JPS5921657A - Novel phenylacetic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention comprises novel phenylacetic acid derivatives of the general formula and their enantiomers and their salts with organic or inorganic acids or bases, in particular their physiologically acceptable salts, these compounds The present invention relates to a pharmaceutical composition and a method for producing the same.

These new compounds have useful pharmacological properties, especially effects on metabolism, as well as favorable hypoglycemic effects.

In the general formula (3) above, human represents a group of the formula or , where R4 is a 1 to 6 carbon atom, optionally substituted by an alkoxy group having 1 to 3 carbon atoms or by a phenyl group. Alkyl group having atoms: Alkyl group having 4 to 7 carbon atoms: Alkenyl group having 3 to 5 carbon atoms Nidiano or alkyleneiminocarbonyl group having 4 to 6 carbon atoms in the alkyl part: Z an aminocarbonyl group optionally substituted with an alkyl or phenylalkyl group having 1 to 6 carbon atoms in the alkyl part of Alkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups may be mono- or di-substituted, if VC, 6-1: Aryl group having up to 10 carbon atoms (where substituted The groups may be the same or different and in each case the alkyl moiety may contain 1 to 3 carbon atoms); or 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms. R5 and R6 may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R5 and R6 represent a carbon atom between them; together represent a phenylalkylidene group having 1 to 4 carbon atoms in its alkylidene moiety; represents a branched argyleneimino group or a dialkylamino group having 1 to 5 carbon atoms in each alkyl moiety, R2 is a hydrogen, fluorine, chlorine, bromine or iodine atom, or hydroxy, trifluoromethyl, nitro, amino , biverizono, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl,
Phenylalkoxy, alkanoyloxy, alkanoylamino, alkylamino or dialkylamino groups (
The alkyl moiety here represents in each case 1 to 6 carbon atoms, R3 represents an alkyl group having 1 to 3 carbon atoms, or a hydrogen or halogen atom, and W represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which the alkyl part may be substituted by a phenyl group, and from the β-carbon atom, from 1 or 2 hydroxy radicals, or from the alkoxy , alkanoyloxy, dialkylamino, alkyleneimino or pyridi/carbonyloxy groups, the alkyl portion of these groups being 1 to 6
carbon atoms, and alkyleneimino groups can contain 4 to 6 carbon atoms): alkenyloxycarbonyl groups containing 4 to 6 carbon atoms in total: 1
Alkyl group with ~6 carbon atoms; hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethynyl, 2,2-bis-(carboxy)-ethyl, alkoxycarbonyl- Methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonyl-ethenyl or 2.
2-bis-(alkoxycarbonyl)-ethyl radical, in which the alkyl group can contain in each case 1 to 6 carbon atoms.

The above definitions for the groups R1 to R6 and W include the following groups, for example: R1 is dimethylamino, diethylamino, di-n-propylamino, cy-n-butylamino, di-n-pentylamino, cyinzo. thylamino, N-methyl-ethylamino, N-methyl-Q propylamine, N-methyl-
Inpropylamino, N-isopropyl-n-zorobi2
Ruamino, N-inbutyl-n-propylamine, N-
Methyl-n-butylamino, N-ethyl-n-butylamino, N-ethyl-isopropylamino, N-ethyl-
n-pentylamino, N-propyl-n-butylamino, pyrrolidino, piperidino 1, xamethyleneimino, heptamethyleneimino, octamethyleneimino, nonamethyleneimino, methyl-pyrrolidino, zomethyl-virolizono, ether-pyrrolidino, methyl-piperidino , ethyl-piperidino, dimethyl-piperidino, diethyl-piperidino, methyl-ethylpiperidino. -pubia-piperidino, methyl-0-propylpiperidino, impropyl-piperidino or di-n-propyl-piperidino groups.

R2 is hydrogen, fluorine, chlorine, bromine or iodine atom, or methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, piperidino, methylmercapto , ethylmercapto, n-
Propylmercapto, isoprobylmercapto, methylsulfinyl, ethylsulfinyl, methylsulfonyl, n-propylsulfonyl, benzyloxy, 1-phenyl-ethoxy, 2-phenyl-ethoxy, 3-phenyl-zolobogysi, acetoxy, propionyloxy, formylamino , acetylamino, propionylamino,
It can represent a methylamino, ethylamino, n-propylamino, dimethylamino, cy-thylamino, di-n-propylamino or methyl-ethylamino group.

R3 can represent hydrogen, fluorine, chlorine or a certain chain atom, or a methyl, ethyl, n-propyl or isopropyl group.

R4 is methyl, ethyl, n-propyl, inzolovir,
n-butyl, n-pentyl, n-hegycyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 6-medoxyp-uvir, benzyl, 1-phenyl Ethyl, 2-phenylethyl, 1-phenyl-n
-propyl, 2-phenyl-n-propyl, 6-enylufrovir, allyl, 3-buten-1-yl, 2-buten-1-yl, 4-penten-1-yl, cyano, carboxy, aminocarbonyl , methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, benzyl-aminocarbonyl, 2-phenyl-ethylaminocarbonyl, pyrrolidinocarbonyl, piperidino Carbonyl, hexamethine/iminocarbonyl, phenyl, nasothyl, fluorophenyl, chlorphenyl.

Propeptaphenyl, methylphenyl, ethylphenyl, isoprobylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl,
Benzyloxy-phenyl, 2-phenyl-ethoxy-
Phenyl, 6-phenylphropoxy-phenyl, methylsulfonyl-phenyl, ethylsulfenyl-phenyl, methylsulfinyl-phenyl, nyQ lobilsulfinyl-phenyl, methylsulfonyl-phenyl, ethylsulfonyl-phenyl, isonoro Bilsulfonyl-phenyl, methyl-naphthyl, hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl, dimethyl-phenyl, diisonorobyl-phenyl, chloro-methyl-phenyl, dimethoxy-phenyl, methoxy-phenyl phenyl, chloromethoxy-phenyl,
Promomethoxy7-phenyl, birisol, pyrimidyl,
It can represent a quinolyl, isoquinolyl or quinazolyl group.

R5 and R6 are hydrogen atoms, methyl, ether, n
-propyl, isopropyl, n-butyl, isobutyl,
It can be represented by a sec-butyl or n-pentyl group.

R5 and R6 together with the carbon atoms between them are benzylidene, 1-phenyl-ethylidene, 2-phenyl-
Ethythene, 1-phenyl-n-propylidene, 1-phenyl-2,2-propylidene, or 6-phenyl-
It can also represent an n-propylidene group.

W is hydroxymethyl, formyl, carboxy, carboxymethyl, 2-carboxy-ethyl, 2-carboxyethenyl, 2.2-bis-(carpoxy)-ethyl,
Methoxycarbonyl, ethoxycarbonyl, n-f lopoxycarbonyl, inobutoxycarbonyl, n-p)oxycarbonyl, inobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, (2-hydroxyethoxy) Carbonyl (2-hyVroxyn-pro4ξoxy)carbonyl, (2-methoxyethoxy)cargynyl, (2-ethoxyethoxy)carbonyl, (2-n-cropoxyethoxy)carbonyl, (2-=cothy) carbonyl, (2-isonicotinoyloxy-ethoxy)carbonyl, (2,3-dihydroxy-11-
(21goxy)cal, 1quel, (2-dimethylamino-ethoxy)carbonyl, (2-diethylamino-ethoxy)carbonyl, (2-piperidino-ethoxy)carbonyl, methyl, ethyl, n-propyl, isopropyl, Cyano, aminocarbonyl, methoxycarbonyl-methyl, conitoxycarbonyl-methyl, n-cropoxycarbonyl-methyl, 2-methoxycarbonyl-
Ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxycarbonyl-ethyl, 2-methoxycarbonyl-ethynyl, 2-ethoxycarbonyl-ethynyl, 2-
n-propoxycarponyl-ethenyl, 2,2-bis-
(methoxycarbonyl)-ethyl, 2,2-bis-(ethoxycarbonyl)-ethyl, or 2,2-bis-(
It can represent an isopropoxycarbonyl)-ethyl group.

Preferred compounds of the general formula (1) are: A represents a group of the formula or , where R4 is a 1 to 6 carbon atom substituted by an alkoxy group having 1 to 3 carbon atoms or a phenyl group; alkyl groups having atoms, n-zolobyl groups, alkyl groups having 4 to 6 carbon atoms, alkenyl groups having 3 to 5 carbon atoms, cyan or aminocarbonyl groups,
mono- or di-substituted by halogen atoms or by alkyl, hydroxy, alkoxy, phenylalkoxy and/or alkylsulfenyl groups,
or an alkyl group having 10 carbon atoms, where these substituents may be the same or different and the alkyl portion can contain from 1 to 6 carbon atoms.
, or represents a naphthyl, pyridyl, quinolyl or isoquinolyl group, and R5 and R6 together with the carbon atoms between them are 3 to
an alkylidene group having 9 carbon atoms, or a phenylalkylidene group having 1 to 6 carbon atoms in the alkylidene part; R1 is an unbranched alkyleneimino group having 4 to 8 carbon atoms, or each is 1-3
represents a piperidino group mono- or di-substituted by an alkyl group having 1 to 3 carbon atoms, R2 is a hydrogen, fluorine, chlorine or bromine atom, or a nitro group, an alkyl group each having 1 to 3 carbon atoms or Alkyl representing an alkoxy group or having 1 to 3 carbon atoms, in which R5 and R6 are as defined above and R4 is substituted by an alkoxy group having 1 to 3 carbon atoms or by a phenyl group base, n
- when representing a propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a nitrile group or an aminocarbonyl group, R2 also represents an iodine atom or a hydroxy or amino group; R3 represents a hydrogen or chlorine atom, and W represents methyl, hydroxymethyl, formyl, cyano, carboxy,
Carboxymethyl, 2-carpoxy-ethyl or 2-
carboxy-nibnyl group, the alkyl part of which is substituted from the β-carbon atom by one or two hydroxyl groups, or by an alkoxy group having 1 to 6 carbon atoms, or by a pyridinecarbonyloxy group; an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, or in each case the alkoxy group having 1 to 6 carbon atoms;
and 4-(N-(6-chloro-α-phenyl-2- piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamate acid and 1-3
3-[4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-phenyl]-propionic acid with 1 to 3 carbon atoms; its alkyl esters with 4-(N-(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl 1-benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-( N-(3-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-aminocarboxylic acid and its alkyl esters with 1 to 6 carbon atoms, 4-(N-(6-methyl -α-phenyl-2(-piperidino-benzyl)-aminocarbonylmethyl]-Yari 1
Froic acid and its alkyl esters with 1 to 5 carbon atoms, 4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid and 1 to 6 carbon atoms its alkyl ester with a carbon atom, 4-[N-(2-(2-methyl-piperidino)-α-
phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid and alkyl esters having 1 to 3 carbon atoms, 4-[N-(2-(3-methyl-piperidino)-α-phenyl-benzyl)- aminocarbonylmethyl]-benzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl-benzaldehyde.

4-[(1-(4-fluoro-2-piperidinophenyl)ethyl)-aminocarbonylmethyl)-benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-((1-(3- Chlor-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-((1-(3-methyl-2-piperidino-quenyl) -ethyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters having 1 to 3 carbon atoms, in particular A of the formula or , where R4 has 1 to 3 carbon atoms. alkyl groups having atoms and substituted with methoxy or phenyl groups: n-propyl, cyanogen or aminocarbonyl alkyl groups: alkyl groups having 4 to 6 carbon atoms, alkenyl groups having 3 to 5 carbon atoms; ; a phenyl group substituted by a fluorine, chlorine or bromine atom or by a methyl, hydroxy, methoxy, benzyloxy or methylsulfenyl group:
or represents a pyridyl group, R5 and R6 together with the carbon atoms between them, 3-
an alkylidene group having 9 carbon atoms, or a phenylalkylidene group having 1 to 3 carbon atoms in the alkyl part thereof, and R1 is an unbranched alkyleneimino group having 4 to 8 carbon atoms, or represents a piperidino group mono- or di-substituted with a methyl group, R2 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl or methoxy group, or R5 and R6 are as defined above, and R4 is an alkyl group having 1 to 6 carbon atoms, n-propyl, nitrile or aminocarbonyl group substituted by a methoxy or phenyl group, or an alkyl group having 4 to 6 carbon atoms or 6 to 5 carbon atoms R2 can also represent an iodine atom or a hydroxy or amino group, R3 represents hydrogen or a chloride atom, and W represents methyl, hydroxymethyl, formyl, cyanide, carboxy , carboxy-methyl, 2-carpoxy-ethyl, or 2-carboxy-ethynyl group, having a total of 2 to 5 carbon atoms, the acrylic moiety of which is derived from the β-carbon atom by one or two hydroxy groups. , or a carbonyl group optionally substituted with a pyridinecarbonyloxy group, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethynyl group (the alkoxy moiety of this is 1 to 3 and 4-(N-(6-chloro-α-phenyl-2-piperidino-benzyl-aminocarbonylmethyl)-benzoic acid and 1 to 3 carbon atoms); its alkyl esters having carbon atoms.

4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid and 1-3
3-[4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-phenyl]-propionic acid with 1 to 3 carbon atoms; its alkyl esters, 4-(N-(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl with 1 to 3 carbon atoms from benzoic acid), 4-[N -(5-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl], -benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-(N-(6-methyl-α -phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid and alkyl esters having 1 to 3 carbon atoms, 4-(N-(4-methyl-α-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-(N-(2-(2-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonylmethyl]- Benzoic acid and its alkyl esters with 1 to 3 carbon atoms, 4-(N-(2-(3-methyl-piperidino)-α-noenyl-benzyl)-aminocarbonylmethyl]-benzoic acid and 1 to 3 its alkyl ester having 4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-henzaldehyde having 4 carbon atoms.

4-((1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl-benzyl ester and its alkyl esters having 1 to 6 carbon atoms, 4-((1-(3 -chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters having 1 to 3 carbon atoms, and 4-((1-(3-methyl-2-piperidino- phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters with 1 to 6 carbon atoms, optically active enantiomers and salts thereof, especially physiologically acceptable salts thereof with inorganic or organic acids or bases is preferred.

However, another group of preferred compounds is that A, R
Compounds in which 1 to R3 and W are as defined above, especially in which W has a carboxy group or a total of 2 to 5 carbon atoms, the alkyl moiety starting from a β-carbon atom and containing 1 or 2 carbon atoms. Compounds representing an alkoxycarbonyl group optionally substituted by a drooxy group, optically active enantiomers and salts thereof, especially physiologically acceptable salts thereof with inorganic or organic acids or bases.

Particularly preferred compounds of the general formula I are those in which A is a radical of the formula represents a substituted phenyl group or pyridyl group, and R5 and R6 together with the carbon atoms between them are 3 to
represents an alkylidene group having 5 carbon atoms, or a phenylalkylidene group having 1 to 6 carbon atoms in the alkylidene part, and R1 is optionally 1 or 2;
represents a piperidino group optionally substituted with 2 methyl groups, R2 represents a hydrogen, fluorine or chlorine atom, or a methyl or methoxy group, R3 represents a hydrogen atom, and W represents a carboxy group, or a total of 2 Compounds representing an alkoxycarbonyl group having ~4 carbon atoms, especially in which A represents a group of the formula or , in which R4 represents an n-propyl group or an alkyl group having 4 or 5 carbon atoms, and R5 and R6 together with the carbon atoms between them are an alkylidene group having 3 to 5 carbon atoms or 1 to 6 in the alkylidene moiety thereof;
compounds representing a phenylalkylidene group having 5 carbon atoms, their optically active enantiomers and their salts with inorganic or organic acids or bases, especially their physiologically acceptable salts.

According to the invention, these target compounds are obtained by the following methods: a) amines of the general formula, in which A, R1 and R2 are as defined above, or when A represents the vinylidene group mentioned above; , its tautomer or its lithium or magnesium halide complex can be represented by the general formula: The carboxylic acid (representing a group), optionally formed in the reaction mixture, is reacted with a reactive derivative and, if necessary, the protective group used is then removed.

Reactive derivatives of the compound of general formula (■) are, for example, methyl,
such as ethyl or benzyl esters.

It can be its esters, its thioesters such as methylthio or ethylthio esters, its halides such as acid chlorides, and its anhydrides or imidazolides.

The reaction is carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activator or dehydrating agent, e.g. ethyl chloroform. mate, thionyl chloride, phosphorus trivalent, phosphorus pentoxide, N, N'-dicyclohexyl-carbodiimide, N, N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N
, N′-carbonyldiimidazole or N,N d-thionyldiimidazole, or in the presence of triphenylphosphine/carbon tetrachloride, or an activator of the amino group,
For example in the presence of phosphorus trichloride and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine (which can simultaneously be used as solvent), from -25° to 250° C.
It is convenient to carry out the reaction at a temperature of 0.degree. C., preferably -10.degree. C. - the boiling temperature of the solvent used. This reaction can also be carried out without the use of solvents, and also by heating the water produced during the reaction by azeotropic distillation, for example with toluene using a water separator, or by heating it with toluene, such as with magnesium sulfate or molecular sieves. It can be removed by adding a drying agent.

If necessary, subsequent removal of the protecting group can be performed by hydrolysis.
Water, methanol, ethanol, ethanol/water, 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/isopropanol or water/dioxane, -
Preferably, the reaction is carried out at a temperature of 10 DEG C. to 120 DEG C., for example room temperature to the boiling temperature of the reaction mixture.

The tertiary-butyl group used as a protecting group can also be prepared preferably in p-)luenesulfonic acid, sulfuric acid, phosphoric acid or Desorption can also be carried out thermally in the presence of a catalytic amount of an acid such as polyphosphoric acid.

Furthermore, the benzyl group used as a protecting group is also
Desorption can also be accomplished by hydrogenation in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide in the presence of a hydrogenation catalyst such as palladium/charcoal.

b) To prepare compounds of the general formula 1 in which W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, in which R1 to R3, A and X are as defined above and B represents a group which can be converted into a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group by hydrolysis, thermal decomposition or hydrogenolysis.

Examples of hydrolysable groups include reactive derivatives of carboxy, carboxymethyl, 2-carboxymethyl or 2-carboxyethenyl groups, such as their unsubstituted or substituted amides, their nitriles, esters, thiol esters, orthoesters, iminoethers. , amicin or anhydride, malonic ester-(1)-yl group, tetrazolyl group, optionally substituted 1,3-oxazole-2-
yl or 1,3-oxazolin-2-yl group.

The thermally removable group can be, for example, an ester with a tertiary alcohol, such as a tertiary butyl ester.

Hydrogenolytically removable groups can be, for example, esters with aralkanols, such as benzyl esters.

Hydrolysis is carried out 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, water, water/methanol, ethanol, water/ethanol. -10 in a suitable solvent such as , water/isopropanol or water/dioxane.
It is convenient to carry out the reaction at a temperature between 120 DEG C. and 120 DEG C., for example between room temperature and the boiling temperature of the reaction mixture.

When B in the compound of general formula IV represents a cyano or aminocarbonyl group, these groups can also be treated using nitrates, e.g. sodium nitrate, acids such as sulfuric acid (which may also be used as solvent). ) in the presence of 0-5
It can be converted to a carboxy group at a temperature of 0°C.

When B in the compound of general formula (2) represents a tertiary butyloxycarbonyl group, for example, this 6th butyl group may be substituted with an inert compound such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane in one possible case. in a solvent, preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at a temperature of the boiling temperature of the solvent used, e.g. Can be thermally split.

When B in the compound of general formula (2) represents a benzyloxycarbonyl group, for example, this benzyl group can also be reacted with methanol, ethanol, ethanol/water, glacial acetic acid in the presence of a hydrogenation catalyst such as palladium/charcoal. , ethyl acetate, dioxane or dimethylformamide, preferably at a temperature of 0 DEG to 50 DEG C., for example at room temperature and a hydrogen pressure of 1 to 5 bar. In this hydrogenolysis, other groups can be reduced simultaneously, for example to ditro and amino groups, benzyloxy groups to hydroxy groups, vinylidene groups to the corresponding alkylidene groups, or silicon The cinnamic acid group can be reduced to the corresponding phenylpropionic acid group, or other groups can also be replaced by hydrogen atoms, for example halogen atoms can be replaced by hydrogen atoms.

C) In order to prepare compounds of the general formula 1, in which A represents a radical of the formula (wherein R4' has the meanings given above for R4, excluding alkenyl and cyano groups) ~R3 and W are as defined above,
and D represents a group of the formula or , where R4" has the meaning given above for R4 except for the cyano group, and R5' and R6'
is an alkylidene group having between 1 and 7 carbon atoms together with the carbon atoms between these or 1 on the alkylidene moiety
- represents a phenylalkylidene group having 3 carbon atoms).

