CA1214773A - Phenylacetic acid derivatives, the preparation thereof and pharmaceutical compositions containing these compounds - Google Patents

Phenylacetic acid derivatives, the preparation thereof and pharmaceutical compositions containing these compounds

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Publication number
CA1214773A
CA1214773A CA000431796A CA431796A CA1214773A CA 1214773 A CA1214773 A CA 1214773A CA 000431796 A CA000431796 A CA 000431796A CA 431796 A CA431796 A CA 431796A CA 1214773 A CA1214773 A CA 1214773A
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Canada
Prior art keywords
group
phenyl
piperidino
carbon atoms
compound
Prior art date
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Application number
CA000431796A
Other languages
French (fr)
Inventor
Wolfgang Grell
Rudolf Hurnaus
Gerhart Griss
Robert Sauter
Eckhard Rupprecht
Joachim Kahling
Bernhard Eisele
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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Priority claimed from DE19823225155 external-priority patent/DE3225155A1/en
Priority claimed from DE19823225188 external-priority patent/DE3225188A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Application granted granted Critical
Publication of CA1214773A publication Critical patent/CA1214773A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent 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
    • 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
    • C07D211/18—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • 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
    • 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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Fertilizers (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

Chemical compounds Compounds of general formula I

(I) (wherein R1 to R3, A and W are as defined in claim 1) and tautomers, optical enantiomers and salts thereof.

The new compounds have valuable pharmacological properties, particularly a hypoglycaemic effect.

Processes for the preparation of the new compounds and pharmaceutical compositions containing them are described.

Description

Chemical Compounds The present invention relates to new phenylacetic acid derivatives, to processes for their preparation, and to their effects on intermediate metabolism and the cardiac cir-culatory system.
According to one feature of the present invention, we provide compounds of general formula I

; - W~l -- CO - C~2 --~ ~}

[wherein A represents a group of formula R5 \ R6 - CH - or - C -[wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; a n-propyl group; an alkyl group containing 4 to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group con-taining 4 to 6 carbon atoms in the alkylene moiety; an amino-carbonyl group optionally mono- or disubs-titute~ by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the al~yl moiety (the substituents in the case of disubstitution beillg the same or different); an aryl group containing 6 or 10 carbon ~ r~
~i~

12~4~73 atoms mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl and/or alkylsulphonyl groups, the substituents in the case of disubstitution being the same or different and each alkyl moiety containing 1 to 3 carbon atoms; or a heteroaryl group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms;
or, when Rl represents a piperidino group and R2 repre-sents in the 4-position a fluorine atom and R3 represents a hydrogen atom and W represents a carboxy group or an alkoxycarb-onyl group, wherein the alkyl part may contain 1 to 3 carbonatoms then R4 may also represent a methyl group;
or, when Rl represents a piperidino group substituted in the 2- or 3-position by a methyl group, or, when R2 represents in the 3-, 4-, or 6-position a chlorine atom or in the 4- or 6-position a methyl group, or when W represents a formyl t carboxyvinylene or alkoxy-carbonylvinylene group, wherein the alkyl part may contain 1 to 3 carbon atoms then R4 may also represent a phenyl group;
R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety~;
Rl represents an unbranched alkyleneimino group con-taining 4 to 9 carbon atoms optionally mono- or disubstituted by alkyl groups containing 1 to 3 carbon atoms (which in the `';~

~2~4773 case of disubstitution may be the same or different); or a dialk~lamino group containing 1 to 5 carbon atoms in each alkyl component;
R2 represents a hydrogen, fluorine, chlorine, bromine, or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group wherein the alkyl component may contain 1 to 3 carbon atoms in each case;
R3 represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom; and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms (wherein the alkyl component may optionally be substituted by a phenyl group and optionally, at any carbon atom except the a-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms, an alkyl group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, ?.-carboxyethyl, 2-carboxyethenyl, 2,2-bis-(carboxy)-ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycar-bonyl-ethenyl or 2,2-bis-(alkoxycarbonyl)-ethyl group (each alkoxy group containing from 1 to 3 carbon atoms )]

~2~773 -3a-and tautomers ~hereof and optical enantiomers thereof and salts of the aforementioned compounds.
The present invention is also directed to a process for preparing the compoundsof gen~ral formula I which process comprises (a) reacting a compound of general formula II

/ ~ A - NH2 R2 t 11 (II) ~/\ Rl ~wherein A, Rl and R2 are as defined above or, if A represents one of the vinylidene groups mentioned above, a tautomer thereof or a lithium or magnesium halide complex thereof) with a compound of general formula III

HO - CO - CH2 ~ ~ ~ W' (III) ~$J

(wherein R3 is as defined above and W' has the meanings given for W above or represents a carboxy group protected by a protecting group) or with a reactive derivative thereof and, if necessary subsequently cleaving any protecting group used;
(b~ for preparing a compound of formula I wherein W
represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, subjecting a compound of general formula IV

123.4773 -3b~

A - NH - CO - CH2 ~ ~ B

~\ ~ R3 (IV) Rl (wherein Rl to R3 and A are as defined above and B represents a group which can be converted into a carboxy, carboxymethyl,
2-carboxy-ethyl or 2-carboxyethenyl group by hydrolysis, thermolysis or hydrogenolysis) to hydrolysis, thermolysis or hydrogenolysis;
(c) for preparing a compound of formula I wherein A re-presents a group of formula Rl 4 ~ CH~

wherein R4~ has the meanings given for R4 above with the ex-ception of an alkenyl group and a cyano group, reducing a com-pound of general formula V
R2 ~ D - CO - CH2 ~ - W (V) Rl R3 wherein Rl to R3 and W are defined as above and D represents a group of formula R "

4 R5 \ / R6 or C
C~ N - - C ~
N--~2~47~3 wherein R4" has the meanings given hereinbefore for R4' with the exception of a cyano group and R5' and R6' together with the carbon atoms between them represent an alkylidene group containing 1 to 7 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety;
(d) for preparing a compound of formula I wherein A
represents a group of formu].a -- CH-wherein R4" has the meanings given hereinbefore for R4' with the exception of a cyano group; reacting a compound of gen-eral formula VI R14"

~ CH OH
R2 ~ \ Rl (VI) wherein R4" represents R4 as defined above with the exception of a cyano group and Rl and R2 are as defined above with a com-pound of general formula VII

N-C - CH2 _ ~ W (VII) wherein R3 and W are as defined above;
(e) Eor preparing a compound of formula I wherein R2 4~73 -3d-represents a h~drogen atom, dehalogenating a compound of gen-eral formula VIII

,~ " A - NH - CO - CH~ - ~ (VIII) Rl R3 wherein Rl, R3, A and W are as defined above and Hal represents a fluorine, chlorine, bromine or iodine atom;
(f) for preparing a compound of formula I where A
represents a group of formula - CH -wherein R4 represents an alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety, re-acting a compound of general formula IX
COOH

2 ~ CH - NH - CO - CH2 -\r \~ W" (IX) Rl R3 (wherein Rl, R2 and R3 are as defined above and W" represents W as defined above with the exception of a carboxy group) with an amine of general formula X

H - R7 (X) ~i4773 -3e-wherein R7 represents an alkyleneimino yroup containing 4 to 6 carbon atoms or an amino group optionally mono- or di-substituted by alkyl or phenylalkyl groups each containing 1 to 3 carbon atoms in the alkyl moiety;
(g) for preparing a compound of formula I wherein A re-presents a group of formula - CH -wherein R4 is as defined above and W represents a carboxy group, oxidising a compound of general formula ~ \ ~C~ NH - CO - CH2- / E (XI) wherein Rl to R4 are as defined above and E represents a group which can be converted into a carboxy group by oxidation;
(h) for preparing a compound of formula I wherein W
represents an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms wherein the al~yl component may be substituted at any carbon atom except the ~-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms, esterifying a carboxylic acid of general formula XII

~2~4773 -3f-R2 ~ ~ A - NH - CO - CH2 ~ ~ COOH (XII) Rl R3 (wherein Rl to R3 and A are as defined above, or a reactive derivative thereof, with an alcohol of yeneral formula XIII

HO - Rg (XIII) wherein Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atom except the -carbon atom by one or two hydroxy groups or by an alkvxy group containing 1 to 3 carbon atoms;
(i) for the preparing a compound of formula I wherein W represents an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxy-carbonylethyl or 2-alkoxycarbonylethenyl group and A represents a group of formula R14"

- CH -wherein R4" represents R4 as hereinbefore defined with the ex-ception of a cyano group, alcoholysing a compound of general formula XIV
R14"

~ CH - NH - CO - CH2 ~ W"' 2 ~ \ Rl R3 ~XIV) ~;~4773 -3g wherein R4" represents R4 as defined above with the exception of a cyano group, Rl to R3 are as defined above and W"' represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethyenyl group;
and, if required converting an obtained compound of formula I into a salt thereof.
It will be appreciated that the term "salts" as used herein includes within its scope salts formed with organic and inorganic acids and bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid. Suitable bases include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine.
For pharmaceutical use, the salts referred to above will, of course, be physiologically compatible salts, but other salts may find use, for example in the preparation of the compounds of general formula I and their physiologically compatible salts.
The term "tautomer" as used herein refers particularly to the tautomeric ketimine form of the compounds of general formula I wherein A represents a substituted viny~idene radical, but the term is not restricted to this interpretation and covers all possible tautomeric forms of the compounds of general formula I.

~2~
- 3h -The definitions given hereinbefore for the groups Rl to R6 and W include the following, for example:

Rl may represent a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-n-pentylamino, diisobutylamino, N-methyl-ethylamino, N-methyl-n-propylamino, N-methyl-isopropylamino, N-isopropyl-S n-propylamino, N-isobutyl-n-propylamino, N-methyl-n-butylamino, N-ethyl-n-butylamino, N-ethyl-isopropyl-amino, N-ethyl-n-pentylamino, N-propyl-n-butylamino, pyrrolidino, piperidino, hexamethyleneimino, hepta-methyleneimino, octamethyleneimino, nonamethyleneimino, methyl-pyrrolidino, dimethyl-pyrrolidino, ethyl-pyrrol-idino, methyl-piperidino, ethyl-piperidino, dimethyl-piperidino, diethyl-piperidino, methyl-ethylpiperidino, n-propyl-piperidino, methyl-n-propylpiperidino, isopropyl-piperidino, or di-n-propyl-piperidino ~roup, R2 may represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, piperidino, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, methylsulphinyl, ethylsulphinyl, methylsulphonyl, n-propylsulphonyl, benzyloxy, l-phenyl-ethoxy, 2-phenyl-ethoxy, 3-phenyl-propoxy, acetoxy, propionyloxy, formylamino, acetylamino, propionylamino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino, di-n-propylamino or methyl-ethylamino group, R3 may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl or isopropyl group, R4 may represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 2-methoxyethyl, 2-ethoxy-ethyl, 3-methoxy-propyl, benzyl, l-phenylethyl, 2-phenylethyl, l-phenyl-n-propyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl,
3-buten-1-yl, 2-buten-1-yl, 4-penten-1-yl, cyano, lZ:14773 aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, diethylamino-carbonyl, di-n-propylaminocarbonyl, benzylaminocarbonyl, 2-phenyl-ethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, phenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl~ benzyloxy-phenyl~ 2-phenyl-ethoxy-phenyl, 3-phenylpropoxy-phenyl, methylsulphenyl-phenyl, ethylsulphenyl-phenyl, methyl-sulphinyl-phenyl, n-propylsulphinyl-phenyl, methyl-sulphonyl-phenyl, ethylsulphonyl-phenyl, isopropyl-sulphonyl-phenyl, methyl-naphthyl, hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl, dimethyl-phenyl, di-isopropyl-phenyl, chloro-methyl-phenyl, dimethoxy-phenyl, methyl-methoxyphenyl, chloro-methoxy-phenyl, bromo-methoxy-phenyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl or quinazolyl group, R5 and ~6 may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl or n-pentyl group, R5 and R6 together with the carbon atoms between them may represent a benzylidene, l-phenyl-ethylidene, 2-phenyl-ethylidene, l-phenyl-n-propylidene, l-phenyl-2,2-propylidene or 3-phenyl-n-propylidene group and W may represent a hydroxymethyl, formyl, carboxy, carboxymethyl, 2-carboxy-ethyl, 2-carboxy-ethenyl, 2,2-bis-(carboxy)-ethyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, (2-hydroxyethoxy)carbonyl, (2-hydroxy-n-propoxy)carbonyl, (l-hydroxy-2-propoxy)carbonyl, (2-methoxyethoxy)carbonyl, (2-ethoxyethoxy)carbonyl, (2-n-propoxyethoxy)carbonyl, (2-nicotinoyloxy-ethoxy)-carbonyl, (2-isonicotinoyloxy-ethoxy)carbonyl, (2,3-12~4773 -- 6 -- .
dihydroxy-n-propoxy)carbonyl, (2-dimethylamino-ethoxy)-carbonyl, (2-diethylamino-ethoxy)carbonyl, (2-piperidino-e~hoxy)carbonyl, methyl, ethyl, n-propyl, isopropyl, cyano, aminocarbonyl, methoxycarbonyl-methyl, ethoxy-carbonyl-methyl, n-propoxycarbonyl-methyl, 2-methoxy-carbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxy-carbonyl-ethyl, 2 methoxycarbonyl-ethenyl, 2-ethoxy-carbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl, 2,2-bis-(methoxycarbonyl)-ethyl, 2,2-bis-(ethoxycarbonyl)-ethyl or 2,2-bis-(isopropoxycarbonyl)-ethyl group.

Preferred compounds of general formula I above are those wherein A represents a group of formula 5~ ~ 6 - CH - or - C -wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group;
an n-propyl group; an alkyl group containing 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atoms mono-or disubstituted by halogen atoms, or by alkyl, hydroxy,alkoxy, phenylalkoxy and/or alkylsulphenyl groups, whilst the substituents may be the same or different and each alkyl component may contain from 1 to 3 carbon atoms; or a naphthyl, pyridyl, quinolyl or isoquinolyl group;

R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety;
Rl represents an unbranched alkyleneimino group containing
4 to S carbon atoms or a piperidino group mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms;
R2 represents a hydrogen, fluorine, chlorine or bromine atom or a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms, or (if R5 ancl R6 are as hereinbefore defined or R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group with 1 to 3 carbon atoms or by a phenyl group, an n-propyl group, an alkyl group containing 4 to 6 carbon atoms, an alkenyl group contain-ing 3 to 5 carbon atoms, or a nitrile or aminocarbonyl group) R2 may also represent an iodine atom or a hydroxy or amino group;
R3 represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group;
an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl component may be substituted at any carbon atom except the c~-carbon atom by 1 or 2 hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbc)nyloxy group; or an alkoxycarbonyl-methyl, 2-alkoxycarbonylethyl or 2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may contain from 1 to 3 carbon atoms and 4-[N-(6-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbollyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-cinnamic acid and Cl 3 alkyl esters ~hereof, 3-~4-[(N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid and Cl 3 alkyl esters thereof, 4-~N-(4-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyll-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(6-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl~-benzoic acid and Cl 3 alkyl esters thereof, 4-rN-(2-(2-methyl-piperidino)-a-phenyl-benzyl)-amino-carbonylmethyl~-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(2-(3-methyl-piperidino)-~-phenyl-benzyl)-amino-carbonyl-methyl~-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl-benzaldehyde, 4-~11-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[~1-(3-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid and Cl_3 aikyl esters thereof, and 4-[~1-(3-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof.

~4773 Particularly preferred are those compounds of general formu}a I wherein A represents a group of formula
5 ~ ~ 6 - CH - or - C -wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano or aminocarbonyl group;
an alkyl group containing 4 to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms; a phenyl group substituted by a fluorine, chlorine or bromine atom or by a methyl, hydroxy, methoxy, benzyloxy or methylsulphenyl group; or a pyridyl group;

R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety, Rl represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by methyl groups, R~ represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group; or (if R5 and R6 are as hereinbefore defined or R4 represents an alkyl group containing 1 to 3 carbon atoms sub tituted by a methoxy or phenyl group, an n-propyl, nitrile or aminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or an alkenyl group containing 3 to 5 carbon atoms) R2 may also represent an iodine atom or a hydroxy or amino group, ~2147 73 R3 represents a hydrogen or chlorine atom; and ~ represents a methyl, hydroxymethyl, formyl, cyano, car-boxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms wherein the alkyl component may be substituted at any carbon atom except the ~-carbon atom by one or two hydroxy groups, by an alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbonyl-oxy group; or ~n alkoxycarbonyl-methyl, 2-alkoxycarbonylethyl or 2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may con-lQ tain from 1 to 3 carbon atoms; and 4-[N-~6-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof with 1 to 3 carbon atoms, 4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid and Cl 3 alkyl esters thereof J
3-[4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid and Cl 3 alkyl esters thereof, - 4-[N-(4-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(3-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-(6-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 1~4~3 4-~N-(4-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl3-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-~2-~2-methyl-piperidino)-~-phenyl-benzyl)-amino-carbonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereofJ
4-[N-~2-~3-methyl-piperidino)-~-phenyl-benzyl)-aminocar-bonyl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[N-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde, 4-[~ 4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbon-yl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, 4-[~ 3-chloro-2-piperidino-phenyl)-ethyl)-aminocarbon-yl-methyl]-benzoic acid and Cl 3 alkyl esters thereof, and 4-[~1-(3-methyl-2-piperidino-phenyl)-ethyl)-amino-carbon-yl-methyl]-benzoic acid and Cl 3 alkyl esters thereof.
Ilowever, another group of preferred compounds are those wherein A, Rl to R3 and W are as hereinbefore defined, more parti-cularly those wherein W represents a carboxy group or an alkoxy-carbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl component may be substituted at any carbon atom except the ~-carbon atom by one or two hydroxy groups, and optically active enantiomers and the salts thereof.
Particularly preferred compounds of general formula I above are those wherein A represents a group of formula - C~ - or - C -wherein R4 represents an n-propyl group, an alkyl group contsining 4 or 5 carbon atoms, a phenyl group substituted by a methyl group or by a fluorine or chlorine atom, or a pyridyl group, R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part;
Rl represents a piperidino group optionally substituted by one or two methyl groups;
R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group:
R3 represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms;
particularly those wherein A represents a group of formula 5~ ~ 6 - CH - or - C -wherein R4 represents an n-propyl group or an alkyl group containing 4 or 5 carbon atoms and R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part, and optically active enantiomers and salts thereof.
The compounds of general formula I as hereinbefore defined and their optical enantiomers and salts thereof may, for example, be prepared by the following processes, which processes constitute further features of the present invention:

a) Reacting a compound of general formula II

~2 t~ R1 (II) (wherein A, Rl and R2 are as hereinbefore defined or, if A represents one of the vinylidene groups mentioned hereinbefore, the tautomers thereof or a lithium or magnesium halide complex thereof) with a compound of general formula III

H0 - CO - C~z ~ - W (I~I) (wherein R3 is as hereinbefore defined and W' has the meanings given for W hereinbefore or represents a carboxy group protected by a protecting group), or with a reactive derivative thereof optionally formed in the reaction mixture and, if necessary, subsequently cleaving any protecting group used.
lS The reactive derivatives of a compound of general formula III may be, for example, the esters thereof, such as the methyl, ethyl or benzyl esters, the thio-esters thereof such as the methylthio- or ethylthio-ester~, the halides thereof 6uch as the acid chloride, or the anhydrides or imidazolides thereof.

The reaction is conveniently 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 agent which activates the acid or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexyl-carbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,~'-thionyldi-imida~ole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino gro~p, 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 serve as solvent, at temperatures of between -25C and 250C, but prefer-ably at temperatures of between -10C and ~he 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 the addition of a drying agent such as magnesium sulphate or a molecular sieve.
If necessary, the subsequent cleaving of a protecting group is preferably effected by hydrolysis, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the pre~ence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent ~uch as water, methanol, ethanol, ethanol/water, water~isopropanol or water/dioxan at temperatures of between -10C and 120C, e~g. at temperatures of between ambient temperature and the boiling temper-ature of the reaction mixture.
A tert.butyl group used as the protecting group may also be cleaved thermally, possibly in an inert ~4773 solvent such as methylene chloride, chloroform, benæene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, pho~phoric or polyphosphoric acid.
Moreover, a ~enzyl group used as a protecting group may also be cleaved 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, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group:
subjecting a compound of general formula IV

2 ~ - N H - CO - C~ ~ 3 (wherein Rl to R3 and A are as hereinbefore defined, and B represents a group which can be converted by hydrolysis, thermolysis or hydrogenolysis into ~ carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxy-ethenyl group) to hydrolysis, thermolysis or hydrogeno-lysis.
The hydrolysable groups in the compounds of general formula IV may be, for example, functional derivatives of carboxy, carboxymethyl, 2-carboxyethyl 121~773 or 2-carboxyethenyl qroups such as the unsubstituted or substituted amides thereof, the nitriles, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides thereof, a malonic ester-(l)-yl group, the tetrazolyl group, an optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group, and the thermolytically cleavable groups may be, for example, esters with tertiary alcohols, e.g.
the tert.butyl ester, the hydrogenolytically cleavable groups may be, for example, esters with aralkanols, e.g. the benzyl ester.
The hydrolysis is conveniently effected 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 -10C and 120C, e.g. at temperatures of between ambient temperature and the boiling temper-ature of the reaction mixture.
If B in a compound of general formula IV represents a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group using a nitrite, e.g. ~odium nitrite, in the presence of an acid such as sulphuric acid, which is conveniently also used as the solvent, at temperatures of between 0 and If B in a compound of general formula IV represents the tert.butyloxycarbonyl group, for example, the tert.butyl group may also be cleaved thermally, option-ally in an ~nert solvent such as methylene chloride, chloroform, ben~ene, tolùene, tetrahydrofuran or 3S dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sul-phuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g.
at temperatures of between 40C and 100C.

