IE861752L

IE861752L - Phenylacetic acid derivatives

Info

Publication number: IE861752L
Application number: IE861752A
Authority: IE
Original assignee: Thomae Gmbh Dr K
Priority date: 1985-07-01
Filing date: 1986-06-30
Publication date: 1987-01-01
Also published as: DE3670636D1; NO167736C; FI83417B; CA1320723C; DE3523466A1; DK310986A; EP0208200B1; FI83417C; JPH0739406B2; ES2003629A6; NO862631L; JPS625974A; AU587263B2; ZA864833B; IE59269B1; NZ216700A; GR861701B; NO862631D0; DK310986D0; NO167736B

Abstract

1. Phenylacetic acid derivatives of general formula see diagramm : EP0208200,P24,F1 wherein R1 represents a pyrrolidino, piperidino, 4-methylpiperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R4 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an allyl group, R3 represents an alkyl group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl part may contain 3 to 7 carbon atoms, an alkenyl group with 3 to 5 carbon atoms or an alkynyl group with 3 or 4 carbon atoms, and W represents methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group, whilst the alkoxy part may contain from 1 to 4 carbon atoms and may be substituted by a phenyl group, and the enantiomers and salts thereof.

Description

59269 10 15 20 EP-A-0.058.779 and EP-A-0.099.017, which is a combination of DE-A-3.225.155 and DE-A-3.225.188, describe phenylacetic acid derivatives which have an effect on the metabolism but more particularly have a hypoglycaemic effect.

It has now been found that the new phenylacetic acid derivatives of general formula which differ from the phenylacetic acid derivatives described previously by their group -OR4, have valuable properties. Thus, the compounds of general formula I wherein R^ represents a alkyl group or an allyl group have superior pharmacological properties, especially an enhanced effect on the metabolism, but preferably a better hypoglycaemic effect; the compounds of general formula I wherein R^ represents a hydrogen atom are valuable intermediates for preparing the above mentioned compounds.

In general formula I above, - 2 - 1 R^ represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, 10 R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R^ represents a hydrogen atom, an alkyl group with 1- to 3 carbon atoms or an allyl group.

R^ represents an alkyl group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl part may contain 3 to 7 carbon atoms, an alkenyl group 15 with 3 to 5 carbon atoms or an alkynyl group with 3 or 4 carbon atoms, and W represents methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group, whilst the alkoxy part 20 may contain from 1 to 4 carbon atoms and may be substituted by a phenyl group.

As examples of the definitions given hereinbefore 25 for the groups r3, r4 and w, R^ may represent a 1-propen-l-yl, 2-methyl-l-propen- 1-yl, 3-methyl-2-buten-2-yl, 2-propen-l-yl, 2-methyl- 2-propen-l-yl, 2-buten-l-yl, 2-methyl-2-buten-l-yl, 3-methyl-2-buten-l-yl, 3-buten-l-yl, 2-methyl- 3-buten-l-yl, 3-methyl-3-buten-l-yl, 2-hexen-l-yl, 1-propyn-l-yl, 2-propyn-l-yl, 2-butyn-l-yl, - 3 - 2-pentyn-l-yl, tetrahydrofuran-2-yl-methyl, 2-(tetra-hydrofuran-2-yl)-ethyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-2-yl-methyl, 2- (tetrahydropyran-2-yl)-ethyl, tetrahydropyran-3-yl-methyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexyl-methyl, cycloheptylmethyl, 2-cyclopropyl-ethyl, 2-cyclobutyl-ethyl, 2-cyclopentyl-ethyl, 2-cyclohexyl-ethyl or 2-cycloheptyl-ethyl group, may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropvl or allyl group and W represents a methyl, hydroxymethyl, formyl, carboxv, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec.butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl or 3-phenylpropoxycarbonyl group. Preferred compounds of general formula I are those wherein R^ represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R^ represents a cycloalkylmethyl group wherein the cycloalkyl part may contain 3 to 7 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a propargyl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-2-yl-methyl or tetrahydro-pyran-3-yl methyl group and W represents a carboxy, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl group.

However, particularly preferred compounds of general 5 formula I above are those wherein R-, represents a piperidino group, R2 represents a hydrogen, fluorine or chlorine 10 atom, represents a methyl or ethyl group, R^ represents a cyclopropylmethyl, cyclobutylmethyl, 15 cyclopentylmethyl, cyclohexylmethyl, tetrahydrofuran- 2-yl-methyl, allyl, methallyl, 2-methyl-vinyl, 2,2-dimethyl-vinyl or propargyl group and W represents a carboxy, methoxycarbonyl or ethoxycarbonyl 20 group, and particularly those compounds wherein Rj represents a piperidino group, Rj represents a hydrogen atom, R^ represents an ethyl group, 25 30 35 R^ represents a cyclohexylmethyl or cyclopropylmethyl group and W represents a carboxy or ethxycarbonyl group, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. - 5 - Particularly preferred compounds of general formula I are those wherein W represents the carboxy group.

According to the invention, the new compounds are 5 obtained by the following methods: a) reacting an amine of general formula 10 15 20 25 30 35 CH-NH2 fII) wherein to R^ are defined as hereinbefore, with a carboxylic acid of general formula HOOC-CH- \ / w 2 \ I / (HI) wherein R^ is defined as hereinbefore and W' has the meanings given for W hereinbefore, whilst any carboxy group contained in the group W may be protected by a protecting group, or with the reactive derivatives thereof optionally prepared in the reaction mixture, if necessary with subsequent splitting off of any protecting group used.

Examples of reactive derivatives of a compound of general formula III which may be used include - 6 - the esters thereof, such as the methyl, ethyl or benzyl esters, the thioesters such as the methylthio or ethylthioesters, the halides such as the acid chloride, the anhydrides or imidazolides thereof.

The reaction is appropriately carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethyl formamide, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexyl-carbodiimide, N,N1-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyl-diimidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously be used as solvent, at temperatures of between -25°C and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. The reaction may also be carried out without a solvent and furthermore any water formed during the reaction may be removed by azeotropic distillation, e.g. by heating with toluene using a water separator, or by adding a drying agent such as magnesium sulphate or a molecular sieve.

If necessary, the subsequent splitting off of a protecting group is preferably carried out by hydrolysis, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide 10 15 20 25 30 in a suitable solvent such as water, methanol, methanol/water, ethanol, ethanol/water, water/isopropanol or water/dioxan at temperatures of between -10 and 120°C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.

