NO820047L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACIDAMIDS - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACIDAMIDS

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Publication number
NO820047L
NO820047L NO820047A NO820047A NO820047L NO 820047 L NO820047 L NO 820047L NO 820047 A NO820047 A NO 820047A NO 820047 A NO820047 A NO 820047A NO 820047 L NO820047 L NO 820047L
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Norway
Prior art keywords
group
general formula
carbon atoms
ethyl
compound
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NO820047A
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Norwegian (no)
Inventor
Wolfgang Grell
Gerhart Griss
Robert Sauter
Rudolf Hurnaus
Eckhard Rupprecht
Nikolaus Kaubisch
Joachim Kaehling
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Thomae Gmbh Dr K
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Publication of NO820047L publication Critical patent/NO820047L/en

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
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Abstract

Compounds of general formula I <IMAGE> (wherein, in outline, R1 and R2 represent alkyl or cycloalkyl groups or together with the nitrogen atom to which they are attached, represent a cyclic imino group, R3 represents a hydrogen or a halogen atom, an optionally substituted hydroxy, mercapto, amino, carboxy or aminocarbonyl group, or a nitro, alkanoyl, aminosulfonyl, alkyl, trifluoromethyl or cyano group, R4 represents a hydrogen atom or an alkyl group, R5 represents a hydrogen or a halogen atom or an alkyl group, A represents a bond or an optionally substituted methylene, ethylene, cycloalkylidene or vinylidene group, B represents a methylene or ethylene group optionally substituted by an alkyl group and W represents a hydrogen or a halogen atom, a cyano, alkanoyl or nitro group, an optionally substituted amino or aminocarbonyl group, a carboxy group, or an ester thereof, a formyl group or an acetal thereof or an optionally substituted alkyl or alkenyl group); and salts thereof formed with acids and bases. Processes for the preparation of the new compounds as well as pharmaceutical compositions containing them are also objects of this invention. The new compounds show valuable pharmaceutical properties, especially effects on intermediary metabolism and a blood-sugar lowering activity.

Description

Denne oppfinnelse angår fremstilling av nye.karboksylsyreamider med den generelle formel This invention relates to the preparation of new carboxylic acid amides with the general formula

og deres salter, særlig deres fysiologisk forlikelige salter med uorganiske eller organiske syrer og baser. and their salts, especially their physiologically compatible salts with inorganic or organic acids and bases.

De nye forbindelser oppviser verdifulle farmakologiske egenskaper, særlig en virkning på stoffskiftet, fortrinnsvis en blodsukkersenkende virkning. The new compounds exhibit valuable pharmacological properties, in particular an effect on the metabolism, preferably a blood sugar-lowering effect.

I den ovenstående generelle formel I betyrIn the above general formula I means

og R2, som kan være like eller forskjellige, alkylgrupper med 1 til 6 karbonatomer eller cykloalkylgrupper med 5 til 7 karbonatomer eller and R 2 , which may be the same or different, alkyl groups of 1 to 6 carbon atoms or cycloalkyl groups of 5 to 7 carbon atoms or

og R2sammen med det mellomliggende nitrogenatom, en uforgrenet alkyleniminogruppe med 3 til 6 karbonatomer som kan være substituert med én eller to alkylgrupper med hver 1 til 3 karbonatomer eller med en hydroksygruppe, eller and R2 together with the intervening nitrogen atom, an unbranched alkyleneimino group of 3 to 6 carbon atoms which may be substituted with one or two alkyl groups of each 1 to 3 carbon atoms or with a hydroxy group, or

hvor en metylengruppe kan være erstattet med en karbonylgruppe, med et oksygen- eller svovelatom eller med en iminogruppe, som kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en aralkylgruppe med 7 til 10 karbonatomer, en fenyl- eller halogenfenylgruppe, eller hvor en etylengruppe kan være erstattet med en o-fenylengruppe; where a methylene group may be substituted by a carbonyl group, by an oxygen or sulfur atom or by an imino group, which may be substituted by an alkyl group of 1 to 3 carbon atoms, an aralkyl group of 7 to 10 carbon atoms, a phenyl or halophenyl group, or where an ethylene group may be replaced by an o-phenylene group;

en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer, eh mettet eller delvis umettet■azabicykloalkylgruppe med 6 til 10 karbonatomer, en aza-1,4-dioksa-spiroalkylgruppe an unbranched alkyleneimino group of 4 to 6 carbon atoms, eh saturated or partially unsaturated ■azabicycloalkyl group of 6 to 10 carbon atoms, an aza-1,4-dioxa-spiroalkyl group

med 6 til 8 karbonatomer, en heptametylenimino-, oktametylenimino-, nonametylenimino- eller dekametyleniminogruppe, with 6 to 8 carbon atoms, a heptamethyleneimino, octamethyleneimino, nonamethyleneimino or decamethyleneimino group,

R^et .hydrogen- eller halogenatom, en trifluormetyl-, alkyl-, R^ is a hydrogen or halogen atom, a trifluoromethyl, alkyl,

hydroksy-, alkoksy-, alkanoyloksy-, merkapto-, alkylmerkapto-, nitro-, amino-, cyano-, alkanoyl-, karboksy-, alkoksykarbonyl-, aminokarbonyl-, alkylaminokarbonyl-, dialkylaminokarbonyl-, aminosulfonyl-, alkylamino-, dialkylamino-, alkanoylamino-, hydroxy-, alkoxy-, alkanoyloxy-, mercapto-, alkylmercapto-, nitro-, amino-, cyano-, alkanoyl-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, aminosulfonyl-, alkylamino-, dialkylamino- , alkanoylamino-,

alk6ksykarbonylami.no- eller alkylsulfonylaminogruppe , idet hver alkyIdel i de ovennevnte grupper i hvert tilfelle kan inneholde 1 til 3 karbonatomer; en aralkoksygruppe med 7 til 10 karbonatomer eller en arylkarbonylaminogruppe, et hydrogenatom eller.en alkylgruppe med 1 til 3 karbon atomer , alkyloxycarbonylamino or alkylsulfonylamino group, each alkyl part in the above-mentioned groups may in each case contain 1 to 3 carbon atoms; an aralkyl group with 7 to 10 carbon atoms or an arylcarbonylamino group, a hydrogen atom or an alkyl group with 1 to 3 carbon atoms atoms,

Ri- et hydrogenatom, et halogenatom eller en alkylgruppe med Ri- a hydrogen atom, a halogen atom or an alkyl group with

1 til 3 karbonatomer,1 to 3 carbon atoms,

A en binding, en eventuelt med en.alkylgruppe med 1 til 5 A a bond, an optionally with an alkyl group with 1 to 5

karbonatomer substituert metylen- eller etylengruppe, en med to alkylgrupper med hver 1 til 3 karbonatomer substituert metylen- eller etylengruppe, en med en cykloalkylgruppe med 3 til 7 karbonatomer, med en hydroksyalkyl-, alkoksyalkyl-, cyano-, karboksyl-, alkoksykarbonyl-, aminokarbonyl-, alkylaminokarbonyl-, dialkylaminokarbony1-, aryl- eller aralkylgruppe substituert metylengruppe, idet hver av de ovennevnte alkyldeler kan inneholde 1 til 3 karbonatomer; en cykloalkylidengruppe med 3 til 7 karbonatomer eller en vinylidengruppe med formelen carbon atoms substituted methylene or ethylene group, one with two alkyl groups with each 1 to 3 carbon atoms substituted methylene or ethylene group, one with a cycloalkyl group of 3 to 7 carbon atoms, with a hydroxyalkyl-, alkoxyalkyl-, cyano-, carboxyl-, alkoxycarbonyl-, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl or aralkyl group substituted methylene group, each of the above-mentioned alkyl moieties may contain 1 to 3 carbon atoms; a cycloalkylidene group of 3 to 7 carbon atoms or a vinylidene group of the formula

idet Rg og R7, som kan være like eller for- where Rg and R7, which can be equal or

skjellige, betyr hydrogenatomer eller alkylgrupper med hver different, means hydrogen atoms or alkyl groups with each

til 3 karbonatomer, eller også- en av restene Rg eller Ry en cykloalkylgruppe med 3 til 7 karbonatomer, en aryl- eller aralkylgruppe, eller R^og R^sammen med det mellomliggende to 3 carbon atoms, or also- one of the residues Rg or Ry a cycloalkyl group with 3 to 7 carbon atoms, an aryl or aralkyl group, or R^ and R^ together with the intermediate

karbonatom en cykloalkylidenrest med 5 til 7 karbonatomer,carbon atom a cycloalkylidene residue with 5 to 7 carbon atoms,

B en eventuelt med en alkylgruppe med 1 til 3 karbonatomer B an optionally with an alkyl group with 1 to 3 carbon atoms

substituert metylen- eller etylengruppe, ogsubstituted methylene or ethylene group, and

W et hydrogen- eller halogenatom, en nitrogruppe, en eventuelt med en alkanoylgruppe med 1 til 3 karbonatomer substituert aminogruppe, en eventuelt med en hydroksy-, karboksy- eller alkoksykarbonylgruppe eller to alkoksykarbonylgrupper med hver ialt 2 til 4 karbonatomer substituert alkylgruppe med 1 til 3 karbonatomer, en med en karboksy- eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer substituert alkenylgruppe med 2 til 5 karbonatomer, en alkanoylgruppe med 1 til 3 karbonatomer, én dialkoksymetyl- eller trialkoksymetylgruppe med 1 til 3 karbonatomer i hver alkyldel, en alkylendioksymetylgruppe med 2 eller 3 karbonatomer i alkylendelen, en 1,3-oksazolin-2-yl- eller cyanogruppe, W a hydrogen or halogen atom, a nitro group, an optionally substituted amino group with an alkanoyl group with 1 to 3 carbon atoms, an optionally substituted with a hydroxy, carboxy or alkoxycarbonyl group or two alkoxycarbonyl groups with a total of 2 to 4 carbon atoms each substituted alkyl group with 1 to 3 carbon atoms, one with a carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a substituted alkenyl group with 2 to 5 carbon atoms, an alkanoyl group with 1 to 3 carbon atoms, one dialkoxymethyl or trialkoxymethyl group with 1 to 3 carbon atoms in each alkyl moiety, an alkylenedioxymethyl group with 2 or 3 carbon atoms in the alkylene part, a 1,3-oxazolin-2-yl or cyano group,

en eventuelt med én eller to alkylgrupper med hver 1 til 4 karbonatomer i hver alkyIdel substituert aminokarbonylgruppe, en uforgrenet alkyleniminokarbonylgruppe med ialt 5 til 8 karbonatomer, en morfolinokarbonylgruppe, en (dialkyl-dioksolanyl)-alkoksykarbonylgruppe med ialt 7 til 10 karbonatomer eller en karboksygruppe og dens estere, idet alkylestere med 1 til 6 karbonatomer i alkyIdelen kan være substituert, med unntagelse av a-stillingen, med en hydroksy-, alkoksy-, amino-, alkylamino-,. dialkylamino-, 1,3-dimetyl-xantin-7-yl-, alkanoyloksy-, aroyloksy-, aralkanoyloksy-eller pyridinkarbonylgruppe eller med to hydroksygrupper, idet en metyl- resp. metylengruppe i hvert tilfelle bare kan være substituert med én hydroksygruppe, eller med en gruppe med formelen an optionally with one or two alkyl groups with each 1 to 4 carbon atoms in each alkyl part substituted aminocarbonyl group, an unbranched alkyleniminocarbonyl group with a total of 5 to 8 carbon atoms, a morpholinocarbonyl group, a (dialkyl-dioxolanyl)-alkoxycarbonyl group with a total of 7 to 10 carbon atoms or a carboxy group and its esters, since alkyl esters with 1 to 6 carbon atoms in the alkyl part can be substituted, with the exception of the a-position, with a hydroxy-, alkoxy-, amino-, alkylamino-,. dialkylamino-, 1,3-dimethyl-xanthine-7-yl-, alkanoyloxy-, aroyloxy-, aralkanoyloxy- or pyridinecarbonyl group or with two hydroxy groups, wherein a methyl- or methylene group in each case can only be substituted with one hydroxy group, or with a group of the formula

hvor A, B og til R,- er som innledningsvis angitt, where A, B and to R, - are as stated at the beginning,

idet hver alkylsubstituent i de ovennevnte alkylestere kan inneholde 1 til 3 karbonatomer. in that each alkyl substituent in the above-mentioned alkyl esters may contain 1 to 3 carbon atoms.

Blant de betydninger som er nevnt innledningsvis ved definisjonen av restene, kommer f.eks. i betraktning for R^og R_ sammen med nitrogenatomet en dimetylamino-, dietylamino-, dipropylamino-, dibutylamino-, diisobutylamino-, dipentylamino-, diheksylamino-, N-metyl-N-etylamino-, N-metyl-N-propylamino-, N-isopropyl-N-propylamino-, N-isobuty1-N-propylamino-, N-metyl-N-isopropylamino-, N-metyl-N-butylamino-, N-etyl-N-butylamino-, N-ety1-N-isopropylamino-, N-ety1-N-pentylamino-, N-propyl-N-butylamino-, N-metyl-N-cyklopenty1-amino-, N-ety1-N-cyklopentylamino-, N-mety1-N-cykloheksylamino-, M-etyl-N-cykloheksylamino-, N-propyl-N-cykloheksylamino-, N-isobutyl-N-cykloheksy lamino^-, pyrrolidino-, piperidino-, heksaraetylenimino-, heptametylenimino-, oktaraetylenimino-, nonametylenimino-, dekametylenimino-, dimetylazetidino-, metyl-pyrrolidino-, dimety1-pyrrolidino-, ety1-pyrrolidino-, mety1-piperidino-, dimety1-piperidino-, ety1-piperidino-, dietyl-piperidino-, metylety1-piperidino-, propy1-piperidino-, mety1-propyl-piperidino-, isopropy1-piperidino-, cis-3,5-dimety1-piperidino-, trans-3,5-dimety1-piperidino-, morfolino-, tiomorfolino-, piperazino-, N-mety1-piperazino-, N-etyl-piperazino-, N-propyl-piperazino-, N-isopropy1-piperazino-, N-benzyl-piperazino-, N-(2-fenyl-etyl)-piperazino-, N- (3-fenyl-prppyl)-piperazino-, N-feny1-piperazino-, N-fluorfeny1-piperazino-, N-klorfenyl-piperazino-, N-bromfenyl-piperazino-, hydroksy-pyrrolidino-, hydroksy-piperidino-, hydrdksy-heksametylenimino-, pyrrolidon-l-yl-, piperidon-l-y1-, heksahydroazepinon-l-yl-, tetrahydro-isokinolin-2-yl-, oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl-, dihydro-isoindol-2-yl-, heksahydro-isoindol-2-yl-, oktahydro-isoindol-2-yl-, tetrahydro-3-benzazepin-3-yl-, dekahydro-3-benzazepin-3-yl-, 3-aza-bicyklo[3.2.0]heptan-3-yl-, 3-aza-bicyklo [3.2.1] oktan-3-yl- , 3-aza-bicyklo [3.2.2] nonan--3-yl- , 1,4-dioksa-7-aza-spiro[4,4]nonan-7-y1-, 1,4-dioksa-7-aza-spiro [4,5]dekan-7-yl-, 1,4-dioksa-8-aza-spiro[4,5]dekan-8-y1-, 1, 4-dioksa-8^-aza-spiro [4 , 6] undekan-8-yl- , pyrrolino- eller tetrahydropyridino-gruppe, Among the meanings that are mentioned at the beginning of the definition of the rest, e.g. in consideration for R^ and R_ together with the nitrogen atom a dimethylamino-, diethylamino-, dipropylamino-, dibutylamino-, diisobutylamino-, dipentylamino-, dihexylamino-, N-methyl-N-ethylamino-, N-methyl-N-propylamino-, N-isopropyl-N-propylamino-, N-isobuty1-N-propylamino-, N-methyl-N-isopropylamino-, N-methyl-N-butylamino-, N-ethyl-N-butylamino-, N-ethy1-N -isopropylamino-, N-ethyl-N-pentylamino-, N-propyl-N-butylamino-, N-methyl-N-cyclopentylamino-, N-ethyl-N-cyclopentylamino-, N-methyl-N-cyclohexylamino- . , dimethylazetidino-, methyl-pyrrolidino-, dimethyl1-pyrrolidino-, ethyl1-pyrrolidino-, methyl1-piperidino-, dimethyl1-piperidino-, ethyl1-piperidino-, diethyl-piperidino-, methylethyl1-piperidino-, propy1-piperidino-, methyl1 -propyl-piperidino-, isopropyl-piperidino-, cis-3,5-dimethyl-piperidino-, trans -3,5-dimethyl-piperidino-, morpholino-, thiomorpholino-, piperazino-, N-methyl-piperazino-, N-ethyl-piperazino-, N-propyl-piperazino-, N-isopropyl-piperazino-, N-benzyl -piperazino-, N-(2-phenyl-ethyl)-piperazino-, N-(3-phenyl-propryl)-piperazino-, N-phenyl-1-piperazino-, N-fluorophenyl-piperazino-, N-chlorophenyl-piperazino- , N-bromophenyl-piperazino-, hydroxy-pyrrolidino-, hydroxy-piperidino-, hydroxy-hexamethyleneimino-, pyrrolidon-1-yl-, piperidon-1-y1-, hexahydroazepinon-1-yl-, tetrahydro-isoquinolin-2- yl-, octahydro-isoquinolin-2-yl-, decahydro-isoquinolin-2-yl-, dihydro-isoindol-2-yl-, hexahydro-isoindol-2-yl-, octahydro-isoindol-2-yl-, tetrahydro- 3-benzazepin-3-yl-, decahydro-3-benzazepin-3-yl-, 3-aza-bicyclo[3.2.0]heptan-3-yl-, 3-aza-bicyclo[3.2.1]octane-3 -yl-, 3-aza-bicyclo [3.2.2] nonan--3-yl-, 1,4-dioxa-7-aza-spiro[4,4]nonan-7-y1-, 1,4-dioxa -7-aza-spiro [4,5]decan-7-yl-, 1,4-dioxa-8-aza-spiro[4,5]decan-8-y1-, 1, 4-dioxa-8^- aza-spiro [4, 6] undecan-8-yl-, pyrrolino- or tetrahydropyr ridino group,

.for- R- et hydrogen-, fluor-, klor-, brom- eller jodatom,.for- R- a hydrogen, fluorine, chlorine, bromine or iodine atom,

en metyl-, etyl-, propy1-, isopropy1-, hydroksy-, metoksy-, etoksy-, propoksy-, isopropoksy-, acetoksy-, propionyloksy-, merkapto-, metylmerkapto-, etylmerkapto-, propylmerkapto-, isopropylmerkapto-, trifluormety1-, nitro-, cyano-, formyl-, acetyl-, propiony1-, aminosulfony1-, amino-, metylamino-, etylamino-, propylamino-, dimetylamino-, dietylamino-, dipropylamino-, diisopropylamino-, N-metyl-N-etylamino-, N-metyl-N-isopropylamino-, N-ety1-N-propylamino-, formylamino-, acetylamino-, propionylamino-, metylsulfonylamino-, etylsulfonyl-amino-, propy lsulf onylamino- , isopropylsulf onylamino-., a methyl-, ethyl-, propy1-, isopropyl1-, hydroxy-, methoxy-, ethoxy-, propoxy-, isopropoxy-, acetoxy-, propionyloxy-, mercapto-, methylmercapto-, ethylmercapto-, propylmercapto-, isopropylmercapto-, trifluoromethyl -, nitro-, cyano-, formyl-, acetyl-, propiony1-, aminosulfony1-, amino-, methylamino-, ethylamino-, propylamino-, dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, N-methyl-N- ethylamino-, N-methyl-N-isopropylamino-, N-ethyl-N-propylamino-, formylamino-, acetylamino-, propionylamino-, methylsulfonylamino-, ethylsulfonylamino-, propylsulfonylamino-, isopropylsulfonylamino-.,

karboksy-, metoksykarbonyl-, etoksykarbonyl-, propoksykarbonyl-, isopropoksykårbonyl-, metoksykarbonylamino-, etoksykarbonylamino-, propoksykarbonylamino-, isopropoksykarbonylamino-, benzoylamino-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, methoxycarbonylamino-, ethoxycarbonylamino-, propoxycarbonylamino-, isopropoxycarbonylamino-, benzoylamino-,

benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, 3-fenylpropoksy-, aminokarbonyl-, metylamin<p>karbonyl-, etylaminokarbonyl-, isopropylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, dipropylaminokarbonyl-, metyletylaminokarbonyl-eller metylpropylaminokarbonylgruppe, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-, 3-phenylpropoxy-, aminocarbonyl-, methylamine<p>carbonyl-, ethylaminocarbonyl-, isopropylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, dipropylaminocarbonyl-, methylethylaminocarbonyl- or methylpropylaminocarbonyl group,

for R, et hydrogenatom, en metyl-, etyl-,, propyl- eller isopropylgruppe, for R, a hydrogen atom, a methyl, ethyl, propyl or isopropyl group,

for Rj. et hydrogen-, fluor-, klor-, brom- eller jodatom,for Rj. a hydrogen, fluorine, chlorine, bromine or iodine atom,

en metyl-, etyl-, propyl- eller isopropylgruppe,a methyl, ethyl, propyl or isopropyl group,

for A en enkeltbinding, en metylen-, etyliden-, ety1-metylen-, propylmetylen-, isopropylmetylen-, butylmetylen-, pentylmetylen-, dimetylmetylen-, dietylmetylen-, dipropylmetylen-, metyletyl-.metylen-, metylpropyl-metylen-, etylpropyl-metylen-, etyl-isopropy1-metylen-, etylen-, metyletylen-, etyl-etylen-, propyl-etylen-, dimety1-etylen-, cyklopropy1-metylen-, cyklobuty1-metylen-, cyklopenty1-metylen-, cykloheksy1-metylen-, cykloheptyl-metylen-, cyklopropyliden-, cyklobutyliden-, cyklopentyliden-, cykloheksyliden-, cykloheptyliden-, karboksy-metylen-, metoksykarbonyl-metylen-, etoksykarbony1-metylen-, propoksykarboiryl-metylen-, hydroksymety1-metylen-, 1-hydroksy-ety1-metylen-, 2-hydroksyetyl-metylen-, 1-hydroksypropy1-metylen-, 3-hydroksypropy1-metylen-, metoksymety1-metylen-, etoksymetyl-metylen-, propoksymetyl-metylen-, 1-metoksyetyl-métylen-, 2-metoksyety1-metylen-, 2-etoksyetyl-metylen-, cyano-metylen-, aminokårbony1-metylen-, metylaminokarbonyl-metylen-, dimetylaminokarbonyl-metylen-, etylaminokarbonyl-metylen-, dietylaminokarbonyl-metylen-, propylaminokarbonyl-metylen-, fenyl-metylen-, benzyl^metylen-, 1-fenyletyl-metylen-, 2-fenyletyl-metylen-, 3-fenylpropyl-metylen-, 2-fenylpropyl-metylen-, vinyliden-, metyl-vinyliden- dimetyl-vinyliden-, ety1-vinyliden-, dietyl-vinyliden-, propy1-vinyliden-, dipropyl-vinyliden-, étylmety1-vinyliden-, etylpropyl-vinyliden-, metylpropyl-vinyliden-, cyklopentyl-vinyliden-, cykloheksyl-vinyliden-, feny1-vinyliden-, benzyl-vinyliden-, 2-fenetyl-vinyliden-, cyklopropyliden-metylen-, cyklopentyliden-metylen-, cykloheksyliden-metylen- eller cykloheptyliden-metylen- for A a single bond, a methylene-, ethylidene-, ethyl1-methylene-, propylmethylene-, isopropylmethylene-, butylmethylene-, pentylmethylene-, dimethylmethylene-, diethylmethylene-, dipropylmethylene-, methylethyl-.methylene-, methylpropyl-methylene-, ethylpropyl -methylene-, ethyl-isopropyl-methylene-, ethylene-, methylethylene-, ethyl-ethylene-, propyl-ethylene-, dimethyl-ethylene-, cyclopropyl-1-methylene-, cyclobuty1-methylene-, cyclopenty1-methylene-, cyclohexy1-methylene -, cycloheptyl-methylene-, cyclopropylidene-, cyclobutylidene-, cyclopentylidene-, cyclohexylidene-, cycloheptylidene-, carboxy-methylene-, methoxycarbonyl-methylene-, ethoxycarbonyl-1-methylene-, propoxycarboyryl-methylene-, hydroxymethyl-1-methylene-, 1-hydroxy -ethyl1-methylene-, 2-hydroxyethyl-methylene-, 1-hydroxypropyl1-methylene-, 3-hydroxypropyl1-methylene-, methoxymethyl-methylene-, ethoxymethyl-methylene-, propoxymethyl-methylene-, 1-methoxyethyl-methylene-, 2 -methoxyethyl1-methylene-, 2-ethoxyethyl-methylene-, cyano-methylene-, aminocarbony1-methylene-, methylaminocarbonyl-methylene-, dimethylaminocarbonyl-methyl n-, ethylaminocarbonyl-methylene-, diethylaminocarbonyl-methylene-, propylaminocarbonyl-methylene-, phenyl-methylene-, benzyl^methylene-, 1-phenylethyl-methylene-, 2-phenylethyl-methylene-, 3-phenylpropyl-methylene-, 2 -phenylpropyl-methylene-, vinylidene-, methyl-vinylidene- dimethyl-vinylidene-, ethyl1-vinylidene-, diethyl-vinylidene-, propy1-vinylidene-, dipropyl-vinylidene-, ethylmethyl-vinylidene-, ethylpropyl-vinylidene-, methylpropyl- vinylidene-, cyclopentyl-vinylidene-, cyclohexyl-vinylidene-, phenyl1-vinylidene-, benzyl-vinylidene-, 2-phenethyl-vinylidene-, cyclopropylidene-methylene-, cyclopentylidene-methylene-, cyclohexylidene-methylene- or cycloheptylidene-methylene-

gruppe,group,

for B en metylen-, etylen-, etyliden-, ety1-metylen-, propy1-metylen- eller isopropyl-metylengruppe, og for B a methylene, ethylene, ethylidene, ethyl1-methylene, propyl1-methylene or isopropyl-methylene group, and

for W et hydrogen-, klor-, brom- eller jodatom, en metyl-, etyl-, propyl-, isopropy1-, hydroksymetyl-, 1-hydroksyetyl-, 2- hydroksyetyl-, 1-hydroksypropyl-, 3-hydroksypropy1-, karboksy-metyl-, 1-karboksyetyl-, 2-karboksyetyl-, 3-karboksypropy1-, metoksykarbonyl-mety1-, etoksykarbony1-metyl-, propoksykarbonyl-metyl-, 2-metoksykarbonyl-etyl-, 2-etoksykarbonyl-etyl-, 3- etoksykarbonyl-propyl-, bis-(metoksykarbonyl)-mety1-, bis-(etoksykarbonyl)-metyl-, 2,2-bis-(etoksykarbonyl)-etyl-, karboksy-viny1-, karboksy-propenyl-, karboksy-pentenyl-, metoksykarbonyl-vinyl-, etoksykarbonyl-vinyl-, propoksykarbonyl-vinyl-, formyl-, acetyl-, propionyl-, dimetoksy-mety1-, dietoksy-metyl-, dipropoksy-metyl-, trimetoksy-mety1-, tri-etoksy-metyl-, 1,2-etylendioksy-metyl-, 1,3-propylendioksy-metyl-, cyano-, nitro-, amino-, formylamino-, acetamino-, propionylamino-, 1,3-oksazolin-2-yl-, aminokarbonyl-, metyl-aminokarbony1-, etylaminokarbonyl-, propylaminokarbonyl-, isopropylaminokarbonyl-, butylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, dipropylaminokarbonyl-, dibutylaminokarbonyl-pyrrolidinokarbony 1-, piperidino-karbonyl-, heksametyleniminokarbonyl-, heptametylenimino-karbonyl-, morfolinokarbonyl-, karboksy-, metoksykarbonyl-, etoksykarbonyl-, propoksykarbony1-, isopropoksykarbony1-, butoksykarbonyl-, tert.butoksykarbonyl-, pentoksykarbonyl-, heksoksykarbonyl-, heptoksykarbonyl-, oktoksykarbonyl-, allyloksykarbonyl-, butenyloksykarbonyl-, benzyloksykarbonyl-, 1- f enyletoksykarbonyl-, 2-f enyletoksy-karbonyl- , 3-'fenyl-propoksykarbonyl-, 2-hydroksyetoksykarbonyl-, 2-hydroksy-propoksykarbony1-, 3-hydroksypropoksykarbonyl-, 2-metoksy-etoksy-karbonyi-, 2-etoksyetoksykarbonyl-, (2,2-dimetyl-dioksolan-4-yl)-metoksykarbonyl-, 2-(2,2-dimetyl-dioksolan-4-yl)-etoksykarbonyl-, (2,2-dietyl-dioksolan-4-yl)-metoksykarbonyl-, 2- (2,2-dietyl-dioksolan-4-yl)-etoksykarbonyl-, 3-(2,2-dimetyl-dioksolan-4-yl) -propoksykarbonyl-, 2-amino-etoksy.karbonyl- , 2-dimetylaminoetoksykarbonyl-', 2-dietylamino-etoksykarbonyl-, 2-(1,3-dimetyl-xantin-7-yl)-etoksykarbonyl-, 2-acetoksy-etoksy-karbonyl-, 2-benzoyloksy-etoksykarbony1-, 2-fenylacetoksy-etoksykarbonyl-, 2-pyridinkarbonyloksy-etoksykarbony1-, 2,3-dihydroksy-propoksykarbonyl-, 3,4-dihydroksy-butoksykarbonyl-, 2-[4-f(1-(2-piperidino-fenyl)-etyl)-aminokarbonyl metyl]-benzoyloksy]-etoksykarbonyl- eller 3-[4-[(l-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoyloksy]-propoksykarbony1-gruppe. for W a hydrogen, chlorine, bromine or iodine atom, a methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, carboxy-methyl-, 1-carboxyethyl-, 2-carboxyethyl-, 3-carboxypropyl-, methoxycarbonyl-methyl-, ethoxycarbonyl-methyl-, propoxycarbonyl-methyl-, 2-methoxycarbonyl-ethyl-, 2-ethoxycarbonyl-ethyl-, 3 - ethoxycarbonyl-propyl-, bis-(methoxycarbonyl)-methyl-, bis-(ethoxycarbonyl)-methyl-, 2,2-bis-(ethoxycarbonyl)-ethyl-, carboxy-vinyl-, carboxy-propenyl-, carboxy-pentenyl -, methoxycarbonyl-vinyl-, ethoxycarbonyl-vinyl-, propoxycarbonyl-vinyl-, formyl-, acetyl-, propionyl-, dimethoxy-methyl-, diethoxy-methyl-, dipropoxy-methyl-, trimethoxy-methyl-, tri-ethoxy- methyl-, 1,2-ethylenedioxy-methyl-, 1,3-propylenedioxy-methyl-, cyano-, nitro-, amino-, formylamino-, acetamino-, propionylamino-, 1,3-oxazolin-2-yl-, aminocarbonyl-, methyl-aminocarbonyl-, ethylaminocarbonyl-, propylaminocarbonyl-, isopropylaminocarbonyl-, butylaminocarbonyl- , dimethylaminocarbonyl-, diethylaminocarbonyl-, dipropylaminocarbonyl-, dibutylaminocarbonyl-pyrrolidinocarbonyl-, piperidino-carbonyl-, hexamethyleneiminocarbonyl-, heptamethyleneiminocarbonyl-, morpholinocarbonyl-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, tert.butoxycarbonyl-, pentoxycarbonyl-, hexoxycarbonyl-, heptoxycarbonyl-, octoxycarbonyl-, allyloxycarbonyl-, butenyloxycarbonyl-, benzyloxycarbonyl-, 1-phenylethoxycarbonyl-, 2-phenylethoxycarbonyl-, 3-phenylpropoxycarbonyl-, 2- hydroxyethoxycarbonyl-, 2-hydroxy-propoxycarbonyl-, 3-hydroxypropoxycarbonyl-, 2-methoxy-ethoxy-carbonyl-, 2-ethoxyethoxycarbonyl-, (2,2-dimethyl-dioxolan-4-yl)-methoxycarbonyl-, 2-(2 ,2-dimethyl-dioxolan-4-yl)-ethoxycarbonyl-, (2,2-diethyl-dioxolan-4-yl)-methoxycarbonyl-, 2-(2,2-diethyl-dioxolan-4-yl)-ethoxycarbonyl- , 3-(2,2-dimethyl-dioxolan-4-yl)-propoxycarbonyl-, 2-amino-ethoxy.carbonyl- , 2-dimethylaminoethoxycarbonyl-', 2 -diethylamino-ethoxycarbonyl-, 2-(1,3-dimethyl-xanthine-7-yl)-ethoxycarbonyl-, 2-acetoxy-ethoxy-carbonyl-, 2-benzoyloxy-ethoxycarbonyl-, 2-phenylacetoxy-ethoxycarbonyl-, 2- pyridinecarbonyloxy-ethoxycarbonyl-, 2,3-dihydroxy-propoxycarbonyl-, 3,4-dihydroxy-butoxycarbonyl-, 2-[4-f(1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl methyl]-benzoyloxy]- ethoxycarbonyl or 3-[4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoyloxy]-propoxycarbonyl group.

Foretrukne forbindelser med den ovenstående generelle formel I er de hvor Preferred compounds of the above general formula I are those wherein

R, og R2sammen med det mellomliggende nitrogenatom betyr en dialkylamino- eller N-alkyl-cykloheksylamiriogruppe, hvor hver alkyldel kan inneholde 1 til 4 karbonatomer; en eventuelt med R, and R2 together with the intervening nitrogen atom means a dialkylamino or N-alkylcyclohexylamirio group, where each alkyl moiety may contain 1 to 4 carbon atoms; one possibly with

én eller to metylgrupper substituert, uforgrenet alkyleniminogruppe med 3 til 6 karbonatomer, en hydroksypiperidino-, piperidon-l-yl-, tetrahydro-pyridino-, morfoliho-, tiomorfolino-, N-metyl-piperazino-, N-benzy1-piperazino-, N-klorfenyl-piperazino-, heptametylenimino- eller oktametyleniminogruppe, one or two methyl substituted unbranched alkyleneimino groups of 3 to 6 carbon atoms, a hydroxypiperidino-, piperidon-1-yl-, tetrahydro-pyridino-, morpholiho-, thiomorpholino-, N-methyl-piperazino-, N-benzyl-1-piperazino-, N-chlorophenyl-piperazino, heptamethyleneimino or octamethyleneimino group,

en mettet eller delvis umettet azabicykloalkylgruppe med 7 til 9 karbonatomer, en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer, hvor en etylengruppe er erstattet med en o-fenylengruppe , eller en 1 ,.4-dioksa-aza-spiro-alkylgruppe med a saturated or partially unsaturated azabicycloalkyl group with 7 to 9 carbon atoms, an unbranched alkyleneimino group with 4 to 6 carbon atoms, where an ethylene group is replaced by an o-phenylene group, or a 1,.4-dioxa-aza-spiro-alkyl group with

7 eller 8 karbonatomer,7 or 8 carbon atoms,

R^betyr et hydrogen-,, fluor-, klor-, brom- eller jodatom,R^ represents a hydrogen, fluorine, chlorine, bromine or iodine atom,

en metyl-, trifluormety1-, hydroksy-, metoksy-, benzyloksy-, acetoksy-, merkapto-, metyimerkapto-, nitro-, amino-, dimetylamino-, acetylamino-, metylsulfonylamino-, benzoylamino-, etoksy-karbonylamino-, cyano-, karboksy-, metoksykarbonyl-, etoksykarbonyl-, aminokarbonyl-, acetyl- eller aminosulfony1-gruppe, a methyl-, trifluoromethyl-, hydroxy-, methoxy-, benzyloxy-, acetoxy-, mercapto-, methylmercapto-, nitro-, amino-, dimethylamino-, acetylamino-, methylsulfonylamino-, benzoylamino-, ethoxycarbonylamino-, cyano- , carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, acetyl or aminosulfony1 group,

R^betyr et hydrogenatom eller en metylgruppe,R^ represents a hydrogen atom or a methyl group,

R,- betyr et hydrogenatom, et kloratom eller en mety lgruppe,R,- means a hydrogen atom, a chlorine atom or a methyl group,

A betyr en binding, en eventuelt med en alkylgruppe medA means a bond, one optionally with an alkyl group with

1 til 3 karbonatomer, en fenyl-, cykloheksyl-, karboksy-, metoksykarbonyl- eller hydroksymetylgruppe substituert metylen-.gruppe, en dimety1-metylen-, cyklopropyliden- eller etylengruppe eller en vinylidengruppe med formelen 1 to 3 carbon atoms, a phenyl, cyclohexyl, carboxy, methoxycarbonyl or hydroxymethyl group substituted methylene group, a dimethylmethylene, cyclopropylidene or ethylene group or a vinylidene group of the formula

hvor Rg og R^, som kan være like eller forskjellige, where Rg and R^, which may be the same or different,

betyr hydrogenatomer eller metylgrupper, eller Rg og R^sammen med det mellomliggende karbonatom betyr en cykloalkylidenrest med 5 eller 6 karbonatomer,. means hydrogen atoms or methyl groups, or Rg and R^ together with the intervening carbon atom means a cycloalkylidene residue with 5 or 6 carbon atoms,.

