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IE831573L - N-substituted phenylacetamides - Google Patents

N-substituted phenylacetamides

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Publication number
IE831573L
IE831573L IE831573A IE157383A IE831573L IE 831573 L IE831573 L IE 831573L IE 831573 A IE831573 A IE 831573A IE 157383 A IE157383 A IE 157383A IE 831573 L IE831573 L IE 831573L
Authority
IE
Ireland
Prior art keywords
group
carbon atoms
general formula
alkyl
phenyl
Prior art date
Application number
IE831573A
Other versions
IE56171B1 (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 DE19823225155 external-priority patent/DE3225155A1/en
Priority claimed from DE19823225188 external-priority patent/DE3225188A1/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

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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

Abstract

Compounds of general formula I <IMAGE> (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. [EP0099017A2]

Description

II I V I Chemical Compounds The present invention relates to new phenylacetic acid derivatives, to processes for their preparation, and to their effects on intermediate metabolism and the cardiac circulatory system. 5 According to one feature of the present invention, we provide compounds of general formula I f wherein h represents a group of formula 10 I4 - CH Rc 5n / 6 C - C [wherein represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group 15 containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkvl group containinci 4 to 7 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alStylenelminocarbonyl group containing 4 to 6 carbon atoms in the alkylene moiety; 20 an eninoc&rbonyl group optionally mono- or disubstituted by elkyl 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 25 mono- or disubstituted by halogen atoms, or by alkyl. hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl and/or alkylsulphonyl groups, the substituents in the case of disubstitution being the same or different and each alkyl moiety containing 1 to 3 carbon 5 atoms; or a heteroaryl group containing 4, 5, 8 or 9 carbon atoms and 1 or 2 nitrogen atoms; or Rs represents a methyl group when, simultaneously, Rj represents a piperidino group, R2 represents a fluorine atom in the 4-position of the aromatic nucleus, R3 represents a hydrogen atom and lo w represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); or represents a phenyl group when Rt 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 15 methyl group in the 4- or 6-position, of the aromatic nucleus, or when M represents a formyl, carboxyvinylene or alkoxycarbonylvinylene group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); or Rs and R6 together with the carbon atom between them represent a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene 20 moiety], Rj 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 S carbon atoms in 2b each alkyl component, R2 represesnts a hydrogen, fluorine, chlorine, bromine or iodine atom, or a hydroxy, trlfluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group wherein the 30 alkyl component may contain 1 to 3 carbon atoms in each case, R3 represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom; and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms (wherein the alkyl component may optionally 35 be substituted by a phenyl group and optionally, at any carbon atom except the a-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkvleneimino or pvrldinecarbonyloxy 3 group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonyl group containing a total of 4 to 6 carbon atoms, 5 an alkyl group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxy- methyl, 2-carbosyethyl, 2-carboxyethenyl, 2,2-bis- * (carbony)-ethyl, alkoxycarbonyl-inethyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonyl-ethenyl or 2,2-bis-falkoxy-10 carbonyl)-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" 15 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 20 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 25 salts, but other salts may find use, for example in the preparation of the compounds of general formula I and their physiologically compatible salts.
The term "tautomer" as used herein refers particularly to the tautomeric ketimine form of the compounds 30 of general formula I wherein h 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 „ 35 groups to R- and w include the following, for example; 4 ® may represent a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-n-pentylamino, diisobutylamino, H-methyl-ethylamino, W-methyl-n-propylamino, W-methyl-isopropylamino, W-isopropyl-5 n-propylamino, W-isobutyl-n-propylamino, BJ-methyl- n-butylamino, M-ethyl-n-butylamino, H-ethyl-isopropyl-smino, S9-ethyl-n-pentylamino, K-propyl-n-butylamino, pyrrolidino, piperidino, hexamethyleneimino, hepfca-methyleneimino, ocfcamethyleneimino, nonamethyleneiiaino, 10 methyl-pyrrolidino, dimethyl-pyrrolidino, ethyl-pyrrol-idino, methyl-piper idino, ethyl-piperidino, dimethyl-piperidino, diethyl-piperidino, methyl-ethylpiperidino, n-propyl-piperidino, methyl-n-propylpiperidino, isopropyl-piperidino, or di-n-propyl-piperidino group, Rj may represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, nitro, amino, piperidino, methylmercapto, ethylmercapto, n-propylmercapto, isopropyIntercapto, methylsulphinyl, ethylsulphinyl, methylsulphonyl, n-propylsulphonyl, benssyloiiy, 1-phenyl-ethoxy, 2-phenyl-ethoxy, 3-phenyl-propoxy, acetoxy, propionyloxy, formylamino, acetylamino, propionylamino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino, di-n-propylamino or methyl-ethylamino group, Rj may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl or isopropyl group, may represent & methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-heiiyl, methoxymethyl, ethoiiymethyl, n-propoitymethyl, isopropoxyEaethyl, 2-methOftyethyl, 2-ethojty-ethyl, 3-raethony-propyl, bsnsyl, 1-phenylethyl, 2-phenylethyl, l-phanyl-n-propyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl, 3-buten-l-yl, 2-buten-l-yl, ^-penten-l-yl, cyano. 20 30 35 5 sminocarbonyl, methylamlnocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylsminocarbonyl, diethylamino-carbonyl, di-n-propylaminocarbonyl, bensylaminocarbonyl, 2-phenyl-ethylaminocarbonyl, pyrrolidinocarbonyl, 5 piperidinocarbonyl, hesamethyleneiminocarbony1, phenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxy-phenyl, 2-phenyl-ethoxy-phenyl, 3-phenylpropoxy-phenyl, 10 methylsulphenyl-phenyl, ethylsulphenyl-phenyl, methyl-sulphinyl-phenyl, n-propylsulphinyl-phenyl, methyl-sulphonyl-phenyl, ethylsulphonyl-phenyl, isopropyl-sulphonyl-phenyl, methyl-naphthyl, hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl, chloro-bromo-phenyl, 15 dimethyl-phenyl, di-isopropyl-phenyl, chloro-methyl-phenyl, dimethoxy-phenyl, methyl-methoxypheny1, chloro-methoxy-phenyl, bromo-methoxy-phenyl, pyridyl, pyrimidyl, guinolyl, isoguinolyl or quinazolyl group, R,. and Rg may represent a hydrogen atom or 20 a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl or n-pentyl group, R5 and Rg together with the carbon atoms between them may represent a bensylidene, 1-phenyl-ethylidene, 2-phenyl-ethylidene, 1-phenyl-n-propylidene, 1-phenyl-25 2,2-propylidene or 3-phenyl-n-propylidene group and W may represent a hydroxy methyl, foi-myl, carboxy, carbosymethyl, 2-carboxy-ethyl, 2-carboiiy-etheny 1, 2,2-bis-(carboxy)-ethyl, methoxycarbonylp efchoxycarbonyl, n-peopoitycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 30 isobufcoity carbonyl, n-pentyloxycarbonyl, allylonycarbonyl, crotyloxycarbonyl, (2-hydroxyethoxy)carbonyl, (2-hydroxy-n-propoxy)carbonyl, (l-hydroxy-2-propoxy)carbonyl, (2-methoxyethoxy)carbonyl, (2-ethosysthoxy)carbonyl, (2-n-propoityethoity)carbonyl, (2-nicotinoyloxy-ethoity)-35 carbonyl^ (2-isonicotinoyloxy-ethoxy)carbonyl, (2,3- 6 dihydroxy-n-propoxy) carbonyl, (2-dimethylamino-ethoxy) -carbonyl, (2-diethylamino-ethoxy)carbonyl, (2-piperidino-ethoxy)carbonyl, methyl, ethyl, n-propyl, isopropyl, cyano, awinocarbony1, raefchoicycarbonyl-raefchyX, ethoxy-5 carbony1-raethyl, n-ptoponycarbonyl-raefchy1, 2-aiethony-carbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxy-carbonyl-ethyl, 2-methoaycarbonyl-ethenyl, 2-ethoxy-carbonyl-ethenyl, 2-si-propoxycarbonyl-ethenyl, 2,2-bis-(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 h represents a group of formula Rs 5^ ^ 6 15 R. C I II - CH - or - C - wherein R„ represents an alkyl group containing 1 to 3 carbon atoms substituted by an alkoxy group 20 containing 1 to 3 carbon atoms or by a phenyl group; an n-propyl group; an alkyl group containing 4 to S carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or amlnocarbonyl group; an aryl group containing 6 or 10 carbon atoms tnono-25 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 way contain from 1 to 3 carbon atoms; or a naphthyl, pyridyl, quinolyl or 30 isoquinolyl group; a5 and Kg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 7 ] 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 5 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 &toms, or (if R5 and Kg are as hereinbefore defined or R4 represents 10 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 c nitrile or amino-15 carbonyl group) R^ may also represent an iodine atom or a hydroxy or amino group; Rj represents a hydrogen or chlorine atom; and W represents a methyl, hydrosrymethyl, formyl, 20 cyano, carboxy, carboxymethyl, 2-carboity-ethyl or 2-carboxy-ethenyl group; an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl ojwt->onent nay be substituted at any carbon Particularly preferred are those compounds of general formula I wherein A represents a group of formula wherein represents en alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group; an n-propyl, cyano or arninocarbonyl group; en 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 methylsulphenyl group; or a pyridyl group; Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 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 disubstituted by methyl groups, R2 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group; or (if R^ and Rg are as hereinbefore defined or represents an alkyl group containing 1 to 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, nitrile or sminocarbonyl group, an alkyl group containing 4 to 6 carbon atoms or en alkenyl group containing 3 to 5 carbon atoms) may also represent an iodine atom or a hydroxy or amino group, 10 represents a hydrogen or chlorine atom; and W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxy-wethy1, 2-carboxy-ethyl or 5 2-carboxy-ethenyl group, an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms wherein tJio ;ilky] '-.mniC'ilL mi,' !«■ iUit.,1 .,t ;my tv.i l> n ill r.<>:o , ■( i.|„. ..-.miUh, atom by one or two hydroxy groups, by an alkoxy gioup containing 1 to 3 carbon atom;; or by a py r it) i nei-ar bony I -10 oxy group; or an alkoxycarbonyl-methyl, 2-aIkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein each alkoxy group may contain from 1 to 3 carbon atoms; and 4-(N-(6-chloro-o-pheny1-2-piperidi no-benzyl)-amino-15 c.;r bony 1 -met hyl ]-benzo i c acid end Cj_^ alkyl erters twrecif, 4-[N-(a-pheny1-2-piper idino-benzyl)-aminocarbonylmethyl] -cinnamic acid and alkyl esters thereof, 4-[N-(4-chloro-a-pheny1-2-piperidino-benzy1)-amino-carbonyl-methyl]-benzoic acid and C1_j alkyl esters thereof, 4-(M-(3-chloi o-a-pheny1-2-piper idino-benzyl)-amino-carbonyl-methyl] -benzoic acid and alkyl esters thereof, 4- [N- (6- lufct hyl - a-pheny 1-2-piper idino-benzyl) -amino-coi boiiylViiyj'i • 1 «.>»;.-• i c c. c.: ctic: C'j_. £ ) ky1 « .• t »• i t tier (rOf , 11 £-[&-( However, another group of preferred compounds 15 are those wherein A, Rj to Rj and W are as hereinbefore defined, more particularly those therein W represents a essbony group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl component nay jjo substituted at any carbon stem except the a-carbon atom 20 by one or two hydroxy groups, and optically active enantiomers and the salts thereof.
Particularly preferred compounds of general formula X above are those wherein ft represents a group of formula 12 RS^ .R6 4 I - CH or C II C - 5 wherein represents an n-propyl group, £in alkyl group containing 4 or 5 carbon atoms, a phenyl group substituted by a wethyl group or by a fluorine or chlorine atom, or a pyridyl group, Rg and Rg together with the carbon atom between 10 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; represents a piperidino group optionally substituted by one or two methyl groups; 15 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group; Rj represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms; 20 particularly those wherein A represents a group of formula 25 - CH - or - C - wherein represents en 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 30 or a pbenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part, and optically active enantiomers and salts thereof.
The compounds of general formula I as hereinbefore defined and their optical enantioraers end salts thereof 35 may, for example, be prepared by the following processes, Mhich processes constitute further features of the present invention: 13 a) Reacting a compound of general formula II NH- (II) (therein A, Rj and Rj are as hereinbefore defined or, if A represents one of the vinylidene groups 5 mentioned hereinbefore, the tautomers thereof or a lithium or magnesium halide complex thereof) &ith a compound of general formula III (therein is as hereinbefore defined and 10 W has the meanings given for W hereinbefore or represents a carbony 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. 15 The reactive derivatives of a compound of general formula III may be, for esample, the esters thereof, such as the methyl, ethyl or benzyl asters, the thio-esters thereof such as the raethylthio- or ethylthio-esters, the hslides thereof such as the acid chloride, 20 or the anhydrides or imidazolides thereof.
The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, diox&n, benzene, toluene, acetonitrlle or dimethylformamide, 5 optionally in the presence of an agent which activates the acid or a dehydrating agent, e.g. in the presence of ethyl chloroformsfee, thionyl chloride, phosphorus trichloride, phosphorus psntoxide, ^,H'-dicyclohesyl-c&rbodiimide, S^M'-dicyclohesylcarbodiimide/H-hydroxy- * 10 succinimlde, M,^'-carbonyldiimidasole or BJjW-thionyldi- iialdasole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic bese such as sodium carbonate or 15 a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of between -25°C and 250°C, bus preferably at temperatures of between -10°C and the boiling temperature of the solvent used. The reaction may 20 also be carried out without a solvent and furthermore any water formed during the reaction may be removed by aseotropic 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 25 molecular sieve.
If necessary, the subsequent cleaving of a protecting group is preferably effected by hydrolysis, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic 30 acid or in the presence of & base such as sodium hyUronide or potasoiua hydros .We in a suitable solvent such as water, methanol, ethanol, ethenol/water, water/isopropanol or watsr/cllosan at temperatures of between -10°C and 120°C, e.g. at temperatures • 35 of between ambient temperature and she boiling temper ature of iha reaction mixture.
A tart.butyl group used the protecting group o may also be cleaved thermally, possibly in an inert 15 solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or diox&n and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic, sulphuric, phosphoric 5 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, 10 ethanol, ethanol/water, glacial acetic acid, ethyl acetate, diouan or dimethylfonaiamide. b) In order to prepare a compound of general formula I therein W represents a carbony, carboxymethyl, 2-carbonyethyl or 2-carbonyethenyl group: 15 subjecting a compound of general formula IV A-NH - CO - CH (TV) (wherein to and h are as hereinbefore defined, and 20 B represents a group which can be converted by hydrolysis, thermolysis or hydrogenolysis into a carboxy, cor bonyme t hy1, 2-carboxyethyl or 2-carbouy-ethenyl group) to hydrolysis, thermolysis or hydrogenolysis. 25 The hydrolysable groups in the compounds of general formula XV may be, for example, functional derivatives of carboxy, carbosymethyl, 2-carboxyethyl « 16 or Z-carboxyethenyl groups such as the unsubstituted or substituted amides thereof, the nitriles, esters, thiolesiers, orthoesters, iminoethers, amidines or anhydrides thereof, a maIonic ester-(l)-yl group, 5 the tetrazolyl group, an optionally substituted 1,3-oxazol-2-yl or l,3-o>tazolin-2-yl group, and the thermolytically cleavable groups may be, for example, esters with tertiary alcohols, e.g. the tert.butyl ester, 10 the hydrogenolytically cleavable groups may be, for example, esters with aralkanols, e.g. the bensyl ester.
The hydrolysis is conveniently effected either in the presence of an acid such as hydrochloric, 15 sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroside or potassium hydroxide in & suitable solvent such as water, water/methanol, ethanol; water/ethanol, watesr/isopropanol or v&ter/dioxan at temperatures 20 of between -10°C and 120°C, e.g. at temperatures of between ambient temperature and the boiling temperature OS the reaction mixture.
