IE57700B1 - Chemical compounds - Google Patents

Chemical compounds

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IE57700B1
IE57700B1 IE3349/84A IE334984A IE57700B1 IE 57700 B1 IE57700 B1 IE 57700B1 IE 3349/84 A IE3349/84 A IE 3349/84A IE 334984 A IE334984 A IE 334984A IE 57700 B1 IE57700 B1 IE 57700B1
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Ireland
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group
methyl
phenyl
piperidino
general formula
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IE3349/84A
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IE843349L (en
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Thomae Gmbh Dr K
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Publication of IE843349L publication Critical patent/IE843349L/en
Publication of IE57700B1 publication Critical patent/IE57700B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
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Abstract

1. Two new solid forms of 2-ethoxy-4-[N-(1-(2-piperidino- phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, the form designated (B) being characterised by the melting point of 140-142 degrees C and by the IR(KBr) spectrum according to Figure B' and the form designated (C) being characterised by a melting point of 75-85 degrees C and by the IR(KBr) spectrum according to Figure C'.

Description

EP-A-0 058 779 and EP-A-0 099 017 have already described phenylacetic acid derivatives which have an effect on the metabolism, but more particularly a hypoglycaemic effect.
It has now been found that the new phenylacetic acid derivatives of general formula which differ from the aforementioned phenylacetic acid derivatives by the group -OR^ have valuable properties. Thus? the compounds of general formula I wherein R^ represents a methylr ethyl or allyl group have superior pharmacological properties, especially a superior effect on the metabolism, but preferably a better hypoglycaemic effect, and compounds of general formula I wherein R^ is a hydrogen atom are valuable intermediates for the preparation of the abovementioned compounds.
The present invention thus relates to new phenylacetic acid derivatives of the above general formula I, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds and processes for preparing them.
In general formula I above: R^ represents a pyrrolidino, piperidino, hexamethyleneimino, methyl-pyrolidino, dimethyl-pyrrolindino, 2-methyl-piperidino, 3-methyl-piperidino, 4-methylpiperidino, 3,3-dimethyl-piperidino, cis-3,5-dimehthylpiperidino or trans-3,5-dimethyl-piperidino group, R^ represents a hydrogen or halogen atom or a methyl or methoxy group, represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an n-pentyl or 3-methyl-n butyl group or a phenyl group optionally substituted by a halogen atom or by a methyl or methoxy group, R^ represents a hydrogen atom,- a methyl, ethyl or allyl group and W represents a methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group with a total of 2 to 5 carbon atoms, whilst the alkyl part of the alkoxy group may be substituted by a phenyl group.
As examples of the definitions of the groups R~ to R, and W mentioned hereinbefore: 4 R2 may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group, R3 may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, 3-methyl-n-butyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl or methoxyphenyl group, and W may represent a methyl, hydroxymethyl, formyl, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl or 3-phenylpropoxycarbonyl group.
However, preferred compounds of general formula I above are those wherein and R^ are defined as hereinbefore, R·^ represents a pyrrolidino, piperidino, 4-methyl3 piperidino# 3-methyl-piperidino, 3 # 3-dimethy1-piperidino# 3,5-dimethyl-piperidino or hexamethyleneimxno group# Rj represents a hydrogen# fluorine or chlorine atom or a methyl or methoxy group# and W represents a carboxy# methyl# hydroxymethyl# formyl or benzyloxycarbonyl group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms# particularly those compounds wherein represents a piperidino group# R2 represents a hydrogen# fluorine or chlorine atom# Rj represents a methyl# ethyl# n-propyl# n-butyl# n-pentyl or phenyl group.
R^ represents a methyl or ethyl group and W represents a carboxy# methoxycarbonyl or ethoxycarbonyl group# the enantiomers and the salts thereof# particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.
Particularly preferred compounds of general formula I above are those wherein W represents a carboxy group.
According to the invention# the new compounds are obtained by the following processes: a) reaction of an amine of general formula R, wherein to Rj are as hereinbefore defined# with a carboxylic acid of general formula HOOC-CH,-/ >-w (III) OR. wherein is as hereinbefore defined and WJ has the meanings given for W hereinbefore or represents a carboxyl group protected by a protecting group, or with a reactive derivative thereof, which may optionally be prepared in the reaction mixture, followed where necessary by removal of any protecting group used.
Examples of reactive derivatives of a compound of general formula III include the esters such as the methyl, ethyl or benzyl esters, the thioesters such as the methylthio or ethylthio esters, the halides such as the acid chloride, the anhydrides and 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 dimethylformamide, 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, Ν,Ν'-dicyclohexylcarbodiimide , N,N’-dicyclohexylearbodi imide/N-hydroxysuccinimide, Ν,N5-carbonyldiimidazole or Ν,N’-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent activating 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 act as solvent, at temperatures of between -25 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, moreover, 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 molecular sieve.
If necessary the subsequent splitting off of a protecting group is preferably 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 temperature of the reaction mixture.
A tert.butyl group used as protecting group may also optionally be split off thermally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric, phosphoric or polyphosphoric acid.
Moreover, a benzyl group used as protecting group may also be split off by hydrogenolysis 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 a compound of general formula I wherein W represents a carboxy group: Splitting of a compound of general formula wherein to R^ are as hereinbefore defined and A represents a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysisExamples of hydrolysable groups include functional derivatives of the carboxy group such as the unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides thereof, the nitrile group, the tetrazolyl group or an optionally substituted 1,3-oxazol-2-yl or 1,3-oxalin-2-yl group and examples of thermolytically removable groups include esters with tertiary alcohols, e.g. the tert.butyl ester, and examples of hydrogenolytically removable groups include aralkyl groups, e.g. the benzyl group.
The hydrolysis is appropriately 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.
If A in a compound of general formula IV represents a nitrile or aminocarbonyl group, these groups may be converted into a carboxy group by means of 100¾ 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, which is appropriately also used as solvent, at temperatures of between 0 and 50°C.
If A in a compound of general formula IV represents, for example, the tert.butyloxycarbonyl group, the tert.butyl group may also be thermally split off, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, 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 compounds of general formula IV represents, for example, a benzyloxycarbonyl group, the benzyl group may also be split off by hydrogenolysis 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 the hydrogenolysis a halogen-containing compound may simultaneously be dehalogenated. c) In order to prepare a compound of general formula I wherein R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms: Reaction of a compound of general formula ZX/CH-OH (V) R,k·. wherein to are as hereinbefore defined, with a compound of general formula C-CH2// (VI) OR, wherein R^ and W are as hereinbefore defined.
The reaction is carried out in the presence of a strong acid, which may simultaneously serve as solvent, preferably in concentrated sulphuric acid, at temperatures of between 0 and 150°C, preferably at temperatures of between 20 and 100°C.
If in a compound of general formula VI represents an acyl, allyl or benzyl group, this is split off during the reaction or after the reaction when water is added. d) 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 (VII) wherein R1 co are as ^ereinks£°re defined, W' has the meanings given for W hereinbefore or represents a group which can be converted into a carboxy group and Rj represents a protecting group for a hydroxy group.
Examples of groups which can be converted into carboxy groups# for W", include an alkoxycarbonyl# aryloxycarbonyl, aralkoxycarbonyl# aminocarbonyl or nitrile group whilst examples of protecting groups for Rj include alkyl# aralkyl# trialkylsilyl or acyl groups# e.g. the methyl# ethyl# propyl, benzyl# trimethylsilyl# acetyl or propionyl group.
Depending on the protecting group used the protecting groups may be split off either by hydrolysis or by hydrogenolysis, optionally in a suitable solvent, at temperatures of between -78 and 250°C.
Ether splitting may be carried out, for example# in the presence of an acid such as hydrogen chloride# hydrogen bromide# sulphuric acid, boron tribromide, aluminium trichloride or pyridine hydrochloride, conveniently in a suitable solvent such as methylene chloride, glacial acetic acid or water or in mixtures thereof at temperatures of between -78 and 250 °C.
Ether splitting in the presence of a protic acid is conveniently carried out at temperatures of 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.
Ester splitting may be carried out, for example# in the presence of a base such as aqueous ammonia# sodium carbonate, potassium carbonate or sodium or potassium hydroxide in a solvent such as water, water/methanol, water/ethanol, water/tetrahydrofuran or water/dioxan at temperatures of between 50 and 100 °C, preferably at the temperature of the solvent used.
Hydrogenolytic splitting off of a protecting group, such as a benzyl group, may be carried out, for example, with hydrogen 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, preferably at ambient temperature and under a hydrogen pressure of from 1 to 5 bar. e) In order to prepare compounds of general formula I wherein represents a methyl, ethyl or allyl group: Reaction of a compound of general formula wherein R^ to R^ and W are as hereinbefore defined, with a compound of general formula r4' - X (IX) wherein R ' is defined as hereinbefore, with the exception of hydrogen, and X represents a nucleophilically exchangeable group such as a halogen atom or a sulphonyloxy group, or, together with an adjacent hydrogen atom, a diazo group, if R^ 3 represents a methyl or ethyl group, followed, if necessary, by hydrolysis.