A tert.butyl group used as protecting group may also be split off thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic acid, sulphuric, phosphoric or polyphosphoric acid.

Furthermore, a benzyl group used as protecting group may also be split off hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide. b) In order to prepare compounds of general formula I wherein W represents a carboxy group: Hydrolysis, thermolysis, hydrogenolysis or alcoholysis of a compound of general formula (IV) wherein , to R4 are as hereinbefore defined, and - 8 - A represents group or a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

Examples of hydrolysable groups include functional derivatives of the carboxy group such as the unsubstituted or substituted amides, esters, thioesters, ortho esters, iminoethers, amidines or anhydrides thereof, the nitrile group, the tetrazolyl group, an optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group, examples of thermolytically cleavable groups include esters with tertiary alcohols, e.g. the tert.butyl ester, examples of hydrogenolytically cleavable groups include aralkyl groups, e.g. the benzyl group, and examples of alcoholytically cleavable groups include the cyano group.

The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water./isopropanol or water/dioxan at temperatures of between -10 and 120°C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture, and the alcoholysis of a cyano group is preferably effected in an excess of the corresponding alcohol such as methanol, ethanol or propanol and in the presence of an acid such as hydrochloric acid at elevated temperatures, e.g. at the boiling temperature of the reaction mixture.

If A in a compound of general formula IV represents a nitrile or aminocarbonyl group, these groups may be converted into a corresponding carboxy compound by means of 100% phosphoric acid at temperatures of between 100 and 180°C, preferably at temperatures of between 120 and 160°C, or with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, the latter conveniently being used as solvent as well, at temperatures of between 0 and 50 °C.

If A in a compound of general formula IV represents the tert.butyloxycarbonyl group for example, the tert.butyl group may also be split off thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g.. at temperatures of between 40 and 100°C.

If A in a compound of general formula IV represents the benzyloxycarbonyl group for example, the benzyl group may also be split off hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, methanol/water, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide, preferably at temperatures of between 0 and 50°C, e.g. at ambient temperature and under a hydrogen pressure of from 1 to 5 bar. During hydrogenolysis, a compound containing halogen may simultaneously be dehalogenated, any double or triple bonds present - 10 - may be hydrogenated and any benzyloxycarbonyl group present may be converted into a carboxy group. c) In order to prepare compounds of general formula I wherein R^ represents a hydrogen atom: Splitting off a protecting group from a compound of general formula 10 15 R, R- .CH - NH - CO - CH (V) OR 20 wherein R^ to R^ and W are as hereinbefore defined and represents a protecting group for a hydroxy group. 25 Examples of protecting groups for include, for example, an alkyl, aralkyl or trialkylsilyl group, e.g. the methyl, ethyl, propyl, allyl, benzyl or trimethylsilyl group. 30 Depending on the protecting group used, the protecting groups mentioned above may be split off either by hydrolysis or by hydrogenolysis, optionally in a suitable solvent, at temperatures of between -78 and 250°C. 35 For example, ether splitting is carried out in the presence of an acid such as hydrochloric, hydrobromic or sulphuric acid, boron tribromide, aluminium trichloride or pyridine hydrochloride, conveniently in a suitable solvent such as methylene chloride, - 11 - glacial acetic acid or water or in mixtures thereof at temperatures of between -78 and 250°C. The ether splitting is carried out in the presence of a proton acid conveniently at temperatures of 5 between 0 and 150°C, preferably at temperatures of between 50 and 150°C or with a Lewis acid preferably in a solvent such as methylene chloride at temperatures of between -78 and 20°C. 10 For example, any protecting group used such as a benzyl group may be split off hydrogenolyticallv with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, 15 glacial acetic acid, ethyl acetate, dioxan or dimethyl- formamide, preferably at ambient temperature, for example, and under a hydrogen pressure of from 1 to 5 bar. 20 d) In order to prepare compounds of general formula I wherein represents an alkyl group with 1 to 3 carbon atoms or an allyl group: 25 Reacting a compound of general formula 30 ?3 CH-NH-C0-CH2 (VI) 35 - 12 - wherein R^ to ^3 and W are as hereinbefore defined, with a compound of general formula 5 X - r6 (VII) wherein Rg represents an alkyl group with 1 to 3 carbon atoms or an allyl group and 10 x represents a nucleophilically exchangeable group such as a halogen atom, a sulphonyloxy group or, together with the adjacent hydrogen atom, a diazo group, if Rg represents an alkyl group with 1 to 3 carbon atoms, if necessary with subsequent hydrolysis. 15 20 25 The reaction is conveniently carried out with a corresponding halide, sulphonic acid ester, sulphuric acid diester or diazoalkane, e.g. with methyl iodide, dimethyl sulphate, ethyl bromide, diethyl sulphate, propyl bromide, isopropyl bromide, allyl bromide, ethyl p-toluenesulphonate, isopropylmethanesulphonate or diazomethane, optionally in the presence of a base such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tert.butoxide or triethylamine in a suitable solvent such as acetone, diethylether, tetrahydrofuran, dioxan or dimethylformamide at temperatures of between 0 and 100°C, preferably at temperatures of between 20 and 50°C. 30 - 13 - 10 15 20 25 30 If in a compound of general formula VI w represents a carboxy. group, this compound may simultaneously be converted into the corresponding ester compound. A compound thus obtained is, if necessary by cleaving the ester group, converted into the desired compound of general formula I.

The cleaving of the ester group is carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol/water, ethanol, ethanol/water, water ,/isopropanol or water/dioxan at temperatures of between -10 and 120°C, e.g. at temperatures of between ambient temperature and the boiling point of the reaction mixture. e) In order to prepare compounds of general formula I wherein R-^ to R^ are defined as hereinbefore, R4 represents a hydrogen atom or a alkyl group and W represents a methyl, formyl, carboxy or alkoxy-carbonyl group, wherein the alkoxy part may contain 1 to 4 carbon atoms: Reacting a compound of general formula D "3 CH - OH (VIII) - 14 - wherein to R^ are as hereinbefore defined, with a compound of general formula V/ \ \ (IX) \ OR 10 15 20 25 30 wherein R4 is as hereinbefore defined and W represents a methyl, formyl, carboxy or alkoxycarbonyl gnoup, wherein the alkoxy part may contain 1 to 4 carbon atoms.