121477~

If B in a compound of general formula IV represents the benzyloxycarbonyl group, for example, the benzyl group may also be cleaved 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, preferably at temperatures of hetween 0 and 50C, e.g. at ambient temperature, and at a hydrogen pressure of from 1 to 5 bar. In the hydrogenolysis, other groups may simultaneously be reduced as well (e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corres-ponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group), or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.

c) In order to prepare compounds of general formula I wherein A represents a group of formula IR4' - CH -wherein R4' has the meanings given hereinbefore for R4, with the exception of an alkenyl group and a cyano group:
Reduction of a compound of general formula V

2 ~ D -CO - C~2 ~ W

~.21477~

wherein Rl to R3 and W are as hereinbefore defined and D represents a group of formula - C~ or It N - - C

H

wherein R4" has the meanings given hereinbefore for R4, with the exception of a cyano group and R5' and R6' together with the carbon atom between them represent an alkylidene group containing 1 to 7 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety.
Reduction is preferably effected 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, ethanol/
water, glacial acetic acid, ethyl acetate, dioxan, tetrahydrofuran, dimethylformamide, benzene or benzene/
ethanol at temperatures of between 0 and 100C, but preferably at temperatures of between 20C and 50C, and under a hydrogen pressure of 1 to 5 bar. When a suitable chiral hydrogenation catalyst such as a metal ligand complex is used, e.g. a complex of ~ dichloro-bis~1,5-cyclooctadiene-rhodium] and (+)- or (-~ O,O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-butane (= DIOP), the addition of hydrogen occurs enantioselectively. Moreover, during catalytic hydrogenation, other groups may be reduced at the ~ame time, e.g~ a nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group or a cinnamic acid group to 1214~73 the phenylpropionic acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.

d) In order to prepare compounds of g neral formula I wherein A represents a gro~p of formula R4~
I

- CH -wherein R4~ has the meanings given hereinbefore for R4, with the exception of a cyano group:

Reacting a compound of general formula VI

~ CH - OH (VI) R
R~

(wherein R4~ is defined as above and Rl and R2 are as hereinbefore defined) with a com]pound of general formula VII

N _ C - C~2 ~ W (VII) wherein lZ~4773 R3 and W are as hereinbefore defined.
The reaction is carried out in the presence of a strong acid which may simultaneously serve as solvent, prefer2bly in concentrated sulphuric acid, at temperatures of between 0C and 150C, but preferably at temperatures of between 20C and 100C.

e) for the preparation of compounds of general formula ~, wherein R2 represents a hydrogen atom:
dehalogenating a compound of general formula VIII

~ A - N H - C~ - CH2 ~ W
10 Hal ~ ~ (VIII) wherein Rl, R3, A and W are as hereinbefore defined and Hal represents a fluorine, chlorine, bromine or iodine atom.
The dehalogenation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide by means of catalytically activated hydrogen, e.g. with hydrogen in the pre~ence of platinum or palladium/charcoal, at temperatures of between 0 and 100C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 5 bar. During the dehalogenation, other groups may be reduced at the same time, e.g. a benzyloxy group may be reduced ~o a hydroxy group, a vinylidene group ~o the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic 12~4773 acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.

f) In order to prepare compounds of general formula I, wherein A represents a group of formula ~4 I

- CH -wherein R4 represents an alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disub-stituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety:
Reacting a compound of general formula COOH

R2 ~ H - NH - CO - CH2 ~ W

(wherein Rl, R2 and R3 are as hereinbefore defined and W~ has the meanings given hereinbefore for W, with the exception of the carboxy group), with ` 20 an amine of general formula X

H - R7 ~X) wherein R7 represents an alkyleneimino group containing ~214773 4 to 6 carbon atoms or an amino group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carb~n atoms in the alkyl moiety.
Amidation is conveniently effected in a solvent such as methylene chloride, chloroform, carbon tetra-chloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, preferably in the presence of an agent which activates the acid or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, ~,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole 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 serve as solvent, at temperatures of between -25C and 250C, but preferably at temper-atures of between -10C and the boiling temperature of the solvent used.

g) In order to prepare compounds ~f general formula I wherein A represents a group of formula - CH -as hereinbefore defined and W represents a carboxy group:

Oxidising a compound of general formula XI

R2 ~ ~ - Nll - C0 - CH~ ~ E (XI) wherein Rl to R4 are as hereinbefore defined and E represents a group which can be converted into a carboxy group by oxidation.
An oxidisable group of this kind may be, for example, a formyl group and the acetals thereof, a hydroxymethyl group and the ethers thereof, a substituted or unsubstituted acyl group such as an acetyl, chloroacetyl J propionyl or malonic acid-ll)-yl group or a malonic ester-(l)-yl group.
The reaction may be carried out with an oxidising agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxan or glycol dimethyl ether at temperatures of between 0 and 100C, but conveniently at temperatures of between 20C and 50C. However, the reaction is preferably effected with silver oxide/
sodium hydroxide solution, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium hydroxide solution, bromine or chlorine/sodium or potassium hydroxide solution, chromium trioxide/-pyridine or pyridinium chlorochromate.
h) In order to prepare compounds of general form-lla I w]lcrei W represents an alkoxycarbollyl group containing a total o~ ~ to (~

carbon atoms wherein the alkyl componellt may be substitutcd at any carbon atom except the ~-carbon atom ~2~7~3 _ 24 --by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms:
Esterifying a carboxylic acid of general formula XII

R2 ~ ~ - ~H - CO - CH2 ~ COO~ (XII) (wherein Rl to R3 and A are as hereinbefore defined) or a reactive derivative thereof optionally prepared in the reaction mixture, with an alcohol of general formula XIII

HO - Rg (XIII) wherein Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atom except the ~-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms.
Examples of reactive derivatives of a compound of general formula XII include the halides thereof, such as the acid chloride, and the anhydrides and imidazolides.
The reaction is conveniently carried out using the corresponding alcohol as solvent or in a suitable solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, dioxan, benzene or toluene, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of hydrogen ~2~4~73 chloride, sulphuric acid, ethyl chloroformate, thionyl chloride, carbon tetrachloride/triphenylphosphine, carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide or the isourea ethers thereof, optionally in the presence of a reaction accelerator such as copper chloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, or by trans-esterification, e.g. with a corresponding carbonic acid diester, at temperatures of between -20C and 100C, but preferably at temperatures of between -10C and the boiling temperature of the solvent used.

i) In order to prepare a compound of general formula I wherein W represents an alkoxycarbonyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group and A represents a group of formula R4~
I

-- C~--where R4" represents R4 as hereinbefore defined with the exception of a cyano group:
Alcoholysis of a compound of general formula XIV

RZ ~tl H - NH - CO - CHZ~ W

(XIV) ~4773 wherein R4~ represents R4 as hereinbefore defined with the exception of a cyano group and Rl to ~3 are as hereinbefore defined and wn~ represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethenyl group.
The alcoholysis is conveniently effected in a corresponding alcohol as a solvent, such as methanol, ethanol or propanol, preferably in the presence of an acid such as hydrochloric or sulphuric acid at temperatures of between 2~C and the boiling temperature of the solvent used, preferably a$ temperatures of between 50 and 100C.
If, according to the invention, a compound of general formula I is initially obtained wherein W represents a carboxy or alkoxycarbonyl group, this may subsequently be converted by reduction into a corresponding compound of general formula I wherein W represents a formyl or hydroxymethyl group, and/or 20 if a compound of general formula I is initially obtained wherein W represents a carboxy group, this may subse-quently be converted by conversion into a sulphonic acid hydrazide and subsequent disproportionation into a corresponding compound of general formula I wherein W represents a formyl group, and/or if a compound of general formula :r is initially obtained wherein W represents a formyl group, this may subsequently be converted by condensation and optional subsequent hydrolysis and/or decarboxylation into a corresponding compound of general formula I wherein W represents a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-ethenyl group, and/or if a compound of general formula I is initially obtained wherein W represents a 2-carboxy-ethenyl or 2-alkoxy-carbonyl-ethenyl group, this may subsequently be ~147 73 converted by catalytic hydrogenation into a corresponding compound of general formula I wherein W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group, and/or if a compound of general formula I is initially obtained wherein W
represents an alkoxycarbonyl group substitute~ at any carbon atom except the ~-carbon atom by a hydroxy group, this may subsequently be converted by acylation by means of a pyridine-carboxylic acid into a corresponding (pyridine-carbonyloxyalkoxy)-carbonyl com-pound of general formula I, and/or if a compound of general formula I is initially obtained wherein W
represents a hydroxymethyl group, this may, after being converted into a corresponding halo-methyl compound, subsequently be con-verted by reaction with a malonic acid diester into a correspond-ing compound of general formula I wherein W represents an ethyl group substituted by two alkoxycarbonyl groups, and/or if a compound of general formula I is initially obtained wherein W
represents an ethyl group substituted by two alkoxycarbonyl groups, this may subsequently be converted by hydrolysis into a correspond-ing compound of general formula I wherein W represents an ethyl group substituted by two carboxy groups, and/or if a compound of general formula I is initially obtained wherein W
represents an ethyl group substituted by two alkoxycarbonyl groups, this may subsequently be converted by hydrolysis and decarboxylation into a corresponding compound of general formula I wherein W repre-sents a 2-carboxyethyl group, and/or if a compound of general formula I is initially obtained wherein R2 represents a nitro group, this may subse-~2147~3 quently be converted by reduction into a corresponding compo~nd of general formula I wherein R2 represents an amino group, and/or if a compound of general formula I is initially obtained wherein R2 represents an amino group, this may subse-quently be converted, via a corresponding diazonium salt, into a corresponding compound of general f~rmula I wherein R2 represents a hydrogen or halogen atom or a hydroxy, alkoxy or alkylsulphenyl group, and/or if a compound of general formula I is initially obtained wherein R2 represents a hydroxy group, this may subse-quently be converted by alkylation into a corresponding compound of general formula I wherein R2 represents an alkoxy group, and/or if a compound of general formula I is initially obtained wherein R2 represents a benzyloxy group and/or R4 represents an aryl group substituted by a benzyloxy group, this may subsequently be converted by debenzyl-ation into a corresponding compound of general formula I wherein R2 represents a hydroxy group and/or R4 represents an aryl group substituted by a hydroxy group, and/or if a compound of general formula I is initially obtained wherein R4 represents an aminocarbonyl group, this may subsequently be converted by dehydration into a corresponding compound of general formula I wherein R4 represents a cyano group.

The subsequent alcoholysis is preferably carried out in a corresponding alcohol such as ethanol, in the presence of an acid such as hydrochloric or sulphuric acid, at temperatures up to the boiling temperature of the solvent used.

12~47~73 The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride such as lithium aluminium hydride, in a solvent such as diethyl ether, tetrahydrofuran or dioxan at temperatures of between 0 and 100C, but preferably at temperatures of-between 20C and 60C.
The subsequent disproportionation of a sulphonic acid hydrazide, which is obtained by reacting a corres-ponding hydrazine with a corresponding reactive carboxylic acid derivative, is carried out in the presence of a base such as sodium carbonate in a solvent such as ethyleneglycol at temperatures of between 100C
and 200C, but preferably at 160 to 170~C.
The subsequent condensation of a formyl compound is conveniently carried out in a solvent such as pyridine or tetrahydrofuran with malonic acid, with a malonic acid ester, with a dialkylphosphono-acetic acid ester or an alkoxycarbonylmethylene-triphenyl-phosphoran, optionally in the presence of a base as the condensing agent, e.g. in the presence of piperidine, potassium tert.butoxide or sodium hydride, at temperatures of between 0 and 100C; the desired compound is obtained by subsPquent acidification, e.g. with hydrochloric or sulphuric acid, or by subse-quent alkaline hydrolysis.
The subsequent catalytic hydrogenation is conveni-ently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal at temperatures of between 0 and 75C, but preferably at ambient temperature and under a hydrogen pressure of 1 to ~ bar.
The subsequent O-acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethyl-formamide, preferably with a reactive derivative ~214773 of the acid, for example a halide such as the acid chloride, an anhydride or imidazolide and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethyl-S amine or pyridine which may simultaneously serveas solvent, at teMperatures of between -25C and 250~C, but preferably at temperatures of between -10C and the boiling temperature of the solvent used.
The subsequent conversion of a hydroxymethyl group into a halomethyl group is effected with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and subsequently reacting with a malonic acid ester, e.g. with an alkali metal salt of diethyl malonate, at temperatures of between 0 and 100C, but preferably at temperatures of between 50C and 80C.
The subsequent hydrolysis or hydrolysis and decarboxylation is conveniently effected in the presence of an acid such as hydrochloric, sulphuric, phosphoric, polyphosphoric or trifluoroacetic acid in a suitable solvent such as water, ethanol, water/ethanol, waterJiso-propanol or water/dioxan at elevated temperatures, e.~. at the boiling temperature oE the reaction mixture.
The subsequent reduction of the nitro compound is preferably effected in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at temperatures of between ~ and 50C, but preferably at ambient temper-ature.

1~4773 The subsequent reaction of a diazonium salt, e.g. the fluoroborate, the fluoride in 40~ hydrofluoric acid, the hydrosulphate in sulphuric acid or the hydrochloride, if necessary in the presence of copper or a corresponding copper(I)salt such as copper(I) chloride/hydrochloric acid or copper(I~bromide/hydro-bromic acid, is carried out at slightly elevated temperatures, e.g. at temperatures of between 1~C
and 100C; the subsequent reaction with hypophosphorous acid is preferably carried out at -5C to 0C. The diazonium salt required is conveniently prepared in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid or dioxan/hydrochloric acid, by diazotising a corresponding amino compound with a nitrite, e.g.
sodium nitrite or an ester of nitrous acid, at low temperatures, e.g. at temperatures of between -10C
and 5C.
The subsequent O-alkylation is conveniently effected with a corresponding halide, sulphonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl-sulphate, ethyl bromide, ethyl p-toluenesulphonate, isopropylmethanesulphonate or diazomethan~, optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert.butoxide and preferably in a solvent such as diethyl ether, tetrahydro-furan, dioxan, methanol, ethanol, pyridine or dimethyl-formamide at temperatures of between 0 and 75C, preferably at ambient temperature.
The ~ubsequent debenzylation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide using catalytically àctivated hydrogen, e.g. using hydrogen in the presence of platinum or palladium~char-coal, at temperatures of between 0 and 75C, but preferably at ambient temperature and at a hydrogen pressure of from 1 to 5 bar.

1~14773 The subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, sulphuric acid or p-toluenesulphonic acid chloride, optionally in a solvent such as methylene chloride S or pyridine at temperatures of between 0 and 100C, preferably at temperatures of between 20 and 80C.
If they have a chiral centre, the compounds of general formula I obtained can also be resolved into their enantiomers by conventional methods.
This may, for example, be effected by column chromato-graphy on a chiral phase.
A compound of general formula I or a tautomer thereof, initially obtained, may subsequently be converted into an addition salt thereof, for example by conventional methods such as reacting the compound of general formula I or tautomer thereof as a base with an acid in a suitable solvent, or reacting the compound of general formula I or tautomer thereof as an acid with a base in a suitable solvent. A
salt of a compound of general formula I or a tautomer thereof, initially obtained, may subsequently be converted by conventional methods into a different salt or into a compound of general formula I or tautomer thereof.
The compounds of general formulae II to XIV
used as starting materials may be obtained by methods known from the literature or are themselves known from the literature.
Thus, for example, a compound of general formula II wherein A represents a group of formula C

Ic or the tautomeric ketimine thereof is obtained by reacting a corresponding nitrile with a corresponding 1214~3 Grignard or lithium compound and subsequently hydrolysing or by reacting a corresponding ketone with ammonia in the presence of titanium tetrachloride. For further reaction with a compound of general formula I~I or the reactive derivatives thereof, more particularly the acid chlorides thereof, it is also possible to use the organometalli~ ketimine complex.
A compound of general formula II wherein A
represents a group of formula ~4 - CH -wherein R4n' has the meanings given hereinbefore for R4 with the exception of the cyano and aminocarbonyl groups, is obtained, for example, by reacting a corre-sponding nitrile with a corresponding Grignard or lithium compound and optionally subsequently carrying out lithium aluminium hydride reduction or subsequent hydrolysis to form the ketimine, which is then 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 cyanoboro-hydride, by reduction of a corresponding oxime with lithium aluminium hydride or with catalytically activated or nascent hydrogen, by reduction of a corresponding N-benzyl- or ~-(l-phenylethyl)-ketimine, e.g. with catalytically activated hydrogen or with a complex metal hydride in ether or tetrahydrofuran at temperatures of between -78C and the boiling temperature of the solvent used and subsequently cleaving the benzyl or l-phenylethyl group by catalytic hydrogenation, by ~itter reaction of a corresponding alcohol with potassium cyanide in sulphuric acid, or by Hofmann, ~2~477~

Curtius, Lossen or Schmidt degradation of a corresponding compound.
A compound of general formula II wherein A
represents the group CN
I
- CH -may be obtained by reacting a corresponding aldehyde with ammonium cyanide or by reacting a corresponding cyanohydrin with ammonia.
An amine of general formula II thus obtained, having a chiral centre, wherein A represents a group of formula - CH -wherein R4" has the meanings given hereinbefore with the exception of the cyano group, may be resolved into the 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 chromatography on a chiral phase, or by forming diastereomeric compounds and then eeparating and splitting them.
Moreover, an optically active amine of general formula II may also be prepared by enantioselective reduction of a corresponding ketimine using complex boron or alu~inium hydrides wherein some of the hydride hydrogen atoms are replaced by optically active alkoxide radicals, or by means of hydrogen in the presence of a su$table chiral hydrogenation catalyst or analo-gously, gtarting from a corresponding N-benzyl- or N-(l-phenethyl)-ketimine or from a corresponding N-acyl-ketimine or enamide and optionally subsequently cleaving the benzyl, l-phenethyl or acyl group.

121~773 Furthermore, 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 b~ron or aluminium hydrides wherein, if desired, some of the hydride hydrogen atoms have been replaced by corresponding alkoxide, phenolate or alkyl radicals, or by means of hydrogen in the presence of a suitable hydrogenation catalyst and optional subse~uent cleaving of the chiral auxiliary radical by catalytic hydrogenolysis or hydrolysis.
In addition, an optically active amine of general formula II may also be prepared by dias.ereoselective addition of a corresponding organometallic compound, lS preferably a Grignard or lithium compound, to a corres-ponding aldimine chirally substituted at the nitrogen atom, by subsequent hydrolysis and optional subsequent cleaving of the chiral auxiliary radical by catalytic hydrogenolysis or hydrolysis.
The compounds of general formulae IV, VIII, IX, XI, XII and XIV used as starting materials are obtained by reacting a corresponding amine with a corresponding compound of general formula III or the reactive derivatives thereof, with optional subse-quent hydrolysis.
A compound of general formula V used as starting material is preferably obtained by acylating a corres-ponding ketimine or the organometallic complex thereof with a corresponding carboxylic acid or the reactive derivatives thereof.
As already mentioned hereinbefore, the new compounds of general formula I as hereinbefore defined, the tautomers and optical enantiomers thereof and acid and base addition salts of the aforementioned compounds have valuable pharmacological properties, namely an effect on the intermediate metabolism, but particularly the hypoglycaemic effect of lowering blood sugar and, to some extent, an effect on the cardiac circulatory system.

