DK159850B - ANALOGY PROCEDURE FOR THE PREPARATION OF PHENYLOIC ACETIC ACID DERIVATIVES - Google Patents

Description

DK 159850 BDK 159850 B

Den foreliggende opfindelse angår en analogifrem-gangsmåde til fremstilling af hidtil ukendte phenyleddi-kesyrederivater med den i krav 1 angivne almene formel I, deres enantiomere og deres fysiologisk acceptable salte 5 heraf med uorganiske eller organiske syrer eller baser. Fremgangsmåden er ejendommelig ved det i krav 1's kendetegnende del angivne.The present invention relates to an analogous process for the preparation of novel phenylacetic acid derivatives of the general formula I as claimed in claim 1, their enantiomers and their physiologically acceptable salts thereof with inorganic or organic acids or bases. The process is characterized by the characterizing part of claim 1.

De hidtil ukendte forbindelser har værdifulde farmakologiske egenskaber, især en virkning på stof-10 skiftet, dog fortrinsvis en blodsukkersænkende virkning.The novel compounds have valuable pharmacological properties, especially an effect on the metabolism, but preferably a blood sugar lowering effect.

I dansk patentansøgning nr. 5365/81, som svarer til EP-A-0.058.779, beskrives forbindelser med formlen I, hvori A imidlertid betegner en med en methyl-, ethyl-, isopropyl-, cyclohexyl- eller phenylgruppe-substitueret 15 methylengruppe eller en af grupperne: iH3 0Danish Patent Application No. 5365/81, corresponding to EP-A-0.058,779, discloses compounds of formula I wherein A denotes one having a methyl, ethyl, isopropyl, cyclohexyl or phenyl group substituted methylene group. or one of the groups: iH3 0

CH2 CH eller CCH 2 CH or C

II II ·· 20 -C-, -C- -c- 25 Det har imidlertid overraskende vist sig, at for bindelserne som fremstilles efter fremgangsmåden ifølge nærværende opfindelse, har en kraftigere virkning, som det vil fremgå af forsøgsresultater anført nedenfor.II II ·· 20 -C-, -C- -c- However, it has surprisingly been found that for the compounds prepared according to the process of the present invention have a stronger effect, as will be seen from the experimental results set forth below.

Indenfor krav 1's definition af grupperne til 30 R og W kommer f.eks. følgende i betragtning:Within the definition of groups 1 to 30 R and W, for example, comes e.g. the following considerations:

OISLAND

For R.j pyrrolidino-, piperidino-, hexamethylenimino-, hepta-methylenimino-, octamethylenimino-, nonamethylenimino-, methyl-pyrrolidino-, dimethyl-pyrrolidino-, ethyl-pyr-35 rolidino-, methyl-piperidino-, ethyl-piperidino-, dimethyl-piperidino-, diethyl-piperidino-, methyl-ethylpiperidino-, n-propyl-piperidino-, methyl-n-pro-For R 1 pyrrolidino, piperidino, hexamethylenimino, heptamethylenimino, octamethylenimino, nonamethylenimino, methylpyrrolidino, dimethylpyrrolidino, ethylpyrrolidino, methylpiperidino, ethylpiperidino, dimethyl-piperidino-, diethyl-piperidino-, methyl-ethylpiperidino-, n-propyl-piperidino-, methyl-n-pro-

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Pyl“Piperidin°-, isopropyl-piperidino- eller di-n-pro- pyl-piper idinogruppeii, 2 5 for R2 et hydrogen-, fluor-, chlor-, brom- eller iod-atom, methyl-, ethyl-, n-propyl-, isopropyl-, hydroxy-, methoxy-, ethoxy-, n-propoxy-, isopropoxy-, trifluor-methyl-, nitro-, amino-, piperidino-, methylmercapto-, ethylmercapto-, n-propylmercapto-, isopropylmercapto-, 10 methylsulfinyl-, ethylsulfinyl-, methylsulfonyl-, n-propylsulfonyl-, benzyloxy-, 1-phenyl-ethoxy-, 2-phenyl-ethoxy-, 3-phenyl-propoxy-, acetoxy-, propio-nyloxy-, formylamino-, acetylamino-, propionylamino-, methylamino-, ethylamino-, n-propylamino-, dimethyl-15 amino-, diethylamino-, di-n-propylamino- eller methyl-ethylamino-gruppen, for R4 n-propyl-, isopropyl-, n-butyl, n-pentyl-, n-hexyl-, methoxymethyl-, ethoxymethyl-, n-propoxymethyl-, isopropoxymethyl-, 2-methoxy-ethyl-, 20 2-ethoxy-ethyl-, 3-methoxy-propyl-, benzyl-, 1-phenyl-ethyl-, 2-phenylethyl-, 1-phenyl-n-propyl-, 2-phenyl-n-propyl-, 3-phenylpropyl-, allyl-, 3-buten-l-yl-, 2-buten-l-yl-, 4-pentyl-l-yl-, cyano-, carboxy-, amino-carbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, 25 n-propylaminocarbonyl-, dimethylaminocarbony1-, diethyl-aminocarbonyl-, di-n-propylaminocarbonyl-, benzylamino-carbonyl-, 2-phenylethylaminocarbonyl-, pyrrolidino-carbonyl-, piperidinocarbonyl-, hexamethyleniminocarbo-nyl-, phenyl-, naphthyl-, fluorphenyl-, chlorphenyl-, 30 bromphenyl-, methylphenyl-, ethylphenyl-, isopropyl- phenyl-, hydroxyphenyl-, methoxyphenyl-, ethoxyphenyl-, n-propoxyphenyl-, benzyloxyphenyl-, 2-phenylethoxy-phe-nyl-, 3-phenylpropoxy-phenyl-, methylsulfenyl-phenyl-, ethylsulfenyl-phenyl-, methylsulfinyl-phenyl-, n-propyl-35 sulfinyl-phenyl-, methylsulfonyl-phenyl-, ethylsulfo- nyl-phenyl-, isopropylsulfonyl-phenyl-, methyl-naphthyl-, hydroxy-naphthyl-, methoxy-naphthyl-, dichlorphenyl-, chlor-brom-phenyl-, dimethyl-phenyl-, di-isopropyl- 3Pyl "Piperidine" -, isopropyl-piperidino or di-n-propyl-piperidino group, for R 2 is a hydrogen, fluoro, chloro, bromo or iodo atom, methyl, ethyl, n -propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoro-methyl, nitro, amino, piperidino, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto -, methylsulfinyl, ethylsulfinyl, methylsulfonyl, n-propylsulfonyl, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, acetoxy, propionylloxy, formylamino -, acetylamino, propionylamino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino, di-n-propylamino or methylethylamino group, for the R4 n-propyl, isopropyl , n-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 3-methoxy-propyl , benzyl, 1-phenyl-ethyl, 2-phenylethyl, 1-phenyl-n-propyl, 2-phenyl-n-propyl, 3-phenylpropyl, allyl, 3-butene-1- yl-, 2-buten-1-yl-, 4-pentyl-1-yl-, cyano-, carboxy-, amino-carbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, n-propylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl -, di-n-propylaminocarbonyl, benzylamino-carbonyl, 2-phenylethylaminocarbonyl, pyrrolidino-carbonyl, piperidinocarbonyl, hexamethyleniminocarbonyl, phenyl, naphthyl, fluorophenyl, chlorophenyl, methylphenyl, methylphenyl , ethylphenyl, isopropylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxyphenyl, 2-phenylethoxy-phenyl, 3-phenylpropoxy-phenyl, methylsulphenyl-phenyl, ethylsulphenyl-phenyl -, methylsulfinyl-phenyl, n-propylsulfinyl-phenyl, methylsulfonyl-phenyl, ethylsulfonyl-phenyl, isopropylsulfonyl-phenyl, methyl-naphthyl, hydroxy-naphthyl, methoxy-naphthyl, dichlorophenyl -, chloro-bromo-phenyl-, dimethyl-phenyl-, di-isopropyl-3

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phenyl-, chlor-methyl-phenyl-, dimethoxy-phenyl-, methyl-methoxy-phenyl-, chlor-methoxy-phenyl-, brom-methoxy-phenyl- eller pyridylgruppen, 5 for og Rg et hydrogenatom, methyl-, ethyl-, n-pro-pyl-, isopropyl-, η-butyl-, isobutyl-, sec. butyl-eller n-pentylgruppen, eller R5 og Rg betegner sammen med det mellemliggende C-atom en alkylidengruppe med 3-9 10 carbonatomer, for Rj. og Rg sammen med det mellemliggende carbonatom benzyliden-, 1-phenyl-ethyliden-, 2-phenyl-ethyliden-, 1- phenyl-n-propyliden-, l-phenyl-2,2-propyliden- eller 15 3-phenyl-n-propylidengruppen og for W hydroxymethyl-, formyl-, carboxy-, carboxy-methyl-, 2- carboxy-ethyl-, 2-carboxy-ethenyl-, 2,2-bis-(carboxy) -ethyl-, methoxycarbonyl-, ethoxycarbonyl-, n-propoxy- 20 carbonyl-, isopropoxycarbonyl-, n-butoxycarbonyl-, isobutoxycarbonyl-, n-pentoxycarbonyl-, allyloxycarbo-nyl-, crotyloxycarbonyl-, (2-hydroxyethoxy)carbonyl-, (2-hydroxy-N-propoxy) carbonyl-, (1-hydroxy-2-propoxy)-carbonyl-, (2-methoxyethoxy)carbonyl-, (2-ethoxyethoxy)-25 carbonyl-, (2-n-propoxyethoxy)carbonyl-, (2-nicotinoyl-oxy-ethoxy) carbonyl-, (2-isonicotinoyloxy-ethoxy) carbonyl- , (2,3-dihydroxy-n-propoxy)carbonyl-, (2-dimethyl-amino-ethoxy) carbonyl-, (2-diethylamino-ethoxy) carbonyl-, (2-piperidino-ethoxy)carbonyl-,methyl-, ethyl-, 30 η-propyl-, isopropyl-, cyano-, aminocarbonyl-, methoxy-carbonyl-methyl-, ethoxycarbonyl-methyl-, n-propoxy-carbonyl-methyl-, 2-methoxycarbonyl-ethyl-, 2-ethoxy-carbonyl-ethyl-, 2-isopropoxycarbonyl-ethyl-, 2-methoxy-carbonyl-ethenyl-, 2-ethoxycarbonylethenyl-, 2-n-prop-35 oxycarbonyl-ethenyl-, 2,2-bis-(methoxycarbonyl)-ethyl-, 2,2-bis-(ethoxycarbonyl)-ethyl- eller 2,2-bis-(isopropoxycarbonyl) -ethylgruppen .the phenyl, chloro-methyl-phenyl, dimethoxy-phenyl, methyl-methoxy-phenyl, chloro-methoxy-phenyl, bromo-methoxy-phenyl or pyridyl group, for and Rg a hydrogen atom, methyl, ethyl , n-propyl, isopropyl, η-butyl, isobutyl, sec. the butyl or n-pentyl group, or R5 and Rg together with the intermediate C atom represent an alkylidene group of 3-9 carbon atoms, for Rj. and Rg together with the intermediate carbon atom benzylidene, 1-phenylethylidene, 2-phenylethylidene, 1-phenyl-n-propylidene, 1-phenyl-2,2-propylidene or 3-phenyl-n -propylidene group and for W hydroxymethyl, formyl, carboxy, carboxy-methyl, 2-carboxy-ethyl, 2-carboxy-ethenyl, 2,2-bis (carboxy) -ethyl, methoxycarbonyl, ethoxycarbonyl -, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, (2-hydroxyethoxy) carbonyl, (2-hydroxy-N-propoxy) ) carbonyl, (1-hydroxy-2-propoxy) carbonyl, (2-methoxyethoxy) carbonyl, (2-ethoxyethoxy) -carbonyl, (2-n-propoxyethoxy) carbonyl, (2-nicotinoyl) carbonyl oxy-ethoxy) carbonyl, (2-isonicotinoyloxy-ethoxy) carbonyl, (2,3-dihydroxy-n-propoxy) carbonyl, (2-dimethylamino-ethoxy) carbonyl, (2-diethylamino-ethoxy) carbonyl, (2-piperidino-ethoxy) carbonyl, methyl, ethyl, 30 η-propyl, isopropyl, cyano, aminocarbonyl, methoxy-carbonyl-methyl, ethoxycarb onyl-methyl, n-propoxy-carbonyl-methyl, 2-methoxycarbonyl-ethyl, 2-ethoxy-carbonyl-ethyl, 2-isopropoxycarbonyl-ethyl, 2-methoxy-carbonyl-ethenyl, 2-ethoxycarbonylethenyl , 2-n-prop-oxycarbonyl-ethenyl, 2,2-bis (methoxycarbonyl) -ethyl, 2,2-bis (ethoxycarbonyl) -ethyl or 2,2-bis (isopropoxycarbonyl) -ethyl group .

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Foretrukne forbindelser indenfor den almene for mel I er de forbindelser, hvori A betegner en gruppe med formlenPreferred compounds within the general for flour I are those compounds in which A represents a group of the formula

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R5 ·— /R6R5 · - / R6

5 R4 C5 R4 C

1 " CH - eller - C - , hvor R4 betegner en med en alkoxygruppe med 1 til 3 carbon-10 atomer eller med en phenylgruppe substitueret alkyl-gruppe med 1 til 3 carbonatomerf en n-propylgruppe, en alkylgruppe med 4 til 6 carbonatomer, en alkenyl-gruppe med 3 til 5 carbonatomer, en cyano- eller amino-carbonylgruppe, en med halogenatomer, med alkyl-, 15 hydroxy-, alkoxy-, phenylalkoxy- og/eller alkylsulfenyl-grupper mono- eller disubstiteuret arylgruppe med 6 eller 10 carbonatomer, hvor substituenterne kan være ens eller forskellige,og alkyIdelen i alle tilfælde kan indeholde 1 til 3 carbonatomer, en naphthylgruppe 20 eller en pyridylgruppe,1 "CH - or - C - wherein R 4 represents one having an alkoxy group having 1 to 3 carbon atoms or a phenyl group substituted alkyl group having 1 to 3 carbon atoms an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cyano or amino carbonyl group, one having halogen atoms, having alkyl, hydroxy, alkoxy, phenylalkoxy and / or alkylsulphenyl groups mono- or disubstituted aryl group having 6 or 10 carbon atoms wherein the substituents may be the same or different and the alkyl moiety may in any case contain 1 to 3 carbon atoms, a naphthyl group 20 or a pyridyl group,

Ri- og Rg sammen med det mellemliggende carbonatom beteg"-ner en alkylidengruppe med 3 til 9 carbonatomer eller en phenylalkylidengruppe med 1 til 3 carbonatomer i 25 alkylidendelen, R^ betegner en uforgrenet alkyleniminogruppe med 4 til 8 carbonatomer eller en med alkylgrupper med hver 1 til 3 carbonatomer mono- eller disubstitueret piperidino-30 gruppe, R2 betegner et hydrogen-, fluor-, chlor- eller bromatom, en nitro-, alkyl- eller alkoxygruppe hver med 1 til 3 carbonatomer eller også, 35 når R^ og Rg har de ovenfor angivne betydninger, og R^ betegner en med en alkoxygruppe med 1 til 3 carbonatomer eller med en phenylgruppe substitueret alkylgruppe med 1 til 3 carbonatomer, en n-propylgruppe, 5R 1 and R 8 together with the intermediate carbon atom denote an alkylidene group having 3 to 9 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety, R 1 represents an unbranched alkylene amino group having 4 to 8 carbon atoms or one having alkyl groups having each 1 to 3 carbon atoms mono- or disubstituted piperidino group, R 2 represents a hydrogen, fluoro, chloro or bromine atom, a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms or also when R denotes the above and R 1 represents an alkoxy group having 1 to 3 carbon atoms or a phenyl group substituted alkyl group having 1 to 3 carbon atoms, an n-propyl group, 5

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en alkylgruppe med 4 til 6 carbonatomer, en alkenyl-gruppe med 3 til 5 carbonatomer, en nitril- eller amino-carbonylgruppe, et iodatom, en hydroxy- eller aminogruppe, 5 W betegner en methyl-, hydroxymethyl-, formyl-, cyano-, carboxy-, carboxy-methyl-, 2-carboxy-ethyl- eller 2-carboxy-ethenylgruppe, en alkoxycarbonylgruppe med ialt 2 til 5 carbonatomer, hvori alkyldelen fra β-car-10 bonatomet kan være substitueret med en eller to hydroxy-grupper, med en alkoxygruppe med 1 til 3 carbonatomer eller med en pyridincarbonyloxygruppe, en alkoxycarbo-nyl-methyl -, 2-alkoxycarbonyl-ethyl- eller 2-alkoxycar-bonyl-ethenylgruppe, hvor alkoxygruppen i alle tilfælde 15 kan indeholde 1 til 3 carbonatomer, dog især de forbindelser med den almene formel I, hvori A betegner en gruppe med formeln _ V /R6an alkyl group of 4 to 6 carbon atoms, an alkenyl group of 3 to 5 carbon atoms, a nitrile or amino carbonyl group, an iodine atom, a hydroxy or amino group, 5 W represents a methyl, hydroxymethyl, formyl, cyano , carboxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl part of the β-carbon atom can be substituted by one or two hydroxy groups , with an alkoxy group having 1 to 3 carbon atoms or with a pyridinecarbonyloxy group, an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein the alkoxy group may contain at least 1 to 3 carbon atoms, however, especially those compounds of general formula I wherein A represents a group of formula _ V / R 6

R4 CR4 C

20 ' » - CH - eller q , hvor R4 betegner en med en methoxy- eller phenylgruppe substitueret alkylgruppe med 1 til 3 carbonatomer, en 25 n-propyl-, cyano- eller aminocarbonylgruppe, en alkylgruppe med 4 til 6 carbonatomer, en alkenylgruppe med 3 til 5 carbonatomer, en med et fluor-, chlor- eller bromatom, med en methyl-, hydroxy-, methoxy-, benzyl-oxy- eller methylsulfenylgruppe substitueret phenyl-30 gruppe eller en pyridylgruppe,20 '- CH - or q, wherein R 4 represents a alkyl group having 1 to 3 carbon atoms substituted by a methoxy or phenyl group, a 25 n-propyl, cyano or aminocarbonyl group, an alkyl group of 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, one having a fluorine, chlorine or bromine atom, with a methyl, hydroxy, methoxy, benzyl-oxy or methylsulphenyl group substituted phenyl group or a pyridyl group,

Rg og Rg sammen med det mellemliggende carbonatom betegner en alkylidengruppe med 3 til 9 carbonatomer eller en phenylalkylidengruppe med 1 til 3 carbonatomer 35 i alkyldelen, 6Rg and Rg together with the intermediate carbon atom represent an alkylidene group having 3 to 9 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms 35 in the alkyl moiety, 6

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betegner en uforgrenet alkyleniminogruppe med 4 til 8 carbonatomer eller en med methylgrupper mono- eller disubstitueret piperidinogruppe, 5 R2 betegner et hydrogen-, fluor-, chlor- eller bromatom, en methyl- eller methoxygruppe eller også, når Rfj og Rg har de ovenfor angivne betydninger, og R^ betegner en med en methoxy- eller phenylgruppe substi-10 tueret alkylgruppe med 1 til 3 carbonatomer, en n-pro-pyl-, nitril- eller aminocarbonylgruppe, en alkylgruppe med 4 til 6 carbonatomer eller en alkenylgruppe med 3 til 5 carbonatomer, et iodatom, en hydroxy- eller aminogruppe, 15 W betegner en methyl-, hydroxymethyl-, formyl-, cyano-, carboxy-, carboxy-methyl-, 2-carboxy-ethyl- eller 2-carboxy-ethenylgruppe, en alkoxycarbonylgruppe med ialt 2 til 5 carbonatomer, hvori alkyldelen fra β-car-20 bonatomet kan være substitueret med en eller to hydroxy-grupper, med en alkoxygruppe med 1 til 3 carbonatomer eller med en pyridincarbonyloxygruppe, en alkoxycarbo-nylmethyl-, 2-alkoxycarbonyl-ethyl- eller 2-alkoxy-carbonyl-ethenylgruppe, hvor alkoxygruppen i alle 25 tilfælde kan indeholde 1 til 3 carbonatomer, samt deres optisk aktive antipoder og deres fysiologisk acceptable salte med uorganiske eller organiske syrer eller baser.represents an unbranched alkylene imino group of 4 to 8 carbon atoms or a mono- or disubstituted piperidino group having methyl groups, 5 R 2 represents a hydrogen, fluoro, chloro or bromine atom, a methyl or methoxy group or also when R f represents a substituted alkyl group having 1 to 3 carbon atoms, an n-propyl, nitrile or aminocarbonyl group, an alkyl group having 4 to 6 carbon atoms, or an alkenyl group having 3 to 5 carbon atoms, an iodine atom, a hydroxy or amino group, 15 W represents a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxy-methyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, a alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl portion of the β-carbon atom may be substituted by one or two hydroxy groups, by an alkoxy group of 1 to 3 carbon atoms or by a pyridinecarbonyloxy group, an alkoxycarbonylmethyl, 2-alkoxycarbon eth yl or 2-alkoxy-carbonyl-ethenyl group, wherein the alkoxy group may contain in all 25 cases 1 to 3 carbon atoms, as well as their optically active antipodes and their physiologically acceptable salts with inorganic or organic acids or bases.

3030

En yderligere gruppe af foretrukne forbindelser er imidlertid de forbindelser, hvori R^ og R2 er som ovenfor defineret, og W betegner en carboxygruppe eller en alkoxycarbonyl-35 gruppe med ialt 2 til 5 carbonatomer, hvor alkyldelen fra 3-carbonatomet kan være substitueret med en eller to hydroxygrupper, samt deres optisk aktive antipoderHowever, a further group of preferred compounds are those compounds wherein R 1 and R 2 are as defined above, and W represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl portion of the 3 carbon atom being substituted by a or two hydroxy groups, as well as their optically active antibodies

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7 og deres fysiologisk acceptable salte med uorganiske eller organiske syrer eller baser.7 and their physiologically acceptable salts with inorganic or organic acids or bases.

Særligt foretrukne forbindelser med den almene 5 formel I er forbindelser, hvori A betegner en gruppe med formlenParticularly preferred compounds of general formula I are compounds wherein A represents a group of formula

Rr ^ R6 5V„ / 6Rr ^ R6 5V "/ 6

R4 ' CR4 ° C

i w 10 _ CH - eller - C - , hvor R4 betegner en n-propylgruppe, en alkylgruppe med 4 eller 5 carbonatomer, en med en methyIgruppe, med et fluor- eller chloratom substitueret phenylgruppe eller 15 en pyridylgruppe,in w 10 - CH - or - C - wherein R 4 represents an n-propyl group, an alkyl group of 4 or 5 carbon atoms, one with a methyl group, a fluorine or chlorine atom substituted phenyl group or a pyridyl group,

Rg og Rg sammen med det mellemliggende carbonatom betegner en alkylidengruppe med 3 til 5 carbonatomer eller en phenylalkylidengruppe med 1 til 3 carbonato-20 mer i alkylidendelen, R^ betegner en eventuelt med en eller to methylgrupper substitueret piperidinogruppe, 25 r2 betegner et hydrogen-, fluor- eller chloratom, methyl- eller methoxygruppen, og W betegner en carboxygruppe eller en alkoxycarbonyl-gruppe med ialt 2 til 4 carbonatomer, og blandt disse 30 især de forbindelser, hvori A betegner en gruppe med formlen V c 35 ' CH - eller - C - , hvor 8Rg and Rg together with the intermediate carbon atom represent an alkylidene group having 3 to 5 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidene moiety, R ^ represents an optionally substituted with one or two methyl groups, piperidino group, R₂ represents a hydrogen, the fluorine or chlorine atom, the methyl or methoxy group, and W represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, and among these, in particular those compounds in which A represents a group of the formula V c 35 'CH - or - C -, where 8

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-betegner en n-propylgruppe eller en alkylgruppe med 4 eller 5 carbonatomer, og og Rg sammen med det mellemliggende carbonatomer betegner en alkylidengrup-pe med 3 til 5 carbonatomer eller en phenylalkyliden-5 gruppe med 1 til 3 carbonatomer i alkylidendelen, deres optisk aktive antipoder og deres fysiologisk acceptable salte med uorganiske eller organiske syrer eller baser.- represents an n-propyl group or an alkyl group of 4 or 5 carbon atoms, and and Rg together with the intermediate carbon atoms represents an alkylidene group of 3 to 5 carbon atoms or a phenylalkylidene group of 1 to 3 carbon atoms in the alkylidene moiety, their optically active antibodies and their physiologically acceptable salts with inorganic or organic acids or bases.

10 Ifølge opfindelsen opnås de hidtil ukendte for bindelser ved de i krav 1's kendetegnende del definerede fremgangsmåder.According to the invention, the novel compounds are obtained by the methods defined in claim 1.

For omsætningen a) gælder bl.a. følgende: 15 Som reaktionsdygtige derivater af en forbindelse med den almene formel III kommer f.eks. dennes estere såsom methyl-, ethyl- eller benzylesteren, dens thio-estere såsom methylthio- eller ethylthioesteren, dens halogenider såsom syrechloridet, dens anhydrider eller 20 imidazolider i betragtning.The turnover (a) applies, inter alia, to: The following: As reactive derivatives of a compound of general formula III, e.g. its esters such as the methyl, ethyl or benzyl ester, its thioesters such as the methylthio or ethylthioester, its halides such as the acid chloride, its anhydrides or imidazolides in consideration.

Omsætningen udføres hensigtsmæssigt i et opløsningsmiddel såsom methylenchlorid, chloroform, tetra-chlorkulstof, ether, tetrahydrofuran, dioxan, benzen,The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, tetrachloro carbon, ether, tetrahydrofuran, dioxane, benzene,

25 toluen, acetonitril eller dimethylformamid, eventuelt i nærværelse af et middel, der aktiverer syren,eller et vandoptagende middel, f.eks. i nærværelse af chlor-myresyreethylester, thionylchlorid, phosphortrichlorid, phosphorpentoxid, Ν,Ν'-dicyclohexylcarbodiimid, N,N*-30 dicyclohexylcarbodiimid/N-hydroxy-succinimid, N,N*-carbonyldiimidazol eller N^'-thionyldiimidazol eller triphenylphosphin/tetrachlorkulstof,eller et aminogrup-pen aktiverende middel, f.eks. phosphortrichlorid, og eventuelt i nærværelse af en uorganisk base såsom 35 natriumcarbonat eller en tertiær organisk base såsom triethylamin eller pyridin, der samtidig kan tjene som opløsningsmiddel, ved temperaturer mellem -25°C og 250°C, dog fortrinsvis ved temperaturer mellem -10°CToluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent, or a water-absorbing agent, e.g. in the presence of chloro-formic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, N, N * -30 dicyclohexylcarbodiimide / N-hydroxy-succinimide, N, N , or an amino group activating agent, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as a solvent, at temperatures between -25 ° C and 250 ° C, but preferably at temperatures between -10 ° C

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9 og det anvendte middels kogetemperatur. Omsætningen kan også udføres uden opløsningsmiddel, desuden kan under omsætningen dannet vand fraskilles ved azeotrop destillation, f.eks, ved opvarmning med toluen i vand-5 fraskiller, eller ved tilsætning af et tørringsmiddel såsom magnesiumsulfat eller ved hjælp af molekularsi.9 and the boiling temperature of the medium used. The reaction can also be carried out without solvent, in addition, during the reaction, water formed can be separated by azeotropic distillation, for example, by heating with toluene in water separator, or by adding a desiccant such as magnesium sulfate or by molecular sieving.

Den eventuelt nødvendige påfølgende fraspaltning af en beskyttelsesgruppe udføres fortrinsvis hydroly-10 tisk, hensigtsmæssigt enten i nærværelse af en syre såsom saltsyre, svovlsyre, phosphorsyre eller trichlor-eddikesyre, eller i nærværelse af en base såsom natriumhydroxid eller kaliumhydroxid i et egnet opløsningsmiddel såsom vand, methanol, ethanol, ethanol/vand, 15 vand/isopropanol eller vand/dioxan ved temperaturer mellem -10°C og 120°C, f.eks. ved temperaturer mellem stuetemperatur og reaktionsblandingens kogetemperatur.Preferably, the subsequent decomposition of a protecting group is preferably carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent. methanol, ethanol, ethanol / water, water / isopropanol or water / dioxane at temperatures between -10 ° C and 120 ° C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.

En som beskyttelsesgruppe anvendt tert. butyl-gruppe kan også fraspaltes termisk eventuelt i et 20 indifferent opløsningsmiddel såsom methylenchlorid, chloroform, benzen, toluen, tetrahydrofuran eller dioxan og fortrinsvis i nærværelse af en katalytisk mængde af en syre såsom p-toluensulfonsyre, svovlsyre, phosphorsyre eller polyphosphorsyre.One used as protective group tert. butyl group may also be thermally decomposed optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

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Desuden kan en som beskyttelsesgruppe anvendt benzylgruppe også fjernes hydrogenolytisk i nærværelse af en hydrogeneringskatalysator såsom palladium/carbon i et egnet opløsningsmiddel såsom methanol, ethanol, 30 ethanol/vand, iseddikesyre, eddikesyreethylester, dioxan eller dimethylformamid.In addition, a benzyl group used as a protecting group may also be removed hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide.

For omsætningen b) gælder bl.a. følgende:The turnover (b) applies, inter alia, to: following:

Som hydrolyserbare grupper kommer f.eks. funk-35 tionelle derivater af carboxy-, carboxymethyl-, 2-carb-oxyethyl- eller 2-carboxyethenylgruppen såsom deres usubstituerede eller substituerede amider, deres nitri-ler, estere, thiolestere, orthoestere, iminoethere, amidiner eller anhydrider, en malonester-(1)-yl-gruppe, tetrazolylgruppen, en eventuelt substitueret 1,3-oxazol- 2-yl- eller 1,3-oxazolin-2-yl-gruppe/ ogAs hydrolyzable groups, e.g. functional derivatives of the carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group such as their unsubstituted or substituted amides, their nitriles, esters, thiol esters, orthoesters, imino ethers, amidines or anhydrides, a malone ester ( 1) -yl group, the tetrazolyl group, an optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group / and

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10 5 som termolytisk fraspaltelige grupper eksempelvis estere med tertiære alkoholer, f.eks. tert. butyleste-ren, og som hydrogenolytisk fraspaltelige grupper, f.eks. este-10 re med aralkanoler, f.eks. benzylesteren, i betragt, ning.As thermolytically leaving groups, for example esters with tertiary alcohols, e.g. tert. butyl ester, and as hydrogenolytically leaving groups, e.g. esters with aralkanols, e.g. the benzyl ester, considered.

Hydrolysen udføres hensigtsmæssigt enten i nærværelse af en syre såsom saltsyre, svovlsyre, phosphor-15 syre eller trichloreddikesyre eller i nærværelse af en base såsom natriumhydroxid eller kaliumhydroxid i et egnet opløsningsmiddel såsom vand, vand/methanol, ethanol, vand/ethanol, vand/isopropanol eller vand/dio-xan ved temperaturer mellem -10°C og 120°C, f.eks. ved 20 temperaturer mellem stuetemperatur og reaktionsblandingens kogetemperatur.The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol. or water / dioxane at temperatures between -10 ° C and 120 ° C, e.g. at 20 temperatures between room temperature and the boiling temperature of the reaction mixture.

Såfremt B i en forbindelse med den almene formel IV betegner en cyano- eller aminocarbonylgruppe, så kan 25 disse grupper også overføres i carboxygruppen med et nitrit, f.eks. natriumnitrit, i nærværelse af en syre såsom svovlsyre, hvorved denne hensigtsmæssigt samtidig tjener som opløsningsmiddel, ved temperaturer mellem 0 og 50°C.If, in a compound of general formula IV, B represents a cyano or aminocarbonyl group, then these groups can also be transferred into the carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulfuric acid, whereby it conveniently simultaneously serves as a solvent, at temperatures between 0 and 50 ° C.

30 Såfremt B i en forbindelse med den almene formel IV f.eks. betegner en tert. butyloxycarbonylgruppe, så kan tert. butylgruppen også fraspaltes termisk eventuelt i et indifferent opløsningsmiddel såsom 35 methylenchlorid, chloroform, benzen, toluen, tetra-hydrofuran eller dioxan og fortrinsvis i nærværelse af en katalytisk mængde af en syre såsom p-toluensul-fonsyre, svovlsyre, phosphorsyre eller polyphosphorsyre, 11If B in a compound of the general formula IV e.g. denotes a pie. butyloxycarbonyl group, so can tert. the butyl group is also optionally thermally decomposed in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, 11

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fortrinsvis ved det anvendte opløsningsmiddels kogetemperatur, f.eks. ved temperaturer mellem 40°C og 100°C.preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 ° C and 100 ° C.

5 Såfremt B i en forbindelse med den almene formel IV f.eks. betegner benzyloxycarbonylgruppen, så kan benzylgruppen også fraspaltes hydrogenolytisk i nærværelse af en hydrogeneringskatalysator såsom palla-dium/carbon i et egnet opløsningsmiddel såsom methanol, 10 ethanol, ethanol/vand, iseddikesyre, eddikesyreethyl-ester, dioxan eller dimethylformamid, fortrinsvis ved temperaturer mellem 0 og 50°C, f.eks. ved stuetemperatur, og et hydrogentryk fra 1 til 5 bar. Ved hydrogeno-lysen kan samtidig andre grupper medreduceres, f.eks.If, in a compound of the general formula IV, e.g. represents the benzyloxycarbonyl group, then the benzyl group may also be hydrogenolytically decomposed in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide, preferably 50 ° C, e.g. at room temperature, and a hydrogen pressure of 1 to 5 bar. At the same time other hydrogen groups can be co-reduced, e.g.

15 en nitrogruppe til aminogruppen, en benzyloxygruppe til hydroxygruppen, en vinylidengruppe til den tilsvarende alkylidengruppe eller en kanelsyregruppe til den tilsvarende phenylpropionsyregruppe,eller de kan erstattes med hydrogenatomer, f.eks. et halogenatom 20 med et hydrogenatom.A nitro group for the amino group, a benzyloxy group for the hydroxy group, a vinylidene group for the corresponding alkylidene group or a cinnamic acid group for the corresponding phenylpropionic acid group, or they can be replaced by hydrogen atoms, e.g. a halogen atom 20 with a hydrogen atom.

Ved fremgangsmåde c) anvendes som hydrogeneringskatalysator for eksempel palladium/carbon eller Raney-nikkel i et egnet opløs-25 ningsmiddel såsom methanol, ethanol, isopropanol, ethanol/vand, iseddikesyre, eddikesyreethylester, dioxan, tetrahydrofuran, dimethylformamid, benzen eller benzen/ethanol ved temperaturer mellem 0 og 100°C, dog fortrinsvis ved temperaturer mellem 20°C og 50°C, 30 og et hydrogentryk fra 1 til 5 bar. Ved anvendelse af en egnet chiral hydrogeneringskatalysator såsom et metalligandkompleks, f.eks. et kompleks af y,p'-di-chlor-bis[1,5-cyclooctadien-rhodium] og (+)- eller (-)-0,0-isopropyliden-2,3-dihydroxy-l,4-bis(diphenylphos-35 phino)-butan (= DIOP), sker hydrogentillejringen enan-tioselektivt. Desuden kan ved den katalytiske hydrogenering andre grupper medreduceres, f.eks. en nitrogruppe til aminogruppen, en benzyloxygruppe til hydroxy-In process c), as the hydrogenation catalyst, for example, palladium / carbon or Raney nickel is used in a suitable solvent such as methanol, ethanol, isopropanol, ethanol / water, glacial acetic acid, acetic acid ethyl ester, dioxane, tetrahydrofuran, dimethylformamide, benzene or benzene / ethanol. temperatures between 0 and 100 ° C, but preferably at temperatures between 20 ° C and 50 ° C, 30 and a hydrogen pressure of 1 to 5 bar. Using a suitable chiral hydrogenation catalyst such as a metal-ligand complex, e.g. a complex of γ, p'-di-chloro-bis [1,5-cyclooctadiene rhodium] and (+) - or (-) - 0,0-isopropylidene-2,3-dihydroxy-1,4-bis ( diphenylphosphino-butane (= DIOP), the hydrogenation occurs enantioselectively. In addition, during the catalytic hydrogenation other groups can be reduced, e.g. a nitro group for the amino group, a benzyloxy group for hydroxy

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12 gruppen eller en kanelsyregruppe til phenylpropionsyre-gruppen, eller de kan erstattes med hydrogenatomer, f. eks. et halogenatom med et hydrogenatom.12 or a cinnamic acid group to the phenylpropionic acid group, or they can be replaced by hydrogen atoms, for example a halogen atom with a hydrogen atom.