The reaction is appropriately carried out with a corresponding halide, anhydride, 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, benzyl chloride, benzyl bromide, acetyl chloride, acetic anhydride, ethyl p-toluenesulphonate, isopropyl methanesulphonate or diazomethane, optionally in the presence of a base such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butoxide or triethylamine or, In the case of acylation, with an anhydride in the presence of an acid such as sulphuric acid, preferably in a suitable solvent such as acetone, diethyl ether, tetrahydroruran, dioxan, pyridine or dimethylformamide at temperatures of between 0 and 100°C, preferably at temperatures of between 20 and 50°C, whereby an anhydride used as acylating agent may also simultaneously serve as solvent.
If W in a compound of general formula VIII represents a carboxy or hydroxymethyl group, this may be converted into the corresponding ester compound.
A compound thus obtained is, if necessary, after the splitting of the ester group, converted into the desired compound of general formula I.
The ester group is preferably split hydrolytically, 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 temperature of the reaction mixture. f) Reduction of a compound of general formula ,Y-C-CH -w // (X) li R, OR, wherein R., R„, R. and W are as hereinbefore defined 1 2 4 and Y represents a group of formula R6 - C - NH - or wherein R^ is as hereinbefore defined and Rz- and R. together with the carbon atom to o 7 which they are attached represent an alkylidene group with 1 to 4 carbon atoms.
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, benzene or benzene/ethanol at temperatures of between 0 and 100°C, but preferably at temperatures of between 20°C and 50°C, under a hydrogen pressure of from 1 to 5 bar. If a suitable chiral hydrogenation catalyst is used such as a metal ligand complex, e.g. a complex of /ι,p’-dichloro-bis-l1,5-cyclooctadiene rhodium] and (+)- or (-) 0,0-isopropylidene-2,3dihydroxy-1,4-bis (diphenylphosphi.no) -butane ( = DIOP), the addition of hydrogen occurs enantioselectively Moreover during the catalytic hydrogenation other groups, e.g. a benzyloxy group on a hydroxy group or a formyl group on a hydroxymethyl group, may also be reduced or be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.
If, according to the invention, a compound of general formula I is obtained wherein R2 represents a halogen atom and/or Rj represents a halophenyl group and/or W represents a hydroxymethyl group which has been converted into a halomethyl group, it may if desired be converted by dehalogenation into a corresponding compound of general formula I wherein R2 represents a hydrogen atom and/or R^ represents a phenyl group and/or W represents a methyl group, and/or a compound of general formula I is obtained wherein W represents a carboxy group, this may if desired be converted by esterification into a corresponding compound of general formula I wherein W represents an alkoxycarbonyl or phenylalkoxycarbonyl group, and/or a compound of general formula I is obtained wherein W represents a carboxy, alkoxycarbonyl or phenylalkoxycarbonyl group, this may be converted by reduction into a corresponding compound of general formula I wherein W represents a formyl or hydroxymethyl group, and/or a compound of general formula I is obtained wherein W represents a hydroxymethyl group, this may be converted by oxidation into a corresponding compound of general formula I wherein W represents a formyl or carboxyl group, and/or a compound of general formula I is obtained wherein W represents a carboxy group, this may be converted, via a sulphonic acid hydrazide and subsequent disproportionation into a corresponding compound of general formula I wherein W represents a formyl group, and/or a racemic compound of general formula I is obtained wherein R^ has the meanings given hereinbefore, with the exception of the hydrogen atom, this may be resolved via the diastereoisomeric adducts, complexes or salts thereof into its enantiomers.
The subsequent dehalogenation is appropriately carried out using catalytic hydrogenation, e.g. with palladium/charcoal, in a suitable solvent, e.g. methanol, ethanol, tetrahydrofuran, dioxan, dimethylformamide or ethyl acetate, optionally in the presence of a base such as triethylamine and at temperatures of between 20 and 100°C, preferably at 20 to 50°C„ The subsequent esterification is appropriately carried out in a suitable solvent, e.g. in a corresponding alcohol, pyridine, toluene, methylene chloride, tetrahydrofuran or dioxan, in the presence of an acid-activating and/or dehydrating agent such as thionyl chloride, ethyl chloroformate, carbonyldiimidazole or Ν,Ν’-dicyclohexylcarbodiimide or the isourea ethers thereof, optionally in the presence of a reaction accelerator such as copper chloride, or by transesterification, e.g. with a corresponding carbonic acid diester, at temperatures of between and 100°C, but preferably at temperatures of between 20°C and the boiling temperature of the solvent used.
The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride such as lithium aluminium hydride, lithium borohydride or lithium borohydride/trimethylborate, in a suitable solvent such as diethyl ether, tetrahydro furan, dioxan or 1,2-dimethoxyethane at temperatures of between 0 and 100°C, but preferably at temperatures of between 20°C and 60°C.
The subsequent oxidation of an alcohol is preferably carried out with an oxidising agent, e.g. with pyridinium chlorochromate or manganese dioxide, in a suitable solvent such as chloroform or methylene chloride at temperatures of between -10 and 50°C, but preferably at temperatures of between 0 and 20°C.
The subsequent disproportionation of a sulphonic acid hydrazide, obtained by reacting a corresponding hydrazine with a suitable reactive carboxylic acid derivative, is carried out in the presence of a base such as sodium carbonate in a solvent such as ethylene glycol at temperatures of between 100°C and 200°C, but preferably at 160-170°C.
The subsequent racemate resolution is preferably carried out using column or HPL chromatography by forming the diastereomeric adducts or complexes in a chiral phase.
The compounds of general formula I obtained may also be converted into their salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid and suitable bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine or lysine.
The compounds of general formulae II to X used as starting materials are in some cases known from the literature or they may be obtained by methods known per se.
Thus, for example, a compound of general formula II may be obtained by reduction of a corresponding nitrile with lithium aluminium hydride or with catalytically activated hydrogen, by reacting a corresponding nitrile with a suitable 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 or with nascent hydrogen, by hydrolysis or hydrazinolysis 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 reducing a corresponding oxime with lithium aluminium hydride, with catalytically activated or nascent hydrogen, by reduction of a corresponding N-benzyl or N-l-phenylethyl-Schiffus base, e.g. with a complex metal hydride in ether or tetrahydrofuran at temperatures of between -78°C and the boiling temperature of the solvent used and subsequently splitting of the benzyl or 1-phenylethyl group by catalytic hydrogenation by a Ritter reaction of a corresponding alcohol with potassium cyanide in sulfuric acid, or by a Hofmann, Curtius, Lossen or Schmidt degradation of a corresponding compound.
An amine of general formula II thus obtained with a chiral centre may be resolved into the enantiomers thereof by racemate resolution, e.g. using fractional crystallisation of the diastereoisomeric salts with optically active acids and subsequent decomposing of the salts or by column or HPL chromatography, optionally in the form of the acyl derivative, or by forming diastereoisomeric compounds, then separating them and subsequently splitting them.
Moreover, an optically active amine of general formula II may also be prepared by enantioselective reduction of a corresponding ketimine using complex boro- or aluminium hydrides in which some of the hydride hydrogen atoms are replaced by optically active alkoxide groups, or using hydrogen in the presence of a suitable chiral hydrogenation catalyst or analogously starting from a corresponding Nbenzyl or N-(1-phenethyl)-ketimine or from a corresponding N-acyl-ketimine or enamide and optionally subsequently splitting off the benzyl, 1-phenethyl or acyl group.
Moreover, an optically active amine of general formula II may also be prepared by diastereoselective reduction of a corresponding ketimine or hydrazone chirally substituted at the nitrogen atom by means of complex or non-complex boro- or aluminium hydrides wherein some of the hydride hydrogens may optionally be replaced by corresponding alkoxide, phenoxide or alkyl groups, or means of hydrogen in the presence of a suitable hydrogenation catalyst and optionally subsequently splitting off the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.
Furthermore, an optically active amine of general formula II may also be prepared by diastereoselective addition of a correspond organometallic compound, preferably a Grignard or lithium compound, to a corresponding aldimine chirally substituted at the nitrogen atom, by subsequent hydrolysis and optionally subsequent splitting off the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.
The compounds of general formulae IV, VII and VIII used as starting materials may be obtained by reacting a corresponding amine with a corresponding carboxylic acid or a reactive derivative thereof and optionally subsequently splitting off any protecting group used.
A compound of general formula V used as starting material may be obtained by reducing a corresponding carbonyl compound or by reacting a corresponding carbonyl compound with a corresponding Grignard or lithium reagent.
A compound of general formula X used as scarfing material may be obtained by acylation of a corresponding imino compoud or an organometallic complex thereof with a corresponding carboxylic acid or a reactive derivative thereof and optionally subsequently splitting an ester group.
As already mentioned hereinbefore, the new compounds of general formula I have valuable pharmacological properties, namely an effect on intermediate metabolism, but particularly a hypoglycaemic effect.