If 3 in a compound of general formula IV represents a cyano or aminocarbonyl group, these groups may 25 also be converted into a carboxy group using a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which is conveniently also used as the solvent, at temperatures of between 0 and 50°C. 30 If B in a compound of general formula IV represents the tert.butyloaycarbonyl group, for example, the tert.butyl group may also be cleaved thersially, optionally in an inert solvent such as methylene chloride, chloroform, besisena, toluene, tetrahydrofur&n or 35 fiioitan and preferably in the presence o£ a catalytic quantity of an acid such as p-tolusnesulphonic, sulphuric, phosphoric or polyphospho?ic acidf preferably at the boiling temperature of the solvent used, e.g. at temperatures of between <30°C and 100°C. 17 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/ 5 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 10 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 15 to the corresponding phenylpropionic acid group), or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom. c) In order to prepare compounds of general formula I wherein % represents a group of formula therein has the meanings given hereinbefore for R^, with the exception of an alkenyl group and a 25 cyano group: Reduction of a compound of general formula V 20 - CH R (V) 1 3 18 wherein and Rj to R^ 6nd w are as hereinbefore defined D represents a group of formula < R5^ 1 5 - c - C or N M - 10 | H wherein a." has the meanings given hereinbefore for S^, with the exception of a cyano group and R^' and R.' together with the carbon atom between them represent 15 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 20 as palladium/charcoal or Haney nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethanol/ water, glacial acetic acid, ethyl acetate, dioxan, tetrahydrofuran, dimethylformamide, benzene or benzene/ ethanol at temperatures of between 0 and 100°C, but 25 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 p, (i ■-d ichloro-bis[1,5-cyclooctediene-rhodium] and 30 (4-)= os (-) 0,0=isopropylAdene-2,3-dihydrO]sy-l,4- bis(diphenylphosphino)-butane (<= 0X0?), the addition of hydrogen occurs enantioselectively. Moreover, during catalytic hydrogenation, other groups may be reduced at the same time, e.g. a nitro group may 35 be reduced to the amino group, a bsnzyloxy group to the hydroxy group or a cinnainic acid group to 19 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 h represents a group of formula V I - CH - wherein R^B has the meanings given hereinbefore for 84, with the exception of a cyano group: 10 Reacting a compound of general formula VI (wherein aj11 is defined as above and R. and a_ are as The reaction is carried out in the presence of & strong acid which may simultaneously serve as solvent, preferably in concentrated sulphuric acid, 5 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 a2 represents a hydrogen atom: dehalogenating & compound of general formula VIII wherein R^, R3, A and W are as hereinbefore defined and Hal represents a fluorine, chlorine, bromine 15 or iodine atom.
The dehalogenation is conveniently effected in a solvent such as methanol, ethanol, ethyl acetate, gl&tcial acetic acid or dimethylform&iaide by means of c&talytic&lly activated hydrogen, ^ Q ^ lit W ith hydrogen 20 in the presence of platinum or palladium/charcoal, at temperatures of between 0 end 100°C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 5 bar. During the dehalogen&tion, other groups taay be seduced at the same time, e.g. a benzyloxy 25 group may be reduced to a hydroxy group, a vinylidene group to the corrsaporciing alkylidene group or a cinnaiaic acid group to the corresponding phenylpropionic 21 acid group, or may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom. i £) Xn order to prepare compounds of general formula 5 I, wherein h represents a group of formula R4 I — CH — wherein Rg represents an alkyleneiminocarbony1 group 10 containing 4 to S carbon atoms in the alkylene ring or an sminocarbonyl group optionally mono- or disub-stituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety: Reacting a compound of general formula (wherein R^, and R3 BSe ®s hereinbefore defined and W has the meanings given hereinbefore for W, with the exception of the carboxy group), with 20 an amine of general formula X R? (X) wherein Ry represents en alkyleneimino group containing 22 4 4 to 6 carbon atoms or an amino group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety. ^nidation 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 10 chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, M,H'-dicyclohexylcarbodiimide, H,W-d icyclohexy Icar bod i imide/W-hydroxysuccin imide, WjM'-carbonyldiimidazole, M,M'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an 15 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 triethylaiaine or pyridine which may simultaneously serve as solvent, at temperatures 20 of between -25°C and 250°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used. g) Xn order to prepare compounds of general formula I wherein h represents a group of formula 25 R.
I - CH — as hereinbefore defined and W represents a carbony group: Oxidising a compound of general formula XI 23 wherein R, to R. are as hereinbefore defined and 1 4 5 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 sub-10 stituted or unsubstituted acyl group such as an acetyl, chloroacetyl, propionyl or malonic acid-(l)-yl group or a malonic ester-(l)-yl group.
The reaction may be carried out with an oxidising agent in a suitable solvent such as water, glacial 15 acetic acid, methylene chloride, dioxan or glycol dimethyl ether at temperatures of between 0 and 100°C, but conveniently at temperatures of between 20°C and 50°C. However, the reaction is preferably effected with silver oxide/sodium hydroxide solution, manganese 20 dioxide/acetone or methylene chloride, hydrogen peroxide/ sodium hydroxide solution, bromine or chlorine/sodium or potassium hydroxide solution, chromium trioicide/-pyridine or pyridinium chlorochromate. h) In order to prepare compounds of general formula 25 I wherein W represents an alkoxycarbonyl group containing a total of 2 to 6 carbon atoms wherein the alkyl oonvoncnt iiiiy be substituted at any carbon atcm except the c-cdrbon atom by one or two hydroxy groups or containing 1 to 3 carbon atoms: by a n alkoxy •iron |> Esterifying a carboxylic acid of general formula XII 5 (wherein R^ to R3 and h are as hereinbefore defined) or a reactive derivative thereof optionally prepared in the reaction mixture, with an alcohol of general formula XIII 10 HO - Rg (XIII) wherein Rg represents an alkyl group containing 1 to 5 carbon atcans which may be substituted at any carbon atom except the clear bon atom by one or two hydroxy groups or oy an 15 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. 20 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 o£ an acid-activating agent or a 25 dehydrating agent, e.g. in the presence of hydrogen 25 10 15 chloride, sulphuric acid, ethyl chloroformste, thionyl chloride, carbon tetrachloride/triphenylphosphine, carbonyIdiimidazole or M,M'-dicyclohej:ylc6rbodiiinide or the isourea ethers thereof, optionally in the presence of a reaction accelerator such as copper chloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, or by trans-ester ification, e.g. 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 to prepare a compound of general formula I wherein W represents an alkoxycarbonyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group and A represents a group of formula where R." represents R„ as hereinbefore defined with the exception of a cyano group: Alcoholysis of a compound of general formula XIV CH- R, '2 (XIV) 26 wherein R^a represents as hereinbefore defined with the exception of a eyeno group and to are as hereinbefore defined and 5 B"1 represents a cyano, cyanomethyl, 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 ?0°C and the boiling temperature of the solvent used, preferably at temperatures of 50 and 100°C.
If, according to the invention, a compound 15 of general formula I is initially obtained wherein 13 represents & carboxy or alkoxycarbonyl group, this may subsequently be converted by reduction into a corresponding compound of general formula I therein W represents a formyl or hydroayiaethyl group, and/or 20 if a compound of general formula X is initially obtained wherein T4 represents a carbony group, this may subsequently be converted by conversion into a sulphonic acid hydraside and subsequent disproportionation into a corresponding compound of general formula 25 I wherein W represents a formyl group, and/or if & compound of general formula I is initially obtained wherein H represents a formyl group, this may subsequently be converted by condensation and optional subsequent hydrolysis and/or decarboxylation into a corresponding 30 compound of general formula £ wherein W represents a 2-islkoiiycarbonyl-ethenyl or a 2-carboisy-ethenyl group, and/or if a compound of general formula 1 is initially obtained therein M represents a 2-carbosy-ethenyl or 2-alkoity-35 carbony1-ethenyl group, this saay subsequently be 27 converted by catalytic hydrogenation into a corresponding compound of general formula I wherein W represents a 2-carboityethyl or 2-alko»ycarbonyl-ethyl group, and/or 5 if a compound of general formula I is initially obtained wherein W represents an alkoxycarbonyl group substituted j l any carbon atom except, the u-cat bun aluii by a hydroxy qroup, this may subsequently be converted by acylation by means of a pyridine-carboxylic acid into a corresponding (pyridine- 10 carbonyloxyalkoxy)-carbonyl compound of general formula I, and/or if a compound of general formula I is initially obtained wherein W represents a hydroxymethyl group, this may, after being converted into & corresponding halo-15 methyl compound, subsequently be converted by reaction with a malonic acid diester into a corresponding compound of general formula I wherein W represents an ethyl group substituted by two alkoxycarbonyl groups, and/or 20 if a compound of general formula I is initially obtained wherein W represents an ethyl group substituted by two alkoxycarbonyl groups, this may subsequently be converted by hydrolysis into a corresponding compound of general formula I wherein V] represents an ethyl 25 group substituted by two carboxy groups, and/or if a compound of general formula I is initially obtained wherein W represents an ethyl group substituted by two alkoxycarbonyl groups, this may■subsequently be converted by hydrolysis and decarboxylation into 30 a corresponding compound of general formula I wherein W represents a 2-carboayethyl group, and/or if a compound of general formula 1 is initially obtained therein R, represents a nitro group, this may subse- 28 quently be converted by reduction into e corresponding compound of general formula I wherein represents an amino group, and/or if & compound of general formula I is initially obtained 5 wherein Rj represents an amino group, this may subsequently be converted, via a corresponding di&zonium salt, into a corresponding compound of general formula I wherein Rj represents a hydrogen or halogen atom or a hydroxy, alkoxy or alkylsulphenyl group, and/or 10 if a compound of general formula I is initially obtained wherein R2 represents a hydroxy group, this may subsequently be converted by alkylation into a corresponding compound of general formula I wherein R, represents an alkoxy group, and/or 15 if a compound of general formula I 1b initially obtained wherein Rj represents a benzyloxy group and/or R;, represents an aryl group substituted by a benzyloxy group, this may subsequently be converted by debensyl-ation into a corresponding compound of general formula 20 I wherein R2 represents a hydrosy group and/or represents an aryl group substituted by a hydroxy group, and/or if compound of general formula I is initially obtained wherein represents an sminocarbonyl group, this 25 may subsequently be converted by dehydration into 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 30 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 5 at temperatures of between 0 and 100°C, but preferably at temperatures of between 20°C and 60°C.
The subsequent disproportionation of a sulphonic acid hydrazide, which is obtained by reacting a corresponding hydrazine with a corresponding reactive carboxylic 10 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 ISO to 170°C.
The subsequent condensation of a formyl compound 15 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 alicoitycarbonylmethylene-triphenyl-phosphoran, optionally in the presence of a base 20 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 subse-25 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 30 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 saethylane chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dionaii, bensene, toluene, acetonitrile or dimethyl- forsnes&iide, preferably with a reactive derivative » 30 of the acid, for example a halide such as the acid chloride, en anhydride or imidazolide and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethyl-5 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. 10 The subsequent conversion of a hydrosymethyl group into a halomethyl group is effected with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, 15 carbon tetrachloride, benzene or nitrobenzene and subsequently reacting with a malonic acid ester, e.g. with an alkali metal salt of diethyl taalonate, at temperatures of between 0 and 100°C, but preferably at temperatures of between 50°C and 80°C„ 20 The subsequent hydrolysis or hydrolysis and decarboxylation is conveniently effected in the presence of an acid such as hydrochloric, sulphuric, phosphoric, polyphosphoric or trifluoroacetic acid in a suitable solvent such as water, ethanol, water/ethanol, water/iso-25 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/ethsnol, methanol, glacial acetic acid, ethyl 30 acetate or diraethylforiitanilde, conveniently with hydrogen in the presence of a hydrogenation catalyst such as iSaney nickel, platinum or palladium/charcoal, with metals such as iron, tin or sine in the presence of an acid, with salts such as iron(II)sulphate, 35 tin(XS)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. 31 The subsequent reaction of a diazonium salt, e.g. the fluoroborate, the fluoride in 40% hydrofluoric acid, the hydrosulphate in sulphuric acid or the hydrochloride, if necessary in the presence of copper 5 or a corresponding copper(I)salt such as copper(I) chloride/hydrochloric acid or copper(I)bromide/hydro-broraic acid, is carried out at slightly elevated temperatures, e.g. at temperatures of between 15°C and 100°C," the subsequent reaction with hypophosphorous 10 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 15 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 20 effected with a corresponding halide, sulphonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl-sulphate, ethyl bromide, ethyl p-toluenesulphonate, isopropylmethanesulphonate or diazomethane, optionally in the presence of a base such as sodium hydride, 25 potassium hydroxide or potassium tert.butoxide and preferably in a solvent such as diethyl ether, tetrahydrofuran, dioxan, methanol, ethanol, pyridine or dimethyl-forsnamide at temperatures of between 0 and 75°C, preferably at ambient temperature. 30 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/char-35 coal, at temperatures of between 0 and 75°C, but preferably at ambient temperature and at a hydrogen pressure of from 1 to 5 bar. 32 The subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, sulphuric acid or p-toluenesulphonic acid chloride, optionally in a solvent such as methylene chloride 5 or pyridine at temperatures o£ between 0 and 100°C, preferably at temperatures of between 20° and S0°C.
If they have a chiral centre, the compounds of general formula I obtained can also be resolved into their enantiomers by conventional methods. 10 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 into an addition salt thereof, for example 15 by conventional methods such as reacting- the compound of general formula I or tautomer thereof as a base with an acid in a suitable solvent, or reacting the compound of general formula I or tautomer thereof as an acid with a base in a suitable solvent. A 20 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. 25 The compounds of general formulae II to XIV used as starting materials may be obtained by methods fcnown from the literature or are themselves known from the literature.
Thus, for example, a compound of general formula 30 II wherein h represents a group of formula 35 or the tautomeric ketiniine thereof is obtained by reacting a corresponding nitrile with a corresponding 33 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 5 the reactive derivatives thereof, more particularly the acid chlorides thereof, it is also possible to use the organometallic ketimine complex.
A compound of general formula II wherein A represents a group of formula 10 - CH - wherein R^"' has the meanings given hereinbefore for R^ with the exception of the cyano and aminocarbonyl 15 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 20 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 25 an ammonium salt in the presence of sodium cyanoboro-hydride, by reduction of a corresponding oxime with lithium aluminium hydride or with catalytically activated or nascent hydrogen, by reduction of a corresponding K-benzyl- or M-(1-phenylechyl)-ketimine, e.g. with 30 catalytically activated hydrogen or with e complex metal hydride in ether or tetrahydrofuran at temperatures of between -78°C and the boiling temperature of the solvent used and subsequently cleaving the benzyl or 1-phenylethyl group by catalytic hydrogenation, 35 by Sitter reaction of a corresponding alcohol with potassium cyanide in sulphuric acid, or by Hofmann, Curtius, Lossen or Schmidt degradation of a corresponding compound. ft compound of general formula II wherein A represents the group CM - CH may be obtained by reacting a corresponding aldehyde with ammonium cyanide or by reacting a corresponding 10 cyanohydrin with ammonia.
An amine of general formula II thus obtained, having a chiral centre, wherein A represents a group of formula wherein R^B has the meanings given hereinbefore with the exception of the cyano group, may be resolved into the enantiomers by racemate splitting, e.g. 20 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. 25 Moreover, an optically active amine of general formula II may also be prepared byenantioselective reduction of a corresponding ketimine using complex boron or aluminium hydrides wherein some of the hydride hydrogen atoms are replaced by optically active alkoxide 30 radicals, or by means of hydrogen in the presence of a suitable chiral hydrogenation catalyst or analogously,, starting from a corresponding M-benzyl- or BJ-(l-phenethyl)-ketimine or from a corresponding H-acyi-ketimine or enatnide and optionally subsequently 35 cleaving the benzyl, 1-phenethyl or acyl group. 35 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 5 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 10 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, IS 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. 20 The compounds of general formulae IV, VIII, IX, XI, XII and XIV used as starting materials are obtained by reacting a corresponding amine with a corresponding compound of general formula III or the reactive derivatives thereof, with optional subse-25 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 30 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 35 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: ft " (Z)-«-[(l-(2-piperidino-phenyl)-l-buten-l-yl)~ 5 aminocarbonylmethyl]-benzoic acid, B = ethyl (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl) -aminocarbonylmethyl] -benzoace, C = (E)—4—[(l-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid, 10 D= ■£-[(2-methy1-1-(2-piperidino-phenyl)-1-propen-1-yl)-aminocarbonylmethyl]-benzoic acid, E -= ethyl (Z)-4-[(1-(2-piperidino-phenyl)-1-hexen-1-yl)-aminocarbonylmethyl]-benzoate, F « (Z)—4—[(3-phenyl-l-(2-piperidino-phenyl)-1-propen-15 1-yl)-aminocarbonylmethyl]-benzoic acid, G = (Z)-4-[(l-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid, H = 4-[(l-(2-pyrrolidino-phenyl)-l-butyl)-aminocarbonyl-methy1]-benzoic acid, 20 J ■ (*)-4-[(l-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl] -benzoic acid, K = {-!■)-«-[ (l-(2-pi.pefridino-phenyl)-l-butyl)-amino-carbonylmethyl]-benzoic acid, L ■ ethyl (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-25 aminocarbonylmethyl]-benzoate, 37 M - ^-t(l-(2-he»ahydroazepino-phenyl)-l-butyl)-aminocarbonylmethyl] -benzoic acid, N = 4-[(l-(2-piperidino-phenyl)-l-hexyl)-aminocarbonyl-methyl]-benzoic acid, 5 0= 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]-benzoic acid, P = «-[(2-methoxy-l-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid, Q » 4-[(a-cyano-2-piperidino-benzyl)-aminocarbonyl-10 methyl]-benzoic acid, R = 4-[(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzyl alcohol, S = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -phenylacetic acid, 15 T = 4-[(1—(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -cinnamic acid, U = 2,3-dihydroity-propyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate, V = <3-[(l-(4-£luoro-2-piperidino-phenyl)-l-butyl)-20 aminocarbonylmethyl]-benzoic acid, W *» 4-[ (l-(4-methoity-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl] -benzoic acid, 38 hh « 4-{ (e-(^-iae8:hyl-phenyl)-2-piperidino-benzyl)-auiinocasrbonylraethyll -benzoic acid.
