NZ204814A - Phenylacetic acid derivatives and pharmaceutical compositions - Google Patents

Phenylacetic acid derivatives and pharmaceutical compositions

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Publication number
NZ204814A
NZ204814A NZ204814A NZ20481483A NZ204814A NZ 204814 A NZ204814 A NZ 204814A NZ 204814 A NZ204814 A NZ 204814A NZ 20481483 A NZ20481483 A NZ 20481483A NZ 204814 A NZ204814 A NZ 204814A
Authority
NZ
New Zealand
Prior art keywords
group
carbon atoms
phenyl
piperidino
alkyl
Prior art date
Application number
NZ204814A
Inventor
W Grell
R Hurnaus
G Griss
R Sauter
E Rupprecht
J Kahling
B Eisele
Original Assignee
Thomae Gmbh Dr K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19823225188 external-priority patent/DE3225188A1/en
Priority claimed from DE19823225155 external-priority patent/DE3225155A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of NZ204814A publication Critical patent/NZ204814A/en

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Classifications

    • 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

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £04814 <br><br> 2 04814 <br><br> Priority Date(s): £ £.. £ .7.". £ ^ ... <br><br> Complete Specification Filed: £*. 7.". £ f. <br><br> Class: 9.9.7. ?.%[£P.. SiOSAf.Zjk'+ <br><br> D..u ' 18 OCt 1986 <br><br> Publication Date: ...... <br><br> P.O. Journal, No: . .../.It.*. <br><br> • ••••••••••••a <br><br> NO DRAWING <br><br> Patents Form No. 5 <br><br> NEW ZEALAND <br><br> PATENTS ACT 1953 <br><br> COMPLETE SPECIFICATION "CHEMICAL COMPOUNDS" <br><br> I7WE DR. KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a Body Corporate organised under the laws of the Federal Republic of Germany of Biberach an der Riss, Federal Republic of Germany hereby declare the invention, for which T/we pray that a patent may be granted to me^us, and the method by which it is to be performed, to be particularly described in and by the following statement <br><br> _1_ (followed by page 1-A.&gt; <br><br> - la- <br><br> 304814 <br><br> 16G141-319 <br><br> Chemical Compounds The present invention relates to new phenylacetic acid derivatives, to processes for their preparation, and to their effects on intermediate metabolism and 5 the cardiac circulatory system. <br><br> According to one feature of the present invention, . we provide compounds of general formula I <br><br> R. <br><br> A - NH - CO - CH <br><br> [where in <br><br> A represents a group of formula <br><br> 10 <br><br> - CH - <br><br> R5 /R6 <br><br> ^C <br><br> or <br><br> - C - <br><br> 15 <br><br> 20 <br><br> -5 MAR 1986 <br><br> [wherein represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkyl group containing 4 to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene moiety; an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety (the substituents in the case of disubstitution being the same or different); an aryl group containing <br><br> 204314 <br><br> - 2 - <br><br> 6 or 10 carbon atoms mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl and/or alkylsulphonyl groups, the substituents in the case of disubstitution being the same or different and each alkyl moiety containing 1 to 3 carbon atoms; or a heteroaryl group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms; or represents a methyl group when, simultaneously, R-^ represents a piperidino group, R2 represents a fluorine atom in the 4-position of the aromatic nucleus, R^ represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); <br><br> or <br><br> R^ represents a phenyl group when R^ represents a piperidino group substituted in the 2- or 3-position by a methyl group, <br><br> or when R£ represents a chlorine atom in the 3-, 20 4- or 6-position, or a methyl group in the 4- or 6-position, of the aromatic nucleus, <br><br> or when W represents a formyl, carboxyvinylene or alkoxycarbonylvinylene group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); <br><br> 6 ' <br><br> 10 <br><br> 15 <br><br> 25 R^ and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety]; <br><br> 30 <br><br> R^ represents an unbranched alkyleneimino group containing 4 to 9 carbon atoms optionally mono- or disubstituted by alkyl groups containing 1 to 3 carbon aXS optioruiUu atoms (which in the case of disubstitution jmjhy be&gt; <br><br> the same or different); or a dialkylamino group containing i-P E \ * <br><br> 304814 <br><br> - 3 - <br><br> 1 to 5 carbon atoms in each alkyl component; <br><br> 1*2 represents a hydrogen, fluorine, chlorine, <br><br> bromine or iodine atom, or a hydroxy, trifluoromethyl, <br><br> 5 nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, <br><br> alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyloxy, <br><br> alkanoylamino, alkylamino or dialkylamino group wherein outruns the alkyl component fm^y contain/ 1 to 3 carbon atoms in each case; <br><br> 10 <br><br> represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom; and <br><br> W represents a carboxy group or an alkoxycarbonyl <br><br> 15 group containing a total of 2 to 6 carbon atoms (wherein is the alkyl component knjky) optionally feef substituted by a phenyl group and optionally, at any carbon atom except the a-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino 20 or pyridinecarbonyloxy group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms; <br><br> an alkyl group containing 1 to 3 carbon atoms; or 25 a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxy-methyl, 2-carboxyethyl, 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 30 from 1 to 3 carbon atoms)] <br><br> and tautomers thereof and optical enantiomers theeof and salts of the aforementioned compounds. <br><br> It will be appreciated that the term "salts" 35 jas used herein includes within its scope salts formed <br><br> with organic and inorganic acids and bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, <br><br> succinic, maleic or fumaric acid. Suitable bases include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine. <br><br> For pharmaceutical use, the salts referred to above will, of course, be physiologically compatible salts, but other salts may find use, for example in the preparation of the compounds of general formula I and their physiologically compatible salts. <br><br> The term "tautomer" as used herein refers particularly to the tautomeric ketimine form of the compounds of general formula I wherein A represents a substituted vinylidene radical, but the term is not restricted to this interpretation and covers all possible tautomeric forms of the compounds of general formula I. <br><br> The definitions given hereinbefore for the groups to Rg and W include the following, for example: <br><br> R^ 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-isopropyl-amino, N-ethyl-n-pentylamino, N-propyl-n-butylamino, pyrrolidino, piperidino, hexamethyleneimino, hepta-methyleneimino, octamethyleneimino, nonamethyleneimino, methyl-pyrrolidino, dimethyl-pyrrolidino, ethyl-pyrrol-idino, methyl-piperidino, ethyl-piperidino, dimethyl-piperidino, diethyl-piperidino, methyl-ethylpiperidino, n-propyl-piperidino, methyl-n-propylpiperidino, isopropyl-piperidino, or di-n-propyl-piperidino group, <br><br> 204 SI 4 <br><br> io <br><br> - 5 - <br><br> R2 may represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, piperidino, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, methylsulphinyl, ethylsulphinyl, methylsulphonyl, n-propylsulphonyl, benzyloxy, 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, <br><br> 15 <br><br> may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl or isopropyl group, <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> R^ may represent a methyl, n-propyl, n-butyl, <br><br> n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 2-methoxyethyl, 2-ethoxy-ethyl, 3-methoxy-propyl, benzyl, 1-phenylethyl, <br><br> 2-phenylethyl, 1-phenyl-n-propyl, 2-phenyl-n-propyl, <br><br> 3-phenylpropyl, allyl, 3-buten-l-yl, 2-buten-l-yl, <br><br> 4-penten-l-yl, cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylamino-carbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, benzylaminocarbonyl, 2-phenyl-ethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethylene-iminocarbonyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxyphenyl, 2-phenyl-ethoxy-phenyl, 3-phenylpropoxy-phenyl, methylsulphenyl-phenyl, ethylsulphenyl-phenyl, methylsulphinyl-phenyl, n-propylsulphinyl-phenyl, methylsulphonyl-phenyl, ethylsulphonyl-phenyl, isopropyl-sulphonyl-phenyl, methyl-naphthyl, hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl, <br><br> 204814 <br><br> - 6 - <br><br> dimethyl-phenyl, di-isopropyl-phenyl, chloro-methyl-phenyl, dimethoxy-phenyl, methyl-methoxyphenyl, chloro-methoxy-phenyl, bromo-methoxy-phenyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl or quinazolyl group, <br><br> 5 R^ and Rg may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl or n-pentyl group, <br><br> R^ and Rg together with the carbon atoms between them may represent a benzylidene, 1-phenyl-ethylidene, 10 2-phenyl-ethylidene, 1-phenyl-n-propylidene, 1-phenyl-2,2-propylidene or 3-phenyl-n-propylidene group and <br><br> W may represent a hydroxymethyl, formyl, carboxy, carboxymethyl, 2-carboxy-ethyl, 2-carboxy-ethenyl, 2,2-bis-(carboxy)-ethyl, methoxycarbonyl, ethoxycarbonyl, 15 n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, (2-hydroxyethoxy)carbonyl, (2-hydroxy-n-propoxy)carbonyl, (l-hydroxy-2-propoxy)carbonyl, (2-methoxyethoxy)carbonyl, (2-ethoxyethoxy)carbonyl, 20 (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, (2-piperidino-ethoxy)carbonyl, methyl, ethyl, n-propyl, isopropyl, 25 cyano, aminocarbonyl, methoxycarbonyl-methyl, ethoxy-carbonyl-methyl, n-propoxycarbonyl-methyl, 2-methoxy-carbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxy-carbonyl-ethyl, 2-methoxycarbonyl-ethenyl, 2-ethoxy-carbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl, 2,2-30 bis-(methoxycarbonyl)-ethyi, 2,2-bis-(ethoxycarbonyl)-ethyl or 2,2-bis-(isopropoxycarbonyl)-ethyl group. <br><br> Preferred compounds of general formula I above are those wherein <br><br> 204814 <br><br> 7 <br><br> A represents a group of formula <br><br> R <br><br> 5 <br><br> R <br><br> 6 <br><br> R <br><br> C <br><br> 4 <br><br> II <br><br> \ <br><br> 5 <br><br> CH <br><br> or <br><br> C <br><br> wherein R4 represents an alkyl group containing 1 <br><br> to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; <br><br> an n-propyl group; an alkyl group containing 4 to <br><br> 10 6 carbon atoms; an alkenyl group containing 3 to <br><br> 5 carbon atoms; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atoms mono- <br><br> or disubstituted by halogen atoms, or by alkyl, hydroxy, <br><br> alkoxy, phenylalkoxy and/or alkylsulphenyl groups, <br><br> aft opcfoTuaUy <br><br> 15 whilst the substituents imtay bcH the same or different and each alkyl component pnay^oontairu from 1 to 3 carbon atoms; or a naphthyl, pyridyl, quinolyl or isoquinolyl group; <br><br> R5 and Rg together with the carbon atom between 20 them represent an alkylidene group containing 3 to <br><br> 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety; <br><br> R^ represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group 25 mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms; <br><br> Rj represents a hydrogen, fluorine, chlorine or bromine atom or a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms, or 30,.., (if R^ and Rg 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 <br><br> 204814 <br><br> - 8 - <br><br> 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 amino-carbonyl group) R2 may also represent an iodine atom 5 or a hydroxy or amino group; n <br><br> Rj represents a hydrogen or chlorine atom; <br><br> and <br><br> W represents a methyl, hydroxymethyl, formyl, <br><br> cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-10 carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl tS OftfoAflJlM <br><br> component ftnjay bof substituted at any carbon atom except the a-carbon atom by 1 or 2 hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms or 15 by a pyridinecarbonyloxy group; or an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl- <br><br> COH talks ethenyl group, wherein each alkoxy group pnojy contain} <br><br> from 1 to 3 carbon atoms and <br><br> 4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-20 methyl]-benzoic acid and alkyl esters thereof, <br><br> 4-[N-(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl]-cinnamic acid and alkyl esters thereof, <br><br> 4-[N-(4-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof, <br><br> 25 4-[N-(3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof, <br><br> 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and C^_.j alkyl esters thereof, <br><br> 4-[N-(4-methyl-a-pheny1-2-piperidino-benzyl)-aminocarbony1- <br><br> 30 <br><br> 204814 <br><br> - 9 - <br><br> methyl]-benzoic acid and alkyl esters thereof, <br><br> 4-[N-(2-(2-methyl-piperidino)-a-phenyl-benzyl)-aminocarbonylmethyl] -benzoic acid and C^_^ alkyl esters thereof, <br><br> 5 4-[N-(2-(3-methyl-piper idino)-a-phenyl-benzyl)-amino-carbonyl-methyl]-benzoic acid and C^_^ alkyl esters thereof, <br><br> 4-[N-(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethy1]-benzaldehyde, and <br><br> 10 4-[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl] -benzoic acid and C-^^ alkyl esters thereof. <br><br> Particularly preferred are those compounds of general formula I wherein <br><br> A represents a group of formula <br><br> 15 <br><br> R, <br><br> RR Rfi <br><br> - CH - <br><br> or <br><br> - C - <br><br> wherein R^ represents an alkyl group containing 1 20 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano or aminocarbonyl group; an alkyl group containing 4 to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms; a phenyl group substituted by a fluorine, chlorine or bromine 25 atom or by a methyl, hydroxy, methoxy, benzyloxy or methylsulphenyl group; or a pyridyl group; <br><br> R^ and Rg together with the carbon atom between fhem represent an alkylidene group containing 3 to carbon atoms or a phenylalkylidene group containing <br><br> \\A <br><br> P E l <br><br> 204814 <br><br> - 10 - <br><br> 1 to 3 carbon atoms in the alkylidene moiety^j represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by methyl groups^ y <br><br> 5 R2 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group; or (if Rg and Rg are as hereinbefore defined or R^ represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, nitrile <br><br> 10 or aminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or an alkenyl group containing optionally icfrfte^cs <br><br> 3 to 5 carbon atoms) R2 fiffayi also jrjbproGontj an iodine atom or a hydroxy or amino group^- <br><br> R^ represents a hydrogen or chlorine atom; <br><br> 15 and <br><br> W represents a methyl, hydroxymethyl, formyl, <br><br> 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 ii ck&gt;cioi\cilUj <br><br> 20 the alkyl component yifay bo} substituted at any carbon atom except the a-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 alkoxy-carbony1-methy1, 2-alkoxycarbonyl-ethyl or 2-alkoxy- <br><br> 25 carbony1-ethenyl group, wherein each alkoxy group eontaiA.S <br><br> oontoinl from 1 to 3 carbon atoms; and <br><br> 4-[N-(6-chloro-a-phenyl-2-piper idino-benzyl)-amino carbonyl-methyl]-benzoic acid and alkyl esters thereof, <br><br> 30 4-[N-(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl]-cinnamic acid and C^-3 alkyl esters thereof, <br><br> 204814 <br><br> 11 - <br><br> 4-[N-(4-chloro-a-phenyl-2-piperidino-benzyl)-amino-carbony 1-methyl]-benzoic acid and C-L_^ alkyl esters thereof, <br><br> 4-[N-(3-chloro-a-phenyl-2-piperidino-benzyl)-amino-5 carbonyl-methyl]-benzoic acid and C1_^ alkyl esters thereof, <br><br> 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-amino-carbony1-methyl]-benzoic acid and C^_3 alkyl esters thereof, <br><br> 10 4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-amino-carbonyl-methyl]-benzoic acid and alkyl esters thereof, <br><br> 4-[N-(2-(2-methyl-piperidino)-a-phenyl-benzyl)-amino-carbonyl-methyl]-benzoic acid and C-^-j alkyl esters 15 thereof, <br><br> 4-[N-(2-(3-methyl-piperidino)-a-phenyl-benzyl)-amino-carbonyl-methyl]-benzoic acid and alkyl esters thereof, <br><br> 4-[N-(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl]-20 benzaldehyde, and <br><br> 4-[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbon-yl-methyl]-benzoic acid and alkyl esters thereof. <br><br> 25 <br><br> 5MAR1986r c ! ^ <br><br> However, another group of preferred compounds are those wherein A, R^ to R^ and W are as hereinbefore defined, more particularly those wherein W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl it component /i^ay be/ substituted at any carbon atom except the a-carbon by one or two hydroxy groups, and optically <br><br> 204814 <br><br> - 12 - <br><br> active enantiomers and the salts thereof. <br><br> Particularly preferred compounds of general formula I above are those wherein <br><br> A represents a group of formula <br><br> R, <br><br> rr Rfi <br><br> - CH - <br><br> or <br><br> - C - <br><br> wherein represents an n-propyl group, an alkyl 10 group containing 4 or 5 carbon atoms, a phenyl group substituted by a methyl group or by a fluorine or chlorine atom, or a pyridyl group, <br><br> Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 15 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part; <br><br> R^ represents a piperidino group optionally substituted by one or two methyl groups; <br><br> R2 represents a hydrogen, fluorine or chlorine 20 atom or a methyl or methoxy group; <br><br> R^ represents a hydrogen atom and <br><br> W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms; particularly those wherein 25 A represents a group of formula <br><br> I4 <br><br> - CH - <br><br> R^ <br><br> II <br><br> or <br><br> - C - <br><br> 30 <br><br> wherein R^ represents an n-propyl group or an alkyl group containing 4 or 5 carbon atoms and Rc and R, <br><br> o o together with the carbon atom between them represent an alkylidene group containing 3 to 5 carbon atoms <br><br> 204814 <br><br> - 13 - <br><br> or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part, and optically active enantiomers and salts thereof. <br><br> The compounds of general formula I as hereinbefore 5 defined and their optical enantiomers and salts thereof may, for example, be prepared by the following processes, which processes constitute further features of the present invention: <br><br> a) Reacting a compound of general formula II <br><br> A ~ NH; <br><br> 10 <br><br> R <br><br> (II) <br><br> (wherein A, R^ 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) 15 with a compound of general formula III <br><br> HO - CO - <br><br> (III) <br><br> (wherein R^ is as hereinbefore defined and <br><br> W* has the meanings given for W hereinbefore or represents a carboxy group protected by a protecting 20 group), or with a reactive derivative thereof optionally <br><br> 204814 <br><br> - 14 - <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> formed in the reaction mixture and, if necessary, subsequently cleaving any protecting group used. <br><br> The reactive derivatives of a compound of general formula III may be, for example, the esters thereof, <br><br> such as the methyl, ethyl or benzyl esters, the thio-esters thereof such as the methylthio- or ethylthio-esters, the halides thereof such as the acid chloride, or the anhydrides or imidazolides thereof. <br><br> The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, <br><br> carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an agent which activates the acid or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexyl-carbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyldi-imidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of between -25 and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. The reaction may also be carried out without a solvent 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. <br><br> If necessary, the subsequent cleaving of a protecting group is preferably effected by hydrolysis, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic <br><br> 204814 <br><br> 15 <br><br> 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. <br><br> A tert.butyl group used as the protecting group may also be cleaved thermally, possibly in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid. <br><br> 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, <br><br> ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide. <br><br> b) In order to prepare a compound of general formula I wherein W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group: <br><br> subjecting a compound of general formula IV <br><br> R <br><br> 2 <br><br> A - NH - CO - CH <br><br> 2 <br><br> R <br><br> (IV) <br><br> 1 <br><br> R <br><br> 3 <br><br> (wherein to R^ and A are as hereinbefore defined, <br><br> and <br><br> 204814 <br><br> - 16 - <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> B represents a group which can be converted by hydrolysis, thermolysis or hydrogenolysis into a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group) to hydrolysis, thermolysis or hydrogenolysis . <br><br> The hydrolysable groups in the compounds of general formula IV may be, for example, functional derivatives of carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl groups such as the unsubstituted or substituted amides thereof, the nitriles, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides thereof, a malonic ester-(l)-yl group, the tetrazolyl group, an optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group, and the thermolytically cleavable groups may be, for example, esters with tertiary alcohols, e.g. the tert.butyl ester, <br><br> the hydrogenolytically cleavable groups may be, for example, esters with aralkanols, ie.g. the benzyl ester. <br><br> The hydrolysis is conveniently effected either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan at temperatures of between -10°C and 120°C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture. <br><br> 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. <br><br> 204814 <br><br> - 17 - <br><br> If B in a compound of general formula IV represents the tert.butyloxycarbonyl group, for example, the tert.butyl group may also be cleaved thermally, optionally in an inert solvent such as methylene chloride, 5 chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. 