Omsætningen d) udføres i nærværelse af en stærk 5 syre, der samtidig kan tjene som opløsningsmiddel, fortrinsvis i koncentreret svovlsyre, ved temperaturer mellem 0°C og 150°C, dog fortrinsvis ved temperaturer mellem 20°C og 100°C.The reaction d) is carried out in the presence of a strong acid, which can simultaneously act as a solvent, preferably in concentrated sulfuric acid, at temperatures between 0 ° C and 150 ° C, but preferably at temperatures between 20 ° C and 100 ° C.

Dehalogeneringen e) udføres fortrinsvis i et op-10 løsningsmiddel såsom methanol, ethanol, eddikesyreester, iseddikesyre eller dimethylformamid ved hjælp af katalytisk aktiveret hydrogen, f.eks. med hydrogen i nærværelse af platin eller palladium/carbon, ved temperaturer mellem 0 og 100°C, dog fortrinsvis ved 15 stuetemperatur, og ved et hydrogentryk på 1 til 5 bar.The dehalogenation e) is preferably carried out in a solvent such as methanol, ethanol, acetic acid ester, glacial acetic acid or dimethylformamide by catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 100 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

Ved dehalogeneringen kan samtidig andre grupper blive medreduceret, f.eks. en benzyloxygruppe til hydroxy-gruppen, en vinylidengruppe til den tilsvarende alky-lidengruppe eller en kanelsyregruppe til den tilsva-20 rende phenylpropionsyregruppe, eller de kan erstattes med hydrogenatomer, f.eks. et halogenatom med et hydrogenatom.At the time of dehalogenation, other groups may also be co-reduced, e.g. a benzyloxy group for the hydroxy group, a vinylidene group for the corresponding alkylidene group or a cinnamic acid group for the corresponding phenylpropionic acid group, or they can be replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom.

Amideringen f) udføres hensigtsmæssigt i et opløsningsmiddel såsom methylenchlorid, chloroform, tetra-25 chlorkulstof, ether, tetrahydrofuran, dioxan, benzen, toluen, acetonitril eller dimethyl formamid, fortrinsvis i nærværelse af et syreaktiverende middel eller et vandudtrækkende middel, f.eks. i nærværelse af chlor-myresyreethylester, thionylchlorid, phosphortrichlorid, 30 phosphorpentoxid, Ν,Ν’-dicyclohexylcarbodiimid, N,N'-dicyclohexylcarbodiimid/N-hydroxysuccinimid, N,N'-car-bonyldiimidazol, Ν,Ν'-thionyldiimidazol eller triphenyl-phosphin/tetrachlorkulstof, eller et middel der aktiverer aminogruppen, f.eks. phosphortrichlorid, og even-35 tuelt i nærværelse af en uorganisk base såsom natrium-carbonat eller en tertiær organisk base såsom triethyl-amin eller pyridin, der samtidig kan tjene som opløsningsmiddel, ved temperaturer mellem -25°C og 250°C,The amidation f) is conveniently carried out in a solvent such as methylene chloride, chloroform, tetrachloro carbon, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethyl formamide, preferably in the presence of an acid activating agent or a water extractant, e.g. in the presence of chloro-formic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimide, or phosphine / tetrachlorocarbon, or an agent that activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as a solvent, at temperatures between -25 ° C and 250 ° C,

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13 dog fortrinsvis ved temperaturer mellem -10°C og det anvendte opløsningsmiddels kogetemperatur.However, preferably at temperatures between -10 ° C and the boiling temperature of the solvent used.

5 105 10

Ved fremgangsmådevariant g) kommer som oxiderbar gruppe for eksempel formylgruppen og dens acetaler, hydroxymethylgruppen og dens ethere, en usubstitueret eller substitueret 15 acylgruppe såsom acetyl-, chloracetyl-, propionyl-, malonsyre-(1)-yl-gruppen eller en malonester -(1)-yl-gruppe i betragtning.In process variant g), as the oxidizable group, for example, the formyl group and its acetals, the hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group such as the acetyl, chloroacetyl, propionyl, malonic acid (1) -yl group or a malone ester - ( 1) -yl group considered.

Omsætningen udføres med et oxidationsmiddel 20 i et egnet opløsningsmiddel såsom vand, iseddikesyre, methylenchlorid, dioxan eller glycoldimethylether ved temperaturer mellem 0 og 100°C, dog hensigtsmæssigt ved temperaturer mellem 20°C og 50°C. Omsætningen udføres dog fortrinsvis med sølvoxid/natronlud, mangan-25 dioxid/acetone eller methylenchlorid, hydrogenperoxid/ natronlud, brom eller chlor/natron- eller kalilud, chromtrioxid/pyridin eller pyridiniumchlorchromat.The reaction is carried out with an oxidizing agent 20 in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether at temperatures between 0 and 100 ° C, however conveniently at temperatures between 20 ° C and 50 ° C. However, the reaction is preferably carried out with silver oxide / sodium hydroxide, manganese dioxide / acetone or methylene chloride, hydrogen peroxide / sodium hydroxide, bromine or chlorine / sodium or potassium liquor, chromium trioxide / pyridine or pyridinium chlorochromate.

Ved fremgangsmåde h) kommer som reaktionsdygtige 30 derivater af en forbindelse med den almene formel XII f.eks. dens halogenider, såsom syrechloridet, dens an-hydrider eller imidazolider i betragtning.In process h), as reactive 30 derivatives of a compound of general formula XII, e.g. its halides, such as the acid chloride, its anhydrides or imidazolides under consideration.

Omsætningen udføres hensigtsmæssigt i den tilsvarende alkohol som opløsningsmddel eller i et egnet 35 opløsningsmiddel såsom methylenchlorid, chloroform, ether, tetrahydrofuran, dioxan, benzen eller toluen, eventuelt i nærværelse af et middel, der aktiverer sy-The reaction is conveniently carried out in the corresponding alcohol as solvent or in a suitable solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, dioxane, benzene or toluene, optionally in the presence of an agent which activates the acid.

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. J4 reseller et vandudtrækkende middel, f.eks. i nærværelse af chlorbrinte, svovlsyre, chlormyresyreethylester, thionylchlorid, tetrachlorkulstof/triphenylphosphin, carbonyldiimidazol eller N^'-dicyclohexylcarbodiimid 5 eller dens isourinstofethere, eventuelt i nærværelse af et reaktionsfremmende middel såsom kobberchlorid, og eventuelt i nærværelse af en uorganisk base såsom natriumcarbonat eller en tertiær organisk base såsom triethylamin eller pyridin, eller ved omestring 10 f.eks. med en tilsvarende kulsyrediester, ved temperaturer mellem -20°C og 100°C, dog fortrinsvis ved temperaturer mellem -10°C og det anvendte opløsningsmiddels kogetemperatur.. J4 resells a water extractant, e.g. in the presence of hydrochloric acid, sulfuric acid, hydrochloric acid ethyl ester, thionyl chloride, tetrachlorocarbon / triphenylphosphine, carbonyldiimidazole or N organic base such as triethylamine or pyridine, or by transesterification 10 e.g. with a corresponding carbonic acid diester, at temperatures between -20 ° C and 100 ° C, but preferably at temperatures between -10 ° C and the boiling temperature of the solvent used.

15 Alkoholysen ved fremgangsmåde i) udføres hensigts mæssigt i en tilsvarende alkohol som opløsningsmiddel, såsom methanol, ethanol eller propanol, fortrinsvis i nærværelse af en syre såsom chlorbrinte eller svovlsyre ved temperaturer mellem 20°C og det anvendte opløsnings-20 middels kogetemperatur, fortrinsvis ved temperaturer mellem 50 og 100°C.The alcoholysis of process i) is conveniently carried out in a corresponding alcohol as solvent, such as methanol, ethanol or propanol, preferably in the presence of an acid such as hydrochloric or sulfuric acid at temperatures between 20 ° C and the boiling temperature of the solvent used, preferably at temperatures between 50 and 100 ° C.

Såfremt man ifølge opfindelsen opnår en forbindelse med den almene formel I, hvori W be-25 tegner en carboxy- eller alkoxycarbonylgruppe, så kan denne ved reduktion overføres i en tilsvarende forbindelse med den almene formel I, hvori W betegner en formyl- eller hydroxymethylgruppe, og/eller en forbindelse med den almene formel I, hvori W be-30 tegner carboxygruppen, så kan denne ved overføring i 35 15If, according to the invention, a compound of the general formula I is obtained, wherein W represents a carboxy or alkoxycarbonyl group, then it can be reduced by reduction into a corresponding compound of the general formula I wherein W represents a formyl or hydroxymethyl group. and / or a compound of the general formula I, wherein W represents the carboxy group, then it may, by transfer in

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et sulfonsyrehydrazid og efterfølgende disproportionering overføres i en tilsvarende forbindelse med den almene formel I, hvori W betegner formylgruppen, og/eller 5 en forbindelse med den almene formel I, hvori W betegner en formylgruppe, så kan denne ved kondensation og eventuelt efterfølgende hydrolyse og/eller decarb-oxylering overføres i en tilsvarende forbindelse med den almene formel I, hvori W betegner en 2-alkoxycarbo-10 nyl-ethenyl- eller 2-carboxy-ethenylgruppe, og/eller en forbindelse med den almene formel I, hvori W betegner en 2-carboxy-ethenyl eller 2-alkoxycarbonyl-ethenylgruppe, så kan denne ved katalytisk hydrogenering overføres i en tilsvarende forbindelse med den 15 almene formel I, hvori W betegner en 2-carboxy-ethyl-eller 2-alkoxycarbonyl-ethylgruppef og/eller en forbindelse med den almene formel I, hvori W betegner en alkoxycarbonylgruppe, der fra β-carbonatomet er substitueret med en hydroxygruppe, så kan denne ved 20 acylering med en pyridincarboxylsyre overføres i et tilsvarende (pyridincarbonyloxyalkoxy)-carbonylforbin-delse med den almene formel I, og/eller en forbindelse med den almene formel I, hvori W betegner en hydroxymethylgruppe, så kan denne, efter 25 overføring i en tilsvarende halogenmethylforbindelse, ved omsætning med en malonsyrediester overføres i en tilsvarende forbindelse med den almene formel I, hvori W betegner en med to alkoxycarbonylgrupper substitueret ethylgruppe, og/eller 30 en forbindelse med den almene formel I, hvori W betegner en med to alkoxycarbonylgrupper substitueret ethylgruppe, så kan denne ved hydrolyse overføres i en tilsvarende forbindelse med den almene formel I, hvori W betegner en med to carboxygrupper substitueret 35 ethylgruppe, og/eller en forbindelse med den almene formel I, hvori W betegner en med to alkoxycarbonylgrupper substitueret ethylgruppe, så kan denne ved hydrolyse og decarboxy-a sulfonic acid hydrazide and subsequent disproportionation are transferred in a corresponding compound of the general formula I wherein W represents the formyl group and / or a compound of the general formula I wherein W represents a formyl group, then it may be condensed and, if necessary, by hydrolysis and / or decarboxylation is carried over in a corresponding compound of general formula I wherein W represents a 2-alkoxycarbonyl-ethenyl or 2-carboxyethhenyl group, and / or a compound of general formula I wherein W represents a 2-carboxy-ethenyl or 2-alkoxycarbonyl-ethenyl group, then it can be transferred by catalytic hydrogenation into a corresponding compound of the general formula I wherein W represents a 2-carboxy-ethyl or 2-alkoxycarbonyl-ethyl group and / or a compound of general formula I wherein W represents an alkoxycarbonyl group substituted from the β-carbon atom by a hydroxy group, then it may be acylated with a pyridinecarboxylic acid by acylation is converted into a corresponding (pyridinecarbonyloxyalkoxy) carbonyl compound of general formula I, and / or a compound of general formula I wherein W represents a hydroxymethyl group, after transferring it to a corresponding halomethyl compound, it can be reacted with a malonic acid diester is transferred in a corresponding compound of general formula I wherein W represents one ethyl group substituted with two alkoxycarbonyl groups and / or a compound of general formula I wherein W represents one ethyl group substituted with two alkoxycarbonyl groups, then it may be transferred by hydrolysis. in a corresponding compound of the general formula I wherein W represents a ethyl group substituted with two carboxy groups and / or a compound of the general formula I wherein W represents a ethyl group substituted with two alkoxycarbonyl groups, then it may be hydrolysis and decarboxylic acid.

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16 lering overføres i en tilsvarende forbindelse med den almene formel X, hvori W betegner en 2-carboxy-ethyl-gruppe, og/eller en forbindelse med den almene formel I, hvori R2 beteg-5 ner nitrogruppe, så kan denne ved reduktion overføres i en tilsvarende forbindelse med den almene formel I, hvori R2 betegner en aminogruppe, og/eller en forbindelse med den almene formel I, hvori R2 betegner en aminogruppe, så kan denne over et tilsvaren-10 de diazoniumsalt overføres i en tilsvarende forbindelse med den almene formel I, hvori R2 betegner et hydrogeneller halogenatom, en hydroxy-, alkoxy- eller alkyl-sulfenylgruppe, og/eller en forbindelse med den almene formel I, hvori R2 be-15 tegner en hydroxygruppe, så kan denne ved alkylering overføres i en tilsvarende forbindelse med den almene formel I, hvori R2 betegner en alkoxygruppe, og/eller en forbindelse med den almene formel I, hvori R2 betegner en benzyloxygruppe og/eller R4 en med en ben-20 zyloxygruppe substitueret arylgruppe, så kanefenne ved debenzylering overføres i en tilsvarende forbindelse med den almene formel I, hvori R2 betegner hydroxy-gruppen, og/eller R^ betegner en med en hydroxygruppe substitueret arylgruppe, og/eller 25 en forbindelse med den almene formel I, hvori R^ betegner en aminocarbonylgruppe, så kan denne dehydra-tisering overføres i en tilsvarende forbindelse med den almene formel I, hvori R^ betegner en cyanogruppe.16 is transferred into a corresponding compound of the general formula X wherein W represents a 2-carboxyethyl group, and / or a compound of the general formula I wherein R 2 represents nitro group and then may be reduced by reduction. in a corresponding compound of the general formula I wherein R 2 represents an amino group and / or a compound of the general formula I wherein R 2 represents an amino group, then it may be transferred over a corresponding diazonium salt to a corresponding compound with the general formula I, wherein R 2 represents a hydrogen or halogen atom, a hydroxy, alkoxy or alkylsulphenyl group, and / or a compound of general formula I wherein R 2 represents a hydroxy group, then it can be converted by alkylation into a hydroxy group. corresponding compound of the general formula I wherein R 2 represents an alkoxy group and / or a compound of the general formula I wherein R 2 represents a benzyloxy group and / or R 4 a aryl group substituted with a benzyloxy group, so the kanbenes by debenzylation are transferred into a corresponding compound of the general formula I wherein R 2 represents the hydroxy group and / or R 2 represents a substituted aryl group with a hydroxy group and / or a compound of the general formula I wherein R an aminocarbonyl group, then this dehydration may be carried over in a corresponding compound of general formula I wherein R 1 represents a cyano group.

Den efterfølgende reduktion udføres fortrinsvis 30 med et metalhydrid, f.eks. et komplekst metalhydrid såsom lithiumaluminiumhydrid i et egnet opløsningsmiddel såsom diethylether, tetrahydrofuran eller dioxan ved temperaturer mellem 0 og 100°C, dog fortrinsvis ved temperaturer mellem 20°C og 60°C.The subsequent reduction is preferably carried out with a metal hydride, e.g. a complex metal hydride such as lithium aluminum hydride in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 ° C and 60 ° C.

35 Den efterfølgende disproportionering af et sul- fonsyrehydrazid som man opnår ved omsætning af en tilsvarende hydrazin med et tilsvarende reaktionsdygtigt carboxylsyrederivat, udføres i nærværelse af enThe subsequent disproportionation of a sulfonic acid hydrazide obtained by reacting a corresponding hydrazine with a corresponding reactive carboxylic acid derivative is carried out in the presence of a

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17 base såsom natriumcarbonat i et opløsningsmiddel såsom ethylenglycol ved temperaturer mellem 100°C og 200°C/ dog fortrinsvis ved 160-170°C.17 base such as sodium carbonate in a solvent such as ethylene glycol at temperatures between 100 ° C and 200 ° C / but preferably at 160-170 ° C.

Den efterfølgende kondensation af en formylfor-5 bindelse udføres hensigtsmæssigt i et opløsningsmiddel såsom pyridin eller tetrahydrofuran med malonsyre, med en malonsyreester, med en dialkylphosphonoeddike-syreester eller en alkoxycarbonylmethylen-triphenyl-phosphoran eventuelt i nærværelse af en base som kon-10 densationsmiddel, f.eks. i nærværelse af piperidin, kalium-tert.butylat eller natriumhydrid ved temperaturer mellem 0 og 100°Cj ved efterfølgende syrning, f.eks. med saltsyre eller svovlsyre, eller ved efterfølgende alkalisk hydrolyse opnår man den ønskede for-15 bindelse.The subsequent condensation of a formyl compound is conveniently carried out in a solvent such as pyridine or tetrahydrofuran with malonic acid, with a malonic acid ester, with a dialkylphosphonoacetic acid ester or an alkoxycarbonylmethylene triphenylphosphorane optionally in the presence of a base such as condensation. .g. in the presence of piperidine, potassium tert.butylate or sodium hydride at temperatures between 0 and 100 ° C by subsequent acidification, e.g. with hydrochloric acid or sulfuric acid, or by subsequent alkaline hydrolysis, the desired compound is obtained.

Den efterfølgende katalytiske hydrogenering udføres hensigtsmæssigt i et opløsningsmiddel såsom methanol, ethanol, eddikesyreethylester, iseddikesyre eller dimethylformamid med hydrogen i nærværelse af 20 en hydrogeneringskatslysator såsom platin eller palla-dium/carbon ved temperaturer mellem 0 og 75°C, dog fortrinsvis ved stuetemperatur, og ved et hydrogentryk på 1 til 5 bar.The subsequent catalytic hydrogenation is conveniently carried out in a solvent such as methanol, ethanol, acetic acid ethyl ester, glacial acetic acid or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium / carbon at temperatures between 0 and 75 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

Den efterfølgende Q-acylering udføres hensigts-25 mæssigt i et opløsningsmiddel såsom methylenchlorid, chloroform, tetrachlorkulstof, ether, tetrahydrofuran, dioxan, benzen, toluen, acetonitril eller dimethylformamid, fortrinsvis med et reaktivt derivat af syren, eksempelvis et halogenid såsom syrechloridet, et an-30 hydrid eller imidazolid og eventuelt i nærværelse af en uorganisk base såsom natriumcarbonat eller eh tertiær organisk base såsom triethylamin eller pyridin, der samtidig kan tjene som opløsningsmiddel, ved temperaturer mellem -25°C og 250°C, dog fortrinsvis ved 35 temperaturer mellem -10°C og det anvendte opløsningsmiddels kogetemperatur.The subsequent Q acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, tetrachlorocarbon, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, preferably with a reactive derivative of the acid, for example a halide such as the acid chloride -30 hydride or imidazolid and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as a solvent, at temperatures between -25 ° C and 250 ° C, but preferably at 35 temperatures between -10 ° C and the boiling temperature of the solvent used.

Den efterfølgende overføring af en hydroxymethyl-gruppe i en halogenmethylgruppe udføres med et halo-The subsequent transfer of a hydroxymethyl group into a halo methyl group is carried out with a halo-

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18 generingsmiddel såsom thionylchlorid, phosphortri-chlorid, phosphortribromid eller phosphorpentachlorid i et opløsningsmiddel såsom methylenchlorid, tetra-chlorkulstof, benzen eller nitrobenzen; herefter om-5 sættes med en malonsyreester, f.eks. med et alkalimetalsalt af malonsyrediethylester, ved temperaturer mellem 0 og 100°C, dog fortrinsvis ved temperaturer mellem 50°C og 80°C.18 generating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, tetrachloro carbon, benzene or nitrobenzene; is then reacted with a malonic ester, e.g. with an alkali metal salt of malonic acid diethyl ester, at temperatures between 0 and 100 ° C, but preferably at temperatures between 50 ° C and 80 ° C.

Den efterfølgende hydrolyse eller hydrolyse og de-10 carboxylering udføres hensigtsmæssigt i nærværelse af en syre såsom saltsyre, svovlsyre, phosphorsyre, polyphosphorsyre eller trifluoreddikesyre i et egnet opløsningsmiddel såsom vand, ethanol, vand/ethanol, vand/isopropanol eller vand/dioxan ved forhøjede 15 temperaturer, f.eks. ved reaktionsblandingens kogetemperatur .The subsequent hydrolysis or hydrolysis and de-carboxylation is conveniently carried out in the presence of an acid such as hydrochloric, sulfuric, phosphoric, polyphosphoric or trifluoroacetic acid in a suitable solvent such as water, ethanol, water / ethanol, water / isopropanol or water / dioxane. temperatures, e.g. at the boiling temperature of the reaction mixture.

Den efterfølgende reduktion af nitroforbindelsen udføres fortrinsvis i et opløsningsmiddel såsom vand, vand/ethanol, methanol, iseddikesyre, eddikesyreethyl-20 ester eller dimethylformamid hensigtsmæssigt med hydrogen i nærværelse af eft hydrogeneringskatalysator såsom Raney-nikke, platin eller palladium/carbon, med metaller såsom jern, tin eller zink i nærværelse af en syre, med salte såsom jern(II)sulfat, tin(II)chlo-25 rid eller natriumdithionit eller med hydrazin i nærværelse af Raney-nikkel ved temperaturer mellem 0 og 50°C, dog fortrinsvis ved stuetemperatur.The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, acetic acid ethyl ester or dimethylformamide suitably with hydrogen in the presence of an hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon, with metals such as iron. , tin or zinc in the presence of an acid, with salts such as iron (II) sulfate, tin (II) chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50 ° C, but preferably at room temperature.

Den efterfølgende omsætning af et diazoniumsalt, f.eks. fluorboratet, fluoridet i 40%'ig flussyre, 30 hydrosulfatet i svovlsyre eller hydrochloridet, om nødvendigt i nærværelse af kobber eller et tilsvarende kobber(I)salt såsom kobber(I)chlorid/saltsyre eller kobber(I)bromid/brombrintesyre, udføres ved let forhøjede temperaturer, f.eks. ved temperaturer mellem 35 15°C og 100°C; den efterfølgende omsætning med hypo- phosphorsyrling udføres fortrinsvis ved -5°C til 0°C.The subsequent reaction of a diazonium salt, e.g. the fluoroborate, the fluoride in 40% hydrofluoric acid, the hydrosulfate in sulfuric acid or the hydrochloride, if necessary in the presence of copper or a corresponding copper (I) salt such as copper (I) chloride / hydrochloric acid or copper (I) bromide / hydrochloric acid. slightly elevated temperatures, e.g. at temperatures between 35 ° C and 100 ° C; the subsequent reaction with hypophosphorous acid is preferably carried out at -5 ° C to 0 ° C.

Det nødvendige diazoniumsalt fremstilles hensigtsmæssigt i et egnet opløsningsmiddel, f.eks. i vand/salt-The required diazonium salt is conveniently prepared in a suitable solvent, e.g. in water / salt

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19 syre, methanol/saltsyre, ethanol/saltsyre eller dioxan/ saltsyre ved diazotering af en tilsvarende aminofor-bindelse med et nitrit, f.eks. natriumnitrit eller en ester af salpetersyrling ved lavere temperaturer, f.eks.19 acid, methanol / hydrochloric acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid by diazotizing a corresponding amino compound with a nitrite, e.g. sodium nitrite or an ester of nitric acid at lower temperatures, e.g.

5 ved temperaturer mellem -10°C og 5°C.5 at temperatures between -10 ° C and 5 ° C.

Den efterfølgende O-alkylering udføres hensigtsmæssigt med et tilsvarende halogenid, en tilsvarende sulfonsyreester eller diazoalkan, f.eks. med methyl-iodid, dimethylsulfat, ethylbromid, p-toluensulfonsyre-10 ethylester, methansulfonsyre-isopropylester eller diazomethan, eventuelt i nærværelse af en base såsom natriumhydrid, kaliumhydroxid eller kalium-tert.butylat og fortrinsvis i et opløsningsmiddel såsom diethyl-ether, tetrahydrofuran, dioxan, methanol· ethanol, py-15 ridin eller dimethylformamid ved temperaturer mellem 0 og 75°C, fortrinsvis ved stuetemperatur.The subsequent O-alkylation is conveniently carried out with a corresponding halide, a corresponding sulfonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, p-toluenesulfonic acid ethyl ester, methanesulfonic acid isopropyl ester or diazomethane, optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert-butylate and preferably in a solvent such as diethyl ether, dioxane, methanol · ethanol, pyridine or dimethylformamide at temperatures between 0 and 75 ° C, preferably at room temperature.

Den efterfølgende debenzylering udføres hensigtsmæssigt i et opløsningsmiddel såsom methanol, ethanol, eddikeester, iseddikesyre eller dimethylformamid ved 20 hjælp af katalytisk aktiveret hydrogen, f.eks. med hydrogen i nærværelse af platin eller palladium/carbon, ved temperaturer mellem 0 og 75°C, dog fortrinsvis ved stuetemperatur, og ved et hydrogentryk på 1 til 5 bar.The subsequent debenzylation is conveniently carried out in a solvent such as methanol, ethanol, acetic ester, glacial acetic acid or dimethylformamide by catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 75 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

Den efterfølgende dehydratisering udføres med 25 et vandudtrækkende middel såsom phosphorpentoxid, svovlsyre eller p-toluensulfonsyrechlorid eventuelt 1 et opløsningsmiddel såsom methylenchlorid eller pyridin ved temperaturer mellem 0 og 100°C, fortrinsvis ved temperaturer mellem 20° og 80°C.The subsequent dehydration is carried out with a water extracting agent such as phosphorus pentoxide, sulfuric acid or p-toluenesulfonic acid chloride optionally in a solvent such as methylene chloride or pyridine at temperatures between 0 and 100 ° C, preferably at temperatures between 20 ° and 80 ° C.

30 De opnåede forbindelser med den almene formel IThe compounds of general formula I obtained

kan endvidere, såfremt de har en chiralt centrum, opdeles i deres enantiomere ved sædvanlige metoder. Denne opdeling sker ved søjlechromatografi til en chiral fase.can also, if they have a chiral center, be divided into their enantiomers by conventional methods. This division occurs by column chromatography to a chiral phase.

35 De opnåede forbindelser med den almene formel IThe compounds of the general formula I obtained

kan endvidere overføres i deres additionssalte, især i deres fysiologisk acceptable salte med uorganiske eller organiske syrer eller også baser. Som syrer kom- 20can also be transferred into their addition salts, especially in their physiologically acceptable salts with inorganic or organic acids or also bases. As acids come 20

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mer herved f.eks. saltsyre, brombrintesyre, svovlsyre, phosphorsyre, mælkesyre, citronsyre, vinsyre, ravsyre, maleinsyre eller fumarsyre i betragtning og som baser natriumhydroxid, kaliumhydroxid, cyclohexylamin, etha-5 nolamin, diethanolamin, triethanolamin eller ethylen-diamin.more thereby e.g. hydrochloric, hydrochloric, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids, and as bases sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylene diamine.

De som udgangsstoffer anvendte forbindelser med de almene formel II til XIV kan fås ved fremgangsmåder kendt fra litteraturen,eller forbindelserne er kendt 10 fra litteraturen.The compounds used as starting materials of general formulas II to XIV can be obtained by methods known from the literature, or the compounds are known from the literature.

Således kan man f.eks. opnå en forbindelse med den almene formel II, hvori A betegner en gruppe med formlen R5 R6 15Thus, e.g. obtain a compound of general formula II wherein A represents a group of formula R5 R6 15

IIII

- C - eller dens tautomere ketimin ved omsætning af en tilsvarende nitril med en tilsvarende Grignard- eller lithium-forbindelse og efterfølgende hydrolyse eller 20 ved omsætning af en tilsvarende keton med ammoniak i nærværelse af titantetrachlorid. Til den yderligere omsætning med en forbindelse med den almene formel III eller dennes reaktionsdygtige derivater, især dens syrechlorid, kan man også anvende det metalorganiske 25 ketiminkompleks.- C - or its tautomeric ketimine by reaction of a corresponding nitrile with a corresponding Grignard or lithium compound and subsequent hydrolysis, or by reaction of a corresponding ketone with ammonia in the presence of titanium tetrachloride. For the further reaction with a compound of general formula III or its reactive derivatives, especially its acid chloride, the metal-organic ketimine complex can also be used.

En forbindelse med den almene formel II, hvori A betegner en gruppe med formlen *4 - CH - , hvor 3 0 har den tidligere angivne betydning med undtagelse af cyano- og aminocarbonylgruppen, kan man f.eks. opnå ved omsætning af en tilsvarende nitril med en tilsvarende Grignard- eller lithiumforbindelse og eventuelt efterfølgende lithiumaluminiumhydrid-reduktion 35 eller efterfølgende hydrolyse til ketiminen, der derpå reduceres med katalytisk aktiveret hydrogen, med et komplekst metalhydrid eller med nascerende hydrogen; ved hydrolyse eller ved hydrazinolyse af en tilsvarendeFor example, a compound of general formula II wherein A represents a group of formula * 4 - CH - wherein 30 has the aforementioned meaning with the exception of the cyano and aminocarbonyl group, obtain by reacting a corresponding nitrile with a corresponding Grignard or lithium compound and optionally subsequent lithium aluminum hydride reduction or subsequent hydrolysis to the ketimine then reduced with catalytically activated hydrogen, with a complex metal hydride or with nascent hydrogen; by hydrolysis or by hydrazinolysis of a corresponding one

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21 phthalimidoforbindelse, ved omsætning af en tilsvarende keton med ammoniumformiat og efterfølgende hydrolyse eller med et ammoniumsalt i nærværelse af natriumcyano-borhydrid, ved reduktion af en tilsvarende oxim med 5 lithiumaluminiumhydrid eller med katalytisk aktiveret eller nascerende hydrogen, ved reduktion af en tilsvarende N-benzyl- eller N-(1-phenylethyl)-ketimin, f.eks. med katalytisk aktiveret hydrogen eller med et komplekst metalhydrid i ether eller tetrahydrofuran ved tempera-10 turer mellem -78°C og det anvendte opløsningsmiddels kogetemperatur og efterfølgende fraspaltning af benzyl-eller 1-phenylethylgruppen ved hjælp af katalytisk hydrogenering, ved Ritter-reaktion af en tilsvarende alkohol med kaliumcyanid i svovlsyre eller ved Hofmann-, 15 Curtius-, Lossen- eller Schmidt-nedbrydning af en tilsvarende forbindelse.21 phthalimido compound, by reacting a corresponding ketone with ammonium formate and subsequent hydrolysis or with an ammonium salt in the presence of sodium cyanoborohydride, by reducing a corresponding oxime with 5 lithium aluminum hydride or with catalytically activated or nascent hydrogen, by reducing a corresponding N-benzyl - or N- (1-phenylethyl) -ketimine, e.g. with catalytically activated hydrogen or with a complex metal hydride in ether or tetrahydrofuran at temperatures between -78 ° C and the boiling temperature of the solvent used and subsequent decomposition of the benzyl or 1-phenylethyl group by catalytic hydrogenation, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulfuric acid or by Hofmann, Curtius, Lossen or Schmidt decomposition of a corresponding compound.

En forbindelse med den almene formel II, hvori A betegner gruppenA compound of general formula II wherein A represents the group

CNCN

20 - CH - kan fås ved omsætning af et tilsvarende aldehyd med ammoniumcyanid eller ved omsætning af en tilsvarende cyanhydrin med ammoniak.20 - CH - can be obtained by reacting a similar aldehyde with ammonium cyanide or by reacting a similar cyanhydrin with ammonia.

En således opnået amin med den almene formel II 25 med chiralt centrum, hvor A betegner en gruppe med formlen R4 f - CH -, hvor 30 R^ har den tidligere angivne betydning med undtagelse af cyanogruppen, kan opdeles i de enantiomere ved racematspaltning, f.eks. ved hjælp af fraktioneret krystallisation af de diastereomere salte med optisk aktive syrer og efterfølgende spaltning af saltene 35 eller ved søjlechromatografi til en chiral fase eller ved dannelse af diastereomere forbindelser, adskillelse af disse og efterfølgende spaltning.An amine thus obtained of the general formula II 25 having a chiral center, where A represents a group of the formula R4 f - CH - wherein 30 R 1 has the previously mentioned meaning with the exception of the cyano group, can be divided into the enantiomers by racemate decomposition .g. by fractional crystallization of the diastereomeric salts with optically active acids and subsequent cleavage of the salts 35 or by column chromatography to a chiral phase or by formation of diastereomeric compounds, separation of these and subsequent cleavage.

Endvidere kan en optisk aktiv amin med den alme- 22Furthermore, an optically active amine with the general 22 may

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ne formel II også fremstilles ved enantio-selektiv reduktion af en tilsvarende ketimin ved hjælp af komplekse bor- eller aluminiumhydrider, hvori en del af hy-dridhydrogenatomerne er erstattet med optisk aktive 5 alkoholatgrupper, eller ved hjælp af hydrogen i nærværelse af en egnet chiral hydrogeneringskatalysator eller analogt ud fra en tilsvarende N-benzyl- eller N-(l-phenethyl)-ketimin eller ud fra en tilsvarende N-acyl-ketimin eller et enamid og eventuelt efterføl-10 gende fraspaltning af benzyl-, 1-phenethyl- eller acylgruppen.Formula II is also prepared by enantio-selective reduction of a corresponding ketimine by complex boron or aluminum hydrides in which a portion of the hydrogen hydrogen atoms is replaced by optically active alcoholate groups, or by hydrogen in the presence of a suitable chiral hydrogenation catalyst. or analogously from a corresponding N-benzyl or N- (1-phenethyl) -ketimine or from a corresponding N-acyl-ketimine or enamide and optionally subsequent cleavage of the benzyl, 1-phenethyl or acyl group .

Endvidere kan en optisk aktiv amin med den almene formel II også fremstilles ved diastereo-selektiv reduktion af en tilsvarende ved nitrogenatomet chiralt 15 substitueret ketimin eller hydrazon ved hjælp af komplekse eller også ikke-komplekse bor- eller aluminium-hydrider, hvori eventuelt en del af hydridhydrogen-atomerne er erstattet af tilsvarende alkoholat-, phe-nolat- eller også alkylgrupper, eller ved hjælp af 20 hydrogen i nærværelse af en egnet hydrogeneringskatalysator og eventuelt efterfølgende fraspaltning af den chirale hjælpegruppe ved katalytisk hydrogenolyse eller hydrolyse.Furthermore, an optically active amine of general formula II can also be prepared by diastereoselective reduction of a corresponding nitrogen-chirally substituted ketimine or hydrazone by complex or also non-complex boron or aluminum hydrides, optionally part of the hydride hydrogen atoms are replaced by corresponding alcoholate, phenolate or also alkyl groups, or by hydrogen in the presence of a suitable hydrogenation catalyst and optionally subsequent decomposition of the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

Endvidere kan en optisk aktiv amin med den alme-25 ne formel II også fremstilles ved diastereo-selektiv addition af en tilsvarende metalorganisk forbindelse, fortrinsvis en Grignard- eller lithiumforbindelse, til en tilsvarende ved nitrogenatomet chiralt substitueret aldimin, ved efterfølgende hydrolyse og eventuelt 30 efterfølgende fraspaltning af den chirale hjælpegruppe ved katalytisk hydrogenolyse eller hydrolyse.Furthermore, an optically active amine of the general formula II can also be prepared by diastereoselective addition of a corresponding metal-organic compound, preferably a Grignard or lithium compound, to a corresponding nitrogen atom chirally substituted aldimine, by subsequent hydrolysis and optionally subsequent cleavage of the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

De som udgangsstoffer anvendte forbindelser med de almene formler IV, VIII, IX, XI, XII og XIV fås ved omsætning af en tilsvarende amin med en tilsvarende 35 forbindelse med den almene formel III eller dens reaktive derivater og eventuelt efterfølgende hydrolyse.The starting compounds of general formulas IV, VIII, IX, XI, XII and XIV are obtained by reacting a corresponding amine with a corresponding compound of the general formula III or its reactive derivatives and optionally subsequent hydrolysis.