B betyr en metylen-, etyliden- eller etylengruppe, ogB means a methylene, ethylidene or ethylene group, and

W betyr et hydrogenatom, en metyl-, etyl-, hydroksymety1-, cyano- eller karboksyvinylengruppe, en med en karboksygruppe eller med én eller to alkoksykarbonylgrupper med hver ialt 2 til 4 karbonatomer substituert alkylgruppe med 1 til 3 karbonatomer, en med et hydrogenatom, en metyl-, etyl-, hydroksy-, alkoksy-, (2,2-dimetyl-dioksolan-4-yl)-metoksy-, benzyloksy-, pyridylmetoksy-, amino-, alkylamino-, dialkylamino-, piperidino- eller morfolinogruppe substituert karbonylgruppe, idet hver alkyldel i de ovennevnte grupper kan inneholde 1 til 3 karbonatomer, eller en gruppe med formelen W means a hydrogen atom, a methyl, ethyl, hydroxymethyl, cyano or carboxyvinylene group, one with a carboxy group or with one or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms substituted alkyl group with 1 to 3 carbon atoms, one with a hydrogen atom, a methyl, ethyl, hydroxy, alkoxy, (2,2-dimethyl-dioxolan-4-yl)-methoxy, benzyloxy, pyridylmethoxy, amino, alkylamino, dialkylamino, piperidino or morpholino group substituted carbonyl group, each alkyl part in the above-mentioned groups may contain 1 to 3 carbon atoms, or a group with the formula

hvor n betyr tallet 2, 3 eller 4 og where n means the number 2, 3 or 4 and

Rg betyr en hydroksy-, metoksy-, etoksy-, acetoksy-, benzoyloksy-, pyridinkarbonyloksy- eller dialkylaminogruppe med 1 til 3 karbonatomer i hver alkyldel, en 1,3-dimetyl-xantin-7-yl-gruppe eller en gruppe med formelen: Rg means a hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, pyridinecarbonyloxy or dialkylamino group with 1 to 3 carbon atoms in each alkyl part, a 1,3-dimethyl-xanthine-7-yl group or a group of the formula :

hvor A, B og R^til R,- er som ovenfor angitt, spesielt de forbindelser hvor resten where A, B and R^ to R,- are as indicated above, especially those compounds where the remainder

står i 2—stilling is in the 2nd position

og resten W i 4'-stilling, ogand the residue W in the 4' position, and

hvis de inneholder et asymmetrisk- karbonatom, deres optisk aktive antipoder og deres salter. if they contain an asymmetric carbon atom, their optically active antipodes and their salts.

Spesielt foretrukne forbindelser ér imidlertid de medHowever, particularly preferred compounds are those with

den generelle formel the general formula

hvor where

og R2sammen med det mellomliggende nitrogenatom betyr en dimetylamino-, pyrrolidino-, metylpyrrolidino-, piperidino-, metylpiperidino-, dimetylpiperidino-, tetrahydro-pyridino-, 2-oktahydro-isoindolo- eller heksametylenimino-gruppe, and R2 together with the intervening nitrogen atom means a dimethylamino, pyrrolidino, methylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, tetrahydropyridino, 2-octahydroisoindolo or hexamethyleneimino group,

R^betyr et hydrogen-, fluor- eller kloratom eller en metylgruppe,.' R^ means a hydrogen, fluorine or chlorine atom or a methyl group,.'

A betyr en eventuelt med en cykloheksyl-, fenyl-, metoksykarbonyl-, etoksykarbonyl- eller en alkylgruppe med 1 til 3 karbonatomer substituert metylengruppe, en dimetyl-metylen-eller en vinylidengruppe med formelen A means a methylene group optionally substituted with a cyclohexyl, phenyl, methoxycarbonyl, ethoxycarbonyl or an alkyl group with 1 to 3 carbon atoms, a dimethyl methylene group or a vinylidene group with the formula

hvor R, og R~hver betyr et hydrogenatom eller where R, and R~each means a hydrogen atom or

sammen med det mellomliggende karbonatom en cykloheksyliden-gruppe, og together with the intermediate carbon atom a cyclohexylidene group, and

W betyr en metyl-, hydroksymety1- eller karboksymetylgruppe, en med et hydrogenatom, en metyl-, hydroksy-, metoksy-, etoksy-, propoksy-, isopropoksy-, 2-hydroksyetoksy-, 2-metoksy-etoksy-, (2,2-dimetyl-dioksolan-4-yl)-metoksy- eller 2-dietyl-aminoetoksy-gruppe substituert karbonylgruppe, W means a methyl, hydroxymethyl or carboxymethyl group, one with a hydrogen atom, a methyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, 2-hydroxyethoxy, 2-methoxyethoxy, (2, 2-dimethyl-dioxolan-4-yl)-methoxy- or 2-diethyl-aminoethoxy group substituted carbonyl group,

deres optisk aktive antipoder og deres fysiologisk forlikelige salter med uorganiske eller organiske syrer resp. baser. their optically active antipodes and their physiologically compatible salts with inorganic or organic acids resp. bases.

De nye forbindelser fremstilles i henhold til oppfinnelsen som følger: The new compounds are produced according to the invention as follows:

a) Acylering av et amin med den generelle formel a) Acylation of an amine with the general formula

hvor A pg R^til R. er som innledningsvis angitt, resp. når where A pg R^to R. is as stated at the beginning, resp. when

A representerer en av de innledningsvis nevnte vinylidengrupper, dets- tautomerer eller dets litium- eller magnesiumhalogenid-kompleks, med en karboksylsyre med den generelle formel A represents one of the initially mentioned vinylidene groups, its tautomers or its lithium or magnesium halide complex, with a carboxylic acid of the general formula

hvor R,, og B er som innledningsvis angitt, og where R,, and B are as indicated at the outset, and

W har de for W innledningsvis nevnte betydninger eller betyrW has the meanings or means mentioned for W at the beginning

en karboksylgruppe som er beskyttet med en beskyttelsesrest, ellér med dens eventuelt i reaksjonsblandingen fremstilte, reaktive derivater.- a carboxyl group that is protected with a protective residue, or with its possibly reactive derivatives produced in the reaction mixture.-

Som reaktive derivater av en forbindelse med den generelle formel III kommer f.eks. i betraktning dens estere så som metyl-, etyl- eller benzylesteren, dens tioestere så som metyltio- As reactive derivatives of a compound with the general formula III, e.g. considering its esters such as the methyl, ethyl or benzyl ester, its thioesters such as methylthio-

eller etyltioesteren, dens halogenider så som syrekloridet,or the ethyl thioester, its halides such as the acid chloride,

dens anhydrider eller imidazolider.its anhydrides or imidazolides.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som metylenklorid, kloroform, karbontetraklorid, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt i nærvær av et syreaktiverende middel eller et vanntiltrekkende middel, f.eks. i nærvær av klormaursyreetylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N'-dicykloheksylkarbodiimid, N,N1-dicykloheksyl-karbodiimid/N-hydroksysuccinimid, N,N1-karbonyldiimidazol eller N,N-'-tionyldiimidazol eller trifenylfosfin/karbontetraklorid, eller et aminogruppe-aktiverende middel, f.eks. fosfortriklorid, og eventuelt i nærvær av en uorganisk base så som natriumkarbonat, eller' en tertiær, organisk base så som trietylamin eller pyridin, som samtidig kan tjene som oppløsningsmiddel, The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a water-attracting agent, e.g. in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N1-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N1-carbonyldiimidazole or N,N-'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or a 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 can simultaneously serve as a solvent,

ved temperaturer mellom -25 og 250°C, fortrinnsvis ved temperaturer mellom -10 og det anvendte oppløsningsmiddels koketemperatur. Omsetningen kan også utføres uten oppløsnings-middel, og videre kan vann dannet under omsetningen fjernes ved azeotropisk destillasjon, f.eks. ved oppvarmning med toluen på en vannutskilier, eller ved tilsetning av et tørremiddel så som magnesiumsulfat eller molekylsikt.. at temperatures between -25 and 250°C, preferably at temperatures between -10 and the boiling temperature of the solvent used. The reaction can also be carried out without a solvent, and further water formed during the reaction can be removed by azeotropic distillation, e.g. by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulphate or molecular sieve..

Hvis nødvendig foretas den påfølgende avspaltning av en beskyttelsesrest fortrinnsvis hydrolytisk, hensiktsmessig enten i nærvær av en syre så som saltsyre, svovelsyre, fosforsyre eller trikloreddiksyre, eller i nærvær av en base så som natriumhydroksyd eller kaliumhydroksyd i et egnet oppløsnings-middel så som vann, metanol, etanol, etanol/vann, vann/ isopropanol eller vann/dioksan ved temperaturer mellom -10 og 120°C, f.eks. ved temperaturer mellom romtemperatur og reaksjonsblandingens koketemperatur. If necessary, the subsequent cleavage of a protective residue is carried out preferably hydrolytically, suitably 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, methanol, ethanol, ethanol/water, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.

En som beskyttelsesrest anvendt tert.butyl-rest kan også avspaltes termisk, eventuelt i et inert oppløsningsmiddel så A tert-butyl residue used as a protective residue can also be cleaved off thermally, possibly in an inert solvent

som metylenklorid, kloroform, benzen, toluen, tetrahydrofuran eller dioksan, og fortrinnsvis i nærvær av en katalytisk'mengde av en syre så som p-toluensulfonsyre, svovelsyre, fosforsyre eller polyfosforsyre. 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.

Videre kan en som beskyttelsesrest anvendt benzylrestFurthermore, a benzyl residue can be used as a protective residue

også avspaltes hydrogenolytisk i nærvær av en hydrogeneringskatalysator så som palladium/kull i et egnet oppløsningsmiddel så som metanol, etanol, etanol/vann, iseddik, eddiksyreetylester, dioksan eller dimetylformamid. b) For fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe: is also cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide. b) For the preparation of a compound of the general formula I where W means a carboxy group:

Spaltning av en forbindelse med den generelle formelCleavage of a compound with the general formula

hvor til , A og B er som innledningsvis angitt, og D betyr en gruppe som ved hydrolyse, termolyse eller hydrogenolyse kan overføres til e.n karboksygruppe. where to , A and B are as indicated at the outset, and D means a group which can be transferred to a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

Som hydrolyserbare grupper kommer f.eks. i betraktning funksjonelle derivater av karboksygruppen, så som dens usubstituerte eller substituerte amider, estere, tioestere, ortoestere, iminoetere, amidiner eller anhydrider, en nitrilgruppe, en malonester-(1)-y1-gruppe, en tetrazolylgruppe, As hydrolyzable groups, e.g. considering functional derivatives of the carboxy group, such as its unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, a nitrile group, a malonester-(1)-y1 group, a tetrazolyl group,

en eventuelt substituert 1,3-oksazol-2-yl- eller 1,3-oksazolin-2-yl-gruppe og som termolytisk avspaltbare grupper f.eks. estere med tertiære alkoholer, f.eks. en tert.butylester, og som hydrogenolytisk avspaltbare grupper f.eks. aralkylgrupper, så som en benzylgruppe. an optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group and as thermolytically cleavable groups, e.g. esters with tertiary alcohols, e.g. a tert.butyl ester, and as hydrogenolytically cleavable groups, e.g. aralkyl groups, such as a benzyl group.

Hydrolysen utføres hensiktsmessig enten i nærvær av en syre så som saltsyre, svovelsyre,' fosforsyre eller triklcr-eddiksyre, eller i nærvær av en base så som natriumhydroksyd eller kaliumhydroksyd, i et egnet oppløsningsmiddel så som vann, vann/metanol, etanol, vann/etanol, vann/isopropanol eller vann/dioksan, ved temperaturer mellom -10 og 120°C, f.eks. 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 and 120°C, e.g.

ved temperaturer mellom.romtemperatur og reaksjonsblandingens koketemperatur. at temperatures between room temperature and the boiling temperature of the reaction mixture.

Hvis D i en forbindelse med den generelle formel IV betyr en nitril- eller aminokarbonylgruppe, kan denne gruppe også overføres til »en karboksygruppe med et nitritt, f.eks. natriumnitritt, i nærvær av en syre så som svovelsyre, idet denne hensiktsmessig samtidig anvendes som oppløsningsmiddel, ved temperaturer mellom 0 og 50°C. If D in a compound of the general formula IV means a nitrile or aminocarbonyl group, this group can also be transferred to »a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulfuric acid, this being suitably used at the same time as a solvent, at temperatures between 0 and 50°C.

Hvis D i en forbindelse med den generelle formel IV f.eks. betyr en tert.butyloksykarbonylgruppe, kan tert.butyl-gruppen også avspaltes termisk, eventuelt i et inert oppløsningsmiddel så som metylenklorid, k.loroform, benzen, toluen, tetrahydrofuran eller dioksan, og. fortrinnsvis i nærvær av en katalytisk mengde av en syre så som p-toluensulfonsyre, svovelsyre, fosforsyre eller polyfosforsyre, fortrinnsvis ved koketemperaturen for det anvendte oppløsningsmiddel, f.eks. ved temperaturer mellom 40 og 100°C. If D in a compound with the general formula IV e.g. means a tert.butyloxycarbonyl group, the tert.butyl group can also be cleaved off thermally, possibly 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, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 100°C.

Hvis D i en forbindelse med den generelle formel IV f.eks. betyr en benzyloksykarbonylgruppe, kan benzylgruppen også avspaltes hydrogénolytisk i nærvær av en hydrogeneringskatalysator så som palladium/kull i et egnet oppløsningsmiddel så som metanol, etanol, etanol/vann, iseddik, eddiksyreetylester, dioksan eller dimetylformamid, fortrinnsvis ved temperaturer mellom 0 og 50°C, f.eks. ved romtemperatur, og et hydrogentrykk på 1 til 5 bar. Ved hydrogenolysen kan samtidig andre grupper medreduseres, f.eks. kan en halogenforbindelsé dehalogeneres, en nitrogruppe kan overføres til den tilsvarende aminogruppe, og en vinylidengruppe kan overføres til den tilsvarende alkylidengruppe. If D in a compound with the general formula IV e.g. means a benzyloxycarbonyl group, the benzyl group can also be removed hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C , e.g. at room temperature, and a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis, other groups can be co-reduced at the same time, e.g. a halogen compound can be dehalogenated, a nitro group can be transferred to the corresponding amino group, and a vinylidene group can be transferred to the corresponding alkylidene group.

c) Omsetning av en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel c) Reaction of a compound with the general formula possibly formed in the reaction mixture

hvor R., til R,-, Å, B og W er som innledningsvis angitt, where R., to R,-, Å, B and W are as indicated at the beginning,

R2' betyr et hydrogenatom eller har de for R2ovenfor angitte betydninger, med en forbindelse med den generelle formel R2' means a hydrogen atom or has the meanings given for R2 above, with a compound of the general formula

hvor R^' har de for R^ innledningsvis angitte betydninger eller sammen med resten R2<1>i formel V betyr en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert, lineær alkylengruppe med 4 til 6 karbonatomer eller en where R^' has the meanings given for R^ at the beginning or together with the residue R2<1> in formula V means an optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted, linear alkylene group with 4 to 6 carbon atoms or a

n-pentylengruppe, hvor den tredje metylengruppe er erstattet med et oksygen- eller svovelatom, og n-pentylene group, where the third methylene group is replaced by an oxygen or sulfur atom, and

E betyr, en nukleofil, utgående gruppe så som et halogenatomE means, a nucleophilic, leaving group such as a halogen atom

eller en sulfonyloksygruppe, f.eks. et klor-, brom- eller jodatom, en meta-nsulfonyloksy- eller p-toluensulfonyloksygruppe , eller også et hydrogenatom når i ' en metylengruppe er erstattet med en aldehyd- eller ketonkarbonylgruppe, or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, or also a hydrogen atom when a methylene group is replaced by an aldehyde or ketone carbonyl group,

om nødvendig i nærvær av et reduksjonsmiddel og eventuelt påfølgende hydrolyse'. if necessary in the presence of a reducing agent and possibly subsequent hydrolysis'.

Som alkyleringsmidler med formel VI kommer f.eks. i betraktning de passende halogenider eller sulfater så som metyljodid, etyljodid, propylbromid, dimetylsulfat eller dietyl-sulfat. As alkylating agents with formula VI, e.g. considering the appropriate halides or sulfates such as methyl iodide, ethyl iodide, propyl bromide, dimethyl sulfate or diethyl sulfate.

' Omsetningen utføres hensiktsmessig i et oppløsningsmiddelThe reaction is conveniently carried out in a solvent

så som aceton, tetrahydrofuran, dimetylformamid, dimetyl-sulfoksyd eller heksametylfosforsyretriamid, eventuelt, i nærvær av en uorganisk base så som natriumkarbonat, kaliumkarbonat eller kalium-tert.butylat, eller en tertiær organisk base så such as acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide, optionally, in the presence of an inorganic base such as sodium carbonate, potassium carbonate or potassium tert-butylate, or a tertiary organic base such

som pyridin, ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 20 og 75°C. Hvis man anvender en forbindelse med den generelle formel V hvor W betyr en karboksyl^-gruppe, kan denne karboksylgruppe alt efter de anvendte reaksjons-betingelser, f.eks. ved temperaturer, over romtemperatur og i nærvær av en egnet base, f.eks. natriumkarbonat, samtidig overføres til den tilsvarende ester. as pyridine, at temperatures between 0 and 150°C, preferably at temperatures between 20 and 75°C. If one uses a compound with the general formula V where W means a carboxyl group, this carboxyl group can, depending on the reaction conditions used, e.g. at temperatures above room temperature and in the presence of a suitable base, e.g. sodium carbonate, is simultaneously transferred to the corresponding ester.

Metyleringen kan også utføres ved at en forbindelse medThe methylation can also be carried out by a compound with

den generelle formel V omsettes med formalin i nærvær av et reduksjonsmiddel, f.eks. maursyre eller hydrogen i nærvær av en hydrogeneringskatalysator, f.eks. palladium eller platina, eventuelt i et oppløsningsmiddel så som maursyre eller iseddik, ved temperaturer opptil reaksjonsblandingens koketemperatur. the general formula V is reacted with formalin in the presence of a reducing agent, e.g. formic acid or hydrogen in the presence of a hydrogenation catalyst, e.g. palladium or platinum, optionally in a solvent such as formic acid or glacial acetic acid, at temperatures up to the boiling temperature of the reaction mixture.

Videre kan alkyleringen også foretas med en tilsvarende karbonylforbindelse i nærvær av et hydrid så som natriumcyanoborhydrid, i et egnet oppløsningsmiddel så som acetonitril/ eddiksyre .eller dimetylformamid/eddiksyre, fortrinnsvis ved pH 7 og ved'temperaturer mellom 0 og 50°C. Furthermore, the alkylation can also be carried out with a corresponding carbonyl compound in the presence of a hydride such as sodium cyanoborohydride, in a suitable solvent such as acetonitrile/acetic acid or dimethylformamide/acetic acid, preferably at pH 7 and at temperatures between 0 and 50°C.

Den eventuelt påfølgende hydrolyse foretas fortrinnsvisAny subsequent hydrolysis is preferably carried out

med et vandig oppløsningsmiddel så som vann/metanol, vann/with an aqueous solvent such as water/methanol, water/

etanol eller vann/dioksan, i nærvær av en syre så som saltsyre ethanol or water/dioxane, in the presence of an acid such as hydrochloric acid

eller svovelsyre, eller I nærvær av en base så som natrium-eller kaliumhydroksyd, ved temperaturer mellom. 50 og,100°C. or sulfuric acid, or in the presence of a base such as sodium or potassium hydroxide, at temperatures between 50 and 100°C.

d) For fremstilling av en forbindelse med den generelle formel I hvor W er en karboksygruppe, en alkanoylgruppe med d) For the preparation of a compound of the general formula I where W is a carboxy group, an alkanoyl group with

1 til 3 karbonatomer eller en alkylgruppe med 1 til 3 karbonatomer : Omsetning av en forbindelse med den generelle formel 1 to 3 carbon atoms or an alkyl group with 1 to 3 carbon atoms : Reaction of a compound with the general formula

hvor til R^, A og B er som innledningsvis angitt, med fosgen^et oksalylhalogenid, et alkyl- eller alkanoylhalogenid med hver 1 til 3 karbonatomer i alkyldelen eller med hydrogencyanid/ hydrogenhalogenid, fortrinnsvis hydrogenklorid, i nærvær av en Lewis-syre. where to R^, A and B are, as indicated at the outset, with phosgene^et oxalyl halide, an alkyl or alkanoyl halide with each 1 to 3 carbon atoms in the alkyl part or with hydrogen cyanide/hydrogen halide, preferably hydrogen chloride, in the presence of a Lewis acid.

Herunder kommer i betraktning som halogenider særlig klorider og bromider, og som Lewis-syre særlig aluminiumklorid. Herein, chlorides and bromides in particular come into consideration as halides, and aluminum chloride in particular as a Lewis acid.

Omsetningen utføres fortrinnsvis i et oppløsningsmiddel så som metylenklorid, nitrobenzen, klorbenzen, diklorbenzen, tetrakloretan eller karbondisulfid eller i polyfosforsyre ved temperaturer mellom 0 og 120°C, fortrinnsvis ved temperaturer mellom 20 og 80°C. Hvis R^ i en forbindelse med den generelle formel VII betyr et hydrogenatom, kan dette samtidig erstattes med en tilsvarende alkyl- eller acylrest. e) For fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe: The reaction is preferably carried out in a solvent such as methylene chloride, nitrobenzene, chlorobenzene, dichlorobenzene, tetrachloroethane or carbon disulphide or in polyphosphoric acid at temperatures between 0 and 120°C, preferably at temperatures between 20 and 80°C. If R 1 in a compound of the general formula VII means a hydrogen atom, this can simultaneously be replaced by a corresponding alkyl or acyl residue. e) For the preparation of a compound of the general formula I where W means a carboxy group:

Omsetning av en forbindelse med den generelle formel:Reaction of a compound with the general formula:

hvor til R^, A og B er som innledningsvis angitt, med et eventuelt i reaksjonsblandingen fremstilt hypohalogenitt. where to R^, A and B are as indicated at the outset, with an optional hypohalogenite produced in the reaction mixture.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som vann/tetrahydrof uran. eller vann/dioksan, og i nærvær av en base så som natriumhydroksyd eller kaliumhydroksyd, ved temperaturer mellom 0 og 80°C, fortrinnsvis ved temperaturer mellom 25 og 50°C. f) For fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe: Oksydasjon av en forbindelse med den generelle formel The reaction is conveniently carried out in a solvent such as water/tetrahydrofuran. or water/dioxane, and in the presence of a base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 80°C, preferably at temperatures between 25 and 50°C. f) For the preparation of a compound of the general formula I where W means a carboxy group: Oxidation of a compound of the general formula

hvor til R^, A og B er som innledningsvis angitt, og G betyr en gruppe som ved oksydasjon kan overføres til en karboksygruppe. where to R^, A and B are as stated at the outset, and G means a group which can be transferred to a carboxy group by oxidation.

Som en slik oksyderbar gruppe kommer f.eks. i betraktning en formylgruppe og dens acetaler, en hydroksymetylgruppe og dens etere, en usubstituert eller substituert acylgruppe så som en acetyl-, kloracetyl-, propionyl-, en malonsyre-(1)-yl-gruppe eller en malonester-(1)-yl-gruppe. As such an oxidizable group comes e.g. in consideration a formyl group and its acetals, a hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group such as an acetyl-, chloroacetyl-, propionyl-, a malonic acid-(1)-yl group or a malonester-(1)-yl -group.

Omsetningen foretas med et oksydasjonsmiddel i et egnet oppløsningsmiddel så som vann, iseddik, pyridin eller karbontetraklorid, ved temperaturer mellom 0 og 100°C, hensiktsmessig ved temperaturer mellom 20 og 50°C. Omsetningen utføres imidlertid fortrinnsvis med sølvoksyd/natronlut, mangandioksyd/ aceton eller metylenklorid, hydrogenperoksyd/natronlut, brom eller klor/natron- eller kalilut eller kromtrioksyd/pyridin. g) For fremstilling av en forbindelse med den generelle formel I hvor betyr en nitrogruppe: Omsetning av en forbindelse med den generelle formel The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, pyridine or carbon tetrachloride, at temperatures between 0 and 100°C, suitably at temperatures between 20 and 50°C. However, the reaction is preferably carried out with silver oxide/sodium hydroxide solution, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium hydroxide solution, bromine or chlorine/sodium hydroxide solution or potassium hydroxide solution or chromium trioxide/pyridine. g) For the preparation of a compound of the general formula I where means a nitro group: Reaction of a compound of the general formula

hvor R^, R,-, A, B og W er som innledningsvis angitt, R^ betyr en nitrogruppe, og Y betyr en nukleofil utskiftbar rest så som et halogenatom, med et amin med den generelle formel where R^, R^-, A, B and W are as indicated at the outset, R^ means a nitro group, and Y means a nucleophilic replaceable residue such as a halogen atom, with an amine of the general formula

hvor R^og R2er som innledningsvis angitt, og eventuelt påfølgende hydrolyse. where R 1 and R 2 are as indicated at the outset, and possibly subsequent hydrolysis.

Med begrepet "et halogenatom" som er anvendt ved definisjonen av den utskiftbare rest Y, forstås særlig et fluor-, klor- eller bromatom, fortrinnsvis i o- eller p-stilling til nitrogruppen. The term "a halogen atom" which is used in the definition of the replaceable residue Y, means in particular a fluorine, chlorine or bromine atom, preferably in the o- or p-position to the nitro group.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som vann, vann/metanol, vann/etanol, vann/isopropano1, vann/dioksan, metanol, etanol, dimetylformamid eller et overskudd av det anvendte amin med den generelle formel XI og/eller dets N-formyl-derivat, eventuelt i nærvær av en uorganisk eller tertiær organisk base, eventuelt i nærvær av en reaksjonsakselerator så som kobber eller et kobbersalt, og eventuelt i et trykk-kar ved temperaturer mellom 20 og 150°C, fortrinnsvis ved reaksjonsblandingens koketemperatur, f.eks. ved 100°C. The reaction is conveniently carried out in a solvent such as water, water/methanol, water/ethanol, water/isopropano1, water/dioxane, methanol, ethanol, dimethylformamide or an excess of the amine used with the general formula XI and/or its N-formyl -derivative, optionally in the presence of an inorganic or tertiary organic base, optionally in the presence of a reaction accelerator such as copper or a copper salt, and optionally in a pressure vessel at temperatures between 20 and 150°C, preferably at the boiling temperature of the reaction mixture, e.g. e.g. at 100°C.

Omsetningen kan imidlertid også utføres uten oppløsningsmiddel. However, the reaction can also be carried out without a solvent.

Den eventuelt påfølgende hydrolyse utføres hensiktsmessigAny subsequent hydrolysis is suitably carried out

i et vandig oppløsningsmiddel så som metanol/vann, etanol/vann eller dioksan/vann, i nærvær av en syre så som saltsyre eller in an aqueous solvent such as methanol/water, ethanol/water or dioxane/water, in the presence of an acid such as hydrochloric acid or

svovelsyre, eller en base så som natrium- eller kaliumhydroksyd, ved temperaturer mellom 50 og 100°C. sulfuric acid, or a base such as sodium or potassium hydroxide, at temperatures between 50 and 100°C.

h) For fremstilling av en forbindelse med den generelle formel I hvor A betyr en gruppe med formelen h) For the preparation of a compound of the general formula I where A means a group of the formula

hvor Rg og R^er som innledningsvis angitt: Reduksjon av et enamid med den generelle formel: where Rg and R^ are as indicated at the outset: Reduction of an enamide with the general formula:

hvor R^til R^, B og W er som innledningsvis angitt. where R^ to R^, B and W are as indicated at the outset.

Reduksjonen foretas fortrinnsvis med hydrogen i nærværThe reduction is preferably carried out with hydrogen in the presence

av en hydrogeneringskatalysator så som palladium/kull eller platina, i et egnet oppløsningsmiddel så som metanol, etanol, isopropanol, etanol/vann, iseddik, eddiksyreetylester, dioksan, tetrahydrofuran, dimetylformamid, benzen eller benzen/etanol, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 50°C, og et hydrogentrykk på 1 til 5 bar. Ved anvendelse av en egnet chiral hydrogeneringskatalysator of a hydrogenation catalyst such as palladium/charcoal or platinum, in a suitable solvent such as methanol, ethanol, isopropanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, benzene or benzene/ethanol, at temperatures between 0 and 100° C, preferably at temperatures between 20 and 50°C, and a hydrogen pressure of 1 to 5 bar. By using a suitable chiral hydrogenation catalyst

så som et metall-ligand-kompleks, f.eks. et kompleks av rhodiumklorid og (+)- eller (-)-0,0-isopropyliden-2,3-dihydroksy-1,4-bis-(difenylfosfino)-butan (= DIOP), skjer hydrogen-tilleiringen enantioselektivt. Videre kan ved den katalytiske hydrogenering også andre reduserbare grupper medreduseres, f.eks. en nitrogruppe til en aminogruppe eller et klor- eller bromatom til et hydrogenatom. such as a metal-ligand complex, e.g. a complex of rhodium chloride and (+)- or (-)-0,0-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)-butane (= DIOP), the hydrogen addition occurs enantioselectively. Furthermore, during the catalytic hydrogenation, other reducible groups can also be co-reduced, e.g. a nitro group to an amino group or a chlorine or bromine atom to a hydrogen atom.

i) For fremstilling av en forbindelse med den generelle formel I hvor R. betyr et hydrogenatom og A en eventuelt med en alkylgruppe med 1 til 5 karbonatomer substituert metylen- eller etylengruppe, en med to alkylgrupper med hver 1 til 3.karbonatomer substituert metylen- eller etylengruppe, en med en cykloalkylgruppe med 3 til 7 karbonatomer, en alkoksyalkyl-, karboksyl-, alkoksykarbonyl-, aryl- eller aralkylgruppe substituert metylengruppe, hvor hver av de ovennevnte alkyldeler kan inneholde 1 til 3 karbonatomer, eller en cykloalkylidengruppe med 4 til 7 karbonatomer: i) For the preparation of a compound with the general formula I where R. means a hydrogen atom and A a methylene or ethylene group optionally substituted with an alkyl group with 1 to 5 carbon atoms, one with two alkyl groups with each 1 to 3 carbon atoms substituted methylene- or ethylene group, one with a cycloalkyl group of 3 to 7 carbon atoms, an alkoxyalkyl, carboxyl, alkoxycarbonyl, aryl or aralkyl group substituted methylene group, where each of the above alkyl parts may contain 1 to 3 carbon atoms, or a cycloalkylidene group of 4 to 7 carbon atoms:

Omsetning av en forbindelse med den generelle formelReaction of a compound with the general formula

hvor R^til R^er som innledningsvis angitt, og A' betyr en eventuelt med en alkylgruppe med 1 til 5 karbonatomer substituert metylen- eller etylengruppe, en med to alkylgrupper med hver 1 til 3 karbonatomer substituert metylen-eller etylengruppe, en med en cykloalkylgruppe med 3 til 7 karbonatomer, en alkoksyalkyl-, karboksyl-, alkoksykarbonyl-, aryl- eller aralkylgruppe substituert metylengruppe, idet hver av de ovennevnte alkyldeler kan inneholde 1 til 3 karbonatomer, eller en cykloalkylidengruppe med 4 til 7 karbonatomer, where R^ to R^ are as indicated at the beginning, and A' means a methylene or ethylene group optionally substituted with an alkyl group with 1 to 5 carbon atoms, one with two alkyl groups with each 1 to 3 carbon atoms substituted methylene or ethylene group, one with a cycloalkyl group with 3 to 7 carbon atoms, an alkoxyalkyl, carboxyl, alkoxycarbonyl, aryl or aralkyl group substituted methylene group, each of the above-mentioned alkyl parts may contain 1 to 3 carbon atoms, or a cycloalkylidene group with 4 to 7 carbon atoms,

med en forbindelse med den generelle formelwith a compound of the general formula

hvor R,-, B og W er som innledningsvis angitt. where R,-, B and W are as indicated at the outset.

Omsetningen utføres i nærvær av en sterk syre som samtidig kan tjene som oppløsningsmiddel, fortrinnsvis i konsentrert svovelsyre, ved temperaturer mellom 20 og 150°C, fortrinnsvis The reaction is carried out in the presence of a strong acid which can also serve as a solvent, preferably in concentrated sulfuric acid, at temperatures between 20 and 150°C, preferably

ved temperaturer mellom 80 og 100°C.at temperatures between 80 and 100°C.

