⁵⁵ ° C results in a spout 81 '% te ^ ie.

Analysis:

calculated: 70.93% C, 6.36% H, 5.71% N, 7.22% Cl found 70.68% C, 6.51% H, 5.73% N, 7.36% Cl.

y ^{/ 4} - ^[N-I2-yl diIneth / m ⁱ i @ - / l ^f / - ^{f ei? lb} enz ^yl amine ° ^to he ar ^{r y} meth ^yl lJrenzo ° ^{C ase alkyl} Selina.

^prod at ^rt EPL ^kt T ^{e th of} the ¹⁸³ and ^{from 184} ° C cut ^l Herein the howling ^EZK 83% of te ^ ie.

Analysis:

calculated: C, 74.20; H, 6.23; H, 7.21. Found: C, 74.31; H, 6.27; N, 7.16.

th ^tup 202-204 ° C results in a discharge of 79%.

temperature of ^{/ 4} - ^[N-l 2- ^di -i-Pr propyl ° / ° Inii - / L ^f / ^"f eiyl EIR ^{r y} l / ^r ar miio ^to Oi ^-yl meth ^yl] benzoic acid To EINN ^ *.

Product o

Analysis:

calculated: C 75.64, H 7.26, 6.30%. Found: C 75.74, H 7.31, N. 6.15%.

^{AA / 4} - ^[N L - ^L 5 ^CH 2 ^L IOR-2-Inet ^{h l} -al ylpiperidii ° ^F and ^"phenoxy-b enz ^y l ^-yl lamiio ^to Arron ^{ylmethyl y} L | benzoic acid.

^{p to} the genus mp 2 O ⁸ and ^{the 282} ° C was obtained in the effluent 5 ^2% of theory.

Analysis:

calculated: C, 70.50; H, 6.13; N, 5.87; Cl, 7.43. Found: C, 70.14; H, 6.10; N, 5.75; Cl, 7.45.

ab / N- 4- £ ^l 5 °-chloro-2-R-L3 methylpiperidii ° ^l '/ L ^f / ei ^{-f ylr} EIR ^yl lamiio ^to Arro ^-yl meth ^yl J ^benzoate and acids.

^P ro ^d u ^kt m.p. ²⁴⁶ and ^{from 248} ° C was obtained in the above ^severe in ^66% yield.

Analysis:

C, 70.50; H, 6.13; N, 5.87; Cl, 7.43; Found: C, 70.18; H, 6.07; N, 5.87; Cl, 7.30.

α (4- [n- (2- (3,3-Dimethylpiperidino) -. alpha.-phenylbenzyl) aminocarbonylmethyl) benzoic acid.

M.p. 238 DEG-240 DEG C. yields 59% of theory.

H, 7.07; N, 6.14. Found: C, 76.38; H, 7.28; N, 6.11.

ad (3-Chloro-4- (N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl) benzoic acid).

M.P. 236-239 C ^U results in a 56% yield.

Analysis:

calculated: 70.04% C, 5.88% H, 6.05% N, 7.66% Cl;

Found: C, 69.88; H, 5.77; N, 5.86; Cl, 7.81.

and [4- (n) 2- (3,5-cis-dimethylpiperidino) -5-nitro-alpha-phenylbenzyl] aminocarbonylmethyl] benzoic acid.

M.p. = 255 DEG C., yielding 81% of theory.

Analysis:

C, 69.44; H, 6.23; N, 8.38. Found: C, 68.95; H, 6.44; N, 8.53.

[4- (N- (2-) octahydro-1H-azonino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid.

M.p. 235 DEG-237 DEG C. yields 62.5% of theory.

Analysis:

C, 76.56; H, 7.28; N, 5.95. Found: C 76.50; H 7.30; N 5.94.

and [4- (N- (5-hydroxy-alpha-phenyl) 2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid.

M.p. 98-101 ° C, 71% of theory.

Analysis:

H, 6.35; N, 6.30.

Found: C, 72.98; H, 6.40; N, 6.47.

Example 4

The product, m.p. 173 DEG-176 DEG C., yields 84% of theory.

4- [N- (alpha- (4-methylphenyl) -2-piperidinobenzyl) (uninocarbonylmethyl) cinnamic acid

The title compound is obtained by alkaline saponification of 4- (N- (alpha) -4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid ethyl ester in an analogous manner to Example 3.

Aialysis:

C, 76.90; H, 6.88; N, 5.98. found 77.24 C, 7.01 H, 5.64 N.

The following compound was prepared in an analogous manner to Example 4:

^{M.P. 177-180} ° C results in a yield of 75 4 Theory

Aialysis:

C, 76.62; H, 6.65; H, 6.16%. Found: 76.75; C, 6.57; H, 6.07.

Example

The compound mentioned. The title compound was prepared in an analogous manner to that in Example 1, starting from alpha-4-methyl-4-cyanophenylacetic acid and 4-cyanophenylacetic acid.

^P roducts ^^ te of about ^the point ^{144 and} 146 ° C in the above rezuKuje ^thee OCT 64 4 theory.

Aialysis:

calculated 79.40 4 C, 6.90 4 H, 9.92 4 Ν »found 79.10 4 C, 6.90 4 H, 9.78 4 N.

Ai and in a logical manner as in Example 5, the following compound was prepared:

The product, te rt ^{pl of} T ^and the 178-181 ° C.rezultaje in the above-OCT 53 ⁴ theory.

Aialysis:

calculated '79.18 4 C, 6.65 4 H, 10.26 4 Nj found 78.84 4 C, 6.55. 4H, 13.24 4 N.

Example '

- * e. .

Ethyl ⁴ - | / 2-methyl) X ^- / 2- benzoic acids.

To a solution of 0.55 g (2.34 mm @ 1) of 2-methyl-1- (2-i-pyridinobenzyl) ethyl in 5 ml of acetonitrile is added successively 0.49 g (2.34 mmole) of 4-ethylcarbonylphenylacetic acid, 0.73. g / 2.78 o ^ Ooi / triphenylphosphine, 0.50 ml / 3.66 Ranovich triethyamine and 0.23 <ol '/ 2.3' ⁴ ONOO- / carbon tetrachloride, the reaction mixture is 20 stirred at holin ofítnnosi,. 'then. evaporate in vacuo and shake the residue with ethyl acetate and water.

The organic extract was dried, filtered and evaporated. with vacuum. The residue is purified by chromatography on a column of silica gel. use of toluene. and acetone (10: 2) as eluent.

The product of the temperature T ^and one ^{from 22} to 123 ° C was obtained in the yield. 0.4 ⁵ g ( ⁴⁵ 4th theory).

. . .... AnlVza:. . . '. ....

calcd. 70.73 4 ° C, 7.60 4 H, 6.60 4 Ν;

found 71.40 4 C, 7.48 4 H, 6.39-4 N. · ·. ·: ...

The following compounds were prepared in an analogous manner to Example 6:

The product, ^p te ture counting ^s НЗ to 141 ° C cut with ^{LT j ý} e in the yields against 55% teofie.

Analysis:

calculated: 68.33%, 7.28% H, 7.76% Cl, 6.13% Ni found 68.30% C, 7.16% H, 8.03% Cl. 6.20% N.

acid.

u ^{d p} ro te ^{p kt} of ^thee lo ^t U ^s 79-82 ° C results in a yield of ^73, 9% of theory.

Analysis:

calculated: 68.33%, 7.28% H, 7.76% Cl, 6.13% Ni found 68.45% C, 7.24% H, 7.80% Cl, 6.09% N.

For ^d in that ^the counting ture te ^{p s} 11 ^6-118 ° C results in a yield of ^62% of the theoretical one.

Analysis:

calculated: C 62.27, H 6.63, Br 15.93, N 5.58%.

Found: C, 62.53; H, 6.48; Br, 15.98; N, 5.66.

d / E ^t h ^y les ^t er 4 - [/ ¹ - / ^{4-n and} nitro-2- ^{piperidinecarboxylic} aminophenyl ^yl / -l- ^b ut ^yl / ^b on ^y aminocarboxylic acids lmethyljbenzoové.

^P ro ^d uct of te ^pl of the ^{I th 127} and ^Z and ³⁰ ° C results in a yield of 7 ^4.6% of theory.

Analysis:

C, 66.79; H, 7.11; N, 8.99.

Found: C, 66.88; H, 7.08; N, 9.15.

e / Et ^{hyl 4-} [/ ^l - ^/ 3-met ^hyl - ² - ^p i ^{p i} dino ^f er en ^yl / -l- ^b ut ^{yl /} amine aminocarbonyl ^{ylmethyl y} l ^{j benzoate} ester.

^P ro ^d uk.to heat · ^I n ^{th I} 1 ^{45-1 47} ° C results in a ^68% effluent.

Analysis:

C, 74.28; H, 8.31; N, 6.42. Found: C, 74.40; H, 8.30; N, 6.41.

^{f / Ethyl} ester ^{of 4} - [/ ^l- / 4-met ^{hyl- 2-piperid} ino ^phenoxy-yl / -l ^-b ut ^yl / ^b ar ^to amino he ^-yl meth ^yl] benzoic acid.

For ^d in that ^the temperature T ^and n ^s 113, and ^from 11 ⁴ ° C results in a yield of 54.7% of theory.

Analysis:

C, 74.28; H, 8.31; N, 6.42.

Found: C, 74.23; H, 8.30; N, 6.55.

g / Ethyl ethyl ester.

M.p. 149 DEG-150 DEG C., yielding 67.9% of theory

Analysis: Calculated: C, 74.28; H, 8.31; N, 6.42. Found: C, 74.38; H, 8.21; N, 6.49.

92 DEG-93 DEG C. yields 47% of theory

Analysis:

C, 74.28; H, 8.31; N, 6.42. Found: C, 74.50; H, 8.46; N, 6.48.

The product, m.p. 122 DEG-125 DEG C., yields 57.3% of theory.

Analysis:

calculated: C, 73.50; H, 7.90; 6.86%. Found: C, 73.63; H, 8.07; N, 7.01.

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

127 DEG-128 DEG C., 71.5% of theory.

Analysis:

C, 73.90; H, 8.11; N, 6.63.

Found: C, 73.90; H, 8.06; N, 6.72.

1) 4- [1- [2- (4-Methylpiperidino) phenyl] -1-butyl] aminocarbonylinethyl] benzoic acid ethyl ester.

153 DEG-155 DEG C., 51.1% of theory.

Analysis:

C, 74.28; H, 8.31; N, 6.42.

Found: C, 74.55; H, 8.33; N, 6.45.

m / Ethyl 4 - [[1- (2-hexahydroazepinophenyl) -1-benzoate]

acid.

145 DEG-147 DEG C., 42.7% of theory

Analysis:

C, 74.28; H, 8.31; N, 6.42 Found: C, 73.98; H, 8.26; N, 6.58.

n / Ethyl ester 4- | acid.

M.p. 128 DEG-130 DEG C. yields 55% of theory

Analysis: Calculated: C, 70.88; H, 7.55; N, 6.36. Found: C, 71.14; H, 7.57; N, 6.49.

o 4 - [[1- ( ^2- piperidin-1-yl) -butyl] aminocarbonylmethyl] benzoic acid methyl ether.

The product, ^l BEP OTE · 1.47 mp 148 ° C results in a yield of 63.2% of theory.

Analysis:

calculated 73.50% C, 7.90% H, 6.86 ·% Ν »found 73.66% C, 7.88% H, 6.80% N.

p ^/ n ^-b u ^t y ^l es ^t er 4- ^[/ L ^{/ 2} - ^pip er ⁱ d ^{i f} no en ^yl / -l- ^b ut ^{yl /} amine aminocarbonyl ^y ljbenzoové ^{ylmethyl ester,} the product of melting PC from ^ether 117-11 ⁸ ° C results in a yield of 50.9% of theory.

Analysis:

calculated: C, 74.63; H, 8.50; N, 6.22. Found: C, 74.49; H, 8.46; N, 6.14.

^{q /} Eth ^yl ester 3-c ^hl or 4- ^£ / l- / ^{2-piperidinyl} ino ^{id f} en ^yl / - ^l - ^b u ^t y ^I / I ⁱ £ ^l aminocarbonyl Jneth ^y lj benzoic acid.

The product melting below ²⁰ ° C resulted in a yield of 14.9% of theory.

Analysis:

calcd: m / e 456/458 (1 chlorine) found: m / e 456/458 (1 chlorine).

r / Eth ^yl ester 4 · R / L / ^d 2-piperidinyl amino ^phenyl / ^-4: -j ^p snten-yl / aninokarlbonyhnethy ^lj benzoic ^yé to ^y petroleum jelly. · ^P ro ^d at ^the temperature of the counting ^s 103 ^and 105 DEG C ^ U is cut in a yield of 183% 'of theory.

Analysis:.

calculated: C, 74.62; H, 7.89; N, 6.45. Found: C, 75.01; H, 8.10;

s / Et ^hyl 4- £ / L / ^3, -C ^{2 H} lor- -p ^ip er ^{f idi} no ^yl en / -le ^th y ^l / ⁱ Amii aminocarbonyl lnKíth ^{y y} J benzoic acid.

^P roducts ^pl of TE OTE counting ^s 166 and ¹⁶⁸ ° C, cut in the above ^l Herein ^heavy at ^58.0% of theory.