10 at temperatures of between 40°C and 100°C. <br><br> 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/ 15 charcoal in a suitable solvent such as methanol, <br><br> ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide, preferably at temperatures of between 0 and 50°C, e.g. at ambient temperature, and at a hydrogen pressure of from 1 20 to 5 bar. In the hydrogenolysis, other groups may simultaneously be reduced as well (e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group 25 to the corresponding phenylpropionic acid group), <br><br> or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom. <br><br> c) In order to prepare compounds of general formula I wherein A represents a group of formula <br><br> 30 <br><br> V <br><br> - CH - <br><br> wherein 1 has the meanings given hereinbefore for R^, with the exception of an alkenyl group and a <br><br> 5 MAR1986) <br><br> 2048: <br><br> - 18 - <br><br> cyano group: <br><br> Reduction of a compound of general formula V <br><br> D - CO - <br><br> R <br><br> (V) <br><br> wherein and <br><br> Rj^ to R^ and W are as hereinbefore defined <br><br> D represents a group of formula <br><br> 10 <br><br> P 11 <br><br> 4 <br><br> C v or <br><br> V <br><br> V V <br><br> 5^c/6 <br><br> - c <br><br> \ <br><br> N — <br><br> H <br><br> 15 wherein R." has the meanings given hereinbefore for <br><br> 20 <br><br> 25 <br><br> -5 MAR 1986, <br><br> R <br><br> 4, with the exception of a cyano group, and R^' and Rg' together with the carbon atom between them represent an alkylidene group containing 1 to 7 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety. <br><br> Reduction is preferably effected with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or Raney nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethanol/ water, glacial acetic acid, ethyl acetate, dioxan, tetrahydrofuran, dimethylformamide, benzene or benzene/ ethanol at temperatures of between 0 and 100°C, but preferably at temperatures of between 20 and 50°C, and under a hydrogen pressure of 1 to 5 bar. When <br><br> 204314 <br><br> - 19 - <br><br> a suitable chiral hydrogenation catalyst such as a metal ligand complex is used, e.g. a complex of u,u1-dichloro-bis[1,5-cyclooctadiene-rhodium] and (+)- or (-) 0,0-isopropylidene-2,3-dihydroxy-l,4-5 bis(diphenylphosphino)-butane (= DIOP), the addition of hydrogen occurs enantioselectively. Moreover, <br><br> during catalytic hydrogenation, other groups may be reduced at the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxy group 10 to the hydroxy group or a cinnamic acid group to the phenylpropionic acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom. <br><br> d) In order to prepare compounds of general formula 15 I wherein A represents a group of formula <br><br> P n <br><br> 4 <br><br> — CH — <br><br> wherein R^" has the meanings given hereinbefore for R^, with the exception of a cyano group: <br><br> 20 Reacting a compound of general formula VI <br><br> CH - 0H (VI) <br><br> (wherein <br><br> R^" is defined as above and R^ and R2 are as hereinbefore defined) with a compound of general 25 formula VII <br><br> I <br><br> - 20 - <br><br> 204814 <br><br> wherein and W are as hereinbefore defined. The reaction is carried out in the presence of a strong acid which may simultaneously serve as solvent, preferably in concentrated sulphuric acid, at temperatures of between 0 and 150°C, but preferably at temperatures of between 20 and 100°C. <br><br> 10 e) for the preparation of compounds of general formula I, wherein R2 represents a hydrogen atom: dehalogenating a compound of general formula VIII <br><br> Hal <br><br> A - N H - CO - CH <br><br> 15 <br><br> wherein and <br><br> R-^, R^, A and W are as hereinbefore defined <br><br> Hal represents a fluorine, chlorine, bromine or iodine atom. <br><br> The dehalogenation is conveniently effected 20 in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide by means of catalytically activated hydrogen, e.g. with hydrogen <br><br> 10 <br><br> - 21 - <br><br> in the presence of platinum or palladium/charcoal, at temperatures of between 0 and 100°C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 5 bar. During the dehalogenation, other groups may be reduced at the same time, e.g. a benzyloxy group may be reduced to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom. <br><br> f) In order to prepare compounds of general formula I, wherein A represents a group of formula <br><br> R4 <br><br> I <br><br> 15 — CH — <br><br> wherein <br><br> R^ represents an alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disub-20 stituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety: <br><br> Reacting a compound of general formula IX <br><br> COOH <br><br> - NH - CO - CH <br><br> (IX) <br><br> R <br><br> (wherein R. , <br><br> R2 and R^ are as hereinbefore defined and <br><br> W" has the meanings given hereinbefore for <br><br> 204814 <br><br> - 22 - <br><br> W, with the exception of the carboxy group), with an amine of general formula X <br><br> H - R? (X) <br><br> wherein <br><br> 5 represents an alkyleneimino group containing <br><br> 4 to 6 carbon atoms or an amino group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety. <br><br> Amidation is conveniently effected in a solvent 10 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 15 chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyIdiimidazole, N,N"-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an 20 agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine which may simultaneously serve as solvent, at temperatures 25 of between -25 and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. <br><br> 30 <br><br> g) In order to prepare compounds of general formula I wherein A represents a group of formula <br><br> R, <br><br> — CH - <br><br> as hereinbefore defined and W represents a carboxy group: <br><br> 204814 <br><br> - 23 - <br><br> Oxidising a compound of general formula XI R. <br><br> CH - NH - CO - CH. <br><br> to are as hereinbefore defined and wherein <br><br> R] <br><br> 5 E represents a group which can be converted into a carboxy group by oxidation. <br><br> 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 sub-10 stituted or unsubstituted acyl group such as an acetyl, chloroacetyl, propionyl or malonic acid-(l)-yl group or a malonic ester-(l)-yl group. <br><br> The reaction may be carried out with an oxidising agent in a suitable solvent such as water, glacial 15 acetic acid, methylene chloride, dioxan or glycol dimethyl ether at temperatures of between 0 and 100°C, but conveniently at temperatures of between 20 and 50°C. However, the reaction is preferably effected with silver oxide/sodium hydroxide solution, manganese 20 dioxide/acetone or methylene chloride, hydrogen peroxide/ sodium hydroxide solution, bromine or chlorine/sodium or potassium hydroxide solution, chromium trioxide/-pyridine or pyridinium chlorochromate. <br><br> h) In order to prepare compounds of general formula I 25 wherein W represents an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms wherein the alkyl Component may be substituted at any carbon atom except the a-carbon atom by one or two hydroxy groups or <br><br> 204814 <br><br> - 24 - <br><br> by an alkoxy group containing 1 to 3 carbon atoms: <br><br> Esterifying a carboxylic acid of general formula <br><br> XII <br><br> R. <br><br> A - N H - CO - CH, <br><br> // \ <br><br> COOH <br><br> (XII) <br><br> R- <br><br> (wherein to R^ and A are as hereinbefore defined) or a reactive derivative thereof optionally prepared in the reaction mixture, <br><br> with an alcohol of general formula XIII <br><br> HO - <br><br> (XIII) <br><br> 10 <br><br> 15 <br><br> 20 <br><br> wherein <br><br> Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atom except the a-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms. <br><br> Examples of reactive derivatives of a compound of general formula XII include the halides thereof, <br><br> such as the acid chloride, and the anhydrides and imidazolides. <br><br> The reaction is conveniently carried out using the corresponding alcohol as solvent or in a suitable solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, dioxan, benzene or toluene, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of hydrogen chloride, sulphuric acid, ethyl chloroformate, thionyl chloride, carbon tetrachloride/triphenylphosphine, <br><br> 204314 <br><br> - 25 - <br><br> carbonyldiimidazole or N,N1-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 5 base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, or by trans-ester if ication, e.g. with a corresponding carbonic acid diester, at temperatures of between -20 and 100°C, but preferably at temperatures of between 10 -10°C and the boiling temperature of the solvent used. <br><br> i) In order to prepare a compound of general formula I wherein W represents an alkoxycarbonyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-15 ethenyl group and A represents a group of formula p " <br><br> 4 <br><br> — CH- <br><br> where R4" represents R4 as hereinbefore defined with the exception of a cyano group: <br><br> 20 Alcoholysis of a compound of general formula <br><br> XIV <br><br> R, " ' <br><br> 4^ «/ •&gt;.. <br><br> ,\\ <br><br> ■5 MAR 1586 <br><br> wherein <br><br> R4" represents R^ as hereinbefore defined with <br><br> 10 <br><br> 15 <br><br> - 26 - <br><br> the exception of a cyano group and to R^ are as hereinbefore defined and <br><br> W"1 represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethenyl group. <br><br> The alcoholysis is conveniently effected in the presence of a solvent, preferably in an excess of a corresponding alcohol such as, for example, <br><br> methanol, ethanol or propanol, and preferably in the presence of an acid such as hydrochloric or sulphuric acid at temperatures of between 20°C and the boiling temperature of the solvent used, preferably at temperatures of between 50 and 100°C. <br><br> If, according to the invention, a compound of general formula I is initially obtained wherein W represents a carboxy or alkoxycarbonyl group, this may subsequently be converted by reduction into a corresponding compound of general formula I wherein W represents a formyl or hydroxymethyl group, and/or if a compound of general formula I is initially obtained 20 wherein W represents a carboxy group, this may subsequently be converted by conversion into a sulphonic acid hydrazide and subsequent disproportionation into a corresponding compound of general formula I wherein W represents a formyl group, and/or <br><br> 25 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 30 a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-ethenyl group, and/or <br><br> -5 MAR 1986 £ <br><br> 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 <br><br> - 27 - <br><br> 204814 <br><br> converted by catalytic hydrogenation into a corresponding compound of general formula I wherein W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group, <br><br> and/or <br><br> 10 <br><br> if a compound of general formula I is initially obtained wherein W represents an alkoxycarbonyl group substituted at any carbon atom except the a-carbon atom by a hydroxy group, this may subsequently be converted by acylation by means of a pyridine-carboxylic acid into a corresponding (pyridinecarbonyloxyalkoxy)-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-15 methyl compound, subsequently be 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, and/or <br><br> 20 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 25 group substituted by two carboxy groups, and/or <br><br> 30 <br><br> F I <br><br> 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 <br><br> It. <br><br> if-5MARI986£I <br><br> 204814- <br><br> - 28 - <br><br> 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 <br><br> 10 <br><br> 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 alkylsulphenyl group, and/or <br><br> 15 <br><br> if a compound of general formula I is initially obtained wherein R2 represents a hydroxy group, this may subsequently be converted by alkylation into a corresponding compound of general formula I wherein R2 represents an alkoxy group, and/or <br><br> 20 <br><br> if a compound of general formula I is initially obtained wherein R2 represents a benzyloxy group and/or R^ represents an aryl group substituted by a benzyloxy group, this may subsequently be converted by debenzyl-ation into a corresponding compound of general formula I wherein R2 represents a hydroxy group and/or R^ represents an aryl group substituted by a hydroxy group, and/or if a compound of general formula I is initially obtained 25 wherein R^ represents an aminocarbonyl group, this may subsequently be converted by dehydration into a corresponding compound of general formula I wherein R^ represents a cyano group. <br><br> 1 E: <br><br> The subsequent alcoholysis is preferably carried 30 out in a corresponding alcohol such as ethanol, in the presence of an acid such as hydrochloric or sulphuric acid, at temperatures up to the boiling temperature <br><br> 5 MAR 1986) <br><br> 204814 <br><br> - 29 - <br><br> of the solvent used. <br><br> 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 5 such as diethyl ether, tetrahydrofuran or dioxan at temperatures of between 0 and 100°C, but preferably at temperatures of between 20°C and 60°C. <br><br> The subsequent disproportionation of a sulphonic acid hydrazide, which is obtained by reacting a corres-10 ponding hydrazine with a corresponding reactive carboxylic acid derivative, is carried out in the presence of a base such as sodium carbonate in a solvent such as ethyleneglycol at temperatures of between 100°C and 200°C, but preferably at 160 to 170°C. 15 The subsequent condensation of a formyl compound is conveniently carried out in a solvent such as pyridine or tetrahydrofuran with malonic acid, with a malonic acid ester, with a dialkylphosphono-acetic acid ester or an alkoxycarbonylmethylene-triphenyl-20 phosphoran, optionally in the presence of a base as the condensing agent, e.g. in the presence of piperidine, potassium tert.butoxide or sodium hydride, at temperatures of between 0 and 100°C; the desired compound is obtained by subsequent acidification, 25 e.g. with hydrochloric or sulphuric acid, or by subsequent alkaline hydrolysis. <br><br> The subsequent catalytic hydrogenation is conveniently effected in a solvent such as methanol, ethanol, <br><br> ethyl acetate, glacial acetic acid or dimethylformamide 30 with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal at temperatures of between 0 and 75°C, but preferably at ambient temperature and under a hydrogen pressure of 1 to 5 bar. <br><br> 35 The subsequent O-acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, <br><br> - 30 - <br><br> dioxan, benzene, toluene, acetonitrile or dimethyl-formamide, preferably with a reactive derivative of the acid, for example a halide such as the acid chloride, an anhydride or imidazolide and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethyl-amine or pyridine which may simultaneously serve as solvent, at temperatures of between -25°C and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. <br><br> The subsequent conversion of a hydroxymethyl group into a halomethyl group is effected with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and subsequently reacting with a malonic acid ester, <br><br> 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. <br><br> The subsequent hydrolysis or hydrolysis and decarboxylation is conveniently effected in the presence f- <br><br> of an acid such as hydrochloric, sulphuric, phosphoric, polyphosphoric or trifluoroacetic acid in a suitable solvent such as water, ethanol, water/ethanol, water/iso-propanol or water/dioxan at elevated temperatures, <br><br> e.g. at the boiling temperature of the reaction mixture. <br><br> The subsequent reduction of the nitro compound is preferably effected in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, <br><br> with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite or with hydrazine <br><br> 204814 <br><br> - 31 - <br><br> in the presence of Raney nickel at temperatures of between 0 and 50°C, but preferably at ambient temperature . <br><br> The subsequent reaction of a diazonium salt, <br><br> 5 e.g. the fluoroborate, the fluoride in 40% hydrofluoric acid, the hydrosulphate in sulphuric acid or the hydrochloride, if necessary in the presence of copper or a corresponding copper(I)salt such as copper(I)-chloride/hydrochloric acid or copper(I)bromide/hydro-10 bromic acid, is carried out at slightly elevated temperatures, e.g. at temperatures of between 15°C and 100°C; the subsequent reaction with hypophosphorous acid is preferably carried out at -5°C to 0°C. The diazonium salt required is conveniently prepared 15 in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid or dioxan/hydrochloric acid, by diazotising a corresponding amino compound with a nitrite, e.g. <br><br> sodium nitrite or an ester of nitrous acid, at low 20 temperatures, e.g. at temperatures of between -10°C and 5°C. <br><br> The subsequent O-alkylation is conveniently effected with a corresponding halide, sulphonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl-25 sulphate, ethyl bromide, ethyl p-toluenesulphonate, <br><br> isopropylmethanesulphonate or diazomethane, optionally in the presence of a base such as sodium hydride, <br><br> potassium hydroxide or potassium tert.butoxide and preferably in a solvent such as diethyl ether, tetrahydro-30 furan, dioxan, methanol, ethanol, pyridine or dimethyl-formamide at temperatures of between 0 and 75°C, <br><br> preferably at ambient temperature. <br><br> The subsequent debenzylation is conveniently effected in a solvent such as methanol, ethanol, <br><br> 35 ethyl acetate, glacial acetic acid or dimethylformamide using catalytically activated hydrogen, e.g. using <br><br> ^ ^ hydrogen in the presence of platinum or palladium/char- <br><br> I <br><br> 1&gt;, <br><br> 204814 <br><br> 32 <br><br> coal, at temperatures of between 0 and 75°C, but preferably at ambient temperature and at a hydrogen pressure of from 1 to 5 bar. <br><br> The subsequent dehydration is carried out with 5 a dehydrating agent such as phosphorus pentoxide, sulphuric acid or p-toluenesulphonic acid chloride, optionally in a solvent such as methylene chloride or pyridine at temperatures of between 0 and 100°C, preferably at temperatures of between 20° and 80°C. 10 If they have a chiral centre, the compounds of general formula I obtained can also be resolved into their enantiomers by conventional methods. <br><br> This may, for example, be effected by column chromatography on a chiral phase. <br><br> 15 A compound of general formula I or a tautomer thereof, initially obtained, may subsequently be converted into an addition salt thereof, for example by conventional methods such as reacting the compound of general formula I or tautomer thereof as a base 20 with an acid in a suitable solvent, or reacting the compound of general formula I or tautomer thereof as an acid with a base in a suitable solvent. A salt of a compound of general formula I or a tautomer thereof, initially obtained, may subsequently be 25 converted by conventional methods into a different salt or into a compound of general formula I or tautomer thereof. <br><br> The compounds of general formulae II to XIV used as starting materials may be obtained by methods 30 known from the literature or are themselves known from the literature. <br><br> Thus, for example, a compound of general formula II wherein A represents a group of formula <br><br> - 33 - <br><br> 204814 <br><br> - c - <br><br> or the tautomeric ketimine thereof is obtained by reacting a corresponding nitrile with a corresponding Grignard or lithium compound and subsequently hydrolysing or by reacting a corresponding ketone with ammonia <br><br> 10 in the presence of titanium tetrachloride. For further reaction with a compound of general formula III or the reactive derivatives thereof, more particularly the acid chlorides thereof, it is also possible to use the organometallic ketimine complex. <br><br> 15 A compound of general formula II wherein A <br><br> represents a group of formula <br><br> 20 <br><br> 25 <br><br> 30 <br><br> -5 MAR 198^4 <br><br> "D n i <br><br> 4 <br><br> - CH - <br><br> wherein R^"' has the meanings given hereinbefore for R4 with the exception of the 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 or with an ammonium salt in the presence of sodium cyanoboro-hydride, by reduction of a corresponding oxime with <br><br> E , <br><br> 204814 <br><br> 10 <br><br> - 34 - <br><br> 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 ether or tetrahydrofuran at temperatures of between -78°C and the boiling temperature of the solvent used and subsequently cleaving the benzyl or 1-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. <br><br> A compound of general formula II wherein A represents the group <br><br> CN <br><br> 25 <br><br> 15 <br><br> - CH - <br><br> may be obtained by reacting a corresponding aldehyde with ammonium cyanide or by reacting a corresponding 20 cyanohydrin with ammonia. <br><br> An amine of general formula II thus obtained, having a chiral centre, wherein A represents a group of formula <br><br> P " <br><br> 4 <br><br> - CH - <br><br> 30 <br><br> wherein R^" has the meanings given hereinbefore with the exception of the cyano group, may be resolved into the enantiomers by racemate splitting, e.g. by fractional crystallisation of the diastereomeric salts with optically active acids and subsequent decomposition of the salts or by column chromatography on a chiral phase, or by forming diastereomeric compounds <br><br> 204814 <br><br> - 35 - <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> and then separating and splitting them. <br><br> 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 of the 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, 1-phenethyl or acyl group. <br><br> Furthermore, an optically active amine of general formula II may also be prepared by diastereoselective reduction of a corresponding ketimine or hydrazone chirally substituted at the nitrogen atom, by means of complex or non-complex boron or aluminium hydrides wherein, if desired, some of the