GB2124220A - Substituted phenylacetamides - Google Patents

Substituted phenylacetamides Download PDF

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Publication number
GB2124220A
GB2124220A GB08318250A GB8318250A GB2124220A GB 2124220 A GB2124220 A GB 2124220A GB 08318250 A GB08318250 A GB 08318250A GB 8318250 A GB8318250 A GB 8318250A GB 2124220 A GB2124220 A GB 2124220A
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Prior art keywords
group
phenyl
carbon atoms
piperidino
alkyl
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GB08318250A
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GB2124220B (en
GB8318250D0 (en
Inventor
Dr Wolfgang Grell
Dr Rudolf Hurnaus
Dr Gerhart Griss
Dr Robert Sauter
Dr Eckhard Rupprecht
Dr Joachim Kahling
Dr Bernhard Eisele
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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Priority claimed from DE19823225188 external-priority patent/DE3225188A1/en
Priority claimed from DE19823225155 external-priority patent/DE3225155A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of GB8318250D0 publication Critical patent/GB8318250D0/en
Publication of GB2124220A publication Critical patent/GB2124220A/en
Application granted granted Critical
Publication of GB2124220B publication Critical patent/GB2124220B/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)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

SPECIFICATION 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 circulatory system.
According to one feature of the present invention, we provide compounds of general formula I
[wherein A represents a group offormula
[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 containing 4to 7 carbon atoms; an alkenyl group containing 3to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene moiety; an aminocarbonyl group optionally mono-ordisubsti- tuted by alkyl orphenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety (the substitutents in the case of disubstitution being the same or different); an aryl group containing 6 or 10 carbon atoms optionally mono- ordisubstituted 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; ora heteroaryl group containing 4,5,8 or 9 carbon atoms and 1 or 2 nitrogen atoms; R5andR6,which maybethesameordifferent, represent hydrogen atoms or alkyl groups containing 1 to 5carbon atoms, or Rand R6togetherwiththe carbon atom between them represent a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety], R1 represents an unbranched alkyleneimino group containing 4to 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 3carbon atoms in each case, R3 represents an alkyl group containing 1 to 3 carbon atoms ora hydrogen or halogen atom, and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2to 6 carbon atoms (wherein the alkyl component may optionally be substituted buy a phenyl group and optionally, at any carbon atom except the cc-carbon atom, by one ortwo 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 4to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 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 - alkoxycarbonyl - ethenyl or 2,2 - bis (alkoxycar- bonyl) - ethyl group (each alkoxy group containing from 1 to 3 carbon atoms)] andtautomersthereofand optical enantiomers thereof and salts of the aforementioned compounds.
It will be appreciated thattheterm "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, maleicorfumaricacid. 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, by physiologically compatible salts, but other salts may fine 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 particu larlytothetautomeric ketimineform ofthecompounds of general formula I wherein A represents a substituted vinylidene radical, but the term is not restricted to this interpretation and covers all possible tautomericforms of the compounds of general formula I.
Thedefinitionsgiven hereinbeforeforthe groups R, to R6 and W includethefollowing, forexample: R1 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 - n - propylamino, N isobutyl - n - propylamino, N - methyl - n - butylamino, N - ethyl - n - butylamino, N - ethyl - isopropylamino, N - ethyl - n - pentylamino, N - propyl - n - butylamino, pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, octamethyleneimino, nonamethyleneimino, methyl-pyrrolidino, dimethylpyrrolidino, ethyl-pyrrolidino, methyl-piperidino, ethyl-piperidino, dimethyl-piperidino, diethyl-piperidino, methyl-ethylpiperidino, n - propyl - piperidino, methyl - n - propylpiperidino, isopropylpiperidino, or di - n - propyl - piperidino group, This print takes account of reptacement documents later filed to enable the application to comply with the formal requirements of the Patents Rutes 1982 R2 may represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, n propylisopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy,trifluoromethyl, nitro, amino, piper idino, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, methylsulphinyl, ethylsulphinyl, methylsulphonyl, n-propylsulphonyl, benzy- loxy, 1 - 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, R4may 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, 1 -phenylethyl, 2-phenylethyl, 1 phenyl - n - propyl, 2 - phenyl - n - propyl, 3 phenylpropyl, allyl, 3- buten -1 - yl, 2 - buten - 1 - yl, 4 penten-1 cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl - n - propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di - n - propylaminocarbonyl, benzylaminocarbonyl, 2- phenyl - ethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, phenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxyphenyl, 2 - phenyl - ethoxy - phenyl, 3 - phenylpropoxy - phenyl, methylsulphenyl - phenyl, ethylsulphenyl - phenyl, methyl - sulphinyl - phenyl, n - propylsulphinyl phenyl, methyl - sulphonyl - phenyl, ethylsulphonyl phenyl, isopropylsulphonyl - 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 orquinazolyl group, R5and R6 may represent a hydrogen atom ora methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl or n-pentyl group, R5 and R6togetherwith the carbon atoms between them may represent a benzylidene, 1 - phenyl ethylidene, 2 - phenyl - ethylidene, 1 - phenyl - n propylidene, 1 - phenyl - 2,2 - propylidene or3 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, isopropxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, (2 - hydroxyethoxy) carbonyl, (2 - hydroxy - n - propoxy) carbonyl, (1 - hydroxy- 2 - propoxy) carbonyl, (2 methoxyethoxy) carbonyl, (2 - ethoxyethoxy) carbonyl, (2 - n - propoxyethoxy) carbonyl, (2 - nicotinoyloxy - ethoxy) carbonyl, (2 - isonicotinoyloxy ethoxy) carbonyl, (2,3 - dihydroxy - n - propoxy) carbonyl, (2 - dimethylamino - ethoxy) carbonyl, (2 - diethylamino-ethoxy)carbonyl, t2 - piperidino - ethoxy) carbonyl, methyl, ethyl, n-propyl, isopropyl, cyano, aminocarbonyl, methoxycarbonyl - methyl, ethoxycarbonyl - methyl, n - propoxycarbonyl - methyl, 2 - methoxycarbonyl - ethyl, 2 - ethoxycar- bonyl - ethyl, 2 - isopropoxycarbonyl - ethyl, 2 methoxycarbonyl - ethenyl, 2 - ethoxycarbonyl ethenyl, 2 - n - propoxycarbonyl -ethenyl, 2,2 - bis (methoxycarbonyl) - ethyl, 2,2 - bis - (ethoxycarbonyl) - ethyl or 2,2 - bis - (isopropoxyca rbonyl) - ethyl group.
Preferred compounds of general formula I above are those wherein A represents a group offormula
or
wherein R4 represents an alkyl group containing 1 to 3 carbonatomssubstituted byan alkoxygroup containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkyl group containing 4to 6 carbon atoms; an alkenyl group containing 3to 5 carbon atoms; a cyano oraminocarbonyl 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, whilstthe 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 3to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety; R1 represents an unbranched alkyleneimino group containing 4to 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 ora nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms, or (if R5 and R5 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 containing 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 - carboxyl - 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 exceptthe 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 and 4- [N - (6- chioro - a - phenyl - 2 - piperidino - benzyl) arninocarbonylmethyll - benzoic acid and Cl-3 alkyl esters thereof, 4- [N - (cc- phenyl -2 - piperidino - benzyl) aminocarbonylmethyl] - cinnamic acid and C13 alkyl esters thereof, 3- [4- [(N - (cc- phenyl - 2 - piperidino - benzyl) aminocarboxylmethyl] - phenyl] - propionic acid and 01-3 aIkyl esters thereof, 4- [N - (4-chloro - cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C1~3 alkyl esters thereof, 4- [N - (3 - chloro - cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C1-3 alkyl esters thereof, 4- [N - (6 - methyl - cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof, 4 - [N - (4 - methyl - cc - phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C1~3 alkyl esters thereof, 4 - [N - (2 - (2 - methyl - piperidino) - a - phenyl - benzyl) - aminocarboxylmethyl] - benzoic acid and C1~3 alkyl esters thereof, 4- [N - (2 - (3 - methyl - piperidino) - a - phenyl - benzyl) - aminocarbonylmethyll - benzoic acid and C13 alkyl esters thereof, 4- [N - (cc - phenyl - 2 - piperidino - benzyl) aminocarbonylmethylbenzaldehyde, 4- [(1 - (4-fluoro -2- piperidino- phenyl) - ethyl) aminocarbonylmethyl] - benzoic acid and C1~3 alkyl esters thereof, 4- [(1 - (3-chloro-2- piperidino- phenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid and C1~3 alkyl esters thereof, and 4- [(1 - (3 - methyl -2- piperidino - phenyl) - ethyl) - aminocarbonylmethyl] benzoic acid and C1~3 alkyl esters thereof.
Particularly preferred are those compounds of general formula I wherein A represents a group offormula
or
wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano oraminocarbonyl group; an alkyl group containing 4to 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; R5and R6 tog ether with the carbon atom between them represent an alkyidene group containing 3to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety, R1 represents an unbranched alkyleneimino group containing 4to 8 carbon atoms or a piperidino group mono-ordisubstituted by methyl groups, R2 represents a hydrogen, fluorine, chlorine or bromine atom ora methyl ormethoxygroup; or(if R5 and Re are as hereinbefore defined or R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, nitrile oraminocarbonly group, an alkyl group containing 4to 6 carbon atoms or an alkenyl group containing 3 to 5 carbon atoms) R2mayalso representan iodine atom ora hydroxyoramino 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 exceptthe carbon atom by one or two hydroxy groups, 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; and 4- [N - (6-chloro -cc- phenyl - 2 - piperidino - benzyl) amino - carbonyl - methyl - benzoic acid and Ci -3 alkyl esters thereof with 1 to 3 carbon atoms, 4- [N - (cc - phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - cinnamic acid and C1~3 alkyl esters thereof, 3 - [4- [(N - (cc- phenyl - 2 - piperidino - benzyl) aminocarbonyl - methyl - phenyl] - propionic acid and C1-3 alkyl estersthereof, 4- [N - (4-chloro - cc- phenyl - 2 - piperidino - benzyl) amino - carbonyl - methyl] - benzoic acid and C1-3 alkyl esters thereof, 4- [N - (3-chloro- cc- phenyl - 2 - piperidino - benzyl) amino - carbonyl - methyl - benzoic acid and C1 ~3 alkyl esters thereof, 4- [N - (6 - methyl - cc- phenyl - 2 - piperidino - benzyl) amino - carbonyl - methyl] - benzoic acid and C1-3 alkyl esters thereof, 4- [N - (4-methyl - cc- phenyl - 2- piperidino - benzyl) amino - carbonyl - methyl - benzoic acid and C13 alkyl esters thereof 4- [N - (2 - (2 - methyl - piperidino) - a - phenyl - benzyl) - amino - carbonyl - methyl - benzoic acid and C1-3 alkyl esters thereof, 4- [N - (2 - (3 - methyl - piperidino) - a - phenyl - benzyl) - amino - carbonyl - methyl] - benzoic acid and C1-3 alkyl esters thereof, 4- [N -(cc-phenyl -2- piperidino - benzyl) aminocarbonylmethyl] - benzaldehyde, 4- [(1 - (4-fluoro -2-piperidino - phenyl) - ethyl) - aminocarbonyl - methyl - benzoic acid and C1~3 alkyl esters thereof, 4- [(1 - (3-chloro -2 - piperidino - phenyi) - ethyl) - aminocarbonyl - methyl] - benzoic acid and C1~3 alkyl esters thereof, and 4- [(1 - (3-methyl -2- piperidino - phenyl) - ethyl) - aminocarbonyl - methyl] - benzoic acid and Ci -3 alkyl esters thereof.
However, another group of preferred compounds are those wherein R1 to R3 and W are as hereinbefore defined, more particularly those where- in W represents a carboxy group or an alkoxycar bonyl group containing atotal 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 enantiom ers and the saltsthereof.
Particularly preferred compounds of general formula I above are those wherein A represents a group offormula
or
wherein R4 represents an n-propyl group, an alkyl group containing 4 or 5 carbon atoms, a phenyl group substituted by a methyl group or by a fluorine or chlorine atom, ora pyridyl group, R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part; R1 represents a piperidino group optionally substituted by one ortwo methyl groups; R2 represents a hydrogen, fluorine or chlorine atom ora 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; particularlythose wherein A represents a group offormula
or
wherein R4represents an n-propyl group oran alkyl group containing 4 or 5 carbon atoms and 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, and optically active enantiomers and salts thereof.
The compounds of general formula las hereinbefore defined and their optical enantiomers and salts thereof may, for example, be prepared by the following processes, which processes constitute furtherfeatures ofthe present invention: a) Reacting a compound of general formula II
(wherein A, R1 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
(wherein R3 is as hereinbefore defined and W' has the meanings given forW hereinbefore or represents a carboxy group protected by a protecting group), or with a reactive derivative thereof optionallyformed in the reaction mixture and, if necessary, subsequently cleaving any protecting group used.
The reactive derivatives of a compound of general formula Ill may be, for example, the esters thereof, such as the methyl, ethyl or benzyl esters, the thio-esters thereof such as the methylthio- or ethyl thio-esters,the halidesthereofsuch astheacid chloride, orthe anhydrides or imidazolides thereof.
The reaction is conveniently carried out in à 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 ora dehydrating agent, e.g. in the presence of ethyl chloroformate,thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N' - dicyclohexylcarbodiimide, N,N' - dicyclohexylcarbodiimide/N hydroxy - succinimide, N,N' - carbonyldiimidazole or N,N' -thionyldiimidazoleortriphenylphosphine/ 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 maysimul- taneously serve as solvent, at temperatures of between - 25"C and 250"C, but preferably at temperatures of between - 1000 and the boiling temperature ofthe 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 ortrichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol water, water/isopropanol or water/dioxan at temperatures of between -10"C and 120 C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.
Atert.butyl group used as the protecting group may also be cleaved thermally, possibly in an inert solvent such as methylene chloride, chloroform, benzene,toluene,tetrahydrofuranordioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid.
Moreover, a benzyl 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
(wherein R1 to R3 and A are as hereinbefore defined, and B represents a group which can be converted by hydrolysis, thermolysis or hydrogenolysis into a ca rboxy, carboxymethyl, 2 - carboxyethyl or 2 carboxyothenyl group) to hydrolysis, thermolysis or hydrogenolysis.
The hydrolysable groups in the compounds of general formula IV may be, for example, functional derivatives ofcarboxy, carboxymethyl, 2 - carboxyethyl or2-carboxyethenyl groups such as the u nsubstituted or substituted amides thereof, the nitriles, esters, thiolesters, orthoesters, iminoethers, amidines or an hydrides thereof, a ma lonic ester - (1) - yl group, the tetrazolyl group, an optionally substi tuted 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 ortrichloroacetic 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 orwater/dioxan attemperatures of between -10"C and 1 20 C, e.g. at temperatures of between ambient temperature and the boiling temperature 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. sodium 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 50"C.
If B in a compound of general formula IV represents thetert.butyloxycarbonyl group, for example, the tert.butyl group may also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene,toluene,tetrahydro- furan or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. attemperatures of between 40"C and 10000.
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 attemperatures of between 0 and 50"C, e.g. at ambienttemperature, and at a hydrogen pressure of from 1 to 5 bar.In the hydrogenolysis, other groups may simultaneously be reduced aswell (e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to a corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpro pionic acid group}, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.
c) In orderto preparecompoundsforgeneralformula I wherein A represents a group of formula
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
wherein R1 to R3 and Ware as herein before defined and D represents a group offormula
wherein R41, has the meanings given hereinbeforefor 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 ora 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, isopropanoi, ethanol / water, glacial acetic acid, ethyl acetate, dioxan, tetrahydrofura n, dimethylformamide, benzeneorbenzene/ethanol attemperatures of between 0 and 100 C, but preferably attemperatures of between 2000and 50"C, 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 p,ji' - dichloro bis[1,5-cyclooctadiene - rhodium] and (+)-or (-) 0,0 - isopropyl idene - 2, 3-dihydroxy- 1,4- bis (diphenylphosphino) - butane (= DIOP), the addition of hydrogen occurs enantioselectively. Moreover, during catalytic hydrogenation, other groups may be F reduced as the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxygrouptothe hydroxygroup ora cinnamic acid grouptothe phenylpropionic acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be ; replaced buy a hydrogen atom.
d) In orderto prepare compounds of general 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 general formula VI
(wherein R4, is defined as above and R, and R2 are as hereinbefore defined) with a compound of general formula VII
wherein R3 and Ware as hereinbefore defined.
The reaction is carried out in the presence of a strong acid which may simultaneously serve as solvent, preferably in concentrated sulphuric acid, at temperatures of between 0 C and 1 500C, but prefer ably attem peratures of between 20"C and 1 00 C.
e)forthepreparation of compounds of general formula I, wherein R2 represents a hydrogen atom: dehalogenating a compound of general formula VIII
wherein R1, R3, A and Ware 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 presence of platinum or palladium / charcoal, at temperatures of between 0 and 1 00 C, but preferably atambienttemperature, and under a hydrogen pressure of from 1 to 5 bar. Duringthedehalogena- tion, other groups may be reduced at the same time, e.g. a benzyloxy group may be reduced to a hydroxy group, a vinylidene group to the corresponding alkylidene group ora cinnamic acid groupto the corresponding phenylpropionic acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.
f) In order ro prepare compounds of general formula I, wherein A represents a group offormula
wherein R4 represents an alkyleneiminocarbonyl group containing 4to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disubsituated by alkyl orphenylalkyl groups each having 1 to to 3 carbon atoms in the alkyl moiety:: Reacting a compound of general formula
(wherein R1, R2 and R3 are as hereinbefore defined and wv has the meanings given hereinbefore for W, with the exception of the carboxy group), with an amine of general formula X H - R7 (X) wherein R7 represents an alkyleneimino group containing 4 to 6 carbon atoms oran amino group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety.
Amidation is conveniently effected in a solvent such as methylene chloride, chloroform, carbon tetrachloride, 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,N' - dicyclohexylcarbodiimide/N hydroxysuccinimide, N,N' - carbonyldiimidazole, N,N' -thionyldiimidazole ortriphenylphosphine/ carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorustrichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such astriethylamineor pyridine which maysimul- taneously serve as solvent, at temperatures of between -25"C and 250"C, but preferably at tempera- tures of between -1 O"C and the boiling temperature of the solvent used.
g) In orderto prepare compounds of general formula I wherein A represents a group offormula
as hereinbefore defined and W represents a carboxy group: Oxidising a compound of general formula Xl
wherein R1 to R4are 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 unsu bstituted acyl group such as an acetyl, chloroacetyl, propionyl or malonic acid-(1 )-yl grouporamalonicester-(1)-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 etherattemperatures of between 0 and 1 00 C, but conveniently at temperatures of between 20"C and 50"C. 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 pyridinim chlorochromate.
h) In orderto prepare compounds of general formula I wherein W represents an alkoxycarbonyl group containing a total of 2to 6 carbon atoms wherein the alkyl component may be substituted at any carbon atom exceptthe 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
(wherein R1 to R3 and A are as hereinbefore defined) ora 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 oc-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 Xll include the halides thereof, such asthe 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 ora dehydrating agent, e.g. in the presence of hydrogen chloride, sulphuric acid, ethyl chlorofor- mate, 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 transesterification, e.g. with a corresponding carbonic acid diester, at temperatures of between -20 C and 1 00 C, but preferably at temperatures of between -1 0 C and the boiling temperature of the solvent used.
i) In orderto 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 ornuo offormula
where R4" represents R4 as hereinbefore defined with the exception of a cyano group: Alcoholysis of a compound of general formula XIV
wherein R4" represents R4 as hereinbefore defined with the exception ofacyano group and R1to R3 are as hereinbefore defined and W"' represents a cyano, cyanomethyl, 2 cyanotheyl or2-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 20"C and the boiling temperature ofthe solvent used, preferably at temperatures of between 50 and 1 00 C.
