IE59487B1 - New cyclic amine derivatives, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

New cyclic amine derivatives, pharmaceutical compositions containing these compounds and processes for preparing them

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Publication number
IE59487B1
IE59487B1 IE311086A IE311086A IE59487B1 IE 59487 B1 IE59487 B1 IE 59487B1 IE 311086 A IE311086 A IE 311086A IE 311086 A IE311086 A IE 311086A IE 59487 B1 IE59487 B1 IE 59487B1
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group
general formula
carbon atoms
compound
methylene
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IE311086A
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IE863110L (en
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Thomae Gmbh Dr K
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Publication of IE59487B1 publication Critical patent/IE59487B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cardiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (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 New cyclic amine derivatives of general formula see diagramm : EP0224794,P49,F1 wherein A represents a -CH2 -CH2 -, -CH=CH-, see diagramm : EP0224794,P49,F2 or see diagramm : EP0224794,P49,F3 group and B represents a methylene, carbonyl or thiocarbonyl group or A represents a -CO-CO- or see diagramm : EP0224794,P49,F4 group and B represents a methylene group, whilst the atom marked x is linked to the phenyl nucleus, E represents a straight-chained alkylene group with 1 to 3 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, G represents a straight-chained alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, whilst a methylene group, adjacent to a phenyl nucleus, of a straight-chained alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group may be replaced by an oxygen or sulphur atom or by an imino, methylimino, sulphinyl or sulphonyl group, R1 represents a hydrogen or halogen atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, R2 represents a hydrogen or halogen atom, a hydroxy, alkoxy, phenylalkoxy or alkyl group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, or R1 and R2 together represent an alkylenedioxy group with 1 or 2 carbon atoms, R3 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, or a hydroxy, nitro, cyano or trifluoromethyl group, R4 represents a hydrogen atom, an alkoxy, alkanesulphonyloxy, amino, alkylamino or dialkylamino group with 1 to 3 carbon atoms in each alkyl moiety or an alkanoylamino group with 2 or 3 carbon atoms in the alkanoyl moiety or R3 and R4 together represent an alkylenedioxy group with 1 or 2 carbon atoms, R5 represents a hydrogen or halogen atom, a hydroxy, alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, m represents the number 1, 2, 3, 4 or 5 and n represents the number 0, 1 or 2, but n + m must represent the number 3, 4 or 5, the enantiomers, diastereomers and acid addition salts thereof. 1. Claims for the contracting states : AT, ES, GR Process for preparing new cyclic amine derivatives of general formula see diagramm : EP0224794,P54,F1 wherein A represents a -CH2 -CH2 -, -CH=CH-, see diagramm : EP0224794,P54,F2 or see diagramm : EP0224794,P54,F3 group and B represents a methylene, carbonyl or thiocarbonyl group or A represents a -CO-CO- or see diagramm : EP0224794,P54,F4 group and B represents a methylene group, whilst the atom marked x is linked to the phenyl nucleus, a methylene group, whilst the atom marked x is linked to the phenyl nucleus, E represents a straight-chained alkylene group with 1 to 3 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, G represents a straight-chained alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, whilst a methylene group, adjacent to a phenyl nucleus, of a straight-chained alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group may be replaced by an oxygen or sulphur atom or by an imino, methylimino, sulphinyl or sulphonyl group, R1 represents a hydrogen or halogen atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, R2 represents a hydrogen or halogen atom, a hydroxy, alkoxy, phenylalkoxy or alkyl group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, or R1 and R2 together represent an alkylenedioxy group with 1 or 2 carbon atoms, R3 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, or a hydroxy, nitro, cyano or trifluoromethyl group, R4 represents a hydrogen atom, an alkoxy, alkanesulphonyloxy, amino, alkylamino or dialkylamino group with 1 to 3 carbon atoms in each alkyl moiety or an alkanoylamino group with 2 or 3 carbon atoms in the alkanoyl moiety or R3 and R4 together represent an alkylenedioxy group with 1 or 2 carbon atoms, R5 represents a hydrogen or halogen atom, a hydroxy, alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, m represents the number 1, 2, 3, 4 or 5 and n represents the number 0, 1 or 2, but n + m must represent the number 3, 4 or 5, the enantiomers, diastereomers and acid addition salts thereof, characterised in that a) a compound of general formula see diagramm : EP0224794,P55,F1 wherein A, B, E, m and n are defined as hereinbefore, R'1 represents a hydroxy, amino or alkylamino group protected by a protecting group or has the meanings given for R1 hereinbefore and R'2 represents a hydroxy group protected by a protecting group or has the meanings given for R2 hereinbefore, is reacted with a compound of general formula see diagramm : EP0224794,P55,F2 wherein R'3 , R'4 and R'5 have the meanings given for R3 , R4 and R5 hereinbefore but the hydroxy, amino or alkylamino groups contained in the groups R3 to R5 may be protected by a protecting group, and U represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, and optionally any protecting group used is subsequently split off, or b) in order to prepare compounds of general formula I wherein G has the meanings given for Gin claims 1 to 5, with the exception of the groups containing a sulphenyl, sulphinyl or sulphonyl group, A represents a -CH2 -CH2 - group, B represents a methylene or carbonyl group and m + n represent the number 4, a compound of general formula see diagramm : EP0224794,P55,F3 wherein R1 to R5 and E are defined as hereinbefore, G' has the meanings given for Gas hereinbefore with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group, A' represents a -CH=CH- or -CH2 CH2 - group and B' represents a methylene or carbonyl group, is hydrogenated in a solvent or mixture of solvents, or c) in order to prepare compounds of general formula I wherein B represents a carbonyl or methylene group, a compound of general formula see diagramm : EP0224794,P56,F1 wherein A is defined as hereinbefore, R'1 represents a hydroxy, amino or alkylamino group protected by a protecting group or has the meanings given for R1 hereinbefore, R'2 represents a hydroxy group protected by a protecting group or has the meanings given for R2 hereinbefore, and B' represents a carbonyl or methylene group, is reacted with a compound of general formula see diagramm : EP0224794,P56,F2 wherein E, G, m and n are defined as hereinbefore, R'3 , R'4 and R'5 have the meanings given for R3 , R4 and R5 hereinbefore, but the hydroxy, amino or alkylamino groups contained in the groups R3 to R5 may be protected by a protecting group, and V represents a nucleophilically exchangeable group such as a halogen atom or a sulphonyloxy group, and optionally any protecting group used is subsequently split off, or d) in order to prepare compounds of general formula I wherein A represents a -CH2 -CH2 - or -CH=CH- group and B represents a thiocarbonyl group, a compound of general formula see diagramm : EP0224794,P57,F1 wherein R1 to R5 , E, G, m and n are defined as hereinbefore and A' represents a -CH2 -CH2 - or -CH=CH- group, is reacted with a sulphurising agent, or e) in order to prepare compounds of general formula I wherein A represents a see diagramm : EP0224794,P57,F2 group and B represents a methylene group, a compound of general formula see diagramm : EP0224794,P57,F3 wherein R1 to R5 , E, G, m and n are defined as hereinbefore is reduced in a suitable solvent, or f) in order to prepare compounds of general formula I wherein A represents a -CH2 -CH2 - or -CH=CH- group and B represents a methylene group, a compound of general formula see diagramm : EP0224794,P57,F4 wherein R1 to R5 , E, G, m and n are defined as hereinbefore and A, represents a -CH2 -CH2 - or -CH=CH- group, is reduced in a suitable solvent, or g) in order to prepare compounds of general formula I wherein A represents a -COCO- group, a compound of general formula see diagramm : EP0224794,P58,F1 wherein R1 to R5 , E, G, m and n are defined as hereinbefore is oxidised in a suitable solvent or mixture of solvents, or h) in order to prepare compounds of general formula I wherein G has the meanings given for G hereinbefore with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group, A represents a -CH2 -CH2 - group and B represents a methylene or carbonyl group, a compound of general formula see diagramm : EP0224794,P58,F2 wherein R1 to R5 , E, m and n are defined as hereinbefore, G' has the meanings given for G hereinbefore, with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group and B' represents a methylene or carbonyl group, is hydrogenated in a solvent or mixture of solvents and subsequently, if desired, a compound of general formula I thus obtained wherein R1 and/or R3 represents a nitro group is converted by reduction into a corresponding amino compound of general formula I, or a compound of general formula I thus obtained wherein R4 represents a hydroxy or amino group is converted by acylation into a corresponding alkanesulphonyloxy or alkanoylamino compound of general formula I, or a compound of general formula I thus obtained which contains at least one chiral centre is resolved into its diastereomers or into its enantiomers and/or a compound of general formula I thus obtained is converted into the acid addition salts thereof, particularly its physiologically acceptable acid addition salts with inorganic or organic acids.

Description

EP-A-O.065.229 and EP-A-0.161.599 already describe t benzazepine and benzodiazepine derivatives substituted in the 3 position by a phenylalkylaminoalkyl group, wherein the methylene group adjacent to the phenyl nucleus can be replaced by an imino group optionally substituted by benzyl or Cv3 alkyl, or by an oxygen or sulphur atom or a sulphinyl or sulphonyl group, and the physiologically acceptable acid addition salts thereof which have valuable pharmacological properties, namely a mild hypotensive effect and, more particularly, a selective heart-rate lowering effect.
Surprisingly, it has now been found that the new cyclic amine derivatives of general formula the enantiomers, diastereomers and acid addition salts thereof, particularly their physiologically acceptable acid addition salts with inorganic or SS -210 ί 35 organic acids, have even more valuable pharmacological properties, namely a long-lasting heart rate reducing activity and the effect of reducing the O2 requirements of the heart. ♦ This invention thus relates to the new cyclic amine derivatives of general formula I above, the enantiomers, the diastereomers and the acid addition salts thereof, particularly to the pharmaceutical use of the physiologically acceptable acid addition salts with inorganic or organic acids, processes for preparing them and pharmaceutical compositions containing these compounds.
In general formula I above A represents a -CH2-CH2-, -CH=CH-, -CH2~CO- or -NH-CO- group and x x B represents a methylene, carbonyl or thiocarbonyl group or OH ι A represents a -CO-CO- or -CH-CO group and B represents x a methylene group, whilst the atom marked x is linked to the phenyl nucleus, E represents a straight-chained alkylene group with 1 to 3 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, G represents a straight-chained alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, whilst a methylene group, adjacent to a phenyl nucleus, of a straight-chained alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl - 3 group may be replaced by an oxygen or sulphur atom or by an imino, methylimino, sulphinyl or sulphonyl group, R^ represents a hydrogen or halogen atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, R2 represents a hydrogen or halogen atom, a hydroxy, alkoxy, phenylalkoxy or alkyl group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, or R^ and R2 together represent an alkylenedioxy group with 1 or 2 carbon atoms, Rg represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, or a hydroxy, nitro, cyano or trifluoromethyl group, R^ represents a hydrogen atom, an alkoxy, alkanesulphony loxy, amino, alkylamino or dialkylamino group with 1 to 3 carbon atoms in each alkyl moiety or an alkanoylamino group with 2 or 3 carbon atoms in the alkanoyl moiety, or Rg and R^ together represent an alkylenedioxy group with 1 or 2 carbon atoms, Rg represents a hydrogen or halogen atom, a hydroxy, alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, m represents the number 1, 2, 3, 4 or 5, and -4n represents the number 0, 1 or 2, but n + m must represent the number 3, 4 or 5.
Examples of the definitions given for the groups hereinbefore include: for R^: a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyln-propylamino, benzyloxy, 1-phenylethoxy, 1-phenylpropoxy, 2-phenylethoxy or 3-phenylpropoxy group, for R2: a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy or 3-phenylpropoxy group or together with R^ a methylenedioxy or ethylenedioxy group, for R^: a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, cyano or trifluoromethyl group, for R^: a hydrogen atom or a methoxy, ethoxy, n-propoxy, isopropoxy, methanesulphonyloxy, ethanesulphonyloxy, n-propanesulphonyloxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, acetylamino or propionylamino group or together with R3 a methylenedioxy or ethylenedioxy group, - 5 for Rg: a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy or isopropoxy group, '' * for E: a methylene, ethylene, n-propylene, ethylidene, v n-propylidene, n-butylidene, 2-methyl-n-propylidene, 1- methy1-ethylene, 1-ethyl-ethylene, 2-methyl-ethylene, 2- ethyl-ethylene, 1-n-propyl-ethylene, 1-methyln-propylene, 2-methyl-n-propylene, 3-methy1-n-propylene, 1- ethyl-n-propylene, 2-n-propyl-n-propylene or 3- ethy1-n-propylene group and for G: a methylene, ethylidene, n-propylidene, n-butylidene, 2-methy1-propylidene, ethylene, 1methy1-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 2- methyl-ethylene, 2-ethyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1- methyl-butylene, 1-methyl-n-pentylene, 1-ethyln-propylene, 2-ethyl-n-propylene, 1-methyl-n-butylene, ethyleneoxy, n-propyleneoxy, n-butyleneoxy, ethylenethio, n-propylenethio, n-butylenethio, ethylenesulphinyl, ethylenesulphonyl, n-propylenesulphinyl, n-propylenesulphonyl, n-butylenesulphinyl, ethyleneamino, n-propyleneamino, n-butyleneamino, N-methyl-ethyleneamino, N-methy1-n-propyleneamino or N-methyl-n-butyleneamino group.
