NO152005B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACID DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACID DERIVATIVES Download PDF

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NO152005B
NO152005B NO802087A NO802087A NO152005B NO 152005 B NO152005 B NO 152005B NO 802087 A NO802087 A NO 802087A NO 802087 A NO802087 A NO 802087A NO 152005 B NO152005 B NO 152005B
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group
benzoic acid
ethyl
carbon atoms
general formula
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NO802087A
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Norwegian (no)
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NO152005C (en
NO802087L (en
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Gerhart Griss
Robert Sauter
Wolfgang Grell
Rudolf Hurnaus
Eckhard Rupprecht
Nikolaus Kaubisch
Joachim Kaehling
Bernhard Eisele
Helmut Pieper
Klaus Noll
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Thomae Gmbh Dr K
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Priority claimed from DE19792928352 external-priority patent/DE2928352A1/en
Priority claimed from DE19792949259 external-priority patent/DE2949259A1/en
Priority claimed from DE19803016650 external-priority patent/DE3016650A1/en
Priority claimed from DE19803016651 external-priority patent/DE3016651A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of NO802087L publication Critical patent/NO802087L/en
Publication of NO152005B publication Critical patent/NO152005B/en
Publication of NO152005C publication Critical patent/NO152005C/en

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    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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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    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having 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, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
    • 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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    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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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
    • C07D295/20—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 carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

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

og deres fysiologisk forlikelige salter med uorganiske eller organiske syrer og også baser når Z betyr eller inneholder en karboksylgruppe. Ved fremstillingen av de nye karboksylsyrederivater med den generelle formel I kan man som mellomprodukt anvende nye 2-amino-benzoesyrederivater med den generelle formel and their physiologically compatible salts with inorganic or organic acids and also bases when Z represents or contains a carboxyl group. In the preparation of the new carboxylic acid derivatives with the general formula I, new 2-amino-benzoic acid derivatives with the general formula can be used as intermediates

og deres salter med uorganiske eller organiske syrer og også baser når W betyr en karboksylgruppe. and their salts with inorganic or organic acids and also bases when W means a carboxyl group.

De nye forbindelser med de generelle formler I og Ia oppviser verdifulle farmakolgiske egenskaper, nemlig en virkning på stoffskiftet. Således har forbindelsene med den generelle formel I særlig en blodsukkersenkende og/eller lipidsenkende virkning. The new compounds of the general formulas I and Ia exhibit valuable pharmacological properties, namely an effect on metabolism. Thus, the compounds of the general formula I in particular have a blood sugar-lowering and/or lipid-lowering effect.

I de ovenstående generelle formler I og Ia betyr In the above general formulas I and Ia mean

R et hydrogen-, klor- eller bromatom eller en cyklisk alkyleniminogruppe med 4 til 7 karbonatomer i minoringen, R a hydrogen, chlorine or bromine atom or a cyclic alkyleneimino group with 4 to 7 carbon atoms in the minor ring,

R^ et hydrogen-, fluor-, klor- eller bromatom, en alkyl- eller alkoksygruppe med hver 1 til 6 karbonatomer, en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, R^ a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group with 1 to 6 carbon atoms each, a phenyl group substituted alkoxy group with 1 to 3 carbon atoms,

en hydroksy-, nitro-, amino-, cyano- eller karboksy-gruppe, a hydroxy, nitro, amino, cyano or carboxy group,

en alkanoylamino-, alkoksykarbonyl- eller dialkylamido-sulfonylgruppe, hvor alkyldelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, an alkanoylamino, alkoxycarbonyl or dialkylamido-sulfonyl group, where the alkyl part in each case may contain 1 to 3 carbon atoms,

R2 og R^, som kan være like eller forskjellige, alkylgrupper med 1 til 7 karbonatomer, alkenylgrupper med 3 til 7 karbonatomer, cykloalkylgrupper med 3 til 7 karbonatomer, med en fenylgruppe substituerte alkylgrupper med 1 til 3 karbonatomer, fenyl- eller adamantylgrupper, eller R2 and R^, which may be the same or different, alkyl groups of 1 to 7 carbon atoms, alkenyl groups of 3 to 7 carbon atoms, cycloalkyl groups of 3 to 7 carbon atoms, alkyl groups of 1 to 3 carbon atoms substituted with a phenyl group, phenyl or adamantyl groups, or

R2 og R^ sammen med det mellomliggende nitrogenatom, en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer i iminoringen som kan være substituert med én eller to alkylgrupper med hver 1 til 4 karbonatomer, en alkoksygruppe med 1 til 3 karbonatomer, en hydroksy-, fenyl-, karboksy- eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer; R2 and R^ together with the intervening nitrogen atom, an unbranched alkyleneimino group with 4 to 6 carbon atoms in the imino ring which may be substituted with one or two alkyl groups with each 1 to 4 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, a hydroxy-, phenyl- , carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms;

og/eller en metylengruppe i de ovenfor angitte alkylenimino-ringer kan være erstattet med en iminogruppe som kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, en fenyl-, halogenfenyl-, benzyl-, pyridyl- eller furoylgruppe; and/or a methylene group in the above-mentioned alkylenimine rings can be replaced with an imino group which can be substituted with an alkyl group with 1 to 3 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a phenyl, halophenyl, benzyl, pyridyl or furoyl group;

med et oksygen- eller svovelatom, med en karboksyl-, sulfoksyd- eller sulfonylgruppe; en mettet eller delvis umettet aza-bicykloalkylgruppe med 7 til 10 karbonatomer, with an oxygen or sulfur atom, with a carboxyl, sulfoxide or sulfonyl group; a saturated or partially unsaturated aza-bicycloalkyl group with 7 to 10 carbon atoms,

en i 3- og 5-stilling med ialt 3 eller 4 alkylgrupper med one in the 3- and 5-position with a total of 3 or 4 alkyl groups

hver 1 til 3 karbonatomer substituert piperidinogruppe, en 1,4-dioksa-8-aza-spiro-alkylgruppe med 6 til 9 karbonatomer, en trimetylenimino-, pyrrolyl-, tetrahydropyridino-, heptametylenimino-, oktametylenimino-, nonametylenimino-, dekametylenimino-, undekametylenimino- eller dodekametylenimino-gruppe, each 1 to 3 carbon atom substituted piperidino group, a 1,4-dioxa-8-aza-spiro-alkyl group of 6 to 9 carbon atoms, a trimethyleneimino-, pyrrolyl-, tetrahydropyridino-, heptamethyleneimino-, octamethyleneimino-, nonamethyleneimino-, decamethyleneimino-, undecamethyleneimino or dodecamethyleneimino group,

R^ et hydrogenatom eller en alkylgruppe med 1 til 3 karbonatomer , R^ a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

Y et oksygenatom, en iminogruppe eller en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert Y an oxygen atom, an imino group or an optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted

metylengruppe, methylene group,

Z et hydrogen- eller halogenatom, en nitro-, amino-, cyano-, Z a hydrogen or halogen atom, a nitro-, amino-, cyano-,

formyl-, hydroksymety1- eller hydroksykarbonyletylengruppe, en eventuelt forestret karboksygruppe, en eventuelt med 2 eller 3 alkoksygrupper, med en karboksy-, alkoksykarbonyl- formyl, hydroxymethyl or hydroxycarbonylethylene group, an optionally esterified carboxy group, an optionally with 2 or 3 alkoxy groups, with a carboxy, alkoxycarbonyl

eller etylendioksygruppe substituert metylgruppe hvor alkoksygruppen i hvert tilfelle kan inneholde 1-3 karbonatomer, en eventuelt med en karboksygruppe eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer substituert acetylgruppe, en med én eller to alkoksykarbonylgrupper med ialt hver 2 til 4 karbonatomer eller med to karboksygrupper substituert etyl- eller etylengruppe, en eventuelt med en alkylgruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7 karbonatomer og/eller alkenylgruppe med 3 til 7 karbonatomer mono- eller disubstituert aminokarbonylgruppe, en piperidinokarbonyl-, morfolinokarbonyl-, tiomorfolinokarbonyl- eller N-alkylpiperazino-karbonylgruppe, hvor alkylgruppen kan inneholde 1 til 3 karbonatomer, eller også en med en karboksygruppe substituert etylgruppe når restene B>2 og R sammen med det mellomliggende nitrogenatom er en or ethylenedioxy group substituted methyl group where the alkoxy group in each case may contain 1-3 carbon atoms, an optionally substituted acetyl group with a carboxy group or alkoxycarbonyl group with a total of 2 to 4 carbon atoms, one with one or two alkoxycarbonyl groups with a total of 2 to 4 carbon atoms each or with two carboxy groups substituted ethyl or ethylene group, one optionally with an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms and/or alkenyl group with 3 to 7 carbon atoms mono- or disubstituted aminocarbonyl group, a piperidinocarbonyl-, morpholinocarbonyl-, thiomorpholinocarbonyl- or N- alkylpiperazino-carbonyl group, where the alkyl group can contain 1 to 3 carbon atoms, or also an ethyl group substituted with a carboxy group when the residues B>2 and R together with the intervening nitrogen atom are a

av de innledningsvis nevnte cykliske iminorester, of the initially mentioned cyclic imino residues,

Rj- et fluor-, klor- eller bromatom, en amino-, cyano- eller hydroksygruppe, en eventuelt med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, eller en alkoksygruppe med 4 til 6 karbonatomer, Rj- a fluorine, chlorine or bromine atom, an amino, cyano or hydroxy group, an optionally substituted by a phenyl group alkoxy group with 1 to 3 carbon atoms, or an alkoxy group with 4 to 6 carbon atoms,

Rg og R^ sammen med det mellomliggende nitrogenatom, en N-alkyl-cykloheksylaminogruppe hvor alkyldelen kan inneholde 2 til 4 karbonatomer, en N-alkyl-fenylamino- eller N-alkyl-benzylaminogruppe hvor alkyldelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, en uforgrenet alkyleniminogruppe med 6 til 12 karbonatomer i iminoringen, en med en alkylgruppe med 1 til 4 karbonatomer, en alkoksygruppe med 1 til 3 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer eller en fenylgruppe substituert piperidinogruppe, en med to, tre eller fire alkylgrupper med hver 1 til 3 karbonatomer substituert piperidinogruppe, en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert Rg and R^ together with the intervening nitrogen atom, an N-alkyl-cyclohexylamino group where the alkyl part may contain 2 to 4 carbon atoms, an N-alkyl-phenylamino- or N-alkyl-benzylamino group where the alkyl part may in each case contain 1 to 3 carbon atoms, an unbranched alkyleneimino group with 6 to 12 carbon atoms in the imino ring, one with an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms or a phenyl group substituted piperidino group, one with two, three or four alkyl groups with each 1 to 3 carbon atoms substituted piperidino group, one optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted

morfolino- eller tiomorfolinogruppe, en i 4-stilling med en alkylgruppe med 1 til 3 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, en fenyl-, halogenfenyl-, pyridyl-, benzyl- eller furoylgruppe substituert piperazinogruppe, en mettet eller delvis umettet aza-bicykloalkylgruppe med 7 til 10 karbonatomer, en 1,4-dioksa- morpholino or thiomorpholino group, one in the 4-position with an alkyl group with 1 to 3 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a phenyl, halophenyl, pyridyl, benzyl or furoyl group substituted piperazino group, a saturated or partially unsaturated aza-bicycloalkyl group of 7 to 10 carbon atoms, a 1,4-dioxa-

8-aza-spiroalkangruppe med ialt 6 til 9 karbonatomer, en 8-aza-spiroalkane group with a total of 6 to 9 carbon atoms, a

pyrrolidino- eller tetrahydro-pyridinogruppe og pyrrolidino or tetrahydro-pyridino group and

W en karboksy-, aminokarbonyl-, cyano- eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer. W a carboxy, aminocarbonyl, cyano or alkoxycarbonyl group with a total of 2 to 4 carbon atoms.

For de ved def inisijonen av restene R, til R^, W, Y For those at the def initiation of the residues R, to R^, W, Y

og Z innledningsvis angitte betydninger kommer således i betraktning and Z meanings given at the outset thus come into consideration

for R betydningen et hydrogen-, klor- eller bromatom, en for R the meaning of a hydrogen, chlorine or bromine atom, a

pyrrolidino-, piperidino- eller heksametyleniminogruppe, for R^ betydningen et hydrogen-, fluor-, klor- eller bromatom, pyrrolidino, piperidino or hexamethyleneimino group, for R^ meaning a hydrogen, fluorine, chlorine or bromine atom,

en metyl-, etyl-, propyl-, isopropyl-, butyl-, isobutyl-, pentyl-, isopentyl-, heksyl-, hydroksy-, metoksy-, etoksy-, propoksy-, isopropoksy-, butoksy-, isobutoksy-, tert.butoksy-, pentyloksy-, isopentyloksy-, neopentyloksy-, tert.pentyloksy-, hekyloksy-, benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert .butoxy-, pentyloxy-, isopentyloxy-, neopentyloxy-, tert.pentyloxy-, hecyloxy-, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-,

1-fenylpropoksy-, 2-fenylpropoksy-, 3-fenylpropoksy-, nitro-, cyano-, amino-, formylamino-, acetamido-, propionylamino-, karboksy-, metoksykarbonyl-, etoksykarbonyl-, propoksykarbonyl-, isopropoksykarbonyl-, dimetylamidosulfonyl-, dietylamidosulfonyl-, dipropylamidosulfonyl-, etyl-metyl-amidosulfonyl-, metyl-propyl-amidosulfonyl- eller etyl-propyl-amidosulfonylgruppe, 1-phenylpropoxy-, 2-phenylpropoxy-, 3-phenylpropoxy-, nitro-, cyano-, amino-, formylamino-, acetamido-, propionylamino-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, dimethylamidosulfonyl- , diethylamidosulfonyl, dipropylamidosulfonyl, ethyl-methyl-amidosulfonyl, methyl-propyl-amidosulfonyl or ethyl-propyl-amidosulfonyl group,

for og R^ sammen med det mellomliggende nitrogenatom betydningen en dimetylamino-, dietylamino-, dipropylamino-, diisopropylamino-, dibutylamino-, diisobutylamino-, dipentylamino-, diheksylamino-, diheptylamino-, N-metyl-etylamino-, N-metyl-propylamino-, N-isopropyl-propylamino-, N-isobutyl-propylamino-, N-metyl-isopropylamino-, N-metyl-butylamino-, N-ety1-butylamino-, N-etyl-isopropylamino-, N-etyl-pentyl-amino-, N-propyl-butylamino-, N-propyl-heptylamino-, dicyklo-heksylamino-, N-metyl-cykloheksylamino-, N-etyl-cykloheksylamino-, N-propy1-cykloheksylamino-, N-isobutyl-cykloheksylamino-, dibenzylamino-, N-metyl-benzylamino-, N-etyl-benzylamino-, N-propyl-benzylamino-, N-isopropyl-benzylamino-, for and R^ together with the intervening nitrogen atom means a dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, dibutylamino-, diisobutylamino-, dipentylamino-, dihexylamino-, diheptylamino-, N-methyl-ethylamino-, N-methyl-propylamino -, N-isopropyl-propylamino-, N-isobutyl-propylamino-, N-methyl-isopropylamino-, N-methyl-butylamino-, N-ethyl-butylamino-, N-ethyl-isopropylamino-, N-ethyl-pentyl- amino-, N-propyl-butylamino-, N-propyl-heptylamino-, dicyclohexylamino-, N-methyl-cyclohexylamino-, N-ethyl-cyclohexylamino-, N-propyl1-cyclohexylamino-, N-isobutyl-cyclohexylamino-, dibenzylamino-, N-methyl-benzylamino-, N-ethyl-benzylamino-, N-propyl-benzylamino-, N-isopropyl-benzylamino-,

N-butyl-benzylamino-, N-heptyl-benzylamino-, N-metyl-fenyletylamino-, N-metyl-fenylpropylamino-, N-etyl-fenyletylamino-, N-propy1-fenyletylamino-, N-butyl-fenylpropylamino-, diallylamino-, dibutenylamino-, dipentenylamino-, diheptenylamino-, N-metyl-adamantylamino-, N-etyl-adamanty1-amino-, N-propyl-adamantylamino-, trimetylenimino-, pyrrolidino-, piperidino-, heksametylenimino-, heptametylenimino-, oktametylenimino-, nonametylenimino-, dekametylenimino-, undekametylenimino-, dodekametylenimino-, metyl-pyrrolidino-, dimetylpyrrolidino-, 1,2,3,6-tetrahydro-pyridino-, mety1-piperidino-, dimetyl-piperidino-, trimety1-piperidino-, tetramety1-piperidino-, etyl-piperidino-, dietyl-piperidino-, metyletyl-piperidino-, propy1-piperidino-, dipropyl-piperidino-, metyl-propyl-piperidino-, isopropy1-piperidino-, etylpropy1-piperidino-, butyl-piperidino-, isobuty1-piperidino-, tert.buty1-piperidino-, cis-3,5-dimetyl-piperidino-, trans-3,5-dimetyl-piperidino-, cis-3,5-diety1-piperidino-, trans-3,5-dipropyl-piperidino-, hydroksy-pyrrolidino-, hydroksy-piperidino-, metoksy-pyrrolidino-, metoksy-piperidino-, etoksy-piperidino-, propoksy-piperidino-, isopropoksy-piperidino-, fenyl-piperidino-, hydroksykarbonyl-pyrrolidino-, hydroksykarbonyl-piperidino-, metoksykarbony1-piperidino-, etoksykarbony1-piperidino-, propoksykarbonyl-piperidino-, isopropoksy-karbony1-piperidino-, 3,3,5,5-tetrametyl-piperidino-, 3,3,5,5-tetraety1-piperidino-, 3,3,5,5-tetrapropyl-piperidino-, pyrrolidon-l-yl-, piperidon-l-yl-, heksahydro-azepinon-1-yl-, morfolino-, metyl-morfolino-, dimety1-morfolino-, propy1-morfolino-, tiomorfolino-, metyltio-morfolino-, dimety1-tiomorfolino-, 1-oksydotiomorfolino-, dimety1-1-oksydotiomorfolino-, 1,1-dioksydotiomorfolino-, dimety1-1,1-dioksydotiomorfolino-, piperazino-, N-metyl-piperazino-, N-ety1-piperazino-, N-propyl-piperazino-, N-isopropyl-piperazino-, N-fenyl-piperazino-, N-klorfenyl-piperazino-, N-bromfenyl-piperazino-, N-pyridyl-piperazino-, N-metoksykarbonyl-piperazino-, N-etoksy-karbonyl-piperazino-, N-propoksykarbony1-piperazino-, N-furoyl-piperazino-, tetrahydro-isokinolin-2-yl-, oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl-, tetrahydro-3-benzazepin-3-yl-, dekahydro-3-benzazepin-3-yl-, oktahydro-isoindol-2-yl-, 3-aza-bicyklo-nonan-3-yl-, 1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl- eller 1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl-gruppe, for R. betydningen et hydrogenatom, en metyl-, etyl-, propyl-eller isopropylgruppe, N-butyl-benzylamino-, N-heptyl-benzylamino-, N-methyl-phenylethylamino-, N-methyl-phenylpropylamino-, N-ethyl-phenylethylamino-, N-propyl-phenylethylamino-, N-butyl-phenylpropylamino-, diallylamino -, dibutenylamino-, dipentenylamino-, diheptenylamino-, N-methyl-adamantylamino-, N-ethyl-adamanty1-amino-, N-propyl-adamantylamino-, trimethyleneimino-, pyrrolidino-, piperidino-, hexamethyleneimino-, heptamethyleneimino-, octamethyleneimino -, nonamethyleneimino-, decamethyleneimino-, undecamethyleneimino-, dodecamethyleneimino-, methyl-pyrrolidino-, dimethylpyrrolidino-, 1,2,3,6-tetrahydro-pyridino-, methyl1-piperidino-, dimethyl-piperidino-, trimethy1-piperidino-, tetramethyl-piperidino-, ethyl-piperidino-, diethyl-piperidino-, methylethyl-piperidino-, propyl-piperidino-, dipropyl-piperidino-, methyl-propyl-piperidino-, isopropyl-piperidino-, ethylpropyl-piperidino-, butyl-piperidino -, isobuty1-piperidino-, tert.buty1-piperidino-, cis-3,5-dimethyl-piperidino-, trans-3,5-dimethyl-piperidino-, cis-3,5-diethyl1-piperidino-, trans-3 , the 5th propyl-piperidino-, hydroxy-pyrrolidino-, hydroxy-piperidino-, methoxy-pyrrolidino-, methoxy-piperidino-, ethoxy-piperidino-, propoxy-piperidino-, isopropoxy-piperidino-, phenyl-piperidino-, hydroxycarbonyl-pyrrolidino-, hydroxycarbonyl-piperidino-, methoxycarbonyl-1-piperidino-, ethoxycarbonyl-1-piperidino-, propoxycarbonyl-piperidino-, isopropoxy-carbonyl-piperidino-, 3,3,5,5-tetramethyl-piperidino-, 3,3,5,5-tetraethyl-1- piperidino-, 3,3,5,5-tetrapropyl-piperidino-, pyrrolidon-l-yl-, piperidon-l-yl-, hexahydro-azepinon-1-yl-, morpholino-, methyl-morpholino-, dimethyl-morpholino -, propy1-morpholino-, thiomorpholino-, methylthio-morpholino-, dimety1-thiomorpholino-, 1-oxidothiomorpholino-, dimety1-1-oxidothiomorpholino-, 1,1-dioxythiomorpholino-, dimety1-1,1-dioxythiomorpholino-, piperazino- , N-methyl-piperazino-, N-ethy1-piperazino-, N-propyl-piperazino-, N-isopropyl-piperazino-, N-phenyl-piperazino-, N-chlorophenyl-piperazino-, N-bromophenyl-piperazino-, N-pyridyl-piperazino-, N-methoxycarbonyl-piperazine o-, N-ethoxy-carbonyl-piperazino-, N-propoxycarbonyl-piperazino-, N-furoyl-piperazino-, tetrahydro-isoquinolin-2-yl-, octahydro-isoquinolin-2-yl-, decahydro-isoquinolin-2- yl-, tetrahydro-3-benzazepin-3-yl-, decahydro-3-benzazepin-3-yl-, octahydro-isoindol-2-yl-, 3-aza-bicyclo-nonan-3-yl-, 1,4 -dioxa-8-aza-spiro[4,5]decan-8-yl or 1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl group, for R. meaning a hydrogen atom , a methyl, ethyl, propyl or isopropyl group,

for Y betydningen et oksygenatom, en imino-, metylen-, metyl- for Y meaning an oxygen atom, an imino-, methylene-, methyl-

metylen-, ety1-metylen-, propyl-metylen-, dimetyl-metylen-, methylene-, ethyl1-methylene-, propyl-methylene-, dimethyl-methylene-,

dietyl-metylen- eller metylpropyl-metylengruppe, og diethyl-methylene or methylpropyl-methylene group, and

for Z betydningen et hydrogen-, klor- eller bromatom, en nitro-, for Z meaning a hydrogen, chlorine or bromine atom, a nitro,

amino-, cyano-, formyl-, hydroksymetyl-, karboksy-, metoksykarbonyl-, etoksykarbonyl-, propoksykarbonyl-, isopropoksykarbonyl-, butoksykarbonyl-, isobutoksykarbonyl-, tert.butoksykarbony1-, pentoksykarbonyl-, heksoksykarbonyl-, heptoksykarbonyl-, allyloksykarbonyl-, fenoksykarbonyl-, benzyloksykarbonyl-, fenyletoksykarbonyl-, cyklopropoksy-karbonyl-, cyklopentoksykarbonyl-, cykloheksyloksykarbonyl-, cykloheptoksykarbonyl-, metyl-, dimetoksymety1-, dietoksy-metyl-, trietoksymety1-, dipropoksymetyl-, tripropoksymetyl-, hydroksykarbonylmetyl-, metoksykarbonylmetyl-, etoksykarbonyl-metyl-, propoksykarbonylmetyl-, 1,3-dioksolan-2-yl-, acetyl-, hydroksykarbonylacetyl-, metoksykarbonylacetyl-, etoksy-karbonylacetyl-, isopropoksykarbonylacetyl-, 2-hydroksykarbonyletylen-, 2-metoksykarbonyletylen-, 2-etoksykarbonyl-etylen-, 2-hydroksykarbonyletyl-, 2-metoksykarbonyl-etyl-, 2-etoksykarbonyl-ety1-, 2-isopropoksykarbonyl-ety1-, 2,2-bis-hydroksykarbonyl-etyl-, 2,2-bis-etoksykarbonyl-etyl-, aminokarbonyl-, metylaminokarbonyl-, etylaminokarbonyl-, isopropylaminokarbony1-, butylaminokarbonyl-, pentylamino-karbonyl-, heksylaminokarbonyl-, heptylaminokarbonyl-, allyl-aminokarbonyl-, diallylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbony1-, dipropylaminokarbonyl-, diheksylamino-karbonyl-, N-metyletylaminokarbonyl-, cyklopropylamino-karbonyl-, cyklopentylaminokarbonyl-, cykloheksylaminokarbonyl-, cykloheptylaminokarbonyl-, dicykloheksylamino-karbonyl-, N-metylcykloheksylaminokarbonyl-, N-etyl-cykloheksylaminokarbonyl-, N-propyl-cykloheksylaminokarbonyl-, N-pentyl-cykloheksylaminokarbonyl-, piperidinokarbonyl-, morfolinokarbony1-, tiomorfolinokarbonyl-, N-mety1-piperazinokarbonyl-, N-etyl-piperazinokarbonyl- eller N-propyl-piperazinokarbonyl-gruppe, amino-, cyano-, formyl-, hydroxymethyl-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, isobutoxycarbonyl-, tert.butoxycarbonyl-, pentoxycarbonyl-, hexoxycarbonyl-, heptoxycarbonyl-, allyloxycarbonyl-, phenoxycarbonyl-, benzyloxycarbonyl-, phenylethoxycarbonyl-, cyclopropoxycarbonyl-, cyclopentoxycarbonyl-, cyclohexyloxycarbonyl-, cycloheptoxycarbonyl-, methyl-, dimethoxymethyl-, diethoxymethyl-, triethoxymethyl-, dipropoxymethyl-, tripropoxymethyl, hydroxycarbonylmethyl, methoxycarbonylmethyl-, ethoxycarbonyl -methyl-, propoxycarbonylmethyl-, 1,3-dioxolan-2-yl-, acetyl-, hydroxycarbonylacetyl-, methoxycarbonylacetyl-, ethoxycarbonylacetyl-, isopropoxycarbonylacetyl-, 2-hydroxycarbonylethylene-, 2-methoxycarbonylethylene-, 2-ethoxycarbonyl-ethylene -, 2-hydroxycarbonylethyl-, 2-methoxycarbonyl-ethyl-, 2-ethoxycarbonyl-ethyl-, 2-isopropoxycarbonyl-ethyl-, 2,2-bis-hydroxycarbonyl-ethyl-, 2,2-bis-ethoxycarbonyl-ethyl-, amino vessels bonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, isopropylaminocarbonyl-, butylaminocarbonyl-, pentylaminocarbonyl-, hexylaminocarbonyl-, heptylaminocarbonyl-, allylaminocarbonyl-, diallylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, dipropylaminocarbonyl-, dihexylaminocarbonyl-, N- methylethylaminocarbonyl-, cyclopropylamino-carbonyl-, cyclopentylaminocarbonyl-, cyclohexylaminocarbonyl-, cycloheptylaminocarbonyl-, dicyclohexylaminocarbonyl-, N-methylcyclohexylaminocarbonyl-, N-ethyl-cyclohexylaminocarbonyl-, N-propyl-cyclohexylaminocarbonyl-, N-pentyl-cyclohexylaminocarbonyl-, piperidinocarbonyl- , morpholinocarbonyl, thiomorpholinocarbonyl, N-methyl-piperazinocarbonyl, N-ethyl-piperazinocarbonyl or N-propyl-piperazinocarbonyl group,

for R,- betydningen et fluor-, klor- eller bromatom, en amino-, for R, - the meaning of a fluorine, chlorine or bromine atom, an amino,

cyano-, hydroksy-, metoksy-, etoksy-, propoksy-, isopropoksy-, butoksy-, isobutoksy-, tert.butoksy-, pentoksy-, heksoksy-, benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, 1-fenyl-propoksy-eller 3-feny1-propoksygruppe, cyano-, hydroxy-, methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, tert.butoxy-, pentoxy-, hexoxy-, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-, 1- phenyl-propoxy or 3-phenyl-propoxy group,

for Rg og R-, sammen med nitrogenatomet, betydningen en N-metyl-fenylamino-, N-etylfenylamino-, N-isopropyl-fenylamino-, N-mety1-benzylamino-, N-etyl-benzylamino-, N-propyl-benzylamino-, N-ety1-cykloheksylamino-, N-propyl-cykloheksylamino-, N-isopropy1-cykloheksylamino-, N-butyl-cykloheksylamino-, pyrrolidino-, heksametylenimino-, heptametylenimino-, oktametylenimino-, nonametylenimino-, dekametylenimino- , undekametylenimino-, dodekametylenimino-, metyl-piperidino-, etyl-piperidino-, propyl-piperidino-, isopropyl-piperidino-, butyl-piperidino-, isobutyl-piperidino-, tert.-buty1-piperidino-, metoksy-piperidino-, etoksy-piperidino-, propoksy-piperidino-, isopropoksy-piperidino-, metoksy-karbony1-piperidino-, etoksykarbonyl-piperidino-, propoksykarbonyl-piperidino-, isopropoksykarbony1-piperidino-, dimetyl-piperidino-, trimetyl-piperidino-, tetrametyl-piperidino-, diety1-piperidino-, dipropy1-piperidino-, tetraetylpiperidino-, metyletyl-piperidino-, etylpropy1-piperidino-, morfolino-, metyl-morfolino-, etyl-morfolino-, propylmorfolino-, dimetylmorfolino-, dietylmorfolino-, tiomorfolino-, metyltio-morfolino-, propy1-tiomorfolino-, dimetyl-tiomorfolino-, N-mety1-piperazino-, N-ety1-piperazino-, N-propyl-piperazino-, N-metoksykarbonyl-piperazino-, N-etoksykarbonyl-piperazino-, N-isopropoksykarbony1-piperazino-, N-fenylpiperazino-, N-fluorfenyl-piperazino-, N-klorfenyl-piperazino-, N-bromfenyl-piperazino-, N-pyridy1-piperazino-, N-benzyl-piperazino-, N-furoyl-piperazino-, oktahydro-isoindol-2-yl-, tetrahydro-isokinolin-2-yl-, oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl-, tetrahydro-3-benzazepin-3-yl-, dekahydro-3-benzazepin-3-yl-, 3-aza-bicyklo-nonan-3-yl-, 1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]-undekan-8-yl- eller tetrahydro-pyridinogruppe, og for Rg and R-, together with the nitrogen atom, the meaning a N-methyl-phenylamino-, N-ethylphenylamino-, N-isopropyl-phenylamino-, N-methyl-benzylamino-, N-ethyl-benzylamino-, N-propyl-benzylamino -, N-ethyl1-cyclohexylamino-, N-propyl-cyclohexylamino-, N-isopropyl1-cyclohexylamino-, N-butyl-cyclohexylamino-, pyrrolidino-, hexamethyleneimino-, heptamethyleneimino-, octamethyleneimino-, nonamethyleneimino-, decamethyleneimino-, undecamethyleneimino- , dodecamethyleneimino-, methyl-piperidino-, ethyl-piperidino-, propyl-piperidino-, isopropyl-piperidino-, butyl-piperidino-, isobutyl-piperidino-, tert.-buty1-piperidino-, methoxy-piperidino-, ethoxy-piperidino -, propoxy-piperidino-, isopropoxy-piperidino-, methoxy-carbonyl-1-piperidino-, ethoxycarbonyl-piperidino-, propoxycarbonyl-piperidino-, isopropoxycarbonyl-piperidino-, dimethyl-piperidino-, trimethyl-piperidino-, tetramethyl-piperidino-, diety1 -piperidino-, dipropylpiperidino-, tetraethylpiperidino-, methylethylpiperidino-, ethylpropylpiperidino-, morpholino-, me tyl-morpholino-, ethyl-morpholino-, propylmorpholino-, dimethylmorpholino-, diethylmorpholino-, thiomorpholino-, methylthio-morpholino-, propy1-thiomorpholino-, dimethyl-thiomorpholino-, N-methyl1-piperazino-, N-ethyl1-piperazino- , N-propyl-piperazino-, N-methoxycarbonyl-piperazino-, N-ethoxycarbonyl-piperazino-, N-isopropoxycarbonyl-piperazino-, N-phenylpiperazino-, N-fluorophenyl-piperazino-, N-chlorophenyl-piperazino-, N- bromophenyl-piperazino-, N-pyridy1-piperazino-, N-benzyl-piperazino-, N-furoyl-piperazino-, octahydro-isoindol-2-yl-, tetrahydro-isoquinolin-2-yl-, octahydro-isoquinolin-2- yl-, decahydro-isoquinolin-2-yl-, tetrahydro-3-benzazepin-3-yl-, decahydro-3-benzazepin-3-yl-, 3-aza-bicyclo-nonan-3-yl-, 1,4 -dioxa-8-aza-spiro[4,5]decan-8-yl-, 1,4-dioxa-8-aza-spiro[4,6]-undecan-8-yl- or tetrahydro-pyridino group, and

for W betydningen en karboksy-, aminokarbonyl-, metoksykarbonyl-, for W the meaning of a carboxy-, aminocarbonyl-, methoxycarbonyl-,

etoksykarbonyl-, propoksykarbonyl- eller cyangruppe. ethoxycarbonyl, propoxycarbonyl or cyano group.

Foretrukne forbindelser med de generelle formler I og Ia Preferred compounds of the general formulas I and Ia

er imidlertid de hvor however, are they where

R er et hydrogenatom, R is a hydrogen atom,

R-^ er et hydrogen-, fluor-, klor- eller bromatom, en alkoksygruppe med 1 til 6 karbonatomer, en alkylgruppe med 1 til 4 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, en hydroksy-, cyano-, karboksy-, nitro-, amino-, acetamido-, dimetylaminosulfonyl- eller benzyloksygruppe, R-^ is a hydrogen, fluorine, chlorine or bromine atom, an alkoxy group with 1 to 6 carbon atoms, an alkyl group with 1 to 4 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a hydroxy-, cyano-, carboxy- , nitro, amino, acetamido, dimethylaminosulfonyl or benzyloxy group,

1*2 er en alkylgruppe med 1 til 6 karbonatomer, en cykloheksy 1-, 1*2 is an alkyl group with 1 to 6 carbon atoms, a cyclohexy 1-,

fenyl-, benzyl-, adamantyl- eller allylgruppe, phenyl, benzyl, adamantyl or allyl group,

R., er en alkylgruppe med 1 til 6 karbonatomer eller en allylgruppe, eller R., is an alkyl group with 1 to 6 carbon atoms or an allyl group, or

R^ og R^ sammen med det mellomliggende nitrogenatom er en uforgrenet alkyleniminogruppe med 4 til 12 karbonatomer i iminoringen, en med en alkylgruppe med 1 til 4 karbonatomer, en fenyl-, hydroksy-, metoksy-, karboksy- eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer substituert piperidinogruppe, en i 3- og 5-stilling hver med en alkylgruppe med 1 til 3 karbonatomer disubstituert piperidinogruppe , en i 3- og 5-stilling hver med to alkylgrupper med hver 1 til 3 karbonatomer tetrasubstituert piperidinogruppe, en eventuelt med én eller to metylgrupper substituert morfolino-, tiomorfolino-, 1-oksydo-tiomorfolino- eller 1,1-dioksydo-tiomorfolino-gruppe, en eventuelt i 4-stilling med en metyl-, benzyl-, fenyl-, klorfenyl-, pyridyl-, furoyl-eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer substituert piperazinogruppe, en pyrrolyl-, piperidon-(2)-yl-(1)-, 1,2,3,6-tetrahydropyridino-, 1,4-diazo-8-aza-spiro-[4,5]dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl-, oktahydro-isoindol-2-yl-, 1,2,3,4-tetrahydro-isokinolin-2-yl-, 1,2,3,4,5,6,7,8-oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl-, 1,2,4,5-tetrahydro-3-benzazepin-3-yl-, dekahydro-3-benzazepin-3-yl- eller 3-aza-bicyklo-nonan-3-yl-gruppe, R^ and R^ together with the intervening nitrogen atom is an unbranched alkyleneimino group with 4 to 12 carbon atoms in the imino ring, one with an alkyl group with 1 to 4 carbon atoms, a phenyl, hydroxy, methoxy, carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms substituted piperidino group, one in the 3- and 5-position each with an alkyl group with 1 to 3 carbon atoms disubstituted piperidino group , one in the 3- and 5-position each with two alkyl groups with each 1 to 3 carbon atoms tetrasubstituted piperidino group, one optionally with one or two methyl groups substituted by a morpholino, thiomorpholino, 1-oxido-thiomorpholino or 1,1-dioxydo-thiomorpholino group, one optionally in the 4-position with a methyl, benzyl, phenyl, chlorophenyl, pyridyl, furoyl or alkoxycarbonyl group with a total of 2 to 4 carbon atoms substituted piperazino group, a pyrrolyl-, piperidon-(2)-yl-(1)-, 1,2,3,6-tetrahydropyridino-, 1,4-diazo-8-aza -spiro-[4,5]decan-8-yl-, 1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl-, octahydro- isoindol-2-yl-, 1,2,3,4-tetrahydro-isoquinolin-2-yl-, 1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl-, decahydro -isoquinolin-2-yl-, 1,2,4,5-tetrahydro-3-benzazepin-3-yl-, decahydro-3-benzazepin-3-yl- or 3-aza-bicyclo-nonan-3-yl- group,

R^ er et hydrogenatom eller en metylgruppe, R^ is a hydrogen atom or a methyl group,

Y er en metylen-, metyl-metylen- eller dimetylmetylen-gruppe, Y is a methylene, methyl-methylene or dimethylmethylene group,

en NH-gruppe eller et oksygenatom, og an NH group or an oxygen atom, and

Z er en karboksy-, cyano-, formyl- eller hydroksymetylgruppe, Z is a carboxy, cyano, formyl or hydroxymethyl group,

en alkoksykarbonylgruppe med ialt 2 til 7 karbonatomer, en cykloheksyloksykarbony1-, benzyloksykarbonyl-, dietoksy-metyl-, hydroksykarbonylmety1-, bis-2,2-etoksykarbonyl-etyl-, 2-hydroksy-karbonyl-etylen- eller 2-etoksykarbonyl-etylgruppe, en eventuelt med en hydroksykarbony1- eller etoksykarbonyl- an alkoxycarbonyl group with a total of 2 to 7 carbon atoms, a cyclohexyloxycarbonyl-, benzyloxycarbonyl-, diethoxy-methyl-, hydroxycarbonylmethyl-, bis-2,2-ethoxycarbonyl-ethyl-, 2-hydroxy-carbonyl-ethylene- or 2-ethoxycarbonyl-ethyl group, one optionally with a hydroxycarbonyl- or ethoxycarbonyl-

gruppe substituert acetylgruppe eller også en 2-hydroksy-karbony1-etylgruppe når restene R~ og R sammen med det mellomliggende nitrogenatom betyr en av de innledningsvis group substituted acetyl group or also a 2-hydroxy-carbonyl-1-ethyl group when the residues R~ and R together with the intervening nitrogen atom mean one of the initially

nevnte cykliske iminorester, said cyclic imino residues,

R,- er et klor- eller bromatom, en hydroksy-, amino-, cyano-eller benzyloksygruppe eller en alkoksygruppe med 1 til 6 R,- is a chlorine or bromine atom, a hydroxy, amino, cyano or benzyloxy group or an 1- to 6-alkyloxy group

karbonatomer, carbon atoms,

Rg og R^ sammen med det mellomliggende nitrogenatom er en N-alkyl-cykloheksylaminogruppe hvor alkyldelen kan inneholde 2 til 4 karbonatomer, en uforgrenet alkyleniminogruppe med Rg and R^ together with the intervening nitrogen atom is an N-alkyl-cyclohexylamino group where the alkyl part may contain 2 to 4 carbon atoms, an unbranched alkyleneimino group with

6 til 12 karbonatomer i iminoringen, en i 4-stilling med en 6 to 12 carbon atoms in the imino ring, one in the 4-position with a

alkylgruppe med 1 til 4 karbonatomer, en fenyl-, metoksy-eller etoksykarbonylgruppe substituert piperidinogruppe, alkyl group with 1 to 4 carbon atoms, a phenyl, methoxy or ethoxycarbonyl group substituted piperidino group,

en i 3- og 5-stilling med hver en metyl- eller etylgruppe disubstituert piperidinogruppe, en i 3- og 5-stilling med metylgrupper tetrasubstituert piperidinogruppe, en i 4-stilling med en metyl-, benzyl-, fenyl-, klorfenyl-, pyridyl-(2)-, etoksykarbonyl- eller furoyl-(2)-gruppe substituert piperazinogruppe, en eventuelt med én eller to metylgrupper substituert morfolino- eller tiomorfolino-gruppe, en pyrrolidino-, tetrahydro-pyridino-, N-mety1-fenylamino-, N-mety1-benzylamino-, 1,4-dioksa-8-aza-spiro-[4,5]dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl-, 3-aza-bicyklo-nonan-3-yl-, 1,2,4,5-tetrahydro-3-benzazepin-3-yl-, dekahydro-3-benzazepin-3-yl-, 1,2,3,4-tetrahydro-isokinolin-2-yl-, 1,2,3,4,5,6,7,8-oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl- eller oktahydro-isoindol-2-yl-gruppe, og one in the 3- and 5-position with each a methyl or ethyl group disubstituted piperidino group, one in the 3- and 5-position with methyl groups tetrasubstituted piperidino group, one in the 4-position with a methyl-, benzyl-, phenyl-, chlorophenyl-, pyridyl-(2)-, ethoxycarbonyl- or furoyl-(2)-group substituted piperazino group, a morpholino or thiomorpholino group optionally substituted with one or two methyl groups, a pyrrolidino-, tetrahydro-pyridino-, N-methyl-phenylamino- , N-methyl-benzylamino-, 1,4-dioxa-8-aza-spiro-[4,5]decan-8-yl-, 1,4-dioxa-8-aza-spiro[4,6]undecane- 8-yl-, 3-aza-bicyclo-nonan-3-yl-, 1,2,4,5-tetrahydro-3-benzazepin-3-yl-, decahydro-3-benzazepin-3-yl-, 1, 2,3,4-tetrahydro-isoquinolin-2-yl-, 1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl-, decahydro-isoquinolin-2-yl- or octahydro -isoindol-2-yl group, and

W er en karboksy-, aminokarbonyl-, metoksykarbonyl- eller W is a carboxy, aminocarbonyl, methoxycarbonyl or

cyangruppe, cyan group,

og salter derav, and salts thereof,

og særlig de forbindelser hvor resten R^ resp. R^ befinner seg i 5-stilling i benzenringen. and especially those compounds where the residue R^ resp. R^ is in the 5-position of the benzene ring.

Spesielt foretrukne forbindelser med de generelle formler I og Ia er de hvor Particularly preferred compounds of the general formulas I and Ia are those where

R er et hydrogenatom, R is a hydrogen atom,

R^ i 5-stilling er et hydrogen-, fluor-, klor- eller bromatom, R^ in the 5-position is a hydrogen, fluorine, chlorine or bromine atom,

en alkyl- eller alkoksygruppe med hver 1 til 3 karbonatomer, en karboksy-, cyano- eller nitrogruppe, an alkyl or alkoxy group each having 1 to 3 carbon atoms, a carboxy, cyano or nitro group,

og R^ sammen med det mellomliggende nitrogenatom er en N,N-dialkylamino- eller N-alkyl-cykloheksylaminogruppe med hver 1 til 3 karbonatomer i alkyldelen, en pyrrolidino-, piperidino-, heksametylenimino-, heptametylenimino-, oktametylenimino- eller nonametyleniminogruppe, en med en alkylgruppe med 1 til 4 karbonatomer, med en metoksy- eller fenylgruppe substituert piperidinogruppe, en i 3- og 5-stilling hver emd én eller to metyl- eller etylgrupper substituert piperidinogruppe, en eventuelt i 2- og 6-stilling hver med en metylgruppe substituert morfolino- eller tiomorfolinogruppe, en 1,4-dioksa-8-aza-spiro [4,5]dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]undekan-yl-, oktahydro-isoindol-2-yl-, 1,2,3,4-tetrahydro-isokinolin-2-yl-, 1,2,3,4,5,6,7,8-oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl-, and R^ together with the intervening nitrogen atom is an N,N-dialkylamino or N-alkylcyclohexylamino group each having 1 to 3 carbon atoms in the alkyl portion, a pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, octamethyleneimino or nonamethyleneimino group, a with an alkyl group with 1 to 4 carbon atoms, with a methoxy or phenyl group substituted piperidino group, one in the 3- and 5-position each emd one or two methyl or ethyl groups substituted piperidino group, one optionally in the 2- and 6-position each with a methyl group substituted morpholino or thiomorpholino group, a 1,4-dioxa-8-aza-spiro [4,5]decan-8-yl-, 1,4-dioxa-8-aza-spiro[4,6]undecan-yl -, octahydro-isoindol-2-yl-, 1,2,3,4-tetrahydro-isoquinolin-2-yl-, 1,2,3,4,5,6,7,8-octahydro-isoquinolin-2- yl-, decahydro-isoquinolin-2-yl-,

1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl-, dekahydro-3H-3-benzazepin-3-yl-, 3-aza-bicyklo[3,2,2]nonan-3-yl- eller 1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl-, decahydro-3H-3-benzazepin-3-yl-, 3-aza-bicyclo[3,2,2]nonan-3- yl- or

N-mety1-adamantyl-(1)-amino-gruppe, N-methyl-adamantyl-(1)-amino group,

R^ er et hydrogenatom eller en metylgruppe, R^ is a hydrogen atom or a methyl group,

Y er en metylen-, metylmetylen-, dimetyl-metylen- eller Y is a methylene, methylmethylene, dimethylmethylene or

NH-gruppe eller et oksygenatom, NH group or an oxygen atom,

Z er en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, Z is an alkoxycarbonyl group with a total of 2 to 4 carbon atoms,

en karboksy-, formyl- eller hydroksymetylgruppe, R,, i 5-stilling er en alkoksygruppe med 1 til 3 karbonatomer, a carboxy, formyl or hydroxymethyl group, R,, in the 5-position is an alkoxy group with 1 to 3 carbon atoms,

et klor- eller bromatom, a chlorine or bromine atom,

Rg og R^ sammen med det mellomliggende nitrogenatom er en uforgrenet alkyleniminogruppe med 6 til 8 karbonatomer i iminoringen, en 1,4-dioksa-8-aza-spiro[4,5]-dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl-, dekahydro-3H-3-ben'zazepin-3-yl- eller 4-metoksy-piperidinogruppe, og Rg and R^ together with the intervening nitrogen atom is an unbranched alkyleneimino group with 6 to 8 carbon atoms in the imino ring, a 1,4-dioxa-8-aza-spiro[4,5]-decan-8-yl-, 1,4- dioxa-8-aza-spiro[4,6]undecan-8-yl, decahydro-3H-3-ben'zazepin-3-yl or 4-methoxy-piperidino group, and

W er en karboksygruppe, W is a carboxy group,

og deres fysiologisk forlikelige syreaddisjonssalter med uorganiske eller organiske syrer og også baser når Z eller W betyr en karboksygruppe. and their physiologically compatible acid addition salts with inorganic or organic acids and also bases when Z or W represents a carboxy group.

De nye forbindelser fremstilles som følger: The new compounds are prepared as follows:

1. Fremstilling av 2-amino-benzoesyre-derivatene med den generelle formel Ia: a) For fremstilling av forbindelser med den generelle formel Ia hvor R^ betyr en aminogruppe: Reduksjon av en nitroforbindelse med den generelle formel 1. Preparation of the 2-amino-benzoic acid derivatives with the general formula Ia: a) For the preparation of compounds with the general formula formula Ia where R^ means an amino group: Reduction of a nitro compound with the general formula

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

Reduksjonen foretas hensiktsmessig i et oppløsningsmiddel så som metanol, etanol, vann, vann/etanol, dioksan, metanol/ dioksan, etylacetat, dimetylformamid eller dioksan/dimetylformamid med katalytisk aktivert hydrogen, f.eks. med hydrogen i nærvær av en hydrogeneringskatalysator så som palladium/kull, platina eller Raney-nikkel ved et hydrogentrykk på 1 til 10 bar, med hydrazin i nærvær av Raney-nikkel, med nascerende hydrogen, f.eks. med sink/eddiksyre, tinn/saltsyre eller jern/saltsyre, eller med et metallsalt, f.eks. tinn(II)klorid/saltsyre eller jern(II)sulfat/svovelsyre, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. b) For fremstilling av forbindelser med den generelle formel Ia, hvor R,, betyr en hydroksygruppe, en cyangruppe, The reduction is conveniently carried out in a solvent such as methanol, ethanol, water, water/ethanol, dioxane, methanol/dioxane, ethyl acetate, dimethylformamide or dioxane/dimethylformamide with catalytically activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal, platinum or Raney nickel at a hydrogen pressure of 1 to 10 bar, with hydrazine in the presence of Raney nickel, with nascent hydrogen, e.g. with zinc/acetic acid, tin/hydrochloric acid or iron/hydrochloric acid, or with a metal salt, e.g. tin(II) chloride/hydrochloric acid or iron(II) sulphate/sulphuric acid, at temperatures between 0 and 50°C, preferably at room temperature. b) For the preparation of compounds of the general formula Ia, where R,, means a hydroxy group, a cyano group,

et fluor-, klor- eller bromatom: a fluorine, chlorine or bromine atom:

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

hvor Rg, R^ og W er som innledningsvis angitt, med et nitritt og derefter oppvarmning av det således erholdte diazoniumsalt, eventuelt i nærvær av kobber eller et passende kobber(I)salt. where Rg, R^ and W are as indicated at the outset, with a nitrite and then heating of the diazonium salt thus obtained, possibly in the presence of copper or a suitable copper (I) salt.

Omsetningen utføres hensiktsmessig ved at en forbindelse med den generelle formel Ia' i et egnet oppløsningsmiddel, f.eks. i vann/saltsyre, metanol/saltsyre eller dioksan/saltsyre, overføres med et nitritt, f.eks. natriumnitritt eller en ester av salpetersyrling, til et diazoniumsalt ved lavere temperaturer, f.eks. ved temperaturer mellom -10 og 5°C. The reaction is suitably carried out by a compound of the general formula Ia' in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid or dioxane/hydrochloric acid, transferred with a nitrite, e.g. sodium nitrite or an ester of nitric acid, to a diazonium salt at lower temperatures, e.g. at temperatures between -10 and 5°C.

Det således erholdte tilsvarende diazoniumsalt overføres derefter, f.eks. som fluorborat, som hydrosulfat i svovelsyre, The corresponding diazonium salt thus obtained is then transferred, e.g. as fluoroborate, as hydrosulfate in sulfuric acid,

som hydroklorid i nærvær av kobber eller i nærvær av et passende kobber(I)salt så som kobber(I)klorid/saltsyre, kobber(I)bromid/ bromhydrogensyre eller trinatrium-kobber(I)tetracyanid ved pH 7, ved oppvarmning, f.eks. til temperaturer mellom 15 og 90°C, as hydrochloride in the presence of copper or in the presence of a suitable copper(I) salt such as copper(I) chloride/hydrochloric acid, copper(I) bromide/hydrobromic acid or trisodium copper(I) tetracyanide at pH 7, upon heating, f .ex. to temperatures between 15 and 90°C,

til den tilsvarende forbindelse. to the corresponding connection.

c) For fremstilling av forbindelser med den generelle formel I hvor R,, betyr en eventuelt med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer eller en alkoksygruppe med 4 til 6 karbonatomer: Alkylering av en hydroksyforbindelse med den generelle formel hvor Rb ,., R_ / og W er som innledningsvis angitt, med en forbindelse med den generelle formel c) For the preparation of compounds of the general formula I where R,, means an optionally substituted phenyl group alkoxy group with 1 to 3 carbon atoms or an alkoxy group with 4 to 6 carbon atoms: Alkylation of a hydroxy compound with the general formula where Rb ,., R_ / and W are as indicated at the outset, with a compound of the general formula

hvor R,- ' er en eventuelt med en fenylgruppe substituert alkylgruppe med 1 til 3 karbonatomer eller en alkylgruppe med 4 til 6 karbonatomer, og D er en nukleofil utgående gruppe eller sammen med det nabostilte H-atom i resten R,- ' en diazogruppe, og om nødvendig, påfølgende hydrolyse. where R,-' is an alkyl group with 1 to 3 carbon atoms or an alkyl group with 4 to 6 carbon atoms, optionally substituted with a phenyl group, and D is a nucleophilic leaving group or together with the adjacent H atom in the residue R,-' a diazo group , and if necessary, subsequent hydrolysis.

Som utgående gruppe kan man f.eks. anvende et klor-, brom-eller jodatom eller en sulfonyloksygruppe så som en metan-sulfonyloksy-, p-toluensulfonyloksy- eller metoksysulfonyloksy-gruppe . As an outgoing group, you can e.g. use a chlorine, bromine or iodine atom or a sulfonyloxy group such as a methanesulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group.

Omsetningen foretas hensiktsmessig i et oppløsningsmiddel så som eter, tetrahydrofuran, etanol, aceton, dimetylformamid eller dimetylsulfoksyd, eventuelt i nærvær av en base så som natriumkarbonat, kaliumkarbonat, bariumhydroksyd, natriumetylat eller kalium-tert.butylat, med et alkyleringsmiddel så som diazometan, diazoetan, metyljodid, etyljodid, isopropyl-bromid, butylbromid, dimetylsulfat, dietylsulfat eller p-toluen-sulfonsyremetylester, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 15 og 70°C. The reaction is conveniently carried out in a solvent such as ether, tetrahydrofuran, ethanol, acetone, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium carbonate, potassium carbonate, barium hydroxide, sodium ethylate or potassium tert-butylate, with an alkylating agent such as diazomethane, diazoethane , methyl iodide, ethyl iodide, isopropyl bromide, butyl bromide, dimethyl sulfate, diethyl sulfate or p-toluene sulfonic acid methyl ester, at temperatures between 0 and 100°C, preferably at temperatures between 15 and 70°C.

Hvis W betyr en karboksygruppe, vil denne ved alkyleringen med et diazoalkan eller ved alkyleringen i nærvær av en sterk base samtidig forestres. Den således erholdte ester overføres eventuelt derefter til den tilsvarende karboksylsyre ved hydrolyse i nærvær av en syre eller base. If W means a carboxy group, this will be simultaneously esterified during the alkylation with a diazoalkane or during the alkylation in the presence of a strong base. The ester thus obtained is optionally then transferred to the corresponding carboxylic acid by hydrolysis in the presence of an acid or base.

En fremstilt forbindelse med den generelle formel Ia hvor W er en cyano-, alkoksykarbonyl- eller aminokarbonylgruppe, A prepared compound of the general formula Ia where W is a cyano, alkoxycarbonyl or aminocarbonyl group,

kan derefter overføres ved hydrolyse til en tilsvarende forbindelse med den generelle formel Ia hvor W betyr en karboksy-gruppe. can then be transferred by hydrolysis to a corresponding compound of the general formula Ia where W means a carboxy group.

Den påfølgende hydrolyse foretas fortrinnsvis i et med vann blandbart oppløsningsmiddel så som metanol, etanol, dioksan, vann/etanol eller vann/tetrahydrofuran i nærvær av en syre så som saltsyre eller svovelsyre eller en base så som natrium-eller kaliumhydroksyd ved forhøyet temperatur, f.eks. ved reaksjonsblandingens koketemperatur. 2. Fremstilling av karboksylsyrederivatene med den generelle formel I: a) Omsetning av en aminobenzoesyre med den generelle formel: hvor R, R^, R2 og R 3 er som innledningsvis angitt, eller et eventuelt i reaksjonsblandingen fremstilt reaktivt derivat derav, med et amin med den generelle formel: The subsequent hydrolysis is preferably carried out in a water-miscible solvent such as methanol, ethanol, dioxane, water/ethanol or water/tetrahydrofuran in the presence of an acid such as hydrochloric or sulfuric acid or a base such as sodium or potassium hydroxide at an elevated temperature, f .ex. at the boiling temperature of the reaction mixture. 2. Preparation of the carboxylic acid derivatives with the general formula I: a) Reaction of an aminobenzoic acid with the general formula: where R, R^, R 2 and R 3 are as indicated at the outset, or a possibly reactive derivative thereof produced in the reaction mixture, with an amine of the general formula:

hvor , Y og Z er som innledningsvis angitt, eller med et eventuelt i reaksjonsblandingen dannet, N-aktivert amin med den generelle formel V når en aminobenzoesyre med den generelle formel IV anvendes og når Z i et N-aktivert amin med den generelle formel V ikke inneholder en karboksy- eller aminogruppe. where , Y and Z are as indicated at the outset, or with an N-activated amine of the general formula V, if any formed in the reaction mixture, when an aminobenzoic acid of the general formula IV is used and when Z in an N-activated amine of the general formula V does not contain a carboxy or amino group.

Fremgangsmåten angår således acylering av et amin med den generelle formel V med en aminobenzoesyre med den generelle formel IV i nærvær av et for syren aktiverende eller et vanntiltrekkende middel, eller med funksjonelle derivater derav, eller The method thus relates to the acylation of an amine of the general formula V with an aminobenzoic acid of the general formula IV in the presence of an activating agent for the acid or a water-attracting agent, or with functional derivatives thereof, or

omsetning av en aminobenzoesyre med den generelle formel IV med et amin med den generelle formel V hvor Z ikke betyr en karboksy-eller aminogruppe, i nærvær av et for aminogruppen aktiverende middel, eller med reaktive derivater derav. reaction of an aminobenzoic acid of the general formula IV with an amine of the general formula V where Z does not mean a carboxy or amino group, in the presence of an amino group activating agent, or with reactive derivatives thereof.

