IE50292B1 - Chemical compounds - Google Patents

Chemical compounds

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Publication number
IE50292B1
IE50292B1 IE1453/80A IE145380A IE50292B1 IE 50292 B1 IE50292 B1 IE 50292B1 IE 1453/80 A IE1453/80 A IE 1453/80A IE 145380 A IE145380 A IE 145380A IE 50292 B1 IE50292 B1 IE 50292B1
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IE
Ireland
Prior art keywords
group
carbon atoms
general formula
ethyl
alkyl
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IE1453/80A
Other versions
IE801453L (en
Original Assignee
Thomae Gmbh Dr K
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Publication date
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 IE801453L publication Critical patent/IE801453L/en
Publication of IE50292B1 publication Critical patent/IE50292B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • C07D207/327—Radicals substituted by 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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—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
    • 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
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • 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
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—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
    • C07D295/205—Radicals derived from carbonic acid
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D491/00—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
    • 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
    • C07D491/10—Spiro-condensed systems

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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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) Carboxylic acid amides of general formula I see diagramm : EP0023569,P97,F1 wherein R represents a hydrogen, chlorine or bromine atom or a cyclic alkyleneimino group with 4 to 7 carbon atoms in the imino ring ; R1 represents a hydrogen, fluorine, chlorine or bromine atom ; an alkyl or alkoxy group with 1 to 6 carbon atoms ; an alkoxy group with 1 to 3 carbon atoms substituted by a phenyl group ; a hydroxy, nitro, amino, cyano or carboxy group ; an alkanoylamino, alkoxycarbonyl or dialkylamidosulphonyl group, wherein the alkyl part may contain 1 to 3 carbon atoms ; R2 and R3 , which may be the same or different, represent alkyl groups with 1 to 7 carbon atoms, alkenyl groups with 3 to 7 carbon atoms, cycloalkyl groups with 3 to 7 carbon atoms, alkyl groups with 1 to 3 carbon atoms substituted by a phenyl group, or phenyl or adamantyl groups, or R2 and R3 together with the nitrogen atom between them represent an unbranched alkyleneimino group with 3 to 12 carbon atoms in the imino ring, an unbranched alkyleneimino group with 4 to 6 carbon atoms in the imino ring which may be substituted by one or two alkyl groups each with 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 wherein a methylene group is replaced by an imino group (which may be substituted by 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), by an oxygen or sulphur atom or by a carbonyl, sulphoxide or sulphonyl group ; a saturated or partially unsaturated azabicycloalkyl group with 7 to 10 carbon atoms, a piperidino group substituted in the 3- and 5-positions by a total of 3 or 4 alkyl groups each with 1 to 3 carbon atoms ; a 1,4-dioxa-8-aza-spiroalkyl group with 6 to 9 carbon atoms, or a pyrrolyl or tetrahydropyridino group ; R4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; Y represents an oxygen atom, an imino group or a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, Z represents a hydrogen or halogen atom, a carboxy, cyano, formyl, hydroxymethyl, hydroxycarbonylethylene, nitro, amino, allyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or phenylethoxycarbonyl group, an alkoxycarbonyl group with a total of 2 to 8 carbon atoms, a cycloalkoxycarbonyl group with a total of 4 to 8 carbon atoms, a methyl group optionally substituted by 2 or 3 alkoxy groups or by a carboxy, alkoxycarbonyl or ethylenedioxy group, wherein the alkoxy group may contain 1 to 3 carbon atoms ; an acetyl group, optionally substituted by a carboxy group or alkoxycarbonyl group with a total of 2 to 4 carbon atoms ; an ethyl or ethylene group substituted by one or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms, or by two carboxy groups ; an aminocarbonyl group optionally mono- or di-substituted by 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 ; a piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinocarbonyl group wherein the alkyl group may contain 1 to 3 carbon atoms ; or an ethyl group substituted by a carboxy group if the groups R2 and R3 together with the nitrogen atom between them represent one of the above-mentioned cyclic imino groups, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents or contains a carboxy group. 1. Claims (for the Contracting State AT) Process for the preparation of new carboxylic acid amides of general formula I see diagramm : EP0023569,P104,F1 wherein R represents a hydrogen, chlorine or bromine atom or a cyclic alkyleneimino group with 4 to 7 carbon atoms in the imino ring ; R1 represents a hydrogen, fluorine, chlorine or bromine atom ; an alkyl or alkoxy group with 1 to 6 carbon atoms ; an alkoxy group with 1 to 3 carbon atoms substituted by a phenyl group ; a hydroxy, nitro, amino, cyano or carboxy group ; an alkanoylamino, alkoxycarbonyl or dialkylamido-sulphonyl group, wherein the alkyl part may contain 1 to 3 carbon atoms ; R2 and R3 , which may be the same or different, represent alkyl groups with 1 to carbon atoms, alkenyl groups with 3 to 7 carbon atoms, cycloalkyl groups with 3 to 7 carbon atoms, alkyl groups with 1 to 3 carbon atoms substituted by a phenyl group, or phenyl or adamantyl groups, or R2 and R3 together with the nitrogen atom between them represent an unbranched alkyleneimino group with 3 to 12 carbon atoms in the imino ring, an unbranched alkyleneimino group with 4 to 6 carbon atoms in the imino ring which may be substituted by one or two alkyl groups each with 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 wherein a methylene group is replaced by an imino group (which may be substituted by 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), by an oxygen or sulphur atom or by a carbonyl, sulphoxide or sulphonyl group ; with 7 to 10 carbon atoms, a piperidino group substituted in the 3- and 5-positions by a total of 3 or 4-alkyl groups each with 1 to 3 carbon atoms ; a 1,4-dioxa-8-aza-spiroalkyl group with 6 to 9 carbon atoms, or a pyrrolyl or tetrahydropyridino group ; R4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; Y represents an oxygen atom, an imino group or a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, Z represents a hydrogen or halogen atom, a carboxy, cyano, formyl, hydroxymethyl, hydroxycarbonylethylene, nitro, amino, allyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or phenylethoxycarbonyl group, an alkoxycarbonyl group with a total of 2 to 8 carbon atoms, a cycloalkoxycarbonyl group with a total of 4 to 8 carbon atoms, a methyl group optionally substituted by 2 or 3 alkoxy groups or by a carboxy, alkoxycarbonyl or ethylene-dioxy group, wherein the alkoxy group may contain 1 to 3 carbon atoms ; an acetyl group, optionally substituted by a carboxy group or alkoxycarbonyl group with a total of 2 to 4 carbon atoms ; an ethyl or ethylene group substituted by 1 or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms, or by two carboxy groups ; an aminocarbonyl group optionally mono- or di-substituted by an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms and/or an alkenyl group with 3 to 7 carbon atoms ; a piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinocarbonyl group wherein the alkyl group may contain 1 to 3 carbon atoms ; or an ethyl group substituted by a carboxy group if the groups R2 and R3 together with the nitrogen atom between them represent one of the above-mentioned cyclic imino groups, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents or contains a carboxy group, characterised in that a) an aminobenzoic acid of general formula II see diagramm : EP0023569,P105,F1 wherein R, R1 , R2 and R3 are as hereinbefore defined, or a reactive derivative thereof, optionally prepared in the reaction mixture, is reacted with an amine of general formula III see diagramm : EP0023569,P105,F2 wherein R4 , Y and Z are as hereinbefore defined, or with an N-activated amine of general formula III optionally formed in the reaction mixture, if an aminobenzoic acid of general formula II is used and if Z in an N-activated amine of general formula III does not contain any carboxy or amino groups, or b) in order to prepare compounds of general formula I wherein R1 has the definitions given hereinbefore, with the exception of the hydroxy and amino group, and Y represents a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, a compound of general formula IV see diagramm : EP0023569,P105,F3 wherein R, R4 and Z are as hereinbefore defined, R1 and Y are defined as above and E represents a halogen atom, is reacted with an amine of general formula V see diagramm : EP0023569,P105,F4 wherein R2 and R3 are as hereinbefore defined, or c) in order to prepare compounds of general formula I wherein Z represents a carboxy group and Y does not represent an NH group a compound of general formula VI see diagramm : EP0023569,P105,F5 wherein R and R1 to R4 are as hereinbefore defined, Y has the meanings given hereinbefore with the exception of the NH group and A represents a group which can be converted into a carboxy group by oxidation, is oxidised or d) in order to prepare compounds of general formula I wherein Z represents a carboxy group, a compound of general formula VII see diagramm : EP0023569,P106,F1 wherein R, R1 to R4 and Y are as hereinbefore defined and B represents a group which can be converted into a carboxy group by hydrolysis, is hydrolysed, or e) in order to prepare compounds of general formula I wherein R2 represents an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group, or an alkenyl group with 3 to 7 carbon atoms, R3 represents an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an alkenyl group with 3 to 7 carbon atoms, an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group, or an adamantyl group, or R2 and R3 together with the nitrogen atom between them represent a 5- to 7-membered alkyleneimino ring, a piperidino group

Description

This invention relates to new carboxylic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use as pharmaceuticals.
According to one feature of the present invention we provide 5 carboxylic acid amides of general formula I, wherein R represents a hydrogen, chlorine or bromine atom or a cyclic alkyleneimino group with 4 to 7 carbon atoms in the imino ring; R^ represents a hydrogen, fluorine, chlorine or bromine atom; an alkyl or alkoxy group with 1 to 6 carbon atoms; an alkoxy group with 1 to 3 carbon atoms substituted by a phenyl group; a hydroxy, nitro, amino, cyano or carboxy group; an alkanoylamino, alkoxycarbonyl or di alkyl amidosulphonyl group, wherein the alkyl part may contain 1 to 3 carbon atoms; R2 and R3, which may be the same or different, represent alkyl groups with 1 to 7 carbon atoms, alkenyl groups with 3 to 7 carbon atoms, cycloalkyl. groups with 3 to 7 carbon atoms, alkyl groups with J'· "’.*·** ’ . to 3 carbon atoms' substituted by a phenyl group, or phenyl or adamantyl groups, or Rg and Rg together with the nitrogen atom between them represent an unbranched alkyleneimino group with 3 to 12 carbon atoms in the imino ring, an unbranched alkyleneimino group with 4 to 6 carbon atoms in the imino ring which may be substituted by one or two alkyl groups each with 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 wherein a methylene group is replaced by an imino group (which may be substituted by 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) by an oxygen or sulphur atom or by a carbonyl, sulphoxide or sulphonyl group; a saturated or partially unsaturated azabicycloalkyl group with 7 to 10 carbon atoms, a piperidino group substituted in the 3- and 5-positions by a total of 3 or 4 alkyl groups each with 1 to 3 carbon atoms; a l,4-dioxa-8-aza-spiroalkyl group with 6 to 9 carbon atoms, or a pyrrolyl or tetrahydropyridino group; R4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; Y represents an oxygen atom, an imino group or a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, Z represents a hydrogen or halogen atom, a carboxy, cyano, formyl, hydroxymethyl, hydroxycarbonylethylene, nitro, amino, allyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or phenylethoxycarbonyl group, an alkoxycarbonyl group with a total of 2 to 8 carbon atoms, a cycloalkoxy25 carbonyl group with a total of 4 to 8 carbon atoms, a methyl group optionally substituted by 2 or 3 alkoxy groups or by a carboxy, alkoxycarbonyl or ethylenedioxy group, wherein the alkoxy group may contain 1 to 3 carbon atoms; an acetyl group, optionally substituted by a carboxy group or alkoxycarbonyl group with a total of 2 to 4 carbon atoms; an 30 ethyl or ethylene group substituted by one or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms, or by two carboxy groups; an aminocarbonyl group optionally mono- or di-substituted by 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; a piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinocarbonyl group wherein the alkyl group may contain 1 to 3 carbon atoms; or an ethyl group substituted by a carboxy group if the groups Rg and Rg together with the nitrogen atom between them represent one of the abovementioned cyclic imino groups, and the physiologically acceptable salts 40 thereof with inorganic or organic acids and also bases if Z represents or contains a carboxy group.
The above compounds according to the invention exhibit interesting pharmacological properties and in particular an effect on intermediary metabolism. Thus these compounds possess a blood-sugar lowering and/or lipid lowering activity.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically compatible. Other salts may find use, however, for example in the preparation of the compounds of general formula I and their physiologically compatible salts.
In the above compounds according to the invention R may, for example, represent a hydrogen, chlorine or bromine atom or a pyrrolidino, piperidino or hexamethylenimino group.
R-j may, for example, represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,jtert. butQxy, pentyloxy, isopentyloxy, neopentyloxy, tert.pentoxy, hexyloxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy, nitro, cyano, amino, formy lamino, acetamido, propionylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, ethyl-methylaminosulfonyl, methy1-propylaminosulfonyl or ethyl-propylaminosulfonyl group.
Rj and R^ together with the nitrogen atom to which they are attached, may, for example, represent a dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamino, diheptylamino, N-methyl ethylamino, N-methyl-propylamino, N-ieopropyl-propylamino, N-isobutyl-propylaraino, N-methyl-isopropylamino, N-methyl35 butylamino, N-ethyl-butylamino, N-ethyl-isopropylamino, N-ethyl-pentylamino, N-propyl-butylamino, N-propyl-heptyl4 5029 3 aaino, dicyclohexylamino, N-aethyl-cyclohexylamino, N-ethylcyclohexylamino, N-propyl-cyclohexylaaino, N-iaobutylcyclohexylamino, dibenzylaaino, N-aethyl-benzylamino, N-ethyl-benzylaaino, N-propyl-benzylaaino, N-iaopropyl5 benzylaaino, H-butyl-benzylaaino, N-heptyl-benzylaaino, N-aethyl-phenylethyitnino, N-methyl-phenylpropylaaino, N-ethyl-phenylethylaaino, N-propyl-phenylethylamino, N-butyl-phenylpropylamino, diallylaaino, dibutenylaaino, dipentenylamino, diheptenylaaino, N-methyl-adaman10 tylaaino, N-ethyl-adaaantylaaino, N-propyl-adaaantylaaino, triaethylenialno, pyrrolidino^piperidino, hexaaethyleniaino, heptaaethyleniaino, octaaethyleniaino, nonaaethyleniaino, decamethylenialno, undecaaethyleniaino, dodecaaetbylenlaino, aethyl-pyrrolidino, diaethyl-pyrrolldino, 1,2,3,6-tetra15 hydro-pyridino, methyl-piperidino, diaethyl-piperidino, triaethyl-piperidino, tetraaethyl-piperidino, ethylpiperidino, diethyl-piperidino, methyl-ethyl-piperidino, propyl-plperidino, dipropyl-plperidino, methyl-propylpiperidino, Isopropyl-piperidino, ethyl-propyl-piperi20 dino, butyl-piperidino, isobutyl-piperidino, tert.butylpiperidino, cis-3,5-diaethyl-piperidino, trans-3,5-dimethylpiperidino, cis-3,5-diethyl-piperidino, trans-3,5-dipropylpiperidino, hydroxy-pyrrolidino, hydroxy-piperidino, aethoxypyrrolidino, aethoxy-piperidino, ethoxy-piperidino, propoxy25 piperidino, isopropoxy-piperidino, phenyl-piperidino, carbo xy-pyrrolidino, carboxy - piperidino, aethoxycarbonyl-piperidino, ethoxycarbonyl-piperidino, propoxycarbonylpiperidino, isopropoxycarbonyl-piperidino, 3,3,5,5-tetramethylpiperidino, 3,3,5,5-tetraethyl-piperidino, 3,3,5,5-tetra30 propyl-piperidino, pyrrolidone-1-yl, piperidone-1-yl, hexahydroazepinone-1-yl, morpholino, methyl-morpholino, dlaethyl-aorpholino, propyl-morpholino, thioaorpholino, aethyl-thioaorpholino, dimethyl-thioaorpholino, 1-oxidothiomorpholino , diaethyl-1-oxidothioaorphollno, 1,1-dioxido35 thioaorpholino, dimethyl-1,1-dioxidothioaorpholino, pipera5 zine, M-aethyl-piperazino, N-ethyl-piperazino, N-propylpiperazino, SJ-isopropyl-piperazino, N-phenyl-piperazino, N-chlorophenyl-piperazino, N-bromophenyl-piperazino, N-pyridyl-piperazino, N-methoxycarbonyl-piperazino, N-ethoxy 5 carbonyl-plperazino, N-propoxycarbonyl-piperazino, N-furoylpiperazino, tetrahydro-isoquinoline-2-yl, octahydro-isoquinoline-2-yl, decahydro-isoquinoline-2-yl, tetrahydro3-beazazepine-3-yl, d@cahydro-3-benzazepine-3-yl, octahydro-isoindole-2-yl, 3-aza-bicydo-nonane-3-yl, io 1,4-dioxa-8-aza«-spiro/£»57decane-8-yl or 1,4-dloxa-8-azaspiro/£,67undecane-8-yl-sroup. r4 maY represent a hydrogen atom or a methyl, ethyl, propyl or isopropyl group. ϊ may for exanple represent an oxygen atom or an 15 imino, methylene, methylmethylene, ethyl-methylene, propyl-methylene, dimethyl-methylene, diethyl-methylene or methyl-propyl-methylene group.
Z may for exanple, represent a hydrogen, chlorine or bromine atom or a nitro, amino, cyano, formyl, hydroxymethyl, carboxy, mathoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, heptoxycarbonyl, allyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, phenylethoxycarbonyl, cyclopropoxy-carbonyl, cyclopentoxycarbonyl, cyclohexyloxycarbonyl, cycloheptoxycarbonyl, methyl, dimethoxymethyl, diethoxymethyl, triethoxymethyl, dipropoxymethyl, tripropoxymethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, 1,3-dioxolan30 2-yl, acetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, isopropoxycarbonylacetyl, 2-carboxyethylene, 2-mathoxycarbonylethylene, 2-ethoxycarbony1ethylene, 2-carboxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbony1-ethyl, 2-isopropoxycarbony1-ethyl, 2,2-bis-carboxy-ethyl, 2,2-bis-ethoxycarbony1-ethyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, iaopropylaminocarbonyl, butylaainocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, heptylaainocarbonyl, allylaminocarbonyl , diallylaminocarbonyl, dimethylaainocarbonyl, 5 diethylaminocarbonyl, dipropylaminocarbonyl, dihexylaminocarbonyl, N-methylethylaminocarbonyl, cyclopropylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, dicyclohexylamlnocarbonyl, N-methylcyclohexylaminocarbonyl, N-ethyl-cyclohexylaminocarbonyl, 10 N-propyl-cyclohexylaminocarbonyl, N-pentyl-cyclohexylaminocarbonyl, plperidinocarbonyl, morpholinocarbonyl, thlomorpholinocarbonyl, N-aethyl-piperazinocarbonyl, N-ethyl-piperazinocarbonyl or N-propyl-piperazinocarbonyl group .
Of the above compounds of the invention, preferred 15 compounds are those wherein R represents a hydrogen atom; Rj represents 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; or a hydroxy, cyano, carboxy, nitro, amino, acetamido, dimethylaminosulphonyl or benzyloxy group; Rg represents an alkyl group with 1 to 6 carbon atoms or a cyciohexyl, phenyl, benzyl, adamantyl or allyl group, Rg represents an alkyl group with 1 to 6 carbon atoms or an allyl group, or 25 R2 and R3 together with the nitrogen atom between them represent an unbranched alkyleneimino group with 4 to 12 carbon atoms in the imino ring; a piperidino group substituted by an alkyl group with 1 to 4 carbon atoms or by a phenyl, hydroxy, methoxy, carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms; a piperidino group substituted in the 3- and 5-positions by an alkyl group with 1 to 3 carbon atoms; a piperidino group substituted in the 3- and 5-positions by two alkyl groups each having 1 to 3 carbon atoms; a morpholino, thiomorpholino, 1- oxidothiomorpholino or 1,1-dioxido-thiomorpholino group, each of which is optionally substituted by 1 or 2 methyl groups, a piperazino group optionally substituted in the 4-position by a methyl, benzyl, phenyl, chlorophenyl, pyridyl, furoyl or alkoxycarbonyl group with a total of 2 to 4 carbon atoms; or a pyrrolyl, piperidon-(2)-yl-(l), 1,2,3,6-tetrahydropyridino, 1,4-dioxa-8-aza-spiro β,δ] decan-8-yl, 1,4-dioxa-8-aza-spiro {4,β] -undecan-8-yl, octahydro-isoindol-2-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, 1,2,3,4,5,6,7,8-octahydroisoquinolin-2-yl, decahydro-isoquinolin-2-yl, 1,2,4,5-tetrahydro-3benzazepin-3-yl, decahydro-3-benzazepin-3-yl or 3-aza-bicyclononan3-yl group; R4 represents a hydrogen atom or a methyl group; Y represents a methylene, methyl-methylene or dimethylmethylene group, an NH group or an oxygen atom; and Z represents a carboxy, cyano, formyl or hydroxymethyl group; an alkoxycarbonyl group with a total of 2 to 7 carbon atoms; a cyclohexyloxycarbonyl, benzyloxycarbonyl, di ethoxymethyl, hydroxycarbonylmethyl, bis-2,2-ethoxycarbonyl-ethyl, 2-hydroxycarbonylethylene or 2-ethoxycarbonyl-ethyl group; an acetyl group optionally substituted by a hydroxycarbonyl or ethoxy carbonyl group; or a 2- hydroxycarbonyl-ethyl group when the groups Rg and Rg together with the nitrogen atom between them represent one of the abovementioned cyclic imino groups, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents or contains a carboxy group.
Of these preferred compounds especially preferred are those wherein R-| is in the 5-position of the phenyl nucleus and R, R-j to R4, Y and Z are as defined above, and the physiologically acceptable salts thereof with inorganic or organic acids or also bases if Z represents or contains a carboxy group or wherein (2) R represents a hydrogen atom, R^ in the 5-position represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl or alkoxy group each with 1 to 3 carbon atoms, or a carboxy, cyano or nitro group, R2 and R^ together with the nitrogen atoms between them represent an Ν,Ν-dialkylamino or N-alkylcyclohexylamino group each having 1 to 3 carbon atoms in the alkyl part; a pyrrolidi no, piperidi no, hexamethyleneimino, heptamethyleneimino, octamethyleneimino or nonamethyleneimino group; a piperidino group substituted by an alkyl group with 1 to 4 carbon atoms or by a methoxy or phenyl group; a piperidino group substituted in the 3- and 5-positions by one or two methyl or ethyl groups; a morpholino or thiomorpholino group optionally substituted in the 2- and 6- positions by a methyl group; or a l,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-iso-quinolin-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, decahydro-3H-3-benzazepin3-yl, 3-aza-bicyclo [3,2,2)-nonan-3-yl or N-methyl-adamantyl-(1,-amino group; R^ represents a hydrogen atom or a methyl group; Y represents a methylene, methyl-methylene, dimethyl-methylene or NH group or an oxygen atom; Z represents an alkoxycarbonyl group with a total of 2 to 4 carbon atoms a carboxy, formyl or hydroxymethyl group, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents the carboxy group, or wherein (3) R, R4, Y and Z are as defined above, R.| represents a chlorine or bromine atom or a methyl, ethyl or methoxy group; Rg and Rg together with the nitrogen atom between them represent a pyrrolidino, piperidino, methylpiperidino, 4-methoxy-piperidino, 4-pheny1-pi peri d i no, hexamethyleneimi no, heptamethyleneimi no, octamethyleneimino, nonamethyleneimino, 3,5-dimethyl-piperidino, morpholino, 2,6-dimethyl-morpholino, thiomorpholino, 2,6-dimethylthiomorpholino, 1,4-dioxa-8-aza-spiro [4,5]-decan-8-yl, 1.2.3.4- tetrahydroisoquinolin-2-yl, decahydro-isoquinolin-2-yl, 1.2.4.5- tetrahydro-3H-3-benzazepi n-3-yl, decahydro-3H-3-benzazepi n-3-yl, octahydro-isoindol-2-yl or N-methyl-adamantyl-(l)-amino group; or a piperidino group substituted in the 4-position by an alkyl group with 2 to 4 carbon atoms, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents the carboxy group.
Particularly preferred of the above compounds according to the invention are the following: a) 4-[2-(5-chloro-2-piperidino-benzoylamino)-ethyl] benzoic acid, b) 4-[2-(5-ethyl-2-piperidino-benzoylamino)-ethyl] benzoic acid, 5 c) 4-[2-(5-chloro-2-(l,4-dioxa-8-aza-spiro Ijl,§]decane-8-yl) benzoyl ami no)ethyl] benzoic acid, d) 4-(2-(5-chloro-2-octamethylenimino-benzoylamino)-ethyjl benzoic acid, e) 4- [2-(5-chloro-2-(2,6-dimethylmorpholino)-benzoylamino)-ethyl] -benzoic acid, f) 4 [2-(5-chloro-2-(cis-3,5-dimethylpiperidino)-benzoylamino)-ethyli benzoic acid, and their Cj_3alkyl esters and acid addition salts thereof.
The compounds of general formula I and of physiologically acceptable salts thereof with inorganic or organic acids and bases, if Z represents a carboxy group, may for example, be prepared by the following processes which processes constitute further features of the present invention: A Reaction of an acid of formula II, βχχ.<:θ0Η (wherein R, Rp Rg, and R3 are as hereinbefore defined), or a reactive derivative thereof which may optionally be prepared in situ in the reaction mixture, with an amine of formula III, (wherein R^, Y and Z are as hereinbefore defined), or, where Z does not contain a carboxy or amino group and an acid of formula II is used, an N-activated derivative thereof.
Thus, the process concerns the acylation of an amine of formula III with either an acid of formula II, preferably in the presence of a dehydrating agent or an acid activating agent or with a functional derivative of the acid of formula II, or the reaction of an acid of formula II with an N-activated derivative of an amine of formula III wherein Z does not represent 5029» or contain a carboxy or amino group, which Nactivated derivatives may optionally be prepared in situ from the amine of formula III by means of an agent serving to activate the amino group.
Functional derivatives of the acid of formula II which may be used and which may also optionally be prepared in situ in the reaction mixture, include for exanple alkyl, aryl and aralkyl esters and thioesters such as e.g. the methyl, ethyl, phenyl or benzyl esters; imidazolides; acid halides such as e.g. the acid chloride or bromide; acid anhydrides; mixed anhydrides with aliphatic or aromatic carboxylic acids, sulfenic acids, sulfinic acids or sulfonic acids or carbonic acid esters, e.g. with acetic acid, propionic acid, jo-toluenesulfonic acid or O-ethyl carbonic acid; O-triphenyl phosphonium complexes; N-acyloxy imides; azides; and nitriles; as well as the corresponding amino-thiobenzoic acid derivatives. The N-activated derivative of the amine of formula V where Z does not represent or contain a carboxy or amino group, may for exanple be a phosphazo derivative.
Acid activating and/or dehydrating agents which may be used include for exemple esters of chloroformic acid such as e.g. ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'dicyclohexylcarbodiimide, N,N’- carbonyldiimidazole, Ν,Ν'-thionyldiimidazole, boron trifluoride etherate and triphenyl phosphine/carbon tetrachloride.
The reaction is conveniently carried out in the presence of a solvent such as e.g. methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene or dimethylformamide and optionally in the presence of an Inorganic base such as e.g. sodium carbonate or a tertiary organic base such as e.g. triethylamine or pyridine. If desired the base may 51)292 simultaneously serve as solvent. The reaction may optionally be effected in the presence of an acid activating agent. Convenient temperatures for the reaction are from -25 to 25O°C, preferably, however, from -10°C to the boiling point of the reaction mixture. Tf a derivative of the compound of formula II or III is formed in situ in the reaction mixture it need not be isolated. The reaction can also if desired be carried out without a solvent and water formed during the reaction may, if desired by removed by azeotropic distillation, e.g. by heating with toluene in a water separator funnel, or by addition of a drying agent such as e.g. magnesium sulfate or a molecular sieve.
B for the preparation of compounds of general formula I wherein represents a hydrogen, fluorine, chlorine or bromine atom; a C3_galkyl or Cj_galkoxy group; a nitro, cyano or carboxy group; or a C^_3alkanoylamino, (Cj-^alkoxy)carbonyl or di(C^_3alkyl)aminosulfonyl gropp; and Y represents a methylene group (optionally substituted by 1 or 2 C^_3alkyl groups): Reaction of a compound of formula IV, [wherein R, R^ and Z are as hereinbefore defined; R represents a hydrogen, fluorine, chlorine or bromine atom; a C3_galkyl or C3_galkoxy group; a nitro, cyano or carboxy group; or a C3_3alkanoylamino, (C^^alkoxy)carbonyl or di(C^_3alkyl)aminosulfonyl group; Y^ represents a methylene group (optionally substituted by 1 or 2 C^_3 alkyl groups); and E represents a halogen atom] with an amine of formula V.
(V) (wherein ί?2 and Rg are as hereinbefore defined).
The halogen atom, mentioned in the definition of the exchangeable radical E, is especially a chlorine or 5 bromine atom, or, where represents a nitro group, alternatively a fluorine atom.
The reaction is conveniently carried out in the presence of a solvent such as e.g. water, water/methanol, water/ethanol, water/isopropanol, dimethylformamide or in an excess of the amine of formula VII. Optionally the reaction is effected in the presence of an inorganic or tertiary organic base. A reaction accelerator such as e.g. copper may also optionally be used is desired. If desired, the reaction may be carried out in a closed vessel, and e.g. at temperatures of from 20 to 150°C, preferably, however, at the boiling point of the reaction mixture, e.g. at 100°C. The reaction can, if desired, be carried out without a solvent.
C for the preparation of compounds of general formula I wherein Z represents a carboxy group and Y represents an oxygen atom or a methylene group (optionally substituted by 1 or 2 0χ_3 alkyl groups)s Oxidation of a compound of formula VI, [wherein R, R^, Rg, Rg, R^ are as hereinbefore defined; Y represents an oxygen atom or a methylene group (optionally substituted by 1 or 2 C^_3 alkyl groups) and A represents a group transformable into a carboxy group by oxidaticn] whereby the desired compound of formula I is obtained.
A in the compound of formula VI may, for example, be a formyl group or an acetal thereof; a hydroxymethyl group or an ether derivative thereof; or an unsubstituted or substituted acyl group such as e.g. an acetyl, chloroacetyl, propionyl, malonic acid-(l)-yl or malonic ester-(l)-yl group.
The reaction is carried out with an oxidising agent conveniently in the presence of a solvent such as water, glacial acetic acid, pyridine or carbon tetrachloride. Preferred temperatures are from 0 to 100°C, more preferably from 20 to 50 °C. Oxidation may, for example, be effected 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 the preparation of compounds of general formuLa I wherein Z represents a carboxy group: Hydrolysis of a compound of formula VII, (VII) (wherein R, R^, Rg, Rg, R^, and Y are as hereinbefore defined and B represents a group transformable into a carboxy group by hydrolysis).
B in the compound of formula VII may, for exanple, be a cyano group or a functional derivative of the carboxy group such as an unsubstituted or substituted amide, ester, thioester, orthoester, iminoether, amidine or anhydride group, a malonic ester-(l)-yl group, a tetrazolyl group or an optionally substituted 1,3-oxazole-(2)-yl or dihydro-1,3-oxazole-(2)-yl group.
The hydrolysis is conveniently carried out in the presence of either 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. Suitable solvents for the hydrolysis include e.g. ethanol, water/ethanol, water/ isopropanol or water/dioxan and preferred temperatures are from -10 to 120°C, e.g. at temperautes of from ambient temperature to the boiling point of the reaction mixture.
If in the compound of formula VII, B represents a cyano group, the reaction may conveniently be carried out, if desired, in the presence of ethanol/hydrogen chloride, whereby the corresponding imino or ortho ester is formed in the reaction mixture which by addition of water may be converted to the corresponding ester which in turn may be hydrolysed.
E for the preparation of compounds of general formula I wherein either R2 represents a alkyl, Cg_7 cycloalkyl, phenyl(C1_3alkyl) or C3_7alkenyl group and Rg represents a C-^alkyl, C3_7cycloalkyl, C3_?alkenyl, phenylicl_3alkyl) or adamantyl group or R2 and Rg, together with the nitrogen atom to which they are attached, represent a C^_g alkylenimino ring, a alkyl-substituted piperidino group or a piperidino group (substituted both in the 3- and in the 5-positions hr a Cg_3 alkyl group); and Y represents a methylene group (optionally substituted by 1 or 2 Cg_3 alkyl groups): Reaction of a compound, optionally formed in situ in the reaction mixture, of formula VIII, (VIII) [(wherein R, R^, R^, Z and Y^ are as hereinbefore defined and Rg' represents a hydrogen atom, a alkyl, C3_7 cycloalkyl, Cg_? alkenyl, phenyl (C^g alkyl) or adamantyl group or, together with Rg' in formula IX, a straight chain alkylene group, a alkylsubstituted n-pentylene group or a n-pentylene group (substituted both in the 2-position and in the 4-position by a C^g alkyl group)] with a compound of formula IX, R2' - G (IX) [wherein Rg' represents a C^_7 alkyl, Cg_7 cycloalkyl, phenyl(Cj-g alkyl) or Cg_7 alkenyl group or, together with Rg' in fonnula IX, a straight chain c^_g alkylene group, a C1_^ alkyl-substituted n-pentylene group or a n-pentylene group (substituted both in the 2- and in the 4 positions by a Cg_3 alkyl group) and G represents a nucleophilically exchangeable group such as for example a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or Iodine atom or a methanesulfonyloxy or ptoluene-sulfonyloxy group].
The alkylating agent of formula IX may for example be a halide or sulfate such as e.g. methyl iodide, ethyl iodide, propyl bromide, benzyl chloride, benzyl bromide, dimethyl sulfate or diethyl sulfate.
The reaction is conveniently carried out in the presence of such as acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or hexamethyl phosphoric acid triamide and optionally in the presence of an inorganic base such as e.g. sodium carbonate, potassium carbonate or potassium tert.butylate or a tertiary organic base such as e.g. pyridine. Preferred temperatures are from 0 to 150°C most preferably from 20 to 75°c.
If a carboxylic acid of formula VIII is used, this acid may, depending on the reaction conditions employed, e.g. at temperatures above ambient temperature and in the presence of an alcoholate as a base, be converted simultaneously into the corresponding ester.
Where R2* in formula IX represents a methyl group, methylation can also be carried out using formaldehyde as the compound of formula IX 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 the presence of a solvent such as e.g. formic acid or glacial acetic acid and conveniently at temperatures up to the boiling point of the reaction mixture.