Thus, according to the invention, the following compounds are covered by general formula I above: 3- [(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-[(N—(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin2- one -63-f (N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-d imethoxy-2,3,4, 5-tetrahvdro1H-3-benzazepine 3-f(N-(2- (3,4-dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-thione 3-f(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-dimethoxy-l,3,4, 5-tetrahydro2H-3-benzazepin-l,2-dione 3-f(N-(2-(3,4-d imethoxy-phenvl)-ethyl)-piper idin3-yl)-methyl]-7,8-dimethoxy-1-hydroxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-f(N-(2-(4-amino-phenyl)-ethyl)-piperidin-3-yl)methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- f(N-(2-(4-acetarnino-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-f(N-(3-(4-amino-3,5-d ibromo-phenoxv)-propyl)piper id in-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-pheny1)-ethyl)-piper idin3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-f(N-(3,4-d imethoxy-benzyl)-piper id in-3-yl)-methyl]7,8-methylened ioxy-1,3,4,5- tetra’nydro-2H-3-benzazepin2- one 3- f(N-(2-phenylethyl)-piperidin-3-yl)-methyl]-7,8- 7 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one 3-((N-(2-(3-nitro-4-acetamino-phenyl)-ethyl)-piper idin3-yl)-methyl1-7,8-dimethoxy-l,3,4,5-tetrahydro- v 2H-3-benzazepin-2-one 3-[(N-(2-(3,4,5-trimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-{(N-(3-(4-methoxy-phenyl)-propyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(4-methoxy-phenyl)-ethyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((n-(2-(4-nitro-phenyl)-ethyl)-piperidin-3-yl)methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-(3-methyl-phenyl)-ethyl)-piperidin-3-yl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-(3-methoxy-phenyl)-ethyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahvdro-2H3-benzazepin-2-one 3-((N-(2-(4-methyl-phenyl)-ethyl)-piperidin-3-yl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(3-(4-bromo-phenyl)-propyl)-piperidin-3-yl)methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-810 2-one 3-( (N- (2- (3,4-dimethoxy-phenyl) -ethyl) -piper idin- '' 3-yl)-methyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin2- one 3- ((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piper idin2- yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- ((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-hexahydroazepin-2-yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3-(4-amino-3,5-dibromo-phenoxy)-propyl) hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one 3-((N—(2-(3,4-dimethoxy-phenyl)-ethyl)-hexahydroazepin-2-yl)-ethyl-2]-7,8-dimethoxy-1,3-d ihydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-methylenedioxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-f(N-(3,4-dichloro-benzyl)-piperidin-3-yl)-methyl]7,8-methylenedioxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N—(2-(3,4-dimethoxy-phenyl)-ethyl)-pyrrolidin3-yl)-methyl]-7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin 2- one 3- ((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-pyrrolidin3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one > 35 -93-((Ν-(3-(3-methoxy-phenoxy)-propyl)-piper idin3-yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one '' *, 3-((N-(3-(3-methy1-phenoxy)-propyl)-piperidin-3- v yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-piperidine3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3,4-methylenedioxy-phenoxy)-propyl)-piperidin3-yl)-methyl]-7,8-methylened ioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(4-(4-methoxy-phenyl)-butyl)-piperidin-3yl) -methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(4-methoxy-phenyl)-ethyl)-piperidin-3yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(phenoxy)-ethyl)-piperidin-3-yl)-methyl]7,8-methylenedioxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-(4-methoxy-phenyl)-ethyl)-piperidin-2yl)-ethyl-2]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(4-methoxy-phenyl)-methyl)-piper idin-2-yl)ethyl-2]7,8-methylenedioxy-l,3,4,5-tetrahydro-2H- ’ 3-benzazepin-2-one 3-((N-(3,4-dimethoxy-phenyl)-methyl)-piperidin-1010 J 35 2- yl)-ethy1-2]-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- [(N-(2-(4-nitro-phenyl)-ethyl)-piper idin-2-yl) ethyl-2]-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3-trifluoromethylphenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-[(N-(3-(3,5—dimethoxy-phenoxy)-propyl)-piperidin2- yl)-ethyl]-7,8-methylened ioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- [(N-(2-(3-methoxy-4-methanesulphonyloxy-phenyl) ethyl)-piper id in-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one 3-((N-(2-(4-benzyloxy-3-methoxy-phenyl)-ethyl)piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro 2H-3-benzazepin-2-one 3-[N-(2-(2-fluorophenyl)-ethyl)-piperidin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin 2- one 3- [N-(2-(4-fluorophenyl)-ethyl)-piperidin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin 2-one 3-((N—(2-(3,4-dimethoxy-phenyl)-ethyl)-hexahydroazepin-2-yl)-ethyl-2]-l,3,4,5-tetrahydro-2H-3-benzazepin 2- one 3- f(N-(2-(4-amino-phenyl)-ethyl)-piperidin-2-yl) ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3- 11 benzazepin-2-one 3-((Ν-(3-(4-amino-3,5-dibromo-phenoxy)-propyl)- ' » piper idin-2-yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one v 3-((N-(3,4-dimethoxy-benzyl)-piperidin-2-yl)-ethyl21 -7 , 8-d imethoxy-1,3,4,5-tetrahyd ro-2H-3-benzazepin2-one 3-((N-(2-phenylethyl)-piperidin-2-yl)-ethyl-2]7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-(3,4,5-trimethoxy-phenyl)-ethyl)-piperidin2- yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- ((N-(3-(4-methoxy-phenyl)-propyl)-piperidin-2yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(4-methoxy-phenyl)-ethyl)-piperidin-2vl)-ethy1-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N—(2-(4-nitro-phenyl)-ethyl)-piper idin-2-yl) ethyl-2]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one 3-[N-(2-(3-methy1-phenyl)-ethyl)-piper idin-2-yl)ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahvdro-2H-3benzazepin-2-one 3-((N-(2-(3-methoxy-phenyl)-ethyl)-piperidin-2yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one -123-({Ν-(2-(4-methyl-phenyl)-ethyl)-piper idin-2-yl)ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-one 3-((N-(3-(4-bromo-phenyl)-propyl)-piperidin-2-yl)ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin2- yl)-ethyl-2]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- ((N—(2-(3,4-dimethoxy-phenyl)-ethyl)-piper idin15 3-yl)-methyl]-7-methoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7-tr ifluoromethy1-1,3,4,5-tetrahydro20 2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7-methylamino-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7-d imethylamino-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-dichloro-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piper id in35 3-yl)-methyl]-7-methylamino-8-methoxy-l,3,4,5-tetrahydro 2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin- 13 3-yl)-methyl]-7-bromo-8-methoxy-l,3, 4 ,5-tetrahydro2H-3-benzazepin-2-one 3-((N—(2-(3,4-dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7-chloro-8-methoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7-hydroxy-8-methoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-phenylethyl)-piperidin-3-yl)-methyl]-7methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 3-((N—(2-phenylethyl)-piperidin-3-yl)-methyl]-7trifluoromethyl-1,3,4, 5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-phenylethyl)-piperidin-3-yl)-methyl]-7methylamino-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-phenylethyl)-piperidin-3-yl)-methyl]-7dimethylamino-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N—(2-phenylethyl)-piper idin-3-yl)-methyl]-7,8dichloro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 3-((N-(2-phenylethyl)-piperidin-3-yl)-methyl]-7methylamino-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-phenylethyl)-piperidin-3-yl)-methvl]-7bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one -143-( (N-(2-phenylethyl)-piper idin-3-yl)-methyl]-7chloro-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-phenylethyl)-piperidin-3-yl)-methyl]-7hydroxy-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(3-(3,4-dimethoxy-phenyl)-propyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-1,3-benzodiazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-1,3-benzodiazepin-2-one 3-((N-(2-(3,4—methylenedioxy-phenyl)-ethyl)-piperidin 3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-1,3-benzodiazepin-2-one 3-((N-(2-(3-methoxy-phenyl)-ethyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H1.3- benzodiazepin-2-one 3-((N-(2-(4-methoxy-phenyl)-ethyl)-piper idin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H1.3- benzodiazepin-2-one 3-((N-(2-(2-methoxy-phenyl)-ethyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H1.3- benzod iazepin-2-one 3-((N-(2-(N-(3,4-dimethoxy-phenyl)-methylamino)ethyl))-piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5 tetrahydro-2H-l,3-benzodiazepin-2-one 3-((N-(3-(3,4-dimethoxy-phenylthio)-propyl)-piperidin - 15 3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-phenylthioethyl)-piperidin-3-yl)-methyl]7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-phenylaminoethyl)-piperidin-3-yl)-methyl]7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-phenoxyethyl)-piperidin-3-yl)-methyl]7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one 3- ((N-(2-(3,5-dichloro-4-methoxy-phenoxy)-ethyl)piperidin-3-yl)-methvl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenylamino)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3-(3,4-dimethoxy-phenylsulphinyl)-propyl)piper idin-3-yl)-methyl]-7,8-d imethoxv-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3-(3,4-dimethoxy-phenylsulphonyl)-propyl)piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3-(4-dimethylamino-phenoxy)-propyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(4-amino-3,5-dibromo-phenylsulphonyl)ethyl)-piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-16tetrahydrο-2H-3-benzazepin-2-one 3-((N-(2-(4-amino-3,5-dibromo-phenylsulphinyl)ethyl)-piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one 3-((N-(2-(4-amino-3,5-dibromo-phenylthio)-ethyl)piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dichloro-phenoxy)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenoxy)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3-(N-phenyl-N-methyl-amino)-propyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(4-methoxy-phenoxy)-ethyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(3,4-methylenedioxy-phenoxy)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(3-(4-amino-3,5-dichloro-phenylamino)-propyl)piper idin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro 2H-3-benzazepin-2-one 3-((N-(2-(4-hydroxy-3-methoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-diraethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one - 17 3-[(Ν-(2-(3,4-dimethoxy-phenyl)-ethyl)-pyrrolidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-pyrrolidin2- yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- ((N-(3-(4-amino-3,5-dibromo-phenoxy)-propyl)pyrrolidin-3-yl)-methyl]-7,8-d imethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one 3-((N-{3-(4-methoxy-phenyl)-propyl)-pyrrolidin3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(4-methoxy-phenyl)-ethyl)-pyrrolidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(3-methyl-phenyl)-ethyl)-pyrrolidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(3-methoxy-phenyl)-ethyl)-pyrrolidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(4-nitro-phenyl)-ethyl)-pyrrolidin-3-yl)methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one 3-((N-(3-(4-bromo-phenyl)-propyl)-pyrrolidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(3-(4-bromo-phenyl)-propyl)-hexahydro-azepin-183-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2Η-3-benzazepin-2-one 3-((N-(2-(4-nitro-phenyl)-ethyl)-hexahydro-azepin— 3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one 3-((N-(2-(4-methoxy-phenyl)-ethyl)-hexahydro-azepin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-(4-methyl-phenyl)-ethyl)-hexahydro-azepin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 3-((N-(2-phenylethyl)-hexahydro-azepin-3-yl)-methyl]7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one 3-((N-(2-phenylethyl)-hexahydro-azepin-2-yl)-ethyl2]—7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one 3-((N-(2-(3-methyl-phenyl)-ethyl)-hexahydro-azepin2- yl)-ethy1]-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one 3- ((N-(2-(4-fluoro-phenyl)-ethyl)-hexahydro-azepin2-yl)-ethy1-2]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one the enantiomers, diastereomers and acid addition salts thereof.
However, the preferred compounds of general formula I above are those wherein A, B, m and n are defined as hereinbefore but m + n -19must represent the number 3, 4 or 5 E represents a methylene or ethylene group, ♦ G represents an n-alkylene group with 1 to 4 carbon atoms, whilst a methylene group of an n-propylene or n-butylene group adjacent to a phenyl nucleus may be replaced by an oxygen or sulphur atom or an imino, methylimino, sulphinyl or sulphonyl group, represents a hydrogen, fluorine, chlorine or bromine atom, or a hydroxy, methoxy, trifluoromethyl, methylamino or dimethylamino group, R2 represents a hydrogen, chlorine or bromine atom or a methoxy group or R^ and R2 together represent a methylenedioxy group, R^ represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, hydroxy, methoxy or nitro group, R^ represents a hydrogen atom or a methoxy, methanesulphonyloxy, amino or acetylamino group or R^ and R^ together represent a methylenedioxy group and Rg represents a hydrogen, chlorine or bromine atom or a methoxy group.