Analysis:

calculated: C, 67.20; H, 6.81; C, 8.27; C, 6.53. Found: C, 67.17; H, 6.85; C, 8.17;

Example 7

Eth ^{yl es} ter 4 J / L / 5-nitro-2-pipBr ⁱ dino ^{phenyl l} / -l-but ^{yl /} amine aminocarbonyl hnethyl ^{y] b} ^ ^é nzoov ^ky ny with ^Li-

To a solution of 15.1 g (54.4 mmol). 1- (5-nitro-2-piperidinophenyl) -1-butylamine and 8.46 ml (61.4 mmol) triethylamine in 55 ml dry methylene chloride were added dropwise with stirring over a period of 30 minutes with a solution of 14.6 g./64.6 mmol / 4-ethoxykarbonylfenyloctové chloride acid in 20 ml of methylene ^id for the FAST verifies ^the st ^ ^. and ^the OTA te ^pl · NEP ^ S ^ ^ up to ³⁰ ° C.

The reaction mixture was stirred at room temperature for 2 hours then. 300 ml of methylene chloride are added thereto, and the mixture is shaken twice. 50 ml water. The organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. .

Reddish-brown colored. The oily residue is purified by silica gel column chromatography using a mixture. toluene and acetone / 10:. 1) as eluent.

Product tai ^s c ^{s p} o teysteKzaci. from ether. ^at 135. to ¹³⁷ . The yield ^{was 17.7} g (69.7% of theory).

Analysis:

C, 66.77; H, 7.11; N, 8.99

found. - 66.73. % C, H 6.99, N. 9.09%

In the same way as in. example. 7.The following is prepared. compounds:

and ^/ Eth ^yl ester 4- | / of 1- / ^{2-P ip} er dlno ^{i f yi} en /-.l-but ^yl / ^{amino to} αrbon ^yl methyl ^t h Jtenzoové ^yl. tyseHny.

Produ ^k to. te ^pl ol ^of melting point 127-129 DEG C. @ U is cut in a yield of ⁸⁰ second % theory.

Analysis: Calculated: C, 73.90; H, 8.11; N, 6.63.

Found: C, 73.98; H, 8.26; N, 6.89.

^b / ^Ethyl 4- ^£ / l- / 4-hydroxy-2-pi | ^p вr dinofeny ^{i i} / -i-butyl / Amien ^to αrbnny ^| lJbenzoové meth ^yl ester.

^of birth ^to t. o-. te rt ^{pl of} T ^and n ^s and 178 ^{1 8} 0 C-section U is ^ ^ yield 13% of theory.

Analysis:

vypočentioh ,; ^33% C, 7.81% H, .6, .39% N; Nal ^ (^: reaper ^ ^<.? 71.27% C 7.82% H 6.40% N

. ·> V '.

c ^/ ^^^ ster ^{4- [/ IC} / ^{5 h} pi ^p ydrnxy ^C2- eridien EEY ^{f i} / ^c i ^{-Butyl l} / αm ⁱ eo ^b ar ^to those methyl ^{L |} j tonzoic acid. ^{: p} ro ^d u ^kt . o-:. te ^pl counting revolutions ^{of 88 s} 1, and ^from 190 ° C cut ^l Herein výtóžku 37 in ^4% yield.

Analysis: Calculated: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.34; H, 7.89; N, 6.38.

.. EXAMPLE 8 ^4- £ / ⁱ - / 2 ^- p ^{i i} -piperidin nnfeey ^l / ^{- b} u ^t i ^l У / αmino ^{to b} nn ar ^{yl meth} y ^| Phenylacetic acid

3.0 g (15.45 mmol) of p-phenyleedinic acid, together with 10 ml of thionyl chloride, were heated under reflux for 90 minutes, then the mixture was evaporated in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride and to this solution is stirred at a temperature of 10-15 ° C / m while stirring.^ěřeno inside^Ř reak^Cn^and mixtures^/ poma^lu p^sayape melts^3.6 g / 1⁵,⁴⁵ mmoV / piperidine. dinofeeyl] -1-but^ylaninu.

Mon. The reaction mixture was evaporated in vacuo. and the residue was partitioned between 100 ml of ice-cold 5% sodium hydroxide solution and ethyl acetate. The mixture is filtered through diatomaceous earth and the organic phase is separated.

The alkaline aqueous phase was acidified to pH 5.5 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered, and the filtrate evaporated in vacuo. The residue was purified by silica gel column chromatography using a 20: 1 mixture of chloroform and methanol as eluent.

Are ^{you Kp} birth ^to the tai ^I C ^{¹H -p} o ^to r ^y s ^t, and ^{if i} zac from. ^mixtures дее ^^^^ и ^{ethe and} Ru ^{at 136 to}

140 ° C ^No. .0 ^others, 10th ^g / ^1, 6% theor ^e /.

Analysis:

. H, 7.90; N, 6.86. found: C, 73.17; H, 8.10; N, 6.85

Ethyl 41- J / ² -methyl -! .- / ^{2 -} pi ^p eri ^{di f} no ^{en-yl / - 1} -j ^p ropen ^- l ^{- yl /} amine aminocarbonyl LRNE ^y ^^ y ^ ^L ^ J benzoic acid

To a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl- (2 ^- piperidinophenyl) ketimine in 62 ml of acetonitrile was added sequentially 5.58 g (26.8 mmol) of 4-ethoxycarbonylphenylacetic acid. 43 (32.2 mmol) of triphenyffosiin, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 mol) of carbon tetrachloride were added and the reaction mixture was stirred at room temperature for 20 hours. vacuum.

The residue is partitioned between ethyl acetate and water, the ethyl acetate extract is dried and, after filtration, evaporated in vacuo. The residue was purified by silica gel column chromatography using toluene / ethyl acetate (5: 1) as eluent.

For ^d u c ^kt taj ^{s s p} o krystalhací. ET ERU ^{h at 82-84} ° C was obtained in the above OCT ^{I -} 3.0 ^g / 26.6% of theory /.

Analysis:

C, 74.26; H, 7.67; N, 6.66. .

Found: C, 74.20; H, 7.49; N, 6.56.

The following compounds were prepared in an analogous manner to Example 9:

and / Ethyl 4- ^j / ~ ^1/2-beta acids. ,

For ^{kt d} u ^t and ^d, and ^P ^ staUzací mesh. ET anol ^{h at 94-97} ° C ^LT U is cut in the above OCT ^I l ^6% of theory.

Analysis:

C, 74.62; H, 7.89; N, 6.45.

Found: C, 74.75; H, 7.71; N, 6.24.

b / Ethyl^Est^Er⁴- £ / 1- / 2-^pnpeiⁿdino^withwoman^l/ -l-^hexen-l-^yl/ amⁿnokaibon^ylme^thyl benzo^E kyse lazy.

For ^d uct melting of crystalline ^p ^ in ^ ET anol ^{h at} 83 and ⁸⁵ ° ^C was obtained in the effluent ^{of 27.4%} of theory.

Analysis:

C, 74.97; H, 8.09; N, 6.24.

Found: C, 75.42; H, 7.95; N, 6.00.

c) 4- (1H-piperidin- ⁴ - ^{yl) -4-methyl- 4} - ^methyl -benzoic acid ethyl ester.

Make the genus ^{kp to} about the melting point ^{of p d 2} 0 ° C / l of ^{IP fil some width} j ^ Omer, ^{p dep} • Similarly Rav ^of E ^ om / ^{or tup} 4.1% of theory.

calculated: m / e 420 found: m / e 420.

Yield ^of obstructions ^to the genus ^{p p} o melting foystaMzaci: ET ^{H L} yes ^{115 s} up to ¹¹⁷ ° ^C / m Step ^E isomer, Z-form probably / amounts to 51.9% of theory.

Analysis:

C, 74.26; H, 7.67; N, 6.66. Found: C, 73.85; H, 7.59; N, 6.44.

d) 4- (2-Phenyl-1- (2-piperidinophenyl) -1-ethenyl) aminocarbonylmethyl) benzoic acid ethyl ester.

The yield of the product melting after crystallization from a mixture of ether and petroleum ether at 75-77 ° C (lipophilic isomer, probably β-form) is 4% of theory.

Analysis:

calculated: C 76.90, H 6.88, N 5.98; Found: C, 77.31; H, 7.20; N, 5.93.

The yield of the product melting after crystallization from ethanol at 157-160 ° C (less lipophilic isomer, probably Z-form) is 42.7% of theory.

Analysis:

Found: C, 77.19; H, 6.95; N, 6.02.

e) 4- (3-Phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl) benzoic acid ethyl ester.

The product melting below 20 ° C resulted in a yield of 62.6% of theory.

calculated: m / e = 482 found: m / e ж 482.

f) 4-β- [2- (3,3-Dimethyl-piperidino) -phenyl] -1-buten-1-yl] -aminocarbonylmethyl-benzoic acid ethyl ester.

The product melting after crystallization from ethanol at 113 DEG-116 DEG C. yielded 33% of theory.

Analysis:

H, 8.09; N, 6.24.

Found: C, 75.37; H, 7.93; N, 6.03.

g / Ethyl esters.

4 - (/

1- (6-Methyl-2-piperidinophenyl) -1-buten-1-yl) aminocarbonylmethylbenzo The yield of the product, m.p.

Analysis:

C, 74.62; H, 7.89; N, 6.45. m / e = 434; Found: C, 74.44; H, 8.00; N, 6.59. m / e = 434.

Example 10

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

A solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidinophenyl) propyl ketidine and

11.5 ml (82.46 mmol) of triethylamine in 190 ml of anhydrous toluene are heated to 85 DEG C. while stirring, a solution of 18.7 g (82.46 mmol) of 4-ethoxycarbonylenenylacetic acid chloride in 95 ml is added dropwise over 10 minutes. ml of anhydrous toluene, the mixture was stirred at 95 ° C (measured inside the reaction mixture) for 30 minutes, then cooled to 20 ° C and shaken twice with water.

The organic phase is dried over sodium sulphate and, after filtration, evaporated under vacuum, the residue is purified by chromatography on a silica gel column several times using toluene / acetone (20: 1 and 50: 1) as eluents.

Yield ^of obstructions ^P ro ^d uktu taj ^^ ^-p o ^{2 d} 0 / ^d s me ^of bile ^{characterized} viscous oil microcapsules / ^c in ^{s 11,} 2 ^g / ^{2 3,} 6% of theory / / lipophilic isomer, presumably E -form/.

Analysis:

C, 74.26; H, 7.67; N, 6.66.

found 73.90% C, 7.92% H, 6.91%, N.

Howl^Ethat^kproduktu te te^plot^E tán^and 11⁴ to 1¹⁶ ° C is 15.9.^G /³³,⁵ % theory / / m^ENo^betterO^fil isomer, probably Z-form.

Analysis:

C, 74.26; H, 7.67; N, 6.66.

Found: C, 74.02; H, 7.69; N, 6.85.

Example 11

4- £ / 1- / 2- ^p i ^{p e} n ^y eridinof l / -l-butyl / ^lb aminocarbonylmethyl enzoová · kyselka

Mixture 1 ^{2 g} / ^2, 84 mmol / 4- ^[/ l- / 2 pi ^p eridinofenyl / u ^{t -lb} yl / ^b aminocarbonyl onyl ^t hy ^l] ~ benzoic acid and 4.26 ml of 1 N sodium hydroxide solution ve.12 ml of ethanol was stirred for 1 hour at 60% ^P and neutralized with 4.26 ml of 1N c ^hl orovo ^{says é} metal and the ^P and ^R · in vacuo ^to about ^d siding ethanol.

The residue was partitioned between ethyl acetate and water, the organic extract was dried, filtered and evaporated in vacuo. The residue was crystallized from ethanol.

The recovery ^from the EC to the te ^d uktu ^I lo ^{p th} her 21 ^3-2 15 ° C ^{and 0.50} g n ^s / ^{44, 6%} EOR ^{t i} e /.

Analysis:

C, 73.07; H, 7.66; N, 7.10.

Found: C, 73.18; H, 7.51; N, 7.10.

The following compounds were prepared in an analogous manner to Example 11:

A / 4 - [/ l- / ^p i 2 ^{p -phenyl-piperidine} / -L ^p entyl / ^b on aminok.ar ^yl methyl ^t h ^y l | ^b enzoov ^á tysehna.

Yield ^of obstructions ^p roducts melting ^p o r ^{y to} become ^pupils of acetone of p ^s and 21 ^{3 of the 215} ° C ^or the teoxrie ^70.2%.

Analysis:

H, 7.90; N, 6.86. Found: C, 73.71; H, 7.70; N, 6.90.

b / 4- ^[/ 1- / 2- ^p i ^p eridinofen ^yl / -1 ^{- yl} hex / ^{amino for} R ^b on ^y lme ^thy lj enzoov ^{b and k y} Selina.

Yield. ^{p to} the genus taj ^ í ^p o r ^{y to} stalizaci acetone ^p s 197 to ²⁰⁰ ° C ^{or tup 72.6%} of theory.

Analysis:.

C, 73.90; H, 8.11; N, 6.63.

Found: C, 73.83; H, 7.93; N, 6.77.

^c / 4 -] / 2-feny1-l- / 2-piperidinophenyl / -1-ethyl / ^b aminocarbonyl onylmethy 1benzoová ^{1 to} y ^el ina.

240970 34

Yield: 68.7% of theory after crystallization from ethanol at 214-215 ° C.

Analysis:

calculated. Found: C, 75.70; H, 6.60; N, 6.32.

d [4- (3-Phenyl-1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl] benzoic acid.

The yield of product melting after crystallization from ethyl acetate at 167-170 ° C is 67.7%.

Analysis:

C, 76.29; H, 7.06; N, 6.14. Found: C, 76.56; H, 7.06; N, 6.23.

^e [4- (2-Methoxy-1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid.

M.p. 196 DEG-198 DEG C., yielding 60.8% of theory.

Analysis:

C, 69.68; H, 7.12; N, 7.07

Found: C, 69.72; H, 6.52; N, 6.71.

