IE56171B1 - N-substituted phenylacetamides - Google Patents

N-substituted phenylacetamides

Info

Publication number
IE56171B1
IE56171B1 IE1573/83A IE157383A IE56171B1 IE 56171 B1 IE56171 B1 IE 56171B1 IE 1573/83 A IE1573/83 A IE 1573/83A IE 157383 A IE157383 A IE 157383A IE 56171 B1 IE56171 B1 IE 56171B1
Authority
IE
Ireland
Prior art keywords
group
carbon atoms
phenyl
alkyl
general formula
Prior art date
Application number
IE1573/83A
Other versions
IE831573L (en
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 IE831573L publication Critical patent/IE831573L/en
Publication of IE56171B1 publication Critical patent/IE56171B1/en

Links

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

Landscapes

  • 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)

Abstract

Compounds of general formula I (wherein R1 is optionally substituted polymethyleneimino or dialkylamino; A is substituted CH2; and R2, R3, and W are as defined in the specification) and tautomers, optical enantiomers and salts thereof. The new compounds have valuable pharmacological properties, particularly a hypoglycaemic effect. Processes for the preparation of the new compound and pharmaceutical compositions containing them are described.

Description

The present invention relates to new phenylacetic acid derivatives, to processes for their preparation, and to their effects on intermediate metabolism and the cardiac circulatory system.
According to one feature of the present invention, we provide compounds of general formula I >1/1 A (wherein A represents a group of formula i4 - CH or RKR* 5V / 6 C [wherein represents an alkyl group containing 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 alkvl group containino 4 to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneiminocarbonyl group containing 4 to $ carbon atoms in the alkylene moiety; an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety (the substituents in the case of disubstitution being the same or different); an aryl group containing 6 or 10 carbon atoms mono- or disubstituted by halogen atoms, or by alkyl. hydroxy, alkoxy, phenylalkoxy, alkylsulphonyl, 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 » R„ represents a methyl group when, simultaneously, R, represents a piperidino group, R2 represents a fluorine atom in the 4-position of the aromatic nucleus, R3 represents a hydrogen atom and -¾ lo w represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); or R* represents a phenyl group when Rr represents a piperidino group substituted in the 2- or 3-position by a methyl group, 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, or when H represents a formyl, carboxyvinylene or alkoxycarbonylvinylene group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); or Rs and Re together with the carbon atom between them represent a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene /0 moiety], represents an unbranched alkvleneimino group containing 4 to 9 carbon atoms optionally mono- or disubstituted by alkyl groups containing 1 to 3 carbon atoms (which in the case of disubstitution may be the same or different); or a dialkylamino group containing 1 to 5 carbon atoms in 2b each alkyl component, R2 represesnts a hydrogen, fluorine, chlorine, bromine or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyl oxy, alkanoylamino, alkylamino or dialkylamino group wherein the alkyl component may contain 1 to 3 carbon atoms in each case, R3 represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom; and H represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms (wherein the alkyl component may optionally be substituted by a phenyl group and optionally, at any carbon atom except ro the α-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkvleneimino or pvridinecarbonyloxy group> each alkyl component containing to 3 carbon atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms, an alkyl group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, 2,2-bis(carboxy)-ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonylethyl, 2-alkoxycarbonyl-ethenyl or 2,2-bis-(alkoxycarbonyl) -ethyl group (each alkoxy group containing from 1 to 3 carbon atoms)] and tautomers thereof and optical enantiomers theeof and salts of the aforementioned compounds„ It will be appreciated that the term salts" as used herein includes within its scope salts formed with organic and inorganic acids and bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid. Suitable bases include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine.
For pharmaceutical use, the salts referred to above will, of course, be physiologically compatible salts, but other salts may find use, for example in the preparation of the compounds of general formula I and their physiologically compatible salts.
The term ''tautomer" as used herein refers particularly to the tautomeric kefimine 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.
The definitions given hereinbefore for the groups to R- and M include the following, for example: R^ may represent a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-n-pentylamino, diisobutylamino, N-methyl-ethylamino, N-methyl-npropylamino, N-methyl-isopropylamino, N-isopropyl5 n-propylamino, N-isobutyl-n-propylamino, N-methyln-butylamino, N-ethyl-n-butylamino, N-ethyl-isopropylt» amino, N-ethyl-n-pentylamino, M-propyl-n-butylamino, pyrrolidino, piper idino, hexamethyleneimino, heptamethylene imino, octamethyleneimino, nonamethyleneimino, methyl-pyrrolidmo, dimethyl-pyrrolidmo, ethyl-pyrrolidino, methyl-piperidino, ethyl-piperidino, dimethylpiperidino, diethyl-piperidino, methyl-ethylpiperidino, n-propyl-piperidino, methyl-n-propylpiperidino, isopropylpiperidino, or di-n-propyl-piperidino group, 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, methylraercapto, ethylmercapto, n-propylmercapto, isopropylmereapto, methylsulphinyl, ethylsulphinyl, methylsulphonyl, n-propylsulphonyl, benzyloxy, 1-phenyl-ethoxy, 2phenyl-ethoxy, 3-phenyl-propoxy, acetoxy, propionyloxy, formylamino, acetylamino, propionylamino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino, di-n-propylamino or methyl-ethylaraino group, may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl or isopropyl g roup, may represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxyraethyl, n-propoxymethyl, ieopropoxymethyl, ® 2-mefhoxyethyl, 2-ethoxy-ethyl, 3-©ethoxy-propyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenyl-npropyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl, α 35 3-buten-l-yl, 2-buten-l-yl, 4-penten-l-yl, cyano. ami noca rbony1, met hyland nocar bony1, e thylam inoca r bony1, n-propylaminocarbonyl, <3imethylaminocarbony1, diethylaminocarbonyl, di-n-propylaminocarbonyl, benzylaminocarbonyl, 2-phenyl-ethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, phenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, methylpheny1, ethylphenyl, isopropylpheny1, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxyphenyl, 2-pheny1-ethoxy-phenyl, 3-phenylpropoxy-phenyl, methylsulphenyl-phenyl, ethylsulphenyl-phenyl, methylsulphinyl-phenyl, n-propylsulphinyl-phenyl, methylsulphonyl-phenyl, ethylsulphonyl-phenyl, isopropylsulphonyl-pheny1, methyl-naphthyl, hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl, dimethyl-phenyl, di-isopropyl-phenyl, chloro-methylphenyl, dime thoxy-phenyl, methyl-raethoxyphenyl, chloromethoxy-phenyl, bromo-methoxy-phenyl, pyridyl, pyrimidyl, quinolyl, isoguinolyl or quinazolyl group, R^ and Rg may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secebutyl or n-pentyl group, R^ and Πθ together with the carbon atoms between them may represent a benzylidene, 1-pheny1-ethylidene, 2-phenyl-ethylidene, 1-pheny1-n-propylidene, 1-phenyl2, 2-propyl idene or 3-phenyl-n-propylidene group and W may represent a hydroxymethyl, formyl, carboxy, carboxymethyl, 2-carboxy-ethyl, 2-carboxy-ethenyl, 2,2-bis-(carboxy)-ethyl, methoxycarbonylP ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbony1, isobutoxycarbonyl, n-pentyloxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, (2-hydroxyethoxy)carbonyl, (2hydroxy-n-propoxy)carbonyl, (1-hydroxy-2-propoxy)carbonyl, (2-methoxyethoxy)carbonyl, (2-ethoxyethoxy)carbonyl, (2-n-propoxyethoxy)carbonyl, (2-nicotinoyloxy-ethoxy)carbonylP (2-isonicotinoyloxy-ethoxy)carbonyl, (2,36 dihydroxy-n-propoxy)carbonyl, (2-diraethylamino-ethoxy)carbonyl, (2-diethylamino-ethoxy)carbonyl, (2-piperidino ethoxy)carbonyl, methyl, ethyl, n-propyl, isopropyl, cyano, ami nocarbonyl, mefchoxycarbonyl-methyX, ethoxy5 carbonyl-methyl, n-propoxycarbonyl-raethy1, 2-methoxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxycarbony1-ethy1, 2-methoxycarbonyl-ethenyl, 2-ethoxycarbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl, 2,2bis-(methoxycarbonyl)-ethyl, 2,2-bis-(ethoxycarbonyl)10 ethyl or 2,2-bis-(isopropoxycarbonyl)-ethyl group* Preferred compounds of general formula I above are those wherein A represents a group of formula II 15 R4 - CH - or wherein 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; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atoms mono25 or disubstituted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy and/or alkylsulphenyl groups, whilst the substituents may be the same or different and each alkyl component may contain from 1 to 3 carbon atoms; or a naphthyl, pyridyl, quinolyl or isoquinolyl group; and Π. together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing to 3 carbon atoms in the alkylidene moiety; represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms; represents a hydrogen, fluorine, chlorine or bromine atom or a nitro, alkyl or alkoxy group * each having 1 to 3 carbon atoms, or (if R^ and Rg are as hereinbefore defined or Rg represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group with 1 to 3 carbon atoms or by a phenyl group, an n-propyl group, an alkyl group containing 4 to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms, or a nitrile or aminocarbonyl group) R£ may also represent an iodine atom or a hydroxy or amino group; R^ represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl component may be substituted at any carbon atom except the a-ciubon atom by 1 or 2 hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbonyloxy group; or an alfcoxycarbonyl-methyl, 2-alkoxycarbonylethyl or 2-alfcoxycarbonyl-ethenyl group, wherein each alkoxy group may contain from 1 to 3 carbon atoms and β 4-[N»(6-chloro-c-phenyl-2-piperidino-benzyl)-aminocarbony1methyl)-benxoic acid and alkyl esters thereof. 4- I(N-(e-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] cinnamic acid and C^3 alkyl esters thereof, 4-(N-(4-chloro-ca-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid and C|_3 alkyl esters thereof, 4-[W-(3-chloro-o-phenyl-2-piperidino-benzyl)-aminocarbonylmethyll -bensoic acid and alkyl esters thereof, 4-[N-(6-methyl-a-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid and asters thereof, 4-[N-(4-methyl-e-phenyl-2-piper idino-benzyl)-aminocarbonyl10 methyl]-benzoic acid and alkyl esters thereof, 4-[N-(2-(2-methy1-piper idino)-a-phenyl-benzyl)-aminocarbonyImethyl]-benzoic acid and alkyl esters thereof, 4-[N-(2-(3-aethy1-piperidino)-α-phenyl-benzyl)-aminocarbonyl-methyl]-benzoic acid and C3-3 alkyl esters thereof, 4-[W-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethy1benzaldehyde, and 4'[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl] -bensoic acid and alkyl esters thereof.
Particularly preferred are those compounds of general formula Σ wherein A represents a group of formula CH or C II wherein R^ represents an alkyl group containing 1 * to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano or aminocarbonyl group? an alkyl group containing 4 to 6 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms? a phenyl group substituted by a fluorine, chlorine or bromine atom or by a methyl, hydroxy, methoxy, bensyloxy or mefhylsulphenyl group? or a pyridyl group? and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing I to 3 carbon atoms in the alkylidene moiety, R^ represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstifuted by methyl groups, 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 or aminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or an alkenyl group containing 3 to 5 carbon atoms) raaY also represent an iodine atom or a hydroxy or amino group. represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms wherein t-lv? alky] ι'(ΐΐί«ΗΐνηΙ liny lx- ;;ub:,l ilubtl .-.t any cmlmn atru! pi i.lu.· <1-i-.iilitm atom by one or two hydroxy groups, by an alkoxy group containing 1 to 3 carbon atoms or by a pyridinecarbony Ioxy group; or an alkoxycarbonyl-methyl, 2-alkoxycarbony]ethyl or 2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may contain from 1 to 3 carbon atoms; and - (N-(6-chloro-a-pheny1-2-piper id ino-benzyl)-amino15 carbonyl-methyl]-benzoic acid and C*_3 alkyl citers thereof, - [N-(o-pheny1-2-piper idino-benzyl)-aminocarbonylmethyl] cinnamic acid and alkyl esters thereof, 4-(N-(4-chloro-a-phenyl-2-piperidino-benzyl)-amino20 carbonyl-methyl]-benzoic acid and alkyl esters thereof, 4-(N-(3-chloro-α-pheny1-2-piper idino-benzyl)-aminocarbonyl-methyl]-benzoic acid and alkyl esters thereof, 4-[N-(6-methyl-a-pheny1-2-piper idino-benzyl)-aminoce. 1 bony 1t hy j i - 1 t i c <- c i end C ilk'.’1 « · 1 t-1 j. thereof , υ 4-[N-(4-n»ethyl- 4-[N-(2- (2-methyl-piper idino)-a-phenyl-benzyl)-amino5 carbonyl-methyl]-benzoic acid and C^_3 alkyl esters thereof, 4-[N-(2-(3-methyl-piper idino)-α-phenyl-benzyl)-aminocarbonyl-methyl]-benzoic acid and alkyl esters thereof, 4- [N- (&-phenyl-2-piper idino-benzyl)-arainocarbonylmethyl] benzaldehyde, and 4-((1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid and C3_3 alkyl esters thereof.
However, another group of preferred compounds 15 are those wherein A, to R^ and H are as hereinbefore defined, more particularly those wherein M represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl conponent may ue substituted at any carbon atom except the α-carbon atom by one or two hydroxy groups, and optically active enantiomers and the salts thereof° Particularly preferred compounds of general formula λ above are those wherein A represents a group of formula «4 I - CH - or ra Re 6 II - c 5 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, and R^ together with the carbon atom between 10 them represent an alkylidene group containing 3 to carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part; R^ represents a piperidino group optionally substituted by one or two methyl groups; R^ represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group; R^ represents a hydrogen atom and & represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms; particularly those wherein A represents a group of formula t) - CH - or - C wherein represents an n-propyl group or an alkyl group containing 4 or 5 carbon atoms and R^ 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, and optically active enantiomers and salts thereof.
The compounds of general formula X as hereinbefore defined and their optical enantiomers and salts thereof may, for example, be prepared by the following processes, which processes constitute further features of the present invention: a) Reacting a compound of general formula II R 2 o - A - NH2 R 1 (II) « (wherein A, R^ and r2 are as hereinbefore def ined or, if A represents one of the vinylidene groups mentioned hereinbefore, the tautomers thereof or a lithium or magnesium halide complex thereof) with a compound of general formula III (wherein R^ is as hereinbefore defined and has the meanings given for U hereinbefore or represents a carboxy group protected by a protecting group), or with, a reactive derivative thereof optionally formed in the reaction mixture and, if necessary, subsequently cleaving any protecting group used.
The reactive derivatives of a compound of general formula III may be, for example, the esters thereof, such as the methyl, ethyl or benzyl esters, the thioesters thereof such as the methylthio- or ethylthioesters, the halides thereof such as the acid chloride, or the anhydrides or imid&zolides thereofo The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxen, bensene, toluene, acetonitrile or dimethylformemide, 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, Ν,Ν'-dicyclohesylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy* 10 succinimide, Μ,Ν'-carbonyldiimidazole or N,N*-ihionyldiiraidazole 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°C and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. The reaction may also be carried out without a solvent and furthermore any wafer 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.
Xi necessary, the subsequent cleaving of a protecting group is preferably effected by hydrolysis, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol/water, w&ter/isopropanol or water/dloxan at temperatures of between -10°C and 120°C, e.g. at temperatures * 35 of between ambient temperature and the boiling temperature of the reaction mixture.
A tert«bufyl 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.
Moreover, a benzyl group used as a protecting group may also be cleaved by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium/ charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide. b) ΐη order io prepare a compound of general formula I wherein W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group: subjecting a compound of general formula IV (wherein to R^ and A are as hereinbefore defined, and 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,, 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 1,3oxazol-2-yl or l,3-oxazolin-2-yl group, and the thermolytically cleavable groups may be, for example, esters with tertiary alcohols, e.g. the tert.butyl ester, the hydrogenolytically cleavable groups may be, for example, esters with aralkanols, e.g. the benzyl ester.