The reaction is carried out in the presence of a strong acid which may simultaneously serve as solvent, preferably in concentrated sulfuric acid, at temperatures of between 0 and 150°C, preferably at temperatures of between 20 and 100°C. f) In order to prepare compounds of general formula I wherein R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R^ represents an alkyl group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranvl or cycloalkyl the cycloalkyl part may contain 5 to 7 carbon atoms and W represents a methyl, hydroxymethyl, carboxyl or alkoxycarbonyl group, whilst the alkoxy part may contain from 1 to 4 carbon atoms: - 15 - Reduction of a compound of general formula (X) wherein 10 Rj, R2i R4 and W are as hereinbefore defined and D represents a group of formula R7 \ /R8 c M 15 * C / \ NH- wherein R^ and Rg together with the carbon atom 20 between them represent an alkylidene group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl part may contain 5 to 7 carbon atoms. 25 The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or Raney-nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxan, tetrahydrofuran, dimethylformamide, 30 benzene or benzene/ethanol at temperatures of between 0 and 100°C, preferably at temperatures of between 20 and 50°C, and under a hydrogen pressure of from 1 to 5 bar. When a suitable chiral hydrogenation catalyst is used, such as a metal ligand complex 35 e.g. [ (2S),(4S)-1-tert.butoxycarbonyl-4-diphenylphosphino- 2-diphenylphosphinomethy1-pyrrolidine-rhodium-cyclo-octadiene(1,5)]-perchlorate, the addition of hydrogen - 16 - occurs enantioselectively. Moreover, in the catalytic hydrogenation, other groups may also be reduced, e.g. a benzyloxy group may be reduced to the hydroxy group or a formyl group may be reduced to the hydroxy 5 methyl group, or they may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.

A racemic compound of general formula I obtained 10 may be resolved into the enantiomers thereof via the diastereomeric adducts, complexes, salts or derivatives thereof.

The subsequent racemate splitting is preferably 15 carried out by column or HPL chromatography by forming diastereomeric adducts or complexes in a chiral phase.

The compounds of general formula I obtained according 20 to the invention may also be converted into the salts thereof and, for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids or bases. Suitable acids include, for example, hydrochloric, hydrobromic, 25 sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic, fumaric, aspartic or glutamic acid and suitable bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine or arginine.

The compounds of general formulae II to X used as starting materials are known from the literature in some cases or may be obtained by methods known per se. 30 35 - 17 - Thus, for example, a compound of general formula II is obtained by reducing a corresponding nitrile with lithium aluminium hydride or with catalytically activated hydrogen, by reacting a corresponding 5 nitrile with a corresponding grignard or lithium compound and subsequent lithium-aluminium hydride reduction or subsequent hydrolysis to form the ketimine which is subsequently reduced with catalytically activated hydrogen, with a complex metal hydride 10 or with nascent hydrogen, by hydrolysis or by hydrazinol- ysis of a corresponding phthalimido compound, by reacting a corresponding ketone with ammonium formate and subsequent hydrolysis or with an ammonium salt in the presence of sodium cyanoborohydride, by 15 reduction of a corresponding oxime with lithium aluminium hydride, with catalytically activated or nascent hydrogen, by reduction of a corresponding N-benzyl or N-l-phenylethyl Schiff's base e.g. with a complex metal hydride in ether or tetrahydrofuran 20 at temperatures of between -78°C and the boiling temperature of the solvent used with subsequent splitting off of the benzyl or 1-phenylethyl group by catalytic hydrogenation, by lithiation.of a corresponding benzylideneimino-benzyl compound, 25 e.g. by means of lithium-diisopropylamide at temperatures of between -78 and 20°C, subsequent reaction with a corresponding halogen compound, e.g. with a corresponding bromoalkyl, bromoalkenyl or bromoalkinyl compound, and subsequent hydrolysis, by Ritter 30 reaction of a corresponding alcohol with potassium cyanide in sulfuric acid, by Hofmann, Curtius, Lossen or Schmidt degradation of a corresponding compound or by converting a corresponding benzaldehyde into a corresponding glycine derivative, e.g. using 35 sodium cyanide/ammonium carbonate in ethanol/water into a corresponding hydantoin derivative, hydrolysis thereof, and, if necessary, subsequent esterification - 18 - and, if necessary, subsequent reduction, e.g. with a complex metal hydride in ether or tetrahydrofuran.

An amine of general formula II thus obtained having 5 a chiral centre can be resolved into its enantiomers by racemate splitting, e.g. by fractional crystallisation of the diastereomeric salts with optically active acids and subsequent decomposition of the salts or by column or HPL chromatograpy, optionally in 10 the form of the acyl derivative thereof, or by forming diasteromeric compounds, separating them and subsequently splitting them.

Moreover, an optically active amine of general 15 formula II may also be prepared by enantioselective reduction of a corresponding ketimine using complex boron or aluminium hydrides in which some of the hydride hydrogen atoms have been replaced by optically active alkoxide groups, or by means of hydrogen 20 in the presence of a suitable chiral hydrogenation catalyst or analogously starting from a corresponding N-benzyl or N-(1-phenethyl)-ketimine or from a corresponding N-acyl-ketimine or enimide and optionally subsequently splitting off the benzyl, 1-phenethyl 25 or acyl group.

Furthermore, an optically active amine of general formula II may also be prepared by diastereoselective reduction of a corresponding ketimine or hydrazone 30 substituted at the nitrogen atom with a chiral group, using a complex or non-complex boron or aluminium hydride in which some of the hydride hydrogens may optionally be replaced by corresponding alkoxide, phenoxide or alkyl groups or using hydrogen 35 in the presence of a suitable hydrogenation catalyst optionally with subsequent splitting off of the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis. - 19 - 10 Moreover, an optically active amine of general formula II may also be prepared by diastereo-selective addition of a corresponding organometallic compound, preferably a grignard or lithium compound, to a corresponding aldimine substituted with a chiral group at the nitrogen atom, by subsequent hydrolysis and optionally subsequent splitting off of the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

The compounds of general formulae IV, V and VI used as starting materials are obtained by reacting a corresponding amine with a suitable carboxylic acid or a reactive derivative thereof and, if necessary, 15 subsequently splitting off any protecting group used.

