Claims for Patent: 4,695,578

Summary for Patent: 4,695,578

Title:	1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances
Abstract:	The invention relates to compounds of formula (I). (I) wherein R1 represents a hydrogen atom or a C1-10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-7 cycloalkyl-(C1-4) alkyl, C3-10 alkynyl, phenyl or phenyl-C1-3 alkyl group, and one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-(C1-3) alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group; and physiologically acceptable salts and solvates, e.g. hydrates thereof. The compounds are potent selective antagonists at "neuronal" 5-hydroxytryptamine receptors and are useful in the treatment of migraine and psychotic disorders such as schizophrenia.
Inventor(s):	Ian H. Coates, James A. Bell, David C. Humber, George B. Ewan
Assignee:	Glaxo Group Ltd
Application Number:	US06/931,032
Patent Claims:	1. A compound of formula (I) ##STR20## wherein R1 represents a hydrogen atom or a C1-10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-7 cycloalkyl-(C1-4)alkyl, C3-10 alkynyl, phenyl or phenyl-C1-3 alkyl group, and one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-(C1-3) alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group; or a physiologically acceptable salt or solvate thereof. 2. A compound according to claim 1 in which one of the groups represented by R2, R3 and R4 represents a C1-3 alkyl, C3-6 cycloalkyl or C3-6 alkenyl group and each of the other two groups, which may be the same or different represents a hydrogen atom or a C1-3 alkyl group. 3. A compound according to claim 1 in which R1 represents a hydrogen atom or a C1-6 alkyl, C5-6 cycloalkyl or C3-4 alkenyl group and either R2 represents a hydrogen atom and R3 and/or R4 represents a C1-3 alkyl group or R2 represents a C1-3 alkyl group and both R3 and R4 represent hydrogen atoms. 4. A compound of formula (I) ##STR21## wherein R1 represents a hydrogen atom or a C1-10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenyl-C1-3 alkyl group; and one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl(C1-3) alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group; or a physiologically acceptable salt or solvate thereof. 5. A compound according to claim 4 in which R1 represents a hydrogen atom or a C1-6 alkyl, C3-6 cycloalkyl or C3-6 alkenyl group. 6. A compound according to claim 4 in which one of the groups represented R2, R3 and R4 represents a C1-3 alkyl, C3-6 cycloalkyl or C3-6 alkenyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-3 alkyl group. 7. A compound according to claim 4 in which R1 represents a hydrogen atom or a C1-6 alkyl, C5-6 cycloalkyl or C3-4 alkenyl group and either R2 represents a hydrogen atom and R3 and/or R4 represents a C1-3 alkyl group or R2 represents a C1-4 3 alkyl group and R3 and R4 both represent hydrogen atoms. 8. A compound of formula (Ia) ##STR22## wherein R1a represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R3a represents a hydrogen atom; and either R2a represents a methyl, ethyl, propyl or prop-2-yl group and R4a represents a hydrogen atom or R2a represents a hydrogen atom and R4a represents a methyl or ethyl group; or a physiologically acceptable salt or solvate thereof. 9. 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof. 10. 1,2,3,9-Tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-9-(prop-2-enyl)-4H-carbazol-4-one; 9-Cyclopentyl-1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one; 1,2,3,9-Tetrahydro-3-[2-methyl-1H-imidazol-1-yl)methyl]-9-(prop-2-yl)-4H-carbazol-4-one; or a physiologically acceptable salt or solvate thereof. 11. A pharmaceutical composition for the treatment of a condition caused by disturbance of "neuronal" 5HT function comprising at least one compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof in an amount effective to relieve said condition together with at least one physiologically acceptable carrier or exipient. 12. A method of treating a condition caused by disturbance of "neuronal" 5HT function which comprises administering to a patient an effective amount of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof to relieve said condition. 13. The compound of claim 9 in the form of a hydrochloride salt. 14. The compound of claim 9 in the form of the hydrochloride dihydrate. 15. A pharmaceutical composition according to claim 11 in which said compound of formula (I) is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4-H-carbazol-4-one or a physiologically acceptable salt or solvate thereof. 16. A pharmaceutical composition according to claim 15 in which said compound is present as a hydrochloride salt. 17. A pharmaceutical composition according to claim 15 in which said compound is present as the hydrochloride dihydrate. 18. A method according to claim 12 in which said compound of formula (I) is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof. 19. A method according to claim 18 in which said compound is used as a hydrochloride salt. 20. A method according to claim 18 in which said compound is used as the hydrochloride dihydrate. 