The hydrolysis is conveniently effected either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan at temperatures of between -10°C and 120°C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.
If B in a compound of general formula IV represents a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group using a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which is conveniently also used as the solvent, at temperatures of between 0 and 50°Ce If B in a compound of general formula IV represents the tert.butyloxycarbonyl group, for example, the tertobutyl group may also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures of between 40°C and 100°C.
If B in a compound of general formula IV represents the benzyloxycarbonyl group, for example, the benzyl group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/ charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethylformamide; preferably at temperatures of between 0 and 50°C, e«.g, at ambient temperature, and at a hydrogen pressure of from 1 to 5 bar. In the hydrogenolysis, other groups may simultaneously be reduced as well (e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group), or may be replaced by hydrogen atoms, eog. a halogen atom may be replaced by a hydrogen atom» c) In order to prepare compounds of general formula I wherein A represents a group of formula V I - CH wherein R^1 has the meanings given hereinbefore for R^, with the exception of an alkenyl group and a cyano group: Reduction of a compound of general formula V 3 wherein R^ to R^ and Ή are as hereinbefore defined and D represents a group of formula C II or wherein R/’ has the meanings given hereinbefore for X» R^, with the exception of a cyano group and R^' and an alkylidene group containing 1 to 7 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety» Reduction is preferably effected with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or Raney nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethanol/ wafer, 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°C and 50°C, and under a hydrogen pressure of 1 to 5 bar, When a suitable chiral hydrogenation catalyst such as a metal ligand complex is used, e^g* a complex of μ,μ1-d ichloro-bis[1,5-cyclooctediene-r hod ium] and (4-)- or (-, 0,0-isopropyXidene-2,3-dihydroxy-l,<3bie(diphenylphosphino)-butane (« DXO?), the addition of hydrogen occurs enantioselecfively. Moreover, during catalytic hydrogenation, other groups may be reduced at the same time, eog« a nitro group may be reduced to the amino group, a benzyloxy group 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. d) In order to prepare compounds of general formula 5 I wherein A represents a group of formula V I - CH wherein RgB has the meanings given hereinbefore for Rg, with the exception of a cyano group: Reacting a compound of general formula VI (wherein is defined as above and R. and R~ are as Ή 1 Λ hereinbefore defined) with a compound of general 15 formula VII wherein r3 and 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°C and 150°C, but preferably at temperatures of between 20°C and 100°C. e) for the preparation of compounds of general formula I, wherein R^ represents a hydrogen atom; dehalogenating a compound of general formula VIII wherein R^, R^, a and W are as hereinbefore defined and Hal represents a fluorine, chlorine, bromine or iodine atom» The dehalogenation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide by means of catalytically activated hydrogen, e.g. with hydrogen in the 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, eogs a benzyloxy group may be reduced to a hydroxy group, a vinylidene group to the correspording alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or may be replaced by hydrogen atoms, eogo a halogen atom may be replaced by a hydrogen atom. f) Xn order to prepare compounds of general formula I, wherein A represents a group of formula R, — CH — wherein Rg represents an alkyleneiminocarbony1 group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having I to 3 carbon atoms in the alkyl moiety: Reacting a compound of general formula COOH (wherein R^, »2 an^ δε hereinbefore defined and has the meanings given hereinbefore for H, with the exception of the carboxy group), with an amine of general formula X H - R? (X) wherein Ry represents an alkyleneimino group containing < 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.
Amidation is conveniently effected in a solvent 5 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 chloroformafe, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,W'-dicyclohexylcarbodiimide, 0-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,M'-carbonyIdiimidazole, Ν,Ν'-thionyIdiimidazole 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°C and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. g) In order to prepare compounds of general formula I wherein A represents a group of formula R4 I - CH — as hereinbefore defined and w represents a carboxy group: Oxidising a compound of general formula XI (XI CH - NH - CO - CH wherein R. to R. are as hereinbefore defined and 1 4 E represents a group which can be converted into a carboxy group by oxidation.
An oxidisable group of this kind may be, for example, a formyl group and the acetals thereof, a hydroxymethyl group and the ethers thereof, a substituted or unsubstituted acyl group such as an acetyl, chloroacetyl, propionyl or malonic acid-(l)-yl group or a malonic ester-(l)-yl groupe The reaction may be carried out with an oxidising agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxan or glycol dimethyl ether at temperatures of between 0 and 100°C, but conveniently at temperatures of between 20°C and 50°C. However/ the reaction is preferably effected with silver oxide/sodium hydroxide solution, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/ sodium hydroxide solution, bromine or chlorine/sodium or potassium hydroxide solution, chromium trioxide/pyridine or pyridinium chlorochromate. h) In order to prepare compounds of general formula I wherein represents an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms wherein the alkyl conponent nuy be substituted at any carbon atari except the σ-earbon atom 24 by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms: Esterifying a carboxylic acid of general formula XII COOH (XT 1) (wherein R^ to and A are as hereinbefore defined) or a reactive derivative thereof optionally prepared in the reaction mixture, with an alcohol of general formula XIII HO - Rg (XIII) wherein Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atcm except the clear bon atom by one or two hydroxy groups or Dy an alkoxy group containing 1 to 3 carbon atoms.
Examples of reactive derivatives of a compound of general formula XII include the halides thereof, such as the acid chloride, and the anhydrides and imidazolides.
The reaction is conveniently carried out using the corresponding alcohol as solvent or in a suitable solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, dioxan, benzene or toluene, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of hydrogen 25 chloride, sulphuric acid, ethyl chloroformste, thionyl chlor ide, carbon fetrachlor ide/tr iphenylphosphine, carbonyldiimidazole or Ν,Ν'-dicyclohexylcarbodiimide or the isourea ethers thereof, optionally in the presence of a reaction accelerator such as copper chloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, or by transesterification, eoge with a corresponding carbonic acid diester, at temperatures of between -20°C and 100°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. i) In order fo prepare a compound of general formula 15 X wherein W represents an alkoxycarbonyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl group and A represents a group of formula V I - CH20 where represents as hereinbefore defined with the exception of a cyano group: Alcoholysis of a compound of general formula XIV (XIV) wherein represents R^ as hereinbefore defined with the exception of a cyano group and Ry to R^ are as hereinbefore defined and !4BI represents a cyano, cyGnomethy1, 2-cyanoethyl or 2-cyanoethenyl group.
The alcoholysis is conveniently effected in the presence of a solvent, preferably in an excess of a corresponding alcohol, such as, for example, methanol, 10 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 50 and 100°C.
Xf, according to the invention, a compound of general formula I is initially obtained wherein H represents a carboxy or alkoxycarbonyl group, this may subsequently be converted by reduction into a corresponding compound of general formula X wherein W represents a formyl or hydroxymethyl group, and/or if a compound of general formula X is initially obtained wherein Ή 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 X wherein W represents a formyl group, and/or if a compound of general formula X is initially obtained wherein T4 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 X wherein W represents a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-©thenyl group, and/or if a compound of general formula X is initially obtained wherein represents a 2-carbouy-ethenyl or 2-alkoxy35 carbonyl-ethenyl group, this may subsequently be 27 converted by catalytic hydrogenation into a corresponding compound of general formula I wherein W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group, and/or if a compound of general formula I is initially obtained wherein W represents an alkoxycarbonyl group substituted ul any carbon atom except lhe n-carbun alun 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 1 is initially obtained wherein W represents a hydroxymethyl group, this may, after being converted into a corresponding halomethyl 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 if a compound of general formula ϊ 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 X wherein W represents an ethyl group substituted by two carboxy groups, and/or if a compound of general formula I is initially obtained wherein W represents an ethyl group substituted by two alkoxycarbonyl groups, this may subsequently be converted by hydrolysis and decarboxylation info a corresponding compound of general formula I wherein W represents a 2-carboxyethyl group, and/or if a compound of general formula ϊ is initially obtained wherein represents a nitro group, this may subsequently be converted by reduction into β corresponding compound of general formula I wherein represents an amino group, and/or if a compound of general formula I is initially obtained wherein represents an amino group, this may subsequently be converted, via a corresponding diazonium salt, info a corresponding compound of general formula I wherein represents a hydrogen or halogen atom or a hydroxy, alkoxy or alkylsulphenyl group, and/or if a compound of general formula I is initially obtained wherein R2 represents a hydroxy group, this may subsequently be converted by alkylation into a corresponding compound of general formula X wherein R^ represents an alkoxy group, and/or if a compound of general formula X 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 debenzylafion info 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 Ϊ is initially obtained wherein R. represents an aminocarbonyl group, this may subsequently be converted by dehydration info a corresponding compound of general formula I wherein R^ represents a cyano group» The subsequent alcoholysis is preferably carried out in a corresponding alcohol such as ethanol, in the presence of an acid such as hydrochloric or Sulphuric acid, at temperatures up to the boiling temperature of the solvent used.
The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride such as lithium aluminium hydride, in a solvent such as diethyl ether, tetrahydrofuran or dioxan at temperatures of between 0 and 100°C, but preferably at temperatures of between 20°C and 60°Ce The subsequent disproportionation of a sulphonic acid hydrazide, which is obtained by reacting a corresponding 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.
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 alfcoxycarbonylmethylene-triphenylphosphoran, 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, e.g. with hydrochloric or sulphuric acid, or by subse25 quent alkaline hydrolysis.
The subsequent catalytic hydrogenation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal at temperatures of between 0 and 75°C, but preferably at ambient temperature and under a hydrogen pressure of 1 to 5 bar.
The subsequent O-acylation is conveniently 3$ carried out in a solvent such as methylene chloride, chloroformf carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, 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 triethyl5 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» The subsequent conversion of a hydroxymethyl group info a halomethyl group is effected with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and subsequently reacting with a malonic acid ester, e.g. with an alkali metal salt of diethyl malonate, at temperatures of between 0 and 100°C, but preferably at temperatures of between 50°C and 80°C» The subsequent hydrolysis or hydrolysis and decarboxylation is conveniently effected in the presence of an acid such as hydrochloric, sulphuric, phosphoric, polyphosphoric or trifluoroacetic acid in a suitable solvent such as wafer, ethanol, water/ethanol, water/iso25 propanol or water/dioxan at elevated temperatures, e.g. at the boiling temperature of the reaction mixture.
The subsequent reduction of the nitro compound is preferably effected in a solvent such as water, water/efhanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(IS)sulphate, tin(XI)chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at temperatures of between 0 and 50°C, but preferably at ambient temperature.
The subsequent reaction of a diazonium salt, e.g* the fluoroborate, the fluoride in 40% hydrofluoric acid, the hydrosulphafe 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/hydrobroraic 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 in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid or dioxan/hydrochloric acid, by diazotising a corresponding amino compound with a nitrite, e.g. sodium nitrite or an ester of nitrous acid, at low temperatures, e.g. at temperatures of between -10°C and 5°C.
The subsequent O-alkylation is conveniently effected with a corresponding halide, sulphonic acid ester or diazoalkane, e.g. with methyl iodide, dimethylsulphate, ethyl bromide, ethyl p-toluenesulphonate, isopropylmethanesulphonate or diazomethane, optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert.bufoxide and preferably in a solvent such as diethyl ether, tetrahydrofuran, dioxan, methanol, ethanol, pyridine or dimethylformamide at temperatures of between 0 and 75°C, preferably at ambient temperature.
The subsequent debenzylation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide using catalytically activated hydrogen, e.g. using hydrogen in the presence of platinum or palladium/charcoal, at temperatures of between 0 and 75°C, but preferably at ambient temperature and at a hydrogen pressure of from 1 to 5 bar.
The subsequent dehydration is carried out with a dehydrating agent such as phosphorus penfoxide, sulphuric acid or p-foluenesulphonic 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.
If they have a chiral centre, the compounds of general formula I obtained can also be resolved info their enantiomers by conventional methods.
This may, for example, be effected by column chromatography on a chiral phase.
A compound of general formula I or a tautomer thereof, initially obtained, may subsequently be converted info an addition salt thereof, for example by conventional methods such as reacting the compound of general formula Ϊ or tautomer thereof as a base with an acid in a suitable solvent, or reacting the compound of general formula I or tautomer thereof as an acid with a base in a suitable solvent. A salt of a compound of general formula I or a tautomer thereof, initially obtained, may subsequently be converted by conventional methods into a different salt or into a compound of general formula I or tautomer thereof.
The compounds of general formulae II fo XIV used as starting materials may be obtained by methods known from the literature or are themselves known from the literature.
Thus, for example, a compound of general formula II wherein A represents a group of formula or the tautomeric kefimine 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 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, if is also possible to use the organometallic ketimine complex.
A compound of general formula II wherein A represents a group of formula - CH wherein R^' has the meanings given hereinbefore for 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 cyanoborohydride, by reduction of a corresponding oxime with lithium aluminium hydride or with catalytically activated or nascent hydrogen, by reduction of a corresponding K-benzyl- or W-(1-phenyIethyl)-ketimine, e.g. with catalytically activated hydrogen or with a complex metal hydride in ether or tefrahydrofuran at temperatures of between -78°C and the boiling temperature of the solvent used and subsequently cleaving the benzyl or 1-phenylefhyl group by catalytic hydrogenation, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulphuric acid, or by Hofmann, Curfius, Lossen or Schmidt degradation of a corresponding compound » A compound of general formula II wherein A represents the group CN I - CH may be obtained by reacting a corresponding aldehyde with ammonium cyanide or by reacting a corresponding cyanohydrin with ammonia.