For example, the following compounds have been examined for their properties as follows:

A = (Z)-4-[(1~(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid, B = ethyl (Z)-4-~(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoate, C = (E)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl~-benzoic acid, D = 4-[(2-methyl-1-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl]-benzoic acid, E = ethyl (Z)-4-~(1-(2-piperidino-phenyl)-1-hexen-l-yl)-aminocarbonylmethyl]-benzoate, F = (Z)-4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl~-benzoic acid, G = (z)-4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-l-buten-l-yl)-aminocarbonylmethyl~-benzoic acid, H = 4-[(1-~2-pyrrolidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid, J = (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid, R S (+) -4-1 ( 1- ( 2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid, L ~ ethyl (~)-4-[(1-~2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate, ~2~4773 M - 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid, N = 4-[(1-(2-pip~ridino-phenyl)-1-hexylj-aminocarbonyl-methyll-benzoic acid, O = 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]-benzoic acid, P = 4-~(2-methoxy-1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl] benzoic acid, Q = 4-~(~-cyan~-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid, R = 4-[~1-(2-piperidino-phenyl)-1-butyl3-aminocarbonyl-methyl]-benzyl alcohol, S = 4-~(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-phenylacetic acid, T = 4-~(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-cinnamic acid, U = 2,3-dihydroxy-propyl 4-[(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate, V = 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoic acid, W = 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid, X 5 4-~(1-(2-octahydroazonino-phenyl)-1-ethenyl)-aminocarbonylmethyl]-benzoic acid, Y - 4-[(1-(3-chloro-2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl~-benzoic acid, ~Z~4773 Z = 4-[tl-(3-methyl-2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl~-benzoic acid, AA = 4-~(~-(4-methyl-phenyl)-2-piperidino-benzyl1-5aminocarbonylmethyl]-benzoic acid, AB = 4-[(-(3-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, AC = 4-[~a-(4-fluoro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl3-benzoic acid, AD = 4-[(~-~2-fluoro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, AE = 4-[(Q-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, AF = 4-[(a-(3-chloro-phenyl)-2-piperidino-benzyl)-15aminocarbonylmethyl]-benzoic acid, AG = 4-[(2-piperidino-a-(2-pyridyl)-benzyl)-amino-carbonylmethyl]-benzoic acid, AH = 4-[(2-piperidino-a-(4-pyridyl3-benzyl)-amino-carbonylmethyl~-benzoic acid, AJ = 4-[~6-chloro-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl~-benzoic acid, AX = 4-l(-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl~-cinnamic acid, AL - 3-[4~[(-phenyl-2-piperidino-benzyl)-aminocarbonyl-25methyl]-phenyl~-propionic acid, AM = 4-[t4-chloro-~-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoic acid, 12~773 AN = 4-[(6-methyl-~-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoic acid, AO = 4-~(4-methyl--phenyl-2-piperidino-benzyl)-amino-carbonylmethyl~-benzoic acid, AP = 4-[(~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzaldehyde, AQ = 4-[(2-(2-methyl-piperidino)-~-phenyl-benzyl)-aminocarbonylmethyl~-benzoic acid, AR = 4-[(2-(3-methyl-piperidino)-a-phenyl-benzyl)-aminocarbonylmethyl~-benzoic acid and AS = 4-[(3-chloro--phenyl-2-piperidino-benzyl~-amino-carbonylmethyl]-benzoic acid:

1. HyPoql~caemic activity - The hypoglycaemic activity of the test substances was tested on female rats of a single strain weighing from 180 to 220 9, which had been kept without food or drink for 24 hours before the start of the test.
The substances to be tested were suspended in 1.5%
methylcellulose immediately before the start cf the test and administered by oesophageal tube.
Blood samples were taken immediately before the administration of the substance and then 1, 2, 3 and 4 hours afterwards, in each case from the retro-orbital venous plexus. From each sample, 50 ~1 were deproteinated with 0.5 ml of 0.33 N perchloric acid and then centrifuged. The glucose in the supernatant phase was determined by the hexokinase method using an analytical photometer. The results were evaluated statistically using the t test according to Student, taking p - 0.05 as the limit of significance.
The following Table contains the values found in percent, compared with the controls:

~Z~4773 _ -5 mg/kg 1 mg/kg Substance 1 2 3 4 1 2 3 4 _ L -42 -45 -31 -22 -14 -18 -14 n.s M -46 -43 -40 -36 -33 -30 -21 n.s O -38+ -31+ n.s.+ n.s.+
P -49 -43 -34 -22 -37 ~19n.s. n.s Q -28 -13 n.s.n.s.

S -49 -42 -30 -17 -29 -20 -10 n.s ~ -45 -41 -46 -40 -37 -23 -30 -18 W -46 -45 -39 -37 -36 -25 -16 n.s X -34+ -21+ -17+ -14 30 AA -30 -33 -14 n.s. -15 -15 -13 n.s AB -43 -38 -36 -27 -26 -15 n.s. n.s AE -3Q -28 -39 -36 -21 -20 -22 n.s ~Z~4773 ~ 41 -5 mg/kg 1 mg/kg Substance1 2 3 4 1 2 3 4 _ AF -43 -39 -30 -26 -17-19 n. 5. n. s AG -49 -50+ -36 -31+ -18n.s. n.s. n.s AH -41 -37 -20 n.s. -26 -14 n.s. n.s AK -48 -47+ -40+ -45+ -32 -19 -10 -17 AL -43+ -41+ -38+ -34 -40 -31 -23 -12 AM -34 -35 -32 -29 -11 -13 n.s. n. s AM -39 -35 -27 -26 -27 -24 n. s. n.s AQ -32 -31 -24 -19 -16 -11 n.s. n. s AR -35 -30 -29 -31 -13 - 9 n.s. n.s AS I-45 -44 -42 -32 -21 -13 n.s. n. s + = at lQ mg/kg n.s. = statistically not significant 2. Acute toxicitY
The toxic effect was tested in male and female mice of the same strain weighing from 20 to 26 9, after oral administration of a single dose (suspended in 1% methylcellulose) over an observation period of 14 days:

~2~ 73 ~ 42 ~

Substance Approximate acute toxicity A > 1 000 mg/kg p.o. (0 out of 6 animals died) C ~2 000 mg/kg p.o. (0 out of 6 animals died) D > soO mg/kg p.o. (0 out of 6 animals diPd) J >2 000 mg/kg p.o. (0 out of 10 animals died) AA >1 000 mg/kg p.o. (0 out of 10 animals died) AB ~l 000 mg/kg p.o. (0 out of 10 animals died) AC ~1 000 mg/kg p.o. (0 out of 10 animals died) AD >1 oon mg/kg p.o. (0 out of 10 animals died) AE ~1 000 mg/kg p.o. (0 out of 10 animals died) AG >1 000 mg/kg p.o. (0 out of 10 animals died) In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of diabetes mellitus.
According to a yet further feature of the present invention, we provide pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula I as hereinbefore defined or a tautomer thereof or a physiologically compatible salt of these compounds, in association with one or more pharmaceutical carriers or excipients.
For pharmaceutical administration the compounds of general formula I or tautomers thereof or their physiologically compatible salts may be incorporated into conventional preparations in either solid or liquid formr optionally in combination with other active ingredients. ~he compositions may, for example, be presented in a form suitable for oral or parenteral admini~tration. Preferred forms include, for example, tablets, coated tablets, capsules, powders or suspensions.
The active ingredient may be incorporated in excipients customarily employed in pharmaceutical ~2~4773 compositions such as, for example, corn starch, lactose, celulose, magnesium stearate, citric acid, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
Advantageously, the compositions may be formulated as dosage units, each dosage unit being adapted to supply a fixed dose of active ingredient.
A suitable single dose for adults is 1-50 mg, preferably 2.5-20 mg of active ingredient, once or twice per day. The total daily dosage may, however, be varied according to the compounds used, the subject treated and the complaint concerned.
According to a still further feature of the present invention, we provide a method of treating a patient suffering from or susceptible to diabetes mellitus or disorders of the intermediate metabolism or the cardiac circulatory system, which comprises administering to the said patient an effective amount of a compound of general formula I as hereinbefore defined or a tautomer thereof or a physiologically compatible salt thereof.

~.214773 The following non-limiting Examples are intended to illustrate the invention:
Example 1 Ethyl 4-[N-~-(4-methYl-phenyl)-2-pi~eridino-ben~l]-5 aminocarbonYlmethyl]-benzoate 4.7 9 (18 mmol) of triphenylphosphine, 3 9 (30 mmol) of triethylamine and 1.5 mm (15 mmol) of carbon tetrachloride are added successively to 4.2 g (15 mmol) of a-(4-methyl-phenyl)-2-piperidino-benzylamine and 3.4 9 (16.5 mmol) of 4-ethoxycarbonyl-phenylacetic acid, dissolved in 40 ml of acetonitrile. The reaction mixture is stirred at 50C for 2 hours, then concentrated by evaporation and, after acidification with 6N hydro-chloric acid, extracted with ethyl acetate. The acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The evaporation residue is triturated 20 with ethanol and suction filtered.
Yield: 4.55 9 (65~ of theory), M.p.: 177-178C
Calculated: C 76.57 H 7.28 N 5.9S
Found: 76.19 7.16 5.82 The following were prepared analogously to Example 1:

(a~ Ethyl 4-[N-I-(3-methyl-phenyl)-2-piperidino-benzyl~-aminocarbonyl-methyl]-benzoate Yield: 48% of theory, .p.: 159-160C
Calculated: C 76.57 H 7.28 N 5.g5 Found: 76.80 7.35 5.76 (b) Ethyl 4-[N-1-(2-methyl-phenyl)-2-piperidino-benzyl~-aminocarbonylmethyl~-benzoate Yield: 35.4~ of theory, M.p.: 196-198C

~21~

Calculated: C 76.57 H 7.28 N 5.95 Found: 76.65 7.35 5.90 (c) Ethyl 4-[N-1-(4-methoxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 45% of theory, M.p.: 167-168C
Calculated: C 74.05 H 7.04 N 5.76 Found: 73.72 6.99 5.62 (d) Ethyl 4-~N-[a-~4-benzyloxy-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoate Yield: 96% of theory, M.p.: 154-155C
Calculated: C 76.84 6.81 N 4.98 Found: 76.68 6.68 S.03 (e) Ethyl 4-~N-[a-(4-fluoro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]benzoate Yield: 58% of theory, M.p.: 174-176C
Calculated: C 73.40 H 6.58 N 5.90 Found: 73.55 6.72 5.91 2S (f) Ethyl 4-~N-[a-(2-fluoro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 83% of theory, M.p.: 173-175C
Cal~ulated: C 73.40 H 6.58 N 5.90 Found: 73.61 S.62 5.85 lg) Ethyl 4-[N-~-(4-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 57~ of theory, M.p.: 178-181~C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 71.10 6.56 5.26 7.11 ~Z14773 (h) Ethyl 4-~N-~-(3-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 71~ of theory, M.p.: 153-156C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.86 6.26 5.65 7.25 li) Ethyl 4-[N-la-(2-chloro-phenyl)-2-piperidin benzyl~-aminocarbonylmethyl]-benzoate Yield: 66% of theory, M.p.: 196-198C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.90 6.30 5.61 7.10 (k) Ethyl 4-[N-Ea-(4-methylmercapto-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 84% of theory, M.p,: 173-175~C
Calculated: C 71.68 ~ 6.82 N 5.57 C1 6.38 Found: 71.92 6.97 5.45 6.21 (1) Ethyl 4-~N-[5-chloro-a-(2-chloro-phenyl~-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 92% of theory, M.p.: 213-215C
Calculated: C 66.28 H 5.75 N 5.33 Cl 13.49 Found: 66.45 5.86 5.25 13.51 (m) ~thyl 4-~N-12-piperidino-a-(2-pyridyl)-benzyl]-aminocarbonylmethyl~-benzoate Yield: 51% of theory, M.p.: 158-159C
Calculated: C 73.50 H 6.83 N 9.18 Found: 73.40 6.95 9.10 (n~ ~thyl 4-tN-~2-piperidino-3-(3-pyridyl)-benzyl]-aminocarbonylmethyl]-benzoate 1~14773 Yield: 85~ of theory, M~p.: 172C
Calculated: C 73.50 H 6.83 N 9.18 Found: 73.42 6.76 9.25 (o) Ethyl 4-~N-[2-piperidino-~-(4~pyridyl)-benzyl]-aminocarbonylmethyl]-benzoate Yield: 20% of theory, M.p.: 150-152C
Calculated: C 73.50 H 6.83 N 9.18 Found: 73.61 6.91 9.15 (p) Ethyl 4-~N-(6-chloro-~-phenyl-2-piperidinO-ben aminocarbonylmethyl~-benzoate Yield: 12% of theory, M.p.: Oil Calculated: molecular ion peak m/e - 490/492 Found: molecular ion peak m/e = 490/492 (q) Ethyl 4-[N-(4-chloro-~-phenyl~2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 37~ of theory, M.p.: 148-150C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.81 6.25 5.61 7.12 (r) Ethyl 4-[N-(3-chloro-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 74% of theory, M~pr 176-178C
Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 ~ound: 70.59 6.25 5.68 7.16 (~ Ethyl 4-~N-(6-methyl-~-phenyl-2-piperidinD-benzyl)-aminocarbonylmethyl]-benzoate Yield: 65% of theory, M.p.: Oil 1;~4773 Calculated: molecular ion peak m/e = 470 Found: molecular ion peak m/e = 470 ~t) Ethyl 4-[N-~5-methyl-~-phenyl-2-piperidino-benzyl)-S aminocarbonylmethyl]-benzoate Yield: 48% of theory, M.p : 171-173C
Calc~lated: C 76.57 H 7.28 N 5.95 Found: 76.75 7.35 5.72 (u) Ethyl 4-~N-(4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoate Yield: 76% of theory, M.p.: 133-135C
Calculated: C 76.57 H 7.28 N 5.~5 Found: 76.51 7.16 5.83 (v) Ethyl 4-~N-(5-methoxy-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 10% of theory, M.p.: 122-125C
Calculated: molecular ion peak m/e = 486 Found: molecular ion peak m/e = 486 (w) Ethyl 4-lN-(6-methoxy-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 97~ of theory, M.p.: Oil Calculated: molecular ion peak m/e = 486 Found: molecular ion peak m/e - 486 (x) ~thyl 3-chloro-4-tN-~n-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Yield: 42% of theory, M.p.: 175-176C
Calculated: C 70.93 H 6.36 N 5.71 Cl 7.22 Found: 70.65 6.36 5.50 7.29 ~l2~4~73 (y) Ethyl 4-[N-(2-dimethylamino-~-phenyl-benzyl)-aminocarbonylmethyl]-benzoate Yield: 67% ~f theory, M.R.: 116-118C
Calculated: C 74.97 H 6.77 N 6.73 Found: 75.13 6.60 6.78 (z) Ethyl 4-lN-(2-di-n-propylamino-a-phenyl-benzyl)-aminocarbonylmethyl~-benzoate Yield: 76~ of theory, M.p.: 38-139C
Calculated: C 76.2~ ~ 7.6~ N 5.93 Found: 76.41 7.79 5.81 lS (aa) Ethyl 4-~N-[2-(octahydro-lH-azonino)~-phenyl-benzyl]-aminocarbonylmethyl]-benzoate Yield: 71% of theory~
M.p.: Oil Calculated: molecular ion peak m/e = 498 Found: molecular ion peak m/e = 498 (ab) Ethyl 4-[N-[5-chloro-2-(2-methyl-piperidino)--phenyl-benzyl]-aminocarbonylmethyl]-benzoate Yield: 36.5% of theory, M.p.: 171-173C
Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01 Found: 71.45 6.68 5.59 7.20 (ac~ Ethyl 4-~N-[2-(3,3-dimethyl-piperidino)-~-phenyl-benzyl]-aminocarbonylmethyl~-benzoate Yield: 91% of theory, M.p. 146-148C
Calculated: C 76.82 H 7.49 N 5.78 Found: 76.91 7.55 5.61 Example 2 Ethyl 4- [N- ~a- ( 4-chloro-phenyl~-2-piperidino-benzyl]-aminocarbonyl-methYl~-benzoate A solution of 5 9 (22.1 mmol) of 4-ethoxycarbonyl-phenylacetyl chloride in 20 ml of chloroform is added dropwise, whilst cooling with ice, to a solution of 6.02 9 (20 mmol) of -(4-chloro-phenyl)-2-piperidino-benzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform. The mixture is stirred for 2 hours at ambient temperature then added to water and extracted with chloroform. The extracts are dried and concentrated by evaporation. The evaporation residue is chromatographed on silica gel using toluene/
ethyl acetate (5:1) as eluant.
Yield: 5.6 9 (57% of theory), M.p.: 178-181C
Calculated: C 70.94 6.36N 5.71Cl 7.22 Found: 71.09 6.47 5.61 7.10 The following was prepared analogously to Example 2:

(a) Ethyl 4-tN-[5-chloro-2-(3-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoate Yield: 54% of theory, M.p.: 178-lB0C
Calculated: C 71.24 H 6.58N 5.54 Cl 7.01 Found: 70.91 6.64 5.75 7.01 Example 3 4-[N-~-(4-methyl-phenyl)-2-piperidino-benzyl]-amin~-carbonyl-methYl]-benzoic acid 4.4 9 (9.35 mmol) of ethyl 4-tN-t~-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl)-benzoate are dissolved in 150 ml of ethanol, with heating. Then 20 ml of lN sodium hydroxide solution ~2147 73 are added and the mixture is stirred for 3 hours at 50~C. 29 ml of lN hydrocloric acid are then added to the reaction mixture and any excess ethanol is eliminated by evaporation in a rotary evaparator.
The remaining aqueous suspension is filtered and the precipitate is thoroughly washed with water.
It is then recrystallised from acetonitrile.
Yield: 2.45 9 (59.3% of theory) M.p.: 226-228C
Calculated: C 75.99 H 6.83 N 6.33 Found: 75.60 6.75 6.29 The following were prepared analogously to Example 3:

(a) 4-[N-ta-(3-Methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl~-benzoic acid Yield: 72% of theory, M.p.: 202-203C
Calculated: C 75.99 H 6.83 N 6.33 Found: 75.64 6.91 6.37 (b) 4-tN-ta-(2-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl~-benzoic acid Yield: 42.6% of theory, M.p.: 285-290C
Calculated: C 75.99 ~ 6.83 N 6.33 Found: 76.05 6.98 6.25 lc) 4-LN-ta-t4-methoxy-phenyl)-2-piperidino-benzyl~-aminocarbonylmethyl]-benzoic acid Yield: 72.4 of theory, M.p.: 228-230C
Calculated: C 73.34 H 6.59 N 6.11 Found: 73.22 6.61 6.13 12~4773 (d) 4~[N-~-(4-benzyloxy-phenyl)-2-piperidino-benzyl~-aminocarbonylmethyl~-benzoic acid Yield: 57~ ~f theory, M.p.: 219-221C
Calculated: C 76.38 6.41 N 5.24 Found: 76.05 6.44 5.24 (e, 4-[N-[-(4-fluoro-phenyl)-2-piperidino-benzyl]-- aminocarbonylmethyl]benzoic acid Yield: 75% of theory, M.p.: 238-240C
Calculated: C 72.63 H 6.09 N 6.27 Found: 72.9B 6.29 6.32 ~f) 4-lN-[~-(2-fluoro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 87% of ~heory, M.p.: 280 283C
Calculated: C 72.63 H 6.09 N 6.27 Found: 72.70 6.10 6.37 (g) 4-[N-[~-(4-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl~-benzoic acid Yield: 89% of theory, M.p.: 241-242C
Calculated: C 70.05 R 5.88 N 6.05 Cl 7.66 Found: 69.74 6.05 6.01 7.64 (h) 4-~N-~-(3-chloro-phenyl)-2-piperidino-benzyl]-~minocarbonylmethyl]-benzoic acid Yield: 53% of theory, M.p.: 223-225C
Cal~ulated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 70.28 5.98 5.78 7.84 (i~ 4-[N-~-52-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl~-benzoic acid ~147~3 Yield: 98% of theory, M.p.: 303-305C
Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 69.88 6.05 ~.87 7.74 (kJ 4-~N-[-(4-methylmercapto-phenyl)-2-piperidin~-ben~yl]-aminocarbonylmethyl]-benzoic acid Yield: 84.6% of theory, M.p.: 225-227C
Calculated: C 70.86 H 6.37 N 5.90 Cl 6.75 Found: 70.34 6.37 5.68 6.82 (1) 4-[N-[5-chloro-a-(2-chloro-phenyl)-2-piperidino-benzyl~-aminocarbonylmethyl]-benzoic acid ~ield: 90% of theory, M.p,: 317-320C
Calculated: C 65.19 H 5.27 N 5.63 Cl 14.25 Found: 64.87 5.34 5.69 14.22 (m) 4-[N-[2-piperidino-~-(2-pyridyl)-benzyl]-amino-carbonylmethyl]-benzoic acid Yield: 81% of theory, M.p,: 160-161C
Calculated: C 72.71 H 6.34 N 9.78 Found: 72.43 6.39 10.00 (n) 4-tN-[2-piperidino-a-(3-pyridyl)-benzyl~-amino-carbonylmethyl3-benzoic acid Yield: 72% of theory, M.p.: 252-253C
Calculated: C 72.71 H 6.34 N 9.78 Found: 72.56 6.53 9.60 (o) 4-[N-~2-piperidino-a-(4-pyridyl)-benzyl]-amino-carbonylmethyl]-benzoic acid Yield: 68.5~ of theory, .p.: from 260C (decomposition) ~14773 Calculated: C 72.71 H 6.34 N 9.7B
Found: 72.31 6.29 9.63 ~p) 4-~N-(6-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 82% of theory, M.p.: 91-94C
Calculated: C 70.04 ~ 5.88 N 6.05 Cl 7.66 Found: 69.61 5.77 5.967.78 (q) 4-~N-(4-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoic acid Yield: 61~ of theory, M.p.: 221-223~C
Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 69.73 5.89 5.87 7.52 (r) 4-~N-(3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 83~ of theory, M.p.: 210-213C
Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 70.31 6.03 5.90 7.79 (s) 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-ben%oic acid Yield: 64% of theory, M.p.: 165-170C (sintering from 150C) Calculated: C 75.99 H 6.83 N 6.33 Found~ 75.73 6.96 6.14 (t3 ~-~N-(5-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ~ield: 97~ of theory, M.p.: 243-245C
C~lculated: C 75.g9 H 6.83 N 6.33 Found: 75.60 7.01 6.31 ~2~477;~