AB « 4-[(e-(3-raethyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, 5 AC = 4-[(q-(4-fluoro-phenyl)-2-piperidino-benzyl)- aminocarbonylmethyl]-benzoic acid, AD = 4-[ ( AO - 4-[(4S-me thy 1-o-pheny 1-2-piper idino-benzyl)-aminocarbonylmethyl] -benzoic acid, 5 AP « ^-[ (ot-phenyl-2-piper idino-benzyl)-aminocarbonylmethyl] -benzaldehyde, AQ « 4-[(2-(2-methyl-piperidino)-a-phenyl-benzyl)~ aminocarbonylmethyl]-benzoic acid, AR = 4-[(2-(3-methyl-piperidino)-o-phenyl-benzyl)-10 aminocarbonylmethyl]-benzoic acid and AS »■ 4-[ (3-chloro-o-phany 1-2-piper idino-benzyl) -aminocarbonylmethyl] -benzoic acid: 1. Hypoqlvcaemic activity The hypoglycaemic activity of the test substances 15 was tested on female rats 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 20 test and administered by oesophageal tube.
Blood samples were taken immediately before the administration of the substance and then 1, 2, 3 and 4 hours afterwards, in each case from the retro- orbital venous plexus. From each sample, 50 pi were 25 deproteinated with 0.5 ml of 0,33 0 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, 30 taking p - 0.05 as the limit of significance.
The following Table contains the values found in percent, compered with the controls: 40 5 nig/kg 1 mg/kg Substance 12 3 4 12 3 4 h -43 -40 -33 -35 B -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 V -36 -32 -27 -25 E -46 -40 -38 -26 -23 -23 -12 -18 F -43 "32 -39 -32 G -44 -42 -37 -31 H -50 -46 -44 -45 J -44 -37 -42 -42 -38 -32 -34 -29 K -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 n.s.
M -46 -43 -40 -36 -33 -30 -21 n.s.
N -42 -42 -37 -33 0 -38^ -31* n.s.+ n.s.* P -49 -43 -34 -22 -37 -19 n.s. n.s. 0 -28 -13 n.B. n.s. a -38 -40 -35 -29 -39 -34 -29 -24 s -49 -42 -30 -17 -29 -20 -10 n.s.
T -48 -46 -42 -40 -42 -42 -40 -32 0 -43 -43 -49 -45 -39 -35 -29 -24 V -45 -41 -46 -40 -37 -23 -30 -IS If -46 -45 -39 -37 -36 -25 -16 n.s.
A& -30 -33 -14 n.s. -15 -15 -13 n.s. fe® -43 -38 -36 -27 -26 -15 n.s. n.s. &c -36 -37 -36 -33 AO -28 -32 -27 -28 -IS -20 -17 -14 11E -30 -28 -39 -36 -21 -20 -22 n.s. 41 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 -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* «*• 0 1 J- -45 -32 -19 -10 - 17 AM -34 -35 -32 -29 -11 -13 n.s. n o s.
AW -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 • Si AS -45 -44 -42 -32 -21 -13 n« s< n «s + = at 10 mg/kg n.s. = statistically not significant 2. ftcute tonicity The tonic effect Mas tested in male and female mice of the same strain Neighing from 20 to 26 g, after oral administration of a single dose (suspended in 1§ methylcellulose) over an observation period of 14 days: 42 Substance Approximate acute toxicity & » 1 000 mg/kg p.o. 0 out of 5 animals died) C > 2 000 mg/kg p.o. 0 out of 6 animals died) D > 500 nig/kg p,o. 0 out of 6 animals died) J >2 000 mg/kg p.o. 0 out of 10 animals died) && >-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) he >1 000 mg/kg p.o. 0 out of 10 animals died) M) >1 000 mg/kg p.o. 0 out of 10 animals died) ftB >1 000 mg/kg p.o. 0 out of 10 animals died) hG >1 000 mg/kg p.o. 0 out of 10 anifa&ls died) In view of their pharmacological properties, the compounds prepared according to the invention 20 are suitable for the treatment of diabetes mellitus.
According to & yet further feature of the present invention, we provide phariii&ceuticel compositions comprising, as active ingredient, at least one compound of general formula X as hereinbefore defined or a 25 tautomer thereof or a physiologically compatible salt of these compounds, in association with one or more pharmaceutical carriers or excipients.
Woz phis rmaceutic«l administration the compounds of general formula X or tisutomsrs thereof or their 30 physiologically compatible salts may be incorporated into conventionel prsperations in either solid or liquid form, optionally is» combination with other active ingredients. The compositions may P for eaaaple, be presented in a £orm suitable for oral or parenteral » 35 administration. Preferred forms include, for example, tabletsP coated tablets, cepoulasp powders or suspensions. r5.'ha active Iftgredisnt raey be incorporated in . esscipients customarily employed in pharmaceutics! 43 compositions 6uch 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. 44 The following non-limiting Examples are intended to illustrate the invention: Example 1 Ethyl 4-rM-[s-(4-methvl-phenyl)-2-piperlflino-bensv11 -5 awinocarbonylwethvll -berisoate 4.7 g (18 mmol) of triphenylphosphine, 3 g (30 mmol) of triethylamine and 1.5 ram (15 mmol) of carbon tetrachloride are added successively to $.2 g (15 snrool) of cs-(«-iaethy 1-phenyl)-2-piperidino-bensylaraine 10 and 3.$ g (19.5 uunol) of 4-ethoi[ycarbonyl-phenylacetic ecid, dissolved in $0 mi! of acetonitrile. The reaction mixture is stirred at 50°C for 2 hours, then concentrated by evaporation and, after acidification with SW hydrochloric acid, extracted with ethyl acetate. The 15 acidic (aqueous phase is then extracted several times with Methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, fir led over magnesium sulphate and concentrated by evaporation. The evaporation residue is triturated 20 with eth&nol end suction filtered.
Yields 4.55 g (§53 of th@orv), M.p.s 177-178°C Calculated; C 75.57 8 7.28 H 5.95 Found: 75.19 7.15 5.82 25 ?he following wer® prepared analogously to Sx&mple 1: (a) Sthyl 6-[0-[e-(3-saethyl-phenyl)-2-piperidino-bengyl] - am i noca r bony X-me t hy 1] -bensoate 30 fields 48% of theory, H.p.t 159-150°C Calculated; C 76.57 H 7.28 M 5.95 Founds 75.80 7.35 5.76 35 (b) Sthyl 5-[M=[e~(2-raetbyl-phenyl)-2-piperidino-bcngyl] -am i nocor bony Itae i hy 1] -bsnsoete Ificjld% 33.4$ of theory, M-P.s 196-198°C 45 Calculated: C 76.57 H 7.28 W 5.95 Found: 76.55 7.35 5.50 (c) Ethyl 4-[0-[e-(4-methojiy-phenyl)-2-piperidino-5 bensyl]-aminocarbonylmethyl] -bensoate Yields 45% of theory, M.p.s 167-168°C Calculated: C 74.05 H 7.04 N 5.75 Founds 73.72 5.99 5.62 10 (d) Ethyl 4- [SJ- [«- (4-benzy losy-phenyl)-2-piperidino-bensyl]-eminocarbonylmefchyl]-bensoate Yield: 96% of theory, M.p.s 154-155°C 15 Ceilculated: C 76.84 6.31 H 4.98 Found: 76.53 6.58 5.03 (e) Sthyl 4-[M-[e- (390/492 20 (q) Ethyl 4-[0-(4-chloro-e-phenyl-2-piperidlno~benzyl) aminocarbonylmethyl]-bensoate Yield: 37% of theory, H.p.j 148-150°C Calculated: C 70.94 H 6.36 H 5.71 CI 7.22 25 Found: 70.81 6.25 5.61 7.12 (r) 2thyl $-l®-{3-chlozo-«i-ptienyl-2-piperidlno-benxyl) arainocasrbonylroethyl] -bensoate Yield: 74% of theory, 30 H„p.s 176-170°C Calculated: C 70.94 H 8.3S S9 5.71 CI 7.22 bounds 70.59 6.25 5.68 7,16 (s) Ethyl (6-raethyl-e-phenyl-2-pipsiridino-benzyl) 35 aminocarbonylmethyl]-bensoate Yields <35% of theory, H.p.s Oil 48 Calculated: molecular ion peak m/e » 470 Found: molecular ion peak m/e « 470 (t) Ethyl 4-[S3-(4-ni2thyl-a-phenyl-2-p1per Idino-benzyl )-ami nocarbonylmethyl]«benzoaie Yield: 75% of theory, M.p.s 133-135°C Calculated: C 76.57 H 7.28 H 5.95 Found: 76.51 7.16 5.83 (u) Ethyl 4~[['3-[5-chloro-2-(2-meihyl-piperidino)-<»-phenyl-10 benzyl]-aainocarbonylmethyl]-benzoate yield: 36.5S of theory, M.p.: 171-173°C Calculated: C 71.2$ H 6.58 (9 5.54 CI 7.01 Found: 71.45 6.68 5.59 7.20. 49.
Eaawple 2 Bthvl 4-[H-[e-(4-chloro-phenyl)-2-plperidino-benzyl]-aialnocarbonvl-methvl]-benstoata a solution of 5 g (22.1 mmol) of 4-eth0Kycarb0nyl-5 phenylacetyl chloride in 20 ml of chloroform is added dropwise, whilst cooling with ice, to a solution o£ 6.02 g (20 mmol) of c-(4-chloro-phenyl)-2-piperidino-bensylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform. The mixture is stirred for 10 2 hours at ambient temperature then added to water and extracted with chloroform. The extracts are dried and concentrated by evaporation. The evaporation residue is chromatographed on silicn gel using toluene/ ethyl acetate (5:1) as eluant. 15 Yields 5.6 g (57% of theory), M.p.s 178-1B1°C Calculated! C 70,94 5.36 V 5.71 CI 7.22 Founds 71.09 6.47 5.61 7.10 20 The following was prepared analogously to Example 2s (a) Ethyl It is than recrystttllieed from acetonitrile.
Yield: 2.45 g (59.3% o£ theory) M.p.s 226-228°C 10 Calculated: C 75,99 H 6,83 H 6.33 Pound: 75.60 6.75 6.29 The following were prepared analogously to Example 3: 15 (a) 20 4-[H-[b-(3-Methy1-phenyl)-2-plper idino-benzyl] - aiainoc&rbonylsiethyl] -benzoic scid Yield: 72% of theory, M.p.s 202-203°C Calculated: C 75.99 H 6.03 H 6.33 Found: 75.S& 6.91 6.37 (b) 4-[IS!- [e- (2-wethy 1-phenyl)-2-piper idino-bensyl] -aminocarbonylmethyl]-bensole acid Yield: 42.6% of theory, 25 M.p.t 285-290°C Calculated: C 75.99 H 6.83 N 6.33 Found: 76.05 6.96 6.25 (c) 4-[H-[ Yield: 720 mg (66,7% of theory), 25 M.p.: 202-204 °C Calculated: C 72.95 H 6.35 H 6.30 Found: 72.65 6.17 5.20 55 5 Example 5 10 4-[63-fc-(4-Hethvl-phenvl)-2-plperIdino-benzvl] -amino-cerbonyliiiethyl] -benzyl alcohol 2 5 g (5.3 mmol) of ethyl 4-[M-[e-(4-mechyl-phenyl) -2-piper idino-bensyl] -aminocarbonylmethyl]-bsnEoate are added in batches to a suspension of 15 05 q (13.2 mmol) of lithium aluminium hydride in 50 sal of absolute tetrahydrofuran. The mixture is stirred for a further 30 minutes at ambient temperature, decomposed by the dropwise addition of 4 H sodium hydroxide solution and filtered to remove the sodium 20 aluminate formed. The filtrate is concentrated by evaporation and the residue is recrystallised from a little toluene.
Yield; 0.S8 g 143% of theory) M.P. 144-146°C 25 Calculated: C 78.47 H 7.53 H 6.54 Founds 78.20 7„39 S.58 56 Example 6 4-ff<5- (aieshyl-phenyl) -2-piperidino-bensv1] -amino-ceirbonyl-methyll -ben 7. aldehyde 0.85 g (20 mmol) of 4-[®-[ts-(4-wethyl-phenyl)-5 2-piper id ino-bensyll -aminocarbony Ibis thy 1] -benzoic acid and 3.35 g (20 mmol) of £>?,®'-carbonyl<3iiiuidesole are reflated in 100 ml of absolute tetrahydrofuran for 2 hours. Then the mixture is concentrated by evaporation and after the addition of 50 ml of pyridine 10 and 3.7 g (20 snmol) of ^-toluenesulphonic acid hydr&side, the mixture is reflusied for a further 2 hours. It is then poured on to ice water and suction filtered end the precipitate is dried. The resulting crude toluenesulphonic acid hydrazide of the carboxylic 15 acid used is nixed with 20 g of anhydrous sodium carbonate and heated to 170°C in SO stl of ethylene glycol for 2 hours. Then it is added to water and extracted with chloroform. The concentrated extracts tare purified by column chromatography on silica gel 20 using toluene/ethyl acet&te 5:1 eis eluant.
Yield: 1.73 g (21% of theory) M.p. 8 J.
After 12 hours at ambient temperature, ether is added, 5 the snixture is filtered and the concentrated filtrate is purified by column chromatography on silica gel (eluant: toluene/ethyl acetate = 5:1).
Yield: 0.3 g (30% of theory) M.p.s 145-1«6°C 10 Calculated: C 78.83 H 7.09 N 6.57 Founds 78.97 7.12 6.57 The following was prepared analogously to Example 7: 15 (a) 4-[K-(e-Phenyl-2-piperidino-benzyl)-esninocarbonyl-methyl]-benzaldehyde Yield: 40% of theory M.p.: 170°C Calculated C 78.31 H 6.84 5.79 20 Pound: 78.59 6.87 6.31 Example 8 Bthvl 4-[M-[c!-(4-aethvl-phenvl)-2-piperidino-benzvl]-aminocarbonvl-methvl]-cinnamate 25 427 lag (1 laraol) of 4-[H-[e-(4-methy1-phenyl)- 2-piperidino-bensyl] -aminocarbonylmethyl] -benzaldehyde are added to an ethereal solution of 450 sag (2 rasnol) of sthyl diethylphosphonoacetate and 100 mg (2 nmiol) of 508 sodium hydride. After the mixture has been 30 stirred overnighte water is added end the resulting mixture is sittracted with chloroform and purified by column chromatography on silica gel using toluene/ethyl acetate (5s1) us eluant.
Yields 0.18 g (36% of theory) 35 H.p.s 176-180°C Calculated? C 77.39 H 7.31 W S.S« Founds 77.64 7.25 5.71 58 The following wes prepared analogously to Example 8: (a) Ethyl 4-[M-( Yield: 84% of theory M.p.s 173-173°C Calculated: C 73.90 H 3.88 M 5.98 20 Pounds 77.24 7.01 5.54 The following was prepared analogously to Es: ample 9s (a) 4-tH-(e-Phenyl-2-pAperidino-b®nsyl)-arainocerbonyl-25 methyl] -cinnamic acid Yield: 75% of theory H.p.s 177-180°C Calculated: C 7fl.a2 H 3.35 1 3.13 Founds 73.75 3.57 3.07 30 Ejtamale 10 Sthyl 4-fM-fe-(3-aethyl-i9henyl)-2--»iperidino-ben8yl] -am 1 aocaebonyIvae t hv 1] -bensoata A sniircure of 0.22 g (0.3 nuaol) of «-(3-saethyl-35 pheny1-2-piperidino-b®nzyl alcohol and 0.15 g (0.8 mmol) of ethyl 4=cyenojaethyl-ben!t;oats in 2 uil of o-dichloro-bensena is added dropwise, at ambient temperature, to 1.5 al of o-dichlorobensene and 1.5 ml of concentrated 5y 0 sulphuric acid. After 2 hours9 stirring, the mixture is poured onto ice-aater, extracted once.with ether, made alkaline with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract 5 is concentrated by evaporation end the residue is recrystallised from ethanol.