En som udgangsstof anvendt forbindelse med den almene formel V fås fortrinsvis ved acylering af enA compound of the general formula V used as a starting material is preferably obtained by acylating one

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23 tilsvarende ketimin eller dens metalorganiske kompleks med en tilsvarende carboxylsyre eller dens reaktive derivater.23 corresponding to ketimine or its metal-organic complex with a corresponding carboxylic acid or its reactive derivatives.

Som allerede nævnt har de hidtil ukendte forbin-5 delser med den almene formel I værdifulde farmakologiske egenskaber, nemlig en virkning på det intermediære stofskifte, dog især en blodsukkersænkende virkning, delvis også en virkning på hjerte-kredsløbssystemet.As already mentioned, the novel compounds of the general Formula I have valuable pharmacological properties, namely an effect on the intermediate metabolism, but in particular a blood sugar lowering effect, partly also an effect on the cardiovascular system.

10 For eksempel undersøgtes følgende forbindelser med hensyn til blodsukkersænkende virkning og akut toxi-citet: A = (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-amino-15 carbonylmethyl]-benzoesyre, B = (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoesyre-ethylester, 20 C = (E)-4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbony lmethyl] -benzoesyre, D = 4-[(2-methyl-l-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl]-benzoesyre, 25 E = (Z)-4-[(1-(2-piperidino-phenyl)-1-hexen-l-yl)-aminocarbony lmethyl ]-benzoesyre-ethylester, F = (Z)-4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propen-3 0 1-yl)-aminocarbonylmethyl]-benzoesyre, G = (Z)-4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoesyre, 35 H = 4- [ (1- (2-pyrrolidino -phenyl) -1-butyl) -aminocarbonyl-methyl]-benzoesyre, J = (-)-4-[(1-(2-piperidino-phenyl)-1-butyl)-amino- carbonylmethyl]-benzoesyre, 24For example, the following compounds were tested for blood glucose lowering action and acute toxicity: A = (Z) -4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -amino-carbonylmethyl ] -benzoic acid, B = (Z) -4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester, C = (E) -4- [ (1- (2-piperidino-phenyl) -1-buten-1-yl) -amino-carbonylmethyl] -benzoic acid, D = 4 - [(2-methyl-1- (2-piperidino-phenyl) -1-propylene) 1-yl) -aminocarbonylmethyl] -benzoic acid, E = (Z) -4 - [(1- (2-piperidino-phenyl) -1-hexen-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester, F = (Z) -4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propen-30-1-yl) -aminocarbonylmethyl] -benzoic acid, G = (Z) -4 - [(1- (2- (3,3-dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid, H = 4- [(1- (2-pyrrolidino-phenyl) -1-butyl ) -aminocarbonyl-methyl] -benzoic acid, J = (-) - 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid, 24

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K = (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbo-5 nylmethyl]-benzoesyre, L = (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre-ethylester, 10 M = 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre, N = 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonyl-methyl]-benzoesyre, 15 O = 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]-benzoesyre, P = 4-[(2-methoxy-l-(2-piperidino-phenyl)-1-ethyl)- 2 0 aminocarbonylmethyl]-benzoesyre, Q = 4-[(a-Cyano-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoesyre, 25 R = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzylalkohol, S = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-phenyleddikesyre, 30 T = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-kanelsyre, j U = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl- 3 5 methyl]-benzoesyre-(2,3-dihydroxy-propyl)ester, V = 4-[(1-(4-fluor-2-piperidino-phenyl)-1-butyl)-aminocarbony lmethyl)-benzoesyre, W = 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)- aminocarbonylmethyl]-benzoesyre, 25K = (+) - 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid, L = (+) - 4 - [(1- (2-piperidino-phenyl) -benzoic acid) phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester, M = 4 - [(1- (2-hexahydroazepino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid, N = 4 [(1- (2-piperidino-phenyl) -1-hexyl) -aminocarbonyl-methyl] -benzoic acid, O = 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propyl) - aminocarbonylmethyl] benzoic acid, P = 4 - [(2-methoxy-1- (2-piperidino-phenyl) -1-ethyl) -2-aminocarbonylmethyl] -benzoic acid, Q = 4 - [(α-Cyano-2-piperidino -benzyl) -aminocarbonyl-methyl] -benzoic acid, R = 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzyl alcohol, S = 4 - [(1- (2) -piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -phenylacetic acid, T = 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -cinnamic acid, 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid (2,3-dihydroxy-propyl) ester, V = 4 - [(1- (4- fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonymethyl) -benz zoic acid, W = 4 - [(1- (4-methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid,

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5 AA = 4-[(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoesyre, AB = 4-[(a-(3-methyl-phenyl)-2-piperidino-benzyi)-aminocarbonylmethyl] -benzoesyre, 10 AC = 4-[(a-(4-fluor-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoesyre, AD = 4-[(a-(2-fluor-phenyl)-2-piperidino-benzyl)-amino-1 5 carbonylmethy1]-benzoesyre, AE = 4-[(a-(4-chlor-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoesyre, 20 AF = 4-t(a-(3-chlor-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl ]-benzoesyre, AG = 4-[(2-piperidino-a-(2-pyridyl)-benzyl)-aminocarbonylmethyl] -benzoesyre, 25 AH = 4-[(2-piperidino-a-(4-pyridyl)-benzyl)-aminocarbonylmethyl ]-benzoesyre, AJ = 4-[(6-chlor-a-phenyl-2-piperidino-benzyl)-amino-30 carbonylmethyl]-benzoesyre, AK = 4-[(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl] -kanelsyre, 35 AM = 4-[(4-chlor-a-phenyl-2-piperidino-benzyl)-amino carbonylmethyl] -benzoesyre, AN = 4-[(6-methyl-a-phenyl-2-piperidino-benzyl)-amino- carbonylmethyl]-benzoesyre, 26AA = 4 - [(α- (4-methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid, AB = 4 - [(α- (3-methyl-phenyl) -2-piperidino-benzyl) ) -aminocarbonylmethyl] -benzoic acid, AC = 4 - [(α- (4-fluoro-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid, AD = 4 - [(α- (2-fluoro-phenyl) ) -2-piperidino-benzyl) -amino-1-carbonylmethyl] -benzoic acid, AE = 4 - [(α- (4-chlorophenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid, AF = 4 -t (a- (3-chloro-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid, AG = 4 - [(2-piperidino-α- (2-pyridyl) -benzyl) -aminocarbonylmethyl] -benzoic acid AH = 4 - [(2-piperidino-α- (4-pyridyl) -benzyl) -aminocarbonylmethyl] -benzoic acid, AJ = 4 - [(6-chloro-a-phenyl-2-piperidino-benzyl) -amino -30 carbonylmethyl] -benzoic acid, AK = 4 - [(α-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -cinnamic acid, AM = 4 - [(4-chloro-α-phenyl-2-piperidino-benzyl) -amino carbonylmethyl] -benzoic acid, AN = 4 - [(6-methyl-α-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid, 26

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AO = 4-[(4-methyl-a-phenyl-2-piperidino-benzyl)-amino-5 carbonylmethyl]-benzoesyre, AP = 4-[(a-phenyl-2-piperidino-benzyl)-aiiiinocarbonyl-methyl]-benzaldehyd, 10 AQ = 4-[(2-(2-methyl-piperidino)-α-phenyl-benzyl)-amino-carbonylmethyl]-benzoesyre, AR = 4-[(2-(3-methyl-piperidino)-α-phenyl-benzyl)-amino-carbonylmethyl]-benzoesyre og 15 AS = 4-[(3-chlor-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoesyre.AO = 4 - [(4-methyl-α-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid, AP = 4 - [(α-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -benzaldehyde, AQ = 4 - [(2- (2-methyl-piperidino) -α-phenyl-benzyl) -amino-carbonylmethyl] -benzoic acid, AR = 4 - [(2- (3-methyl-piperidino) - α-phenyl-benzyl) -amino-carbonylmethyl] -benzoic acid and AS = 4 - [(3-chloro-α-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid.

1. Blodsukkersænkende virkning.1. Blood glucose lowering effect.

20 Den blodsukkersænkende virkning af de stoffer, der skulle undersøges blev prøvet på hunrotter af egen avl med en vægt på 180-220 g, der havde fastet i 24 timer før forsøgets begyndelse. De stoffer, der skulle undersøges, blev limiddelbart før forsøgets begyndelse 25 suspenderet i 1,5%'ig methylcellulose og indgivet med svælgsonde.The blood glucose lowering effect of the substances to be tested was tested on female breeders of their own breed with a weight of 180-220 g, which had fasted for 24 hours before the start of the experiment. The substances to be tested were suspended immediately before the start of the experiment in 1.5% methyl cellulose and administered with pharyngeal probe.

Blodudtagelsen skete umiddelbart før stofindgivel-sen samt 1, 2, 3 og 4 timer efter, hver gang fra den retroorbitale veneplexus. Af blodet blev hver gang 50 μΐ 30 afproteiniseret med 0,5 ml 0,33 N perchlorsyre og centrifugeret. I den klarede væske bestemtes glucose efter hexokinase-metoden ved hjælp af et analysefoto-meter. Den statistiske vurdering skete efter t-prøven ifølge student med p = 0,05 som signifikansgrænse.The blood sampling occurred immediately before the drug administration and 1, 2, 3 and 4 hours after each time from the retroorbital vein plexus. Each time, 50 μΐ 30 of the blood was deproteinized with 0.5 ml of 0.33 N perchloric acid and centrifuged. In the clarified liquid, glucose was determined by the hexokinase method using an assay photometer. The statistical assessment was done after the t-test according to the student with p = 0.05 as the significance limit.

35 Nedenstående tabel indeholder de fundne værdier i procent i forhold til kontrollen:35 The following table contains the percentages found in relation to the control:

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27 5 mg/kg , 1 mg/kg27 5 mg / kg, 1 mg / kg

Stof 1234 123 4 A -43 -40 -33 -35 B -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 D -36 -32 -27 -25 E -46 -40 -38 -26 -23 -23 -12 -18 P -43 -42 -39 -32 G . -44 -42 -37 -31 H -50 -46 -44 -45 j -44 -37 -42 -42 -38 -32 -34 -29 K -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 rus.Fabric 1234 123 4 A -43 -40 -33 -35 B -44 -39 -26 -35 -39 -19 -26 -30 C -43 -43 -37 -38 D -36 -32 -27 -25 E - 46 -40 -38 -26 -23 -23 -12 -18 P -43 -42 -39 -32 G. -44 -42 -37 -31 H -50 -46 -44 -45 j -44 -37 -42 -42 -38 -32 -34 -29 K -41 -43 -38 -31 L -42 -45 -31 -22 -14 -18 -14 rest.

M -46 -43 -40 -36 -33 -30 -21 n.s.M -46 -43 -40 -36 -33 -30 -21 n.s.

N -42 -42 -37 -33 + + + + O -38 -31 n.s. n.s.N -42 -42 -37 -33 + + + + O -38 -31 n.s. n.s.

P -49 -43 -34 -22 -37 -19 n.s. n.s.P -49 -43 -34 -22 -37 -19 n.s. n.s.

q -28 -13 n.s. n.s.q -28 -13 n.s. n.s.

R -38 -40 -35 -29 -39 -34 -29 -24 S -49 -42 -30 -17 -29 -20 -10 n.s.R -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 U -43 -43 -49 . -45 -39 -35 -29 -24 V -45 -41 -46 . -40 .-37 -23 -30 -18 W -46 -45 -39 -37 -36 -25 -16 n.s.T -48 -46 -42 -40 -42 -42 -40 -32 U -43 -43 -49. -45 -39 -35 -29 -24 V -45 -41 -46. -40.-37 -23 -30 -18 W -46 -45 -39 -37 -36 -25 -16 n.s.

AA -30 -33 -14 n.s. -15 -15 -13 n.s.AA -30 -33 -14 n.s. -15 -15 -13 n.s.

AB -43 -38 -36 -27 -26 - -15 n.s. n.s.AB -43 -38 -36 -27 -26 - -15 n.s. n.s.

AC -36 -37 -36 -33 AD -28 -32 -27 -28 -16 -20 -17 -14 AE -30 -28 -39 -36 -21 -20 -22 n.s.AC -36 -37 -36 -33 AD -28 -32 -27 -28 -16 -20 -17 -14 AE -30 -28 -39 -36 -21 -20 -22 n.s.

.. . 28... 28

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Stof 5 in9/k9 1 mg/kg 1 2 3 4. 1 2 3 4 AF -43 -39 -30 -26 -17 -19 n.s. n.s.Substance 5 in9 / k9 1 mg / kg 1 2 3 4. 1 2 3 4 AF -43 -39 -30 -26 -17 -19 n.s. n.s.

+ + + + 5 AG -49 -50 -36 -31 -18 n.s. n.s. n.s.+ + + + 5 AG -49 -50 -36 -31 -18 n.s. n.s. n.s.

AH -41 -37 -20 n.s. -26 -14 n.s. n.s.AH -41 -37 -20 n.s. -26 -14 n.s. n.s.

AJ -44 -40 -39 -40 -35 -34 -28 -20 AK -48+ -47+‘ -40+ -45+ -32 -19 -10 -17 10 AM -34 -35 -32 -29 -11 -13 n.s. n.s.AJ -44 -40 -39 -40 -35 -34 -28 -20 AK -48+ -47+ '-40+ -45+ -32 -19 -10 -17 10 AM -34 -35 -32 -29 - 11 -13 ns n.s.

AN -39 -35 -27 -26 -27 -24 n.s. n.s.AN -39 -35 -27 -26 -27 -24 n.s. n.s.

AO -37 -34 -32 -31 -21 -17 -15 -11 AP -26 -28 -22 -17 AQ -32 -31 -24 -19 -16 -11 n.s. n.s.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.

15 AR -35 -30 -29 -31 -13 - 9 n.s. n.s.15 AR -35 -30 -29 -31 -13 - 9 n.s. n.s.

AS -45 -44 -42 -32 -21 -13 n.s. n.s.AS -45 -44 -42 -32 -21 -13 n.s. n.s.

+ = ved 10 mg/kg 2o n.s. = statistisk ikke signifikant 2. Akut toxicitet.+ = at 10 mg / kg 2o n.s. = statistically not significant 2. Acute toxicity.

Den toxiske virkning blev undersøgt overfor hunmus og hanmus af egen avl med en vægt på 20-26 g 25 efter oral indgift (suspension i 1%'ig methylcellulose) af en enkelt dosis med en efteriagttagelsestid på 14 dage:The toxic effect was investigated against female and male mice of their own weight weighing 20-26 g 25 after oral administration (suspension in 1% methylcellulose) of a single dose with a 14 day observation time:

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29 --Orienterende akut toxic it et_ A > 1 000 mg/kg p.0. (o af 6 dyr døde) C > 2 000 mg/kg p.0. (0 af 6 dyr døde) 5 D >500 mg/kg P.o. (0 af 6 dyr døde) J > 2 000 mg/kg p.o. (0 af 10 dyr døde) AA *> 1 000 mg/kg P.o. (0 af 10 dyr døde) AB >1 000 mg/kg p.o. (o af 10 dyr døde) AC >1 000 mg/kg P.o. {0 af 10 dyr døde) 10 AD >1 000 mg/kg p.o. (0 af 10 dyr døde) AE >1 000 mg/kg p.o. (o af 10 dyr døde) AG > 1 000 mg/kg p.o. (O af 10 dyr døde) 15 Under anvendelse af den ovenfor beskrevne metode til bestemmelse af den blodsukkersænkende virkning er der endvidere blevet udført en serie sammenligningsforsøg, ved hvilke den blodsukkersænkende virkning af forbindelser, som fremstilles ifølge nedenstående Eksempler, 20 sammenlignes med virkningen af forbindelser, som fremstilles ifølge eksempler i EP-A-0.058.779.29 - Oriental acute toxicity it> A> 1000 mg / kg p.0. (o of 6 animals died) C> 2,000 mg / kg p.0. (0 of 6 animals died) 5 D> 500 mg / kg P.o. (0 of 6 animals died) J> 2,000 mg / kg p.o. (0 of 10 animals died) AA *> 1,000 mg / kg P.o. (0 out of 10 animals died) AB> 1,000 mg / kg p.o. (o of 10 animals died) AC> 1000 mg / kg P.o. {0 of 10 animals died) 10 AD> 1,000 mg / kg p.o. (0 of 10 animals died) AE> 1,000 mg / kg p.o. (o of 10 animals died) AG> 1,000 mg / kg p.o. (O of 10 animals died) 15 Using the above-described method for determining the blood sugar lowering effect, a series of comparative experiments have also been performed in which the blood sugar lowering effect of compounds prepared according to the Examples below is compared with the effect of compounds. , which is prepared according to examples in EP-A-0.058.779.

Forbindelsen A = 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylme-thyl]-phenyleddikesyre (Eksempel 20) 25 blev sammenlignet medCompound A = 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenylacetic acid (Example 20)

Va = 4[(1-{2-Piperidino-phenyl)-1-ethyl)-aminocarbonyl-methylj-phenyleddikesyre (EP-A-0.058.779: Eksempel 3.4), forbindelsen 30 B = 4-[(1-(6-Methyl-2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoesyreethylester (Eksempel 21 g) blev sammenlignet medVa = 4 [(1- (2-Piperidino-phenyl) -1-ethyl) -aminocarbonyl-methyl] -phenylacetic acid (EP-A-0.058.779: Example 3.4), compound B = 4 - [(1- (6) -Methyl-2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester (Example 21 g) was compared with

Vb = 4-[(1-(6-Methyl-2-piperidino-phenylM-ethenyl)-ami-3 5 nocarbonylmethy1)-benzoesyreethylester (EP-A- 0.058.779: Eksempel 6.2),Vb = 4 - [(1- (6-Methyl-2-piperidino-phenylM-ethenyl) -amino-carbonylmethyl) -benzoic acid ethyl ester (EP-A-0.058.779: Example 6.2),

Forbindelsen C = 4[(2-Methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-Compound C = 4 [(2-Methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -

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30 aminocarbonylmethyl]-benzoesyre (Eksempel 26) blev sammenlignet med30 aminocarbonylmethyl] -benzoic acid (Example 26) was compared

Vc = 4-[(1-Cyclohexyliden-2-piperidino-benzyl)-aminocarbonylmethyl] -benzoesyre (EP-A-0.058.779: Eksempel 5 9.37), forbindelsen D = 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-(2,3-dihydro-propyl)ester (Eksempel 39) og 10 E = 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl ]-benzoesyre-2-(2-hydroxy-ethyl)ester (Eksempel 39a) blev sammenlignet medVc = 4 - [(1-Cyclohexylidene-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid (EP-A-0.058.779: Example 5 9.37), compound D = 4 - [(1- (2-Piperidino-phenyl) ) -1-Butyl) -aminocarbonyl-methyl] -benzoic acid (2,3-dihydropropyl) ester (Example 39) and E = 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid 2- (2-hydroxyethyl) ester (Example 39a) was compared to

Vd = 4-[(1-(2-Piperidino-phenyl)-1-ethyl)-aminocarbonyl-15 methyl]-benzoesyre-(2-hydroxy-ethyl)ester (EP-A-0.058.779): Eksempel 46.9), forbindelsen F = 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-2(2-methoxy-ethyl)ester (Eksem-20 pel 39b) blev sammenlignet medVd = 4 - [(1- (2-Piperidino-phenyl) -1-ethyl) -aminocarbonyl-methyl] -benzoic acid (2-hydroxy-ethyl) ester (EP-A-0.058.779): Example 46.9) , Compound F = 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid-2 (2-methoxy-ethyl) ester (Example 20b) was compared to

Ve = 4-[(1-(2-Piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl ]-benzoesyre-(2-methoxy-ethyl)ester (EP-A-0.058.779: Eksempel 46.6), 25 Forbindelsen G = 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl ]-benzoesyre-(2-nicotinoyloxy-ethyl)ester (Eksempel 40) blev sammenlignet med 30 Vf = 4-[(1-(2-Piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl ]-benzoesyre-(2-nicotinoyloxy-ethyl)ester (EP-A-0.058.779: Eksempel 50), forbindelsen H = 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-35 methyl]-benzylalkohol (Eksempel 42) blev sammenlignet medVe = 4 - [(1- (2-Piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid (2-methoxy-ethyl) ester (EP-A-0.058.779: Example 46.6), Compound G = 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid (2-nicotinoyloxy-ethyl) ester (Example 40) was compared with 30 Vf = 4 - [(1- ( 2-Piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid (2-nicotinoyloxy-ethyl) ester (EP-A-0.058.779: Example 50), compound H = 4 - [(1- (2- Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzyl alcohol (Example 42) was compared with

Vg = 4-[(1-(2-Piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl ]-benzylalkohol (EP-A-0.058.779: Eksempel 25), 31Vg = 4 - [(1- (2-Piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzyl alcohol (EP-A-0.058,779: Example 25), 31

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forbindelsen I = 4-[(1-(2-Pyrrolidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre (Eksempel 25y) blev sammenlignet med 5 Vh = 4-[(1-(2-Pyrrolidino-phenyl)-1-ethyl)-aminocarbonyl-methyl]-benzoesyre (EP-A-0.058.779: Eksempel 29.4), forbindelsen K = 4-[ {1-(2-Hexahydroazepino-phenyl)-1 -butyl)-ami.no-10 carbonylmethylj-benzoesyre (Eksempel 25aa) blev sammenlignet medCompound I = 4 - [(1- (2-Pyrrolidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid (Example 25y) was compared with 5Vh = 4 - [(1- (2-Pyrrolidino-phenyl) ) -1-ethyl) -aminocarbonyl-methyl] -benzoic acid (EP-A-0.058.779: Example 29.4), the compound K = 4- [{1- (2-Hexahydroazepino-phenyl) -1-butyl) -amide. no-10 carbonylmethyl-benzoic acid (Example 25aa) was compared

Vi = 4-[(1-(2-Hexahydroazepino-phenyl)-1-ethyl)-amino-carbonylmethyl]-benzoesyre (EP-A-0.058.779: Eksempel 9.1) 15 forbindelsen L = 3-[4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocar-bonyl-methyl]-phenylJ-propionsyre (Eksempel 46) blev sammenlignet medVi = 4 - [(1- (2-Hexahydroazepino-phenyl) -1-ethyl) -amino-carbonylmethyl] -benzoic acid (EP-A-0.058.779: Example 9.1) Compound L = 3- [4 - [( 1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -phenyl] -propionic acid (Example 46) was compared to

Vk = 4~[(1-(2-Piperidino-phenyl)-1-ethyl)-aminocarbonyl-20 methyl]-phenyleddikesyre (EP-A-0.058.779: Eksempel 3.4).Vk = 4 ~ [(1- (2-Piperidino-phenyl) -1-ethyl) -aminocarbonyl-methyl] -phenylacetic acid (EP-A-0.058.779: Example 3.4).

Det bemærkes, at den bogstavbetegnelse, som umiddelbart ovenfor i forbindelse med sammenligningsforsøgene er benyttet for forbindelserne, som fremstilles ef-25 ter fremgangsmåden ifølge opfindelsen, dvs. forbindelserne A-L. afviger fra den bogstavbetegnelse (A-AS), som er benyttet tidligere i forbindelse med de først refererede forsøg til bestemmelse af den blodsukkersænkende virkning.It should be noted that the letter designation used immediately above in the comparison experiments for the compounds prepared according to the process of the invention, i. compounds A-L. differs from the letter designation (A-AS) used earlier in the first referenced trials to determine the blood sugar lowering effect.

30 Resultaterne af sammenligningsforsøgene fremgår af nedenstående Tabel.30 The results of the comparison experiments are shown in the Table below.

3535

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32 --1--—32 --1 --—

Blodudtagelse efterBlood sampling after

Stof Dosis i mg/kg 123 4 ___timer_ A 5 -49 -43 -30 -17Substance Dose in mg / kg 123 4 ___hours_ A 5 -49 -43 -30 -17

Va 5 -27 -18 n.s. n.s.Va 5 -27 -18 n.s. n.s.

B 10 -46 -43 -33 -28B 10 -46 -43 -33 -28

Vb 25 -33 -29 -12 n.s.Vb 25 -33 -29 -12 n.s.

C 1 -36 -32 -27 -25C 1 -36 -32 -27 -25

Vc 1 n.s. n.s.n.s.n.s.Vc 1 n.s. n.s.n.s.n.s.

D 1 -39 -35 -29 -24 E 1 -14 n.s. n.s. n.s.D 1 -39 -35 -29 -24 E 1 -14 n.s. n.s. n.s.

Vd 1 n.s. n.s.n.s.n.s.Vd 1 n.s. n.s.n.s.n.s.

F 5 -43 -43 -49 -45F 5 -43 -43 -49 -45

Ve 5 -36 -36 -24 -22 G 5 -37 -24 -21 -13Ve 5 -36 -36 -24 -22 G 5 -37 -24 -21 -13

Vf 5 -21 -21 -14 n.s.Vf 5 -21 -21 -14 n.s.

H 5 -38 -40 -35 -29H 5 -38 -40 -35 -29

Vg 5 -35 -29 n.s. n.s.Vg 5 -35 -29 n.s. n.s.

I 5 -49 -46 -44 -45I 5 -49 -46 -44 -45

Vh 5 -38 -18 n.s. n.s.Vh 5 -38 -18 n.s. n.s.

K 5 -46 -43 -40 -36K 5 -46 -43 -40 -36

Vi 5 -29 -18 n.s. n.s.We 5 -29 -18 n.s. n.s.

L 5 -37 -41 -40 -39L 5 -37 -41 -40 -39

Vk 5 -27 -18 n.s. n.s.Vk 5 -27 -18 n.s. n.s.

n.S. * ikke statistisk signifikant 33N.S. * not statistically significant 33

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Det fremgår af ovenstående Tabel, at forbindelserne, som fremstilles efter fremgangsmåden ifølge opfindelsen, har en overlegen virkning i forhold til sammenligningsforbindelserne, idet de enten ved samme dosis 5 eller ved en lavere dosis end sammenligningsforbindelserne overgår disse, hvad angår virkningsintensitet og/ eller varighed.It can be seen from the above Table that the compounds prepared according to the method of the invention have a superior effect over the comparator compounds, in that they exceed either the intensity of action and / or duration at the same dose 5 or at a lower dose than the comparator compounds.

På grund af deres farmakologiske egenskaber egner 10 de ifølge opfindelsen fremstillede forbindelser med den almene formel I og deres fysiologisk acceptable salte sig til behandling af diabetes mellitus. Til dette formål kan de indarbejdes, eventuelt i kombination med andre virksomme stoffer, i de sædvanlige galeniske tilbered-15 ningsformer såsom tabletter, drageer, kapsler, pulvere eller suspensioner. Enkeltdosis for voksne andrager herved 1-50 mg, fortrinsvis 2,5-20 mg, 1 eller 2 gange daglig.Because of their pharmacological properties, the compounds of the present invention of general formula I and their physiologically acceptable salts are suitable for the treatment of diabetes mellitus. For this purpose, they may be incorporated, optionally in combination with other active substances, into the usual galenic formulations such as tablets, dragons, capsules, powders or suspensions. The single dose for adults is hereby 1-50 mg, preferably 2.5-20 mg, 1 or 2 times daily.

20 Fremgangsmåden ifølge opfindelsen belyses nær mere gennem nedenstående eksempler.The process of the invention is elucidated in more detail by the following examples.

Eksempel 1 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl)-amino-25 carbonylmethyl]-benzoesyre-ethylester.Example 1 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid ethyl ester.

Til 4,2 g (15 mmol) a-(4-methyl-phenyl)-2-pipe-ridino-benzylamin og 3,4 g (16,5 mmol) 4-ethoxycarbonyl-phenyleddikesyre, opløst i 40 ml acetonitril, sætter man efter hinanden 4,7 g (18 mmol) triphenylphosphin, 30 3 g (30 mmol) triethylamin og 1,5 ml (15 mmol) tetra-chlorkulstof. Reaktionsblandingen omrøres i 2 timer ved 50°C, derpå inddampes og efter syrning med 6 N saltsyre ekstraheres med eddikesyreethylester. Den sure vandige 35To 4.2 g (15 mmol) of α- (4-methyl-phenyl) -2-piperidino-benzylamine and 3.4 g (16.5 mmol) of 4-ethoxycarbonyl-phenylacetic acid, dissolved in 40 ml of acetonitrile, One after another was 4.7 g (18 mmol) of triphenylphosphine, 3 g (30 mmol) of triethylamine and 1.5 ml (15 mmol) of tetrachloro carbon. The reaction mixture is stirred for 2 hours at 50 ° C, then evaporated and extracted with 6N hydrochloric acid with acetic acid ethyl ester. The acidic aqueous 35

DK 159850 BDK 159850 B

34 fase ekstraheres derpå flere gange med methylenchlorid.The 34 phase is then extracted several times with methylene chloride.

Methylenchloridekstrakterne vaskes med natriumbicarbonat-opløsning, tørres over magnesiumsulfat og inddampes. Inddampningsresten udrives med ethanol og frasuges.The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue is evaporated with ethanol and extracted.

5 Udbytte: 4f55 g (65% af det teoretiske), smeltepunkt: 177-178°C Beregnet: C76,57 H7,28 N 5,95Yield: 4f55 g (65% of theory), m.p .: 177-178 ° C Calculated: C76.57 H7.28 N 5.95

Fundet : 76,19 7,16 5,82 10 Følgende forbindelser blev fremstillet analogt med eksempel 1: (a) 4-[N-[a-(3-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoesyre-ethylester 15 udbytte: 48% af det teoretiske, smeltepunkt: 159-160°C Beregnet: C 76,57 H 7,28 N 5,95Found: 76.19 7.16 5.82 The following compounds were prepared analogously to Example 1: (a) 4- [N- [α- (3-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonyl-methyl ] -benzoic acid ethyl ester Yield: 48% of theory, m.p .: 159-160 ° C Calculated: C 76.57 H 7.28 N 5.95

Fundet : 76,80 7,35 5,76 20 (b) 4-[N-[a-(2-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 35,4% af det teoretiske, smeltepunkt: 196-198°C Beregnet; C 76,57 H 7,28 N 5,95 25 Fundet : 76,65 7,35 5,90 (c) 4-[N-[a-(4-methoxy-phenyl)-2-piperidino-benzyl]-carbonylmethyl]-benzoesyre-ethylester udbytte; 45% af det teoretiskeFound: 76.80 7.35 5.76 (b) 4- [N- [α- (2-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 35.4% of the theoretical melting point: 196-198 ° C Calculated; C 76.57 H 7.28 N 5.95 Found: 76.65 7.35 5.90 (c) 4- [N- [α- (4-methoxy-phenyl) -2-piperidino-benzyl] - carbonylmethyl] -benzoic acid ethyl ester yield; 45% of the theoretical

30 smeltepunkt; 167-168°C30 melting point; 167-168 ° C

Beregnet: C 74,05 H 7,04 N 5,76Calculated: C 74.05 H 7.04 N 5.76

Fundet ; 73,72 6,99 5,62 (d) 4-[N-[a-(4-benzyloxy-phenyl)-2-piperidino-benzyl]- 3 5 aminocarbonylmethyl]-benzoesyre-ethylesterFound; 73.72 6.99 5.62 (d) 4- [N- [α- (4-Benzyloxy-phenyl) -2-piperidino-benzyl] -3-aminocarbonylmethyl] -benzoic acid ethyl ester

udbytte; 96% af det teoretiske, smeltepunkt; 154-155°Cyield; 96% of the theoretical melting point; 154-155 ° C

3535

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Beregnet: C 76,84 H 6,81 N 4,98Calculated: C 76.84 H 6.81 N 4.98

Fundet : 76,82 6,68 5,03 (e) 4-[N-[a-(4-fluor-phenyl)-2-piperidino-benzyl]-ami- 5 nocarbonylmethyl]-benzoesyre-ethylester udbytte: 58% af det teoretiske, smeltepunkt: 174-176°C Beregnet: C 73,40 H 6,58 N 5,90Found: 76.82 6.68 5.03 (e) 4- [N- [α- (4-fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 58% of the theoretical, melting point: 174-176 ° C Calculated: C 73.40 H 6.58 N 5.90

Fundet : 73,55 6,72 5,91 10 (f) 4- [N- [<x- (2-fluor-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl]-benzoesyre-ethylesterFound: 73.55 6.72 5.91 (f) 4- [N- [<x- (2-fluoro-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzoic acid ethyl ester

udbytte: 83% af det teoretiske, smeltepunkt: 173-175°Cyield: 83% of theory, melting point: 173-175 ° C

15 Beregnet: C 73,40 H 6,58 N 5,90Calculated: C 73.40 H 6.58 N 5.90

Fundet : 73,61 6,62 5,85 (g) 4-[N-[a-(4-chlor-phenyl)-2-piperidino-benzylI-amino carbonylmethyl]-benzoesyre-ethylester 20 udbytte: 57% af det teoretiske,Found: 73.61 6.62 5.85 (g) 4- [N- [α- (4-Chloro-phenyl) -2-piperidino-benzyl] -amino carbonylmethyl] -benzoic acid ethyl ester Yield: 57% of the theoretical,

smeltepunkt: 178-181QCmp: 178-181 ° C

Beregnet: C 70,94 H 6,36 N 5,71 Cl 7,22Calcd. C 70.94 H 6.36 N 5.71 Cl 7.22

Fundet : 71,10 6,56 5,26 7,11 25 (h) 4-[N-[a-(3-chlor-phenyl)-2-piperidino-benzyl]-amino-Found: 71.10 6.56 5.26 7.11 (h) 4- [N- [α- (3-Chloro-phenyl) -2-piperidino-benzyl] -amino

carbonylmethyl]-benzoesyre-ethylester udbytte: 71% af det teoretiske, smeltepunkt: 153-156°Ccarbonylmethyl] -benzoic acid ethyl ester yield: 71% of theory, melting point: 153-156 ° C

Beregnet: C 70,94 H 6,36 N 5,71 Cl 7,22 30 Fundet : 70,86 6,26 5,65 7,25 (i) 4-[N-[a-(2-chlor-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoesyre-ethylester udbytte: 66% af det teoretiske,Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.86 6.26 5.65 7.25 (i) 4- [N- [α- (2-chloro-phenyl) ) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzoic acid ethyl ester yield: 66% of theory,

35 smeltepunkt: 196-198°CMp: 196-198 ° C

Beregnet: C 70,94 H 6,36 N 5,71 Cl 7,22Calcd. C 70.94 H 6.36 N 5.71 Cl 7.22

Fundet : 70,90 6,30 5,61 7,10 36Found: 70.90 6.30 5.61 7.10 36

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(k) 4-[N-[a-(4-methoxymercapto-benzyl)-2-piperidino-benzyl]-aminocarbonylmethylJ-benzoesyre-ethylester udbytte: 84% af det teoretiske,(k) 4- [N- [α- (4-methoxymercapto-benzyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 84% of theory,

smeltepunkt: 173-175°Cmp: 173-175 ° C

5 Beregnet: C 71,68 H 6,82 N 5,57 S 6,38Calculated: C 71.68 H 6.82 N 5.57 S 6.38

Fundet : 71,92 6,97 5,45 6,21 (l) 4-[N-[5-chlor-a-(2-chlor-phenyl)-2-piperidino-ben-zyl]-aminocarbonylmethyl]-benzoesyre-ethylesterFound: 71.92 6.97 5.45 6.21 (1) 4- [N- [5-chloro-α- (2-chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

10 udbytte: 92% af det teoretiske, smeltepunkt: 213-215°CYield: 92% of theory, melting point: 213-215 ° C

Beregnet: C 66,28 H 5,75 N 5,33 Cl 13,49Calculated: C 66.28 H 5.75 N 5.33 Cl 13.49

Fundet : 66,45 5,86 5,25 13,51 15 (m) 4-[N-[2-piperidino-a-(2-pyridyl)-benzyl]-aminocarbonylmethyl J-benzoesyre-ethylester udbytte: 51% af det teoretiske, smeltepunkt: 158-159°C Beregnet: C 73,50 H 6,83 N 9,18 20 Fundet : 73,40 6,95 9,10 (n) 4-[N-[2-piperidino-a-(3-pyridyl)-benzyl]-amino-c arbonylmethyl]-benzoesyre-ethy1ester udbytte: 85% af det teoretiske,Found: 66.45 5.86 5.25 13.51 (m) 4- [N- [2-piperidino-α- (2-pyridyl) benzyl] aminocarbonylmethyl J-benzoic acid ethyl ester yield: 51% of theoretical, melting point: 158-159 ° C Calculated: C 73.50 H 6.83 N 9.18 Found: 73.40 6.95 9.10 (n) 4- [N- [2-piperidino-α - (3-pyridyl) -benzyl] -amino-c arbonylmethyl] -benzoic acid ethyl ester yield: 85% of theory,

25 smeltepunkt: 172°CMelting point: 172 ° C

Beregnet: C 73,50 H 6,83 N 9,18Calcd. C 73.50 H 6.83 N 9.18

Fundet : 73,42 6,76 9,25 (o) 4-[N-[2-piperidino-a-(4-pyridyl)-benzyl]-amino- 30 carbonylmethyl]-benzoesyre-ethylester udbytte: 20% af det teoretiske, smeltepunkt: 150-152°C Beregnet: C 73,50 H 6,83 N 9,18Found: 73.42 6.76 9.25 (o) 4- [N- [2-piperidino-α- (4-pyridyl) -benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 20% of the theoretical, melting point: 150-152 ° C Calculated: C 73.50 H 6.83 N 9.18

Fundet : 73,61 6,91 9,15 37Found: 73.61 6.91 9.15 37

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(p) 4-[N-(6-chlor-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethy1]-benzoesyre-ethylester udbytte: 12% af det teoretiske, smeltepunkt: olie 5 Beregnet: molpeak m/e = 490/492(p) 4- [N- (6-Chloro-a-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield: 12% of theory, melting point: oil Calculated: molpeak m / e = 490/492

Fundet : molpeak m/e = 490/492 (q) 4-[N-(4-chlor-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethy1]-benzoesyre-ethylester 10 udbytte: 37% af det teoretiske,Found: molpeak m / e = 490/492 (q) 4- [N- (4-Chloro-a-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid ethyl ester 10 Yield: 37% of theory .

smeltepunkt: 148-150°Cmp: 148-150 ° C

Beregnet: C 70,94 H 6,36 N 5,71 Cl 7,22Calcd. C 70.94 H 6.36 N 5.71 Cl 7.22

Fundet : 70,81 6,25 5,61 7,12 15 (r) 4-[N-(3-chlor-a-phenyl-2-piperidino-benzyl)-amino-Found: 70.81 6.25 5.61 7.12 (r) 4- [N- (3-chloro-α-phenyl-2-piperidino-benzyl) -amino

carbonylmethyl]-benzoesyre-ethylester udbytte: 74% af det teoretiske, smeltepunkt: 176-178°Ccarbonylmethyl] -benzoic acid ethyl ester yield: 74% of theory, melting point: 176-178 ° C

Beregnet: C 70,94 H 6,36 N 5,71 Cl 7,22 20 Fundet : 70,59 6,25 5,68 7,16 (s) 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethy1]-benzoesyre-ethylester udbytte: 65% af det teoretiske, 25 smeltepunkt: olieCalculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.59 6.25 5.68 7.16 (s) 4- [N- (6-methyl-α-phenyl) 2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield: 65% of theory, melting point: oil

Beregnet: molpeak m/e = 470 Fundet : molpeak m/e = 470 (t) 4-[N-(5-methyl-a-phenyl-2-piperidino-benzyl)-amino- 30 carbonylmethyl]-benzoesyre-ethylester udbytte: 48% af det teoretiske, smeltepunkt: 171-173°C Beregnet: C 76,57 H 7,28 N 5,95Calculated: mole peak m / e = 470 Found: mole peak m / e = 470 (t) 4- [N- (5-methyl-α-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield : 48% of theory, melting point: 171-173 ° C Calculated: C 76.57 H 7.28 N 5.95

Fundet : 76,75 7,35 5,72 35Found: 76.75 7.35 5.72 35

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38 (u) 4-[N-[5-chlor-2-(2-methyl-piperidino)-a-phenyl- benzyl]-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 36,5% af det teoretiske,38 (u) 4- [N- [5-chloro-2- (2-methyl-piperidino) -α-phenylbenzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 36.5% of theory,

5 smeltepunkt: 171-173°CM.p .: 171-173 ° C

Beregnet: C 71,24 H 6,58 N 5,54 Cl 7,01Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01

Fundet : 71,45 6,68 5,59 7,20 10 Eksempel 2 4-[N-[α-Chlor-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl] -benzoesyre-ethylester.Found: 71.45 6.68 5.59 7.20 Example 2 4- [N- [α-Chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester.