However, particularly preferred compounds of general formula I are those wherein m and n are defined as hereinbefore but m + n must represent the number 3, 4 or 5, -20A represents a or -CH=CH- group and B represents a methylene or carbonyl group or A represents a -CO-CO- group and B represents a methylene group, E represents a methylene or ethylene group, Ιθ G represents an n-alkylene group with 2 to 4 carbon atoms, whilst a methylene group of an n-propylene or n-butylene group adjacent to a phenyl nucleus may be replaced by an oxygen atom, R-^ represents a hydrogen atom or a methoxy group, R2 represents a hydrogen atom or a methoxy group or Rj and R2 together represent a methylenedioxy group, R3 represents a hydrogen atom or a methyl, hydroxy or methoxy group, R4 represents a hydrogen atom or a methoxy group or Rg and R4 together represent a methylenedioxy group and Ri- represents a hydrogen atom, and the enantiomers, diastereomers and acid addition salts thereof.
According to the invention, the new compounds of 35 general formula I are obtained by the following processes: a) reacting a compound of general formula Ν - Ε - CH ' N-H (ID wherein A, Β, E, m and n are as hereinbefore defined, R^’ represents a hydroxy, amino or alkylamino group protected by a protecting group or has the meanings given for R^ hereinbefore and R2' represents a hydroxy group protected by a protecting group or has the meanings given for R2 hereinbefore, with a compound of general formula R, * (III) wherein R3’, R4* and ’ have the meanings given for Rg, R4 and Rg hereinbefore, but the hydroxy, amino or alkylamino groups contained in the groups R^ to Rg may be protected by a protecting group, and U represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group, with optional subsequent splitting off of any protecting group used. -22The protecting group used for a hydroxy group may be, for example, a trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl group and 5 the protecting group used for an amino or alkylamino group may be an acetyl, benzoyl, ethoxycarbonyl or benzyl group.
The reaction is conveniently carried out in a solvent or mixture of solvents such as acetone, diethylether, methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxan or in an excess of the compounds of general formulae II and/or III used and optionally in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, whilst the latter may simultaneously also serve as solvent, or a reaction accelerator such as potassium iodide depending on the reactivity of the nucleophilically exchangeable group, conveniently at temperatures of between 0 and 150°C, preferably at temperatures of between 50 and 120°C, e.g. at the boiling temperature of the solvent used. However the reaction may also be carried out without a solvent. It is, however, particularly advantageous to perform the reaction in the presence of a tertiary organic base or an excess of the amine of general formula III used.
The optional subsequent splitting off of a protecting group used is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, - 23 tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 100°C, preferably at the boiling β temperature of the reaction mixture. However, a benzyl group is preferably split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures of between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar. b) In order to prepare compounds of general formula I wherein G has the meanings given for G hereinbefore, with the exception of the groups containing a sulphenyl, sulphinyl or sulphonyl group, A represents a -CHg-CH^ group, B represents a methylene or carbonyl group and m + n represent the number 4: hydrogenating a compound of general formula wherein Rj to Rg and E are as hereinbefore defined, G' has the meanings given for G hereinbefore with the exception of the radicals containing a sulphur -24atom or a sulphinyl or sulphonyl group, A’ represents a -CH=CH- or -CI^CH^ group and B' represents a methylene or carbonyl group.
The hydrogenation is preferably carried out in a solvent or mixture of solvents such as methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/charcoal, optionally in the presence of a base such as an alkoxide, e.g. sodium methoxide, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar, and at temperatures of between 0 and 75°C but preferably at temperatures of between 20 and 50°C.
In the reaction, any benzyloxy group present may be converted into the corresponding hydroxy group. c) In order to prepare compounds of general formula I wherein B represents a carbonyl or methylene group: reacting a compound of general formula N-H B' (V) wherein A is as hereinbefore defined, Rj' represents a hydroxy, amino or alkylamino group protected by a protecting group or has the meanings given for Rj hereinbefore, R2’ represents a hydroxy group protected by a protecting group or has the meanings given for R2 hereinbefore. -25B* represents a carbonyl or methylene group, with a compound of general formula (VI) and CH m n wherein E, G, m and n are as hereinbefore defined, Rg’, R^' and Rg’ have the meanings given for Rg, R4 and Rg hereinbefore, but the hydroxy, amino or alkylamino groups contained in the groups Rg to Rg may be protected by a protecting group, and V represents a nucleophilically exchangeable group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group, with optional subsequent splitting off of any protecting groups used.
Suitable protecting groups for a hydroxy group include, for example, trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl groups and suitable protecting groups for an amino or alkylamino group include acetyl, benzoyl, ethoxycarbonyl or benzyl groups.
The reaction is conveniently carried out in a solvent or mixture of solvents such as methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran -26or dioxan in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide or an alkali metal hydride such as sodium hydride, conveniently at temperatures of between 0 and 150°C, preferably at temperatures of between 0 and 50°C.
The optional subsequent splitting off of any protecting group used is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures of between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.
In the reaction, any benzyloxy group present may be converted into the corresponding hydroxy group. d) In order to prepare compounds of general formula I wherein A represents a -CHg-CHg or -CH=CH- group and B represents a thiocarbonyl group: reacting a compound of general formula - 27 (VII) wherein Rj to Rg, E, G, m and n are as hereinbefore defined and A’ represents a or -CH=CH- group, with a sulphurising agent.
The reaction is carried out with a sulphurising agent such as phosphorus pentasulphide or 2,4-bis(4methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4disulfide conveniently in a solvent such as toluene or xylene at temperatures of between 50 and 150°C, e.g. at the boiling temperature of the reaction mixture. e) In order to prepare compounds of general formula OH t I wherein A represents a -CH-CO- group and B represents a methylene group: reduction of a compound of general formula wherein -28E, G, m and n are as hereinbefore defined.
Rj to Rg, The reaction is carried out in the presence of a suitable reducing agent such as a metal hydride, e.g. sodium borohydride, in a suitable solvent such as water/methanol or methanol/ether at temperatures of between 0 and 80°C, but preferably at temperatures of between 15 and 40°C. f) In order to prepare compounds of general formula I wherein A represents a or -CH=CH- group and B represents a methylene group: reduction of a compound of general formula wherein Rj to Rg, E, G, m and n are as hereinbefore defined and A* represents a or -CH=CH- group.
The reduction is preferably carried out with a metal hydride such as lithium aluminium hydride or diborane or with a complex of borane and a thioether, e.g. with a borane-dimethylsulfide complex, in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures between 0 and 50°C, but preferably at temperatures of between 10 and 25°C. g) In order to prepare compounds of general formula I wherein A represents a -COCO- group: - 29 oxidation of a compound of qeneral formula wherein Rj to Rg, E, G, m and n are as hereinbefore defined.
The oxidation is preferably carried out with an oxidizing agent such as potassium permanganate, selenium dioxide or sodium dichromate in a suitable solvent or mixture of solvents such as water, water/dioxan, glacial acetic acid, water/glacial acetic acid or acetic anhydride at temperatures of between and 100°C, preferably at temperatures of between 20 and 80°C. h) In order to prepare compounds of general formula I wherein G has the meanings given for G hereinbefore, with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group, A represents a -CHj-CHj- group and B represents a methylene or carbonyl group: hydrogenation of a compound of general formula -30wherein R1 to r5' E' m an<^ n are as hereinbefore defined, G' has the meanings given for G hereinbefore, with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group and B' represents a methylene or carbonyl group.
The hydrogenation is carried out in a solvent or mixture of solvents such as methanol, ethanol, ethyl acetate or glacial acetic acid preferably with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/charcoal, under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar, and at temperatures of between 0 and 75°C, preferably at temperatures of between 20 and 50°C.
If a compound of general formula XI contains a benzyloxy group, this is converted during reduction into the corresponding hydroxy group.
If, according to the invention, a compound of general formula I wherein and/or Rg represents a nitro group is obtained, this can be converted by reduction into a corresponding amino compound of general formula I, or if a compound of general formula I is obtained wherein R^ represents a hydroxy or amino group, this may be converted by acylation into a corresponding alkanesulphonyloxy or alkanoylamino compound of general formula I.
The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic - 31 acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/ charcoal, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(II)sulphate, tin(II) chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at temperatures of between 0 and 50°C, but preferably at ambient temperature.
The subsequent acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, preferably with a reactive derivative of the acid, for example with methanesulphonic acid chloride, ethanesulphonic acid chloride, n-propanesulphonic acid chloride, acetyl chloride, acetic anhydride or propionic anhydride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of between -25°C and 100°C, but preferably at temperatures of between -10 °C and the boiling temperature of the solvent used.
Since they have at least one chiral centre, the compounds of general formula I obtained can be resolved by conventional methods into their diastereomers, for example by column chromatography, and into their enantiomers, for example by column chromatography on a chiral phase or by crystallisation with optically active acids, e.g. with D- or L-monomethyl tartaric acid, D- or L-diacetyl tartaric acid, D- or L-tartaric acid, D- or L-lactic acid or D- or L-camphoric acid.
The compounds of general formula I obtained may -32also be converted into the acid addition salts thereof, particularly for pharmaceutical use into the physiologically acceptable acid addition saltsthereof with inorganic or organic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids.
The compounds of general formulae II to XI used as starting materials are known from the literature in some cases or may be obtained using methods known per se.
Thus, for example, a starting compound of general formula II is obtained by reacting a corresponding benzazepine with a corresponding halogen compound and optionally by subsequently reacting with a corresponding amine. The corresponding benzazepine of general formula V unsubstituted in the 3-position which is required for this is obtained by cyclising a corresponding compound, e.g. by cyclising a compound of general formula H N—CHO-CH / 2 (XII) or a compound of general formula R, (XIII) H2CH2"nH-C0CH2C1 - 33 optionally followed by catalytic hydrogenation and/or reduction of the carbonyl group, for example with sodium borohydride/glacial acetic acid (see EP-Al-0,007,070, EP-Al-0,065,229 and EP-Al-0,109,639) and/or oxidation, e.g. with selenium dioxide.
A compound of general formulae IV and VII to XI used as starting material is preferably obtained by reacting a corresponding halogen compound with a corresponding amine, optionally followed by quaternisation and/or the splitting off of protecting groups used to protect hydroxy and/or amino groups.
As already mentioned hereinbefore, the new compounds of general formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, particularly a long-lasting lowering effect on heart rate and the effect of reducing the requirement of the heart, with only minor side-effects on the central nervous system.
For example, the following compounds: A = 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one, B = 3-((N-(2-(3-methyl-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one, C = 3-((N—(3-(4-methoxy-phenyl)-propyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one and «*· D = 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-342-yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one were tested for their biological properties as follows: Effect on heart rate in rats: The activity of the test substances on the heart rate was investigated, for each dosage, on 2 rats with an average weight of 250-300 g. The rats were anaesthetised with pentobarbital (50 mg/kg i.p. and 20 mg/kg s.c.). The test substances were injected in aqueous solution into the jugular vein (0.1 ml/100 g).
The blood pressure was measured using a cannula inserted in a carotid artery and the heart rate was recorded from an ECG (second or third derivation) derived with needle electrodes. The heart rate of the animals in the control period was between 350 and 400 beats per minute (b/min).
The following Table contains the values found: Substance Dosage Lowering of heart rate measured (mg/kg] 20 minutes after administration of substance [b/min] A 5.0 - 208 B 5.0 - 148 C 5.0 - 135 D 5.0 - 125 When administered in therapeutic doses the compounds - 35 prepared according to the invention show no toxic side effects of any kind. Thus, when administered intravenously to mice, even in a high dosage of mg/kg, substances A and D showed no toxic side effects apart from a slight sedation.
In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prevention and treatment of ischaemic heart disease.
The dosage required to achieve this effect is conveniently from 0.01 to 0.2 mg/kg of body weight, preferably from 0.03 to 0.15 mg/kg of body weight, once or twice a day. The compounds of general formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids produced according to the invention may be incorporated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The following Examples are intended to illustrate the invention: -36Example A N-Benzyl-3-(hydroxymethyl)-piperidine A mixture of 40.3 g (0.35 mol) of 3-(hydroxymethyl)piperidine, 97.4 ml (0.70 mol) of triethylamine and 40.3 ml (0.35 mol) of benzyl chloride is heated to 95°C within 30 minutes and left at this temperature for 2 hours. After cooling the reaction mixture is dissolved in a mixture of 2 molar sodium hydroxide solution and ethyl acetate. The organic phase is washed with water, separated off, dried over magnesium sulphate and concentrated by evaporation in vacuo.