The following compounds, for example: A = 2-methoxy-4-[N~(1-(2-piperidino-phenyl)-1ethyl)-aminocarbonylmethyl]-benzoic acid, B = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1butyl)-aminocarbonyImethyl]-benzoic acid, C = 2-methoxy-4"[N-(a-phenyi-2-piperidino-benzyl) aminocarbonyImethyl]-benzoic acid, D = 2-ethoxy-4~[N-(c-phenyl-2-piperidino-benzyl)aminocarbonyImethyl]-benzoic acid, E = (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)1-butyl)-aminocarbonyimethyl]-benzoic acid, F = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1ethyl)-aminocarbonyImethyl]-benzoic acid, G = sodium 2-ethoxy-4-[N-(1-(2-pyrrolidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate, H = 2-ethoxy-4-{N-(1-(2-hexamethylenimino-phenyl)1-butyl)-aminocarbonylmethyl]-benzoic acid, I = 2-methoxy-4-lN-(1-(2-piperidino-phenyl)-1butyl)-aminocarbonylmethylj-benzoic acid, K = 2-ethoxy-4-[N-(l-(2-piperidino-phenyl)-1pentyl)-aminocarbonylmethyl]-benzoic acid and I. = 2-ethoxy-4-[N-(4-methyl-a-phenyl-2-piper idinobenzyl) -aminocarbonylmethyl]-benzoic acid were tested for their hypoglycaemic properties as follows: Hypoglycaemic Effect The hypoglycaemic effect of the test substances was tested on female rats of a particular strain weighing from 180-220 g which had been fasted for 24 hours before the start of the test. The test substances were suspended in 1.5¾ methyl cellulose immediately before the start of the test and administered by oesophageal tube.
Blood samples were taken immediately before the administration of the substance and 1, 2, 3 and 4 hours afterwards, in each case from the retroorbital Venous plexus. 50 pi of each sample were deprotenated with 0.5 ml of 0.33 N perchloric acid and centrifuged.
The glucose in the supernatant was measured using the hexokinase method with the aid of an analytical photometer. The statistical evaluation was made using the t-test according to Student with p = 0.05 as the limit of significance.
The following table shows the values found in percent compared with the control: Substance 1 1 mg/kg 2 3 4 h 1 0.5 mg/kg 2 3 4 h Λ -37 -46 -23 -14 B -38 -49 -38 -33 -43 -36 -34 -35 C -38 -41 -38 -34 D -42 -54 -37 -34 E -40 -39 -36 -36 F -44 -44 -40 -30 G -40 -33 -30 -17 H -42 -34 -18 n. s T -42 -39 -37 -30 K -41 -45 -38 -39 L -44 -41 -35 -27 n.s. = not statistically significant In the tests for hypogiycaernic activity of the substances# 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 2,000 mg/kg p.o. (suspension in 1% methyl cellulose) of substances B and D to 5 male and 5 female mice# only one animal in this group died during the observation period of 14 days.
In the light 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# optionally together with other active substances# in the usual galenic preparations such as tablets# coated tablets# capsules# powders or suspension. The single dose in adults is from 1-50 mg# preferably 2.5-20 mg# once or twice a day.
The Examples which follow are intended to illustrate the invention: Example 1 Ethyl 2-ethoxy-4-[N-(1- (2-piperidino-phenyl)-1butvl)aminocarbonylmethyl]-benzoate To a solution of 1.84 g (7.9 mmol) of 1-(2piperidinophenyl)-1-butylamine in 19 ml of acetonitrile, are added 2 g (7.9 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 2.46 g (9.38 mmol) of triphenylphosphine, 1.7 ml (12.3 mmol) of triethylamine and 0.76 ml (7.9 mmol) of carbon tetrachloride and the mixture is stirred for two days at ambient temperature. It is then evaporated in vacuo and the residue is distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1).
Yield: 3g (81% of theory), Μρ: 113-115°C (petroleum ether) Calculated·. C 7 2.07 H 8.21 N 6.00 Found: 72.18 8.27 6.16 The following compounds were obtained analogously to Example 1: a) Methyl 2-methoxy-4-[N-(1-(2-piperidino-phenyl)1-ethyl)aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and 3-methoxy-4-methoxycarbonyl-phenyIacetic acid.
Yield: 78% of theory, Mp: 82-85°C Calculated: C 70.22 H 7.37 N 6.82 Found: 70.54 7.49 6.75 b) Ethyl 2-ethoxy-4-[N-(a-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl]-benzoate Prepared from a-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 77% of theory, Mp: 149-151°C Calculated: C 74.37 H 7.25 N 5.60 Found: 74.69 7.44 5.59 c) Methyl 2-methoxy-4-lN-(ot-phenyl-2-piper idinobenzyl)-aminocarbonyImethyl]-benzoate Prepared from e-phenyl-2-piperidino-benzylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 65% of theory, Mp: 189-190 °C Calculated: C 73.70 H 6.83 N 5.93 Found: 73.51 6.75 5.86 d) Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl) 1~ethyl)-aminocarbonvlmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and 3-ethoxy-4-ethoxycarbonyl~phenylacetic acid.
Yield: 69% of theory, Mp: 92-93 °C Calculated: C 71.21 H 7.81 N 6.36 Found: 71.29 8.03 6.58 e) Ethyl 2-ethoxy-4-[N-(1-(5-chloro-2-piperidinophenyl) -1-propyl)-aminocarbonylmethvl]-benzoate Prepared from 1-(5-chloro-2-piperidino-phenyl)1-propylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid .
Yield: 80% of theory, Mp: 110-112°C Calculated: C 66.58 H 7.24 N 5.75 Cl 7.28 Found: 66.61 7.34 5.86 7.35 f) Ethyl 2-ethoxy-4-[N-(2-piperidino-phenyl)1-pentyl)-aminocarbonyImethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1pentylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid .
Yield: 63% of theory, Mp: 113-115°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.66 8.26 5.99 q) Ethyl 2-ethoxy-4-[N-(1-(2-pyrrolidino-phenyl)1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-pyrroiidino-phenyl)-1-butylamin and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 50% of theory# Mp: 85-87°C Calculated: C 71.65 H 8.02 N 6.19 Found: 71.90 8.37 6.34 h) Ethyl 2-ethoxy-4-[N-(1-(2-(4-methyl-piperidino) phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-(4-methyl-piperidino)-phenyl) 1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 44% of theory# Mp: 127-128°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.20 8.23 5.69 i) Ethyl 2-ethoxy-4-[N-(1-(2-hexamethyleneiminophenyl)-l-butvl)-aminocarbonylmethylj-benzoate Prepared from 1-(2-hexamefchyleneiminophenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid.
Yield: 44% of theory# Mp: 97-100°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.41 8.50 5.66 k) Ethyl 2-ethoxy-4-[N-(1-(4-methyl-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methyl-2-piperidino-phenyl)1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 68% of theory, Mp: 113-114°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.36 8.31 5.91 l) Ethyl 2-ethoxy-4-jΝ-(1- (6-methyl-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(6-methyl-2-piperidino-phenyl)1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 62% of theory, Mp: 20 °C Calculated; C 72.47 H 8.39 N 5.83 Found: 72.30 8.50 5.72 m) Ethyl 2-ethoxy-4-[N-(l- (6-chloro-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(6-chloro-2-piperidino-phenyl) ~ 1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 85% of theory, Mp: 20 °C Calculated: C 67.12 H 7.44 N 5.50 Cl 7.08 Found: 67.60 7.77 5.92 7.24 n) Ethyl 2-ethoxy-4-[N-(1-(4-methoxy-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methoxy-2-piperidino-phenyl)1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 65% of theory, Mp: 109-110°C Calculated: Mol. peak m/e = 496 Found: Mol. peak m/e = 496 o) Ethyl 2-ethoxy-4-[N-(l- (5-methoxy-2-piperidinophenyl) -1-butyl)-ami nocarbonylmethyl]-benzoate Prepared from 1-(5-methoxy-2-piperidino-phenyl) 1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid .
Yield: 31% of theory, Mp: 117-120°C Calculated: Found: mol peak m/e = 436 mol peak m/e = 496 p) Ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-ethoxycarbonyl-3-hydroxy-phenylacetic acid.
Yield: 46% of theory, Mp: 133-134°C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.08 7.91 6.45 q) Methyl 2-methoxy-4-[N-(1-(2-piperidino-phenyl)1-butyl)-aminocarbonyImethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-methoxy-4-methoxycarhonyl-phenvlacetic acid.