Til en opløsning af 6,02 g (20 mmol) a-(4-chlor-phenyl)-2-piperidino-benzylamin og 3,5 ml (25 mmol) 15 triethylamin i 50 ml chloroform drypper man under isafkøling en opløsning af 5 g (22,1 mmol) 4-ethoxycarbo-nyl-phenylacetylchlorid i 20 ml chloroform. Man omrører i 2 timer ved stuetemperatur, hælder derpå ud på vand og ekstraherer med chloroform. Ekstrakterne tørres og 20 inddampes. Inddampningsresten chromatograferes på kiselgel med toluen/eddikesyre-ethylester 5:1 som flydemiddel. Udbytte: 5,6 g (57% af det teoretiske),To a solution of 6.02 g (20 mmol) of α- (4-chloro-phenyl) -2-piperidino-benzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform is added dropwise under ice-cooling a solution of 5 g (22.1 mmol) of 4-ethoxycarbonylphenylacetyl chloride in 20 ml of chloroform. The mixture is stirred for 2 hours at room temperature, then poured into water and extracted with chloroform. The extracts are dried and evaporated. The residue is chromatographed on silica gel with toluene / acetic acid ethyl ester 5: 1 as a liquid. Yield: 5.6 g (57% of theory),

smeltepunkt: 178-181°Cmp: 178-181 ° C

Beregnet: C 70,94 H 6,36 N 5,71 Cl 7,22 25 Fundet : 71,09 6,47 5,61 7,10Calculated: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 71.09 6.47 5.61 7.10

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3939

Analogt med eksempel 2 fremstilledes: (a) 4-[N-[5-Chlor-2-(3-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoesyre-ethylester 5 udbytte: 54% af det teoretiske,Analogously to Example 2: (a) 4- [N- [5-Chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester 5 yield: 54% of theory .

smeltepunkt: 178-180°Cmp: 178-180 ° C

Beregnet: C 71,24 H 6,58 N 5,54 Cl 7,01Calculated: C 71.24 H 6.58 N 5.54 Cl 7.01

Fundet : 70,91 6,64 5,75 7,01 10 Eksempel 3 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl] -benzoesyre.Found: 70.91 6.64 5.75 7.01 Example 3 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid.

4,4 g (9,35 mmol) 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre-ethy 1-15 ester opløses i 150 ml ethanol under opvarmning. Derefter tilsætter man 20 ml 1 N natronlud og omrører i 3 timer ved 50°C. Derpå tilsætter man til reaktionsblandingen 20 ml 1 N saltsyre og fjerner overskydende ethanol ved inddampning på rotationsfordamper. Den tilbage-20 værende vandige suspension filtreres, og bundfaldet vaskes godt med vand. Derpå omkrystalliseres af aceto-nitril.4.4 g (9.35 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl 1-ester is dissolved in 150 ml of ethanol under heating. . Then 20 ml of 1N sodium hydroxide solution is added and stirred for 3 hours at 50 ° C. Then, 20 ml of 1N hydrochloric acid is added to the reaction mixture and the excess ethanol removed by evaporation on a rotary evaporator. The remaining aqueous suspension is filtered and the precipitate is washed well with water. Then it is recrystallized from acetonitrile.

Udbytte: 2,45 g (59,3% af det teoretiske), smeltepunkt: 226-228°C 25 Beregnet: C 75,99 H 6,83 N 6,33Yield: 2.45 g (59.3% of theory), m.p .: 226-228 ° C Calculated: C 75.99 H 6.83 N 6.33

Fundet : 75,60 6,75 6,29 Følgende forbindelser blev fremstillet analogt med eksempel 3: 30Found: 75.60 6.75 6.29 The following compounds were prepared analogously to Example 3: 30

(a) 4-[N-[a-(3-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre udbytte: 72% af det teoretiske, smeltepunkt: 202-203°C(a) 4- [N- [α- (3-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid yield: 72% of theory, m.p .: 202-203 ° C

35 Beregnet: C 75,99 H 6,83 N 6,33Calc'd: C 75.99 H 6.83 N 6.33

Fundet : 75,64 6,91 6,37Found: 75.64 6.91 6.37

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40 (b) 4-[N-[a-(2-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre(B) 4- [N- [α- (2-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid

udbytte: 42,6% af det teoretiske, smeltepunkt: 285-290°Cyield: 42.6% of theory, melting point: 285-290 ° C

5 Beregnet: C75,99 H 6,83 W 6,33Calculated: C75.99 H 6.83 W 6.33

Fundet : 76,05 6,98 6,25 (c) 4-[N-[a-(4-methoxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre 10 udbytte: 72,4% af det teoretiske,Found: 76.05 6.98 6.25 (c) 4- [N- [α- (4-methoxy-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid yield: 72.4% of the theoretical,

smelteounkt: 228-230°Cmelting point: 228-230 ° C

Beregnet: C73,34 H 6,59 N 6,11Calculated: C73.34 H 6.59 N 6.11

Fundet : 73,22 6,61 6,13 15 (d) 4-[N-[a-(4-benzyloxy--phenyl)-2-piperidino-benzyl]-Found: 73.22 6.61 6.13 (d) 4- [N- [α- (4-Benzyloxy-phenyl) -2-piperidino-benzyl] -

aminocarbonylmethyl]-benzoesyre udbytte: 57% af det teoretiske, smeltepunkt: 219-221°Caminocarbonylmethyl] benzoic acid yield: 57% of theory, melting point: 219-221 ° C

Beregnet: C 76,38 H 6,41 N 5,24 20 Fundet : 76,05 6,44 5,24 (e) 4-[N-[a-(4-fluor-phenyl)-2-piperidino-benzyl]-amino-c arbonyIméthy1-benzoesyre udbytte: 75% af det teoretiske,Calculated: C 76.38 H 6.41 N 5.24 Found: 76.05 6.44 5.24 (e) 4- [N- [α- (4-fluoro-phenyl) -2-piperidino-benzyl ] -amino-c arbonyIméthy1-benzoic acid yield: 75% of theory,

25 smelteounkt: 238-240°CMelting point: 238-240 ° C

Beregnet: C 72,63 H 6,09 N 6,27Calculated: C, 72.63; H, 6.09; N, 6.27

Fundet : 72,98 6,29 6,32 (f) 4-[N-[a-(2-fluor-phenyl)-2-piperidino-benzyl]-amino- 30 carbonylmethyl]-benzoesyre udbytte: 87% af det teoretiske, smeltepunkt: 280-283°C Beregnet: C 72,63 H 6,09 N 6,27Found: 72.98 6.29 6.32 (f) 4- [N- [α- (2-fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid yield: 87% of the theoretical, melting point: 280-283 ° C Calculated: C 72.63 H 6.09 N 6.27

Fundet : 72,70 6,10 6,37 35 (g) 4-[N-[a-(4-chlor-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl] -benzoesyre udbytte: 89% af det teoretiske,Found: 72.70 6.10 6.37 (g) 4- [N- [α- (4-Chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid yield: 89% of theory,

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4141

smeltepunkt: 241-242°Cmp: 241-242 ° C

Beregnet: C 70,05 H 5,88 N 6,05 Cl 7,66Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Fundet : 69,74 6,05 6,01 7,64 5 (h) 4-[N-[a-(3-chlor-phenyl)-2-piperidino-benzyl]-amino-Found: 69.74 6.05 6.01 7.64 (h) 4- [N- [α- (3-chloro-phenyl) -2-piperidino-benzyl] -amino

carbonylmethyl]-benzoesyre udbytte: 53% af det teoretiske, smeltepunkt: 223-225°Ccarbonylmethyl] -benzoic acid yield: 53% of theory, melting point: 223-225 ° C

Beregnet: C 70,05 H 5,88 N 6,05 Cl 7,66 10 Fundet : 70,28 5,98 5,78 7,84 (i) 4-[N-[a-(2-chlor-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoesyre udbytte: 98% af det teoretiske,Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 70.28 5.98 5.78 7.84 (i) 4- [N- [α- (2-chloro-phenyl) ) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzoic acid yield: 98% of theory,

15 smeltepunkt: 303-305°CMp: 303-305 ° C

Beregnet: C70,05 H 5,88 N 6,05 Cl 7,66Calculated: C70.05 H 5.88 N 6.05 Cl 7.66

Fundet : 69,88 6,05 5,87 7,74 (k) 4-[N-ta-(4-methylmercapto-phenyl)-2-piperidino- 2 0 benzyl]-aminocarbonylmethyl]-benzoesyreFound: 69.88 6.05 5.87 7.74 (k) 4- [N-ta- (4-methylmercapto-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid

udbytte: 84,6% af det teoretiske, smeltepunkt: 225-227°Cyield: 84.6% of theory, melting point: 225-227 ° C

Beregnet: C 70,86 H 6,37 N 5,90 S 6,75Calcd. C 70.86 H 6.37 N 5.90 S 6.75

Fundet : 70,34 6,37 5,68 6,82 25Found: 70.34 6.37 5.68 6.82 25

(l) 4-[N-[5-chlor-a-(2-chlor-phenyl)-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoesyre udbytte: 90% af det teoretiske, smeltepunkt: 317-320°C(1) 4- [N- [5-chloro-α- (2-chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid yield: 90% of theory, m.p .: 317-320 ° C

30 Beregnet: C 65,19 H 5,27 N 5,63 Cl 14,25Calc'd: C 65.19 H 5.27 N 5.63 Cl 14.25

Fundet : 64,87 5,34 5,69 14,22 (m) 4-[N-[2-piperidino-a-(2-pyridyl)-benzyl]-aminocarbonylmethyl] -benzoesyre 35 udbytte: 81% af det teoretiske, smeltepunkt: 160-161°C Beregnet: C 72,71 H 6,34 N 9,78Found: 64.87 5.34 5.69 14.22 (m) 4- [N- [2-piperidino-α- (2-pyridyl) -benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 81% of theory Melting point: 160-161 ° C Calculated: C 72.71 H 6.34 N 9.78

Fundet : 72,43 6,39 10,00Found: 72.43 6.39 10.00

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42 (n) 4- [N- [2-piperidino-oc- (3-pyridyl) -benzyl] -amino-carbonylmethyl]-benzoesyre42 (n) 4- [N- [2-piperidino-α- (3-pyridyl) -benzyl] -amino-carbonylmethyl] -benzoic acid

udbytte: 72% af det teoretiske, smeltepunkt: 252-253°Cyield: 72% of theory, melting point: 252-253 ° C

5 Beregnet: C 72,71 H 6,34 N 9,78Calculated: C, 72.71; H, 6.34; N, 9.78

Fundet : 72,56 6,53 9,60 (o) 4-[N-[2-piperidino-a-(4-pyridyl)-benzyl]-amino-carbonylmethyl]-benzoesyre 10 udbytte: 68,5% af det teoretiske, smeltepunkt: fra 260°C (sønderdeling)Found: 72.56 6.53 9.60 (o) 4- [N- [2-piperidino-α- (4-pyridyl) -benzyl] -amino-carbonylmethyl] -benzoic acid yield: 68.5% of the theoretical, melting point: from 260 ° C (dec.)

Beregnet: C 72,71 H 6,34 N 9,78Calculated: C 72.71 H 6.34 N 9.78

Fundet : 72,31 6,29 9,63Found: 72.31 6.29 9.63

15 (p) 4-[N-(6-chlor-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoesyre udbytte: 82% af det teoretiske, smeltepunkt: 91-94°C(P) 4- [N- (6-chloro-α-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid yield: 82% of theory, m.p .: 91-94 ° C

Beregnet: C 70,04 H 5,88 N 6,05 Cl 7,66 20 Fundet : 69,61 5,77 5,96 7,78 (q) 4- [N- (4-chlor-a-phenyl-2-piperidino-benzyl) -aanino-carbonylmethyl]-benzoesyre udbytte: 61% af det teoretiske,Calculated: C 70.04 H 5.88 N 6.05 Cl 7.66 Found: 69.61 5.77 5.96 7.78 (q) 4- [N- (4-Chloro-a-phenyl) 2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid yield: 61% of theory,

25 smeltepunkt: 221-223°CMelting point: 221-223 ° C

Beregnet: C70,05 H 5,88 N 6,05 Cl 7,66Calculated: C70.05 H 5.88 N 6.05 Cl 7.66

Fundet : 69,73 5,89 5,87 7,52 (r) 4-[N-(3-chlor-a-phenyl-2-piperidino-benzyl)-amino- 3 0 carbonyl]-benzoesyreFound: 69.73 5.89 5.87 7.52 (r) 4- [N- (3-chloro-α-phenyl-2-piperidino-benzyl) -amino-carbonyl] -benzoic acid

udbytte: 83% af det teoretiske, smeltepunkt: 210-213°Cyield: 83% of theory, melting point: 210-213 ° C

Beregnet: C 70,05 H 5,88 N 6,05 Cl 7,66Calculated: C 70.05 H 5.88 N 6.05 Cl 7.66

Fundet : 70,31 6,03 5,90 7,79 35 (s) 4-[N-(6-methyl-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoesyre udbytte: 64% af det teoretiske,Found: 70.31 6.03 5.90 7.79 (s) 4- [N- (6-methyl-α-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid yield: 64% of the theoretical,

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4343

(t) 4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoesyre udbytte: 96% af det teoretiske, smeltepunkt: 202-203°C(t) 4- [N- (4-methyl-α-phenyl-2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid yield: 96% of theory, m.p .: 202-203 ° C

5 Beregnet: C 75,99 H 6,83 N 6,33Calculated: C, 75.99; H, 6.83; N, 6.33

Fundet : 76,04 6,78 6,23 ( u) 4-[N-[5-chlor-2-(2-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoesyre 10 udbytte: 52% af det teoretiske,Found: 76.04 6.78 6.23 (u) 4- [N- [5-Chloro-2- (2-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 52% of the theoretical,

smeltepunkt: 280-282°Cmp: 280-282 ° C

Beregnet: C 70,50 H 6,13 N 5,87 Cl 7,43C, 70.50; H, 6.13; N, 5.87; Cl, 7.43

Fundet : 70,14 6,10 5,75 7,45Found: 70.14 6.10 5.75 7.45

15 ( v) 4-[N-[5-chlor-2-(3-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoesyre udbytte: 66% af det teoretiske, smeltepunkt: 246-248°C(V) 4- [N- [5-chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid yield: 66% of theory, m.p .: 246-248 ° C

Beregnet: C 70,50 H 6,13 N 5,87 Cl 7,43 20 Fundet : 70,16 6,07 5,87 7,30Calculated: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: 70.16 6.07 5.87 7.30

Eksempel 4 4-[N-[a-(4-hydroxy-phenyl)-2-piperidino-benzyl]-amino-25 carbonylmethyl]-benzoesyre.Example 4 4- [N- [α- (4-hydroxy-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzoic acid.

1,1 g (2 mmol) 4-[N-[a-(4-benzyloxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre suspenderes i 200 ml ethanol og debenzyleres katalytisk ved 50°C og et hydrogentryk på 5 bar i nærværelse af 30 0,4 g 10%'ig palladium/carbon. Derpå filtreres fra katalysatoren, inddampes og omkrystalliseres af aceto-nitril.1.1 g (2 mmol) of 4- [N- [α- (4-benzyloxy-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid are suspended in 200 ml of ethanol and catalytically debenzylated at 50 ° C and a hydrogen pressure of 5 bar in the presence of 30 0.4 g of 10% palladium / carbon. The catalyst is then filtered, evaporated and recrystallized from acetonitrile.

Udbytte: 720 mg (66,7% af det teoretiske),Yield: 720 mg (66.7% of theory),

smeltepunkt: 202-204°Cmp: 202-204 ° C

35 Beregnet: C 72,95 H 6,35 N 6,30Calculated: C, 72.95; H, 6.35; N, 6.30

Fundet : 72,65 6,17 6,20 44 .Found: 72.65 6.17 6.20 44.

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Eksempel 5 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzylalkohol.Example 5 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzyl alcohol.

2,5 g (5,3 mmol) 4-[N-[a-(4-methyl-phenyl)-2-5 piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre-ethyl-ester sættes portionsvistil en suspension af 0,5 g (13,2 mmol) lithiumaluminiumhydrid i 50 ml absolut tetrahydro-furan. Man omrører endnu 30 minutter ved stuetemperatur, sønderdeler ved tildrypning af 4 N natronlud 10 og filtrerer fra det dannede natriumaluminat. Filtratet inddampes, og remanensen omkrystalliseres af en ringe mængde toluen.2.5 g (5.3 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-5-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester are added portionwise to a suspension of 0.5 g (13.2 mmol) of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran. Stir another 30 minutes at room temperature, decompose by dripping 4 N of soda liquor 10 and filtering from the sodium aluminate formed. The filtrate is evaporated and the residue is recrystallized from a small amount of toluene.

Udbytte: 0,98 g (43% af det teoretiske), smeltepunkt: 144-146°C 15 Beregnet: C 78,47 H 7,53 N 6,54Yield: 0.98 g (43% of theory), m.p .: 144-146 ° C Calculated: C 78.47 H 7.53 N 6.54

Fundet : 78,20 7,39 6,58 20 25 30 35Found: 78.20 7.39 6.58 20 25 30 35

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4545

Eksempel 6 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzaldehyd.Example 6 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzaldehyde.

8,85 g (20 mmol) 4-[N-[a-(4-methyl-phenyl)-2-5 piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre og 3,25 g (20 mmol) N,N'-carbonyldiimidazol opvarmes i 100 ml absolut tetrahydrofuran under tilbagesvaling i 2 timer. Derpå inddampes og koges yderligere 2 timer under tilbagesvaling efter tilsætning af 50 ml pyridin 10 og 3,7 g (20 mmol) 4-toluensulfonsyrehydrazid. Derpå udhældes på isvand og frasuges, og bundfaldet tørres.8.85 g (20 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-5-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid and 3.25 g (20 mmol) of N, N'- Carbonyl diimidazole is heated in 100 ml of absolute tetrahydrofuran under reflux for 2 hours. Then, reflux and boil for an additional 2 hours under reflux after the addition of 50 ml of pyridine 10 and 3.7 g (20 mmol) of 4-toluenesulfonic acid hydrazide. Then poured onto ice water and suctioned and the precipitate dried.

Til det således opnåede rå toluensulfonsyrehydrazid af den anvendte carboxylsyre sættes 20 g vandfrit natrium-carbonat og der opvarmes i 2 timer til 170°C i 50 ml 15 ethylenglycol. Derpå udhældes på vand og ekstraheres med chloroform. De inddampedes ekstrakter renses søjle-chromatografisk på kiselgel med toluen/eddikesyreethyl-ester 5:1 som flydemiddel.To the crude toluene sulfonic acid hydrazide thus obtained of the carboxylic acid used is added 20 g of anhydrous sodium carbonate and heated for 2 hours to 170 ° C in 50 ml of 15 ethylene glycol. Then poured onto water and extracted with chloroform. The evaporated extracts are purified column chromatographically on silica gel with toluene / acetic acid ethyl ester 5: 1 as a liquid.

Udbytte: 1,73 g (21% af det teoretiske),Yield: 1.73 g (21% of theory),

20 smeltepunkt: 144-146°CMp: 144-146 ° C

Beregnet: C 78,84 H 7,09 N 6,57Calculated: C 78.84 H 7.09 N 6.57

Fundet : 78,95 7,19 6,50Found: 78.95 7.19 6.50

Nedenstående forbindelse blev fremstillet ana-25 logt med eksempel 6: (a) 4- [N- [a-phenyl-2-piperidino-benzyl)'-aminocarbonylmethyl] -benzaldehyd udbytte: 29% af det teoretiske,The following compound was prepared analogously to Example 6: (a) 4- [N- [α-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzaldehyde yield: 29% of theory,

30 smeltepunkt: 168-170°CMp: 168-170 ° C

Beregnet: C 78,61 H 6,84 N 6,79Calculated: C 78.61 H 6.84 N 6.79

Fundet : 78,60 7,00 6,72Found: 78.60 7.00 6.72

Eksempel 7 35 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl ]-benzaldehyd.Example 7 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzaldehyde.

0,5 g (1,2 mmol) 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzylalkohøl 460.5 g (1.2 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzyl alcohol 46

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sættes til en suspension af 0,4 g (1,5 mmol) pyridinium-chlbrchromat i 2 ml chloroform. Efter 12 timer ved stuetemperatur tilsættes ether, der filtreres, og det inddampede filtrat renses søjlechromatografisk på 5 kiselgel (flydemiddel: toluen/eddikesyreethylester 5:1). Udbytte: 0,3 (60% af det teoretiske), smeltepunkt: 145-146°C Beregnet; C 78,84 H 7,09 N 6,57is added to a suspension of 0.4 g (1.5 mmol) of pyridinium chlorobromat in 2 ml of chloroform. After 12 hours at room temperature, ether which is filtered is added and the evaporated filtrate is purified column chromatographically on silica gel (liquid: toluene / acetic acid ethyl ester 5: 1). Yield: 0.3 (60% of theory), m.p .: 145-146 ° C Calculated; C, 78.84; H, 7.09; N, 6.57

Fundet : 78,97 7,12 6,57 10Found: 78.97 7.12 6.57 10

Nedenstående forbindelse blev fremstillet analogt med eksempel 7: (a) 4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonyl-15 methyl]-benzaldehydThe following compound was prepared analogously to Example 7: (a) 4- [N- (α-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -benzaldehyde

udbytte: 40% af det teoretiske, smeltepunkt: 170°Cyield: 40% of theory, melting point: 170 ° C

Beregnet: C 78,61 H 6,84 N 6,79Calculated: C 78.61 H 6.84 N 6.79

Fundet : 78,59 6,87 6,61 20Found: 78.59 6.87 6.61 20

Eksempel 8 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-amino-car bonylmethyl]-kanelsyre-ethylester.Example 8 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -cinnamic acid ethyl ester.

427 mg (1 mmol) 4-[Ν-[α-(4-methyl-phenyl)-2-25 piperidino-benzyl]-aminocarbonylmethyl]-benzaldehyd sættes til en etherisk opløsning af 450 mg (2 mmol) diethylphosphonoeddikesyre-ethylester og 100 mg (2 mmol) 50%'ig natriumhydrid. Efter omrøring natten over tilsættes vand og der ekstraheres med chloroform og renses 30 søjlechromatografisk på kiselgel med toluen/eddikesyreethylester 5:1 som flydemiddel.427 mg (1 mmol) of 4- [Ν- [α- (4-methyl-phenyl) -2-25-piperidino-benzyl] -aminocarbonylmethyl] -benzaldehyde are added to an ethereal solution of 450 mg (2 mmol) of diethylphosphonoacetic acid ethyl ester and 100 mg (2 mmol) of 50% sodium hydride. After stirring overnight, water is added and extracted with chloroform and purified column chromatographically on silica gel with toluene / acetic acid ethyl ester 5: 1 as a liquid.

Udbytte: 0,18 g (36% af det teoretiske), smeltepunkt: 176-180°C Beregnet: C 77,39 H 7,31 N 5,64 35 Fundet : 77,64 7,25 5,71Yield: 0.18 g (36% of theory), m.p .: 176-180 ° C Calculated: C 77.39 H 7.31 N 5.64 Found: 77.64 7.25 5.71

Nedenstående forbindelse blev fremstillet analogt med eksempel 8:The following compound was prepared analogously to Example 8:

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4747

(a) 4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-kanelsyre-ethylester udbytte: 28,6% af det teoretiske, smeltepunkt: 159-161°C(a) 4- [N- (α-Phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -cinnamic acid ethyl ester yield: 28.6% of theory, m.p .: 159-161 ° C

5 Beregnet: C 77,14 H 7,10 N 5,80Calculated: C 77.14 H 7.10 N 5.80

Fundet : 77,28 7,21 5,65Found: 77.28 7.21 5.65

Eksempel 9 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino-10 carbonylmethyl]-kanelsyre.Example 9 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -cinnamic acid.

Fremstillet ved alkalisk forsæbning af 4-[N-[a-(4-methyl-phenyl) -2-piper idino-benzyl]- aminocarbonyl-methyl]-kanelsyre-ethylester analogt med eksempel 3.Prepared by alkaline saponification of 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonyl-methyl] -cinnamic acid ethyl ester analogous to Example 3.

Udbytte: 84% af det teoretiske,Yield: 84% of theory,

15 smeltepunkt: 173-176°CMp 173-176 ° C

Beregnet: C 76,90 H 6,88 N 5,98Calculated: C 76.90 H 6.88 N 5.98

Fundet : 77,24 7,01 5,64Found: 77.24 7.01 5.64

Nedenstående forbindelse blev fremstillet ana-20 logt med eksempel 9: (a) 4-[N-(<x-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl]-kanelsyre udbytte: 75% af det teoretiske,The following compound was prepared analogously to Example 9: (a) 4- [N - (<x -phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -cinnamic acid yield: 75% of theory,

25 smeltepunkt: 177-180°CMelting point: 177-180 ° C

Beregnet: C 76,62 H 6,65 N 6,16Calculated: C 76.62 H 6.65 N 6.16

Fundet : 76,75 6,57 6,07Found: 76.75 6.57 6.07

Eksempel 10 30 4-[N-[a-(3-Methyl-phenyl)-2-piperidino-benzyl]-amino- carbonylmethyl]-benzoesyre-ethylester.Example 10 4- [N- [α- (3-Methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester.

Til 1,5 ml o-dichlorbenzen og 1,5 ml koncentreret svovlsyre drypper man ved stuetemperatur en blanding af 0,22 g (0,8 mmol) a-(3-methyl-phenyl)-2-piperi-35 dino-benzylalkohol og 0,15 g (0,8 mmol) 4-cyanomethyl-benzoesyre-ethylester i 2 ml o-dichlorbenzen. Efter 2 timers omrøring udhælder man på isvand, ekstraherer en gang med ether, indstiller på alkalisk reaktion med 48To 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated sulfuric acid, a mixture of 0.22 g (0.8 mmol) of α- (3-methyl-phenyl) -2-piperidino-benzyl alcohol is added dropwise at room temperature. and 0.15 g (0.8 mmol) of 4-cyanomethyl-benzoic acid ethyl ester in 2 ml of o-dichlorobenzene. After 2 hours of stirring, pour on ice water, extract once with ether, adjust to alkaline reaction with 48

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fortyndet natronlud og ekstraherer med chloroform.dilute baking soda and extract with chloroform.

Chloroformekstrakten inddampes, og remanensen omkrystalliseres af ethanol.The chloroform extract is evaporated and the residue is recrystallized from ethanol.

Udbytte: 0,22 g (60% af det teoretiske),Yield: 0.22 g (60% of theory),

5 smeltepunkt: 158-159°CMp: 158-159 ° C

Beregnet: C 76,57 H 7,28 N 5,95Calculated: C 76.57 H 7.28 N 5.95

Fundet : 76,41 7,39 5,76 10 Eksempel 11 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino- carbonyImethyl]-benzoesyre.Found: 76.41 7.39 5.76 Example 11 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid.

240 mg (5 mmol) 4-[N-[5-chlor-a-(4-methyl-phenyl) - 2-piperidino-benzyl]-aminocarbonylmethyl]-benzoesyre 15 dehalogeneres katalytisk i 80 ml ethanol/dioxan 1:1 i nærværelse af 0,1 g palladium på carbon (10%'ig) ved o 50 C og et hydrogentryk på 5 bar. Efter afkøling filtreres fra katalysatoren. Filtratet inddampes, og remanensen omkrystalliseres af ethanol.240 mg (5 mmol) of 4- [N- [5-chloro-α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid is catalytically dehalogenated in 80 ml of ethanol / dioxane 1: 1 the presence of 0.1 g of palladium on carbon (10% µg) at 50 ° C and a hydrogen pressure of 5 bar. After cooling, the catalyst is filtered. The filtrate is evaporated and the residue is recrystallized from ethanol.

20 Udbytte: 0,16 g (72% af det teoretiske), smeltepunkt: 226-228°C Beregnet: C 75,99 H 6,83 N 6,33Yield: 0.16 g (72% of theory), m.p .: 226-228 ° C Calculated: C 75.99 H 6.83 N 6.33

Fundet : 75,81 6,73 6,10 25 Følgende forbindelser blev fremstillet analogt med eksempel 11: (a) 4-[N-[2-(2-methyl-piperidino)-α-phenyl-benzyl]-aminocarbony lmethyl] -benzoesyre ud fra 4-[N-[5-chlor-2-(2-methyl-piperidino)-a-phe-30 nyl-benzyl]-aminocarbonylmethyl]-benzoesyreFound: 75.81 6.73 6.10 The following compounds were prepared analogously to Example 11: (a) 4- [N- [2- (2-methyl-piperidino) -α-phenyl-benzyl] -aminocarbony-methyl] -benzoic acid from 4- [N- [5-chloro-2- (2-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid

udbytte: 68% af det teoretiske, smeltepunkt: 246-248°Cyield: 68% of theory, melting point: 246-248 ° C

Beregnet: C 75,99 H 6,83 N 6,33Calculated: C, 75.99; H, 6.83; N, 6.33

Fundet : 75,57 7,10 6,44 35 *9Found: 75.57 7.10 6.44 35 * 9

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(b) 4-[N-[2-(3-methyl-piperidino)-α-phenyl-benzyl]-ami-nocarbonylmethyl]-benzoesyre(b) 4- [N- [2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid

ud fra 4-[N-[5-chlor-2-(3-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoesyre 5 udbytte: 43% af det teoretiske, smeltepunkt: 228-230°Cfrom 4- [N- [5-chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 43% of theory, m.p .: 228-230 ° C

Beregnet: C 75,99 H 6,83 N 6,33Calculated: C, 75.99; H, 6.83; N, 6.33

Fundet : 75,91 6,82 6,33 10 Eksempel 12 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoesyre-ethylester.Found: 75.91 6.82 6.33 Example 12 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzoic acid ethyl ester.

Til en opløsning af 2,78 g (10 mmol) frisk fremstillet (4-methyl-phenyl)-(2-piperidino-phenyl)-ketimin 15 i 50 ml methylenchlorid sætter man 1,5 ml (11 mmol) triethylamin og derpå under isafkøling dråbevis en opløsning af 2,5 g (11 mmol) 4-ethoxycarbonyl-phenyl-eddikesyrechlorid i 20 ml methylenchlorid. Efter 1 time ved stuetemperatur hælder man ud på isvand og ekstrahe-20 rer med methylenchlorid. Ekstrakterne tørres og inddampes, og inddampningsresten renses søjlechromatografisk på kiselgel (flydemiddel: toluen/eddikesyreethylester 10:1). Den rå acylimin opløses i dimethylformamid og hydrogeneres ved stuetemperatur efter tilsætning af 0,5 g 25 palladium (10%1ig på carbon) ved 5 bar hydrogentryk.To a solution of 2.78 g (10 mmol) of freshly prepared (4-methyl-phenyl) - (2-piperidino-phenyl) -ketimine 15 in 50 ml of methylene chloride is added 1.5 ml (11 mmol) of triethylamine and then under ice-cooling dropwise a solution of 2.5 g (11 mmol) of 4-ethoxycarbonyl-phenyl-acetic acid chloride in 20 ml of methylene chloride. After 1 hour at room temperature, pour into ice water and extract with methylene chloride. The extracts are dried and evaporated and the residue is purified column chromatographically on silica gel (liquid: toluene / acetic acid ethyl ester 10: 1). The crude acylimine is dissolved in dimethylformamide and hydrogenated at room temperature after the addition of 0.5 g of 25 palladium (10% 1g on carbon) at 5 bar hydrogen pressure.

Efter optagelse af den beregnede hydrogenmængde filtreres fra katalysatoren, der inddampes, og remanensen omkrystalliseres af en ringe mængde alkohol.After taking up the calculated amount of hydrogen, the catalyst is evaporated and the residue is recrystallized from a small amount of alcohol.

Udbytte: 2,8 g (60% af det teoretiske),Yield: 2.8 g (60% of theory),

30 smeltepunkt: 175-177°CMp 175-177 ° C

Beregnet: C 76,57 H 7,28 N 5,95Calculated: C 76.57 H 7.28 N 5.95

Fundet : 76,41 7,19 5,76Found: 76.41 7.19 5.76

Eksempel 13 35 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzonitril.Example 13 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzonitrile.