A compound of general formula XVII used as starting material is obtained by reducing a corresponding 20 carbonyl compound or by reacting a corresponding carbonyl compound with a corresponding grignard or lithium reagent.

A compound of general formula X used as starting 25 material is obtained by acylating a corresponding ketimine or the organometallic complex thereof with a corresponding carboxylic acid or reactive derivatives thereof, optionally with tautomerisation. 30 As already mentioned hereinbefore, the new compounds of general formula I and the physiologically active acceptable salts thereof have valuable pharmacological properties, namely an effect on the intermediate metabolism, but particular a hypoglycaemic effect. 35 For example, the following compounds: - 20 - A = ethyl 2-ethoxy-4 - [ N- (a-cyc lohexy line thy 1-2- piperidino-benzyl)-aminocarbonylmethyl]-benzoate, 3 = 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-piperidino-5 benzyl)-aminocarbonylmethyl]-benzoic acid, C = 2-ethoxy-4-[N-(a-cyclopropylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid, 10 D = 2-ethoxy-4-[N-(a-(tetrahydrofuran-2-yl-methyl)- 2-piper idino-benzyl)-aminocarbonylmethy1]-benzoic acid, E = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-15 - buten-l-yl)-aminocarbonylmethyl]-benzoic acid, F = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-l-yl)-aminocarbonylmethyl]-benzoic acid, and 20 25 30 35 G = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3- butyn-l-yl)-aminocarbonylmethyl]benzoic acid were investigated for their hypoglycaemic properties as follows: Hypoglycaemic activity The hypoglycaemic activity of the test substances was investigated in female rats bred by the company weighing from 180-220 g and kept without food for 24 hours before the start of the test. The test substances were suspended in 1.5% methylcellulose immediately before the start of the test and administered by oesophageal tube. - 21 - Blood samples were taken immediately before administration of the substance and 1, 2, 3 and 4 hours afterwards from the retroorbital venus plexus in each case. 50 mcl batches were deproteinated with 0.5 ml of 5 0.33 N perchloric acid and centrifuged. Glucose in the supernatant was determined by the hexokinase method using an analytical photometer. Statistical evaluation was carried out using the Student's t-test with p 0.05 as the limit of significance. 0 The following table contains the values found in percentages relative to the control: 15 Sub 10 mg/kg 0.5 mg/kg stance 1 2 3 4h 1 2 3 4h 20 A -16 -14 -17 -16 B -22 -47 -45 -45 C -45 -45 -36 -36 D -46 -25 -13 -10 E -42 -39 -28 -35 25 F -44 -41 -31 -28 G -33 -18 -11 n.s. n.s. = statistically not significant In tests on the substances for their hypoglycaemic activity, no toxic side effects were observed even at a dosage of 10 mg/kg p.o.

The new compounds are virtually non-toxic; for example, after a single dose of 500 mg/kg p.o. (suspension in 1% methycellulose) of substances - 22 - D and F to 3 male and 3 female mice, none of the animals died in the observation period of 14 days. 10 15 20 25 30 35 - 23 - In view of their pharmacological properties, the compounds of general formula I prepared according to the invention and the physiologically acceptable salts thereof are suitable for the treatment of diabetes mellitus. For this purpose, they may be incorporated in conventional galenic preparations such as tablets, coated tablets, capsules, powders or suspensions, optionally combined with other active substances. The single dose in adults is from 1 to 50 mg, preferably 2.5 to 20 mg, once or twice a day.

The examples which follow are intended to illustrate the invention: Example 1 Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-piperidino- benzyl) -aminocarbonylmethyl]-benzoate 5 To a solution of 1.13 g (3.96 mmol) of a-cyclohexylmethyl-2-piperidino-benzylamine in 11 ml of acetonitrile are added, successively, 1 g (3.96 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid, 1.25 g (4.76 mmol) 10 of triphenylphosphine, 1.11 ml (7.92 mmol) of triethyl- amine and 0.38 ml (3.96 mmol) of carbon tetrachloride and the mixture is stirred for 15 hours at ambient temperature. It is then concentrated by evaporation in vacuo and partitioned between ethyl acetate 15 and water. The organic extract is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Yield: 1.4 g (68% of theory), 20 Melting point: 95-97°C (petroleum ether/cyclohexane =1/1) Calculated: C 73.81 H 8.52 N 5.38 Found: 73.98 8.49 5.61 25 Example 2 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid 1.15 g (2.21 mmol) of ethyl 2-ethoxy-4-[N-(a-cyclohexyl-30 methyl-2-piperidino-benzyl)-aminocarbonylmethyl]- benzoate in 12 ml of ethanol are stirred together with 3.3 ml of IN sodium hydroxide solution for 2 hours at 50°C. Then 3.3 ml of IN hydrochloric acid are added and the mixture is cooled in ice. 35 The precipitate formed is filtered off, washed with a little ice cold ethanol and dried iji vacuo at 100°C. - 24 - Yield: 0.9 g (82% of theory), Melting point: 153-156°C Calculated: C 73.14 H 8.18 N 5.69 Found: 73.30 8.17 5.66 - 25 - Example 3 Ethyl 2-ethoxy-4-[N-(a-cyclopropylmethyl-2-piperidino- benzyl) -aminocarbonylmethyl]-benzoate 5 Prepared analogously to Example 1 from a-cyclopropylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 29.5% of theory, 10 Melting point: 126-127°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.85 7.74 5.84 Example 4 15 2-Ethoxy-4-[N-(a-cyclopropylmethyl-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid hemihydrate Prepared analogously to Example 2 by alkaline 20 saponification of ethyl 2-ethoxy-4-[N-(a-cyclopropylmethyl- 2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 88% of theory, Melting point: 103-104°C Calc. (x 0.5 H20): C 70.55 H 7.68 N 6.10 25 Found: 70.67 7.67 6.37 Example 5 Ethyl 2-ethoxy-4-[N-(g-cyclobutylmethyl-2-piper idino-30 benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from a-cyclobutylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid. 35 Yield: 14% of theory, Melting point: 116-118°C Calculated: C 73.14 H 8.18 N 5.69 Found: 73.14 8.32 5.64 - 26 - Example 6 2-Ethoxy-4-[N-(a-cyclobutylmethy1-2-piper idino- benzyl) -aminocarbonylmethyl]-benzoic acid 5 Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(a-cyclobutylmethyl-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 33% of theory, 10 Melting point: 140-142°C Calculated: C 72.39 H 7.81 N 6.03 Found: 7 2.15 7.79 5.97 15 Example 7 Ethyl 2-ethoxy-4-lN-(a-cyclopentylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from a-cyclopentyl-20 methyl-2-piperidino-benzylamine and 3-ethoxy-4- ethoxycarbonyl-phenyl-acetic acid.