The compound of formula VIII may, if desired, be prepared in situ by reaction of a corresponding substituted isatoic acid enhydride with an appropriate amine of formula III.
F for the preparation of compound^ cf general formula I 293 wherein Y represent an oxygen atom or an imino group: Reaction of a compound of formula X, (X) (wherein R, R^, R2, and Rg are as hereinbefore defined and Yg represents an oxygen atom or an imino group), or an alkali metal salt thereof, with a compound of formula XI, (wherein and Z are as hereinbefore defined and L represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom or a methylsulfonyloxy, £-toluenesulfonyloxy or raethoxysulfonyloxy group).
The reaction is conveniently carried out in the presence of a solvent such as water/ethanol, water/ isopropanol, tetrahydrofuran, dioxan, acetone, dimethylformamide, dimethyl sulfoxide or hexamethyl phosphoric acid triamide, preferably in the presence of a base such as e.g. sodium carbonate, sodium hydroxide, potassium hydroxide or potassium tert.butylate. Preferred temperatures are from 0 to 15O°C preferably the boiling point of the reaction mixture, e.g, at temperatures of from 50 to 1OO°C. If an eeter is used, this ester may, depending on the reaction conditions employed, e.g. at elevated temperatures and in the presence of an excess of base, be simultaneously converted into the corresponding carboxylic acid.
E for the preparation of compounds of general formula I wherein represents a hydrogen, fluorine, chlorine, or bromine atom, a Cj_g alkyl or Cj_g alkoxy group, a phenyl(C1_3 alkoxy) group, a nitro or cyano group or a 10 ^1-3 alkoxy)carbonyl or di(C3_3 alkyl)aminosulfonyl group; and Y represents a methylene group (optionally substituted by 1 or 2 C^_3 alkyl groups): Reaction of an amide of formula ΧΠ, (wherein R, R2 and R3 are as hereinbefore defined and represents a hydrogen, fluorine, chlorine or bromine atom, a C}_g alkyl or C^_g alkoxy group, a phenyl(Cj_3 alkoxy) group, a nitro or cyano group or a (C3_3 alkoxy)20 carbonyl or di(C3_3 alkyl)aminosulfonyl group), or an alkali metal salt thereof with a compound of formula XIII, (wherein Y^, R^ and Z are as hereinbefore defined, and M represents a nucleophilically exchangeable group such as e.g. a halogen atom or a sulfonyloxy group).
The reaction is conveniently carried out in the presence of a solvent such as tetrahydrofuran, dioxan, toluene, dimethylformamide, dimethylsulfoxide or hexamethyl phosphoric acid triamide optionally in the presence of a base such as e.g. sodium hydride or potassium ^^butylate. Preferred temperatures are from 20 to 180°C, most preferably from 50 to 150°C.
H for the preparation of compounds of general formula I wherein represents a hydrogen, fluorine, chlorine or bromine atom, a alkyl or C^_6 alkoxy group, a phenyl(Cl-3 alkoxy) grouP or a hydroxy, nitro, carboxy or C^_3 alkanoylamino group; Y represents a methylene group (optionally substituted by 1 or 2 Cj_3 alkyl groups) and Z represents a carboxy group: Acylation of a compound of formula XIV, (XIV) (wherein R, Rg, R3, R^ and are as hereinbefore defined and represents a hydrogen, fluorine, chlorine or bromine atom, C^_g alkyl or c1_g alkoxy group, a phenyl— (C^_3 alkoxy) group or a hydroxy, nitro, carboxy or C1_3 alkanoylamino grouj) with an oxalyl halide or phosgene in the presence of a Lewis acid.
This Friedel-Crafts acylation is conveniently carried out in the presence of a solvent such as nitrobenzene or carbon disulfide. The Lewis acid is preferably aluminium chloride and preferred temperatures are from 0 to 80°C most preferably from 2θ to 60°C.
I for the preparation of compounds of general formula I wherein Rg represents a hydrogen, fluorine, chlorine or bromine atom, a Cg_g alkyl or Cg_g alkoxy group, a phenyl(Cg_g alkoxy) group or a nitro, carboxy, Cg_3 alkanoylamino or (Cg_3 alkoxy)carbonyl group; Y represents a methylene group (optionally substituted by 1 or 2 Cg_3 alkyl groups); and Z represents a carboxy group; Reaction of a compound of formula XV, (wherein R, Rg, Rg, R^ and Yg are as hereinbefore defined and Rg represents a hydrogen, fluorine, chlorine or bromine atom, a Cg_g alkyl or Cg_g alkoxy group, a phenyl(Cg_3 alkoxy) group or a nitro, carboxy, Cg_3 alkanoylamino or (Cg_3 alkoxy)carbonyl group) with a hypohalite which hypohalite may optionally be prepared in situ in the reaction mixture.
The reaction is conveniently carried out in the presence of a solvent such as water/tetrahydrofuran or water/dioxan and at temperatures of from 0 to 80°C, most preferably from 25 to 50°C.
J for the preparation of compounds of general formula 1 wherein Z represents an esterified carboxy group: Esterification of a compound of formula I 5 (wherein Z represents a carboxy group).
K for the preparation of compounds of general formula I wherein Z represents an aminocarbonyl group (substituted by one or two substitutents selected from Cg_7 alkyl groups, Cg_7 cycloalkyl groups and Cg_7 alkenyl groups) or a piperidino carbonylj morpholinocarbonyl, thiomorpholinocarbonyl or N-(Cj_g alkyl)-piperazinocarbonyl group: Amidation of a compound of formula X (wherein Z represents a carboxy group).
The esterification or amidation in processes J and K above is conveniently carried out in the presence of a solvent, such as the corresponding alcohol or amine, pyridine, toluene or dioxan and conveniently in the presence of an acid activating and/or dehydrating agent such as e.g. thionyl chloride, ethyl chloroformate, Ν,Ν’-dicyclohexylcarbodiimide or carbonyldiimidazole or by transesterification, e.g. with a corresponding carbonate. Preferred temperatures are from 0 to 50°C, most preferably ambient temperature. l for the preparation of compounds of general formula I wherein R^ and/or Z represents an amino group: Reduction of a compound of formula I (wherein R7 and/or Z represents a nitro group).
The reduction of the nitro compound is preferably carried out in the presence of a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide. Conveniently reduction may be effected with hydrogen in the presence of a hydrogenation catalyst such as e.g. Raney nickel, platinum or palladium/charcoal; with metals such as iron, tin or zinc in the presence of an acid; with salts such as iorn(II) sulfate, tin(II) chloride or sodium dithionite; or with hydrazine in the presence of Raney nickel.
Preferred temperatures are from 0 to 50°C, most preferably, ambient temperature.
M for the preparation of compounds of general formula I wherein R^ represents a hydroxy or cyano group or a fluorine, chlorine or bromine atom and/or Z represents a chlorine or bromine atom cr a cyano group: Conversion of a compound of formula I (wherein R^ and/or Z represents a amino group) via the corresponding diazonium salt into the desired compound of formula I.
The diazonium salt is conveniently prepared in the presence of a suitable solvent, e.g. in water/ hydrochloric acid, methanol/hydrochloric acid or dioxan/ hydrochloric acid, by diazotisation of the amino compound with a nitrite, e.g. sodium nitrite or an ester of nitrous acid, preferably at low temperature, e.g. at temperatures of from -10 to 5°C.
The subsequent reaction of the diazonium salt, e.g. the fluoroborate, the hydrosulfate in sulfuric acid or the hydrochloride is carried out in the presence of copper or a corresponding copper(I) salt such as e.g. copper(I) chloride/hydrochloric acid, copper(I) bromide/ hydrobromic acid or trisodium-copper(I) tetracyanide at pH 7, preferably at slightly elevated temperature, e.g. at temperatures of from 15 to 100°C.
N for the preparat ion of compounds of general formula I wherein represents ft C^g alkoxy or phenyl (Cg^ alkoxy) group: Alkylation of a compound of formula I (wherein R^ represents a hydroxy group). 50283 The O-alkylation is conveniently carried out with a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, benzyl g-toluenesulfonate or isopropyl methanesulfonate, optionally in the presence of a base such as e.g. sodium hydride, potassium hydroxide or potassium tert-butylate and preferably in the presence of s solvent such as e.g. diethyl ether, tetrahydrofuran, dioxan·., ethanol, pyridine or d ί methylfnrmami de. Preferred temperatures are from 0 to 75°C, most preferably, ambient temperature . for the preparation of compounds of general formula I wherein Rg represents a Cg_g alkanoylamiiP group: Acylation of a compound of formula I (wherein Rg represents an amino group).
The acylation is conveniently carried out in the presence of a solvent such as methylene chloride, ether, tetrahydrofuran or an excess of the acylating agent, e.g. formic acid, acetic acid or propionic acid or their acid anhydrides, acid chlorides or esters. Optionally the acylation may be effected in the presence of an inorganic base or a tertiary organic base, which simultaneously may also serve as a solvent. Also optionally present is an acid activating or dehydrating agent. Preferred temperatures are from -25 to 150°C, most preferably from -10 to the boiling point reaction mixture.
P for the preparation of compounds of general formula I wherein Rg represents a carboxy group and/or Rg and Rg, together with the nitrogen atom to which they are attached, represent a alkylenimino group substituted by a carboxy group: Hydrolysis of a compound of formula I (wherein Rg represents a (Cg_g alkoxy)carbonyl group and/or Rg and Rg, together with the nitrogen atom to which they are attached, represent a C^_g alkylenimino group substituted by a alkoxycarbonyl group).
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphroic acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide, in the presence of a solvent such as e.g. ethanol, water/ethanol, water/isopropanol or water/dioxan and preferably at elevated temperatures, e.g. at the boiling point of the reaction mixture.
Q for the preparation of compounds of general formula I wherein R2 and R^, together with the nitrogen atom to which they are attached, represent a piperazino group: Debenzylation of a compound of formula I (wherein R2 and Rj, together with the nitrogen atom to which they are attached, represents an N-benzylplperazino group).
R for the preparation of compounds of general formula I wherein R^ represents a hydrogen atom: Dehalogenation of a compound of formula I (wherein R^ represents a chlorine or bromine atom).
The debenzylation and the dehalogenation in processes Q and R above are conveniently carried out in the presence of a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid by means of catalytically activated hydrogen, e.g. with hydrogen,preferably at a pressure of 1 to 5 bar, in the presence of platinum or palladium/charcoal. Preferred temperatures are from 0 to 75°C, most preferably ambient temperature.
S for the preparation of compounds of general formula I wherein Z represents a hydroxymethyl group: Reduction of a compound of formula I (wherein Z represents an optionally esterified carboxy group) by means of a complex metal hydride.
The reduction with the metallic hydride is conveniently carried out with for example lithium aluminium hydride, preferably in the presence of a solvent such as e.g. diethyl ether, tetrahydrofuran or dioxan. Preferred temperatures are from 0 to 100°C, most preferably the boiling point of the reaction mixture. τ for the preparation of compounds of general formula I wherein Z represents a foray 1 group: Oxidation of a compound of formula I (wherein Z represents a hydroxymethyl group).
The oxidation of the hydroxymethyl grotpis conve10 niently carried out with a metallic oxide such as e.g. manganese dioxide preferably in the presence of a solvent such as e.g. acetone or dichloromethane. Preferred temperatures are from 0 to 50°C, most preferably, ambient temperature. ' u for the preparation of compounds of general formula I wherein Z represents an ethyl group substituted by 2 C2_4 alkoxycarbonyl groups.
Subjection of a compound of formula I (wherein Z represents a hydroxymethyl group) to halogenation and subsequent reaction with a malonic acid ester.
The conversion of a hydroxymethyl group into a halomethyl group is carried out with a halogenating agent such as e.g. thionyl chloride, phosphorus. trichloride, phosphorus tribromide or phosphorus pentachloride, preferably in the presence of a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene. Subsequent reaction is preferably with an alkali metal salt of the malonic acid ester, e.g. diethyl malonate. Preferred temperatures are from 0 to 100°C, most preferably from 20 to 50°C.
V for the preparation of compounds of general formula I wherein Z represents a ditC^j alkoxy)methyl group: Acetalisation of a compound of formula I (wherein Z 3represents a formyl group) .
The acetal formation is conveniently carried out in the presence of a corresponding alcohol as solvent, > e.g. in methanol or ethanol and in the presence of an acid such as e.g. hydrochloric acid or sulfuric acid or by reacetalisation with a corresponding orthoester, e.g. triethyl orthoformate. Preferred temperatures are from 0 to 100°C, most preferably from 30 to 60°C.
W for the preparation of conpounds of general formula I wherein Z represents an ethylene group substituted by a carboxy or C2_4 alkoxycarbonyl groups Condensation of a conpound of formula I (wherein Z represents a formyl group) followed, if required by hydrolysis of the product thus obtained whereby the desired conpound of formula I is obtained.
The condensation of the formyl conpound is conveniently carried out in the presence of a solvent such as pyridine or tetrahydrofuran, with malonic acid, with a malonic acid ester or a trialkylphosphone acetate optionally in the presence of a base as condensating agent, e.g. in the presence of potassium tertbutylate, sodium hydride or piperidine. Preferred temperatures are from 0 to 100°C. The acid,where required, is obtained by subsequent acidification, e.g. with hydrochloric acid or sulfuric acid.
X for the preparation of compounds of general formula I wherein Z represents an acetyl group optionally substituted by a C2_4 alkoxycarbonyl group: Subjection of a compound of formula I (wherein Z represents a hydrogen at can) to Friedel-Crafts acylation.
The Friedel-Crafts acylation is conveniently carried out with a corresponding acid halide or acid anhydride in a solvent such as e.g. carbon disulfate, methylene chloride, dlchloroethane or nitrobenzene and in the presence of a Friedel-Crafts catalyst such as e.g. aluminium chloride. Preferred temperatures are from 0 to 50°C, most preferably ambient temperature.
Y for the preparation of compounds of general formula I wherein Z represents a tri(Cg_3 alkoxy)methyl group: Subjection of a compound of formula I (wherein Z represents a cyano group) to alcoholysis via the corresponding imino ester.
The alcoholysis is preferably carried out in the presence of a corresponding anhydrous alcohol as solvent, e.g. in anhydrous methanol, ethanol or propanol, and in the presence of an acid such as e.g. hydrochloric or sulfuric acid, preferably at elevated temperatures, most preferably at the boiling point of the reaction mixture.
Z for the preparation of compounds of general formula I wherein Z represents a C2-4 alkoxycarbonyl group: Hydrolysis of a compound of formula X (wherein Z represents a tri(Cg_3 alkoxy)methyl group).
The hydrolysis of the orthoester is conveniently carried out in the presence of a solvent such as water/ methanol, water/dioxan, water/ethanol or water/propanol and in the presence of an acid such as e.g. hydrochloric acid, preferably at low temperatures, e.g. ambient temperature.
AA for the preparation of compounds of general formula I wherein Z represents a carboxymethyl group: Heating of a compound of formula I (wherein Z represents an acetyl group) with an amine and sulfur and subsequent heating of the thioamide thus obtained with an inorganic base, i.e. according to the Willgerodt reaction.
The Willgerodt reaction is conveniently carried out in the presence of 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 sulfur. The thus obtained thioamine is subsequently converted to the corresponding acetic acid derivative by heating in the presence of an inorganic base such as e.g. sodium hydroxide. According to a particularly advantageous embodiment the reaction is carried out at the boiling point of the reaction mixture.
AB for the preparation of compounds of general formula I wherein Z represents a formyl group: Conversion of a compound of formula I (wherein Z represents a carboxy group) into a corresponding sulfonic acid hydrazide and subsequent subjection of the said sulfonic acid hydrazide to disproportionation.
The disproportionation of the sulfonic acid hydrazide, preferably obtained by reaction of a hydrazine with an appropriate reactive carboxylic acid derivative, is conveniently carried out in the presence of a base such as e.g. sodium carbonate and in a solvent such as e.g. ethylene glycol preferably at temperatures of from 100 to 200°C, most preferably at from 1(·0 to 170°C.
AC for the preparation of compounds of general formula I wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom or a Cj_g alkyl, C^_g alkoxy or phenyl(C^_3 alkoxy) group; . Y represents a methylene group (optionally substituted by 1 or 2 Cj_3 alkyl groups); and Z represents a carboxy group: Conversion of a compound of formula I [wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom or a Cg_g alkyl, C^_g alkoxy or phenyl(Cj_3 alkoxy) group; Y represents a methylene group (optionally substituted by 1 or 2 Cj_3 alkyl groups); and Z represents a chlorine or bromine atom] into a corresponding organometallic derivative and reaction of the said organometallic derivative with carbon dioxide.
The conversion of an acid of formula I into a corresponding organometallic compound is conveniently carried out in the presence of an inert solvent such as e.g. diethyl ether, tetrahydrofuran, dioxan or tetrahydrofuran/n-hexane optionally under an inert gas, e.g. nitrogen, preferably with an appropriate lithium compound, e.g. butyl lithium in n-hexane. Preferred temperatures are from -60 to +50°C. The thus obtained solution of the organometallic derivative may then be added to solid carbon dioxide under an inert gas.
Compounds of general formula I wherein Rg and Rg, together with the nitrogen atom to which they are attached represent a cyclic imino group as hereinbefore defined may, if desired, be converted into their acid addition salts, e.g. their physiologically compatible acid addition salts, by reaction with an acid. Suitable acids include, for example hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic and fumaric acids. Compounds of general formula I wherein Z represents or contains a carboxy group may also be converted into their salts with bases, e.g. their physiologically compatible salts, by reaction with a base. Suitable bases include, for example, sodium hydroxide, potassium hydroxide and cyclohexylamine.
The compounds of general formulae II and XV are in general known from the literature or may be obtained according to processes known from the literature.
A number of the compounds useful in the above described processes and in particular a number of those of formulae II and XV are novel compounds which are not only useful as intermediates in the preparation of compounds of general formula I but also themselves exhibit interesting pharmacological properties and in particular a lipid lowering activity.
For examples the compounds A = 4-L2-(5-Chloro-2-dimethylaraino-benzoylamino)-ethyf] -benzoic acid, B = 4-(2-(5-Bromo-2-dimethylamino-benzoylamino)-ethyj]- benzoic acid, C = 4-[2-(5-Ch1oro-2-piperi di no-benzoyl amino)-ethyj}-benzoic acid methyl 5 ester, D = 4-[2-(5-Chloro-2-piperidino-benzoylamino)-ethyi] benzoic acid, E = 4-f2-(5-Chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyi] benzoic acid, F = 4-[2-(5-Chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl] benzoic 10 ’ acid, G » 4-/5-(5-Chloro-2-(4-aethyl-piperidlno)-benzoylamino)ethyl/benzoic acid, H » 4-/5-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)ethyl/benzoic acid methyl ester, I - 4-/5-(5-Chloro-2-(3,5-diaethyl-piperidino)-benzoylamino)ethyl/benzoic acid, K * 4-/5-(5-Chloro-2-(4-methoxy-piperidi.no)-benzoylamino)ethyl7benzoic acid, L = 4-/5-(5-Methoxy-2-piperidino-benzoylamino)-ethyl7benzoic 20 acid hydrochloride, M = 4-/5-(5-Chloro-2-heptamethylenimino-benzoylamino)-ethyl7benzoic acid, N « 4-/5-(5-Chloro-2-(1,4-dioxa-8-aza-spiro/5,£7decane-8-ylbenzoylaminoj-ethyl/benzoic acid, 0 4-/5-(5-Chloro-2-hexamethylenimino-benzoylamino)-ethyl7benzoic acid, P « 4-/5-(5-Chloro-2-thiomorpholino-benzoylamino)-ethy27benzoic acid, Q = 4-/2-(5-Bromo-2-piperidino-benzoylamino)-ethyl/benzoic acid, R = 4-/2-(5-Chloro-2-piperldino-benzoylamino)-1-methylethyl/benzoic acid, 5 S = 4-/2-(5-Bromo-2-(2-methyl-piperidino)-benzoylamiHo)ethyiybenzoic acid, T = 4-/5_(5-Chloro-2-(2,6-dimethyl-morpholino)-benzoylamino)-ethyl/benzoic acid, U =, 4-/2-(5-Chloro-2-(2,6-dimethyl-thiomorpholino)-benzoyl10 amino)-ethyl/benzoic acid, V = 4-/2-(5-Bromo-2-heptamethylenimino-benzoylamino)-ethyl7benzoic acid ethyl ester, W = 4-/2-(5-Bromo-2-heptamethylenimino-benzoylamino)-ethyl7benzoic acid, X = 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7benzolc acid, Y = 4-/?-(5-Chloro-2-(decahydro-isoquinoline-2-yl)-benzoylamino)-ethyl/benzoic acid hydrochloride, Z = 4-/2- (5-Bromo-2-octamethylenimino-benzoylamino)-ethyl/2u benzoic acid hydrochloride, AA = 4-/2-(5-Ethyl-2-piperldlno-benzoylamino)-ethyl/benzoic acid, BB = 4-/?-(5-Methyl-2-piperidino-benzoylamino)-ethyl/benzoic acid, CC = 4-/2-(2-(N-Adamantyl-(1)-N-methylamino)-5-chloro-benzoylamino)-ethyl/benzoic acid, DD = 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7benzoic acid ethyl ester, EE = 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyi7benzyl alcohol, FF > N^-(1-(4-Carboxyphenyl)-ethyl)-N2-(5-chloro-2-piperidino-benzoyl)-hydrazine, and GG - 4-/T-(5-Chloro-2-octamethylenimlno-benzoylaainoxy)ethyl/benzoic acid were tested in conparison to HH 4-/?-(2-Ethylamino-5-chloro-benzoylamino)-ethyl7benzoic acid (see Example 5 of Belgian Patent Specification No. 837,311) 50392 1, Blood-sugar lowering activity; The blood-sugar lowering activity of the test compounds was determined in home-bred female rats with a weight of 180 - 220 g. 24 hours before starting the test the animals were starved. Before the test the compounds were suspended in 1.5% methyl cellulose and administered to the animals by means of an oesophageal tube.
Blood was taken before administering the test 10 compounds as well at 1, 2, 3 and 4 hours after administration each from the retroorbital plexus vein. /ig of each sample were deproteinized with 0.5 ml of / J 0.33 N perchloric acid and centrifuged. The glucose content was determined in the supernatant according to the Hexokinase method by means of an analysis photometer. The statistical evaluation was performed with the t-test according to Student with p = 0.05.
The following table contains the obtained values in percent compared with the controls: Table 1 Test 25 mg/kg 10 mg/kg 5 mg/kg com- .j pound 2 3 hours 4 1 2 3 hours 4 1 2 3 hours 4 A -31 -21 -10 -10 -32 -18 n.s. n.s. -12 n.s. n.s. n.s. B -33 -23 i a„s. n.s. -14 - 9 n.s. n.s. n.s. n.s. n.s. n.s. C -44 -37 -23 -24 -41 -26 -23 -14 -31 -21 -18 -15 D -44 -45 -41 -38 -33 -37 -36 -26 -37 -34 -28 -30 E -42 -43 -38 -31 -34 -24 -14 n.s. -31 -18 n.s. n.s. F -51 -48 -41 -40 -41 -40 -44 -39 -44 -42 -38 -35 G -30 -24 -27 -25 -24 -26 n.s. n.s. -24 -20 -21 -13 H -35 -41 -44 -38 -39 -46 -33 -20 -42 -47 -42 -43 I -41 -37 -38 -40 -39 -38 -30 -40 -47 -46 -49 -50 Continuation of table 1: Test 25 ag/kg compound 12 3 hours ag/kg 3 4 hours ag/kg 3 4 hours K -43 -44 -39 -34 -40 -34 -16 n.s. -40 -32 -20 n.s. L -47 -39 -29 -27 -34 n.s. -15 -16 -37 -29 n.s. n.s. M -38 -40 -38 -36 -38 -37 -38 -36 -42 -41 -40 -34 N -43 -41 -36 -25 -35 -34 -24 -19 -36 -17 -10 n.s. 0 -41 -37 -33 -24 -42 -39 -25 -22 -33 -26 -28 -15 P -37 -41 -32 -30 -37 -30 -26 -21 -29 -19 n.s. n.s. Q -38 -39 -34 -37 -40 -42 -43 -44 -32 -40 -32 -23 R -52 -37 -37 -30 -25 -28 -21 -21 -27 -25 n.s. n.s. S -42 -44 -38 -32 -39 -34 -24 -12 T -48 -29 -25 -33 U -41 -43 -41 -40 V -34 -43 -39 -40 -19 -19 -24 -26 W -44 -49 -41 -46 -34 -36 -38 -38 X -51 -44 -39 -41 -45 -43 -45 -46 -37 -43 -37 -49 Y -40 -45 -45 -49 -46 -79 -38 -46 z -45 -43 -42 -35 AA -40 -44 -29 -39 -41 -40 -32 -32 RB -40 -31 -14 n.s. CC -39 -42 -41 -38 DD -39 -26 -22 -25 -37 -18 n.s. n.s. -28 -17 n.s. n.s. EE -42 -41 -43 -41 -42 -41 -40 -43 -42 -41 -40 -43 FF -35 -36 -28 -23 GG n.s . -31 -33 -22 -15 -25 -13 n.s. HH -41 -21 n. s. n.s. n.s. » statistically not significant 3, Acute Toxicity: The acute toxicity was determined in home-bre^ female and male mice with a body weight of 20 - 26 g after oral administration (suspension in 1% methyl cellulose) of a single dose. Observation time: at least 7 days.
The following table contains the values obtained: Test peroral toxicity compound A >2000 mg/kg (0 out of 6 animals died) B >1000 mg/kg (0 out of 5 animals died) D >2000 mg/kg (0 out of 6 animals died) H >1000 mg/kg (0 out of 6 animals died) 0 >1000 mg/kg (0 out of 10 animals died) T >1000 mg/kg (0 out of 10 animals died) V >1000 mg/kg o out of 10 animals died) VI >1000 mg/kg (0 out of 6 animals died) X >1000 mg/kg (0 out of 6 animals died) Based on their pharmacological properties the compounds of general formula I according to the invention and their physiologically compatible salts are suitable for the treatment of diabetes mellitus whilst the compounds of general formula la are suitable for the treatment of artherosclerosis and of hyperlipidemic conditions, particularly of type IIA, IIB and IV.
The following non-limiting examples serve to illustrate the present invention. Preparation of the starting products: EXAMPLE A 2-(Decahydro-laoqulnollne-2-yl)-5-nitro-benzoic acid 19 g (0.1}6 aol) of decahydro-ieoquinoline, 27.3 g (0.136 aol) of 2-chloro-5-nitro-benzoic acid and 38.6 g of potassiua carbonate were refluxed in 500 al of ethanol for 18 hours whilst stirring. After distilling off the ethanol, the residue was dissolved in 800 al of water and waa adjusted to pH 4 by addition of 2N hydrochloric acid, whereby the reaction product was obtained in crystalline fora.
Yield: 38 g (92 % of theory), M.p.: 132 - 134°C (ieopropanol) Calc.: C 63.14 H 6.62 M 9.20 Found: 63.02 6.48 9.38 EXAMPLE B 2-(1.4-Dioxa-8-aza-8piro/5.57decane-8-vl)-5-nitro-benzolc acid A aixture of 20.1 g (0.1 aol) of 2-chloro-5-nltro-benzoic acid and of 42.9 g (0.3 aol) of 1,4-dioxa-8-aza-spiro/5,^7decane was heated for 8 hours in 200 al of ethanol up to the reflux temperature. After distilling off the solvent, the evaporation residue was taken up in water and adjusted to pH 5.2 by addition of 2N hydrochloric acid, whereby the product was precipitated. Subsequently, the reaction product was extracted with chloro25 fora and dried over sodiua sulfate and after distilling off the solvent, the coapound was crystallized.
Yield: 12 g (39 % of theory), M.p.: 155°C (ethanol).
Calc.: C 54.54 H 5.24 N 9.09 Found: 54.20 5.13 8.97 Analogously to the Examples A and B the following compounds were prepared; 2-(2-Hathyl-piperidino)-5-®itro-bemzoic acid Yields 99 55 of theory, B.p.s 164°C. 2-(3-Hethyl-piperidino)-5-nitro-benzoic acid 5 Yields 85 $ of theory, m.p. s 161°C. 2-(4-Hethyl-piperidino)-5-nltro-bsnzoic acid Yields 85 % of theory, m.p.s 155°C. 2-(3-Ethyl-6-nethyl-piperidino)-5-nitro-benzoic acid Yields 76 % of theory, B.p.s <20°C. 2-(3,5-Dimethyl-piperidino)-5-nitro-benzoic acid Yields 65 % of theory, m.p.s 172°C. 2-(4-Methoxy-piperidino)-5-nitro-benzoic acid Yields 68 % of theory, B.p. s 140°C.
-Mitro-2-(4-phenyl-piperidino)-benzoic acid 15 Yields 88 % of theory, m.p.s 196°C. 2-(4-Ethoxycarbonyl-piperidino)-5-nitro-benzoic acid Yields 82 % of theory, m.p.s 16O°C.
-Mitro-2-thioaorpholino-benzoic acid Yields 80 % of theory, m.p.: 235°C.
-Nitro-2-(1,2,4,5-tetrafaydro-3 benzazepino)-benzoic acid Yield: 68 % of theory, m.p.s 222°C.
-Nitro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid Yields 70 % of theory, B.p.s 195°C. 5029 2 _ 5-Nitro-2-(4-phenyl-piperazino)-benzoic acid Yield; 88 % of theory, a.p.: 196°C.
-Nitro-2-(4-pyridyl-(2)-piperazino)-benzoic acid Yield; 66 % of theory, a.p.; 192°C. 2-(trana-3,5-Diaethylpiperidino)-5-nitro-benzoic acid Yield; 63 % of theory, a.p.; 132°C. 2-(3,3,5,5-Tetraaethyl-piperidiao)-5-nitro-benzoic acid Yield; 98 % of theory, a.p.; 138°C. 2-(3,5-Diaethyl-aorpholino)-5-nitro-benzoic acid 10 Yield; 75 % of theory, a.p.; 164°C. 2-(3,5-Diaethyl-thioaorpholino)-5-nitro-benzoic acid Yield; 70 % of theory, a.p.: 118°C. 2-(3-Aza-bicyclo/?,2,27nonane-3-yl)-5-nitro-benzoic acid Yield: 72 % of theory, a.p.: 221°C.
-Kitro-2-nonaaethyleniaino-benzoic acid Yield: 80 % of theory, a.p.: 127°C.
-Hitro-2-decaaethylenlaino-benzoic acid Yield: 92 % of theory, a.p.: 128°C.
-Nitro-2-undecaaethyleniaino-benzoic acid 20 Yield: 91 % of theory, a.p.: 120°C.
-Nitro-2-dodecaaethylenialno-benzoic acid Yield: 95 % of theory, a.p.: 115°C. 2-(N-Methyl-M-phenylaaino)-5-nitro-benzoic acid Yield: 10 % of theory, a.p.: 115°C. 2-(W-Etfeiyl-M-cyclohe7qzlai3ira.o)=5-iaiiiff©-bea2oic acid Yield! 78 % of theory,, a.p. s 74°C. 2-(H-Butyl-H-cyclohesylamino S-S-nitro-baazoic acid Yields 84 Si of theory, a.p.s 56°C. 2-(H-Cyclohesyl-Ei-isobutylai3imo)"5"nitro-b@nzoic acid Yields 63 % of theory, a.p.s < 20®C. 2-(B3cahydro-3-bemzasepij»e-3-yi)=5"ffiitro-beiffl2©ic acid Yields 98 % oi theory, a.p.s < 20°C. 2-(0ctahydro-isoindole-2-yl)-5=mitro-benzole acid 10 Yields 80 % of theory, m.p.s 128°C. 2-(4-Isopropyl=piperidino)"5-nitro-bemsoic acid Yields 79 $ of theory, s.p.s 142°C. 2-(4-tert.Butyl-piperidino)-5-nitro-benzoic acid Yields 57 % of theory, a.p.s 136°C. 2-(1,4-Dioxa-8-aza-spiro25,67umdecane-8-yl)-5-nitro-benzoic acid Yields 75 % of theory, m.p.s 135°C. 2,4-Dipiperidino-5-nitro-benzoic acid Yields 31 % of theory, m.p.s 152°C. 4- Chloro-2=piperidino-5-nitro-benzoic acid 20 Yields 18 % of theory, m.p.s 133°C.
- Nitro-2-(l„2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 5Θ % of theory, a.p.s 215°C. 2-(N-Ifethyl-N-benzylamino)-5-nitro-benzoic acid Yields 93 Si of theory, m.p.s 123 - 126°C. 2-/5- (4-Chlorophenyl)-plperazino7-5-nitro-benzoic acidhydrochloride Yield: 71.5 % of theory, a.p.: 225 - 227°C (decoap.). 2-(4-Carbethoxy-piperazino)-3-nitro-benzoic acid 5 Yield: 23.1 % of theory, a.p.: 155 - 156°C. 2-/5-(2-Furoyl)-piperazino7-5-nitro-benzoic acid Yield: 64.8 % of theory, a.p.: 200 - 205°C. 2-(4-Benzyl-piperazino)-5-nitro-benzoic acid hydrochloride Yield: 86.6 % of theory, a.p.: 142 - 145°C.
EXAMPLE C 2-Hexaaethylenlalno-5-nltro-benzolc acid nitrile A aixture of 18.4 ( (0.11 aol) of 2-chloro-5-nitTo-benzoic add nitrile and of 22.4 g (0.21 aol) of hexaaethyleniaine was refluxed for 4 hours in 250 al of ethanol. After cooling the product was oily precipitated by addition of 500 al of water. The precipitate was taken up in chlorofora and after drying with sodiua sulfate and distilling off the chlorofora, the evaporation residue was recrystallized froa ethanol. Yield: 19.7 g (73 % of theory), M.p.: 70°C.
Calc.: C 63.65 H 6.16 H 17.13 Found: 63.80 6.07 17.05 29 2 Example D.
-Ainlno-2-(decahydro-lgoqulnoXine-2-yl)-b8azolc acid g (0.118 nol) of 2-(deoahydro-isoquinoline-2-yl)-5-nitrobenzoic acid were dissolved in 250 ml of dimethyl formamide and the solution was hydrogenated at room teaparature with a hydrogen pressure of 5 bar hy addition of 10 % palladium charcoal as catalyst. After finished hydrogen absorption, the catalyst was filtered off, the solvent was distilled off in vacuo and the residue was recrystallized from ethanol.