Hvis man ifølge oppfinnelsen oppnår en forbindelse medIf, according to the invention, a compound is obtained with

den generelle formel I hvor W betyr en karboksygruppe, kan denne eventuelt ved forestring eller amidering overføres til en tilsvarende forbindelse med- den generelle formel I,'og/eller, en forbindelse med den generelle formel I hvor R 3 og/eller W betyr en nitrogruppe, kan ved reduksjon overføres til en tilsvarende forbindelse med den generelle formel I hvor R^og/eller W betyr en amindgruppe, og/eller the general formula I where W means a carboxy group, this can possibly be transferred by esterification or amidation to a corresponding compound with the general formula I,' and/or, a compound with the general formula I where R 3 and/or W means a nitro group, can be transferred by reduction to a corresponding compound with the general formula I where R^ and/or W means an amine group, and/or

en forbindelse med den generelle formel I hvor R^og/eller W betyr en aminogruppe, kan over et tilsvarende diazoniumsalt overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr et hydrogen- eller halogenatom, en hydroksy-, alkoksy-, merkapto-, alkylmerkapto-, klorsulfony1-eller cyanogruppe og/eller W betyr et hydrogen- eller halogenatom eller en cyanogruppe, idet en således eventuelt oppnådd forbindelse med den generelle formel I hvor R^ betyr en hydroksygruppe, derefter ved alkylering kan overføres til en tilsvarende forbindelse med den generelle formel I hvor R^betyr en alkoksygruppe, eller ehsåledes eventuelt fremstilt forbindelse med den generelle formel I hvor R^ betyr en klor-sulf ony lgruppe , kan derefter med ammoniakk overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en aminosulfonylgruppe, og/eller a compound of the general formula I where R^ and/or W means an amino group can be transferred via a corresponding diazonium salt to a corresponding compound of the general formula I where R^ means a hydrogen or halogen atom, a hydroxy, alkoxy, mercapto-, alkylmercapto-, chlorosulphonyl- or cyano group and/or W means a hydrogen or halogen atom or a cyano group, a compound thus possibly obtained with the general formula I where R^ means a hydroxy group, then by alkylation can be transferred to a corresponding a compound of the general formula I where R^ means an alkoxy group, or a compound of the general formula I where R^ means a chloro-sulfonyl group, can then be transferred with ammonia to a corresponding compound of the general formula I where R ^ means an aminosulfonyl group, and/or

en forbindelse med den generelle formel I hvor R., betyr, en aminogruppe, kan ved acylering overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ er en alkanoylamino-, aroylamino-, alkoksykarbonylamino- eller alkylsulfonyl-amino-gruppe, og/eller a compound of the general formula I where R. means an amino group can be transferred by acylation to a corresponding compound with the general formula I where R. is an alkanoylamino, aroylamino, alkoxycarbonylamino or alkylsulfonylamino group, and /or

en forbindelse med den generelle formel I hvor R^ betyr en aminogruppe, kan ved alkylering overføres til en tilsvarende forbindelse med den generelle formel I hvor R^betyr én alkylamino-eller dialkylaminogruppe, og/eller a compound of the general formula I where R^ means an amino group can be transferred by alkylation to a corresponding compound of the general formula I where R^ means one alkylamino or dialkylamino group, and/or

en forbindelse med den generelle formel I hvor R^ betyr et klor- eller bromatom, kan ved dehalogenering overføres til en tilsvarende'forbindelse med den generelle formel I hvor R^betyr et hydrogenatom, og/eller a compound of the general formula I where R^ means a chlorine or bromine atom can be transferred by dehalogenation to a corresponding compound of the general formula I where R^ means a hydrogen atom, and/or

en forbindelse med den generelle formel I hvor R^ betyr en a compound of the general formula I wherein R 1 means a

. nitrilgruppe, kan ved hydrolyse resp. alkoholyse overføres til . nitrile group, can by hydrolysis resp. alcohololysis is transferred to

en tilsvarende forbindelse med den generelle formel I hvor R., betyr en aminokarbonyl-, karboksy- resp. alkoksykarbony1-gruppe, og/eller a corresponding compound with the general formula I where R. means an aminocarbonyl, carboxy- or alkoxycarbonyl group, and/or

en forbindelse med den generelle formel I hvor R^ betyr en karboksy- eller alkoksykarbonylgruppe og/eller W en eventuelt forestret karboksygruppe, kan ved reduksjon overføres til en tilsvarende forbindelse med den generelle formel I hvor R^og/eller W betyr en formyl- eller hydroksymetylgruppe, og/eller en forbindelse med den generelle formel I hvor W betyr en gruppe med formelen -C00-(CH2)^-OH, kan ved acylering overføres til en tilsvarende forbindelse med den generelle formel I hvor W betyr en gruppe med formelen -C00- (CH2)n-Rg/ a compound of the general formula I where R^ means a carboxy or alkoxycarbonyl group and/or W an optionally esterified carboxy group can be transferred by reduction to a corresponding compound of the general formula I where R^ and/or W means a formyl or hydroxymethyl group, and/or a compound of the general formula I where W means a group of the formula -C00-(CH2)^-OH, can be transferred by acylation to a corresponding compound of the general formula I where W means a group of the formula - C00-(CH2)n-Rg/

og/ellerand or

en forbindelse med den generelle formel I hvor W betyr en hydroksymetylgruppe, kan efter overføring til en tilsvarende halogenmetylforbindelse, ved omsetning med en malonsyrediester overføres til en tilsvarende forbindelse med den generelle formel I hvor W betyr en med to alkoksykarbonylgrupper substituert etylgruppe, og/eller a compound of the general formula I where W means a hydroxymethyl group, after transfer to a corresponding halomethyl compound, by reaction with a malonic acid diester can be transferred to a corresponding compound of the general formula I where W means an ethyl group substituted with two alkoxycarbonyl groups, and/or

en forbindelse med den generelle formel I hvor W betyr en formylgruppe, kan ved'kondensasjon og eventuelt påfølgende hydrolyse og/eller dikarboksylering overføres til en tilsvarende forbindelse med den generelle formel I hvor W betyr en med en hydroksykarbonyl- eller alkoksykarbonylgruppe substituert vinylgruppe, og/eller a compound of the general formula I where W means a formyl group can by condensation and possibly subsequent hydrolysis and/or dicarboxylation be transferred to a corresponding compound of the general formula I where W means a vinyl group substituted with a hydroxycarbonyl or alkoxycarbonyl group, and/ or

en forbindelse med den generelle formel I hvor W betyr en med to alkoksykarbonylgrupper substituert etylgruppe, kan ved hydrolyse og dekarboksylering overføres til en tilsvarende forbindelse med den generelle formel I hvor W betyr en med en karboksygruppe substituert etylgruppe, og/eller a compound of the general formula I where W means an ethyl group substituted with two carboxycarbonyl groups, can by hydrolysis and decarboxylation be transferred to a corresponding compound of the general formula I where W means an ethyl group substituted with a carboxy group, and/or

en forbindelse med den generelle formel I hvor W betyr en karboksylgruppe, kan ved overføring til et sulfonsyrehydrazid og påfølgende disproporsjonering overføres til en tilsvarende-forbindelse med den generelle formel I hvor W betyr en formylgruppe, og/eller a compound of the general formula I where W means a carboxyl group can, by transfer to a sulfonic acid hydrazide and subsequent disproportionation, be transferred to a corresponding compound of the general formula I where W means a formyl group, and/or

en forbindelse.med den generelle formel I hvor R^og R2sammen med det mellomliggende nitrogenatom betyr en aza-1,4-dioksa-spiro-alkylgruppe med 6 til 8 karbonatomer, kan ved hydrolyse i nærvær av en syre overføres til en tilsvarende forbindelse med a compound of the general formula I where R₂ and R₂ together with the intervening nitrogen atom mean an aza-1,4-dioxa-spiro-alkyl group with 6 to 8 carbon atoms, can by hydrolysis in the presence of an acid be transferred to a corresponding compound with

den generelle formel I hvor R^ og R- sammen med det mellomliggende nitrogenatom betyr en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer, hvor en metylengruppe er erstattet med en karbonylgruppe, og/eller the general formula I where R^ and R- together with the intervening nitrogen atom mean an unbranched alkyleneimino group with 4 to 6 carbon atoms, where a methylene group is replaced by a carbonyl group, and/or

en forbindelse med den generelle formel I hvor R^og R2sammen med det mellomliggende nitrogenatom betyr en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer, hvor én metylengruppe er erstattet med en karbonylgruppe, kan ved reduksjon overføres til "en tilsvarende hydroksyalkyleniminoforbindelse med den generelle formel I, og/eller a compound of the general formula I where R₂ and R₂ together with the intervening nitrogen atom mean an unbranched alkyleneimino group with 4 to 6 carbon atoms, where one methylene group is replaced by a carbonyl group, can by reduction be transferred to "a corresponding hydroxyalkyleneimino compound of the general formula I, and or

en forbindelse med den generelle formel I hvor W betyr en aminokarbonylgruppe, kan ved dehydratisering overføres til en tilsvarende forbindelse med den generelle formel I hvor W betyr en cyangruppe. a compound of the general formula I where W means an aminocarbonyl group can be transferred by dehydration to a corresponding compound of the general formula I where W means a cyano group.

Den etterfølgende dehydratisering foretas med et vanntiltrekkende middel så som fosforpentoksyd, svovelsyre eller p-toluensulfonsyreklorid, eventuelt i et oppløsningsmiddel så som metylenklorid eller pyridin, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 80°C. The subsequent dehydration is carried out with a water-attracting agent such as phosphorus pentoxide, sulfuric acid or p-toluenesulphonic acid chloride, possibly in a solvent such as methylene chloride or pyridine, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

Den efterfølgende forestring foretas hensiktsmessig i et egnet oppløsningsmiddel, f.eks. i en passende alkohol, pyridin, toluen, metylenklorid, tetrahydrofuran eller dioksan, i nærvær av et syreaktiverende og/eller vanntiltrekkende middel så som tionylklorid, klormaursyreetylester, karbonyldiimidazol eller N,N'-dicykloheksyIkarbodiimid eller dets isourinstoff-etere, eventuelt i nærvær av en reaksjonsakselerator så som kobber-klorid, eller ved omestring, f.eks. med en tilsvarende karbonsyre-diester, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20°C pg det anvendte oppløsningsmiddels koketemperatur. The subsequent esterification is conveniently carried out in a suitable solvent, e.g. in a suitable alcohol, pyridine, toluene, methylene chloride, tetrahydrofuran or dioxane, in the presence of an acid-activating and/or water-attracting agent such as thionyl chloride, chloroformate ethyl ester, carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide or its isourea ethers, optionally in the presence of a reaction accelerator such as copper chloride, or by transesterification, e.g. with a corresponding carbonic acid diester, at temperatures between 0 and 100°C, preferably at temperatures between 20°C due to the boiling point of the solvent used.

Den etterfølgende amidering foretas hensiktsmessig i et: oppløsningsmiddel så som metylenklorid, kloroform, karbontetraklorid, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt i nærvær av et syreaktiverende middel eller et vanntiltrekkende middel, The subsequent amidation is conveniently carried out in a: solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a water-attracting agent,

f.eks. i nærvær av klormaursyreetylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N<1->dicykloheksylkarbodiimid, N,N'-dicykloheksylkarbodiimid/N-hydroksy-succinimid, N,N'-karbonyldiimidazol, N,N<1->tionyldiimidazol eller trifenyl- e.g. in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N<1->dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole, N,N<1->thionyldiimidazole or triphenyl -

fosfin/karbontetraklorid, eller et aminogruppe-aktiverende middel, f.eks. fosfortrikl<p>rid, og eventuelt i nærvær av en uorganisk1 base så som natriumkarbonat, eller en tertiær organisk base så som trietylamin eller pyridin, som samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom -25 phosphine/carbon tetrachloride, or an amino group activating agent, e.g. phosphorus trichloride, and optionally in the presence of an inorganic1 base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25

pg 250°C, fortrinnsvis ved temperaturer mellom -10°C og det anvendte oppløsningsmiddels koketemperatur. Omsetningen kan også utføres uten oppløsningsmiddel, og dessuten kan under omsetningen dannet vann fraskilles ved azeotropisk destillasjon, f.eks. ved oppvarmning med toluen på en vannutskilier, eller ved tilsetning av et tørremiddel så som magnesiumsulfat eller molekylsikt. pg 250°C, preferably at temperatures between -10°C and the boiling temperature of the solvent used. The reaction can also be carried out without a solvent, and furthermore water formed during the reaction can be separated by azeotropic distillation, e.g. by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieve.

Den etterfølgende reduksjon av nitroforbindelsen foretas fortrinnsvis i et oppløsningsmiddel så som vann, vann/etanol, metanol, iseddik, eddiksyreetylester eller dimetylformamid, hensiktsmessig med hydrogen i nærvær av en hydrogeneringskatalysator så som Raney-nikkel, platina eller palladium/kull, The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, suitably with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal,

med metaller så som jern, tinn eller sink, i nærvær av en syre, med salter så som jern(II)sulfat, tinn(II)klorid eller natrium-ditionitt, eller med hydrazin i nærvær av Raney-nikkel ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. with metals such as iron, tin or zinc, in the presence of an acid, with salts such as iron(II) sulphate, tin(II) chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50°C, preferably at room temperature.

Den etterfølgende omsetning av et diazoniumsalt, f.eks. fluorboratet, hydrosulfatet i svovelsyre, hydrokloridet eller hydfojodidet, hvis nødvendig i nærvær av kobber eller et passende kobber (I)-salt så som kobber (I)'klorid/saltsyre , kobber(I)bromid/bromhydrogensyre, trinatrium-kobber(I)tetracyanid ved pH 7 eller et alkalixantogenat, eller av kobber(II)klorid/ svoveldioksyd i iseddik, eventuelt under tilsetning av magnesiumklorid, ved svakt forhøyede temperaturer, f.eks. ved temperaturer mellom 15 og 100°C; idet den etterfølgende omsetning med underfosforsyrling fortrinnsvis foretas ved -5 til 0°C. Det for formålet nødvendige diazoniumsalt fremstilles hensiktsmessig i et egnet oppløsningsmiddel, f.eks. i vann/saltsyre, metanol/ saltsyre, etaxiol/saltsyre eller dioksan/saltsyre, ved diazotering av en tilsvarende aminoforbindelse med et nitritt, f.eks. natriumnitritt eller en ester av salpetersyrling, ved lavere temperaturer, f.eks. ved temperaturer mellom -10 og 5°C. The subsequent reaction of a diazonium salt, e.g. the fluoroborate, the hydrosulfate in sulfuric acid, the hydrochloride or hydphoiodide, if necessary in the presence of copper or a suitable copper (I) salt such as copper (I) chloride/hydrochloric acid, copper (I) bromide/hydrobromic acid, trisodium copper (I) tetracyanide at pH 7 or an alkali xanthogenate, or of copper (II) chloride/sulphur dioxide in glacial acetic acid, possibly with the addition of magnesium chloride, at slightly elevated temperatures, e.g. at temperatures between 15 and 100°C; the subsequent reaction with hypophosphoric acid is preferably carried out at -5 to 0°C. The diazonium salt required for the purpose is suitably prepared in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethoxyol/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. at temperatures between -10 and 5°C.

Den etterfølgende acylering foretas hensiktsmessig i et oppløsningsmiddel så som metylenklorid, eter, tetrahydrofuran eller i et overskudd av det anvendte acyleringsmiddel, f.eks. maursyre, eddiksyre eller propionsyre resp. deres anhydrider, syreklorider eller estere, eventuelt i nærvær av en uorganisk eller en tertiær organisk base som samtidig også kan tjene som oppløsningsmiddel, og eventuelt i nærvær av et syreaktiverende eller vanntiltrekkende middel ved temperaturer mellom -25 og 150°C, fortrinnsvis ved temperaturer mellom -10 og reaksjons-blaridingens koketemperatur. The subsequent acylation is conveniently carried out in a solvent such as methylene chloride, ether, tetrahydrofuran or in an excess of the acylating agent used, e.g. formic acid, acetic acid or propionic acid resp. their anhydrides, acid chlorides or esters, optionally in the presence of an inorganic or a tertiary organic base which can also serve as a solvent, and optionally in the presence of an acid-activating or water-attracting agent at temperatures between -25 and 150°C, preferably at temperatures between -10 and the reaction boiling temperature.

Den etterfølgende N-alkylering foretas hensiktsmessig med et passende halogenid eller en sulfonsyreester, f.eks. med metyljodid, dimetylsulfat, etylbromid eller p-toluensulfonsyre-etylester, eventuelt i nærvær av en base så som natriumhydrid, kaliumhydroksyd eller kalium-tert.butylat, og fortrinnsvis i et oppløsningsmiddel så som dietyleter, tetrahydrofuran, dioksan, etanol, pyridin eller dimetylformamid, ved temperaturer mellom 0 og 75°C, fortrinnsvis ved romtemperatur. Metyleringen kan dessuten foretas med formaldehyd/maursyre, hensiktsmessig ved reaksjonsblandingens koketemperatur, og alkyleringen med en passende karbonylforbindelse i nærvær av et hydrid så som natriumcyanoborhydrid, i et oppløsningsmiddel så som acetonitril/ eddiksyre eller dimetylformamid/eddiksyre, fortrinnsvis ved pH 7 og ved temperaturer mellom 0 og 50°C. The subsequent N-alkylation is suitably carried out with a suitable halide or a sulphonic acid ester, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide or p-toluenesulfonic acid ethyl ester, 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, tetrahydrofuran, dioxane, ethanol, pyridine or dimethylformamide, at temperatures between 0 and 75°C, preferably at room temperature. The methylation can also be carried out with formaldehyde/formic acid, conveniently at the boiling temperature of the reaction mixture, and the alkylation with a suitable carbonyl compound in the presence of a hydride such as sodium cyanoborohydride, in a solvent such as acetonitrile/acetic acid or dimethylformamide/acetic acid, preferably at pH 7 and at temperatures between 0 and 50°C.

Den etterfølgende dehalogenering foretas hensiktsmessig i ét oppløsningsmiddel så som metanol, etanol, etylacetat, iseddik eller dimetylformamid, ved hjelp av katalytisk aktivert hydrogen, f.eks. med hydrogen i nærvær av platina eller palladium/kull, ved temperaturer mellom 0 og 75°C, fortrinnsvis ved romtemperatur, og ved et hydrogentrykk på 1-5 bar. The subsequent dehalogenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide, using catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/carbon, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1-5 bar.

Den påfølgende hydrolyse foretas hensiktsmessig enten i nærvær av. en syre så som saltsyre, svovelsyre, fosforsyre, polyfosforsyre eller trifluoreddiksyre, eller i nærvær av en båse så som natriumhydroksyd eller kaliumhydroksyd i et egnet oppløsningsmiddel så som vann, etanol, vann/etanol, vann/ isopropanol eller vann/dioksan ved forhøyede temperaturer,• f.eks. ved reaksjonsblandingens koketemperatur. Hydrolysen kan imidlertid også utføres med et nitritt, f.eks. natriumnitritt, The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid, or in the presence of a buffer such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, ethanol, water/ethanol, water/isopropanol or water/dioxane at elevated temperatures, • e.g. at the boiling temperature of the reaction mixture. However, the hydrolysis can also be carried out with a nitrite, e.g. sodium nitrite,

i nærvær av en syre så som svovelsyre, idet denne hensiktsmessig samtidig anvendes som oppløsningsmiddel, ved temperaturer mellom 0 og 50°C. Den etterfølgende alkoholyse foretas in the presence of an acid such as sulfuric acid, this being suitably used at the same time as a solvent, at temperatures between 0 and 50°C. The subsequent alcoholysis is carried out

hensiktsmessig i nærvær av hydrogenhalogenid, fortrinnsvis hydrogenklorid, ved temperaturer mellom 20°C og kdketempera-turen for den anvendte alkohol. suitably in the presence of hydrogen halide, preferably hydrogen chloride, at temperatures between 20°C and the boiling temperature of the alcohol used.

Den etterfølgende reduksjon foretas fortrinnsvis med et metallhydrid, f.eks. med et komplekst metallhydrid så som litiumaluminiumhydrid, i et egnet oppløsningsmiddel så som dietyleter, tetrahydrofuran eller dioksan, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 60°C. The subsequent reduction is preferably carried out with a metal hydride, e.g. with 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, preferably at temperatures between 20 and 60°C.

Den påfølgende O-alkylering foretas hensiktsmessig medThe subsequent O-alkylation is conveniently carried out with

et passende halogenid, en sulfonsyreester eller et diazoalkan, f.eks. med metyljodid, dimetylsulfat/etylbromid, p-toluensulfonsyre-etylester, metansulfonsyre-isopropylester eller diazometan, eventuelt i nærvær av en base så som natriumhydrid, kaliumhydroksyd eller kalium-tert.butylat, og fortrinnsvis i et oppløsningsmiddel så som dietyleter, tetrahydrofuran, dioksan, metanol, etanol, pyridin eller dimetylformamid, ved temperaturer mellom 0 og 75°C, fortrinnsvis ved romtemperatur. a suitable halide, a sulphonic acid ester or a 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, tetrahydrofuran, dioxane, methanol, ethanol, pyridine or dimethylformamide, at temperatures between 0 and 75°C, preferably at room temperature.

Den etterfølgende overføring av en hydroksymetylgruppeThe subsequent transfer of a hydroxymethyl group

til en halogenmetylgruppe foretas med et halogeneringsmiddel så som tionylklorid, fos fortriklorid, fosfortribromid eller fosforpentaklorid, i et oppløsningsmiddel så som metylenklorid, karbontetraklorid, benzen eller nitrobenzen, og dens påfølgende omsetning med en malonsyreester, f.eks. med et alkalisalt av malons.yredietylester, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 50°C. to a halomethyl group is carried out with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene, and its subsequent reaction with a malonic acid ester, e.g. with an alkali salt of malonide diethyl ester, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C.

Den. etterfølgende kondensasjon av en formylforbindeIse foretas hensiktsmessig i et oppløsningsmiddel så som pyridin eller tetrahydrofuran, med malonsyre, med en malonsyreester, It. 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,

med en dialkylfosfono-eddiksyreester eller et alkoksykarbony1-metylen-trifenyl-fosfon, eventuelt i nærvær av en base som kondensasjonsmiddel, f.eks. i nærvær av piperidin, kalium-tert. butylat eller natriumhydrid, ved temperaturer mellom 0 og 100°C. Ved påfølgende surgjøring, f.eks. med saltsyre eller svovelsyre, resp. ved påfølgende alkalisk hydrolyse, with a dialkylphosphono-acetic acid ester or an alkoxycarbonyl-1-methylene-triphenyl-phosphone, optionally in the presence of a base as condensing agent, e.g. in the presence of piperidine, potassium tert. butylate or sodium hydride, at temperatures between 0 and 100°C. In case of subsequent acidification, e.g. with hydrochloric or sulfuric acid, resp. by subsequent alkaline hydrolysis,

får man denønskede syre.you get the desired acid.

Den etterfølgende hydrolyse og dekarboksylering foretas hensiktsmessig i nærvær av en syre så som saltsyre, svovelsyre, fosforsyre, polyfosforsyre eller trifluoreddiksyre, i et egnet oppløsningsmiddel så som vann, etanol, vann/etanol, vann/ isopropanol eller vann/dioksan, ved forhøyede temperaturer, f.eks. ved reaksjonsblandingens koketemperatur. The subsequent hydrolysis and decarboxylation is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid, in a suitable solvent such as water, ethanol, water/ethanol, water/isopropanol or water/dioxane, at elevated temperatures, e.g. at the boiling temperature of the reaction mixture.

Den etterfølgende disproporsjonering av et sulfonsyrehydrazid, som man får ved omsetning av et tilsvarende hydrazin med et tilsvarende reaktivt karboksylsyrederivat, foretas i nærvær av en base så som natriumkarbonat, i et oppløsningsmiddel' så som etylenglykol, ved temperaturer mellom 100 og 200°C, fortrinnsvis ved 160-170°C. The subsequent disproportionation of a sulphonic acid hydrazide, which is obtained by reacting a corresponding hydrazine with a corresponding reactive carboxylic acid derivative, is carried out in the presence of a base such as sodium carbonate, in a solvent such as ethylene glycol, at temperatures between 100 and 200°C, preferably at 160-170°C.

De oppnådde forbindelser.med den generelle formel I kan dessuten overføres til sine addisjonssalter, særlig sine fysiologisk forlikelige salter med uorganiske eller organiske syrer eller også baser. Som syrer kommer her f.eks. i betraktning saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, melkesyre, sitronsyre, vinsyre, ravsyre, maleinsyre eller fumarsyre, og som baser natriumhydroksyd, kaliumhydroksyd eller cykloneksylamin. The obtained compounds with the general formula I can also be transferred to their addition salts, in particular their physiologically compatible salts with inorganic or organic acids or also bases. As acids, e.g. considering hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and as bases sodium hydroxide, potassium hydroxide or cyclohexylamine.

De som utgangsstoffer anvendte forbindelser med de generelle formler II til XIV er .delvis kjent fra litteraturen, resp. The compounds with the general formulas II to XIV used as starting materials are partly known from the literature, resp.

kan fremstilles ved i og for seg kjente fremgangsmåter.can be produced by methods known per se.

Således får man f.eks. en.forbindelse med den generelle formel II hvor A betyr en binding, ved reduksjon av en tilsvarende nitroforbindelse, f.eks. ved hjelp av katalytisk aktivert eller nascerende hydrogen, eller ved hjelp av natrium-ditionitt eller ved Hofmann-, Curtius-, Lossen- eller Schmidt-•avbygning av en tilsvarende forbindelse. Thus, you get e.g. a compound with the general formula II where A means a bond, by reduction of a corresponding nitro compound, e.g. by means of catalytically activated or nascent hydrogen, or by means of sodium dithionite or by Hofmann, Curtius, Lossen or Schmidt decomposition of a corresponding compound.

Man oppnår f.eks. en forbindelse med den generelle formel II hvor A betyr en vinylidengruppe, resp. dens tautomere ketimi.n, ved omsetning av et tilsvarende nitril med en tilsvarende Grignard- eller litium-forbindeIse og påfølgende hydrolyse, eller ved omsetning av et tilsvarende keton med et tilsvarende amin i nærvær av titantetraklorid. For videre omsetning med en forbindelse med den generelle formel III resp. dens reaktive derivater, særlig dens syreklorider, kan også det metall-organiske-ketimin-kompleks anvendes. One achieves e.g. a compound of the general formula II where A means a vinylidene group, resp. its tautomeric ketimi.n, by reaction of a corresponding nitrile with a corresponding Grignard or lithium compound and subsequent hydrolysis, or by reaction of a corresponding ketone with a corresponding amine in the presence of titanium tetrachloride. For further conversion with a compound of the general formula III or its reactive derivatives, especially its acid chlorides, the metal-organic-ketimine complex can also be used.

Man oppnår f.eks. en forbindelse med den generelleOne achieves e.g. a connection with the general

formel II hvor A ikke betyr en binding og ikke en vinylidengruppe, ved reduksjon av et tilsvarende nitril med litiumaluminiumhydrid, ved omsetning av et tilsvarende nitril med formula II where A does not mean a bond and not a vinylidene group, by reduction of a corresponding nitrile with lithium aluminum hydride, by reaction of a corresponding nitrile with

en tilsvarende Grignard- eller litium-forbindelse og eventuelt påfølgende litiumaluminiumhydrid-reduksjon og påfølgende hydrolyse til ketiminet, som derefter reduseres'med katalytisk aktivert hydrogen, med et komplekst metallhydrid eller med nascerende hydrogen, ved hydrolyse resp. ved hydrazinolyse av en tilsvarende ftalimidoforbindelse ved omsetning av et tilsvarende keton med ammoniumformiat og påfølgende hydrolyse resp. med et ammoniumsalt i nærvær av natriumcyanoborhydrid, ved reduksjon av et tilsvarende oksim med litiumaluminiumhydrid, med katalytisk aktivert eller nascerende hydrogen, ved reduksjon med en tilsvarende N-benzyl- eller N-l-fenyletyl-Schiffsk base, f.eks. med et komplekst metallhydrid i eter eller tetrahydrofuran ved temperaturer mellom ~ 78°C og det anvendte oppløsningsmiddels koketemperatur, og påfølgende avspaltning av benzyl- eller 1-fenyletylgruppen ved katalytisk hydrogenering, ved Ritter-reaksjon med en tilsvarende alkohol med kalijmcyanid i svovelsyre, eller ved Hofmann-, Curtius-, Lossen- eller Schmidt-avbygning av en tilsvarende forbindelse. Et således oppnådd amin med den generelle formel II med et chiralitetssentrum kan ved racematspaltning, f.eks. ved fraksjonert krystallisasjon av de diastereomere salter med optisk aktive syrer og påfølgende oppspaltning av saltene eller ved dannelse av diastereomere forbindelser, deres adskiHelse og påfølgende spaltning, separeres i sine enantiomerer. Videre kan et optisk aktivt amin med den generelle formel II også fremstilles ved enantio-selektiv reduksjon av et tilsvarende ketimin ved hjelp av komplekse bor- eller aluminiumhydrider i hvilke en del av hydrid-hydrogenatomene er erstattet med optisk aktive alkoholatrester, eller ved hjelp av hydrogen i nærvær av en egnet chiral hydrogeneringskatalysator resp. analogt ved å gå ut fra en tilsvarende N-benzyl- eller eventuelt optisk aktiv N-l-fenetyl-Schiffsk base og eventuelt påfølgende avspaltning av benzyl- eller 1-fenetylresten. a corresponding Grignard or lithium compound and possibly subsequent lithium aluminum hydride reduction and subsequent hydrolysis to the ketimine, which is then reduced with catalytically activated hydrogen, with a complex metal hydride or with nascent hydrogen, by hydrolysis resp. by hydrazinolysis of a corresponding phthalimido compound by reaction of a corresponding ketone with ammonium formate and subsequent hydrolysis resp. with an ammonium salt in the presence of sodium cyanoborohydride, by reduction of a corresponding oxime with lithium aluminum hydride, with catalytically activated or nascent hydrogen, by reduction with a corresponding N-benzyl or N-1-phenylethyl Schiff base, e.g. with a complex metal hydride in ether or tetrahydrofuran at temperatures between ~ 78°C and the boiling temperature of the solvent used, and subsequent cleavage of the benzyl or 1-phenylethyl group by catalytic hydrogenation, by Ritter reaction with a corresponding alcohol with potassium cyanide in sulfuric acid, or by Hofmann, Curtius, Lossen or Schmidt degradation of a corresponding compound. An amine thus obtained with the general formula II with a chirality center can by racemate cleavage, e.g. by fractional crystallization of the diastereomeric salts with optically active acids and subsequent splitting of the salts or by formation of diastereomeric compounds, their separation and subsequent splitting, are separated into their enantiomers. Furthermore, an optically active amine with the general formula II can also be prepared by enantio-selective reduction of a corresponding ketimine with the help of complex boron or aluminum hydrides in which part of the hydride hydrogen atoms are replaced with optically active alcohol residues, or with the help of hydrogen in the presence of a suitable chiral hydrogenation catalyst resp. analogously by starting from a corresponding N-benzyl or optionally optically active N-1-phenethyl Schiff base and possibly subsequent cleavage of the benzyl or 1-phenethyl residue.

En forbindelse med den generelle formel II hvor R^betyr en lavere alkylrest, kan fremstilles ved reduksjon av en tilsvarende N-acyl-forbindelse, f.eks. ved hjelp av litiumaluminiumhydrid. A compound of the general formula II where R 2 means a lower alkyl residue can be prepared by reduction of a corresponding N-acyl compound, e.g. using lithium aluminum hydride.

De som utgangsstoffer anvendte forbindelser med de generelle formler IV, V og VII til X får man ved omsetning av The compounds with the general formulas IV, V and VII to X used as starting materials are obtained by reacting

et tilsvarende amin med en tilsvarende karboksylsyre resp.a corresponding amine with a corresponding carboxylic acid resp.

dens reaktive derivater, og eventuelt påfølgende hydrolyse.its reactive derivatives, and possibly subsequent hydrolysis.

En forbindelse med den generelle formel VIII får man ogsåA compound of the general formula VIII is also obtained

ved Friedel-Crafts-acetylering av en tilsvarende forbindelse.by Friedel-Crafts acetylation of a corresponding compound.

En som utgangsstoff anvendt forbindelse med den generelle formel XII får man fortrinnsvis ved acylering, av et tilsvarende ketimin med en tilsvarende karboksylsyre, resp. dens reaktive derivater under tautomerisering. A compound with the general formula XII used as starting material is preferably obtained by acylation of a corresponding ketimine with a corresponding carboxylic acid, resp. its reactive derivatives during tautomerization.

En som utgangsstoff anvendt forbindelse med den generelle formel XIII får man ved reduksjon av en tilsvarende karbonylforbindelse eller ved omsetning av en tilsvarende, karbonylforbindelse med et tilsvarende Grignard- eller litiumreagens. A compound of the general formula XIII used as starting material is obtained by reduction of a corresponding carbonyl compound or by reacting a corresponding carbonyl compound with a corresponding Grignard or lithium reagent.

Som nevnt innledningsvis oppviser de nye forbindelser med den generelle formel I verdifulle farmakologiske egenskaper, nemlig en virkning på det intermediære stoffskiftet, særlig en blodsukkersenkende virkning. As mentioned at the outset, the new compounds of the general formula I exhibit valuable pharmacological properties, namely an effect on intermediate metabolism, in particular a blood sugar-lowering effect.

Som eksempler ble forbindelseneAs examples were the compounds

A = 4- [.(2-pyrrolidino-benzyl)-aminokarbonylmetyl]-benzoesyre,A = 4-[.(2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoic acid,

B = 4-[(1-(2-pyrrolidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre, B = 4-[(1-(2-pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

C = 4- [ (1-(5-klor-2-pyrrolidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre, C = 4-[(1-(5-chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

D = 4-[(2-piperidino-benzyl)-aminokarbonylmetyl]-benzoesyre,D = 4-[(2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid,

E = 4-[ (1-(2-<p>i<p>eridino-fen<y>l)-eten<y>l)-aminokarbon<y>lmet<y>l]-benzoesyre, E = 4-[(1-(2-<p>i<p>eridino-phen<y>l)-ethene<y>l)-aminocarbon<y>lmeth<y>l]-benzoic acid,

F = 4-[(1-(6-klor-2-piperidino-fenyl)-etenyl)-aminokarbonylmetyl]-benzoesyre, F = 4-[(1-(6-chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid,

G = 4-[(1-(6-metyl-2-piperidino-fenyl)-etenyl)-aminokarbonylmetyl] -benzoesyre, G = 4-[(1-(6-methyl-2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid,

H = 4-[ (1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre, H = 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

I = 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester, I = 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester,

K = (+) 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester, K = (+) 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester,

L .= 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-(2,2-dimetyl-dioksolan-4-yl)-metylester, L .= 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid-(2,2-dimethyl-dioxolan-4-yl)-methyl ester,

M = 4- [(1- (2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-toluen, M = 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-toluene,

N = 4-[(1-(2-piperidino-fenyl)-ety1)-aminokarbonylmety1]-■benzylalkohol, N = 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzyl alcohol,

0 = 4- [(1- (2-piperidino-fenyl)-ety1)-aminokarbonylmetyl]-benzaldehyd, 0 = 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzaldehyde,

P 4-[ (1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-fenyleddiksyre, P 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-phenylacetic acid,

Q = 4- [ (1- (4-klor-2-piperidino-fenyl)--etyl) -aminokarbonylmetyl] - Q = 4-[(1-(4-chloro-2-piperidino-phenyl)--ethyl)-aminocarbonylmethyl]-

benzoesyre,benzoic acid,

R = 4-(1-(5-klor-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre, R = 4-(1-(5-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

S =' 4-[(1-(6-klor-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester, S =' 4-[(1-(6-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester,

T = 4- [ (1-(5-fluor-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl] -benzoesyre, T = 4-[(1-(5-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

U = 4-[ (1-(4-metyl-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre , U = 4-[(1-(4-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

V = 4-[ (1-(5-metyl-i2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre , V = 4-[(1-(5-methyl-12-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

W = 4-[(2-(2-piperidino-fenyl)-2-propyl)-aminokarbonylmetyl]-benzoesyre, W = 4-[(2-(2-piperidino-phenyl)-2-propyl)-aminocarbonylmethyl]-benzoic acid,

X = 4-[(1^(2-piperidino-fenyl)-2-mety1-propyl)-aminokarbonylmetyl] -benzoesyre, X = 4-[(1^(2-piperidino-phenyl)-2-methyl-propyl)-aminocarbonylmethyl]-benzoic acid,

Y = 4-t(2-piperidino-benzhydryl)-aminokarbonylmetyl]-benzoesyre , Y = 4-t(2-piperidino-benzhydryl)-aminocarbonylmethyl]-benzoic acid,

Z = 4-[(l-(2-(l,2,3, 6-tetrahydro-pyridino) - f eny.l) - etyl) - aminokarbonylmetyl]-benzoesyre , Z = 4-[(1-(2-(1,2,3,6-tetrahydro-pyridino)-phenyl.1)-ethyl)-aminocarbonylmethyl]-benzoic acid,

AA = 4-[(1-(2-(3-mety1-piperidino)-fenyl)-etyl)-aminokarbonylmetyl] -benzoesyre , AA = 4-[(1-(2-(3-methyl-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

AB = 4-[(1-(2-heksahydroazepino-fenyl)-etyl)-aminokarbonylmetyl] -benzoesyre , AB = 4-[(1-(2-hexahydroazepino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

AC = 4-[(1-(2-oktahydroisoindolo-fenyl)-etyl)-aminokarbonylmetyl] -benzoesyre , AC = 4-[(1-(2-octahydroisoindolo-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid,

AD = 4-[(a-metoksykarbonyl-2-piperidino-benzyl)-aminokarbonylmetyl] -benzoesyre-etylester og AD = 4-[(α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester and

AE = (+)-4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre AE = (+)-4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

undersøkt med hensyn til sine blodsukkersenkende egenskaper som følger: investigated for its blood sugar-lowering properties as follows:

1. Blodsukkersenkende virkning:1. Blood sugar-lowering effect:

Den blodsukkersenkende virkning av prøveforbindelsen ble undersøkt på hunnrotter av egen avl med en vekt på 180-220 g, som før forsøkets' begynnelse ble holdt fastende i 24 timer. Prøveforbindelsene ble umiddelbart før forsøkets begynnelse suspendert i l,5%ig metylcellulose og administrert via svelg-sonde. The blood sugar-lowering effect of the test compound was investigated on female rats of own breeding with a weight of 180-220 g, which were fasted for 24 hours before the start of the experiment. The test compounds were immediately before the beginning of the experiment suspended in 1.5% methylcellulose and administered via throat probe.

Blodprøve ble tatt umiddelbart før administrering av prøveforbindelsen, og likeledes 1, 2, 3 og 4 timer derefter, hver gang fra den retroorbitale veneplexus. Fra 50 ul av hver av disse ble proteiner fjernet med 0,5 ml 0,33N perklorsyre, Blood samples were taken immediately before administration of the test compound, and likewise 1, 2, 3 and 4 hours thereafter, each time from the retroorbital venous plexus. From 50 ul of each of these, proteins were removed with 0.5 ml of 0.33N perchloric acid,

og de ble sentrifugert. I væsken på toppen ble glukose bestemt efter heksokinase-metoden ved hjelp av et analysefotometer. and they were centrifuged. In the liquid on top, glucose was determined according to the hexokinase method using an analytical photometer.

Den statistiske vurdering ble foretatt ifølge t-testen i henhold til Student med p = 0,05 som signifikans-grense. The statistical assessment was carried out according to the t-test according to Student with p = 0.05 as the significance limit.

Den følgende tabell inneholder de fundne verdier i prosent sammenlignet med kontroll: The following table contains the values found in percentage compared to control:

2. Akutt toksisitet 2. Acute toxicity

På hunn- og- hann-mus av egen avl med vekt på 20-2 6 gOn female and male mice of our own breeding with a weight of 20-26 g

ble den toksiske virkning av forbindelsene H, R og Y undersøkt efter oral administrering (suspensjon i l%ig metylcellulose) av en enkeltdose med en efterobservasjonstid på 14 dager. Den følgende tabell inneholder de fundne verdier: the toxic effect of the compounds H, R and Y was examined after oral administration (suspension in 1% methyl cellulose) of a single dose with a follow-up period of 14 days. The following table contains the values found:

På grunn av sine farmakologiske egenskaper er de nye forbindelser med den generelle formel I og deres fysiologisk forlikelige salter egnet til behandling av diabetes mellitus. For dette formål kan de, eventuelt sammen med andre virkestoffer, innarbeides i de vanlige galeniske tilberedelsesformer så som tabletter, dragéer, kapsler, pulvere eller suspensjoner. Enkeltdosen for voksne er 1-50 mg, fortrinnsvis 2,5-20 mg, Due to their pharmacological properties, the new compounds of the general formula I and their physiologically compatible salts are suitable for the treatment of diabetes mellitus. For this purpose, they can, possibly together with other active substances, be incorporated into the usual galenic preparation forms such as tablets, dragées, capsules, powders or suspensions. The single dose for adults is 1-50 mg, preferably 2.5-20 mg,

1 eller 2 ganger daglig.1 or 2 times daily.