hydride hydrogen atoms have been replaced by corresponding alkoxide, phenolate or alkyl radicals, or by means of hydrogen in the presence of a suitable hydrogenation catalyst and optional subsequent cleaving of the chiral auxiliary radical by catalytic hydrogenolysis or hydrolysis. <br><br> In addition, an optically active amine of general formula II may also be prepared by diastereoselective addition of a corresponding organometallic compound, preferably a Grignard 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. <br><br> The compounds of general formulae IV, VIII, <br><br> IX, XI, XII and XIV used as starting materials are obtained by reacting a corresponding amine with a corresponding compound of general formula III or the reactive derivatives thereof, with optional subsequent hydrolysis. <br><br> i <br><br> - 36 - <br><br> A compound of general formula V used as starting material is preferably obtained by acylating a corresponding ketimine or the organometallic complex thereof with a corresponding carboxylic acid or the reactive derivatives thereof. <br><br> As already mentioned hereinbefore, the new compounds of general formula I as hereinbefore defined, the tautomers and optical enantiomers thereof and acid and base addition salts of the aforementioned compounds have valuable pharmacological properties, namely an effect on the intermediate metabolism, but particularly the hypoglycaemic effect of lowering blood sugar and, to some extent, an effect on the cardiac circulatory system. <br><br> For example, the following compounds have been examined for their properties as follows; <br><br> A = (Z)— 4—[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid, <br><br> B = ethyl (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl) -aminocarbonylmethyl]-benzoate, <br><br> i <br><br> I <br><br> C = (E)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid, <br><br> D = 4-[ (2-methy 1-1- (2-piper idino-phenyl) ^-1-propen-1-yl)-aminocarbonylmethyl]-benzoic acid, <br><br> E = ethyl (Z)-4-[(1-(2-piperidino-phenyl)-1-hexen-1-yl)-aminocarbonylmethyl]-benzoate, <br><br> F = (Z)-4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propen-1-yl)-aminocarbonylmethyl]-benzoic acid, <br><br> G = (Z)—4—[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid, <br><br> a ©4 $14 <br><br> - 37 - <br><br> H = 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid, <br><br> J = (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid, <br><br> 5 K = (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid, <br><br> L = ethyl (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate, <br><br> M = 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-amino-10 carbonylmethyl]-benzoic acid, <br><br> N = 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonylmethyl] -benzoic acid, <br><br> 0 = 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]-benzoic acid, <br><br> 15 P = 4-[(2-methoxy-l-(2-piperidino-phenylj-1-ethyl)-aminocarbonylmethyl]-benzoic acid, <br><br> Q = 4-[(a-cyano-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid, <br><br> R = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-20 methyl]-benzyl alcohol, <br><br> S = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -phenylacetic acid, <br><br> T = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -cinnamic acid, <br><br> 25 U = 2,3-dihydroxy-propyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate, <br><br> 204814 <br><br> - 38 - <br><br> V = 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid, <br><br> W = 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid, <br><br> 5 AA = 4-[(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, <br><br> AB = 4-[(a-(3-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, <br><br> AC = 4-[(a-(4-fluoro-phenyl)-2-piperidino-benzyl)-10 aminocarbonylmethyl]-benzoic acid, <br><br> AD = 4-[(a-(2-fluoro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, <br><br> AE = 4-[(a-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, <br><br> 15 AF = 4-[(a-(3-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, , <br><br> AG = 4-[(2-piperidino-a-(2-pyridyl)-benzyl)-aminocarbonylmethyl] -benzoic acid, <br><br> AH = 4-[(2-piperidino-a-(4-pyridyl)-benzyl)-amino-20 carbonylmethyl]-benzoic acid, <br><br> AJ = 4-[(6-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid, <br><br> AK = 4-[(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -cinnamic acid, <br><br> 25 AM = 4-[(4-chloro-a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid, <br><br> 204814 <br><br> - 39 - <br><br> AN = 4-[(6-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid, <br><br> AO = 4-[(4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid, <br><br> AP = 4-[(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzaldehyde , <br><br> AQ = 4-[(2-(2-methyl-piperidino)-a-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid, <br><br> 10 <br><br> AR = 4-[(2-(3-methyl-piperidino)-a-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid and <br><br> AS = 4-[(3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid: <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 1. Hypoglycaemic activity <br><br> 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 of the test. The substances to be tested were suspended in 1.5% methylcellulose immediately before the start of the test and administered by oesophageal tube. <br><br> Blood samples were taken immediately before the administration of the substance and then 1, 2, 3 and 4 hours afterwards, in each case from the retro-orbital venous plexus. From each sample, 50 pi were deproteinated with 0.5 ml of 0.33 N perchloric acid and then centrifuged. The glucose in the supernatant phase was determined by the hexokinase method using an analytical photometer. The results were evaluated statistically using the t test according to Student, taking p = 0.05 as the limit of significance. <br><br> The following Table contains the values found in percent, compared with the controls: <br><br> h ii6 6 <br><br> 2048.14 <br><br> - 40 - <br><br> 5 <br><br> 15 <br><br> 20 <br><br> 30 <br><br> p E * / <br><br> 5 MAR 1986rn <br><br> 5 mg/kg <br><br> 1 mg/kg <br><br> Substance <br><br> 1 <br><br> 2 <br><br> 3 <br><br> 4 <br><br> 1 <br><br> 2 <br><br> 3 <br><br> 4 <br><br> A <br><br> -43 <br><br> -40 <br><br> -33 <br><br> -35 <br><br> B <br><br> -44 <br><br> -39 <br><br> -26 <br><br> -35 <br><br> -39 <br><br> -19 <br><br> -26 <br><br> -30 <br><br> C <br><br> -43 <br><br> -43 <br><br> -37 <br><br> -38 <br><br> D <br><br> -36 <br><br> -32 <br><br> -27 <br><br> -25 <br><br> E <br><br> -46 <br><br> -40 <br><br> -38 <br><br> -26 <br><br> -23 <br><br> -23 <br><br> -12 <br><br> -18 <br><br> F <br><br> -43 <br><br> -42 <br><br> -39 <br><br> -32 <br><br> G <br><br> -44 <br><br> -42 <br><br> -37 <br><br> -31 <br><br> H <br><br> -50 <br><br> -46 <br><br> -44 <br><br> -45 <br><br> J <br><br> -44 <br><br> -37 <br><br> -42 <br><br> -42 <br><br> -38 <br><br> -32 <br><br> -34 <br><br> -29 <br><br> K <br><br> -41 <br><br> -43 <br><br> -38 <br><br> -31 <br><br> L <br><br> -42 <br><br> -45 <br><br> -31 <br><br> -22 <br><br> -14 <br><br> -18 <br><br> -14 <br><br> n.s. <br><br> M <br><br> -46 <br><br> -43 <br><br> -40 <br><br> -36 <br><br> -33 <br><br> -30 <br><br> -21 <br><br> n.s. <br><br> N <br><br> -42 <br><br> -42 <br><br> -37 <br><br> -33 <br><br> 0 <br><br> i u&gt; <br><br> 00 + <br><br> -31+ <br><br> + <br><br> n.s. <br><br> + <br><br> n.s. <br><br> P <br><br> -49 <br><br> -43 <br><br> -34 <br><br> -22 <br><br> -37 <br><br> -19 <br><br> n.s. <br><br> n.s. <br><br> Q <br><br> -28 <br><br> -13 <br><br> n.s. <br><br> n.s. <br><br> R <br><br> -38 <br><br> -40 <br><br> -35 <br><br> -29 <br><br> -39 <br><br> -34 <br><br> -29 <br><br> -24 <br><br> S <br><br> -49 <br><br> -42 <br><br> -30 <br><br> -17 <br><br> -29 <br><br> -20 <br><br> -10 <br><br> n.s. <br><br> T <br><br> -48 <br><br> -46 <br><br> -42 <br><br> -40 <br><br> -42 <br><br> -42 <br><br> -40 <br><br> -32 <br><br> U <br><br> -43 <br><br> -43 <br><br> -49 <br><br> -45 <br><br> -39 <br><br> -35 <br><br> -29 <br><br> -24 <br><br> V <br><br> -45 <br><br> -41 <br><br> -46 <br><br> -40 <br><br> -37 <br><br> -23 <br><br> -30 <br><br> -18 <br><br> W <br><br> -46 <br><br> -45 <br><br> -39 <br><br> -37 <br><br> -36 <br><br> -25 <br><br> -16 <br><br> n.s. <br><br> AA <br><br> -30 <br><br> -33 <br><br> -14 <br><br> n.s. <br><br> -15 <br><br> -15 <br><br> -13 <br><br> n.s. <br><br> AB <br><br> -43 <br><br> -38 <br><br> -36 <br><br> -27 <br><br> -26 <br><br> -15 <br><br> n.s. <br><br> n.s. <br><br> AC <br><br> -36 <br><br> -37 <br><br> -36 <br><br> -33 <br><br> AD <br><br> -28 <br><br> -32 <br><br> -27 <br><br> -28 <br><br> -16 <br><br> -20 <br><br> -17 <br><br> -14 <br><br> AE <br><br> -30 <br><br> -28 <br><br> -39 <br><br> -36 <br><br> -21 <br><br> -20 <br><br> -22 <br><br> n.s. <br><br> 20 48 1 4 204814 <br><br> - 41 - <br><br> Substance <br><br> 1 <br><br> 5 mg/kg 2 3 <br><br> 4 <br><br> 1 <br><br> 1 mg/kg 2 3 <br><br> 4 <br><br> AF <br><br> -43 <br><br> -39 <br><br> -30 <br><br> -26 <br><br> -17 <br><br> -19 <br><br> n <br><br> . s. <br><br> n <br><br> . s. <br><br> AG <br><br> -49 + <br><br> -50+ <br><br> -36 + <br><br> -31+ <br><br> -18 <br><br> n.s. <br><br> n <br><br> . s. <br><br> n <br><br> . s. <br><br> AH <br><br> -41 <br><br> -37 <br><br> -20 <br><br> n.s. <br><br> -26 <br><br> -14 <br><br> n <br><br> . s. <br><br> n <br><br> . s. <br><br> AJ <br><br> -44 <br><br> -40 <br><br> -39 <br><br> -40 <br><br> -35 <br><br> -34 <br><br> - <br><br> 28 <br><br> - <br><br> 20 <br><br> AK <br><br> i <br><br> 00 + <br><br> -47+ <br><br> i o + <br><br> -45+ <br><br> -32 <br><br> -19 <br><br> - <br><br> 10 <br><br> - <br><br> 17 <br><br> AM <br><br> -34 <br><br> -35 <br><br> -32 <br><br> -29 <br><br> -11 <br><br> -13 <br><br> n <br><br> . s. <br><br> n <br><br> . s. <br><br> AN <br><br> -39 <br><br> -35 <br><br> -27 <br><br> -26 <br><br> -27 <br><br> -24 <br><br> n <br><br> .s. <br><br> n <br><br> . s. <br><br> AO <br><br> -37 <br><br> -34 <br><br> -32 <br><br> -31 <br><br> -21 <br><br> -17 <br><br> - <br><br> 15 <br><br> - <br><br> 11 <br><br> AP <br><br> -26 <br><br> -28 <br><br> - <br><br> 22 <br><br> - <br><br> 17 <br><br> AQ <br><br> -32 <br><br> -31 <br><br> -24 <br><br> -19 <br><br> -16 <br><br> -11 <br><br> n <br><br> . s. <br><br> n <br><br> . s. <br><br> AR <br><br> -35 <br><br> -30 <br><br> -29 <br><br> -31 <br><br> -13 <br><br> - 9 <br><br> n <br><br> •s • <br><br> n <br><br> . s. <br><br> AS <br><br> -45 <br><br> -44 <br><br> -42 <br><br> -32 <br><br> -21 <br><br> -13 <br><br> n <br><br> . s. <br><br> n <br><br> . s <br><br> + = at 10 mg/kg n.s. = statistically not significant <br><br> 20 2. Acute toxicity <br><br> The toxic effect was tested in male and female mice of the same strain weighing from 20 to 26 g, after oral administration of a single dose (suspended in 1% methylcellulose) over an observation period 25 of 14 days: <br><br> - 42 - <br><br> 204814 <br><br> 10 <br><br> 15 <br><br> Substance <br><br> Approximate acute toxicity <br><br> A <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 6 animals died) <br><br> C <br><br> &gt; <br><br> 2 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 6 animals died) <br><br> D <br><br> 500 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 6 animals died) <br><br> J <br><br> &gt; <br><br> 2 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> AA <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> AB <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> AC <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> AD <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> AE <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> AG <br><br> &gt; <br><br> 1 <br><br> 000 <br><br> mg/kg p.o. <br><br> (0 <br><br> out of <br><br> 10 animals died) <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of diabetes mellitus. <br><br> According to a yet further feature of the present invention, we provide pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula I as hereinbefore defined or a tautomer thereof or a physiologically compatible salt of these compounds, in association with one or more pharmaceutical carriers or excipients. <br><br> For pharmaceutical administration the compounds of general formula I or tautomers thereof or their physiologically compatible salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral or parenteral administration. Preferred forms include, for example, tablets, coated tablets, capsules, powders or suspensions <br><br> The active ingredient may be incorporated in excipients customarily employed in pharmaceutical <br><br> m <br><br> 10 <br><br> 04814 <br><br> - 43 - <br><br> 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. <br><br> Advantageously, the compositions may be formulated as dosage units, each dosage unit being adapted to supply a fixed dose of active ingredient. <br><br> A suitable single dose for adults is 1-50 mg, preferably 2.5-20 mg of active ingredient, once or twice per day. The total daily dosage may, however, be varied according to the compounds used, the subject treated and the complaint concerned. <br><br> -5MAR1986J <br><br> 2048.14 <br><br> The following non-limiting Examples are intended to illustrate the invention: <br><br> Example 1 <br><br> Ethyl 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-5 aminocar bonylmethyl]-benzoate <br><br> 4.7 g (18 mmol) of triphenylphosphine, 3 g (30 mmol) of triethylamine and 1.5 mm (15 mmol) of carbon tetrachloride are added successively to 4.2 g (15 mmol) of a-(4-methyl-phenyl)-2-piperidino-benzylamine 10 and 3.4 g (16.5 mmol) of 4-ethoxycarbonyl-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 15 acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The evaporation residue is triturated 20 with ethanol and suction filtered. <br><br> Yield: 4.55 g (65% of theory), <br><br> M.p.: 177-178°C <br><br> Calculated: C 76.57 H 7.28 N 5.95' <br><br> Found: 76.19 7.16 5.82 <br><br> 25 The following were prepared analogously to <br><br> Example 1: <br><br> Ethyl 4-[N-[ot-(3-methyl-phenyl)-2-piperidino-benzyl] -aminocarbony 1-methyl] -benzoate Yield: 48% of theory, <br><br> M.p.: 159-160°C <br><br> Calculated: C 76.57 H 7.28 N 5.95 Found: 76.80 7.35 5.76 <br><br> Ethyl 4-[N-[a-(2-methyl-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoate Yield: 35.4% of theory, <br><br> M.p.: 196-198°C <br><br> 2 <br><br> Calculated: C 76.57 Found: 76.65 <br><br> - 45 - <br><br> H 7.28 7.35 <br><br> 204814 <br><br> JL <br><br> N 5.95 5.90 <br><br> 10 <br><br> 15 <br><br> (c) Ethyl 4-[N-[a-(4-methoxy-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl]-benzoate <br><br> Yield: 45% of theory, <br><br> M.p.: 167-168 °C <br><br> Calculated: C 74.05 H 7.04 N 5.76 Found: 73.72 6.99 5.62 <br><br> (d) Ethyl 4-[N-[a-(4-benzyloxy-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl]-benzoate <br><br> Yield: 96% of theory, <br><br> M.p.: 154-155°C <br><br> Calculated: C 76.84 6.81 N 4.98 Found: 76.68 6.68 5.03 <br><br> (e) Ethyl 4-[N-[a-(4-fluoro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl]benzoate 20 Yield: 58% of theory, <br><br> M.p.: 174-176°C <br><br> Calculated: C 73.40 H 6.58 N 5.90 Found: 73.55 6.72 5.91 <br><br> 25 (f) <br><br> 30 <br><br> Ethyl 4-[N-[a-(2-fluoro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl]-benzoate Yield: 83% of theory, <br><br> M.p.: 173-175°C <br><br> Calculated: C 73.40 H 6.58 N 5.90 Found: 73.61 6.62 5.85 <br><br> 35 <br><br> (g) Ethyl 4-[N-[a-(4-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate Yield: 57% of theory, <br><br> M.p.: 178-181°C <br><br> Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 Found: 71.10 6.56 5.26 7.11 <br><br> 204814 <br><br> - 46 - <br><br> (h) Ethyl 4-[N-[a-(3-chloro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl]-benzoate Yield: 71% of theory, <br><br> M.p.: 153-156°C 5 Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 <br><br> Found: 70.86 6.26 5.65 7.25 <br><br> (i) Ethyl 4-[N-[a-(2-chloro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoate <br><br> 10 Yield: 66% of theory, <br><br> M.p.: 196-198°C <br><br> Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 Found: 70.90 6.30 5.61 7.10 <br><br> 15 (k) <br><br> 20 <br><br> Ethyl 4-[N-[a-(4-methylmercapto-phenyl)-2-piperidino-benzyl] -ami nocar bony lniethyl] -benzoate Yield: 84% of theory, <br><br> M.p.: 173-175°C <br><br> Calculated: C 71.68 H 6.82 N 5.57 CI 6.38 Found: 71.92 6.97 5.45 6.21 <br><br> 25 <br><br> (1) Ethyl 4-[N-[5-chloro-a-(2-chloro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoate Yield: 92% of theory, <br><br> M.p.: 213-215 °C <br><br> Calculated: C 66.28 H 5.75 N 5.33 CI 13.49 Found: 66.45 5.86 5.25 13.51 <br><br> 30 <br><br> 35 <br><br> (m) Ethyl 4-[N-[2-piperidino-a-(2-pyridyl)-benzyl]-aminocarbonylmethyl]-benzoate Yield: 51% of theory, <br><br> M.p.: 158-159 °C <br><br> Calculated: C 73.50 H 6.83 N 9.18 Found: 73.40 6.95 9.10 <br><br> (n) Ethyl 4-[N-[2-piperidino-a-(3-pyridyl)-benzyl]-aminocarbonylmethyl]-benzoate <br><br> 204814 <br><br> - 47 - <br><br> Yield: 85% of theory, <br><br> M.p.: 172°C <br><br> Calculated: C 73.50 H 6.83 N 9.18 Found: 73.4 2 6.76 9.25 <br><br> 10 <br><br> (o) Ethyl 4-[N-[2-piperidino-a-(4-pyridyl)-benzyl]-aminocarbonylmethyl]-benzoate Yield: 20% of theory, <br><br> M.p.: 150-152°C <br><br> Calculated: C 73.50 H 6.83 N 9.18 Found: 73.61 6.91 9.15 <br><br> (p) Ethyl 4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate 15 Yield: 12% of theory, <br><br> M.p.: Oil <br><br> Calculated: molecular ion peak m/e = 490/492 Found: molecular ion peak m/e = 490/492 <br><br> 20 (q) <br><br> 25 <br><br> Ethyl 4^[N-(4-chloro-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate Yield: 37% of theory, <br><br> M.p.: 148-150 °C <br><br> Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 Found: 70.81 6.25 5.61 7.12 <br><br> 30 <br><br> (r) Ethyl 4-[N- (3-chloro-ot-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate Yield: 74% of theory, <br><br> M.p.: 176-178 °C <br><br> Calculated: C 70.94 H 6.36 N 5.71 CI 7.22 Found: 70.59 6.25 5.68 7.16 <br><br> 35 <br><br> (s) Ethyl 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate Yield: 65% of theory, <br><br> M.p.: Oil <br><br> 1 4a04S14 <br><br> Calculated: molecular ion peak m/e = 470 Found: molecular ion peak m/e = 470 <br><br> 10 <br><br> 15 <br><br> (t) Ethyl 4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoate Yield: 76% of theory, <br><br> M.p.: 133-135°C <br><br> Calculated: C 76.57 H 7.28 N 5.95 Found: 76.51 7.16 5.83 <br><br> (u) Ethyl 4-[N-[5-chloro-2-(2-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoate Yield: 36.5% of theory, <br><br> M.p.: 171-173°C <br><br> Calculated: C 71.24 H 6.58 N 5.54 CI 7.01 Found: 71.45 6.68 5.59 7.20 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> Example 2 <br><br> Ethyl 4-[N-[g-(4-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoate <br><br> A solution of 5 g (22.1 mmol) of 4-ethoxycarbonyl-phenylacetyl chloride in 20 ml of chloroform is added dropwise, whilst cooling with ice, to a solution of 6.02 g (20 mmol) of a-(4-chloro-phenyl)-2-piperidino-benzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform. The mixture is stirred for 2 hours at ambient temperature then added to water and extracted with chloroform. The extracts are dried and concentrated by evaporation. The evaporation residue is chromatographed on silica gel using toluene/ethyl acetate (5:1) as eluant. <br><br> Yield: 5.6 g (57% of theory), <br><br> M.p.: 178-181°C <br><br> Calculated: C 70.94 6.36 N 5.71 CI 7.22 <br><br> Found: 71.09 6.47 5.61 7.10 <br><br> The following was prepared analogously to Example 2: <br><br> - 49 - <br><br> (a) Ethyl 4-[N-[5-chloro-2-(3-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoate Yield: 54% of theory, <br><br> M.p.: 178-180°C <br><br> Calculated: C 71.24 H 6.58 N 5.54 CI 7.01 Found: 70.91 6.64 5.75 7.01 <br><br> Example 3 <br><br> 4-[N-g-(4-methyl-phenyl)-2-piperidino-benzyl]-amino-car bonyl-methyl] -benzoic acid <br><br> 4.4 g (9.35 mmol) of ethyl 4-[N-[a-(4-methyl-phenyl) -2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate are dissolved in 150 ml of ethanol, with heating. Then 20 ml of IN sodium hydroxide solution are added and the mixture is stirred for 3 hours at 50°C. 20 ml of IN hydrocloric acid are then added to the reaction mixture and any excess ethanol is eliminated by evaporation in a rotary evaparator. The remaining aqueous suspension is filtered and the precipitate is thoroughly washed with water. <br><br> It is then recrystallised from acetonitrile. <br><br> Yield: 2.45 g (59.3% of theory) <br><br> M.p.: 226-228°C <br><br> Calculated: C 75.99 H 6.83 N 6.33 <br><br> Found: 75.60 6.75 6.29 <br><br> The following were prepared analogously to Example 3: <br><br> (a) 4-[N-[a-(3-Methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid Yield: 72% of theory, <br><br> M.p.: 202-203°C <br><br> Calculated: C 75.99 H 6.83 N 6.33 Found: 75.64 6.91 6.37 <br><br> 204814 <br><br> - 50 - <br><br> (b) 4— [N— [ot— (2-methyl-phenyl) -2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 42.6% of theory, <br><br> M.p.: 285-290°C 5 Calculated: C 75.99 H 6.83 N 6.33 <br><br> Found: 76.05 6.98 6.25 <br><br> (c) 4-[N-[a-(4-methoxy-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl]-benzoic acid <br><br> 10 Yield: 72.4 of theory, <br><br> M.p.: 228-230°C <br><br> Calculated: C 73.34 H 6.59 N 6.11 Found: 73.22 6.61 6.13 <br><br> 15 <br><br> 20 <br><br> (d) 4-[N-[a-(4-benzyloxy-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]-benzoic acid Yield: 57% of theory, <br><br> M.p.: 219-221°C <br><br> Calculated: C 76.38 6.41 N 5.24 Found: 76.05 6.44 5.24 <br><br> (e) 4-[N-[a-(4-fluoro-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]benzoic acid 25 Yield: 75% of theory, <br><br> M.p.: 238-240°C <br><br> Calculated: C 72.63 H 6.09 N 6.27 Found: 72.98 6.29 6.32 <br><br> 30 (f) <br><br> 35 <br><br> 4-[N-[a-(2-fluoro-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]-benzoic acid Yield: 87% of theory, <br><br> M.p.: 280-283°C <br><br> Calculated: C 72.63 H 6.09 N 6.27 Found: 72.70 6.10 6.37 <br><br> A (g) <br><br> 5 MAR 1986! <br><br> 4-[N-[a-(4-chloro-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]-benzoic acid <br><br> 2048.14 <br><br> - 51 - <br><br> Yield: 89% of theory, M.p.: 241-242°C Calculated: C 70.05 H 5.88 Found: 69.74 6.05 <br><br> N 6.05 6.01 <br><br> CI 7.66 7.64 <br><br> 