An amine of general formula II thus obtained, having a chiral centre, wherein A represents a group of formula RZ - CH wherein has the meanings given hereinbefore with the exception of the cyano group, may be resolved into the enantiomers by racemate splitting, e.g» by fractional crystallisation of the diastereomeric salts with optically active acids and subsequent decomposition of the salts or by column chromatography on a chiral phase, or by forming diastereomeric compounds and then separating and splitting them.
Moreover, an optically active amine of general formula II may also be prepared by enanfioselecfive 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, 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.
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.
The compounds of general formulae IV, VIII, IX, XI, XII and XIV used as starting materials are obtained by reacting a corresponding amine with a corresponding compound of general formula III or the reactive derivatives thereof, with optional subse25 quent hydrolysis.
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.
As already mentioned hereinbefore, the new compounds of general formula I as hereinbefore defined, the tautomers and optical enantiomers thereof and acid and base addition salts of the aforementioned compounds have valuable pharmacological properties, namely an effect on the intermediate metabolism, but particularly the hypoglycaemic effect of lowering ► blood sugar and, to some extent, an effect on the cardiac circulatory system.
For'example, the following compounds have been examined for their properties as follows: A * (2)-4-((1-(2-piperidino-phenyl)-1-buten-l-yl)aminocarbonyImethyl]-benzoic acid, B = ethyl (2)-4-((1-(2-piperidino-phenyl)-1-butenl-yl) -aminocarbony Imethyl] -benzoate, C = (E)-4-[(l-(2-piperidino-phenyl)-1-buten-l-yl)aminocarbonyImethyl]-benzoic acid, 0=4-((2-methy1-1-(2-piperidino-phenyl)-1-propen1-yl)-aminocarbonyImethyl] -benzoic acid, E = ethyl (Z)-4-[(l-(2-piperidino-phenyl)-l-hexen1-yl)-aminocarbonyImethyl]-benzoate, F * (Z)-4-[(3-phenyl-l-(2-piperidino-phenyl)-l-propen1-yl)-aminocarbonyImethyl] -benzoic acid, G = (Z)-4-[(l-(2-(3,3-dimethyl-piperidino)-phenyl)1-buten-l-yl)-aminocarbonyImethyl]-benzoic acid, H = 4-((1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonyl methyl]-benzoic acid, j (^)-4-((l-(2-piperidino-phenyl)-1-butyl)-aminocarbony Imethyl] -benzoic acid, K c (+)-4-[(l-(2-piperidino-phenyl)-l-butyl)-aminocarbonyImethyl]-benzoic acid, L = ethyl (<-)-4-[(l-(2-piperidino-phenyl)-l-butyl)aminoc&rbonylmethy1]-benzoate, Μ 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-aminocarbony lmethy 1] -benzoic acid, N = 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonylmethyl] -benzoic acid, 0= 4-[(3-phenyl-l-(2-piperidino—phenyl)-1-propyl)aminocarbonylmethy1] -benzoic acid, P = 4-[(2-methoxy-l-(2-piperidino-phenyl)-1-ethyl)aminocarbonylmethy1] -benzoic acid, Q 4-[(a-cyano-2-piperidino-benzyl)-aminocarbonyl10 methyl]-benzoic acid, R = 4-[(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzyl alcohol, S = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -pheny lacetic acid, T = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -cinnamic acid, U = 2,3-dihydroxy-propyl 4-[(l-(2-piperidino-phenyl)1-butyl)-aminocarbonylmethy1] -benzoate, V « 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)20 aminocarbonylmethy1]-benzoic acid, W « 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)aminocarbonylmethy1]-benzoic acid, AA « 4-((c-(4-raethyl-phenyl)-2-piperidino-benzyl)and nocar bonyImethy11-benzoic acid, AB « 4-1(a-(3-methyl-phenyl)-2-piperidino-benzyl)aminocarbonyImethy1]-benzoic acid, AC e 4-((o-(4-fluoro-phenyl)-2-piperidino-benzyl)aminocarbonyImethy1]-benzoic acid, AD = 4-f(©-(2-fluoro-phenyl)-2-piperidino-benzyl)sminocarbonyImethy1]-benzoic acid, AE m 4-((a-(4-chloro-phenyl)-2-piperidino-benzy1)10 aminocarbonyImethy1]-benzoic acid, AF » 4-((c-(3-chloro-phenyl)-2—piperidino-benzyl)aminocarbonyImethy1) -benzoic acid, AG e 4-((2-piperidino-©-(2-pyridyl)-benzyl)-aminocarbonyImethy1]-benzoic acid, AH * 4-((2-piperidino-c-(4-pyridyl)-benzyl)-aminocarbonyImethy1)-benzoic acid, AJ ™ 4-((6-chloro-c-phenyl-2-piperidino-benzyl)-amino carbonyImethy1]-benzoic acid, AR 4-((e-phenyl-2-piperidino-benzyl)-aminocarbonyl20 methyl]-cinnamic acid, AM = 4- Q4-chloro-a-phenyl-2-piperidino-benzyl)-ann'noI carbonylmethylj -benzoic acid, AN ® 4-( (6-methyl-te-phenyl-2-piper idino-benzyl)-aminocarbonyImethy1] -benzoic acid, AO 4-((4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid, AP « 4-[(®-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzaldehyde, AQ ® 4-((2-(2-methyl-piperidino)-α-phenyl-benzyl)aminocarbonylmethyl)-benzoic acid, AR « 4-((2-(3-methyl-piperidino)-α-phenyl-benzyl)10 aminocarbonylmethyl]-benzoic acid and AS ·· 4-((3-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl) -benzoic acid: 1* Hypoglycaemic activity The hypoglycaemic activity of the test substances was tested on female rate of a single strain weighing from 160 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.
Blood samples were taken immediately before the administration of the substance and then 1, 2, and 4 hours afterwards, in each case from the retroorbital venous plexus. From each sample, 50 pi were deprofeinated with 0.5 ml of 0.33 ft perchloric acid and then centrifuged. The glucose in the supernatant phase was determined by the hexokinase method using an analytical photometer. The results were evaluated statistically using the t test according to Student, taking p « 0.05 as the limit of significance.
The following Table contains the values found in percent, compared with the controls: , Substance 5 mg/kg 4 1 1 mg/kg 1 2 3 2 3 4 A -43 -40 -33 -35 Β -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 Z> -36 -32 -27 -25 E -46 -40 -38 -26 -23 -23 -12 -18 F -43 -42 -39 -32 G — 44 -42 -37 -31 H -50 -46 -44 -45 J -37 -42 -42 -38 -32 -34 -29 K -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 n. s. M -46 -43 -40 -36 -33 -30 -21 n-s. N -42 -42 -37 -33 0 -38* -31+ 4» n.s.' n.s. P -49 -43 -34 -22 -37 -19 n.s. rus, Q -28 -13 n. s. n.s. R -38 -40 -35 -29 -39 -34 -29 -24 S -49 -42 -30 -17 -29 -20 -10 iLS. T -48 -46 -42 -40 -42 -42 -40 -32 ϋ -43 -43 -49 -45 -39 -35 -29 -24 V -45 -41 -46 -40 -37 -23 -30 -1Θ -46 -45 -39 -37 -36 -25 -16 n.s. AA -30 -33 -14 n.s, -15 -15 -13 n.s. AS -43 -38 -36 -27 -26 -15 n.s. n«s. AC -36 -37 -36 -33 AD -20 -32 -27 -28 -16 -20 -17 -14 AS -30 -28 -39 -36 -21 -20 -22 ftoSo Substance 1 5 mg/kg 2 3 4 1 1 mg/kg 2 3 4 AF -43 -39 -30 -26 -17 -19 n.s. n.s. AG -49* -50* -36* -31* -18 n.s. n.s. n.s. AH -41 -37 -20 n.s. -26 -14 n.s. n.s. AJ -44 -40 -39 -40 -35 -34 -28 -20 AK -48* -47* -40' Λ. -45’ -32 -19 -10 -17 AM -34 -35 -32 -29 -11 -13 n.s. n.s. AN -39 -35 -27 -26 -27 -24 n.s. n.s. AO -37 -34 -32 -31 -21 -17 -15 -11 AP -26 -28 -22 -17 AQ -32 -31 -24 -19 -16 -11 n.s. n.s. AR -35 -30 -29 -31 -13 - 9 n.s. n.s. AS -45 1 -44 -42 -32 -21 -13 n.s. n.s 4- = at 10 mg/kg n.se = statistically not significant 2. Acute toxicity The toxic effect was tested in male and female mice of the same strain weighing from 20 to 26 g, after oral administration of a single dose (suspended in 1§ raethylcellulose) over an observation period of 14 days: Substance Approximate acute toxicity A > 1 000 mg/kg p.o. (0 out of 6 animals died) C > 2 000 mg/kg p.Oe (0 out of 6 animals 1 lied) 0 > 500 mg/kg p.o, (0 out of 6 animals died) a >2 000 mg/kg p.o. <° out of 10 animals died) AA >1 000 mg/kg p.o. (0 out of 10 animals died) AB > 1 000 mg/kg p.o. (0 out of 10 animals died) AC >1 000 mg/kg p.O. (0 out of 10 animals died) AD >1 000 mg/kg p.o. (0 out of 10 animals died) AB >1 000 mg/kg po Oo (0 out of 10 animals died) AG >1 000 mg/kg p. o. (0 out of 10 animals died) Xn view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of diabetes mellitus.
According to a yet further feature of the present invention, we provide pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula X as hereinbefore defined or a tautomer thereof or a physiologically compatible salt of these compounds, in association with one or more pharmaceutical carriers or excipients.
For pharmaceutical administration the compounds of general formula X 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 The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, foe example, corn starch, lactose, celulose, magnesium stearate, citric acid, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
Advantageously, the compositions may be formulated as dosage units, each dosage unit being adapted to supply a fixed dose of active ingredient.
A suitable single dose for adults is 1-50 mg, preferably 2,5-20 mg of active ingredient, once or twice per day. The total daily dosage may, however, be varied according to the compounds used, the subject treated and the complaint concerned.
The following non-limiting Examples are intended to illustrate the invention: Example 1 Ethyl 4- [N-[a-(4-methyl-phenyl)-2-piPer idino-benzy 1] 5 aminocarbonylmethyl] -benzoate 4o7 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 ©-(4-methyl-phenyl)-2-piperidino-bensylaraine and 3.4 g (16.5 mmol) of 4-ethoxycarbonyl-phenylacefcic 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 SN hydrochloric acid, extracted with ethyl acetate. The acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The evaporation residue is triturated with ethanol and suction filtered.
Yield: 4.55 g (65^ of theory), H.p.s 177-178¾ Calculated: C 76.57 B 7.28 N 5.95 Found: 76.19 7.16 5.82 The following were prepared analogously to Example Is (a) Ethyl 4-fN-fe-(3-methyl-phenyl)-2-piperidinobenzyl] -aminoc&rbonyl-methyX]-benzoate Yield: 48% of theory, M.pe: 159-160¾ Calculated: C 76.57 fl 7.28 N 5.95 Founds 76.80 7.35 5.75 (b) Sthyl 4-[N-[©-(2-aethyl-phenyl)-2-piperidinobsnsyl] -aminocarbonylmethyl] -benzoate Yields 35.4¾ of theory, M.p.s 196-198¾ Calculated: C 76.57 H 7.28 N 5.95 Found; 76.65 7.35 5.90 (c) Ethyl 4-[N-[e-(4-methoxy-phenyl)-2-piperidinobenzyl) -arainocarbonylmethyl] -benzoate Yields 45% of theory, E^.p.s 167-158eC Calculated: C 74.05 H 7.04 H 5.76 Found: 73.72 6.99 5.52 M„p.s 154-155°C Calculated: C 76.84 6.31 is 4.93 Found: 76.88 6.68 5.03 (e) Ethyl (4-fluoro-phenyl)-2-piperidinobenzyl] -arainocarbonylmethyl] benzoate Yield: 58% of theory, H.p.s 174-176°C Calculated; C 73.40 H 5.58 N 5.90 Founds 73.55 6.72 5.91 (f) Ethyl d-rW-le-(2-fluoro-phenyl)-2-piperidinobenzyl] -arainocarbonylmethyl] -benzoate Yield: 83% of theory, H.p.s 173-175°C Calculated: C 73.40 H 5.58 5.90 Found: 73.51 5.52 5.85 (g) Ethyl 4-[N-[e-(4-cbloro-phenyl)~2"piperidinobenzyl] -arainocarbonylmethyl] -benzoate Yields 57% of theory, M.pos 178-101°C Calculated; C 70.94 3 6.36 N 5.71 Cl 7.22 Founds 71.10 5.56 5.26 7.11 M.p. s 153-155¾ Calculated: C 70.04 H 6.36 M 5.71 Cl 7.22 Found: 70.06 5.26 5.55 7.25 (1) Ethyl 4-(N-[c-(2-chloro~phenyl)-2-piperidinobenzyl]-aminocarbonyImethy1]-benzoate Yield: 56% of theory, M.p.s 106-108¾ Calculated: C 70.04 H 5.35 N 5.71 Cl 7.22 Found: 70.00 6.30 5.61 7.10 (k) Ethyl <£- [N- [c- (4-methylmercapto-pheny1)-2-piper idinobensyl] -awinoc&rbonyImethy1]-benzoate Yield: 04% of theory, M.p.: 173-175¾ Calculated: C 71.58 H 5.82 N 5.57 Cl 5.38 Found: 71.02 5.07 5.45 6.21 (l) Ethyl 4-(W-[5-chloro- Yields 02% of theory, M.p.: 213-215¾ Calculated: C 56.28 H 5.75 N 5.33 Cl 13.49 Found: 66.45 5.86 5.25 13.51 (ra) Ethyl 4-[$-[2-piperidino-a-(2-pyridyl)-benzyl]~ aminocarbony Imethy 1] -benzoate Yields 51% of theory, M.p. 8 150-150¾ Calculated C 73.50 B 6.83 N 0.18 Founds 73.40 6.05 0.10 (a) Ethyl 4-[M-[2-piperidino-e-(3-pyridyl)-benzyl] arainocarbony Imethy 1] -benzoate « 35 Yields 859 of theory, M.p.: 172¾ Calculated: C 73.50 H 6.83 ft 9.18 Found: 73.42 6.78 9.25 (o) Ethyl 4-[ft-[2-piperidino-c- (4-pyridyl)-bensyl] aminocarbonylmethyl]-benzoate Λ Yields 20% of theory, M.p.: 150-152¾ Calculated; C 73.50 H 6.83 ft 9.18 Founds 73.61 6.91 9.15 (p) Ethyl 4-[N-(6-chloro-fc-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate Yield: 129 of theory, M.p.: Oil Calculated: molecular ion peak m/e = 490/492 Found: molecular ion peak m/e = 490/492 (q) Ethyl 4-[ft-(4*chloro-e-phenyl-2-piperidino-benzyl)aminocarbonyImethy1]-benzoate Yields 37% of theory, H.p„: 148-150¾ Calculated: C 70.94 fl 6.36 ft 5.71 Cl 7.22 Found: 70.81 6.25 5.61 7.12 (r) Ethyl 4-[ft-(3-chloro-©-phenyl-2-piperidino-benzyl)aminocarbonylmethyl] -benzoate Yields 74% of theory, Mop. 8 176-178¾ Calculated: C 70.94 H 6.36 ft 5.71 Cl 7.22 Fouads 70.59 8.25 5.88 7.18 (s) Ethyl 4-[ft-(6-raethyl-6-phenyX-2-piperidino-benzyl,aminocarbonylmethyl]-benzoate * Yields 65% of theory, Hop.s Oil Calculated: molecular ion peak m/e *° 470 Found: molecular ion peak m/e « 470 (t) Ethyl 4-[P3»(4-methyl-a-phenyl-2-piperidinO"benzyl)anri nocarbonyl methy 1 ]~benzoate Yield: 75¾ of theory, M.p.: 133-135°C Calculated: C 76.57 H 7.28 5.95 Found: 76.51 7.16 5.83 (u) Ethyl 4~[i1-[5-chloro-2-(2-msthyl-piperidino)-« -phenylbenzyl ]-aminocarbony1methyl ]-benzoate Yield: 36,5% of theory, M.p.: 171"173°C Calculated: C 71.24 H 6.58 ΰ 5.54 Cl 7.01 Found: 71.45 6.68 5.59 7.20.
Example 2 Ethyl (4-chloro-phenyl)-2-piperidino-benzyl]aiainocarbonv 1-methyl] -benzoate A solution of 5 g (22.1 mmol) of 4-ethoxycacbonyl5 phenylacetyl chloride in 20 ml of chloroform is added dropwise, whilst cooling with ice, to a solution of 6.02 g (20 mmol) of e-(4-chloro-phenyl)-2-piperidinobenzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform. The mixture is stirred for 2 hours et 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.
Yields 5.6 g (57% of theory), M.p.5 178-181¾ Calculated: C 70.94 5.36 N 5.71 Cl 7.22 Founds 71.09 6.47 5.51 7.10 The following was prepared analogously to Example 2s (a) Ethyl 4-(N-(5-chloro-2-(3-methyl-piperidino)e-phenyl-benzyl]-aminocarbonylmethyl] -benzoate Yield: 54% of theory, M.p.s 178-180¾ Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01 Found: 70.91 6.64 5.75 7.01 Example 3 4-iW-E -(4-aethyl-phenyl)-2-piperidino-benzyl] -aminocarbonyl-methyl] -benzoic acid 4.4 g (9.35 mmol) of ethyl &-[N-[a-(4-aethylphenyl)-2-piper idino-bensyl] -aminocarbony lme thyl] benzoate are dissolved An 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 hydroclorig 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 waterθ it is then recrystallised from acetonitrile.
Yield: 2.45 g (59.3% of theory) M.p.s 226-22S°C Calculated: C 75.99 H 6.83 N 6,33 Found: 75.80 6.75 6.29 The following were prepared analogously to Example 3: (a) 4-[Ν-[κ-(3-Methyl-phenyl)-2-piperidino-benzyl] aminocarbonyImethy1] -benzoic acid Yield: 72% of theory, H.p.s 202-203°C Calculated: C 75.99 H 6,83 N 6.33 Found: 75.64 6.91 6.37 (b) 4"[N-[e"(2"Methyl-phenyl)-2-piperidino-bensyl] aminocarbonyImethy1] -benzoic acid Yield: 42.6% of theory, M.p.s 285-29O°C Calculated: C 75.99 H 6.83 N 6.33 Found: 76.05 6.98 8.25 (c) 4- [N- [a- (^methoxy-phenyl) -2-piper idino-benzyl] aminocarbonylmethyl] -benzoic acid Yields 72.4 of theory, Hep.s 228-23O°C Calculated: C 73.34 H 6.59 N 6.11 Found: 73.22 6.61 6.13 (d) 4-[N-[β-(4-benzyloxy-phenyl)-2-piper idino-benzyl]aminocarbonylraethyl] -benzoic acid Yields 57% of theory, H.p.: 219-221°C Calculated: C 76.38 5.41 M 5.24 Found: 76.05 6.44 5.24 (e) 4-[N-[e-{4-fluoro-phenyl)-2-piperidino-benzyl] arainocarbonylmethyl] benzoic acid Yield: 75% of theory, £3.p.s 238-24O°C Calculated: C 72.63 H 5.09 N 5.27 Found: 72.98 6.29 6.32 (f) 4-[»-[«-(2-fluoro-phenyl)-2-piperidino-benzyl] aminocarbonylmethyl]-benzoic acid Yield: 87% of theory, H.p.s 28O-283°C Calculated: C 72.63 H 6.09 H 6.27 Found: 72.70 5^10 6.37 (g) 4-[N-[ Yield: 89% of theory, bH.p.s 241-242°C Calculated: C 70.05 H 5.88 H 5.05 Cl 7.56 Found: 59.74 5.05 5.01 7.64 (h) 4-[Η-1e-(3-chloro-phenyl)-2-piper idino-benzyl] arainocarbonylmethyl] -benzoic acid Yields 53% of theory, M.p.s 223-225°C Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 70.28 5.98 5.78 7.84 (i) 4-(N-[a*(2-chloro-ph^nyl)-2-piperidino-benzyl] arainocarbonylmethyl] -benzoic acid Yield: 98% of theory, H„p.s 3O3-3O5°C Calculated: C 70.05 H 5.08 N 6.05 Cl 7.66 Found: 69.80 6.05 5.07 7.74 (k) 4-[K-[e-(4-»ethyl»ercapto-phenyl)-2-piperidino«· benzyl] -aminocarbonylmethy 1] -bensoic acid Yield: 04.5% of theory, H.peS 225-227°C » 10 Calculated: C 70.86 H 6.37 N 5.90 Cl 5.75 Found: 70.34 6.37 5.68 5.82 (l) 4-IM-[5-chloro-e-(2-chloro-pheny1)-2-piper id i no benzyl]-aminocarbonylmethy1] -benzoic acid Yield: 90% of theory, H.p.s 317-32O°C Calculated: C 65.19 H 5.27 N 5.63 Cl 14.25 Found: 64.87 5.34 5.69 14.22 (m) 4-[N-[2-piperidino-a-(2-pyridyl)-benzyl] -rainocarbonylmethyl]-benzoic acid Yields 01% of theory, Hepe: 16O-151°C Calculated: C 72.71 H 6.34 N 9.70 Found: 72.43 6.39 10.00 (n) 4-[W-12-piperidino-e-(3-pyridyl)-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 72% of theory, M.p.g 252-253°C Calculated: C 72.71 H 5.34 ΗΓ 9.78 Found: 72.55 5.53 9.50 (o) 4-[^-[2-piperidino"ts- (4-pyr idyl) -benzyl] -aminoo 35 carbonylmethyl] -benzoic fcdd Yields 58.5% of theory, H«p.s from 250°C (decomposition) Calculated; C 72.71 H 6.34 N 9.78 Found: 72.31 5.29 9.53 (p) 4-[N-(6-chloro-©-phenyl-2-piperidino-bensyl)aminocarbonylraethyl]-bensoic acid Yields 82% of theory, M.p.s 91-94¾ Calculated: C 70.04 H 5.88 N 6.05 Cl 7.66 Found: 69.51 5.77 5.96 7.78 (q) 4-[W- (4-chloro-a-phenyl-2-piperidino-benzyl) aminocarbonyImethy1]-benzoic acid Yield: 61% of theory, H.p.s 221-223¾ Calculated: C 70.05 H 5.88 N 6.05 Cl 7.56 Founds 69.73 5.89 5.87 7.52 (r) 4-[N-(3-chloro-e-pheny1-2-piperidino-bensyl)MinocarbonyImethy 1] -benzoic acid Yields 83% of theory, M.p.s 210-213¾ Calculated: C 70.05 H 5.88 N 5.05 Cl 7.66 Founds 70.31 6.03 5.90 7.79 (s) 4-[N-(6-methyl-c-pheny1-2-piper idino-bensyl)&m i nocar bony lrae thyl]-benzoic acid Yield: 64% of theory, M.p.: 165-170¾ (sintering from 150¾) Calculated: C 75.99 H 6.83 N 6.33 Found: 75.73 6.96 5.14 (t) 4- [k*5- (4-raethyl-©-pbenyl-2-piper id ino-bensyl) era i nocar bony line thyl] -benzoic acid Yields 96% of theory, M.p.: 2O2-2O3°C Calculated: C 75.99 B 6.83 6.33 Found: 76.04 6.78 6.23 (u) 4-[W-[5-chloro-2- (2-methyl-piperidino)-e-phenylbenzyl] -aminocarbonylmethyl]-benzoic acid yields 52% of theory, M.p.s 28O-282°C 5 Calculated: C 70.50 H 6.13 M 5.87 Cl 7.43 Found: 70.14 8.10 5.75 7.45 (v) 4-lN-t 5-chloro-2- (3-methyl-piper icii.o; a-phenylbenzyl] -aminocarbonylmethyl] -benzoic acid Yield: 66% of theory, 1° M.p.: 246-248°C Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: 70.16 6.07 5.87 7.30 Example 4 4-[N-[g_- (4-hydroxy-phenyl)-2-piper idino-benzyl] -_araino15 catbonyl-methyl]-benzoic acid 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 bar, in the presence of 0.4 g of 10$ palladium/charcoal Then the catalyst is filtered off, and the filtrate is concentrated by evaporation and recrystallised from acetonitrile.