Yield: 57.2 g (79.6% of theory), Rf value: 0.45 (aluminium oxide neutral, eluant: 3% ethanol in methylene chloride).
Example B N-Benzyl-3-(bromomethyl)-piperidine 55.1 g (0.268 mol) of N-benzyl-3-(hydroxymethyl)piperidine are added to 400 ml of 48% hydrobromic acid with vigorous stirring and the mixture is refluxed for 1 hour. Then hydrogen bromide is introduced to saturation point (about 1 hour), the mixture is refluxed for another hour and left to stand overnight. It is then neutralised with solid potassium carbonate whilst cooling with ice and then extracted with methylene chloride. The organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo.
Yield: 52.0 g (72.2% of theory), Rf value: 0.85 (aluminium oxide neutral, eluant: methylene chloride). -37Example C 3-[(N-Benzyl-piperidin-3-yl)-methyl]-7,8-dimethoxy1,3-dihydro-2H-3-benzazepin-2-one 17.54 g (0.08 mol) of 7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one are suspended in 150 ml of dimethylsulphoxide and 8.98 g (0.08 mol) of potassium tert.butoxide are added with stirring. After 45 minutes, 21.45 g (0.08 mol) of N-benzyl-3-(bromomethyl)piperidine dissolved in 50 ml of dimethylsulphoxide are added dropwise to the resulting solution with stirring. After 2 hours the mixture is poured onto ice water. The aqueous phase is extracted three times, each time with 150 ml of ethyl acetate.
The combined organic phases are washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo ahd purified over 800 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 3%).
Yield: 14.3 g (44% of theory), Rf value: 0.35 (aluminium oxide neutral, eluant: 1% ethanol in methylene chloride).
Example D 3-[(Piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one 14.3 g (0.0352 mol) of 3-((N-benzyl-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin2-one are hydrogenated in 120 ml of glacial acetic acid in the presence of 1.5 g of 10% palladium/charcoal for 4 hours at 50°C under 5 bar of hydrogen. The catalyst is then removed by suction filtering, the glacial acetic acid is distilled off in vacuo -38and, after the addition of water, the residue is neutralised with potassium carbonate. The greasy precipitate is extracted with methylene chloride, the organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo.
Yield: 9.3 g (83% of theory), Melting point: 152-156°C.
Example E 3-[(Pyridin-3-yl)-methyl]-7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one 2.2 g (0.01 mol) of 7,8-dimethoxy-l,3-dihydro-2H3-benzazepin-2-one are suspended in 10 ml of dimethylsulphoxide and 1.12 g (0.01 mol) of potassium tert.butoxide are added with stirring. After 60 minutes, 1.3 g (0.01 mol) of 3-picolylchloride dissolved in 10 ml of dimethylsulphoxide are added dropwise to the resulting solution with stirring. After hour it is poured onto ice water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 200 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing quantities of methanol (up to 0.8%).
Yield: 1-4 g (45.2% of theory), Melting point: 144-146°C. - 39 Example F 3-((N-(2-(3, 4-Dimethoxy-phenyl)-ethyl)-pyridinium- 3-yl)-methyl]-7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin2-one bromide A mixture of 1.1 g (0.0035 mol) of 3-((pyridin3-vl)-methyl]-7,8-d imethoxy-1,3-d ihydro-2H-3-benzazepin2-one and 2-(3,4-dimethoxyphenyl)-ethyl bromide is heated to 110°C for 6 hours. After cooling, the reaction mixture is dissolved in a little methanol/ methylene chloride and added dropwise to 200 ml of diethylether, with vigorous stirring. The precipitate obtained is suction filtered and dried.
Yield: 1.6 g (80% of theory), Melting point: 147-150°C.
Example G N-(2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(hydroxymethyl)piperidine A mixture of 2.30 g (0.02 mol) of 3-(hydroxymethyl)piperidine, 5.5 ml (0.04 mol) of triethylamine and 4.90 g (0.02 mol) of 2-(3,4-dimethoxy-phenyl)ethyl bromide is refluxed for 2 hours. After cooling, the reaction mixture is dissolved ini a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is washed with water, separated off, dried over magnesium sulphate, evaporated down in vacuo and purified over 300 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 2%) .
Yield: 4.4 g (78.7% of theory), Melting point: 87.5-89°C. -40Example Η N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(bromomethyl)piperidine 4.4 g (0.0157 mol) of N-(2-(3,4-dimethoxy-phenyl) ethyl]-3-(hydroxymethyl)-piperidine are dissolved in 70 ml of carbon tetrachloride and cooled to 0°C. Then 1.63 ml (0.0173 mol) of phosphorus tribromide is added, whereupon a bulky precipitate is immediately formed. The mixture is stirred for 15 hours at ambient temperature, water is added and the mixture is neutralised with 2 molar sodium hydroxide solution. The organic phase is separated off, washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Yield: 2.0 g (37.2% of theory), Rf value: 0.5 (aluminium oxide neutral, eluant: 2% ethanol in methylene chloride).
Example I N-Benzyl-caprolactarn 33.9 g (0.3 mol) of caprolactam are dissolved in 200 ml of absolute dimethylsulphoxide and 100 ml of absolute tetramethyl urea and 14.4 g (0.33 mol) of 55% sodium hydride/oil dispersion is added in batches. The resulting jelly-like precipitate is stirred for 2 hours at ambient temperature. Then 38 g f 34.4 ml (0.3 mol) of benzyl chloride are added dropwise, the mixture is stirred for hours at ambient temperature and then poured - 41 onto ice water. The aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed four times with water, dried over, magnesium sulphate and concentrated by evaporation in vacuo. The residue remaining is distilled in vacuo.
Yield: 49.9 g (81.8% of theory), Bpn m σ : 110-114°C.
H0.27 mm Hg Example K l-Benzyl-caprolactam-3-carboxylie acid 180 ml of 1.6 molar butyl lithium solution in nhexane are added at -60°C to 33.9 g = 47.1 ml (0.33 mol) of diisopropylamine in 450 ml of absolute ether, with stirring and under nitrogen. Then, whilst cooling is continued, 48.8 g (0.24 mol) of N-benzyl-caprolactam dissolved in 150 ml of absolute ether are added dropwise thereto. After the mixture has been stirred for 10 minutes the cooling bath is taken away and carbon dioxide is bubbled in for 15 minutes. The reaction mixture is poured onto ice, the ethereal phase is separated off and extracted twice with 2 molar sodium hydroxide solution. The aqueous/alcoholic phases are combined, extracted with ether, acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined methylene chloride phases are dried over magnesium sulphate and the solvent is distilled off in vacuo.
Yield: 15.7 g (26.5% of theory), IR spectrum (methylene chloride): 1735 and 1600 cm 1 (CO) . -42Example L l-Benzyl-3-hydroxymethyl-hexahydro-azepine 14.8 g (0.06 mol) of l-benzyl-caprolactam-3-carboxylic acid dissolved in 300 ml of absolute tetrahydrofuran are added dropwise to 6.84 g (0.18 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran.
The mixture is then refluxed for 6 hours, then 6.8 ml of water, 6.8 ml of 2-molar sodium hydroxide solution and 21 ml of water are added, whilst cooling with ice water. The precipitate is removed by suction filtering, washed with tetrahydrofuran and the filtrate is concentrated by evaporation in vacuo. The residue is purified by column chromatography over aluminium oxide N (activity II, eluant: methylene chlor ide).
Yield: 8.4 g (63.8% of theory), IR spectrum (methylene chloride): 3620 cm (OH) Example M 1- Benzyl-3-bromomethyl-hexahydro-azepine 8.3 g (0.038 mol) of l-benzyl-3-hydroxymethyl-hexahydroazepine are dissolved in 200 ml of carbon tetrachloride and 16 ml of phosphorus tribromide are added.
The mixture is stirred for 6 hours at ambient temperature, water is then added whilst the mixture is cooled with ice and it is made slightly alkaline with 2- molar sodium hydroxide solution. The aqueous solution is separated off and extracted twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated by evaporation in vacuo.
Yield: 8.9 g (82% of theory). -43Example Ν 3-[(N-Benzyl-hexahydro-azepin-3-yl)-roethyl]-7,8dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one 2.3 g (0.02 mol) of potassium tert.butoxide are added to a solution of 4.4 g (0.02 mol) of 7,8dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one in 100 ml of absolute dimethylsulphoxide. After stirring for 30 minutes at ambient temperature, 5.6 g (0.020 mol) of l-benzyl-3-bromomethyl-hexahydro-azepine are added and the resulting mixture is stirred for hours at ambient temperature. The reaction mixture is dissolved in ethyl acetate and extracted several times with water. The organic phase is dried over magnesium sulphate and evaporated down in vacuo.
The residue is purified by column chromatography over aluminium oxide N (activity II, eluant: methylene chloride, methylene chloride + 0.3% ethanol).
Yield: 4.2 g (50% of theory), IR spectrum (methylene chloride): 1655 cm (CO) Example O 3-[(Hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxv1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 4.2 g (0.01 mol) of 3-[(N-benzyl-hexahydro-azepin3-yl)-methyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin2-one are hydrogenated in 100 ml of glacial acetic acid in the presence of 0.5 g of 10% palladium/charcoal for 14 hours at 50 psi and at 50°C. The catalyst is removed by suction filtering and the glacial acetic acid is distilled off in vacuo. The residue is taken up in water, made alkaline with 2-molar sodium hydroxide solution and extracted several times with methylene chloride. The organic extract -44is dried over magnesium sulphate and concentrated by evaporation in vacuo. Purification by column chromatography is carried out over aluminium oxide N (activity II, eluant: methylene chloride + 1% ethanol).
Yield: 2.6 g (78.2% of theory), IR spectrum (methylene chloride) : 1650 cm-'1' (CO) .
Example P 7-Carbethoxymethyl-caprolactam At 0°C 9.2 g = 9 ml (0.05 mol) of ethyl cyclohexanone2-acetate are added dropwise to 50 ml of concentrated sulphuric acid. Then 3.25 g (0.05 mol) of sodium azide are added in batches. After stirring for 10 hours at 0°C the reaction mixture is poured onto ice water and neutralised with concentrated ammonia with further cooling. After the solution has been saturated with sodium chloride it is extracted several times with n-butanol to which 10% methylene chloride is added. The extract is evaporated down in vacuo and the residue is separated by column chromatography over aluminium oxide N (activity II, eluant: methylene chloride + 0.5% ethanol).
Yield: 5.7 g (56.6% of theory), Melting point: 108-109°C.
Example Q 2-(2-Hydroxyethyl)-hexahydro-azepine-hydrochlor ide .6 g (0.028 mol) of 7-carbethoxymethyl-caprolactam dissolved in 50 ml of absolute dioxan are added dropwise to 2.6 g (0.06 mol) of lithium aluminium hydride in 100 ml of absolute dioxan, with stirring and refluxing. The mixture is refluxed for 18 - 45 hours and then whilst it is cooled with ice water, 2.3 ml of water, 2.3 ml of 15% socium hydroxide z solution and 6.9 ml of water are added. The precipitate is removed by suction filtering and washed with ether. The filtrate is concentrated by evaporation in vacuo^. th.e residue is dissolved in ether and precipitated with ethereal hydrochloric acid.
Yield: 3 g (59.6% of theory), Melt i_ng-7po int: 75^07 Example R N-[2-(3,4-Pimethoxv-phenvl)-ethyl]-2-(2-hvcroxyethyl) 15 hexahvdro-azepine 2.9 g (Q.016 mol) of 2-(2-hycroxyethyl)-hexahycroazepine—hycrochior ide are liberated with concentrates socium hydroxide solution, taken up in methylene chloride anc,'after crying, evaporated'down over magnesium sulphate. The residue is refluxed for 2"hours with 3.9 g (0.016 mol) of 2- (3,4-dimethoxyphenyl) -ethylbromide in 10 ml of triethylaminerAfter cooliho, the reaction mixture is combined with 2 molar sodium hydroxide BOlution/methylene cnioride. ^he alkaline phase is separated off and extracted twice with methylene chloride and the combined organic phases are dried over magnesium sulphate. The solvent is distilled off in vacuo and the residue is purified by column chromatographyover aluminium oxide N (activity II, eluant: methylene chloride).