If, according to the invention, a compound of general formula I is initially obtained wherein W rep resents 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 ifacompoundofgeneralformula lisinitiallyobtained wherein W represents a carboxy g rou p, this may subsequently be converted by conversion into a sulphonicacid hydrazideand subsequentdisproportionation into a corresponding compound ofgeneral formula I wherein W represents a formyl group, and/or if a compound of general formula I 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 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 substituted at any carbon atom exceptthe oc - 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 compound 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 converted 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 alkoxy carbonyl 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 corresponding compound of general formula I wherein W represents an ethyl group substituted bytwo 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 represents a 2 - carboxyethyl group, and/or if a compound of general formula I is initially obtained wherein R2 represents a nitro group, this may subsequently be converted by reduction into a corresponding compound 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 subsequently be 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 alkylsul phenyl group, and/or if a compound of general formula I is initially obtained whereinR2representsa hydroxygroup,this may subsequently 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 maysubsequently beconverted by debenzylation into a corresponding compound of generalformula Iwherein R2 represents a hydroxy group and/or R4 represents an aryl group substituted bya hydroxygroup, 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 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, attemperatures up to the boiling temperature of ) the solvent used.
The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride such as lithium aluminium hydride, in a solvent such as diethyl ether, tetrahydrofu ran or 3 dioxan attemperatu res of between 0 and 100 C, but preferably at temperatures of between 20"C and 60"C.
The subsequent disproportionation of a sulphonic acid hydrazide,which is obtained by reacting a corresponding hydrazinewith a corresponding reac tive carboxylic acid derivative, is carried out in the presence of a base such as sodium carbonate in a solvent such as ethyleneglycol attemperatu res of between 1 00 C and 200"C, but preferably at 160 to 1 70 C.
The subsequent condensation of a formyl com pound is conveniently carried out in a solvent such as pyridine ortetrahydrofuran 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 hyd ride, at temperatures of between 0 and 1 00'C; the desired compound is obtained bysubsequentacidi fication, e.g. with hydrochloric or sulphuric acid, or by subsequent alkaline hydrolysis.
The subsequent catalytic hydrogenation is conve niently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethyl formamidewith hydrogen in the presence of a hydrogenation catalyst such as platinum or palla dium/charcoal attemperatures of between 0 and 75"C, but preferably at ambient temperature and under a hydrogen pressure of 1 to 5 bar.
The subsequent 0 - acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydro- furan, dioxan, benzene, toluene, acetonitrile or dimethylformamide, preferably with a reactive de rivative ofthe acid, for example a halide such as the acid chloride, and anhydride or imidazolide 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 simul taneously serve as solvent, at temperatures of between -25"C and 250 C, but preferably at tempera- tures of between -1 0 C 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 asthionyl chloride, phos phorustrichloride, phosphorustribromide orphos phorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nit robenzene and subsequently reacting with a malonic acid ester, e.g. with an alkali metal salt of diethyl malonate, at temperatures of between 0 and 100 C, but preferably at temperatures of between 50"C and 80"C.
The subsequent hydrolysis or hydrolysis and decarboxylation is conveniently effected in the pre sence of an acid such as hydrochloric, sulphuric, phosphoric, polyphosphoric ortrifluoroacetic acid in a suitable solvent such as water, ethanol, water/ i etha nol, water/iso propa nol orwater/dioxan atele vated temperatures, e.g. at the boiling temperature of the reaction mixture.
The subsequent reduction ofthe nitro compound is preferably effected in a solvent such as water, I 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(ll)sulphate, tin(ll)chloride or sodium dithionite or with hydrazine in the presence of Raney nickel attemperatures of between 0 and 50"C, but preferably at ambient temperature.
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(l)salt such as copper(l)ch- loride/hydrochloricacid orcopper(I)bromide/hydrob- romic acid, is carried out at slightly elevated temperatures, e.g. attemperatures of between 1 5"C and 1 00 C;; the subsequent reaction with hypophosphorous acid is preferably carried out at -50C to OOC. The diazonium salt required is conveniently prepared in a suitable solvent, e.g. in water/hyd roch lo ric 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. attemperatures of between -1 0 C and 5"C.
The subsequent 0 - alkylation is conveniently effected with a corresponding halide, sul phonic acid ester or diazoalkane, e.g. with methyl iodide, dimethylsulphate, ethyl bromide, ethyl p - toluene- sulphonate, isopropylmethanesulphonate or di azomethane, 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, tetrahydrofu ran, dioxan, methanol, ethanol, pyridine or dimethylformamide at temperatures of between 0 and 75"C, preferably at ambienttemperature.
The subsequent debenzylation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide using catalytically acitvated hydrogen, e.g. using hydrogen in the presence of platinum or palladium/ charcoal, at temperatures of between 0 and 75"C, but preferably at ambienttemperatures and at a hydrogen pressureoffrom 1 to 5 bar.
The subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, sulphuric acid or p -tolrenesulphonic acid chloride, optionally in a solvent such as methylene chloride or phyridine at temperatures of between 0 and 1 00 C, preferably at temperatures of between 20 and 80"C.
If they have a chiral centre, the compounds of general formula I obtained can also be resolved into theirenantiomers by conventional methods. This may, for example, be effected by column chromatography on a chiral phase.
A compound of general formula loratautomer thereof, initially obtained, may subsequently be converted into an addition salt thereof, of example by conventional methods such as reacting the compound of general formula I ortautomerthereof as a base with an acid in a suitable solvent, or reacting the compound of general formula I ortautomerthereof as an acid with a base in a suitable solvent. A salt of a compound of general formula loratautomerthereof, initially obtained, may subsequently be converted by conventional methods into a different salt or into a compound of general formula I ortautomerthereof.
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 offormula
orthetautomeric ketimine thereof is obtained by reacting a corresponding nitrilewith a corresponding Grignard or lithium compound and subsequently hydrolysing or by reacting a corresponding ketone with ammonia in the presence of titanium tetrachloride. Forfurther reaction with a compound of general formula Ill or the reactive derivatives thereof, more particularly the acid chlorides thereof, it is also possible to use the organometallic ketimine complex.
A compound ofthe general formula II wherein A represents a group offormula
wherein R4,,, has the meanings given hereinbefore for R4with the exception ofthe cyano and aminocarbonyl groups, is obtained, for example, by reacting a corresponding 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 orwith an ammonium salt in the presence of sodium cyanoborohydride, 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 N - (1 - phenylethyl) - ketimine, e.g. with catalytically activated hydrogen or with a complex metal hydride in etheroftetrahydrofuran attemperatures of between -78 C and the boiling temperature of the solvent used and subsequently cleaving the benzyl orl-phenylethyl group by catalytic hydrogenation, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulphuric acid, or by Hofmann, Curtius, Lossen or Schmidt degradation of a corresponding compound.
A compound of general formula 11 wherein A represent the group
may be obtained by reacting a corresponding aldehy de with ammonium cyanide or by reacting a corres- ponding cyanohydrin with ammonia.
An amine of general formula II thus obtained, having a chiral centre, wherein A represents a group offormula
wherein R4" has the meanings given hereinbefore with the exception ofthe cyano group, may be resolved into the enantiomers by racemate splitting, e.g. by fractional crystallisation of the diastereomeric saltswith optially active acids and subsequent decomposition ofthe salts or by column chroma tographyonachiral phase, orbyforming di astereomericcompoundsandthen separating 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 aluminium hydrides wherein some ofthe hydride hydrogen atoms are replaced by optically active alkoxide radicals, or by means of hydrogen in the presence of a suitable chiral hydrogenation catalyst or analogously, starting from a corresponding N-benzyl- or N - (1 - phenethyl) - ketimine or from a corresponding N - acyl - ketimine or enamide and optionally subsequently cleaving the benzyl, 1phenethyl or acyl group.
Furthermore, an optically active amine of general formula II may also be prepared by diastereoselective reduction of a corresponding ketimine or hydrazone chirallysubstituted at the nitrogen atom, by means of complex or non-complex boron of aluminium hyd rides wherein, if desired, some ofthe hydride hydrogen atoms have been replaced by correspond ing alkoxide, phenolate or alkyl radicals, or by means of hydrogen in the presence of a suitable hydrogenation catalyst and optional subsequent cleaving ofthe chiral auxialiary radical by catalytic hydrogenolysis or hydrolysis.
In addition, an optically active amine of general formula 11may also be prepared bydiastereoselective addition of a corresponding organometalliccom- pound, preferably a Gringnard or lithium compound, to a corresponding 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, VEIL, IX, Xl, 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 subsequent hyd rolysis.
A compound of general formula V used as starting material is preferably obtained by acylating a corres ponding ketimine ofthe organometallic complex thereofwith a corresponding carboxylic acid orthe reactive derivatives thereof.
As already mentioned hereinbefore, the new com pounds of general formula las hereinbefore defined, thetautomers and optical enantiomers thereof and acid and base addition salts of the aforementioned compounds have valuable pharmacological prop erties, namely an effect on the intermediate metabol ism, 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 fortheir 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 - 1 - yl) - aminocarbonylmethyl] - benzoate, C = (E)-4-[(1 -(2-piperidino-phenyl)-1 - buten -1 - yI) - aminocarbonylmethyl] - benzoic acid, D =4- [(2-methyl -1 - (2 - piperidino - phenyl)- 1- propen - 1 - yl) - aminocarbonylmethyl] - benzoicacid, E = ethyl (Z) -4- [(1 - (2- piperidino - phenyl)- 1 - hexen -1 - yl) - aminocarbonylmethyl] - benzoate, F= (Z)-4- [(3- phenyl - 1 -(2- piperidino- phenyl) - 1 - propen - 1 - yl) - aminocarbonylmethyl] - benzoic acid, G = (Z) -4- [(1 - (2 - (3,3 - dimethyl - piperidino) phenyl) - 1 - buten - 1 -yl) - aminocarbonylmethyl] benzoic acid, H = 4- [(1 - (2- pyrrolidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid, J = (+) -4- [(1 -(2-piperidino-phenyl)-1 - butyl) - aminocarbonylmethyl] - benzoic acid, K (+)-4- [(1 -(2-piperidino-phenyl)- 1 - butyl)- aminocarbonylmethyl] - benzoic acid, L = ethyl (+) -4- [(1 - (2- piperidino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoate, M = 4 - [(1 - (2 - hexahydroazepino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid, N = 4- [(1 - (2- piperidino - phenyl) - 1 - hexyl) - aminocarbonylmethyl] - 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- [(cc -cyano - 2 - piperidino - benzyl) am inocarbonyl methyl] - benzoic acid, R = 4- [(1 - (2 - piperidino- phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzyl alcohol, S = 4- [(1 - (2- piperidino- phenyl) - 1 - butyl) - aminocarbonylmethyl] - phenylacetic acid, T = 4- [(1 - (2- piperidino - phenyl) -1 - butyl) - aminocarbonylmethyl] -cinnamic acid, U = 2,3-dihydroxy-propyl 4- [(1 -(2- piperidino phenyl) - 1 - butyl) - aminocarbonylmethyl] benzoate, V = 4- [(1 - (4-fluoro -2- piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid, W = 4- [(1 - (4- methoxy-2- piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid, X = 4- [(1 - (2 - octahydroazonino - phenyl) - 1 - ethenyl) - aminocarbonylmethyl] - benzoic acid, Y = 4- [(1 - (3-chloro -2- piperidino - phenyl) - 1 - ethyl) - aminocarbonylmethyl] - benzoic acid, Z = 4- [(1 - (3 - methyl -2- piperidino - phenyl) - 1 - ethyl) - aminocarbonylmethyl] - benzoic acid, AA = 4- [( - (4- methyl - phenyl) - 2- piperidino benzyl) - aminocarbonylmethyl] - benzoic acid, AB = 4- [(cx- (3methyl - phenyl) - 2 - piperidino benzyl) - aminocarbonylmethyl] - benzoic acid, AC = 4- [(cx- (4-fluoro- phenyl) - 2- piperidino benzyl) - aminocarbonylmethyl] - benzoic acid, AD = 4- [(cc- (2-fluoro - phenyl)- 2- piperidino benzyl) - aminocarbonylmethyl] - benzoic acid, AE = 4 - [(α - 4- [(α-(4-chloro-phenyl)-2-piperidino- benzyl) - aminocarbonylmethyl] - benzoic acid, AF = 4- [(a - (3 - chloro - phenyl) - 2 - piperidino benzyl) - aminocarbonylmethyl] - benzoic acid, AG = 4- [(2 - piperidino - a - (2 - pyridyl) - benzyl) aminocarbonylmethyl] - benzoic acid, AH = 4- [(2- piperidino - cc- (4-pyridyl) - benzyl) aminocarbonylmethyl] - benzoic acid, AJ = 4- [(6- chloro- α;- phenyl - 2 - piperidino- benzyl) - aminocarbonylmethyl] - benzoic acid, AK = 4- [(oc - phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - cinnamic acid, AL = 3 - [4- [(oc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - phenyl] - propionic acid, AM = 4- [(4-chloro-cc- phenyl-2-piperidino benzyl) - aminocarbonylmethyl] - benzoic acid, AN = 4-[(6 - methyl -α- phenyl - 2 - piperidino - benzyl) -aminocarbonylmethyl] - benzoic acid, AO = 4- [(4-methyl - α- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid, AP = 4 - [(oc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benza Idehyde, AO = 4- [(2 - (2 - methyl - piperidino) - α;- phenyl benzyl) - aminocarbonylmethyl] - benzoic acid, AR = 4- [(2- (3-methyl - piperidino) - cc- phenyl benzyl) - aminocarbonylmethyl] - benzoic acid and AS = 4 - [(3 - chloro α-phenyl - 2 - piperidino- benzyl) - aminocarbonylmethyl] - benzoic acid: 1. Hypoglycaemic activity The hypoglycaemic activity of the test substances was tested on female rats of a single strain weighing from 180 to 220 g,which had been kept without food or drink for 24 hours before the start ofthe test. The substances to be tested were suspended in 1.5% methylcellulose immediately before the start of the test and administered by oesophageal tube.
Blood samples were taken immediately before the administration ofthe substance and then 1,2,3 and 4 hours afterwards, in each case from the retro-orbital venous plexus. From each sample, 50 l 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 ttest 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:
5 mg/kg 1 .g/kg Substance 1 2 3 4 1 2 3 4 A -43 -40 -33 -35 B -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 D -36 -32 -27 -25 H -46 -40 -38 -26 -23 -23 -12 -18 F - 43 -42 -39 -32 G -44 -42 -37 -31 H -50 -46 -44 -45 J -44 -37 -42 -42 -38 -32 -34 -29 K -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 n.s.
N -46 -43 -40 -36 -33 -30 -21 n.s.
N -42 -42 -37 -33 O -38+ -31+ n.s.+ n.s.+ P -49 -43 -34 -22 -37 -19 n.s. n.s.
Q -28 -13 n.s. n.s.
R -38 -40 -35 -29 -39 -34 -29 -24 8 -49 -42 -30 -17 -29 -20 -10 n.s.
T -48 -46 -42 -40 -42 -42 -40 -32 U -43 -43 -49 -45 -39 -35 -29 -24 V -45 -41 -46 -40 -37 -23 -30 -18 W -46 -45 -39 -37 -36 -25 -16 n. s x -34+ -21+ -17+ -14+ Y -32 -24 -16 -18 Z -22 -33 -28 -26 AA -30 -33 -14 n. s, -15 -15 -13 n.s.
AB -43 -38 -36 -27 - -26 -15 n.s. n.s.
AC -36 -37 -36 -33 AD -28 -32 -27 -28 -16 -20 -17 -14 AH -30 -28 -39 -36 -21 -20 -22 n.s.
5 mg/kg 1 mg/kg Substance 1 2 3 4 1 2 3 4 AF -43 -39 -30 -26 -17 -19 n. s. n.s AG - 49+ -50+ -36+ -31+ -18 n . s . n . s . n . s AH -41 -37 -20 n.s. -26 -14 n.s. n.s AJ -44 -40 -39 -40 -35 -34 -28 -20 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.
AN -39 -35 -27 -26 -27 -24 n. s. n.s.
A0 -37 -34 -32 -31 -21 -17 -15 -11 AP -26 -28 -22 -17 AO -32 -31 -24 -19 -16 -11 n-s. n.s.
AR -35 -30 -29 -31 -13 - 9 n.e. n.e.
AS -45 -44 -42 -32 -21 -13 n.s. n.s + = at 10 mg/kg n.s. = statistically not significant 2. Acute toxicity Thetoxiceffectwastested in maleandfemale mice ofthe same strain weighing from 20to 26 g, after oral administration of a single dose (suspended in 1% methylcellulose) over an observation period of 14 days:
Substance Approximate acute toxicity A z 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 > 500 mg/kg p.o. (0 out of 6 animals died) 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 > 1 000 mg/kg p.o. (0 out of 10 animals died) AC > 1 000 mg/kg p.o. (0 out of 10 animals died) AD > 1 000 mg/kg p.o. (0 out of 10 animals died) AH 81 000 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 mel litus.
According to a yetfurtherfeature ofthe present invention, we provide pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula las hereinbefore defined or atautomerthereofora 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 ortautomers thereof ortheir phsiologicallycompatible salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for exam ple, be presented in a form suitable for oral or parenteral administration. Preferred forms include, for for example, tablets, coated tablets, capsules, pow- ders or suspensions.
The active ingredient may be incorporated in excipients customarily employed in pharmaceutical 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 subjecttreated and the complaint concerned.
According to a still furtherfeature of the present invention,we provide a method of treating a patient suffering from orsusceptibleto 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 las hereinbefore defined or a tautomerthereof or a physiologically compatible saltthereof.
The following non-limiting Examples are intended to illustrate the invention: Example 1 Ethyl 4 - [N - [os - (4 - methyl - phenyl) - 2 - piperidino benzyl] - aminocarbonylmethyl] - benzoate 4.7 g (18 mmol) oftriphenylphosphine,3 g (30 mmol) oftriethylamine and 1.5 mm (15 mmol) of carbon tetrachloride are added successively to 4.2 9 (15 mmol) of α - (4 - methyl - phenyl) - 2 - piperidino benzylamine and 3.49 (16.5 mmol) of 4-ethoxycar bonyl - phenylacetic acid, dissolved in 40 ml of acetonitrile. The reaction mixture is stirred at 50 C for 2 hours, then concentrated by evaporation and, after acidification with 6N hydrochloric 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 sul phate and concentrated by evaporation. The evapora tion residueistriturated with ethanol and suction filtered.