10 <br><br> (h) 4-[N-[o-(3-chloro-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]-benzoic acid Yield: 53% of theory, <br><br> M.p.: 223-225°C <br><br> Calculated: C 70.05 H 5.88 N 6.05 CI 7.66 Found: 70.28 5.98 5.78 7.84 <br><br> (i) 4-[N-[a-(2-chloro-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]-benzoic acid 15 Yield: 98% of theory, <br><br> M.p.: 303—305°C <br><br> Calculated: C 70.05 H 5.88 N 6.05 CI 7.66 Found: 69.88 6.05 5.87 7.74 <br><br> 20 (k) <br><br> 25 <br><br> 4-[N-[a-(4-methylmercapto-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 84.6% of theory, <br><br> M.p.: 225-227°C <br><br> Calculated: C 70.86 H 6.37 N 5.90 CI 6.75 Found: 70.34 6.37 5.68 6.82 <br><br> 30 <br><br> (1) 4-[N-[5-chloro-a-(2-chloro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 90% of theory, <br><br> M.p.: 317-320°C <br><br> Calculated: C 65.19 H 5.27 N 5.63 CI 14.25 Found: 64.87 5.34 5.69 14.22 <br><br> /v <br><br> 5 MAR 1986 <br><br> (m) 4-[N-[2-piperidino-a-(2-pyridyl)-benzyl]-aminocarbonylmethyl] -benzoic acid Yield: 81% of theory, <br><br> M.p.: 160-161°C <br><br> 4204814 <br><br> Calculated: Found: <br><br> C 72.71 72.43 <br><br> -; 52 - <br><br> H 6.34 6.39 <br><br> N 9.78 10.00 <br><br> 10 <br><br> 15 <br><br> (n) 4-[N-[2-piperidino-a-(3-pyridyl)-benzyl]-aminocarbonylmethyl] -benzoic acid Yield: 72% of theory, <br><br> M.p.: 252-253°C <br><br> Calculated: C 72.71 H 6.34 N 9.78 Found: 72.56 6.53 9.60 <br><br> (o) 4-[N-[2-piperidino-a-(4-pyridyl)-benzyl]-aminocarbonylmethyl] -benzoic acid Yield: 68.5% of theory, <br><br> M.p.: from 260°C (decomposition) <br><br> Calculated: C 72.71 H 6.34 N 9.78 Found: 72.31 6.29 9.63 <br><br> (P) 4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid 20 Yield: 82% of theory, <br><br> M.p.: 91-94°C <br><br> Calculated: C 70.04 H 5.88 N 6.05 CI 7.66 Found: 69.61 5.77 5.96 7.78 <br><br> 25 (q) <br><br> 30 <br><br> 4-[N-(4-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid Yield: 61% of theory, <br><br> M.p.: 221-223°C <br><br> Calculated: C 70.05 H 5.88 N 6.05 CI 7.66 Found: 69.73 5.89 5.87 7.52 <br><br> 35 <br><br> (r) 4-[N-(3-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid Yield: 83% of theory, <br><br> M.p.: 210-213°C <br><br> Calculated: C 70.05 H 5.88 N 6.05 CI 7.66 Found: 70.31 6.03 5.90 7.79 <br><br> I 4.2048.14 <br><br> (s) 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 64% of theory, <br><br> M.p.: 165-170°C (sintering from 150°C) 5 Calculated: C 75.99 H 6.83 N 6.33 <br><br> Found: 75.73 6.96 6.14 <br><br> : (t) 4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-10 aminocarbonylmethyl]-benzoic acid <br><br> Yield: 96% of theory, <br><br> M.p.: 202-203°C <br><br> Calculated: C 75.99 H 6.83 N 6.33 Found: 76.04 6.78 6.23 <br><br> 15 <br><br> (u) 4-[N-[5-chloro-2-(2-methyl-piperidino)-a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 52% of theory, <br><br> M.p.: 280-282°C 20 Calculated: C 70.50 H 6.13 N 5.87 CI 7.43 <br><br> Found: 70.14 6.10 5.75 7.45 <br><br> (v) 4-[N-[5-chloro-2-(3-methyl-piperidino)-a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid 25 Yield: 66% of theory, <br><br> M.p.: 246-248 °C <br><br> Calculated: C 70.50 H 6.13 N 5.87 CI 7.43 Found: 70.16 6.07 5.87 7.30 <br><br> 30 <br><br> 35 <br><br> Example 4 <br><br> 4-[N-[a-(4-hydroxy-phenyl)-2-piperidino-benzyl]-amino-carbonyl-methyl]-benzoic acid <br><br> 1.1 g (2 mmol) of 4-[N-[a-(4-benzyloxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid are suspended in 200 ml of ethanol and catalytically debenzylated at 50°C, under a hydrogen pressure of 5 bar, in the presence of 0.4 g of 10% palladium/charcoal. Then the catalyst is filtered off, and the filtrate i ^ <br><br> - 54 - <br><br> is concentrated by evaporation and recrystallised from acetonitrile. <br><br> Yield: 720 mg (66.7% of theory), M.p.: 202-204°C 5 Calculated: C 72.95 H 6.35 N 6.30 <br><br> Found: 72.65 6.17 6.20 <br><br> - The following was prepared analogously to Example 4: 10 (a) Ethyl 4-[N-(5—hydroxy-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoate Yield: 93% of theory, <br><br> M.p.: 191-193°C <br><br> Calculated: C 73.70 H 6.82 N 5.93 15 Found: 73.52 6.57 5.61 <br><br> Example 5 <br><br> 4-[N-[ot- (4-Methyl-phenyl) -2-piper idino-benzyl] -aminocarbonylmethyl]-benzyl alcohol 20 2.5 g (5.3 mmol) of ethyl 4-[N-[a-(4-methyl- <br><br> phenyl) -2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate are added in batches to a suspension of 0.5 g (13.2 mmol) of lithium aluminium hydride in 50 ml of absolute tetrahydrofuran. The mixture is 25 stirred for a further 30 minutes at ambient temperature, decomposed by the dropwise addition of 4 N sodium hydroxide solution and filtered to remove the sodium aluminate formed. The filtrate is concentrated by evaporation and the residue is recrystallised from 30 a little toluene. <br><br> Yield: 0.98 g (43% of theory) <br><br> M.P. 144-146°C <br><br> Calculated: C 78.47 H 7.53 N 6.54 <br><br> Found: 78.20 7.39 6.58 <br><br> - 55 - <br><br> Example 6 <br><br> 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-amino-carbonyl-methyl]-benzaldehyde <br><br> 8.85 g (20 mmol) of 4-[N-[a-(4-methyl-phenyl)-5 2-piper idino-benzyl]-aminocarbonylmethyl]-benzoic acid and 3.25 g (20 mmol) of N ,N'-carbonyldiimidazole are refluxed in 100 ml of absolute tetrahydrofuran for 2 hours. Then the mixture is concentrated by evaporation and after the addition of 50 ml of pyridine 10 and 3.7 g (20 mmol) of 4-toluenesulphonic acid hydrazide, the mixture is refluxed for a further 2 hours. It is then poured on to ice water and suction filtered and the precipitate is dried. The resulting crude toluenesulphonic acid hydrazide of the carboxylic 15 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 chromatography on silica gel 20 using toluene/ethyl acetate 5:1 as eluant. <br><br> Yield: 1.73 g (21% of theory) <br><br> M.p.: 144-146°C <br><br> Calculated: C 78.84 H 7.09 N 6.57 <br><br> Found: 78.95 7.19 6.50 <br><br> 25 <br><br> The following was prepared analogously to Example 6: <br><br> (a) 4-[N-[a-Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzaldehyde 30 Yield: 29% of theory <br><br> M.p.: 168-170°C <br><br> Calculated: C 78.61 H 6.84 N 6.79 Found: 78.60 7.00 6.72 <br><br> A £ u r <br><br> 5 MAR 1986 <br><br> 35 Example 7 <br><br> 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino-carbonyl-methyl]-benzaldehyde <br><br> 0.5 g (1.2 mmol) of 4-[N-[a-(4-methyl-phenyl)- <br><br> 4814 <br><br> 56 <br><br> 2-piper idino-benzyl]-aminocarbonylmethyl]-benzyl alcohol are added to a suspension of 0.4 g (1.5 mmol) of pyridinium chlorochromate in 2 ml of chloroform. <br><br> After 12 hours at ambient temperature, ether is added, 5 the mixture is filtered and the concentrated filtrate is purified by column chromatography on silica gel (eluant: toluene/ethyl acetate = 5:1). <br><br> Yield: 0.3 g (60% of theory) <br><br> , M.p.: 145-146°C * <br><br> 10 Calculated: C 78.84 H 7.09 N 6.57 <br><br> Found: 78.97 7.12 6.57 <br><br> The following was prepared analogously to Example 7: <br><br> 15 (a) 4-[N-(o-Phenyl-2-piperidino-benzyl)-aminocarbonyl- <br><br> 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 30 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. <br><br> Yield: 0.18 g (36% of theory) <br><br> 35 M.p.: 176-180°C <br><br> Calculated: C 77.39 H 7.31 N 5.64 <br><br> Found: 77.64 7.25 5.71 <br><br> The following was prepared analogously to Example 8: <br><br> 20 <br><br> methyl]-benzaldehyde Yield: 40% of theory M.p.: 170°C <br><br> Calculated C 78.61 H 6.84 N 6.79 Found: 78.59 6.87 6.61 <br><br> Example 8 <br><br> Ethyl 4-[N-[ot- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonyl-methyl]-cinnamate <br><br> 25 <br><br> 427 mg (1 mmol) of 4-[N-[a-(4-methyl-phenyl)- <br><br> 3048.14 <br><br> - 57 - <br><br> (a) Ethyl 4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -cinnamate Yield: 28.6% of theory M.p.: 159-161°C 5 Calculated: C 77.14 H 7.10 N 5.80 <br><br> Found: 77.28 7.21 5.65 <br><br> Example 9 <br><br> 4-[N-[a-(4-Methyl-phenyl)-2-piper idino-benzyl]-amino-10 carbonyl-methyl]-cinnamic acid <br><br> Prepared by alkaline saponification of ethyl 4- [N-[ct- (4-methyl-phenyl) -2-piper idino-benzyl]-amino-carbony1-methyl]-cinnamate analogously to Example 3. <br><br> 15 Yield: 84% of theory M.p.: 173-176°C <br><br> Calculated: C 76.90 H 6.88 N 5.98 <br><br> Found: 77.24 7.01 5.64 <br><br> 20 The following was prepared analogously to Example 9: <br><br> (a) 4-[N- (ct-Phenyl-2-piper idino-benzyl) -aminocarbonylmethyl]-cinnamic acid Yield: 75% of theory 25 M.p.: 177-180°C <br><br> Calculated: C 76.62 H 6.65 N 6.16 <br><br> Found: 76.75 6.57 6.07 <br><br> Example 10 <br><br> 30 Ethyl 4-[N-[a-(3-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate <br><br> A mixture of 0.22 g (0.8 mmol) of a-(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-35 benzene is added dropwise, at ambient temperature, <br><br> to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated f9- ( sulphuric acid. After 2 hours' stirring, the mixture is poured onto ice-water, extracted once with ether, <br><br> V <br><br> " -5MARI986 <br><br> Zl <br><br> 048.14 <br><br> - 58 - <br><br> made alkaline with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is concentrated by evaporation and the residue is recrystallised from ethanol. <br><br> 5 Yield: 0.22 g (60% of theory) <br><br> M.p.: 158-159°C <br><br> Calculated: C 76.57 H 7.28 N 5.95 <br><br> Pound: 76.41 7.39 5.76 <br><br> 10 Example 11 <br><br> 4-[N-[ot- (4-methyl-phenyl) -2-piper idino-benzyl] -amino-carbonyl-methyl]-benzoic acid <br><br> 240 mg (5 mmol) of 4-[N-[5-chloro-a-(4-methyl-phenyl) -2-piperidino-benzyl]-aminocarbonylmethyl]-15 benzoic acid are catalytically dehalogenated 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 20 evaporation and the residue is recrystallised from ethanol. <br><br> Yield: 0.16 g (72% of theory) <br><br> M.p.: 226-228°C <br><br> Calculated: C 75.99 H 6.83 N 6.33 <br><br> 25 Found: 75.81 6.73 6.10 <br><br> # <br><br> 30 <br><br> 35 <br><br> The following were prepared analogously to Example 11: (a) 4-[N-[2-(2-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid From 4-[N-[5-chloro-2-(2-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 68% of theory M.p.: 246-248°C <br><br> Calculated C 75.99 H 6.83 N 6.33 Found: 75.57 7.10 6.44 <br><br> /5 <br><br> 2048.14 <br><br> - 59 - <br><br> (b) 4-[N-[2-(3-Methy1-piper idino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid From 4-[N-[5-chloro-2-(3-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid <br><br> Calculated: 43% of theory M.p.: 228-230°C <br><br> Calculated: C 75.99 H 6.83 N 6.33 Found: 75.91 6.82 6.33 <br><br> Example 12 <br><br> Ethyl 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoate <br><br> A solution of 2.78 g (10 mmol) of freshly prepared (4-methyl-phenyl)-(2-piperidinophenyl)-ketimine in 50 ml of methylenechloride is mixed with 1.5 ml (11 mmol) of triethylamine and 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 ambient temperature 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, after the addition of 0.5 g of palladium (10% on charcoal), it is hydrogenated at ambient temperature under a hydrogen pressure of 5 bar. After the calculated quantity of hydrogen has been taken up the catalyst is removed by filtering, the filtrate is concentrated by evaporation and the residue is recrystallised from a little alcohol. <br><br> Yield: 2.8 g (60% of theory) <br><br> M.p.: 175-177°C <br><br> Calculated: C 76.57 H 7.28 N 5.95 <br><br> Found: 76.41 7.19 5.76 <br><br> 04814 <br><br> - 60 - <br><br> Example 13 <br><br> 4-[N-[g-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbony1-methyl]-benzonitr ile <br><br> Prepared from a-(4-methyl-phenyl)-2-piperidino-benzylamine and 4-cyano-phenylacetic acid analogously to Example 1. <br><br> Yield: 64% of theory M.p.: 144-146°C <br><br> Calculated: C 79.40 H 6.90 N 9.92 <br><br> Found: 79.10 6.90 9.78 <br><br> Example 14 <br><br> Ethyl 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoate <br><br> 4.2 g (10 mmol) of 4-[N-[a-(4-methyl-phenyl)-2-piper id ino-benzy1]-ami nocar bonylmethy1]-benzon i t r ile are refluxed for 24 hours with 50 ml of ethanolic hydrochloric acid. The mixture is then 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. <br><br> Yield: 2.9 g (61.6% of theory) <br><br> M.p.: 177-179 °C <br><br> Calculated: C 76.57 H 7.28 N 5.95 <br><br> Found: 76.41 7.35 5.76 <br><br> Example 15 <br><br> Ethyl 4-[N-[5-chloro-g-(2-chloro-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoate <br><br> 10 mmol of ethyl 4-[N-[a-(2-chloro-phenyl)-5-nitro-2-piper idino-benzyl]-aminocar bonylmethy1]-benzoate are dissolved in 50 ml of dimethylformamide and, after the addition of 1 g of Raney nickel, hydro-genated at 60°C under a hydrogen pressure of 6 bar. <br><br> Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue, consisting <br><br> 61 <br><br> 4 <br><br> of ethyl 4-[N-[5-amino-ot- (2-chloro-phenyl)-2-piper idino-benzyl] -amino-carbonylmethyl]-benzoate is dissolved in 100 ml of concentrated hydrochloric acid. Whilst the mixture is cooled with ice, a solution of 1.0 g 5 (14 mmol) of sodium nitrite in 10 ml of water is added dropwise thereto and the resulting mixture is stirred for 1 hour at 0 to 5°C. The reaction mixture is then added dropwise to a solution- of 3 g .of copper (I) chloride in 25 ml of concentrated hydro-10 chloric acid. After 1 hour's stirring, the mixture is made alkaline with sodium hydroxide solution and extracted with chloroform. The concentrated chloroform extracts are purified by column chromatography on silica gel using toluene/ethyl acetate (5:1) as eluant. 15 Yield: 1.5 g (28.6% of theory) <br><br> M.p.: 213-215°C <br><br> Calculated: C 66.28 H 5.75 N 5.33 CI 13.49 <br><br> Found: 66.40 5.91 5.41 13.40 <br><br> 20 Example 16 <br><br> 3-[4-[N-(a-(4-Methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid <br><br> 0.91 g (2 mmol) of 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic 25 acid are dissolved in 50 ml of methanol and, after the addition of 0.5 g of palladium (10% on charcoal), the mixture is catalytically hydrogenated at ambient temperature under a hydrogen pressure of 3 bar. <br><br> After the hydrogen uptake has ended, the catalyst 30 is filtered off and recrystallised from a little acetonitrile. <br><br> Yield: 0.68 g (74% of theory) <br><br> M.p.: 146-148°C <br><br> Calculated: C 76.57 H 7.28 N 5.95 <br><br> 35 Found: 76.41 7.19 5.61 <br><br> - 62 - <br><br> Example 17 <br><br> Sodium salt of 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid <br><br> 442 mg (1 mmol) 4-[N-(a-(4-methyl-phenyl)-2-5 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 10 suction filtered and washed with ethyl acetate. <br><br> Yield: 410 mg (85% of theory) <br><br> M.p.: 295-300°C <br><br> Calculated: C 72.40 H 6.29 N 6.03 <br><br> Found: 72.15 6.46 5.93 <br><br> 15 The following were prepared analogously to Example 17: <br><br> (a) Ethanolamine salt of 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid <br><br> 20 Yield: 75% of theory <br><br> M.p.: 188-191°C <br><br> Calculated: C 71.55 H 7.41 N 8.34 Found: 71.16 7.48 8.52 <br><br> (b) Diethanolamine salt of 4-[N-(a-(4-methyl-phenyl)-25 2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 81% of theory M.p.: 178-180°C <br><br> Calculated: C 70.70 H 6.86 N 7.73 30 Found: 70.25 6.75 7.58 <br><br> (c) Triethanolamine salt of 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 76% of theory 35 M.p.: 160-165°C <br><br> Calculated: C 69.01 H 7.67 N 7.10 Found: 68.91 7.64 7.45 <br><br> (d) Ethylenediamine salt of 4-[N-(a-(4-methyl-phenyl)- <br><br> 20 48 i $04814 <br><br> - 63 - <br><br> 2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 65% of theory M.p.: 160-163°C 5 Calculated: C 71.69 H 7.62 N 11.15 <br><br> Found: 72.04 7.80 10.96 <br><br> * <br><br> 10 <br><br> 15 <br><br> 20 <br><br> Example 18 <br><br> Ethyl 4-[(2-methoxy-l-(2-piperidino-phenyl)-ethyl)-ami nocar bonyl-methy1j-benzoate <br><br> 0.49 g (2.34 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 0.73 g (2.78 mmol) of triphenylphosphine, 0.50 ml (3.66 mmol) of triethylamine and 0.23 ml (2.34 mmol) of carbontetrachloride are added successively to a solution of 0.55 g (2.34 mmol) of 2-methoxy-l-(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 iji vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/2). <br><br> Yield: 0.45 g (45% of theory) <br><br> M.p.: 122-123 °C Calculated: C 70.73 H 7.60 N 6.60 <br><br> Found: 71.04 7.48 6.39 <br><br> The following were prepared analogously to Example 18: <br><br> 30 (a) Ethyl 4-[(1-(3-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 55% of theory M.p.: 141-143°C <br><br> Calculated: C 68.33 H 7.28 CI 7.76 N 6.13 Found: 68.30 7.16 8.03 6.20 <br><br> (b) Ethyl 4-[(1-(6-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 73.9% of theory <br><br> 25 <br><br> 4;2 °4 8.14 <br><br> - 64 - <br><br> # <br><br> 15 <br><br> M.p.: 79-82°C <br><br> Calculated: C 68.33 H 7.28 CI 7.76 N 6.13 Found: 68.45 7.24 7.80 6.09 <br><br> (c) Ethyl 4-[(1-(4-bromo-2-piperidino-phenyl)-1-5 butyl)-aminocarbonylmethyl]-benzoate <br><br> Yield: 62.1% of theory, <br><br> M.p.: 116-118°C <br><br> Calculated: C 62.27 H 6.63 Br 15.93 N 5.58 Found: 62.53 6.48 15.98 5.66 <br><br> 10 (d) Ethyl 4-[(1-(4-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 74.6% of theory, <br><br> M.p.: 127-130°C <br><br> Calculated: C 66.79 H 7.11 N 8.99 Found: 66.88 7.08 9.15 <br><br> (e) Ethyl 4-[(1-(3-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 68% of theory, <br><br> M.p.: 145-147°C <br><br> Calculated: C 74.28 H 8.31 N 6.42 Found: 74.40 8.30 6.41 <br><br> (f) Ethyl 4-[(1-(4-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 54.7 of theory, <br><br> M.p.: 113-114°C <br><br> Calculated: C 74.28 H 8.31 N 6.42 Found: 74.23 8.30 6.55 <br><br> (g) Ethyl 4-[(1-(5-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 67.9% of theory, <br><br> M.p.: 149-150°C <br><br> Calculated: C 74.28 H 8.31 N 6.42 Found: 74.38 8.21 6.49 <br><br> (h) Ethyl 4-[(1-(6-methy1-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 47% of theory, <br><br> M.p.: 92-93°C <br><br> Calculated: C 74.28 H 8.31 N 6.42 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> - 65 - <br><br> # <br><br> Found: 74.50 8.46 6.48 <br><br> (i) Ethyl 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 57.3% of theory, 5 M.p.: 122-125°C <br><br> Calculated: C 73.50 H 7.90 N 6.86 Found: 73.63 8.07 7.01 <br><br> (k) Ethyl 4-[(1-(2-piperidino-phenyl)-l-butyl)-amino-carbonylmethyl]-benzoate 10 Yield: 71.5% of theory, <br><br> M.p.: 127-128°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 Found: 73.90 8.06 6.72 <br><br> (1) Ethyl 4-[(1-(2-(4-methyl-piperidino)-phenyl)-15 1-butyl)-aminocarbonylmethyl]-benzoate <br><br> Yield: 51.1% of theory, <br><br> M.p.: 153-155°C <br><br> Calculated: C 74.28 H 8.31 N 6.42 Found: 74.55 8.33 6.45 <br><br> 20 (m) Ethyl 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoate Yield: 42.7% of theory, j <br><br> M.p.: 145-147°C : <br><br> Calculated: C 74.28 H 8.31 N 6.42^ 25 Found: 73.98 8.26 6.58 <br><br> (n) Ethyl 4-[(1-(5-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 55% of theory, <br><br> M.p.: 128-130°C 30 Calculated: C 70.88 H 7.55 N 6.36 <br><br> Found: 71.14 7.57 6.49 <br><br> (o) Methyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoate Yield: 63.2% of theory, 35 M.p.: 147-148°C <br><br> Calculated: C 73.50 H 7.90 N 6.86 Found: 73.66 7.88 6.80 <br><br> (p) n-Butyl 4-[l-(2-piperidino-phenyl)-1-butyl)- <br><br> - 66 - <br><br> amino-carbonylmethyl]-benzoate Yield: 50.9% of theory, <br><br> M.p.: 117-119°C (ether) <br><br> Calculated: C 74.63 H 8.50 N 6.22 Found: 74.49 8.46 6.14 <br><br> (q) Ethyl 3-chloro-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 14.9% of theory, <br><br> M.p.: 20°C <br><br> Calculated: m/e = 456/458 (1 chloro) <br><br> Found: m/e = 456/458 (1 chloro) <br><br> (r) Ethyl 4-[(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoate Yield: 18.9% of theory, <br><br> M.p.: 103-105°C <br><br> Calculated: C 74.62 H 7.89 N 6.45 Found: 75.01 8.10 6.26 <br><br> Example 19 <br><br> Ethyl 4-[(1-(5-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate <br><br> A solution of 14.6 g (64.6 mmol) of 4-ethoxy-carbonyl-phenyl acetic acid chloride in 20 ml of methylene chloride is added dropwise to a 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) of triethyl-amine in 55 ml of dry methylene chloride within 30 minutes in such a way that the 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 over sodium 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), <br><br> M.p.: 135-137°C (ether) <br><br> i <br><br> - 67 - <br><br> Calculated: C 66.79 H 7.11 N 8.99 <br><br> Found: 66.73 6.99 9.09 <br><br> The following were prepared analogously to Example 19: (a) Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-5 aminocarbonylmethyl]-benzoate <br><br> Yield: 80.2% of theory, <br><br> M.p.: 127-129°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 Found: 73.98 8.26 6.89 <br><br> 10 (b) Ethyl 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 13.5% of theory, <br><br> M.p.: 178-180°C <br><br> Calculated: C 71.21 H 7.81 N 6.39 15 Found: 71.27 7.82 6.40 <br><br> (c) Ethyl 4-[(1-(5-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 37.4% of theory, <br><br> M.p.: 188-190°C 20 Calculated: C 71.21 H 7.81 N 6.39 <br><br> Found: 71.34 7.89 6.38 <br><br> 25 <br><br> 30 <br><br> Example 20 <br><br> 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] phenyl acetic acid <br><br> 3.0 g (15.45 mmol) of p-phenylene-diacetic acid and 10 ml of thionyl chloride are refluxed for 90 minutes and then concentrated by evaporation in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride. Then a solution of 3.6 g (15.45 mmol) of 1-(2-piperidino-phenyl)-1-butyl-amine is slowly added dropwise to this solution, <br><br> with stirring, at an internal temperature of 10 -15°C. After 2 hours at ambient temperature, the mixture is concentrated by evaporation in vacuo and the evaporation residue is distributed between 100 ml of ice cold 5% sodium hydroxide solution and ethyl acetate. It is filtered through kieselguhr and the <br><br> 204 <br><br> 204814 <br><br> 68 <br><br> # <br><br> organic phase is separated off. The alkaline-aqueous phase is adjusted to pH 5.5 with semi-concentrated hydrochloric acid and extracted with ethyl acetate. The extract