The reduction is carried out in the presence of a hydrogenation catalyst such as palladium/charcoal or Raney nickel, with hydrogenation catalysts such as methanol, ethanol, isopropanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, benzene, or benzene/ethanol. in a suitable solvent at a temperature of 0 to 100°C, preferably 20°C.
Preferably, it is carried out with hydrogen at a temperature of from 0.degree. C. to 50.degree. C. and under a hydrogen pressure of 1 to 5 bar. Metal ligand complexes such as μ,μ-dichloro-bis(1,5-cyclooctadiene-rhodium) and (+) or (−)o,0-isopropylidene-2,3-dihydroxy-1,4-bis( When using a suitable chiral hydrogenation catalyst such as diphenylphosphino)-butane (=DIOP), the addition of hydrogen occurs selectively.Furthermore, during the catalytic hydrogenation, other groups can be They can be simultaneously reduced, for example a nitro group can be reduced to an amino group, a benzyloxy group can be reduced to a hydroxyl group, or a cinnamic acid group can be reduced to a phenylpropionic acid group, or other groups can be replaced by hydrogen atoms, for example halogen atoms. can be replaced with a hydrogen atom.

d) To prepare compounds of the general formula (3), in which R4' has the meaning defined for R4, excluding the cyano group, in which R4' is as defined above, and R1 and R2 are A compound of formula (as defined above) is reacted with a compound of general formula (wherein R3 and W are as defined above).

The reaction is carried out using a strong acid (which can simultaneously be used as a solvent),
a temperature of 0°C to 150°C, preferably in the presence of concentrated sulfuric acid;
Preferably it is carried out at a temperature of 20°C to 100°C.

e) Dehalogenating compounds of the general formula in which R1, R3, A and W are as defined above and Hal represents a fluorine, chlorine, bromine or iodine atom.

For dehalogenation, methanol, ethanol, ethyl acetate,
in a solvent such as glacial acetic acid or dimethylformamide,
0 to 10 using catalytically activated hydrogen, for example using hydrogen in the presence of platinum or palladium/charcoal.
Conveniently it is carried out at a temperature of 0 DEG C., preferably at room temperature, and under a hydrogen pressure of 1 to 5 bar. During this dehalogenation, other groups can be simultaneously reduced. For example, a benzyloxy group can be reduced to a hydroxy group, a vinylidene group to the corresponding alkylidene group, or a cinnamic acid group to the corresponding phenylpropionic acid group. Alternatively, other groups may be substituted with hydrogen, for example, a halogen atom may be substituted with a hydrogen atom.

r) an aminocarbonyl group in which R4 is optionally mono- or di-substituted by an alkyl or phenylalkyl group each having 1 to 3 carbon atoms in its alkyl moiety or 4 to 6 in its alkylene ring; In order to prepare a compound of the general formula (3) representing an alkyleneiminocarbonyl group having carbon atoms of having the meanings given above for compounds of the general formula H-R7, where each R7 is optionally mono- or di-substituted by an alkyl or phenylalkyl group having 1 to 3 carbon atoms in its alkyl moiety. (representing an optional amino group or an alkyleneimino group having 4 to 6 carbon atoms).

This amidation is carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, preferably in the presence of an acid activator or dehydrating agent, e.g. Chlorformate,
Thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole, N,N'-thionyl in the presence of diimidazole, or triphenylphosphine/carbon tetrachloride, or in the presence of an amino group activator, for example phosphorus trichloride, preferably an inorganic base such as sodium carbonate or triethylamine or pyridine. It is convenient to carry out the reaction in the presence of a tertiary organic base, which can simultaneously be used as a solvent, at a temperature of from -25 DEG C. to 250 DEG C., preferably from -10 DEG C. to the boiling temperature of the solvent used.

g) To prepare compounds of general formula 1, in which W represents a carboxy group, compounds of the general formula (wherein R1 to R4 are as defined above and E
represents a group that can be converted into a carboxy group by oxidation).

Oxidizable groups of this type include, for example, formyl groups and their acetals, hydroxymethyl groups and their ethers, substituted or unsubstituted acyl groups (such as acetals, chloroacetyl, propionyl or malonic acid-(
1)-yl group or malonic acid ester-(1)-yl group).

The reaction is carried out in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane, or glycol dimethyl ether.
It is carried out using an oxidizing agent at a temperature of from 0 to 100°C, preferably from 20 to 50°C.

However, this reaction can be performed using silver oxide/sodium hydroxide solution, diacid ratio manganese/acetone or methylene chloride, hydrogen peroxide/sodium hydroxide solution, bromine or chlorine/aqueous sodium or potassium hydroxide solution, chromium trioxide/
It is preferable to use pyridine or pyridinium chlorochromate.

h) the W has a total of 2 to 6 carbon atoms and the alkyl part is from a β-carbon atom, by 1 or 2 hydroxy groups, or by an alkoxy group having 1 to 3 carbon atoms; In order to produce a compound of general formula 1 that does not represent an optionally substituted alkoxycarbonyl group, the general formula (wherein R1 to R3 and A are as defined above)
of the carboxylic acid or its reactive derivative optionally formed in the reaction mixture with the general formula HO-R9 (■■), where R9 is from the β-carbon atom, by one or two hydroxy groups, or by one - represents an alkyl group with 1 to 5 carbon atoms, optionally substituted by an alkoxy group with 3 carbon atoms).

Examples of reactive derivatives of the general formula include its halide (
(eg acid chlorides), anhydrides and imidazolides.

The reaction is carried out by addition of the corresponding alcohol as a solvent, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane, benzene, etc. in a suitable solvent such as toluene, optionally in the presence of an acid activator or dehydrating agent. For example, hydrogen chloride, oxalic acid, ethyl chloroformate, thionyl chloride, carbon tetrachloride/triphenylphosphine, carbonylsiimidazole or N,N'-
in the presence of dicyclohexylcarbosiimide or its isourea ether, preferably in the presence of a reaction promoter such as steel chloride, and optionally an inorganic base such as sodium carbonate or 6 adsorption such as triethylamine or bilysin. It is carried out in the presence of an organic base or by transesterification, for example with the corresponding carbonic acid zoester, at a temperature of -20°C to 100°C, preferably -10°C.
℃ or the boiling temperature of the solvent used.

1) of the general formula 1, in which W represents an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or 2-alkogoxycarbonyl-ethenyl group, and R4/ has the meanings given above for R4, excluding the cyano group; To prepare compounds of the general formula Alcohol-added decomposition of the compound

Alcohol addition decomposition uses the corresponding alcohol as a solvent,
for example in methanol, ethanol or zolopanol, preferably in the presence of an acid such as hydrochloric acid or sulfuric acid,
It is convenient to carry out the reaction at a temperature of 20°C to the boiling temperature of the solvent used, preferably 50 to 100°C.

If, according to the invention, a compound of the general formula I is obtained, in which W represents a carboxy or alkoxycarvinyl group, this can be converted by reduction into a corresponding compound of the general formula I, in which W represents a formyl or hydroxymethyl group. and (or) if a compound of the general formula 1 is obtained in which W represents a carboxy group, it is converted into a sulfonic acid hydracite and then subjected to a disproportionation reaction such that W represents a formyl group. and (or) if a compound of general formula I is obtained in which W represents a formyl group, 1 can be converted into the corresponding compound of general formula 1 represented by With carzexyl, its W is 2-alkoxycarbonyl-ethynyl or 2
-carboxy-ethynyl group can be converted into the corresponding compound of general formula I: and/or if a compound of general formula I is obtained in which W represents a 2-carboxy-ethynyl or 2-alkoxycarbonyl-ethynyl group. , which can be converted by catalytic hydrogenation into the corresponding compounds of general formula 1 in which W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group; and/or in which W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group; If a compound of the general formula 1 representing an alkoxycarbonyl group substituted by a group is obtained, this can be converted into the corresponding (pyridinecarbonyloxy-alkoxy)-carbonyl compound of the general formula 1 by acylation with pyridine-carboxylic acid. and (or) if a compound of the general formula l is obtained, in which W represents a hydroxymethyl group, this can be converted into the corresponding halomethyl compound by reaction with a malonic diester, in which W represents a hydroxymethyl group. A corresponding compound of the general formula 1 representing an ethyl group substituted by an alkoxycarbonyl group can be converted; and (or) a compound of the general formula If you can get
This can be converted by hydrolysis into the corresponding compounds of general formula I in which W represents an ethyl group substituted by two carboxy groups; and/or in which W is substituted by two alkoxycarbonyl groups. and ( and (
or) When a compound of the general formula (2) in which R2 represents an amino group is obtained, it can be obtained through a corresponding diazonium salt by the general formula 1; and (or) if a compound of the general formula 1 is obtained, in which R2 represents a hydroxy group, this can be converted by alkylation into a corresponding compound of the general formula 2, in which R2 represents an alkoxy group. and (or) in which R2 represents a benzyloxy group and (or) R4 represents an aryl group substituted by a benzyloxy group is obtained, this is a debenzylated compound. can be converted into corresponding compounds of general formula 1 in which R2 represents a hydroxy group and/or R4 represents an aryl group substituted by a hydroxy group; and (or) a general compound in which R4 represents an aminocarbonyl group. If a compound of formula 1 is obtained, it can be converted by dehydration into the corresponding compound of general formula 1 in which each R4 represents a cyano group.

The subsequent reduction uses 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 20°C. Preferably it is carried out at a temperature of ~60°C.

The subsequent disproportionation reaction of the sulfonic acid hydrazide obtained by reaction of 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, from 100°C to 20°C
It is carried out at a temperature of 0°C, preferably 160-170°C.

Subsequent condensation of the formylated compound is optionally carried out using malonic acid, a malonic acid ester, or a sialkylphospho-triphenylphosphorane in a solvent such as pyridine or tetrahydrofuran. from 0 to 1 in the presence of an agent such as piperidine, potassium tert-butoxide or sodium hydride.
It is advantageous to work at a temperature of 0.000 C; the desired compound is obtained by subsequent acidification, for example with hydrochloric acid or sulfuric acid, or by subsequent alkaline hydrolysis.

Subsequent catalytic hydrogenation is performed using hydrogen in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide, in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal, from 0 to 75°C. Preferably, the reaction is carried out at a temperature of from 1 to 5 bar, preferably at room temperature, and under a hydrogen pressure of 1 to 5 bar.

The subsequent O-acylation is preferably performed using a reactive derivative of the acid, such as an acid chloride, in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide. halides, anhydrides or imidazolides, optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine (which can simultaneously be used as a solvent), from -25°C to 250°C. temperature in °C,
Preferably, the reaction is carried out at a temperature of -10°C to the boiling temperature of the solvent used.

Subsequent conversion of hydroxymethyl groups to halomethyl groups is performed using halogenating agents such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, and using halogenating agents such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene. It is carried out in a solvent and then with a malonic acid ester, such as an alkali metal salt of diethyl malonate, at a temperature of 0 to 100°C, preferably 50°C to 80°C.

For subsequent hydrolysis or hydrolysis and decarboxylation, water, ethanol, water/ethanol, water/isopropanol or water/in the presence of acids such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid Preferably, the reaction is carried out in a suitable solvent such as dioxane at an elevated temperature, for example 5 parts of the reaction mixture.

The subsequent reduction of the nitro compound is carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate, dimethylformamide, and hydrogen, suitably Raney nickel, platinum or palladium/charcoal. by hydrogen in the presence of added catalysts, or by metals such as iron, tin or zinc in the presence of acids, or by iron sulfate (■), tin chloride (
■) or by salts such as sodium dithionate, or by hydrazine in the presence of Raney nickel.
Preferably it is carried out at a temperature of 50°C, preferably at room temperature.

Diazonium salts, e.g. fluoroborate, fluoride in 40% hydrofluoric acid (subsequent reaction of hydrosulfate or hydrochloride in flowing acid, optionally contain copper or the corresponding copper(1) salt, e.g. chloride) carried out in the presence of copper(1)/hydrochloric acid or copper(1) bromide/hydrobromic acid at slightly elevated temperatures, e.g. from 15°C to 100°C; subsequent reaction with hypophosphorous acid Preferably, the reaction is carried out at a temperature between -5°C and 0°C.
In a suitable solvent such as hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid, or dioxane/hydrochloric acid, at low temperature with a nitrite salt of the corresponding amino compound, e.g. sodium nitrite, or with an ester of nitrous acid, e.g.
Conveniently, it is produced at a temperature of 10°C to 5°C.

Subsequent O-alkylation with the corresponding halide, sulfonic acid ester or diazoalkane, for example with methyl iodide, dimethyl sulfate, ethyl bromide, ethyl p-toluenesulfonate, isopropyl methanesulfonate or diazomethane, optionally with sodium hydride. preferably diethyl ether, tetrahydrofuran,
Preferably it is carried out in a solvent such as dioxane, methanol, ethanol, pyridine or dimethylformamide at a temperature of 0 to 75°C, preferably at room temperature.

Subsequent debenzylation is carried out in solvents such as methanol, ethanol, ethyl acetate, glacial acetic acid or cyclomethylformamide using catalyst activated hydrogen, e.g. using hydrogen in the presence of platinum or palladium/charcoal. , 0-75
C., preferably at room temperature, and under a hydrogen pressure of 1 to 5 bar.

Subsequent dehydration uses a dehydrating agent such as phosphorous pentoxide, sulfuric acid or p-toluenesulfonic acid chloride, optionally in a solvent such as methylene chloride or pyridine.
It is carried out at a temperature of 20°C to 80°C, preferably 20 to 80°C.

If the compounds of general formula I obtained have chiral centres, these compounds can also be resolved into their enantiomers by customary methods. This is carried out by column chromatography with chiral (1).

The compounds of general formula 1 obtained can also be converted into their addition salts, especially in physiologically acceptable order, with inorganic or organic acids or bases. Examples of suitable acids include hydrochloric acid,
Hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid,
Examples of suitable bases include succinic acid, maleic acid or fumaric acid; examples of suitable bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine and ethylenediamine.

The compounds of the general formulas (1) to (X) used as starting compounds can be obtained by methods known from the literature or are themselves known from the literature.

Thus, for example, a compound of general formula (3) or its tautomeric ketimine, in which A represents a group of formula, can be prepared by reaction of the corresponding nitrile with the corresponding Grignard or lithium compound and subsequent hydrolysis.
Alternatively, it can be obtained by reaction of the corresponding ketone with ammonia in the presence of titanium tetrachloride. It is also possible to use organometallic ketimine complexes for the subsequent reaction with the general formula (1) or its reactive derivatives, in particular its acid chlorides.

Compounds of the general formula (3) in which A represents a group of the formula (in which R4 has the meaning given above, excluding cyano and aminocarbonyl groups) can be prepared, for example, by reaction of the corresponding nitrile with the corresponding Grignard or lithium compound and formation of ketimines, optionally by subsequent lithium aluminum hydride reduction or subsequent hydrolysis, by reduction of this ketimine with catalytically activated hydrogen with complex metal hydrides or with generator hydrogen, or by hydrolysis of the corresponding phthalimide compounds; , or by reaction of the corresponding ketone with ammonium formate and subsequent hydrolysis, or by reaction with an ammonium salt in the presence of sodium cyanoborohydride, or by lithium aluminum hydride of the corresponding oxime, or by catalytic activity. ethers of the corresponding N-benzyl- or N-(1-phenylethyl)-ketimines, for example by catalytically activated hydrogen or by complex metal hydrides. or by reduction in tetrahydrofuran at −78° C. to the boiling temperature of the solvent used and subsequent elimination by catalytic hydrogenation of the benzyl or 1-phenylbenzyl group, or in sulfuric acid with the corresponding alcohol and potassium cyanide. (Ritter) reaction or by Hofmann, Curtius, Rossen or Schmidt decomposition of the corresponding compounds.

Compounds of the general formula (3) in which A represents a group are obtained by reaction of the corresponding aldehyde with ammonium cyanide or by reaction of the corresponding cyanohydrin with ammonia.

The thus obtained amine of the general formula (3) having a chiral center and in which A represents a group of the formula (in which R4 has the above-mentioned meaning except for the cyan group) can be purified by racemic resolution, for example, with any active acid. by fractional crystallization of the diastereomeric salt and subsequent decomposition of this salt, or by column chromatography on a chiral phase, or by the formation of diastereomeric compounds and their separation and resolution,
Can be divided into enantiomers.

Furthermore, the optically active amine of general formula
some of these hydrides have an optically active alkoxide group in place of a hydrogen atom), or by using hydrogen in the presence of a suitable gyrral hydrogenation catalyst, or the like. starting from the corresponding N-benzyl- or N-(1-phenethyl)-ketimines or from the corresponding N-acyl-ketimines or enamines, optionally with subsequent removal of the benzyl, 1-phenethyl or acyl group. It can also be generated by

Furthermore, the optically active amines of general formula (2) can also be prepared by the herastereoselective, electrical engineering of the corresponding ketimines or hydrazones gyralically substituted in the first position of the nitrogen atom, or by complexed or non-complexed boron f or with aluminum hydrides (some of these hydrides by some reason have a corresponding alkoxide, fertoma or alkyl group in place of the hydrogen) or in the presence of a suitable hydrogenation catalyst. It can also be generated by hydrogen and optionally subsequent separation of the chiral auxiliary by catalytic hydrogenolysis or hydrolysis.

Furthermore, the optically active amines of general formula (2) can also diastereoselectively add corresponding organometallic compounds, preferably Grignard or lithium compounds, to the corresponding aldoimines which are chirally substituted in the position of the native atom. It can also be produced by subsequent hydrolysis and, optionally, chiral Sodesuke Kabura by catalytic hydrogenolysis or elimination during hydrolysis.

Compounds of the general formulas ■, ■, ■, ■■■■ and ■■ used as raw materials are prepared by reacting the corresponding amines with the corresponding compounds of the general formula m or their reactive derivatives, optionally followed by hydrolysis. It can be obtained by

The compounds of general formula V used as starting materials are preferably obtained by acylation with the corresponding ketimines or organometallic complexes thereof with the corresponding carboxylic acids or reactive derivatives thereof.

As already mentioned above, the new compounds of the general formula (2) have useful medicinal properties, namely an effect on intermediary metabolism, in particular a hypoglycemic effect, and an effect on the cardiovascular system.

By way of example, the following compounds were tested for their effects as follows: A=(Z)-4-((1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl )-benzoic acid B=ethyl (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoate, C=(E)-4-[ (1-(
(2-piperidino-phenyl)-1-buten-1-yl)
-aminocarbonylmethyl]-benzoic acid D = 4-((2-methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-aminocarbonylmethyl]-benzoic acid, E = ethyl (Z )-4-((1-
(2-Piperidino-phenyl)-1-hexen-1-yl)-aminocarbonylmethyl F=(Z)-4-((3-phenyl-1-(2-piperidino-phenyl)-1-propene-1 -yl)-aminocarbonylmethyl]-benzoic acid, G=(Z)-4-[(
1-(2-(3.3-dimethyl-piperidino)-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid, H=4-((1-(2-pyrrolidino-phenyl) -1-
butyl)-aminocarbonylmethyl]-benzoic acid, J=(±)-4-[(1-(2-piperidino-phenyl)]-benzoic acid, K=(+)-4-[(1-(2-piperidino-phenyl)-benzoic acid, -phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid, L=ethyl(+)4-[(1-(2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl)-benzoate, M =4-((1-(2-hexahydroazepinophenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid, N=4-((1-(2-piperidino-phenyl)-1-
hexyl)-aminocarbonylmethyl]-benzoic acid, 0=4-((3-phenyl-1-(2-piperidinophenyl)-1-propyl)-aminocarbonylmethyl)
-benzoic acid.