Yield: 720 mg (66.7% of theory), M.p.: 2O2-2O4°C Calculated; C 72,95 Η 6θ35 N 6.30 Founds 72,65 6.17 6.20 Example 5 4-[ft-[a-(4-Methvl-phenyl)-2-plperidino-benzyl] -aminocarbonyImethy1] -benzyl alcohol g (5.3 mmol) of ethyl 4-[»-[«-(4-methylphenyl)-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 stirred for a further 30 minutes at ambient temperature, decomposed by the dropwise addition of 4 ft sodium hydroxide solution and filtered to remove the sodium aluminate formed. The filtrate is concentrated by evaporation and the residue is recrystallised from a little toluene.
Yield; 0.96 g (43% of theory) M.P. U4-146°C Calculated: C 78.47 H 7.53 ft 6.54 Found: 78.20 7.39 6.58 Example 5 4- [$-f 0.85 g (20 mmol) of (4-methyl-phenyl)5 2-piper id ino-bensyl] -aminocarbonyImethyl] -benzoic acid and 3.25 g (20 mmol) of $,$'-C£irbonyldiiniidazole are refluxed in 100 ml of absolute tetrahydrofuran for 2 hours. Then the mixture is concentrated by evaporation and after the addition of 50 ml of pyridine and 3.7 g (20 mmol) of 4-toluenesulphonic acid hydrazide, the mixture is refluxed for a further 2 hours. Xt is then poured on to ice water and suction filtered and the precipitate is dried. The resulting crude toluenesulphonic acid hydrazide of the carboxylic acid used is mixed with 20 g of anhydrous sodium carbonate and heated to 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 using toluene/ethyl acetate 5:1 as eXuant.
Yield: 1.73 g (21¾ of theory, M.p,: 144-X46°C Calculated: C 78,84 H 7.09 $6.57 Found: 78.95 7.19 6.50 The 6: (a, following was prepared analogously to Example 4-[$-(c-?henyl-2-piperidino-benzyl)-aminocarbonyl* methyl] -benzaldehyde Yields 29¾ of theory M.p.s 168-170°C Calculateds C 78.61 H 6.84 $ 6.79 Found: 78.60 7.00 6.72 Example 7 4-[$-[&-(4-Methv1-phenyl)-2-piperidino-benzyl] -aminocarbonyl-methyl] -benzaldehyde 0«5 g (1.2 mmol) of &-i$-[©-(4-methyX-phenyl)57 2-piperidino-bensyl] -aminocarbonylmethyl] -benzyl alcohol are added to a suspension of 0.4 g (1.5 mmol) of pyrldinium chlorochromiate in 2 ml of chloroform.
After 12 hours at ambient temperature, ether is added, the mixture is filtered and the concentrated filtrate is purified by column chromatography on silica gel (eluants toluene/ethyl acetate = 5:1).
Yields 0.3 g (60% of theory) H.p.s 145-146¾ Calculated: C 78.04 H 7.09 N 6.57 Found: 78.97 7.12 6.57 The following was prepared analogously to Example 7: (a) 4-[N-(a-Phenyl-2-piper idino-benzyl)-aminocarbonylmethyl] -benzaldehyde Yields 40% of theory M.p.: 170¾ Calculated C 78.61 H 5.84 N 5.79 Found: 78.59 6.87 5.51 Example 8 Bthvl 4-[H-[ci-(4-methyl-phenyl)-2-piperidino-benzyl] aminocarbonvl-methyl] -cinnamate 427 rag (1 mmol) of 4-[N-[e-(4-methyl-phenyl)2-piperidino-bensyl]-aminocarbonylmethyl] -benzaldehyde are added to an ethereal solution of 450 mg (2 mmol) of ethyl diethylphosphonoacetate and 100 mg (2 smaol) „ of 50% sodium hydride. After the mixture has been stirred overnight, water is added and the resulting mixture is eictracted with chloroform and purified by column chromatography on silica gel using toluene/ethyl acetate (5s1) as eluant.
Yield: 0.18 g (35% of theory) H.p.s 175-180¾ Calculated: C 77.39 H 7.31 N 5.64 Founds 77.64 7.25 5.71 The following was prepared analogously to Example 8: (a) Ethyl 4-[N-(c-phenyl-2-piperidino-benzyl)-arainocarbonylmethyl] -cinnamate Yield: 23.5% of theory M.p.s 159-161°C Calculated: C 77.14 H 7.10 N 5.80 Found: 77.2© 7.21 5.65 Example 9 4-[N-(<&- (4-Methyl-phenyl)-2-piperidino-b_enzyI] -aminocarbpnyl-meehyl]-cinnamic acid Prepared by alkaline saponification of ethyl 4-[N-[©- (4-snethyl~phenyI)-2-piperidino-benzyl] -amino15 carbonyl-methyl] -cinnamate analogously to Example 3* Yield: 84% of theory M.p.: 173-176eC Calculated: C 76.90 H 5.83 N 5.93 Found: 77.24 7.01 5.64 The following was prepared analogously to Example 9: (a) 4-[N"(e-Phenyl-2-piperidino-benzyl)-aminocarbony125 methyl)-cinnamic acid Yield: 75% of theory M.p.: 177-180°C Calculated; C 75.52 H 6.65 N 6.16 Found: 76.75 6.57 5.07 Example 10 gthyl 4-fN-ffc-(3-methyI-phenyl) -2-piperidino-benasy 1] aminoca rbonyIme thy11 -ben zoate A mixture of 0.22 g (0.3 mmol) of ts-(3-methyl35 phenyl-2-piperidino-benzyl alcohol and 0.15 g (0«8 mmol) of -uthyl 4-cyanomethyl-benzoate in 2 ml of o-dichlorobensene is added dropwise, at ambient temperature, to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated 5y sulphuric acid, After 2 hours6 stirring, the mixture is poured onto ice-water, extracted once with etherp made alkaline with dilute sodium hydroxide solution and extracted with chloroform, The chloroform extract Is concentrated by evaporation and the residue is recrystallised from ethanolθ Yields 0,22 g (60% of theory) H.p.s 150-159°C Calculated: C 76.57 H 7,20 N 5,95 Founds 76.41 7.39 5.76 Example 1ΐ (4-methyl-phenyl)-2-piperidino-benzyl] -aminocarbonyl-methyl]-benzoic acid 240 mg (5 mmol) of 4-[M-[5-chloro-<&-(4-methyl15 phenyl)-2-piper idino-benzyl]-aminocar bony lmethyl] 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 20 is filtered off. The filtrate Is concentrated by evaporation and the ethanol.
Yields 0.16 g (72% H.p.s 226-228°C 25 Calculated; C Found s residue is recrystallised from of theory) 75.99 H .6.03 N 8.33 75.91 6.73 8.10 1! The following was prepared analogously to Example Ils (a) 4-[N-[2-(2-methyl-piperidino)-a-phenyl-bensyl]aminocarbony lmethy 1] -benzoic acid From 4-(N-[5-chloro-2-(2-wethyl-piperidino)a-phenyl-bensyl]-aminocarbonylmethy1]-bensoic acid Yields 68% of theory H.p.s 246-248¾ Calculated C 75.99 H 6.83 N 6.33 Found: 75.57 7.10 6.44 (b) 4-[E3-[2-(3-Hethyl-piper idino)-c-pheny1-benzyl]aminocarbonylmethyl] -bensoic acid From 4-(N-[5-chloro-2-(3-methyI-piper idino)e-pheny1-benzyl]-aminocarbonylmethyl] -bensoic acid Calculated: 43% of theory Mep.: 228-230°C Calculated: C 75.99 H 6.83 M 6.33 Founds 75.91 5.82 6.33 Example 12 Ethyl 4-[N-[6-(4-methyl-phenyl)-2-piperidlno-bensyl]aminocarbonyl-methyl] -bensoate A solution of 2.78 g (10 mmol) of freshly prepared (4-raethyl-pheny1)-(2-piperidinopheny1)-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 its 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% bl 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 arid the residue is recrystallised from a little alcohol.
Yield: 2.0 g (60% of theory) M.p.s 175-177¾ Calculated: C 76.57 a 7.28 ft 5.95 Founds 76.41 7.19 5.76 Example 13 4-[ft-[ Prepared from ci-(4-methyX-phenyl)-2-piperidinobenzylamine and 4-cyano-phenyXacetic acid analogously to Example 1.
Yields 64% of theory M.p. s 144-146¾ Calculated: C 79.40 H 6.90 ft 9.92 Founds 79.10 6.90 9.78 Example 14 Ethyl 4-[ft-[c-(4-methyl-phenyl)-2-piper idino-benzvl] aminocarbonylmethyl] -benzoate 4.2 g (10 mmol) of 4-[ft-[c-(4-methyl-phenyl)2-piperidino-benzyl]-aminocarbonylmethyl] -benzonitrile 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.
Yields g (51.5% of theory) M.p. s 177-179¾ Calculated: C 76.57 S 7.20 N 5.95 Founds 76.41 7.35 5.76 Example 15 Ethyl 4-[N-[5-chloro-ci-(2-chloro-phenyl)-2-piperidinobensyl] -aminocarbonylmethyl] -benzoate uniol of ethyl 4-[N-[ Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue, consisting of ethyl 4-[N-[5-awino-©-(2-chloro-phenyl)-2-piperidinobensyl)-amino-carbonylaethyl]-bensoate ie dissolved in 100 ml of concentrated hydrochloric acid. Whilst the mixture is cooled with ice, a solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of wafer is added dropwise thereto and the resulting mixture is stirred for 1 hour at 0 to 5¾. The reaction mixture is then added dropwise to a solution of 3g of copper (I) chloride in 25 ml of concentrated hydro63 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. « Yields 1.5 g (23.6% of theory) M.p.s 213-215¾ Calculated: C 66.28 H 5.75 ft 5.33 Cl 13.49 Founds 5δ„40 5.91 5.41 13.40 10 Example 16 3-[4-[ft-( 0.91 g (2 mmol) of 4-[ft-(cv-(4-methyI-phenyl)2-piperidino-benzyl)-aminocarbonyImethy1] -cinnamic 15 acid are dissolved in 50 ml of methanol and, after the addition of 0.5 g of palladium (10% on charcoal), the mixture is catalytically hydrogenated at ambient temperature under a hydrogen pressure of 3 bar.
After the hydrogen uptake has ended, the catalyst is filtered off and recrystallised from a little acetonitrile.
Yields 0.68.g (74% of theory) M.p,§ 146-148¾ Calculated^ C 76.57 H 7.23 ft 5.95 Founds 76n4l 7.19 5.61 Example 17 Sodium salt of 4-[N-(c;-(4-methyl-phenyl)-2-pip&ridinobenzyl)-aminocarbonylmethyl] -benzoic acid 442 mg (1 mmol) 4-[N-(«-(4-methyl-phenyl)-25 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 auction filtered and washed with ethyl acetate.
Yields 410 mg (85¾ of theory) M.p.s 295-300¾ Calculated: C 72.40 H 6,29 N 6,03 Found: 72.15 6,46 5,93 The following was prepared analogously to Example 17: (a) Ethanolamine salt of 4-[N-(G-(4-®ethyl-phenyl)2-piperidino-bensyl)-aminocarbonylmethyl] -benzoic acid Yield; 75% of theory Mepes 188-191¾ Calculateds C 71.55 H 7,41 N 8.34 Found: 71,16 7,48 8.52 (b) Diethanolamine salt of 4-tN-(a-(4~saethyl-phenyl)25 2-piper idino-benzyl)-aminocarbonylmethyl] -benzoic acid Yields 81% of theory Eiope,2 170-180¾ Calculated: C 70,70 H 6,86 H 7,73 30 bounds 70,25 6.75 7.58 (c) Triethanolamine salt of 4-[N-(e-f4-methyl~phenyl)2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield: 76% of theory 5 M.p.: 160-165°C Calculated: C 69.01 H 7.67 W 7.10 Found: 68.91 7.64 7.45 Bthylenediamine salt of 4-[N-(a-(4-methyl-phenyl,2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid Yield; 65% of theory M.p.: 160-163°C Calculated: C 71.69 H 7.62 W 11.15 Found: 72.04 7.80 10.96 ExampleIg Bthvl_4-[(2-methoxy-l-(2-piperidino-phenyl)-ethyllaffllnocarbonyl-methyl]-benzoate 0,49 g (2o34 nmol) of 4-ethosycarbonyl-phenylacetic acid, 0.73 g (2.78 mmol) of triphenylphosphine, 0.50 ml (3.66 nunol) of triethylamine and 0.23 ini (2.34 mmol) of carbontetrachloride are added successively to a solution of 0.55 g (2.34 mmol) of 2-methoxy-l-(2piper idino-phenyl)-ethylaniine in 5 ml of acetonitrile and the resulting mixture is stirred for 20 hours at ambient temperature. It is then concentrated by evaporation in vacuo and distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/2).
Yield; 0.45 g (45% of theory) M.p.i 122-123°C Calculated; C 70.73 H 7.60 8 M0 Pound: 71.0« 7.«8 6.3S The following ^re prepared analogously to Example 18: (a) Ethyl 4-[(l-(3-chloro-2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl] -benzoate Yield: 558 of theory M.p.: 1«1-1«3°C Calculated: C S8.33 H 7.20 Cl 7.76 H S.13 Found: 68.30 7.16 8.03 6.20 (b) Ethyl 4-((l-(6-chloro-2-plperidino-phenyl)1-butyl)-aminocarbonylmethyl]-benzoate Yield: 73.9% of theory M.p.s 79-82¾ Calculated.» C 68.33 H 7.28 Cl 7.76 ft 6.13 Found: 68.45 7.24 7.80 6.09 (c) Ethyl 4-[(1-(4-bromo-2-piperidino-pheny1)-1buty1)-aminocarbonylmethyl]-benso&te Yields 62.1% of theory, M.p. 8 116-118¾ Calculated: C 62.27 H 6.63 Br 15.93 ft 5.58 Founds 62.53 6.48 15.98 5.66 (d) Ethyl 4-((l-(4-nitro-2-piperidino-phenyl)-lbutyl)-aminocarbonylmethyl]-benzoate θ7 Yield: 74.6% of theory, M.p.: 127-13OeC Calculated: C 66.79 H 7.11 N 8-99 Founds 66.88 7.08 9.15 (e) Ethyl 4-[(l-(3-methyl-2-piperidino-phenyl)1-buty1)-arainocarbonylmethyl]-benzoate Yield: 68% of theory, M.p.: 145-147°C Calculated: C 74.28 H 8.31 N 6.42 10 Found: 74.40 8.30 6.41 (f) Ethyl 4-[(l-(4-methyl*2-piperidino-phenyl)1-butyl)-arainocarbonylmethyl] -benzoate Yield: 54.7 of theory, M.p.: 113-114°C Calculated: C 74.28 H 8.31 N 6.42 Found: 74.23 8.30 6.55 (g) Ethyl 4-((1-(5-methyl-2-piper idino-phenyl)1-butyl)-arainocarbonylmethyl] -benzoate Yield: 67.9% of theory, M.p.: 149-15O°C Calculated: C 74.28 H 8.31 H 6.42 Found: 74.38 8.21 6.49 (h) Ethyl 4-[(1*(6-methyl-2-piperidino-phenyl)1-butyl)-aminocarbonylmethy 1] -benzoate Yield; 47% of theory, M.p.: 92-93°C Calculated: C 74.28 H 8.31 N 6.42 Found: 74.50 3.45 5.48 (i) Ethyl fi-[(l-(2-pyrrolidino-pbenyl)-l-butyl) arainocsrbonylmethyl-benzoate Yields 57.3% of theory, M.p.s 122-125°C Calculated? C 73.50 H 7.90 Ϊ3 6.86 Founds 73.63 8.07 7.01 (k) Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)amino-carbonylmethyl]-benzoate Yields 71.5% of theory, M.p.s 127-128°C Calculated: C 73.90 H 8.11 N 6.63 Found: 73.90 0.06 6.72 (l) Ethyl 4-[(1- (2-(4-methyl-piperidino)-phenyl)1-butyl)-aminocarbonylmethyl] -benzoate Yield: 51.1% of theory, M.p.: 153-155¾ Calculated: C 74.28 H 0.31 N 5.42 Found: 74.55 8.33 6.45 (m) Ethyl 4-[(1-(2-hexahydroasepino-phenyl)-1-butyl)10 aminocarbonylmethyl]-benzoate Yield: 42.7% of theory, H.pu 145-147¾ Calculated: C 74.28 H 8.31 N 6.42 Found: 73.98 8.26 6.58 (n) Ethyl 4-[(l-(5-£luoro-2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl] -benzoate Yield: 55% of theory, M.p.: 128-130¾ Calculated: C 70.88 H 7.55 N 6.36 Found: 71.14 7.57 6.49 (o) Methyl 4-[(1-(2-piperidino-phenyl)-1-butyl)amino-carbonylmefhyl] -benzoate Yield: 63.2% of theory, M.p.: 147-148¾ Calculated: C 73.50 H 7.90 N 6.86 Found: 73.65 7.88 6.00 (p) n-Butyl 4-[l-(2-piperidino-phenyl)-1-butyl)am1no-car bonylmethy1] -benzoate Yield: 50.9% of theory, M.p.? 117-119¾ (ether) Calculated? C 74.53 H 8.50 N 6.22 Found: 74.49 8.45 6«14 (q) Ethyl 3-chloro-4-[ (1-(2-piperIdino-phenyIll-butyl) -aminocarbonylmethyl] -benzoate Yield: 14.9% of theory, H«p.s <2O°C Calculated: ra/e = 456/450 (1 chloro) Found: m/e - 456/458 (1 chloro) (r) Ethyl 4-[(1-(2-piperidino-phenyl)-4-penten1-yl)-aminocarbonylmethy11 -benzoate Yield: 18.9% of theory, M.p.: 103-105°C Calculated: C 74.62 H 7.89 N 6.46 Found: 75.01 8.10 6.26 Example 19 Ethyl 4-[(1-(S-nitro-2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoate A solution of 14.6 g (64θβ mmol) of 4-ethoxycarbonyl-phenyl acetic acid chloride in 20 ml of methylene chloride is added dropwise to a stirred solution of 15.1 g (54n4 mmol) of 1-(5-nitro-2-piperidi.nophenyl)-1-butylamine and 8.46 ml (61.4 mmol) of triethyl15 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 reddishbrown oily evaporation residue is purified by column chromatography on silica gel (toluene/acetone - 10:1).
Yields 17.7 g (69..7% of theory), H.p.s 135-137¾ (ether) Calculated: C 66.79 H 7.11 H 8.99 Found: 66®73 6,99 9.09 The following were prepared analogously to Example 19: (a) Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethy1] -benzoate 70 Yield: 80.2% of theory, M.p.: 127-129¾ Calculated: C 73.90 H 8.11 ft 6.63 Found: 73.98 8.26 6.89 (b) Bthyl 4-[(l-(4-hydroxy-2-piperidino-phenyl)1-butyl)-aminocarbonyImethy1] -benzoate Yield: 13.5% of theory, M.p.: 178-180¾ Calculated: C 71.21 H 7.81 ft 6.39 .
Found: 71.27 7.82 6.40 (c) Ethyl 4-((1-(5-hydroxy-2-piperidino-phenyl)1-butyl)-aminocarbonyImethy1]-benzoate Yield: 37.4% of theory, Mop.: 188-190¾ Calculated: C 71.21 H 7.81 ft 6.39 Found: 71.34 7.89 6.38 Example ?n 4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyImethy1] phenyl acetic acid 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)-l-butylaraine is slowly added dropwise to this solution, 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 organic phase Is separated off. The alkaline-aqueous phase is adjusted to pH 5θ5 with semi-concentrated hydrochloric acid and extracted with ethyl acetate.
The extract ic dried over sodium sulphate and filtered and the filtrate is concentrated by evaporation in 7, vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol - 20/1).
Yield: 0.10 g (1-6% of theory), M.p.s 136-14O°C (acetonitrile/ether) Calculated: C 73.50 H 7.90 N 6.86 Found: 73.17 8.10 6.85 * Example 21 Ethyl 4-[(2-methyl-l-(2-piperidino-phenyl)-l-propen1-yl)-aminocarbonylmethyl]-benzoate .58 g (26.8 mmol) of 4-ethoxycacbonyl-phenylacetic acid, 8.43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2,6 ml (0.0268 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. If is then concentrated by evaporation in vacuo and distributed between ethyl acetate and wafer. The dried and filtered ethyl acetate extract is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (foluene/ethyl acetate = 5/1).