Yield: 4.559 (65% oftheory), M.p.: 177-178 C Calculated: C76.57 H7.28 N 5.95 Found: C76.19 H 7.16N 5.82 Thefollowing were prepared analogouslyto Exam ple 1: (a) Ethyl4-[N -(cc-(3-methyl-phenyl)-2- piperidino - benzyll - aminocarbonyl - methyl] benzoate Yield: 48% of theory, M.p.: 159-160 C Calculated: C 76.57 H 7.28 N 5.95 Found: C 76.80 H 7.35 N 5.76 (b) Ethyl 4-[N-[oc-(2-methyl- phenyl)-2 piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 35.4% of theory, M.p.: 196-198 C Calculated: C76.57 H 7.28 N 5.95 Found:C 76.65 H 7.35 N 5.90 (c) Ethyl 4- [N - [cc- (4- methoxy- phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 45% of theory, M.p.: 167-168 C Calculated: C 74.05 H 7.04 N 5.76 Found: C 73.72 H 6.99 N 5.62 (d) Ethyl 4- [N -[cc- (4-benzyloxy- phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 96% oftheory, M.p.: 154-155 C Calculated:C76.84H 6.81 N 4.98 Found: C76.68 H 6.68 N 5.03 (e) Ethyl 4- [N -[cc-(4-fluoro-phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 58% oftheory, M.p.: 174-176 C Calculated: C73.40 H 6.58 N 5.90 Found:C 73.55 H 6.72 N 5.91 (f) Ethyl 4- [N - [cc- (2 -fluoro - phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] - benzoate Yield: 83% of theory, M.p.: 173-175 C Calculated: C 73.40 H 6.58 N 5.90 Found: C73.61 H 6.62 N 5.85 (g) Ethyl 4 - [N - [cc-(4-chloro-phenyl)-2- piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 57% of theory, M.p.: 178-1810C Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found:C71.10H6.56N5.26Cl7.11 (h) Ethyl 4-[N-[oc-(3-chloro- phenyl)-2- piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 71% of theory, M.p.: 153-156 C Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found:C70.86 H 6.26 N 5.65 CI 7.25 (i) Ethyl 4-[N-[oc-(2-chloro- phenyl)-2- piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 66% of theory, M.p.: 196-198 C Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 Found: C70.90 H 6.30 N 5.61 Cl 7.10 (k) Ethyl 4 - [N - [cc - (4 - methylmercapto - phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] benzoate Yield: 84% oftheory, M.p.: 173-175 C Calculated: C71.68 H 6.82 N 5.57 Cl 6.38 Found: C71.92 H 6.97 N 5.45CI 6.21 (I) Ethyl 4-[N-[5-chloro-α- (2-chloro-phenyl)-2 - piperidino- benzyl] - aminocarbonylmethyl] benzoate Yield: 92% of theory, M.p.: 213-215 C Calculated:C 66.28 H 5.75 N 5.33 Cl 13.49 Found: C66.45H 5.86 N 5.25 CI 13.51 (m) Ethyl 4- [N - [2- piperidino - α-(2-pyridyl)- benzyl] - aminocarbonylmethyl] - benzoate Yield: 51% of theory, M.p.: 158-159'C Calculated: C73.50 H 6.83 N 9.18 Found: C73.40 H 6.95 N 9.10 (n) Ethyl 4 - [N -[2- piperidino -cc- (3 - pyridyl) - benzyl] - aminocarbonylmethyl] - benzoate Yield: 85% oftheory, M.p.: 172 C Calculated: C73.50 H 6.83 N 9.18 Found: C73.42 H 6.76 N 9.25 (o) Ethyl 4- [N - [2- piperidino -cc- (4- pyridyl) - benzyl] - aminocarbonylmethyl] - benzoate Yield: 20% oftheory, M.p.: 150-152 C Calculated:C73.50 H 6.83 N 9.18 Found:C73.61 H6.91 N9.15 (p) Ethyl 4- [N - (6-chloro - cc- phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 12% oftheory, M.p.: Oil Calculated: molecular ion peakm/e = 490/492 Found: molecularion peak m/e = 490/492 (q) Ethyl 4- [N - (4 - chloro - a - phenyl -2- piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 37% oftheory, M.p.: 148-150 C Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: C 70.81 H6.25N5.61 Cl 7.12 (r) Ethyl 4- [N - (3-chloro -cc- phenyl - 2 - piperidino benzyl) - aminocarbonylmethyl] - benzoate Yield: 74% of theory, M.p.: 176-178 C Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: C 70.59 H 6.25 N 5.68 CI 7.16 (s) Ethyl 4- [N - (6-methyl - cc- phenyl -2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 65% oftheory, M.p.Oil Calculated: molecular ion peakm/e = 470 Found: molecular ion peak m/e = 470 (t) Ethyl 4- [N - (5 - methyl - cc - phenyl 2- piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 48% oftheory, M.p.: 171-173"C Calculated: C 76.57 H 7.28 N 5.95 Found: C76.75 H 7.35 N 5.72 (u) Ethyl 4 - [N - (4 - methyl - - phenyl -2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 76% oftheory, M.p.: 133-135 C Calculated: C 76.57 H 7.28 N 5.95 Found:C76.51 H7.16N5.83 (v) Ethyl4-[N -(5-methoxy-α-phenyl -2piperidino - benzyl) - aminocarbonylmethyl] benzoate Yield: 10% oftheory, M.p.122-125 C Calculated: molecular ion peak m/e = 486 Found: molecular ion peak m/e = 486 (w) Ethyl4-[N -(6-methoxy-oc-phenyI -2- piperidino - benzyl) - aminocarbonylmethyl] benzoate Yield: 97% of theory, M.p.Oil Calculated: molecular ion peak me = 486 Found: molecular ion peakm/e = 486 (x) Ethyl 3 - chloro - 4 - [N - (a - phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 42% oftheory, M.p.: 175-176 C Calculated: C70.93 H 6.36 N 5.71 Cl 7.22 Found: C 70.65 H 6.36 N 5.50 CI 7.29 (y) Ethyl 4- [N - (2 - dimethylamino - - phenyl benzyl) - aminocarbonylmethyl] - benzoate Yield: 67% oftheory, M.p.: 116-118 C Calculated: C74.97 H 6.77 N 6.73 Found: C 75.13 H 6.60 N 6.78 (z) Ethyl 4- [N - (2-di - n - propylamino- α-phenyl- benzyl) - aminocarbonylmethyl] - benzoate Yield: 76% oftheory, M.p.: 38-1390C Calculated: C 76.24 H 7.68 N 5.93 Found:C76.41 H7.79 N 5.81 (aa) Ethyl 4- [N - [2-octahydro - 1 H-azonino)-α- 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) - a- phenyl - benzyl] - aminocarbony lmethyl] - benzoate Yield: 36.5% oftheory M.p.: 171-173 C Calculated: C 71.24 H 6.58 N. 5.54 Cl 7.01 Found: C71.45 H 6.68 N 5.59 Cl 7.20.
(ac) Ethyl 4 - [N - [2 - (3,3 - dimethyl - piperidino) - cc - phenyl - benzyl]- aminocarbonylmethyi] - benzoate Yield: 91% of theory, M.p.: 146-148 C Calculated: C 76.82 H 7.49 N. 5.78 Found: C76.91 H7.55N5.61 Example 2 Ethyl4-[N-[α;-(4-chloro-phenyl)-2 - piperidino benzyl] - aminocarbonyl - methyl benzoate A solution of 5 9 (22.1 mmol) of 4- ethoxycarbonylphenylacetyl chloride in 20 ml of chloroform is added dropwise, whilst cooling with ice, to a solution of 6.02 9 (20 mmol) of cc- (4- chloro - phenyl) - 2 piperidino-benzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml I ml ofchloroform.The mixture is stirred for 2 hours at ambienttemperature 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: 5.69 (57% oftheory), M.p.: 178-181 C Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 Found:C71.09H6.47N5.61 Cl 7.10 Thefollowing was prepared analogouslyto Example 2: (a) EthyI4-[N -[5-chloro-2-(3-methyl piperidino) - a- phenyl - benzyl] - aminocarbony lmethyl] - benzoate Yield: 54% of theory, M.p.: 178-180 C Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01 Found:C 70.91 H 6.64 N 5.75 CI 7.01 Example 3 4 - [N - cc - (4 - methyl - phenyl) - 2 - piperidino - benzyl] aminocarbonyl - methyl] benzoic acid 4.4g (9.35 mmol) of ethyl 4- [N - [oc - (4-methyl phenyl) - 2 - piperidino - benzyl] - aminocarbony lmethyl] - benzoate are dissolved in 150 ml of ethanol, with heating. Then 20 ml of 1 N sodium hydroxide solution are added and the mixture is stirred for 3 hours at 50 C. 20 ml of 1 N hydrochloric acid are then added to the reaction mixture and any excess ethanol is eliminated by evaporation in a rotary evaporator.
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.: 226-228"C Calculated: C 75.99 H 6.83 N 6.33 Found: C75.60 H 6.75 N 6.29 The following were prepared analogously to Example 3: (a) 4- [N - [cc-(3- Methyl - phenyl) - 2- piperidino benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 72% oftheory M.p.: 202-203 C Calculated: C75.99 H 6.83 N 6.33 Found: C75.64H6.91 N 6.37 (b) 4- [N - [cc-(2- methyl - phenyl) -2-piperidino - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 42.6% oftheory, M.p.: 285-290"C Calculated: C 75.99 H 6.83 N 6.33 Found:C76.05 H 6.98 N 6.25 (c) 4- [N - [cc - (4 - methoxy - phenyl) - 2 - piperidino benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 72.4oftheory, M.p.: 228-230 C Calculated: C 73.34 H 6.59 N 6.11 Found:C73.22H6.61 N6.13 (d) 4 - [N - [cc - (4- benzyloxy - phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 57% of theory, M.p.219-221 C Calculated: C76.38 H 6.41 N 5.24 Found: C76.05 H 6.44 N 5.24 (e) 4- [N -[α-(4-fluoro-phenyl)-2-piperidino benzyl] - aminocarbonylmethyl] benzoic acid Yield: 75% oftheory, M.p.: 238-240 C Calculated: 72.63 H 6.09 N 6.27 Found:C72.98 H 6.29 N 6.32 (f) 4- [N - [cc- (2-fluoro - phenyl) - 2 - piperidino benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 87% of theory, M.p.: 280-283 C Calculated: C 72.63 H 6.09 N 6.27 Found: C 72.70 H 6.10 N 6.37 (9) 4- [N - [cc- (4-chloro - phenyl) - 2 - piperidino benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 89% oftheory, M.p.: 241-242 C Calculated: C70.05H 5.88N 6.05CI7.66 Found: C 69.74 H 6.05 N 6.01 Cl 7.64 (h) 4- [N - [cc-(3-chloro- phenyl) -2 piperidino- benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 53% of theory, M.p.: 223-225 C Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found:C 70.28 H 5.98 N 5.78 Cl 7.84 (i) 4- [N - [cc- (2-chlorn- phenyl) -2- piperidino benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 98% oftheory, M.p.: 303-305 C Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: C 69.88 H 6.05 N 5.87 Cl 7.74 (k) 4 - [N - [cc - (4 - methylmercapto - phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 84.6% oftheory, M.p.225-227 C Calculated: C 70.86 H 6.37 N 5.90 Cl 6.75 Found: C70.34H 6.37 N 5.68 Cl 6.82 (I) 4-[N-[5-chloro-oc- (2-chloro-phenyl)-2 - piperidino - benzyl] - aminocarbonylmethyli - benzoic acid Yield: 90% oftheory, M.p.: 317-320 C Calculated:C 65.19 H 5.27 N 5.63 Cl 14.25 Found: C 64.87 H 5.34 N 5.69 Cl 14.22 (m) 4- [N - [2- piperidino - a- (2 - pyridyl) - benzyl] aminocarbonylmethyl] - benzoic acid Yield: 81% of theory, M.p.: 160-161 C Calculated: C72.71 H 6.34 N 9.78 Found: C 72.43 H 6.39 N 10.00 (n) 4- [N - (2 -piperidino - α-(3-pyridyl) - benzyl] aminocarbonxylmethyl] - benzoic acid Yield: 72% of theory, M.p.: 252-253 C Calculated: C72.71 H 6.34N 9.78 Found:C 72.56 H 6.53 N 9.60 (o) 4- [N - [2 - piperidino - α-(4-pyridyl) - benzyl] aminocarbonylmethyl] - benzoic acid Yield: 68.5% oftheory, M.p,: from 260 C (decomposition) Calculated: C72.71 H 6.34 N 9.78 Found: C 72.31 H 6.29 N 9.63 (p) 4- [N - (6-chloro - cc- phenyl-2-piperidino benzyl)-aminocarbonylmethyl] - benzoic acid Yield: 82% of theory, M.p.: 91-94 C Calculated: C 70.04 H 5.88 N 6.05 CI 7.66 Found: C 69.61 H 5.77 N 5.96 Cl7.78 (q) 4- [N - (4 - chloro - a - phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 61% oftheory, M.p.: 221-223 C Calculated: C70.05 H 5.88 N 6.05 CI 7.66 Found:C 69.73 H 5.89 N 5.87 Cl 7.52 (r) 4- [N - (3 -chloro- cc- phenyl-2-piperidino benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 83% of theory, M.p.: 210-213 C Calculated: C 70.05 H 5.88 N 6.05 CI 7.66 Found: C70.31 H 6.03 N 5.90 Cl 7.79 (s) 4- [N - (6-methyl - cc- phenyl - 2- piperidino benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 64% oftheory, M.p.: 165-170 C(sintering from 1500C) Calculated: C75.99 H 6.83 N 6.33 Found: C75.73 H 6.96 N 6.14 (t) 4- [N - (5-methyl - cc- phenyl-2-piperidino benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 97% oftheory, M.p.: 243-245 C Calculated: C 75.99 H 6.83 N 6.33 Found:C 75.60 H 7.01 N 6.31 (u) 4- [N - (4-methyl - α-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: C 76.04 H 6.78 N 6.23 (v) 4- [N - (5- methoxy-cc- phenyl - 2 - piperidino benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 27% oftheory, M.p.: 217-220 C (sintering from 203 C) Calculated: C73.34H 6.59 N 6.11 Found: C72.92 H 6.68 N 5.99 (w) 4-[N-(6-methoxy-cx- phenyl-2-piperidino - benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 51.5% oftheory, M.p.: 90-95 C Calculated: C73.34H6.59N6.11 Found: C 73.03 H 6.42 N 5.86 (x) 4-[N-[5-chloro-2- (3,5- cis- dimethyl- piperidino) - α-phenyl-benzyl]- aminocarbony Imethyl] - benzoic acid Yield: 81% oftheory, M.p.: 253-255 C Calculated: C70.93 H 6.36 N 5.71 Cl 7.22 Found: C70.68 H 6.51 N 5.73 Cl 7.36 (y) 4- [N - (2 - dimethylamino - a - phenyl - benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 83% oftheory, M.p.: 183-184 C Calculated: C74.20 H 6.23 N 7.21 Found: C74.31 H 6.27 N7.16 (z) 4-[N-(2-di-n- propylamino- oc-phenyl- benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 79% of theory, M.p.: 202-204 C Calculated: C 75.64 H 7.26 N 6.30 Found:C75.74 H 7.31 N 6.15 (aa) 4- [N - [5 - chloro - 2 - (2 - methyl - piperidino) - cc - phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 52% of theory, M.p.: 280-282 C Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: C70.14H6.10N5.75Cl7.45 (ab) 4- [N - [5-chloro -2- (3 - methyl - piperidino) - a - phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 66% of theory, M.p.: 246-2480C Calculated: C70.50 H 6.13 N 5.87 Cl 7.43 Found:C70.16H6.07 N5.87Cl7.30 (ac) 4- [N - [2 - (3,3 - dimethyl - piperidino) - oc- phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 59% oftheory, M.p.: 238-240 C Calculated: C76.28H7.07 N 6.14 Found: C76.38H7.28N 6.11 (ad) 3-chloro -4- [N -(cc- phenyl-2- piperidino benzyl) - aminocarbonylmethyl) - benzoic acid Yield: 56% oftheory, M.p.: 236-239 C Calculated: C70.04H 5.88 N 6.05 CI 7.66 Found:C 69.88 H 5.77 N 5.86 CI 7.81 (ae) 4-[N-[2-(3,5-cis-dimethyl-piperidino)-5- nitro - a- phenyl - benzyl] - aminocarbonylmethyl] benzoic acid Yield: 81% of theory, M.p.: from 255 C (decomposition) Calculated: C69.44H 6.23 N 8.38 Found: C 68.95 H 6.44 N 8.53 (af) 4- [N - [2 - (octohydro - 1 H - azonino) - cc - phenyl - benzyl] - amino - carbonylmethyl] - benzoic acid Yield: 62.5% oftheory, M.p.: 235-237 C Calculated: C76.56 H 7.28 N 5.95 Found:C76.50 H 7.30 N 5.94 (ag) 4- [N - (5 - hydroxy - a - phenyl - 2 - piperidino - benzyl) - amino - carbonylmethyl] - benzoic acid Yield: 71% oftheory, M.p.: 98-101 C Calculated: C72.95 H 6.35 N 6.30 Found:C72.98H 6.40 N 6.47 Example 4 4-[N-[cc- (4 - hydroxy - phenyl) - 2 - piperidino - benzyl]- amino - carbonyl - methyl] - benzoic acid 1.1 9 (2 mmol) of4- [N - [α- (4- benzyloxy - phenyl) 2 - piperidino - benzyl] - aminocarbonylmethyl] benzoic acid are suspended in 200 ml of ethanol and catalytically debenzylated at 50 C, under a hydrogen pressure of 5 bar, in the presence of 0.49 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.: 202-204 C Calculated: C 72.95 H 6.35 N 6.30 Found: C72.65 H 6.17 N 6.20 Thefollowing was prepared analogouslytoExample 4: (a) Ethyl 4 - [N - (5 - hydroxy - oc - phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 93% of theory, M.p.: 191-193 C Calculated: C 73.70 H 6.82 N 5.93 Found:C 73.52 H 6.57 N 5.61 Example 5 4 - [N - [a - (4 - Methyl - phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] - benzyl alcohol 2.5 9 (5.3 mmol) of ethyl 4 - [N - [a - (4 - methyl phenyl) - 2 - piperidino - benzyl] - aminocarbony Imethyl] - benzoate are added in batches to a suspension of 0.5 9 (13.2 mmol) of lithium aluminium hydride in 50 ml of absolutetetrahydrofuran.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 removethesodium aluminateformed.Thefiltrateis concentrated by evaporation and the residue is recystallisedfrom a littletoluene.
Yield: 0.989 (43% oftheory) M.P.144-146 C Calculated: C 78.47 H 7.53 N 6.54 Found: C78.20 H 7.39 N 6.58 The following was prepared analogously to Example 5: (a) 4- [N - [cc- phenyl - 2 - piperidino - benzyl] aminocarbonylmethyl] - benzyl alcohol Yield: 31.5% oftheory M.p.143-145 C Calculated: C78.23 H 7.29 N 6.76 Found:C78.13 H 7.30 N 6.62 Example 6 4-[N-[α-(4-methyl - phenyl) - 2 - piperidino - benzyl] - amino - carbonyl - methyl] - benzaldehyde 8.85 9 (20 mmol) of4- [N - [oc- (4- methyl - phenyl) 2 - piperidino - benzyl] - aminocarbonylmethyl] benzoic acid and 3.25 9 (20 mmol) of N,N' carbonyldiimidazole are refluxed in 100 ml of abso lute tetrahydrofuran for 2 hours. Then the mixture is concentrated by evaporation and afterthe addition of 50 ml of pyridine and 3.7 9 (20 mmol) of 4 toluenesulphonicacid 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 ofthe carboxylic acid used is mixed with 20 g of anhydrous sodium carbonate and heated to 170"C 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 chro matography on silica gel using toluene/ethyl acetate 5:1 aseluant.
Yield: 1.73 9 (21% oftheory) M.p.: 144-146 C Calculated: C 78.84 H 7.09 N 6.57 Found: C78.95 H 7.19 N 6.50 The following was prepared analogouslyto Exam ple6: tal 4- [N - [cc- Phenyl - 2 - piperidino - benzyl) - aminocarbonyl - methyl]- benzaldehyde Yield: 29% oftheory M.p.: 168-170 C CalcuFated: C 78.61 H6.84 N6.79 Found:C78.60 H 7.00 N 6.72 Example 7 4-[N-[cc - (4-Methyl-phenyl) - 2 - piperidino - benzyl] - amino - carbonyl - methyl] - benzaldehyde 0.5 g (1.2 mmol) of4- [N - [α- (4-methyl - phenyl) -2 - piperidino - benzyl] - aminocarbonylmethyl] - benzyl alcohol are added to a suspension of 0.4 g (1.5 mmol) of pyridinium chlorochromate in 2 ml of chloroform.
After 12 hours atambienttemperature, ether is added, the mixture is filtered and the concentrated filtrate is purified by column chromatography on silica gel (eluant: toluene/ethyl acetate = 5:1).