Fremstillet ud fra a-(4-methyl-phenyl)-2-pipe-Prepared from α- (4-methylphenyl) -2-pipe

DK 159850 BDK 159850 B

50 ridino-benzylamin og 4-cyano-phenyleddikesyre analogt med eksempel 1.50 ridino-benzylamine and 4-cyano-phenylacetic acid analogous to Example 1.

Udbytte; 64% af det teoretiske, smeltepunkt; 144-14 6°C 5 Beregnet; C 79,40 H 6,90 N 9,92 Fundet : 79,10 6,90 9,78Yield; 64% of the theoretical melting point; 144-14 6 ° C Calculated; C 79.40 H 6.90 N 9.92 Found: 79.10 6.90 9.78

Eksempel 14 4-[N-[a-(4-Methyl-phenyl)-2-piperidino-benzyl]-amino-10 carbonylmethyl]-benzoesyre-ethylester.Example 14 4- [N- [α- (4-Methyl-phenyl) -2-piperidino-benzyl] -amino-carbonylmethyl] -benzoic acid ethyl ester.

4,2 g (10 mmol) 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzonitril koges i 24 timer under tilbagesvaling med 50 ml ethano-lisk saltsyre. Derpå inddamper man, sætter vandig na-15 triumbicarbonatopløsning til inddampningsresten og eks-traherer med chloroform. Chloroformekstrakten inddampes, og remanensen udrives med ethanol og frasuges.4.2 g (10 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzonitrile are boiled for 24 hours under reflux with 50 ml of ethanolic hydrochloric acid. Then, evaporate, add aqueous sodium bicarbonate solution to the evaporation residue and extract with chloroform. The chloroform extract is evaporated and the residue is triturated with ethanol and extracted.

Udbytte: 2,9 g (61,6% af det teoretiske), smeltepunkt: 177-179°C 20 Beregnet: C 76,57 H 7,28 N 5,95Yield: 2.9 g (61.6% of theory), m.p .: 177-179 ° C Calculated: C 76.57 H 7.28 N 5.95

Fundet : · 76,41 7,35 5,76Found: · 76.41 7.35 5.76

Eksempel 15 4-[N-[5-Chlor-a-(2-chlor-phenyl)-2-piperidino-benzyl]-25 aminocarbonylmethyl]-benzoesyre-ethylester.Example 15 4- [N- [5-Chloro-α- (2-chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester.

10 Mmol 4-[N-[a-(2-chlor-phenyl)-5-nitro-2-pipe-ridino-benzyl]-aminocarbonylmethyl]-benzoesyre-ethylester opløses i 50 ml dimethylformamid og hydrogeneres efter tilsætning af 1 g Raney-nikkel ved 60°C og et 30 hydrogentryk på 6 bar. Derpå filtreres fra katalysatoren, filtratet inddampes og remanensen, der består af 4-[N-[5-amino-a-(2-chlor-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl] -benzoesyre-ethylester , opløses i 100 ml koncentreret saltsyre. Under isafkøling tildryppes nu 35 en opløsning af 1,0 g (14 mmol) natriumnitrit i 10 ml vand og der efterrøres i 1 time ved 0-5°C. Derpå drypper man reaktionsblandingen til en opløsning af 3 g kobber-il) -chiorid i 25 ml koncentreret saltsyre. Efter 1 ti-10 mmol of 4- [N- [α- (2-chloro-phenyl) -5-nitro-2-pipe-pyridino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester is dissolved in 50 ml of dimethylformamide and hydrogenated after adding 1 g of Raney nickel at 60 ° C and a hydrogen pressure of 6 bar. The filtrate is then filtered off, the filtrate is evaporated and the residue consisting of 4- [N- [5-amino-α- (2-chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester is dissolved in 100 ml. ml of concentrated hydrochloric acid. Under ice-cooling, a solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water is now added dropwise and stirred for 1 hour at 0-5 ° C. Then, the reaction mixture is dripped to a solution of 3 g of copper II chloride in 25 ml of concentrated hydrochloric acid. After 1 hour

DK 159850 BDK 159850 B

51 mes efterrøring gøres alkalisk med natronlud og der ekstraheres med chloroform. De inddampede chloroformekstrakter renses søjlechromatografisk på kiselgel i flydemidlet toluen/eddikesyreethylester 5:1.After 51 minutes stirring is made alkaline with baking soda and extracted with chloroform. The evaporated chloroform extracts are purified column chromatographically on silica gel in the liquid toluene / acetic acid ethyl ester 5: 1.

5 Udbytte: 1,5 g (28,6% af det teoretiske), smeltepunkt: 213-215°CYield: 1.5 g (28.6% of theory), m.p .: 213-215 ° C

Beregnet: C 66,28 H 5,75 N 5,33 Cl 13,49Calculated: C 66.28 H 5.75 N 5.33 Cl 13.49

Fundet : 66,40 5,91 5,41 13,40 10 Eksempel 16 3- [4-[N-(a-(4-Methyl-phenyl)-2-piperidino-benzyl)-ami-nocarbonylmethyl]-phenyl]-propionsyre.Found: 66.40 5.91 5.41 13.40 Example 16 3- [4- [N- (α- (4-Methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -phenyl] propionic acid.

0,91 g (2 mmol) 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-kanelsyre 15 opløses i 50 ml methanol og efter tilsætning af 0,5 g palladium (10%’ig på carbon) hydrogeneres katalytisk ved stuetemperatur og et hydrogentryk på 3 bar. Efter afslutning af hydrogenoptagelsen filtreres fra katalysatoren og omkrystalliseres af en ringe mængde aceto-20 nitril.Dissolve 0.91 g (2 mmol) of 4- [N- (α- (4-methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -cinnamic acid in 50 ml of methanol and after addition of 0.5 g of palladium (10% µg on carbon) is catalytically hydrogenated at room temperature and a hydrogen pressure of 3 bar. Upon completion of the hydrogen uptake, the catalyst is filtered and recrystallized from a small amount of acetonitrile.

Udbytte: 0,68 g (74% af det teoretiske), smeltepunkt: 146-148°C Beregnet: C 76,57 H 7,28 N 5,95Yield: 0.68 g (74% of theory), m.p .: 146-148 ° C Calculated: C 76.57 H 7.28 N 5.95

Fundet : 76,41 7,19 5,61 25Found: 76.41 7.19 5.61 25

Eksempel 17 4- [N-(a~(4-Methyl-phenyl)-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoesyre-natriumsalt.Example 17 4- [N- (α ~ (4-Methyl-phenyl) -2-piperidino-benzyl) -amino-carbonylmethyl] -benzoic acid sodium salt.

442 mg (1 mmol) 4-[N-(a-(4-methyl-phenyl)-2-pipe-30 ridino-benzyl)-aminocarbonylmethyl]-benzoesyre opløses i 25 ml ethanol og der tilsættes 1 ml 1 N natronlud.Dissolve 442 mg (1 mmol) of 4- [N- (a- (4-methyl-phenyl) -2-pipe-pyridino-benzyl) -aminocarbonylmethyl] -benzoic acid in 25 ml of ethanol and add 1 ml of 1 N sodium hydroxide solution.

Derpå inddampes i vakuum, der tilsættes 20 ml acetone, suges fra udfældet bundfald og eftervaskes med eddike-syre-ethylester.Then, evaporate in vacuo, add 20 ml of acetone, suction from precipitated precipitate and wash with acetic acid ethyl ester.

35 Udbytte: 410 mg (85% af det teoretiske), smeltepunkt: 295-300°CYield: 410 mg (85% of theory), m.p .: 295-300 ° C

Beregnet: C 72,40 H 6,29 N 6,03Calculated: C 72.40 H 6.29 N 6.03

Fundet : 72,15 6,46 5,93Found: 72.15 6.46 5.93

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52 Følgende forbindelser blev fremstillet analogt med eksempel 17: (a) 4-[N-(a- (4-methyl-phenyl)-2-piperidino-benzyl)-5 aminocarbonylmethyl]-benzoesyre-ethanolaminsalt udbytte: 75% af det teoretiske, smeltepunkt: 188-191°C Beregnet: C 71,55 H 7,41 N 8,34The following compounds were prepared analogously to Example 17: (a) 4- [N- (α- (4-methyl-phenyl) -2-piperidino-benzyl) -5-aminocarbonylmethyl] -benzoic acid ethanolamine salt yield: 75% of theory Melting point: 188-191 ° C Calculated: C 71.55 H 7.41 N 8.34

Fundet : 71,16 7,48 8,52 10 (b) 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoesyre-diethanolaminsalt udbytte: 81% af det teoretiske,Found: 71.16 7.48 8.52 (b) 4- [N- (α- (4-methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid diethanolamine salt yield: 81% of the theoretical,

smeltepunkt: 178-180°Cmp: 178-180 ° C

15 Beregnet: C 70,79 H 6,86 N 7,73Calculated: C 70.79 H 6.86 N 7.73

Fundet : 70,25 6,75 7,58 (c) 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoesyre-triethanolaminsaltFound: 70.25 6.75 7.58 (c) 4- [N- (α- (4-methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid triethanolamine salt

20 udbytte: 76% af det teoretiske, smeltepunkt: 160-165°CYield: 76% of theory, melting point: 160-165 ° C

Beregnet: C 69,01 H 7,67 N 7,10Calculated: C, 69.01; H, 7.67; N, 7.10

Fundet : 68,91 7,64 7,45 25 (d) 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-Found: 68.91 7.64 7.45 (d) 4- [N- (α- (4-methyl-phenyl) -2-piperidino-benzyl) -

aminocarbonylmethyl]-benzoesyre-ethylendiaminsalt udbytte: 65% af det teoretiske, smeltepunkt: 160-163°Caminocarbonylmethyl] -benzoic acid-ethylenediamine salt yield: 65% of theory, melting point: 160-163 ° C

Beregnet: C 71,69 H 7,62 N 11,15 30 Fundet : 72,04 7,80 10,96Calculated: C 71.69 H 7.62 N 11.15 Found: 72.04 7.80 10.96

Eksempel 18 4-[(2-Methoxy-l-(2-piperidino-phenyl)-ethyl]-aminocarbonylmethyl] -benzoesyre-ethylester.Example 18 4 - [(2-Methoxy-1- (2-piperidino-phenyl) -ethyl] -aminocarbonylmethyl] -benzoic acid ethyl ester.

35 Til en opløsning af 0,55 g (2,34 mmol) 2-methoxy- 1-(2-piperidino-phenyl)-ethylamin i 5 ml acetonitril sætter man successivt 0,49 g (2,34 mmol) 4-ethoxycarbo-nyl-phenyleddikesyre, 0,73 g (2,78 mmol) triphenylphos-To a solution of 0.55 g (2.34 mmol) of 2-methoxy-1- (2-piperidino-phenyl) -ethylamine in 5 ml of acetonitrile is added successively 0.49 g (2.34 mmol) of 4-ethoxycarboxylic acid. -Nyl-phenylacetic acid, 0.73 g (2.78 mmol) of triphenylphosphorus

53 DK 159850 B53 DK 159850 B

phin, 0,50 ml (?,66 mmol) triethylamin og 0,23 ml (2,34 mmol) tetrachlorkulstof og omrører i 20 timer ved stuetemperatur. Derpå inddamper man i vakuum og fordeler mellem ethylacetat og vand. Den organiske 5 ekstrakt tørres, filtreres og inddampes i vakuum. Ind-dampningsresten renses ved søjlechromatografi på kiselgel (toluen/acetone = 10/2).phin, 0.50 mL (?, 66 mmol) of triethylamine and 0.23 mL (2.34 mmol) of tetrachloro carbon and stirring for 20 hours at room temperature. Then it is evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried, filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (toluene / acetone = 10/2).

Udbytte: 0,45 g (45% af det teoretiske), smeltepunkt: 122-123°C 10 Beregnet: C 70,73 H 7,60 N 6,60Yield: 0.45 g (45% of theory), m.p .: 122-123 ° C Calc'd: C 70.73 H 7.60 N 6.60

Fundet : 71,04 7,48 6,39 Følgende forbindelser blev fremstillet analogt med eksempel 18:Found: 71.04 7.48 6.39 The following compounds were prepared analogously to Example 18:

15 (a) 4-[(1-(3-chlor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre-ethylester udbytte: 55% af det teoretiske, smeltepunkt: 141-143°C(A) 4 - [(1- (3-Chloro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield: 55% of theory, m.p .: 141-143 ° C

Beregnet: C 68,33 H 7,28 Cl 7,76 N 6,13 20 Fundet : 68,30 7,16 8,03 6,20 (b) 4-[(1-(6-chlor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre-ethylester udbytte: 73,9% af det teoretiske,Calculated: C 68.33 H 7.28 Cl 7.76 N 6.13 Found: 68.30 7.16 8.03 6.20 (b) 4 - [(1- (6-chloro-2-piperidino) -phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield: 73.9% of theory,

25 smeltepunkt: 79-82°CMelting point: 79-82 ° C

Beregnet: C 68,33 H 7,28 Cl 7,76 N 6,13Calculated: C 68.33 H 7.28 Cl 7.76 N 6.13

Fundet : 68,45 7,24 7,80 6,09 (c) 4-[(1-(4-brom-2-piperidino-phenyl)-1-butyl)-amino- 30 carbonylmethyl]-benzoesyre-ethylesterFound: 68.45 7.24 7.80 6.09 (c) 4 - [(1- (4-bromo-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

udbytte: 62,1% af det teoretiske, smeltepunkt: 116-118°Cyield: 62.1% of theory, melting point: 116-118 ° C

Beregnet: C 62,27 H 6,63 Br 15,93 N 5,58Calculated: C 62.27 H 6.63 Br 15.93 N 5.58

Fundet : 62,53 6,48 15,98 5,66 35 (d) 4-[(1-(4-nitro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre-ethylester udbytte: 74,6% af det teoretiske,Found: 62.53 6.48 15.98 5.66 (d) 4 - [(1- (4-Nitro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield : 74.6% of theory,

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5454

smeltepunkt: 127-130°Cmp 127-130 ° C

Beregnet: C 66,79 H 7,11 N 8,99Calculated: C 66.79 H 7.11 N 8.99

Fundet : 66,88 7,08 9,15 5 (e) 4-[(1-(3-methyl-2-piperidino-phenyl)-1-butyl)-ami-nocarbonylmethyl]-benzoesyre-ethylester udbytte: 68% af det teoretiske, smeltepunkt: 145-147°C Beregnet; C 74,28 H 8,31 N 6,42 10 Fundet : 74,40 8,30 6,41 (f) 4-[(l-(4-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 54,7% af det teoretiske,Found: 66.88 7.08 9.15 (e) 4 - [(1- (3-methyl-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester yield: 68% of the theoretical melting point: 145-147 ° C Calculated; C 74.28 H 8.31 N 6.42 Found: 74.40 8.30 6.41 (f) 4 - [(1- (4-methyl-2-piperidino-phenyl) -1-butyl) - aminocarbonylmethyl] -benzoic acid ethyl ester yield: 54.7% of theory,

15 smeltepunkt: 113-114°CMp: 113-114 ° C

Beregnet: C 74,28 H 8,31 N 6,42Calculated: C, 74.28; H, 8.31; N, 6.42

Fundet : 74,23 8,30 6,55 (g) 4-[(1-(5-methyl-2-piperidino-phenyl)-1-butyl)- 20 aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 67,9% af det teoretiske, smeltepunkt: 149-150°G Beregnet: C 74,28 H 8,31 N 6,42Found: 74.23 8.30 6.55 (g) 4 - [(1- (5-methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 67.9% of the theoretical, melting point: 149-150 ° G Calculated: C 74.28 H 8.31 N 6.42

Fundet : 74,38 8,21 6,49 25Found: 74.38 8.21 6.49 25

(h) 4-[(1-(6-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonyImethyl]-benzoesyre-ethylester udbytte: 47% af det teoretiske, smeltepunkt: 92-93°C(h) 4 - [(1- (6-methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 47% of theory, m.p .: 92-93 ° C

30 Beregnet: C 74,28 H 8,31 N 6,42Calcd: C 74.28 H 8.31 N 6.42

Fundet : 74,50 8,46 6,48 (i) 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoesyre-ethylesterFound: 74.50 8.46 6.48 (i) 4 - [(1- (2-Pyrrolidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

35 udbytte: 57,3% af det teoretiske, smeltepunkt: 122-125°CYield: 57.3% of theory, melting point: 122-125 ° C

Beregnet: C 73,50 H 7,90 N 6,86Calculated: C, 73.50; H, 7.90; N, 6.86

Fundet : 73,63 8,07 7,01Found: 73.63 8.07 7.01

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55 (k) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-ethylester55 (k) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester

udbytte: 71,5% af det teoretiske, smeltepunkt: 127-128°Cyield: 71.5% of theory, m.p .: 127-128 ° C

5 Beregnet: C 73,90 H 8,11 N 6,63Calculated: C 73.90 H 8.11 N 6.63

Fundet : 73,90 8,06 6,72 (l) 4-[(-(2-(4-methyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester 10 udbytte: 51,1% af det teoretiske, smeltepunkt: 153-155°C Beregnet: C 74,28 H 8,31 N 6,42Found: 73.90 8.06 6.72 (1) 4 - [(- (2- (4-methyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 51.1 % of theory, melting point: 153-155 ° C Calculated: C 74.28 H 8.31 N 6.42

Fundet : 74,55 8,33 6,45 15 (m) 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-aminocarbonylmethyl ]-benzoesyre-ethylester udbytte: 42,7% af det teoretiske, smeltepunkt: 145-147°C Beregnet: C 74,28 H 8,31 N 6,42 20 Fundet : 73,98 8,26 6,58 (n) 4-[(1-(5-fluor-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl ]-benzoesyre-ethylester udbytte: 55% af det teoretiske,Found: 74.55 8.33 6.45 (m) 4 - [(1- (2-Hexahydroazepino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 42.7% of theory, Melting point: 145-147 ° C Calculated: C 74.28 H 8.31 N 6.42 Found: 73.98 8.26 6.58 (n) 4 - [(1- (5-fluoro-2-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 55% of theory,

25 smeltepunkt: 128-130°CMp: 128-130 ° C

Beregnet: C 70,88 H 7,55 N 6,36Calculated: C 70.88 H 7.55 N 6.36

Fundet : 71,14 7,57 6,49 (o) 4-[(1-(2-piperidino)-1-butyl)-aminocarbonylmethyl]- 30 benzoesyre-methylester udbytte: 63,2% af det teoretiske, smeltepunkt: 147-148°C Beregnet: C 73,50 H 7,90 N 6,86Found: 71.14 7.57 6.49 (o) 4 - [(1- (2-piperidino) -1-butyl) aminocarbonylmethyl] benzoic acid methyl ester yield: 63.2% of theory, m.p. 147-148 ° C Calculated: C, 73.50; H, 7.90; N, 6.86

Fundet : 73,66 7,88 6,80 35Found: 73.66 7.88 6.80 35

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56 (p) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-n-butylester udbytte: 50,9% af det teoretiske, smeltepunkt: 117-119°C (ether) 5 Beregnet: C 74,63 H 8,50 N 6,2256 (p) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid n-butyl ester yield: 50.9% of theory, m.p .: 117-119 ° C (ether) Calculated: C 74.63 H 8.50 N 6.22

Fundet : 74,49 8,46 6,14 (q) 4- [ (1- (2-piperidino-phenyl) -4-penten-l-yl).-amino-carbonylmethy1]-benzoesyre-ethylester 10 udbytte: 18,9% af det teoretiske, smeltepunkt: 103-105°C Beregnet: C 74,62 H 7,89 N 6,45Found: 74.49 8.46 6.14 (q) 4- [(1- (2-Piperidino-phenyl) -4-penten-1-yl) amino-carbonylmethyl] -benzoic acid ethyl ester Yield: 18 , 9% of theory, melting point: 103-105 ° C Calculated: C 74.62 H 7.89 N 6.45

Fundet : 75,01 8,10 6,26 15 Eksempel 19 4-[(1-(5-Nitro-2-piperidino-phenyl)-1-butyl)-aminocarbo-nylmethyl]-benzoesyre-ethylesterFound: 75.01 8.10 6.26 Example 19 4 - [(1- (5-Nitro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Til en omrørt opløsning af 15,1 g (54,4 mmol) 1-(5-nitro-2-piperidino-phenyl)-l-butylamin og 8,46 ml 20 (61,4 mmol) triethylamin i 55 ml tør methylenchlorid drypper man i løbet af 30 minutter en opløsning af 14,6 g (64,6 mmol) 4-ethoxycarbonyl-phenyleddikesyrechlorid i 20 ml methylenchlorid på en sådan måde, at temperaturen ikke overstiger 30°C. Man omrører endnu i 2 timer 25 ved stuetemperatur, tilsætter 300 ml methylenchlorid og ryster to gange, hver gang med 50 ml vand. Den organiske fase tørres over natriumsulfat, den filtreres og inddampes i vakuum. Den rødbrune olieagtige inddampnings-rest renses ved søjlechromatografi på kiselgel (toluen/ 30 acetone = 10:1).To a stirred solution of 15.1 g (54.4 mmol) of 1- (5-nitro-2-piperidino-phenyl) -1-butylamine and 8.46 ml of 20 (61.4 mmol) of triethylamine in 55 ml of dry methylene chloride a solution of 14.6 g (64.6 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 20 ml of methylene chloride is dropped over 30 minutes in such a way that the temperature does not exceed 30 ° C. Stir for another 2 hours at room temperature, add 300 ml of methylene chloride and shake twice, each time with 50 ml of water. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The reddish-brown oily residue is purified by column chromatography on silica gel (toluene / 30 acetone = 10: 1).

Udbytte: 17,7 g (69,7% af det teoretiske), smeltepunkt: 135-137°C (ether)Yield: 17.7 g (69.7% of theory), m.p .: 135-137 ° C (ether)

Beregnet: C66,79 H 7,11 N 8,99Calculated: C66.79 H 7.11 N 8.99

Fundet : 66,73 6,99 9,09 35 Følgende forbindelser blev opnået analogt med eksempel 19:Found: 66.73 6.99 9.09 The following compounds were obtained analogously to Example 19:

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57 (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-ethylester57 (a) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester

udbytte: 80,2% af det teoretiske, smeltepunkt: 127-129°Cyield: 80.2% of theory, melting point: 127-129 ° C

5 Beregnet: C 73,90 H 8,11 N 6,63Calculated: C 73.90 H 8.11 N 6.63

Fundet : 73,98 8,26 6,89 (b) 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylesterFound: 73.98 8.26 6.89 (b) 4 - [(1- (4-hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

10 udbytte: 13,5% af det teoretiske, smeltepunkt: 178-180°CYield: 13.5% of theory, melting point: 178-180 ° C

Beregnet: C 71,21 H 7,81 N 6,39Calculated: C, 71.21; H, 7.81; N, 6.39

Fundet : 71,27 7,82 6,40 15 (c) 4-[(l-(5-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 37,4% af det teoretiske, smeltepunkt: 188-190°C Beregnet: C 71,21 H 7,81 N 6,39 20 Fundet : 71,34 7,89 6,38Found: 71.27 7.82 6.40 (c) 4 - [(1- (5-hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 37.4% of theoretical, melting point: 188-190 ° C Calculated: C 71.21 H 7.81 N 6.39 Found: 71.34 7.89 6.38

Eksempel 20 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylme-methyl]-phenyleddikesyre.Example 20 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenylacetic acid.

25 Man opvarmer 3,0 g (15,45 mmol) p-phenylen-di- eddikesyre og 10 ml thionylchlorid 90 minutter under tilbagesvaling og inddamper derpå i vakuum. Det rå di-syrechlorid opløser man i 100 ml methylenchlorid. Til denne opløsning drypper man langsomt under omrøring en 30 opløsning af 3,6 g (15,45 mmol) 1-(2-piperidino-phenyl)-1-butylamin ved en indre temperatur på 10-15°C.25 g (15.45 mmol) of p-phenylene acetic acid and 10 ml of thionyl chloride are heated at reflux for 90 minutes and then evaporated in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride. To this solution is slowly added dropwise with stirring a solution of 3.6 g (15.45 mmol) of 1- (2-piperidino-phenyl) -1-butylamine at an internal temperature of 10-15 ° C.

Efter 2 timer ved stuetemperatur inddamper man i vakuum og fordeler inddampningsresten mellem 100 ml iskold 5%'ig natronlud og ethylacetat. Man filtrerer gennem 35 kiselgur og fraskiller den organiske fase. Den alkalivandige fase indstiller man med halvkoncentreret saltsyre på pH 5,5 og ekstraherer med ethylacetat. Man tørrer over natriumsulfat, filtrerer og inddamper fil-After 2 hours at room temperature, evaporate in vacuo and distribute the residue between 100 ml of ice cold 5% sodium hydroxide solution and ethyl acetate. Filter through 35 diatomaceous earth and separate the organic phase. The alkali aqueous phase is adjusted to pH 5.5 with semi-concentrated hydrochloric acid and extracted with ethyl acetate. Dry sodium sulfate, filter and evaporate the filtrate.

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58 tratet i vakuum. Inddampningsresten renser man ved søjlechromatografi på kiselgel (chloroform/methanol = 20:1) .58 in a vacuum. The residue is purified by column chromatography on silica gel (chloroform / methanol = 20: 1).

Udbytte: 0,10 g (1,6% af det teoretiske), 5 smeltepunkt: 136-140°C (acetonitril/ether)Yield: 0.10 g (1.6% of theory), m.p .: 136-140 ° C (acetonitrile / ether)

Beregnet: C 73,50 H 7,90 N 6,86Calculated: C, 73.50; H, 7.90; N, 6.86

Fundet : 73,17 8,10 6,85Found: 73.17 8.10 6.85

Eksempel 21 10 4-[(2-Methyl-l-(2-piperidino-phenyl)-l-propen-l~yl)- aminocarbonylmethyl]-benzoesyre-ethylester.Example 21 4 - [(2-Methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Til en opløsning af 6,17 g (26,8 mmol) frisk fremstillet isopropyl-(2-piperidino-phenyl)-ketimin i 62 ml acetonitril sætter man successivt 5,58 g 15 (26,8 mmol) 4-ethoxycarbonylphenyleddikesyre, 8,43 g (32,2 mmol) triphenylphosphin, 11,2 ml (80,4 mmol) triethylamin og 2,6 ml (0,0268 mol) tetrachlorkulstof og omrører i 20 timer ved stuetemperatur. Derpå inddamper man i vakuum og fordeler mellem ethylacetat og 20 vand. Den tørrede og filtrerede ethylacetatekstrakt inddampes i vakuum. Inddampningsresten renser man ved søjlechromatografi på kiselgel (toluen/ethylacetat = 5:1) .To a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl (2-piperidino-phenyl) -ketimine in 62 ml of acetonitrile is added 5.58 g (26.8 mmol) of 4-ethoxycarbonylphenylacetic acid, successively. , 43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine, and 2.6 ml (0.0268 mol) of tetrachloro carbon, stirring for 20 hours at room temperature. Then it is evaporated in vacuo and partitioned between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated in vacuo. The residue is purified by column chromatography on silica gel (toluene / ethyl acetate = 5: 1).

Udbytte: 3,0 g (26,6% af det teoretiske), 25 smeltepunkt: 82-84°C (ether)Yield: 3.0 g (26.6% of theory), m.p .: 82-84 ° C (ether)

Beregnet: C 74,26 H 7,67 N 6,66Calculated: C 74.26 H 7.67 N 6.66

Fundet : 74,20 7,49 6,56 Følgende forbindelser blev opnået analogt med 3 0 eksempel 21.Found: 74.20 7.49 6.56 The following compounds were obtained by analogy with Example 21.

(a) 4-[(1-(2-piperidino-phenyl)-1-penten-l-yl)-aminocarbonylmethyl ]-benzoesyre-ethylester udbytte: 16% af det teoretiske, 35 smeltepunkt: 94-97°C (ethanol)(a) 4 - [(1- (2-piperidino-phenyl) -1-penten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 16% of theory, m.p .: 94-97 ° C (ethanol )

Beregnet: C 74,62 H 7,89 N 6,45Calculated: C 74.62 H 7.89 N 6.45

Fundet : 74,75 7,71 6,24Found: 74.75 7.71 6.24

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59 (b) 4-[(1-(2-piperidino-phenyl)-1-hexen-l-yl)-amino-carbonylmethyl]-benzoesyre-ethylester udbytte: 27,4% af det teoretiske, smeltepunkt: 83-85°C (ethanol) 5 Beregnet: C 74,97 H 8,09 N 6,2459 (b) 4 - [(1- (2-piperidino-phenyl) -1-hexen-1-yl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield: 27.4% of theory, m.p .: 83-85 C (ethanol) Calculated: C 74.97 H 8.09 N 6.24

Fundet : 75,42 7,95 6,00 (c) 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-amino-carbonylmethyl]-benzoesyre-ethylester 10 udbytte (mere lipophil isomer; sandsynligvis E-form): 4,1% af det teoretiske, smeltepunkt: < 20°C Beregnet: m/e = 420Found: 75.42 7.95 6.00 (c) 4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield (more lipophilic isomer; probably E form): 4.1% of theoretical, melting point: <20 ° C Calculated: m / e = 420

Fundet : m/e =420 15 udbytte (mindre lipophil isomer; sandsynligvis Z-form): 51,9% af det teoretiske, smeltepunkt: 115-117°C (ethanol)Found: m / e = 420 yield (minor lipophilic isomer; probably Z form): 51.9% of theory, m.p .: 115-117 ° C (ethanol)

Beregnet: C 74,26 H 7,67 N 6,66 20 Fundet : 73,85 7,59 6,44 (d) 4-[(2-phenyl-l-(2-piperidino-phenyl)-ethen-l-yl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte (mere lipophil isomer; sandsynligvis 25 E-form): 4% af det teoretiske, smeltepunkt: 75-77°C (ether/petroleumsether)Calculated: C 74.26 H 7.67 N 6.66 Found: 73.85 7.59 6.44 (d) 4 - [(2-phenyl-1- (2-piperidino-phenyl) -ethene-1 -yl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield (more lipophilic isomer; probably E form): 4% of theory, m.p .: 75-77 ° C (ether / petroleum ether)

Beregnet: C 76,90 H 6,88 N 5,98Calculated: C 76.90 H 6.88 N 5.98

Fundet : 77,31 7,20 5,93 30 udbytte (mindre lipophil isomer; sandsynligvis Z-form): 42,7% af det teoretiske, smeltepunkt: 157-160°C (ethanol)Found: 77.31 7.20 5.93 Yield (minor lipophilic isomer; probably Z-form): 42.7% of theory, m.p .: 157-160 ° C (ethanol)

Fundet: C 77,19 H 6,95 N 6,02Found: C 77.19 H 6.95 N 6.02

35 (e) 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 62,6% af det teoretiske, smeltepunkt: < 20°C(E) 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 62.6% of theory, melting point: < 20 ° C

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6060

Beregnet: m/e = 482 Fundet : m/e = 482 (f) 4-[(1-(2-( 3,3-dimethyl-piperidino)-phenyl)-1-buten- 5 1-yl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 33% af det teoretiske, smeltepunkt: 113-116°C (ethanol)Calculated: m / e = 482 Found: m / e = 482 (f) 4 - [(1- (2- (3,3-dimethyl-piperidino) -phenyl) -1-buten-5-yl) -aminocarbonylmethyl ] -benzoic acid ethyl ester yield: 33% of theory, m.p .: 113-116 ° C (ethanol)

Beregnet: C 74,97 H 8,09 N 6,24Calculated: C, 74.97; H, 8.09; N, 6.24

Fundet : 75,37 7,93 6,03 10 (g) 4-[(l-(6-methyl-2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 60,4% af det teoretiske (sandsynligvis Z-form),Found: 75.37 7.93 6.03 (g) 4 - [(1- (6-methyl-2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 60.4% of theoretical (probably Z-form),

15 smeltepunkt: 95-96°CMelting point: 95-96 ° C

Beregnet: C 74,62 H 7,89 N 6,45 m/e = 434Calculated: C 74.62 H 7.89 N 6.45 m / e = 434

Fundet : 74,44 8,00 6,59 m/e = 434Found: 74.44 8.00 6.59 m / e = 434

Eksempel 22 20 4-[(1-(2-Piperidino-phenyl)-1-buten-l-yl)-aminocarbo nylmethyl] -benzoesyre-ethylester.Example 22 4 - [(1- (2-Piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Man opvarmer en omrørt opløsning af 19,0 g (82,46 mmol) frisk fremstillet (2-piperidino-phenyl)-propyl-ketimin og 11,5 ml (82,45 mmol) triethylamin i 25 190 ml vandfri toluen til en indre' temperatur på 85°C og tildrypper derpå i løbet af 10 minutter en opløsning af 18,7 g (82,46 mmol) 4-ethoxycarbonyl-phe-nyleddikesyrechlorid i 95 ml vandfri toluen og omrører i 30 minutter ved en indre temperatur på 95°C. Man 30 afkøler til 20°C og udryster to gange med vand. Den organiske fase tørrer man over natriumsulfat, filtrerer og inddamper i vakuum. Inddampningsresten renser man ved gentagen søjlechromatografi (toluen/acetone = 20:1 og 50;1).A stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidino-phenyl) -propyl-ketimine and 11.5 ml (82.45 mmol) of triethylamine is heated in 190 ml of anhydrous toluene to an inner layer. at a temperature of 85 ° C and then drop over 10 minutes a solution of 18.7 g (82.46 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 95 ml of anhydrous toluene and stir for 30 minutes at an internal temperature of 95 ° C. 30 is cooled to 20 ° C and equiped twice with water. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by repeated column chromatography (toluene / acetone = 20: 1 and 50; 1).

35 Udbytte: (mere lipophil isomer? sandsynligvis E-form): 11,2 g (23,6% af det teoretiske), smeltepunkt: < 20°C (honninggul, sej olie).Yield: (more lipophilic isomer? Probably E-form): 11.2 g (23.6% of theory), melting point: <20 ° C (honey yellow, chewy oil).

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6161

Beregnet: C 74,26 H 7,67 N 6,66Calculated: C 74.26 H 7.67 N 6.66

Fundet : 73,90 7,92 6,91Found: 73.90 7.92 6.91

Udbytte (mindre lipophil isomer; sandsynligvis Z-form): 5 15,9 g (33,5% af det teoretiske), smeltepunkt: 114-116°C Fundet: C 74,02 H 7,69 N 6,85Yield (minor lipophilic isomer; probably Z form): 5 15.9 g (33.5% of theory), m.p .: 114-116 ° C Found: C 74.02 H 7.69 N 6.85

Eksempel 23 10 (E)- og (Z)-4-[(l-(2-Piperidino-phenyl)-l-buten-l-yl)- aminocarbonylmethyl]-benzoesyre-ethylester.Example 23 (E) - and (Z) -4 - [(1- (2-Piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Man opvarmer 1,0 g Z-ester (se eksempel 22c) langsomt i et forvarmet oliebad på 230°C. Efter afkøling renses det opnåede produkt ved søjlechromato-15 grafi på kiselgel (toluen/acetone = 20:1).1.0 g of Z-ester (see Example 22c) is slowly heated in a preheated 230 ° C oil bath. After cooling, the obtained product is purified by column chromatography on silica gel (toluene / acetone = 20: 1).

Udbytte: (E-ester): 0,365 g (36,5% af det teoretiske), smeItepunkt: < 20°CYield: (E-ester): 0.365 g (36.5% of theory), m.p .: <20 ° C

udbytte: (Z-ester) · 0,380 g (38,0% af det teoretiske),yield: (Z-ester) · 0.380 g (38.0% of theory),

20 smeltepunkt: 115-117°CMp: 115-117 ° C

Ved 3 1/2 times opvarmning af (E)-esteren med katalytiske mængder iod i benzen opnår man ifølge tyndt-lagschromatografisk undersøgelse (toluen/acetone = 25 10:1) en 1/1-blanding af (E)-og (Z)-ester.By 3 1/2 hours heating the (E) ester with catalytic amounts of iodine in benzene, a 1/1 mixture of (E) and (Z) is obtained according to thin-layer chromatographic study (toluene / acetone = 25 10: 1). ) ester.