De følgende eksempler skal illustrere oppfinnelsen ytterligere. The following examples shall further illustrate the invention.

Eksempel 1 Example 1

4- [ ( 1- ( 5- klor- 2- dimetylamino- f enyl) - etyl) - aminokarbonylmetyl] - r benzoesyre- metylester 4- [ ( 1- ( 5- chloro- 2- dimethylamino- phenyl) - ethyl) - aminocarbonylmethyl] - r benzoic acid methyl ester

Til en oppløsning av 2,00 g (0,0103 mol) 4-metoksykarbony1-fenyl-eddiksyre i 13,5 ml absolutt tetrahydrofuran setter man ved 20°G under omrøring 1,67 g (0,0103 mol) karbonyldiimidazol og oppvarmer derefter under utelukkelse av fuktighet i 45 minutter til tilbakeløpstemperatur. Efter avkjøling til romtemperatur tilsetter man 2,05 g (0,0103 mol) 1-(5-klor-2-dimetylamino-fenyl)-etylamin i 7 ml absolutt tetrahydrofuran og omrører natten over ved 20°C. Man inndamper i vakuum og renser inndampningsresiduet ved kolonnekromatografi på silikagel (toluen/aceton = 10/1). To a solution of 2.00 g (0.0103 mol) of 4-methoxycarbonyl-1-phenyl-acetic acid in 13.5 ml of absolute tetrahydrofuran, 1.67 g (0.0103 mol) of carbonyldiimidazole is added at 20°G with stirring and then heated under the exclusion of moisture for 45 minutes to reflux temperature. After cooling to room temperature, 2.05 g (0.0103 mol) of 1-(5-chloro-2-dimethylamino-phenyl)-ethylamine are added in 7 ml of absolute tetrahydrofuran and stirred overnight at 20°C. Evaporate in vacuum and purify the evaporation residue by column chromatography on silica gel (toluene/acetone = 10/1).

Utbytte: 2,6 g (66,7% av det teoretiske),Yield: 2.6 g (66.7% of the theoretical),

Smeltepunkt: 153-155°C (fra eter). Melting point: 153-155°C (from ether).

Analogt med eksempel 1 ble følgende forbindelser fremstilt: 4— [ ( 1- ( 5- klor- 2- dipropylaminofenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- metylester Analogously to example 1, the following compounds were prepared: 4-[(1-(5-chloro-2-dipropylaminophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid methyl ester

Utbytte: 42% av det teoretiske,Yield: 42% of the theoretical,

Smeltepunkt: 135-137°C (fra eter/petroleter) Melting point: 135-137°C (from ether/petroleum ether)

4-[( 1-( 5- klor- 2- dibutylaminofenyl)- ety1)- aminokarbonylmety1]-benzoesyre- metylester Utbytte: 64,8% av. det teoretiske, 4-[(1-(5-chloro-2-dibutylaminophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid methyl ester Yield: 64.8% of the theoretical,

Smeltepunkt: 110-112°C. Melting point: 110-112°C.

4-[( 1- ( 5- klor- 2- N- cykloheksyl- N- metylaminofenyl)- etyl) - aminokarbonylmetyl]- benzoesyre- metylester 4-[( 1- ( 5- chloro- 2- N- cyclohexyl- N- methylaminophenyl)- ethyl) - aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 63,9% av det teoretiske,Yield: 63.9% of the theoretical,

Smeltepunkt: 152-153°C (eter) Melting point: 152-153°C (ether)

4-[( 5- klor- 2- pyrrolidino- benzyl)- aminokarbonylmetyl]- benzoesyre-metylester 4-[(5-chloro-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoic acid methyl ester

Utbytte: 68,1% av det teoretiske,Yield: 68.1% of the theoretical,

Smeltepunkt: 13 9-141°C (metanol) Melting point: 13 9-141°C (methanol)

4-[( 1-( 5- klor- 2- pyrrolidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- metylester 4-[( 1-( 5- chloro- 2- pyrrolidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 5 8,3% av det teoretiske,Yield: 5 8.3% of the theoretical,

Smeltepunkt: 133-135°C (metanol) Melting point: 133-135°C (methanol)

]-[ ( 5- klor- 2- piperidino- benzy1)- aminokarbonylmetyl]- benzoesyre-metylester ]-[ ( 5- chloro- 2- piperidino- benzyl 1)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 75,1% av det teoretiske,Yield: 75.1% of the theoretical,

Smeltepunkt: 123-125°C (eter) Melting point: 123-125°C (ether)

4-[( 1-( 5- klor- 2- piperidino- benzy1)- aminokarbonyl)- etyl]-benzoesyre- metylester 4-[( 1-( 5- Chloro- 2- Piperidino- Benzy1)- Aminocarbonyl)- Ethyl]- Benzoic Acid Methyl Ester

Utbytte: 70,4% av det teoretiske,Yield: 70.4% of the theoretical,

Smeltepunkt: 142-144°C (eter). Melting point: 142-144°C (ether).

4-[( 1-( 5- klor- 2- piperidino- fenyl)- ety1)- aminokarbonylmetyl]-benzoesyre- metylester 4-[( 1-( 5- chloro- 2- piperidino- phenyl)- ethyl 1)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 69,5% av det teoretiske,Yield: 69.5% of the theoretical,

Smeltepunkt: 147-149°C (eter) Melting point: 147-149°C (ether)

4-[( 1-( 5- klor- 2-( 3- metyl- pierpidino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- metylester 4-[( 1-( 5- chloro- 2-( 3- methyl- pierpidino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid methyl ester

Utbytte: 54,3% av det teoretiske,Yield: 54.3% of the theoretical,

Smeltepunkta 160-162°C (metanol) Melting point 160-162°C (methanol)

4-]( 1-( 5- klor- 2-( 3, 5- cis- dimety1- piperidino)- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre- metylester 4-]( 1-( 5- chloro- 2-( 3, 5- cis- dimethyl-piperidino)- phenyl)- ethyl)-aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 4 4% av det teoretiske,Yield: 4 4% of the theoretical,

Smeltepunkt: 190-193°C (metanol) Melting point: 190-193°C (methanol)

4- [ ( 1-( 5- klor- 2- piperidino- fenyl)- propyl)- aminokarbonylmetyl]-benzoesyre- metylester 4- [ ( 1-( 5- chloro- 2- piperidino- phenyl)- propyl)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 65,9% av det teoretiske,Yield: 65.9% of the theoretical,

Smeltepunkt: 142-144°C (eter). Melting point: 142-144°C (ether).

4-[( 1-( 5- klor- 2- piperidino- fenyl)- 2- metyl- propyl)- aminokarbonylmetyl ]- benzoesyre- metylester 4-[( 1-( 5- chloro- 2- piperidino- phenyl)- 2- methyl- propyl)- aminocarbonylmethyl ]- benzoic acid methyl ester

Utbytte: 61,4% av det teoretiske,Yield: 61.4% of the theoretical,

Smeltepunkt: 156-158°C (eter) Melting point: 156-158°C (ether)

, 4- [ ( 1- (. 5- klor- 2- morfolinofenyl) - etyl) - aiainokarbonylmetyl] - benzoesyre- metylester , 4- [ ( 1- (. 5- chloro- 2- morpholinophenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid methyl ester

Utbytte: 6 9,8% av det teoretiske,Yield: 6 9.8% of the theoretical,

Smeltepunkt: 156-158°C (eter) Melting point: 156-158°C (ether)

4-[( 1-( 5- klor- 2- tiomorfolino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- metylester 4-[( 1-( 5- chloro- 2- thiomorpholino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 68,2% av det teoretiske,Yield: 68.2% of the theoretical,

Smeltepunkt: 167-169°C (eter) Melting point: 167-169°C (ether)

4-[( 1-( 5- klor- 2- ( heksahydro- lH- azepino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- metylester 4-[( 1-( 5- chloro- 2- ( hexahydro- 1H- azepino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid methyl ester

Utbytte: 41,7% av det teoretiskeYield: 41.7% of the theoretical

Smeltepunkt': 146-147°C (mety lenklorid/petroleter) Melting point': 146-147°C (methylene chloride/petroleum ether)

4-[( 1-( 5- klor- 2- oktahydroazocino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- metylester 4-[( 1-( 5- chloro- 2- octahydroazocino- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid methyl ester

Utbytte: 30% av det teoretiske,Yield: 30% of the theoretical,

Smeltepunkt: 15 4-15 6°C Melting point: 15 4-15 6°C

4-[( 1-( 5- klor- 2-( oktahydro- lH- azonino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- metylester 4-[( 1-( 5- chloro- 2-( octahydro- 1H- azonino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid methyl ester

Utbytte: 38% av det teoretiske,Yield: 38% of the theoretical,

Smeltepunkt: 184-185°C (kloroform/toluen) Melting point: 184-185°C (chloroform/toluene)

4-[( 2-( 5- klor- 2- piperidino- fenyl)- 2- propyl)- aminokarbonylmetyl]-benzoesyre- metylester Utbytte: 84,4% av det teoretiske, Smeltepunkt: 162-164°C 4-[( 2-( 5- chloro- 2-piperidino-phenyl)- 2- propyl)- aminocarbonylmethyl]-benzoic acid methyl ester Yield: 84.4% of the theoretical, Melting point: 162-164°C

4-[( 1- ( 5- nitro- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- metylester 4-[( 1-( 5- nitro- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid methyl ester

Utbytte: 68,3% av det teoretiske,Yield: 68.3% of the theoretical,

Smeltepunkt: 178-180°C (toluen) Melting point: 178-180°C (toluene)

4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-metylester 4- [ ( 1- ( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 59,1% av det teoretiske,Yield: 59.1% of the theoretical,

Smeltepunkt: 145-147°C Melting point: 145-147°C

4- [ ( 5- metyl- 2- piperidino- benzyl) aminokarbonylmetyl]- benzoesyre-metylester 4- [ (5- methyl- 2- piperidino- benzyl) aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 32,9% av det teoretiske,Yield: 32.9% of the theoretical,

Smeltepunkt: 12 4-12 6°C (petroleter/aceton) Melting point: 12 4-12 6°C (petroleum ether/acetone)

N-( 4- nitro- fenacetyl)- N-[ 1-( 2- piperidino- fenyl- ety1]- amin Utbytte: 62,4% av det teoretiske, Smeltepunkt: 165-167° (eter) N-(4-nitro-phenacetyl)-N-[1-(2-piperidino-phenyl-ethy1]-amine Yield: 62.4% of theory, Melting point: 165-167° (ether)

N-( 4- acety1- fenacetyl)- N-[ 1-( 2- piperidino- fenyl)- etyl]- amin Utbytte: 32,4% av det teoretiske. N-(4-acetyl-phenacetyl)-N-[1-(2-piperidino-phenyl)-ethyl]-amine Yield: 32.4% of the theoretical.

Smeltepunkt: 162-164°C (eter) Melting point: 162-164°C (ether)

N-( 4- acetyl- fenacetyl)- N-[ 1-( 5- klor- 2- piperidinofenyl)- etyl] amin Utbytte: 50,3% av det teoretiske, Smeltepunkt: 162-163°C (eter) N-(4-acetyl-phenacetyl)-N-[1-(5-chloro-2-piperidinophenyl)-ethyl]amine Yield: 50.3% of the theoretical, Melting point: 162-163°C (ether)

2- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-metylester 2- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid methyl ester

Utbytte: 82% av det teoretiskeYield: 82% of the theoretical

Smeltepunkt: 107-108°C Melting point: 107-108°C

3-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-etylester 3-[( 1-( 2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 47% av det teoretiske,Yield: 47% of the theoretical,

Smeltepunkt: 155°C Melting point: 155°C

3- klor- 4-[( 1-( 2- piperidino- fenyl)- etyl) aminokarbonylmetyl]-benzoesyre- etylester 3- chloro- 4-[( 1-( 2- piperidino-phenyl)- ethyl) aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 63% av det teoretiskeYield: 63% of the theoretical

Smeltepunkt: 12 3-12 4°C Melting point: 12 3-12 4°C

4-[( 1-( 2-( 1, 2, 3, 4- tetrahydro- isokinolin- 2- yl)- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre- etylester 4-[( 1-( 2-( 1, 2, 3, 4- tetrahydro- isoquinolin- 2- yl)- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 43% av det teoretiskeYield: 43% of the theoretical

Smeltepunkt: 142-144°C Melting point: 142-144°C

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- toluen Utbytte: 59% av det teoretiske Smeltepunkt: 136-138°C • 4-[( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- toluene Yield: 59% of the theoretical Melting point: 136-138°C •

4-[( 5- klor- 2- piperidino- anilino)- karboriylmety1]- benzoesyre-metylester 4-[(5-chloro-2-piperidino-anilino)- carborylmethyl]-benzoic acid methyl ester

Utbytte: 40,3% av det teoretiskeYield: 40.3% of the theoretical

Smeltepunkt: 156-158°C (metanol/toluen) Melting point: 156-158°C (methanol/toluene)

4- [- ( 2- piperidino- anilino- karbonyl)- etyl]- benzoesyre- metylester Utbytte: 2 6,9%. av det teoretiske Smeltepunkt: 71-7 3°C (petroleter) 4- [- ( 2- piperidino- anilino-carbonyl)- ethyl]- benzoic acid methyl ester Yield: 2 6.9%. of the theoretical Melting point: 71-7 3°C (petroleum ether)

4-[( 1- ( 2-( 1, 2r 3, 6- tetrahydro- pyridino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- etylester 4-[( 1- ( 2-( 1, 2r 3, 6- tetrahydro- pyridino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid ethyl ester

Utbytte:. 63,4% av det teoretiskeDividend:. 63.4% of the theoretical

Smeltepunkt: 125-127°C (eter) Melting point: 125-127°C (ether)

4- [ ( 2-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonyl metyl]-benzoesyre- etylester Utbytte: 68% av det teoretiske Smeltepunkt: 95-97°C (etanol) 4- [ ( 2-( 5- chloro- 2- piperidino- phenyl)- ethyl)- aminocarbonyl methyl]-benzoic acid ethyl ester Yield: 68% of the theoretical Melting point: 95-97°C (ethanol)

4-[( 1-( 5- fluor- 2- piperidino- fenyl)- etyl) aminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 5- fluoro- 2-piperidino-phenyl)- ethyl) aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: '47,3% av det teoretiskeYield: '47.3% of the theoretical

Smeltepunkt: 138-140°C (eter) Melting point: 138-140°C (ether)

4-[( 1—( 5- nitro- 2- piperidino- fenyl)- etyl)- aminokarbony lmetyl]-benzoesyre- etylester 4-[(1-(5-nitro-2-piperidino-phenyl)-ethyl)- aminocarbonyl methyl]-benzoic acid ethyl ester

Utbytte: 5 6,5% av det teoretiskeYield: 5 6.5% of the theoretical

Smeltepunkt: 144-147°C (etanol)' Melting point: 144-147°C (ethanol)'

A - [ ( 2- ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonyl)- etyl]-benzoesyre- metylester A - [ ( 2- ( 1-( 2-piperidino-phenyl)- ethyl)- aminocarbonyl)- ethyl]-benzoic acid methyl ester

Utbytte: 90% av det teoretiskeYield: 90% of the theoretical

Smeltepunkt: 12 9-131°C Melting point: 12 9-131°C

4-[ ( 2- hydroksy- l-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[(2-Hydroxy-1-(2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 44,4% av det teoretiske,Yield: 44.4% of the theoretical,

Smeltepunkt: 132-135°C (petroleter/aceton) Melting point: 132-135°C (petroleum ether/acetone)

4-[ ( 1-( 5- hydroksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[ ( 1-( 5- hydroxy- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 64,2% av det teoretiskeYield: 64.2% of the theoretical

Smeltepunkt: 150-151°C (eter) Melting point: 150-151°C (ether)

4- [ ( a- metoksykarbonyl- 2- piperidino- benzy1)- aminokarbonylmetyl]-benzoesyre- etylester 4-[(α-Methoxycarbonyl-2-piperidino-benzy1)-aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 59% av det teoretiskeYield: 59% of the theoretical

Smeltepunkt: 110-112°C (petroleter/aceton) Melting point: 110-112°C (petroleum ether/acetone)

4-[( 1-( 5- klor- 2-( 2- metyi- piperidino)- fenyl)- ety1)- aminokarbonylmetyl] - benzoesyre- etylester 4-[( 1-( 5- chloro- 2-( 2- methyl- piperidino)- phenyl)- ethyl 1)- aminocarbonylmethyl] - benzoic acid ethyl ester

Utbytte: 71,3% av det teoretiske,Yield: 71.3% of the theoretical,

Smeltepunkt: < 20°C Melting point: < 20°C

4- [ ( 1- ( 2- heksahydroaz. epino- fenyl) - etyl) - aminokarbonylmetyl] - benzoesyre- etylester 4- [ ( 1- ( 2- hexahydroaz. epino- phenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid - ethyl ester

Utbytte: 68% av det teoretiskeYield: 68% of the theoretical

Smeltepunkt: 145-148°C (toluen)Melting point: 145-148°C (toluene)

4-[( 1-( 2-[ 1, 4- dioksa- 8- azaspiro[ 4, 5] decyl-( 8)]- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre- etylester 4-[( 1-( 2-[ 1, 4- dioxa- 8- azaspiro[ 4, 5] decyl-( 8)]- phenyl)- ethyl)-aminocarbonylmethyl]- benzoic acid- ethyl ester

Utbytte: 64,3% av det teoretiskeYield: 64.3% of the theoretical

Smeltepunkt: 143-145°C (petroleter/aceton)Melting point: 143-145°C (petroleum ether/acetone)

4- [ ( 1- ( 2-( 2- metyl- pyrrolidino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- etylester 4- [ ( 1- ( 2-( 2- methyl- pyrrolidino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid- ethyl ester

Utbytte: 72,0% av det teoretiskeYield: 72.0% of the theoretical

Smeltepunkt: 94-97°CMelting point: 94-97°C

4- [ ( 1-( 3- metyl- 2- piperidino- feny1)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1-( 3- methyl- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 39,5% av det teoretiske,Yield: 39.5% of the theoretical,

Smeltepunkt: 17 8-17 9°C ..Melting point: 17 8-17 9°C ..

4-[ ( 1-( 3- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[ ( 1-( 3- chloro- 2-piperidino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 52,6% av det teoretiske,Yield: 52.6% of the theoretical,

Eksempel 2 Example 2

4- [ ( 1- ( 2- piperidino- fenyl) - etyl) - aminokarbonylmetyl] - benzoesyre- etylester 4- [ ( 1- ( 2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Til en oppløsning av 290,9 mg (1,40 mmol) 4-etoksy-karbonylfenyleddiksyre i 6 ml tetrahydrofuran setter man 2 31,4 mg (1,43 mmol) karbonyldiimidazol og oppvarmer derefter under utelukkelse av fuktighet i 1,5 timer til tilbakeløpstemperatur. Efter avkjøling til romtemperatur tilsetter man 0,385 ml 2,78 mmol) trietylamin (tørret over kaliumhydroksyd) og 360 mg (1,30 mmol) (+)-1-(2-piperidino-fenyl)-etylamin-dihydroklorid [smeltepunkt 242°C (spaltn.), [a]^°= +14,8° To a solution of 290.9 mg (1.40 mmol) of 4-ethoxy-carbonylphenylacetic acid in 6 ml of tetrahydrofuran is added 2 31.4 mg (1.43 mmol) of carbonyldiimidazole and then heated under exclusion of moisture for 1.5 hours to return temperature. After cooling to room temperature, 0.385 ml (2.78 mmol) of triethylamine (dried over potassium hydroxide) and 360 mg (1.30 mmol) of (+)-1-(2-piperidino-phenyl)-ethylamine dihydrochloride [melting point 242°C (split.), [a]^°= +14.8°

(c = 1, metanol)] sammen med 2 ml tetrahydrofuran. Man omrører i et 50°C varmt oljebad i 4 timer. Man inndamper i vakuum og fordeler inndampningsresiduet mellom kloroform og vann. Kloroformekstrakten tørrer man over natriumsulfat, filtrerer den gjennom en G3 glassfritte og inndamper den i vakuum til tørrhet. Det oppnådde residuum renser man ved kolonnekromatografi på silikagel (kloroform/metanol = 6:1). (c = 1, methanol)] together with 2 ml of tetrahydrofuran. Stir in a 50°C hot oil bath for 4 hours. One evaporates in a vacuum and distributes the evaporation residue between chloroform and water. The chloroform extract is dried over sodium sulphate, filtered through a G3 glass frit and evaporated in a vacuum to dryness. The obtained residue is purified by column chromatography on silica gel (chloroform/methanol = 6:1).

Utbytté: 229 mg (44,7%' av det teoretiske)Yield: 229 mg (44.7% of the theoretical)

Smeltepunkt: 89-90°C (eter)Melting point: 89-90°C (ether)

[a]^° + 8,2° (c = 1, metanol)[a]^° + 8.2° (c = 1, methanol)

Analogt med eksempel 2 ble fremstilt: (-)- 4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester Analogous to example 2 was prepared: (-)-4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

fra (-)-1-(2-piperidino-fenyl)-etylamin-dihydroklorid [smeltepunkt: 239-242° (spaltn.), [a]£°: -19,6° (c =1, metanol) ] . from (-)-1-(2-piperidino-phenyl)-ethylamine dihydrochloride [mp: 239-242° (dec.), [α]£°: -19.6° (c =1, methanol) ] .

Utbytte: 41,1% av det teoretiskeYield: 41.1% of the theoretical

Smeltepunkt: 77-79°C (eter/cykldheksan)Melting point: 77-79°C (ether/cyclohexane)

[ot]j?°= -6,2° (c = 1, metanol)[ot]j?°= -6.2° (c = 1, methanol)

Eksempel 3 Example 3

4-[ ( 1- ( 4- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 4- chloro- 2-piperidino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Til en oppløsning av 5,5 g (0,023 mol) 1-(4-klor-2-piperidino-fenyl)-etylamin, 4,8 g (0,023 mol) 4-etoksykarbony1-fenyl-eddiksyre, 7,3 g (0,028 mol) trifenylfosfin og 3,2 ml (0,023 mol) trietylamin i 50 ml acetonitril setter man 2,3 ml (0,023 mol) karbontetraklorid og omrører i 24 timer ved romtemperatur. Derefter inndamper man i vakuum og fordeler mellom 100.ml vann og eddiksyreetylester. De samlede, over natriumsulfat tørrede organiske ekstrakter filtrerer man,, inndamper dem i vakuum og renser inndampningsresiduet ved kolonne kromatografi på silikagel (toluen/eddiksyreetylester = 4/1) Utbytte: 6,1 g (62% av det teoretiske) To a solution of 5.5 g (0.023 mol) 1-(4-chloro-2-piperidino-phenyl)-ethylamine, 4.8 g (0.023 mol) 4-ethoxycarbonyl-1-phenyl-acetic acid, 7.3 g (0.028 mol) of triphenylphosphine and 3.2 ml (0.023 mol) of triethylamine in 50 ml of acetonitrile, 2.3 ml (0.023 mol) of carbon tetrachloride are added and stirred for 24 hours at room temperature. It is then evaporated in a vacuum and distributed between 100 ml of water and acetic acid ethyl ester. The combined organic extracts, dried over sodium sulfate, are filtered, evaporated in vacuo and the evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 4/1) Yield: 6.1 g (62% of the theoretical)

Smeltepunkt: 12 6-12 8°C Melting point: 12 6-12 8°C

Analogt med eksempel 3 ble følgende forbindelser fremstilt: 4- [ ( 1-( 4- metyl- 2- piperidino- feny1)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester Analogous to example 3, the following compounds were prepared: 4-[(1-(4-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 48,2% av det teoretiskeYield: 48.2% of the theoretical

Smeltepunkt: 120-122°C. Melting point: 120-122°C.

4-[( 1-( 2-( 4- metyl- piperidino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 2-( 4- methyl- piperidino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 55,8% av det teoretiskeYield: 55.8% of the theoretical

Smeltepunkt: 125-128°C (eter) Melting point: 125-128°C (ether)

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-etylester 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 71% av det teoretiskeYield: 71% of the theoretical

Smeltepunkt: 147-148°C Melting point: 147-148°C

4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- fenyleddiksyre 4- [ ( 1- ( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- phenylacetic acid

Fremstilt fra 1-(2-piperidino-fenyl)-etylamin og p-fenylen-dieddiksyre. Prepared from 1-(2-piperidino-phenyl)-ethylamine and p-phenylenediacetic acid.

Utbytte: 27% av det teoretiskeYield: 27% of the theoretical

Smeltepunkt: 186-189°C Melting point: 186-189°C

4-[( 2- piperidino- benzhydryl)- aminokarbonylmetyl]- benzoesyre-etylester 4-[( 2- piperidino- benzhydryl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 87,4% av det teoretiskeYield: 87.4% of the theoretical

Smeltepunkt: 160-162°C Melting point: 160-162°C

4-[( 5- klor- 2- piperidino- benzhydryl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[(5-Chloro-2-piperidino-benzhydryl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 78% av det teoretiskeYield: 78% of the theoretical

Smeltepunkt: 202-204°C Melting point: 202-204°C

4-[( 1-( 4- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre^ etylester Utbytte: 39% av det teoretiske Smeltepunkt: 118-120°C 4-[( 1-( 4- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid^ ethyl ester Yield: 39% of the theoretical Melting point: 118-120°C

4- [ ( 1-( 2-( 4- metyl- piperazino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1-( 2-( 4- methyl- piperazino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 5 3% av det teoretiskeYield: 5 3% of the theoretical

Smeltepunkt: 130-132°C Melting point: 130-132°C

4- [ ( 1- ( 2- ( 4- benzyl- piperazino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1- ( 2- ( 4- benzyl-piperazino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 75% av det teoretiskeYield: 75% of the theoretical

Smeltepunkt: 135-136°C Melting point: 135-136°C

4- [ ( 1- ( 2-( 4- p- klorfenyl- piperazino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- etylester 4- [ ( 1- ( 2-( 4- p- chlorophenyl- piperazino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid- ethyl ester

Utbytte: 4 8,5% av det teoretiskeYield: 4 8.5% of the theoretical

Smeltepunkt: 17 8-180°C Melting point: 17 8-180°C

4- [ ( a- cykloheksyl- 2- piperidino- benzyl)- aminokarboriylmety1]-benzoesyre- etylester 4-[(α-Cyclohexyl-2-piperidino-benzyl)-aminocarboriylmethyl]-benzoic acid ethyl ester

Utbytte: 7 5,0% av det teoretiskeYield: 7 5.0% of the theoretical

Smeltepunkt: 135°CMelting point: 135°C

N- ( 4- klor- fenacetyl)- N-[ 1-( 2- piperidino- fenyl)- etyl]- amin Utbytte: 7 9% av det teoretiske Smeltepunkt: 150-152°C N- ( 4- chlorophenacetyl)- N-[ 1-( 2- piperidino- phenyl)- ethyl]- amine Yield: 7 9% of the theoretical Melting point: 150-152°C

4-[ ( 2- pyrrolidino- benzhydry1)- aminokarbonylmetyl]- benzoesyre-etylester 4-[(2- pyrrolidino- benzhydry1)- aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 57% av det teoretiskeYield: 57% of the theoretical

Smeltepunkt: 163-165°CMelting point: 163-165°C

4-[( 2- heksametylenimino- benzhydryl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[( 2- hexamethyleneimino-benzhydryl)-aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 68% av det teoretiskeYield: 68% of the theoretical

Smeltepunkt: 151-15 4°CMelting point: 151-15 4°C

Eksempel 4 Example 4

4- [ ( 1- ( 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[(1-(2-piperidino-phenyl)-ethenyl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Til en oppløsning av 10,9 g (0,0539 mol) friskt fremstilt (2-piperidinofenyl)-mety1-ketimin i 110 ml acetonitril setter man under omrøring i rekkefølge 11,2 g (0,05 3 9 mol) 4-etoksy-karbonyl-fenyleddiksyre, 17 g (0,0647 mol) trifenyl-fosf.in, 22,6 ml (0,162 mol) trietylamin og 5,2 ml (0,0539 mol) karbontetraklorid'. Den efter kort tid klare oppløsning omrører man i 20 timer ved 20°C. Man frafiltrerer utfelt bunnfall 11.2 g (0.05 3 9 mol) of 4-ethoxy -carbonyl-phenylacetic acid, 17 g (0.0647 mol) triphenyl-phosphine, 22.6 ml (0.162 mol) triethylamine and 5.2 ml (0.0539 mol) carbon tetrachloride'. After a short time clear solution is stirred for 20 hours at 20°C. Precipitated sediment is filtered off

(trietylaminhydroklorid) og inndamper filtratet i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 10/1). (triethylamine hydrochloride) and evaporates the filtrate in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Utbytte: 15 g (70,1% av det teoretiske)Yield: 15 g (70.1% of the theoretical)

Smeltepunkt: 112-115°C (eter) Melting point: 112-115°C (ether)

Analogt med eksempel 4 ble følgende forbindelser Analogous to example 4, the following compounds were obtained

fremstilt: 4-[( g- cykloheksyliden- 2- piperidinc— benzyl)- aminokarbonylmetyl]-benzoesyre- etylester prepared: 4-[(g-cyclohexylidene-2-piperidinc-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 2 4% av det teoretiskeYield: 2 4% of the theoretical

Smeltepunkt: 131-133°CMelting point: 131-133°C

4-[ ( 1-( 2- piperidino- fenyl)- propenyl)- aminokarbonylmetyl]-benzoesyre- etylester Utbytte: 65,0% av det teoretiske (E- og Z-isomer-blanding) Smeltepunkt for den polare isomer: 82-84°C Eksempel 5 4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-etylester Til en omrørt oppløsning av 49,6 g (0,243 mol) 1-(2-piperidino-fenyl) -etylamin [k.p.0 g: 100-107°C, smeltepunkt for dihydrokloridet: 234-237°C (spaltn.)] og 37,3 ml (0,267 mol) trietylamin i 245 ml metylenklorid setter man dråpevis under • lett isavkjøling ved en indre temperatur på 20-30°C en opp-løsning av 60,6 g (0,267 mol) 4-etoksykarbony1-fenacetylklorid 1 120 ml metylenklorid. Derefter omrører man i ytterligere 2 timer ved romtemperatur. Det utfelte bunnfall frafiltrerer man, vasker det en gang med metylenklorid og utrister de samlede metylenklorid-faser i rekkefølge to ganger med vann, en gang med 10%ig vandig.ammoniakk, to ganger med vann, en gang med 100 ml 3%ig saltsyre og to ganger med vann. Man tørrer metylenklorid-fasen over natriumsulfat, filtrerer den og inndamper den i vakuum. -Inndampningsresiduet krystalliserer man fra eter. 4-[ ( 1-( 2-piperidino-phenyl)- propenyl)- aminocarbonylmethyl]-benzoic acid ethyl ester Yield: 65.0% of the theoretical (E- and Z-isomer mixture) Melting point for the polar isomer: 82- 84°C Example 5 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester To a stirred solution of 49.6 g (0.243 mol) 1-(2-piperidino-phenyl) -ethylamine [b.p.0 g: 100-107°C, melting point for the dihydrochloride: 234-237°C (decomposition)] and 37.3 ml (0.267 mol) triethylamine in 245 ml methylene chloride are added dropwise under • slight ice cooling at a internal temperature of 20-30°C a solution of 60.6 g (0.267 mol) of 4-ethoxycarbonyl-phenacetyl chloride in 1120 ml of methylene chloride. It is then stirred for a further 2 hours at room temperature. The precipitate that has formed is filtered off, washed once with methylene chloride and the combined methylene chloride phases are successively extracted twice with water, once with 10% aqueous ammonia, twice with water, once with 100 ml of 3% hydrochloric acid and twice with water. The methylene chloride phase is dried over sodium sulphate, filtered and evaporated in vacuo. -The evaporation residue is crystallized from ether.

Utbytte: 88,8 g (92,7% av det teoretiske)Yield: 88.8 g (92.7% of the theoretical)

Smeltepunkt: 148-150°C.Melting point: 148-150°C.

Analogt med eksempel 5 ble følgende forbindelser oppnådd: 4- [ ( 5- metyl- 2- piperidino- benzyl)- aminokarbonylmetyl]- benzoesyre-etylester Analogous to example 5, the following compounds were obtained: 4-[(5-methyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 22,5% av det teoretiskeYield: 22.5% of the theoretical

Smeltepunkt: 116,5-117°C (etanol/petroleter) Melting point: 116.5-117°C (ethanol/petroleum ether)

4- [ ( 1- ( 5- metyl- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1- ( 5- methyl- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid- ethyl ester

Utbytte: 20,2% av det teoretiskeYield: 20.2% of the theoretical

Smeltepunkt: 132-132,5°C (etanol) Melting point: 132-132.5°C (ethanol)

4-[( 1-( 5- metoksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 5- methoxy- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 35,8% av det teoretiskeYield: 35.8% of the theoretical

Smeltepunkt: 131-132°C (etanol) Melting point: 131-132°C (ethanol)

4-[( 1-( 2- piperidino- fenyl)- etyl)- N- metylaminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 2-piperidino-phenyl)-ethyl)- N- methylaminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 65,2% av det teoretiske-Yield: 65.2% of the theoretical

Smeltepunkt: < 20°C Melting point: < 20°C

4-[ ( 1-( 2-( dekahydro- isokinolin- 2- y1)- fenyl)- etyl)- aminokarbonylmetyl ]- benzoesyre- etylester 4-[ ( 1-( 2-( decahydro- isoquinolin- 2- y1)- phenyl)- ethyl)- aminocarbonylmethyl ]- benzoic acid ethyl ester

Utbytte: 44% av det teoretiskeYield: 44% of the theoretical

Smeltepunkt: 15 9°C Melting point: 15 9°C

4- [ ( 1- ( 2- ( l, 2, 3, 4, 5, 6, 7, 8- oktahydro- isokinolin- 2- yl)- fenyl)-etyl)- aminokarbonylmetyl]- benzoesyre- etyleser 4- [ ( 1- ( 2- ( 1, 2, 3, 4, 5, 6, 7, 8- octahydro- isoquinolin- 2- yl)- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid- ethyles

Utbytte: 35% av det teoretiskeYield: 35% of the theoretical

Smeltepunkt: 115-117°C Melting point: 115-117°C

4-[( 1-( 2- oktahydro- isoindol- 2- yl)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- etylester 4-[( 1-( 2- octahydro- isoindol- 2- yl)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid ethyl ester

Utbytte: 36% av det teoretiskeYield: 36% of the theoretical

Smeltepunkt: 141°CMelting point: 141°C

4-[ ( 1-( 3- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-etylester Utbytte: 2 4% av det teoretiske Smeltepunkt: 16 4°C 4-[ ( 1-( 3- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester Yield: 2 4% of the theoretical Melting point: 16 4°C

4- [ fl- ( 6- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[fl-(6-chloro-2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 17 av det teoretiskeYield: 17 of the theoretical

Smeltepunkt: < 20°CMelting point: < 20°C

4- [ ( 1- ( 6- metyl- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1- ( 6- methyl- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Utbytte: 3,5% av det teoretiskeYield: 3.5% of the theoretical

Smeltepunkt: < 20°CMelting point: < 20°C

4- [ ( 1-( 2-( 3- aza- bicyklo[ 3, 2, 2] nonan- 3- yl)- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre- etylester 4- [ ( 1-( 2-( 3- aza-bicyclo[ 3, 2, 2] nonan- 3- yl)- phenyl)- ethyl)-aminocarbonylmethyl]- benzoic acid ethyl ester

Utbytte: 0,5% av det teoretiskeYield: 0.5% of the theoretical

Smeltepunkt: < 20°C.Melting point: < 20°C.

N-[ 1-( 5- klor- 2- piperidino- fenyl)- etyl]- N- fenacetyl- amin N-[ 1-( 5- chloro- 2- piperidino- phenyl)- ethyl]- N- phenacetyl- amine

Utbytte: 5 3,5% av det teoretiske Smeltepunkt: 134-136°C (etanol) Yield: 5 3.5% of the theoretical Melting point: 134-136°C (ethanol)

Eksempel 6 Example 6

4-[( 1-( 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Til en omrørt oppløsning av 2,02 g (0,010 mol) friskt fremstilt metyl-(2-piperidino-fenyl)-ketimin og 1,53 ml To a stirred solution of 2.02 g (0.010 mol) freshly prepared methyl-(2-piperidino-phenyl)ketimine and 1.53 ml

(0,011 mol) trietylamin i 10 ml metylenklorid setter man dråpevis under isavkjøling ved en indre temperatur på 1 til 6°C i løpet av 15 minutter en oppløsning av 2,49 g (0,011 mol) 4-etoksykarbonyl-fenacetylklorid i 10 ml metylenklorid. Man omrører i ytterligere 20 timer ved 20°C og heller reaksjonsblandingen i en kald natriumhydrogenkarbonatoppløsning. Man ekstraherer flere ganger med metylenklorid, vasker den organiske ekstrakt en gang med vann, tørrer over natriumsulfat; filtrerer og inndamper i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 50/1). (0.011 mol) of triethylamine in 10 ml of methylene chloride, a solution of 2.49 g (0.011 mol) of 4-ethoxycarbonyl-phenacetyl chloride in 10 ml of methylene chloride is added dropwise under ice-cooling at an internal temperature of 1 to 6°C over the course of 15 minutes. The mixture is stirred for a further 20 hours at 20°C and the reaction mixture is poured into a cold sodium bicarbonate solution. It is extracted several times with methylene chloride, the organic extract is washed once with water, dried over sodium sulphate; filter and evaporate in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 50/1).