Yield: 0.22 g (50% of theory) M.p.s 158-155°C Calculated: C 76.57 H 7.28 EU 5.95 10 Founds 76.41 7.39 5.76 Example It 4-[B-[e-(4-methyl-phenyl)-2-piperidino-benzyl] -aaino-carbonyl-iaethvll-benzoic acid 240 mg (5 mmol) of ^-[^-[S-chloro-cs-(4-methyl-15 phenyl)-2-piper idino-benzyl] -eminoctarbonylaiethyl] - bensolc acid ere catalytically dehalogsnated 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 ber. After cooling, the catalyst 20 is filtered off. The filtrate is concentrated by evaporation and the residue is recrystollised from ethanol.
Yields 0.16 g (72% of theory) M.p.8 226-228°C 25 Calculated; C 75.99 H 5.83 If 5.33 Founds 75.81 6.73 5.10 60 The following was prepared analogously to Example Hi (e) 10 (b) 20 Biiample 12 Ethyl 4-[M-[e-(4-methyl-piienvl)-2-aiper idino-bensvl]-aia i noca c bony 1-ae t hv 11 -bensoate 25 & solution of 2.78 g (10 mmol) of freshly prepared (4-raethyl-pheny 1) - (2-piper idinopheny 1) -Etetinline in SO nil of sisthylenschloride is raised with 1.5 ml (11 raraol) of triethylamine end then a solution of 2.5 g (11 suaol) of 4~ethoizycarbonyl-phenylac@tlc acid chloride in 30 20 ml of (aethylens chloride is added dropvise thereto, whilst the mixture is cooled with ics. raster 1 hour est ambient temperature it is poured onto ice-water and a site-acted with methylene chloride, 'i'hs eitfcsacts ere dried and concentrated by evaporation and the 35 evaporation residue itt purified by column chromatography on tziiZlcei gel (sluauts toluene/ethyl acetate lOsl). The cruds acyl imine iu dissolved in disiethylform&saide «nd» after the addition of 0.S g of palladium (10% bl 4-[K-[2-(2-saethyl-piperidino)-cs-phenyl-bensyl] -aminoc&rbonylstethyl] -benzoic acid From 4-[H-[5-chloro-2-(2-methyl-piperidino)-©-phenyl-bensyl]-aminocarbonylmethyl]-bensoic acid Yislds 68% of theory M.p.s 2«6-248pC Calculated C 75.99 H 3.83 0 3.33 Found; 75.57 7.10 6.44 4-[M-[2-(3-Methyl-piper idino)-e-pheny1-benzyl]-aminocarbonylmethyl] -bensoic acid From 4-[W-[5-chloro-2-(3-methvl-piperidino)-e-phenyl-benssyl]-aminocarbonylmethyl]-bensoic acid Calculated: 43% of theory M.p.: 228-230°C Calculated: C 75.99 H 6.83 N 6.33 Found: 75.91 6.82 6.33 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 5 by evaporation arid the residue is recryst&llised from e little alcohol* Yield: 2.8 g (60% of theory) M.p„: 175-177°C Calculateds C 76.57 H 7.28 M 5.S5 10 Founds 76.41 7.1© 5.76 Example 13 4-fB- rethvl-phenyl)-2-piper idino-bensvl] -aminocarbonyl-laethvlT -bensonitr ile 15 Prepared from e-(4-methy1-phenyl)-2-piperidino- bansylaraitve and 4-cyano-phenylacetic acid analogously to Example 1.
Yield: 54% of theory M.p.s 144-146°C 20 Calculated: C 79.40 H 6.SO B 9.S2 Founds 79.10 6.90 9.78 Example 14 25 Bthvl 4-[M-[c- (i-roethv 1-phenyl)-2-wiperidino-bensvn -atainocarbonvlmethvl] -bensoate 4.2 g (10 Baaol) of 4-[$i-[E-('Sl-s>ethyl-phenyl)-2-piper idino-benssyl]-aminocarbonylsisthyl] -bensonitrila are refluxed for 24 hours with 50 ml of ethanol ic hydrochloric acid. The mixture is then concentrated 62 by asportation eind the evaporation residue Is mined with aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform entrees is concentrated by evaporation and the residue is triturated with 5 ethanol and suction filtered.
Yield: 2.9 g (51=5% of theory) M.p.s 177-179°C Calculated: C 76.57 H 7.28 N 5.95 Pounds 76.41 7.35 5.7S 10 Example 15 Ethyl *g-f®-[5-chloro-E-(2-chloro-phenvl)-2-piperidino-bensyll-aminocarbonylmethyll-bensoate 10 uuaol of ethyl 4-[SS-[e-{2-chloro-phenyl)-5-nitro-2-piperidino-benzyl) -tsminocarbonylaethyl) -15 bengo&te are dissolved in 50 ml of dimethylformaHiide «ndp after the addition of 1 g of Haney nickel, hydrogenated ut 60°C under & hydrogen pressure of 6 bar,.
Then the catalyst is filtered off? the filtrate is concentrated by evaporation and the residue, consisting 20 of ethyl «-[M-[5-awino-e-(2-chloro-phenyl)-2-piperidino-bensy.VJ -emino-cerbonylraethyl]-bensoate is dissolved in 100 ml of concentrated hydrochloric acid. Whilst the mistuue is cooled with ice, a solution of 1„0 g (14 mmol) of sodium nitrite in 10 ml of water is 25 added clrop&iss thereto and the resulting mimtur® is stirred for 1 hour at 0 to 5°C. The reaction mixture is then added dropuise to ei solution of 3g of copper (I) chloride in 25 ml of concentrated hydro 63 chloric acid. &fter 1 hour's stirring, the mixture is sa&ds alkaline with sodium hydroxide solution and extracted! with chloroform. The concentrated chloroform extracts ere purified by column chromatography on silica gel using toluene/ethyl acetate (5il) as eluant. Yield; 1.5 g (28„6% of theory) M.p„s 213-215°C Calculated: C 65.28 H 5.75 Founds 56.40 5.51 N 5.33 CI 13.49 5.<61 13.40 Example 16 3- [48-[S3- fe- (d-Hethyl-phenyl) -2-piper idino-benzyl)-aaiinocagbonvlmethyl]-phenyl]-propionic acid 0„S1 g (2 sunol) of: 4-[H-(ei-(4-methy 1-phenyl) -2-piper idino-benzyl)-aminocarbonyImethy1)-cinnamic acid are dissolved in 50 nil o£ methanol and, after the addition of 0.5 g of palladium (10% on charcoal) , the mixture is catalytically hydrogeneted ©t ambient temperature under a hydrogen pressure of 3 bar. ftfter the hydrogen uptake has ended, the catalyst is filtered off end recrystallised from & little ncetonitrile.
Yields 0.68.g (745 of theory) M.p.i 1^S-148°C Calculateds C 75.57 H 7.20 H 5.95 Founds 75.41 7.19 5.51 64 Example 17 Sodium salt of 4-[H-(cs-(4-inethyl-phenyl)-2-piperidino-benzvl)-aminocarbonylmethyl]-benzoic acid 442 sag (1 msaol) 4-[M-(o-(«-ipethyl-phenyl)-2-piperidino-bensyl)-aminocarbonylmethyl]-benzoic acid are dissolved in 25 ml of ethanol and mined with 1 al of 1 19 sodium hydroxide solution. The mixture is then concentrated by evaporation jjj vacuo, 20 ml of ocstone are added, the precipitate obtained is auction filtered and washed with ethyl acetate,, Yield; ^10 mg (85% of theory) M.p.s 295-300°C Calculateds C 72.40 H 3.29 H 5.03 bounds 72,15 3.43 5.93 Ths following wes prepared analogously to Example 17s (a) Ethanolamine salt of <3- [ST-(c-(4-methy1-phenyl)-2-piper idino-benzyl) -eiainocarbonylsnethyl] -bensoic acid Yields 75% of theory M.p.s 188-m°C Calculated: C 71.55 H 7.Si N 8„3« bounds 71.19 7.48 8.52 (b) Diethanolasnine salt of 4-t®-(tj-(4-saethy 1-phenyl) -2-piper idino-bensyX)-aminoc&rbouylra&thyX] -bensoic acid Yields 01% of theory M.p.s 170=180°C Calculated! C 70.70 H <5.85 H 7.73 Pounds 70.25 5.75 7.58 65 (c) Triethanolamine salt of 4-[N-( Yield: 0.45 g (45% of theory) M.p.: 122-123°C 15 Calculateds C 70.73 H 7.50 M 5.50 Found: 71.0$ 7.48 6.39 The following prepared analogously to Example 18: (a) Ethyl 4-[(1-(3-chloro-2-piperidino-phenyl)-20 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 558 of theory M.p.: lfll-143°C Calculated: C 60,33 H 7.26 CI 7.76 K 5.13 Found: 68.30 7.16 8.03 5.20 25 (b) Ethyl 4-t(1-(S-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate Yield: 73.9% of theory M.p.s 79-82°C Calculated: C 68.33 H 7.28 CI 7.76 N 6.13 30 Found: 68.45 7.24 7.80 6.09 (c) Ethyl 4-[ (l-(4-b»cosito-2~piperidino-phenyl)-1-bu ty 1) - am i noca r bony Iwe t hy 1] --be n soa t e Yield: 52.1% of theory, M.p.s 115-118°C 35 Calculated: C 52.27 H 6.63 Br 15.93 H 5,58 Found: 62.53 5.48 15.98 5.66 (d) Ethyl 4-[(1-(4-nitro-2=piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate 67 Yield: 74.6S of theory, M.p.; 127-130°C Calculated: C 66.79 H 7.11 N 8.99 Founds 66.88 7.08 9=15 5 (e) Ethyl 4-[(l-(3-methyl-2-piperidino-phenyl)-1-buty1)-aminocarbonylmethyl]-bensoate Yield: 63% of theory, fS.p.: 145-147°C Calculated: C 74.28 H 8.31 W 6.42 10 Pound; 74.40 8.30 6.41 (f) Ethyl 4-[ (l-(4-«nethyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate Yield: 54.7 of theory, M.p.s 113-114°C 15 Calculated: C 74.28 H 8.31 M 6.42 Found: 74.23 8.30 6.55 (q) Ethyl 4-[(l-(5-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Yield: 67.6% of theory, 20 M.p.: 149-150°C Calculated: C 74.28 H 8.31 H 6.42 Found: 74.38 8.21 6.49 (h) Ethyl 4-[(1-(6-iaethy 1-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -bensoate 25 Yield; 47% of theory, M.p.: 92-93°C Calculated: C 74.28 H 8.31 H 6.42 Found: 74.50 3.43 6.48 (i) Bthyl «-[(l-(2-pyErolidino~phenyl)-I-butyl)-30 aminocsrbonylmethyl-benzoate Yields 57.3% of theory, M.p.s 122-125°C Calculatedt C 73.50 H 7.90 H 6.86 Found: 73.63 8.07 7.01 35 (k) Ethyl 4-[(l-(2-piperidino-phenyl)-l-butyl)-arflino-cerbonylmethyl]-bensoate Yield: 71.5% of theory, M.p.s 127-128°C 68 Calculated: C 73.90 H 8.11 M 6=63 Found: 73.90 8.06 6.72 Ethyl 4-[(1-(2-(4-raethyl-piperidino)-phenyl)- 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 51.18 of theory, M.p.: 153-155°C Calculated; C 74.28 H 8.31 H 6.42 Found: 74.55 8.33 6.45 Ethyl 3-1(1-(2-hexahydroazepino-phenyl)-1-butyl)- aminocarbonylmethyl]-benzoate Yield: 42.7% of theory, M.p.; 145-1«7°C Calculated: C 74.28 H 8.31 S3 6.42 Found: 73.98 8.26 6.58 Ethyl 4-[(l-(5-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate Yield: 55% of theory, M.p.: 3L28-130°C Calculated: C 70.88 H 7.55 ift 6.33 Found: 71.14! 7.57 6.49 Methyl >5-[ (l-(2-piperidino-phenyl)-l-butyl)-araino-carbonylmethyl] -bensoate Yield: 63.2% of theory, M.p.: 1^7-148°C Calculated? C 73.50 H 7.90 N 6.86 Found: 73.63 7.88 6.80 n-Buty1 «-[!-(2-piper id ino-pheny1)-1-butyl)- am i no- c tar bony Imethyl] -benxoats Yield: 50„9% of theory, M.p.s 117-119°C (ether) Cfalculateds C 74.53 H 8.50 S5 $.22 Found: 74.49 8.46 6.14 Bthyl 3-chloro-4-[(1-(2-piperidino-phenyl)- 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 14.9% of theory, M.p.s <20°C Calculated? m/e 3 456/458 (1 chloro) Found: a/e = 456/458 (1 chloro) 69 (r) Ethyl 4-[(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl] -benzoate Yield: 18.9% of theory, M.p.: 103-105°C Calculated: C 74.62 H 7.89 N 6.45 Found: 75.01 8.10 6.26 Example 19 Ethyl 4-[(1-(5-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate h solution of 14.6 g (6*3.6 mmol) of 4-ethoxy-carbonyl-phenyl acetic acid chloride in 20 ml of methylene chloride is added dropwise to a stirred solution of 15.1 g (54,4 mmol) of 1-(5-nitro-2-piperidino-phenyl)-l-butylamine and 8.46 ml (61.4 mmol) of triethyl-araine 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 Mater. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. The reddish-brown oily evaporation residue is purified by coluran chromatography on silica gel (toluene/acetone = 10:1). Yields 17.7 g (S9.7S of theory), M.p.s 135-137°C (ether) Calculated: C 66.79 H 7.11 S 8.99 Found: 66.73 3.99 9.09 The following were prepared analogously to Ejtaraple 19: (a) Ethyl fl-[(l-(2-piperidino-phenyl)-l-butyl)-asninocarbonylmethyl] -benzoate 70 Yield: 0O.2% of theory, M.p.: 127-129°C Calculated: C 73.90 H 8.11 H 6.63 Found: 73.98 8.23 6.89 5 (b) Bthyl 4-[ (l-(4-hydroxy-2-piperidino-phenyl)-1-bufcyl)-aminocarbonylmethyl]-benzoate Yield: 13.5% of theory, M.p.: 178-180°C Calculated: C 71.21 H 7.81 N 6.39 . 10 Found: 71.27 7.82 5.^0 (c) Ethyl 4-[(l-(5-hydrosy-2-piperidino-phenyl) -1-butyl)-arainocarbonylmethy1] -bensoate Yield: 37.4% of theory, M.p.: 188-190°C 15 Calculated: C 71.21 H 7.81 N 5.39 Found: 71.34 7.89 6.38 Example ?n fl-f(1-(2-piperidino-phenyl)-l-butvl)-aminocarbonylmethyl] -20 phenyl acetic acid 3.0 g (15.45 mmol) of p-phenylene-diacetic acid and 10 ml of thionyl chloride are reflusted Cor 90 minutes and then concentrated by evaporation in vacuo. The crude diacid chloride is dissolved in 25 lOO ml of methylene chloride. Then a solution of 3.5 g (15.45 imaol) of 1-(2-piperidino-phenyl)-1-butyl-aiaine is slowly added dropvise so this solution, with stirring, at an Internal temperature of 10 -15°C. After 2 hours at ambient temperature, the 30 mixture is concentrated by evaporation in vacuo and the evagraration residue is distributed between lOO ml of ice cold 5% sodium hydroxide solution and ethyl acetate. Xt is filtered through Hleselguhr and the organic phase is separated off. The alkaline-aqueous 35 phase is adjusted to pH 5.5 with semi-concentrated hydrochloric acid and eittrocted with ethyl acetate. 1'he sstract ic drisd over sodium sulphate and filtered and the filtrate is concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol - 20/1).