Yield: 3.7 g (75.2% of theory). -46Example S 2-(2-Bromoethyl)-1-f 2-(3,4-dimethoxy-phenyl)-ethyT]hexahydro-azepine ml of phosphorus tribromide are added dropwise to 2.9 g (9.4 mmol) of N-[2-(3,4-dimethoxy-phenyl)ethyl]-2-(2-hydroxyethyl)-hexahydro-azepine in 100 ml of carbon tetrachloride, whilst cooling with ice, and the mixture is stirred for 15 hours at ambient temperature. Then water is added, whilst cooling with ice water is continued, and the mixture is made slightly alkaline with 2 molar sodium hydroxide solution. The aqueous/alkaline solution is separated off and extracted twice with methylene chloride.
The combined organic solutions are dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 3.6 g (100% of theory).
Example T 3-[(Pyridin-3-yl)-methyl]-7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one a) (Pyridin-3-yl)-methylamino-N-acetaldehyde-dimethyl acetal .36 g (0.050 mol) of pyridine-3-aldehyde and 5.26 g (0.050 mol) of aminoacetaldehyde-dimethylacetal are hydrogenated in 80 ml of ethanol in the presence of 0.8 g of 10% palladium/activated charcoal for 2 hours at 20°C under 5 bar. The catalyst is then removed by suction filtering and the ethanol is distilled off in vacuo.
Yield: 9.4 g (96% of theory), Rf value: 0.25 (aluminium oxide, eluant: 2% ethanol in methylene chloride). - 47 b) 3,4-Dimethoxy-phenylacetic acid-N-(acetaldehydedimethyl-acetal)-N-f(pyridin-3-yl)-methyl]) amide 7.85 g (0.040 mol) of (pyridin-3-yl)-methylaminoN-acetaldehyde-dimethylacetai and 4.4 g (0.044 mol) of triethylamine are dissolved in 50 ml of methylene chloride. Whilst cooling with ice, 8.58 g (0.040 mol) of 3,4-dimethoxy-phenylacetic acid chloride are added dropwise to this mixture and the resulting mixture is stirred for 1 hour at 20°C. It is then extracted 3 times with water and the organic phase is dried over magnesium sulphate and then concentrated by evaporation.
Yield: 12.6 g (84% of theory) Rf value: 0.5 (on silica gel, eluant: 5% ethanol in methylene chloride). c) 3-f(Pyridin-3-yl)-methyl]-7,8-dimethoxy-l,3dihydro-2H-3-benzazepin-2-one 3.74 g (0.010 mol) of 3,4-dimethoxy-phenylacetic acid-N-(acetaldehyde-dimethylacetal)-N-[(pyridin3-yl)-methyl]-amide are dissolved in 10 ml of concentrated hydrochloric acid and 10 ml of glacial acetic acid and stirred for 60 hours at 20°C. The mixture is then poured onto ice water, neutralised with 25% sodium hydroxide solution and extracted twice with methylene chloride. The organic phase is dried over magnesium sulphate, filtered off and concentrated by rotation.
Yield: 1.85 g (60% of theory), Melting point: 144-146°C (from acetone). -48Example U N—[ 2- (3,4-Dimethoxy-phenyl) -ethyl]-3-tosyloxymethyl·pyrrolid ine a) N-Benzyl-2-pyrrolidone 14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil are added in batches to 25.5 g (0.3 mol) of 2-pyrrolidone in 300 ml of absolute dimethylsulphoxide.
The mixture is then stirred for 5 hours at 40 to 50°C and at 25-30°C 56.4 g = 39.2 ml (0.33 mol) of benzyl bromide are added dropwise. After stirring for 10 hours at ambient temperature the reaction mixture is dissolved in 500 ml of ethyl acetate and extracted several times with water. The organic phase is separated off, dried over magnesium sulphate and the solvent is eliminated in vacuo. The residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and 0.1% ethanol.
Yield: 35.6 g (67.7% of theory), Rf value: 0.77 (aluminium oxide, neutral, eluant: % ethanol in methylene chloride). b) N-Benzyl-2-pyrrolidone-3-carboxylie acid At -60°C, 150 ml of 1.6 molar butyl lithium solution in n-hexane are added to 28.3 g = 39.3 ml (0.28 mol) of di isopropylamine in 400 ml of absolute ether, with stirring and under nitrogen. 35.1 g (0.2 mol) of N-benzyl-2-pyrrolidone dissolved in 150 ml of absolute ether are added dropwise thereto at -60°C.
The cooling bath is taken away and dry carbon dioxide is introduced for 15 minutes. After stirring for minutes the mixture is poured onto ice, the organic phase is separated off and extracted twice - 49 with 2 molar sodium hydroxide solution. The combined aqueous phases are extracted once with ether and then acidified with concentrated hydrochloric acid,with cooling. The aqueous phase is extracted twice with methylene chloride and, after the organic phase has been dried over magnesium sulphate, it is concentrated by evaporation in vacuo.
Yield: 35 g (79.8% of theory), Rf value: 0.42 (silica gel, eluant: 5% ethanol in methylene chloride). c) N-Benzyl-3-hydroxymethy1-pyrrolidine g (0.16 mol) of N-benzyl-2-pyrrolidone-3-carboxylic acid dissolved in 250 ml of absolute tetrahydrofuran is added dropwise, with stirring, to 12.2 g (0.32 mol) of lithium aluminium hydride in 350 ml of absolute tetrahydrofuran. After refluxing for 6 hours, 18.2 ml of water, 12.2 ml of 15% sodium hydroxide solution and 36.6 ml of water are added, whilst cooling with ice water. The precipitate formed is suction filtered and washed with tetrahydrofuran.
The combined filtrates are concentrated by evaporation in vacuo and the residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and then with increasing amounts of ethanol (up to 2%).
Yield: 16 g (52.3% of theory), Rf value: 0.42 (aluminium oxide, neutral, eluant: % ethanol in methylene chloride). d) 3-Hydroxymethy1-pyr rolid ine g (0.073 mol) of N-Benzyl-3-hydroxymethyl-pyrrolidine are hydrogenated for 7 hours at 50°C and at 5 bar in 300 ml of methanol and in the presence of 1.5 g of 20% palladium hydroxide/activated charcoal. -5GThe catalyst is then removed by suction filtering and the filtrate is concentrated by evaporation in vacuo.
Yield: 7.3 g (99% of theory), Mass spectrum: molecular peak 101 e) N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-hydroxymethylpyrrolidine g (0.03 mol) of 3-hydroxymethyl-pyrrolid ine and 7.5 g of 2-(3,4-dimethoxy-phenyl)-ethylbromide are heated in 20 ml of triethylamine for 7 hours at 100°C. The excess triethylamine is then distilled off in vacuo and the residue obtained is dissolved in methylene chloride and 6 molar sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue obtained is then purified over 400 g of alumium oxide (neutral, activity II) with methylene chloride and with increasing amounts of ethanol (up to 1%).
Yield: 5.4 g (67.8% of theory), Rf value: 0.41 (aluminium oxide, neutral, eluant: % ethanol in methylene chloride). f) N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-tosyloxymethy1pyrrolidine 1.3 g (0.005 mol) of N-[2-(3,4-dimethoxy-phenyl)ethyl]-3-hydroxymethyl-pyrrolidine are dissolved in 10 ml of pyridine, 1.05 g (0.0055 mol) of ptoluenesulphonic acid chloride are added and the mixture is stirred for 6 hours at ambient temperature. The excess pyridine is then distilled off in vacuo, the residue obtained is dissolved in methylene chloride and the organic phase is extracted with ice water. After the organic phase has been dried - 51 over magnesium sulphate it is concentrated by evaporation in vacuo.
Yield: 1.4 g (66.7% of theory), Rf value: 0.40 (aluminium oxide, neutral, eluant: 2% ethanol in methylene chloride). -52Example 1 3-((Ν-(2-(3,4-Pimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochlor ide A mixture of 6.37 g (0.020 mol) of 3-((piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one, 5.6 ml (0.040 mol) of triethylamine and 4.90 g (0.020 mol) of 2-(3,4-dimethoxy-phenyl) ethyl bromide is refluxed for 2 hours. The initial suspension changes into a clear solution and after about 30 minutes begins to precipitate in a jellylike form. After cooling, the reaction mixture is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is separated off, washed with water, dried over magnesium sulphate, evaporated down in vacuo and purified over 800 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing quantities of ethanol (up to 2%).
The hydrochloride is precipitated from a solution in acetone with methanolic hydrochloric acid.
Yield: 6.2 g (59.7% of theory), Melting point: 218-219°C Calculated: C 64.79 H 7.57 N 5.40 Found: 64.88 7.55 5.21 Example 2 3-((N- (2-(3,4-Pimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrobromide 3.7 g (0.0067 mol) of 3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-pyridinium-3-yl)-methyl]-7,8-dimethoxy-l, 3dihydro-2H-3-benzazepin-2-one-bromide are hydrogenated - 53 in 70 ml of methanol in the presence of 0.7 g of platinum dioxide for 3 hours at ambient temperature and under 5 bar. The catalyst is removed by suet Γόη filtering, the methanol is distilled off in vacuo and the residue is dissolved in a little methanol and mixed with acetone. The precipitate is suction filtered and dried.
Yield: 2.7 g (71.4% of theory).
Melting point: 225-227°C Calculated: C 59.68 H 6.98 N 4.97 Found: 59.45 7.10 5.00 Example 3 3-[(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methylj-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin2-one-hydrochloride 1.01 g (0.005 mol) of 7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one are suspended in 10 ml of dimethylsulphoxide and 0.56 g (0.005 mol) of potassium tert.butoxide are added with stirring. After 45 minutes, 1.7 g (0.005 mol) of N-[2-(3,4-dimethoxyphenyl) -ethyl]-3-(bromomethyl)-piperidine dissolved in 5 ml of dimethylsulphoxide are added dropwise to the resulting solution with stirring. After 40 minutes it is poured onto ice water. The aqueous phase is extracted three times with ethyl acetate.
The combined organic phases are washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 200 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 0.5%). The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
Yield: 0.62 g (23.9% of theory), -54Melting point: 117-121OC Calculated: C 65.04 H 7.21 N 5.42 ♦ Found: 64.86 7.18 5.35 Example 4 3-[ (N-(2-(3,4—Dimethoxy-phenyl)-ethyl)-piperidin10 3-yl)-methyl]-7,8-dimethoxy-2,3,4,5-tetrahydrolH-3-benzazepine-dihydrochloride A solution of 0.96 g (0.002 mol) of 3-[(N-(2-(3,4dimethoxy-phenyl)-ethyl)-piper idin-3-yl)-methyl]15 7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one in 20 ml of tetrahydrofuran is added dropwise, under a nitrogen atmosphere, to a solution of 0.24 ml (0.002 mol) of boron trifluoride etherate and 0.3 ml (0.003 mol) of borane dimethylsulphide complex (10 2θ molar solution in toluene) and the resulting mixture is then refluxed for 3 hours. After the reaction mixture has cooled, methanol is added dropwise thereto. Then 2 ml of methanolic hydrochloric acid are added and the mixture is refluxed for OC hours. The methanol and tetrahydrofuran are distilled off and the residue is mixed with water and then neutralised with 2 molar sodium hydroxide solution. The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 50 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 0.5%). The dihydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
Yield: 0.28 g (27.7% of theory), Melting point: 238-240°C Calculated: C 62.09 H 7.81 N 5.17 - 55 Found : 61.88 7.84 .42 Example 5 3-f (N- (2- (3,4-Dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahvdro2H-3-benzazepin-2-th ione-hydrochloride 1.4 g (0.0029 mol) of 3-f(N- (2-(3,4-dimethoxy-phenyl) ethyl)-piper idin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one and 0.41 g (0.0018 mol) of phosphorus pentasulpnide are heated to 100°C in 20 ml of pyridine for 3 hours. After concentration in vacuo the residue obtained is purified over 120 g of aluminium oxide (neutral, activity II-III) with ethyl acetate/cyclohexane (80/20).. The hydrochloride is precipitated from a solution in acetone with methanolic hydrochloric acid.
Yield: 0.47 g (30.3% of theory), Melting point: 206-207°C Calculated: C 62.84 H 7.35 N 5.24 S 5.99 Found: 62.54 7.43 5.35 6.15 Example 6 3-f(N-(2-(3,4-Dimethoxv-phenvl)-ethyl)-pjperidin3-y1)-methyl]-7,8-d imethoxv-1,3,4,5-tetrahydro2K-3-benzazepin-l,2-dione 3.8 g (0.0079 mol) of 3-f(N-(2-(3,4-dimethoxy-phenyl) ethyl)-piper idin-3-yl)-methyl]-7,8-d imethoxy-1,3,4,5tetrahvdro-2H-3-benzazepin-2-one are added at 70°C to a suspension of 1.4 g (0.0128 mol) of selenium dioxide and 0.8 g of kieselguhr in dioxan/water and refluxed for 16 hours. After cooling, the mixture is diluted with a little ethanol and suction filtered. The filtrate is evaporated down in vacuo -56and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and increasing amounts of ethanol (up to 1%).