Yields 31.2 g (96 % of theory), M.p. s 252°C.
Calc.: C 70.04 H 8.08 ft 10.20 Found: 70.09 7.85 10.12 Example E.
-Affllao-2-(1„4-dloxa-8-aza-spiro/^.57decane-8-yl)-benzoic acid g (0.039 mol) of 2-(1,4-dioxa-8-aza-spiro/£,27decane-8-yl)5-nitro-benzoic acid were hydrogenated at room temperature in 100 ml of dimethyl foraanide at a hydrogen pressure of 5 bar by addition of 10 % palladium charcoal as catalyst. After finished hydrogen absorption the catalyst was filtered off, the solvent was distilled off and recrystallized from ethanol.
Yields 9 g (83 % of theory), M.p.: 2O9°C.
Calc.: C 60.42 H 6.56 N 10.07 Found: 60.18 6.58 10.12 Analogously to the Example 0 and E the following compounds were prepared: -Aaino-2~pyrrolidino-benzoic acid Yield: 79 % of theory, m.p.: 208°C. 5-Amino-2-(2-aethyl-piperidino)-benzoic acid Yield: 84 % of theory, m.p.: 240°C.
-Amino-2-(3-aethy -piperidino)-benzoic acid Yield: 75 % of theory, a.p.: 192°C.
-Aaino-2-(4-aethyl-piperidino)-benzoic acid ,0 Yield: 88 % of theory, a.p.: 215°C.
-Aaino-2-(3-ethyl-6-aethyl-piperidino)-benzolc acid Yield: 59 % of theory, a.p.: 219°C.
~Aaino-2-(cis-3,5-diaethyl-piperidino)-benzoic acid Yield: 87 % of theory, a.p.: 234°C.
-Amino-2-(4-aethoxy-piperidino)-benzoic acid Yield: 80 % ot theory, a.p.: 228°C.
-Aaino-2-heptaaethyleniaino-benzoic acid Yield; 64 % of theory, m.p.: 214°C.
-Aaino-2-(4-phenyl-piperidino)-benzoic acid 20 Yield: 76 % of theory, a.p.: 275°C.
-Amino-2-(4-ethoxycarbonyl-piperidino)-benzoic acid Yield: 85 % of theory, a.p.: 203°C.
-Amino-2-thioaorpholino-benzoic acid Yield: 76 % of theory, a.p.: 193°C. - 5-Anirao-2-(l,2,4,5-tetrahydro-3 bemzazepino)-benzoic acid Yield: 86 % of theory, a.p.: 258°C.
-Aaino-2-(1,2,3,4-tetrahydro-iaoqniaolino)-benzoic acid Yield: 66 % of theory, m.p.: 220°C.
-Asino-2-(4-phemyl-piperazino)~beazoic acid Yield: 83 $ of theory, m.p.: 255°C.
-AQino-2-(4-pyridyl-(2)-piperazino)-benzoic acid Yield: 80 % of theory, m.p.: 248°C.
-Amino-2-(trans-3,5-dimethyl-piperidino)-benzoic acid IO Yield: 89 % of theory, m.p.: 156°C.
-Amino-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid Yield: 98 % of theory, m.p.: <20°C.
-Asaino-2- (3,5-dimethyl-iaorpholino) -benzoic acid Yield: 83 % of theory, m.p.: 255°C. 5-Amino-2-(3,5-dimethyl-thlomorpholino)-benzoic acid Yield: 50 % of theory, m.p.: 233°C.
-Amino-2-(3-aza-bicyclo/^,2,27nonane-3-yl)-benzoic acid Yield: 86 S$ of theory, m.p.: 288°C. t -Araino-2-octamethylenimino-benzoic acid 20 Yield: 88 % of theory, m.p.: 191°C.
-Amino-2-nonaiaethylenimino-benzoic acid Yield: 80 % of theory, m.p.: 212°C.
-Amino-2-decamethylenimino-benzoic acid Yield: 52 % of theory, m.p.: 202°C. s- 5-Amino-2-undecamethylenimino-benzoic acid Yield: 93 % of theory, a.p.: 242°C.
-Aaino-2-dodecaaethylenimino-benzoic acid Yield: 59 % of theory, a.p.: 224°C.
-Amino-5-(N-methyl-N-phenylamino)-benzoic acid Yield: 47 # of theory, a.p.: 184°C.
-Amino-2-(N-ethyl-N-cyclohexylaalno)-benzoic acid Yield: 66 % of theory, a.p.: 16O°C.
-Aaino-2-(N-butyl-N-cyclohexylaalno)-benzoic acid 10 Yield: 48 % of theory, a.p.: 14O°C.
-Aaino-2-(H-cyclohexyl-N-isobutylamino)-benzoic acid Yield: 62 # of theory, a.p.: < 20°C.
-Amino-2-(decahydro-3 benzazepine-3-yl)-benzoic acid Yield: 54 % of theory, a.p.: 204°C.
-Aaino-2-(octahydro-isoindole-2-yl)-benzoic acid Yield: 43 % of theory, m.p.: 228°C.
-Amino-2-(4-ieopropyl-piperidino)-benzoic acid Yield: 50 % of theory, m.p.: 231°C.
-Amino-2-(4-tert.butyl-piperidino)-benzoic acid 20 Yield: 81 % of theory, m.p.: 276°C.
-Amino-2-(1,4-dioxa-8-aza-spiro/5,67undecane-8-yl)-benzoic acid Yield: 49 % of theory, m.p.: 235°C.
-Amino-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 51 % of theory, m.p.: 232°C. '*'5-Aaino-2-(4-methyl-piperazimo)"benzoic acid hydrochloride Yield! 90 % of theory, a.p.: <20°C.
-Anino-2-(N-B®thyl-N-benzylaaino)-benzoic acid Yield: 95 % of theory, m.p.: <20°C -Aaino-2-/5-(4-chloro-phemyl)-plperazino7benzoic acid hydrochloride Yield: 80.5 % of theory, m.p.: 3O5°C (decoap.). -taino-2-(4-carbethoxy-piperazino)-benzoic acid Yield: 87.5 # of theory, m.p.: 195 - 197°C. -toino-2-/5-(2-furoyl)-piperazino7benzoic acid Yield: 97 % of theory, a.p.: 420°C.
-Amino-2-(4-benzyl-piperazino)-benzoic acid hydrochloride Yield: 80 % of theory, m.p.: 200 - 210°C.
Example F l5 5-Chloro-2-(decahydro-isoquinoline-2-vl)-benzolc acid g (Ο.Ο365 sol) of 5-amino-2-(decahydro-isoquinoline-2-yl)benzoic acid were dissolved in 55 ml of semi-conc. hydrochloric acid and the solution was diazotized at 0°C by dropwise addition of a solution of 2.7 g (0.039 mol) of sodium nitrate in 10 ml of water. After the addition was finished the reaction mixture was stirred for 15 minutes and subsequently, the diazonium salt solution was dropped into a suspension of 4 g of copper powder in 40 al of cone, hydrochloric acid. After stirring over night a deep green homogeneous solution was obtained, which was di25 luted with 100 ml of water and subsequently was completely extracted with chloroform. After drying over sodium sulfate the chloroform evaporation residue was purified by chromatography over a silicagel column with an eluant of ethyl acetate/ methanol = 9-5 : 0.5. soaa Yield: 4.8 g (45 % of theory), M.p.: 138°C.
Calc.: C 65.41 H 6.85 M 4.76 Found: 65.51 7.07 4.89 Cl 12.06 12.32 5 Example G -Chloro-2-(1.4-dloxa-8-a2a-8plro/?.57decane-8-yl)-benzolc acid 8.5 g (0.031 mol) of 5-aaino-2-(1,4-dioxa-8-aza-splro25,^7decane-8-yl)-benzoic acid were dissolved in 28 al of seaiconc. hydrochloric acid and diazotized at 0°C with a solu10 tion of 2.4 g (0.034 mol) of sodium nitrite in 10 al of water.
The diazonium salt solution was dropped whilst stirring to a suspension of 3 g of copper powder in 3 al of cone, hydrochloric acid. After finished nitrogen formation the reaction mixture was stirred for 2 hours, diluted with water and extracted with chloro fora. After drying over sodium sulfate the solvent was distilled off and when digesting the evaporation residue with petroleum ether, 6.1 g (66 Ji of theory) of the compound were obtained.
M.p.: 180°C.
Calc.: C 56.47 H 5.42 N 4.71 Found: 56.11 5.37 4.83 Analogously to the Examples F and G the following compounds were prepared: -Chloro-2-pyrrolidino-benzoic acid Yield: 30 % of theory, m.p.: 164°C.
-Chloro-2-(2-aethyl-piperidino)-benzoic acid Yield: 74 % of theory, m.p.: 124°C.
-Chloro-2-(3-methyl-piperidino)-benzoic acid Yield: 47 % of theory, m.p.: 165°C. — 5-Chloro-2-(4-methyl-piperidino)-benzoic acid Yield: 52 $ of theory, B.p.: 107°C. 2-(3-Ethyl-6-aethyl-piperidino)-5-cfaloro-benzoic acid Yields 75 % oi theory, m.p.: <20°C.
=Chloro-2-(cis-3,5-diaethyl-piperidino)-beazoic acid Yields 46 % of theory, m.p.: 167°C.
-Chloro-2-(trans-3,5-diaethyl-piperidino)-benzoic acid Yields 63 % of theory, m.p.s 132°C.
-Chloro-2-(4-iaethoxy-piperidino)-benzoic acid 10 Yields 63 % of theory, m.p.s 136°C.
-Chloro-2-heptaaethylenimino-benzoic acid Yields 58 % of theory, m.p.s < 20°C.
-Chloro-2-(4-phenyl-piperidino)-benzoic acid Yields 51 % of theory, m.p.: 217°C.
-Chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid Yield: 97 % of theory, m.p.s<20°C.
-Chloro-2-hexamethylenimino-benzoic acid Yields 34 % of theory, m.p.s 113°C.
-Chloro-2-thiomorphollno-benzoic acid 20 Yields 16 % of theory, m.p.: 16O°C.
-Chloro-2-(1,2,4,5-tetrahydro-3 benzazepino)-benzoic acid Yield: 59 % of theory, m.p.: 174°C.
-Chloro-2-(l,2,3,4-tetrahydro-isoquinolino)-benzoic acid Yield: 50 % of theory, m.p.s 182°C.
-Chloro-2-(4-phenyl-plperazino)-benzoic acid Yield; 42 % of theory, a.p.: 154°C.
-Chloro-2-(4-pyridyl-(2)-plperazlno)-benzoic acid Yield: 45 % of theory, a.p.: 168°C.
-Broao-2-(2-aethyl-piperidino)-benzoic acid Yield: 31 % of theory, a.p,: 168°C.
-Chloro-2-(3,3,5,5-tetraaethyl-piperidino)-benzoic acid Yield: 62 % of theory, a.p.: <20°C.
-Broao-2-(4-aethoxy-piperidino)-benzoic acid 10 Yield: 48 % of theory, a.p.: 138°C.
-Chloro-2-(3,5-dlaethylaorpholino)-benzoic acid Yield: 50 X of theory, a.p.: 174°C.
-Chloro-2-(3,5-diaethyl-thioaorpholino)-benzoic acid Yield: 18 X of theory, a.p.: 134°C.
-Broao-2-heptaaethyleniaino-benzoic acid Yield: 15 X of theory, a.p.: 104°C.
-Chloro-2-(3-aza-bicyclo/J,2,27nonane-3-yl)-benzoic acid Yield: 16 X of theory, a.p.: 199°C.
-Chloro-2-octaaethyleniaino-benzoic acid 20 Yield: 70 X of theory, a.p.: 84°C.
-Chloro-2-nonaaethyleniaino-benzoic acid Yield: 30 X of theory, a.p.: 78°C.
-Chloro-2-decaaethyleniaino-benzoic acid Yield: 65 X of theory, a.p.: 70°C. — 5-Chloro-2-undecamethylenimino-benzoic acid Yield: 41 $ of theory, m.p.: 41°C.
-Chloro-2-dodecaaethyleniaino-benzoic acid Yield: 56 % of theory, m.p.: 40°C.
-Chloro-2-(N-phenyl-M-methylamino)-benzoic acid Yield: 27 % of theory, a.p.: 164°C. 2-(W-Ethyl-N-cyclohexylamino)-5-chloro-benzoic acid Yield: 24 % of theory, m.p.: 152°C. 2-(N-Butyl-N-cyclohexylamino)-5-chloro-benzoic acid 10 Yield: 16 % of theory, m.p.s 145°C.
-Chloro-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid Yield: 22 % of theory, m.p.s 131°C.
-Chloro-2-(decahydro-3 benzazepine-3-yl)-benzoic acid Yield: 70 % of theory, m.p.s 153°C.
-Brorao-2-(decahydro-3 benzazepine-3-yl)-benzoic acid Yield: 54 % of theory, m.p.: 154°C.
-Chloro-2-(octahydro-isoindole-2-yl)-benzoic acid Yield: 33 % of theory, m.p.: 164°C.
-Bromo-2-octamethylenimino-benzoic acid 20 Yields 48 % of theory, m.p.: 94°C.
-Chloro-2-(4-isopropyl-pipt ridino)-benzoic acid Yield: 43 % of theory, m.p.: 172°C.
-Chloro-2-(4-tert. butyl-pip -iridino)-benzoic acid Yield: 35 % of theory, m.p.: 161°C.
-Chloro-2-(l,4-dioxa-8-aza-spiro/5,67undecane-8-yl)-benzoic acid Yield: 42 % of theory, a.p.: 163°C.
-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 73 % ot theory, a.p.: 173°C.
-Chloro-2-(4-aethyl-piperazino)-benzoic acid hydrochloride Yield: 75 % of theory, a.p.: 132°C (decoap.).
-Chloro-2-(N-aethyl-N-benzylaaino)-benzoic acid Yield: 18.2 % ot theory, a.p.: 156 - 157°C.
-Chloro-2-/5-(4-chloro-phenyl)-piperazino7benzoic acid Yield: 30.5 % of theory, a.p.: 228 - 230°C.
-Chloro-2-/5-(2-furoylj-piperazino/benzoic acid Yield: 33.1 % of theory, a.p.: 200 - 202°C. 2-(4-Benzyl-piperazino)-5-chloro-benzoic acid hydrochloride Yield: 42.8 % of theory, a.p.: 230 - 232°C (decoap.).
Example H -Amino-hexaaethylenialno-benzolc acid nitrile 21.4 g (0.087 aol) of 2-hexaaethyleniaino-5-nitro-benzoic acid nitrile were dissolved in 200 al of dioxane and 500 al of me20 thanol and the solution was hydrogenated at rooa temperature with a hydrogen pressure of 5 bar in the presence of 10 % palladium charcoal as catalyst. After filtering off the catalyst and distilling off the solvent, 20 g (100 % of theory) of the coapound were obtained.
M.p.: i 20°C.
Example ι -Chloro-2-he3MiaethvlenlBlno-benzoic acid, nitrile g (0.092 Qol) of 5-amino-2-hexamethylenimino-benzoic acid nitrile were dissolved in 90 nl of semi-conc. hydrochloric acid and at 0°C the solution was diazotized by dropwlsely adding a solution of 6.5 g (0.094 mol) of sodium nitrite in 50 ml of water. After finished addition the reaction mixture was stirred for 15 minutes. The diazonium salt solution was dropped whilst stirring to a solution of copper-(I)-chloride in cone, hydrochloric acid, which was warmed up to 70°C.
After the nitrogen formation was finished, the reaction solution was extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the evaporation residue was purified by chromatography over a silicagel column (eluent: toluene).
Yields 5 g (25 % of theory), M.p.s <20°C.
Example J -Chloro-2-hexamethylenlmlno-benzoic acid g (0.021 mol) of 5-chloro-2-hexamethylenimino-benzoic acid nitrile were heated in 32 g of potassium hydroxide solution and 20 ml of water for 8 hours up to 170°C. The cold melt was dissolved in water and the amide was precipitated quantitatively by acidifying to a pH value of 5. By hydrolysis with semi-conc. hydrochloric acid 3.6 g (67.4 % of theory) of the compound were obtained.
M.p.: 113°C.
Analogously to the Examples H to J the following compounds were prepared: 2-Morpholino-5-nitro-benzoic acid nitrile Yield: 78 % of theory, m.p.: 138°C.
-Aaino-2-aorphollno-benzoic acid nitrile Yield: 68 % of theory, a.p.: 142°C.
-Chloro-2-«orpholino-benzoic acid nitrile YieLd: 20 % of theory, a.p.: 57°C.
-Chloro-2-aorpholino-benzaaide Yield: 98 % of theory, a.p.: 280°C.
-Chloro-2-aorpholino-benzoic acid Yield: 60 % of theory, a.p.: 157°C.
Example K -Cyano-2-octaaethylenlalno-benzolc acid 26.2 g (0.1 aol) of 5-aaino-2-octaaethyleniaino-benzoic acid were dissolved in 38 al of cone, hydrochloric acid, 280 al of water were added and the solution was diazotized at 0°C by dropwise addition of a solution of 7.6 g (0.11 aol) of sodium nitrite in 30 al of water. After stirring for 30 ainutes the solution was adjusted to pH 7 by aeans of sodiua carbonate. Subsequently, a solution of trisodium-tetracyano-copper-(I)coaplex was dropwisely added at 0°C to the diazonium salt solution.
This copper-(I)-complex solution was obtained in the following way: 32 g (0.128 aol) of copper sulfate x 5 HgO and 8.7 g of sodiua chloride in 100 al of water were reduced to the copperdi-chloride by aeans of a sodiua hydrogen· sulfite solution, consisting of 6.6 g (0.0635 aol) of soditai hydrogene sulfite, 4.4 g of sodiua hydroxide in 50 al of water. The precipitated copper-(i)-chlorlde was suc-ion filtered, suspended in 50 al of water and dissolved in a solution of 17 g (0.346 aol) of sodiua cyanide in 30 al of water.
After the nitrogen formation was finished, the reaction mix30 ture was heated for 1 hour up to 70°C. After cooling the reaction mixture was adjusted to pH 5.5 by aeans of 2N hydrochloric acid and extracted with chlorofora. The chlorofora phases were dried over sodiua sulfate and after distilling off the chloro55 fora, the obtained crude product was purified over a silicagel column with ethyl acetate aa eluant.
Yield: 9 g (30 % of theory), H.p.: 20°C.
Calc.: C 70.56 H 7.40 N 10.28 Found: 70.38 7.20 10.10 Exanple L 2-Heptaaethvlenlmino-5-hydroxy-benzoic acid 26.7 g (0.107 mol) of 5-amino-2~heptamethylenimino-benzoic acid were dissolved in 190 ml of 3N sulfuric acid and the solution was diazotized at 0°C with a solution of 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water, which was added dropwisely. After stirring for 30 minutes, 2 g of finely pulverized urea were added. The diazonium salt solution was dropped whilst stirring to 320 ml of 50 % sulfuric acid, which was warmed trp to 90°C. After finished nitrogen formation, the reaction mixture was adjusted at r©0H temperature to pH 4 by means of ammonia and extracted with chloroform. After drying over sodium sulfate and distilling off th® chloroform, the obtained dry residue was purified over a silicagel column by means of chloroform as eluant.
After recrystallization from isopropanol, 8 g (30 % of theory) of the compound were obtained.
M.p.: 199°C Calc.: C 67.45 H 7.68 N 5.61 Found: 66.87 7.71 5.65 Analogously to the Example L Che following compounds were prepared: 2-Hexamethylenimino-5-hydroxy-benzoic acid Yield: 24 % of theory, m.p.: 214°C.
-Hydroxy-2-oxtamethylenimino-benzoic acid Yield: 27 % of theory, a.p.s 208°C.
-Hydroxy-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 33 X of theory, a.p.: 24O°C -Hydroxy-2-(cis-3,5-diaethyl-piperidino)-benzoic acid Yield: 67.4 X of theory, a.p.: 248 - 250°C.
Example M -Methoxy-2-ootaaethTlenlaino-benzoic acid 0.6 g (25 aaol) of sodiua hydroxide were mixed with 3.2 g (12.2 aaol) of 5-hydroxy-2-octaaethyleniaino-benzoic acid in 20 al of absolute diaetbyl foraaaide and the reaction mixture was warmed up to 50°C, whereby the the sodiua salt partly precipitated. After addition of 5.2 g (36.6 aaol) of aethyl iodide in 3 ! of absolute diaethyl foraaaide the mixture was stirred for 5 hours at rooa temperature. After distilling off the diaethyl foraaaide the crude -methoxy-2-octaaethylenimino-benzoic acid-aethyl ester was purified over a silicagel coluan by Beans of chloroform as eluant.
Yield: 90 X of theory, m.p.: 20°C.
This ester was hydrolyzed at 80°C by means of sodiua hydro20 xide solution. After acidifying to a pH value of 5.2, the ester was extracted with chloroform, dried over sodiua sulfate and the evaporation residue was digested with petroleum ether.
Yield: 85 X of theory, M.p.: 84°C.
Calc.: C 69.28 H 8.35 N 5.04 Found: 69.12 8.29 4.95 Analogously to Example M the following compounds were prepared: 2-Hexaaethyleniaino-5-aethoxy-benzoic acid Yield: 88 X of theory, a.p.: 141°C, 2-HeptanethylenIsino-5-Esthylenimino-5"E0thoxy-benzoic acid Yields 30 % of theory, m.p.: 120°C. 2-Heptanethylenimino-5-isopropyloxy-benzoic acid Yield: 78 % of theory, ο-p.: 120°C.
-Ethoxy-2-octaaethylenimino-behzoic acid Yield: 87 % of theory, a.p.: 4 20°C.
-Isopropyloxy-2-octanethylenimino-benzoic acid Yield: 60 % of theory, m.p.: 78°C.
-Butyl-(2)-oxy-2-octamethylenimino-benzoic acid 10 Yields 48 % of theory, m.p.: < 20°C.
-Methoxy-2-(4-tert. butyl-piperidino)-benzoic acid Yield: 22 % of theory, m.p.: 156°C.
-Methoxy-2-(3,5-cis-dimethyl-piperidino)-benzoic acid Yield: 90 % of theory, m.p.: 124°C. 5-Hexyloxy-2-piperidino-benzolc acid Yield: 73 % of theory, m.p.: 72°C.
-Benzyloxy-2-piperidino-benzoic acid Yield: 41 % of theory, m.p.: 188°C.
Preparation of the end products of general formula I: Exaaple 1 4-/5-(5-Chloro-2-dimethylamlno-benzoylamino)-ethyl7-benzoic acid methylester 1.03 g (6.3 m mole) of N,N’-carbonyl-diimidazole were added to a solution of 1.06 g (5.3 mole) of 5-chloro-2-dimethylaminobenzoic acid in 5 ml of absolute tetrahydrofurane at room temperature. After 1-2 hours a solution of 1.13 g (6.3 m mole) of 4-(2-amino-ethyl)-benzoic acid methyl ester in 2 ml of tetrahydrofurane was added to the formed imidazolide. After standing for 16 hours at room temperature the tetrahydrofurane was distilled off in a rotation evaporator. The crude ester was purified by chromatography over a silicagel column with toluene/ethyl acetate (9:1). The dry residue of the combined fractions, which contain the purified ester, were treated with petroleum ether.
Yield: 0.9 g (47.5 % of theory), M.p.: 94°C Calc.: C 62.7 H 5-88 N 7.57 Found: 63.3 5.86 7.75 Example 2 4-/2-(5-Chloro-2-dlmethylamlno-ben2oylamino)-ethvl7-benzoic acid 0.55 g (1.56 m mole) of 4-/5-(5-chloro-2-dimethylamino-benzoylamino)-ethyl7-benzoic acid methylester were dissolved in 40 ml of a mixture consisting of methanol/dioxane (2:1). After addition of 0.29 g (4.8 m mole) of potassium hydroxide, dissolved in 3 ml of water, at room temperature 30 ml of water were dropped to the solution so slowly that no precipitation of the ester took place. After some hours the organic solvent was distilled off in a rotation evaporator, the aqueous phase was extracted with chloroform and adjusted to a pH value of 5.5 by means of 2N hydrochloric acid, whereby the acid precipitated.
Yield: 0.38 g (70 % of theory), M.p.: 165°C Calc.: C 62.45 H 5.52 N 8.06 Found: 62.30 5.62 7.87 Example 3 4-/2-(5-Chloro-2-dimethvlamino-benzovlamino)-ethvl7-benzoic acid 0.32 g (1 m mole) of 4-/5-(2-amino-5-chloro-benzoylamino)-ethyl7benzoic acid (m.p.: 196°C, prepared from 2-amino-5-chloro-benzoic acid and 4-(2-amino-ethyl-benzoic acid methylester analogously to Example 1 and subsequent alkaline saponification analogously to Example 2) were treated in 10 ml of formalin and 30 ml of glacial acetic acid after addition of 500 mg of 10 % palladium charcoal at room temperature in an autoclave at a pressure of 5 bar with hydrogen. After filtration and distilling off the solvents, the acid was dissolved in sodium hydroxide solution and precipitated with 2N hydrochloric acid.
Yield: 0.11 g (30 % of theory) M.p.: 165°C Calc.: C 62.45 H 5.52 N 8.06 Found: 62.38 5.68 7.90 Example 4 4-/2-(5-Chloro-2-dlmethylamlno-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-chloro-2-methylamino-benzoylamino)-ethyl7benzoic acid (m.p.: 205°C) analogously to Example 3.
Yield: 30 % of theory, M.p.: 165°C Example 5 4-/5-(5-Chloro-2-dimethylamino-benzoylamino)-ethyl7-benzoic acid methylester 1.06 g (5.3 m mole) of 5-chloro-2-dimethylamino-benzoic acid were converted to the acid chloride by means of 7 ml of thionyl chloride at 40 - 50°C. After distilling off the thionyl chloride the crude acid chloride was reacted in 10 ml of absolute pyridine with 0.95 g (5.3 mole) of 4-(2-aminoethyl)-benzoic acid methylester. After stirring for 2 hours at room temperature, the reaction mixture was heated to 50 - 70°C for approx. 20 minutes and subsequently the pyridine was distilled off in a rotation evaporator. The dry residue was dissolved in ice water, made alkaline with sodium hydroxide solution and this solution was extracted with chloroform. The dry residue of the chloroform extracts, dried over sodium sulfate, was purified by chromatography over a silicagel column (eluens: toluene/ethyl acetate = 9:1).
Yield: 1.4 g (73 X of theory), M.p.: 94°C Calc.: C 62.7 H 5.88 N 7.57 Found: 62.9 5.73 7.63 Example 6 4-/5-(5-Bromo-2-dimethylamino-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-bromo-2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1. Yield: 93.5 % of theory, M.p.: 99°C Calc.: C 56.35 H 5.21 N 6.90 Found: 56.10 5.32 7.01 292 Example 7 4-/2- (5-bromo-2-dliaethylamlno-benzoylamino)-ethyl7-ben2olc acid Prepared from 4-/2-(5-bromo-2-dimethylamino-benzoylamino)ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 77 % of theory, M.p.: 187°C Calc.: C 55.4 H 4.89 N 7.16 Found: 55.2 4.97 7.01 Example 8 4-/2-(5-Fluoro-2-dimethylamino-benzoylamino)-ethyl/-benzoic acid methylester Prepared from 5-fluoro-2-dimethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 44 % of theory, M.p.: 56°C Calc.: C 66.30 H 6.14 N 8.13 Found: 66.28 6.22 8.13 Example 9 4-/2-(5-Fluoro-2-dlmethylamlno-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-fluoro-2-dimethylamino-benzoylamino)-ethyl7 benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 73 % of theory, M.p.: 108°C Calc.: C 65.55 H 5.80 N 8.47 Found: 64.98 5.68 8.38 Example 10 4-/5-(2-Dimethylaaino-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 2-dimethylamino-benzoic acid and 4-(2-amino5 ethyl)-benzoic acid methylester analogously to Example 1.
The reaction was carried out at 60 - 70°C.
Yield: 98 % of theory, M.p.: 74°C Calc.: C 70.0 H 6.78 N 8.56 Found: 69.8 6.92 8.54 Example 11 4-/5- (2-Dlmethylamino-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/5-(2-dimethylamino-benzoylamino)-ethyl7benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 84 % of theory, M.p.: 107°C Calc.: C 69.25 H 6.45 N 8.96 Found: 69.50 6.62 9.00 20 Example 12 4-/5-(5-Chloro-2-diethylamino-benzoylamino)-ethyl7-benzoic acid-methylester Prepared from 5-chloro-2-diethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 51 % of theory, M.p.: 93°C Calc.: C 64.86 H 6.48 N 9.12 Found: 65 01 6.54 9.38 Example 13 4-/2-(5-Chloro~2-diethylamino-benzovlamlno)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-diethylamino-benzoylamino)ethyl7-benzoic acid methylester by alkaline hydrolysis ana5 logously to Example 2.
Yield: 80 % of theory, M.p.: 95°C Calc.: C 64.10 H6.17 N 7.46 Found: 64.20 6.09 7.32 Example 14 4-/2-(5-Chloro-2-diisobutylamino-benzoylamino)-ethyl7-benzoic acid ethylester Prepared from 5-chloro-2-diisobutylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 20 % of theory, M.p.: <20°C Calc.: C 68.03 H 7.69 N 6.10 Cl 7.72 Found: 68.59 7.68 5.93 7.51 Example 15 4-/2-(5-Chloro-2-diisobutylamino-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-diisobutylamino-benzoylamino)ethyl7-benzoic acid ethylester by alkaline hydrolysis analogous25 ly to Example 2.
Yield: 90 % of theory, M.p.: 113°C Calc.: C 66.88 H 7.24 N 6.49 Found: 66.50 7.28 6.32 Cl 8.22 8.40 Example 16 4-/2-(5-Chloro-2~dipentylawino-benzoylamino)-ethyl7-benzoic acid ethylester Prepared from 5-chloro-2-dipentylamino-benzoic acid and 4-(2-aaino-ethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 83 % of theory, M.p.: 118 - 120°C Calc.: C 69.05 H 8.07 N 5.75 Cl 7.28 Found: 68.84 7.99 6.05 7.54 Example 17 4-/?-(5-Chloro-2-dlpentvlamlno-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-ehloro-2-dipentylanino-benzoylaminoethyl7-benzoic acid ethylester by alkaline hydrolysis analogously to Example 2.
Yield: 36.5 % of theory, M.p.: < 20°C.
Calc.: C 68.03 H 7.68 N 6.10 Cl 7.72 Found: 67.93 7.64 6.02 7.86 50282 — Example 18 4-/2-(5-Chloro-2-(1-pyrrolyl)-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-chloro-2-(l-pyrrolyl)-benzoic acid and 5 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 64 % of theory, M.p.: 120 - 121°C Calc.: C 65.88 H 5.00 N 7.52 Cl 9.26 10 Found: 65.86 4.85 7.47 9-38 Example 19 4-/2-(5-Chloro-2-(1-pvTrolyl)-benzovlamino)-ethyl7-benzolc acid Prepared from 4-/5-(5-chloro-2-(1-pyrrolyl)-benzoylamino)ethyl7-benzoic acid methylester by alkaline hydrolysis analo15 gously to Example 2.
Yield: 26 % of theory, M.p.: 250 - 255°C Calc.: C 65.13 H 4.65 N 7.59 Cl 9.61 Found: 65.07 4.74 7.34 9.07 Example 20 4-/2-(5-Chloro-2-(N-cyclohexyl-methylamino)-benzoylamino)ethyl7-benzoic acid ethylester Prepared from 2-(N-cyclohexyl-methylamino)-5-chloro-benzoic acid and 4-(2-amino-ethyl-benzoic acid ethylester analogous- ly to Example 1. Yield: 45 % of theory, M.p. : 98°C Calc.: C 67.78 H 7.05 N 6.33 Found: 67.60 6.81 6.28 Example 21 4-/2-(5-Chloro-2-/R-cyclohexyl-methylamino7-benzoylamino)ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-/N-cyclohexylmethylaaino7benzoylamino)-ethyl7-benzoic acid ethylester by alkaline hydrolysis analogously to Example 2.
Yield: 58 % of theory, M.p.: 166°C Calc.: C 66.58 H 6.56 N 6.75 Pound: 66.63 6.79 6.66 Example 22 4-/2-(5-Bromo-2-piperidino-benzoylamino)-ethyl7-benzoic acid ethylester Prepared from 5-bromo-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 87 % of theory, M.p.: 76°C Calc.: C 60.13 H 5.92 N 6.09 Found: 60.35 5.97 6.19 Example 23 4-/2-(5-Bromo-2-plperldino-benzovlamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-bromo-2-piperidino-benzoylamino)-ethyl7benzoic acid ethylester by alkaline hydrolysis analogously to Example 2.
Yield: 99 % of theory, M.p.: 201°C Calc.; C 58.47 H 5.37 N 6.49 Found: 5θ.56 5.40 6.55 — Example 24 4-/2-(5-Chloro-2-pyrrolidino-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-chloro-2-pyrrolidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1. Yield: 43 % of theory, M.p.: 164°C Calc.: C 65.19 H 5.99 N 7.24 Found: 65.35 6.00 7.23 Example 25 4-/2-(5-Chloro-2-pyrrolldlno-benzovlamino)-ethvl7-ben20lc acid Prepared from 4-/2-(5-chloro-2-pyrrolidino-benzoylamino)-ethyl7benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 68 % of theory, M.p.: 184°C Calc.: C 64.42 H 5.68 N 7.52 Cl 9.51 Found: 64.46 5.96 7.47 9.38 Example 26 4-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-chloro-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid methylester analogously to Example 1.
Yield: 72 % of theory, M.p.: 98°C Calc.: C 66.00 H 6.29 N 7.00 Found: 66.00 6.37 6.81 — Example 27 k-fS-(5-Chloro-2-piperldlno-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/5-(5-chloro-2-piperldlno-benzoylamino)-ethyl7benzoic acid methylester by alkaline hydrolysis analogously to Example 2. >, Yield: 82 X of theory, M.p.: 200°C Calc.: C 65.20 H 5.98 N 7.24 Pound: 65.10 6.00 7.30 Example 28 4-/2-(5-Chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl7benzoic acid methylester Prepared from 5-chloro-2-(2-methyl-piperidino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid methylester analogously to Example 1.
Yield: 23 X of theory, M.p.: 82°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.82 6.42 6.78 2o Example 29 4-/2-(5-Chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl7benzoic acid Prepared from 4-/?-(5-chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl7-benzoic acid methylester by alkaline saponifica25 tion analogously to Example 2.