P=4-[(2-methoxy-1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-
Benzoic acid, Q=4-((α-cyan-2-piperidino-benzyl)
-aminocarbonylmethyl]-benzoic acid, R=4-[(1-(2-piperidino-phenyl)-1-
butyl)-aminocarbonylmethyl]-benzyl alcohol, S=4-((1-(2-piperidino-phenyl)-1-
butyl)-aminocarbonylmethyl]-phenylacetic acid, T=4-((1-(2-piperidino-phenyl)-1-
butyl]-aminocarbonylmethyl]-cinnamic acid, U=2,3-dihydroxy-propyl 4-((1-(2
-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate, V=4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-
Benzoic acid, W=4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-
Benzoic acid, piperidinophenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid, Z=4-[(1-(3-methyl-2-piperidinophenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid , AA=4-[(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid, AB=4-[(α-(3-methyl-phenyl)-2- piperidino-penzol)-aminocarbonylmethyl]-benzoic acid, AC=4-((α-(4-fluoro-phenyl)-2-
piperidino-benzol)-aminocarbonylmethyl]-
Benzoic acid, AD=4-((α-(2-fluoro-phenyl)-2-
piperidino-benzyl)-aminocarbonylmethyl]-
Benzoic acid, AE=4-((α-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, AF=4-[(α-(3-chloro-phenyl)- 2-Piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, AG=4-((2-piperidino-α-(2-pyridyl)
-benzyl)-aminocarbonylmethyl)-benzoic acid, AH=4-((2-piperidino-α-(4-pyrisol)
-benzyl)-aminocarbonylmethyl]-benzoic acid, AJ=4-[(6-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid, AK=4-[(α-phenyl -2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid, AL=3-(4-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid, AM=4 -[(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, AN=4-((6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl methyl]-benzoic acid, AO=4-((4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarvinylmethyl]-benzoic acid, AP=4-((α-phenyl-2-piperidino- benzyl)-aminocarbonylmethyl]-benzaldehyde, AQ=4-((2-(2-methyl-piperidino)-α-
phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid, AR=4-[(2-(3-methyl-piperidino)-α-
1. Hypoglycemic activity tested The hypoglycemic activity of the compounds was tested in single-species female rats weighing 180-220 g. Rats were kept without food or drinking water for 24 hours before starting the study. The test substance was suspended in 1.5% methylcellulose immediately before the start of the test and administered via the esophageal tube.

Blood samples were taken from the retroorbital venous sinus in each case immediately before administration of the test substance and at 1, 2, 3 and 4 hours after administration. 50 μl from each sample was deproteinized with 0.5 ml of 0.33N perchloric acid and then centrifuged. Glucose in the supernatant phase was measured by the hexokinase method using an analytical photometer.

The results were statistically evaluated using Student's t-test with a significance limit of P=0.05.

The following table shows the measured values in % compared to the control.

2. Acute toxicity Toxic effects were tested in male and female mice of the same species weighing 20-26 g after a single oral administration (as a 1% methylcellulose suspension) with an observation period of 14 days.

In view of their pharmacological properties, the compounds of general formula I and their physiologically acceptable salts prepared according to the invention are suitable for the treatment of diabetes mellitus. For this purpose, these compounds may be combined with other active substances.
It can be made into conventional pharmaceutical formulations such as tablets, coated tablets, capsules, powders or suspensions. The single dose is 1 to 50 mg, preferably 2.5 to 20 mg, administered once or twice per day for adults.

The following examples further illustrate the invention.

Example 1 4.7 g of triphenylphosphine (18 mmol) containing 3 g (30 mmol) of triethylamine and 1 carbon tetrachloride
．． 5 ml (15 mmol) of 4-ethoxycarbonyl-phenylacetic acid dissolved in 40 ml of acetonitrile.
g (16.5 mmol) and α-(4-methyl-phenyl)-2-piperidino-benzolamine 4.2 g (1
5 mmol). The reaction mixture is stirred at 50° C. for 2 hours, concentrated by evaporation and then acidified with 6N hydrochloric acid and then extracted with ethyl acetate. The acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extract is washed with sodium bicarbonate solution, dried over magnesium sulphate and then evaporated to dryness. Mix the evaporation residue with ether,
Filter by suction.

Yield: 4.55g (65% of theory), melting point: 177~
178°C Elemental analysis: Calculated: C76.57 H7.28 N5.95 Observed: 76.19 7.16 5.82 The following compound is prepared analogously to Example 1: (a) Ethyl 4-[ N-
[α-[3-Methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 48% of theory Melting point: 159-160°C Elemental analysis: Calculated value: C76.57 N7.28 N5.95 actual value: 76.80 7.35 5.76 (b) Ethyl 4-[N-[α-(2-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate yield : 35.4% of theoretical amount Melting point: 196-198°C Elemental analysis: Calculated value: C76.57 N7.28 N5.95 Actual value: 76.65 7.35 5.90 (c) Ethyl 4-[N- [α-(4-Methoxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 45% of theory Melting point: 167-168°C Elemental analysis: Calculated value: C74.05 N7.04 N5.76 actual value: 73.72 6.99 5.62 (d) Ethyl 4-(N-(α-(4-benzoloxy-phenyl)-
2-Piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 96% of theory Melting point: 154-155°C Elemental analysis: Calculated: C76.84 H6.81 N4.98 Actual: 76.68 6. 68 5.03(e) Ethyl 4-[N-(α-(4-fluoro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 58% of theory.

Melting point: 174-176°C Elemental analysis: Calculated value: C73.40 H6.58 N5.90 Actual value: 71.55 6.72 5.91(f) Ethyl 4-[N-[α-(2-fluoro- Phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 83% of theory Melting point: 173-175°C Elemental analysis: Calculated: C73.40 H6.58 N5.90 Observed: 73. 61 6.62 5.85 (g) Ethyl 4-(N-(α-(4-chloro-phenyl)-2-piperidino-benzyl]-aminocarzenylmethyl]-benzoate Yield: 57% of theory Melting point :178-181℃ Elemental analysis: Calculated value: C70.94 H6.36 N5.71 Cl
7.22 Actual value: 71.10 6.56 5.2
6 7.11(h) Ethyl 4-[N-[α-(3-
Chlor-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 71% of theory Melting point: 153-156°C Elemental analysis: Calculated values: C70.94 H6.66 N5.71 Cl
7.22 Actual value: 70.86 6.26 5.6
5 7.25(i) Ethyl 4-[N-[α-(2-
Chlor-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 66% of theory Melting point: 196-198°C Elemental analysis: Calculated: C70.94 H6.36 N5.71 Cl
7.22 Actual value: 70.90 6.30 5.6
1 7.10(k) Ethyl 4-(N-(α-(4-
Methylmercapto-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 84% of theory Melting point: 173-175°C Elemental analysis: Calculated values: C71.68 H6.82 N5.57 Cl
6.38 Actual value: 71.92 6.92 5.4
5 6.21(l) Ethyl 4-(N-(5-chloro-α-(2-chloro-phenyl)2-hydroxy)-benzyl]-aminocarbonylmethyl]-benzoate Yield: 92% of theory Melting point :213-215℃ Elemental analysis: Calculated value: C66.28 H5.75 N5.33 Cl
13.49 Actual value: 66.45 5.86 5.
25 15.51(m) Ethyl 4-4N-[2-piperidino-α-(2-pyridyl)-benzyl]-aminocarbonylmethyl]-benzoate Yield: 51% of theory Melting point: 158-159°C Elemental analysis : Calculated value: C73.50 H6.83 N9.18 Actual value: 73.40 6.95 9.10 (n) Ethyl 4-[N-42-piperidino-α-(6-pyridyl)-
Benzyl]-aminocarbonylmethyl]-benzoate Yield: 85% of theory Melting point: 172°C Elemental analysis: Calculated value: C73.50 H6.83 N9.18 Actual value: 73.42 6.76 9.25 (o ) Ethyl 4-(N-(2-piperidino-α-(4-pyridyl)-
Benzyl]-aminocarbonylmethyl]-benzoate Yield: 20% of theory Melting point: 150-152°C Elemental analysis: Calculated value: C73.50 H6.85 N9.18 Actual value: 73.61 6.91 9.15 (p) Ethyl 4-[N-(6-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 12% of theory Melting point: Oil Calculated value: Molecular-ion Beak m/e = 490/492 Actual value: Molecular-ionic peak m/e = 490/492 (q) Ethyl 4-(N-(4-chloro-α-phenyl-
2-Piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 37% of theory Melting point: 148-150°C Elemental analysis: Calculated: C70.94 H6.56 N5.71 Cl
7.22 Actual value: C70.81 H6.25 N5.6
1 Cl7.12(r)Ethyl 4-[N-(3-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl-benzoate Yield: 74% of theory Melting point: 176-178°C Elemental analysis : Calculated value: C70.94 H6.36 N5.71 Cl
7.22 Actual value: 70.59 6.25 5.6
8 7.16(s) Ethyl 4-[N-(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 65% of theory Melting point: Oil calculated: Molecular-ion beak m/e=470 actual value:
Molecular - ion beak m/e = 470 (t) ethyl 4-
(N-(5-methyl-α-phenyl-2-piperidino-
Benzyl)-aminocarbonylmethyl]-benzoate Yield: 48% of theory Melting point: 171-173°C Elemental analysis: Calculated: C76.57 H7.28 N5.95 Observed: 76.75 7.35 5.72 (u) Ethyl 4-(N-(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 76% of theory Melting point: 133-135°C Elemental analysis: Calculated value :C76.57 H7.28 N5.95 Actual value: 76.51 7.16 5.86 (v) Ethyl 4-(N-(5-methoxy-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl ]-Benetoate Yield: 10% of theoretical amount Melting point: 122-125°C Calculated value: Molecular-ion peak m/e = 486 Actual value:
Molecular - ion beak m/e = 486 (w) ethyl 4-
4N-(6-methoxy-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 97% of theory Melting point: Oil Calculated value: Molecular-ion peak m/e = 486 actual measurement value:
Molecular - ion beak m/e = 486 (x) ethyl 6-
Chlor-4-(N-(α-phenyl-2-piperidino-
Benzyl)-aminocarbonylmethyl]-benzoate Yield: 42% of theory Melting point: 175-176°C Elemental analysis: Calculated values: C70.95 H6.56 N5.71 Cl
7.22 Actual value: 70.65 6.36 5.5
0 7.29(y) Ethyl 4-(N-(2-dimethylamino-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoate Yield: 67% of theory Melting point = 116-118°C Elemental analysis: Calculation Value: C74.97 H6.77 N6.73 Actual value: 75.13 6.60 6.78 (z) Ethyl 4-[N-(2-cy n-propylamino-α-phenyl-bencyl)-aminocarbonyl Methyl]-benzoate yield: 76% of theory Melting point: 138-139°C Elemental analysis: Calculated: C76.24 H7.68 N5.93 Actual value: 76.41 7,79 5.81 (aa)
Ethyl 4-CN-(2-(octahydro-11(-abdi))-α-phenyl-bencyl)-aminocarbonyl methylate Yield: 71% of theory Melting point: Oil Calculated value: Molecular-ion peak m/e=498 actual measurement value:
Molecular - ion beak m/e = 498 (ab) ethyl 4
-[N-45-chloro-2-(2-methyl-piperidino)-α-phenyl-benzyl)-aminecarbonylmethyl]-benzoate Yield: 36.5% of theory Melting point: 171-173°C Elemental analysis: Calculation Value: C71.24 H6.58 N5.54 Ce
7.01 Actual value: 71.45 6.68 5.5
9 7.20(ac) Ethyl 4-[N-[2-(3
, 3-dimethyl-piperidino)-α-phenyl-benzyl]-aminocarbonylmethyl]-benzoate Yield: 91% of theoretical Melting point: 146-148"C Elemental analysis: Calculated: C76.82 H7.49 N5. 78 Actual value: 76.91 7.55 5.61 Example 2 A solution of 5 g (22.1 mmol) of 4-ethoxycarbonyl-phenylacetyl chloride in 20 ml of chloroform in vinegar and 3.5 g of triethylamine in 50 ml of chloroform.
ml (25 mmol) and α-(4-chloro-phenyl)-2-piperidino-benzylamine 6.02 g (2
0 mmol) dropwise while cooling with ice. The mixture is stirred at room temperature for 2 hours, then added to water and extracted with chloroform. The extract is dried and then evaporated.

The evaporation residue was transferred onto a silica sol using toluene/as eluent.
Chromatography using ethyl acetate (5:1).

Yield: 5.6g (57% of theory) Melting point: 178-181°C Elemental analysis: Calculated values: C70.94 H6.36 N5.71 Cl
7.22 Actual value: 71.09 6.47 5.6
1 7.10 Analogously to Example 2, the following compounds are prepared: (a) Ethyl 4-[N-(5-chloro-2-(3
-Methyl-piperidino)-α-phenyl-benzyl]-
Aminocarbonylmethyl]-benzoate yield: 54% of theory Melting point: 178-180°C Elemental analysis: Calculated values: C71.24 H6.58 N5.54 Cl
7.01 Actual value: 70.91 6.64 5.7
5 7.01 Example 3 Ethyl 4-(N-(α-(4-methyl-phenyl)-2
-piperidino-penzol'-aminocarbonylmethyl]
-benzony) 4.4 g (9.65 mmol)
was heated and dissolved in 15 Q ml of ethanol.

Then 20 ml of 1N sodium hydroxide solution are added and the mixture is stirred at 50° C. for 3 hours. 20 ml of 1N hydrochloric acid are added to the reaction mixture and the excess ethanol is then removed by evaporation in a rotary evaporator.

The remaining aqueous suspension is filtered and the precipitate is thoroughly washed with water. Next, it is recrystallized from acetonitrile.

Yield: 2.45g (59.3% of theory) Melting point: 226
~228°C Elemental analysis: Calculated: C75.99 H6.83 N6.33 Observed: 75.60 6.75 6.29 The following compound is prepared analogously to Example 3: (a) 4-(N −(α−(
(3-methyl-phenyl)-2-piperidino-benzyl)
-Aminocarbonylmethyl]-benzoic acid Yield: 72% of theory Melting point: 202-203°C Chlorine analysis: Calculated value: C75.99 H6.83 N6.33 Actual value: 75.64 6.91 6.37 (b )4-(
N-1: α-(2-tatyl-phenyl)-2-piperidino-phenylcouaminocalcinylmethyl)-benzoic acid Yield: 42.6% of theory Melting point: 285-290°C Elemental analysis: Calculated value :C75.99 H6.03 N6.33 Actual value: 76.05 6.98 6.25 (c) 4-(
N-4α-(4-methoxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 72.4% of theory Melting point: 228-230°C Elemental analysis: Calculated value: C73. 34 H6.59 N6.11 Actual value: 73.22 6.61 6.13(d) 4-(
N-(α-(4-penzyloxy-phenyl)-2-1
Peridino-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 57% of theory Melting point: 219-221°C Elemental analysis: Calculated value: C76.38 H6.41 N5.24 Actual value: 76.05 6.44 5.24(e)4-(
N-(α-(4-fluoro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 75% of theory Melting point: 268-240°C Elemental analysis: Calculated value: C72. 63 H6.09 N6.27 Actual value: 72.98 6.29 6.32 (f) 4-(
N-[α-(2-fluoro-phenyl)-2-piperidino-genzyl)-aminocarbonylmethyl]-benzoic acid Yield: 87% of theory Melting point: 280-283°C Elemental analysis: Calculated value: C72.63 H6.09 N6.27 Actual value: 72.70 6.10 6.37 (g) 4-(
N-(α-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 89% of theory Melting point: 241-242°C Elemental analysis: Calculated value: C70.05 H5.88 N6.05 Cl
7.66 Actual value: 69.74 6,05 6.0
1 7.64(h)4-(N-(α-(6-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 56% of theory Melting point: 226-225 °C Elemental analysis: Calculated value: 070.05 H5,88N6.05 (
J7.66 actual value: 70.28 5.98 5
．． 78 7.84(1) 4-(N-(α-(2-chloro-phenyl)-2-piperidino-benzylcouaminocarbonylmethyl)-benzoic acid Yield: 98% of theory Melting point: 303-305°C Elemental analysis: Calculated values: C70.05 H5.88 N6.05 Cl
7.66 Actual value: 69.88 6.05 5.8
7 7.74(k)4-(N-(α-(4-methylmercapto-phenyl)-2-piperidino-benzyl)
-Aminocarbonylmethyl)-benzoic acid Yield: 84.6% of theory Melting point: 225-227°C Elemental analysis: Calculated values: C70.86 H6.37 H5.90 Cl
6.75 Actual value: 70.34 6.37 5.6
8 6.82(l)4-(N-(5-chloro-α-
(2-Chlor-phenyl)-2-L'peridino-penzol]-aminocarbonylmethyl)-benzoic acid Yield: 90% of theory Melting point: 317-320°C Elemental analysis: Calculated value: C65.19 H5.27 H5.63 Cl
14.25 Actual value: 64.87 5.34 5.
69 14.22(m)4-(N-(2-piperidino-α-(2-birisol)-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 81% of theory Melting point: 160-161°C Element Analysis: Calculated value: C72.71 H6.34 N9.78 Actual value: 72.43 6.39 10.00 (n)
4-(N-(2-Piperidino-α-(3-bilisolun-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 72% of theory Melting point: 252-256°C Elemental analysis: Calculated value: C72. 71 H6.34 N9.78 Actual value: 72.56 6.53 9.60(o)4-(
N-(2-piperidino-α-(4-pyridyl)-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 68.5% of theory Melting point: from 260°C (decomposition) Elemental analysis: Calculated value: C72 .71 H6.34 N9.78 Actual value: 72.31 6.29 9.63 (p) 4-[
N-(6-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 82% of theory Melting point: 91-94°C Elemental analysis: Calculated value: C70.04 H5. 88 N6.05 Cl
7.66 Actual value: 69.61 6.77 5.9
6 7.78(q)4-(N-(4-chloro-α-
Phenyl-2=piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 61% of theory Melting point: 221-223°C Elemental analysis: Calculated values: C70.05 H5.88 N6.05 Cl
7.66 Actual value: 69.73 5.89 5.8
7 7.52(r)4-(n-(3-chloro-α-
Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 86% of theory Melting point: 210-213°C Elemental analysis: Calculated values: C70.05 H5.88 N6.05 Cl
7.66 Actual value: 70.31 6.05 5.9
0 7.79(s)4-(N-(6-methyl-α-
Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 64% of theory Melting point = 165-170°C (sintered from 150°C) Elemental analysis: Calculated value: C75.99 H6.83 y6 .55 Actual value: 75.73 6.96 6.14 (a4-(n
-(5-Methyl-α-phenyl-2=piperizono-benzyl-aminotriponylmethyl)-benzoic acid Yield: 97% of theoretical amount Melting point: 246-245°C Elemental analysis: Calculated value: C75.99 H6.85 N6 .33 Actual value: 75.60 7.01 6.31(u)4-(
N-(4-Methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 96% of theory Melting point = 202-206°C Elemental analysis: Calculated value: C75.99 H6. 85 N6.33 actual value: 76.04 6.78 6.23 (v) 4-(
N-(5-methoxy-α-phenyl-2-piperidino-
Benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 27% of theory Melting point: 217-220°C (sintered from 2O2°C) Elemental analysis: Calculated: C73.34 H6.59 N6.11 Actual value: 72 .92 6.68 5.99 (w) 4-(
N-(6-methoxy-α-phenyl-2-piperidino-
Benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 51.5% of theory Melting point: 90-95°C Elemental analysis: Calculated value: C73. lS, 34 H6, 59N6.11
Actual value: 76.06 6.42 5.86
(x)4-(N-(5-chloro-2-(3,5-cis-
dimethyl-piperidino)-α-phenyl-benzyl]-
(aminocarbonylmethyl)-benzoic acid Yield: 81% of theory Melting point: 256-255°C Elemental analysis: Calculated values: C70.93 H6.36 H5.71 Cl
7.22 Actual value: 70.68 6.51 5.7
5 7.36(y)4-[N-(2-dimethylamino-α-phenyl-bencyl)-aminocarbonylmethylbenzoic acid Yield: 86% of theory Melting point: 183-184°C Elemental analysis: Calculation Value: C74.20 H6.23 N7.21 Actual value: 74.31 6.27 7.16 (z) 4-(
N-(2-di-n-propylamino-α-phenyl-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 79% of theory Melting point: 202-204°C Elemental analysis: Calculated value: C75.64 H7 .26 N6.30 actual value: 75.74 7.31 6.15(an)4(
N-(5-chloro-2-(2-methyl-piperidinone-
α-phenyl-benzyl)-aminocarbonylmethyl]
- Benzoic acid yield: 52% of theory Melting point: 280-282°C Elemental analysis.

Calculated value: C70.50 H6.13 H5.87 Cl
7.43 Actual value: 70.14 6.10 5.7
5 7.45(ab)4-(N-(5-chloro-2
-(6-Methyl-piperidino)-α-phenyl-benzyl)-aminocarbonylmethylcoubenzoic acid Yield: 66% of theory Melting point: 246-248°C Elemental analysis: Calculated value: C70.50 H6.13 H5 .87 Cl
7.66 Actual value: 70.16 6.07 5.8
7 7.30(ac)4-(N-(2-(3,5-
dimethyl-piperidino9-α-phenyl-benzyl)-
(aminocarbonylmethyl)-benzoic acid Yield: 59% of theory Melting point: 238-240°C Elemental analysis.