Yield: 0.10 g (1.6% of theory), 5 M.p.s 136-140°C (scetonitrile/ether) Calculated: C 73.50 H 7.90 M 6.86 Found: 73.17 8.10 6.85 Example 21 10 Ethyl 4-[(2-methyl-l-(2-piperidino-phenyl)-l-propen-1-vl)-aminocarbonylmethyll -benzoate 5.58 g (26.8 mmol) of 4-ethouycarbonyl-phenylacetic acid, 8.43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 15 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 52 ml of acetonitrile and the resulting mixture is stirred for 20 hours at an ambient temperature. It is then 20 concentrated by evaporation in vacuo and distributed between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 5/1), 25 Yield: 3.0 g (26.5% of theory), M.p.s 82-84°C (ether) Calculateds C 74.25 H 7.57 6H S.SS Found: 74,20 ■ 7.49 5.55 The following were prepared analogously to Example 21: 30 (a) Ethyl ■§-[(1-(2~piperidino-phenyl)-1-penten-l-yl)-aminocarbonylmethyl]-bensoate Yield: 15% of .theory, M.p.s 9^-97°C (ethanol) Calculated: C 74.52 H 7.89 0 5.45 35 Found: 7<9.75 7.71 6.24 (b) Ethyl S-[(1-(2-piperidino-phenyl)=l-hexen-l-yl)-aminocarbonylmethyl] -bensoate Yields 27.4% of theory, 72 M.p.: 83-85°C (ethanol) Calculated: C 74.97 H 8.09 H 6.24 Found: 75.42 7.95 6.00 Ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-l- yl) -aminocarbonylmethyl]-benzoate Yield (more lipophilic isomer; probably E form) 4.1% of theory, M.p.: < 20°C Calculated: m/e = 420 Pound: m/e = 420 Yield (less lipophilic isomer; probably Z form) 51.9% of theory, 13.p.: 115-117°C (ethanol) Calculated: C 74.26 H 7.67 H 6.66 Found: 73.85 7.59 6.44 Ethyl 4-[(2-phenyl-l-(2-piperidino-phenyl)-ethen-l-yl)-aminocarbonylmethyl]-benzoate Yield (more lipophilic isomer; probably E form) of theory, M.p.: 75-77°C (ether/petroleum ether) Calculated: C 76.90 H S.88 H 5.98 Found: 77,31 7.20 5.93 Yield (less lipophilic isomer; probably Z form) 42.7% of theory, M.p.s 157-160°C (ethanol) Found: C 77.19 H 6.95 H 6.02 Ethyl 4-[(3-pheny1-1-(2-piperidino-phenyl)- l-propen-l-yl)-aminocarbonylraethyl)-bensoate Yields 62.6% of theory, M.p.s <20°C Calculated: m/e = 482 Pounds m/e " 482 Ethyl e-[(1-(2-(3,3-diraeshyl-piperidino-phenyl) 1-buten-l-yl)-aminocarbonylmethyl]-bensoate Yields 33% of theory, M.p.s 113-116°C (ethanol) 73 Calculated: C 74.97 H 8.09 H 6.24 Found: 75.37 7.93 6.03 (g) Ethyl 4-[(1-(6-methyl-2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-bensoate 5 Yield: 60.4$ of theory (probably Z form) M.p.: 95-96°C Calculated: C 74.62 H 7.89 H 6.45 m/e = 434 Found: 74.44 8.00 6.59 m/e = 434 10 Example 22 Ethyl 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-amino-catbonylmethyH-benzoate & stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidino-phenyl)-propyl-ketimine 15 and 11.5 ml (82.46 mmol) of triethylamine in 190 ml of anhydrous toluene is heated to an internal temperature of 85°C, then a solution of 18.7 g (82,46 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 95 ml of anhydrous toluene is added drop&ise thereto within 20 10 minutes and the resulting mixture is stirred for 30 minutes at an internal temperature of 95°C. It is then cooled to 20°C and extracted twice with water. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation _in vacuo. 25 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 cheory), M.p.s <20°C (honey-yellow viscous oil) 30 Calculated: C 74.26 H 7.37 H 6,55 Founds 73.90 7.92 6.61 Yield (less lipophilic isomer; probably Z form): 15.9 g (33.5% of theory), 35 M.p.s 114-116°C Found: C 74.02 H 7.69 H 6.65 74 Example ?■* Ethyl (E)- and (Z)-<3-f(1-(2-piperidino-phenyl)-l-buten-l-y 1) -aminoctarbonylmethy 11 -benzoate 1.0 g of Z gster (see Example 21c) is heated 5 for 30 minutes in a pre-heated oil bath et 230°C.
After cooling, the product obtained is purified by column chromatography on silica gel (toluene/acetone = 20/1).
Yield (E ester): 0=365 g (36.5$ of theory), 10 M.p.s <20°C Yield (Z ester): 0.380 g (38.08 of theory), M.p.i 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 20 to Example 23: (a) Bthyl (E) — and (Z)-4-[ (1- (S-rnei:hyl-2-oipstridino-phenyl) -1-buten-l-vl) -aminocarbonylmethyl) -benzoate 25 According to thin layer chromatography,, a 1/1 mixture of (E) and (Z) esters is obtained from the (Z) ester (see Example 22g).
Upper spot (E): Calculated: m/e = 434 Founds a/e => 434 30 lower spot (z): Founds m/e = 434 Example 24 Bthyl 4-[(l-(2-aiperidino-phenyl)-l-butyl)-aminocarbonvl-Methvll-bensoate 35 2.9 g (5.90 mmol) of ethyl 4-[(1-(2-piperidino- phenyl)-1-butan-l-yl)-arainocacbonylmethyl]-bensoate in 100 ritl of ethanol is hydrogenated on 0.77 g of 10% palladium/charcoal at 50°C under a hydrogen pressure 75 of 1 bar. After 2 hours, the catalyst is filtered off over Eiieselguhr end the filtrate is concentrated by evaporation j_n vacuo. The evaporation residue is crystallised from ethanol. 5 Yield: 1.5 g (51.5$ of theory), M.p.: 126-128 °C Calculated: C 73.90 H 8.11 H 6.63 Found: 73.97 8.22 6.57 10 The following compounds were obtained analogously to Example 24: (a) Ethyl 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoate 15 Yield: 45% of theory, M.p.: 117-120°C (ether) Calculated: C 74.28 H 8.31 W 6.42 Pound: 74.50 8.13 6.27 20 (b) Ethyl 4-[(l-(2-piperidino-phenyl)-l-hexyl)-aminocarbonylmethyl]-bensoate Yield: 50$ of theory, M.p.s 108-110°C (ether) Calculated: C 74.63 H 8.50 H 6.22 25 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, 30 M.p.: 1S1-162°C (ethanol) Calculated; C 76.57 H 7.28 n 5.95 Found: 76.71 7.19 5.99 (d) Ethyl 4-[(3-pheny1-1-(2-piperidino-phenyl)-35 1-propyl)-aminocarbonylmethyl] -benzoate Yield: 57.6$ o£ theory, M.p.: 118-119°C (ethanol) 76 Calculated; C 76.83 H 7.S9 N 5.78 Found: 76.70 7.<39 5.90 (e) Ethyl 4-[(1-(2-(3,3-d iiae thy 1-piper idino)-phenyl)-5 1-butyl)-aminocarbonylmethyl] -benzoate Yield: 36.58 of theory, M.p.s 1«0-141°C (ethanol) Calculated: C 74.33 H 8.50 M 6.22 Found: 7^.30 8.23 6.12 10 Eaample 25 4-[(1-(2-Piperidino-phenyl)-l-butvl)-aminocarbonylmethyl]-bensoic acid h mixture of 1.2 g (2*84 mmol) of ethyl «-[(l-15 (2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bensoate and 4.26 ml of IK 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. 20 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 (4^.6% of theory), 25 M.p.s 213-215°C Calculated: C 73.07 H 7.6S N 7.10 Found: 73.18 7.51 7.10 The following compounds were obtained analogously 30 to Sxample 25: (a) 4-[(l-(2-piperidino-phenyl)-l-pentyl)-aminocarbonyl-methyl]-bensoic acid Yield: 70.2S of theory, 35 M.p.s 213-215°C (acetone) Calculated: C 73.50 H 7.SO M 6.86 Found: 73.71 7.70 £.20 77 (b) «-[(l-(2-piperidino-phenyl)-l-henyl)-aminocarbonyl-methyl]-benzoic acid Yield: 72.6§ of theory, M.p.2 197-200°C (acetone) 5 Calculated: C 73.90 H 8.11 B 6.63 Found: 73.83 7.93 6.77 (c) 4-[(2-phenyl-l-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid 10 Yield: 68.7% of theory, M.p.: 2HS-215°C (acetone) Calculated: C 75.99 H S.83 R 6.33 Found: 75.70 6.60 6.32 15 (d) «-[(3-Phenyl-l-(2-piperidino-phenyl)-l-propyl)~ aminocarbonylraethyl]-benzoic acid Yield: 67.7S of theory, M.p.s 167-170°C (ethyl acetate) Calculated: C 76.29 H 7.06 M 6.14 20 Found: 76.56 7.06 6.23 (e) 4-[2-Methosy-l-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 60.8% of theory, 25 M.p.s 196-198°C (ether) Calculated: C 69.56 H 7.12 ft 7.07 Found: 69.72 6.52 6.71 (f) 4-[(l-(2-Pipeeidino-phenyl)-4-penten-l-yl)-30 arainocarbonylmethyl] -benzoic acid s 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 6.69 Found: 71.33 7.21 6.34 35 (9) 4-[(l-(2-(3,3-Dimethyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 48.2% of theory, 78 M.p.s 168-170°C (petroleum ether) C&lculated: C 73.91 H 8.11 H 6.63 Found: 73.51 7.89 6.32 5 (h) 4-[(1—(3-Methyl-2-piperidino-phenyl)-1-butyl) aminocarbonylmethyl]-benzoic acid Yield: 53% of theory, M.p.: 179-182°C Calculated: C 73.50 H 7.90 W 6.86 10 Pound: 73.50 7.82 7.01 (i) 4-1(1-(4-Methyl-2-pipeeidino-phenyl)-l-butyl) aminocarbonylmethyl]-bensoic acid Yield: 85.6% of theory, 15 M.p.: 170-172°C Calculated: C 73.50 H 7.90 S3 6.86 Found: 73.25 7.34 6.89 (k) 4-[(1-(5-Methy1-2-piperidino-phenyl)-1-butyl) 20 aminocarbonylmethyl]-benzoic acid Yield: 62.1§ of theory, M.p.s 219-221°C Calculated: C 73.50 H 7.90 N 6.86 Found: 73.20 7.74 6.89 25 (1) 4-[(l-(6-Methyl-2-piperidino-phenyl)-l-butyl) aminocarbonylmethyl]-benzoic acid x 0.3 H^O Yield: 89§ of theory, M.p.s 158-160°C 30 Calculateds C 72.53 H 7.93 N 6.77 Found: 72.40 7.91 3.92 (a) 4-[(l-(3-Chloro-2-piperidino-phenyl)-l-butyl) aminocarbonylmethyl]-benzoic acid 35 Yields 70S of theory, M.p.s 189-191°C Calculated: C 67.20 H 3.81 CI 8.27 N 6.53 Found: 67.30 6.85 8.36 6.58 79 (n) ^-[(1-(4-Chloro-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 57.8§ of theory, M.p.: 188-189°C 5 Calculated: C 67.20 H 6.81 CI 8.27 N 6.53 Found: 66.90 7.00 8.22 6.53 (o) 4-[(1-(5-Chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid 10 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 15 (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 20 Found; 67.18 6.91 8.42 6.77 (q) d-[(l-(4-Bromo-2-piperidino-phenyl)-l-butyl)~ aminocarbonylmethyl]-benzoic acid Yield: 84.4§ of theory, 25 M.p.: 198-201°C Calculated: C 60.89 H 6.17 Br 16.88 W 5.92 Found: 60.88 5.98 17.20 5.98 (r) 4-[ (1-(5-Bromo-2-piper idino-phenyl)-1-butyl) -30 aminocarbonylmethyl]-benzoic acid Yield: 90.7% of theory, M.p.s 232-235°C Calculated: C 60.89 H 6.17 Br 16.88 W 5.92 Found: 60.96 5.13 16.85 5.90 35 (s) 4-[(1-(^-Witro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 70.9% of theory, 80 M.p.: 188-1S0°C Calculated: C 65.59 H 6.35 H 9.56 Found: 65.30 6.44 9.53 «-[(1-(5-Hifcro-2-piperidino-phenyl)-1-buty1)-aiainocarbonylffiethyl] -benzoic acid Yield: 90.7% of theory, M.p.s 225-227°C Calculated: C 65.59 H 6.65 H 9.56 Found: 65.80 6.61 9.72 4-[ (1- (4-Hydroxy-2-piper id ino-pheny1)-1-buty1)- aminocarbonylmethyl]-benzoic acid « 0.5 H^O Yield: 85.7® of theory, M.p.: softening from 70°C (foam) Calculated: (:c 0.5 H20) C 38.71 H 7.45 M 6.68 Found: 38.33 7.55 6.26 4—[(1-(5-Hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 89.3% of theory, M.p.: 186-190°C Calculated: C 70.22 H 7.37 B 6.82 Found: 70.31 7.58 6.51 4-[(1-(4-Methoxy-2-piper idino-pheny1)-1-butyl)-aminocarbonylmethyl]-bensoic acid Yield: 78.5% of theory, M.p.: 185-187°C Calculated; C 70.73 H 7.60 S3 3.60 Found: 70.46 7.77 3,56 4-[(1-(S-Methoxy-2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 75% of theory, M.p.: 182-185°C (decomp.) Calculated; C 70,73 H 7.60 N 6.60 Found: 70.52 7.50 3.70 81 (y) 4-[(l-(2-Pyrrolidino-phenyl)-l-butyl)-aminocarbonyl-methyl]-benzoic acid Yield: 64.5§ of theory, M.p.: 200-203°C 5 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 10 Yield: 81.4% of theory, M.p.: 197-201°C Calculated: C 73.50 H 7.90 M 6.86 Pound: 73.90 8.06 7.00 15 (aa) 4-[(1-(2-Hexahydroazepino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 65.6% of theory, M.p.: 199-202°C Calculated: C 73.50 H 7.90 W 6.86 20 Found: 73.50 7.90 6.76 (ab) 4-[(1-(4-Fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Yield: 87.IS of theory, 25 M.p.i 204-207°C Calculated: C 69.88 H 7.09 N 6.79 Pound: 70.25 7.02 7.12 (ac) 4-[(1-(5-Fluoro-2-piperidino-phenyl)-l-butyl)-30 aminocarbonylmethyl] -bensoic acid Yield:,., 53.9% of theory, M.p.: 200-202°C Calculated: C 69.88 H 7.09 H 6.79 Found: 69.67 7.24 5.90 35 (ad) 3-Chloro-4-[(1-(2-piperidino-phenyl)-l-bueyl)-aminocarbonylmethyl]-benzoic acid Yield: 51S of theory. 82 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-f(2-Methvl-l-(2-plperidino-phenyl)-1-propen-l-vl)-aminocarbonylmethyl] -benzoic acid A mixture of 3o5 g (8.3 mmol) of ethyl 4-[(2-methy1-1-(2-piper id ino-pheny1)-1-propen-l-y1)-amlno-carbonyliaethyl]benzoate and 12.5 ml of IN sodium hydroxide solution in 35 ml of ethanol is stirred at S0°C for 2 hours. It is neutralised with 12.5 ml of Its hydrochloric acid, concentrated by evaporation in vacuo and distributed between ethyl acetate and water. The dried, filtered organic extract is evaporated in vacuo. The evaporation residue is crystallised from ethanol.
Yield: 2.41 g (73.S§ of theory), M.p.i 1Q8-191°C Calculated: C 73.M H 7.IS S3 7.14 Pound: 73.60 7.19 7.02 83 The following compounds were obtained analogously to Example 26: 10 (a) (E)—4—I(l-(2-Piperidino-phenyl)-l-buten-l-yl)-aminocarbonylmethyl]-benzoic acid Yield: 71.5% of theory, M.p.: 188-190°C Calculated: C 73.44 H 7.19 N 7.14 Found: 73.15 7.13 7.10 Olefinic proton: *H-NMR (CDClj):J» 6.42 ppm (b) (Z)-4-[(1-(2-Piper idino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid .
Yield: 57.8% of theory, 15 M.p.: 174-175°C (ethanol) Calculated: C 73.44 H 7.19 S 7.14 Found: 73.54 6.97 7.17 Olefinic proton: (CDCl^) :6.9 ppm (d) (Z)-4-[(2-Pheny1-1-(2-piperidino-phenyl)-ethen-30 l-yl)-aminocarbonyliaethyl]-benzoic acid it 1 H2° Yield: 728 of theory, M.p.s 18 2-18 5 °C (methanol) Calculated: (it 1 HjO): C 73.34 H 5.SO N 6.11 35 Found: 73.55 5.45 $.00 olefinic proton: ^H-HMR (CDC13): £ » 6.50 ppm 84 (e) fl-[(3-Phenyl-l-(2-piperidino-pheny1)-1-propen-1-yl)-aminocarbonylmethyl] -benzoic acid Yield: 48.3% of theory, M.p.s 152-164°C (ether); probably (Z) form 5 Calculated: C 76.63 H 6.65 S3 6.16 Found: 76.30 6.47 6.31 Olefinic proton: ^B-KMR (CDClj)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 15 Found: 73.93 7.57 6.50 Olefinic proton: ^H-HMR (CDClj)s <£ = 5-55 ppm (g) (Z)-4-[(1-(5-Methy1-2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid 20 Yield: 53.3§ of theory, M.p.: 142-145°C Calculated: C 73.66 H 7.44 N 6.89 Found: 73.56 7.73 7.15 olefinic proton: ^H-HMR (CDClj): £ = 5.38 ppm 25 Eitample 27 4-[(1-(2-Plperidlno-phenvl)-1-butvl)-aminocarbonylmethyl] ■ benaoic acid 200 tag (0.51 wmol) of 4-[(1-(2-piperidino-phenyl)-30 1-buten-l-yl)-aminocarbonylmethyl]-benzoic acid in 10 nil of absolute ethanol are hydrogenated over 100 mg of palladium/charcoal (109) 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. 35 Yield: 68% of theory, M.p.s 213-21 <3°C Calculated: C 73.07 H 7.66 M 7.10 Found: 73.21 7.82 7.02 85 The yield is 56§ of theory if hydrogenation is carried out at 50°C and under 1 bar of hydrogen on Raney nickel. 5 Example ?r Sodium salt of 4-[(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bensoic acid s 0.5 HjO 10.0 g (25.35 mmol) of «-[(l-(2-piperidino-10 phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid are dissolved at 50°C in 200 ml of ethanol and 25.35 ml of IK sodium hydroxide solution are added thereto. The mixture is evaporated to dryness in vacuo and the evaporation residue is dissolved in the minimum 15 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 cashed with ether and dried at 140°C/15 torr.
Yields 9 g (85.3% of theory), 20 M.p.s 280-285°C (decomp.); softening from 255°C Calculated: (x 0.5 H20) C 67.74 H 6.87 W 6.58 Pound: 67.86 7.13 6.49 Example 29 25 Ethyl (■!•)-£- C (1-(2-plper idlno-phenvl)-l-butv 1)-aminocarbonylmethyl] -benzoate To a stirred solution of 2.58 g (11.1 mmol) of (4-)-l-(2-piperidino-phenyl)-l-butylemine [Bp g g3s 87°C? ee = 86 (HPLC, after derivatising with (•«■)-30 1-phenethyl-isocyanate)] in 26 ml of, acetoni&rlie, there fcsre added, at 20°C, one after another, 2.31 g (11.1 mmol) of 4-ethosycarbony1-phenyl acetic acid, 3.50 g (13.3 mmol) of triphenylphosphine, 4.SO ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) 35 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 end etfisr. The organic phase is dried over sodium 86 sulphate, then filtered, and concentrated by evaporation In vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6s1) .
Yield; 2.63 g (56% of theory), M.p.s 118-120°C Calculated: C 73.SO H 8.11 K 6.63 Pounds 74.02 7.97 6.51 [ Yield: 0.53 g (38.2% of theory), 25 M.p.: 120-122°C Calculated: C 73.90 H 8.11 K 6.63 Found: 73.96 7.98 6.61 = +9.0° (c =■ 1, methanol) 30 Example 31 (4-)-4-[(1-(2-Piperidino-phenyl)-l-butvl)-aminocarbonylmethyl] -benzoic acid 2.0 g (4.73 mmol) of ethyl (4-)-^-[ (1-(2-piperidino- 20 phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate [[b] £ 35 « 4-9.2° (c » 1, methanol)] in 20 ml of ethanol are stirred with 7.0 ml of 1H sodium hydroxide solution for 2.5 hours in a bath at S5°C. The mixture is cooled and 7.0 ml of isa hydrochloric acid are added.
B8 The crystals which are slowly precipitated are filtered off, washed with water and dried at 100°C/$ torr.
Yield: 1.65 g (88.2% of theory), M.p.: 185-187°C 5 Calculated: C 73.07 H 7.66 » 7.10 Found: 72.90 7.80 7.17 [e]p° = +7.9° (c - 1, methanol) The following compound was obtained analogously to 10 Example 31: (a) (—)—4— f(1- (2-P-iper idino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid Yield: 80% of theory, 15 M.p.: 187-190°C Calculated: C 73.07 H 7.66 N 7.10 Found: 72.98 7.44 7.22 [c]p° = -7.9° (c =» 1, methanol) 20 Example 32 4-f(1-(2-Piperidino-phenvl)-l-butvl)-aminocarbonylmethyl] -benzonitrile Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-cyano-phenyltacetic acid analogously to Example 25 19.
Yield: 57.3% of theory, M.p.: 147-148°C Calculated: C 76.76 H 7.78 N 11.19 Found: 76.46 7.81 11.10 30 1'he following compound was obtained analogously to Sx&Eaple 32: (a) 4-[(l-(2=Piperidino-phenyl)-l-butyl)-eminocarbonyl-35 saethyl] -toluene Prepared with 4-tolyl-acetic acid.
Yield: 60.4% of theory, M.p.s 150-153°C 89 Calculated: C 79.08 H 8.85 N 7.68 Pound: 78.97 8.58 7.77 Example 33 5 Ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonvl-methyll -benzoate prepared from 4-[(1-(2-piperidino-pheny1)-1-butyl)-aminocarbonylmethyl]-benzonitrile with ethanolic hydrochloric acid analogously to Example 14. 10 Yield: 58% of theory, M.p.: 127-128°C Calculated: C 73.90 H 8.11 W 6.63 Found: 74.07 8.23 6.87 15 Example 34 Ethyl 4-T(l-(2-piperidino-phenvl)-l-butvl)-aminocarbonyl-methyll -benzoate prepared analogously to Example 10 from l-(2-piperidino-phenyl)-1-butanol and ethyl 4-cyanomethyl-20 benzoate with concentrated sulphuric acid in o-dichloro-benzene at ambient temperature.
Yield: 21% of theory, M.p.: 126-128°C Calculated: C 73.90 H 8.11 H 6.63 25 Found s 74.12 8.20 3.45 The following compound was obtained analogously to Example 34: 30 (a) 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid Prepared from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanoraethyl-benzoic acid. Extraction at pH 5.5. 35 Yield: 29% of theory, M.p.s 215-217°C Calculated; C 73.07 H 7.66 N 7.10 Found: 72.82 7.39 3.95 90 Example 35 4-f(1-(4-ftmino-2-pjperidino-phenvl)-1-butyl)-aminocarbonvl-methyl]-benzoic acid x 0.5 H^O 5 0.60 g (1.365 mmol) of 4-[(1-(4-nitro-2-piperidino- phenyl)-l-bufcyl)-aminocarbonylmethyl]-bensoic ecid 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 10 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.: 118-120°C 15 Calculated: (« 0.5 HjO) : C 68.87 H 7.71 H 10.04 Found: 68.62 7.64 10.08 The following compounds were obtained analogously to Example 36: 20 (a) Ethyl 4-[(l-(4-amino-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 81.7% of theory, M.p.: 145-146°C (ether/petroleum ether) 25 Calculated: C 71.37 H 8.03 N 9.60 Found: 71.50 8.08 9.68 (b) 4-[(1-(5-Amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoic acid 30 Yield: 64® of theory, M.p.i 227-230°C Calculated: C 70.39 H 7.63 N 10.23 Found: 70.54 7.54 10.35 35 (c) Ethyl 4-[(1-(5-aaino-2-piperidino-phenyl)-1-bu ty1)-em i nocorbonylaethyl]-bensoate Yield: 84.3% of theory, M.p.s 162-1S5°C 91 Calculated: C 71.37 H 8.06 N 9.60 Found: 71.58 7.83 §.65 Example 36 Ethyl 4-[(1-(5-chloro-2-piperidino-phenyl)-l-butvl)-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-2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 4.8 ml of semiconcentrsted hydrochloric 10 acid and 0.315 g (4.57 tnmol) of sodium nitrite in 1.S6 ml of water. 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 conc. hydrochloric acid and the resulting mixture is then heated in 15 a bath at 50°C. After the development of gas has ended (about 15 minutes), the mixture is cooled, added to ice/conc. ammonia and extracted four times, each time with 100 ml of ethyl acetate. The combined organic extracts are shaken with water, dried and 20 filtered and evaporated _in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).
Yield: 0.80 g (40% of theory), M.p.: 137-140°C (ether) 25 Calculated: C 68.32 H 7.27 Cl 7.75 M 6.13 Found: 68.42 7.09 8.06 6.05 The following compounds were obtained analogously to Example 36: 30 (a) Ethyl 4-[(l-(4-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate Yield: 21°9§ of theory, M.p.s 123-125°C 35 Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13 Found: S8..70 7.18 7.77 6.08 92 (b) Ethyl 4-[(l-(5-bromo-2-piperidino-phenyl)-1-bufcyl)-awinocarbonylmethyl]-bensoate Yield: 53.0% of theory, M.p.: U0-1«2°C 5 Calculated: C 62.27 H S.63 Br 15.93 N 5.58 Pound: 62.39 6.78 15.85 5.59 (c) Ethyl 4-[ (1- (43-f luoro-2-piper idino-phenyl) -1-bu ty1)-am i noca r bony line t hyl] -benzoete 10 Yield: 21.3® of theory, M.p.: 110-112°C Calculated: C 70.88 H 7.55 H 6.36 Pound: 71.01 7.53 S.21 15 tn addition, «i0® of ethyl 4-[ (l-(4-hydroity-2-piperidino-phenyl)-1-butyl)-aiainocarbonylmethyl] -bensoate are isolated (solid foam). (d) Ethyl 4-[(1—(5-fluoro-2—piper idino-phenyl) — 20 1-butyl)-aminocarbonylmethyl]-benzoate Yield: 2% of theory, M.p.: 127-129°C Calculated: m/e « 4140 Pound: m/e ■ 440 25 (e) 4-[(l-(«-Fluoro-2-piperidino-phenyl)-ethyl)-aiainocarbonylmethyl] -benzoic acid Yield: 16.of fchaory, 13.p. s 172-175°C 30 Calculated: C•68.73 H 6.55 S3 7.29 Found: 68.70 S.62 7.31 Baawple 37 g-[(1-(2-Piperidino-phenyl)-l-butvl)-amlnocarbonvl-35 Biethyl] -benzoic acid 1.0 g (2.33 mmol) of 4-[ (1-(5-chloro-2-piperidino-phenyl) -1-butyl)-erainocarbonyImethy1] -bensoic acid in 40 ml of absolute ethanol are hydrogenated on 93 0.5 g of 10® palladium/charcoal at 50°C and under 5 bar of hydrogen. After 2 hours, the catalyst is filtered off over kieselguhr and the filtrate is concentrated by evaporation ^n vacuo. The evaporation 5 residue is distributed at pH 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated iji vacuo.
Yield: 0.61 g (660 of theory), M.p.s 213-215°C 10 Calculated: C 73.07 H 7.66 M 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 IS starting products.
Example 38 Ethyl 4-[(1-(4-Methoxv-2-piperidino-phenvl)-1-butyl)-aminocarbonylmethyl] -benzoate 20 A solution of 5.0 g (11.4 mmol) of ethyl 4- f(1-(4-hydroxy-2-piper idino-phenyl)-1-bueyl)-aminocarbonylmethyl]-benzoate in 45 ml of absolute dimethylformamide is added dropwise, with stirring, at ambient temperature, to 548 mg (11.4 mmol) of sodium hydride (50® in 25 oil) in 10 ml of absolute dimethylformamide. The mixture is stirred for a further 15 minutes and then a solution of 0.71 sal (11„4 mmol) of methyliodide in 3 ml of absolute dimethylformamide is slowly added dropvise thereto. The mixture is stirred for a further 30 2.5 hours at ambient temperature, evaporated _in vacuo and distributed between water and ether. The ether phase is dried end filtered and concentrated by evaporation ij> vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone 35 = 20/1).
Yields 1.8 g (34.©$ of theory), M.p.s 115-117°C Calculated: Found: C 71.55 H 8.02 N 6.1© 71.47 7.86 6.19 The following compound was obtained analogously to 5 Example 33. (a) Bthyl 4-[(l-(5-raethoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate Yield: S8.fl% of theory, 10 M.p.: 1«2-1«5°C Calculated: C 71.65 H 8.02 H 6.19 Found: 71.87 8.06 6.38 Example 39 15 2,3-Dihydroxy-propyl 4-[(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate ft solution of 2.0 g (5.07 ramol) of 4-[(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -bensoic acid and 0.85 g (5.27 nuaol) of '-carbonyldi-20 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 echyl 25 acetate, the organic solution is dried and filtered and evaporated ijfi vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 1:1).
Yield: 1.1 g (46.2% of theory), 30 M.p.s 120-122°C Calculated: C 69.21 H 7,74 £3 5.98 Found: 69.23 7.78 S.93 The following compounds were obtained analogously 35 to Example 39: (a) 2-hydroxy-ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate 95 Yield: 80$ of theory, M.p.: 125-127°C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.35 7.54 6.33 5 (b) 2-methoxy-ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoate Yield: 55.9§ of theory, M.p.s 120-123°C 10 Calculated: C 71.65 H 8.02 M 6.19 Found: 72.03 8.03 6.24 Example 40 2-nicotinoylo«v-ethyl 4-[(l-(2-piperidino-phenvl)- "" 15 1-butyl)-aminocarbonylmethyl] -benzoate h 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)-20 aminocarbonylmethyl]-benzoate in 40 ml of methylene chloride and 0.7 ml (4.81 mmol) of triethylamine.
The resulting mixture is stirred at 20°C for 2.5 hours, extracted with water, then the organic phase is dried and filtered and evaporated in vacuo. The 25 evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1).
Yield: 1.1 g (44% of theory), M.p.s 132-135°C Calculated; C 70.70 H 6.86 6S 7.73 30 Founds 70.82 5.82 7.91 Example 4-1 4-[(l-(2-Piperidino-phenvl)-l-butvl)-aminocarbonvlmethvl]-bengyl alcohol 35 A solution of 5.0 g (11.83 mmol) of ethyl 4- • [(1-(2-piper idino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoate in 75 ml of absolute tetrahydrofuran is added dropwise, at an internal temperature of 0°C, • 96 to a stirred suspension of 0.68 9 (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 4W sodium hydroxide 5 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 10 residue is distributed between water and ether.
The ether phase is dried and filtered and concentrated by evaporation ^n vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone ■ 5/1). 15 yields 1.0 g (22% of theory), M.p.s 152-154°C Calculated: C 75.75 H 8.48 N 7.36 Founds 75.90 8.45 7.28 20 Example &2 4-T (1- (2-P iper idino-phenyl) -1-butyl) -aminocarbonylmethyl') -benzaldehyde 6.3 g (62 mmol) of sodium carbonate are heated together with 32 ml of ethylene glycol in & bath 25 at 170°C and, within 1 minute, 3,2 g (11 mmol) of E31—[4—[(1-(2-piperidino-pheny1)-1-butyl)-arainocarbony1-methyl] -benzoyl]-0 -tosyl-hydresine (melting point 195°C (decomposition)) are added thereto, with rapid stirring, whereupon there is a vigorous development 30 of gas. The mixture is then heated for a further 2o5 minutes at 170°C and then imraediately 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 35 by column chromatography on silica gel (chloroform/ acetone = 20/1). yields 2.2 g (52.9% of theory), M.p.s 142-145°C 97 Calculated: Pound: C 76.16 H 7.99 N 7.40 76.26 7.96 7.37 Example 43 5 Bthvl 4-[(1-(2-Plperidino-phenyl)-1-butyl)-aminocarbonyl-methvll -cinnamate A solution of 2.80 g (12.5 mmol) of ethyl diethyl-phosphonoacetate in 10 ml of absolute dimethylformamide is added dropwise, at ambient temperature, to 0.60 g 10 (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-[(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-15 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 20 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) 25 Calculated: C 74.97 H 8.09 H 6.24 Found: 74.91 7.89 6.29 Example 44 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyliaethyll-30 clnnamic acid Prepared by alkaline saponification of ethyl 4-[ (l-(2-piperidino-phenyl)-l-butyl)-aminocas:bonylmethyl] -cinnamate analogously to Example 26.