Yield: 57 % of theory, M.p.: 178°C Calc.: C 65.91 H 6.29 N 6.99 Found: 65.73 6.28 7.13 Example 30 4-/5-(5-Chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl/benzolc acid methylester Prepared from 5-chloro-2-(3-methyl-piperidino)-benzoic acid 5 and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 51 % of theory, M.p.: 93°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.52 6.38 6.81 Example 31 4-/5-(5-Chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl7benzolc acid Prepared from 4-/5-(5-chloro-2-(3-methyl-piperidino)-benzoyl15 amino)-ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 83 % of theory, M.p.: 194°C Calc.: C 65.91 H 6.29 N 6.99 Found: 66.20 6.25 6.95 Example 32 4-/5-(5-Chloro-2-(4-methyl-piperidino)-benzoylamino)-ethyl7benzolc acid methylester Prepared from 5-chloro-2-(4-methyl-piperidino)-benzoic acid 25 and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 48 % of theory, M.p.: 55°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.3θ 6.35 6.82 Example 33 4-/2-(5-Chloro-2-(4-methyl-piperldlno)-benzoylamino)-ethyl7benzoic acid Prepared from 4-/5-(5-chloro-2-(4-methyl-piperidino)-benzoyl5 amino)-ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 83 % of theory, M.p.: 211°C Calc.: C 65.91 H 6.29 N 6.99 10 Found: 66.07 6.25 7.02 Example 34 4-/5-(5-Chloro-2-(5-ethyl-2-methyl-piperidino)-benzoylamino)ethyl7-benzoic acid methylester Prepared from 5-chloro-2-(5-ethyl-2-methyl-piperidino)-benzoic15 acid and 4-(2-amlno-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 10 % of theory, M.p.: i. 20°C Calc.: C 67.78 H 7.05 N 6.33 Found: 68.00 7.10 6.50 Example 35 4-/5- (5-Chloro-2-(5-ethyl-2-methyl-piperidino)-benzoylamino)ethyl7-benzoic acid Prepared from 4-/5-(5-chloro-2-(5-ethyl-2-methyl-piperidino)25 benzoylamino)-ethyl7-benzolc acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 60 % of theory, M.p.: 40°C Calc.: Found: C 67.19 H 6.01 N 6.53 67.30 6.98 6.42 Example 36 4-/2-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl7benzoic acid methylester Prepared from 5-chloro-2-(3,5-dimethyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 85 % of theory, M.p.: 95°C Calc.: C 67.20 H 6.81 N 6.53 Found: 67.14 6.62 6.68 Example 37 4-/2-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl7benzolc acid methylester 2.7 g (0.01 mole) of 5-chloro-2-(3,5-dimethyl-piperidino)-benzoic acid were refluxed for 4.5 hours with 3.57 g (0.03 mole) of thionyl chloride in 20 ml of chloroform. Subsequently the reaction mixture was evaporated in vacuo. The residue was dissolved in 10 ml of chloroform and at room temperature dropped whilst stirring to a solution consisting of 2.16 g (0.01 mole) of 4-(2-amino-ethyl)-benzoic acid methylester hydrochloride and 3.03 g (0.03 mole) of triethylamine, dissolved in 15 ml of chloroform. The addition was finished after 15 minutes. Subsequently the reaction mixture was refluxed for 30 minutes.
After cooling the reaction mixture was washed two times with water and one time with diluted acetic acid. The chloroform phase was dried over sodium sulfate and evaporated. The obtained residue was further purified over a silicagel column (chloroform/acetone = 9:1). After evaporating the solvent, the pure fractions were recrystallized from methylene72 0292 chloride/petroleum ether (20/1).
Yield: 3-3 g (77 % of theory), M.p.: 94 - 95°C Calc.: C 67.20 H 6.81 N 6.53 Cl 8.27 Found: 67.11 6.78 6.70 8.39 Example 38 4-/5-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)ethyl7-benzolc acid 2.15 g (0.005 mole) of 4-/2-(5-chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl7-be»zoic acid methylester were refluxed for 30 minutes in 50 ml of ethanol and 10 ml of 1N sodium hydroxide solution. After cooling the greatest part of the alcohol was removed in vacuo and the residue was mixed with 60 ml of water. After weakly acidifying with acetic acid to approx. pH 6, a precipitate was obtained, which after some standing was suction filtered and recrystallized from isopropanol .
Yield: 1.82 g (87.5 % of theory), M.p.: 204 - 206°C Calc.: C 66.58 H 6.56 N 6.75 Cl 8.55 Found: 66.59 6.48 6.71 8.45 Example /9 4-/2-(5-i'hloro-2-(4-methoxy-piperidino)-benzoylamino)-eth/17benzolc acid ethylester Prepared from 5-chloro—‘-(4- methoxy-piperidino)-benzoic :. id and 4-(2~aminoethyl)-benzoid Example 1.
Yield: 60 % of theory, M.p.: < 20°C.
Calc.: C 64.78 H 6.57 Found: 64.95 6.62 acid ethylester analogously o N 6.30 6.15 S0292 Example 40 4_/2-(5-Chloro-2-(4-methoxy-piperldino)-benzoylamino)-ethyl7benzolc acid_ Prepared from 4-/2-(5-chloro-2-(4-methoxy-piperidino)-benzoyl5 amino)-ethyl7-benzolc acid ethylester by alkaline hydrolysis analogously to Example 2.
Yield: 85 % of theory, M.p.: 188°C Calc.: C 63.38 H 6.04 N 6.72 Found: 63.46 5.95 6.72 Example 41 4-/5- (5-Methoxy-2-piperidino-benzoylamino)-ethyl7-benzoic acid ethylester Prepared from 5-methoxy-2-piperidino-benzoic acid and 4-(2-ami15 noethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 66 % of theory, M.p.: 118°C Calc.: C 70.22 H 7.36 N 6.82 Found: 70.76 7.42 7.36 Example 42 4-/5-(5-Methoxy-2-piperidino-benzoylamino)-ethyl7-benzoic acid hydrochloride Prepared from 4-/2-(5-methoxy-2-piperidino-benzoylamino)-ethyl7 benzoic acid ethylester by alkaline hydrolysis analogously to Example 2. The obtained compound was converted to the hydrochlo ride in acetone with isopropanolic hydrochloric acid.
Yield: 91 % of theory, M.p.: 158°C. 5029 Calc.: C 63.07 Found: 63.00 H 6.49 N 6.68 6.31 6.61 Example 43 4-/5-(5-Chloro-2-heptamethyleneimino-benzoylamino)-ethyl/5 benzoic acid ethylester Prepared from 5-chloro-2-heptamethyleneimino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 24 % of theory, 10 M.p.: <20°C Calc.: C 67.78 H 7.05 N 6.33 Found: 67.95 7.16 6.33 Example 44 4-/5-(5-Chloro-2-heptamethyleneimino-benzoylamino)-ethyl/15 benzoic acid_ Prepared from 4-/5-(5-chloro-2-heptamethyleneimino-benzoylamino) ethyl7-benzoic acid ethylester by alkaline hydrolysis analogously to Example 2.
Yield: 47 % of theory, M.p.: 186°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.45 6.43 6.70 — Example 45 4-/2-(5-Nitro-2-piperidino-benzoylamino)-ethylT-benzoic acid ethylester Prepared from 5-nitro-2-piperidino-benzoic acid and 4-(2-aminoethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 70 % of theory, M.p.: 104°C Calc.: C 64.92 H 6.40 N 9.87 Found: 65.17 6.38 9.67 Example 46 4-/2- (5-Nltro-2-plperidino-benzoylamlno)-ethyl7-benzoic acid Prepared from 4-/2-(5-nitro-2-piperidino-benzoylamino)-ethyl7 benzoic acid ethylester by alkaline hydrolysis analogously to Example 2.
Yield: 69 % of theory, M.p.: 194 - 195°C Calc.: C 63.46 H 5.83 N 10.57 Found: 63.20 5.79 10.38 Example 47 4-/2-(5-Chloro-2-(4-phenyl-piperidino)-benzoylamino)-ethyl7benzolc acid methylester Prepared from 5-chlcro-2-(4-phenyl-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1. Yield: 62 % oi theory, M.p.: 124°C Calc.: C 70.50 H 6.13 N 5.87 Found: 70.60 6.26 5.84 Example 48 4-/5-(5-Chloro-2-(4-phenyl-piperidino)-benzoylamino)-ethyl/benzoic acid Prepared from 4-/5-(5-chloro-2-(4-phenyl-piperidino)-benzoyl5 amino)-ethyl/-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 92 % of theory, M.p.: 188°C Calc.: C 70.04 H 5.88 N 6.05 10 Pound: 70.12 6.08 6.05 Example 49 4-/5-(5-Chloro-2-(l,4-dioxa-8-aza-spiro/£,£7-decane-yl-(8))benzoylamino)-ethYl7-benzolc acid methylester Prepared from 5-chloro-2-(1,4-dioxa-8-aza-spiro/5,^7-decane-yl15 (8))-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 45 % of theory, M.p.: 167°C Calc.: C 62.81 H 5.93 N 6.11 Found: 62.80 5.89 5.93 Example 50 4-/5- (5-Chloro-2-(l,4-dioxa-8-aza-epiro/2T,^7- Prepared from 4-/5-(5-chloro-2-(1,4-dioxa-8-aza-spiro/5,£725 decane-yl-(8))-benzoylamino)-ethyl/-benzoic acid methylester by alkaline hydrolysis analogously to Example 2. 29 2 Yield: 82 % of theory, M.p.: 190°C Calc.: C 61.95 H 5.88 N 6.28 Found: 61.74 6.03 6.52 Example 51 4-/2-(5-Chloro-2-(4-ethoxycarbonyl-piperidino)-benzoylamino)ethyl7-benzoic acid methylester Prepared from 5-chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid methylester analogously to Example 1.
Yield: 17 % of theory, M.p.: 70°C Calc.: C 63.48 H 6.18 N 5.92 Found: 63.30 6.08 5·91 Example 52 4-/2-(5-Chloro-2-(4-hydroxy arbonyl-piperidino)-benzoylamino)ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-(4-ethoxycarbonyl-piperidino)~ benzoylamino)-ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example Yield: 71 % of theory, M.p.: 238°C Calc.: C 61.32 H 5.38 W 6 Found: 61.32 5.33 6 50202 Example 55 4-/2-(5-Chloro-2-hexamethyleneimino-benzoylaaino)-ethyl/-benzolc acid methylester Prepared from 5-chloro-2-hexamethyleneimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 72 X of theory, M.p.: 81 °C Calc.: C 66.60 H 6.56 N 6.75 Found: 66.28 6.30 6.67 Example 54 4-/2-(5-Chloro-2-hexamethyleneimino-benzoylamino)-ethyl7benzoic acid Prepared from 4-/2-(5-chloro-2-hexamethyleneimino-benzoylamino)ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 89 X of theory, M.p.: 182°C Calc.: C 66.00 H 6.29 N 6.99 Found: 66.20 6.40 7.15 Example 55 4-/2-(5-Chloro-2-morpholino-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-chloro-2-morpholino-benzoic acid and 4-(2-aminoethyl)-benzoic acid methylester analogously to Example 1.
Yield: 80 X of theory, M.p.: 111°C Calc.: C 62.55 H 5.75 N 6.95 Found: 62.48 5.74 6.94 Example 56 4-/5-(5-Chloro-2-morphollno-benzoylamlno)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-morpholino-benzoylamino)-ethyl7benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 78 % of theory, M.p.: 186°C Calc.: C 61.75 H 5.44 N 7.20 Found: 61.60 5.41 7.10 Example 57 4-/2-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-chloro-2-thiomorpholino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1. Yield: 45 % of theory, M.p.: 160°C Calc.: C 60.20 H 5.53 N 6.69 Found: 60.62 5.76 6.96 Example 58 4-/2-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyi7-benzolc acid Prepared from 4-/2-(5-chloro-2-thiomorpholino-benzoylamino)ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield: 57 % of theory, M.p.: 210°C Calc.: C 59.32 H 5-23 N 6.92 Found: 59.25 5.19 6.80 Example 59 4-/2-(5-Chloro-2-thiomorpholino-benzoyla*ino)-ethylj-benzoic acid methylester-S-oxide Prepared from 5-chloro-2-thiomorpholino-benzoic acid-S-oxide and 4-(2-aaino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 63 % of theory, M.p.: 152°C Calc.: C 57.99 H 5.33 H 6.44 Found: 58.30 5.22 6.52 Example 60 4-/2-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyl7-benzoic acld-S-oxide Prepared from 4-/2-(5-chloro-2-thiomorpholino-benzoylamino)ethyl7-benzoic acid methylester-S-oxide by alkaline hydrolysis analogously to Example 2. Yield: 82 % ot theory, M.p.: 202°C Calc.: C 57.07 H 5.03 Found: 57.46 5.07 N 6.66 6.30 Example 61 4-/2-(5-Chloro-2-/T,2,4,5-tetrahydro-3H-3-benzazepine-yl-(3/7benzoylamino)-ethvl7-benzoic acid methylester Prepared from 5-chloro-2-/T,2,4,5-tetrahydro-3H-3-benzazepineyl-(3/7-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 69 % of theory, M.p.: 126°C Calc.: C 70.04 H 5.88 N 6.05 Found: 70.20 5.81 5.94 Example 62 4- /2-(5-Chloro-2-/T,2„4 , 5-tetrahydro-3H-3-benzazepine-yl-(3J7benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-/T„2,4!)5-tetrahydro-3H-3-benz5 azepine-yl-(3/7-benzoylaaino)-ethyl7"beEizoic acid methylester by alkaline hydrolysis analogously to Example 2.
Yield; 89 % of theory, M.p.s 148°C Calc.; C 69.55 H 5.61 PJ 6.24 10 Found; 69.87 5.90 6.10 Example 63 4-/2-(5-Chloro-2-/T,2,3,4-tetrahydro-isoquinoline-yl-(2j/benzoylamino)-ethyl7-benzoic acid methylester Prepared from 5-chloro-2-^’,2,3,4-tetrahydro-isoquinolyl-(2/715 benzoic acid and 4-(2-amino-ethyl)-benzoic acid methylester analogously to Example 1 .
Yield: 43 % of theory, M.p.: 94°C Calc.: C 69.55 H 5.61 M 6.24 Found: 69.65 5.65 6.14 Example 64 4-/2-(5-Chloro-2-/T,2,3,4-tetrahydro-isoquinoline-yl-(2/7benzoylamino)-ethvl7-benzoic acid_ Prepared from 4-/2-(5-chloro-2-/T,2,3,z!-tetrahydro-isoquinoline 25 yl-(2/7-benzoylamino)-ethyl7-benzoic acid methylester by alka82 50298 -Ίΐηβ hydrolysis analogously to Example 2.
Yield: 86 % of theory, M.p.: 173°C Calc.: C 69.04 H 5.33 M 6.44 Cl 8.15 5 Found: 66.45 5.56 6.21 8.57 Example 65 4-/?-(5-Chloro-2-(4-phenyl-piperazino)-beazoylamlno)-ethy^7benzolc acid methylester Prepared froa 5-chloro-2-(4-pfaenyl-plperazino)-benzoic aoid 10 and 4-(2-amino-ethyl)-benzoic add methylester analogously to Exaaple 1.
Yield: 40 % of theory, M.p.: 132°C Calc.: C 67.84 H 5.90 M 8.79 15 Found: 67.72 5.92 8.66 Example 66 4-/2- (5-Chloro-2-(4-phenyl-piperazlno)-benzoylamino)-ethyl7benzoic acid Prepared from 4-/5-(5-chloro-2-(4-phenyl-piperazino)-benzoyl20 amino)-ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Exaaple 2.
Yield: 82 % of theory, W.p.: 166°C Calc.: C 67.07 H 5.65 M 9.06 Found: 67.30 5.96 8.99 4-/2- (5-CMLor©"2- (4->yridyl- (2) -piperazia® )-feenzoylaeiao)- ethyl7-benzoic acid aathyleator Prepared from 5-eM.oro-2-^-i2-pyridyl)"piperasiffl®7-b®BZoic acid and 4-(2-aiaimo-©thyl)-benzoic acid Eathylcatsr hydrochloride in th® presence of tMenylcMorid® and triethylaeine analogously to Example 37.
Yields 44.6 % of theory, M.p. of the hydrochlorides 153 - 154°C Calc.; C 60.5® H 5.48 ft 10.87 Cl 13.76 Founds 60.31 5o52 10.68 13.93 Example 68 4-/5- (5-Chloro-2= (4-pyridyl- (2)-pipera3ia®)-b©azoylaiBino-ethyl7benzoic acid Prepared from 4-/5=(5-cM.oro~2-(4-pyridy3.-(2)-plpepazino)benzoylaiaino-©thyi7-bemsoic acid astSaylaster by alkaline hydrolysis analogously to Example 2.
Yields 27 % of theory, M.p.: 120°C (decoop.).
Calc.s C 64.58 H 5.42 ft 12.05 Cl 7.63 Founds 64.36 5.49 11.87 7.48 5029S Example 69 (5-Chloro-2-piperldino-benzoylamino)-1-methyl-ethyl/benzolc acid methylester Prepared from 5-chloro-2-piperidino-benzoic acid and 5 4-(2-amino-1-aethyl-ethyl)-benzoic acid methylester analogously to Example 1.
Yield: 42.7 % of theory, M.p.: 93 - 94°C Calc.: C 66.57 H 6.56 Cl 8.54 M 6.75 10 Pound: 66.82 6.57 8.47 6.58 Example 70 4-/2- (5-Chloro-2-piperidino-benzoylamino)-1-methyl-ethyl/benzoic acid Prepared from 4-/5-(5-chloro-2-plperidino-benzoylamino)-1-methyl 15 ethyl7-benzoic acid methylester hy alkaline hydrolysis analogously to Example 2.
Yield: 76 % of theory, M-p.: 192 - 194°C Calc.: C 65.91 H 6.28 Cl 8.84 M 6.99 Found: 66.00 6.30 8.77 6.87 Example 71 4-/2- (5-Chloro-2-dimethylaaino-benzoylamino)-1-methyl-ethyl/benzoic acid Prepared from 4-/2-(5-chloro-2-dlmethylamino-benzoylamino)25 1-methyl-ethyl7-benzoic acid methylester by alkaline hydrolysis analogously to Example 2.
- Yields 86 $ of theory, M.p.s 159 - 161°C Calc.s C 63.23 535.87 Cl 9,83 N 7.76 Found: 63.42 6.07 9.56 7.67 5 Example 72 4-/5- (5-Chloro=2=dinethylania®-hen3oylaaiB© )=1 -aethyl-ethyljbenzolc acid methylester Prepared from 5-chloro-2-dinotEiylQnin©-hoia2©ie acid and 4-(2=anino=1»nethyl-etbyl)~bea2@ic aeid nsthylester analogous10 ly to Exanple 1.
Yields 61.5 ?5 of theory, M.p.s 79 - 80°C Calc.s C 64.07 H 6.18 Cl 9.46 H 7.47 Founds 64.40 6.52 9.14 7.20 Example 75 I,-//-(5-Jtaino-2-piperidiao=ben2oylQHino)"ethyl7"benzoic acid ethylester g (70.5 b nolo) of 4-/2-(5-nitro~2-piperidino-bens©ylamino)ethylj-benzoic acid ethylester were hydrogenated at room tempe20 rature in 500 al of methanols ethanol (isi) and palladium charcoal as catalyst at a hydrogen pressure of 5 bar. After separating the catalyst and distilling off the solvent the compound was purified by filtration over silicagel with ethyl acetate as eluens.
Yield! 93 % of theory, M.p.s 4 20°C Calc.s C 69.84 H 7.39 N 10.62 Founds 70.10 7.20 10.43 Example 74 4-/2-(5-Amino-2-plperidino-benzoylamino)-athyi7-benzoic acid dihydrochloride Prepared fro· 4-/2-(5-amino-2-piperidino-benzoylamino)-ethyl75 benzoic acid ethylester by alkaline hydrolysis analogously to Example 2. Subsequently the product was converted in acetone to the dihydrochloride by mans of isopropanolic hydrochloric acid. field: 87 % of theory, M.p.: 7O°C Calc.: C 57.26 H 6.18 »9.54 Found: 57.40 6.30 9.52 Example 75 4-/2-(5-Acetamino-2-piperidino-benzoylamino)-ethyl7-benzoic 15 acid ethylester Prepared from 2.5 g (6.3 m mole) of 4-/2-(5-amino-2-piperidinobenzoylaaino)-ethyl7-benzoic acid ethylester and 25 ml of acetic acid anhydride at room temperature. The precipitated reaction product was washed with ether.
Yield: 1.9 g (69 * of theory), M.p.: 165°C Calc.: C 68.62 H 7.14 »9.60 Found: 68.92 7.09 9.50 Example 76 4-/2-(5-AcetaQimo-2-piparidino-bansoylaHino)-ethyl7-ben2oic acid Prepared iron 4-//-(5=Acetsffliao-2-piperidifflo-ben2oyla®ino)5 ©thylJ-bGmaoie acid ethylester by allsaline hydrolysis analogously to Exanple 2.
Yields 98 % of theory, H.p.s 212°C Calc.: C 67.46 Η 6.64 010.26 io Pounds 67.00 6.67 10.04 Exanple TL 4_/2-.(5-DiQsthylaniaosulfojayl-2-piperidino-beaz0ylaBiao)ethyl7°-beazoic acid nethylestar Prepared from 5-dinethylaQinoBuXfoayX~2=piperidino-banzoIc 15 acid and 4-(2-ethylasino)-benzoic acid sethylestes· analogous· ly to Exanple 1.
Yield: 77 % of theory, M.p. s 138 - 140°C Calc.: C 60.87 H 6.60 08.87 56.77 Founds 61.08 6.67 8.86 6.80 Example 78 4-/2-(5-DisethylaninoBulfonyl-2-piperidine-benzoylaBiino)ethyl7-benzolc acid Prepared from 4-/2-(i-dinethylaninosulf ©nyl-2-pIperidino25 benzoylanino)-ethyJ-7-benzoic acid aethylester by alkaline saponification analogously to Exanple 2.
Yield: 91 % of theory, M.p.: 220°C Calc.: C 60.11 H 6.36 M 9.14 S 6.98 Found: 60.30 6.42 8.96 6.98 Example 79 4-/2-(5-Cyano-2-piperidino-benzoylamino)-ethyl7-benzoic acid ethylester Prepared from 5-cyano-2-piperidino-benzolc acid and 4-(2-aminoethyl)-benzoic acid ethylester analogously to Example 1.
Yield: 76 % of theory, M.p.: 97°C Calc.: C 71.08 H 6.71 M 10.36 Found: 71.37 6.74 10.33 Example 60 4-/2-(5-Cyano-2-piperidlno-henxoTlamlno)-ethyl7-benzolc acid Prepared from 4-/2-(5-Cyano-2-plperidino-benzoylamino)ethyl7-benzolc acid ethylester hy alkaline hydrolysis analogously to Example 2.
Yield: 40 J< of theory, M.p.: 190°C Calc.: C 70.00 H 6.14 M 11.13 Found: 69.81 6.03 10.98 Example 81 4-/2-(5-Et-hoxyeQr'aoayl-2-pto®ri.dija0-&sasoylQaino)-©thyl7famzoic acid ethylestor hydrochloride 2.5 g (6.2 a mole) of 4-/S-(5-cyaao-2-piperidino-benzoylaaino)5 ethylT-bonzoic acid ethylester wer© dissolved in 80 al of ethanol and saturated with hydrogen chloride. After standing for 6 days at room temperature the solvent was evaporated, the residue was dissolved in ie©=wat©r, adjusted to a pH value of 9 hy raeans of sodiua hydroxide solution and extracted with chloro10 fora. After drying over aediua sulfate and distilling off the solvent, the evaporation residue was converted in ether to the hydrochloride hy neons of ©theric hydroefelorie acid.
Yields 2.5 g (89.1 # of theory), H.p.s 86 - 88°C Calc.s C 63.85 Η 6.8Θ S 5.72 Cl 7.24 Founds 63.71 6.69 5.74 7.11 Example 82 4-/2-(5-Hydroxycarbonyl-2-pip©ridimo=b®nzoylamino)-ethyl7benzoic acid 2o Prepared by alkaline hydrolysis froa 4=/2-(5-stfiOJ:ycarbonyl·2-piperidino=b©nzoylaQino)-ethyi7=benz0ie acid ethylester hy- drochloride analogously to Example 2. Yields 92 $$ of theory. H.p. : 242°C 25 Calc, s C 66.65 H 6.10 kJ 7.06 Founds 65.96 6.18 7.23 5029a Example 83 4-/5- (2-(4-Hydroxy-piperidino)-5-nitro-benzoylaaino)-ethyl7banzolc acid «ethylester a) 4-/5-(2-chloro-5-nitro-benzoylaaino)-ethyl7-benzoic acid 5 aethyleater g (40 a aole) of 2-chloro-5-nitro-benzoic acid ware converted in 40 al of absolute tetrahydrofurane to the iaidazollde by aeana of 6.8 g (44 a aole) of Ν,Ν'-carbonyl-diiaidazole. After a reaction tiae of 2 hours, 7.9 g (44 a 1θ aole) of 4-(2-aaino-ethyl)-benzoie acid aethyleater were added at rooa taaperature and the aixture waa stirred for approx. 16 hours. After distilling off the solvent, the crude product was purified by chromatography over a silicagel column (eluena: toluene/ethyl acetate 1:1).
Yield: 12 g (83 % of theory), M.p.: 163°C Calc.: C 56.28 H 4.17 N 7.72 Found: 56.58 4.41 7.82 b) 4-/5-(2-(4-hydroxy-piperidino)-5-nitro-benzoylaaino)-ethyl/20 benzoic acid aethvlester A solution of 5 g (14 a aole) of 4-/5-(2-ehloro-5-nitrobenzoylaaino)-ethyl7-benzoic acid aethyleater in 100 al of ethanol waa refluxed with 2.83 g (28 a aole) of 4-hydroxy-piperidlne for 14 hours. After distilling off the solvent in a rotation evaporator, the dry residue waa dissolved in ice water, adjusted with diluted hydrochloric acid to pH 5 and extracted with chlorofora. After drying over sodiua sulfate, distilling off the chlorofora, the residue was crystallized froa ieopropanol.
Yield: 5.5 g (92 % of theory), M.p.: 147°C Exanple 84 4-/2- (5-Aniao=2- (4-hydroxy-pi peridin® ) "fesnsoylaolno )-ethyl/benzoic acid aathyleater .3 g (12.4 □ nolo) of 4-/?-(2-(4-i!ydrosjr-pip0ridiao)-5-Bitro5 benzoylanimo)-©thy^’-feenzoic acid aettoylester were hydrogenated in 100 ral of nethaaol with 10 $ palladira etoroeal at roon temperature and Qt a hydrogen pressure of 1 fear.
Yields 91 / of theory, M.p.s 78°C.
Example 85 4-/2- (5-CM.oro-2-(4-hydroxy-pipsridiao)=feQn2oylaiaine)"®thyi7" benzoic acid oethyleater .5 g (52 m nole) of 4-/2-(5~aQi0o-2-(4"feydr©ay-pip®ridiHi©)benzoylaQino)-sthyl7"beiaEOic nethyloster ware dissolved in 80 nl of seni-concentrated ice-cold hydrochloric aeid and diazotized uith a solution of 4 g of sodiua nitrite in 25 ml of ice-cold water, This solution uas dropped to a suspension of 6 g of copper powder and 10 al of hydrochloric acid. After finished development of nitrogen a viscous oil uas precipita20 ted. This oil uas extracted uith chloroform and after drying over sodium sulfate purified over a silieagel column with ethyl acetates aethasol (9:1) as eluens.
Yield: 30 $ of theory, M.p.s 4 20°C Calc.: 063.38 H 6.04 H 6.72 Founds 63.62 6.21 6,55 50293 Ex—pie 86 4-/5-(5-Chloro-2-(4-hydroxy-piperidino)-benzoyl—ino)-ethyl7~ benzoic acid 4.5 g (11.3 «ole) of 4-/5-(5-aaino-2-(4-hydroxy-piparidino)benzoyl—ino)-ethyl7-benzoic acid methylester were dissolved in 20 «1 of s—i-concentrated hydrochloric acid and the solution was diazotized with 0.87 g (12.4 mole) of sodium nitrite, dissolved in 6 «1 of water, at 0°C. This solution was added dropwisely to a suspension of 1.2 g of copper powder in· 3 «1 of concentrated hydrochloric acid. After stirring for 2 hours the reaction Mixture was heated to 75°C for approx. 20 «inutes. The cooled solution was extracted with chloroform, the chlorofora solution was dried with sodiua sulfate and the evaporation residue was purified over a silicagel column with chloroform: methanol (9:1) as eluens.
Yield: 2.4 g (52 % of theory), M.p.: 190°C Calc.: C 62.6 H 5.75 M 6.93 Found: 62.14 5.84 6.83 Example 87 4-/2-(5-Chloro-2-(3-hydroxy-piperidino)-benzoyl—ino)-ethyl7benzoic acid methylester Prepared from 4-/?-(5-amlno-2-(3-hydroxy-piperidino)-benzoyl—ino)-ethyj7-benzoic acid methylester analogously to Exaaple 85.
Yield; 30 % of theory, M.p.; 20°C Calc.: C 63.38 H 6.04 M 6.72 Found: 63.48 6.21 6.65 Example 88 4-/5-(5=Chl©ro-2-(3=hydr©sy-piperidi®®)™hsa2oylaaino)-ethyl7banzole acid tedrate Prepared froa 4-/5- (5-osiiao-2-(J-feydroay-piperidi»® )-feenzoyl5 anime)-ethyiy-biaasoie acid aathyleator analogously to Sample 86.
Yields 40 Si of theory, M.p.s 100 - 110°C Calc.s C 59.93 B 5.98 S3 6.65 1° Founds 60.19 6.08 6.62 4- /2- ( 2- (3-Hydr®xy=piperi din©)=5~®itr®-bareoylaniffl®)-ethyl7beasolc acid methylester Prepared fron 4-/5- (2-chl®ro-5-nitra-hc5n3oyleiain®)-ethy^" benzoic acid methylester and 3=hydroxy-piperifiine analogously to Example 83.
Yields 43.5 Si of theory, H.p.s 78 - 80°C Exaaple 90 4-/5- (5-Anino-2- (3-hydroxy-pip®ridiao ) -henzoylaaino )-ethyl7benzoic acid methylester Prepared from 4-/5-( 3-hydroxy=piperidimo)=5"nitro-b®nzoylaaino) etbylj-bensoic acid nethylester by eatalyticsl hydrogenation analogously to Exanple 84.
Yields 90 Si of theory, M.p.s 82°C Example 91 Ethyl 4- [2(2-piperidino-5-propyloxy-benznylaaino)-ethyl7benzoate 1.3 g (8mmol) of N,N'-carbonyl-diimidazole were added to a solution of 2 g (7.6 «mol) of 2-plperidino-5-propyloxybenzoic acid in 60 ml of absolute tetrahydrofurane. Subsequently the solution was heated to reflux temperature for 10-14 hours excluding aoisture. After the iaidazolide was foraed approx, quantitatively, the solution was mixed with 1.5 g (Smmol) of ethyl 4-(2-amino-ethyl)-benzoate and was heated to boiling for further 4-6 hours. After distilling off the tetrahydrofurane in a rotation evaporator, the crude ester was purified chromatographically over a ailicagel column with toluene/ethyl acetate (9:1) as solvent. The fractions containing the purified ester, were combined and the solvent was distilled off.
Yield: 2.4 g (72 % of theory), M.p.: 4.20°C Calc.: C 71.20 H 7.81 M 6.38 Found: 71.30 8.02 6.54 Example 92 4-/5-(2-Piperidino-5-propyloxy-benzoylamino)-ethyl7benzoic acid hydrochloride 1.8 g (4.1 mmol) of ethyl 4-/5-(2-piperidino-5-propyloxy-benzoylamino)-ethyl7benzoate were dissolved in a mixture of 15 ml of methanol and 15 ml of dioxane. At room temperature 1 ml of 30 # sodium hydroxide solution, diluted with 30 ml of water, was added so slowly to the ester solution that no permanent precipitation of the ester was formed. The addition was finished after approx. hours. After stirring for a few hours the organic solvents were distilled off in a rotation evaporator, the aqueous phase was extracted with chloroform and was adjusted to pH 4 with 2 N hydrochloric acid. After extraction with chlorofora, drying the chlorof om phase and distilling off tho chloroform, the hydrochloride ana precipitated frea a eolation la eootone with iaopropanolie hydrochloric acid, Yields 1.65 g (SO 0 of theory)', H.p.s 236®C Calc.. C 64.48 H 7.00 El 6,26 Cl 7.93 Founds 64.24 7.06 6.17 @.13 Exanplo S3 Ethyl /2-(5"isopropylosy-2=piperidino~heffi2©yl0i3ino)«-®thyl7·10 benzoate Prepared analogously to Exanple 91 froa 5"is©pr©pyl©xy« 2-piperidino-beasoic acid and ethyl 4-(2-s£3iao=ethyl)«-benseat®. Yields 58 $ of theory, M.p.s 70 - 72°C Calc.s C 71.20 @7.81 £3 6.33 Founds 71.10 7.74 6.40 Exanple 94 4-/2- (5-IsopropyloKy-2=piperidisio-heaz©ylaHi®©)-ethy37fe®Jazolc acid hydrochloride Prepared analogously to Exanple 92 froa ethyl 4-/2-(5··1ώο·propylo:qr-2-piperidino-benzoylanino)-ethyi7feensoate by alkaline hydrolysis.
Yields 82 % of theory, M.p.: 225 - 226°C Calc.: C 64.48 H 6.98 W 6.26 Cl 7.93 Founds 64.77 7.30 6.40 7.79 0 282 *- Example 95 Ethyl 4-/2-(5-hexyloxy-2-plperidino-benzoylamino)-ethyl7benzoate Prepared analogously to Example 92 from 5-hexyloxy-2-plperidino5 benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 61 % of theory, M.p.: 66°C Calc.: C 72.47 H 8.38 H 5.82 Found: 72.68 8.29 5.87 Example 96 · 4-/2- (5-Hexyloxy-2-piperidino-benzoylamino)-ethyl/benzolc acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/?-(5-hexyloxy2-piperidino-benzoylanino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 87 % of theory, M.p.: 152 - 154°C Calc.: C 66.30 H 7.62 M 5.72 Cl 7.24 Found: 66.43 7.98 5.77 7.26 Example 97 Ethyl 4-/2-(5-benzyloxy-2-piperidino-benzoylamino)-ethyl7benzoate Prepared analogously to Example 91 from 5-benzyloxy-2-piperidinobenzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 55 % of theory, 25 M.p.: 120°C Calc.: C 74.04 H 7.04 N 5.75 Found: 73.90 7.14 6.03 Example 98 4-[ί- (5-Benzyloxy-2-piperidino-benzoylaaino ) -ethyl/benzolc acid Prepared analogously to Example 92 fro· ethyl 4-/2-(5-benzyl5 oxy-2-piperidimo-b«azoylamine)-ethyl7benzaate by alkaline hydrolysis.