1-yl / aminocarbonylmethyl] benzoic acid contained 4 - [[1- (2-piperidinophenyl) -4-pentene] 0.67 mol of water.

The product melting after crystallization from a mixture of ether and petroleum ether at 193 DEG-197 DEG C. yielded 30.7% of theory.

Analysis:

calculated: C, 71.74; H, 7.38; N, 6.69. Found: C, 71.63; H, 7.21; N, 6.34.

g [4- [[1- (2- (3,3-dimethylpiperidino) phenyl] -1-butyl] aminocarbonylmethyl] benzoic acid.

The product melting after crystallization from petroleum ether at 168 DEG-170 DEG C. yields 48.2% of theory.

Analysis:

calculated: C, 73.91; H, 8.11; N, 6.63. Found: C, 73.81; H, 7.89; N, 6.32.

h) 4- [1- (3-Methyl-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

The product melting at 179-182 ° C yielded 53% of theory.

Analysis:

. H, 7.90; N, 6.86. Found: C, 73.50; H, 7.82; N, 7.01.

[4- (4-Methyl-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

170 DEG-172 DEG C., 85.6% of theory.

Analysis:

H, 7.90; N, 6.86.

found 73.25 t _of C, H 7.64, N 6.89%

(4-p1- (5-Methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl) benzoic acid.

M.p. 219-221 ° C; yield 62.1% of theory.

Analysis:

H, 7.90; N, 6.86.

Found: C, 73.20; H, 7.74; N, 6.89.

1/4 - [[1- (6-methyl-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid containing 0.3 mol of water.

M.p. 158 DEG-160 DEG C., yielding 89% of theory.

Analysis:

C, 72.53; H, 7.93; N, 6.77.

Found: C, 72.40; H, 7.91; N, 6.92.

m / 4- [[1- (3-Chloro-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid ·

M.p. 189-191 ° C, yielding 70% of theory.

Analysis:

C, 67.20; H, 6.81; Cl, 8.27; N, 6.53.

Found: C, 67.30; H, 6.85; Cl, 8.36.

N- [4- [[1- (4-chloro-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

M.p. 188-189 ° C, yielding 57.8% of theory.

Analysis:

calculated: C, 67.20; H, 6.81; Cl, 8.27; N, 6.53. Found: C, 66.90; H, 7.00; Cl, 8.22;

o 4 - [[1- (5-Chloro-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid. Melting point 226 DEG-229 DEG C. yields 81.6% of theory.

Analysis:

C, 67.20; H, 6.81; Cl, 8.27; N, 6.53.

Found: C, 67.17; H, 6.59; Cl, 8.51; N, 6.60.

p - 4 - [[1- (6-chloro-2-piperidinophenyl) -1]

-butyl / aminocarbonylmethyl] benzoic acid.

The product, m.p. 150 DEG-153 DEG C., yields 69.4% of theory.

Analysis: Calculated: C, 67.20; H, 6.81; Cl, 8.27; N, 6.53. Found: C, 67.18; H, 6.91; Cl, 8.42; N, 6.77.

4- [4- [1- (4-bromo-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

M.p. 198 DEG-201 DEG C. yields 84.4% of theory.

Analysis:

calculated: 60.89% H, 6.17% H, 16.88% Br, 5.92% N, found C 60.88%, 5.98% H, 17.20% Br, 5.98% N.

r) 4 - [(1- (5-bromo-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid. M.p. 232 DEG-235 DEG C. yields 90.7% of theory.

Analysis:

calculated: C, 60.89; H, 6.17; H, 16.88; N, 5.92. Found: C, 60.96; H, 6.13; Br, 16.88; N, 5.90.

_a ) 4 - [(- (4-Nitro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid. M.p. 188-190 ° C; yield 70.9% of theory. Analysis:

H, 6.65; N, 9.56 Found: C, 65.30; H, 6.44; N, 9.53.

tert-4- [1- (5-Nitro-2-plperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

M.p. 225 DEG-227 DEG C. yields 90.7% of theory.

Analysis:

C, 65.59; H, 6.65; N, 9.56. Found: C, 65.80; H, 6.61; N, 9.72.

(4 - [[1- (4-Hydroxy-2-piperidinylphenyl) -1-butyl] aminocarbonylmethyl) benzoic acid containing 0.5 mol of water.

The product, which on heating softens from 70 ° C (foaming) results in a yield

85.7% of theory.

Analysis / XO 5 H ₂ 0 / calculated 68.71% C, 7.45% H, 6.68% Ν »Found 68.63% C, 7.55% H, 6.26 l N.

[1- (5-Hydroxy-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

Melting point 186 DEG-190 DEG C. yields 89.3% of theory.

Analysis:

C, 70.22; H, 7.37; N, 6.82. Found: C, 70.31; H, 7.58; N, 6.51.

[1- (4-Methoxy-2-piperidinophenyl) -1-butyl] aroinocarbonylmethyl] benzoic acid.

M.p. 185 DEG-187 DEG C., yielding 78.6% of theory. , '

Analysis:

C, 70.73; H, 7.60; N, 6.60

Found: C, 70.46; H, 7.77; N, 6.56.

x (4- [1- (5-Methoxy-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid.

M.p. 182 DEG-185 DEG C., yielding 75 l of theory.

Analysis:

calculated: C, 70.73; H, 7.60; H, 6.60. Found: C, 70.52; H, 7.50; N, 6.70%. (1-Butyl) aminocarbonylmethyl methyl benzoic acid.

M.p. 200 DEG-203 DEG C., yielding 64.5 l of theory. .

Ainlýza:

C, 72.61; H, 7.42; N, 7.36. Found: C, 72.64; H, 7.50;

z [4-] [1- ( ^2,4 ) 4-Methylpiperidinomethyl] benzoic acid.

Pr ^^ a temperature ^TA n ^{s 197,} and ^from 201 ° C results in a yield off ^z to. 81 ^, 4 '. % theory.

Aialysis:

H, 7.90; N, 6.86. Found: C, 73.90; H, 8.06; N, 7.00.

^AA / 4-J ^/ L / ² - ^h exa ^h y ^d r ° αzepin ° ^F ei ^yl / ^-l-yl rut / carb amine ° and ^y ° Уmeth ^y lJbenzoová tyselirnb

Pr ^ uJct temperature reading of 199 to 202 ° C in the above rezulteje ^eěžk with 65.6% of theory.

Analysis:

C, 73.50; H, 7.90; 6.86%. % H, 6.76% N.

^{ab /} 4- | ^l l- ^L4 - ^fl at ² ° N -piperidin ino ^{id f} en ^y l / ^{-l-Butyl /} amine carb n ° ° n ^{y |} Ineth ^y lJreiz °° va tyselina.

^Pr of ^{d kt} in the counting Tepe ^{s 204 and 2} 07 ° C results in a yield off ^YC at ^87, 1% of theory.

Analysis:

C 69.88%, H 7.09%, 6.79%. N, Found: C, 70.25; H, 7.02; N, 7.12.

ac / ⁴ "| / ^{L-55ffluor-2-yl} piperidinofen l / -l-but ^yl llcШιin ° ^to a R ^b N ° meth ^{yl y |} ] beiZOOv ^á tyselina.

^P ro ^d u ^to the pulse ^L o ^{I th} n ^e 2 ⁰ 0 ² and ²⁰ ° C rezuKuje ye. ^EZK howl at ^53.9% · theory :.

Analysis:

H, 7.09; N, 6.79.

Found: C, 69.67; H, 7.24; N, 6.90.

AD / 3-chloro-4- | / l- / ^{2-piperidino-phenyl} / ^-l-butyl-l / well ^to Ain ^and R ^b oi ^{y |} met ^{hy |} ] ^B enzo ° ^{C ase} .tyseHna ^P ro ^d u ^k that te lo ^{p I} T ^and the 165 and ^{1 68} ° C in the above rezulteje ^severe in 51% yield.

Analysis:

calculated: C, 67.20; H, 6.81; N, 6.53. m / e 428/430 (1 chlorine);

Found: C, 66.92; H, 6.69; N, 6.55. m / e = 428/430 (1 chlorine).

e / 4- [/ I- / methyll2 ^{3-yl 4} piperidinofei / llleth ^yl / αmiio ^to Arron ^{y |} meth ^y lj benzoic acid.

^P ro ^d u te ^{P to} a lot ^of T ^{ck 230-23} ° C, 1 U is cut-in in the howl ^EZK 79% :.

Analysis:.

C, 72.60; H, 7.42; N, 7.36. found 72.75% · C, 7.58% H, 7.30% N.

af /. 4- ^[[ 1- (3-Chloro-2-piperidinophenyl) -1-ethyl] chlorocarbonyl] ethyl} benzoic acid.

^P ro ^d u ^k t taj ^I C ^{s p} o r ^{y to} ISATIO hundred ^l of a 75% EtO ^ eteanolu at I ⁹² and ^from 195 ° C. re ^{of LT} in ^a yield of 54%.

Aialysis:

calculated: 65.91 ° C, 6.28 ° H, 8.84 ° Cl, 6.99 ° C, found 66.00% C, 6.44 ° H, 8.67% Cl, 6.78 «N.

Example 12 ^4- [/ ^ - yl nMíl ^ i - ^ - en pijparidinof ^yl / -l-propen-l- ^yl / -amlnokarbon ^ylmethyl benzoic KYSE ^{lj l} 'ina

Smee 3, ⁵ g / ^8, 3 ¹ mmol / e ^thy ester of 4- £ / 2-meth ^yl ll- / 2 ^PL-yl e5rldinofen ^p / ^p ro ^p -L- en-l- ^yl / amlnotartonyhne ^ ^alkyl yljtenzoové se ^li n ^y a 12, ⁵ ' ^m l' 1 'N ^l ou ^hu sodiéto ve. ^'35 m ^l ^ e ^ yes' 2 ^h of ^di ny MIC ^{HA in} te ^p ture 60% ^P and the zneutraHzuje '12 ^5' ml of 1N ^{alkyl when} n is ^y ^ c orovodíkové and evaporated.

with vacuum. .

The residue was partitioned between ethyl acetate and water, the organic extract after drying was filtered and evaporated in vacuo. The residue was crystallized from ethanol.

Gain ^and 04.02 ^g / 73.6% / ^P species ^to the temperature ^T U ^{s 188-19} 1 ° C.

Analysis:

C, 73.44; H, 7.19; N, 7.14 Found: C, 73.60; H, 7.19; N, 7.02.

The following compounds were obtained in an analogous manner to Example 13:

and / / E / -4-PL- / 2- ^PIP eridinofeny ^l / -l-buten-l- ^yl / ^b ar ^to amino onylmet ^h y ^l J ^b enzoov ^and acids.

Du P ^ro t ^{of the} pulse ^L o ^T e ^'s Counting l ⁸⁸ and ^Z 19 (° C results in a yield of ⁷ 1. ^5% of theory.

Analysis:. C, 73.44; H, 7.19; N, 7.14. Found: C, 73.15; H, 7.13. 7.10% N.

Olefinic proton: ity-NMR (deuteirooHorofoam): δ = 6.42 ppm.

L1- the ^{b-l- -} llamnno ^the Cr ^b bnyllnethyl benzoic ^l k ^y sel: Loa.

B / R / G / -4- ^[/ L / 2 ^{n p} lperídinofee llProdukt ^M.P.: recrystallization from anol et ^h p ^{r 174-175} ° C zu ^ ^ ^e U is ^z to yield off 5 ⁷ 8% of theory. '

Analysis:

C, 73.44; H, 7.19; N, 7.14

Found: C, 73.54; H, 6.97; N, 7.17.

CKY OLFI ^ ^p roton: ¹ H ^- NMR / ^ u ^ Io Io ^ ¹ ^ ¹ ^ ©:

δ 5.60 ppm.

^'C / / E / -4- ^p / ^y 2ere yl / -l- / ^p i 2 ^p eridinefenyl / ethene-l-yl / ^b on ^y гшllnokar lmethl ^lb enzoová] klsrl ^and cycloalkyl containing 0.4 mole of water. ·

Product melting of Cr ^ ^{p 1} from taHzac. SMSS ⁿ et ^h interruption and petroleum ≤ t ≤ ^s ru p ^165-167 DEG C. ^IE zu ^lt uj ^e in a yield of 33.2% of theory.

Analysis: - (x 0.4 H 2 O) calculated 75.11% C, 6.48%. H, 6.26% N;

Found: C, 75.22; H, 6.39; N, 6.26.

O ^{l F} e ioic characterized ^for proton ¹ H-NMR / deutero lo ^ ^^ ™ /:

δ> 6.9 ppm.

D) (z) -4- (2-Phenyl) -1- (2-piperidinophenyl) ethen-1-yl) aminocarbonylmethyl] benzoic acid containing 1 mol of aqueous.

The product melting after crystallization from methanol at 182 DEG-185 DEG C. yielded 72% of theory.

Analysis: Found: C, 73.34; H, 6.60; N, 6.11.

found 73.55% C, 6.45 4 H, 6.00 4 N.

Olefinic proton: ¹ H-NMR (deuterochloroform):

The product melting after crystallization from ether at 162-164 ° C resulted in a yield of 48.3% of theory (presumably (2) -form).

Analysis:

C, 76.63; H, 6.65; N, 6.16.

found 76.30 4 C, 6.4? % H, 6.31% N.

Olefinic proton: ¹ H-NMR (deuterochloroform):

The product melting after crystallization from ethyl acetate at 152-153 ° C resulted in yield

64.1% of theory (probably / Z) -form).

Analysis:

C, 74.26; H, 6.67; N, 6.67;

Found: C, 73.93; H, 7.57; N, 6.50.