is dried over sodium sulphate and filtered 5 and the filtrate is concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 20/1). <br><br> Yield: 0.10 g (1.6% of theory), <br><br> 10 M.p.: 136-140°C (acetonitrile/ether) <br><br> Calculated: C 73.50 H 7.90 N 6.86 <br><br> Found: 73.17 8.10 6.85 <br><br> Example 21 <br><br> 15 Ethyl 4-[(2-methyl-l-(2-piperidino-phenyl)-1-propen-1-yl)-aminocarbonylmethyl]-benzoate <br><br> 5.58 g (26.8 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 8.43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 20 mol) of carbon tetrachloride are successively added to a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl-(2-piperidino-phenyl)-ketimine in 62 ml of acetonitrile and the resulting mixture is stirred for 20 hours at an ambient temperature. It is then 25 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). <br><br> 30 Yield: 3.0 g (26.6% of theory), <br><br> M.p.: 82-84°C (ether) <br><br> Calculated: C 74.26 H 7.67 N 6.66 <br><br> Found: 74.20 7.49 6.56 <br><br> The following were prepared analogously to Example 21: 35 (a) Ethyl 4—[1—(2-piperidino-phenyl)-1-penten-l- <br><br> yl)-aminocarbonylmethyl]-benzoate Yield: 16% of theory, M.p.: 94-97°C (ethanol) <br><br> \\ w <br><br> ,7 <br><br> / <br><br> - 69 - <br><br> Calculated: C 74.62 H 7.89 N 6.45 <br><br> Found: 74.75 7.71 6.24 <br><br> Ethyl 4-[1-(2-piperidino-phenyl)-1-hexen-l- <br><br> yl)-aminocarbonylmethyl]-benzoate <br><br> Yield: 27.4% of theory, <br><br> M.p.: 83-85°C (ethanol) <br><br> Calculated: C 74.97 H 8.09 N 6.24 <br><br> Found: 75.42 7.95 6.00 <br><br> Ethyl 4-[1-(2-piperidino-phenyl)-1-buten-l- <br><br> yl) -aminocarbonylmethyl]-benzoate <br><br> Yield (more lipophilic isomer; probably E form) <br><br> 4.1% of theory, <br><br> M.p.: &lt; 20°C Calculated: m/e = 420 Found: m/e = 420 <br><br> Yield (less lipophilic isomer; probably Z form) <br><br> 51.9% of theory, <br><br> M.p.: 115-117°C (ethanol) <br><br> Calculated: C 74.26 H 7.67 N 6.66 Found: 73.85 7.59 6.44 <br><br> Ethyl 4-[(2-pheny1-1-(2-piperidino-phenyl)-ethen-l-yl)-aminocarbonylmethyl]-benzoate Yield (more lipophilic isomer; probably E form) <br><br> 4% of theory, <br><br> M.p.: 75-77°C (ether/petroleum ether) Calculated: C 76.90 H 6.88 N 5.98 Found: 77.31 7.20 5.93 <br><br> Yield (less lipophilic isomer; probably Z form) <br><br> 42.7% of theory, <br><br> M.p.: 157-160°C (ethanol) <br><br> Found: C 77.19 H 6.95 N 6.02 <br><br> Ethyl 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl)-benzoate Yield: 62.6% of theory, <br><br> M.p.: &lt; 20°C <br><br> Calculated: m/e = 482 Found: m/e = 482 <br><br> - 70 - <br><br> 10 <br><br> (f) Ethyl 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl) 1-buten-l-yl)-aminocarbonylmethyl]-benzoate Yield: 33% of theory, <br><br> M.p.: 113-116°C (ethanol) <br><br> Calculated: C 74.97 H 8.09 N 6.24 Found: 75.37 7.93 6.03 <br><br> (g) Ethyl,4-[(1-(6-methyl-2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoate Yield: 60.4% of theory (probably Z form) M.p.: 95-96 °C <br><br> Calculated: C 74.62 H 7.89 N 6.45 m/e = 434 Found: 74.44 8.00 6.59 m/e = 434 <br><br> Example 22 <br><br> 15 Ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl] -benzoate <br><br> A stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidino-phenyl)-propyl-ketimine and 11.5 ml (82.46 mmol) of triethylamine in 190 ml 20 of anhydrous toluene 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 of anhydrous toluene is added dropwise thereto within 10 minutes and the resulting mixture is stirred for 25 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, <br><br> filtered and concentrated by evaporation iji vacuo. The evaporation residue is purified by repeated column 30 chromatography (toluene/acetone = 20/1 and 50/1). <br><br> Yield: (more lipophilic isomer; probably E form): 11.2 g (23.6% of theory), <br><br> M.p.: &lt; 20°C (honey-yellow viscous oil) <br><br> Calculated: C 74.26 H 7.67 N 6.66 <br><br> 35 Found: 73.90 7.92 6.91 <br><br> Yield (less lipophilic isomer; probably Z form) 15.9 g (33.5% of theory), <br><br> - 71 - <br><br> M.p.: 114-116°C <br><br> Found: C 74.02 H 7.69 N 6.85 <br><br> Example 23 <br><br> 5 Ethyl (E)- and (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoate <br><br> 1.0 g of Z ester (see Example 21c) is heated for 30 minutes in a pre-heated oil bath at 230°C. . After cooling, the product obtained is purified by 10 column chromatography on silica gel (toluene/acetone = 20/1). <br><br> Yield (E ester): 0.365 g (36.5% of theory), M.p.: &lt; 20°C <br><br> 15 Yield (Z ester): 0.380 g (38.0% of theory), M.p.: 115-117°C <br><br> If the (E)-ester is heated for 3.5 hours with catalytic quantities of iodine in benzene, a 1/1 20 mixture of (E) and (Z) esters is obtained, according to thin layer chromatography (toluene/acetone = 10/1). <br><br> The following compounds were obtained analogously to Example 23: <br><br> 25 (a) <br><br> 30 <br><br> Ethyl (E)- and (Z)-4-[(1-(6-methyl-2-piperidino-phenyl) -1-buten-l-yl)-aminocarbonylmethyl)- <br><br> benzoate <br><br> According to thin layer chromatography, a 1/1 mixture of (E) and (Z) esters is obtained from the (Z) ester (see Example 21g). <br><br> Upper spot (E): Calculated: m/e = 434 <br><br> Found: m/e = 434 <br><br> lower spot (Z): Found: m/e = 434 <br><br> 35 Example 24 <br><br> Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate ^ 2.9 g (6.90 mmol) of ethyl 4-[(1-(2-piperidino- <br><br> j x <br><br> 'n-,i jj <br><br> I v <br><br> 10 <br><br> M. <br><br> 048.14 <br><br> - 72 - <br><br> phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoate in 100 ml of ethanol is hydrogenated on 0.77 g of <br><br> 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. <br><br> Yield: 1.5 g (51.5% of theory), <br><br> M.p.: 126-128°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 <br><br> Found: 73.97 8.22 6.57 <br><br> 15 <br><br> 20 <br><br> The following compounds were obtained analogously to Example 24: <br><br> (a) Ethyl 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoate Yield: 45% of theory, <br><br> M.p.: 117-120°C (ether) <br><br> Calculated: C 74.28 H 8.31 N 6.42 Found: 74.60 8.13 6.27 <br><br> (b) Ethyl 4-[(1-(2-piperidino-phenyl)-1-hexyl) aminocarbonylmethyl]-benzoate 25 Yield: 50% of theory, <br><br> M.p.: 108-110°C (ether) <br><br> Calculated: C 74.63 H 8.50 N 6.22 Found: 74.85 8.33 6.01 <br><br> 30 (c) <br><br> Ethyl 4-[(2-phenyl-l-(2-piperidino-phenyl) 1-ethyl)-aminocarbonylmethyl]-benzoate Yield: 87.6% of theory, <br><br> M.p.: 161-162°C (ethanol) <br><br> Calculated: C 76.57 H 7.28 N 5.95 Found: 76.71 7.19 5.99 <br><br> Ethyl 4-[(3-phenyl-l-(2-piperidino-phenyl) 1-propyl)-aminocarbonylmethyl]-benzoate <br><br> 8.14 <br><br> - 73 - <br><br> Yield: 57.6% of theory, M.p.: 118-119°C (ethanol) Calculated: C 76.83 H 7.49 N 5.78 Found: 76.70 7.49 5.90 <br><br> 10 <br><br> (e) Ethyl 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 36.5% of theory, <br><br> M.p.: 140-141°C (ethanol) <br><br> Calculated: C 74.63 H 8.50 N 6.22 Found: 74.30 8.23 6.12 <br><br> Example 25 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-15 benzoic acid <br><br> A mixture of 1.2 g (2.84 mmol) of ethyl 4—[(1— (2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate and 4.26 ml of IN sodium hydroxide solution in 12 ml of ethanol is stirred for 1 hour at 60°C, <br><br> 20 then neutralised with 4.26 ml of IN hydrochloric acid and the ethanol is evaporated off In vacuo. The residue is distributed between ethyl acetate and water; the organic extract is dried and filtered and concentrated by evaporation i^i vacuo. The evaporation 25 residue is crystallised from ethanol. <br><br> Yield: 0.50 g (44.6% of theory), <br><br> M.p.: 213-215°C <br><br> Calculated: C 73.07 H 7.66 N 7.10 <br><br> Found: 73.18 7.51 7.10 <br><br> 30 <br><br> The following compounds were obtained analogously to Example 25: <br><br> 35 <br><br> (a) 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl] -benzoic acid Yield: 70.2% of theory, <br><br> M.p.: 213-215°C (acetone) <br><br> % <br><br> 8.14 <br><br> Calculated: C 73.50 Found: 73.71 <br><br> - 74 - <br><br> H 7.90 7.70 <br><br> N 6.86 6.90 <br><br> 10 <br><br> 15 <br><br> (b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonylmethyl] -benzoic acid <br><br> Yield: 72.6% of theory, <br><br> M.p.: 197-200°C (acetone) <br><br> Calculated: C 73.90 H 8.11 N 6.63 Found: 73.83 7.93 6.77 <br><br> (c) 4-[(2-phenyl-l-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid ; <br><br> Yield: 68.7% of theory, <br><br> M.p.: 214-215°C (acetone) <br><br> Calculated: C 75.99 H 6.83 N 6.33 Found: 75.70 6.60 6.32 <br><br> (d) 4-[ (3-Phenyl-l- (2-piper idino-phenyjl)-1-propyl) aminocarbonylmethyl]-benzoic acid ^ 20 Yield: 67.7% of theory, <br><br> i <br><br> M.p.: 167-170°C (ethyl acetate) <br><br> Calculated: C 76.29 H 7.06 N 6.14 <br><br> I <br><br> Found: 76.56 7.06 6.23 <br><br> 25 (e) <br><br> 30 <br><br> 4-[2-Methoxy-l-(2-piperidino-phenyl)-1-ethyl) <br><br> aminocarbonylmethyl]-benzoic acid <br><br> Yield: 60.8% of theory, <br><br> M.p.: 196-198°C (ether) <br><br> Calculated: C 69.68 H 7.12 N 7.07 <br><br> Found: 69.72 6.52 6.71 <br><br> (f) <br><br> 35 <br><br> 4-[(1- (2-Piperidino-phenyl)-4-penten-l-yl)-aminocarbonylmethyl]-benzoic acid x 0.67 H20 Yield: 30.7% of theory, <br><br> M.p.: 193-197°C (ether/petroleum ether) Calculated: C 71.74 H 7.38 N 6.69 Found: 71.63 7.21 6.34 <br><br> 104814 <br><br> - 75 - <br><br> (g) 4-[(1-(2-(3,3-Dimethyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 48.2% of theory, <br><br> M.p.: 168-170°C (petroleum ether) 5 Calculated: C 73.91 H 8.11 N 6.63 <br><br> Found: 73.51 7.89 6.32 <br><br> (h) 4-[(1-(3-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid <br><br> 10 Yield: 53% of theory, <br><br> M.p.: 179-182°C <br><br> Calculated: C 73.50 H 7.90 N 6.86 Found: 73.50 7.82 7.01 <br><br> 15 (i) <br><br> 20 <br><br> 4-[(1-(4-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 85.6% of theory, <br><br> M.p.: 170-172°C <br><br> Calculated: C 73.50 H 7.90 N 6.86 Found: 73.25 7.64 6.89, <br><br> 25 <br><br> (k) 4-[(1-(5-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 62.1% of theory, <br><br> M.p.: 219-221°C <br><br> Calculated: C 73.50 H 7.90 N 6.86, <br><br> Found: 73.20 7.74 6.89 <br><br> 30 <br><br> (1) 4-[(1-(6-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid x 0.3 1^0 Yield: 89% of theory, <br><br> M.p.: 158-160°C <br><br> Calculated: C 72.53 H 7.93 N 6.77 Found: 72.40 7.91 6.92 <br><br> (m) 4-[(1-(3-Chloro-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 70% of theory, <br><br> M.p.: 189-191°C Calculated: C 67.20 Found: 67.30 <br><br> - 76 - <br><br> H 6.81 6.85 <br><br> CI 8.27 8.36 <br><br> N 6.53 6.58 <br><br> to4814 <br><br> 5 (n) <br><br> 10 <br><br> 15 <br><br> 4-[(1-(4-Chloro-2-piperidino-phenyl)-1-butyl) -aminocarbonylmethyl]-benzoic acid Yield: 57.8% of theory, j <br><br> M.p.: 188-189°C <br><br> Calculated: C 67.20 H 6.81 CI 8.27 N 6.53 Found: 66.90 7.00 8.22 6.53 <br><br> (o) 4-[(1-(5-Chloro-2-piperidino-phenyl)-1-butyl) -aminocarbonylmethyl]-benzoic acid Yield: 81.6% of theory, <br><br> M.p.: 226-229°C <br><br> Calculated: C 67.20 H 6.81 CI 8.27 N 6.53 Found: 67.17 6.59 8.51 6.60 <br><br> (P) 4-[(1-(6-Chloro-2-piperidino-phenyl)-1-butyl) -20 aminocarbonylmethyl]-benzoic acid <br><br> Yield: 69.4% of theory, <br><br> M.p.: 150-153°C <br><br> Calculated: C 67.20 H 6.81 CI 8.27 N 6.53 Found: 67.18 6.91 8.42 6.77 <br><br> 25 <br><br> (q) 4-[(1- (4-Bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ! <br><br> Yield: 84.4% of theory, <br><br> M.p.: 198-201°C 30 Calculated: C 60.89 H 6.17 Br 16.88 N 5.92 <br><br> Found: 60.88 5.98 17.20 5.98 <br><br> 35 <br><br> 5 MAR 1986 J <br><br> (r) 4-[(1-(5-Bromo-2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 90.7% of theory, <br><br> M.p.: 232-235°C <br><br> Calculated: C 60.89 H 6.17 Br 16.88 N 5.92 Found: 60.96 6.13 16.85 5.90 <br><br> 2048 ap«i4 <br><br> - 77 - <br><br> (s) 4-[(1-(4-Nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 70.9% of theory, <br><br> M.p.: 188-190°C 5 Calculated: C 65.59 H 6.65 N 9.56 <br><br> Found: 65.30 6.44 9.53 <br><br> r <br><br> (t) 4-[(1-(5-Nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid 10 Yield: 90.7% of theory, <br><br> M.p.: 225-227°C <br><br> Calculated: C 65.59 H 6.65 N 9.56 Found: 65.80 6.61 9.72 <br><br> 15 (u) <br><br> 20 <br><br> 4-[(1-(4-Hydroxy-2-piperidino-phenyl)-1-butyl)- <br><br> aminocarbonylmethyl]-benzoic acid x 0.5 H20 <br><br> Yield: 85.7% of theory, <br><br> M.p.: softening from 70°C (foam) <br><br> Calculated: (x 0.5 H20) C 68.71 H 7.45 N 6.68 <br><br> Found: <br><br> 68.63 <br><br> 7.55 <br><br> 6.26 <br><br> 25 <br><br> (v) 4-[(1-(5-Hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 89.3% of theory, <br><br> M.p.: 186-190°C <br><br> Calculated: C 70.22 H 7.37 N 6.82 Found: 70.31 7.58 6.51 <br><br> (w) <br><br> 30 <br><br> 45 <br><br> , ^ £ N * <br><br> ^ 5 MAR 1986 id <br><br> : i} <br><br> F i V <br><br> &lt;r&gt;. <br><br> 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 78.6% of theory, <br><br> M.p.: 185-187 °C <br><br> Calculated: C 70.73 H 7.60 N 6.60 Found: 70.46 7.77 6.56 <br><br> 4-[(1-(5-Methoxy-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 75% of theory, <br><br> 2048 il"""1" <br><br> - 78 - <br><br> M.p.: 182-185°C (decomp.) <br><br> Calculated: C 70.73 H 7.60 N 6.60 Found: 70.52 7.50 6.70 <br><br> 5 (y) 4-[(1-(2-Pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid Yield: 64.5% of theory, <br><br> M.p.: 200-203°C <br><br> Calculated: C 72.61 H 7.42 N 7.36 10 Found: 72.64 7.50 7.38 <br><br> (z) 4-[(1-(2-(4-Methyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 81.4% of theory, <br><br> 15 M.p.: 197-201°C <br><br> Calculated: C 73.50 H 7.90 N 6.86 Found: 73.90 8.06 7.00 <br><br> (aa) 4-[(1-(2-Hexahydroazepino-phenyl)-1-butyl)-20 aminocarbonylmethyl]-benzoic acid <br><br> Yield: 65.6% of theory, <br><br> M.p.: 199-202°C <br><br> Calculated: C 73.50 H 7.90 N 6.86 Found: 73.50 7.90 6.76 <br><br> 25 <br><br> (ab) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 87.1% of theory, <br><br> M.p.: 204-207°C <br><br> 30 Calculated: C 69.88 H 7.09 N 6.79 <br><br> Found: 70.25 7.02 7.12 <br><br> (ac) 4-[(1-(5-Fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid <br><br> 35 Yield: 53.9% of theory, <br><br> M.p.: 200-202°C //,&lt;r Calculated: C 69.88 H 7.09 N 6.79 <br><br> j&lt;*J -oYV <br><br> Hg -\\ Found: 69.67 7.24 6.90 <br><br> v.... <br><br> SiV f- <br><br> 204814 <br><br> - 79 - <br><br> (ad) 3-Chloro-4-[(1-(2-piperidino-phenyl)-1-butyl) -aminocarbonylmethyl]-benzoic acid Yield: 51% of theory, <br><br> M.p.: 165-168°C 5 Calculated: C 67.20 H 6.81 N 6.53 m/e = 428/430 <br><br> (1 chlorine) <br><br> Found: 66.92 6.69 6.55 m/e = 428/430 <br><br> (1 chlorine) <br><br> 10 Example 26 <br><br> 4-[(2-Methyl-l-(2-piperidino-phenyl)-l-propen-l-yl)-aminocarbonylmethyl]-benzoic acid <br><br> A mixture of 3.5 g (8.3 mmol) of ethyl 4—[(2— methyl-1-(2-piperidino-phenyl)-1-propen-l-yl)-amino-15 carbonylmethyl]benzoate and 12.5 ml of IN sodium hydroxide solution in 35 ml of ethanol is stirred at 60°C for 2 hours. It is neutralised with 12.5 ml of IN hydrochloric acid, concentrated by evaporation in vacuo and distributed between ethyl acetate and 20 water. The dried, filtered organic extract is evaporated in vacuo. The evaporation residue is crystallised from ethanol. <br><br> Yield: 2.4 g (73.6% of theory), <br><br> M.p.: 188-191°C 25 Calculated: C 73.44 H 7.19 N 7.14 <br><br> Found: 73.60 7.19 7.02 <br><br> 30 <br><br> 35 <br><br> The following compounds were obtained analogously to Example 26: <br><br> (a) (E)-4-[(1-(2-Piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid Yield: 71.5% of theory, <br><br> M.p.: 188-190°C <br><br> Calculated: C 73.44 H 7.19 N 7.14 <br><br> Found: 73.15 7.13 7.10 <br><br> lt <br><br> Olefinic proton: J-H-NMR <br><br> (CDCl^):S= 6.42 ppm <br><br> 1204814 <br><br> 10 <br><br> 15 <br><br> - 80 - <br><br> (b) (Z)-4-[(1-(2-Piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 57.8% of theory, <br><br> M.p.: 174-175°C (ethanol) <br><br> Calculated: C 73.44 H 7.19 N 7.14 Found: 73.54 6.97 7.17 <br><br> Olefinic proton: "hl-NMR (CDCl^) :$= 5.60 ppm <br><br> (c) (E)-4-[(2-Phenyl-l-(2-piperidino-phenyl)-ethen-l-yl) -aminocarbonylmethyl] -benzoic acid x 0.4 <br><br> h2o <br><br> Yield: 33.2% of theory, <br><br> M.p.: 165-167°C (ether/petroleum ether) Calculated: (x 0.4 H20) C 75.11 H 6.48 N 6.26 <br><br> Found: <br><br> 75.22 <br><br> 6.39 <br><br> 6.26 <br><br> olefinic proton: ^"H-NMR (CDCl^) : S &gt; 6.9 ppm <br><br> 20 <br><br> 25 <br><br> (d) (Z)-4-[(2-Phenyl-l-(2-piperidino-phenyl)-ethen-l-yl) -aminocarbonylmethyl] -benzoic acid x 1 <br><br> H2° <br><br> Yield: 72% of theory, <br><br> M.p.: 182-185°C (methanol) <br><br> Calculated: (x 1 H20): C 73.34 H 6.60 N 6.11 Found: 73.55 6.45 6.00 <br><br> olefinic proton: ^H-NMR (CDCl^): 8 = 6.50 ppm <br><br> 30 <br><br> (e) 4-[(3-Phenyl-l-(2-piperidino-phenyl)-1-propen-l-yl) -aminocarbonylmethyl]-benzoic acid Yield: 48.3% of theory, <br><br> M.p.: 162-164°C (ether); probably (Z) form Calculated: C 76.63 H 6.65 N 6.16 Found: 76.30 6.47 6.31 <br><br> Olefinic proton: "'"H-NMR (CDCl^) : 8 = 5.80 ppm <br><br> (f) 4-[(1-(2-(3,3-Dimethyl-piperidino)-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid <br><br> Yield: 64.1% of theory, <br><br> 1 42048.14 <br><br> - 81 - <br><br> M.p.: 152-153°C (ethyl acetate); probably (Z) form Calculated: C 74.26 H 7.67 N 6.67 Found: 73.93 7.57 6.50 <br><br> Olefinic proton: "'"H-NMR (CDCl-j) : S = 5.55 ppm <br><br> 5 <br><br> (g) (Z)—4—[(1-(6-Methyl-2-piperidino-phenyl)-1- <br><br> buten-l-yl)-aminocarbonylmethyl]-benzoic acid Yield: 53.3% of theory, <br><br> M.p.: 142-145°C 10 Calculated: C 73.66 H 7.44 N 6.89 <br><br> Found: 73.56 7.73 7.15 <br><br> olefinic proton: ^"H-NMR (CDCl^) ' S; = 5.38 ppm <br><br> Example 27 <br><br> 15 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoic acid <br><br> 200 mg (0.51 mmol) of 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid in 10 ml of absolute ethanol are hydrogenated over 100 mg 20 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 iji vacuo. Yield: 68% of theory, <br><br> M.p.: 213-214 °C 25 Calculated: C 73.07 H 7.66 N 7.10 <br><br> Found: 73.21 7.82 7.02 <br><br> The yield is 56% of theory if hydrogenation is carried out at 50°C and under 1 bar of hydrogen on Raney 30 nickel. <br><br> 35 <br><br> Example 28 <br><br> Sodium salt of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 1^0 <br><br> 10.0 g (25.35 mmol) of 4-[ (1-(2-piperidino-phenyl) -1-butyl)-aminocarbonylmethyl]-benzoic acid are dissolved at 50°C in 200 ml of ethanol and 25.35 ml <br><br> 481 <br><br> 048.14 <br><br> 10 <br><br> - 82 - <br><br> of IN 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/15 torr. * <br><br> Yield: 9 g (85.3% of theory), <br><br> M.p.: 280-285°C (decomp.); softening from 255°C Calculated: (x 0.5 H20) C 67.74 H 6.87 N 6.58 <br><br> Found: 67.86 7.13 6.49 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> Example 29 <br><br> Ethyl (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocar bonylmethy1]-ben zoate <br><br> To a stirred solution of 2.58 g (11.1 mmol) of (+)-1-(2-piperidino-phenyl)-1-butylamine [Bp q q^: 87°C; ee = 86 (HPLC, after derivatising with (+)-1-phenethyl-isocyanate)] in 26 ml of acetonitrile, <br><br> there are added, at 20°C, one after another, 2.31 g (11.1 mmol) of 4-ethoxycarbonyl-phenyl acetic acid, 3.50 g (13.3 mmol) of triphenylphosphine, 4.60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of carbon tetrachloride. After 14 hours at 20°C and 1.5 hours at 40°C the mixture is concentrated by evaporation jin vacuo and distributed between water and ether. The organic phase is dried over sodium sulphate, then filtered, and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6:1). <br><br> Yield: 2.63 g (56% of theory), <br><br> M.p.: 118-120°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 <br><br> 74.02 7.97 6.51 <br><br> Found: 20 <br><br> = +9.2° (c = 1; methanol) <br><br> j[ ZI04814 <br><br> - 83 - <br><br> The following compound was obtained analogously to Example 29: <br><br> 10 <br><br> 15 <br><br> (a) Ethyl (-)-4-[(1-(2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoate Prepared from (-)-1-(2-Piperidino-phenyl)-1-butylamine x 1.4 HC1 [[a]^ = -20.0° (c = 1, methanol), <br><br> Melting range: 90-100°C; ee = 80 (HPLC, after derivatising the base with (+)-1-phenethyl-isocyanate)] <br><br> Yield: 52.6% of theory, <br><br> M.p.: 115-120°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 73.83 8.01 6.47 <br><br> Found: <br><br> r-,i 20 LaJr» <br><br> = -9.0° (c = 1, methanol) <br><br> 20 <br><br> 25 <br><br> 30 <br><br> 5 MAR 1986 <br><br> p t xi <br><br> Example 30 <br><br> Ethyl (+)-4-[(1-(2-piperidino-phenyl)-1—butyl)-aminocarbonylmethyl] -benzoate <br><br> 1.0 g (3.27 mmol) of (+)-1-(2-piperidino-phenyl)- <br><br> on l-butylamine-dihydrochloride [[a]D = +18.7° (c = 1, methanol); m.p.: decomposition from ll5°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: <br><br> twice with 10 ml of water, <br><br> once with 10 ml of 2N hydrochloric acid and once with 10 ml of water. <br><br> The organic phase is dried over sodium sulphate, <br><br> filtered and concentrated by evaporation _in vacuo. <br><br> 204814 <br><br> - 84 - <br><br> The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6/1). <br><br> Yield: 0.53 g (38.2% of theory), <br><br> M.p.: 120-122°C 5 Calculated: C 73.90 H 8.11 N 6.63 <br><br> Found: 73.96 7.98 6.61 <br><br> [a]p° = +9.0° (c = 1, methanol) ; <br><br> _ Example 31 <br><br> 10 (+)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid <br><br> 2.0 g (4.73 mmol) of ethyl (+)-4-[(1-(2-piperidino- <br><br> 20 <br><br> phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate [[a]D = +9.2° (c = 1, methanol)] in 20 ml of ethanol are 15 stirred with 7.0 ml of IN sodium hydroxide solution for 2.5 hours in a bath at 65°C. The mixture is cooled and 7.0 ml of IN hydrochloric acid are added. The crystals which are slowly precipitated are filtered off, washed with water and dried at 100°C/4 torr. 20 Yield: 1.65 g (88.2% of theory), <br><br> M.p.: 185-187°C <br><br> Calculated: C 73.07 H 7.66 N 7.10 <br><br> Found: 72.90 7.80 7.17 <br><br> [ct]p° = +7.9° (c = 1, methanol) <br><br> 25 <br><br> The following compound was obtained analogously to Example 31: <br><br> (a) (-)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-amino-30 carbonylmethyl]-benzoic acid <br><br> Yield: 80% of theory, <br><br> M.p.: 187-190°C <br><br> Calculated: C 73.07 H 7.66 N 7.10 <br><br> V ° <br><br> y <br><br> 2 5 MAR 1986 3 <br><br> // <br><br> Found: 72.98 7.44 7.22 <br><br> 2( <br><br> D <br><br> on <br><br> 35 ["In ~ -7.9° (c = 1, methanol) <br><br> p r s <br><br> 04814 <br><br> - 85 - <br><br> Example 32 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzonitr ile <br><br> Prepared from 1-(2-piperidino-phenyl)-1-butylamine 5 and 4-cyano-phenylacetic acid analogously to Example 18. <br><br> Yield: 57.3% of theory, <br><br> M.p.: 147-148°C <br><br> Calculated: C 76.76 H 7.78 N 11.19 <br><br> 10 Found: 76.46 7.81 11.10 <br><br> 20 <br><br> The following compound was obtained analogously to Example 32: <br><br> 15 (a) <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -toluene <br><br> Prepared with 4-tolyl-acetic acid. <br><br> Yield: 60.4% of theory, <br><br> M.p.: 150-153°C <br><br> Calculated: C 79.08 H 8.85 N 7.68; <br><br> Found: 78.97 8.58 7.77 <br><br> Example 33 <br><br> Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate <br><br> Prepared from 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzonitrile with ethanolic hydrochloric acid analogously to Example 14. <br><br> Yield: 58% of theory, <br><br> M.p.: 127-128°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 <br><br> Found: 74.07 8.23 6.87 <br><br> 25 <br><br> 30 <br><br> Example 34 <br><br> Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate <br><br> Prepared analogously to Example 10 from l-(2-piperidino-phenyl)-1-butanol and ethyl 4-cyanomethyl- <br><br> 86 <br><br> benzoate with concentrated sulphuric acid in o-dichloro-benzene at ambient temperature. <br><br> Yield: 21% of theory, <br><br> M.p.: 126-128°C <br><br> The following compound was obtained analogously to Example 34: <br><br> (a) 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid <br><br> Prepared from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanomethyl-benzoic acid. Extraction at pH 5.5. <br><br> Yield: 29% of theory, <br><br> M.p.: 215-217°C <br><br> Calculated: C 73.07 H 7.66 N 7.10 Found: 72.82 7.69 6.95 <br><br> Example 35 <br><br> 4— [.