(u) 4-[N-(4-methyl--phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 96% of theory, M.p.: 202-203~C
Calculated: C 75.99 H 6.83 N 6.33 Found: 76.04 6.78 6.23 (v) 4-[N-(5-methoxy-a~phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 27% of theory, M.p.: 217-220~C (sintering from 203C) Calculated: C 73.34 H 6.5~ N 6.11 Found: 72.92 6.68 5.99 (w) 4-[N-(6-methoxy-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 51.5% of theory, M.p.: 90-95C
Calculated: C 73.34 H 6.59 N 6.11 Found: 73.03 6.42 5.86 (x) 4-1N-[5-chloro-2-(3,5-cis-dimethyl-piperidino)-c-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 81~ of theory, M.p.: 253-255C
Calculated: C 70.93 H 6.36 N 5.71 Cl 7.22 Found: 70.68 6.51 5.73 7.36 ty) ~-tN-(2-dimethylamino-a-phenyl-benzyl)-aminocarbonyl-methyl~-benzoi~ acid Yield: 83~ of theory, M.p.: 183-lô4C
Calculated: C 74.20 ~ 6.23 N 7.21 Found: 74.31 6.27 7.16 (z) 4-[N-(2-di-n-propylamino-a-phenyl-benzyl)-amino-carbonylmethyl]-benzoic acid ~Z14773 Yield: 79% of theory, M.p,: 202-204C
Calculated: C 75.64 H 7.2~ N 6.30 Found: 75.74 7.31 6.15 (aa~ 4-[N-[5-chloro-2-(2-methyl-piperidino)-~-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 52% of theory, M.p.: 280-282C
Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: 70.14 6.10 5.75 7.45 (ab) 4-[N-[5-chloro-2-(3-methyl-piperidino)--phenyl-benzyl~-aminocarbonylmethyl~-benzoic acid Yield: 66% of theory, M.p.: 246-248~C
Calculated: C 70.50 ~ 6.13 N 5.87 Cl 7.43 Found: 70.16 6.07 5.87 7.30 (ac) 4-~N-[2-(3,3-dimethyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl~-benzoic acid Yield: s9% of theory, M.p.: 238-240C
Calculated: C 76.28 H 7.07 N 6.14 Found: 76.38 7.28 6.11 (ad) 3-chloro-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: ~6~ of theory, M.p.: 236-239C
- Calculated: C 70.04 H 5.88 N 6.05 Cl 7.66 Found: 69.88 5.77 5.86 7.ôl ~ae) 4-lN-[2-(3,5-cis-dimethyl-piperidino)-5-niero-~-phenyl-benzyl]-aminocarbonylmethyl~-benzoic acid Yield: 81% of theory, M.p~: from 255C ~decomposition) 47~3 Calculated: C 69.44 H 6.23 N 8 . 38 Found: 68.95 6.44 8.53 (af) 4-lN-~2-(octahydro-lH-azonino)-~-phenyl-benzyl]-amino-carbonylmethyl~-benzoic acid Yield~ 62.5% of theory, M.p.: 235-237C
Calculated: C 76.56 H 7.28 N 5.95 Found: 76.50 7. 30 5 . 9 4 (ag) 4-[N-(5-hydroxy--phenyl-2-piperidino-benzyl)-amino-~arbonylmethyl]-benzoic acid Yield: 71% of theory, M.p.: 98-101C
Calculated: C 72.95 H 6.35 N 6.30 Found: 72.98 6.406.47 Example 4 4-~N-[~-(4-hydroxv-phenyl)-2-piperidino-benzyl]-amino- 0 carbonYl-methyl]-benzoic acid 1.1 9 (2 mmol) of 4-[N-[a- (4-benzyloxy-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl~-benzoic acid are suspended in 200 ml of ethanol and catalytically debenzylated at 50C, under a hydrogen pressure of S bar, in the presence of 0.4 9 of 10% palladium/charcoal.
Then the catalyst is filtered off, and the filtrate is concentrated by evaporation and recrystallised from acetonitrile.
Yield: 720 mg (66.7% of theory), M.p.: 202-204C
Calculated: C 72.95 ~ 6.35 N S.30 Found: 72.65 6.176.20 ~2147 73 The following was prepared analogously to Example 4:
~a) Ethyl 4-[N-(5-hydroxy-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoate Yield: 93~ of theory, M.p.: 191-193C
Calculated: C 73.70 H 6.82 N 5.93 Found: 73.52 6.57 5.61 Example 5 4-[N-[~-(4-Methyl-phenyl)-2-Pi~eeridino-benzyl]-amino-carbonylmethYl]-benzyl alcohol 2.5 9 (5.3 mmol) of ethyl 4-[N-~-(4-methyl-phenyl)-2-piperidino-benzyl~-aminocarbonylmethyl]-benzoate are added in batches to a suspension of 0.5 9 (13.2 mmol) of lithium aluminium hydride in 50 ml of absolute tetrahydrofuran. The mixture is stirred for a further 30 minutes at ambient temperature, decomposed by the dropwise addition of 4 N sodium hydroxide solution and filtered to remove the sodium aluminate formed. The filtrate is concentrated by evaporation and the residue is recrystallised from a little toluene.
Yield: 0.98 9 ~43~ of theory) M.P. 144-146C
Calculated: C 78.47 H 7.53N 6.54 Found: 78.20 7.39 6.58 The following was prepared analogously to Example 5:
(a) 4-[N-[~-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzyl alcohol Yield: 31.S% of theory ; M.p. 143-145C
Calculated: C 78.23 H 7.29 N 6.76 Found: 78.13 7.30 6.62 12~4 773 ExamPle 6 4-tN-ta-~4-methYl-phenyl1-2-piperidino-benzYll-amino-carbonyl-methyl]-benzaldehyde 8.85 9 (20 mmol) of 4-[N-[-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylme~hyl]-benzoic acid and 3.25 9 (20 mmol) of N,N'-carbsnyldiimidazole are refluxed in 100 ml of absolute tetrahydrofuran for 2 hours. Then the mixture is concentrated by evaporation and after the addition of 50 ml of pyridine and 3.7 9 (20 mmol) of 4-toluenesulphonic acid hydrazide, the mixture is refluxed for a further 2 hours. It is then poured on to ice water and suction filtered and the precipitate is dried. The resulting crude toluenesulphonic acid hydrazide of the carboxylic acid used is mixed with 20 g of anhydrous sodium carbonate and heated to 170C in 50 ml of ethylene glycol for 2 hours. Then it is added to water and extracted with chloroform. The concentrated extracts are purified by column chromatography on silica gel using toluene/ethyl acetate 5:1 as eluant.
Yield: 1.73 9 (21% of theory) M.p.: 144-146C
Calculated: C 78.84 H 7.09N 6.57 Found: 78.95 7.19 6.50 The following was prepared analogously to Example
6:
(a) 4-[N-[a-Phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl~-benzaldehyde Yield: 29~ of theory M.p.: 168-170C
Calculated: C 78.61 H 6.84 N 6.79 Found: 78.60 7.00 6.72 3S Example 7 4-tN-~a-~4-Methyl-phen~-2-piperidino-benzyl~-amino-carbonyl-methYl~-benzaldehyde 0.5 9 ~1.2 mmol) of 4-tN-ta-(4-methyl-phenyl)-~Z~4~73 2-piperidino-benzyl]-aminocarbonylmethyl]-benzyl alcohol are added to a suspension of 0.4 9 (1.5 mmol) of pyridinium chlorochromate in 2 ml of chloroform.
After 12 hours at ambient temperature, ether is added, the mixture is filtered and the concentrated filtrate is purified by column chromatography on silica gel (eluant: toluene/ethyl acetate = S:1).
Yield: 0.3 9 (60~ of theory) M.p.: 145-146C
Calculated: C 78.84 H 7.09 N 6.57 Found: 78.97 7.12 6.57 The following was prepared analogously to Example
7:
(a) 4-tN-(~-Phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzaldehyde Yield: 40% of theory M.p.: 170C
Calculated C 78.61 H 6.84 ~ 6.79 Found: 78.59 6.87 6.61 Example 8 Ethyl 4-[N-ta-(4-methY1-phenyl)-2-piperidino-benzyl~-aminocarbonyl-methyl]-cinnamate 427 mg (1 D ol) of 4-[N-[~-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzaldehyde are added to an ethereal solution of 450 mg (2 mmol) of ethyl diethylphosphonoacetate and 100 mg (2 mmol) of 50% sodium hydride. After the mixture has been stirred overnight, water is added and the resulting mixture is extracted with chloroform and purified by column chromatography on silica gel using toluene/ethyl acetate (5:1) as eluant.
Yield: 0.18 9 ~36% of theory) M.p.: 176-180C
Calculated: C 77~39 ~ 7.31 N 5.64 Found: 77.64 7.25 5.71 ~2~ 73 The following was prepared analogously to Example
8:
~a) Ethyl 4-[N-(a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-cinnamate Yield: 28.6~ of theory M.p~: 159-161C
Calculated- C 77.14 H 7.10 N 5.80 Found: 77.28 7.21 5.65 Example 9 4-[N-[a-(4-Methyl-ehenyl)-?-pi~eridino-benzyl)-amin carbonyl-methyl~-cinnamic acid Prepared by alkaline saponification of ethyl 4-[N-Cc-(4-methyl-phenyl)-2-piperidino-benzyl]-amino-carbonyl-methyl~-cinnamate analogously to ~xample 3.
Yield: 84~ of theory M.p.: 173-176C
Calculated: C 76.90H 6.88N 5.98 Found: 77.24 7.01 5.64 The following was prepared analogously to Example
9:
(a) 4-[N-(a-Phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-cinnamic acid Yield: 75~ of theory M.p.: 177-180C
Calculated: C 76.62 H 6.~5 N 6.16 Found:76.75 6.57 6.07 Exa~le 10 Ethyl 4-~N-~-(3-methyl-~e~nvl~-2-piperidino-benzyl~-aminocarbonylmethyl~-benzoate A mixture of 0.22 9 ~0.8 mmol) of ~-(3-methyl-phenyl-2-piperidino-benzyl alcohol and 0.15 9 (0.8 mmol) of ethyl 4-cyanomethyl-benzoate ~n 2 ml of o-dichloro-benzene i~ added dropwise, at ambient temperature, to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated ~2147~3 sulphuric acid. After 2 hours' stirring, the mixture is poured onto ice-water, extracted once with ether, made alkaline with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is concentrated by evaporation and the residue is recrystallised from ethanol.
Yield: 0.22 9 (60% of theory) M.p.: 158-159C
Calculated: C 76.57 H 7.28 N 5.95 Found: 76.41 7.39 5.76 The following was prepared analogously to Example
10:
(a) Ethyl 4-[N-~2-(3,5-cis-dimethyl-piperidino)-5-nitro-a-phenyl-benzyl~-aminocarbonylmethyl~-benzoate Yield: 57~ of theory M.p.: 170-173C
, Calculated: C 70.30 H 6.66 N 7.93 Found: 70.05 6.687.81 Example 11 4-tN-la-(4-methYl-Phen~l)-2-piperidino-benzyl]-amin carbonyl-methyl3-benzoic acid 240 mg (5 mmol) of 4-[N-t5-chloro-~-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid are catalytically dehalogenated in 80 ml of ethanol/dioxan (1/1) in the presence of 0.1 9 of 10~ palladium on charcoal at 50C and under a hydrogen pressure of 5 bar. After cooling, the catalyst is filtered off. The filtrate is concentrated by evaporation and the residue is recrystallised from ethanol.
Yield: 0.16 g (72% of theory) M.p.: 226-228C
Calculated: C 75.99 H 6.83 N 6.33 Found: 75.81 6.736.10 ~2~4773 The following was prepared analogou~ly to Example
11:
(a) 4-[N-L2-(2-methyl~piperidino)-~-phenyl-benzyl]-aminocarbonylmethyl)-benzoic acid From 4-[N-[5-chloro-2-(2-methyl-piperidino)-a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 68% of theory M.p.: 246-248C
Calculated C 75.~9 H 6.83 N 6.33 Follnd: 75.57 7.10 6.44 (b) 4-[N-[2-(3-Methyl-piperidino)-Q-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid From 4-[N-~5-chloro-2-(3-methyl-piperidino)-a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Calculated: 43% of theory M.p.: 22B-230C
Calculated: C 75.99 H 6.83 N 6.33 Found: 75.91 Ç.82 6.33 Example 12 Ethyl 4-tN-[~-(4-methyl-phenyl)-2-~iperidino-benzyl] -aminocarbonyl-methyl] -benzoate A solution of 2.78 9 (10 mmol) of freshly prepared (4-methyl-phenyl)-(2-piperidinophenyl)-ketimine in 50 ml of methylenechloride is mixed with 1.5 ml (11 mmol) of triethylamine and thPn a solution of 2.5 9 (11 mmol) of 4-ethoxycarbonyl-phenylacetic acid c:hloride in 20 ml of methylene chloride is added dropwise thereto, whilst the mixture is cooled with ice. After 1 hour at ambient temperature it is poured onto ice-water and extr~acted with methylene chloride. The extracts are dried and concentrated by evaporation and the evaporation residue is purified by column chromatography on ~ilica gel (eluant: toluene/ethyl acetate 10:1).
The crude acylimine is dissolved in dimethylformamide and, after the addition of 0.5 g of palladium (10%

1~14773 ~ - 64 -on charcoal), it is hydrogenated at ambient temperature under a hydrogen pressure of 5 bar. After the calculated quantity of hydrogen has been taken up the catalyst is removed by filtering, the filtrate is concentrated by evaporation and the residue is recrystallised from a little alcohol.
Yield: 2.8 g (60% of theory) M.p.: 175-177C
Calculated: C 76.57 H 7.28 N 5.95 Found: 76.41 7.19 5.76 ExamPle 13 4-[N-[a-(4-methyl-~henyl)-2-piperidino-~enzyl]-aminocarbonyl-methyl]-benzonitrile Prepared from ~-(4-methyl-phenyl)-2-piperidino-benzylamine and 4-cyano-phenylacet;c acid analogously to Example 1.
Yield: 64% of theory M.p.: 144-146C
Calculated: C 79.40R 6.90N 9.92 Found: 79.10 6.90 9.78 The following was prepared analogously to Example 13:
(a) 4-~N-(a-Phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl~-benzonitrile Yield: 53% of theory M.p. 178-181C
Calculated: C 79.18R 6.65 N 10.26 Found: 78.84 6.55 10.24 Example 14 Ethyl 4-[N-~a-(4-methyl-phenYl)-2-Piperidino-benzyl]
minocarbonylmethyl~-benzoate 4.2 9 (10 mmol) of 4-~N-~a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyll-benzonitrile are refluxed for 24 hours with 50 ml of ethanolic hydrochloric ~cid. The mixture is then concentrated ~14773 by evaporation and the evaporation residue is mixed with aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract i6 concentrated by evaporation and the residue is triturated with ethanol and suction filtered.
Yield: 2.9 9 (61.6% of theory) M.p.: 177-179C
Calculated: C 76.57 H 7.28N 5.95 Found: 76.41 7.35 5.76 The following was prepared analogously to Example 14:
(a~ Ethyl 4-[N-(5-methyl-~-phenyl-2-piperidin~-benzyl)-aminocarbonylmethyl]-benzoate Yield: 57% of theory M.p.: 170-173C
Calculated: C 76.57 H 7.28 N 5.95 Found: 76.41 7.19 5.65 ExamPle 15 Ethyl 4-[N-[5-chloro-~-(2-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethYl]-benzoate 10 mmol of ethyl 4-[N-[~-(2-chloro-phenyl)-5-nitro-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate are dissolved in 50 ml of dimethylformamideand, after the addition of 1 9 of Raney nickel, hydro-genated at 60C under a hydrogen pressure of 6 bar.
Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue, consisting of ethyl 4-~N-[5-amino-~-(2-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoate is dissolved in 100 ~1 of ~oncentrated hydrochloric acid. Whilst the mixture is cooled with ~ce, a solution of 1.0 9 ~14 mmol) of sodium nitrite in 10 ml of water is added dropwise thereto and the resulting mixture is stirred for 1 hour at 0 to 5C. The reaction mixture is then added dropwise to a solution of 3 g of copper ~I) chloride in 2~ ml of concentrated hydro-~2~4~73 chloric acid. After 1 hour's stirring, the mixture is made alkaline with sodium hydroxide solution and extracted with chloroform~ The concentrated chloroform extracts are purified by column chr~mat~graphy on silica gel using toluene/ethyl acetate (5:1) as eluant.
Yield: 1.5 g ~28.6~ of theory) M.p.: 213-215C
Calculated: C 66.28 H 5.75N 5.33Cl 13.49 Found: 66.40 5.91 5.41 13.40 The followinq was prepared anal~g~usly t~ Example 1~
(a) Ethyl 4-[N-15-chloro-2-(3,5-cis-dimethyl-piperidino)-a-phenyl-benzylj-aminocarbonylmethyl]-benzoate ~ield: 28% of theory M.p.: 188-191C
Calculated: C 71.72 H 6.80 N 5.40 Cl 6.83 Found: 71.95 6.85 5.35 6.77 Example 16 3-[4-~N-(a-(4-MethYl-PhenYl)-2-piperidino-benzyl) aminocarbon~lmethyl]-phenyl]-pro~ionic acid 0.91 9 (2 mmol) of 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarb~nylmethyl]-cinnamic acid are dissolved in 50 ml of methanol and, after the addition of 0.5 g of palladium (10% on charcoal), the mixture is catalytically hydrogenated at ambient temperature under a hydrogen pressure of 3 bar.
After the hydrogen uptake has ended, the catalyst ls filtered off and recrystallised from a little acetonitrile.
Y~eld: 0.68 9 (74% of theory) M.p.: 146-148C
Calculated: C 76.57 H 7.28N 5.95 Found: 76.41 7.19 5.61 The following was prepared analogously to Example 16:

121~773 (a) 3-[4-[N-(-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl3-phenyl]-propionic acid Yield: 65~ of theory M.p.: 97-99C
CalculatedO C 76.30H 7.06 N 6.13 Found: 76.35 6.95 5.91 Example 17 Sodium salt of 4-[N-(a-(4-methyl-phenyl~-2-piperidino- 0 benzyl)-aminocarbonylmethyl]-benzoic acid 442 mg (1 mmol) 4-~N~(a-(4-methyl-phènyl)-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoic acid are dissolved in 25 ml of ethanol and mixed with 1 ml of 1 N sodium hydroxide solution. The mixture 5 is then concentrated by evaporation in vacuo, 20 ml of acetone are added, the precipitate obtained is suction filtered and washed with ethyl acetate.
Yield: 410 mg ~85% of theory) M.p.: 295-300C
Calculated: C 72.40 H 6.29 N 6.03 Found: 72.15 6.46 5.93 The following was prepared analogously to Example 17:
(a) Ethanolamine salt of 4-tN-(-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoic acid Yield: 75% of theory M.p.: 188-191C
Cal~ula~ed: C 71.55~ 7.41 N 8.34 Found: 71.16 7.48 8.52 b) Diethanolamine salt of 4-tN-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 81~ of ~heory M.p.: 178-180C
Calculated: C 70.70~ 6.86 N 7.73 Found: 70.25 6.75 7.58 ~Z147~73 (c) Triethanolamine salt of 4~[N-(-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 76~ of theory M.p.: 160-165C
Calculated: C 69.01 H 7.67 N 7.10 Found: 68.91 7.64 7.45 (d) Ethylenediamine salt of 4-~N- (a- (4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoic acid Yield: 65% of theory M.p.: 160-163C
Calculated: C 71.69 H 7.62 N 11.15 Found: 72.04 7.80 10.96 Example 18 Ethyl 4-[N-(5-methoxy-a-Phenyl-2-piperidino-ben aminocarbonyl-methYl]-benzoate 472 mg ~1 mmol) of ethyl 4-[N-(5-hydroxy-~-phenyl-2-piperidino-benzyl~-aminocarbonylmethyl)-benzoate are dissolved in 25 ml of absolute dimethyl-formamide. After the addition of 50 mg of 50% sodium hydride the mixture is stirred for 30 minutes. Then 0.5 9 of methyl iodide are added dropwise and the resulting mixture is stirred overnight. To work it up, it is poured onto ice-water and extracted with methylene chloride. The concentrated extracts are purified by column chromat~graphy on silica gel using toluene/ethyl acetate 4:1 as eluant.
Yield: 260 mg (53% of theory) M.p.: 123-125C
Calculated: C 74.05 H 7.04 N 5.76 Found: 73.ô6 6.95 5.61 Example 19 Ethyl 4-~(2-methoxY-1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl methyl~-benzoate 0.49 9 ~2.34 mmol) of 4-ethoxycarbonyl-phenylacetic ~214773 acid, 0.73 9 (2.78 mmol) of triphenylphosphine, 0.50 ml (3.66 mmol) of triethylamine and 0.23 ml (2.34 mmol) of carbontetrachloride are added successively to a solution of 0.55 9 (2.34 mmol) of 2-methoxy-1-(2-piperidino-phenyl)-ethylamine in 5 ml of acetonitrile and the resultin~ mixture is stirred for 20 hours at ambient temperature. It is then concentrated by evaporation in vacuo and 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 = 10/2).
Yield: 0.45 9 (45% of theory) M.p.: 122-123C
Calculated: C 70.73 H 7.60N 6.60 Found: 71.04 7.48 6.39 The following was prepared analogously to Example 19:
(a) Ethyl 4-~ (3-chloro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 55% of theory M.p.: 141-143C
Calculated: C 68.33 H 7. 20 Cl 7.76 N 6.13 Found: 68.30 7.16 8.03 6.20 (b) Ethyl 4-[(1-(6-chloro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 73.9% of theory M.p.: 79-82~C
Calcula ed: C 68.33 R 7.28 Cl 7.76 N 6.13 Found: 68.45 7.24 7.ôO 6.09 (c) Ethyl 4-1(1-(4-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoate Yield: 62.1~ of theory, M.p.: 116-118C
Calculated: C 62.27 ~ 6.63 Br 15.93 N 5.58 Found: 62.53 6.48 15.38 5.66 ~d~ Ethyl 4-1(1-(4-nitro~2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoate ~Z~4773 Yield: 74.6% of theory, M.p.: 127-130C
Calculated: C 66.79 H 7.11 N 8.99 Fou~d: 66.88 7.08 9.15 (e) Ethyl 4-[(1-(3-methyl-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 68% of theory, M.p.: 145-147C
Calculated: C 74.28 ~ 8.31 N Ç.42 Found: 74.40 8.30 6.41 (f~ Ethyl 4-[(1-(4-methyl-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 54.7 of theory, M.p.: 113-114C
Calculated: C 74.28 H 8031 N 6.42 Found: 74.23 8.30 6.55 (g) Ethyl 4-[(1-(5-methyl-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 67.g~ of theory, M.p.: 149-150C
Calculated: C 74.28 H 8.31 N 6.42 Found: 74.38 8.21 6.49 (h) Ethyl 4-[(1-(6-methyl-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 47~ of theory, M.p.: 92-93C
Calculated: C 74.28 ~ 8.31 N 6.42 Found: 74.50 8.46 6.48 ~ thyl 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl-benzoate Yield: 57.3% of theory, M.p.: 122-125~C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.63 8.07 7.01 5 (k) Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-amin~-carbonylmethyl]-benzoate Yield: -71.5~ of theory, M.p.: 127-128C