Yield: 2.15 g (54.8% of theory), Melting point: 130-132°C Calculated: C 67.72 H 7.31 N 5.64 Found: 67.53 7.14 5.65 Example 7 3-[(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l-hydroxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride 0.70 g (0.0014 mol) of 3-[(N-(2-(3,4-dimethoxyphenyl) -ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-l,2-dione are dissolved in a mixture'of methanol and water (95:5), 0.060 g (0.0016 mol) of sodium borohydride are added and the mixture is stirred for 20 minutes at ambient temperature. Then it is acidified with 2 molar hydrochloric acid, neutralised with ammonia and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue obtained is purified over 100 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 15%).
The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
Yield: 0.47 g (62.3% of theory), Melting point: 118-124°C Calculated: C 62.85 H 7.35 N 5.24 Found: 62.60 7.39 5.30 - 57 Example 8 3-[(N-(2-(4-Amino-phenyl)-ethyl)-piperidin-3-yl)- methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one-dihydrochloride 1.7 g (0.0036 mol) of 3-f (N- (2-(4-nitro-phenyl)ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one are hydrogenated in 40 ml of methanol in the presence of 0.3 g of 10% palladium/charcoal for 2 hours at ambient temperature and under 5 bar of hydrogen. Then the catalyst is removed by suction filtering and the methanol is distilled off in vacuo. The hydrochloride is precipitated from a solution of the residue in acetone using methanolic hydrochloric acid.
Yield: 1.1 g (59.8% of theory), Melting point: 236-240°C Calculated: C 61.17 H 7.31 N 8.23 Found: 60.85 7.63 8.12 Example 9 3- f(N-(2-(4-Acetamino-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride 0.88 g (0.002 mol) of 3-f(N-(2-(4-amino-phenyl)ethyl)-piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one and 0.3 ml (0.0022 mol) of triethylamine are dissolved in 10 ml of methylene chloride and 0.16 ml (0.0022 mol) of acetyl chloride are added dropwise with stirring. After 30 minutes water is added. The aqueous phase is extracted three times with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The hydrochloride is precipitated -58from a solution of the residue in acetone using methanolic hydrochloric acid.
Yield: 0.61 g (59.1% of theory).
Melting point: 187-192°C Calculated: C 65.16 H 7.42 N 8.14 Found: 64.95 7.45 7.94 Example 10 3-[(N-(3-(4-Amino-3,5-dibromo-phenoxy)-propyl)piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxyl,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3(4-amino-3,5-dibromo-phenoxy)-propyl chloride analogously to Example 1.
Yield: 20.4% of theory, Melting point: > 95°C (decomp.) Calculated: C 49.00 H 5.48 N 6.35 Br 24.15 Found: 49.12 5.80 5.83 24.00 Example 11 3-[(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-methylenedioxy-l ,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(3,4-dimethoxy-phenyl)-ethylbromide analogously to Example 1.
Yield: 31.7% of theory, Melting point: 142-143°C Calculated: C 64.47 H 7.01 N 5.57 Found: 64.36 7.17 5.42 - 59 Example 12 3-[(Ν-(3,4-Dimethoxy-benzyT)-piper idin-3-yl)-methyl·]7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one-hydrochlor ide Prepared from 3-((piperidin-3-yl)-methyl]-7, 8-methylened ioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3,4-dimethoxy-benzyl chloride analogously to Example 1.
Yield: 30.7% of theory, Melting point: 135°C (decomp Calculated: C 63.68 H 6.80 7.02 Found: 63.45 Example 13 3-[(N-(2-Phenylethyl)-piperidin-3-yl)-methyl]-7,8dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxyl,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2phenylethylbromide analogously to Example 1.
Yield: 43.5% of theory, Melting point: 241-243°C Calculated: C 68.03 H 7.69 N 6.10 Found: 67.89 7.89 6.36 Example 14 3-[(N-(2-(3-Nitro-4-acetamino-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydrΟΣΗ- 3-benzazep in- 2-one-hyd roch lor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxyl,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-60(3-nitro-4-acetamino-phenyl)-ethyl bromide analogously to Example 1.
Yield: 22.3% of theory, Melting point: } 173°C (decomp.) Calculated: C 59.94 H 6.65 N 9.99 Found: 59.92 6.77 9.98 Example 15 3-[(N-(2-(3,4,5-Trimethoxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride Prepared from 3-f(piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(3,4,5-trimethoxy-phenyl)-ethyl bromide analogously to Example 1.
Yield: 22.6% of theory, Melting point: 135-137°C Calculated: C 63.53 H 7.53 N 5.10 Found: 63.50 7.82 5.09 Example 16 3-f(N-(3-(4-Methoxy-phenyl)-propyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one-hydrochloride Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3(4-methoxyphenyl)-propyl bromide analogously to Example 1.
Yield: 29.4% of theory Melting point: 215-218°C Calculated: C 66.85 H 7.81 N 5.57 Found: 66.67 7.65 5.53 - 61 Example 17 3-[ (Ν-(2-(3,4-Dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-dimethoxy-2,3-d ihydro-lH-benzazepine A suspension of 0.06 g (0.0016 mol) of lithium aluminium hydride in 20 ml of absolute tetrahydrofuran is mixed with 0.31 g (0.00065 mol) of 3—[(N—{2— (3,4-dimethoxy-phenyl)-ethyl)-piper idin-3-yl)-methyl]7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one and then stirred for 1 hour at ambient temperature. % ammonium chloride solution is added, whilst cooling with ice water, and the precipitate formed is suction filtered. The filtrate is concentrated by evaporation in vacuo and the residue is purified over 30 g of aluminium oxide (neutral, activity II-III) with methylene chloride.
Yield: 0.05 g (16.5% of theory), Rf value: 0.5 (aluminium oxide, eluant: 2% ethanol in methylene chloride) Calculated: C 72.07 H 8.21 N 6.00 Found: 71.90 8.39 5.89 Example 18 3-f(N-(2-(4-Methoxy-phenyl)-ethyl)-piper idin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(4-methoxy-phenyl)-ethylbromide analogously to Example 1.
Yield: 19.8% of theory, Melting point: 227-230°C Calculated: C 66.31 H 7.63 N 5.73 Found: 66.46 7.57 5.73 -62Example 19 3-[(N-(2-(4-Nitro-phenyl)-ethyl)-piper idin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one-hydrochloride Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1.3.4.5- tetrahydro-2H-3-benzazepin-2-one and 2(4-nitro-phenyl)-ethylbromide analogously to Example 1. Yield: 66.8% of theory, Melting point: 239-245°C Calculated: C 61.91 H 6.80 N 8.34 Found: 62.25 6.66 8.23 Example 20 3- [(N-(2-(3-Methyl-phenyl)-ethyl)-piperidin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one-hydrochloride Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1.3.4.5- tetrahydro-2H-3-benzazepin-2-one and 2(3-methyl-phenyl)-ethylbromide analogously to Example 1. Yield: 38.1% of theory, Melting point: 234-237°C Calculated: C 68.55 H 7.88 N 5.92 Found: 68.68 7.87 6.14 Example 21 3- [(N-(2-(3-Methoxy-phenyl)-ethyl)-piperidin-3yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one-hydrochloride Prepared from 3-((piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(3-methoxy-phenyl)-ethylbromide analogously to - 63 Example 1.
Yield: 23.7% of theory, Melting point: 199-202°C Calculated: C 66.31 H 7.63 N 5.73 Found: 66.61 7.59 5.91 Example 22 3-[(N-(2-(4-Methyl-phenyl)-ethyl)-piperidin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1.3.4.5- tetrahydro-2H-3-benzazepin-2-one and 2(4-methyl-phenyl)-ethylbromide analogously to Example 1. Yield: 34.7% of theory, Melting point: 233-236°C Calculated: C 68.55 H 7.88 N 5.92 Found: 68.30 7.89 5.84 Example 23 3- [(N-(3-(4-Bromo-phenyl)-propyl)-piperidin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1.3.4.5- tetrahydro-2H-3-benzazepin-2-one and 3(4-bromophenyl)-propyl bromide analogously to Example 1.
Yield: 34.8% of theory, Melting point: 100-104°C Calculated: C 58.75 H 6.57 N 5.08 Br 14.48 Found: 58.40 6.66 4.79 14.21 -64Example 24 3-f(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-piper idin3-yl)-methyl]-7,8-methylenedioxy-l,3-dihydro-2H3-benzazepin-2-one-hydrochloride Prepared from 7,8-methylenedioxy-l,3-dihydro-2H3-benzazepin-2-one and N-f2-(3,4-dimethoxy-phenyl) ethyl]-3-bromontethyl) -piperidine analogously to Example 3.
Yield: 8.6% of theory, Melting point: 199-201°C Calculated: C 64.73 H 6.64 N 5.59 Found: 64.77 6.55 5.57 Example 25 3-f(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-oiperidin2-yl) -ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride Prepared from 3-f(piperidin-2-yl)-ethyl-2]-7,8dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one and 2-(3,4-dimethoxy-phenyl)-ethylbromide analogously to Example 1.
Yield: 23.8% of theory, Melting point: 113-115°C Calculated: C.65.33 H 7.75 N 5.26 Found: 65.11 7.67 5.04 Example 26 3-f(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-hexahydroazepin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride 660 mg (2 mmol) of 3-f(hexahydro-azepin-3-yl)-methyl]- 65 7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one and 540 mg (2.2 mmol) of 2-(3,4-dimethoxyphenyl)ethylbromide are refluxed for 1 hour in 3 ml of triethylamine. The reaction mixture is cooled and taken up in methylene chloride and 2-molar sodium hydroxide solution. The alkaline phase is separated off and extracted twice with methylene chloride. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo. Purification is carried out by column chromatography over 100 g of aluminium oxide (activity II, eluant: methylene chloride + 0.3% ethanol).
The fractions obtained are concentrated by evaporation in vacuo, the residue is dissolved in acetone and the hydrochloride is precipitated using ethereal hydrochloric acid.
Yield: 600 mg (56.3% of theory), Melting point: 164-165°C Calculated: C 65.33 H 7.75 N 5.25 Found: 65.12 7.59 5.22 Example 27 3-f(N-(3-(4-Amino-3,5-dibromo-phenoxy)-propyl)hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one-dihydrochlor ide Prepared from 1.2 g (3.6 mmol) of 3-f(hexahydro-azepin-3-yl) methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one and 1.36 g (3.96 mmol) of 3-(4-amino-3,5-dibromophenoxy)-propyl chloride in 5 ml triethylamine analogously to Example 26.
Yield: 350 mg (13.7% of theory), Melting point: 134-136°C Calculated: C 47.22 H 5.52 Br 22.42 N 5.36 Found: 47.40 5.86 22.22 5.49 -66Example 28 3-[(N-(2-(3 ,4-Pimethoxy-phenyl)-ethyl)-hexahydroazepin-2-yl)-ethyl-2]-7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one Prepared from 3.6 g (9.4 mmol) of 2-(2-bromoethyl)1—[2-(3,4-dimethoxy-phenyl)-ethyl]-hexahydro-azepine and 2.06 g (9.4 mmol) of 7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one analogously to Example 3.
Yield: 1.3 g (27.2% of theory), Oil, IR spectrum (methylene chloride): 1655 cm~^ (CO) Calculated: C 70.83 H 7.93 N 5.51 Found: 70.56 7.80 5.27 Example 29 3-[(N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-hexahydroazepin-2-yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one 1.2 g (2.36 mol) of 3-[N-(2-(3,4-dimethoxy-phenyl)ethyl)-hexahydro-azepin-2-yl)-ethyl-2]-7,8-dimethoxyl,3-dihydro-2H-3-benzazepin-2-one are hydrogenated in 80 ml of glacial acetic acid for 4 hours at 45°C and under 5 bar in the presence of 1 g of 10% palladium/activated charcoal (10%). The catalyst is removed by suction filtering, the filtrate is concentrated by evaporation in vacuo, the residue is dissolved in 100 ml of methylene chloride and extracted once with 50 ml of 2N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. Purification is carried out by column chromatography over 100 g of aluminium oxide (neutral, eluant: methylene chloride + 1% ethanol).
Yield: 200 mg (17% of theory), -67Calculated: C 70.56 H 8.29 N 5.49 Found: 70.60 8.34 5.37 IR spectrum (methylene chloride): 1650 cm (CO) Example 30 3-f(N-(2-(3,4-Methylenedioxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-methylened ioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride Prepared from 3-f(piperidin-3-yl)-methyl]-7,8-methylenedioxy-l ,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(3,4-methylenedioxy-phenyl)-ethylbromide analogously to Example 1.