Yield: 64% of theory, 35 M.p.s 180-183°C Calculated; C 74.26 H 7.67 83 5.66 Found; 74.03 7. <<.17 6.80 98 Example 45 Ethyl 3-f4-[(l-(2-piperldino-phenyl)-l-butyl)-amino-carbonvlaethvll-phenyl! -propionate 0.50 g (1.3® mmol) of ethyl 4-[(l-(2-piperidino-5 phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate ate 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. 10 Yield: 0.53 g (88% of theory), M.p.s 98-99°C (petroleum ether) Calculated: C 74.63 H 8.50 N 6.22 Found: 74.54 3.58 6.23 15 The following compound was obtained analogously to Example 45: (a) 3-[4-[(1-(2-P iper id ino-pheny1)-1-buty1)-aminocarbonylmethyl] -phenyl]-propionic acid 20 Yield: 63% of theory, M.p.s 131-133°C Calculated: C 73.90 H 8=11 0 6.33 Found: 73.96 8.30 6.56 25 Example 3-f 4-[(1-(2-P iper id ino-pheny1)-1-butvl)-aminocarbonv1-methv11-phenyl]-propionic acid Prepared by alkaline saponification of ethyl 3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-eminocarbonyl-30 methyl]-phenyl]-propionate analogously to Example 25: Yields 50% of theoryp M.p.s 131-133°C Calculated: C 73.90 H 8.11 ft 6.53 Founds 73.82 8.07 6,41 99 Example m Ethyl 4-[(g-aminocarbonyl-2-pipecIdino-benzyl)-aminocarbonv lwethvl] -benzoate At 20°C, 0.90 g (5.5 mmol) of K^W'-carbonyldi-5 imidazole ere added to a stirred solution of 2.0 g {<3.7 lamol) of ethyl «-[(o-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 10 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 l_n vacuo, distributed between water and chloroform, then the 15 combined chloroform extracts are shaken with a little water, dried, filtered end 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), 20 M.p.s 160-162°C (acetone) Calculated; C 68.07 H 6.90 S3 9.92 Found: 68.40 6.92 9.84 Example 48 25 Ethyl 4-[(cs-cyano-2-piperIdino-benzyl)-aminocarbonylmethyl] -benzoate 234 mg (1„22 mmol) of 4-toluenesulphochloride are added in two batches to 520 mg (1.22 tamol) of ethyl 4-[(e-arainocarbonyl-2-piperidino-benzyl)-araino-30 carbonylmethyl] -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 is further hour at 35 50°C. After It has been left to stand for 2 days at 2t)°C, 2M ammonia is added and the mixture is extracted with chloroform. The chloroform solution is extracted twice with water. After drying and filtering, it is concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol a 10/1).
Yields 325 mg (65.7% of theory), 5 M.p.s 114-117°C (ether/petroleum ether) Calculated: C 71.06 H 5.71 N 10.36 Founds 70.79 5.56 10.10 Example 49 10 4-f(cs-Cyano-2-piperidino-bengyl)-aminocarbonylmethyl] -benzoic acid 1.5 g (3.7 mmol) of ethyl 4-[(c-cyano-2-piperidino-benasyl) -aminocarbonylmethyl] -benzoate in 15 ml of dioxan ere stirred together with 3.7 ml of 1ft sodium 15 hydroxide solution for 45 minutes in a bath at 60°C and for a further £5 minutes in & beth at 80°C.
After cooling with ice, the mixture is combined with 3.7 Ml of IN hydrochloric acid, the dioxan is evaporated off in vacuo and the residue is distributed between 20 water and chloroform. The organic solution is extracted with a little water, then dried and filtered and concentrated by evaporation ^n vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethanol ■ 5/1). 25 Yield: 0.50 g (35.7§ of theory), M.p.s 176-180°C (decomposition) Calculated: C 70.01 H S.l« 0 11.13 Found: 70.02 S.19 11.05 30 Eh ample j;n 4-t(l-(2-piperidino-phenvl)-l-butvl)-aminocarbonylmethyl] -bensoic acid n H^SOf 5 ul (2.50 mmol) of 1ft sulphuric acid are added to a solution of 1.0 g (2.53 sunol) of 4-[(1-(2-piperidino-35 phenyl)-1-butyl)-aminocarbonylmethyl]-bensoic acid in 50 ml o£ ethanol, the mixture is concentrated to dryness jjj vacuo and triturated with acetone. 101 Yield: 0.80 g (65§ of theory), M.p.: 192-197°C (decomposition).
Calculated: C 58.53 H 5.55 H 5.69 S 6.^9 Pound: 58.05 6.5« 5.49 6.35 The following addition salt was obtained analogously to Example 5Q; (a) 4-[(1-(2-P iper id ino-pheny1)-l-butvl)-aminocarbonylmethyl]-benzoic acid x 0.5 H^SO^ a 1.5 H^O Prepared analogously to Example 50 with half the quantity of sulphuric acid.
Yield: 59.3® of theory, M.p.: 180-185°C decomposition at 207-210°C Calculated C 61„26 H 7.28 H 5.95 S 3.«0 Found: 61.28 6.99 6.10 3.23 102 Example ft Tablets containing 5 mg of 4-[(l-(2-piperidino-phenvl)-1-butyl)-aminocerbonvliaethvll -bensolc acid 5 Composition: 1 tablet contains: Active substance (1) 5 .0 ing Corn starch (2) 52 .0 mg Lactose (3) 48 .0 mg Polyvinylpyrrolidone (4) <3 .0 mg Magnesium ste&rate (5) 1 .0 tug 120 .0 mg Method of preparation: 15 1, 2, 3 end 4 are mixed together end moistened with water. The Moist mixture is pressed through & screen with a mesh width of 1.5 aim and dried at about 45°C. The dry granulate is passed through a screen with a mesh width of 1.0 cua and mined with 20 5. The finished mixture is compressed in a tablet press, using punches 7 mm in diameter provided with a dividing slot, to form tablets.
Height of tablet: 120 mg 25 Sit staple S Coated tablets containing 2.5 mg of 4-[(1-(2-piperidino-phenvl) -1-butvl) -amlnocarbonylmethvll -benzoic acid 1 tablet core contains: 30 Active substance (1) 2.5 mg Potato starch (2) 44.0 iag tactose (3) 30.0 mg Polyvinylpyrrolidone (4) 3.0 mg Magnesium stesrote (5) 0.5 mq 35 @0.0 ntg 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 5 the granulate is again passed through the same screen. After the addition of 5, convex tablet cores 6 mm in diameter are produced in a tablet-making machine by compression. The tablet cores thus produced are coated in known manner with a coating consisting 10 essentially of sugar and talc. The finished coated tablets are polished with wax.
Height of coated tablet: 120 mg Example C 15 Tablets containing 10 mg of 4-[(1-(2-plperidino-phenyl)-1-butyl)-amlnocarbonylmethvll -benzoic acid Composition: 1 tablet contains: 20 Active substance Powdered lactose Corn starch Polyvinylpyrrolidone Magnesium stearate 25 10.0 mg 70.0 mg 31.0 mg 8.0 mg 1.0 mg 120.0 mg Method of preparation h mixture of the active substance, lactose and corn starch is moistened with a 20% solution 30 of polyvinyl pyrrolidone in water. The moist mass is granulated through a screen with a mesh width of 1.5 nam and then dried at 45°C. The dried granulate is zubbed through a screen with a mesh size of 1 mm and homogeneously mined with magnesium eteerate. 35 Height o£ tablets 120 mg • Punch: 7 mm in diameter with dividing slot. 104 Example D Coated tablets containing 5 mg of 4-[(1-(2-piperidino-phenyl) -1-butvl)-aminocarbonylmethyl] -benzoic acid S 1 tablet core contains: Active substance 5.0 mg Secondary calcium phosphate 70.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 4.0 mg 10 Magnesium stearate 1.0 mg 130.0 mg Method of preparation A mixture of active substance, calcium phosphate 15 and corn starch is moistened with a 15% solution of polyvinylpyrrolidone in water. The moist mass is passed through a screen with a mesh size of 1 mm,. then dried at «55°C and passed through the same screen again. After the specified amount of magnesium stearate 20 has been added, tablet cores are compressed from the mixture.
Weight of core: 130 mg Punch: 7 mm in diameter. 25 A coating of sugar and t&lc 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 105 r2

Claims (1)

1. CLAIMS Compounds of general formula I „ A - NH - CO - CH ■M V" W 17 2 y (1) ri R, [wherein h represents a group of formula RS RS f: - 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 aminocarbonyl group optionally raono-or ^.substituted 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 atoras, or by alkyl, hydrony, edkojty, phenylalftoity P jslltylsulphenyl, 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, ft] represents a piperidino group, Rz represents a fluorine atom in the 4-position of the aromatic nucleus, R, represents a hydrogen atom and H represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); or R4 represents a phenyl group when R, 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 W represents a formyl, carboxyvinylene or alkoxycarbonylvinylene group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); R3 and Ra together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 4 carbon atoms in the alkylidene moiety]; Rj 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 disubstitution may be the same or different); or a dialkylamino group containing 1 to 5 carbon atoms in each alkyl component; Rz represents a hydrogen, fluorine, chlorine, bromine or iodine atom, or a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylalkoxy, alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group wherein the alkyl component may contain 1 to 3 carbon atoms in each case; R, represents an alkyl group containing 1 to 3 carbon atoms or a hydrogen or halogen atom, and W represents a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms (wherein the alkyl component may optionally be substituted by a phenyl group and optionally, at any carbon atom except the o-carbon atom, by one or two hydroxy groups or by an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyrldinecarbonyloxy group, each alkyl component containing 1 to 3 carbon atoms and the alkyleneimino group containing 4 to 6 carbon atoms); an alkenyloxycarbonvl group containing a total of 4 to 5 carbon atoms, an alkyl 107. group containing 1 to 3 carbon atoms; or a hydroxymethyl, formyl, cyano, amlnocarbonyl, carboxymethyl, 2-carbo it y-ethyl, 2-carboxyethenyl, 2,2-bis-(carboxy)-ethyl, &I Jcoiry car bony 1-riet hyl, 2-eilkOKycer bonyl-ethyl, 2-5 alkoxycarbonyl-ethenyl or 2,2-bis-(alko»rycarbonyl)-ethyl group (each alkoxy group containing from 1 to 3 carbon atoms)] and cautowers thereof and optical enantiomers thereof find salts of the aforementioned compounds. 10 2. Salts of compounds of general formula I as defined in claim 1 and bautomers thereof, and optical enantiomers thereof, formed with hydrochloric, hydro-bromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid or with sodium hydrox-15 ide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine. 3. Physiologically compatible salts of compounds of general formula I as defined in claim 1 and tautomers thereof, and optical enantiomers thereof. 20 4. Compounds as claimed in claim 1, wherein A represents a group of formula 25 I4 CH - Rd vRC 5^/6 C or C - 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 30 5 carbon atoms; an til teeny 1 group containing 3 to 5 carbon atoms; a cyano or aminocarbonyl group; an aryl group containing 6 or 10 carbon atotns mono-or tSiaubstituted by halogen atoms, or by alkyl, hydroxy, alliOiiy, phenylalkoxy and/or alkylsulphenyl groups; 35 whilst the substituents may be the same os different and each alkyl component may contain from 1 to 3 108 carbon atoms; or a pyridyl, quinolyl or isoqulnolyl group; R_ and R, 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; R^ represents an unbranched alkyleneimino group containing 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups each having 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 Rg 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 sminocarbonyl group) Rj may also represent an iodine atom or a hydroxy or amino group; Rj represents a hydrogen or chlorine atom; and W represents a methyl, hydrosymethyl, 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 fcas- 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 pyridinecarbonyl-oxy grohp ; or an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein 109 each alkoxy group may contain from 1 to 3 carbon atoms; end 4-[a-(6-chloro-e-ph«ny1-2-piperidino-benzy1)-amino-carbonyliaethyl]-bensoic acid and alkyl esters thereof, 4-[H- (cs-phenyl-2-piper idino-benzyl) -aminocarbonyliaethyl] cinnantic tcid and Cj_3 alkyl esters thereof; 4- [H- (<5-chloro-«-pheny 1-2-piper id ino-benzy 1) -aminocarbonylmethyl]-benzoic acid and CjL_j alkyl esters thereof 4-[&I-(3-chloro-«-pheny1-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid and alkyl esters thereof 4-[K-{6-methyl-e~pheny1-2-piperidino-benzy1)-araino-ca r bony line i hyl]-bensoic acid and C^_3 alkyl esters thereof 4-lis-(4-methyl-e-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoic acid end Cj_^ alkyl esters thereof 4-18- (2- (2-methyl-piper idino) -e-pheny 1-bensy 1) -aminocarbonylmethyl]-bensoic acid and alkyl esteics thereof 4- IB- (2- (3-snethy 1-piper idino) -n atom by one or two hydroxy groups. 7. Compounds as claimed in claim 5 wherein VI represents a carboxy group or an alkoxycarbonyl group 5 containing a total of 2 to 5 carbon atoms. 8. . Compounds as claimed in claim 1, wherein A represents a group of formula R5^ xR6 10 - CH - - C 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 15 chlorine atom, or a pyridyl group; 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; 20 represents a piperidino group optionally substituted by one or two methyl groups; Rj represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group; Rj represents a hydrogen atom; and 25 W represents a carboxy group or an tilkoitycorbonyl group containing a total of 2 to 4 cerbon atoms. Compounds as claimed in claim 8, wherein A represents a group of formula 30 5^ ^ S CH - or - c - wherein represents an n-propyl group or an alkyl group containing 6 114 4 or 5 carbon atoms and Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 5 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene part. 10. (6-Chloro-o-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl] -benzoic acid and alkyl esters thereof. 11. 4-|N-(o-Phenyl-?-piperidino-benzy1)-aminocarbonyl-methyl] -cinnamic acid and alkyl esters thereof. 12. 4—[N—{4-Chloro-a-pheny1-2-piperidino-benzyl) -aminocarbonyl-methyl]-benzoic acid and alkyl esters thereof. 13. 4- [N-(3-Chloro-a-pheny1-2-piper idino-benzyl)-eminocarbonyl-methy1] -benzoic acid and C^_3 alkyl esters thereof. 14. 4-[N-(6-Methy1-a-pheny1-2-piper idino-benzyl)-aminocarbonyl-methy 11-benzoic acid and alkyl esters thereof. 15. 4-[N-(4-Methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid and C1_j alkyl esters thereof. 16. 4-[N-(2-(2-Methyl-piperidino)-a-phenyl-benzyl)-aminocarbonyl-methyl) -benzoic acid and Cj_^ alkyl esters thereof. 17. 4-[N-(2-(3-Methyl-piperidino)-o-phenyl-benzyl)- ami nocarbonyl-methyl] -benzoic acid and alkyl esters thereof. 18. 4-fN-((g-Phenyl-2-piperidi no-benzyl )-aminocarbonyl-methyl]-benzaldehyde. 19. 4-Q1-14-F1uoro-2-pi peri di no-pheny1)-ethyl)-ami nocarbony1-methyf]-benzoic acid and C^-j alkyl esters thereof. 20. uoro-phenyl) -2-pi peri di no-benzy£] -ami nocarbonylmethy l] -benzoic acid and C-jalKyi esters thereof. 115 21. 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-bensoic acid end alkyl esters thereof. 22. 4-[(l-(2-Piperidino-phenyl)-l-buten-l-yl)-amino-carbonyImethyl]-benzoic acid end alkyl esters 5 thereof. 23. 4-[(1-(2-Piperidino-phenyl)-l-pentyl)-aminocarbonyl-methyl]-benzoic acid and alkyl esters thereof. 24. Tautomers and optical enantiomers of compounds as claimed in any one of claims 10 to 23, and salts 10 thereof. 25, Enantiomers and salts of compounds as claimed in any one of claims 20 to 23. Compounds as claimed in claim 1 wherein h represents a group of formula 15 I — CH — therein R^ represents an aryl group containing S or 10 carbon atoms mono- or di-substituted by halogen atoms, or by alkyl, hydroxy, alkoxy, 20 phenylaltcoxy, alkyleulpheny 1, 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 to 3 carbon atoms; or a heteroaryl 25 group containing 4,5, 8 or 9 carbon atoms and 1 os 2 nitrogen atoms; R^ represents an unbranched alkyleneimino group containing 4 to 5 carbon atoms optionally substituted by one or two elkyl groups each containing 30 1 to 3 carbon atoms; an octahydro&ssocino, octahydro- lH-asonino or decahydroazecino group; or a 116 fir 5 t 10 15 20 25 & 30 dialkylamino group containing 1 to 5 carbon atoms in «2£Ch alkyl component; represents a hydrogen or halogen atom; represents a carboxy, foriayl, hydroayiaethyl, cyano, aiainoc&rbonyl, 2-carboxyethenyl, 2-carbony-ethyl, or 2,2-bis-(carbony)-ethyl group, an alkojtycarbonyl group containing a total of 2 to 5 carbon atoms, an ethenyl group monosub-stituted at the 2-position by an alkoxycarbonyl group or an ethyl gcoup 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); end represents a fluorine or bromine atom, a chlorine atom in the 3-, 4- or 6-position (relative to the substituent A), a nitro group or an alkyl or alkoxy group containing 1 to 3 carbon atoms; or (»hen eithers represents an unbranched alkyleneimino group substituted by one or two alkyl groups; an octahydroazocino, ocfc a hyd r o- 1H- is xon i no or decahydro-asacino group, or a dialkylamino group; and/or represents an aryl group mono- or di-substituted by halogen atoms or by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsul'ionyi groups; a naphthyl group; or a heteroaryl group containing 4,5,8 or 9 carbon atoms and 1 or 2 nitrogen atoms; and/or represents a hydroxymethyl, £ormyl, cyano, aminocarbonyl, 2-carbosysthenyl, 2-carboxyethyl or 2,2-bis-(carboxy)-ethyl group; an ethenyl group substituted at the 2-position by on alkoxycar- 117 bony3. group or an ethyl group mono- or di-substituted fit the 2-position by alkoxycarbonyl groups; and/or represents* a halogen atom) P may ileo eep»rssent a hydrogen atom or a chlorine the 5-position. Compounds as claimed in claim 1, wherein represents a group of formula •8 5 - / o I or C I li - CH- — C — wherein R^ represents an alkyl group containing 1 to 3 carbon atoms substituted by en alkoxy group containing 1 'o 3 carbon atoms or by s phanyl group; an n-propyl group; an alfcyl group containing 4 to 6 carbon atoms; an alkenyl group containing 3 to 5 carbon atoms; a cyano or alkyleneimino group containing 4 to 3 carbon atoms in the slkylene 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-j represents a piperidino group, R? represents a fluorine atom in the 4-position of the aromatic nucleus, R^ represents a hydrogen atom and W represents a carboxy group or an alkoxycarbonyl group (wherein the alkyl moiety may contain 1 to 3 carbon atoms); and Rg and Rg together with the carbon atom between them represent an alkylidene group containing 3 to 9 carbon atoms or a phenylalkylidene group containing 1 to 3 carbon atoms in the alkylidene moiety; 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 R2 represents a hydrogen, flourine, chlorine, bromine or iodine atom, an alkyl or alkoxy group therein the alkyl component may contain 1 to 3 carbon atoms; or a hydroxy, nitro, amino 5 or piperidino group; S3 represents a hydrogen, fluorine, chlorine or bromine atom; and W represents* a carboxy group or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms, 10 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 speci-15 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 II A - NH. (ID 119 (wherein A, and R2 arc defined as in claim 1 or. If & represents one of the vinylidene groups mentioned in claim 1, the tautomers thereof or a lithium or magnesium halide complex thereof) with a compound 5 of general formula III (wherein is defined as in claim 1 and ?!' has the meanings given for & in claim 1 10 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, therein the 15 reactive derivative of the compound of general formula III is an ester, thioester, halide, anhydride or imid&zolide thereof. 