Følgende forbindelser blev opnået analogt med eksempel 23: 30 (a) (E)- og (Z)-4-[(1-(6-methyl-2-piperidino-phenyl)-1- buten-l-yl)-aminocarbonylmethyl]-benzoesyre-ethyl-ester.The following compounds were obtained analogously to Example 23: (a) (E) - and (Z) -4 - [(1- (6-methyl-2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl ] -benzoic acid ethyl ester.

Ud fra (Z)-esteren (se eksempel 22g) opnår man ifølge tyndtlagschromatogrammet en 1/1-blanding af 35 (E)- og (Z)-ester, øvre plet (E): Beregnet: m/e = 434From the (Z) ester (see Example 22g), according to the thin layer chromatogram, a 1/1 mixture of 35 (E) and (Z) ester upper spot (E) is obtained: Calculated: m / e = 434

Fundet : m/e = 434 nedre plet (Z): Fundet : m/e = 434Found: m / e = 434 lower spot (Z): Found: m / e = 434

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6262

Eksempel 24 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylme-thyl]-benzoesyre-ethylester.Example 24 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Man hydrogenerer ved 50°C og 1 bar hydrogen 5 2/9 g (6/90 mmol) 4-[(1-(2-piperidino-phenyl)-1-buten- 1-yl)-aminocarbonylmethyl]-benzoesyre-ethylester i 100 ml ethanol i nærværelse af 0,77 g palladium/carbon (10%'ig). Efter 2 timers forløb filtrerer man fra katalysatoren over kiselgur og inddamper i vakuum. Ind-10 dampningsresten krystalliseres af ethanol.Hydrogen at 50 ° C and 1 bar hydrogen 5 2/9 g (6/90 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 100 ml of ethanol in the presence of 0.77 g of palladium / carbon (10% µg). After 2 hours, the catalyst is filtered over the diatomaceous earth and evaporated in vacuo. The evaporation residue is crystallized by ethanol.

Udbytte: 1,5 g (51,5% af det teoretiske), smeltepunkt: 126-128°C Beregnet: C 73,90 H 8,11 N 6,63Yield: 1.5 g (51.5% of theory), m.p .: 126-128 ° C Calculated: C 73.90 H 8.11 N 6.63

Fundet : 73,97 8,22 6,57 15 Følgende forbindelser blev opnået analogt med eksempel 24: (a) 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonyl- 20 methyl]-benzoesyre-ethylester udbytte: 45% af det teoretiske, smeltepunkt: 117-120°C (ether)Found: 73.97 8.22 6.57 The following compounds were obtained analogously to Example 24: (a) 4 - [(1- (2-piperidino-phenyl) -1-pentyl) -aminocarbonylmethyl] -benzoic acid -ethyl ester yield: 45% of theory, melting point: 117-120 ° C (ether)

Beregnet: C 74,28 H 8,31 N 6,42Calculated: C, 74.28; H, 8.31; N, 6.42

Fundet : 74,60 8,13 6,27 25 (b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonyl-methyl]-benzoesyre-ethylester udbytte: 50% af det teoretiske, smeltepunkt: 108-110°C (ether) 30 Beregnet: C 74,63 H 8,50 N 6,22Found: 74.60 8.13 6.27 (b) 4 - [(1- (2-piperidino-phenyl) -1-hexyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester yield: 50% of theory, Melting point: 108-110 ° C (ether) Calculated: C 74.63 H 8.50 N 6.22

Fundet : 74,85 8,33 6,01 (c) 4-[(2-phenyl-l-(2-piperidino-phenyl)-1-ethyl)-ami-nocarbonylmethyl]-benzoesyre-ethylester 35 udbytte: 87,6% af det teoretiske, smeltepunkt: 161-162°C (ethanol)Found: 74.85 8.33 6.01 (c) 4 - [(2-phenyl-1- (2-piperidino-phenyl) -1-ethyl) aminocarbonylmethyl] -benzoic acid ethyl ester yield: 87, 6% of theory, melting point: 161-162 ° C (ethanol)

Beregnet: C 76,57 H 7,28 N 5,95Calculated: C 76.57 H 7.28 N 5.95

Fundet : 76,71 7,19 5,99Found: 76.71 7.19 5.99

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63 (d) 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propyl)-ami-nocarbonylmethyl]-benzoesyre-ethylester udbytte: 57,6% af det teoretiske, smeltepunkt: 118-119°C (ethanol) 5 Beregnet: C 76,83 H 7,49 N 5,7863 (d) 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propyl) aminocarbonylmethyl] -benzoic acid ethyl ester yield: 57.6% of theory, m.p .: 118-119 C (ethanol) Calc'd: C 76.83 H 7.49 N 5.78

Fundet : 76,70 7,49 5,90 (e) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester 10 udbytte: 36,5% af det teoretiske, smeltepunkt: 140-141°C (ethanol)Found: 76.70 7.49 5.90 (e) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 36.5% of theory, melting point: 140-141 ° C (ethanol)

Beregnet: C 74,63 H 8,50 N 6,22Calculated: C 74.63 H 8.50 N 6.22

Fundet : 74,30 8,23 6,12 15 Eksempel 25 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl ]-benzoesyre.Found: 74.30 8.23 6.12 Example 25 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid.

Man omrører en blanding af 1,2 g (2,84 mmol) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylme-20 thyl]-benzoesyre-ethylester og 4,26 ml 1 N natronlud i 12 ml ethanol i 1 time ved 60°C; derpå neutraliseres med 4,26 ml 1 N saltsyre og ethanolen afdampes i vakuum. Man fordeler mellem ethylacetat og vand; den organiske ekstrakt tørres og filtreres og inddampes i 25 vakuum. Inddampningsresten krystalliseres af ethanol.A mixture of 1.2 g (2.84 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester and 4.26 ml of 1 N is stirred. baking soda in 12 ml of ethanol for 1 hour at 60 ° C; then neutralize with 4.26 ml of 1 N hydrochloric acid and evaporate the ethanol in vacuo. Partition between ethyl acetate and water; the organic extract is dried and filtered and evaporated in vacuo. The residue is crystallized by ethanol.

Udbytte: 0,50 g (44,6% af det teoretiske), smeltepunkt: 213-215°C Beregnet: C 73,07 H 7,66 N 7,10Yield: 0.50 g (44.6% of theory), m.p .: 213-215 ° C Calculated: C 73.07 H 7.66 N 7.10

Fundet : 73,18 7,51 7,10 30 Følgende forbindelser blev opnået analogt med eksempel 25: (a) 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonyl- 35 methyl]-benzoesyre udbytte: 70,2% af det teoretiske, smeltepunkt: 213-215°C (acetone)Found: 73.18 7.51 7.10 The following compounds were obtained analogously to Example 25: (a) 4 - [(1- (2-piperidino-phenyl) -1-pentyl) -aminocarbonylmethyl] -benzoic acid yield: 70.2% of theory, melting point: 213-215 ° C (acetone)

Beregnet: C 73,50 H 7,90 N 6,86Calculated: C, 73.50; H, 7.90; N, 6.86

Fundet : 73,71 7,70 6,90Found: 73.71 7.70 6.90

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64 (b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbo-nylmethyl]-benzoesyre udbytte: 12,6% af det teoretiske, smeltepunkt: 197-200°C (acetone) 5 Beregnet: C 73,90 H 8,11 N 6,6364 (b) 4 - [(1- (2-piperidino-phenyl) -1-hexyl) -aminocarbonylmethyl] -benzoic acid yield: 12.6% of theory, m.p .: 197-200 ° C (acetone) Calculated: C, 73.90; H, 8.11; N, 6.63

Fundet : 73,83 7,93 6,77 (c) 4-r(2-phenyl-l-(2-piperidino-phenyl)-l-ethyl)-amino-carbonylmethyl]-benzoesyre 10 udbytte: 68,7% af det teoretiske, smeltepunkt: 214-215°C (ethanol)Found: 73.83 7.93 6.77 (c) 4 - [(2-Phenyl-1- (2-piperidino-phenyl) -1-ethyl) -amino-carbonylmethyl] -benzoic acid Yield: 68.7% of the theoretical melting point: 214-215 ° C (ethanol)

Beregnet: C 75,99 H 6,83 N 6,33Calculated: C, 75.99; H, 6.83; N, 6.33

Fundet : 75,70 6,60 6,32 15 (d) 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propyl)-ami-nocarbonylmethyl]-benzoesyre udbytte: 67,7% af det teoretiske, smeltepunkt: 167-170°C (ethylacetat)Found: 75.70 6.60 6.32 (d) 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propyl) aminocarbonylmethyl] -benzoic acid yield: 67.7% of the theoretical melting point: 167-170 ° C (ethyl acetate)

Beregnet: C 76,29 H 7,06 N 6,14 20 Fundet : 76,56 7,06 6,23 (e) 4-[2-methoxy-l-(2-piperidino-phenyl)-1-ethyl)-ami-nocarbonylmethyl]-benzoesyre udbytte: 60,8% af det teoretiske, 25 smeltepunkt: 196-198°C (ether)Calculated: C 76.29 H 7.06 N 6.14 Found: 76.56 7.06 6.23 (e) 4- [2-methoxy-1- (2-piperidino-phenyl) -1-ethyl) -amino-nocarbonylmethyl] -benzoic acid yield: 60.8% of theory, m.p .: 196-198 ° C (ether)

Beregnet: C 69,68 H 7,12 N 7,07Calculated: C, 69.68; H, 7.12; N, 7.07

Fundet : 69,72 6,52 6,71 (f) 4-[(l-(2-piperidino-phenyl)-4-penten-l-yl)-amino- 30 carbonylmethyl]-benzoesyre x 0,67 H20 udbytte: 30,7% af det teoretiske, smeltepunkt: 193-197°C (ether/petroleumsether)Found: 69.72 6.52 6.71 (f) 4 - [(1- (2-piperidino-phenyl) -4-penten-1-yl) -aminocarbonylmethyl] -benzoic acid x 0.67 H2 O yield : 30.7% of theory, melting point: 193-197 ° C (ether / petroleum ether)

Beregnet: C 71,74 H 7,38 N 6,69Calculated: C 71.74 H 7.38 N 6.69

Fundet : 71,63 7,21 6,34 35 (g) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre udbytte: 48,2% af det teoretiske,Found: 71.63 7.21 6.34 (g) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid yield: 48, 2% of theoretical,

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65 smeltepunkt: 168-170°C (petroleumsether)65 mp: 168-170 ° C (petroleum ether)

Beregnet: C 73,91 H 8,11 N 6,63Calculated: C, 73.91; H, 8.11; N, 6.63

Fundet : 73,51 7,89 6,32Found: 73.51 7.89 6.32

5 (h) 4-[(1-(3-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 53% af det teoretiske, smeltepunkt: 179-182°C5 (h) 4 - [(1- (3-methyl-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 53% of theory, m.p .: 179-182 ° C

Beregnet: C 73,50 H 7,90 N 6,86 10 Fundet : 73,50 7,82 7,01 (i) 4-[(1-(4-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 85,6% af det teoretiske,Calculated: C 73.50 H 7.90 N 6.86 Found: 73.50 7.82 7.01 (i) 4 - [(1- (4-methyl-2-piperidino-phenyl) -1-butyl ) -amino-carbonylmethyl] -benzoic acid yield: 85.6% of theory,

15 smeltepunkt: 170-172°CMp 170-172 ° C

Beregnet: C 73,50 H 7,90 N 6,86Calculated: C, 73.50; H, 7.90; N, 6.86

Fundet : 73,25 7,64 6,89 (k) 4-[(1-(5-methyl-2-piperidino-phenyl)-1-butyl)-amino- 2 0 carbonylmethyl]-benzoesyre udbytte: 62,1% af det teoretiske, smeltepunkt: 219-221°C Beregnet: C 73,50 H 7,90 N 6,86Found: 73.25 7.64 6.89 (k) 4 - [(1- (5-methyl-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 62.1 % of theory, melting point: 219-221 ° C Calculated: C 73.50 H 7.90 N 6.86

Fundet : 73,20 7,74 6,89 25 (l) 4-t(1-(6-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre x 0,3 H20Found: 73.20 7.74 6.89 (1) 4-t (1- (6-methyl-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid x 0.3 H 2 O

udbytte: 89% af det teoretiske, smeltepunkt: 158-160°Cyield: 89% of theory, melting point: 158-160 ° C

30 Beregnet: C 72,53 H 7,93 N 6,77Calcd: C 72.53 H 7.93 N 6.77

Fundet : 72,40 7,91 6,92 (m) 4-[(1-(3-chlor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyreFound: 72.40 7.91 6.92 (m) 4 - [(1- (3-Chloro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid

35 udbytte: 70% af det teoretiske, smeltepunkt: 189-191°CYield: 70% of theory, melting point: 189-191 ° C

Beregnet: C 67,20 H 6,81 Cl 8,27 N 6,53Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53

Fundet : 67,30 6,85 8,36 6,58Found: 67.30 6.85 8.36 6.58

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66 (n) 4-[(1-(4-chlor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre66 (n) 4 - [(1- (4-Chloro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid

udbytte: 57,8% af det teoretiske, smeltepunkt: 188-189°Cyield: 57.8% of theory, melting point: 188-189 ° C

5 Beregnet: C 67,20 H 6,81 Cl 8,27 N 6,53Calc'd: C 67.20 H 6.81 Cl 8.27 N 6.53

Fundet : 66,90 7,00 8,22 6,53 (o) 4-[(1-(5-chlor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre 10 udbytte: 81,6% af det teoretiske,Found: 66.90 7.00 8.22 6.53 (o) 4 - [(1- (5-Chloro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid Yield: 81 , 6% of theory,

smeltepunkt: 226-229°Cmp: 226-229 ° C

Beregnet: C 67,20 H 6,81 Cl 8,27 N 6,53Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53

Fundet : 67,17 6,59 8,51 6,60 15 (p) 4-[(1-(6-chlor-2-piperidino-phenyl)-1-butyl)-amino-Found: 67.17 6.59 8.51 6.60 (p) 4 - [(1- (6-Chloro-2-piperidino-phenyl) -1-butyl) -amino

carbonylmethyl]-benzoesyre udbytte: 69,4% af det teoretiske, smeltepunkt: 150-153°Ccarbonylmethyl] -benzoic acid yield: 69.4% of theory, melting point: 150-153 ° C

Beregnet: C 67,20 H 6,81 Cl 8,27 N 6,53 20 Fundet : 67,18 6,91 8,42 6,77 (q) 4-[(1-(4-brom-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 84,4% af det teoretiske,Calculated: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.18 6.91 8.42 6.77 (q) 4 - [(1- (4-bromo-2-piperidino) -phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 84.4% of theory,

25 smeltepunkt: 198-201°CMp: 198-201 ° C

Beregnet: C 60,89 H 6,17 Br 16,88 N 5,92Calculated: C 60.89 H 6.17 Br 16.88 N 5.92

Fundet : 60,88 5,98 17,20 5,98 (r) 4-[(1-(5-brom-2-piperidino-phenyl)-1-butyl)-amino- 30 carbonylmethyl]-benzoesyreFound: 60.88 5.98 17.20 5.98 (r) 4 - [(1- (5-bromo-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

udbytte: 90,7% af det teoretiske, smeltepunkt: 232-235°Cyield: 90.7% of theory, melting point: 232-235 ° C

Beregnet: C 60,89 H 6,17 Nr 16,88 N 5,92C, 60.89; H, 6.17; No. 16.88; N, 5.92

Fundet : 60,96 6,13 16,85 5,90 35 (s) 4-[(1-(4-nitro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 70,9% af det teoretiske, 67Found: 60.96 6.13 16.85 5.90 (s) 4 - [(1- (4-nitro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 70 , 9% of theoretical, 67

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smeltepunkt: 188-190°Cmp 188-190 ° C

Beregnet: C 65,59 H 6,65 N 9,56Calculated: C 65.59 H 6.65 N 9.56

Fundet : 65,30 6,44 9,53 5 (t) 4-[(1-(5-nitro-2-piperidino-phenyl)-1-butyl)-amino- carbonylmethyl]-benzoesyre udbytte: 90,7% af det teoretiske, smeltepunkt: 225-227°C Beregnet: C 65,59 H 6,65 N 9,56 10 Fundet : 65,80 6,61 9,72Found: 65.30 6.44 9.53 5 (t) 4 - [(1- (5-nitro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid yield: 90.7% of theoretical, melting point: 225-227 ° C Calculated: C 65.59 H 6.65 N 9.56 10 Found: 65.80 6.61 9.72

(u) 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-ami-nocarbonylmethyl]-benzoesyre x 0,5 I^O(u) 4 - [(1- (4-hydroxy-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid x 0.5 l

udbytte: 85,7% af det teoretiske, 15 smeltepunkt: blødgøring fra 70°C (skum)yield: 85.7% of theory, 15 melting point: softening from 70 ° C (foam)

Beregnet: (x 0,5 E^O) C 68,71 H 7,45 N 6,68Calculated: (x 0.5 E 2 O) C 68.71 H 7.45 N 6.68

Fundet : 68,63 7,55 6,26 (v) 4-[(1-(5-hydroxy-2-piperidino-phenyl)-1-butyl)-ami- 20 nocarbonylmethyl]-benzoesyre udbytte: 89,3% af det teoretiske, smeltepunkt: 18 6-190°C Beregnet: C 70,22 H 7,37 N 6,82Found: 68.63 7.55 6.26 (v) 4 - [(1- (5-hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid yield: 89.3% of the theoretical, melting point: 18 6-190 ° C Calculated: C 70.22 H 7.37 N 6.82

Fundet : 70,31 7,58 6,51 25 (w) 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyreFound: 70.31 7.58 6.51 (w) 4 - [(1- (4-Methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

udbytte: 78,6% af det teoretiske, smeltepunkt: 185-187°Cyield: 78.6% of theory, m.p .: 185-187 ° C

30 Beregnet: C 70,73 H 7,60 N 6,60Calc'd: C 70.73 H 7.60 N 6.60

Fundet : 70,46 7,77 6,56 (x) 4-[(1-(5-methoxy-2-piperidino-phenyl)-l-butyl)-ami-nocarbonylmethyl]-benzoesyre 35 udbyttes 75% af det teoretiske, smeltepunkt: 182-185°c (sønderdeling)Found: 70.46 7.77 6.56 (x) 4 - [(1- (5-Methoxy-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid, 75% of theory is exchanged , mp: 182-185 ° C (dec.)

Beregnet: C70,73 H 7,60 N 6,60Calculated: C70.73 H 7.60 N 6.60

Fundet : 70,52 7,50 6,70Found: 70.52 7.50 6.70

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68 (y) 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbo-nylmethyl]-benzoesyre68 (y) 4 - [(1- (2-pyrrolidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

udbytte: 64,5% af det teoretiske, smeltepunkt: 200-213°Cyield: 64.5% of theory, melting point: 200-213 ° C

5 Beregnet: C 72,61 H 7,42 N 7,36C, 72.61; H, 7.42; N, 7.36

Fundet : 72,64 7,50 7,38 (z) 4-[(1-(2-(4-methyl-piperidino)-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre 10 udbytte: 81,4 % af det teoretiske, smeltepunkt: 197-201°C Beregnet: C 73,50 H 7,90 N 6,86Found: 72.64 7.50 7.38 (z) 4 - [(1- (2- (4-methyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid yield: 81.4% of the theoretical, melting point: 197-201 ° C Calculated: C 73.50 H 7.90 N 6.86

Fundet : 73,90 8,06 7,00 15(aa) 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 65,6% af det teoretiske, smeltepunkt: 199-102°C Beregnet: C 73,50 H 7,90 N 6,86 20 Fundet : 73,50 7,90 6,76 (ab) 4-[(1-(4-fluor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 87,1% af det teoretiske,Found: 73.90 8.06 7.00 (aa) 4 - [(1- (2-Hexahydroazepino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 65.6% of theory, Melting point: 199-102 ° C Calculated: C 73.50 H 7.90 N 6.86 Found: 73.50 7.90 6.76 (ab) 4 - [(1- (4-fluoro-2-piperidino) -phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 87.1% of theory,

25 smeltepunkt: 204-207°CMelting point: 204-207 ° C

Beregnet: C 69,88 H 7,09 N 6,79Calculated: C, 69.88; H, 7.09; N, 6.79

Fundet : 70,25 7,02 7,12 (ac) 4-[(1-(5-fluor-2-piperidino-phenyl)-1-butyl)-amino- 30 carbonylmethyl]-benzoesyre udbytte: 53,9% af det teoretiske, smeltepunkt: 200-202°C Beregnet: C 69,88 H 7,09 N 6,79Found: 70.25 7.02 7.12 (ac) 4 - [(1- (5-fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid yield: 53.9% of the theoretical, melting point: 200-202 ° C Calculated: C 69.88 H 7.09 N 6.79

Fundet : 69,67 7,24 6,90 35Found: 69.67 7.24 6.90 35

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6969

Eksempel 26 4-[(2-Methyl-l-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl]-benzoesyre.Example 26 4 - [(2-Methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] -benzoic acid.

5 Man omrører en blanding af 3,5 g (8,3 mmol) 4-[(2-methyl-l-(2-piperidino-phenyl)-1-propen-l-yl)-aminocarbonylmethyl]-benzoesyre-ethylester og 12,5 ml 1 N natronlud i 35 ml ethanol i 2 timer ved 60°C.A mixture of 3.5 g (8.3 mmol) of 4 - [(2-methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester is stirred. 12.5 ml of 1 N sodium hydroxide solution in 35 ml of ethanol for 2 hours at 60 ° C.

Man neutraliserer med 12,5 ml 1 N saltsyre, inddamper 10 i vakuum og fordeler mellem ethylacetat og vand. Den tørrede filtrerede organiske ekstrakt inddampes i vakuum. Inddampningsresten krystalliseres af ethanol.Neutralize with 12.5 ml of 1 N hydrochloric acid, evaporate 10 in vacuo and partition between ethyl acetate and water. The dried filtered organic extract is evaporated in vacuo. The residue is crystallized by ethanol.

Udbytte: 2,4 g (73,6% af det teoretiske), smeltepunkt: 188-191°C 15 Beregnet: C 73,44 H 7,19 N 7,14Yield: 2.4 g (73.6% of theory), m.p .: 188-191 ° C Calculated: C 73.44 H 7.19 N 7.14

Fundet : 73,60 7,19 7,02 Følgende forbindelser blev opnået analogt med eksempel 26: 20Found: 73.60 7.19 7.02 The following compounds were obtained analogously to Example 26: 20

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70 (a) (E)-4-[(1-(2-piperidino-phenyl)-l-buten-l-yl)-amino-carbonylmethyl]-benzoesyre70 (a) (E) -4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -amino-carbonylmethyl] -benzoic acid

udbytte: 71,-5% af det teoretiske, smeltepunkt: 188-190°Cyield: 71, -5% of theory, m.p .: 188-190 ° C

5 Beregnet: C 73,44 H 7,19 N 7,14C, 73.44; H, 7.19; N, 7.14

Fundet : 73,15 7,13 7,10Found: 73.15 7.13 7.10

Olefinisk proton: ^H-NMR (CDCl^) : δ = 6,42 ppm (b) (Z) —4—[(1-(2-piperidino-phenyl)-l-buten-l-yl)-amino- 10 carbonylmethyl]-benzoesyre udbytte: 57,8% af det teoretiske, smeltepunkt: 174-175°C (ethanol)Olefinic Proton: 1 H-NMR (CDCl 3): δ = 6.42 ppm (b) (Z) -4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -amino] 10 carbonylmethyl] -benzoic acid yield: 57.8% of theory, m.p .: 174-175 ° C (ethanol)

Beregnet: C 73,44 H 7,19 N 7,14Calculated: C 73.44 H 7.19 N 7.14

Fundet : 73,54 6,97 7,17 15 Olefinisk proton:' 1H-NMR (CDCl-j) : δ = 5,60 ppm (c) (E)-4-[(2-phenyl-1-(2-piperidino-phenyl)-ethen-l-yl)-aminocarbonylmethyl]-benzoesyre x 0,4 H20 udbytte 33,2% af det teoretiske, 20 smeltepunkt 165-167°C (ether/petroleumsether)Found: 73.54 6.97 7.17 Olefinic proton: 1 H NMR (CDCl3): δ = 5.60 ppm (c) (E) -4 - [(2-phenyl-1- (2) -piperidino-phenyl) -ethen-1-yl) -aminocarbonylmethyl] -benzoic acid x 0.4 H 2 O yield 33.2% of the theoretical 20 mp 165-167 ° C (ether / petroleum ether)

Beregnet: (x 0,4 H20): C 75,11 H 6,48 N 6,26Calculated: (x 0.4 H 2 O): C 75.11 H 6.48 N 6.26

Fundet : 72,22 6,39 6,26Found: 72.22 6.39 6.26

Olefinisk proton: ^H-NMR (CDCl^): δ >6,9 ppm 25 (d) (Z)-4-[(2-phenyl-l-(2-piperidino-phenyl)-ethen-1-yl)-aminocarbonylmethyl]-benzoesyre x 1 H20 udbytte: 72% af det teoretiske, smeltepunkt: 182-185°C (methanol)Olefinic Proton: 1 H-NMR (CDCl3): δ> 6.9 ppm (d) (Z) -4 - [(2-phenyl-1- (2-piperidino-phenyl) -ethen-1-yl) -aminocarbonylmethyl] -benzoic acid x 1 H 2 O yield: 72% of theoretical, melting point: 182-185 ° C (methanol)

Beregnet: (x 1 H20): C 73,34 H 6,60 N 6,11 30 Fundet : 73,55 6,45 6,00Calculated: (x 1 H 2 O): C 73.34 H 6.60 N 6.11 Found: 73.55 6.45 6.00

Olefinisk proton: ^H-NMR (CDC13): δ = 6,50 ppm (e) 4-[(3-phenyl-l-(2-piperidino-phenyl)-1-propen-l-yl)- aminocarbonylmethyl]-benzoesyre 35 udbytte: 48,3% af det teoretiske, smeltepunkt: 162-164°C (ether); sandsynligvis (Z)-formOlefinic Proton: 1 H NMR (CDCl 3): δ = 6.50 ppm (e) 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] - yield: 48.3% of theory, melting point: 162-164 ° C (ether); probably (Z) form

Beregnet: C 76,63 H 6,65 N 6,16Calculated: C 76.63 H 6.65 N 6.16

Fundet : 76,30 6,47 6,31Found: 76.30 6.47 6.31

Olefinisk proton: 1H-NMR (CDCl^): δ = 5,80 ppmOlefinic Proton: 1 H NMR (CDCl 3): δ = 5.80 ppm

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71 (f) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoesyre udbytte: 64,1% af det teoretiske, smeltepunkt: 152-153°C (ethylacetat); sandsynligvis 5 (Z)-form71 (f) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid yield: 64.1% of theory, melting point : 152-153 ° C (ethyl acetate); probably 5 (Z) shape

Beregnet: C 74,26 H 7,67 N 6,67Calculated: C 74.26 H 7.67 N 6.67

Fundet : 73,93 7,57 6,50Found: 73.93 7.57 6.50

Olefinisk proton: 1H-NMR (CDClg): δ = 5,55 ppm 10 (g) (Z)-4-[(1-(6-methyl-2-piperidino-phenyl)-1-buten-l-Olefinic Proton: 1 H-NMR (CDCl 3): δ = 5.55 ppm 10 (g) (Z) -4 - [(1- (6-methyl-2-piperidino-phenyl) -1-butene-1-

yl)-aminocarbonylmethyl]-benzoesyre udbytte: 53,3% af det teoretiske, smeltepunkt: 142-145°CYl) -aminocarbonylmethyl] -benzoic acid yield: 53.3% of theory, m.p .: 142-145 ° C

Beregnet: C73,66 H 7,44 N 6,89 15 Fundet : 73,56 7,73 7,15Calculated: C73.66 H 7.44 N 6.89 Found: 73.56 7.73 7.15

Olefinisk proton: 1H-NMR (CDClg): δ = 5,38 ppmOlefinic Proton: 1 H NMR (CDCl 3): δ = 5.38 ppm

Eksempel 27 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylme-20 thyl]-benzoesyre.Example 27 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid.

Man hydrogenerer ved 50°C og 1 bar hydrogen 200 mg (0,51 mmol) 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoesyre i 10 ml absolut éthanol i nærværelse af 100 mg palladium/carbon (10%'ig) under 25 omrøring. Efter 1 1/2 times forløb filtrerer man og inddamper i vakuum.Hydrogen at 50 ° C and 1 bar hydrogen 200 mg (0.51 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid in 10 ml of absolute ethanol in the presence of 100 mg of palladium / carbon (10% µg) with stirring. After 1 1/2 hours, filter and evaporate in vacuo.

Udbytte: 68% af det teoretiske, smeltepunkt: 213-214°CYield: 68% of theory, melting point: 213-214 ° C

Beregnet: C 73,07 H 7,66 N 7,10 30 Fundet : 73,21 7,82 7,02Calculated: C 73.07 H 7.66 N 7.10 Found: 73.21 7.82 7.02

Udbyttet andrager 56% af det teoretiske, når man hydrogenerer ved 50°C og 1 bar hydrogen i nærværelse af Raney-nikkel.The yield is 56% of theory when hydrogenated at 50 ° C and 1 bar of hydrogen in the presence of Raney nickel.

35 Eksempel 28 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoesyre-natriumsalt x 0,5 H20.Example 28 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid sodium salt x 0.5 H2 O.

Man opløser 10,0 g (25,35 mmol) 4-[(1-(2-piperi- 7210.0 g (25.35 mmol) of 4 - [(1- (2-piperidine) 72) are dissolved

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dino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre i 200 ml ethanol ved 50°C og tilsætter 25,35 ml 1 N natronlud. Man inddamper til tørhed i vakuum og opløser inddampningsresten i den mindst mulige mængde ethanol 5 under opvarmning på dampbad. Man afkøler i isbad, filtrerer fra de udfældede krystaller, vasker med ether og tørrer ved 140°C/15 Torr.dino-phenyl-1-butyl) -aminocarbonylmethyl] -benzoic acid in 200 ml of ethanol at 50 ° C, adding 25.35 ml of 1 N sodium hydroxide solution. Evaporate to dryness in vacuo and dissolve the residue in the least amount of ethanol 5 while heating on a steam bath. It is cooled in an ice bath, filtered from the precipitated crystals, washed with ether and dried at 140 ° C / 15 Torr.

Udbytte: 9 g (85,3% af det teoretiske), smeltepunkt: 280-285°C (sønderdeling); blødgøring fra 10 255°CYield: 9 g (85.3% of theory), mp: 280-285 ° C (dec.); softening from 10 255 ° C

Beregnet (x 0,5 H20): C 67,74 H 6,87 N 6,58Calcd (x 0.5 H 2 O): C 67.74 H 6.87 N 6.58

Fundet : 67,86 7,13 6,49Found: 67.86 7.13 6.49

Eksempel 29 15 (+)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl methyl] -benzoesyre-ethylester.Example 29 (+) - 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl methyl] -benzoic acid ethyl ester.

Til en omrørt opløsning af 2,58 g (11,1 mmol) (+)-1-(2-piperidino-phenyl)-1-butylamin [K^ ^ q2:87°C; ee = 86 (HPLC, efter derivatisering med (+)-l-phen-20 ethyl-isocyanat)] i 26 ml acetonitril sætter man ved 20°C successivt 2,31 g (11,1 mmol) 4-ethoxycarbonyl-phenyleddikesyre, 3,50 g (13,3 mmol) triphenylphosphin, 4,60 ml (33,9 mmol) triethylamin og 1,03 ml (11,1 mmol) tetrachlorkulstof. Efter 14 timer ved 20°C og 1 1/2 ti-25 me ved 40°C inddamper man i vakuum og fordeler mellem vand og ether. Den organiske fase tørres over natriumsulfat, filtreres og inddampes i vakuum. Inddampningsresten renses ved søjlechromatografi på kiselgel (toluen/acetone = 6:1).To a stirred solution of 2.58 g (11.1 mmol) (+) - 1- (2-piperidino-phenyl) -1-butylamine [K ee = 86 (HPLC, after derivatization with (+) - 1-phenethyl-isocyanate)] in 26 ml of acetonitrile, at 20 ° C, 2.31 g (11.1 mmol) of 4-ethoxycarbonyl-phenylacetic acid is successively added, 3.5hen g (13.3 mmol) of triphenylphosphine, 4.60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of tetrachloro carbon. After 14 hours at 20 ° C and 1 1/2 hours at 40 ° C, evaporate in vacuo and partition between water and ether. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (toluene / acetone = 6: 1).

30 Udbytte: 2,63 g (56% af det teoretiske), smeltepunkt: 118-120°C.Yield: 2.63 g (56% of theory), m.p .: 118-120 ° C.

Beregnet: C 73,90 H 8,11 N 6,63Calculated: C, 73.90; H, 8.11; N, 6.63

Fundet : 74,02 7,97 6,51 [a]^ = +9,2° (c = 1; methanol) 35Found: 74.02 7.97 6.51 [α] D = + 9.2 ° (c = 1; methanol)

Nedenstående forbindelse blev opnået analogt med eksempel 29:The following compound was obtained analogously to Example 29:

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73 (a) (-)-4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-car bony lme thyl] -benzoesyre-ethylester fremstillet ud fra (-)-1-(2-piperidino-phenyl)-1-butylamin x 1,4 HC1 [[a]^ = -20,0° (c = 1, methanol), 5 sonelteområde: 90-100°C; ee = 80 (HPLC, efter derivati-sering af basen med (+)-1-phenethyl-isocyanat)] udbytte: 52,6% af det teoretiske, smeltepunkt: 115-120°C Beregnet: C 73,90 H 8,11 N 6,63 10 Fundet : 73,83 8,01 6,47 [a]^ = -9,0° (c = 1, methanol)73 (a) (-) - 4 - [(1- (2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester prepared from (-) - 1- (2- piperidino-phenyl) -1-butylamine x 1.4 HCl [[α] D = -20.0 ° (c = 1, methanol), zone area: 90-100 ° C; ee = 80 (HPLC, after derivatization of the base with (+) - 1-phenethyl-isocyanate)] yield: 52.6% of theory, m.p .: 115-120 ° C Calculated: C 73.90 H 8, 11 N 6.63 Found: 73.83 8.01 6.47 [α] D = -9.0 ° (c = 1, methanol)

Eksempel 30 (+) -4- [ CL—(2-Piperidino-phenyl) -1-butyl) -aminocarbonyl- 15 methyl]-benzoesyre-ethylester.Example 30 (+) -4- [CL - (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Man suspenderer 1,0 g (3,27 mmol) (+)-1-(2-pipe- 20 ridino-phenyl) -1-butylamin-dihydrochlorid [ [ <x ] = + 18,7° (c = 1, methanol), smeltepunkt: fra 115°C sønderdeling; ee = 91,6 (HPLC, efter derivatisering 20 af basen med (+)-1-phenethyl-isocyanat)] i 6 ml methy-lenchlorid, tilsætter under omrøring 1,4 ml (10 mmol) triethylamin og tildrypper derefter en opløsning af 0,82 g (3,64 mmol) 4-ethoxycarbonyl-phenyleddikesyre-chlorid i 2,4 ml methylenchlorid, hvorved reaktions-25 temperaturen stiger fra 22°C til 38°C. Man omrører i 6 timer ved stuetemperatur og udryster successivt: to gange med vand, hver gang 10 ml, en gang med 10 ml 2 N saltsyre og en gang med 10 ml vand.1.0 g (3.27 mmol) of (+) - 1- (2-piperidino-phenyl) -1-butylamine dihydrochloride is suspended [[<x] = + 18.7 ° (c = 1, methanol), melting point: from 115 ° C decomposition; ee = 91.6 (HPLC, after derivatization of the base with (+) - 1-phenethyl-isocyanate)] in 6 ml of methylene chloride, with stirring, add 1.4 ml (10 mmol) of triethylamine and then drop a solution of 0.82 g (3.64 mmol) of 4-ethoxycarbonylphenylacetic acid chloride in 2.4 ml of methylene chloride, increasing the reaction temperature from 22 ° C to 38 ° C. Stir for 6 hours at room temperature and shake successively: twice with water, each time 10 ml, once with 10 ml of 2N hydrochloric acid and once with 10 ml of water.

30 Man tørrer den organiske fase over natriumsulfat, filtrerer den og inddamper i vakuum. Inddampningsresten renses ved søjlechromatografi på kiselgel (toluen/ace-tone = 6:1).The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (toluene / ace tone = 6: 1).