Calculated value: C76.28 H7.07 N6.14 Actual value: 76.38 7.28 6.11 (ad) 3-
Chlor-1-(N-(α-phenyl-2-piperidino-
Benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 56% of theory Melting point: 236-239°C Elemental analysis: Calculated values: C70.04 H5.88 N6.05 Cl
7.66 Actual value: 69.88 5.77 5.8
6 7.81(ae)4-(N-(2-(3,5-
cis-dimethyl-piperidino)-5-nitro-α-phenyl-benzyl)-aminocarbonylmethyl)-benzoic acid yield: 81% of theory Melting point: from 225°C (decomposition) Elemental analysis: Calculated value: C69. 44 H6.23 N8.38 Actual value: 68.95 6.44 8.56 (af) 4-
(N-(2-(octahydro-1H-azonino)-α-
Phenyl-benzyl]-aminocarbonylmethylcoubenzoic acid Yield: 62.5% of theory Melting point: 265-267°C Elemental analysis: Calculated value: C76.56 H7.28 N5.95 Actual value: 76.50 7. 30 5.94 (ag) 4-
(N-(5-hydroxy-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 71% of theory Melting point: 98-101°C Elemental analysis: Calculated value: C72.95 H6 .65 N6.30 actual value: 72.98 6.40 6.47 Example 4 4-(N-(α-(4-benzyloxy-phenyl)-
1.1 g (2 mmol) of 2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid was dissolved in 20 ml of ethanol.
0 ml and at 50° C. under 5 bar hydrogen pressure for 10
Catalytic debenzylation in the presence of 0.4 g of % palladium/charcoal. The catalyst is then filtered off and the filtrate is concentrated by evaporation and recrystallized from acetonitrile.

Yield: 720 mg (66.7% of theory) Melting point: 202
~204°C Elemental analysis: Calculated: C72.95 H6.35 N6.30 Observed: 72.65 6.17 6.20 The following compounds are prepared in the same manner as in Example 4: (a) Ether 4-(N-
(5-Hydroxy-α-phenyl-2-biveridino-penzol-aminotriponylmethyl)-benzoate Yield: 96% of theory Melting point: 191-193°C Elemental analysis: Calculated value: C73.70 H6.82 N5.93 Actual value: 73.52 6.57 5.61 Example 5 Ethyl 4-(N-(α-(4-methyl-phenyl)-2
-piperidino-benzyl)-aminocarbonylmethyl]
- 2.5 g (5.3 mmol) of benzoate are added in portions to a suspension of 0.5 g (13.2 mmol) of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran. The mixture was stirred for a further 60 min at room temperature and then 4N*
It is decomposed by adding dropwise a sodium oxide bath and then the sodium aluminate formed is removed. The filtrate is concentrated by evaporation and the residue is recrystallized from a small amount of toluene.

Yield: 0.98 g (43% of theory) Melting point: 144-146°C Elemental analysis: Calculated value: C78.47 H7.53 N6.54 Actual value: 78.20 7.39 6.58 Same as Example 5 to produce the following compound: (a) 4-(N-(α-
Phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzyl alcohol Yield: 61.5% of theory Melting point: 143-145°C Elemental analysis: Calculated values: C78.23 H7.29 N6.76 Actual values : 78.13 7.30 6.62 Example 6 8.85 g (20 mmol) of 4-(N-(α-(4-methyl-phenyl)-2-piperidino-benzyl"-aminocarbonylmethyl)-benzoic acid and 3.25 g (20 mmol) of N,N'-carbonylsiimidazole are refluxed for 2 hours in 100 ml of anhydrous tetrahydrofuran.

The mixture was then concentrated by evaporation and added with 50 ml of pyridine and 4
-) After adding 3.7 g (20 mmol) of luenesulfonic acid hydrazide, the mixture is refluxed for a further 2 hours.

Next, pour into ice water, filter with suction, and dry the precipitate.

The resulting crude toluenesulfone-related hydrazide of the used carboxylic acid is mixed with 20 g of anhydrous sodium carbonate and heated to 170° C. for 2 hours in 50 ml of ethylene glycol.

Then add to water and extract with chloroform. The concentrated extract was subjected to column chromatography on silica sol.
Purify using toluene/ethyl acetate 5:1 as eluent.

Yield: 1.73 g (21% of theory) Melting point: 144-146°C Elemental analysis: Calculated: C78.84 H7.09 N6.57 Actual value: 78.95 7,19 6.50 Same as Example 6 to prepare the following compound: (a) 4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethylnsaldehyde Yield: 29% of theory Melting point: 168-170°C Elemental analysis : Calculated value: C78.61 H6.84 N6.79 Actual value: 78.60 7.00 6.72 Example 7 4-(N-(α-(4-methyl-phenyl)-2-piperidino-benzyl) 0.5 g (1.2 mmol) of benzyl alcohol (aminocarbonylmethyl) to 0.4 g of birizonium chlorochromate in 2 ml of chloroform.
(1.5 mmol) into a suspension. After 12 hours at room temperature, ether is added, the mixture is filtered and the concentrated filtrate is purified by column chromatography on silica gel (eluent: toluene/ethyl acetate = 5:1).

Yield: 0.3 g (60% of theory) Melting point: 145-146°C Elemental analysis: Calculated values: C78.84 H7.09 N6.57 Actual values: 78.97 7.12 6.57 Same as Example 7 The following compound is prepared: (a+4-4N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde Yield: 40% of theory Melting point: 170°C Elemental analysis: Calculated: C78.61 H6.84 N6.79 Actual value: 78.59 6.87 6.61 Example 8 4-(N-(α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl) - Add 427 mg (1 mmol) of benzaldehyde to an ethereal solution of 450 mg (2 mmol) of ethylzoethylphosphonoacetate and 100 mg (2 mmol) of 50% sodium hydride. After the mixture has been stirred overnight, water is added and the product The mixture is extracted with chloroform and purified by column chromatography on silica gel using toluene/ethyl acetate (5:1) as eluent.

Yield: 0.18 g (36% of theory) Melting point: 176-180°C Elemental analysis: Calculated value: C77.39 H7,31N5.64 Actual value: 77.64 7,25 5.71 Same as Example 8 Prepare the following compound = (a) ethyl 4-4N-(
α-phenyl-2-piperidino-benzyl)-amino-
Carbonylmethylcoucinnamate yield: 28.6% of theory Actual value: 77.28 7.21 5.65 Example 9 4-CN-Cα-(4-methyl-phenyl)-2-piperidino-benzyl]- Aminocarbonylmethyl]-cinnamic acid Analogously to Example 3, by alkaline saponification of ethyl 4-(N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamate. Manufacture.

Yield: 84% of theory Melting point: 176-176°C Elemental analysis: Calculated values: C76.90 H6.88 N5.98 Actual values: 77.24 7.01 5.64 In the same manner as in Example 9, the following Prepare the compound: (a) 4-(N-(α-phenyl-2-piperidino-benzyl)-aminecarbonylmethyl]-cinnamic acid Yield: 75% of theory Melting point: 177-180°C Elemental analysis: Calculated value: C76.62 H6.65 N6.16 Actual value: 76.75 6.57 6.07 Example 10 α-(6-Methyl-phenyl-2-piperidino-benzyl alcohol in 2 ml of O-dichlorobenzene 0 .22
g (0.8 mmol) and ethyl 4-cyanomethyl-
A mixture of 0.15 g (0.8 mmol) of benzoate was dissolved in 1.5 ml of O-dichlorobenzene and 1.5 ml of concentrated sulfuric acid.
ml dropwise at room temperature. After stirring for 2 hours, the mixture is poured onto ice water, extracted once with ether, made alkaline with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is evaporated and the residue is recrystallized from ethanol.

Yield: 0.22 g (60% of theory) Melting point: 158-159°C Elemental analysis: Calculated value: C76.57 H7.28 N5.95 Actual value: 76.41 7.39 5.76 Same as Example 10 to prepare the following compound: (a) ethyl 4-(N
-(2-(3,5-cis-dimethyl-piperidino)-5
-Nitro-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoate Yield: 57% of theory Melting point: 170-175°C Elemental analysis: Calculated value: C70.50 H6.66 N7.93 Actual value: 70. 05 6.68 7.81 Example 11 240 mg (5 mmol) of 4-(N-[α-chloro-α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid in ethanol Catalytic dehalogenation in the presence of 0.1 g of 10% palladium on charcoal in 80 ml of /dioxane (1/1) at 50 DEG C. under a hydrogen pressure of 5 bar. After cooling, the catalyst is filtered off, the filtrate is evaporated and the residue is crystallized from ethanol.

Yield: 0.16 g (72% of theory) Melting point: 226-228°C Elemental analysis: Calculated value: C75.99 H6.85 N6.55 Actual value: 75.81 6.73 6.10 Same as Example 11 (a) 4-CN-((2
-methyl-piperidino)-α-phenyl-benzyl]-
Aminocarbonylmethyl]-benzoic acid 4-(N<5-chloro-2-(2-methyl-piperidino)-α-phenyl-benzylcouaminocarbonylmethyl]-benzoic acid.

Yield: 68% of theory Melting point: 246-248°C Elemental analysis: Calculated value: C75.99 H6,83 N6.33 Actual value: 75.57 7.1 tJ 6.44 (b) 4-[
N-(2-(3-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid 4-(N-(5-chloro-2-(6-methyl-piperidino)-α-phenyl -benzyl)-aminocarbonylmethyl]-benzoic acid.

Yield: 46% of theory Melting point: 228-260°C Elemental analysis: Calculated: C75.99 H6.83 N6.33 Observed: 75.91 6.82 6.33 Example 12 Warm methylene in 5Qml A solution of (4-methyl-phenyl)-(2-piperidinophenyl]-ketimine 2.78.F (10 mmol) prepared in the rth step was mixed with 1.5 ml (11 mmol) of triethylamine and then chlorinated. A solution of 2.5 g (11 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 2 Q ml of Methyref is added dropwise thereto while cooling the mixture on ice. After 1 hour at room temperature, it is poured onto ice water. , and extracted with methylene chloride. The extract is dried, evaporated, and the evaporated residue is purified by column chromatography on silica gel (eluent: toluene/ethyl acetate = 10:1).

The crude anlimine is dissolved in dimethylformamide and, after addition of 0.5 g of palladium (10% on charcoal), hydrogenated at room temperature under a hydrogen pressure of 5 bar. After the hydrogen on the plate has been absorbed, the catalyst is filtered off, the filtrate is evaporated and condensed, and the residue is recrystallized from a small amount of alcohol.

Yield: 2.8 g (60% of theory) Melting point: 175-177°C Elemental analysis: Calculated value: C76.57 H7.28 N5.95 Actual value: 76.41 7.19 5.76 Example 16 Example 1 and Similarly, α-(4-methyl-phenyl)-2
-piperidino-benzylamine and 4-cyano-phenylacetic acid.

Yield: 64% of theory Melting point: 144-146°C Elemental analysis: Calculated value: C79.40 H6.90 N9.92 Actual value: 79.10 6.90 9.78 The following compound was prepared in the same manner as in Example 13. (a) 4-(N-(α-
Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzonitrile Yield: 53% of theory Melting point: 178-181°C Elemental analysis: Calculated value: C79.18 H6.65 N10.26 Actual value: 78 .84 6.55 10.24 Example 14 4-(N-(α-(4-methyl-phenyl)-2-piperidino-benzyl"-aminocarbonylmethyl)-benzonitrile 4.2 g (10 mmol) ethanolic Reflux with 50 ml of hydrochloric acid for 24 hours.

The mixture is then concentrated by evaporation, the evaporation residue is mixed with aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is concentrated by evaporation, the residue is triturated with ethanol and filtered with suction.

Yield: 2.9g (61.6% of theory) Melting point: 177~
179°C Elemental analysis: Calculated value: C76.57 H7.28 N5.95 Observed value: 76.41 7.35 5.76 Analogously to Example 14, the following compound is prepared: (a) Ethyl 4-( N
-(5-Methyl-α-phenyl-2-piperidino-benzylno-aminocarponylmethyl]-benzoate Yield: 57% of theory Melting point: 170-173°C Elemental analysis: Calculated: C76.57 H7.28 N5. 95 Actual value: 76.41 7.19 5.65 Example 15 Ethyl 4-(N-(α-(2-chloro-phenyl)-5
10 mmol of ditro2-eperidino-benzyl]-aminocarbonylmethylcubenzoate are dissolved in 50 ml of dimethylformamide and, after removal of 1 g of Raney nickel, hydrogenated at 60 DEG C. under a hydrogen pressure of 6 bar. The catalyst was then filtered off, the filtrate was concentrated by evaporation, and ethyl 4
-(N-[5-amino-α-(2-chloro-phenyl)
-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoate in 100 mg of concentrated hydrochloric acid.
dissolve in The mixture is cooled with ice and a solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water is added dropwise thereto, and the resulting mixture is added dropwise for 1 hour at 0-5°C. The reaction mixture is then added dropwise to a solution of 3 g of copper(1) chloride in 25 ml of concentrated hydrochloric acid. After stirring for 1 hour, the mixture is made alkaline with sodium hydroxide solution and extracted with chloroform. Extract with concentrated chloroform and purify by column chromatography over silica using toluene/ethyl acetate (5:1) as eluent.

Yield: 1.5 g (28.6% of theory) Melting point: 213~
215℃ Elemental analysis: Calculated values: C66.28 H5.75 N5.33 Cl
13.49 Actual value: 66.40 5.91 5.
41 13.40 The following compounds are prepared analogously to Example 15: (a) Ethyl 4-(N-(5-chloro-2-
(3.5-cis-dimethyl-piperidino)-α-phenyl-benzyl]-aminocarbonylmethyl]-benzoate yield; 28% of theoretical amount Melting: 188-191°C Elemental analysis; Calculated value: C71.72 H6 .80 N5.40 Cf
6.83 Median: 71.95 6.85 5.3
5 6.77 Example 16 0.91 g (2 mmol) of 2-piperidino-benzyl)-aminocarbonylmethyl)-cinnamic acid was dissolved in methanol 5
0.5 g of palladium (10% on charcoal) dissolved in 0 ml
After the addition of , the mixture is catalytically hydrogenated at room temperature under a hydrogen pressure of 3 bar. After hydrogen absorption has stopped, the catalyst is filtered off,
Recrystallize from a small amount of acetonitrile.

Yield: 0.68 g (74% of theory) Melting point: 146-148°C Elemental analysis: Calculated value: C76.57 H7.28 H5.95 Actual value: 76.41 7.19 5.61 Same as Example 16 (a) 3-(4-(N-)
(α-Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid Yield: 65% of theory Melting point: 97-99°C Elemental analysis: Calculated: C76.30 H7.06 N6. 13 Observed value: 76.35 6.95 5.91 Example 17 4-(N-(α-(4-methyl-phenyl9-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid 442 mg (1 mmol) is dissolved in 25 ml of ethanol and mixed with 1 ml of 1N sodium hydroxide solution.

The mixture is then evaporated under reduced pressure, 2 Q ml of acetone are added and the resulting precipitate is filtered off with suction and washed with ethyl acetate.

Yield: 410 mg (85% of theoretical amount) Melting point: 296-300°C Elemental analysis: Calculated value: c72.40 H6.29 H6.03 Actual value: 72.15 6.46 5.93 In the same manner as Example 17, the following Manufacture the attached products.

(a) 4-(N-(α-(4-methyl-phenyl)-2
Ethanolamine salt yield of -piperidino-benzyl 9-aminocarbonylmethylcoubenzoic acid; 75% of theory Melting point: 188-191°C Elemental analysis: Calculated value: C71.55 H7,41 H8,54 Actual value: 71. 16 7.48 8.52 (b) 4-(
Jetanolamine salt of N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminecarbonylmethyl]-benzoic acid Yield: 81% of theory Melting point: 178-180°C Elemental analysis: Calculation Value: C70.70 H6.86 N7.73 Actual value: 70.25 6.75 7.58 (c) 4-(
Triethanolamine salt of N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl 51-benzoic acid Yield: 76% of theory Melting point: 160-165°C Elemental analysis: Calculation Value: C69.01 H7.67 N7.10 Actual value: 68.91 7.64 7.45 (cl) 4-
Ethylenediamine salt of CN-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 65% of theory Melting point: 160-166°C Elemental analysis: Calculated value :C71.69 H7.62 N11.15 Actual value: 72.04 7.80 10.96 Example 18 Ethyl 4-(N-(5-hydroxy-α-phenyl-2
-piperidino-benzyl)-aminocarbonylmethyl]
- 472 mg (1 mmol) of benzoate are dissolved in 25 ml of anhydrous dimethylformamide. After addition of 50 mg of 50% sodium hydride, the mixture is stirred for 60 minutes. Then 0.5 g of methyl iodide is added dropwise and the resulting mixture is stirred overnight. For finishing, pour on ice water and extract with methylene chloride. The gillnet extract is purified by column chromatography on silica gel using toluene/ethyl acetate 4:1 as eluent.

Yield: 260 mg (56% of theory) Melting point: 123-125°C Elemental analysis: Calculated: C74.05 H7.04 N5.76 Observed: 73.86 6.95 5.61 Example 19 In 5 ml of acetonitrile 0.55 g of 2-methoxy-1-(2-piperidino-phenyl)-ethylamine (2.
0.49 g (2.34 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 0.73 g (2.78 mmol) of triphenylphosphine, 0.50 ml (3.66 mmol) of triethylamine and 0.23 ml (2.34 mmol) of carbon chloride are added in succession and the resulting mixture is stirred at room temperature for 20 hours. It is then condensed by FK evaporation under reduced pressure and partitioned between ethyl acetate and water. The organic extract is dried, filtered and evaporated under reduced pressure.

The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=10/2).

