Patent EP0372962A2 successfully refreshed from Google Patents.
EP0372962A2
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EP
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Quinindolinone derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them
Assignee: Beecham Group PLC
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Filing: 1989-12-07
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Granted: —
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Expires: 2009-12-07
Abstract
Abstract A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R₁ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; R₂, R₃ and R₄ are independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylthio, hydroxy, C₂₋₇ alkanoyl, chloro, fluoro, trifluoromethyl, nitro, amino optionally substituted by one or two C₁₋₆ alkyl groups or by C₂₋₇ alkanoyl, cyano, carbamoyl and carboxy, and phenyl, phenyl C₁₋₄ alkyl or phenyl C₁₋₄ alkoxy in which any phenyl moiety is optionally substituted by any of these groups; R₅ and R₆ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₂₋₆ alkenyl, C₁₋₇ alkanoyl, C₁₋₆ alkylsulphonyl, di-(C₁₋₆ alkyl)amino C₁₋₆ alkyl, 3-oxobutyl, 3-hydroxybutyl, and phenyl, phenyl C₁₋₄ alkyl, benzoyl, phenyl C₂₋₇ alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, amino or carboxy, or R₅ and R₆ together are C₂₋₆ polymethylene optionally interrupted by oxygen or NR₁₁ wherein R₁₁ is hydrogen or C₁₋₆ alkyl optionally substituted by hydroxy; R₇, R₈, R₉ and R₁₀ are independently selected from hydrogen, C₁₋₈ alkyl optionally substituted by one or two hydroxy, oxo, C₁₋₄ alkoxy, halogen or CF₃ groups, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₂₋₇ alkanoyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl either being optionally substituted by one, two or three halogen atoms or C₁₋₄ alkyl, C₃₋₇ cycloalkenyl optionally substituted by one or two halogen or C₁₋₄ alkyl groups, C₃₋₇ cycloalkenyl-C₁₋₄ alkyl in which the cycloalkenyl ring is optionally substituted by one or two halogen or C₁₋₄ alkyl groups, and phenyl optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, amino or carboxy, or R₇ and R₈ together and/or R₉ and R₁₀ together are C₃₋₆ polymethylene optionally substituted by C₁₋₆ alkyl or C₂₋₆ alkenyl; and Z is (CR₁₄R₁₅) n where n is 0, 1 or 2 and R₁₄ and R₁₅ are independently selected from hydrogen, C₁₋₆ alkyl or C₂₋₆ alkenyl.
Inventors
- 👤 Ian Thomson Beecham Pharmaceuticals Forbes
- 👤 Roger Thomas Beecham Pharmaceuticals Martin
- 👤 Mervyn Beecham Pharmaceuticals Thompson
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-09 09:15
CPC Classifications
C; C07; C07D; C07D471/00; C07D471/02; C07D471/04; A; A61; A61P; A61P25/00; A61P25/20; A61P25/24; A61P25/26; C07D209/00; C07D209/02; C07D209/04; C07D209/30; C07D209/42
Claims Analysis
Total Claims: 22
Claim 1
Independent Claim
324 words
A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R₁ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; R₂, R₃ and R₄ are independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylthio, hydroxy, C₂₋₇ alkanoyl, chloro, fluoro, trifluoromethyl, nitro, amino optionally substituted by one or two C₁₋₆ alkyl groups or by C₂₋₇ alkanoyl, cyano, carbamoyl and carboxy, and phenyl, phenyl C₁₋₄ alkyl or phenyl C₁₋₄ alkoxy in which any phenyl moiety is optionally substituted by any of these groups; R₅ and R₆ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₂₋₆ alkenyl, C₁₋₇ alkanoyl, C₁₋₆ alkylsulphonyl, di-(C₁₋₆ alkyl)amino C₁₋₆ alkyl, 3-oxobutyl, 3-hydroxybutyl, and phenyl, phenyl C₁₋₄ alkyl, benzoyl, phenyl C₂₋₇ alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, amino or carboxy, or R₅ and R₆ together are C₂₋₆ polymethylene optionally interrupted by oxygen or NR₁₁ wherein R₁₁ is hydrogen or C₁₋₆ alkyl optionally substituted by hydroxy; R₇, R₈, R₉ and R₁₀ are independently selected from hydrogen, C₁₋₈ alkyl optionally substituted by one or two hydroxy, oxo, C₁₋₄ alkoxy, halogen or CF₃ groups, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₂₋₇ alkanoyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl either being optionally substituted by one, two or three halogen atoms or C₁₋₄ alkyl, C₃₋₇ cycloalkenyl optionally substituted by one or two halogen or C₁₋₄ alkyl groups, C₃₋₇ cycloalkenyl-C₁₋₄ alkyl in which the cycloalkenyl ring is optionally substituted by one or two halogen or C₁₋₄ alkyl groups, and phenyl optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, amino or carboxy, or R₇ and R₈ together and/or R₉ and R₁₀ together are C₃₋₆ polymethylene optionally substituted by C₁₋₆ alkyl or C₂₋₆ alkenyl; and Z is (CR₁₄R₁₅) n where n is 0, 1 or 2 and R₁₄ and R₁₅ are independently selected from hydrogen, C₁₋₆ alkyl or C₂₋₆ alkenyl.
