IE881559L - Cyclic amine derivatives - Google Patents

Cyclic amine derivatives

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Publication number
IE881559L
IE881559L IE881559A IE155988A IE881559L IE 881559 L IE881559 L IE 881559L IE 881559 A IE881559 A IE 881559A IE 155988 A IE155988 A IE 155988A IE 881559 L IE881559 L IE 881559L
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Ireland
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methyl
oxo
tetrahydro
dimethoxy
piperid
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IE881559A
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IE68842B1 (en
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Joachim Dr Heider
Manfred Dr Psiorz
Andreas Dr Bomhard
Norbert Dr Hauel
Berthold Dr Narr
Klaus Dr Noll
Jurgen Dr Dammgen
Christian Dr Little
Walter Prof Dr Kobinger
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Express Foods Group Ltd
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Publication of IE881559L publication Critical patent/IE881559L/en
Publication of IE68842B1 publication Critical patent/IE68842B1/en

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    • 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
    • A61P9/12—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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (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)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Gears, Cams (AREA)
  • Valve-Gear Or Valve Arrangements (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cyclic amine derivatives of the formula <IMAGE> in which A, B, E, G, R, R1, R2, m and n are as defined in Claim 1, their enantiomers, their diastereomers, their N-oxides and their acid addition salts have useful pharmacological properties, in particular a bradycardic action. The novel compounds can be prepared by processes known per se.

Description

36842 - 1 - New cyclic amine derivatives, pharmaceutical compositions containing these compounds and processes for their preparation British Patent 1 548 844 describes 3,4-dihydro-2-isoquinolin-l-ones and l,2,3,4-tetrahydro-5H-2-benzazepin-l-ones and EP-A-O,065,229 describes 2H-3-benzazepines. Thus, Example 82 of EP-A-0,065,229 describes the one compound in which E denotes a branched alkylene group, namely 1- [7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -2-methyl-3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino]propane. The abovementioned compounds and the physiologically acceptable acid addition salts thereof have valuable pharmacological properties, namely, not only a mild hypotensive activity but more particularly a selective heart rate lowering activity.
Surprisingly, it has now been found that the new cyclic amine derivatives of general formula /CHA CH H - G - R (I) X The present invention thus relates to the new cyclic amine derivatives of general formula (I) above, the enantiomers, diastereomers, N-oxides and acid addition 68842 - 2 - salts thereof, and more particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof with inorganic or organic acids, processes for their preparation and pharmaceutical compositions 5 containing these compounds.
In general formula (I) above: A represents a or -CH=CH- group, 10 y B represents a -CH^-, -CH2-CH2-, -CO- or -CH2CO group, whilst the carbon atom marked x is linked to the phenyl nucleus, 15 E represents a straight-chained C^-alkylene group, G represents a straight-chained Ci-g-alkylene group, wherein a methylene group, linked to an aromatic or heteroaromatic group R, of a straight-chained C3.6-20 alkylene group may be replaced by an oxygen atom, or by a methylimino or ethylimino group, m represents the number 1, 2, 3, 4, 5 or 6 and n represents the number 0, 1, 2 or 3, although 25 n + m must represent the number 3, 4, 5 or 6, represents a methyl or methoxy group, R2 represents a methyl or methoxy group or R^ and R2 30 together represent a methylenedioxy group and u i R represents an optionally methyl-substituted furyl, thienyl, pyridyl, benzo [b] furyl or benzo [b] thienyl group, a benzo [b] thienyl group substituted by a halogen 35 atom or by a methoxy or methanesulphonyloxy group, an indolyl or N-methyl-indolyl group optionally substituted by a hydroxy, methoxy or benzyloxy group, a dimethyl-thienyl or dimethoxy-isoquinolyl group, a r t t i - 3 - naphthyl group optionally mono- or disubstituted by methyl or methoxy groups, whilst the substituents may be identical or different, or, if B represents a -CH2~ or -CO- group, a phenyl group optionally substituted by a 5 methylenedioxy group, a phenyl group mono- or disubstituted by a chlorine or bromine atom or methyl or methoxy groups, whilst the substituents may be identical » or different, a phenyl group substituted by a hydroxy, benzyloxy, methanesulphonyloxy, trifluoro-* 10 methanesulphonyloxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetamido, methanesulphonylamino or bis (methanesulphonyl) amino group, or a trimethoxy-phenyl, tetramethylphenyl or dihaloaminophenyl group. 15 The following compounds which fall within the scope of protection of this invention but are not explicitly described in the Examples will now be mentioned by way of example: 20 2-[ (N-(2-(naphth-2-yl)-ethyl)-hexahydro-azepin-3-yl) -methyl] -6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (naphth-2-yl) -ethyl) -azacyclooct-3-yl) -25 methyl] -6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline, 2 - [ (N- (2- (naphth-l-yl) -ethyl) -hexahydro-azepin-* 3 -yl) -methyl] - 6,7-dimethoxy-1 -oxo-1,2,3,4-tetrahydro- isoquinoline, % 30 2- [ (N- (2- (naphth-l-yl) -ethyl) -azacyclooct-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 35 2-[ (N-(2-methyl-naphth-l-yl)-methyl)-pyrrolid-3- yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, { 4 \ » - 4 - 2- [3- (N- (2-methyl-naphth-l-yl) -methyl) -piperid- 3-yl) -propyl] -6, 7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-i soquinol ine, 5 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) - pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline, 2-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl)-10 azacyclooct-3-yl)-methyl]-6#7-dimethoxy-l-oxo-l/2/3/4-tetrahydro-isoquinoline, 2-[(N-(2-(6-methoxy-naphth-2-yl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-15 tetrahydro-isoquinol ine, 2-[(N-(2-(6-methoxy-naphth-2-yl)-ethyl)-azacyclooct- 3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 20 2- [3- (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -pyrid- 3-yl) -propyl] - 6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, 25 2-[(N-(4-(naphthyl-2-oxy)-butyl)-azacyclooct-3-yl)-methyl]-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline, / 2- [2-(N-(4-(naphthy1-2-oxy)-butyl)-piperid-2-yl)-30 ethyl]-S^-dimethoxy-l-oxo-l^.S^-tetreJiydro- J isoquinoline, k 2-[(N-(3-(naphthyl-2-oxy)-propyl)-azacyclooct-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-35 isoquinoline, 2- [ (N- (3- (naphth-2-yl) -propyl) -piperid-3-yl) -methyl] -6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline, - 5 - 2- [ (N- (3- (naphth-2-yl) -propyl) -azacyclooct-3-yl) -methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoguinoline, 5 2 - [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] -6, 7-methylenedioxy-1, 2,3,4-tetrahydro-isoquinoline, 2- [ (N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl) -methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-1 q isoquinoline, 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -pyrrolid-3- yl) -methyl] -6,7 -methylenedioxy- 1-oxo-1,2,3,4-tetrahydro- isoquinoline, 15 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -piperid-3- yl) -methyl] - 6, 7 -methylenedioxy-1,2,3,4-tetrahydro-isoquinoline, 20 2- t (N- (2-methyl-naphth-l-yl) -methyl) -azacyclooct- 3-yl) -methyl] -6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -25 azacyclooct-3-yl) -methyl] -6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline, 2- [2- (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -piperid-3-yl) -methyl]-6,7-methylenedioxy-1-oxo-30 1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid- 3-yl) -methyl] -6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline, 35 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -pyrrolid-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l, 2,3,4 - tetrahydro -isoquinoline, - 6 - 2- t (N- (4- (naphthyl-2-oxy) -butyl) -piperid-3-yl) -methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 5 2-f (N- (4- (naphthyl-2-oxy) -butyl) - hexahydr o - a z ep in - 3-yl)-methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-i soquinoline, 2- [ (N- (2- (naphth-2-yl) -ethyl) -pyrrolid-3-yl) -methyl] -10 6,7-dimethyl-1-oxo-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] -6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline, 15 2-[(N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl)-methyl]-6,7-dimethyl-1-oxo-l,2,3,4-tetrahydro-isoquinoline, 2-[(N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl)-20 methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (naphth-l-yl) -ethyl) -pyrrolid-3-yl) -methyl] -6,7-dimethyl-l# 2,3,4-tetrahydro-isoquinoline, 25 2- [ (N- (2- (naphth-l-yl) -ethyl) -hexahydro-azepin- 3-yl)-methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [3- (N- (2- (naphth-l-yl) -ethyl) ^-piperid-3-yl) -propyl] -30 6,7-dimethyl-1-oxo-l, 2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -piperid-3-yl)-methyl]-6,7-dimethyl-1-oxo-l,2,3,4-tetrahydro-isoquinoline , 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -piperid-3-yl)-methyl]-6,7-dimethyl-1,2,3,4-tetrahydro- » isoquinoline. - 7 - 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -azacyclooct- 3-yl) -methyl] -6, 7-dimethyl-l-oxo-l, 2,3,4-tetrahydro-isoquinoline , 5 2- [2-(N- (2-methyl-naphth-l-yl)-methyl)-piperid- 2-yl)-ethyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline , 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -10 piperid-3-yl) -methyl] -6, 7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -hexahydro-azepin-3-yl) -methyl] -6,7-dimethyl-1-oxo-15 1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -azacyclooct-3-yl) -methyl] -6, 7-dimethyl-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, 20 2 - [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -azacyclooct-3-yl) -methyl] -6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 25 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -pyrrol id- 3-yl)-methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid-30 3-yl)-methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -hexahydro-azepin-3-yl) -methyl] -1,2,3,4-tetrahydro-isoquinoline, 35 2- [2- (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid-2-yl)-ethyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline, - 8 - 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -piperid-3-yl) -methyl] -6,7-dimethyl - 1-oxo-1,2,3,4-tetrahydro-isoquinoline, 5 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -hexahydro-azepin- 3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -azacyclooct-3-yl) -10 methyl] -6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (3- (6 -methoxy-naphthyl - 2 - oxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 15 2- [ (N- (3- (6-methoxy-naphthyl-2-oxy) -propyl) -azacyclooct- 3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline , 20 2- t (N- (3- (5, 6-dimethoxy-naphthyl-2-oxy) -propyl) - azacyclooct-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (3- (naphthyl) -propyl) -azacyclooct-3-yl) -methyl] -25 6,7 -dimethyl - 1-oxo-l ,2,3,4- tetrahydro-isoquinoline, 3- [ (N- (3- (pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl] -7,8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro-2H- 3-benzazepinei 30 3- [ (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] -7,8 -methylenedioxy-1,3,4,5-tetrahydro-2H- 3 -benzazepine, 3- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid-3-yl) -methyl] -35 7,8- dimethyl -1,3,4,5- tetrahydro- 2H- 3 -benzazepine, 2- [ (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] -6,7-dimethyl-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, - 9 - 2- [ (N- (3- (pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl] -5,6-methylenedioxy-1-oxo-l, 3-dihydro-isoindole, 2- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid-3-yl) -methyl] -5 5,6 -methylenedioxy-1,3 -dihydro-isoindole, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid- 3-yl) -methyl] -5,6-methylenedioxy-1-oxo-l,3-dihydro-isoindole, 10 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid- 3-yl) -methyl] -5,6-methylenedioxy-1,3-dihydro-isoindole, 2- [ (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] -15 5,6- dimethyl -1,3 -dihydro- isoindole, 3- [ (N- (3- (pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl] -7,8- dimethoxy-1,3,4,5- tetrahydro- 2H- 3 -benzazepine, 20 2- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid-3-yl) -methyl] -5,6 -dimethoxy-1,3 -dihydro- isoindole, 2- [ (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] -5,6-dimethoxy-1,3-dihydro-isoindole, 25 2- t (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] -5,6-dimethoxy-1-oxo-l, 3-dihydro-isoindole, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid-30 3-yl) -methyl] -6,7-dimethoxy-l, 2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid- 3-yl) -methyl] -5,6-dimethoxy-1,3-dihydro-isoindole, 35 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid- 3-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, - 10 - 2 - [ (N- (2 - (6-methyl -pyrid-2-yl) -ethyl) -pyrrolid- 3-yl) -methyl] -5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] -5 6, 7-dimethoxy-l, 2,3,4-tetrahydro-isoquinoline, 2- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, 10 3- [ (N- (2- (6,7-dimethoxy-isoquinol-4-yl) -ethyl) -piperid-2-yl) -methyl] -7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 2- [ (N- (1- (pyrid-4-yl) -methyl) -piperid-3-yl) -methyl] -15 6,7 -dimethyl -1,2,3,4- tetrahydro- isoquinoline, 2-[ (N-(2-(6, 7-dimethoxy-isoquinol-4-yl)-ethyl) -piperid-3-yl) -methyl] -5,6-methyl enedi oxy-1-oxo-1,3-dihydro-isoindole, 20 2- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] -5,6-methylenedioxy-1,3-dihydro-isoindole, 2- [ (N- (3- (pyrid-3-yl) -propyl) -hexahydro-azepin-25 3-yl) -methyl] -6,7-dimethyl-l-oxo-1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (3- (pyrid-3-yl) -propyl) -hexahydro-azepin- 3-yl) -methyl] -6,7-dimethyl-l, 2,3,4-tetrahydro-30 isoquinoline, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxy-1,3-dihydro-isoindole, 35 2 - [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxy-1 -oxo-1,3-dihydro-isoindole, t i - 11 - 3- [ (N- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 5 2- [ (N- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid- 3-yl)-methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline , iat 3- [ (N- (3- (5-methoxy-indol-3-yl) -propyl) -pyrrolid-10 3-yl)-methyl]-7,8-dimethyl-l,3,4,5-tetrahydro-2H-3-benzazepine, 2 - [ (N- (3 - (5 -methoxy- indol -3 -yl) -propyl) -pyrrolid-3-yl) -methyl] -5,6-methylenedioxy-1,3-dihydro-isoindole, 15 2- t (N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid- 3-yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline, 20 2- [ (N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid-3-yl)-methyl]-5,6-methylenedioxy-l-oxo-l,3-dihydro-isoindole, 3-[(N-(3-(N-methyl-indol-3-yl)-propyl)-pyrrolid-25 3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepine, 2-[ (N-(3-(N-methyl-indol-3-yl)-propyl)-pyrrolid- 3-yl)-methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-30 isoquinoline, 2- [ (N- (3- (indol-3-yl) -propyl) -pyrrolid-3-yl) -methyl] -5,6-dimethyl-1,3-dihydro-isoindole, 35 3- [ (N- (3- (indol-3-yl) -propyl) -pyrrolid-3-yl) -methyl] - 7,8-dimethoxy-2-oxo-1,3,4,5 - tetrahydro-2H-3-benzazepine, 2- [ (N- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid- I - 12 - 3-yl)-methyl]-5,6-dimethyl-1-oxo-l,3-dihydro-isoindole, 2-[(N-(3-(5-hydroxy-indol-3-yl)-propyl)-pyrrolid- 3-yl)-methyl]-6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-5 isoquinoline, 3- [ (N- (3- (5-methoxy-indol-3-yl) -propyl) -pyrrolid-3-yl) -methyl] -7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine, 10 2- [ (N- (3- (5-methoxy-indol-3-yl) -propyl) -pyrrolid- 3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2- [ (N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid-15 3-yl) -methyl] -6,7-dimethoxy-l,2,3,4-tetrahydro-isoindole, 2- [ (N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid- 3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-20 isoquinoline, 2-[ (N-(3- (N-methyl-indol-3-yl)-propyl)-pyrrolid- 3-yl)-methyl]-5,6-dimethyl-1-oxo-l,3-dihydro-isoindole, 25 2- [ (N- (3- (N-methyl-indol-3-yl) -propyl) - pyrrol id-3-yl) -methyl] -5,6-dimethoxy-1,3-dihydro-isoindole, 2- [ (N- (2- (3,4 -dimethoxy-phenyl) -ethyl) - hexahydro-azepin-3-yl) -methyl] -6,7-methylenedio^-l-oxo-l, 2,3,4-30 tetrahydro-isoquinoline, 2- [ (N-(3- (3,4 -methylenedioxy-phenoxy) -propyl) - hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, 35 2-[ (N-(2-(4-trifluoromethoxy-phenyl)-ethyl)-piperid- 3-yl) -methyl] -5# 6-dimethoxy-l-oxo-l, 3-dihydro-isoindole, - 13 - * 2-[(N-(2-(4-trifluoromethyl-phenyl)-ethyl)-piperid- 3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[ (N-(2-(3,4-dichloro-phenyl)-ethyl)-piperid-3-5 yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole,. 2-[(N-(2-(3,4,5-1 rimethoxy-phenyl)-ethyl)-piperid- 3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 10 2-[(N-(2-(4-methoxy-phenyl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(3-methyl-phenyl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 15 2-[(N-(2-(3,4-dimethyl-phenyl)-ethyl)-piperid-3-yl) -methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(2,3,4,5-tetramethyl-phenyl)-ethyl)-piperid-20 3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(4-benzyloxy-phenyl)-ethyl)-piperid-3- yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 25 2-[(N-(2-(4-hydroxy-phenyl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[ (N-(2-(4-methanesulphonyloxy-phenyl)-ethyl)-piperid-3-yl) -methyl] -5,6-dimethoxy-l-oxo-l,3-dihydro-30 isoindole, 2-[(N-(2-(4-trifluoromethanesulphonyloxy-phenyl)-ethyl) -piperid-3-yl) -methyl] -5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole, 35 2-[(N-(2-(4-methanesulphonylamino-phenyl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, - 14 - 2- [ (N- (2- (4-dimethanesulphonylamino-phenyl) -ethyl) -piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 5 2-[(N-(3-(4-bromo-phenyl)-propyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(3-(4-methoxy-phenyl)-propyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 10 2- [ (N- (3- (3-methoxy-phenyl) -propyl) -piperid-3-yl) -methyl]-5,6-dimethoxy-1-oxo-l,3-dihydro-isoindole, 2-[(N-(3-(3,4-dimethoxy-phenyl)-propyl)-piperid-15 3-yl) -methyl] -5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2- [ (N- (4- (4-methoxy-phenyl) -butyl) -piperid-3-yl) -methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 20 2- [ (N- (3-(4-amino-3,5-dibromo-phenoxy)-propyl)- piperid-3-yl) -methyl] -5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 3-[(N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-piperid- 25 3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N--(2- (5-methoxy-benzo [b] thienyl-3) -ethyl) -piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-30 2H-3-benzazepine, 3- [ (N- (2- (6-methoxy-benzo[b] thienyl-3) -ethyl) -piperid-3-yl)-methyl]-7,8-diraethoxy-2-oxo-l,3,4# 5-tetrahydro-2H-3-benzazepine, 35 3- [ (N- (2- (6-bromo-benzo [b] thienyl-3) -ethyl) -piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, - 15 - 3- [ (N-(2- (benzo [b] thienyl-2) -ethyl) -piperid-3-yl) -methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 5 3-[(N-(2-(benzo[b]furyl-3)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-piperid-10 3-yl)-methyl]-7,8-dimeth.yl-2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(2-(5-methoxy-benzo[b]thienyl-3)-ethyl)-piperidy-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-15 2H-3-benzazepine, 3-[(N-(2-(6-methoxy-benzo[b]thienyl-3)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 20 3-[(N-(2-(6-bromo-benzo[b]thienyl-3)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 25 3-[(N-(2-(benzo[b]thienyl-2)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-3)-ethyl)-piperid-3-yl)-30 methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-35 tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (5-methoxy-benzo [b] thienyl-3) -ethyl) -piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5- - 16 - tetrahydro-2H-3-benzazepine, 3-I(N-(2-(6-methoxy-benzotb]thienyl-3)-ethyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-5 tetrahydro-2H-3-benzazepine, 3-[(N-(2-(6-bromo-benzo[b]thienyl-3)ethyl)-piperid-3 -yl) -methyl ] - 7,8 -methylenedioxy- 2 - oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 10 3- [ (N- (2- (benzo [b] thienyl-2) -ethyl) -piperid-3-yl) -methyl[-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 15 3- [ (N- (2- (benzo[b] furyl-3) -ethyl) -piperid-3-yl) - methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(3-(2,5-dimethyl-thien-3-yl)-propyl)-piperid-20 3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (3- (5-methoxy-benzo[b] thienyl-3) -propyl) -piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-25 tetrahydro-2H-3-benzazepine, 3- [ (N- (3- (6-methoxy-benzo[b] thienyl-3) -propyl) -piperid-3 -yl) -methyl] -7,8-dimethoxy-2 -oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 30 3- [ (N- (3- (6-bromo-benzo[b] thienyl-3) -propyl) -piperid-3-yl) methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 35 3- [ (N- (3- (benzo [b] thienyl-2) -propyl) -piperid-3- yl) methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, I - 17 - 3- [ (N- (3- (benzo [bl furyl-3) -propyl) -piperid-3-yl) -methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 5 3-[(N-(3-(2,5-dimethyl-thien-3-yl)-propyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (3- (6-methoxy-benzo [b] thienyl-3) -propyl) -10 piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(3-(benzo[b]thienyl-2)-propyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-15 2H-3-benzazepine, 3-[(N-(3-(benzo[b]furyl-3)-propyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 20 3-[(N-(3-(2,5-dimethyl-thien-3-yl)-propyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 25 3- [ (N- (3- (6-methoxy-benzo [b] thienyl-3) -propyl) -piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(3-(benzo[b]thienyl-2)-propyl)-piperid-3-30 yD-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (3- (benzo[b] furyl-3) -propyl) -piperid-3-yl) -methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-35 2H-3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, I - 18 - 3- [ (N- (2- (benzo [b] thienyl-3) -ethyl) -piperid-3-yl) -methyl] -7, 8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine 5 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -piperid-3-yl) -methyl] -7, 8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (thien-2-yl) -ethyl) -piperid-3-yl) -methyl] -10 7, 8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (benzo[b] thienyl-3) -ethyl) -piperid-3-yl) -methyl] -7, 8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro-15 2H-3-benzazepine, 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -piperid-3-yl) -methyl] -7, 8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 20 3- [ (N- (2- (thien-2-yl) -ethyl) - hexahydro-azepin-3- yl) methyl] -7, 8-dimethyl-2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine, 25 3- [ (N- (2- (benzo [b] thienyl-3) -ethyl) -hexahydro-azepin-3-yl) -methyl] -7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- (N- (2- (benzo [b] furyl-2) -ethyl) -hexahydro-azepin-30 3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (thien-2-yl) -ethyl) -hexahydro-azepin-3-yl) -methyl] -7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-35 2H-3-benzazepine, 3- [ (N- (2- (benzo[b] thienyl-3) -ethyl) -hexahydro-azepin? 3-yl) -methyl] -7,8-methylenedioxy-2-oxo-l,3,4,5- - 19 - tetrahydro-2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-5 tetrahydro-2H-3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 10 3-[(N-(2-(benzo [b]thienyl-3)-ethyl)-pyrrolid-3- yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3-t(N-(2-(benzo[b]furyl-2)-ethyl)-pyrrolid-3-yl)-15 methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-Z0 3-benzazepine, 3- [ (N- (2- (benzo[b] thienyl-3) -ethyl) -pyrrolid-3- yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro- 2H-3-benzazepine, 25 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -pyrrolid-3-yl) -methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 30 3 - [ (N- (2- (thien-2-yl) -ethyl) -pyrrolid-3-yl) -methyl] - 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (benzo[b] thienyl-3) -ethyl) -pyrrolid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-35 2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-pyrrolid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro- - 20 - 2H-3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-5 2H-3-benzazepine, 3-[(N-(2-(benzo[b]thienyl-3)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 10 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 15 3-[(N-(4-(thien-2-yl)-butyl)-piperid-3-yl)-methyl]- 7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(4-(benzo[b]thienyl-3)-butyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-20 3-benzazepine, 3-[(N-(4-(benzo[b]furyl-2)-butyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-l,3/4,5-tetrahydro-2H-3-benzazepine, 25 3- [ (N- (5- (thien-2-yl) -pentyl) -piperid-3-yl) -methyl] -7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(5-(benzo[b]thienyl-3)-pentyl)-piperid-3-30 yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (5- (benzo[b] furyl-2) -pentyl) -piperid-3-yl) -methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-35 3-benzazepine, 3-t(N-(4-(thien-2-yl)-butyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H- - 21 - 3-benzazepine, 3-[(N-(4-(benzo[b]thienyl-3)-butyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-5 2H-3-benzazepine, 3-[(N-(4-(benzo[b]furyl-2)-butyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 10 3-[(N-(5-(thienyl-2)-pentyl)-piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 15 3-[(N-(5-(benzo[b]thienyl-3)-pentyl)-piperid-3- yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-t(N-(5-(benzo[b]furyl-2)-pentyl)-piperid-3-yl)-20 methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(4-(benzo[b]thienyl-3)-butyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-25 2H-3-benzazepine, 3-[(N-(4-(benzo[b]furyl-2)-butyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H- 3-benzazepine, 30 3- [ (N- (5- (benzo [b] thienyl-3) -pentyl) -piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 35 3-[(N-(5-(benzo[b]furyl-2)-pentyl)-piperidyl-3)-methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and - 22 - the enantiomers, diastereomers, N-oxides and acid addition salts thereof, more particularly, for pharmaceutical use, the physiologically acceptable acid addition salts thereof.
Preferred compounds of general formula (I) above, however, are those of general formula (la) 10 1 v r~ (CHJ \ N-E-CH n - G - R (la) / v_.} n 15 wherein R, R1# R2, R, A, B, E, 6, m and n are defined as hereinbefore , and the enantiomers, diastereomers, N-oxides and acid 20 addition salts thereof.
Particularly preferred compounds of general formula (I), however, are those wherein 25 A represents a -CH2CH2- group, x B represents a -CH2-CH2_, -CO- or -CH2CO- group, wherein the carbon atom designated x is linked to the phenyl nucleus 30 E represents a methylene or ethylene group, 6 represents a straight-chained C2_4-alkylene group, wherein a methylene group of a straight-chained C3.4-35 alkylene group, linked to an aromatic or heteroaromatic group R, may be replaced by an oxygen, R1 represents a methoxy group,. - 23 - R2 represents a methoxy group or R1 and R2 tpgether represent a methylenedioxy group, m represents the number 2, 3 or 4, n represents the number 1 and R represents a naphth-2-yl, 6-methoxy-naphth-2-yl, .5-methyl-6-methoxy-naphth-2-yl, thien-2-yl, 6-methyl-pyrid-2-yl, benzo[b]fur-2-yl or benzo[b]thien-3-yl group or, if B represents a -CO- group, a 4-methoxyphenyl or 3,4-dimethoxyphenyl group, the enantiomers, diastereomers and acid addition salts thereof.
The following are particularly preferred compounds: a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, b) 3- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) -piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, c) 3- [2- (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid- 2-yl) -ethyl] -7, 8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, d) 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) - hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline, e) 2- [ (N- (2- (naphth-2-yl) -ethyl) -hexahydro-azepin- 3-yl) -methyl] -6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline, - 24 - f) 2- [ (N- (2- (3,4-dimethoxy-phenyl)-ethyl)-piperid-3 -yl) -methyl] -6,7-dimethyl-1,2,3,4- tetrahydro-isoquinoline, g) 2- [ (N- (2- (3,4-dimethoxy-phenyl) -ethyl) -piperid-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro isoquinoline, h) 2- [ (N- (3- (4-methoxy-phenoxy) -propyl) -piperid-3- yl) -methyl] -6, 7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline , i) 3- [ (N- (4- (thien-2-yl) -butyl) -piperid-3-yl) -methyl] -7,8 -dimethoxy-2 -oxo-1,3,4,5 - tetrahydro-2H-3 -benzazepine, i k) 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -piperid-3-yl) -methyl] -7,8 -dimethoxy-2 -oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 1) 3- [ (N- (2- (benzo [b] thienyl-3) -ethyl) -piperid-3-yl) -methyl] -7, 8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, m) 2- [ (N- (3- (6-methoxy-naphthyl-oxy) -propyl) -pyrrol id-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and n) 2 - [ (N- (2 - (6 -methoxy-naphth-2 -yl) -ethyl) - hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline, but particularly the following compounds: a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine. - 25 - b) 2- [ (N- (3- (4-methoxy-phenoxy) -propyl) -piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline, c) 3-[(N-(4-(thienyl-2)-butyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, d) 2-[(N-(3-(6-methoxy-naphthyl-2-oxy)-propyl)-pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline, e) 2-[(N- (2-(6-methoxy-naphth-2-yl)-ethyl)-hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo- 1.2.3.4-tetrahydro-isoquinoline, f) 3-[(N-(2-(4-methoxy-phenyl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and g) 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo- 1.3.4.5-tetrahydro-2H-3-benzazepine, the enantiomers, diastereomers and acid addition salts thereof• According to the invention, the new compounds of general formula (I) are obtained by the following methods: a) Reacting a compound of general formula (II) - E - / If Z1 represents a nucleophilic leaving group, the reaction is conveniently carried out in a solvent or mixture of solvents such as acetone, diethylether, 20 methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetra-hydrofuran, 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 25 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 30 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 150aC, 35 -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 5 10 15 20 25 - 27 - reaction in the presence of a tertiary organic base or an excess of the amine of general formula (II) used.
