Patent EP0200444A2 successfully refreshed from Google Patents.
EP0200444A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity
Assignee: F Hoffmann La Roche AG
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Filing: 1986-04-21
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Granted: —
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Expires: 2006-04-21
Abstract
Abstract @ Compounds of formula (I) and pharmaceutically acceptable salts thereof: wherein X is CO and Y is NH or 0, or X is NH and Y is CO; Z is CH 2 , 0, S or NR 3 wherein R 3 is hydrogen, C 1-6 alkyl, C 3-7 alkenyl-methyl, phenyl or phenyl C 1-4 alkyl either of which phenyl moieties may be substituted by one or two of halogen, CF 3 , C 1-6 alkoxy or C 1-6 alkyl; and R a is not present; or Z is CH or N and R a is as defined for R 3 above; R b is present when X-Y-R 2 is attached at the phenyl ring and is selected from hydrogen, halogen, CF 3 , hydroxy, C 1-6 alkoxy or C 1-6 alkyl; R 1 is hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-7 acyl, C 1-7 acylamino, C 1-6 alkylsulphonylamino, N-(C 1-6 alkylsulphonyl)-N-C 1-4 alkylamino, C 1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C 1-4 alkylamino optionally N-substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, phenyl or phenyl C 1-4 alkyl groups or optionally N-disubstituted by C 4-5 polymethylene; R 2 is a group of formula (a), (b) or (c) wherein n is 2 or 3; p and q are independently 1 to 3; and R 4 or R 5 is C 1-7 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-c 1-2 alkyl, or a group (CH 2 ) t R 6 where t is 1 or 2 and R 6 is thienyl, pyrrolyl or furyl optionally substituted by one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy, having 5-HT antagonist activity and / or gastric motility en- chancing activity, a process for their preparation and their use as pharmaceuticals.
Inventors
- 👤 Francis David C/O Smithkline Beecham King
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-05 09:13
CPC Classifications
C; C07; C07D; C07D451/00; C07D451/02; C07D451/04; A; A61; A61P; A61P1/00; A61P1/08; A61P25/00; A61P25/04; A61P25/06; A61P25/20; A61P3/00; A61P3/04; A61P43/00; A61P9/00; A61P9/06; C07D403/00; C07D403/02; C07D403/12; C07D451/06; C07D451/12; C07D451/14; C07D453/00; C07D453/06
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
375 words
A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X is CO and Y is NH or O, or X is NH and Y is CO; Z is CH 2 , O, S or NR 3 wherein R 3 is hydrogen, C l - 6 alkyl, C3-7 alkenyl-methyl, phenyl or phenyl C l - 4 alkyl either of which phenyl moieties may be substituted by one or two of halogen, CF 3 , C l - 6 alkoxy or C l - 6 alkyl; and R a is not present; or Z is CH or N and R a is as defined for R 3 above; R b is present when X-Y-R 2 is attached at the phenyl ring and is selected from hydrogen, halogen, CF 3 , hydroxy, C l - 6 alkoxy or C 1-6 alkyl; R 1 is hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C l - 6 alkylthio, C 1-7 acyl, C l - 7 acylamino, C 1-6 alkylsulphonylamino, N-(C l-6 alkylsulphonyl)-N-C 1-4 alkylamino, C 1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C 1-4 alkylamino optionally N-substituted by one or two groups selected from C l - 6 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl C l - 4 alkyl, phenyl or phenyl C l - 4 alkyl groups or optionally N-disubstituted by C 4 - 5 polymethylene; R 2 is a group of formula (a), (b) or (c) wherein n is 2 or 3; p and q are independently 1 to 3; and R 4 or R 5 is C 1-7 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl-C l - 2 alkyl, or a group (CH 2 ) t R 6 Where t is 1 or 2 and R 6 is thienyl, pyrrolyl or furyl optionally substituted by one or two substituents selected from C l - 6 alkyl, C l - 6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C l - 4 alkyl optionally substituted by hydroxy, C l - 4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy.
Claim 2
Dependent Claim
375 words
A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X is CO and Y is NH or O, or X is NH and Y is CO; Z is CH 2 , O, S or NR 3 wherein R 3 is hydrogen, C l - 6 alkyl, C3-7 alkenyl-methyl, phenyl or phenyl C l - 4 alkyl either of which phenyl moieties may be substituted by one or two of halogen, CF 3 , C l - 6 alkoxy or C l - 6 alkyl; and R a is not present; or Z is CH or N and R a is as defined for R 3 above; R b is present when X-Y-R 2 is attached at the phenyl ring and is selected from hydrogen, halogen, CF 3 , hydroxy, C l - 6 alkoxy or C 1-6 alkyl; R 1 is hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C l - 6 alkylthio, C 1-7 acyl, C l - 7 acylamino, C 1-6 alkylsulphonylamino, N-(C l-6 alkylsulphonyl)-N-C 1-4 alkylamino, C 1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C 1-4 alkylamino optionally N-substituted by one or two groups selected from C l - 6 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl C l - 4 alkyl, phenyl or phenyl C l - 4 alkyl groups or optionally N-disubstituted by C 4 - 5 polymethylene; R 2 is a group of formula (a), (b) or (c) wherein n is 2 or 3; p and q are independently 1 to 3; and R 4 or R 5 is C 1-7 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl-C l - 2 alkyl, or a group (CH 2 ) t R 6 Where t is 1 or 2 and R 6 is thienyl, pyrrolyl or furyl optionally substituted by one or two substituents selected from C l - 6 alkyl, C l - 6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C l - 4 alkyl optionally substituted by hydroxy, C l - 4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy.