(1— (4-Amino-2-piper idino-phenyl) -1-butyl) -aminocarbonyl-methyl]-benzoic acid x 0.5 1^0 <br><br> 0.60 g (1.365 mmol) of 4-[(1-(4-nitro-2-piperidino-phenyl) -1-butyl)-aminocarbonylmethyl]-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 kieselguhr and the filtrate is concentrated by evaporation iji vacuo. The evaporation residue is crystallised from ether. <br><br> Yield: 0.41 g (73.2% of theory), <br><br> M.p.: 118-120 °C <br><br> Calculated: (x 0.5 H20): C 68.87 H 7.71 N 10.04 Found: 68.62 7.64 10.08 <br><br> Calculated Found: <br><br> C 73.90 H 8.11 N 6.63 74.12 8.20 6.45 <br><br> 204814 <br><br> - 87 - <br><br> The following compounds were obtained analogously to Example 35: <br><br> 10 <br><br> 15 <br><br> (a) Ethyl 4-[(1-(4-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 81.7% of theory, <br><br> M.p.: 145-146°C (ether/petroleum ether) Calculated: C 71.37 H 8.06 N 9.60 Found: 71.50 8.08 9.68 <br><br> (b) 4-[(1-(5-Amino-2-piperidino-phenyl)-1-butyl) -aminocarbonylmethyl]-benzoic acid : <br><br> Yield: 64% of theory, <br><br> M.p.: 227-230°C <br><br> Calculated: C 70.39 H 7.63 N 10.26 Found: 70.54 7.54 10.36 <br><br> (c) Ethyl 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-ami nocarbonylmethyl]-benzoate 20 Yield: 84.3% of theory, <br><br> M.p.: 162-165°C <br><br> Calculated: C 71.37 H 8.06 N 9.60 Found: 71.58 7.83 9.6^ <br><br> -5 MAR 1986; <br><br> 25 Example 36 <br><br> Ethyl 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate <br><br> A cold diazonium salt solution (0°C) is prepared from 2.0 g (4.57 mmol) of ethyl 4-[(1-(5-amino-2-30 piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-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 0 to 5°C, to a stirred mixture of 0.59 g (5.94 mmol) 35 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, <br><br> I £04814 <br><br> 10 <br><br> - 88 - <br><br> 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 jji vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1). <br><br> Yield: 0.80 g (40% of theory), <br><br> M.p.: 137-140°C (ether) <br><br> Calculated: C 68.32 H 7.27 CI 7.75 N 6.13 <br><br> Found: 68.42 7.09 8.06 6.05 <br><br> The following compounds were obtained analogously to Example 36: <br><br> 15 (a) <br><br> 20 <br><br> Ethyl 4-[(1-(4-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 21.9% of theory, <br><br> M.p.: 123-125°C <br><br> Calculated: C 68.32 H 7.27 CI 7.75 N 6.13 Found: 68.70 7.18 7.77 6.08 <br><br> 25 <br><br> (b) Ethyl 4-[(1-(5-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 53.8% of theory, <br><br> M.p.: 140-142°C <br><br> Calculated: C 62.27 H 6.63 Br 15.93 N 5.58 Found: 62.39 6.78 15.85 5.59 <br><br> 30 <br><br> 35 <br><br> ~5 MAR 1986; <br><br> (c) Ethyl 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 21.6% of theory, <br><br> M.p.: 110-112°C <br><br> Calculated: C 70.88 H 7.55 N 6.36 Found: 71.01 7.53 6.21 <br><br> In addition, 40% of ethyl 4-[(1-(4-hydroxy-2-piperidino-phenyl) -1-butyl)-aminocarbonylmethyl]-benzoate are isolated (solid foam). <br><br> 2 <br><br> iO 1 <br><br> 048.14 <br><br> - 89 - <br><br> (d) Ethyl 4-[(1-(5-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 2% of theory, <br><br> M.p.: 127-129°C 5 Calculated: m/e = 440 <br><br> Found: m/e = 440 <br><br> (e) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid <br><br> 10 Yield: 16.9% of theory, <br><br> M.p.: 172-175°C <br><br> Calculated: C 68.73 H 6.55 N 7.29 Found: 68.78 6.62 7.31 <br><br> 15 Example 37 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid <br><br> 1.0 g (2.33 mmol) of 4-[(1-(5-chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid 20 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 kieselguhr and the filtrate is concentrated by evaporation jji vacuo. The evaporation 25 residue is distributed at pH 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated Jji vacuo. <br><br> Yield: 0.61 g (66% of theory), <br><br> M.p.: 213-215°C 30 Calculated: C 73.07 H 7.66 N 7.10 <br><br> Found: 73.18 7.42 7.27 <br><br> The same compound is also obtained from the corresponding 4-chloro-, 3-chloro- or 6-chloro-substituted 35 starting products. <br><br> %048.14 <br><br> - 90 - <br><br> Example 38 <br><br> Ethyl 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate <br><br> A solution of 5.0 g (11.4 mmol) of ethyl 4-5 [(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbony1-methyl]-benzoate in 45 ml of absolute dimethylformamide is added dropwise, with stirring, at ambient temperature, to 548 mg (11.4 mmol) of sodium hydride (50% in - oil) in 10 ml of absolute dimethylformamide. The 10 mixture is stirred for a further 15 minutes and then a solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of absolute dimethylformamide is slowly added dropwise thereto. The mixture is stirred for a further 2.5 hours at ambient temperature, evaporated in vacuo 15 and distributed between water and ether. The ether phase is dried and filtered and concentrated by evaporation iri vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 20/1) . <br><br> 20 Yield: 1.8 g (34.9% of theory), <br><br> M.p.: 115-117°C <br><br> Calculated: C 71.65 H 8.02 N 6.1$ <br><br> Found: 71.47 7.86 6.19 <br><br> 25 The following compound was obtained analogously to Example 38: <br><br> (a) Ethyl 4-[(1-(5-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate 30 Yield: 68.4% of theory, <br><br> M.p.: 142-145°C <br><br> Calculated: C 71.65 H 8.02 N 6.19 Found: 71.87 8.06 6.38 <br><br> 35 Example 39 <br><br> „ pE N <br><br> /• &lt;3 ^ o x tl <br><br> ■5 MAR I986i <br><br> / <br><br> 2,3-Dihydroxy-propyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate <br><br> A solution of 2.0 g (5.07 mmol) of 4—[ (1—(2- <br><br> 04814 <br><br> - 91 - <br><br> piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid and 0.85 g (5.27 mmol) of N,N'-carbonyldi-imidazole in 20 ml of absolute tetrahydrofuran is refluxed for 1 hour, then 3.7 ml (50.7 mmol) of glycerol 5 are added and the resulting mixture is refluxed for a further 15 hours. It is then concentrated by evaporation iji vacuo, distributed between water and ethyl acetate, the organic solution is dried and filtered and evaporated iri vacuo. The evaporation residue 10 is purified by column chromatography on silica gel (toluene/acetone = 1:1). <br><br> Yield: 1.1 g (46.2% of theory), <br><br> M.p.: 120-122°C <br><br> Calculated: C 69.21 H 7.74 N 5.98 <br><br> 15 Found: 69.23 7.78 5.93 <br><br> The following compounds were obtained analogously to Example 39: <br><br> 20 (a) 2-hydroxy-ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 80% of theory, <br><br> M.p.: 125-127°C <br><br> Calculated: C 71.21 H 7.81 N 6.39 25 Found: 71.35 7.54 6.33 <br><br> 30 <br><br> (b) 2-methoxy-ethyl 4-[(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 55.9% of theory, <br><br> M.p.: 120-123 °C <br><br> Calculated: C 71.65 H 8.02 N 6.19 Found: 72.03 8.03 6.24 <br><br> 35 <br><br> Example 40 <br><br> 2-Nicotinoyloxy-ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate <br><br> A solution of 0.7 g (4.68 mmol) of nicotinic acid chloride in 20 ml of methylene chloride is rapidly <br><br> - 92 - <br><br> added dropwise to a stirred solution of 2.0 g (4.56 mmol) of 2-hydroxyethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 40 ml of methylene chloride and 0.7 ml (4.81 mmol) of triethylamine. The resulting mixture is stirred at 20°C for 2.5 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). <br><br> Yield: 1.1 g (44% of theory), <br><br> M.p.: 132-135°C <br><br> Calculated: C 70.70 H 6.86 N 7.73 <br><br> Found: 70.82 6.82 7.91 <br><br> Example 41 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzyl alcohol <br><br> A solution of 5.0 g (11.83 mmol) of ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 75 ml of absolute tetrahydrofuran is added dropwise, at an internal temperature of 0°C, to a stirred suspension of 0.68 g (17.95 mmol) of lithium aluminium hydride in 25 ml of absolute tetrahydro-furan. The mixture is stirred for 20 hours at ambient temperature then cooled to 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. <br><br> The ether phase is dried and filtered and concentrated by evaporation iji vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1). <br><br> Yield: 1.0 g (22% of theory), <br><br> M.p.: 152-154 °C <br><br> Calculated Found: <br><br> C 75.75 75.90 <br><br> - 93 - <br><br> H 8.48 8.45 <br><br> N 7.36 7.28 <br><br> 41 <br><br> 204814 <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> Example 42 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde <br><br> 6.6 g (62 mmol) of sodium carbonate! are heated together with 62 ml of ethylene glycol in a bath at 170°C and, within 1 minute, 6.2 g (11 mmol) of N^"- [ 4- [ (1- (2-piper idino-phenyl) -1-butyl) -aminocarbony 1-methyl]-benzoyl]-N -tosyl-hydrazine (melting point 195°C (decomposition)) are added thereto, with rapid stirring, whereupon there is a vigorous development of gas. The mixture is then heated for a further 2.5 minutes at 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) . <br><br> Yield: 2.2 g (52.9% of theory), <br><br> M.p.: 142-145°C <br><br> Calculated: C 76.16 H 7.99 N 7.40 <br><br> Found: 76.26 7.96 7.37 <br><br> Example 43 <br><br> Ethyl 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -cinnamate <br><br> A solution of 2.80 g (12.5 mmol) of ethyl diethyl-phosphonoacetate in 10 ml of absolute dimethylformamide is added dropwise, at ambient temperature, 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 2.4 g (6.34 mmol) of 4-[ (1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde in 10 ml of absolute dimethylformamide is added dropwise thereto. The mixture is stirred <br><br> - 94 - <br><br> for 2 hours at ambient temperature, concentrated by evaporation _in vacuo and distributed between water and ether. The ether phase is dried and filtered and then evaporated in vacuo. The evaporation residue 5 is purified by column chromatography on silica gel (toluene/acetone = 10/1). <br><br> Yield: 0.85 g (29.9% of theory), <br><br> M.p.: 135-137°C (ether/petroleum ether) <br><br> ■ Calculated: C 74.97 H 8.09 N 6.24 <br><br> 10 Found: 74.91 7.89 6.29 <br><br> Example 44 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] cinnamic acid <br><br> 15 Prepared by alkaline saponification of ethyl <br><br> 4-[(1-(2-piper id i no-phenyl)-1-butyl)-aminocarbonylmethyl] cinnamate analogously to Example 25. <br><br> Yield: 64% of theory, <br><br> M.p.: 180-183°C 20 Calculated: C 74.26 H 7.67 N 6.66 <br><br> Found: 74.03 7.47 6.80 <br><br> 25 <br><br> 30 <br><br> 35 <br><br> Example 45 <br><br> Ethyl 3—[4—[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -phenyl] -propionate <br><br> 0.60 g (1.34 mmol) 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 at ambient temperature under 5 bar of hydrogen. The mixture is filtered and concentrated by evaporation in vacuo. <br><br> Yield: 0.53 g M.p.: 98-99°C Calculated: Found: <br><br> (88% of theory), (petroleum ether) C 74.63 H 8.50 74.64 8.58 <br><br> N <br><br> 6.22 <br><br> 6.23 <br><br> The following compound was obtained analogously to Example 45: <br><br> 481 <br><br> 04814 <br><br> - 95 - <br><br> (a) 3—[4 — [(1-(2-Piperidino-phenyl)-1-butyl)-amino-carbonylmethyl] -phenyl] -propionic acid Yield: 63% of theory, <br><br> M.p.: 131-133°C 5 Calculated: C 73.90 H 8.11 N 6.63 <br><br> Found: 73.96 8.30 6.56 <br><br> Example 46 <br><br> 3—[4 —[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-10 methyl]-phenyl]-propionic acid <br><br> Prepared by alkaline saponification of ethyl 3-[4-[(1-(2-piper idino-phenyl)-1-butyl)-aminocarbony1-methyl]-phenyl]-propionate analogously to Example 25. <br><br> 15 Yield: 50% of theory, <br><br> M.p.: 131-133°C <br><br> Calculated: C 73.90 H 8.11 N 6.63 <br><br> Found: 73.8 2 8.07 6.41 <br><br> 20 Example 47 <br><br> Ethyl 4-[(a-aminocarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoate <br><br> At 20°C, 0.90 g (5.5 mmol) of N,N'-carbonyIdi-imidazole are added to a stirred solution of 2.0 g 25 (4.7 mmol) of ethyl 4-[(a-carboxy-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoate x 0.167 ^0 (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 then cooled to 60°C 30 and at this temperature a vigorous current of dry ammonia is introduced over a period of half an hour. Then the resulting mixture is evaporated jln vacuo, distributed between water and chloroform, then the combined chloroform extracts are shaken with a little 35 water, dried, filtered and evaporated i_n vacuo. <br><br> The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 5/1). Yield: 1.0 g (50.2% of theory), <br><br> 5MARI98&amp;; <br><br> /) <br><br> - 96 - <br><br> M.p.: 160-162°C (acetone) <br><br> Calculated: C 68.07 H 6.90 N 9.92 <br><br> Found: 68.40 6.92 9.84 <br><br> 5 Example 48 <br><br> Ethyl 4-[(a-cyano-2-piperidino-benzyl)-aminocarbonyl- <br><br> i methyl]-benzoate <br><br> 234 mg (1.22 mmol) of 4-toluenesulphochloride are added in two batches to 520 mg (1.22 mmol) of 10 ethyl 4-[(a-aminocarbony1-2-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 15 resulting mixture is heated for a further hour at 50°C. After it has been left to stand for 2 days 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 20 is concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1). <br><br> Yield: 325 mg (65.7% of theory), <br><br> M.p.: 114-117°C (ether/petroleum ether) <br><br> 25 Calculated: C 71.09 H 6.71 N 10.36 <br><br> Found: 70.79 6.56 10.10 <br><br> Example 49 <br><br> 4-[(a-Cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-30 benzoic acid <br><br> 1.5 g (3.7 mmol) of ethyl 4-[(a-cyano-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoate in 15 ml of dioxan are stirred together with 3.7 ml of IN sodium hydroxide solution for 45 minutes in a bath at 60°C 35 and for a further 45 minutes in a bath at 80°C. <br><br> t&gt;- T £ A' <br><br> * q\ After cooling with ice, the mixture is combined with <br><br> ' ^\3.7 ml of IN hydrochloric acid, the dioxan is evaporated <br><br> *5 MAR 1986 Zi off in vacuo and the residue is distributed between <br><br> - 97 - <br><br> water and chloroform. The organic solution is extracted with a little water, then dried and filtered and concentrated by evaporation iji vacuo. The evaporation residue is purified by column chromatography on silica 5 gel (chloroform/ethanol = 5/1). <br><br> Yield: 0.50 g (35.7% of theory), <br><br> M.p.: 176-180°C (decomposition) <br><br> Calculated: C 70.01 H 6.14 N 11.13 <br><br> - Found: 70.02 6.19 11.05 <br><br> 10 <br><br> Example 50 <br><br> 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x H^SQ^ <br><br> 5 ml (2.50 mmol) of IN sulphuric acid are added 15 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 iii vacuo and triturated with acetone. <br><br> Yield: 0.80 g (65% of theory), <br><br> 20 M.p.: 192-197°C (decomposition). <br><br> Calculated: C 58.53 H 6.55 N 5.69 <br><br> Found: 58.05 6.54 5.49 <br><br> The following addition salt was obtained analogously 25 to Example 50: <br><br> (a) <br><br> 30 <br><br> 35 <br><br> S 6.49 6.35 <br><br> 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid x 0.5 H^SO^ x 1.5 H^O Prepared analogously to Example 50 with half the quantity of sulphuric acid. <br><br> Yield: 59.3% of theory, <br><br> M.p.: 180-185°C decomposition at 207-210°C Calculated C 61.26 H 7.28 N 5.95 S 3.40 Found: 61.28 6.99 6.10 3.23 <br><br> 1204814 <br><br> - 98 - <br><br> Example A <br><br> 10 <br><br> 1-butyl)-aminocarbonylmethyl] <br><br> -benzoic acid <br><br> Composition: <br><br> 1 tablet contains: <br><br> Active substance <br><br> (1) <br><br> 5 JO <br><br> mg <br><br> Corn starch <br><br> (2) <br><br> 62.0 <br><br> mg <br><br> Lactose <br><br> (3) <br><br> 48.0 <br><br> mg <br><br> Polyvinylpyrrolidone <br><br> (4) <br><br> 4.0 <br><br> mg <br><br> Magnesium stearate <br><br> (5) <br><br> 1.0 <br><br> mg <br><br> 120.0 <br><br> mg <br><br> Method of preparation: <br><br> 15 1, 2, 3 and 4 are mixed together and moistened with water. The moist mixture is pressed through a screen with a mesh width of 1.5 mm and dried at about 45°C. The dry granulate is passed through a screen with a mesh width of 1.0 mm and mixed with 20 5. The finished mixture is compressed in a tablet press, using punches 7 mm in diameter provided with a dividing slot, to form tablets. <br><br> Weight of tablet: 120 mg <br><br> 25 Example B <br><br> E *7 <br><br> o <br><br> Coated tablets containing <br><br> 2.5 mg of 4 <br><br> -[ (1- <br><br> (2-piperidino phenyl)-1-butyl)-aminocar bonylmethyl] <br><br> -benzoic acid <br><br> 1 tablet core contains: <br><br> 30 <br><br> Active substance <br><br> (1) <br><br> 2.5 <br><br> mg <br><br> Potato starch <br><br> (2) <br><br> 44.0 <br><br> mg <br><br> Lactose <br><br> (3) <br><br> 30.0 <br><br> mg <br><br> Polyvinylpyrrolidone <br><br> (4) <br><br> 3.0 <br><br> mg <br><br> Magnesium stearate <br><br> (5) <br><br> 0.5 <br><br> mg <br><br> 35 <br><br> 80.0 <br><br> mg <br><br> 5 MAR1986 <br><br> R 1 4*048.14 <br><br> cs <br><br> - 99 - <br><br> Method of preparation: <br><br> 1, 2, 3 and 4 are thoroughly mixed and moistened with water. The moist mass is passed through a screen with a mesh width of 1 mm, then dried at 45°C and 5 the granulate is again passed through the same screen. After the addition of 5, convex tablet cores 6 mm in diameter are produced in a tablet-making machine by compression. The tablet cores thus produced are coated in known manner with a coating consisting 10 essentially of sugar and talc. The finished coated tablets are polished with wax. <br><br> Weight of coated tablet: 120 mg <br><br> Example C <br><br> 15 Tablets containing 10 mg of 4-[(1-(2-piperidino-phenyl) 1-butyl)-aminocarbonylmethyl]-benzoic acid <br><br> Composition: <br><br> 1 tablet contains: <br><br> 20 Active substance 10.0 mg <br><br> Powdered lactose 70.0 mg <br><br> Corn starch 31.0 mg <br><br> Polyvinylpyrrolidone 8.0 mg <br><br> Magnesium stearate 1.0 mg <br><br> 25 120.0 mg <br><br> Method of preparation <br><br> A mixture of the active substance, lactose and corn starch is moistened with a 20% solution 30 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 45°C. The dried granulate is rubbed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate. 35 Weight of tablet: 120 mg <br><br> Punch: 7 mm in diameter with dividing slot. <br><br></p> </div>

Claims (10)

  1. <div class="application article clearfix printTableText" id="claims">
    <p lang="en">
    48 IAS.14<br><br>
    - 100 -<br><br>
    Example D<br><br>
    Coated tablets containing 5 mg of 4-[(1-(2-piperidino-phenyl) -1-butyl)-aminocarbonylmethyl]-benzoic acid<br><br>
    5 1 tablet core contains:<br><br>
    Active substance 5.0 mg<br><br>
    Secondary calcium phosphate 70.0 mg<br><br>
    Corn starch 50.0 mg<br><br>
    Polyvinylpyrrolidone 4.0 mg<br><br>
    10 Magnesium stearate 1.0 mg<br><br>
    130.0 mg<br><br>
    Method of preparation<br><br>
    A mixture of active substance, calcium phosphate 15 and corn starch is moistened with a 15% solution of polyvinylpyrrolidone in water. The moist mass is passed through a screen with a mesh size of 1 mm,<br><br>
    then dried at 45°C and passed through the same screen again. After the specified amount of magnesium stearate 20 has been added, tablet cores are compressed from the mixture.<br><br>
    Weight of core: 130 mg Punch: 7 mm in diameter.<br><br>
    25 A coating of sugar and talc is applied to the tablet cores thus produced in known manner. The finished coated tablets are polished with wax.<br><br>
    Weight of coated tablet: 180 mg.<br><br>
    - 101 -<br><br>
    •Claims- WHAT-ty WE CLAIM; IS:-1. Compounds of general formula I<br><br>
    [wherein<br><br>
    A represents a group of formula<br><br>
    - CH - or<br><br>
    [wherein 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 gro.up; an alkyl group containing 4 to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene moiety; an aminocarbonyl group optionally mono-or disubstituted by alkyl or phenylalkyl groups r<br><br>