~14773 Calculated: C 73.90 H 8.11 N 6.63 Found: 73.9~ 8.~6 6.72 (1) Ethyl 4-[(1-(2-(4-methyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmethyl3-benzoate S Yield: 51.1~ of theory, M.p.: 153-155C
Calculated: C 74.28 H 8.31 N 6.42 Found: 74.55 8.33 6.45 (m) Ethyl 4-~(1-(2-hexahydr~azepino-phenyl~-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 42.7~ of theory, M.p.: 145-147C
Calculated: C 74.28 H 8.31 N 6.42 Found: 73.98 8.26 6.58 (n) Ethyl 4-lll-(5-fluoro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 55% of theory, M.p.: 128-130C
Calculated: C 70.88 H 7.55 ~ 6.36 Found: 71.14 7.57 6.49 (o) Methyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl~-benzoate Yield: 63.2% of theory, M.p.: 147-148C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.66 7.ô8 6.80 (p) n-Butyl 4-[1-(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoate Yield: 50.9% of theory, M.p.: 117-119C (ether) Calculated: C 74.63 H ô.50 N 6.22 Found: 74.49 8.46 6.14 (q) Ethyl 3-chloro-4-[(1-~2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 14.9~ of theory, M.p.: ~20C
Calculated: m/e = 456/458 (1 chloro) Found: m/e = 456/450 (1 chloro)
12~4773 tr) Ethyl 4-[(1-(2-piperidino-phenyl)-4-penten-1 yl)-aminocarbonylmethyl]-benzoate Yield: 18.9% of theory, M.p.: 103-105C
S Calculated: C 74.62 H 7.89 N 6.45 F~und: 75.01 8.10 6.26 (s) Ethyl 4-~ 3-chloro-2-piperidino-phenyl)-l-ethyl)-aminocarbonylmethyl~-benzoate Yield: 58.~% of theory, M.p.: 166-168C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.17 6.858.17 6.45 Example 20 Ethyl 4-[(1-~5-nitro-2-piperidino-PhenYl)-l-butyl)-aminocarbonylmethy~-benzoate A solution of 14.6 g (64.6 mmol) of 4-ethoxy-carbonyl-phenyl acetic acid chloride in 20 ml of methylene chloride is added dropwise to a ~tirred solution of lS.l 9 (54.4 mmol) of 1-(5-nitro~2-piperidino-phenyl)-l-butylamine and 8.46 ml (61.4 mmol) of triethyl-amine in 55 ml of dry methylene chloride within 30 minutes in such a way that the temperature does not exceed 30C. The mixture is stirred for a further 2 hours at ambient temperature, 300 ml of methylene chloride are added and the result~ng mixture is extracted twice, each time with S0 ml of water. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. The reddish-brown oily evaporation residue is purified by columnchromatography on silica gel (toluene/acetone = 10:1).
Yield: 17.7 g (69.7% of theory), M.p.: 135-137C (ether) Calculated: C 66.79 H 7.11 N 8.99 Found: 66.73 6.99 9.09 ~he following ~ere prepared analogously to Example 20:
(a) ~thyl 4~ (2-piPeridino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate 12~4773 Yield: 80.2~ of theory, M.p.: 127-129C
Calculated: C 73.90 H 8.11 N 6.63 Found: 73.98 8.26 6.89 (b) ~thyl 4-[(1-(4-hydroxy-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 13.5% of theory, M.p.: 178-180C
Calculated: C 71.21 H 7.al ~ 6.39 Found: 71.27 7.82 6.40 ~c) Ethyl 4~ -hydroxy-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 37.4% of theory, M.p.- 188-190C
Calculated: C 71.21 H 7.81 N 6.39 Found: 71.34 7.89 6.38 Example 21 4-[~1-(2-piperidino-~henYl)-l-butyl)-aminocarbonylmethYl]- 0 phenvl acetic acid3.0 9 (15.45 mmol) of p-phenylene-diacetic acid and 10 ml of thionyl chloride are refluxed for 90 minutes and then concentrated by evaporation in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride. Then a solution of 3.6 g (15.45 mmol) of 1-(2-piperidino-phenyl)-1-butyl-amine is slowly added dropwise to this solution, with stirring, at an internal temperature of 10 -15C. After 2 hours at ambient temperature, the mixture is concentrated by evaporation in vacuo and the evaporation residue is distributed between 100 ml of ice cold 5% sodium hydroxide solution and ethyl acetate. It is filtered through kieselguhr and the organic phase is separated off. The alkaline-aqueous phase i8 adjusted to pH 5~5 with semi-concentrated hydrochloric acid and extracted with ethyl acetate.
The extract i6 dried over sodium sulphate and filtered and the filtrate is concentrated by evaporation in 12~4773 vacuo. The evaporation residue is purified by column chromatography on silica gel ~chloroform/methanol = 20/1)-Yield: 0.10 9 (1.6% of theoryJ, M.p.: 136-140C (acetonitrile/ether) Calculated: C 73.50 H 7.90 N 6.86 Found: 73.17 8.10 6.85 ~xample 22 Ethyl 4-[(2-methyl-1-(2-piperidino-phenyl)-1-~ropen-l-yl)-aminocarbonylmethyl]-benæoate 5.58 9 (26.8 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 8.43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (~.0268 mol) of carbon tetrachloride are successively added to a solution of 6.17 9 (26.8 mmol) of freshly prepared isopropyl-(2-piperidino-phenyl)-ketimine in 62 ml of acetonitrile and the resulting mixture is stirred for 20 hours at an ambient temperature. It is then concentrated by evaporation in vacuo and distributed between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 5/1).
Yield: 3.0 9 126.6~ of theory), M.p.: 82-84C (ether) Calculated: C 74.26 H 7.67 N 6.66 Found: 74.20 7.49 6.~6 The following were prepared analogously to Example 22:
(a) Ethyl 4-t(l-2-piperidino-phenyl)-1-penten-1-yl)-amino~arbonylmethyl~-benzoate Yield 16% of theory, M,p.: 94-97C (ethanol) Calculated: C 74.62 H 7.89 N 6.45 Found: 74.75 7.71 6.24 5b) Ethyl 4-[(1-2-piperidino-phenyl)-1-hexen-1-yl)-aminocarbonylmethyl]-benzoate Yield: 27.4% of theory, 7~3 M.p.: 83-85C (ethanol) Calculated: C 74.97 H 8.09 N 6.24 Found: 75.42 7.95 6.00 (c) Ethyl 4-[(1-2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl)-benzoate Yield (more lipophilic isomer; probably E form):
4.1~ of theory, M~p.: <20C
Calculated: m/e = 42 Found: m/e = 420 Yield (less lipophilic isomer; probably Z form):
~1.9% of theory, M.p.: 115-117C (ethanol) Calculated: C 74.26 H 7.67 N 6.66 Found: 73.85 7.59 6.44 (d) Ethyl 4-[(2-phenyl-1-(2-piperidino-phenyl)-ethen-l-yl)-aminocarbonylmethyl3-benzoate Yield (more lipophilic isomer; probably E form):
4% of theory, M.p.: 75-77C (ether/petroleum ether3 Calculated: C 76.90 H 6.88 N 5.98 Found: 77.31 7.20 5.93 Yield (less lipophilic isomer; probably Z form):
42.7~ of theory, M.p.: lS7-160C tethanol) Found: C 77.19 H 6.95 N 6.02 (e) Ethyl 4-[(3-phenyl-1-(2-piperidino-phenyl)-l-propen-l-yl)-aminocarbonylmethyl)-benzoate Yield: 62.6~ of theory, M.p.: <20C
Calculated: m/e = 482 Found: m/e - 482 (f) Ethyl 4-~(1-(2-~3,3-dimethyl-piperidino-phenyl)-3S l-buten~l-yl)-aminocarbonylmethyl]-benzoate Yield: 33~ of theory, M~p.: 113-116C tethanol) 1~14773 Calculated: C 74.97 H 8.09 N 6.24 Found: 75.37 7.93 6.03 (g) Ethyl 4-~(1-(6-methyl-2-piperidino-phenyl)-l-buten-l-yl)-aminocarbonylmethyl3-benzoate Yield: S0.4% of theory (probably ~ form) M.p.: 95-96C
Calculated: C 74.62 H 7.89 N 6.45 m/e = 434 Found: 74.44 B.OO 6.59 m/e = 434 ExamPle 23 Ethyl 4-t(1-(2-piPeridino-~henyl)-l-buten-l-yl)-amin carbonYlmethy~]-benzoate A stirred solution of 19.0 9 (82.46 mmol) of freshly prepared (2-piperidino-phenyl)-propyl-ketimine and 11.5 ml ~82.46 mmol) of triethylamine in 190 ml of anhydrous toluene is heated to an internal temperature of 85C, then a solution of 18.7 g (82.46 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 95 ml of anhydrous toluene is added dropwise thereto within 10 minutes and the resulting mixture is stirred for 30 minutes at an internal temperature of 95C. It is then cooled to 20C and extracted twice with water.
The organic phase is dried over sodium sulphate, fil~ered and concentrated by evaporation in vacuo.
The evaporation residue is purified by repeated column chromatography (toluene/acetone = 20/1 and 50/1).
Yield: (more lipophilic isomer; probably E form):
11.2 g (23.6% of theory), M.p.: <20C (honey-yellow viscous oil) Calculated: C 74.26 H 7.67 N 6.66 Found: 73.90 7.92 6.91 Yield (less lipophilic isomer; probably Z form):
15.9 9 ~33.5% of theory), M.p.: 114-116C
Found: C 74.02 H 7.69 N 6.85 ~;~14773 Example 24 Ethyl (E)- and (Z)-4-~(1-(2-piperidino-Phenyl)-l-buten-l-yl)-aminocarbonylmethyl]-benzoate 1.0 9 of Z ester (see Example 22c) is heated for 30 minutes in a pre-heated oil bath at 230C.
After cooling, the product obtained is purified by column chromatography on silica gel (toluene/acetone = 20/1).
Yield (E ester): 0.36S 9 (36.5% of theory), M.p.: <20C

Yield (z esterl: 0.380 9 ~38.0~ of theory), M.p.: 115-117C

If the (E)-ester is heated for 3.5 hours with catalytic quantities of iodine in benzene, a 1/1 mixture of (E) and (Z) esters is obtained, according to thin layer chromatography (toluene/acetone = 10/1).
The following compounds were obtained analogously to Example 24:

(a) Ethyl (E)- and (Z)-4-~(1-(6-methYl-2-piperidino-phenYl)-l-buten-l-Yl)-aminocarbonylmethyl)-benzoate According to thin layer chromatography, a 1/1 mixture of (E) and (Z) esters is obtained from the (Z) ester (see Example 229).
Upper spot (E): Calculated: m/e = 434 Found: m/e = 434 lower spot (Z): Found: m/e = 434 ExamPle 25 Ethyl 4-[(1-(2-Piperidino-phenyl~ butyl)-aminocarbon methyl]-benzoate 2.9 9 (~.90 mmol) of ethyl 4-[(1-(2-piperidino-phenyl),-l-buten-l-yl)-aminocarbonylmethyl~-benzoate in 100 ml of ethanol is hydrogenated on 0.77 9 of 10% palladium/charcoal at 50C under a hydrogen pressure ~LZ1~773 of 1 bar After 2 hours, the catalyst is filtered off over kieselguhr and the filtrate is concentrated by evaporation in vacuo. The evaporation residue .
is crystallised from ethanol.
5Yield: 1.5 9 (51.5% of theory3, M .p.: 126-128 C
Calculated: C 73.90 H 8 .11 N 6 . 63 Found: 73.97 8.22 6.57 The following compounds were obtained analogously to Example 25:

(a) Ethyl 4-~ (2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl~-benzoate Yield: 45~ of theory, M.p.: 117-120C (ether) Calculated: C 74.28 H 8.31 N 6.42 Found: 74.60 8.13 6.27 0 (b) Ethyl 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonylmethyl]-benzoate Yield: 50% of theory, M.p.: 108-110C (ether) Calculated: C 74.63 H 8.50 N 6.22 Found: 74.85 8.33 6.01 (c) Ethyl 4-[(2-phenyl-1-(2-piperidino-phenyl)-l-ethyl)-aminocarbonylmethyl]-benzoate Yield: 87.6% of theory, M p.: 161-162C (ethanol) Calculated: C 76.57 ~ 7.28 N 5.95 Found: 76.71 7.19 5.99 (d) Ethyl 4-t(3-phenyl-1-(2-piperidino-phenyl)-l-propyl)-aminocarbonylmethyl]-benzoate Yield: 57.6% of theory, M.p.: 118-119C (ethanol) Calculated: C 76.83 H 7.49 N 5.78 F~und: 76.70 7.49 5.90 (e) Ethyl 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 36.S% of theory, M.p.: 140-141C (ethanol) - Calculated: C 74.63 H 8.50 N 6.22 Found: 74.30 8.23 6.12 Example 26 4-~[1-(2-P~peridino-phenyl)-l-butyl)-aminocarbonylmethvl~-benzoic acid A mixture of 1.2 g (2.84 mmol) of ethyl 4-~(1-1~ (2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoate and 4.26 ml of lN sodium hydroxide solution in 12 ml of ethanol is stirred for 1 hour at 60~C, then neutralised with 4.26 ml of lN 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 concentrated by evaporation in vacuo. The evaporation residue is crystallised from ethanol.
Yield: 0.50 9 (44.6% of theory), M.p.: 213-215C
Calculated: C 73.07 H 7.66 N 7.10 Found: 73.18 7.51 7.10 The following compounds were obtained analogously to Example 26:

(a) 4-t(1-(2-PiPeridino-phenyl)-l-Pentyl)-aminocarbonyl-methyl~-benzoic acid Yield: 70.~% of theory, M.p.: 213-215C (acetone) Calculated: C 73.50 H 7.90 N 6.86 Found: 73.71 7.70 6.90 ~Z~4773 (b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonyl-methyl~-benzoic acid Yield: 72.6~ of theory, M.p.: 197-200CC (acetone) Calculated: C 73.90 H 8.11 N 6.63 Found: 73.83 7.93 6.77 (c) 4-~(2-phenyl-1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 68.7% of theory, M.p.: 214-215C (acetone) Calculated: C 7~.99 H 6.83 N 6.33 Found: 75.70 6.60 6.32 (d) 4-[(3-Phenyl-1-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl~-benzoic acid Yield: 67.7% of theory, M.p.: 167-170C (ethyl acetate) Calcula~ed: C 76.29 H 7.06 N 6.14 Found: 76.56 7.06 6.23 (e) 4-[2-Methoxy-1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 60.8% of theory, M.p.: 196-198C (ether) Calculated: C 69.68 H 7.12 N 7.07 Found: 69.72 6.52 6.71 (f) 4-1(1-(2-PiPeridino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoic acid x 0.67 H20 Yield: 30.7~ of theory, M.p.: 193-197C (ether/petroleum ether) Calculated: C 71.74 ~ 7.38 N 6.69 Found: 71.63 7.21 6.34 (9) 4-1(1-(2-(3,3-Dimethyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 48.2% of theory, lZ14773 -- %l --M.p.: 168-170C ~petroleum ether) Calcula~ed: C 73.91 H 8.11 N 6.63 Found: 73.51 7.89 6.32 (h) 4-[(1-(3-Methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 53% of theory, M.p.: 179-182C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.50 7.82 7.01 (i) 4~ 4-Methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoic acid Yield: 85.6% of theory, ~.p.: 17~-172C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.25 7.64 6.89 (k) 4-t~l-(5-Methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 62.1% of theory, M.p.: 219-221C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.20 7.74 6.89 (1) 4-[(1-(6-Methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl)-benzoic acid x 0.3 H20 Yield: 89~ of theory, M.p.: 158-160C
Calculated: C 72.53 H 7.93 N 6.77 Found: 72.40 7.91 6.92 (m) 4-[(1-(3-Chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 70% of theory, M.p.~ 189-191C
Calculated: C 67.2Q ~ 6.81 Cl 8.27 N 6.53 Found: 67.30 6.858.36 6.58 lZ~4773 (n) 4-[ (1- ~4-Chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]~benzoic acid Yield: 57.8% of theory, ~.p.: 188-189C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 66.90 7.00 8.Z2 6.53 (o~ 4~ 5-Chloro-2-piperidino-phenyl)-1-bu~yl)- ;
aminocarbonylmethyl]-benzoic acid Yield: 81.6% of theory, M.p.: 226-229C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.17 6.59 8.51 6.60 (p) 4-[(1-(6-Chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 69.4% of theory, M.p.: 150-153C
Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 2Q Found: 67.18 6.91 8.42 6.77 (q) 4-[(1-(4-Bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 84.4% of theory, M.p.: 198-201C
Calculated: C 60.89 H 6.17 Br 16.88 N 5.92 Found: 60.88 5.98 17.20 5.98 (r~ 4-t(1~(5-8romo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 90.7% of theory, M.p.: 232-235~C
Calculated: C 60.89 H 6.17 Br 16.88 N 5.92 Found: 60.96 6.13 16.85 5.90 ~5 ~s) 4-t~l-(4-Nitro-2-p$peridino-pheny~ -butyl) aminocarbonylmethyl~-benzoic acid Yield: 70.9% of theory, ~2~4773 M.p.: 188-190C
Calculated: C 65.59 H 6.65 N 9.56 Found: 65.30 6.44 9.53 (t) 4-[(1-(5-Nitro-2-piperidino-phenyl)-1-butyl)-aminocarb~nylmethyl~-benzoic acid Yield: 90.7% of theory, M.p.: 225-227C
Calculated: C 65.59 H 6.65 N 9.56 Found: 65.80 6.61 9.72 (u) 4-[(1-(4-Hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 H20 Yield: 85.7% of theory, M.p.: softening from 70C (foam) Calculated: (x 0.5 H20) C 68.71 H 7.45 N 6.68 Found: 68.63 7.55 6.26 (v) 4-[(1-(5-~ydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoic acid Yield: 89.3% of theory, M.p.: 186-190C
Calculated: C 70.22 H 7.37 N 6.82 Found: 70.31 7.58 6.51 (w) 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic: acid Yield: 78.6% of theory, M.p.: 185-187C
Calculated: C 70.73 H 7.60 N 6.60 Found: 70.46 7.77 6.56 (x) 4-~(1-(5-Methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 75% of theory, M.p.: 182-185C tdecomp.) Calculated: C 70.73 ~ 7.60 N 6.60 Found: 70.52 7.50 6.70 (y) 4-[(1-~2-Pyrrolidino-phenyl)-l-butyl)-aminocarbonyl-methyl]-benzoic acid Yield: 64.5~ of theory, M.p.: 200-203C
Calculated: C 72.61 H 7 42 N 7.36 Found: 72.64 7.50 7.38 (z) 4-1(1-(2-(4-Methyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 81.4% of theory, M.p.: 197-201~C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.90 8.06 7.00 (aa) 4-[(1-(2-Hexahydroazepino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoic acid Yield: 65.6% of theory, M.p.: 199-202~C
Calculated: C 73.50 H 7.90 N 6.86 Found: 73.50 7.90 6.76 (ab) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoic acid Yieldo 87.1% of theory, M.p.: 204-207C
Calculated: C 69.88 H 7.09 N 6.79 Found: 70.25 7.02 7.12 (ac) 4-[(1-(5-Fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 53.9% of theory, M.p.: 200-202C
Calculated: C 69.88 H 7.09 N 6.79 Found: 69.67 7.24 6.90 (ad) ~-Chloro-4-~ 2-piperidino-phenyl)-1-butyl)-- aminocarbonylmethyl~-benzoic acid Yield: 51~ of theory, 1214~73 M.p.: 165-168~C
Calculated: C 67.20H 6.81 N 6.53 m/e - 428/430 (1 chlorine) Found^ 66.92 6.696.55 m/e = 428/430 (1 chlorine) (ae) 4-[(1-(3-Methyl-2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl)-benzoic acid Yield: 79% of theory, M.p.: 230-231C
Calculated: C 72.60 H 7.42 N 7.36 Found: 72.75 7~58 7.30 (af ) 4-[ (1- (3-Chloro-2-piperidino-ph~nyl)-1-ethyl-aminocarbonylmethyl]-benzoic acid Yield: 54~ of theory, M.p.: 192-195C (75% aqueous ethanol) Calculated: C 65.91 H 6.28 Cl 8.84 ~ 6.99 Found: 66.00 6.44 8.67 6.78 Example 27 4-[(2-Methyl-1-(2-piperidino-phenyl)-l-propen-l-yl) aminocarbonylmethyl~-benzoic acid A mixture of 3.5 g (8.3 mmol) of ethyl 4-[(2-methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-carbonylmethyl]benzoate and 12.5 ml of lN sodium hydroxide solution in 35 ml of ethanol is stirred at 60C for 2 hours. It is neutralised with 12.5 ml of lN hydrochloric acid, concentrated by evaporation in vacuo and distributed between ethyl acetate and water~ The dried, filtered organic extract is evaporated in vacuo. The evaporation residue is crystallised from ethanol.
Yield: 2.4 9 (73.6~ of theory), M.p.: 188-191C
Calculated: C 73.44 B 7.19 ~ 7.14 Found: 73.60 7.19 7.02 ~2~4773 The following compounds were obtained analogously to Example 27:

(a) (E)-4-[(1-(2-Piperidino-phenyl)-l-buten-l-yl)-aminocarbonylmethyl~-benzoic acid Yield: 71.5~ of theory, M.p.: lB8-190C
Calculated: C 73.44 H 7.19 N 7.14 Found: 73.15 7.13 7.10 Olefinic proton: lH-NMR (CDC133:~= 6.42 ppm (b) (Z)-4-~(1-(2-Piperidino-phenyl)-l-buten-l-yl)-aminocarbonylmethyl]-benzoic acid Yield: 57.8% of theory, lS M.p.: 174-175C (ethanol) Calculated: C 73.44 H 7.19 N 7.14 Found: 73.54 6.97 7.17 Olefinic proton: lH-NMR ~CDC13):~= 5.60 ppm 0 (c) (E)-4-[(2-Phenyl-1-(2-piperidino-phenyl)-ethen-l-yl)-aminocarbonylmethyl]-benzoic acid x 0.4 Yield: 33.2% of theory, M.p.: 165-167C (ether/petroleum ether) 25 Calculated: (x 0.4 H20) C 75.11 H 6.48 N 6.26 Found: 75.22 6.39 6.26 olefinic proton: lH-NMR (CDC13):~ ~6.9 ppm (d) (z)-4-t(2-phenyl-l-(2-piperidino-phenyl)-ethen l-yl)-aminocarbonylmethyl]-benzoic acid x 1 ~2 Yield: 72~ of theory, M.p.: 182-185C ~methanol) Calculated: (x 1 H20): C 73.34H 6.60 N 6.11 Found: 73.55 6.45 6.00 olefinic proton: lH-NMR (CDC13): ~ = 6.50 ppm - ~7 -(e) 4-t(3-Phenyl-l-t2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl]-benzoic acid Yield: 48.3% of theory, M.p.: 162-164~C (ether); probably (z) form Calculated: C 76.63 H 6.65 N 6.16 Found: 76.30 6.47 6.31 Olefinic proton: 1H-NMR (CDC13): ~ = S80 PPm (f) 4-[(1-(2-(3,3-Dimethyl-piperidino)-phenyl)-l-buten-l-yl~-aminocarbonylmethyl~-benzoic:
acid Yield: 64.1% of theory, M.p.: 152-153C (ethyl acetate); probably (Z) form Calculated: C 74.26 ~ 7.67 N 6.67 Found: 73.93 7.57 6.50 O1efiniC PrOtOn: 1H-NMR (CDC13): ~ = 5.55 ppm (g) lZ)-4-[(1-(6-Methyl-2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid Yield: 53.3~ of theory, M.p.: 142-145C
Calculated: C 73.66 H 7.44 N 6.89 Found: 73.56 7.73 7.15 olefinic proton: lH-~M~ (CDC133: S = 5.38 ppm Example 28 4-[~1-(2-Piperidino-Phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid 200 mg (0.51 mmol~ of 4-[(1-(2-piperidino-phenyl)-l-buten-l-yl)-aminocarbonylmethyl]-benzoic acid in 10 ml of absolute ethanol are hydrogenated over 100 mg of palladium/charcoal (10%) at 50C and under 1 bar of hydrogen, with shaking. After 1.5 hours the mixture is f iltered and concentrated by evaporation in vacuo.
Yield: 68% of theory, M.p.: 213-214C
Calculated: C 73.07 H 7.6S N 7.10 Found: 73.21 7.82 7.02 ~14773 The yield is 56~ of theory if hydrogenation is carried out at 50 DC and under 1 bar of hydrogen on Raney nickel.

Example 29 Sodium salt of 4-[(1-(2-Piperidino-Phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 H20 _ 10.0 9 (25.3~ mmol) of 4-[(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoic acid are dissolved at 50C in 200 ml of ethanol and 25.35 ml of lN sodium hydroxide solution are added thereto.
The mixture is evaporated to dryness in vacuo and the evaporation residue is dissolved in the minimum amount of ethanol, whilst being heated over a steam bath. The solution is cooled in an ice bath, the crystals precipitated are filtered off and washed with ether and dried at 140C/15 torr.
Yield: 9 9 (85.3% of theory), M.p.: 280-285C (decomp.); softening from 255C
Calculated: (x 0.5 H20) C 67.74 H 6.87 N 6.58 Found: 67.86 7.13 6.49 Example 30 EthYl (+~-4-l~1-(2-Piperidino-phenyl)-l-butyl)-amino-carbonyl~ethYl~-benzoate To a stirred solution of 2.58 9 (11.1 mmol) of (+)-1-(2-piperidino-phenyl)-1-butylamine [Bp 0 03:
87C; ee = 86 (HPLC, after derivatising with (+)-l-phenethyl-isocyanate)] in 26 ml of acetonitrile, there are added, at 20C, one after another, 2.31 9 (11.1 mmol) of 4-ethoxycarbonyl-phenyl acetic acid, 3.50 9 (13.3 mmol1 of triphenylphosphine, 4.60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of carbon tetrachloride. After 14 hours at 20C
and 1.5 hours at 40C the mixture is concentrated by evaporation in vacuo and distributed between water and ether. The organic phase is dried over sodium lZ14773 sulphate, then filtered, and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6:1).
Yield: 2.63 9 (56% of theory), M.p.: 118-120~C
Calculated: C 73.90 H 8.11 N 6.63 Found: 74.02 7.97 6.51 [~]20 = +9.2 (c = l; methanol) The foll~wing compound was obtained analogously to Example 30:

(a) Ethyl (-)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Prepared from (-)-1-(2-Piperidino-phenyl)-l-butylamine x 1.4 HCl [[]D0 = -20.0 (c = 1, methanol ), Mel~ing range: 90-100C; ee = 80 (HPLC, after derivatising the base with (+)-l-phenethyl-isocyanate)]
Yield: 52.6% of theory, M.p.: 115-120C
Calculated: C 73.90 H ô.llN 6.63 Found: 73.83 8.01 6.47 ~a]20 = _g,o (c = 1, methanol) ~'~14773 Example 31 Ethyl (+)-4-[(1-~2-piperidino-Phen~l)-l-butYl)-amino-carbonvlmethyl]-benzoate 1.0 9 (3.27 mmol) of (~0-1-(2-piperidino-phenyl)-l-butylamine-dihydrochloride [~a) 20= +18.7 (c ~
1, methanol); m.p.: decomposition from 115C; ee = 91.6 (HPLC, after derivatising the base with (+)-l-phenethyl-isocyanate)3 is suspended in 6 ml of methylene chloride, then 1.4 ml (10 mmol) of triethylamine are added, with stirring, and then the solution of 0.82 9 (3.64 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 2.4 ml of methylene chloride is added dropwise thereto, whereupon the reaction temperature rises from 22C to 38C. The mixture is stirred for 6 hours at ambient temperature and then extracted successively:
twice with 10 ml of water, once with 10 ml of 2N hydrochloric acid and once with 10 ml of water.
The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo.
The evaporation residue is purified by column chromat-ography on silica gel (toluene/acetone = 6/1).
Yield: 0.53 9 (38.2~ of theory), M.p.: 120-122C
Calculated: C 73.90 H 8.11 N 6.63 Found: 73.96 7.98 6.61 ~]20 = +g o (c = 1, methanol) xamPl-e 32 (+)-4-[tl-~-PiPeridino-phenyl)-l-butyl)-aminocarbonyl-methyl]-benzoic acid 2.0 9 ~4.73 mmol) of ethyl (+)-4-1(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate ¦~]20 = l9.2 (c = 1, methanol)] in 20 ml of ethanol are stirred with 7.0 ml of lN sodium hydroxide solution for 2.5 hours in a bath at 65C. The mixture is cooled and 7.0 ml of lN hydrochloric acid are added.

The crystals which are slowly precipitated are filtered off, washed with water and dried at 100C/4 torr.
Yield: 1.65 9 (88.2% of theory), M.p.: 185-187C
Calculated: C 73.07 ~ 7.66N 7.10 Found: ~2.90 7.80 7.17 t]20 = +7.9 (c = 1, methanol) The following compound was obtained analogously to iO Example 32:

(a) (-)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid Yield: 80% of theory, M.p.: 187-190C
Calculated: C 73.07 H 7.66 N 7.10 Found: 72.98 7.44 7.22 [a]20 = _7.9 (c = 1, methanol) Exam~le 33 4-[(1-(2-Piperidino-phenYl)-l-butYl)~aminocarbonyl-Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-cyano-phenylacetic acid analogously to Example 19.
Yield: 57.3% of theory, M.p.: 147-148C
Calculated: C 76.76H 7.78N 11.19 Found: 7Ç.46 7.81 11.10 The following compound was obtained analogously to Example 33:

(a) 4-~(1-(2-Piperidino-phenyl)-l-butyl)-aminocarbonyl-methyl~-toluene Prepared with 4-tolyl-acetic acid.
Yield: 60.4~ of theory, M.p.: 150-153~C

lZ147~3 Calculated: C 79.08 H 8.85 N 7.68 Found: 78.97 8.58 7.77 Example 34 Ethyl 4~ (2-piPeridino-phenyl)-l-butyl)-aminocar-bon methyl]-benzoate Prepared from 4-~(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzonîtrile with ethanolic hydrochloric acid analogously to Example 14.
10 Yield: 58% of theory, M.p.: 127-12BC
Calculated: C 73.90H 8.11N 6.63 Found: 74.07 8.23 6.87 Example 35 Ethyl 4-[(1-(2-~iperidino-phenyl)-1-butyl)-aminocarbonyl-meth~l]-benzoate Prepared analogously to Example 10 from 1-(2-piperidino-phenyl)-l-butanol and ethyl 4-cyanomethyl-benzoate with concentrated sulphuric acid in o-dichloro-benzene at ambient temperature.
Yield: 21% of theory, M.p.: 126-128C
Calculated: C 73.90 H 8.11N 6.63 Found: 74.12 8.20 6.45 The following compound was obtained analogously to Example 35:
0 (a) 4-t(1-(2-Piperidino-phenyl)-l-butyl)-aminocarbon methyl]-benzoic acid Prepared from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanomethyl-benzoic acid. Extraction at pH 5.5.
Yield: 29~ of theory, M.p.: 215-217C
Calculated: C 73.07 H 7.66 N 7.10 Found: 72.82 7.69 6.95 lZ1~773 Example 36 4-[~1-(4-Amino-2-~iPeridino-PhenYl)-l-butyl)-aminocarbonyl-methyl~-benzoic acid x O.S H20 -0.60 9 (1.365 mmol) of 4-[(1-(4-nitro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid in 10 ml of dimethylformamide are hydrogenated on 0.1 9 of 10% palladium/charcoal for 3 hours at 25C
and under a hydrogen pressure of 1 bar. The catalyst is filtered off using kieselguhr and the filtrate i5 concentrated by evaporation in vacuo. The evaporation residue is crystallised from ether.
Yield: 0.41 9 (73.2~ of theory), M.p.: 118-120C
Calculated: (x 0.5 H20): C 68.87 H 7.71 N 10.04 Found: 68.62 7.64 10.08 The following compounds were obtained analogously to Example 36:
(a) Ethyl 4-[(1-(4-amino-2-piperidino-phenyl)-1-- butyl)-aminocarbonylmethyl]-benzoate Yield: 81.7% of theory, M.p.: 145-146C (ether/petroleum ether) Calculated: C 71.37 H 8.06 N 9.60 Found: 71.50 8.08 9.68 (b) 4-[(1-(5-Amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoic acid Yield: 64% of theory, M.p.: 227-230C
Calculated: C 70.39 H 7.63 N 10.26 Found: 70.54 7.S4 10.36 (c) Ethyl 4-t(1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 84.3% of theory, M.p.: 162-16SC

Calculated: C 71.37 H 8.06 N 9.60 Found: 71.58 7.83 9.65 Example 37 Eth~l 4-~(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocar~ylmethyl~-benzoate A cold diazonium salt solution (0C) is prepared from 2.0 9 (4.57 mmol) of ethyl 4-[(1-(5-amino-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl)-benzoate in 4.8 ml of semiconcentrated hydrochloric acid and 0.31S 9 (4.57 mmol) of sodium nitrite in 1.66 ml of water. This solution is added dropwise, at 0 to 5C, to a stirred mixtur~ of 0.59 9 (5.94 mmol) of copper(I)chloride and 2.4 ml of conc. hydrochloric acid and the resulting mixture is then heated in a bath at 50C. Af ter the development of gas has ended (about 15 minutes), the mixture is cooled, added to ice/conc. ammonia and extracted four times, each time with 100 ml of ethyl acetate. The combined organic extracts are shaken with water, dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).
Yield: 0.80 9 (40% of theory), M.p.: 137-140~C (ether) Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13 Found: 68.42 7.09 8.06 6.05 The followin~ compounds were obtained analogously to Example 37:
(a) Ethyl 4-t(1-(4-chloro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 21.9% of theory, M.p.: 123-125C
Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13 Found: 68.70 7.18 7.77 6.08 ~2~47~3 (b) Ethyl 4-[(1-(5~bromo-2-piperidino-phenyl~-1-butyl)-aminocarbonylmethyl3-benzoate Yield: 53.8% of theory, M.p.: 140-142C
Calculated: C 62.27 H 6.63 Br 1~.93 ~ 5.58 Found: 62.39 6.78 15.85 5.59 (c~ Ethyl 4-[(1-(4-fluoro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl)-benzoate Yield: 21.6~ of theory, M.p.: 110-112C
Calculated: C 70.88 H 7.55 N 6.36 Found: 71.01 7.53 6.21 15 In addition, 40% of ethyl 4-~(1-(4-hydroxy-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate are isolated (solid foam).

(d) Ethyl 4-l(1-(5-fluoro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 2% of theory, Mop~ 127-129C
Calculated: m/e = 440 Found: m/e = 440 (e) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-ethyl)-~minocarbonylmethyl~-benzoic acid Yield: 16.9% of theory, M.p.: 172-175C
Calculated: C 68.73 H 6.55 N 7.29 Found: 68.78 6.62 7.31 4-[(1-(2-Piperidino-phenyl~-l-butyl)-aminocarbonyl- 5 methyl~-benzoic acid 1.0 g ~2.33 mmol) of 4-~(1-(5-chloro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzQic acid in 40 ml of absolute ethanol are hydrogenated on ~214773 0.5 9 of 10% palladium/charcoal at 50~C and under 5 bar of hydrogen. After 2 hours, the catalyst is filtered off over kieselguhr and the filtrate is concentrated by evaporation in vacuo. The evaporation residue is distributed at pH 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated in vacuo.
Yield: 0.61 y (66% of theory), M.p.: 213-215C
Calculated: C 73.07 H 7.66 N 7.10 Found: 73.18 7.42 7.27 The same compound is also obtained from the corresponding 4-chlorine-, 3-chlorine- or 6-chlorine-substituted lS starting products.

Example 39 Ethyl 4-[(1-(4-Meth~y-2-piPeridino-pheny~ -butyl) aminocarbonYlmethyl]-benzoate A solution of 5.0 g (11.4 mmol) of ethyl 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoate in 45 ml of absolute dimethylformamide is added dropwis~, with stirring, at ambient temperature, to 548 mg (11.4 mmol) of sodium hydride (50% in oil) in 10 ml of absolute dimethylformamide. The mixture is stirred for a further 15 minutes and then a solution of 0.71 ml (11.4 mmol) of methyliodide in 8 ml of absolute dimethylformamide is slowly added dropwise thereto. The mixture is stirred for a further 2.5 hours at ambient temperature, evaporated in vacuo and distributed between water and ether. The ether phase i5 dried and filtered and concentrated by evapor-ation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 20/1).
Yield: 1.8 9 (34.9~ of theory), M.p.: 115-117C

~2~47~3 Calculated: C 71.65 H 8.02 N 6.19 Found: 71.47 7.86 6.19 The following compound was obtained analogously to Example 39:

(a) Ethyl 4-~(1-(5-me~hoxy-2-piperidino-phenyl)-l-butyl~-aminocarbonylmethyl~-benzoate Yield: 68.4~ of theory, M.p.: 142-145C
Calculated: C 71.65 H 8.02 N 6.19 Found: 71.87 8.06 6.38 Exam~le 40 2,3-Dih~droxy-propyl 4-l(l (2-piperidino-phenyl?-l-butyl)-aminocarbonylmethyl]-benzoate A solution of 2.0 9 (5.07 mmol) of 4-[(1-(2-piperidino-phenyl~-l-butyl)-aminocarbonylmethyl]-benzoic acid and 0.85 g (5.27 mmol) of N,~'-carbonyldi-imida~ole in 20 ml of absolute tetrahydrofuran i~refluxed for 1 hour, then 3.7 ml (50.7 mmol) of glycerol are added and the resulting mixture is refluxed for a further 15 hours. It is then concentrated by evapor-ation _ vacuo, distributed between water and ethyl acetate, the organic solution is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 1:1).
Yield: 1.1 g ~46.2% of theory), M.p.: 120-122C
Calculated: C 69.21 ~ 7.74 N 5.98 Found: 69.23 7.73 5.g3 The following compounds were obtained analogously to Example 40:

(a) 2-hydroxy-ethyl 4-[(1-(2-piperidino-phenyl~-l-butyl)-aminocarbonylmethyl]-ben~oate Yield: 80~ of theory, M.p.: 125-127~C
Calculated: C 71.21 H 7.81 N 6.39 Found: 71.35 7.54 6.33 (b) 2-methoxy-ethyl 4-[(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Yield: 55.9~ of theory, M.p.: 120-123~C
Calculated: C 71.65 H 8.02 N 6.19 Fo~nd: 72.03 8.03 6.24 Example 41 2-nicotinoyloxy-ethY1 4-r(l-(2-piperidino-phenyl)- 5 l-butyl)-aminocarbonYlmethyl~-benzoate A solution of 0.7 9 (4.68 mmol) of nicotinic acid chloride in 20 ml of methylen~ chloride is rapidly added dropwise to a stirred solution of 2.0 g (4.56 mmol) of 2-hydroxyethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 40 ml of methylene chloride and 0.7 ml ~4.81 mmol) of triethylamine.
The res~lting mixture is stirred at 20C for 2.5 hour~, extracted with water, then the organic phase is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = S/l).
Yield: 1.1 9 (44~ of theory), M.p.: 132-135C
Calculated: C 70.70 H 6.86 N 7.73 Found: 70.82 6.82 7.91 Exam~le 42 4-[(1-~2-Pi~eridino-phenvl)-l-butyl)-aminocarbonylmethyl~-benzYl alcohol A ~olution of 5.0 9 (11.83 mmol) of ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl~-benzoate in 7S ml of absolute tetrahydrofuran is added dropwi~e, at an internal temperature of 0C, 12~4773 to a stirred suspension of 0.68 9 (17.95 mmol) of lithium aluminium hydride in 25 ml of absolute tetrahydro-furan. The mixture is stirred for 20 hours at ambient temperature then cooled to 0C and 4N sodium hydroxide solution is slowly added dropwise thereto until a filterable precipitate has formed. The mixture is filtered and the precipitate is decocted several times with ether. The combined organic solutions are concentrated by evaporation in vacuo. The evaporation residue is distributed between water and ether.
The ether phase is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1).
15 Yield: 1.0 g (22% of theory), M.p.: 152-154C
Calculated: C 75.75 H 8.48 N 7.36 Found: 75.90 8.45 7.28 Example 43 4-~(1-(2-Piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzaldehyde 6.6 9 (62 mmol) of sodium carbonate are heated together with 62 ml of ethylene glycol in a bath at 170C and, within 1 minute, 6.2 g (11 mmol) of Nl-~4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl~-benzoyl]-N2-tosyl-hydrazine (melting point 195C (decomposition~) are added thereto, with rapid stirring, whereupon there is a vigorous development of gas. The mixture is then heated for a further 2.5 minutes at 170C and then immediately poured onto ice. It is extracted with ether and the ether solution is dried, filtered and concentrated by evapor-ation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/
acetone = 20/1).
Yield: 2.2 9 (S2.g% of theory), M.p.: 142-145C