Yield: 36.8% of theory, Melting point: 120-121°C Calculated: C 73.49 H 8.36 N 5.53 25 Found: 73.31 8.55 5.39 Example 8 2-Ethoxy-4-[N-(a-cyclopentylmethy1-2-piperidino-30 benzyl)-aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(a-cyclopentyl-methyl-2-piperidino-benzyl)-aminocarbonylmethyl]-35 benzoate.

Yield: 75% of theory, Melting point: 85-88°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.50 8.02 6.03 - 27 - Example 9 Ethyl 2-ethoxy-4-[N-(2-piperidino-a-(tetrahydrofuran- 2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from 2-piperidino-a-(tetrahydrofuran-2-yl-methy1)-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 38% of theory, Melting point: 111-113°C Calculated: C 70.84 H 7.93 N 5.51 Found: 70.76 7.73 5.51 Example 10 2-Ethoxy-4-[N-(2-piperidino-a-(tetrahydrofuran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(2-piperidino-a-(tetrahydrofuran-2-yl-methyl)-benzyl)-aminocarbonylmethyl] -benzoate .

Yield: 75% of theory, Melting point: 121-123°C Calculated: C 69.98 H 7.55 N 5.83 Found: 69.90 7.78 5.71 Example 11 Ethyl 2-ethoxy-4-[N-(a-cycloheptylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from a-cycloheptyl-methyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 48% of theory, Melting point: 96-98°C - 28 - Calculated: C 74.12 H 8.67 N 5.24 Found: 74.40 8.87 5.39 Example 12 5 2-Ethoxy-4-[N-(a-cycloheptylmethyl-2-piper idino-benzyl) -aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline 10 saponification of ethyl 2-ethoxy-4-[ N-(ot-cycloneptylmethyl- 2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 83% of theory, Melting point: 127-130°C Calculated: C 73.49 H 8.36 N 5.53 15 F<5und: 73.54 8.62 5.47 Example 13 Ethyl 2-ethoxy-4-[N-(g-cyclohexylmethyl-2-piperidino-20 benzyl)-aminocarbonylmethyl]-benzoate a) Ethyl 2-ethoxy-4-[N-(a-(cyclohexyl-methylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate 25 Prepared analogously to Example 1 from a-cycloheptyl- methyl-(2-piperidino-phenyl)-ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 25% of theory, Melting point: 85-88°C 30 Calculated: C 74.10 H 8.16 N 5.10 Found: 74.37 8.00 5.45 According to the 80 MHz-^H-NMR spectrum (CDCl^) there is a mixture of E/Z = 1/2. [Olefinic H: 35 (E) D 6.26, (Z) 5.42 ppm]. - 29 - b) Ethyl 2-ethoxy-4-|.N- (a-cyclohexylmethyl-2-piper idino- benzyl) -aminocarbonylmethyl]-benzoate Prepared by catalytic 5 hydrogenation of ethyl 2-ethoxy-4-[N-(a-(cyclohexyl- methylidene) -2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate on 10% palladium/charcoal in ethanol at a.nbier'.t: temperature and 3 bars of hydrogen.

Yield: 61% of theory, 10 Melting point: 95-97°C Calculated: C 73.81 H 8.52 N 5.38 Found: 73.92 8.74 5.29 Example 14 15 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-piper idino-benzyl) -aminocarbonylmethyl]-benzoic acid a) 2-Ethoxy-4-[N-(a-(cyclohexyl-methylidene)-2-20 piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(a-(cyclohexyl-25 methylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]- benzoate.

Yield: 87% of theory, Melting point: 95-100°C Calculated: C 73.44 H 7.81 N 5.71 30 Found: 73.38 7.73 5.75 b) 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid 35 Prepared analogously to Example 13 by catalytic hydrogenation of 2-ethoxy-4-[N-(a-(cyclohexyl-methylidene)- 2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid. - 30 - 10 20 25 30 Yield: 52% of theory, Melting point: 154-156°C Calculated: C 73.14 H 8.18 N 5.69 Found: 73.31 8.25 5.71 Example 15 Ethyl 2-ethoxy-4-[N-(1-(2-piper idino-phenyl)-3-buten-l-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from 1-(2-piperidino-phenyl) -3-buten-l-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 32.7% of theory, 15 Malting point: 110-112°C Calculated: C 72.39 H 7.81 N 6.03 Found: 72.10 7.66 5.94 35 Example 16 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-l-yl) -aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(1-(2-piperidino- phenyl) -3-buten-l-yl)-aminocarbonylmethyl]-benzoate.

Yield: 68% of theory, Melting point: 92-95°C Calculated: C 71.53 H 7.39 N 6.42 Found: 71.27 7.42 6.42 Example 17 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-l-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from 3-methyl- - 31 - 1-(2-piperidino-phenyl)-3-buten-l-yl)-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 33.6% of theory, Melting point: 126-128°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.82 8.22 5.78 Example 18 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl- 3-buten-l-yl)-aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-pfienyl)-3-methyl-3-buten-l-yl)-aminocarbonylmethyl]-benzoate.

Yield: 74% of theory, Melting point: 64-66°C Calculated: C 71.97 H 7.61 N 6.22 Found: 71.70 7.50 5.98 Example 19 Ethyl 2-ethoxy-4-[N-(1-(2-piper idino-phenyl)-3-methyl-2-buten-l-yl)-aminocarbonylmethyl]-benzoate [with 25% of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonylmethyl]-benzoate] Prepared analogously to Example 1 from 3-methyl-1-(2-piperidino-phenyl)-2-buten-l-yl-amine [containing 25% of 3-methyl-l-(2-piperidino-phenyl)-1-butylamine] and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 37% of theory, Melting point: 141-142°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.60 7.77 5.73 - 32 - The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristic signals in the 400 MHz-^H-NMR spectrum (CDCl^). The position of the signals is: 3-methyl-2-buten-l-yl compound: olefinic H: 5.25 (d), CH^: 1.64 (s) and 1.77 (s), benzylic ^>CH- 6.00 (t), benzylic CH2~: 3.52 ppm (s) 3-methyl-l-butyl compound: CH3: 0.90 (d) , benzylic ^>CH- 5.35 (m), benzylic -CH2~: 3.54 ppm (s).