Udbytte: 0,53 g (38,2% af det teoretiske),Yield: 0.53 g (38.2% of theory),

35 smeltepunkt: 120-122°CMp 120-122 ° C

Beregnet: C 73,90 H 8,11 N 6,63Calculated: C, 73.90; H, 8.11; N, 6.63

Fundet : 73,96 7,98 6,61 [a]^ = +9,0° (c = 1, methanol) 74Found: 73.96 7.98 6.61 [α] D = + 9.0 ° (c = 1, methanol) 74

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Eksempel 31 (+)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre.Example 31 (+) - 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid.

Man omrører 2,0 g (4,73 mmol) (+)-4-[(1-(2-pipe-5 ridino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoe-syre-ethylester [[a]^° = +9,2° (c = 1, methanol)] i 20 ml ethanol sammen med 7,0 ml 1 N natronlud i 2 1/2 time i et bad på 65°C. Man afkøler og tilsætter 7,0 ml 1 N saltsyre. De krystaller, der langsomt udskilles 10 frafiltrerer man, vasker dem med vand og tørrer ved 100°C/4 Torr.2.0 g (4.73 mmol) of (+) - 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester are stirred [[a] = + 9.2 ° (c = 1, methanol)] in 20 ml of ethanol together with 7.0 ml of 1N sodium hydroxide for 2 1/2 hours in a 65 ° C bath. Cool and add 7.0 ml of 1N hydrochloric acid. The crystals which are slowly separated are filtered off, washed with water and dried at 100 ° C / 4 Torr.

Udbytte: 1,65 g (88,2% af det teoretiske), smeltepunkt: 185-187°C Beregnet: C 73,07 H 7,66 N 7,10 15 Fundet : 72,90 7,80 7,17 [a]p° = +7,9° (c = 1, methanol) Følgende forbindelse blev opnået analogt med eksempel 31: 20Yield: 1.65 g (88.2% of theory), m.p .: 185-187 ° C Calculated: C 73.07 H 7.66 N 7.10 Found: 72.90 7.80 7.17 [ a] p ° = + 7.9 ° (c = 1, methanol) The following compound was obtained analogously to Example 31: 20

(a) (-)-4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoesyre udbytte: 80% af det teoretiske, smeltepunkt: 187-190°C(a) (-) - 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid yield: 80% of theory, m.p .: 187-190 ° C

25 Beregnet: C 73,07 H 7,66 N 7,10Calculated: C 73.07 H 7.66 N 7.10

Fundet : 72,98 7,44 7,22 [a]^° = -7,9° (c - 1, methanol)Found: 72.98 7.44 7.22 [a] + = -7.9 ° (c - 1, methanol)

Eksempel 32 30 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl methyl] -benzonitril.Example 32 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl methyl] -benzonitrile.

Fremstillet ud fra 1-(2-piperidino-phenyl)-1-butylamin og 4-cyano-phenyleddikesyre analogt med eksempel 19.Prepared from 1- (2-piperidino-phenyl) -1-butylamine and 4-cyano-phenylacetic acid analogous to Example 19.

35 Udbytte: 57,3% af det teoretiske, smeltepunkt: 147-148°C Beregnet: C 76,76 H 7,78 N 11,19Yield: 57.3% of theory, melting point: 147-148 ° C Calculated: C 76.76 H 7.78 N 11.19

Fundet : 76,46 7,81 11,10 75Found: 76.46 7.81 11.10 75

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Følgende forbindelse blev opnået analogt med eksempel 32: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-5 methyl]-toluen fremstillet med 4-tolyl-eddikesyre.The following compound was obtained analogously to Example 32: (a) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-5-methyl] -toluene prepared with 4-tolyl acetic acid.

Udbytte: 60,4% af det teoretiske, smeltepunkt: 150-153°C Beregnet: C 79,08 H 8,85 N 7,68 10 Fundet : 78,97 8,58 7,77Yield: 60.4% of theory, melting point: 150-153 ° C Calculated: C 79.08 H 8.85 N 7.68 Found: 78.97 8.58 7.77

Eksempel 33 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-ethylester.Example 33 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester.

15 Fremstillet ud fra 4-[(1-(2-piperidino-phenyl)-1- butyl)-aminocarbonylmethyl]-benzonitril med ethanolisk saltsyre analogt med eksempel 14.Prepared from 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzonitrile with ethanolic hydrochloric acid analogous to Example 14.

Udbytte: 58% af det teoretiske, smeltepunkt: 127-128°C 20 Beregnet: C 73,90 H 8,11 N 6,63Yield: 58% of theory, melting point: 127-128 ° C Calc'd: C 73.90 H 8.11 N 6.63

Fundet : 74,07 8,23 6,87Found: 74.07 8.23 6.87

Eksempel 34 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-25 methyl]-benzoesyre-ethylester.Example 34 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester.

Fremstillet analogt med eksempel 10 ud fra 1—(2— piperidino-phenyl)-1-butanol og 4-cyanomethyl-benzoesy-re-ethylester med koncentreret svovlsyre i o-dichlor-benzen ved stuetemperatur.Prepared analogously to Example 10 from 1- (2-piperidino-phenyl) -1-butanol and 4-cyanomethyl-benzoic acid ethyl ester with concentrated sulfuric acid in o-dichlorobenzene at room temperature.

30 Udbytte: 21% af det teoretiske, smeltepunkt: 126-128°CYield: 21% of theory, melting point: 126-128 ° C

Beregnet: C 73,90 H 8,11 N 6,63Calculated: C, 73.90; H, 8.11; N, 6.63

Fundet : 74,12 8,20 6,45 35 Føgende forbindelse blev opnået analogt med eksempel 34: 76Found: 74.12 8.20 6.45 The following compound was obtained by analogy with Example 34: 76

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(a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre fremstillet ud fra 1-(2-piperidino-phenyl)-1-buta-nol og 4-cyanomethyl-benzoesyre. Ekstraktion ved 5 pH 5,5.(a) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid prepared from 1- (2-piperidino-phenyl) -1-butanol and 4-cyanomethyl benzoic acid. Extraction at pH 5.5.

Udbytte: 29% af det teoretiske, smeltepunkt: 215-217°C Beregnet: C 73,07 H 7,66 N 7,10Yield: 29% of theory, melting point: 215-217 ° C Calculated: C 73.07 H 7.66 N 7.10

Fundet : 72,82 7,69 6,95 10Found: 72.82 7.69 6.95 10

Eksempel 35 4-[(1-(4-Amino-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre x 0,5 ^O.Example 35 4 - [(1- (4-Amino-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid x 0.5

Man hydrogenerer 0,60 g (1,365 mmol) 4-[(1-(4-15 nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylme-thyl]-benzoesyre i 10 ml dimethylformamid i 3 timer ved 25°C og 1 bar hydrogen i nærværelse af 0,1 g palladium/carbon (10%'ig). Man filtrerer fra katalysatoren over kiselgur og inddamper i vakuum. Inddamp-20 ningsresten krystalliseres af ether.0.60 g (1.365 mmol) of 4 - [(1- (4-nitro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid is hydrogenated in 10 ml of dimethylformamide for 3 hours at 25 ° C. C and 1 carry hydrogen in the presence of 0.1 g of palladium / carbon (10% µg). The catalyst is filtered over the diatomaceous earth and evaporated in vacuo. The residue is crystallized by ether.

Udbytte: 0,41 g (73,2% af det teoretiske), smeltepunkt: 118-120°CYield: 0.41 g (73.2% of theory), m.p .: 118-120 ° C

Beregnet (x 0,5 Η2<0) : C 68,87 H 7,71 N 10,04Calcd (x 0.5 Η 2 <0): C 68.87 H 7.71 N 10.04

Fundet : 68,62 7,64 10,08 25 Følgende forbindelser blev opnået analogt med eksempel 35: (a) 4-[(1-(4-amino-2-piperidino-phenyl)-1-butyl)-amino- 30 carbonylmethyl]-benzoesyre-ethylester udbytte: 81,7% af det teoretiske, smeltepunkt: 145-146°C (ether/petroleumsether)Found: 68.62 7.64 10.08 The following compounds were obtained analogously to Example 35: (a) 4 - [(1- (4-Amino-2-piperidino-phenyl) -1-butyl) -amino-30 carbonylmethyl] -benzoic acid ethyl ester yield: 81.7% of theory, melting point: 145-146 ° C (ether / petroleum ether)

Beregnet: C 71,37 H 8,06 N 9,60Calculated: C, 71.37; H, 8.06; N, 9.60

Fundet : 71,50 8,08 9,68 35 (b) 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre udbytte: 64% af det teoretiske, 77Found: 71.50 8.08 9.68 (b) 4 - [(1- (5-Amino-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid yield: 64% of that theoretical, 77

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smeltepunkt: 227-230°Cmp: 227-230 ° C

Beregnet: C 70,39 H 7,63 N 10,26Calculated: C, 70.39; H, 7.63; N, 10.26

Fundet : 70,54 7,54 10,36 5 (c) 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-amino-Found: 70.54 7.54 10.36 (c) 4 - [(1- (5-Amino-2-piperidino-phenyl) -1-butyl) -amino

carbonylmethyl]-benzoesyre-ethylester udbytte: 84,3% af det teoretiske, smeltepunkt: 162-165°Ccarbonylmethyl] -benzoic acid ethyl ester yield: 84.3% of theory, melting point: 162-165 ° C

Beregnet: C 71,37 H 8,06 N 9,60 10 Fundet : 71,58 7,83 9,65Calculated: C 71.37 H 8.06 N 9.60 Found: 71.58 7.83 9.65

Eksempel 36 4-[(1-(5-Chlor-2-piperidino-phenyl)-1-butyl)-aminocar-bonylmethy1]-benzoesyre-ethylester.Example 36 4 - [(1- (5-Chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

15 Man fremstiller ud fra 2,0 g (4,57 mmol) 4—[(1— (5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-ethylester i 4,8 ml halvkoncentreret saltsyre og 0,315 g (4,57 mmol) natriumnitrit i 1,66 ml vand en 0°C kold diazoniumsaltopløsning. Denne drypper 20 man ved 0-5°C til en omrørt blanding af 0,59 g (5,94 mmol) kobber(I)chlorid og 2,4 ml koncentreret saltsyre og opvarmer derpå i et bad på 50°C. Efter at gasudviklingen er ophørt (ca. 15 minutter) afkøler man, indfører reaktionsblandingen i is/koncentreret ammoniak og 25 ekstraherer fire gange, hver gang med 100 ml ethylace-tat. De forenede organiske ekstrakter udrystes med vand, tørres og filtreres og inddampes i vakuum. Ind-dampningsresten renses ved søjlechromatografi på kiselgel (toluen/ethylacetat = 10:1).Prepare from 2.0 g (4.57 mmol) of 4 - [(1- (5-amino-2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester in 4.8 ml of semi-concentrated hydrochloric acid and 0.315 g (4.57 mmol) of sodium nitrite in 1.66 ml of water a 0 ° C cold diazonium salt solution. This is dripped at 0-5 ° C to a stirred mixture of 0.59 g (5.94 mmol) of copper (I) chloride and 2.4 ml of concentrated hydrochloric acid and then heated in a 50 ° C bath. After gas evolution has ceased (about 15 minutes), cool the reaction mixture into ice / concentrated ammonia and extract four times, each time with 100 ml of ethyl acetate. The combined organic extracts are shaken with water, dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / ethyl acetate = 10: 1).

30 Udbytte: 0,80 g (40% af det teoretiske), smeltepunkt: 137-140°C (ether)Yield: 0.80 g (40% of theory), m.p. 137-140 ° C (ether)

Beregnet: C 68,32 H 7,27 Cl 7,75 N 6,13Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13

Fundet : 68,42 7,09 8,06 6,05 35 Følgende forbindelser blev opnået analogt med eksempel 36:Found: 68.42 7.09 8.06 6.05 The following compounds were obtained analogously to Example 36:

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78 (a) 4-[(1-(4-chlor-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre-ethylester78 (a) 4 - [(1- (4-Chloro-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester

udbytte: 21,9% af det teoretiske, smeltepunkt: 123-125°Cyield: 21.9% of theory, melting point: 123-125 ° C

5 Beregnet: C 68,32 H 7,27 Cl 7,75 N 6,13Calculated: C 68.32 H 7.27 Cl 7.75 N 6.13

Fundet : 68,70 7,18 7,77 6,08 (b) 4-[(1-(5-brom-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoesyre-ethylester 10 udbytte: 53,8% af det teoretiske,Found: 68.70 7.18 7.77 6.08 (b) 4 - [(1- (5-bromo-2-piperidino-phenyl) -1-butyl) -amino-carbonylmethyl] -benzoic acid ethyl ester yield : 53.8% of theory,

smeltepunkt: 140-14 2°Cmelting point: 140-14 2 ° C

Beregnet: C 62,27 H 6,63 Br 15,93 N 5,58Calculated: C 62.27 H 6.63 Br 15.93 N 5.58

Fundet : 62,39 6,78 15,85 5,59 15 (c) 4-[(1-(4-fluor-2-piperidino-phenyl)-1-butyl)-amino- carbonylmethyl]-benzoesyre-ethylester udbytte: 21,6% af det teoretiske, smeltepunkt: 110-112°C Beregnet: C 70,88 H 7,55 N 6,36 20 Fundet : 71,01 7,53 6,21Found: 62.39 6.78 15.85 5.59 (c) 4 - [(1- (4-Fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield : 21.6% of theory, melting point: 110-112 ° C Calculated: C 70.88 H 7.55 N 6.36 Found: 71.01 7.53 6.21

Desuden isoleres 40% 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester (fast skum).In addition, 40% of 4 - [(1- (4-hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester (solid foam) is isolated.

25 (d) 4-[(1-(5-fluor-2-piperidino-phenyl)-1-butyl)-aminocarbony lme thyl] -benzoesyre-ethylester udbytte: 2% af det teoretiske, smeltepunkt: 127-129°C 30 Beregnet: m/e = 440(D) 4 - [(1- (5-Fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 2% of theory, m.p .: 127-129 ° C Calculated: m / e = 440

Fundet : m/e = 440 (e) 4-[(1-(4-fluor-2-piperidino-phenyl)-ethyl)-amino-carbonylmethyl]-benzoesyre 35 udbytte: 16,9% af det teoretiske, smeltepunkt: 172-175°C Beregnet: C 68,73 H 6,55 N 7,29Found: m / e = 440 (e) 4 - [(1- (4-fluoro-2-piperidino-phenyl) -ethyl) -amino-carbonylmethyl] -benzoic acid yield: 16.9% of theory, m.p. 172-175 ° C Calculated: C 68.73 H 6.55 N 7.29

Fundet : 68,78 6,62 7,31Found: 68.78 6.62 7.31

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Eksempel 37 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre.Example 37 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid.

Man hydrogenerer 1,0 g (2,33 mmol) 4-[(1-(5-chlor-5 2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre i 40 ml absolut ethanol ved 50°C og 5 bar hydrogen i nærværelse af 0,5 g palladium/carbon (10%*ig). Efter 2 timers forløb filtreres fra katalysatoren over kiselgur og inddampes i vakuum. Inddampningsresten for-10 deles ved pH 6 mellem vand og ethylacetat. Den organiske ekstrakt vaskes med vand, tørres og filtreres og inddampes i vakuum.1.0 g (2.33 mmol) of 4 - [(1- (5-chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid is hydrogenated in 40 ml of absolute ethanol at 50 ° C and 5 bar of hydrogen in the presence of 0.5 g of palladium / carbon (10% * g). After 2 hours, the catalyst is filtered over the diatomaceous earth and evaporated in vacuo. The residue is partitioned at pH 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated in vacuo.

Udbytte: 0,61 g (66% af det teoretiske), smeltepunkt: 213-215°C 15 Beregnet: C 73,07 H 7,66 N 7,10Yield: 0.61 g (66% of theory), m.p .: 213-215 ° C Calculated: C 73.07 H 7.66 N 7.10

Fundet : 73,18 7,42 7,27Found: 73.18 7.42 7.27

Man opnår også denne forbindelse ud fra de tilsvarende 4-chlor-, 3-chlor- eller 6-chlor-substituerede udgangsprodukter.This compound is also obtained from the corresponding 4-chloro, 3-chloro or 6-chloro substituted starting products.

2020

Eksempel 38 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl ]-benzoesyre-ethylester.Example 38 4 - [(1- (4-Methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Til 548 mg (11,4 mmol) natriumhydrid (50%'ig i 25 olie) i 10 ml absolut dimethylformamid drypper man under omrøring ved stuetemperatur en opløsning af 5,0 g (11,4 mmol) 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester i 45 ml absolut dimethylformamid. Man efterrører i 15 30 minutter og tildrypper derpå langsomt en opløsning af 0,71 ml (11,4 mmol) methyliodid i 8 ml absolut dimethylformamid. Man omrører endnu 2 1/2 time ved stuetemperatur, inddamper i vakuum og fordeler mellem vand og ether. Etherfasen tørres og filtreres og inddampes i 35 vakuum. Inddampningsresten renses ved søjlechromato-grafi på kiselgel (toluen/acetone = 20:1).To 548 mg (11.4 mmol) of sodium hydride (50% in 25 oil) in 10 ml of absolute dimethylformamide, a solution of 5.0 g (11.4 mmol) of 4 - [(1- ( 4-hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 45 ml of absolute dimethylformamide. Stir for 30 minutes and then slowly drop a solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of absolute dimethylformamide. Stir another 2 1/2 hours at room temperature, evaporate in vacuo and partition between water and ether. The ether phase is dried and filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (toluene / acetone = 20: 1).

Udbytte: 1,8 g (34,9% af det teoretiske), smeltepunkt: 115-117°CYield: 1.8 g (34.9% of theory), m.p .: 115-117 ° C

' * 80'* 80

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Beregnet: C 71,65 H 8,02 N 6,19Calculated: C 71.65 H 8.02 N 6.19

Fundet : 71,47 7,86 6,19 Følgende forbindelse blev opnået analogt med 5 eksempel 3 9; (a) 4-[(1-(5-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester udbytte: 68,4% af det teoretiske,Found: 71.47 7.86 6.19 The following compound was obtained by analogy with Example 29; (a) 4 - [(1- (5-methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester yield: 68.4% of theory,

10 smeltepunkt: 142-145°CM.p .: 142-145 ° C

Beregnet: C 71,65 H 8,02 N 6,19Calculated: C 71.65 H 8.02 N 6.19

Fundet : 71,87 8,06 6,38Found: 71.87 8.06 6.38

Eksempel 39 15 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl- methyl]-benzoesyre-(2,3-dihydroxy-propyl)ester.Example 39 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid (2,3-dihydroxy-propyl) ester.

Man opvarmer en opløsning af 2,0 g (5,07 mmol) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoesyre Og 0,85 g (5,27 mmol) Ν,Ν'-carbonyl-20 diimidazol i 20 ml absolut tetrahydrofuran i 1 time under tilbagesvaling, tilsætter 3,7 ml (50,7 mmol) glycerin og opvarmer yderligere i 15 timer under tilbagesvaling. Man inddamper i vakuum, fordeler mellem vand og ethylacetat, tørrer og filtrerer den organiske 25 opløsning og inddamper den i vakuum. Inddampningsresten renses ved søjlechromatografi på kiselgel (toluen/ace-tone = 1:1).A solution of 2.0 g (5.07 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid was heated and 0.85 g (5.27 mmol) Ν , Ν'-carbonyl-20 diimidazole in 20 ml of absolute tetrahydrofuran for 1 hour under reflux, adds 3.7 ml (50.7 mmol) of glycerine and further warms for 15 hours under reflux. Evaporate in vacuo, partition between water and ethyl acetate, dry and filter the organic solution and evaporate in vacuo. The residue is purified by column chromatography on silica gel (toluene / ace tone = 1: 1).

Udbytte: 1,1 g (46,2% af det teoretiske), smeltepunkt: 120-122°C 30 Beregnet: C 69,21 H 7,74 N 5,98Yield: 1.1 g (46.2% of theory), m.p .: 120-122 ° C Calculated: C 69.21 H 7.74 N 5.98

Fundet : 69,23 7,78 5,93 Følgende forbindelser blev opnået analogt med eksempel 39: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -benzoesyre- (2-hydroxyethyl)ester udbytte: 80% af det teoretiske, 35Found: 69.23 7.78 5.93 The following compounds were obtained analogously to Example 39: (a) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid- (2- hydroxyethyl) ester yield: 80% of theory, 35

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8181

smeltepunkt: 125-127°Cmp: 125-127 ° C

Beregnet: C 71,21 H 7,81 N 6,39Calculated: C, 71.21; H, 7.81; N, 6.39

Fundet : 71,35 7,54 6,33 5 (b) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl- methyl]-benzoesyre-(2-methoxy-ethyl)ester udbytte: 55,9% af det teoretiske.Found: 71.35 7.54 6.33 (b) 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid (2-methoxy-ethyl) ester yield : 55.9% of theory.

Smeltepunkt: 120-123°CMelting point: 120-123 ° C

Beregnet: C 71,65 H 8,02 N 6,19 10 Fundet : 72,03 8,03 6,24Calculated: C 71.65 H 8.02 N 6.19 Found: 72.03 8.03 6.24

Eksempel 40 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-(2-nicotinoyloxy-ethyl)ester.Example 40 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid (2-nicotinoyloxy-ethyl) ester.

15 Til en omrørt opløsning af 2,0 g (4,56 mmol) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoesyre-(2-hydroxy-ethyl)ester i 40 ml methylenchlorid og 0,7 ml (4,81 mmol) triethylamin drypper man hurtigt en opløsning af 0,7 g (4,68 mmol) 20 nicotinsyrechlorid i 20 ml methylenchlorid. Man omrører 2 1/2 time ved 20°C, udryster med vand, tørrer og filtrerer den organiske fase og inddamper den i vakuum. Inddampningsresten renses ved søjlechromatografi på kiselgel (toluen/acetone = 5:1).To a stirred solution of 2.0 g (4.56 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid (2-hydroxyethyl) ester in 40 ml of methylene chloride and 0.7 ml (4.81 mmol) of triethylamine, a solution of 0.7 g (4.68 mmol) of 20 nicotinic acid chloride in 20 ml of methylene chloride is rapidly dropped. Stir for 2 1/2 hours at 20 ° C, shake with water, dry and filter the organic phase and evaporate in vacuo. The residue is purified by column chromatography on silica gel (toluene / acetone = 5: 1).

25 Udbytte: 1,1 g (44% af det teoretiske), smeltepunkt: 132-135°C Beregnet: C 70,70 H 6,86 N 7,73Yield: 1.1 g (44% of theory), m.p .: 132-135 ° C Calculated: C 70.70 H 6.86 N 7.73

Fundet : 70,82 6,82 7,91 30 Eksempel 41 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzylalkohol.Found: 70.82 6.82 7.91 Example 41 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzyl alcohol.

Til en omrørt suspension af 0,68 g (17,95 mmol) lithiumaluminiumhydrid i 25 ml absolut tetrahydrofuran 35 drypper man ved en indre temperatur på 0°C en opløsning af 5,0 g (11,83 mmol) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre-ethylester i 75 ml absolut tetrahydrofuran. Man omrører i 20 timer ved stuetemperatur, afkøler til 0°C og tildrypper lang-To a stirred suspension of 0.68 g (17.95 mmol) of lithium aluminum hydride in 25 ml of absolute tetrahydrofuran 35, drop a solution of 5.0 g (11.83 mmol) of 4 - [(1) - (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 75 ml of absolute tetrahydrofuran. Stir for 20 hours at room temperature, cool to 0 ° C and drop slowly.

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82 somt så meget 4 N natronlud, at der dannes et filtrer-bart bundfald. Man frafiltrerer og udkoger bundfaldet flere gange med ether. De forenede organiske opløsninger inddampes i vakuum. Inddampningsresten fordeles 5 mellem vand og ether. Etherfasen tørres og filtreres, og inddampes i vakuum. Inddampningsresten renses ved søjlechromatografi på kiselgel (toluen/acetone = 5:1). Udbytte: 1,0 g (22% af det teoretiske), smeltepunkt: 152-154°C 10 Beregnet: C 75,75 H 8,48 N 7,3682 times so much 4 N sodium hydroxide solution that a filterable precipitate is formed. The precipitate is filtered off and boiled several times with ether. The combined organic solutions are evaporated in vacuo. The residue is partitioned between water and ether. The ether phase is dried and filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel (toluene / acetone = 5: 1). Yield: 1.0 g (22% of theory), m.p .: 152-154 ° C. Calculated: C 75.75 H 8.48 N 7.36

Fundet : 75,90 8,45 7,28Found: 75.90 8.45 7.28

Eksempel 42 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl- 15 methyl]-benzaldehyd.Example 42 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzaldehyde.

Man opvarmes 6,6 g (62 mmol) natriumcarbonat sammen med 62 ml ethylenglycol i et bad på 170°C og tilsætter under rask omrøring i løbet af et minut 6,2 g (11 mmol) N^-[4-[(1-(2-piperidino-phenyl)-1-bu- 2 20 tyl)-aminocarbonylmethyl]-benzoyl]-N -tosyl-hydrazin med et smeltepunkt på 195°C (sønd.), hvorved der iagttages en heftig gasudvikling. Derefter opvarmes yderligere 2 1/2 minut ved 170°C og udhældes derpå straks på is. Man ekstraherer med ether, tørrer, filtrerer 25 og inddamper etheropløsningen i vakuum. Inddampningsresten renses ved søjlechromatografi på kiselgel (chloroform/acetone = 20:1).6.6 g (62 mmol) of sodium carbonate are heated together with 62 ml of ethylene glycol in a bath of 170 ° C and 6.2 g (11 mmol) of N 2 - [4 - [(1 - (2-piperidino-phenyl) -1-butyl] -aminocarbonylmethyl] -benzoyl] -N-toosyl-hydrazine having a melting point of 195 ° C (Sunday), thereby observing intense gas evolution. Then heat for another 2 1/2 minutes at 170 ° C and then immediately pour on ice. Extract with ether, dry, filter and evaporate the ether solution in vacuo. The residue is purified by column chromatography on silica gel (chloroform / acetone = 20: 1).

Udbytte: 2,2 g (52,9% af det teoretiske), smeltepunkt: 142-145°C 30 Beregnet: C 76,16 H 7,99 N 7,40Yield: 2.2 g (52.9% of theory), m.p .: 142-145 ° C Calculated: C 76.16 H 7.99 N 7.40

Fundet : 76,26 7,96 7,37Found: 76.26 7.96 7.37

Eksempel 43 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-3 5 methyl]-kanelsyre-ethylester.Example 43 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -cinnamic acid ethyl ester.

Til 0,60 g (12,5 mmol) natriumhydrid (50%'ig i olie) i 15 ml absolut dimethylformamid drypper man ved stuetemperatur en opløsning af 2,80 g (12,5 mmol)To 0.60 g (12.5 mmol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide is added dropwise at room temperature a solution of 2.80 g (12.5 mmol)

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83 diethylphosphono-eddikesyreethylester i 10 ml absolut dimethylformamid. Man omrører i 15 minutter (til gasudviklingen er ophørt) og tildrypper derpå en opløsning af 2,4 g (6,34 mmol) 4-[(1-(2-piperidino-phenyl)-5 1-butyl)-aminocarbonylmethyl]-benzaldehyd i 10 ml absolut dimethylformamid. Man omrører i 2 timer ved stuetemperatur, inddamper i vakuum og fordeler mellem vand og ether. Man tørrer og filtrerer etherfasen og inddamper den i vakuum. Inddampningsresten renses ved 10 søjlechromatografi på kiselgel (toluen/acetone = 10:1). Udbytte: 0,85 g (29,9% af det teoretiske), smeltepunkt: 135-137°C (ether/petroleumsether)83 diethylphosphonoacetic acid ethyl ester in 10 ml of absolute dimethylformamide. Stir for 15 minutes (until gas evolution has ceased) and then a solution of 2.4 g (6.34 mmol) of 4 - [(1- (2-piperidino-phenyl) -5-butyl) -aminocarbonylmethyl] is added dropwise. benzaldehyde in 10 ml of absolute dimethylformamide. The mixture is stirred for 2 hours at room temperature, evaporated in vacuo and partitioned between water and ether. The ether phase is dried and filtered and evaporated in vacuo. The residue is purified by 10 column chromatography on silica gel (toluene / acetone = 10: 1). Yield: 0.85 g (29.9% of theory), m.p .: 135-137 ° C (ether / petroleum ether)

Beregnet: C 74,97 H 8,09 N 6,24Calculated: C, 74.97; H, 8.09; N, 6.24

Fundet : 74,91 7,89 6,29 15Found: 74.91 7.89 6.29 15

Eksempel 44 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonylmethyl] -kanelsyre.Example 44 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -cinnamic acid.

Fremstillet ved alkalisk forsæbning af 4-[(1-(2-20 piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-kanel-syre-ethylester analogt med eksempel 25.Prepared by alkaline saponification of 4 - [(1- (2-20 piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -cinnamic acid ethyl ester analogous to Example 25.

Udbytte: 64% af det teoretiske, smeltepunkt: 180-183°CYield: 64% of theory, melting point: 180-183 ° C

Beregnet: C 74,26 H7,67 N 6,66 25 Fundet : 74,03 7,47 6,80Calculated: C 74.26 H7.67 N 6.66 Found: 74.03 7.47 6.80

Eksempel 45 3r-[4r t (L“(2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenyl]-prbpionsyre-ethylester.Example 45 3r- [4r t (L “(2-Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenyl] -propionic acid ethyl ester.

30 Man hydrogenerer 0,60 g (1,34 mmol) 4-[ (1-(2- piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-kanel-syre-ethylester i 10 ml ethanol ved stuetempeatur og 5 bar hydrogen i nærværelse af 0,20 g palladium/carbon (10%). Man filtrerer og inddamper i vakuum.0.60 g (1.34 mmol) of 4- [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -cinnamic acid ethyl ester is hydrogenated in 10 ml of ethanol at room temperature and 5 bar of hydrogen. in the presence of 0.20 g palladium / carbon (10%). Filter and evaporate in vacuo.

35 Udbytte: 0,53 g (88% af det teoretiske), smeltepunkt: 98-99°C (petroleumsether)Yield: 0.53 g (88% of theory), m.p .: 98-99 ° C (petroleum ether)

Beregnet: C 74,63 H 8,50 N 6,22Calculated: C 74.63 H 8.50 N 6.22

Fundet : 74,64 8,58 6,23Found: 74.64 8.58 6.23

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84 Følgende forbindelse blev opnået analogt med eksempel 45: (a) 3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-amino-5 carbonylmethyl]-phenyl]-propionsyre udbytte: 63% af det teoretiske, smeltepunkt: 131-133°C Beregnet: C 73,90 H 8,11 N 6,6384 The following compound was obtained analogously to Example 45: (a) 3- [4 - [(1- (2-piperidino-phenyl) -1-butyl) -amino-5-carbonylmethyl] -phenyl] -propionic acid yield: 63% of theoretical, melting point: 131-133 ° C Calculated: C 73.90 H 8.11 N 6.63

Fundet : 73,96 8,30 6,56 10Found: 73.96 8.30 6.56 10

Eksempel 46 3- [4-[(1-(2-Piperidino-phenyl)-1-butyl-aminocarbonyl-methyl]-phenyl]-propionsyre.Example 46 3- [4 - [(1- (2-Piperidino-phenyl) -1-butyl-aminocarbonyl-methyl] -phenyl] -propionic acid.

Fremstillet ved alkalisk forsæbning ud fra 15 3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl- methyl]-phenyl]-propionsyre-ethylester analogt med eksempel 26.Prepared by alkaline saponification from 3- [4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenyl] -propionic acid ethyl ester analogous to Example 26.

Udbytte: 50% af det teoretiske, smeltepunkt: 131-133°C 20 Beregnet: C 73,90 H 8,11 N 6,63Yield: 50% of theory, m.p .: 131-133 ° C Calculated: C 73.90 H 8.11 N 6.63

Fundet : 73,82 8,07 6,41Found: 73.82 8.07 6.41

Eksempel 47 4- [(a-Aminocarbonyl-2-piperidino-benzyl)-aminocarbonyl-2 5 methyl]-benzoesyre-ethylester.Example 47 4- [(α-Aminocarbonyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester.

Til en omrørt opløsning af 2,0 g (4,7 mmol) 4-[(a-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoesyre-ethylester x 0,167 (smeltepunkt 156-159°C) i 20 ml vandfri tetrahydrofuran sætter man ved 20°C 30 0,90 g (5,5 mmol) N,Ν'-carbonyldiimidazol og opvarmer derpå i 1/2 time i et bad på 80°C. Derpå afkøler man til 60°C og indleder ved denne temperatur i 1/2 time en kraftig strøm tør ammoniak. Derpå inddamper man i vakuum, fordeler mellem vand og chloroform, udryster 35 de forenede chloroformekstrakter med en lille mængde vand, tørrer, filtrerer og inddamper i vakuum. Inddamp-ningsresten renses ved søjlechromatografi på kiselgel (chloroform/methanol = 5:1).To a stirred solution of 2.0 g (4.7 mmol) of 4 - [(α-carboxy-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester x 0.167 (mp 156-159 ° C) in 20 ml of anhydrous tetrahydrofuran is added at 20 ° C 0.90 g (5.5 mmol) of N, Ν'-carbonyldiimidazole and then heated for 1/2 hour in an 80 ° C bath. Then, it is cooled to 60 ° C and a strong stream of dry ammonia is introduced at this temperature for 1/2 hour. Then, in vacuo, evaporate, distribute between water and chloroform, equip the combined chloroform extracts with a small amount of water, dry, filter and evaporate in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 5: 1).

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8585

Udbytte: 1,0 g (50,2% af det teoretiske), smeltepunkt: 160-162°C (acetone)Yield: 1.0 g (50.2% of theory), m.p .: 160-162 ° C (acetone)

Beregnet: C 68,07 H 6,90 N 9,92Calculated: C 68.07 H 6.90 N 9.92

Fundet : 68,40 6,92 9,84 5Found: 68.40 6.92 9.84 5

Eksempel 48 4-[(a-Cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoesyre-ethylester.Example 48 4 - [(α-Cyano-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Til 520 mg (1,22 mmol) 4-[(a-aminocarbonyl-2-pi-10 peridino-benzyl)-aminocarbonylmethyl]-benzoesyre-ethylester i 0,22 ml pyridin sætter man i to portioner 234 mg (1,22 mmol) 4-toluensulfochlorid og opvarmer til 50°C.To 520 mg (1.22 mmol) of 4 - [(α-aminocarbonyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 0.22 ml of pyridine is added in two portions of 234 mg (1.22). mmol) 4-toluene sulfochloride and warms to 50 ° C.

Efter 2 timers forløb og efter yderligere 1 times forløb tilsætter man atter de samme mængder pyridin 15 og 4-toluensulfochlorid og opvarmer yderligere 1 time ved 50°C. Efter henstand i 2 dage ved 20°C tilsætter man 2 N ammoniak og ekstraherer med chloroform. Chloro-formopløsningen udrystes to gange med vand. Efter tørring og filtrering inddamper man i vakuum. Inddampnings-20 resten renses ved søjlechromatografi på kiselgel (chloroform/methanol = 10:1).After 2 hours and after another 1 hour, the same amounts of pyridine 15 and 4-toluene sulfochloride are added again and heated at 50 ° C for an additional 1 hour. After standing for 2 days at 20 ° C, 2N ammonia is added and extracted with chloroform. Shake the chloroform solution twice with water. After drying and filtering, evaporate in vacuo. The residue is purified by column chromatography on silica gel (chloroform / methanol = 10: 1).

Udbytte: 325 mg (65,7% af det teoretiske), smeltepunkt: 114-117°C (ether/petroleumsether)Yield: 325 mg (65.7% of theory), m.p .: 114-117 ° C (ether / petroleum ether)

Beregnet: C 71,09 H 6,71 N 10,36 25 Fundet : 70,79 6,56 10,10Calculated: C 71.09 H 6.71 N 10.36 Found: 70.79 6.56 10.10

Eksempel 49 4- [ (ot-Cyano-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoesyre.Example 49 4- [(o-Cyano-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid.