Calculated:C 76.16 H 7.99 N 7.40 Found: 76.26 7.96 7.37 ExamPle 44 Ethyl 4-[(1-(2-PiPeridino-phenyl)-l-butYl)-aminocarbonyl-methvl]-cinnamate A s~lution of 2.80 9 (12.5 mmol) of ethyl diethyl-phosphonoacetate in 10 ml of absolute dimethylformamide is added dropwise, at ambient temperature, to 0.60 9 (12.5 mmol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide. The mixture is stirred for 15 minutes (until the development of gas ceases) and then a solution of 2.4 ~ (6.34 mmol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde in 10 ml of absolute dimethylformamideis added dropwise thereto. The mixture is stirred for 2 hours at ambient temperature, concentrated by evaporation in vacuo and distributed between water and ether. The ether phase is dried and filtered and then evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).
Yield: 0.8S g (29.9% of theory), M.p.: 135-137C (ether/petroleum ether) 2S Calculated: C 74.97 H 8.09 N 6.24 Found: 74.91 7.89 6.29 ExamPle 45 4-[(1-(2-Piperidino-phenyl)-l-butYl)-aminocarbonYlmethyl]-cinnamic acid Prepared by alkaline saponification of ethyl4-t(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]
c~nnamate analogou~ly to Example 26.
Yield: 64% of theory, M.p.: 180-183~C
Calcula~ed: C 74.26 H 7.67 N 6.66 Found: 74.03 7.47 6.80 12~4773 ExamPle 46 Ethyl 3-r4-r~1-(2-Piperidino-phenyl)-l-butvl)-amin carbonYlmethYl]-Phenyl]-PrOpiOnate 0.60 9 (1.34 mmol) of ethyl 4-[tl-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-cinnamate are hydrogenated in lO ml of ethanol on 0.20 9 of 10%
palladium/charcoal at ambient temperature under 5 bar of hydrogen. The mixture is filtered and concentrated by evaporation in vacuo.
Yield: 0.53 g ~88% of theory), M.p.: 98-99C (petroleum ether) Calculated: C 74.63 H 8.50 N 6.22 Found: 74~64 8.58 6.23 The following compound was obtained analogously to Example 46:

(a) 3-[4-[(1-(2-Piperidino-phenyl)-l-butyl)-amino-carbonylmethyl]-phenyl]-propionic acid Yield: 63% of theory, M.p.: 131-133C
Calculated: C 73.90 H 8.11 N 6.63 Found: 73.96 8.30 6.56 Example 47 3-[4-[(1-(2-Piperidino-phenYl)-l-butYl)-aminocarbonyl-methyl~-phenyl~-proPionic acid Prepared by alkaline saponification of ethyl 3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-phenyl]-propionate analogously to Example ; 26.
Yield: 50~ of theory, M.p.: 131-133C
Calculated: C 73.90 H 8.11 N 6.63 Found: 73.82 8.07 6.41 1~14773 Example 48 Ethyl 4-[~-aminocarbonyl-2-piperidino-benzYl)-amin carbonylmethYl~-benzoate At 20C, 0.90 9 (5.5 mmol~ of N,N'-carbonyldi-imidazole are added to a stirred solution of 2.0 9 (4.7 mmol) of ethyl 4-[(a-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoate x 0.167 H20 (melting point 156-159~C~ in 20 ml of anhydrous tetrahydrofuran and the mixture is then heated for half an hour in a bath at 80C. The mixture is then cooled to 60C
and at this temperature a vigorous current of dry ammonia is introduced over a period of half an hour.
Then the re6ulting mixture is evaporated in vacuo, distributed between water and chloroform, then the combined chloroform extracts are shaken with a little water, dried, filtered and evaporated in vacuo.
The evaporation residue is purified by column chromat-ography on silica gel tchloroform/methanol = S/l).
Yield: 1.0 9 (S0.2~ of theory), M.p.: 160-162C (acetone) Calculated: C 68.07 H 6.90 N 9.92 Found: 68.40 6.92 9.84 Example 49 Ethvl 4-[(a-cYano-2-Piperidino-benzyl)-aminocarbonyl-methYl]-benzoate 234 mg (1.22 mmol) of 4-toluenesulphochloride are added in two batches to 520 mg (1.22 mmol) of ethyl 4-[(u-aminocarbonyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoate in 0.22 ml of pyridine and the mixture is heated to 50C. ~fter 2 hours and then 1 hour later, the same quantities of pyridine and 4-toluenesulphochloride are again added and the resulting mixture is heated for a further hour at 50C. After it has been left to stand for 2 days at 20C, 2N ammonia is added and the mixture is extracted with chloroform. The chloroform solution is extracted twice with water. After drying and filtering, it ~ 214773 is concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1~.
Yield: 325 mg (6S.7% of theory), M.p.: 114-117C (ether/petroleum ether) Cal~ulated: C 71.09 H 6.71 N 10.36 Found: 70.79 6.56 10.10 Example 50 4-[(a-CYano-2-PiPeridino-benzvl)-aminocarbonYlmeth~l]
benzoic acid 1.5 9 (3.7 mmol) of ethyl 4-[(~-cyano-2-piperidino-benzyl)-aminocarbonylmethyl3 benzoate in 15 ml of dioxan are stirred together with 3.7 ml of lN sodium hydroxide solution for 45 minutes in a bath at 60C
and for a further 45 minutes in a bath at 80~C.
After cooling with ice, the mixture is combined with 3.7 ml of lN hydrochloric acid, the dioxan is evaporated off in vacuo and the residue is distributed between water and chloroformr The organic solution is extracted with a little water, then dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethanol - 5/1).
Yield: 0.50 9 (35.7% of theory), M.p.: 176-180C (decomposition) Calculated: C 70.01 H 6.14 N 11.13 Found: 70.02 6.19 11.05 ExamPle 51 4-~(1-(2-piPeridino-pheny~ butyl)-aminocarbonylmethyl]
benzoic acid x H SO

5 ml (2.50 mmol) of lN sulphuric acid are added to a solution of 1.0 9 l2.53 mmol) of 4-[(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid in 50 ml of ethanol, the mixture is concentrated to dryness in vacuo and triturated with acetone~

~Z14773 Yield: 0.80 9 (65~ of theory), M.p.: 192~197C (decomposition).
Calculated: C 58.53 H 6.55 N 5.69 S 6.49 Found: 58.05 6.54 5.49 6.35 The following addition salt was obtained analogously to Example 51:

(a) 4-[(1-(2-Piperidino-phenyl)-l-butYl)-aminocarbonYl-methyl]-benzoic acid x 0.5 H2SO1 x 1.5 H20 Prepared analogously to Example 51 with half the quantity of sulphuric acid.
Yield: 59.3~ of theory, M.p.: 180-185C decomposition at 207-210C
Calculated C 61.26 H 7.28 N 5.95 S 3.40 Found: 61.28 6.99 6.10 3.23 1~14773 Example A
Tablets containing 5 mg of 4-[(1-(2-Piperidino-phenyl) l-butyl)-aminocarbonylmethyl]-benzoic acid 5 Composition:
1 tablet contains:
Active substance (1)5.0 mg Corn starch (2)62.0 mg Lactose (3)48.0 mg 10 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 pressed through a screen with a mesh width of 1.5 mm and dried at about 45C. The dry granulate is passed through a screen with a mesh width of 1.0 mm and mixed with 5. The finished mixture is compressed in a tablet press, using punches 7 mm in diameter provided with a dividing slot, to form tablets.
Weight of tablet: 120 mg Exam~e B
Coated tablets containinq 2.5 mg of 4-[(1-(2-piperidino-~hen~ bu~ aminocarbonYlmethyl]-benzoic acid 1 tablet core contains:
30 Active substance (1)2.5 mg Potat~ starch (2)44.0 mg Lactose (3)30.0 mg Polyvinylpyrrolidone (4)3.0 mg Magnesium stearate ~5)0.5 mg 80.0 mg 121~773 Method of pre~aration:
1, 2, 3 and 4 are thoroughly mixed and moistened with water. The moist mass is passed through a screen with a mesh width of 1 mm, then dried at 45C and the granulate is again passed through the same screen.
After the addition of 5, convex tablet cores 6 mm in diameter are produced in a tablet-making machine by compression. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax.
Weight of coated tablet: 120 mg Example C
Tablets containinq 10 mg of 4-[(1-(2-piPeridino-phenYl)-l-but~ aminocarbonylmethyl]-benzoic acid Composition:
1 tablet contains:
20 Active substance 10.0 mg Powdered lactose 70.0 mg Corn starch 31.0 mg Polyvinylpyrrolidone 8.0 mg Magnesium stearate 1.0 mq 120.0 mg Method of Preparation A mixture of the active substance, lactose and corn starch is moistened with a 20~ solution of polyvinyl pyrrolidone in water. The moist mass is granulated through a screen with a mesh width of 1.5 mm and then dried at 45C. The dried granulate is rubbed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate.
Weight of tablet: 120 mg Punch: 7 mm in diameter with dividing slot.

~.214773 Example D
Coated tablets containinq 5 m~ of 4-[(1-(2-piPeridin -E~henyl)-l-butyl)-aminocarbonylmethYl]-benzoic acid 5 1 tablet core contains:
Active substance 5.0 mg Secondary calcium phosphate70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 4.0 mg 10 Magnesium stearate 1.0 mq 130.0 mg Method of ~reparation A 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 screen with a mesh size of 1 mm, then dried at 45~C and passed through the same screen again. After the specified amount of magnesium stearate has been added, 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 tablet cores thus produced in known manner. The finished coated tablets are polished with wax.
Weight of coated tablet: 180 mg

Claims (127)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general for-mula I

(I) [wherein A represents a group of formula [wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; a n-propyl group; an alkyl group containing 4 to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene moiety; an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety (the substituents in the case of disubstitution being the same or different); an aryl group containing 6 or 10 carbon atoms mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkyl-sulphinyl and/or alkysulphonyl groups, the substituents in the case of disubstitution being the same or different and each alkyl moiety containing 1 to 3 carbon atoms; or a heteroaryl group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms;
or, when R1 represents a piperidino group and R2 represents in the 4-position a fluorine atom and R3 represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group, wherein the alkyl part may contain 1 to 3 carbon atoms then R4 may also represent a methyl group;
or when R1 represents a piperidino group substituted in the 2- or 3-position by a methyl group, then R4 may also represent a phenyl group, or when R2 represents in the 3-, 4- or 6-position a chlorine atom or in the 4- or 6-position a methyl group, then R4 may also represent a phenyl group or when W represents a formyl, carboxyvinylene or alkoxy-carbonylvinylene group, wherein the alkyl part may contain 1 to 3 carbon atoms; then R4 may also represent a phenyl group;
R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety];
R1 represents an unbranched alkyleneimino group con-taining 4 to 9 carbon atoms optionally mono- or disubstituted by alkyl groups containing 1 to 3 carbon atoms (which in the case of disubstitution may be the same or different); or a dialkylamino group containing 1 to 5 carbon atoms in each alkyl component;
R2 represents a hydrogen, fluorine, chlorine, bromine or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group wherein the alkyl component may contain 1 to 3 carbon atoms in each case;
R3 represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom; and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms (wherein the alkyl component may optionally be substituted by a phenyl group and optionally, at any carbon atom except the .alpha.-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms, an alkyl group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, 2,2-bis-(carboxy)-ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycar-bonyl-ethenyl or 2,2-bis-(alkoxycarbonyl)-ethyl group (each alkoxy group containing from 1 to 3 carbon atoms)]
or a tautomer or optical enantiomer or salt thereof, which process comprises:
(a) reacting a compound of general formula II

(II) (wherein A, R1 and R2 are as defined above or, if A represents one of the vinylidene groups mentioned above, a tautomer thereof or a lithium or magnesium halide complex thereof) with a compound of general formula III

III

(wherein R3 is as defined above and W' has the meanings given for W above or represents a carboxy group protected by a protecting group) or with a reactive derivative thereof and, if necessary subsequently cleaving any protecting group used;
(b) for preparing a compound of formula I wherein W
represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, subjecting a compound of general for-mula IV

(IV) (wherein R1 to R3 and A are as defined above and B represents a group which can be converted into a carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxyethenyl group by hydrolysis, thermolysis or hydrogenolysis) to hydrolysis, thermolysis or hydrogenolysis;
(c) for preparing a compound of formula I wherein A re-presents a group of formula wherein R4' has the meanings given for R4 above with the ex-ception of an alkenyl group and a cyano group, reducing a com-pound of general formula V

(V) wherein R1 to R3 and W are defined as above and D represents a group of formula wherein R4" has the meanings given hereinbefore for R4, with the exception of a cyano group and R5' and R6' together with the carbon atoms between them represent an alkylidene group containing 1 to 7 carbon atoms or a phenylalkylidene group con-taining 1 to 3 carbon atoms in the alkylidene moiety;
(d) for preparing a compound of formula I wherein A
represents a group of formula wherein R4" has the meanings given hereinbefore for R4, with the exception of a cyano group; reacting a compound of gen-eral formula VI

(VI) (wherein R4" represents R4 as defined above with the exception of a cyano group and R1 and R2 are as defined above with a com-pound of general formula VII

(VII) wherein R3 and W are as defined above;
(e) for preparing a compound of formula I wherein R2 represents a hydrogen atom, dehalogenating a compound of gen-eral formula VIII

(VIII) wherein R1, R3, A and W are as defined above and Hal represents a fluorine, chlorine, bromine or iodine atom;
(f) for preparing a compound of formula I wherein A
represents a group of formula wherein R4 represents an alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety, re-acting a compound of general formula IX

(IX) (wherein R1, R2 and R3 are as defined above and W" represents W as defined above with the exception of a carboxy group) with an amine of general formula X

H - R7 (X) wherein R7 represents an alkyleneimino group containing 4 to 6 carbon atoms or an amino group optionally mono- or di-substituted by alkyl or phenylalkyl groups each containing 1 to 3 carbon atoms in the alkyl moiety;
(g) for preparing a compound of formula I wherein A re-presents a group of formula wherein R4 is as defined above and W represents a carboxy group, oxidising a compound of general formula (XI) wherein R1 to R4 are as defined above and E represents a group which can be converted into a carboxy group by oxidation;
(h) for preparing a compound of formula I wherein W
represents an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms wherein the alkyl component may be sub-stituted at any carbon atom except the .alpha.-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms, esterifying a carboxylic acid of general for-mula XII

(XII) (wherein R1 to R3 and A are as defined above, or a reactive derivative thereof, with an alcohol of general formula XIII

HO - R9 (XIII) wherein R9 represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atom except the .alpha.-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms;
(i) for the preparing a compound of formula I wherein W
represents an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxy-carbonylethyl or 2-alkoxycarbonylethenyl group and A represents a group of formula wherein R4" represents R4 as hereinbefore defined with the ex-ception of a cyano group, alcoholysing a compound of general formula XIV

(XIV) wherein R4" represents R4 as defined above with the exception of a cyano group, R1 to R3 are as defined above and W"' represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethyenyl group;
and, if required converting an obtained compound of formula I into a salt thereof.
2. A process as claimed in claim 1, wherein A represents a group of formula wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkyl group containing 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atoms mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy and/or alkylsulphenyl groups, which substituents may be the same or different and each alkyl component may contain from 1 to 3 carbon atoms; or a naphthyl; pyridyl, quinolyl or iso-quinolyl group;
R5 and R6 together with the carbon atom between then represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety;

R1 represents an unbranched alkyleneimino group con-taining 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms;
R2 represents a hydrogen, fluorine, chlorine or bromine atom or a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms;
or if R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkyl group containing 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms, or a nitrile or aminocarbonyl group, then R2 may also represent an iodine atom or a hydroxy or amino group;
R3 represents a hydrogen or chlorine, atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl component may be substituted at any carbon atom except the .alpha.-carbon atom by 1 or 2 hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbonyloxy group; or an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may contain from 1 to 3 carbon atoms.
3. A process as claimed in claim 1, wherein:
A represents a group of formula wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano or aminocarbonyl group; an alkyl group containing 4 to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms;
a phenyl group substituted by a fluorine, chlorine or bromine atom or by a methyl, hydroxy, methoxy, benzyloxy or methylsul-phenyl group; or a pyridyl group;
R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety, R1 represents an unbranched alkyleneimino group con-taining 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by methyl groups, R2 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group; or, if R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, nitrile or aminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or an alkenyl group containing 3 to 5 carbon atoms, then R2 may also represent an iodine atom or a hydroxy or amino group;
R3 represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms wherein the alkyl component may be substituted at any carbon atom except the .alpha.-carbon atom by one or two hydroxy groups, by an alkoxy group containing 1 to 3 carbon atoms or by a pyridine-carbonyloxy group; or an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may contain from 1 to 3 car-bon atoms.
4. A process as claimed in claim 3, wherein W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl component may be substituted at any carbon atom except the .alpha.-carbon atom by one or two hydroxy groups.
5. A process as claimed in claim 3, wherein W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms.
6. A process as claimed in claim 1, wherein A represents a group of formula wherein R4 represents an n-propyl group, an alkyl group con-taining 4 or 5 carbon atoms, a phenyl group substituted by a methyl group or by a fluorine or chlorine atom, or a pyridyl group;

R5 and R5 together with the carbon atom between them represent an alkylidene group containing 3 to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part;

R1 represents a piperidino group optionally sub-stituted by one or two methyl groups;
R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group;
R3 represents a hydrogen atom; and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms.
7. A process as claimed in claim 6, wherein A represents a group of formula wherein R4 represents an n-propyl group or an alkyl group con-taining 4 or 5 carbon atoms and R5 and R6 together with the carbon atom between them represent an alkylidene group contain-ing 3 to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part.
8. A process as claimed in claim 1 wherein A represents a group of formula wherein R4 represents an aryl group containing 6 or 10 carbon atoms mono- or di-substituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl, and/or alkylsulphonyl groups, which substituents in the case of disubstitution may be the same or different and each alkyl moiety may contain from 1 to 3 carbon atoms; or a heteroaryl group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms;
R1 represents an unbranched alkyleneimino group con-taining 4 to 6 carbon atoms optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; an acta-hydroazocino, octahydro-1H-azonino or decahydroazecino group;
or a dialkylamino group containing 1 to 5 carbon atoms in each alkyl component;
R3 represents a hydrogen or halogen atom;
W represents a carboxy, formyl, hydroxymethyl, cyano, aminocarbonyl, 2-carboxyethenyl, 2-carboxyethyl, or 2,2-bis-(carboxy)-ethyl group, an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms, an ethenyl group monosubstituted at the 2-position by an alkoxycarbonyl group or an ethyl group mono- or di-substituted at the 2-position by alkoxycarbonyl groups (wherein each alkoxycarbonyl group may contain from 2 to 4 carbon atoms in total); and R2 represents a fluorine or bromine atom, a chlorine atom in the 3-, 4- or 6-position (relative to the substituent A), a nitro group or an alkyl or alkoxy group containing 1 to 3 carbon atoms; or (when either:
R1 represents an unbranched alkyleneimino group sub-stituted by one or two alkyl groups; an octahydroazocino, octahydro-1H-azonino or decahydroazecino group, or a dialkyl-amino group; and/or R4 represents an aryl group mono- or di-substituted by halogen atoms or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups; a naphthyl group; or a heteroaryl group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms; and/or W represents a hydroxymethyl, formyl, cyano, amino-carbonyl, 2-carboxyethenyl, 2-carboxyethyl or 2,2-bis-(carboxy)-ethyl group; an ethenyl group substituted at the 2-position by an alkoxycarbonyl group or an ethyl group mono- or di-substituted at the 2-position by alkoxycarbonyl groups; and/or R3 represents a halogen atom), R2 may also represent a hydrogen atom or a chlorine atom at the 5-position.
9. A process as claimed in claim 1, wherein A represents a group of formula wherein R4 represents an alkyl group containing 1 to 3 carbon atoms optionally substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; an alkyl group con-taining 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneimino group containing 4 to 6 carbon atoms in the alkylene moiety; or an aminocarbonyl group optionally mono-disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety;