Yield; 3.0 g (26,,6% of theory), M.p® 3 82-84°C (ether) Calculated; C 74.26 H 7,67 M 6,66 Found: 74,20 7.49 6,56 The following were prepared analogously to Example 21: (a) Ethyl 4-[(1-(2-piperidino-phenyl)-l-penten-lyl)-aminocarbony lme thyl] «benzoate Yield: 16% of .theory, M.p.s 94-97°C (ethanol) Calculated: C 74.62 H 7,89 N 6.45 Found: 74.75 7.71 6.24 (b) Ethyl 4-[(1 - (2-piper idino-phenyl)-X-hexen-1yl)-aminocarbonylmethyl] -benzoate Yields 27,4% of theory, M.p.s 83-85¾ (ethanol) Calculated: C 74.97 H 8.09 N 6.24 Found: 75.42 7.95 6.00 (c) Ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-l5 yl)-aminocarbonylmethyl] -benzoate Yield (more lipophilic isomer; probably E form): 4.1% of theory, M.p.: <20QC Calculated: m/e = 420 Found: m/e = 420 Yield (less lipophilic isomer; probably Z form): 51.9% of theory, M.p.: 115-117¾ (ethanol) Calculated: C 74.26 H 7.67 N 6.66 Found: 73.85 7.59 6.44 (d) Ethyl 4-[(2-phenyl-l-(2-piperidino-phenyl)ethen-l-yl)-aminocarbonylmethyl] -benzoate Yield (more lipophilic isomer; probably E form): 4% of theory, M.p.: 75-77¾ (ether/petroleum ether) Calculated: C 76.90 H 5.88 N 5.98 Found: 77.31 7.20 5.93 Yield (less lipophilic isomer; probably Z form): 42.7% of theory, M.p.: 157-160¾ (ethanol) Found: C 77O19 H 5.95 N 6.02 (e) Ethyl 4-[(3-phenyl-l-(2-piperidino-phenyl)X-propen-l-yl)-aminocarbonylmethyl)-benzoate Yield: 62.5% of theory, M.p.: <20°C Calculated: m/e e 482 Found: m/e =3 482 (f) Ethyl 4-[(1-(2-(3,3-dimethy1-piperidino-phenyl)35 X-buten-I-yl)-aminocarbonylmethyl] -benzoate Yield: 33% of theory, M.p.3 113-116¾ (ethanol) Calculated: C 74.97 H 8.09 $ 6.24 Found: 75.37 7.93 6.03 (g) Ethyl 4-[(l-(6-methyl-2-piperidino-phenyl)1-buten-l-yl)-aminocarbonylmethyl]-benzoate Yield: 60,4% of theory (probably Z form) M.p.: 95-96°C Calculated: C 74.62 H 7.89 $ 6.45 m/e = 434 Found: 74.44 8.00 6.59 m/e = 434 Example 22 Ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocat bony lme thy I] -benzoate A stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidino-phenyl)-propyl-kefimine and 11θ5 ml (82.46 mmol) of triethylamine in 190 ml of anhydrous toluene is heated to an infernal 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 30 minutes at an infernal temperature of 95°C. It is then cooled to 20°C and extracted twice with wafer.
The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo.
The evaporation residue is purified by repeated column chromatography (toluene/acetone - 20/1 and 50/1).
Yield: (more lipophilic isomer? probably E form): 11.2 g (23.6% of theory), M.p.: <20°C (honey-yellow viscous oil) Calculated: C 74.26 H 7.67 N 6.66 Found: 73.90 7.92 6.91 Yield (less lipophilic isomer? probably 2 form): ,9 g (33.5% of theory), M.p. s il4-HSeC Found: C 74.02 H 7.SS H 6.85 Example Ethyl (E)- and £Z)-4-f(l-(2-piperidino-phenyl)-lbuten-l-yl) -aminocarbony Imethy 1]-benzoate loO g of £ ester (see Example 21c) Is heated 5 for 30 minutes in a pre-heated oil bath at 230°C.
After cooling, the product obtained is purified by column chromatography on silica gel (toluene/acetone = 20/1).
Yield (E ester)s 0.365 9 (36.5% of theory), 10 M.p.: <20 °C Yield (Z ester): 0.380 9 (38.0% of theory), M.p. S 115-117°C 15 If the (E)-ester is heated for 3.5 hours with catalytic quantities of iodine in benzene, a 1/1 mixture of (E) and (Z) esters is obtained, according to thin layer chromatography (toluene/acetone = 10/1)» The following compounds were obtained analogously fo Example 23: (a) Ethyl (B)~ and (Z)-4-[(l-(S-methyl-2-piperidinopheny1)-1-buten-l-yl)-aminocarbonylmethyl)benzoate According to thin layer chromatography, a 1/1 mixture of (Ξ) and (2) esters is obtained from the (Z) ester (see Example 22g)θ Upper spot (B): Calculated: m/e « 434 Found: m/e « 434 lower spot (z): Founds m/e a 434 Example 24 Ethyl 4-[ (l-Ca-pipecidino-phenyll-l-butyli-aminocgirbonyl methyl]-benzoate 2o9 g (6.90 mmol) of ethyl 4-[(1-(2-piperAdinophenyl)-1-buten-l-yl)-aminocarbonyImethy1] -benzoate in 100 ml of ethanol is hydrogenated on 0.77 g of 10% palladium/oharcoal at 50°C under a hydrogen pressure of 1 bar. After 2 hours, the catalyst is filtered off over kieselguhr and the filtrate is concentrated by evaporation In vacuo. The evaporation residue is crystallised from ethanol.
Yield: 1.5 g (51.5% of theory), M.p.: 126-128¾ Calculated: C 73.90 H 8.11 N 6.63 Found: 73.97 8.22 6.57 The following compounds were obtained analogously * to Example 24: (a) Ethyl 4-[(1-(2-piperidino-phenyl)-1-pentyl)aminocarbonylmethyl]-benzoate Yield: 45% of theory, M.p.s 117-120¾ (ether) Calculated: C 74.28 H 8.31 M 6.42 Found: 74.60 8.13 6.27 (b) Ethyl 4-[(1-(2-piperidino-phenyl)-1-hexyl)aminocarbonylmethyl]-bensoate Yield: 50% of theory, M.p.? 108-110¾ (ether) Calculated: C 74.63 H 8.50 N 6.22 Found: 74«85 8.33 6.01 (c) Ethyl 4-[(2-phenyl-l-(2-piperidino-phenyl)1-ethyl)-aminocarbonylmethyl] -bensoate Yield: 87.6% of theory, M.p.: 161-162¾ (ethanol) Calculated: C 76.57 H 7.28 W 5.95 Found: 76.71 7.19 5.99 (d) Ethyl 4»[(3-phenyl-l-(2-piperidino-phenyl)1-propyl)-aminocarbonylmethyl] -benzoate Yield: 57.6% of theory, M.p.: 118-119¾ (ethanol) Calculated: C 76.03 H 7.«9 M 5.78 Pound: 76.70 7.«9 5.90 (e) Ethyl 4-((1-(2-(3,3-dimethyl-piperidino)-pheny1)5 1-butyl)-aminocarbonylmethyl] -benzoate Yield; 36.5% of theory, s 140-141°C (ethanol) Calculated: C 74.63 H 0.50 N 6.22 Found: 74.30 8.23 6.12 Example 25 4-((1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoic acid A mixture of 1.2 g (2.84 mmol) of ethyl 4-((115 (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, 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 in vacuo. The evaporation residue is crystallised from ethanol.
Yield: 0.50 g (44.6% of theory), M.p.s 213-215°C Calculated; C 73.07 H 7.66 N 7.10 Found; 73.18 7.51 7.10 The following compounds were obtained analogously 30 to Example 25: (a) 4-((1-(2-piper idino-phenyl)-1-penfyl)-aminocarbonylmefhyl] -benzoic acid Yield: 70.2% of theory, M.p.s 213-215°C (acetone) Calculated; C 73.50 H 7.90 N 6.86 Found: 73,71 7.70 6.90 (b) 4-[(l-(2-piperidino-phenyl)-l-hexyl)-aminocarbonylmethyl]-benzoic acid Yield: 72.6% of theory, M.p.s 197-200°C (acetone) Calculated: C 73.90 H 8.11 N 6.63 Found: 73.83 7.93 6.77 (c) 4-[(2-pheny1-1-(2-piperidino-phenyl)-1-ethyl)aminocarbonylmethyl]-benzoic acid Yield: 68.7% of theory, M.p.: 214-215°C (acetone) Calculated: C 75.99 H 6.83 N 6.33 Found: 75.70 6.60 6.32 (d) 4-[(3-P heny1-1-(2-p ipe r i d i no-pheny1)-1-pr opy1) aminocarbonylmethyl]-benzoic acid Yields 67*7% of theory, M.p.s 167-170°C (ethyl acetate) Calculated: C 76.29 H 7.06 N 6.14 Found: 76.56 7.06 6.23 (e) 4-[2-Methoxy-l-(2-piperidino-phenyl)-1-ethyl)aminocarbonylmethyl]-benzoic acid Yield: 60.8% of theory, M.p.s 196-198°C (ether) Calculated: C 59.66 H 7.12 M 7.07 Found: 69.72 5.52 6.71 (f) 4-[(1-(2-Piper idino-phenyl)-4-penten-l-yl)30 afAinocarbonylmethyl]-benzoic acid x 0.67 H^O Yield: 30.7% of theory, M.p.s 193-197°C (ether/petroleum ether) Calculated: C 71.74 H 7.38 N 5.69 Found: 71.53 7.21 6.34 (g) 4-1(1-(2-(3,3-Dimethyl-piperidino)-phenyl)1-butyl)-aminocarbonylmethyl] -benzoic acid Yields 48.2% of theory, 78 M.p.: 168-170¾ (petroleum ether) Calculated: C 73.91 H 8.11 N 6.63 Found: 73.51 7.89 6.32 (h) 4-[(1-(3-Methy1-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 53% of theory, M.p.: 179-182¾ Calculated: C 73.50 H 7.90 W 6.86 10 Found: 73.50 7.82 7.01 (i) 4-1(1-(4 -Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 85.6% of theory, Μ.ρθ: 170-172¾ Calculated: C 73.50 H 7.90 N 6.86 Found: 73.25 7.64 6.89 (k) 4-[(l-(5-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 62.1% of theory, Mop®: 219-221¾ Calculated: C 73.50 H 7.90 N 6.86 Found: 73.20 7.74 6.89 (l) 4-[(l-(6-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid x 0.3 H^O Yield: 89% of theory, M.p.s 158-160¾ Calculated: C 72.53 H 7®93 N 6.77 Found: 72.40 7.91 6.92 (m) 4-[(l-(3-Chloro-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yields 70% of theory, H.p.s 189-191¾ Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.30 6.85 8.35 6.58 (η) 4-((1-(4-Chloro-2-piperidino-phenyl)-l-butyl)aminocarbonyImethyl]-benzoic acid Yield: 57,8% of theory, M.p.: 188-189°C Calculated: C 67.20 H 6.81 Cl 8.27 $ 6.53 Found: 66.90 7.00 8.22 6.53 (o) 4-((1-(5-Chloro-2-piper idino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid Yield: 81.6% of theory, M.p.s 226-229°C Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.17 6.59 8.51 6.60 (p) 4-((1-(6-Chloro-2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl] -benzoic acid Yield: 69.4% of theory, M.p.s 150-153°C Calculated: C 67.20 H 6,81 Cl 8.27 N 6.53 Founds 67.18 6.91 8.42 6.77 (q) 4-((l-(4-Bromo-2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid Yield: 84.4% of theory, M.p.: 198-201°C Calculated: C 60.89 H 6.17 Br 16.88 N 5.92 Found: 60.88 5.98 17.20 5.98 (r) 4-((1-(5-Brorao-2-piperidino-phenyl)-1-butyl)30 aminocarbonylmethyl]-benzoic acid Yield: 90.7% of theory, M.p.s 232-235°C Calculated: C 60.89 H S.17 Br 16.88 $ 5.92 Found: 60.96 6.13 16.85 5.90 (s) 4-((1-(4-Nitro-2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl] -bensoic acid Yields 70.9% of theory, M.p.: 188-190¾ Calculated: C 65.59 H 6.65 ft 9.56 Found: 65.30 6.44 9.53 (t) 4-((1-(5-ftitro-2-piperidino-phenyl)-1-butyl)swinocarbonyImethy1]-benzoic acid Yield: 90.7% of theory, M.p.s 225-227¾ Calculated: C 65.59 H 6.65 ft 9.56 10 Found: 65.80 6.61 9.72 (u) 4-[(1-(4-Hydroxy-2-piperidino-phenyl)-1-butyl)aminocarbonyImethy1]-benzoic acid it 0.5 H^O Yield: 85.7% of theory, M.p.: softening from 70¾ (foam) Calculated: (x 0.5 H20) C 68.71 H 7.45 ft 6.68 Found: 68.63 7.55 6.26 (v) 4-((1-(5-Hydroxy-2-piperidino-phenyl)-1-butyl)20 aminocarbonylmethyl]-benzoic acid Yield: 89.3% of theory, M.p.: 186-190¾ Calculated: C 70.22 H 7.37 ft 6.82 Found: 70.31 7.58 6.51 (w, 4-((1-(4-Methoxy-2-piper idino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid Yield: 78.6% of theory, M.p.: 185-187¾ Calculated: C 70.73 H 7.60 ft 6.60 Found: 70.46 7.77 6«56 (x) 4-[(1-(S-Methoxy-2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl] -benzoic acid Yield: 75% of theory, M.p.: 182-185¾ (decomp.) Calculated: C 70.,73 H 7.60 ft 6.60 Found: 70.52 7.50 6.70 (y) 4-((1-(2-Pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid Yield: 64.5% of theory, M.p.: 200-203¾ Calculated: C 72,61 H 7.42 N 7.36 Pound: 72.64 7.50 7.38 (z) 4-[(1-(2- (4-Methy1-piperidino)-phenyl)-1-butyl)aminocarbonylmethyl] -benzoic acid Yield: 81.4% of theory, M.p.: 197-201¾ Calculated: C 73.50 H 7.90 N 6.86 Found: 73.90 8.06 7.00 (aa) 4-((l-(2-Hexahydroazepino-phenyl)-l-butyl)aminocarbonylmethyl]-benzoic acid Yield: 65.6% of theory, M.p.: 199-202¾ Calculated: C 73.50 H 7.90 N 6.86 Found: 73,50 7.90 6.76 (ab) 4-((1-(4-Fluoro-2-piper idino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid Yield: 87.1% of theory, M.p. s 204-207¾ Calculated: C 69.88 H 7,09 N 6.79 Found: 70.25 7.02 7.12 (ac) 4-((1-(5-Fluoro-2-piperidino-phenyl)-l-butyl)aminocarbonylmethyl] -benzoic acid Yield:* 53.9% of theory, M.p.: 200-202¾ Calculated: C 69.88 H 7.09 H 6.79 Found: 69.67 7.24 6.90 (ad) 3-Chloro-4-((1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid Yield: 51% of theory.
M.P.: 165-168°C Calculated: C 67.20 H 6.81 N 6.53 m/e = 428/430 (1 chlorine) Found: C 66.92 6.69 6.55 m/e = 428/430 ( 1 chlorine) Example 26 4-[(2-Methvl-l (2-piperidino-phenyl)-l-propen-l-yl)aminocarbonylmethyl] -benzoic acid A mixture of 3.5 g (8.3 mmol) of ethyl 4-((210 methyl-1-(2-piper id ino-pheny1)-1-propen-l-y1)-aminocarbony lmethyl] benzoate and 12.5 ml of IN sodium hydroxide solution in 35 ml of ethanol is stirred at 60°C for 2 hours. If is neutralised with 12.5 ml of IN hydrochloric acid, concentrated by evaporation in vacuo and distributed between ethyl acetate and wafer. The dried, filtered organic extract is evaporated in vacuo. The evaporation residue is crystallised from ethanol.
Yields 2.4 g (73.6% of theory), H.p.s 1Q8-191°C Calculated: C 73,44 H 7.19 N 7.14 Found: 73.60 /.19 7.02 The following compounds were obtained analogously to Example 26: (a) (E)-4-[(1-(2-Piperidino-phenyl)-1-buten-l-yl)aminocarbonylmethyl]-benzoic acid Yield: 71.5% of theory, M.p.: 188-190¾ Calculated; C 73.44 H 7.19 N 7.14 Found: 73.15 7.13 7.10 Olefinic proton: ^H-NMR (CDCl^):^* 6.42 ppm (b) (Z)-4-[(1-(2-Piperidino-phenyl)-1-buten-l-y1)aminocarbonylmethyl]-benzoic acid .
Yield: 57.8% of theory, M.p.: 174-175¾ (ethanol) Calculated: C 73.44 H 7.19 N 7.14 Found: 73.54 6.97 7.17 Olefinic proton: ^H-NMR (CDCl^ltJ» 5*60 ppm (c) (E)-4-[(2-Pheny1-1-(2-piperidino-phenyl)-ethenl-yl)-aminocarbonylmethyl]-benzoic acid x 0.4 H2° Yield: 33.2% of theory, M.p·: 165-167°C (ether/petroleum ether) Calculated: (n 0.4 H^O) C 75.11 H 6.48 N 6.26 Found: 75,22 6.39 6.26 olefinic proton: ^H-NMR (CDCl^)s& >6.9 ppm (d) (Z)-4-[(2-Phenyl-l-(2-piper id ino-phenyl)-ethen1-yl)-aminocarbonylmethyl]-benzoic acid x 1 «2° Yield: 72% of theory, M.p.: 182-185¾ (methanol) Calculated: (x 1 H20): C 73.34 H 5.50 N 6.11 Found: 73.55 6.45 6.00 olefinic proton: (CDCl^); £ 6.50 ppm (e) 4-((3-Phenyl-l~(2-piperidino-phenyl)-l-propen1-yl)-aminocarbonylmethyl] -benzoic acid Yield: 48.3% of theory, H.poS 162-164°C (ether); probably (2) form 5 Calculated: C 76.63 H 6.65 $ 6.16 Found: 76.30 6.47 6.31 Olefinic proton: ^H-$MR (CDC13)s £ = 5.80 ppm (f) 4-((1-(2-(3,3-Dimethyl-piperidino)-phenyl)10 1-buten-l-yl)-aminocarbonylmethyl] -benzoic acid Yield: 64.1% of theory, 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 Olefinic proton: ^H-HMR (CDClj): £ = 5.55 ppm (g) (2)-4-((l-(6-Methyl-2-piperidino-phenyl)-lbuten-l-yl)-aminocarbonylmethyl] -benzoic acid Yield: 53.3% of theory, M.p.: 142-145°C Calculated: C 73.66 H 7.44 $ 6.89 Found: 73.56 7.73 7.15 olefinic proton: 1H-HMR (CDC13): £= 5.38 ppm Example 27 4-( (1-(2-Piper idino-phenyl) -1-butyl) -aminocarbonyImethyl] benzoic acid 200 mg (0.51 mmol) of 4-[(1-(2-piperidino-phenyl)30 1-buten-l-yl)-aminocarbonylmethyl]-bensoic acid in ml of absolute ethanol are hydrogenated over 100 mg of palladium/charcoal (10%) at 50°C and under 1 bar of hydrogen, with shaking. After 1.5 hours the mixture is filtered and concentrated by evaporation in vacuo.
Yield: 68% of theory, M.p.: 213-214°C Calculated: C 73.07 H 7.66 K 7.10 Found: 73.21 7,82 7.02 The yield is 56% of theory if hydrogenation is carried out at 50°C and under 1 bar of hydrogen on Raney nickel.
Example ?r Sodium salt of 4-[(1-(2-piperidino-phenyl)-l-butyl)aminocarbonylmethyl]-benzoic acid x 0.5 HjO .0 g (25.35 mmol) of 4-((l-(2-piperidino10 phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid are dissolved at 50°C in 200 ml of ethanol and 25.35 ml 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.
Yields 9 g (85.3% of theory), M.p.s 280-285°C (decomp.)? softening from 255°C Calculated: (x 0.5 HjO) C 67.74 H 6.87 N 6.58 Founds 67.86 7.13 6.49 Example 29 Ethyl (1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate To a stirred solution of 2.58 g (11.1 mmol) of (4-)-l-(2-piperidino-phenyl)-l-butylamine (Bp θ Q3s 87°C? ee = 86 (HPLC, after derivatising with (-5-)30 1-phenethyl-isocyanate)] in 26 ml of, acetonitrile, there are added, at 20°C, one after another, 2.31 g (11.1 mmol) of 4-ethoxycarbonyl-phenyl acetic acid, 3.50 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 in 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 (foluene/acetone * 6:1).
Yields 2.63 g (56% of theory), M.p.s 118-120¾ Calculated: C 73.90 H 8.11 N 6.63 Founds 74.02 7.97 6.51 (a]p° = 4-9.2° (c = 1; methanol) The following compound was obtained analogously to Example 29: (a) Ethyl (-)-4-((1-(2-piperidino-phenyl)-1-butyl)15 aminocarbonylmethyl]-benzoate Prepared from (-)-l-(2-Piperidino-phenyl)-lbutylamine ie 1.4 HC1 [[ο]^θ a -20.0° (c = 1, methanol), Melting range: 90-100°C; ee 3 80 (HPLC, after 20 derivatising the base with {^j-l-phenethylisocyanate)] Yield: 52.6% of theory, M.p.: 115-120¾ Calculated: C 73.90 H 8.11 M 6.63 25 Found: 73.83 8.01 6.47 [e]^0 " -9.0° (c « 1, methanol) Example 30 Ethyl (+)-4-( (l-(2-PiPeridino-phenyl)-1-butyl)-aminoca r bonylmet hyl)-be n goa te 1.0 g (3.27 mmol) of (+0-1-(2-piperidino-phenyl)1-butylamine-dihydrochloride [(©Ip = +18.7° (c « 1, methanol); m.p.: decomposition from 115°C; ee = 91.6 (HPLC, after derivatising the base with (+)1-phenethyl-isocyanate)) is suspended in 6 ml of methylene chloride, then 1.4 ml (10 mmol) of triethylamine are added, with stirring, and then the solution of 0.82 g (3.64 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 2.4 ml of methylene chloride is added dropwise thereto, whereupon the reaction temperature rises from 22¾ to 38°C. The mixture is stirred for 6 hours at ambient temperature and then extracted successively: twice with 10 ml of water, once with 10 ml of 2N hydrochloric acid and once with 10 ml of water.
The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo.
The evaporation residue is purified by column chromatography on silica gel (toluene/acetone 6/1).
Yield; 0.53 g (38.2% of theory), M.p.: 120-122¾ Calculated: C 73.90 H 8.11 N 6.63 Found: 73.96 7.98 6.61 [©Ιφθ = +9-0° (c ® 1, methanol) Example 31 (+)-4-[(1-(2-Piperidino-phenyl)-l-butvl)-aminocarbony1methyl]-benzoic acid 2.0 g (4.73 mmol) of ethyl (+)-4-((1-(2-piperidino20 phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate [(a] D • +9.2° (c « 1, methanol)] in 20 ml of ethanol are 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. i The crystals which are slowly precipitated are filtered off, washed with water and dried at 100°C/4 torr.
Yield: 1,,55 g (88.2% of theory), M.p.: 185-187°C Calculated: C 73.07 H 7.66 ft 7.10 Found: 72.90 7.80 7.17 - +7..9° (c - 1, methanol) The following compound was obtained analogously fo Example 31: (a) (-)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbony Imethy1]-benzoic acid Yield: 80% of theory, MupoS 187-190°C Calculated: C 73.07 H 7.66 ft 7.10 Found: 72.98 7.44 7.22 [α]2θ s -7.9° (c » 1, methanol) Example 32 4-[(1-(2-Piperj. dino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzonitrile Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-cyano-phenylacetic acid analogously to Example 19.