Som eventuelt i reaksjonsblandingen fremstilte, funksjonelle derivater av en aminobenzoesyre med den generelle formel IV kommer f.eks. i betraktning dens alkyl-, aryl- eller aralkylestere eller -tioestere så som metyl-, etyl-, fenyl- eller benzyl-esteren, dens kobber-komplekser, dens imidazolider, dens syre-halogenider så som syrekloridet eller -bromidet, dens anhydrider, dens blandede anhydrider med alifatiske eller aromatiske karboksyl-, sulfen-, sulfin- eller sulfonsyrer eller karbonsyre-estere, f.eks. med eddiksyre, propionsyre, p-toluensulfonsyre eller O-etyl-karbonsyre, dens O-trifenylfosfoniumkomplekser, As possibly produced in the reaction mixture, functional derivatives of an aminobenzoic acid with the general formula IV come, e.g. in consideration of its alkyl, aryl or aralkyl esters or thioesters such as the methyl, ethyl, phenyl or benzyl ester, its copper complexes, its imidazolides, its acid halides such as the acid chloride or bromide, its anhydrides, its mixed anhydrides with aliphatic or aromatic carboxylic, sulfenic, sulfinic or sulfonic acids or carboxylic acid esters, e.g. with acetic acid, propionic acid, p-toluenesulfonic acid or O-ethyl-carboxylic acid, its O-triphenylphosphonium complexes,

dens N-acyloksyimider, dens azider eller nitriler eller de tilsvarende amino-tiobenzoesyre-derivater, og som eventuelt i reaksjonsblandingen fremstilte, reaktive derivater av et amin med den generelle formel V når Z ikke inneholder en karboksy-eller aminogruppe, dens fosfazoderivater. its N-acyloxyimides, its azides or nitriles or the corresponding amino-thiobenzoic acid derivatives, and optionally produced in the reaction mixture, reactive derivatives of an amine with the general formula V when Z does not contain a carboxy or amino group, its phosphazo derivatives.

Som syreaktiverende og/eller vanntiltrekkende midler kan f.eks. anvendes en klormaursyreester så som klormaursyreetylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N'-dicyklo-heksylkarbodi imid, N,N'-karbonyIdi imidazol, N,N * -1ionyldiimidazol, bortrifluorideterat eller trifenylfosfin/karbontetraklorid. As acid-activating and/or water-attracting agents, e.g. a chloroformic acid ester such as chloroformic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, N,N*-1ionyldiimidazole, boron trifluoride etherate or triphenylphosphine/carbon tetrachloride is used.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel The reaction is conveniently carried out in a solvent

så som metylenklorid, kloroform, karbontetraklorid, eter, tetrahydrofuran, dioksan, benzen, toluen eller dimetylformamid, 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, og eventuelt i nærvær av et syreaktiverende middel ved temperaturer mellom -25 og 250°C, fortrinnsvis ved temperaturer mellom -10°C og det anvendte oppløsningsmiddels koketemperatur. Herunder er det ikke nødvendig å isolere et eventuelt i reaksjonsblandingen dannet, funksjonelt derivat av en forbindelse med den generelle formel IV eller V, og videre kan omsetningen også utføres uten opp-løsningsmiddel. Videre kan vann som er dannet under omsetningen, fjernes ved azeotropisk destillasjon, f.eks. ved oppvarmning med toluen på en vannutskiller, eller ved tilsetning av et tørre-middel så som magnesiumsulfat eller molekylsikt. such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene or dimethylformamide, 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, and optionally in the presence of an acid activating agent at temperatures between -25 and 250°C, preferably at temperatures between -10°C and the boiling temperature of the solvent used. Here, it is not necessary to isolate any functional derivative of a compound of the general formula IV or V formed in the reaction mixture, and furthermore the reaction can also be carried out without a solvent. Furthermore, 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 sulfate or molecular sieves.

b) For fremstilling av forbindelser med den generelle b) For making connections with the general

formel I hvor er som innledningsvis angitt med unntagelse formula I where is as initially stated with exception

av en hydroksy- eller aminogruppe, og of a hydroxy or amino group, and

Y er en eventuelt med én eller to alkylgrupper med hver 1 til Y is an optionally with one or two alkyl groups with each 1 more

3 karbonatomer substituert metylengruppe: 3 carbon atoms substituted methylene group:

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

hvor R, R^ og Z er som innledningsvis angitt, og R^ og Y er som umiddelbart ovenfor angitt, og E er et halogenatom, where R, R^ and Z are as indicated at the outset, and R^ and Y are as indicated immediately above, and E is a halogen atom,

med et amin med den generelle formel with an amine of the general formula

hvor R^°9 R3 er som innledningsvis angitt. where R^°9 R3 is as indicated at the outset.

Med begrepet "et halogenatom" som er anvendt ved defini-sjonen av den utskiftbare rest E, skal særlig forstås et klor-eller bromatom eller også et fluoratom, når R, betyr en nitrogruppe. The term "a halogen atom" used in the definition of the replaceable residue E is to be understood in particular as a chlorine or bromine atom or also a fluorine atom, when R means a nitro group.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som vann, vann/metanol, vann/etanol, vann/isopropanol, dimetylformamid eller i et overskudd av det anvendte amin med den generelle formel VII, eventuelt i nærvær av en uorganisk eller tertiær organisk base, eventuelt i nærvær av en reaksjons-akselerator så som kobber, og eventuelt i et trykkar ved temperaturer mellom 20 og 150°C, fortrinnsvis ved reaksjonsblandingens koketemperatur, f.eks. ved 100°C. Omsetningen kan imidlertid også utføres uten oppløsningsmiddel. c) For fremstilling av forbindelser med den generelle formel I hvor Z betyr en karboksygruppe og Y ikke en NH-gruppe: The reaction is suitably carried out in a solvent such as water, water/methanol, water/ethanol, water/isopropanol, dimethylformamide or in an excess of the amine used with the general formula VII, optionally in the presence of an inorganic or tertiary organic base, optionally in presence of a reaction accelerator such as copper, and optionally in a pressure vessel at temperatures between 20 and 150°C, preferably at the boiling temperature of the reaction mixture, e.g. at 100°C. However, the reaction can also be carried out without a solvent. c) For the preparation of compounds of the general formula I where Z is a carboxy group and Y is not an NH group:

Oksydasjon av en forbindelse med den generelle formel Oxidation of a compound with the general formula

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

Y er som innledningsvis angitt med unntagelse av en NH-gruppe, og A betyr en gruppe som ved oksydasjon kan overføres til en karboksygruppe. Y is, as stated at the outset, with the exception of an NH group, and A means a group which can be transferred to a carboxy group by oxidation.

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

Omsetningen utføres 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 fortrinnsvis med sølvoksyd/natronlut, mangandioksyd/aceton eller metylenklorid, hydrogenperoksyd/natronlut, brom eller klor/ natron- eller kalilut eller kromtrioksyd/pyridin. 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. 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.

d) For fremstilling av forbindelser med den generelle formel I hvor Z betyr en karboksygruppe: Hydrolyse av en forbindelse med den generelle formel d) For the preparation of compounds of the general formula I where Z represents a carboxy group: Hydrolysis of a compound of the general formula

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

Som slike hydrolyserbare grupper kommer f.eks. i betraktning en nitrilgruppe, funksjonelle derivater av en karboksygruppe så som dens usubstituerte eller substituerte amider, estere, tioestere, ortoestere, iminoetere, amidiner eller anhydrider, As such hydrolyzable groups come e.g. in consideration of a nitrile group, functional derivatives of a carboxy group such as its unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides,

en malonester-(1)-yl-gruppe, en tetrazolylgruppe, en eventuelt substituert 1,3-oksazol-(2)-yl- eller dihydro-1,3-oksazol-(2)-yl-gruppe. a malonester-(1)-yl group, a tetrazolyl group, an optionally substituted 1,3-oxazol-(2)-yl or dihydro-1,3-oxazol-(2)-yl group.

Hydrolysen foretas 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 oppløsningsmiddel så som etanol, vann/ etanol, vann/isopropanol eller vann/dioksan ved temperaturer mellom -10 og 120°C, f.eks. ved temperaturer mellom romtemperatur og reaksjonsblandingens koketemperatur. The hydrolysis is suitably 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 ethanol, water/ethanol, 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.

Hvis B i en forbindelse med den generelle formel IX betyr If B in a compound of the general formula IX means

en cyangruppe, utføres omsetningen hensiktsmessig i nærvær av etanol/hydrogenklorid, hvorved det i reaksjonsblandingen dannes den tilsvarende imino- og ortoester resp. efter vanntilsetning den tilsvarende ester, som hydrolyseres efter tilsetning av vann. e) For fremstilling av forbindelser med den generelle formel I hvor R^ betyr en alkylgruppe med 1 til 7 karbonatomer, a cyano group, the reaction is suitably carried out in the presence of ethanol/hydrogen chloride, whereby the corresponding imino- and ortho-ester resp. after addition of water the corresponding ester, which is hydrolysed after addition of water. e) For the preparation of compounds of the general formula I where R^ means an alkyl group with 1 to 7 carbon atoms,

en cykloalkylgruppe med 3 til 7 karbonatomer, en med en fenylgruppe substituert alkylgruppe med 1 til 3 karbonatomer eller en alkenylgruppe med 3 til 7 karbonatomer, R^ betyr en alkyl- a cycloalkyl group of 3 to 7 carbon atoms, a phenyl group substituted alkyl group of 1 to 3 carbon atoms or an alkenyl group of 3 to 7 carbon atoms, R^ means an alkyl-

gruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7 karbonatomer, en alkenylgruppe med 3 til 7 karbonatomer, en med en fenylgruppe substituert alkylgruppe med 1 til 3 karbonatomer eller en adamantylgruppe, eller R- og R., sammen med det mellomliggende nitrogenatom betyr en 5- til 7-leddet alkylen-iminoring, en med en alkylgruppe med 1 til 4 karbonatomer substituert piperidinogruppe eller en i hver av stillingene 3 og 5 med en alkylgruppe med 1 til 3 karbonatomer substituert piperidinogruppe, og Y betyr en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe: Omsetning av en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel group of 1 to 7 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, an alkenyl group of 3 to 7 carbon atoms, a phenyl group substituted alkyl group of 1 to 3 carbon atoms or an adamantyl group, or R- and R., together with the intervening nitrogen atom means a 5- to 7-membered alkylene imino ring, one with an alkyl group of 1 to 4 carbon atoms substituted piperidino group or one in each of the 3 and 5 positions with an alkyl group of 1 to 3 carbon atoms substituted piperidino group, and Y means a optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted methylene group: Reaction of an optionally formed in the reaction mixture connection with the general formula

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

R^' betyr et hydrogenatom eller har de ovenfor for R^ angitte betydninger, og Y har de ovenfor angitte betydninger, R^' means a hydrogen atom or has the meanings indicated above for R^, and Y has the meanings indicated above,

med en forbindelse med den generelle formel with a compound of the general formula

R2' - G (XI) R2' - G (XI)

hvor R2' har de for R2 innledningsvis angitte betydninger eller betyr sammen med resten R3<1> i formel XI en lineær alkylengruppe med 4 til 6 karbonatomer, en med en alkylgruppe med 1 til 4 karbonatomer substituert n-pentylengruppe eller en i 2- og 4-stilling hver med en alkylgruppe med 1 til 3 karbonatomer substituert n-pentylengruppe, og G betyr en nukleofil, utgående gruppe så som et halogenatom eller en sulfonyloksygruppe, f.eks. et klor-, brom- eller jodatom, en metansulfonyloksy-eller p-toluensulfonyloksygruppe. where R2' has the meanings given for R2 at the beginning or means together with the residue R3<1> in formula XI a linear alkylene group with 4 to 6 carbon atoms, one with an alkyl group with 1 to 4 carbon atoms substituted n-pentylene group or one in 2- and 4-position each with an alkyl group of 1 to 3 carbon atoms substituted n-pentylene group, and G means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group.

Som et alkyleringsmiddel med formel XI kommer således f.eks. i betraktning de tilsvarende halogenider eller sulfater så som metyljodid, etyljodid, propylbromid, benzylklorid, benzylbromid, As an alkylating agent with formula XI, e.g. considering the corresponding halides or sulfates such as methyl iodide, ethyl iodide, propyl bromide, benzyl chloride, benzyl bromide,

dimetylsulfat eller dietylsulfat. dimethyl sulfate or diethyl sulfate.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel The reaction is conveniently carried out in a solvent

så som aceton, tetrahydrofuran, dimety1formamid, dimetylsulfoksyd eller heksametylfosforsyretriamid, eventuelt i nærvær av en uorganisk base så som natriumkarbonat, kaliumkarbonat eller kalium-tert.butylat eller en tertiær organisk base så som pyridin, ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 20 og 75°C. Hvis man anvender en karboksylsyre med den generelle formel X, kan denne alt efter de anvendte reaksjonsbetingelser, f.eks. ved temperaturer over romtemperatur og i nærvær av et alkoholat som base, samtidig overføres til den tilsvarende ester. 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 as pyridine, at temperatures between 0 and 150°C, preferably at temperatures between 20 and 75°C. If a carboxylic acid with the general formula X is used, this can, depending on the reaction conditions used, e.g. at temperatures above room temperature and in the presence of an alcoholate as a base, is simultaneously transferred to the corresponding ester.

Metyleringen kan også foretas ved at en forbindelse med The methylation can also be carried out by a compound with

den generelle formel X 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 opp til reaksjonsblandingens koketemperatur. the general formula X 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.

En forbindelse med den generelle formel X kan også fremstilles i reaksjonsblandingen ved omsetning av et passende substituert isatosyreanhydrid med et tilsvarende amin med den generelle formel V. f) For fremstilling av forbindelser med den generelle formel I hvor Y betyr en NH-gruppe eller et oksygenatom: A compound of the general formula X can also be prepared in the reaction mixture by reacting a suitably substituted isatoic anhydride with a corresponding amine of the general formula V. f) For the preparation of compounds of the general formula I where Y means an NH group or an oxygen atom :

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

hvor R og R-^ til R., er som innledningsvis angitt, og Y har de ovenfor angitte betydninger, eller dens alkalisalt, med et fenylderivat med den generelle formel where R and R-^ to R., are as initially indicated, and Y has the meanings indicated above, or its alkali salt, with a phenyl derivative of the general formula

hvor R. og Z er som innledningsvis angitt, og L betyr en nukleofil, utgående gruppe så som et halogenatom eller en sulfonyloksygruppe, f.eks. et klor-, brom- eller jodatom, en metylsulfonyloksy-, p-toluensulfonyloksy- eller metoksysulfonyl-oksygru<p>pe . where R. and Z are as indicated at the outset, and L means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methylsulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som vann/etanol, vann/isopropanol, tetrahydrofuran, dioksan, aceton, dimetylformamid, dimetylsulfoksyd eller heksametylfosforsyretriamid, fortrinnsvis i nærvær av en base så som natriumkarbonat, natriumhydroksyd, kaliumhydroksyd eller kalium-tert.butylat ved temperaturer mellom 0 og 150°C, fortrinnsvis ved reaksjonsblandingens koketemperatur, f.eks. ved temperaturer mellom 50 og 100°C. Hvis man her anvender en ester, kan denne alt efter de anvendte reaksjonsbetingelser, f.eks. The reaction is conveniently carried out in a solvent such as water/ethanol, water/isopropanol, tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide, preferably in the presence of a base such as sodium carbonate, sodium hydroxide, potassium hydroxide or potassium tert-butylate at temperatures between 0 and 150°C, preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 50 and 100°C. If an ester is used here, this can, depending on the reaction conditions used, e.g.

ved forhøyede temperaturer og i nærvær av et overskudd av den anvendte base, samtidig overføres til den tilsvarende karboksylsyre. at elevated temperatures and in the presence of an excess of the base used, is simultaneously transferred to the corresponding carboxylic acid.

g) For fremstilling av forbindelser med den generelle formel I hvor R^ er som innledningsvis angitt med unntagelse g) For the preparation of compounds of the general formula I where R^ is as stated at the outset with an exception

av en hydroksy-, karboksy-, amino- og alkanoylaminogruppe, of a hydroxy, carboxy, amino and alkanoylamino group,

og Y er en med én eller to alkylgrupper med and Y is one with one or two alkyl groups

hver 1 til 3 karbonatomer substituert metylengruppe: every 1 to 3 carbon atoms substituted methylene group:

Omsetning av et amid med den generelle formel Reaction of an amide with the general formula

hvor R, R2 og R^ er som innledningsvis angitt, og R^ har de ovenfor angitte betydninger, eller dets alkalisalt, med en forbindelse med den generelle formel where R, R 2 and R 3 are as initially indicated, and R 3 has the meanings indicated above, or its alkali salt, with a compound of the general formula

hvor R. og Z er som innledningsvis angitt, Y har de ovenfor angitte betydninger, og M betyr en nukleofil, utgående gruppe så som et halogenatom eller en sulfonyloksygruppe. where R. and Z are as indicated at the outset, Y has the meanings indicated above, and M means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som tetrahydrofuran, dioksan, toluen, dimetylformamid, dimetylsulfoksyd eller heksametylfosforsyretriamid, eventuelt i nærvær av en base så som natriumhydrid eller kalium-tert.butylat ved temperaturer mellom 20 og 180°C, fortrinnsvis ved temperaturer mellom 50 og 150°C. The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, toluene, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide, optionally in the presence of a base such as sodium hydride or potassium tert.butylate at temperatures between 20 and 180°C, preferably at temperatures between 50 and 150°C.

h) For fremstilling av forbindelser med den generelle formel I hvor R^ er et hydrogen-, fluor-, klor- eller bromatom, en alkyl- eller alkoksygruppe med hver 1 til 6 karbonatomer, en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, en hydroksy-, nitro-, karboksy- eller alkanoylaminogruppe, y er en eventuelt h) For the preparation of compounds of the general formula I where R^ is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group with 1 to 6 carbon atoms each, a phenyl group substituted alkoxy group with 1 to 3 carbon atoms , a hydroxy, nitro, carboxy or alkanoylamino group, y is an optionally

med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, og Z er en karboksygruppe: with one or two alkyl groups with each 1 to 3 carbon atoms substituted methylene group, and Z is a carboxy group:

Acylering av en forbindelse med den generelle formel Acylation of a compound of the general formula

hvor R og R2 til R^ er som innledningsvis angitt, R^ og Y har de ovenfor angitte betydninger, med et oksalylhlaogenid eller fosgen i nærvær av en Lewis syre. where R and R 2 to R 1 are as initially indicated, R 1 and Y have the meanings indicated above, with an oxalyl halogenide or phosgene in the presence of a Lewis acid.

Friedel-Crafts acyleringen foretas hensiktsmessig i et opp-løsningsmiddel så som nitrobenzen eller karbondisulfid i nærvær av en Lewis syre så som aluminiumklorid, ved temperaturer mellom O og 80°C, fortrinnsvis temperaturer mellom 20 og 60°C. The Friedel-Crafts acylation is conveniently carried out in a solvent such as nitrobenzene or carbon disulphide in the presence of a Lewis acid such as aluminum chloride, at temperatures between 0 and 80°C, preferably temperatures between 20 and 60°C.

i) For fremstilling av forbindelser med den generelle formel I hvor betyr et hydrogen-, fluor-, klor- eller bromatom, en alkyl- eller alkoksygruppe med hver 1 til 6 karbonatomer, en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, en nitro-, karboksy-, alkanoylamino-eller alkoksykarbonylgruppe med hver 1 til 3 karbonatomer i alkyldelen, Y er en eventuelt med én eller i) For the preparation of compounds of the general formula I where means a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, a phenyl group substituted alkoxy group having 1 to 3 carbon atoms, a nitro-, carboxy-, alkanoylamino- or alkoxycarbonyl group with each 1 to 3 carbon atoms in the alkyl part, Y is an optionally with one or

to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, og Z er en karboksygruppe: two alkyl groups with each 1 to 3 carbon atoms substituted methylene group, and Z is a carboxy group:

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

hvor R og R2 til R^ er som innledningsvis angitt, where R and R2 to R^ are as indicated at the outset,

R^ og Y har de ovenfor angitte betydninger, med et eventuelt R^ and Y have the meanings indicated above, with an optional

i reaksjonsblandingen fremstilt hypohalogenitt. hypohalite produced in the reaction mixture.

Omsetningen foretas hensiktsmessig i et oppløsningsmiddel så som vann/tetrahydrofuran eller vann/dioksan ved temperaturer mellom 0 og 80°C, fortrinnsvis ved temperaturer mellom 25 og 50°C. The reaction is conveniently carried out in a solvent such as water/tetrahydrofuran or water/dioxane at temperatures between 0 and 80°C, preferably at temperatures between 25 and 50°C.

Hvis man i henhold til oppfinnelsen fremstiller et karboksylsyreamid med den generelle formel I hvor Z betyr en karboksygruppe, kan dette eventuelt ved forestring resp. ved amidering overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en forestret karboksygruppe eller en eventuelt med en alkylgruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7 karbonatomer og/eller alkenylgruppe med 3 til 7 karbonatomer mono- eller disubstituert aminokarbonylgruppe, en piperidinokarbonyl-, ncrfolinokarbonyl-, tiomorfolinokarbonyl- eller N-alkyl-piperazinokarbonylgruppe, og/eller et fremstilt karboksylsyreamid med den generelle formel I hvor R^ og/eller Z betyr en nitrogruppe, kan ved reduksjon overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ og/eller Z betyr en aminogruppe, og/eller et fremstilt karboksylsyreamid med den generelle formel I hvor R^ og/eller Z betyr en aminogruppe, kan over et tilsvarende diazoniumsalt overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en hydroksy- eller cyangruppe, et fluor-, klor- eller bromatom og/eller Z et klor- If, according to the invention, a carboxylic acid amide of the general formula I is prepared where Z means a carboxy group, this can possibly be done by esterification or by amidation is transferred to a corresponding compound with the general formula I where Z is an esterified carboxy group or one optionally with an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms and/or an alkenyl group with 3 to 7 carbon atoms mono- or disubstituted aminocarbonyl group, a piperidinocarbonyl, ncrfolinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinocarbonyl group, and/or a prepared carboxylic acid amide of the general formula I where R^ and/or Z is a nitro group, can be transferred by reduction to a corresponding compound with the general formula I where R^ and/or Z denotes an amino group, and/or a prepared carboxylic acid amide of the general formula I where R^ and/or Z denotes an amino group, can be transferred via a corresponding diazonium salt to a corresponding compound of the general formula I where R^ means a hydroxy or cyano group, a fluorine, chlorine or bromine atom and/or Z a chlorine

eller bromatom eller en nitrilgruppe, idet en således eventuelt erholdt forbindelse med den generelle formel I hvor R^ betyr en hydroksygruppe, derefter ved alkylering kan overføres til den tilsvarende forbindelse med den generelle formel I hvor R^or a bromine atom or a nitrile group, a compound thus possibly obtained with the general formula I where R^ means a hydroxy group can then be transferred by alkylation to the corresponding compound with the general formula I where R^

betyr en alkoksygruppe med 1 til 6 karbonatomer eller en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, og/eller means an alkoxy group with 1 to 6 carbon atoms or a phenyl group substituted alkoxy group with 1 to 3 carbon atoms, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor R^ er en aminogruppe, kan ved acylering overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ er en alkanoylaminogruppe med 1 til 3 karbonatomer i alkanoyldelen, og/eller a prepared carboxylic acid amide of the general formula I where R^ is an amino group can be transferred by acylation to a corresponding compound of the general formula I where R^ is an alkanoylamino group with 1 to 3 carbon atoms in the alkanoyl part, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor R^ er en alkoksykarbonylgruppe og/eller R^ og R^ sammen med det mellomliggende nitrogenatom er en med en alkoksykarbonylgruppe substituert iminogruppe med 4 til 6 karbonatomer, idet alkoksydelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, a prepared carboxylic acid amide of the general formula I where R^ is an alkoxycarbonyl group and/or R^ and R^ together with the intervening nitrogen atom is an imino group substituted with an alkoxycarbonyl group with 4 to 6 carbon atoms, the alkoxy part in each case may contain 1 to 3 carbon atoms,

kan ved hydrolyse overføres til en tilsvarende forbindelse med den generelle formel I hvor R^ er en karboksygruppe og/eller R^ og R^ sammen med det mellomliggende nitrogenatom er en med en karboksygruppe substituert iminogruppe med 4 til 7 karbonatomer i iminoringen, og/eller can by hydrolysis be transferred to a corresponding compound with the general formula I where R^ is a carboxy group and/or R^ and R^ together with the intervening nitrogen atom is an imino group substituted with a carboxy group with 4 to 7 carbon atoms in the imino ring, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor R^ og R-j sammen med det mellomliggende nitrogenatom er en N-benzylpiperazinogruppe, overføres ved debenzylering til en tilsvarende forbindelse med den generelle formel I hvor R^ og R^ sammen med det mellomliggende nitrogenatom betyr en piperazinogruppe, og/eller a prepared carboxylic acid amide of the general formula I where R^ and R^ together with the intermediate nitrogen atom is an N-benzylpiperazino group is transferred by debenzylation to a corresponding compound of the general formula I where R^ and R^ together with the intermediate nitrogen atom means a piperazino group , and or

et fremstilt karboksylsyreamid med den generelle formel I hvor R^ er et klor- eller bromatom, overføres ved dehalogenering til en tilsvarende forbindelse med den generelle formel I hvor R^a prepared carboxylic acid amide of the general formula I where R^ is a chlorine or bromine atom is transferred by dehalogenation to a corresponding compound of the general formula I where R^

er et hydrogenatom, og/eller is a hydrogen atom, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en eventuelt forestret karboksygruppe, kan ved reduksjon a prepared carboxylic acid amide of the general formula I where Z is an optionally esterified carboxy group, can by reduction

med et metallhydrid overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en hydroksymetylgruppe, og/eller with a metal hydride is transferred to a corresponding compound of the general formula I where Z is a hydroxymethyl group, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en hydroksymetylgruppe, kan ved oksydasjon overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en formylgruppe, og/eller a prepared carboxylic acid amide of the general formula I where Z is a hydroxymethyl group can be transferred by oxidation to a corresponding compound of the general formula I where Z is a formyl group, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en hydroksymetylgruppe, kan ved halogenering og påfølgende omsetning med en malonsyreester overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en med to alkoksykarbonylgrupper substituert etylgruppe, og/eller et karboksylsyreamid med den generelle formel I hvor Z er en formylgruppe, kan ved acetalisering overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en dialkoksymetylgruppe, og/eller a prepared carboxylic acid amide with the general formula I where Z is a hydroxymethyl group can, by halogenation and subsequent reaction with a malonic acid ester, be transferred to a corresponding compound with the general formula I where Z is an ethyl group substituted with two alkoxycarbonyl groups, and/or a carboxylic acid amide with the general formula I where Z is a formyl group, can be transferred by acetalization to a corresponding compound with the general formula I where Z is a dialkoxymethyl group, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en formylgruppe, kan ved kondensasjon og eventuelt på-følgende hydrolyse overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en med en hydroksykarbonyl-eller alkoksykarbonylgruppe substituert etylengruppe, a prepared carboxylic acid amide with the general formula I where Z is a formyl group, can by condensation and possibly subsequent hydrolysis be transferred to a corresponding compound with the general formula I where Z is an ethylene group substituted with a hydroxycarbonyl or alkoxycarbonyl group,

og/eller and or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er et hydrogenatom, kan ved Friedel-Crafts acylering overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en eventuelt med en alkoksykarbonylgruppe substituert acetylgruppe og/eller a prepared carboxylic acid amide of the general formula I where Z is a hydrogen atom can be transferred by Friedel-Crafts acylation to a corresponding compound of the general formula I where Z is an acetyl group optionally substituted with an alkoxycarbonyl group and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en nitrilgruppe, kan ved alkoholyse over en tilsvarende iminoester overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en trialkoksymetylgruppe, a prepared carboxylic acid amide with the general formula I where Z is a nitrile group, can be transferred by alcoholysis over a corresponding iminoester to a corresponding compound with the general formula I where Z is a trialkoxymethyl group,

og/eller and or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en trialkoksymetylgruppe, overføres ved hydrolyse til en tilsvarende forbindelse med den generelle formel I hvor Z er en alkoksykarbonylgruppe, og/eller a prepared carboxylic acid amide of the general formula I where Z is a trialkoxymethyl group is transferred by hydrolysis to a corresponding compound of the general formula I where Z is an alkoxycarbonyl group, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en acetyltruppe, kan ved oppvarmning med et amin og svovel og derefter med en uorganisk base, overføres til en tilsvarende a prepared carboxylic acid amide of the general formula I where Z is an acetyl group can, by heating with an amine and sulfur and then with an inorganic base, be transferred to a corresponding

forbindelse med den generelle formel I hvor Z er en 2-hydroksy-karbonylmetylgruppe, og/eller compound of the general formula I where Z is a 2-hydroxycarbonylmethyl group, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor Z er en karboksygruppe, kan ved overføring til et sulfonsyrehydrazid og påfølgende disproporsjonering overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en formylgruppe, og/eller a prepared carboxylic acid amide of the general formula I where Z is a carboxy group can, by transfer to a sulfonic acid hydrazide and subsequent disproportionation, be transferred to a corresponding compound of the general formula I where Z is a formyl group, and/or

et fremstilt karboksylsyreamid med den generelle formel I hvor R^ er et hydrogen-, fluor-, klor- eller bromatom, en alkyl-eller alkoksygruppe med hver 1 til 6 karbonatomer eller en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, Y er en eventuelt med én eller to a prepared carboxylic acid amide of the general formula I where R^ is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms or a phenyl group substituted alkoxy group having 1 to 3 carbon atoms, Y is one possibly with one or two

alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, og Z er et klor- eller bromatom, kan efter overføring til en tilsvarende metallorganisk forbindelse med karbondioksyd, overføres til en tilsvarende forbindelse med den generelle formel I hvor Z er en karboksygruppe. alkyl groups with every 1 to 3 carbon atoms substituted methylene group, and Z is a chlorine or bromine atom, can, after transfer to a corresponding organometallic compound with carbon dioxide, be transferred to a corresponding compound with the general formula I where Z is a carboxy group.

Den påfølgende forestring resp. amidering foretas hensiktsmessig i et egnet oppløsningsmiddel, f.eks. i en passende alkohol eller amin, pyridin, toluen eller dioksan, i nærvær av et syreaktiverende og/eller vanntiltrekkende middel så som tionylklorid, klormaursyreetylester, N,N'-dicykloheksy1-karbodiimid eller karbonyldiimidazol eller ved omforestring, f.eks. med en passende karbonsyrediester, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. The subsequent esterification or amidation is conveniently carried out in a suitable solvent, e.g. in a suitable alcohol or amine, pyridine, toluene or dioxane, in the presence of an acid-activating and/or water-attracting agent such as thionyl chloride, chloroformate ethyl ester, N,N'-dicyclohexy1-carbodiimide or carbonyldiimidazole or by transesterification, e.g. with a suitable carbonic acid diester, at temperatures between 0 and 50°C, preferably at room temperature.

Den påfølgende 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, 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. 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, 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 påfølgende omsetning av et diazoniumsalt, f.eks. fluor-boratet, hydrosulfatet i svovelsyre eller hydrokloridet i nærvær av kobber eller et passende kobber(I)salt, så som kobber(I)-klorid/saltsyre, kobber(I)bromid/bromhydrogensyre eller trinatrium-kobber(I)tetracyanid ved pH 7, foretas ved svakt forhøyede temperaturer, f.eks. ved temperaturer mellom 15 og 100°C. Det for formålet nødvendige diazoniumsalt fremstilles hensiktsmessig i et egnet oppløsningsmiddel, f.eks. i vann/ saltsyre, metanol/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, or the hydrochloride in the presence of copper or a suitable copper(I) salt, such as copper(I) chloride/hydrochloric acid, copper(I) bromide/hydrobromic acid, or trisodium copper(I) tetracyanide at pH 7, is carried out at slightly elevated temperatures, e.g. at temperatures between 15 and 100°C. The diazonium salt required for the purpose is suitably prepared in a suitable solvent, e.g. in water/hydrochloric acid, methanol/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 påfølgende 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 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°C og reaksjonsblandingens koketemperatur. The subsequent acylation is suitably 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 tertiary organic base, which at the same time 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°C and the boiling temperature of the reaction mixture.

Den påfølgende hydrolyse foretas hensiktsmessig enten i nærvær av en syre så som saltsyre, svovelsyre, fosforsyre eller trifluoreddiksyre, eller i nærvær av en base så som natriumhydroksyd eller kaliumhydroksyd, i et egnet oppløsningsmiddel så som etanol, vann/etanol, vann/isopropanol eller vann/dioksan, ved forhøyet temperatur, f.eks. ved reaksjonsblandingens koketemperatur. The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as ethanol, water/ethanol, water/isopropanol or water /dioxane, at elevated temperature, e.g. at the boiling temperature of the reaction mixture.

Den påfølgende debenzylering og/eller dehalogenering foretas hensiktsmessig i et oppløsningsmiddel så som metanol, etanol, etylacetat eller iseddik, 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 debenzylation and/or dehalogenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, 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 O-alkylering foretas hensiktsmessig med et tilsvarende halogenid eller en sulfonsyreester, f.eks. med metyljodid, dimetylsulfat, etylbromid, p-toluensulfonsyre-benzylester eller metansulfonsyre-isopropylester, 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. The subsequent O-alkylation is suitably carried out with a corresponding halide or a sulphonic acid ester, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, p-toluenesulfonic acid benzyl ester or methanesulfonic acid isopropyl 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.

Den påfølgende reduksjon med et metallhydrid foretas hensiktsmessig med et komplekst metallhydrid så som litium-aluminiumhydrid i et oppløsningsmiddel så som dietyleter, tetrahydrofuran eller dioksan ved temperaturer mellom 0 og 100°C, fortrinnsvis ved reaksjonsblandingens koketemperatur. The subsequent reduction with a metal hydride is conveniently carried out with a complex metal hydride such as lithium aluminum hydride in a solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture.

Den påfølgende oksydasjon av en hydroksymetylgruppe foretas hensiktsmessig med et metalloksyd så som mangandioksyd, i et oppløsningsmiddel så som aceton eller diklormetan, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. The subsequent oxidation of a hydroxymethyl group is conveniently carried out with a metal oxide such as manganese dioxide, in a solvent such as acetone or dichloromethane, at temperatures between 0 and 50°C, preferably at room temperature.

Den påfølgende overføring av en hydroksymetylgruppe til The subsequent transfer of a hydroxymethyl group to

en halogenmetylgruppe foretas med et halogeneringsmiddel så som tionylklorid, fosfortriklorid, fosfortribromid eller fosfor-pentaklorid, i et oppløsningsmiddel så som metylenklorid, karbontetraklorid, benzen eller nitrobenzen, og den påfølgende omsetning med en malonsyreester, f.eks. med et alkalisalt av malonsyredietylester, foretas ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 50°C. 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 the subsequent reaction with a malonic acid ester, e.g. with an alkali salt of malonic acid diethyl ester, is carried out at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C.

Den påfølgende acetaldannelse foretas hensiktsmessig i den tilsvarende alkohol som oppløsningsmiddel, f.eks. i metanol eller etanol, i nærvær av en syre så som saltsyre eller svovelsyre, eller ved omacetalisering med en tilsvarende orto-ester, f.eks. ortomaursyretrietylester, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 30 og 60°C. The subsequent acetal formation is conveniently carried out in the corresponding alcohol as solvent, e.g. in methanol or ethanol, in the presence of an acid such as hydrochloric or sulfuric acid, or by omacetalization with a corresponding ortho-ester, e.g. triethyl orthoformic acid, at temperatures between 0 and 100°C, preferably at temperatures between 30 and 60°C.

Den påfølgende kondensasjon av en formyl-forbindelse fore- The subsequent condensation of a formyl compound pre-

tas hensiktsmessig i et oppløsningsmiddel så som pyridin eller tetrahydrofuran, med malonsyre, med en malonsyreester eller en trialkylfosfon-eddiksyreester, 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, og ved påfølgende surgjøring, f.eks. med saltsyre eller svovelsyre, får man den ønskede syre. is suitably taken in a solvent such as pyridine or tetrahydrofuran, with malonic acid, with a malonic acid ester or a trialkylphosphonic acetic acid ester, optionally in the presence of a base as a condensing agent, e.g. in the presence of piperidine, potassium tert.butylate or sodium hydride, at temperatures between 0 and 100°C, and with subsequent acidification, e.g. with hydrochloric or sulfuric acid, the desired acid is obtained.

Den påfølgende Friedel-Crafts acylering foretas med et tilsvarende syrehalogenid eller syreanhydrid i et egnet opp-løsningsmiddel så som karbondisulfid, metylenklorid, dikloretan eller nitrobenzen, og i nærvær av en Friedel-Crafts-katalysator så som aluminiumklorid, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. The subsequent Friedel-Crafts acylation is carried out with a corresponding acid halide or acid anhydride in a suitable solvent such as carbon disulfide, methylene chloride, dichloroethane or nitrobenzene, and in the presence of a Friedel-Crafts catalyst such as aluminum chloride, at temperatures between 0 and 50° C, preferably at room temperature.

Den påfølgende alkoholyse foretas fortrinnsvis i en tilsvarende, vannfri alkohol som oppløsningsmiddel, f.eks. i vann- The subsequent alcoholysis is preferably carried out in a corresponding, anhydrous alcohol as solvent, e.g. in water

fri metanol, etanol eller propanol, i nærvær av en syre så som hydrogenklorid eller svovelsyre, ved forhøyet temperatur, fortrinns- free methanol, ethanol or propanol, in the presence of an acid such as hydrogen chloride or sulfuric acid, at elevated temperature, preferably

vis ved reaksjonsblandingens koketemperatur. show at the boiling temperature of the reaction mixture.

Den påfølgende Willgerodt-reaksjon foretas hensiktsmessig The subsequent Willgerodt reaction is carried out appropriately

i et alkoholisk oppløsningsmiddel så som metanol, etanol eller isopropanol, ved oppvarmning av acetylforbindelsen med et amin, f.eks. med morfolin, i nærvær av svovel; det således erholdte, tilsvarende tioamid overføres derefter ved oppvarmning i nærvær av en uorganisk base så som natriumhydroksyd, til det tilsvarende eddiksyre-derivat, og særlig fordelaktig foretas omsetningen ved reaksjonsblandingens koketemperatur. in an alcoholic solvent such as methanol, ethanol or isopropanol, by heating the acetyl compound with an amine, e.g. with morpholine, in the presence of sulphur; the corresponding thioamide thus obtained is then transferred by heating in the presence of an inorganic base such as sodium hydroxide to the corresponding acetic acid derivative, and the reaction is particularly advantageously carried out at the boiling temperature of the reaction mixture.

Den påfølgende hydrolyse av en ortoester foretas hensiktsmessig i et oppløsningsmiddel så som vann/metanol, vann/dioksan, vann/etanol eller vann/propanol i nærvær av en syre så som saltsyre eller svovelsyre, ved lavere temperatur, f.eks. ved romtemperatur. The subsequent hydrolysis of an orthoester is conveniently carried out in a solvent such as water/methanol, water/dioxane, water/ethanol or water/propanol in the presence of an acid such as hydrochloric acid or sulfuric acid, at a lower temperature, e.g. at room temperature.

Den påfølgende 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.

overføringen av en passende forbindelse med den generelle formel I til en tilsvarende metallorganisk forbindelse foretas hensiktsmessig i et inert oppløsningsmiddel så som dietyleter, tetrahydrofuran, dioksan eller tetrahydrofuran/n-heksan, eventuelt under beskyttelsesgass, f.eks. under nitrogen, fortrinnsvis med en tilsvarende litiumforbindelse, f.eks. butyl-litium i n-heksan, ved temperaturer mellom -60 og 50°C. Derefter innføres en således erholdt oppløsning av en tilsvarende metallorganisk forbindelse, eventuelt under beskyttelsesgass, the transfer of a suitable compound of the general formula I to a corresponding organometallic compound is conveniently carried out in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane or tetrahydrofuran/n-hexane, optionally under protective gas, e.g. under nitrogen, preferably with a corresponding lithium compound, e.g. butyl lithium in n-hexane, at temperatures between -60 and 50°C. A solution of a corresponding organometallic compound thus obtained is then introduced, possibly under protective gas,

i fortrinnsvis fast karbondioksyd. in preferably solid carbon dioxide.

De erholdte forbindelser med de generelle formler I og Ia kan dessuten overføres til sine fysiologisk forlikelige salter med uorganiske eller organiske syrer eller også baser når W eller Z er en karboksygruppe eller Z inneholder en karboksy-gruppe. Som syrer kommer f.eks. i betraktning saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, melkesyre, sitronsyre, vinsyre, ravsyre, maleinsyre eller fumarsyre, og som baser natriumhydroksyd, kaliumhydroksyd eller cykloheksylamin. The obtained compounds with the general formulas I and Ia can also be transferred to their physiologically compatible salts with inorganic or organic acids or also bases when W or Z is a carboxy group or Z contains a carboxy group. As acids come 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 They used compounds with those as starting materials

generelle formler II til XVII er kjent fra litteraturen, resp. man får dem ved i og for seg kjente fremgangsmåter. Således får man f.eks. en forbindelse med den generelle formel II eller IV ved omsetning av en 2-klor- eller 2-brom-nitro-karboksylsyre eller derivater derav, med et tilsvarende amin, påfølgende reduksjon av nitrogruppen i en således erholdt 2-amino-forbindelse ved katalytisk aktivert hydrogen, ved hjelp av nascerende hydrogen, med metaller eller metallsalter, og overføring av den således erholdte aminogruppe over et tilsvarende diazoniumsalt til en tilsvarende forbindelse med den generelle formel II general formulas II to XVII are known from the literature, resp. they are obtained by methods known per se. Thus, you get e.g. a compound of the general formula II or IV by reaction of a 2-chloro- or 2-bromo-nitrocarboxylic acid or derivatives thereof, with a corresponding amine, subsequent reduction of the nitro group in a thus obtained 2-amino compound by catalytically activated hydrogen, by means of nascent hydrogen, with metals or metal salts, and transfer of the amino group thus obtained over a corresponding diazonium salt to a corresponding compound of the general formula II

eller IV. For fremstilling av en utgangsforbindelse med den generelle formel II eller IV hvor R^ er en alkoksy- eller fenylalkyloksygruppe, alkyleres derefter en således fremstilt hydroksy-karboksylsyre og hydrolyseres eventuelt derefter. or IV. For the preparation of a starting compound of the general formula II or IV where R 1 is an alkoxy or phenylalkyloxy group, a hydroxy carboxylic acid thus prepared is then alkylated and possibly then hydrolysed.

En forbindelse med den generelle formel V hvor Y ikke A compound of the general formula V where Y does not

betyr en NH-gruppe og ikke et oksygenatom, får man f.eks. ved omsetning av et tilsvarende 4-(a-bromalkyl)-benzen-derivat med natriumcyanid og påfølgende katalytisk hydrogenering av den således erholdte cyanoforbindelse. means an NH group and not an oxygen atom, you get e.g. by reaction of a corresponding 4-(α-bromoalkyl)-benzene derivative with sodium cyanide and subsequent catalytic hydrogenation of the thus obtained cyano compound.

En forbindelse med den generelle formel V hvor Y betyr en NH-gruppe eller et oksygenatom, får man f.eks. ved omsetning av et tilsvarende 4-(a-bromalkyl)-benzen-derivat med en hydroksam-syre eller en ester derav eller med et acyl-hydrazin og eventuelt påfølgende hydrolyse. A compound with the general formula V where Y means an NH group or an oxygen atom, you get e.g. by reaction of a corresponding 4-(α-bromoalkyl)-benzene derivative with a hydroxamic acid or an ester thereof or with an acyl-hydrazine and possibly subsequent hydrolysis.

En forbindelse med den generelle formel V hvor Y er en NH-gruppe, får man også ved omsetning av et 4-formyl- eller 4-acyl-benzen-derivat med et N-acyl-hydrazin, påfølgende reduksjon av det erholdte hydrazon, f.eks. ved katalytisk hydrogenering, og påfølgende hydrolytisk avspaltning av acyIresten. A compound with the general formula V where Y is an NH group is also obtained by reacting a 4-formyl or 4-acyl-benzene derivative with an N-acyl-hydrazine, followed by reduction of the resulting hydrazone, f .ex. by catalytic hydrogenation, and subsequent hydrolytic cleavage of the acyl residue.

En således erholdt rest med den generelle formel V kan eventuelt overføres til den tilsvarende karboksylsyre ved hydrolyse. A thus obtained residue with the general formula V can optionally be transferred to the corresponding carboxylic acid by hydrolysis.

En som utgangsstoff anvendt forbindelse med de generelle formler VI, VIII til X, XIV, XVI og XVII får man ved omsetning av en tilsvarende karboksylsyre med ammoniakk eller et tilsvarende amin i nærvær av et syreaktiverende eller vanntiltrekkende middel. A compound of the general formulas VI, VIII to X, XIV, XVI and XVII used as starting material is obtained by reacting a corresponding carboxylic acid with ammonia or a corresponding amine in the presence of an acid-activating or water-attracting agent.

En som utgangsstoff anvendt forbindelse med den generelle formel XII får man ved omsetning av en tilsvarende karboksylsyre-ester med hydrazin eller hydroksylamin. A compound with the general formula XII used as starting material is obtained by reacting a corresponding carboxylic acid ester with hydrazine or hydroxylamine.

En som utgangsstoff anvendt forbindelse med de generelle formler XIII eller XV får man ved halogenering av en tilsvarende alkohol eller omsetning av et sulfonsyrehalogenid med en tilsvarende alkohol i nærvær av en base. A compound of the general formulas XIII or XV used as a starting material is obtained by halogenating a corresponding alcohol or reacting a sulfonic acid halide with a corresponding alcohol in the presence of a base.

Som nevnt innledningsvis oppviser de nye forbindelser med den generelle formel I verdifulle farmakologiske egenskaper, nemlig en virkning på stoffskiftet. Således er forbindelsene med den generelle formel I særlig i besittelse av en blodsukkersenkende og/eller lipid-senkende virkning. Forbindelsene med den generelle formel Ia og forbindelsene med den generelle formel I hvor Z er et hydrogen- eller halogenatom, en nitro-, amino- eller cyangruppe, representerer verdifulle mellomprodukter for fremstilling av de nye forbindelser med den generelle formel I. As mentioned at the outset, the new compounds with the general formula I exhibit valuable pharmacological properties, namely an effect on metabolism. Thus, the compounds of the general formula I particularly possess a blood sugar-lowering and/or lipid-lowering effect. The compounds of the general formula Ia and the compounds of the general formula I where Z is a hydrogen or halogen atom, a nitro, amino or cyano group, represent valuable intermediates for the preparation of the new compounds of the general formula I.

Som eksempler ble forbindelsene As examples were the compounds

A = 4-[2-(5-klor-2-dimetylamino-benzoylamino)-etyl]-benzoesyre, A = 4-[2-(5-chloro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid,

B = 4-[2-(5-brom-2-dimetylamino-benzoylamino)-etyl]-benzoesyre, B = 4-[2-(5-bromo-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid,

C = 4-[2-(5-klor-2-piperidino-benzoylamino)-etyl]-benzoesyre-metylester, C = 4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid methyl ester,

D = 4-[2-(5-klor-2-piperidino-benzoylamino)-etyl]-benzoesyre, D = 4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid,

E = 4-[2-(5-klor-2-(2-metyl-piperidino)-benzoylamino)-etyl]-benzoesyre, E = 4-[2-(5-chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid,

F = 4-[2-(5-klor-2-(3-metyl-piperidino)-benzoylamino)-etyl]-benzoesyre, F = 4-[2-(5-chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid,

G = 4-[2-(5-klor-2-(4-mety1-piperidino)-benzoylamino)-etyl]-benzoesyre, G = 4-[2-(5-chloro-2-(4-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid,

H = 4-[2-(5-klor-2-(3,5-dimetyl-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester, H = 4-[2-(5-chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester,

I = 4-[2-(5-klor-2-(3,5-dimetyl-piperidino)-benzoylamino)-etyl]-benzoesyre, I = 4-[2-(5-chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid,

K = 4-[2-(5-klor-2-(4-metoksy-piperidino)-benzoylamino)-etyl]-benzoesyre, K = 4-[2-(5-chloro-2-(4-methoxy-piperidino)-benzoylamino)-ethyl]-benzoic acid,

L = 4-[2-(5-metoksy-2-piperidino-benzoylamino)-etyl]-benzoesyre-hydroklorid, L = 4-[2-(5-methoxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid hydrochloride,

M = 4-[2-(5-klor-2-heptametylenimino-benzoylamino)-etyl]-benzoesyre, M = 4-[2-(5-chloro-2-heptamethyleneimino-benzoylamino)-ethyl]-benzoic acid,

N = 4-[2-(5-klor-2-(1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl)-benzoylamino)-ety1]-benzoesyre, N = 4-[2-(5-chloro-2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-benzoylamino)-ethyl]-benzoic acid,

0 = 4-[2- (5-klor-2-heksametylenimino-benzoylamino)-etyl]-benzoesyre, 0 = 4-[2-(5-chloro-2-hexamethyleneimino-benzoylamino)-ethyl]-benzoic acid,

P = 4-[2-(5-klor-2-tiomorfolino-benzoylamino)-etyl]benzoe- P = 4-[2-(5-chloro-2-thiomorpholino-benzoylamino)-ethyl]benzoe-

syre, acid,

Q = 4-[2-(5-brom-2-piperidino-benzoylamino)-ety1]-benzoesyre, Q = 4-[2-(5-bromo-2-piperidino-benzoylamino)-ethyl]-benzoic acid,

R = 4-[2-(5-klor-2-piperidino-benzoylamino)-1-metyl-etyl]-benzoesyre, R = 4-[2-(5-chloro-2-piperidino-benzoylamino)-1-methyl-ethyl]-benzoic acid,

S = 4-[2-(5-brom-2-(2-mety1-piperidino)-benzoylamino)-etyl]-benzoesyre, S = 4-[2-(5-bromo-2-(2-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid,

T = 4- [2- (5-klor-2-(2,6-dimety1-morfolino)-benzoylamino)-ety1]-benzoesyre, T = 4-[2-(5-chloro-2-(2,6-dimethyl-morpholino)-benzoylamino)-ethyl]-benzoic acid,

U = 4-[2-(5-klor-2-(2,6-dimety1-tiomorfolino)-benzoylamino)-etyl]-benzoesyre, U = 4-[2-(5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoylamino)-ethyl]-benzoic acid,

V - 4-[2-(5-brom-2-heptametylenimino-benzoylamino)-etyl]-benzoesyre-etylester, V - 4-[2-(5-bromo-2-heptamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester,

W = 4-[2-(5-brom-2-heptametylenimino-benzoylamino)-etyl]-benzoesyre, W = 4-[2-(5-bromo-2-heptamethyleneimino-benzoylamino)-ethyl]-benzoic acid,

X = 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre, X = 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid,

Y = 4-[2-(5-klor-2-(dekahydro-isokinolin-2-yl)-benzoylamino)-etyl]-benzoesyre-hydroklorid, Y = 4-[2-(5-chloro-2-(decahydro-isoquinolin-2-yl)-benzoylamino)-ethyl]-benzoic acid hydrochloride,

Z = 4-[2-(5-brom-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-hydroklorid, Z = 4-[2-(5-bromo-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid hydrochloride,

AA= 4-[2-(5-etyl-2-piperidino-benzoylamino)-etyl]-benzoesyre, BB= 4-[2-(5-metyl-2-piperidino-benzoylamino)-etyl]-benzoesyre, CC= 4-[2-(2-(N-adamantyl-(1)-N-metyl-amino)-5-klor-benzoylamino)-etyl]-benzoesyre, AA= 4-[2-(5-ethyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid, BB= 4-[2-(5-methyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid, CC= 4-[2-(2-(N-adamantyl-(1)-N-methyl-amino)-5-chloro-benzoylamino)-ethyl]-benzoic acid,

DD= 4-[2- (2-piperidino-nikotinoylamino)-etyl]-benzoesyre, DD= 4-[2-(2-piperidino-nicotinoylamino)-ethyl]-benzoic acid,

EE= 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre -etylester, EE= 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid -ethyl ester,

FF= 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzyl-alkohol, FF= 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzyl alcohol,

GG= N 1 -(1-(4-karboksyfenyl)-etyl)-N 2-(5-klor-2-piperidino-benzoyl)-hydrazin og GG= N 1 -(1-(4-carboxyphenyl)-ethyl)-N 2-(5-chloro-2-piperidino-benzoyl)-hydrazine and

HH= 4-[1-(5-klor-2-oktametylenimino-benzoylaminoksy)-etyl]-benzoesyre HH= 4-[1-(5-chloro-2-octamethyleneimino-benzoylaminooxy)-ethyl]-benzoic acid

undersøkt i sammenligning med examined in comparison with

11= 4-[2-(2-etylamino-5-klor-benzoylamino)-etyl]-benzoesyre 11= 4-[2-(2-ethylamino-5-chloro-benzoylamino)-ethyl]-benzoic acid

(se eksempel 5 i belgisk patent 837 311) (see example 5 in Belgian patent 837 311)

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

Den blodsukkersenkende virkning av prøveforbindelsene ble undersøkt på hunnrotter av egen avl med en vekt på 180-220 g, som ble holdt fastende 24 timer før forsøkets begynnelse. 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 compounds was investigated on female rats of own breeding with a weight of 180-220 g, which were fasted 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 dessuten 1, 2, 3 og 4 timer derefter, hver gang fra den retroorbitale veneplexus. Av hver prøve ble 50 pl behandlet med 0,5 ml 0,33N perklorsyre for å fjerne eggehvite og ble sentrifugert. I væsken på toppen ble glukose bestemt ved heksokinase-metoden ved hjelp av et analysefoto-meter. Den statistiske beregning ble foretatt efter t-testen ifølge Student med p = 0,05 som signifikansgrense. Blood was sampled immediately prior to administration of the test compound and also 1, 2, 3 and 4 hours thereafter, each time from the retroorbital venous plexus. Of each sample, 50 µl was treated with 0.5 ml of 0.33N perchloric acid to remove egg white and was centrifuged. In the liquid on top, glucose was determined by the hexokinase method using an analytical photometer. The statistical calculation was carried out according to Student's t-test with p = 0.05 as the significance limit.

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

n.s. - statistisk ikke signifikant n.s. - statistically not significant

3. A kutt toksisitet 3. A cut toxicity

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

ble den toksiske virkning av forbindelsene efter oral administrering (suspensjon i l%ig metylcellulose) av en enkelt dose undersøkt ved en påfølgende observasjonstid på minst 7 dager. Den følgende tabell inneholder de fundne verdier: the toxic effect of the compounds after oral administration (suspension in 1% methylcellulose) of a single dose was investigated with a subsequent observation period of at least 7 days. The following table contains the values found:

På grunn av sine farmakologiske egenskaper er de nye forbindelser med den generelle formel I fremstilt ifølge oppfinnelsen og deres fysiologisk forlikelige salter egnet for behandling av Diabetes mellitus. For dette formål kan de, eventuelt i kombinasjon med andre aktive stoffer, 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, 1 eller 2 ganger daglig. Due to their pharmacological properties, the new compounds of the general formula I prepared according to the invention and their physiologically compatible salts are suitable for the treatment of Diabetes mellitus. For this purpose, they can, possibly in combination 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 or 2 times a day.

Dessuten er forbindelsene med den generelle formel I på grunn av sine farmakologiske egenskaper egnet til behandling av hyperlipidemier, særlig av typene Ila, Ilb og IV, og derav betingede arterosklerotiske forandringer i karsystemet, og kan anvendes for farmasøytiske formål, eventuelt i kombinasjon med andre aktive stoffer, i de vanlige farmasøytiske tilberedninger så som dragéer, tabletter, kapsler, suppositorier, suspensjoner eller oppløsninger, idet enkeltdosen er 5 til 200 mg, fortrinnsvis 5 til 50 mg, og den daglige dose er 10 til 500 mg, fortrinnsvis 15-150 mg. Moreover, the compounds of the general formula I are, due to their pharmacological properties, suitable for the treatment of hyperlipidemias, particularly of types Ila, Ilb and IV, and the resulting arteriosclerotic changes in the vascular system, and can be used for pharmaceutical purposes, possibly in combination with other active substances, in the usual pharmaceutical preparations such as dragees, tablets, capsules, suppositories, suspensions or solutions, the single dose being 5 to 200 mg, preferably 5 to 50 mg, and the daily dose being 10 to 500 mg, preferably 15-150 mg .

De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere: The following examples shall serve to further illustrate the invention:

Fremstilling av utgangsforbindelsene: Preparation of the output compounds:

Ek sempel A Ek sample A

2- ( dekahydro- isokinolin- 2- y1)- 5- nitro- benzoesyre 2- ( decahydro- isoquinoline- 2- y1)- 5- nitro- benzoic acid

I 500 ml etanol oppvarmes 19 g (0,136 mol) dekahydro-isokinolin, 27,3 g (0,136 mol) 2-klor-5-nitro-benzoesyre og 38,6 g kaliumkarbonat under omrøring i 18 timer under tilbake-løpskjøling. Efter avdestillering av etanolen oppløses residuet i 800 ml vann og innstilles på pH 4 ved tilsetning av 2N saltsyre, hvorved produktet utkrystalliserer. In 500 ml of ethanol, 19 g (0.136 mol) of decahydro-isoquinoline, 27.3 g (0.136 mol) of 2-chloro-5-nitro-benzoic acid and 38.6 g of potassium carbonate are heated with stirring for 18 hours under reflux. After distilling off the ethanol, the residue is dissolved in 800 ml of water and adjusted to pH 4 by adding 2N hydrochloric acid, whereby the product crystallizes out.

Utbytte: 38 g (92% av det teoretiske), Yield: 38 g (92% of the theoretical),

Smeltepunkt: 132-134°C (isopropanol). Melting point: 132-134°C (isopropanol).

Beregnet: C 63,14, H 6,62, N 9,20 Calculated: C 63.14, H 6.62, N 9.20

Funnet: 63,02 6,48 9,38. Found: 63.02 6.48 9.38.

Eksempel B Example B

2- ( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- 8- yl)- 5- nitro- benzoesyre 2-( 1, 4- dioxa- 8- aza- spiro[ 4, 5] decan- 8- yl)- 5- nitro- benzoic acid

20,1 g (0,1 mol) 2-klor-5-nitro-benzoesyre oppvarmes i 20.1 g (0.1 mol) of 2-chloro-5-nitro-benzoic acid is heated in

200 ml etanol med 42,9 g (0,3 mol) 1,4-dioksa-8-aza-spiro-[4.5]dekan i 8 timer til tilbakeløpstemperatur. Efter avdestillering av oppløsningsmidlet opptas inndampningsresiduet i vann og innstilles på pH 5,2 med 2N saltsyre, hvorved produktet utfelles. Efter ekstraksjon med kloroform og tørring over natriumsulfat utkrystalliserer forbindelsen efter avdestillering av oppløsningsmidlet. 200 ml of ethanol with 42.9 g (0.3 mol) of 1,4-dioxa-8-aza-spiro-[4.5]decane for 8 hours at reflux temperature. After distilling off the solvent, the evaporation residue is taken up in water and adjusted to pH 5.2 with 2N hydrochloric acid, whereby the product is precipitated. After extraction with chloroform and drying over sodium sulfate, the compound crystallizes after distilling off the solvent.

Utbytte: 12 g (39% av det teoretiske), Yield: 12 g (39% of the theoretical),

Smeltepunkt: 155°C (etanol). Melting point: 155°C (ethanol).

Beregnet: C 54,54, H 5,23, N 9,09 Calculated: C 54.54, H 5.23, N 9.09

Funnet: 54,20 5,13 8,97. Found: 54.20 5.13 8.97.