Yield: 86 % of theory, H.p.: 176°C Calc.: C 73.34 H 6.59 N 6.10 Found: 73.34 6,76 6.13 Example 99 Methyl 4-/2- (5-chloro-2-piperidino-benzoylamino)-2-methylethyl7benzoate Prepared analogously to Example 91 from 5-chloro-2-piperidino15 henzoic acid and methyl 4-(2-amino-propyl)-benzoate.
Yield: 54 % of theory, M.p.: < 20°C.
Example 100 4-/2-(5-Chloro-2-piperidino-benzoylamino)-2-methyl-ethyl720 benzoic acid________________________ Prepared analogously to Example 92 from methyl 4-/2-(5-chloro2-piperidino-benzoylamina)-2-methyl-ethyl7benzoate by alkaline hydrolysis.
Yield: 49 % of theory, M.p.: 142 - 145°C Calo.: C 65-90 H 6.28 Cl 8.84 N 6.98 Found: 65.85 6.45 8.83 6.99 Example 101 Methyl 4-/5-(3-chloro-2-piperidino-benzoylamino)-ethyl/5 benzoate Prepared analogously to Example 91 from 3-chloro-2-piperldinobenzoic acid and methyl 4-(2-amino-ethyl)-benzoate.
Yield: 63 % of theory, M.p.: 92 - 94°C Calc.: C 65.91 »6.28 Cl 8.85 M 6.99 Found: 65-71 6.19 9.07 6.93 Example 102 4-/5-(3-Chloro-2-plpcrldlno-benzovlamlno)-ethvl7benzolc acid Prepared analogously to Example 92 from methyl 4-/5-(3-chloro 2-piperidino-benzoylamino) lysis.
Yield: 57 % of theory, M.p.: 155 - 158°C Calc.: C 65.19 H 5.99 Found: 64.96 5·99 ethyl7~benzoate by alkaline hydroC1 9.17 H 7.24 9.38 7.50 Example 103 Ethyl 4-/3-(4-chloro-2-plperldino-benzoylaaino)-ethyl7benzoate Prepared analogously to Example 91 from 4-chloro-2-piperidino 5 benzoic acid and ethyl 4-(2-aaino-ethyl)-benzoate.
Yield: 71 % of theory, M.p.: < 20°C Calc.s C 66-58 H 6.56 N 8.54 Cl 6.75 Founds 66.58 6.57 8.42 6.99 Exaaple 104 4-/5- (4-Chloro-2-plperidlno-benzoylamino)-ethylTbenzolc acid Prepared analogously to Example 92 from ethyl 4-/3-(4-chloro2-piperIdino-benzoylamino)-ethylTbenzoate by alkaline saponification.
Yield: 66.7 % of theory, M.p.: 164 - 166°C Calc.: C 65.20 H 5.99 H 9-16 Cl 7.24 Found: 65.31 5.96 9·25 7.48 Example 105 Ethyl 4-/2-(5-broso-2-(2-sethyl-piperidino)-benzoylamino)ethylTbenzoate Prepared analogously to Example 91 from 5-bromo-2-(2-methylpiperidino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 74 % of theory, M.p.: 98°C 100 Calc.: C 60.89 Found: 60.99 H 6.18 N 5.92 6.43 5.78 Example 106 4-/5-(5-Bromo-2-(2-methyl-piperidino)-benzoylamino)-ethyl/5 benzoic acid Prepared analogously to Example 92 from ethyl 4-/?-(5-bromo2-(2-methyl-piperidino)-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 73 % of theory, M.p.: 183°c Calc.: C 65.91 H 6.29 M 6.99 Found: 65.70 6.35 6.80 Example 107 Methyl 4-/?- (5-chloro-2-(3,5-trans-dimethyl-piperidino)-benzoyl15 amino)-ethylTbenzoate Prepared analogously to Example 91 from 5-chloro-2-(3,5-transdimethyl-piperidino) -benzoic acid and ethyl 4-(2-amino-ethyl)benzoic acid.
Yield: 75 % of theory, M.p.: 105 - 107°C Calc.: C 67.20 H 6.81 M 6.53 Cl 8.27 Found: 67.40 6.92 6.47 8.26 101 Example 108 4-/5-(5-Chloro-2-(3,5-trans-dimethyl-piperidino)-benzoylamino) ethyl7benzoic acid .
Prepared analogously to Exanple 92 from methyl 4-/5-(5-chloro5 2-(3,5-trans-diiaethyl-piperidino)-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yields 86 0 of theory, M.p..· 164 - 167°C Calc.s C 66.58 H 6.56 N 6.75 Cl 8.55 10 Pound; 66.80 6.71 6.65 8.63 Example 109 Methyl 4-/5- (5-bromo-2-(3,S-cis-dimethyl-piperidino)-benzoylamino)-ethyl7ben2oate Prepared analogously to Example 91 from 5-bro«o-2-(3,5-cis15 dimethyl-piperidino)-benzoic acid and methyl 4-(2-amino-ethyl) benzoate.
Yield: 82 % of theory, M.p.: 142 - 144°C Calc.: C 60.89 H 6.17 N 5.92 Cl 16.88 Pound: 60.81 6.08 5.85 16.72 102 Example 110 4-/2-(5-Bromo-2-(3,5-cis-dimethyl-piperidino)-benzoylamino)ethTl7benzoie acid Prepared analogously to Example 92 from methyl 4-/2-(5-brono5 2-(3,5-cis-dimethyl-piperidino)-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 88 % of theory, M.p.: 184 - 185°C Calc.: C 60.13 H 5.92 M 6.10 Cl 17.40 Found: 59-98 5.87 6.02 17.30 Exanple 111 Ethyl 4-g.-(5-methoxy-2-(3,5-cis-dimethyl-piperidino)-benzoylamino) -ethyl/benzoate Prepared analogously to Exaaple 91 from 5-methoxy-2-(3,5-cis15 dimethyl-piperidino)-benzoic acid and ethyl 2-(aaino-ethyl)-benzoYield: 14 % oi theory, ate M.p.: 97 - 99°C Calc.: C 71.21 H 7.81 M 6.39 Found: 71.29 7.78 6.16 Example 112 4-/2-(5-Methoxy-2-(3,5-cia-dimethyl-piperidino)-benzoylamino)ethyl/beazoic acid Prepared analogously to Example 92 from ethyl 4-/2-(5-methoxy2-(3,5-c is-dimethyl-piperid ino)-benzoylamino)-ethyl/benzoate 25 by alkaline hydrolysis.
Yield: 53 % of theory, M.p.: 200 - 2O3°C 103 50892 Calc.: C 70.22 H 7.37 N 6.82 Found: 70.22 7.38 6.82 Example 115 Ethyl 4-/2-(5-chloro-2-(3,3,5»5-tetramethyl-piperidino)-benzoyl5 amino)-ethyl7baPzoate_ Prepared analogously to Example 91 from 5-chloro-2-(3,3,5»5-tetra methyl-piperidino)-benzoic acid and ethyl 4-(2-amino-ethyl)benzoate.
Yield: 34 % of theory, M.p.: Calc.: Found: 108°C C 68.85 H 7.49 68.75 7.37 N 5.94 5.79 Cl 7.52 7-69 Example 114 4-/2-(5-Chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoylamino)15 ethylTbenzoic acid_ -______________________ Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro2-(3,3,5,5-tetramethyl-piperidino)-benzoylamino)-ethyl7benzoate by alkaline hydrolysis. Yield: 99 % of theory, M.p.: 170 - 172°C Calc.: C 67.78 H 7.05 Found: 67.60 7.09 N 6.32 Cl 8.00 6.13 7.95 104 5029a Example 115 Ethyl 4-/5-(5-chloro-2-(piperidone-(2)-yl-(1))-benzoylamino)ethyl7benzoate Prepared analogously to Example 91 from 5-chloro-2-(piperidone5 (2)-yl-(l))-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 42 % ot theory, M.p.: 118°C Calc.: C 64.40 H 5.88 »6.53 Found: 64.32 5.87 6.58 Example 116 4-/2-(5-Chloro-2-(piperidone-(2)-yl-(1))-benzoylamino)-ethyl7benzolc acid hydrate Prepared analogously to Example 92 from ethyl 4-/?-(5-chloro2-(piperidone-(2)-yl-(1))-benzoylamino)-ethyl7benzoate by alka15 line hydrolysis.
Yield: 64 % of theory, M.p.: 190 - 193°C Calc.: C 60.48 H 5.56 »6.72 Found: 60.74 5.47 6.96 20 Exanple 117 Ethyl 4-/J-(5-bromo-2-(4-methoxy-piperidino)-benzoylamino)ethylTben2oate Prepared analogously to Example 91 from 5-brono-2-(4-methoxypiperidino) -benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. ?5 Yield: 82 % of theory, M.p.: < 20°C 105 50392 Calc.: Found: C 58.90 H 5.97 N 5-72 59.25 6.08 5.27 Example 118 4-/2-(5-Bromo-2-(4-methoxy-piperidino)-benzoylamino)-ethyl75 benzoic acid_____________________________ Prepared analogously to Example 92 from ethyl 4-/2-(5-bromo2-(4-methoxy-piperidino)-benzoylamino)-ethylTbenzoate by alkaline hydrolysis.
Yield: 65 % of theory, M.p.: 186°C Calc.: C 57.28 H 5.46 N 6.07 Found: 56.40 5.46 5-85 Example 119 Ethyl 4-/2- (5-chloro-2-(2,6-dimethyl-morpholino)-benzoylamino)15 ethyl7benzoate______________________________________ Prepared analogously to Example 91 from 5-chloro-2-(2,6-dimethylmorpholino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 52 % of theory, M.p.: 111 - 112°C Calc.: C 64.78 H 6.57 N 6.30 Found: 64.72 6.64 6.24 106 293 Example 120 4-/2- (5-Chloro-2-(2,6-dimethyl-morpholino)-benzoylamino)-ethyl7benzoic acid Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro5 2-(2,6-dimethyl-morpholino)-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 86 % of theory, M.p. ί 232°C Calc.: C 63.38 H 6.04 M 6.72 10 Found: 63.38 6.28 6.69 Example 121 Ethyl 4-/2-(5-chloro-2-(2,6-dimathyl-thiomorpholino)-benzoylamlno) -ethvlTbenzoate Prepared analogously to Example 91 from 5-chloro-2-(2,6-dimethyl15 thiomorpholino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 71 % of theory, M.p.: C 20°C Calc.: C 62.53 H 6.34 N 6.08 Found: 62.60 6.52 6,08 Example 122 4-/2-(5-Chloro-2-(2,6-dimethyl-thiomorpholino)-benzoylamino)ethvl7benzoic acid Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro2-(2,6-dimethyl-thiomorpholino)-benzoylamino)-ethyl7benzoate by alkaline hydrolysis. 107 Yield: 51 % of theory, M.p.: 183 - 185°C Calc.: C 61.03 H 5-82 N 6.47 Found: 60.62 6.01 6.30 Example 123 Ethyl 4-/5-(5-chloro-2-(thiomorpholino-·?,1-dioxyde)-benzoylanlno)-ethylTbenzoate Prepared analogously to Example 91 from 5-chloro-2-(thioaorpholino-1,1-dioxyde)-benzoic acid and ethyl 4-(2-amino-ethyl) benzoate.
Yield: 40 % of theory, M.p.: 158°C Calc.: C 56.83 H 5.42 N 6.02 Found: 56.78 5.78 6.15 Example 124 Ethyl 4-/5-(2-hexamethyleneimino-5-methoxy-benzoylamino)ethyl7benzoate Prepared analogously to Example 91 from 2-hexamethyleneimino5-metho:cy-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 46 % of theory, M.p.: 92°C Calc.: C 70.73 H 7.60 N 6.60 Found: 70.46 7.53 6.72 108 50392 Exaaple 125 4-/2-(2-HexaaethylenelBlno-5-aethoxy-benzoylaalno)-ethyl/benzoic acid hydrochloride Prepared analogously to Exaaple 92 froa ethyl 4-/2- (2-hexa5 methyleneiaino-5-aethoxy-benzoyl-aaino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 92 % oi theory, M.p.: 126°C Calc.: C 63.50 H 6.75 H 6.46 Cl 8.18 10 Found: 63.80 7.24 6.57 7.62 Exaaple 126 Ethyl 4-/2-(2-heptaaethyleneiaino-5-aethoxy-benzoylaaino)ethyl7benzoate Prepared analogously to Exaaple 91 froa 2-heptaaethyleneiaino15 5-aethoxy-benzoic acid and ethyl 4-(2-aaino-ethyl)-benzoate.
Yield: 30 K of theory, M.p.: < 20°C.
Exaaple 127 4-/2-(2-Heptaaetbyleneiaino-5-methoxy-benzoylaaino)-ethyl720 benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/2-(2-heptaaethyleneiaino-5-aethoxy-benzoylaaino)-ethyl7benzoate by alkaline saponification.
Yield: 97 % of theory, M.p.: 110 - 112°C Calc.: C 59.68 H 6.88 N 5.80 Found: 60.80 6.87 5.63 109 Ethyl 4-/5- (2-heptaEethylaneimino-5-isopropyloxy-benzoylamino)ethylTbenzoate _ __ __——;:Prepared analogously to Exaaple 92 from 2-heptamethyleneiaino5 5-ieopropyloxy-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yields 62 % of theory, M.p.: C 20°C Calc.s C 72.07 H 8.20 N 6.00 10 Found: 72.20 8.16 5.90 Example 129 4-/2-(2-Heptamethyleneimlno-5-isopropyloxy-benzoylamino)ethylTbenzolc acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/5-(2-hepta] 5 methyleneimino-5-isopropyloxy-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 91 % of theory, M.p.s 202°C Calc.: C 65-73 H 7.42 N 5.90 Cl 7-46 Found: 65.85 7.58 5.82 7-23 Example 130 Ethyl 4-/5-(5-hromo-2-heptamethyleneimino-benzoylamino)-ethyl7benzoate Prepared analogously to Example 91 from 5-bromo-2-heptamethylene imino-benzoic acid and ethyl 4-(2-amino-ethyl-benzoate.
Yield: 42.5 % of theory, M.p.: 81°C Calc.: C 61.80 H 6.50 Found: 61.60 6.40 N 5.78 Br 16.40 .74 16.40 no Example 131 4-/2-(5-Broao-2-heptamethyleneimlno-benzoylanino)-ethyl7benzoic acid Prepared analogously to Example 92 from ethyl 4-/2- (5-brono2-heptamethyleneimino-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 94 % of theory, M.p.: 189°C Calc.: C 60.13 H 5.92 M 6.10 Br 17.39 Pound: 59.97 6.01 6.05 17.51 Example 132 Ethyl 4-/2-(2-(3-aza-bicyclo/5,2,2/nonane-3-yl)-5-chloro-benzoylamlno )-ethYl7benzo«te Prepared analogously to Example 91 from 2-(3-aza-bicyclo/J,2 ^/nonane-3-yl)-5-chloro-benzoic acid and ethyl 4-(2-amino-ethyl)benzoate.
Yield: 82 % ot theory, M.p.: 114°C Calc.: C 68.63 H 6.87 N 6.16 Found: 68.78 7.08 6.16 Example 133 4-/2-(2-(3-aza-bicyclo/?,2,2/nonane-3-yl)-5-chloro-benzoylanino)-ethyl7benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/2-(2-(3-azabicyclo/J,2,27nonane~3-yl)-5-chloro-benzoylanino)-ethyl7benzoate by alkaline hydrolysis.
Ill Yield: 98 % of theory, M.p.: 158°C Calc.: C 62.20 H 6.03 Found: 62.76 6.37 H 6.05 6.07 Cl 15.30 15.25 Example 134 Ethyl 4-/2-(5-chloro-2-octamethyleneimino-benzoylamino)ethylTbenzoate Prepared analogously to Example 91 from 5-chloro-2-octamethylene imimo-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 41 of theory, M.p.: 4 20°C Calc.: C 68.33 H 7.28 Found: 68.15 7.10 N 6.13 6.09 Example 135 4-jJL- (5-Chloro-2-octamethyleneimino-benzoylamino )-ethyl/benzoic acid Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro2-octamethyleneimino-benzoylamino)-ethylTbenzoate by alkaline hydrolysis.
Yield: M.p.: Calc.: Found: % of theory, 172°C C 67.20 66.90 H 6.81 6.76 N 6.53 6.39 112 Example 136 Ethyl 4-/5- (5-chioro-2-nonamethyleneimlno-benzoylamino)ethylTbenzoate Prepared analogously to Example 91 from 5-chloro-2-nonamethylene- imino-benzole acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 24 % of theory, M.p.: < 20°C Calc.: C 69.14 H 7.09 M 5.97 Cl 7.56 Found: 69.38 7.28 6.13 7.88 Example 137 4-/5-(5-Chloro-2-nonamethyleneimino-benzoylamino)-ethyl/benzoic acid Prepared analogously to Example 92 from ethyl 4-/5-(5-chloro2-nonamethyleneimino-benzoylamino)-ethylTbenzoate by alkaline hydrolysis.
Yield: 82 % of theory, M.p.: 173 - 174°C Calc.: C 68.00 H 6.63 N 6.35 Cl 8.04 Found: 67.62 6.78 6.23 7.60 Example 138 Ethyl 4-/5-(5-chloro-2-decamethyleneimino-benzoylamino)-ethyl7benzoate Prepared analogously to Example 91 from 5-chloro-2-decamethyleneimino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 65 % of theory, M.p.: <20°C Calc.: C 69.33 H 7.69 N 5.78 Found: 69.29 7.64 5.92 113 ~ Rrmaple 159 4-/2-(5-Chloro-2-decam@thyleneimino-benzoylamino)-ethyl/benzole acid Prepared analogously to Example 92 from ethyl 4-/5-(5-chloro5 2-dsca2aethyleneimlno-bonzoylaHlno)-ethyl/benzoate by alkaline hydrolysis.
Yield: 58 % of theory, M.p.: 177°C Calc.: C 68.33 H 7.28 N 6.13 10 Found: 68.43 7.28 6.41 Example 140 Ethyl 4-/5- (5-chloro-2-undecamethyleneiaino-benzoylamino)etfayl7benzoate .
Prepared analogously to Example 91 from 5-chloro-2-undecamethyle 15 neimino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 71 % of theory, M.p.: 80°C Calc.j C 69.79 H 7.88 N 5.61 Found: 69-35 7·66 5·84 Example 141 4-/2-(5-Chloro-2-undecaaethyleneimino-benzoylamino)-ethyl/benzoic acid Prepared analogously to Example 92 from ethyl 4-/5-(5-chloro2-undecamethyleneimino-benzoylamino)-ethyl^)enzoate by alkali25 ne hydrolysis. 114 Yield: 77 % of theory, M.p.: 21« - 220°C Calc.: C 6β.84 H 7.49 M 5.95 Found: 68.34 7.21 6.19 Example 142 Ethyl 4-/2- (5-chloro-2-dodecamethyleneinino-benzoylaaino ) ethvlTbenzoate Prepared analogously to Example 92 from 5-ehloro-2-dodecamethyleneimino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 53 X of theory, M.p.: < 20°C Calc.: C 70.22 H 8.05 M 5.46 Found: 70.56 7.77 5.71 Exanple 143 4-/2- (5-Chloro-2-dodecamethyleneimino-benzoylamino)-ethyl7benzolc acid Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro2-dodecamethyleneimino-benzoylamino)-ethyl7benzoate by alkaline saponification.
Yield: 33 % of theory, M.p.: 185 - 187°C Calc.: C 69.33 H 7.69 N 5.78 Found: 69.17 7-54 5.95 115 Example 144 Ethyl 4-/5- (5-chloro-2- (H-methyl-anilino)-b@nzoylamlno )ethyiZbenzoate Prepared analogously to Example 91 from 5-cfaloro-2~(N-methyl5 anilino)-benzoic acid and ethyl 4-(2-amino-ethyl}-benzoate.
Yield; 70 % of theory, M.p.: <20°C.
Example 145 4-/5-(5-Chloro-2-(N-aethyl-anilino)-benzoylamino)-ethyl/10 benzoic acid_____ Prepared analogously to Example 92 from ethyl 4-/5-(5-chloro2-(N-methyl-anilino)-benzoylamino)-ethyl7ben2oate by alkaline hydrolysis.
Yield: 65 % of theory, IS M.p.: 186 - 188°C Calc.: C 67.56 H 5.80 N 6.85 Found: 67.81 5.66 6.87 Example 146 Ethyl 4-/5-(2-(N-ethyl-cyclohexylamino)-5-chloro-benzoylamino) 20 ethylTbenzoate___________________ Prepared analogously to Example 91 from 2-(N-ethyl-cyclohexylamino)-5-chloro-benzoic acid and ethyl 4-(2-amino-ethyl)-benzo ate.
Yield: 41 % of theory, M.p.: 94°C.
Calc.: C 68.33 H 7.28 N 6.13 Found: 68.00 7.10 6.03 116 Example 147 4-/2-(2-(N-Ethyl-cyclohexylamino)-5-chloro-benzoylamino)ethylTbenzolc acid Prepared analogously to Example 92 fro· ethyl 4-/2-(2-(N-ethyl5 cyclohexylamlno)'-5-chloro-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 63 % of theory, M.p.: 163°C Calc.: C 67.20 H 6.81 N 6.53 10 Found: 67.25 6.67 6.45 Example 148 Ethyl 4-/2- (2-(N-butyl-cyclohexylamino)-5-chloro-benzoylamino)ethylTbenzoate Prepared analogously to Example 91 from 2-(N-butyl-cyclohexyl15 amino)-5-chloro-beazoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 46 % of theory, M.p.: 77°C Calc.: C 69.33 H 7.60 N 5.78 Found: 69.12 7.69 5.78 Example 149 4-/2-(2-(N-Butyl-cyclohexylamino)-5-chloro-benzoylamino)-ethylTbenzoic acid Prepared analogously to Example 92 from ethyl 4-/2-(2-(N-butyl25 cyclohexylamino)-5-chloro-benzoylamino)-ethylTbenzoate by alkaline hydrolysis. 117 Yield: 79 % of theory, M.p.: 05°C Calc.: C 68.33 H 7.28 H 6.13 Found: 68.44 7.18 6.40 Example 150 Ethyl 4-/5-(5-chloro-2-(ti-isobutyl-cyclohexylaaino)-benzoylamino)-ethylTbenzoate Prepared analogously to Example 91 from 5-chloro-2-(N-iaobutylcyclohexylamino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzo ate. Yield: 46 % of theory. M.p.: 83°C Calc.: C 69.33 H 7.69 N 5.78 Found: 69.17 7.54 5.66 15 Example > 151 4-/2-(5-Chloro-2-(N-isobutyl-cyclohexyla mLno)-benzoylamino)ethylTbenzolc acid Prepared analogusly to Example 92 from ethyl 4-/5-(5-chloro2-(N-isobutyl-cyclohexylaraino)-benzoylamino)-ethylTbenzoate by alkaline saponification.
Yield: 62 % of theory, M.p.: 129°C Calc.: C 68.33 H 7.28 N 6.13 Found: 68.30 7.18 6.17 118 _ Example 152 Methyl 4-/5-(5-chloro-2-dlmethylamlno-benzoylamino)-2-methylethyl7benzoate Prepared analogously to Example 91 from 5-chloro-2-dimethyl5 amino-benzoic acid and methyl 4-(2-amino-propyl)-benzoate.
Yield: 34 % of theory, M.p.: <20°C.
Example 153 4-/2-(5-Chloro-2-diaethylanino-benzoylamino)-2-eethyl-ethyl710 benzoic acid Prepared analogously to Exanple 92 from methyl 4-/2- (5-chloro2-dimethylamino-benzoylamino)-2-methyl-ethyl7benzoate by alkaline hydrolysis.
Yield: 49 % of theory, M.p.: 142 - 145°C.
Calc.: C 63.22 H 5.86 N 7.76 Found: 62.90 5.98 7.54 Exanple 154 Methyl 4-/2-(3-chloro-2-dimethylamino-benzoylamino)-ethyl72o benzoate _ . Prepared analogously to Example 91 from 3-chloro-2-dimethylamino-benzoic acid and methyl 4-(2-amino-ethyl)-benzoate. Yield: 76 % of theory, M.p.: < 20°C. 119 Example 155 4-/2-(5-Chloro-2-dimetfaylamino-benzoylamino)-ethyl7benzoic acid Prepared analogously to Example 92 from methyl 4-/5-(3-chloro5 2-dimethylamino-benzoylamino)-ethyl7bemzoate by alkaline hydrolysis.
Yields ?6 % of theory, M.p.s 175 - 178°C Calc.s C 62.33 H 5-52 N 8.08 Cl 10.22 10 Founds 62.60 5.56 8.26 10.27 Example 156 Methyl 4-/5-(2-dimethylamino-5-methoxy-benzoylamino)-ethyl7benzoate Prepared analogously to Example 91 from 2-dimethylamino-5-methoxy 15 benzoic acid and methyl 4-(2-amino-ethyl)-benzoate.
Yield: 81 % of theory, M.p.: 4. 20°C.
Example 157 4-/2-(2-Dlmethylamlno-5-methoxy-benzoylamino)-ethyl7benzolc acid Prepared analogously to Example 92 from methyl 4-/5-(2-dimethylamino-5-methoxy-benzoylamino)-ethyl7ben2oate by alkaline hydrolysis.
Yield: 71 % of theory, M.p.: 147 - 150°C Calc.: C 66.65 H 6.48 N 8.18 Found: 66.85 6.35 8.12 120 50392 Example 158 Ethyl 4-/2-(4-chloro-2-dimethylamino-benzoylamino)-ethyi7benzoate 5 3.55 g (10 mmol) of ethyl 4-/2-(4-amino-2-dimethylamino-benzoylamino)-ethyl/benzoate (m.p.: 135 - 136°C, prepared by hydrogenation of ethyl 4-/2-(2-dimethylamino-4-nitro-benzoylamino)-ethyl/benzoate with palladium/charcoal) were diazotized in 4 ml of cone, hydrochloric acid and approx. 5 g of ice by dropwisely adding a solution of 820 mg (11.6 mmol) of sodiua nitrite in 5 nl of water. After 30 ainutes the diazonium salt solution was dropped to a suspension of 1.2 g of copper bronze in 1 al of cone, hydrochloric acid at room temperature. After standing over night, the reaction mixture was diluted with water and ex15 tracted with chloroform. The evaporated chloroform extracts were purified column-chromatographically on silicagel (eluens: toluene/ethyl acetate - 1:1; * 0.75).
Yield: 27 % of theory, M.p.: 97 - 99°C.
Calc.: C 64.08 H 6.18 N 9.46 Cl 7.47 Found: 64.37 6.42 9.32 7.44 Example 159 4-/2-(4-Chloro-2-dimethYlamino-benzoylamlno)-ethvl7benzolc acid Prepared analogously to Example 92 from ethyl 4-/2-(4-chloro25 2-dimethylamino-benzoylamino)-ethyl/benzoate by alkaline saponification.
Yield: 95 % of theory, M.p.: 163 - 165°C Calc.: C 62.34 H 5.52 N 10.22 Cl 8.08 Found: 61.92 5.55 10.60 8.15 121 30292 Braspla.160 Ethyl 4-/5- (2-dia®tfayl«mi»o-4-nitro-beiizoyl Prepared analogously to Exanple 91 iron 2-diaethylanino5 4-nitro-beaxoie aeid and ethyl 4-(2~anine-ethyl)-benzoate.
Yield: 95 % of theory, M.p.s 145°C Calc.s C 62.33 H 6.01 »10.90 Founds 62.73 6.00 11.09 Exanple 161 Methyl 4-/5-(6-ehl©re~2-diaethylaBinO"benzeylanino)-ethy^benaoate Prepared analogously to Example 91 fron 6-chloro-2-dinethylaaino-benzoic aoid and methyl 4-(2*>anlno-etliyl)-benzeat·. Yields 25 % of theory, M.p.: 115 - 117®C Calc.s C 63.24 H 5.87 »7.76 Cl 9.83 Pounds 63.33 5.73 7.90 9.92 Example 162 4-/5-(6-Chloro-2-dimethYlaBino-benzoylanlno)-athyl7beazoio acid Prepared analogously to Example 92 fron Methyl 4-/5-(6-ehloro2-diaethylanino-beazoylanino)-ethyl7benzaate hy alkaline hydrolysis.
Yields 35 % ot theory, M.p.s 155^158®C Calc.. C 62.34 H 5.52 Founds 62.9© 5.73 N 8.08 7.92 Cl 10.22 10.11 122 Example Ιοί Ethyl 4-/5-/5- (4-benzyl-plperazino)-5-chloro-benzoylamino7ethYl7benzoate Prepared analogously to Exaaple 91 froa 2-(4-benzyl-piperazi5 no)-5-chloro-benzoic acid.
Yield: 39 Ii of theory, M.p.: <20°C Calc.: C 68.83 H 6.37 »7.00 Cl 8.30 Found: 68.97 6.52 6.93 8.21 W Exaaple 164 Ethyl 4-/5-/5-plperazlno-benzoylamino7ethyl7benzoate Prepared from ethyl 4-/2-/5-(4-benzyl-piperazino)-5-chlorobenzoylaaino7ethyl7benzoate by catalytical hydrogenation with palladiua/charcoal at room temperature and at a hydrogen pressu15 re of 1 bar.
Yield: 60 % of theory, M.p.: <20°C Calc.: C 69.27 H 7.13 N 11.01 Found: 69.22 7.11 10.90 123 _ Example 165 4-/2-(5-Chloro-2-(decahydro-isoquinoline-2-yl)-benzoylamino)ethylTbenzolc acid ethyl ester A mixture oi 2.5 g (8.5 mmol) of 5-chloro~2-(decahydro5 isoquinoline-2-yl)-benzoic acid and 1.4 g (8.6 mmol) of carbonyl diimidazole was heated to boiling in 30 ml of absolute tetrahydrofuran for 8 hours. 1.64 g (8.6 mmol) of 4-(2-aminoethyl)-benzoic acid ethyl ester were added to the formed imidazolide and the reaction mixture was refluxed for further 12 hours. After distilling off the solvent, the ester was purified over a silicagel column by means of toluene/ethyl acetate (9:1) as eluant.
Yield: 2.7 g (68 % of theory), M.p.: <20°C.
Calc.: C 69.14 H 7.09 »5-97 Cl 7.55 Found: 69.43 6.98 6.10 7.76 Example 166 4-/2-(5-Chloro-2-(decahydro-isoquinoline-2-yl)-benzoylamino)ethvlTbenzoic acid hydrochloride 1.9 g (4.1 mmol) of 4-/2-(5-chloro-2-(decahydro-isoquinoline2-yl)-benzoylamino)-ethyl7benzoic acid ethyl ester were dissolved in a mixture of 20 ml of dioxane and 20 ml of methanol. After addition of 5 ml of 30 % sodium hydroxide solution, diluted with 20 ml of water, the ester was hydrolized at room tem25 perature. After some hours the organic solvents were distilled off. After extraction with chloroform the aqueous phase was adjusted to pH 4 - 5 by means of 2N hydrochloric acid and the acid, which precipitated at this pH value, was extracted with chloroform. After drying ari distilling off the chloroform, the hydrochloride was precipitated in acetone by means of isopropanolic hydrochloric acid. 124 50392 '-Yield: 1.5 g (77 % of theory), M.p.: 226°C.
Calc.: C 62.88 H 6.33 N 3.86 Found: 62.60 6.36 5.93 Cl 14.85 14.76 Example 167 4-/2-(5-Cbloro-2-(decahydro-3-benzazepine-3-yl)-benzoylamino)ethylTbenzoic acid ethyl eater Prepared analogously to Example 165 from 5-chloro-2-(decahydro3- benzazepine-3-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 97 fi oi theory, M.p.: <20°C.
Calc.: C 69.62 H 7.30 N 5.80 Cl 7.33 Found: 69.88 7.22 5.63 7.46 15 Example 168 4- /2- (5-Chloro-2-(decahydro-3-benzazepine-3-yl)-benzoylamino)ethvlTbenzolc acid hydrochloride Prepared fron 4-/5-(5-chloro-2-(decahydro-3-benzazepine-3-yl)benzoyla«lno)-ethyl7benzoic acid ethyl ester by alkaline hydro20 lysis analogously to Example 166.
Yield: 84 % of theory, M.p.: 216°C.
Calc.: C 63.53 H 6.56 M 5.69 Cl 14.42 Found: 63.51 6.59 5.76 14.35 125 29 2 ~Example 169 4-/2-(5-Bromo-2-(decahydro-3-benzazepine-3-yl)-benzoylamino)ethvl7banzolc acid ethyl eater Prepared analogously to Example 165 from 5-broao-2-(decahydro5 3-benzazepirae-3-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 98 % of theory, M.p.: < 20°C.
Calc.s C 63.75 H 6.68 N 5.31 Br 15.14 10 Found: 64.06 6.56 5.16 15.00 Example 170 4-/2-(5-Bromo-2-(decahydro-3~benzazepine-3-yl)-benzoylamino)etfayl7benzolc acid hydrochloride t, Prepared analogously to Exaaple 166 froa 4-/2-(5-broao-2-(deca15 hydro-3-benzazepine-3-yl)-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 84 % of theory, M.p.: 216°C.
Calc.s C 58.26 H 6.01 N 5.22 Cl 6.61 Br 14.91 20 Founds 58.22 5.85 5.34 6.65 15.00 Example 171 4-/2- (5»Chloro-2-(octahydro-ΐεcindole-2-yl)-benzoylamino)ethyl7benzolc acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-(octahydro25 isoindole-2-yl)-benzoic acid end 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 72 % of theory, M.p.s <20°C.