If Z1 represents a hydroxy group, the reaction is preferably carried out in a suitable solvent.such as methanol, ethanol, tetrahydrofuran, dioxan, ethyl acetate or glacial acetic acid with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel under a hydrogen pressure of from 2- to 10 bar, preferably 5 bar, and at temperatures of between 20 and 120°C, preferably at temperatures between 50 and 100°C.
If Z1 together with a hydrogen atom of the adjacent methylene group represents an oxygen atom, the reaction is preferably carried out in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxan, ethyl acetate or glacial acetic acid with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel under a hydrogen pressure of from 2 to 10 bar, preferably 5 bar, and at temperatures of between 20 and 120°C, preferably at temperatures of between 50 and 100°C, or in the presence of a suitable complex metal hydride such as sodium cyanoborohydride in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxan or acetonitrile at temperatures of between 0 and 50°C, but preferably at ambient temperature. b) Reacting a compound of general formula (IV) 35 (IV) wherein 10 15 20 25 30 - 28 - R1, R2, A and B are as hereinbefore defined, with a compound of general formula (V) wherein R, E, G, m and n are defined as hereinbefore' and Z2 represents a nucleophilic leaving group such as a halogen atom or a sulphonyl oxy group, e.g. a chlorine, bromine or iodine atom or a me thane sulphonyl oxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group.
The reaction is preferably carried out in a solvent or mixture of solvents such as methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or 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. c) In order to prepare compounds of general formula (I) wherein B represents a -CH2- or -CH2CH2- group: reduction of a compound of general formula (VI) Z 2 -E-CH N-G-R 'Nay/ (V) *1 R. 2 1 V«Z>n N-G-R (VI) 15 20 25 - 29 - R, R1# R2, A, E, G, m and n are defined as hereinbefore wherein R, I and x 5 B1 represents a -CO- or -CH2CO- group, the carbon atom designated x being linked to the phenyl nucleus.
The reduction is preferably carried out with a metal hydride such as lithium aluminium hydride or diborane or 10 a complex of borane and a thioether, e.g. with borane-dimethylsulphide complex, in a suitable solvent such as diethylether or tetrahydrofuran at temperatures of between 0 and 80*C, but preferably at temperatures between 10 and 45"C. d) In order to prepare compounds of general formula (I) wherein A represents a -CH2- group and B represents a -CO- or -CH2CO- group: reduction of a compound of general formula (VII) co /cha n-B-CH N-O-R (VII) J \cHj,){ wherein R, R1# R2, e, 6, m and n are defined as hereinbefore and 30 B2 represents a -co- or -cxh2co- group, the carbon atom designated x being linked to the phenyl nucleus, with nascent hydrogen.
The reduction is carried out in a suitable solvent such 35 as glacial acetic acid, glacial acetic acid/water or glacial acetic acid/ethanol with nascent hydrogen, e.g. in the presence of zinc/glacial acetic acid, tin/hydrochloric acid or tin dichloride/hydrochloric - 30 - acid at temperatures between 20 and 150°C, but preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 80 and 100°C. 5 e) In order to prepare compounds of general formula I wherein 6 has the meanings given for 6 hereinbefore, with the exception of the groups containing a sulphur atom, a sulphinyl or sulphonyl group, and A represents the -CH2-CH2- group and B represents a methylene or 10 carbonyl group: hydrogenation of a compound of general formula (VIII) 15 25 35 H-E-CH H-0, - R / \ / (cHa)n 20 wherein R, R1# R2, B, E, m and n are defined as hereinbefore, G1 has the meanings given for G hereinbefore with the exception of the groups containing a sulphur atom or a sulphinyl or sulphonyl group and B3 represents a -CH2- or -CO- group.
The hydrogenation is carried out in a solvent or mixture of solvents such as methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated 30 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, but preferably at temperatures between 20 and 50°C.
In the reaction described above, any reactive groups present such as hydroxy, amino, alky 1 amino or imino groups may be protected during.the reaction by means of - 31 - conventional protecting groups which are cleaved again after the reaction.
For example, a suitable protecting group for a hydroxy 5 group is a trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl group and a suitable protecting group for an amino, alkylamino or imino group is an acetyl, benzoyl, ethoxycarbonyl or benzyl group. 10 The optional subsequent cleaving of a protecting group 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 15 the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures 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 20 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 between 0 and 50°C, 25 but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.
If, according to the invention, a compound of general formula (I) wherein R contains a nitro group is 30 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 contains an amino group, this may be converted by 35 acylation into a corresponding alkanoylamino compound of general formula (I).
The subsequent reduction of the nitro compound is - 32 - preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic 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 acetyl chloride or acetic 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-monoraethy1 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 also be converted into the acid addition salts thereof, particularly for pharmaceutical use into the 33 10 15 20 .25 physiologically acceptable acid addition salts thereof 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 (VIII) 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 alkylation of a corresponding imino compound of general formula (IV) with a cyclic amine protected at the N atom by a conventional protecting group, said cyclic amine being substituted in the carbon structure by an alkyl group which is in turn substituted in the terminal position by a nucleophilic leaving group, and subsequently cleaving the protecting group used. The cyclic amine required for this is obtained by converting a corresponding cyclic amine substituted by a hydroxyalkyl group into a suitable halogen- or sulphonic acid ester thereof and the imino compound of general formula (IV) required for this is obtained by cyclising a corresponding compound, e.g. by cyclising a compound of general formula (IX) R 2 (IX) or of general formula (X) 35 - 34 - optionally followed by catalytic hydrogenation and/or reduction of the carbonyl group, for example with sodium borohydride/glacial acetic acid (see EP-A1 0,007,070, EP-A1 0,065,229 and EP-A1 0,109,639). i 5 A compound of general formula (V) used as starting material is obtained by N-alkylation of a corresponding cyclic amine, substituted in the carbon structure by a hydroxyalkyl group, with a corresponding compound or 10 with a corresponding ot,G>-dihaloalkane and subsequent reaction with a corresponding HO or HN compound and if necessary subsequent oxidation, a hydroxyalkyl compound thus obtained then being converted into its reactive halogen- or sulphonic acid esters. 15 A compound of general formulae (VI), (VII) and (VIII) used as starting material is preferably obtained by reacting a corresponding halogen compound with a corresponding amine, optionally followed by the 20 splitting off of protecting groups used to protect amino groups.
As already mentioned hereinbefore, the new compounds of general formula (I) and the physiologically acceptable 25 acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, particularly a hypotensive effect and em especially long-lasting lowering effect on heart rate and the effect of reducing the 02 requirement of the heart, with 30 only minor side-effects on the.central nervous system. - 35 - For example, the following compounds: A = 3-[(N-(2-(naphth-2-yl)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-5 benzazepine-hydrochloride, 3-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine-hydrochloride, 3-[2-(N-(2-(6-methoxy-naphth-2-yl)-ethyl)-piperid-2-yl)-ethyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine-hydrochloride, B = 10 C = 15 D = 2- [ (N- (2- (6 -methoxy-naphth- 2 -yl) - ethyl) -hexahydro -azepin-3-yl) -methyl] -6,7-methylenedioxy- 1-oxo-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, E = 2-[(N-(2-(naphth-2-yl)-ethyl)-hexahydro-azepin-3-20 yl) -methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4- tetrahydro-isoquinoline-hydrobromide, F = 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperid-3-yl)-methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-25 isoquinoline-dihydrochloride, G = 2- t (N- (2- (3,4-dimethoxy-phenyl) -ethyl) -piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline - hydrochloride , 30 H = 2- [ (N- (3- (4-methoxy-phenoxy) -propyl) -piperid-3-yl) methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline-hydrochloride, 35 I = 3- [ (N- (4- (thienyl-2) -butyl) -piperid-2-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine-hydrochloride, - 36 - K = 3-[ (N- (2-(benzo[b] furyl-2) -ethyl) -piperid-3-yl) -methyl] -7, 8-dimethoxy-2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine-hydrochloride and 5 L= 3-[ (N- (2-(benzo[b] thienyl-3) -ethyl) -piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine-hydrochloride were tested for their biological properties as follows: 10 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 15 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 iii aqueous solution into the jugular vein (0.1 ml/100 g) . 20 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 25 (b/min) .
The following Table contains the values found: 30 - 37 - Substance Dosage Lowering of heart Lowering of blood rate in b/m after pressure in mmHg after [mg/kg] 5 min. 20 min. 5 min. 20 min.
A 5.0 - 218 - 259 - 46 - 32 B 5.0 - 188 - 218 - 22 - 15 C o • in - 236 - 194 - 40 - 31 D o • in - 173 - 123 - 21 - 16 E o • m - 169 - 150 - 30 - 16 F 5.0 - 150 - 120 - 49 - 27 6 5.0 - 207 - 101 - 57 - 8 H o • m - 190 - 180 - 57 - 33 I 5.0 - 320 - 253 - 65 - 32 K 2.5 - 138 - 156 - 36 L 2.5 - 110 - 163 - 40 - 24 When administered in therapeutic doses the compounds prepared according to the invention show no toxic side effects of any kind. Thus, for example when administered intravenously to mice, even in a high dosage of 20 mg/kg, substances A and L 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 - 38 - 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, 5 microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, carboxymethyl- cellulose or fatty substances such as 10 hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories. 15 The following Examples are intended to illustrate the invention: Examples A-K relate to preliminary products. 20 25 30 35 - 39 - Example A 2- T (Piperid-3-yl) -methyl! -6 . 7-dlmethoxv-l-oxo-l .2.3.4-tetrahydro-isoauinoline a) N-Benzvl-3-fhvdroxvmethvl)-pineridine A mixture of 40.3 g (0.35 raol) of 3-(hydroxymethyl)-piperidine, 97.4 ml (0.70 mol) of triethylaraine and 40.3 ml (0.35 mol) of benzyl chloride is heated to 95°C within 30 minutes and kept at this temperature for 2 hours. The reaction mixture is cooled down and 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 evaporated down in vacuo.
Yield: 57.2 g (79.6% of theory), Rf value: 0.45 (aluminium oxide, neutral, eluant: 3% ethanol in methylene chloride). b) XT-Benzyl-3- (henzeneBulphonvloxvmethvl) -pineridine A mixture of 6.8 g (0.033 mol) of N-benzyl-3-(hydroxymethyl) -piperidine, 6.7 ml (0.052 mol) of benzenesulphonic acid chloride, 50 ml of 20% aqueous sodium hydroxide solution, 100 ml of toluene and 1 spatula tip of tetrabutyl ammonium bromide is stirred for 3 hours at ambient temperature. The mixture is then diluted with 250 ml of ethyl acetate and the organic phase is washed with water. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness jji vacuo. The residue is purified over 200 g of silica gel (0.063 - 0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Yield: 9.4 g (92% of theory), Rf value: 0.5 (silica gel, eluant: 5% ethanol in methylene chloride). - 40 - C) 2- r m-Benzyl-niperid-3-yl) -methyl 1 -6 ■ 7-dimftf-hniry-1-oxn-l. 2.3.4 - tie trahvdro -1 soaulnol Ine 5.2 g (0.025 mol) of 6,7-dimethoxy-l-oxo-l,2,3,4-5 tetrahydro-isoquinoline are dissolved in 70 ml of dimethylsulphoxide and 3.1 g (0.025 mol) of potassium tert.butoxide are added with stirring. After half an hour, 9.3 g (0.0275 mol) of N-benzyl-3-(benzenesulphonyloxymethyl) -piperidine in 20 ml of 10 dimethyl sulphoxide are added to the resulting potassium salt suspension and the mixture is stirred for 2 hours at 40°C. It is then poured onto ice water and extracted three times, each time with 120 ml of ethyl acetate. The combined organic phases are washed with water, dried 15 over magnesium sulphate and evaporated down in vacuo. The residue obtained is purified over 200 g of silica gel (0.063 - 0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 2%).
Yield: 7.7 g (78.5% of theory), 20 Rf value: 0.5 (silica gel, eluant: 5% ethanol in methylene chloride and 1 drop of ammonia) . d) 2r r I Piperid-3-yl) -methvll -6. 7-dimethoxy-1-oxo-1.2.3 .4-tet:r-ahvflro-ifiomiri nol ine 25 9.4 g (0.0238 mol) of 2-[ (N-benzyl-piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline are hydrogenated in 200 ml of methanol in the presence of 2 g of 20% palladium hydroxide/charcoal 30 for 3 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated to dryness in vacuo.
Yield: 7.2 g (99% of theory), 35 Rf value: 0.15 (silica gel, eluant: 10% ethanol in methylene chloride and 1 drop of ammonia). - 41 - Example B 3-rhlnromethvl-N-T3-(naphthvl-2-oxv)-propyl! -piperidine 5 a) 3- (Hvdroxvmethv 1) -N- T3- (naphthyl-2-oxv) -propyl 1 -piperidine A mixture of 11.5 g (0.2 mol) of 3-hydroxymethyl-piperidine and 11 g of 2-(3-chloropropoxy)-naphthalene 10 is heated to 120°C-for 1 hour. The residue is purified over silica gel (0.063 - 0.2 mm) with ethyl acetate/ethanol/ammonia = 90:10:1.
Yield: 11.5 g (76.6% of theory), Melting point: 99-101°C. 15 b) 3-Chloromethvl-N- f3- (naphthvl-2-oxv) -propyl! - pipfirifline A solution of 1.5 g (5 mmol) of 3-(hydroxymethyl)-20 N-[3-(naphthyl-2-oxy)-propyl]-piperidine in 25 ml of chloroform is mixed with 1.5 ml of thionyl chloride and refluxed for 1% hours. The mixture is evaporated to dryness in vacuo. The residue is taken up in methylene chloride, washed with water, 2 molar sodium hydroxide 25 solution and again with water. After the methylene chloride phase has been dried over magnesium sulphate it is evaporated down in YacilQ.
Yield: 1.4 g (87.5% of theory), Rf value: 0.8 (silica gel, eluant: ethyl 30 acetate/ethanol/ammonia a 90:40:2). 35 - 42 - Example C 2-f (He3cahydrr>-azeptn-3-vl)-methyl! -6.7-methvlenedioxv-1-nxn-1.2.3.4-tetrahydro-isopuinoline 5 a) N-Benzyl-caprolactam 33.9 g (0.3 mol) of caprolactam are dissolved in 250 ml of dimethylsulphoxide and 37 g (0.33 mol) of potassium 10 tert.butoxide are added with stirring. The reaction temperature rises to 60*C. It is stirred for half an hour at 60°C and then 35 ml (0.3 mol) of benzyl bromide are added dropwise. After another 2M hours at 60°C it is poured onto 1 litre of ice water and extracted three 15 times with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate and evaporated down in vacuo.
Yield: 60.3 g (99% of theory), Rf value: 0.6 (silica gel, eluant: 5% ethanol in 20 methylene chloride). b) 1-Benzyl-naprolactam-3-carboxvlic acid 180 ml of 2.6 molar butyllithium solution in n-hexane 25 are added at -60"C, with stirring and under nitrogen, to 33.9 g = 47.1 ml (0.33 mol) of diisopropylamine in 450 ml of absolute ether. Then, while cooling is continued, 48.8 g (0.24 mol) of N-benzyl-caprolactam dissolved in 150 ml of absolute ether are added 30 dropwise. After stirring for 10 minutes, the cooling bath is removed and carbon dioxide is piped 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-35 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 - 43 - 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) . 5 c) 1-Benzvl-3-hvdroxymethvl-hexahydro-azepine 14.8 g (0.06 mol) of l-benzyl-caprolactam-3-carboxylic acid dissolved in 300 ml of absolute tetrahydrofuran are 10 added dropwise to 6.84 g (0.28 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran. Then the mixture is 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 15 precipitate is suction filtered, washed with tetrahydrofuran and the filtrate is evaporated down In' vacuo. The residue is purified by column chromatography over aluminium oxide N (activity II, eluantmethylene chloride). 20 Yield: 8.4 g (63.8% of theory), IR spectrum (methylene chloride): 3620 cm-1 (OH). d) l-Benzyl-3- U-toluenefiulphonyloxymethyl) -hexahvdro- azepine 25 15 g (0.0684 mol) of 1 -benzyl-3-hydroxymethyl-hexahydro-azepine are dissolved in 150 ml of pyridine and 14.3 g (0.075 mol) of p-toluenesulphonic acid chloride are added with stirring and the resulting mixture is stirred 30 for 1 hour at ambient temperature. It is evaporated down in vacuo, taken up in methylene chloride and washed with 2 molar sodium hydroxide solution and water. After drying over magnesium sulphate the organic phase is evaporated down in vacuo. 35 Yield: 23.3 g (91.3% of theory), Rf value: 0.45 (silica gel, eluant: 5% ethanol in methylene chloride). - 44 - e) 2- T (N-Benzyl-hexahvdro-azenin-3-vl) -methyl! -6.7-methvlenedioxv-1-oxo-l .2.3.4-tetrahydro-isoouinnl i r»e 7.4 g (0.0387 mol) of 6,7-methylenedioxy-1-oxo-5 1,2,3,4-tetrahydro-isoquinoline are dissolved in 100 ml of dimethylsulphoxide, 4.5 g (0.04 mol) of potassium tert.butoxide are added and the mixture is stirred for half an hour at ambient temperature. Then 16.8 g (0.044 mol) of l-benzyl-3-(4-toluenesulphonyloxymethyl)-10 hexahydro-azepine are added and the mixture is stirred for 3 hours at ambient temperature. The reaction mixture is dissolved in ethyl acetate and extracted twice with water. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The 15 residue is purified over aluminium oxide N (activity II, eluant: methylene chloride, methylene chloride + 2% ethanol).
Yield: 3.0 g (19.6% of theory), Rf value: 0.6 (silica gel, eluant: 5% ethanol in 20 methylene chloride). f) 2-f(Hexahvdro-azepin-3-vl)-methvll-6.7-methylenedioxy-l-oxo-1. 2.3.4-tetrahydro-iTsocniinnl ine 25 6.7 g (0.017 mol) of 2-[(N-benzyl-hexahydro-azepin-3- yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline are hydrogenated in 250 ml of methanol in the presence of 2 g of 20% palladium hydroxide/charcoal for 4 hours at ambient temperature under 5 bar of 30 hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated down to dryness in vacuo. The residue is crystallised from acetone. Yield: 4.9 g (95% of theory), M.p.: 267-269°C. 35 - 45 - Example P 3-Chlornmethvl-N-T3-(naphthvl-2-oxv)-propyl!-hexahvdrn- azepine 5 a) 3 - Hydroxyme t hv 1 -hexahvdro-azepine 16.6 g (0.0757 mol) of 1-benzyl-3-hydroxymethyl-hexahydro-azepine are hydrogenated in 500 ml of methanol 10 in the presence of-16.6 g of 20% palladium hydroxide/charcoal for 2 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated down in vacuo. 15 Yield: 8 g (81.8% of theory), Rf value: 0.5 (silica gel, eluant: methylene chloride/ ethanol/ammonia = 5:4:1). b) 3-Hydroxymethvl-N- T3- (naphthvl-2-oxv) -propyl! -20 hexahvdro-azeplne-hvdrochloride A mixture of 7.8 g (0.06 mol) of 3-hydroxymethyl-hexahydro-azepine and 6.7 g (0.03 mol) of 2-(3-chloropropoxy)-naphthalene is heated for 1 hour to 25 120°C. The reaction mixture is purified over silica gel (0.063 - 0.2 mm) with ethyl acetate/ethanol/ ammonia 90:10:1.
Yield: 2.3 g (24.3% of theory), Melting point: 127-129°C. 30 c) 3-GhlQromethyl-N- T3- (naphthyl-2-oxy) -propyl! - hexahydro-azepine 2.4 g (6.86 mmol) of 3-hydroxymethyl-N-[3-(naphthyl-35 2-oxy)-propyl]-hexahydro-azepine hydrochloride dissolved in 30 ml of chloroform are mixed with 5 ml of thionyl chloride and refluxed for 1 hour. The mixture is evaporated to dryness in vacuo. The residue is - 46 - dissolved in methylene chloride, and extracted with water, 2 molar sodium hydroxide solution and-again with water. The methylene chloride phase is dried over magnesium sulphate and evaporated down in vacuo. 5 Yield: 1.1 g (48.5% of theory), Rf value: 0.55 (silica gel, eluant: 5% ethanol in methylene chloride).
Example E 10 2- f (Pvtrnlid-3-yl) -methyl! -6. 7-dimethoxy-1-oxo-l. 2 . 3 .4-tetrahydro-isoquinoline a) N-Benzvl - 2 -pyrrol idona 15 14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil is 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 20 and, at 25 to 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 25 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), 30 Rf value: 0.77 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride). b) N-Benzyl - 2 -pyrrol idone - 3 - carhoxyl i c acid 35 150 ml of 1.6 molar butyllithium solution in n-hexane are added with stirring and under nitrogen at -60"C to 28.3 g = 39.3 ml (0.28 mol) of diisopropylamine in 400 ml of absolute ether. 35.1 g (0.2 mol) of - 47 - N-benzyl-2-pyrrolidone dissolved in 150 ml of absolute ether are added dropwise thereto at -60°C. The cooling bath is removed and dry carbon dioxide is introduced for 15 minutes. After stirring for 10 minutes, the mixture 5 is poured onto ice, the organic phase is separated off and extracted twice with 2 molar sodium hydroxide solution. The combined aqueous phases are extracted once with ether and then acidified with concentrated hydrochloric acid whilst being cooled. The aqueous 10 phase is extracted twice with methylene chloride and after the organic phase has been dried over magnesium sulphate it is evaporated down in vacuo.
Yield: 35 g (79.8% of theory), Rf value: 0.42 (silica gel, eluant: 5% ethanol in 15 methylene chloride). c) N-Benzyl - 3 -hvdroxvmethyl -pyrrol idine 35 g (0.16 mol) of N-benzyl-2-pyrrolidone-3-carboxylic 20 acid dissolved in 250 ml of absolute tetrahydrofuran are 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% aqueous sodium hydroxide 25 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 evaporated down in vacuo and the residue obtained is purified over 900 g of aluminium oxide 30 (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: 5% ethanol in methylene chloride) . 35 d) 3- (Benzeneaulphonyloxymethyl) -l-benzvl-pvrrolidine 40 ml of 20% sodium hydroxide solution are added - 48 - dropwise, for a period of 1 hour, to a mixture of 3.8 g (20 mmol) of N-benzyl-3-hydroxy-pyrrolidine and 3.7 ml (24 mmol) of benzenesulphonic acid chloride. 150 ml of toluene are added, the organic phase is washed with 5 water, dried over magnesium sulphate and evaporated to dryness in vacuo.
Yield: 5.9 g (89.4% of theory), Rf value: 0.4 (silica gel, eluant: 5% ethanol in methylene chloride). 10 e) 2- fN- (Benzyl -pyrrol id-3-yl) -methyl! -6 . 7-d.imethoxy-l-oxo-l. 2.3.4 - tetrahydro-ifioquinol ine 3.3 g (15.9 mmol) of 6,7-dimethoxy-l-oxo-l,2,3,4-15 tetrahydro-isoquinoline are dissolved in 50 ml of dimethylsulphoxide and combined with 2 g (17.5 mmol) of potassium tert.butoxide with stirring at ambient temperature. After half an hour, 5.8 g (17.5 mmol) of 3-(benzenesulphonyloxymethyl)-1-benzyl-pyrrolidine in 20 10 ml of dimethylsulphoxide are added to the resulting potassium salt suspension and the mixture is stirred for 3 hours at 60°C. It is poured onto ice water and extracted with ethyl acetate. The combined organic phases are washed with water and dried over magnesium 25 sulphate. The organic phase is evaporated down in vacuo and the residue obtained is purified over 350 g of aluminium oxide N (activity II) with methylene chloride and then with increasing quantities of ethanol (up to 1%) . 30 Yield: 3.3 g (54.4% of theory), Rf value: 0.74 (aluminium oxide N, eluant: 5% ethanol in methylene chloride). f) 2- T (Pyrr-olid-3-yl! -methyl! -6.7-dimathoxy-l-oxo-35 1.2.3.4-tetrahydro-i Bnmilnoline 3.2 g (8.4 mmol) of 2-[ (N-benzyl-pyrrolidyl)-methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline are - 49 - dissolved in 250 ml of methanol and hydrogenated in the presence of 1 g of 20% palladium hydroxide/charcoal for 3 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and 5 the filtrate is evaporated to dryness in vacuo- The residue is purified over 150 g of silica gel (0.063 -0.2 mm) with methylene chloride/ ethanol/ammonia = 6:1:0.5.
Yield: 0.9 g (37.5% of theory), 10 Rf value: 0.6 (silica gel, eluant: methylene chloride/ ethanol/ammonia = 5:4:1).
Example F 15 3- (p-TolueneBnlphonvloxvmefchvl) -N-T2- (6-methoxv-naphth-2-yl)-ethyl1-pyrrolidine a) 3 - Hydroxyme t-.hvl -pyrrol idine 20 14 g (0.073 mol) of N-benzyl-3-hydroxymethyl-pyrrolidine are hydrogenated for 7 hours at 50°C and under 5 bar in 300 ml of methanol and in the presence of 1.5 g of 20% palladium hydroxide/activated charcoal. The catalyst is then removed by suction filtering and the filtrate is 25 evaporated down in vacuo.
Yield: 7.3 g (99% of theory), Mass spectrum: molecular peak 101. b) 3-Hydroxymetihyl-N- T2- (fi-met-hoxy-naphfch-2-vl) -30 ethyll-pyrrolidine A mixture of 3.6 g (29.4 mmol) of 3-hydroxymethyl-pyrrolidine and 4.7 g (14.7 mmol) of 2-(2-bromoethyl)-6-methoxy-naphthalene is heated to 120°C for 2 hours. 35 The reaction mixture is purified over 200 g of silica gel (0.063 - 0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Yield: 3.48 g (82.5% of theory). - 50 - Melting point: 121-123*C.
C) 3- In-Toluenesulphonvloxymethvl) -N- \2- (6-methoxv-naphthalene-2) -ethyl 1 -pyrrolidine 5 0.8 g (2.8 mmol) of 3-hydroxymethyl-N- [2- (6-methoxy-naphth-2-yl) -ethyl] -pyrrolidine are dissolved in 10 ml of pyridine and 1.2 g (6.3 mmol) of p-toluenesulphonic acid chloride are added with stirring. After 2 hours at 10 ambient temperature the mixture is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride, washed with 2 molar sodium hydroxide solution and water. The organic phase is then dried over magnesium sulphate and evaporated down in vacuo. The 15 residue is purified over 150 g of silica gel (0.063 -0.2 mm) with ethyl acetate and then with increasing amounts of ethanol.
Yield: 0.6 g (48.8% of theory), Rf value: 0.45 (silica gel, eluant: 5% ethanol in 20 methylene chloride) .
Example Gt 2- T (Azacyclooct-vl-3) -methyl! -6 . 7 - dime f.hoxv -1 - oxo -25 1.2.3. 4-tetrahydro-i fionuinoline a) 1-Benzyloxv-azacyclooctane 25 g (0.196 mol) of 2-azacyclooctanone are dissolved in 30 150 ml of dimethylsulphoxide and combined, with stirring, with 24.2 g (0.216 mol) of potassium tert.butoxide and stirred for half an hour at 40°C.
Then 24 ml (0.2 mol) of benzylbromide are added dropwise over a period of a quarter of an hour, during which time 35 the temperature rises to 80aC. The mixture is stirred for 2 hours, during which the reaction temperature falls back to ambient temperature. The reaction mixture is poured onto 1 litre of ice water and extracted 4 times, - 51 - each time with 150 ml of ethyl acetate. The combined organic phase is washed with water, dried over magnesium sulphate and evaporated down in vacuo.
Yield: 42.7 g (100% of theory), 5 Rf value: 0.55 (silica gel, eluant: 5% ethanol in methylene chloride). b) 1 - Benzyl - a zacylooc t ane - 2 - oxo- 3 - carboxvl ic acid 10 147 ml of 1.6 molar butyl lithium solution in n-hexane are added dropwise at -60#C, with stirring and under nitrogen, to 26.7 g = 38.4 ml (0.26 mol) of diisopropylamine in 250 ml of absolute ether. Then at -60°C, 42.7 g (0.196 mol) of 1-benzyl-2-oxo-15 azacyclooctane in 100 ml of absolute ether were added dropwise thereto. After 10 minutes, dry carbon dioxide was introduced for 20 minutes. The reaction mixture is poured onto ice, the ethereal phase is separated off and extracted twice with 2 molar sodium hydroxide solution. 20 The combined aqueous phases are extracted once with ether and then acidified with concentrated hydrochloric acid, whilst being cooled. The mixture was extracted 3 times with methylene chloride, and the methylene chloride phase is dried over magnesium sulphate and 25 evaporated down in vacuo.