Analogt med eksemplene A og B ble følgende forbindelser fremstilt: Analogous to examples A and B, the following compounds were prepared:

2- (2-metyl-piperidino)-5-nitro-benzoesyre, 2-(2-methyl-piperidino)-5-nitro-benzoic acid,

Utbytte: 99% av det teoretiske, smeltepunkt: 164°C, Yield: 99% of the theoretical, melting point: 164°C,

2-(3-mety1-piperidino)-5-nitro-benzoesyre, 2-(3-methyl-piperidino)-5-nitro-benzoic acid,

utbytte: 85% av det teoretiske, smeltepunkt: 161°C, yield: 85% of the theoretical, melting point: 161°C,

2- ( 4-mety1-piperidino)-5-nitro-benzoesyre, 2-(4-methyl-piperidino)-5-nitro-benzoic acid,

utbytte: 85% av det teoretiske, smeltepunkt: 155°C, yield: 85% of the theoretical, melting point: 155°C,

2-(3-ety1-6-mety1-piperidino)-5-nitro-benzoesyre, utbytte: 76% av det teoretiske, smeltepunkt: <20°C, 2-(3-ethyl-6-methyl-piperidino)-5-nitro-benzoic acid, yield: 76% of theory, melting point: <20°C,

2-(3,5-dimetyl-piperidino)-5-nitro-benzoesyre, 2-(3,5-dimethyl-piperidino)-5-nitro-benzoic acid,

utbytte: 65% av det teoretiske, smeltepunkt: 172°C, yield: 65% of the theoretical, melting point: 172°C,

2-(4-metoksy-piperidino)-5-nitro-benzoesyre, 2-(4-Methoxy-piperidino)-5-nitro-benzoic acid,

utbytte: 68% av det teoretiske, smeltepunkt: 140°C, yield: 68% of the theoretical, melting point: 140°C,

5-nitro-2-(4-fenyl-piperidino)-benzoesyre, 5-nitro-2-(4-phenyl-piperidino)-benzoic acid,

utbytte: 88% av det teoretiske, smeltepunkt: 196°C, yield: 88% of the theoretical, melting point: 196°C,

2-(4-etoksykarbony1-piperidino)-5-nitro-benzoesyre, utbytte: 82% av det teoretiske, smeltepunkt: 160°C, 2-(4-ethoxycarbonyl-1-piperidino)-5-nitro-benzoic acid, yield: 82% of theory, melting point: 160°C,

5-nitro-2-tiomorfolino-benzoesyre, 5-nitro-2-thiomorpholino-benzoic acid,

utbytte: 80% av det teoretiske, smeltepunkt: 235°C, yield: 80% of the theoretical, melting point: 235°C,

5-nitro-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoesyre, utbytte: 68% av det teoretiske, smeltepunkt: 222°C, 5-nitro-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoic acid, yield: 68% of the theoretical, melting point: 222°C,

5-nitro-2-(1,2,3,4-tetrahydro-isokinolino)-benzoesyre, utbytte: 70% av det teoretiske, smeltepunkt: 195°C, 5-nitro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid, yield: 70% of the theoretical, melting point: 195°C,

5-nitro-2-(4-fenyl-piperazino)-benzoesyre, 5-nitro-2-(4-phenyl-piperazino)-benzoic acid,

utbytte: 88% av det teoretiske, smeltepunkt: 196°C, yield: 88% of the theoretical, melting point: 196°C,

5-nitro-2-(4-pyridyl-(2)-piperazino)-benzoesyre, utbytte: 66% av det teoretiske, smeltepunkt: 192°C, 5-nitro-2-(4-pyridyl-(2)-piperazino)-benzoic acid, yield: 66% of theory, melting point: 192°C,

2-(trans-3,5-dimetylpiperidino)-5-nitro-benzoesyre, utbytte: 63% av det teoretiske, smeltepunkt: 132°C, 2-(trans-3,5-dimethylpiperidino)-5-nitro-benzoic acid, yield: 63% of theory, melting point: 132°C,

2-(3,3,5,5-tetramety1-piperidino)-5-nitro-benzoesyre, utbytte: 98% av det teoretiske, smeltepunkt: 138°C, 2-(3,3,5,5-tetramethyl-piperidino)-5-nitro-benzoic acid, yield: 98% of theory, melting point: 138°C,

2-(3,5-dimetyl-morfolino)-5-nitro-benzoesyre, 2-(3,5-dimethyl-morpholino)-5-nitro-benzoic acid,

utbytte: 75% av det teoretiske, smeltepunkt: 164°C, yield: 75% of the theoretical, melting point: 164°C,

2-(3,5-dimetyl-tiomorfolino)-5-nitro-benzoesyre, utbytte: 70% av det teoretiske, smeltepunkt: 118°C, 2-(3,5-dimethyl-thiomorpholino)-5-nitro-benzoic acid, yield: 70% of the theoretical, melting point: 118°C,

2- (3-aza-bicyklo[3,2,2]nonan-3-y1)-5-nitro-benzoesyre, utbytte: 72% av det teoretiske, smeltepunkt: 221°C, 2-(3-aza-bicyclo[3,2,2]nonan-3-y1)-5-nitro-benzoic acid, yield: 72% of the theoretical, melting point: 221°C,

5-nitro-2-nonametylen imino-benzoesyre, 5-nitro-2-nonamethylene imino-benzoic acid,

utbytte: 80% av det teoretiske, smeltepunkt: 127°C, yield: 80% of the theoretical, melting point: 127°C,

5-nitro-2-dekametylenimino-benzoesyre, 5-nitro-2-decamethyleneimino-benzoic acid,

utbytte: 92% av det teoretiske, smeltepunkt: 128°C, yield: 92% of the theoretical, melting point: 128°C,

5-nitro-2-undekametylenimino-benzoesyre, 5-nitro-2-undecamethyleneimino-benzoic acid,

utbytte: 91% av det teoretiske, smeltepunkt: 120°C, yield: 91% of the theoretical, melting point: 120°C,

5-nitro-2-dodekametylenimino-benzoesyre, 5-nitro-2-dodecamethyleneimino-benzoic acid,

utbytte: 95% av det teoretiske, smeltepunkt: 115°C, yield: 95% of the theoretical, melting point: 115°C,

2-(N-metyl-N-fenylamino)-5-nitro-benzoesyre, 2-(N-methyl-N-phenylamino)-5-nitro-benzoic acid,

utbytte: 10% av det teoretiske, smeltepunkt: 115°C, yield: 10% of the theoretical, melting point: 115°C,

2- (N-etyl-N-cykloheksylamino)-5-nitro-benzoesyre, 2-(N-ethyl-N-cyclohexylamino)-5-nitro-benzoic acid,

utbytte: 78% av det teoretiske, smeltepunkt: 74°C, yield: 78% of the theoretical, melting point: 74°C,

2- (N-butyl-N-cykloheksylamino)-5-nitro-benzoesyre, 2-(N-butyl-N-cyclohexylamino)-5-nitro-benzoic acid,

utbytte: 84% av det teoretiske, smeltepunkt: 56°C, yield: 84% of the theoretical, melting point: 56°C,

2- (N-cykloheksyl-N-isobutylamino)-5-nitro-benzoesyre, 2-(N-cyclohexyl-N-isobutylamino)-5-nitro-benzoic acid,

utbytte: 63% av det teoretiske, smeltepunkt: < 20°C, yield: 63% of the theoretical, melting point: < 20°C,

2- (dekahydro-3-benzazepin-3-yl)-5-nitro-benzoesyre, 2-(decahydro-3-benzazepin-3-yl)-5-nitro-benzoic acid,

utbytte: 98% av det teoretiske, smeltepunkt: < 20°C, yield: 98% of the theoretical, melting point: < 20°C,

2-(oktahydro-isoindol-2-yl)-5-nitro-benzoesyre, 2-(octahydro-isoindol-2-yl)-5-nitro-benzoic acid,

utbytte: 80% av det teoretiske, smeltepunkt: 12 8°C, yield: 80% of the theoretical, melting point: 12 8°C,

2-(4-isopropy1-piperidino)-5-nitro-benzoesyre, 2-(4-isopropyl-piperidino)-5-nitro-benzoic acid,

utbytte: 79% av det teoretiske, smeltepunkt: 142°C, yield: 79% of the theoretical, melting point: 142°C,

2- (4-tert.butyl-piperidino)-5-nitro-benzoesyre, 2-(4-tert.butyl-piperidino)-5-nitro-benzoic acid,

utbytte: 57% av det teoretiske, smeltepunkt: 136°C, yield: 57% of the theoretical, melting point: 136°C,

2-(1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-5-nitro-benzoesyre, utbytte: 75% av det teoretiske, smeltepunkt: 135°C, 2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-5-nitro-benzoic acid, yield: 75% of theory, melting point: 135°C,

2,4-dipiperidino-5-nitro-benzoesyre, 2,4-dipiperidino-5-nitro-benzoic acid,

utbytte: 31% av det teoretiske, smeltepunkt: 152°C, yield: 31% of the theoretical, melting point: 152°C,

4-klor-2-piperidino-5-nitro-benzoesyre, 4-chloro-2-piperidino-5-nitro-benzoic acid,

utbytte: 18% av det teoretiske, smeltepunkt: 133°C, yield: 18% of the theoretical, melting point: 133°C,

5~nitro-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre, 5~nitro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid,

utbytte: 58% av det teoretiske, smeltepunkt: 215°C, yield: 58% of the theoretical, melting point: 215°C,

2-(N-metyl-N-benzylamino)-5-nitro-benzoesyre, 2-(N-methyl-N-benzylamino)-5-nitro-benzoic acid,

utbytte: 93% av det teoretiske, smeltepunkt: 123-126°C, yield: 93% of the theoretical, melting point: 123-126°C,

2-[4-(4-klorfenyl)-piperazino]-5-nitro-benzoesyre-hydroklorid, utbytte: 71,5% av det teoretiske, smeltepunkt: 225-227°C (spaltn.). 2-[4-(4-Chlorophenyl)-piperazino]-5-nitro-benzoic acid hydrochloride, yield: 71.5% of theory, melting point: 225-227°C (dec.).

2-(4-karbetoksy-piperazino)-5-nitro-benzoesyre, 2-(4-carbethoxy-piperazino)-5-nitro-benzoic acid,

utbytte: 23,1% av det teoretiske, smeltepunkt: 155-156°C, yield: 23.1% of the theoretical, melting point: 155-156°C,

2-[4-(2-furoyl)-piperazino]-5-nitro-benzoesyre, 2-[4-(2-furoyl)-piperazino]-5-nitro-benzoic acid,

utbytte: 64,8% av det teoretiske, smeltepunkt: 200-205°C, yield: 64.8% of the theoretical, melting point: 200-205°C,

2-(4-benzyl-piperazino)-5-nitro-benzoesyre-hydroklorid, utbytte: 86,6% av det teoretiske, smeltepunkt: 142-145°C. 2-(4-benzyl-piperazino)-5-nitro-benzoic acid hydrochloride, yield: 86.6% of theory, melting point: 142-145°C.

E ksempel C Example C

2- heksametylenimino- 5- nitro- benzoesyrenitril 2- hexamethyleneimino- 5- nitro- benzoic acid nitrile

18,4 g (0,11 mol) 2-klor-5-nitro-benzoesyrenitril oppvarmes i 250 ml etanol med 22,4 g (0,21 mol) heksametylenimin i 4 timer til tilbakeløpstemperatur. Efter avkjøling utfelles det oljeaktige produkt ved tilsetning av 500 ml vann. Felningen opptas i kloroform. Efter tørring med natriumsulfat og avdestillering av kloroformen omkrystalliseres inndampningsresiduet fra etanol. Utbytte: 19,7 g (73% av det teoretiske). 18.4 g (0.11 mol) of 2-chloro-5-nitro-benzoic acid nitrile are heated in 250 ml of ethanol with 22.4 g (0.21 mol) of hexamethyleneimine for 4 hours to reflux temperature. After cooling, the oily product is precipitated by adding 500 ml of water. The precipitate is recorded in chloroform. After drying with sodium sulfate and distilling off the chloroform, the evaporation residue is recrystallized from ethanol. Yield: 19.7 g (73% of the theoretical).

Smeltepunkt: 70°C. Melting point: 70°C.

Beregnet: C 63,65, H 6,16, H 17,13 Calculated: C 63.65, H 6.16, H 17.13

Funnet: 63,80 6,07 17,05. Found: 63.80 6.07 17.05.

Fremstilling av mellomproduktene med den generelle formel Ia: Preparation of the intermediates of the general formula Ia:

Eksempel I Example I

5- amino- 2-( dekahydro- isokinolin- 2- yl)- benzoesyre 5-amino-2-(decahydro-isoquinolin-2-yl)-benzoic acid

I 250 ml dimetylformamid oppløses 36 g (0,118 mol) 2-(dekahydro-isokinolin-2-yl)-5-nitro-benzosyre og hydrogeneres ved et hydrogentrykk på 5 bar med 10%ig palladium-kull som katalysator ved romtemperatur. Efter avsluttet hydrogenopptagelse frafUtreres katalysatoren, oppløsningsmidlet avdestilleres i vakuum, og residuet omkrystalliseres fra etanol. Utbytte: 31,2 g (96% av det teoretiske). In 250 ml of dimethylformamide, 36 g (0.118 mol) of 2-(decahydro-isoquinolin-2-yl)-5-nitro-benzoic acid are dissolved and hydrogenated at a hydrogen pressure of 5 bar with 10% palladium charcoal as catalyst at room temperature. After completion of hydrogen absorption, the catalyst is filtered off, the solvent is distilled off in a vacuum, and the residue is recrystallized from ethanol. Yield: 31.2 g (96% of the theoretical).

Smeltepunkt: 252°C. Melting point: 252°C.

Beregnet: C 70,04, H 8,08, N 10,20 Calculated: C 70.04, H 8.08, N 10.20

Funnet: 70,09, 7,85 10,12. Found: 70.09, 7.85 10.12.

Eksempel II Example II

5- amino- 2- ( 1, 4- dioksa- 8- aza-sp iro[ 4, 5] dek an- 8- yl)- benzoesyre 5- amino- 2- ( 1, 4- dioxa- 8- aza- spiro[ 4, 5] dec an- 8- yl)- benzoic acid

12 g (0,039 mol) 2-(1,4-dioksa-8-aza-spiro[4,5]dekan-8-y1)-5-nitro-benzoesyre hydrogeneres i 100 ml dimetylformamid ved et hydrogentrykk på 5 bar ved romtemperatur med 10%ig palladium-kull som katalysator. Efter avsluttet hydrogenopptagelse frafiltreres katalysatoren, oppløsningsmidlet avdestiUeres, og residuet omkrystalliseres fra etanol. 12 g (0.039 mol) of 2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-5-nitro-benzoic acid are hydrogenated in 100 ml of dimethylformamide at a hydrogen pressure of 5 bar at room temperature with 10% palladium charcoal as catalyst. After completion of hydrogen absorption, the catalyst is filtered off, the solvent is distilled off, and the residue is recrystallized from ethanol.

Utbytte: 9 g (83% av det teoretiske), Yield: 9 g (83% of the theoretical),

Smeltepunkt: 209°C. Melting point: 209°C.

Beregnet: C 60,42, H 6,52, N 10,07 Calculated: C 60.42, H 6.52, N 10.07

Funnet: 60,18 6,58 10,12 Found: 60.18 6.58 10.12

Analogt med eksemplene <1> og II ble følgende forbindelser fremstilt: Analogous to examples <1> and II, the following compounds were prepared:

5-amino-2-pyrrolidino-benzoesyre, 5-amino-2-pyrrolidino-benzoic acid,

utbytte: 79% av det teoretiske, smeltepunkt: 208°C, yield: 79% of the theoretical, melting point: 208°C,

5-amino-2-(2-mety1-piperidino)-benzoesyre, 5-amino-2-(2-methyl-piperidino)-benzoic acid,

utbytte: 84% av det teoretiske, smeltepunkt: 240°C, yield: 84% of the theoretical, melting point: 240°C,

5-amino-2-(3-mety1-piperidino)-benzoesyre, 5-amino-2-(3-methyl-piperidino)-benzoic acid,

utbytte: 7 5% av det teoretiske, smeltepunkt: 19 2°C, yield: 7 5% of the theoretical, melting point: 19 2°C,

5-amino-2-(4-mety1-piperidino)-benzoesyre, 5-amino-2-(4-methyl-piperidino)-benzoic acid,

utbytte: 88% av det teoretiske, smeltepunkt: 215°C, yield: 88% of the theoretical, melting point: 215°C,

5-amino-2-(3-ety1-6-mety1-piperidino)-benzoesyre, 5-amino-2-(3-ethyl-6-methyl-piperidino)-benzoic acid,

utbytte: 59% av det teoretiske, smeltepunkt: 219°C, yield: 59% of the theoretical, melting point: 219°C,

5-amino-2-(cis-3,5-dimetyl-piperidino)-benzoesyre, 5-amino-2-(cis-3,5-dimethyl-piperidino)-benzoic acid,

utbytte: 87% av det teoretiske, smeltepunkt: 234°C, yield: 87% of the theoretical, melting point: 234°C,

5-amino-2-(4-metoksy-piperidino)-benzoesyre, 5-amino-2-(4-methoxy-piperidino)-benzoic acid,

utbytte: 80% av det teoretiske, smeltepunkt: 228°C, yield: 80% of the theoretical, melting point: 228°C,

5-amino-2-heptametylenimino-benzoesyre, 5-amino-2-heptamethyleneimino-benzoic acid,

utbytte: 64% av det teoretiske, smeltepunkt: 214°C, yield: 64% of the theoretical, melting point: 214°C,

5-amino-2-(4-feny1-piperidino)-benzoesyre, 5-amino-2-(4-phenyl-piperidino)-benzoic acid,

utbytte: 76% av det teoretiske, smeltepunkt: 275°C, yield: 76% of the theoretical, melting point: 275°C,

5-amino-2-(4-etoksykarbony1-piperidino)-benzoesyre, 5-amino-2-(4-ethoxycarbonyl-piperidino)-benzoic acid,

utbytte: 85% av det teoretiske, smeltepunkt: 203°C, yield: 85% of the theoretical, melting point: 203°C,

5-amino-2-tiomorfolino-benzoesyre, 5-amino-2-thiomorpholino-benzoic acid,

utbytte: 76% av det teoretiske, smeltepunkt: 193°C, yield: 76% of the theoretical, melting point: 193°C,

5-amino-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoesyre, utbytte: 86% av det teoretiske, smeltepunkt: 258°C, 5-amino-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoic acid, yield: 86% of the theoretical, melting point: 258°C,

5-amino-2-(1,2,3,4-tetrahydro-isokinolino)-benzoesyre, utbytte: 66% av det teoretiske, smeltepunkt: 220°C, 5-amino-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid, yield: 66% of the theoretical, melting point: 220°C,

5-amino-2-(4-fenyl-piperazino)-benzoesyre, 5-amino-2-(4-phenyl-piperazino)-benzoic acid,

utbytte: 83% av det teoretiske, smeltepunkt: 255°C, yield: 83% of the theoretical, melting point: 255°C,

5-amino-2-(4-pyridyl-(2)-piperazino)-benzoesyre, utbytte: 80% av det teoretiske, smeltepunkt: 248°C, 5-amino-2-(4-pyridyl-(2)-piperazino)-benzoic acid, yield: 80% of theoretical, melting point: 248°C,

5-amino-2-(trans-3,5-dimetyl-piperidino)-benzoesyre, utbytte: 89% av det teoretiske, smeltepunkt: 156°C, 5-amino-2-(trans-3,5-dimethyl-piperidino)-benzoic acid, yield: 89% of theory, melting point: 156°C,

5-amino-2-(3,3,5,5-tetrametyl-piperidino)-benzoesyre, utbytte: 98% av det teoretiske, smeltepunkt: < 20°C, 5-amino-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid, yield: 98% of theory, melting point: < 20°C,

5-amino-2-(3,5-dimetyl-morfolino)-benzoesyre, utbytte: 83% av det teoretiske, smeltepunkt: 255°C, 5-amino-2-(3,5-dimethyl-morpholino)-benzoic acid, yield: 83% of the theoretical, melting point: 255°C,

5-amino-2-(3,5-dimety1-tiomorfolino)-benzoesyre, utbytte: 50% av det teoretiske, smeltepunkt: 233°C, 5-amino-2-(3,5-dimethyl-thiomorpholino)-benzoic acid, yield: 50% of the theoretical, melting point: 233°C,

5-amino-2-(3-aza-bicyklo[3,2,2]nonan-3-yl)-benzoesyre, utbytte: 86% av det teoretiske, smeltepunkt: 288°C, 5-amino-2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-benzoic acid, yield: 86% of the theoretical, melting point: 288°C,

5-amino-2-oktametylenimino-benzoesyre, 5-amino-2-octamethyleneimino-benzoic acid,

utbytte: 88% av det teoretiske, smeltepunkt: 191°C, yield: 88% of the theoretical, melting point: 191°C,

5-amino-2-nonametylenimino-benzoesyre, 5-amino-2-nonamethyleneimino-benzoic acid,

utbytte: 80% av det teoretiske, smeltepunkt: 212°C, yield: 80% of the theoretical, melting point: 212°C,

5-amino-2-dekametylenimino-benzoesyre, 5-amino-2-decamethyleneimino-benzoic acid,

utbytte: 52% av det teoretiske, smeltepunkt: 202°C, yield: 52% of the theoretical, melting point: 202°C,

5-amino-2-undekametylenimino-benzoesyre, 5-amino-2-undecamethyleneimino-benzoic acid,

utbytte: 93% av det teoretiske, smeltepunkt: 242°C, yield: 93% of the theoretical, melting point: 242°C,

5-amino-2-dodekametylenimino-benzoesyre, 5-amino-2-dodecamethyleneimino-benzoic acid,

utbytte: 59% av det teoretiske, smeltepunkt: 224°C, yield: 59% of the theoretical, melting point: 224°C,

5-amino-2-(N-mety1-N-fenylamino)-benzoesyre, 5-amino-2-(N-methyl-N-phenylamino)-benzoic acid,

utbytte: 47% av det teoretiske, smeltepunkt: 184°C, yield: 47% of the theoretical, melting point: 184°C,

5-amino-2-(N-ety1-N-cykloheksylamino)-benzoesyre, utbytte: 66% av det teoretiske, smeltepunkt: 160°C, 5-amino-2-(N-ethyl1-N-cyclohexylamino)-benzoic acid, yield: 66% of the theoretical, melting point: 160°C,

5-amino-2-(N-butyl-N-cykloheksylamino)-benzoesyre, utbytte: 48% av det teoretiske, smeltepunkt: 140°C, 5-amino-2-(N-butyl-N-cyclohexylamino)-benzoic acid, yield: 48% of the theoretical, melting point: 140°C,

5-amino-2-(N-cykloheksyl-N-isobutylamino)-benzoesyre, utbytte: 62% av det teoretiske, smeltepunkt: < 20°C, 5-amino-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid, yield: 62% of the theoretical, melting point: < 20°C,

5-amino-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre, utbytte: 54% av det teoretiske, smeltepunkt: 204°C, 5-amino-2-(decahydro-3-benzazepin-3-yl)-benzoic acid, yield: 54% of theory, melting point: 204°C,

5-amino-2-(oktahydro-isoindo1-2-yl)-benzoesyre, 5-amino-2-(octahydro-isoindo1-2-yl)-benzoic acid,

utbytte: 43% av det teoretiske, smeltepunkt: 228°C, yield: 43% of the theoretical, melting point: 228°C,

5-amino-2-(4-isopropy1-piperidino)-benzoesyre, 5-amino-2-(4-isopropyl-piperidino)-benzoic acid,

utbytte: 50% av det teoretiske, smeltepunkt: 231°C, yield: 50% of the theoretical, melting point: 231°C,

5-amino-2-(4-tert.butyl-piperidino)-benzoesyre, 5-amino-2-(4-tert.butyl-piperidino)-benzoic acid,

utbytte: 81% av det teoretiske, smeltepunkt: 276°C, yield: 81% of the theoretical, melting point: 276°C,

5-amino-2-(1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-benzoesyre, utbytte: 49% av det teoretiske, smeltepunkt: 235°C, 5-amino-2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-benzoic acid, yield: 49% of theory, melting point: 235°C,

5-amino-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre, 5-amino-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid,

utbytte: 51% av det teoretiske, smeltepunkt: 232°C, yield: 51% of the theoretical, melting point: 232°C,

5-amino-2-(4-mety1-piperazino)-benzoesyre-hydroklorid, 5-amino-2-(4-methyl-piperazino)-benzoic acid hydrochloride,

utbytte: 90% av det teoretiske, smeltepunkt: < 20°C, yield: 90% of the theoretical, melting point: < 20°C,

5-amino-2-(N-mety1-N-benzylamino)-benzoesyre, 5-amino-2-(N-methyl-N-benzylamino)-benzoic acid,

utbytte: 95% av det teoretiske, smeltepunkt: < 20°C, yield: 95% of the theoretical, melting point: < 20°C,

5-amino-2-[4-(4-klorfenyl)-piperazino]-benzoesyre-hydroklorid, utbytte: 80,5% av det teoretiske, smeltepunkt: 305°C (spaltn.), 5-amino-2-[4-(4-chlorophenyl)-piperazino]-benzoic acid hydrochloride, yield: 80.5% of the theoretical, melting point: 305°C (dec.),

5-amino-2-(4-karbetoksy-piperazino)-benzoesyre, 5-amino-2-(4-carbethoxy-piperazino)-benzoic acid,

utbytte: 87,5% av det teoretiske, smeltepunkt: 195-197°C, yield: 87.5% of the theoretical, melting point: 195-197°C,

5-amino-2-[4-(2-furoyl)-piperazino]-benzoesyre, 5-amino-2-[4-(2-furoyl)-piperazino]-benzoic acid,

utbytte: 97% av det teoretiske, smeltepunkt: < 20°C, yield: 97% of the theoretical, melting point: < 20°C,

5-amino-2-(4-benzy1-piperazino)-benzoesyre-hydroklorid, 5-amino-2-(4-benzy1-piperazino)-benzoic acid hydrochloride,

utbytte: 80% av det teoretiske, smeltepunkt: 200-210°C. yield: 80% of the theoretical, melting point: 200-210°C.

Eksempel III Example III

5- klor- 2-( dekahydro- isokinolin- 2- yl)- benzoesyre 5-chloro-2-(decahydro-isoquinolin-2-yl)-benzoic acid

I 55 ml halvkonsentrert saltsyre oppløses 10 g (0,0365 mol) 5-amino-2-(dekahydro-isokinolin-2-yl)-benzoesyre og diazoteres ved 0°C med en oppløsning av 2,7 g (0,039 mol) natriumnitritt i 10 ml vann ved dråpevis tilsetning. Efter avsluttet tilsetning omrøres videre i 15 minutter, og derefter settes diazoniumsaltoppløsningen dråpevis til en suspensjon av 4 g kobberpulver i 40 ml konsentrert saltsyre. Efter omrøring natten over dannes en dypgrønn, homogen oppløsning, som efter fortynning med 100 ml vann ekstraheres uttømmende med kloroform. Efter tørring over natriumsulfat renses residuet efter kloroform-avdampningen kromatografisk over en silikagelkolonne med en In 55 ml of semi-concentrated hydrochloric acid, 10 g (0.0365 mol) of 5-amino-2-(decahydro-isoquinolin-2-yl)-benzoic acid are dissolved and diazotized at 0°C with a solution of 2.7 g (0.039 mol) of sodium nitrite in 10 ml of water by dropwise addition. After the addition has been completed, stirring continues for 15 minutes, and then the diazonium salt solution is added dropwise to a suspension of 4 g of copper powder in 40 ml of concentrated hydrochloric acid. After stirring overnight, a deep green, homogeneous solution is formed, which after dilution with 100 ml of water is extracted exhaustively with chloroform. After drying over sodium sulfate, the residue after the chloroform evaporation is purified chromatographically over a silica gel column with a

blanding av eddiksyreetylester/metanol = 9,5 : 0,5. mixture of acetic acid ethyl ester/methanol = 9.5 : 0.5.

Utbytte: 4,8 g (45% av det teoretiske), Yield: 4.8 g (45% of the theoretical),

Smeltepunkt: 138°C. Melting point: 138°C.

Beregnet: C 65,41, H 6,85, N 4,76, Cl 12,06 Calculated: C 65.41, H 6.85, N 4.76, Cl 12.06

Funnet: 65,51 7,07 4,89 12,32 Found: 65.51 7.07 4.89 12.32

E ksempel IV Example IV

5- klor- 2-( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- 8- yl)- benzoesyre 5- chloro- 2-( 1, 4- dioxa- 8- aza- spiro[ 4, 5] decan- 8- yl)- benzoic acid

8,5 g (0,031 mol) 5-amino-2-(1,4-dioksa-8-aza-spiro[4,5]-dekan-8-yl)-benzoesyre oppløses i 28 ml halvkonsentrert saltsyre og diazoteres ved 0°C med en oppløsning av 2,4 g (0,034 mol) natriumnitritt i 10 ml vann. Diazoniumsaltoppløsningen settes under omrøring dråpevis til en suspensjon av 3 g kobberpulver i 3 ml konsentrert saltsyre. Efter avsluttet nitrogenutvikling omrøres videre i 2 timer, reaksjonsblandingen fortynnes med vann og utristes med kloroform. Efter tørring over natriumsulfat avdestilleres oppløsningsmidlet. Ved oppslutning av inndampningsresiduet med petroleter får man 6,1 g (66% utbytte). 8.5 g (0.031 mol) of 5-amino-2-(1,4-dioxa-8-aza-spiro[4,5]-decan-8-yl)-benzoic acid are dissolved in 28 ml of semi-concentrated hydrochloric acid and diazotized at 0 °C with a solution of 2.4 g (0.034 mol) of sodium nitrite in 10 ml of water. The diazonium salt solution is added dropwise with stirring to a suspension of 3 g of copper powder in 3 ml of concentrated hydrochloric acid. After completion of nitrogen evolution, stirring continues for 2 hours, the reaction mixture is diluted with water and shaken out with chloroform. After drying over sodium sulphate, the solvent is distilled off. Digesting the evaporation residue with petroleum ether gives 6.1 g (66% yield).

Smeltepunkt: 180°C. Melting point: 180°C.

Beregnet: C 56,47, H 5,42, N 4,71 Calculated: C 56.47, H 5.42, N 4.71

Funnet: 56,11 5,37 4,83 Found: 56.11 5.37 4.83

Analogt med eksemplene III og IV ble følgende forbindelser fremstilt: Analogous to examples III and IV, the following compounds were prepared:

5-klor-2-pyrroiidino-benzoesyre, 5-Chloro-2-pyrrolidino-benzoic acid,

utbytte: 30% av det teoretiske, smeltepunkt: 164°C, yield: 30% of the theoretical, melting point: 164°C,

5-klor-2-(2-metyl-piperidino)-benzoesyre, 5-chloro-2-(2-methyl-piperidino)-benzoic acid,

utbytte: 74% av det teoretiske, smeltepunkt: 124°C, yield: 74% of the theoretical, melting point: 124°C,

5-klor-2-(3-mety1-piperidino)-benzoesyre, 5-chloro-2-(3-methyl-piperidino)-benzoic acid,

utbytte: 47% av det teoretiske, smeltepunkt: 165°C, yield: 47% of the theoretical, melting point: 165°C,

5-klor-2-(4-metyl-piperidino)-benzoesyre, 5-chloro-2-(4-methyl-piperidino)-benzoic acid,

utbytte: 52% av det teoretiske, smeltepunkt: 107°C, yield: 52% of the theoretical, melting point: 107°C,

2-(3-ety1-6-mety1-piperidino)-5-klor-benzoesyre, 2-(3-ethyl-6-methyl-piperidino)-5-chloro-benzoic acid,

utbytte: 73% av det teoretiske, smeltepunkt: < 20°C, yield: 73% of the theoretical, melting point: < 20°C,

5-klor-2-(cis-3,5-dimetyl-piperidino)-benzoesyre, 5-chloro-2-(cis-3,5-dimethyl-piperidino)-benzoic acid,

utbytte: 46% av det teoretiske, smeltepunkt: 167°C, yield: 46% of the theoretical, melting point: 167°C,

5-klor-2- (trans-3,5-dimety1-piperidino)-benzoesyre, 5-chloro-2-(trans-3,5-dimethyl-piperidino)-benzoic acid,

utbytte: 63% av det teoretiske, smeltepunkt: 132°C, yield: 63% of the theoretical, melting point: 132°C,

5-klor-2-(4-metoksy-piperidino)-benzoesyre, 5-chloro-2-(4-methoxy-piperidino)-benzoic acid,

utbytte: 63% av det teoretiske, smeltepunkt: 136°C, yield: 63% of the theoretical, melting point: 136°C,

5-klor-2-heptametylenimino-benzoesyre, 5-chloro-2-heptamethyleneimino-benzoic acid,

utbytte: 58% av det teoretiske, smeltepunkt: < 20°C, yield: 58% of the theoretical, melting point: < 20°C,

5-klor-2- (4-fenyl-piperidino)-benzoesyre, 5-chloro-2-(4-phenyl-piperidino)-benzoic acid,

utbytte: 51% av det teoretiske, smeltepunkt: 217°C, yield: 51% of the theoretical, melting point: 217°C,

5-klor-2- (4-etoksykarbonyl-piperidino)-benzoesyre, utbytte: 97% av det teoretiske, smeltepunkt: < 20°C, 5-chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid, yield: 97% of theory, melting point: < 20°C,

5-klor-2-heksametylenimino-benzoesyre, 5-chloro-2-hexamethyleneimino-benzoic acid,

utbytte: 34% av det teoretiske, smeltepunkt: 113°C, yield: 34% of the theoretical, melting point: 113°C,

5-klor-2-tiomorfolino-benzoesyre, 5-chloro-2-thiomorpholino-benzoic acid,

utbytte: 16% av det teoretiske, smeltepunkt: 160°C, yield: 16% of the theoretical, melting point: 160°C,

5-klor-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoesyre, utbytte: 59% av det teoretiske, smeltepunkt: 174°C, 5-chloro-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoic acid, yield: 59% of theory, melting point: 174°C,

5-klor-2- (1,2,3,4-tetrahydro-isokinolino)-benzoesyre, utbytte: 50% av det teoretiske, smeltepunkt: 182°C, 5-chloro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid, yield: 50% of the theoretical, melting point: 182°C,

5-klor-2- (4-fenyl-piperazino)-benzoesyre, 5-chloro-2-(4-phenyl-piperazino)-benzoic acid,

utbytte: 42% av det teoretiske, smeltepunkt: 154°C, yield: 42% of the theoretical, melting point: 154°C,

5-klor-2- (4-pyridyl-(2)-piperazino)-benzoesyre, utbytte: 45% av det teoretiske, smeltepunkt: 168°C, 5-chloro-2-(4-pyridyl-(2)-piperazino)-benzoic acid, yield: 45% of theory, melting point: 168°C,

5-brom-2-(2-metyl-piperidino)-benzoesyre, 5-bromo-2-(2-methyl-piperidino)-benzoic acid,

utbytte: 31% av det teoretiske, smeltepunkt: 168°C, yield: 31% of the theoretical, melting point: 168°C,

5-klor-2-(3,3,5,5-tetramety1-piperidino)-benzoesyre, utbytte: 62% av det teoretiske, smeltepunkt: < 20°C, 5-chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid, yield: 62% of theory, melting point: < 20°C,

5-brom-2-(4-metoksy-piperidino)-benzoesyre, 5-bromo-2-(4-methoxy-piperidino)-benzoic acid,

utbytte: 48% av det teoretiske, smeltepunkt: 138°C, yield: 48% of the theoretical, melting point: 138°C,

5-klor-2-(3,5-dimetylmorfolino)-benzoesyre, 5-chloro-2-(3,5-dimethylmorpholino)-benzoic acid,

utbytte: 50% av det teoretiske, smeltepunkt: 174°C, yield: 50% of the theoretical, melting point: 174°C,

5-klor-2-(3,5-dimetyl-tiomorfolino)-benzoesyre, utbytte: 18% av det teoretiske, smeltepunkt: 134°C, 5-chloro-2-(3,5-dimethyl-thiomorpholino)-benzoic acid, yield: 18% of the theoretical, melting point: 134°C,

5-brom-2-heptametylenimino-benzoesyre, 5-bromo-2-heptamethyleneimino-benzoic acid,

utbytte: 15% av det teoretiske, smeltepunkt: 104°C, yield: 15% of the theoretical, melting point: 104°C,

5-klor-2-(3-aza-bicyklo[3,2,2]nonan-3-y1)-benzoesyre, utbytte: 16% av det teoretiske, smeltepunkt: 199°C, 5-chloro-2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-benzoic acid, yield: 16% of the theoretical, melting point: 199°C,

5-klor-2-oktametylenimino-benzoesyre, 5-chloro-2-octamethyleneimino-benzoic acid,

utbytte: 70% av det teoretiske, smeltepunkt: 84°C, yield: 70% of the theoretical, melting point: 84°C,

5-klor-2-nonametylenimino-benzoesyre, 5-chloro-2-nonamethyleneimino-benzoic acid,

utbytte: 30% av det teoretiske, smeltepunkt: 78°C, yield: 30% of the theoretical, melting point: 78°C,

5-klor-2-dekametylenimino-benzoesyre, 5-chloro-2-decamethyleneimino-benzoic acid,

utbytte: 65% av det teoretiske, smeltepunkt: 70°C, yield: 65% of the theoretical, melting point: 70°C,

5-klor-2-undekametylenimino-benzoesyre, 5-chloro-2-undecamethyleneimino-benzoic acid,

utbytte: 41% av det teoretiske, smeltepunkt: 41°C, yield: 41% of the theoretical, melting point: 41°C,

5-klor-2-dodekametylenimino-benzoesyre, 5-chloro-2-dodecamethyleneimino-benzoic acid,

utbytte: 36% av det teoretiske, smeltepunkt: 40°C, yield: 36% of the theoretical, melting point: 40°C,

5-klor-2-(N-fenyl-N-metylamino)-benzoesyre, 5-chloro-2-(N-phenyl-N-methylamino)-benzoic acid,

utbytte: 27% av det teoretiske, smeltepunkt: 164°C, yield: 27% of the theoretical, melting point: 164°C,

2-(N-ety1-N-cykloheksylamino)-5-klor-benzoesyre, 2-(N-ethyl-1-N-cyclohexylamino)-5-chloro-benzoic acid,

utbytte: 24% av det teoretiske, smeltepunkt: 152°C, yield: 24% of the theoretical, melting point: 152°C,

2-(N-butyl-N-cykloheksylamino)-5-klor-benzoesyre, 2-(N-butyl-N-cyclohexylamino)-5-chloro-benzoic acid,

utbytte: 16% av det teoretiske, smeltepunkt: 145°C, yield: 16% of the theoretical, melting point: 145°C,

5-klor-2- (N-cykloheksyl-N-isobutylamino)-benzoesyre, 5-chloro-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid,

utbytte: 22% av det teoretiske, smeltepunkt: 131°C, yield: 22% of the theoretical, melting point: 131°C,

5-klor-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre, 5-chloro-2-(decahydro-3-benzazepin-3-yl)-benzoic acid,

utbytte: 70% av det teoretiske, smeltepunkt: 153°C, yield: 70% of the theoretical, melting point: 153°C,

5-brom-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre, 5-bromo-2-(decahydro-3-benzazepin-3-yl)-benzoic acid,

utbytte: 54% av det teoretiske, smeltepunkt: 154°C, yield: 54% of the theoretical, melting point: 154°C,

5-klor-2-(oktahydro-isoindol-2-yl)-benzoesyre, 5-chloro-2-(octahydro-isoindol-2-yl)-benzoic acid,

utbytte: 33% av det teoretiske, smeltepunkt: 164°C, yield: 33% of the theoretical, melting point: 164°C,

5-brom-2-oktametylenimino-benzoesyre, 5-bromo-2-octamethyleneimino-benzoic acid,

utbytte: 48% av det teoretiske, smeltepunkt: 94°C, yield: 48% of the theoretical, melting point: 94°C,

5-klor-2-(4-isopropy1-piperidino)-benzoesyre, 5-chloro-2-(4-isopropyl-piperidino)-benzoic acid,

utbytte: 43% av det teoretiske, smeltepunkt: 172°C, yield: 43% of the theoretical, melting point: 172°C,

5-klor-2-(4-te rt.buty1-piperidino)-benzoesyre, 5-chloro-2-(4-tert.buty1-piperidino)-benzoic acid,

utbytte: 35% av det teoretiske, smeltepunkt: 161°C, yield: 35% of the theoretical, melting point: 161°C,

5-klor-2-(l,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-benzoesyre, utbytte: 42% av det teoretiske, smeltepunkt: 163°C, 5-chloro-2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-benzoic acid, yield: 42% of theory, melting point: 163°C,

5-klor-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre, 5-chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid,

utbytte: 73% av det teoretiske, smeltepunkt: 173°C, yield: 73% of the theoretical, melting point: 173°C,

5-klor-2-(4-mety1-piperazino)-benzoesyre-hydroklorid, 5-chloro-2-(4-methyl-piperazino)-benzoic acid hydrochloride,

utbytte: 75% av det teoretiske, smeltepunkt: 132°C (spaltn.), yield: 75% of the theoretical, melting point: 132°C (dec.),

5-klor-2-(N-mety1-N-benzylamino)-benzoesyre, 5-chloro-2-(N-methyl-N-benzylamino)-benzoic acid,

utbytte: 18,2% av det teoretiske, smeltepunkt: 156-157°C, yield: 18.2% of the theoretical, melting point: 156-157°C,

5-klor-2-[4-(4-klorfenyl)-piperazino]-benzoesyre, 5-chloro-2-[4-(4-chlorophenyl)-piperazino]-benzoic acid,

utbytte: 30,5% av det teoretiske, smeltepunkt: 228-230°C, yield: 30.5% of the theoretical, melting point: 228-230°C,

2-(4-karbetoksy-piperazino)-5-klor-benzoesyre, 2-(4-carbethoxy-piperazino)-5-chloro-benzoic acid,

utbytte: 52% av det teoretiske, smeltepunkt: 129-130°C, yield: 52% of the theoretical, melting point: 129-130°C,

5-klor-2-[4-(2-furoyl)-piperazino]-benzoesyre, 5-chloro-2-[4-(2-furoyl)-piperazino]-benzoic acid,

utbytte: 33,1% av det teoretiske, smeltepunkt: 200-202°C, yield: 33.1% of the theoretical, melting point: 200-202°C,

2-(4-benzyl-piperazino)-5-klor-benzoesyre-hydroklorid, 2-(4-benzyl-piperazino)-5-chloro-benzoic acid hydrochloride,

utbytte: 42,8% av det teoretiske, smeltepunkt: 230-232°C (spaltn.). yield: 42.8% of the theoretical, melting point: 230-232°C (dec.).

Eksempel y Example y

5- amino- 2- heksametylenimino- benzoesyrenitril 5- amino- 2- hexamethyleneimino- benzoic acid nitrile

21,4 g (0,087 mol) 2-heksametylenimino-5-nitro-benzoesyrenitril oppløses i 200 ml dioksan og 500 ml metanol og hydrogeneres ved romtemperatur og et hydrogentrykk på 5 bar i nærvær av 10%ig palladium-kull som katalysator. Efter frafiltrering av katalysatoren og avdestillering av oppløsningsmidlet får man 20 g (100% av det teoretiske). 21.4 g (0.087 mol) of 2-hexamethyleneimino-5-nitro-benzoic acid nitrile is dissolved in 200 ml of dioxane and 500 ml of methanol and hydrogenated at room temperature and a hydrogen pressure of 5 bar in the presence of 10% palladium charcoal as a catalyst. After filtering off the catalyst and distilling off the solvent, you get 20 g (100% of the theoretical).

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

Eksempel VI Example VI

5- klor- 2- hkesametylenimino- benzoesyrenitril 5-chloro-2-hexamethyleneimino-benzoic acid nitrile

20 g (0,092 mol) 5-amino-2-hkesametylenimino-benzoesyrenitril oppløses i 90 ml halvkonsentrert saltsyre og diazoteres ved 0°C med en oppløsning av 6,5 g (0,094 mol) natriumnitritt i 30 ml vann ved dråpevis tilsetning. Efter avsluttet tilsetning omrøres videre i 15 minutter. Diazoniumsaltoppløsningen settes dråpevis under omrøring til en oppløsning av kobber(I)-klori-d i konsentrert saltsyre, som er oppvarmet til 70°C. Efter avsluttet nitrogenutvikling ekstraheres med kloroform. Efter tørring over natriumsulfat og avdestillering av kloroformen renses inndampningsresiduet kromatografisk over en silikagelkolonne. Som elueringsmiddel anvendes toluen. 20 g (0.092 mol) of 5-amino-2-hexamethyleneimino-benzoic acid nitrile are dissolved in 90 ml of semi-concentrated hydrochloric acid and diazotized at 0°C with a solution of 6.5 g (0.094 mol) of sodium nitrite in 30 ml of water by dropwise addition. After the addition is finished, continue stirring for 15 minutes. The diazonium salt solution is added dropwise with stirring to a solution of copper (I) chloride in concentrated hydrochloric acid, which has been heated to 70°C. After completion of nitrogen evolution, extract with chloroform. After drying over sodium sulfate and distilling off the chloroform, the evaporation residue is purified chromatographically over a silica gel column. Toluene is used as an eluent.

Utbytte: 5 g (23% av det teoretiske), Yield: 5 g (23% of the theoretical),

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

Eksempel VII Example VII

5- klor- 2- heksametylenimino- benzoesyre 5- chloro- 2- hexamethyleneimino- benzoic acid

5 g (0,021 mol) 5-klor-2-heksametylenimino-benzoesyrenitril oppvarmes i 32 g kalilut og 20 ml vann i 8 timer til 170°C. Den avkjølte smelte oppløses i vann. Ved surgjøring til pH 5 utfelles amidet kvantitativt og hydrolyseres derefter med halvkonsentrert saltsyre. 5 g (0.021 mol) of 5-chloro-2-hexamethyleneimino-benzoic acid nitrile are heated in 32 g of potassium hydroxide and 20 ml of water for 8 hours at 170°C. The cooled melt is dissolved in water. When acidified to pH 5, the amide precipitates quantitatively and is then hydrolysed with semi-concentrated hydrochloric acid.

Utbytte: 3,6 g (67,4% av det teoretiske), Yield: 3.6 g (67.4% of the theoretical),

Smeltepunkt: 113°C. Melting point: 113°C.

Analogt med eksemplene V og VII ble følgende forbindelser fremstilt: Analogous to examples V and VII, the following compounds were prepared:

2-morfolino-5-nitro-benzoesyrenitril, 2-morpholino-5-nitro-benzoic acid nitrile,

utbytte: 78% av det teoretiske, smeltepunkt: 138°C, yield: 78% of the theoretical, melting point: 138°C,

5-amino-2-morfolino-benzoesyrenitril, 5-amino-2-morpholino-benzoic acid nitrile,

utbytte: 68% av det teoretiske, smeltepunkt: 142°C, yield: 68% of the theoretical, melting point: 142°C,

5-klor-2-morfolino-benzoesyrenitril, 5-chloro-2-morpholino-benzoic acid nitrile,

utbytte: 20% av det teoretiske, smeltepunkt: 57°C, yield: 20% of the theoretical, melting point: 57°C,

5-klor-2-morfolino-benzamid, 5-chloro-2-morpholino-benzamide,

utbytte: 98% av det teoretiske, smeltepunkt: 280°C, yield: 98% of the theoretical, melting point: 280°C,

5-klor-2-morfolino-benzoesyre, 5-chloro-2-morpholino-benzoic acid,

utbytte: 60% av det teoretiske, smeltepunkt: 157°C. yield: 60% of the theoretical, melting point: 157°C.

Eksempel VIII Example VIII

5- cyano- 2- oktametylenimino- benzoesyre 5- cyano- 2- octamethyleneimino- benzoic acid

26,2 g (0,1 mol) 5-amino-2-oktametylenimino-benzoesyre oppløses i 38 ml konsentrert saltsyre, fortynnes med 280 ml vann og diazoteres ved 0°C med en oppløsning av 7,6 g (0,11 mol) natriumnitritt i 30 ml vann ved dråpevis tilsetning. Efter 1/2 times efterrøring innstilles oppløsningen på pH 7 26.2 g (0.1 mol) of 5-amino-2-octamethyleneimino-benzoic acid are dissolved in 38 ml of concentrated hydrochloric acid, diluted with 280 ml of water and diazotized at 0°C with a solution of 7.6 g (0.11 mol ) sodium nitrite in 30 ml of water by dropwise addition. After 1/2 hour of stirring, the solution is adjusted to pH 7

med natriumkarbonat. Til diazoniumsaltoppløsningen settes derefter dråpevis en oppløsning av trinatrium-tetracyano-kobber(I)-kompleks ved 0°C. with sodium carbonate. A solution of trisodium-tetracyano-copper(I) complex at 0°C is then added dropwise to the diazonium salt solution.

Denne kobber (I)kompleks-oppløsning fremstilles som følger: This copper (I) complex solution is prepared as follows:

32 g (0,128 mol) kobbersulfat x 5 H20 og 8,7 g natriumklorid 32 g (0.128 mol) copper sulfate x 5 H2O and 8.7 g sodium chloride

i 100 ml vann reduseres med en natriumhydrogensulfittoppløsning bestående av 6,6 g (0,0635 mol) natriumhydrogensulfitt og 4,4 g natriumhydroksyd i 50 ml vann, til kobber (I)klorid. Det utfelte in 100 ml of water is reduced with a sodium hydrogen sulphite solution consisting of 6.6 g (0.0635 mol) sodium hydrogen sulphite and 4.4 g of sodium hydroxide in 50 ml of water, to copper (I) chloride. It precipitated

kobber (I)klorid avsuges, suspenderes i 50 ml vann og oppløses i en oppløsning av 17 g (0,346 mol) natriumcyanid i 30 ml vann. Efter avsluttet nitrogenutvikling oppvarmes reaksjonsblandingen 1 1 time til 70°C. Efter avkjøling innstilles pH-verdien på 5,5 med 2N saltsyre, og reaksjonsblandingen ekstraheres med kloroform. Kloroformfåsene tørres over natriumsulfat, og efter avdestillering av kloroformen renses det erholdte råprodukt over en silikagelkolonne med eddiksyreetylester som elueringsmiddel. Utbytte: 9 g (30% av det teoretiske), copper (I) chloride is filtered off, suspended in 50 ml of water and dissolved in a solution of 17 g (0.346 mol) of sodium cyanide in 30 ml of water. After completion of nitrogen evolution, the reaction mixture is heated to 70°C for 1 hour. After cooling, the pH value is adjusted to 5.5 with 2N hydrochloric acid, and the reaction mixture is extracted with chloroform. The chloroform phases are dried over sodium sulfate, and after distilling off the chloroform, the crude product obtained is purified over a silica gel column with acetic acid ethyl ester as eluent. Yield: 9 g (30% of the theoretical),

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

Beregnet: C 70,56, H 7,40, N 10,28 Calculated: C 70.56, H 7.40, N 10.28

Funnet: 70,38 7,20 10,10 Found: 70.38 7.20 10.10

Eksempel ix Example ix

2- heptametylenimino- 5- hydroksy- benzoesyre 2- heptamethyleneimino- 5- hydroxy-benzoic acid

26,7 g (0,107 mol) 5-amino-2-heptametylenimino-benzoesyre oppløses i 190 ml 3N svovelsyre og diazoteres ved 0°C med en oppløsning av 8,3 g (0,12 mol) natriumnitritt i 30 ml vann ved dråpevis tilsetning. Efter 1/2 times efterrøring tilsettes 2 g finpulverisert urinstoff. Under god omrøring settes diazoniumsaltoppløsningen dråpevis til 320 ml 50%ig svovelsyre oppvarmet til 90°C. Efter avsluttet nitrogenutvikling innstilles pH-verdien ved romtemperatur på 4 med ammoniakk, og reaksjonsblandingen ekstraheres med kloroform. Det tørre residuum som oppnås efter tørring over natriumsulfat og avdestillering av kloroformen, renses over en silikagelkolonne med kloroform som elueringsmiddel. Efter omkrystallisering fra isopropanol får man 8 g (30% av det teoretiske). Smeltepunkt: 199°C. 26.7 g (0.107 mol) of 5-amino-2-heptamethyleneimino-benzoic acid are dissolved in 190 ml of 3N sulfuric acid and diazotized at 0°C with a solution of 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water dropwise addition. After stirring for 1/2 hour, add 2 g of finely powdered urea. With good stirring, the diazonium salt solution is added dropwise to 320 ml of 50% sulfuric acid heated to 90°C. After completion of nitrogen evolution, the pH value at room temperature is adjusted to 4 with ammonia, and the reaction mixture is extracted with chloroform. The dry residue obtained after drying over sodium sulfate and distilling off the chloroform is purified over a silica gel column with chloroform as eluent. After recrystallization from isopropanol, 8 g are obtained (30% of the theoretical). Melting point: 199°C.

Beregnet: C 67,45, H 7,68, N 5,61 Calculated: C 67.45, H 7.68, N 5.61

Funnet: 66,87 7,71 5,65 Found: 66.87 7.71 5.65

Analogt med eksempel IX ble følgende forbindelser fremstilt: Analogously to Example IX, the following compounds were prepared:

2-hekametylenimino-5-hydroksy-benzoeysre, 2-hexamethyleneimino-5-hydroxybenzoic acid,

utbytte: 24% av det teoretiske, smeltepunkt: 214°C, yield: 24% of the theoretical, melting point: 214°C,

5-hydroksy-2-oktametylenimino-benzoesyre, 5-hydroxy-2-octamethyleneimino-benzoic acid,

utbytte: 27% av det teoretiske, smeltepunkt: 208°C, yield: 27% of the theoretical, melting point: 208°C,

5-hydroksy-2- (4-tert.buty1-piperidino)-benzoesyre, 5-hydroxy-2-(4-tert.buty1-piperidino)-benzoic acid,

utbytte: 33% av det teoretiske, smeltepunkt: 240°C, yield: 33% of the theoretical, melting point: 240°C,

5-hydroksy-2-(cis-3,5-dimetyl-piperidino)-benzoesyre, 5-hydroxy-2-(cis-3,5-dimethyl-piperidino)-benzoic acid,

utbytte: 67,4% av det teoretiske, smeltepunkt: 248-250°C. yield: 67.4% of the theoretical, melting point: 248-250°C.

Eksempel X Example X

5- metoksy- 2- oktametylenimino- benzoesyre 5- methoxy- 2- octamethyleneimino- benzoic acid

3,2 g (12,2 mmol) 5-hydroksy-2-oktametylenimino-benzoesyre i 20 ml absolutt dimetylformamid tilsettes 0,6 g (25 mmol) natriumhydroksyd og oppvarmes til 50°C, hvorved natriumsaltet delvis utfelles. Efter tilsetning av 5,2 g (36,6 mmol) metyljodid i 3 ml absolutt dimetylformamid omrøres i 5 timer ved romtemperatur. Efter avdestillering av dimetylformamidet renses den rå 5-metoksy-2-oktametylenimino-benzoesyre-metylester over en silikagelkolonne med kloroform som elueringsmiddel. 3.2 g (12.2 mmol) of 5-hydroxy-2-octamethyleneimino-benzoic acid in 20 ml of absolute dimethylformamide is added to 0.6 g (25 mmol) of sodium hydroxide and heated to 50°C, whereby the sodium salt is partially precipitated. After adding 5.2 g (36.6 mmol) of methyl iodide in 3 ml of absolute dimethylformamide, the mixture is stirred for 5 hours at room temperature. After distilling off the dimethylformamide, the crude 5-methoxy-2-octamethyleneimino-benzoic acid methyl ester is purified over a silica gel column with chloroform as eluent.

Utbytte: 90% av det teoretiske, smeltepunkt: < 20°C. Yield: 90% of the theoretical, melting point: < 20°C.

Denne ester hydrolyseres med natronlut ved 80°C. Efter sur-gjøring til pH 5,2 foretas ekstraksjon med kloroform, tørring over natriumsulfat og oppslutning av inndampningsresiduet med petroleter. This ester is hydrolysed with caustic soda at 80°C. After acidification to pH 5.2, extraction is carried out with chloroform, drying over sodium sulphate and digestion of the evaporation residue with petroleum ether.

Utbytte: 85% av det teoretiske, Yield: 85% of the theoretical,

Smeltepunkt: 84°C. Melting point: 84°C.

Beregnet: C 69,28, H 8,35, N 5,04 Calculated: C 69.28, H 8.35, N 5.04

Funnet: 6 9,12 8,2 9 4,95. Found: 6 9.12 8.2 9 4.95.

Analogt med eksempel X ble følgende forbindelser fremstilt: Analogous to example X, the following compounds were prepared:

2-heksametylenimino-5-metoksy-benzoesyre, 2-hexamethyleneimino-5-methoxy-benzoic acid,

utbytte: 88% av det teoretiske, smeltepunkt: 141°C, yield: 88% of the theoretical, melting point: 141°C,

2-heptametylenimino-5-metoksy-benzoesyre, 2-heptamethyleneimino-5-methoxy-benzoic acid,

utbytte: 30% av det teoretiske, smeltepunkt: 120°C, yield: 30% of the theoretical, melting point: 120°C,

2-heptametylenimino-5-isopropyloksy-benzoesyre, 2-heptamethyleneimino-5-isopropyloxy-benzoic acid,

utbytte: 78% av det teoretiske, smeltepunkt: 120°C, yield: 78% of the theoretical, melting point: 120°C,

5-etoksy-2-oktametylenimino-benzoesyre, 5-ethoxy-2-octamethyleneimino-benzoic acid,

utbytte: 87% av det teoretiske, smeltepunkt: < 20°C, yield: 87% of the theoretical, melting point: < 20°C,

5-isopropyloksy-2-oktametylenimino-benzoesyre, 5-isopropyloxy-2-octamethyleneimino-benzoic acid,

utbytte: 60% av det teoretiske, smeltepunkt: 78°C, yield: 60% of the theoretical, melting point: 78°C,

5-butyl- (2)-oksy-2-oktametylenimino-benzoesyre, 5-butyl-(2)-oxy-2-octamethyleneimino-benzoic acid,

utbytte: 48% av det teoretiske, smeltepunkt: < 20°C, yield: 48% of the theoretical, melting point: < 20°C,

5-metoksy-2- (4-tert.butyl-piperidino)-benzoesyre, 5-Methoxy-2-(4-tert-butyl-piperidino)-benzoic acid,

utbytte: 22% av det teoretiske, smeltepunkt: 156°C, yield: 22% of the theoretical, melting point: 156°C,

5-metoksy-2-(3,5-cis-dimety1-piperidino)-benzoesyre, 5-Methoxy-2-(3,5-cis-dimethyl-piperidino)-benzoic acid,

utbytte: 90% av det teoretiske, smeltepunkt: 124°C, yield: 90% of the theoretical, melting point: 124°C,

5-heksyloksy-2-piperidino-benzoesyre, 5-hexyloxy-2-piperidino-benzoic acid,

utbytte: 73% av det teoretiske, smeltepunkt: 72°C, yield: 73% of the theoretical, melting point: 72°C,

5-benzyloksy-2-piperidino-benzoesyre, 5-benzyloxy-2-piperidino-benzoic acid,

utbytte: 41% av det teoretiske, smeltepunkt: 188°C. yield: 41% of the theoretical, melting point: 188°C.