/Л encourag.aaV 1 awa ^ amw. / * '

M.p. 142-145 ° C, yielding 53.3% of theory.

Analysis:

C, 73.66; H, 7.44; N, 6.89.

found 73.56% C, 7.73 4 H, 7.15 4 N.

Olefinic proton: ³ H-NMR (deuterochloroform):

5.38 ppm.

Example 13

(+) - 4-p1- (2-Piperidinophenyl) -1-butyl / aminocarbonylmethyl] benzoic acid ethyl ester

X of a solution of 2.58 g (11.1 mmol) of (+) - 1- (2-piperidinophenyl) -1-butylamine [boiling point> 87 ° C / 4 Pa> ee - 86] high pressure liquid chromatography after conversion to the derivative в (+) - 1-phenethylisocyanate (J) in 26 ml of acetonitrile at 20 ° C is gradually added 2.31 g (11.1 mmol) of 4-ethoxycarbonylphenylacetic acid, 3.50 g (13.3 mmol) of triphenylphosphine, 60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of tetrachloroethane.

The mixture was allowed to react for ¹⁴ hours at 20 ° C and 1.5 hours at 40 ° C, then evaporated in vacuo and the residue was shaken between water and ether. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. '

The residue was purified by chromatography on a silica column using toluene / acetone (6: 1) as the eluent.

2.63 ^g (56% of theory) of product are obtained. Mp 120 ° C.

Analysis:

H, 8.11; N, 6.63.

found: C, 74.20; H, 7.97; N, 6.51.

(alpha] 2 ⁰ + 9.2 ° / o = 1, nethanol /.

The following compound was obtained in an analogous manner to Example 13:

^Thylester E / - / - ^{4- (/} L / 2-PII ^P »ridinofónyl / -l-butyl / ^{Aminocarbonyl} me ^{th yl] b} e ^nzoov and acids.

The title compound was prepared from l- / 2-piperidlnofenyl / -l-butylamine 1.4 x HC1 ^{(al f a]} = ^-20.0 DEG ^/ c = Ъ ^meth yes ^{l /} te ^pl OTA t ^ck . ⁹ 0-100 ° ^C; ee - 80 I / ^s of ^{the l} ot ^sic and apa ^- Lin chromatography after conversion to the base derivative /// - llfene Thy lisokyanátem /.

For ^{kt d} u ^l a ^t ep OTE ^th n ⁱ 11 ⁵ to 120 ° C cut Herein ^l in the effluent ^{of 52.6%} teorj.e.

Analysis:

C, 73.90; H, 8.11; N, 6.63.

Found: C, 73.83; H, 8.01; N, 6.47.

[alpha] 2 = ^{0 -9} 0 ° / ^c = b methsmol /.

Example 14

Eth ^yl ester of N - 4-p-22- ^l l ^p i ^p er ± dinof en ^y l / -l-Bu those // <mnÍTioJaairbony ^{mnethyX] BE} nzoové to ^{y if y} N

^1, 0 ^g '/ ^3, 2 7 mmol / L / L ^p 2 ^{p 0} ee ⁱ dino ^yl en / ^{-lb -Butyl} am ⁱ ndih ^y droc oeidu ^hl] [and ^{l0 and]} + ·! ^8.7 ° / c - 1, methano ^{I /;} tep ^l OTA point: ^{d 1} of 15 ° C extended ^{kl AD; e} e ⁹ 1 ^{6 '/ L} significantly, and ^coffee liquid ^ag c ^{Thunder g} ra ^{p fi} e ^RX eve ^d en ^I B, ^{and d} on the weighing ^t er ⁱ s - ^/ - ene ^{-lf l th} У iaoky ^and n ^carboxylate θm / J ^^^ susp in 6 ^{ml of} methylene chloride is added with stirring 1.4 ml / 10 mmol / triethylamine mixture and přlkape solution of 0.82 · g / 3.64 mmol / chloride, ^{4-ethoxycarbonyl-yl} lfenyloctové acid 2,4' ml methylenc ^hl ori ^d u ^{r 'C} p ^F em rea ^CZK her te ^pl · ^pi OTA outp from 22 ° C to 38 ° C. 'Rea It overlooks ^the mixture ^of S' ⁶ it stirred ^DIN · · at room temperature and then washed successively twice with 10 ml of water, once with 10 ml 2nd N hydrochloric acid and once with 10 ml of water.

The organic phases over sodium sulfate vysu6i * ⁴ filtered and evaporated in vacuo. The residue is purified by chromatography on silica gel using toluene / acetone (6: 1) as the eluent. .

Gains ^and 0.53 ^g / 38.2% of theory / product te ^ otf '^ the ¹²⁰ and ¹²² ° C.

Analysis:

C, 73.90; H, 8.11; N, 6.63.

found 73.96 «C, 7.98« H, 6.61% · N.

[Al ^f a] 2 ° + 9.0 ° e / c -. 1, mtl ^ and ^ f ^ nl).

Example 15 [+] - 4- [[1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid]

2.0 g / 4.73 mmol / ethyl / + / - 4 J / L / 2-piperidinophenyl / -l-butyl / aminokarbonylmethylJbenzoové acid Jalfa] ^ ⁰ «+ 9.2 ° / с and 1 methanol / in 20 ml of ethanol together with 7.0 ml of 1 N sodium hydroxide solution for 2.5 hours in a 65 ° C bath, after which the reaction mixture is cooled and 7.0 ml of 1 N hydrochloric acid are precipitated. the crystals are filtered off and, after washing with water, dried at 100 DEG C./0.5 mbar.

1.65 g (88.2% of theory) of the product with a melting point of 185 DEG-187 DEG C. are obtained.

Analysis:

C, 73.07; H, 7.66; N, 7.10. Found: C, 72.90; H, 7.80; N, 7.17.

{alpha ^ + + 7.9 ° / с 1, methanol / ·

The following compound was obtained in an analogous manner to Example 15:

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

M.p. 187 DEG-190 DEG C., in 80% yield. Analysis:

C, 73.07; H, 7.66; N, 7.10.

Found: C, 72.98; H, 7.44; N, 7.22.

[alpha] 2 °. -7.9 ° (m -1, methanol).

Example 16

4 - [(2-piperidinophenyl) -butyl] aminocarbonylmethyl] benzonitrile

The title compound was prepared in an analogous manner to Example 6 from 1- (2-piperidinophenyl) -1-butylamine and 4-cyanophenylacetic acid.

147 DEG-148 DEG C., yielding 57.3% of theory. Analysis:

C, 76.76; H, 7.78; N, 11.19

Found: C, 76.46; H, 7.81; N, 11.10.

The following compound was obtained in an analogous manner to Example 16:

4- [[1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] toluene.

The product, m.p. 150-153 ° C, was obtained using 4-tolylacetic acid as starting material in a yield of 60.4% of theory.

Analysis:

C, 79.08; H, 8.85; N, 7.68.

Found: C 78.97, H 8.58, N 7.77.

Example 17

4- [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] cinnamic acid

The title compound is obtained by alkaline saponification of 4- [[1- (2-piperidyl) ethyl ester.

dinophenyl [1-butyl] aminocarbonylmethyl] cinnamic acid in a manner analogous to Example 11.

180 DEG-183 DEG C. yields 64% of theory.

Product o

Analysis: Calculated Found

H, 7.67; N, 6.66.

H, 7.47; N, 6.80.

Example

3- | 4- [1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] phenyl] propionic acid

The title compound is obtained by alkaline saponification of 3- (4 - [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] phenyl] propionic acid ethyl ester in an analogous manner to Example 11.

Melting point 131 DEG-133 DEG C. yields 50% of theory.

Analysis: Calculated Found

C,

C,

8.11

8.07

H, 6.63% N;

H, 6.41% N.

Analogous niny method:

as follows: 4- (N- (alpha) - (4-hydroxyphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzoic acid, m.p. 202 DEG-204 DEG C., 4- (N- (5-hydroxy-alpha-phenyl) ethyl ester). -2-piperidinobenzyl / aminocarbonylmethyl] benzoic acid, m.p. 191-193 ° C;

4 '* [N' (alpha) - [4 '-raethylphenyl] -2-piperidinobenzyl / aminocarbonylmethyl] benzyl alcohol, m.p. 144-146 ° C,

4- [N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzyl alcohol at temperatures up to 145 ° C,

144 DEG -146 DEG C., N- (.alpha .- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzaldehyde, m.p.

4- [N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde, m.p. 16 DEG-170 DEG C .;

145 DEG -146 DEG C. 4-N- (.alpha .- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzaldehyde;

170 [deg.] C. 4- [N- (alpha-4-methyl-4-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzaldehyde, m.p. 176 DEG-180 DEG C., 4- (N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl) cinnamic acid ethyl ester, m.p. 159-161 DEG C., 4- (N- (alpha) - (3-methylphenyl) -2-ethyl ester) -piperidinobenzyl / aminocarbonylmethyl-benzoic acid, m.p. 158-159 ° C; * 4- [n- [2- (3,5-cis-dimethylpiperidino) -5-nitro-alpha-phenylbenzyl] aminocarbonylmethyl] benzoic acid ethyl ester, m.p. 170-173 ° C;

4 | N / alpha / 4-methylphenyl / 2-piperidinobenzyl / hnethyl aminocarbonyl] benzoic acid, m.p. 226-228 ° C, _y

4- {N- [2- (2-methylpiperidino) -alpha-phenylbenzyl] aminocarbonylmethyl] benzo m.p.

4- [N- (2- (3-methylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid, m.p. 228 DEG-230 DEG C., ethyl acid 4- [N- (alpha) - (4-methylphenyl) -2- 175-177 ° C, 4- [n- [alpha] - (4-methylphenyl) -2-piperidinobenzyl] aminocarbonylethyl] benzoic acid ethyl ester, m.p. 177-179 ° C, ethyl ester 4- [N- (5-methyl-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, m.p. 170-173 ° C.

4- [N- (5-chloro-alpha- / 2-chlorophenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester, m.p. 213 DEG-215 DEG C., 4- [N- (5-chloro-2-) ethyl ester. (3,5-cis-dimethylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid, m.p. 188-191 ° C;

3-p- [N- (alpha- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] phenyl] propionic acid, m.p. 146-148 ° C;

3- [4- (N- [alpha] -phenyl-2-piperidinobenzyl / aminocarbonylmethyl) phenyl] propionic acid, m.p. 97-99 [deg.] C, 4- [N- (alpha) - [4-methylphenyl] -2- piperidinobenzyl / aminocarbonylmethyl] benzoic acid, m.p. 295-300 ° C _; 4- [N- [alpha / 4-methylphenyl] -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid, ethanolammonium salt, m.p. 188-191 ° C, diethanolammonium salt 4 178 DEG-180 DEG C. triethanolammonium salt of 4- [N- [alpha / 4-methylphenyl] -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid, m.p. 160 DEG-165 DEG C., 4- [N- [alpha / 4-methylphenyl] -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethylandiammonium salt, m.p. 160 DEG-163 DEG C., 4- [N] ethyl ester - (5-Methoxy-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, m.p. 123-125 ° C, (E) -4- {(1 -) - 2-plperidine ethyl ester Ophenyl (-2-buten-1-yl) aminocarbonylmethyl] benzoic acid melting below 20 ° C, [Z] -4 - [[1- (2-piperidinophenyl) -1-buten-1-yl] aminocarbonylmethyl] benzoic acid ethyl ester 115 DEG-117 DEG C., (E) - and (Z) -4- (1- (6-methyl-2-piperidinophenyl) -1-buten-1-yl) aininocarbonylmethyl] benzoic acid ethyl ester

Ε / ρς ^ υΓ: calculated m / e 434 found m / e в434

Z / ester found m / e · 434 ,:

ethyl 4 - (/ L ^{h /} 2 ^{/ piperidinecarboxylic edi} no ^f ENL ^{l / h] Hb of TLL} / am ^e come ^to Arbon ^yl meth ^l] Jbenzoov ^e k ^y Selin ^yl mp 126-128 ° ^C, e ^th YLE ^{ster 4 / edi} n ^OEE phenyl / ^{/] /} PEN ^t y ^l / am ^e nokar ^b on ^y lme ^thy l] ^b enzoov ^e k ^{y where} n ^y taj ⁱ c ^ip on krystaHzaci of ether ^at 117-120 e ^{th yl} ester 4 ^{з [/] /} / ^{2 / PE} per ^ide no ^e en ^LL / ^{2] /} hex ^yl / ^{amino for} r ^b on ^-yl meth ^{yl] b} enzoov ^{e kl} selenium ^l ta ^j IC ^after toystaMza ^ eT ^h interruption ^p s 108-110 DEG C. e ^th y ^l e ^{te r 4з [/} 2 ^зf en ^{yl /] з} / 2 ^{з piperidinecarboxylic idi} no ^f en ^y l / з] зet ^hyl / aM ^e aminocarbonyl ^l thyl ^l l] Ьenzoov ^e k ^y seíHny m.P. it ^ taHzaci from ethanol ^p s 161-162 ° ^ et ^ lestei · ⁴ - ^{[/ c} - ^e enl ^{l /] /} / 2 ^{/ PE} per ^idl no ^f ENL ^l / ^2] / ^T ro ^pollen / am ^e come ^to Arbon ^ll meth ^{l] b} enzoov ^{e kY} / lazy ^t and ⁱ c ⁱ 'after ^the y / ^y hundred ^If pupils of ethanol ^p s 118 to 119 ° C, ^e t ^h y ^le a ^ter 4- ^{[/ 1з} / 2/3, ^{C /} hl ^di me ^t er ^{LPep Ede} nO / en ^{e l} l / ² l ^2b ut ^{ll /} amine nokarbonylmethllJ enzoove carbamic acid ^{t b} and ⁱ c ⁱ p o ^ staHzaci. of ettanoL · 140 ^to 1 ⁴ 1 ° C ^4з [/ 1з / ^з 2 / C. ^{C / hl} meth ^de l ^p Eper ^de no / ^e en ^yl / 212buten21 / ^L L / ^{amino for} R ^b online ^yl methyl ^t h ^y l] ^b enzoov ^{and KI le} Taj ⁱ c o ^ ^ip staHzad. ETH = acetate p ^ ^s 15 ² and ^{15 3} ° C / right EPO ^{d d b} a NE / ^^ orma /, / z / з4з ^{[/] /} / 6 ^{2 methylcarbazole} з2 / ^pep eri no ^de en ^{f LL} //] / butenз] o ^t e ^pl OTE t ^{i o} n 1 ^42-145 ° C,