Claim 2
Dependent Claim
324 words
A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R₁ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; R₂, R₃ and R₄ are independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylthio, hydroxy, C₂₋₇ alkanoyl, chloro, fluoro, trifluoromethyl, nitro, amino optionally substituted by one or two C₁₋₆ alkyl groups or by C₂₋₇ alkanoyl, cyano, carbamoyl and carboxy, and phenyl, phenyl C₁₋₄ alkyl or phenyl C₁₋₄ alkoxy in which any phenyl moiety is optionally substituted by any of these groups; R₅ and R₆ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₂₋₆ alkenyl, C₁₋₇ alkanoyl, C₁₋₆ alkylsulphonyl, di-(C₁₋₆ alkyl)amino C₁₋₆ alkyl, 3-oxobutyl, 3-hydroxybutyl, and phenyl, phenyl C₁₋₄ alkyl, benzoyl, phenyl C₂₋₇ alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, amino or carboxy, or R₅ and R₆ together are C₂₋₆ polymethylene optionally interrupted by oxygen or NR₁₁ wherein R₁₁ is hydrogen or C₁₋₆ alkyl optionally substituted by hydroxy; R₇, R₈, R₉ and R₁₀ are independently selected from hydrogen, C₁₋₈ alkyl optionally substituted by one or two hydroxy, oxo, C₁₋₄ alkoxy, halogen or CF₃ groups, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₂₋₇ alkanoyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl either being optionally substituted by one, two or three halogen atoms or C₁₋₄ alkyl, C₃₋₇ cycloalkenyl optionally substituted by one or two halogen or C₁₋₄ alkyl groups, C₃₋₇ cycloalkenyl-C₁₋₄ alkyl in which the cycloalkenyl ring is optionally substituted by one or two halogen or C₁₋₄ alkyl groups, and phenyl optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, amino or carboxy, or R₇ and R₈ together and/or R₉ and R₁₀ together are C₃₋₆ polymethylene optionally substituted by C₁₋₆ alkyl or C₂₋₆ alkenyl; and Z is (CR₁₄R₁₅) n where n is 0, 1 or 2 and R₁₄ and R₁₅ are independently selected from hydrogen, C₁₋₆ alkyl or C₂₋₆ alkenyl.
Claim 3
Dependent Claim
13 words
A compound according to claim 1, wherein R₂, R₃ and R₄ are hydrogen.
Claim 4
Dependent Claim
19 words
A compound according to claim 1 or 2, wherein R₅ is hydrogen and R₆ is hydrogen or C₁₋₆ alkyl.
Claim 5
Dependent Claim
20 words
A compound according to any one of claims 1 to 3, wherein R₁ is hydrogen, methyl, ethyl, propyl or prop-2-enyl.
Claim 6
Dependent Claim
24 words
A compound according to any one of claims 1 to 4, wherein R₇ is hydrogen, methyl or ethyl and R₈ is hydrogen or methyl.
Claim 7
Dependent Claim
24 words
A compound according to any one of claims 1 to 5, wherein R₉ is hydrogen or methyl and R₁₀ is hydrogen, methyl or phenyl.
Claim 8
Dependent Claim
28 words
A compound according to any one of claims 1 to 6 wherein n in Z is 1 or 2, R₁₄ is hydrogen and R₁₅ is hydrogen or methyl.
Claim 9
Dependent Claim
17 words
A compound according to any one of claims 1 to 7, wherein n in Z is 1.