Yield: 25.9 g (50.6% of theory), Rf value: 0.15 (aluminium oxide, eluant: 5% ethanol in methylene chloride). 30 C) 1-Benzyl -3 -hydroxvmefchvl -azacvclooctane 53.6 g (0.205 mol) of l-benzyl-2-oxo-azacydooctane-3-carboxylic acid dissolved in 100 ml of absolute tetrahydrofuran is added dropwise with stirring to 35 22.7 g (0.6 mol) of lithium aluminium hydride in 800 ml of absolute ether. After refluxing for half an hour, the mixture is combined with 28.4 ml of water, 19 ml of 15% sodium hydroxide solution and 57 ml of water, whilst I • - 52 - cooling with ice water. The precipitate formed is suction filtered and washed with tetrahydrofuran. The combined filtrates are evaporated down In vacuo and the residue obtained is purified over 700 g of aluminium 5 oxide (neutral, activity II) with 1% ethanol in methylene chloride.
Yield: 9.3 g (19.6% of theory), Rf value: 0.5 (silica gel, eluant: 5% ethanol in methylene chloride). 10 d) 1 -Benzyl - 3 - chloromethvl - azacvclooctane 9.3 g (39.8 mmol) of l-benzyl-3-hydroxymethyl-azacyclo-octane are combined in 30 ml of pyridine with 10 ml 15 (79.6 mmol) of benzenesulphonic acid chloride and stirred for 2% hours at ambient temperature. The reaction mixture is evaporated down in vacuo. The residue remaining is dissolved in 150 ml of methylene chloride, then washed with 2N sodium hydroxide solution 20 and water. The organic phase is dried over magnesium sulphate, evaporated to dryness and purified over 150 g of silica gel (0.063- 0.2 mm) with methylene chloride. Yield: 3.5 g (35% of theory) Rf value: 0.75 (silica gel, eluant: 5% ethanol in 25 methylene chloride). e) 2- f (N-Benzvl-azacvcloncfc-3-yll -methyl! -6. 7-dimethoxv- l-oxo-1.2,3,4 - tetrahydro- i soqutnoJ. ine 3g 2.3 g (11.1 mmol) of 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline are dissolved in 40 ml of dimethylsulphoxide and 1.33 g (12.2 mmol) of potassium tert.butoxide are added with stirring. After half em hour, 3.5 g (9.4 mmol) of 1-benzyl-3-chloromethyl-35 azacyclooctane in 40 ml of dimethylsulphoxide are added to the resulting potassium salt suspension and the mixture is stirred for 2% hours at 120°C. It is poured onto ice water and extracted 3 times, each time with - 53 - 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate and evaporated down in vacuo. The residue obtained is purified over 150 g of silica gel (0.063-0.2 mm) with 1% 5 ethanol in methylene chloride.
Yield: l g (25.1% of theory), Rf value: 0.5 (silica gel, eluant: 2% ethanol in methylene chloride). 10 f) 2-f(Azacyclooct-3-vl)-methvll-6.7-dimethoxy-1-oxo-l .2.3 .4-tetrahydro-isocruinoline 0.85 g (2 mmol) of 2-[ (N-benzyl-azacyclooctyl-3) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-15 isoquinoline are hydrogenated in 50 ml of methanol in the presence of 0.85 g of 20% palladium hydroxide/charcoal for 4M hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated to 20 dryness.
Yield: 0.5g (74.6% of theory) , Rf value: 0.45 (silica gel, eluant: 25% ethanol in methylene chloride and 1 drop of ammonia) 25 Example H l-aUQro-3- (4-methoxy-N-mefchylamino-phenyl) -propane 10 g (0.073 mol) of N-methyl-4-methoxy-aniline are 3Q dissolved in 50 ml of dimethylsulphoxide and 9 g (0.08 mol) of potassium tert .butoxide are added with stirring. After half an hour, 10 ml of l-bromo-3-chloropropane are added and the mixture is stirred for 3 hours at ambient temperature. It is poured onto ice 35 water, extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness. The residue is purified over silica gel (0.063 - 0.2 mm) with methylene chloride. - 54 - Yield: 9.1 g (58.3% of theory), Rf value: 0.55 (silica gel, eluant: methylethyl ketone/xylene = 1:6) 5 Calculated: C 61.82 H 7.55 N 6.55 CI 16.59 Found: 61.71 7.88 6.69 16.24.
Example I 10 2- r (N- (3- (Pvrid-3-yl) -propyl) -pinerHd-3-vl) -methyl! -5.6-methylenedioxv-phthalimide 2.1 g (0.011 mol) of 5,6-methylenedioxy-phthalimide are dissolved in 100 ml of dimethylsulphoxide and 1.25 g 15 (0.012 mol) of potassium tert.butoxide are added with stirring. The potassium salt is precipitated. It is stirred for a further & hour at ambient temperature, a solution of 2.5 g (0.01 mol) of 3-chloromethyl-N-(3-(pyrid-3-yl)-propyl)-piperidine in 20 ml of 20 dimethylsulphoxide is added and the mixture is heated to 120DC for 8 hours. It is poured onto ice water, extracted three times, each time with 150 ml of ethyl acetate, and after drying over magnesium sulphate, the organic phase is evaporated down ill vacuo. The residue 25 is purified over 200 g of silica gel (0.063 1 0.2 mm) with ethyl acetate/ethanol/ ammonia - 80:10:0.5.
Yield: 3 g (74% of theory), Calc. (2 x HC1) C 55.42 H 5.86 N 8.43 CI 14.22 Found: 55.28 6.06 8.26 14.64 30 Example K 2- TN- (3-Chloropropyl) -pinerld-3-yl-methvll -fi. 7- dimfif.hQxy-l-pxQ-3. .2.3.4-nerxahydro-iBpgttinQline 35 3 g (0.01 mol) of 2-[ (piperid-3-yl) -methyl] -6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline are dissolved in 50 ml of dimethylsulphoxide and 1.3 g - 55 - (0.011 mol) of potassium tert.butoxide are added with stirring. After half an hour, 3 ml of l-bromo-3-chloro-propane are added and the mixture is stirred for 1 hour at ambient temperature. It is poured into ice water, extracted with ethyl acetate, and the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness in vacuo.
Yield: 2.7 g (71% of theory), Rf value: 0.65 (silica gel, eluant: ethyl acetate/ethanol/ ammonia = 50:45:5). - 56 - Example 1 2- f (N- (3- (Naphr,h-2-yl) -propyl) -piperid-3-yl) 7 methyl! - 6. 7-dimethoxy-l-nxo-1 .2.3.4-tetrahydro-iBoauinolinft-hydrochloride A mixture of 1 g (3.2 mmol) of 2-(piperid-3-yl-methyl)-6,7 -dimethoxy-1 - oxo-1,2,3,4- tetrahydro- isoquinoline, 5 ml of dimethylsulphoxide, 0.5 g (0.36 mmol) of potassium carbonate and 0.75 g (3.66 mmol) of 2-(3-chloropropyl) -naphthalene is heated to 120°C for 3 hours. The reaction mixture is poured onto ice water and extracted three times, each time with 50 ml of ethyl acetate. The combined organic phases are washed with 2 molar sodium hydroxide solution and water, dried over magnesium sulphate, evaporated down in vacuo and the residue obtained is purified over silica gel (0.063 -0.2 mm) with 1% ethanol in methylene chloride. The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid and recrystallised from acetone.
Yield: 0.74 g (44% of theory), Melting point: 179-181*C Calculated: C 70.77 H 7.37 N 5.50 CI 6.96 Pound: 70.47 7.40 5.47 7.06.
Example 2 2- r (N- (3- (Naphthyl-2-oxy) -propyl) -piperifl-3-yl) - methyl 1 -6. 7-dimethyl- 1-oxo-l .2.3 .4-tetrahvdro-i soqu inol ine -hydrochloride 1.58 g (9 mmol) of 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline are dissolved in 30 ml of dimethylsulphoxide and l.l g (9.9 mmol) of potassium tert.butoxide are added with stirring. After 1 hour, a solution of 2.9 g (9.1 tmnol) of 3-chloromethyl-N-[3-(naphthyl- 2-oxy)-propyl]-piperidine in 10 ml of - 57 - dimethylsulphoxide is added and the reaction mixture is stirred for 16 hours at 80°C. It is then poured onto ice water, extracted 3 times, each time with 50 ml of ethyl acetate, the organic phase is washed with water, 5 dried over magnesium sulphate and, after evaporation, purified on silica gel (0-63 - 0.2 mm) with ethyl acetate/ethanol/ammonia = 95:5:0.5. The hydrochloride is obtained as a hydrate from a solution in acetone using ethereal hydrochloric acid. 10 Yield: 2 g (45.1% of theory), Melting point: 152-154°C Calculated: C 70.50 H 7.69 N 5.49 CI 6.93 Found: 70.31 7.52 5.49 7.10 15 Example 3 2- f (N- (3- (Nanhth-2-vl) -propyl) -piperid-3-vl) -methyl! -6.7-dimethyl-l .2.3 .4-tetrahydro-isocruinoline-dihvdro- 20 chloride 0.8 g (18 mmol) of 2-[ (N- (3-(naphth-2-yl) -propyl) r-piperid-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline are dissolved in 10 ml of 25 absolute tetrahydrofuran and 20 ml of absolute ether, 70 mg (18 mmol) of lithium aluminium hydride are added and the mixture is refluxed for 1 hour. The reaction mixture is decomposed by the addition of 5 ml of saturated aqueous sodium sulphate solution, filtered to 30 remove the sodium sulphate precipitated and washed with tetrahydrofuran. The filtrate is dried over magnesium sulphate and after evaporation, purified over 150 g of silica gel (0-063 -0.2 mm) with ethyl acetate/ethanol/ammonia & 90:10:0.05. The hydrochloride 35 is precipitated from a solution in acetone with ethereal hydrochloric acid.
Yield: 0.49 g (54.4% of theory).
Melting point: 148-150°C - 58 - Calculated: C 69.61 H 8.18 N 5.41 CI 13.70 Found: 69.46 8,32 5.26 14.17 Example 4 5 2-f(N-(3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methyl 1 -5. S-metrhylenedioxy-l-oxo-l. 3 -dihydro-isoinflole-dihydrochloride 10 2.4 g (5.9 mmol) of 2-[(N-(3-(pyrid-3-yl)-propyl)- piperid-3-yl) -methyl] -5,6-methylenedioxy-phthalimide are dissolved in 50 ml of glacial acetic acid and refluxed for 5 hours. At intervals of 1 hour, 1 g batches of zinc powder are added. After the reaction time has 15 ended, the mixture is suction filtered and evaporated with ethanol. The residue is dissolved in methylene chloride, extracted with concentrated ammonia, dried over magnesium sulphate and after evaporation in vacuo purified over 150 g of silica gel (0.063 - 0.2 mm) ethyl 20 acetate/ethanol/ammonia = 90:10:0.2. The hydrochloride is precipitated from a solution in acetone.
Yield: 2.05 g (75% of theory), Melting point: 165-167*C Calculated: C 59.22 H 6.27 N 9.00 CI 15.20 25 Found: 59.03 6.45 8.85 15.06 Example 5 3- f (N- (3- (Pvrid-3-vl) -tvropvl) -Pvrrolid-3-vl) -methyl! -30 7. 8 -flinn»f.hoxy-2 -oxo-1.3.4.5-t:efcrahvdro-2H-3- benzna^epine-dihydrochloride 1.1 g (2.6 mmol) of 3-[(N-(3-(pyrid-3-yl)-propyl)-pyrrol id-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l, 3-dihydro-35 2H-3-benzoazepine, dissolved in 50 ml of ethanol, are hydrogenated in the presence of 1 g of 10% palladium on activated charcoal at 80°C and under 5 bar of hydrogen for 2 hours. Then the catalyst is removed by suction - 59 - filtering and, after being evaporated down in vacuo. the filtrate is purified over 100 g of silica gel (0.063 -0.2 mm) with ethyl acetate/ethanol/ammonia =-80:40:1. The hydrochloride is precipitated from a solution in 5 acetone.
Yield: 0.37 g (33% of theory).
Melting point: 96-98°C Calculated: C 60.42 H 7.11 N 8.46 CI 14.28 Found: 60.35 7.46 8.43 14.58 10 Example 6 3- f (N- (3- (Indolyl-3) -propyl) -hexahvdro-azepinvl-3) -methyl! -7.8-dimethoxy-1.3.4.5-tetrahydro-2H-3- 15 bettzazepine-dihydrochloride monohydrate Prepared from 3-[(N-(3-(indolyl-3)-propyl)-hexahydro-azepinyl-3)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and lithium aluminium 20 hydride in tetrahydrofuran and diethylether analogously to Example 3.
Yield: 53% of theory.
Melting point: 158-160°C Calculated: C 63.58 H 8.00 N 7.41 CI 12.51 25 Found: 63.41 8.18 7.36 12.23 Example 7 2- r (N- (?.-(4-Amino-phenvl) -ethvl) -piperid-3-vl) -methvll -30 5. 6-dimethoxy-1 -oxo-1. 3-dihvdro-iBoindole- dihydrQchlor3.de 2.1 g (4.78 mmol) of 2-[(N-(2-(4-nitro-phenyl)-ethyl) -piperid - 3 - yl) -methyl] -5,6-dimethoxy-1-oxo-35 1,3-dihydro-isoindole are dissolved in 50 ml of glacial acetic acid and 0.4 ml (8.22 mmol) of hydrazine hydrate and 1 spatula tip of Raney nickel are added with stirring. The addition of 0.2 ml of hydrazine and 1 - 60 - spatula tip of Raney nickel is repeated 3 times at intervals of 1 hour. The catalyst is removed by suction filtering, the residue is washed with methanol, the filtrate is dried with magnesium sulphate, evaporated 5 down la vacuo and the residue obtained is purified over aluminium oxide (neutral, activity II) with methylene chloride and then with increasing quantities.of ethanol. Yield: 1.8 g (91.8% of theory), 1 g is dissolved in acetone and the dihydrochloride is 10 precipitated with ethereal hydrochloric acid.
Yield: 1.02 g (86.4% of theory based on the base), Melting point: 232-235°C Calculated: C 59.72 H 6.89 N 8.71 CI 14.69 Found: 59.54 7.08 8.56 14.45 15 Example 8 2- T (W- (2- (4-Acetama.no-phenyl) -ethyl) -pipftrid-3-yl) - methyll^5.6-dimethoxy-l-oxo-l.3-dihvdro-isoindole 20 819 mg (2 mmol) of 2-[(N-(2-(4-amino-phenyl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole are mixed with 10 ml of methylene chloride and after the addition of 0.3 ml (2.2 mmol) of .25 triethylamine, 0.16 ml (2.2 mmol) of acetyl chloride are added dropwise. The reaction temperature rises to 30°C. The mixture is stirred for half an hour at ambient temperature, extracted twice with water, the organic phase is dried over magnesium sulphate and evaporated 30 down in vacuo. The residue is crystallised from acetone.
Yield: 660 mg (73.2% of theory), M.p.: 195-196°C Calculated: C 69.16 H 7.37 N 9.31 35 Found: 69.33 7.11 9.16 - 61 - Example 9 3- T (N- (3- (Furvl-2) -propyl) -piperid-3-vl) -methvll -7. fi-dimethoxy-2-oxo-1. 3.4. 5-tetrahydro-2H-3-hpn7a7.RniiiP- hydrochloride 3.2 g (0.010 mol) of 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine are hydrogenated in 100 ml of absolute ethanol in the presence of 1.3 g (0.010 mol) of 3-(furyl-2)-propanal and 1 g of Raney nickel at 80°C for 2 days under 5 bar. The catalyst is removed by suction filtering; the filtrate is evaporated down and purified over a silica gel column with methylene chloride/methanol as eluant. The hydrochloride is precipitated with ethereal hydrochloric acid and crystallised from acetone.
Yield: 0.50 g (11% of theory).
Melting point: 204-206wC Calculated: C 64.85 H 7.62 N 6.05 CI 7.66 Found: 64.88 7.76 5.93 7.55 Rf value: 0.69 (silica gel; methylene chloride/methanol = 10:1; ammonia/atmosphere) Example 10 2- f (N- (3 - (3-Mefchylphenoxy) -propyl) -piperid-3-yl) - methyl! - 6.7-dimethoxy-1.2.3.4 -tetrahydro-isoauinol ine - dihydrochloride Prepared from 2-[ (N- (3-(3-methylphenoxy) -propyl) -piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 92.9% of theory, Melting point: 100-103*C Calculated: C 61.23 H 7.99 N 5.29 CI 13.39 Found: 61.21 .8.13 5.10 13.15 - 62 - Example 11 2- T (N- (3- (Naphthyl-2-oxy) -propyl) -pyrrolid-3-yl) -methyl! -6. 7-dimethoxy-1 -oxo-1 .2.3.4-tetrahvdro-5 isocruinoline-hvdrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(naphthyl-2-oxy)-propyl]-pyrrolidine analogously to Example 2. 10 Yield: 22% of theoiy, Melting point: 78-80°C Calc. (x H20): C 65.83 H 7.04 N 5.29 CI 6.70 Pound: 65.79 7.00 5.03 6.99 15 Example 12 2- f (N- (3- (Naphthvl-2-oxv) -propyl)-pvrrolid- 3-yl) -methyl 1 -6,7-menhylenedioxy-l-oxo-a, .2.3.4-tetrahydro-i.soquinoline-hydrochloride 20 Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N- [3-(naphthyl-2-oxy)-propyl]-pyrrolidine analogously to Example 2. 25 Yield: 53% of theory.
Melting point: 78-80#C Calc. (x H20): C 65.56 H 6.48 N 5.46 CI 6.91 Found: 65.44 6.32 5.38 7.13 30 Example 13 2- f (N- (7-maphth-2-yl) -ethvl) -pvrrolid-3-yl) -methyll -6.7-dlmftthovy-l .2.3.4-tftfcrahvdro-iBomiinoli ne- hyflrochlorifle 35 Prepared from 2- [ (N- (2- (naphth-2-yl) -ethyl) -pyrrblid-3-yl)-methyl]- 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in - 63 - tetrahydrofuran and ether analogously to Example 3. Yield: 66.2% of theory, Melting point: 239-241°C Calc. (X H20): C 64.48 H 7.44 N 5.37 CI 13.91 5 Found: 64.30. 7.34 5.52 13.69 Example 14 2-r (N-12-(Methyl-naphth-l-yl)-methyl)-hexahvdro-10 azepin-3-yl)-methyl!-6.7-dimethoxy-1.2.3.4-tetrahvdro- isoquinoline-hydrochloride Prepared from 2-[(N-(2-(methyl- naphth-l-yl)-methyl)-hexahydro-azepin-3-y1)-methyl]-6,7-dimethoxy-1-oxo-15 1,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran and ether analogously to Example 3.
Yield: 73.8% of theory, Melting point: 182-184"C 20 Calc. (x H20): C 65.56 H 7.70 N 5.09 CI 12.90 Found: 65.52 7.57 5.32' 12.72.
Example 15 25 2- r (N- (4- (Naphthyl - 2 - oxy) -butyl) -pvrrolid-3-vl) -methyl!-6.7-dimethyl-1-oxo-1.2.3.4-tetrahvdro- isoquiinQline-hytirpchlorifle Prepared from 2-(pyrrolid-3-yl-methyl)-6,7-dimethyl-30 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(4- bromo-butyloxy)-naphthalene analogously to Example l. Yield: 30% of theory.
Melting point: 133-136#C Calculated: C 67.02 H 6.92 N 5.21 Br 14.86 35 Found: 67.26 7.03 5.36 14.89 Example 16 - 64 - 2- r (N- (2-Mer.hyl-napht.h-l-yl,) -methyl) -pyrrol id-3-yl) - methyl! -6. 7-dimethyl-1 -oxo-1. 2 . 3 .4-tetrahvdro-5 isonuinoline-hydrochloride Prepared from 2-(pyrrolid-3-yl-methyl)-6,7-dimethyl- 1-oxo-isoquinoline and 1-chloromethyl-2-methyl-naphthalene analogously to Example l. 10 Yield: 32.5% of theory, Melting point: 142-144°C Calculated: C 69.34 H 7.69 N 5.77 Br 7.37 Found: 69.59 7.63 5.72 7.89 15 Example 17 2-f (N- (2-(5-Methyl-6-methoxy-naphth-2-vl)-ethvl)-pyrrolid-3-yl)-methvll-6.7-dimethyl-1-oxo-l.2.3.4-tetrahvdro-isoquinoline-hydrobromide 20 Prepared from 2- [N- (pyrrolid-3-yl-methyl) ] -6, 7-dimethyl- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl) -5-methyl-6-methoxy-naphthalene analogously to Example l. 25 Yield: 19% of theory.
Melting point: 230-232°C Calculated: C 67.02 H 6.93 N 5.21 Br 14.86 Found: 67.10 7.12 5.33 15.01 30 Example 18 2- r fM-fa- (Naohth-2-vll -ethvl) -Pvrrolid-3-vl) -methvll -6. 7-dimgfchmcv-1 -oxo-1.2.3.4 - tet r-ahvdro- i noouinol ine -hydrochloride 35 Prepared from 2 - (pyrrolid-3 -yl -methyl) - 6,7 -dimethoxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2- (2-bromoethyl)-naphthalene analogously to Example 1. - 65 - Yield: 7.8% of theory, Melting point: 219-221°C Calc. (x H20): C 67.39 H 7.07 N 5.61 CI 7.10 Found: 67.21 7.23 5.57 7.63 5 Example 19 2- f (N- llr- (6-Methoxy-naphth-2-vl) -ethyl) -pyrrolid-3-vl) -methvll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdro- 10 isoqutinoline-hydrochloride Prepared from 2- (pyrrolid-3-yl) -methyl) -6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl) - 6 -methoxy-naphthalene analogously to Example 15 1.
Yield: 39.2% of theory.
Melting point: 224-226°C Calc. (x H20) : C 65.84 H 7.05 N 5.29 CI 7.05 Found: 66.08 7.13 5.39 6.77 20 Example 20 2-r Melting point: 85-87'C Calc. (x H20): C 66.59 H 6.89 N 5.17 CI 6.53 Found: 66.77 6.98 4.95 6.74 15 Example 22 2- f (N- (3- (Naphthyl-2-oxy) -propyl) -piperid-3-vl) -methvll -6 .7-dimethyl-l .2.3.4-tetrahydro-i soquinol ine - flihyflrochloride 20 Prepared from 2-[(N-(3-(naphthyl-2-oxy)-propyl)-piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3. 25 Yield: 53% of theory, Melting point: 133-135"C Calc. (x H20): C 68.30 H 6.87 N 5.31 CI 13.44 Found: 68.05 6.85 5.23 13.03 30 Example 23 2- r (N- (3- (Naphthyl-2-oxv) -propyl) -piperid-3-yl) -methvll -6.7-methylenedioxy-1.2.3.4-tetrahydro- IfipquAnolMft-aihyflrQcMoricte • 35 Prepared from 2-[ (N- (3-(naphthyl-2-oxy) -propyl) -piperid-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in - 67 - tetrahydrofuran/ether analogously to Example 3.
Yield: 44.7% of theory, Melting point: 130-132°C Calc. (x H20): C 63.62 H 6.62 N 5.11 CI 12.95 5 Found: 63.49 6.86 4.97 12.64 Example 24 2- T fN- ((2 -Methyl -naphth-1 - vl) -methvl) -piperid-3-vl) -10 methyl! -6.7-dimethoxy-l.2.3.4-tetrahydro-isoaruinoline-dihydrochloride Prepared from 2-[(N-((2-methyl-naphth-l-yl)-methyl)-piperid-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,4-15 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 80.5% of theory.
Melting point: 210-212°C Calc. (X H20): C 65.05 H 7.53 N 5.23 20 Found: 65.23 7.78 5.03 Example 25 2-f2-(N-(2-f6-Methoxy-naphth-2-yl)-ethyl)-piperid-2-yl)-25 ethyl! -6. 7-methylenedioxy-1-oxo-1. 2 . 3 .4-tetrahvdro- ispquinpline-hyflrpchlorifle Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-methylene-dioxy-1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 30 2- (2-bromo-ethyl) -6-methoxy-naphthalene analogously to Example l.
Yield: 27.6% of theory, Melting point: 112-117"C Calc. (XH20): C 67.74 H 6.82 N 5.26 CI 6.65 35 Found: 67.54 6.73 5.47 6.86 - 68 - Example 26 2- f (N- (2 - (6-Naphth-l-vl) -ethyl) -piperid-3-vl) -methvl 1 -6 .7-dimethoxy- 1-oxo-1. 2 . 3 .4-tetrahvdro-isoauinollne- 5 hydrochloride Prepared from 2-[ (piperid-3-yl) -methyl]-6,7-dimethoxy- 1-oxo-l ,2,3,4-tetrahydro-isoquinoline and 1-(2-benzene-sulphonyloxy-ethyl)-naphthalene analogously to Example 10 1.
Yield: 26.9% of theory, Melting point: 220-225°C Calculated: C 67.89 H 7.27 N 5.46 CI 6.91 Found: 67.75 .6.92 5.56' 7.00 15 Example 27 2- f m- 12-(Naphth-2-vl) -ethvl) -pjperid-3-vl) -methvll -6. 7-methvlenedioxy-l-oxo-l.2.3.4-tetrahvdro- 20 ifioquinoline-hvdrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2- (2 -benzene - sulphonyl oxy-ethyl) -naphthalene analogously 25 to Example 1.
Yield: 27.9% of theory, Melting point: 128-130°C Calc. (x H20) : C 67.66 H 6.69 N 5.63 CI 7.13 Found: 67.64 6.70 5.76" 7.35 30 Example 28 2- r (N- (2- (5-Methvl-6-methoxy-naphth-2-vl) -ethyl) -pjperid-3-yl) -methvll -fi. 7-methylenedioxy-1 -oxo-1.2.3.4-35 tetrahydro- i Bomii nol ine-hvdrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-l, 2,3,4-tetrahydro-isoquinoline and - 69 - 2-(2-bromoethyl)-5-methyl-6-methoxy-naphthalene analogously to Example l.
Yield: 51.2% of theory, Melting point: 128-131*C 5 Calculated: C 68.88 H 6.74 N 5.34 CI 6.77 Found: 68.90 6.61 5.30 7.05 Example 29 10 2-r(N-((2-Methyl-naphth-1 - vl)-methyl)-piperid-3-vl) -methyl!-6.7-dimethoxy-1-oxo-l.2.3.4-tetrahvdro- isoqiiinQline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethoxy-15 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloromethyl-2-methyl-naphthalene analogously to Example 1.
Yield: 57.9% of theory, Melting point: 212-214°C 20 Calc. (x 2 H20):C 67.63 H 7.63 N 5.44 CI 6.88 Found: 67.46 7.56 5.54 6.67 Example 30 25 2- r fN- (4- (Naphthyl-2-oxy) -hutvl) -piperid-3-vl) -methvll - 6.7 - dime f.hoxy-1 - oxo -1,2.3.4-tetrahydro-isoquinoline-hydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethoxy-30 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(4- bromo-butoxy)-naphthalene analogously to Example l. Yield: 46.3% Of theory.
Melting point: 80-84°C Calc. (x H20): C 66.83 H 7.41 N 5.03* CI 6.36 35 Found: 66.79 7.22 4.90 6.64 - 70 - Example 31 2- T fN- I?.-f6-Methoxv-naphth-2-vl) -ethvl) -pjperid-3-yl) -methyl1-fi.7-di methoxy-1-oxo-1.2.3.4-tetrahvdro- 5 isoquinol ine - hydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-t2-bromo-ethyl) -6-methoxy-naphthalene analogously to 10 Example 1.
Yield: 22.8% of theory, Melting point: 80-85°C Calc.: (x H20 x HC1 x CH3COCH3) : C 64.01 H 7.65 N 4.52 CI 5.72 Found: 64.26 7.70 4.62 5.49 15 Example 32 2- T3- fN- 12-16-Methoxy-naphth-2-yl) -ethyl) -piperid-3-vl) -Propyl!-6.7-methylenedioxy-1-nxn-1.2.3.4-tetrahvdro- 20 isocniinoline Prepared from 2-[N-(3-(piperid-3-yl)-propyl]-6,7-methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and 2- (2-bromo-ethyl) -6-methoxy-naphthalene analogously to 25 Example 1.
Yield: 36.8% of theory, Melting point: 118-121°C Calculated: C 74.37 H 7.25 N 5.60 Found: 74.60 7.43 5.65 30 Example 33 2. f3- fN- (2-fNaphth-1 - vl) -ethyl) -piperid-3-vl) -propyl! -6.7-methylenedioxy-l-oxo-l .2.3.4-tetrahvdro-35 isoquinol ine-hydronhlori.de Prepared from 2- [N- (3- (piperid-3-yl) -propyl] -6,7-methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and - 71 - 1-(2 benzenesulphonyloxy-ethyl)-naphthalene analogously to Example 1.