Calc.: C 68.63 H 6.86 N 6.15 Cl 7.79 Found: 68.72 6.92 6.20 7.94 126 50282 _ Example 172 4-/5-(5-Chloro-2-(octahydro-isoindole-2-yl)-benzoylamino)ethylTbenzoic acid hydrochloride Prepared analogously to Example 166 from 4-/5-(5-chloro5 2-(octahydro-iaolndole-2-yl)-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 83 fi of theory, M.p.: 214°C.
Calc.: C 62.20 H 6.09 N 6.04 Cl 15.32 Found: 62.45 6.23 6.13 15.70 Example 173 4-/5-(5-Broao-2-octamethyleniaino-benzoylaaino)-ethyl7benzoic acid ethyl ester Prepared analogously to Example 165 from 5-bromo-2-octamethylen15 imino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 84 % of theory, M.p.: 420°C.
Calc.: C 62.27 H 6.63 M 5.58 Br 15.93 Found: 62.40 6.66 5.53 15.96 Example 174 4-/5-(5-Bromo-2-octamethylenimino-benzoylamino)-ethyl7benzoic acid hydrochloride Prepared analogously to Example 166 from 4-/5-(5-bromo-2-octamethylenimino-benzoylaaino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 90 Ί of theory, M.p.: 164°C.
Calc.: C 56.53 H 5.92 N 5.49 Br 15.67 Cl 6.95 Found: 56.82 5.96 5.47 14.85 6.59 127 0 292 Example 175 4-/2-(5-Cyaao-2-octsaethyleniHlno-benzoyla»iao)-ethyl/benzoic acid ethyl ester Prepared analogously to Exaaple 165 froa 5-cyano-2-octaaethylen iaino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 30 % of theory, M.p.: 94°C.
Calc.: C 72.45 H 7-43 »9.38 Found: 72.50 7.50 9.41 Example 176 4-/2-(5-Cyano-2-octamethylenimino-benzoylaaino)-ethyl7benzoic acid, .
Prepared analogously to Example 166 from 4-/2-(5-cyano-2-octamethylenioino-benzoylaaino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 87 % of theory, M.p.: 186°C.
Calc.: C 71.57 H 6.96 N 10.01 Found: 71.50 7.14 9.66 Example 177 4- /2-(2-0ctamethylenimino-5-n itro-benzoylamino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 165 from 2-octamethylenimino5- nitro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 50 % of theory, M.p.: 116°C.
Calc.: C 66.79 H 7.11 N 8.98 Found: 67.00 7.17 9.04 128 — Example 178 4-/5-(2-Octamethylenimino-5-nitro-benzoylamino)-ethyl7benzoic >cld hydrochloride Prepared analogously to Example 166 from 4-/5-(2-octamethy5 lenimino-5-nitro-benzoylamino)-ethylTbenzoic acid ethyl eater by alkaline hydrolysis.
Yield: 93 % of theory, M.p.: 148°C.
Calc.: C 62.06 H 6,.74 M 9.24 Cl 4.53 Founds 62.46 6.46 9.10 4.76 Example 179 4-/5-(5-Amino-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester dihydroohloride Prepared from 4-/5-(2-octamethylenimino-5-nltro-benzoylamino)15 ethyl/benzoic acid ethyl ester by catalytic hydrogenation in methanolic solution at a hydri gen pressure of 5 bar at room temperature by means of 10 % palladium charcoal aa catalyst. Yield: 79 % of theory, M.p.: 162°C.
Calc.: C 61.16 H 7.30 N 8.22 Cl 13.90 Found: 61.50 7.84 8.54 13.50 Example 180 4-/5-(5-Aa4no-2-octamethylenisitno-benzoylamino)-ethyl7benzoic acid hydrochloride Prepared analogously to Example- 166 from 4-/5-(5-amino-2-octamethylenimno-benzoylamino)-ethyl/benzoic acid ethyl ester hydrochloride by alkaline hydrolysis. 129 S02S2 Yield: 50 % of theory, M.p.: 130°C.
Calc.s C 64.62 H 7.23 Found; 63.90 7.10 H 9.42 Cl 7.94 9.20 7.74 Example 181 4- /2.- (2-0ctaaethyleniadno-5-aethoxy-benzoylamino )-ethyl7benzoic acid ethyl eater Prepared analogously to Example 165 from 2-oetaaethylenimino5- methoxy-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yields 80 % of theory, M.p.: < 20°C.
Calc.: C 71.65 H 8.01 N 6.18 Found: 71.65 8.15 6.25 Example 182 4-/2-(2-0ctamethylenimino-5-methoxy-benzoylamino)-ethy^benzoic acid hydrochloride Prepared analogously to Example 166 from 4-/2-(2-octamethylenimino-5-methoxy-benzoylamino)-ethyl7b®hzoic acid ethyl ester by alkaline hydrolysis.
Yield: 83 % of theory, M.p.: 216°C.
Calc.: C 65.13 H 7.21 N 6.07 Cl 7.68 Found: 64.53 7.39 5.96 7.70 Example 183 4-/2-(5-Ethoxy-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 165 from 5-ethoxy-2-octamethylen 130 0293 lnino-benzoic acid and 4-(2-anino-ethyl)-benzolc acid ethyl ester.
Yield: 66 % of theory, M.p.: < 2O°C.
Calc.: C 72.07 H 8.20 W 6.00 Found: 72.25 8.21 6.06 Exanple 184 4-/5-(5-Ethoxy-2-octanethylenlnino-benzoylanino)-ethyl7benzoic acid hydrochloride Prepared analogously to Exanple 166 iron 4-/5-(5-ethoxy-2-octa10 nethyleninino-benzoylanino)-ethyl7benzoic add ethyl ester by alkaline hydrolysis.
Yield: 98 % of theory, n.p.: 172°C.
Calc.: C 65.73 H 7.42 II 5.89 Cl 7.46 Found: 65.50 7.20 5.79 7.19 Exanple 185 4-/5-(5-Iaopropyloxy-2-octanethyleninino-benzoylanino)-ethyl7benzoic acid ethyl ester Prepared analogously to Exanple 165 fron 5-isopropyloxy-2-octa20 nethyleninino-benzoic acid and 4-(2-anino-ethyl)-benzoic acid ethyl ester.
Yield: 87 % of theory, M.p.: < 20°C.
Calc.: C 72.47 H 8.38 M 5.82 Found: 73.04 8.44 5.76 131 50392 Exaaple 186 4-/5-(5-Isopropyloxy-2-octamethylenimino-benzoylamino)-ethyi7benzoic acid hydrochloride Prepared analogously to Example 166 froa 4-/5-(5-isopropyloxy5 2-octaiaethylenis!ino-hemzoylaaino)-ethyX7benzoic acid ethyl ester by alkaline hydrolysis.
Yields 93 % of theory, M.p.: 152°C.
Calc.s C 66.30 H 7.62 N 5.72 Cl 7.24 Found! 66.40 7.50 5.54 7.11 Example 187 4-/5-(5-Butyl-(2)-oxy-2-octamethyleniniino-benzoylamino)-ethyl7benzoic acid ethyl ester Prepared analogously to Example 165 from 5-butyl-(2)-oxy-2-octa15 methyleniaiino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 64 Ί of theory, M.p.: 420°C.
Calc.: C 72.84 H 8.56 N 5.66 Found: 72.58 8.48 5.27 Example 188 4-/5-(5-Butyl-(2)-oxy-2-octamethylenimino-benzoylamino)-ethyl/benzolc acid hydrochloride Prepared analogously to Example 166 from 4-/5-(5-butyl-(2)-oxy2-octasethylenimino-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis. Yield: 88 % of theory, M.p.: 142°C.
Calc.: C 66.84 H 7.81 Found: 66.40 7.84 N 5.56 Cl 7.04 5.20 6.71 132 — Example 189 4-/2-(5-Cbloro-2-(4~isopropyl-piperidino)-benzoylanino)-ethyl7benzoic acid ethyl eater Prepared analogously to Example 165 from 5-chloro-2-(4-isopropylpiperidino)-benzoic acid and 4-(2-amino-ethyl)-benzolc acid ethyl eater.
Yield: 72 Ji of theory, M.p.: < 2O°C.
Calc.: C 68.03 H 7.69 M 6.10 Cl 7.73 Found: 68.20 7.62 6.20 7.41 Example 190 4-/2- (5-Chloro-2-(4-isopropyl-piperidino)-benzoylamlno)-ethyl7benzolc acid Prepared analogously to Example 166 from 4-/2-(5-chloro-215 (4-isopropyl-piperidino)-benzoylanino)-ethyl7benzoic acid ethyl eater by alkaline hydrolysis.
Yield: 75 % of theory, M.p.: 164°C.
Calc.: C 67.20 H 6.81 M 6.53 Cl 8.27 Found: 67.40 6.94 6.74 8.41 Exanple 191 4-/2-(5-Chloro-2-(4-tert.butyl-piperidino)-benzoylamino)-ethyl7~ benzolc acid ethyl eater Prepared analogously to Example 165 from 5-chloro-2-(4-tert.butylpiperidino) -benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
M 5.95 Cl 7.53 6.20 7.90 Yield: 63 % of theory, M.p.: 103°C.
Calc.: C 68.84 H 7.49 Found: 69.10 7.60 133 -- -Example 192 4-/2-(5-Chloro-2-(4-tert.butyl-piperidino)-benzoylamino)-ethyl7benzoic acid Prepared analogously to Example 166 fro· 4-/2-(5Chloro-25 (4-tert.butyl-piperidimo)-benzoylamino)-ethyl7benzoic acid ethyl ester.
Yield: 87 % of theery, M.p.: 16O°C.
Calc.: C 67.78 H 7.05 N 6.33 01 8.00 Found: 67.93 7.21 6.50 8.20 Example 193 4-/2-(5-Chloro-2-(1,4-dioxa-8-aza-spiro/5,67undecane-8-yl)-benzoylaalno)-ethylTbenzolc acid ethyl eater Prepared analogously to Exaaple 165 from 5-chloro-2-(1,4-dioxa8-aza-spiro/7T,67undecane-8-yl)-benzoic acid and 4-(2-aainoethyl)-benzoic acid ethyl ester.
Yield: 43 % of theory, M.p.: <20°C.
Calc.: C 64.12 H 6.42 N 5.75 Cl 7.28 Found: 64.40 6.31 6.01 7.62 Example 194 4-/2- (5-Chloro-2-(1,4-dioxa-8-aza-spiro/5,67undecane-8-yl)benzoylamino)-ethyl7benzoic acid Prepared analogously to Example 166 from 4-/2-(5-chloro-2(1,4-dioxa-8-aza-spiro/5,67undecane-8-yl)-benzcylamino)ethylTbenzoic acid ethyl ester by alkaline hydrolysis.
Yield: 71 % of theory, M.p.: 185°C.
Calc.: C 62.81 H 5.93 Found: 63.02 6.05 N 6.10 Cl 7.72 6.11 7.98 134 Exaaple 195 4-/2-(2-Diallylamino-5-chloro-benzoylamino)-ethyl/benzoic acid ethyl eater Prepared analogously to Example 165 froa 2-dlallylamino5 5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 48 % ot theory, M.p.: < 20°C.
Calc.: C 67.52 H 6.29 16.55 10 Found: 67.64 6.38 6.56 Exaaple 196 4- /2- (2-Diallylaaino-5-chloro-benxoylaalno)->thyl/benzolc acid Prepared analogously to Example 166 from 4-/2-(2-dlallylamino5- chloro-benzoylamino)-ethyl/benzoic acid ethyl ester by alka15 line hydrolysis.
Yield: 75 % of theory, M.p.: 13O°C.
Calc.: C 66.24 H 5.81 II 7.02 Found: 66.50 5.83 6.92 Example 197 4-/2-(5-Mitro-2,4-dipiperidino-benzoylamino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 165 from 5-nitro-2,4-dipiperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 40 £ of theory, M.p.: 4 20°C.
Calc.: C 66.12 H 7.13 M 11.01 Found: 66.13 7.09 11.05 135 50293 Exanple 198 4-/2-(5-Mitro-2,4-diplperidlno-benzoylaaino)-ethyl7benzolc acid Prepared analogously to Example 166 from 4-/2-(5-nitro-2,4-dipiperidino~toenzoylaMlno)-etSiyl7bfflM5oic acid ethyl eater by alkaline hydrolysis.
Yields 95 % of theory, M.p.s 208°C, Calc.s C 64.98 H 6.71 N 11.65 Found: 64.40 6.72 11.03 Example 199 4-/5-(5-Anino-2,4-dipiperidino-benzoylamino)-ethyl/benzoic acid ethyl ester 1.4 g (2.8 mol) of 4-/2-(5-nitro-2,4-diplperidino-benzoylamino)-ethyl/benzoic acid ethyl ester were dissolved in 100 al of ethanol and the solution was hydrogenated at room temperature at a hydrogen pressure of 5 bar by means of 10 % palladium charcoal as catalyst. After filtering off the cata lyst and distilling off the methanol 0.8 g (60 % of theory) of th® compound were obtained 20 acetone.
M.p.s 172°C Calc..· C 70.26 H 8.00 Founds 70.39 8,19 Example 200 by crystallization from N 11.70 11.72 25 4-/2-(5-Amino-2,4-dipiperidino-benzoylamino)-ethyl/benzoic acid hydrochloride Prepared analogously to Example 166 from 4-/2-(5-amino-2,4-dipiperidino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis. 136 Yield: 95 % of theory, n.p.: 271°C.
Calc.: C 64.11 Π 7.24 M 11.50 Cl 7.27 Found: 64.40 7.27 11.33 7.50 Example 201 4-/5-(2-(M-Adaaantyl-(1)-N-aethyl-aaino)-5-cbloro-benzoylaaino)ethTl7benzolc acid ethyl eeter Prepared analogously to Exaaple 165 froa 2-(I-adaaantyl-(1)H-aethyl-aaino)-5-chloro-benzole acid and 4-(2-aaino-ethyl)10 benzoic acid ethyl ester.
Yield; 0.85 g (34 % of theory), M.p.: < 20°C.
Calc.: C 70.36 H 7.13 » 5.66 Cl 7.16 Found: 70.05 7.08 5.46 7.07 Rrample 202 4-/5-(2-(N-Adaaantyl-(1)-N-aethyl-aalno)-5-chloro-benzoylaaino)ethvlTbenzolc acid Prepared analogously to Exaaple 166 froa 4-/5-(2-(N-adaaantyl(1)-N-aethyl-aaino)-5-chloro-benzoylaaino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 0.33 g (64 % of theory), M.p.: 207°C.
Calc.: C 69.44 H 6.69 N 6.00 Cl 7.59 Found: 69.13 6.44 6.02 7.93 137 Example 203 4-/2-(5-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)ethyl/benzoic acid ethyl eater Prepared analogously to Example 165 from 5-chloro-25 (1„2,3,6-tetrahydro-pyridino)-benzoic aoid and 4-(2-aminoethyl)-benzoic acid ethyl ester.
Yields 4.7 g (88 $ of theory), M.p. j 4 20°C.
Calc.s C 66.90 H 6.10 N 6.78 Cl 8.59 10 Founds 67.60 6.21 7.02 8.54 Example 204 4-/2-(5-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)ethyl/benzolc acid Prepared analogously to Example 166 from 4-/5-(5-chloro-215 (1,2,3,6-tetrahydro-pyridino)-benzoylaaino)-etfayl7benzoic acid ethyl ester by alkaline hydrolysis.
Yields 2.27 g (73.7 % of theory), M.p.: 181 - 182°C.
Calc.s C 65.54 H 5.50 N 7.28 Cl 9.21 20 Found: 65.50 5.49 7.32 9.12 Example 205 4-/2-(5-Chloro-2-(N-isobutyl-N-propyl-amino)-benzoylamino)ethyl/benzolc acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-(N-isobutyl 25 N-propyl-anino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 5.8 g (86.8 % of theory), M.p.: 4 20°C.
Calc.: C 67.48 H 7.47 N 6.30 Cl 7.97 Founds 67.70 7.63 6.26 7.96 138 Example 206 4-(5-Chloro-2- (N-ieobutyl-N-propyl-anino ) -benzoylamino) ethyl7benzolc acid Prepared analogously to Example 166 from 4-/2-(5-chloro-25 (N-isobutyl-N-propyl-amino)-benzoylamino)-ethyl/benzoic acid ethyl eater by alkaline hydrolysis.
Yield: 2.7 g (79 % ot theory), M.p.: 128°C.
Calc.: C 66.25 H 7.01 K 6.72 Cl 8.50 Found: 66.60 7.Ο8 6.66 8.64 Exanple 207 4-/2-(2-N,N-Diethylamino-5-methyl-benzoylamino)-ethyl/benzoic acid methyl eater Prepared analogously to Example 165 from 2-N,N-diethylamlno 15 3-methyl-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester.
Yield: 57 % of theory, M.p.: < 20°C.
Calc.: C 71.71 H 7.66 N 7.61 Found: 71.71 7.83 7.55 Exanple 208 4-/2-(2-H,H-Diethylanino-3-nethyl-benzoylanino)-ethyl/benzolc acid Prepared analogously to Example 166 from 4-/2-(2-N,N-diethyl25 amino-3-metbyl-benzoylanino)-ethyl/benzoic acid methyl ester by alkaline saponification.
Yield: 63.1 % of theory, M.p.: 150 - 152°C Calc.: C 71.15 H 7.39 N 7.91 Found: 71.01 7.3® 8.13 139 S0292 '—Example 209 4-(5-Chloro-2-(4-(2-furayl)-piperazino/-benzoylamino)ethylTbenzolc acid aethyl ester Prepared analogously to Example 165 from 5-chloro-2-(45 (2-furoyl)-piperazino)-benzoic acid and 4~(2-amino-ethyl)benzoic acid methyl ester.
Yields 88.4 % of theory, M.p.; 93 - 95°C.
Calc.: C 62.97 H 5.28 H 8.47 Cl 7.15 Pounds 62.88 5.30 8.36 7.32 Exaapia 21Q 4-/2-(5'Chloro-2-(4-(2-furayl)-piperazino)-benzoylamlno)ethylTbenzolc acid Prepared analogously to Example 166 from 4-/2-(5-chloro15 2-(4-(2-furoyl)-piperazino)-benzoylamino)-ethyl7benzoio acid aethyl ester by alkaline saponification.
Yields 26.4 % of theory, M.p.s 187 " 188°C.
Calc.s C 62.31 H 5.02 ii 8.72 Cl 7.36 20 Founds 62.08 4.95 8.56 7.61 Example 211 4-/2- (5-Chloro-2- (N-methyl-lJ-benzylamino )-benzoyl ami no) -ethyl] benzoic acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-(N-methylN-benzylamino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yields 47 % of theory, M.p. s 93 - 95°C.
Calc.s C 69.25 H 6.03 Pounds 69.50 6.35 N 6.21 Cl 7.86 6.31 7.90 140 . ixanple 212 4-/2-(5-Chiorο-2-(N-methyl-N-benzylamino)-benzoylamino)ethvlTbenzolc acid Prepared analogously to Example 166 from 4-/2-(5-chloro5 2-(N-methyl-N-benzylamino)-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline saponification.
Yield: 64.2 % of theory, M.p.: 127 - 128°C.
Calc.: C 68.16 H 5.48 M 6.62 Cl 8.38 Found: 68.01 5.59 6.81 8.54 Example 213 4-/2-(2-(4-Ethoxycarbonyl-piperazino)-5-chloro-benzoylamlno)-ethyl7benzolc acid ethyl eater Prepared analogously to Exanple 165 from 2-(4-ethoxycarbonylpiperazino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 71.2 % of theory, M.p.: < 20°C.
Calc.: C 61.53 H 6.20 N 8.61 Cl 7.26 Found: 61.78 6.30 8.23 7.21 Example 214 4-/2-(2-(4-Ethoxycarbonyl-piperazino)-5-chloro-benzoylamlno)ethyl7benzoic acid Prepared analogously to Example 166 from 4-/2-(2-(4-ethoxy25 carbonyl-piperazino)-5-chloro-benzoylanino)-ethyl/benzoic acid ethyl ester by alkaline saponification. 141 S Ο 29 2 _ Yield: 93 % of theory, M.p.: 168 - 17O°C.
Calc.: C 60.06 H 5.70 H 9.14 Cl 7.71 Found: 59.93 5.91 9.20 7.97 BsaaplQ 21^ 4-/5-(5-Ethyl-2-piperidino-bemzoylamimQ)"ethyX7benzoic acid ethyl eater , Prepared analogously to Example 217 from 6-ethyl-1-(5-bromopentyl)-4H-3,1-baazoxazime-2,4-(1H)-dione and 4-(2-amino10 ethyl)-benzoic acid ethyl ester.
Yield: 55.6 % of theory, M.p.: £20°C.
Calc.: C 73.50 BI 7.90 H 6.86 Founds 73.26 7.88 6.97 Example 216 4- /2-(5-Ethyl-2-piperidino-benzoYlaaino)-ethyl7benzoic acid Prepared analogously to Example 166 from 4--/5-(5-ethyl-2piperidino-benzoylaraiao)-ethyl7benzoic acid ethyl ester by alkaline saponification.
Yield: 84.5 % of theory, M.p.: 177°C.
Calc.: C 72.60 H 7.42 N 7.36 Found: 72.59 7.28 7.16 Example 217 4-/2-(5-Methyl-2-piperidino-benzoylamino)-ethyl7benzoic acid ethyl ester .6 g (32.5 mmol) of 1-(5-bromo-pentyl)-6-methyl-4H-3»1-benz oxazine-2,4-(1H)-dione/prepared from 1,5-dibromopentane and 142 5029 6-«ethyl-4H-3,1-banzoxazine-2,4-(1H)-dione7 were stirred at room temperature In 100 al of absolute dioxane with 19·3 β (0.1 nol) of 4-(2-aaino-ethyl)-benzoic acid ethyl ester and 13 g of M-ethyl-diisopropylaaine for 4 days.
The reaction aixture was evaporated, nixed with water and extracted with chlorofora. The dried chlorofora extracts were evaporated and chroaatographad on silicagel with toluene/ethyl acetate (10:1) as eluant.
Yield: 6.85 g (53.5 % of theory), M.p.: < 20°C.
Calc.: C 73.07 H 7.66 N 7.10 Found: 72.62 7.15 7.12 Exaaple 218 4-/5-(5-Methyl-2-plperldlno-benzoylaalno)-ethvl7benzolc acid Prepared analogously to Example 166 from 4-/5-(5-aethyl2-piperidino-benzoylanino)-ethylTbenzoic acid ethyl ester by alkaline saponification.
Yield: 80 % of theory, M.p.: 199 - 200°C.
Calc.: C 72.11 H 7.15 M 7.64 Found: 72.10 6.95 7.70 Exaaple 219 4-/5-(5-Chloro-2-(4-p-chlorophenyl-piperazino)-benzoylaaino)ethyl7benzolc acid ethyl ester Prepared analogously to Exaaple 165 froa 5-chloro-2-(4-p-chloro phenyl-piperazino)-benzoic acid and 4-(2-aaino-ethyl)-benzoic acid ethyl ester.
Yield: 64.1 % of theory, M.p.: 153 - 155°C.
Calc.: C 63.88 H 5.55 Found: 63.77 5.47 M 7.98 Cl 13.47 7.93 13.40 143 Example 220 4-/2-(5-Chloro-2-(4-s»ethyl-piperazino)-benzoylamino)-ethyl/benzolc acid methyl eater Prepared analogously to Example 165 from 5-chloro-2-(4-methyl5 piperazino)-benzoic acid hydrochloride and 4-(2-amino-ethyl)benzoic acid methyl ester.
Yield: 52 % of theory, M.p.: 4 20°C.
Calc.: C 63.53 H 6.30 N 10.11 Cl 8.52 10 Found: 63.62 6.05 10.23 8.28 Example 221 4-/2-(5-Chloro-2-piperidino-benzoylamino)-2-methyl-propyl7benzoic acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-piperidino15 benzoic acid and 4-(2-amino-2-methyl-propyl)-benzoic acid ethyl ester hydrochloride (m. Yield: 51 % of theory, M.p.: e. 20°C. ρ.: 199Ο0). Calc. : C 67.78 H 7-05 N 6.32 Cl 8.00 Found: 67.75 6.91 6.05 7.87 144 Example .222 4-/5-(5-Chloro-2-piperidino-benzoylamino)-2-methyl-propyl7benzolc acid Prepared analogously to Example 166 from k-/Z-(5-ctaloro-25 piperidino-benzoylanino)-2-nethylpropyl7benzolc acid ethyl ester by alkaline saponification.
Yields 62 fi of theory, M.p.: 208°C.
Calc.: C 66.58 H 6.56 M 6.75 Cl 8.55 Found: 66.90 6.71 6.50 8.52 Example. 223 4-/2-(5-Chloro-2-(1,2,3,4,5,6,7,8-octahydro-isoquinoline-2-yl) benzovlanlno)-ethyl7benzolc acid ethyl eater Prepared analogously to Example 165 from 5-chloro-2~(1,2,3,415 5,6,7,8-octahydro-iaoquinoline-2-yl)-henzoic acid and 4-(2-aminoethyl) -benzoic acid ethyl eater.
Yield: 58 % of theory, M.p.: 4 20°C.
Calc.: C 69.44 H 6.68 M 5.99 Cl 7.59 20 Found: 69.62 6.72 6.10 7.72 Exaaple 224 4-/2-(5-Chloro-2-(1,2,3,4,5,6,7,8-octahydro-isoquinoline-2-yl)benzoylamino)-ethyl7ben2oic acid hydrochloride Prepared analogously to Example 166 from 4-/5-(5-chloro-225 (1,2,3,4,5,6,7,8-octahydro-isoquinoline-2-yl)-benzoylaminoethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 82 % of theory, M.p.: 220°C.
Calc.: C 63.15 H 5-93 N 5.89 Cl 14.93 Found: 63.45 6.09 6.02 15.90 145 Example ..225 4-/2-(5-Chloro-2-octaaethylenimino-bensoylafflino)-ethyl/benzoic acid methyl eater Prepared analogously to Example 165 from 5-chloro-2-octa5 methylenlalno-benzolc acid and 4-(2-araino-ethyl)-benzoic acid methyl eater.
Yield: 83 % of theory, M.p.: <. 20°C.
Calc.: C 67.78 H 7.05 K 6.32 Cl 8.00 io Founds 67.96 7.21 6.54 8.20 Example 226 4-/2-(5-Chloro-2-octaaethyleninino-benzoylamino)-ethyl7benzolc acid ethyl ester Prepared from 4-/2-(5-Chloro-2-oetaraethylenimino-benzoyl15 amino)-ethyl/benzoic acid and absolute ethanol with stoichiometric amounts of thionyl chloride.
Yield: 86 % of theory, M.p.: < 20°C.
Calc.: C 68.33 H 7.27 H 6.13 Cl 7.75 20 Found: 68.21 7.40 6.20 7.62 Example 227 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid cyclohexyl ester g (7 mmol) of 4-/2-(5-chloro-2-octamethylenimino-benzoyl25 amino)-ethyl/benzoic acid in 30 ml of absolute pyridine were converted at room temperature into the imidazolide by means of 1.2 g (7.4 mmol) of carbonyl diimidazole. After addition of 1.48 g (14.8 mmol) of cyclohexanol the reaction mixture was heated to the boiling temperature for 2 to 3 hours. After distilling off the solvent the crude product was purified by 146 ^^chromatography over a silicagel column by means of toluene/ ethyl acetate aa eluant.
Yields 2.7 g (75 % of theory), M.p. : 88°C.
Calc.s C 70.50 H 7.70 1(5.48 Cl 6.93 Found: 70.60 8.23 5.26 6.69 Example 228 4-/5-(5-Chloro-2-octamethylenimlno-benzoylaBino)-ethyl7benzoic acid tert.butyl eater 4.3 g (0.01 mol) of 4-/5-(5-chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid were suspended in 150 ml of acetic acid-tert.butyl ester. After addition of 1.43 g (0.011 mol) of 70 % perchloric acid the reaction mixture was stirred for 24 houra at room temperature. The reaction mixture was taken up in 500 ml of chloroform and the chloroform solution was carefully extracted with water. The crude product obtained from the chloroform phase after drying over sodium sulfate was purified by chromatography over a silicagel column by means of toluene/ethyl acetate as eluant.
Yield: 3 g (62 % of theory), H 5.77 5.78 Cl 7.30 7.40 M.p.: <20°C. Calc.: C 69.33 Found: 69.64 H 7.68 7.78 Analogously to the Examples 225 to 227 the following compounds were prepared: 4-/5-(5-Chloro-2-octamethylenimino-benzoylaaino)-ethyl7benzoic acid propyl eater Yield: 70 % ot theory, m.p.: <20°C. 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl730 benzoic acid isopropyl ester Yield: 84 % of theory, m.p.: 4 20°C. 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethylTbenzolc 147 acid butyl ester Yields 90 Si of theory, a.p.s <20°C. 4-/2- (5=Chloro-2-0Ctaaethyle&iMino-benzoylamino)-ethyl7benzoic acid isobutyl ester Yields 74 % of theory, B.p. <20°C. 4-/2- (5-Chloro-2-octaaethyleniaino-benzoylamino) -ethyl7banzoic acid hexyl ester Yields 63 % of theory, a.p.s < 20°C. 4-/2- (5-Chloro-2-octamethyleni®ino-benzoylaminG)-ethyl710 benzoic acid benzyl ester Yields S3 % of theory, a.p.s <2O°C.
Example 229 4-/2-(5-CM.oro-2-octaaetfayleniEsino-benzoylanino)-*thyl7benzyl alcohol 4.57 g (0.01 mol) of 4-/2-(5-chloro-2-octamethyleniminobenzoylaminoJ-ethylTbenzoic· acid ethyl ester were dissolved in 100 oi of absolute ether. This solution was added to. a suspension of 0.72 g (0.011 mol) of lithium aluminium hydride in 30 ml of absolute ether and the reaction mixture was heated to the boiling temperature for 1 hour. After cooling 15 ml of wafer were added cautiously and the reaction mixture was filtered. The ether phase was dried over sodium sulfate and the crude product was purified by chromatography over a silicagel column by means of toluene/ethyl acetate (1s1) as eluant. 25 Yield: 3.5 g (84 % of theory), M.p.: <20°C. Calc.s C 69.46 H 7.52 N 6.75 Cl 8.54 Found: 69.32 7.58 6.75 8.80 148 292 Example 230. 4-/5-(5-Chloro-2-octaaethyleniaino-benzoylaaino)-ethyl/benzyl malonic add diethyl eater A solution of 2.58 g (5.5 aaol) of 4-/5-(5-chloro-2-octaethyleniaino-benzoylaaino)-ethyl7benzyl chloride hydrochloride (prepared fro· 2.3 g (5.5 mol) of 4-/?-(5-chloro-2-octaaethylenialno-benzoylaaino)-ethyl7benzyl alcohol and thionyl chloride in chlorofora) in 25 al of absolute ethanol was added dropwisely to a solution of 3.2 g (20 mol) of aalonic acid diethyl ester and 20 mol of oodlua ethylate in absolute ethanol. Subsequently, the reaction mixture was refluxed for 4 hours, evaporated, acidified with diluted hydrochloric acid and extracted with chlorofora. After evaporation of the extracts, the reaction product was purified by chroaatography over a silicagel coluan with toluene/ethyl acetate (10:1).
Yields 1.7 g (60.7 % of theory), M.p.s 80 - 82°C.
Calc.s c 66.83 H 7.42 H 6.36 Cl 5.03 Found: 66.83 7.51 6.62 5.07 Exaaple 231 . /5- (5-Chloro-2-octaaethylenlalno-benzoylaaino )-ethyl7benzene Prepared analogously to Exaaple 165 froa 5-chloro-2-octaaethyleniaino-benzoic acid and 2-phenyl-ethylaaine.
Yields 69 % of theory, M.p.s 66°C.
Calc.s C 71.76 H 7.59 M 7.17 Cl 9.39 Found: 72.00 7.65 7.27 9.21 Example 232 4-/5-(5-Chloro-2-plperidlno-benzoylaaino)-ethyl7acetophenone g (15 mol) of aluainiua chloride in 10 al of dichloro ethane 149 50392 ’'were reacted with 0.6 g (7.6 aaol) of acetyl chloride whilst cooling. After addition of 1 .g (2.92 mmol) of /5-(5-chloro2-piperidino-benzoylamino)-ethyl7benzene the reaction mixture was stirred for 3 hours at 40 - 45°C. After evaporation the residue was mixed with ice-cold diluted hydrochloric acid, extracted with chloroform and the extracts were dried over sodiua sulfate and evaporated. The reaction product was purified hy chromatography over silicagel hy means of chlorofors/ethyl acetate (10:1) as eluant.
Yield: 0.42 g (37.4 % of theory), M.p.: 61 - 63°C.
Calc.: C 68.65 H 6.55 M 7.28 Cl 9.01 Found: 68.73 6.76 7.33 9.16 Example 4-/5- (5-Chloro-2-octaaethyleniBino-benzoylamino)-ethy37acetophenone hydrochloride Prepared analogously to Example 232 by reaction of /5-(5-ohloro2-octamethylenimino-benzoylamino)-ethylTbenzene with acetyl chloride in the presence of aluminium chloride. jO Yield: 41 % of theory, M.p.: 16O°C.
Calc.: C 64.79 H 6.96 N 6.04 Cl 15.30 Found: 64.91 7.05 5.98 15.11 Example 234 4-/5-(5-Chloro-2-piperidino-benzoylamino)-ethyl7phenyl acetic acid 4.86 g (10 mmol) of 4-/5-(5-chloro-2-piperidino-benzoylamino)ethyl7phenyl-thioacetic acid morpholide (m.p.s <20°C, prepared from 4-/5-(5-chloro-2-piperidiao-benzoylamino)-ethy^acetophenone with sulfur and morpholine according to the method of Villgerodt) 150 'were boiled for 2 days in 50 ml of ethanol with 2 g (50 mmol) of soditai hydroxide. Subsequently, the reaction mixture was evaporated, mixed with water and extracted with ether. The aqueous phase was acidified, the formed precipitate was auction filtered and recrystallized from acetonitrile.
Yield: 0.96 g (24 % of theory), M.p.: 151°C.