2 ^l l / amι ^e nokar ^{b he'll} meth ^{l l}} benzoic acid to ^{y if 4 /} [/ l · ^з / ^4з aιl ^and NO 2 ^{з piperidinecarboxylic e} d ^e amino ^phenyl / - ¹ - ^{-Butyl l /} amine nokar ^{b he'll} meth ^{l] b} enzoov ^s tyserina ohsahuj ^ C ^{i 0,} 5 mL of in ^soil, for te ^pl revolutions ^of counting ^as 118 and ¹²⁰ ° C, the ETH-ester ⁴ з [/] - / ^{4-amino-2з pep} er ^e d ^{e f} no en ^yl // 1 ^/ -but ^yl / ^{amino for} r ^b on ^{methylthiophenyl ll} l ^{t} »e} enzoov lazy M.P. ^^ ^ in ^ that from ether of petroleum ether at 145 to 146 ° C

4- [/] ^з / 5 ^E No ^з am ^{з 2з pep ide} well er ^{f ll} en / ^{з 1з b} ut ^l / well ^e am ^to he ar ^b] methylamino ^ll j ^b ^ enzoová tyse melting at about 227-230 C, eth ^yl ester of 4 / [/] - / 5-aIηino-2-piperidino ^f en ^y l / ^з] - ^b ut ^yl / ^{amino to} arbonllme ^t h ^l lj ^b enz ^{oo e} a ^t e ^p counting ture ^and 1.65 to 1 ⁶² ° C.

et ^hyl ester 4 ^[/ 1з / 5 ^з _C Chloro / 2 / ^PE per ^EDI well ^{phenylpropan-l} / 2] / ^b ut ^l l / am ^e come ^to r ^b on ^l methyl ^t h ^l J ^b enzoov ^e taj ⁱ Ci ^p ^ taHzari of the ether ^at 13 ^7-140 ° C, lazy ny of lazy ^e th ^yl ester ^{4з [/] з} / ^{з 4з} chloro-2 ρ ^e per ⁱ d ^{i f} no en ^l] ./2]2butyl ^/ amine ^b nokar ^yl methyl ^t he h ^yl ben'zoov J ^e o te ^p lo ^t e ^t U ^s 123-125 ° ≤ ^{kY -} teplokyselikyselikyseeth ^{yl es} ter 4 / ^[/ l- / 5 ^зb ROM ^з 2 ^з piperidino ^phenyl] / ^з] ut ^{зb yl} / well ^to an ⁱ r ^b on me ^{th yl. yl} Jbenzoov ^e . 'tyseU / ^t e ^pl ot ^{of th} n ⁱ 1 ^40-142 ° ^' eth ^y le ^s ter ⁴ "[/ l ^з / 4 ^з eluor ^з 2 ^з pi ^p eri ^d inofen ^yl / з] ^зb ut ^yl / An ^i: no ^b ar ^to one ^{ll ll} meth J ^EK YSE enzoov ^{b /} a lot ^of te ^{p th} n ⁱ 110 and ¹¹² ° C, lazy eth ^y le 4 ^with ter / ^[/ l- / of 5-fluoro / 2 - ^pip er ⁱ d ⁱ no ^l // en ^{e] / b} UTL ^l / nokar am ^{e b y online]} benzoic JnethylJ lse ^{ek p h} o te ture mp 127-129 ° C

4- [1- (4-fluoro-2-piperidinophenyl) ethyl / aminocarbonylmethyl] benzoic acid, m.p. 172-175 ° C, 4 - [[1- (4-methoxy-2-piperidinophenyl) -butyl] ethyl ester (aminocarbonylmethyl) benzoic acid, m.p. 115-117 ° C; 4 - [[1- (5-methoxy-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid ethyl ester, m.p. 142-145 ° C; dihydroxypropyl / 4- [[1- (2-piperidinophenyl) -1-butyl] aininocarbonylmethyl] benzoic acid ester, m.p. 120 DEG-122 DEG C. (2-hydroxyethyl) 4 - [[1- (2-piperidinophenyl)] - ester 125 DEG -127 DEG C. 1-Butyl / aminocarbonylmethyl] benzoic acid, m.p. 125 DEG -127 DEG C., 4 - [[1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid, m.p. (2-nicotinoyloxyethyl) 4 - [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid ester, m.p. 132-135 ° C;

152 DEG-154 DEG C. 4 - [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzyl alcohol;

142 DEG-145 DEG C. 4 - [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzaldehyde, m.p. crystallization from a mixture of ether and petroleum ether at 135-137 ° C, 3- (4- (2-piperidinophenyl) -1-butyl aminocarbonylmethyl) -phenyl propionic acid ethyl ester melting after crystallization of 2 petroleum ether at 98-99 ° C, ethyl ester 4 - [/ alpha] -aminocarbonyl-2-piperidinobenzyl (aminocarbonylmethyl) benzoic acid melting after crystallization from acetone at 160-162 ° C, after ethyl 4- (alpha-cyano-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester crystallized from ether / petroleum ether at 114 to 162 ° C; 117 ° C

Kysekysetající

4 - [[alpha] -cyano-2-piperidinobenzyl / aminocarbonylmethyl] benzoic acid melting at 176-180 ° C;

4 - [(1- (2-piperidinecinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid containing a mole of sulfuric acid melting at 192 to 197 ° C with decomposition,

4- [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid containing 0.5 moles of sulfuric acid and 1.5 moles of water, melting at 180-185 ° C and decomposing at 207-210 ° C.

Example 19

4- (N- (alpha) - (4-hydroxyphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzoic acid

1.1 g (2 mmol) of 4- (N- [alpha] - (4-benzyloxyphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid are suspended in 200 ml of ethanol and catalytically debenzylated at 0 DEG C. under a hydrogen pressure of 0.5. MPa in the presence of 0.4 g of 10% palladium on activated carbon. The catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from acetonitrile.

720 mg (66.7% of theory) of the product with a melting point of 202 DEG-204 DEG C. are obtained.

Analysis:

found: C, 72.65; H, 6.17; N, 6.20.

The following compound was also prepared in an analogous manner to Example 19:

eth ^yl ester of 4- [N / ^{5-hydroxy-alpha-phenylpropan-2- yl PIP} eridincbenzy ^l / ^l aminocarbonyl ^{methylcarbazole} Jbenzoové acid.

Of the product of ^t ^ te OTE point ¹ 91 and ^Z 19 3 C ^l-sectional Herein 3 in a yield of ^9% of theory.

Analysis:

H, 6.82; N, 5.93.

Found: C, 73.52; H, 6.57; N, 5.61.

Example 20

4- [N / alpha / -4-methyl-phenyl / -2- ^p i ^p eridinobenz ^yl / ^t h ^y aminocarbonyl ljbenzylalkohol

To a suspension of 0.5 g / 13.2 mmol / lithiumaluminiiimhydridu in 50 ml dry tetrahydrofuran was added portionwise 2.5 ^g / ⁵ 3 MMD / ET ^HY ester of 4- [N ^- / Al ^f and ^- / 4 ^- meth ^{y f} l ^-yl en / ^- 2 ^- p ⁱ piperidin enzymes ^{CB 1} / amino ^for r ^b CN ^ylmethyl] benzcové ^kY] .in ^y.

The reaction mixture was stirred at room temperature for 30 minutes, then quenched by the dropwise addition of 4 N sodium hydroxide solution and the precipitated sodium aluminate was filtered off. The filtrate was evaporated and the residue was recrystallized from a small amount of toluene.

Z ⁱ with a ^Ka of 0.98 g / ⁴ 3% yield / product temperature Subtraction ⁱ 1 ⁴⁴ to 1 ⁴⁶ ° C.

Analysis:

C, 78.47; H, 7.53; N, 6.54.

Found: C, 78.20; H, 7.39; N, 6.58.

The following compound was prepared in an analogous manner to Example 20:

4- N ^ / ^{alpha-phenyl-2- p} iperidinc ^b enz ^y l / amino ^for R ^b CN ^{ylmethyl y} ^ lj nzylalkohol.

Te The product of ^p lot ^of mp 143-1 ° C, ^45-U is the cut ³ in a yield of 1.5% of theory.

Analysis:

C, 78.23; H, 7.29; N, 6.76.

Found: C 78.13, H 7.30, N 6.62.

EXAMPLE 21 • Methylpheyl / -2 2-piperidinobenzene / amino} ka rbonylime th^y1j benzaldehyde^8,85^G / 20 mec^|/⁴-jN²/and^ffand²/⁴“Mtthl^fftyy^F/²2²pietridiyobtyz^l1/ aeiyckar^bcУ^lfetthl¹J^btУzo The gums and 3.25 g (20 mmol) of N, N ' 2-carbonyldiidazate were refluxed in 100 ml of absolute tetrahydrofuran for 2 hours.

The mixture was evaporated and the residue was refluxed again for 2 hours after addition of 50 ml of pyridine and 3.7 g (20% eecf) of 4-trifluorosulfonic acid hydrazide. The reaction mixture is poured into ice water, the precipitate formed is filtered off with suction and dried.

G of anhydrous sodium carbonate was added to the crude carboxylic acid tert-bluesulfonyl phosphide thus obtained, the mixture was heated at 170 DEG C. in 50 ml of ethylene glycol for 2 hours, then taken up in water and extracted with chloroform. silica gel, eluting with toluene / ethyl acetate (5: 1).

1.73 g (21% of theory) of product are obtained.

Analysis:

C, 78.84; H, 7.09; N, 6.57. Found: C, 78.95; H, 7.19; N, 6.50.

The following compound was prepared in an analogous manner to Example 21:

4-N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde.

M.p. 168-170 ° C, yielding 29% of theory.

Analysis: Calculated: C 78.61, H 6.84, N 6.79. Found: C, 78.60; H, 7.00; N, 6.72.

Example 22

4- (N- (alpha) - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzaldehyde

0.5 g (1.2 mmol) of 4- [N- (alpha- [4-methylphenyl] -2-piperidinobenzyl) aminocarbonylmethyl] benzyl alcohol was added to a suspension of 0.4 g (1.5 mmol) of pyridinium chlorochromate in 2 ml of chloroform. After reaction at room temperature for 12 hours, ether was added to the reaction mixture, the mixture was filtered, the filtrate was evaporated and the residue was purified by silica gel column chromatography using toluene / ethyl acetate (5: 1) as eluent.

145 DEG-146 DEG C. 0.3 g (60% of theory) of product is obtained.

Analysis:

C, 78.84; H, 7.09; N, 6.57.

Found: C, 78.97; H, 7.12; N, 6.57.

The following compound was prepared in an analogous manner to Example 22:

4- [N- (alpha- Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde.

Melting point 170 DEG C. yields 40% of theory.

Analysis:

C, 78.61; H, 6.84; N, 6.79. Found: C, 78.59; H, 6.87; N, 6.61.

Example 23

4- (N- (alpha) - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) cinnamic acid ethyl ester

To an ethereal solution of 450 mg (2 mmol) of ethyl ethylphosphonoacetic acid ethyl ester and 100 mg (2 mmol) of 50% sodium hydride was added 427 mg (1 mmol) of benzyl (aminocarbonylmethyl) benzaldehyde.

4-N - [alpha] - (4-methylphenyl) -2-piperidino 244070

The reaction mixture was stirred overnight, then quenched with water and extracted with chloroform. The chloroform evaporation residue was purified by chromatography on a silica gel column using toluene / ethyl acetate (5: 1) as eluent.

Yield ^EZ prctóuk ^to e ^{j t} e ^p a lot ^of the ^T 176 ^{1 8} 0 C is ^0, 1β g / 36% /.

Analysis: Calculated: 77.39% CCl, 31% H, 5.64% N;

Found: C, 77.64; H, 7.25; N, 5.71.

Following the procedure of Example 23, the following compound was prepared.

e ^ethyl ester, ⁴ - [N / ^LF and A- ^{phenoxy-l- yl 2} -p ^ip eri ^di No ^B enz ^yl / ^b ar ^to amino onylmet ^h ylJsfoHcové acid.

For ^d in that ^the temperatures ^of T ^and n ^s and 159 ^{1 6} 1 C ^ U is cut in ^two by the howl ^EZK 8, ^6% of theory.

Analysis:

calculated: C, 77.14; H, 7.10; N, 5.80. Found: C, 77.28; H, 7.21; N, 5.65.

Example 24

4- [N / alpha / ^{4-methylcarbazole} phen ^yl / -2- ^p i ^{p i} erid aminobenzo ^{l /} amine ^b nokar he ^{methylcarbazole yl]} s) co ^{COV s} to ^y Selina.

The title compound is prepared analogously to Example 3, alkaline saponification et ^hyl ester ⁴ - £ N / Al a- ^f / ^{4-methylstyrene} l ^f l ^y en / -2 ^"id ino ^{piperidin b} enzymes ^l / AM but ^{also to the carbonyl} ar e ^{t hyl]} cinnamic acid.