    each having 1 to 3 carbon atoms in the alkyl moiety (the substituents in the case of disubstitution being the same or different); an aryl group containing 6 or 10 carbon atoms mono- or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl and/or alkylsulphonyl groups, the substituents in the case of disubstitution being the same or different and each alkyl moiety containing 1 to 3 carbon atoms; or a heteroaryl<br><br>
    5/6 C<br><br>
    - C -<br><br>
    04814<br><br>
    - 102 -<br><br>
    group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms; or<br><br>
    R^ represents a methyl group when, simultaneously, R^ represents a piperidino group, R2 represents 5 a fluorine atom in the 4-position of the aromatic nucleus, R^ represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group (wherein _ ' the alkyl moiety may contain 1 to 3 carbon atoms);' or<br><br>
    R^ represents a phenyl group when R-^ represents 10 a piperidino group substituted in the 2- or 3-position by a methyl group,<br><br>
    or when R2 represents a chlorine atom in the 3-, 4- or 6-position, or a methyl group in the 4- or 6-position, of the aromatic nucleus,<br><br>
    15 or when W represents a formyl, carboxyvinylene or alkoxycarbonylvinylene group (wherein the alkyl moiety may contain 1 to 3 carbon atoms);<br><br>
    I<br><br>
    Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 20 to 9 carbon atoms or a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety];<br><br>
    R1 represents an unbranched alkyleneimino group containing 4 to 9 carbon atoms optionally mono- or disubstituted by alkyl groups containing<br><br>
    25 1 to 3 carbon atoms (which in the case of disubstitution are ojdowaUy pnjay bo| the same or different) ; or a dialkylamino group containing 1 to 5 carbon atoms in each alkyl component;<br><br>
    R2 represents a hydrogen, fluorine, chlorine, 30 bromine or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyl-<br><br>
    j_ 214814<br><br>
    - 103 -<br><br>
    oxy, alkanoylamino, alkylamino or dialkylamino<br><br>
    Contains group wherein the alkyl component tmajly oontainl 1 to 3 carbon atoms in each case;<br><br>
    represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom; and<br><br>
    W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms ii<br><br>
    (wherein the alkyl component pRjsty optionally feel 10 substituted by a phenyl group and optionally, at any carbon atom except the a-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy group, each alkyl component containing 1 to 3 carbon 15 atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms; an alkyl group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxy-20 ethyl, 2-carboxyethenyl, 2,2-bis-(carboxy)-ethyl, alkoxycarbony1-methyl, 2-alkoxycarbony1-ethyl, 2-alkoxycarbonyl-ethenyl or 2,2-bis-(alkoxycarbonyl)-ethyl group (each alkoxy group containing from 1 to 3 carbon atoms)]<br><br>
    25 and tautomers thereof and optical enantiomers thereof and salts of the aforementioned compounds.<br><br>
  2. 2. Salts of compounds of general formula I as defined in claim 1 and tautomers thereof, and optical enantiomers thereof, formed with hydrochloric, hydro-30 bromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid or with sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, dethanolamine, triethanolamine or ethylenediamine.<br><br>
    4814<br><br>
    - 104 -<br><br>
  3. 3. Physiologically compatible salts of compounds of general formula I as defined in claim 1 and tautomers thereof, and optical enantiomers thereof.<br><br>
  4. 4. Compounds as claimed in claim 1, wherein A represents a group of formula<br><br>
    - CH -<br><br>
    or<br><br>
    R5 *6<br><br>
    ^c'<br><br>
    II<br><br>
    - c -<br><br>
    10<br><br>
    15<br><br>
    20<br><br>
    wherein represents an alkyl group containing 1<br><br>
    to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group;<br><br>
    an n-propyl group; an alkyl group containing 4 to<br><br>
    6 carbon atoms; an alkenyl group containing 3 to<br><br>
    5 carbon atoms; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atoms ;mono-<br><br>
    or disubstituted by halogen atoms, or by alkyl, hydroxy,<br><br>
    alkoxy, phenylalkoxy and/or alkylsulphenyl groups,<br><br>
    are t&gt;pt"ia*xUu whilst the substituents fmhy bo&gt; tne same or different<br><br>
    COvtuitf and each alkyl component pnayj^ oontainl from 1 to 3 carbon atoms; or a pyridyl, quinolyl or isoquinolyl group;<br><br>
    25<br><br>
    R^ and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety;<br><br>
    R^ represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups each having 30 1 to 3 carbon atoms;<br><br>
    R2 represents a hydrogen, fluorine, chlorine<br><br>
    04814<br><br>
    10<br><br>
    - 105 -<br><br>
    or bromine atom or a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms; or<br><br>
    (if Rg and Rg are as hereinbefore defined or R^ represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group, an n-propyl group, an alkyl group containing 4 to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms, or a nitrile or aminocarbonyl group) R2 may also represent an iodine atom or a hydroxy or amino group;<br><br>
    and<br><br>
    R^ represents a hydrogen or chlorine atom;<br><br>
    W represents a methyl, hydroxymethyl, formyl,<br><br>
    cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or<br><br>
    15 2-carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which is cpttonallu the alkyl component frrjay bef substituted at any carbon atom except the a-carbon atom by 1 or 2 hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms 20 or by a pyridinecarbonyloxy group; or an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-<br><br>
    cuntAinj ethenyl group, wherein each alkoxy group ftiayji oontainl from 1 to 3 carbon atoms; and<br><br>
    4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl)-amino-25 carbonylmethyl]-benzoic acid and alkyl esters thereof,<br><br>
    4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] cinnamic acid and alkyl esters thereof,<br><br>
    4-[N-(4-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof,<br><br>
    - 106 -<br><br>
    4- [N- (3-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl]-benzoic acid and C^_2 alkyl esters thereof,<br><br>
    4-[N-(6-methy1-a-phenyl-2-piperidino-benzyl)-amino-5 carbonylmethyl]-benzoic acid and alkyl esters thereof,<br><br>
    4-[N-(4-methy1-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and C^_3 alkyl esters thereof,<br><br>
    10 4- [N-(2-(2-methyl-piperidino)-a-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid and C^_3 alkyl esters thereof,<br><br>
    4-[N-(2-(3-methyl-piperidino)-a-phenyl-benzyl)-aminocarbony1-methyl]-benzoic acid and alkyl<br><br>
    15 esters thereof,<br><br>
    4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzaldehyde,<br><br>
    4-[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl] -benzoic acid and C^_g alkyl esters thereof,<br><br>
    20 and tautomers and optical enantiomers of the above-named compounds and salts thereof.<br><br>
  5. 5. Compounds as claimed in claim 1, wherein: A represents a group of formula<br><br>
    - 204814<br><br>
    204814<br><br>
    107<br><br>
    wherein represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano or aminocarbonyl group; an alkyl group containing 4 to 6 carbon 5 atoms, an alkenyl group containing 3 to 5 carbon atoms; a phenyl group substituted by a fluorine,<br><br>
    chlorine or bromine atom or by a methyl, hydroxy,<br><br>
    methoxy, benzyloxy or methylsulphenyl group; or a pyridyl group;<br><br>
    10 Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moietyx^*<br><br>
    R^ represents an unbranched alkyleneimino group 15 containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by methyl groups^ •<br><br>
    R2 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group; or,<br><br>
    if Rg and Rg are as hereinbefore defined or R^ represents 20 an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, nitrile or aminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or an alkenyl group containing<br><br>
    OftionaMu rt*nJe*tS<br><br>
    3 to 5 carbon atoms, R0 also pr^procont} an iodine 25 atom or<br><br>
    W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-30 ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms wherein the alkyl<br><br>
    IS Optimally component fmjay—bej substituted at any carbon atom except and<br><br>
    R<br><br>
    '2048 14 204®!4<br><br>
    - 108 -<br><br>
    the a-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-alkoxycarbony1-ethyl or 2-alkoxycarbonyl-<br><br>
    COrttq Tnj<br><br>
    5 ethenyl group, wherein each alkoxy group ima^ oontainl from 1 to 3 carbon atoms, and<br><br>
    4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl] -benzoic acid and C^_g alkyl esters thereof,<br><br>
    10 4-[N-(a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl] cinnamic acid and alkyl esters thereof,<br><br>
    4-[N-(4-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and C-^_g alkyl esters thereof,<br><br>
    4-[N-(3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarb-15 onylmethyl]-benzoic acid and C^_g alkyl esters thereof,<br><br>
    4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof,<br><br>
    4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and C13 alkyl esters thereof,<br><br>
    20 4-[N-(2-(2-methyl-piperidino)-a-phenyl-benzyl)-amino-carbonyl-methyl]-benzoic acid and alkyl esters thereof,<br><br>
    4-[N-(2-(3-methyl-piperidino)-a-phenyl-benzyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof,<br><br>
    25 4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde,<br><br>
    2048.14<br><br>
    - 109 -<br><br>
    4-[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl] -benzoic acid and C^_g alkyl esters thereof,<br><br>
    and tautomers and optical enantiomers of the above-named compounds and salts thereof.<br><br>
    10<br><br>
  6. 6. Compounds as claimed in claim 5, wherein<br><br>
    W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in is eptiDnatiy which the alkyl component |m|ay bol substituted at any carbon atom except the a-carbon atom by one or two hydroxy groups.<br><br>
  7. 7. Compounds as claimed in claim 5 wherein W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms.<br><br>
    15<br><br>
  8. 8. Compounds as claimed in claim 1, wherein A represents a group of formula r,<br><br>
    Rfi<br><br>
    5-c" 6<br><br>
    - CH -<br><br>
    or<br><br>
    - C -<br><br>
    20 wherein R^ 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, or a pyridyl group;<br><br>
    Rg and Rg together with the carbon atom between 25 them represent an alkylidene group containing 3 to<br><br>
    5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part;<br><br>
    R^ represents a piperidino group optionally substituted by one or two methyl groups;<br><br>
    R,<br><br>
    2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group;<br><br>
    R^ represents a hydrogen atom; and<br><br>
    04814<br><br>
    - no -<br><br>
    W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms.<br><br>
  9. 9. Compounds as claimed in claim 8, wherein A represents a group of formula r,<br><br>
    - CH -<br><br>
    or<br><br>
    Rfi<br><br>
    5-c-6<br><br>
    II<br><br>
    - C -<br><br>
    wherein R^ represents an n-propyl group or an alkyl 10 group containing 4 or 5 carbon atoms and Rg and Rg 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.<br><br>
    15 10. 4-[N-(6-Chloro-o-phenyl-2-piperidino-benzyl)-aminocarbony 1-methyl]-benzoic acid and C-^j3 alkyl esters thereof.<br><br>
    11. 4-[N-(a-Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -cinnamic acid and C^_^ (alkyl esters thereof.<br><br>
    20 12. 4-[N-(4-Chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and C^_3 alkyl esters thereof.<br><br>
    13. 4-[N-(3-Chloro-a-phenyl-2-piper idino-benzyl)-aminocarbonyl-methyl]-benzoic acid and C^_^ alkyl 25 esters thereof.<br><br>
    T E /v ;<br><br>
    o<br><br>
    ~ 5 MAR 1986<br><br>
    //<br><br>
    14. 4-[N-(6-Methyl-a-phenyl-2-piperidino-benzyl) aminocarbonyl-methyl]-benzoic acid and C^_^ alkyl esters thereof.<br><br>
    15. 4-[N-(4-Methy1-a-phenyl-2-piperidino-benzyl)-<br><br>
    - Ill -<br><br>
    aminocarbonyl-methyl]-benzoic acid and alkyl esters thereof.<br><br>
    16. 4-[N-(2-(2-Methyl-piperidino)-a-phenyl-benzyl)-aminocarbonyl-methyl]-benzoic acid and alkyl<br><br>
    5 esters thereof.<br><br>
    17. 4-[N-(2-(3-Methyl-piper idino)-a-phenyl-benzyl)-- aminocarbonyl-methyl]-benzoic acid and alkyl esters thereof.<br><br>
    18. 4-[N-(a-Phenyl-2-piper idino-benzyl)-aminocarbony1-10 methyl]-benzaldehyde.<br><br>
    19. 4-[(1-(4-Fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid and C^^ alkyl esters thereof.<br><br>
    20. 4-[N-[a-(4-Fluoro-phenyl)-2-piperidino-benzyl]-15 aminocar bony Ijbethyl] -benzoic acid and alkyl esters thereof.<br><br>
    21. 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof.<br><br>
    22. 4-[(1-(2-Piperidino-phenyl)-1-buten-l-yl)-amino-20 carbonylmethyl]-benzoic acid and alkyl esters thereof.<br><br>
    23. 4-[(1-(2-Piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl] -benzoic acid and C-^_3 alkyl esters thereof.<br><br>
    24. Tautomers and optical enantiomers of compounds 25 as claimed in any one of claims 10 to 23, and salts thereof.<br><br>
    25. Enantiomers and salts of compounds as claimed<br><br>
    = 5 MAR 1986^<br><br>
    048.14<br><br>
    - 112 -<br><br>
    in any one of claims 20 to 23.<br><br>
    26. Compounds as claimed in claim 1 wherein A represents a group of formula<br><br>
    R4<br><br>
    I<br><br>
    —CH —<br><br>
    wherein 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, whilst the substitu-<br><br>
    are optfonaliu ents in the case of disubstitution jmhy bofxhe<br><br>
    *■ coHtaiiS<br><br>
    same or different and each alkyl moiety ftjay -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;<br><br>
    R^ represents an unbranched alkyleneimino group containing 4 to 6 carbon atoms optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; an octahydroazocino, octahydro-lH-azonino or decahydroazecino group; or a dialkylamino group containing 1 to 5 carbon atoms in each alkyl component;<br><br>
    R^ represents a hydrogen or halogen atom;<br><br>
    W represents a carboxy, formyl, hydroxymethyl,<br><br>
    cyano, aminocarbonyl, 2-carboxyethenyl, 2-carboxyethyl, or 2,2-bis-(carboxy)-ethyl group, an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms, an ethenyl group monosub-stituted at the 2-position by an alkoxycarbonyl group or an ethyl group mono- or di-substituted at the 2-position by alkoxycarbonyl groups<br><br>
    , contains<br><br>
    (wherein each alkoxycarbonyl group frnay/ oonta-inj<br><br>
    - 113 -<br><br>
    from 2 to 4 carbon atoms in total); and represents a fluorine or bromine atom, a chlorine atom in the 3-, 4- or 6-position (relative to the substituent A), a nitro group or an alkyl or alkoxy group containing 1 to 3 carbon atoms; or (when either:<br><br>
    represents an unbranched alkyleneimino group substituted by one or two alkyl groups; an octahydroazocino, octahydro-lH-azonino or decahydro azecino group, or a dialkylamino group; and/or represents an aryl group mono- or di-substituted by halogen atoms or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups; a naphthyl group; or a heteroaryl group containing 4,5,8 or 9 carbon atoms and 1 or 2 nitrogen atoms; and/or<br><br>
    ' J' '<br><br>
    represents a hydroxymethyl, formyl, qyano, aminocarbonyl, 2-carboxyethenyl, 2-carboxyethyl or 2,2-bis-(carboxy)-ethyl group; an ethenyl group substituted at the 2-position by an alkoxycar bonyl group or an ethyl group mono- or di-sub-stituted at the 2-position by alkoxycarbonyl groups; and/or represents a halogen atom),<br><br>
    optionally refuc^ts tn^ayl also [rjaprooontt a hydrogen atom or a chlorine atom at the 5-position.<br><br>
    Compounds as claimed in claim 1, wherein represents a group of formula<br><br>
    - 114 -<br><br>
    wherein represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkyl group containing 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneimino group containing 4 to 6 carbon atoms in the alkylene moiety; or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety; or R^ represents a methyl group when, simultaneously, Rj represents a piperidino group, R2 represents a fluorine atom in the 4-position of the aromatic nucleus, R^ represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); and<br><br>
    R5 and Rg together with the carbon atiom 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;<br><br>
    represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups containing 1 to 3 carbon atoms;<br><br>
    represents a hydrogen, fluorine, chlorine,<br><br>
    bromine or iodine atom, an alkyl or alkoxy coi\tnZnt group wherein the alkyl component jmay^oontainj 1 to 3 carbon atoms; or a hydroxy, nitro, amino or piperidino group;<br><br>
    represents a hydrogen, fluorine, chlorine or bromine atom; and represents a carboxy group or an alkoxycarbonyl<br><br>
    4<br><br>
    JA.<br><br>
    - 115 -<br><br>
    group containing a total of 2 to 5 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms.<br><br>
    28. Compounds as claimed in claim 1 as herein speci-5 fically disclosed.<br><br>
    i r<br><br>
    29. Compounds as claimed in claim 1 as herein specifically disclosed in any of Examples 1 to 50.<br><br>
    30. Compounds as claimed in claim 26 as herein specifically disclosed in any of Examples 1 to 14.<br><br>
    10 31. Compounds as claimed in claim 27 as herein specifically disclosed in any of Examples 21, 26, 37, 47 and 48.<br><br>
    32. Compounds as claimed in any preceding claim for use in a method of treatment of diabetes mellitus<br><br>
    15 and disorders of the intermediate metabolism or the cardiac circulatory system.<br><br>
    33. A process for the preparation of compounds as claimed in claim 1, which comprises reacting a compound of general formula II<br><br>
    A - NH.<br><br>
    R<br><br>
    20<br><br>
    (II)<br><br>
    if v<br><br>
    (wherein A, and R2 are defined as in claim 1 or, if A represents one of the vinylidene groups mentioned in claim 1, the tautomers thereof or a lithium or<br><br>
    | '5MARI986Z<br><br>
    tf,<br><br>
    2048 If814<br><br>
    - 116 -<br><br>
    magnesium halide complex thereof) with a compound of general formula III<br><br>
    HO - CO -<br><br>
    (III)<br><br>
    (wherein<br><br>
    5 is defined as in claim 1 and<br><br>
    W has the meanings given for W 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, 10 subsequently cleaving any protecting group used.<br><br>
    34. A process as claimed in claim 33, wherein the reactive derivative of the compound of general formula III is an ester, thioester, halide, anhydride or imidazolide thereof.<br><br>
    15 35. A process as claimed in claim 33 or claim 34 wherein the subsequent cleaving of the protecting . group of W1, if present, is effected by hydrolysis, thermolysis or hydrogenolysis.<br><br>
    36. A process as claimed in claim 35 wherein the 20 hydrolytic cleaving is effected in the presence of an acid or of a base.<br><br>
    one.<br><br>
    37. A process as claimed in any^of claims 33 to 36 wherein the reaction is effected in the presence of a solvent.<br><br>
    19 AUG 1986 S)<br><br>
    "OV<br><br>
    :n<br><br>
    JiL<br><br>
    - 117 -<br><br>
    048.14<br><br>
    38. A process as claimed in any one of claims 33<br><br>
    to 37 wherein the reaction is effected in the presence of an acid-activating or dehydrating agent.<br><br>
    39. A process as claimed in any one of claims 33<br><br>
    5 to 37 wherein the reaction is effected in the presence of an amine-activating agent.<br><br>
    40. A process as claimed in any one of claims 33<br><br>
    to 39 wherein the reaction is effected in the presence of an inorganic or tertiary organic base.<br><br>
    10 41. A process as claimed in any one of claims 33 to 40 wherein water formed during the reaction is removed by azeotropic distillation or by the use of a drying agent.<br><br>
    42. A process as claimed in any one of claims 33<br><br>
    15 to 41 wherein the reaction is effected at temperatures of between -25 and 250°C.<br><br>
    43. A process as claimed in any one of claims 33 to 42 wherein a solvent is present and the reaction is effected at temperatures of between -10°C and the<br><br>
    20 boiling temperature of the solvent used.<br><br>
    44. A process for the preparation of compounds as claimed in claim 1 wherein W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, which comprises subjecting a compound of general 25 formula IV<br><br>
    !9sKH<br><br>
    A - NH - CO - CH<br><br>
    (IV)<br><br>
    (wherein to R^ 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-5 ethenyl group by hydrolysis, thermolysis or hydrogenolysis) to hydrolysis, thermolysis or hydrogenolysis.<br><br>
    45. A process as claimed in claim 44 wherein the group B in the compound of general formula IV represents a functional derivative (if hydrolysis is desired),<br><br>
    10 an ester with a tertiary alcohol (if thermolysis is desired) or an aralkyl ester (if hydrogenolysis is desired) of a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group. |<br><br>
    46. A process as claimed in claim 45 wherein the<br><br>
    15 functional derivative is an unsubstituted or substituted amide, nitrile, ester, thioester, orthoester, imino ether, amidine or anhydride or a malonic ester-(1)-yl, tetrazolyl or optionally substituted 1,3-oxazol-2-yl or l,3-oxazolin-2-yl group, the ester with a 20 tertiary alcohol is a tertiary butyl ester or the aralkyl ester is a benzyl ester.<br><br>
    47. A process as claimed in any one of claims 44<br><br>
    to 46, wherein the reaction is effected in the presence of a solvent.<br><br>
    '2^ 48. A process as claimed in any one of claims 44<br><br>
    -tM -nil<br><br>
    2048 12448"<br><br>
    119<br><br>
    to 47, wherein the hydrolysis is effected in the presence of an acid or a base, and the thermolysis is effected in the presence of an acid.<br><br>
    49. A process as claimed in any one of claims 44 5 to 47 wherein B in the compound of general formula<br><br>
    IV represents a cyano or aminocarbonyl group and the reaction is effected using a nitrite in the presence of an acid.<br><br>