Calc.: C 65.91 H 6.28 M 6.99 Cl 8.84 Found: 65.61 6.34 7.18 8.77 Exanple 235 4-/2- (5-Chloro-P-octamethylenimino-benzoylamino)-ethyl/benzaldehyde 0.35 g (0.59 nmol) of N1-fr-(2-(5-ehloro-2-octanethyleninino)Λ benzoylamino)-ethyl)-benzoyl)-N -tosyl-hydrazine ( m.p.: 153 158°C, prepared from 4-/5-(5-chloro-2-octamethyleniminobenzoylamino)-ethyl/benzoic acid and toayl hydrazine with carbonyl diimidazole in tetrahydrofuran)were added to a suspension of 0.35 g of finely pulverized anhydrous sodiua carbonate in 3.5 ml of ethylene glycol, heated in an oil bath up to 160 - 170°C. After 1.5 minutes (formation of gas was finished) the oil bath was removed. Some minutes later the reaction mixture was mixed with a lot of ice, extracted twice with ether and dried. The combined extracts were filtered and evaporated in vacuo, whereby a slight yellow resinous oil was obtained. This oil was purified by chromatography over a silicagel column by means of chloroform/ acetone (20:1) as eluant.
Yield: 66 % of theory, M.p.: <20°C.
Calc.: mol peak m/e - 412/414 (1 Cl) Found: mol peak m/e 412/414 (1 Cl) M.p. of the hydrochloride x 0.5 HgO: 156°C.
Calc.: C 62.88 H 6.82 N 6.11 Cl 15.46 Found: 62.85 7.11 6.05 15.43 151 5029 2 — Exaaple 236 4-/2-(5-Chloro-2-octaiaettoyl®nifflino-benzoylaBino)-ethyl7benzaldehyde A solution of 0.50 g (1.2 araol) of 4-/2-(5-chloro-2-octa5 Bethylenisino-benzoylaHinoJ-ethyl/benzyl alcohol in 75 el of absolute acetone was shaked for 2 hours with 7.5 g of active manganese dioxide at rooa temperature. The reaction mixture was filtered over celite on a G4-frlt and the filtrate was evaporated in vacuo. The obtained brownish viscous oil was purified by chromatography over a silicagel column with chlorofona/acetone (20:1) as eluant.
Yields 5 % of theory, M p.: <2O°C.
Calc.: mol peak m/e « 412/414 (1 Cl) Founds mol peak m/e <= 412/414 (1 Cl).
Example 237 4-/2- (5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzaldehvde diethyl acetal A mixture of 0.23 g (0.56 nmol) of 4-/2-(5-chloro-2-oetamethy20 lenimino-benzoylamino)-ethyl7benzaldehyde, 0.20 ml (1.2 mmol) of orthoformic acid-triethyl ester, 0.02 g of ammonium chloride and 0.2 ml of anhydrous ethanol was heated for 30 minutes at 90°C. After cooling the mixture was poured into 2N-ammonia and extracted with ether. The extract was dried 25 over sodium sulfate and evaporated in vacuo. The evaporation residue was purified by chromatography over a silicagel column with toluene/acetone (10:1) as eluant.
Yield: 23 % of theory, M.p.: <20°C.
Calc.: mol peak m/e = 486/488 Found: mol peak m/e 486/488. 152 Example 238. 4-/5-(5-Chloro-2-octamethylenimlno-benzoylamino)-ethyl/cinnamic acid A mixture of 1 g (2.4 mmol) of 4-/5-(5-chloro-2-octamethylen5 imino-benzoylamino)-ethyl7benzaldehyde and 1 g (10 mmol) of malonic acid was heated in 10 al of absolute pyridine for 1 hour up to 100°C after adding 0.5 ml of piperidine. Icecold diluted hydrochloric acid was added and the formed precipitate was suction filtered. The precipitate was purl- fied by chromatography over silica gel with toluene/ethyl 15 acetate (1:1) as eluant. Yield: 21 % of theory, M.p.: 9CPC. Calc.: C 68.63 H 6.87 Found: 68.69 6.82 N 6.16 6.10 Cl 7.79 7.83 Exaaple ?3Q 4-/5- (5-Chloro-2-piperidino-benzoylamino)-ethyl7benzoylacetic acid ethyl ester Prepared analogously to Example 232 by acylation of /2-(5-chloro2-piperidino-benzoylamino)-ethylTbenzene with malonic acid ethyl ester according to the method of Friedel-Crafts.
Yield: 21 ft of theory, M.p.: <20°C.
Calc.: m/e 456/458 (1 Cl) Found: m/e 456/458 (1 Cl).
Example 240 4-/5- (5-Chloro-2-octamethyleniaino-benzoylamino)-ethyl7nitro benzene Prepared analogously to Example 165 from 5-chloro-2-octamethylenimino-benzoic acid and 4-(2-amino-etbyl)-nitro benzene.
Yield : 85 % of theory, 153 50293 M.p.: 102°C.
Calc.: C 64.25 H 6.56 N 9.77 Cl 8.24 Found: 64.45 6.57 9.73 8.24 Example 241 4° /2- (5-Chloro-2-octametfayleniniino-benzoylamlno) -ethyl7anlline Prepared from 4-/2-(5-chloro-2-octamethylenimino-benzoylamino)ethyl/nltro benzene by reduction with tin.-(II)-chloride in hydrochloric acid.
Yield: 74 % of theory, M.p.s Calc.: Found: 87 C. C 69.07 H 7.56 69.10 7.77 N 10.50 10.61 Cl 8.86 9.10 Example 242 4-/2-(5-Chloro-2-octamethylenimino-benzoylaraino J-ethyl/toluene hydrochloride_ Prepared analogously to Example 165 from 5-chloro-2-octamethylenimlno-benzoic acid and 4-(2-amino-ethyl)-toluene.
Yield: 69 % of theory, M.p.: 167 - 171°C.
Calc.: C 66.20 H 7.41 N 6.44 Cl 16.29 Found: 66.78 7.39 6.87 15.90 Example 443 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/chlorobenzene Prepared analogously to Example 165 from 5-chloro-2-octamethylenimino-benzoic acid and 4-(2-amino-ethyl)-chlorobenzene. Yield: 66 % of theory, M.p.: 58°C.
Calc.: C 65.87 H 6.73 N 6.68 Found: 65.99 6.55 6.51 154 Example 244 4-/2-(5-Chloro-2-octamethylenimlno-benzoylamino)-ethyl/benzoic acid nitrile 4.36 g (0.01 aol) of 4-/2-(5-chloro-2-octamethyleniminobenzoylamino)-ethyl/aniline were dissolved in 3.8 al of cone, hydrochloric acid. The solution was diluted with 28 al of water and diazotized at 0° by dropwise addition of a solution of 0.76 g (0.011 aol) of aodiua nitrite in 3 al of water. After stirring for 30 ainutes the reaction mixture was adjusted to pH 6 by aeans of aodiua carbonate.
The diazonium salt solution was added dropwiae at 0°C to a newly prepared solution of triaodium-tetracyano-copper(I)-complex.
/This complex solution was prepared froa 3.2 g (0.0128 aol) of copper sulfate x 5 HgO and 0.87 g of sodium chloride, dissolved in 10 al of water. After reduction to the copper(i)-chlorlde with a solution of 0.66 g of sodium hydrogene sulfite and 0.44 g of aodiua hydroxide in 5 al of water, the washed copper-(I)-chloride was added to a solution of 1.7 g of sodiua cyanide in 30 ml of water/.
After finished nitrogen formation the reaction mixture was warmed for 1 hour up to 70°C. After cooling the reaction mixture was extracted with chloroform at a pH value of 8. The crude product obtained froa the chloroform extracts was purified over a silica gel column (eluant: toluene/ethyl acetate · 8:2). Yield: 38 % of theory, M.p.: 102°C.
Calc.: C 70.31 H 6.88 N 10.25 Cl 8.64 Found: 70.50 6.59 10.45 8.92 Example ?45 4-/2-(5-Chloro-2-octimethylenimlno-benzoylamino)-ethyl/orthobenzoio acid ethyl ester Equimolar amounts of 4-/2- (5-chloro-2-octaaethyleniaino-benzoyl amino)-ethyl/benzoic acid nitrile and absolute ethanol were saturated with hydrogen chloride in ether. The reaction mixture 155 SQ292 "was allowed to rest for 4 days at 4°C, whereby the Imino ether precipitated as hydrochloride, partly in oily and partly in crystalline form. After decanting the solvent and washing with ether an excess of absolute ethanol was added at 4°C and the reaction mixture was left standing for 2 days at thia temperature. After distilling off the solvent, the crude product was purified by chromatography over a silica gel column with toluene as eluant.
Yields 30 % of theory, H.p. s &20°C.
Calc.s C 67.84 H 8.16 N 5.27 Cl 6.67 Founds 67.60 8.05 5.14 6.43 Example 246 4-/2-(5-Chloro-2-octaaethylenlmino-benzoylamino)-ethyl7iS benzoic acid morphollde__________ g (4.7 mmol) of 4-/2-(5-chloro-2-octamethylenimino-benzoylamino)-ethyl7benzoic acid were dissolved in 20 ml of absolute pyridine and converted quantitatively into the imidazolide by addition of 0.83 g (5.1 mmol) of carbonyl diimldazole at room temperature. After addition of 0.41 g of morpholine the reaction mixture was refluxed for 6 hours. Subsequently, the pyridine was distilled off and the evaporation residue was purified by chromatography over a silica gel column with toluene/ethyl acetate (6:4) as eluant.
Yields 1.8 g (76.5 % of theory), M.p.: <20°C.
Calc.s C 67.52 H 7.29 N 8.44 Found: 67.01 7.35 8.17 Example 247 A-/2-(5-Chloro-2-octamethyleniraino-benzoylamino)-ethyl7benzoic acid piperidide g (4.7 mmol) of 4-/2-(5-chloro-2-octamethylenimino-benzoyl15S amino)-ethyl/benzoic acid were suspended in 30 al of absolute toluene and converted by aeana of 0.65 al of triethylaaine into the salt. After cooling to -10°C, 0.5 g (4.7 aaol) of ethyl chloroforaate were added and the mixture was stirred for 30 ainutes. Subsequently, 0.4 g (4.7 aaol) of piperidine were added to the fined anhydride. After 2 hours the solvents were distilled off end the crude product was purified by chroaatography over a silica gel coluan with ethyl acetate aa eluant.
Yield: 2 g (86 % of theory), M.p.: <20°C.
Calc.: C 70.21 H 7.72 M 8.47 Found: 70.42 7.83 8.51 Analogously to the Examples 246 and 247 the following coals pounds were prepared: 4-/5- (5-Chloro-2-octaaethyleniaino-benzoylaaino)-ethyl7benzoic acid aaide Yield: 75 % ot theory, a.p.: 122°C.
Calc.: C 67.35 H 7.07 W 9.82 Found: 67.95 7-48 9.78 4-/5-(5-Chloro-2-octaaethyleniaino-benzoylaaino)-ethyl/benzoic acid dipropylaaide Yield: 75 % of theory, a.p.: < 20°C.
Calc.: C 70.35 H 8.27 H 8.21 Found: 69.95 8.04 7.94 4-/5-(5-Chloro-2-octaaethyleniaino-benzoylaaino)-ethyl/benzoic acid diallylaaide Yield: 70 % of theory, a.p.: < 20°C.
Calc.: C 70.90 H 7.54 M 8.27 Found: 70.23 7.30 7.98 4-/5-(5-Chloro-2-octaaethylenialno-benzoylaaino)-ethyl/benzoic acid thioaorpholide Yield: 70 % of theory, a.p.: <20°C.
Calc.: C 65.41 H 7.06 N 8.17 Found: 65.54 7-14 7.93 157 50293 4-/2-( 5-Chloro-2-octamethylenioino-benzoylamiao)-ethyl/benzoic acid-H-aethyl-piperazide Yields 75 % of theory, m.p.s <2Q°C.
Calc.s C 68.15 H 7.69 H 10.96 Found; 68.23 7.73 11.08 4-/2-(5-Chloro-2-octamethyleniaino-benzoylaaino)-ethyl/benzoic acid-N-ethyl-N-cyclohexylaaide Yields 58 % of theory, B.p.; < 20°C.
Calc.s C 71.42 H 8.24 »7.81 Founds 71.60 8.30 7.57 4-/2-(5-Chloro-2-octamethylenlmino-beazoylaBino)-ethy^benzoic acid isopropylaaide Yields 54 % of theory, m.p.s 171°C Calc.s C 68.99 H 7.72 N 8.94 15 Found; 69.34 7.52 8.74 4-/2-(5-Chloro-2-octamethylenimino-benzoylaaino)-ethyl7benzoic acid butylamide Yield: 53 0 of theory, m.p.: 163°C.
Calc.: C 69.47 H 7.91 N 8.68 Found: 69.53 7.95 8.72 Example 248 N1-(1-(4-Ethoxycarbonyl-phenyl)-ethyl)-N2-(5-chloro-2-plperidlno-benzoyl)-hydrazine A mixture of 2.4 g (10 mmol) of 5-chloro-2-piperidino-benzoic 2-j acid and 15 ml of anhydrous tetrahydrofuran was reacted with 1.62 g (10 mmol) of Ν,Ν-carbonyl diimidazole. The reaction mixture was stirred for 5 minutes at 20°C and then was refluxed for 45 minutes. The solution was cooled and at 20°C a solution of 2.08 g (10 mmol) of 4-(1-hydrazine-ethyl)-benzoic acid ethyl ester (freshly prepared from the corresponding quantity of 4-(1-hydrazino-ethyl)-benzoic acid ethyl ester hydrochloride of 158 m.p.: 98 - 100°C by reaction with the stoichiometric amount of aqueous sodium hydroxide solution with ice cooling, extraction with chloroform and evaporation of the dried chloroform extract at 3O°C in vacuo/ in 9 al of anhydrous tetrahydrofuran was added. After stirring over night at rooa temperature the reaction aixture was evaporated in vacuo and the residue was distributed between water and chlorofora. The combined chlorofora extracts were dried and filtered and the filtrate was evaporated in vacuo. The red-brown oily evaporation residue was purified by chromatography over a silica gel coluan with toluene/acetane (8:1) as eluant.
Yield: 41.9 % of theory, M.p.: c. 20°C (slight yellow oil).
Calc.: mol peak a/e 429/431 (1 Cl) Found: aol peak a/e « 429/431 (1 Cl).
Rgamnle 249 -(1-(4-Ethoxycarbonyl-phenyl)-ethyl)-N2-(5-chloro-2-diaethylaaino-benzovl)-hydrazine Prepared analogously to Exaaple 248 from 5-chloro-2-diaethylamino-benzoic acid, carbonyl diiaidazole and 4-(1-hydrazinoethyl)-benzoic acid ethyl ester in anhydrous tetrahydrofuran. Yield: 18 % of theory, M.p.: < 20°C.
Calc.: aol peak a/e » 389/391 (1 Cl) Found: mol peak m/e 389/391 (1 Cl).
Exaaple 250 N1-(1-(4-Carboxyphenyl)-ethyl)-N2-(5-chloro-2-piperidlnobenzovl)-hydrazine A mixture of 1.8 g (4.2 aaol) of N1-(l-(4-ethoxycarbonyl-phenyl)ethyl)-N2-(5-chloro-2-piperidino-benzoyl)-hydrazine and 0.20 g 159 - of (5 mmol) of sodium hydroxide was stirred for 5 hours at 60°C in 8 ml of ethanol and 8 al of water. After removing the ethanol in vacuo the reaction mixture was adjusted to pH 6 by means of 2M hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were washed with water, dried over aodium sulfate, filtered and evaporated in vacuo. The solid evaporation residue was recrystallized from methanol.
Yield: 45.8 # of theory, M.p.8 212 - 215°C.
Calc.: C 62.76 H 6.02 H 10.45 Found: 62.90 6.07 10.44 Example . 251 -(1-(4-Carboxyphenyl)-ethyl)-N2-(5-chloro-2-diaethylaminobenzoyl)-hvdrazlne «1 Prepared analogously to Example 250 froa N-(1-(4-ethoxycarbonyl-phenyl)-ethyl)-N2-(5-chloro-2-diaethylamino-benzoyl)-hydrazine by saponification with sodium hydroxide.
Yield: 34.4 % of theory, M.p.: 210 - 212°C Calc.: C 59.75 H 5.57 H 11.61 Found: 59.52 5.60 11.41 Example 252 4-/T- (5-Chloro-2-octaaethylenimino-benzoylaminoxy)-ethyl7benzoic acid methyl ester A mixture of 2 g (7.1 mmol) of 5-chloro-2-octamethyleniminobenzoic acid and 1.2 g (7.4 mmol) of carbonyl diimidazole was stirred for 40 minutes at 20°C in 10 ml of anhydrous pyridine. 1.4 g (7.2 mmol) of 4-(1-aminoxy-ethyl)-benzoic acid methyl ester /freshly prepared analogously to Example 248 from 4-(1-aainoxy-ethyl)-benzoic acid methyl ester hydrochloride of m.p. 158 - 16O°C7 were added and the mixture was stirred over night 160 80292 at 100°C. After evaporation in vacuo to dryness the residue was purified by chromatography over a silica gel column with toluene/ethyl acetate (9:1) as eluant.
Yield: 41 % of theory, M.p.: < 20°C.
Example 253 4-(5-Chloro-2-octamethyleniBlno-benzoylaminoxy-methyl)benzoic acid methyl eater Prepared analogously to Example 252 from 5-chloro-2-octamethy10 lenimino-benzoic acid, carbonyl-diimidazole and 4-(aainoxymethyl)-benzoic acid methyl eater /freshly prepared from the hydrochloride of m.p. 252 - 255°c7 in anhydrous pyridine. Yield: 38 % of theory, M.p.: 420°C.
Calc.: mol peak m/e - 444/446 (1 Cl) Found: mol peak m/e » 444/446 (1 Cl).
Example 254 4-/T- (5-Chloro-2-dlmethylaaino-benzoylaminoxy)-ethyl7benzoic acid methyl eater iiO Prepared analogously to Example 252 from 5-chloro-2-dimethylamino-benzoic acid, carbonyl diimidazole and 4-(1-aminoxyethyl)-benzoic acid methyl ester, but in anhydrous tetrahydrofuran at 20°C and a reaction time of 16 hours.
Yield: 59 % of theory, M.p.: <20°C. 161 S0292 4-/7-(5-Cfoloro-2=(cis-3,S-dioethyl-piporidiao )-hensoyl£ininosy)" eth?l7fesa2olc acid nethvl eator Prepared analogously to Exanple 252 fron 5"CMLoro=2=(eis= 3,5-dinetayl-piperIdino)-beagoie acid, carbonyl diinidssole and 4-(1-anin.oxy-ethyl)-bens©ic acid nethyl ester.
Yields 85 Si of theory, M.p.; <20°C.
Exanple 256 4-/T- (5-CUoro-2-piperidin©=feea2©ylQnia®xy)~Qthyl7lfl)ea2©ie acid nethyl eater A mixture of 7.55 g (25.8 nnol) of 5-chl0ro=2-piperldiiao= benzhydroxanic acid potassium salt (n.p. 153®C, (fieconp.)) and 6.30 g of 4-(1-broso-ethyl)-benzoic acid nethyl ester was stirred for 18 hours at 20®C in 20 nl ©f dinethyl foraanide. Subsequently, the reaction nixture uas nixed uith the 3-fold quantity of water and extraetGd with ether. The ether extract was dried and filtered and the filtrate was evaporated in vacuo. The evaporation residue was purified by chronatography over a silica gel coluna with cyclohexane/ ethyl acetate (1;1) as eluant.
Yield; 69.2 % of theory, M.p.; «20°0.
Calc.; C 63.37 H 6.04 Cl 8.50 M 6.72 Found; 63.54 6.17 8.49 6.63 Example 257 4-(5-Chloro-2-dlBethylanlno-benzovlaninoxy-nethyl)-benzoic acid 4.2 g (19 maol) of 4-broao-nethyl-benzoic acid were added to a mixture of 4.8 g (19 mmol) of 5-chXoro-2=dinethylanino-bems3Q hydroxaaic acid potassium salt (n.p. 14O°C, (deconp.)) and 1.06 g (19 enol) of potassium hydroxide in 50 ol of ethanol/ 162 water (1:1) and the mixture was refluxed for 6 hours. After evaporating in vacuo the evaporation residue was dissolved in water by addition of potassium hydroxide solution. After extraction with ethyl acetate the aqueous phase was adjusted to pH 7 and again extracted with ethyl acetate. This ethyl acetate extract was dried and filtered and evaporated in vacuo. The evaporation residue was purified twice by chromatography over a silica gel coluan with chlorofora/aethanol (9:1 and 4:1) as eluant. The uniform fractions were combined and evaporated and the evaporation residue was partitioned between water and ethyl acetate. The ethyl acetate extract was evaporated in vacuo and a colorless oil was obtained, which crystallized when triturating with ether.
Yield: 1.5 * of theory, M.p.: 160 - 161°C.
Calc.: C 58.53 H 4.91 H 8.03 Found: 58.49 5.10 7.88 Example 258 4-/T-(5-Chloro-2-piperldino-benzovlaalnoxy)-ethyl7benzolc acid A solution of 6,0 g (14.4 mmol) of 4-/T-(5-chloro~2-piperldinobenzoylaainoxy)-ethyl/benzoic acid methyl ester and 1.15 g (28.8 aaol) of sodium hydroxide was heated In 100 al of ethanol for 6 hours at 50 - 60°C. After evaporating in vacuo the residue was distributed between diluted hydrochloric acid and chlorofora. The chlorofora extract was dried and filtered and the filtrate was evaporated in vacuo. The evaporation residue was recrystallized froa a chlorofore/methanol mixture by addition of petroleum ether.
Yield: 44.8 % of theory, M.p.j 201 - 203°C.
Calc.: C 62.61 H 5.76 Found: 62.68 5.67 Cl 8.80 H 6.96 8.76 6.96 163 S0292 Example 259 4-/T- (5-Chloro-2-dimethylamIno-benzoylaminoxy)-ethyl7benzoic acid Prepared analogously to Exanple 248 from 4-/T-(5-chloro-2-di5 methylamino-benzoylamiaoxy)-ethyl/benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water.
The reaction nixture was, however, extracted with ethyl acetate and recrystallized from ethanol.
Yields 65.7 % of theory, M.p.s 202 - 205°C.
Calc.s C 59-58 H 5.28 Cl 9.77 H 7.72 Found; 59.70 5.34 10.00 7.90 Example 260 4-/T-(5-Chloro-2-(cis-3»5-dimethyl-plperidino)-benzoylaminoxy)15 ethyl/benzoic acid Prepared analogously to Example 248 from 4-/T-(5-chloro-2-(cis3,5-dimethyl-piperidino)-benzoylaminoxy)-ethyl/benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water.
Yield; 63.8 % of theory, M.p.: 205 - 208°C.
Calc.: C 64.10 H 6,32 Cl 8.23 N 6.50 Found: 64.40 6.66 8.44 6.50 Example 261 4-(5-Chloro-2-octamethyleniaino-benzoylaminoxy-methyl)-benzoic acid Prepared analogously to Example 248 from 4-(5-chloro-2-octamethylenimino-benzoylaminoxy-methylj-benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water. 164 Yield: 43.1 H of theory, M.p.: 135 - 138°C (fro· ether).
Calc.: C 64.10 H 6.32 Cl 8.23 M 6.50 Found: 64.29 6.29 8.33 6.73 Example 262 4-/T-(5-Chloro-2-octamethylenimino-benzoylaminoxy)-ethyl7benzolc acid Prepared analogously to Example 248 from 4-/T-(5-chloro2- octaBethylenimino-benzoylaminoxy)-ethyi7benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/ water.
Yield: 69 % of theory, M.p.: 187 - 19O°C.
Calc.: C 64.78 H 6.57 Cl 7.97 H 6.30 Found: 64.60 6.58 7.88 6.16 Example ,263 3- /7-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl7phenyl7proplonlc acid ethyl ester 0.5 ml (5 mmol) of carbon tetrachloride and subsequently 2.45 ml (17.5 mmol) of triethylamine were added to a mixture of 1.2 g (5 mmol) of 5-chloro-2-plperidino-benzoie acid, 1.5 g (5.8 mmol) of 3-/5--(2-amino-ethyl)-phenyl7propionic acid ethyl ester hydrochloride and 1.84 g (7 mmol) of triphenylphosphine in 30 ml of absolute acetonitrile. The reaction was stirred for 20 hours at room temperature, the precipitate was filtered off and the filtrate was evaporated. The evaporation residue was purified by chromatography over a silica gel column with toluene/ethyl acetate (5:1) as eluant.
Yield: 1.2 g (54.5 % of theory), M.p.: <20°C.
Calc.: C 67.78 H 7.05 N 6.32 Cl 8.00 Found: 67.33 6.91 6.16 8.09 165 S0292 3-/5-/2-(S-Chloro^-piperidino-benzoyloninoJ-othyS/pheayiypropionic acid --------- .
Prepared analogously to Gteonple 166 by capsaification of 5 3-/5- /2= (5-chloro=2=piperidine=&Qn3@ylcnlsi@ J-ethyl/pheayl/propionic acid ethyl ester.
Yields 80 % of theory, M.p.s 139°C.
Calc, s C 66.57 H 6.56 »6.75 Cl 0.54 Founds 66.51 6.62 6.60 8.40 Example .265. 3-/5-/5-(5-CUoro-2-octasethyleaAnta©~bea20yXania©)~et5iyiy= phenyl7proplonlc acid ethyl ester Prepared analogously to Exanple 263 fron 5=chXoro=2=06ten©thyXea 15 inino-benzoic acid and 3-/5=(2=ania0=ethyl)=phe®yX7]9>r®p2.©iaie acid ethyl ester hydrochloride.
Yields 76 of theory, M.p.s 4 20°C.
Calc,8 C 69.33 H 7.69 H 5.7® Cl 7.31 20 Founds 69.22 7.59 5.66 7.26 Example 266 3-/5- /2- (5-Chloro-2- ootaaethyleninino-bemaoylanino)-ethyl/phenyl/propionlc acid Prepared analogously to Exanple 166 froa 3-/5=/2=(5=chloro= 2=octamethyleniHino-benzoylaminoJ-ethyl/phenyl/propionic acid ethyl ester by alkaline saponification.
Yields 79 % of theory, 166 50282 M.p.; 92 - 94°C. Calc.: C 68.33 Found: 68.54 H 7.28 M 6.13 7.38 6.28 Cl 7.76 7.81 Exaaple 267 4-/5-(2-Piperidino-5-propyl-benzoylamino)-ethyl7benzoic acid ethyl ester Prepared analogously to Exaaple 213 from 1-(5-bromo-pentyl)6-propyl-4H-3,1-benzoxazine-2,4-(1H)-dione and 4-(2-aainoethyl)-benzoic acid ethyl ester.
Yield: 41 % of theory, M.p.: 4 20°C.
Calc.: C 73.90 H 8.11 N 6.63 Found: 73.45 7.92 6.42 Exaaple 268 4-/5-(5-Butyl-2-piperidino-benzoylaaino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 213 froa 6-butyl-1-(5-bromopentyl)-4H-3,1-benzoxazine-2,4-(1H)-dione and 4-(2-aminoethyl)-benzoic acid ethyl ester.
Yield: 59 % of theory, M.p.: <.20°C.
Calc.: C 74.28 H 8.31 H 6.42 Found: 73.90 8.05 6.13 167 S0292 4-[ί- (4-Chloro-5-nitro=2=piperidino=bengoylQniia0) -ethyl/= benzoic acid ethyl ester Prepared analogously to Exanple 165 fron 4-chl®ro-5-aitr©5 2-piperidino-benzolc acid and 4~(2~onin©-QthyX)~&Ga2©ie acid ethyl eater.
Yields 20 £ of theory, M.p.: 4 20°C.
Calc.: C 60.06 H 5.70 0 9.13 Cl 7.70 Founds 60.20 5.78 9.25 7.85 Exaaple 270 4-/2-(5-Chloro=2-octaHethyleninino=beia3@ylQniB®)-Gthy^beng©ie acid A mixture of 0.45 g (1 enol) of 4-/2=(5=chloro-2=octaEsthylen= imino-benzoylaniaoJ-ethyjTbcasalddlaiy&o· hyeteaeM-eridOo 5„o2. ®f 0.5 M-sodiua hydroxide solution and 0.30 g (1.3 nmol) of silver oxide ms heated on a steaa bath whilst heavy stirring for 45 minutes. After cooling the reaction ai:iture was acidified with 2N-sulfuric acid and extracted with ether. The or20 ganic phase was dried, filtered and evaporated in vacuo. The evaporation residue was purified by chrosatography over a silica gel column with chlorofom/aethanol (10:1).
Yield: 34 Ί of theory, M.p.s 172®C.
Example 271. 4-/2-(5-Chloro-2=octamethyleninino-benzoylaQino)=ethyl7= benzoic acid sodium salt g (11.7 mmol) of 4-/2-(5-chloro-2-octaaethylGniQiao-bes2oylamino)-ethyl/benzoic acid were dissolved in 20 si of absolute tetrahydrofuran. The solution was nixed with a sodiua ethylate solution, which was prepared from 0.27 g (11.7 enol) of sodiua 158 ~ and 10 ml of ethanol, Whereby the sodium salt was precipitated. After addition of 80 ml of ether the reaction mixture was stirred for 1 hour, suction filtered and dried at 80°C in a circulation air drier.
Yield: 4.5 g (85 % of theory), M.p.: 290°C.
Calc.: C 63.92 H 6.26 M 6.21 Fouad: 63.90 6.35 6.18 Example 77? 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyj7benzoic acid hydrochloride g (11.7 mmol) of 4-/2-(5-chloro-2-octamethylenimino-benzoylamino)-ethyl7benzoic acid were hot dissolved in 150 ml of acetone The solution was filtered and the hydrochloride was precipitated by means of isopropanolic hydrochloric acid.
Yield: 5 g (92 % of theory), M.p.: 205°C.
Calc.: C 61.93 H 6.50 N 6.01 Cl 15-23 Found: 62.10 6.86 6.24 14.85 Example 273 4-/2-(5-Ethyl-2-octamethylenimino-benzoylamino)-ethyl7benzoic acid ethyl ester Prepared analogously to Example 165 from 5-ethyl-2-octamethylenimino-henzoic acid aid 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 78 % of theory, M.p.: 4 20°C.
Calc.: C 74.63 H 8.50 Found: 74.41 8.10 N 6.22 6.01 169 50203 Example 274 4-/2- (5-Ethyl"2~octaaQthyleainiHO=befflg0yXQnfa®)»ethyl7teiagsic acid Prepared analogously to Exanple 166 fr®3 4-/2-(5-ethyl2-octanethylesiaiao=beazoylanAa©)=Qthyl7fe©ia2@ie acid ethyl ester by alkaline saponification.
Yield: 85 0 of theory, M.p.s 145°C.
Calc.s C 73.90 H 8.11 Kt 6-65 Founds 74.15 8.15 6.42 Exanple 275 4-/2- (5-Chloro-2-oc tanethyleniniao-beaseylsDia©)-QthyJ/bsngoie acid ethyl ester .6 g (0.02 nol) of 5-cM.oro-2-octanethyleninino-beagoicacid in 50 nl of absolute toluene were reacted with 2 g (0.02 nol) of triethylamine and oubooguoatly converted at -5eC to the bixed anhydride by means of 2.2 g (0.02 nol) of ethyl chloroformate. After stirring for 30 ninutes a s©lutioa of 4-(2=ani= no-ethyl)-benzoic acid ethyl ester ia 30 nl of chlorof©ra was added. The solution uas prepared iron 4.59 (0.02 aol) of 4-(2-aaino-ethyl)-bensoic acid ethyl ester hydrochloride and the equlaolar quantity of 2 g (0.02 nol) of triethylaaine. After stirring for 3 hours at roon tenperature, hydrochloric acid uas added, the organic phases were separated and dried over sodium sulfate. After distilling off the solvent the 4(2-sthoxycarbonylaiaino-ethyl)-bensoic acid ethyl ester famed as side product uas soparatofi ®a q oiliea gol with t®« luene/Qthyl acetate (9s1) ao eluant.
Yields 1.6 g (18 % of theory), M.p.: Calc.: C 68.33 H 7.28 N 6.13 Found: 68.62 7.25 5.90 17Θ - Example 276 4-/?-(5-Chloro-2-octamethylenimino-benzoylamlno)-ethyl7benzolc acid .6 g (0.02 mol) of 5-chloro-2-octamethylenialno-benzoic acid in 50 ml of absolute toluene were reacted with 2 g (0.02 mol) of triethylamine and subsequently converted at -5°C to the mixed anhydride by means of 2.2 g (0.02 mol) of ethyl chloroformate. After stirring for 30 minutes a solution of 3.3 g (0.02 mol) of 4-(2-amino10 ethyl)-benzoic acid in 20 ml of 1N sodiua hydroxide solution was added and the reaction mixture was stirred for 4 hours at room temperature. Subsequently, 30 ml of water were added, the organic phase was separated and again extracted with chloroform. From the aqueous phase the acid was precipitated by acidifying with 1N hydrochloric acid to pH 5.5. The obtained acid was recrystallized from ethyl acetate and a yield of 1.2 g (14 % of theory) was obtained.
M.p.: 172°C.
Calc.: C 67.20 H 6.81 N 6.53 Found: 66.92 6.77 6.43 Exaaple 2774-/5- (5-Chloro-2-octamethyleniaino-benzoylamino)-ethyj7_ benzoic acid 8.87 g (12.6 mmol) of copper-(lI)-di-/^-chloro-2-octamethylen25 imino-benzoate7dihydrochloride (prepared from 5-amino-2octamethylen-benzoic acid via the diazonium salt with copper(i)-chlorlde, m.p. 177 - 178°C) were dissolved in 25 ml of absolute pyridine. Whilst ice-cooling 3 g (25.3 mmol) of thionyl chloride were added dropwise, so that the temperature re30 mains at 20 - 30°C. After stirring for 30 minutes 4.9 g (25.3 mmol) of 4-(2-aaino-ethyl)-benzoic acid ethyl ester, dissolved in 5 ml of absolute pyridine, were added and the reaction mixture was warmed for 3 hours up to 70°C. After 171 50S93 distilling off the pyridine, the residue uas dissolved in a mixture of 50 ml of methanol and 50 nl of dioxane and the solution uas stirred for 16 hours at room temperature after addition of 4.6 g of potassium hydroxide, dissolved in 90 ml of water. Subsequently, the solvents uer© distilled off, the evaporation residue uas dissolved in 140 ml of uater and after adjusting to α pH of 5=9, the product ms precipitated and recrystallised fron ethyl acetate.
Yields 4.1 g (38 $ of theory), M.p.s 172°C.