Yield: 57.3% of theory, M.p·: 147-148°C Calculated: C 76.76 H 7.78 ft 11.19 Found: 76.46 7.81 11.10 The following compound was obtained analogously to Example 32: (a) 4-[(l-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl methyl] -toluene Prepared with 4-tolyl-acetic acid.
Yields 60.4% of theory, M.p.s 150-153°C Calculated: C 79.00 H 8.85 ft 7.68 Found: 78.97 8.58 7.77 Example 33 Ethyl 4-((1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl·] -benzoate Prepared from 4-[(1-(2-piperidino-phenyl)-1butyl)-aminocarbonylmethyl]-benzonitrile with ethanolic hydrochloric acid analogously to Example 14.
Yield: 58% of theory, M.p.: 127-128°C Calculated: C 73.90 H 8.11 ft 6.63 Found: 74.07 8.23 6.87 Example 34 Ethyl 4-( (l-(2-piperidino-phenYl)-l-butYl)-aroinocarbonylmethyl] -benzoate Prepared analogously to Example 10 from 1-(2piperidino-phenyl)-1-butanol and ethyl 4-cyanomethylbenzoate with concentrated sulphuric acid in o-dichlorobenzene at ambient temperature.
Yields 21% of theory, M.p.: 12S-128°C Calculated: C 73.90 H 8.11 ft 6.63 Founds 74.12 8.20 6.45 The following compound was obtained analogously to Example 34: (a) 4-[(1-(2-Piper idino-phenyl)-1-butyl)-aminocarbony1methyl]-benzoic acid Prepared from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanomethyl-benzoic acid. Extraction at pH 5.5.
Yield: 29% of theory, M.p. 8 215-217°C Calculated: C 73.07 H 7.66 ft 7.10 Found: 72.82 7.69 6.95 Example 35 4-( (1-(4-&mlno-2-pjper idino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 H^O 0.60 g (1.365 mmol) of 4-((1-(4-nitro-2-piperidinophenyl) -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 in vacuo. The evaporation residue is crystallised from ether.
Yield: 0.41 g (73.2% of theory), M.p.: 118-120¾ Calculated: (x 0.5 H20): C 68.87 H 7.71 N 10.04 Found: 68.62 7.64 10.08 The following compounds were obtained analogously to Example 3θ: (a) Ethyl 4-( (l-(4-amino-2-piperidino-phenyl)-lbutyl)-aminocarbonylmethyl] -benzoate Yield: 81.7% of theory, M.p.: 145-146¾ (ether/petroleura ether) Calculated: C 71.37 H 8.06 N 9.60 Found: 71.50 8.08 9.68 (b) 4-((1-(5-Amino-2-piper id ino-pheny1)-1-butyl)aminocarbonylmethyl]-benzoic acid Yield: 64% of theory, M.p.s 227-230¾ Calculated: C 70.39 H 7.63 ft 10.26 Found: 70.54 7.54 10.36 (c) Ethyl 4-[(1-(5-aaino-2-piperidino-phenyl)-1bu ty1)-am i noca rbonylme thyl] -benzoa te Yield: 04.3% of theory, H.p.s 162-165¾ Calculated: C 71.37 H 8.06 N 9.60 Found: 71*58 7.83 9.65 Example 36 Ethyl 4-[(l-(5-chIoco-2-piperidino-phenyl)-l-butyl)5 aminocarbonylmethyl] -benzoate A cold diazonium salt solution (0°C) is prepared from 2.0 g (4.57 mmol) of ethyl 4-[(1-(5-amino-2piper idino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoate in 4.8 ml of semiconcentrated hydrochloric acid and 0.315 g (4.57 mmol) of sodium nitrite in 1.6$ ml of wafer. This solution is added dropwise, at 0 to 5°C, to a stirred mixture of 0.59 g (5.94 mmol) of copper(I)chloride and 2.4 ml of cone, hydrochloric acid and the resulting mixture is then heated in a bath at 50°C. After the development of gas has ended (about 15 minutes), the mixture is cooled, added to ice/conc. ammonia and extracted four times, each time with 100 »1 of ethyl acetate. The combined organic extracts are shaken with water, dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/efhyl acetate = 10/1).
Yield: 0.80 g (40% of theory), M.p.s 137-140°C (ether) Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13 Found: 68.42 7.09 8.06 6.05 The following compounds were obtained analogously to Example 36: (a) Ethyl 4-[(l-(4-chloro-2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl] -benzoate Yield: 21.9% of theory, M.p.s 123-125°C Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13 Found: 58.70 7.18 7.77 S.08 (b) Ethyl 4-[(1-(5-brorao-2-piperidino-phenyl)-1butyl)-aminocarbonylmethyl] -benzoate Yield: 53.0% of theory, M.p.: 140-142¾ Calculated: C 62.27 H 6.63 Br 15,93 N 5.58 Found: 62,39 6.78 15.85 5.59 (c) Ethyl 4-[(l-(4-f!uoro-2-piperidino-phenyl)1-butyl)-am i noca rbonylme thy1]-benzoate Yield: 21.6% of theory, M.p.: 110-112¾ Calculated; C 70.88 H 7.55 N 6.36 Found: 71.01 7.53 6.21 In addition, 40% of ethyl 4-[(l-(4-hydroxy-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl] -benzoate are isolated (solid foam). (d) Ethyl 4-[(1—(5-fluoro-2—piperidino—phenyl)— 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 2% of theory, M.p.: 127-129¾ Calculated: m/e 440 Found: m/e e 440 (e) 4-[(l-(4-Fluoro-2-piperidino-phenyl)-ethyl)aminocarbonylmethyl] -benzoic acid Yield: 16.9% of theory, M.p. s 172-175¾ Calculated: C 68.73 H 6.55 N 7.29 Found: 68.78 6.62 7.31 Example 37 £ί-[ (1- (ji-Piper idino-phenyl)-l-butvl)-aminocarbony 135 Mfe^hYll -benzoic acid 1.0 g (2.33 mmol) of 4-[(1-(5-chloro-2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl] -benzoic acid in 40 ml of absolute ethanol are hydrogenated on 0.5 g of 10% palladium/charcoal at 50°C and under bar of hydrogen. After 2 hours, the catalyst is filtered off over kieselguhr and the filtrate is concentrated by evaporation in vacuo. The evaporation residue is distributed at pH 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated in vacuo.
Yield: 0.61 g (66% of theory), M.p.: 213-215°C Calculated: C 73.07 H 7.66 N 7.10 Found: 73.18 7.42 7.27 The same compound is also obtained from the corresponding 4-chlorine-, 3-chlorine- or 6-chlorine-substituted starting products® Example 38 Ethyl 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl] -benzoate A solution of 5.0 g (11.4 mmol) of ethyl 4[(l-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate in 45 ml of absolute dimethylformamide is added dropwise, with stirring, at ambient temperature, to 548 mg (11.4 nunol) of sodium hydride (50% In oil) in 10 ml of absolute dimethylformamide. The mixture is stirred for a further 15 minutes and then a solution of 0,71 ml (11.4 mmol) of methyliodide in 8 ml of absolute dimethylformamide is slowly added dropwise thereto. The mixture is stirred for a further 2.5 hours at ambient temperature, evaporated in vacuo and distributed between water and ether. The ether phase is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 20/1).
Yields 1.8 g (34.9% of theory), M.p®s 115-117°C Calculated: C 71.65 H 8.02 ft 6.19 Found: 71.47 7.86 6.19 The following compound was obtained analogously fo 5 Example 33. (a) Bthyl 4-[(l-(5-methoxy-2-piperidino-phenyl)1-butyl)-aminocarbonyImethy1]-benzoate Yield: $8.4% of theory, M.p. S 1«2-K5°C Calculated: C 71.65 H 8.02 a 6.19 Found: 71.87 8.06 6.38 Example 39 2,3-Dihydroxy-propyl 4-[(1-(2-piperidino-phenyl)1-butyl)-aminocarbonylmethv1) -benzoate A solution of 2.0 g (5.07 mmol) of 4-[(1-(2piperidino-phenyl)-1-butyl)-aminocarbonyImethy1]benzoic acid and 0.85 g (5.27 mmol) of ft,ft'-carbonyldi20 imidazole in 20 ml of absolute tetrahydrofuran is refluxed for 1 hour, then 3.7 ml (50.7 mmol) of glycerol are added and the resulting mixture is refluxed for a further 15 hours. It is then concentrated by evaporation in vacuo, distributed between water and ethyl acetate, the organic solution is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone e 1:1).
Yield: 1.1 g (46.2% of theory), M.p.s 120-122°C Calculated: C 69.21 H 7.74 ft 5.98 Found: 69.23 7.78 5.93 The following compounds were obtained analogously to Example 39: (a) 2-hydroxy-ethyl 4-[(1-(2-piperidino-phenyl)1-butyl)-aminocarbonyImethy1]-benzoate Yield: 80% of theory, M.p.: 125-127°C Calculated: C 71.21 H 7.81 M 6.39 Founds 71.35 7.54 6.33 (b) 2-methoxy-ethyl 4-[(1-(2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl] -benzoate Yield: 55.9% of theory, M.p.: 12O-123°C Calculated: C 71.65 H 8.02 N 6.19 Found: 72.03 8.03 6.24 Example 40 2-nicotinoyloxy-ethyl 4-[ (1-(2-piperidi.no-phenyl)- 1-butyl)-aminocarbonylmethyl] -benzoate A solution of 0.7 g (4.68 mmol) of nicotinic acid chloride in 20 ml of methylene chloride is rapidly added 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 wafer, then the organic phase is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (foluene/acetone - 5/1).
Yields 1.1 g (44% of theory), M.p.s 132-135°C Calculated: C 70.70 H 6.86 H 7.73 Founds 70.82 5.82 7.91 Example 41 4-[(1-(2-Piperidino-phenyl)-1-butyl)-arainocarbonylmethyl]benzyl alcohol A solution of 5.0 g (llo83 mmol) of ethyl 4[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] benzoate in 75 ml of absolute tetrahydrofuran is added dropwise, at an infernal temperature of 0°C, to a stirred suspension of 0.68 g (17.95 mmol) of lithium aluminium hydride in 25 ml of absolute tetrahydrofuran. The mixture is stirred for 20 hours at ambient temperature then cooled to 0°C and sodium hydroxide solution is slowly added dropwise thereto until a filterable precipitate has formed. The mixture is filtered and the precipitate is decocted several times with ether. The combined organic solutions are concentrated by evaporation in vacuo. The evaporation residue is distributed between water and ether.
The ether phase is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone * 5/1).
Yield: 1.0 g (22% of theory), M.p.s 152-154°C Calculated: C 75.75 H 8.«8 H 7.36 Founds 75.90 8.«5 7.28 Example 42 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzaldehyde 6.6 g (62 mmol) of sodium carbonate are heated together with 62 ml of ethylene glycol in a bath at 170°C and, within 1 minute, 6.2 g (11 mmol) of (1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoyl]-N -toeyl-hydresine (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)« Yields 2.2 g (52.9% of theory), M.p. 2 142-145¾ Calculated: Found: C 76.16 H 7.99 ft 7.40 76.26 7.96 7.37 Example 43 Ethyl 4-((1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl·] -cinnamate A solution of 2.80 g (12.5 mmol) of ethyl diethylphosphonoacetate 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 for 2 hours at ambient temperature, concentrated by evaporation in vacuo and distributed between water and ether. The ether phase is dried and filtered and then evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).
Yield: 0.85 g (29.9% of theory), M.p.s 135-137°C (ether/petroleum ether) Calculated: C 74.97 H 0.09 ft 6.24 Found: 74.91 7.89 6.29 Example 44 4-((1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]cinnamic acid Prepared by alkaline saponification of ethyl 4-((l-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]cinnamate analogously to Example 26.
Yields 64% of theory, h.pes 180-183¾ Calculated: C 74.26 H 7.67 ft 6.66 Founds 74.03 7.47 6.80 Example 45 Ethyl 3-[4-[(l-(2-Piperidino-phenyl)-I-butyl)-aroinocarbonylmethyl]-phenyl]-propionate 0.60 g (1.34 mmol) of ethyl 4-[(l-(2-piperidino5 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.
Yield: 0.53 g (88% of theory), M.p.: 98-99°C (petroleum ether) Calculated: C 74.53 H 8.50 N 6.22 Found: 74.54 3.58 6.23 The following compound was obtained analogously to Example 45: (a) 3-(4-((l-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -phenyl] -propionic acid Yield: 63% of theory, H.p.s 131-133°C Calculated: C 73.90 H 8.11 H 6.S3 Found: 73.96 8.30 5.56 Example 46 3-[4-((1-(2-Piper idino-phenyl)-1-butyl)-aminocarbonylmethyl] -phenyl]-propionic acid Prepared by alkaline saponification of ethyl 3-(4-((1-(2-pxperidino-phenyl)-1-butyl)-aminocarbonyl30 methyl]-phenyl]-propionate analogously to Example 25: Yield: 50% of theory, M.p.s 131-133°C Calculated: C 73.90 H 8.11 N 5.53 Founds 73.82 8.07 6.41 Example 47 Ethyl 4-[(a-aminocacbonyl-2-pipecidino-benzyl)-aminoca r bonylme t hy1]-benzoa te At 20°C, 0.90 g (5.5 mmol) of Μ,Μ’-carbonyldiimidazole are added to a stirred solution of 2.0 g (4.7 mmol) of ethyl 4-((a-carboxy-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate x 0.167 HjO (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 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 in vacuo, distributed between water and chloroform, then the combined chloroform extracts are shaken with a little water, dried, filtered and evaporated in vacuo.
The evaporation residue Is purified by column chromatography on silica gel (chloroform/methanol - 5/1).
Yield; 1.0 g (50.2% of theory), M.p.s 160-162°C (acetone) Calculated; C 68.07 H 6.90 $ 9.92 Found: 68.40 6.92 9.84 Example 48 Ethyl 4-((G-cyano-2-piperidino-benzyl)-aminocarbonylmethyll -benzoate 234 mg (1.22 mmol) of 4-toluenesulphochloride are added in two batches to 520 mg (1.22 mmol) of ethyl 4-((e-aminocarbonyl-2-piperidino-benzyl)-arainocarbonylmethyl] -bensoate in 0.22 ml of pyridine and the mixture is heated to 50°C, After 2 hours and then 1 hour later, the same quantities of pyridine and 4-toluenesulphochloride are again added and the resulting mixture is heated for a further hour at 50°Co After it has been left to stand for 2 days at 20°C, 2$ ammonia is added and the mixture is extracted with chloroform. The chloroform solution is extracted twice with wafer. After drying and filtering, it 700 is concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol 10/1)· Yield: 325 rag (65.7% of theory), M.p.s 114-117°C (ether/petroleum ether) Calculated: C 71.09 H 6.71 ft 10.36 Found: 70.79 6.56 10.10 Example 49 4-((cs-Cyano-2-piperidino-bengylj-aminocarbonyImethy1]benzoic acid 1.5 g (3.7 mmol) of ethyl 4-((a-cyano-2-piperidinobenxyl)-aminocarbonyImethy1] -benzoate in 15 ml of dioxan are stirred together with 3.7 ml of 1ft sodium hydroxide solution for 45 minutes in a bath at 60°C and for a further 45 minutes in a bath at 80°C.
After cooling with ice, the mixture is combined with 3.7 ml of 1ft hydrochloric acid, the dioxan is evaporated off in vacuo and the residue is distributed between water and chloroform. The organic solution is extracted with a little water, then dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethanol e 5/1).
Yield: 0.50 g (35.7% of theory), M.p.s 176-180°C (decomposition) Calculated: C 70.01 H 6.14 ft 11.13 Found: 70.02 6.19 11.05 30 Sxamole j;n 4-( (1-(2-piper idino-phenyl)-l-butvl)-aminocarbonyImethy 1] benzoic acid x H2SQ^ ml (2.50 mmol) of 1ft sulphuric acid are added to a solution of 1.0 g (2.53 mmol) of 4-[(1-(2-piperidino phenyl)-1-butyl)-aminocarbonyImethy1] -benzoic acid in 50 ml of ethanol, the mixture is concentrated fo dryness jLn vacuo and triturated with acetone. 101 Yield: 0.80 g (65% of theory), M.p.: 192-197¾ (decomposition).
Calculated: C 58.53 H 6.55 ft 5.69 S 6.49 Found: 58.05 6.54 5.49 6.35 The following addition salt was obtained analogously to Example 5θ; (a) 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl10 methyl]-benzoic acid x 0.5 H2SOa 1.5 H2 0 Prepared analogously to Example 50 with half the quantify of sulphuric acid.
Yield: 59.3% of theory, M.p.: 180-185¾ decomposition at 207-210¾ Calculated C 61.26 H 7.28 ft 5.95 S 3.40 Found: 61.28 6.99 6.10 3.23 102 Example A Tablets containing 5 mg of ^-[(1-(2-piperidino-phenvl·)1-butyl)-aminocarbonylmethyl] -benzoic acid Composition: tablet contains: Active substance (1) 5.0 mg Corn starch (2) 62.0 mg Lactose (3) 48.0 mg * 10 Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate (5) 1.0 mg 120.0 mg Method of preparation: lr 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 . The finished mixture is compressed in a tablet press, using punches 7 mm in diameter provided with a dividing slot, fo form tablets.
Height of tablet: 120 mg 25 Example 3 Coated tablets containing 2.5 mg of 4-[(1-(2-piperidinophenyl) -1-butyl) -aminocarbony lmethyl) -benzoic acid tablet core contains: Active substance (1) 2.5 mg Potato starch (2) 44.0 mg Lactose (3) 30.0 mg Polyvinylpyrrolidone (4) 3.0 mg Magnesium stearate (5) 0®5 mg 30.0 mg 103 Method of preparation: 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 the granulate is again passed through the same screen. After the addition of 5, convex tablet cores 6 mm in diameter are produced in a tablet-making machine by compression. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax.
Weight of coated tablet: 120 mg Example C *· Tablets containing 10 mg of 4-[(1-(2-piperidino-phenyl)1-butyl)-aminocarbonylmethyl] -benzoic acid Composition: 1 tablet contains: Active substance 10.0 mg Powdered lactose 70.0 mg Corn starch 31.0 mg Polyvinylpyrrolidone 8.0 mg Magnesium stearate 1.0 mg 120.0 mg Method of preparation A mixture of the active substance, lactose and corn starch is moistened with a 20% solution of polyvinyl pyrrolidone in water. The moist mass is granulated through a screen with a mesh width of 1.5 mm and then dried at 45°C. The dried granulate is rubbed through a screen with a mesh size of 1 mm and homogeneously mixed with magnesium stearate. height of tablets 120 mg * Punch: 7 mm in diameter with dividing slot. 104 Example D Coated tablets containing 5 mg of 4-[(l-(2-piperidinophenyl) -1-butyl)-aminocarbonylmethyl] -benzoic acid 1 tablet core contains: Active substance 5.0 rog Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 4.0 mg * 10 Magnesium stearate 1.0 mq 130.0 mg Method of preparation A mixture of active substance, calcium phosphate and corn starch is moistened with a 15% solution of polyvinylpyrrolidone in water. The moist mass is passed through a screen with a mesh size of 1 ram, then dried at 45°C and passed through the same screen again. After the specified amount of magnesium stearate has been added, tablet cores are compressed from the mixture.
Weight of core: 130 mg Punch: 7 mm in diameter.
A coating of sugar and talc is applied to the tablet cores thus produced in known manner. The finished coated tablets are polished with wax.
Weight of coated tablet: 130 mg