Claim 3
Dependent Claim
32 words
A compound according to claim 1 of formula (II): wherein n l is 2 or 3, Y 1 is NH or O and the remaining variables are as defined in claim 1.
Claim 4
Dependent Claim
10 words
A compound according to claim 2 wherein n is 3.
Claim 5
Dependent Claim
28 words
A compound according to claim 1 of formula (IV): wherein q l is 1 or 2 and the remaining variables are as defined in claims 1 and 2.
Claim 6
Dependent Claim
43 words
A compound according to any one of claims 1 to 4 wherein Z is NR 3 as defined in claim 1 and R a is not present or Z is N and R a is as defined in claim 1 for R 3
Claim 7
Dependent Claim
14 words
A compound according to claim 5 wherein R 3/ Ra is hydrogen or methyl.
Claim 8
Dependent Claim
31 words
7, A compound according to any one of claims 1 to 6 wherein the X-Y-R 2 side chain is attached at position 3, as depicted in formula (I) in claim 1.
Claim 9
Dependent Claim
18 words
A compound according to any one of claims 1 to 7 wherein R 1 is hydrogen or 5-halo.
Claim 10
Dependent Claim
20 words
A compound according to any one of claims 1 to 8 wherein wherein R4 or R5 is C l-7 alkyl.
Claim 11
Dependent Claim
14 words
A compound according to claim 9 wherein R 4 or R 5 is methyl.
Claim 12
Dependent Claim
27 words
3-Indazolecarboxylic acid (endo-8-methyl-8-azabiclo-[3.2.1]oct-3-yl)ester, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-indazole-3-carboxamide, l-methyl-3-indazolecarboxylic acid(endo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)ester, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-5-fluoro-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-5-chloro-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-methyl-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo]3,3,1]non-3-yl)-2-methyl-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-ethyl-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1,2-benz-isoxazole-3-carboxamide, 5a-N-(2-methyl-2-azabicyclo[2,2,2]oct-5-yl) -1-methyl-indazole-3-carboxamide, N-(exo-2-methyl-2-azabicyclo[2,2,l]hept-5-yl)-l-methylindazole-3-carboxamide, N-(endo-2-methyl-2-azabicyclo[2.2,1]hept-5- yl)-l-methylindazole-3-carboxamide, or a pharmaceutically acceptable salt of any of the foregoing.
Claim 13
Dependent Claim
27 words
3-Indazolecarboxylic acid (endo-8-methyl-8-azabiclo-[3.2.1]oct-3-yl)ester, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-indazole-3-carboxamide, l-methyl-3-indazolecarboxylic acid(endo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)ester, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-5-fluoro-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-5-chloro-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-methyl-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo]3,3,1]non-3-yl)-2-methyl-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-ethyl-indazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1,2-benz-isoxazole-3-carboxamide, 5a-N-(2-methyl-2-azabicyclo[2,2,2]oct-5-yl) -1-methyl-indazole-3-carboxamide, N-(exo-2-methyl-2-azabicyclo[2,2,l]hept-5-yl)-l-methylindazole-3-carboxamide, N-(endo-2-methyl-2-azabicyclo[2.2,1]hept-5- yl)-l-methylindazole-3-carboxamide, or a pharmaceutically acceptable salt of any of the foregoing.
Claim 14
Dependent Claim
132 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 reacting a compound of formula (V): with a compound of formula (VI): wherein G is COQ 1 where Q 1 is a group displaceable by a nucleophile, and L is NH 2 or OH or a reactive derivative thereof and the remaining variables are as defined in claim 1 and thereafter optionally converting any R l , R 3 , R 4 , R 5 , R a amd R b group to another R l , R 3 , R 4 , R 5 , R a or R b group respectively, and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
Claim 15
Dependent Claim
72 words
A process for the preparation of a compound of formula (I) wherein R 2 is of formula (a) or (c), as defined in claim 1, which process comprises the reaction of a compound of formula (VII): wherein R2 1 is of formula (d) or (e) with R 4 Q 2 or R 5 Q 2 wherein Q 2 is a leaving group and the remaining variables are as defined in claim 1.
Claim 16
Dependent Claim
10 words
A compound of formula (VII) as defined in claim 13.
Claim 17
Dependent Claim
26 words
A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Claim 18
Dependent Claim
18 words
A compound according to any one of claims 1 to 11 for use as an active therapeutic substance.
Claim 19
Dependent Claim
24 words
A compound according to any one of claims 1 to 11 for use in the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.
References Cited (Backward Citations)
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