Yield: 20.8% of theory, Melting point: 195-197°C 5 Calculated: C 71.07 H 6.95 N 5.53 CI 6.99 Found: 71.30 6.95 5.65 6.80 Example 34 10 2-T2-(N-(2-(5-Methyl-6-methoxy-naphth-2 - vl)-ethvl)-piperid-2-yl)-ethvll-6.7-dimethoxv-l-oxo-l.2.3.4-tet:rahvdro-i soquinol ine -hydrochloride Prepared from 2-[2-(piperid-2-yl.) -ethyl] -6,7-dimethoxy-15 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl)-5-methyl-6-methoxy-naphthalene analogously to Example 1.
Yield: 33.6% of theory, Melting point: 95-100°C 20 Calc. (x H20) : C 68.38 H 7.52 N 4.98 CI 6.30 Found: 68.14 7.43 4.92 6.77 Example 35 25 2-T(N-(3-(Naphfthyl-2-oxy)-propyl)-piperafl-S-yl)- methyl 1 -6.7-rf-i mPt-hyl pnpdio-xy- 1-oyo-1 .2.3.4-tetrahvdro-i soqu inoline-hydrochloride Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4-30 tetrahydro-isoquinoline and 3-chloromethyl-N-[3- (naphthyl-2-oxy)-propyl]-piperidine analogously to Example 2.
Yield: 27.3% of theory.
Melting point: 104-106*C 35 Calc. (x H20) : C 66.09 H 6.69 N 5.31 CI 6.72 found: 66.19 6.34 5.24 7.22 - 72 - Example 36 2- f (N- (3- (Naphthvl - 2 - oxy) -propyl) -piperid-3-vl) - methyl 1-6 ■7-dimethQ^y-l-oxo-l.2.3.4-tetrahydro- 5 isoauinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(naphthyl-2-oxy)-propyl]-piperidine analogously to Example 2. 10 Yield: 28.6% of theory, Melting point: 191-193#C Calc. (x H20): C 66.34 H 7.23 N 5.15 CI 6.53 Found: 66.59 7.19 5.03 6.65 15 Example 37 2- f (N- (3- (Naphthyl-2-oxy) -propyl) -hexahvdro-azepin-3-vl)-methvll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdro-i soqu inoline-hvdrochloride 20 Prepared from 2 - [ (hexahydro-azepin-3-yl) -methyl] -6,7-dimethoxy-l-oxo-isoquinoline and 2-(3-chloropropoxy)-naphthalene analogously to Example l. Yield: 16.1% of theory, 25 Melting point: 86-88°C Calc. (x H20) : C 66.83 H 7.42 Found: 66.90 7.40 Example 38 30 2- f fN- fa. fNaphthvl-2-oxy) -propyl) -hexahydro-agepln- 3-vl)-methyl1-6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdro- i soquinoline-hydrochloride 35 Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(naphthyl-2-oxy)-propyl]-hexahydro-azepine analogously to Example 2.
N 5.03 5.26 CI 6.36 6.87 - 73 - Yield: 22.5% of theory, Melting point: 191-193°C Calculated: C 73.42 H 7.75 N 5.52 CI 6.99 Found: 73.37 7.67 5.52 7.12 5 Example 39 2-r fN-(2-(5-Methyl-6-methoxv-naphth-2 - vl)-ethvl)-hexahydro-azepin-3-yl)-methyl! -6.7-dimethoxy-1-oxo-10 1.2.3.4-tetrahydro-isoauinoline-dihvdrochloride Prepared from 2-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl) -hexahydro-azepin-3-yl) -methyl] -6,7-dimethoxy- 1-oxo-l ,2,3,4-tetrahydro-isoquinoline and lithium 15 aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 77.6% of theory, Melting point: 170-172°C Calc. (X H20): C 64.96 H 7.49 N 4.73 CI 11.98 20 Found: 65.11 7.62 4.95 11.84 Example 40 2-f fN-f2-f5-Methvl-6-methoxv-nanhth-2-vl)-ethvl)-25 hexahvdro-azepin-3-vl)-methvll -6.7-dimethoxv-l-oxo- 1.2.3.4-tetrahydro-isorminoline Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 30 2-(2-bromoethyl)-5-methyl-6 -methoxy-naphthalene analogously to Example 1.
Yield: 43.5% of theory, Melting point: 125-127°C Calculated: C 74.39 H 7.80 N 5.42 35 Found: 74.31 7.82 5.35 - 74 - Example 41 2- T fN- (2-Methyl-naphth-l-yl) -methyl) -hexahydro-azepin- 3-yl) -methvl 1 -6. 7-dimethoxv-l-oxo-l. 2 . 3 .4-tetrahvdro-5 isocminoline-hvdrochloride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloromethyl-2-methyl-naphthalene analogously to 10 Example 1.
Yield: 67.5% of theory, Melting point: 128-130"C Calc. (x 2 H20): C 66.10 H 7.58 N 5.13 CI 6.50 Found: 66.24 7.44 5.23 6.85 15 Example 42 2- r fN- (4- fNaphthyl-2-oxv) -butvl) -hexahvdro-azepin-3-vl) -methvll -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro- 20 iaoeniinol ine-hvdrochloride Prepared from 2- t (hexahydro-azepin-3-yl) -methyl] -6,7 -dimethoxy- 1-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-(4-bromo-butyloxy)-naphthalene analogously to Example 25 1- Yield: 26% of theory, Melting point: 192-194"C Calculated: C 69.22 H 7.80 N 5.04 CI 6.38 Found: 70.01 7.70 5.15 6.48 30 Example 43 2- f (N- 12-(Naphth-l-vl) -ethvl) -hexahvdro-azepin-3-vl) -methvll -6.7-methylenedioxy- 1-oxo-l .2.3.4-tetrahvdro-35 iBoqiiinolxne-hydrochloride Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline - 75 - and 2- (2-benzenesulphonyloxy-ethyl) -naphthalene analogously to Example 1.
Yield: 15.4% of theory, Melting oint: 236-238°C 5 Calc. (x H20): C 69.40 H 6.82 N 5.58 CI 7.06 Found: 69.07 6.74 6.13 7.29 Example 44 10 2- r (N- (2- fNanhth-2- vl) -ethyl) -hexahvdro-azepin-3-vl) - mftthyl! -6.7 -methylenedioxy- 1-oxo-l ,2.3,4-tetrahydro-isoquinoline-hydrobromide Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-15 6,7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl)-naphthalene analogously to Example 1.
Melting point: 100-102°C Yield: 31.6% of theory, 20 Calculated: C 64.80 H 6.18 N 5.21 Br 14.86 Found: 65.02 6.07 5.39 14.78 Example 45 25 2- T (N- (?.- (6-Methoxy-naphth-2-yl) -ethvl) -hexahvdro- azepin-3-yl) -methyl! -6,7 -methylenedioxy-1 - oxo-1,2,3,4-tetrahydro- ifioquinol i ne - hydrochl oride Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] -30 6,7 -methylenedioxy-1 - oxo -1,2,3,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl)-6-methoxy-naphthalene analogously to Example 1.
Yield: 34.1% of theory.
Melting point: 147.-149°C 35 Calc. (x H20) : C 68.62 H 7.10 N 5.33 CI 6.75 Found: 68.88 6.98 5.41 6.78 - 76 - Example 46 2- r fN- (2- f5 -Methyl - fi -methoxy-naphth- 2 - vl) -ethyl) -hexahvdro-azepin-3-vl)-methvll -6.7-methvlenedioyv- 5 i-qxq-3. . 2,3.4-tetrahydro-isosMinQlinft-hydrochloridft Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-6#7-methylenedioxy-l-oxo-isoquinoline and 2-(2-bromo-ethyl)-5-methyl-6-methoxy-naphthalene analogously 10 to Example 1.
Yield: 36.1% of theory, Melting point: 112-114°C Calc. (x H20): C 67.07 H 7.08 N 5.04 CI 6.38 Found: 67.13 7.15 4.97 6.56 15 Example 47 2- r (N- fa- f4-Methoxy-phenoxv) -propyl) -piperid-3-vl) -methyl! -6.7-dimethoxy-1.2.3.4-tetrahvdro-isoauinoline- 20 dihydrochloride Prepared from 2-[(N-(3-(4-methoxy-phenoxy)-propyl)-piperid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 25 tetrahydrofuran analogously to Example 3.
Yield: 88.5% of theory, Melting point: 189-191°C Calculated: C 59.44 H 7.76 N 5.13 CI 12.99 Found: 59.55 7.99 5.12 12.61 30 Example 4B 2- f fN- (2- fa .4-Dimethoxv-phenvl) -ethyl) -niney-i rt-l-vl) -methyl! -6.7-dimethoxy-1.2.3.4-tetT-ahydro-iBo^uinoline-35 dihydroohloride Prepared from 2- [ (N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4- - 77 - tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 92.8% of theory.
Melting point: 175-176#C 5 Calculated: C 60.66 H 7.35 N 5.33 CI 13.49 Pound: 60.58 7.56 5.32 13.22 Example 49 10 3 - r fN- fa - (Indolyl-31 -propyl) -pvrrolidvl-3) -methvll - 7. 8-methylenedioxy-1.3.4. S-tetrahydro-2H-3-bfenzazenine- dihydrpchl pride - 3. .5 x hydrate Prepared from 7,8 -methylenedioxy-1,3,4,5- tetrahydro- 2H-15 3-benzazepine and 3- (benzene-sulphonyloxymethyl) -N- [3-indolyl-3)-propyl]-pyrrolidine analogously to Example 2. Yield: 75% of theory.
Melting point: 191-193"C Calculated: C 61.01 H 7.21 N 7.90 CI 13.34 20 Found: 60.90 7.27 7.85 13.70 Example 50 2 - r fN- f3 - f 3-Methoxy-phenoxy) -propyl) -piperid-3-vl) -25 methyl 1 -6. 7 -methylenedioxy-1.2.3.4-tetrahvdro-isoquinoline-dihydrochloride Prepared from 2- [ (N- (3- (3-methoxy-phenoxy) -propyl) -piperid-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,4-30 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 94.5% of theory, Melting point: 169-171*C Calculated: C 57.03 H 7.36 N 5.11 CI 13.86 35 Found: 56.91 7.26 5.15 13.68 - 78 - Example 51 2- f fN- 12- (3.4-Dimethoxy-phenvl) -ethvl) -pjperid-3-vl) -methvll -fi . 7-dimethyl-l .2.3. 4-tetrahvdro-i Rngiiinoline-5 dihvdrochl nrri.de Prepared from 2- [ (N- (2- (3,4-dimethoxy-phenyl) -ethyl) -piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 10 tetrahydrofuran analogously to Example 3.
Yield: 91.3% of theory.
Melting point: 140-142#C Calculated: C 62.00 H 8.34 N 5.27 CI 13.44 Found: 61.85 8.27 5.31 13.33 15 example 52 2- f (N- (3 - (4-Methoxy-phenoxv) -propyl) -piperid-3-vl) -methvll -6 . 7-dimethyl -1 .7.2.4- tetrahydro-i soon inol Ine -20 dihydrochloride Prepared from 2- [ (N- (3- (4 - me t hoxy - phenoxy) -propyl) -piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 25 tetrahydrofuran analogously to Example 3.
Yield: 88.3% of theory.
Melting point: 170-172°C Calculated: C 63.14 H 8.24 N 5.65 CI 14.31 Found: 63.09 8.33 5.82 14.02 30 Example 53 2- f Yield: 93.3% of theory, Melting point: 150-154°C 5 Calculated: C 60.01 H 7.34 N 5.39. CI 13.64 Found: 59.96 7.41 5.25 13.43 Example 54 10 2-r(N-(3-(4-Methoxy-phenoxv)-propyl)-piperid-3-vl)-methyl!-6.7-methylenedioxy-1.2.3.4-tetrahydro-isoquinoline-dihydrochloride Prepared from 2-[ (N-(3-(4-methoxy-phenoxy)-propyl) -15 piperid-3-yl-3)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4- tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 95.3% of theory.
Melting point: 182-185"C 20 Calculated: C 61.05 H 7.09 N 5.48 CI 13.86 Found: 61.10 6.95 5.68 13.55 Example 55 25 2-T2-m-(3-(3.4-Methylenedioxy-phenoxy)-propyl)-piperid-3-vl)-ethyl! -6.7-dimethoxy-1-oxo-1.2.3.4-tetrahvdro-isoouinoline-hydrochloride Prepared from 2- [ (piperid-3-yl) -ethyl] -6,7-dimethoxy-30 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloro- 3-(3,6-methylenedioxy-phenoxy)-propane analogously to Example 1.
Yield: 35.5% of theory, Melting point: 97-100°C 35 Calculated: C 59.09 H 7.28 N 4.62 CI 6.65 Found: 58.97 7.36 4.66 6.52 - 80 - Example 56 2- T2- (N- (2- (2 .4-Dimet--hoxv-phenvl) -ethvl) -piperid-3-vl) -ethvl! -fi . 7-dimethoxy-1 -oxo-1. 2 .2.4-tetrahvdro-5 i a oou ino1ine-hydrochloride Prepared from 2-[(piperid-3-yl)-ethyl]-6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo- 2-(3,4-dimethoxy-phenyl)-ethane analogously to Example 10 1.
Yield: 35.9% of theory, Melting point: 103-105°C Calculated: C 62.60 H 7.79 N 5.21 CI 6.83 Found: 62.41 7.82 5.09 7.19 15 Example 57 2- f3- (N- 12-12.4-Dimethoxy-Phenyl) -ethvl) -pjperid-3-vl) -propyl! -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdro-20 isoguinoline-hydrochloride Prepared from 2- [3- (piperid-3-yl) -propyl] -6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo- 2-(3,4-dimethoxy-phenyl)-ethane analogously to Example 25 1- Yield: 32.6% of theory.
Melting point: 102-106°C Calculated: C 63.20 H 7.86 N 5.08 CI 6.43 Found: 63.39 7.90 4.86 6.13 30 Example 58 2- n- (N- n- (2 .4-Met-hyl enedloxv-phenoxv) -propyl) -piperid-a-vl) -propyl! -fi .7-dimethoxv-l-oxo-l .2.3.4-or tetrahydro- ifiocniinol ine-hvdrochlori.de Prepared from 2- [3- (piperid-3-yl) -propyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro- - 81 - 3-(3,4-methylenedioxy-phenoxy)-propane analogously to Example 1.
Yield: 29.7% of theory, Melting point: 97-100°C 5 Calculated: C 61.63 H 7.31 N 4.96 CI 6.47 Found: 61.94 7.46 5.16 6.48 Example 59 10 2-T(N-f3. 4-Dimethoxv-henzvl) -piperid-3-vl) -methvll -fi.7-dimethoxy-l-oxo-l.2.3.4-tetrahydro-isoquinoline- hyflrochlpride 15 Prepared from 2-(piperid-3-yl-methyl)-6,7-dimethoxy- l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 3,4-dimethoxy-benzylbromide analogously to Example 1.
Yield: 53.3% of theory.
Melting point : 127-132°C 20 Calculated: C 63.58 H 7.18 N 5.70 CI 7.22 Found: 63.30 7.22 5.52 7.14 Example 60 25 2- f (N- (3- (4-Methoxy-phenvl) -propyl) -piperid-3-vl) -methyl! -fi. 7-dimethoxy-l-oxo-l .2.3 .4-tetrahvdro-isopiiinolinft-hydroghloride Prepared from 2 - (piperid- 3 -yl -methyl) - 6,7 -dimethoxy -30 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-bromo- 3- (4-methoxyphenyl) -propane analogously to Example l. Yield: 42% of theory, Melting point: 229-231°C Calculated: C 66.31 H 7.63 N 5.73 CI 7.25 35 Found: 66.27 7.64 5.65 7.33 - 82 - Example 61 2-12- (N-(2-(3-Methyl-nhsnoxv) -propyl) -Piperld-2-vl) -ethvl! -6. 7 - dimethoxy-1 - oxo -1. 2 . 3 4-netrahvdro- 5 i s noil inol ine - hvdronhl or i de Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy- 1-oxo-l, 2 ,3, 4-tetrahydro-isoquinoline and 1-chloro- 3-(3-methyl-phenoxy) -propane analogously to Example 1. 10 Yield: 52.4% of theory, Melting point: 142-144#C Calculated: C 66.85 H 7.81 N 5.57 CI 7.05 Found: 66.73 7.68 5.53 6.94 15 Example 62 2-f2-(N-(2-(3.4-Dimethoxy-phenyl1-ethvl)-piperid-2-vl)-ethyl!-6.7-dimethoxy-l-oxo-l.2.3.4-t-.etrahvdro- i s ocru inol. .ine - hvdrochl or ide 20 Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo- 2-(3,4-dimethoxy-phenyl)-ethane analogously to Example 1. 25 Yield: 47.3% of theory.
Melting point: 150-155"C Calculated: C 64.72 H 7.68 N 5.39 CI 6.82 Found: 64.40 7.83 5.27 6.90 30 Example 63 2- \2-(N- I 3 -Bengvloxy-propyl) -piperid-2-yl) -ethyl! -6. 7 -dimethoxy-1 - oxo-1. 2. 3 . 4-tetrahydro-i finqmlnoline- hyflrochloriflft 35 Prepared from 2- [2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-benzyloxy-propane analogously to Example 1. - 83 - Yield: 56.3% of theory, Melting point: 116-120°C Calculated: C 66.85 H 7.81 N 5.57 CI 7.05 Found: 66.60 7.75 5.25 7.25 Example 64 2-T2-(N-(4-(4-Methoxv-phenvl)-butvl)-piperid-2-vl)-ethyl1-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdrO-isoguinoline-hydrochloride Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo- 4-(4-methoxy-phenyl)-butane analogously to Example l. Yield: 42.8% of theory, Melting point: 107-112°C Calculated: C 67.36 H 7.99 N 5.42 CI 6.86 Found: 67.16 8.05 5.35 7.34 Example 65 2-T2-(N-(3-(3. 5-Dimethoxv-phenoxv)-propyl)-pjperid- 2-yl)-ethyl! -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-isoqiiinoline-hydrochloride Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-l-oxo-l, 2, 3, 4-tetrahydro-isoquinoline and 1-chloro- 3-(3,5-dimethoxy-phenoxy)-propane analogously to Example 1.
Yield: 56.3% of theory, Melting point: 127-132DC Calculated: C 61.41 H 7.64 N 5.10 CI 6.46 Found: 61.56 7.65 5.28 6.89 - 84 - Example 66 2- f2- fN- (3- f3 . 4-MPhhvl PTiPdinyy-nhpnoYv) -propyl) -pjperid-2-vl)-ethvll-6.7-dimethoxv-l-oxo-l.2.3.4- 5 tetrahydro - i socni inol ine - hydrochl or ide Prepared from 2-[2- (piperid-2-yl) -ethyl]-6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro- 3-(3,4-methylenedioxy-phenoxy)-propane analogously to 10 Example l.
Yield: 49% of theory.
Melting point: 118-120QC Calculated: C 63.09 H 7.00 N 5.26 CI 6.65 Found: 62.90 7.04 5.46* 6.79 15 Example 67 2 - HN- (3 - (3 .5-Dimethoxv-phenoxy)-propyl)-piperid-3-vl)-methvll -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-20 isopiiinol. ine- hydrochloride Prepared from 2 - [ (piperid-3 -yl) -methyl] - 6,7-dimethoxy- 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloro- 3-(3,5-dimethoxy-phenoxy)-propane analogously to Example 25 1 • Yield: 37.5% of theory, Melting point: 98-102#C Calculated: C 62.85 H 7.35 N 5.24 CI 6.63 Found: 62.81 7.41 5.10* 6.75 30 Example 68 2-T(N-(3-(3.4-Methvlenedloxy-phenoxv)-propyl)-piperid- 3-yl) -methyl 1 -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydro-TBoquinoline-hvdrochloride 35 Prepared from 2- [ (piperid-2-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and l-chloro-3-(3,4-methylenedioxy-phenyl)-propane analogously to - 85 - Example 1.
Yield: 50% of theory, Melting point: 236-238°C Calculated: C 64.46 H 7.01 N 5.57 CI 7.04 5 Found: 64.30 6.97 5.59 7.08 Example 69 2 - r fN- (3- (3.4-Methylanedioxv-phenoxv) -nronvl ) -pjperid-10 3-yl) -methyl! -6. 7-rfimpthow-1 -nxo-1. 2.3.4-tPtrahvdro- ispquinpiJ. ine-hyflrorrhlpriflft Prepared from 2- [ (piperid-2-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro-15 3- (3,4-methylenedioxy-phenoxy) -propane analogously to Example 1.
Yield: 46.2% of theory, Melting point: 149-153°C Calculated: C 60.38 H 6.94 N 5.21 CI 6.60 20 Found: 60.30 6.93 5.29 6.37 Example 70 2 - f (N- (3- (2. 6-Dimethyl-phenoxy) -propyl) -pjparid-25 3-vl) -methyl! -6. 7-dimethoxy-l-oxo-l .2.3.4-tetrahvdro-isomiinol i ne-hydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloro-30 3- (2,6-dimethyl-phenoxy) -propane analogously to Example 1.
Yield: 53.3% of theory.
Melting point: 131-135°C Calculated: C 66.85 H 7.81 N 5.57 CI 7.05 35 Found: 66.88 7.95 5.59 6.85 Example 71 - 86 - 2- T fN- (A- (2 .4-Dichl oro-phenoxv) -hntyl) -pjperid- 3-yl)-methvll-6.7-dimethoxy-1-oxo-1.2.3.4-tetrahvdro-5 i b orni inol ine - h vdronhl or ide Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro- 4-(2,4-dichloro-phenoxy)-butane analogously to Example 10 1.
Yield: 54.1% of theory.
Melting point: 125-128°C Calculated: C 58.12 H 6.32 N 5.02 CI 19.06 Found: 58.21 6.38 5.08 18.85 15 Example 72 2-r(N-(2-(3.4-Dimethoxv-phenvl)-ethvl)-pioerid- 3-yl)-methvll-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-20 i soquinoline-hvdronhloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethoxy- 1-oxo-l , 2,3,4-tetrahydro-isoquinoline and 1-bromo- - 2- (3,4-dimethoxy-phenyl) -ethane analogously to Example 25 l.
Yield: 57.5% of theory, Melting point: 118-121°C Calculated: C 64.21 H 7.38 N 5.55 Found: 64.18 7.36 5.19 30 Example 73 2- T (N- (3- (3 .4-Dimathoxv-phenoxv) -propyl) -pjperid-3 - vl-) -methvll -6.7-dimethoxy^!-oxo-1 .2.3.4-tet-rahydro-35 i soquinoli ne-hvdroehloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro- 87 - 3-(3,4-dimethoxy-phenoxy)-propane analogously to Example 1.
Yield: 62.5% of theory, Melting point: 112-115°C 5 Calculated: C 60.80 H 7.47 N 5.24 Pound: 60.65 7.69 5.27 Example 74 10 2- T (N- (3- (3.4-Dimethoxy-phenoxv) -propyl) -pjperidvl-3) -methvll -6 . 7-methylenedioxy-1-oxo-1. 2.3.4-tetrahvdro-isoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-15 methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1 -chloro-3 -(3,4 -dimethoxy-phenoxy) -propane analogously to Example 1.
Yield: 60% of theory, Melting point: 97-100#C 20 Calculated: C 60.38 H 6.94 N 5.40 CI 6.60 Found: 60.20 6.97 5.21 6.83 Example 75 25 2- r (N- (7.-(4-Methoxy-phenvl) -ethvl) -piperid-3-vl) - methvll -6. 7-methylenedioxy-1-oxo-3 .2.3.4-tetrahydro-isoouinoline-hydrochloride Prepared from 2-[ (piperid-3-yl)-methyl]-6,7-30 methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and l-chloro-2- (4-methoxy-phenyl) -ethane analogously to Example l.
Yield: 71.4% of theory.
Melting point: 195-197°C 35 Calculated: C 62.94 H 6.97 N 5.87 CI 7.73 Found: 62.90 6.98 5.68 8.04 - 88 - Example 7fi 2-r(N- 12- I 3.4-Dimethoxy-phenyl)-ethvl)-pjperid- 3-vl ) -methyl 1 -6 .7-dimethyl -1 -oxo-1 . 2 a 4-tetrahydr-o-5 A P hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethyl- 1-oxo-l, 2, 3# 4-tetrahydro-isoquinoline and 1-bromo- 2-(3,4-dimethoxy-phenyl)-ethane analogously to Example 10 1- Yield: 41.9% of theory, Melting point: 132-134°C Calculated: C 63.57 H 8.10 N 5.49 CI 6.95 Found: 63.70 8.26 5.45 7.13 15 Example 77 2- r fN- (3- 14-Methoxy-phenoxv) -propyl) -pjperid-3-yl)-methyl1-6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdro- 20 isoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethyl- 1-oxo-l, 2, 3, 4-tetrahydro-isoquinoline and l-chloro- 3-(4-methoxy-phenoxy)-propane analogously to Example 1. 25 Yield: 57.8% of theory, Melting point: 144-146°C Calculated: C 68.55 H 7.88 N 5.92 CI 7.49 Found: 68.45 7.80 6.11 7.33 30 Example 78 2- T fN- 13- 13-Methoxy-phenoxy) -propyl) -pjperid73- vl) -methyl 1 -6.7-methyl enedioxy-1-oxo-1. 2.3.4-tetrahvdro-iaoqiiinol ine-hydrochloride 35 Prepared from 2-[(piperid-3-yl)-methyl]-6,7-methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and l-chloro-3-(3-methoxy-phenoxy) rpropane analogously to - 89 - Example 1.
Yield: 32.5% of theory, Melting point: 142-145°C Calculated: C 60.58 H 6.95 N 5.52 CI 6.99 5 Found: 60.42 6.92 5.50 7.18 Example 79 2- f fN- (3- (3-Methyl-phenoxy 1 -propyl) -piperid-3-vl) -10 methvll -6 . 7-methylenedioxy-l-oxo-l .2.3.4-tetrahydro-i soquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 15 3- (3-methyl-phenoxy) -1-chloro-propane analogously to Example 1.
Yield: 31.6% of theory, Melting point: 178-180°C Calculated: C 63.59 H 6.97 N 5.70 CI 7.22 20 Found: 63.59 6.92 5.86 7.50 Example.80 2-T(N- f3- f4-Mei-hnyy-N-methyl-phenylamino) -propyl) -25 piperid-3-yl)-methyl!-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdro- i Bogninoline-dihydrochloride Prepared from 2 - [ (piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and l-chloro-30 3- (4-methoxy-N-methyl-phenylamino) -propane analogously to Example l.
Yield: 52.5% of theory.
Melting point: 180-183°C Calculated: C 60.64 H 7.45 N 7.58 CI 12.79 35 Found: 60.50 7.35 7.56 12.87 - 90 - Example 81 2-r fN-(3-(4-Methoxv-phenoxv)-propyl)-pvrrolidvl-3) -methvll -6. 7-dimethoxv-l-oxo-l. 2 . 3 .4-tetrahvdro-5 isoauinol ine -hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and N-(3-(4-methoxy-phenoxy)-propyl)-3 -benzenesulphonyloxymethyl-pyrrolidine analogously to 10 Example 2.
Yield: 84.4% of theory, Melting point: 142-144°C Calculated: C 63.60 H 7.18 N 5.71 CI 7.22 Found: 63.75 7.12 5.64 7.32 15 Example B2 2- f (N—(3- f6-Methoxv-naphthyl-2-oxv) -propyl) -pvrrolid- 3-vl)-fi-7-dimethoxv-l-oxo-l.2.3.4-tetrahydro-20 isoquinoline Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3- (p-toluenesulphonyloxymethyl) -N-(6-methoxy-naphthyl-2-oxy) -pyrrolidine analogously to 25 Example 2.
Yield: 47% of theory.
Melting point: 142-144°C Calculated: C 71.41 H 7.19 N 5.55 Found: 71.14 7.16 5.53 30 2- T (N-.f3- (4-Methoxv-phenoxv) -propyl) -Pvrrolld-3-vl)-methvll-6.7-dimethoxv-l.2.3.4-tetrahydro-35 iBoquinoline-dihydrochloride Prepared from 2-[ (N-(3-(4-methoxy-phenoxy)-propyl)-pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4- I - 91 - tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 90.9% of theory, Melting point: 248-250"C 5 Calculated: C 60.81 H 7.46 N 5.46 CI 13.81 Found: 60.79 7.61 5.48 13.84 Example 84 10 2-r fN-f3- (4-Methoxv-phenoxv) -propyl) -pyrrolid-3- yl) -methyl! -6. 7-dimethyl-1-oxo-l. 2.3. 4-tetrahvdro-isoquinoline-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l, 2,3,4-tetrahydro-15 isoquinoline and N-[3-(4-methoxy-phenoxy)-propyl]- 3-benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 60.6% of theory, Melting point: 118-121°C 20 Calculated: C 68.03 H 7.69 N 6.10 CI 7.72 Found: 67.90 7.71 6.04 7.90 Example 85 25 2- r fN- f 2- f 3 .4-Dimethoxy-phenyl) -ethyl) -pyrrolid- 3-yl)-methyl1-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-iRogninoline-hydroehloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-30 isoquinoline and N- [2- (3,4-dimethoxy-phenoxy)-ethyl]-3-benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 56.7% of theory, Melting point: 116-118BC 35 Calculated: C 63.60 H 7.19 N 5.71 CI 7.22 Found: 63.82 7.32 5.60 7.66 i * • ■ - 92 - Exanrole 86 2- T (N- (3- U-Methoxv-phenoxv) -propyl) -Pvrrolid-3-yl) -methvll -6 . 7-dimethvl-l .2.3 .4-tetrahvdro-5 isoquinollne-dihydroohloride Prepared from 2- [N- (3- (4-methoxy-phenoxy) -propyl) -pyrrolid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 10 tetrahydrofuran analogously to Example 3.