For ^d uct of te ^pl ot ^{th of} n ^s 173 and ¹⁷⁶ DEG C ^ U is cut in a yield of ^84%.

Analysis: Calculated: C 76.90, H 6.88, N 5.98.

Found: C 77.24, H 7.01, N 5.64.

The following compound was prepared in an analogous manner to Example 24:

⁴ -ΓN- / AIFA-phenyl-2-pi ^{and p} Benzyl-piperidine ^{b) B} ON aIπinokar ^yl Mathy ^and .ls ořicová ^{to the} y ina ^sel.

Pr ^of the duct te ^p lot ^of point 177 and ^{1 8} 0 C-U is cut ^{and ease of product} in ^75% howl ^te orie.

Analysis:

C, 76.62; H, 6.65; N, 6.16. Found: C, 76.75; H, 6.57; N, 6.07.

Example

Eth ^yl ester of ⁴ - [N / 5-chloro-alpha- / 2-chloro or ^f · en ^y l / ^2-e pi rridiob enz ^{i e} l / aαlino ^to Ar ^b onylmethyl] ^- benzoic acid methyl ester mmol th ^{e y} ester of ⁴ -iN- / ^IF and a- / ^{l 2-chloro-phenyl} or ^l / n ⁱ -5-nitro-2-pi ^p eri ^d ino enzymes ^{l b} / ^b amlnokar they ^{l m} eth ^yl] -benzo ^memory for ^{y L} in ^{y-extended p} US ^children in ⁵⁰ m ^{l di} me ^th yl ^LFO rmamidu and after ^adding 1 g of Raney-Kyu to h ^y d ^r o ^ge n ^{u is p} s te ^p ture of 60 ° C under pressure ⁱⁿ water ^CART 0.6 u ^'p and M. Kata yzá ^{L T} or the wind ^{dfil J} e. ^f i ^l lo ss ^t was evaporated and the residue consisting of N £ 4- / 5- <Anino-alpha / 2-chlorophenyl / ^ - piperidino benzyVam inokartor ^ ^b ^ ^-alkyl enzoové ^Li ny ^r a ^way Usti ^{in 100 ml o} n t ^r a ^{price of not} '^^ KYSE HCl.

24Q970

A solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water was added dropwise to this solution under ice-cooling, and the mixture was stirred at 0-5 ° C for 1 hour. The reaction mixture was then added dropwise to a solution of 3 g of specific chloride in 25 ml of concentrated hydrochloric acid, the resulting mixture was stirred for 1 hour, then basified with sodium hydroxide solution and extracted with chloroform.

The evaporation residue of the chloroform extracts was purified by silica gel column chromatography using toluene / ethyl acetate (5: 1) as eluent.

M.p. 213 DEG-215 DEG C., yielding 1.5 g (28.6% of theory).

Analysis:

C, 66.28; H, 5.75; N, 5.33; Cl, 13.49;

Found: C, 66.40; H, 5.91; N, 5.41.

The following compound was prepared in an analogous manner to Example 25:

4- [N- (5-chloro-2- (3,3-cis-dimethylpiperidino) -alpha-phenylbenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

M.p. 188-191 ° C, yielding 28% of theory.

Analysis:

C, 71.12; H, 6.80; N, 5.40; Cl, 6.83;

Found: C, 71.95; H, 6.85; N, 5.35; Cl, 6.77.

Example 26

3- [4- (N- (alpha) - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) phenyl] propionic acid

0.91 g (2 mmol) of 4- (N- [alpha] - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) cinnamic acid are dissolved in 50 ml of methanol and, after addition of 0.5 g of 10% palladium on charcoal, catalytic hydrogenation at room temperature under a hydrogen pressure of 0.3

MPa

Upon completion of hydrogen uptake, the catalyst was charged with an amount of acetonitrile.

The product was recrystallized from a small yield of 0.68 g (74%), m.p. 146-148 ° C.

Analysis:

C, 76.57; H, 7.28; N, 5.95.

found 76.41% c, 7.19% H, 5.61% N.

The following compound was prepared in an analogous manner to Example 26:

3? - [N- (alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] phenyl] propionic acid.

M.p. 97 DEG-99 DEG C. yields 65% of theory.

Example

Sodium acid salt

4- (N- (alpha) - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl) benzoic acid

442 mg (1 mmol) of 4- (N- [alpha] - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid are dissolved in 25 ml of ethanol and 1 ml of 1 N sodium hydroxide solution is added.

The reaction mixture is evaporated in vacuo, the residue is stirred with 20 ml of acetone, the precipitate formed is filtered off with suction and washed with ethyl acetate.

410 mg (85% of theory) of product, m.p.

Analysis:

calculated: C, 72.40; H, 6.29; N, 6.03. Found: C, 72.15; H, 6.46; N, 5.93.

The following compounds were prepared in an analogous manner to Example 27:

and [4- (N- [alpha] - (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethanolammonium salt.

188 DEG-191 DEG C., 75% of theory.

Analysis;

C, 71.55; H, 7.41; N, 8.34. Found: C, 71.16; H, 7.48; N, 8.52.

b) diethanolammonium methyl] benzoic acid.

4- [N- [alpha] - (4-methylphenyl) -2-piperidinobenzyl] aminocarbonyl salt, m.p. 178 DEG-180 DEG C., yielding 81% of theory.

Analysis:

C, 70.70; H, 6.86; N, 7.73. Found: C, 70.25; H, 6.75; N, 7.58.

(4-) N- [alpha / [4- (4-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid triethanolammonium salt.

M.p. 160 DEG-165 DEG C. yields 76% of theory.

Analysis: Calculated: C, 69.01; H, 7.67; N, 7.10. Found: C, 68.91; H, 7.64; N, 7.45.

d) 4-p4- [alpha] - [4-Methylphenyl] -2-piperidinobenzyl] aminocarbonylmethyl 1J benzoic acid ethylenediammonium salt.

M.p. 160 DEG-163 DEG C., yielding 65% of theory.

Analysis:

calculated: C, 71.69; H, 7.62; N, 11.15. Found: C, 72.04; H, 7.80; N, 10.96.

Example 1 and d 28 of an acid

4- [N- (5-Ethyl) ethyl ester

5-methoxy-alpha-phenyl-2-piperidinobenzyl / aminocarbonylmethyl] benzoate

In 25 ml of absolute dimethylformamide:

releases 472 mg (1 mmol) of the 4- [n- (5-hydroxy-alpha-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ether ester and added 50 mg

50% sodium hydride was stirred for 30 minutes, then 0> 5 g methyl iodide was added dropwise and the mixture was stirred overnight.

For work-up, the reaction mixture was poured into ice-water and extracted with methylene chloride. The evaporation residue was purified by silica gel column chromatography using toluene / ethyl acetate (4: 1) as eluent.

(53% of theory) of the product, m.p. 123-125 c.

H, 7.04; N, 5.76; C, 6.95% H, 5.61% N.

[Z] -4- [1- (2-Piperidinophenyl) -1-buten-1-yl] aminocarbonylmethyl] benzo [0315] 260 mg are obtained.

Analysis: Calculated: 74.05 Found: 73.86

P. í í 1 and d 29

Ethyl ester (s)

1.0 g of the Z-ester, see Example 9c / J, was heated to 230 ° C in a preheated oil bath for 30 minutes. After cooling, the product was purified by silica gel column chromatography using toluene / acetone (20: 1) as eluent.

The yield of the E-ester melting below 20 ° C is 0.365 g (36.5% of theory).

The yield of the 2-ester, m.p. 115 DEG-117 DEG C. _, is 0.380 g (38.0% of theory).

Heating of the (E) ester with a catalytic amount of iodine in benzene by heating for 3.5 hours affords a mixture of equal parts ([E] - and (Z) -ester according to thin layer chromatography (toluene / acetone 10: 1 as solvent system). .

In analogy to Example 29, the following compound was obtained:

(R) - and (Z) -4- [1- (6-methyl-2-piperidinophenyl-1-buten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester.

A mixture of equal parts (E) - and (Z) -ester is obtained from the corresponding (Z) -ester according to thin-layer chromatography.

Upper spot (Е): calculated m / e = 434 found m / e = 434 Lower spot (Z): found m / e 434.

Example 30

4- [1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid sodium salt containing 0.5 mol of water

Dissolve 10.0 g (25.35 mmol) of 4 - [[1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl benzoic acid at 50 ° C in 200 ml of ethanol and add 25,35 ml of 1 ml of the solution to 50 ° C. N sodium hydroxide solution. The mixture is evaporated to dryness in vacuo and the residue is dissolved in a minimum of ethanol under heating on a steam bath.

The solution is cooled in ice, the precipitated crystals are filtered off and, after washing with ether, dried at 140 DEG C./20 mbar.

9 g (85.3% from 255 ° C) are obtained.

of theory (m.p. 280 DEG-285 DEG C.) melts with decomposition

Analysis: (x 0.5 H ₂ O) calculated C, 67.74; found, C, 67.86.

H, 6.87; N, 6.58;

H, 7.13; N, 6.49.

Example. 31

4 ~ [/ l- / 4-ain oo ^{n-3 -} P ⁿ When no ^{NDI f} ro ^ll / ^-lb ut ^l l / ⁿ am ookaíboo lmrt ^hIL Jbenzoová ^y to ^{y ln} cycloalkyl containing 0.5 mol of water;

0.60 ^g / ¹ 365 mmol / 4- ^[/ l- / 4-nitro-2-ρiper ⁿ d ^{i f} no en ^y l / ^- l ^- -but ^LL / am ^{n b} Ooka ^he'll MRT ^hl lJbenzoové acid in 10 ml dnmrthllfornamndu in the presence of 0.1 g of 10% palladium-activated OA • Magyars 3 h ⁿ o ^{l l} díogroujr h ^at rt ^t ep ^{l of 25} ° C under hydrogen at button ^{for Mp} and ^0.1.

The catalyst is filtered off through silica and stabilized from ether.

the filtrate was evaporated in vacuo. The residue was crystallized to give 0.41 g (73.2% of theory) of product, m.p. 118-120 ° C

Analysis: / x 0.5 calculated 68.87 found 68.62 _{2 2} о /% C,% C,

7.71

7.64

H, 10.04

H, 10.08% Nj% N.

Analogous procedure

and.

acid.

By way of example, the following compounds are obtained:

- _. _ In _ _ _ _ ^ h ^ ster 4 - [/ l- / 4-amino-2 oo ^N p ^N When ^ndn OQ ^f ro ^l l / -l- ^b ut ^yl / am ⁿ Ooka ^b oo ^l LNet ^h l ^{l] b} enzoové ^p ro ^d u ^k t ^s after melting Cr ^ taHzací. ze smfoi. ether prtío ^l rthrru ^{BC, from 145} to ¹⁴⁶ ° C results in a yield of 81.7% of theory.

Analysis:

C, 71.37; H, 8.06;

Found: C, 71.50; H, 8.08; N, 9.68.

b / ⁴ - [/ l- / ^5-AMNOTE-2-n Prepn diooero ^l l / -l- ^b ut ^l / n ⁿ oo Ooka ^b mr ^{thll yl] á} beozoov RyseHoa.

^P roducts of te ^pl ol ^E t ^and RI ^227, and ^from 230 ° C results in a ^64% effluent.

Analysis:

C, 70.39; H, 7.63; N, 10.26.

Found: C, 70.54; H, 7.54; N, 10.36.

c) ethyl acid.

⁴ - ^[/ l- / 5-amino- ^{N oo-2} p ⁿ at ⁿ d ^{e n} oo rn ^l / -l- ^b ut l ^y / n ^{b n} Ooka lmrth oo ^{l l} l ^{j p} benzoic birth ^to it tejolotě táoí 1 ⁶² to ¹⁶⁵ ° C results in a howl ^EZK at ^84.3% of theory.

Analysis:

calculated: C, 71.37; H, 8.06; N, 9.60. Found: C, 71.58; H, 7.83; N, 9.65.

Example 32

E ^ kst ^ lioy

4 - [/ l- / 5-Chloro-2-Prepn ⁿ d ^{e n} oo ro ^ll / ^- l- ^b ut ^{l / h} aniookarЬoollnrt llJ benzoic KYSE ^-

From 2.0 g / 4.5 7 mmol / TEM ethyl-4 - [/ l- / 5- ^<Amino-2-yl piperidnnoeen l / -l-but ^y L / шniookaíbonllmrth ^l l] ^ brnzoové гНо ¹ 4.8 ml of děoé ^ ^ sel ^ ¹ s ^ rovodíkové and ^0, 3, ¹⁵ g / ⁴ l 57 ^mmol / sodium nitrite in 1.66 ml of water to prepare a solution diazooiové salt at 0 ^o C.

The mites ^{on PRN} ture te ^P O ^{and 5} ° C, eg about ^{d nk} APE stirred mixture ^of 0.59 g of ^{n / 5,} 94 ^{mmol /} c ^hl o240970 measuring chloride and 2.4 ml of concentrated hydrochloric acid and the mixture was then heated in a bath at 50 ° C. After completion of the gas evolution (about 15 minutes), the reaction mixture was cooled, added to ice / concentrated ammonia, and extracted four times with 100 ml of ethyl acetate each time.

The combined organic extracts were shaken with water and, after drying and filtration, evaporated in vacuo. The residue is purified by silica gel column chromatography using toluene / ethyl acetate / 10:

1) as eluent,

0.80 g is obtained

140 [deg.] C.

40% of theory

Analysis: calculated 68.32 found 68.42% C,% C,

7.27

7.09

The following compounds were obtained in an analogous manner to Example 32:

and [4- [1- (4-chloro-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid ethyl ester.