Yield: 85.7% of theory, Melting point: 234-235eC Calculated: C 66.73 H 6.03 N 5.99 Found: 66.58 6.31 5.94 Example 31 3-f(N-(3,4-dichloro-benzyl)-piperidin-3-yl)-methyl]7,8-methylenedioxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one-hydrochloride Prepared from 3-f(piperidiny1-3-yl)-methyl]-7,8methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one and 3,4-dichloro-benzyl chloride analogously to Example 1.
Yield: 80% of theory, Melting point: 240-242°C Calculated: C 57.90 H 5.47 N 5.63 Found: 57.77 5.35 5.46 -68Example 32 3-[(N—(2-(3,4-Dimethoxy-phenyl)-ethyl)-pyrrolidin-* 3-yl)-methyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin2-one 0.79 g (3.6 mmol) of 7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one are suspended in 30 ml of absolute dimethylsulphoxide and 160 ml (3.6 mmol) of 55% sodium hydride dispersion in oil are added. After stirring for 2 hours at ambient temperature and for half an hour at 40°C 1.3 g (3 mmol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-tosyloxy-methy1pyrrolidine are added and the resulting mixture is heated for 3 hours to 50 to 55°C. After cooling, the reaction mixture is then dissolved in ethyl acetate and extracted several times with water and then twice with 25% acetic acid. The acid extract obtained is made alkaline with 6 molar sodium hydroxide solution and extracted twice with methylene chloride. After the organic phase has been dried the solvent is eliminated in vacuo and the residue obtained is purified over 100 g of aluminium oxide (neutral, activity II) with methylene chloride and then with increasing amounts of ethanol (up to 2%).
Yield: 270 mg (19.3% of theory), IR spectrum (methylene chloride) : 1655 cni"^ (CO) Calculated: C 69.50 H 7.35 N 6.00 Found: 69.37 7.38 6.12 - 69 Example 33 3-((N-(2 - (3,4-Dimethoxy-phenyl)-ethyl)-pyr rol id in3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one Prepared from 3-((N-(2-(3,4-dimethoxy-phenyl)-ethyl) pyrrolidin-3-yl)-methyl]-7,8-dimethoxy-l,3-dihydro2H-3-benzazepin-2-one analogously to Example 29. Yield: 21.7% of theory, IR spectrum (methylene chloride): 1650 cm"^ (CO) Calculated: C 69.29 H 7.75 N 5.98 Found: 69.20 7.84 5.92 Example 34 3-((N-(3-(3-Methoxy-phenoxy)-propyl)-piperidin3-yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one Prepared from 3-((piperidin-3-yl)-methyl]-7,8-methylenedioxy-l ,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3-(3-methoxy-phenoxy)-propyl chloride analogously to Example 1.
Yield: 42% of theory, Melting point: 135-138°C Calculated: C 64.46 H 7.01 N 5.57 Found: 64.46 7.02 5.57 Example 35 3-((N—(3-(3-Methyl-phenoxy)-propyl)-piperidin-3yl)-methyl]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochlor ide Prepared from 3-((piperidin-3-yl)-methyl]-7,8-methylenedioxy-l ,3,4,5-tetrahydro-2H-3-benzazepin-2-one -70Example 38 3- [(Ν-(4-(4-Methoxy-phenyl)-butyl)-piper id in-3- * yl)-methylJ-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 4-(4-methoxy-phenyl)-butyl bromide analogously to Example 1.
Yield: 42% of theory, Melting point: 158-163°C Calculated: C 67.12 H 7.44 N 5.59 Found: 66.98 7.27 5.51 Example 39 3-[(N-(2-(4-Methoxy-phenyl)-ethyl)-piperidin-3yl) -methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(4-methoxy-phenyl)-ethylchloride in dimethylformamide/potassium carbonate at 120°C analogously to Example 1.
Yield: 55.6% of theory, Melting point: 226-228°C Calculated: C 66.02 H 7.03 N 5.92 Found: 66.18 7.03 5.87 -72methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin2- one and 4-methoxy-benzylbromide analogously to Example 1.
Yield: 52% of theory, Melting point: 148-152°C Calculated: C 66.02 H 7.03 N 5.92 Found: 65.90 7.10 5.98 Example 43 3- ((N-(3,4-Dimethoxy-phenyl)-methyl)-piperidin2-yl)-ethyl-2]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrobromide Prepared from 3-((piperidin-2-yl)-ethy1-2]-7,8methylenedioxy-l ,3,4,5-tetrahydro-2H-3-benzazepin2- one and 3,4-dimethoxy-benzylbromide analogously to Example 1.
Yield: 27% of theory, Melting point: 138-140°C Calculated: C 59.23 H 6.42 N 5.11 Found: 59.40 6.49 5.23 Example 44 3- ((N-(2-(4-Nitro-phenyl)-ethyl)-piper idin-2-yl)ethy1-2]-7,8-methylenedioxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one-hydrochloride Prepared from 3-((piperidin-2-yl)-ethyl-2]-7,8methylenedioxy-l, 3,4,5-tetrahydro-2H-3-benzazepin2-one and 2-(4-nitro-phenyl)-ethylbromide analogously to Example 1.
Yield: 22% of theory, Melting point: 130-132°C Calculated: C 62.20 H 6.43 N 8.37 Found: 62.16 6.57 8.32 -74Example 45 3-[(Ν-(2-(3-Tr ifluoromethylphenyl)-ethyl)-piper idin— 3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazejginy 2-one-hydrochlor ide Prepared from 3-((piperidin-3-yl)-methyl]-7,3-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(3-trifluoromethyl-phenyl)-ethylbromide analogously to Example 1.
Yield: 32% of theory, Melting point: from 150°C (decomp.) Calculated: C 61.53 H 6.50 N 5.32 Found: 61.70 6.42 5.27 Rf value: 0.36 (silica gel, methylene chloride/methanol = 10/1) Example 46 3- [ (N- (3,y (3,5-Dimethoxy-phenoxy) yjp ropy 1.) -_piper idin 3-yl)-ethyl]-7,8-methylenedioxy-1,3,4,5ytetrahydrof 2H-3-benzazepin-2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-methylenedioxy-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3-(3,5-dimethoxy-phenoxy)-propylchloride analogously to Example 1.
Yield: 46.4% of theory, Melting point: 102-107°C Calculated: C 63.09 H 7.00 N 5.25 Found: 62.96 6.86 5.50 - 75 Example 47 3-((N-(2-PhenyT-ethyT)-piperidin-2-yl)-ethyl-2]7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- one-hydrochlor ide Prepared from 3-((piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-phenyl-ethylbromide analogously to Example 1.
Yield: 37% of theory, Melting point: 130-132°C Calculated: C 68.55 H 7.88 N 5.92 Found: 68.42 7.97 5.75 Example 48 3- ((N-(3-(4-Methoxy-phenyl)-propyl)-piperidin-2yl)-ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H3-benzazepin-2-one-hydrochloride Prepared from 3-((piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 3-(4-methoxyphenyl)propylbromide analogously to Example 1.
Yield: 43% of theory, Melting point: 109-112°C Calculated: C 67.36 H 7.99 N 5.42 Found: 67.19 7.88 5.38 Example 49 3-((N-(2-(3-Methyl-phenyl)-ethyl)-piperidin-2-yl) ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-one-hydrochloride Prepared from 3-((piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-(3-methylphenyl)ethylbromide analogously to Example 1. -76Yield: 31% of theory, Melting point: 124-126°C Calculated: C 69.04 H 8.07 N 5.75 Found: 68.91 7.69 5.72 Example 50 3-f(N-(2-(4-Methoxy-phenyl)-ethyl)-piperidin-2yl)-ethy1-2]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H3-benzazepin-2-one-hydrochloride Prepared from 3-[(piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-(4-methoxyphenyl)ethylbromide analogously to Example 1.
Yield: 48% of theory, Melting point: 112-114eC Calculated: C 66.85 H 7.81 N 5.57 Found: 66.69 7.86 5.65 Example 51 3-f(N-(2-(4-Nitro-phenyl)-ethyl)-piperidin-2-yl)ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-one-hydrochloride Prepared from 3-f(piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-(4-nitrophenyl)ethylbromide analogously to Example 1.
Yield: 8% of theory, Melting point: 126-128°C Calculated: C 62.59 H 7.00 N 8.11 Found: 62.56 6.91 8.16 - 77 Example 52 3-[ (N- (2- (4-Methyl-phenyl) -ethyl)-piperidin-2-yl)- ethyl-2]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-one-hydcochlor ide Prepared from 3-[(piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-(4-methylphenyl)ethyl-bromide analogously to Example 1.
Yield: 23% of theory, Melting point: 109-lll°C Calculated: C 69.04 H 8.07.· N 5.75 Found: 68.84 7.90 6.03 Example 53 3-[(N-(2-(3-Methoxy-phenyl)-ethyl)-piperidin-2yl)-ethyl-2 ]-7,8-d imethoxy-1,3,4,5-tetrahydro-2H3-benzazepin-2-one-hydrochlor ide Prepared from 3-((piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-(3-methoxyphenyl)ethyl-bromide analogously to Example 1.
Yield: 25% of theory, Melting point: 125-127°C Calculated: C 66.85 H 7.81 N 5.57 Found: 65.68 7.67 5.20 Example 54 3-[(N-(2-(3,4,5-Trimethoxy-phenyl)-ethyl)-piper idin2-yl)-ethyl-2 ]-7,8-dimethoxy-l,3,4,5-tetrahydrΟΣΗ- 3-benzazepin-2-one-hydrochloride Prepared from 3-[(piperidin-2-yl)-ethyl-2]-7,8dimethoxy-2H-3-benzazepin-2-one and 2-(3,4,5-trimethoxyphenyl) -ethylbromide analogously to Example 1. -78Yield: 15% of theory, Melting point: 138-140°C Calculated: C 63.98 H 7.70 N 4.97 Found: 63.74 7.55 4.65 Example 55 3-[(N-(2-(3-Methoxy-4-methanesulphonyloxy-phenyl)ethyl)-piper idin-3-yl)-methyl 3 — 7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one-hydrochlor ide Prepared from 3-[(N-(2-(3-methoxy-4-hydroxy-phenyl)ethyl)-piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one-hydrochlor ide and methanesulphonic acid chloride analogously to Example 9.
Yield: 66% of theory, Melting point: 202-204°C Calculated: C 57.67 H 6.74 N 4.80 S 5.50 Found: 57.72 6.91 4.87 6.31 Example 56 3-[(N-(2-(3-Methoxy-4-hydroxy-phenyl)-ethyl)-piperidin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one a) 3-[(N-(2-(4-Benzyloxy-3-methoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one Prepared from 3-((piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(4-benzyloxy-3-methoxy-phenyl)-ethylbromide analogously to Example 1.
Yield: 56% of theory, Melting point: 216-217°C - 79 Calculated: C 68.61 H 7.28 N 4.71 Found: 68.80 7.38 4.73 b) 3-[(N-(2-(3-Methoxy-4-hydroxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one Prepared from 3-[(N-(2-(4-benzyloxy-3-methoxy-phenyl)ethyl)-piper idin-3-yl)-methyl]-7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-one in glacial acetic acid analogously to Example 8.
Yield: 77% of theory, Melting point: 173-175°C Calculated: C 69.21 H 7.74 N 5.98 Found: 69.07 7.79 6.06 Example 57 3-[N-(2-(2-Fluorophenyl)-ethyl)-piper idin-3-yl)methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2-one-dihydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxyl,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(2—fluorophenyl)-ethylbromide analogously to Example 1. Yield: 49% of theory, Melting point: from 210°C Calculated: C 60.82 H 6.87 N 5.46 Found: 60.88 6.73 5.60 Rf value: 0.33 (silica gel, methylene chloride/methanol = 10/1) -80Example 58 3-(N-(2-(4-Fluorophenyl)-ethyl)-piperidin-3-yl)methyl]-7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one-hydrochlor ide Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxyl,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2(4-fluorophenyl)-ethylbromide analogously to Example 1. Yield: 56% of theory, Melting point: 245°C (decomp.) Calculated: C 65.47 H 7.18 -N 5.87 Found: 65.78 7.25 5.99 Rg value: 0.31 (silica gel, methylene chloride/methanol = 10/1) - 81 Example I Tablets containing 7.5 mq of 3-[(N-(2-(3,4-dimethoxyphenyl) -ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one Composition: tablet contains: Active substance 7.5 mg Corn starch 59.5 mg Lactose 48.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg 120.0 mg Method of preparation The active substance, corn starch, lactose and polyvinylpyrrolidone were mixed together and moistened with water. The moist mixture is pushed through a screen with a mesh size of 1.5 mm and dried at about 45°C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The final mixture is compressed in a tablet press with dies 7 mm in diameter provided with a dividing notch to form tablets.
