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Claims for Patent: 5,202,333

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Claims for Patent: 5,202,333

Title: Tricyclic 5-HT.sub.3 receptor antagonists
Abstract:The present invention is directed to 5-HT.sub.3 receptor antagonist compounds of formula I: ##STR1## in which the dashed line denotes an optional double bond; n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2; each R.sup.1 is independently selected from halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; each R.sup.2 is lower alkyl; and R.sup.3 is a group selected from Formulae (a), (b), (c) and (d): ##STR2## in which u is 0 or 1; z is 1, 2 or 3; and R.sup.4 is C.sub.1-7 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-2 alkyl, or a group (CH.sub.2).sub.t R.sup.5 where t is 1 or 2 and R.sup.5 is thienyl, pyrrolyl, or furyl, each optionally further substituted by one or two substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C.sub.1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C.sub.1-4 alkyl optionally substituted by hydroxy, C.sub.1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.
Inventor(s): Berger; Jacob (Los Altos Hills, CA), Clark; Robin D. (Palo Alto, CA), Eglen; Richard M. (Mountain View, CA), Smith; William L. (Sunnyvale, CA), Weinhardt; Klaus K. (San Francisco, CA)
Assignee: Syntex (U.S.A.) Inc. (Palo Alto, CA)
Application Number:07/704,565
Patent Claims: 1. A compound of Formula I ##STR19## in which the dashed line denotes an optional double bond;

n is 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1 or 2;

each R.sup.1 is independently selected from halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino;

each R.sup.2 is lower alkyl; and

R.sup.3 is a group selected from Formulae (a), (b), (c) and (d): ##STR20## in which u is 0 or 1;

z is 1, 2 or 3; and

R.sup.4 is C.sub.1-7 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-2 alkyl, or a group (CH.sub.2).sub.t R.sup.5 where t is 1 or 2 and R.sup.5 is thienyl, pyrrolyl, or furyl, each optionally further substituted by one or two substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C.sub.1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C.sub.1-4 alkyl optionally substituted by hydroxy, C.sub.1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; the pharmaceutically acceptable salts, individual isomers, or mixtures of isomers thereof.

2. A compound of claim 1 in which both q and u are 0, p is 0, 1 or 2, each R' is independently selected from halogen, lower alkoxy or amino and R.sup.4 is lower alkyl.

3. A compound of claim 2 in which p is 0, and R.sup.4 is methyl.

4. A compound of claim 3 in which R.sup.3 is one of the following groups:

1-azabicyclo[2.2.2]oct-3-yl;

1-azabicyclo-[2.2.2]oct-4-yl;

endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl;

exo-9-methyl-9-azabicyclo[3.3.1]non-3-yl;

endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl;

exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl;

endo-1-azabicyclo[3.3.1]non-4-yl; or

exo-1-azabicyclo[3.3.1]non-4-yl.

5. A compound of claim 4 in which the optional bond is present.

6. A compound of claim 5 in which n is 1.

7. A compound of claim 6 in which R.sup.3 is 1-azabicyclo[2.2.2]oct-3-yl, namely 2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4,5-tetrahydrocyclopent[de]isoquinolin -1-one or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7 which is (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4,5-tetrahydrocyclopenta[de]isoqui nolin-1-one or a pharmaceutically acceptable salt thereof.

9. A compound of claim 8 which is (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4,5-tetrahydrocyclopenta[de]isoqui nolin-1-one hydrochloride.

10. A compound of claim 6 in which R.sup.3 is 8-methyl-8-azabicyclo[3.2.1]oct-3-yl, namely, 2-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1,2,4,5-tetrahydro-cyclopent[de] isoquinolin-1-one or a pharmaceutically acceptable salt thereof.

11. A compound of claim 10 which is 2-(endo-8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1,2,4,5-tetrahydro-cyclopen t[de]isoquinolin-1-one or a pharmaceutically acceptable salt thereof.

12. A compound of claim 11 which is 2-(endo-8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1,2,4,5-tetrahydro-cyclopen t[de]isoquinolin-1-one hydrochloride.

13. A compound of claim 5 in which n is 2.

14. A compound of claim 13 in which R.sup.3 is 1-azabicyclo[2.2.2]oct-3-yl, namely 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin- 1-one or a pharmaceutically acceptable salt thereof.

15. A compound of claim 14 which is (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquino lin-1-one or a pharmaceutically acceptable salt thereof.

16. A compound of claim 15 which is (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquino lin-1-one hydrochloride.

17. A compound of claim 14 which is (R)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquino lin-1-one or a pharmaceutically acceptable salt thereof.

