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Claims for Patent: 5,360,800

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Claims for Patent: 5,360,800

Title: Tetrahydro-1H-pyrido[4,3-b]indol-1-one derivatives
Abstract:The invention relates to tricyclic lactams of the general formula (I) ##STR1## wherein Im represents an imidazolyl group of the formula: ##STR2## and R.sup.1 represents a hydrogen atom or a group selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenyl, phenyl C.sub.1-3 alkyl, phenylmethoxymethyl, phenoxyethyl or phenoxymethyl, 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.3-6 alkenyl, phenyl 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 alkhyl group; n represents 2 or 3; and physiologically acceptable salts and solvates thereof. The compounds are potent and selective antagonists of the effect of 5-HT at 5-HT.sub.3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety, and nausea and vomiting.
Inventor(s): Coates; Ian H. (Hertford, GB2), North; Peter C. (Royston, GB2), Oxford; Alexander W. (Royston, GB2)
Assignee: Glaxo Group Limited (London, GB2)
Application Number:07/741,570
Patent Claims: 1. A compound of formula (I) ##STR21## wherein Im represents an imidazolyl group of the formula: ##STR22## and R.sup.1 represents a hydrogen atom or a group selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-4 alkyl, phenyl, phenylC.sub.1-3 alkyl, phenylmethoxymethyl, phenoxyethyl phenoxymethyl;

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.3-6 alkenyl, phenyl or phenylC.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;

n represents 2 or 3;

or a physiologically acceptable salt or solvate thereof.

2. A compound according to claim 1 in which R.sup.1 represents a C.sub.1-4 alkyl, C.sub.3-4 alkynyl, C.sub.5-6 cycloaklyl, C.sub.5-6 cycloalkylmethyl, phenylC.sub.1-2 alkyl, or phenylmethoxymethyl.

3. A compound according to claim 1 in which R.sup.2, R.sup.3 and R.sup.4 each independently represent a hydrogen atom or a C.sub.1-3 alkyl group.

4. A compound according to claim 1 in which R.sup.1 represents a hydrogen atom or a C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4 alkynyl, C.sub.5-6 cycloaklyl, C.sub.5-6 cycloalkylmethyl, phenylC.sub.1-2 alkyl, or phenylmethoxymethyl, R.sup.2 represents a hydrogen atom; and R.sup.3 and R.sup.4 each represent a hydrogen atom or a C.sub.1-3 alkyl group.

5. A compound according to claim 1 in which R.sup.1 represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, or benzyl; R.sup.2 and R.sup.3 each represent a hydrogen atom; and R.sup.4 represents a methyl group.

6. A compound according to claim 4 in which n represents 2.

7. A compound according to claim 5 in which n represents 2.

8. 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-y l)methyl]-1H-pyrido[4,3-b]indol-1-one; or a physiologically acceptable salt or solvate thereof.

9. A compound selected from:

2,3,4,5-Tetrahydro-5-(phenylmethyl)-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1 H-pyrido[4,3-b]indol-1-one;

5-cyclopentyl-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-p yrido[4,3-b]indol-1-one;

2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-propyl-1H-pyrido [4,3-b]indol-1-one;

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)meth yl]-1H-pyrido[4,3-b]indol-1one;

3,4,5,6-tetrahydro-6-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-azepino[4 ,3-b]indol-1(2H)-one;

2,3,4,5-tetrahydro-N,N-dimethyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1-oxo -5H-pyrido[4,3-b]indole-5-carboxamide;

2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl-5-(2-propynyl)-1H-p yrido[4,3-b]indol-1-one;

or a physiologically acceptable salt and solvate thereof.

10. A compound according to claim 1 in the form of a hydrochloride, hydrobromide, sulphate, alkylsulphonate, arylsulphonate, phosphate, acetate, citrate, succinate, tartrate, fumarate or maleate salt.

11. The compound of claim 8 in the form of a hydrochloride salt.

12. The compound of claim 8 in the form of a maleate salt.

13. A pharmaceutical composition which comprises an effective amount of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient.

14. A pharmaceutical composition according to claim 13 in a form adapted for oral or parenteral administration.

15. A pharmaceutical composition according to claim 13 wherein the active ingredient is 2,3,4,5- tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b] indol-1-one or a physiologically acceptable salt or solvate thereof.

16. A pharmaceutical composition according to claim 13 wherein the active ingredient is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl-1H-pyrido [4,3-b]indol-1-one hydrochloride.

17. A method of treating a condition which is ameliorated by antagonism of 5HT.sub.3 receptors 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.

18. A method according to claim 17 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

19. A method according to claim 17 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one hydrochloride.

20. A method according to claim 17 wherein the condition which is ameliorated by antagonism of 5HT.sub.3 receptors is anxiety.

21. A method according to claim 20 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

22. A method according to claim 20 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one hydrochloride.

23. A method according to claim 17 wherein the condition which is ameliorated by antagonism of 5HT.sub.3 receptors is schizophrenia.

24. A method according to claim 23 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

25. A method according to claim 23 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one hydrochloride.

26. A compound according to claim 1 which is 5-ethyl-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido [4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

27. A method according to claim 17 for the treatment of irritable bowel syndrome.

28. A method according to claim 27 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl-1H-pyrido [4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

29. A method according to claim 27 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one hydrochloride.

30. A method according to claim 17 wherein the condition which is ameliorated by antagonism of 5HT.sub.3 receptors is dyspepsia.

31. A method according to claim 30 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

32. A method according to claim 30 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrid o[4,3-b]indol-1-one hydrochloride.

33. A method according to claim 17 wherein the condition which is ameliorated by antagonism of 5-HT.sub.3 receptors is reflux oesophagitis.

34. A method according to claim 33 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido [4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

35. A method according to claim 33 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido [4,3-b]indol-1-one hydrochloride.
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