The product, m.p. 123 DEG-125 DEG C., yields 21.9% of theory

Analysis: calculated 4-J [1- (5-bromo-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid b) ethyl ester.

M.p. 140 DEG-142 DEG C., yielding 53.8% of theory.

Analysis: Calculated Found

C, 6.63; H, 15.93

C, 6.78% H, 15.85

N;

N.

(4-J) 1- (4-Fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Melting point 110 DEG-112 DEG C. yields 21.6% of theory.

Analysis:

C, 70.88; H, 7.55; N, 6.36.

Found: C, 71.01; H, 7.53; N, 6.21.

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

d) 4-I [1- (5-fluoro-2-piperidinophenyl) -1-butyl] aminocarbonylmethyl 1-benzoic acid ethyl ester.

M.p. 127 DEG-129 DEG C. yields 2% of theory.

Analysis:

calculated: m / e «440 found: m / e = 440.

e / 4c [/ i / f ^{i c} 4 ^c 2cpiperidinofeny fluoro ^and / ethyl / aminokarbonylmethylj benzoic acid to ^{α y} SEII.

Melting point product

172 DEG-1.75 DEG C., in a yield of 16.9% of theory.

Analysis: calculated 6 8.73 i C, 6.55% I, N, 7.29 found 68.78 3 C, 6.62% H, 7.31% N

Example 33

Eth ^yl ester of 4 - [/ 1- / 4 -methhxy ^y 2 ^p i ^p erLdinofenyll-I-bu ^t yl / amieokαrbney Bnethy ^ tenzoové acid.

To the 548 mg / 11.4 mmol / NaH / 50% dispersion in oil / in 10 ml of absolute dimethylformamide was added dropwise at RT a solution of 5.0 g / 11.4 mmol / ethyl ^{4c [/ IC} / ^4CH 2 ^c ydrnxy ^c piperidienfeey ^and / ^CIC butyl ^{l /} amine enkar ^b nn ^{y |} met ^{hy |} Jbenzoové KYSE ^If ny in 45 ml. of absolute dimethylformamide.

After stirring for 15 minutes, a solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of absolute dimethylformamide was slowly added dropwise. The reaction mixture was stirred at room temperature for 2.5 hours, then evaporated in vacuo and partitioned between water and ether.

The ether phase was dried, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with toluene / acetone (20: 1).

To afford 1, ^{8 g / 34,} 9% of theory / ^p roducts ^pl of TE OTE counting ^I 115 and ^from 117 ° C.

Analysis:

C, 71.65; H, 8.02; N, 6.19.

Found: C, 71.47; H, 7.86; N, 6.19.

In analogy to Example 33, the following compound was obtained:

^Ethyl ester ^{4 of the} acid. ^[/ 1c / ^2c 5cmethnxyc ^p i ^p er ⁱ dieofeey ^| / c1c ^b uty ⁱ / α-thiocarbonyl methylbenzoates

^P roducts for counting a temperature between approximately ¹⁴² to 1 ^{s 45} ° C ^l Herein incision in ^the mined at ^68.4% of theoretical ^and e.

Analysis:

C, 71.65; H, 8.02; N, 6.19. Found: C, 71.87; H, 8.06; N, 6.38.

Example 34 / '2cni ^to ntinnylnxyethyl / ester oic acid

4- ^| / 'lc / 2-β-piperidinophenyls ⁱ / cl- ^b uty ^l / amien ^to αr ^b ney ^| Methyl ^j benzoK solution of ^{2. 0} g / ^{l 4.5} 6 mmol / ^^ ydroxyeteyVesteru ⁴ - ^[/ l- / 2- ^beta iperidinnfeey ^l / ^- l. ^{- t} Bu У ^l / AM ^IC but ^{also to} αrboey ^{methylphenoxy]} beezonvé ^k yse ⁱ ie ^y at 40 m ^l met ^h y ^| eec ^hl NR du ⁱ and ⁰ 7.ml './ ⁴ ^ _i ^ J ⁸ 1 mmoV ^l triethyl amine. a solution of 0.7 g (4.68 mmol) of hicotinic acid chloride in 20 ml of methylene chloride is rapidly added dropwise with stirring.

^The reaction ^{mixture flows} with 2.5 hrs It is stirred ^Pr I ^{m p} te Lot ^{of 2} ^ ^p 0 and in ^{row y} t e ^p e ^d in ou organteká ^FA from ^{an e} dried, filtered and evaporated in vacuo. The residue is purified by chromatography. on a silica gel column using toluene / acetone (5: 1) as the eluent.

^Ne with ^k and ^1, 1 g ^{/ 44%} / ^{p on} the genus. about the temperature of melting. ^132-135 ° C.

Analysis:

C, 70.70; H, 6.86; N, 7.73.

Found: C, 70.82; H, 6.82; N, 7.91.

! Example 35

AND

11- [1- (2-Piperidinophenyl) -1-butyl / aminocarbonylmethyl] benzyl alcohol

To a suspension of 0.68 g (17.95 mmol) of lithium aluminum hydride in 25 ml of absolute tetrahydrofuran at 0 ° C was added dropwise a solution of 5.0 g (11.83 mmol) of ethyl 4- (1- (2-piperidinophenyl)) ethyl ester. of 1-butyl / aminocarbonylmethyl] benzoic acid in 75 ml of absolute tetrahydrofuran.

The reaction mixture was stirred at room temperature for 20 hours, then cooled to 0 ° C and 4 N sodium hydroxide solution was slowly added dropwise until a filterable precipitate formed. The precipitate was filtered off and boiled several times with ether.

The combined organic solutions were evaporated in vacuo and the residue partitioned between water and ether. The ether phase was dried, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using toluene / acetone (5: 1) as eluent.

Yield: 1.0 g (22% of theory);

Example 36

4- [1- (2-Piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzaldehyde

6.6 g (62 mmol) of sodium carbonate together with 62 ml of ethylene glycol are heated in a 170 [deg.] C. bath and 6.2 g (11 mmol) of N &^lt; 4 &gt; (2-Piperidinophenyl) -1-butyl (aminocarbonylmethyl) benzoyl -N- ^2- tosylhydrazine, m.p. 195 DEG C. (decomposition), with vigorous gas evolution.

The reaction mixture was then heated at 170 ° C for a further 2.5 minutes before being poured onto ice. The mixture is extracted with ether, the extract is dried and, after filtration, evaporated in vacuo. The residue was purified by silica gel column chromatography using a 20: 1 mixture of chloroform and acetone as eluent.

2.2 / 52.9% of theory / product of melting point 142 DEG-145 DEG C. are obtained.

Analysis:

H, 7.99; N, 7.40. Found: C, 76.26; H, 7.96; N, 7.37.

Example 37

4-J [1- (2-Piperidinophenyl) -1-butyl / aminocarbonylmethyl] cinnamic acid ethyl ester

To 0.60 g (12.5 mmol) of sodium hydride (50% dispersion in oil) in 15 ml of absolute dimethylformamide was added dropwise a solution of 2.80 g (12.5 mmol) of ethyl ethylphosphonoacetic acid ethyl ester in 10 ml of absolute dimethylformamide dropwise at room temperature.

The mixture was stirred for 15 minutes (until gas evolution ceased) and a solution of 2.4 g (6.34 mmol) of 4-p'- (2-piperidinophenyl) -1-butyl / aminocarbonylmethyl] benzaldehyde in 10 ml was added dropwise. of absolute dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours, then evaporated in vacuo and the residue partitioned between water and ether. The ether phase was dried, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using silica gel column chromatography using toluene / acetone (10: 1) as eluent.

0.85 g / 29.9% of theory / melting after kryytalizaci from ether ^O 137 <

and petroleum ether at 1335 to

C.

Analysis: Calculated Found

74.97%

74.91%

C, c,

H, 8.09; N, 6.24.

H, 7.89; N, 6.29.

Example ⁴ - (/ L / 2-piperidinofeny ^l / ^{-l-butyl-l /} amine aminocarbonyl ^-yl meth ^yl] SKO ico ^{weighing of y} to Selina

The title compound is prepared analogously to Example 11 ^while alkaline ^{saponification} e ^{e th} yl smear ⁴ - ^{(/ L} - ^/ 2- ^ Iper amino ^{phenyl idi l} / - ^l - ^b l ^y ut / ^{amino to} Arbon ^{ylmethyl yl] sk} ° ^s Cove acid.

Produ ^to the te ture ^{p th} n ^s IL80 to 183 ° C, ^T U is in a resulting howl ^EZK at 64%.

Analysis: Calculated Found

74.26%

74,03%

H, 7.67; N, 6.66.

H, 7.47; N, 6.80.

Example

Ethyl 3-m - (/ L - / 2-piperidinophenyl / -1-butyl / aminocarbonyl ^{ylmethyl yl]} fenyljpropionové acid

0.60 ^g / 1, ³⁴ mmol / řlcové acid in 10 ml hydrogenated at eth ^yl ester of 4- (/ L / ^2-f piperidno en ^y l / -l-but ^y l / ^l an aminocarbonyl ^ylmethyl] skoethanolu The reaction mixture was then filtered and evaporated in vacuo to give 0.20 g of 10% palladium on charcoal at room pressure under 50 psi of hydrogen.

to

0.53 g ° C is obtained.

(88% of theory) of product melting after crystallization from petroleum ether at 98

Analysis: Calculated: C, 74.63;

H, 8.50; N, 6.22.

zeno

% C, 74.64;% H, 8.58;% N, 6.23.

By analogy to Example 39, the following compound was obtained;

^{3- [4} - [/ ^l - / ^2-piperid aminophenyl ^yl / -l- ^b ut ^yl / Aminocarbonyl ^{ylmethyl yl] phenoxy-sulfonic yljp} ro ^pi to ^gamma Selina.

^P roducts of te Lot ^E t ^{p ck} 131 and ^{1 33} ° C results ^from the ^63% yield of theory.

'Analysis:

C, 73.90; H, 8.11; N, 6.63. Found: C, 73.96; H, 8.30; N, 6.56.

he said

3- [4 - [/ l- / 2 ^p i ^{p d} eri amino ^phenyl / -l-but ^y l / ^{amino b} ar ^to those me ^{th l yl] phenyl]} propionic acid.

The title compound is prepared analogously to Example 11 by alkaline saponification ^of n ^e m eth ^yl ester of 3- 4- £ ^j / L / 2-P ^ip er ^driver aminophenyl ^yl / -l-but ^yl / ^{amino to} ar ^b he ^ylmethyl-yl Jfenyl ^{J '-} propionate.

Melting point 131 DEG-133 DEG C. yields 50% of theory.

Analysis:

C, 73.90; H, 8.11; N, 6.63.

Found: C, 73.82; H, 8.07; N, 6.41.

Example 41

4- | [alpha-Cyano-2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester

To 520 mg (1.22 mmol) of 4 - [(. Alpha.-aminocarbonyl-4-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester in 0.22 mL of pyridine was added 234 mg (1.22 mmol) of 4-toluenesulfochloride in two portions and warmed further. at 50 ° C.

After 2 hours, again the same amounts of pyridine and 4-toluenesulfochloride were added after 1 hour as above, and the resulting mixture was stirred at 50 ° C for an additional hour. After standing at 20 ° C for 2 days, 2 N NH 4 OH was added and the reaction mixture was extracted with chloroform.

The chloroform solution is shaken twice with water, dried and, after filtration, evaporated in vacuo. The residue was purified by silica gel column chromatography using a 10: 1 mixture of chloroform and methanol as eluent.

325 mg (65.7% of theory) of product melting after crystallization from a mixture of ether and petroleum ether at 114 DEG-117 DEG C. are obtained.

Analysis:

C, 71.09; H, 6.71; N, 10.36.

Found: C, 70.79; H, 6.56; N, 10.10.

Example 42

4- [1- (2-piperidinophenyl) -1-butyl / aminocarbonylmethyl] benzoic acid containing mole of sulfuric acid

To a solution of 1.0 g (2.53 mmol) of 4 - [[1- (2-piperidinophenyl) -1-butyl / aminocarbonylmethyl] benzoic acid in 50 ml of ethanol was added 5 ml (2.50 mmol) of 1 N sulfuric acid. The reaction mixture was evaporated in vacuo to dryness and the residue triturated with acetone.

0.80 g (65% of theory) of product melting with decomposition at 192 DEG-197 DEG C. is obtained.

Analysis:

C, 58.53; H, 6.55; N, 5.69; S, 6.49; found: C 58.05, H 6.54, N 5.49, S 6.35.

In the same manner as in Example 42, the following addition salt was obtained:

4- [1- (2-piperidinophenyl) -1-butyl] aminocarbonylmethyl] benzoic acid containing

0.5 mol sulfuric acid and 1.5 mol water.

The title compound was prepared in an analogous manner to Example 42 using half the amount of sulfuric acid.

The product melting at 180-185 ° C and decomposing at 207-210 ° C resulted in a yield of 59.3% of theory.