Yield: 0.3g (60% oftheory) M.p.: 145-1460C Calculated: C78.84H7.09 N 6.57 Found: C78.97H7.12N6.57 The following was prepared analogously to Example7: (a) 4- [N - (cc - Phenyl-2- piperidino - benzyl) aminocarbonyl - methyl]- benzaldehyde Yield: 40% oftheory M.p.: 170 C Calculated C 78.61 H 6.84N 6.79 Found:C 78.59 H 6.87 N 6.61 Example 8 Ethyl4 - [N-[cc - (4 - methyl - phenyl) - 2 - piperidino - benzyl] - aminocarbonyl - methyl] - cinnamate 427 mg (1 mmol) of4- [N - [a - (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: 0.189 (36% of theory) M.p.: 176-180 C Calculated: C 77.39 H 7.31 N 5.64 Found: C77.64H7.25N5.71 The following was prepared analogously to Exam ple 8: (a) Ethyl 4- [N - (cc- phenyl - 2 - piperidino - benzyl) amino - carbonylmethyl] - cinnamate Yield: 28.6% of theory M.p.: 159-161CC Calculated: C77.14H7.10N5.80 Found: C77.28 H 7.21 N 5.65 Example 9 4 - [N - [cc - (4 - Methyl -phenyl) - 2- piperidino - benzyl] - amino - 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 Example 3.
Yield: 84% oftheory M.p.: 173-176 C Calculated: C76.90 H 6.88 N 5.98 Found: C 77.24 H 7.01 N 5.64 The following was prepared analogously to Exam ple 9: (a) 4- [N - (cc- Phenyl -2-piperidino - benzyl) aminocarbonyl - methyl] - cinnamic acid Yield: 75% oftheory M.p.: 177-180 C Calculated: C 76.62 H 6.65 N 6.16 Found:C76.75 H 6.57 N 6.07 Example 10 Ethyl4 - [N - [cc - (3 - methyl - phenyl) - 2- piperidino - benzyl] - aminocarbonylmethyl]- benzoate A mixture of 0.22 g (0.8 mmol) of cx - (3-methyl phenyl - 2 - piperidino - benzyl alcohol and 0.15 g (0.8 mmol) of ethyl 4 - cyanomethyl - benzoate in 2 ml of o - dichloro - benzene is added dropwise, at ambient temperature, to 1.5 ml of o - dichlorobenzene and 1.5 ml of concentrated sulphuric acid. After 2 hours' stirring, the mixture is poured onto ice-water, ex tractedoncewith ether, madealkalinewith dilute sodium hydroxide solution and extracted with chlor oform.The chloroform extract is concentrated by evaporation and the residue is recrystallised from ethanol.
Yield: 0.22g (60% oftheory) M.p.: 158-159 C Calculated: C 76.57 H 7.28 N 5.95 Found: C76.41 H7.39 N 5.76 The following was prepared analogously to Exam ple 10: (a) Ethyl 4 - [N - [2 - (3,5 - cis - dimethyl - piperidino) 5 - nitro - a - phenyl - benzyl] - aminocarbonylmethyl] benzoate Yield: 57% oftheory M.p.: 170-173OC Calculated: C 70.30 H 6.66 N 7.93 Found:C 70.05 H 6.68 N 7.81 5 Example 11 4 - [N - [a - (4 - methyl - phenyl) - 2 - piperidino - benzyl] - amino - carbonyl - methyl] - benzoic acid 240 mg (5 mmol)of4- [N - [5-chloro-cc-(4-methyl - phenyl) - 2 - piperidino - benzyl] - aminocarbony Imethyl] - benzoic acid are catalytically dehalogen ated in 80 ml of ethanol/dioxan (1/1) in the presence of 0.1 g of 10% palladium on charcoal at 50 C 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: 0.16g (72% of theory) M.p.: 226-228 C Calculated: C 75.99 H 6.83 N 6.33 Found:C75.81 H6.73N6.10 The following was prepared analogouslyto Exam plell: (a) 4- [N - [2- (2-methyl - piperidino)- a- phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid From 4- [N - [5 - chloro - 2 - (2 - methyl - piperidino) - oc- phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid Yield: 68% of theory M.p.: 246-248'C Calculated C 75.99 H 6.83 N 6.33 Found:C75.57 H 7.10 N 6.44 (b) 4- [N - [2- (3-Methyl - piperidino) - cc- phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid From 4- [N - [5-chloro-2 (3-methyl - piperidino) - cx - phenyl - benzyl] - aminocarbonylmethyl] - benzoic acid Calculated: 43% of theory M.p.: 228-230 C Calculated: C75.99 H 6.83 N 6.33 Found:C75.91 H 6.82 N 6.33 Example 12 Ethyl4 - [N - [cc - (4-methyl -phenyl) - 2 - piperidino - benzyl]-aminocarbonyl- methyl]- benzoate A solution of 2.78 g (10 mmol) offreshly prepared (4 - methyl - phenyl) - (2 - piperidinophenyl) - ketimine in 50 ml of methylenechloride is mixed with 1.5 ml (11 mmol) oftriethylamine and then a solution of 2.5 g (11 mmol) of 4 - ethoxycarbonyl - phenylacetic acid chloride in 20 ml of methylene chloride is added dropwise thereto, whilst the mixture is cooled with ice. After 1 hour at ambienttemperature it is poured onto ice-water and extracted with methylene chloride. The extracts are dried and concentrated by evaporation and the evaporation residue is purified by column chromatography on silica gel (eluant: toluene/ethyl acetate 10:1).The crude acylimine is dissolved in dimethylformamide and, afterthe addition of 0.5 g of palladium (10% on charcoal), it is hydrogenated atambienttemperature 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 recrystallisedfrom a little alcohol.
Yield: 2.8g (60% oftheory) M.p.: 175-177 C Calculated: C76.57 H 7.28 N 5.95 Found; C76.41 H 7.19 N 5.76 Example 13 4 - [N - [cc - (4 - methyl - phenyl) - 2 -piperidino - benzyl] - aminocarbonyl - methyl] - benzonitrile Prepared from oc - methyl - phenyl) - 2 piperidino-benzylamine and 4-cyano - phenylacetic acid analogously to Example 1.
Yield: 64% oftheory M.p.: 144-146 C Calculated: C79.40 H 6.90 N 9.92 Found: C 79.10 H 6.90 N 9.78 The following was prepared analogously to Example 13: (a) 4- [N - (cc- Phenyl - 2 - piperidino - benzyl) aminocarbonyl - methyl] - benzonitrile Yield: 53% oftheory M.p.: 178-1810C Calculated: C79.18 H 6.65 N 10.26 Found:C 78.84 H 6.55 N 10.24 Example 14 Ethyl4 - [N - [cc - (4 - methyl - phenyl) - 2 - piperidino - benzyl] - aminocarbonylmethyl] - benzoate 4.2 9 (10 mmol) of 4 - [N - [α-(4- methyl-phenyl)-2 - piperidino - benzyl] - aminocarbonylmethyl] benzonitrile are refluxed for 24 hours with 50 ml of ethanolichydrochloricacid.The mixtureisthen concentrated by evaporation and the evaporation residue is mixed with aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is concentrated by evaporation and the residue is triturated with ethanol and suction filtered.
Yield: 2.9g (61.6% of theory) M.p.: 177-179 C Calculated: C 76.57 H 7.28 N 5.95 Found: C 76.41 H 7.35 N 5.76 The following was prepared analogously to Example 14: (a) Ethyl 4- [N - (5 - methyl - a - phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate Yield: 57% oftheory M.p.: 170-173 C Calculated: C76.57 H 7.28 N 5.95 Found:C76.41 H 7.19 N 5.65 Example 15 Ethyl4 - [N - [5- chloro - a - (2- chloro -phenyl) - 2- piperidino - benzyl] - aminocarbonylmethyl] benzoate lOmmol of ethyl 4- [N - [cx [α-(2-chloro-phenyl) - 5- nitro - 2 - piperidino - benzyl] - aminocarbonylmethyl] - benzoate are dissolved in 50 ml of dimethylformamide and, afterthe addition of 1 g of Raney nickel, hydrogenated at 600C 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 - a - (2 - chloro phenyl) - 2 - piperidino - benzyl] - amino - carbony lmethyl] - benzoate is dissolved in 100 ml of concentrated hydrochloric acid.Whilst the mixture is cooled with ice, a solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water is added dropwise thereto and the resulting mixture is stirred for 1 hour atOto 5 C.The reaction mixture is then added dropwise to a solution of 3 g of copper (I) chloride in 25 ml of concentrated hydrochloric 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 chromatography on silica gel using toluene/ethyl acetate (5:1) as eluant.
Yield: 1.5 9 (28.6% oftheory) M.p.: 213-215 C Calculated: C66.28H 5.75 N 5.33 CI 13.49 Found: C 66.40 H 5.91 N 5.41 Cl 13.40 The following was prepared analogouslyto Example 15 (a) Ethyl 4- [N - [5-chloro -2 (3,5-cis-dimethyl piperidino) - a - phenyl - benzyl) - aminocarbony lmethyl] - benzoate Yield: 28% oftheory M.p.: 188-191'C Calculated: C 71.72 H 6.80 N 5.40 CI 6.83 Found: C71 .95 H 6.85 N 5.35 Cl 6.77 Example 16 3- [4 - [N - (a - (4 - Methyl-phenyl) -2-piperidino benzyl) - aminocarbonylmethyll - phenyl] - propionic acid 0.91 g (2 mmol) of4- [N - (α- (4-methyl - phenyl) -2 - piperidino - benzyl) - aminocarbonylmethyl] cinnamic acid are dissolved in 50 ml of methanol and, afterthe addition of 0.5 g of palladium (10% on charcoal), the mixture is catalytically hydrogenated at ambienttemperature under a hydrogen pressure of 3 bar. After the hydrogen uptake has ended, the catalyst is filtered off and recrystalised from a little acetonitrile.
Yield: 0.68g (74% of theory) M.p.: 146-148 C Calculated: C76.57 H 7.28 N 5.95 Found: C76.41 H 7.19 N 5.61 The following was prepared analogously to Exam ple16: (a) 3- [4- [N-(cc- phenyl - 2- piperidino - benzyl)aminocarbonylmethyl] - phenyl] - propionic acid Yield: 65% oftheory M.p.: 97-99"C Calculated: C76.30 H 7.06 N 6.13 Found: C76.35 H 6.95 N 5.91 Example 17 Sodium salt of 4-[N-(α-(4- methyl-phenyl)-2- piperidinobenzyl) - aminocarbonylmethyl] - benzoic acid 442 mg (1 mmol)4- [N -(cx-(4- methyl - phenyl)-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 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.:295-300 C Calculated: C72.40 H 6.29 N 6.03 Found: C72.15 H 6.46 N 5.93 The following was prepared analogously to Example17: (a) Ethanolamine saltof 4- [N - (cc - (4-methyl - phenyl)-2-piperidino-benzyl)-aminocarbony- Imethyl] - benzoic acid Yield: 75% oftheory M.p.: 188-191 C Calculated: C71.55 H 7.41 N 8.34 Found:C71.16H7.48N8.52 (b) Diethanolamine salt of 4 - [N - (oc - (4 - methyl phenyl) - 2 - piperidino - benzyl) - aminocarbony Imethyl] - benzoic acid Yield: 81% of theory M.p.: 178-180 C Calculated: C70.70 H 6.86 N 7.73 Found:C 70.25 H 6.75 N 7.58 (c) Triethanolamine salt of4 - [N - (a - (4 - methyl - phenyl) - 2 - piperidino - benzyl) - aminocarbony lmethyl] - benzoic acid Yield: 76% of theory M.p.:160-165 C Calculated: z C C69.01 H7.67N7.10 Found: C68.91 H7.64N7.45 (d) Ethylenediamine saltof4 - [N -(cx -(4- methyl-phenyl) - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoic acid Yield: 65% oftheory M.p.: 160-1630C Calculated: C 71.69 H 7.62 N 11.15 Found:C72.04H7.80N 10.96 Example 18 Ethyl 4 - [N - {5 - methoxy - a - phenyl - 2 - piperidino benzyl) - aminocarbonyl - methyl]- benzoate 472 mg (1 mmol) of ethyl 4- [N - (5 - hydroxy- cc- phenyl - 2 - piperidino - benzyl) - aminocarbonmethyl] - benzoate are dissolved in 25 ml of absolute dimethylformamide. Afterthe 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 chromatography on silica gel using toluene/ethyl acetate 4:1 as eluant.
Yield: 260mg (53% oftheory) M.p.:123-125 C Calculated: C74.05H7.04N 5.76 Found: C 73.86 H 6.95 N 5.61 Example 19 Ethyl4-[(2.methoxy- 1- (2 - piperidino phenyl) - ethyl) - aminocarbonyl - methyl] - benzoate 0.49 g (2.34 mmol) of 4- ethoxycarbonyl - pheny lacetic acid, 0.73 g (2.78 mmol) oftriphenylphosphine, 0.50 ml (3.66 mmol) oftriethylamine and 0.23 ml (2.34 mmol) of carbontetrachloride are added successivelyto a solution of 0.55 9 (2.34 mmol) of 2 methoxy - 1 - (2 - piperidino - phenyl) - ethylamine in 5 ml of acetonitrile and the resulting 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: 0.459 (45% oftheory) M.p.: 122-123 C Calculated: C70.73 H 7.60 N 6.60 Found: C71.04 H 7.48 N 6.39 The following was prepared analogously to Example19: (a) Ethyl 4- [(1 - (3-chloro -2- piperidino - phenyl)-1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 55% oftheory M.p.: 141-143 C Calculated: C 68.33 H 7.28 CI 7.76 N 6.13 Found: C68.30H7.16C18.03N 6.20 (b) Ethyl 4- [(1 - (6-chloro -2- piperidino - phenyl) 1 - butyl) - aminocarborlylmethyl] - benzoate Yield: 73.9% oftheory M.p.: 79-82"C Calculated: C 68.33 H 7.28 CI 7.76 N 6.13 Found:C 68.45 H 7.24 Cl 7.80 N 6.09 (c) Ethyl 4- [(1 - (4- bromo - 2 - piperidino - phenyl) 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 62.1% oftheory, M.p.: 116-118 C Calculated: C 62.27 H 6.63 Br 15.93 N 5.58 Found: C62.53H6.48Br15.98N5.66 (d) Ethyl 4- [(1 - (4- nitro -2 - piperidino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoate Yield: 74.6% oftheory, M.p.: 127-130 C Calculated: C 66.79 H 7.11 N 8.99 Found: C66.88H7.08N9.15 (e) Ethyl 4 - [(1 - (3 - methyl - 2 - piperidino - phenyl) 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 68% oftheory, M.p.: 145-147"C Calculated: C74.28 H 8.31 N 6.42 Found:C74.40 H 8.30 N 6.41 (f) Ethyl [(1 - (4-methyl -2- piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 54.7 oftheory, M.p.: 113-114 C Calculated: C74.28 H 8.31 N 6.42 Found: C74.23 H 8.30 N 6.55 (g) Ethyl 4- [(1 - (5 - methyl - 2 - piperidino - phenyl) 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 67.9% oftheory, M.p.: 149-150"C Calculated: C74.28H8.31 N6.42 Found:C74.38 H 8.21 N 6.49 (h) Ethyl 4- [(1 - (6-methyl - 2 - piperidino - phenyl - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 47% oftheory, M.p.: 92-93"C Calculated: C74.28H8.31 N 6.42 Found: C74.50 H 8.46 N 6.48 (i) Ethyl 4- [(1 - (2 - pyrrolidino - phenyl) - 1 - butyl) aminocarbonylmethyl - benzoate Yield: 57.3% oftheory, M.p.: 122-125 C Calculated: C 73.50 H 7.90 N 6.86 Found: C73.63 H 8.07 N 7.01 (k) Ethyl 4 - [(1 - (2 - piperidino - phenyl) - 1 - butyl) - amino - carbonylmethyl] - benzoate Yield: 71.5% oftheory, M.p.: 127-128 C Calculated: C73.90 H 8.11 N 6.63 Found:C73.90 H 8.06 N 6.72 (I) Ethyl 4- ((1 - (2 - (4 - methyl - piperidino) - phenyl) 1 - butyl( - aminocarbonylmethyl] - benzoate Yield: 51.1% oftheory, M.p.: 153-155 C Calculated: C74.28H8.31 N 6.42 Found: C74.55 H 8.33 N 6.45 (m) Ethyl 4- [(1 - (2 - hexahydroazepino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoate Yield: 42.7% oftheory, M.p.: 145-147"C Calculated: C74.28H8.31 N 6.42 Found: C73.98 H 8.26 N 6.58 (n) Ethyl 4- [(1 - (5-fluoro 2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 55% of theory, M.p.: 128-130"C Calculated: C70.88 H 7.55 N 6.36 Found:C71.14H7.57 N 6.49 (o) Methyl 4- [(1 - (2 - piperidino - phenyl) - 1 - butyl) amino-carbonylmethyl] - benzoate Yield: 63.2% of theory, M.p.: 147-1480C Calculated: C73.50 H 7.90 N 6.86 Found: C 73.66 H 7.88 N 6.80 (p) n - Butyl 4- [1 - (2 - piperidino - phenyl ) - 1 - butyl) amino - carbonylmethyl] - benzoate Yield: 50.9% oftheory, M.p.: 117-119"C (ether) Calculated: C74.63 H 8.50 N 6.22 Found:C74.49 H 8.46 N 6.14 (q) Ethyl 3-chloro-4- [(1 -(2- piperidino - phenyl) 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 14.9% oftheory, M.p.: < 20 C Calculated: m/e = 456/458(1 chloro) Found: m/e = 456/458(1 chloro) (r) Ethyl 4 - [(1 - (2 - piperidino - phenyl) - 4 - penten 1 -yl) - aminocarbonylmethyl] - benzoate Yield: 18.9% oftheory, M.p.: 103-105 C Calculated: C 74.62 H 7.89 N 6.45 Found:C75.01 H8.10N6.26 (s) Ethyl 4- [(1 - (3 - chloro - 2 - piperidino - phenyl) - 1 - ethyl) - aminocarbonylmethyl] - benzoate Yield: 58.0% oftheory, M.p.: 166-168 C Calculated: C 67.20 H 6.81 CI 8.27 N 6.53 Found:C 67.17 H 6.85 CI 8.17 N 6.45 Example 20 Ethyl4 - [(1 - (5- nitro - 2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate A solution of 14.6 9 (64.6 mmol) of 4- ethoxy - carbonyl - phenyl acetic acid chloride in 20 ml of methylene chloride is added dropwiseto a stirred solution of 15.1 g (54.4 mmol) of 1 - (5 - nitro - 2 - piperidino - phenyl) - 1 - butylamine and 8.46 ml (61.4 mmol) oftriethylamine in 55 ml of dry methylene chloride within 30 minutes in such awaythatthe temperature does not exceed 30"C. The mixture is stirred for a further 2 hours at ambient temperature, 300 ml of methylene chloride are added and the resulting mixture is extracted twice, each time with 50 ml of water. The organic phase is dried oversodium sulphate, filtered and concentrated by evaporation in vacuo.The reddish-brown oily evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10:1).
Yield: 17.7 g (69.7% of theory), M.p.: 135-137 C(ether) Calculated: C 66.79 H 7.11 N 8.99 ) Found: C66.73 H 6.99 N 9.09 The following were prepared analogously to Example 20: (a) Ethyl 4- t(1 - (2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 80.20% oftheory, M.p.: 127-129 C Calculated: C73.90 H 8.11 N 6.63 Found: C73.98 H 8.26 N 6.89 (b) Ethyl 4 - [(1 - (4- hydroxy - 2 - piperidino - phenyl) ) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 13.5% oftheory, M.p.: 178-180 C Calculated:C 71.21 H 7.81 N 6.39 Found: C71.27H7.82N6.40 5(c) Ethyl 4 - [(1 - (5 - hydroxy - 2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 37.4% oftheory, M.p.: 188-190 C Calculated: C 71.21 H 7.81 N 6.39 ) Found: C71.34H7.89 N 6.38 Example 21 4 - [(1 - (2 -piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl]- phenyl acetic acid 3.0 g (15.45 mmol) of p - phenylene - diacetic acid 5 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 ) butylamine is slowly added dropwise to this solution, with stirring, at an internal temperature of 1 0-1 5"C.
after 2 hours at ambient temperature, the mixture is concentrated by evaporation in vacuo and the eva poration residue is distributed between 100 ml of ice cold 5% sodium hydroxide solution and ethyl acetate.