Fremstilling av sluttproduktene med den generelle formel I: Eksempel 1 Preparation of the final products of the general formula I: Example 1

4-[ 2- ( 5- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

Til en oppløsning av 1,06 g (5,3 mmol) 5-klor-2-dimetylamino-benzoesyre i 5 ml absolutt tetrahydrofuran settes ved romtemperatur 1,03 g (6,3 mmol) N,N'-karbonyl-diimidazol. To a solution of 1.06 g (5.3 mmol) of 5-chloro-2-dimethylamino-benzoic acid in 5 ml of absolute tetrahydrofuran is added at room temperature 1.03 g (6.3 mmol) of N,N'-carbonyldiimidazole.

Efter 1-2 timer settes til det dannede imidazolid en oppløsning av 1,13 g (6,3 mmol) 4-(2-amino-etyl)-benzoesyremetylester i 2 ml tetrahydrofuran. Efter 16 timers henstand ved romtemperatur avdestilleres tetrahydrofuranet på en rotasjonsinndamper. Den rå ester renses kromatografisk over en silikagelkolonne med toluen/eddiksyreetylester (9:1) som elueringsmiddel. Den tørre rest av de samlede fraksjoner som inneholder den rensede ester, behandles med petroleter. After 1-2 hours, a solution of 1.13 g (6.3 mmol) of 4-(2-amino-ethyl)-benzoic acid methyl ester in 2 ml of tetrahydrofuran is added to the imidazolide formed. After standing for 16 hours at room temperature, the tetrahydrofuran is distilled off on a rotary evaporator. The crude ester is purified chromatographically over a silica gel column with toluene/acetic acid ethyl ester (9:1) as eluent. The dry residue of the combined fractions containing the purified ester is treated with petroleum ether.

Utbytte: 0,9 g (47,5% av det teoretiske), Yield: 0.9 g (47.5% of the theoretical),

Smeltepunkt: 94°C. Melting point: 94°C.

Beregnet: C 62,7, H 5,88, N 7,57 Calculated: C 62.7, H 5.88, N 7.57

Funnet: 63,3 5,86 7,75. Found: 63.3 5.86 7.75.

Eksempel 2 Example 2

4-[ 2-( 5- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid

0,55 g (1,56 mmol) 4-[2-(5-klor-2-dimetylamino-benzoylamino)-etyl]-benzoesyre-metylester oppløses i 40 ml av en blanding av metanol og dioksan (2:1). Efter tilsetning av 0,29 g (4,8 mmol) kaliumhydroksyd oppløst i 3 ml vann, tilsettes dråpevis ved romtemperatur 30 ml vann så langsomt at det ikke kommer til noen utfelling av esteren. Efter noen timer avdestilleres det organiske oppløsningsmiddel på en rotasjonsinndamper, den vandige fase utrystes med kloroform, og den vandige fase innstilles på pH 5,5 med 2N saltsyre, hvorved syren utfelles. 0.55 g (1.56 mmol) of 4-[2-(5-chloro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester is dissolved in 40 ml of a mixture of methanol and dioxane (2:1). After adding 0.29 g (4.8 mmol) of potassium hydroxide dissolved in 3 ml of water, 30 ml of water is added dropwise at room temperature so slowly that no precipitation of the ester occurs. After a few hours, the organic solvent is distilled off on a rotary evaporator, the aqueous phase is shaken off with chloroform, and the aqueous phase is adjusted to pH 5.5 with 2N hydrochloric acid, whereby the acid is precipitated.

Utbytte: 0,38 g (70% av det teoretiske), Yield: 0.38 g (70% of the theoretical),

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

Beregnet: C 62,45, H 5,52, N 8,06, Calculated: C 62.45, H 5.52, N 8.06,

Funnet: 62,30 5,62 7,87. Found: 62.30 5.62 7.87.

Eksempel 3 ' Example 3 '

4-[ 2- ( 5- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[2-(5-chloro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid

0,32 g (1 mmol) 4-[2-(2-amino-5-klor-benzoylamino)-etyl]-benzoesyre (smeltepunkt: 196°C, fremstilt fra 2-amino-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1 og påfølgende alkalisk forsepning analogt med eksempel 2) i 10 ml formalin og 30 ml iseddik behandles med hydrogen efter tilsetning av 500 mg 10%ig palladium-kull ved romtemperatur i autoklav ved 5 bar. Efter filtrering og avdestillering av oppløsningsmidlet oppløses syren i natronlut og utfelles med 2N saltsyre. 0.32 g (1 mmol) 4-[2-(2-amino-5-chloro-benzoylamino)-ethyl]-benzoic acid (melting point: 196°C, prepared from 2-amino-5-chloro-benzoic acid and 4- (2-amino-ethyl)-benzoic acid methyl ester analogous to example 1 and subsequent alkaline saponification analogous to example 2) in 10 ml formalin and 30 ml glacial acetic acid treated with hydrogen after addition of 500 mg 10% palladium charcoal at room temperature in an autoclave at 5 bar. After filtering and distilling off the solvent, the acid is dissolved in caustic soda and precipitated with 2N hydrochloric acid.

Utbytte: 0,11 g (30% av det teoretiske), Yield: 0.11 g (30% of the theoretical),

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

Beregnet: C 62,45, H 5,52, N 8,06, Calculated: C 62.45, H 5.52, N 8.06,

Funnet: 62,38 5,68 7,90. Found: 62.38 5.68 7.90.

Eksempel 4 Example 4

4-[ 2-( 5- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-metylamino-benzoylamino)-ety1]-benzoesyre (smeltepunkt: 205°C ( analogt med eksempel 3. Utbytte: 30% av det teoretiske. Prepared from 4-[2-(5-chloro-2-methylamino-benzoylamino)-ethyl]-benzoic acid (melting point: 205°C (analogous to example 3). Yield: 30% of the theoretical.

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

Eksempel 5 Example 5

4-[ 2-( 5- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre-mety lester 4-[ 2-( 5- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

1,06 g (5,3 mmol) 5-klor-2-dimetylamino-benzoesyre over-føres med 7 ml tionylklorid ved 40-50°C til syrekloridet. Efter avdestillering av tionylkloridet omsettes det rå syreklorid i 10 ml absolutt pyridin med 0,95 g (5,3 mmol) 4-(2-aminoetyl)-benzoesyre-metylester. Efter 2 timers omrøring ved romtemperatur oppvarmes i ca. 20 minutter til 50-70°C, og derefter avdestilleres pyridinet på en rotasjonsinndamper. Det tørre residuum oppløses i isvann, gjøres alkalisk med natronlut, og 1.06 g (5.3 mmol) of 5-chloro-2-dimethylamino-benzoic acid are transferred with 7 ml of thionyl chloride at 40-50°C to the acid chloride. After distilling off the thionyl chloride, the crude acid chloride is reacted in 10 ml of absolute pyridine with 0.95 g (5.3 mmol) of 4-(2-aminoethyl)-benzoic acid methyl ester. After stirring for 2 hours at room temperature, heat for approx. 20 minutes at 50-70°C, and then the pyridine is distilled off on a rotary evaporator. The dry residue is dissolved in ice water, made alkaline with caustic soda, and

denne oppløsning ekstraheres med kloroform. Det tørre residuum av kloroformekstraktene som er tørret over natriumsulfat, renses kromatografisk over en silikagelkolonne med toluen:etylacetat = 9:1 som elueringsmiddel. this solution is extracted with chloroform. The dry residue of the chloroform extracts, which has been dried over sodium sulphate, is purified chromatographically over a silica gel column with toluene:ethyl acetate = 9:1 as eluent.

Utbytte: 1,4 g (73% av det teoretiske), Yield: 1.4 g (73% of theoretical),

Smeltepunkt: 94°C. Melting point: 94°C.

Beregnet: C 62,7, H 5,88, N 7,57 Calculated: C 62.7, H 5.88, N 7.57

Funnet: 62,9 5,73 7,63 Found: 62.9 5.73 7.63

Eksempel 6 Example 6

4- [ 2- ( 5- brom- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre-metylester 4- [ 2- ( 5- bromo- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-brom-2-dimetylamino-benzoesyre og 4-(2-amino-etyl)-benzoesyremetylester analogt med eksempel 1. Utbytte: 93,5% av det teoretiske, Prepared from 5-bromo-2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 93.5% of the theoretical,

Smeltepunkt: 99°C. Melting point: 99°C.

Beregnet: C 56,35, H 5,21, N 6,90 Calculated: C 56.35, H 5.21, N 6.90

Funnet: 56,10 5,32 7,01. Found: 56.10 5.32 7.01.

Eksempel 7 Example 7

4-[ 2- ( 5- brom- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[2-(5-bromo-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-brom-2-dimetylamino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-bromo-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 77% av det teoretiske, Yield: 77% of the theoretical,

Smeltepunkt: 187°C. Melting point: 187°C.

Beregnet: C 55,4, H 4,89, N 7,16 Calculated: C 55.4, H 4.89, N 7.16

Funnet: 55,2 4,9 7 7,01. Found: 55.2 4.9 7 7.01.

Eksempel 8 Example 8

4-[ 2-( 5- fluor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- fluoro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-fluor-2-dimetylamino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 44% av det teoretiske, Prepared from 5-fluoro-2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 44% of the theoretical,

Smeltepunkt: 56°C. Melting point: 56°C.

Beregnet: C 66,30, H 6,14, N 8,13 Calculated: C 66.30, H 6.14, N 8.13

Funnet: 66,28 6,22 8,13. Found: 66.28 6.22 8.13.

Eksempel 9 Example 9

4-[ 2-( 5- fluor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- fluoro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-fluor-2-dimetylamino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-fluoro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 73% av det teoretiske. Yield: 73% of the theoretical.

Smeltepunkt: 108°C. Melting point: 108°C.

Beregnet: C 65,55, H 5,80, N 8,47, Calculated: C 65.55, H 5.80, N 8.47,

Funnet: 64,98, 5,68, 8,38. Found: 64.98, 5.68, 8.38.

Eksempel 10 Example 10

4-[ 2-( 2- dimetylamino- benzoylamino)- etyl]- benzoesyre- metylester 4-[ 2-( 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 2-dimetylamino-benzoesyre og 4-(2-amino-etyl )-benzoesyre-metylester analogt med eksempel 1. Reaksjonen utføres ved 60-70°C. Prepared from 2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. The reaction is carried out at 60-70°C.

Utbytte: 98% av det teoretiske, Yield: 98% of the theoretical,

Smeltepunkt: 74°C. Melting point: 74°C.

Beregnet: C 70,0, H 6,78, N 8,56, Calculated: C 70.0, H 6.78, N 8.56,

Funnet: 69,8 6,92 8,54. Found: 69.8 6.92 8.54.

Eksempel 11 Example 11

4-[ 2-( 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[2-(2-dimethylamino-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(2-dimetylamino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(2-dimethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 84% av det teoretiske, Yield: 84% of the theoretical,

Smeltepunkt: 107°C. Melting point: 107°C.

Beregnet: C 69,25, H 6,45, N 8,96, Calculated: C 69.25, H 6.45, N 8.96,

Funnet: 69,50 6,62 9,00. Found: 69.50 6.62 9.00.

Eksempel 12 Example 12

4-[ 2-( 5- klor- 2- dietylamino- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- chloro- 2- diethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-dietylamino-benzoesyre og 4-(2-amino-etyl )-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-diethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 51% av det teoretiske, Yield: 51% of the theoretical,

Smeltepunkt: 93°C. Melting point: 93°C.

Beregnet: C 64,86, H 6,48, N 9,12 Calculated: C 64.86, H 6.48, N 9.12

Funnet: 65,01 6,54 9,38. Found: 65.01 6.54 9.38.

Eksempel 13 Example 13

4-[ 2-(5-klor-2- dletylam ino- benzoylamino)- etyl]- benzoesyre 4-[2-(5-Chloro-2-dlethylamino-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-dietylamino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-diethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 80% av det teoretiske, Yield: 80% of the theoretical,

Smeltepunkt: 95°C. Melting point: 95°C.

Beregnet: C 64,1, H 6,17, N 7,46 Calculated: C 64.1, H 6.17, N 7.46

Funnet: 64,2 6,09 7,32 Found: 64.2 6.09 7.32

Eksempel 14 Example 14

4-[ 2-( 5- klor- 2- diisobutylamino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- chloro- 2- diisobutylamino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-diisobutylamino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 20% av det teoretiske, Prepared from 5-chloro-2-diisobutylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 20% of the theoretical,

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

Beregnet: C 68,03, H 7,69, N 6,10, Cl 7,72 Calculated: C 68.03, H 7.69, N 6.10, Cl 7.72

Funnet: 68,59 7,68 5,93 7,51 Found: 68.59 7.68 5.93 7.51

Ek sempel 15 Oak sample 15

4-[ 2-( 5- klor- 2- diisobutylamino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- Chloro- 2- diisobutylamino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-diisobutylamino-benzoylamino)-ety1]-benzoesyreetylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-diisobutylamino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 90% av det teoretiske. Yield: 90% of the theoretical.

Smeltepunkt: 113°C. Melting point: 113°C.

Beregnet: C 66,88, H 7,24, N 6,49, Cl 8,22 Calculated: C 66.88, H 7.24, N 6.49, Cl 8.22

Funnet: 66,50 7,28 6,32 8,40 Found: 66.50 7.28 6.32 8.40

Eksempel 16 Example 16

4-[ 2- ( 5- klor- 2- dipentylamino- benzoylamino)- etyl]- benzoesyre-ety lester 4-[ 2-( 5- chloro- 2- dipentylamino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-dipentylamino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 83% av det teoretiske, Prepared from 5-chloro-2-dipentylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 83% of the theoretical,

Smeltepunkt: 118-120°C. Melting point: 118-120°C.

Beregnet: C 69,05, H 8,07, N 5,75, Cl 7,28 Calculated: C 69.05, H 8.07, N 5.75, Cl 7.28

Funnet: 68,84 7,99 6,05 7,54. Found: 68.84 7.99 6.05 7.54.

Eksempel 17 Example 17

4-[ 2-( 5- klor- 2- dipentylamino- benzoylamino)-ety 1]- benzoesyre 4-[ 2-( 5- chloro- 2- dipentylamino- benzoylamino)-ethy 1]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-dipentylamino-benzoylamino-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-dipentylamino-benzoylamino-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 36,5% av det teoretiske. Yield: 36.5% of the theoretical.

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

Beregnet: C 68,03, H 7,68, N 6,10, Cl 7,72 Calculated: C 68.03, H 7.68, N 6.10, Cl 7.72

Funnet: 67,93 7,64 6,02 7,86 Found: 67.93 7.64 6.02 7.86

E ksempel 18 Example 18

4- [ 2- ( 5- klor- 2- ( 1- pyrrolyl)- benzoylamino)- etyl]- benzoesyre-metylester 4- [ 2- ( 5- chloro- 2- ( 1- pyrrolyl)- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2- (1-pyrrolyl)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 64% av det teoretiske, Prepared from 5-chloro-2-(1-pyrrolyl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 64% of the theoretical,

Smeltepunkt: 120-121°C. Melting point: 120-121°C.

Beregnet: C 65,88, H 5,00, N 7,32, Cl 9,26 Calculated: C 65.88, H 5.00, N 7.32, Cl 9.26

Funnet: 65,86 4,85 7,47 9,38. Found: 65.86 4.85 7.47 9.38.

Eksempel 19 Example 19

4-[ 2- ( 5- klor- 2-( 1- pyrrolyl)- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2-( 1- pyrrolyl)- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(1-pyrrolyl)-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(1-pyrrolyl)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 26% av det teoretiske, Yield: 26% of the theoretical,

Smeltepunkt: 250-255°C. Melting point: 250-255°C.

Beregnet: C 65,13, H 4,65, N 7,59, Cl 9,61 Calculated: C 65.13, H 4.65, N 7.59, Cl 9.61

Funnet: 65,07 4,74 7,34 9,07 Found: 65.07 4.74 7.34 9.07

Eksempel 20 Example 20

4-[ 2-( 5-k lor- 2-( N- cykloheksy1- metyl amino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5-chloro- 2-( N- cyclohexy1- methyl amino)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 2- (N-cykloheksyl-metylamino)-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 1. Prepared from 2-(N-cyclohexyl-methylamino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 1.

Utbytte: 45% av det teoretiske, Yield: 45% of the theoretical,

Smeltepunkt: 98°C. Melting point: 98°C.

Beregnet: C 67,78, H 7,05, N 6,33 Calculated: C 67.78, H 7.05, N 6.33

Funnet: 67,60 6,81 6,28. Found: 67.60 6.81 6.28.

Eksempel 21 Example 21

4- [ 2- ( 5- klor- 2-[ N- cyklohe ksy1- metylamino]-ben zoylamino)- etyl]-benzoesyre 4- [ 2- ( 5- chloro- 2-[ N- cyclohexy1- methylamino]-benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-[N-cykloheksylmetylamino]-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-[N-cyclohexylmethylamino]-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 58% av det teoretiske, Yield: 58% of the theoretical,

Smeltepunkt: 166°C. Melting point: 166°C.

Beregnet: C 66,58, H 6,56, N 6,75 Calculated: C 66.58, H 6.56, N 6.75

Funnet: 66,63 6,79 6,66. Found: 66.63 6.79 6.66.

Eksempel 22 Example 22

4-[ 2-( 5- brom- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- bromo- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-brom-2-piperidino-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 87% av det teoretiske. Prepared from 5-bromo-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 87% of the theoretical.

Smeltepunkt: 76°C. Melting point: 76°C.

Beregnet: C 60,13, H 5,92, N 6,09 Calculated: C 60.13, H 5.92, N 6.09

Funnet: 60,35 5,97 6,19. Found: 60.35 5.97 6.19.

Eksempel 2 3 Example 2 3

4-[ 2-( 5- brom- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- bromo- 2- piperidino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-brom-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-bromo-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 99% av det teoretiske. Yield: 99% of the theoretical.

Smeltepunkt: 201°C. Melting point: 201°C.

Beregnet: C 58,47, H 5,37, N 6,49 Calculated: C 58.47, H 5.37, N 6.49

Funnet: 58,56 5,40 6,55. Found: 58.56 5.40 6.55.

Eksempel 24 Example 24

4-[ 2-( 5- klor- 2-pyrrolid ino-ben zoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- chloro- 2-pyrrolide ino-benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-pyrrolidino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-pyrrolidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 43% av det teoretiske. Yield: 43% of the theoretical.

Smeltepunkt: 16 4°C. Melting point: 16 4°C.

Beregnet: C 65,19, H 5,99, N 7,24 Calculated: C 65.19, H 5.99, N 7.24

Funnet: 65,35 6,00 7,23. Found: 65.35 6.00 7.23.

E ksempel 2 5 Example 2 5

4-[ 2- ( 5- klor- 2- pyrrolidino- benzoylamino)- etyl]- benzoesyre 4-[2-(5-chloro-2-pyrrolidino-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-pyrrolidino-benzoylamino)-ety1]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-pyrrolidino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

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

Smeltepunkt: 184°C. Melting point: 184°C.

Beregnet: C 64,42, H 5,68, N 7,52, Cl 9,51 Calculated: C 64.42, H 5.68, N 7.52, Cl 9.51

Funnet: 64,46 5,96 7,47 9,38. Found: 64.46 5.96 7.47 9.38.

Eksempel 2 6 Example 2 6

4-[ 2- ( 5- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre-m ety lester 4-[2-(5-Chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-piperidino-benzoesyre og 4-(2-amino-etyl ) -benzoesyre-mety lester analogt med eksempel 1. Prepared from 5-chloro-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 72% av det teoretiske, Yield: 72% of the theoretical,

Smeltepunkt: 98°C. Melting point: 98°C.

Beregnet: C 66,00, H 6,29, N 7,00 Calculated: C 66.00, H 6.29, N 7.00

Funnet: 66,00 6,37 6,81. Found: 66.00 6.37 6.81.

Eksempel 2 7 Example 2 7

4-[ 2-( 5- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- Chloro- 2- Piperidino- Benzoylamino)- Ethyl]- Benzoic Acid

Fremstilt fra 4-[2-(5-klor-2-piperidino-benzoylamino)-ety1]-benzoesyre-raetylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid raethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 82% av det teoretiske, Yield: 82% of the theoretical,

Smeltepunkt: 200°C. Melting point: 200°C.

Beregnet: C 65,20, H 5,98, N 7,24 Calculated: C 65.20, H 5.98, N 7.24

Funnet: 65,10 6,00 7,30 Found: 65.10 6.00 7.30

Ek sempel 28 Oak sample 28

4- [ 2- ( 5- kl or- 2- ( 2- metyl- piperidino)-benzoy lamino)- etyl]- benzoesyre- mety lester 4- [ 2- ( 5- cl or- 2- ( 2- methyl- piperidino)-benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-(2-metyl-piperidino)-benzoesyre Prepared from 5-chloro-2-(2-methyl-piperidino)-benzoic acid

og 4-(2-aminoetyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 23% av det teoretiske. and 4-(2-aminoethyl)-benzoic acid methyl ester analogously to example 1. Yield: 23% of the theoretical.

Smeltepunkt: 82°C. Melting point: 82°C.

Beregnet: C 66,57, H 6,56, N 6,75 Calculated: C 66.57, H 6.56, N 6.75

Funnet: 66,82, H 6,42 6,78. Found: 66.82, H 6.42 6.78.

Eksempel 29 Example 29

4- [ 2- ( 5- klor- 2- ( 2- metyl- piperidino)- benzoylamino)- etyl]-benzoesyre 4- [ 2- ( 5- chloro- 2- ( 2- methyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(2-metyl-piperidino)-benzoylamino)-etyl ]-benzoesyre-metylester ved alkalisk forsepning analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline saponification analogously to example 2.

Utbytte: 57% av det teoretiske, Yield: 57% of the theoretical,

Smeltepunkt: 178°C. Melting point: 178°C.

Beregnet: C 65,91, H 6,29, N 6,99 Calculated: C 65.91, H 6.29, N 6.99

Funnet: 65,73 6,28 7,13. Found: 65.73 6.28 7.13.

Eksempel 30 Example 30

4-[ 2-( 5- klor- 2-( 3- metyl- piperidino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- Chloro- 2-( 3- Methyl- Piperidino)- Benzoylamino)- Ethyl]- Benzoic Acid Methyl Ester

Fremstilt fra 5-klor-2-(3-metyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 51% av det teoretiske, Prepared from 5-chloro-2-(3-methyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 51% of the theoretical,

Smeltepunkt: 93°C. Melting point: 93°C.

Beregnet: C 66,57, H 6,56, N 6,75 Calculated: C 66.57, H 6.56, N 6.75

Funnet: 66,52 6,38 6,81. Found: 66.52 6.38 6.81.

Eksempel 31 Example 31

4- [ 2- ( 5- klor- 2- ( 3- metyl- piperidino)- benzoylamino)- etyl]-b enzoesyre 4- [ 2- ( 5- chloro- 2- ( 3- methyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2- (5-klor-2-(3-metyl-piperidino)-benzoylamino) -etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 83% av det teoretiske. Yield: 83% of the theoretical.

Smeltepunkt: 194°C. Melting point: 194°C.

Beregnet: C 65,91, H 6,29, N 6,99 Calculated: C 65.91, H 6.29, N 6.99

Funnet: 66,20 6,25 6,95. Found: 66.20 6.25 6.95.

Eksempel 32 Example 32

4-[ 2-( 5- klor- 2-( 4- metyl- piperidino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 4- methyl- piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-(4-metyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 48% av det teoretiske, Prepared from 5-chloro-2-(4-methyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 48% of the theoretical,

Smeltepunkt: 55°C. Melting point: 55°C.

Beregnet: C 66,57, H 6,56, N 6,75. Calculated: C 66.57, H 6.56, N 6.75.

Funnet: 66,38 6,35 6,82. Found: 66.38 6.35 6.82.

Eksempel 33 Example 33

4-[ 2-( 5- klor- 2-( 4- metyl- piperidino)- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 5- chloro- 2-( 4- methyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4-metyl-piperidino)-benzoylamino) -etyl ] -benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(4-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 83% av det teoretiske, Yield: 83% of the theoretical,

Smeltepunkt: 211°C. Melting point: 211°C.

Beregnet: C 65,91, H 6,29, N 6,99, Calculated: C 65.91, H 6.29, N 6.99,

Funnet: 66,07 6,25 7,02. Found: 66.07 6.25 7.02.

Eksempel 34 Example 34

4-[ 2-( 5- klor- 2- ( 5- etyl- 2- metyl- piperidino)- benzoylamino)- etyl]-benz oesyre- metylester 4-[ 2-( 5- chloro- 2-( 5- ethyl- 2- methyl-piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-(5-etyl-2-metyl-piperidino)-benzoesyre og 4-(2-amino-ety1)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-(5-ethyl-2-methyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

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

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

Beregnet: C 67,78, H 7,05, N 6,33 Calculated: C 67.78, H 7.05, N 6.33

Funnet: 68,00 7,10 6,50 Found: 68.00 7.10 6.50

Eksempel 35 Example 35

4- [ 2- ( 5- klor— 2- ( 5- ety l- 2- mety1- piperidino)- benzoylamino)- etyl]-b enzoesyre 4-[2- (5-chloro-2- (5-ethyl-2-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(5-etyl-2-metyl-piperidino)-benzoylamino)-ety1]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(5-ethyl-2-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 60% av det teoretiske, Yield: 60% of the theoretical,

Smeltepunkt: 40°C. Melting point: 40°C.

Beregnet: C 67,19, H 6,81, N 6,53 Calculated: C 67.19, H 6.81, N 6.53

Funnet: 67,30 6,98 6,42 Found: 67.30 6.98 6.42

Eksempel 36 Example 36

4-[ 2- ( 5- klor- 2-( 3, 5- dimetyl- piperidino)- benzoylamino)- etyl]-b enzoesyre- metylester 4-[ 2-( 5- Chloro- 2-( 3, 5-Dimethyl- Piperidino)- Benzoylamino)- Ethyl]- Benzoic Acid Methyl Ester

Fremstilt fra 5-klor-2-(3,5-dimetyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-(3,5-dimethyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 85% av det teoretiske. Yield: 85% of the theoretical.

Smeltepunkt: 95°C. Melting point: 95°C.

Beregnet: C 67,20, H 6,81, N 6,53. Calculated: C 67.20, H 6.81, N 6.53.

Funnet: 67,14 6,62 6,68. Found: 67.14 6.62 6.68.

Eksempel 37 Example 37

4-[ 2-( 5- klor- 2-( 3, 5- dimetyl- piperidino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 3, 5- dimethyl-piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

2,7 g (0,01 mol) 5-klor-2-(3,5-dimetyl-piperidino)-benzoesyre oppvarmes under tilbakeløpskjøling i 4,5 timer med 3,57 g (0,03 mol) tionylklorid i 20 ml kloroform. Derefter inndampes reaksjonsblandingen i vakuum. Residuet oppløses i 10 ml kloroform og settes dråpevis under omrøring ved romtemperatur til en oppløsning av 2,16 g (0,01 mol) 4-(2-amino-etyl) -benzoesyre-metylester-hydroklorid og 3,03 g (0,03 mol) trietylamin, oppløst i 15 ml kloroform. Efter 15 minutter er tilsetningen avsluttet. Derefter oppvarmes i ytterligere 30 minutter under tilbakeløpskjøling. Efter avkjøling vaskes reaksjonsblandingen to ganger med vann og én gang med fortynnet eddiksyre. Kloroformfasen tørres over natriumsulfat og inndampes. Den erholdte rest renses videre over en silikagelkolonne (kloroform/aceton = 9:1). Efter avdampning av opp- 2.7 g (0.01 mol) of 5-chloro-2-(3,5-dimethyl-piperidino)-benzoic acid are heated under reflux for 4.5 hours with 3.57 g (0.03 mol) of thionyl chloride in 20 ml chloroform. The reaction mixture is then evaporated in vacuo. The residue is dissolved in 10 ml of chloroform and added dropwise with stirring at room temperature to a solution of 2.16 g (0.01 mol) 4-(2-amino-ethyl)-benzoic acid methyl ester hydrochloride and 3.03 g (0. 03 mol) of triethylamine, dissolved in 15 ml of chloroform. After 15 minutes, the addition is finished. It is then heated for a further 30 minutes under reflux. After cooling, the reaction mixture is washed twice with water and once with dilute acetic acid. The chloroform phase is dried over sodium sulfate and evaporated. The residue obtained is further purified over a silica gel column (chloroform/acetone = 9:1). After evaporation of up-

løsningsmidlet omkrystalliseres de rene fraksjoner påny fra metylenklorid/petroleter (20:1). the solvent, the pure fractions are recrystallized again from methylene chloride/petroleum ether (20:1).

Utbytte: 3,3 g (77% av det teoretiske). Yield: 3.3 g (77% of theoretical).

Smeltepunkt: 94-95°C. Melting point: 94-95°C.

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

Funnet: 67,11 6,78 6,70 8,39. Found: 67.11 6.78 6.70 8.39.

Eksempel 38 Example 38

4-[ 2-( 5- klor- 2-( 3, 5- dimetyl- piperidino)- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 5- chloro- 2-( 3, 5- dimethyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

2,15 g (0,005 mol) 4-[2-(5-klor-2-(3,5-dimetyl-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester oppvarmes under tilbakeløpskjøling i 50 ml etanol og 10 ml IN natronlut i 30 minutter. Efter avkjøling fjernes mesteparten av alkoholen i vakuum, og 60 ml vann tilsettes. Ved svak surgjøring med eddiksyre til ca. pH 6 utfelles et bunnfall som efter en tids henstand avsuges og omkrystalliseres fra isopropanol. Utbytte: 1,82 g (87,5% av det teoretiske), 2.15 g (0.005 mol) of 4-[2-(5-chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester is heated under reflux in 50 ml of ethanol and 10 ml of IN baking soda for 30 minutes. After cooling, most of the alcohol is removed under vacuum, and 60 ml of water is added. By slightly acidifying with acetic acid to approx. At pH 6, a precipitate is precipitated which, after a period of time, is suctioned off and recrystallized from isopropanol. Yield: 1.82 g (87.5% of the theoretical),

Smeltepunkt: 204-206°C. Melting point: 204-206°C.

Beregnet: C 66,58, H 6,56, N 6,75, Cl 8,55 Calculated: C 66.58, H 6.56, N 6.75, Cl 8.55

Funnet: 66,59 6,48 6,71 8,45. Found: 66.59 6.48 6.71 8.45.

E ksempel 39 Example 39

4-[ 2-( 5- klor- 2-( 4- metoksy- piperidino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- chloro- 2-( 4- methoxy-piperidino)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(4-metoksy-piperidino)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 60% av det teoretiske, Prepared from 5-chloro-2-(4-methoxy-piperidino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 60% of the theoretical,

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

Beregnet: C 64,78, H 6,57, N 6,30 Calculated: C 64.78, H 6.57, N 6.30

Funnet: 64,95 6,62 6,15 Found: 64.95 6.62 6.15

Eksempel 40 Example 40

4- [ 2- ( 5- klor- 2- ( 4- metoksy- piperidino)- benzoylamino)- ety1]-ben zoesyre 4- [ 2- ( 5- chloro- 2- ( 4- methoxy-piperidino)- benzoylamino)- ethyl1]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4-metoksy-piperidino)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(4-methoxy-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 85% av det teoretiske, Yield: 85% of the theoretical,

Smeltepunkt: 188°C. Melting point: 188°C.

Beregnet: C 63,38, H 6,04, N 6,72 Calculated: C 63.38, H 6.04, N 6.72

Funnet: 63,46 5,95 6,72. Found: 63.46 5.95 6.72.

E ksempel 41 Example 41

4-[ 2-( 5- metoksy- 2- piperidino-b enzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- methoxy- 2- piperidino-benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-metoksy-2-piperidino-benzoesyre og 4- (2-aminoety1)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 66% av det teoretiske, Prepared from 5-methoxy-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 66% of the theoretical,

Smeltepunkt: 118°C. Melting point: 118°C.

Beregnet: C 70,22, H 7,36, N 6,82 Calculated: C 70.22, H 7.36, N 6.82

Funnet: 70,76 7,42 7,36. Found: 70.76 7.42 7.36.

E ksempel 42 Example 42

4- [ 2-( 5- metoksy- 2- piperidino- benzoylamino)- ety1]- benzoesyre-h ydroklorid 4-[2-(5-Methoxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-metoksy-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Den erholdte forbindelse ble i aceton overført til hydrokloridet med isopropanolisk saltsyre. Prepared from 4-[2-(5-methoxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2. The compound obtained was transferred in acetone to the hydrochloride with isopropanolic hydrochloric acid.

Utbytte: 91% av det teoretiske, Yield: 91% of the theoretical,

Smeltepunkt: 15 8°C Melting point: 15 8°C

Beregnet: C 63,07, H 6,49, N 6,68 Calculated: C 63.07, H 6.49, N 6.68

Funnet: 63,00 6,31 6,61. Found: 63.00 6.31 6.61.

E ksempel 43 Example 43

4- [ 2- ( 5- klor- 2- heptametylenimino- benzoylamino)- etyl]- benzoesyre- etylester 4- [ 2- ( 5- chloro- 2- heptamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-heptametylenimino-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 24% av det teoretiske. Prepared from 5-chloro-2-heptamethyleneimino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 24% of the theoretical.

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

Beregnet: C 67,78, H 7,05, N 6,33 Calculated: C 67.78, H 7.05, N 6.33

Funnet: 67,95 7,16 6,33 Found: 67.95 7.16 6.33

Eksempel 4 4 Example 4 4

4-[ 2-( 5- klor- 2- heptametylenimlno- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- heptamethylenenimlno- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-heptametylenimino-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-heptamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

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

Smeltepunkt: 186°C. Melting point: 186°C.

Beregnet: C 66,57, H 6,56, N 6,75 Calculated: C 66.57, H 6.56, N 6.75

Funnet: 66,45 6,43 6,70 Found: 66.45 6.43 6.70

Eksempel 45 Example 45

4-[ 2-( 5- nitro- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- nitro- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-nitro-2-piperidino-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 70% av det teoretiske, Prepared from 5-nitro-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 70% of the theoretical,

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

Beregnet: C 64,92, H 6,40, N 9,87 Calculated: C 64.92, H 6.40, N 9.87

Funnet: 65,17 6,38 9,67 Found: 65.17 6.38 9.67

Eksempel 46 Example 46

4-[ 2-( 5- nitro- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- nitro- 2- piperidino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-nitro-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-nitro-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

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

Smeltepunkt: 194-195°C. Melting point: 194-195°C.

Beregnet: C 63,46, H 5,83, N 10,57 Calculated: C 63.46, H 5.83, N 10.57

Funnet: 63,20 5,79 10,38. Found: 63.20 5.79 10.38.

Eksempel 47 Example 47

4-[ 2-( 5- klor- 2-( 4- feny1- piperidino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 4- phenyl-piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-(4-fenyl-piperidino)-benzoesyre Prepared from 5-chloro-2-(4-phenyl-piperidino)-benzoic acid

og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 62% av det teoretiske. and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 62% of the theoretical.

Smeltepunkt: 124°C. Melting point: 124°C.

Beregnet: C 70,50, H 6,13, N 5,87 Calculated: C 70.50, H 6.13, N 5.87

Funnet: 70,60 6,26 5,84. Found: 70.60 6.26 5.84.

Eksempel 4 8 Example 4 8

4-[ 2-( 5- klor- 2-( 4- feny1-pip eridi no)- benzoylamino)- etyl]-benzoesyre 4-[2-(5-chloro-2-(4-phenyl-piperidino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4-fenyl-piperidino)-benzoylamino) -etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(4-phenyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 92% av det teoretiske, Yield: 92% of the theoretical,

Smeltepunkt: 188°C. Melting point: 188°C.

Beregnet: C 70,04, H 5,88, N 6,05 Calculated: C 70.04, H 5.88, N 6.05

Funnet: 70,12, 6,08 6,05. Found: 70.12, 6.08 6.05.

Eksempel 49 Example 49

4-[ 2-( 5- klor- 2- ( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- yl-( 8))-benzoylamino)- etyl]- benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 1, 4- dioxa- 8- aza- spiro[ 4, 5] decanyl-( 8))- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-(1,4-dioksa-8-aza-spiro[4,5]dekan-yl- (8) ) -benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-(1,4-dioxa-8-aza-spiro[4,5]decan-yl-(8))-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously with example 1.

Utbytte: 45% av det teoretiske. Yield: 45% of the theoretical.

Smeltepunkt: 167°C. Melting point: 167°C.

Beregnet: C 62,81, H 5,93, N 6,11 Calculated: C 62.81, H 5.93, N 6.11

Funnet: 62,80 5,89 5,9 3 Found: 62.80 5.89 5.9 3

Eksempel 50 Example 50

4-[ 2-( 5- klor- 2-( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- yl-( 8))-benzoylamino)- etyl]- benz oesyre 4-[ 2-( 5- chloro- 2-( 1, 4- dioxa- 8- aza- spiro[ 4, 5] decanyl-( 8))-benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(1,4-dioksa-8-aza-spiro-[4,5]dekanyl-(8))-benzoylamino)-etyl]-benzoesyre-metylester Prepared from 4-[2-(5-chloro-2-(1,4-dioxa-8-aza-spiro-[4,5]decanyl-(8))-benzoylamino)-ethyl]-benzoic acid methyl ester

ved alkalisk hydrolyse analogt med eksempel 2. by alkaline hydrolysis analogous to example 2.

Utbytte: 82% av det teoretiske, Yield: 82% of the theoretical,

Smeltepunkt: 190°C. Melting point: 190°C.

Beregnet: C 61,95, H 5,88, N 6,28 Calculated: C 61.95, H 5.88, N 6.28

Funnet: 61,74 6,03 6,52. Found: 61.74 6.03 6.52.

Eksempel 51 Example 51

4-[ 2-( 5- klor- 2-( 4- etoksykarbonyl- piperidino)- benzoylamino)- ety1]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 4- ethoxycarbonyl- piperidino)- benzoylamino)- ethyl1]-benzoic acid- methyl ester

Fremstilt fra 5-klor-2-(4-etoksykarbonyl-piperidino)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 17% av det teoretiske, Yield: 17% of the theoretical,

Smeltepunkt: 70°C. Melting point: 70°C.

Beregnet: C 63,48, H 6,18, N 5,92 Calculated: C 63.48, H 6.18, N 5.92

Funnet: 63,30 6,08 5,91 Found: 63.30 6.08 5.91

Eksempel 52 Example 52

4-[ 2-( 5- klor- 2-( 4- hydroksykarbony1- piperidino)- benzoylamino)-etyl]- benzoesyre 4-[ 2-( 5- chloro- 2-( 4- hydroxycarbonyl-piperidino)- benzoylamino)-ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4-etoksykarbonyl-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(4-ethoxycarbonyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

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

Smeltepunkt: 2 38°C. Melting point: 2 38°C.

Beregnet: C 61,32, H 5,38, N 6,50 Calculated: C 61.32, H 5.38, N 6.50

Funnet: 61,32 5,33 6,71 Found: 61.32 5.33 6.71

Eksempel 53 Example 53

4-[ 2-( 5- klor- 2- heksametylenimino- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- chloro- 2- hexamethyleneimino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-heksametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 72% av det teoretiske, Prepared from 5-chloro-2-hexamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 72% of the theoretical,

Smeltepunkt: 81°C. Melting point: 81°C.

Beregnet: C 66,60, H 6,56, N 6,75 Calculated: C 66.60, H 6.56, N 6.75

Funnet: 66,28 6,30 6,67. Found: 66.28 6.30 6.67.

Eksempel 5 4 Example 5 4

4-[ 2-( 5- klor- 2- heksametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- hexamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-heksametylenimino-benzoylamino)-ety1]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-hexamethyleneimino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 89% av det teoretiske, Yield: 89% of the theoretical,

Smeltepunkt: 182°C. Melting point: 182°C.

Beregnet: C 66,00, H 6,29, N 6,99 Calculated: C 66.00, H 6.29, N 6.99

Funnet: 66,20 6,40 7,15. Found: 66.20 6.40 7.15.

Eksempel 55 Example 55

4-[ 2-( 5- klor- 2- morfolino- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- chloro- 2- morpholino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-morfolino-benzoesyre og 4-(2-amino-etyl )-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-morpholino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 80% av det teoretiske, Yield: 80% of the theoretical,

Smeltepunkt: 111°C. Melting point: 111°C.

Beregnet: C 62,55, H 5,75, N 6,95. Calculated: C 62.55, H 5.75, N 6.95.

Funnet: 62,48 5,74 6,94. Found: 62.48 5.74 6.94.

Eksempel 56 Example 56

4-[ 2-( 5- klor- 2- morfolino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- morpholino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-morfolino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-morpholino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 78% av det teoretiske, Yield: 78% of the theoretical,

Smeltepunkt: 186°C. Melting point: 186°C.

Beregnet: C 61,75, H 5,44, N 7,20 Calculated: C 61.75, H 5.44, N 7.20

Funnet: 61,60 5,41 7,10. Found: 61.60 5.41 7.10.

Eksempel 57 Example 57

4- [ 2- ( 5- klor- 2- tiomorfolino- benzoylamino)- etyl]- benzoesyre-metylester 4- [ 2- ( 5- chloro- 2- thiomorpholino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-tiomorfolino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 45% av det teoretiske, Prepared from 5-chloro-2-thiomorpholino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 45% of the theoretical,

Smeltepunkt: 160°C. Melting point: 160°C.

Beregnet: C 60,20, H 5,53, N 6,69 Calculated: C 60.20, H 5.53, N 6.69

Funnet: 60,62 5,76 6,96. Found: 60.62 5.76 6.96.

Eksempel 58 Example 58

4-[ 2-( 5- klor- 2- tiomorfolino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- thiomorpholino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-tiomorfolino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-thiomorpholino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 57% av det teoretiske, Yield: 57% of the theoretical,

Smeltepunkt: 210°C. Melting point: 210°C.

Beregnet: C 59,32, H 5,23, N 6,92 Calculated: C 59.32, H 5.23, N 6.92

Funnet: 59,25 5,19 6,80. Found: 59.25 5.19 6.80.

Eksempel 59 Example 59

4-[ 2-( 5- klor- 2- tiomorfolino- benzoylamino)- etyl]- benzoesyre-mety lester- S- oksyd 4-[ 2-( 5- chloro- 2- thiomorpholino- benzoylamino)- ethyl]- benzoic acid methyl ester- S- oxide

Fremstilt fra 5-klor-2-tiomorfolino-benzoesyre-S-oksyd og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 63% av det teoretiske. Prepared from 5-chloro-2-thiomorpholino-benzoic acid S-oxide and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 63% of the theoretical.

Smeltepunkt: 152°C. Melting point: 152°C.

Beregnet: C 57,99, H 5,33, N 6,44, Calculated: C 57.99, H 5.33, N 6.44,

Funnet: 58,30 5,22 6,52. Found: 58.30 5.22 6.52.

Eksempel 60 Example 60

4- [ 2-( 5- klor- 2- tiomorfolino- benzoylamino)- etyl]- benzoesyre-5- oksyd 4- [ 2-( 5- chloro- 2- thiomorpholino- benzoylamino)- ethyl]- benzoic acid-5- oxide

Fremstilt fra 4-[2-(5-klor-2-tiomorfolino-benzoylamino)-etyl]-benzoesyre-metylester-S-oksyd ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-thiomorpholino-benzoylamino)-ethyl]-benzoic acid methyl ester-S-oxide by alkaline hydrolysis analogously to example 2.

Utbytte: 82% av det teoretiske, Yield: 82% of the theoretical,

Smeltepunkt: 202°C. Melting point: 202°C.

Beregnet: C 57,07, H 5,03, N 6,66 Calculated: C 57.07, H 5.03, N 6.66

Funnet: 57,46 5,07 6,30. Found: 57.46 5.07 6.30.

E ksempel 61 Example 61

4-[ 2-( 5- klor- 2-[ 1, 2, 4, 5- tetrahydro- 3H- 3- benzazepin- yl-( 3)]-benzoylamino)- etyl]- benzoesyre- metylester 4-[ 2-( 5- chloro- 2-[ 1, 2, 4, 5- tetrahydro- 3H- 3- benzazepin- yl-( 3)]-benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-[1,2,4,5-tetrahydro-3H-3-benzazepin-yl-(3)]-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-[1,2,4,5-tetrahydro-3H-3-benzazepin-yl-(3)]-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 69% av det teoretiske. Yield: 69% of the theoretical.

Smeltepunkt: 126°C. Melting point: 126°C.

Beregnet: C 70,04, H 5,88, N 6,05 Calculated: C 70.04, H 5.88, N 6.05

Funnet: 70,20 5,81 5,94 Found: 70.20 5.81 5.94

Eksempel 62 Example 62

4-[ 2-( 5- klor- 2-[ 1, 2, 4, 5- tetrahydro- 3H- 3- benzazepin- y1-( 3)]-benzoyla mino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2-[ 1, 2, 4, 5- tetrahydro- 3H- 3- benzazepin- y1-( 3)]- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-[1,2,4,5-tetrahydro-3H-3-benzazepin-y1-(3)]-benzoylamino)-ety1]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-[1,2,4,5-tetrahydro-3H-3-benzazepin-y1-(3)]-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogous to example 2.

Utbytte: 89% av det teoretiske, Yield: 89% of the theoretical,

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

Beregnet: C 69,55, H 5,61, N 6,24 Calculated: C 69.55, H 5.61, N 6.24

Funnet: 69,87 5,90 6,10 Found: 69.87 5.90 6.10

Eksempel 6 3 Example 6 3

4-[ 2-( 5- klor- 2-[ 1, 2, 3, 4- tetrahydro- isokinolin- yl-( 2)]- benzoylamino) - ety1]- benzoesyre- metylester 4-[ 2-( 5- chloro- 2-[ 1, 2, 3, 4- tetrahydro- isoquinolin- yl-( 2)]- benzoylamino) - ethyl 1]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-[1,2,3,4-tetrahydro-isokinolyl-(2)]-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-[1,2,3,4-tetrahydro-isoquinolyl-(2)]-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 43% av det teoretiske, Yield: 43% of the theoretical,

Smeltepunkt: 94°C. Melting point: 94°C.

Beregnet: C 69,55, H 5,61, N 6,24 Calculated: C 69.55, H 5.61, N 6.24

Funnet: 69,65 5,65 6,14 Found: 69.65 5.65 6.14

Eksempel 64 Example 64

4-[ 2-( 5- klor- 2-[ 1, 2, 3, 4- tetrahydro- isokinolin- yl-( 2)]- benzoylamino) - etyl]- benzoesyre 4-[ 2-( 5- chloro- 2-[ 1, 2, 3, 4- tetrahydro- isoquinolin- yl-( 2)]- benzoylamino) - ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-[1,2,3,4-tetrahydro-isokinolin-yl- (2)]-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-[1,2,3,4-tetrahydro-isoquinolin-yl-(2)]-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogous to example 2 .

Utbytte: 86% av det teoretiske, Yield: 86% of the theoretical,

Smeltepunkt: 17 3°C. Melting point: 17 3°C.

Beregnet: C 69,04, H 5,33, N 6,44, Cl 8,15 Calculated: C 69.04, H 5.33, N 6.44, Cl 8.15

Funnet: 68,45 5,56 6,21 8,57. Found: 68.45 5.56 6.21 8.57.

Ekse mpel 6 5 Example 6 5

4-[ 2-( 5- klor- 2-( 4- fenyl- piperazino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 4- phenyl-piperazino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-(4-fenyl-piperazino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 40% av det teoretiske, Prepared from 5-chloro-2-(4-phenyl-piperazino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 40% of the theoretical,

Smeltepunkt: 132°C. Melting point: 132°C.

Beregnet: C 67,84, H 5,90, N 8,79 Calculated: C 67.84, H 5.90, N 8.79

Funnet: 67,72 5,92 8,66. Found: 67.72 5.92 8.66.

Eksempel 66 Example 66

4-[ 2- ( 5- klor- 2- ( 4- fenyl- piperazino)- benzoylamino)- ety1]- benzoesyre Fremstilt fra 4-[2-(5-klor-2-(4-fenyl-piperazino)-benzoyl- 4-[2-(5-chloro-2-(4-phenyl-piperazino)-benzoylamino)-ethyl]-benzoic acid Prepared from 4-[2-(5-chloro-2-(4-phenyl-piperazino)-benzoyl -

amino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. amino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 82% av det teoretiske. Yield: 82% of the theoretical.

Smeltepunkt: 166°C. Melting point: 166°C.

Beregnet: C 67,07, H 5,65, N 9,06 Calculated: C 67.07, H 5.65, N 9.06

Funnet: 67,30 5,96 8,99. Found: 67.30 5.96 8.99.

Eksempel 67 Example 67

4-[ 2-( 5- klor- 2-( 4- pyridyl-( 2)- piperazino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- Chloro- 2-( 4- Pyridyl-( 2)- Piperazino)- Benzoylamino)- Ethyl]- Benzoic Acid Methyl Ester

Fremstilt fra 5-klor-2-[4-(2-pyridyl)-piperazino]-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester-hydroklorid i nærvær av tionylklorid og trietylamin analogt med eksempel 37. Utbytte: 44,6% av det teoretiske, Prepared from 5-chloro-2-[4-(2-pyridyl)-piperazino]-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester hydrochloride in the presence of thionyl chloride and triethylamine analogously to example 37. Yield: 44.6% of the theoretical,

Smeltepunkt for hydrokloridet: 153-154°C. Melting point for the hydrochloride: 153-154°C.

Beregnet: C 60,58, H 5,48, N 10,87, Cl 13,76 Calculated: C 60.58, H 5.48, N 10.87, Cl 13.76

Funnet: 60,31 5,52 10,68 13,93 Found: 60.31 5.52 10.68 13.93

Eksempel 6 8 Example 6 8

4-[ 2-( 5- klor- 2-( 4- pyridyl-( 2)- piperazino)- benzoylamino- ety1]-benzoesyre 4-[ 2-( 5- Chloro- 2-( 4- Pyridyl-( 2)- Piperazino)- Benzoylamino- Ethyl]- Benzoic Acid

Fremstilt fra 4-[2-(5-klor-2-(4-pyridyl-(2)-piperazino)-benzoylamino-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-(4-pyridyl-(2)-piperazino)-benzoylamino-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 27% av det teoretiske, Yield: 27% of the theoretical,

Smeltepunkt: 120°C (spaltn.). Melting point: 120°C (dec.).

Beregnet: C 64,58, H 5,42, N 12,05, Cl 7,63. Calculated: C 64.58, H 5.42, N 12.05, Cl 7.63.

Funnet: 64,36 5,49 11,87 7,48. Found: 64.36 5.49 11.87 7.48.

Eksempel 69 Example 69

4-[ 2-( 5- klor- 2- piperidino- benzoylamino)- 1- metyl- etyl]- benzoesyre-metylester 4-[ 2-( 5- Chloro- 2- Piperidino- Benzoylamino)- 1- Methyl- Ethyl]- Benzoic Acid Methyl Ester

Fremstilt fra 5-klor-2-piperidino-benzoesyre og 4-(2-amino-1-metyl-etyl)-benzoesyre-metylester analogt med eksempel 1. Utbytte: 42,7% av det teoretiske, Prepared from 5-chloro-2-piperidino-benzoic acid and 4-(2-amino-1-methyl-ethyl)-benzoic acid methyl ester analogously to example 1. Yield: 42.7% of the theoretical,

Smeltepunkt: 93-94°C. Melting point: 93-94°C.

Beregnet: C 66,57, H 6,56, Cl 8,54, N 6,75 Calculated: C 66.57, H 6.56, Cl 8.54, N 6.75

Funnet: 66,82 6,57 8,47 6,58. Found: 66.82 6.57 8.47 6.58.

Eksempel 70 Example 70

4- [ 2- ( 5- klor- 2- piperidino- benzoylamino)- 1- metyl- etyl]- benzoesyre 4- [ 2- ( 5- chloro- 2- piperidino- benzoylamino)- 1- methyl- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-piperidino-benzoylamino)-1-metyletyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-piperidino-benzoylamino)-1-methylethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 76% av det teoretiske. Yield: 76% of the theoretical.

Smeltepunkt: 192-194°C. Melting point: 192-194°C.

Beregnet: C 65,91, H 6,28, Cl 8,84, N 6,99 Calculated: C 65.91, H 6.28, Cl 8.84, N 6.99

Funnet: 66,00 6,30 8,77 6,87 Found: 66.00 6.30 8.77 6.87

Eksempel 71 Example 71

4-[ 2-( 5- klor- 2- dimetylamino- benzoylamino)- 1- metyletyl]-benzoesyre 4-[ 2-( 5- chloro- 2- dimethylamino- benzoylamino)- 1- methylethyl]-benzoic acid

Fremstilt fra 4-[ 2-(5-klor-2-dimetylamino-benzoylamino)-1-metyletyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-chloro-2-dimethylamino-benzoylamino)-1-methylethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 86% av det teoretiske, Yield: 86% of the theoretical,

Smeltepunkt: 159-161°C. Melting point: 159-161°C.

Beregnet: C 63,23, H 5,87, Cl 9,83, N 7,76 Calculated: C 63.23, H 5.87, Cl 9.83, N 7.76

Funnet: 63,42 6,07 9,56 7,67. Found: 63.42 6.07 9.56 7.67.

E ksempel 72 Example 72

4-[ 2-( 5- klor- 2- dimetylamino- benzoylamino)- 1- metyletyl]- benzoesyre- metylester 4-[ 2-( 5- chloro- 2- dimethylamino- benzoylamino)- 1- methylethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-dimetylamino-benzoesyre og 4-(2-amino-l-metyletyl)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-chloro-2-dimethylamino-benzoic acid and 4-(2-amino-1-methylethyl)-benzoic acid methyl ester analogously to example 1.

Utbytte: 61,5% av det teoretiske, Yield: 61.5% of the theoretical,

Smeltepunkt: 79-80°C. Melting point: 79-80°C.

Beregnet: C 64,07, H 6,18, Cl 9,46, N 7,47 Calculated: C 64.07, H 6.18, Cl 9.46, N 7.47

Funnet: 64,40 6,52 9,14 7,20 Found: 64.40 6.52 9.14 7.20

Eksempel 73 Example 73

4-[ 2-( 5- amino- 2- piperidino- benzoylamino)- etyl]- benzoesyre-e ty les ter 4-[ 2-( 5- amino- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

30 g (70,5 mmol) 4-[2-(5-nitro-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester hydrogeneres i 500 ml metanol:etanol (1:1) med palladium-kull som katalysator ved romtemperatur og et hydrogentrykk på 5 bar. Efter fraskillelse av katalysatoren og avdestillering av oppløsningsmidlet renses forbindelsen ved filtrering over silikagel med eddiksyreetylester som oppløsningsmiddel ("løpemiddel"). 30 g (70.5 mmol) 4-[2-(5-nitro-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester is hydrogenated in 500 ml of methanol:ethanol (1:1) with palladium charcoal as catalyst at room temperature and a hydrogen pressure of 5 bar. After separation of the catalyst and distillation of the solvent, the compound is purified by filtration over silica gel with acetic acid ethyl ester as solvent ("eluent").

Utbytte: 93% av det teoretiske, Yield: 93% of the theoretical,

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

Beregnet: C 69,84, H 7,39, N 10,62 Calculated: C 69.84, H 7.39, N 10.62

Funnet: 70,10 7,20 10,43. Found: 70.10 7.20 10.43.

Eksempel 74 Example 74

4-[ 2-( 5- amino- 2- piperidino- benzoylamino)- etyl]- benzoesyre-dihydroklorid 4-[ 2-( 5- amino- 2- piperidino- benzoylamino)- ethyl]- benzoic acid dihydrochloride

Fremstilt fra 4-[2-(5-amino-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Derefter overføres produktet til dihydro-kloridet i aceton med isopropanolisk saltsyre. Prepared from 4-[2-(5-amino-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2. The product is then transferred to the dihydrochloride in acetone with isopropanolic hydrochloric acid.

Utbytte: 87% av det teoretiske, Yield: 87% of the theoretical,

Smeltepunkt: 70°C. Melting point: 70°C.

Beregnet: C 57,26, H 6,18, N 9,54 Calculated: C 57.26, H 6.18, N 9.54

Funnet: 57,40 6,30 9,52. Found: 57.40 6.30 9.52.

E ksempel 75 Example 75

4-[ 2-( 5- acetamino-2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- acetamino-2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 2,5 g (6,3 mmol) 4-[2-(5-amino-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester og 25 ml eddiksyre-anhydrid ved romtemperatur. Reaksjohsproduktet utfelles og eftervaskes med eter. Prepared from 2.5 g (6.3 mmol) of 4-[2-(5-amino-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester and 25 ml of acetic anhydride at room temperature. The reaction product is precipitated and washed with ether.

Utbytte: 1,9 g (69% av det teoretiske). Yield: 1.9 g (69% of theoretical).

Smeltepunkt: 165°C Melting point: 165°C

Beregnet: C 68,62, H 7,14, N 9,60 Calculated: C 68.62, H 7.14, N 9.60

Funnet: 68,92 7,09 9,50. Found: 68.92 7.09 9.50.

Eksempel 76 Example 76

4- [2- ( 5- acetamino- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4- [2- ( 5- acetamino- 2- piperidino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-acetamino-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 2. Prepared from 4-[2-(5-acetamino-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 2.

Utbytte: 98% av det teoretiske, Yield: 98% of the theoretical,

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

Beregnet: C 67,46, H 6,64, N 10,26 Calculated: C 67.46, H 6.64, N 10.26

Funnet: 67,OO 6,67 10,04 Found: 67.OO 6.67 10.04

Eksempel 77 Example 77

4-[ 2-( 5- dimetylaminosulfonyl- 2- piperidino- benzoylamino)- etyl]-b enzoesyre- metylester 4-[ 2-( 5- dimethylaminosulfonyl- 2-piperidino- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 5-dimetylaminosulfonyl-2-piperidino-benzoesyre og 4-(2-etylamino)-benzoesyre-metylester analogt med eksempel 1. Prepared from 5-dimethylaminosulfonyl-2-piperidino-benzoic acid and 4-(2-ethylamino)-benzoic acid methyl ester analogously to example 1.

Utbytte: 77% av det teoretiske, Yield: 77% of the theoretical,

Smeltepunkt: 138-140°C. Melting point: 138-140°C.

Beregnet: C 60,87, H 6,60, N 8,87, S 6,77 Calculated: C 60.87, H 6.60, N 8.87, S 6.77

Funnet: 61,08 6,67 8,86 6,80 Found: 61.08 6.67 8.86 6.80

Eksempel 78 Example 78

4-[ 2-( 5- dimetylaminosulfonyl- 2- piperidino- benzoylamino)- etyl]-benzoesyre 4-[2-(5-Dimethylaminosulfonyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-dimetylaminosulfonyl-2-piperidino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk forsepning analogt med eksempel 2. Prepared from 4-[2-(5-dimethylaminosulfonyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline saponification analogously to example 2.