Yield: 67% of theory, Mp: 128-131°C Calculated C 71.21 H 7.81 N 5.39 Found: 71.46 7.80 6.07 r) Ethyl 2-ethoxy-4-[N-(5-chloro-2-piperidinobenzyl) -aminocarbonyImethyl]-benzoate Prepared from 5-chloro-2-piperidino-benzylamine and 3-efchoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 65% of theory, Mp: 106-108°C Calculated C 65.41 H 6.81 N 6.10 Cl 7,73 Found: 65.81 6.89 6.11 7.62 s) Ethyl (-)-2-ethoxy-4-[N-(a-phenyl-2-piperidinobenzyl) -aminocarbonyImethyl]-benzoate Prepared from (-)-a-phenyl-2-piperidino-phenyl)1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 87% of theory, Mp: UO-lll’C Calculated mol peak m/e = 500 Found; mol peak m/e = 500 Specific rotation: [odD - -6-3° (c = 1, methanol) t) Ethyl 2-ethoxy-4-[N- (6-methyl-et-phenyl-2piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from 6-methyl-a-phenyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 39¾ of theory, Mp; <20 °C Calculated: C 74.68 H 7.44 N 5.44 Found: 74.81 7,56 5.32 u) Ethyl 2-ethoxy-4-[N-(c-(4-methyl-phenyl)2-piper idino-benzyl)-aminocarbonylmethyl]benzoate Prepared from a-(4-methyl-phenyl)-2-pxperidinobenzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 34% of theory, Mp: 150-152°C Calculated C 74.68 H 7.44 N 5.44 Found; 74.71 7.51 5.29 v) Ethyl 2-ethoxy-4-[N-(α-phenyl-2-pyrrolidinobenzvl) -aminocarbonylmethyl]-benzoate Prepared from a-phenyl-2-pyrrolxdino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 45% of theory, Mp: 85-87°C Calculated C 74.05 H 7.04 N 5.76 Found: 73.95 7.07 5.70 w) Methyl 2-methoxy-4-[N-(2-hexamethyleniminog-phenyl- benzy1)-ami nocarbonylmethyl]-benzoate Prepared from 2-hexamethylenexmino-a-phenylbenzylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 45% of theory. - 27 Mp: 181-183°C Calculated: C 74.05 H 7.04 N 5.74 Found: 74.09 6.62 5.74 x) Ethyl 2-gthoxy-4-[N~(2-hexamethyleneiminog-phenyl-benzyl)-aminocarbonylmethyl]-benzoate Prepared from 2-hexamethyleneimino-ot-phenylbenzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 41% of theory, Mp: 140~141°C Calculated: C 74.68 H 7.44 N 5.44 Found: 74.46 7.62 5.45 y) 2-Etboxv-4-[N-(1-(2-pyrrolidino-phenyl)-1butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-methyl-phenylacetic acid.
Yield: 55% of theory, Μρ: 107-108°C Calculated: C 76.43 H 8.88 N 6.86 Found: 76.38 8.99 6.97 Example 2 Ethyl ( + ) -2-ethoxy-4-[N-(1-(2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl]-benzoate 0.90 g (3.57 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.61 g (3.73 mmol) of N,N'carbonyldiimidazole are refluxed for 5 hours in 9 ml of absolute tetrahydrofuran. Then a solution of 0.85 g (3.67 mmol) of (+)-1-(2-piperidino-phenyl)1-butylamine (ee = 94.2) in 9 ml of absolute tetrahydrofuran is added and the mixture is refluxed for 3 hours. It is concentrated in vacuo and the evaporation residue is distributed between chloroform and water.
The organic phase is dried, filtered and evaporated in vacuo. The evaporated extract is purified by column chromatography on silic gel (toluene/acetone = 10:1).
Yield: 0.85 g (51.2% of theory), Mp: 118-119°C (petrolum efcher/toluene = 50/2) Calculated: C 72.07 H 8.21 N 6.00 Found: 72.43 8.34 6.00 Specific rotation: [α]θ = + 7.1° (c = 1.06 in methanol) The following compounds were obtained analogously to Example 2; Example 3 Ethyl 2-ethoxy-4~[N-(a-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate To a mixture of 30 ml of concentrated sulphuric acid and 30 ml of o-dichlorobenzene, a solution of 4.7 g (20 mmol) of ethyl 2-ethoxy-4-cyanomethylbenzoate and 5.3 g (20 mmol) of c-phenyl-2-piperidinobenzyl alcohol in 30 ml of O-dichlorobenzene is added dropwise at 32-25°C. The mixture is stirred for 2 hours at ambient temperature. Then the odichlorobenzene phase is separated off and the residue is added to ice. After it has been made alkaline with soda solution, it is extracted with chloroform. The extracts are dried over magnesium sulphate and concentrated by evaporation. The residue is trituated with petroleum ether (30-60°), filtered off and purified on silica gel (toluene/ethyl acetate = 5.1) by column chromatography.
Yield; 5.6 g (56% of theory), Mp: 150-151°C Calculated: C 74,37 H 7.25 N 5.60 Found: 74.59 7.41 5.45 The following compounds were obtained analogously to Example 3: a) Methyl 2-methoxy-4-lN-(c-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate Prepared from ct-phenyl-2-piper idino-benzyl alcohol and methyl 4-cyanomethyl-2-methoxy-benzoate. Yield: 34% of theory, M.p.: 189-191°C Calculated: C 73.70 H 6.83 N 5.93 Found: 73-63 7.05 5.95 b) 2-Ethoxy-4-[N-(a-phenyl-2-piperidino-benzyl)aminocarbonyImethyl]benzoic acid Prepared from c.-phenyl-2-piperidino-benzyl alcohol and 2-etnoxy-4-cyanomethyl-benzoic acid. Extraction at pH 5.
Yield: 47% of theory, M.p.: 154-155°C Calculated: C 73.70 H 6.83 N 5.93 Found: 73.61 6.72 5.65 c) 2-Methoxy-4-[N-(G-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoic acid Prepared from os-phenyl-2-piper idino-benzyl alcohol and 4-cyanomethyl-2-methoxy-benzoic acid. Extraction at pH 5.
Yield: 30% of theory, M.p.: 202-204°C Calculated: C 73.34 H 6.59 N 6.11 Found: 73.17 6.41 6.05 d) Ethyl 2-ethoxy-4-[N- (1-(2-piper idi no-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butanol and ethyl 2-ethoxy-4-cyanomethyl-benzoate.
Yield: 5% of theory, M.p. : 112-114 °C Calculated: C 72.07 H 8.21 N 6.00 Found: 72.29 8.46 6.31 e) Methyl 2-methoxy-4-[N-(1-(2-piperidino-phenyl)1-ethyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-ethanol and methyl 4-cyanomethyl-2-methoxy~benzoate.
Yield: 18% of theory, M.p.: 83-85°C Calculated: C 70.22 H 7.37 N 6,82 Found: 70.60 7.29 6.97 f) 2-Methoxy-4-[N-(1-(2-piperidino-phenyl)-1ethyl)-aminocarbonylmethyl]-benzoic acid Prepared from 1-(2-piperidino-phenyl)-1-ethanol and 4-cyanomethyl-2-methoxy-benzoic acid. Extraction at pH 5.5.
Yield: 21% of theory, M.p.: 118-120°C Calculated: m/e = 396 Found: m/e = 396 g) Ethyl 2-ethoxy-4-[N-(4-methyl-K-phenyl-2piperidino-benzyl)-aminocarbonylmethyl]-benzoat Prepared from 4-methyl-a-phenyl-2-piperidinobenzyl alcohol and ethyl 2-ethoxy-4-cyanomethylbenzoate.
Yield: 46% of theory, M.p.: 124-125°C Calculated: C 74.68 H 7.44 N 5.44 Found: 74.81 7.56 5.32 h) Methyl 2-methoxy-4-[N-(a-(4-chloro-phenyl) 2-piperidino-benzyl)-aminocarbonyImethyl]benzoate Prepared from a-(4-chlorophenyl)-2-piperidinobenzyl alcohol and methyl 2-methoxy-4-cyanomethylbenzoate.
Yield: 47% of theory, M.p. : 176-178 °C Calculated: C 68.70 H 6.17 N 5.53 Cl 6.99 Found: 69.05 5.93 5.76 7.10 i) Ethyl 2-hydroxv-4-1N-(a-phenvl-2-piperidinobenzyl) -aminocarbonylmethyl]-benzoate Prepared from es-phenyl-2-piperidino-benzyi alcohol and ethyl 4-cyanomethyl-2-hydroxy-benzoate. Yield; 78% of theory, M.p.: 172-174°C Calculated: C 73.70 H 6.83 N 5.93 Found: 73.80 6.81 5.83 Example 4 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid A mixture of 2 g (4.3 mmol) of ethyl 2-ethoxy4-[N-(1-(2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate and 5.3 ml of IN sodium hydroxide solution in 20 ml of ethanol is stirred for 3 hours at 60 °C, then neutralised with 5.3 ml of IN hydrochloric acid and the ethanol is evaporated off in vacuo.
The residue is distributed between ethyl acetate and water; the organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is crystallised from petroleum ether with the addition of ethanol.
Yield: 1.3 g (69% of theory), M.p.: 88-90°C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.62 7.73 6.54 The following compounds were obtained analogously to Example 4; a) 2-Methoxy-4-[N-(1-(2-piperidino-phenyl)-1ethyl)-aminocarbonylmethyl]-benzoic acid x 0.67 H2O Prepared from methyl 2-methoxy-4-[N-(1-(2piperidi no-phenyl)-1-ethyl)-aminocarbonylmethyl]benzoate.