Example 20 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-2-buten-l-yl)-aminocarbonylmethyl]-benzoic acid [Containing 25% of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl) -3-methyl-l-butyl)-aminocarbonylmethyl]-benzoic acid] Prepared analogously to Example 2 by alkaline saponification of the corresponding ethyl ester mixture from Example 68.

Yield: 91% of theory, Melting point: 154-156°C Calculated: C 71.97 H 7.61 N 6.22 Found: 71.80 7.57 5.98 Example 21 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-l-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from 1-(2-piperidino- phenyl) -3-butyn-l-yl-amine and 3-ethoxy-4-ethoxycarbonyl- phenylacetic acid.

Yield: 52% of theory, Melting point: 86-90°C Calculated: C 72.70 H 7.41 N 6.06 - 33 - Found: 72.60 7.40 6.04 Example 22 5 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn- 1-yl)-aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-10 phenyl)-3-butyn-l-yl)-aminocarbonylmethyl]-benzoate.

Yield: 68% of theory, Melting point: 66-69°C Calculated: C 71.87 H 6.96 N 6.45 Found: 71.60 6.95 6.38 15 20 30 Example 23 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-4■ penten-l-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from 1-(2-piperidino-phenyl) -4-penten-l-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield; 58% of theory, 25 Melting point: 117-120°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.73 7.97 6.07 Example 24 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoic acid Prepared analogously to Example 2 by alkaline 35 saponification of ethyl 2-ethoxy-4-[N-(1-(2-piperidino- phenyl) -4-penten-l-yl)-aminocarbonylmethyl]-benzoate. Yield: 61% of theory, - 34 - 10 20 Melting point: 82-85°C Calculated: C 71.97 H 7.61 N 6.22 Found: 71.97 7.59 5.98 Example 25 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-a-(tetrahydropyran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 1 from 2-piperidino-a-(tetrahydropyran-2-yl-methyl)-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 29% of theory, 15 Melting point: 82-85°C Calculated: C 71.24 H 8.10 N 5.36 Found: 71.28 7.96 5.29 Example 26 2-Ethoxy-4-[N-(1-(2-piperidino-a-(tetrahydropyran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoic acid 25 Prepared analogously to Example 2 by alkaline saponification of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-a-(tetrahydropyran-2-yl-methyl)-benzyl)-aminocarbonylmethyl] -benzoate .

Yield: 85% of theory, 30 Melting point: 140-142°C (sinters from 70°C, partial softening at 105°C) Calculated: C 70.42 H 7.74 N 5.66 Found: 70.15 7.88 5.40 35 - 35 - Example 2 7 Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-piperidino- benzyl) -aminocarbonylmethyl]-benzoate At 23-25°C, a solution of 2.35 g (10 mmol) of ethyl 2-ethoxy-4-cyanomethyl-benzoate and 2.88 g (10 mmol) of a-cyclohexylmethyl-2-piperidino-benzyl alcohol in 15 ml of o-dichlorobenzene is added dropwise to a mixture of 15 ml of concentrated sulphuric acid and 15 ml of o-dichlorobenzene. The mixture is stirred for 2 hours at ambient temperature. The o-dichlorobenzene phase is then separated off and the residue is added to ice.

After being made alkaline with soda solution, it is extracted with chloroform. The extracts are dried over sodium sulphate and concentrated by evaporation. The residue is purified by column chromatography on silica gel (toluene/acetone = 10/1) .