Yield: 0.45 g (45% of theory) Melting point: 122-126°C Elemental analysis: Calculated value: C70.73 H7.60 H6.60 Actual value: 71.04 7.48 6.39 Same as Example 19 to prepare the following compound 1i12I: (a) ethyl 4
-11. (1-(3-chloro-2-piperidino-phenyl)-1-decyl]-aminosulfonylmethyl]-benzoate Yield: 55% of theory Melting point: 141-143°C Elemental analysis: Calculated value: C68.33 H7.28 Cl7.76 N
6.13 Actual measurement value: 68.30 7.16 8.
03 6.20(b) Ethyl 4-((1-(6-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate Yield: 73.9% of theory Melting point: 79 ~82℃ Elemental analysis: Calculated values: C68.33 H7.28 Cl7.76 N
6.13 Actual measurement value: 68.45 7.24 7.
80 6.09(c) Ethyl 4-[(1-(4-bromo-2-2peridino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 62.1% of theory Melting point: 116-118℃ Elemental analysis; Calculated value: C62.27 H6.63 Br15.93
N5.58 actual value: 62.53 6.48 1
5.98 5.66(d) Ethyl 4-((1-(4-
Nitro-2-piperidino-phenyl)-1-butyl)-
Aminocarbonylmethyl)-benzoate yield: 74.6% of theory Melting point: 127-160°C Elemental analysis calculation: C66.79 N7.11 N8.99 Actual value: 66.88 7.08 9.15 (e ) Ethyl 4-[(1-(3-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-pengueate Yield: 68% of theory Melting point: 145-147°C Elemental analysis: Calculation Value: C74.28 HIJ, 31 N6.42 Observed value: 74.40 8.5[J 6.41(f) Ethyl 4-((1-(4-methyl-2-piperidino-phenyl)-1-butyl )-aminocarbonylmethyl)-benzoate yield: 54.7% of theory Melting point: 113-114°C Elemental analysis: Calculated value: C74.28 H8.31 N6.42 Observed value: 74.23 8.30 6. 55(g) Ethyl 4-((1-(5-methyl-2-piperidinophenyl)-1-butyl) --t mi/carbonylmethyl"-
Benzonite yield: 67.9% of theoretical amount Melting point: 149-150°C Elemental analysis/calculated value: C74.28 H8.31 N6.42 Actual value: 74.38 8.21 6.49 (h) Ethyl 4 -[(1-(6-Methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate Yield: 47% of theory Melting point: 92-96°C Elemental analysis: Calculated value: C74. 28 H8.31 N6.42 Actual value: 74.50 8.46 6.48 (1) Ethyl 4-((1-(2-pyrrolidino-phenyl)-1-gutyl)-aminocarbonylmethylcubenzoate yield: 57.3% of theory Melting point, 122-125°C Point elemental analysis: Calculated value: C73.50 N7.90 N6.86 Actual value: 73.63 8.07 7.01(k) Ethyl 4-((1 -(2-Piperidino-phenyl)-1-butylno-aminocarbonylmethyl]-benzoate Yield: 71.5% of theory Melting point: 127-128°C Elemental analysis: Calculated value: C73.90 H8.11 N6.63 Actual value: 73.90 8.06 6.72 (1) Ethyl 4-C(1-(2-(4-methyl-piperidino)-phenyl)-1-gutyl)-aminocarbonylmethyl)-benzoate yield: 51.1% of theory Melting point: 153-155°C Elemental analysis: Calculated value: C74.28 H8.31 N6.42 Actual value: 74.55 8.33 6.45 (m) Ethyl 4-((1- (2-hexahydroazebino-phenyl)
-1-Butyl)-aminocarbonylmethyl"-benzoate Yield: 42.7% of theory Melting point: 145-147°C Elemental analysis: Calculated value: C74.28 H8.61 N6.42 Actual value: 73.98 8 .26 6.58(n) Ethyl 1-((1-(5-fluoro-2-bihelidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 55% of theory Melting point: 128~ 130°C Elemental analysis: Calculated value: C70.88 N7.55 N6.36 Actual value: 71.14 7.57 6.49 (o) Methyl 41(1-(2-piperidino-phenyl)-1-glutyl)- 7minocarbonylmethyl"-penzoate yield, 63.2% of theory Melting point: 147-148°C Elemental analysis; Calculated value: C73.50 H7.90 N6.86 Actual value: 73.66 7.88 6.80 (p) n-butyl 4-((1-(2-piperidino-phenyl)-1-
Butyl)-aminocarbonylmethyl)-benzoate Yield: 50.9% of theory Melting point: 117-119°C (ether) Elemental analysis: Calculated: C74.63 H8.50 N6.22 Actual value: 74.49 8 .46 6.14 (a) Ethyl 3-chloro-4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 14.9% of theory Melting point: <20℃ Calculated value: m/e=456/458 (1 chlor) Actual value:
m/e=456/458 (1 chlor) (r) ethyl 4-
((1-(2-Piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethylcubenzoate Yield: 18.9% of theory Melting point: 106-105°C Elemental analysis: Calculated value: 074 .62 H7.89 N6.45 Actual value: 75.01 8.10 6.26 (8) Ethyl 4-((1-(3-chloro-2-bipe,rizono-phenyl)-1-ethyl-amino -
Benzoate yield: 58.0% of theory Melting point: 166-168"C Elemental analysis: Calculated value: 067.20 H6,81 (J8.27
N6.53 actual value: 67.17 6.85 8.
17 6.45 Example 20 4-Ethoxy-carbonyl- in 2Qml of methylene chloride
A solution of 14.6 g (64.6 mmol) of phenylacetic acid chloride) in 55 ml of dry methylene chloride and 8.46 ml (61.4 mmol) of triethylamine and 1
15.1 g (54.4 mmol) of (5-nitro-2-piperidino-phenyl)-1-butylamine are added dropwise to a stirred bath within 6 U minutes, such that the temperature does not exceed 60°Q. The mixture was stirred for a further 2 hours at room temperature, 300 ml of methylene chloride was added and the resulting mixture was
Extract twice with 0 ml of water.

The organic phase is dried over sodium sulfur, filtered once and concentrated under reduced pressure. The reddish-brown oily distillation residue is purified by column chromatography on silica gel (toluene/acetone=10:1).

Collection gong: 17.7g (69.7% of theoretical amount) Melting point = 155
~167°C (ether) Elemental analysis: Calculated: C66.79 H7.11 N8.99 Observed: 66.73 6.99 9.09 The following compound is prepared in the same manner as in Example 20: (a) Ethyl 4-((1
-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate Yield: 80.2% of theory Melting point: 127-129°C Elemental analysis: Calculated value: C73.90 H8.11 N6. 63 Actual value: 73.98 8.26 6.89 (b) Ethyl 4-((1-(4-hydroxy-2-piperidinophenyl)-1-gutyl)-aminocarbonylmethyl)-benzoate yield: Theory 16.5% of the amount Melting point: 178-180°C Elemental analysis: Calculated: C71.21 H7.81 N6.39 Observed: 71.27 7.82 6.40 (c) Ethyl 4-((1-( 5-Hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate Yield: 37.4% of theory Melting point: 188-190°C Elemental analysis: Calculated value: C71.21 N7.81 N6.69 actual value: 71.34 7.89 6.38 Example 21 3.0 g (15.45 mmol) of p-phenylene-diacetic acid and 10 mg of thionyl chloride are refluxed for 90 minutes, then concentrated under reduced pressure. . The crude diacid chloride is dissolved in 100 ml of methylene chloride. To this dissolution, 3.6 g (1
5.45 mmol) solution at 10-15°C with stirring.
Add slowly dropwise at an internal temperature of . After 2 hours at room temperature, the mixture was concentrated by evaporation under reduced pressure and the evaporation residue was dissolved in ice-cold 5% sodium hydroxide solution and 100% of ethyl acetate.
Distribute into ml. Filter through Kieselgar and separate off the organic phase. The pH of the alkaline-aqueous phase is adjusted to 5.5 with semi-concentrated hydrochloric acid and extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered and the filtrate is evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=20/1).

Yield: 0.10g (1.6% of theory) Melting point: 136~
140°C (acetonitrile/ether) Elemental analysis: Calculated: C73.50 N7.90 N6.86 Observed: 73.17 8.10 6.85 Example 22 Freshly formed isopropyl-(2- Biperidino-phenyl)-ketimine 6.1
In a solution of 7 g (26.8 mmol), 5.58 g (26.8 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 8.43 g (52.2 mmol) of triphenylphosphine, and 11.2 ml (80.4 mmol) of triethylamine. and carbon tetrachloride 2.6 ml (0.0268 mol)
are added sequentially and the resulting mixture is stirred at room temperature for 24 hours. It is then concentrated under reduced pressure and partitioned between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 5/
1).

Yield: 3.0 g (26.6% of theory) Melting point: 82-8
4°C (ether) Elemental analysis: Calculated value: C74.26 N7.67 N6.66 Observed value: 74.20 7.49 6.56 The following compound is prepared by isolating Example 22; (a) Ethyl 4 -(1-
(2-Piperidino-phenyl)-1-penten-1-yl)-aminocarbonylmethyl]-benzoate Yield: 16% of theory Melting point: 94-97°C (ethanol) Elemental analysis: Calculated value: C74.62 N7 .89 N6.45 actual value: 74.75 7.71 6.24(b) Ethyl 4-((1-(2-piperidinophenyl)-1-hexen-1-yl)-aminocarbonylmethyl]-benzoate Yield: 27.4% of theory Melting point = 83-85°C (ethanol) Elemental analysis: Calculated value: C74.97 H8.09 N6.24 Actual value: 75.42 7.95 6.00 (c) Ethyl 4-C(1-42-Piperidino-phenyl)-1-buten-1-yln (reminocarbonylmethyl)-benzonylic acid yield (the more lipophilic isomer rod; probably form E) of the two-theoretical demonstration. 4.1% Melting point: 20℃ Calculated value: m/e = 420 Actual value: m/e = 420 Yield (less lipophilic isomer: probably form 2): 51.9% of theory Melting point =115-117°C (ethanol) Elemental analysis: Calculated value: C74.26 H7.67 N6.66 Actual value: 76.85 7.59 6.44 (d) Ethyl 4-((2-phenyl-1-( 2-piperidino-phenyl)-ethen-1-yl)-aminocarbonylmethyl)
-benzoate yield (more lipophilic isomer; probably E
Form): 4% of the temperature Melting point: 75-77°C (ether/petroleum ether) Calculated value: C76.90 H6.88 N5.98 Actual value: 7
7.31 7.20 5.95 Yield (less lipophilic isomer; probably Z form): 42.7% of theory Melting point: 157-160°C (ethanol) Elemental analysis: Observed value: C77. 19 H6.95 N6.02(a)
Ethyl 4-4(3-phenyl-1-(2-piperidino-
phenyl)-1-propen-i-yl)-aminocarbonylmethyl]-benzoate Yield: 62.6% of theory Melting point: <20°C Calculated value: m/e = 482 Actual value: m/e = 482 ( f) Ethyl 4-((1'-(2-(3,3-dimethyl-biperidino)-phenyl)-1-buten-1-yl)
-aminocarbonylmethyl)-benzoate yield: 33% of theory Melting point: 113-116°C (ethanol) Elemental analysis: Calculated value: O74.97 H8.09 N6.24 Observed value: 75.67 7.93 6. 03(g) Ethyl 4-((1-(6-methyl-2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl"-benzoate Yield: 60.4% of theory (probably Z type) Melting point: 95-96℃ Elemental analysis: Calculated value: C74.62 H7.89 N6.45 m/
e=434 actual value: 74.44 8.00 6.
59 m/e=434 Example 23 Ethyl 4-[(1-(2-piperidino-phenyl)-1
-buten-1-yl)-aminocarbonylmethyl]-benzoate 11.5 triethylamine in 190 mg of anhydrous toluene
mA (82.46 mmol) and freshly prepared (2
-Piperidino-phenyl)-propyl-ketimine19.
0 g (82.46 mmol) of stirred a were heated to an internal temperature of 85 °C, then 18.7 g (82.46 mmol) of 4-ethoxycarbonyl-phenylacetic acid in 95 ml of anhydrous toluene
mmol) solution dropwise within 10 minutes,
The resulting mixture is stirred for 60 minutes at an internal temperature of 95°C. Cool to 20°C and extract twice with water. The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The evaporation residue was purified by repeated column chromatography.
(toluene/acetone = 20/1 and 50/1
).

Container lid (more lipophilic isomer: probably E type): 11.2
g (23.6% of theory) Melting point: <20°C (honey-like yellow viscous oil) Elemental analysis: Calculated value: C74.26 H7,67 N6.66 Actual value: 73.90 7.92 6. 91 Yield (less lipophilic isomer; probably form Z): 15.9 g (33.5% of theory) Melting point: 114-116°C Elemental analysis: Found: C74.02 H76.9 N6.85 Example 24 1.0 g of Z ester (see Example 22c) is heated in a preheated oil bath at 230° C. for 60 minutes. After cooling, the product obtained is purified by column chromatography on silica gel (toluene/acetone = 20/1).

Yield (E ester): 0.365 g (theoretical amount of 36.5
%) Melting point: <20°C Yield: (Z ester): 0.380 g (38.
0%) Melting point: 115-117°C (toluene/acetone - 10/1).

Analogously to Example 24, the following compounds are obtained: (a) ethyl (
E)- and (Z)-4-((1-(6-methyl-2-
Biperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl)-benzoate (Z)-ester (see Example 22g) was purified by thin layer chromatography into a 1/1 mixture of (E) and (Z) esters. can get.

Upper spot (E): Calculated value: m/e=434 Actual value:
m/e=434 Lower spot (Z): Observed value: m/e=434 Example 25 Ethyl 4-((1-(2-piperidino-phenyl)-1-buten-1-yl)-amino in 100 ml of ethanol carbonylmethyl)-benzoate 2.9 g (6.9
0 mmol) is hydrogenated over 0.77 g of 10% palladium/charcoal at 50° C. under a hydrogen pressure of 1 bar. After 2 hours, the catalyst is filtered off on a kieselger and the filtrate is concentrated under reduced pressure.

The evaporation residue is crystallized from ethanol.

Yield: 1.5g (51.5% of theory) Melting point: 126~
128°C Elemental analysis: Calculated value: C73.90 H8.11 N6.65 Observed value: 75.97 8.22 6.57 Analogously to Example 25, the following compound is obtained: (a) Ethyl 4-(( 1
-(2-Biperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoate Yield: 45% of theory Melting point: 117-120°C (ether) Elemental analysis: Calculated value: C74.28 H8.31 N6 .42 Observed value: 74.60 8.13 6.27 (b) Ethyl 4-((1-(2-piperidinophenyl)1-hexyl)-aminocarbonylmethyl)-benzoate Yield: 50% of theory Melting point: 108-110°C (ether) Elemental analysis: Calculated value: C74.63 H8.50 N6.22 Actual value: 74.85 8.33 6.01(c) Ethyl 4-((2-phenyl-1- (2-Piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoate Yield: 87.6% of theory Melting point: 161-162°C (ethanol) Elemental analysis: Calculated value: C76.57 H7.28 N5.95 actual value: C76.71 H7.19 N5.99 (d) Ethyl 4-((3-phenyl-1-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl)-benzoate yield : 57.6% of theoretical amount Melting point: 118-119°C (ethanol) Elemental analysis: Calculated value: C76.85 H7.49 N5.78 Actual value: 76.70 7.49 5.90 (e) Ethyl 4- ((1-(2(3,3-dimethyl-piperidino)-
phenyl)-1-butyl)-aminocarbonylmethyl]
- Benzoate yield: 36.5% of theory Melting point: 140-141°C (ethanol) Elemental analysis; Calculated value: C74.63 H8.50 N6.22 Measured value: 74.50 8.23 6.12 aroma Acid Example 26 1.2 g (2.84 mmol) of ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminotriponylmethyl]-benzoate in 12 ml of ethanol.
and 4.26 ml of 1N sodium hydroxide solution was stirred at 60°C for 1 hour, then 4.26 ml of 1N hydrochloric acid
and then evaporate the ethanol under reduced pressure. The residue is partitioned between ethyl acetate and water; the organic extract is dried, filtered and evaporated under reduced pressure. The evaporation residue is crystallized from ethanol.

Yield: 0.50 g (44.6% of theory) Melting point: 213
~215°C Elemental analysis: Calculated: C75.07 H7.66 N7.10 Observed: 73.18 7.51 7.10 Analogously to Example 26, the following compound is obtained: (a) 4-((1 -(2-Piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoic acid Yield: 70.2% of theory Melting point: 213-215°C (acetone) Elemental analysis: Calculated value: C73.50 H7 .90 N6.86 actual value: 73.71 7.70 6.90(b)4-(
(1-(2-piperidino-phenyl)-1-hexyl)
-Aminocarbonylmethyl)-benzoic acid Yield: 72.6% of theory Melting point: 197-200°C (acetone) Elemental analysis: Calculated value: C73.90 H8.11 N6.63 Actual value: 73.83 7. 93 6.77(c)4-C
(2-phenyl-1-(2-piperidino-phenyl)-
1-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 68.7% of theory Melting point: 214-215°C (acetone) Elemental analysis: Calculated value: C75.99 H6.83 N6.66 Actual value: 75 .70 6.60 6.52(d) 4-(
(3-phenyl-1-(2-piperidino-phenyl)-
1-Propyl)-aminocarbonylmethyl)-benzoic acid Yield: 67.7% of theory Melting point: 167-170°C (ethyl acetate) Elemental analysis: Calculated value: C76.29 H7.06 N6.14 Actual value: 76.56 7.06 6.23(e)4-[
2-methoxy-1-(2-piperidinophenyl)-1
-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 60.8% of theory Melting point: 196-198°C (ether) Elemental analysis: Calculated value: C69.68 H7.12 N7.07 Actual value: 69. 72 6.52 6.71 (f) 4-(
(1-(2-piperidinophenyl)-4-pentene-
1-yl)-aminocarbonylmethyl)-benzoic acid x 0
．． 67H2O yield: 30.7% of theory Melting point: 193-197°C (ether/petroleum ether) Elemental analysis: Calculated: C71.74 H7.38 N6.69 Actual: 71.63 7.21 6.34 (g)4-(
(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 48.2% of theory Melting point = 168-170°C (petroleum ether ) Elemental analysis: Calculated value: C73.91 H8.11 N6.63 Actual value: 73.51 7.89 6.32 (h) 4-(
(1-(3-methyl-2-piperidino-phenyl)-1
-Butyl)-aminocarbonylmethyl]-benzoic acid Yield: 53% of theoretical value Melting point: 179-182°C Elemental analysis: Calculated value: C75.50 H7.90 N6.86 Actual value: 73.50 7.82 7 .01(i)4-(
(1-(4-methyl-2-piperidino-phenyl)-1
-Butyl)-aminocarbonylmethy)-benzoic acid Yield: 85.6% of theory Melting point: 170-172°C Elemental analysis: Calculated values: C73.50 H7.90 N6.86 Actual values: 73.25 7. 64 6.89(k)4-(
(1-(5-methyl-2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl)-benzoic acid Yield: 62.1% of theory Melting point: 219-221°C Elemental analysis: Calculated values: C76.50 H7.90 N6.86 Actual values: 73.20 7. 74 6.89(l)4-(
(1-(6-methyl-2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl]-benzoic acid x 0
．． 3H2O Yield: 89% of theory Melting point: 158-160°C Elemental analysis: Calculated value: C72.53 H7.93 N6.77 Actual value: 72.4 7.91 6.92 (m) 4-(
(1-(3-chloro-2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 70% of theory Melting point: 189-191°C Elemental analysis: Calculated values: C67.20 H6.81 Cl8.27 N
6.53 Actual value: 67.50 6.85 8.
36 6.58(n)4-((1-(4-chloro-2
-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 57.8% of theory Melting point: 188-189°C Elemental analysis: Calculated value: C67.20 H6.81 CL8.27 1 size 6.56 Actual value: 66.90 7. On 8,2
2 6.53(o)4- ((1-(5-chloro-2-
Piperidino-phenyl)-1-butyl)-aminocar 7
1 Cnylmethyl]-benzoic acid Yield: 81.6% of theoretical Melting point = 226-229°C Elemental analysis: Calculated values: C67.20 H6.81 Cl8.27 N
6.53 Actual value: 67.17 6.59 8.
51 6.60(p)4-((1-(6-chloro-2
'-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 69.4% of theory Melting point = 150-153°C Elemental analysis: Calculated values: C67.20 H6.81 Cl8.27 N
6.53 Actual value: 67.18 6.91 8.
42 6.77(q)4-((1-(4-bromo-2
-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 84.4% of theory Melting point = 198-201°C Elemental analysis: Calculated value: C60.89 H6.17 Br16.88
N5.92 actual value: 60.88 5.98 1
7.20 5.98(r) 4-((1-(5-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 90.7% of theory Melting point :262-235℃ Elemental analysis: Calculated value: C60.89 H6.17 Br16.88
N5.92 actual value: 60.96 6.15 1
6.85 5.90 (s) 4-((1-(4-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 70.9% of theory Melting point : 188-190°C Elemental analysis: Calculated value: C65.59 H6.65 N9.56 Actual value: 65.50 6.44 9.53(t)4-(
(1-(5-nitro-2-piperidino-phenyl)-1
-Butyl)-aminocarbonylmethyl)-benzoic acid Yield: 90.7% of theory Melting point = 225-227°C Elemental analysis: Calculated value: C65.59 H6.65 N9.56 Actual value: 65.80 6. 61 9.72(u)4-(
(1-(4-hydroxy-2-piperidino-phenyl)
-1-Butyl)-aminocarbonylmethyl)-benzoic acid x 0.5H2O Yield: 85.7% of theory Melting point: Softening from 70°C (foamy) Elemental analysis: Calculated value (x0.5H2O): C68.71 H7.45
N6.68 actual value: 68.63
7.55 6.26(v) 4-((1-(5-hydroxy-2-piperidino-phenyl)-1-butyl)
-aminocarbonylmethyl)-benzoic acid Yield: 89.3% of theory Melting point: 186-190°C Elemental analysis: Calculated values: C70.22 H7.37 N6.82 Actual values: 70.31 7.58 6. 51(w)4-(
(1-(4-methoxy-2-piperidinophenyl)-
1-Butyl)-aminocarbonylmethylbenzoin Yield: 78.6% of theory Melting point: 185-187°C Elemental analysis: Calculated value: C70.76 H7.60 N6.60 Actual value: 70.46 7. 77 6.56(x)4-(
(1-(5-methoxy-2-piperidinophenyl)-
1-Butyl)-aminocarbonylmethyl)-benzoic acid Yield: 75% of theory Melting point: 182-185°C (decomposition) Elemental analysis: Calculated value: C70.73 H7.60 N6.60 Actual value: 70.52 7.50 6.70(y)4-(
(1-(2-pyrrolidino-phenyl)-1-butyl)-
Aminocarbonylmethyl-benzoic acid Yield: 64.5% of theoretical amount Melting point: 200-203°C Elemental fraction: Calculated value: C72.61 H7.42 N7.36 Actual value: 72.64 7.50 7.38 (z)4-(
(1-(2-(4-methyl-piperidino)-phenyl)
-1-Butyl)-aminocarbonylmethyl]-benzoic acid Yield: 81.4% of theory Melting point: 197-201°C Elemental analysis: Calculated value: C73.50 H7.90 N6.86 Actual value: 73.90 8.06 7.00 (aa) 4-
((1-(2-hegizahydroazepinophenyl)-1
-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 65.6% of theory Melting point: 199-202°C Elemental analysis: Calculated values: C73.50 H7.90 N6.86 Actual values: 73.50 7. 90 6.76(ab)4-
C(1-(4-fluoro-2-piperidino-phenyl)
-1-Butyl)-aminocarbonylmethyl)-benzoic acid Yield: 87.1% of theoretical amount Melting point: 204-207°C Elemental analysis: Calculated value: C69.88 H7.09 N6.79 Actual value: 70.25 7.02 7.12(ac)4-
((1-(5-fluoro-2-piperidino-phenyl)
-1-Butyl)-aminocarbonylmethyl)-benzoic acid Yield: 56.9% of theory Melting point: 200-202°C Elemental analysis: Calculated value: C69.88 H7.09 N6.79 Actual value: 69.67 7.24 6.90 (ad) 3-
Chlor-4-((1-(2-piperidinophenyl)-
1-Butyl)-aminocarbonylmethyl-benzoic acid Yield: 51% of theory Melting point: 165-168'0 Elemental analysis: Calculated value: C67.2u H6-81 N6.53 m/
e=428/430 (1 chlorine) Actual value: 66.92 6-69 6.55 m/
e=428/430 (1 chlorine) (ae) 4-((1-(3-methyl-2-piperidino-
phenyl)-1-ethyl)-aminocarbonylmethyl)
- Benzoic acid yield: 79% of theoretical amount Melting point: 230-231°C Elemental analysis: Calculated value: C72.60 H7.42 N7.36 Actual value: 72.75 7.58 7.30 (af) 4-
((1-(3-chloro-2-piperidinophenyl)-
1-Ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 54% of theory Melting point: 192-195°C (75% aqueous ethanol) Elemental analysis: Calculated: C65.91 H6.28 C18.84 N
6.99 Actual value: 66.00 6.44 8.
67 6.78 Example 27 Ethyl 4-(2-methyl-1-
(2-Piperidino-phenyl)-1-propen-1-yl)-aminocarbonylmethyl]-benzoate 3.5
A mixture of g (8.3 mmol) and 12.5 ml of 1N sodium hydroxide solution is stirred at 60° C. for 2 hours. 1N
Neutralize with 12.5 ml of hydrochloric acid, evaporate under reduced pressure and partition between ethyl acetate and water. The dried and filtered organic extracts are evaporated under reduced pressure. The evaporation residue is crystallized from ethanol.