Yield: 60% of theory, · M.p.: 116-120°C Calculated: C 67.62 H 7.07 N 6.85 Found: 67.60 6.87 6.55 b) 2-Ethoxy-4-[N-(c-phenyl-2-piperidino-benzyl)aminocar bonyImethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(R-phenyl2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate.
Yield: 89% of theory, M.p.: 155-156°C Calculated: C 73.70 H 6.83 N 5.93 Found: 73.60 6.96 6.12 c) 2-Methoxy-4-{N-(κ-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-[N-(e-phenyl2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate. Yield: 68% of theory, M.p. : 202-204 °C Calculated: C 73.34 H 6.59 N 6.11 Found: 73.60 6.77 6.20 d) 2-Ethoxy-4 -[N-(1-(5-chloro-2-piper idino-phenyl) 1-propyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(5-chloro2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]ben zoate.
Yield: 74% of theory, M.p.: 115-118°C Calculated: C 65.42 H 6.81 N 6.10 Cl 7.72 Found: 65.54 6.94 5.81 7.89 e) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1propyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-1-propyl)-aminocarbonylmethyl]-benzoate.
Yield: 73% of theory, M.p.: 81-83°C - 33 Calculated; C 70.73 H 7.60 N 6.60 Found; 70.90 7.47 6.77 f) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl) -1pentyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidinophenyl) -1-pentyl)-aminocarbonylmethyl]-benzoate.
Yield; 92% of theory, M.p.: 82-85°C Calculated: C 71.65 H 8.02 N 6.19 Found: 71.45 8.01 6.13 g) 2-Ethoxy-4-[H-(1-(2-pyrrolidino-phenyl)-1butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N- (1- (2-pyrrolidino~ phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate.
Yield: 77% of theory, M.p.; 120-123°C Calculated: C 70.33 H 7.60 N 6.60 Found: 70.71 7.44 6.33 h) 2-Ethoxy-4-[N-(1-(2-(4-methy1-piperidino) phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-(4methyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]benzoate.
Yield: 71% of theory, M.p.: 83-85°C Calculated; C 71,65 H 8.02 N 6.19 Found: 71.60 7.94 6.09 i) 2-Ethoxy-4-[N-(1-(2-hexamethyleneimino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[M-(1-(2-hexamethyleneimino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoate.
Yield: 81% of theory.
M.p.: 101-105°C Calculated: C 71.65 H 8.02 N 6.19 Found: 71.31 7.79 6.18 k) 2-Ethoxy-4- [N- (1- (6-chloro-2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(6-chloro2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoate.
Yield: 82% of theory, M.p.: 133-136°C Calculated: C 66.02 H 7.03 N 5.92 Cl 7.50 Found: 66.48 7.47 5.98 7.88 l) 2-Ethoxy-4-[N-(1-(4-methoxy-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy~4-[N-(1-(4-methoxy 2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoate.
Yield: 81% of theory, M.p. : 98-100 °C Calculated: C 69.21 H 7.74 N 5.98 Found: 69.12 7.62 5.78 m) 2-Ethoxy-4-[N-(1-(5-methoxy-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(5-methoxy 2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoate.
Yield: 74% of theory, M.p.: 145-148°C Calculated: C 69.21 H 7.74 N 5.98 Found: 69.00 7.65 5.89 n) 2-Methoxy-4-[N-(1-(2-piperidino-phenyl)-1butyl)-aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-(N-(l-(2piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]ben zoace.
Yield: 85% of theory, M.p.: 140-143°C Calculated: C 70.73 H 7.60 N 6.60 Found: 70.49 7.58 6.31 o) 2-Ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)aminocarbonylmethyl]-benzoic acid x 0.5 H^O Prepared from ethyl 2-ethoxy-4-[N-(5-chIoro2-piperidi no-be nzy1) -am inocar bonyIme t hy1[-be n zoa t e. Yield: 93% of theory, M.p.: 153-155°C Calculated: C 62.79 H 6.41 N 6.36 Cl 8.06 Found: 63.21 6.34 5.89 8.46 p) 2-Ethoxy-4 - [ N- (2-piper idino-benzyl)-aminocarbonyl methyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(2-piperidinobenzyl) -aminocarbonylmethyl] -benzoate .
Yield: 77% of theory, M.p.: 108-109 °C Calculated: C 69.68 H 7.12 N 7.07 Found: 70.00 7.99 7.31 I q) 2-Hydroxy-4-[N-(1- (2-piper idino-phenyl)-1butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-hydroxy-4-[ N-(1-( 2piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoate .
Yield: 61% of theory, M.p.: 136-138 °C Calculated: C 70.22 H 7.37 N 6.82 Found: 70.40 7.64 6.60 r) 2-Allyloxy-4-[N-(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-aliyloxy-4-[N-(1-(2piperidino-phenvl)-1-bufcyl)-aminocarbonylmethyl]benzoate.
Yield: 92% of theory# M.p.: 110-112°C Calculated: C 71.97 H 7.61 N 6.22 Found; 71.90 7.62 6.21 s) ( + )-2-Efchoxy-4-[N-(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl (+)-2-ethoxy-4-[N-(1(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] · benzoate.
Yield: 81% of theory, M.p.: 122-123°C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.19 7.77 6.29 Specific rotation [κ]θ = + 4.75° (c = 1.03 in methanol) t) 2-Ethoxy-4-[N-(4-methyl-r-phenyl-2-pxperidino benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(4-mefchylα-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate.
Yield: 41% of theory, M.p.: 127-129°C Calculated: C 74.05 H 7.04 N 5.76 Found; 73.80 7.09 5.74 u) 2-Ethoxy-4-[N-(6-methyl-c-phenyl-2-piper idi no benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(6-methyla-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate .
Yield: 40% of theory, M.p.: 118-121°C Calculated: C 74.05 H 7.04 N 5.76 Found: 73.71 6.92 5.76 v) 2-Ethoxy-4-[N- (c- (4-methyl-phenyl) -2~piperidinobenzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(cs-(4-methylphenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate .
Yield: 94% of theory, M.p.: 148-151°C Calculated: C 74.05 H 7.04 N 5.76 Found: 74.20 7.15 5.81 w) 2-Methoxy-4-[N- (ce- (4-chloro-phenyl) -2-piperidinobenzyl)-aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-(N-(Ci-(4-’ chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate .
Yield: 77% of theory, M.p.: 177-180°C Calculated: C 68.21 H 5.93 N 5.68 Cl 7.19 Found: 68.10 5.78 5.53 7.43 x) 2-Ethoxy-4-[M-(cs-phenyl-2-pyr rol idi no-benzyl) aminocarbonyImethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(a-phenyl2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoate.
Yield: 67% of theory, M.p.: 141-143°C Calculated: C 73.34 H 6.59 N 6.11 Found; 73.33 6.74 6.02 y) 2-Methoxy-4-N-(2-hexamethyleneimino-a-phenylbenzyl)-aminocar bonyImethyl]-benzoic acid Prepared from methyl 2-methoxy-4-N-(2-hexamethyleneimino-a-phenyl-benzyi)-aminocarbonylmethyl]-benzoate. Yield: 90% of theory, M.p.: 154-156°C Calculated: C 73.70 H 6.83 N 5.93 Found: 73.70 7.00 5.95 z) 2-Ethoxy-4-[N- (2-hexamethyleneimino-a-phenylbenzvl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(2-hexamethylene imino-κ-phenyl-benzy1)-aminocarbonylmethyl]-benzoate. Yield: 75% of theory, M.p.; 139-141°C Calculated: C 74.05 H 7.04 N 5.76 Found: 73.90 7.14 5.79 aa) 2-Hydroxy~4-[N-(g-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-hydroxy-4~[N-(g-phenyl2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate by saponification with 4 equivalents of IN sodium hydroxide solution in ethanol/dioxan.
Yield: 35% of theory, M.p.: 222-224°C Calculated: C 72.95 H 6.35 N 6.30 Found: 73.00 6.54 6.28 ab) 2-Allyloxy-4-[N- (α-phenyl-2-piper idino-benzyl) aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-allyIoxy-4-[N-(a-phenyl2-piper idino-benzyl)-ami nocarbonylmethyl]-benzoate. Yield: 69% of theory, M.p.: 172-173°C Calculated: C 74.35 H 6.66 N 5.78 Found:' 74.11 6.50 5.74 ac) (-)-2-Ethoxy-4-[N-(a-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl]-benzoic acid Prepared from ethyl (-)-2-ethoxy-4-[N-(apheny1-2-piper idino-benzyl)-aminocarbonylmethyl]benzoate.
Yield: 89% of theory, M.p.: 90-95 °C Calculated: C 73.70 H 6.83 Found: 73.59 6.81 Spec.! tie rotation: icj^ N 5.93 5.83 -2.2° (c = 1 in methanol) Example 5 Sodium salt of 2-ethoxv-4-[N-(1-(2-piperidino-phenyl)1- ethyl)-aminocarbonylmethyl]-benzoic acid x 1.5 Η2θ Prepared from ethyl 2-ethoxy-4-(N-(1-(2-piperidino phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoate analogously to Example 4. After purification by column chromatography the evaporation residue obtained is dissolved in ethanol and mixed with 1 equivalent of IN sodium hydroxide solution. By evaporation in vacuo and trituration with acetone, the crystalline sodium salt is obtained.