30 Man omrører 1,5 g (3,7 mmol) 4-[(a-cyano-2-pipe- ridino-benzyl)-aminocarbonylmethyl]-benzoesyre-ethylester i 15 ml dioxan sammen med 3,7 ml 1 N natronlud i 45 minutter i et bad på 60°C og yderligere i 45 minutter i et bad på 80°C. Efter afkøling med is til-35 sætter man 3,7 ml 1 N saltsyre, afdamper dioxanen i vakuum og fordeler mellem vand og chloroform. Den organiske opløsning udrystes med en lille mængde vand, tørres og filtreres og inddampes i vakuum. Inddamp- ' 861.5 g (3.7 mmol) of 4 - [(α-cyano-2-pyridino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester are stirred in 15 ml of dioxane together with 3.7 ml of 1 N sodium hydroxide solution. 45 minutes in a 60 ° C bath and further 45 minutes in an 80 ° C bath. After cooling with ice, 3.7 ml of 1 N hydrochloric acid is added, the dioxane is evaporated in vacuo and partitioned between water and chloroform. The organic solution is shaken with a small amount of water, dried and filtered and evaporated in vacuo. Evaporation

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ningsresten renses ved søjlechromatografi på kiselgel (chloroform/ethanol = 5:1).The residue is purified by column chromatography on silica gel (chloroform / ethanol = 5: 1).

Udbytte: 0,50 g (35,7% af det teoretiske), smeltepunkt: 176-180°C (sønderdeling) 5 Beregnet: C 70,01 H 6,14 N 11,13Yield: 0.50 g (35.7% of theory), m.p. 176-180 ° C (dec.) Calculated: C 70.01 H 6.14 N 11.13

Fundet : 70,02 6,19 11,05Found: 70.02 6.19 11.05

Eksempel 50 4-[(1-(2-Piperidino-phenyl)-1-butyl)-aminocarbonyl-10 methylJ-benzoesyre x H^SO^.Example 50 4 - [(1- (2-Piperidino-phenyl) -1-butyl) -aminocarbonyl-methyl] -benzoic acid x H

Til en opløsning af 1,0 g (2,53 mmol) 4—[(1—(2— piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre i 50 ml ethanol sætter man 5 ml (2,50 mmol) 1 N svovlsyre, inddamper til tørhed i vakuum og udriver 15 med acetone.To a solution of 1.0 g (2.53 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid in 50 ml of ethanol is added 5 ml (2.50 mmol 1 N sulfuric acid, evaporates to dryness in vacuo and elutes 15 with acetone.

Udbytte: 0,80 g (65% af det teoretiske), smeltepunkt: 192-197°C (sønderdeling).Yield: 0.80 g (65% of theory), mp: 192-197 ° C (dec.).

Beregnet: C 58,53 H 6,55 N 5,69 S 6,49Calculated: C, 58.53; H, 6.55; N, 5.69; S, 6.49

Fundet : 58,05 6,54 5,49 6,35 20Found: 58.05 6.54 5.49 6.35 20

Nedenstående additionssalt blev opnået analogt med eksempel 50: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbony1-25 methyl]-benzoesyre x 0,5 x 1,5 ^O.The following addition salt was obtained analogously to Example 50: (a) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbony-25-methyl] -benzoic acid x 0.5 x 1.5

Fremstillet med den halve mængde svovlsyre analogt med eksempelPrepared with half the amount of sulfuric acid by example

Udbytte: 59,3% af det teoretiske, smeltepunkt: 180-185°Cj sønderdeling ved 207-210°C.Yield: 59.3% of theory, melting point: 180-185 ° C decomp. At 207-210 ° C.

30 Beregnet: C 61,26 H 7,28 N 5,95 S 3,40Calculated: C 61.26 H 7.28 N 5.95 S 3.40

Fundet : 61,28 6,99 6,10 3,23Found: 61.28 6.99 6.10 3.23

Claims (6)

1. Analogifremgangsmåde til fremstilling af phe-nyleddikesyrederivater med den almene formel A - NH - CO - CH Jf \_W h-t I \=/ 10 hvori A betegner en gruppe med formlen Rc Rc R4 nc 15 ' « - CH - eller - C - hvor R^ betegner en med en alkoxygruppe med 1 til 3 carbon-20 atomer eller med en phenylgruppe substitueret alkylgruppe med 1 til 3 carbonatomer, en n-propylgruppe, en alkylgruppe med 4 til 6 carbonatomer, en alkenylgruppe med 3 til 5 carbonatomer, en cyano- eller alkyleniminocarbonyl-gruppe med 4 til 6 carbonatomer i alkylendelen, en even-25 tuelt med alkyl- eller phenylalkylgrupper, hver med 1 til 3 carbonatomer i alkyldelen, mono- eller disubstitueret aminocarbonylgruppe, en med halogenatomer, med alkyl-, hydroxy-, alkoxy-, phenylalkoxy-, alkylsulfenyl-, alkyl-sulfinyl- og/eller alkylsulfonylgrupper mono- eller di-30 substitueret arylgruppe med 6 til 10 carbonatomer, idet substituenterne kan være ens eller forskellige, og alkyldelen i alle tilfælde kan indeholde 1 til 3 carbonatomer, en naphthylgruppe, eller en pyridylgruppe, eller en methylgruppe, hvis R.j betegner en piperidinogruppe og R2 betegner fluor i 4-stillingen, og W betegner carboxy- eller alkoxycarbo- 35 DK 159850 B nylgruppe, hvori alkyldelen har 1-3 carbonatomer, eller en phenylgruppe, hvis betegner en piperidinogruppe substitueret med en en methylgruppe i 2- eller 3-stillingen, er hydrogen, 5 og W er carboxy eller alkoxycarbonyl, hvori alkyldelen kan have 1-3 carbonatomer, eller hvis R.j er en piperidinogruppe, R£ er chlor i 3-, 4-eller 6-stilling eller methyl i 4- eller 6-stilling, og W er carboxy eller alkoxycarbonyl, hvori alkyldelen kan have 10 1-3 carbonatomer, eller hvis R^ er en piperidinogruppe, er hydrogen, og W er formyl, 2-carbonylethenyl eller 2-alkoxycarbonylethenyl med 1-3 carbonatomer i alkyldelen, R5 og Rg betegner sammen med det mellemliggende carbon-1 5 atom en alkylidengruppe med 3-9 carbonatomer eller en phenyl-alkylidengruppe med 1-3 carbonatomer i alkylidendelen, R.j betegner en eventuelt med alkylgrupper med 1 til 3 carbonatomer mono- eller disubstitueret uforgrenet alky-leniminogruppe med 4 til 8 carbonatomer,An analogous process for the preparation of phenylacetic acid derivatives of the general formula A - NH - CO - CH Jf \ _W ht I \ = / 10 wherein A represents a group of the formula Rc Rc R4 nc 15 '' - CH - or - C - R 1 represents one having an alkoxy group having 1 to 3 carbon atoms or a phenyl group substituted alkyl group having 1 to 3 carbon atoms, an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cyano or alkylene iminocarbonyl group having 4 to 6 carbon atoms in the alkylene moiety, optionally having alkyl or phenylalkyl groups, each having 1 to 3 carbon atoms in the alkyl moiety, mono- or disubstituted aminocarbonyl group, one having halogen atoms, with alkyl, hydroxy , alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulfinyl and / or alkylsulfonyl groups mono- or di-substituted aryl group having 6 to 10 carbon atoms, the substituents may be the same or different and the alkyl moiety may contain at least 1 1 3 carbon atoms, a naphthyl group, or a pyridyl group, or a methyl group if R 1 represents a piperidino group and R 2 represents fluorine at the 4-position and W represents a carboxy or alkoxycarbonyl group wherein the alkyl moiety has 1-3 carbon atoms , or a phenyl group, which represents a piperidino group substituted with a one methyl group at the 2- or 3-position, is hydrogen, 5 and W is carboxy or alkoxycarbonyl, wherein the alkyl moiety may have 1-3 carbon atoms or R 1 is a piperidino group, R Is chloro at the 3-, 4- or 6-position or methyl at the 4- or 6-position, and W is carboxy or alkoxycarbonyl wherein the alkyl moiety may have 1-3 carbon atoms or if R 1 is a piperidino group, hydrogen is and W is formyl, 2-carbonylethenyl or 2-alkoxycarbonylethenyl having 1-3 carbon atoms in the alkyl moiety, R5 and Rg together with the intermediate carbon atom represent an alkylidene group of 3-9 carbon atoms or a phenyl alkylidene group of 1-3 carbon atoms ia represents an optionally with alkyl groups of 1 to 3 carbon atoms mono- or disubstituted unbranched alkylene imino group of 4 to 8 carbon atoms, 20 R2 betegner et hydrogen-, fluor-, chlor-, brom- eller iodatom, en hydroxy-, trifluormethyl-, nitro-, amino-, piperidino-, alkyl-, alkoxy-, alkylsulfenyl-, alkylsul-finyl-, alkylsulfonyl-, phenylalkoxy-, alkanoyloxy-, alkanoylamino-, alkylamino- eller dialkylaminogruppe, 25 hvori alkyldelen i alle tilfælde kan indeholde 1 til 3 carbonatomer, W betegner en carboxygruppe eller en alkoxycarbonylgrup-pe med ialt 2 til 5 carbonatomer,hvori alkyldelen kan være substitueret med en phenylgruppe, og, fra (3-carbon-30 atomet med en eller to hydroxygrupper, med en alkoxy-, alkanoyloxy-, dialkylamino-, alkylenimino- eller pyri-dincarbonyloxygruppe, idet hver alkyldel kan indeholde 1 til 3 carbonatomer, og alkyleniminogruppen kan indeholde 4 til 6 carbonatomer, en alkenyloxycarbonylgruppe 35 med ialt 4 til 6 carbonatomer, en alkylgruppe med 1 til 3 carbonatomer, en hydroxymethyl-, formyl-, cyano-, aminocarbonyl-, carboxy-methyl-, 2-carboxy-ethyl-, 2-carboxy-ethenyl-, 2,2-bis-(carboxy)-ethyl-, alkoxy- DK 159850B carbonyl-methyl-, 2-alkoxycarbonyl-ethyl-, 2-alkoxy-carbonyl-ethenyl- eller 2,2-bis-(alkoxycarbonyl)-ethyl-gruppe, hvorved alkoxygruppen i alle tilfælde kan indeholde 1 til 3 carbonatomer, 5 eller deres optisk aktive antipoder eller deres fysiologisk acceptable syreadditionssalte heraf med uorganiske eller organiske syrer eller baser, kendetegnet ved, at man 10 a) omsætter en amin med den almene formel II (^YA '1,112 15 1 hvori A, R og R9 har den ovenfor angivne betydning, eller, når A betegner en af de ovenfor nævnte vinylidengrupper, dens tautomere elle'r dens lithium- eller magnesiumhalo-20 genidkompleks med en carboxylsyre med den almene formel III HO - CO - ch2-^ )-*, m 25 hvori W har de for W ovenfor angivne betydninger eller beteg-30 ner en gennem en beskyttelsesgruppe beskyttet carboxy-gruppe, eller med dennes eventuelt i reaktionsblandingen dannede reaktionsdygtige derivater, og om nødvendigt fraspalter en anvendt beskyttelsesgruppe, eller 35 b) til fremstilling af en forbindelse med den almene formel I, hvori W betegner en carboxy-, carboxymethyl-, 2-carboxyethyl- eller 2-carboxyethenylgruppe, ved hjælp af hydrolyse, termolyse eller hydrogenolyse overfører DK 159850 B en forbindelse med den almene formel Vv* - - “s / V „ * v R hvori og A har den ovenfor angivne betydning, og B 10 betegner en gruppe, der kan overføres i en carboxy-, carboxymethyl-, 2-carboxyethyl- eller 2-carboxyethenyl-gruppe, i den tilsvarende carboxyforbindelse, eller c) til fremstilling af en forbindelse med den almene . 15 formel I, hvori A betegner en gruppe med formlen V - CH - hvori R^' med undtagelse af alkenylgruppen og cyano-20 gruppen har de for ovenfor angivne betydninger, reducerer en forbindelse med den almene formel ί -CO - CB2-/~VvR 2 represents a hydrogen, fluoro, chloro, bromo or iodo atom, a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, , phenylalkoxy, alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group, wherein the alkyl moiety may in any case contain 1 to 3 carbon atoms, W represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms wherein the alkyl moiety may be substituted by a phenyl group, and, from the (3-carbon atom with one or two hydroxy groups) having an alkoxy, alkanoyloxy, dialkylamino, alkyleneimino or pyridine carbonyloxy group, each alkyl moiety can contain 1 to 3 carbon atoms and the alkyleneimino group can contain 4 to 6 carbon atoms, an alkenyloxycarbonyl group 35 having a total of 4 to 6 carbon atoms, an alkyl group of 1 to 3 carbon atoms, a hydroxymethyl, formyl, cyano, aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2 -carboxy-ethenyl-, 2,2-bis- (carboxy) -ethyl-, alkoxy-carbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxy-carbonyl-ethenyl or 2,2-bis (alkoxycarbonyl) -ethyl group, whereby the alkoxy group can in any case contain 1 to 3 carbon atoms , Or their optically active antibodies or their physiologically acceptable acid addition salts thereof with inorganic or organic acids or bases, characterized by reacting an amine of general formula II (^ YA '1,112 15 1 wherein A, R and R9 has the meaning given above or, when A represents one of the above-mentioned vinylidene groups, its tautomeric or its lithium or magnesium halide complex with a carboxylic acid of the general formula III HO - CO - (CH2 - 2) - *, m 25 wherein W has the meanings given to W or denotes a carboxy group protected by a protecting group, or with its reactive derivatives optionally formed in the reaction mixture, and if necessary, a used protecting group is decomposed, or B) for the preparation of a compound of general formula I, wherein W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, by hydrolysis, thermolysis or hydrogenolysis, DK 159850 B transfers a compound with the general Formula Vv * - - "s / V" * v R wherein and A is as defined above, and B 10 represents a group which can be transferred into a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group , or in the corresponding carboxy compound, or c) to prepare a compound with the general. Formula I wherein A represents a group of formula V - CH - wherein R 1, with the exception of the alkenyl group and the cyano group, has the meanings given above, reduces a compound of the general formula ί -CO - CB 2 - vv 25. J''- R1 hvori R1, R2 og W har den ovenfor angivne betydning, og 30 D betegner en gruppe med formlen *4” R5' « C - c " . eller - c 35 ^ -33 N - H DK 159850B hvori R^" med undtagelse af cyanogruppen har de tidligere for angivne betydninger, og R,.' og ' sammen med det mellemliggende carbonatom betegner en propyliden-gruppe, en alkylidengruppe med 4 til 6 carbonatomer el-5 ler en phenylalkylidengruppe med 1 til 3 carbonatomer i alkylidendelen, med hydrogen under tilstedeværelse af en hydrogeneringskatalysator, eller d) til fremstilling af forbindelser med den almene for-10 mel I, hvori R^" med undtagelse af cyanogruppen har de for R^ ovenfor angivne betydninger, omsætter en forbindelse med den almene formel ·. -or hvori25. J '- R1 wherein R1, R2 and W have the meaning given above and 30 D represents a group of the formula * 4 "R5" "C - c" or - c 35 ^ -33 N - H DK 159850B wherein, with the exception of the cyano group, R 2 has the meanings previously indicated and R 1. and 'together with the intermediate carbon atom represents a propylidene group, an alkylidene group of 4 to 6 carbon atoms or a phenylalkylidene group of 1 to 3 carbon atoms in the alkylidene moiety, with hydrogen in the presence of a hydrogenation catalyst, or d) to prepare compounds having the general formula I wherein R 1, with the exception of the cyano group, has the meanings given for R 2, translates into a compound of the general formula · wherein R 20 R^" er som ovenfor defineret, og R^ og R2 har de tid ligere angivne betydninger, med en forbindelse med den almene formel 25 nsc ch2 v v11 hvori W er som tidligere defineret, eller 30 e) til fremstilling af forbindelser med formlen I, hvori R2 er hydrogen, og A er en gruppe med formlen R4 - CH - 35 hvori R^ har den ovenfor anførte betydning, dehalogenerer en forbindelse med den almene formel DK 159850 B αΑ - NH - CO - CH Μ V- W20 R 2 is as defined above and R 2 and R 2 have the more recently defined meanings, with a compound of the general formula 25 nsc ch 2 v v 11 wherein W is as previously defined, or 30 e) for the preparation of compounds of the formula I, wherein R 2 is hydrogen and A is a group of formula R 4 - CH - 35 wherein R 1 is as defined above, dehalogenates a compound of the general formula DK 159850 B αΑ - NH - CO - CH Μ V-W 2. Fremgangsmåde ifølge krav 1, kendeteg net ved, at der fremstilles phenyleddikesyrederiva-ter med den almene formel I, hvori A betegner en gruppe med formlen R5\ /*« 30 r4 c i eller " , hvor - CH - - C - R^ betegner en med en alkoxygruppe med 1-3 carbonatomer 35 eller phenylgruppe substitueret alkylgruppe med 1 til 3 carbonatomer, en n-propyl-, cyano- eller aminocarbonyl-gruppe, en alkylgruppe med 4 til 6 carbonatomer, en al-kenylgruppe med 3 til 5 carbonatomer, en med et fluor-, DK 159850 B chlor- eller bromatom, med en alkyl-, hydroxy-, alkoxy-, phenylalkoxy-, alkylsulfenyl-, alkylsulfinyl- eller al-kylsulfonylgruppe substitueret phenylgruppe, idet alkyl-delen i hvert tilfælde kan have 1-3 carbonatomer, eller 5 en pyridyl- eller naphthylgruppe, R,- og Rg sammen med det mellemliggende carbonatom betegner en alkylidengruppe med 3 til 5 carbonatomer eller en phenylalkylidengruppe med 1 til 3 carbonatomer i alkyl-10 delen R.J betegner en uforgrenet alkyleniminogruppe med 4 til 8 carbonatomer eller en med alkylgrupper med 1-3 carbonatomer mono- eller disubstitueret piperidinogruppe, R2 betegner et hydrogen-, fluor-, chlor- eller bromatom 15 eller en nitro-, alkyl- eller alkoxygruppe med 1-3 carbonatomer , og W betegner en carboxy-, hydroxymethyl-, formyl-, cyano-, carboxyl-, carboxy-methyl-, 2-carboxy-ethyl-, 2-hydroxy-ethoxycarbonyl-, 2-methoxy-ethoxycarbonyl-, 2-nicotinoyl-20 oxy-ethoxycarbonyl-, 2,3-dihydroxy-n-propoxycarbonyl- eller 2-carboxy-ethenylgruppe, en alkoxycarbonylgruppe med ialt 2 til 5 carbonatomer, en 2,2-bis(carboxy)ethylgrup-pe eller betegner en alkoxycarbonylmethyl-, 2-alkoxycar-bonylethyl- eller 2-alkoxycarbonylethenyl-, el. 2,2-bis(alk. 25 oxycarbonyl)-ethylgruppe, hvor alkoxygruppen i alle tilfælde kan indeholde 1-3 carbonatomer, deres optisk aktive antipoder eller deres salte med uorganiske eller organiske syrer eller baser.Process according to claim 1, characterized in that phenylacetic acid derivatives of the general formula I are prepared, wherein A represents a group of the formula R5 / R4 c1 or "wherein - CH - - C - R4 represents an alkyl group having 1-3 carbon atoms or phenyl group substituted alkyl group having 1 to 3 carbon atoms, an n-propyl, cyano or aminocarbonyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a chlorine or bromine atom with a fluorine, with an alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulfinyl or alkylsulfonyl group substituted phenyl group, the alkyl moiety in each case being have 1 to 3 carbon atoms, or 5 a pyridyl or naphthyl group, R 1 - and R 8 together with the intermediate carbon atom represent an alkylidene group having 3 to 5 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkyl part RJ represents an unbranched alkylene amino group with 4 to 8 carbon atoms or an alkyl group having 1-3 carbon atoms mono- or disubstituted piperidino group, R 2 represents a hydrogen, fluoro, chloro or bromine atom or a nitro, alkyl or alkoxy group of 1-3 carbon atoms, and W represents a carboxy, hydroxymethyl, formyl, cyano, carboxyl, carboxy-methyl, 2-carboxy-ethyl, 2-hydroxy-ethoxycarbonyl-, 2-methoxy-ethoxycarbonyl-, 2-nicotinoyl-oxy- ethoxycarbonyl, 2,3-dihydroxy-n-propoxycarbonyl or 2-carboxyethhenyl group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, a 2,2-bis (carboxy) ethyl group or represents an alkoxycarbonylmethyl, 2-alkoxycar -bonylethyl or 2-alkoxycarbonylethenyl, el. 2,2-bis (alk. Oxycarbonyl) ethyl group wherein the alkoxy group may in any case contain 1-3 carbon atoms, their optically active antibodies or their salts with inorganic or organic acids or bases. 2 Xj m hvori , A og W er som tidligere defineret, og Hal betegner et fluor-, chlor-, brom- eller iodatom, eller 10 f) til fremstilling af forbindelser med den almene formel I, hvori A betegner en gruppe med formlen R4 f - CH - 15 hvori R4 betegner en alkyleniminocarbonylgruppe med 4 til 6 carbonatomer i alkylenringen eller en eventuelt med alkyl- eller phenylalkylgrupper, hver med 1 til 3 carbonatomer i alkyldelen, mono- eller disubstitueret amino-gruppe, 20 omsætter en forbindelse med den almene formel COOH2 Xj m wherein, A and W are as previously defined, and Hal represents a fluorine, chlorine, bromine or iodine atom, or f) for the preparation of compounds of general formula I wherein A represents a group of formula R4 f - CH-15 wherein R 4 represents an alkylene iminocarbonyl group having 4 to 6 carbon atoms in the alkylene ring or an optionally having alkyl or phenylalkyl groups, each having 1 to 3 carbon atoms in the alkyl moiety, mono- or disubstituted amino group, reacting a compound with the general formula COOH 25 CH - HH - CO - CHz -tf v· ix *2—Γ UL 30 hvori R.j og R2 har de tidligere angivne betydninger, og W" med undtagelse af carboxy, carboxymethyl- 2-carboxyethyl-2-carboxyethenyl og 2,2-bis(carboxy)-ethyl har de tidligere for W angivne betydninger, 35 med en amin med den almene formel H - R? X hvori DK 159850 B Κγ betegner en alkyleniminogruppe med 4 til 6 carbon-atomer eller en eventuelt med alkyl- eller phenylalkyl-grupper, alle med 1 til 3 carbonatomer i alkyldelen, mono- eller disubstitueret aminogruppe, eller 5 g) til fremstilling af forbindelser med den almene formel I, hvori W betegner carboxygruppen, oxiderer en forbindelse med den almene formel 10 '4 J~\. CH -m -c0 - ch2 y- s XI 15 hvori og R^ har de ovenfor angivne betydninger, og E betegner en gruppe, der ved oxidation kan overføres i en carboxygruppe, eller 20 h) til fremstilling af forbindelser med den almene formel I, hvori W betegner en alkoxycarbonylgruppe med ialt 2 til 5 carbonatomer, hvori alkyIdelen fra β-car-bonatomet kan vasre substitueret med en eller to hydroxy- 25 grupper eller med en alkoxygruppe med 1 til 3 carbon-atomer, forestrer en carboxylsyre med den almene formel 30 - NH - CO - CH -ff COOH xn *2+l| \=/ hvoriCH - HH - CO - CH 2 -tf v · ix * 2 — Γ UL 30 wherein R 1 and R 2 have the meanings previously defined, and W "with the exception of carboxy, carboxymethyl-2-carboxyethyl-2-carboxyethenyl and 2.2 -bis (carboxy) ethyl has the meanings previously defined for W, with an amine of the general formula H - R? X wherein DK 159850 B Κγ represents an alkyleneimino group of 4 to 6 carbon atoms or an optionally alkyl or phenylalkyl groups, all having 1 to 3 carbon atoms in the alkyl moiety, mono- or disubstituted amino group, or 5 g) for the preparation of compounds of the general formula I wherein W represents the carboxy group oxidizes a compound of the general formula 10 Wherein X and R 2 have the meanings given above, and E represents a group which, by oxidation, can be transferred into a carboxy group, or 20 hours) to prepare compounds of the general Formula I wherein W represents an alkoxycarbonyl group having a total of 2 to 5 carbon atoms wherein alkyl the member of the β-carbon atom can be substituted by one or two hydroxy groups or by an alkoxy group of 1 to 3 carbon atoms esterifies a carboxylic acid of the general formula 30 - NH - CO - CH -ff COOH xn * 2 + L | \ = / where 35 R^ til R^ og A har de ovenfor angivne betydninger, eller dens eventuelt i reaktionsblandingen dannede derivater . 94 DK 159850 B med en alkohol med den almene formel HO - R XIII 9 hvori Rg betegner en alkylgruppe med 1 til 4 carbonatomer, 5 der fra Ø-carbonatomet kan være substitueret med en eller to hydroxygrupper eller en alkoxygruppe med 1 til 3 carbonatomer, eller i) til fremstilling af en forbindelse med den almene 10 formel I, hvori W betegner en alkoxycarbonyl-, alkoxy-carbonylmethyl-, 2-alkoxycarbonylethyl- eller 2-alkoxy-carbonylethenylgruppe, og A betegner en gruppe med formlen R,,4 15 ' - CH - hvori R"4 med undtagelse af cyanogruppen har de for R^ ovenfor angivne betydninger, overfører en forbindelse med den 20 almene formel r; I' -jF\_ CCH - NH - GO - CH2 -{/ y— W'3' xiv hvori R1, R2 og R"4 har de ovenfor angivne betydninger, og 30 w"' betegner en cyano-, cyanomethyl-, 2-cyanoethyl-eller 2-cyanoethenylgruppe, i en tilsvarende ester, 35 DK 159850 B % og derpå om ønsket ved reduktion overfører en opnået forbindelse med den almene formel I, hvori W betegner en carboxy- eller alkoxycarbonylgruppe, i en tilsvarende forbindelse med den almene formel I, hvori W be-5 tegner en formyl- eller hydroxymethylgruppe, og/eller overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori W betegner carboxygruppen, i en tilsvarende forbindelse med den almene formel I, 10 hvori W betegner formylgruppen, ved overføring i et sulfonsyrehydrazid og efterfølgende disproportionering, og/eller overfører en ifølge opfindelsen opnået forbindelse med 15 den almene formel I, hvori W betegner formylgruppen, i en tilsvarende forbindelse med den almene formel I, hvori W betegner en 2-alkoxycarbonylethenyl- eller 2-carboxyethenylgruppe, ved kondensation og eventuelt efterfølgende hydrolyse og/eller decarboxylering, 20 og/eller overfører en ifølge opfindelsen fremstillet forbindelse med den almene formel I, hvori W betegner en 2-carb-oxyethenyl- eller 2-alkoxycarbonylethenylgruppe, i en 25 tilsvarende forbindelse med den almene formel I, hvori W betegner en 2-carboxyethyl- eller 2-alkoxycarbonyl-ethylgruppe, ved katalytisk hydrogenering, og/eller overfører en ifølge opfindelsen opnået forbindelse 30 med den almene formel I, hvori W betegner en alkoxycarbonylgruppe, der fra β-carbonatomet er substitueret med en hydroxygruppe,i en tilsvarende (pyridincarbonyl-oxyalkoxy)-carbonylforbindelse med den almene formel I ved acylering med en pyridincarboxylsyre, og/eller 35 efter overføring af en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori W betegner en hydroxymethylgruppe, i en tilsvarende halogenmethylfor- DK 159850 B bindelse overfører den i en tilsvarende forbindelse med den almene formel I, hvori W betegner en med to alkoxy-carbonylgrupper substitueret ethylgruppe, ved omsætning med en malonsyrediester, og/eller 5 overfører en ifølge opfindelsen opnået forbindelse med den.almene formel I, hvori W betegner en med to alkoxy-carbonylgrupper substitueret ethylgruppe, i en tilsvarende forbindelse med den almene formel I, hvori W belt) tegner en med 2-carboxygrupper substitueret ethylgruppe, ved hydrolyse, og/eller overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori W betegner en med to alkoxy-15 carbonylgrupper substitueret ethylgruppe, i en tilsvarende forbindelse med den almene formel I, hvori W betegner en 2-carboxyethylgruppe, ved hydrolyse og de-carboxylering, og/eller 20 overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori betegner en nitrogruppe, i en tilsvarende forbindelse med den almene formel I, hvori R£ betegner en aminogruppe, ved reduktion, og/eller 25 overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori R2 betegner en aminogruppe, i en tilsvarende forbindelse med den almene formel I, hvori R2 betegner et hydrogen- eller halogenatom, en 30 hydroxy-, alkoxy- eller alkylsulfenylgruppe, over et tilsvarende diazoniumsalt, og/eller overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori R2 betegner en hydroxygrup-35 pe, i en tilsvarende forbindelse med den almene formel I, hvori R2 betegner en alkoxygruppe, ved alkylering, og/eller DK 159850 B overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori betegner en benzyloxy-gruppe, og/eller betegner en med en benzyloxygruppe substitueret arylgruppe; i en tilsvarende forbindelse 5 med den almene formel I, hvori betegner hydroxy-gruppen, og/eller R^ betegner en med en hydroxygruppe substitueret arylgruppe, ved hjælp af debenzylering, og/eller 10 overfører en ifølge opfindelsen opnået forbindelse med den almene formel I, hvori R^ betegner en aminocarbonyl-gruppe, i en tilsvarende forbindelse med den almene formel I, hvori R^ betegner en cyanogruppe, ved dehy-dratisering, og/eller 15 opdeler en ifølge opfindelsen opnået forbindelse med den almene formel I, der har et chiralt centrum,i dens enantiomere ved chromatografi til chirale faser, og/eller 20 overfører en ifølge opfindelsen opnået forbindelse med den almene formel I i sine salte, især i fysiologisk acceptable salte med uorganiske eller organiske syrer eller baser.R ^ to R₂ and A have the meanings given above, or their derivatives optionally formed in the reaction mixture. 94 DK 159850 B having an alcohol of the general formula HO - R XIII 9 wherein Rg represents an alkyl group having 1 to 4 carbon atoms, 5 which from the E carbon can be substituted by one or two hydroxy groups or an alkoxy group having 1 to 3 carbon atoms, or i) for the preparation of a compound of general formula I wherein W represents an alkoxycarbonyl, alkoxy-carbonylmethyl, 2-alkoxycarbonylethyl or 2-alkoxy-carbonylethenyl group, and A represents a group of formula R '- CH - wherein R4, with the exception of the cyano group, has the meanings given for R4 above, conveys a compound of the general formula r; I' -jF \ _ CCH - NH - GO - CH2 - {/ y— W '3' xiv wherein R 1, R 2 and R "4 have the meanings given above and 30 w" denote a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoethenyl group, in a corresponding ester, and then, if desired by reduction, transmits an obtained compound of the general formula I wherein W represents a carboxy or alkoxycarbonyl group, in a corresponding compound of the general formula I, wherein W represents a formyl or hydroxymethyl group, and / or transfers a compound of the invention of the general formula I wherein W represents the carboxy group, in a corresponding compound of general formula I, 10 wherein W represents the formyl group, by transfer into a sulfonic acid hydrazide and subsequent disproportionation, and / or transfers a compound of the invention of general formula I wherein W represents the formyl group in a corresponding compound with the general formula I, wherein W represents a 2-alkoxycarbonylethenyl or 2-carboxyethenyl group, by condensation and optionally subsequent hydrolysis and / or decarboxylation, and and or transfers a compound of the invention with general formula I wherein W represents a 2- carb-oxyethenyl or 2-alkoxycarbonylethenyl group, in a corresponding compound with the general fo compound I, wherein W represents a 2-carboxyethyl or 2-alkoxycarbonyl-ethyl group, by catalytic hydrogenation, and / or transfers a compound of the invention obtained by the general formula I wherein W represents an alkoxycarbonyl group which is from the β-carbon atom substituted with a hydroxy group, in a corresponding (pyridinecarbonyl-oxyalkoxy) carbonyl compound of the general formula I by acylation with a pyridinecarboxylic acid, and / or after transferring a compound of the invention of general formula I wherein W represents a hydroxymethyl group, in a corresponding halo methyl compound, in a corresponding compound of the general formula I wherein W represents a ethyl group substituted with two alkoxy-carbonyl groups by reaction with a malonic acid diester and / or 5 transferring a compound obtained according to the invention with the general formula I, wherein W represents a ethyl group substituted with two alkoxy-carbonyl groups in a corresponding compound of general formula I, wherein W belt) represents a ethyl group substituted by 2-carboxy groups, by hydrolysis, and / or transfers a compound of the invention of general formula I wherein W represents one substituted by two alkoxy-carbonyl groups ethyl group, in a corresponding compound of the general formula I, wherein W represents a 2-carboxyethyl group, by hydrolysis and de-carboxylation, and / or 20 transfers a compound of the invention of the general formula I wherein a nitro group represents a corresponding compound of the general formula I, wherein R 5 represents an amino group, by reduction, and / or 25 transfers a compound of the invention obtained with the general formula I wherein R 2 represents an amino group, in a corresponding compound of the general formula I, wherein R 2 represents a hydrogen or halogen atom, a hydroxy, alkoxy or alkylsulfenyl group, over a corresponding diazonium salt, and / or compound of the invention obtained by the general formula I wherein R 2 represents a hydroxy group, in a corresponding compound of the general formula I wherein R 2 represents an alkoxy group, by alkylation, and / or DK 159850 B transfers a compound obtained according to the invention with the general formula I wherein a benzyloxy group represents and / or represents a substituted aryl group with a benzyloxy group; in a corresponding compound 5 of the general formula I wherein the hydroxy group represents and / or R1 represents a aryl group substituted by a hydroxy group by debenzylation and / or 10 transfers a compound of the formula I obtained according to the invention wherein R 1 represents an aminocarbonyl group, in a corresponding compound of general formula I, wherein R 2 represents a cyano group, by dehydration, and / or 15 divides a compound of the invention obtained with the general formula I having a chiral center, in its enantiomers, by chromatography to chiral phases, and / or transfer a compound of the general formula I obtained in its salts, especially in physiologically acceptable salts with inorganic or organic acids or bases. 3. Fremgangsmåde ifølge krav 1, kendeteg-30 net ved, at der fremstilles phenyleddikesyrederivater med den almene formel I i krav 1, hvori A betegner en gruppe med formlen R? ^R« r, • eller H , hvor : cb - . c - \ DK 159850 B betegner en n-propylgruppe, en alkylgruppe med 4 eller 5 carbonatomer, en med en methylgruppe, et fluoreller chloratom substitueret phenylgruppe eller en pyridylgruppe,Process according to claim 1, characterized in that phenylacetic acid derivatives of the general formula I of claim 1 are prepared, wherein A represents a group of formula R? ^ R «r, • or H, where: cb -. c represents an n-propyl group, an alkyl group of 4 or 5 carbon atoms, one having a methyl group, a fluoro or chlorine atom substituted phenyl group or a pyridyl group, 4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoesyre, dens 20 alkylestere. med 1 til 3 carbonatomer, dens optisk aktive antipoder eller dens salte.Process according to claim 1, characterized in that 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid, its alkyl esters are prepared. with 1 to 3 carbon atoms, its optically active antibodies or its salts. 5. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles 4-[(1-(2-piperidino-phenyl)-1-buten-l-yl)-aminocarbonylmethyl]-benzoesyre, 25 dens alkylestere: med 1 til 3 carbonatomer eller dens salte.Process according to claim 1, characterized in that 4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid, its alkyl esters: having 1 to 3 carbon atoms, is prepared. or its salts. 5 R,- og Rg sammen med det mellemliggende carbonatom be tegner en alkylidengruppe med 3 til 5 carbonatomer eller en phenylalkylidengruppe med 1 til 3 carbonatomer i alkyIdelen, R^ betegner en eventuelt med en eller to methylgrupper 10 substitueret piperidinogruppe, R2 betegner et hydrogen-, fluor- eller chloratom, methyl- eller methoxygruppen, W betegner en carboxylgruppe eller en alkoxycarbonyl-gruppe med ialt 2 til 4 carbonatomer, 15 deres optisk aktive antipoder eller deres salte med uorganiske eller organiske syrer eller baser.R R and Rg together with the intermediate carbon atom represent an alkylidene group having 3 to 5 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkyl portion, R ^ represents an optionally substituted piperidino group with one or two methyl groups, R₂ , fluorine or chlorine atom, methyl or methoxy group, W represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, their optically active antibodies or their salts with inorganic or organic acids or bases. 6. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoesyre, 30 dens alkylestere,med 1 til 3 carbonatomer, dens optisk aktive antipoder eller dens salte. 35Process according to claim 1, characterized in that 4 - [(1- (2-piperidino-phenyl) -1-pentyl) -aminocarbonylmethyl] -benzoic acid, its alkyl esters, having 1 to 3 carbon atoms, its optically active antipodes or its salts. 35