It is filtered through kieselghur and the organic phase is separated off. The alkaline-aqueous phase is adjusted to pH 5.5 with semi-concentrated hydroch loric acid and extracted with ethyl acetate. The extract is dried over sodium sulphate and filtered and the filtrate is concentrated by evaporation in vacuo. The evaporation residue is purified by column ch roma tographyon silica gel (chloroform/methanol = 20/1).
Yield: 0.10g (1.6% oftheory), M.p.: 136-140 C (acetonitrile/ether) Calculated: C73.50 H 7.90 N 6.86 Found: C73.17 H 8.10 N 6.85 Example 22 Ethyl4-[(2-methyl- 1 (2-methyl (2-piperidino- phenyl) - 7- pro pen - 1- yl) - aminocarbonylmethyl] benzoate 5.58 g (26.8mmol) of 4 ethyoxycarbonyl - pheny lacetic acid, 8.43 g (32 mmol) oftriphenylphosphine, 11.2 ml (80.4 mmol) oftriethylamine and 2.6 ml (0.0268 mol) of carbon tetrachloride are successively added to a solution of 6.17 g (26.8 mmol) offreshly prepared isopropyl - (2 - piperidino - phenyl) ketimine in 62 ml of acetonitrile and the resulting mixture is stirred for 20 hours at an ambient F 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 g (26.6% oftheory), M.p.: 82-84"C (ether) Calculated: C 74.26 H 7.67 N 6.66 Found: C74.20 H 7.49 N 6.56 The following were prepared analogouslyto Example 22: (a) Ethyl 4- [(1 -2-piperidino -phenyl)- 1 -penten - 1 - yl) - aminocarbonylmethyl] - benzoate Yield: 16% of theory, M.p.: 94-97"C (ethanol) Calculated"C C 74.62 H 7.89 N 6.45 Found: C74.75 H 7.71 N 6.24 (b) Ethyl 4- [(1-2 - piperidino -phenyl) - 1 - hexen - 1 - yl) - aminocarbonylmethyli - benzoate Yield: 27.4% oftheory, M.p.: 83-85"C (ethanol) Calculated: C 74.97 H 8.09 N 6.24 Found:C75.42 H 7.95 N 6.00 (c) Ethyl 4- [(1-2- piperidino - phenyl) - 1 - buten - 1 -yl) - aminocarbonylmethyl] - benzoate Yield (more lipophilic isomer; probably E form): 4.1% oftheory, M.p.: (20"C Calculated: m/e = 420 Found: m/e = 420 Yield (less lipophilic isomer; probably Zform): 51.9% oftheory, M.p.: 115-117 C (ethanol) Calculated: C 74.26 H 7.67 N 6.66 Found: C73.85 H 7.59 N 6.44 (d) Ethyl 4- [(2 - phenyl - 1 - (2 - piperidino - phenyl) - ethen - 1 -yl) - aminocarbonylmethyl] - benzoate Yield (more lipophilic isomer; probably E form): 4% oftheory, M.p.: 75-77"C (ether/petroleum ether) Calculated: C76.90 H 6.88 N 5.98 Found:C77.31 H7.20N5.93 Yield (less lipophilic isomer; probably Z form): 42.7% of theory, M.p.: 157-1600C (ethanol) Found:C77.19H6.95N6.02 (e) Ethyl 4- [(3 - phenyl - 1 - (2 - piperidino - phenyl) - 1 - propen - 1 - yl) - aminocarbonylmethyl) - benzoate Yield: 62.6% oftheory, M.p.: < 200C Calculated: m/e = 482 Found: m/e = 482 (f) Ethyl 4 - [(1 - (2 - (3,3 - dimethyl - piperidino phenyl) - 1 - buten - 1 - yl) - a minoca rbonyl methyl] benzoate Yield: 33% of theory, M.p.: 113-116 C(ethanol) Calculated: C74.97 H 8.09 N 6.24 Found:C75.37 H 7.93 N 6.03 (g) Ethyl 4- [(1 - (6 - methyl - 2 - piperidino - phenyl) - I - buten - 1 -yI) - aminocarbonylmethyl] - benzoate Yield: 60.4% of theory (probablyZform) M.p.: 95-96 C Calculated: C74.62 H 7.89 N 6.45 m/e = 434 Found:C 74.44 H 8.00 N 6.59 m/e = 434 Example 23 Ethyl 4 - [(1- (2 - piperidino - phenyl) 7- buten - 1- yl) aminocarbonylmethyl]- benzoate A stirred solution of 19.0 g (82.46 mmol) offreshly prepared (2 - piperidino - phenyl) - propyl - ketimine and 11.5 ml (82.46 mmol) oftriethylamine in 190 ml of anhydroustoluene is heated to an internal temperature of 85"C, then a solution of 18.7 g (82.46 mmol) of 4 - ethoxycarbonyl - phenylacetic acid chloride in 95 ml ofanhydroustoluene is added dropwisethereto within 10 minutes and the resulting mixture is stirred for 30 minutes at an internal temperature of 95"C. It is then cooled to 20"C and extracted twice with water.
The organic phase is dried over sodium sulphate, filtered 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: < 20 C (honey-yellowviscous oil) Calculated: C74.26 H 7.67 N 6.66 Found: C 73.90 H 7.92 N 6.91 Yield (less lipophilic isomer; probably Z form): 15.9 g (33.5% oftheory), M.p.: 114-116 C Found: C 74.02 H 7.69 N 6.85 Example 24 Ethyl (E)- and (Z) - 4 - [(7- (2 - piperidino - phenyl) - 1 - buten - 1- yl) - aminocarbonylmethyU- benzoate 1.0 g of Z ester (see Example 22c) is heated for 30 minutes in a pre-heated oil bath at 230 C. After cooling, the product obtained is purified by column chromatography on silica gel (toluene/acetone = 20/1).
Yield (E ester): 0.365 9 (36.5% oftheory), M.p.: < 20 C Yield (Z ester): 0.380 g (38.0% of theory), M.p.: 115-117 C 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 analogouslyto Example 24: (a) Ethyl(E).and(Z)-4-[(1-(6-methyl-2- piperidinophenyl) - 1- buten -1- yl) - aminocarbony lmethyl) - benzoate According to thin layer chromatography, a 1/1 mixture of (E) and (Z) esters is obtained from the (Z) ester (see Example 229).
Upperspot(E): Calculated: m/e= 434 Found: m/e = 434 lower spot (Z): Found: m/e = 434 Example 25 Ethyl4 -[(1(2 (2 - piperidino - phenyl) -1- butyl) aminocarbonylmethyl]- benzoate 2.9 g (6.90 mmol) of ethyl 4- [(1 - (2 - piperidinophenyl) - 1 - buten - 1 -yl) - aminocarbonylmethyl] benzoate in 100 ml of ethanol is hydrogenated on 0.77 g of 10% palladium/charcoal at 50"C under a hydrogen pressure of 1 bar. After 2 hours, the catalyst is filtered off over kieselguhr and the filtrate is concentrated by evaporation in vacuo. The evaporation residue is crystallised from ethanol.
Yield: 1.59 (51.5% oftheory), M.p.: 126-128"C Calculated: C73.90H 8.11 N 6.63 Found: C 73.97 H 8.22 N 6.57 The following compounds were obtained analogouslyto Example 25: (a) Ethyl 4 - [(1 - (2 - piperidino - phenyl) - 1 - pentyl) -aminocarbonylmethyl] - benzoate Yield: 45% of theory, M.p.: 117-120 C (ether) Calculated: C74.28H8.31 N6.42 Found: C74.60H8.13 N 6.27 (b) Ethyl 4- [(1 - (2 - piperidino - phenyl) - 1 - hexyl) aminocarbonylmethyl] - benzoate Yield: 50% of theory, M.p.: 108-1 100C (ether) Calculated:C74.63 H 8.50 N 6.22 Found C74.85 H 8.33 N 6.01 (c) Ethyl 4- [(2 - phenyl - 1 - (2 - piperidino - phenyl) 1 - ethyl) - aminocarbonyl methyl] - benzoate Yield: 87.6% of theory, M.p.: 161-162"C (ethanol) Calculated: C 76.57 H 7.28 N 5.95 Found: C76.71 H7.19 N 5.99 (d) Ethyl 4- [(3 - phenyl - 1 - (2 - piperidino - phenyl) - 1 - propyl) -aminocarbonylmethyl] - benzoate Yield: 57.6% oftheory, M.p.: 118-119"C (ethanol) Calculated: C76.83 H 7.49 N 5.78 Found: C 76.70 H 7.49 N 5.90 (e) Ethyl 4 - [(1 - (2 - (3,3 - dimethyl - piperidino) phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 36.5% of theory, M.p.: 140-141 C (ethanol) Calculated: C74.63 H 8.50 N 6.22 Found:C74.30H8.23N6.12 Example 26 4-[(l-(2-Piperidino - phenyl) - 1- butyl) - aminocarbonylmethyl]- benzoic acid A mixture of 1.29 (2.84 mmol) of ethyl 4- [(1 -(2 piperidino - phenyl) - 1 - butyl) - aminocarbony Imethyl] - benzoate and 4.26 ml of 1 N sodium hydroxide solution in 12 ml of ethanol is stirred for 1 hour at 60"C, then neutralised with 4.26 ml of 1 N 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: 0.50g (44.6% oftheory), M.p.: 213-215 C Calculated: C73.07 H 7.66 N 7.10 Found:C73.18H7.51 N7.10 The following compounds were obtained analogouslyto Example 26: (a) 4- [(1 - (2 - piperidino - phenyl) - 1 - pentyl) aminocarbonylmethyl] - benzoic acid Yield: 70.2% oftheory, M.p.: 213-215 C(acetone) Calculated: C73.50 H 7.90 N 6.86 Found: C73.71 H 7.70 N 6.90 (b) 4- [(1 -(2- piperidino- phenyl)- 1 - hexyl) - aminocarbonylmethyl] - benzoic acid Yield: 72.6% of theory, M.p.: 197-200 C(acetone) Calculated: C73.90 H 8.11 N 6.63 Found:C 73.83 H 7.93 N 6.77 (c) 4 - [(2 - phenyl - 1 - (2 - piperidino - phenyl) - 1 ethyl) - aminocarbonylmethyl] - benzoic acid Yield: 68.7% oftheory, M.p.: 214-215 C (acetone) Calculated: C75.99 H 6.83 N 6.33 Found: C 75.70 H 6.60 N 6.32 (d) 4- [(3- Phenyl - 1 - (2 - piperidino - phenyl) - 1 - propyl) - aminocarbonylmethyl] - benzoic acid Yield: 67.7% oftheory, M.p.: 167-170 C (ethyl acetate) Calculated: C76.29 H 7.06 N 6.14 Found: C 76.56 H 7.06 N 6.23 (e) 4- [2 - Methoxy - 1 - (2 - piperidino - phenyl) - 1 ethyl) - aminocarbonylmethyl] - benzoic acid Yield: 60.8% of theory, M.p.: 196-198 C(ether) Calculated: C 69.68 H 7.12 N 7.07 Found: C69.72 H 6.52 N 6.71 (f) 4- [(1 - (2- Piperidino - phenyl) - 4 - penten - 1 -yl) - aminocarbonylmethyl] - benzoic acid x 0.67 H20 Yield: 30.7% of theory, M.p.: 193-197 C (ether/petroleum ether) Calculated: C71.74H7.38 N 6.69 Found: C71.63 H 7.21 N 6.34 (9) 4 - [(1 - (2 - (3,3 - Dimethyl - piperidino) - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid Yield: 48.2% oftheory, M.p.: 168-170 C (petroleum ether) Calculated:C73.91 H8.11 N 6.63 Found:C73.51 H 7.89 N 6.32 (h) 4- [(1 - (3-Methyl -2- piperidino-phenyl)- 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 53% of theory, M.p.: 179-182 C Calculated: C 73.50 H 7.90 N 6.86 Found: C 73.50 H 7.82 N 7.01 (i) 4- [(1 - (4-Methyl - 2- piperidino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 85.6% oftheory, M.p.: 170-172 C Calculated: C 73.50 H 7.90 N 6.86 Found: C 73.25 H 7.64 N 6.89 (k) 4- [(1 - (5-Methyl -2- piperidino- phenyl) - 1 butyl)- aminocarbonylmethyl] - benzoic acid Yield: 62.1% oftheory, M.p.: 219-221 C Calculated:C 73.50 H 7.90 N 6.86 Found: C73.20 H 7.74 N 6.89 (I) 4- [(1 -(6-Methyl -2- piperidino- phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid x 0.3 H20 Yield: 89% oftheory, M.p.: 158-160 C Calculated: C72.53H7.93 N 6.77 Found: C72.40H7.91 N 6.92 (m) 4- [(1 - (3-Chloro -2- piperidino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 70% of theory, M.p.: 189-191 C Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: C67.30 H 6.85 Cl 8.36 N 6.58 (n) 4- [(1 - (4-Chloro -2-piperidino- phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 57.8% of theory, M.p.: 188-189 C Calculated:C67.20 H 6.81 Cl 8.27 N 6.53 Found: C 66.90 H 7.00 Cl 8.22 N 6.53 (o) 4- [(1 - (5-Chloro -2- piperidino - phenyl ) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid Yield: 81.6% of theory, M.p.: 226-229 C Calculated: C67.20 H 6.81 Cl 8.27 N 6.53 Found: C67.17H6.59 Cl 8.51 N6.60 (p) 4- [(1 - (6-Chloro - 2 piperidino- phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid Yield: 69.4% of theory, M.p.: 150-153 C Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: C67.18H6.91 Cl8.42N6.77 (q) 4- [(1 - (4- Bromo-2- piperidino- phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 84.4% oftheory, M.p.: 198-201 C Calculated:C 60.89 H 6.17 Br 16.88 N 5.92 Found: C60.88H5.98Br17.20N 5.98 (r) 4- [(1 - (5-Bromo-2- piperidino-phenyl)- 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 90.7% of theory, M.p.: 232-235 C Calculated: C60.89 H 6.17 Br16.88 N 5.92 Found: C 60.96 H 6.13 Br 16.85 N 5.90 (s) 4- [(1 - (4- Nitro- 2- piperidino- phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid Yield: 70.9% oftheory, M.p.: 188-190 C Calculated: C 65.59 H 6.65 N 9.56 Found: C 65.30 H 6.44 N 9.53 (t) 4- [(1 -(5- Nitro -2 - piperidino - phenyl)- 1 - I - aminocarbonylmethyl] - benzoic acid Yield: 90.7% oftheory, M.p.: 225-227 C Calculated:C 65.59 H 6.65 N 9.56 Found: C 65.80 H 6.61 N 9.72 (u) 4- [(1 - (4- Hydroxy- 2 - piperidino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid x 0.5 H20 Yield: 95.7% oftheory, M.p.: softening from 70 C (foam) Calculated: (x 0.5H20)C68.71 H7.45 N6.68 Found C 68.63 H 7.55 N 6.26 (v) 4- [(1 - (5-Hydroxy-2-piperidino-phenyl)-1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 89.3% oftheory, M.p.: 186-190 C Calculated: C70.22 H 7.37 N 6.82 Found: C70.31 H7.58N6.51 (w) 4- [(1 - (4- Methoxy- 2- piperidino- phenyl) - 1 butyl)-aminocarbonylmethyl] -benzoicacid Yield: 78.6% oftheory, M.p.: 185-187 C Calculated: C70.73 H 7.60 N 6.60 Found:C 70.46 H 7.77 N 6.56 (x) 4- [(1 - (5 - Methoxy - 2- piperidino - phenyl) - 1- butyl) - aminocarbonylmethyl] - benzoic acid Yield: 75% of theory, M.p.: 182-185"C(decomp.) Calculated: C 70.73 H 7.60 N 6.60 Found: C 70.52 H 7.50 N 6.70 (y) 4 - [(1 - (2 - Pyrrolidino - phenyl) - 1 - butyl ) - aminocarbonylmethyl] - benzoic acid Yield: 64.5% oftheory, M.p.: 200-203 C Calculated: C72.61 H7.42N7.36 Found: C72.64H7.50 N 7.38 (z) 4- [(1 - (2- (4-Methyl - piperidino) - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid Yield: 81.4% of theory, M.p.: 197-201"C Calculated: C73.50 H 7.90 N 6.86 Found:C 73.90 H 8.06 N 7.00 (aa) 4 - [(1 - (2 - Hexahydroazepino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 65.6% oftheory, M.p.: 199-202 C Calculated: C73.50 H 7.90 N 6.86 Found: C73.50 H 7.90 N 6.76 (ab) 4 - [(1 - (4 - Fluoro - 2 piperidino - phenyl ) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 87.1% of theory, M.p.: 204-2070C Calculated: C 69.88 H 7.09 N 6.79 Found: C 70.25 H 7.02 N 7.12 (ac) 4- [(1 - (5- Fluoro - 2- piperidino- phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 53.9% oftheory, M.p.: 200-202 C Calculated: C 69.88 H 7.09 N 6.79 Found:C 69.67 H 7.24 N 6.90 (ad) 3-Chloro -4- [(1 - (2- piperidino - phenyl) - 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 51% of theory, M.p.: 165-168 C Calculated: C67.20 H 6.81 N 6.53 m/e = 428/430 (1 chlorine) Found: C 66.92 H 6.69 N 6.55 m/e = 428/430 (1 chlorine) (ae) 4- [(1 -(3-Methyl -2 - piperidino- phenyl) - 1 ethyl) - aminocarbonylmethyl] - benzoic acid Yield: 79% oftheory, M.p.: 230-231 C Calculated: C 72.60 H 7.42 N 7.36 Found: C72.75 H 7.58 N 7.30 (af) 4- [(1 - (3 - Chioro - 2 - piperidino - phenyl) - 1 ethyl - aminocarbonylmethyl] - benzoic acid Yield: 54% oftheory, M.p.: 192-195 C(75% aqueous ethanol) Calculated: C 65.91 H 6.28 Cl 8.84 N 6.99 Found:C 66.00 H 6.44 Cl 8.67 N 6.78 Example 27 4- [(2-Methyl- 1 - (2- piperidino - phenyl) - 1 - propen 1- ylJ - 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) - aminocarbonylmethyl] benzoate and 12.5 ml of 1 N sodium hydroxide solution in 55 ml of ethanol is stirred at 60 C for 2 hours. It is neutralised with 12.5 ml of 1 N 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: 2.49 (73.6% oftheory), M.p.: 188-191 C Calculated: C73.44H7.19N7.14 Found: C73.60 H 7.19 N 7.02 The following compounds were obtained analogous lyto Example 27: (a) (E) -4- [(1 - (2 - Piperidino - phenyl) - 1 - buten - 1 yI) - aminocarbonylmethyl] - benzoic acid Yield: 71.5% of theory, M.p.: 188-190 C Calculated: C73.44H7.19N7.14 Found:73.15H7.13N7.10 Olefinicproton: 1H-NMR (CDCl3) : # = 6.42 ppm (b) (Z) - 4- [(1 - (2 - Piperidino - phenyl) - 1 - buten - 1 yl) - aminocarbonylmethyl] - benzoic acid Yield: 57.8% oftheory, M.p.: 174-175 C (ethanol) Calculated: C73.44H7.19N7.14 Found:C73.54 H 6.97 N 7.17 Olefinic proton: 1H-NMR (CDCl3) : 5= 5.60 ppm (c) (E) -4- [(2-Phenyl - 1 - (2- piperidino- phenyl) ethen - 1 - yl) - aminocarbonylmethyl] - benzoic acid x 0.4 H20 Yield: 33.2% oftheory, M.p.:165-1 (ether/petroleum ether) Calculated: (x 0.4 H20) C 75.11 H 6.48 N 6.26 Found: C 75.22 H 6.39 N 6.26 olefinic proton: 1H-NMR (CDCI3): :5 > 6.9 ppm (d) (Z) -4- [(2- Phenyl - 1 - (2- piperidino - phenyl) ethen - 1 -yl) - aminocarbonylmethyl] - benzoic acid x 1 H20 Yield: 72% oftheory, M.p.: 182-185 C (methanol) Calculated: (x 1 H20) : C 73.34 H 6.60 N 6.11 Found:C 73.55 H 6.45 N 6.00 olefinic proton: 1H-NMR (CDCI3): :5=6.50 ppm (e) 4- [(3 - Phenyl - 1 - (2 - pi peridino - phenyl) - 1 - propen - 1 - yl) - aminocarbonylmethyl] - benzoic acid Yield: 48.3% oftheory, M.p.: 162-164 C (ether); probably (Z) form Calculated: C76.63 H 6.65 N 6.16 Found: C 76.30 H 6.47 N 6.31 Olefinic proton: 1H-NMR (CDCI3): : # = 5.80 ppm (f) 4 - [(1 - (2 - (3,3 - Dimethyl- piperidino) - phenyl - 1 buten - 1 - yl) - aminocarbonylmethyl] - benzoic acid Yield: 64.1 % of theory, M.p.:152-1 530C (ethyl acetate); probably (Z) form Calculated: C74.26 H 7.67 N 6.67 Found:C73.93 H 7.57 N 6.50 Olefinic proton: 'H-NMR (CDCl3) : # = 5.55 ppm (g) (Z)-4- [(1 - (6-Methyl - 2 - piperidino - phenyl) - f - buten - 1 -yl) - yl)- aminocarbonylmethyll - benzoic acid Yield: 53.3% oftheory, M.p.: 142-145 C Calculated: C 73.66 H 7.44 N 6.89 Found: C73.56H7.73N7.15 olefinic proton: 1H-NMR (CDCI3): : # = 5.38 ppm Example 28 4 - [(1- (2 - Piperidino - phenyl)-1- butyl) - aminocarbonylmethyl] - benzoic acid 200 mg (0.51 mmol) of 4 - [(1 - (2 - piperidino phenyl) - 1 - buten - 1 - yl) - aminoca rbonylmethyl] benzoic acid in 10 ml of absolute ethanol are hydrogenated over 100 mg of palladium /charcoal (10%) at 50 C and under 1 bar of hydrogen, with shaking.After 1.5 hours the mixture is filtered and concentrated by evaporation in vacuo.