Yield: 2.4g (73.6% of theory) Melting point: 188~
191°C Elemental analysis: Calculated: C73.44 H7.19 N7.14 Observed: 73.60 7.19 7.02 The following compound is obtained in the same manner as in Example 27: (a) (E)-4- ((1-
(2-Piperidino-phenyl)-1-buten-1-1l)-aminocarbonylmethyl]-benzoic acid Yield: 71.5% of theory Melting point: 188-190°C Elemental analysis: Calculated value: C73.44 H7.19 N7.14 Actual value: 73.15 7.13 7.10 Olefinic proton: 1H-NMR (CDCl3) = 6.42pp
m(b)(Z)-4-((1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid yield: 57.8% of theory Melting point = 174-175°C (ethanol) Elemental analysis: Calculated value: C73.44 H7.19 N7.14 Actual value: 73.54 6.97 7.17 Olefinic proton: 1H-NMR (CD (J3) = 5.60
ppm(c)(E)-4-((2-phenyl-1-(2
-Piperidino-phenyl)-ethen-1-yl)-aminocarbonylmethyl)-benzoic acid x 0.4H2O Yield: 33.2% of theory Melting point: 165-167°C (ether/petroleum ether) Elemental analysis: Calculation Value (X0.4H2O): C75.11 H6.48
N6.26 actual value: 75.22
6.69 6.26 Olefinic proton: 1H
-NMR(CDCl3)=δku6.9ppm(d)(Z
)-4-((2-phenyl-1-(2-biheridino=phenyl)-ethen-1-yl)-aminocarbonylmethyl)-benzoic acid x1H2O Yield: 72% of theory Melting point: 182-185°C Methanol) Elemental analysis: Calculated value (×1H2O): C73.34 H6.60 N
6.11 Actual value: 73.55 6.
45 6.00 Olefinic proton: 1H-NMR
(CDCl3): δ=6.50ppm(e)4-((3
-phenyl-1-(2-piperisino-phenyl)-1-
Propan-1-yl)-aminocarbonylmethyl)-benzoic acid Yield: 48.3% of theory Melting point = 162-164C (ether); Possible (Z) form Elemental analysis: Calculated value: C76.63 H6.65 N6.16 actual value: 76.30 6.47 6.31 Olefinic proton: 1H-NMR (CDCl3): δ = 5.80
ppm(r)4-((1-(2-(3,5-dimethyl-
piperidino)-phenyl)-1-buten-1-yl)-
Aminocarbonylmethylcoubenzoic acid yield: theoretical amount of 6
4.1% Line point: 152-153°C (ethyl acetate): Possible (Z) type Elemental analysis: Calculated value: C74.26 H7.67 N6.67 Actual value: 73.93 7.57 6.50 Olefinicity Proton:'H-NMR (CDCf3): δ=5.55
ppm (g) (2)-4-((1-(6-methyl-2-
Piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid yield: 53 of the theoretical amount
．． 3% Melting point: 142-145°C Elemental analysis: Calculated value: C73.66 H7.44 N6.89 Actual value: 73.56 7.73 7.15 Olefinic proton: 1H-NMR (CDCl3): δ=5. 38
ppm Example 28 200 mg (0.51 mmol) of 4-((1-(2-piperidino-phenyl)-buten-1-yl)-aminocarbonylmethyl)-benzoic acid in 10 ml of absolute ethanol was dissolved in palladium/charcoal (10% ) on 100mg, 50
C. and hydrogen pressure of 1 bar with stirring. After 1.5 hours, the mixture is filtered and evaporated under reduced pressure.

Yield: 68% of theoretical amount Melting point: 216-214°C Elemental analysis: Calculated value: C73.07 H7.66 N7.10 Actual measurement: 73.21 7.82 7.02 Hydrogenation 5
Working on Raney nickel at 0° C. and 1 bar of hydrogen, a yield of 56% of theory is obtained.

Example 29 4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid 10.0 g
(25.35 mmol) in 200 ml of ethanol
Dissolve at ℃ and add 1N sodium hydroxide solution 25.3
Add 5ml. The mixture is evaporated to dryness under reduced pressure and the evaporation residue is dissolved in a minimum amount of ethanol with heating on a steam bath. The bath liquid is cooled in an ice bath and the precipitated crystals are filtered off, washed with ether and dried at 140° C./15 torr.

Yield: 9g (85.3% of theory) Melting point: 280-285°C (decomposition); Softening from 255°C Elemental analysis: Calculated value (x0.5H2O): C67.74 H6.87
N6.58 Actual value: 67.86
7.13 6.49 Example 30 Ethyl (+)-4-[(1-(2-piperidino-(+)-1-(2-piperidino-) in 26 ml of acetonitrile
Phenyl)-1-butylamine Cj F point 0.03:87
°C; ee=86 (HPLC, (+)-1-phenethyl-
after derivatization from isocyanate)] 2.58 g (1
2.31 g (11.1 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 3.50 g (13.3 mmol) of triphenylphosphine, and 4.60 ml (33.3 mmol) of triethylamine at 20°C. 9 mmol) and 1.05 ml (11.1 mmol) of carbon tetrachloride.

After 14 hours at 20°C and then 1.5 hours at 40°C, the mixture is evaporated under reduced pressure and partitioned between water and ether.

The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=
6:1) Yield: 2.63 g (56% of theory) Melting point: 118-120°C Elemental analysis: Calculated value: C75.90 H8.11 N6.63 Actual value: 74.02 7.97 6.51 (α)20D
=+9.2° (C=1: methanol) Analogously to Example 30, the following compounds are obtained: (a) Ethyl(-)-4-((1
-(2-biperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate(-)-1-(2-piperidino-phenyl)-1-butylamine x 1.4HCl(α)20D = -20.0゜(
c=1, methanol), melting point: 90-100°C: ee=80 (HPLC, tjf
, after derivatizing the group with (+)-1-phenethylisocyanate)].

Yield: theoretical amount of 52.6 line point = 115-120'C Elemental analysis: Calculated value: 073.9D H8,11 N6.63 Actual value: 73.83 8.01 6.47 (α) 20D
=-9,0° (c=1, methanol) Example 31 (+)-1-(2-piperidino-phenyl)-1-butylamine-dihydrochloride ((α)20D=+18.7°(C
= 1, methanol): melting point: decomposed from 115°C; ee
=91.6 (HPLC, after derivatization of the base with (+)-1-phenethylisocyanate)) 1.0 g (3.2
7 mmol) in 6 ml of methylene chloride, then 1.4 ml (10 mmol) of triethylamine are added with stirring, to which 0.82 g (3.
64 mmol) is added dropwise. The reaction temperature thus rises from 22°C to 38°C. The mixture is stirred for 6 hours at stormy temperature and then extracted successively twice with 10 ml of water, once with 10 ml of 2N hydrochloric acid and once with 10 ml of water. Dry the organic phase over sodium sulfate,
Filter and evaporate under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=6/1).

Yield: 0.53g (38.2% of theory) Melting point: 120
~122°C Elemental analysis: Calculated value: C73.90 H8.11 N6.63 Actual value: 75.96 7.98 6.61 [α] 20D
=+9.0° (C=1, methanol).

Example 32 Ethyl(+)-4-((1-(
2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate [[α] = +9.2°
(c=1, methanol))2. Og (4,73 mmol) with Y1N sodium hydroxide solution 7.0-65
Stir in bath at 0.degree. C. for 2.5 hours. Cool the mixed vlJ;
Add 7.0 ml of 1N hydrochloric acid.

The crystals that precipitate slowly are collected by filtration, washed with water, and heated at 100°C.
Dry at /4 torr.

Yield: 1.65g (88.2% of theory) Melting point: 185
~187°C Elemental analysis: Calculated value: C73.07 N7.66 N7.10 Actual value: 72.90 7.80 7.17 [α]20=
+7.9° (c=1, methanol) Analogously to Example 32, the following compound is obtained: (a) (-)-4-((1-(2-
Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoic acid Yield: 80% of theoretical value Melting point: 187-190°C Elemental analysis: Calculated value: C73.07 N7.66 N7.10 Actual value: 72 .98 7.44 7.22 [α) D=-
7.9° (c=1, methanol) Example 33 Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-1-butylamine and 4-cyano-phenylacetic acid.

Yield: 57.3% of theoretical value Melting point: 147-148°C Elemental analysis: Calculated value: C76.76 N7.78 N11.19 Actual value: 76.46 7.81 11.10 Follow the same procedure as in Example 33. (a) 4-((1-(2
-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-toluene Produced using 4-tolyl-acetic acid.

Yield: 60.4% of theoretical value Melting point: 150-153°C Elemental analysis: Calculated value: C79.08 H8.85 N7.68 Actual value: 78.97 8.58 7.77 Example 34 Same as Example 14 , 4-((1-(2-piperidino-
Prepared from phenyl)-1-butyl)-aminocarbonylmethylcubenzonitrile and ethanolic hydrochloric acid.

Yield: 58% of theory Melting point: 127-128°C Elemental analysis: Calculated values: C71.90 H8.11 N6.63 Actual values: 74.07 8.23 6.87 Example 35 - Benzoate Same as Example 10 and 1-(2-piperidino-phenyl)-1-butanol and ethyl 4-cyanomethyl-
Prepared from benzoate using concentrated sulfuric acid in 0-dichlorobenzene at room temperature.

Yield: 21% of theory Melting point: 126-128°C Elemental analysis: Calculated value: C73.90 H8.11 N6.63 Actual value: 74.12 8.20 6.45 In the same manner as Example 35, the following Obtain the compound: (a) 4-((1-(2-
Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid prepared from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanomethyl-benzoic acid. pH5
．． Extract with 5.

Yield: 29% of theory Melting point: 215-217°C Elemental analysis: Calculated: C73.07 H7.66 H7.10 Found: 72.82 7.69 6.95 Example 36 4- in 10 ml of dimethylformamide ((1-(4-
Nitro-2-piperidino-phenyl)-1-butyl)-
(aminocarbonylmethyl)-benzoic acid 0.60 g (1.
365 mmol) are hydrogenated over 0.1 g of 10% palladium/charcoal at 25° C. under 1 bar of hydrogen pressure for 3 hours.

The catalyst is filtered off through a kieselger filter and the filtrate is evaporated under reduced pressure. The evaporation residue is crystallized from ether.

Yield: 0.41 g (73.2% of theory) Melting point: 118
~120℃ Elemental analysis: Calculated value (×0.5H2O): C68.87 H7.71
N10.04 actual value: 68.6
2 7.64 10.08 Analogously to Example 36, the following compound is obtained: (a) Ethyl 4-((1-(4-amino-2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl) -Henzoate yield: 81.7% of theory Melting point: 145-146°C (Nietel/Petroleum ether) Elemental analysis: Calculated: C71.57 H8.06 N9.60 Actual value: 71.50 8.08 9. 68(b)4-(
(1-(5-amino-2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 64% of theory Melting point: 227-230°C Elemental analysis: Calculated value: C70.39 H7.66 N10.26 Actual value: 70.54 7.54 10 .36(c) Ethyl 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate Yield: 84.3% of theory Melting point: 162-165 °C Elemental analysis: Calculated value: C71.37 H8.06 N9.60 Actual value: 71.58 7.85 9.65 Example 37 Cold diazonium salt solution (0°C) was added to 4.8 ml of semi-concentrated hydrochloric acid.
2.0 g (4.57 mmol) of ethyl 4-((1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate and nitrous acid in 1.66 ml of water. Sodium 0.315g (4
．． 57 mmol). Copper chloride (1
) 0.59 g (5.94 mmol) and 2.4 ml of concentrated hydrochloric acid
dropwise at 0-5°C and the resulting mixture is then heated in a bath at 50°C. After the evolution of gas has stopped (approximately 15 minutes), the mixture is cooled, added to ice/concentrated ammonia and extracted four times with 100 ml of ethyl acetate each time. The resulting organic extract is mixed with water, dried, filtered and evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate=10/1).

Yield: 0.80 g (40% of theory) Melting point = 137-140°C (ether) Elemental analysis: Calculated values: C68.32 H7.27 Cl7.75 N
6.13 Actual measurement value: 68.42 7.09 8.
06 6.05 Analogously to column 37 the following compounds are obtained; (a) Ethyl 4-((1-(4-chloro-2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl)-benzoate yield Rate: 21.9% of theory Melting point: 123-125°C Elemental analysis: Calculated values: C68.32 H7.27 Cl7.75 N
6.13 Actual value: 68.70 7.18 7.
77 6.08(b) Ethyl 4-((1-(5-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 53.8% of theory Melting point: 140 ~142℃ Elemental analysis: ' Calculated value: C62.27 H6.63 Br15.95
N5.58 actual value: 62.39 6.78 1
5.85 5.59(c) Ethyl 4-((1-(4-
Fluoro-2-piperidino-phenyl)-1-butyl)
-Aminocarbonylmethyl]-benzoate yield: 21.6% of theory Melting point: 110-112°C Elemental analysis: ' Calculated value: C70.88 H7.55 N6.36 Actual value: 71.01 7.53 6. 21 Furthermore, ethyl 4-((1-(4-hydroxy-2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl)-
40% of benzoate is isolated (solid foam).

(d) Ethyl 4-[(1-(5-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate Yield: 2% of theory Melting point: 127-129°C Calculated value: m/e=440 Actual value: m/e=440 (e) 4-((1-(4-fluoro-2-piperidino-
Phenyl)-ethyl)-aminocarbonylmethyl)-benzoic acid Yield: 16.9% of theory Melting point: 172-175°C Elemental analysis: Calculated: C68.73 H6.55 N7.29 Actual value: 68.78 6.62 7.31 Example 38 1.0 g (2.33 mmol) is hydrogenated over 0.5 g of palladium/charcoal at 50° C. and under 5 bar of hydrogen.

After 2 hours, the catalyst is filtered off on a kieselger and the filtrate is concentrated under reduced pressure. The evaporation residue is partitioned between water and ethyl acetate at pH 6. The organic extract is washed with water, dried, filtered and evaporated under reduced pressure.

Yield: 0.61 g (66% of theory) Melting point: 213-215°C Elemental analysis: Calculated: C73.07 H7.66 H7.10 Observed value: 73.18 7.42 7.27 Same compound corresponds It can also be obtained from 4-chlorine, 6-chlorine- or 6-chlorine-substituted feedstock products.

Example 39 Ethyl 4-((
1-(4-hydroxy-2-piperidino-phenyl)-
A solution of 5.0 g (11.4 mmol) of 1-butyl)-aminocarbonylmethyl)-benzoate was added with stirring at room temperature to 548 mg (11.4 mmol) of sodium hydride (50% in oil) in 10 ml of anhydrous dimethylformamide. ) and add it dropwise. The mixture is stirred for a further 15 minutes and then a solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of anhydrous dimethylformamide is slowly added dropwise thereto. The mixture was further heated at room temperature for 2.
Stir for 5 hours, evaporate under reduced pressure and partition between water and ether. The ether phase is dried, filtered and evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 20/
1).

Yield: 1.8g (34.9% of theory) Melting point: 115~
117°C Elemental analysis: Calculated value: C71.65 H8.02 N6.19 Observed value: 71.47 7.86 6.19 The following compound is obtained in the same manner as in Example 39: (a) Ethyl 4-((1 −(
5-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 68.4% of theory Melting point: 142-145°C Elemental analysis: Calculated value: C71.65 H8.02 N6.19 Actual value: 71.87 8.06 6.38 Example 40 (2,3-dihydroxy-propyl)4-((1-(2
-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate 4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoic acid in 20 ml of anhydrous tetrahydrofuran 2. Og (5.07 mmol) and N,N'-carbonyldiimidazole 0.85 g (5.27 mmol)
The solution was refluxed for 1 hour, then 3.7 ml of glycerol (
50.7 mmol) and the resulting mixture was further diluted with 1
Reflux for 5 minutes. It is then evaporated under reduced pressure, partitioned between water and ethyl acetate, the organic solution is dried, filtered and evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=1:1).

Yield: 1.1g (46.2% of theory) Melting point: 120~
122°C Elemental analysis: Calculated: C69.21 H7.74 N5.98 Self-sufficiency: 69.21 7.78 5.95 Analogously to Example 40, the following compound is obtained: (a) (2-Hydroxy-ethyl )4-((1-(2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl]-benzoate Yield: 80% of theory Melting point: 125-127°C Elemental analysis: Calculated values: C71.21 H7.81 N6.39 Observed values: 71.35 7.54 6. 33(b)(2-
methoxy-ethyl)4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-
Benzoate yield: 55.9% of theory Melting point: 120-126°C Elemental analysis: Calculated: C71.65 H8.02 N6.19 Observed: 72.03 8.03 6.24 Example 41 In 20 ml of methylene chloride of nicotinic acid chloride 0.7g
(4.68 mmol) in methylene chloride 40 ml and triethylamine 0.7 ml (4.81 mmol)
2.0 g (4.56 mmol) of (2-hydroxyethyl) 4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate
Add rapidly dropwise to the stirred solution. The resulting mixture is stirred for 2.5 hours at 20° C. and extracted with water, then the organic phase is dried, filtered and evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=5/1).

Yield: 1.1 g (44% of theory) Melting point: 132-135°C Elemental analysis: Calculated values: C70.70 H6.86 N7.76 Actual values: 70.82 6.82 7.91 Example 42 Anhydrous tetrahydrofuran 75 ml Ethyl 4-[(1
-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoate 5.0 g (11.
83 mmol) in 25 m of anhydrous tetrahydrofuran.
0.68 g of lithium aluminum hydride (17
．． 95 mmol) dropwise at an internal temperature of 0°C. The mixture is stirred at room temperature for 20 hours, then cooled to 0° C. and 4N sodium hydroxide is slowly added dropwise thereto until a precipitate forms which can be filtered off. The mixture is filtered, the precipitate is shaken out several times with ether and the dyed organic solution is evaporated under reduced pressure. The evaporation residue is partitioned between water and ether. The ether phase is dried, filtered and evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=5/1).