Utbytte: 1,86 g (47,7% av det teoretiske)Yield: 1.86 g (47.7% of the theoretical)

Smeltepunkt: 113-116°C (etanol)Melting point: 113-116°C (ethanol)

Analogt med eksempel 6 ble følgende forbindelser fremstilt: 4-[( 1-( 6- klor- 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre- etylester Analogous to example 6, the following compounds were prepared: 4-[(1-(6-chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 37% av det teoretiskeYield: 37% of the theoretical

Smeltepunkt: 102-105°CMelting point: 102-105°C

4-[( 1-( 6- metyl- 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-, benzoesyre- etylester 4-[( 1-( 6- methyl- 2- piperidino- phenyl)- ethenyl)- aminocarbonylmethyl]-, benzoic acid- ethyl ester

Utbytte: 41% av det teoretiskeYield: 41% of the theoretical

Smeltepunkt: 116-118°CMelting point: 116-118°C

Eksempel 7 Example 7

4- [ ( 1-( 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1-( 2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Til en suspensjon av 2,20 g (6,24 mmol) jodmagnesium-. [metyl-(2-piperidino-fenyl)-ketimino]-kompleks i 15 ml metylenklorid setter man dråpevis en oppløsning av 1,55 g (6,86 mmol) 4-etoksykarbonyl-fenacetylklorid i' 5 ml metylenklorid. To a suspension of 2.20 g (6.24 mmol) of magnesium iodo-. [methyl-(2-piperidino-phenyl)-ketimino]-complex in 15 ml of methylene chloride, a solution of 1.55 g (6.86 mmol) of 4-ethoxycarbonyl-phenacetyl chloride in 5 ml of methylene chloride is added dropwise.

Derved stiger den indre temperatur fra 20°C til 30°C. Man omrører i ytterligere 2 timer ved romtemperatur, tilsetter vann under omrøring og ekstraherer flere ganger med metylenklorid. Metylenklorid-oppløsningen vasker man tre ganger med vann, tørrer den over natriumsulfat, filtrerer den og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 50/2). Thereby, the internal temperature rises from 20°C to 30°C. The mixture is stirred for a further 2 hours at room temperature, water is added while stirring and extracted several times with methylene chloride. The methylene chloride solution is washed three times with water, dried over sodium sulphate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 50/2).

Utbytte: 1,1 g (45,8% av det teoretiske) Yield: 1.1 g (45.8% of the theoretical)

Smeltepunkt: 115-118°C (etanol)Melting point: 115-118°C (ethanol)

Analogt med eksempel 7 ble følgende forbindelser fremstilt: 4- [ ( 1-( 5- klor- 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre- etylester Analogous to example 7, the following compounds were prepared: 4-[(1-(5-chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 39,5% av det teoretiskeYield: 39.5% of the theoretical

Smeltepunkt: 142-145°C (etanol)Melting point: 142-145°C (ethanol)

Eksempel 8 Example 8

4- [ ( 1- ( 5- klor- 2- dimetylamino- fenyl)- etyl)- aminokafbonylmetyl]_-benzoesyre 4- [ ( 1- ( 5- chloro- 2- dimethylamino- phenyl)- ethyl)- aminocabonylmethyl]_-benzoic acid

En oppløsning av 2,0 g (0,00534 mol) 4-[(1-(S-klor-2-dimetylamino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-metylester og 0,32 g (0,00801 mol) natriumhydroksyd i 23 ml etanol og 7 ml vann omrører man i 2 timer ved 50°C. Man inndamper i vakuum, opptar i vann, innstiller pH-verdien på 6 med 2N saltsyre og ekstraherer med etylacetat. Den organiske fase rister man med vann, tørrer over natriumsulfat, filtrerer den og inndamper den i vakuum. Inndampningsresiduet omkrystalliserer man fra eter. A solution of 2.0 g (0.00534 mol) 4-[(1-(S-chloro-2-dimethylamino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid methyl ester and 0.32 g (0.00801 mol ) sodium hydroxide in 23 ml of ethanol and 7 ml of water is stirred for 2 hours at 50°C. Evaporate in a vacuum, take up in water, adjust the pH value to 6 with 2N hydrochloric acid and extract with ethyl acetate. The organic phase is shaken with water, dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is recrystallized from ether.

Utbytte: 1,7 g (88% av det teoretiske) Yield: 1.7 g (88% of theoretical)

Smeltepunkt: 190-192°C Melting point: 190-192°C

Analogt med eksempel 8 ble følgende forbindelser fremstilt: 4-[( 1-( 5- klor- 2- dipropylamino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre Analogous to example 8, the following compounds were prepared: 4-[(1-(5-chloro-2-dipropylamino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 87,6% av det teoretiskeYield: 87.6% of the theoretical

Smeltepunkt: 203-205°C Melting point: 203-205°C

4-[ ( 1-( 5- klor- 2- dibutylamino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[(1-(5-chloro-2-dibutylamino-phenyl)-ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 7 7,3% av det teoretiskeYield: 7 7.3% of the theoretical

Smeltepunkt: 200-202°C Melting point: 200-202°C

4-[( 1-( 5- klor- 2- N- cykloheksyl- N- metylamino- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre 4-[( 1-( 5- chloro- 2- N- cyclohexyl- N- methylamino- phenyl)- ethyl)-aminocarbonylmethyl]- benzoic acid

Utbytte: 88,2% av det teoretiskeYield: 88.2% of the theoretical

Smeltepunkt: 198-200°C (eter) Melting point: 198-200°C (ether)

4- [ ( 5- klor- 2- pyrrolidino- benzyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 84,2% av det teoretiske Smeltepunkt: 208-210°C (etylacetat) 4-[( 1-( 5- klor- 2- pyrrolidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre Utbytte: 81,1% av det teoretiske Smeltepunkt: 202-204°C (etylacetat) 4-[( 5- klor- 2- piperidino- benzyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 78% av det teoretiske Smeltepunkt: 164-166°C 4- [ ( 1- ( 5- klor- 2- piperidino- benzyl)- aminokarbonyl)- etyl] benzoesyre Utbytte: 81,1% av det teoretiske Smeltepunkt: 213-216°C (aceton/eter) 4- [ ( 5- chloro- 2- pyrrolidino- benzyl)- aminocarbonylmethyl]- benzoic acid Yield: 84.2% of the theoretical Melting point: 208-210°C (ethyl acetate) 4-[( 1-( 5- chloro- 2 - pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 81.1% of the theoretical Melting point: 202-204°C (ethyl acetate) 4-[(5-chloro-2- piperidino-benzyl)-aminocarbonylmethyl]- benzoic acid Yield: 78% of the theoretical Melting point: 164-166°C 4- [ ( 1- ( 5- chloro- 2- piperidino- benzyl)- aminocarbonyl)- ethyl] benzoic acid Yield: 81.1% of the theoretical Melting point: 213-216°C (acetone/ether)

4-[( 1-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 5- chloro- 2-piperidino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 84,9% av det teoretiskeYield: 84.9% of the theoretical

Smeltepunkt: 213-215°C (eter) Melting point: 213-215°C (ether)

4- [ ( 1-( 5- klor- 2-( 3- mety1- piperidino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4- [ ( 1-( 5- chloro- 2-( 3- methyl1- piperidino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 6 9,2% av det teoretiskeYield: 6 9.2% of the theoretical

Smeltepunkt: 208-210°C (etylacetat) Melting point: 208-210°C (ethyl acetate)

4-[( 1-( 5- klor- 2-( 3, 5- cis- dimety1- piperidino)- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre 4-[( 1-( 5- chloro- 2-( 3, 5- cis- dimethyl-piperidino)- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Utbytte: 82,2% av det teoretiskeYield: 82.2% of the theoretical

Smeltepunkt: 212-214°C (eter) Melting point: 212-214°C (ether)

4- [ ( 1- ( 5- klor- 2- piperidino- fenyl)- propyl)- aminokarbonylmetyl]-benzoesyre 4-[(1-(5-chloro-2-piperidino-phenyl)-propyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 81,5% av det teoretiskeYield: 81.5% of the theoretical

Smeltepunkt: 200-203°C (eter) Melting point: 200-203°C (ether)

4-[( 1-( 5- klorJ2- piperidino- fenyl)- 2- metyl- propyl)- aminokarbonylmetyl] - benzoesyre 4-[( 1-( 5- chloroJ2- piperidino-phenyl)- 2- methyl- propyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 82,7% av det teoretiskeYield: 82.7% of the theoretical

Smeltepunkt: 2 36-2 40°C (etylacetat) Melting point: 2 36-2 40°C (ethyl acetate)

4- [ (■!- ( 5- klor- 2- morfolino- f enyl) - etyl) - aminokarbonylmety 13 - benzoesyre 4- [ (■!- ( 5- chloro- 2- morpholino- phenyl) - ethyl) - aminocarbonylmethyl 13 - benzoic acid

Utbytte: 85,6% av. det teoretiskeYield: 85.6% of. the theoretical

Smeltepunkt: 201-203°C (eter) Melting point: 201-203°C (ether)

4-[( 1-( 5- klor- 2- tiomorfolino- fenyl)- etyl)- aminokarbonylmety13 - benzoesyre 4-[( 1-( 5- chloro- 2- thiomorpholino- phenyl)- ethyl)- aminocarbonylmethyl 13 - benzoic acid

Utbytte: 87,6% av det teoretiskeYield: 87.6% of the theoretical

Smeltepunkt: 216-217°C (eter) Melting point: 216-217°C (ether)

4-[( 1-( 5- klor- 2- ( heksahydro- lH- azepino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4-[( 1-( 5- chloro- 2- ( hexahydro- 1H- azepino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 81,2% av det teoretiskeYield: 81.2% of the theoretical

Smeltepunkt: 202-204°C (kloroform/toluen) Melting point: 202-204°C (chloroform/toluene)

4-[( 1-( 5- klor- 2- oktahydroazocino- fenyl)- etyl)- aminokarbony1-metyl]- benzoesyre 4-[( 1-( 5- chloro- 2- octahydroazocino- phenyl)- ethyl)- aminocarbonyl-1-methyl]- benzoic acid

Utbytte:'44,4% av det teoretiskeYield: '44.4% of the theoretical

Smeltepunkt: 196-197°C (kloroform/petroleter) Melting point: 196-197°C (chloroform/petroleum ether)

4-[( 1-( 5- klor- 2-( oktahydro- lH- azocino)- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre 4-[( 1-( 5- chloro- 2-( octahydro- 1H- azocino)- phenyl)- ethyl)-aminocarbonylmethyl]- benzoic acid

Utbytte: 7 4,7% av det teoretiskeYield: 7 4.7% of the theoretical

Smeltepunkt-: 204-206°C (etylacetat/petroleter) Melting point: 204-206°C (ethyl acetate/petroleum ether)

4-[( 2-( 5- klor- 2- piperidino- fenyl)- 2- propyl)- aminokarbonylmetyl]-benzoesyre 4-[( 2-( 5- chloro- 2-piperidino-phenyl)- 2- propyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 82,9% av det teoretiskeYield: 82.9% of the theoretical

Smeltepunkt:'227-229°C (aceton) Melting point: '227-229°C (acetone)

4- [ ( 1-( 5- nitro- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[(1-(5-nitro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 95,6% av det teoretiskeYield: 95.6% of the theoretical

Smeltepunkt': 252-254°C (eter) Melting point': 252-254°C (ether)

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 85% av det teoretiske Smeltepunkt: 170-172°C 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 85% of the theoretical Melting point: 170-172°C

4- [ ( 2-( 2- piperidino- fenyl)- 2- propyl)- aminokarbonylmetyl]-benzoesyre 4-[(2-(2-piperidino-phenyl)-2-propyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 72,7% av det teoretiskeYield: 72.7% of the theoretical

Smeltepunkt: 213-215°C Melting point: 213-215°C

4- [ ( 5^ metyl- 2- piperidino- benzyl)- aminokarbonylmetyl]-benzoesyre 4-[(5^methyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 64,6% av det teoretiskeYield: 64.6% of the theoretical

Smeltepunkt: 120-122°C Melting point: 120-122°C

Smeltepunkt for hydrokloridet: 266°C (spaltn.) Melting point of the hydrochloride: 266°C (dec.)

4-[ ( 2- piperidino- anilino)- karbonylmetyl]- benzoesyre x 0, 25 HC1 Utbytte: 72',5% av det teoretiske 4-[(2-piperidino-anilino)-carbonylmethyl]-benzoic acid x 0.25 HCl Yield: 72'.5% of the theoretical

Smeltepunkt: 216-217°C Melting point: 216-217°C

4-[( 5- klor- 2- piperidino- anilino)- karbonylmetyl]- benzoesyre-hydroklorid 4-[(5-Chloro-2-piperidino-anilino)-carbonylmethyl]-benzoic acid hydrochloride

Utbytte: 51,3% av det teoretiskeYield: 51.3% of the theoretical

Smeltepunkt: 232°C (spaltn.) Melting point: 232°C (dec.)

4-[ 2-( 2- piperidino- anilino- karbonyl)- etyl]- benzoesyre- semihydrat Utbytte: 69,9% av det teoretiske Smeltepunkt: 151-15 3°C (petroleter/aceton) 4-[ 2-( 2- piperidino-anilino-carbonyl)- ethyl]- benzoic acid hemihydrate Yield: 69.9% of the theoretical Melting point: 151-15 3°C (petroleum ether/acetone)

4-[ 2- ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonyl)- etyl]-benzoesyre x 0, 2 H^ O 4-[2-(1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl)-ethyl]-benzoic acid x 0.2 H^O

Utbytte: 71,4% av det teoretiskeYield: 71.4% of the theoretical

Smeltepunkt: 171-172°C (aceton/petroleter) Melting point: 171-172°C (acetone/petroleum ether)

Eksempel 9 Example 9

4- [ ( 1- ( 5- benzyloksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1- ( 5- benzyloxy- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

244 mg (0,487 mmol) 4-[ (1-(5-benzyloksy-2-piperidino-fenyl)-ety1)-aminokarbonylmetyl]-benzoesyre-etylester i 2,5 ml etanol oppvarmer man under omrøring med 0,7 3 ml IN natronlut i et bad på 50°C, inntil (efter 3 timer) det ikke mer kan påvises noen ester tynnskiktkromatografisk. Man tilsetter 0,73 ml IN saltsyre, inndamper i vakuum og fordeler mellom etylacetat og vann. 244 mg (0.487 mmol) of 4-[(1-(5-benzyloxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 2.5 ml of ethanol is heated while stirring with 0.7 3 ml of IN caustic soda in a bath at 50°C, until (after 3 hours) no ester can be detected by thin-layer chromatography. 0.73 ml IN hydrochloric acid is added, evaporated in vacuo and distributed between ethyl acetate and water.

Den organiske ekstrakt tørrer man over natriumsulfat, filtrerer den og inndamper den i vakuum. Inndampningsresiduet omkrystalliserer man fra metanol. The organic extract is dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is recrystallized from methanol.

Utbytte: 1-91 mg (83% av det teoretiske)Yield: 1-91 mg (83% of theoretical)

Smeltepunkt: 220-222°C Melting point: 220-222°C

Analogt med eksempel 9 ble følgende forbindelser fremstilt: 4-[( 1-( 2- heksahydroazepino- fenyl)- etyl)- aminokarbonylmetyl]-. benzoesyre" Analogous to example 9, the following compounds were prepared: 4-[(1-(2-hexahydroazepino-phenyl)-ethyl)-aminocarbonylmethyl]-. benzoic acid"

Utbytte: 68,5% av det teoretiskeYield: 68.5% of the theoretical

Smeltepunkt: 174-176°C (etylacetat) Melting point: 174-176°C (ethyl acetate)

4-[( l-( 2-( l, 2, 3, 6- tetrahydro- pyridino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4-[( l-( 2-( l, 2, 3, 6- tetrahydro- pyridino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 68,2% av det teoretiskeYield: 68.2% of the theoretical

Smeltepunkt: 158-160°C (etylacetat) Melting point: 158-160°C (ethyl acetate)

4-[( 2-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[( 2-( 5- chloro- 2-piperidino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 75% av det teoretiskeYield: 75% of the theoretical

Smeltepunkt: 192-195°C (etylacetat) Melting point: 192-195°C (ethyl acetate)

4- [ ( 1-( 5- fluor- 2- piperidino- fenylji- etyl)- aminokarbonylmetyl]-benzoesyre 4-[(1-(5-fluoro-2- piperidino-phenylji-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 52,9% av det teoretiskeYield: 52.9% of the theoretical

Smeltepunkt: 17 4-17 6°C (etylacetat) . 4-[( 5- metyl- 2- piperidino- benzyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 53,9% av det teoretiske Smeltepunkt: 120-122°C (etanol) Melting point: 17 4-17 6°C (ethyl acetate). 4-[( 5- methyl- 2- piperidino- benzyl)- aminocarbonylmethyl]- benzoic acid Yield: 53.9% of the theoretical Melting point: 120-122°C (ethanol)

4-^ [ ( 1- ( 5- cyano- 2- piperidino- fenyl) - etyl) - aminokarbonylmetyl] - benzoesyre 4-^ [ ( 1- ( 5- cyano- 2- piperidino- phenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid

Utbytte: 71,6% av det teoretiskeYield: 71.6% of the theoretical

Smeltepunkt: 198-200°C (eter) Melting point: 198-200°C (ether)

4-[( 1-( 5- karboksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 5- carboxy- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Fremstilt fra den tilsvarende dietylester ved forsepning med 2,5 ekvivalenter natriumhydroksyd. Prepared from the corresponding diethyl ester by saponification with 2.5 equivalents of sodium hydroxide.

Utbytte: 73,5% av det teoretiskeYield: 73.5% of the theoretical

Smeltepunkt: 260°C (spaltn.) Melting point: 260°C (dec.)

4-[( 1-( 2- [ 1, 4- dioksa- 8- azas piro[ 4, 5] dekan- 8- yl]- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre- semihydrat 4-[( 1-( 2- [ 1, 4- dioxa- 8- azas pyro[ 4, 5] decan- 8- yl]- phenyl)- ethyl)-aminocarbonylmethyl]- benzoic acid hemihydrate

Utbytte: 85,7% av det teoretiskeYield: 85.7% of the theoretical

Smeltepunkt: 130-135°C (petroleter/aceton) . Melting point: 130-135°C (petroleum ether/acetone).

4-[ 2- hydroksy- l-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre Utbytte: 65% meltepunkt: 155-157°C (spaltn.) (petroleter/+aceton) 4-[2- Hydroxyl-1-(2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]-benzoic acid Yield: 65% Melting point: 155-157°C (dec.) (petroleum ether/+acetone)

4-[( 1-( 5- klor- 2-( 2- mety1- piperidino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4-[( 1-( 5- chloro- 2-( 2- methyl-1- piperidino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 64,1% av det teoretiskeYield: 64.1% of the theoretical

Smeltepunkt: 195-198°C (etylacetat) Melting point: 195-198°C (ethyl acetate)

4-[( 1-( 5- aminokarbony1- 2- piperidino- fenyl) etyl)- aminokarbonylmetyl] - benzoesyre 4-[( 1-( 5- aminocarbonyl- 2- piperidino- phenyl) ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 86% av det teoretiskeYield: 86% of the theoretical

Smeltepunkt: 231-235°C (etylacetat) Melting point: 231-235°C (ethyl acetate)

4-[( 1-( 2-( 4- metyl- piperidino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 2-( 4- methyl-piperidino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 67,7% av det teoretiskeYield: 67.7% of the theoretical

Smeltepunkt: 173-175°C (kloroform) Melting point: 173-175°C (chloroform)

4-[( 1-( 2- piperidino- fenyl)- etyl)- N- metylamino- karbonylmety1]-benzoesyre- hydroklorid 4-[( 1-( 2-piperidino-phenyl)-ethyl)- N- methylamino- carbonylmethyl]-benzoic acid hydrochloride

Overføring av det viskøse betain (72% rått) til hydrokloridet ved hjelp av hydrogenklorid i isopropanolisk oppløsning. Transfer of the viscous betaine (72% crude) to the hydrochloride using hydrogen chloride in isopropanol solution.

Utbytte: 32% av det teoretiskeYield: 32% of the theoretical

Smeltepunkt: 222-230°C (spaltn.) (etanol) Melting point: 222-230°C (dec.) (ethanol)

2-[ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 7% av det teoretiske Smeltepunkt: 135°C (spaltn.) 3- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 86% av det teoretiske Smeltepunkt: 205-207°C 2-[ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 7% of the theoretical Melting point: 135°C (dec.) 3- [ ( 1- ( 2- piperidino-phenyl) - ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 86% of the theoretical Melting point: 205-207°C

3- klor- 4-[( 1-( 2- piperidino- fenyl)- ety1)- aminokarbonylmetyl]-benzoesyre 3- Chloro- 4-[( 1-( 2-piperidino- phenyl)-ethyl 1)- aminocarbonylmethyl]-benzoic acid

Utbytte: 38% av det teoretiskeYield: 38% of the theoretical

Smeltepunkt: fra 175°C, sintrer, fra 190°C klar smelte Melting point: from 175°C, sinters, from 190°C clear melt

4-[( l-( 2-( l, 2, 3, 4- tetrahydro- isokinolin- 2- yl)- fenyl)- etyl)-aminokarbonylmetyl]- benzoesyre 4-[(l-(2-(l,2,3,4-tetrahydro-isoquinolin-2-yl)-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 59% av det teoretiskeYield: 59% of the theoretical

Smeltepunkt: 207-209°C Melting point: 207-209°C

4-[( 1-( 3- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 33% av det teoretiske 4-[( 1-( 3- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 33% of the theoretical

Smeltepunkt: 206-208°C. Melting point: 206-208°C.

4- [ ( 1-( 6- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre Utbytte: 35% av det teoretiske Smeltepunkt: 148-150°C 4-[(1-(6-chloro-2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]-benzoic acid Yield: 35% of the theoretical Melting point: 148-150°C

4- [ ( 1- ( 6- metyl- 2- piperidino- fenyl)- etyl)- aminokarbon ylmetyl]-benzoesyre 4-[(1-(6-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 33% av det teoretiskeYield: 33% of the theoretical

Smeltepunkt: 170°C Melting point: 170°C

4-[( 1-( 2-( oktahydro- isoindol- 2- yl)- fenyl)- etyl)- aminokarbonylmetyl ] - benzoesyre 4-[( 1-( 2-( octahydro- isoindol- 2- yl)- phenyl)- ethyl)- aminocarbonylmethyl ] - benzoic acid

Utbytte: 6 4% av det teoretiskeYield: 6 4% of the theoretical

Smeltepunkt: 130°C Melting point: 130°C

4-[( 1-( 2-( dekahydro- isokinolin- 2- yl)- fenyl)- etyl)- amin okarbony1-metyl]- benzoesyre 4-[( 1-( 2-( decahydro- isoquinolin- 2- yl)- phenyl)- ethyl)- amino carbonyl-1-methyl]- benzoic acid

Utbytte: 71% av det teoretiskeYield: 71% of the theoretical

Smeltepunkt: 220-221°C Melting point: 220-221°C

4- [ ( 1-( 2-( 1, 2, 3, 4, 5, 6, 7, 8- oktahydro- isokinolin- 2- y1)- fenyl)-etyl)- aminokarbonylmetyl]- benzoesyre- semihydrat Utbytte: 99% av det teoretiske Smeltepunkt: 70°C (spaltn.) 4- [ ( 1-( 2-( 1, 2, 3, 4, 5, 6, 7, 8- octahydro- isoquinolin- 2- y1)- phenyl)-ethyl)- aminocarbonylmethyl]- benzoic acid hemihydrate Yield: 99 % of the theoretical Melting point: 70°C (dec.)

4- [ ( 1- ( 4- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[(1-(4-chloro-2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 82,1% av det teoretiskeYield: 82.1% of the theoretical

Smeltepunkt: 200-202°C Melting point: 200-202°C

4- [■(!-■ ( 4- metyl- 2- piperidino- fenyl) - etyl) - aminokarbonylmetyl]-benzoesyre 4- [■(!-■ ( 4- methyl- 2- piperidino- phenyl) - ethyl) - aminocarbonylmethyl]-benzoic acid

Utbytte: 66,5% av det teoretiskeYield: 66.5% of the theoretical

Smeltepunkt: 110-115°C Melting point: 110-115°C

4-[( 2- piperidino- benzhydryl)- aminokarbonylmetyl]- benzoesyre Utbytte: 88% av det teoretiske Smeltepunkt: 232-234°C 4-[( 2- piperidino- benzhydryl)- aminocarbonylmethyl]- benzoic acid Yield: 88% of the theoretical Melting point: 232-234°C

4-[( 5- klor- 2- piperidino- benzhydryl)- aminokarbonylmetyl]- benzoesyre 4-[(5-chloro-2- piperidino-benzhydryl)- aminocarbonylmethyl]- benzoic acid

Utbytte: 7 8,5% av det teoretiskeYield: 7 8.5% of the theoretical

Smeltepunkt: 255-260°C Melting point: 255-260°C

4-[( 1-( 4- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 81% av det teoretiske Smeltepunkt: 208-210°C 4-[( 1-( 4- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 81% of the theoretical Melting point: 208-210°C

4- [ ( 1-( 2- ( 4- metyl- piper azino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1-( 2- ( 4- methyl- piper azino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 65%-av det teoretiskéYield: 65% of the theoretical

Smeltepunkt: 150-153°C Melting point: 150-153°C

4-[( 1-( 2-( 4- benzyl- piperazino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- hydroklorid 4-[( 1-( 2-( 4- benzyl-piperazino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid hydrochloride

Utbytte: 32% av det teoretiskeYield: 32% of the theoretical

Smeltepunkt: 180°C Melting point: 180°C

4- [ ( 1- ( 2- ( 4- p- klorfeny 1- piperazino) - fenyl") - etyl) - aminokarbonylmetyl] - benzoesyre .Utbytte: 75% av det teoretiske Smeltepunkt: 212°C (spaltn.) 4- [ ( 1- ( 2- ( 4- p- chloropheny 1- piperazino) - phenyl") - ethyl) - aminocarbonylmethyl] - benzoic acid. Yield: 75% of the theoretical Melting point: 212°C (dec.)

4-[( a- cykloheksyl- 2- piperidino- benzyl)- aminokarbonylmetyl]-benzoesyre 4-[(α-cyclohexyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 33% av det teoretiskeYield: 33% of the theoretical

Smeltepunkt: 199-202°C Melting point: 199-202°C

(+)- 4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre x 0, 3 H^ O (+)- 4-[( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid x 0.3 H^ O

Utbytte: 40% av det teoretiske.Yield: 40% of the theoretical.

Smeltepunkt: 107°C (spaltn.) (isopropanol/eter)Melting point: 107°C (dec.) (isopropanol/ether)

[a]D° = + 7,3° (c = 1, metanol)[a]D° = + 7.3° (c = 1, methanol)

(-)- 4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- natriumsalt Råutbytte- av betain: 77% av det teoretiske (-)- 4- [ ( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid sodium salt Crude yield of betaine: 77% of the theoretical

Overføring til natriumsaltet ved hjelp av 1 ekvivalent natronlut i etanol. Transfer to the sodium salt using 1 equivalent of caustic soda in ethanol.

Smeltepunkt for natriumsaltet: 190°C (spaltn.) Melting point of the sodium salt: 190°C (splitting)

4-[( 1- 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre 4-[(1-2- piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 53,6% av det teoretiskeYield: 53.6% of the theoretical

Smeltepunkt: 158-160°C (etanol) Melting point: 158-160°C (ethanol)

4-[( 1-( 5- klor- 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl] - benzoesyre 4-[( 1-( 5- chloro- 2- piperidino- phenyl)- ethenyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 7 8,7% av det teoretiskeYield: 7 8.7% of the theoretical

Smeltepunkt: 198-200°C (aceton) Melting point: 198-200°C (acetone)

4-[( g- cykloheksyliden- 2- piperidino- benzy1)- aminokarbonylmetyl]-benzoesyre 4-[(g-cyclohexylidene-2-piperidino-benzy1)-aminocarbonylmethyl]-benzoic acid

Utbytte: 21% av det teoretiskeYield: 21% of the theoretical

Smeltepunkt: 213-216°C Melting point: 213-216°C

4-[( 1-( 6- klor- 2- piperidino- fenyl)- etenyl)- aminokarbonylmetyl]-benzoesyre Utbytte: 39% av det teoretiske Smeltepunkt: 162°C 4-[( 1-( 6- chloro- 2- piperidino- phenyl)- ethenyl)- aminocarbonylmethyl]-benzoic acid Yield: 39% of the theoretical Melting point: 162°C

4-[( 1-( 6- metyl- 2- piperidino- feny1)- etenyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 6- methyl- 2-piperidino- phenyl)- ethenyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 49% av det teoretiskeYield: 49% of the theoretical

Smeltepunkt: 128-130°C Melting point: 128-130°C

4-[( 1-( 2- piperidino- fenyl)- propenyl)- aminokarbonylmetyl]-benzoesyre Utbytte: 65% av det teoretiske Smeltepunkt: (Z-form) 185-187°C (etylacetat) (E-form) 108-110°C. 4-[( 1-( 2-piperidino-phenyl)-propenyl)-aminocarbonylmethyl]-benzoic acid Yield: 65% of the theoretical Melting point: (Z-form) 185-187°C (ethyl acetate) (E-form) 108- 110°C.

4-[( 1-( 5- hydroksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- semihydrat 4-[( 1-( 5- hydroxy- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid hemihydrate

Forsepning- med 2,5 ekvivalenter natriumhydroksyd.Saponification - with 2.5 equivalents of sodium hydroxide.

Utbytte: 55,9% av det teoretiskeYield: 55.9% of the theoretical

Skum (fra eter) Foam (from ether)

4- [ ( 1-( 2-( 2- metyl- pyrrolidino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1-( 2-( 2- methyl- pyrrolidino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 62% av det teoretiskeYield: 62% of the theoretical

Smeltepunkt: 169-172°CMelting point: 169-172°C

4-[( 1-( 5- aminosulfonyl- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4-[( 1-( 5- aminosulfonyl- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 19,2% av det teoretiskeYield: 19.2% of the theoretical

Smeltepunkt: 210°C (spaltn.)Melting point: 210°C (dec.)

4-[ ( 1-( 2- piperidino- fenyl)- propyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 71,4% av det teoretiske Smeltepunkt: 208-210°C (etanol) 4-[ ( 1-( 2- piperidino-phenyl)- propyl)- aminocarbonylmethyl]- benzoic acid Yield: 71.4% of the theoretical Melting point: 208-210°C (ethanol)

Eksempel 10 Example 10

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre 4-[( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Til 88,8 g (0,225 mol) 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester i 890 ml etanol setter man en .oppløsning av 13,5 g (0, 338 mol) natriumhydroksyd i 50 ml vann og omrører ved en indre temperatur på 60°C inntil det A solution of 13.5 g (0.338 mol) of sodium hydroxide in 50 ml of water and stir at an internal temperature of 60°C until it

ikke lenger kan påvises noe utgangsprodukt tynnskiktkromatografisk (ca. 45 minutter). Derefter tilsetter man 400 ml vann og innstiller ved ca. 25°C pH på 5,8 med halvkonséntrert saltsyre no starting product can be detected by thin-layer chromatography (approx. 45 minutes). Then add 400 ml of water and set at approx. 25°C pH of 5.8 with semi-concentrated hydrochloric acid

under pH-metrisk kontroll. Efter kort tid begynner krystallisasjon. Efter henstand natten over ved 20°C frafiltrerer man, vasker krystallisatet flere ganger med vann, løser krystallisatet i metylenklorid og fraskiller den vandige fase. Metylenklorid-oppløsningen tørrer man over natriumsulfat, filtrerer den og inndamper den i vakuum og får således-57,5 g fast inndampningsrest. under pH-metric control. After a short time, crystallization begins. After standing overnight at 20°C, the mixture is filtered off, the crystallisate is washed several times with water, the crystallisate is dissolved in methylene chloride and the aqueous phase is separated. The methylene chloride solution is dried over sodium sulphate, filtered and evaporated in a vacuum, thus obtaining 57.5 g of solid evaporation residue.

Det eta.nolisk-saltsure filtrat (pH = 5,8) innstiller manThe ethanolic-hydrochloric acid filtrate (pH = 5.8) is adjusted

med halvkonséntrert saltsyre på pH = 5,0, avdestillerer derefter etanolen i vesentlig utstrekning i vakuum og avkjøler den inn-dampede oppløsning i is. Det utfelte bunnfall frafiltrerer man, oppløser det i .metylenklorid, fraskiller den vandige fase, tørrer with half-concentrated hydrochloric acid at pH = 5.0, then distills off the ethanol to a substantial extent in vacuum and cools the evaporated solution in ice. The precipitate that precipitates is filtered off, dissolved in methylene chloride, the aqueous phase separated, dried

metylénkloridoppløsningen, filtrerer den og inndamper den i vakuum. Det faste inndampningsresiduum utgjør 13,0 g. De to inndampningsresiduer (tilsammen 70,5 g) omkrystalliserer man fra den 5- til 6-dobbelte mengde etanol/vann (80/20) under tilsetning av aktivt kull. the methylene chloride solution, filter it and evaporate it in vacuo. The solid evaporation residue amounts to 13.0 g. The two evaporation residues (together 70.5 g) are recrystallized from the 5- to 6-fold amount of ethanol/water (80/20) while adding activated charcoal.

Utbytte: 62% av det teoretiskeYield: 62% of the theoretical

Smeltepunkt: 162-164°CMelting point: 162-164°C

Hvis man efter avsluttet forsepning, efter tilsetning If one finishes saponification, after addition

av vann og avkjøling til 25°C, innstiller på pH = 5,0, får man - som beskrevet ovenfor, men uten opparbeidelse av det etanolisk-saltsure filtrat - 75,9% tørret inndampningsresiduum, som allerede før den avsluttende omkrystallisasjon gir en riktig elemeritæranalyse. of water and cooling to 25°C, setting to pH = 5.0, you get - as described above, but without working up the ethanolic-hydrochloric filtrate - 75.9% dried evaporation residue, which even before the final recrystallization gives a correct elementary analysis.

Smeltepunkt: 172-176°CMelting point: 172-176°C

Analogt med eksempel 10 ble følgende forbindelser oppnådd: 4-[( 1- ( 5- metyl- 2- piperidino- fényl)- etyl)- aminokarbonylmetyl]-benzoesyre' Analogous to example 10, the following compounds were obtained: 4-[(1-(5-methyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid'

Utbytte: 5 6,6% av det teoretiskeYield: 5 6.6% of the theoretical

Smeltepunkt: 215-217°C (etanol) 'Melting point: 215-217°C (ethanol) '

4-[ ( a- karboksy- 2- piperidino- benzyl)- aminokarbonylmetyl]- benzoe-'syre x 0, 66 H^ O 4-[(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid x 0.66 H^O

Fremstilt ved forsepning av 4-[ (a-metoksykarbonyl-2-piperidino-benzyl)-aminokarbonylmetyl]-benzoesyre-etylester med 2,5 ekvivalenter natriumhydroksyd. Prepared by saponification of 4-[(α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester with 2.5 equivalents of sodium hydroxide.

Utbytte: 72,2% av det teoretiskeYield: 72.2% of the theoretical

Smeltepunkt: 235-240°C (spaltn.) (metanol/kloroform)Melting point: 235-240°C (dec.) (methanol/chloroform)

Eksempel 11 Example 11

4-[( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre- natriumsalt- monohydrat 4-[( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid sodium salt monohydrate

Man omrører 500 mg (1,26 mmol) 4-[(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester i 5 ml etanol sammen med 1,26 ml IN natronlut i 1 time ved 50°C. Derefter avkjøler man til 0°C, frafiltrerer utfelt krystallisat og vasker det med kald etanol og med eter. 500 mg (1.26 mmol) of 4-[(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 5 ml of ethanol are stirred together with 1.26 ml of 1N caustic soda for 1 hour at 50°C. It is then cooled to 0°C, the precipitated crystallisate is filtered off and washed with cold ethanol and with ether.