Yield: 1.1 g (21% of theory), Melting point: 95-97°C Calculated: C 73.81 H 8.52 N 5.38 Found: 73.95 8.64 5.42 Analogously to the preceding Examples, the following compounds are obtained: - 36 - Ethyl 2-ethoxy-4-[N- (a-cyclopropylmethyl-2-pyrrolidino- benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclopropylmethyl-2-pyrrolidino-5 benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-cyclopropylmethyl-2-hexamethy-leneimino-benzyl)-aminocarbonylmethyl]-benzoate 10 2-Et'noxy-4-lN- (a-cyclopropylmethyl-2-hexamethyleneimino- benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-cyclopropylmethyl-2-(4-methyl-piper idino)-benzyl)-aminocarbonylmethyl]-benzoate 15 2-Ethoxy-4-(.N-(a-cyclopropylmethyl-2-(4-methyl-piper idino)-benzyl)-aminocarbonylmethyl]-benzoic acid 20 Ethyl 4-[N-(a-cyclopropylmethy1-2-piper idino-benzyl)- aminocarbonylmethyl]-2-methoxy-benzoate 4-1N-(a-Cyclopropylmethyl-2-piper idino-benzyl)-aminocarbonylmethyl]-2-methoxy-benzoic acid 25 Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-pyrrolidino-30 benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-hexamethy-leneimino-benzyl)-aminocarbonylmethyl]-benzoate 35 2-Ethoxy-4-IN-(a-cyclohexylmethyl-2-hexamethyleneimino- benzyl) -aminocarbonylmethyl] -benzoic acid - 37 - <. ' 10 Ethyl 2-ethoxy-4-lN-(a-cyclohexylmethyl-2-(4-methyl- piperidino)-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-(4-methyl-piperidino) benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-(3,5-dimethy1-piperidino)-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-(3,5-dimethyl-piperidino) -benzyl ) -aminocarbonylmethyl]-benzoic acid 15 Efhyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-2-(3,3- dimethy1-piper idino)-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-(3,3-dimethyl-20 piperidino)-benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 4-[N-(a-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-2-hydroxy-benzoate 25 4-[N-(a-CyclohexyImethy1-2-piperidino-benzyl)-aminocarbonylmethyl] -2-hydroxy-benzoic acid Ethyl 4-[N-(a-Cyclohexylmethyl-2-piperidino-benzyl)-30 aminocarbonylmethyl]-2-methoxy-benzoate 4-[N-(a-Cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl] -2-methoxy-benzoic acid 35 Ethyl 2-allyloxy-4-[N-(a-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoate - 38 - 4 2-Allyloxy-4-[N-fa-cyclohexylmethyl-2-piperidino- benzyl) -aminocarbonylmethyl]-benzoic acid Ethyl 4 — [M—(a-cyclohexylmethyl-2-piperidino-benzyl)-5 aminocarbonylmethyl]-2-n-propoxy-benzoate 4-lN-(a-Cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl ]-2-n-propoxy-benzoic acid 10 Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-4-fluoro- 2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexylmethyl-4-fluoro-2-piper idino-benzyl) -aminocarbonylmethyl]-benzoic acid 15 Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-3-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexyImethy1-3-chloro-2-piperidino-20 benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-6-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate 25 2-Ethoxy-4-[N-(a-cyclohexylmethyl-6-chloro-2-piper idino- benzyl) -aminocarbonylmethyl]-benzoate Ethyl 2-ethoxy-4-|.N- (a-cyclohexylmethyl-3-methyl-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate 30 2-Ethoxy-4-[N-(a-cyclohexyImethy1-3-methyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoate Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-4-methyl-35 2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cyclohexyImethy1-4-methy1-2-piper idino-benzyl) -aminocarbonylmethyl]-benzoic acid - 39 - Ethyl 2-ethoxy-4-IN-(a-cyclohexylmethyl-6-methyl- 2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-cvclohexylmethyl-6-methyl-2-piperidino-5 benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-cyclohexylmethyl-4-methoxy-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate 10 2-Ethoxy-4-[N-(a-cyclohexylmethyl-4-methoxy-2- piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(a-(2-cyclohexyl-ethyl)-2-15 ptperidino-benzyl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(a-(2-cyclohexyl-ethyl)-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid 20 Ethyl 3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)- 1-ethyl)-aminocarbonylmethyl]-phenyl]-propionate 3-[2-E thoxy-4-[N-(1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-phenyl]-propionic acid 25 Ethyl 3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]-phenyl]-propionate 3-[2-Ethoxy-4-[N-(1-(2-piper idino-phenyl)-1-propyl)-30 aminocarbonylmethyl]-phenyl]-propionic acid Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-2-buten-1-yl)-aminocarbonylmethyl]-benzoate 35 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-2-buten-l- yl-aminocarbonyImethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-methyl-3-penten-l-yl)-aminocarbonylmethyl]-benzoate - 40 - 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-methy1-3- penten-l-yl)-aminocarbonylmethyl]-benzoic acid Ethyl 2-ethoxy-4-[N-(1-(2-piper idino-phenyl)-3-penten-5 1-yl)-aminocarbonylmethyl]-benzoate 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-penten-l-yl)-aminocarbonylmethyl]-benzoic acid 10 Example A 15 20 Tablets containing 5 mg of 2-ethoxy-4-[N-(a-cyclohexy Imethy1-2-piperidino-benzyl)-aminocarbonylmethyl] ■ benzoic acid Composition: 1 tablet contains: Active substance (1) 5 .0 mg Corn starch (2) 62 .0 mg Lactose (3) 48 .0 mg Polyvinylpyrrolidone (4) 4 .0 mg Magnesium stearate (5) 1 .0 mg 120 .0 mg 25 Method of preparation 1, 2, 3 and 4 are mixed together and moistened with water. The moist mixture is pressed through a screen with a 1.5 mm mesh size and dried at 30 about 45°C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with 5. The finished mixture is compressed in a tablet press with dies 7 mm in diameter, provided with a dividing notch, to form tablets. 35 Weight of tablet: 120 mg - 41 - 10 15 Example B Coated tablets containing 2.5 mg of 2-ethoxy-4- [N-(a-cyclohexylmethyl-2-piper idino-benzyl)-aminocarbonyl methyl]-benzoic acid 1 tablet core contains: Active substance (1) 2. 5 mg Potato starch (2) 44 . 0 mg Lactose (3) 30 . 0 mg Polyvinylpyrrolidone (4) 3. 0 mg Magnesium stearate (5) 0. 5 mg o CO 0 mg Method of preparation 1, 2, 3 and 4 are thoroughly mixed and moistened with water. The moist mass is forced through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same 20 screen again. After 5 has been added, tablet cores 6 mm in diameter are pressed out in a tablet making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets 25 are polished with wax.

Weight of coated tablet: 120 mg Example C 30 Tablets containing 10 mg of 2-ethoxy-4-[N-(a-cyclo hexy Ime thy 1- 2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid 35 - 42 - Composition: 1 tablet contains: Active substance 10. .0 mg Powdered lactose 70. , 0 mg Corn starch 31. . 0 mg Polyvinylpyrrolidone 8. .0 mg Magnesium stearate 1. .0 mg 120. . 0 mg 10 Method of preparation: The mixture of active substance, lactose and corn starch is moistened with a 20% solution of polyvinylpyrrolidone in water. The moist mass is granulated 15 through a screen with a mesh size of 1.5 mm and dried at 45°C. The dried granulate is passed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate.

Weight of tablet: 120 mg 20 Die: 7 mm diameter with dividing notch Example D Coated tablets containing 5 mg of 2-ethoxy-4-[N-25 (a-cyclohexylmethyl-2-piper idino-benzyl)-aminocarbonyl methyl]-benzoic acid 1 tablet core contains: Active substance 5.0 mg 30 Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg 130.0 mg 35 - 43 - Method of preparation: A mixture of active substance, calcium phosphate and corn starch is moistened with a 15% solution 5 of polyvinylpyrrolidone in water. The moist mass is passed through a screen with a mesh size of 1 mm, dried at 45°C and then passed through the same screen again. After mixing with the specified quantity of magnesium stearate, tablet cores are 10 compressed therefrom.