Claim 10
Dependent Claim
43 words
11-Amino-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-3,3-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-3-phenyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-6-methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-6-ethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-6-n-propyl-1,2,3,4-tetrahydro-6H- quinindolin-1-one, 11-amino-6-(2-propenyl)-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-1,2,3,4-tetrahydro-3,3,6-trimethyl-6H-quinindolin-1-one, (±) 11-amino-6-methyl-3-phenyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-3,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-2,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-2,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (-) 11-amino-2,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-2-ethyl-6-methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-1,2,3,4-tetrahydro-2,2,6-trimethyl-6H-quinindolin-1-one, (±) 11-amino-6-methyl-2-(2-propynyl)-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-1,2,3,4-tetrahydro-2,4,6-trimethyl-6H-quinindolin-1-one, 12-amino-7-methyl-cyclohepta[5,6]pyrido[2,3-b]indol-1-one, 10-amino-5-methyl-cyclopenta[5,6]pyrido[2,3-b]indol-1-one or (±) 12-amino-2,7-dimethyl-cyclohepta[5,6]pyrido[2,3-b]indol-1-one or a pharmaceutically acceptable salt of any of the foregoing compounds.
Claim 11
Dependent Claim
43 words
11-Amino-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-3,3-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-3-phenyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-6-methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-6-ethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-6-n-propyl-1,2,3,4-tetrahydro-6H- quinindolin-1-one, 11-amino-6-(2-propenyl)-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-1,2,3,4-tetrahydro-3,3,6-trimethyl-6H-quinindolin-1-one, (±) 11-amino-6-methyl-3-phenyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-3,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-2,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-2,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (-) 11-amino-2,6-dimethyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-2-ethyl-6-methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-1,2,3,4-tetrahydro-2,2,6-trimethyl-6H-quinindolin-1-one, (±) 11-amino-6-methyl-2-(2-propynyl)-1,2,3,4-tetrahydro-6H-quinindolin-1-one, (±) 11-amino-1,2,3,4-tetrahydro-2,4,6-trimethyl-6H-quinindolin-1-one, 12-amino-7-methyl-cyclohepta[5,6]pyrido[2,3-b]indol-1-one, 10-amino-5-methyl-cyclopenta[5,6]pyrido[2,3-b]indol-1-one or (±) 12-amino-2,7-dimethyl-cyclohepta[5,6]pyrido[2,3-b]indol-1-one or a pharmaceutically acceptable salt of any of the foregoing compounds.
Claim 12
Dependent Claim
289 words
A process for the preparation of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises the condensation of a compound of formula (IV): with a compound of formula (V): wherein R₁′ is R₁ as defined in claim 1 or an N-protecting group, R₂, R₃ and R₄ are as defined in claim 1, R₁₆, R₁₇, R₁₈ and R₁₉ are each hydrogen or R₁₆ and R₁₇, and R₁₈ and R₁₉ together represent a bond, L is a leaving group, Y is a group CN or COL₁, where L₁ is a leaving group, R₂₀ is hydrogen or an N-protecting group and R₇′, R₈′, R₉′, R₁₀′ and Z′ are R₇, R₈, R₉, R₁₀ and Z respectively, as defined in claim 1 or a group convertible to R₇, R₈, R₉, R₁₀ and Z, respectively, to give an acyclic enamine intermediate of formula (VI): wherein Y, R₁′, R₂, R₃, R₄, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are as defined in formula (IV) and R₇′, R₈′, R₉′, R₁₀′ and Z′ are as defined in formula (V); and thereafter, optionally or as necessary, and in any appropriate order, cyclising the enamine intermediate, separating any enantiomers, converting R₂₀ when hydrogen to an N-protecting group, converting R₇′, R₈′, R₉′, R₁₀′ and Z′ to R₇, R₈, R₉, R₁₀ and Z, respectively, when Y is a group COL₁, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR₅R₆, removing any R₁′ N-protecting group, removing any R₂₀ N-protecting group, converting R₁₆, R₁₇, R₁₈ and R₁₉ when hydrogen to two bonds, interconverting R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ or Z and/or forming a pharmaceutically acceptable salt of the compound of formula (I).
Claim 13
Dependent Claim
32 words
A compound of formula (VI) or a salt thereof: wherein Y, R₁′, R₂, R₃, R₄, R₇′, R₈′, R₉′, R₁₀′, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and Z are as defined in claim 10.