Aialysis:

C, 61.26; H, 7.28. 5.95%. N, 3.40% N Found: C 61.28, H 6.99, 6,10% N, 3.23% S

SUBJECT MATTER

Claims (6)

A process for the manufacture of substituted phenylalkylamides of a substituted phenylacetic acid of the general formula I (1), in which A represents the remainder of the formula CH or where R ₄ is C 1 -C 3 alkoxy or phenyl substituted C 1 -C 3 alkyl, n-propyl, C 4 -C 6 alkyl, C 3 -C 5 alkenyl, cyano, aminocarbonyl , aryl of 6 or 10 carbon atoms, optionally mono- or disubstituted halogen atoms, alkyl, hydroxyl, alkoxy, phenylalkoxy and / or alkylsulfenyl groups, the substituents may be the same or different and each alkyl moiety may each contain 1 to 3 atoms carbon, or is a naphthyl, pyridyl, quinolyl or isoquinolyl group, R 5 and R 6 are either the same or different and are each a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R 8 and R 8 together with the intervening carbon atom form a phenylalkylidene group having 1 to 4 carbon atoms in the alkylidene moiety, R ^R represents an optionally alkyl groups having from 1 · to 3 carbon atoms mono- or disubstituted with straight alkylene- '4-9 carbon atoms or containing dialkylaminoskuplnu in each alkyl moiety has 1 to 5 carbon atoms, R 1 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro group, an alkyl or alkoxy group containing in each case 1 to 3 carbon atoms or the like. in the case where R5 and R8 are as defined above, and R5 denotes an alkoxy group having from 1 to 3 carbon atoms or a phenyl group substituted by an alkyl group having from 1 to 3 carbon atoms, n-propyl, an alkyl group having from 4 to 3 carbon atoms; C 6 -C 3 alkenyl, C 3 -C 5 alkenyl, nitrile or aminocarbonyl represents R iodo, hydroxyl or amino, C 1 -C 3 alkyl, hydrogen or halogen; and W represents a methyl group, a hydroxymethyl group, a formyl group, a cyano group, a carboxyl group, a carboxymethyl group, a 2-carboxyethyl group, a 2-carboxyethenyl group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms one or two hydroxy, (C1-C3) alkoxy or pyridinecarbonyloxy, furthermore alkoxycarbonylmethyl, 2-alkoxycarbonylethyl or 2-alkoxycarbonylethenyl, the alkoxy groups may in each case contain 1 to 3 carbon atoms, their optical antipodes and their salts, in particular their salts, physiologically tolerable addition salts with inorganic or organic acids or bases, characterized in that the amine of the formula II (II) in which: A, R ₃ and R ₂ are as defined above, or, if A is the aforementioned vinylidene group, its tautomer or its lithium or magnesium halide complex, it is reacted in a solvent with a carboxylic acid of formula III (III) in which R ₃ is as defined above and W * is as defined above for W or represents a carboxyl group protected by a protecting group, or a reactive derivative thereof prepared in a reaction mixture thereof, and the protecting group used is optionally cleaved, followed by optionally obtaining a compound of formula I wherein W represents a carboxyl group or the aforementioned alkoxycarbonyl group and the other substituents are as defined above, by conversion to the corresponding compound of formula I wherein W is a formyl or hydroxymethyl group and the other substituents are as defined above, and / or the optionally obtained compound of formula I, in which w represents a carboxyl group and the other substituents are as defined above, by conversion to an acid hydrazide and subsequent disproportionation to convert to the corresponding compound of formula I wherein W represents a formyl group and TATE substituents have the abovementioned meaning _{of T} and / or optionally the obtained compound of formula I wherein W is formyl and the other substituents are as defined above, condensation and optional subsequent hydrolysis and / or decarboxylation into the corresponding compound of formula I, wherein W is the aforementioned 2-alkoxycarbonylethenyl or 2-carboxyethenyl group and the other substituents are as defined above, and / or the optionally obtained compound of formula I wherein W is a 2-carboxlethenyl or the aforementioned 2) alkoxycarbonylethenyl group and the other substituents have the above catalytic hydrogenation converts to the corresponding compound of formula (I) wherein W is 2 (carboxyethyl or the aforementioned 2-alkoxycarbonyl ethyl group and the other substituents are as defined above) and / or the compound obtained is A compound of formula (I) wherein W represents the above-mentioned alkoxycarbonyl group substituted by a beta / carbon group and the other substituents are as defined above converts acylation with a plenecarboxylic acid to the corresponding (pyridine) carbonyloxy alkoxy / carbonyl compound of formula (I), and / or the resulting compound of formula I in which R2 is nitro and the other substituents are as defined above, the reduction is converted to the corresponding compound of formula I in which R2 is amino and the other substituents are as defined above, and / or the optionally obtained compound of formula In which R2 represents an amino group and the substituents have the meaning given above, the corresponding diazonium salt is converted to the corresponding compound of formula I in which R2 represents a hydrogen or halogen atom, a group or aforementioned alkoxy group and the other substituents have the aforesaid and / or popřip and a number of other hydroxyl responses obtained. a compound of formula (I) wherein R 2 is hydroxy and the other substituents are as defined above will convert the alkylation to the corresponding compound of formula (I) wherein R 2 is the above alkoxy and the other substituents are as defined above and / or the compound obtained of formula (I), wherein R 4 represents an aminocarbonyl group and the other substituents have the meaning given above, dehydrates to the corresponding one. a compound of formula I wherein R is cyano and the other substituents are as defined above, and / or the optionally obtained compound of formula I, if it contains a chiral center, has been separated into the enantiomers on the chiral phase, and / or the compound of formula (I) is converted into a salt thereof, especially a compatible salt with an inorganic or organic acid or base. chromatography. its physiologically 2. A process according to claim 1 for the preparation of compounds of the formula Ia in which ^R @ 4a (Ia), ^R @ ¹ or disubstituted (heptamethylene) is optionally C1 -C3 -alkyl or mono- or branched C4 -C6 -alkyleneimino; , an octamethylene methylene group, a nonamethylene methylene group or a dealkylamino group having 1 to 5 carbon atoms in each alkyl moiety,. ^{R 2a} represents a fluorine or bromine atom, a chlorine atom in the 3, 4 or 6 position, a nitro group, an alkyl or alkoxy group containing 1 to 3 carbon atoms in each case, or a hydrogen or chlorine atom in position 5 if either ^{R 1a} represents an unbranched 6 carbon atoms substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, hepta / methyleneimino, octamethyleneimino, nonamethyleneimino or dialkylamino of 1 to 5 carbon atoms in each alkyl moiety, and / or R _4a represents an aryl group having 6 or 10 carbon atoms, optionally mono- or disubstituted halogen atoms, alkyl, hydroxyl, alkoxy, phenylalkoxy and / or alkylsulfenyl groups, which substituents may each contain 1 to 3 carbon atoms in the alkyl moiety; naphthyl, pyridyl, quinolyl or isoquinolyl groups, and / or W a is hydroxymethyl, formyl, cyano, 2-hydroxycarbonylethenyl, 2-hydroxycarbonylethyl, 2-position alkoxycarbonyl substituted with ethylene, or 2-position substituted one or two alkoxycarbonyl groups, wherein the alkoxycarbonyl group may each contain a total of 2 to 2 4 carbon atoms, and / or R _3a represents a halogen atom, ^R 4a represents optionally halogen atoms, alkyl, hydroxyl, alkoxy, phenylalkoxy, and / or alkylsulfenyl groups of mono- or disubstituted aryl of 6 or 10 carbon atoms, which substituents may be the same or different and their alkyl groups the moieties may each contain 1 to 3 carbon atoms or represent a pyridyl, quinolyl or isoquinolyl group, R _3a represents a hydrogen or halogen atom and W a represents a carboxyl group, a formyl group, a hydroxymethyl group, a cyano group, a 2-hydroxycarbonylethenyl group, a 2-hydroxycarbonylethyl group, a C 2 -C 5 alkoxycarbonyl group, an 2-position substituted alkoxycarbonyl group or wherein the alkoxycarbonyl group may in each case contain a total of 2 to 4 carbon atoms, their optically active antipodes and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, characterized in that the amine of the formula (IIa) wherein ^R 1a, ^R 2a ^{and R} 4a are as defined above, reacted in a solvent with a carboxylic acid of formula IIIa HOOC-CH. / Ша / in which R _3a is as defined above and W a is as defined above for W a or represents a carboxyl group protected by a protecting group or a reactive derivative prepared therefrom in the reaction mixture, and the protecting group used is cleaved, whereupon the optionally obtained compound of formula Ia is cleaved wherein Wa represents a carboxy group and the other substituents have the meaning given point, is converted by esterification or amidation 'to the corresponding compound of - formula Ia and / or nebo'se obtained compound of formula Ia wherein R2 is nitro _and the other substituents are at this point, by reducing to the corresponding compound of formula (Ia) in which R _2a is amino and the other 'substituents' are as defined in this point, and the compound thus obtained. of formula (Ia) wherein R _2a is amino and the other substituents are as defined herein, is converted, via the appropriate diazonium salt, into the corresponding compound of formula (Ia) wherein R _2a is hydrogen, fluorine, chlorine or bromine or hydroxyl and the other substituents at this point as above, whereby thus possibly resulting compound of formula Ia in which R _2a represents a hydroxyl group and the other substituents found in this point as above, optionally alkylating to a corresponding compound of formula Ia wherein R 2 _and represents the above "alkoxy, and other substituents found in this Section above, and / or optionally the resulting compound of formula Ia, read in conjunction with R" _and means Aton chlorine or bromine and the other substituents at this point as above, by dehalogenation into the corresponding compound of the general formula e Ia, wherein R 1 represents a hydrogen atom and the other substituents are as defined herein, and / or the optionally obtained compound of formula Ia, wherein Wa is a carboxyl or alkoxycarbonyl group as defined above, and the other substituents are as defined herein is converted to the corresponding compound of formula (Ia) in which Wa represents a formyl or hydroxymethyl group and the other substituents are as defined at this point, and / or the optionally obtained compound of formula (Ia) in which -Wa represents a formyl group and others . the substituents have the meaning given at this point, by condensation and optionally subsequent hydrolysis and / or decarboxylation to convert to the corresponding compound of formula Ia in which Wa represents an ethenyl group substituted by a hydroxycarboryl or alkoxycarbonyl group and the other substituents find at this point, and / or the optionally obtained compound of formula (Ia) in which Wa is a carboxyl group and the other substituents * are as defined at this point by conversion to sulfonic acid hydrazide and subsequent disproportionation to the corresponding compound of formula (Ia) in which Wa is a formyl group and others the substituents have the meaning given at this point, and / or the optionally obtained compound of formula (Ia) is separated into the individual enantiomers by resolution of the racemate, and / or the obtained compound of formula (Ia) is converted into its salt , in particular to a physiologically tolerable salt thereof with an inorganic or organic acid or base. 3. Process according to claim 1 for the manufacture of compounds of general 'formula lb / lb / in which _RJB ^ředstavu P i ^E unbranched alkylene- with 4-8 carbon atoms or a mono- or piperidino dlsubstltuovanou alkyl groups having 1 to 3 carbon atoms, R _2b represents a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl or alkoxy group containing from 1 to 3 carbon atoms, a hydroxy group, a nitro group or an amino group, and represents a hydrogen, fluorine, chlorine or bromine atom, Wb represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and Ab represents the remainder of the formula wherein R @ _b is optionally C1 -C3 alkoxy or phenyl substituted C1 -C3 alkyl, C4 -C6 alkyl, C3 -C5 alkenyl, cyano or aminocarbonyl, and Rg _b and Rg _b are bus same or different and are hydrogen or alkyl having 1-5 carbon atoms, or RGB and Rg _b together with the carbon atom which is between the two symbols constitute fenylalkylide radical containing 1-3 carbon atoms in the alkylidene part, the optically active antipodes and salts thereof, in particular their physiologically tolerated salts with inorganic or organic acids or bases, characterized in that the amine of formula (IIb) in which (ИЬ), Ab, R _1b and R _2b are as defined above, or, if Ab is the abovementioned vinylidene group, its tautomer, its lithium or magnesium halide complex, is reacted in a solvent with a compound of formula IIIb (ШЬ) in which R _3b is as defined above and Wb 'has the meaning given above for Wb or is. a carboxyl group protected by a protecting group, or a β reactive derivative thereof prepared in the reaction mixture, and the optionally used protecting group is cleaved off, whereupon the optionally obtained compound of the general formula (Ib),. wherein W b represents a carboxyl group and others. the substituents have the meaning given herein, by esterification to the corresponding compound of the general formula. Ib, and / or optionally the resulting compound of formula Ib, wherein R 2b represents nltroskupinu · and other substituents at this point as above, by reduction into the corresponding compound of formula Ib ·, .in which R b represents ₂ - amino and the other the substituents are as defined at this point, and / or the optionally obtained compound of the formula Ib in which R 2b is amino and the other substituents are as defined at this point is converted to the corresponding compound of the formula Ib in which R 2 is represents a hydrogen or halogen atom, a hydroxy group or the aforementioned alkoxy group and the other substituents are as defined herein, the compound of formula Ib thus obtained, wherein R 2b represents a hydroxy group. and the other substituents are as defined herein, optionally converted by alkylation to the corresponding compound of formula Ib, wherein R R is the above alkoxy, and other substituents are as defined herein, and / or the optionally obtained compound of formula Ib wherein R 4b represents an aminocarbonyl group and the other substituents are as defined herein, dehydrated to the corresponding compound of formula Ib, wherein ₽ 4г is cyano, and the other substituents are as defined herein, and / or the racemate optionally obtained the compounds of formula Ib are cleaved into individual salts, and / or the optionally obtained compound of formula Ib is converted into a salt thereof, in particular into a physiologically compatible salt thereof with inorganic or organic acids or bases. 4. The process according to claim 1, wherein the reaction is carried out in the presence of an acid activating or dehydrating agent, optionally in the presence of an inorganic or tertiary organic base. 5. The process according to claim 1, wherein the reaction is carried out in the presence of an amine activating agent, optionally in the presence of an inorganic or tertiary organic base. 6. Process according to claims 1-5, characterized in that the reaction is carried out at R25 ° to 120 ° C, preferably ^p s ^p te Lot ^of -10 DEG C., ^and the boiling point of the pulse-use ^zit e ^H o ^ maiden u ^ ědJa.