18. A compound of claim 17 which is (R)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquino lin-1-one or hydrochloride.

19. A compound of claim 13 in which R.sup.3 is 1-azabicyclo[2.2.2]oct-4-yl, namely 2-(1-azabicyclo[2.2.2]oct-4-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin- 1-one or a pharmaceutically acceptable salt thereof.

20. A compound of claim 13 in which R.sup.3 is endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl, namely 2-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2,4,5,6-tetrahydro-1H-benz[d e]isoquinolin-1-one.

21. A compound of claim 13 in which R.sup.3 is 8-methyl-8-azabicyclo[3.2.1]oct-3-yl, namely 2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]iso quinolin-1-one or a pharmaceutically acceptable salt thereof.

22. A compound of claim 21 which is 2-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[d e]isoquinolin-1one or a pharmaceutically acceptable salt thereof.

23. A compound of claim 21 which is 2-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de ]isoquinolin-1-one or a pharmaceutically acceptable salt thereof.

24. A compound of claim 13 in which R.sup.3 is endo-1-azabicyclo[3.3.1]non-4-yl, namely 2-(endo-1-azabicyclo[3.3.1]non-4-yl)-2,3,5,6-tetrahydro-1H-benz[de]isoquin olin-1-one or a pharmaceutically acceptable salt thereof.

25. A compound of claim 5 in which n is 3.

26. The compound of claim 25 in which R.sup.3 is 1-azabicyclo[2.2.2]oct-3-yl, namely 2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4,5,6,7-hexahydrocyclohept[de]isoquino lin-1-one or a pharmaceutically acceptable salt thereof.

27. A compound of claim 4 in which the optional bond is absent.

28. A compound of claim 27 in which n is 1.

29. A compound of claim 27 in which n is 2.

30. A compound of claim 29 in which R.sup.3 is 1-azabicyclo[2.2.2]oct-3-yl, namely 2-(1-azabicyclo-[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquin olin-1-one.

31. A compound of claim 30 which is 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one or a pharmaceutically acceptable salt thereof.

32. A compound of claim 31 which is 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one hydrochloride.

33. A compound of claim 30 which is 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aR,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one or a pharmaceutically acceptable salt thereof.

34. A compound of claim 33 which is 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aR,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one hydrochloride.

35. A compound of claim 30 which is 2-(1-azabicyclo-[2.2.2]oct-3R-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one a pharmaceutically acceptable salt thereof.

36. A compound of claim 35 which is 2-(1-azabicyclo-[2.2.2]oct-3R-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one hydrochloride.

37. A compound of claim 30 which is 2-(1-azabicyclo-[2.2.2]oct-3R-yl)-2,3,3aR,4,5,6, -hexahydro-1H-benz[de]isoquinolin-1-one or a pharmaceutically acceptable salt thereof.

38. A compound of claim 37 which is 2-(1-azabicyclo-[2.2.2]oct-3R-yl)-2,3,3aR,4,5,6-hexahydro-1H-benz[de]isoqu inolin-1-one hydrochloride.

39. A compound of claim 27 in which n is 3.

40. A pharmaceutical composition for treating a condition chosen from emesis, a gastrointestinal disorder treatable with prokinetic agents, anxiety/depressive state, and pain, which composition comprises a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

41. A method for treating a condition chosen from emesis, a gastrointestinal disorder treatable with prokinetic agents, anxiety/depressive state, and pain in an animal in need of such treatment, which method comprises administering a therapeutically effective amount of a compound of claim 1 to such animal.

42. A method of claim 41 in which the condition is a gastrointestinal disorder treatable with prokinetic agents.

43. A method of claim 41 in which the condition is pain.

44. A method of claim 41 in which the condition is anxiety/depressive state.

45. A method of claim 44 in which the condition is the side effects caused by withdrawal from an addictive substance.

46. A method of claim 41 in which the condition is emesis.

47. A method of claim 46 in which the condition is emesis in humans undergoing cancer treatment with a cytotoxic pharmaceutical agent or radiation at levels sufficient to induce emesis, or recovering from surgical anesthesia or undergoing drug therapy in general in which a significant side effect is emesis.

48. A method of claim 47 in which the compound is (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquino lin-1-one or a pharmaceutically acceptable salt thereof.

49. A method of claim 47 in which the compound is 2-(3S-1-azabicyclo-[2.2.2]oct-3-yl-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoq uinolin-1-one or a pharmaceutically acceptable salt thereof.

50. A method of claim 42 in which the compound is (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquino lin-1-one.
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