Yield: 1.0 g (22% of theory) Melting point: 152-154°C Elemental analysis: Calculated values: C75.75 H8.48 N7.56 Actual values: 75.90 8.45 7.28 Example 46 Sodium carbonate 6.6 g (62 mmol) was heated with 62 ml of ethylene glycol in a bath at 170°C, and 1
Within minutes, N1-(4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-
benzoyl)-N2-tosyl-hydrazine [melting point 195
°C (decomposed)] is added thereto with rapid stirring. Vigorous evolution of gas occurs. The mixture was heated at 170°C for an additional 2.5
Heat for a minute, then immediately pour onto ice. Extract with ether, dry the ether solution, filter and evaporate under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone = 20/1).

Yield: 2.2g (52.9% of theory) Melting point: 142~
145°C Elemental analysis: Calculated: C76.16 H7.99 N7.40 Observed: 76.26 7.96 7.37 Example 44 2.80 mg of ethyl diethyl-phosphonoacetate (12,5 A solution of 0.60 g (12.5 mmol) of sodium hydride (50% in oil) in 15 ml of anhydrous dimethylformamide is added dropwise at room temperature.

The mixture was stirred for 15 minutes (until gas evolution ceased) and then 4-((1-
(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde 2.4 g (6,
A solution of 34 mmol) is added dropwise thereto. The mixture is stirred at room temperature for 2 hours, evaporated under reduced pressure and partitioned between water and ether.

The ether phase is dried, filtered and then evaporated under reduced pressure. Purify the evaporation residue by column chromatography on silica sol (toluene/acetone = 10/1)
.

Yield: 0.85g (29.9% of theory) Melting point: 165
~167°C (ether/petroleum ether) Elemental analysis: Calculated: C74.97 H8.09 N6.24 Observed: 74.91 7.89 6.29 Example 45 Ethyl 4-[( It is produced by alkaline saponification of 1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate.

Yield: 64% of theory Melting point: 180-183°C Elemental analysis: Calculated value: C74.26 H7.67 N6.66 Actual value: 74.03 7.47 6.80 Example 46 Ethyl 4-((1- (2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl]-cinnamate 0.60 g (1.64 mmol) in 10 ml of ethanol
Hydrogenate over 0.20 g of 10% palladium/charcoal in a room temperature to 5 bar F of hydrogen. Filter the mixture;
Evaporate under reduced pressure.

Yield: 0.53 g (88% of theory) Melting point: 98-99°C (petroleum ether) Elemental molecule: Calculated value: C74.63 H8.50 N6.22 Actual value: 74.64 8.58 6.25 Examples 46 to obtain the following compound: (a) 3-(4-((1-(
2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionic acid Yield: 63% of theory Melting point: 131-133°C Elemental analysis: Calculated: C73.90 H8.11 N6. 63 actual value: 73.96 8.30 6.56 Example 47 3-(4-((1-(2-piperidino-phenyl)-1
-butyl)-aminocarbonylmethyl)-phenyl)-
Ethyl 3-(4-((1-(2-
It is prepared by alkaline saponification of piperidinophenyl)-1-butyl)-minocarbonylmethyl]-phenyl)-propionate.

Yield: 50% of theory Melting point: 131-133°C Elemental analysis: Calculated value: C73.90 H8.11 N6.63 Actual value: 76.82 8,07 6.41 Example 48 Ethyl 4-[(α- Aminocarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoate N,N'-carbonyldiimidazole 0.90 g (5.
5 mmol) of ethyl 4-((α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate x 0.5 mmol) in 20 ml of anhydrous tetrahydrofuran.
167H2O (melting point 156-159 °C) at 20 °C and the mixture was then heated for 0.5 h at 80 °C in a bath.
Heat at ℃. The mixture is then cooled to 60° C. and flushed with dry ammonia vigorously at this temperature for half an hour. The resulting mixture is evaporated under reduced pressure, partitioned between chloroform and water, and the collected chloroform extracts are then squeezed with a small amount of water, dried, filtered, and then evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=
5/1).

Yield: 1.0g (50.2% of theory) Melting point: 160~
162°C (acetone) Elemental analysis: Calculated value: C68.07 H6.90 N9.92 Actual value: 68.40 6.92 9.84 Example 49 234 mg (1.22 mmol) of 4-toluenesulfochloride was added in two doses. In portions, ethyl 4-((α-aminocarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoate 5 in 0.22 ml pyridine
20 mg (1.22 mmol) and the mixture was heated at 50°C.
Heat to. After 2 hours, then after 1 hour, equal amounts of pyridine and 4-toluenesulfochloride were added again;
The resulting mixture is heated at 50° C. for an additional hour. 20
After standing for 2 days at °C, 2N ammonia is added and the mixture is extracted with chloroform. Extract the chloroform solution twice with water. After drying and filtration, it is evaporated under reduced pressure. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=
10/1) Yield: 325 mg (65.7% of theory) Melting point: 114
~117°C (ether/petroleum ether) Elemental analysis: Calculated: C71.09 H6.71 N10.36 Found: 70.79 6.56 10.10 Example 50 Ethyl 4-((α-cyano) in 15 ml dioxane -2
-piperidino-benzyl)-aminocarbonylmethyl]
- 1.5 g (3.7 mmol) of benzoate with 3.7 ml of 1N sodium hydroxide solution for 45 minutes in a bath for 6 hours.
Stir at 0°C and then for a further 45 minutes at 80°C in a bath.

After cooling with ice, the mixture is combined with 3.7 ml of 1N hydrochloric acid, the dioxane is evaporated off under reduced pressure and the residue is partitioned between water and chloroform. The organic solution is extracted with a little water, then dried, filtered and evaporated under reduced pressure.

The evaporation residue is purified by column chromatography on silica gel (chloroform/ethanol=5/1).

Yield: 0.50g (35.7% of theory) Melting point: 176
~180°C (decomposition) Elemental analysis: Calculated value: C70.01 H6.14 N11.13 Actual value: 70.02 6.19 11.05 Example 51 5 ml (2.50 mmol) of 1N sulfuric acid was dissolved in ethanol 50
4-((1-(2-piperidino-phenyl)-
1-Butyl)-aminocarbonylmethyl]-benzoic acid 1
．． 0 g (2.56 mmol) of solution and the mixture is concentrated to dryness under reduced pressure and triturated with acetone.

Yield: 0.80g (65% of theory) Melting point: 192-197°C (decomposition) Elemental analysis: Calculated values: C58.53 H6.55 N5.69 S6
．． 49 actual measurement position: 58.05 6.54 5.49
6.65 Analogously to example 51 the following addition salts are obtained: (
a) 4-[(1-(2-piperidino-1-butyl, -aminocarbonylmethyl)-benzoic acid x 0.5H2SO4
x1.5H2O Prepared similarly to Example 51 using half the amount of sulfuric acid.

Yield: 59.3% of theory Melting point: 180-185°C, decomposition at 207-210°C Elemental analysis: Calculated value: C61.26 H7.28 N5.95 S3
．． 40 Actual value: 61.28 6.99 6.10
3.23 Example A Composition: One tablet contains the following ingredients; oily component
(1) 5.0mg corn starch (2) 62.0mg lactose
(3) 48.0mg polyvinylpyrrolidone
(4) 4.0mg magnesium stearate (5
) 1.0mg 1
20.0mg Manufacturing method: Mix 1, 2, 3 and 4 together and moisten with water. Pass the wet mixture through a sieve with a 1.5 mm mesh width, approx.
Dry at °C. Pass the dried granules through a 1.0 mm mesh width sieve and mix with 5. The finished mixture is compressed in a tablet press using a 7 mm diameter punch with dividing grooves to form tablets.

Tablet weight: 120 mg Example B One ash core contains the following ingredients: Active ingredients (1) 2.5 mg potato starch (2) 44.0 mg lactose
(3) 30.0mg polyvinylpyrrolidone (4) 3.0mg magnesium stearate (5) 0.5mg
80.0 mg Preparation Methods 1, 2, 3 and 4 are thoroughly mixed and moistened with water. The wet mass is passed through a 1 mm mesh width sieve, dried at 45°C and the granules are passed through the same sieve again. After adding 5, diameter 6
mm curved tablet cores are formed by compression on a tablet making machine.

The tablet cores thus produced are coated by known methods with a coating consisting essentially of sugar and talc. Polish the finished coated tablet with wax. Weight of coated tablet: 120mg
Example C Composition: One tablet contains the following ingredients; active ingredient
10.0mg powdered lactose
70.0mg corn starch 31.0mg
Polyvinylpyrrolidone 8.0mg Magnesium stearate 1.0mg
120.0 mg Manufacturing method: A mixture of active substance, lactose and corn starch is moistened with a 20% aqueous solution of polyvinylpyrrolidone. The wet mass is passed through a 1.5 mm mesh width sieve to produce granules and dried at 45°C. The dried granules are rubbed through a 1 mm mesh size sieve and then mixed homogeneously with the magnesium stearate.

Tablet weight: 120 mg Punch: 7 mm diameter with dividing groove Example D One tablet core contains the following ingredients: Active ingredient 5.0 mg dibasic calcium phosphate 70. omg corn starch
50.0mg polyvinylpyrrolidone 4.0m
g Magnesium stearate 1.0mg
130.0 mg Manufacturing method: Wet the mixture of viscous ingredients, calcium phosphate and corn starch with a 15% aqueous solution of polyvinylpyrrolidone. Pass the wet mass through a sieve with a mesh size of 1 mm.
Dry at 5°C and then pass again through the same sieve. After adding a predetermined amount of magnesium stearate, tablet cores are compressed from the mixture.

Tablet weight: 130 mg Punch: diameter 7 mm A disrupting agent of sugar and talc is applied to the tablet core thus produced. Polish the finished coated tablet with wax.

Weight of coated tablet: 180mg Agent: Akira Asamura Continuation of page 1 @Int, C1,3 identification code Internal reference number C0
7C121/78 7731-
4H1471002104-4H 149/42 2104-4
HC07D 211/14 7
138-4C213, /40
7138-4 C295/12
6917-4 C priority claim @July 1982 6 ■ West Germany (DE) ■ P 3225188.2 ■ Inventor Rudolf Furnaus Biberach 1 Silkelstrasse 19 0 Federal Republic of Germany Inventor Gerhard Gris Germany Federal Republic of Biberach 1 Shobelbeg 1 0 Inventor Robert Saracil Federal Republic of Germany Laupheim Albertoschvaitzerbeg 9 0 Inventor Nickhard Rupprecht Federal Republic of Germany Aulendorzutanhausen Rietbarakstrasse 15 (Sha Inventor: Joachim Carling, Federal Republic of Germany, Biberach 1°, Heytonbeg 8, L?Multiple Intermediate, Bernhard Eiseled, Federal Republic of ISO, Biberach 1, Beitbenstrasse 12

Claims (40)