Yield: 68% of theory, M.p.: 213-214 C Calculated: C73.07 H 7.66 N 7.10 Found: C 73.21 H 7.82 N 7.02 The yield is 56% oftheory if hydrogenation is carried out at 50 C and under 1 bar of hydrogen on Raney nickel.
Example 29 Sodium salt of 4 - [(1 - (2 - piperidino - phenyl) - 1 butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 H20 10.0 9 (25.35 mmol) of4- [(1 - (2 - piperidino phenyl) -1 - butyl) - aminocarbonylmethyl] - benzoic acid are dissolved at 50 C in 2000 ml of methanol and 25.35 ml of 1N 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 140 C/15torr.
Yield: 9g (85.3% of theory), M.p.: 280-285 C (decomp.); softening from 255 C Calculated: (x 0.5 H20) C 67.74 H 6.87 N 6.58 Found: C67.86H7.13N6.49 Example 30 Ethyl (+) - 4 - [(1- (2 - piperidino - phenyl) - 1- butyl) aminocarbonylmethyl] - benzoate To a stirred solution of 2.58 g (11.1 mmol) of(+) - 1 (2 - piperidino - phenyl) - 1 - butylamine [Bpo.03: : 87"C; ee = 86 (HPLC, after derivatising with (+) - 1 phenethyl - isocyanate)j in 26 ml of acetonitrile, there are added, at 20"C, one after another, 2.31 g (11.1 mmol) of 4 - ethoxycarbonyl - phenyl acetic acid,3.50 9 (13.3 mmol) oftriphenylphosphine, 4.60 ml (33.9 mmol) oftriethylamine and 1.03 ml (11.1 mmol) of carbon tetrachloride. After 14 hours at 20 C and 1.5 hours at400C the mixture is concentrated by evapora- tion in vacuo and distributed between water and ether. The organic phase is dried over sodium sulphate, then filtered, and concentrated by evapora tion in vacuo.The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 6:1).
Yield: 2.639 (56% oftheory), M.p.: 118-120 C Calculated: C73.90 H 8.11 N 6.63 Found: C74.02 H 7.97 N 6.51 [cc]20= +9.2 (c= 1; methanol) Thefollowing compound was obtained analogously to Example 30: (a) Ethyl (-)-4- [(1 - (2- piperidino- phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Prepared from (-) - 1 - (2 - Piperidino - phenyl) - 1 butylamine x 1.4 HCI [[C(]20 = 20.00 (c = 1, methanol), Melting range: 90-100 C; ee = 80 (HPLC, after derivatising the base with (+) - 1 - phenethyl isocyanate)1 Yield: 52.6% of theory, M.p.: 115-120 C Calculated:C73.90 H 8.11 N 6.63 Found: C73.83H8.01 N6.47 [&alpha;]D20 = -9.0 (c = 1, methanol) Example 31 Ethyl (+) - 4 - -(2-piperidino-phenyl)- 1- butyl) - aminocarbonylmethyl]- benzoate 1.0 g (3.27 mmol) of(+O 1 -(2- piperidino- phenyl) - 1 - butylamine - dihydrochloride [[OC]D = + 18.7 (c = 1, methanol); m.p.; decomposition from 115 C; ee = 91.6 (HPLC, after derivatising the base with (+) - 1 phenethyl - isocyanate)] 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 g (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 22 C to 38 C. 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 my of water.
The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo.
The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6/1).
Yield: 0.53 g (38.2% oftheory), M.p.: 120-122 C Calculated: C73.90 H 8.11 N 6.63 Found: C73.96 H 7.98 N 6.61 [oc]O = +9.0 (c = 1, methanol) = 1,methanol) Example 32 (+) - 4- [(1 - (2- Piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid 2.0 g (4.73 mmol) of ethyl ( +) -4- [(1 - (2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] benzoate [&alpha;]D20 = +9.2 (c = 1, methanol)] in 20 mi of ethanol are stirred with 7.0 ml of 1 N sodium hydroxide solution for 2.5 hours in a bath at 650C. The mixture is cooled and 7.0 ml of1N hydrochloric acid are added.The crystals which are slowly precipitated are filtered off, washed with water and dried at 100 C/4torr.
Yield: 1.65g (88.2% oftheory), M.p.: 185-187 C Calculated: C73.07 H 7.66 N 7.10 Found: C 72.90 H 7.80 N 7.17 [cc]20- +7.9 (c = 1,methanol) Thefollowing compound was obtained analogouslyto Example 32: (a) (-)-4- [(1(2- Piperidino-phenyl)- 1 - butyl) - aminocarbonylmethyl] - benzoic acid.
Yield: 80% of theory, M.p.: 187-190 C Calculated: C73.07 H 7.66 N 7.10 Found: C 72.98 H 7.44 N 7.22 [cc]020= -7.9 (e = 1,methanol) Example 33 - (2-Piperidino-phenyl)- 1- butyl) - aminocarbonylmethyl]- benzonitrile Prepared from 1 - (2 - piperidino - phenyl) - 1 butylamine and 4 - cyano - phenylacetic acid analogouslyto Example 19.
Yield: 57.3% of theory, M.p.: 147-148 C Calculated: C76.76H7.78N 11.19 Found:C76.46H7.81 N 11.10 The following compound was obtained analogously to Example 33: (a) 4-[(1-(2-Piperidino - phenyl) - 1 - butyl) aminocarbonylmethyl] -toluene Prepared with 4 - tolyl - acetic acid.
Yield: 60.4% oftheory, M.p.: 150-1539C Calculated: C 79.08 H 8.85 N 7.68 Found: C78.97 H 8.58 N 7.77 Example 34 Ethyl 4-[(1 - (2 - piperidino - phenyl) - 1- butyl) aminocarbonylmethyl] - benzoate Prepared from 4 - [(1 - (2 - piperidino- phenyl)- 1 butyl) - aminocarbonylmethyl] - benzonitrile with ethanolic hydrochloric acid analogously to Example 14.
Yield: 58% oftheory, M.p.: 127-1280C Calculated: C73.90 H 8.11 N 6.63 Found: C74.07 H 8.23 N 6.87 Example 35 Ethyl 4 - [(1 - (2 piperidino - phenyl) - 1- butyl) - aminocarbonylmethyl] - benzoate Prepared analogously to Example 10 from 1 - (2 piperidino - phenyl) - 1 - butanol and ethyl 4cyanomethylbenzoate with concentrated sulphuric acid in o-dichlorobenzene at ambienttemperature.
Yield: 21% oftheory, M.p.: 126-128 C Calculated: C 73.90 H 8.11 N 6.63 Found: C74.12H8.20N6.45 The following compound was obtained analogously to Example 35: (a) 4- [(1 - (2 - Piperidino - phenyl) - 1 - butyl) aminocarbonylmethyl] - benzoic acid Prepared from 1 - (2 - piperidino - phenyl) - 1 - butanol and 4- cyanomethyl - benzoic acid. Extraction at pH 5.5.
Yield: 29% oftheory, M.p.: 215-217 C Calculated: z C C73.07 H 7.66 N 7.10 Found: C72.82H7.69N 6.95 Example 36 4 -[(1-(4-Amino-2 piperidino-phenyl)-1-butyl) - aminocarbonylmethyl] - benzoic acid x 0.5 H2O 0.60 g (1.365 mmol) of4- [(1 - (4 - nitro - 2 piperidino - phenyl) - 1 - butyl) - aminocarbony lmethyl]- benzoic acid in 10 ml of dimethylformamide are hydrogenated on 0.1 g of 10% palladium/charcoal for 3 hours at 25 C and under a hydrogen pressure of 1 bar. The catalyst is filtered off using kieselguhrand the filtrate is concentrated by evaporation in vacuo.
The evaporation residue is crystallised from ether.
Yield: 0.41 g (73.2% oftheory), M.p.: 118-120 C Calculated: (x 0.5 H20): C 68.87 H 7.71 N 10.04 Found: C 68.62 H 7.64 N 10.08 Thefollowing compoundswere obtained analogouslyto Example 36: (a) Ethyl 4- [(1 - (4-amino - 2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 81.7% oftheory, M.p.: 145-146 C (ether/petroleum ether) Calculated: C71.37 H 8.06 N 9.60 Found: C71 .50 H 8.08 N 9.68 (b) 4 - [(1 - (5-Amino-2- piperidino- phenyl)- 1 butyl) - aminocarbonylmethyl] - benzoic acid Yield: 64% of theory, M.p.: 227-230 C Calculated: C70.39H7.63N 10.26 Found:C70.54H7.54N 10.36 (c) Ethyl 4- [(1 -(5-amino-2- piperidino-phenyl)- 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 84.3% oftheory, M.p.: 162-165 C Calculated: C 71.37 H 8.06 N 9.60 Found: C 71.58 H 7.83 N 9.65 Example 37 Ethyl4-[(1-(5-chloro-2-piperidino-phenyl)-1 - butyl) - aminocarbonylmethyl] - benzoate Acold diazonium salt solution (0 C) is prepared from 2.0g (4.57 mmol) of ethyl 4 - [(1 - (5 - amino - 2 piperidino - phenyl) - 1 - butyl) - aminocarbony Imethyl] - benzoate in 4.8 ml of semiconcentrated hydrochloric acid and 0.315 g (4.57 mmol) of sodium nitrite in 1.66 ml of water.This solution is added dropwise, at O to 5"C, to a stirred mixture of 0.59 g (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 50 C. After 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 chroma tographyon silica gel (toluene/ethyl acetate = 10/1.
Yield: 0.80 g (40% oftheory), M.p.: 137-1400C (ether) Calculated: C68.32 H 7.27 Cl 7.75 N 6.13 Found: C68.42 H7.09Cl 8.06 N 6.05 The following compounds were obtained analogouslyto Example 37: (a) Ethyl 4- [(1 - (4-chloro -2 - piperidino- phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 21.9% oftheory, M.p.: 123-125 C Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13 Found: C68.70H7.18C17.77N6.08 (b) Ethyl 4 - [(1 - (5 - bromo - 2 - piperidino - phenyl) 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 53.8% oftheory, M.p.: 140-142 C Calculated: C62.27 H 6.63Br15.93 N 5.58 Found:C 62.39 H 6.78 Br 15.85 N 5.59 (c) Ethyl 4- [(1 -(4-fluoro-2- piperidino-phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 21.6% oftheory, M.p. : 110-112 C Calculated: C70.88H7.55N 6.36 Found:C71.01 H7.53N6.21 In addition, 40% of ethyl 4 - [(1 - (4 - hydroxy - 2 piperidino - phenyl) - 1 - butyl) - aminocarbony Imethyl] - benzoate are isolated (solid foam).
(d) Ethyl 4 - [(1 - (5-fluoro - 2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 2% oftheory, M.p.: 127-129 C Calculated: m/e = 440 Found: m/e = 440 (e) 4 - [(1 - (4- Fluoro - 2 - piperidino - phenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid Yield 16.9% of theory, M.p.: 172-175 C Calculated: C 68.73 H 6.55 N 7.29 Found:C 68.78 H 6.62 N 7.31 Example 38 4-[{1- (2-Piperidino - phenyl) -1 - butyl) - aminocarbonylmethyl] - benzoic acid 1.0g (2.33 mmol) of4- [(1 - (5-chloro -2- piperidino - phenyl) - 1 -butyl)-aminocarbonylmethyl] -benzoic acid in 40 ml of absolute ethanol are hydrogenated on 0.5 g of 10% palladium/charcoal at 50"C and under 5 bar of hydrogen. After 2 hours, the catalyst is filtered off over kieselguh rand 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: 0.619 (66% oftheory), M.p.: 213-215 C Calculated: C73.07 H7.66 N 7.10 Found: C73.18 H 7.42 N 7.27 The same compound is also obtained from the corresponding 4-chlorine-, 3-chlorine- or 6-chlorine- substituted starting products.
Example 39 Ethyl 4 - [(1- (4 - Methoxy - 2 - piperidino - phenyl) - 1butyl) - aminocarbonylmethyl]- benzoate A solution of 5.0 g (1 mmol) of ethyl 4 - [(1 - (4- hydroxy - 2 - piperidino - phenyl) - 1 - butyl) aminocarbonylmethyl] - benzoate in 45 ml of absolute dimethylformamide is added dropwise, with stirring, at ambienttemperature, to 548 mg (11.4 mmol) of sodium hydride (50% in oil) in 10 ml of absolute dimethylformamide. The mixture is stirred forafurther 15 minutesandthen a solution of 0.71 ml (11.4 mmol) of methyliodide in 8 ml of absolute dimethylformamide is slowly added dropwisethereto. 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 is dried and filtered and concentrated by evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ace tone = 20/1).
Yield: 1.8 9 (34.9% oftheory), M.p.: 115-117 C Calculated: C71.65 H 8.02 N 6.19 Found:C71.47H7.86N6.19 Thefollowing compound was obtained analogously to Example 39: (a) Ethyl 4 - [(1 - (5 - methoxy - 2 - piperidino - phenyl) - 1 - butyl) -aminocarbonylmethyli - benzoate Yield: 68.4% oftheory, M.p.: 142-1450C Calculated: C71.65 H 8.02 N 6.19 Found:C71.87 H 8.06 N 6.38 Example 40 2,3 - Dihydroxy - propyl 4 - [(1- (2 - piperidino - phenyl) -1- butyl) - aminocarbonylmethyl] - benzoate Asolution of 2.0 g (5.07 mmol) of4- [(1 - (2 piperidino - phenyl) - 1 - butyl) - aminocarbony Imethyl] - benzoic acid and 0.85 g (5.27 mmol) of N,N'-carbonyldiimidazole in 20 ml of absolutetet- rahydrofuran is 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 evaporation in 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% oftheory), M.p.: 120-122 C Calculated: C 69.21 H 7.74 N 5.98 Found: C 69.23 H 7.78 N 5.93 Thefollowing compounds were obtained analogouslyto Example 40: (a) 2 - hydroxy - ethyl 4 - [(1 - (2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 80% oftheory, M.p.: 125-127 C Calculated: C71.21 H 7.81 N 6.39 Found: C71.35 H 7.54N 6.33 (b) 2 - methoxy - ethyl 4 - [(1 - (2 - piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoate Yield: 55.9% of theory, M.p.: 120-123 C Calculated: C71.65 H 8.02 N 6.19 Found:C72.03 H 8.03 N 6.24 Example 41 2 - nicotinoyloxy- ethyl 4 - [(1- (2 - piperidino - phenyl) - 1- butyl) - aminocarbonylmethyl] - benzoate A solution of 0.7 g (4.68 mmol) of nicotinic acid chloride in 20 ml of methylene chloride is rapidly added dropwiseto 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) oftriethylamine. The resulting mixture is stirred at 20 Cfor2.5 hours, 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 = 5/1).
Yield: 1.1 g (44% oftheory), M.p.: 132-135"C Calculated: C 70-70 H 6.86 N 7.73 Found: C 70.82 H 6.82 N 7.91 Example 42 4 - [(1- (2 - Piperidino - phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzyl alcohol Asolution of5.0g (11.83 mmol) of ethyl 4- [(1 - (2 piperidino - phenyl) - 1 - butyl) - aminocarbony lmethyl] - benzoate in 75 ml ofabsolutetetrahydrofur- an is added dropwise, at an internal temperature of 00cato a stirred suspension of 0.68 g (17.95 mmol) of lithium aluminium hydride in 25 ml of absolute tetrahydrofuran.The mixture is stirred for 20 hours at ambienttemperature then cooled to 0"C 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).
Yield: 1.0 9 (22% oftheory), M.p.: 152-154 C Calculated: C 75.75 H 8.48 N 7.36 Found: C75.90 H 8.45 N 7.28 Example 43 4-[(1- (2-Piperidino - phenyl) -1 - butyl) - aminocarbonylmethyl] - benzaldehyde 6.6 g (62 mmol) of sodium carbonate are heated together with 62 ml of ethylene glycol in a bath at 1700Cand,within 1 minute, 6.2 g (11 mmol) of N1 - [4- [(1 - (2- piperidino- phenyl) - 1 - butyl) - aminocarbonyl - methyl] - benzoyl] - N2 -tosyl - hydrazine (melting point 1 950C (decomposition)) are added thereto, with rapid stirring, whereupon there is a vigorous development of gas.The mixtureisthen heated for a further 2.5 minutes at 170"C and then immediately poured onto ice. It is extracted with ether and the ether solution is dried, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone = 20/1).
Yield: 2.2 g (52.9% oftheory), M.p.: 142-145"C Calculated: C 76.16 H 7.99 N 7.40 Found: C 76.26 H 7.96 N 7.37 Example 44 Ethyl4 - [(1- (2 - Piperidino - phenyl) - 1- butyl) aminocarbonylmeth yl] - cinnamate Asolution of 2.80 g (12.5 mmol) of ethyl diethyl phosphonoacetate in 10 ml of absolute dimethylformamide is added dropwise, at ambienttemperature, to 0.60 g (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 2.49 (6.34mmol) of4- [(1 - (2- piperidino - phenyl) - 1 - butyl) - aminocar bonylmethyl] - benzaldehyde in 10 ml of absolute dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at ambienttemperature, 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 residueispurified bycolumnchromatography on silica gel (toluene/acetone = 10/1).
Yield: 0.85g (29.9% oftheory), M.p.:135-1 (ether/petroleum ether) Calculated: C 74.97 H 8.09 N 6.24 Found: C74.91 H 7.89 N 6.29 Example 45 4. [(1- (2 - Piperidino - phenyl) -1 - butyl) - aminocarbonylmethyl] - cinnamic acid Prepared by alkaline saponification of ethyl 4 - [(1 (2 - piperidino - phenyl) - 1 - butyl) - aminocarbony Imethyl] - cinnamate analogously to Example 26.