35. A process as claimed in claim 33 or claim 34 wherein the subsequent cleaving of the protecting 20 group of W', if present, is effected by hydrolysis, thermolysis or hydrogenolysis. 36. A process as claimed in claim 35 therein the hydrolytic cleaving is effected in the presence of an acid or of a base. 25 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 claists 33 120 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 ^3 to 37 wherein the reaction is effected in the presence 5 of an araine-activeting agent. 40. a process as claimed in any one of claims 33 to 39 therein the reaction is effected in the presence of an inorganic or tertiary organic base. 41. h 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. h process as claimed in any one of claims 33 to 41 therein the reaction is effected at tempertures 15 of from -25 and 250°C. 43. h process as claimed in any one of claims 33 to 42 ^herein a solvent is present and the reaction is effected at temperatures of from -10°C to the boiling temperature of the solvent. 20 44. h process for the preparation of compounds as claimed in claim 1 wherein W represents a carboxy, carbojtyraethy 1, 2-carbosyethyl or 2-cerboisyethenyl group, &hich comprises subjecting a compound of general formula XV ■Ul A - NH - CO » CH2 x>—B (XV) R 3 25 (whesrein to and & are as defined in claim 1 and B represents a group &hich can be converted into a cferbosyf carboxymethyl, 2-carbo#y-efchyl or 2-carbosy-eehenyl group by hydrolysis, thermolysis or hydrogenolysis) to hydrolysis, thermolysis or hydrogenolysis. 121 45. a process as claimed in claim 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 5 aralkyl ester (if hydrogenolysis is desired) of a carboxy, carboxymethyl, 2-cerbonyethyl or 2-csrboxyethenyl group. » 46. a process as claimed in claim 45 wherein the functional derivative is tan unsubstituted or substituted 10 emide, nitrlle, ester, thiolester, orthoester, imino » ether, amidine or anhydride or a malonic ester-(1)-yl, tetrasolyl or optionally substituted 1,3-osaaol-2-yl or l,3-oxasolin-2-yl group, the ester with a tertiary alcohol is a tertiary butyl ester or the aralkyl ester is a benzyl ester. 15 47. A process as claimed in any one of claims ^ to 46, therein the reaction is effected in the presence of a solvent. 48-. A process as claimed in any one of claims 44 to 47, wherein the hydrolysis is effected in the presence of an acid or 20 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 sminocarbonyl group and the reaction is effected using a nitrite in the presence 25 of en acid. 50. A process as claimed in claim 49 therein the nitrite Is sodium nitrite and the acid used is sulphuric acid, 51. A process os claimed in any one of claims 44 30 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 35 of the reaction mixture. ^ 53. a process for the preparation of compounds as claimed in claim 1 wherein A represents a group of formula . n a •a I — CH — wherein has the meanings given for 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 R3 and W are defined as in claim 1 and D represents © group of formula 8 15 Rs' Rs' 5 . ^ S N wherein K." has the meanings given hereinbefore for 20 3., wish the exception of a cyano group (and 3 ' and «ji J 3^° together with the carbon atoms between them represent an alkylidene group containing 1 to 7 carbon atows or a phenylalkylidane group containing 1 to 3 carbon atoms in the (alkylidene moiety. 123 54. A process as claimed in claim 53, wherein the reduction is carried out with hydrogen in the presence of a hydrogenation catalyst. b5. A process bs claimed in claim 54 wherein a 5 hydrogen pressure of 1 to 5 bar is used. 56. A process as claimed in any one of claim? 53 to 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 - CH — wherein R<;," has the meanings given hereinbefore for R^r with the exception of a cyano group; which comprises 20 reacting a compound of general formula VI (wherein represents R^ as defined in claim 1 with the exception of to cyano group and R, and E- are x a si 25 defined in clisim 1) with a compound of general formula VII 124 > (VII) R 3 wherein and W are defined as in claim 1. 60. ^ process as cl a lined in claim 59, wherein the reaction is effected in the presence of a strong acid. 61. h process as claimed in claim 59 or claim 60, ^herein the reaction is effected in the presence of concentrated sulphuric acid. 62. a process as claimed in any one of claims 69 to 61 therein the r&action is effected at temperatures of between 0 and 150°C. A process as claimed in claim 62 wherein the reaction is effected at temperatures of between 20 and 100°C. 64. A process for the preparation of compounds as claimed in claim 1 wherein R, represents a hydrogen atom, which comprises dehalogenating a compound of general formula VIII Hal -NH- CO - CH 2 w (VIII) 1 R 3 125 therein 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 64 wherein 5 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 10 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 15 of formula wherein represents an alkyleneiminocarbonyi group containing 4 to 6 carbon atoms in the alkylene ring 20 or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety, which comprises reacting a compound of general formula IX R — CH — C00H 126 (wherein , K? rand are as defined in clain* 1 and t?n represents fj as defined in claim 1 with the eiiception of a carbosty group) with an amine of general formula x h - r_ (x) therein R? represents an alkyleneimino group containing 4 to 9 carbon atoms or an amino group optionally mono- or di-substituted by alkyl or phenylalkyl groups 10 each containing 1 to 3 carbon atoms in the alkyl moiety. 69. A 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. & process as claimed in any one of claims 68 to 70, wherein the reaction is effected in the presence 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 b8 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 f>8 to 73 wherein the reaction is effected in the presence of a solvent and at temperatures of between -10°C and 30 the boiling temperature of the solvent used- 75. & process for the preparation of compounds as claimed in claim 1 wherein A represents a group g£ formula f -CH- wherein H,, is as defined in claim 1 and W represents Ti a carbony group, which comprises oxidising a compound 5 of general formula XI R. 1 CH - NH - CO - CH2 —(/ nV-E (XI) wherein to are defined as in claim 1 and E represents a group which can be converted 10 into a carbony group by oxidation. 76. h process as claimed in claim 75 therein E represents a formyl group, an acetal of a formyl group, a hydroxymethyl group, an ether of a hydroxymethyl group, a substituted or unsubstituted ecyl group 15 - or ci malonic ester-(l)-yl group. 77. & process ma claimed in claim 75 or claim 76 therein the oxidising agent used is selected from; silver oxide/sodium hydroxide solution, manganese dioxide, hydrogen per oitifie/sodium hydroxide solution, 20 chromium trioxide/pyridine, pyridinium chlorochromate, bromine/sodium hydroxide solution, chlorine/sodium hydsofiide solution, bromine/potassium hydromide solution and chlorine/potassium hydroside solution. 78.. h process eis claimed in any one of claims ^ 25 to 77 wherein the oxidation is effected in the presence of a solvent. 79. a process as claimed in any one of claims 75 to'® wherein the oxidation is effected at temperatures of between 0 and 100°C. 8q h process as claimed in claim 79 wherein the 5 "reaction is effected at temperatures of between 20 and 50°C. 81- h 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 cucUm atom except the a-c.irbcn atom >-y one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms, which comprises esterifying a carbonylic acid of general formula XII 15 (wherein to R^ and h ere as defined in claim 1), or a reactive derivative thereof optionally prepared in the reaction mixture, with an alcohol of general formula JIXII HO - Rg (XIII) 20 therein Rg represents an alkyl group containing 1 to 5 carbon atoms which may be substituted at any carbon atom except the a-carbon atom by one or two hydroxy groups or by an alkoxy group containing 1 to 3 carbon atoms. 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 itnidazolide thereof. 83. A process as claimed in claim 81 or claim 82 wherein the 5 esterlflcation 1s 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 10 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. & process as claimed in any one o£ claims 81 to 86 wherein the esterification is effected in the 15 presence of en inorganic or tertiary organic base. 88. A process as claimed in any one oi claims 81 to 87 therein the esterification is effected at temperatures of between -20 and 100°C. 89. A process as claimed in any one of claims 81 20 to 88, wherein the esterification is effected in the presence of a solvent and at temperatures of between -10°C and the boiling temperature of the solvent used. 90. ^ process for the preparation of compounds as claimed in cl£ifii 1 wherein W represents an alfcoxy-25 carbonyl, alftoiiycarbonylmethyl, 2-alkOJiy-carbonyl- ethyl or 2-alkojty ear bony lethenyl group and ft represents a group of formula H « V -CH — wherein H^" represents as hereinbefore defined 30 with the exception of a cyano group, which comprises alcoholysing a compound of general formula XXV 130 wherein represents R^ as defined in claim 1 with the exception of a cyano group, S to are defined as in claim 1 and »"• 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. ft process as caiftied in claim 91 wherein the acid is hydrochloric or sulphuric acid. 93. ft process as claimed in any one of claims 90 to 92, therein the alcoholysis is effected 15 in the presence of a solvent. 94. ft process as claimed in claira 93 wherein the solvent is an excess of the alcohol used in the alcoholysis reaction. (J5. ft process as claimed in any one of claims 20 90 to 94, wherein the reaction is effeoted 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 temperatures 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, therein W represents a carboxy or alkoxycarbonyl group is subsequently converted *1 131 by reduction into a corresponding compound of general formula I wherein tl represents a formyl or hydrosy-methyl 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 hydrazine and subsequent disproportionate, into 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, therein W represents a formyl group, is subsequently converted, by condensation 15 and optional subsequent hydrolysis and/or decarboxylation, into a corresponding compound of general formula I wherein W represents a 2-alitosycarbony1-ethenyl or a 2-carbosy-ethenyl group. 100. h process es claimed in any one of claims 20 33 to 99, therein a compound of general formula I initially obtained, wherein H represents a 2-carboay-ethenyl or 2-alkoxycarbonyl-eihenyl g?oup»Is subsequently converted by catalytic hydrogenation into a corresponding compound of general formula I -wherein W represents 25 a 2-carbosyethyl or 2-aJ.koirycarbonyl-ethyl group. 101. & process as claimed in any one of claims 33 to 100, therein a compound of general formula I initially obtained, wherein w represents an alStosty-carbanyl group substituted at any carton atcm except the a-carbon atcm 30 by a hydroxy group* is subsequently converted by acyla&ion by means of a pyridine-cerboitylic acid into a corresponding (py r id ine-carbony lo::y&l!to::y)-carbonyl compound of general formula J. 102. & 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 bydroity-methyl group is, after being converted into a corresponding halosnethyl compound, subsequently converted 132 by reaction with a malonic acid diesier into a corresponding compound of general formula I wherein W represents an ethyl group substituted by two {alkoxycarbonyl groups. 5 103. & process as claimed in any one of claims 33 to 102, wherein a compound of general formula i I 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 I wherein W represents an ethyl group substituted by two carboxy groups. 104 process cs claimed in any one of claims 33 to 103, wherein a compound of general formula 15 I initially obtained, wherein m represents an ethyl group substituted by two alkoxycarbonyl groups is subsequently converted by hydrolysis and decarboxylation into a corresponding compound of general formula I wherein W represents a 2-carboxyethyl 20 group. 105. A process as claimed in any one of claims 33 to 104, therein a compound of general formula t I initially obtained, therein represents a nitro group is subsequently converted by reduction into 35 a corresponding compound of general formula I wherein K, represents an amino group. 106. a process as claimed in any one of claims 33 to 105, therein a compound of general formula I initially obtained, wherein a, represents an amino 30 group is subsequently converted, via a corresponding diassonium salt, into a corresponding compound of gensral formula X wherein Kg represents a hydrogen or halogen atom or a hydroxy, alkoxy or alkylsulphenyl group. t 35 107. A process as claimed in any one of claims 33 to 106, wherein a compound of general formula 1 initially obtained, whsrsin Hg represents a hydroxy c group is subsequsntly converted by alkylation into 133 e corresponding compound of general formula I wherein Rg represents an alkosy group. 108. h process £s claimed in any one of claims 33 to 107, therein a compound of general formula 5 r initially obtained, therein represents a benzyloxy group and/or K. represents an aryl group substituted by a bensyloxy group is subsequently converted 1 by debenssylation into a corresponding compound of general formula X wherein Rj 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 amino-15 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 therein 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. & process as claimed in any one of claims 33 to 110, wherein a compound of general formula 25 I or a tautomer or optical enantiosner thereof, initially obtained, is subsequently converted to a salt thereof, or a salt of a compound of general formula X or a tautomer or optical enantioraer thereof, initially obtained, is subsequently converted to 30 a compound of general formula X or a tautomer or optical enantiomer thereof. 112. & process as claimed in any one of claims 33 to 111 for the preparation of compounds as claimed in claim 26. 35 113. & process as claimed in any one of claims t 33 to 111 for the preparation of compounds us claimed in claim 27. 114. A process as claimed in any one of claims 33 to 113 > 1,14 substantially as herein described. 115. & process as claimed in any one of claims 33 to 124 substantially as herein described in any of Examples 1 to 50. 5 116. ti process as claimed in claim 112 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 I 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 £ as defined in claim 1 or a tautomer or optical enenfciomee 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 leaBt 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. 135 125. Compositions as claimed 1n 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. 127. Pharmaceutical compositions as claimed in claim 121 substantially as herein described. 128. Pharmaceutical compositions substantially as herein described in any one of Examples A to 0. Dated this 5th day of July, 1983, (signed) TWINS & CO., $ppTfc~ants' Agents, 5 Dartmouth Road, DUBLIN 6 136
IE1573/83A 1982-07-06 1983-07-05 N-substituted phenylacetamides IE56171B1 (en)

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

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US5312924A (en) 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
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
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