1. A compound of formula (I) ##STR20## wherein R.sup.1 represents a hydrogen atom or a C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, C.sub.3-7 cycloalkyl-(C.sub.1-4)alkyl, C.sub.3-10 alkynyl, phenyl or phenyl-C.sub.1-3 alkyl group, and one of the groups represented by R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-6 alkenyl or phenyl-(C.sub.1-3) alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C.sub.1-6 alkyl group; or a physiologically acceptable salt or solvate thereof. 2. A compound according to claim 1 in which one of the groups represented by R.sup.2, R.sup.3 and R.sup.4 represents a C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl or C.sub.3-6 alkenyl group and each of the other two groups, which may be the same or different represents a hydrogen atom or a C.sub.1-3 alkyl group. 3. A compound according to claim 1 in which R.sup.1 represents a hydrogen atom or a C.sub.1-6 alkyl, C.sub.5-6 cycloalkyl or C.sub.3-4 alkenyl group and either R.sup.2 represents a hydrogen atom and R.sup.3 and/or R.sup.4 represents a C.sub.1-3 alkyl group or R.sup.2 represents a C.sub.1-3 alkyl group and both R.sup.3 and R.sup.4 represent hydrogen atoms. 4. A compound of formula (I) ##STR21## wherein R.sup.1 represents a hydrogen atom or a C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, phenyl or phenyl-C.sub.1-3 alkyl group; and one of the groups represented by R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-6 alkenyl or phenyl(C.sub.1-3) alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C.sub.1-6 alkyl group; or a physiologically acceptable salt or solvate thereof. 5. A compound according to claim 4 in which R.sup.1 represents a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.3-6 alkenyl group. 6. A compound according to claim 4 in which one of the groups represented R.sup.2, R.sup.3 and R.sup.4 represents a C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl or C.sub.3-6 alkenyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C.sub.1-3 alkyl group. 7. A compound according to claim 4 in which R.sup.1 represents a hydrogen atom or a C.sub.1-6 alkyl, C.sub.5-6 cycloalkyl or C.sub.3-4 alkenyl group and either R.sup.2 represents a hydrogen atom and R.sup.3 and/or R.sup.4 represents a C.sub.1-3 alkyl group or R.sup.2 represents a C.sub.1-4 3 alkyl group and R.sup.3 and R.sup.4 both represent hydrogen atoms. 8. A compound of formula (Ia) ##STR22## wherein R.sup.1a represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R.sup.3a represents a hydrogen atom; and either R.sup.2a represents a methyl, ethyl, propyl or prop-2-yl group and R.sup.4a represents a hydrogen atom or R.sup.2a represents a hydrogen atom and R.sup.4a represents a methyl or ethyl group; or a physiologically acceptable salt or solvate thereof. 9. 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)met hyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof. 10. 1,2,3 ,9-Tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-9-(prop-2-enyl)-4H-car bazol-4-one; 9-Cyclopentyl-1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H- carbazol-4-one; 1,2,3,9-Tetrahydro-3-[2-methyl-1H-imidazol-1-yl)methyl]-9-(prop-2-yl)-4H-c arbazol-4-one; or a physiologically acceptable salt or solvate thereof. 11. A pharmaceutical composition for the treatment of a condition caused by disturbance of "neuronal" 5HT function comprising at least one compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof in an amount effective to relieve said condition together with at least one physiologically acceptable carrier or exipient. 12. A method of treating a condition caused by disturbance of "neuronal" 5HT function which comprises administering to a patient an effective amount of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof to relieve said condition. 13. The compound of claim 9 in the form of a hydrochloride salt. 14. The compound of claim 9 in the form of the hydrochloride dihydrate. 15. A pharmaceutical composition according to claim 11 in which said compound of formula (I) is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4-H-carb azol-4-one or a physiologically acceptable salt or solvate thereof. 16. A pharmaceutical composition according to claim 15 in which said compound is present as a hydrochloride salt. 17. A pharmaceutical composition according to claim 15 in which said compound is present as the hydrochloride dihydrate. 18. A method according to claim 12 in which said compound of formula (I) is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1yl)methyl]-4H-carbaz ol-4-one or a physiologically acceptable salt or solvate thereof. 19. A method according to claim 18 in which said compound is used as a hydrochloride salt. 20. A method according to claim 18 in which said compound is used as the hydrochloride dihydrate.