Yield: 90.9% of theory, Melting point: 243-246°C Calculated: C 64.85 H 7.95 N 5.82 CI 14.73 Found: 64.88 7.92 5.63 14.80 15 Example 87 2-T(N-(2-(3.4-Pi methoxy-phenvl)-ethvl)-pvrrolid- 3-vl) -methyl!-6.7-dimethoxy-1.2.3.4-tetrahvdro-20 i R omi inol ine - dihydrochloride Prepared from 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 25 tetrahydrofuran analogously to Example 3.
Yield: 92.9% of theory, Melting point: 240-242°C Calculated: C 60.81 H 7.46 N 5.46 CI 13.81 Found: 60.64 7.61 5.31 13.50 30 Example 88 2-f(N-(3-(Pyrxri-4-yl)-propyl)-pyrrolid-3-vl)-methvll -5.6-dimethyl-1-oxo-l.3-dihvdro-isoindole- 35 dihydroohl oride- aemihvdrate Prepared from 2- [ (N-(3-pyrid-4-yl)-propyl)-pyrrolid- 3-yl) -methyl] -5,6-dimethyl-phthalimide and zinc/glacial - 93 - acetic acid analogously to Example 4.
Yield: 65% of theory, Melting point: 119-122°C Calculated: C 62.02 H 7.24 N 9.43 CI 15.92 5 Found: 62.25 7.47 9.39 15.90 Example 89 2- f3 - (N- (3- (Pvrid-3-vl) -propyl) -piperid-3-vl) -propyl 1 -10 5. 6-dimethoxy-l-oxo-l. 3-dihvdro-isoindole- dihydrQffhlQra.de -monohyflrate Prepared from 2-[3-(N-(3-(pyrid-3-yl)-propyl)-piperid- 3-yl) -propyl] -5,6-dimethoxy-phthalimide and zinc/glacial 15 acetic acid analogously to Example 4.
Yield: 72% of theory.
Melting point: 118-121"C Calculated: C 59.08 H 7.43 N 7.95 CI 13.41 Found: 59.02 7.23 7.12 13.27 20 Example 90 2- r fN- (3- (Pyrxfl-3-vl) -propyl) -piperid-3-vl) -methvll -S.6-dimethoxy-3-oxo-1.3-dihvdro-isoindole- 25 dihydrochloride-monohvdrate Prepared from 2- [ (N- (3- (pyrid-3-yl) -propyl) -piperid- 3-yl)-methyl]-5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Example 4. 30 Yield: 42% of theory.
Melting point: 91-96°C Calculated: C 59.08 H 7.43 N 7.95 CI 13.41 Found: 59.02 7.23 7.12 13.27 35 - 94 - Example qi 2- T (N- 12- (d . 7-Dimethoxy-isocm inol - 4 - vl) -ethvl) -piperid-3-yl)-methyl!-5.fi-dimethoxv-l-oxo-1.3-dihvdro-5 isoindole Prepared from 2-[(N- (2-(6,7-dimethoxy-isoquinol-4-yl) -ethyl) -piperid-3-yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to 10 Example 4.
Yield: 64% of theory, Melting point: 85-88°C Calculated: C 65.39 H 7.19 N 7.88 Found: 65.16 7.27 7.53 15 Example 92 2-F2- (N-12-(Pyrid-4-yl)-propyl)-piperid-2-vl)-ethvl!-5.6-dimethyl-1-oxo-l.3-dihvdro-isoindole 20 Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid-2-yl)-ethyl]-5,6-dimethyl-phthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 73% of theory, 25 Melting point: 103-104"C Calculated: C 76.68 H 8.49 N 10.73 Found: 76.57 8.54 10.60 Example 93 30 2- T (N- (3- (Pyrid-4-vl) -propyl) -pyrrolid-3vl) -methvll -5.6-dimethyl-l. 3-dihydro-isoindole-trihydroohlorxde- semihydrate 35 Prepared from 2 - [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid- 3-yl) -methyl] -5,6-dimethyl-1-oxo-l, 3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3. - 95 - Yield: 68% of theory, Melting range: 118-127°C (amorphous) Calculated: C 59.03 H 7.54 N 8.98 CI 22.73 Found: 58.93 7.48 8.84 22.92 5 Example 94 2-r2-(N-(3-(Pyrid-4-yl)-propyl)-piperid-2-vl)-ethvll - 5.6-dimethyl-1. 3-dihydro-isoindole 10 Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid-2-yl)-ethyl]-5,6-dimethyl-1-oxo-l,3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3. 15 Yield: 70% of theory, Melting range: 135-148'C (amorphous) Calculated: C 54.59 H 8.24 N 7.63 CI 19.33 Found: 54.48 8.26 7.51 19.60 20 Example 95 2- T (N- (l- (Pvrxd-4-vl) -methvl) -piperid-3-vl) -methvll -5.6-dimethoxy-1.3-dihydro-isoindole-trihvdrochloride- trihydrate 25 Prepared from 2- [ (N- (1- (pyrid-4-yl) -methyl) -piperid- 3-yl)-methyl]-5,6-dimethoxy-phthalimide and lithium aluminium hydride in ether analogously to Example 3. Yield: 68% of theory, 30 Melting range: 176-189°C (amorphous) Calculated: C 49.76 H 7.21 N 7.91 CI 20.03 Found: 49.93 7.12 8.00 20.44 35 f f - 96 - Example 96 2- f m- (2- (6. 7-nimethoyv-isocniino.l-4-vl) -ethvl) -piperid-3-yl)-methyl 1 -5.6-dimethyl-1.3-dihvdro-5 isoindole-dihydrochloride-semihvdrate Prepared from 2-[(N-(2-(6,7-dimethoxy-isoquinol-4-yl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethy1- 1-oxo-l,3-dihydro-isoindole and lithium aluminium 10 hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 22.7% of theory, Melting range: 222-236°C (amorphous) Calculated: C 62.22 H 7.20 N 7.50 CI 15.83 15 Found: 62.01 7.64 7.08 15.79 Example 97 2-r(N-(l-(Pyrid-4-yl)-methvl)-piperid-3-vl)-methvll-20 5.6-methylenedioxy-1.3-dihvdro-isoindole- trihydrochlorifle-semihyctorate Prepared from 2-[(N- (1-(pyrid-4-yl)-methyl)-piperid- 3-yl)-methyl]-5,6-methylenedioxy-phthalimide and lithium 25 aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 55% of theory, Melting range: 215-225°C (amorphous) Calculated: C 53.68 H 6.22 N 8.94 CI 22.63 30 Found: 53.60 6.45 8.65 22.28 Example 98 2- f (K- f 3- fPyrjd-4-yl) -propyl) -pvrrolid-3-vl) -methvll -35 6. 7-dimethyl-l .2.3.4-tetrahydro-i gocniinoliTie-trihvdro-chloride-monohydrate Prepared from 2-[ (N-(3-(pyrid-.4-yl)-propyl)-pyrrolid- t f 10 - 97 - 3 -yl) -methyl] - 6, 7-dimethyl -1-oxo-l ,2,3,4 - tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 63% of theory, Melting point: 254-256°C Calculated: C 58.71 H 7.80 N 8.56 CI 21.66 Found: 58.53 7.72 8.25 21.53 Example 99 2 - r (N- (3.- (Pyrid-4-yl) -methyl) -piperid-3-yl) -methyl 1 - 6. 7-dimethoxy-l. 2.3.4-tetrahydT-o-isonuinoline-trihvdro- chloride-dihydrate 15 Prepared from 2 - [ (N- (1- (pyrid-4-yl) -methyl) -piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 63% of theory, 20 Melting range: 158-169°C (amorphous) Calculated: C 52.42 H 7.27 N 7.97 CI 20.18 Found: 52.55 7.49 7.57 20.25 25 Example 1QQ 2- T2- fN- (3- (Pyrid-4-vl) -propyl) -piperid-2-vl) -ethyl! -6. 7-methylenedioxy-1. 2. 3.4-tetrahydro-isoouinoline-t ^hydrochloride- trihvdrate 30 Prepared from 2- [2-(N- (3-(pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] -6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 90% of theory, 35 Melting range: 108-119°C (amorphous) Calculated: C 52.58 H 7.41 N 7.36 CI 18.62 Found: 52.56 7.25 7.38 19.49 - 98 - Example 101 2- f fN- f3-fPvrid-3-vl) -propyl) -piperid-3-vl) -methyl! -fi. 7-methylenedioxy-1. 2 . 3 .4-tetrahvdro-isoauinoline- 5 dihydrochloride-monQhydrate Prepared from 2-[(N-(3-(pyrid-3-yl)-propyl)-piperid- 3-yl)-methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4- tetrahydro-isoquinoline and lithium aluminium hydride in 10 tetrahydrofuran/ether analogously to Example 3.
Yield: 72% of theory, Melting range: 126-138°C (amorphous) Calculated: C 59.50 H7.28 N 8.67 CI 14.64 Found: 59.57 7.29 8.49 , 14.51 15.
Example 102 2- T fN- (3- fPvrid-3-vl) -propyl) -piperid-3-vl) -methvll - fi.7-dimethyl-l.2.3.4-tetrahydro-isocminoline-trihvdro- 20 ffh3Lori.de Prepared from 2-[(N-(3-(pyrid-3-yl)-propyl)-piperid- 3-yl)-methyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 25 tetrahydrofuran/ether analogously to Example 3.
Yield: 59% of theory.
Melting range: 138-154°C (amorphous) Calculated: C 61.66 H 7.86 N 8.62 CI 21.84 Found: 61.53 8.00 8.64 21.35 30.
Example 103 2- f fN- (3- (Pyrid-4-yl) -propyl) -pvrrolid-3-vl) -methvll -6.7-dimethyl-l-oxo-l. 2.3.4-tetrahvdro-iBoquinoline-35 dihydrochloride -monohvdrate Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(pyrid-4-yl)- ? « - 99 - propyl] -pyrrolidine analogously to Example 2.
Yield: 39% of theory, Melting range: 74-86°C (amorphous) Calculated: C 61.53 H 7.53 N 8.97 Cl 15.13 5 Found: 61.42 7.62 8.83 15.05 Example 104 2-r (N-(3-(Pyrid-3-vl)-propyl)-piperid-3-vl)-methvll-10 6. 7-dimethoxy-1-oxo-1.2.3.4-tetrahvdro-isoauinoline-dihydrochloride-monohydrate Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(benzenesulphonyloxy-methyl-N-15 [3-(pyrid-3-yl)-propyl]piperidine in dimethylsulphoxide with potassium tert.butoxide analogously to Example 2. Yield: 45% of theory, Melting range: 140-148°C (amorphous) Calc. (X 2 HC1 x H20): C 58.36 H 7.25 N 8.16 Cl 13.78 20 Found: 58.35 7.32 8.04 13.65 Example 105 2-f3- (N-(3-(Pvrid-4-vl)-propyl)-piperid-3-vl)-propyl! -25 6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdro-isoouinoline-dihyflrochlpride-flihyflrate Prepared from 2- [3- (pyrid-3-yl) -propyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 4-(3-30 chlorppropyl) -pyridine analogously to Example 1.
Yield: 48% of theory.
Melting range: 85-96°C (amorph) Calculated: C 57.84 H 7.73 N 7.49 Cl 12.65 Found: 57.71 7.91 7.35 13.04 35 - 100 - Example 106 2- T3- fN- f2- f6. 7-Dimethoxy-iBogtiinol-4-vl) -ethvl) - piperid-3-yl)-propyl! -6.7-dimethoxy-1-oxo-l.2.3.4-5 tetrahydro-isoguinoline-dihydrochloride-monohvdrate Prepared from 2-[3-(pyrid-3-yl)-propyl]-6,7-dimethoxy- 1-oxo-l, 2, 3, 4 -tetrahydro-isoquinoline and 4- (2-chloroethyl)-6,7-dimethoxy-isoquinoline analogously to 10 Example 1.
Yield: 34% of theory, Melting range: 162-171°C (amorphous) Calculated: C 60.17 H 7.10 N 6.57 Cl 11.10 Found: 59.85 7.00 6.86 11.04 15 Example 107 2-f(N-(3-(Pyrid-3-yl)-propyl)-piperid-3-yl)-methyl!- 6.7-methylenedioxy-1-oxo-l.2.3:4-tetrahvdro-20 isoguinoline-hydrochloride Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(pyrid-3-yl)-propyl]-piperidine analogously to Example 25 2.
Yield: 60% of theory.
Melting range: 194-196°C (amorphous) Calculated: C 64.92 H 6.81 N 9.46 Cl 7.98' Found: 64.91 6.95 9.67 7.80 30 Example 1,08 2- r fN- (1- fPyrid-4-vl) -methvl) -niperid-3-vl) -methyl! -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahydro-iRooujnoline-35 dihydrochloride-monohvdrate Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline in dimethylsulphoxide with potassium - 101 - tert.butoxide and 3-chloromethyl-N-[1-(pyrid-4-yl)-methyl]-piperidine analogously to Example 2.
Yield: 41% of theory, Melting range: 142-158"C (amorphous) 5 Calculated: C 56.78 H 6.83 N 8.63 Cl 14.58 Found: 56.45 6.59 8.66 14.62 Example 109 10 2- r (N- (2- (6.7-Dimethoxy-isoquinol-4-yl) -ethyl) - piperid-3-yl)-methyl! -6.7-dimethyl-l-oxo-l.2.3.4-tetrahydro-isocruinoline-dihvdrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-15 isoquinoline in dimethylsulphoxide with potassium tert.butoxide and 3-chloromethyl-N-[2-(6,7-dimethoxy-isoquinol-4-yl)-ethyl]-piperidine analogously to Example 2.
Yield: 62% of theory, 20 Melting range: 148-162°C (amorphous) Calculated: C 64.27 H 7.01 N 7.49 Cl 12.65 Found: 64.11 7.20 7.59 12.89 Example HQ 25 2- T2- fN- (3- fPvrid-4-vl) -propyl) -piperid-2-vl) -ethvl! - 6,7-methylenedioxy-1-oxo-l , 2,3,4-tetrahydro- isoguinoline-dihydrochloride-dihydrate 30 Prepared from 6,7-methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2-chloroethyl)-N-[3-(pyrid-4-yl)-propyl]-piperidine analogously to Example 2.
Melting range: 115-128°C (amorphous) 35 Calculated: C 56.59 H 7.03 N 7.92 Cl 13.37 Found: 56.61 6.90 7.84 13.41 - 102 - Example 111 2- r fN- f3-fPvrid-3-vl) -propyl) -piperid-3-vl) -methvll -6.7-dimethyl-l-oxo-l.2.3.4-tetrahydro-isoquinoline-5 dihydrochloride-dihydrate Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline in dimethylsulphoxide with potassium tert.butoxide and 3 -chloromethyl-N- [3 - (pyrid-3 -10 yl)-propyl]-piperidine analogously to Example 2.
Yield: 62% of theory, Melting range: 118-127°C (amorphous) Calculated: C 60.00 H 7.85 N 8.39 Cl 14.16 Found: 60.24 8.07 8.36 14.62 15 Example 112 2-T(N-(3-(Pyrid-3-yl)-propyl)-pyrrolid-3-yl)-methyl!- 6.7-methylenedioxy-1-oxo-1.2.3.4-tetrahvdro- 20 isoguinoline-dihydroshloride Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(pyrid-3-yl)-propyl]-pyrrolidine analogously to Example 25 2.
Yield: 26% of theory.
Melting range: 102-113°C (amorphous) Calculated: C 59.22 H 6.27 N 9.01 Cl 15.20 Found: 59.27 6.49 8.92 14.48 30 Example 113 2- r fN- (3-fPyrid-4-vl) -propyl) -pvrrolid-3-vl) -methvll -7.8 -methvl enedioxv- 2 -oxo-1.3 -dihvdro- 2H- 3 -benzazeoine- 35 dihydrochloride Prepared from 7#8-methylenedioxy-2-oxo-l,3-dihydro-2H-benzazepine and 3-chloromethyl-N-[3-(pyrid-4- - 103 - yl)-propyl]-pyrrolidine analogously to Example 2.
Yield: 58% of theory, Melting range: 132-141"C (amorphous) Calculated: C 60.25 H 6.11 N 8.78 Cl 14.82 5 Found: 60.00 6.40 8.52 14.56 Example 114 2- r (N- (3- (Pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl! - 10 7. 8 -dimethoxy- 2 - oxo-1.3-dihvdro-2H-3-benzazepine-. dihydrochloride-dihvdrate Prepared from 7,8-dimethoxy-2-oxo-1,3-dihydro-2H-benzazepine and 3-chloromethyl-N-[3-(pyrid-3-yl) -15 propyl]-piperidine analogously to Example 2.
Yield: 67% of theory, Melting range: 128-134°C (amorphous) Calculated: C 57.34 H 7.21 N 7.71 Cl 13.02 Found: 57.80 7.37 7.92 13.06 20 Example 1X5 3- r (N- (3 - (Pvrid-3-vl) -propyl) -piperid-3-vl) -methvll -7. 8-dimethyl-2-oxo-1. 3-dihvdro-2H-3-benzazepine- 25 dihydroohl or ide - dihydrat e Prepared from 7,8-dimethyl-2-oxo-l,3-dihydro-2H-benzazepine and 3-chloromethyl-N-[3-(pyrid-3-yl)-propyl] -piperidine analogously to Example 2. 30 Yield: 94% of theory, Melting range: 77-86°C (amorphous) Calculated: C 60.92 H 7.67 N 8.19 Cl 13.83 Found: 60.75 7.60 8.37 13.72 35 - 104 - Bxamnle; 116 3- T2- (N- (3- (Pvrid-4-yl) -propyl) -piperid-2-vl) -ethvll -7. fl-dimethyl-2-oxo-1. 3-dihvdro-2H-3 -benzazepine-5 dihydrochloride Prepared from 7,8-dimethyl-2-oxo-1,3-dihydro-2H-benzazepine and 2-(2-chloroethyl)-N-[3-(pyrid-4-yl)-propyl]-piperidine analogously to Example 2. 10 Yield: 94% of theory, Melting range: 118-130°C (amorphous) Calculated: C 66.11 H 7.60 N 8.56 Cl 14.45 Found: 65.92 7.86 8.33 14.09 15 Example 117 3-T (N-(2-(6.7-Dimethoxv-isoauinol-4-vl)-ethvl)-piperid-3-yl)-methvll-7.8-dimethoxy-2-oxo-1.3-dihvdro-2H-3 -henzazepine-monohvdrate 20 Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H-3-benzazepine and 3-chloromethyl-N- [2- (6,7-dimethoxy-isoquinol-4-yl)-ethyl]-piperidine analogously to Example 2. 25 Yield: 69% of theory.
Melting range: 85-96°C (amorphous) Calculated: C 67.73 H 7.15 N 7.64 Found: 67.96 7.19 7.75 30 Sxaiqple 11B 3- T3- fN- (3- (Pyrid-3-yl) -propyl) -piperid-3-vl) -propyl! -7. B-dimftthmcv-2-oxo-l. 3-dihvdro-2H-3-henzazepine-d ihvdroohl pride -monohvdrat e 35 Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H-3-benzazepine and 3-(3-chloropropyl) -N- [3-(pyrid-3-yl)-propyl]-piperidine analogously to Example 2. - 105 - Yield: 72% of theory, Melting range: 94-106°C (amorphous) Calculated: C 60.64 H 7.45 N 7.57 Cl 12.78 Found: 60.80 7.44 7.46 12.59 5 Example 119 3-T2-(N-(3-(Pyrid-4-yl)-propyl)-piperid-2-yl)-ethyl1 -7.8-methylenedioxy-2-oxo-1.3-dihydro-2H-3-benzazepine- 10 dihydrochloride-dihydrate Prepared from 7, 8-raethylenedioxy-2-oxo-l, 3-dihydro-2H-3-benzazepine and 2- (2-chloroethyl) -N- [3- (pyrid- 4-yl) -propyl] -piperidine in dimethylsulphoxide and 15 potassium tert .butoxide analogously to Example 2.
Yield: 67% of theory, Melting range: 148-161'C (amorphous) Calculated: C 57.56 H 6.87 N 7.74 Cl 13.07 Found: 57.72 7.03 7.61 13.62 20 Example 120 3- r (N- (1- (Pyrid-4-yl) -methvl) -piperid-3-vl) -methvll - 7,8-dimethyl-2-oxo-l. 3-dihydro-2H-3-benzazepine - 25 dihydrochl ori.de -monohydrat e Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H-3-benzazepine and 3-chloromethyl-N- [1- (pyrid-4-yl) -methyl] -piperidine in dimethylsulphoxide and 30 potassium tert .butoxide analogously to Example 2.
Yield: 75% of theory, Melting range: 113-127"C (amorphous) Calculated: C 61.79 H 7.13 N 9.01 Cl 15.20 Found: 61.55 7.32 9.04 15.11 - 106 - Example 121 3-r Yield: 71% of theory, Melting range: 95-l06°C (amorphous) Calculated: C 57.83 H 6.67 N 8.43 Cl 14.22 15 Found: 57.67 6.82 8.27 14.05 Example 122 3-T2-IN-(3-(Pvrid-4-vl)-propyl)-piperid-2-vl)-ethvll -20 7.a-dimethyl-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepine- flAhydrpchlpride-semihyflrate Prepared from 3-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid-2-yl)-ethyl]-7,8-dimethyl-2-oxo-1,3-dihydro-2H-25 3-benzazepine and 10% palladium/charcoal under a hydrogen pressure of 5 bar at 80°C analogously to Example 5.
Yield: 73% of theory.
Melting point: 236-238®C 30 Calculated: C 64.65 H 8.04 N 8.37 Cl 14.14 Found: 64.91 8.02 ,8.25 13.92 35 - 107 - Example 123 3-T3-(N-(2-(2-Methyl-pyrid-6-vl)-ethyl)-pjperid- 3-yl) -propyl] -7.8-dimethoxy-2-oxo-l. 3.4.5-tetrahydro-, 2H- 3 -benzasepine-dihydrochloride-monohydrate Prepared from 3-[3-(piperid-3-yl)-propyl)]-7, 8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2- (benzenesulphonyloxy-ethyl) -6-methyl-pyridine in dimethylsulphoxide with potassium carbonate at 120°C analogously to Example 1.
Yield: 29% of theory, Melting range: 105-113°C (amorphous) Calculated: C 60.42 H 7.78 N 7.55 Found: 60.68 7.50 7.42 Example 124 3-r(N-(3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methyl 1 - 7. 8-dimethoxy-2-oxn-l. 3.4. 5-tetrahydro-2H-3-benzazepine- dihydrochloride Prepared from 3-[ (N- (3-(pyrid-3-yl) -propyl) -piperid-3-yl) -methyl] -7, 8-dimethoxy-2-oxo-l, 3-dihydro-2H-3-benzazepine by hydrogenation at 5 bar hydrogen pressure in ethauiol with 10% palladium charcoal at 70°C analogously to Example 5.
Yield: 52% of theory* Melting range: 113-122°C (amorphous) Calculated: C 61.17 H 7.30 N 8.23 Found: 61.31 7.50 8.28 Example 125 - 108 - 3-f(N-12-f6.7-Dimethoxy-isoouinol-4-vl)-ethvl)-piperid-3-vl)-methvll -7.8-dimethoxy-2-oxo-1,3.4.5- 5 tetrahvdro-2H-3 -benzazepine x H_,Q Prepared from 3- [ (N- (2- (6,7 - dimethoxy-isoquinol- 4-yl) -ethyl) -piperid-3-yl) -methyl] -7,8-dimethoxy- 2-oxo-l,3-dihydro-2H-3-benzazepine by hydrogenation at 5 10 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 70°C analogously to Example 5.
Yield: 50% of theory, Melting range: 82-86°C (amorphous) Calculated: C 66.40 H 7.55 N 7.48 15 Found: 66.26 7.50 7.59 Example 126 3- T3- (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-vl) -propvll -20 7. 8 - dimethoxy- 2 - oxo -1.3.4. 5-tetrahvdro-2H-3-benzazepine- dihydrochlori.de -d,i,hydrate Prepared from 3- [3- (N- (3- (pyrid-3-yl) -propyl) -piperid-3-yl) -propyl] -7,8-dimethoxy-2-oxo-l,3-dihydro-2H-25 3-benzazepine by hydrogenation at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 70°C analogously to Example 5.
Yield: 64% of theory, Melting range: 106-115°C (amorphous) 30 Calculated: C 58.53 H 7.89 N 7.31 Cl 12.34 Found: 58.46 7.61 7.14 12.57 35 - 109 - Example 3 27 3- T fN- (3- (Pyrid-3-yl) -propyl) -piperid-3-vl) -methvll -7. 8-methylenedioxy-2-oxo-1 .3.4. 5-tetrahydro-2H-3 - benzaz ep ine - dihydr ochl or .ide -monohvdra t e Prepared from 3 - [ (N- (3- (pyrid-3-yl) -propyl) -piperid-3-yl) -methyl] -7,8-methylenedioxy-2-oxo-1,3-dihydro-2H-3-benzazepine at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 80°C analogously to Example 5.
Yield: 81% of theory, Melting range: 126-138°C (amorphous) Calculated: C 58.58 H 6.88 N 8.19 Cl 13.83 Found: 58.43 7.00 7.85 13.71 Example 128 3- T2- (N- (3- (Pyrid-4-vl) -propyl) -piperid-2-vl) -ethvll -7. 8-methylenedioxy-2-oxo-1 .3.4. 5-tetrahvdro-2H-3-henzazepine-dihvdrochloride-monohvdrate Prepared from 3-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid-2-yl) -ethyl] -7,8-methylenedioxy-2-oxo-l,3-dihydro-2H-3-benzazepine at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 80"C analogously to Example 5.
Yield: 74% of theory, Melting range: 132-146'C (amorphous) Calculated: C 59.31 H 7.08 N 7.98 Cl 13.46 Found: 59.18 7.41 7.80 13.25 - 110 - Example 129 3- f (N- (3- (Pvrid-3-yll -propyl 1 -piper i d-3 - vl) -methyl! -7. 8-dimethyl-2-oxo-1.3.4. 5-tetrahvdro-2H-3-benzazep.ine-5 dihydrochloride Prepared from 3-[ (N-(3-(pyrid-3-yl)-propyl)-piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3-dihydro-2H-3-benzazepine and 5 bar hydrogen pressure with 10% 10 palladium/charcoal in ethanol at 80°C analogously to Example 5.
Yield: 54% of theory.
Melting range: 92-105°C (amorphous) Calculated: C 62.90 H 7.92 N 8.46 Cl 14.28 15 Found: 63.19 7.90 8.45 14.30 Example 3.3 Q 3-r (N- (3- (Pyrid-4-vl)-pvrrolid-3-vl)-methvll-7.8-20 methylenedioxy-1.3.4.5-tetrahvdro-2H-3-benzazepine- trihydrochloride-monohydratft Prepared from 3- [ (N-(3-(pyrid-4-yl)-propyl)-pyrrolid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-25 tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 73% of theory, Melting range: 96-108°C (amorphous) 30 Calculated: C 55.53 H 6.97 N 8.06 Cl 20.42 Found: 55.06 7.28 ' 7.77 20.07 Example 131 35 3- r (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methyl 1 - 7. 8-dimethoxy-1 . 3 .4. g-tetrahvdro-2H-3-henzazepine-di hydrochloride - Ill - Prepared from 3-[(N-(3-(pyrid-3-yl)-propyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3. 5 Yield: 71% of theory, Melting point: 208-210°C Calculated: C 62.89 H 7.91 N 8.46 Cl 14.28 Pound: 62.70 7.53 8.22 14.50 10 Example 132 3-\2-fN-(3-(Pyrid-4-yl)-propyl)-pjperid-2-vl)-ethvll-7.8-methylenedioxy-1.3.4.5-tetrahvdro-2H-3-benzazepine- trihyflroGhlorifle 15 Prepared from 3-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid- 2-yl)-ethyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 20 3.
Yield: 63% of theory.