Utbytte: 91% av det teoretiske, Yield: 91% of the theoretical,

Smeltepunkt: 220°C. Melting point: 220°C.

Beregnet: C 60,11, H 6,36, N 9,14, S 6,98 Calculated: C 60.11, H 6.36, N 9.14, S 6.98

Funnet: 60,30 6,42 8,96 6,98. Found: 60.30 6.42 8.96 6.98.

Eksempel 79 Example 79

4-[ 2-( 5- cyano- 2- pi peridino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- cyano- 2- pi peridino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-cyano-2-piperidino-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 1. Utbytte: 76% av det teoretiske, Prepared from 5-cyano-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 1. Yield: 76% of the theoretical,

Smeltepunkt: 9 7°C. Melting point: 9 7°C.

Beregnet: C 71,08, H 6,71, N 10,36 Calculated: C 71.08, H 6.71, N 10.36

Funnet: 71,37 6,74 10,33. Found: 71.37 6.74 10.33.

E ksempel 80 Example 80

4-[ 2-( 5- cyano- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- cyano- 2- piperidino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-cyano-2-piperidino-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med Prepared from 4-[2-(5-cyano-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogous to

eksempel 2. example 2.

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

Smeltepunkt: 190°C. Melting point: 190°C.

Beregnet: C 70,00, H 6,14, N 11,13 Calculated: C 70.00, H 6.14, N 11.13

Funnet: 69,81 6,03 10,98. Found: 69.81 6.03 10.98.

Eksempel 81 Example 81

4- [ 2- ( 5- etoksykarbonyl- 2- piperidino- benzoylamino)- etyl]-b enzoesyre- etylester- hydroklorid 4- [ 2- ( 5- ethoxycarbonyl- 2- piperidino- benzoylamino)- ethyl]-benzoic acid ethyl ester hydrochloride

2,5 g (6,2 mmol) 4-[2-(5-cyano-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester oppløses i 80 ml etanol og mettes med hydrogenklorid. Efter 6 dagers henstand ved romtemperatur avdampes oppløsningsmidlet, residuet oppløses i isvann, innstilles på pH 9 med natronlut og ekstraheres med kloroform. Efter tørring over natriumsulfat og avdestillering av opp-løsningsmidlet overføres inndampningsresiduet i eter til hydrokloridet med eterisk saltsyre. 2.5 g (6.2 mmol) of 4-[2-(5-cyano-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester are dissolved in 80 ml of ethanol and saturated with hydrogen chloride. After standing for 6 days at room temperature, the solvent is evaporated, the residue is dissolved in ice water, adjusted to pH 9 with caustic soda and extracted with chloroform. After drying over sodium sulphate and distilling off the solvent, the evaporation residue in ether is transferred to the hydrochloride with ethereal hydrochloric acid.

Utbytte: 2,5 g (89,1% av det teoretiske), Yield: 2.5 g (89.1% of the theoretical),

Smeltepunkt: 86-88°C. Melting point: 86-88°C.

Beregnet: C 63,85, H 6,80, N 5,72, Cl 7,24 Calculated: C 63.85, H 6.80, N 5.72, Cl 7.24

Funnet: 63,71 6,69 5,74 7,11. Found: 63.71 6.69 5.74 7.11.

Eksempel 82 Example 82

4- [ 2-( 5- hydroksykarbonyl- 2- piperidino- benzoylamino)- etyl]-benzoesyre 4- [ 2-( 5- hydroxycarbonyl- 2-piperidino- benzoylamino)- ethyl]-benzoic acid

Fremstilt ved alkalisk hydrolyse av 4-[2-(5-etoksy-karbonyl-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester-hydroklorid analogt med eksempel 2. Prepared by alkaline hydrolysis of 4-[2-(5-ethoxy-carbonyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester hydrochloride analogously to example 2.

Utbytte: 92% av det teoretiske. Yield: 92% of the theoretical.

Smeltepunkt: 242°C. Melting point: 242°C.

Beregnet: C 66,65, H 6,10, N 7,06 Calculated: C 66.65, H 6.10, N 7.06

Funnet: 65,96 6,18 7,23. Found: 65.96 6.18 7.23.

Eksempel 8 3 Example 8 3

4-[ 2- ( 2- ( 4- hydroksy- piperidino)- 5- nitro- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2- ( 2- ( 4- hydroxy-piperidino)- 5- nitro- benzoylamino)- ethyl]-benzoic acid methyl ester

a) 4- [ 2- ( 2- klor- 5- nitro- benzoylamino)- etyl]- benzoesyre-m etylester a) 4-[2-(2-chloro-5-nitro-benzoylamino)-ethyl]-benzoic acid methyl ester

8 g (40 mmol) 2-klor-5-nitro-benzoesyre i 40 ml absolutt tetrahydrofuran overføres til imidazolidet med 6,8 g (44 mmol) N,N'-karbonyl-diimidazol. Efter en reaksjonstid på 2 timer tilsettes 7,9 g (44 mmol) 4-(2-amino-etyl)-benzoesyre-metylester ved romtemperatur, og blandingen omrøres i ca. 16 timer. Efter avdestillering av oppløsningsmidlet renses råproduktet kromatografisk over en silikagelkolonne med toluen:eddiksyreetylester (1:1) som løpemiddel. 8 g (40 mmol) of 2-chloro-5-nitro-benzoic acid in 40 ml of absolute tetrahydrofuran is transferred to the imidazolide with 6.8 g (44 mmol) of N,N'-carbonyl-diimidazole. After a reaction time of 2 hours, 7.9 g (44 mmol) of 4-(2-amino-ethyl)-benzoic acid methyl ester are added at room temperature, and the mixture is stirred for approx. 16 hours. After distilling off the solvent, the crude product is purified chromatographically over a silica gel column with toluene: ethyl acetate (1:1) as eluent.

Utbytte: 12 g (83% av det teoretiske), Yield: 12 g (83% of the theoretical),

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

Beregnet: C 56,28, H 4,17, N 7,72 Calculated: C 56.28, H 4.17, N 7.72

Funnet: 56,58 4,41 7,82. Found: 56.58 4.41 7.82.

b) 4-[ 2-( 2- ( 4- hydroksy- piperidino)- 5- nitro- benzoylamino)-etyl]- benzoesyre- metylester b) 4-[ 2-( 2-( 4- hydroxy-piperidino)- 5- nitro- benzoylamino)-ethyl]- benzoic acid methyl ester

En oppløsning av 5 g (14 mmol) 4-[2-(2-klor-5-nitro-benzoylamino)-ety1]-benzoesyre-metylester i 100 ml etanol oppvarmes med 2,83 g (28 mmol) 4-hydroksy-piperidin i 14 timer til tilbakeløpstemperatur. Efter avdestillering av oppløsnings-midlet på en rotasjonsinndamper oppløses den tørre rest i isvann, innstilles på pH 5 med fortynnet saltsyre og ekstraheres med kloroform. Efter tørring over natriumsulfat og avdestillering av kloroformen krystalliseres residuet fra isopropanol. Utbytte: 5,5 g (92% av det teoretiske), A solution of 5 g (14 mmol) of 4-[2-(2-chloro-5-nitro-benzoylamino)-ethyl]-benzoic acid methyl ester in 100 ml of ethanol is heated with 2.83 g (28 mmol) of 4-hydroxy- piperidine for 14 hours to reflux temperature. After distilling off the solvent on a rotary evaporator, the dry residue is dissolved in ice water, adjusted to pH 5 with dilute hydrochloric acid and extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the residue is crystallized from isopropanol. Yield: 5.5 g (92% of the theoretical),

Smeltepunkt: 147°C. Melting point: 147°C.

Eksempel 84 Example 84

4-[ 2-( 5- amino- 2-( 4- hydroksy- piperidino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- amino- 2-( 4- hydroxy-piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

5,3 g (12,4 mmol) 4-[2-(2-(4-hydroksy-piperidino)-5-nitro-benzoylamino) -etyl] -benzoesyre-metylester hydrogeneres i 100 ml metanol med 10%ig palladium-kull ved romtemperatur og et hydrogentrykk på 1 bar. 5.3 g (12.4 mmol) of 4-[2-(2-(4-hydroxy-piperidino)-5-nitro-benzoylamino)-ethyl]-benzoic acid methyl ester is hydrogenated in 100 ml of methanol with 10% palladium- coal at room temperature and a hydrogen pressure of 1 bar.

Utbytte: 91% av det teoretiske, Yield: 91% of the theoretical,

Smeltepunkt: 78°C. Melting point: 78°C.

Eksempel 85 Example 85

4-[ 2-( 5- klor- 2- ( 4- hydroksy- piperidino)- benzoylamino)- ety1]-be nzoesyre- met ylester 4-[ 2-( 5- chloro- 2-( 4- hydroxy-piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

20,5 g (52 mmol) 4-[2-(5-amino-2-(4-hydroksy-piperidino)- 20.5 g (52 mmol) 4-[2-(5-amino-2-(4-hydroxy-piperidino)-

benzoylamino)-etyl]-benzoesyre-metylester oppløses i 80 ml halvkonsentrert, iskold saltsyre og diazoteres med en opp-løsning av 4 g natriumnitritt i 25 ml iskaldt vann. Denne oppløsning settes dråpevis til en suspensjon av 6 g kobberpulver og 10 ml HC1. Efter avsluttet nitrogenutvikling utfelles en seig olje. Denne olje ekstraheres med kloroform, benzoylamino)-ethyl]-benzoic acid methyl ester is dissolved in 80 ml of half-concentrated, ice-cold hydrochloric acid and diazotized with a solution of 4 g of sodium nitrite in 25 ml of ice-cold water. This solution is added dropwise to a suspension of 6 g of copper powder and 10 ml of HC1. After completion of nitrogen evolution, a viscous oil precipitates. This oil is extracted with chloroform,

og efter tørring over natriumsulfat renses den over en silikagelkolonne med eddiksyreetylester:metanol (9:1) som løpemiddel. Utbytte: 30% av det teoretiske, and after drying over sodium sulfate, it is purified over a silica gel column with ethyl acetate:methanol (9:1) as eluent. Yield: 30% of the theoretical,

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

Beregnet: C 63,38, H 6,04, N 6,72 Calculated: C 63.38, H 6.04, N 6.72

Funnet: 63,62 6,21 6,55. Found: 63.62 6.21 6.55.

Eksempel 86 Example 86

4- [ 2- ( 5- klor- 2- ( 4- hydroksy- piperidino)- benzoylamino)- etyl]-benzoesyre 4- [ 2- ( 5- chloro- 2- ( 4- hydroxy-piperidino)- benzoylamino)- ethyl]-benzoic acid

4,5 g (11,3 mmol) 4-[2-(5-amino-2-(4-hydroksy-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester oppløses i 20 ml halvkonsentrert saltsyre og diazoteres ved 0°C med 0,87 g 4.5 g (11.3 mmol) of 4-[2-(5-amino-2-(4-hydroxy-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester are dissolved in 20 ml of semi-concentrated hydrochloric acid and diazotized at 0° C with 0.87 g

(12,4 mmol) natriumnitritt, oppløst i 6 ml vann. Denne opp-løsning settes dråpevis til en suspensjon av 1,2 g kobberpulver i 3 ml konsentrert saltsyre. Efter 2 timers omrøring oppvarmes til 75°C i ca. 20 minutter. Den avkjølte oppløsning ekstraheres med kloroform, kloroformoppløsningen tørres med natriumsulfat, og inndampningsresiduet renses over en silikagelkolonne med kloroform:metanol (9:1) som løpemiddel. (12.4 mmol) of sodium nitrite, dissolved in 6 ml of water. This solution is added dropwise to a suspension of 1.2 g of copper powder in 3 ml of concentrated hydrochloric acid. After stirring for 2 hours, heat to 75°C for approx. 20 minutes. The cooled solution is extracted with chloroform, the chloroform solution is dried with sodium sulfate, and the evaporation residue is purified over a silica gel column with chloroform:methanol (9:1) as eluent.

Utbytte: 2,4 g (52% av det teoretiske), Yield: 2.4 g (52% of the theoretical),

Smeltepunkt: 190°C Melting point: 190°C

Beregnet: C 62,6, H 5,75, N 6,93 Calculated: C 62.6, H 5.75, N 6.93

Funnet: 62,14 5,84 6,83 Found: 62.14 5.84 6.83

Eksempel 87 Example 87

4-[ 2-( 5- klor- 2- ( 3- hydroksy- piperidino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 3- hydroxy-piperidino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 4-[2-(5-amino-2-(3-hydroksy-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester analogt med eksempel 85. Prepared from 4-[2-(5-amino-2-(3-hydroxy-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester analogously to example 85.

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

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

Beregnet: C 63,38, H 6,04, N 6,72 Calculated: C 63.38, H 6.04, N 6.72

Funnet: 63,48 6,21 6,65. Found: 63.48 6.21 6.65.

Eksempel 88 Example 88

4-[ 2-( 5- klor- 2-( 3- hydroksy- piperidino)- benzoylamino)- etyl]-be nzoesyre- hydrat 4-[ 2-( 5- chloro- 2-( 3- hydroxy-piperidino)- benzoylamino)- ethyl]-benzoic acid hydrate

Fremstilt fra 4-[2-(5-amino-2-(3-hydroksy-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester analogt med eksempel 86. Prepared from 4-[2-(5-amino-2-(3-hydroxy-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester analogously to example 86.

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

Smeltepunkt: 100-110°C. Melting point: 100-110°C.

Beregnet: C 59,93, H 5,98, N 6,65 Calculated: C 59.93, H 5.98, N 6.65

Funnet: 60,19 6,08 6,62 Found: 60.19 6.08 6.62

Eksempel 89 Example 89

4-[ 2-( 2-( 3- hydroksy- piperidino)- 5- nitro- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 2-( 3- hydroxy-piperidino)- 5- nitro- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 4-[2-(2-klor-5-nitro-benzoylamino)-etyl]-benzoesyre-metylester og 3-hydroksy-piperidin analogt med eksempel 83. Prepared from 4-[2-(2-chloro-5-nitro-benzoylamino)-ethyl]-benzoic acid methyl ester and 3-hydroxy-piperidine analogously to example 83.

Utbytte: 43,5% av det teoretiske, Yield: 43.5% of the theoretical,

Smeltepunkt: 7 8-80°C. Melting point: 7 8-80°C.

Eksempel 90 Example 90

4- [ 2- ( 5- amino- 2- ( 3- hydroksy- piperidino)- benzoylamino)- etyl] - benzoesyre- metylester 4- [ 2- ( 5- amino- 2- ( 3- hydroxy- piperidino)- benzoylamino)- ethyl] - benzoic acid methyl ester

Fremstilt fra 4-[ 2- (3-hydroksy-piperidino)-5-nitro-benzoylamino) -etyl]-benzoesyre-metylester ved katalytisk hydrogenering analogt med eksempel 84. Prepared from 4-[2-(3-hydroxy-piperidino)-5-nitro-benzoylamino)-ethyl]-benzoic acid methyl ester by catalytic hydrogenation analogously to example 84.

Utbytte: 90% av det teoretiske, Yield: 90% of the theoretical,

Smeltepunkt: 82°C. Melting point: 82°C.

Eksempel 91 Example 91

4-[ 2-( 2- piperidino- 5- propyloksy- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 2- piperidino- 5- propyloxy- benzoylamino)- ethyl]- benzoic acid ethyl ester

Til en oppløsning av 2 g (7,6 mmol) 2-piperidino-5-propy1-oksy-benzoesyre i 60 ml absolutt tetrahydrofuran settes 1,3 g (8 mmol) N,N'-karbonyl-diimidazol, og under utelukkelse av fuktighet oppvarmes derefter i ca. 10-14 timer til tilbakeløps-temperatur. Efter at imidazolidet er dannet nesten kvantitativt, tilsettes oppløsningen 1,5 g (8 mmol) 4-(2-amino-etyl)-benzoesyre-etylester og oppvarmes i ytterligere 4-6 timer til kokning. Efter avdestillering av tetrahydrofuranet på en rotasjonsinndamper renses den rå ester kromatografisk over en silikagelkolonne med toluen/etylacetat (9:1) som elueringsmiddel. Fraksjonene som inneholder den rensede ester, samles, og oppløsningsmidlet avdestilleres. To a solution of 2 g (7.6 mmol) of 2-piperidino-5-propyl-oxy-benzoic acid in 60 ml of absolute tetrahydrofuran is added 1.3 g (8 mmol) of N,N'-carbonyl-diimidazole, and to the exclusion of moisture is then heated for approx. 10-14 hours to reflux temperature. After the imidazolide has formed almost quantitatively, 1.5 g (8 mmol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester is added to the solution and heated for a further 4-6 hours to boiling. After distilling off the tetrahydrofuran on a rotary evaporator, the crude ester is purified chromatographically over a silica gel column with toluene/ethyl acetate (9:1) as eluent. The fractions containing the purified ester are collected, and the solvent is distilled off.

Utbytte: 2,4 g (72% av det teoretiske), Yield: 2.4 g (72% of the theoretical),

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

Beregnet: C 71,20, H 7,81, N 6,38 Calculated: C 71.20, H 7.81, N 6.38

Funnet: 71,30 8,02 6,54 Found: 71.30 8.02 6.54

Eksempel 92 Example 92

4-[ 2- ( 2- piperidino- 5- propyloksy- benzoylamino)- etyl]- benzoesyre-hydroklorid 4-[2-(2-piperidino-5-propyloxy-benzoylamino)-ethyl]-benzoic acid hydrochloride

1,8 g (4,1 mmol) 4-[2-(2-piperidino-5-propyloksy-benzoylamino)-etyl]-benzoesyre-etylester oppløses i en blanding av 15 ml metanol og 15 ml dioksan. Ved romtemperatur settes dråpevis 1 ml 30%ig natronlut, fortynnet med 30 ml vann, 1.8 g (4.1 mmol) of 4-[2-(2-piperidino-5-propyloxy-benzoylamino)-ethyl]-benzoic acid ethyl ester is dissolved in a mixture of 15 ml of methanol and 15 ml of dioxane. At room temperature, add drop by drop 1 ml of 30% caustic soda, diluted with 30 ml of water,

under omrøring så langsomt til esteroppløsningen at det ikke dannes noen varig utfelning av esteren. Tilsetningen er avsluttet efter ca. 2 timer. Efter noen timers videre omrøring avdestilleres de organiske oppløsningsmidler på en rotasjonsinndamper, den vandige fase utristes med kloroform, og den vandige fase innstilles på pH 4 med 2N saltsyre. Efter ekstraksjon med kloroform, tørring av kloroformfasen og avdestillering av kloroformen utfelles hydrokloridet fra en oppløsning i aceton med isopropanolisk saltsyre. while stirring so slowly into the ester solution that no permanent precipitation of the ester is formed. The addition is finished after approx. 2 hours. After a few hours of further stirring, the organic solvents are distilled off on a rotary evaporator, the aqueous phase is decanted with chloroform, and the aqueous phase is adjusted to pH 4 with 2N hydrochloric acid. After extraction with chloroform, drying of the chloroform phase and distillation of the chloroform, the hydrochloride is precipitated from a solution in acetone with isopropanolic hydrochloric acid.

Utbytte: 1,65 g (90% av det teoretiske), Yield: 1.65 g (90% of the theoretical),

Smeltepunkt: 236°C. Melting point: 236°C.

Beregnet: C 64,48, H 7,00, N 6,26, Cl 7,93 Calculated: C 64.48, H 7.00, N 6.26, Cl 7.93

Funnet: 64,24 7,06 6,17 8,13. Found: 64.24 7.06 6.17 8.13.

Eksempel 9 3 Example 9 3

4-[ 2-( 5- isopropyloksy- 2- piperidino- benzoylamino)- etyl]- benzoesyre- etylester 4-[ 2-( 5- isopropyloxy- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-isopropyloksy-2-piperidino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 58% av det teoretiske, Prepared from 5-isopropyloxy-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 58% of the theoretical,

Smeltepunkt: 70-72°C. Melting point: 70-72°C.

Beregnet: C 71,20, H 7,81, N 6,38 Calculated: C 71.20, H 7.81, N 6.38

Funnet: 71,10 7,74 6,40 Found: 71.10 7.74 6.40

Eksempel 9 4 Example 9 4

4-[ 2- ( 5- isopropyloksy- 2- piperidino- benzoylamino)- etyl]- benzoesyre- hydroklorid 4-[ 2-( 5- isopropyloxy- 2- piperidino- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-isopropyloksy-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-isopropyloxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 82% av det teoretiske, Yield: 82% of the theoretical,

Smeltepunkt: 225-226°C. Melting point: 225-226°C.

Beregnet: C 64,48, H 6,98, N 6,26, Cl 7,93 Calculated: C 64.48, H 6.98, N 6.26, Cl 7.93

Funnet: 64,77 7,30 6,40 7,79. Found: 64.77 7.30 6.40 7.79.

Eksempel 95 Example 95

4-[ 2- ( 5- heksyloksy- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[2-(5-hexyloxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-heksyloksy-2-piperidino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 92. Utbytte: 61% av det teoretiske, Prepared from 5-hexyloxy-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 92. Yield: 61% of the theoretical,

Smeltepunkt: 66°C. Melting point: 66°C.

Beregnet: C 72,47, H 8,38, N 5,82 Calculated: C 72.47, H 8.38, N 5.82

Funnet: 72,68 8,29 5,87. Found: 72.68 8.29 5.87.

Eksempel 96 Example 96

4-[ 2-( 5- heksyloksy- 2- piperidino- benzoylamino)- etyl]- benzoesyre-hydroklorid 4-[ 2-( 5- hexyloxy- 2- piperidino- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-heksyloksy-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-hexyloxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 87% av det teoretiske, Yield: 87% of the theoretical,

Smeltepunkt: 152-154°C. Melting point: 152-154°C.

Beregnet: C 66,30, H 7,62, N 5,72, Cl 7,24 Calculated: C 66.30, H 7.62, N 5.72, Cl 7.24

Funnet: 66,43 7,98 5,77 7,26 Found: 66.43 7.98 5.77 7.26

Eksempel 97 Example 97

4- [ 2- ( 5- benzyloksy-2-piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4- [ 2- ( 5- benzyloxy-2-piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-benzyloksy-2-piperidino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 55% av det teoretiske, Prepared from 5-benzyloxy-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 55% of the theoretical,

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

Beregnet: C 74,04, H 7,04, N 5,75 Calculated: C 74.04, H 7.04, N 5.75

Funnet: 73,90 7,14 6,03. Found: 73.90 7.14 6.03.

Eksempel 98 Example 98

4- [ 2- ( 5- benzyloksy-2-piper idino- benzoylamino)- etyl]- benzoesyre 4- [ 2- ( 5- benzyloxy-2-piper idino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4- [2- (5-benzyloksy-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-benzyloxy-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 86% av det teoretiske, Yield: 86% of the theoretical,

Smeltepunkt: 176°C. Melting point: 176°C.

Beregnet: C 73,34, H 6,59, N 6,10 Calculated: C 73.34, H 6.59, N 6.10

Funnet: 73,34 6,76 6,13. Found: 73.34 6.76 6.13.

Eksempel 99 Example 99

4-[ 2-( 5- klor- 2- piperi dino- benzoyla mino)- 2- metyl-e tyl]-b enzoe syre-me ty le s te r 4-[ 2-( 5- chloro- 2-piperidino- benzoylamino)- 2- methyl-ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-piperidino-benzoesyre og 4-(2-amino-propyl)-benzoesyre-metylester analogt med eksempel 91. Prepared from 5-chloro-2-piperidino-benzoic acid and 4-(2-amino-propyl)-benzoic acid methyl ester analogously to example 91.

Utbytte: 54% av det teoretiske. Yield: 54% of the theoretical.

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

Eksempel 100 Example 100

4-[ 2-( 5- klor- 2- pipe ridino- benzoylamino)- 2- metylety1]- benzoesyre 4-[ 2-( 5- chloro- 2-piperidino- benzoylamino)- 2- methylethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-piperidino-benzoylamino)-2-metyletyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-piperidino-benzoylamino)-2-methylethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 49% av det teoretiske, Yield: 49% of the theoretical,

Smeltepunkt: 142-145°C. Melting point: 142-145°C.

Beregnet: C 65,90, H 6,28, Cl 8,84, N 6,98 Calculated: C 65.90, H 6.28, Cl 8.84, N 6.98

Funnet: 65,85 6,45 3,83 6,99 Found: 65.85 6.45 3.83 6.99

Eksempel 101 Example 101

4- [2- (3-klor-2-pip_eridino- benzoy 1 amino) - ety 1 ] - benzoesyre-m etylester 4- [2- (3-Chloro-2-pipe_eridino- benzoy 1 amino) - ety 1 ] - benzoic acid methyl ester

Fremstilt fra 3-klor-2-piperidino-benzoesyre og 4-(2-amino-etyl) -benzoesyre-mety lester analogt med eksempel 91. Prepared from 3-chloro-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 91.

Utbytte: 63% av det teoretiske. Yield: 63% of the theoretical.

Smeltepunkt: 92-94°C. Melting point: 92-94°C.

Beregnet: C 65,91, H 6,28, Cl 8,85, N 6,99 Calculated: C 65.91, H 6.28, Cl 8.85, N 6.99

Funnet: 65,71 6,19 9,07 6,93 Found: 65.71 6.19 9.07 6.93

Eksempel 102 Example 102

4-[ 2-( 3- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 3- Chloro- 2- Piperidino- Benzoylamino)- Ethyl]- Benzoic Acid

Fremstilt fra 4-[2-(3-klor-2-piperidino-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(3-chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 57% av det teoretiske, Yield: 57% of the theoretical,

Smeltepunkt: 155-158°C. Melting point: 155-158°C.

Beregnet: C 65,19, H 5,99, Cl 9,17, N 7,24 Calculated: C 65.19, H 5.99, Cl 9.17, N 7.24

Funnet: 64,96 5,99 9,38 7,50 Found: 64.96 5.99 9.38 7.50

Eksempel 103 Example 103

4-[ 2-( 4- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 4- chloro- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 4-klor-2-piperidino-benzoeysre og 4-(2-amino-etyl) -benzoesyre-etylester analogt med eksempel 91. Prepared from 4-chloro-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

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

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

Beregnet: C 66,58, H 6,56, N 8,54, Cl 6,75 Calculated: C 66.58, H 6.56, N 8.54, Cl 6.75

Funnet: 66,58 6,57 8,42 6,99. Found: 66.58 6.57 8.42 6.99.

Eksemp el 104 Example el 104

4-[ 2-( 4- klor- 2- piperidino- benzoylamino)- ety1]- benzoesyre 4-[ 2-( 4- Chloro- 2- Piperidino- Benzoylamino)- Ethy1]- Benzoic Acid

Fremstilt fra 4-[2- (4-klor-2-piperidino-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 92. Prepared from 4-[2-(4-chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 92.

Utbytte: 66,7% av det teoretiske. Yield: 66.7% of the theoretical.

Smeltepunkt: 164-166°C. Melting point: 164-166°C.

Beregnet: C 65,20, H 5,99, N 9,16, Cl 7,24 Calculated: C 65.20, H 5.99, N 9.16, Cl 7.24

Funnet: 65,31 5,96 9,25 7,48. Found: 65.31 5.96 9.25 7.48.

Eksempel 105 Example 105

4-[ 2-( 5- brom- 2-( 2- metyl- piperidino)- benzoylamino)- ety1]-ben zoesyre- etylester 4-[ 2-( 5- bromo- 2-( 2- methyl-piperidino)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-brom-2-(2-metyl-piperidino)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 74% av det teoretiske, Prepared from 5-bromo-2-(2-methyl-piperidino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 74% of the theoretical,

Smeltepunkt: 98°C. Melting point: 98°C.

Beregnet: C 60,89, H 6,18, N 5,92 Calculated: C 60.89, H 6.18, N 5.92

Funnet: 60,99 6,43 5,78. Found: 60.99 6.43 5.78.

Eksempel 106 Example 106

4-[ 2-( 5- brom- 2-( 2- metyl- piperidino)- benz oylamino)- etyl]-benzoesyre 4-[ 2-( 5- bromo- 2-( 2- methyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-brom-2-(2-metyl-piperidino)-benzoylamino) -etyl ] -benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-bromo-2-(2-methyl-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 73% av det teoretiske, Yield: 73% of the theoretical,

Smeltepunkt: 18 3°C. Melting point: 18 3°C.

Beregnet: C 65,91, H 6,29, N 6,99 Calculated: C 65.91, H 6.29, N 6.99

Funnet: 65,70 6,35 6,80 Found: 65.70 6.35 6.80

Eksempel 107 Example 107

4- [ 2- ( 5- klor- 2- ( 3, 5- trans- dimetyl- piperidino)- benzoylamino)-etyl]- benzoesyre- mety lester 4- [ 2- ( 5- chloro- 2- ( 3, 5- trans- dimethyl-piperidino)- benzoylamino)-ethyl]- benzoic acid- methyl ester

Fremstilt fra 5-klor-2-(3,5-trans-dimetyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-chloro-2-(3,5-trans-dimethyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

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

Smeltepunkt: 105-107°C. Melting point: 105-107°C.

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

Funnet: 67,40 6,92 6,47 8,26 Found: 67.40 6.92 6.47 8.26

Ekse mpel 108 ' Example 108'

4-[ 2- ( 5- klor- 2-( 3, 5- tran s- dimetyl- piperidino)- benzoylamino)-etyl]- benzoesyre 4-[2-(5-chloro-2-(3,5-trans-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(3,5-trans-dimety1-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(3,5-trans-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 86% av det teoretiske, Yield: 86% of the theoretical,

Smeltepunkt: 164-167°C. Melting point: 164-167°C.

Beregnet: C 66,58, H 6,56, N 6,75, Cl 8,55 Calculated: C 66.58, H 6.56, N 6.75, Cl 8.55

Funnet: 66,80 6,71 6,65 8,63 Found: 66.80 6.71 6.65 8.63

Eksempel 109 Example 109

4-[ 2-( 5- brom- 2-( 3, 5- cis- dimety1- piperidino)- benzoylamino)-etyl]- benzoesyre- metylester 4-[ 2-( 5- bromo- 2-( 3, 5- cis- dimethyl- piperidino)- benzoylamino)-ethyl]- benzoic acid methyl ester

Fremstilt fra 5-brom-2-(3,5-cis-dimetyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 91. Prepared from 5-bromo-2-(3,5-cis-dimethyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 91.

Utbytte: 82% av det teoretiske. Yield: 82% of the theoretical.

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

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

Funnet: 60,81 6,08 5,85 16,72. Found: 60.81 6.08 5.85 16.72.

Eksempel 110 Example 110

4-[ 2-( 5- brom- 2-( 3, 5- cis- dimetyl- piperidino)- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 5- bromo- 2-( 3, 5- cis- dimethyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-brom-2-(3,5-cis-dimetyl-piperidino)-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-bromo-2-(3,5-cis-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogous to example 92.

Utbytte: 88% av det teoretiske, Yield: 88% of the theoretical,

Smeltepunkt: 184-185°C. Melting point: 184-185°C.

Beregnet: C 60,13, H 5,92, N 6,10, Cl 17,40 Calculated: C 60.13, H 5.92, N 6.10, Cl 17.40

Funnet: 59,98 5,87 6,02 17,30 Found: 59.98 5.87 6.02 17.30

Eksempel 111 Example 111

4-[ 2-( 5- metoksy- 2-( 3, 5- cis- dimetyl- piperidino)- benzoylamino)-e tyl]- benzoesyre- etylester 4-[ 2-( 5- methoxy- 2-( 3, 5- cis- dimethyl- piperidino)- benzoylamino)-ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-metoksy-2-(3,5-cis-dimetyl-piperidino)-benzoesyre og 2-(amino-ety1)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-methoxy-2-(3,5-cis-dimethyl-piperidino)-benzoic acid and 2-(amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

Utbytte: 14% av det teoretiske, Yield: 14% of the theoretical,

Smeltepunkt: 97-99°C. Melting point: 97-99°C.

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

Funnet: 71,29 7,78 6,16 Found: 71.29 7.78 6.16

Eksempel 112 Example 112

4-[ 2-( 5- metoksy- 2-( 3, 5- cis- dimetyl- piperidino)- benzoylamino)-ety1]- benzoesyre 4-[ 2-( 5- methoxy- 2-( 3, 5- cis- dimethyl- piperidino)- benzoylamino)-ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-metoksy-2-(3,5-cis-dimetyl-piperidino ) -benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-methoxy-2-(3,5-cis-dimethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 53% av det teoretiske, Yield: 53% of the theoretical,

Smeltepunkt: 200-203°C. Melting point: 200-203°C.

Beregnet: C 70,22, H 7,37, N 6,82 Calculated: C 70.22, H 7.37, N 6.82

Funnet: 70,22 7,38 6,82. Found: 70.22 7.38 6.82.

Eksempel 113 Example 113

4- [ 2- ( 5- klor- 2- ( 3, 3, 5, 5- tetrametyl- piperidino)- benzoylamino)-etyl]- benzoesyre- etylester 4- [ 2- ( 5- chloro- 2- ( 3, 3, 5, 5- tetramethyl-piperidino)- benzoylamino)-ethyl]- benzoic acid- ethyl ester

Fremstilt fra 5-klor-2-(3,3,5,5-tetrametyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

Utbytte: 34% av det teoretiske. Yield: 34% of the theoretical.

Smeltepunkt: 108°C. Melting point: 108°C.

Beregnet: C 68,85, H 7,49, N 5,94, Cl 7,52. Calculated: C 68.85, H 7.49, N 5.94, Cl 7.52.

Funnet: 68,75 7,37 5,79 7,69. Found: 68.75 7.37 5.79 7.69.

Eksempel 114 Example 114

4-[ 2-( 5- klor- 2- ( 3, 3, 5, 5- tetramety1- piperidino)- benzoylamino) - etyl]- benzoesyre 4-[ 2-( 5- Chloro- 2-( 3, 3, 5, 5- Tetramethyl- Piperidino)- Benzoylamino)- Ethyl]- Benzoic Acid

Fremstilt fra 4-[2-(5-klor-2-(3,3,5,5-tetrametyl-piperidino)-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 99% av det teoretiske. Yield: 99% of the theoretical.

Smeltepunkt: 170-172°C. Melting point: 170-172°C.

Beregnet: C 67,78, H 7,05, N 6,32, Cl 8,00 Calculated: C 67.78, H 7.05, N 6.32, Cl 8.00

Funnet: 67,60 7,09 6,13 7,95. Found: 67.60 7.09 6.13 7.95.

Eksempe 1 1 15 Example 1 1 15

4- [ 2- ( 5- klor- 2- ( pi peridon-( 2)- yl-( 1))- benzoylamino)- ety11 - benzoesyre- etylester 4- [ 2- ( 5- chloro- 2- ( pi peridon-( 2)- yl-( 1))- benzoylamino)- ethyl 11- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(piperidon-(2)-yl-(1))-benzoesyre Prepared from 5-chloro-2-(piperidon-(2)-yl-(1))-benzoic acid

og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 42% av det teoretiske. and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 42% of the theoretical.

Smeltepunkt: 118°C. Melting point: 118°C.

Beregnet: C 64,40, H 5,88, N 6,53 Calculated: C 64.40, H 5.88, N 6.53

Funnet: 64,32 5,87 6,58. Found: 64.32 5.87 6.58.

Eksempel 116 Example 116

4-[ 2-( 5- klor- 2-( piperidon-( 2)- yl( 1))- benzoylamino)- etyl]-benzoesyre- hydrat 4-[ 2-( 5- chloro- 2-( piperidon-( 2)-yl( 1))- benzoylamino)- ethyl]-benzoic acid hydrate

Fremstilt fra 4-[ 2- (5-klor-2-(piperidon-(2)-yl-(1))-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(piperidon-(2)-yl-(1))-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 64% av det teoretiske, Yield: 64% of the theoretical,

Smeltepunkt: 190-193°C. Melting point: 190-193°C.

Beregnet: C 60,48, H 5,56, N 6,72 Calculated: C 60.48, H 5.56, N 6.72

Funnet: 60,74 5,47 6,96. Found: 60.74 5.47 6.96.

Eksempel 117 Example 117

4-[ 2-( 5- brom- 2-( 4- metoksy- piperidino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- bromo- 2-( 4- methoxy-piperidino)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-brom-2-(4-metoksy-piperidino)-benzoesyre Prepared from 5-bromo-2-(4-methoxy-piperidino)-benzoic acid

og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 83% av det teoretiske. and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 83% of the theoretical.

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

Beregnet: C 58,90, H 5,97, N 5,72 Calculated: C 58.90, H 5.97, N 5.72

Funnet: 59,25 6,08 5,27 Found: 59.25 6.08 5.27

Eksempel 118 Example 118

4-[ 2-( 5- brom- 2-( 4- metoksy- piperidino)- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 5- bromo- 2-( 4- methoxy-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-brom-2-(4-metoksy-piperidino)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-bromo-2-(4-methoxy-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 65% av det teoretiske. Yield: 65% of the theoretical.

Smeltepunkt: 186°C. Melting point: 186°C.

Beregnet: C 57,28, H 5,46, N 6,07 Calculated: C 57.28, H 5.46, N 6.07

Funnet: 56,40 5,46 5,85. Found: 56.40 5.46 5.85.

Eksempel 119 Example 119

4-[ 2-( 5- klor- 2-( 2 , 6- dimetyl- morfolino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- chloro- 2-( 2 , 6- dimethyl- morpholino)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(2,6-dimetyl-morfolino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-chloro-2-(2,6-dimethyl-morpholino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

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

Smeltepunkt: 111-112°C. Melting point: 111-112°C.

Beregnet: C 64,78, H 6,57, N 6,30. Calculated: C 64.78, H 6.57, N 6.30.

Funnet: 64,72 6,64 6,24. Found: 64.72 6.64 6.24.

Eksempel 120 Example 120

4-[ 2-( 5- klor- 2-( 2, 6- dimetyl- morfolino)- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 5- chloro- 2-( 2, 6- dimethyl- morpholino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(2,6-dimetyl-morfolino)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(2,6-dimethyl-morpholino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 86% av det teoretiske. Yield: 86% of the theoretical.

Smeltepunkt: 232°C. Melting point: 232°C.

Beregnet: C 63,38, H 6,04, N 6,72 Calculated: C 63.38, H 6.04, N 6.72

Funnet: C 63,38 6,28 6,69. Found: C 63.38 6.28 6.69.

Eksempel 121 Example 121

4-[ 2-( 5- klor- 2-( 2, 6-d imety1- tiomorfolino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- Chloro- 2-( 2, 6-Dimethyl- thiomorpholino)- Benzoylamino)- Ethyl]- Benzoic Acid Ethyl Ester

Fremstilt fra 5-klor-2-(2,6-dimetyl-tiomorfolino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

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

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

Beregnet: C 62,53, H 6,34, N 6,08 Calculated: C 62.53, H 6.34, N 6.08

Funnet: 62,60 6,52 6,08. Found: 62.60 6.52 6.08.

Ek sempel 122 Oak sample 122

4-[ 2-( 5- klor- 2-( 2, 6- dimety1- tiomorfolino)- benzoylamino)- etyl]-benzoesyre 4-[2-(5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(2,6-dimetyl-tiomorfolino)-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 51% av det teoretiske, Yield: 51% of the theoretical,

Smeltepunkt: 183-185°C. Melting point: 183-185°C.

Beregnet: C 61,03, H 5,82, N 6,47 Calculated: C 61.03, H 5.82, N 6.47

Funnet: 60,62 6,01 6,30 Found: 60.62 6.01 6.30

Eksempel 12 3 Example 12 3

4-[ 2-( 5- klor- 2-( tiomorfolino- 1, 1- dioksyd)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- chloro- 2-( thiomorpholino- 1, 1- dioxide)- benzoylamino)- ethyl]-benzoic acid- ethyl ester

Fremstilt fra 5-klor-2-(tiomorfolino-1,1-dioksyd)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-chloro-2-(thiomorpholino-1,1-dioxide)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

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

Smeltepunkt: 158°C. Melting point: 158°C.

Beregnet: C 56,83, H 5,42, N 6,02. Calculated: C 56.83, H 5.42, N 6.02.

Funnet: 56,78 5,78 6,15. Found: 56.78 5.78 6.15.

Eksempel 124 Example 124

4-[ 2-( 2- heksametylenimino- 5- metoksy- benzoylamino)- etyl]- benzoesyre- etylester 4-[ 2-( 2- hexamethyleneimino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 2-heksametylenimino-5-metoksy-benzoesyre Prepared from 2-hexamethyleneimino-5-methoxy-benzoic acid

og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 91. and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 91.

Utbytte: 46% av det teoretiske, Yield: 46% of the theoretical,

Smeltepunkt: 92°C. Melting point: 92°C.

Beregnet: C 70,73, H 7,60, N 6,60 Calculated: C 70.73, H 7.60, N 6.60

Funnet: 70,46 7,53 6,72. Found: 70.46 7.53 6.72.

Eksempel 125 Example 125

4-[ 2-( 2- heksametylenimino- 5- metoksy- benzoylamino)- etyl]- benzoesyre- hydroklorid 4-[ 2-( 2- hexamethyleneimino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(2-heksametylenimino-5-metoksy-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(2-hexamethyleneimino-5-methoxy-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 92% av det teoretiske. Yield: 92% of the theoretical.

Smeltepunkt: 126°C. Melting point: 126°C.

Beregnet: C 63,30, H 6,75, N 6,46, Cl 8,18 Calculated: C 63.30, H 6.75, N 6.46, Cl 8.18

Funnet: 63,80 7,24 6,57 7,62. Found: 63.80 7.24 6.57 7.62.

Eksempel 126 Example 126

4-[ 2-( 2- heptametylenimino- 5- metoksy- benzoylamino)- etyl]- benzoesyre- etylester 4-[ 2-( 2- heptamethyleneimino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 2-heptametylenimino-5-metoksy-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 30% av det teoretiske, Prepared from 2-heptamethyleneimino-5-methoxy-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 30% of the theoretical,

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

Ek sempel 127 Oak sample 127

4-[ 2-( 2- heptametylenimino- 5- metoksy- benzoylamino)- etyl]- benzoesyre- hydroklorid 4-[ 2-( 2- heptamethyleneimino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(2-heptametylenimino-5-metoksy-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 92. Prepared from 4-[2-(2-heptamethyleneimino-5-methoxy-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 92.

Utbytte: 97% av det teoretiske, Yield: 97% of the theoretical,

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

Beregnet: C 59,68, H 6,88, N 5,80 Calculated: C 59.68, H 6.88, N 5.80

Funnet: 60,80 6,87 5,63. Found: 60.80 6.87 5.63.

E ksempel 12 8 Example 12 8

4-[ 2-( 2- heptametylenimino- 5- isopropyloksy- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 2- heptamethyleneimino- 5- isopropyloxy- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 2-heptametylenimino-5-isopropyloksy-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 92. Utbytte: 62% av det teoretiske, Prepared from 2-heptamethyleneimino-5-isopropyloxy-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 92. Yield: 62% of the theoretical,

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

Beregnet: C 72,07, H 8,20, N 6,00 Calculated: C 72.07, H 8.20, N 6.00

Funnet: 72,20 8,16 5,90 Found: 72.20 8.16 5.90

E ksempel 129 Example 129

4-[ 2-( 2- heptametylenimino- 5- isopropyloksy- benzoylamino)- etyl]-benzoesyre- hydroklorid 4-[ 2-( 2- heptamethyleneimino- 5- isopropyloxy- benzoylamino)- ethyl]-benzoic acid hydrochloride

Fremstilt fra 4-[2-(2-heptametylenimino-5-isopropyloksy-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(2-heptamethyleneimino-5-isopropyloxy-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 91% av det teoretiske, Yield: 91% of the theoretical,

Smeltepunkt: 202°C. Melting point: 202°C.

Beregnet: C 65,73, H 7,42, N 5,90, Cl 7,46. Calculated: C 65.73, H 7.42, N 5.90, Cl 7.46.

Funnet: 65,85 7,58 5,82 7,23. Found: 65.85 7.58 5.82 7.23.

Eksempel 130 Example 130

4- [2- ( 5- brom- 2- heptametylenimino- benzoylamino)- etyl]- benzoesyre- etylester 4- [2- ( 5- bromo- 2- heptamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-brom-2-heptametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 42,5% av det teoretiske, Prepared from 5-bromo-2-heptamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 42.5% of the theoretical,

Smeltepunkt: 81°C. Melting point: 81°C.

Beregnet: C 61,80, H 6,50, N 5,78, Br 16,40. Calculated: C 61.80, H 6.50, N 5.78, Br 16.40.

Funnet: 61,60 6,40 5,74 16,40. Found: 61.60 6.40 5.74 16.40.

Eksempel 131 Example 131

4-[ 2-( 5- brom- 2- heptametylenimino- benzoylamino)- etylj- benzoesyre 4-[ 2-( 5- bromo- 2- heptamethyleneimino- benzoylamino)- ethyl j- benzoic acid

Fremstilt fra 4-[2-(5-brom-2-heptametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-bromo-2-heptamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 94% av det teoretiske. Yield: 94% of the theoretical.

Smeltepunkt: 189°C. Melting point: 189°C.

Beregnet: C 60,13, H 5,92, N 6,10, Br 17,39 Calculated: C 60.13, H 5.92, N 6.10, Br 17.39

Funnet: 59,97 6,01 6,05 17,51 Found: 59.97 6.01 6.05 17.51

Eksempel 132 Example 132

4-[ 2- ( 2- ( 3- aza- bicyklo[ 3. 2. 2] nonan- 3- yl)- 5- klor- benzoylamino)-etyl]- benzoesyre- etylester 4-[ 2- ( 2- ( 3- aza-bicyclo[ 3. 2. 2] nonan- 3- yl)- 5- chloro- benzoylamino)-ethyl]- benzoic acid ethyl ester

Fremstilt fra 2-(3-aza-bicyklo[3,2,2]nonan-3-yl)-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

Utbytte: 82% av det teoretiske, Yield: 82% of the theoretical,

Smeltepunkt: 114°C. Melting point: 114°C.

Beregnet: C 68,63, H 6,87, N 6,16 Calculated: C 68.63, H 6.87, N 6.16

Funnet: 68,78 7,08 6,16. Found: 68.78 7.08 6.16.

E ksempel 133 Example 133

4-[ 2-( 2-( 3- aza- bicyklo[ 3, 2, 2] nonan- 3- yl)- 5- klor- benzoylamino)-etyl]- benzoesyre- hydroklorid 4-[ 2-( 2-( 3- aza-bicyclo[ 3, 2, 2] nonan- 3- yl)- 5- chloro- benzoylamino)-ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(2-(3-aza-bicyklo[3,2,2]nonan-3-yl)-5-klor-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-5-chloro-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogous to example 92 .

Utbytte: 98% av det teoretiske, Yield: 98% of the theoretical,

Smeltepunkt: 158°C. Melting point: 158°C.

Beregnet: C 62,20, H 6,03, N 6,05, Cl 15,30 Calculated: C 62.20, H 6.03, N 6.05, Cl 15.30

Funnet: 62,76 6 ,37 6,07 15,25 Found: 62.76 6 .37 6.07 15.25

Eksempel 134 Example 134

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 41% av det teoretiske, Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 41% of the theoretical,

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

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

Funnet: 68,15 7,10 6,09 Found: 68.15 7.10 6.09

Eksempel 135 Example 135

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4- [2- (5-klor-2-oktametylenimino-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 94% av det teoretiske, Yield: 94% of the theoretical,

Smeltepunkt: 172°C. Melting point: 172°C.

Beregnet: C 67,20, H 6,81, N 6,53. Calculated: C 67.20, H 6.81, N 6.53.

Funnet: 66,90 6,76 6,39. Found: 66.90 6.76 6.39.

Eksempel 136 Example 136

4-[ 2-( 5- klor- 2- nonametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- chloro- 2- nonamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-nonametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 24% av det teoretiske, Prepared from 5-chloro-2-nonamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 24% of the theoretical,

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

Beregnet: C 69,14, H 7,09, N 5,97, Cl 7,56 Calculated: C 69.14, H 7.09, N 5.97, Cl 7.56

Funnet: 69,38 7,28 6,13 7,88 Found: 69.38 7.28 6.13 7.88

Eksempel 137 Example 137

4-[2-(5- klor- 2- noname tylenimino-b enz oylamino)- etyl]- benzoesyre 4-[2-(5- chloro- 2- noname tylenimino-benz oylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-nonametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-nonamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 82% av det teoretiske. Yield: 82% of the theoretical.

Smeltepunkt: 173-174°C. Melting point: 173-174°C.

Beregnet: C 68,00, H 6,63, N 6,35, Cl 8,04 Calculated: C 68.00, H 6.63, N 6.35, Cl 8.04

Funnet: 67,62 6,78 6,23 7,60 Found: 67.62 6.78 6.23 7.60

Ek sempel 138 Oak sample 138

4-[ 2-( 5- klor- 2- dekame tylenimi no- benzoylami no)- etyl]- benzoesyre-e tylester 4-[ 2-( 5- chloro- 2- decamotylenimi no- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-dekametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 65% av det teoretiske, Prepared from 5-chloro-2-decamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 65% of the theoretical,

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

Beregnet: C 69,33, H 7,69, N 5,78 Calculated: C 69.33, H 7.69, N 5.78

Funnet: 69,29 7,64 5,92. Found: 69.29 7.64 5.92.

Eksempel 139 Example 139

4-[ 2-( 5- klor- 2- dekametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- Chloro- 2- decamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-dekametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-decamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 58% av det teoretiske, Yield: 58% of the theoretical,

Smeltepunkt: 177°C. Melting point: 177°C.

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

Funnet: 68,43 7,28 6,41. Found: 68.43 7.28 6.41.

E ksempel 140 Example 140

4-[ 2-( 5- klor- 2- undekametylenimino- benzoylamino)- etyl]- benzosyre-etylester 4-[ 2-( 5- chloro- 2- undecamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-undekametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 71% av det teoretiske, Prepared from 5-chloro-2-undecamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 71% of the theoretical,

Smeltepunkt: 80°C. Melting point: 80°C.

Beregnet: C 69,79, H 7,88, N 5,61 Calculated: C 69.79, H 7.88, N 5.61

Funnet: 69,35 7,66 5,84. Found: 69.35 7.66 5.84.

Ekse mpel 141 Example 141

5~ [ 2- ( 5- klor- 2- undekametylenimino- benzoylamino)- etyl]- benzoesyre 5~ [ 2- ( 5- chloro- 2- undecamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-undekametylenimino-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-undecamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 77% av det teoretiske, Yield: 77% of the theoretical,

Smeltepunkt: 218-220°C. Melting point: 218-220°C.

Beregnet: C 68,84, H 7,49, N 5,95 Calculated: C 68.84, H 7.49, N 5.95

Funnet: 68,34 7,21 6,19 Found: 68.34 7.21 6.19

Eksempel 142 Example 142

4-[ 2-( 5- klor- 2- dodekametylenimino- benzoylamino)- etyl]- benzoesyre- etylester 4-[ 2-( 5- chloro- 2- dodecamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-dodekametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 92. Utbytte: 53% av det teoretiske, Prepared from 5-chloro-2-dodecamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 92. Yield: 53% of the theoretical,

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

Beregnet: C 70,22, H 8,05, N 5,46 Calculated: C 70.22, H 8.05, N 5.46

Funnet: 70,56 7,77 5,71. Found: 70.56 7.77 5.71.

Eksempel 14 3 Example 14 3

4- [ 2- ( 5- klor- 2- dodekametylenimino- benzoylamino)- etyl]- benzoesyre 4- [ 2- ( 5- chloro- 2- dodecamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-dodekametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-dodecamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 92.

Utbytte: 33% av det teoretiske, Yield: 33% of the theoretical,

Smeltepunkt: 185-187°C. Melting point: 185-187°C.

Beregnet: C 69,33, H 7,69, N 5,78 Calculated: C 69.33, H 7.69, N 5.78

Funnet: 69,17 7,54 5,95. Found: 69.17 7.54 5.95.

Eksempel 144 Example 144

4-[ 2-( 5- klor- 2-( N- metyl- anilino)- benzoylamino)- etyl]- benzoesyre-etyleste r 4-[ 2-( 5- chloro- 2-( N- methyl- anilino)- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(N-metyl-anilino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 70% av det teoretiske. Prepared from 5-chloro-2-(N-methyl-anilino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 70% of the theoretical.

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

Ekse mpel 145 Example 145

4-[ 2-( 5- klor- 2-( N- metyl- anilino)- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2-( N- methyl- anilino)- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(N-metyl-anilino)-benzoylamino) -ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(N-methyl-anilino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 65% av det teoretiske. Yield: 65% of the theoretical.

Smeltepunkt: 186-188°C. Melting point: 186-188°C.

Beregnet: C 67,56, H 5,80, N 6,85 Calculated: C 67.56, H 5.80, N 6.85

Funnet: 67,81 5,66 6,87 Found: 67.81 5.66 6.87

Eksempel 146 Example 146

4- [ 2- ( 2- ( N- ety1- cykloheksylamino)- 5- klor- benzoylamino)- etyl]-benzoesyre- etylester 4- [ 2- ( 2- ( N- ethyl1- cyclohexylamino)- 5- chloro- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 2-(N-etyl-cykloheksylamino)-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 41% av det teoretiske, Prepared from 2-(N-ethyl-cyclohexylamino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 41% of the theoretical,

Smeltepunkt: 94°C. Melting point: 94°C.

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

Funnet: 68,00 7,10 6,03. Found: 68.00 7.10 6.03.

Eksempel 147 Example 147

4- [ 2- ( N- etyl- cykloheksylamino)- 5- klor- benzoylamino)- etyl]-benzoesyre 4- [ 2- ( N- ethyl- cyclohexylamino)- 5- chloro- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(2-(N-etyl-cykloheksylamino)-5-klor-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(2-(N-ethyl-cyclohexylamino)-5-chloro-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

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

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

Beregnet: C 67,20, H 6,81, N 6,53. Calculated: C 67.20, H 6.81, N 6.53.

Funnet: 67,25 6,67 6,45. Found: 67.25 6.67 6.45.

Eksempel 14 8 Example 14 8

4- [ 2- ( 2- ( N- butyl- cykloheksylamino)- 5- klor- benzoylamino)- etyl]-benzoesyre- etylester 4- [ 2- ( 2- ( N- butyl- cyclohexylamino)- 5- chloro- benzoylamino)- ethyl]-benzoic acid- ethyl ester

Fremstilt fra 2-(N-butyl-cykloheksylamino)-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 2-(N-butyl-cyclohexylamino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

Utbytte: 46% av det teoretiske, Yield: 46% of the theoretical,

Smeltepunkt: 7 7°C. Melting point: 7 7°C.

Beregnet: C 69,33, H 7,60, N 5,78 Calculated: C 69.33, H 7.60, N 5.78

Funnet: 69,12 7,69 5,78. Found: 69.12 7.69 5.78.

Eksempel 149 Example 149

4-[ 2-( 2-( N- butyl- cykloheksylamino)- 5- klor- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 2-( N- butyl- cyclohexylamino)- 5- chloro- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(2-(N-butyl-cykloheksylamino)-5-klor-benzoylamino) -etyl ] -benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(2-(N-butyl-cyclohexylamino)-5-chloro-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 79% av det teoretiske. Yield: 79% of the theoretical.

Smeltepunkt: 85°C. Melting point: 85°C.

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

Funnet: 68,44 7,18 6,40 Found: 68.44 7.18 6.40

Eksempel 150 Example 150

4-[ 2-( 5- klor- 2- ( N- isobuty1- cykloheksylamino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- chloro- 2-( N- isobuty1- cyclohexylamino)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(N-isobutyl-cykloheksylamino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Prepared from 5-chloro-2-(N-isobutyl-cyclohexylamino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91.

Utbytte: 46% av det teoretiske, Yield: 46% of the theoretical,

Smeltepunkt: 83°C. Melting point: 83°C.

Beregnet: C 69,33, H 7,69, N 5,78. Calculated: C 69.33, H 7.69, N 5.78.

Funnet: 69,17 7,54 5,66. Found: 69.17 7.54 5.66.

E ksempel 151 Example 151

4- [ 2-( 5- klor- 2-( N- isobutyl- cykloheksylamino)- benzoylamino)- etyl]-benzoesyre 4- [ 2-( 5- chloro- 2-( N- isobutyl- cyclohexylamino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2- (5-klor-2-(N-isobutyl-cykloheksylamino)-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-(N-isobutyl-cyclohexylamino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 92.

Utbytte: 62% av det teoretiske, Yield: 62% of the theoretical,

Smeltepunkt: 129°C. Melting point: 129°C.

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

Funnet: 68,30 7,18 6,17. Found: 68.30 7.18 6.17.

Eksempel 152 Example 152

4-[ 2-( 5- klor- 2- dimetylamino-benzoylamino)- 2- mety1- ety1]-benzoesyre- me tylester 4-[ 2-( 5- chloro- 2- dimethylamino-benzoylamino)- 2- methyl 1- ethyl 1]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-dimetylamino-benzoesyre og 4-(2-amino-propyl)-benzoesyre-metylester analogt med eksempel 91. Prepared from 5-chloro-2-dimethylamino-benzoic acid and 4-(2-amino-propyl)-benzoic acid methyl ester analogously to example 91.

Utbytte: 34% av det teoretiske, Yield: 34% of the theoretical,

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

Eksempel 153 Example 153

4-[ 2-( 5- klor- 2- di metyl amino- benzoylamino)- 2- metyl- etyl]-benzoesyre 4-[ 2-( 5- chloro- 2- dimethyl amino- benzoylamino)- 2- methyl- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-dimetylamino-benzoylamino)-2-metyletyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(5-chloro-2-dimethylamino-benzoylamino)-2-methylethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 49% av det teoretiske, Yield: 49% of the theoretical,

Smeltepunkt: 142-145°C. Melting point: 142-145°C.

Beregnet: C 63,22, H 5,86, N 7,76 Calculated: C 63.22, H 5.86, N 7.76

Funnet: 62,90 5,98 7,54. Found: 62.90 5.98 7.54.

E ksempel 154 Example 154

4- [ 2- ( 3- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre-m etylester 4- [ 2- ( 3- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 3-klor-2-dimetylamino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 91. Utbytte: 76% av det teoretiske, Prepared from 3-chloro-2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 91. Yield: 76% of the theoretical,

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

Eksempel 155 Example 155

4-[ 2 -( 3- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[ 2 -( 3- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(3-klor-2-dimetylamino-benzoylamino)-ety1]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(3-chloro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 76% av det teoretiske, Yield: 76% of the theoretical,

Smeltepunkt: 175-178°C. Melting point: 175-178°C.