Calc.s C 67.20 H 6.81 ' tJ 6.52 Cl 8.26 Fouads 61.10 6.72 6.45 8.20 Exaaple 278 4-/2-(5--Chloro-2-octaEethylesiniao-benz0ylamino)=ethyl7~ benzoic acid ethyl ester .5 g (15 aaol) of copper-(II)=di-^’-chloro°2-octasethylen= imino-benzoate/dihydrochloride-coaplex (prepared froa 5~amiao2-octamethyleaiaino-benzoic acid via the diazonium salt and copper-(I)-chloride, a.p. 177 - 178°C) in 25 Ql of absolute pyridine were reacted uith 5.4 g (33 mmol) of carbonyl diioMa sole, uhereby carbon dioxide uas formed. After stirring for 30 minutes at room temperature 6.8 g (35 mmol) of 4=(2-aminoethyl)-benzoic acid ethyl ester, dissolved in 5 ml of absolute pyridine, uere added and the reaction mixture uas heated for 3 hours up to 70°C. After distilling off the pyridine, the residue uas dissolved in uater and extracted at pH 4 by means of chloroform. The chloroform extracts uere dried over sodium sulfate and evaporated. The residue uas purified by chromatography over a silica gel coluan uith toluene/ethyl acetate as eluant.
Yields 10 g (66 $ of theory), M.p.s < 20°C.
Calc.s C 68.33 H 7.28 M 6.13 Cl 7.75 Found: 68.30 7.22 5.91 7.66 172 80292 Exaaple 4-/5- (5-Chloro-2-octaaethyleniaino-benzoylanino)-ethyl/benzoic acid 8.4 g (0.02 aol) of 4-/5-(5-chloro-2-octaaethyleniainobenzoylaaino)-ethyl/chloro benzene (a.p.: 58°C) were dissolved in 80 al of tetrahydrofuran. The solution was cooled to -60°C and 18 al (0.04 aol) of a pre-cooled 2,3 aolar solution of n-butyl-llthiua in hexane were added under nitrogen ataosphere. After 15 ainutes this reaction nixture was added to approx. 10 g of finely pulverized carbon dioxide under nitrogen atonosphere. After warning to rooa teaperature the reaction nixture was evaporated and the evaporation residue was dissolved in water. The product was adjusted to pH 5.5 and precipitated in water. After recrystallization froa ethyl acetate the product was purified chroaatographically.
Yield: 1 g (12 % of theory), M.p.: 172°C.
Calc.: C 67.20 H 6.81 H 6.52 Cl 8.26 Found: 67.00 6.72 6.46 8.19 Exaaple 280 4-/5-(5-Chloro-2-octaaethylenaaino-benzoylaaino)-ethyl/benzoic acid 7.6 g (0.06 aol) of oxalyl chloride were added dropwisely at 0 to 5°C to a solution of 11.5 g (0.03 aol) of 2-(5-chloro2-octaaethyleniaino-benzoylanino)-ethylbenzene in 50 al of carbon disulfide. Subsequently, 8 g (0.06 aol) of aluainiua chloride were added and after stirring for 1 hour again the sane quantities of o 173 The dried evaporation residue was recryotallized twice fr©a ethyl acetate by adding etaresnl.
Yields 2.4 g (19 £ of theory),, M.p.: 172°C.
Calc.s C 67.20 IS 6.81 EI 6.52 Cl 8.26 Founds 67.11 6.45 6.45 8.19 Exaanle 281 4-/2-(5°Chloro-2-olperldlno-beBgovlaaiEta)°Qthyl7b6ngQie asld A solution of 0.60 g (1.56 mol) of 4=/2= (5=chlor©-2-pip©ridino benzoylaainoj-ethyl/acetophenone ia 6 nl of dioxane ms added dropwisely within 15 ninutes at 35 - 40®C to a stirred sodiua hypobroaite solution (prepared fron 0.92 g (23 caol) of sodiua hydroxide, dissolved in 4.5 si of waters and fron 0.36 hX (7 aaol) of broaine whilst ice cooling). After 40 climates at 35 - 40°C an aqueous sodiua hydrogens sulfite-solution and water ms added and the aijrfcure was evaporated in vacuo.
The residue ms dissolved in water, the solution was acidified with 2K hydrochloric acid whilst cooling and the obtained precipitate was taken up in a aixture of ether/ethyl acetate.
The organic phase was dried over sodiua sulfate, filtered and evaporated is vacuo. The nearly colorless solid residue ms recrystallized froa acetone, filtered and dried at 110°C/ torr.
Yield: 0.06 g (10 % of theory), M.p.: 201 - 203°C.
Calc.: C 65.19 H 5.99 Cl 9.16 ft 7.24 Found; 65.53 5.91 9.32 7.10 Bxaaple 282 4-/2-(5-Chloro-2-octaQethylenisino-benzoyXaHino)-ethyX7benzoic acid Prepared analogously to Exaaple 281 froa 4-/2-(5-ohloro-2-octa= methyleniaino-benzoylaainoj-ethyl/acetophenone with sodiua hypobroaite solution. 174 — Yield: 11 % of theory, M.p.: 171 - 172°C.
Calc.: C 67.19 H 6.81 Found: 67.50 6.75 Cl 8.26 M 6.53 8.53 6.24 Example 283. 4-/2-(5-Chloro-2-piperidino-benzoylaaino)-ethyl7benzoic acid ethyl eater 0.82 g (0.002 aol) of 4-/2-(2-bromo-5-chloro-benzoylamino)ethyl7benzoic acid ethyl eater (a.p.: 116 - 118°C, prepared by reaction of 2-bromo-5-chloro-benzoic acid with 4-(2-aainoethyl)-benzoic acid ethyl eater analogously to procea a)) were heated whilst stirring with 0.85 & (0.01 aol) of piperidine and with a catalytical aaount of copper powder for 1 hour up to 100°C. After cooling the reaction aixture was acidified with acetic acid and extracted thrice with chloroform. The combined chloroform phases were dried over sodium sulfate. After distilling off the solvent, the remaining residue was purified over a silica gel coluan with chloroform/ethyl acetate (19:1) as eluant.
Yield: 0.49 g (48 % of theory), Calc.: aol peak m/e: 414/416 (1 Cl) Found: mol peak m/e: 414/416 (1 Cl).
Example 284 4-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl7benzoic acid ethyl ester 0.48 g (0.002 aol) of 5-chloro-2-piperidino-benzoic acid amide (m.p.: 140 - 142°C, prepared from 5-chloro-2-plperidino-benzoic acid by reaction with carbonyl diimidazole and ammonia) were heated whilst stirring in 5 ml of absolute toluene with 0.09 g (0.002 mol) of 55 % sodium hydride for 10 minutes up to approx. 60°C. After finished hydrogen formation the reaction mixture was cooled to room temperature and the solution of 0.51 g (0.002 mol) of 4-(2-bromo-ethyl)-benzoic acid ethyl eater (M+ = 256/258 a/e 1 Br, prepared from 4-(2-hydroxyethyl175 S0292 benzoic acid ethyl ester with thionyl bronide) in 2 nl ®f absolute toluene was added dropuisely. Subsequently, the reaction mixture was refluxed for 6 h@uro„ Zystor ©e&lflsg aqueous ethanol was added thereto and the reaction atefeu= re uas extracted several tines. She sonbteefi chl©r®f®sa extracts uere dried over sodiun sulfate and the solvent lias distilled off. The residue uas purified over a silica gel caiman uith chlor®f®ra/ethyl acetate (19:1) as eluant. Yields 0.2 g (25 8 of theory), Calc.s nol peak □/© = 414/416 (1 Cl) Founds nol peak α/e a 414/416 (1 Cl).
Evamole 285 4-^-(5-Chloro=2=octanethyle!ainino=bens®yianiao)=ethy^’= benzoic acid ethyl ester 8.2 g (0.02 nol) of 4-/2=(5-chloro=2=octQnethyleninin®=benz®yl= anino)=ethyl/beagoic acid nitrile (n.p. s 102°C) uere dissolved in 80 si of ethanol and saturated uith hydrogen ©hlerido. After 24 hours the reaction nixture uas warned for 1 hour up to 50®C and the solvents uere distilled off. The evaporation residue uas dissolved in ice water, adjusted to pB 9 and extracted uith chloroforn. After evaporating the organic phase the residue uas purified by chroriatography over a silica gel colunn.
Yield: 6.4 g (70 % of theory), M.p.: < 20°C.
Calc.: C 68.33 H 7.27 »6.12 Cl 7.75 Found: 68.32 7.29 6.12 7.90. 176 PHARMACEUTICAL COMPOSITIONS Example ;T Tablets containing 5 ag of 4-/5-(5-chloro-2-(3,5-diaethylplperldlno)-bepzoylaMlno)-ethvl7-bepzoic acid Composition: tablet contains: Active ingredient (1) 5.0 ng Corn starch (2) 62.0 ag Lactose (3) 48.0 ng Polyvinyl pyrrolidone (4) 4.0 ng Magnesium stearate (5) 1.0 ag 120.0 ng Method of preparation: 1, 2, 3 and 4 were mixed and moistened with water. The moist 15 mixture was granulated through a screen of mesh size 1.5 mat and dried at approx. 45°C. The dry granulate was granulated through a screen of 1.0 nm mesh size and mixed with 5. The finished mixture wa3 pressed to tablets on a tablets press with punches of 7 ma diameter and an unilateral notch.
Weight of tablets: 120 ag Example II Coated tablets containing 2.5 mg of 4-/3-(5-chloro-2-octamethvlenlmlpo-benzoylamlno)-ethyl7benzolcacld coated tablet core contains: Active ingredient (1) 2.5 mg Potato starch (2) 44.0 mg Lactose (3) 30.0 ng Polyvinyl pyrrolidone (4) 3.0 mg Magnesium stearate (5) 0.5 mg 80.0 ng 177 — Method of preparation; 1,2,3 and 4 were mixed wall and moistened uitJa water» The moist ciass uas granulated througsa a sorec® of meeh size 1 cm, dried at approx. 45®S end tho granulate was again granulated through the sone screen» After adding ®f 5, curratured eoated tablet cores of a diameter of β sa uere pressed os a tablets pressing cssateo» She eoated tablet cores thus prepared, uoro severed in ©Qraat&eaoX Earner with a coating, uhich essentially consists of sugar and talcum» io The finished eoated tablets were polishod with wax.
Weigh of coated tablets; 120 ng Example III Tablets containing 10 ng of 4=^=(S=ehl®ro=2<=hexQQethylcae= iaino-benzoylamino)-othvl7-boiaaoic acid Compositions tablet contains; Active ingredient 10.0 sg Lactose pulverized 70.0 mg Cora starch 31.0 mg Polyvinyl pyrrolidino 8.0 mg Magaosiua stearate 1.0 Eg 120.0 mg 178 Method of preparation; The mixture of active Ingredient, lactose and corn starch was moistened with a 20 % solution of polyvinyl pyrrolidone in water. The moist mass was granulated through a screen with a mesh size of 1.5 mm and dried at 45°C. The dried granulate was granulated through a screen of 1 mm mash size and homogeneously mixed with magnesium stearate.
Veight of tablets: 120 ag Punch: 7 aa 0 with a notch.
Example IV Coated tablets containing 5 ng of 4-/2-(5-chloro-2-hexaaethyleneimino-benzovlanino)-ethylTbenzoic acid coated tablet core contains: Active ingredient 5.0 ag Calcium phosphate secondary 70.0 ag Corn starch 50.0 ag Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 1.0 mg 130.0 mg Method of preparation: The mixture, consisting of the active ingredient, the calcium phosphate and the corn starch, was moistened with a 15 % solution of polyvinylpyrrolidone in water. The moist mass was granulated through a screen of 1 am mesh size, dried at 45°C and again passed through the same screen.
The granulate was mixed with the above mentioned amount of magnesium stearate and the aixture thus obtained was pressed into coated tablet corea. 179 - Ueight of core; 130 ng Punch; 7 cm 0 The thus prepared coated tablet ceres were severed aeserdfag to conventional manner with a layer censistteg ©f sugar end talcum. The finished coated tablets uere p@lished uith uas. Ueight of coated tablets 180 mg Example v Tablets containing 10 mg ©f 4=^=(5=ehl@re=2-piporidiiao=bon3©yl" amino)-ethyl7°bs®gele acid ' Compositions Tablet contains; Active ingredient Lactose pulverised Corn starch Polyvinyl pyrrolidone Magnesium stearate 10.0 ng 70.0 mg 31.0 ng 8.0 mg 1.0 mg 120.0 mg Method of preparations The tablets uere prepared analogously t® Example in. 180 Example VI Coated tablets containing 5 mg of 4-(7-(5-ch1oro-2-piperidinO' benzoyl amino)-ethyl] benzoic acid Coated table core contains: Active ingredient 5.0 mg Calcium phosphate secondary 70.0 mg Corn starch 50.0 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 1.0 mg 130.0 mg Method of preparation: The coated tablets were prepared analogously to Example IV,

Claims (17)

1. Carboxylic acid amides of general formula wherein 5 R represents a hydrogen, chlorine or bromine atom, or a cyclic alkyleneimino group with 4 to 7 carbon atoms in the imino ring; R-j represents a hydrogen, fluorine, chlorine or bromine atom; an alkyl or alkoxy group with 1 to 6 carbon atoms; an alkoxy group with 1 to 3 carbon atoms substituted by a phenyl group; a hydroxy, nitro, 10 amino, cyano or carboxy group; an alkanoylamino, alkoxycarbonyl or dialkylamidosulphonyl group, wherein the alkyl part may contain 1 to 3 carbon atoms; R 2 and Rg which may be the same or different, represent alkyl groups with 1 to 7 carbon atoms, alkenyl groups with 3 to 7 carbon atoms, 15 cycloalkyl groups with 3 to 7 carbon atoms, alkyl groups with 1 to 3 carbon atoms substituted by a phenyl group, or phenyl or adamantyl groups, or 182 50392 R z and Rg together with the nitrogen atom between them represent an unbranched alkyleneimino group with 3 to 12 carbon atoms in the imino ring, an unbranched alkyleneimino group with 4 to 6 carbon atoms in the imino ring which may be substituted by one or two alkyl groups each with 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 wherein a methylene group is replaced by an imino group (which may be substituted by 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) by an oxygen or sulphur atom or by a carbonyl, sulphoxide or sulphonyl group; a saturated or partially unsaturated azabicycloalkyl group with 7 to 10 carbon atoms, a piperidino group substituted in the 3- and 5-positions by a total of 3 or 4 alkyl groups each with 1 to 3 carbon atoms; a 1,4-dioxa-8-aza-spiroalkyl group with 5 to 9 carbon atoms, or a pyrrolyl or tetrahydropyridino group; R 4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; Y represents an oxygen atom, an imino group or a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, Z represents a hydrogen or halogen atom, a carboxy, cyano, formyl, hydroxymethyl, hydroxycarbonylethylene, nitro, amino, allyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or phenyl ethoxycarbonyl group, an alkoxycarbonyl group with a total of 2 to 8 carbon atoms, a cycloalkoxycarbonyl group with a total of 4 to 8 carbon atoms, a methyl group optionally substituted by 2 or 3 alkoxy groups or by a carboxy, alkoxycarbonyl or ethylenedioxy group, wherein the alkoxy group may contain 1 to 3 carbon atoms; an acetyl group, optionally substituted by a carboxy group or alkoxycarbonyl group with a total of 2 to 4 carbon atoms; an ethyl or ethylene group substituted by one or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms, or by two carboxy groups; an aminocarbonyl group optionally mono- or di-substituted by 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; a pi peridi nocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkyl-piperazinocarbonyl group wherein the alkyl group may contain 1 to 3 carbon atoms; or an ethyl group substituted by a carboxy group if the groups R 2 and Rg together with the nitrogen atom between them represent one of the abovementioned cyclic imino groups, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents or contains a carboxy group. 183
2. Carboxylic acid amines of general formula I as claimed in claim 1, wherein R represents a hydrogen atom; R-| represents a hydrogen, fluorine, chlorine or bromine atom; 5 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; or a hydroxy, cyano, carboxy, nitro, amino, acetamido, dimethylaminosulphonyl or benzyloxy group; R 2 represents an alkyl group with 1 to 6 carbon atoms or a 10 cyclohexyl, phenyl, benzyl, adamantyl or allyl group, R 3 represents an alkyl group with 1 to 6 carbon atoms or an allyl group, or Rg and R 3 together with the nitrogen atom between them represent an unbranched alkyleneimino group with 4 to 12 carbon atoms in the imino 15 ring; a piperidino group substituted by an alkyl group with 1 to 4 carbon atoms or by a phenyl, hydroxy, methoxy, carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms; a piperidino group substituted in the 3- and 5-positions by an alkyl group with 1 to 3 carbon atoms; a piperidino group substituted in the 3- and 5-positions 20 by two alkyl groups each having 1 to 3 carbon atoms; a morpholino, thiomorpholino, 1-oxidothiomorpholino or 1,1-dioxido-thiomorpholino group, each of which is optionally substituted by 1 or 2 methyl groups, a piperazino group optionally substituted in the 4-position by a methyl, benzyl, phenyl, chiorophenyl, pyridyl, furoyl or alkoxycarbonyl 25 group with a total of 2 to 4 carbon atoms; or a pyrrolyl, pi peri don-(2)-yl-(1)- 1,2,3,6-tetrahydropyridino, 1,4-dioxa-8aza-spiro [4,5j decan-8-yl, 1,4-dioxa-8-aza-spiro jj4,6]-undecan-8-yl, octahydro-isoindol-2-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, 184 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. -azabicyclononan-3-yl group; R 4 represents a hydrogen atom or a methyl group; Y represents a methylene, methyl-methylene or dimethylmethylene group, an NH group or an oxygen atom; and Z represents a carboxy, cyano, formyl or hydroxymethyl group; an alkoxycarbonyl group with a total of 2 to 7 carbon atoms; a cyclohexyloxycarbonyl, benzyloxycarbonyl, diethoxymethyl, hydroxycarbonylmethyl, bis-2,2-ethoxycarbonyl-ethyl, 2-hydroxycarbonyl-ethylene or 2-ethoxycarbonyl-ethyl group; an acetyl group optionally substituted by a hydroxycarbonyl or ethoxy carbonyl group; or a 2-hydroxycarbonyl-ethyl group when the groups R 2 and Rg together with the nitrogen atom between them represent one of the above-mentioned cyclic imino groups, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents or contains a carboxy group.
3. Carboxylic acid amides of general formula I as claimed in claim 1, wherein R^ is in the 5-position of the phenyl nucleus and R, R ] to R 4 , Y and Z are defined as in claim 2, and the physiologically acceptable salts thereof with inorganic or organic acids or also bases if Z represents or contains a carboxy group.
4. Carboxylic acid amines of general formula I as claimed in claim 1, wherein R represents a hydrogen atom, R 1 in the 5-position represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl or alkoxy group each with 1 to 3 carbon atoms, or a carboxy, cyano or nitro group. 185 R 2 and R 3 together with the nitrogen atoms between them represent an Ν,Ν-dialkylamino or N-alkylcyclohexylamino group each having 1 to 3 carbon atoms in the alkyl part; a pyrrolidino, piperidino, hexamethylene imino, heptamethyleneimino, octamethyleneimino or nonamethyleneimino 5. Group; a piperidino group substituted by an alley! group with 1 to 4 carbon atoms or by a methoxy or phenyl group; a piperidino group substituted in the 3- and 5-positions by one or two methyl or ethyl groups; a morpholino or thiomorpholino group optionally substituted in the 2- and 6-positions by a methyl group; or a 1,4-dioxa-8-aza-spiro 10 |4,5]-decan-8-yl, 1,4-dioxa-8-aza-spiro [4,6} undecan-yl, octahydroi soi ndol-2-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, 1,2,3,4,5,6,7,8octahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl, 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-methyl-adamantyl-(l)-amino group; 15 R^ represents a hydrogen atom or a methyl group; Y represents a methylene, methyl-methylene, dimethyl-methylene or NH group or an oxygen atom; Z represents an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a carboxy, formyl or hydroxymethyl group, and the physiologically 20 acceptable salts thereof with inorganic or organic acids and also bases if Z represents the carboxy group.
5. Carboxylic acid amides of general formula I as claimed in claim 3, wherein R, R^, Y and Z are defined as in claim 3, 25 R.j represents a chlorine or bromine atom, or a methyl, ethyl or methoxy group; 186 50382 R£ and together with the nitrogen atom between them represent a pyrrolidino, piperidino, methyl-piperidino, 4-methoxy-piperidino, 4-phenyl-piperidino, hexamethyleneimino, heptamethyleneimino, octamethyleneimi no, nonamethyleneimi no, 3,5-dimethy1-pi peri di no, morpholino, 2,6-dimethyl-morpholino, thiomorpholino, 2,6-dimethylthiomorpholino, l,4-dioxa-8-aza-spiro £4,53-decan-8-yl, 1.2.3.4- tetrabydro-isoquinolin-2-yl, decahydro-i soqui noli n-2-yl, 1.2.4.5- tetrahydro-3H-3-benzazepin-3-yl, decahydro-3H-3-benzazepin-3-yl, octahydro-isoindol-2-yl or N-methyl-adamantyl-(l)-amino group; or a piperidino group substituted in the 4-position by an alkyl group with 2 to 4 carbon atoms, and the physiologically acceptable salts thereof with inorganic or organic acids and also bases if Z represents the carboxy group.
6. 4-[2-(5-Chloro-2-pipen'dino-benzoylannno)-ethyij-benzoic acid, the alkyl esters thereof with 1 to 3 carbon atoms and the acid addition salts thereof.
7. 4-[2-(5-Ch1oro-2-nonamethy 1ene imi no-benzoylami no)- ethy f]-benzoi c acid, the alkyl esters thereof with 1 to 3 carbon atoms and the acid addition salts thereof.
8. 4-[2-(5-Chloro-2-(l,4-dioxa-8-aza-spiro [4,5j-decan-8-yl)benzoylamino)-ethyf]~benzoic acid, the alkyl esters thereof with 1 to 3 carbon atoms and the acid addition salts thereof.
9. 4-^2-(5-Chloro-2-octamethyleneimi no-benzoylami no) -ethyfj-benzoi c acid, the alkyl esters thereof with 1 to 3 carbon atoms and the acid addition salts thereof.
10. 4-[2-(5-Bromo-octamethyleneimino-benzoyl-amino)-ethyl]-benzoic acid, the alkyl esters thereof with 1 to 3 carbon atoms and the acid addition salts thereof. 187 50282
11. 4-^2-(5-Chl oro-2- (cj_s^-3,5-dimethyl pi peri di no)-benzoyl ami no)-ethyTj benzoic acid, the alkyl esters thereof with 1 to 3 carbon atoms and the acid addition salts thereof.
12. Pharmaceutical compositions containing a compound as claimed in 5 claims 1 to 11 together with one or more inert carriers and/or diluents.
13. Pharmaceutical compositions as claimed in claim 12 for the treatment of diabetes mellitus.
14. Process for the preparation of new carboxylic acid amides of general formula I as claimed in claims 1 to 11, and of the physiologically 10 acceptable salts thereof with inorganic or organic acids Z represents or contains a carboxy group, wherein a) an aminobenzoic acid of general formula II and also bases if (Π) or a reactive in which R, Rp R 2 and R 3 are as hereinbefore defined, 15. Derivative thereof, optionally prepared in the reaction mixture, is reacted with an amine of general formula III 188 in which R4, Y and Z are as hereinbefore defined, or with an N-activated amine of general formula III optionally formed in the reaction mixture, if an aminobenzoic acid of general formula II is used and if 5 Z in an N-activated amine of general formula III does not contain any carboxy or amino groups, or b) in order to prepare compounds of general formula I wherein R 1 has the definitions given hereinbefore, with the exception of the hydroxy and amino group, and Y represents a methylene group 10 optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, a compound of general formula IV (IV) in which R, R^ and Z are as hereinbefore defined, R^ and Y are defined as above and E represents a halogen atom, is reacted with an amine of general formula V H-N / R 2 (V) 189 in which Rg and Rg are as hereinbefore defined, or c) in order to prepare compounds of general formula I wherein Z represents a carboxy group and Y does not represent an NH group 5 a compound of general formula VI in which R and R.| to R^ are as hereinbefore defined, Y has the meanings given hereinbefore with the exception of the 10 NH group and A represents a group which can be converted into a carboxy group by oxidation, is oxidised or d) in order to prepare compounds of general formula I wherein Z represents a carboxy group, a compound of general formula VII (VII) 190 in which R, Rj to R 4 and Y are as hereinbefore defined and B represents a group which can be converted into a carboxy group by hydrolysis, is hydrolysed, or e) in order to prepare compounds of general fonnula I wherein R 2 represents an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group, or an alkenyl group with 3 to 7 carbon atoms, Rg represents an alkyl group with 1 to 7 carbon atoms, a cycloalkyl 10 group with 3 to 7 carbon atoms, an alkenyl group with 3 to 7 carbon atoms, an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group, or an adamantyl group, or R 2 and Rg together with the nitrogen atom between them represent a 5- to 7-membered alkyleneimino ring, a piperidino group substituted 15 by an alkyl group with 1 to 4 carbon atoms, or a piperidino group substituted in the 3- and 5-positions by an alkyl group with 1 to 3 carbon atoms and Y represents a methylene group optionally substituted by one or two alkyl groups each with 1 to 3 carbon atoms, a compound of general 20 formula VIII (optionally formed in the reaction mixture) R. CO—NH—Y — CH (VIII) 191 in which R, Rp R^ and Z are as hereinbefore defined, R 3 ' represents a hydrogen atom or has the meanings given for R 3 hereinbefore and Y is defined as above, is reacted with a compound of general formula IX (IX) in which R 2 ' has the meanings given for R 2 hereinbefore or together with 10 the group R 3 ' of formula VIII represents a straight-chained alkylene group with 4 to 6 carbon atoms, an n-pentylene group substituted by an alkyl group with 1 to 4 carbon atoms, or an n-pentylene group substituted in the 2- and 4-positions by an alkyl group with 1 to 3 carbon atoms, and 15 G represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, or f) in order to prepare compounds of general formula I wherein Y represents the NH group or an oxygen atom, a compound of general formula X R. CO-NH-Y-H R. (X) '2 R. ‘3 192 in which R and R-j to R 3 are as hereinbefore defined and Y is defined as above, or an alkali metal salt thereof, is reacted with a phenyl derivative of general formula XI (xi) in which R4 and Z are as hereinbefore defined and L represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, or 10 g) in order to prepare compounds of general formula I wherein R-j has the meanings given hereinbefore with the exception of the hydroxy, carboxy, amino or alkanoylamino group and Y represents a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, an amide of 15 general formula XII in which R, Rg and R 3 are as hereinbefore defined and R 1 has the meanings given above, or an alkali metal salt thereof, is reacted with a compound of general formula XIII 193 502S2 I 4 Μ - Υ —CH — (XIII) in which R 4 and Z are as hereinbefore defined, Y has the meanings given above and 5 M represents 3 nucleophilic leaving group such as. a halogen atom or a sulphonyloxy group, or h) in order to prepare compounds of general formula I wherein Rj represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl or alkoxy group each having 1 to 6 carbon atoms, an alkoxy group 10 with 1 to 3 carbon atoms substituted by a phenyl group, or a hydroxy, nitro, carboxy or alkanoylamino group, Y represents a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, and Z represents a carboxy group, a compound of general formula XIV in which R and Rg to R^ are as hereinbefore defined, R-| and Y have the meanings given above, is acylated with an oxalyl halide or phosgene in the presence of a Lewis acid or 194. 50293 i) in order to prepare compounds of general formula I wherein R·] represents a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each with 1 to 6 carbon atoms, an alkoxy group with 1 to 3 carbon atoms substituted by a phenyl group, or a nitro, 5 carboxy, alkanoylamino or alkoxycarbonyl group each having 1 to 3 carbon atoms in the alkyl part, Y represents a methylene group optionally substituted by one or two alkyl groups each with 1 to 3 carbon atoms, and Z represents a carboxy group, a compound of general formula XV in which R and Rg to R 4 are as hereinbefore defined, and R.j and Y have the meanings given above, is reacted with a hypohalite optionally prepared in the reaction mixture and, if desired, 15 a compound of general formula I thus obtained wherein Z represents a carboxy group is subsequently converted by esterification or amidation into a corresponding compound of general formula I wherein Z represents an esterified carboxy group or an aminocarbonyl group optionally mono- or disubstituted by an alkyl group with 1 to 7 carbon 195 atoms or by a cycloalkyl group with 3 to 7 carbon atoms and/or by an alkenyl group with 3 to 7 carbon atoms, or into a pi peri dinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkylpiperazinocarbonyl group, and/or 5 a compound of general formula I obtained wherein Rj and/or Z represents a nitro group is converted by reduction into a corresponding compound of general formula I wherein Rj and/or Z represents an amino group, and/or a compound of general formula I obtained wherein 10 Rj and/or Z represents an amino group is converted, via a corresponding diazonium salt, into a corresponding compound of general formula I wherein Rj represents the hydroxy or cyano group or a fluorine, chlorine or bromine atom and/or Z represents a chlorine or bromine atom or the cyano group, whilst a 15 compound of general formula I optionally obtained in this way wherein Rj represents a hydroxy group may be converted by alkylation into a corresponding compound of general formula I wherein Rj represents an alkoxy group with 1 to 6 carbon atoms or an alkoxy group with 1 to 3 carbon atoms substituted by a phenyl group, and/or 20 a compound of general formula I obtained wherein Rj represents an amino group is converted by acylation into a corresponding compound of general formula I wherein Rj represents an alkanoylamino group with 1 to 3 carbon atoms in the alkanoyl part, and/or 25 a compound of general formula I obtained wherein Rj represents an alkoxycarbonyl group and /or R 2 and R 3 together with the nitrogen atom between them represent an 196 alkyleneimino group with 4 to 6 carbon atoms substituted by an alkoxycarbonyl group, whilst the alkoxy part may contain 1 to 3 carbon atoms, is converted by hydrolysis into a corresponding compound of general formula I wherein R-j represents a carboxy group and/or Rg and R 3 together with the nitrogen atom between them represent an alkyleneimino group with 4 to 6 carbon atoms in the imino ring substituted by a carboxy group, and/or a compound of general formula I obtained wherein Rg and R 3 together with the nitrogen atom between them represent an N-benzylpiperazino group is converted by debenzylation into a corresponding compound of general formula I wherein Rg and R 3 together with the nitrogen atom between them represent a piperazino group, and/or a compound of general formula I obtained wherein R-| represents a chlorine or bromine atom is converted by dehalogenation into a corresponding compound of general formula I wherein R-j represents a hydrogen atom, and/or a carboxylic acid amine of general formula I wherein Z represents an optionally esterified carboxy group is converted by reduction with a metal hydride into a corresponding compound of general formula I wherein Z represents the hydroxymethyl group, and/or a compound of general formula I obtained wherein Z represents a hydroxymethyl group is converted by oxidation into a corresponding compound of general formula I wherein Z represents a formyl group, and/or 197 a compound of general formula I obtained wherein Z represents a hydroxymethyl group is converted by halogenation and subsequent reaction with a malonic acid ester into a corresponding compound of general formula I wherein 5 Z represents an ethyl group substituted by two alkoxycarbonyl groups, and/or a compound of general formula I obtained wherein Z represents the formyl group is converted by acetalisation into a corresponding compound of general formula I wherein Z represents a di alkoxymethyl group, and/or 10 a compound of general formula I obtained wherein Z represents a formyl group is converted by condensation and optional subsequent hydrolysis into a corresponding compound of general formula I wherein Z represents an ethylene group substituted by a hydroxycarbonyl or alkoxycarbonyl group, and/or 15 a compound of general formula I obtained wherein Z represents a hydrogen atom is converted by Friedel-Crafts acylation into a corresponding compound of general formula I wherein Z represents an acetyl group optionally substituted by an alkoxycarbonyl group, and/or 20 a compound of general formula I obtained wherein Z represents a nitrile group is converted by alcoholysis, via a corresponding imino ester, into a corresponding compound of general formula I wherein Z represents a tri alkoxymethyl group, and/or a compound of general formula I obtained wherein 25 Z represents a trialkoxymethyl group is converted by hydrolysis into a corresponding compound of general formula I wherein Z represents an alkoxycarbonyl group, and/or 198 a compound of general formula I obtained wherein Z represents the acetyl group is converted by heating with an amine and sulphur and subsequently in the presence of an inorganic base, into a corresponding compound of general formula I wherein I represents a hydroxy5 carbonylmethyl group, and/or a compound of general formula I obtained wherein Z represents a carboxy group is converted, by conversion into a sulphonic acid hydrazide and subsequent disproportionation, into a corresponding compound of general formula I wherein Z represents a formyl group, and/or a compound of general formula I obtained wherein 10 R-| represents a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each with 1 to 6 carbon atoms or an alkoxy group with 1 to 3 carbon atoms, substituted by a phenyl group and Y represents a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms and 15 Z represents a chlorine or bromine atom, is converted, via its corresponding organometallic compound, by means of carbon dioxide, into a corresponding compound of general formula I wherein Z represents a carboxy group, and/or a compound of general formula I obtained is converted into the physiologically acceptable salts thereof 20 with inorganic or organic acids and also bases when Z contains a carboxy group.
15. A process for preparing carboxylic acid amides of general formula I as defined in claim 1 substantially as hereinbefore described with reference to Examples 1 to 285. 25
16. , Carboxylic acid amides of general formula I as defined in claim 1 whenever prepared by a process as claimed in either claim 14 or claim 15.
17. Pharmaceutical compositions comprising a carboxylic acid amide of general formula I as defined in claim 1, said compositions being substantially as described herein with reference to Examples I to VI.
IE1453/80A 1979-07-13 1980-07-11 Chemical compounds IE50292B1 (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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US5741926A (en) * 1997-02-12 1998-04-21 Shaman Pharmaceuticals, Inc. Aniline derivatives having antihyperglycemic activity
ES2300151T3 (en) * 1998-09-22 2008-06-01 Astellas Pharma Inc. Cyanophenyl derivatives.
US7112594B2 (en) 2000-08-09 2006-09-26 Mitsubishi Pharma Corporation Fused bicyclic amide compounds and medicinal use thereof
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US7250518B2 (en) 2001-01-31 2007-07-31 Pfizer Inc. Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes
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US7601868B2 (en) 2003-02-12 2009-10-13 Takeda Pharmaceutical Company Limited Amine derivative
US7691894B2 (en) 2003-07-24 2010-04-06 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
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