Melting range: 123-136°C (amorphous) Calculated: C 58.81 H 7.21 N 7.91 Cl 20.00 Pound: 58.51 7.41 7.92 19.86 25 Example? 133 3- r fN- (3- (Pyrid-3-yl) -propyl) -p.iperid-3-vl) -methvll - 7.8-methylenedioxy-1.3.4.5-tetrahvdro-2H-3-benzazepine-30 trihvdrochloride-semihvdrate Prepared from 3 - [ (N- (3- (pyrid-3-yl) -propyl) -piperid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and lithium aluminium 35 hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 75% of theory, Melting range: 126-138#C (amorphous) - 112 - Calculated: C 57.09 H 7.10 N 7.99 Cl 20.22 Found: 57.05 7.32 8.05 20.37 Example 134 5 3- T2- fN- (3- fPyrid-4-vl) -propyl) -piperid-2-vl) -ethvll -7. 8-dimethyl-l -3.4.5-tetrahydro-2H-3-benzazepine-trihvdrochloride 10 Prepared from 3- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid- 2-yl)-ethyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 92% of theory, 15 Melting point: 180-182°C Calculated: C 62.96 H 8.22 N 8.16 Cl 20.65 Found: 63.00 8.29 8.16 20.34 Example 135 20 3- r fN- f3 - fPyrid-3-vl) -propyl) -piperid-3-vl) -methvll -7.fl-dimethyl -1.3.4.5-tetrahydro-2H-3-benzazepine-trihydrochloride 25 Prepared from 3-[ (N-(3-(pyrid-3-yl)-propyl)-piperid-3-yl) -methyl] -7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 81% of theory, 30 Melting range: 184-196°C (amorphous) Calculated: C 60.17 H 8.16 N 8.10 Cl 20.49 Found: 60.28 8.25 8.00 20.39 Example 136 35 3- T2- fN- f2- f6-Methnxv-nanhth-2-vl) -ethvl) -pjperid-2-yll-ethyl1-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3 -benzazepine-hydrochloride - 113 - Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2- (6-methoxy-naphth-2-yl) -ethyl bromide analogously to Example l. 5 Yield: 20% of theory, Melting point: 158-160°C Calculated: C 69.48 H 7.47 N 5.06 Cl 6.41 Found: 69.40 7.56 5.17 6.62 Example 137 3-T2-(N-(2-(5-Methvl-6-methoxv-naphth-2-vl)-ethvl)-piperid-2-yl)-ethyl)-7.B-dimethoxv-2-oxo-1.3.4.5- tetrahydro-2H-3-benzazepine-hydrochlffra.de 15 Prepared from 3- [2- (piperid-2-yl) -ethyl]-7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl bromide analogously to Example 1. 20 Yield: 28% of theory.
Melting point: 140-143°C Calculated: C 69.88 H 7.64 N 4.94 Cl 6.25 Found: 69.06 7.57 4.84 6.44 25 Example 138 3-f 2-IN-(2-(Naphthyl-l-oxv)-ethvl)-piperid-2-vl)-ethyll-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H- 3-benzazepine-hydrochloride 30 Prepared from 3- [2- (piperid-2-yl) -ethyl] -7,8 - dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(naphthyl-l-oxy) -ethyl bromide analogously to Example 1. Yield: 27% of theory, 35 Melting point: 146-148*C Calculated: C 69.06 H 7.29 N 5.20 Cl 6.58 Found: 69.00 7.07 5.31 6.68 - 114 - Example 139 3- T2- m- 12-fNaphth-l-vl) -et-.hvl) -piperid-2-vl) -ethvll -7.fi-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine- 5 hydrochloride Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(naphth-l-yl)-ethyl bromide analogously to Example l. 10 Yield: 24% of theory.
Melting point: 148-150°C Calculated: C 71.18 H 7.51 N 5.36 Cl 6.78 Found: 70.92 7.44 5.57 7.06 15 Example 140 3- f2- (N- U- (Naphthyl-2-oxy) -butvl) -piperid-2-vl) -ethvll -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-benzaz epine-hvdronhloride 20 Prepared from 3- [2- (piperid-2-yl) -ethyl] -7,8-dimethoxy -2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 4-(naphthyl-2-oxy)-butyl bromide analogously to Example l. Yield: 39% of theory, 25 Melting point: 112-114*C Calculated: C 69.88 H17.64 N 4.64 Cl 6.25 Found: 69.69 7.58 4.82 6.52 Example 141 30 a-12-(N-12-fNaphth-2-yl)-ethvl)-piperid-2-vl)-ethvll -7.ft-dimethoxy-2-oxo-l.3.4.5-tetrahvdro-2H-3-benzazepine- hydrochloride 35 Prepared from 3- [2- (piperid-2-yl) -ethyl] -7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(naphth-2-yl) -ethyl bromide analogously to Example 1. Yield: 41% of theory. - 115 - Melting point: 120-122°C Calculated: C 71.18 H 7.51 N 5.36 Cl 6.78 Found: 71.10 7.31 5.40 7.05 5 Example 142 3- T2- (N- I 12-Methyl-naohth-l-vl) -methvl) -pjperid-2-vl) - ethyl 1 -7 . 8-dimethoxy-2 -oxo-1.3.4. 5-tetrahydro-2H-3-benzazepine-hydrochloride 10 Prepared from 3- [2- (piperid-2-yl) -ethyl] - 7,8 - dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 1-chloromethyl-2-methyl-naphthalene analogously to Example 1. 15 Yield: 24% of theory, Melting point: 144-146°C Calculated: C 71.18 H 7.51 N 5.36 Cl 6.78 Found: 70.93 7.38 5.48 6.89 20 Example 143 3-f fN-12-(Naphth-2-yl)-ethyl)-hexahvdro-azepin-3-yl) -methyl! -7 . 8-dimethoxy-2-oxo-1. 3.4. 5-tetrahvdro- 2H-3-benzazepine-hydrochlpr.ide 25 Prepared from 3- [ (hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy-2 -oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2-(naphth-2-yl)-ethyl bromide analogously to Example 1. 30 Yield: 58% of theory, Melting point: 204-205°C Calculated: C 71.18 H 7.52 N 5.36 Cl 6.78 Found: 71.41 7.51 5.35 6.50 35 - 116 - Example 144 3- r (N- (2- (Naphth-2-vl) -ethvl) -piperid-3-vl) -methvll -7. 8-dimethoxy-2-oxo-l. 3.4. 5-tetrahvdro-2H-3-benzazepi:ng-5 hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy- 2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine and 2- (naphth-2-yl)-ethylbromide analogously to Exaiiqple 1. 10 Yield: 35% of theory, Melting point: 239-240"C Calculated: C 70.78 H 7.33 N 5.50 Cl 6.96 Found: 70.70 7.10 5.46 7.16 15 Example 145 3- r (N- ((Naphth-2-yl) -methvl) -pinerid-3-vl) -methvll - 7.8-dimethoxy-2-oxo-l .3.4.5-tetrahvdro-2H-3-benzazepine 20 Prepared from 3- [ (piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2-bromomethyl-naphthalene analogously to Example 1.
Yield: 27% of theory, Melting point: 176-177°C 25 Calculated: C 75.95 H 7.47 N 6.11 Found: 76.11 7.28 6.10 Example 146 30 3- r m- (4- (Naphthyl-2-oxy) -hutvl) -piperid-3-vl) -methyl! -7 . B-dxmethoxv-2-oxo-1.3.4. 5-tetrahvdro-2H-3 -bengay.ftnine-hvdrochloride Prepared from 3- [ (piperid-3-yl)-methyl]-7,8-dimethoxy-35 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 4- (naphthyl-2-oxy)-butylbromide analogously to Example l. Yield: 24% of theory, Melting point: 196-197*C - 117 - Calculated: C 69.48 H 7.47 N 5.06 Cl 6.41 Found: 69.30 7.36 4.99 6.56 Example 147 5 3- r fN- (4- (Naphth-l-vl) -ethvl) -piperid-3-vl) -methvll - 7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepine- hydrochloride 1Q prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(naphth-l-yl)-ethyl bromide analogously to Example l. Yield: 18% of theory, Melting point: 230-231°C 15 Calculated: C 70.78 H 7.33 N 5.50 Cl 6.96 Found: 70.71 7.07 5.67 6.99 Example 148 20 3- r fN- (2-(Naphthyl-1-oxy) -ethvl) -piperid-3-vl) -methyl 1 -7. fi - dime thoxv- 2 - oxo -1.3.4. 5-tetrahvdro-2H-3-benzazepine-hyflgQchlQrifle Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy-25 2-oxo-l,3#4,5-tetrahydro-2H-3-benzazepine and 2- (naphthyl-l-oxy)-ethyl bromide analogously to Example 1. Yield: 40% of theory, Melting point: 214-215°C Calculated: C 68.62 H 7.10 N 5.34 Cl 6.75 30 Found: 68.40 7.10 5.21 6.77 Example 149 3- f fN- ((2 -Methvl -naphth-l-vl) -methvl) -pjperid-3- 35 yl) -methyl 1 -7. 8-dimethoxy-2-oxo-1. 3.4.5-tetrahvdro-2H- 3 -hen?: a y.epine - hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy- 10 - 118 - 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 1-chloromethyl-2-methyl-naphthalene analogously to Example 1.
Yield: 67% of theory.
Melting point: 242-243°C Calculated: C 70.78 H 7.33 N 5.50 Cl 6.96 Found: 70.50 7.22 5.34 6.89 Example 150 3-T m-12-(6-Methoxv-naphth-2-vl)-ethvl)-pjperid-3-vll-methvll -7.a-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepine-hydrochloride 15 Prepared from 3- [ (piperid-3-yl) -methyl] -7, 8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2-(6-methoxy-naphth-2-yl)-ethyl bromide analogously to Example 1.
Yield: 50% of theory, 20 Melting point: 156-157#C Calculated: C 74.07 H 7.62 N 5.57 Found: 73.90 7.55 5.64 25 Example 151 3-r fN-(2-(5-Methyl-6-methoxv-naphth-2- vl)-ethvl)-piperid-3-vl)-methvll-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepine-hydrochloride 30 Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(5-methyl-6-methoxy-naphthyl)-ethyl bromide analogously to Example 1.
Yield: 53% of theory, 35 Melting point: 240-241°C Calculated: C 69.48 H 7.47 N 5.06 Cl 6.41 Found: 69.58 7.48 5.00 6.54 Example 152 - 119 - 2-fN-f2-(3.4-Dimethoxy-phenvl)-ethvl)-piperid-3-yl)-methvll-5.6-dimethoxy-1-oxo-1.3-dihvdro-isoindole-5 hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-5,6-dimethoxy -1,3-dihydro-isoindole and 2-(3,4-dimethoxy-phenyl)-ethyl bromide analogously to Example 1. 10 Yield: 68% of theory.
Melting point: 225-226"C Calculated: C 63.60 H 7.18 N 5.20 Cl 7.22 Found: 63.61 7.30 5.70 7.44 15 Example 153 2-r (N-(2-f 6-Methoxy-naphth-2-vl)-ethvl)-pjperid- 3-yl) -methyl!-5.6-dimethoxy-l-oxo-l.3-dihvdro-isoindole-hydrochloride 20 Prepared from 2-[(piperid-3-yl)-methyl]-5,6-dimethoxy- 1-oxo-l, 3-dihydro-isoindole and 2-(6-methoxy-naphth- 2-yl)-ethyl bromide analogously to Example l.
Yield: 75% of theory, 25 Melting point: 234-236°C Calculated: C 68.16 H 6.90 N 5.48 Cl 6.94 Found: 68.10 7.10 5.39 7.10 Example 154 30 2- r fN- f 2- fNaphthvl-1 -oxv) -ethvl) -piperid-3-vl) -methyl! -5.6-dimethoxy-l-oxo-l.3-dihvdro-isoindole-hydrochloride 35 Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethoxy-l-oxo-l, 3-dihydro-isoindole and 2-(naphthyl-1-oxy)-ethyl bromide analogously to Example 1.
Yield: 60% of theory. - 120 - Melting point: 150-152°C Calculated: C 67.66 H 6.69 N 5.63 Cl 7.13 Found: 67.50 6.76 5.74 7.54 5 Example 3,55 2-T(N-(2-(4-Methvl-phenyl)-ethvl)-piperid-3-vl)-methyl1-5.6-dimethoxy-1-oxo-l.3-dihvdro-isoindole 10 Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethoxy- 1-oxo-isoindole and 2-(4-methyl-phenyl)-ethyl bromide analogously to Example 1.
Yield: 57% of theory, Melting point: 134-136°C 15 Calculated: C 73.50 H 7.90 N 6.86 Found: 73.40 8.04 7.06 Example 156 20 2- T (N- (2-(3-Methoxv-phenvl) -ethvl) -piperid-3-vl) -methyl! -5.6-dimethoxy- 1-oxo-l.3-dihvdro-isoindole- hyflrochilprifle Prepared from 2- t (piperid-3-yl) -methyl] -5,6-dimethoxy-25 1-oxo-isoindole and 2-(3-methoxy-phenyl)-ethyl bromide analogously to Example l.
Yield: 54% of theory, Melting point: 226-228°C Calculated: C 65.28 H 7.01 N 6.09 Cl 7.71 30 Found: 65.30 7.37 5.91 7.61 Example 3.57 2- r (N- (7- (5 -Methyl - 6 -methoxv-naphth- 2 - vl) -ethvl) - 35 piperid- 3 - vl) -methvll -5.6-dimethoxy-1-oxo-l. 3-dihvdro-TBoindolg-livrirnchloride Prepared from 2- [ (piperid-3-yl) -methyl) -5,6-dimethoxy- - 121 - 1-oxo-l, 3-dihydro-isoindole and 2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl bromide analogously to Example 1. Yield: 38% of theory, Melting point: 214-216°C 5 Calculated: C 68.62 H 7.10 N 5.33 Cl 6.75 Found: 68 .«94 7.23 4.98 6.61 Example 158 10 2- f (N- (2 - (4-Nitro-phenyl) -ethvl) -piperid-3-vl) - methyl! -5.6-dimethoxy-l-oxo-l.3-dihydro-isoindole- hyflrochlorifle Prepared from 2-[ (piperid-3-yl)-methyl]-5,6-dimethoxy-15 1-oxo-l, 3-dihydro-isoindole and 2-(4-nitro-phenyl)-ethyl bromide analogously to Example 1.
Yield: 79% of theory, Melting point: 215-218°C Calculated: C 60.56 H 6.35 N 8.83 Cl 7.45 20 Found: 60.41 6.26 8.84 7.62 159 3- f (N- (2- (Thien-2-yl) -ethyl) -piperid-3-yl) -methyl! - 25 7. 8-dimethoxy-2-oxo-l .3.4. 5-tetrahydro-2H-3-benzazepine-hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2- 30 (2-bromo-ethyl) -thiophene analogously to Example l. Yield: 43% of theory, Melting point: 232-236°C Calculated: C 1.99 H 7.15 N 6.02 Cl 7.62 S 6.89 Found: 61.90 7.06 5.78 7.96 6.84 35 Bxamplft 16Q 3- r (N- 12-(Thien-3-yl) -ethyl) -piperid-3-vl) -methvll - - 122 - 7 . 8-dimethoxy- 2-nyo-l .3. A. 5-tetrahydro-2H-3 -benzazepine-hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy-5 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3- (2-bromo-ethyl)-thiophene analogously to Example l. Yield: 36% of theory, Melting point: sinters at 75-80°, melts at 225-230°C Calculated: C 61.99 H 7.15 N 6.02 Cl 7.62 S 6.89 10 Found: 62.00 7.08 5.98 8.43 6.62 Example 161 3-f fN-(A-(Thien-2-yl)-hutvl)-piperid-3-vl)-methvll -15 7.8-dimethoxy-2-oxo-1.3.4.S-tetrahvdro-2H-3-benzazepine-hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2- 20 (4-bromo-butyl)-thiophene analogously to Example 1. Yield: 68% of theory.
Melting range: 190-196°C Calculated: C 63.33 H 7.56 N 5.68 Cl 7.19 S 6.50 Found: 63.18 7.72 5.72 7.29 6.59 25 Example 162 3-f(N-(2-(BenzoThlfur-2-vl)-ethvl)-piperid-3-vl)-methyl 1 -7.8-dimethoxv-2-oxo-l .2.3.4-tetrahvdro- 30 2H-3 -benzazepine-hydrochloride Prepared from 3 - [ (piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(2-bromo-ethyl)-benzo[b]furan analogously to Example 1. 35 Yield: 22% of theory.
Melting point: above 216"C (decomp.) Calculated: C 67.39 H 7.07 N 5.61 Found: 67.14 . 7.36 5.53 - 123 - Examnle 163 3-T(N-(2-(Benzofbl thien-3-vl)-ethvl)-pjperid-3-yl)-methyl 1 -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-5 2H-3-benzazepine-hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3- (2-bromo-ethyl)-benzo [b] thiophene analogously to Example 10 1.
Yield: 73% of theory.
Melting range: 70-75°C (decomp.) Calculated: C 65.29 H 6.85 N 5.44 Found: 65.10 6.87 5.73 15 Example 3.64 3- f (N- (2- (4-Methoxv-benzo fbl thien-3-vl) -ethvl) -piperid-3-yl)-methyl1 -7.8-dimethoxy-2-oxo-1.3.4.5- 20 tetrahydro-2H-3-benzazepine-hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3- (2-chloroethyl)-4-methoxy-benzo[b]thiophene analogously 25 to Example 1.
Yield: 25% of theory, Melting range: 85-105 (decomp.) Calculated: C 63.96 H 6.84 N 5.14 Cl 6.50 S 5.88 Found: 63.95 6.85 4.99 6.53 5.75 30 Example 165 3-f(N-(2-(6-Methvlenlphonyloxy-benzo fblthien-3-yl) -ethyl) -piperid-3-yl) -methyl! -7. 8-dimethoxy- 35 2-oxo-l .3.4.5-tetrahydro-2H-3-benzazepine-hydrochloride Prepared from 3-[ (piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3- - 124 - [2-(methylsulphonyloxy)-ethyl]-6-methylsulphonyloxy-benzo[b]thiophene analogously to Example 1.
Yield: 55% of theory.
Melting point: 90°C (decomp.) 5 Calculated: C 57.18 H 6.12 N 4.60 Cl 5.82 S 10.53 Found: 57.25 6.14 4.50 5.97 10.36 Example 166 10 3-f (N-(5-(Thien-2-vl)-pentyl)-piperid-3-vl)-methvll - 7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine- hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy-15 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2- (5-methylsulphonyloxy-pentyl) -thiophene analogously to Example 1.
Yield: 39% of theory, Melting point: 177°C 20 Calculated: C 63.95 H 7.75 N 5.52 C16.99 S 6.32 Found: 63.70 7.92 5.40 7.24 6.62 Example 167 25 3 - f (N- 12.- (Pnr-2-yl) -ethyl ) -niperid-3-vll -methvll - 7. 8- dimethoxy-2- oxo -1. .3.4.5-tetrahydro-2H-3-benzazepine- hyflrQshlQrifle prepared from 3 - [ (piperid-3-yl) ^methyl] - 7,8-dimethoxy -30 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2-(2-methylsulphonyloxy-ethyl) -furan analogously to Example 1.
Yield: 44% of theory.
Melting range: 205-215°C 35 Calculated: C 64.20 H 7.41 N 6.24 Cl 7.90 Found: 64.00 7.45 6.00 7.80 - 125 - Example 168 3-r(N-(3-(Fur-2-yl)-propyl 1-piperid-3-vl)-methyl-7 . R-dimethoxy-2-oxo-1. 3.4. 5-tetrahvdro-2H-3-benzazep-ine-5 hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3-(fur-2-yl)-propionaldehyde analogously to Example 9. 10 Yield: 11% of theory, Melting point: 201-206°C Calculated: C 64.85 H 7.62 N 6.05 Cl 7.66 Found: 64.88 7.76 5.93 7.55 15 Example 169 3-f(N-(6-(Thien-2-yl)-hexyl)-piperid-3-yl)-methyl!- 7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepine- hyflrpchlpride 20 Prepared from 3 - [ (piperid-3-yl) -methyl] -7,8-dimethoxy- 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2- (6-methylsulphonyloxy-hexyl) -thiophene analogously to Example l. 25 Yield: 27% of theory.
Melting point: 160"C Calculated: C 64.39 H 8.10 N 5.40 Cl 6.79 Found: 64.55 7.90 5.23 7.00 30 Example 170 3- T (N- (3- (Inflpl-3-yl) -propyl) -piperid-3-yl) -methyl 1 - 7.8 -dimethoxy- 2 - oxo-1.3.4.5-tetrahydro-2H-3-benzazepine -hvdrochlpride 35 Prepared from 3- [ (piperid-3-yl) -methyl] - 7,8 - dimethoxy-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3-(3 -methyl sulphonyloxy-propyl) -indole analogously to - 126 - Example l.
Yield: 19% of theory, Melting point: greater than 80°C (decomp.) Calculated: C 60.42 H 6.30 N 6.45 5 Found: 60.32 6.57 6.67 Example 171 3- f (N- (2- (Tndol-3-yl) -ethvll -piperid-3-vl) -mpf-.hvl 1 -10 7. 8-dimethoxy-2-oxo-1.3.4. 5-tetrahvdro-2H-3-hf»nza*pp-ing-hvdrochloride .Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy-2 - oxo-1,3,4,5- tetrahydro- 2H- 3 -benzazepine and 3 -15 (2-methylsulphonyloxy-ethyl)-indole analogously to Example l.
Yield: 23% of theory, Melting point: greater than 80°C (decomp.) Calculated: C 65.53 H 6.42 N 7.69 20 Found: 65.33 6.55 7.80 Example 172 2-f (N-(3-(Naphthyl-2-oxv)-propyl)-hexahvdro-azepin-25 3-vll -methvll -6. 7-methylenedioxy-l-oxo-ifioquinoline Prepared from 6,7-methylenedioxy-1-oxo-l,3,4,5-tetrahydro-isoquinoline and 3-chloromethyl-[N-(3-naph t hy 1 - 2 - oxy) -propyl] -hexahydro-azepine analogously to 30 Example 2.
Yield: 21% of theory, Melting point: 74-76'C Calc. (x 2 H20): C 64.45 H 7.02 N 5.01 Cl 6.34 Found: 64.32 7.20 5.28 6.44 35 Example 173 2- f (N- (3- (Naphth-2-vl) -propvll-Pvrrolid-3-vll -methvll - - 127 - 6. 7-dimethyl-1 -oxo-1.2.3.4-tetrahvdro-isoauinoline Prepared from 6,7-dimethyl-l-oxo-l,3,4,5-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-5 N-[3-(naphth-2-yl)-propyl]-pyrrolidine analogously to Example 2.
Yield: 20% of theory, Melting point: 72-76°C Calc. (x H20): C 72.41 H 7.75 N 5.82 Cl 7.36 10 Found: 72.27 7.85 5.70 7.96 Example 174 2-r(N-(3-(5.6-Dimethoxv-naphthvl-2-oxv)-propyl)-15 pyrrolid-3-yl)-methyll -6.7-dimethoxv-l-oxo-l.2.3.4- tetrahyflro-isoguinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,3,4,5-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-20 N-[3-(5,6-dimethoxy-naphthyl-2-oxy)-propyl]-pyrrolidine analogously to Example 2.
Yield: 9.5% of theory, Melting point: 60-63°C Calc. (x H20): C 63.20 H 7.01 N 4.75 . Cl 6.02 25 Found: 63.40 7.04 4.49 6.38 Example 175 2-f(N-(3-(5.6-Dimethoxv-naphthvl-2-oxv)-propyl)-30 hexahydro-azepin-3-yl)-methvll-6.7-dimethoxv-l- oxo-l .2.3.4-tetrahydro-isocniinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-35 N- [3- (5,6 -dimethoxy - naphthyl - 2 - oxy) -propyl] -hexahydro-azepine analogously to Example 2.
Yield: 63.2% of theory.
Melting point: 199-201°C - 128 - Calculated: C 66.15 H 7.23 N 4.67 Cl 5.92 Found: 65.99 7.00 4.44 6.02 Example 176 5 2-f(N-(3-(5.6-Dimethoxv-naphthvl-2-oxv)-propyl)-hexahvdro-azepin-3-yl)-methvll -6.7-dimethoxv-l.2.3.4-tetrahydro-isoouinoline-dihydrochloride 10 Prepared from 2- [ (N- (3- (5,6-dimethoxy-naphthyl- 2-oxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3. 15 Yield: 86.3% of theory, Melting point: 114-116°C Calculated: C 61.97 H 7.56 N 4.38 Cl 11.08 Found: 62.05 7.65 4.06 10.84 20 Example 177 2-f(N-(2-(4-Methoxy-phenvl)-ethvl)-Pvrrolid-3-vl)-methyl ] -6,7 -methylenedioxy-1,2,3,4- tetrahydro-i sorminol ine -dihydrochloride 25 Prepared from 2- [ (N- (2- (4-methoxy-phenyl) -ethyl) -pyrrol id-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride/tetrahydrofuran analogously to Example 3. 30 Yield: 86.7% of theory, Melting point: 213-215°C Calculated: C 60.49 H 6.98 N 5.87 Cl 14.88 Found: 60.59 6.96 5.84 14.98 35 Example 178 2 - T (N- (3 - (3. 4-Dimet-hoYy-nhenoxv) -propyl) -pvrrolid-3-yl)-methvl 1-6.7-methylenedioxv-l-oxo-l.2.3.4- - 129 - t et rahydro-isoauinoline-hvdrochloride Prepared from 1-oxo-l,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinoline and N- [3 - (3,4 -dimethoxy-5 phenoxy) -propyl] -3-benzosulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 57.4% of theory, Melting point: 108-110*0 Calculated: C 59.76 H 6.74 N 5.35 Cl 7.02 10 Found: 60.07 6.87 5.23 7.61 Example 179 2-r (N-(2-(4-Methoxy-phenyl)-ethvl)-pvrrolid-3-vl)-15 methvll -6.7-methylenedioxv-l-oxo-l.2.3.4-tetrahvdro- isoquinoline-hydrochloride Prepared from 1-oxo-l,2,3,4-tetrahydro-6,7-methylene-dioxy-isoquinoline and N- [2- (4-methoxyphenyl) -ethyl] -20 3 -benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 54.7% of theory, Melting point: 105-108°C Calculated: C 62.26 H 6.74 N 6.05 Cl 7.97 25 Found: 62.34 6.74 5.88 8.05 Example 180 3- f (N- (2- (6-Methyl-pyrid-2-yl) -ethyl) -pyrrolid-30 3-yl) -methyl!-7,fi-dimethyl-1,3.4.5-tetrahydro-2H- 3-benzazepine x 2,5 HC1 x Prepared from 3- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid-3-yl) -methyl] -7,8-dimethyl-2-oxo-l,3,4,5-35 tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 50% of theory. - 130 - Melting point: 80-91°C amorphous Calculated: C 61-68 H 8.18 N 8.63 Cl 18.21 Pound: 61.55 8.36 8.44 18.10 5 Example 183. 3-r(N-(2-(6-Methyl-pyrid-2-vl)-ethvl)-pvrrolid-3-yl)-methyl1-7.fl-dimethvl-2-oxo-l.3.4.5-tetrahvdro-2H-3-benzazepine-dihydrochloride-fiemihvdrate 10 prepared from 3-[(N-(2-(6-methyl-pyrid-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3-dihydro-, 2H-3-benzazepine with 10% palladium/charcoal at 5 bar hydrogen and at 80°C in ethanol analogously to Example 15 5.
Yield: 92% of theory, Melting point: 86-94°C amorphous Calculated: C 63.41 H 7.66 N 8.87 Cl 14.97 Found: 63.52 7.14 8.81 14.94 20 Example 182 2- T (N~ (3- (6-Mftthoxy-naphthyl-2-oxy) -propyl) -pyrrolid- 3-yl)-methyl 1-6.7-dimethyl-1-oxo-1.2.3.4-tetrahvdro- 25 isogvunoline Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-N- [3- (6 -me thoxy-naphthy 1 - 2 - oxy) -propyl] -pyrrolidine 30 analogously to Example 2.
Yield: 44.7% of theory.
Melting point: 102-104"C Calculated: C 76.24 H 7.68 N 5.93 Found: 75.90 7.62 5.94 - 131 - Example 183 2- f (N- (3-(6-Methoxv-naphthvl-2-oxv) -propyl 1 -pyrrol-M- 3-yll -methvll-6.7-dimethoxy-l.2.3.4-tetrahydro- 5 ispquinpline Prepared from 2-[N-(3-(6-methoxy-naphthyl-2-oxy)-propyl) -pyrrolid-3-yl) -methyl] -6, 7-dimethoxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and lithium 10 aluminium hydride in tetrahydrofuran and ether analogously to Example 3.
Yield: 68% of theory, Melting point: 106-108°C Calculated: C 73.44 H 7.82 N 5.71 15 Found: 73.26 7.72 5.81 Example 184 3-r (N-(3-(Indol-3-vl)-propyl)-pvrrolid-3-vl)-methvll-20 7.8 -methylenedioxy-2-oxo-1.3.4.5-tetrahydro-2H- 3 -benzazepine-mpiiphyflrate Prepared from 3-[(N- (3-(indol-3-yl)-propyl)-pyrrolid-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3-dihydro-25 2H-3-benzazepine with 20% palladium/charcoal at 5 bar hydrogen in ethanol at 80°C analogously to Example 5. Yield: 40% of theory.