Beregnet: C 62,33, H 5,52, N 8,08, Cl 10,22 Calculated: C 62.33, H 5.52, N 8.08, Cl 10.22

Funnet: 62,60 5,56 8,26 10,27. Found: 62.60 5.56 8.26 10.27.

Eksempel 156 Example 156

4- [ 2- ( 2- dimetylamino- 5- metoksy- benzoylamino)- etyl]- benzoesyre-m etylester 4- [ 2- ( 2- dimethylamino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 2-dimetylamino-5-metoksy-benzoesyre og 4-(2-aminoetyl)-benzoesyre-metylester analogt med eksempel 91. Utbytte: 81% av det teoretiske, Prepared from 2-dimethylamino-5-methoxy-benzoic acid and 4-(2-aminoethyl)-benzoic acid methyl ester analogously to example 91. Yield: 81% of the theoretical,

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

Eksempel 157 Example 157

4-[ 2-( 2-dim etylamino- 5- metok sy- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 2-dimethylamino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(2-dimetylamino-5-metoksy-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(2-dimethylamino-5-methoxy-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

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

Smeltepunkt: 147-150°C. Melting point: 147-150°C.

Beregnet: C 66,65, H 6,48, N 8,18 Calculated: C 66.65, H 6.48, N 8.18

Funnet: 66,85 6,35 8,12. Found: 66.85 6.35 8.12.

E ksempel 15 8 E xample 15 8

4-[ 2-( 4- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 4- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid ethyl ester

3,55 g (10 mmol) 4-[2-(4-amino-2-dimetylamino-benzoylamino)-etyl]-benzoesyre-etylester (smeltepunkt: 135-136°C, fremstilt ved hydrogenering av 4-[2-(2-dimetylamino-4-nitrobenzoylamino)-ety1]-benzoesyre-etylester med palladium/kull) i 4 ml konsentrert saltsyre og ca. 5 g is diazoteres ved dråpevis tilsetning av en oppløsning av 820 mg (11,6 mmol) natriumnitritt i 5 ml vann. Efter 30 minutter settes diazoniumsaltoppløsningen ved romtemperatur dråpevis til en suspensjon av 1,2 g kobberbronse i 1 ml konsentrert saltsyre. Efter henstand natten over fortynnes blandingen med vann og ekstraheres med kloroform. De inndampede kloroformekstrakter renses kolonnekromatografisk på silikagel (elueringsmiddel: toluen/etylacetat = 1:1, 3.55 g (10 mmol) 4-[2-(4-amino-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid ethyl ester (melting point: 135-136°C, prepared by hydrogenation of 4-[2-( 2-dimethylamino-4-nitrobenzoylamino)-ethyl]-benzoic acid ethyl ester with palladium/charcoal) in 4 ml of concentrated hydrochloric acid and approx. 5 g of ice are diazotized by the dropwise addition of a solution of 820 mg (11.6 mmol) of sodium nitrite in 5 ml of water. After 30 minutes, the diazonium salt solution is added dropwise at room temperature to a suspension of 1.2 g of copper bronze in 1 ml of concentrated hydrochloric acid. After standing overnight, the mixture is diluted with water and extracted with chloroform. The evaporated chloroform extracts are purified by column chromatography on silica gel (eluent: toluene/ethyl acetate = 1:1,

Rf 0,75). Rf 0.75).

Utbytte: 27% av det teoretiske. Yield: 27% of the theoretical.

Smeltepunkt: 97-99°C. Melting point: 97-99°C.

Beregnet: C 64,08, H 6,18, N 9,46, Cl 7,47 Calculated: C 64.08, H 6.18, N 9.46, Cl 7.47

Funnet: 64,37 6,42 9,32 7,44. Found: 64.37 6.42 9.32 7.44.

Ekse mpel 159 Example 159

4- [ 2- ( 4- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4- [ 2- ( 4- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid

Fremstilt ved alkalisk forsepning av 4-[2-(4-klor-2-dimetylamino-benzoylamino)-etyl]-benzoesyre-etylester analogt med eksempel 92. Prepared by alkaline saponification of 4-[2-(4-chloro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid ethyl ester analogously to example 92.

Utbytte: 95% av det teoretiske, Yield: 95% of the theoretical,

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

Beregnet: C 62,34, H 5,52, N 10,22, Cl 8,08 Calculated: C 62.34, H 5.52, N 10.22, Cl 8.08

Funnet: 61,92 5,55 10,60 8,15. Found: 61.92 5.55 10.60 8.15.

Eksempe l 160 Example l 160

4-[ 2- ( 2- dimetylamino- 4- nitro- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 2- dimethylamino- 4- nitro- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt analogt med eksempel 91 fra 2-dimetylamino-4-nitrobenzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester. Utbytte: 95% av det teoretiske, Prepared analogously to example 91 from 2-dimethylamino-4-nitrobenzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 95% of the theoretical,

Smeltepunkt: 145°C. Melting point: 145°C.

Beregnet: C 62,33, H 6,01, N 10,90 Calculated: C 62.33, H 6.01, N 10.90

Funnet: 62,73 6,00 11,09 Found: 62.73 6.00 11.09

Eksempel 161 Example 161

4-[ 2-( 6- klor- 2- dimetylamino- benzoylamino)- ety1]- benzoesyre-mety lester 4-[ 2-( 6- chloro- 2- dimethylamino- benzoylamino)- ethyl 1]- benzoic acid methyl ester

Fremstilt fra 6-klor-2-dimetylamino-benzoesyre og 4- (2-amino-etyl)-benzoesyre-metylester analogt med eksempel 91. Utbytte: 25% av det teoretiske, Prepared from 6-chloro-2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 91. Yield: 25% of the theoretical,

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

Beregnet: C 63,24, H 5,87, N 7,76, Cl 9,83 Calculated: C 63.24, H 5.87, N 7.76, Cl 9.83

Funnet: 63,33 5,73 7,90 9,92. Found: 63.33 5.73 7.90 9.92.

Eksempel 162 Example 162

4-[ 2-( 6- klor- 2- dimetylamino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 6- chloro- 2- dimethylamino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(6-klor-2-dimetylamino-benzoylamino)-ety1]-benzoesyre-metylester ved alkalisk hydrolyse analogt med eksempel 92. Prepared from 4-[2-(6-chloro-2-dimethylamino-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline hydrolysis analogously to example 92.

Utbytte: 35% av det teoretiske. Yield: 35% of the theoretical.

Smeltepunkt: 155-158°C. Melting point: 155-158°C.

Beregnet: C 62,34, H 5,52, N 8,08, Cl 10,22. Calculated: C 62.34, H 5.52, N 8.08, Cl 10.22.

Funnet: 62,98 - 5,73 7,92 10,11. Found: 62.98 - 5.73 7.92 10.11.

Eksempel 16 3 Example 16 3

4-[ 2-[ 2-( 4- benzyl- piperazino)- 5- klor- benzoylamino]- etyl]-benzoesyre- etylester 4-[ 2-[ 2-( 4- benzyl- piperazino)- 5- chloro- benzoylamino]- ethyl]-benzoic acid ethyl ester

Fremstilt fra 2-(4-benzyl-piperazino)-5-klor-benzoesyre Prepared from 2-(4-benzyl-piperazino)-5-chloro-benzoic acid

og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 91. Utbytte: 39% av det teoretiske, and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 91. Yield: 39% of the theoretical,

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

Beregnet: C 68,83, H 6,37, N 7,00, Cl 8,30 Calculated: C 68.83, H 6.37, N 7.00, Cl 8.30

Funnet: 68,97 6,52 6,93 8,21. Found: 68.97 6.52 6.93 8.21.

Eksempel 164 Example 164

4-[ 2-[ 2- piperazino- benzoylamino]- etyl]- benzoesyre- etylester 4-[ 2-[ 2- piperazino- benzoylamino]- ethyl]- benzoic acid ethyl ester

Fremstilt fra 4-[2-[2-(4-benzyl-piperazino)-5-klor-benzoylamino] -etyl]-benzoesyre-etylester ved katalytisk hydrogenering med palladium/kull ved romtemperatur og et hydrogentrykk på 1 bar. Prepared from 4-[2-[2-(4-benzyl-piperazino)-5-chloro-benzoylamino]-ethyl]-benzoic acid ethyl ester by catalytic hydrogenation with palladium/charcoal at room temperature and a hydrogen pressure of 1 bar.

Utbytte: 60% av det teoretiske. Yield: 60% of the theoretical.

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

Beregnet: C 69,27, H 7,13, N 11,01 Calculated: C 69.27, H 7.13, N 11.01

Funnet: 69,22 7,11 10,90. Found: 69.22 7.11 10.90.

Eksempel 165 Example 165

4- [ 2-( 5- klor- 2-( dekahydro- isokinolin- 2- yl)- benzoylamino)- etyl]-benzoesyre- etylester 4- [ 2-( 5- chloro- 2-( decahydro- isoquinolin- 2- yl)- benzoylamino)- ethyl]-benzoic acid- ethyl ester

I 30 ml absolutt tetrahydrofuran oppvarmes 2,5 g (8,5 mmol) 5- klor-2-(dekahydro-isokinolin-2-yl)-benzoesyre sammen med 1,4 g (8,6 mmol) karbonyldiimidazol i 8 timer til kokning. Til det dannede imidazolid settes 1,64 g (8,6 mmol) 4-(2-aminoetyl)-benzoesyre-etylester, og reaksjonsblandingen oppvarmes til tilbakeløpstemperatur i ytterligere 12 timer. Efter avdestillering av oppløsningsmidlet renses esteren kromatografisk over en silikagelkolonne med toluen/etylacetat (9:1) som elueringsmiddel. In 30 ml of absolute tetrahydrofuran, 2.5 g (8.5 mmol) of 5-chloro-2-(decahydro-isoquinolin-2-yl)-benzoic acid are heated together with 1.4 g (8.6 mmol) of carbonyldiimidazole for 8 hours to boiling. To the formed imidazolide is added 1.64 g (8.6 mmol) of 4-(2-aminoethyl)-benzoic acid ethyl ester, and the reaction mixture is heated to reflux temperature for a further 12 hours. After distilling off the solvent, the ester is purified chromatographically over a silica gel column with toluene/ethyl acetate (9:1) as eluent.

Utbytte: 2,7 g (68% av det teoretiske), Yield: 2.7 g (68% of theoretical),

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

Beregnet: C 69,14, H 7,09, N 5,97, Cl 7,55 Calculated: C 69.14, H 7.09, N 5.97, Cl 7.55

Funnet: 69,43 6,98 6,10 7,76. Found: 69.43 6.98 6.10 7.76.

Eksempel 166 Example 166

4-[ 2- ( 5- klor- 2- ( dekahydro- isokinolin- 2- yl)- benzoylamino)- etyl]-ben zoesyre- hydroklorid 4-[2-(5-chloro-2-(decahydro-isoquinolin-2-yl)-benzoylamino)-ethyl]-benzoic acid hydrochloride

1,9 g (4,1 mmol) 4-[2-(5-klor-2-(dekahydro-isokinolin-2-yl)-benzoylamino)-ety1]-benzoesyre-etylester oppløses i 40 ml av en blanding av dioksan og metanol (1:1). Efter tilsetning av 5 ml 30%ig natronlut, fortynnet med 20 ml vann, foretas hydrolyse 1.9 g (4.1 mmol) of 4-[2-(5-chloro-2-(decahydro-isoquinolin-2-yl)-benzoylamino)-ethyl]-benzoic acid ethyl ester is dissolved in 40 ml of a mixture of dioxane and methanol (1:1). After adding 5 ml of 30% caustic soda, diluted with 20 ml of water, hydrolysis is carried out

ved romtemperatur. Efter noen timer avdestilleres det organiske oppløsningsmiddel. Efter ekstraksjon med kloroform innstilles den vandige fase på pH 4-5 med 2N saltsyre, og syren, som utfelles ved denne pH-verdi, ekstraheres med kloroform. Efter tørring og avdestillering av kloroformen utfelles hydrokloridet i aceton med isopropanolisk saltsyre. at room temperature. After a few hours, the organic solvent is distilled off. After extraction with chloroform, the aqueous phase is adjusted to pH 4-5 with 2N hydrochloric acid, and the acid, which precipitates at this pH value, is extracted with chloroform. After drying and distilling off the chloroform, the hydrochloride is precipitated in acetone with isopropanolic hydrochloric acid.

Utbytte: 1,5 g (77% av det teoretiske), Yield: 1.5 g (77% of the theoretical),

Smeltepunkt: 226°C. Melting point: 226°C.

Beregnet: C 62,88, H 6,33, N 5,86, Cl 14,85 Calculated: C 62.88, H 6.33, N 5.86, Cl 14.85

Funnet: 62,60 6,36 5,93 14,76. Found: 62.60 6.36 5.93 14.76.

Eksempel 16 7 Example 16 7

4- [ 2- ( 5- klor- 2- ( dekahydro- 3- benzazepin- 3- yl)- benzoylamino)-etyl]- benzoesyre- etylester 4- [ 2- ( 5- chloro- 2- ( decahydro- 3- benzazepin- 3- yl)- benzoylamino)-ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 16 5. Prepared from 5-chloro-2-(decahydro-3-benzazepin-3-yl)-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 16 5.

Utbytte: 97% av det teoretiske, Yield: 97% of the theoretical,

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

Beregnet: C 69,62, H 7,30, N 5,80, Cl 7,33 Calculated: C 69.62, H 7.30, N 5.80, Cl 7.33

Funnet: 69,88 7,22 5,63 7,46. Found: 69.88 7.22 5.63 7.46.

Eksempel 16 8 Example 16 8

4-[ 2-( 5- klor- 2-( dekahydro- 3- benzazepin- 3- yl)- benzoylamino)-etyl1- benzoesyre- hydroklorid 4-[ 2-( 5- chloro- 2-( decahydro- 3- benzazepin- 3- yl)- benzoylamino)-ethyl 1- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-klor-2-(dekahydro-3-benzazepin-3-yl)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(decahydro-3-benzazepin-3-yl)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166.

Utbytte: 84% av det teoretiske. Yield: 84% of the theoretical.

Smeltepunkt: 216°C. Melting point: 216°C.

Beregnet: C 63,53, H 6,56, N 5,69, Cl 14,42 Calculated: C 63.53, H 6.56, N 5.69, Cl 14.42

Funnet: 63,51 6,59 5,76 14,35. Found: 63.51 6.59 5.76 14.35.

Eksempel 169 Example 169

4-[ 2- ( 5- brom- 2-( dekahydro- 3- benzazepin- 3- yl)- benzoylamino)- etyl]-benzoesyr e- etylester 4-[2-(5-bromo-2-(decahydro-3-benzazepin-3-yl)-benzoylamino)-ethyl]-benzoic acid e-ethyl ester

Fremstilt fra 5-brom-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-bromo-2-(decahydro-3-benzazepin-3-yl)-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to Example 165.

Utbytte: 98% av det teoretiske, Yield: 98% of the theoretical,

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

Beregnet: C 63,75, H 6,68, N 5,31, Br 15,14 Calculated: C 63.75, H 6.68, N 5.31, Br 15.14

Funnet: 64,06 6,56 5,16 15,00. Found: 64.06 6.56 5.16 15.00.

E ksempel 170 Example 170

4-[ 2-( 5- brom- 2- ( dekahydro- 3- benzazepin- 3- yl)- benzoylamino)-etyl]- benzoesyre- hydroklorid 4-[ 2-( 5- bromo- 2-( decahydro- 3- benzazepin- 3- yl)- benzoylamino)-ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-brom-2-(dekahydro-3-benzazepin-3-yl)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-bromo-2-(decahydro-3-benzazepin-3-yl)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166.

Utbytte: 84% av det teoretiske, Yield: 84% of the theoretical,

Smeltepunkt: 216°C. Melting point: 216°C.

Beregnet: C 58,26, H 6,01, N 5,22, Cl 6,61, Br 14,91 Funnet: 58,22 5,85 5,34 6,65 15,00. Calculated: C 58.26, H 6.01, N 5.22, Cl 6.61, Br 14.91 Found: 58.22 5.85 5.34 6.65 15.00.

Eksempel 171 Example 171

4-[ 2-( 5- klor- 2-( oktahydro- isoindol- 2- yl)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- chloro- 2-( octahydro- isoindol- 2- yl)- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(oktahydro-isoindol-2-yl)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(octahydro-isoindol-2-yl)-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 72% av det teoretiske, Yield: 72% of the theoretical,

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

Beregnet: C 68,63, H 6,86, N 6,15, Cl 7,79 Calculated: C 68.63, H 6.86, N 6.15, Cl 7.79

Funnet: 68,72 6,92 6,20 7,94. Found: 68.72 6.92 6.20 7.94.

Eksempel 172 Example 172

4-[ 2-( 5- klor- 2-( oktahydro- isoindol- 2- yl)- benzoylamino)- etyl]-b en zoesyre- hydroklorid 4-[ 2-( 5- chloro- 2-( octahydro- isoindol- 2- yl)- benzoylamino)- ethyl]-b en zoic acid hydrochloride

Fremstilt fra 4- [2- (5-klor-2-(oktahydro-isoindol-2-yl)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(octahydro-isoindol-2-yl)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 83% av det teoretiske, Yield: 83% of the theoretical,

Smeltepunkt: 214°C. Melting point: 214°C.

Beregnet: C 62,20, H 6,09, N 6,04, Cl 15,32 Calculated: C 62.20, H 6.09, N 6.04, Cl 15.32

Funnet: 62,45 6,23 6,13 15,70 Found: 62.45 6.23 6.13 15.70

Eksempel 173 Example 173

4-[ 2-( 5- brom- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- bromo- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-brom-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 84% av det teoretiske. Prepared from 5-bromo-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 84% of the theoretical.

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

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

Funnet: 62,40 6,66 5,53 15,96. Found: 62.40 6.66 5.53 15.96.

Eksempel 174 Example 174

4-[ 2-( 5- brom- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-hydroklorid 4-[ 2-( 5- bromo- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-brom-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-bromo-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 90% av det teoretiske, Yield: 90% of the theoretical,

Smeltepunkt: 16 4°C. Melting point: 16 4°C.

Beregnet: C 56,53, H 5,92, N 5,49, Br 15,67, Cl 6,95 Funnet: 56,82 5,96 5,47 14,85 6,59. Calculated: C 56.53, H 5.92, N 5.49, Br 15.67, Cl 6.95 Found: 56.82 5.96 5.47 14.85 6.59.

Eksempel 175 Example 175

4-[ 2-( 5- cyano- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- cyano- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-cyano-2-oktametylenimino-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 30% av det teoretiske, Prepared from 5-cyano-2-octamethyleneimino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 30% of the theoretical,

Smeltepunkt: 94°C. Melting point: 94°C.

Beregnet: C 72,45, H 7,43, N 9,38 Calculated: C 72.45, H 7.43, N 9.38

Funnet: 72,50 7,50 9,41. Found: 72.50 7.50 9.41.

Eksempel 176 Example 176

4-[ 2- ( 5- cyano- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- cyano- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-cyano-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-cyano-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 87% av det teoretiske. Yield: 87% of the theoretical.

Smeltepunkt: 186°C. Melting point: 186°C.

Beregnet: C 71,57, H 6,96, N 10,01 Calculated: C 71.57, H 6.96, N 10.01

Funnet: 71,50 7,14 9,66. Found: 71.50 7.14 9.66.

E ksempel 177 Example 177

4-[ 2-( 2- oktametylenimino- 5- nitro- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 2- octamethyleneimino- 5- nitro- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 2-oktametylenimino-5-nitro-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 50% av det teoretiske, Prepared from 2-octamethyleneimino-5-nitro-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 50% of the theoretical,

Smeltepunkt: 116°C. Melting point: 116°C.

Beregnet: C 66,79, H 7,11, N 8,98 Calculated: C 66.79, H 7.11, N 8.98

Funnet: 67,00 7,17 9,04. Found: 67.00 7.17 9.04.

Eksempel 178 Example 178

4-[ 2-( 2- oktametylenimino- 5- nitro- benzoylamino)- etyl]- benzoesyre-hydroklorid 4-[ 2-( 2- octamethyleneimino- 5- nitro- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(2-oktametylenimino-5-nitro-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(2-octamethyleneimino-5-nitro-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 93% av det teoretiske. Yield: 93% of the theoretical.

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

Beregnet: C 62,06, H 6,74, N 9,24, Cl 4,53 Calculated: C 62.06, H 6.74, N 9.24, Cl 4.53

Funnet: 62,46 6,46 9,10 4,76 Found: 62.46 6.46 9.10 4.76

Eksempel 179 Example 179

4-[ 2-( 5- amino- 2- okta metylenimino- benzoylamino)- etyl]- benzoesyre-ety les ter- dihyd rok lor id 4-[ 2-( 5- amino- 2- octa methyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl les ter- dihydro chloride

Fremstilt fra 4-[2-(2-oktametylenimino-5-nitro-benzoylamino)-etyl]-benzoesyre-etylester ved katalytisk hydrogenering i metanolisk oppløsning ved et hydrogentrykk på 5 bar ved romtemperatur med 10%ig palladium-kull som katalysator. Prepared from 4-[2-(2-octamethyleneimino-5-nitro-benzoylamino)-ethyl]-benzoic acid ethyl ester by catalytic hydrogenation in methanolic solution at a hydrogen pressure of 5 bar at room temperature with 10% palladium charcoal as catalyst.

Utbytte: 79% av det teoretiske, Yield: 79% of the theoretical,

Smeltepunkt: 162°C. Melting point: 162°C.

Beregnet: C 61,16, H 7,30, N 8,22, Cl 13,90 Calculated: C 61.16, H 7.30, N 8.22, Cl 13.90

Funnet: 61,50 7,84 8,54 13,50. Found: 61.50 7.84 8.54 13.50.

Eksempel 180 Example 180

4- [ 2- ( 5- amino- 2- oktametylenimino- benzoylamino)- etyl3- benzoesyre-hydroklorid 4- [ 2- ( 5- amino- 2- octamethyleneimino- benzoylamino)- ethyl 3- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-amino-2-oktametylenimino-benzoylamino)-ety1]-benzoesyre-etylester-hydroklorid ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-amino-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester hydrochloride by alkaline hydrolysis analogously to example 166.

Utbytte: 50% av det teoretiske. Yield: 50% of the theoretical.

Smeltepunkt: 130°C. Melting point: 130°C.

Beregnet: C 64,62, H 7,23, N 9,42, Cl 7,94 Calculated: C 64.62, H 7.23, N 9.42, Cl 7.94

Funnet: 63,90 7,10 9,20 7,74. Found: 63.90 7.10 9.20 7.74.

Eksempel 181 Example 181

4-[ 2-( 2- oktametylenimino- 5- metoksy- benzoylamino)- etyl]- benzoesyre- etylester 4-[ 2-( 2- octamethyleneimino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 2-oktametylenimino-5-metoksy-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 80% av det teoretiske, Prepared from 2-octamethyleneimino-5-methoxy-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 80% of the theoretical,

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

Beregnet: C 71,65, H 8,01, N 6,18 Calculated: C 71.65, H 8.01, N 6.18

Funnet: 71,65 8,15 6,25. Found: 71.65 8.15 6.25.

Eksempel 182 Example 182

4-[ 2- ( 2- oktametylenimino- 5- metoksy- benzoylamino)- etyl]- benzoe-sy re- hydroklorid 4-[ 2-( 2- octamethyleneimino- 5- methoxy- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(2-oktametylenimino-5-metoksy-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(2-octamethyleneimino-5-methoxy-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 83% av det teoretiske, Yield: 83% of the theoretical,

Smeltepunkt: 216°C. Melting point: 216°C.

Beregnet: C 65,13, H 7,21, N 6,07, Cl 7,68 Calculated: C 65.13, H 7.21, N 6.07, Cl 7.68

Funnet: 64,53 7,39 5,96 7,70 Found: 64.53 7.39 5.96 7.70

Eksempel 183 Example 183

4-[ 2-( 5- etoksy- 2- oktametylenimino- benzoylamino)- etyl]- benzosyre-etylester 4-[ 2-( 5- ethoxy- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-etoksy-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 66% av det teoretiske, Prepared from 5-ethoxy-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 66% of the theoretical,

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

Beregnet: C 72,07, H 8,20, N 6,00 Calculated: C 72.07, H 8.20, N 6.00

Funnet: 72,25 8,21 6,06. Found: 72.25 8.21 6.06.

Eksempel 184 Example 184

4-[ 2-( 5- etoksy- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-hydroklorid 4-[ 2-( 5- ethoxy- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-etoksy-2-oktametylenimino-benzoy1-amino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-ethoxy-2-octamethyleneimino-benzoy1-amino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 98% av det teoretiske, Yield: 98% of the theoretical,

Smeltepunkt: 172°C. Melting point: 172°C.

Beregnet: C 65,73, H 7,42, N 5,89, Cl 7,46 Calculated: C 65.73, H 7.42, N 5.89, Cl 7.46

Funnet: 65,50 7,20 5,79 7,19. Found: 65.50 7.20 5.79 7.19.

Eksempel 185 Example 185

4-[ 2-( 5- isopropyloksy- 2- oktametylenimino- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- isopropyloxy- 2- octamethyleneimino- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-isopropyloksy-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-isopropyloxy-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 87% av det teoretiske. Yield: 87% of the theoretical.

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

Beregnet: C 72,47, H 8,38, N 5,82 Calculated: C 72.47, H 8.38, N 5.82

Funnet: 73,04 8,44 5,76. Found: 73.04 8.44 5.76.

Eksempel 186 Example 186

4-[ 2-( 5- isopropyloksy- 2- oktametylenimino- benzoylamino)- etyl]-benzoesyre- hydrokl orid 4-[ 2-( 5- isopropyloxy- 2- octamethyleneimino- benzoylamino)- ethyl]-benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-isopropyloksy-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-isopropyloxy-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 93% av det teoretiske, Yield: 93% of the theoretical,

Smeltepunkt: 152°C. Melting point: 152°C.

Beregnet: C 66,30, H 7,62, N 5,72, Cl 7,24 Calculated: C 66.30, H 7.62, N 5.72, Cl 7.24

Funnet: 66,40 7,50 5,54 7,11. Found: 66.40 7.50 5.54 7.11.

Eksempel 187 Example 187

4-[ 2-( 5- butyl-( 2)- oksy- 2- oktametylenimino- benz oylamino)- etyl]-b enzoesyre- etylester 4-[ 2-( 5- butyl-( 2)- oxy- 2- octamethyleneimino- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-butyl-(2)-oksy-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-butyl-(2)-oxy-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 64% av det teoretiske, Yield: 64% of the theoretical,

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

Beregnet: C 72,84, H 8,56, N 5,66 Calculated: C 72.84, H 8.56, N 5.66

Funnet: 72,58 8,48 5,27 Found: 72.58 8.48 5.27

Eksempel 188 Example 188

4-[ 2-( 5- butyl-( 2)- oksy- 2- oktametylenimino- benzoylamino)- ety1]-benzoesyre- hydroklorid 4-[ 2-( 5- butyl-( 2)- oxy- 2- octamethyleneimino- benzoylamino)- eth1]-benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-butyl-(2)-oksy-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-butyl-(2)-oxy-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 88% av det teoretiske, Yield: 88% of the theoretical,

Smeltepunkt: 142°C. Melting point: 142°C.

Beregnet: C 66,84, H 7,81, N 5,56, Cl 7,04. Calculated: C 66.84, H 7.81, N 5.56, Cl 7.04.

Funnet: 66,40 7,84 5,20 6,71. Found: 66.40 7.84 5.20 6.71.

E ksempel 189 Example 189

4- [ 2- ( 5- klor- 2-( 4- isopropyl- piperidino)- benzoylamino)- etyl]-benzoesyre- etylester 4- [ 2- ( 5- chloro- 2-( 4- isopropyl-piperidino)- benzoylamino)- ethyl]-benzoic acid- ethyl ester

Fremstilt fra 5-klor-2-(4-isopropyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 72% av det teoretiske, Prepared from 5-chloro-2-(4-isopropyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 72% of the theoretical,

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

Beregnet: C 68,03, H 7,69, N 6,10, Cl 7,73 Calculated: C 68.03, H 7.69, N 6.10, Cl 7.73

Funnet: 68,20 7,62 6,20 7,41. Found: 68.20 7.62 6.20 7.41.

E ksempel 190 Example 190

4- [ 2- ( 5- klor- 2 - ( 4- isopropyl- piperidino)- benzoylamino)- etyl]-benzoesyre 4- [ 2- ( 5- chloro- 2 - ( 4- isopropyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4-isopropyl-piperidino)-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(4-isopropyl-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

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

Smeltepunkt: 164°C. Melting point: 164°C.

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

Funnet: 67,40 6,94 6,74 8,41. Found: 67.40 6.94 6.74 8.41.

Eksempel 191 Example 191

4- [ 2- ( 5- klor- 2- ( 4- tert. butyl- piperidino)- benzoylamino) - etyl] - benzoesyre- etylester 4- [ 2- ( 5- chloro- 2- ( 4- tert. butyl- piperidino)- benzoylamino) - ethyl] - benzoic acid- ethyl ester

Fremstilt fra 5-klor-2-(4-tert.butyl-piperidino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(4-tert.butyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 63% av det teoretiske. Yield: 63% of the theoretical.

Smeltepunkt: 103°C. Melting point: 103°C.

Beregnet: C 68,84, H 7,49, N 5,95, Cl 7,53. Calculated: C 68.84, H 7.49, N 5.95, Cl 7.53.

Funnet: 69,10 7,60 6,20 7,90. Found: 69.10 7.60 6.20 7.90.

Eksempel 192 Example 192

4-[ 2-( 5- klor- 2-( 4- tert. butyl- piperidino)- benzoylamino)- etyl]-benzoesyre 4-[ 2-( 5- chloro- 2-( 4- tert. butyl-piperidino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4-tert.butyl-piperidino)-benzoylamino)-etyl]-benzoesyre-etylester analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(4-tert.butyl-piperidino)-benzoylamino)-ethyl]-benzoic acid ethyl ester analogously to Example 166.

Utbytte: 87% av det teoretiske. Yield: 87% of the theoretical.

Smeltepunkt: 160°C. Melting point: 160°C.

Beregnet: C 67,78, H 7,05, N 6,33, Cl 8,00 Calculated: C 67.78, H 7.05, N 6.33, Cl 8.00

Funnet: 67,93 7,21 6,50 8,20. Found: 67.93 7.21 6.50 8.20.

Eksempel 19 3 Example 19 3

4-[ 2 - ( 5- klor- 2- ( l, 4- dioksa- 8- aza- spiro[ 4, 6] undekan- 8- yl)-b enzoylamino)- etyl]- benzoe syre- etylester 4-[ 2 - ( 5- chloro- 2- ( 1, 4- dioxa- 8- aza- spiro[ 4, 6] undecan- 8- yl)-benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 43% av det teoretiske, Yield: 43% of the theoretical,

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

Beregnet: C 64,12, H 6,42, N 5,75, Cl 7,28 Calculated: C 64.12, H 6.42, N 5.75, Cl 7.28

Funnet: 64,40 6,31 6,01 7,62. Found: 64.40 6.31 6.01 7.62.

E ksempel 19 4 Example 19 4

4-[ 2-( 5- klor— 2-( 1,4-dioksa- 8-aza-s piro[ 4, 6]- undek an- 8- yl)-b enzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro— 2-( 1,4-dioxa- 8-aza-s pyro[ 4, 6]-undec an- 8- yl)-benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(1,4-dioksa-8-aza-spiro[4,6]-undekan-8-yl)-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(1,4-dioxa-8-aza-spiro[4,6]-undecan-8-yl)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogous to example 166.

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

Smeltepunkt: 185°C. Melting point: 185°C.

Beregnet: C 62,81, H 5,93, N 6,10, Cl 7,72. Calculated: C 62.81, H 5.93, N 6.10, Cl 7.72.

Funnet: 63,02 6,05 6,11 7,98. Found: 63.02 6.05 6.11 7.98.

Eksempel 19 5 Example 19 5

4-[ 2-( 2- diallylamino- 5- klor- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 2- diallylamino- 5- chloro- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 2-diallylamino-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 48% av det teoretiske, Prepared from 2-diallylamino-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 48% of the theoretical,

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

Beregnet: C 67,52, H 6,29, N 6,55 Calculated: C 67.52, H 6.29, N 6.55

Funnet: 67,64 6,38 6,56. Found: 67.64 6.38 6.56.

Eksempel 196 Example 196

4-[ 2-( 2- diallylamino- 5- klor- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 2- diallylamino- 5- chloro- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(2-diallylamino-5-klor-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(2-diallylamino-5-chloro-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

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

Smeltepunkt: 130°C. Melting point: 130°C.

Beregnet: C 66,24, H 5,81, N 7,02 Calculated: C 66.24, H 5.81, N 7.02

Funnet: 66,50 5,83 6,92. Found: 66.50 5.83 6.92.

Eksempel 19 7 Example 19 7

4-[ 2- ( 5- nitro- 2, 4- dipiperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[2-(5-nitro-2,4-dipiperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester

Fremstilt fra 5-nitro-2,4-dipiperidino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 40% av det teoretiske, Prepared from 5-nitro-2,4-dipiperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 40% of the theoretical,

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

Beregnet: C 66,12, H 7,13, N 11,01 Calculated: C 66.12, H 7.13, N 11.01

Funnet: 66,13 7,09 11,05. Found: 66.13 7.09 11.05.

Ek sempel 198 Oak sample 198

4" [ 2- ( 5- nitro- 2, 4- dipiperidino- benzoylamino)- etyl]- benzoesyre 4" [ 2- ( 5- nitro- 2, 4- dipiperidino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-nitro-2,4-dipiperidino-benzoylamino)-etyl ]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-nitro-2,4-dipiperidino-benzoylamino)-ethyl ]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 95% av det teoretiske. Yield: 95% of the theoretical.

Smeltepunkt: 208°C, Melting point: 208°C,

Beregnet: C 64,98, H 6,71, N 11,65. Calculated: C 64.98, H 6.71, N 11.65.

Funnet: 64,40 6,72 11,03. Found: 64.40 6.72 11.03.

Eksempel 199 Example 199

4- t[ 2- ( 5- amino- 2, 4- dipiperidino- benzoylamino)- etyl]- benzoesyre-etylester 4- t[ 2- ( 5- amino- 2, 4- dipiperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

1,4 g (2,8 mmol) 4-[2-(5-nitro-2,4-dipiperidino-benzoylamino)-etyl ]-benzoesyre-etylester oppløses i 100 ml etanol og hydrogeneres ved romtemperatur og et hydrogentrykk på 5 bar med 10%ig palladium-kull som katalysator. Efter frafiltrering av katalysatoren og avdestillering av metanolen får man ved krystallisering fra aceton 0,8 g (60% av det teoretiske) 1.4 g (2.8 mmol) of 4-[2-(5-nitro-2,4-dipiperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester is dissolved in 100 ml of ethanol and hydrogenated at room temperature and a hydrogen pressure of 5 bar with 10% palladium charcoal as catalyst. After filtering off the catalyst and distilling off the methanol, crystallization from acetone yields 0.8 g (60% of the theoretical)

med smeltepunkt 172°C. with melting point 172°C.

Beregnet: C 70,26, H 8,00, N 11,70 Calculated: C 70.26, H 8.00, N 11.70

Funnet: 70,39, 8,19 11,72. Found: 70.39, 8.19 11.72.

Eksempel 200 Example 200

4-[ 2-( 5- amino- 2, 4- dipiperidino- benzoylamino)- etyl]- benzoesyre-h ydroklorid 4-[ 2-( 5- amino- 2, 4- dipiperidino- benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2-(5-amino-2,4-dipiperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-amino-2,4-dipiperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 95% av det teoretiske. Yield: 95% of the theoretical.

Smeltepunkt: 2 71°C. Melting point: 2 71°C.

Beregnet: C 64,11, H 7,24, N 11,50, Cl 7,27 Calculated: C 64.11, H 7.24, N 11.50, Cl 7.27

Funnet: 64,40 7,27 11,33 7,50. Found: 64.40 7.27 11.33 7.50.

Eksempel 201 Example 201

4- [ 2- ( 2- ( N- adamanty1-(1)-N- metylam ino)- 5- kl or- benzoylamino)-etyl]-b enzoes yre- etylester 4- [ 2- ( 2- ( N-adamanty1-(1)-N- methylamino)- 5- chlor- benzoylamino)-ethyl]-benzoic acid ethyl ester

Fremstilt fra 2-(N-adamanty1-(1)-N-metylamino)-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 2-(N-adamanty1-(1)-N-methylamino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 0,85 g (34% av det teoretiske). Yield: 0.85 g (34% of the theoretical).

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

Beregnet: C 70,36, H 7,13, N 5,66, Cl 7,16 Calculated: C 70.36, H 7.13, N 5.66, Cl 7.16

Funnet: 70,05 7,08 5,46 7,07 Found: 70.05 7.08 5.46 7.07

Eksempel 202 Example 202

4-[ 2-( 2-( N- adamantyl-( 1)- N- metylamino)- 5- klor- benzoylamino)-etyl]- benzoesyre 4-[ 2-( 2-( N- adamantyl-( 1)- N- methylamino)- 5- chloro- benzoylamino)-ethyl]- benzoic acid

Fremstilt fra 4-[2-(2-(N-adamantyl-(1)-N-metylamino)-5-klorbenzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(2-(N-adamantyl-(1)-N-methylamino)-5-chlorobenzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogous to example 166.

Utbytte: 0,33 g (64% av det teoretiske), Yield: 0.33 g (64% of theoretical),

Smeltepunkt: 207°C. Melting point: 207°C.

Beregnet: C 69,44, H 6,69, N 6,00, Cl 7,59 Calculated: C 69.44, H 6.69, N 6.00, Cl 7.59

Funnet: 69,13 6,44 6,02 7,93. Found: 69.13 6.44 6.02 7.93.

Eksempel 203 Example 203

4- [ 2- ( 5- klor- 2-( 1, 2, 3, 6- tetrahydro- pyridino)- benzoylamino)-ety11- benzoesyre- etylester 4- [ 2- ( 5- chloro- 2-( 1, 2, 3, 6- tetrahydro- pyridino)- benzoylamino)-ethyl 11- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 4,7 g (88% av det teoretiske) Yield: 4.7 g (88% of theoretical)

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

Beregnet: C 66,90, H 6,10, N 6,78, Cl 8,59 Calculated: C 66.90, H 6.10, N 6.78, Cl 8.59

Funnet: 67,60 6,21 7,02 8,54. Found: 67.60 6.21 7.02 8.54.

Eksempel 204 Example 204

4-[ 2- ( 5- klor- 2-( 1, 2, 3, 6- tetrahydro-pyridino)-benz oylamino)-ety1]- benzoesyre 4-[2-(5-chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 2,27 g (73,7% av det teoretiske), Yield: 2.27 g (73.7% of the theoretical),

Smeltepunkt: 181-182°C. Melting point: 181-182°C.

Beregnet: C 65,54, H 5,50, N 7,28, Cl 9,21 Calculated: C 65.54, H 5.50, N 7.28, Cl 9.21

Funnet: 65,50 5,49 7,32 9,12. Found: 65.50 5.49 7.32 9.12.

Eksempel 205 Example 205

4- [ 2- ( 5- klor- 2- ( N- isobutyl- N- propylamino)- benzoylamino)- etyl]-benzoesyre- etylester 4- [ 2- ( 5- chloro- 2- ( N- isobutyl- N- propylamino)- benzoylamino)- ethyl]-benzoic acid- ethyl ester

Fremstilt fra 5-klor-2-(N-isobutyl-N-propyl-amino)-benzoesyre og 4-(2-aminoetyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(N-isobutyl-N-propyl-amino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 5,8 g (86,8% av det teoretiske). Yield: 5.8 g (86.8% of the theoretical).

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

Beregnet: C 67,48, H 7,47, N 6,30, Cl 7,97 Calculated: C 67.48, H 7.47, N 6.30, Cl 7.97

Funnet: 67,70 7,63 6,26 7,96 Found: 67.70 7.63 6.26 7.96

Eksempel 206 Example 206

4-[ 2- ( 5- klor- 2-( N- isobutyl- N- propylamino)- benzoylamino)- etyl]-benzoesyre 4-[2-(5-chloro-2-(N-isobutyl-N-propylamino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(N-isobutyl-N-propylamino)-benzoylamino)-ety1]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(N-isobutyl-N-propylamino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogously to example 166.

Utbytte: 2,7 g (79% av det teoretiske). Yield: 2.7 g (79% of theoretical).

Smeltepunkt: 128°C. Melting point: 128°C.

Beregnet: C 66,25, H 7,01, N 6,72, Cl 8,50 Calculated: C 66.25, H 7.01, N 6.72, Cl 8.50

Funnet: 66,60 7,08 6,66 8,64 Found: 66.60 7.08 6.66 8.64

Eksempel 207 Example 207

4-[ 2-( 2- N, N- dietylamino- 3- mety1- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 2- N, N- diethylamino- 3- methyl1- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 2-N,N-dietylamino-3-metyl-benzoesyre og 4-(2-amino-ety1)-benzoesyre-metylester analogt med eksempel 165. Utbytte: 57% av det teoretiske, Prepared from 2-N,N-diethylamino-3-methyl-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 165. Yield: 57% of the theoretical,

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

Beregnet: C 71,71, H 7,66, N 7,61 Calculated: C 71.71, H 7.66, N 7.61

Funnet: 71,71 7,83 7,55. Found: 71.71 7.83 7.55.

Eksempel 208 Example 208

4- [2- (2-N,N-dietylamino-3-mety1-benz oylamino)- ety1]- benzoesyre 4-[2-(2-N,N-diethylamino-3-methyl-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(2-N,N-dietylamino-3-metyl-benzoy1-amino)-ety1]-benzoesyre-metylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(2-N,N-diethylamino-3-methyl-benzoy1-amino)-ethyl]-benzoic acid methyl ester by alkaline saponification analogously to example 166.

Utbytte: 63,1% av det teoretiske, Yield: 63.1% of the theoretical,

Smeltepunkt: 150-152°C. Melting point: 150-152°C.

Beregnet: C 71,15, H 7,39, N 7,91 Calculated: C 71.15, H 7.39, N 7.91

Funnet: 71,01 7,38 8,13. Found: 71.01 7.38 8.13.

Eksempel 209 Example 209

4-[ 2- ( 5- klor- 2-( 4-( 2- furoyl)- piperazino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 4-( 2- furoyl)-piperazino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt analogt med eksempel 165 fra 5-klor-2-(4-(2-furoyl)-piperazino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester. Utbytte: 88,4% av det teoretiske, Prepared analogously to example 165 from 5-chloro-2-(4-(2-furoyl)-piperazino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester. Yield: 88.4% of the theoretical,

Smeltepunkt: 93-95°C. Melting point: 93-95°C.

Beregnet: C 62,97, H 5,28, N 8,47, Cl 7,15 Calculated: C 62.97, H 5.28, N 8.47, Cl 7.15

Funnet: 62,88 5,30 8,36 7,32. Found: 62.88 5.30 8.36 7.32.

Eksempel 210 Example 210

4- [ 2- ( 5- klor- 2-( 4- ( 2- furoyl)- piperazino)- benzoylamino)- etyl]-benzoesyre 4- [ 2- ( 5- chloro- 2-( 4- ( 2- furoyl)-piperazino)- benzoylamino)- ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(4- (2-furoyl)-piperazino)-benzoylamino)-etyl]-benzoesyre-metylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(4-(2-furoyl)-piperazino)-benzoylamino)-ethyl]-benzoic acid methyl ester by alkaline saponification analogously to example 166.

Utbytte: 26,4% av det teoretiske, Yield: 26.4% of the theoretical,

Smeltepunkt: 187-188°C. Melting point: 187-188°C.

Beregnet: C 62,31, H 5,02, N 8,72, Cl 7,36 Calculated: C 62.31, H 5.02, N 8.72, Cl 7.36

Funnet: 62,08 4,95 8,56 7,61. Found: 62.08 4.95 8.56 7.61.

Eksempel 211 Example 211

4- [ 2- ( 5- klor- 2- ( N- mety1- N- benzylamino)- etyl]- benzoesyre-etylester 4- [ 2- ( 5- chloro- 2- ( N- methyl 1- N- benzylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(N-metyl-N-benzylamino)-benzoesyre Prepared from 5-chloro-2-(N-methyl-N-benzylamino)-benzoic acid

og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 47% av det teoretiske, and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 47% of the theoretical,

Smeltepunkt: 93-95°C. Melting point: 93-95°C.

Beregnet: C 69,25, H 6,03, N 6,21, Cl 7,86 Calculated: C 69.25, H 6.03, N 6.21, Cl 7.86

Funnet: 69,50 6,35 6,31 7,90. Found: 69.50 6.35 6.31 7.90.

E ksempel 212 Example 212

4-[ 2-( 5- klor- 2-( N- mety1- N- benzylamino)- benzoylamino)- ety1]-benzoesyre 4-[2-(5-chloro-2-(N-methyl-N-benzylamino)-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-(N-metyl-N-benzylamino)-benzoylamino) -etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(N-methyl-N-benzylamino)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 166.

Utbytte: 64,2% av det teoretiske. Yield: 64.2% of the theoretical.

Smeltepunkt: 127-128°C. Melting point: 127-128°C.

Beregnet: C 68,16, H 5,48, N 6,62, Cl 8,38 Calculated: C 68.16, H 5.48, N 6.62, Cl 8.38

Funnet: 68,01 5,59 6,81 8,54. Found: 68.01 5.59 6.81 8.54.

Eksempel 213 Example 213

4-[ 2- ( 2- ( 4- etoksykarbony1- piperazino)- 5- klor- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2- ( 2- ( 4- ethoxycarbonyl-piperazino)- 5- chloro- benzoylamino)- ethyl]-benzoic acid ethyl ester

Fremstilt fra 2-(4-etoksykarbonyl-piperazino)-5-klor-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 2-(4-ethoxycarbonyl-piperazino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

Utbytte: 71,2% av det teoretiske, Yield: 71.2% of the theoretical,

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

Beregnet: C 61,53, H 6,20, N 8,61, Cl 7,26 Calculated: C 61.53, H 6.20, N 8.61, Cl 7.26

Funnet: 61,78 6,30 8,23 7,21. Found: 61.78 6.30 8.23 7.21.

Eksempel 214 Example 214

4-[ 2-( 2-( 4- etoksykarbonyl- piperazino)- 5- klor- benzoylamino)-etyl]- ben zoesyre 4-[ 2-( 2-( 4- ethoxycarbonyl- piperazino)- 5- chloro- benzoylamino)-ethyl]- benzoic acid

Fremstilt fra 4-[2-(2-(4-etoksykarbony1-piperazino)-5-klor-oenzoylamino)-etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(2-(4-ethoxycarbonyl-1-piperazino)-5-chloro-oenzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 166.

Utbytte: 93% av det teoretiske, Yield: 93% of the theoretical,

Smeltepunkt: 168-170°C. Melting point: 168-170°C.

Beregnet: C 60,06, H 5,70, N 9,14, Cl 7,71 Calculated: C 60.06, H 5.70, N 9.14, Cl 7.71

Funnet: 59,93 5,91 9,20 7,97 Found: 59.93 5.91 9.20 7.97

Eksempel 215 Example 215

4- [ 2- ( 5- ety1- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4- [ 2- ( 5- ethyl1- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 6-etyl-l-(5-brom-pentyl)-4H-3,1-benzoxazin-2,4-(1H)-dion og 4- (2-amino-etyl)-benzoesyre-etylester analogt med eksempel 217. Prepared from 6-ethyl-1-(5-bromo-pentyl)-4H-3,1-benzoxazine-2,4-(1H)-dione and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 217.

Utbytte: 55,6% av det teoretiske, Yield: 55.6% of the theoretical,

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

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

Funnet: 73,26 7,88 6,97 Found: 73.26 7.88 6.97

E ksempel 216 Example 216

4-[ 2- ( 5- etyl- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[2-(5-ethyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid

Fremstilt fra 4-[2-(5-ety1-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(5-ethyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 166.

Utbytte: 84,5% av det teoretiske, Yield: 84.5% of the theoretical,

Smeltepunkt: 177°C. Melting point: 177°C.

Beregnet: C 72,60, H 7,42, N 7,36 Calculated: C 72.60, H 7.42, N 7.36

Funnet: 72,59 7,28 7,16. Found: 72.59 7.28 7.16.

Eksempel 217 Example 217

4-[ 2-( 5- mety1- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[2-(5-methyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester

10,6 g (32,5 mmol) 1-(5-brom-pentyl)-6-metyl-4H-3,1-benzoksazin-2,4-(1H)-dion [fremstilt fra 1,5-dibrompentan og 6-metyl-4H-3,l-benzoksazin-2,4-(1H)-dion] omrøres i 100 ml absolutt dioksan sammen med 19,3 g (0,1 mol) 4-(2-aminoetyl)-benzoesyre-etylester og 13 g N-etyl-diisopropylamin i 4 dager ved romtemperatur. Derefter foretas inndampning, tilsetning av vann og ekstraksjon med kloroform. De tørrede kloroformekstrakter inndampes og kromatograferes på silikagel med toluen/etylacetat 10:1 som elueringsmiddel. 10.6 g (32.5 mmol) 1-(5-bromopentyl)-6-methyl-4H-3,1-benzoxazine-2,4-(1H)-dione [prepared from 1,5-dibromopentane and 6-methyl-4H-3,1-benzoxazine-2,4-(1H)-dione] is stirred in 100 ml of absolute dioxane together with 19.3 g (0.1 mol) of 4-(2-aminoethyl)-benzoic acid ethyl ester and 13 g of N-ethyl-diisopropylamine for 4 days at room temperature. Evaporation, addition of water and extraction with chloroform are then carried out. The dried chloroform extracts are evaporated and chromatographed on silica gel with toluene/ethyl acetate 10:1 as eluent.

Utbytte: 6,85 g (53,5% av det teoretiske). Yield: 6.85 g (53.5% of the theoretical).

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

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

Funnet: 72,62 7,15 7,12. Found: 72.62 7.15 7.12.

Eksempel 218 Example 218

4- [ 2- ( 5- metyl- 2- piperidino- benzoy lamino)- etyl]- benzoesyre 4- [ 2- ( 5- methyl- 2- piperidino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-mety1-2-piperidino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(5-methyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 166.

Utbytte: 80% av det teoretiske. Yield: 80% of the theoretical.

Smeltepunkt: 199-200°C. Melting point: 199-200°C.

Beregnet: C 72,11, H 7,15, N 7,64. Calculated: C 72.11, H 7.15, N 7.64.

Funnet: 72,10 6,95 7,70. Found: 72.10 6.95 7.70.

Eksempel 219 Example 219

4-[ 2-( 5- klor- 2-( 4- p- klorfenyl- piperazino)- benzoylamino)- etyl]-benzoesyre- etylester 4-[ 2-( 5- chloro- 2-( 4- p- chlorophenyl-piperazino)- benzoylamino)- ethyl]-benzoic acid- ethyl ester

Fremstilt fra 5-klor-2-(4-p-klorfenyl-piperazino)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(4-p-chlorophenyl-piperazino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165.

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

Smeltepunkt: 153-155°C. Melting point: 153-155°C.

Beregnet: C 63,88, H 5,55, N 7,98, Cl 13,47 Calculated: C 63.88, H 5.55, N 7.98, Cl 13.47

Funnet: 63,77 5,47 7,93 13,40. Found: 63.77 5.47 7.93 13.40.

Eksempel 220 Example 220

4-[ 2-( 5- klor- 2-( 4- mety1- piperazino)- benzoylamino)- etyl]-benzoesyre- metylester 4-[ 2-( 5- chloro- 2-( 4- methyl-1-piperazino)- benzoylamino)- ethyl]-benzoic acid methyl ester

Fremstilt fra 5-klor-2-(4-metyl-piperazino)-benzoesyre-hydroklorid og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 16 5. Prepared from 5-chloro-2-(4-methyl-piperazino)-benzoic acid hydrochloride and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 16 5.

Utbytte: 52% av det teoretiske. Yield: 52% of the theoretical.

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

Beregnet: C 63,53, H 6,30, N 10,11, Cl 8,52 Calculated: C 63.53, H 6.30, N 10.11, Cl 8.52

Funnet: 63,62 6,05 10,23 8,28 Found: 63.62 6.05 10.23 8.28

Eksempel 221 Example 221

4-[ 2-( 5- klor- 2- piperid ino- benzoylamino)- 2- metyl- propyl]- benzoesyre- etylester 4-[ 2-( 5- chloro- 2- piperidino- benzoylamino)- 2- methyl- propyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-piperidino-benzoesyre og 4-(2-amino-2-mety1-propy1)-benzoesyre-etylester-hydroklorid (smeltepunkt: 199°C) analogt med eksempel 165. Prepared from 5-chloro-2-piperidino-benzoic acid and 4-(2-amino-2-methyl-propyl)-benzoic acid ethyl ester hydrochloride (melting point: 199°C) analogously to example 165.

Utbytte: 51% av det teoretiske, Yield: 51% of the theoretical,

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

Beregnet: C 67,78, H 7,05, N 6,32, Cl 8,00 Calculated: C 67.78, H 7.05, N 6.32, Cl 8.00

Funnet: 67,75 6,91 6,05 7,87. Found: 67.75 6.91 6.05 7.87.

Eksempel 222 Example 222

4-[ 2-( 5- klor- 2- piperidino- benzoylamino)- 2- metyl- propyl]-benzoesyre 4-[2-(5-Chloro-2-piperidino-benzoylamino)-2-methyl-propyl]-benzoic acid

Fremstilt fra 4-[2-(5-klor-2-piperidino-benzoylamino)-2-metylpropyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-piperidino-benzoylamino)-2-methylpropyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 166.

Utbytte: 62% av det teoretiske, Yield: 62% of the theoretical,

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

Beregnet: C 66,58, H 6,56, N 6,75, Cl 8,55 Calculated: C 66.58, H 6.56, N 6.75, Cl 8.55

Funnet: 66,90 6,71 6,50 8,52. Found: 66.90 6.71 6.50 8.52.

Eksempel 223 Example 223

4- [ 2- (5-klor-2- ( 1, 2, 3, 4, 5, 6, 7, 8- oktahydro- isokinolin- 2- yl)-benzoylamino)- etyl]- benzoesyre- etylester 4- [ 2- (5-chloro-2-( 1, 2, 3, 4, 5, 6, 7, 8- octahydro- isoquinolin- 2- yl)-benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-klor-2-(1,2,3,4,5,6,7,8-oktahydro-isokinolin-2-yl)-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Prepared from 5-chloro-2-(1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously with example 165.

Utbytte: 58% av det teoretiske, Yield: 58% of the theoretical,

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

Beregnet: C 69,44, H 6,68, N 5,99, Cl 7,59 Calculated: C 69.44, H 6.68, N 5.99, Cl 7.59

Funnet: 69,62 6,72 6,10 7,72. Found: 69.62 6.72 6.10 7.72.

Eksempel 224 Example 224

4-[ 2-(5-klor-2-( 1, 2, 3, 4, 5, 6, 7, 8- oktahydro- lsokinolln- 2- yl)-benzoylamino)- etyl]- benzoesyre- hydroklorid 4-[ 2-(5-chloro-2-( 1, 2, 3, 4, 5, 6, 7, 8- octahydro- lsoquinolin- 2- yl)-benzoylamino)- ethyl]- benzoic acid hydrochloride

Fremstilt fra 4-[2- (5-klor-2-(1,2,3,4,5,6,7,8-oktahydro-isokinolin-2-yl)-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk hydrolyse analogt med eksempel 166. Prepared from 4-[2-(5-chloro-2-(1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl)-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline hydrolysis analogous to example 166.

Utbytte: 82% av det teoretiske, Yield: 82% of the theoretical,

Smeltepunkt: 220°C. Melting point: 220°C.

Beregnet: C 63,15, H 5,93, N 5,89, Cl 14,93 Calculated: C 63.15, H 5.93, N 5.89, Cl 14.93

Funnet: 63,45 6,09 6,02 15,90 Found: 63.45 6.09 6.02 15.90

Eksempel 225 Example 225

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-metylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-metylester analogt med eksempel 165. Utbytte: 83% av det teoretiske, Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester analogously to example 165. Yield: 83% of the theoretical,

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

Beregnet: C 67,78, H 7,05, N 6,32, Cl 8,00 Calculated: C 67.78, H 7.05, N 6.32, Cl 8.00

Funnet: 67,96 7,21 6,54 8,20. Found: 67.96 7.21 6.54 8.20.

Eksempel 226 Example 226

4-[ 2- ( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre og absolutt etanol med støkiometriske mengder tionylklorid. Prepared from 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid and absolute ethanol with stoichiometric amounts of thionyl chloride.

Utbytte: 86% av det teoretiske, Yield: 86% of the theoretical,

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

Beregnet: C 68,33, H 7,27, N 6,13, Cl 7,75 Calculated: C 68.33, H 7.27, N 6.13, Cl 7.75

Funnet: 68,21 7,40 6,20 7,62. Found: 68.21 7.40 6.20 7.62.

Eksempel 227 Example 227

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-cykloheksylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid cyclohexyl ester

3 g (7 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre i 30 ml absolutt pyridin overføres til imidazolidet med 1,2 g (7,4 mmol) karbonyldiimidazol ved romtemperatur. Efter tilsetning av 1,48 g (14,8 mmol) cykloheksanol oppvarmes 3 g (7 mmol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid in 30 ml of absolute pyridine is transferred to the imidazolide with 1.2 g (7.4 mmol) of carbonyldiimidazole at room temperature. After adding 1.48 g (14.8 mmol) of cyclohexanol, the mixture is heated

i 2 til 3 timer til koketemperatur. Efter avdestillering av oppløsningsmidlet renses råproduktet kromatografisk over en silikagelkolonne med toluen-eddiksyreetylester som elueringsmiddel. for 2 to 3 hours to boiling temperature. After distilling off the solvent, the crude product is purified chromatographically over a silica gel column with toluene-acetic acid ethyl ester as eluent.

Utbytte: 2,7 g (75% av det teoretiske), Yield: 2.7 g (75% of the theoretical),

Smeltepunkt: 88°C. Melting point: 88°C.

Beregnet: C 70,50, H 7,70, N 5,48, Cl 6,93 Calculated: C 70.50, H 7.70, N 5.48, Cl 6.93

Funnet: 70,60 8,23 5,26 6,69. Found: 70.60 8.23 5.26 6.69.

Eksempel 228 Example 228

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-tert. butylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid-tert. butyl ester

4,3 g (0,01 mol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre suspenderes i 150 ml eddiksyre-tert.-butylester, tilsettes 1,43 g (0,011 mol) 70%ig perklorsyre og omrøres i 2 4 timer ved romtemperatur. Reaksjonsblandingen opptas i 500 ml kloroform. Kloroformoppløsningen utristes omhyggelig med vann. Råproduktet utvunnet fra kloroformfasen efter tørring over natriumsulfat renses kromatografisk over en silikagelkolonne med toluen-eddiksyreetylester som elueringsmiddel. 4.3 g (0.01 mol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid is suspended in 150 ml of acetic acid tert-butyl ester, 1.43 g (0.011 mol ) 70% perchloric acid and stirred for 2 4 hours at room temperature. The reaction mixture is taken up in 500 ml of chloroform. The chloroform solution is carefully shaken off with water. The crude product recovered from the chloroform phase after drying over sodium sulfate is purified chromatographically over a silica gel column with toluene-acetic acid ethyl ester as eluent.