Yield: 64% oftheory, M.p.: 180-183 C Calculated: C74.26 H 7.67 N 6.66 Found: C 74.03 H 7.47 N 6.80 Example 46 Ethyl3-[4-[(1 r2 - piperidino - phenyl) - 1- butyl) - aminocarbonylmethyl] - phenyl] - propionate 0.60 g (1.34mmol) of ethyl 4 - [(1 - (2 - piperidino phenyl) - 1 - butyl) - aminocarbonylmethyl] - cinnamate are hydrogenated in 10 ml of ethanol on 0.20 g of 10% palladium/charcoal atambienttemperature under 5 bar of hydrogen. The mixture is filtered and concentrated by evaporation in vacuo.
Yield: 0.53 g (88% oftheory), M.p.: 98-99"C (petroleum ether) Calculated: C 74.63 H 8.50 N 6.22 Found: C 74.64 H 8.58 N 6.23 The following compound was obtained analogouslyto Example46: (a) 3 - [4 - [(1 - (2 - Piperidino - phenyl) - 1 - butyl) amino - carbonylmethyl] - phenyl] - propionic acid Yield: 63% oftheory, M.p.: 131-133"C Calculated: C73.90H8.11 N6.63 Found: C73.96 H 8.30 N 6.56 Example 47 3- [4- [(1- (2 - Piperidino - phenyl) - 1- butyl) aminocarbonylmethyl]- 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% oftheory, M.p.: 131-1330C Calculated: C73.90H8.11 N6.63 Found: C73.82 H 8.07 N 6.41 Example 48 Ethyl 4 - [(cc - aminocarbonyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoate At 20 C, 0.90 g (5.5 mmol) of N,N' - carbonyldi imidazole are added to a stirred solution of 2.0 g (4.7 mmol) of ethyl 4 - [(&alpha;-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 80 C.The mixture is than cooled to 60"C and atthistemperature a vigorous current of dry ammonia is introduced over a period of halfan hour. Then the resulting 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 chromatography on silica gel (chloroform/methanol =5/1).
Yield: 1.0g (50.2% of theory), M.p.: 160-162 C (acetone) Calculated: C 68.07 H 6.90 N 9.92 Found: C 68.40 H 6.92 N 9.84 Example 49 Ethyl4-[(cc -cyano -2-piperidino - benzyl) - aminocarbonylmethyl] - benzoate 234 mg (1.22 mmol) of 4- toluenesulphochloride are added in two batches to 520 mg (1.22 mmol) of ethyl 4 - [(oc - aminocarbonyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoate in 0.22 ml of pyridine and the mixture is heated to 50"C. After 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 at50 C. After it has been lefttostandfor2days at 20"C, 2N ammonia is added and the mixture is extracted with chloroform. The chloroform solution is extracted twice with water. After drying and filtering, it concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatogra phy on silica gel (chloroform/methanol = 10/1).
Yield: 325 mg (65.7% oftheory), M.p.: 114-117"C (ether/petroleum ether) Calculated:C71.09H6.71 N 10.36 Found: C70.79 H 6.56 N 10.10 Example 50 4 - [(cc - Cyano - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoic acid 1.5 9 (3.7 mmol) of ethyl 4 - [(or - cyano - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoate in 15 ml of dioxan are stirred togetherwith 3.7 ml of 1 N sodium hydroxide solution for 45 minutes in a bath at60 C 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 IN hydrochloric acid, the dioxan is evaporated off in vacuo and the residue is distributed between water and chloroform.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 g (35.7% oftheory), M.p.: 176-180"C (decomposition) Calculated: C70.01 H 6.14N 11.13 Found: C70.02 H 6.19 N 11.05 Example 51 4 - [(1- (2 - piperidino - phenyl) - I - butyl) - aminocarbonylmethyl] - benzoic acidx H2S04 5 ml (2.50 mmol) of 1 N sulphuric acid are added to a solution of 1.0 g (2.53 mmol) of 4- [(1 - (2 - piperidino phenyl) - 1 - butyl) - aminocarbonylmethyl] - benzoic acid in 50 ml of ethanol, the mixture is concentrated to dryness in vacuo and triturated with acetone.
Yield: 0.80g (65% of theory), M.p.: 192-197"C (decomposition).
Calculated: C 58.53 H 6.55 N 5.69 S 6.49 Found: C 58.05 H 6.54 N 5.49 S 6.35 The following addition salt was obtained analogouslyto Example 51: (a) 4-[(1-(2-Piperidino-phenyl)-1-butyl)- aminocarbonylmeth ylj - benzoic acidx a 5 H2 504 x 1.5H20 Prepared analogously to Example 51 with half the quantity of sulphuric acid.
Yield: 59.3% of theory, M.p.: 180-185"C decomposition at 207-21 O"C Calculated C 61.26 H 7.28 N 5.95 S 3.40 Found:C61.28H6.99N6.10S3.23 Example A Tablets containing 5 mg of 4 - [(1- (2 - piperidino phenyl) - 1- butyl) aminocarbonylmethyl] benzoic acid Composition: 1 tablet contains: Active substance (1) 5.0 mg Corn starch (2) 62.0 mg Lactose (3) 48.0 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesiumstearate (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 pressedthrough a screen with a mesh width of 1.5 mm and dried at about 45 C.
The dry granulate is passed through a screen with a mesh width of 1.0 mm and mixed with 5. Thefinished mixture is compressed in a tablet press, using punches7 mm in diameter provided with a dividing slot, to form tablets.
Weightoftablet: 120 mg Example B Coated tablets containing 2.5 mg of4 1 - 111(2 piperidino - phenyl) - 1- butyl) - aminocarbony Imethyl] - benzoic acid 1 tablet core contains: Active substance (1) 2.5 mg Potato starch (2) 44.0 mg Lactose (3) 30.0 mg Polyvinylpyrrolidone (4) 3.0 mg Magnesiumstearate (5) 0.5 mg 80.0 mg Method ofpreparation: 1,2,3and4arethoroughly mixed and moistened with water. The moist mass is passed through a screen with a mesh width of 1 mm, then dried at 45 C and the granulate is again passed through the same screen. After the addition of 5, convex tablet cores 6 mm in diameterare produced in atablet-making machine by compression.The tablet cores thus produced are coated in known mannerwith 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 containing 10 mg of4 - [(1- (2 - piperidino phenyl) - 1- butyl) - aminocarbonylmethyl] - benzoic acid Composition: 1 tabletcontains: Active substance 10.0 mg Powdered lactose 70.0 mg Corn starch 31.0 mg Polyvinylpyrrolidone 8.0 mg Magnesium stearate 1.0 mg 120.0 mg Method 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 450C. The dried granulate is rubbed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate.
Weightoftablet: 120 mg Punch: 7 mm diameter with dividing slot.
Example D Coated tablets containing 5 mg of4 - [(1- (2 piperidino - phenyl) - 1- butyl) - aminocarbony Imethyl] - benzoic acid 1 tablet core contains: Active substance 5.0 mg Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg 130.0 mg Method ofpreparation A mixture of active substance, calcium phosphate and corn starch is moistened with a 15% solution of I polyvinylpyrrolidone in water. The moist mass is passed through a screen with a mesh size of 1 mm, then dried at45C and passed through the same screen again. After the specified amount ofmagne- sium stearate has been added, tablet cores are compressed fro m th e m ixtu re.
Weight of core: 130 mg Punch: 7 mm in diameter Acoating 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 (1)

1. Compounds of general formula I
[wherein A represents a group offormula
or
[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 buy a phenyl group; an alkyl group containing 4to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano oralkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene moiety; an aminocarbonyl group optionally mono- ordisubstituted 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 optionally mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkyisulphinyl and/oralkylsulphonyl 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; R5andR6,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 between them represent a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety]; R1 represents an unbranched alkyleneimino group containing 4to 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, ora hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alka noyloxy, alkanoylamino, alkylamino ordialkylamino groupwhereinthealkyl 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 exceptthe oc-carbon atom, by one or two hydroxygroups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino group containing 4to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4to 6 carbon atoms, an alkyl group containing 1 to 3 carbon atoms; ora hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2 - carboxy- ethyl, 2 - carboxyethenyl, 2,2 - bis - (carboxy) - ethyl, alkoxycarbonyl - methyl, 2 - alkoxycarbonyl - ethyl, 2 alkoxycarbonyl - ethenyl or 2,2 - bis - (alkoxycarbonyl) - ethyl group (each alkoxy group containing from 1 to 3 carbon atoms)] and tautomers thereof and optical enantiomers theeof and salts ofthe aforementioned compounds.
2. Salts of compounds of general formula las defined in claim 1 and tautomers thereof, and optical enantiomers thereof, formed with hydrochloric, hyd robromic, sulphuric, phosphoric, lactic,citric,tartaric, succinic, maleicorfumaric acid or with sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, dethanolamine, triethanolamine or ethylenediamine.
3. Physiologically compatible salts of compounds of general formula I as defined in claim 1 and tautomers thereof, and optical enaniomersthereof.
4. Compounds as claimed in claim 1, wherein A represents a group offormula
or
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 4to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano oraminocarbonyl group; an aryl group containing 6 or 10 carbon atoms mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy and/oralkylsulphenyl groups, whilstthe substitutents may be the same or different and each alkyl component may contain from 1 to 3 carbon atoms; ora naphthyl, pyridyl, quinolyl or isoquinolyl group; R5 and R6 together with the carbon atom between them represent an alkylidene group containing 3to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety; R1 represents an unbranched alkyleneimino group containing 4to 8 carbon atoms or a piperidino group mono-ordisubstitutedbyalkylgroupseach having 1 to3carbon 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(ifR5and R6 are as hereinbefore defined or 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 4to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms, or a nitrileor aminocarbonyl group) R2 may also represent an iodine atom or a hydroxy or amino group; R3 representsa hydrogen orchlorine atom; and W 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 exceptthe oc-carbon atom by 1 or 2 hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbonyl-oxy group; or an alkoxycarbonyl-methyl, 2 - alkoxyca rbonyl - ethyl or 2 - alkoxycarbonyl - ethenyl group, wherein each i alkoxygroup group may contain from 1 to 3 carbon atoms; ; and 4- [N - (6-chloro - cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C1 3 alkyl esters thereof, 4- [N - (cc- phenyl -2-piperidino - benzyl) aminocarbonylmethyl] - cinnamic acid and C1 3 alkyl esters thereof;; 3 - [4- [(N - (cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl]phenyl] - propionic acid and i Cl3 alkyl esters thereof, 4- [N - (4- chloro - cc- phenyl - 2 - piperidino - benzyi) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof, 4- [N - (3-chloro - cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof, 4 - [N - (6 - methyl - cc - phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof, 4- [N - (4-methyl - cc- phenyl - 2- piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof, 4- [N-(2 - (2 - methyl- piperidino) - cc - phenyl - benzyl) - aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof 4- [N - (2 - (3 - methyl - piperidino) - or - phenyl - benzyl) - aminocarbonyl - methyl] - benzoic acid and C13 alkyl esters thereof 4- [N - (cc- phenyl -2- piperidino - benzyl) aminocarbonyl - methylbenzaldehyde, 4- [(1 - (4-fluoro-2-piperidino - phenyl) - ethyl) - aminocarbonyl - methyl] - benzoic acid and C13 alkyl esters thereof 4- [(1 - (3 - chloro - 2 - piperidino - phenyl) - ethyl) - aminocarbonyl - methyl] - benzoic acid and C1-3 alkyl esters thereof and 4- [(1 - (3-methyl - 2- piperidino - phenyl) - ethyl) - aminocarbonyl - methyl] - benzoic acid and C13 alkyl esters thereof, and tautomers and optical enantiomers ofthe above-named compounds and salts thereof.
5. Compoundsasclaimed in claim 1,wherein: A represents a group offormula
or
wherein R4 represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano oraminocarbonyl group; an alkyl group containing 4to 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, benzyloxyormethylsulphenyl group; ora pyridyl group; R5 and R6togetherwith 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 containing 4to 8 carbon atoms ora piperidino group mono-ordisubstituted by methyl groups, R2 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 substituted by a methoxy or phenyl group, an n-propyl, nitrile or aminocarbonyl group, an alkyl group containing 4to 6 carbon atoms or an alkenyl group containing 3to 5 carbon atoms, 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 exceptthe oc-carbon atom by one ortwo hydroxy groups, 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, and 4-[N-(6-chloro-&alpha;- phenyl -2- piperidino- benzyl) aminocarbonylmethyl] - benzoic acid and C1 -3 alkyl esters thereof, 4- [N - (cc - phenyl - 2 - piperdino - benzyl) - aminocarbonylmethyl] - cinnamic acid and C13 alkyl esters thereof 3- [4- [(N - (cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - phenyl] - propionic acid and C13 alkyl esters thereof 4- [N -(4-chloro- cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyli - benzoic acid and C13 alkyl esters thereof, 4- [N - (3 - chloro - cc - phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof, 4- [N - (6-methyl - cc- phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C1 -3 alkyl esters thereof 4- [N - (4-methyl - cc- phenyl - 2- piperidino - benzyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof 4- [N - (2 - (2 - methyl - piperidino) - or - phenyl - benzyl) - aminocarbonylmethyl] - benzoic acid and C1-3 alkyl esters thereof 4- [N - (2 - (3 - methyl - piperidino) - oc - phenyl - benzyl ) - aminocarbonylmethyl] - benzoic acid and the alkyl esters with 1 to3carbon atoms, 4- [N - (cc - phenyl - 2 - piperidino - benzyl) aminocarbonylmethyl] - benzaldehyde, 4- [(1 - (4-fluoro-2- piperidino- phenyl) -ethyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof - (3-chloro-2-piperidino - phenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid and C1 -3 alkyl estersthereofand 4 - [(1 - (3 - methyl - 2 - piperidino - phenyl) - ethyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof and tautomers and optical enantiomers ofthe above-named compounds and salts thereof.
6. Compounds as claimed in claim 5, wherein W represents a carboxy group or an alkoxycarbonyl group containing a total of to 5 carbon atoms in which the alkyl component may be substituted at any carbon atom except the oc-carbon atom by one or two hydroxy groups.
7. Compounds as claimed in claim 5wherein W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms.
8. Compounds as claimed in claim 1,wherein A represents a group offormula
or
wherein R4 represents an n-propyl group, an alkyl group containing 4to 5 carbon atoms, a phenyl group substituted by a methyl group or by a fluorine or chlorine atom, or a pyridyl group; R5 and R6together with the carbon atom between them represent an alkylidene group containing 3 to 5 carbon atoms or a phenylakylidene group containing 1 to 3 carbon atoms in the alkylidene part; R1 represents a piperidino groupoptionallysubstituted by one ortwo methyl groups; R2 represents a hydrogen, fluorine or chlorine atom ora 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.
9. Compounds as claimed in claim 8, wherein A represents a group offormula
or
wherein R4 represents an n-propyl group or an alkyl group containing 4to 5 carbon atoms and R5 and R6 together with the carbon atom between them repre sent an alkylidene group containing 3to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part.
10. 4 - [N - 4- [N-(6.Chloro-cc-phenyl -2-piperidino- benzyl) - aminocarbonyl - methyl] - benzoic acid and C1 -3 alkyl esters thereof.
11. 4- [N - (cc-Phenyl -2 - piperidino- benzyl) aminocarbonylmethyl] - cinnamic acid and C13 alkyl esters thereof.
12. 3- [4- [(N -(cc- Phenyl - 2 - piperidino - aminocarbonylmethyl] - phenyl] - propionic acid and C1 -3 alkyl esters thereof.
13. 4- [N-(4-Chloro- cc- phenyl-2-piperidino - benzyl) - aminocarbonyl - methyl - benzoic acid and C13 alkyl esters thereof.
14. 4-[N-(3-Chloro-cc-phenyl -2- piperidino - benzyl) - aminocarbonyl - methyl] - benzoic acid and C1-3 alkyl esters thereof.
15. 4.[N-(6-Methyl -cc-phenyl -2-piperidinobenzyl) - aminocarbonyl - methyl] - benzoic acid and C1-3alkyl esters thereof.
16. 4-[N-(4-Methyl-oc- phenyl-2-piperidino - benzyl) - aminocarbonyl - methyl] - benzoic acid and C13 alkyl esters thereof.
17. 4- [N - (2- (2-Methyl - piperidino) - cc- phenyl - benzyl) - aminocarbonyl - methyl] - benzoic acid and C13 alkyl esters thereof.
18. 4- [N- (2- (3-Methyl - piperidino) - cc- phenyl - benzyl) - aminocarbonyl - methyl] - benzoic acid and C1--3alkyl esters thereof.
19. 4-[N - (cc-Phenyl -2- piperidino - benzyl) aminocarbonylmethyl - benzaldehyde.
20. 4- [(1 - (4- Fluoro - 2 - piperidino - phenyl) ethyl) - aminocarbonyl - methyl] - benzoic acid and C1 -3 alkyl esters thereof.
21. 4- [(1 - (3-Chloro-2-piperidino-phenyl)- ethyl) - aminocarbonyl - methyl - benzoic acid and C13alkyl esters thereof.
22. 4- [(1 - (3-Methyl - 2- piperidino- phenyl) ethyl) - aminocarbonyl - methyl] - benzoic acid and C13 alkyl esters thereof.
23. 4- [N - (6-Chloro - cc- phenyl - 2 - piperidino benzyl) - aminocarbonyl - methyl] - benzoic acid and C1 -3 alkyl esters thereof.
24. 4- [N - (cc - Phenyl - 2 - piperidino - benzyl) aminocarbonyl - methyl] - cinnamic acid and C1 -3 alkyl esters thereof.
25. 3- [4- [(N - (cc- Phenyl - 2 - piperidino - benzyl) - aminocarbonylmethyl] - phenyl] - propionic acid and C1 -3 alkyl esters thereof.
26. 4- [N - (6-Chloro- cc- phenyl - 2 - piperidino benzyl) - aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof.
27. 4-[N-[&alpha;-(4- Fluoro - phenyl) - 2- piperidinobenzyl] - aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof.
28. 4- [N - (4-Methyl - cc- phenyl - 2 - piperidino benzyl) - aminocarbonylmethyl] - benzoic acid and C1 -3 alkyl esters thereof.
29. 4- [(1 - (2 - Piperidino - phenyl) - 1 - butyl) aminocarbonylmethyl] - benzoic acid and C13 alkyl esters thereof.
30. 4 - [(1 - (2 - Piperidino - phenyl) - 1 buten - 1 -yl) - aminocarbonylmethyl] - benzoic acid and C13 alkyl.
esters thereof.
31. 4- [(1 - (2 - Piperidino - phenyl) - 1 - pentyl) aminocarbonylmethyl] - benzoic acid and C1 -3 alkyl esters thereof.
32. Tautomersandoptical enantiomersofcompounds as claimed in any one of claims 10 to 31, and salts thereof.
33. Enantiomers and salts of compounds as claimed in any one of claims 23 to 31.
34. Compounds as claimed in claim 1 wherein A represents a group offormula
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,whilstthe 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 alkylenemino group containing 4to 6 carbon atoms optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; an octahydroazocino, octahydro - 1 H azonino or decahydroazecino group; or a dialkylami- no 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-carboxy- ethyl, or 2,2 - bis - (carboxy) - ethyl group, an alkoxycarbonyl group containing 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 atthe 2-position by alkoxycarbonyl groups (wherein each alkoxycarbonyl group may contain from 2 to 4 carbon atoms in total); and R2 represents afluorine orbromineatom, a chlorine atom in the 3-, 4- or 6-position (relative to the substituentA), a nitro group or an alkyl or alkoxy group containing 1 to 3 carbon atoms; or (when either: R1 represents an unbranched alkyleneimino group substituted by one or two alkyl groups; an octahydroazocino, octahydro - 1 H - azonino or decahydroazecino group, or a dialkylamino 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, 9 carbon atoms and 1 or 2 nitrogen atoms; and/or W represents a hydroxymethyl, formyl, cyano, ami nocarbonyl, 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 atthe 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.