Utbytte: 238 mg (48,6% av det teoretiske)Yield: 238 mg (48.6% of the theoretical)

Smeltepunkt: 2 45-250°CMelting point: 2 45-250°C

A-nalogt med eksempel 11 ble følgende forbindelse oppnådd: 4-[( 1-( 5- metoksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- natriumsalt- monohydrat Analogous to example 11, the following compound was obtained: 4-[(1-(5-Methoxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid sodium salt monohydrate

Utbytte: 17,5% av det teoretiskeYield: 17.5% of the theoretical

Smeltepunkt: 212-215°C.Melting point: 212-215°C.

Fra dette natriumsalt får man analogt med eksempel 9 den tilsvarende syre som monohydrat: Analogous to example 9, the corresponding acid is obtained as monohydrate from this sodium salt:

Smeltepunkt: 187-189°C (etanol/vann)Melting point: 187-189°C (ethanol/water)

Eksempel 12 Example 12

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre- 4- [ ( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-

natriumsalt x 0,6 H„0sodium salt x 0.6 H„0

— —

Man oppløser 8,4 g (0,0229 mol) 4-[(1-(2-piperidino-feny1)-etyl)-aminokarbonylmetyl]-benzoesyre ved 60 til 65°C i 80 ml etanol, tilsetter under omrøring 22,9 ml IN natronlut og omrører i ytterligere 30 minutter. Derefter lar man det hele avkjøles til 20°C, hvorved et bunnfall utfelles. Man avkjøler til 0°C, filtrerer og vasker bunnfallet med kald etanol og eter. Det således oppnådde bunnfall med smeltepunkt 250-251°C omkrystalliserer man fra etanol/vann (7/3). Dissolve 8.4 g (0.0229 mol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid at 60 to 65°C in 80 ml of ethanol, add while stirring 22.9 ml IN caustic soda and stir for a further 30 minutes. The whole is then allowed to cool to 20°C, whereby a precipitate is precipitated. Cool to 0°C, filter and wash the precipitate with cold ethanol and ether. The thus obtained precipitate with a melting point of 250-251°C is recrystallized from ethanol/water (7/3).

Utbytte: 7,2 g (78,6% av det teoretiske)Yield: 7.2 g (78.6% of the theoretical)

Smeltepunkt: 253-255°CMelting point: 253-255°C

Eksempel 13 Example 13

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre 4-[( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Man oppvarmer 100 mg (0,237 mmol) 4-[(1-(2-piperidino-fenyl) -etyl)-aminokarbonylmetyl]-benzoesyre-tert.butylester i 5 ml benzen sammen med noen krystaller av p-toluensulfonsyre-hydrat 1/2 dag under tilbakeløpskjøling. Derefter er det ifølge tynnskiktkromatogrammet ikke mer utgangsmateriale til stede, og isteden er det ifølge R^-verdien og massespektrum dannet det ønskede produkt. 100 mg (0.237 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid tert-butyl ester are heated in 5 ml of benzene together with some crystals of p-toluenesulfonic acid hydrate 1/2 day under reflux cooling. After that, according to the thin-layer chromatogram, no more starting material is present, and instead, according to the R^ value and mass spectrum, the desired product has been formed.

Smeltepunkt: 162-165°CMelting point: 162-165°C

Beregnet: m/e = 366Calculated: m/e = 366

Funnet: m/e = 366Found: m/e = 366

Eksempel 14 4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Example 14 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Man hydrogenerer 0,46 g (1 mmol) 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-benzylester i 20 ml etanol med 0,25 g palladium/kull (I0%ig) ved 50°C og 5 bar hydrogentrykk. Efter 5 timer frafiltrerer man katalysatoren over "Celite" og inndamper i vakuum. Inndampningsresiduet omkrystalliserer man fra etanol/vann (8/2). 0.46 g (1 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid benzyl ester in 20 ml of ethanol is hydrogenated with 0.25 g of palladium/charcoal (10% strength) at 50°C and 5 bar hydrogen pressure. After 5 hours, the catalyst is filtered off over "Celite" and evaporated in a vacuum. The evaporation residue is recrystallized from ethanol/water (8/2).

Utbytte: 0,26 g (71% av det teoretiske).Yield: 0.26 g (71% of theoretical).

Smeltepunkt: 163-165°C.Melting point: 163-165°C.

Eksempel. 15 Example. 15

4- [ ( 1- ( 5- klor- 2- piperidino- feny1)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1- ( 5- chloro- 2-piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

I en omrørt oppløsning av 3,57 g (0,01 mol) N-[1-(5-klor-2-piperidino-fenyl)-etyl]-N-[fenacetyl]-amin i 16 ml karbondisulfid settes dråpevis ved 0 til 5°C 2,54 g (0,02 mol) oksalylklorid, og derefter tilsettes 2,67 g (0,02 mol) aluminiumklorid. Efter 1 time tilsetter man igjen de samme mengder oksalylklorid og aiuminiumklorid og oppvarmer derefter i 3 timer til 50°C. Man avkjøler, tilsetter isvann og saltsyre og ekstraherer med kloroform. ' Den organiske ekstrakt tørrer og filtrerer man og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/ metanol = 10/1) In a stirred solution of 3.57 g (0.01 mol) N-[1-(5-chloro-2-piperidino-phenyl)-ethyl]-N-[phenacetyl]-amine in 16 ml of carbon disulfide is added dropwise at 0 to 5°C 2.54 g (0.02 mol) of oxalyl chloride, and then 2.67 g (0.02 mol) of aluminum chloride are added. After 1 hour, the same amounts of oxalyl chloride and aluminum chloride are again added and then heated for 3 hours to 50°C. Cool, add ice water and hydrochloric acid and extract with chloroform. The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1)

Utbytte: 0,60 g (15% av det teoretiske)Yield: 0.60 g (15% of the theoretical)

Smeltepunkt: 213-214°C (eter)Melting point: 213-214°C (ether)

Eksempel 16. Example 16.

N- [ 4- acety1- fenacetyl]- N-[ 1-( 5- klor- 2- piperidino- fenyl) etyl] - amin N- [ 4- acety1- phenacetyl]- N-[ 1-( 5- chloro- 2- piperidino- phenyl) ethyl] - amine

Til 1,12 g (8,43 mmol) aluminiumklorid i 10 ml metylenklorid tilsetter man ved en indre temperatur på 0 til 5°C en oppløsning av 0,6 ml (8,43 mmol) acetylklorid i 5 ml metylenklorid. Derefter tilsetter man dråpevis under omrøring ved 0 til 5°C en oppløsning av 1 g (2,81 mmol) N-[1-(5-klor-2-piperidino-fenyl)-etyl]-N-[fenacetyl]-amin i 5 ml metylenklorid. Man omrører i 1 time ved 3°C og 2 dager ved 20°C. Man spalter under avkjøling med isvann og saltsyre, fraskiller metylenklorid-fasen og ekstraherer med kloroform. De samlede organiske faser tørrer man over natriumsulfat, filtrerer og inndamper dem i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 4/1). To 1.12 g (8.43 mmol) of aluminum chloride in 10 ml of methylene chloride, a solution of 0.6 ml (8.43 mmol) of acetyl chloride in 5 ml of methylene chloride is added at an internal temperature of 0 to 5°C. A solution of 1 g (2.81 mmol) N-[1-(5-chloro-2-piperidino-phenyl)-ethyl]-N-[phenacetyl]-amine is then added dropwise with stirring at 0 to 5°C in 5 ml of methylene chloride. The mixture is stirred for 1 hour at 3°C and 2 days at 20°C. It is split while cooling with ice water and hydrochloric acid, the methylene chloride phase is separated and extracted with chloroform. The combined organic phases are dried over sodium sulphate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 4/1).

Utbytte: 0,28 g (25% av det teoretiske)Yield: 0.28 g (25% of theoretical)

Smeltepunkt: 160-161°CMelting point: 160-161°C

Eksempel 17 Example 17

4 - [ ( 1- ( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4 - [(1-(5-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Til en omrørt natriumhypobromitt-oppløsning [fremstilt fra 1,84 g (0,046 mol) natriumhydroksyd, oppløst- i 9 ml vann, og 0,72 ml (0,014 mol) brom under isavkjøling] setter man dråpevis i løpet av 15 minutter ved 35-40°C en oppløsning av 1,2 3 g (0,0031 mo.l) N- [4-acetyl-f enacetyl]-N- [1- (5-klor-2-piperidino-fenyl)-etylj-amin i 12 ml dioksan. Efter 40 minutter ved 35-40°C tilsetter man vandig natriumhydrogensulfitt-oppløsning og vann og inndamper blandingen i vakuum. Residuet oppløser man i vann, surgjør under avkjøling med 2N saltsyre og ekstraherer med eter/etylacetat. Den organiske fase tørrer og filtrerer man og inndamper den i vakuum. Inndampningsresiduet krystalliserer man fra eter. To a stirred sodium hypobromite solution [prepared from 1.84 g (0.046 mol) of sodium hydroxide, dissolved in 9 ml of water, and 0.72 ml (0.014 mol) of bromine under ice cooling] is added dropwise over 15 minutes at 35- 40°C a solution of 1.2 3 g (0.0031 mol.l) N-[4-acetyl-phenacetyl]-N-[1-(5-chloro-2-piperidino-phenyl)-ethylj-amine in 12 ml of dioxane. After 40 minutes at 35-40°C, aqueous sodium hydrogen sulphite solution and water are added and the mixture is evaporated in vacuo. The residue is dissolved in water, acidified while cooling with 2N hydrochloric acid and extracted with ether/ethyl acetate. The organic phase is dried and filtered and evaporated in a vacuum. The evaporation residue is crystallized from ether.

Utbytte,: 0,14 g (11% av det teoretiske)Yield: 0.14 g (11% of the theoretical)

Smeltepunkt: 213-215°CMelting point: 213-215°C

Analogt med eksempel 17 ble følgende forbindelse oppnådd: 4-[ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonyImetyl]- benzoesyre Utbytte: 15% av det teoretiske Analogous to example 17, the following compound was obtained: 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid Yield: 15% of the theoretical

Smeltepunkt: 170-171°CMelting point: 170-171°C

Eksempel 18 Example 18

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzaldehyd 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzaldehyde

Fremstilt fra 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl] -benzylalkohol ved oksydasjon med aktivt mangandioksyd i absolutt aceton og påfølgende rensning ved kolonnekromatografi på silikagel (kloroform/aceton = 20/1). Prepared from 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzyl alcohol by oxidation with active manganese dioxide in absolute acetone and subsequent purification by column chromatography on silica gel (chloroform/acetone = 20/1).

Utbytte: 4% av det teoretiskeYield: 4% of the theoretical

Smeltepunkt: 15 9°C.Melting point: 15 9°C.

Eksempel 19 Example 19

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Fremstilt fra 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbony lmetyl]-benzaldehyd ved oppvarmning med sølvoksyd i nærvær av IN natronlut .i 20 minutter på dampbad, derefter surgjøring med 2N svovelsyre ved pH = 5, ekstraksjon med etylacetat og rensning ved kolonnekromatografi på silikagel (toluen/aceton = 1/1) . Prepared from 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzaldehyde by heating with silver oxide in the presence of 1N caustic soda for 20 minutes on a steam bath, then acidifying with 2N sulfuric acid at pH = 5, extraction with ethyl acetate and purification by column chromatography on silica gel (toluene/acetone = 1/1).

Utbytte: 3% av det teoretiskeYield: 3% of the theoretical

Smeltepunkt: 168-170°CMelting point: 168-170°C

Beregnet: m/e = 366Calculated: m/e = 366

Funnet: m/e = 366Found: m/e = 366

Eksempel 20 Example 20

4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-etylester 4- [ ( 1- ( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Man hydrogenerer 5,5 g (0,014 mol) 4-[(1-(2-piperidino-fenyl) -etenyl) -aminokarbonylmetyl] -benzoesyre-etylester i HO ml etanol på 1,5 g palladium/kull (10%ig) ved 20°C og 5 bar hydrogen. Efter 30 minutter frafiltrerer man katalysator over "Celite" og inndamper filtratet i vakuum. 5.5 g (0.014 mol) of 4-[(1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester is hydrogenated in 10 ml of ethanol on 1.5 g of palladium/charcoal (10% strength) at 20°C and 5 bar hydrogen. After 30 minutes, the catalyst is filtered off over "Celite" and the filtrate is evaporated in a vacuum.

Utbytte: 4,7 g (85,5% av det teoretiske)Yield: 4.7 g (85.5% of the theoretical)

Smeltepunkt: 152-154°C (etanol/petroleter)Melting point: 152-154°C (ethanol/petroleum ether)

Analogt med eksempel 20 ble følgende forbindelse oppnådd: 4- [ 1- ( 2- piperidino- fenyl)- propyl)- aminokarbonylmetyl]- benzoesyre-etylester Utbytte: 70,8% av det teoretiske Analogously to example 20, the following compound was obtained: 4-[1-(2-piperidino-phenyl)-propyl)-aminocarbonylmethyl]-benzoic acid ethyl ester Yield: 70.8% of the theoretical

Smeltepunkt: 132-134°C (eter)Melting point: 132-134°C (ether)

Eksempel 21 Example 21

4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre 4- [ ( 1- ( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Man hydrogenerer 100 mg (0,274.4 mmol) 4-[ (1-(2-piperidino-fenyl)-etenyl)-aminokarbonylmetyl]-benzoesyre i 5 ml absolutt etanol på 50 mg palladium/kull (10%ig) ved 20°C og 1 bar hydrogen under risting. Efter 1,5 timer filtrerer man og inndamper"i vakuum. 100 mg (0.274.4 mmol) of 4-[(1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid is hydrogenated in 5 ml of absolute ethanol on 50 mg of palladium/coal (10%) at 20°C and 1 bar of hydrogen while shaking. After 1.5 hours, filter and evaporate in vacuo.

Utbytte: 91% av det teoretiskeYield: 91% of the theoretical

Smeltepunkt: 170-171°C.Melting point: 170-171°C.

Beregnet: m/e = 366Calculated: m/e = 366

Funnet: m/e = 366Found: m/e = 366

Eksempel 22 Example 22

4 - [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-semihydrat 4 - [ ( 1 - ( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid hemihydrate

Man hydrogenerer 200 mg (0,5015 mmol) 4-[ (l-'(5-klor-2-piperidino-fenyl)-etenyl)-aminokarbonylmetyl]-benzoesyre i 10 ml absolutt etanol på 100 mg palladium/kull (10%ig) ved 50°C og 1 bar hydrogen under risting. Efter 1,5 timer filtrerer man, tilsetter 5 ml vann og innstiller pH på 6 med IN natronlut og avdamper etanolen i vakuum. Det utfelles et farveløst bunnfall som man frafiltrerer efter avkjøling. 200 mg (0.5015 mmol) of 4-[(1-'(5-chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid is hydrogenated in 10 ml of absolute ethanol on 100 mg of palladium/charcoal (10% ig) at 50°C and 1 bar hydrogen with shaking. After 1.5 hours, filter, add 5 ml of water and adjust the pH to 6 with IN caustic soda and evaporate the ethanol in a vacuum. A colorless precipitate is precipitated which is filtered off after cooling.

Utbytte: 100 mg (53,1% av det teoretiske)Yield: 100 mg (53.1% of the theoretical)

Smeltepunkt: 135°C.Melting point: 135°C.

Eksempel 2 3 Example 2 3

4-[( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-etylester 4-[( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid ethyl ester

Til en blanding av 2 g (9,74 mmol) 1-(2-piperidino-feny1)-etanol og 4 g (21,1 mmol) 4-cyanometyl-benzoesyre-etylester setter man under omrøring og avkjøling med is 1,6 ml konsentrert svovelsyre i små dråper slik at den indre temperatur ikke over-stiger 35-40°C. Derefter oppvarmer man i 2,5 timer i et bad på 80°C, tilsetter derefter ytterligere 2 g (10,5 mmol) 4-cyano-metylbenzoesyre-etylester og 0,8 ml konsentrert svovelsyre og oppvarmer i ytterligere 1 time ved 80°C og 3 timer ved 100°C. Derefter kan utgangsalkohol ikke mer påvises tynnskiktkromatografisk. To a mixture of 2 g (9.74 mmol) 1-(2-piperidino-phenyl)-ethanol and 4 g (21.1 mmol) 4-cyanomethyl-benzoic acid ethyl ester, while stirring and cooling with ice, 1.6 ml of concentrated sulfuric acid in small drops so that the internal temperature does not exceed 35-40°C. It is then heated for 2.5 hours in a bath at 80°C, then a further 2 g (10.5 mmol) of 4-cyano-methylbenzoic acid ethyl ester and 0.8 ml of concentrated sulfuric acid are added and heated for a further 1 hour at 80° C and 3 hours at 100°C. After that, the starting alcohol can no longer be detected by thin-layer chromatography.

Efter avkjøling til 20°C dekker man over med et lag av etylacetat og tilsetter isvann under omrøring og avkjøling. Man.ekstraherer flere ganger med'etylacetat, tørrer den organiske ekstrakt over natriumsulfat, filtrerer og inndamper i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 10/1). Fra forfraksjonen isolerer man 0,5 g 2-piperidino-styren. After cooling to 20°C, cover with a layer of ethyl acetate and add ice water while stirring and cooling. The mixture is extracted several times with ethyl acetate, the organic extract is dried over sodium sulphate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1). 0.5 g of 2-piperidinostyrene is isolated from the preliminary fraction.

Utbytte: 0,66 g (17,4% av det teoretiske)Yield: 0.66 g (17.4% of the theoretical)

Smeltepunkt: 147-150°C (etanol).Melting point: 147-150°C (ethanol).

Eksempel 2 4 Example 2 4

4-[( 1-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 5- chloro- 2-piperidino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Til en omrørt oppløsning av 1 g (5,55 mmol) 4-karboksy-fenyl-eddiksyre og 1,32 g (5,55 mmol) 1-(5-klor-2-piperidino-fenyl)-etylamin i 10 ml absolutt pyridin setter man dråpevis 0,4 ml (.5,55 mmol) tionylklorid, hvorved den indre temperatur stiger' fra 20°C til 35°C. Den mørkebrune reaksjonsblanding omrører man i ytterligere 3 timer ved 20°C og inndamper den derefter i vakuum. Inndampningsresiduet fordeler man mellom vann (ved pH = 3 efter tilsetning av 2N saltsyre) og.kloroform. Den organiske ekstrakt tørrer og filtrerer man og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/metanol = 10/1). To a stirred solution of 1 g (5.55 mmol) of 4-carboxy-phenyl-acetic acid and 1.32 g (5.55 mmol) of 1-(5-chloro-2-piperidino-phenyl)-ethylamine in 10 ml of absolute pyridine, 0.4 ml (.5.55 mmol) of thionyl chloride is added dropwise, whereby the internal temperature rises from 20°C to 35°C. The dark brown reaction mixture is stirred for a further 3 hours at 20°C and then evaporated in vacuo. The evaporation residue is distributed between water (at pH = 3 after the addition of 2N hydrochloric acid) and chloroform. The organic extract is dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1).

Utbytte: 1,06 g (48% av det teoretiske). Yield: 1.06 g (48% of theoretical).

Smeltepunkt: 212-214°C (eter)Melting point: 212-214°C (ether)

Analogt med eksempel 2 4 ble følgende forbindelser oppnådd: 4- [ (. 1- ( 2- piperidino- fenyl) - etyl) - aminokarbonylmetyl] - benzoesyre Utbytte: 52% av det teoretiske Analogous to example 2 4, the following compounds were obtained: 4- [ (. 1- ( 2- piperidino-phenyl) - ethyl) - aminocarbonylmethyl] - benzoic acid Yield: 52% of the theoretical

Smeltepunkt: 16 9-171°CMelting point: 16 9-171°C

4- [ ( 1- ( 2-( 4- okso- piperidino)- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1- ( 2-( 4- oxo-piperidino)- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 32% av det teoretiskeYield: 32% of the theoretical

Smeltepunkt: 177-180°C (spaltn.) (aceton/petroleter)Melting point: 177-180°C (dec) (acetone/petroleum ether)

Beregnet: C 69,46, H 6,36, N 7,36 Funnet: 69,62 6,41 7,50 Calculated: C 69.46, H 6.36, N 7.36 Found: 69.62 6.41 7.50

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzonitril Fremstilt med 4-cyano-fenyleddiksyre. 4-[( 1-( 2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]- benzonitrile Prepared with 4-cyano-phenylacetic acid.

Utbytte: 51% av det teoretiskeYield: 51% of the theoretical

Smeltepunkt: 155-157°C (etylacetat)Melting point: 155-157°C (ethyl acetate)

Eksempel 25 Example 25

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzyl-alkohol 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzyl alcohol

Fremstilt fra 4-[ (1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester ved litiumaluminiumhydrid-reduksjon i tetrahydrofuran. Prepared from 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester by lithium aluminum hydride reduction in tetrahydrofuran.

Utbytte: 39% av det teoretiskeYield: 39% of the theoretical

Smeltepunkt: 104-106°C.Melting point: 104-106°C.

Eksempel 2 6 Example 2 6

4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzyl-malonsyre- dietylester 4- [ ( 1- ( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzyl malonic acid diethyl ester

Til en oppløsning av natrium-malonsyre-dietylester [tilberedt fra 0,7 g (30 mmol) natrium i 25 ml absolutt etanol og 4,8 g (30 mmol) malsyre-dietylester] setter man dråpevis en oppløsning av 3,7 g (10 mmol) 4-[(1-(2-piperidinb-feny1)-etyl)-aminokarbonylmety1]-benzylklorid [smeltepunkt: 123-125°C, fremstilt fra den i eksempel 25 beskrevne alkohol ved hjelp av tionylklorid i kloroform] i 35 ml absolutt etanol. Man tilsetter en katalytisk mengde kaliumjodid og oppvarmer i 16 timer til tilbakeløp. Derefter inndamper man i vakuum, nøytraliserer med saltsyre og ekstraherer med metylenklorid. Den organiske ekstrakt tørrer man over natriumsulfat, filtrerer og inndamper i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 6/1). Utbytte: 3,0 g (60% av det teoretiske). To a solution of sodium malonic acid diethyl ester [prepared from 0.7 g (30 mmol) sodium in 25 ml absolute ethanol and 4.8 g (30 mmol) malic acid diethyl ester] is added dropwise a solution of 3.7 g ( 10 mmol) 4-[(1-(2-piperidinb-phenyl)-ethyl)-aminocarbonylmethyl]-benzyl chloride [melting point: 123-125°C, prepared from the alcohol described in example 25 using thionyl chloride in chloroform] in 35 ml absolute ethanol. A catalytic amount of potassium iodide is added and heated to reflux for 16 hours. It is then evaporated in a vacuum, neutralized with hydrochloric acid and extracted with methylene chloride. The organic extract is dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6/1). Yield: 3.0 g (60% of the theoretical).

Smeltepunkt: < 20°CMelting point: < 20°C

Beregnet: m/e = 494Calculated: m/e = 494

Funnet: m/e =49 4Found: m/e =49 4

Eksempel 2 7 Example 2 7

3-[ 4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- fenyl]-propionsyre 3-[ 4-[( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- phenyl]- propionic acid

Til en oppløsning av 0,85 g (1,7 mmol) 4-[(1-(2-piperidino-fenyl) -etyl)-aminokarbonylmetyl]-benzylmalonsyre-dietylester i 18 ml etanol setter man 5 ml IN natronlut og omrører. i 2 timer ved 50°C. Derefter inndamper man i vakuum, tilsetter vann og 5 ml IN saltsyre. Det dannede bunnfall frafiltrerer man, tørrer det i vakuum og oppvarmer det derefter i 30 minutter til 120°C hvorved karbondioksyd avspaltes. Derefter renser To a solution of 0.85 g (1.7 mmol) 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzylmalonic acid diethyl ester in 18 ml of ethanol, 5 ml of 1N caustic soda is added and stirred. for 2 hours at 50°C. It is then evaporated in a vacuum, water and 5 ml IN hydrochloric acid are added. The precipitate formed is filtered off, dried in a vacuum and then heated for 30 minutes to 120°C, whereby carbon dioxide is released. Then cleanse

i in

man ved kolonnekromatografi på silikagel (kloroform/metanol = 20/1) . by column chromatography on silica gel (chloroform/methanol = 20/1).

Utbytte: 0,15 g (22,4% av det teoretiske)Yield: 0.15 g (22.4% of theoretical)

Smeltepunkt: 6 8-70°C.Melting point: 6 8-70°C.

Eksempel 2 8 Example 2 8

4-[( l-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-b enzaldehyd 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzaldehyde

Fremstilt ved oppvarmning av rått N"1"- [4- [ (1- (2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoyl]-N 2-tosy1-hydrazin [frémstilt fra 4-[(1-(2-piperidino-fenyl)-etyl)aminokarbonylmetyl]-benzoesyre og tosyl-hydrazin med karbonyldiimidazol i tetrahydrofuran] med vannfritt natriumkarbonat ved 160-170°C Prepared by heating crude N"1"- [4- [ (1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoyl]-N 2-tosy1-hydrazine [prepared from 4-[(1-( 2-piperidino-phenyl)-ethyl)aminocarbonylmethyl]-benzoic acid and tosylhydrazine with carbonyldiimidazole in tetrahydrofuran] with anhydrous sodium carbonate at 160-170°C

i etylenglykol.in ethylene glycol.

•Utbytte: 10% av det teoretiske•Yield: 10% of the theoretical

Smeltepunkt: 15 9°C.Melting point: 15 9°C.

Eksempel 2 9 Example 2 9

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Man hydrogenerer 0,50 g (1,247 mmol) 4-[(1-(5-klor-2-piperidinofenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i 20 ml absolutt etanol på 0,25 g palladium/kull (10%ig) ved 50°C og 5 bar hydrogentrykk. Efter 2 timer frafiltrerer man katalysatoren over "Celite" og inndamper i vakuum. Inndampningsresiduet fordeler man ved pH = 6 mellom vann og etylacetat. Den organiske ekstrakt vakser man med vann, tørrer og filtrerer og inndamper i vakuum. 0.50 g (1.247 mmol) of 4-[(1-(5-chloro-2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid is hydrogenated in 20 ml of absolute ethanol on 0.25 g of palladium/charcoal (10% ) at 50°C and 5 bar hydrogen pressure. After 2 hours, the catalyst is filtered off over "Celite" and evaporated in a vacuum. The evaporation residue is distributed at pH = 6 between water and ethyl acetate. The organic extract is diluted with water, dried and filtered and evaporated in a vacuum.

Utbytte: 0,31 g (67% av det teoretiske)Yield: 0.31 g (67% of theoretical)

Smeltepunkt: 170-172°C (eter)Melting point: 170-172°C (ether)

Analogt med eksempel 2 9 ble følgende forbindelser fremstilt: 4-[( 2-( 2- piperidino- fenyl)- 2— propyl)- aminokarbonylmetyl]-benzoesyre Analogous to example 29, the following compounds were prepared: 4-[(2-(2-piperidino-phenyl)-2-propyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 68,5% av det teoretiskeYield: 68.5% of the theoretical

Smeltepunkt: 213-215°C Melting point: 213-215°C

4-[( 1-( 2- dimetylamino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 2-Dimethylamino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 53,3% av det teoretiskeYield: 53.3% of the theoretical

Smeltepunkt: 165-168°C (aceton/petroleter) Melting point: 165-168°C (acetone/petroleum ether)

4-[( 2- pyrrolidino- benzyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 55% av det teoretiske, Smeltepunkt: 212-215°C (metanol) 4- [ ( 1- ( 2- pyrrolidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 25% av det teoretiske Smeltepunkt: 155-157°C (aceton/eter) 4- [ ( 2- piperidino- benzyl)- aminokarbonylmetyl]- benzoesyre Utbytte:. 60,4% av det teoretiske Smeltepunkt: 175-177°C (aceton) 4-[( 2- pyrrolidino- benzyl)- aminocarbonylmethyl]- benzoic acid Yield: 55% of the theoretical, Melting point: 212-215°C (methanol) 4- [ ( 1- ( 2- pyrrolidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 25% of the theoretical Melting point: 155-157°C (acetone/ether) 4- [ ( 2- piperidino-benzyl)- aminocarbonylmethyl]- benzoic acid Yield:. 60.4% of the theoretical Melting point: 175-177°C (acetone)

4- [ ( 2-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre Utbytte: 60,4% av det teoretiske 4- [ ( 2-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid Yield: 60.4% of the theoretical

Smeltepunkt: 164-166°C (etylacetat) Melting point: 164-166°C (ethyl acetate)

4-[( 1-( 2-( 2- metyl- piperidino)- feny1)- ety1)- aminokarbonyl metyl]-benzoesyre 4-[( 1-( 2-( 2- methyl-piperidino)- phenyl)- ethyl 1)- aminocarbonyl methyl]-benzoic acid

Utbytte: 90,9% av det teoretiskeYield: 90.9% of the theoretical

Smeltepunkt: 171-173°C (petroleter/aceton) Melting point: 171-173°C (petroleum ether/acetone)

4- [ ( 1-( 2-( 3- metyl- piperidino)- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4- [ ( 1-( 2-( 3- methyl- piperidino)- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Utbytte: 86,3% av det teoretiskeYield: 86.3% of the theoretical

Smeltepunkt: 170-173°C (petroleter/aceton) Melting point: 170-173°C (petroleum ether/acetone)

4- [ ( 1-( 2- dipropylamino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1-( 2- dipropylamino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 51,1% av det teoretiskeYield: 51.1% of the theoretical

Smeltepunkt: 175-178°C (etylacetat) Melting point: 175-178°C (ethyl acetate)

4 -[( 1-( 2- piperidino- fenyl)- 2- metyl- propyl)- aminokarbonylmetyl]-benzoesyre 4-[( 1-( 2- piperidino-phenyl)- 2- methyl- propyl)- aminocarbonylmethyl]-benzoic acid

Utbytte: 68% av det teoretiskeYield: 68% of the theoretical

Smeltepunkt: 215-217°C (aceton) Melting point: 215-217°C (acetone)

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-metylester Fremstilt fra 4-[(1-(5-klor-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl] -benzoesyre-metylester. 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid methyl ester Prepared from 4-[(1-(5-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid -methyl ester.

Utbytte: 37,2% av det teoretiskeYield: 37.2% of the theoretical

Smeltepunkt: 145-147°C. Melting point: 145-147°C.

4-[( 2- piperidino- anilino)- karbonylmetyl]- benzoesyre- metylester Fremstilt fra 4-[(5-klor-2-piperidino-anilino)-karbonylmetyl]-benzoesyre-metylester. 4-[(2-piperidino-anilino)-carbonylmethyl]-benzoic acid methyl ester Prepared from 4-[(5-chloro-2-piperidino-anilino)-carbonylmethyl]-benzoic acid methyl ester.

Utbytte: 60% av det teoretiske.Yield: 60% of the theoretical.

Smeltepunkt: 85-86°C (toluen/petroleter) Melting point: 85-86°C (toluene/petroleum ether)

N- fenacetyl- N-[ 1-( 2- piperidino- fenyl)- etyl]- amin Fremstilt fra N-[1-(S-klor-2-piperidino-fenyl)-etyl]-N-fenacetyl-amin. N-phenacetyl-N-[1-(2-piperidino-phenyl)-ethyl]-amine Prepared from N-[1-(S-chloro-2-piperidino-phenyl)-ethyl]-N-phenacetyl-amine.

Utbytte: 5 4,6% av det teoretiske, Yield: 5 4.6% of the theoretical,

Smeltepunkt: 120-121°C (petroleter/aceton). Melting point: 120-121°C (petroleum ether/acetone).

Eksempel 30 Example 30

4- [ ( 1- ( 5- amino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- metylester' 4- [ ( 1- ( 5- amino- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- methyl ester'

Man hydrogenerer 2,0 g (0,0047 mol) 4-[(1-(5-nitro-2-piperidinofenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-metylester i 20 ml dimetylformamid på 0,2 g palladium/kull (10%ig) i et Parr-apparat ved 20°C og 1 bar hydrogentrykk. Efter at hydrogenopptagelsen er opphørt (2 timer) frafiltrerer man katalysatoren over "Celite" og inndamper til tørrhet i vakuum. 2.0 g (0.0047 mol) of 4-[(1-(5-nitro-2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid methyl ester is hydrogenated in 20 ml of dimethylformamide on 0.2 g of palladium/charcoal ( 10%) in a Parr apparatus at 20°C and 1 bar hydrogen pressure. After the hydrogen uptake has ceased (2 hours), the catalyst is filtered off over "Celite" and evaporated to dryness in a vacuum.

Utbytte: 1,8 g (95% av det teoretiske)Yield: 1.8 g (95% of theoretical)

Smeltepunkt: 140-142°C (toluen)Melting point: 140-142°C (toluene)

Analogt med eksempel 30 ble følgende forbindelser fremstilt: 4-[( 1-( 5- amino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester Utbytte: 97,8% av det teoretiske Smeltepunkt: 148-149,5°C (cykloheksan) Analogous to example 30, the following compounds were prepared: 4-[( 1-( 5-amino- 2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester Yield: 97.8% of the theoretical Melting point: 148-149 .5°C (cyclohexane)

4- [ ( 1-( 5- amino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre 4- [ ( 1-( 5- amino- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid

Fremstilt fra 4-[ (1-(5-nitro-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre. Prepared from 4-[(1-(5-nitro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid.

Utbytte: 85.7% av det teoretiskeYield: 85.7% of the theoretical

Smeltepunkt: 223-225°C (eter) Melting point: 223-225°C (ether)

N-[ 4- amino- fenacetyl]- N-[ 1-( 2- piperidino- fenyl)- etyl]- amin-dihydroklorid- semihydrat N-[ 4- amino- phenacetyl]- N-[ 1-( 2- piperidino- phenyl)- ethyl]- amine dihydrochloride hemihydrate

Fremstilt fra N-[4-nitro-fenacetyl]-N- [1-(2-piperidino-fenyl)-etyl]-amin. Overføring av den rå amino-forbindelse til dihydrokloridet i etanol ved hjelp av eterisk saltsyre. Utbytte: 17,5% av det teoretiske. Prepared from N-[4-nitro-phenacetyl]-N-[1-(2-piperidino-phenyl)-ethyl]-amine. Transfer of the crude amino compound to the dihydrochloride in ethanol using ethereal hydrochloric acid. Yield: 17.5% of the theoretical.

Smeltepunkt: 238°C (spaltn.)Melting point: 238°C (dec.)

Eksempel 31 Example 31

4- [ ( 1- ( 5- brom- 2- piperidino- fenyl) - etyl) - aminokarbonylmetyl]_-benzoesyre 4-[(1-(5-bromo-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]_-benzoic acid

'Til 0,40 g (1,05 mmol) 4-[(1-(5-amino-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i 2 ml halvkonséntrert vandig bromhydrogensyre setter man dråpevis ved en indre temperatur på 0 til 5°C en oppløsning av 0,072 g (1,05 mmol) natriumnitritt i 0,5 ml vann. Den således oppnådde diazoniumsalt-oppløsning setter man derefter dråpevis til 0,196 g kobber(I)bromid i 2 ml 48%ig bromhydrogensyre, hvorved en kraftig gassutvikling følger. Man omrører i ytterligere 1,5 timer ved en indre temperatur på 45-50°C, avkjøler og innstiller pH-verdien på 4 med 4N natronlut. Man ekstraherer med varm. etylacetat, vasker ekstrakten med vann, tørrer og filtrerer den. Efter inndampning i vakuum renser man det erholdte residuum ved kolonnekromatografi på silikagel (kloroform/metanol = 7/1). To 0.40 g (1.05 mmol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 2 ml of semi-concentrated aqueous hydrobromic acid is added dropwise at an internal temperature at 0 to 5°C a solution of 0.072 g (1.05 mmol) of sodium nitrite in 0.5 ml of water. The diazonium salt solution thus obtained is then added dropwise to 0.196 g of copper (I) bromide in 2 ml of 48% hydrobromic acid, whereby a strong evolution of gas follows. The mixture is stirred for a further 1.5 hours at an internal temperature of 45-50°C, cooled and the pH value is adjusted to 4 with 4N caustic soda. One extracts with hot. ethyl acetate, wash the extract with water, dry and filter it. After evaporation in a vacuum, the residue obtained is purified by column chromatography on silica gel (chloroform/methanol = 7/1).

Utbytte: 0,08 g (17% av det teoretiske)Yield: 0.08 g (17% of theoretical)

Smeltepunkt: 212-213°C (etylacetat/petroleter)Melting point: 212-213°C (ethyl acetate/petroleum ether)

Analogt med eksempel 31 ble følgende forbindelse fremstilt: 4-[ ( 1-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre Analogous to example 31, the following compound was prepared: 4-[(1-(5-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Fremstilt ved diazotering av 4-[ (1-(5-amino-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i konsentrert HC1 og Sandmeyer-reaksjon med kobber(I)klorid. Prepared by diazotization of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in concentrated HCl and Sandmeyer reaction with copper (I) chloride.

Utbytte: 25,2% av det teoretiskeYield: 25.2% of the theoretical

Smeltepunkt: 213-215°C.Melting point: 213-215°C.