Utbytte: 3 g (62% av det teoretiske), Yield: 3 g (62% of the theoretical),

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

Beregnet: C 69,33, H 7,68, N 5,77, Cl 7,30 Calculated: C 69.33, H 7.68, N 5.77, Cl 7.30

Funnet: 69,64 7,78 5,78 7,40 Found: 69.64 7.78 5.78 7.40

Analogt med eksemplene 225 til 227 fremstilles følgende forbindelser: 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-ety1]-benzoesyre-propylester, Analogous to examples 225 to 227, the following compounds are prepared: 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid propyl ester,

Utbytte: 70% av det teoretiske, smeltepunkt: < 20°C. Yield: 70% of the theoretical, melting point: < 20°C.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre- } isopropylester, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid- } isopropyl ester,

Utbytte: 84% av det teoretiske, smeltepunkt: < 20°C. Yield: 84% of the theoretical, melting point: < 20°C.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-butylester, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid butyl ester,

Utbytte: 90% av det teoretiske, smeltepunkt: < 20°C. Yield: 90% of the theoretical, melting point: < 20°C.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-isobutylester, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid isobutyl ester,

Utbytte: 74% av det teoretiske, smeltepunkt: < 20°C. Yield: 74% of the theoretical, melting point: < 20°C.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-heksylester, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid hexyl ester,

Utbytte: 63% av det teoretiske, smeltepunkt: < 20°C. Yield: 63% of the theoretical, melting point: < 20°C.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-benzylester, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid benzyl ester,

Utbytte: 83% av det teoretiske, smeltepunkt: < 20°C. Yield: 83% of the theoretical, melting point: < 20°C.

Eksempel 229 Example 229

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzyl-alkohol 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzyl alcohol

4.57 g (0,01 mol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-etylester oppløses i 100 ml absolutt eter og settes til en suspensjon av 0,72 g (0,011 mol) litium-aluminiumhydrid i 30 ml absolutt eter og oppvarmes i 1 time til koketemperatur. Efter avkjøling tilsettes 15 ml vann for-siktig. Efter filtrering tørres eterfasen over natriumsulfat. Råproduktet renses kromatografisk over en silikagelkolonne 4.57 g (0.01 mol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester are dissolved in 100 ml of absolute ether and added to a suspension of 0.72 g (0.011 mol ) lithium aluminum hydride in 30 ml of absolute ether and heated for 1 hour to boiling temperature. After cooling, carefully add 15 ml of water. After filtration, the ether phase is dried over sodium sulphate. The crude product is purified chromatographically over a silica gel column

med toluen/eddiksyreetylester =1:1 som elueringsmiddel. Utbytte: 3,5 g (84% av det teoretiske), with toluene/acetic acid ethyl ester =1:1 as eluent. Yield: 3.5 g (84% of the theoretical),

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

Beregnet: C 69,46, H 7,52, N 6,75, Cl 8,54. Calculated: C 69.46, H 7.52, N 6.75, Cl 8.54.

Funnet: 69,32 7,58 6,75 8,80. Found: 69.32 7.58 6.75 8.80.

Eksempel 230 Example 230

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzyl-malonsyre- dietylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzyl-malonic acid- diethyl ester

2.58 g (5,5 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzylklorid-hydroklorid (fremstilt fra 2,3 g 2.58 g (5.5 mmol) 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzyl chloride hydrochloride (prepared from 2.3 g

(5,5 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzylalkohol og tionylklorid i kloroform) oppløses i 25 ml absolutt etanol og settes dråpevis til en oppløsning av 3,2 g (20 mmol) malonsyredietylester og 20 mmol natriumetylat i absolutt etanol. Derefter oppvarmer man i 4 timer til tilbake-løpstemperatur, inndamper derefter, surgjør med fortynnet saltsyre og ekstraherer med kloroform. Efter inndampning av ekstraktene foretas rensning kolonnekromatografisk på silikagel med toluen/etylacetat = 10:1. (5.5 mmol) 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzyl alcohol and thionyl chloride in chloroform) are dissolved in 25 ml of absolute ethanol and added dropwise to a solution of 3.2 g ( 20 mmol) malonic acid diethyl ester and 20 mmol sodium ethylate in absolute ethanol. It is then heated to reflux temperature for 4 hours, then evaporated, acidified with dilute hydrochloric acid and extracted with chloroform. After evaporation of the extracts, purification is carried out by column chromatography on silica gel with toluene/ethyl acetate = 10:1.

Utbytte: 1,7 g (60,7% av det teoretiske), Yield: 1.7 g (60.7% of the theoretical),

Smeltepunkt: 80-82°C. Melting point: 80-82°C.

Beregnet: C 66,83, H 7,42, N 6,36, Cl 5,03 Calculated: C 66.83, H 7.42, N 6.36, Cl 5.03

Funnet: 66,83 7,51 6,62 5,07. Found: 66.83 7.51 6.62 5.07.

E ksempel 231 Example 231

[ 2 -( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzen [ 2 -( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzene

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 2-fenyl-etylamin analogt med eksempel 165. Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 2-phenyl-ethylamine analogously to example 165.

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

Smeltepunkt: 66°C. Melting point: 66°C.

Beregnet: C 71,76, H 7,59, N 7,17, Cl 9,39 Calculated: C 71.76, H 7.59, N 7.17, Cl 9.39

Funnet: 72,00 7,65 7,27 9,21. Found: 72.00 7.65 7.27 9.21.

Eksempel 232 Example 232

4-[ 2-( 5- klor- 2- piperidino- benzoylamino)- etyl]- acetofenon 4-[ 2-( 5- Chloro- 2- Piperidino- Benzoylamino)- Ethyl]- Acetophenone

2 g (15 mmol) aluminiumklorid i 10 ml dikloretan tilsettes under avkjøling 0,6 g (7,6 mmol) acetylklorid. Efter påfølgende tilsetning av 1 g (2,92 mmol) [2-(5-klor-2-piperidino-benzoylamino)-etyl]-benzen omrøres i 3 timer ved 40-45°C. Derefter foretas inndampning, og residuet spaltes med iskald, fortynnet saltsyre. Efter ekstraksjon med kloroform og tørring av ekstrakten over natriumsulfat foretas inndampning, og for rensning kromatograferes derefter på silikagel med kloroform/etylacetat = IO:1 som elueringsmiddel. 2 g (15 mmol) of aluminum chloride in 10 ml of dichloroethane are added while cooling to 0.6 g (7.6 mmol) of acetyl chloride. After the subsequent addition of 1 g (2.92 mmol) [2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-benzene, the mixture is stirred for 3 hours at 40-45°C. Evaporation is then carried out, and the residue is decomposed with ice-cold, dilute hydrochloric acid. After extraction with chloroform and drying of the extract over sodium sulphate, evaporation is carried out, and for purification it is then chromatographed on silica gel with chloroform/ethyl acetate = 10:1 as eluent.

Utbytte: 0,42 g (37,4% av det teoretiske), Yield: 0.42 g (37.4% of the theoretical),

Smeltepunkt: 61-63°C. Melting point: 61-63°C.

Beregnet: C 68,65, H 6,55, N 7,28, Cl 9,01 Calculated: C 68.65, H 6.55, N 7.28, Cl 9.01

Funnet: 68,73 6,76 7,33 9,16. Found: 68.73 6.76 7.33 9.16.

Eksempel 233 Example 233

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- acetofenon-hydroklorid 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- acetophenone hydrochloride

Fremstilt analogt med eksempel 232 ved omsetning av [2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzen med acetylklorid i nærvær av aluminiumklorid. Prepared analogously to example 232 by reacting [2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzene with acetyl chloride in the presence of aluminum chloride.

Utbytte: 41% av det teoretiske, Yield: 41% of the theoretical,

Smeltepunkt: 160°C. Melting point: 160°C.

Beregnet: C 64,79, H 6,96, N 6,04, Cl 15,30 Calculated: C 64.79, H 6.96, N 6.04, Cl 15.30

Funnet: 64,91 7,05 5,98 15,11. Found: 64.91 7.05 5.98 15.11.

Eksempel 234Example 234

4-[ 2-( 5- klor- 2- piperidino- benzoylamlno)- etyl]- fenyleddiksyre 4-[ 2-( 5- chloro- 2- piperidino- benzoylamino)- ethyl]- phenylacetic acid

4,86 g (10 mmol) 4-[2-(5-klor-2-piperidino-benzoylamino)-etyl]-fenyl-tioeddiksyre-morfolid (smeltepunkt: < 20°C, fremstilt fra 4-[2-(5-klor-2-piperidino-benzoylamino)-etyl]-acetofenon ved Willgerodt-reaksjon med svovel og morfolin) kokes i 50 ml etanol med 2 g (50 mmol) natriumhydroksyd i 2 dager. Derefter foretas inndampning, vann tilsettes, og ekstraksjon foretas med eter. Den vandige fase surgjøres derefter, det dannede bunnfall avsuges og omkrystalliseres fra acetonitril. 4.86 g (10 mmol) 4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-phenyl-thioacetic acid morpholide (melting point: < 20°C, prepared from 4-[2-(5 -chloro-2-piperidino-benzoylamino)-ethyl]-acetophenone by Willgerodt reaction with sulfur and morpholine) is boiled in 50 ml of ethanol with 2 g (50 mmol) of sodium hydroxide for 2 days. Evaporation is then carried out, water is added and extraction is carried out with ether. The aqueous phase is then acidified, the precipitate formed is filtered off with suction and recrystallized from acetonitrile.

Utbytte: 0,96 g (24% av det teoretiske), Yield: 0.96 g (24% of the theoretical),

Smeltepunkt: 151°C. Melting point: 151°C.

Beregnet: C 65,91, H 6,28, N 6,99, Cl 8,84 Calculated: C 65.91, H 6.28, N 6.99, Cl 8.84

Funnet: 65,61 6,34 7,18 8,77. Found: 65.61 6.34 7.18 8.77.

Eksempel 235 Example 235

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzaldehyd 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzaldehyde

Til en i et bad på 160-170°C omrørt suspensjon av 0,35 g finpulverisert, vannfritt natriumkarbonat i 3,5 ml etylenglykol setter man 0,35 g (0,59 mmol) N^-4-(2- (5-klor-2-oktametylenimino-benzoylamino)-etyl(-benzoyl-N 2-tosy1-hydrazin med smeltepunkt 153-158°C, fremstilt fra 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre og tosylhydrazin med karbonyldiimidazol i tetrahydrofuran. Efter 1,5 minutter (gassutvikling opphørt) fjerner man varmebadet og tilsetter noen minutter senere mye is. Man ekstraherer to ganger med eter, tørrer og filtrerer de samlede ekstrakter og inndamper dem i vakuum. Den erholdte, lysegule, harpiksaktige olje renser man ved kolonnekromatografi på silikagel med kloroform/ aceton = 20:1 som løpemiddel. 0.35 g (0.59 mmol) N^-4-(2- (5 -chloro-2-octamethyleneimino-benzoylamino)-ethyl(-benzoyl-N 2-tosy1-hydrazine with melting point 153-158°C, prepared from 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl] -benzoic acid and tosylhydrazine with carbonyldiimidazole in tetrahydrofuran. After 1.5 minutes (gas evolution has ceased), the heating bath is removed and a few minutes later a lot of ice is added. The extracts are extracted twice with ether, the combined extracts are dried and filtered and evaporated in vacuo. The obtained , pale yellow, resinous oil is purified by column chromatography on silica gel with chloroform/acetone = 20:1 as eluent.

Utbytte: 66% av det teoretiske. Yield: 66% of the theoretical.

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

Beregnet: Moltopp m/e = 412/414 (1 Cl) Calculated: Mole peak m/e = 412/414 (1 Cl)

Funnet: Moltopp m/e ] 412/414 (1 Cl) Found: Mole top w/e ] 412/414 (1 Cl)

Smeltepunkt for hydrokloridet x 0,5 H20: 156°C. Melting point of the hydrochloride x 0.5 H20: 156°C.

Beregnet: C 62,88, H 6,82, N 6,11, Cl 15,46 Calculated: C 62.88, H 6.82, N 6.11, Cl 15.46

Funnet: 62,85 7,11 6,05 15,43. Found: 62.85 7.11 6.05 15.43.

E ksempel 236 Example 236

4- [2- (5-klor-2-o ktamety lenimino-be nzoylamino)-e tyl]- benzaldehyd 4-[2-(5-Chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzaldehyde

Man ristet en oppløsning av 0,50 g (1,2 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzylalkohol i 75 ml absolutt aceton med 7,5 g aktivt mangandioksyd i 2 timer ved romtemperatur, filtrerer over et "Celite"-skikt på et G4-glassfilter og inndamper filtratet i vakuum. Den erholdte, brunlige, seige olje renser man ved kolonnekromatografi på silikagel (kloroform/aceton = 20:1). A solution of 0.50 g (1.2 mmol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzyl alcohol in 75 ml of absolute acetone was shaken with 7.5 g of active manganese dioxide in 2 hours at room temperature, filter over a "Celite" layer on a G4 glass filter and evaporate the filtrate in vacuo. The brownish, viscous oil obtained is purified by column chromatography on silica gel (chloroform/acetone = 20:1).

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

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

Beregnet: Moltopp m/e = 412/414 (1 Cl) Calculated: Mole peak m/e = 412/414 (1 Cl)

Funnet: Moltopp m/e = 412/414 (1 Cl). Found: Mole peak m/e = 412/414 (1 Cl).

Eksempel 237 Example 237

4-[ 2- ( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzaldehyd-dietylacetal 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzaldehyde diethyl acetal

En blanding av 0,23 g (0,56 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzaldehyd, 0,20 ml (1,2 mmol) ortomaursyre-trietylester, 0,02 g ammoniumklorid og 0,2 ml vannfri etanol oppvarmer man i 30 minutter ved 90°C. Efter avkjøling heller man blandingen i 2N ammoniakk og ekstraherer det hele med eter. Ekstrakten som er tørret over natrium-sulf at, inndamper man i vakuum, og inndampningsresiduet renses ved kolonnekromatografi på silikagel (toluen/aceton = 10:1). Utbytte: 23% av det teoretiske. A mixture of 0.23 g (0.56 mmol) 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzaldehyde, 0.20 ml (1.2 mmol) triethyl orthoformic acid, 0 .02 g of ammonium chloride and 0.2 ml of anhydrous ethanol are heated for 30 minutes at 90°C. After cooling, the mixture is poured into 2N ammonia and the whole is extracted with ether. The extract, which has been dried over sodium sulfate, is evaporated in a vacuum, and the evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10:1). Yield: 23% of the theoretical.

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

Beregnet: Moltopp m/e = 486/488 Calculated: Mole top m/e = 486/488

Funnet: Moltopp m/e = 486/488 Found: Mole top m/e = 486/488

Eksempel 238 Example 238

4- [ 2- ( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- kanelsyre 4- [ 2- ( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- cinnamic acid

lg (2,4 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzaldehyd og 1 g (10 mmol) malonsyre i 10 ml absolutt pyridin oppvarmes i 1 time til 100°C efter tilsetning av 0,5 ml piperidin. Derefter setter man det hele til is/ fortynnet saltsyre og avsuger det dannede bunnfall. For rensning foretas kromatografi på silikagel med toluen/etylacetat = 1:1 som elueringsmiddel. 1 g (2.4 mmol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzaldehyde and 1 g (10 mmol) of malonic acid in 10 ml of absolute pyridine are heated for 1 hour to 100°C after addition of 0.5 ml of piperidine. The whole thing is then put on ice/diluted hydrochloric acid and the precipitate formed is sucked off. For purification, chromatography is carried out on silica gel with toluene/ethyl acetate = 1:1 as eluent.

Utbytte: 21% av det teoretiske, Yield: 21% of the theoretical,

Smeltepunkt: 90°C. Melting point: 90°C.

Beregnet: C 68,63, H 6,87, N 6,16, Cl 7,79 Calculated: C 68.63, H 6.87, N 6.16, Cl 7.79

Funnet: 68,69 6,82 6,10 7,83. Found: 68.69 6.82 6.10 7.83.

Eksempel 239 Example 239

4-[ 2-( 5- klor- 2- piperidinobenzoylamino)- etyl]- benzoyle ddiksyre-etylester 4-[ 2-( 5- chloro- 2- piperidinobenzoylamino)- ethyl]- benzoyl acetic acid ethyl ester

Fremstilt ved Friedel-Crafts-acylering av [2-(5-klor-2-piperidino-benzoylamino)-etyl]benzen med malonsyreetylester-klorid analogt med eksempel 232 . Prepared by Friedel-Crafts acylation of [2-(5-chloro-2-piperidino-benzoylamino)-ethyl]benzene with malonic acid ethyl ester chloride analogously to example 232.

Utbytte: 21% av det teoretiske, Yield: 21% of the theoretical,

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

Beregnet: m/e 456/458 (1 Cl) Calculated: m/e 456/458 (1 Cl)

Funnet: m/e 456/458 (1 Cl) Found: m/e 456/458 (1 Cl)

E ksempel 240Example 240

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- nitrobenzen 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- nitrobenzene

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 4-(2-aminoetyl)-nitrobenzen analogt med eksempel 165. Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4-(2-aminoethyl)-nitrobenzene analogously to Example 165.

Utbytte: 85% av det teoretiske. Yield: 85% of the theoretical.

Smeltepunkt: 102°C. Melting point: 102°C.

Beregnet: C 64,25, H 6,56, N 9,77, Cl 8,24 Calculated: C 64.25, H 6.56, N 9.77, Cl 8.24

Funnet: 64,45 6,57 9,73 8,24. Found: 64.45 6.57 9.73 8.24.

Eksempel 2 41 Example 2 41

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- anilin 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- aniline

Fremstilt fra 4- [2-(5-klor-2-oktametylenimino-benzoylamino)-ety1]-nitrobenzen ved reduksjon med tinn(II)klorid i saltsyre. Utbytte: 74% av det teoretiske, Prepared from 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-nitrobenzene by reduction with stannous chloride in hydrochloric acid. Yield: 74% of the theoretical,

Smeltepunkt: 87°C. Melting point: 87°C.

Beregnet: C 69,07, H 7,56, W 10,50, Cl 8,86 Calculated: C 69.07, H 7.56, W 10.50, Cl 8.86

Funnet: 69,10 7,77 10,61 9,10. Found: 69.10 7.77 10.61 9.10.

Eksempel 242 Example 242

4-[ 2-( 5- klor- 2- oktametylenim ino-benzoylamino)-etyl]- to luen-hydrok lorid 4-[ 2-( 5- chloro- 2- octamethyleneimino-benzoylamino)-ethyl]- toluene hydrochloride

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-toluen analogt med eksempel 165. Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-toluene analogously to Example 165.

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

Smeltepunkt: 167-171°C. Melting point: 167-171°C.

Beregnet: C 66,20, H 7,41, N 6,44, Cl 16,29 Calculated: C 66.20, H 7.41, N 6.44, Cl 16.29

Funnet: 66,78 7,39 6,87 15,90 Found: 66.78 7.39 6.87 15.90

Eksempel 243 Example 243

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- klorbenzen 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- chlorobenzene

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-klorbenzen analogt med eksempel 165. Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-chlorobenzene analogously to Example 165.

Utbytte: 66% av det teoretiske, Yield: 66% of the theoretical,

Smeltepunkt: 58°C. Melting point: 58°C.

Beregnet: C 65,87, H 6,73, N 6,68 Calculated: C 65.87, H 6.73, N 6.68

Funnet: 65,99 6,55 6,51. Found: 65.99 6.55 6.51.

Eksempel 244 Example 244

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyrenitril 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid nitrile

4,36 g (0,01 mol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-anilin oppløses i 3,8 ml konsentrert saltsyre, fortynnes med 28 ml vann og diazoteres ved 0°C med en oppløsning av 0,76 g (0,011 mol) natriumnitritt i 3 ml vann ved dråpevis tilsetning. Efter 1/2 times påfølgende omrøring innstilles pH-verdien på 6 med natriumkarbonat. Denne diazoniumsalt-oppløsning settes dråpevis til en nytilberedt op<p>løsning av trinatrium-tetracyano-kobber(I)kompleks ved 0°C. 4.36 g (0.01 mol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-aniline is dissolved in 3.8 ml of concentrated hydrochloric acid, diluted with 28 ml of water and diazotized at 0° C with a solution of 0.76 g (0.011 mol) sodium nitrite in 3 ml of water by dropwise addition. After 1/2 hour of subsequent stirring, the pH value is adjusted to 6 with sodium carbonate. This diazonium salt solution is added dropwise to a freshly prepared solution of trisodium-tetracyano-copper(I) complex at 0°C.

[Denne kompleksoppløsning fremstilles fra 3,2 g (0,0128 mol) kobbersulfat x 5 H^O og 0,87 g natriumklorid oppløst i 10 ml vann. Efter reduksjon til kobber (I)klorid med en oppløsning av 0,66 g natriumhydrogensulfat og 0,44 g natriumhydroksyd i 5 ml vann settes det vaskede kobber(I)klorid til en oppløsning av 1,7 g natriumcyanid i 30 ml vann]. [This complex solution is prepared from 3.2 g (0.0128 mol) of copper sulfate x 5 H^O and 0.87 g of sodium chloride dissolved in 10 ml of water. After reduction to copper (I) chloride with a solution of 0.66 g of sodium hydrogen sulphate and 0.44 g of sodium hydroxide in 5 ml of water, the washed copper (I) chloride is added to a solution of 1.7 g of sodium cyanide in 30 ml of water].

Efter avsluttet nitrogenutvikling oppvarmes reaksjonsblandingen i 1 time til 70°C. Efter avkjøling foretas ekstraksjon med kloroform ved pH 8. Råproduktet som erholdes fra kloroformekstraktene renses over en silikagelkolonne (elueringsmiddel: toluen/etylacetat = 8:2). After completion of nitrogen evolution, the reaction mixture is heated to 70°C for 1 hour. After cooling, extraction is carried out with chloroform at pH 8. The crude product obtained from the chloroform extracts is purified over a silica gel column (eluent: toluene/ethyl acetate = 8:2).

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

Smeltepunkt: 102°C. Melting point: 102°C.

Beregnet: C 70,31, H 6,88, N 10,25, Cl 8,64 Calculated: C 70.31, H 6.88, N 10.25, Cl 8.64

Funnet: 70,50 6,59 10,45 8,92. Found: 70.50 6.59 10.45 8.92.

Eksempel 245 Example 245

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- orto-benzoesyre- etylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- ortho-benzoic acid ethyl ester

Ekvimolare mengder av 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyrenitril og absolutt etanol mettes med hydrogenklorid i eter. Reaksjonsblandingen får stå i 4 dager ved 4°C, hvorved iminoeteren som hydroklorid utskilles tildels i oljeaktig form og tildels krystallinsk. Efter av-dekantering av oppløsningsmidlet og eftervasking med eter tilsettes et overskudd av absolutt etanol ved 4°C, og reaksjonsblandingen får stå i 2 dager ved denne temperatur. Efter avdestillering av oppløsningsmidlet renses råproduktet kromatografisk over en silikagelkolonne med toluen som elueringsmiddel. Utbytte: 30% av det teoretiske, Equimolar amounts of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid nitrile and absolute ethanol are saturated with hydrogen chloride in ether. The reaction mixture is allowed to stand for 4 days at 4°C, whereby the imino ether is separated as hydrochloride partly in oily form and partly crystalline. After decanting off the solvent and washing with ether, an excess of absolute ethanol is added at 4°C, and the reaction mixture is allowed to stand for 2 days at this temperature. After distilling off the solvent, the crude product is purified chromatographically over a silica gel column with toluene as eluent. Yield: 30% of the theoretical,

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

Beregnet: C 67,84, H 8,16, N 5,27, Cl 6,67 Calculated: C 67.84, H 8.16, N 5.27, Cl 6.67

Funnet: 67,60 8,05 5,14 6,43. Found: 67.60 8.05 5.14 6.43.

Eksempel 246 Example 246

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-morfolid 2 g (4,7 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-ety1]-benzoesyre oppløses i 20 ml absolutt pyridin og overføres ved romtemperatur kvantitativt til imidazolidet ved tilsetning av 0,83 g (5,1 mmol)karbonyldiimidazol. Efter tilsetning av 0,41 g morfolin oppvarmes i 6 timer til tilbakeløps-temperatur. Derefter avdestilleres pyridinet, og inndampningsresiduet renses kromatografisk over en silikagelkolonne med toluen/eddiksyreetylester =6:4 som elueringsmiddel. 4-[ 2-( 5- chloro- 2- octamethyleneimino-benzoylamino)- ethyl]- benzoic acid morpholide 2 g (4.7 mmol) 4-[2-(5-chloro-2- octamethyleneimino-benzoylamino)-ethyl] -benzoic acid is dissolved in 20 ml of absolute pyridine and transferred at room temperature quantitatively to the imidazolide by adding 0.83 g (5.1 mmol) of carbonyldiimidazole. After the addition of 0.41 g of morpholine, it is heated for 6 hours to the reflux temperature. The pyridine is then distilled off, and the evaporation residue is purified chromatographically over a silica gel column with toluene/acetic acid ethyl ester = 6:4 as eluent.

Utbytte: 1,8 g (76,5% av det teoretiske). Yield: 1.8 g (76.5% of the theoretical).

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

Beregnet: C 67,52, H 7,29, N 8,44 Calculated: C 67.52, H 7.29, N 8.44

Funnet: 67,01 7,35 8,17. Found: 67.01 7.35 8.17.

Eksempel 247 Example 247

4-[ 2-( 5- klor- 2- ok tamet ylenimino- benz oylamino)- ety1]- benzoesyre-p iperidid 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- eth1]- benzoic acid piperidide

2 g (4,7 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoy1-amino)-ety1]-benzoesyre suspenderes i 30 ml absolutt toluen og overføres til saltet med 0,65 ml trietylamin. Efter av-kjøling til -10°C tilsettes 0,5 g (4,7 mmol) klormaursyre-etylester, og det hele omrøres videre i 30 minutter. Til det blandede anhydrid settes 0,4 g (4,7 mmol) piperidin. Efter 2 timer avdestilleres oppløsningsmidlet, og råproduktet renses kromatografisk over en silikagelkolonne med eddiksyreetylester som elueringsmiddel. 2 g (4.7 mmol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoyl-amino)-ethyl]-benzoic acid is suspended in 30 ml of absolute toluene and transferred to the salt with 0.65 ml of triethylamine. After cooling to -10°C, 0.5 g (4.7 mmol) chloroformic acid ethyl ester is added, and the whole is stirred further for 30 minutes. 0.4 g (4.7 mmol) of piperidine is added to the mixed anhydride. After 2 hours, the solvent is distilled off, and the crude product is purified chromatographically over a silica gel column with ethyl acetate as eluent.

Utbytte: 2 g (86% av det teoretiske). Yield: 2 g (86% of the theoretical).

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

Beregnet: C 70,21, H 7,72, N 8,47 Calculated: C 70.21, H 7.72, N 8.47

Funnet: 70,42 7,83 8,51 Found: 70.42 7.83 8.51

Analogt med eksemplene 246 og 247 fremstilles de følgende forbindelser: 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-amid, Analogous to examples 246 and 247, the following compounds are prepared: 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid amide,

Utbytte: 75% av det teoretiske, smeltepunkt: 122°C. Yield: 75% of the theoretical, melting point: 122°C.

Beregnet: C 67,35, H 7,07, N 9,82 Calculated: C 67.35, H 7.07, N 9.82

Funnet: 67,95 7,48 9,78. Found: 67.95 7.48 9.78.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-dipropy1amid, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid dipropylamide,

Utbytte: 75% av det teoretiske, smeltepunkt: < 20°C. Yield: 75% of the theoretical, melting point: < 20°C.

Beregnet: C 70,35, H 8,27, N 8,21 Calculated: C 70.35, H 8.27, N 8.21

Funnet: 69,95 8,04 7,94. Found: 69.95 8.04 7.94.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-diallylamid, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid diallylamide,

Utbytte: 70% av det teoretiske, smeltepunkt: < 20°C. Yield: 70% of the theoretical, melting point: < 20°C.

Beregnet: C 70,90, H 7,54, N 8,27 Calculated: C 70.90, H 7.54, N 8.27

Funnet: 70,23 7,30 7,98. Found: 70.23 7.30 7.98.

4-[2- (5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-tiomorfolid, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid thiomorpholide,

Utbytte: 70% av det teoretiske, smeltepunkt: < 20°C. Yield: 70% of the theoretical, melting point: < 20°C.

Beregnet: C 65,41, H 7,06, N 8,17 Calculated: C 65.41, H 7.06, N 8.17

Funnet: 65,54 7,14 7,93. Found: 65.54 7.14 7.93.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-N-metyl-piperazid, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid-N-methyl-piperazide,

Utbytte: 75% av det teoretiske, smeltepunkt: < 20°C. Yield: 75% of the theoretical, melting point: < 20°C.

Beregnet: C 68,15, H 7,69, N 10,96 Calculated: C 68.15, H 7.69, N 10.96

Funnet: 68,23 7,73 11,08 Found: 68.23 7.73 11.08

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-N-etyl-N-cykloheksylamin, 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid-N-ethyl-N-cyclohexylamine,

Utbytte: 58% av det teoretiske, smeltepunkt: < 20°C, Yield: 58% of the theoretical, melting point: < 20°C,

Beregnet: C 71,42, H 8,24, N 7,81 Calculated: C 71.42, H 8.24, N 7.81

Funnet: 71,60 8,30 7,57. Found: 71.60 8.30 7.57.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre- is opropyl amid , 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid isopropyl amide,

Utbytte: 54% av det teoretiske, smeltepunkt: 171°C. Yield: 54% of the theoretical, melting point: 171°C.

Beregnet: C 68,99, H 7,72, N 8,94 Calculated: C 68.99, H 7.72, N 8.94

Funnet: 69,34 7,52 8,74. Found: 69.34 7.52 8.74.

4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-butylamid 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid-butylamide

Utbytte: 53% av det teoretiske, smeltepunkt: 163°C Yield: 53% of the theoretical, melting point: 163°C

Beregnet: C 69,47, H 7,91, N 8,68 Calculated: C 69.47, H 7.91, N 8.68

Funnet: 69,53 7,95 8,72. Found: 69.53 7.95 8.72.

Eksempel 248 Example 248

N 1 -( 1-( 4- etoksykarbonyl- fenyl)- etyl)- N 2- ( 5- klor- 2- piperidino-benzoyl)- hydrazin N 1 -( 1-( 4- ethoxycarbonyl- phenyl)- ethyl)- N 2- ( 5- chloro- 2- piperidino-benzoyl)- hydrazine

Til 2,4 g (10 mmol) 5-klor-2-piperidino-benzoesyre i To 2.4 g (10 mmol) of 5-chloro-2-piperidino-benzoic acid i

15 ml vannfri tetrahydrofuran setter man 1,62 g (10 mmol) N,N-karbonyldiimidazol, og omrører i 5 minutter ved 20°C og 45 minutter under tilbakeløpskjøling. Til den avkjølte oppløsning setter man ved 20°C en oppløsning av 2,08 g ((10 mmol) 4-(1-hydrazin-etyl)-benzoesyre-etylester [friskt fremstilt fra den tilsvarende mengde 4- (1-hydrazino-etyl)-benzoesyre-etylester-hydroklorid med smeltepunkt 98-100°C ved tilsetning av den støkiometriske mengde vandig natronlut under isavkjøling, ekstraksjon med kloroform og inndampning av den tørrede kloroformekstrakt ved 30°C i vakuum] i 9 ml vannfri tetrahydrofuran. 1.62 g (10 mmol) of N,N-carbonyldiimidazole is added to 15 ml of anhydrous tetrahydrofuran, and stirred for 5 minutes at 20°C and 45 minutes under reflux. To the cooled solution is added at 20°C a solution of 2.08 g ((10 mmol) 4-(1-hydrazine-ethyl)-benzoic acid ethyl ester [freshly prepared from the corresponding amount of 4-(1-hydrazino-ethyl )-benzoic acid ethyl ester hydrochloride with a melting point of 98-100°C by adding the stoichiometric amount of aqueous caustic soda under ice-cooling, extraction with chloroform and evaporation of the dried chloroform extract at 30°C in vacuum] in 9 ml of anhydrous tetrahydrofuran.

Efter omrøring natten over ved romtemperatur inndamper man i vakuum og fordeler residuet mellom vann oq kloroform. De samlede kloroformekstrakter tørrer og filtrerer man og inndamper dem i vakuum. Det rødbrune, oljeaktige inndampningsresiduum renser man ved kolonnekromatografi på silikagel (toluen/aceton = 8/1). Utbytte: 41,9% av det teoretiske. After stirring overnight at room temperature, it is evaporated in a vacuum and the residue is distributed between water and chloroform. The combined chloroform extracts are dried and filtered and evaporated in vacuo. The reddish-brown, oily evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 8/1). Yield: 41.9% of the theoretical.

Smeltepunkt: < 20°C (lysegul olje). Melting point: < 20°C (light yellow oil).

Beregnet: Moltopp m/e = 429/431 (1 Cl) Calculated: Mole peak m/e = 429/431 (1 Cl)

Funnet: Moltopp m/e = 429/431 (1 Cl) Found: Mole peak m/e = 429/431 (1 Cl)

Eksempel 249 Example 249

N 1 -( 1-( 4- etoksykarbonyl- fenyl)- etyl)- N 2- ( 5- klor- 2- dimetylamino- benzoyl)- hydrazin N 1 -( 1-( 4- ethoxycarbonyl- phenyl)- ethyl)- N 2- ( 5- chloro- 2- dimethylamino- benzoyl)- hydrazine

Fremstilt fra 5-klor-2-dimetylamino-benzoesyre, karbonyldiimidazol og 4-(1-hydrazino-etyl)-benzoesyre-etylester i vannfri tetrahydrofuran analogt med eksempel 248. Prepared from 5-chloro-2-dimethylamino-benzoic acid, carbonyldiimidazole and 4-(1-hydrazino-ethyl)-benzoic acid ethyl ester in anhydrous tetrahydrofuran analogously to example 248.

Utbytte: 18% av det teoretiske, Yield: 18% of the theoretical,

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

Beregnet: Moltopp m/e = 389/391 (1 Cl) Calculated: Mole peak m/e = 389/391 (1 Cl)

Funnet: Moltopp m/e = 389/391 (1 Cl). Found: Mole peak m/e = 389/391 (1 Cl).

E ksempel 250 Example 250

N 1 - ( 1- ( 4- karboksyfenyl)- etyl)- N 2- ( 5- klor- 2- piperidino- benzoyl)-hydrazin N 1 - ( 1- ( 4- carboxyphenyl)- ethyl)- N 2- ( 5- chloro- 2- piperidino- benzoyl)- hydrazine

Man omrører 1,8 g (4,2 mmol) N"<*>"-(1-(4-etoksykarbonyl-fenyl)-etyl)-N 2-(5-klor-2-piperidino-benzoyl)-hydrazin og 0,20 g (5 mmol) natriumhydroksyd i 8 ml etanol og 8 ml vann i 5 timer ved 60°C. Efter avdampning av etanolen i vakuum innstilles pH-verdien på 6 med 2N saltsyre, og ekstraksjon foretas flere ganger med etylacetat. De samlede ekstrakter vasker man med vann, tørrer dem over natriumsulfat, filtrerer dem og inndamper i vakuum. Det faste inndampningsresiduum omkrystalliseres fra metanol. 1.8 g (4.2 mmol) of N"<*>"-(1-(4-ethoxycarbonyl-phenyl)-ethyl)-N 2-(5-chloro-2-piperidino-benzoyl)-hydrazine are stirred and 0.20 g (5 mmol) of sodium hydroxide in 8 ml of ethanol and 8 ml of water for 5 hours at 60°C. After evaporation of the ethanol in a vacuum, the pH value is adjusted to 6 with 2N hydrochloric acid, and extraction is carried out several times with ethyl acetate. The combined extracts are washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. The solid evaporation residue is recrystallized from methanol.

Utbytte: 45,8% av det teoretiske, Yield: 45.8% of the theoretical,

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

Beregnet: C 62,76, H 6,02, N 10,45 Calculated: C 62.76, H 6.02, N 10.45

Funnet: 62,90 6,07 10,44. Found: 62.90 6.07 10.44.

Eksempel 251 Example 251

N 1 -( 1-( 4- karboksyfenyl)- etyl)- N 2-( 5- klor- 2- dimetylamino- benzoyl )- hydrazin N 1 -( 1-( 4- carboxyphenyl)- ethyl)- N 2-( 5- chloro- 2- dimethylamino- benzoyl )- hydrazine

Fremstilt fra N 1 - (1-(4-etoksykarbonyl-fenyl)-etyl)-N 2-(5-klor-2-dimetylamino-benzoyl)-hydrazin ved forsepning med natriumhydroksyd analogt med eksempel 250. Prepared from N 1 - (1-(4-ethoxycarbonyl-phenyl)-ethyl)-N 2-(5-chloro-2-dimethylamino-benzoyl)-hydrazine by saponification with sodium hydroxide analogously to example 250.

Utbytte: 34,4% av det teoretiske, Yield: 34.4% of the theoretical,

Smeltepunkt: 210-212°C. Melting point: 210-212°C.

Beregnet: C 59,75, H 5,57, H 11,61 Calculated: C 59.75, H 5.57, H 11.61

Funnet: 59,32 5,60 11,41. Found: 59.32 5.60 11.41.

Eksempel 252 Example 252

4-[ 1-( 5- klor- 2- oktametylenimino- benzoylaminoksy)- etyl]- benzoesyre- metylester 4-[ 1-( 5- chloro- 2- octamethyleneimino- benzoylaminooxy)- ethyl]- benzoic acid methyl ester

Man omrører 2 g (7,1 mmol) 5-klor-2-oktametylenimino-benzoesyre og 1,2 g (7,4 mmol) karbonyldiimidazol i 10 ml vannfritt pyridin i 40 minutter ved 20°C. Derefter tilsetter man 1,4 g (7,2 mmol) 4-(1-aminoksy-etyl)-benzoesyre-metylester [friskt fremstilt analogt med eksempel 252 fra 4-(1-aminoksy-etyl) -benzoesyre-metylester-hydroklorid med smeltepunkt 158-160°C] og omrører natten over ved 100°C. Man inndamper til tørrhet i vakuum og renser inndampningsresiduet ved kolonne-kromatograf i på silikagel (toluen/etylacetat = 9:1). 2 g (7.1 mmol) of 5-chloro-2-octamethyleneimino-benzoic acid and 1.2 g (7.4 mmol) of carbonyldiimidazole in 10 ml of anhydrous pyridine are stirred for 40 minutes at 20°C. 1.4 g (7.2 mmol) of 4-(1-aminooxy-ethyl)-benzoic acid methyl ester [freshly prepared analogously to example 252 from 4-(1-aminooxy-ethyl)-benzoic acid methyl ester hydrochloride with melting point 158-160°C] and stirring overnight at 100°C. Evaporate to dryness in vacuo and purify the evaporation residue by column chromatography on silica gel (toluene/ethyl acetate = 9:1).

Utbytte: 41% av det teoretiske, Yield: 41% of the theoretical,

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

Eksempel 253 Example 253

3-( 5- klor- 2- oktametylenimino- benzoylaminoksy- metyl)- benzoesyre-metylester 3-( 5- chloro- 2- octamethyleneimino- benzoylaminooxy- methyl)- benzoic acid methyl ester

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre, karbony1-diimidazol og 4-(aminoksymetyl)-benzoesyre-metylester Prepared from 5-chloro-2-octamethyleneimino-benzoic acid, carbonyl-diimidazole and 4-(aminooxymethyl)-benzoic acid methyl ester

[friskt fremstilt fra hydrokloridet med smeltepunkt 252-255°C] [freshly prepared from the hydrochloride with melting point 252-255°C]

i vannfritt pyridin analogt med eksempel 252. in anhydrous pyridine analogously to example 252.

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

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

Beregnet: Moltopp m/e = 444/446 (1 Cl) Calculated: Mole peak m/e = 444/446 (1 Cl)

Funnet: Moltopp m/e = 444/446 (1 Cl). Found: Mole peak m/e = 444/446 (1 Cl).

E ksempel 2 54 Example 2 54

3- [ 1- ( 5- klor- 2- dimetylamino-b enzoylaminoksy)- etyl3- benzoesyre-metylester 3- [ 1- ( 5- chloro- 2- dimethylamino-benzoylaminooxy)- ethyl 3- benzoic acid methyl ester

Fremstilt fra 5-klor-2-dimetylamino-benzoesyre, karbonyldiimidazol og 4-(1-aminoksy-etyl)-benzoesyre-metylester analogt med eksempel 252 , men i vannfritt tetrahydrofuran ved 20°C og 16 timers reaksjonstid. Prepared from 5-chloro-2-dimethylamino-benzoic acid, carbonyldiimidazole and 4-(1-aminooxy-ethyl)-benzoic acid methyl ester analogously to example 252, but in anhydrous tetrahydrofuran at 20°C and 16 hours reaction time.

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

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

Eksempel 255 Example 255

4- [ 1-( 5- klor- 2-( cis- 3, 5- dimetyl- piperidino)- benzoylaminoksy)-e tyl]- benzoesyre- metylester 4- [ 1-( 5- chloro- 2-( cis- 3, 5- dimethyl-piperidino)- benzoylaminooxy)-ethyl]- benzoic acid methyl ester

Fremstilt fra 5-klor-2-(cis-3,5-dimetyl-piperidino)-benzoesyre, karbonyldiimidazol og 4-(1-aminoksy-etyl)-benzoesyre-metylester analogt med eksempel 252. Prepared from 5-chloro-2-(cis-3,5-dimethyl-piperidino)-benzoic acid, carbonyldiimidazole and 4-(1-aminooxy-ethyl)-benzoic acid methyl ester analogously to Example 252.

Utbytte: 85% av det teoretiske, Yield: 85% of the theoretical,

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

Eksempel 256 Example 256

4- [ 1- ( 5- klor- 2- piperidino- benzoylaminoksy)- etyl]- benzoesyre-metylester 4- [ 1- ( 5- chloro- 2- piperidino- benzoylaminooxy)- ethyl]- benzoic acid methyl ester

Man omrører 7,55 g (25,8 mmol) 5-klor-2-piperidino-benzhydroksamsyre-kaliumsalt (smeltepunkt: 153°C (spaltn.)) og 6,30 g 4-(1-brometyl)-benzoesyre-metylester i 20 ml dimetylformamid i 18 timer ved 20°C, tilsetter derefter den tre-dobbelte mengde vann og ekstraherer med eter. Den tørrede og filtrerte eterekstrakt inndamper man i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (cykloheksan/etylacetat = 1/1). 7.55 g (25.8 mmol) of 5-chloro-2-piperidino-benzhydroxamic acid potassium salt (melting point: 153°C (dec.)) and 6.30 g of 4-(1-bromomethyl)-benzoic acid methyl ester are stirred in 20 ml of dimethylformamide for 18 hours at 20°C, then add three times the amount of water and extract with ether. The dried and filtered ether extract is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate = 1/1).

Utbytte: 69,2% av det teoretiske, Yield: 69.2% of the theoretical,

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

Beregnet: C 63,37, H 6,04, Cl 8,50, N 6,72 Calculated: C 63.37, H 6.04, Cl 8.50, N 6.72

Funnet: 63,54 6,17 8,49 6,63. Found: 63.54 6.17 8.49 6.63.

Eksempel 257 Example 257

4- ( 5- klor- 2- dimetylamino- benzoylaminoksy- metyl)- benzoesyre 4- ( 5- chloro- 2- dimethylamino- benzoylaminooxy- methyl)- benzoic acid

Til 4,8 g (19 mmol) 5-klor-2-dimetylamino-benzhydroksam-syre-kaliumsalt (smeltepunkt: 140°C (spaltn.) og 1,06 g To 4.8 g (19 mmol) 5-chloro-2-dimethylamino-benzhydroxamic acid potassium salt (melting point: 140°C (dec.) and 1.06 g

(19 mmol) kaliumhydroksyd i 50 ml etanol/vann (1/1) setter man 4,2 g (19 mmol) 4-brommetyl-benzoesyre og oppvarmer i 6 timer under tilbakeløpskjøling. Man inndamper i vakuum og oppløser inndampningsresiduet i vann under tilsetning av kalilut. Efter ekstraksjon med etylacetat innstiller man den vandige fase på pH 7 og ekstraherer påny med etylacetat. Denne etylacetat-ekstrakt tørrer og filtrerer man og inndamper den i vakuum. Inndampningsresiduet renser man ved to gangers kolonnekromatografi på silikagel (kloroform/metanol = 9/1 og 4/1). De enhetlige fraksjoner samler man, inndamper dem og fordeler inndampningsresiduet mellom vann og etylacetat. Fra etylacetat-ekstrakten får man ved inndampning i vakuum en fast, farveløs olje som krystalliseres ved utgnidning med eter. Utbytte: 1,5% av det teoretiske. (19 mmol) of potassium hydroxide in 50 ml of ethanol/water (1/1), 4.2 g (19 mmol) of 4-bromomethyl-benzoic acid are added and heated for 6 hours under reflux. Evaporate in a vacuum and dissolve the evaporation residue in water while adding potash. After extraction with ethyl acetate, the aqueous phase is adjusted to pH 7 and extracted again with ethyl acetate. This ethyl acetate extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography twice on silica gel (chloroform/methanol = 9/1 and 4/1). The uniform fractions are collected, evaporated and the evaporation residue distributed between water and ethyl acetate. From the ethyl acetate extract, a solid, colorless oil is obtained by evaporation in a vacuum, which is crystallized by trituration with ether. Yield: 1.5% of the theoretical.

Smeltepunkt: 160-161°C. Melting point: 160-161°C.

Beregnet: C 58,53, H 4,91, N 8,03. Calculated: C 58.53, H 4.91, N 8.03.

Funnet: 5 8,49, 5,IO 7,88. Found: 5 8.49, 5.IO 7.88.

Eksempel 258 Example 258

4-[ 1-( 5- klor- 2- piperidino- benzoylaminoksy)- etyl]- benzoesyre 4-[ 1-( 5- Chloro- 2- Piperidino- Benzoylaminooxy)- Ethyl]- Benzoic Acid

Man oppvarmer en oppløsning av 6,0 g (14,4 mmol) 4- [1- (5-klor-2-piperidino-benzoylaminoksy)-etyl]-benzoesyre-metylester og 1,15 g (28,8 mmol) natriumhydroksyd i 100 ml etanol i 6 timer ved 50-60°C. Efter inndampning i vakuum fordeler man residuet mellom fortynnet saltsyre og kloroform. Den tørrede og filtrerte kloroformekstrakt inndamper man i vakuum og omkrystalliserer inndampningsresiduet fra en kloroform/ metanol-blanding under tilsetning av petroleter. A solution of 6.0 g (14.4 mmol) of 4-[1-(5-chloro-2-piperidino-benzoylaminooxy)-ethyl]-benzoic acid methyl ester and 1.15 g (28.8 mmol) of sodium hydroxide is heated in 100 ml of ethanol for 6 hours at 50-60°C. After evaporation in a vacuum, the residue is divided between dilute hydrochloric acid and chloroform. The dried and filtered chloroform extract is evaporated in a vacuum and the evaporation residue is recrystallized from a chloroform/methanol mixture while adding petroleum ether.

Utbytte: 44,8% av det teoretiske. Yield: 44.8% of the theoretical.

Smeltepunkt: 201-203°C. Melting point: 201-203°C.

Beregnet: C 62,61, H 5,76, Cl 8,80, N 6,96 Calculated: C 62.61, H 5.76, Cl 8.80, N 6.96

Funnet: 62,68 5,67 8,76 6,96. Found: 62.68 5.67 8.76 6.96.

Eksempel 259 Example 259

4-[ 1-( 5- klor- 2- dimetylamino- benzoylaminoksy)- etyl]- benzoesyre 4-[ 1-( 5- chloro- 2- dimethylamino- benzoylaminooxy)- ethyl]- benzoic acid

Fremstilt fra 4-[1-(5-klor-2-dimetylamino-benzoylaminoksy)-etyl]-benzoesyre-metylester ved forsepning med natriumhydroksyd i etanol/vann analogt med eksempel 248, bortsett fra at det ble ekstrahert med etylacetat og omkrystallisert fra etanol. Prepared from 4-[1-(5-chloro-2-dimethylamino-benzoylaminooxy)-ethyl]-benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water analogously to Example 248, except that it was extracted with ethyl acetate and recrystallized from ethanol .

Utbytte: 65,7% av det teoretiske, Yield: 65.7% of the theoretical,

Smeltepunkt: 202-205°C. Melting point: 202-205°C.

Beregnet: C 59,58, H 5,28, Cl 9,77, N 7,72. Calculated: C 59.58, H 5.28, Cl 9.77, N 7.72.

Funnet: 59,70 5,34 10,00 7,90. Found: 59.70 5.34 10.00 7.90.

Eksempel 260 Example 260

4-[ 1- ( 5- klor- 2-( cis- 3, 5- dimetyl- piperidino)- benzoylaminoksy)-etyl]- benzoesyre 4-[1-(5-chloro-2-(cis-3,5-dimethyl-piperidino)-benzoylaminooxy)-ethyl]-benzoic acid

Fremstilt fra 4-[1-(5-klor-2-(cis-3,5-dimetyl-piperidino)-benzoylaminoksy)-etyl]-benzoesyre-metylester ved forsepning med natriumhydroksyd i etanol/vann analogt med eksempel 248. Utbytte: 63,8% av det teoretiske, Prepared from 4-[1-(5-chloro-2-(cis-3,5-dimethyl-piperidino)-benzoylaminooxy)-ethyl]-benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water analogously to example 248. Yield: 63.8% of the theoretical,

Smeltepunkt: 205-208°C. Melting point: 205-208°C.

Beregnet: C 64,10, H 6,32, Cl 8,23, N 6,50 Calculated: C 64.10, H 6.32, Cl 8.23, N 6.50

Funnet: 64,40 6,66 8,44 6,50. Found: 64.40 6.66 8.44 6.50.

Eksempel 261 Example 261

4- ( 5- klor- 2- oktametylenimino- benzoylaminoksy- metyl)- benzoesyre 4-( 5- chloro- 2- octamethyleneimino- benzoylaminooxy- methyl)- benzoic acid

Fremstilt fra 4-(5-klor-2-oktametylenimino-benzoylaminoksy-metyl)-benzoesyre-metylester ved forsepning med natriumhydroksyd ietanol/vann analogt med eksempel 248. Utbytte: 43,1% av det teoretiske, Prepared from 4-(5-chloro-2-octamethyleneimino-benzoylaminooxy-methyl)-benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water analogously to example 248. Yield: 43.1% of the theoretical,

Smeltepunkt: 135-138°C (fra eter). Melting point: 135-138°C (from ether).

Beregnet: C 64,10, H 6,32, Cl 8,23, N 6,50. Calculated: C 64.10, H 6.32, Cl 8.23, N 6.50.

Funnet: 64,29 6,29 8,33 6,73. Found: 64.29 6.29 8.33 6.73.

Eksempel 262 Example 262

4- [ 1- ( 5- klor- 2- oktametylenimino- benzoylaminoksy)- etyl]- benzoesyre 4- [ 1- ( 5- chloro- 2- octamethyleneimino- benzoylaminooxy)- ethyl]- benzoic acid

Fremstilt fra 4-[1-(5-klor-2-oktametylenimino-benzoylaminoksy)-etyl]-benzoesyre-metylester ved forsepning med natriumhydroksyd i etanol/vann analogt med eksempel 248 . Utbytte: 69% av det teoretiske, Prepared from 4-[1-(5-chloro-2-octamethyleneimino-benzoylaminooxy)-ethyl]-benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water analogously to example 248. Yield: 69% of the theoretical,

Smeltepunkt: 187-190°C. Melting point: 187-190°C.

Beregnet: C 64,78, H 6,57, Cl 7,97, N 6,30 Calculated: C 64.78, H 6.57, Cl 7.97, N 6.30

Funnet: 64,60 6,58 7,88 6,16. Found: 64.60 6.58 7.88 6.16.

Eksempel 263 Example 263

3-[ 4-[ 2-( 5- klor- 2- piperidino- benzoylami no)- etyl]- fenyl]-propionsyre- etylester 3-[ 4-[ 2-( 5- Chloro- 2- Piperidino- Benzoylamino)- Ethyl]- Phenyl]- Propionic Acid Ethyl Ester

1,2 g (5 mmol) 5-klor-2-piperidino-benzoesyre, 1,5 g 1.2 g (5 mmol) 5-chloro-2-piperidino-benzoic acid, 1.5 g

(5,8 mmol) 3-[4-(2-amino-etyl)-fenyl]-propionsyre-etylester-hydroklorid og 1,84 g (7 mmol) trifenylfosfin innføres i 30 ml absolutt acetonitril, og til denne blanding settes derefter i rekkefølge 0,5 ml (5 mmol) karbontetraklorid og 2,45 ml (17,5 mmol) trietylamin. Efter at man har omrørt i 20 timer ved romtemperatur frafiltreres bunnfallet, og filtratet inndampes. Inndampningsresiduet renses kolonnekromatografisk på silikagel i toluen/etylacetat = 5:1. (5.8 mmol) of 3-[4-(2-amino-ethyl)-phenyl]-propionic acid ethyl ester hydrochloride and 1.84 g (7 mmol) of triphenylphosphine are introduced into 30 ml of absolute acetonitrile, and to this mixture is then added in sequence 0.5 ml (5 mmol) of carbon tetrachloride and 2.45 ml (17.5 mmol) of triethylamine. After stirring for 20 hours at room temperature, the precipitate is filtered off and the filtrate is evaporated. The evaporation residue is purified by column chromatography on silica gel in toluene/ethyl acetate = 5:1.

Utbytte: 1,2 g (54,5% av det teoretiske) Yield: 1.2 g (54.5% of the theoretical)

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

Beregnet: C 67,78, H 7,05, N 6,32, Cl 8,00 Calculated: C 67.78, H 7.05, N 6.32, Cl 8.00

Funnet: 67,33 6,91 6,18 8,09. Found: 67.33 6.91 6.18 8.09.

Eksempel 264 Example 264

3-[ 4-[ 2-( 5- kIor- 2- piperidino- benzoylamino)- etyl]- fenyl]-propionsyre 3-[ 4-[ 2-( 5-chloro- 2-piperidino-benzoylamino)-ethyl]- phenyl]-propionic acid

Fremstilt ved alkalisk forsepning av 3-[4-[2-(5-klor-2-piperidino-benzoylamino)-etyl]-fenyl]-propionsyre-etylester analogt med eksempel 166. Prepared by alkaline saponification of 3-[4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-phenyl]-propionic acid ethyl ester analogously to example 166.

Utbytte: 80% av det teoretiske, Yield: 80% of the theoretical,

Smeltepunkt: 139°C. Melting point: 139°C.

Beregnet: C 66,57, H 6,56, N 6,75, Cl 8,54. Calculated: C 66.57, H 6.56, N 6.75, Cl 8.54.

Funnet: 66,51 6,62 6,60 8,40. Found: 66.51 6.62 6.60 8.40.

Eksempel 265 Example 265

3-[ 4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- fenyl]-pro pionsyre- etylester 3-[ 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- phenyl]- propionic acid ethyl ester

Fremstilt fra 5-klor-2-oktametylenimino-benzoesyre og 3-[4-(2-amino-etyl)-fenyl]-propionsyre-etylester-hydroklorid analogt med eksempel 263• Prepared from 5-chloro-2-octamethyleneimino-benzoic acid and 3-[4-(2-amino-ethyl)-phenyl]-propionic acid ethyl ester hydrochloride analogously to example 263•

Utbytte: 76% av det teoretiske, Yield: 76% of the theoretical,

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

Beregnet: C 69,33, H 7,69, N 5,78, Cl 7,31 Calculated: C 69.33, H 7.69, N 5.78, Cl 7.31

Funnet: 69,22 7,59 5,66 7,26. Found: 69.22 7.59 5.66 7.26.

Eksempel 266 Example 266

3- [ 4-([ 2-( 5- klor- 2- oktamet ylenimino- benzoylamino)- etyl]- fenyl]-propionsyre 3- [ 4-([ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- phenyl]- propionic acid

Fremstilt fra 3-[4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-fenyl]-propionsyre-etylester ved alkalisk forsepning analogt med eksempel 166. Prepared from 3-[4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-phenyl]-propionic acid ethyl ester by alkaline saponification analogously to example 166.

Utbytte: 79% av det teoretiske, Yield: 79% of the theoretical,

Smeltepunkt: 92-94°C. Melting point: 92-94°C.

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

Funnet: 68,54 7,38 6,28 7,81. Found: 68.54 7.38 6.28 7.81.

Eksempel 2 67 Example 2 67

4- [ 2- ( 2- piperidino- 5- propyl- benzoylamino)- etyl]- benzoesyre-etylester 4- [ 2- ( 2- piperidino- 5- propyl- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 1-(5-brom-pentyl)-6-propyl-4H-3,1-benz-oksazin-2,4-(1H)-dion og 4-(2-amino-etyl)-benzoeysre-etylester analogt med eksempel 213. Prepared from 1-(5-bromo-pentyl)-6-propyl-4H-3,1-benz-oxazine-2,4-(1H)-dione and 4-(2-amino-ethyl)-benzoyl-re-ethyl ester analogously with example 213.

Utbytte: 41% av det teoretiske, Yield: 41% of the theoretical,

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

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

Funnet: 73,45 7,92 6,42. Found: 73.45 7.92 6.42.

Eksempel 268 Example 268

4-[ 2-( 5- butyl- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- butyl- 2- piperidino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 6-butyl-l-(5-brom-pentyl)-4H-3,1-benzoksazin-2,4-(1H)-dion og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 213. Prepared from 6-butyl-1-(5-bromo-pentyl)-4H-3,1-benzoxazine-2,4-(1H)-dione and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 213.

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

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

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

Funnet: 73,90 8,05 6,13. Found: 73.90 8.05 6.13.

Eksempel 269 Example 269

4-[ 2- ( 4- klor- 5- nitro- 2- piperidino- benzoylamino)- ety1]- benzoe-s yre- etylester 4-[2-(4-Chloro-5-nitro-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester

Fremstilt fra 4-klor-5-nitro-2-piperidino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 20% av det teoretiske. Prepared from 4-chloro-5-nitro-2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 20% of the theoretical.

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

Beregnet: C 60,06, H 5,70, N 9,13, Cl 7,70 Calculated: C 60.06, H 5.70, N 9.13, Cl 7.70

Funnet: 60,20 5,78 9,25 7,85. Found: 60.20 5.78 9.25 7.85.