Yield: 76% of theory, M.p.: 242-244°C Calculated: C 62.73 H 7.01 N 6.01 Found: 62.74 7.17 6.05 The following compounds were obtained analogously to Example 5: a) Sodium salt of 2-ethoxv-4-[N-(1-(4-methyl2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoic acid x 0.5 H^O Prepared from ethyl 2-ethoxy-4-[N-(1-(4-methyl2- piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoate .
Yield: 72% of theory, M.p.; 255-260°C Calculated: C 67.06 H 7.50 N 5.79 Found: 66.94 7.28 5.50 b) Sodium salt of 2-ethoxy-4-[N-(1-(6-methyl2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl benzoic acid x 2.5 H^O Prepared from ethyl 2-ethoxy-4-(N-(1-(6-methyl2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoate.
Yield: 81% of theory, M.p.: 232-240°C Calculated: C 62.39 H 7.75 N 5.39 Found: 62.22 7.46 5.61 c) Sodium salt of 2-ethoxy-4-[N-(1-(2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate.
Yield: 87% of theory, M.p.: 250-258°C Calculated: C 67.79 H 7.22 N 6.08 Found: 67.60 7.37 6.04 d) Sodium salt of 2-ethoxy-4-[N-(a-phenyl-2piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(a-phenyl2-piper idino-benzyl)-aminocarbonylmethyl]-benzoate . Yield: 89% of theory, M.p.: 233-235°C Calculated: C 70.42 H 6.32 N 5.67 Found: 70.20 6.41 5.49 Example 6 Ethyl 2-hydroxy-4-[N-(g-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate To a stirred solution of 2 g (4 mmol) of ethyl 2-ethoxy-4- [N- (a-phenyl-2-piper idino-benzyl) aminocarbonylmethyl]-benzoate in 20 ml of 1,2-dichloroethane, 1 ml (10.4 mmol) of boron tribromide is added dropwise at -20 °C under anhydrous conditions.
The mixture is allowed to reach ambient temperature and then stirred for a further 17 hours. It is then poured into ethanol, evaporated in vacuo, ice is added and the resulting mixture is distributed between chloroform and water. The organic extract is dried and filtered and evaporated in vacuo.
The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 5/1). Yield: 0.37 g (21% of theory), M.p.: 172-173°C Calculated: C 73.70 H 6.83 N 5.93 Found: 73.95 7.05 6.12 The following compounds were obtained analogously to Example 6: a) 2-Hydroxy-4-[N-(a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoic acid Prepared from 2-ethoxy-4-[N- (a-phenyl-2-piperidino benzyl)-aminocarbonylmethyl]-benzoic acid.
Yield: 40% of theory, M.p.-. 221-223°C Calculated: C 72.95 H 6.35 N 6.30 Found: 72.68 6.45 6.49 b) Ethyl 2-hydroxy-4-(N-(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 19% of theory, M.p.: 132-134°C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.43 7.91 6.55 c) 2-Hydroxy-4 -[N-(1-(2-pi per i d ino-phenyl)-1butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 42% of theory, M.p.: 136-137°C Calculated: C 70.22 Found: 70.19 H 7.37 7.39 N 6.82 6.99 Example 7 tert.Butyl 2-ethoxy-4-[N-(1- (2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate A mixture of 1.98 g (9.6 mmol) of Ν,Ν-dicyclohexylcarbodiimide, 1.06 ml (11.2 mmol) of absolute tert.butanol and 0.020 g (0.20 mmol) of copper(I) chloride is stirred for 60 hours at ambient temperature, then 6.6 ml of methylene chloride are added and the resulting solution is added dropwise to a solution of 0.44 g (1 mmol) of 2-ethoxy-4-[N- (1-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoic acid in 15 ml of methylene chloride. After 60 hours' stirring at 20 °C, the precipitate is filtered off, washed with methylene chloride and the methylene chloride solution is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethyl acetate = 9/1) .
Yield: 0.30 g (60% of theory), M.p.: 74-77°C (from petroleum ether) Calculated: C 72.84 H 8.56 N 5.66 Found: 73.00 8.65 5.79 Example 8 Ethyl 2-allyloxy-4-1N-(a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate To a solution of 1.1 g (2.3 mmol) of ethyl 2-hydroxy—4 -[N-(a-phenyl-2-piperidino-benzyl)-aminocar bonylmethyl]-benzoate in 10 ml of anhydrous dimethylformamide are added 0.10 g (2.3 mmol) of sodium hydride (55% in oil) and the resulting mixture is stirred for 0.5 hours at ambient temperature.
Then a solution of 0.27 ml (2.3 mmol) of allyl bromide in 5 ml of anhydrous dimethylformamide is added dropwise and the mixture is stirred for 5 hours at ambient temperature. It is evaporated in vacuo, the residue is distributed between dilute sodium hydroxide solution and chloroform, the organic extract is dried, filtered and evaporated in vacuo.
The evaporation residue is recrystallised from acetonitrile and then from ethanol.
Yield: 0.55 g ( 4G % of theory), M.p.: 117-119°C Calculated: C 74.97 H 7.08 N 5.47 Found: 74.90 7.14 5.38 The following compound was obtained analogously to Example 8: a) Ethyl 2-allyloxy-4-[N-(1-(2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-hydroxy-4-[N-(1-(2piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoate using allyl bromide.
Yield: 72% of theory, M.p.: 105-106°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.90 7.90 5.87 Example 9 Ethyl 2-ethoxy-4-[N-(2-piperidino-benzyl)-aminocarbonyl methyl]-benzoate 1.0 g (2.18 mmol) of ethyl 2-ethoxy-4-[N(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate is hydrogenated in 20 ml of ethanol with _ 0.5 g of 10% palladium/charcoal at 50°C under 1 bar of hydrogen for 45 minutes. It is filtered over kieselguhr, evaporated in vacuo and purified by column chromatography on silica gel (chloroform/meth anol - 10/1) .
Yield: 0.71 g (77% of theory), M.p.: 83-84°C (from petroleum ether) Calculated: C 70.73 H 7.60 N 6.60 Found: 70.89 7.66 6.76 The following compound was obtained analogously to Example 9: a) Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)1-propyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-ethoxy-4-[N-(1-(5-chloro2-piperi di no-phenyl)-1-propyl)-aminocarbonylmethyl]benzoate .
Yield: 74% of theory, M.p.: 115-117°C Calculated: C 71.55 H 8.02 N 6.19 Found: 71.47 8.11 6.25 Example 10 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl1-butyl)-aminocarbonylmethyl]-benzoic acid i) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3methyl-l-buten-1-yl)-aminocarbonylmethyl] benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-3-methyl-l-buten-l-yl)-aminocarbonylmethyl]benzoate Yield: 85% of theory, M.p.: 110-113°C Calculated: C 71.97 H 7.61 N 6.22 Found: 71.92 7.80 5.98 ii) 0.21 g (0.39 mmol) of 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-3-methyl-l-buten-l-yl)-aminocarbonylmethyl]benzoic acid are hydrogenated in 10 ml of absolute ethanol with 0.10 g of 10% palladium/charcoal at 50°C under 1 bar of hydrogen for 7 hours. The mixture is filtered over kieselguhr, evaporated in vacuo and the residue is purified by column chromatography on silica gel (chloroform/methanol - 10/1) .
Yield: 0.10 g (47% of theory), M.p.: 90-92°C Calculated: C 71.65 H 8,02 N 6.19 Found: 71.50 8,12 6.45 The following compound was obtained analogously to Example 10: a) Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino phenyl)-3-methyl-l-buten-l-yl)-aminocarbonylmethyl]benzoate, melting point 125-126°C [prepared from (2-piperidino-phenyl)-isobutyl-ketimine and 3-ethoxy4-ethoxycarbonyl-phenyl-acetic acid analogously to Example 1].
Yield: 51% of theory, M.p.: 139-141°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.30 8.20 5.87 Example 11 2-Ethoxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzyl alcohol To 0.28 g (7.4 mmol) of lithium aluminium hydride in 50 ml of absolute tetrahydrofuran, a solution of 1.8 g (3.6 mmol) of ethyl 2-ethoxy4-IN-(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl] benzoate in 20 ml of absolute tetrahydrofuran are added dropwise at -5°C and the mixture is stirred for 3 hours at 0°C. It is then diluted with absolute ether and 4N sodium hydroxide solution is added.
The mixture is filtered over kieselguhr, the residue is concentrated by evaporation in vacuo and purified by column chromatography on silica gel (toluene/ethyl acetate = 2/1).