    50. A process as claimed in claim 49 wherein the<br><br>
    10 nitrite is sodium nitrite and the acid used is sulphuric<br><br>
    51. A process as claimed in any one of claims 44 to 50 wherein the reaction is effected at temperatures of from -10 to 120°C.<br><br>
    15 52. A process as claimed in any one of claims 44<br><br>
    to 51 wherein the reaction is effected at temperatures of from ambient temperature to the boiling temperature of the reaction mixture.<br><br>
    53. A process for the preparation of compounds<br><br>
    20 as claimed in claim 1 wherein A represents a group of formula wherein R41 has the meanings given for in jblaimd 25 1 with the exception of an alkenyl group and a cyano acid.<br><br>
    CH —<br><br>
    claim group,<br><br>
    general formula V<br><br>
    which comprises reduction of a compound of y<br><br>
    1 formula V A,*"<br><br>
    n<br><br>
    1<br><br>
    304814<br><br>
    - 120 -<br><br>
    6<br><br>
    D - CO - CH<br><br>
    • R<br><br>
    (V)<br><br>
    R<br><br>
    wherein to Rg and W are defined as in claim 1 and D represents a group of formula<br><br>
    10<br><br>
    V I<br><br>
    %<br><br>
    or<br><br>
    N —<br><br>
    R5'<br><br>
    R6'<br><br>
    - C<br><br>
    \<br><br>
    N —<br><br>
    I<br><br>
    H<br><br>
    wherein R." has the meanings given hereinbefore for<br><br>
    R<br><br>
    4, with the exception of a cyano group and Rg' and<br><br>
    15 R ' together with the carbon atoms between them represent o an alkylidene group containing 1 to 7 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety.<br><br>
    54. A process as claimed in claim 53, wherein the<br><br>
    20 reduction is carried out with hydrogen in the presence of a hydrogenation catalyst.<br><br>
    55. A process as claimed in claim 54 wherein a hydrogen pressure of 1 to 5 bar is used.<br><br>
    56. A process as claimed in any one of claims 53 to 55 wherein the reduction is carried out in the<br><br>
    (Q<br><br>
    O<br><br>
    /jQ048.14<br><br>
    - 121 -<br><br>
    presence of a solvent.<br><br>
    57. A process as claimed in any one of claims 53 to 56 wherein the reduction is carried out at temperatures of between 0 and 100°C.<br><br>
    5 58. A process as claimed in claim 57 wherein the reduction is carried out at temperatures of between 20 and 50°C.<br><br>
    59. A process for the preparation of compounds as claimed in claim 1 wherein A represents a group 10 of formula<br><br>
    R4"<br><br>
    —CH —<br><br>
    wherein R4" has the meanings given hereinbefore for R4, with the exception of a cyano group, which comprises<br><br>
    15 reacting a compound of general formula VI<br><br>
    R<br><br>
    ii<br><br>
    CH - OH<br><br>
    R<br><br>
    (VI)<br><br>
    (wherein R.1<br><br>
    represents R4 as defined in claim 1 with the exception of a cyano group and R^ and R2 are 20 defined in claim 1) with a compound of general formula VII<br><br>
    5 Mar1986?!)<br><br>
    h<br><br>
    122<br><br>
    (VII)<br><br>
    R<br><br>
    3<br><br>
    - wherein and W are defined as in claim 1.<br><br>
    60. A process as claimed in claim 59, wherein 5 the reaction is effected in the presence of a strong<br><br>
    61. A process as claimed in claim 59 or claim 60, wherein the reaction is effected in the presence of concentrated sulphuric acid.<br><br>
    10 62. A process as claimed in any one of claims<br><br>
    59 to 61 wherein the reaction is effected at temperatures of between 0 and 150°C.<br><br>
    63. A process as claimed in claim 62 wherein the reaction is effected at temperatures of between 15 20 and 100°C.<br><br>
    64. A process for the preparation of compounds as claimed in claim 1 wherein R2 represents a hydrogen atom, which comprises dehalogenating a compound of general formula VIII<br><br>
    acid.<br><br>
    V E /y"^x<br><br>
    A<br><br>
    123<br><br>
    Hal<br><br>
    A - N H - CO - CH<br><br>
    2<br><br>
    (VIII)<br><br>
    R<br><br>
    1<br><br>
    R<br><br>
    3V<br><br>
    wherein , R^, A and W are as defined in claim 1 and Hal represents a fluorine, chlorine, bromine 5 or iodine atom.<br><br>
    65. A process as claimed in claim 64 wherein the dehalogenation is effected with hydrogen in the presence of a hydrogenation catalyst.<br><br>
    66. A process as claimed in claim 64 or claim 65<br><br>
    10 wherein the dehalogenation is effected in the presence of a solvent.<br><br>
    67. A process as claimed in any one of claims 64 to 66, wherein the dehalogenation is effected at temperatures of between 0 and 100°C and under a hydrogen<br><br>
    15 pressure of from 1 to 5 bar.<br><br>
    68. A process for the preparation of compounds as claimed in claim 1 wherein A represents a group of formula<br><br>
    R<br><br>
    4<br><br>
    20<br><br>
    —CH —<br><br>
    wherein R^ represents an alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or di-<br><br>
    3<br><br>
    JL<br><br>
    204814<br><br>
    - 124 -<br><br>
    substituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety, which comprises reacting a compound of general formula IX<br><br>
    COOH<br><br>
    CH - NH - CO - CH<br><br>
    (IX)<br><br>
    (wherein R^, R2 and R^ are as defined in claim 1<br><br>
    and W" represents W as defined in claim 1 with the exception of a carboxy group) with an amine of general formula X<br><br>
    H - R.<br><br>
    (X)<br><br>
    10 wherein<br><br>
    R^ 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 15 moiety.<br><br>
    69. A process as claimed in claim 68, wherein the reaction is effected in the presence of an acid-activating or dehydrating agent.<br><br>
    70. A process as claimed in claim 68 or claim 69, wherein the reaction is effected in the presence of an inorganic or tertiary organic base.<br><br>
    2048 14*814<br><br>
    - 125 -<br><br>
    71. A process as claimed in any one of claims 68<br><br>
    to 70, wherein the reaction is effected in the presence of an amine-activating agent.<br><br>
    72. A process as claimed in any one of claims 68<br><br>
    5 to 71 wherein the reaction is effected in the presence of a solvent.<br><br>
    73. A process as claimed in any one of claims 68<br><br>
    to 72, wherein the reaction is effected at temperatures of between -25 and 250°C.<br><br>
    10 74. A process as claimed in any one of claims 68<br><br>
    to 73 wherein the reaction is effected in the presence of a solvent and at temperatures of between -10°C and the boiling temperature of the solvent used.<br><br>
    75. A process for the preparation of compounds 15 as claimed in claim 1 wherein A represents a group of formula<br><br>
    R4 ^<br><br>
    I<br><br>
    — CH —<br><br>
    wherein is as defined in claim 1 and W represents 20 a carboxy group, which comprises oxidising a compound of general formula XI<br><br>
    o<br><br>
    V-c<br><br>
    5 MAR 1986^<br><br>
    4814<br><br>
    - 126 -<br><br>
    wherein<br><br>
    R, to R. are defined as in claim 1 and 1 4<br><br>
    E represents a group which can be converted into a carboxy group by oxidation.<br><br>
    5 76. A process as claimed in claim 75 wherein E represents a formyl group, an acetal of a formyl group, a hydroxymethyl group, an ether of a hydroxymethyl group, a substituted or unsubstituted acyl group or a malonic ester-(l)-yl group.<br><br>
    10 77. A process as claimed in claim 75 or claim 76 wherein the oxidising agent used is selected from:<br><br>
    silver oxide/sodium hydroxide solution, manganese dioxide/acetone, manganese dioxide/methylene chloride, hydrogen peroxide/sodium hydroxide solution, chromium 15 trioxide/pyridine, pyridinium chlorochromate, bromine/sodium hydroxide solution, chlorine/sodium hydroxide solution, bromine/potassium hydroxide solution and chlorine/potassium hydroxide solution.<br><br>
    78. A process as claimed in any one of Claims 75<br><br>
    20 to 77 wherein the oxidation is effected in the presence of a solvent.<br><br>
    79. A process as claimed in any one of claims 75<br><br>
    to 78 wherein the oxidation is effected at temperatures of between 0 and 100°C.<br><br>
    25 80. A process as claimed in claim 79 wherein the reaction is effected at temperatures of between 20 and 50°C.<br><br>
    81. A process for the preparation of compounds as claimed in claim 1 wherein W represents an alkoxycarbonyl group containing a total of 2 to 6 carbon 30 atoms wherein the alkyl component may be substituted at any carbon atom except the a-carbon atom by one<br><br>
    204814<br><br>
    - 127 -<br><br>
    or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms, which comprises esterifying a carboxylic acid of general formula XII<br><br>
    A - NH - CO - CH<br><br>
    5 (wherein to R^ and A are as defined in claim 1), or a reactive derivative thereof optionally prepared in the reaction mixture, with an alcohol of general formula XIII<br><br>
    HO -<br><br>
    (XIII)<br><br>
    10 wherein<br><br>
    Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at; any carbon atom except the a-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon 15 atoms.<br><br>
    82. A process as claimed in claim 81, wherein the reactive derivative of the compound of general formula XII, if present, is a halide, anhydride or imidazolide thereof.<br><br>
    20 83. A process as claimed in claim 81 or claim 82<br><br>
    wherein the ester ification is effected in the presence of a solvent.<br><br>
    83<br><br>
    84. A process as claimed in claim -8-5* wherein the solvent is an excess of the alcohol of general formula<br><br>
    5 MAR 1986<br><br>
    ° I<br><br>
    l»?/.<br><br>
    .204814<br><br>
    - 128 -<br><br>
    XIII.<br><br>
    85. A process as claimed in any of one of claims 81 to 84 wherein the ester ification is effected in the presence of an acid-activating or dehydrating<br><br>
    5 agent.<br><br>
    86. A process as claimed in any one of claims 81 to 85 wherein the ester ification is effected in the presence of a reaction accelerator.<br><br>
    87. A process as claimed in any one of claims 81 10 to 86 wherein the ester ification is effected in the presence of an inorganic or tertiary organic base.<br><br>
    88. A process as claimed in any one of claims 81<br><br>
    to 87 wherein the ester ification is effected at temperatures of between -20 and 100°C.<br><br>
    15 89. A process as claimed in any one of claims 81 to 88, wherein the ester ification is effected in the presence of a solvent and at temperatures of between -10°C and the boiling temperature of the solvent used.<br><br>
    20 90. A process for the preparation of compounds as claimed in claim 1 wherein W represents an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxy-carbonyl-ethyl or 2-alkoxycarbonylethenyl group and A represents a group of formula<br><br>
    25<br><br>
    V<br><br>
    — CH —<br><br>
    !h<br><br>
    \ "5 MAR 1986<br><br>
    wherein " represents R^ as hereinbefore defined with the exception of a cyano group, which comprises alcoholysing a compound of general formula XIV<br><br>
    204814<br><br>
    - 129 -<br><br>
    R, "<br><br>
    wherein R^" represents R^ as defined in claim 1 with the exception of a cyano group,<br><br>
    R-^ to Rg are defined as in claim 1 and W"' represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethyenyl group.<br><br>
    91. A process as claimed in claim 90, wherein the alcoholysis is effected in the presence of an acid.<br><br>
    92. A process as claimed in claim 91 wherein the acid is hydrochloric or sulphuric acid.<br><br>
    93. A process as claimed in any one of claims 90 to 92, wherein the alcoholysis is effected in the presence of a solvent.<br><br>
    94. A process as claimed in claim 93 wherein the solvent is an excess of the alcohol used in the alcoholysis reaction.<br><br>
    95. A process as claimed in any one of claims 90 to 94, wherein the reaction is effected in the presence of a solvent and at temperatures of between 20°C and the boiling temperature of the solvent used.<br><br>
    96. A process as claimed in any one of claims<br><br>
    Hgf V/ j~L V<br><br>
    1<br><br>
    204814<br><br>
    - 130 -<br><br>
    90 to 95, wherein the reaction is effected at temperatures of between 50 and 100°C.<br><br>
    97. A process as claimed in any one of claims 33 to 96 wherein a compound of general formula 5 I initially obtained, wherein W represents a carboxy or alkoxycarbonyl group, is subsequently converted by reduction into a corresponding compound of general formula I wherein W represents a formyl or hydroxymethyl group.<br><br>
    10 98. A process as claimed in any one of claims 33 to »?, 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 15 disproportionation, into a corresponding compound of general formula I wherein W represents a formyl group.<br><br>
    99. A process as claimed in any one of claims 33 to 98, wherein a compound of general formula<br><br>
    20 I intially obtained, wherein W represents a formyl group, is subsequently 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 25 or a 2-carboxy-ethenyl group.<br><br>
    100. A process as claimed in any one of claims ltW( q&lt;]<br><br>
    33 to W, wherein a compound of general formula I initially obtained, wherein W represents a 2-carboxy-ethenyl or 2-alkoxycarbonyl-ethenyl group, is subsequently 30 converted by catalytic hydrogenation into a corresponding compound of general formula I wherein W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl grou]<br><br>
    ^ „ _ - - 204814<br><br>
    204814<br><br>
    101. A process as claimed in any one of claims 33 to JtOtT, wherein a compound of general formula I initially obtained, wherein W represents an alkoxycarbonyl group substituted at any carbon atom 5 except the a-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.<br><br>
    10 102. A process as claimed in any one of claims 33 to J-01, 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 15 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.<br><br>
    103. a process as claimed in any one of claims<br><br>
    Sfc CLrtof lO'i<br><br>
    20 33 to i€r2, 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 25 W represents an ethyl group substituted by two carboxy groups.<br><br>
    104. A process as claimed in any one of claims<br><br>
    % aid io3L<br><br>
    33 to HW, wherein a compound of general formula I initially obtained wherein W represents an ethyl 30 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.<br><br>
    105. A process as claimed in any one of claims 33 to 104, wherein a compound of general formula<br><br>
    I initially obtained wherein R2 represents a nitro group is subsequently converted by reduction into 5 a corresponding compound of general formula I wherein R2 represents an amino group.<br><br>
    106. A process as claimed in any one of claims 33 to 105, wherein a compound of general formula<br><br>
    I initially obtained wherein R2 represents an amino 10 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.<br><br>
    15 107. A process as claimed in any one of claims<br><br>
    IOif OLStcl I OS<br><br>
    33 to AGS, 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 20 R2 represents an alkoxy group.<br><br>
    108. A process as claimed in any one of claims 33 to 107, wherein a compound of general formula I initially obtained wherein R2 represents a benzyloxy group and/or R4 represents an aryl group substituted 25 by a benzyloxy group is subsequently converted by debenzylation into a corresponding compound of general formula I wherein R2 represents a hydroxy group and/or R4 represents an aryl group substituted by a hydroxy group.<br><br>
    30 109. A process as claimed in any one of claims |j^ J9 33 to 108, wherein a compound of general formula I initially obtained wherein R^ represents an amii carbonyl group is subsequently converted by dehydration<br><br>
    481<br><br>
    04814<br><br>
    - 133 -<br><br>
    into a corresponding compound of general formula I wherein represents a cyano group.<br><br>
    110. A process as claimed in any one of claims 33 to 109 wherein a compound of general formula<br><br>
    5 I initially obtained is subsequently resolved,<br><br>
    by chromatography on a chiral phase, into^ the enantiomers thereof, if it contains a chiral centre.<br><br>
    111. A process as claimed in any one of claims 33 to 110, wherein a compound of general formula<br><br>
  10. 10 I or a tautomer or optical enantiomer thereof,<br><br>
    initially obtained, is subsequently converted to a salt thereof, or a salt of a compound of general formula I or a tautomer or optical enantiomer thereof, initially obtained, is subsequently converted to 15 a compound of general formula I or a tautomer or optical enantiomer thereof.<br><br>
    112. A process as claimed in any one of claims<br><br>
    33 to 111 for the preparation of compounds as claimed in claim 26.<br><br>
    20 113. A process as claimed in any one of claims 33 to 111 for the preparation of compounds as claimed in claim 27.<br><br>
    114. A process as claimed in any one of claims 33 to 113 substantially as herein described.<br><br>
    115. A process as claimed in any one of claims 25 33 to 114 substantially as herein described in any of Examples 1 to 50.<br><br>
    5 MAR 1986<br><br>
    e\±<br><br>
    116. A process as claimed in claim 112 substantially as herein described in any of Examples 1 to 14.<br><br>
    117. A process as claimed in claim 113 substantially<br><br>
    I<br><br>
    204814<br><br>
    - 134 -<br><br>
    as herein described in any of Examples 21, 26, 37, 47 and 48.<br><br>
    118. Compounds of general formula I as defined in claim 1 and tautomers and optical enantiomers<br><br>
    5 thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in any one of claims 35 to 111, 114 and 115.<br><br>
    119. Compounds of general formula I as defined in claim 26 and tautomers and optical enantiomers<br><br>
    10 thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in claim<br><br>
    112 or claim 116.<br><br>
    120. Compounds of general formula I as defined in claim 27 and tautomers and optical enantiomers<br><br>
    15 thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in claim<br><br>
    113 or claim 117.<br><br>
    121. Pharmaceutical compositions comprising, as active ingredient, at least one compound 6f general<br><br>
    20 formula I as defined in claim 1 or a tautomer or optical enantiomer thereof, or a physiologically compatible salt of these compounds, in association with at least one pharmaceutical carrier or excipient.<br><br>
    122. Compositions as claimed in claim 121 containing 25 at least one additional active ingredient.<br><br>
    123. Compositions as claimed in claim 121 or claim 122 in a form suitable for oral or parenteral administration.<br><br>
    124. Compositions as claimed in any one of claims 121 to 123 in the form of tablets, coated tablets,<br><br>
    I<br><br>
    2048.14<br><br>
    - 135 -<br><br>
    capsules, powders or suspensions.<br><br>
    125. Compositions as claimed in any one of claims 121 to 124 in the form of dosage units.<br><br>
    126. Compositions as claimed in claim 121 wherein<br><br>
    5 the active ingredient comprises a compound as claimed in claim 26 or claim 27.<br><br>
    127. Pharmaceutical compositions as claimed in claim 121 substantially as herein described.<br><br>
    128. Pharmaceutical compositions substantially<br><br>
    10 as herein described in any one of Examples A to D.<br><br>
    BALDWIN, SON &amp; CAREY<br><br>
    ATTORNEYS FOR THE APPLICANTS<br><br>
    I<br><br>
    </p>
    </div>
NZ204814A 1982-07-06 1983-07-05 Phenylacetic acid derivatives and pharmaceutical compositions NZ204814A (en)

Applications Claiming Priority (2)

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

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NZ204814A true NZ204814A (en) 1986-10-08

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US5312924A (en) * 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
DE3347565A1 (en) * 1983-12-30 1985-07-11 Thomae Gmbh Dr K NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
GB8903592D0 (en) * 1989-02-16 1989-04-05 Boots Co Plc Therapeutic agents
FR2763590B1 (en) * 1997-05-22 2000-03-24 Synthelabo ACID DERIVATIVES [[[(ARYLMETHYL) AMINO] CARBONYL] ALKYL] - AROMATICS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
WO2004108673A2 (en) * 2003-06-09 2004-12-16 Boehringer Ingelheim International Gmbh Inhibitors of papilloma virus
EP2364977A1 (en) 2010-01-26 2011-09-14 Reuter Chemische Apparatebau KG Process for the enantiomeric enrichment of 3-methyl-1-(2-piperidinophenyl)-1-butylamine

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BE764238A (en) * 1971-03-17 1971-09-13 Lilly Industries Ltd PHENYLALKYLAMINE DERIVATIVES
NL7305171A (en) * 1973-04-13 1974-10-15
DE3100575A1 (en) * 1981-01-10 1982-09-02 Dr. Karl Thomae Gmbh, 7950 Biberach "NEW BENZOESAEURS, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS"

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GB8318250D0 (en) 1983-08-10
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DD210907A5 (en) 1984-06-27
ES8500923A1 (en) 1984-11-01
PL242873A1 (en) 1984-09-10
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IE56171B1 (en) 1991-05-08
ES8501382A1 (en) 1984-11-16
GR78661B (en) 1984-09-27
GB2124220B (en) 1985-11-13
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FI832374L (en) 1984-01-07
ES529808A0 (en) 1984-11-01
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CA1214773A (en) 1986-12-02
ES8500742A1 (en) 1984-11-01
IL69172A0 (en) 1983-11-30
ES529807A0 (en) 1984-11-01
DE3375783D1 (en) 1988-04-07
NO832430L (en) 1984-01-09
IE831573L (en) 1984-01-06
ES523869A0 (en) 1984-11-16
KR900004925B1 (en) 1990-07-12
YU146883A (en) 1986-04-30
PL143992B1 (en) 1988-04-30
FI832374A0 (en) 1983-06-29
KR840005438A (en) 1984-11-12
IL69172A (en) 1987-10-20
DK310883D0 (en) 1983-07-05
CS240970B2 (en) 1986-03-13
EP0099017A2 (en) 1984-01-25
HU195651B (en) 1988-06-28
EP0099017A3 (en) 1984-02-22
PT76986B (en) 1986-04-11
NO159590B (en) 1988-10-10
GB2124220A (en) 1984-02-15
PT76986A (en) 1983-08-01
NO159590C (en) 1989-01-18
DK310883A (en) 1984-01-07
FI78477C (en) 1989-08-10
ES529806A0 (en) 1984-11-01
AU1657683A (en) 1984-01-12

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