Melting range: 67-74°C Calculated: C 69.95 H 7.17 N 9.06 30 Found: 70.00 7.03 8.97 Example IBS 3- f (N- 12- (6-Methyl-t^yrld-2-vl) -ethvl) -methvll -7.8-35 dimethyl -2-oxo-l. 3-riihydro-2H-3-benzagepine-dihvdro-chloride-gemihydrate Prepared from 7,8-dimethyl-2-oxo-1,3-dihydro12H- - 132 - 3-benzazepine and 3-chloromethyl-N-[2-(6-methyl-pyrid-2-yl)-ethyl]-pyrrolidine analogously to Example 2. Yield: 81% of theory, Melting point: 86-98°C amorphous 5 Calculated: C 63.68 H 7.27 N 8.91 Cl 15.04 Found: 63.39 7.43 8.87 14.93 Example 186 10 2-f(N-(3-13-Methylphenoxv)propyl)-piperid-3-vl)-methvll -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-i socruinol ine - hvdrochl or ide Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-15 isoquinoline and N- [3-(3-methylphenoxy) -propyl] - 3-benzenesulphonyloxymethyl-piperidine analogously to Example 2.
Yield: 75.6% of theory, Melting point: 106-109°C amorphous 20 Calculated: C 63.95 H 7.75 N 5.52 Cl 7.25 Found: 64.66 7.91 5.48 7.28 Example 187 25 2- f fN- (2-(5-Methvl-6-methoxv-naphthyl) -pyrrolid-3-yl)-methvll-6.7-methylenedioxy-1-oxo-l.2.3.4-te t rahydro- i aoqu tno.1. ine - hydrochloride Prepared from 6,7-methylenedioxy-1-oxo-l,2,3,4-30 tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl) -N-[2-(5-methyl-6-methoxy-naphthyl)-ethyl]-pyrrolidine analogously to Example 2.
Yield: 27.1% of theory, Melting point: 249-251°C 35 Calculated: C 68.43 H 6.53 N 5.50 Cl- 6.96 Found: 68.47 6.66 5.30 7.16 - 133 - Example 188 2- r (N- (3- (Nanhth-2-vl) -propyl) -nvrrolid-3-vl) -methyl 1 -6 . 7 -dimethoxy-1 - oxo- Isoguinol ine -hydrochloride 5 Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl) -N-[3-(naphth-2-yl)-propyl]-pyrrolidine ainalogously to Example 2. 10 Yield: 20.2% of theory, Melting point: 84-86°C Calculated: C 67.88 H 7.26 N 5.46 Cl 6.91 Found: 67.86 7.40 5.40 7.17 15 Example 189 2-T(N-(3- (3 .4-Dimethoxv-phenoxy) -propyl) -pyrrolid- 3-yl)-methvll-6.7-dimethoxy-l.2.3.4-tetrahvdro- isoquinoline-dihydrochloride 20 Prepared from 2- [ (N- [3- (3,4-dimethoxy-phenoxy) -propyl) -pyrrolid-3-yl) -methyl] -6, 7-dimethoxy-l-oxo-l, 2 , 3,4-tetrahydro-isoquinoline auid lithium aluminium hydride in diethyl ether and tetrahydrofuran 25 analogously to Example 3.
Yield: 92.3% of theory, Melting point: 220-221'C Calculated: C 59.20 H 6.88 N 5.31 Cl 13.44 Found: 59.28 6.97 5.20 13.44 30 Example 19Q 2- r (N- (2 - (3.4-Dimethoxyphenvl) -ethyl) -ovrrolid- 3-yl) -methyl! -6.7 -dimethyl-I- oxo -1.2.3.4-tetrahyflro-35 isoquinoline Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and N- [2- (3,4-dimethoxyphenyl) -ethyl] - - 134 - 3-benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 70% of theory, Melting point: 168-170°C 5 Calculated: C 73.90 H 8.11 N 6.63 Found: 73.96 8.11 6.55 Example 191 10 2-f(N-12-14-Methoxyphenoxv)-propyl)-piperid-3-vl)-methyl1-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-i socru inol In* - h vdronh 1oride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-15 isoquinoline and N-[3-(4-methoxyphenoxy)-propyl] - 3 -benzenesulphonyloxymethyl-piperidine analogously to Example 2.
Yield: 78.7% of theory.
Melting point: 98-102°C 20 Calculated: C 63.08 H 7.51 N 5.35 Cl 7.02 Found: 62.87 7.69 5.16 7.28 Example 192 25 2- f (N- (3-(3-Methoxvphenoxv) -propyl) -piperid-3-vl) -methvll -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-iBoquinoline-hydroohloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-30 isoquinoline and N- [3- (3-methoxyphenoxy) -propyl] - 3-benzenesulphonyloxymethyl-piperidine analogously to Example 2.
Yield: 87% of theory.
Melting point: 103-105°C 35 Calculated: C 64.21 H 7.38 N 5.55 Cl 7.02 Found: 64.00 7.55 5.37 7.12 - 135 - Example? 193 2-f fN-(3-f3-Methoxvphenoxv)-propyl)-piperid-3-vl)-methyl 1 -6.7-dimethoxy-l.2.3.4-tetrahydro-isoquinoling-5 dihydrochloride Prepared from 2-[ (N-(3-(3-methoxyphenoxy)-propyl) -piperid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tet rahydro-isoquinoline and lithium aluminium hydride in 10 diethylether and tetrahydrofuran analogously to Example 3.
Yield: 95.4% of theory, Melting point: 170-173"C Calculated: C 60.43 H 7.70 N 5.22 Cl 13.21 15 Found: 60.50 7.71 4.91 12.97 Example 194 2-r fN-f2-(3.4-Dimethoxyphenvl)-ethvl)-pvrrolid- 20 3-yl)-methyl!-6.7-dimethyl-l.2.3.4-tetrahyflro-isoquAnQline-dihydrQChloride Prepared from 2-[ (N-(2-(3,4-dimethoxyphenyl)-ethyl)-pyrroiid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-25 tetrahydro-isoquinoline and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 94.1% of theory, Melting point: 260-262#C 30 Calculated: C 64.85 H 7.96 N 5.82 Cl 14.73 Found: 64.60 8.11 5.91 14.67 35 - 136 - Example 195 2-r (N- (3- (6-Mefchoxv-nanhthvl- 2 -racv)-propyl)-azacvclo-QGt-3-yl)-methyl!-6.7-dimethoxy-1-oxo-1.2.3.4-5 tetrahydro-ifioqminoline-hydrochloride Prepared from 2-[(azacyclooct-3-yl)-methyl]-6,7-dimethoxy- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) - 6-methoxy-naphthalene analogously to 10 Example 1.
Yield: 24.4% of theory.
Melting point: 176-178°C Calculated: C 67.96 H 7.43 N 4.80 Cl 6.08 Found: 67.74 7.29 4.71 6.23 15 Example 196 3- f (N- (3- (IiKiol-3-yl) -propyl) -pyrrolid-3-yl) -methyl! - 7 . 8-dimethyl-2-oxo-1. .3.4. 5-tetrahydro-2H-benzazepine-20 hydrochloride Prepared from 3-[(pyrrolid-3-yl)-methyl]-7,8-dimethyl-2-oxo-l,2,3,4-tetrahydro-2H-3-benzazepine and 3-(3-benzenesulphonyloxy-propyl)-indole analogously to 25 Example 1.
Yield: 62% of theory, Melting point: 106-108°C Calculated: C 69.47 H 7.91 N 8.68 Cl 7.32 Found: 69.57 7.80 8.67 8.51 30 35 - 137 - Exaiqple 197 3- T (N- (3- (6-Methoxy-naphthyl-2-oxy) -propyl) -hexahydro-, azepin-3-yl) -methvll -7. 8-dimethoxy-1. 2. 3 . 4-tetrahydrn-5 2H-3-benzazepine Prepared from 3-[ (N-(3-(6-methoxy-naphthyl-2-oxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy-1,2,3,4-tetrahydro-2-oxo-2H-3-benzazepine and lithium 10 aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 26.8% of theory, Melting point: 98-100°C Calc. (x H20): C 71.97 H8.42 N5.09 15 Found: 72.07 8.23 5.10 Example 198 3-r fN-(3-f6-Methoxy-naphthyl-2-oxv)-propyl)-hexahvdro-20 azepin-3-yl)-methyl!-1.2.3.4-tetrahydro-2-oxo-2H- 3-benzazepine Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]-l,2,3,4-tetrahydro-2-oxo-2H-3-benzazepine and 2-25 (3-chloropropoxy)-6-methoxy-naphthalene analogously to Example l.
Yield: 45% of theory.
Melting point: 109-111°C Calculated: C 72.50 H 7.74 N 5.12 30 Found: 72.35 7.68 4.93 Example 199 2- f fN- (3- f-Methoxy-naphthvl-2-oxv) -propyl) -hexahvdro-35 azepin-3-yl) -methyl 1 -1.3-dihvdro-5.6-dimethoxy- isoindole Prepared from 2- [ (N- (3- (6 -methoxy-naphthyl - 2 - oxy) - - 138 - propyl) - hexahydro - azepin-3-yl) -methyl] -5,6-dimethoxy-phthalimide and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 49.2% of theory, Melting point: 104-146BC Calculated: C 73.78 H 7.99 N 5.55 Found: 73.63 7.99 5.39 Example 200 10 3- r (N- (3- (Indol-3-vl) -propyl! -pvrrolid-3-vl! -methvll -7.8-dimethyl-1.3.4.5-tetrahvdro-2H-3-benzazepine-dihvdroohloride-monohydrate 15 prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-pyrrolid-3-yl) -methyl] -7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 65% of theory, 20 Melting point: 168-170°C Calculated: C 66.39 H 8.16 N 8.29 Cl 13.99 Found: 66.29 8.44 8.08 14.08 Example 201 25 3- T (N- (3- (fi-Methoxv-naphthvl-2-oxv! -propyl! -hexahvdro- azepin-3-yl) -methyl! -1.3.4.5-ter.rahyflro-7«8- methylenedioxy-2H-3-benzazepine 30 Prepared from 3-[(N-(3-(6-methoxy-naphthyl-2-oxy)-propyl)-hexahydro-azepin-3-yl)-methyl]-1,3,4,5-tetrahydro-7,8-methylenedioxy-2-oxo-2H-3-benzazepine and lithium aluminium hydride/tetrahydrofuran/ether analogously to Example 3. 35 Yield: 25% of theory, Melting point: 109-111*C Calculated: C 74.39 H 7.80 N 5.42 Found: 74.27 . 7.94 5.43 - 139 - Example 202 3- T (N- (3-(6-Methoxv-naphthvl-2-oxv) -propyl) -hexahvdro- azepin-3-yl)-methyl1-1.3.4.5-tetrahydro-7.8- 5 methylenedioxy-2-oxo-2H-3-benzazepine-hvdrochlnride Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]-1,3,4,5-tetrahydro-7,8-methylenedioxy-2-oxo-2H-3-benzazepine and 2- (3-chloropropoxy) -6-methoxy-10 naphthalene analogously to Example 1.
Yield: 68.1% of theory, Melting range: 104-108"C Calc. (X 2 H20): C 65.46 H 7.38 N 4.79 Cl 6.06 Found: 65.60 7.25 5.01 6.43 15 Example 203 2-fIN-13-(6-Methoxv-naphthvl-2-oxv)-propyl)-hexahvdro-azepin-3-vl)-methyl!-6.7-methvlenedioxv-l-oxo-l.3.4.5- 20 tetrahydro-isQquinoline-hydroohlora.de Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-6,7-methylenedioxy-l-oxo-l,3,4,5-tetrahydro-isoquinoline and 2-(3-chloro-propoxy)-6-methoxy-naphthalene 25 analogously to Example 1.
Yield: 18.2% of theory.
Melting point: 65-67°C Calc. (x H20): C 65.19 H 6.88 N 4.90 Cl 6.20 Found: 65.20 6.75 4.82 6.54 30 Example 204 2- f (N- (3- 16-Methoxy-naphthvl-2-oxvv-propvl) -pjperid- 3-vll -methyl! -6.7 -methylenedioxy-1 - oxo -1.2.3.4-35 tetrahydro - i Boqti inol tne Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-.(benzenesulphonyloxy- - 140 - methyl)-N-[3-(6-methoxy-naphthalene-2-oxy)-propyl]-piperidine analogously to Example 2.
Yield: 5.3% of theory.
Melting point: 144-146°C 5 Calculated: C 71.69 H 6.82 N 5.57 Found: 71.52 6.62 5.46 .
Example 205 10 2 - T (N- (3 - (6-Methoxy-naphthv.l-2 -oxv) -nrnnvl) -hexahvdro-azepin-3-yl)-methyl! -5.6-dimethyl-1.3-dihvdro-l-oxo-isoindole Prepared from 2-[(N-(3-(6-methoxy-naphthyl-2-oxy) -15 propyl)-hexahydro-azepin-3-yl)-methyl]-4,5-dimethyl- phthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 18.2% of theory, Melting point: 232-234°C 20 Calc. (x acetone): C 74.97 H 8.14 N 5.14 Found: 74.96 7.90 5.30 Example 206 25 2- T fN- (3- (a-Methoxy-naphthyl-2-oxy) -propyl) -hexahvdro-azepln-3-vl)-methyl!-6.7-dimethvl-1-oxo-1.2.3.4- tetrahydro-isoffittinoline-hydrochlQride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-30 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(3-chloro-propoxy)-6-methoxy-naphthalene analogously to Example 1.
Yield: 17.3% of theory, Melting range: 68-73°C 35 calc. (x 2 H20): C 67.06 H 7.93 N 4.46 Cl 6.66 Found: 67.05 7.73 4.88 6.18 Example 207 - 141 - 2- f (N- (3- (6-Methoxy-naphthyl-2-Qxy) -propyl) -pa.pera.d- 3-vl) -methyl! -6 . -7-dimethoxy-1-oxo-l. 2 . 3 .4-tetrahydro- isoquinoline 5 Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(benzenesulphonyloxymethyl) -N- [3- (6-methoxy-naphthyl-2-oxy) -propyl] -piperidine analogously to Example 2.
Yield: 12.9% of theory, 10 Melting point: 124-126°C Calculated: C 71.79 H 7.38 N 5.40 Found: 71.83 7.33 5.21 Example 208 15 3-r(N-(3-(5.6-Dimethoxy-naphthvl-2-oxv)-propyl)-hexahydro-azepin-3-yl)-methyl 1 -1.3.4.5-tetrahvdro- 7,8-dimethoxy-2H-3-benzazepine 20 Prepared from 3-[(N-(3-(5,6-dimethoxy-naphthyl- 2-oxy)-propyl)-hexahydro-azepin-3-y1)-methyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2-oxo-2H-3-benzazepine and lithium aluminium hydride/tetrahydrofuran/ether analogously to Example 3. 25 Yield: 29.1% of theory, Melting point: 94-96*C Calculated: C 72.57 H 8.24 N 4.98 Found: 72.56 8.35 4.94 30 Example 209 2-f(N-(3-(6-Methoxy-naphthyl-2-oxy)-propyl)-hexahvdro-azepin-3-yl) -methyl! -1.3-dihyd:ro-g . 6 - dimethoxy-1-oxo-isoindole 35 Prepared from 2- [ (N- (3- (6-methoxy-naphthyl-2-oxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to 142 - Example 4.
Yield: 20.5% of theory, Melting point: 265-267°C Calc. (X 2 H20): C 67.13 H 7.63 N 5.05 5 Found: 67.11 7.64 5.07 Example 21Q ■1- f fN- f3- fs. 6-D.imethoxy-naphthvl-2-oxv) -propyl) -10 hexahvdro-azepin-3-yl) -methvll -1.3.4.5-tetrahvdro-7 . 8-dimethoxy- 2-oxo-2H- 3 -benzazepine Prepared from 3- [ (hexahydro-azepin-3-yl) -methyl] -1,3,4,5-tetrahydro-7,8-dimethoxy-2-oxo-2H-3-benzazepine 15 and 2-(3-chloropropoxy) -5,6-dimethoxy-naphthalene analogously to Example 1.
Yield: 52.4% of theory, Melting point: 129-131°C Calculated: C 70.81 H 7.69 N 4.86 20 Found: 70.66 7.84 4.63 Example 211 2- T fN- f 3- fS . 6-Dimethoxy-naphthvl-2-oxv) -propyl) -25 hexahydro-azepin-3 -yl) -methvll -5. 6 - dimethoxy-1.3- flihyflrp-iBpinflple-flihyflrpchlpricte Prepared from 2- [ (N- (3- (5,6-dimethoxy-naphthyl-2-oxy) -propyl) - hexahydro-azepin-3-yl) -methyl] -4,5-30 dimethoxy-phthalimide said lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 48.2% of theory, Melting range: 172-177°C Calc. (x H20): C 61.43 H 7.41 N 4.47 Cl 11.33 35 Found: 61.50 7.71 4.59 11.45 - 143 - Example 212 2- f(N-(3-(5.6-Dimethoxy-naphthvl-2-oxv)-propyl)-hfixahydro-azepin-3-yl)-methvll-5.6-dimethoxv-l.3-5 dihvdro-1-oxo-isoindole-hydrochloride Prepared from 2-[(N-(3-(5,6-dimethoxy-naphthyl-2-oxy)-propyl)-hexahydro-azepin-3-yl)-methyl]-4,5-dimethoxy-phthalimide and zinc/glacial acetic acid 10 analogously to Example 4.
Yield: 36.4% of theory, Melting range: 215-223°C Calc. (X H20): C 61.87 H 7.30 N 4.50 Cl 5.70 Found: 62.08 7.15 4.55 5.80 15 Example 213 2-f(N-(3-(Inflol-3-yl)-propyl)-pyrrolid-3-yl)-methyl! - 5.6-dimethoxy-1.3-dihvdro-isoindole-dihvdrochloride- 20 monofayflrate Prepared from 2-[(N-(3-(indol-3-yl)-propyl)-pyrrolid- 3-yl)-methyl]-5,6-dimethoxy-phthalimide and lithium aluminium hydride in tetrahydrofuran analogously to 25 Example 3.
Yield: 87% of theory, Melting point: 262-264°C Calculated: C 61.17 H 7.30 N 8.23 Cl 13.89 Found: 61.34 7.26 7.92 13.90 30 Example 214 3- r (N- (3- (5 .6 -Dimethoxv-naphthvl - 2 - oxv) -propyl) -hexahvdro-a zepin-3-yl)-methvll-1.3.4.5-tetrahvdro-35 7. 8-dimethyl -2h-3 -henzazepine-dihvdrochloride Prepared from 3- [ (N- (3- (5,6-dimethoxy-naphthyl-2-oxy)-propyl)-hexahydro-azepin-3-yl)-methyl]-1,3,4,5- - 144 - tetrahydro-7,8-dimethyl-2-oxo-2H-3-benzazepine and lithium aluminium hydride/tetrahydrofuran/ether analogously to Example 3.
Yield: 76.9% of theory, 5 Melting range*. 138-144"C Calculated: C 67.64 H 8.01 N 4.64 Cl 11.74 Found: 67.73 8.26 4.47 11.50 Example 215 10 3- f (N- (3- (5 . 6 -Dimfithoxv-nanhthvl - 2 - oxv) -propyl) -hexahvdro-a zepin-3-yl) -methvll -1.3.4. 5-tetrahvdro-7.8 -dimethyl - 2 -oxo- 2H- 3 -benzazepine -hydrochloride 15 Prepared from 3- ((hexahydro-azepin-3-yl) -methyl] - 1,3,4,5-tetrahydro-7,8-dimethyl-2-oxo-2H-3-benzazepine and 2- (3-chloro-propoxy) -5,6-dimethoxy-naphthalene analogously to Example 1.
Yield: 47.5% of theory, 20 Melting range: 90-96°C Calc. (x H20): C 68.15 H 7.90 N 4.67 Cl 5.91 Found: 67.93 7.94 5.05 6.09 Example 216 25 2- r rw- (3 - lR . 6-Dimethoxv-naphthvl-2-oxv) -propyl) -piperid-3-yl) -methvll -6. 7-methylenedioxy-1-oxo-l.. 2.3.4 - tetrahydro- isoguinol ine - hydrochloride 3q Prepared from 2- [ (piperid-3-yl) -methyl] -6,7- methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) -5,6-dimethoxy'naphthalene analogously to Example 1.
Yield: 22.5% of theory, 35 Melting range: 93-98°C Calc. (x H20) : C 63.42 H 6.69 N 4.77 Cl 6.03 Found: 63.59 6.80 4.70 6.28 - 145 - Example 217 2- f fN- (3- (5 . 6 - Dime* thoxv-naphthv 1 - 2 - oxv) -propyl) -pyrrol id-3-yl) -methyl! -6. 7-methylenedioxy-1-oxo- 5 1,2.3,4-tetrahydro-isoquinoline-hydrochloride Prepared from 2-[(pyrrolid-3-yl)-methyl]-6,7-methylenedioxy-l-oxo-l, 2 ,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) -5,6-dimethoxy-naphthalene 10 analogously to Example 1.
Yield: 22.5% of theory, Melting point: 87-90°C Calc. (x H20): C 62.87 H 6.50 N 4.88 Cl 6.18 Pound: 62.72 6.38 4.93 6.30 15 Example 218 2-T (N-(3-(5,6-Pimethoxy-naphthyl-2-pxy)-propyl)- piperid-3-yl)-methvl1 -6.7-dimethyl-1-oxo-l.2:3.4- 20 tetrahydrp-isoquinoline-hydrochlQr3.de Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethyl- 1-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) -5,6-dimethoxy-naphthalene analogously to 25 Example 1.
Yield: 21.3% of theory, Melting range: 72-78°C Calc. (x H20) : C 67.30 H 7.59 N 4.90 Cl 6.21 Found: 67.44 7.74 5.06 6.53 30 Rxampls 219 2- r (N- (3- (5 . 6-DimethQ3cv-naphthvl-2-oxv) -propyl) -hexahvdro-azepin-3-yl) -methvll -6 .7-dimethyl-1-oxo- 35 1.2.3.4 - tetrahydro - i Boquinol ine - hydrochl oride Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] -6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline and - 146 - 2-(3-chloropropoxy)-5, 6-dimethoxy-naphthalene analogously to Example 1.
Yield: 12% of theory, Melting range: 84-90®C 5 Calc. (x H20): C 67.73 H 7.73 N4.78 Cl 6.06 Found: 67.64 7.81 4.94 6.20 Example 220 10 2-T(N-(2-(4-Methoxv-phenvl)-ethvl)-hexahvdro-azepin- 3-vl)-methyl1-6.7-methylenedioxy-1-oxo-l.2.3.4-tetrahvdro-isoquinoline-hvdrochloride Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-15 tetrahydro-isoquinoline and N-[2-(4-methoxy-phenyl)- ethyl] -3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 46.7% of theory, Melting point: 101-105°C 20 Calculated: C 62.44 H 7.26 N 5.60 Cl 7.50 Found: 62.62 7.27 5.48 7.66 Example 221 25 2-r fN-(3-U-Methoxv-phenoxv)-propyl)-hexahvdro- azepin-3-yl) -methyl 1 -6.7-mfithylfmfKUQxy-l-oxo-l .2.3.4- tetrahydro-ifiQCTiiinoline-hvdrochloride Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4-30 tetrahydro-2-isoquinoline and N-[3-(4-methoxy-phenoxy)-propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 43.8% of theory, Melting point: 123-126°C 35 Calculated: C 62.23 H 7.16 N 5.37 Cl 7.05 Found: 62.42 7.34 5.30 6.94 Example 222 - 147 - 2- f fN- (3- (4-Methoxv-phenoxv) -propyl) -hexahvdro-azepiri-3-vl)-methyl1-6.7-dimethyl-1-oxo-l.2.3.4- tetrahydro-isoquinoline-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro- 2-isoquinoline and N- [3-(4-methoxy-phenoxy) -propyl] - 3-chl or omethyl-hexahydro-azepine analogously to Example 2.
Yield: 42% of theory, Melting point: 172-173°C Calculated: C 69.04 H 8.07 N 5.75 Cl 7.28 Found: 69.06 8.25 5.57 7.39 Example 223 2-r fN-(3-f4-Methoxy-phenoxy)-propyl)-hexahvdro-azepin-3-yl)-methyl!-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro - i socfuinol ine - hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and N-[3-(4-methoxy-phenoxy)-propyl]- 3-chloromethyl-hexahydro-benzazepine analogously to Example 2.
Yield: 63.3% of theory, Melting range: 115-120°C Calculated: C 62.58 H 7.67 N 5.21 Cl 6.83 Found: 62.44 7.68 4.91 6.81 Example 224 2- f fN- f 2- f 4-Methoxy-ohenvl) -ethvl) - hexahvdro-azeuin- 3-yl) -methyl! -6. 7-dimethoxv- 1-oxo-1.2.3 .4-tetrahvdro- isoscuinol ine-hydrochloride Prepared from 5,6 -dimethoxy- 1-oxo-l, 2,3,4 - tetrahydro-isoquinoline and N-[2-(4-methoxy-phenyl)-ethyl] - - 148 - 3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 51.6% of theory, Melting point: HO-llS^C 5 Calculated: C 61.75 H 7.87 N 5.28 Cl 7.25 Found: 61.84 8.02 5.16 7.22 Example 225 10 2- r (N- (2- (3.4-Dlme1-.hoxy-phenvl) -ethvl) -hexahvdro-azepin-3-yl)-methyl!-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro-isoguinoline-hvdrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-15 isoquinoline and N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 45.5% of theory, Melting point: 107-111°C 20 Calculated: C 62.61 H 7.69 N 5.21 Cl 6.60 Found: 62.78 8.00 5.00 6.43 Example 226 25 2-r (N-12-n■4-Dimethoxy-phenyl)-ethyl)-hexahvdro-aggpin-3-yl)-methyl!-6.7-dimethyl-1-oxo-l.2.3.4-tetrahydro-isoguinoline-hvdrochloride Prepared from 6,7-dimethyl-l-oxo-l/2,3,4-tetrahydro-30 isoquinoline and N- [2- (3,4-dimethoxy-phenyl) -ethyl] -3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 44.8% of theory.
Melting point: 162-163°C 35 Calculated: C 66.57 H 8.18 N 5.54 Cl 7.02 Found: 66.67 8.47 5.35 * 7.11 - 149 - Example 227 2- f (N- 13-(3-Methyl-ohenoxv) -propyl) -hexahvdro-azepin- 3-yl)-methyl!-6.7-methylenedioxy-l-oxo-l.2.3.4- 5 tetrahydro-isoquinoline-hydrochloride Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and N- [3-(3-methyl-phenoxy) -propyl]-3-chloromethyl-hexahydro-azepine analogously to 10 Example 2, Yield: 46.8% of theory, Melting point: 159-161°C Calculated: C 65.37 H 7.31 N 5.64 Cl 7.28 Found: 65.44 7.40 5.39 7.23 15 Example 228 2- f (N- (3- (3-Methyl-phenoxy) -propyl) -hexahvdro-azepin- 3-vl)-methyl1-6.7-dimethoxv-l-oxo-l.2.3.4-tetrahvdro- 20 isoguinol ine-hydrochloride Prepared from 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and N- [3- (3-methoxy-phenoxy) -propyl] -3-chloromethyl-hexahydro-azepine analogously to Example 25 2.
Yield: 55.2% of theory, Melting point: 107-111°C Calculated: C 65.67 H 7.87 N 5.47 Cl 7.05 Found: 65.47 8.00 5.50 6.97 30 Example 229 2- T fN- (3- (3.4-Methvlenedioxv-phenoxv) -propyl) -hexahvdro-agepin-3-yl) -methyl! -6.7 - dimethyl -1 - oxo -1.2.3.4- 35 tetrahydrff-isoqtti,nQline-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and N-[2-(3,4-methylenedioxy-phenoxy) - - 150 - propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 40.6% of theory, Melting point: 123-126°C 5 Calculated: C 64.78 H 7.57 N 5.39 Cl 6.83 Found: 64.88 7.59 5.29 7.18 Example 230 10 2-r(N- (3-(3.4-Dimethoxv-phenoxv)-propyl)-hexahvdro-azepin-3-vl)-methyl! -6.7-dimethoxv-l-oxo-l.2.3.4- tetrahydro - i soquj.no! ine - hydrochloride Prepared from 6, 7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-15 isoquinoline and N-[3-(3,4-dimethoxy-phenoxy)-propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 30.6% of theory, Melting point: 101-105°C 20 Calculated: C 62.61 H 7.59 N 5.01 Cl 6.46 Found: 62.56 7.76 4.94 6.39 Example 231 25 2- r (N- (2- (3.4-DimethQ3cv-phenvl) -ethvl) -hexahvdro- azepin-3-yl) -methyl! -5. 6-dimethoxy-1-oxo-1.3-dihvdro- iBoindole-hydrochloride Prepared from 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-3Q hexahydro-azepin-3 -yl) -methyl] -5,6-dimethoxy- phthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 41.8% of theory.