Hvis man utfører omsetningen i saltsyre uten kobber(I)-klorid, utgjør utbyttet 19% av det teoretiske. Dessuten dannes ytterligere 9% av den tilsvarende 5-hydroksy-forbindelse.n. If the reaction is carried out in hydrochloric acid without copper(I) chloride, the yield is 19% of the theoretical. Moreover, a further 9% of the corresponding 5-hydroxy compound is formed.n.

Eksempel 32 Example 32

4- [ ( 1- ( 5- jod- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1- ( 5- iodo- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid- ethyl ester

,Til 1,0 g (2,44 mmol) 4- [ (1-(5-amino-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester i 1,9 ml halvkonséntrert jodhydrogensyre setter man dråpevis under om-røring langsomt ved 0 til 5°C en oppløsning av 0,17 g (2,44 mmol) natriumnitritt i 0,52 ml vann og lar derefter blandingen opp-varmes til 20°C i løpet av 1 time. Derefter oppvarmer man i 2 timer ved 100°C. Efter avkjøling ekstraherer man med etylacetat, vasker den organiske fase med fortynnet natriumbikarbonat-oppløsning og derefter med vann, tørrer over natriumsulfat, filtrerer og inndamper i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 5/1). ,To 1.0 g (2.44 mmol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 1.9 ml of semi-concentrated hydroiodic acid is added dropwise under stirring slowly at 0 to 5°C a solution of 0.17 g (2.44 mmol) sodium nitrite in 0.52 ml water and then allowing the mixture to warm to 20°C over 1 hour. It is then heated for 2 hours at 100°C. After cooling, the mixture is extracted with ethyl acetate, the organic phase is washed with dilute sodium bicarbonate solution and then with water, dried over sodium sulphate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1).

Utbytte: 0,011 g (0,93% av det teoretiske)Yield: 0.011 g (0.93% of theoretical)

Smeltepunkt: 145-147°C (eter)Melting point: 145-147°C (ether)

Eksempel 3 3 Example 3 3

4- [ ( 1- ( 5- cyano- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4- [ ( 1- ( 5- cyano- 2-piperidino- phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid- ethyl ester

Til 2,0 g (4,88 mmol) 4-[(1-(5-amino-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester i 4,0 ml vann + 3,5 ml konsentrert saltsyre setter man dråpevis under omrøring ved -5 til 0°C en oppløsning av 0,34 g (4,88 mmol) natriumnitritt i 2,3 ml vann. Man omrører videre i 15 minutter og nøytraliserer derefter med 1,1 g kalsiumkarbonat. Den således oppnådde suspensjon spyler man ved hjelp av.2 x 15 ml vann inn i en 0°C kald oppløsning som man har tilberedt av 0,568 g To 2.0 g (4.88 mmol) 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 4.0 ml water + 3.5 ml conc. hydrochloric acid, a solution of 0.34 g (4.88 mmol) sodium nitrite in 2.3 ml of water is added dropwise while stirring at -5 to 0°C. The mixture is stirred for 15 minutes and then neutralized with 1.1 g of calcium carbonate. The thus obtained suspension is flushed using 2 x 15 ml of water into a 0°C cold solution which has been prepared from 0.568 g

(6,34 mmol) kobber(I)cyanid, 1,24 g (19 mmol) kaliumcyanid og 5,8 ml vann- Derved utfelles straks et rødfarvet bunnfall. Under omrøring oppvarmer man reaksjonsblandingen i 30 minutter ved en indre temperatur på 45°C, derefter i 30 minutter ved 70°C og 60 minutter ved 95°C. I tynnskiktkromatogrammer mangler nu den rødfarvede flekk som tidligere var til stede. Man avkjøler (6.34 mmol) copper(I) cyanide, 1.24 g (19 mmol) potassium cyanide and 5.8 ml of water - A red-colored precipitate immediately precipitates. While stirring, the reaction mixture is heated for 30 minutes at an internal temperature of 45°C, then for 30 minutes at 70°C and 60 minutes at 95°C. In thin-layer chromatograms, the red spot that was previously present is now missing. One cools down

til 20°C og ekstraherer med etylacetat. Den organiske ekstrakt tørrer man over natriumsulfat, filtrerer og inndamper den i vakuum. Inndampningsresiduet renser man ved to kolonne-kromatograf ibehandlinger på silikagel ((a) toluen/aceton = lp/l, (b) metylenklorid/acetonitril/iseddik = 10/1/0,05) . to 20°C and extract with ethyl acetate. The organic extract is dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is purified by two column chromatography treatments on silica gel ((a) toluene/acetone = lp/l, (b) methylene chloride/acetonitrile/glacial acetic acid = 10/1/0.05).

Ved siden av de tilsvarende 5-C1- og 5-H-forbindelser får man den ønskede 5-cyano-forbindelse. Next to the corresponding 5-C1 and 5-H compounds, the desired 5-cyano compound is obtained.

Utbytte: 0,186 g (9% av det teoretiske)Yield: 0.186 g (9% of theoretical)

Smeltepunkt: 165-167°C (eter)Melting point: 165-167°C (ether)

Eksempel 34 4- [ ( 1- ( 5- aminosulfonyl- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- etylester a) Til en suspensjon av 2,0 g (4,88 mmol) 4-[(1-(5-amino-2-piperidino-fenyl)-aminokarbonylmetyl]-benzoesyre-etylester i 2,02 ml halvkonséntrert saltsyre setter man dråpevis under omrøring ved 4 til 6°C en oppløsning av 0,37 g (5,36 mmol). natriumnitritt i 0,7 ml vann. Derefter tilsetter man 0,37 g (3,89 mmol) magnesiumklorid. Den således oppnådde blanding setter man derefter dråpevis ved 30°C til en oppløsning som man har tilberedt av 4,9 ml iseddik (mettet med svoveldioksyd) og 0,27 g kobber(II)klorid-dihydrat. Derved stiger den indre temperatur til 40°C, og nitrogen utvikles kraftig. Man omrører i ytterligere 15 minutter iet bad på 50°C, tilsetter derefter 7,5 ml vann og ekstraherer med kloroform. Den organiske ekstrakt tørrer man over natriumsulfat, filtrerer og inndamper i vakuum. Den viskøse, rødbrune inndampningsrest (2,7 g, noe kloroformholdig) inneholder ved siden av den tilsvarende 5- klor-forbindelse den ønskede 4-[(1-(5-klorsulfonyl-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester. b) Oppløsningen av den under a) oppnådde inndampningsrest i 10 ml kloroform setter man dråpevis ved 2°C under omrøring til 50 ml konsentrert ammoniakk. 30 minutter senere tilsetter man en mettet koksaltoppløsning for å oppnå faseseparering. Man ekstraherer påny med kloroform, tørrer og filtrerer den organiske ekstrakt og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/metanol = 10/1). Ved siden av 55% av den tilsvarende 5-klor-forbindelse får man den ønskede 5-aminosulfonyl-forbindelse som skum. Example 34 4-[(1-(5-aminosulfonyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester a) To a suspension of 2.0 g (4.88 mmol) 4-[(1 -(5-amino-2-piperidino-phenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 2.02 ml of semi-concentrated hydrochloric acid is added dropwise with stirring at 4 to 6°C a solution of 0.37 g (5.36 mmol) . sodium nitrite in 0.7 ml of water. 0.37 g (3.89 mmol) of magnesium chloride is then added. The mixture thus obtained is then added dropwise at 30°C to a solution that has been prepared from 4.9 ml of glacial acetic acid ( saturated with sulfur dioxide) and 0.27 g of copper(II) chloride dihydrate. The internal temperature thereby rises to 40°C, and nitrogen is strongly evolved. Stirring is carried out for a further 15 minutes in a bath at 50°C, then 7.5 ml of water and extract with chloroform. The organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. The viscous, red-brown evaporation residue (2.7 g, somewhat chloroform-containing) contains of the corresponding 5-chloro compound the desired 4-[(1-(5-chlorosulfonyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester. b) The solution of the evaporation residue obtained under a) in 10 ml of chloroform is added dropwise at 2°C with stirring to 50 ml of concentrated ammonia. 30 minutes later, a saturated sodium chloride solution is added to achieve phase separation. Extract again with chloroform, dry and filter the organic extract and evaporate it in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1). Next to 55% of the corresponding 5-chloro compound, the desired 5-aminosulfonyl compound is obtained as a foam.

Utbytte: 32% av det teoretiskeYield: 32% of the theoretical

Beregnet: m/e = 473Calculated: m/e = 473

Funnet: m/e = 473Found: m/e = 473

Eksempel 35 4-[( 1-( 5- dimetylamino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre Example 35 4-[(1-(5-Dimethylamino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Til en omrørt oppløsning av 0,20 g (0,5242 mmol) 4- [ (1-(5-amino-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre og 0,45 ml 40%ig formalin i 2 ml acetonitril + 1 ml absolutt dimetylformamid setter man ved 20°C 0,10 g (1,589 mmol) natfium-cyanborhydrid og efter 2 minutter 0,056 ml iseddik. Efter 1,5 timer inndamper man i vakuum. Inndampningsresiduet oppløser man i vann under tilsetning av saltsyre ved pH 2-3/ Efter flere gangers ekstraksjon med vann innstiller man den vandige fase med mettet natriumhydrogenkarbonat-oppløsning på To a stirred solution of 0.20 g (0.5242 mmol) 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and 0.45 ml of 40% formalin in 2 ml of acetonitrile + 1 ml of absolute dimethylformamide are added at 20°C to 0.10 g (1.589 mmol) of sodium cyanoborohydride and after 2 minutes 0.056 ml of glacial acetic acid. After 1.5 hours, it is evaporated in a vacuum. The evaporation residue is dissolved in water with the addition of hydrochloric acid at pH 2-3/ After several extractions with water, the aqueous phase is adjusted with saturated sodium bicarbonate solution to

pH 6-7 og ekstraherer flere ganger med kloroform. Denne organiske ekstrakt tørrer og filtrerer man. Efter inndampning i vakuum utkrystalliserer man inndampningsresiduet fra isopropanol.' De farveløse krystaller vasker man med absolutt eter. pH 6-7 and extract several times with chloroform. This organic extract is dried and filtered. After evaporation in vacuum, the evaporation residue is crystallized from isopropanol.' The colorless crystals are washed with absolute ether.

Utbytte: 0,09 g (42,8% av det teoretiske).Yield: 0.09 g (42.8% of theoretical).

Smeltepunkt: 185°C (spaltning fra 175°C)Melting point: 185°C (decomposition from 175°C)

Eksempel 3 6 Example 3 6

4- [ ( 1-( 5- acetylamino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4- [ ( 1-( 5- acetylamino- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Man omrører 0,10 g (0,262 mmol) 4-[(1-(5-amino-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i 1 ml eddiksyreanhydrid i 6 timer ved 20°C, inndamper derefter i vakuum, avdestillerer flere ganger med toluen og krystalliserer inndampningsresiduet fra eter. 0.10 g (0.262 mmol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid is stirred in 1 ml of acetic anhydride for 6 hours at 20°C, then evaporated in vacuum, distill off several times with toluene and crystallize the evaporation residue from ether.

Utbytte: 0,08 g (72,7% av det teoretiske).Yield: 0.08 g (72.7% of theoretical).

Smeltepunkt: 2 4.1-2 43°C.Melting point: 2 4.1-2 43°C.

Eksempel 37 Example 37

4- [ ( 1-( 5- benzoylamino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4- [ ( 1-( 5- benzoylamino- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Til en oppløsning av 1 g (2,62 mmol) 4-[ (1-(5-amino-2-piperidinofenyl)-etyl)-aminokarbonylmetyl]-benzoesyre og 0,37 ml (2,62 mmol) trietylamin i 10 ml vannfritt dimetylformamid setter man dråpevis 0,30 ml (2,62 mmol) benzoylklorid. Man omrører i 2 timer ved 20-30°C, inndamper i vakuum og fordeler mellom vann og etylacetat. Den organiske fase tørrer og filtrerer man og inndamper den i vakuum. Inndampningsresiduet (1,12 g) omkrystalliserer man fra etanol under tilsetning av aktivt kull. To a solution of 1 g (2.62 mmol) of 4-[(1-(5-amino-2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and 0.37 ml (2.62 mmol) of triethylamine in 10 ml anhydrous dimethylformamide, 0.30 ml (2.62 mmol) of benzoyl chloride is added dropwise. Stir for 2 hours at 20-30°C, evaporate in vacuo and distribute between water and ethyl acetate. The organic phase is dried and filtered and evaporated in a vacuum. The evaporation residue (1.12 g) is recrystallized from ethanol with the addition of activated charcoal.

Utbytte: 0,5 g (39,4% av det teoretiske).Yield: 0.5 g (39.4% of the theoretical).

Smeltepunkt: 225-227°C.Melting point: 225-227°C.

Analogt med eksempel 37 ble følgende forbindelse fremstilt: 4- [ ( 1-( 5- etoksykarbonylamino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre Analogous to example 37, the following compound was prepared: 4-[(1-(5-ethoxycarbonylamino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Utbytte: 34,2% av det teoretiskeYield: 34.2% of the theoretical

Smeltepunkt: 220°C (spaltn.)Melting point: 220°C (splitting)

Eksempel 38 Example 38

4- [ ( 1- ( 5- metylsulfonylamino- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre 4- [ ( 1- ( 5- methylsulfonylamino- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid

Til en oppløsning av 0,10 g (0,262 mmol) 4-[ (1-(5-amino-2-piperidino-fenyl)-ety1)-aminokarbonylmetyl]-benzoesyre i 1 ml vannfritt pyridin setter man 0,20 ml (0,262 mmol) mesylklorid. Efter opphør av den eksoterme reaksjon lar man det hele stå i ytterligere 4 timer ved 20°C. Inndampningsresiduet fordeler man ved pH 2-3 mellom vann og kloroform. Den sure, vandige fase innstiller man på pH 6 til 7 med natriumhydrogenkarbonat-oppløsning.og ekstraherer med.kloroform. Denne kloroform-ekstrakt tørrer og filtrerer man. Det ved inndampning i vakuum oppnådde residuum renser man ved kolonnekromatografi på silikagel (kloroform/metanol = 4/1). 0.20 ml (0.262 mmol) mesyl chloride. After the end of the exothermic reaction, the whole is allowed to stand for a further 4 hours at 20°C. The evaporation residue is distributed at pH 2-3 between water and chloroform. The acidic, aqueous phase is adjusted to pH 6 to 7 with sodium bicarbonate solution and extracted with chloroform. This chloroform extract is dried and filtered. The residue obtained by evaporation in vacuum is purified by column chromatography on silica gel (chloroform/methanol = 4/1).

Utbytte: 0,03 g (25% av det teoretiske).Yield: 0.03 g (25% of the theoretical).

Smeltepunkt: 210-220°C (spaltn.) (eter)Melting point: 210-220°C (dec.) (ether)

Beregnet: Moltopp m/e = 45 9Calculated: Mole top m/e = 45 9

Funnet: m/e = 45 9Found: m/e = 45 9

Eksempel 39 4-[( 1-( 5- acetoksy- 2- piperidino-f eny1)- etyl)- aminokarbonylmetyl]-benzoesyre Example 39 4-[(1-(5-acetoxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid

Man oppvarmer 0,35 g (0,915 mmol) 4-[ (1-(5-hydroksy-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre sammen med 0,103 ml (1,098 mmol) eddiksyreanhydrid på dampbad og lar det hele stå i ytterligere 4 dager ved 20°C. Man omkrystalliserer fra metanol. 0.35 g (0.915 mmol) of 4-[(1-(5-hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid is heated together with 0.103 ml (1.098 mmol) of acetic anhydride on a steam bath and the whole stand for a further 4 days at 20°C. It is recrystallized from methanol.

Utbytte: 0,16 g (41,2% av det teoretiske)Yield: 0.16 g (41.2% of theoretical)

Smeltepunkt: 218-221°C.Melting point: 218-221°C.

Eksempel 40 Example 40

4- [ ( 1-( 5- metoksy- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- metylester 4- [ ( 1-( 5- methoxy- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid methyl ester

En oppløsning av 60 mg (0,157 mmol) 4-[(1-(5-hydroksy-2-piperidirio-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i 1 ml metanol (+ 1 dråpe vann) tilsettes dråpevis en eterisk diazometan-oppløsning inntil det ikke' lenger skjer noen gassutvikling. For å ødelegge overskudd av diazometan tilsettes 2N eddiksyre. Derefter inndamper man i vakuum. Inndampningsresiduet fordeler man mellom toluen/eter og fortynnet natronlut. Efter tørring, filtrering og inndampning av den organiske fase i vakuum renser man inndampningsresiduet ved kolonnekromatografi på silikagel A solution of 60 mg (0.157 mmol) of 4-[(1-(5-hydroxy-2-piperidirio-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 1 ml of methanol (+ 1 drop of water) is added dropwise to an ethereal diazomethane solution until no more gas evolution occurs. To destroy excess diazomethane, 2N acetic acid is added. It is then evaporated in a vacuum. The evaporation residue is divided between toluene/ether and diluted caustic soda. After drying, filtering and evaporating the organic phase in vacuum, the evaporation residue is purified by column chromatography on silica gel

(kloroform/metanol = 5/1).(chloroform/methanol = 5/1).

Utbytte: 27% av det teoretiskeYield: 27% of the theoretical

Smeltepunkt: skumMelting point: foam

Beregnet: Moltopp m/e = 410Calculated: Moltop m/e = 410

Funnet: m/e = 410Found: m/e = 410

Eksempel 41 4- [ ( 1-( 5- benzyloksy- 2- piperidino-fenyl)-e tyl)- aminok arbonyl-metyl] - benzoesyre- etylester Example 41 4-[(1-(5-benzyloxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester

Til en suspensjon av 1, 353 mmol natriumhydrid . (32,5 mgTo a suspension of 1.353 mmol sodium hydride. (32.5 mg

av en 50%ig suspensjon i olje) i 2 ml vannfritt dimetylformamid of a 50% suspension in oil) in 2 ml of anhydrous dimethylformamide

setter man dråpevis litt efter litt en oppløsning av 0,50 g (1,218 mmol) 4-[(1-(5-hydroksy-2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre-etylester i 10 ml vannfritt dimetylformamid. Efter 1,5 timers omrøring ved 20°C tilsetter man dråpevis 0,16 ml (1,353 mmol) benzylbromid, oppløst i 2,3 ml vannfritt dimetylformamid, og omrører i 16 timer ved 20°C. Efter inndampning i vakuum fordeler man mellom vann og eter. Den organiske ekstrakt tørrer og filtrerer man og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 10/1). a solution of 0.50 g (1.218 mmol) of 4-[(1-(5-hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 10 ml of anhydrous dimethylformamide is added dropwise. After stirring for 1.5 hours at 20°C, 0.16 ml (1.353 mmol) of benzyl bromide, dissolved in 2.3 ml of anhydrous dimethylformamide, is added dropwise and stirred for 16 hours at 20°C. After evaporation in a vacuum, partition between water and ether. The organic extract is dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Utbytte: 0,34 g (55,7% av det teoretiske)Yield: 0.34 g (55.7% of theoretical)

Smeltepunkt: 155-157°C (eter).Melting point: 155-157°C (ether).

Eksempel 42 Example 42

4-[( 1-( 5- aminokarbonyl- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl] - benzoesyre- etylester 4-[( 1-( 5- aminocarbonyl- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl] - benzoic acid ethyl ester

Man omrører 3,8 g (9,06 mmol) 4-[(1-(5-cyano-2-piperidino-fenyl)-ety1)-aminokarbonylmetyl]-benzoesyre-etylester og 38 g polyfosforsyre i 2,5 timer ved 80-90°C. Under avkjøling med is tilsetter man vann forsiktig. Man dekker det hele med et lag av etylacetat og gjør blandingen alkalisk med konsentrert ammoniakk. Den organiske fase vasker man med vann, tørrer den og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/metanol = 20/1). Utbytte: 1 g (25,2% av det teoretiske). 3.8 g (9.06 mmol) of 4-[(1-(5-cyano-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester and 38 g of polyphosphoric acid are stirred for 2.5 hours at 80 -90°C. While cooling with ice, add water carefully. The whole is covered with a layer of ethyl acetate and the mixture is made alkaline with concentrated ammonia. The organic phase is washed with water, dried and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 20/1). Yield: 1 g (25.2% of the theoretical).

Smeltepunkt: 188-189°C (etanol)Melting point: 188-189°C (ethanol)

Eksempel 4 3 Example 4 3

4- [ ( 1- ( 5- etoksykarbonyl- 2- piperidino- fenyl) - etyl)_- aminokarbonylmetyl]- benzoesyre- etylester 4- [ ( 1- ( 5- ethoxycarbonyl- 2- piperidino- phenyl)- ethyl)_- aminocarbonylmethyl]- benzoic acid- ethyl ester

I en til tilbakeløp oppvarmet oppløsning av 1,1 g (2,62 mmol) 4- [ (1- (5-cyano-2-piperidino-feny.l) -etyl) -aminokarbonylmetyl] - benzoesyre-etylester i 22 ml absolutt etanol leder man inn tørt hydrogenklorid inntil det efter 4 timer ikke lenger kan påvises noe nitril. Man inndamper i vakuum, tilsetter vann og eter og gjør blandingen alkalisk med natriumhydrogenkarbonat- oppløsning. Den fraskilte eterfase rister man en gang med vann, tørrer og filtrerer den og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel-(metylenklorid/acetonitril/iseddik = 10/1/0,05). In a reflux heated solution of 1.1 g (2.62 mmol) of 4-[(1-(5-cyano-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 22 ml of absolute ethanol, dry hydrogen chloride is introduced until after 4 hours no more nitrile can be detected. Evaporate in a vacuum, add water and ether and make the mixture alkaline with sodium bicarbonate solution. The separated ether phase is shaken once with water, dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (methylene chloride/acetonitrile/glacial acetic acid = 10/1/0.05).

Utbytte: 0,6 g (49,2% av det teoretiske).Yield: 0.6 g (49.2% of the theoretical).

Smeltepunkt: 136-138°C (eter)Melting point: 136-138°C (ether)

Eksempel 44 Example 44

4- [ ( 1- ( 2- ( 4- okso- piperidino)- fenyl)- ety1)- aminokarbonylmety1] - benzoesyre 4- [ ( 1- ( 2- ( 4- oxo-piperidino)- phenyl)- ethyl1)- aminocarbonylmethyl] - benzoic acid

En oppløsning av 2,9 g (6,86 mmol) 4-[ (1-(2-[1,4-dioksa-8-azaspiro [4,5 ].dekan-8-yl] -fenyl) -etyl) -aminokarbonylmetyl] - benzoesyre-semihydrat i 40 ml aceton innstiller man på pH = 2 ved tilsetning av'2N saltsyre. Efter 6 timers omrøring ved 50°C tilsetter man 5 dråper konsentrert saltsyre og lar det hele stå i 16 timer ved 20°C. Man inndamper i vakuum, tilsetter vann og etylacetat og innstiller på pH = 6 ved tilsetning av 2N ammoniakk. Man utrister flere ganger med etylacetat, vasker de samlede organiske ekstrakter med vann, tørrer og filtrerer dem og inndamper i vakuum. Inndampningsresiduet omkrystalliserer man fra aceton/petroleter. A solution of 2.9 g (6.86 mmol) of 4-[(1-(2-[1,4-dioxa-8-azaspiro[4,5].decan-8-yl]-phenyl)-ethyl) -aminocarbonylmethyl]-benzoic acid hemihydrate in 40 ml of acetone is adjusted to pH = 2 by adding 2N hydrochloric acid. After stirring for 6 hours at 50°C, 5 drops of concentrated hydrochloric acid are added and the whole mixture is allowed to stand for 16 hours at 20°C. Evaporate in a vacuum, add water and ethyl acetate and adjust to pH = 6 by adding 2N ammonia. The mixture is decanted several times with ethyl acetate, the combined organic extracts are washed with water, dried and filtered and evaporated in vacuo. The evaporation residue is recrystallized from acetone/petroleum ether.

Utbytte: 1,9 g (7 3,1% av det teoretiske).Yield: 1.9 g (7 3.1% of the theoretical).

Smeltepunkt: 177-180°C (spaltn.).Melting point: 177-180°C (dec.).

Eksempel 45 4- [ ( 1- ( 2-( 4- hydroksy- piperidino- fenyl)- etyl)- aminokarbonylmet yl]-benzoesyre x 0, 66 H^ O Tilen oppløsning av 1 g (2,63 mmol) 4- [(1- (2-(4-okso-piperidino) -fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i 20 ml absolutt etanol setter man under omrøring porsjonsvis 0,22 4 g (5,92 mmol) natriumborhydrid. Efter 1,5 timers omrøring ved romtemperatur surgjør man først med 2N saltsyre, inndamper i vakuum, tilsetter vann og etylacetat og innstiller på pH = 6 med 2N natronlut. Man ekstraherer flere ganger med etylacetat, tørrer og filtrerer ekstrakten og inndamper den i vakuum. Inndampningsresiduet krystalliserer man fra petroleter. Utbytte: 0,78 g (75% av det teoretiske), Smeltepunkt: 175-180°C (spaltn.) Example 45 4- [ ( 1- ( 2-( 4- hydroxy-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid x 0.66 H^O Thilene solution of 1 g (2.63 mmol) 4- [ (1-(2-(4-oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 20 ml of absolute ethanol, 0.22 4 g (5.92 mmol) of sodium borohydride are added in portions while stirring. After 1, After stirring for 5 hours at room temperature, first acidify with 2N hydrochloric acid, evaporate in vacuum, add water and ethyl acetate and adjust to pH = 6 with 2N caustic soda. Extract several times with ethyl acetate, dry and filter the extract and evaporate it in vacuum. The evaporation residue is crystallized from petroleum ether Yield: 0.78 g (75% of theory), Melting point: 175-180°C (dec.)

Eksempel 46 Example 46

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- bénzoesyre-propylester 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid propyl ester

Til en oppløsning av 2 g (5,46 mmol) 4-[(1-(2-piperidino-fenyl)-ety 1)-aminokarbony lmety 1 ]-benzoesyre i 20 ml absolutt tetrahydrofuran setter man 0,94 g (5,80 mmol) karbonyldiimidazol og oppvarmer i 30 minutter under tilbakeløpskjøling under utelukkelse av fuktighet. Derefter tilsetter man 1,64 ml (22 mmol) 1-propanol, omrører i 18 timer ved 20°C og oppvarmer i ytterligere 8 timer til tilbakeløp. Derefter inndamper man i vakuum og renser inndampningsresiduet ved kolonnekromatografi på silikagel (toluen/aceton = 10/1). 0.94 g (5, 80 mmol) of carbonyldiimidazole and heat for 30 minutes under reflux while excluding moisture. 1.64 ml (22 mmol) of 1-propanol are then added, stirred for 18 hours at 20°C and heated for a further 8 hours to reflux. It is then evaporated in a vacuum and the evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Utbytte: 1,3 g (58,3% av det teoretiske).Yield: 1.3 g (58.3% of the theoretical).

Smeltepunkt: 150-151°C (etylacetat). Melting point: 150-151°C (ethyl acetate).

Analogt med eksempel 46 ble følgende forbindelser oppnådd': 4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-is opropylester Analogous to example 46, the following compounds were obtained': 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid isopropyl ester

Utbytte: 45% av det teoretiske.Yield: 45% of the theoretical.

Smeltepunkt: 141-143°C (eter). Melting point: 141-143°C (ether).

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-butylester 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid butyl ester

Utbytte: 4 9% av det teoretiskeYield: 4 9% of the theoretical

Smeltepunkt: 148°C (eter/toluen). Melting point: 148°C (ether/toluene).

4-[( 1-( 5- klor- 2-piper idino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- etylester 4-[( 1-( 5- chloro- 2-piper idino-phenyl)- ethyl)- aminocarbonylmethyl]-benzoic acid ethyl ester

Utbytte: 41% av det teoretiskeYield: 41% of the theoretical

Smeltepunkt: 130-133°C (eter). Melting point: 130-133°C (ether).

4- [ ( 1-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- butylester 4- [ ( 1-( 5- chloro- 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid- butyl ester

Utbytte: 30,7% av det teoretiskeYield: 30.7% of the theoretical

Smeltepunkt: 115-118°CMelting point: 115-118°C

4-[( 1-( 5- klor- 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]-benzoesyre- tert. butylester 4-[(1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid tert. butyl ester

Utbytte: 1% av det teoretiskeYield: 1% of the theoretical

Beregnet: Moltopp m/é = 45 6/8Calculated: Moletop m/é = 45 6/8

Funnet: m/e = 45 6/8 Found: m/e = 45 6/8

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-( 2- metoksy- etylester) 4-[( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-( 2- methoxy- ethyl ester)

Utbytte: 56% av det teoretiskeYield: 56% of the theoretical

Smeltepunkt: 155-157°C (etylacetat)Melting point: 155-157°C (ethyl acetate)

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-[ ( 2, 2- dimetyl- dioksolan- 4- yl)- metyl]- ester 4-[( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-[ ( 2, 2- dimethyl- dioxolan-4- yl)- methyl]- ester

Utbytte: 30,5% av det teoretiskeYield: 30.5% of the theoretical

Smeltepunkt: 110-112°C (eter)Melting point: 110-112°C (ether)

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-benzylester 4-[( 1-( 2-piperidino-phenyl)-ethyl)- aminocarbonylmethyl]- benzoic acid benzyl ester

Utbytte: 73,7% av det teoretiskeYield: 73.7% of the theoretical

Smeltepunkt: 126-128°C (etylacetat)Melting point: 126-128°C (ethyl acetate)

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-( 2- hydroksy- etyl)- ester 4- [ ( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-( 2- hydroxy- ethyl)- ester

Efter tilsetning av 10 ekvivalenter etylenglykol ble oppvarmning under tilbakeløpskjøling foretatt i 17 timer.. After adding 10 equivalents of ethylene glycol, heating under reflux cooling was carried out for 17 hours.

Utbytte: 71,4% av det teoretiske.Yield: 71.4% of the theoretical.

Smeltepunkt: 128-129°C (etylacetat/e.ter) .Melting point: 128-129°C (ethyl acetate/ether).

1, 2- bis- [ 4- [ ( 1-( 2- piperidino- fenyl)-e tyl)- ami nokarbonylmetyl]-benzoyloksy] etan 1, 2-bis-[4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoyloxy] ethane

Efter tilsetning av 0,5 ekvivalenter etylenglykol ble opp-varming til tilbakeløp foretatt i l'7 timer. After the addition of 0.5 equivalents of ethylene glycol, heating to reflux was carried out for 17 hours.

Utbytte: 43,5% av det teoretiskeYield: 43.5% of the theoretical

Smeltepunkt: 188-191°C (toluen)Melting point: 188-191°C (toluene)

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-( 2- dietylamino- etyl)- ester 4- [ ( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-( 2- diethylamino- ethyl)- ester

Utbytte: 5 6,7% av det teoretiskeYield: 5 6.7% of the theoretical

Smeltepunkt: 99-101°C (petroleter)Melting point: 99-101°C (petroleum ether)

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-[ 2-( 1, 3- dimetyl- xantin- 7- yl)- etyl]- ester 4-[( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-[ 2-( 1, 3- dimethyl-xanthine- 7- yl)- ethyl]- ester

Som oppløsningsmiddel ble anvendt absolutt pyridin. Efter tilsetning av 1 ekvivalent 7-(2-hydroksy-etyl)-teofyllin og efter tilsetning av et ganske lite stykke metallisk natrium fant omrøring sted i 4 timer i et bad. på. 130°C. Absolute pyridine was used as solvent. After adding 1 equivalent of 7-(2-hydroxyethyl)-theophylline and after adding a rather small piece of metallic sodium, stirring took place for 4 hours in a bath. on. 130°C.

Utbytte: 40,9% av det teoretiskeYield: 40.9% of the theoretical

Smeltepunkt: 121-123°C (eter)Melting point: 121-123°C (ether)

Eksempel 47 Example 47

4-[ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-metylester 4-[(1-(2- piperidino-phenyl)-ethyl)- aminocarbonylmethyl]- benzoic acid methyl ester

Man oppvarmer en blanding av 2 g (5,46 mmol) 4-[(l-(2-piperidinofenyl)-etyl)-aminokarbonylmetyl]-benzoesyre, A mixture of 2 g (5.46 mmol) of 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid is heated,

0,53 g metanol, 0,38 ml konsentrert svovelsyre og 1,65 ml 1,2-dikloretan i 24 timer til tilbakeløpstemperatur, inndamper den i vakuum, oppløser den i kloroform og utrister med fortynnet natriumhydrogenkarbonat-oppløsning. Den organiske vase vasker man med vann, tørrer og filtrerer og inndamper i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på 0.53 g of methanol, 0.38 ml of concentrated sulfuric acid and 1.65 ml of 1,2-dichloroethane for 24 hours at reflux temperature, evaporate it in vacuo, dissolve it in chloroform and decant with dilute sodium bicarbonate solution. The organic vase is washed with water, dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography

silikagel (toluen/aceton = 5/1). silica gel (toluene/acetone = 5/1).

Utbytte: 0,93 g (44,8% av det teoretiske) Yield: 0.93 g (44.8% of the theoretical)

Smeltepunkt: 146-147°CMelting point: 146-147°C

Eksempel 4 8 Example 4 8

4-[( 2-( 2- piperidino- fenyl)- 2- propyl)- aminokarbonylm etyl]-benzoesyre- etylester 4-[( 2-( 2- piperidino-phenyl)- 2- propyl)- aminocarbonyl methyl]-benzoic acid ethyl ester

Man omrører 0,20 g (0,526 mmol) 4-[(2-(2-piperidino-fenyl)-2-propyl)-aminokarbonylmetyl]-benzoesyre og 2 ml 4N etanolisk saltsyre ved 20°C. Efter 36 timer inndamper man i vakuum og fordeler inndampningsresiduet mellom vann (ved pH = 8 ved tilsetning av 10%ig ammoniakk) og etylacetat. Man vasker den organiske fase med vann, tørrer og filtrerer den og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 10/1). 0.20 g (0.526 mmol) of 4-[(2-(2-piperidino-phenyl)-2-propyl)-aminocarbonylmethyl]-benzoic acid and 2 ml of 4N ethanolic hydrochloric acid are stirred at 20°C. After 36 hours, evaporate in a vacuum and distribute the evaporation residue between water (at pH = 8 with the addition of 10% ammonia) and ethyl acetate. The organic phase is washed with water, dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Utbytte: 0,079 g (36,7% av det teoretiske).Yield: 0.079 g (36.7% of theoretical).

Smeltepunkt: 151-153°C (eter)Melting point: 151-153°C (ether)

Eksempel 49 Example 49

4- [ ( 1- ( 2- piperidino- fenyl) - etyl)-- aminokarbonylmetyl] - ben zoesyre-tert. butylester 4-[(1-(2-piperidino-phenyl)-ethyl)--aminocarbonylmethyl]-benzoic acid-tert. butyl ester

Man omrører en blanding av 3,60 g (17,4 mmol) N,N<1->dicyklo-heksylkarbodiimid, 1,9 ml (20,4 mmol) tert.butanol og 0,036 g (0,36 mmol) kobber(I)klorid i 3 dager ved romtemperatur, tilsetter derefter 12 ml metylenklorid og setter den således oppnådde oppløsning dråpevis til en oppløsning av 2 g (5,46 mmol). 4- [ (1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre i 80 ml metylenklorid. Efter 16 timers omrøring ved 20°C frafiltrerer man utfelt bunnfall, vasker med metylenklorid og inndamper metylenklorid-oppløsningen i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (toluen/aceton = 15/1). A mixture of 3.60 g (17.4 mmol) N,N<1->dicyclohexylcarbodiimide, 1.9 ml (20.4 mmol) tert-butanol and 0.036 g (0.36 mmol) copper ( I) chloride for 3 days at room temperature, then add 12 ml of methylene chloride and add the solution thus obtained dropwise to a solution of 2 g (5.46 mmol). 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 80 ml of methylene chloride. After stirring for 16 hours at 20°C, the precipitate is filtered off, washed with methylene chloride and the methylene chloride solution is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 15/1).

Utbytte: 0,45 g (19,7% av det teoretiske).Yield: 0.45 g (19.7% of the theoretical).

Smeltepunkt: 125-127°C (eter)Melting point: 125-127°C (ether)

Eksempel 50 Example 50

4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-( 2- nikotinoyloksy- etyl)- ester 4-[( 1-( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid-( 2- nicotinoyloxy- ethyl)- ester

Til en oppløsning av 0,45 g (1,10 mmol) 4-[(1-(2-piperidino-fenyl) -etyl)-aminokarbonylmetyl]-benzoesyre-(2-hydroksyetyl)-ester og 0,16 ml (1,16 mmol) trietylamin i .10 ml metylenklorid setter man dråpevis litt efter litt en oppløsning av 0,16 g (1,13 mmol) nikotinsyreklorid i. 5 ml metylenklorid. Efter 4 timers omrøring ved 20°C utrister man med vann, tørrer og filtrerer metylenklorid-oppløsningen og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/aceton = 3/1). To a solution of 0.45 g (1.10 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid-(2-hydroxyethyl)-ester and 0.16 ml (1 .16 mmol) of triethylamine in .10 ml of methylene chloride is added drop by drop a solution of 0.16 g (1.13 mmol) of nicotinic acid chloride in .5 ml of methylene chloride. After stirring for 4 hours at 20°C, decant with water, dry and filter the methylene chloride solution and evaporate it in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone = 3/1).