E ksempel 270 Example 270

4- [ 2- ( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4- [ 2- ( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

En blanding av 0,45 g (1 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzaldehyd-hydroklorid, 5 ml 0,5N natronlut og 0,30 g (1,3 mmol) sølvoksyd oppvarmer man under kraftig omrøring i 45 minutter på dampbad. Efter avkjøling surgjør man med 2N svovelsyre og ekstraherer med eter. Den organiske fase tørrer og filtrerer man, og den inndampes i vakuum. Inndampningsresiduet renser man ved kolonnekromatografi på silikagel (kloroform/metanol = 10/1). A mixture of 0.45 g (1 mmol) 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzaldehyde hydrochloride, 5 ml of 0.5N caustic soda and 0.30 g (1.3 mmol) of silver oxide is heated with vigorous stirring for 45 minutes on a steam bath. After cooling, acidify with 2N sulfuric acid and extract with ether. The organic phase is dried and filtered, and it is evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1).

Utbytte: 34% av det teoretiske, Yield: 34% of the theoretical,

Smeltepunkt: 172°C. Melting point: 172°C.

E ksempel 271 Example 271

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-natriumsalt 5 g (11,7 mmol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre oppløses i 20 ml absolutt tetrahydrofuran, og til oppløsningen settes en natriumetylatoppløsning, fremstilt fra 0,27 g (11,7 mmol) natrium og 10 ml etanol, hvorved natriumsaltet utfelles. Efter tilsetning av 80 ml eter omrøres videre i 1 time, avsugning foretas, og produktet tørres ved 80°C i et tørreskap med luftsirkulasjon. 4-[ 2-( 5-chloro-2- octamethyleneimino-benzoylamino)-ethyl]-benzoic acid sodium salt 5 g (11.7 mmol) 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl] -benzoic acid is dissolved in 20 ml absolute tetrahydrofuran, and to the solution is added a sodium ethylate solution, prepared from 0.27 g (11.7 mmol) sodium and 10 ml ethanol, whereby the sodium salt is precipitated. After adding 80 ml of ether, the mixture is stirred for 1 hour, suction is carried out, and the product is dried at 80°C in a drying cabinet with air circulation.

Utbytte: 4,5 g (85% av det teoretiske), Yield: 4.5 g (85% of the theoretical),

Smeltepunkt: 290°C. Melting point: 290°C.

Beregnet: C 63,92, H 6,26, N 6,21 Calculated: C 63.92, H 6.26, N 6.21

Funnet: 63,90 6,35 6,18. Found: 63.90 6.35 6.18.

Eksempel 272 Example 272

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-hydroklorid 5 g (11,7 mmol) 4-[2-(5-klpr-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre oppløses under oppvarmning i 150 ml aceton og filtreres. Med isopropanolisk saltsyre utfelles hydrokloridet. 4-[ 2-( 5-chloro-2- octamethyleneimino-benzoylamino)-ethyl]-benzoic acid hydrochloride 5 g (11.7 mmol) 4-[2-(5-klpr-2-octamethyleneimino-benzoylamino)-ethyl] -benzoic acid is dissolved while heating in 150 ml of acetone and filtered. The hydrochloride is precipitated with isopropanolic hydrochloric acid.

Utbytte: 5 g (92% av det teoretiske), Yield: 5 g (92% of the theoretical),

Smeltepunkt: 205°C. Melting point: 205°C.

Beregnet: C 61,93, H 6,50, N 6,01, Cl 15,23. Calculated: C 61.93, H 6.50, N 6.01, Cl 15.23.

Funnet: 62,10 6,86 6,24 14,85. Found: 62.10 6.86 6.24 14.85.

Eksempel 273 Example 273

4-[ 2-( 5- ety1- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-e tylester 4-[ 2-( 5- ethyl1- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

Fremstilt fra 5-etyl-2-oktametylenimino-benzoesyre og 4-(2-amino-etyl)-benzoesyre-etylester analogt med eksempel 165. Utbytte: 78% av det teoretiske. Prepared from 5-ethyl-2-octamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester analogously to example 165. Yield: 78% of the theoretical.

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

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

Funnet: 74,41 8,10 6,01. Found: 74.41 8.10 6.01.

E ksempel 274 Example 274

4-[ 2-( 5- etyl- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- ethyl- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

Fremstilt fra 4-[2-(5-etyl-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre-etylester ved alkalisk forsepning analogt med eksempel 16 6. Prepared from 4-[2-(5-ethyl-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid ethyl ester by alkaline saponification analogously to example 16 6.

Utbytte: 85% av det teoretiske, Yield: 85% of the theoretical,

Smeltepunkt: 145°C. Melting point: 145°C.

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

Funnet: 74,15 8,15 6,42. Found: 74.15 8.15 6.42.

E ksempel 27 5 E xample 27 5

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoe-s yre- etylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid- ethyl ester

5,6 g (0,02 mol) 5-klor-2-oktametylenimino-benzoesyre 5.6 g (0.02 mol) 5-chloro-2-octamethyleneimino-benzoic acid

i 50 ml absolutt toluen tilsettes 2 g (0,02 mol) trietylamin og overføres ved -5°C til det blandede anhydrid med 2,2 g (0,02 mol) klormaursyre-etylester. Efter 1/2 times omrøring tilsettes en 4-(2-amino-etyl)-benzoesyre-etylester-oppløsning 1 30 ml kloroform, fremstilt fra 4,59 g (0,02 mol) 4-(2-amino-etyl ) -benzoesyre-ety lester-hydroklorid og den ekvivalente mengde 2 g (0.02 mol) of triethylamine are added to 50 ml of absolute toluene and transferred at -5°C to the mixed anhydride with 2.2 g (0.02 mol) of chloroformic acid ethyl ester. After stirring for 1/2 hour, a 4-(2-amino-ethyl)-benzoic acid-ethyl ester solution 1 30 ml of chloroform, prepared from 4.59 g (0.02 mol) 4-(2-amino-ethyl)- benzoic acid ethyl ester hydrochloride and the equivalent amount

2 g (0,02 mol) trietylamin. Efter 3 timers omrøring ved romtemperatur tilsettes fortynnet saltsyre, og de organiske faser fraskilles og tørres over natriumsulfat. Efter avdestillering av oppløsningsmidlet fraskilles den som biprodukt dannede 4-(2-etoksykarbonylamino-etyl)-benzoesyre-etylester på en silikagelkolonne med toluen/eddiksyreetylester = 9:1 som elueringsmiddel. 2 g (0.02 mol) of triethylamine. After stirring for 3 hours at room temperature, dilute hydrochloric acid is added, and the organic phases are separated and dried over sodium sulphate. After distilling off the solvent, the by-product 4-(2-ethoxycarbonylamino-ethyl)-benzoic acid ethyl ester is separated on a silica gel column with toluene/acetic acid ethyl ester = 9:1 as eluent.

Utbytte: 1,6 g (18% av det teoretiske), Yield: 1.6 g (18% of the theoretical),

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

Beregnet: 68,33, H 7,28, N 6,13 Calculated: 68.33, H 7.28, N 6.13

Funnet: 68,62 7,25 5,90. Found: 68.62 7.25 5.90.

Eksempel 27<6>Example 27<6>

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

5,6 g (0,02 mol) 5-klor-2-oktametylenimino-benzoesyre 5.6 g (0.02 mol) 5-chloro-2-octamethyleneimino-benzoic acid

i 50 ml absolutt toluen tilsettes 2 g (0,02 mol) trietylamin og overføres ved -5°C til det blandede anhydrid med 2,2 g 2 g (0.02 mol) of triethylamine are added to 50 ml of absolute toluene and transferred at -5°C to the mixed anhydride with 2.2 g

(0,02 mol) klormaursyre-etylester. Efter 1/2 times videre omrøring tilsettes en oppløsning av 3,3 g (0,02 mol) 4-(2-amino-etyl ) -benzoesyre i 20 ml IN natronlut, og omrøring foretas ved romtemperatur i 4 timer. Derefter tilsettes 30 ml vann, den organiske fase fraskilles og utristes påny med kloroform. (0.02 mole) chloroformic acid ethyl ester. After 1/2 hour of further stirring, a solution of 3.3 g (0.02 mol) 4-(2-amino-ethyl)-benzoic acid in 20 ml of 1N caustic soda is added, and stirring is carried out at room temperature for 4 hours. 30 ml of water are then added, the organic phase is separated and shaken out again with chloroform.

Fra den vandige utfelles syren ved surgjøring med IN saltsyre til pH 5,5, og omkrystallisering foretas fra eddiksyreetylester. Utbytte: 1,2 g (14% av det teoretiske), The acid is precipitated from the aqueous by acidification with 1N hydrochloric acid to pH 5.5, and recrystallization is carried out from acetic acid ethyl ester. Yield: 1.2 g (14% of the theoretical),

Smeltepunkt: 172°C. Melting point: 172°C.

Beregnet: C 67,20, H 6,81, N 6,53 Calculated: C 67.20, H 6.81, N 6.53

Funnet: 66,92 6,77 6,43. Found: 66.92 6.77 6.43.

Eksempel 27<7>Example 27<7>

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

8,87 g (12,6 mmol) kobber(II)-di-[5-klor-2-oktametylenimino-benzoat]-dihydroklorid-kompleks [fremstilt fra 5-amino-2-oktametylen-benzoesyre over diazoniumsaltet med kobber(I)-klorid, smeltepunkt: 177-178°C] oppløses i 25 ml absolutt pyridin og tilsettes dråpevis under isavkjøling 3 g (25,3 mmol) tionylklorid, slik at temperaturen holder seg ved 20-30°C. Efter 1/2 times videre omrøring tilsettes 4,9 g (25,3 mmol) 4-(2-amino-etyl)-benzoesyre-etylester, oppløst i 5 ml absolutt pyridin, og det hele oppvarmes i 3 timer til 70°C. Efter avdestillering av pyridinet oppløses residuet i en blanding av 50 ml metanol og 50 ml dioksan, og efter tilsetning av 4,6 g kaliumhydroksyd, oppløst i 90 ml vann, omrøres i 16 timer ved 8.87 g (12.6 mmol) copper(II)-di-[5-chloro-2-octamethyleneimino-benzoate]-dihydrochloride complex [prepared from 5-amino-2-octamethylene-benzoic acid over the diazonium salt with copper(I ) chloride, melting point: 177-178°C] is dissolved in 25 ml of absolute pyridine and 3 g (25.3 mmol) thionyl chloride is added dropwise under ice-cooling, so that the temperature remains at 20-30°C. After 1/2 hour of further stirring, 4.9 g (25.3 mmol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester, dissolved in 5 ml of absolute pyridine, are added, and the whole is heated for 3 hours at 70°C . After distilling off the pyridine, the residue is dissolved in a mixture of 50 ml of methanol and 50 ml of dioxane, and after the addition of 4.6 g of potassium hydroxide, dissolved in 90 ml of water, it is stirred for 16 hours at

romtemperatur. Derefter avdestilleres oppløsningsmidlet, inndampningsresiduet oppløses i 140 ml vann, ved innstilling av pH-verdien på 5,5 utfelles produktet, og omkrystallisering foretas fra eddiksyreetylester. room temperature. The solvent is then distilled off, the evaporation residue is dissolved in 140 ml of water, when the pH value is set to 5.5 the product is precipitated, and recrystallization is carried out from acetic acid ethyl ester.

Utbytte: 4,1 g (38% av det teoretiske), Yield: 4.1 g (38% of the theoretical),

Smeltepunkt: 172°C. Melting point: 172°C.

Beregnet: C 67,20, H 6,81, N 6,52, Cl 8,26. Calculated: C 67.20, H 6.81, N 6.52, Cl 8.26.

Funnet: 61,10 6,72 6,45 8,20. Found: 61.10 6.72 6.45 8.20.

Ek sempel 2~ Oak sample 2~

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

10,5 g (15 mmol) kobber(II)-di-[5-klor-2-oktametylenimino-benzoat]-dihydroklorid-kompleks [fremstilt fra 5-amino-2-oktametylenimino-benzoesyre over diazoniumsaltet og kobber (I)-klorid, smeltepunkt: 177-178°C] i 25 ml absolutt pyridin tilsettes 5,4 g (33 mmol) karbonyldiimidazol, hvorved karbon-dioksydutvikling finner sted. Efter 1/2 times omrøring ved romtemperatur tilsettes 6,8 g (35 mmol) 4-(2-amino-etyl)-benzoesyre-etylester, oppløst i 5 ml absolutt pyridin, og derefter oppvarmes i 3 timer til 70°C. Efter avdestillering av pyridinet oppløses residuet i vann, utristes med kloroform ved pH 4, og kloroformuttrekkene tørres over natriumsulfat. Efter inndampning renses residuet kromatografisk over en silikagelkolonne med toluen/eddiksyreetylester som elueringsmiddel. 10.5 g (15 mmol) copper(II)-di-[5-chloro-2-octamethyleneimino-benzoate]-dihydrochloride complex [prepared from 5-amino-2-octamethyleneimino-benzoic acid over the diazonium salt and copper (I)- chloride, melting point: 177-178°C] in 25 ml of absolute pyridine, 5.4 g (33 mmol) of carbonyldiimidazole are added, whereby carbon dioxide evolution takes place. After stirring for 1/2 hour at room temperature, 6.8 g (35 mmol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester, dissolved in 5 ml of absolute pyridine, are added and then heated for 3 hours to 70°C. After distilling off the pyridine, the residue is dissolved in water, shaken out with chloroform at pH 4, and the chloroform extracts are dried over sodium sulphate. After evaporation, the residue is purified chromatographically over a silica gel column with toluene/acetic acid ethyl ester as eluent.

Utbytte: 10 g (66% av det teoretiske), Yield: 10 g (66% of the theoretical),

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

Beregnet: C 68,33, H 7,28, N 6,13, Cl 7,75 Calculated: C 68.33, H 7.28, N 6.13, Cl 7.75

Funnet: 68,30 7,22 5,91 7,66. Found: 68.30 7.22 5.91 7.66.

979 979

Eksempel Example

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid

8,4 g (0,02 mol) 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-klorbenzen (smeltepunkt: 58°C) oppløses i 80 ml tetrahydrofuran, avkjøles til -60°C og tilsettes 18 ml (0,04 mol) av en forhåndsavkjølt 2,3 molar oppløsning av n-butyl-litium i heksan under nitrogen. Denne reaksjons-blanding innføres efter 15 minutter i ca. 10 g finknust karbon- 8.4 g (0.02 mol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-chlorobenzene (melting point: 58°C) are dissolved in 80 ml of tetrahydrofuran, cooled to -60°C and 18 ml (0.04 mol) of a pre-cooled 2.3 molar solution of n-butyl lithium in hexane under nitrogen is added. This reaction mixture is introduced after 15 minutes for approx. 10 g finely crushed carbon-

dioksyd under nitrogen. Efter oppvarmning til romtemperatur foretas inndampning, og inndampningsresiduet oppløses i vann. Produktet utfelles ved innstilling av pH-verdien på 5,5 i dioxide under nitrogen. After heating to room temperature, evaporation is carried out, and the evaporation residue is dissolved in water. The product precipitates when the pH value is set to 5.5 i

vann, omkrystalliseres fra eddiksyreetylester og renses derefter kromatografisk. water, recrystallized from ethyl acetate and then purified chromatographically.

Utbytte: 1 g (12% av det teoretiske), Yield: 1 g (12% of the theoretical),

Smeltepunkt: 172°C. Melting point: 172°C.

Beregnet: C 67,20, H 6,81, N 6,52, Cl 8,26. Calculated: C 67.20, H 6.81, N 6.52, Cl 8.26.

Funnet: 67,00 6,72 6,46 8,19. Found: 67.00 6.72 6.46 8.19.

^ i <280>^ in <280>

Eksempel Example

4-[ 2-( 5- klor- 2- oktametylenamino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- chloro- 2- octamethyleneamino- benzoylamino)- ethyl]- benzoic acid

Til en oppløsning av 11,5 g (0,03 mol) 2-(5-klor-2-okta-metylen-imino-benzoylamino)-etylbenzen i 50 ml karbondisulfid settes dråpevis ved 0-5°C 7,6 g (0,06 mol) oksalylklorid, og derefter innføres 8 g (0,06 mol) aluminiumklorid. Efter 1 times omrøring tilsettes påny den samme mengde oksalylklorid og aluminiumklorid, og derefter oppvarmes i 2-3 timer til 50°C. Efter tilsetning av isvann og saltsyre til den avkjølte opp-løsning ekstraheres med kloroform. Det tørrede kloroform-inndampningsresiduum omkrystalliseres to ganger fra eddiksyreetylester under anvendelse av aktivt kull. 7.6 g ( 0.06 mol) of oxalyl chloride, and then 8 g (0.06 mol) of aluminum chloride are introduced. After stirring for 1 hour, the same amount of oxalyl chloride and aluminum chloride is added again, and then heated for 2-3 hours to 50°C. After adding ice water and hydrochloric acid to the cooled solution, extract with chloroform. The dried chloroform evaporation residue is recrystallized twice from ethyl acetate using activated carbon.

Utbytte: 2,4 g (19% av det teoretiske), Yield: 2.4 g (19% of the theoretical),

Smeltepunkt: 172°C. Melting point: 172°C.

Beregnet: C 67,20, H 6,81, N 6,52, Cl 8,26 Calculated: C 67.20, H 6.81, N 6.52, Cl 8.26

Funnet: 67,11 6,45 6,45 8,19. Found: 67.11 6.45 6.45 8.19.

Eksempel 281 Example 281

4-[ 2-( 5- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre 4-[ 2-( 5- Chloro- 2- Piperidino- Benzoylamino)- Ethyl]- Benzoic Acid

Til en omrørt natriumhypobromitt-oppløsning [fremstilt To a stirred sodium hypobromite solution [prep

fra 0,92 g (23 mmol) natriumhydroksyd, oppløst i 4,5 ml vann, from 0.92 g (23 mmol) of sodium hydroxide, dissolved in 4.5 ml of water,

og 0,36 ml (7 mmol) brom under isavkjøling] setter man dråpevis i løpet av 15 minutter ved 35-40°C en oppløsning av 0,60 g (1,56 mmol) 4-[2-(5-klor-2-piperidino-benzoylamino)-etyl]-acetofenon i 6 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, man surgjør oppløsningen med 2N saltsyre under avkjøling og opp-tar det utfelte bunnfall i en eter/etylacetat-blanding. Den and 0.36 ml (7 mmol) bromine under ice-cooling] a solution of 0.60 g (1.56 mmol) 4-[2-(5-chloro- 2-piperidino-benzoylamino)-ethyl]-acetophenone in 6 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, the solution is acidified with 2N hydrochloric acid while cooling and the precipitate formed is taken up in an ether/ethyl acetate mixture. It

organiske fase tørrer man over natriumsulfat, filtrerer den og inndamper den i vakuum. Det nesten farveløse, faste residuum (0,45 g) omkrystalliserer man fra varm aceton, filtrerer og tørrer ved 110°C/30 Torr. organic phase is dried over sodium sulphate, filtered and evaporated in vacuum. The almost colourless, solid residue (0.45 g) is recrystallized from hot acetone, filtered and dried at 110°C/30 Torr.

Utbytte: 0,06 g (10% av det teoretiske), Yield: 0.06 g (10% of the theoretical),

Smeltepunkt: 201-203°C. Melting point: 201-203°C.

Beregnet: C 65,19, H 5,99, Cl 9,16, N 7,24 Calculated: C 65.19, H 5.99, Cl 9.16, N 7.24

Funnet: 65,53 5,91 9,32 7,10. Found: 65.53 5.91 9.32 7.10.

-. 2 82 -. 2 82

Eksempel Example

4-[ 2- ( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid

Fremstilt analogt med eksempel 281 fra 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-acetofenon med natrium-hypobromittoppløsning. Prepared analogously to Example 281 from 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-acetophenone with sodium hypobromite solution.

Utbytte: 11% av det teoretiske, Yield: 11% of the theoretical,

Smeltepunkt: 171-172°C. Melting point: 171-172°C.

Beregnet: C 67,19, H 6,81, Cl 8,26, N 6,53. Calculated: C 67.19, H 6.81, Cl 8.26, N 6.53.

Funnet: 67,50 6,75 8,53 6,24. Found: 67.50 6.75 8.53 6.24.

Eksempel 283 Example 283

4-[ 2- ( 5- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[2-(5-Chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid ethyl ester

0,82 g (0,002 mol) 4-[2-(2-brom-5-klor-benzoylamino)-etyl]-benzoesyre-etylester [smeltepunkt: 116-118°C, fremstilt ved omsetning av 2-brom-5-klor-benzoesyre med 4-(2-amino-etyl)-benzoesyre-etylester analogt med fremgangsmåte a)] oppvarmes med 0,85 g (0,01 mol) piperidin og 1 spatelspiss kobberpulver i 1 time under omrøring til 100°C. Efter avkjøling surgjøres reaksjonsblandingen med eddiksyre og ekstraheres 3 ganger med kloroform. De samlede kloroformfaser tørres over natriumsulfat. Efter avdestillering av oppløsningsmidlet renses det gjenværende residuum på en silikagelkolonne (elueringsmiddel: kloroform/etylacetat = 19:1). 0.82 g (0.002 mol) 4-[2-(2-bromo-5-chloro-benzoylamino)-ethyl]-benzoic acid ethyl ester [melting point: 116-118°C, prepared by reaction of 2-bromo-5- chlorobenzoic acid with 4-(2-amino-ethyl)-benzoic acid ethyl ester analogous to method a)] is heated with 0.85 g (0.01 mol) piperidine and 1 spatula tip of copper powder for 1 hour while stirring to 100°C. After cooling, the reaction mixture is acidified with acetic acid and extracted 3 times with chloroform. The combined chloroform phases are dried over sodium sulfate. After distilling off the solvent, the remaining residue is purified on a silica gel column (eluent: chloroform/ethyl acetate = 19:1).

Utbytte: 0,49 g (48% av det teoretiske), Yield: 0.49 g (48% of theoretical),

Beregnet: Moltopp m/e: 414/416 (1 Cl) Calculated: Moltopp m/e: 414/416 (1 Cl)

Funnet: Moltopp m/e: 414/416 (1 Cl). Found: Moletop m/e: 414/416 (1 Cl).

Eksempel <284>Example <284>

4-[ 2-( 5- klor- 2- piperidino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- Chloro- 2- Piperidino- Benzoylamino)- Ethyl]- Benzoic Acid Ethyl Ester

0,48 g (0,002 mol) 5-klor-2-piperidino-benzoesyre (smeltepunkt: 140-142°C, fremstilt fra 5-klor-2-piperidino-benzoesyre ved omsetning med karbonyldiimidazol og ammoniakk) oppvarmes med 0,09 g (0,002 mol) 55%ig natriumhydrid under omrøring i 5 ml absolutt toluen i 10 minutter til ca. 60°C. Efter avsluttet hydrogenutvikling avkjøles det hele til romtemperatur, og oppløsningen av 0,51 g (0,002 mol) 4-(2-brom-etyl)-benzoesyre-etylester (M<+> = 256/258 m/e 1 Br, fremstilt fra 4-(2-hydroksyetyl-benzoesyre-etylester med tionylbromid) settes dråpevis til 2 ml absolutt toluen. Derefter oppvarmes i ytterligere 6 timer til tilbakeløpstemperatur. Efter av-kjøling tilsettes reaksjonsblandingen vandig etanol og ekstraheres flere ganger med kloroform. De samlede kloroformekstrakter tørres over natriumsulfat, og oppløsningsmidlet avdestilleres. Residuet renses på en silikagelkolonne (elueringsmiddel: kloroform/etylacetat = 19:1). 0.48 g (0.002 mol) of 5-chloro-2-piperidino-benzoic acid (melting point: 140-142°C, prepared from 5-chloro-2-piperidino-benzoic acid by reaction with carbonyldiimidazole and ammonia) is heated with 0.09 g (0.002 mol) of 55% sodium hydride with stirring in 5 ml of absolute toluene for 10 minutes to approx. 60°C. After completion of hydrogen evolution, the whole is cooled to room temperature, and the solution of 0.51 g (0.002 mol) 4-(2-bromo-ethyl)-benzoic acid ethyl ester (M<+> = 256/258 m/e 1 Br, prepared from 4-(2-Hydroxyethyl-benzoic acid ethyl ester with thionyl bromide) is added dropwise to 2 ml of absolute toluene. It is then heated for a further 6 hours to reflux temperature. After cooling, aqueous ethanol is added to the reaction mixture and extracted several times with chloroform. The combined chloroform extracts are dried over sodium sulfate, and the solvent is distilled off.The residue is purified on a silica gel column (eluent: chloroform/ethyl acetate = 19:1).

Utbytte: 0,2 g (25% av det teoretiske), Yield: 0.2 g (25% of the theoretical),

Beregnet: Moltopp m/e = 414/416 (1 Cl) Calculated: Mole peak m/e = 414/416 (1 Cl)

Funnet: Moltopp m/e = 414/416 (1 Cl). Found: Mole top m/e = 414/416 (1 Cl).

Eksempel 285 Example 285

4-[ 2-( 5- klor- 2- oktametylenimino- benzoylamino)- etyl]- benzoesyre-etylester 4-[ 2-( 5- chloro- 2- octamethyleneimino- benzoylamino)- ethyl]- benzoic acid ethyl ester

8,2 g (0,02 mol) 4- [2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyrenitril (smeltepunkt: 102°C) oppløses i 80 ml etanol og mettes med hydrogenklorid. Efter 24 timer oppvarmes i 1 time til 50°C, og oppløsningsmidlet avdestilleres. Inndampningsresiduet oppløses i isvann, innstilles på pH 9 og utristes med kloroform. Efter inndampning av den organiske fase renses residuet kromatografisk over en silikagelkolonne. Utbytte: 6,4 g (70% av det teoretiske), 8.2 g (0.02 mol) of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid nitrile (melting point: 102°C) are dissolved in 80 ml of ethanol and saturated with hydrogen chloride. After 24 hours, heat for 1 hour to 50°C, and the solvent is distilled off. The evaporation residue is dissolved in ice water, adjusted to pH 9 and extracted with chloroform. After evaporation of the organic phase, the residue is purified chromatographically over a silica gel column. Yield: 6.4 g (70% of the theoretical),

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

Beregnet: C 68,33, H 7,27, N 6,12, Cl 7,75. Calculated: C 68.33, H 7.27, N 6.12, Cl 7.75.

Funnet: 68,32 7,29 6,12 7,90. Found: 68.32 7.29 6.12 7.90.

Claims (7)

1. Analogifremgangsmåte for fremstilling av terapeutisk aktive karboksylsyreamider med den generelle formel hvor R betyr et hydrogen-, klor- eller bromatom eller en cyklisk alkyleniminogruppe med 4 til 7 karbonatomer i iminoringen, R^ betyr et hydrogen-, fluor-, klor- eller bromatom, en alkyl-eller alkoksygruppe med hver 1 til 6 karbonatomer, en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, en hydroksy-, nitro-, amino-, cyano- eller karboksy-gruppe, en alkanoylamino-, alkoksykarbonyl- eller dialkyl-amidosulfonylgruppe, hvor alkyldelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, R^ og R^, som kan være like eller forskjellige, betyr alkylgrupper med 1 til 7 karbonatomer, alkenylgrupper med 3 til 7 karbonatomer, cykloalkylgrupper med 3 til 7 karbonatomer, med en fenylgruppe substituerte alkylgrupper med 1 til 3 karbonatomer, fenyl- eller adamantylgrupper, eller R2 og R^ sammen med det mellomliggende nitrogenatom betyr en uforgrenet alkyleniminogruppe med 4 til 6 karbonatomer i iminoringen som kan være substituert med én eller to alkylgrupper med hver 1 til 4 karbonatomer, en alkoksygruppe med 1 til 3 karbonatomer, en hydroksy-, fenyl-, karboksy- eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer; og/eller en metylengruppe i de ovenfor angitte alkylenimino-ringer kan være erstattet med en iminogruppe som kan være substituert med en alkylgruppe med 1 til 3 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, en fenyl-, halogenfeny1-, benzyl-, pyridyl- eller furoylgruppe; med et oksygen- eller svovelatom, med en karboksyl-, sulfoksyd- eller sulfonylqruppe; en mettet eller delvis umettet aza-bicykloalkylqruppe med 7 til 10 karbonatomer, en i 3- oq 5-stilling med ialt 3 eller 4 alkylqrupper med hver 1 til 3 karbonatomer substituert piperidinogruppe, en 1,4-dioksa-8-aza-spiro-alkylgruppe med 6 til 9 karbonatomer, en trimetylenimino-, pyrrolyl-, tetrahydropyridino-, heptametylenimino-, oktametylenimino-, nonametylenimino-, dekametylenimino-, undekametylenimino- eller dodekametylenimino-gruppe, R4 betyr et hydrogenatom eller en alkylgruppe med 1 til 3 karbonatomer, Y betyr et oksygenatom, en iminogruppe eller en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, Z betyr et hydrogen- eller haloqenatom, en nitro-, amino-, cyano-, formyl-, hydroksymety1- eller hydroksykarbonyl-etylenqruppe, en eventuelt forestret karboksyqruppe, en eventuelt med 2 eller 3 alkoksyqrupper, med en karboksy-, alkoksykarbonyl- eller etylendioksyqruppe substituert metylgruppe hvor alkoksyqruppen i hvert tilfelle kan inneholde 1-3 karbonatomer, en eventuelt med en karboksygruppe eller alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer substituert acetylgruppe, en med én eller to alkoksykarbonylgrupper med ialt hver 2 til 4 karbonatomer eller med to karboksygrupper substituert etyl- eller etylengruppe, en eventuelt med en alkylgruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7 karbonatomer og/eller alkenylgruppe med 3 til 7 karbonatomer mono- eller disubstituert aminokarbonylqruppe, en piperidinokarbonyl-, morfolinokarbonyl-, tiomorfolinokarbonyl- eller N-alkylpiperazino-karbonylqruppe, hvor alkylgruppen kan inneholde 1 til 3 karbonatomer, eller oqså en med en karboksygruppe substituert etylgruppe når restene R2 og R.^ sammen med det mellomliggende nitroqenatom er en av de innledningsvis nevnte cykliske iminorester, og fysioloqisk forlikeliqe salter derav med uorqaniske eller organiske syrer og også baser når Z betyr eller inneholder en karboksyqruppe, karakterisert ved at a) en aminobenzoesyre med den generelle formel hvor R, R-^, R2 og R^ er som ovenfor angitt, eller et eventuelt i reaksjonsblandingen fremstilt reaktivt derivat derav, omsettes med et amin med den generelle formel hvor R^, Y og Z er som ovenfor angitt, eller med et eventuelt i reaksjonsblandingen dannet N-aktivert amin med den generelle formel V når det anvendes en aminobenzoesyre med den generelle formel IV og når Z i et N-aktivert amin med den generelle formel V ikke inneholder en karboksy- eller aminogruppe, eller b) for fremstilling av forbindelser med den generelle formel I hvor R^ er som ovenfor angitt med unntagelse av en hydroksy- eller aminogruppe, og Y er en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, omsettes en forbindelse med den generelle formel hvor R, R^ og Z er som innledningsvis angitt, R1 og Y har de ovenfor angitte betydninger, og E er et halogenatom, med et amin med den generelle formel hvor R~ og R^ er som innledningsvis angitt, eller c) for fremstilling av forbindelser med den generelle formel I hvor Z er en karboksygruppe og Y ikke er en NH-gruppe, oksyderes en forbindelse med den generelle formel hvor R og R^ til R^ er som innledningsvis angitt, Y er som innledningsvis angitt med unntagelse av en NH-gruppe, og A betyr en gruppe som ved oksydasjon kan overføres til en karboksygruppe, eller d) for fremstilling av forbindelser med den generelle formel I hvor Z er en karboksygruppe, hydrolyseres en for- bindelse med den generelle formel hvor R, R-^ til R^ og Y er som innledningsvis angitt, og B betyr en gruppe som ved hydrolyse kan overføres til en karboksygruppe, eller e) for fremstilling av forbindelser med den generelle formel I hvor R2 er en alkylgruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7 karbonatomer, en med en fenylgruppe substituert alkylgruppe med 1 til 3 karbonatomer eller en alkenylgruppe med 3 til 7 karbonatomer, R^ er en alkylgruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7 karbonatomer, en alkenylgruppe med 3 til 7 karbonatomer, en med en fenylgruppe substituert alkylgruppe med 1 til 3 karbonatomer eller en adamantylgruppe, eller R_ og R^ sammen med et mellomliggende nitrogenatom er en 5- til 7-leddet alkylen-iminoring, en med en alkylgruppe med 1 til 4 karbonatomer substituert piperidinogruppe eller en med en alkylgruppe med 1 til 3 karbonatomer i 3- og 5-stilling substituert piperidinogruppe, og Y er en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, omsettes en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel hvor R, R^, R^ og Z er som innledningsvis angitt, R^' er et hydrogenatom eller har de ovenfor for R^ angitte betydninger, og Y har de ovenfor angitte betydninger, med en forbindelse med den generelle formel hvor R2' har de for R2 innledningsvis angitte betydninger eller danner sammen med resten R^' i formel X en lineær alkylengruppe med 4 til 6 karbonatomer, en med en alkylgruppe med 1 til 4 karbonatomer substituert n-pentylengruppe eller en i 2- og 4-stilling med en alkylgruppe med 1 til 3 karbonatomer substituert n-pentylengruppe, og G er en nukleofil, utgående gruppe så som et halogenatom eller en sulfonylgruppe, eller f) for fremstilling av forbindelser med den generelle formel I hvor Y betyr en NH-gruppe eller et oksygenatom, omsettes en forbindelse med den generelle formel hvor R og R^ til R^ er som innledningsvis angitt, og Y har de ovenfor angitte betydninger, eller et alkalisalt derav, med et fenylderivat med den generelle formel hvor R^ og Z er som innledningsvis angitt, og L betyr en nukleofil utgående gruppe så som et halogenatom eller en sulfonylgruppe, eller g) for fremstilling av forbindelser med den generelle formel I hvor R^ er som innledningsvis angitt med unntagelse av en hydroksy-, karboksy-, amino- eller alkanoylaminogruppe, og Y er en eventuelt med én eller to alkyl grupper med hver 1 til 3 karbonatomer substituert metylengruppe, omsettes et amid med den generelle formel hvor R, R2 og R^ er som innledningsvis angitt, og R^ har de ovenfor angitte betydninger, eller et alkalisalt derav, med en forbindelse med den generelle formel hvor R og Z er som innledningsvis angitt, Y har de ovenfor angitte betydninger, og M betyr en nukleofil, utgående gruppe så som et halogenatom eller en sulfonyloksygruppe, eller h) for fremstilling av forbindelser med den generelle formel I hvor R-^ er et hydrogen-, fluor-, klor- eller bromatom, en alkyl- eller alkoksygruppe med hver 1 til 6 karbonatomer, en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, en hydroksy-, nitro-, karboksy- eller alkanoylaminogruppe, Y er en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, og Z er en karboksygruppe, acyleres en forbindelse med den generelle formel hvor R og R2 til R^ er som innledningsvis angitt, og R^ og Y har de ovenfor angitte betydninger, med et oksalyl-halogenid eller fosgen i nærvær av en Lewis-syre, eller i) for fremstilling av forbindelser med den generelle formel I hvor R^ er et hydrogen-, fluor-, klor- eller bromatom, en alkyl- eller alkoksygruppe med hver 1 til 6 karbonatomer, en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, en nitro-, karboksy-, alkanoylamino- eller alkoksykarbonylgruppe med hver 1 til 3 karbonatomer i alkyldelen, Y er en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, og Z er en karboksygruppe, omsettes en forbindelse med den generelle formel hvor R og R2 til R^ er som innledningsvis angitt, og R^ og Y har de ovenfor angitte betydninger, med et eventuelt i reaksjonsblandingen fremstilt hypohalogenitt, og eventuelt overføres derefter en således erholdt forbindelse med den generelle formel I hvor Z er en karboksygruppe, ved forestring resp. amidering til en tilsvarende forbindelse med den generelle formel I hvor Z er en forestret karboksygruppe eller en eventuelt med en alkylgruppe med 1 til 7 karbonatomer, en cykloalkylgruppe med 3 til 7- karbonatomer og/eller alkenylgruppe med 3 til 7 karbonatomer mono- eller disubstituert aminokarbonylgruppe, en piperidinokarbony1-, morfolinokarbonyl-, tiomorfolinokarbonyl- eller N-alkyl-piperazinokarbonylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor R^ og/eller Z betyr en nitrogruppe, overføres ved reduksjon til en tilsvarende forbindelse med den generelle formel I hvor R^ og/eller Z betyr en aminogruppe, og/eller en erholdt forbindelse med den generelle formel I hvor R^ og/ eller Z betyr en aminogruppe, overføres over et tilsvarende diazoniumsalt til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en hydroksy- eller cyangruppe, et fluor-, klor- eller bromatom og/eller Z et klor- eller bromatom eller en cyangruppe, idet en således eventuelt erholdt forbindelse med den generelle formel I hvor R^ betyr en hydroksygruppe, ved alkylering kan overføres til den tilsvarende forbindelse med den generelle formel I hvor R^ betyr en alkoksygruppe med 1 til 6 karbonatomer eller en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, og/eller en erholdt forbindelse med den qenerelle formel I hvor R^ betyr en aminogruppe, overføres ved acylering til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en alkanoylaminogruppe med 1 til 3 karbonatomer i alkanoyIdelen, og/eller en erholdt forbindelse med den generelle formel I hvor R^ betyr en alkoksykarbonylgruppe og/eller R^ ocf R3 sammen med det mellomliggende nitrogenatom betyr en med en alkoksykarbonylgruppe substituert alkyleniminogruppe med 4 til 6 karbonatomer, hvor alkoksydelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, overføres ved hydrolyse til en tilsvarende forbindelse med den generelle formel I hvor R^ betyr en karboksy-gruppe og/eller R2 og R^ sammen med det mellomliggende nitrogenatom betyr en med en karboksygruppe substituert alkyleniminogruppe med 4 til 6 karbonatomer i iminoringen, og/eller en erholdt forbindelse med den generelle formel I hvor R2 og R^ sammen med det mellomliggende nitrogenatom betyr en N-benzylpiperazinogruppe, overføres ved debenzylering til en tilsvarende forbindelse med den generelle formel I hvor R^ og R^ sammen med det mellomliggende nitrogenatom betyr en piperazinogruppe, og/eller en erholdt forbindelse med den generelle formel I hvor R^ betyr et klor- eller bromatom, overføres ved dehalogenering til den tilsvarende forbindelse med den generelle formel I hvor R^ betyr et hydrogenatom, og/eller en karboksylsyreamid med den generelle formel I hvor Z betyr en eventuelt forestret karboksygruppe, overføres ved reduksjon med et metallhydrid til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en hydroksymetylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en hydroksymetylgruppe, overføres ved oksydasjon til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en formylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en hydroksymetylgruppe, overføres ved halogenering og påfølgende omsetning med en malonsyreester til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en med to alkoksy karbonylgrupper substituert etylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en formylgruppe, overføres ved acetalisering til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en dialkoksymetylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en formylgruppe, overføres ved kondensasjon og eventuelt på-følgende hydrolyse til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en med en hydroksykarbonyl-eller alkoksykarbonylgruppe substituert etylengruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr et hydrogenatom, overføres ved Friedel-Crafts-acylering til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en eventuelt med en alkoksykarbonylgruppe substituert acetylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en nitrilgruppe, overføres ved alkoholyse over en tilsvarende iminoester til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en trialkoksymetylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en trialkoksymetylgruppe, overføres ved hydrolyse til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en alkoksykarbonylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en acetylgruppe, overføres ved oppvarmning med et amin og svovel og derefter i nærvær av en uorganisk base til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en hydroksy-karbonylmetylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor Z betyr en karboksygruppe, overføres ved overføring til en sulfonsyrehydrazid og påfølgende disproporsjonering til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en formylgruppe, og/eller en erholdt forbindelse med den generelle formel I hvor R^ betyr et hydrogen-, fluor-, klor- eller bromatom, en alkyl- eller alkoksygruppe med hver 1 til 6 karbonatomer eller en med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer. Z betyr en CH-gruppe, Y betyr en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert metylengruppe, og Z betyr et klor- eller bromatom, overføres over den tilsvarende metallorganiske forbindelse ved hjelp av karbondioksyd til en tilsvarende forbindelse med den generelle formel I hvor Z betyr en karboksygruppe, og/eller en erholdt forbindelse med den generelle formel I overføres til sine fysiologisk forlikelige salter med uorganiske eller organiske syrer eller også baser når Z inneholder en karboksy-gruppe .1. Analogous method for the preparation of therapeutically active carboxylic acid amides of the general formula where R means a hydrogen, chlorine or bromine atom or a cyclic alkyleneimino group with 4 to 7 carbon atoms in the imino ring, R^ means a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group with each 1 to 6 carbon atoms, a phenyl group substituted alkoxy group with 1 to 3 carbon atoms, a hydroxy -, nitro, amino, cyano or carboxy group, an alkanoylamino, alkoxycarbonyl or dialkylamidosulfonyl group, where the alkyl part in each case may contain 1 to 3 carbon atoms, R^ and R^, which may be the same or different , means alkyl groups of 1 to 7 carbon atoms, alkenyl groups of 3 to 7 carbon atoms, cycloalkyl groups of 3 to 7 carbon atoms, alkyl groups of 1 to 3 carbon atoms substituted by a phenyl group, phenyl or adamantyl groups, or R 2 and R 1 together with the intervening nitrogen atom mean one unbranched alkyleneimino group with 4 to 6 carbon atoms in the imino ring which may be substituted with one or two alkyl groups with each 1 to 4 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, a hydroxy, phenyl, carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms ; and/or a methylene group in the above-mentioned alkylenimine rings can be replaced by an imino group which can be substituted with an alkyl group with 1 to 3 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a phenyl-, halophenyl-, benzyl-, pyridyl or furoyl group; with an oxygen or sulfur atom, with a carboxyl, sulfoxide or sulfonyl group; a saturated or partially unsaturated aza-bicycloalkyl group with 7 to 10 carbon atoms, a piperidino group in the 3- and 5-position with a total of 3 or 4 alkyl groups with each 1 to 3 carbon atoms substituted, a 1,4-dioxa-8-aza-spiro-alkyl group of 6 to 9 carbon atoms, a trimethyleneimino, pyrrolyl, tetrahydropyridino, heptamethyleneimino, octamethyleneimino, nonamethyleneimino, decamethyleneimino, undecamethyleneimino or dodecamethyleneimino group, R4 means a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, Y means an oxygen atom, an imino group or an optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted methylene group, Z means a hydrogen or halogen atom, a nitro-, amino-, cyano-, formyl-, hydroxymethyl- or hydroxycarbonyl-ethylene group, an optionally esterified carboxyl group, an optionally with 2 or 3 alkoxy groups, with a carboxy, alkoxycarbonyl or ethylenedioxy group substituted methyl group where the alkoxy group in each case can contain 1-3 carbon atoms, an optionally with a carboxy group or alkoxycarbonyl group with a total of 2 to 4 carbon atoms substituted acetyl group, one with one or two alkoxycarbonyl groups with a total of 2 to 4 carbon atoms each or an ethyl or ethylene group substituted with two carboxy groups, an optionally with an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms and/or alkenyl group with 3 to 7 carbon atoms, a mono- or disubstituted aminocarbonyl group, a piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkylpiperazinocarbonyl group, where the alkyl group can contain 1 to 3 carbon atoms, or also an ethyl group substituted with a carboxy group when the residues R2 and R1 together with the intervening nitrogen atom are one of the initially mentioned cyclic imino residues, and physiologically similar salts thereof with inorganic or organic acids and also bases when Z represents or contains a carboxyl group, characterized in that a) an aminobenzoic acid of the general formula where R, R-^, R 2 and R^ are as indicated above, or any reactive derivative thereof produced in the reaction mixture, is reacted with an amine of the general formula where R^, Y and Z are as indicated above, or with an N-activated amine of the general formula V formed in the reaction mixture when an aminobenzoic acid of the general formula IV is used and when Z in an N-activated amine of the general formula V does not contain a carboxy or amino group, or b) for the preparation of compounds of the general formula I where R^ is as indicated above with the exception of a hydroxy or amino group, and Y is a optionally with one or two alkyl groups with every 1 to 3 carbon atoms substituted with a methylene group, a compound with the general formula is reacted where R, R^ and Z are as indicated at the outset, R 1 and Y have the meanings given above, and E is a halogen atom, with an amine of the general formula where R~ and R^ are as indicated at the outset, or c) for the preparation of compounds of the general formula I where Z is a carboxy group and Y is not an NH group, a compound of the general formula is oxidized where R and R^ to R^ are as indicated at the outset, Y is, as stated at the outset, with the exception of an NH group, and A means a group which can be transferred to a carboxy group by oxidation, or d) for the preparation of compounds of the general formula I where Z is a carboxy group, a for- bond with the general formula where R, R-^ to R^ and Y are as indicated at the outset, and B means a group which can be transferred to a carboxy group by hydrolysis, or e) for the preparation of compounds of the general formula I where R 2 is an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, a phenyl group substituted alkyl group of 1 to 3 carbon atoms or an alkenyl group of 3 to 7 carbon atoms, R^ is an alkyl group of 1 to 7 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, an alkenyl group of 3 to 7 carbon atoms, a phenyl group substituted alkyl group of 1 to 3 carbon atoms or an adamantyl group, or R_ and R^ together with an intervening nitrogen atom is a 5 to 7 membered alkylene imino ring, one with an alkyl group of 1 to 4 piperidino group substituted by carbon atoms or a piperidino group substituted with an alkyl group with 1 to 3 carbon atoms in the 3- and 5-position, and Y is an optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted methylene group, a compound formed in the reaction mixture is reacted with the general formula where R, R^, R^ and Z are as indicated at the outset, R^' is a hydrogen atom or has the meanings given above for R^, and Y has the meanings given above, with a compound of the general formula where R2' has the meanings given for R2 at the beginning or forms together with the residue R^' in formula X a linear alkylene group with 4 to 6 carbon atoms, one with an alkyl group with 1 to 4 carbon atoms substituted n-pentylene group or one in 2- and 4 -position with an alkyl group with 1 to 3 carbon atoms substituted n-pentylene group, and G is a nucleophilic leaving group such as a halogen atom or a sulfonyl group, or f) for the preparation of compounds of the general formula I where Y means an NH group or an oxygen atom, a compound of the general formula where R and R^ to R^ are as indicated at the outset, and Y has the meanings indicated above, or an alkali salt thereof, is reacted with a phenyl derivative of the general formula where R^ and Z are as indicated initially, and L means a nucleophilic leaving group such as a halogen atom or a sulfonyl group, or g) for the preparation of compounds of the general formula I where R^ is as indicated initially with the exception of a hydroxy , carboxy, amino or alkanoylamino group, and Y is an optionally with one or two alkyl groups with every 1 to 3 carbon atoms substituted with a methylene group, an amide with the general formula is reacted where R, R2 and R^ are as indicated at the outset, and R^ has the meanings indicated above, or an alkali salt thereof, with a compound of the general formula where R and Z are as indicated at the outset, Y has the meanings given above, and M means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, or h) for the preparation of compounds of the general formula I where R-^ is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, a phenyl group substituted alkoxy group having 1 to 3 carbon atoms, a hydroxy, nitro, carboxy or alkanoylamino group, Y is a possibly with one or two alkyl groups with each 1 to 3 carbon atoms substituted methylene group, and Z is a carboxy group, a compound of the general formula is acylated where R and R2 to R^ are as indicated at the outset, and R^ and Y have the meanings indicated above, with an oxalyl halide or phosgene in the presence of a Lewis acid, or i) for the preparation of compounds of the general formula I where R^ is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms, a phenyl group substituted alkoxy group having 1 to 3 carbon atoms, a nitro, carboxy, alkanoylamino or alkoxycarbonyl group with each 1 to 3 carbon atoms in the alkyl part, Y is a optionally with one or two alkyl groups with every 1 to 3 carbon atoms substituted with a methylene group, and Z is a carboxy group, a compound of the general formula is reacted where R and R2 to R^ are as indicated at the outset, and R^ and Y have the meanings indicated above, with any hypohalogenite produced in the reaction mixture, and optionally a compound thus obtained is then transferred with the general formula I where Z is a carboxy group, by esterification or amidation to a corresponding compound of the general formula I where Z is an esterified carboxy group or an optionally with an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms and/or alkenyl group with 3 to 7 carbon atoms mono- or disubstituted aminocarbonyl group , a piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinocarbonyl group, and/or an obtained compound of the general formula I where R^ and/or Z is a nitro group is transferred by reduction to a corresponding compound of the general formula I where R^ and/or Z is an amino group, and/or an obtained compound of the general formula I where R^ and/or Z represents an amino group is transferred over a corresponding diazonium salt to a corresponding compound of the general formula I where R^ represents a hydroxy or cyano group, a fluorine, chlorine or bromine atom and/or Z a chlorine or bromine atom or a cyano group, a compound thus possibly obtained with the general formula I where R^ means a hydroxy group, by alkylation can be transferred to the corresponding compound of the general formula I where R 1 means an alkoxy group with 1 to 6 carbon atoms or an alkoxy group substituted with a phenyl group of 1 to 3 carbon atoms, and/or an obtained compound of the general formula I where R ^ means an amino group, is transferred by acylation to a corresponding compound of the general formula I where R^ means an alkanoylamino group with 1 to 3 carbon atoms in the alkanoyl part, and/or an obtained compound with the general formula I where R^ means an alkoxycarbonyl group and/or R^ ocf R3 together with the intervening nitrogen atom means an alkyleneimino group substituted with an alkoxycarbonyl group with 4 to 6 carbon atoms, where the alkoxy part in each case may contain 1 to 3 carbon atoms , is transferred by hydrolysis to a corresponding compound with the general formula I where R^ means a carboxy group and/or R2 and R^ together with the intervening nitrogen atom means an alkyleneimino group substituted with a carboxy group with 4 to 6 carbon atoms in the imino ring, and/ or an obtained compound of the general formula I where R2 and R^ together with the intermediate nitrogen atom mean an N-benzylpiperazino group, is transferred by debenzylation to a corresponding compound of the general formula I where R^ and R^ together with the intermediate nitrogen atom mean a piperazino group, and/or an obtained compound of the general formula I where R^ denotes a chlorine or bromine atom is transferred by dehalogenation to the corresponding compound of the general formula I where R^ denotes a hydrogen atom, and/or a carboxylic acid amide of the general formula I where Z means an optionally esterified carboxy group is transferred by reduction with a metal hydride to a corresponding compound of the general formula I where Z means a hydroxymethyl group, and/or an obtained compound of the general formula I where Z means a hydroxymethyl group, is transferred by oxidation to a corresponding compound of the general formula I where Z means a formyl group, and/or an obtained compound of the general formula I where Z means a hydroxymethyl group is transferred by halogenation and subsequent reaction with a malonic acid ester to a corresponding compound of the general formula I where Z means one with two alkoxy carbonyl groups substituted ethyl group, and/or an obtained compound of the general formula I where Z means a formyl group, is transferred by acetalization to a corresponding compound of the general formula I where Z means a dialkyloxymethyl group, and/or an obtained compound of the general formula I where Z means a formyl group is transferred by condensation and possibly subsequent hydrolysis to a corresponding compound of the general formula I where Z means an ethylene group substituted with a hydroxycarbonyl or alkoxycarbonyl group, and/or an obtained compound with the general formula I where Z means a hydrogen atom, is transferred by Friedel-Crafts acylation to a corresponding compound with the general formula I where Z means an acetyl group optionally substituted with an alkoxycarbonyl group, and/or an obtained compound of the general formula I where Z represents a nitrile group is transferred by alcoholysis over a corresponding iminoester to a corresponding compound of the general formula I where Z represents a trialkoxymethyl group, and/or an obtained compound of the general formula I where Z represents a trialkoxymethyl group, is transferred by hydrolysis to a corresponding compound of the general formula I where Z means an alkoxycarbonyl group, and/or an obtained compound of the general formula I where Z is an acetyl group is transferred by heating with an amine and sulfur and then in the presence of an inorganic base to a corresponding compound of the general formula I where Z is a hydroxycarbonylmethyl group, and/or an obtained compound of the general formula I where Z 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 Z means a formyl group, and/or an obtained compound of the general formula I where R 1 means a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each having 1 to 6 carbon atoms or a phenyl group substituted alkoxy group having 1 to 3 carbon atoms. Z means a CH group, Y means a methylene group optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted, and Z means a chlorine or bromine atom, is transferred over the corresponding organometallic compound by means of carbon dioxide to a corresponding compound with the general formula I where Z means a carboxy group, and/or an obtained compound with the general formula I is transferred to its physiologically compatible salts with inorganic or organic acids or also bases when Z contains a carboxy group. 2. Fremgangsmåte som angitt i krav 1 for fremstilling av 4-[2- (5-klor-2-piperidino-benzoylamino)-etyl]-benzoesyre og C-j^-alkylestere derav, karakterisert ved at det anvendes utgangsmaterialer hvor R er hydrogen,R^ er 5-klor, R2 og R^ sammen med det mellomliggende nitrogenatom er piperidino, Y er metylen, R^ er hydrogen og Z er en karboksygruppe eller en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, eller omdannes til nevnte betydninger.2. Process as set forth in claim 1 for the production of 4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid and C 1-4 alkyl esters thereof, characterized in that starting materials are used where R is hydrogen, R₂ is 5-chloro, R₂ and R₂ together with the intervening nitrogen atom is piperidino, Y is methylene, R₂ is hydrogen and Z is a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or is converted to the aforementioned meanings. 3. Fremgangsmåte som angitt i krav 1 for fremstilling av 4-[2-(5-etyl-2-piperidino-benzoylamino)-etyl]-benzoesyre og C^_2_alkylestere derav, karakterisert ved at det anvendes utgangsmaterialer hvor R er hydrogen, R^ er 5-ety 1, R2 og R^ sammen med det mellomliggende nitrogenatom er piperidino, Y er metylen, R^ er hydrogen og Z er en karboksygruppe eller en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, eller omdannes til nevnte betydninger.3. Process as set forth in claim 1 for the production of 4-[2-(5-ethyl-2-piperidino-benzoylamino)-ethyl]-benzoic acid and C 2 -alkyl esters thereof, characterized in that starting materials are used where R is hydrogen, R ^ is 5-ethyl 1, R2 and R^ together with the intervening nitrogen atom are piperidino, Y is methylene, R^ is hydrogen and Z is a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or is converted to the aforementioned meanings. 4. Fremgangsmåte som angitt i krav 1 for fremstilling av 4-[2-(5-klor-2-(1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl)-benzoylamino) -etyl ] -benzoesyre og Cj^-alkylestere derav, karakterisert" ved at det anvendes utgangsmaterialer hvor R er hydrogen, Rj^ er 5-klor, R2 og R3 sammen med det mellomliggende nitrogenatom er 1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl, Y er metylen, R. er hydrogen og Z er en karboksygruppe eller en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, eller omdannes til nevnte betydninger.4. Process as stated in claim 1 for the production of 4-[2-(5-chloro-2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-benzoylamino)- ethyl ]-benzoic acid and C 1-4 alkyl esters thereof, characterized in that starting materials are used where R is hydrogen, R 1 is 5-chloro, R 2 and R 3 together with the intervening nitrogen atom are 1,4-dioxa-8-aza-spiro [4,5]decan-8-yl, Y is methylene, R. is hydrogen and Z is a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or is converted to the aforementioned meanings. 5. Fremgangsmåte som angitt i krav 1 for fremstilling av 4-[2-(5-klor-2-oktametylenimino-benzoylamino)-etyl]-benzoesyre og C-j^^-alky lestere derav, karakterisert ved at det anvendes utgangsmaterialer hvor R er hydrogen,R^ er 5-klor, R^ og R^ sammen med det mellomliggende nitrogenatom er oktametylenimino, Y er metylen, R^ er hydrogen og Z er en karboksygruppe eller en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, eller omdannes til nevnte betydninger.5. Process as set forth in claim 1 for the production of 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl]-benzoic acid and C-12-alkyl esters thereof, characterized in that starting materials are used where R is hydrogen, R^ is 5-chloro, R^ and R^ together with the intervening nitrogen atom are octamethyleneimino, Y is methylene, R^ is hydrogen and Z is a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or converted to the aforementioned meanings . 6. Fremgangsmåte som angitt i krav 1 for fremstilling av 4-[2-(5-klor-2-(2,6-dimetylmorfolino)-benzoylamino)-etyl]-benzoesyre og Cj^-alkylestere derav, karakterisert ved at det anvendes utgangsmaterialer hvor R er hydrogen, R-^ er 5-klor,, R2 og R^ sammen med det mellomliggende nitrogenatom er 2,6-dimetylmorfolino, Y er metylen, R^ er hydrogen og Z er en karboksygruppe eller en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, eller omdannes til nevnte betydninger.6. Process as stated in claim 1 for the production of 4-[2-(5-chloro-2-(2,6-dimethylmorpholino)-benzoylamino)-ethyl]-benzoic acid and C 1-4 alkyl esters thereof, characterized in that it is used starting materials where R is hydrogen, R-^ is 5-chloro, R 2 and R^ together with the intervening nitrogen atom is 2,6-dimethylmorpholino, Y is methylene, R^ is hydrogen and Z is a carboxy group or an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, or are converted to the aforementioned meanings. 7. Fremgangsmåte som angitt i krav 1 for fremstilling av 4- [2- (5-klor-2- (cis-3,5-dimetylpiperidino)-benzoylamino)-etyl]-benzoesyre og Cj^-alkyles tere derav, karakterisert ved at det anvendes utgangsmaterialer hvor R er hydrogen, R^ er 5-klor, R^ og R^ sammen med det mellomliggende nitrogenatom er cis-3,5-dimetylpiperidino, Y er metylen, R^ er hydrogen og Z er en karboksygruppe eller en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, eller omdannes til nevnte betydninger.7. Process as stated in claim 1 for the production of 4-[2- (5-chloro-2- (cis-3,5-dimethylpiperidino)-benzoylamino)-ethyl]-benzoic acid and C 1 -alkyl esters thereof, characterized by that starting materials are used where R is hydrogen, R^ is 5-chloro, R^ and R^ together with the intervening nitrogen atom is cis-3,5-dimethylpiperidino, Y is methylene, R^ is hydrogen and Z is a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or converted to the aforementioned meanings.
NO802087A 1979-07-13 1980-07-11 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACID DERIVATIVES NO152005C (en)

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DE19792928352 DE2928352A1 (en) 1979-07-13 1979-07-13 Hypoglycaemic 2-amino-benzamido-ethyl-benzoic acid derivs. - prepd. e.g. by reaction of 2-amino-benzoic acid derivs. with 4-aminoethyl-benzoic acid derivs.
DE19792949259 DE2949259A1 (en) 1979-07-13 1979-12-07 Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity
DE19803016650 DE3016650A1 (en) 1979-07-13 1980-04-30 Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity
DE19803016651 DE3016651A1 (en) 1980-04-30 1980-04-30 Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity

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