R5 and R6, which may be the same or different, represent hydrogen atoms or alkyl groups containing 1 to 5 carbon atoms; or R5 and R6 together with the carbon atom be-tween them represent a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety;
R1 represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono-or disubstituted by alkyl groups containing 1 to 3 carbon atoms;
R2 represents a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl or alkoxy group wherein the alkyl com-ponent may contain 1 to 3 carbon atoms; or a hydroxy, nitro, amino or piperidono group;
R3 represents a hydrogen, fluorine, chlorine or bromine atom; and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms.
10. A process as claimed in claim 1, wherein R1 re-presents a piperidine, 2-methylpiperidene or 3-methylpiperidine group, R2 represents a hydrogen atom, a chlorine atom in the 3-, 4- or 6-position, a fluorine atom in the 4-position or a methyl group in the 4- or 6-position, R3 represents a hydrogen atom and W represents a formyl group, a carboxyl group or a C1-3 alkyl ester thereof or a 2-carboxyethenyl group or a C1-3 alkyl ester thereof.
11. A process as claimed in claim 10 wherein A represents a group of formula and R4 represents a methyl, n-propyl, n-butyl, phenyl or 4-fluorophenyl group, or A represents a group of formula wherein R5 represents an ethyl group and R6 represents a hydro-gen atom.
12. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I, initially obtained, wherein W
represents a carboxy or alkoxycarbonyl group is subsequently converted by reduction into a corresponding compound of general formula I wherein W represents a formyl or hydroxymethyl group.
13. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I, initially obtained, wherein W
represents a carboxy group is subsequently converted, by con-version into a sulphonic acid hydrazide and subsequent dispro-portionation, into a corresponding compound of general formula I wherein W represents a formyl group.
14. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained, wherein W

represents a formyl group is subsequently converted by conden-sation and optional subsequent hydrolysis and/or decarboxylation into a corresponding compound of general formula I wherein W
represents a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-ethenyl group.
15. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein W
represents a 2-carboxy-ethenyl or 2-alkoxycarbonyl-ethenyl group is subsequently converted by catalytic hydrogenation into a corresponding compound of general formula I wherein W
represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group.
16. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein W
represents an alkoxycarbonyl group substituted at any carbon atom except the .alpha.-carbon atom by a hydroxy group is subsequent-ly converted by acylation by means of a pyridine-carboxylic acid into a corresponding (pyridine-carbonyloxyalkoxy)-carbonyl com-pound of general formula I.
17. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein W
represents a hydroxymethyl group is, after being converted into a corresponding halomethyl compound, subsequently con-verted by reaction with a malonic acid diester into a corres-ponding compound of general formula I wherein W represents an ethyl group substituted by two alkoxycarbonyl groups.
18. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein W
represents an ethyl group substituted by two alkoxycarbonyl groups is subsequently converted by hydrolysis into a corres-ponding compound of general formula I wherein W represents an ethyl group substituted by two carboxy groups.
19. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein W
represents an ethyl group substituted by two alkoxycarbonyl groups is subsequently converted by hydrolysis and decarboxy-lation into a corresponding compound of general formula I
wherein W represents a 2-carboxyethyl group.
20. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein R2 represents a nitro group is subsequently converted by reduc-tion into a corresponding compound of general formula I wherein R2 represents an amino group.
21. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein R2 represents an amino group is subsequently converted, via a corresponding diazonium salt, into a corresponding compound of general formula I wherein R2 represents a hydrogen or halogen atom or a hydroxy, alkoxy or alkylsulphenyl group.
22. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein R2 represents a hydroxy group is subsequently converted by alkyl-ation into a corresponding compound of general formula I wherein R2 represents an alkoxy group.
23. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein R2 represents a benzyloxy group and/or R4 represents an aryl group substituted by a benzyloxy group is subsequently converted by debenzylation into a corresponding compound of general formula I wherein R2 represents a hydroxy group and/or R4 represents an aryl group substituted by a hydroxy group.
24. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained wherein R4 represents an aminocarbonyl group is subsequently converted by dehydration into a corresponding compound of general formula I
wherein R4 represents a cyano group.
25. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I initially obtained which con-tains a chiral centre is subsequently resolved, by chromato-graphy on a chiral phase, into the enantiomers thereof.
26. A process as claimed in claim 1, 2 or 3, wherein a compound of general formula I or a tautomer or optical enan-tiomer thereof, initially obtained, is subsequently converted to a salt thereof, or a salt of a compound of general formula I or a tautomer or optical enantiomer thereof, initially ob-tained, is subsequently converted to a compound of general formula I or a tautomer or optical enantiomer thereof.
27. A process as claimed in claim 1(a), wherein the re-active derivative of the compound of general formula III is an ester, thioester, halide, anhydride or imidazolide thereof.
28. A process as claimed in claim 1(a), wherein the sub-sequent cleaving of the protecting group of W', if present, is effected by hydrolysis, thermolysis or hydrogenolysis.
29. A process as claimed in claim 28, wherein the hydro-lytic cleaving is effected in the presence of an acid or of a base.
30. A process as claimed in claim 1(a), 27 or 28, wherein the reaction is effected in the presence of a solvent.
31. A process as claimed in claim 1(a), 27 or 28, wherein the reaction is effected in the presence of an acid-activating or dehydrating agent.
32. A process as claimed in claim 1(a), 27 or 28, wherein the reaction is effected in the presence of an amine-activating agent.
33. A process as claimed in claim 1(a), 27 or 28, wherein the reaction is effected in the presence of an inorganic or tertiary organic base.
34. A process as claimed in claim 1(a), 27 or 28, wherein water formed during the reaction is removed by azeotropic dis-tillation or by the use of a drying agent.
35. A process as claimed in claim 1(a), 27 or 28, wherein the reaction is effected at a temperature of from -25 and 250°C.
36. A process as claimed in claim 1(a), 27 or 28, wherein a solvent is present and the reaction is effected at temperatures of from -10°C to the boiling temperature of the solvent.
37. A process as claimed in claim 1(b) wherein the group B in the compound of general formula IV represents a functional derivative (if hydrolysis is desired), an ester (if thermolysis is desired) or an aralkyl ester (if hydrogenolysis is desired) of a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group.
38. A process as claimed in claim 37, wherein the func-tional derivative is an unsubstituted or substituted amide, ni-trile, ester, thiolester, orthoester, imino ether, amidine or anhydride or a malonic ester-(1)-yl, tetrazolyl or optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group, the ester is a tertiary alkyl ester or the aralkyl ester is a benzyl ester.
39. A process as claimed in claim 1(b), 37 or 38, wherein the reaction is effected in the presence of a solvent.
40. A process as claimed in claim 1(b), 37 or 38, wherein the hydrolysis or thermolysis is effected in the presence of an acid or a base.
41. A process as claimed in claim 1(b), 37 or 38, wherein B in the compound of general formula IV represents a cyano or aminocarbonyl group and the reaction is effected using a nitrite in the presence of an acid.
42. A process as claimed in claim 1(b), 37 or 38, wherein B in the compound of general formula IV represents a cyano or aminocarbonyl group and the reaction is effected using sodium nitrite in the presence of sulphuric acid.
43. A process as claimed in claim 1(b), 37 or 38, wherein the reaction is effected at temperatures of from -10 to 120°C.
44. A process as claimed in claim 1(b), 37 or 38, wherein the reaction is effected at temperature of from ambient tem-perature to the boiling temperature of the reaction mixture.
45. A process as claimed in claim 1(c), wherein the re-duction is carried out with hydrogen in the presence of a hydro-genation catalyst.
46. A process as claimed in claim 45, wherein a hydrogen pressure of 1 to 5 bar is used.
47. A process as claimed in claim 1(c), 45 or 46, wherein the reduction is carried out in a solvent.
48. A process as claimed in claim 1(c), 45 or 46, wherein the reduction is carried out at a temperature of from 0 to 100°C.
49. A process as claimed in claim 1(c), 45 or 46, wherein the reduction is carried out at a temperature of from 20 to 50°C.
50. A process as claimed in claim 1(d), wherein the re-action is effected in the presence of a strong acid.
51. A process as claimed in claim 1(d), wherein the re-action is effected in the presence of sulphuric acid.
52. A process as claimed in claim 1(d), 50 or 51, wherein the reaction is effected in the presence of a solvent.
53. A process as claimed in claim 1(d), 50 or 51, wherein the reaction is effected at a temperature of from 0 to 150°C.
54. A process as claimed in claim 1(d), 50 or 51, wherein the reaction is effected at a temperature of from 20 to 100°C.
55. A process as claimed in claim 1(e), wherein the dehalo-genation is effected with hydrogen in the presence of a hydro-genation catalyst.
56. A process as claimed in claim 1(e), wherein the dehalo-genation is effected in a solvent.
57. A process as claimed in claim 1(e), 55 or 56, wherein the dehalogenation is effected at temperatures of between 0 and 100°C and under a hydrogen pressure of from 1 to 5 bar.
58. A process as claimed in claim 1(f), wherein the re-action is effected in the presence of an acid-activating or de-hydrating agent.
59. A process as claimed in claim 1(f), wherein the re-action is effected in the presence of an inorganic or tertiary organic base.
60. A process as claimed in claim 1(f), 58 or 59, wherein the reaction is effected in the presence of an amine-activating agent.
61. A process as claimed in claim 1(f), 58 or 59, wherein the reaction is effected in the presence of a solvent.
62. A process as claimed in claim 1(f), 58 or 59, wherein the reaction is effected at a temperature of from -25°C to 25°C.
63. A process as claimed in claim 1(f), 58 or 59, wherein the reaction is effected in the presence of a solvent and at temperatures of from -10°C to the boiling temperature of the solvent.
64. A process as claimed in claim 1(g), wherein E repre-sents a formyl group, an acetal of a formyl group, a hydroxy-methyl group, an ether of a hydroxymethyl group, a substituted or unsubstituted acyl group or a malonic ester-(1)-yl group.
65. A process as claimed in claim 1(g), wherein the oxi-dising agent used is selected from: silver oxide/sodium hydroxide solution, manganese dioxide, hydrogen peroxide/sodium hydroxide solution, chromium trioxide/pyridine, pyridinium chlorochromate, bromine/sodium hydroxide solution, chlorine/sodium hydroxide solution, bromine/potassium hydroxide solution and chlorine/
potassium hydroxide solution.
66. A process as claimed in claim 1(g), 64 or 65, wherein the oxidation is effected in the presence of a solvent.
67. A process as claimed in claim 1(g), 64 or 65, wherein the oxidation is effected at temperatures of from 0 to 100°C.
68. A process as claimed in claim 1(g), 64 or 65, wherein the oxidation is effected at temperatures of from 20 to 50°C.
69. A process as claimed in claim 1(h), wherein the re-active derivative of the compound of general formula XII, if present, is a halide, anhydride or imidazolide thereof.
70. A process as claimed in claim 1(h), wherein the esterification is effected in the presence of a solvent.
71. A process as claimed in claim 70, wherein the solvent is an excess of the alcohol of general formula XIII.
72. A process as claimed in claim 1(h), 69 or 70, wherein the esterification is effected in the presence of a reaction accelerator.
73. A process as claimed in claim 1(h), 69 or 70, wherein the esterification is effected in the presence of an inorganic or tertiary organic base.
74. A process as claimed in claim 1(h), 69 or 70, wherein the esterification is effected at a temperature of from -20 to 100°C.
75. A process as claimed in claim 1(h), 69 or 70, wherein the esterification is effected in the presence of a solvent and at a temperature of from -10°C to the boiling temperature of the solvent.
76. A process as claimed in claim 1(i), wherein the alco-holysis is effected in the presence of an acid.
77. A process as claimed in claim 76, wherein the acid is hydrochloric or sulphuric acid.
78. A process as claimed in claim 1(i), 76, or 77, wherein the alcoholysis is effected in the presence of a solvent.
79. A process as claimed in claim 1(i), 76 or 77, wherein the alcoholysis is effected in the presence of a solvent which is an excess of the alcohol used in the alcoholysis reaction.
80. A process as claimed in claim 1(i), 76 or 77, wherein the reaction is effected in the presence of a solvent and at temperatures of from 20°C to the boiling temperature of the solvent.
81. A process as claimed in claim 1(i), 76 or 77, wherein the reaction is effected at temperatures of between 50 and 100°C.
82. A process according to claim 1, 2 or 3, wherein pro-cess variant (b), (e), (h) or (i) is used and the starting material is obtained by process variant (a), (c), (d), (f) or (g).
83. A process as claimed in claim 1, which includes the step of recovering the obtained compound of formula I as a physiologically acceptable salt or converting the obtained compound of formula I into a physiologically acceptable salt thereof.
84. A process as claimed in claim 1, 2 or 3, wherein the compound of formula I is obtained as, or converted into, a salt of hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid or with sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenedi-amine.
85. A compound of formula I as defined in claim 1 or a tautomer or an optical enantiomer or salt thereof when pre-pared by a process according to claim 1 or an obvious chemical equivalent thereof.
86. A physiologically acceptable salt of a compound of formula I, as defined in claim 1, when prepared by a process according to claim 83, or an obvious chemical equivalent thereof.
87. A process as claimed in claim 1, wherein A represents a group of formula , in which R4 represents an n-propyl group, R1 represents a piperidine group, R2 and R3 both re-present hydrogen atoms and W represents a carboxyl group or a C1-4 alkoxycarbonyl group.
88. A process as claimed in claim 85, wherein W represents a carboxyl group.
89. A process for preparing ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises reacting 1-(2-piperidinophenyl)butylamine in acetonitrile with 4-ethoxycarbonyl-phenylacetic acid in the presence of triphenyl-phosphine carbon tetrachloride and triethylamine.
90. A process for preparing ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises reacting 4-ethoxycarbonyl-phenylacetic acid with 1-(2-piperi-dino-phenyl)-1-butylamine in the presence of triethylamine.
91. A process for preparing ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoate which comprises hydrogenating ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoate in the presence of a palladium charcoal catalyst.
92. A process as claimed in claim 91, wherein the ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoate is obtained by reacting 4-ethoxycarbonylphenylacetic acid with n-propyl-(2-piperidino-phenyl)-ketimine in the pre-sence of triphenylphosphine, carbon tetrachloride and triethyl-amine.
93. A process for preparing ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises refluxing 4-[(1-(2-piperidino-phenyl)-1-butyl-aminocarbonyl-methyl]-benzonitrile with ethanolic hydrochloric acid.
94. A process according to claim 93, wherein the 4-[(1-(2-piperidino-phenyl)-1-butyl-aminocarbonylmethyl]-benzonitrile is obtained by reacting 4-cyanophenylacetic acid with 1-(2-piperidino-phenyl)-1-butylamine in the presence of triphenyl-phosphine, carbon tetrachloride and triethylamine.
95. A process for preparing ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises reacting 1-(2-piperidino-phenyl)-1-butanol with ethyl 4-cyano-methyl-benzoate in o-dichlorobenzene and in the presence of conc.sulphuric acid.
96. The compound ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]benzoate when prepared by a process according to claim 89, 90, 91 or an obvious chemical equiva-lent thereof.
97. The compound ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]benzoate when prepared by a process according to claim 92, 93, 94 or an obvious chemical equiva-lent thereof.
98. The compound ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]benzoate when prepared by a process according to claim 95 or an obvious chemical equivalent thereo-of.
99. A process for preparing methyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises reacting 1-[2-piperidino-phenyl)butylamine in acetonitrile with 4-methoxycarbonyl-phenylacetic acid in the presence of triphenylphosphine carbon tetrachloride and triethylamine.
100. A process for preparing n-butyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises reacting 1-(2-piperidino-phenyl)butylamine in acetonitrile with 4-n-butoxycarbonyl-phenylacetic acid in the presence of tri-phenylphosphine carbon tetrachloride and triethylamine.
101. The compound methyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate when prepared by a process according to claim 99 or an obvious chemical equivalent thereof.
102. The compound n-butyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate when prepared by a pro-cess according to claim 100 or an obvious chemical equivalent thereof.
103. A process for preparing 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof which comprises hydroly-sing ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoate and if required converting the acid to the sodium salt or, if required, reacting the acid with sulphuric acid to obtain the dihydrogen sulphate salt.
104. A process according to claim 101 wherein the ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate is obtained by a process according to claim 89 or or an obvious chemical equivalent thereof.
105. A process according to claim 101 wherein the ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate is obtained by a process according to claim 91 or 92 or an obvious chemical equivalent thereof.
106. A process according to claim 101 wherein the ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate is obtained by a process according to claim 93 or 94 or an obvious chemical equivalent thereof.
107. A process according to claim 101 wherein the ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoate is obtained by a process according to claim 95 or an obvious chemical equivalent thereof.
108. A process for preparing 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof, which comprises hydrogenating 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl]-benzoic acid in the presence of a palladium on charcoal catalyst and, if required, converting the acid to the sodium salt or, if required, reacting the acid with sulphuric acid to obtain the dihydrogen sulphate salt.
109. A process according to claim 108 wherein the 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid is obtained by reacting 4-ethoxycarbonylphenyl-acetic acid with n-propyl(2-piperidino-phenyl)-ketimine in the presence of triphenylphosphine, carbon tetrachloride and tri-ethylamine to form ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoate and hydrolysing this ester to the acid.
110. A process for preparing 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof which comprises re-acting 1-(2-piperidino-phenyl)-1-butanol with 4-cyanomethyl-benzoic acid in the presence of concentrated sulphuric acid and, if required, converting the acid to the sodium salt or, if required, reacting the acid with sulphuric acid to obtain the dihydrogen sulphate salt.
111. A process for preparing 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof which comprises hydro-genating 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid in the presence of a palladium/
charcoal catalyst and, if required, converting the acid to the sodium salt, or if required, reacting the acid with sulphuric acid to obtain the dihydrogen sulphate salt.
112. A process according to claim 111 wherein the 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid is obtained by hydrolysing ethyl 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate.
113. A process according to claim 112 wherein the ethyl 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoate is obtained by diazotizing ethyl 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate with sodium nitrite and hydrochloric acid and re-acting the diazonium salt with copper (I) chloride and hydro-chloric acid.
114. A process according to claim 113 wherein the ethyl 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoate is obtained by hydrogenating ethyl 4-[(1-(5-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in the presence of a palladium/charcoal catalyst.
115. A process according to claim 114 wherein the ethyl 4-[(1-(5-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoate is obtained by reacting 4-ethoxycarbonyl-phenyl acetic acid chloride with 1-(5-nitro-2-piperidino-phenyl)-1-butylamine in the presence of triethylamine.
116. The compound 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof when prepared by the pro-cess according to claim 103, 108 or 109 or an obvious chemi-cal equivalent thereof.
117. The compound 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof when prepared by the process according to claim 110, 111 or 112 or an obvious chemical equivalent thereof.
118. The compound 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or the sodium salt or the dihydrogen sulphate salt thereof when prepared by the process according to claim 113, 114 or 115 or an obvious chemical equivalent thereof.
119. A process for preparing ethyl (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate which comprises derivatising (+)-1-(2-piperidino-phenyl)-1-butylamine with (+)-1-phenethyl isocyanate and reacting the derivatised product in acetonitrile with 4-ethoxycarbonyl-phenylacetic acid in the presence of triphenylphosphine, carbon tetrachloride and tri-ethylamine.
120. A process for preparing ethyl (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoate which comprises derivatising (+0-1-(2-piperidino-phenyl)-1-butylamine-dihydro-chloride with (+)-1-phenethyl-isocyanate and reacting the de-rivatised product in methylene chloride with 4-ethoxycarbonyl-phenylacetic acid chloride in the presence of triethylamine.
121. The compound ethyl (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate when prepared by a pro-cess according to claim 119 or 120 or an obvious chemical equivalent thereof.
122. A process according to claim 119 which comprises the further step of hydrolysing the ethyl ester to obtain the free acid.
123. A process according to claim 120 which comprises the further step of hydrolysing the ethyl ester to obtain the free acid.
124. The compound (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid when prepared by a process according to claim 122 or 123 or an obvious chemical equivalent thereof.
125. A process according to claim 1 wherein A represents a group of formula in which R4 is an n-propyl group, R1 represents a piperidine group, R2 and R3 both represent hydrogen atoms and W represents a carboxymethyl group.
126. A process for preparing 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenylacetic acid which comprises reacting p-phenylene-diacetic acid chloride with ]-(2-piper-idino-phenyl)-1-butylamine, followed by hydrolysis to obtain the free acid.
127. The compound 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenylacetic acid when prepared by a process according to claim 126 or an obvious chemical equiva-lent thereof.
CA000431796A 1982-07-06 1983-07-05 Phenylacetic acid derivatives, the preparation thereof and pharmaceutical compositions containing these compounds Expired CA1214773A (en)

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DEP3225188.2 1982-07-06
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DE19823225155 DE3225155A1 (en) 1982-07-06 1982-07-06 Novel N-benzylamides and their salts, their preparation and pharmaceuticals containing these compounds
DE19823225188 DE3225188A1 (en) 1982-07-06 1982-07-06 Novel phenylacetic acid derivatives, their preparation and pharmaceuticals containing these compounds

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US5312924A (en) * 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
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FR2763590B1 (en) * 1997-05-22 2000-03-24 Synthelabo ACID DERIVATIVES [[[(ARYLMETHYL) AMINO] CARBONYL] ALKYL] - AROMATICS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
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