Utbyjtte: 0,34 g (60% av det teoretiske)Yield: 0.34 g (60% of theoretical)

Smeltepunkt: 103-105°C (eter)Melting point: 103-105°C (ether)

Eksempel 51 Example 51

. 4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzamid . 4-[( 1-( 2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzamide

Til 4,76 g (0,013 mol) 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmety1]-benzoesyre i 60 ml absolutt pyridin setter man 2,3 g (0,0142 mol) karbonyldiimidazol og oppvarmer derefter To 4.76 g (0.013 mol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 60 ml of absolute pyridine is added 2.3 g (0.0142 mol) of carbonyldiimidazole and heated thereafter

i 45 minutter til 50°C. Efter avkjøling i et karbonsyre-metanol-bad tilsetter man 7 ml flytende ammoniakk og oppvarmer blandingen-i autoklav i 20 timer til 80°C. Derefter avkjøler man reaksjonsblandingen og inndamper den i vakuum. Residuet oppløser man for 45 minutes at 50°C. After cooling in a carbonic acid-methanol bath, 7 ml of liquid ammonia is added and the mixture is heated in an autoclave for 20 hours to 80°C. The reaction mixture is then cooled and evaporated in vacuo. The residue is dissolved

i 50 ml varm metanol, setter 200 ml vann til dette og lar det hele stå natten over. Det krystallinske bunnfall avsuges og omkrystalliseres fra metanol under tilsetning av aktivt kull. Utbytte: 3,5 g (73,6% av det teoretiske). in 50 ml of hot methanol, add 200 ml of water to this and let it all stand overnight. The crystalline precipitate is suctioned off and recrystallized from methanol while adding activated carbon. Yield: 3.5 g (73.6% of the theoretical).

Smeltepunkt: 197-199°CMelting point: 197-199°C

Eksempel 52 4-[ ( 1-( 2- piperidino- fenyl)- etyl)-a minokarbonylmetyl]-N-metyl-benzamid Example 52 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-N-methyl-benzamide

Man oppvarmer 2 g (5,46 mmol) 4-[(1- (2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre og 0,94 g (5,80 mmol) karbonyldiimidazol i 20 ml absolutt pyridin i 1 time til tilbakeløpstemperatur. Derefter tilsetter man 0,41 g (6,07 mmol) metylaminhydroklorid og omrører i 1 time ved 20°C og i 2 timer under tilbakeløpskjøling. Man inndamper i vakuum, fordeler mellom vann og metylenklorid, tørrer og filtrerer den organiske ekstrakt og inndamper den i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/metanol/ konsentrert ammoniakk = 10/1/0,05). 2 g (5.46 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and 0.94 g (5.80 mmol) of carbonyldiimidazole are heated in 20 ml of absolute pyridine in 1 hour to reflux temperature. 0.41 g (6.07 mmol) methylamine hydrochloride is then added and stirred for 1 hour at 20°C and for 2 hours under reflux cooling. One evaporates in a vacuum, distributes between water and methylene chloride, dries and filters the organic extract and evaporates it in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol/concentrated ammonia = 10/1/0.05).

Utbytte: 1,7 g (82% av det teoretiske)Yield: 1.7 g (82% of theoretical)

Smeltepunkt: 218-220°C (isopropanol) Melting point: 218-220°C (isopropanol)

Analogt med eksempel 52 ble følgende forbindelse fremstilt: 4-[ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- N, N- dimetyl-benzamid Analogous to example 52, the following compound was prepared: 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-N,N-dimethyl-benzamide

Utbytte: 52,5% av det teoretiskeYield: 52.5% of the theoretical

Smeltepunkt: 14 8-150°C (etylacetat) Melting point: 14 8-150°C (ethyl acetate)

Eksempel 5 3 Example 5 3

4- [ ( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- N- butyl-benzamid 4- [ ( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- N- butyl-benzamide

Til en oppløsning av 2 g (5 ,46 mmol) 4-[(1- (2-piperidino-fenyl) -etyl)-aminokarbonylmetyl]-benzoesyre i 20 ml absolutt tetrahydrofuran setter man 0,94 g (5,80 mmol) karbonyldiimidazol. Man oppvarmer i 30 minutter til tilbakeløps-temperatur, tilsetter 0,44 g (6,1 mmol) 1-butylamin og oppvarmer i 2 timer til tilbakeløp. Man inndamper i vakuum og renser inndampningsresiduet ved kolonnekromatografi på silikagel (kloroform/aceton = 6/1). To a solution of 2 g (5.46 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 20 ml of absolute tetrahydrofuran is added 0.94 g (5.80 mmol) carbonyldiimidazole. It is heated for 30 minutes to reflux temperature, 0.44 g (6.1 mmol) of 1-butylamine is added and heated for 2 hours to reflux. Evaporate in a vacuum and purify the evaporation residue by column chromatography on silica gel (chloroform/acetone = 6/1).

Utbytte: 1,65 g (71,7% av det teoretiske)Yield: 1.65 g (71.7% of the theoretical)

Smeltepunkt: 178-181°C (etylacetat) Melting point: 178-181°C (ethyl acetate)

Analog't med eksempel 5 3 ble følgende forbindelser oppnådd: 4-[( 1-( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-piperidid Analogously to example 5 3, the following compounds were obtained: 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid piperidide

Utbytte: 7 3,8% av det teoretiskeYield: 7 3.8% of the theoretical

Smeltepunkt: 131-133°C (toluen)Melting point: 131-133°C (toluene)

4-[( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzoesyre-morfolid 4-[( 1-( 2- piperidino-phenyl)- ethyl)- aminocarbonylmethyl]- benzoic acid morpholide

Utbytte: 60,5% av det teoretiskeYield: 60.5% of the theoretical

Smeltepunkt: 148-150°C (etylacetat/eter)Melting point: 148-150°C (ethyl acetate/ether)

Eksempel 5 4 Example 5 4

4- [ ( 1- ( 2- piperidino- fenyl)- etyl)- aminokarbonylmetyl]- benzonitril 4- [ ( 1- ( 2- piperidino- phenyl)- ethyl)- aminocarbonylmethyl]- benzonitrile

Til en blanding av 2,19 g (6 mmol) 4-[(1-(2-piperidino-fenyl) -ety 1) -aminokarbonylmetyl] -benzamid og 1,07 g (13,5 mmol) absolutt pyridin setter man ved romtemperatur under omrøring 1,14 g (6 mmol) p-toluensulfonsyreklorid i 2 porsjoner. Man omrører i 15 minutter ved 20°C og derefter i 2 timer ved 50°C. Efter avkjøling tilsetter man vann, gjør blandingen alkalisk med konsentrert ammoniakk og ekstraherer 3 ganger med kloroform. To a mixture of 2.19 g (6 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl 1)-aminocarbonylmethyl]-benzamide and 1.07 g (13.5 mmol) of absolute pyridine is added at room temperature with stirring 1.14 g (6 mmol) p-toluenesulfonic acid chloride in 2 portions. The mixture is stirred for 15 minutes at 20°C and then for 2 hours at 50°C. After cooling, water is added, the mixture is made alkaline with concentrated ammonia and extracted 3 times with chloroform.

De samlede kloroformekstrakter vaskes med vann, tørres over natriumsulfat, filtreres og inndampes i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/etylacetat - 4/1). The combined chloroform extracts are washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethyl acetate - 4/1).

Utbytte: 1,15 g (55,3% av dét teoretiske).Yield: 1.15 g (55.3% of the theoretical).

Smeltepunkt: 155-157°C (etylacetat)Melting point: 155-157°C (ethyl acetate)

Claims (3)

1. Analogifremgangsmåte for fremstilling av terapeutisk aktive karboksylsyreamider med den generelle formel 1. Analogous method for the preparation of therapeutically active carboxylic acid amides of the general formula hvor og R2 , som kan være like eller forskjellige, betyr alkyl grupper med 1 til 6 karbonatomer eller cykloalkylgrupper med 5 til 7 karbonatomer, eller R^ og R2 sammen med det mellomliggende nitrogenatom betyr en uforgrenet alkyleniminogruppe med 3 til 6 karbonatomer som kan være substituert med én eller to alkylgrupper med hver 1 til 3 karbonatomer eller med en hydroksygruppe, eller hvor en metylengruppe kan være erstattet med en karbonylgruppe, med et oksygen- eller svovelatom eller med en iminogruppe -som kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en aralkylgruppe med 7 til 10 karbonatomer, en fenyl- eller halogenfenylgruppe, eller hvor en etylen gruppe kah være erstattet med en o-fenylengruppe; en uforgrenet alkenyleniminogruppe med 4 til 6 karbonatomer, en mettet eller delvis umettet azabicykloalkylgruppe med 6 til 10 karbonatomer, en aza-1,4-dioksa-spiro-alkylgruppe med 6 til 8 karbonatomer, en heptametylenimino-, oktametylenimino-, nonametylenimino- eller dekametyleniminogruppe, R^ betyr et hydrogen- eller halogenatom, en trifluormetyl-, alkyl-, hydroksy-, alkoksy-, alkanoyloksy-, merkapto-, alkylmerkapto-, nitro-, amino-, cyano-, alkanoyl-, karboksy-, alkoksykarbonyl-, aminokarbonyl-, alkylaminokarbonyl-, dialkylaminokarbonyl-, aminosulfonyl-, alkylamino-, dialkylamino-, alkanoylamino-, alkoksykarbonylamino- eller alkylsulfonylaminogruppe, hvor hver alkyldel i de ovennevnte grupper kan inneholde 1 til 3 karbonatomer, en aralkoksygruppe med 7 til 10 karbonatomer eller en arylkarbonylaminogruppe, betyr et hydrogenatom eller en alkylgruppe med 1 til 3 karbon atomer, R,- betyr et hydrogenatom, et halogenatom eller en alkylgruppe med 1 til 3 karbonatomer, A betyr en binding, en eventuelt med en alkylgruppe med 1 til 5 karbonatomer substituert metylen- eller etylengruppe, en med to alkylgrupper med hver 1 til 3 karbonatomer substituert metylen- eller etylengruppe, en med en cykloalkylgruppe med 3 til 7 karbonatomer, med en hydroksyalky1-, alkoksyalkyl-, - cyano-, karboksyl-, alkoksykarbonyl-, aminokarbonyl-, alkylaminokarbonyl-, dialkylaminokarbonyl-, aryl- eller aralkylgruppe substituert metylengruppe, hvor hver av de ovennevnte alkyldeler kan inneholde 1 til 3 karbonatomer; en cykloalkylidengruppe med 3 til 7 karbonatomer eller en vinylidengruppe med formelen where and R 2 , which may be the same or different, means alkyl groups with 1 to 6 carbon atoms or cycloalkyl groups with 5 to 7 carbon atoms, or R 1 and R 2 together with the intervening nitrogen atom mean an unbranched alkyleneimino group of 3 to 6 carbon atoms which may be substituted by one or two alkyl groups of each 1 to 3 carbon atoms or by a hydroxy group, or where a methylene group may be replaced by a carbonyl group, with an oxygen or sulfur atom or with an imino group -which may be substituted with an alkyl group of 1 to 3 carbon atoms, an aralkyl group of 7 to 10 carbon atoms, a phenyl or halophenyl group, or where an ethylene group kah be replaced by an o-phenylene group; an unbranched alkenylenimino group of 4 to 6 carbon atoms, a saturated or partially unsaturated azabicycloalkyl group of 6 to 10 carbon atoms, an aza-1,4-dioxa-spiro-alkyl group of 6 to 8 carbon atoms, a heptamethyleneimino, octamethyleneimino, nonamethyleneimino or decamethyleneimino group, R^ means a hydrogen or halogen atom, a trifluoromethyl-, alkyl-, hydroxy-, alkoxy-, alkanoyloxy-, mercapto-, alkyl mercapto-, nitro-, amino-, cyano-, alkanoyl, carboxy-, alkoxycarbonyl, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, aminosulfonyl-, alkylamino-, dialkylamino-, alkanoylamino-, alkoxycarbonylamino or alkylsulfonylamino group, where each alkyl moiety in the above mentioned groups may contain 1 to 3 carbon atoms, an aralkyl group with 7 to 10 carbon atoms or an arylcarbonylamino group, means a hydrogen atom or an alkyl group of 1 to 3 carbons atoms, R,- means a hydrogen atom, a halogen atom or an alkyl group with 1 to 3 carbon atoms, A means a bond, a methylene or ethylene group optionally substituted by an alkyl group with 1 to 5 carbon atoms, one with two alkyl groups with each 1 to 3 carbon atoms substituted methylene or ethylene group, one with a cycloalkyl group with 3 to 7 carbon atoms, with a hydroxyalkyl1-, alkoxyalkyl-, - cyano-, carboxyl-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl, aryl or aralkyl group substituted methylene group, where each of the above alkyl moieties may contain 1 to 3 carbon atoms; a cycloalkylidene group with 3 to 7 carbon atoms or a vinylidene group with the formula hvor R, og R_, som kan være like eller forskjellige, er hydrogenatomer eller alkylgrupper med hver 1 til 3 karbonatomer eller også en av restene Rg eller Ry en cykloalkylgruppe med 3 til .7 karbonatomer, en aryl-eller aralkylgruppe, eller Rg og R^ sammen med det mellom liggende karbonatom er en cykloalkylidenrest med 5 til 7 karbonatomer, B betyr en eventuelt med- en alkylgruppe med 1 til 3 karbonatomer substituert metylen- eller etylengruppe, og W betyr et hydrogen- eller halogenatom, en nitrogruppe, en eventuelt med en alkanoylgruppe med 1 til 3 karbonatomer substituert aminogruppe, en eventuelt med en hydroksy-, karboksy- eller alkoksykarbonylgruppe eller to alkoksy karbonylgrupper med hver ialt 2 til 4 karbonatomer substituert alkylgruppe med 1 til 3 karbonatomer, en med en karboksy- eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer substituert alkenylgruppe med 2 til 5 karbonatomer, en alkanoylgruppe med 1 til 3 karbonatomer, en dialkoksymety1-eller trialkoksymetylgruppe med 1 til 3 karbonatomer i hver alkyldel, en alkylendioksymetylgruppe med 2 eller 3 karbon atomer i alkylendelen, en 1,3-oksazolin-2-yl- eller cyanogruppe, en eventuelt med én eller to alkylgrupper med hver 1 til 4 karbonatomer i hver alkyldel substituert aminokarbonylgruppe, en uforgrenet alkyleniminokarbonylgruppe med ialt 5 til 8 karbonatomer, en morfolinokarbonylgruppe, en (dialkyl-dioksolan-yl)-alkoksykarbonylgruppe med ialt 7 til 10 karbonatomer eller en karboksygruppe og dens estere, idet alkylestere med 1 til.6 karbonatomer i alkyldelen med unntagelse av a-stillingen, hver kan være substituert med en hydroksy-, alkoksy-,.amino-, alkylamino-, dialkylamino-, 1,3-dimetyl-xantin-7-yl-, alkanoyloksy-, arylkarbonyloksy-, aralkanoyloksy- eller pyridinkarbonyloksygruppe eller med to hydroksygrupper, idet en metyl- resp. metylengruppe bare kan være substituert med en hydroksygruppe, eller med en gruppe med formelen where R, and R_, which may be the same or different, are hydrogen atoms or alkyl groups each with 1 to 3 carbon atoms or also one of the residues Rg or Ry a cycloalkyl group of 3 to 7 carbon atoms, an aryl or aralkyl group, or Rg and R^ together with that between lying carbon atom is a cycloalkylidene residue with 5 to 7 carbon atoms, B means an optionally co-an alkyl group with 1 to 3 carbon atoms substituted methylene or ethylene group, and W means a hydrogen or halogen atom, a nitro group, a optionally with an alkanoyl group with 1 to 3 carbon atoms substituted amino group, an optionally with a hydroxy, carboxy or alkoxycarbonyl group or two alkoxy carbonyl groups each with a total of 2 to 4 carbon atoms, a substituted alkyl group with 1 to 3 carbon atoms, one with a carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a substituted alkenyl group with 2 to 5 carbon atoms, an alkanoyl group with 1 to 3 carbon atoms, a dialkoxymethyl- or trialkyloxymethyl group with 1 to 3 carbon atoms in each alkyl part, an alkylene dioxymethyl group with 2 or 3 carbon atoms in the alkylene part, a 1,3-oxazolin-2-yl or cyano group, an optionally with one or two alkyl groups with each 1 to 4 carbon atoms in each alkyl part substituted aminocarbonyl group, an unbranched alkyleneiminocarbonyl group with a total of 5 to 8 carbon atoms, a morpholinocarbonyl group, a (dialkyl-dioxolan-yl)-alkoxycarbonyl group with a total of 7 to 10 carbon atoms or a carboxy group and its esters, wherein alkyl esters with 1 to 6 carbon atoms in the alkyl part with the exception of the a-position, each may be substituted with a hydroxy-, alkoxy-,.amino-, alkylamino-, dialkylamino-, 1,3-dimethyl-xanthine-7-yl -, alkanoyloxy-, arylcarbonyloxy-, aralkanoyloxy- or pyridinecarbonyloxy group or with two hydroxy groups, as a methyl- or methylene group can only be substituted with a hydroxy group, or with a group of the formula hvor A, B og til R<- er som innledningsvis angitt, idet hver alkylsubstituent i de ovennevnte alkylestere kan inneholde 1 til 3 karbonatomer, og deres optisk aktive antipoder og deres salter, særlig deres fysiologisk forlikelige salter med uorganiske eller organiske syrer eller baser, karakterisert ved at a) et amin med den generelle formel where A, B and to R<- are as stated at the beginning, in that each alkyl substituent in the above-mentioned alkyl esters may contain 1 to 3 carbon atoms, and their optically active antipodes and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases, characterized in that a) an amine of the general formula hvor A og til R^ er som innledningsvis angitt, resp. når A representerer en av de innledningsvis nevnte vinylidengrupper, dens tautomer, dens litium- eller magnesiumhalogenid-kompleks, omsettes med en karboksylsyre med den generelle formel where A and to R^ are as stated at the beginning, resp. when A represents one of the initially mentioned vinylidene groups, its tautomer, its lithium or magnesium halide complex, is reacted with a carboxylic acid of the general formula hvor Rj. og B er som innledningsvis angitt, og W har de for W innledningsvis angitte betydninger eller er en med en beskyttelsesrest beskyttet karboksylgruppe, eller med dens eventuelt i reaksjonsblandingen fremstilte reaktive derivater, og eventuelt avspaltes en anvendt beskyttelsesrest, eller b) for fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe, spaltes en for- bindelse med den generelle formel where Rj. and B is, as stated at the outset, and W has the meanings given for W at the beginning or is a carboxyl group protected with a protective residue, or with its optionally produced reactive derivatives in the reaction mixture, and optionally a used protective residue is split off, or b) for the preparation of a compound of the general formula I where W means a carboxy group, a for- bond with the general formula hvor R^ til R,-, A og B er som innledningsvis angitt, og D betyr en gruppe som ved hydrolyse, termolyse eller hydrogenolyse kan overføres til en karboksygruppe, hydrolytisk, térmolytisk eller hydrogenolytisk, eller c) en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel where R^ to R,-, A and B are as stated at the outset, and D means a group which by hydrolysis, thermolysis or hydrogenolysis can be transferred to a carboxy group, hydrolytically, thermolytically or hydrogenolytically, or c) an optionally formed compound of the general formula in the reaction mixture hvor R_ til R^, A, B og W er som innledningsvis angitt, og R21 betyr et hydrogenatom eller har de for R2 innledningsvis angitte betydninger, alkyleres med en forbindelse med den generelle formel where R_ to R^, A, B and W are as indicated initially, and R21 represents a hydrogen atom or has the meanings indicated for R2 initially, is alkylated with a compound of the general formula hvor R^ ' har de for R^ innledningsvis angitte betydninger eller sammen med resten R2<1> i formel V en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert, lineær alkylengruppe med 4 til 6 karbonatomer eller en n-pentylengruppe, hvor 3. metylengruppe er erstattet med et oksygenr eller svovelatom, og E betyr en nukleofil utgående gruppe eller også et hydrogen atom når en metylengruppe i R^ ' er erstattet med en aldehyd-eller ketonkarbonylgruppe, eventuelt i nærvær av et reduksjonsmiddel, og hydrolyseres eventuelt derefter, eller d) for fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe, en alkanoylgruppe med .1 til 3 karbonatomer eller en alkylgruppe med 1 til 3 karbon- atomer, omsettes en forbindelse med den generelle formel hvor R^ til R^ , A og B er som innledningsvis angitt, med fosgen, et oksalylhalogenid, et alkyl- eller alkanoylhalogenid med hver 1 til 3 karbonatomer i alkyldelen eller med hydrogencyanid/hydrogenhalogenid i nærvær av en Lewis syre, eller e) for fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe, omsettes en forbindelse med den generelle formel where R^' has the meanings given for R^ at the beginning or together with the residue R2<1> in formula V an optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted, linear alkylene group with 4 to 6 carbon atoms or an n-pentylene group , where the 3rd methylene group is replaced by an oxygen or sulfur atom, and E means a nucleophilic leaving group or also a hydrogen atom when a methylene group in R^' is replaced by an aldehyde or ketone carbonyl group, optionally in the presence of a reducing agent, and optionally hydrolyzed thereafter, or d) for the preparation of a compound of the general formula I where W means a carboxy group, an alkanoyl group with .1 to 3 carbon atoms or an alkyl group with 1 to 3 carbon- atoms, a compound with the general formula where R^ to R^ , A and B are as indicated at the outset, is reacted with phosgene, an oxalyl halide, an alkyl or alkanoyl halide with each 1 to 3 carbon atoms in the alkyl part or with hydrogen cyanide/hydrogen halide in the presence of a Lewis acid, or e) for the preparation of a compound of the general formula I where W means a carboxy group, a compound of the general formula is reacted hvor til R,-, A og B er som innledningsvis angitt, med et eventuelt i reaksjonsblandingen fremstilt hypohalogenitt i nærvær av en alkalibase, eller f) for fremstilling av en forbindelse med den generelle formel I hvor W betyr en karboksygruppe, oksyderes en for- bindelse med den generelle formel where to R,-, A and B are, as indicated at the outset, with an optional hypohalogenite produced in the reaction mixture in the presence of an alkali base, or f) for the preparation of a compound of the general formula I where W means a carboxy group, a pre- bond with the general formula hvor R^ til R^ , A og B er som innledningsvis angitt, og G betyr en gruppe som ved oksydasjon kan overføres til en karboksygruppe, eller g) for fremstilling av en forbindelse med den generelle formel I hvor R^ betyr en nitrogruppe, omsettes en forbindelse med den generelle formel where R^ to R^ , A and B are as indicated at the outset, and G means a group which can be transferred to a carboxy group by oxidation, or g) for the preparation of a compound of the general formula I where R^ denotes a nitro group, a compound of the general formula is reacted hvor R^ , R,- , A, B og W er- som innledningsvis angitt, R^ er en nitrogruppe, og Y er en nukleofil utskiftbar rest, med en amin med den generelle formel where R^ , R,- , A, B and W are- as indicated at the outset, R^ is a nitro group, and Y is a nucleophilic replaceable residue, with an amine of the general formula hvor R^ og R2 er som innledningsvis angitt, og eventuelt hydrolyseres derefter, eller h) for fremstilling av en forbindelse med den generelle formel I hvor A betyr en gruppe med formelen where R^ and R2 are as indicated at the outset, and optionally hydrolyzed thereafter, or h) for the preparation of a compound of the general formula I where A means a group of the formula hvor Rfi og R7 er som innledningsvis angitt, reduseres en forbindelse med den generelle formel where Rfi and R7 are as stated at the beginning, reduces a compound with the general formula hvor R^ til R^ , B og W er som innledningsvis angitt, med hydrogen i nærvær av en hydrogeneringskatalysator, eller i) for fremstilling av en forbindelse med den generelle formel I hvor R. betyr et hydrogenatom og A en eventuelt med en alkylgruppe med 1 til' 5 karbonatomer substituert metylen-eller etylengruppe, en med to alkylgrupper med hver 1 til 3 karbonatomer substituert metylen- eller etylengruppe, en med en cykloalkylgruppe med 3 til 7 karbonatomer, en alkoksyalkyl-, karboksyl-, alkoksykarbonyl-, aryl- eller aralkylgruppe substituert metylengruppe, hvor hver av de ovennevnte alkyldeler kan inneholde 1 til 3 karbonatomer; eller en cykloalkylidengruppe med 4 til 7 karbonatomer, omsettes en forbindelse med den generelle formel where R^ to R^ , B and W are as indicated at the outset, with hydrogen in the presence of a hydrogenation catalyst, or i) for the preparation of a compound of the general formula I where R. means a hydrogen atom and A a methylene or ethylene group optionally substituted by an alkyl group with 1 to' 5 carbon atoms, one with two alkyl groups with each 1 to 3 carbon atoms substituted methylene or ethylene group, one with a cycloalkyl group of 3 to 7 carbon atoms, an alkoxyalkyl, carboxyl, carboxycarbonyl, aryl or aralkyl group substituted methylene group, where each of the above alkyl moieties may contain 1 to 3 carbon atoms; or a cycloalkylidene group with 4 to 7 carbon atoms, a compound of the general formula is reacted hvor R^ til R^ er som innledningsvis angitt, og A' betyr en eventuelt med en alkylgruppe med 1 til 5 karbonatomer substituert metylen- eller etylengruppe, en med to alkylgrupper med hver 1 til 3 karbonatomer substituert metylen-eller etylengruppe, en med en cykloalkylgruppe med 3 til 7 karbonatomer, en alkoksyalkyl-, karboksyl-, alkoksykarbonyl-, aryl-'eller aralkylgruppe substituert metylengruppe, hvor hver av de ovennevnte alkyldeler kan inneholde 1 til 3 karbonatomer; eller en cykloalkylidengruppe med 4 til 7 karbonatomer, med en forbindelse med den generelle formel where R^ to R^ are as indicated at the beginning, and A' means a methylene or ethylene group optionally substituted with an alkyl group with 1 to 5 carbon atoms, one with two alkyl groups with each 1 to 3 carbon atoms substituted methylene or ethylene group, one with a cycloalkyl group with 3 to 7 carbon atoms, an alkoxyalkyl, carboxyl, alkoxycarbonyl, aryl or aralkyl group substituted methylene group, where each of the above-mentioned alkyl parts may contain 1 to 3 carbon atoms; or a cycloalkylidene group of 4 to 7 carbon atoms, with a compound of the general formula hvor Rj., B og W er som innledningsvis angitt, i nærvær av'en sterk syre, og eventuelt overfø res derefter en således fremstilt forbindelse med den generelle formel I hvor W betyr en karboksygruppe, ved forestring eller amidering til en tilsvarende for bindelse med den generelle formel I, og/eller en fremstilt forbindelse med den generelle formel I hvor R_. og/eller W betyr en nitrogruppe, overføres ved reduksjon til en tilsvarende forbindelse med den generelle formel I hvor R^ og/eller W betyr en aminogruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ og/eller W betyr en aminogruppe, overføres over et tilsvarende diazoniumsalt til en tilsvarende forbindelse'med den generelle formel I hvor R^ betyr et hydrogen- eller halogenatom, en hydroksy-, alkoksy-, merkapto-, alkylmerkapto-, klorsulfonyl-eller cyangruppe og/eller W et hydrogen- eller halogenatom eller en cyangruppe, idet en således eventuelt fremstilt forbindelse med den generelle formel I hvor R^ betyr en hydroksygruppe, ved alkylering kan overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en alkoksygruppe, eller en således eventuelt fremstilt forbindelse med den generelle formel I hvor R^ betyr en klorsulfonylgruppe, kan ved hjelp av ammoniakk overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en aminosulfonylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ betyr en aminogruppe, overføres ved acylering til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en alkanoylamino-, afoylamino-, alkoksykarbonylamino- eller alkylsulfonylaminogruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ betyr en aminogruppe, overfø res ved alkylering til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en alkylamino- eller dialkylaminogruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ betyr et klor- eller bromatom, overføres ved dehalogenering til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr et hydrogenatom, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ betyr en nitrilgruppe, overføres ved hydrolyse resp. alkoholyse til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en aminokarbonyl-, karboksy- resp. alkoksykarbonyl-gruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ betyr en karboksy- eller alkoksykarbonylgruppe og/eller W en eventuelt forestret■karboksygruppe, overføres ved reduksjon til en tilsvarende forbindelse med den generelle formel I hvor R 3 og/eller W betyr en formyl- eller hydroksymetylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor W betyr en alkoksykarbonylgruppe hvor alkoksygrupperi kan inneholde 2 til 6 karbonatomer og er substituert- med en hydroksygruppe med unntagelse av a-stillingen, overføres ved acylering til en tilsvarende forbindelse med den generelle formel I og/eller en fremstilt forbindelse med den generelle formel I hvor W betyr en hydroksymetylgruppe, overføres ved halogenering og påfølgende omsetning med en malonsyrediester til en tilsvarende forbindelse med den generelle formel I hvor W betyr en med to alkoksykarbonylgrupper substituert etylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor W betyr en formylgruppe, overføres ved kondensasjon og eventuelt påfølgende hydrolyse og/eller dekarboksylering til en tilsvarende forbindelse med den generelle formel I hvor W betyr en med en hydroksykarbonyl- eller alkoksykarbonylgruppe substituert vinylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor W betyr en med to alkoksykarbonylgrupper substituert etylgruppe, overføres ved hydrolyse og dekarboksylering til en tilsvarende forbindelse med den generelle formel I hvor W betyr en med en karboksygruppe substituert etylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor W betyr en karboksygruppe, overføres ved overføring til et sulfonsyrehydrazid og påfølgende disproporsjonering til en tilsvarende forbindelse med den generelle formel I hvor W betyr en formylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ og R^ sammen med det mellomliggende nitrogenatom betyr en azå-1,4-dioksa-spiro-alkylgruppe med 6 til 8 karbonatomer, overføres ved hydrolyse til en tilsvarende forbindelse med den generelle formel I hvor R^ og R^ sammen med det mellom liggende nitrogenatom betyr en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer, hvor en metylengruppe er erstattet med en karbonylgruppe, og/eller en fremstilt forbindelse med den generelle formel I hvor R^ og R^ sammen med det mellomliggende nitrogenatom betyr en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer hvor én metylengruppe er erstattet med en karbonylgruppe, overføres ved reduksjon til en tilsvarende hydroksy-alkylen-imino-forbindelse med den generelle formel I, og/eller en fremstilt forbindelse med den generelle formel I hvor W betyr en aminokarbonylgruppe, overføres ved dehydratisering til en tilsvarende forbindelse med den generelle formel I hvor W betyr en cyangruppe, og/eller en fremstilt forbindelse med den generelle formel I over- føres til sine salter, særlig sine fysiologisk forlikelige salter med uorganiske eller organiske syrer og baser.where Rj., B and W are as stated at the beginning, in the presence of a strong acid, and optionally, a thus prepared compound with the general formula I where W means a carboxy group is then transferred by esterification or amidation to a corresponding bond with the general formula I, and/or a prepared compound of the general formula I wherein R_. and/or W means a nitro group, is transferred by reduction to a corresponding compound of the general formula I where R^ and/or W means an amino group, and/or a prepared compound of the general formula I where R^ and/or W means an amino group is transferred over a corresponding diazonium salt to a corresponding compound of the general formula I where R^ means a hydrogen or halogen atom, a hydroxy, . with the general formula I where R 1 means an alkoxy group, or a thus optionally prepared compound of the general formula I where R^ means a chlorosulfonyl group, can be transferred by means of ammonia to a corresponding compound of the general formula I where R^ means an aminosulfonyl group, and/or a prepared compound of the general formula I where R^ denotes an amino group is transferred by acylation to a corresponding compound of the general formula I where R^ denotes an alkanoylamino, afoylamino, alkoxycarbonylamino or alkylsulfonylamino group, and/or a prepared compound of the general formula I where R^ denotes an amino group is transferred by alkylation to a corresponding compound of the general formula I where R^ denotes an alkylamino or dialkylamino group, and/or a prepared compound of the general formula I where R^ denotes a chlorine or bromine atom is transferred by dehalogenation to a corresponding compound of the general formula I where R^ denotes a hydrogen atom, and/or a prepared compound of the general formula I where R^ denotes a nitrile group, is transferred by hydrolysis resp. alcoholysis to a corresponding compound with the general formula I where R^ means an aminocarbonyl, carboxy- or alkoxycarbonyl group, and/or a prepared compound of the general formula I where R 3 means a carboxy or alkoxycarbonyl group and/or W an optionally esterified carboxy group is transferred by reduction to a corresponding compound of the general formula I where R 3 and/or W means a formyl or hydroxymethyl group, and/or a prepared compound of the general formula I where W means an alkoxycarbonyl group where the alkoxy group can contain 2 to 6 carbon atoms and is substituted by a hydroxy group with the exception of the a-position, is transferred by acylation to a corresponding compound of the general formula I and/or a prepared compound of the general formula I where W means a hydroxymethyl group is transferred by halogenation and subsequent reaction with a malonic acid diester to a corresponding compound of the general formula I where W means an ethyl group substituted with two alkoxycarbonyl groups, and/or a prepared compound of the general formula I where W means a formyl group is transferred by condensation and possibly subsequent hydrolysis and/or decarboxylation to a corresponding compound of the general formula I where W means a vinyl group substituted with a hydroxycarbonyl or alkoxycarbonyl group, and/or a prepared compound of the general formula I where W means an ethyl group substituted with two carboxycarbonyl groups is transferred by hydrolysis and decarboxylation to a corresponding compound of the general formula I where W means an ethyl group substituted with a carboxy group, and/or a prepared compound of the general formula I where W means a carboxy group is transferred by transfer to a sulfonic acid hydrazide and subsequent disproportionation to a corresponding compound of the general formula I where W means a formyl group, and/or a prepared compound of the general formula I where R^ and R^ together with the intervening nitrogen atom mean an aza-1,4-dioxa-spiro-alkyl group with 6 to 8 carbon atoms is transferred by hydrolysis to a corresponding compound of the general formula I where R^ and R^ together with the intervening nitrogen atom mean an unbranched alkyleneimino group with 4 to 6 carbon atoms, where a methylene group is replaced by a carbonyl group, and/or a prepared compound of the general formula I where R^ and R^ together with the intervening nitrogen atom mean an unbranched alkyleneimino group of 4 to 6 carbon atoms in which one methylene group is replaced by a carbonyl group, is transferred by reduction to a corresponding hydroxy-alkylene-imino compound with the general formula I, and/or a prepared compound of the general formula I where W means an aminocarbonyl group is transferred by dehydration to a corresponding compound of the general formula I where W means a cyano group, and/or a prepared compound of the general formula I above- are taken to their salts, especially their physiologically compatible salts with inorganic or organic acids and bases. 2. Fremgangsmåte ifølge krav 1, karakterisert ved at man fremstiller 4-[(1-(2-piperidino-fenyl)-etyl)-aminokarbonylmetyl]-benzoesyre, dens alkylestere med 1 til 3 karbonatomer, dens optisk aktive antipoder og dens salter.2. Method according to claim 1, characterized in that one prepares 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid, its alkyl esters with 1 to 3 carbon atoms, its optically active antipodes and its salts. 3. Fremgangsmåte ifølge krav 1, karakterisert ved at man fremstiller 4- [ (2-piperidino-benzhydryl)-aminokarbonylmetyl]-benzoesyre, dens alkylestere med 1 til 3 karbonatomer, dens optisk aktive antipoder og dens salter.3. Method according to claim 1, characterized in that one prepares 4-[(2-piperidino-benzhydryl)-aminocarbonylmethyl]-benzoic acid, its alkyl esters with 1 to 3 carbon atoms, its optically active antipodes and its salts.
NO820047A 1981-01-10 1982-01-08 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACIDAMIDS NO820047L (en)

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US4735959A (en) * 1981-01-10 1988-04-05 Dr. Karl Thomae Gmbh Carboxylic acid amides and pharmaceutical compositions containing them
SU1170969A3 (en) * 1982-07-06 1985-07-30 Др.Карл Томэ,Гмбх (Фирма) Method of producing derivatives of phenylacetic acid or their salts
US5312924A (en) * 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
DE3523466A1 (en) * 1985-07-01 1987-01-08 Thomae Gmbh Dr K NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
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US5905080A (en) * 1993-08-20 1999-05-18 Smithkline Beecham, P.L.C. Amide and urea derivatives as 5HT1D receptor antagonists
FR2763590B1 (en) * 1997-05-22 2000-03-24 Synthelabo ACID DERIVATIVES [[[(ARYLMETHYL) AMINO] CARBONYL] ALKYL] - AROMATICS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
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