Yield: 0.51 g (31% of theory), M.p.: 133-135°C Calculated: C 75.95 H 7.47 N 6.11 Found: 75.97 7.55 5.95 The following compound was obtained analogously to Example 11: a) 2-Ethoxy-4 -(N-(1-(2-piperidi no-phenyl)-1butyl)-aminocarbonylmethyl]-benzyl alcohol Prepared from ethyl 2-ethoxy-4-IN-(1-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate by reduction with lithium borohydride in boiling tetrahydrofuran with the addition of 10% of trimethyl borate.
Yield: 68% of theory, M.p.: 112-115°C Calculated: C 73.55 H 8.55 N 6.60 Found: 73.60 8.38 6.69 Example 12 2-Ethoxy-4-[N-(a-phenyl-2-piper idi no-benzyl)-aminocarbonylmethyl] -benzaldehyde To a stirred solution of 0.28 g (1.3 mmol) of pyridinium chlorochromate in 5 ml of chloroform, a solution of 0.4 g (0.87 mmol) of 2-ethoxy-4-[N(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]benzyl alcohol is added dropwise at ambient temperature. The mixture is stirred overnight at ambient temperature, evaporated in vacuo, mixed with ether, filtered, evaporated in vacuo and purified by column chromatography on silica gel (toluene/ethyl acetate = 2/1).
Yield: 0.16 g (40% of theory), M.p.: 154-156°C Calculated: C 76.29 H 7.06 N 6.14 Found: 76.30 7.15 6.10 The following compound was obtained analogously to Example 12: a) 2-Ethoxy-4-[N-(1-(2-piper idi no-phenyl)-1butyl)-aminocarbonylmethyl]-benzaldehyde - 47 ι Prepared from 2-ethoxy-4-[N-(1-(2-piperidinophenyl )-1-butyl)-aminocarbonylmethyl]-benzyl alcohol. Yield: 47% of theory, M.p.: 109-lll°C Calculated: C 73 .90χ^Η 8.11 N 6.63 Found: 74<22 8,14 6.73 '/' Example 13 2-Ethoxy-4-[N-(a-phenyl-2-piper idino-benzyl)-aminocarbony! methyl I-benzaldehyde ./ 0.67 g (5.6 mmol) of sodium carbonate are heated together with 6 ml of ethylene glycol in a bath at 170°C and then, with rapid stirring, 0.70 g (1.1 mmol) of N^-l2-ethoxy-4-[N-(a-phenyl2-piperidino-benzyl)-aminocarbonylmethyl]-benzoyl]2 N -tosyl-hydrazine are added thereto within a minute, and a violent evolution of gas is observed. Then the mixture is heated for a further 2 minutes at 170 °C and poured immediately onto ice. It is extracted with ether, dried, filtered and the ether solution is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 2/1).
Yield: 0.25 g (50% of theory), M.p.: 153-156°C Calculated: C 76.29 H 7.06 N 6.14 Found: 76.42 7.33 6.28 The following compound was obtained analogously to Example 13: a) 2-E thoxy-4 -[N-(1-(2-piperidino-phenyl)-1butyl)-ami nocar bonyImethyl]-benzaldehyde Prepared from N^-I2-ethoxy-4-IN-(1-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoyl]2 N -tosyl-hydrazine.
Yield: 51% of theory, M.p.: 108-lll°C Calculated: C 73.90 H 8.11 n 6.63 Found: 73.79 8.29 6.75 Example 14 Benzyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl) -1butyl)-aminocarbonylmethyl]-benzoate 0.35 g (0.8 mmol) of 2-ethoxy-4-[N-(1-(2piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoic acid are refluxed together with 0.15 g (0.9 mmol) of Ν,N’-carbonyldiimidazole in 15 ml of absolute tetrahydrofuran for 2 hours. Then 1.03 ml (10 mmol) of benzyl alcohol are added and the mixture is refluxed for 3.5 hours. It is evaporated in vacuo and purified by column chromatography on silica gel (chloroform/acetone = 9/1) .
Yield: 0.10 g (23.6% of theory), M.p.: -<20 °C Calculated: Mol peak m/e = 528 Found; Mol peak m/e - 528 Example 15 Ethyl ( + ) - 2-ethoxy-4-[N-(1-(2-piper idi no-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate and Ethyl (-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate mg of ethyl (+)-2-ethoxy-4-[N-(1-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate are added in single doses of 0.02 mg_to a chiral phase HPLC column made by Messrs. Baker, in which (R)-N-3,5-dinitrobenzoyl-phenylglycine is covalently bound to aminopropyl-silica gel (5 pm particle size, spherical, pore size 60S; 4.6 mm internal diameter, 25 cm in length).
Flow agent: hexane/ethanol = 100/5; Flow rate: 0.75 ml/minufce; Temperature: 2^2°C„* The fractions eluted at 31.2 minutes and at 32.9 minutes (UV detection at 254 nm) are separately recovered, collected and evaporated in vacuo.
The following is obtained from the 31.2 minute eluate: 7.5 mg of ethyl ( + )-2-ethoxy-4-1N-(1-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate M.p.: 117-119°C 9Π Specific rotation: [α]β ~ + 7.0° (c = 1.03 in methanol) The following is obtained from the 32.9 minute eluate: 9.4 mg of ethyl (-)-2-ethoxy-4-[N-(1-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl]-benzoate M.p.: 115-117°C Specific rotation: lalD= + 6-9° (c = 1.02 in methanol) Analogously to Example 15 a) ethyl (—)-2-ethoxy-4-[N- (a-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl]-benzoate can be resolved into its (+) enantiomer and its (-) enantiomer.
Example 16 2-Ethoxy-4-1 N-(1-(2-piperidino-phenyl)-1-butyl) aminocarbonyl]-toluene 0.54 g (1.2 mmol) of 2-ethoxy-4-[N-(1-(2piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzyl chloride [melting point 114-115°C, prepared from 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzyl alcohol using thionyl chloride in chloroform] in 10 ml of absolute dioxan are hydrogenated for 3 hours at 20°C and under 5 bar of hydrogen. The mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and aqueous sodium carbonate solution.
The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone = 19/1).
Yield: 0.23g (47% of theory), M.p.: 107-108°C Calculated: C 76.43 H 8.88 N 6.86 Found: 76.40 8.88 6.90 Example 17 2-Ethoxy-4-(N-(1-(2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid 100 mg (0.20 mmol) of tert.butyl 2-ethoxy4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl]benzoate are refluxed in 5 ml of benzene together with a few crystals of p-toluenesulphonic acid hydrate for half a day. Then the desired product is obtained, according to a thin layer chromatograph, by the R- value and mass spectrum.
JL M.p.: 87-89°C Calculated: m/e = 438 Found: m/e = 438 Example 18 2-Ethoxy-4-[N-(1-(2-piper idino-phenyl)-1-butylami nocar bony Ime thyl] -benzoic acid 0.25 g (0.47 mmol) of benzyl 2-ethoxy-4-[N(1-(2-piperidino-phenyl)-1-buty1-aminocarbonyImethyl]benzoate are hydrogenated in 10 ml of ethanol with 0.12 g of 10% palladium/charcoal at 50°C under 5 bar of hydrogen. After 5 hours the catalyst is filtered off over kieselguhr and the filtrate is evaporated in vacuo. The evaporation residue is crystallised from petroleum ether/ethanol.
Yield: 0.14 g (70% of theory), M.p.: 87-90°C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.46 7.95 6.51 Example 19 Ethyl 2-ethoxy-4-[ N-(1-(2-piperidino-phenyl)-1n-hexyl)-aminocar bonylmethyl-benzoate Prepared from 1-(2-piperidino-phenyl)-1-nhexylamine and 3-efchoxy-4-ethoxycarbonyl-phenylacetic acid analogousely to Example 1.
Yield: 43% of theory, M.p.: 101-105°C Calculated: C 72.84 H 8.56 N 5.66 Found: 72.72 8.52 5.63 Example 20 2-Ethoxy-4-[N-(1-(2-piperidi no-phenyl)-1-n-hexyl)aminocarbonylmethyl-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidinophenyl) -1-n-hexyl)-aminocarbonylmethyl]-benzoate analogously to Example 4.
Yield: 77% of theory, M.p.: 117-120°C Calculated: C 72.07 H 8,21 N 6.00 Found: 72.00 8.06 5.90 t Example A Tablets containing 5 mg of 2-ethoxy-4-[N-(ot-phenyl2-piper idino-benzyl)-ami nocarbonyImethyl]-benzoic acid Compos i ti on: 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 Method of preparation: 1, 2, 3 and 4 are mixed together and moistened with water. The moist mixture is passed through a 1.5 mm mesh screen and dried at 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 7 mm diameter punches comprising a dividing slot, to form tablets. Weight of tablet: 120 mg Example B Coated tablets containing 2.5 mg of 2-ethoxy- •4- f N-(a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] 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 80.0 mg Method 1, 2S 3 and 4 are thoroughly mixed and moist θπθ<3 with water. The moist mass is passed through a 1 mm mesh screen, dried at about 45 °C and the granulate is then passed through the same screen. After 5 has been added, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine.
The tablet cores thus produced are covered in known manner with a coating consisting essentially of sugar and talc. The finished tablets are polished with wax.