Claims (28)

1. l o Compounds of general formula I I wherein A represents a group of formula 5 R, C I II - CH - or - C [wherein R- represents an alkyl group containing 1 to 3 carbon atoms substituted by an 10 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 15 moiety; an arainocarbonyl group optionally monoor 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 20 5 or 10 carbon atoms optionally 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 25 and each alkyl moiety containing 1 to 3 carbon 106 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, Rj represents a piper Idino group, R z represents a fluorine atom in the 5 4-position of the aromatic nucleus, R, represents a hydrogen atom and « represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); or R 4 represents a phenyl group when represents a plperidino group substituted in the 2- or 3-position by a methyl group, 10 or when R 2 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, or when W represents a formyl, carboxyvinylene or alkoxycarbonylvinylene group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); R 3 and R a together with the carbon atom between them represent lb an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety]; Ri represents an unbranched alkyleneimino group containing 4 to 9 carbon atoms optionally mono- or disubstituted by alkyl groups containing 1 to 3 carbon atoms (which in the case of di substitution may be the same 20 or different); or a dialkylamino group containing 1 to 5 carbon atoms in each alkyl component; R z represents a hydrogen, fluorine, chlorine, bromine or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino, plperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, 25 alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group wherein the alkyl component may contain 1 to 3 carbon atoms in each case; r, represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom, and ϋ represents a carboxy group or an alkoxycarbonyl group containing 30 a total of 2 to δ carbon atoms (wherein the alkyl component may optionally be substituted by a phenyl group and optionally, at any carbon atom except the »-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino 35 group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms, an alkyl 107. group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, arainocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyetheny1, 2,2-bis-(carboxy)-ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2alkoxycarbonyl-ethenyl or 2,2-bis-(alkoxycarbonyl)ethyl group (each alkoxy group containing from 1 fo 3 carbon atoms)] and tautomers thereof and optical enantiomers thereof and salts of the aforementioned compounds.
2. E Salts of compounds of general formula I as defined in claim 1 and tautomers thereof, and optical enantiomers thereof, formed with hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid or with sodium hydroxide, potassium hydroxide, cyclohexyIamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine.
3. Physiologically compatible salts of compounds of general formula X as defined in claim 1 and tautomers thereof, and optical enantiomers thereof.
4. Compounds as claimed in claim 1, wherein A represents a group of formula - CH - or wherein 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 a-propyl group; an alkyl group containing 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atoms monoor disubstifuted by halogen atoms, or by alkyl, hydroxy, alkoxy, phenylalkoxy and/or alkylsulphenyl groups, whilst the substituents may be the same or different and each alkyl component may contain from 1 to 3 108 carbon atoms; or a pyridyb quinolyl or isoquinolyl group; R c and Re together with the carbon atom between 5 o them represent an alkylidene group containing 3 to 5 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety? * represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstifcuted by alkyl groups each havinq 10 1 to 3 carbon atoms? Rj represents a hydrogen, fluorine, chlorine or bromine atom or a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms; or (if R^ and Rg are as hereinbefore defined or R^ represents 15 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 20 or aminocarbonyl group) Rj may also represent an iodine atom or a hydroxy or amino group; R^ represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, 25 cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group? an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl conponent may hs· substituted at any carbon atom except the a-carbon < atom by 1 or 2 hydroxy groups or by an alkoxy group 30 containing 1 to 3 carbon atoms or by a pyridinecarbonyloxy groiip; or an alkoxy carbonyl-me thyl, 2-alkoxycarbonyl* ethyl or 2-alkoxycarbonyl-ethenyl group, wherein 109 each alkoxy group may contain from 1 to 3 carbon atoms; and 4-[ft- (6-chloro-©-phenyl-2-pipee idino-benzyl) -aminocarbonylmethyl] -benzoic acid and alkyl esters 5. Thereof, 4-[ft-(c-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl] cinnamic ticid and alkyl esters thereof; 4- [ft- (il-chloro-cx-phenyl-2-piper idino-benzyl) -aminocarbonylmethyl]-benzoic acid and ϋ^_ 3 alkyl esters thereof 4-[ft-(3-chloro-e-phenyl-2-piper idino-bensyl)-aminocarbonylmethyl]-benzoic acid and Cp_ 3 alkyl esters thereof 4-[ft-{6-methyl-s-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl]-benzoic acid and Cj_ 3 alkyl esters thereof 4-[ft- (4-methyl-ci~phenyl-2-piper idino-benzyl) -aminocarbonylmethyl] -benzoic acid and alkyl esters thereof 4-[ft- (2- (2-methyl-piperidino) -c-phenyl-bensy!) aminocarbonylmethyl] -benzoic acid and C 1-3 alkyl esters thereof 4-[ft“(2-(3-methyl-piper£dino)-a-phenyX-benzyl)- * aminocarbonyl-methyl]-bengoic acid and C^_ 3 alkyl esters thereof no 4-[B-(e-pheny1-2-ρ ipe r id ino-bensy1)-am inoca rbony1methylbensaldehyde, 4-((1-(4-fluoro-2-plper idino-phenyl)-ethyl)-aminocarbonyl methyl]-benzoic acid and Cj_3 alkyl esters thereof, 5 and tautomers and optical enantiomers of the above-named compounds and salts thereof.
5. Compounds as claimed in claim 1, wherein: A represents a group of formula C II -ε- CH - or 10; wherein represents an alkyl group containing 1 to 3 carbon atoms substituted by & methoxy or phenyl group; an n-propyl, cyano or audnocarbonyl group; an alkyl group containing 4 to 5 carbon atoms, an alkenyl group containing 3 to 5 carbon atoms; & phenyl 15 group substituted by a fluorine, chlorine or bromine atom or by a methyl, hydroxy, methoxy, bensyloxy or methylsulphenyl group; or β pyridyl group; R e and R-. together with the carbon atom between 5 6 them represent an alkylidene group containing 3 to 20 g carbon atoms or a phenylalkylldene group containing 1 to 3 carbon atoms in the alkylidene moiety, πί R| represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by methyl groups, ft2 represents a hydrogen, fluorine, chlorine or brom-ine atom or a methyl or methoxy group; or, if R. and R- are as hereinbefore defined or R, represents an alkyl group containing 1 fo 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, nitrile or aminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or an alkenyl group containing 3 fo 5 carbon atoms, R^ may also represent an iodine atom or a hydroxy or amino group; R^ represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms wherein the alkyl conponent may be substituted at any carbon atom except the 4-[ft-(6-chloro-a-pheny1-2-piperidino-benzyl)-aminocarbony Imethy1]-benzoic acid and alkyl esters thereof, (c-phenyl-2-piperidino-benzyl)-aminocarbonylmefhyl] cinnamic acid and alkyl esters thereof 112 (4-chloro-G-phenyl-2-piper idino-benzyl) - ami nocar bonylmefhyl] -bensoic acid and alkyl esters thereof, 4-IN-(3-chloro-c-phenyl-2-piperidino-benzyl)-aminocarbonylraethyl]“bensoic acid end Cj_ 3 alkyl esters thereof, 5 41-[R- (S*-i»ethyl-ei-phenyl“2-piper id ino-benzyl)-aminocarbonylmethyl]-bensoic acid and C]_j alkyl esters thereof * 4-[H-($-methyl-cs-pbenyl-2-piperidino-benzyl)-aniinoc&rbonylmethyl]-benzoic acid and alkyl esters thereof 4t-(»-(2- (2-methyl-piper idino)-e-phenyl-bensyl)-end no10 carbonyl-methyl]-benzoic acid and alkyl esters thereof 4-[R-(2-(3-methyl-piper idino)-a-pheny1-benzyl)-erainocarbonylmefhyl] -benzoic acid and alkyl esters thereof; 15 4-[R-(e-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]benzaldehyde, 4-[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and alkyl esters thereof^ and tautomers and optical enantiomers of the above-named compounds 20 and salts thereof.
6. 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 in 113 which Liu? alkyl CUii|X)iK2it imy lx? subst..i Lut t ·<Ι *it «-ιιιγ <:. 11 Ia «i πΙλιιι except the α-cnrbon atom by one or two hydroxy groups.
7. Compounds as claimed in claim 5 wherein W repre- sents a carboxy group or an ι alkoxycarbonyl group containing a total of 2 to 5 carbon atoms.
8. . Compounds as claimed in claim 1, wherein A represents a group of formula R 5^ x R S t *4 | C II 1 - CH - 1 or H - C - wherein 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; R^ 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; Ry represents a plperidino group optionally substituted by one or two methyl groups; &2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group; represents a hydrogen atom; and E represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms. 7.
9. Compounds as claimed in claim 8, wherein A represents a group of formula R», I II ~ CH - or - C wherein represents an n-propyl group or an alkyl group containing 4 or 5 carbon atoms and Rg and Rg 114 together with the carbon atom between them represent en alkylidene group containing 3 to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part. 5
10. 4-[N-(6-Chloro-ot-phenyl-2-piperidino-benzyl)aminocarbonyl-methyl]-benzoic acid and C^_ 3 alkyl esters thereof.
11. 4-|N-(α-Phenyl-?-piperidino-benzyl)-aminocarbonyl methyl]-cinnamic acid and C 3 _ 3 alkyl esters thereof.
12. 4-(N-(4-Chloro-o-phenyl-2-piperidino-benzyl)aminocarbonyl-methyl] -benzoic acid and alkyl esters thereof.
13. 4-[N-(3-Chloro-a-phenyl-2-piper idino-benzyl)aminocarbonyl-methyl] -benzoic acid and C^_ 3 alkyl 15 esters thereof.
14. 4-[N-(6-Methyl-a-phenyl-2-piper idino-benzyl)aminocarbonyl-methyl]-benzoic acid and Cj_ 3 alkyl esters thereof.
15. 4-[N-(4-Methyl-a-phenyl-2-piperidino-benzyl) 20 aminocarbonyl-methyl]-benzoic acid and C 3 _ 3 alkyl esters thereof.
16. 4-[N-(2-(2-Methyl-piperidino)-α-phenyl-benzyl)aminocarbonyl-methyl)-benzoic acid and Cj_ 3 alkyl esters thereof.
17. 4-(N-(2-(3-Methyl-piperidino)-o-phenyl-benzyl)ami nocarbonyl-methyl] benzoic acid and Cj_ 3 alkyl esters thereof.
18. 4-fw- (
19. 4-[]l-{4-Fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyfj-benzoic acid and C 1-3 alkyl esters thereof.
20. 4-Ql -£a-(4-Fluoro-phenyl)-2-piperi di no-benzy fj -ami nocarbonylmethy' -benzoic acid and Cj_ 3 alkyl esters thereof. 115
21. 4·[{1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoic acid and C 1-3 alkyl esters thereof.
22. 4-((1-(2-Piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl] -benzoic acid and C 1-fc3 alkyl esters thereof.
23. 4-[(1-(2-Piperidino-phenyl)-l-pentyl)-aminocarbonylmethyl]-benzoic acid and C 1-3 alkyl esters thereof.
24. Tautomers and optical enantiomers of compounds as claimed in any one of claims 10 to 23, and salts thereof.
25. Enantiomers and salts of compounds as claimed in any one of claims 20 fo 23. 26 · Compounds as claimed in claim 1 wherein A represents a group of formula *4 I — CH — wherein F^ represents an aryl group containing 6 or 10 carbon atoms mono- or di-subsfifuted by halogen atoms, or by alkyl, hydroxy, alkoxy, pbenylalkoxy, alkylsulphenyl, alkylsulphinyl and/or alkylsulphonyl groups, whilst the substituents in the case of disubstitution may be the same or different and each alkyl moiety may contain from 1 fo 3 carbon atoms; or a heferoaryl group containing 4,5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms; F^ represents an unbranched alkylenelmlno group containing 4 to 6 carbon atoms optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; an ocfahydroazocino, octahydroIB-azonino or decahydroazecino group; or a y 116 dialkylamino group containing 1 to 5 carbon atoms in each alkyl component; R^ represents a hydrogen or halogen atom; £7 represents a carboxy, formyl, hydroxymethyl, 5 cyano, aminocarbonyl, 2-carboxyethenyl, 2-carboxyethyl, or 2,2-bis-(carboxy)-ethyl group, an alkoxycarbonyl group containing a total of 9 2 to 5 carbon atoms, an ethenyl group monosubstituted at the 2-position by an alkoxycarbonyl 8. 10 group or an ethyl group mono- or di-substituted at the 2-position by alkoxycarbonyl groups (wherein each alkoxycarbonyl group may contain from 2 to 4 carbon atoms in total); and represents a fluorine or bromine atom, a chlorine 9. 15 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? R^ represents an unbranched alkyleneimino group 20 substituted by one or two alkyl groups; an octahydroazocino, octahydro-lH-axonino or decahydro azecino group, or a dialkylamino group; and/or R^ represents an aryl group mono- or di-substituted by halogen atoms or by alkyl, hydroxy, alkoxy, 25 phenylalkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups; a naphthyl group; or a heteroaryl group containing 4,5,3 or 9 carbon atoms and 1 or 2 nitrogen atoms; and/or , W represents a hydroxymethyl, formyl, cyano, 30 aminocarbonyl, 2-carboxyethenyl, 2-cerboxyethyl or 2,2-bis-(carboxy)-ethyl group; an ethenyl 5 group substituted at the 2-position by an alkoxycar 117 bony! group or an ethyl group mono- or di-subutituted at the 2-position by alkoxycarbonyl groups; and/or represents a halogen atom), may also represent a hydrogen atom or a chlorine the 5-posltion. 27. Compounds as claimed in claim 1, wherein A represents a group of formula or — CH — C II — C — wherein represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group containing 1 to 3 carbon &toms 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, R 1 represents a piperidino group, R? represents a fluorine atom in the 4-position of the aromatic nucleus, 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 Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenyl alkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety; R^ 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; 118 represents a hydrogen, flourine, chlorine, bromine or iodine atom, an alkyl or alkoxy group wherein the alkyl component may contain 1 to 3 carbon atoms; or a hydroxy, nitro, amino or piperidino group; represents a hydrogen, fluorine, chlorine or bromine atom; and represents' a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms. 28. Compounds as claimed in claim 1 as herein specifically disclosed. 29. Compounds as claimed in claim 1 as herein speci15 fically disclosed in any of Examples 1 to 50. 30. Compounds as claimed in claim 26 as herein specifically disclosed in any of Examples 1 to 14. 31. Compounds as claimed in claim 27 as herein specifically disclosed as in any of Examples 21, 26, 20 37, 47 and 48. 32. Compounds as claimed in any preceding claim for use in a method of treatment of diabetes mellitus and disorders of the intermediate metabolism or the cardiac circulatory system. 25 33 . A process for the preparation of compounds as claimed in claim 1, which comprises reacting a compound of general formula IX (IX) 119 (wherein A, R 1 and R 2 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 magnesium halide complex thereof) with a compound of general formula III (wherein is defined as in claim 1 and W* has the meanings given for E in claim 1 or represents a carboxy group protected by a protecting group) or with a reactive derivative thereof optionally formed in the reaction mixture and, if necessary, subsequently cleaving any protecting group used. 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. 35. A process as claimed in claim 33 or claim 34 wherein the subsequent cleaving of the protecting group of E', if present 9 is effected by hydrolysis, thermolysis or hydrogenolysis. 36. A process as claimed in claim 35 wherein the hydrolytic cleaving is effected in the presence of an acid or of a base. 37. A process as claimed in any of claims 33 to 36 wherein the reaction is effected in the presence of a solvent. 38. A process as claimed in any one of claims 33 120 t) to 37 wherein the reaction is effected in the presence of an acid-activating or dehydrating agent. 39. A process as claimed in any one of claims 33 to 37 wherein the reaction is effected in the presence 5 of an amine-activating agent. 40. a process as claimed in any one of claims 33 to 39 wherein the reaction is effected in the presence of an inorganic or tertiary organic base. 41. A process as claimed in any one of claims 33 10 to 40 wherein water formed during the reaction is removed by azeotropic distillation or by the use of a drying agent. 42. a process as claimed in any one of claims 33 to 41 wherein the reaction is effected at tempertures 15 of from -25 and 250°C. 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 from -10°C to the boiling temperature of the solvent. 20 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 formula XV 25 (wherein R^ to R^ βη< ^ & are as defined in claim 1 and B represents a group which can be converted into a carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxyethenyl group by hydrolysis, thermolysis or hydrogenolysis) to hydrolysis, thermolysis or hydrogenolysis. 121 4 5. 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), 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. 46. a process as claimed in claim 45 wherein the functional derivative is an unsubstituted or substituted amide, nitrile, ester, thiolester, ofthoester, imino ether, amidine or anhydride or a malonic ester-(1)yl, tetrasolyl or optionally substituted 1,3-oxazol2-yl or l,3-oxa2olin-2-yl group, the ester with a tertiary alcohol is a tertiary butyl ester or the aralkyl ester is a benzyl ester. 47. A process as claimed in any one of claims 44 to 46, wherein the reaction is effected in the presence of a solvent. 4θ·, A process as claimed in any one of claims 44 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. 49. a process as claimed in any one of claims 44 to 47 wherein B in the compound of general formula IV represents a cyano or aminocarbonyl group and the reaction is effected using a nitrite in the presence of an acid. 50. A process as claimed in claim 49 wherein the nitrite is sodium nitrite and the acid used is sulphuric acid. 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. 52. A process as claimed in any one of claims 44 to 51 wherein the reaction is effected at temperature of from ambient temperature to the boiling temperature of the reaction mixture» 53. a process for the preparation of compounds as claimed in claim 1 wherein A represents a group of formula 122 R.' — CH — tl wherein has the meanings given for R^ in claims 1 with the exception of an alkenyl group and a cyano 5 group, which comprises reduction of a compound of general formula V wherein 10 R^ to R^ and K are defined as in claim 1 and D represents a group of formula or - C <9 H wherein R,/ has the meanings given hereinbefore for % 20 R., with the exception of a cyano group and R ’ and together with the carbon atoms between them represent an alkylidene group containing 1 to 7 carbon atoms or a phenyl&lkylidene group containing 1 to 3 carbon atoms In the alkylidene moiety. 123 54. A process as claimed in claim $3, wherein the reduction is carried out with hydrogen in the presence of a hydrogenation catalyst. 55. A process as claimed in claim 54 wherein a 5 hydrogen pressure of 1 fo 5 bar is used. 56. A process as claimed in any one of claims 5 3 t° 55 wherein the reduction is carried out in the presence of a solvent. 57. A process as claimed in any one of claims 53 to 56 wherein the reduction is curried out at temperatures of from 0 to 100°C. 58. A process as claimed in claim 57» wherein the reduction is carried out at temperatures of between 20 and 50°C. 59. A process for the preparation of compounds as claimed in claim 1 wherein A represents a group 15 of formula V I - CH — wherein R^ B has the meanings given hereinbefore for R^, with the exception of a cyano group; which comprises 20 reacting a compound of general formula VI (wherein R^ ra represents as defined in claim 1 with the exception of a cyano group and R^ and r 2 are 25 defined in claim 1) with a compound of general formula VII 124 (VII) wherein R^ and E are defined as in claim 1. 60. A process as claimed in claim 59, wherein the reaction is effected in the presence of a strong acid. 61. A process as claimed in claim 59 or claim 60, wherein the reaction is effected in the presence of concentrated sulphuric acid. 10 62. a process as claimed in any one of claims 59 to 61 wherein the reaction is effected at temperatures of between 0 and 150°C. ¢3 A process as claimed in claim 62 wherein the reaction is effected at temperatures of between 20 and 100°C. 10. 16 64. A process for the preparation of compounds as claimed in claim 1 wherein R o represents a hydrogen atom, which comprises dehalogenating a compound of general formula VIII A ™ NH - CO - CH W (VIII) 125 wherein R^, R^» A and W are as defined in claim 1 and Hal represents a fluorine, chlorine, bromine or iodine atom. 65. A process as claimed in claim wherein the dehalogenation is effected with hydrogen in the presence of a hydrogenation catalyst® 66. A process as claimed in claim 64 or claim 65 wherein the dehalogenation is effected in the presence of a solvent. 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 pressure of from 1 to 5 bar. 68. A process for the preparation of compounds as claimed in claim 1 wherein A represents a group of formula — CH — wherein represents an alkyleneiminocarbonyl group containing 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having the alkyl moiety, which comprises general formula IX 1 to 3 carbon atoms in reacting a compound of C00H 126 (wherein R^, R? and R^ are ae defined In claim 1 and W R represents W as defined in claim 1 with the exception of a carboxy group) with an amine of general formula x ’ 5 H - (X) t wherein 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 10 each containing 1 fo 3 carbon atoms in the alkyl moietyo 69. & process as claimed in claim 68, wherein the reaction is effected in the presence of an acid-activating or dehydrating agent. 15 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. 71* A process as claimed in any one of claims 68 to 70, wherein the reaction is effected in the presence 11. 20 of an amine-activating agent. 72. A process as claimed in any one of claims 68 to 71 wherein the reaction is effected in the presence of a solvent. 73. a process as claimed in any one of claims 68 12. 25. to 72, wherein the reaction is effected at temperatures of between -25°C and 25°C. 74. A process as claimed in any one of claims 68 to 73 wherein the reaction is effected in the presence of a solvent and at temperatures of between -10°C and 13. 30 the boiling temperature of the solvent usec *· c 75. A process for the preparation of compounds as claimed in claim 1 therein A represents a group of formula 127 — CH — wherein ft. is as defined in claim 1 and W represents a carboxy group, which comprises oxidising a compound of general formula XI wherein fo are defined as in claim 1 and E represents a group which can be converted info a carboxy group by oxidation. 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 unsubsfifuted acyl group or a malonic ester-(l)-yl group. 77. A process as claimed in claim 75 or claim 76 wherein the oxidising agent used is selected from: silver oxide/sodium hydroxide solution, manganese dioxide, hydrogen peroxide/sodium hydroxide solution, chromium trioxide/pyridine, pyridinium chlorochromate, bromine/βodium hydroxide solution, chlorine/sodium hydroxide solution, bromine/potasslum hydroxide solution and chlorine/potassium hydroxide solution. 78. a process as claimed in any one of claims to 77 wherein the oxidation Is effected in the presence of a solvent. 128 ) 79. a process as claimed in any one of claims 75 to78 wherein the oxidation is effected at temperatures of between 0 and 100°C. βθ A process as claimed in claim 79 wherein the 5 reaction is effected at temperatures of between 20 and 50°C. 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 5 carbon atoms wherein the alkyl component may be Substituted at any 10 carbon atom except the e-carbon atom one or two hydroxy tjroupy or by an alkoxy group containing 1 to 3 carbon atoms, which comprises esterifying a carboxylic acid of general formula XII A R COOH (XII) 15 (wherein R^ 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 Kill HO - R^ (XIII) 20 wherein represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atom except the ο-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms. 129 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. 83. A process as claimed in claim 81 or claim 82 wherein the esterification is effected in the presence of a solvent. 84. A process as claimed in claim 83 wherein the solvent is an excess of the alcohol of general formula XIII. 35 A process as claimed in any one of claims 81 to 84 wherein the esterification is effected in the Dresence of an acid-activating or dehydrating agent. 86. A process as claimed in any one of claims 81 to 85 wherein the esterification is effected in the presence of a reaction accelerator. > 67. a process as claimed in any one of claims 81 to 86 wherein the esterification is effected in the presence of an inorganic or tertiary organic base. 88. A process as claimed in any one of claims 81 to 87 wherein the esterification is effected at temperatures of between -20 and 100°C. 89. A process as claimed in any one of claims 81 to 88, wherein the esterification is effected in the presence of a solvent and at temperatures of between -10 u C and the boiling temperature of the solvent used. 90. a process for the preparation of compounds as claimed in claim 1 wherein W represents an alkoxycarbonyl , alfcoifycarbonylmethyl, 2-alkoxy-carbonylethyl or 2-alkoxycarbonylethenyl group and A represents a group of formula -CH — wherein Rg® represents Rg as hereinbefore defined with the exception of a cyano group, which comprises alcoholysing a compound of general formula XXV 130 II 1 wherein R^ ra represents R^ ©s defined in claim 1 with the exception of a cyano group, 5 R| to R 3 are defined as in claim 1 and W“· represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethenyl group. 91. A process as claimed in claim 90, wherein the alcoholysis is effected in the presence of 10 an acid. 92. A process as caimed in claim 91 wherein the acid is hydrochloric or sulphuric acid. 93. a process as claimed in any one of claims 90 to 92, wherein the alcoholysis is effected 15 In the presence of a solvent. 94. A process as claimed in claim 93 wherein the solvent is an excess of the alcohol used in the alcoholysis reaction. 95. A process as claimed in any one of claims 20 @0 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. 96. A process as claimed in any one of claims 90 to 95, wherein the reaction is effected at 25 ten^eratures of between 50 and 100°C. 97. A process as claimed in any one of claims 33 to 96, wherein a compound of general formula I % initially obtained, wherein ® represents a carboxy or alkoxycarbonyl group is subsequently converted 131 by reduction info a corresponding compound of general formula ΐ wherein U represents a formyl or hydroxymethyl group. 98. A process as claimed in any one of claims 5 33 to 97, wherein a compound of general formula I initially obtained, wherein & represents a carboxy groups is subsequently converted, by conversion into a sulphonic acid hydrazide and subsequent disproportionation, info a corresponding compound of general formual j 10 I wherein W represents a formyl group. 99. A process as claimed in any one of claims 33 to 98, wherein a compound of general formula I initially obtained, wherein w represents a formyl group, is subsequently converted, by condensation 15 and optional subsequent hydrolysis and/or decarboxylation, info a corresponding compound of general formula ϊ wherein W represents a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-efhenyl group. 100. A process as claimed in any one of claims 20 33 to 99, wherein a compound of general formula I initially obtained, wherein W represents a 2-carboxyethenyl or 2-alkoxycarbonyl-ethenyl group» is subsequently converted by catalytic hydrogenation into a corresponding compound of general formula X wherein W represents 25 a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group, 101. A process as claimed in any one of claims 33 to 100, wherein a compound of general formula X initially obtained, wherein & represents an alkoxy-carbonyl group substituted at any carbon atcan except the α-carbon atom 30 by a hydroxy group, is subsequently converted by acylation by means of a pyridine-carboxylic acid info a corresponding (pyridine-carbonyloxyalkoxy)carbonyl compound of general formula X, 102. A process as claimed in any one of claims 35 33 to 101, wherein a compound of general formula I initially obtained, wherein W represents a hydroxymethyl group is, after being converted info a corresponding halomethyl compound, subsequently converted 132 by reaction with a malonic acid diester into a corresponding compound of general formula X wherein W represents an ethyl group substituted by two alkoxycarbonyl groups. 5 103. A process as claimed in any one of claims 14. 33 to 102, wherein a compound of general formula X initially obtained, wherein W represents an ethyl group Substituted by two alkoxycarbonyl groups is subsequently converted by hydrolysis into a 10 corresponding compound of general formula X wherein w represents an ethyl group substituted by two carboxy groups. 104 A process as claimed in any one of claims 33 to 103» wherein a compound of general formula 15 I initially obtained, wherein W represents an ethyl group substituted by two alkoxycarbonyl groups is subsequently converted by hydrolysis and decarboxylation into a corresponding compound of general formula X wherein W represents a 2-carboxyethyl 20 group. 105. A process as claimed in any one of claims 33 to 104, wherein a compound of general formula I initially obtained, wherein represents a nitro group is subsequently converted by reduction into 25 a corresponding compound of general formula I wherein represents an amino group. 106. A process as claimed in any one of claims 33 to 105» wherein a compound of general formula 1 initially obtained, wherein represents an amino 30 group is subsequently converted, via a corresponding diasonium salt, into a corresponding corapound of general formula X wherein represents a hydrogen or halogen atom or a hydroxy, alkoxy or alkylsulphenyl group. 15. 35 107. A process as claimed in any one of claims 33 to 106, wherein a compound of general formula X initially obtained, wherein represents a hydroxy group is subsequently converted by alkylation into 133 a -corresponding compound of general formula I wherein represents an alkoxy group. 108. A process as claimed in any one of claims 33 to 107, wherein a compound of general formula 5 Γ initially obtained, wherein ft^ represents a benzyloxy group and/or R. represents an aryl group substituted •a by a benzyloxy group is subsequently converted 4 by debenzylation info a corresponding compound of general formula X wherein ft^ represents a hydroxy 10 group and/or represents an aryl group substituted * by a hydroxy group* 109. A process as claimed in any one of claims 33 to 108, wherein a compound of general formula I initially obtained, wherein represents an amino15 carbonyl group is subsequently converted by dehydration into a corresponding compound of general formula I wherein R^, represents a cyano group. 110. A process as claimed in any one of claims 33 to 109 wherein a compound of general formula 20 I initially obtained, is subsequently resolved, by chromatography on a chiral phase, into the enantiomers thereof, if it contains a chiral centre□ 111. A process as claimed in any one of claims 33 to 110, wherein a compound of general formula 25 I or a tautomer or optical enantiomer thereof, initially obtained, is subsequently converted fo a salt thereof, or a salt of a compound of general formula X or a tautomer or optical enantiomer thereof, initially obtained, is subsequently converted to 30 a compound of general formula X or a tautomer or optical enantiomer thereof. 112. A process as claimed in any one of claims 33 to 111 for the preparation of compounds as claimed In claim
26. 35 113. A process as claimed in any one of claims t 33 to 111 for the preparation of compounds as claimed in claim
27. 114. A process as claimed in any one of claims 33 to 113 > 1¾ substantially as herein described. 115. a process as claimed in any one of claims 33 to 124 substantially as herein described in any of Examples 1 to 50. 5 116. a process as claimed in claim Π2 substantially as herein described in any of Examples 1 to 14. 117. a process as claimed in claim 113 substantially as herein described in any of Examples 21, 26, 37, 47 and 48 118- Compounds of general formula ϊ as defined 10 in claim 1 and tautomers and optical enantiomers thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in any one of claims 35 to 111, 114 and 115. 119. Compounds of general formula I as defined 15 in claim 26 and tautomers and optical enantiomers thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in claim 112 or claim 116. 120. Compounds of general formula X as defined 20 in claim 27 and tautomers and optical enantiomers thereof, and salts of the afore-mentioned compounds, when prepared by a process as claimed in claim 113 or claim 117. 121. Pharmaceutical compositions comprising, an 25 active ingredient, at least one compound of general formula X 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. 30 122. Compositions as claimed in claim 121 containing at least one additional active ingredient 123. Compositions as claimed in claim 121 or claim 122 in a form suitable for oral or parenteral administration. 35 124. Compounds as claimed in any one of claims 121 to 123 in the form of tablets, coated tablets, capsules, powders or suspensions. <1 135 125. Compositions as claimed in any one of claims 121 to 124 in the form of dosage units. 126. Compositions as claimed in claim 121 wherein the active ingredient comprises a compound as claimed in claim 26 or claim 27. 5 127. Pharmaceutical compositions as claimed in claim 121 substantially as herein described. 1
28. Pharmaceutical compositions substantially as herein described in any one of Examples A to D.
IE1573/83A 1982-07-06 1983-07-05 N-substituted phenylacetamides IE56171B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
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