Claim 14
Dependent Claim
13 words
1-(4-Methoxyphenyl)methyl-2-[(3-oxo-1-cyclohexen-1-yl)amino]-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile, 2-[(5,5-dimethyl-3-oxo-1-cyclohexen-1-yl)amino]-1-(4-methoxyphenyl)methyl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile, (±) 2-[(5-methyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, (±) 2-[(4-methyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, (±) 2-[(4-ethyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, 2-[(4,4-dimethyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, 1-methyl-2-[3-oxo-1-cyclopenten-1-yl)amino]-1H-indole-3-carbonitrile, 1-methyl-2-[(3-oxo-1-cyclohepten-1-yl)amino]-1H-indole-3-carbonitrile or 1-methyl-2-[(3-oxo-1-cyclohexen-1-yl)amino]-1H-indole-3-carbonitrile.
Claim 15
Dependent Claim
13 words
1-(4-Methoxyphenyl)methyl-2-[(3-oxo-1-cyclohexen-1-yl)amino]-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile, 2-[(5,5-dimethyl-3-oxo-1-cyclohexen-1-yl)amino]-1-(4-methoxyphenyl)methyl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile, (±) 2-[(5-methyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, (±) 2-[(4-methyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, (±) 2-[(4-ethyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, 2-[(4,4-dimethyl-3-oxo-1-cyclohexen-1-yl)amino]-1-methyl-1H-indole-3-carbonitrile, 1-methyl-2-[3-oxo-1-cyclopenten-1-yl)amino]-1H-indole-3-carbonitrile, 1-methyl-2-[(3-oxo-1-cyclohepten-1-yl)amino]-1H-indole-3-carbonitrile or 1-methyl-2-[(3-oxo-1-cyclohexen-1-yl)amino]-1H-indole-3-carbonitrile.
Claim 16
Dependent Claim
77 words
A compound of formula (VII) or a salt thereof: wherein X is NH₂, OH or chloro, R₁′, R₂, R₃, R₄, R₇′, R₈′, R₉′, R₁₀′, R₁₆, R₁₇, R₁₈, R₁₉ and Z′ are as defined in claim 10, with the proviso that when R₁′, R₇′, R₈′, R₉′, R₁₀′, and Z′ are R₁, R₇, R₈, R₉, R₁₀ and Z as defined in claim 1 and R₁₆ and R₁₇, and R₁₈ and R₁₉ together represent a bond, X is not NH₂.
Claim 17
Dependent Claim
9 words
11-Amino-6-(4-methoxyphenyl)methyl-1,2,3,4,7,8,9,10-octahydro-6H-quinindolin-1-one, 11-amino-3,3-dimethyl-6-(4-methoxyphenyl)methyl-1,2,3,4,7,8,9,10-octahydro-6H-quinindolin-1-one, (±) 11-amino-6-(4-methoxyphenyl)methyl-1,2,3,4,7,8,9,10-octahydro-3-phenyl-6H-quinindolin-1-one, 11-amino-6-(4-methoxyphenyl)methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-3,3-dimethyl-6-(4-methoxyphenyl)methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one or (±) 11-amino-6-(4-methoxyphenyl)methyl-3-phenyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one.
Claim 18
Dependent Claim
9 words
11-Amino-6-(4-methoxyphenyl)methyl-1,2,3,4,7,8,9,10-octahydro-6H-quinindolin-1-one, 11-amino-3,3-dimethyl-6-(4-methoxyphenyl)methyl-1,2,3,4,7,8,9,10-octahydro-6H-quinindolin-1-one, (±) 11-amino-6-(4-methoxyphenyl)methyl-1,2,3,4,7,8,9,10-octahydro-3-phenyl-6H-quinindolin-1-one, 11-amino-6-(4-methoxyphenyl)methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one, 11-amino-3,3-dimethyl-6-(4-methoxyphenyl)methyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one or (±) 11-amino-6-(4-methoxyphenyl)methyl-3-phenyl-1,2,3,4-tetrahydro-6H-quinindolin-1-one.
Claim 19
Dependent Claim
21 words
A pharmaceutical composition which comprises a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.
Claim 20
Dependent Claim
18 words
A compound according to any one of claims 1 to 9, for use as an active therapeutic substance.
Claim 21
Dependent Claim
22 words
A compound according to any one of claims 1 to 9, for use in the treatment of anxiety or depression in mammals.
Claim 22
Dependent Claim
28 words
Use of a compound according to any one of claims 1 to 9, in the manufacture of a medicament for the treatment of anxiety or depression in mammals.
References Cited (Backward Citations)
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