Weight of coated tablet: 120 mg Example C Tablets containing 10 mg of 2-ethoxy-4-[N-(g-phenyl2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid I Composition: 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 Method : The mixture of active substance, lactose and corn starch is moistened with a 20% solution of polyvinylpyrrolidone in water. The moist mass is passed through a 1.5 mm mesh screen and dried at 45°C. The dried granulate is passed through a .1 mm mesh screen and homogeneously mixed with magnesium stearate.
Weight of tablet: 120 mg Punch: 7 mm diameter with dividing slot.
Example D Coated tabl ets containing 5 mg of 2-efchoxy-4-ίN(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl] benzoic acid tablet core contains: Active substance 5.0 mg Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg 130.0 mg Method: The mixture of active substance, calcium phosphate and corn starch is moistened with a 15% solution of polyvinylpyrrolidone in water. The moist mass is passed through a 1 mm mesh screen, dried at 45°C and then rubbed through the same screen. After being mixed with the stated quantity of magnesium stearate, tablet cores are compressed from the mixture.
Weight of core: 130 mg Punch: 7 mm in diameter A coating of sugar and talc is applied to the cores thus produced in known manner. The finished coated tablets are polished with wax.
Weight of coated tablet: 180 mg

Claims (15)

Claims
1. Phenylacetic acid derivatives of general formula wherein R represents a pyrrolidino, piperidino, hexamethyleneimino, methyl-pyrrolidino, dimethyl-pyrrolidino, 2-methyl-piperidino, 3-methyl-piperidino, 4-methylpiperidino, 3,3-dimethyl-piperidino, cis-3,5-dimethylpiperidino or trans-3,5-dimethyl-piperidino group, R? represents a hydrogen or halogen atom or a methyl or methoxy group, R^ represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an n-pentyl or 3-methyl-nbutyl group or a phenyl group optionally substituted by a halogen atom or by a methyl or methoxy group, R^ represents a hydrogen atom, a methyl, ethyl or allyl group and -J represents a methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group with a total of 2 to 5 carbon atoms, whilst the alkyl part of the alkoxy group may be substituted by a phenyl group, the enantiomers and salts thereof.
2. Phenylacetic acid derivatives of general formula T as claimed in claim 1, wherein Rj and R^ are defined as in claim 1, R-j represents a pyrrolidino, oiperidino, 4-methylpiperidino, 3-methy1-piperidino , 3,3-dimethyl-piperidino, 3. ,5-dimethyl-piperidino or hexamethylene imino group, R 2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group and W represents a carboxy, methyl, hydroxymethyl, formyl or benzyloxycarbonyl group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, the enantiomers and salts thereof.
3. Phenylacetic acid derivatives of general formula I as claimed in claim 1, wherein R^ represents a piperidino group, R? represents a hydrogen, fluorine or chlorine atom , Rj represents a methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl or phenyl group, R^ represents a methyl or ethyl group and W represents a carboxy, methoxycarbonyl or ethoxycarbonyl group, the enantiomers and salts thereof.
4. Phenylacetic acid derivatives of general formula I as claimed in claim 1, wherein R^ to R^ are defined as in claim 3 and W represents the carboxy group, the enantiomers and salts thereof.
5. . 2-Ethoxy-4-[N-(1-(2-piper id ino-ohenyl)-1butyl)-aminocarbonylmethyl]-benzoic acid, the enantiomers and salts thereof.
6. . 2-Ethoxy-4-[N-(1-(2-piperidino-pheny1)-3raethyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, the enantiomers and salts thereof.
7. Physiologically acceptable salts of the compounds as claimed in claims 1 to 6 with inorganic or organic acids or bases, if the latter contain a carboxy group.
8. Pharmaceutical compositions containing a compound as claimed in claims 1 to 6, wherein represents a methyl, ethyl or allyl group or a physiologically acceptable salt thereof together with one or more inert carriers and/or diluents.
9. FJse of the compounds as claimed in claims 1. to 6, wherein R^ represents a methyl, ethyl or allyl group, or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition which is suitable for treating Diabetes mellitus.
10. Process for preparing a pharmaceutical composition as claimed in claim 8, characterised in that, by a non-chemical method, a compound as claimed in claims 1 to 6, wherein R^ represents a methyl, ethyl or allyl group, or a physiologically acceptable salt thereof is incorporated in one or more inert carriers and/or diluents.
11. Process for preparing new phenylacetic acid derivatives as claimed in claims 1 to 7, characterised in that a) an amine of general formula RP CH - NH. ill) wherei n R, to R^ are defined as in claims 1 to 6 is acvlated with a carboxvlic acid of general formula wherein R, is defined as in claims 1 to 6 and 4 W 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, which may optionally he prepared in the reaction mixture, and if necessary any protecting group used is split off, or b) in order to prepare a compound of qeneral formula T wherein W represents a carboxy group, a group Λ in a compound of qeneral formula wherein to are defined as in claims 1 to 6 and A represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, is converted into a carboxy group, c) in order to prepare a compound of general formula I wherein R^ represents a hydrogen atom or a methyl or ethyl group, a compound of general formula f wherein R^ to R^ are defined as in claims 1 to 6 is reacted with a compound of general formula } (VI) wherein R^ and W are defined as in claims 1 to 6, or d) in order to prepare compounds of general formula I wherein R^ represents a hydrogen atom, a protecting group is cleaved from a compound of general formula wherein to are defined as in claims 1 to 6, W' has the meanings given for W in claims 1 to 6 or represents a group which can be converted into a carboxy group and R^ represents a protecting group for a hydroxy group or e) in order to prepare compounds of general formula T wherein R^ represents a methyl, ethyl or allyl group, a compound of general formula It wherein R.] to R^ and W are defined is reacted with a compound as in claims 1 to 6, of general formula X (IX) wherein P^ ' has the meanings given for R^, in claims 1 to 6 e with the exception of the hydrogen atom, and v represents a nucleophi1ically exchangeable group or, together with the ad5acent hydrogen atom, represents a diazo group if R^ ! represents a methyl or ethyl group, and subseouently, if necessary, a compound thus obtained is hydrolysed, cr (X) wherein P-j , R 2 ‘· R 4 a °d w are defined as in claims 1 to 6 and Y represents a group of formula - C - WH or wherein R-, is defined as in claims 1 to 6 and P r and t? together with the carbon atom between them represent an alkylidene group with 1 to 4 carbon atoms, is reduced and subseouentlv, if desired, a compound of general formula I thus obtained wherein R? represents a halogen atom and/or R^ represents a halophenyl ο group and/or W represents a hvdroxymethyl qroup which has been converted into a halomethyl group, is converted by dehaloqenation into a corresponding compound of general formula I wherein R 2 represents 1' a hydrogen atom and/or represents a phenyl qroup and/or W represents a methyl group, and/or r a compound of anneral formula I thus obtained wherein W represents the carboxy group is converted by esterification into a corresponding compound of general formula I wherein w represents an alkoxycarbonyl or phenylalkoxvcarbonyl group, and/or a compound of general formula I thus obtained wherein W represents a carboxy, alkoxycarbonyl or phenylalkoxycarbonyl group i s converted by reduction into a corresponding compound of qeneral formula I wherein W represents a formvl or hydroxymethyl group, and/or a compound of qeneral formula I thus obtained wherein W represents a hydroxymethyl qroup is converted by oxidation into a corresponding compound of qeneral formula I wherein W represents a formyl or carboxy group, and/or a compound of general formula I thus obtained wherein W represents a carboxy qroup is converted by conversion t into a sulphonic acid hydrazide and subsequent disproportionation into a corresponding compound of genera). formula I wherein W represents a formyl group, and/or a racemic compound of general formula I thus obtained wherein R^ has the meanings qiven in claims 1. to 6, with the exception of the hydrogen atom, is resolved by chromatography on chiral phases into the enantiomers thereof, and/or a compound of general formula I thus obtained is converted into the salts thereof, more particularly the physiologically acceptable salts thereof with Y inorqanic or organic acids or bases. t
12. Process for preparing phenyl acetic acid derivatives as defined in Claim 1 substantially as hereinbefore described with reference to any of Examples 1 to 20.
13. Process for preparing a pharmaceutical composition as defined in Claim 8 substantially as hereinbefore described with reference to any of Examples A to D.
14. A phenylacetic acid derivative whenever prepared by a process as claimed in either of Claims 11 or 12.
15. A pharmaceutical composition whenever prepared by a process as claimed in either of Claims 10 or 13.
IE3349/84A 1983-12-30 1984-12-28 Chemical compounds IE57700B1 (en)

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DE19853522604 DE3522604A1 (en) 1983-12-30 1985-06-25 NEW SOLID FORMS OF 2- (GAMMA) THOXY-4- (N- (1- (2- (2-PIPERIDINO-PHENYL) -3-METHYL-1-BUTYL) -AMINOCARBONYLMETHYL) -BENZOESIC ACID, MEDICINAL PRODUCTS CONTAINING THESE FORMS

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