[Claims] (1) General formula % Formula % Here, R4 is an alkyl group having 1 to 6 carbon atoms and optionally substituted by an alkoxy group having 1 to 3 carbon atoms or by a phenyl group: 4 Alkyl group with ~7 carbon atoms, alkenyl group with 3 to 5 carbon atoms, cy, ano group, 4 to 6 in the alkylene moiety
an alkyleneiminocarbonyl group having 4 carbon atoms;
or an aminocarbonyl group optionally mono- or di-substituted by an alkyl or phenylalkyl group each having 1 to 6 carbon atoms in the alkyl moiety, having 6 or 10 carbon atoms and optionally a halogen by an atom or by an alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl group (these substituents may be the same or different, the alkyl moiety is 1 to 3 in the case represents an aryl group which may be mono- or di-substituted (which may contain 4,5, 8 or 6 carbon atoms and 1 or 2 nitrogen atoms); R5 and R6 may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R5 and R6 together with the carbon atoms between them contain 1 in the alkylidene moiety. represents a phenylalkylidene group having ~4 carbon atoms; unbranched alkyleneimino groups having, or 1 to 5 on each alkyl moiety
represents a dialkylamino group having 4 carbon atoms: hydrogen, fluorine, chlorine, bromine or iodine atom, or hydroxy, trifluoromethyl, nitro, amine, biverizono, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl , alkylsulfonyl,
a phenylalkoxyalkanoyloxy, alkanoylamino, alkylamino or sialkylamino group (in each case the alkyl moiety can contain 1 to 6 carbon atoms); the representation: l (3 has 1 to 6 carbon atoms); represents an alkyl group, a hydrogen atom or a halogen atom: and W is a carboxy group or an alkoxycarboxylic group having a total of 2 to 6 carbon atoms (!: the alkyl part of cotezo is substituted by a phenyl group); C may also be substituted by a β-carbon atom, one or two hydroxy groups, or alkoxy, alkanoyloxy, sialkylamino,
optionally substituted by alkyleneimino or pyridinecarbonyloxy groups, the alkyl part of these groups can contain 1 to 3 carbon atoms, and the alkyleneimino group can contain 4 to 6 carbon atoms), or an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms,
Hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethynyl, 2.2-bis-C carboxy)-ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2- alkoxycarbonyl-ethynyl or 2,2-bis-(7l:Jxycarbonyl)-ethyl group, where the alkyl group can contain in each case from 1 to 6 carbon atoms] Derivatives and their optically active enantiomers and their conversion with inorganic or organic acids or groups. (2) has the general formula ■, in which A represents the formula Atomic alkyl groups: n-propyl groups, alkyl groups with 4 to 6 carbon atoms, alkenyl groups with 3 to 5 carbon atoms, cyano or aminocarbonyl groups, halogen atoms, or alkyl groups , mono- or di-substituted by human roxy, alkoxy, phenylalkoxy and/or alkylsulfinyl group e, 6-1. or an aryl group having 10 carbon atoms, in which these substituents may be the same or different and the alkyl part can contain from 1 to 6 carbon atoms, or naphthyl, pyridyl, quinolyl Or isoquinolyl group. l (5 and R6 together with the carbon atoms between them, 6
represents an alkylidene group having ~9 carbon atoms, or a phenylalgylidene group having 1 to 3 carbon atoms in the alkylidene portion; - represents an unbranched alkyleneimino group, or a piperidino group substituted with a mono- or sheep by an alkyl group each having 1 to 5 carbon atoms (-
1 R2 represents a hydrogen, fluorine, chlorine or bromine atom, or a nitro group, an alkyl or alkoxy group each having 1 to 3 carbon atoms, or R5 and R6 are as defined above, and R6 is an alkyl group having 1 to 6 carbon atoms substituted by an alkogia group having 1 to 6 carbon atoms or by a phenyl group,
When R represents an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 6 to 5 carbon atoms, or a nitrile or aminocarbonyl group,
2 can also represent an iodine atom or a hydroxy or amino group, I (3 represents a hydrogen or chlorine atom and W represents methyl, hydroxymethyl, formyl, cyano, carboxy, carboxymethyl, 2-carbogyethyl or 2
-carboxy-ethynyl (, whose alkyl moiety is β-
from carbon atoms, by 1 or 2 droxy groups, or by alkoxy groups having 1 to 3 carbon atoms,
or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, optionally substituted by a bilysine carbonyloxy group, in each case in which the alkoxy group is
alkoxycarbonyl- containing ~6 carbon atoms
Methyl, 2-alkoxycarbonyl-ethyl or 2-
A phenylacetic acid derivative representing an alkoxycarbonyl-ethynyl group, 4-[N-((5-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoyl relative and its 1 to 3 carbon atoms) alkyl esters containing atoms, 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid and its 1
Alkyl esters having ~3 carbon atoms, 6-C4-CN-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid and its having from 1 to 6 carbon atoms Alkyl ester. 4-[Seal-(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 6 carbon atoms, 4-(N-i-chloro- 4-[N-(<S-methyl-α-phenyl-2- piperidino-benzyl)-aminocarbonylmethyl-benzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-(N-(4-methyl-α-phenyl-2-biperidino-benzyl)-aminocarbonylmethyl-benzoic acid) Benzoic acid and its alkyl esters having 1 to 6 carbon atoms, 4-CN-(2-(2-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonylmethyltobenzoic acid and 1 to 5 thereof an alkyl ester having carbon atoms of 4-(N-(2-(,3-methyl-piperidino)-α-
Phenyl-benzyl)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 3 carbon atoms V. 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde. 41(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-[(1-(3- Chlor-2-piperidino-phenyl)-ethy,l)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-((1-(3-methyl-2-piperidino-phenyl) )-ethyl)-aminocarbonylmethyl]-benzoic acid-
and its alkyl esters having 1 to 3 carbon atoms and 4-[(1-(3-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyltobenzoic acid and its 1 to 3 carbon atoms and optically active enantiomers thereof and salts thereof with inorganic or organic acids or bases. (3) has the general formula (■), in which A represents a group of the formula -, where R4 is 1 to 1 substituted by a methoxy or phenyl group;
an alkyl group containing 3 carbon atoms, n-probyl,
cyan or triaminocarbonyl group, alkyl group having 4 to 6 carbon atoms, alkenyl group having 6 to 5 carbon atoms; fluorine, salt, a-bromine atom, or methyl, hydroxy, methyl) = A-, represents a phenyl group substituted with benzyloxy or methylsulfenyl group, or a pyridyl group, 1 (5 o, J: h) (6 together with the carbon atoms between them is 6 to 9 alkylizo/groups having 1 to 6 carbon atoms, and also ('1zoσ) having 1 to 6 carbon atoms in the alkyl moiety.
44) Represents a phenylalgylidene group, +(1 is 4-
represents an unbranched alkyl having 8 carbon atoms, a piperidino group mono- or cy-substituted by an imino group or a methyl group, R3 represents a water atom, a fluorine, chlorine or bromine atom, a methyl or methoxy group; or R5 and )(6 is as defined above, and R
1-6 in which 4 is substituted with methoxy or phenyl group
Alkyl group having 4 to 6 carbon atoms: n-propyl, nitrile or aminocarbonyl group: Alkyl group having 4 to 6 carbon atoms or 6 to ! When representing an alkenyl group having 5 carbon atoms, R2 represents an atom, a hydroxyl or an amino group, 2, (, represents a hydrogen or chlorine atom, and , formyl, cyanide, carboxy, carboxy-methyl, 2-carpoxy-ethyl or 2-carboxy-ethynyl group, the alkyl part of which is β
- from a carbon atom, by one or two hydroxy groups,
or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, alkoxycarbonyl-methyl, which may be substituted by an alcogine group having 1 to 6 carbon atoms or by a pyridinecarboxyoxy group;
phenylacetic acid derivatives, representing a 12-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethynyl group (these alkoxy groups can contain 1 to 6 carbon atoms), and 4-[N-(6-chloro-α) -phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic: R6 and its 1 to 3 alkyl esters containing 1ω carbon atoms, 4-CN -(α-phenyl-2-piperidino-benzyl) -minocarbonylmethyl]-cinnamic acid and its alkyl esters having 1 to 6 carbon atoms, ro-[4-CN-(α-phenyl-2-piperisino-
benzyl)-aminocarbonylmethyl]-phenyl]-
Noropionic acid and its 1 to 6 carbon atoms -4-
alkyl esters of Esters: 4-CN-(3-chloro-α-phenyl-2-bi′-rizono-benzyl)-aminocarbonylmethyl]-benzenyl and its 7:1 alkyl esters having 1 to 6 carbon atoms, 4-CkJ-(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-[N-(4-methyl -α-phenyl-2-piperidino-benzol)-aminocarbonylmethyl]-benzoic acid and its alkylnisder having 1 to 3 carbon atoms, 4-[N-(2-(2-methyl-piperidino)- α-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters having 1 to 6 carbon atoms, 4-[1(-(2-(3-methyl-piperidino)-α)
-phenyl-benzyl)-aminocar4cnylmethyl]
-benzoic acid and its alkyl esters with 1 to 6 carbon atoms, 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde, 4-[(1-(4- Fluoro-2-biperidino-phenyl)-ethyl)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 6 carbon atoms. 4-[(1-(3-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyltobenzoic acid and alkyl esters having 1 to 6 carbon atoms, and 4-[(1-(3- selected from methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 6 carbon atoms, as well as its optically active enantiomers and its salts with inorganic or organic acids or bases. A compound according to claim 1. (4) It has the general formula I, and its A, R~R3 and W
A compound according to claim 1 selected from phenylacetic acid derivatives, optically active enantiomers thereof and salts thereof with inorganic or organic acids or bases as defined in claim 6. (5) alkoxycarbonyl having the general formula I, in which A and R1-R3 are as defined in claim 3, and W is a carboxy group or alkoxycarbonyl having 2 to 5 carbon atoms in total; group (where this alkyl part is
(optionally substituted by one or two hydroxy groups from the β-carbon atom), as well as its optically active enantiomers and salts thereof with inorganic or organic acids or bases. Compound of item 1. (6) having the general formula (■), in which A and R1-R3 are as defined in claim 6, and W is a carboxy group or alkoxycarbonyl having 2 to 5 carbon atoms in total; A compound according to claim 1 selected from phenylacetic acid derivatives, their optically active enantiomers and their salts with inorganic or organic acids or bases. (7) having the general formula I, in which A represents a group of the formula or , and R4 is substituted by an n-propyl group, an alkyl group having 4 or 5 carbon atoms, a methyl group or by a fluorine or chlorine atom; R5 and R6 together with the carbon atoms between them represent an alkylidene group having 6 to 5 carbon atoms, or having 1 to 6 carbon atoms in the alkylidene part thereof R1 represents a phenylalkylidene group, R1 represents a piperidino group optionally substituted with one or two methyl groups, R2 represents hydrogen, a fluorine or chlorine atom, or a methyl or methoxy group, and R3 represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, selected from phenylacetic acid derivatives, their optically active enantiomers and their salts with inorganic or organic acids or bases. A compound with a range of 1. (8) It has the general formula (■), in which A represents a group of the formula or , and R4 is an n-propyl group or 4 or 5
represents an alkyl group having R5 carbon atoms;
and phenylacetic acid derivatives in which R6 together with the carbon atoms between these represents an alkylidene group having 3 to 5 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety, optically active enantiomers thereof and its salts with inorganic or organic acids or bases. (9) 4-(N-(6-chloro-α-phenyl-2-piperidino-benzol)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-[N -(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-, inamic acid and 1-
its alkyl esters with 6 carbon atoms, 3-[4-[N-(α-phenyl-2-bi-capped dino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid and 1 to 3 thereof; Alkyl esters having carbon atoms of alkyl esters in which an atom is i, 4-1': N-(3-chloro-α-phenyl-2-piperisono-benzyl)-aminocarbonylmethyltobenzoic acid and its 1 to 3 carbon atoms are i -4-roalkyl ester, 4-CN-(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl']-F, Q
Konic acid and its alkyl esters having 1 to 3 carbon atoms, 4-[1: N-(4-methyl-α-phenyl-2
-gyl ester, 4-CN-(2-(2-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonylmethyl]-an,
is acid and its alkyl ester having 1 to 3 carbon atoms, 4-[N-(2-(3-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonylmethyl]-bensikoic acid and Alkyl esters having 1 to 3 carbon atoms thereof, 4-4 N-(α-phenyl-2-piperidino-benzyl)-buminolponylmethyl-henozaldehyde, 4-[(1-(4-fluoro-2 -piperidinophenyl)-ethyl)-aminocarbonylmethyltobenzoic acid and its alkyl esters having 1 to 6 carbon atoms, 4-[(1-(3-chloro-2-piperidinophenyl)- 4-[(1-(3-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and its alkyl esters having 1 to 6 carbon atoms; 2. A compound according to claim 1 selected from benzoic acid and its alkyl esters having 1 to 3 carbon atoms, as well as its optically active isomers and salts thereof with inorganic or organic acids or bases. (10) 4-[N-(6-chloro-α-phenyl-2-
piperidino-benzol)-aminocarbonylmethyl]-
Benzoic acid and its alkyl esters having 1 to 3 carbon atoms, 4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-cinnamic acid and its 1
alkylnisters having ~3 carbon atoms, and 3-(4((N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-phenyl)-propionic acid and its 1 to 3 J) carbons; A compound according to claim 1 selected from alkyl esters having an atom. (11) 4-[N-(6-chloro-α-phenyl-2-
piperidino-benzyl)-aminocarbonylmethyl]-
The compound according to claim 1, which is benzoic acid, an alkyl ester thereof having 1 to 3 carbon atoms, an optically active enantiomer thereof, or a salt thereof. (12) 4-(N-(α-(4-fluoro-phenyl)
-2-Piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid, an alkyl ester thereof having 1 to 6 carbon atoms, an optically active enantiomer thereof, or a salt thereof; . (13) 4-[N-(4-methyl-α-phenyl-2-
piperidino-benzyl)-aminocarbonylmethyl)-
The compound according to claim 1, which is benzoic acid, an alkyl ester thereof having 1 to 3 carbon atoms, an optically active enantiomer thereof, or a salt thereof. (14) 4-((1-(2-piperidino-phenyl)-
1-butyl)-aminocarbonylmethyl)-benzoic acid,
The compound according to claim 1, which is an alkyl ester thereof having 1 to 3 carbon atoms, an optically active enantiomer thereof, or a salt thereof. (15) 4-((1-(2-piperidino-phenyl)-
1-buten-1-yl)-aminocarbonyl, methyl]
- The compound according to claim 1, which is benzoic acid, an alkyl ester thereof having 1 to 3 carbon atoms, an optically active enantiomer thereof, or a salt thereof. (16) 4-((1-(2-piperidino-phenyl)-
1-Pentyl)-aminocarbonylmethyl]-an, monozoic acid, an alkyl ester thereof having 1 to 6 carbon atoms, an optically active enantiomer thereof, or a salt thereof. (17) Compounds according to any one of claims 1 to 16, which are physiologically acceptable salts with inorganic or organic acids or with bases when they have a carpoxy group. (18) General formula [wherein A represents a group of the formula or , where R4 represents 1 to 6 carbon atoms, and optionally 1
an alkyl group optionally substituted by an alkoxy group having ~6 carbon atoms or by a phenyl group, 4~
Alkyl group with 7 carbon atoms, alkenyl group with 6 to 5 carbon atoms, cyano group, alkyleneiminocarbonyl group with 4 to 6 carbon atoms in the alkylene portion, or 1 to 3 in the alkyl portion an aminocarbonyl group optionally mono- or cy-substituted by an alkyl or phenylalkyl group, each having 6 or 10 carbon atoms, optionally by a halogen atom, or an alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups (these substituents may be the same or different and the alkyl moiety may contain in each case 1 to 3 carbon atoms) represents an aryl group optionally substituted with 7- or di-substituted by , or a heteroaryl group containing 8 or 6 carbon atoms and 1 or 2 nitrogen atoms; R5 and R6 are the same or represents a hydrogen atom or an argyl group having 1 to 5 carbon atoms, which may be different, or 1 (5 and R6 together with the carbon atoms between them have 1 to 4 carbon atoms in the alkylidene part); R1 represents an unbranched alkyleneimino group having 4 to 9 carbon atoms, optionally mono- or di-substituted by an alkyl group having 1 to 3 carbon atoms; group, or each alkyl moiety has 1 to
represents a dialkylamino group having 5 carbon atoms: R2 is a hydrogen, fluorine, chlorine, bromine or iodine atom, or hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl,
Phenylalkoxy. represents an alkanoyloxy, alkanoylaminoalkylamino or sialkylamino group (in each case the alkyl moiety can contain 1 to 6 carbon atoms); R3 is an alkyl group having 1 to 3 carbon atoms, or hydrogen or a halogen atom; and W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, the alkyl part of which may be substituted by a phenyl group (and from the β-carbon atom); , 1 or 2 hydroxy groups, or by alkoxy, alkanoyloxy, dialkylamino, argyleneimino or pyridinocarbonyloxy groups, the alkyl portion of these groups being 1 to 6
carbon atoms and the alkyleneimino group can contain 4 to 6 carbon atoms), or a total of 4 to 6 carbon atoms)
alkenyloxycarbonyl group containing 6 carbon atoms, alkyl group having 1 to 6 carbon atoms, hydroxymethyl, formyl, cyano, aminocarbonyl group rpoxymethyl, 2-carboxyethyl, 2-carboxyethyl, 2.2 -bis-(carboxy)-ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonyl-ethenyl or 2.2-bis-(alkoxycarbonyl)-ethyl group (
from phenylacetic acid derivatives and their optically active enantiomers and their physiologically acceptable salts with inorganic or organic acids or bases. The selected compound is 1
Pharmaceutical compositions containing together with one or more inert carriers and/or diluents. (19) The pharmaceutical composition according to claim 18, which has hypoglycemic activity. (20) General formula [wherein A represents a group of the formula or ], where R4 has 1 to 6 carbon atoms, optionally by an alkoxy group having 1 to 3 carbon atoms as a substituent, or Alkyl group optionally substituted by phenyl group, alkyl group having 4 to 7 carbon atoms, 3 to 7 carbon atoms
by an alkenyl group having 5 carbon atoms, a cyano group, an alkyleneiminocarbonyl group having 4 to 6 carbon atoms in the alkylene part, or an alkyl or phenylalkyl group each having 1 to 3 carbon atoms in the alkyl part; Aminocarbonyl groups optionally mono- or di-substituted, having 6 or 10 carbon atoms, optionally with halogen atoms, or alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfinyl, alkylsulfinyl and (or) an alkylsulfonyl group (these substituents may be the same or different, the alkyl moiety being in each case from 1 to
mono- or di-
represents an optionally substituted aryl group or a heteroaryl group containing 4, 5, 8 or 6 carbon atoms and 1 or 2 nitrogen atoms: R5 and R6 may be the same or different represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R5 and R6 together with the carbon atoms between them represent a phenylalkylidene group having 1 to 4 carbon atoms in the alkylidene part; Representation: R1 is an unbranched alkyleneimino group having 4 to 9 carbon atoms optionally mono- or cy-substituted by an alkyl group having 1 to 3 carbon atoms, or ~5
R2 represents a dialkylamino group having 4 carbon atoms: R2 is a hydrogen, fluorine, chlorine, bromine or iodine atom, or hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkyl sulfonyl,
represents a phenylalkoxy, alkanoyloxy, alkanoylaminoalkylamino or dialkylamino group (in each case the alkyl moiety can contain 1 to 6 carbon atoms; R3 has 1 to 3 carbon atoms); represents an alkyl group, or a hydrogen or halogen atom; and W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which the alkyl part may be substituted by a phenyl group, and - may be substituted from the carbon atom by 1 or 2 hydroxy groups or by alkoxy, alkanoyloxy, dialkylamino, alkylenoid or pyridinoyloxy groups, the alkyl part of these groups being 1 to 2;
6 carbon atoms and the alkyleneimino group can contain 4 to 6 carbon atoms), or a total of 4
alkenyloxycarbonyl group containing ~6 carbon atoms, alkyl group having 1 to 6 carbon atoms, hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethynyl, 2 .2-bis-(carboxy)-ethyl,
Alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonyl-ethynyl or 2,2-bis-(alcokynecarbonyl)-ethyl group, in which the alkyl group contains in each case VC 1 to 6 carbon atoms A process for producing phenylacetic acid derivatives and their optically active enantiomers and their salts with inorganic or organic acids or bases, especially physiologically acceptable acid addition salts, represented by the general formula (a) In the formula A, R8 and R2 are as defined above), or when 8 represents one of the above vinylidene groups, its tautomer or its lithium or magnesium oxide complex; a carboxylic acid of the formula (wherein R3 is as defined above and W' has the meaning given above for W or represents a carboxy group as defined above), or optionally its or b) each W carries a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethynyl group by reacting with a reactive derivative thereof generated in situ and, depending on the packaging, then separating the substituent group; To prepare compounds of general formula I represented by two general formulas (wherein 81 and A are as defined above, and B is carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethynyl group VC conversion (representing a group that can be formed) by hydrolysis, thermal decomposition or hydrogenolysis to the corresponding carboxy compound, or C) whose A is of the formula In order to prepare compounds of general formula I representing a group of the general formula (having the meaning given above),
and D represents a group of the formula, where R1' has the meaning given above for R4, excluding the cyano group, and Rb2 and R, /
is an alkylidene group having 1 to 7 carbon atoms together with carbon atoms between them or
phenylalkylidene radicals having 6 carbon atoms, or d) to prepare compounds of the general formula (2) in which R4' has the meanings given above for R4, with the exception of the cyan group: Reacting a compound of general formula (wherein R4'' is as defined above and R1 and R2 are as defined above) with a compound of general formula (wherein R3 and W are as defined above) or e) dehalocenating a compound of the general formula in which R1, R3, A and W are as defined above and Hal represents a fluorine, chlorine, bromine or iodine atom. or f) an aminocarbonyl group in which R4 is optionally mono- or di-substituted by an alkyl or phenylalkyl group each having 1 to 3 carbon atoms in its alkyl moiety or 4 to its purkylene ring; To prepare compounds of the general formula (1) representing an alkyleneiminocarbonyl group having ~6 carbon atoms: (with the meanings given above for W except for or g) to prepare compounds of the general formula I in which W represents a carboxy group. : General formula (in the formula, R1 to R4 are as defined above, and E
represents a group that can be converted into a carboxy group by oxidation), or h) its W is 2 to 6 in total.
It has carbon atoms. Manufacture a compound of general formula (2) whose alkyl moiety represents an alkoxycarbonyl group, which is optionally substituted by one or two hydroxy groups or by an alkoxy group having 1 to 3 carbon atoms, from the β-carbon atom. To: General formula (3 (wherein R1 to R3 and A are as defined above)
of the carboxylic acid or its reactive derivative optionally formed in the reaction mixture with the general formula HO-R9 (■■), where R9 is from a β two carbon atom, with one or two hydroxy groups, or 1) where W is alkoxy or carbonyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-
To prepare compounds of the general formula (1) representing an ethynyl group and in which R4' has the meanings given above for R4 except for the cyano group: in which R1 to R3 are as defined above, and W
'' represents a cyano, cyanomethyl, 2-cyanomethyl or 2-cyanomethyl group) into the corresponding ester; and then optionally obtained according to the invention, in which W is a carboxy or alkoxycarbonyl group. A compound of the general formula (1) is converted by reduction into a corresponding compound of the general formula (2) in which W represents a formyl or hydroxymethyl group, and (or) a compound of the general formula (2) obtained according to the invention in which W represents a carboxy group By converting the compound of I into a sulfonic acid hydrazide and then subjecting it to a disproportionation reaction, it may be converted to a corresponding compound of the general formula (■) in which W represents a formyl group,
and (or) compounds of the general formula I obtained according to the invention, in which W represents a formyl group, by condensation and optionally reaction, W representing a 2-ackoxycarbonyl-ethenyl or 2-calfoxyethynyl group. A general formula in which W represents a 2-carboxy-ethynyl or 2-alkoxycarbonyl-ethynyl group, which may be converted into a corresponding compound or product of the general formula (2), and (or) is dissolved according to the present invention. By catalytic hydrogenation of the compound of 1, a compound corresponding to the general formula 2, in which W represents a 2-carboxy, ethyl or 2-alkoxycarbonyl-ethyl group, is obtained. The compound of the general formula (1) obtained according to the present invention and in which W represents an alkoxy or carbonyl group substituted from the β-carbon atom by a hydroxy group may be converted into a compound of the general formula to acid,
may be converted into the corresponding (bilysine-carbonyloxy:alkoxy)-carbonyl compound of the general formula (2) by acylation with Takae converted the compound of general formula I into the corresponding halomethyl compound, and by reaction with malonic acid diester, converted it into the corresponding compound of general formula I, in which W represents an ethyl group substituted by two alkoxycarbonyl groups. (also 9) is obtained according to the present invention and represents an ethyl group in which W is substituted with two alkoxycarbonyl groups;
may be converted by hydrolysis into the corresponding compounds of the general formula I in which W represents an ethyl group substituted by two carboxy groups, and/or the W obtained according to the invention is an ethyl group substituted with two alkoxycarbonyl groups, by hydrolysis and decarboxylation to obtain its W
may be converted into the corresponding compounds of the general formula (i) in which R2 represents a 2-carboxy-ethyl group, and/or the compounds of the general formula f obtained according to the invention, in which R2 represents a nitro group, may be converted by reduction into , in which 2 represents an amino group, may be converted into the corresponding compound of the general formula (1) and/or obtained according to the present invention. A compound of the general formula (3) in which R2 represents an amino group is added to a compound of the general formula (3) in which R2 represents an amino group through a corresponding diazonium salt,
may be converted into corresponding compounds of the general formula (2) representing an alkoxy or alkylsulfenyl group, and/or by alkylation of compounds of the general formula (2), in which R2 represents a hydroxy group, as contemplated according to the invention. It may be converted into a corresponding compound of the general formula (3) in which R2 represents an alkoxy group and/or obtained according to the invention, in which R2 represents a benzyloxy group and J6 and/or R4 represent a benzyloxy group. By debenzylation of a compound of the general formula l representing an aryl group substituted by a group, the corresponding compound of the general formula It may be converted into compound knowledge. and/or) by dehydration of a compound of the general formula (1), in which R4 represents an aminocarbonyl group, obtained according to the present invention. It may be converted into the corresponding compound of the general formula I in which R4 represents a cyano group and/or the compound of the general formula I obtained according to the invention may be converted into a compound of the general formula I obtained according to the invention, if it has a chiral center, The enantiomeric pressure conversion thereof may be carried out by chromatography and/or the compound of the general formula ■ obtained according to the invention may be converted into its salts, in particular physiologically acceptable salts, with inorganic or organic acids or bases. May be: A method characterized by: (21) The method according to claim 20, wherein the reaction is carried out in a solvent. (22) The method according to claim 20 a) or claim 21, wherein the reaction is carried out in the presence of an acid activator or a dehydrating agent, optionally in the presence of an inorganic or tertiary organic base. (23) The method according to claim 20 a) or claim 21, wherein the reaction is carried out in the presence of an amine activator, optionally in the presence of an inorganic or tertiary organic base. (24) Claim 21a, in which the water produced during the reaction is removed by azeotropic distillation or by adding a drying agent.
) or the method of paragraph 21. (25) The reaction is carried out at a temperature of -25 to 120°C, preferably -
The method according to claim 20 a) or 21, which is carried out at a temperature of 10° C. to the boiling temperature of the solvent used. (26) The method according to claim 20 b) or 21, wherein the hydrolysis or thermal decomposition is carried out in the presence of an acid or a base. (27) the reaction is carried out in the presence of a nitrite, for example sodium nitrite, and, when B represents a nitrile or an aminocarbonyl group, in the presence of an acid such as sulfuric acid; or The method of Section 21. (28) The method according to claim 20 b), 21 or 26, wherein the reaction is carried out at a temperature of -10 to 120°C, preferably at room temperature to the boiling temperature of the reaction mixture. (29) Reduction or dehalogenation is carried out with hydrogen in the presence of a hydrogenation catalyst, Claim 20 c) 2
Section 1 e) or the method of Section 21. (30) The reaction is carried out at a temperature of 0 to 100°C, preferably 20 to 100°C.
20. The process according to claim 20 c), 20 e), 21 or 29, carried out at a temperature of 50 DEG C. and under a hydrogen pressure of 1 to 5 par. (31) The method according to claim 20 d) or claim 21, wherein the reaction is carried out in the presence of a strong enemy, such as sulfuric acid. (32) Reaction at 0 to 150°C, preferably 20 to 100°C
The method according to claims 20 d), 21 and 31, carried out at a temperature of . (33) Claims 20f), 20h) or 21, wherein the reaction is carried out in the presence of an acid activator or dehydrating agent, optionally in the presence of an inorganic or tertiary organic base. Method. (34) The method according to claim 20 f) or claim 21, wherein the reaction is carried out in the presence of an amine activator, optionally in the presence of an inorganic or tertiary organic base. (35) The reaction is carried out at a temperature of -25 to 250°C, preferably -
The method according to claim 20 f), 21, 66 or 34, which is carried out at a temperature of 10° C. to the boiling temperature of the solvent used. (36) Claims in which the oxidation is carried out with silver oxide/sodium hydroxide solution, manganese dioxide, hydrogen peroxide/sodium hydroxide solution, chromium trioxide/pyridine, pyridinium chlorochromate, bromine or chlorine/sodium or potassium hydroxide solution The method of Range 20g) or 21. (37) The reaction is carried out at a temperature of 0 to 100 °C, preferably 20 to
A method according to claim 20g), 21 or 36, carried out at a temperature of 50°C. (38) The reaction is carried out at a temperature of ~20 to 100 °C, preferably -
The method according to claim 20 h), 21 or 33, which is carried out at 10° C. to the boiling temperature of the solvent used. (39) The method according to claim 20 (1) or 21, wherein the reaction is carried out in the presence of an acid such as hydrochloric acid or sulfuric acid. (40) The method according to claim 20 i), 21 or 39, wherein the reaction is carried out at a temperature of 20°C to the boiling temperature of the solvent used, preferably 50 to 100°C.