Claims for Patent: 4,886,808

Summary for Patent: 4,886,808

Title:	Indazolyl carboxylic acid amides useful for treating migraine clusters headache, trigeminal neuralgia or emesis
Abstract:	Compounds of formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein X is CO and Y is NH;Z is NR3 wherein R3 is hydrogen, C1-6 alkyl, C3-7 alkenyl-methyl, phenyl or phenyl C1-4 alkyl either of which phenyl moieties may be substituted by one or two of halogen, CF3, C1-6 alkoxy or C1-6 alkyl; and Ra is not present; orZ is N and Ra is as defined for R3 above;Rb is present when X-Y-R2 is attached at the phenyl ring and is selected from hydrogen, halogen, CF3, hydroxy, C1-6 alkoxy or C1-6 alkyl;R1 is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-7 acyl, C1-7 acylamino, C1-6 alkylsulphonylamino, N(C1-6 alkylsulphonyl)-N-C1-4 alkylamino, C1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C1-4 alkylamino optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, phenyl or phenyl C1-4 alkyl groups or optionally N-disubstituted by C4-5 polymethylene;R2 is a group of formula (a) ##STR2## wherein n is 2 or 3; and R4 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-2 alkyl, or a group (CH2)t R6 where t is 1 or 2 and R6 is thienyl, pyrrolyl or furyl optionally substituted by one or two substituents selected from C1-6 alkyl, C1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents having 5-HT antagonist activity and/or gastric motility enhancing activity.
Inventor(s):	Francis D. King
Assignee:	Beecham Group PLC , Hoffmann La Roche Inc
Application Number:	US07/171,141
Patent Claims:	1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR22## wherein X is CO and Y is NH;Z is NR3 wherein R3 is hydrogen, C1-6 alkyl, C3-7 alkenyl-methyl, phenyl or phenyl C1-4 alkyl either of which phenyl moieties may be substituted by one or two of halogen, CF3, C1-6 alkoxy or C1-6 alkyl; Rb is present when X-Y-R2 is attached at the phenyl ring and is selected from hydrogen, halogen, CF3, hydroxy, C1-6 alkoxy or C1-6 alkyl; R1 is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-7 acyl, C1-7 acylamino, C1-6 alkylsulphonylamino, N-(C1-6 alkylsulphonyl)-N-C1-4 alkylamino, C1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C1-4 alkylamino optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, phenyl or phenyl C1-4 alkyl groups or optionally N-disubstituted by C4-5 polymethylene; R2 is a group of formula (a), ##STR23## wherein n is 2 or 3; and R4 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-2 alkyl, or a group (CH2)t R6 where t is 1 or 2 and R6 is thienyl, pyrrolyl or furyl optionally substituted by one or two substituents selected from C1-6 alkyl, C1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C1-4 alkyl optionally substituted by hydroxy, C1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy. 2. A compound according to claim 1 wherein n is 3. 3. A compound according to claim 1 wherein R3 is hydrogen or methyl. 4. A compound according to claim 1 wherein the X-Y-R2 side chain is attached at position 3, as depicted in formula (I) in claim 1. 5. A compound according to claim 1 wherein R1 is hydrogen or 5-halo. 6. A compound according to claim 1 wherein R4 is C1-7 alkyl. 7. A compound according to claim 4 wherein R4 is methyl. 8. A compound selected from the group consisting of:N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-indazole-3carboxamide, N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-5-fluoroindazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-5-chloroindazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3.3.2]non-3-yl)-1-methylindazole-3-carboxamide, N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-ethylindazole-3-carboxamide, and pharmaceutically acceptable salts of any of the foregoing. 9. A compound according to claim 1 wherein Y-R2 is in the endo configuration. 10. N-(Endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methylindazole-3-carboxamide monohydrochloride. 11. A pharmaceutical composition for the treatment of migraine or cluster headache, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition for the treatment of trigeminal neuralgia, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition for the treatment of emesis, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A method of treatment or prophylaxis of migraine or cluster headache in mammals, which comprises the administration to the mammal of an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 15. A method of treatment or prophylaxis of trigeminal neuralgia in mammals, which comprises the administration to the mammal of an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 16. A method of treatment or prophylaxis of emesis in mammals, which comprises the administration to the mammal of an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 17. A method of treatment of anxiety in mammals, which comprises the administration to the mammal of an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 18. A method of treatment of psychosis in mammals, which comprises the administration to the mammal of an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition for the treatment of anxiety, comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. 20. A pharmaceutical composition for the treatment of psychosis, comprising an effective amount of a compond according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.