Publications (2)

Publication Number Publication Date
IE831573L IE831573L (en) 1984-01-06
IE56171B1 true IE56171B1 (en) 1991-05-08

Family

ID=25802849

Family Applications (1)

Application Number Title Priority Date Filing Date
IE1573/83A IE56171B1 (en) 1982-07-06 1983-07-05 N-substituted phenylacetamides

Country Status (21)

Country Link
EP (1) EP0099017B1 (en)
KR (1) KR900004925B1 (en)
AU (1) AU561274B2 (en)
CA (1) CA1214773A (en)
CS (1) CS240970B2 (en)
DD (1) DD210907A5 (en)
DE (1) DE3375783D1 (en)
DK (1) DK159850C (en)
ES (4) ES523869A0 (en)
FI (1) FI78477C (en)
GB (1) GB2124220B (en)
GR (1) GR78661B (en)
HU (1) HU195651B (en)
IE (1) IE56171B1 (en)
IL (1) IL69172A (en)
NO (1) NO159590C (en)
NZ (1) NZ204814A (en)
PL (1) PL143992B1 (en)
PT (1) PT76986B (en)
SU (1) SU1170969A3 (en)
YU (1) YU146883A (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5312924A (en) * 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
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
US7582766B2 (en) 2003-06-09 2009-09-01 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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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"

Also Published As

Publication number Publication date
DK310883A (en) 1984-01-07
IE831573L (en) 1984-01-06
EP0099017B1 (en) 1988-03-02
DD210907A5 (en) 1984-06-27
IL69172A0 (en) 1983-11-30
ES8500923A1 (en) 1984-11-01
KR840005438A (en) 1984-11-12
DE3375783D1 (en) 1988-04-07
ES8500742A1 (en) 1984-11-01
NO832430L (en) 1984-01-09
FI832374A0 (en) 1983-06-29
EP0099017A2 (en) 1984-01-25
GB8318250D0 (en) 1983-08-10
PT76986B (en) 1986-04-11
GR78661B (en) 1984-09-27
AU1657683A (en) 1984-01-12
DK310883D0 (en) 1983-07-05
EP0099017A3 (en) 1984-02-22
NZ204814A (en) 1986-10-08
CS240970B2 (en) 1986-03-13
FI832374L (en) 1984-01-07
PT76986A (en) 1983-08-01
SU1170969A3 (en) 1985-07-30
HU195651B (en) 1988-06-28
ES529806A0 (en) 1984-11-01
GB2124220A (en) 1984-02-15
PL242873A1 (en) 1984-09-10
CA1214773A (en) 1986-12-02
ES529807A0 (en) 1984-11-01
ES529808A0 (en) 1984-11-01
FI78477B (en) 1989-04-28
FI78477C (en) 1989-08-10
YU146883A (en) 1986-04-30
DK159850C (en) 1991-05-06
KR900004925B1 (en) 1990-07-12
NO159590B (en) 1988-10-10
GB2124220B (en) 1985-11-13
ES8500924A1 (en) 1984-11-01
NO159590C (en) 1989-01-18
ES8501382A1 (en) 1984-11-16
ES523869A0 (en) 1984-11-16
AU561274B2 (en) 1987-05-07
DK159850B (en) 1990-12-17
PL143992B1 (en) 1988-04-30
IL69172A (en) 1987-10-20

Similar Documents

Publication Publication Date Title
DK167439B1 (en) PHENYL ACETIC ACID DERIVATIVES OR SALTS THEREOF, PHARMACEUTICALS CONTAINING THESE COMPOUNDS, APPLICATION OF THE COMPOUNDS FOR THE PREPARATION OF A MEDICINE, PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PRODUCT AND THE PRODUCT
US5681954A (en) Piperazine derivatives
US4954502A (en) 1-indolyalkyl-4-(substituted-pyridinyl)piperazines
KR100228608B1 (en) Piperazine derivatives
US5409931A (en) 1,3-substituted cycloalkenes and cycloalkanes as central nervous system agents
KR19990077127A (en) Substituted Aza- and Diazacycloheptane and Cyclooctane Compounds and Uses thereof
US4735959A (en) Carboxylic acid amides and pharmaceutical compositions containing them
Dallanoce et al. Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M
US5594144A (en) Tropolone derivatives and pharmaceutical composition thereof for preventing and treating ischemic diseases
US4792562A (en) N-(pyrrol-1-yl)pyridinamines having memory enhancing activity
HU186024B (en) Process for preparing new carboxylic acid amides
IE56171B1 (en) N-substituted phenylacetamides
CA2320971A1 (en) Cyclic amide compounds
HU187561B (en) Process for preparing new carboxylic acid derivatives
US4442102A (en) 1,5-Diphenylpyrazolin-3-one compounds, process and intermediates for preparation thereof and pharmaceutical compositions containing same
US5051424A (en) Substituted aromatic compounds having an action on the central nervous system
US4282223A (en) Isoquinoline derivatives, processes for their manufacture and their use for the manufacture of medicaments
KR20040075905A (en) Heteroaryl-substituted aminocyclohexane derivatives
US5364860A (en) Naphthyridine compounds which inhibit tyrosine kinase and their pharmaceutical compositions
US5089497A (en) Substituted piperazines as central nervous system agents
US5032599A (en) N-(pyrrol-l-yl)pyridinamines
US5166157A (en) Naphthyl piperazines useful as 5-HT1A receptor ligands
US4480100A (en) [2-[(Nitropyridinyl)amino]phenyl]arymethanones
JPS5921657A (en) Novel phenylacetic acid derivative
US5162321A (en) 1-naphthyl piperazines useful as 5-HT1A receptor ligands

Legal Events

Date Code Title Description
MM4A Patent lapsed