Weight of core: 130 mg Die: 7 mm in diameter A coating of sugar and talc is applied in a known 15 manner to the tablet cores thus produced. The finished coated tablets are polished with wax. Weight of coated tablet: 180 mg 20 25 30 35 - 44 -

Claims

1. Patent Claims 1. Phenylacetic acid derivatives of general formula 10 I) ti- 15 wherein R^ represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, 20 R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R4 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an allyl group. 25 30 R^ represents an alkyl group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl part may contain 3 to 7 carbon atoms, an alkenyl group with 3 to 5 carbon atoms or an alkynyl group with 3 or 4 carbon atoms, and 35 W represents methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group, whilst the alkoxy part may contain from 1 to 4 carbon atoms and may be substituted by a phenyl group, and the enantiomers and salts thereof. - 45 - 10 2. Phenylacetic acid derivatives of general formula I as claimed in claim 1, wherein represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, r2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R^ represents a cycloalkylmethyl group in which 15 the cycloalkyl part may contain from 3 to 7 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a propargyl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-2-yl-methyl or tetrahydro-pyran-3-yl-methyl group and 20 W represents a carboxy, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl group, the enantiomers and salts thereof. 25 3. Phenylacetic acid derivatives of general formula I as claimed in claim 1, wherein R1 represents a piperidino group, 30 represents a hydrogen, fluorine or chlorine atom, R4 represents a methyl or ethyl group, 35 R^ represents a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydrofuran-2-yl-methyl, allyl, methallyl, 2-methyl-vinyl, 2,2-dimethyl-vinyl or propargyl group and - 46 - W represents a carboxy, methoxycarbonyl or ethoxycarbonyl group, 10 20 25 the enantiomers and the salts thereof. 4. Phenylacetic acid derivatives of general formula I as claimed in claim 1, wherein R ^ represents a piperidino group, R2 represents a hydrogen atom, R 4 represents an ethyl group, 15 R^ represents a cyclohexylmethyl or cyclopropylmethyl group, and W represents a carboxy or ethoxycarbonyl group, the enantiomers and salts thereof. 5. Phenylacetic acid derivatives of general formula I as claimed in claim 1, wherein R^ to R^ are defined as in claims 1 to 4 and W represents a carboxy group, the enantiomers and the salts thereof. 6. 2-Ethoxy-4-[N-(a-cyclohexylmethyl-2-piperidino-30 benzyl)-aminocarbonylmethyl]-benzoic acid, the enantiomers and the salts thereof. 7. Physiologically acceptable salts of the compounds as claimed in claim 1 to 6 with inorganic or organic 35 acids or bases. - 47 - 8. Pharmaceutical compositions containing a compound as claimed in claims 1 to 6 or a physiologically acceptable salt as claimed in claim 7 optionally together with one or more inert vehicles and/or diluents. 10 9. Use of a compound as claimed in claims 1 to 6 or the physiologically acceptable salts thereof as claimed in claim 7 for preparing a pharmaceutical composition suitable for the treatment of Diabetes mellitus. 15 10. Process for preparing a pharmaceutical composition as claimed in claim 8, Wherein a compound as claimed in claims 1 to 6 or a physiologically acceptable salt thereof as claimed in claim 7 is incorporated in one or more inert vehicles and/or diluents. 20 11. Analogous process for preparing the phenylacetic acid derivatives as claimed in claims 1 to 7, wherein 25 a) an amine of general formula 30 R. - NH, (II) 35 wherein to are defined as in claims 1 to 6, is reacted with a carboxylic acid of general formula - 48 - J X (III) HOCC-CH 2 15 20 25 30 wherein * R^ is defined as in claims 1 to 6 and W1 has the meanings given for W in claims 1 to 6, or represents a carboxy group protected by a protecting group, or with the reactive derivatives thereof optionally prepared in the reaction mixture, and if necessary any protecting group used is subsequently split off, or b) in order to prepare compounds of general formula I wherein W represents a carboxy group: a compound of general formula wherein R-^ to R^ are defined as in claims 1 to 6, and A represents a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis is converted into a corresponding compound by hydrolysis, thermolysis, hydrogenolysis or alcoholysis, or c) in order to prepare compounds of general formula I wherein R4 represents a hydrogen atom: - 49 - a protecting group is split off from a compound of general formula 10 15 R, R. CH-NH-CO-CH (V) wherein to R3 and W are defined as in claims 1 to 6 and R^ represents a protecting group for a hydroxy group, or 20 d) in order to prepare compounds of general formula I wherein R^ represents an alkyl group with 1 to 3 carbon atoms or an allyl group: a compound of general formula 25 R< R. ch-nh-co-ch2 (vi) 30 wherein R^ to R^ and w are defined as in claims 1 to 6, is reacted with a compound of general formula x - rg (vii) 35 wherein Rg represents an alkyl group with 1 to 3 carbon atoms or an allyl group and - 50 - X represents a nucleophilically exchangeable group such as a halogen atom, a sulphonyloxy group or, together with the adjacent hydrogen atom, a diazo group, if represents an alkyl group with 1 to 3 carbon atoms, and if necessary the compound thus obtained is subsequently hydrolysed, or e) in order to prepare compounds of general formula i wherein R-, , r2 and r^ are defined as in claims 1 to 6, R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms and W represents a methyl, formyl, carboxy or alkoxycarbonyl group, wherein the alkoxy part may contain 1 to 4 carbon atoms, a compound of general formula wherein R^ to R^ are defined as in claims 1 to 6, is reacted with a compound of general formula R 3 CH - OH (viii) OR 4 (ix) wherein - 51 - R. is defined as in claims 1 to 6 and 4 5 10 15 20 25 30 W" represents a methyl, formyl, carboxy or alkoxycarbonyl group, whilst the alkoxy part may contain 1 to 4 carbon atoms, or f) in order to prepare compounds of general formula I wherein represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R3 represents an alkyl group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl part may contain 5 to 7 carbon atoms, and \"l represents a methyl, hydroxymethyl, carboxy or alkoxycarbonyl group, whilst the alkoxy part may contain from 1 to 4 carbon atoms, a compound of general formula wherein R^, R2, R4 and W are defined as in claims 1 to 6 and D represents a group of formula R. 7 C II c - 52 - wherein Ry and Rg together with the carbon atom between them represent an alkylidene group with 1 or 2 carbon atoms substituted by a tetrahydrofuranvl, tetrahydropyranyl or cycloalkyl group, wherein the cycloalkyl part may contain 5 to 7 carbon atoms, is reduced and subsequently, if desired, a racemic compound of general formula I thus obtained is resolved into the enantiomers thereof by chromatography on chiral phases, and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bar^s. m 16. A pharmaceutical composition whenever prepared by a process as claimed in claim 10 or claim 15. 5 Dated this 30th day of June, 1986. BY: TOMKINS & CO., Applicants' Agents, (Signed) /w\. u«. 10 5, Dartmouth Road, DUBLIN 6.( 15 20 25 30 35 - 54 -