Melting point: 150-151*C 35 Calculated: C 61.99 H 7.57 N 5.35 Cl 6.57 Found: 61.89 7.48 5.17 6.52 Example 232 - 151 - 2-T(N-(2-(3-Methvl-phenoxy)-propyl)-hexahydro-azepin- 3-yl) -methvll -5 . 6-dimethoxv-l-oxo-l. 3-dihvdro-isoindole- 5 hydrochloride Prepared from 2-[(N-(3-(3-methyl-phenoxy)-propyl)-hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Example 4. 10 Yield: 88.9% of theory, Melting point: 95-100°C Calculated: C 63.95 H 7.75 N 5,52 Cl 7.25 Found: 64.09 7.64 5.35 7.37 15 Example 233 2 - f (N- (3- (4-Methoxy-phenoxv) -propyl) -hexahvdro-azepin-3-yl)-methyl! -5.6-dimethoxv-l-oxo-l.3-dihvdro- isoindole-hydrochlpride 20 Prepared from 2 - [ (N- (3- (4-methoxy-phenoxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Example 4. Yield: 87.1% of theory, 25 Melting point: 107-112°C Calculated: C 61.99 H 7.51 N 5.35 Cl 7.02 Found: 62.07 7.37 5.28 7.31 Example 234 30 2- f (N- (3- (3.4-Methylenedioxy-phenoxy) -propyl) -hexahydro- azepin-3-yl1^methyl!-5.6-dimethoxy-l-oxo-l.3-dihvdro- isoindole-hydrQChloride 35 Prepared from 2- [ (N- (3- (3,4-methylenedioxy-phenoxy) -propyl) - hexahydro-azepin-3 -yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Example 4. - 152 - Yield: 59% of theory, Melting point: 104-107°C Calculated: C 60.38 Found: 60.40 5 Example 235 2 - r (N- (3- (3 .4-Methvlenedioxv-phenoxv) -propyl) -hexahvdro-azenin-3 - vl) -methyl! -5. 6-dimethoxy-1-oxo-1.3~dihvdro- 10 i s pjndple-hydrpchlpride Prepared from 2 - [ (N- (3- (3,4-methylenedioxy-phenoxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -5, 6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to 15 Example 4.
Yield: 79.4% of theory, Melting point: 112-116°C Calculated: C 62.23 H 7.15 N 5.37 Cl 7.05 Found: 62.16 7.25 4.96 7.03 20 Example 236 3- f (N- (3- (Pyrid-3-yl) -prppyl) -hexahydrp-azepin- 3-yl) -methyl 1 -7.8-dimethoxy-2-oxo-1. 3-dihvdro-2H-25 3-benzazepine-dihydrochloride-dihvdrate Prepared from 7,8-dimethoxy-2-oxo-l/3-dihydro-2H-3-benzazepine and N- [3-(pyrid-3-yl)-prppyl]-3-chl or omethyl-hexahydro-azepine in dimethylsulphoxide 30 with potassium tert.butoxide analogously to Example 2. Yield: 86% of theory.
Melting point: 106-108°C Calculated: C 58.05 H 7.40 N 7.52 Cl 12.69 Found: 57.94 7.55 7.75 12.42 H 6.94 N 5.20 Cl 7.31 7.15 4.95 7.25 35 - 153 - Example 237 3- r fN- (3- fPvrid-3-vl) -propyl) -hexahvdro-azepin-3-yl) -methyl 1 -7 . R-dimet-.hoxv-2-oxo-1. 3.4. 5-tetrahvdro- 5 2H-3-benzazftpinft-dihydrQChlQride-dih,ydrate Prepared from 3-[(N-(3-(pyrid-3-yl)-propyl)-hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3-dihydro -2H-3-benzazepine and 5 bar hydrogen in the presence of 10 10% palladium on charcoal in dimethylformamide at 80°C analogously to Example 5.
Yield: 43% of theory, Melting point: 119-121°C Calculated: C 57.85 H 7.73 N 7.49 Cl 12.65 15 Found: 57.74 7.79 7.23 12.50 Example 238 3-f fN-(3-fPyrid-3-yl)-propyl)-hexahvdro-azepin-20 3-vl)-methyl!-7.8-dimethoxy-1.3.4.5-tetrahvdro-2H-3-benzazepine-trihvdrochloride-monohvdrate Prepared from 3- [ (N- (3- (pyrid-3-yl) -propyl) -hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-25 tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran and diethylether einalogously to Exaiiqple 3.
Yield: 82% of theory.
Melting point: 139-141*C 30 Calculated: C" 57.39 H 7.85 N 7.43 Cl 18.82 Found: 57.42 8.15 7.56 19.04 35 - 154 - Example 239 2- T fN- (1- fPvrid-3-yl) -methyl) -pvrrolid-3-vl) -methyll -6.7-methylenedioxy-l-oxo-l.2.3.4-tetrahvdro-isocniinol Ine - dlhydrnr.hl nr Ide - d ihydrate Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[(pyrid- 3-yl)-methyl]-pyrrolidine and dimethylsulphoxide with potassium tert.butoxide analogously to Example 2.
Yield: 46% of theory, Melting point: 91-93°C Calculated: C 53.17 H 6.16 N 8.85 Cl 14.95 Found: 53.31 5.93 8.71 15.01 Example 240 2- T fN- f 1- fPvrid-3-vl) -methvl) -pvrrolid-3-vl) -methvll -6.7-methylenedioxy-1.2.3.4-tetrahvdro-isoouinoline-trihvdrochloride - 1.5 x hvdrate Prepared from 2-[(N-(1-(pyrid-3-yl)-methyl)-pyrrolid- 3-yl) -methyl] -6, 7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran and diethylether analogously to Example 3.
Yield: 67% of theory.
Melting point: 178-181°C Calculated: C 51.70 H 6.41 N 8.61 Cl 21.80 Found: 51.63 6.62 8.45 21.07 Example 241 3- r fN- (?.-I fi -Methyl -pyrid- 2 - vl) -ethvl) -hexahvdro-azepin- 3 -yl) -methvll -7. R - dime thoxv - 2 - oxo -1 . 3-dihvdro-2H- 3 -heng:azep j ne-dihydrochloride-dihydrate Prepared from 7,8-dimethoxy-2 toxo- 1,3 -dihydro-2H- ft - 155 - 3-benzazepine and N- [2- (6-methyl-pyrid-2-yl) -ethyl] -3-chloromethyl-hexahydro-azepine in dimethylsulphoxide with potassium tert .butoxide analogously to Example 2. Yield: 63% of theory, 5 Melting point: 134-136"C Calculated: C 58.05 H 7.40 N 7.52 Cl 12.69 Found: 58.15 7.60 7.45 12.45 Example 242 10 3- T (N- (2- (6-Methyl-pyrid-2-yl) -ethyl) -pyrrolid- 3-vl) -methvll -7. 8-dimethoxy-2-oxo-1. 3-dihvdro-2H-3-benzazepine-dihydrochloride x 1.5 hydrate 15 Prepared from 7,8-dimethoxy-2-oxo-l, 3-dihydro-2H-3-benzazepine and 3-chloromethyl-N- [2-(6-methyl-pyrid-2-yl) -ethyl] -pyrrolidine in dimethylsulphoxide with potassium tert .butoxide analogously to Example 2. Yield: 61% of theory, 20 Melting point: 78-80°C Calculated: C 57.58 H 6.96 N 8.06 Cl 13.60 Found: 57.40 7.18 8.24 13.39 Example 243 25 3- T fN- (2-{6 -Methyl -pyrid- 2 -yl) -ethvl) - hexahvdro-azepin-3-vl)-methyl!-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepine-dihydrochloride x 2.5 hydrate 30 Prepared from 3-[ (N- (2-(6-methyl-pyrid-2-yl) rethyl) -hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3 -dihydro-2H-3 -benzazepine and 5 bar hydrogen in the presence of palladium/charcoal and dimethyl-35 formamide analogously to Example 5.
Yield: 34% of theory, Melting point: 112-114°C Calculated: C 56.93 H 7.78 N 7.38 Cl 12.45 Found: - 156 - 56.83 8.04 7.43 12.26 Example 244 5 3- f (N- (2- (6-Methyl-pyrid-2-yl) -ethyl) -hexahydro- azepin-3-yl) -methyl! -7. 8-dimethoxv-l. 3.4. 5-tetrahvdro- 2H- 3 -benzazepine- trihydrochloride -dihydrate Prepared from 3- [ (N- (2-(6-methyl-pyrid-2-yl)-ethyl)-10 hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2- oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran and diethylether analogously to Example 3.
Yield: 74% of theory, 15 Melting point: 148-150°C Calculated: C 55.61 H 7.95 N 7.20 Cl 18.24 Found: 55.72 8.10 7.03 18.00 Example 245 20 3- r (N- (2-f6-Methvl-pyrid-2-vl) -ethvl) -pyrrolid-3-vl) methyl! -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H- 3 -benzazepine-dihydrochloride-dihvdrate 25 prepared from 3-[(N-(2-(6-methyl-pyrid-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3-dihydro-2H-3-benzazepine and palladium/charcoal in dimethylformamide at 50DC and 6 bar hydrogen pressure analogously to Example 5. 30 Yield:. 28% of theory.
Melting point: 87-90°C Calculated: C 56.38 H 7.38 N 7.89 Cl 13.31 Found: 56.33 7.53 8.09 13.43 35 - 157 - Example 246 3-r fN-f 2 -f 6-Methvl-pvrid-2-vl)-ethvl)-pvrrolid-3-yl)-methyl! -7.8-dimethoxv-l.3.4.5-tetrahvdro-5 2H-3-benzazepine-trihvdrochloride-dihvdrate Prepared from 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine and N-[2-(6-methyl-pyrid-2-yl)-ethyl] -3- (benzenesulphonyloxymethyl) -pyrrolidine in 10 dimethylformamide and triethylamine analogously to Example 2.
Yield: 42% of theory, Melting point: 225-227°C Calculated: C 54.10 H 7.62 N 7.57 Cl 19.16 15 Found: 54.18 7.55 7.51 19.30 Example 247 2- f (N- (3 - (Indol-3-yl) -propyl) -piperid-3-yl) -methyl 1 - 20 5.6-dimethoxy-1-oxo-1.3-dihvdro-isoindole x 1.5 benzenesulphonate-trihvdrate Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethoxy- 1-oxo-l, 3-dihydro-isoindole and 3-(3- 25 benzenesulphonyloxy-propyl) - indole in dimethylformamide and triethylamine analogously to Example l.
Yield: 45% of theory, Melting point: 87-89°C Calculated: C 58.51 H 6.54 N 5.68 30 Found: 58.66 6.43 5.34 Example 248 2- f (N- (3- (Indol-3-yl) -propyl) -piperid-3-yl) -methyl 1 - 35 6.7-dimethyl-1-oxo-l .2.3.4 - tgtrahvdro-isoguinol ine - benzenesulphonate-dihydrate Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethyl- - 158 - 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(3-benz ene sulphonyl oxypropyl) - indol e in dimethyl f ormamide and triethylamine analogously to Example 1.
Yield: 94% of theory, 5 Melting point: 117-119°C Calculated: C 65.46 H 7.27 N 6.73 Found: 65.51 6.91 6.72 Example 249 10 3 - f (N- (3- (Indol-3-vl) -propyl) -pyrrolid-3-vl) -methvll -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine- hyflrQchlorifle-monghydratfi 15 Prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-pyrrolid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3-dihydro-2H-3-benzazepine and 5 bar hydrogen in the presence of palladium/charcoal in dimethylformamide at 80°C analogously to Example 5. 20 Yield: 58% of theory, Melting point: 128-130°C Calculated: C 65.16 H 7.42 N 8.14 Cl 6.87 Found: 65.12 7.55 8.il 7.06 25 Example 250 3- f (N- (3- (Inflol-3-yl) -propyl) -hftxahyflrp-azepin- 3-yl)-methyl1-7.B-dimethoxy-2-oxo-1.3.4.5-tetrahvdro- 2H-3-benzazepinft-mpnohyflrate 30 Prepared from 3- [ (hexahydro-azepin-3-yl) -methyl] -7,8 - dimethoxy- 2 - oxo -1,3,4,5-tetrahydro-2H-3 -benzazepine and 3-(3-benzenesulphonyloxy-propyl)-indole in dimethylformamide and triethylamine analogously to 35 Example 1.
Yield: 49% of theory, Melting point: 56-58°C Calculated: C 70.98 H . 8.14 N 8.27 - 159 - Found: 71.08 8.10 8.16 Example 251 3-f fN- (3-(Indnl-3-vl)-propyl)-hexahvdro-azepin-3-yl)-methyl1-7.8-methylenedlo:xy-l.3.4.5-tetrahydro-2H-3-benzazepine-dihydrochloride -monohvdrate Prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-hexahydro- azepin-3-yl) -methyl] -7, 8-methylenedioxy-2-oxo-1,3,4,5- tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 56% of theory, Melting point: 155-158°C Calculated: C 62.26 H 7.50 N 7.63 Cl 12.88 Found: 62.31 7.82 7.40 12.89 Bx&mPle 252 3- r (N- (3- (Indol-3-yl) -propyl) -pyrrplid-3-yl) -methyl! - 7.8-dimethoxy-1.3.4.5-tetrahydro-2H-3-benzazepine- dihydrpchlpride-monohydrate Prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-pyrrolid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 60% of theory, Melting point: 125-128°C Calculated: C 62.44 H 7.67 N 7.80 Cl 13.16 Found: 62.35 7.87 7.59 13.67 - 160 - Example 253 2- r fN- (3 - (Indol-3-vl) -nronvl) -piperid-3-vl) -methvll - 6.7-dimethyl-l.2.3.4-tetrahydro-1soouinoline-dihvdro- 5 chl orj.de-monohydrate Prepared from 2-[(N-(3-(indol-3-yl)-propyl)-piperid- 3-yl)-methyl]-6,7-dimethyl-1-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in 10 diethylether and tetrahydrofuran analogously to Example 3.
Yield: 90% of theory, Melting point: 198-201°C Calculated: C 66.38 H 8.16 N 8.29 Cl 14.00 15 Found: 66.29 8.21 8.46 13.82 Example 254 3-T(W- (3-(Inflol-3-yl)-propyl)-hftxahydro-azepin- 20 1~vin -methvll-7.8-methylenedioxy-2-oxo-1.3.4.5-tetrahydrn-2H-3-henzazeplne-monohvdrate Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]- 7.8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H- 25 3-benzazepine and 3-(3-benzenesulphonyloxy-propyl)-indole analogously to Example 1.
Yield: 61.5% of theory, Melting point: 62-64°C Calculated: C 70.84 H 7.59 N 8.55 30 Found: 70.73 7.59 8.42 Example 255 2-f fN- (3-(Indol-3-vl)-propyl)-nvrrolid-3-vl)-methvll -35 6.7-dimethyl-1.2.3.4-tetrahvdro-lsoauinollne-dihydro-chlnride-fiemihvdrate Prepared from 2-[(N-(3-(indol-3-yl)-propyl)-pyrrolid- - 161 - 3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in ether analogously to Example 3.
Yield: 86% of theory, 5 Melting point: 143-145°C Calculated: C 67.06 H 7.92 N 8.69 Cl 14.66 Found: 66.92 8.07 8.48 14.87 Example 256 10 2- r (N- (3- (Indol-3-vl) -propyl) -pvrrolid-3-vl) -methvll -6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdro-isoauinoline- hydrochloride x 1.5 hydrate 15 Prepared from 2-I (pyrrolid-3-yl) -methyl]-6,7-dimethyl-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 3-(3-benzenesulphonyloxy-propyl) -indole analogously to Example 1.
Yield: 67% of theory, 20 Melting point: 117-120°C Calculated: C 67.69 H 7.78 N 8.77 Cl 7.40 Found: 67.62 7.80 8.72 7.93 25 Example 257 Tablets containing 7.5 mo of 3-f(N-(2-(nanhth-2- yl) -ethyl) -piperid-3-yl) -methyl! -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine-hydrochloride 30 Composition: 1 tablet contains: Active substance 7.5 mg Com starch 59.5 mg Lactose 48.0 mg 35 Polyvinylpyrrolidone 4.0 mg Magnesium stearate l.Q mg 120.0 mg - 162 - Method of preparation The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed together and moistened with water. The moist mixture is pushed through a 5 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 10 tablets.
Weight of tablet: 120 mg.
Example 258 Coated tablets containing 5 ma of 3 - T(N-(2-(naohth- 15 2-yl)-ethyl)-piperid-3-yl)-methyl1-7.8-dimethoxy- 2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine-hydrochloride 1 tablet core contains: Active substance 5.0 mg 20 Corn starch 41.5 mg Lactose 30.0 mg Polyvinylpyrrolidone 3.0 mg Magnesium stearate 0.5 mg 25 80.0 mg Method of Preparation The active substance, corn starch, lactose and polyvinylpyrrolidone are throughly mixed and moistened 30 with water. The moist mass is forced through a 1 mm screen, dried at about 45°C said 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 35 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. - 163 - Weight of coated tablet: 130 mg.
Example 259 Aigponles containing 5 ma of 3- T (N- (2- (naphth-2-vl) -5 piperid-3-yl)-methvll-7.8-dimethoxv-2-oxo-l.3.4.5-tei-.rahvdro- 2H- 3 -benzazepin- 2 -one-hvdrochloride 1 ampoule contains: Active substance 5.0 mg 10 Sorbitol 50.0 mg Water for injections ad 2.0 mg Method pf Preparation 15 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 20 solution is transferred under a current of N2 into purified and sterilized ampoules and auto-claved for 20 minutes in a jet of steam.
Example 260 25 Suppositories containing 10 ma of 3-T (N- (2-(naphth-2-yl) -et-.hyl) -piperid-3-yl) -methyl! -7. 8-dimethoxy-2-oxo-l .3.4. 5-tetrahydro-2H-3-benzazepine-hydrochloride 30 1 suppository contains: Active substance 0.010 g Hard fat (e.g. Witepsol H 19 and W 45) 1.690 a 1.700 g 35 Method of Preparation The hard fat is melted. At 38"C the ground active substance is homogeneously dispersed in the melt. It is - 164 - cooled to 35°C and poured into slightly chilled suppository moulds.
Example 261 5 Drops solution containing 10 ma of 3-\(N-(2-(naphth-2-vl) -ethyl) -piperid-3-yl) -methvll -7 . 8-dimethoxv-2-0X0-1.3.4.5-tetrahydro-2H-3^benzazepine-hydrochloride 100 ml of solution contain: Active substance 0 -2 g Hydroxyethylcellulose 0 . 15g Tartaric acid 0 .1 g Sorbitol solution with 70% dry matter 30 .0 g Glycerol 10 .0 g Benzoic acid 0 . 15g Dist. water aji 100 ml Method of Preparation 20 The distilled water is heated to 70°C. The hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The mixture is cooled to ambient temperature and the glycerol and 25 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. 30 35 - 165 -

Claims (16)

Claims
1. Cyclic amine derivatives of general formula (I) R1 R2 —t— | N-E-CH N-G-R \cH2)
2. N wherein A represents a -CH2~, -CH2~CH2- or -CH=CH- group, x 15 B represents a -CH2~, -CH2-CH2~, -CO- or -CH2CO group, whilst the carbon atom marked x is linked to the phenyl nucleus, E represents a straight-chained Ci_3-alkylene group, 20 G represents a straight-chained Ci_6-alkylene group, wherein a methylene group, linked to an aromatic or heteroaromatic group R, of a straight-chained C3.6-alkylene group may be replaced by an oxygen atom, or by 25 a methyl imino or ethylimino group, m represents the number 1, 2, 3, 4, 5 or 6 and n represents the number 0, 1, 2 or 3, although n + m must represent the number 3, 4, 5 or 6, 30 R1 represents a methyl or methoxy group, R2 represents a methyl or methoxy group or R1 and R2 together represent a methylenedioxy group and 35 R represents an optionally methyl-substituted furyl, 5 *;10;- 166 -;thienyl, pyridyl, benzo[b]furyl or benzo[b]thienyl group, a benzo[b]thienyl group substituted by a halogen atom or by a methoxy or methanesulphonyloxy group, an indolyl or N-methyl-indolyl group optionally substituted 5 by a hydroxy, methoxy or benzyloxy group, a dimethyl-thienyl or dimethoxy-isoquinolyl group, a naphthyl group optionally mono- or disubstituted by methyl or methoxy groups, whilst the substituents may be identical or different,., or, if B represents a -CH2~ or 10 -CO- group, a phenyl group optionally substituted by a methylenedioxy group, a phenyl group mono- or disubstituted by a chlorine or bromine atom or methyl or methoxy groups, whilst the substituents may be identical or different, a phenyl group substituted by a hydroxy, 15 benzyloxy, me thane sulphonyloxy, trifluoro-;methanesulphonyloxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetamido, methanesulphonylamino or bis (methanesulphonyl) amino group, or a trimethoxy-phenyl, tetramethylphenyl or dihaloaminophenyl group,;20;the enantiomers, diastereomers, N-oxides and acid addition salts thereof.;2. Cyclic amine derivatives of general formula (la);25;30;/2m;- E - CH - „;- G - R;(la);wherein;35 R, R1# R2, A, B, E, G, m and n are defined as in claim;1, the enantiomers, diastereomers, N-oxides and acid addition salts thereof.;- 167 -;
3. Cyclic amine derivatives of general formula Xa according to claim 2, wherein;A represents a -CH2CH2- group,;5 x;B represents a -CH2-CH2_, -CO- or -CH2CO- group, wherein the carbon atom designated x is linked to the phenyl nucleus,;10 E represents a methylene or ethylene group,;G represents a straight-chained C2-4-alkylene group, wherein a methylene group of a straight-chained C3_4-alkylene group, linked to an aromatic or heteroaromatic 15 group R, may be replaced by an oxygen,;R1 represents a methoxy group,;R2 represents a methoxy group or R1 and R2 together 20 represent a methylenedioxy group,;m represents the number 2, 3 or 4,;n represents the number 1 and;25;R represents a naphth-2-yl, 6-methoxy-naphth-2-yl, 5-methyl-6 -methoxy-naphth-2-yl, thien-2-yl, 6-methyl-pyrid-2-yl, benzo[b]fur-2-yl or benzo[b]thien-3-yl group or, if B represents a -CO- group, a 4-methoxyphenyl or 30 3,4-dimethoxyphenyl group,;the enantiomers, diastereomers and acid addition salts thereof.;35
4. Cyclic amine derivatives of general formula (la) according to claim 2;- 168 -;a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine,;5 b) 3-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl)-piperid-3-yl) -methyl] -7, 8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine,;c) 3-[2-(N-(2-(6-methoxy-naphth-2-yl)-ethyl)-piperid-10 2-yl)-ethyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-;2H-3-benzazepine,;d) 2 - [ (N- (2 - (6 -methoxy-naphth-2 -yl) -ethyl) - hexahydro-azepin-3-yl) -methyl] -6, 7-methylenedioxy-l-oxo-l,2,3,4-;15 tetrahydro-isoquinoline,;e) 2-[(N-(2-(naphth-2-yl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline,;20;f) 2- [ (N- (2- (3,4-dimethoxy-phenyl) -ethyl) -piperid-3-yl)-methyl]-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline,;25 g) 2- [ (N- (2- (3,4-dimethoxy-phenyl)-ethyl)-piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline ,;h) 2 - [ (N- (3- (4-methoxy-phenoxy) -propyl) -piperid-;30 3-yl) -methyl] -6, 7-dimethyl-l-oxo-l, 2,3,4-tetrahydro-isoquinoline ,;i) 3- [ (N- (4- (thien-2-yl) -butyl) -piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine,;35;k) 3- [ (N- (2- (benzo [b] fur-2-yl) -ethyl) -piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-;- 169 -;2H-3-benzazepine,;1) 3-[(N-(2-(benzo[b]thien-3-yl)-ethyl)-piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro-5 2H-3-benzazepine,;m) 2-[(N-(3-(6-methoxy-naphth-2-yl-oxy)-propyl)-pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and;10;n) 2-[(N- (2-(6-methoxy-naphth-2-yl)-ethyl)-hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline,;*15 the enantiomers, diastereomers and acid addition salts thereof.
5. Cyclic amine derivatives of general formula (la) according to claim 2 20 a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 25 b) 2-[ (N-(3-(4-methoxy-phenoxy)-propyl)-piperid- 3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline , c) 3- [ (N- (4- (thien-2-yl) -butyl) -piperid-3-yl) -methyl] -30 7,8-dimethoxy-2-oxo-l, 3,4,5 - tetrahydro-2H-3-benzazepine, d) 2-[(N- (3-(6-methoxy-naphthyl-2-oxy)-propyl)-pyrrol id-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro- isoquinoline, 35 e) 2- [ (N- (2- (6 -methoxy-naphth- 2 -yl) -ethyl) - hexahydro-azepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,4- - 170 - tetrahydro-isoquinoline, f) 3-[(N-(2-(4-methoxy-phenyl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5- 5 tetrahydro-2H-3-benzazepine and g) 3- [ (N- (2-(3,4-dimethoxy-phenyl)-ethyl)-hexahydro-azepin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine 10 the enantiomers, diastereomers and acid addition salts thereof.
6. 3-[(N-(2-(Naphth-2-yl)-ethyl)-piperid-3-yl)-15 methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro- 2H-3-benzazepine, the enantiomers, diastereomers and acid addition salts thereof.
7. Physiologically acceptable acid addition salts of 20 the compounds according to claims 1 to 6 with inorganic or organic acids.
8. Pharmaceutical compositions containing a compound of general formula I according to claims 1 to 6 or a 25 physiologically acceptable acid addition salt thereof according to claim 7 together with one or more inert carriers and/or diluents.
9. Pharmaceutical compositions according to claim 8 30 suitable for the treatment of sinus tachycardia and ischaemic heart disease.
10. Process for the preparation of a pharmaceutical preparation according to claims 8 and 9, characterised 35 in that a compound according to claims 1 to 6 or a physiologically acceptable acid addition salt thereof according to claim 7 is incorporated in one or more - 171 - inert carriers and/or diluents by a non-chemical method.
11. Process for the preparation of cyclic amine derivatives according to claims 1 to 7, characterised in 5 that a) a compound of general formula (II) 10 /
12. Process for preparing cyclic amine derivatives of general formula (I) according to claims 1 to 7 wherein B denotes a -CH2- or -CH2CH2 group, characterised in that c) a compound of general formula (VI) \ / \ (VI) . N - E - CH N-G-R B1/ X/ 15 wherein R, R2, : to 6 and R, R^, R2, A, E, G, m and n are defined as in claims 1 20 B1 represents a -CO- or -CH2CO- group, whilst the carbon atom marked x is linked t8 the phenyl nucleus, is reduced, and subsequently, if desired, a compound of general formula 25 I thus obtained wherein R contains a nitro group, is converted by reduction into a corresponding amino compound of general formula I and/or a compound of general formula I thus obtained wherein R 3q contains an amino group is converted by acylation into a corresponding alkanoylamino compound of general formula I and/or a compound of general formula I thus obtained which 35 contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or - 174 - a compound of general formula I thus obtained is converted into the acid addition salts thereof, more particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.
13. Process for preparing cyclic amine derivatives of general formula I according to claims 1 to 7, wherein A represents a -CH2~ group and B represents a -CO- or -CH2CO- group, characterised in that a compound of general formula (VII) ^CH2^m (VII) E - CH N-G-R wherein R, R1# R2, E, Gf m and n are defined as in claims 1 to 6 and x B2 represents a -CO- or -CH^CO- group, the carbon atom marked x being linked to the phenyl nucleus, is reduced with nascent hydrogen, and a compound of general formula I thus obtained wherein R contains an amino group is converted by acylation into a corresponding alkanoylamino compound of general formula I and/or a compound of general formula I thus obtained which contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or a compound of general formula I thus obtained is converted into the acid addition salts thereof, more - 175 - particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids.
14. Process for preparing new cyclic amine derivatives according to claims l to 7, wherein A represents a -CH2CH2- group and B represents a methylene or carbonyl group, characterised in that 10 15 e) a compound of general formula (VIII) (CH 9) 2'm \ N - G. - R (VIII) (CH?) / 2'n wherein R, R1# R2, B, E, G, m and n are defined as in claims 1 20 to 6, and B3 represents a -CH2~ or -CO- group, is hydrogenated, and subsequently, if desired, a compound of general formula I thus obtained wherein R contains an amino group is converted by acylation into a corresponding alkanoylamino compound of general formula I and/or a compound of general formula I thus obtained which contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or 25 30 a compound of general formula I thus obtained is converted into the acid addition salts thereof, more 35 particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids. - 176 -
15. Process for the preparation of cyclic amine derivatives as claimed in any of claims 11 to 14 substantially as described herein with reference to the Examples.
16. Cyclic amine derivatives whenever prepared by a process as claimed in any of claims 11 to 15. TOMKINS & CO.
IE155988A 1987-05-25 1988-05-24 New cyclic amine derivatives pharmaceutical compositions containing these compounds and processes for their preparation IE68842B1 (en)

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