Weight of tablet: 120 mg.
Example II Coated tablets containing 5 mg of 3-[(N-(2-(3,430 dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one tablet core contains: Active substance 5.0 mg 35 Corn starch 41.5 mg Lactose 30.0 mg Polyvinylpyrrolidone 3.0 mg -82Magnesium stearate 0.5 mg 80.0 mg Method of Preparation The active substance, corn starch, lactose and polyvinylpyrrolidone are throughly mixed and moistened with water. The moist mass is forced through a 1 nun screen, dried at about 45°C and then the granulate is passed through the same screen. After magnesium stearate has been added, convex tablet cores with a diameter of 6 mm are compressed in a tablet making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax.
Weight of coated tablet: 130 mg.
Example III Ampoules containing 5 mg of 3-f (N-(2-(3,4-dimethoxyphenyl) -ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one ampoule contains: Active substance 5.0 mg Sorbitol 50.0 mg Water for injections ad. 2.0 ml Method of Preparation In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol.
After being filtered through a diaphragm filter the solution is transferred under a current of N2 into purified and sterilized ampoules and autoclaved for 20 minutes in_a jet of steam. - 83 cellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The mixture is cooled to ambient temperature and the glycerol and sorbitol . solution are added with stirring. At ambient temperature the active substance is added and stirred until completely dissolved. The syrup is then evacuated of any air with stirring.

Claims (18)

1. New cyclic amine derivatives of general formula wherein A represents a -C^-C^-, -CH=CH-, -C^-CO- or -NH-CO- group and x x B represents a methylene, carbonyl or thiocarbonyl group or OH ι A represents a -CO-CO- or -CH-CO- group and B represents V a methylene group, whilst tne atom marked x is linked to the phenyl nucleus, E represents a straight-chained alkylene group with 1 to 3 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, G represents a straight-chained alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, whilst a methylene group, adjacent to a phenyl nucleus, of a straight-chained alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group may be replaced by an oxygen or sulphur atom or by an imino, methylimino, sulphinyl or sulphonyl group, -86represents a hydrogen or halogen atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, R 2 represents a hydrogen or halogen atom, a hydroxy, alkoxy, phenylalkoxy or alkyl group, whilst each alkyl moiety may contain from 1 to 3 carbon atoms, or Rj and R
2. Together represent an alkylenedioxy group with 1 or 2 carbon atoms, R^ represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to
3. Carbon atoms in the alkyl moiety, or a hydroxy, nitro, cyano or trifluoromethyl group, R 4 represents a hydrogen atom, an alkoxy, alkanesulphonyloxy, amino, alkylamino or dialkylamino group with 1 to 3 carbon atoms in each alkyl moiety or an alkanoylamino group with 2 or 3 carbon atoms in the alkanoyl moiety or R^ and R^ together represent an alkylenedioxy group with 1 or 2 carbon atoms, Rg represents a hydrogen or halogen atom, a hydroxy, alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl moiety, m represents the number 1, 2, 3,
4. Or 5 and n represents the number 0, 1 or 2, but n + m must represent the number 3, 4 or 5, the enantiomers, diastereomers and acid addition salts thereof. - 87 2. New cyclic amine derivatives of general formula I as claimed in claim 1, wherein A, B, ra and n are defined as hereinbefore but m + π must represent the number 3, 4 or 5, E represents a methylene or ethylene group, G represents an n-alkylene group with 1 to 4 carbon atoms, .whilst a. methylene group of an n-propylene or n-butylene group adjacent to a phenyl nucleus may be replaced by an oxygen or sulphur atom or an imino, methylimino, sulphinyl or sulphonyl group, R^ represents a hydrogen, fluorine, chlorine or bromine atom, or a hydroxy, methoxy, trifluoromethyl, methylamino or dimethylamino group, R 2 represents a hydrogen, chlorine or bromine atom or a methoxy group or R^ and R 2 together represent a methylenedioxy group, Rg represents a hydrogen, fluorine, chlorine or bromine'atom or a methyl, hydroxy, methoxy or nitro group, R 4 represents a hydrogen atom or a methoxy, methanesulphonyloxy, amino or acetylamino group or Rg and R^ together represent a methylenedioxy group and Rg represents a hydrogen, chlorine or bromine atom or a methoxy group, and the enantiomers, diastereomers and acid addition salts thereof. -883. New cyclic amine derivatives of general formula I as claimed in claim 1, wherein m and n are defined as in claim 1 but m + n must represent the number 3, 4 or 5, A represents a- CH 2 CH 2 or -CH=CH- group and B represents a methylene or carbonyl group or A represents a- CO-CO- group and B represents a methylene group, E represents a methylene or ethylene group, G represents an n-alkylene group with 2 to 4 carbon atoms, whilst a methylene group of an n-propylene or n-butylene group adjacent to a phenyl nucleus may be replaced by an oxygen atom, represents a hydrogen atom or a methoxy group, R 2 represents a hydrogen atom or a methoxy group or R^ and R 2 together represent a methylenedioxy group, R 2 represents a hydrogen atom or a methyl, hydroxy or methoxy group, R^ represents a hydrogen atom or a methoxy group or Rg and R^ together represent a methylenedioxy group and R5 represents a hydrogen atom, and the enantiomers, diastereomers and acid addition salts thereof. -894. 3-( (Ν-(2-(3,4-Dimethoxy-phenyl)-ethy1)-piper idin3-yl)-methyl]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one, the enantiomers and the acid addition salts thereof.
5. 3-((N-(2-(3,4-Dimethoxy-phenyl)-ethyl)-piperidin2-yl)-ethy1-2]-7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-one, the enantiomers and the acid addition salts thereof.
6. Physiologically acceptable acid addition salts of the compounds as claimed in claims 1 to 5 with inorganic or organic acids.
7. Pharmaceutical compositions containing a compound of general formula I as claimed in claims 1 to 5 or a physiologically acceptable acid addition salt thereof as claimed in claim 6 together with one or more inert carriers and/or· diluents.
8. Pharmaceutical compositions as claimed in claim 7 suitable for the treatment of sinus tachycardia and ischaemic heart disease.
9. Process for preparing a pharmaceutical composition as claimed in claims 7 and 8, wherein a compound as claimed in claims 1 to 5 or a physiologically acceptable acid addition salt thereof as claimed in claim 6 is incorporated in one or more inert carriers and/or diluents by a non-chemical method .
10. Process for preparing new cyclic amine derivatives as claimed in claims 1 to 6, wherein a) a compound of general formula -90(II) wherein A, Β, E, m and n are defined as in claims 1 to 5, R-^' represents a hydroxy, amino or alkylamino group protected by a protecting group or has the meanings given for in claims 1 to 5 and Rg' represents a hydroxy group protected by a protecting group or has the meanings given for Rg in claims 1 to 5, is reacted with a compound of general formula V (III) wherein Rg’, ’ and Rg’ have the meanings given for Rg, R 4 and Rg in claims 1 to 5 but the hydroxy, amino or alkylamino groups contained in the groups Rg to Rg may be protected by a protecting group, and U represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, and optionally any protecting group used is subsequently split off, or - 91 b) in order to prepare compounds of general formula I wherein G has the meanings given for G in claims 1 to 5, with the exception of the groups containing a sulphenyl, sulphinyl or sulphonyl group, A represents a -CH 2 ~CH^ group, B represents a methylene or carbonyl group and m + n represent the number 4, a compound of general formula (IV) where in R^ to Rg and E are defined as in claims 1 to 5, G' has the meanings given for G in claims 1 to 5 with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group, A’ represents a- CH=CH- or -CH 2 CH^ group and B’ represents a methylene or carbonyl group, is hydrogenated in a solvent or mixture of solvents, or c) in order to prepare compounds of general formula I wherein B represents a carbonyl or methylene group, a compound of general formula R * (V) -92where in A is defined as in claims 1 to 5, ' represents a hydroxy, amino or alkylamino group protected by a protecting group or has the meanings, given for R^ in claims 1 to 5, Rg’ represents a hydroxy group protected by a protecting group or has the meanings given for Rg in claims 1 to 5, and B’ represents a carbonyl or methylene group, is reacted with a compound of general formula V - E - CH (VI) wherein E, G, m and n are defined as in claims 1 to 5, Rg’, R 4 ’ and Rg' have the meanings given for Rg, R 4 and Rg in claims 1 to 5, but the hydroxy, amino or alkylamino groups contained in the groups Rg to Rg may be protected by a protecting group, and V represents a nucleophilically exchangeable group such as a halogen atom or a sulphonyloxy group, and optionally any protecting group used is subsequently split off, or d) in order to prepare compounds of general formula I wherein A represents a -CHg-CHg or -CH=CH- group and B represents a thiocarbonyl group, a compound of general formula CH N \ch 2 )/ wherein Rj to Rg, E, G, m and n are defined as in claims 1 to 5 and A’ represents a -CHj-CH^ or -CH=CH- group, is reacted with a sulphurising agent, or e) in order to prepare compounds of general formula OH t I wherein A represents a -CH-CO- group and B represents a methylene group, a compound of general formula rr CH N \c h 2)/ (VIII) wherein to Rg, E, G, m and n are defined as in claims 1 to 5, is reduced in a suitable solvent, or f) in order to prepare compounds of general formula I wherein A represents a -CH 2 -CH 2 - or -CH=CH- group and B represents a methylene group, -94a compound of general formula wherein Rj to Rg, E, G, m and n are defined as in claims 1 to 5 and A’ represents a -CHj-CI^ - or -CH=CHgroup, is reduced in a suitable solvent, or g) in order to prepare compounds of general formula I wherein A represents a -COCO- group, a compound of general formula wherein Rj to Rg, E, G, m and n are defined as in claims 1 to 5, is oxidised in a suitable solvent or mixture of solvents, or h) in order to prepare compounds of general formula I wherein G has the meanings given for G in claims 1 to 5 with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group, 25 A represents a -CI^-CHj- group and B represents a methylene or carbonyl group, - 95 a compound of general formula wherein R^ to R^, E, m and n are defined as in claims 1 to 5 , G’ has the meanings given for G in claims 1 to 5, with the exception of the radicals containing a sulphur atom or a sulphinyl or sulphonyl group and B' represents a methylene or carbonyl group, is hydrogenated in a solvent or mixture of solvents and subsequently, if desired, a compound of general formula I thus obtained wherein and/or Rg represents a nitro group is converted by reduction into a corresponding amino compound of general formula I, or a compound of general formula I thus obtained wherein R 4 represents a hydroxy or amino group is converted by acylation into a corresponding alkanesulphonyloxy or alkanoylamino compound of general formula I, or a compound of general formula I thus obtained which contains at least one chiral centre is resolved into its diastereomers or into its enantiomers and/or -96a compound of general formula I thus obtained is converted into the acid addition salts thereof, particularly its physiologically acceptable acid addition salts with inorganic or organic acids.
11. Process as claimed in claim 10, wherein the reaction is carried out in a solvent.
12. Process as claimed in claims 10a or 10c, wherein the reaction is carried out in a solvent and in the presence of an acid-binding agent.
13. New cyclic amine deri vati ves as defined in claim 1 or the physiologically acceptable acid addition salts thereof substantially as hereinbefore described with reference to any of Examples A to U or 1 to 58.
14. Pharmaceutical compositions as claimed in-claim 7 or the physiologically acceptable salts thereof substantially as hereinbefore described with reference to any of Examples I to V.
15. A process fdr preparing a pharmaceutical composition as claimed in claim 9 substantially as hereinbefore described with reference to any of'Examples I to V.
16. A pharmaceutical composition whenever prepared by a process as claimed in claim 9 or claim 15.
17. A process for preparing new cyclic amine derivatives as claimed in claim 10 or the physiologically acceptable acid addition salts thereof substantially as hereinbefore described with reference to any of Examples A to U or 1 to 58.
18. A cyclic amine derivative whenever prepared by a process as claimed in claim 10 or claim 17.
IE311086A 1985-11-27 1986-11-26 New cyclic amine derivatives, pharmaceutical compositions containing these compounds and processes for preparing them IE59487B1 (en)

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CA1298427C (en) * 1987-03-13 1992-03-31 Johannes Adrianus Maria Van Broekhoven Process for removing palladium catalyst remnants from copolymers of carbon monoxide with one or more olefinically unsaturated compounds
FI95572C (en) * 1987-06-22 1996-02-26 Eisai Co Ltd Process for the preparation of a medicament useful as a piperidine derivative or its pharmaceutical salt
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US20040138306A1 (en) 2002-07-25 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of a specific cyclic amine derivative or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure
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IE863110L (en) 1987-05-27
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