35. Compounds as claimed in claim 1, wherein A represents a group offormula
or
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 containing 4to 6 carbon atoms; an alkenyl groups containing 3 to 5 carbon atoms; a cyano or alkyleneimino group containing 4to 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 i n the al kyl moiety; Rg and R6, which may be the same or different, represent hydrogen atoms or alkyl groups containing 1 to 5 carbon atoms; or R5 and R6togetherwith the carbon atom between them represent a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety; R1 represents an unbranched alkyleneimino group containing 4to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups containing 1 to 3 carbon atoms; R2 represents a hydrogen, flourine, chlorine, bromine or iodine atom, an alkyl or alkoxy group wherein the alkyl component may contain 1 to 3 carbon atoms; or a hydroxy, nitro, amino or piperidino 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 to3carbonatoms.
36. Compounds as claimed in claim 1 as herein specifically described.
37. Compounds as claimed in claim 1 as herein specifically described in any of Examples 1 to 51.
38. Compounds as claimed in claim 34 as herein specifically described in any of Examples 1 to 14.
39. Compounds as claimed in claim 35 as herein specifically described as in any of Examples 22,27, 38,48and49.
40. Compounds as claimed in any preceding claim for use in a method of treatment of diabetes mellitus and disorders of the intermediate metabolism or the cardiac circulatory system.
41. Aprocessforthe preparation ofcompounds as claimed in claim 1, which comprises reacting a compound of general formula II
(wherein A, R1 and R2 are defined as in claim 1 or, if A represents one ofthevinylidenegroups mentioned in claim 1, thetautomers thereof or a lithium or magnesium halide complex thereof) with a compound of general formula Ill
(wherein R3 is defined as in claim 1 and W' has the meanings given forW in claim 1 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.
42. A process as claimed in claim 41,wherein the reactive derivative of the compound of general formula Ill is an ester, thioester, halide, anhydride or imidazolide thereof.
43. A process as claimed in claim 41 or claim 42 wherein the subsequent cleaving of the protecting group of W', if present, is effected by hydrolysis, thermolysis or hydrogenolysis.
44. A process as claimed in claim 43 wherein the hydrolytic cleaving is effected in the presence of an acid or of a base.
45. A process as claimed in any of claims 41 to 44 wherein the reaction is effected in the presence of a solvent.
46. A process as claimed in any one of claims 41 to 45whereinthe reaction is effected in the presence of an acid-activating or dehydrating agent.
47. A process as claimed in anyoneofclaims41 to 45 wherein the reaction is effected in the presence of an amine-activating agent.
48. A process as claimed in any one of claims 41 to 47 wherein the reaction is effected in the presence of an inorganic or tertiary organic base.
49. A process as claimed in any one of claims 41 to 48whereinwaterformed during the reaction is removed byazeotropic distillation or by the use of a drying agent.
50. A process as claimed in any one of claims 41 to 49 wherein the reaction is effected at temperatures of from -25 and 250"C.
51. A process as claimed in any one of claims 41 to 50 wherein a solvent is present and the reaction is effected attemperatures of from - 10C to the boiling temperature ofthe solvent.
52. A processforthe preparation ofcompounds as claimed in claim 1 wherein W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, which comprises subjecting a compound of general formula IV
(wherein R1 to R3 and A are as defined in claim 1 and B represents a group which can be converted into a carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group by hydrolysis, thermolysis or hydrogenolysis) to hydrolysis, thermolysis or hydrogenolysis.
53. A process as claimed in claim 52 wherein the group Bin 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, 2carboxyethyl or 2- car boxyethenyl group.
54. A process as claimed in claim 53 wherein the functional derivative is an unsubstituted or substituted amide, nitrile, ester, thiolester, orthoester, imino ether, amidine or anhydride or a malonic ester (1) -yl, tetrazolyl or optionally substituted 1,3 - oxazol - 2 - yl our1,3 oxazolin - 2 -yl group, the ester is a tertiary alkyl esterorthe aralkyl ester is a benzyl ester.
55. A process as claimed in any one of claims 52 to 54,wherein the reaction is effected in the presence of a solvent.
56. A process as claimed in any one of claims 52 to 55, wherein the hydrolysis orthermolysis is effected in the presence of an acid or a base.
57. A process as claimed in any one of claims 52 to 55 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.
58. A process as claimed in claim 57 wherein the nitrite is sodium nitrite and the acid used is sulphuric acid.
59. A process as claimed in any one of claims 52 to 58 wherein the reaction is effected attemperatures of from -lOto 1200C.
60. A process as claimed in any one of claims 52 to 59 wherein the reaction is effected at temperature of from ambienttemperature to the boiling temperature ofthe reaction mixture.
61. Aprocessforthe preparation of compounds as claimed in claim 1 wherein A represents a group of formula
wherein R4, has the meanings given for R4 in claims 1 with the exception of an alkenyl group and a cyano group, which comprises reduction of a compound of general formula V
wherein R1 to R3 and Ware defined as in claim 1 and D represents a group offormula
wherein R4" has the meanings given hereinbeforefor 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 carbonatomsora phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety.
62. A process as claimed in claim 61, wherein the reduction is carried outwith hydrogen in the presence of a hydrogenation catalyst.
63. A process as claimed in claim 62 wherein a hydrogen pressure of 1 to 5 bar is used.
64. A process as claimed in any one of claims 61 to 63 wherein the reduction is carried out in a solvent.
65. A process as claimed in any one of claims 61 to 64 wherein the reduction is carried out at a tempera to rue of from Oto 100 C.
66. A process as claimed in claim 65, wherein the temperatu re is from 20 to 50"C.
67. A processforthe preparation of compounds as claimed in claim 1 wherein A represents a group of formula
wherein R4" has the meanings given hereinbefore for R4,with the exception of a cyano group; which comprises reacting a compound ofgeneralformula VI
(wherein R4" represents R4 as defined in claim 1 with the exception of a cyano group and R1 and R2 are defined in claim 1 with a compound of general formula VII
wherein R3 and Ware defined as in claim 1.
68. A process as claimed in claim 67, wherein the reaction is effected in the presence of a strong acid.
69. A process as claimed in claim 67 or claim 68, wherein the reaction is effected in the presence of sulphuric acid.
70. A process as claimed in any one of claims 67 to 69, wherein the reaction is effected in the presence of a solvent.
71. A process as claimed in any one ofclaims 67 to 70 wherein the reaction is effected at temperatures of from 0 to 1500C.
72. A process as claimed in claim 71 wherein the temperatures are from 20 to 100 C.
73. A processforthe preparation of compounds as claimed in claim 1 wherein R2 represents a hydrogen atom, which comprises dehalogenating a compound of general formula VIII
wherein R1, R3, A and Ware as defined in claim 1 and Hal represents a fluorine, chlorine, bromine or iodine atom.
74. A process as claimed in claim 73 wherein the dehalogenation is effected with hydrogen in the presence of a hydrogenation catalyst.
75. A process as claimed in claim 73 or claim 74 wherein the dehalogenation is effected in a solvent.
76. A process as claimed in any one of claims 73 to 75, wherein the dehalogenation is effected attemperatures of between Oto 1000Cand under a hydrogen pressure offrom 1 to 5 bar.
77. A processforthe preparation of compounds as claimed in claim 1 wherein A represents a group of formula
wherein R4 represents an alkyleneiminocarbonyl group containing 4to 6 carbon atoms in the alkylene ring oran aminocarbonyl group optionally mono- or di-substituted byalkyl orphenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety, which comprises reacting a compound of general formula IX
wherein R1, R2 and R3 are as defined in claim 1 and W" represents Was defined in claim 1 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.
78. A process as claimed in claim 77, wherein the reaction is effected in the presence of an acidactivating or dehydrating agent.
79. A process as claimed in claim 77 or claim 78, wherein the reaction is effected in the presence of an inorganic or tertiary organic base.
80. A process as claimed in any one of claims 77 to 79, wherein the reaction is effected in the presence of an amine-activating agent.
81. A process as claimed in anyone of claims 77 to 80 wherein the reaction is effected in the presence of a solvent.
82. A process as claimed in any one of claims 77 to 81, wherein the reaction is effected at temperatures of from -25 Cto 25"C.
83. A process as claimed in any one of claims 77 to 82 wherein the reaction is effected in the presence of a solvent and attemperatures of from - 1 to the boiling temperature of the solvent.
84. A processforthe preparation of compounds as claimed in claim 1 wherein A represents a group of formula
wherein R4 is as defined in claim 1 and W represents a carboxy group, which comprises oxidising a compound of general formula Xl
wherein R1 to R4 are defined as in claim 1 and E represents a group which can be converted into a carboxy group by oxidation.
85. A process as claimed in claim 84 wherein E represents a formyl group, an acetal of a formyl group, a hydroxymethyl group, an thereof a hydroxymethyl group, a substituted or unsubstituted acyl group ore malonicester-(1)-yl group.
86. A process as claimed in claim 84 or claim 85 wherein the oxidising 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.
87. A process as claimed in any one of claims 84 to 86 wherein the oxidation is effected in the presence of a solvent.
88. A process as claimed in any one of claims 84to 87 wherein the oxidation is effected attemperatures offrom Oto 100 C.
89. A process as claimed in claim 88 wherein the temperatures are from 20to 500C.
90. A process forthe preparation of compounds as claimed in claim 1 wherein W represents an alkoxy-carbonyl group containing a total of 2 to 6 carbon atoms wherein the alkyl component may be substituted at any carbon atom except the oc-carbon atom by one ortwo hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms, which comprises esterifying a carboxylic acid of general formula Xll
(wherein R1 to R3 and A are as defined in claim 1), ora reactive derivative thereof optionally prepared in the reaction mixture, with an alcohol of general formula XIII HO -- Rg (oil) wherein Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at the carbon atom by one ortwo hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms.
91. A process as claimed in claim 90, wherein the reactive derivative ofthe compound of general formula XII, if present, is a halide, anhydride or imidazolidethereof.
92. A process as claimed in claim 90 or claim 91 wherein the esterification is effected in the presence of a solvent.
93. A process as claimed in claim 92 wherein the solvent is an excess of the alcohol of general formula XIII.
94. A process as claimed in any one of claims 90 to 93 wherein the esterification is effected in the presence of a reaction accelerator.
96. A process as claimed in any one of claims 90 to 95 wherein the esterification is effected in the presence of an inorganic ortertiary organic base.
97. A process as claimed in any one of claims 90 to 96 wherein the esterification is effected at tempera turesoffrom -20 to 100 C.
98. A process as claimed in any one of claims 90 to 97, wherein the esterification is effected in the presence of a solvent and at temperatures of from - 1 00Cto the boiling temperature of the solvent.
99. A processforthe preparation of compounds as claimed in claim 1 wherein W represents an alkoxy-carbonyl, afkoxycarbonylmethyl,2 - alkoxy carbonylethyl or 2 - a Ikoxyca rbonylethenyl group and A represents a group offormula
wherein R4" represents R4as hereinbefore defined with the exception of a cyano group,which comprises alcoholysing a compound ofgeneratformulaXlV
wherein R4" represents R4as defined in claim 1 with the exception of a cyano group, R1 to Rs are defined as in claim 1 and W"' represents a cyano, cyanomethyl, 2cyanoethyl or2-cyanoethyenyl group.
100. A process as claimed in claim 99, wherein the alcoholysis is effected in the presence of an acid.
101. A process as caimed in claim 100wherein the acid is hydrochloric or sulphuric acid.
102. A process as claimed in any one of claims 99 to 101, wherein the alcoholysis is effected in the presence of a solvent.
103. A process as claimed in claim 102 wherein the solvent is an excess ofthe alcohol used in the alcoholysis reaction.
104. A process as claimed in any one of claims 99 to 103, wherein the reaction is effected in the presence of a solvent and attemperatures of from 20into the boiling temperature ofthe solvent.
105. A process as claimed in any one of claims 99 to 104, wherein the reaction is effected at temperatures of between 50 and 1 OO"C.
106. A process as claimed in any one of claims 41 to 105 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 hydroxy methyl group.
1107. A process as claimed in any one of claims 41 to 106, wherein a compound of general formula I, initially obtained wherein W represents a carboxy group is subsequently converted by conversion into a sulphonic acid hydrazide and subsequent dispropor tionation into a corresponding compound of general formual I wherein W represents a formyl group.
108. A process as claimed in any one of claims 41 to 107, wherein a compound of general formula I, intially obtained wherein W represents a formyl group is subsequently converted by condensation and optional subsequent hydrolysis and/ordecarboxylation into a corresponding compound of general formula I wherein W represents a 2 - alkoxycar bonyl - ethenyl or a 2 - carboxy - ethenyl group.
109. Aprocessasclaimed in anyoneof claims41 to 108, 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.
110. A process as claimed in any one of claims 41 to 109, wherein a compound of general formula I initially obtained wherein W represents an alkoxycarbonyl group substituted at any carbon atom exceptthe carbon atom by a hydroxy group is subsequently converted by acylation by means of a pyridine-carboxylic acid into a corresponding (pyridine - carbonyloxyalkoxy) - carbonyl compound of general formula I.
111. A process as claimed in any one of claims 41 to 110,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 converted by reaction with a malonic acid diester into a corresponding compound of general formula I wherein W represents an ethyl group substituted by two alkoxycarbonyl groups.
112. A process as claimed in any one of claims 41 to 111, 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 corresponding compound of general formula I wherein W represents an ethyl group substituted bytwo carboxy groups.
113. A process as claimed in any one of claims 41 to 112,wherein a compound of general tormula I initially obtained wherein W represents an ethyl group substituted by two alkoxycarbonyl groups is subsequently converted by hydrolysis and decarboxylation into a corresponding compound of general formula I wherein W represents a 2-carboxyethyl group.
114. A process as claimed in any one of claims 41 to 113,wherein a compound of general formula I initially obtained wherein R2 represents a nitro group is subsequently converted by reduction into a corresponding compound of general formula I wherein R2 represents an amino group.
115. A process as claimed in any one of claims 41 to 114, 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.
116. A process as claimed in any one of claims 41 to 115, wherein a compound of general formula I initially obtained wherein R2 represents a hydroxy group is subsequently converted by alkylation into a corresponding compound of general formula I wherein R2 represents an alkoxy group.
117. A process as claimed in any one of claims 41 to 1 16, 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 buy a hydroxy group.
118. A process as claimed in any one of claims 41 to 117, wherein a compound of general formula I initially obtained wherein R4 represents an aminocarbonylgroup is subsequently converted by dehydration into a corresponding compound of general formula I wherein Ra represents a cyano group.
119. A process as claimed in any one of claims 41 to 118 wherein a compound of general formula I initially obtained is subsequently resolved, by chromatography on a chiral phase, into the enantiomers thereof, if it contains a chiral centre.
120. A process as claimed in any one of claims 41 to 119, wherein a compound of general formula I ora tautomeroroptical enantiomerthereof, initially obtained, is subsequently converted to a salt thereof, ora salts a compound of general formula I ora tautomer or optical enantiomerthereof, initially obtained, is subsequently converted to a compound of general formula I or a tautomer or optical enantiomerthereof.
121. A process as claimed in any one of claims 41 to 120 for the preparation of compounds as claimed in claim 34.
122. A process as claimed in any one of claims 41 to 120 for the preparation of compounds as claimed in claim 35.
123. A process as claimed in any one of claims 41 to 122 substantially as herein described.
124. A process as claimed in any one of claims 41 to 123 substantially as herein described in any of Examples 1 to 51.
125. A process as claimed in claim 121 substan tiallyas herein described in any of Examples 1 to 14.
126. A process as claimed in claim 122substan- tally as herein described in any of Examples 22,27, 38,48and49.
127. Compoundsofgeneralformula las defined in claim 1 and tautomers and optical enantiomers thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in any one of claims 41 to 120,123 and 124.
128. Compounds of general formula las defined in claim 34 and tautomers and optical enantiomers thereof, and salts of the afore-mentioned compounds, when prepared buy a process as claimed in claim 121 orclaim 125.
129. Compounds of general formula las defined in claim 35 and tautomers and optical enantiomers thereof, and salts ofthe afore-mentioned com pounds,when prepared bya process as claimed in claim 122 or claim 126.
130. Pharmaceutical compositions comprising, an active ingredient, at least one compound of general formula I as defined in claim 1 or a tautomer or optical enantiomerthereof, ora physiologically compatible salt of these compounds, in association with at least one pharmaceutical carrierorexcipient.
131. Compositions as claimed in claim 130 containing at least one additional active ingredient.
132. Compositionsasclaimed in claim 130 or claim 131 in a form suitable for oral or parenteral administration.
133. Compounds as claimed in any one of claims 130 to 132 in the form oftablets, coated tablets, capsules, powders or suspensions.
134. Compositions as claimed in anyone of claims 130 to 133 in the form of dosage units.
135. Compositions as claimed in claim 130 wherein the active ingredient comprises a compound as claimed in claim 34 or claim 35.
136. Pharmaceutical compositions as claimed in claim 130 substantially as herein described.
137. Pharmaceutical compositions as claimed in claim 130 having hypoglycaemic activity.
138. Pharmaceutical compositions substantially as herein described in any one of Examples Ato D.
139. A method oftreatment of patients suffering from, orsusceptibleto, diabetes mellitus or disorders ofthe intermediate metabolism or the cardiac circulatorysystem,which comprises administering to the said patient an effective amount of a compound of general formula las defined in claim 1 ora tautomer ora physiologically compatible salt thereof.
140. Each and every novel method, process, compound or composition herein disclosed.
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EP0058779A2 (en) * 1981-01-10 1982-09-01 Dr. Karl Thomae GmbH Carboxamides, their preparation and their use as medicines

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6143769A (en) * 1983-12-30 2000-11-07 Karl Thomae Gmbh Phenylacetic acid benzylamides
USRE37035E1 (en) 1983-12-30 2001-01-30 Boehringer Ingelheim Kg Phenylacetic acid benzylamides
US5223498A (en) * 1989-02-16 1993-06-29 The Boots Company Plc Phenylamidine and phenylguanidine derivatives and their use as antidiabetic agents
WO2004108673A2 (en) * 2003-06-09 2004-12-16 Boehringer Ingelheim International Gmbh Inhibitors of papilloma virus
WO2004108673A3 (en) * 2003-06-09 2005-01-27 Boehringer Ingelheim Int Inhibitors of papilloma virus
US7582766B2 (en) 2003-06-09 2009-09-01 Boehringer Ingelheim International Gmbh Inhibitors of papilloma virus

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ES8501382A1 (en) 1984-11-16
PL143992B1 (en) 1988-04-30
ES8500923A1 (en) 1984-11-01
GB2124220B (en) 1985-11-13
DK310883D0 (en) 1983-07-05
FI832374L (en) 1984-01-07
FI78477C (en) 1989-08-10
ES523869A0 (en) 1984-11-16
CA1214773A (en) 1986-12-02
IL69172A0 (en) 1983-11-30
PL242873A1 (en) 1984-09-10
FI832374A0 (en) 1983-06-29
GB8318250D0 (en) 1983-08-10
KR900004925B1 (en) 1990-07-12
SU1170969A3 (en) 1985-07-30
EP0099017A3 (en) 1984-02-22
ES529808A0 (en) 1984-11-01
IE56171B1 (en) 1991-05-08
AU1657683A (en) 1984-01-12
NO159590C (en) 1989-01-18
CS240970B2 (en) 1986-03-13
HU195651B (en) 1988-06-28
KR840005438A (en) 1984-11-12
GR78661B (en) 1984-09-27
FI78477B (en) 1989-04-28
ES8500924A1 (en) 1984-11-01
PT76986A (en) 1983-08-01
NO832430L (en) 1984-01-09
DK159850C (en) 1991-05-06
DD210907A5 (en) 1984-06-27
DE3375783D1 (en) 1988-04-07
IE831573L (en) 1984-01-06
AU561274B2 (en) 1987-05-07
EP0099017A2 (en) 1984-01-25
EP0099017B1 (en) 1988-03-02
ES529807A0 (en) 1984-11-01
ES529806A0 (en) 1984-11-01
YU146883A (en) 1986-04-30
DK310883A (en) 1984-01-07
IL69172A (en) 1987-10-20
NZ204814A (en) 1986-10-08
NO159590B (en) 1988-10-10
ES8500742A1 (en) 1984-11-01
PT76986B (en) 1986-04-11
DK159850B (en) 1990-12-17

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