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Claims for Patent: 5,403,847

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Claims for Patent: 5,403,847

Title: Use of .alpha..sub.1C specific compounds to treat benign prostatic hyperlasia
Abstract:A method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of a compound which binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, a human .alpha..sub.1B adrenergic receptor, and a human histamine H.sub.1 receptor, and, binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor. Compounds meeting these criteria are provided.
Inventor(s): Gluchowski; Charles (Wayne, NJ), Forray; Carlos C. (Waldwick, NJ), Chiu; George (Bridgewater, NJ), Branchek; Theresa A. (Teaneck, NJ), Wetzel; John M. (Elmwood Park, NJ), Hartig; Paul R. (Princeton, NJ)
Assignee: Synaptic Pharmaceutical Corporation (Paramus, NJ)
Application Number:07/975,867
Patent Claims: 1. A method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of a compound which:

a. binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, a human .alpha..sub.1B adrenergic receptor, and a human histamine H.sub.1 receptor; and

b. binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

2. A method of claim 1, wherein the compound additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

3. A method of claim 1 or 2, wherein the compound additionally binds to a human dopamine D.sub.2 or human H.sub.2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

4. A method of claim 3, wherein the compound additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

5. A method of claim 4, wherein the compound additionally binds to a dopamine D.sub.3, D.sub.4, or D.sub.5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

6. A method of claim 1, wherein the compound has the structure: ##STR5##

7. A method of claim 1, wherein the compound has the structure: ##STR6##

8. A method of claim 1, wherein the compound has the structure: ##STR7##

9. A method of claim 1, wherein the compound has the structure: ##STR8##

10. A method of inhibiting contraction of prostate tissue which comprises contacting the prostate tissue with an effective contraction-inhibiting amount of a compound which:

a. binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, a human .alpha..sub.1B adrenergic receptor, and a human histamine H.sub.1 receptor; and

b. binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

11. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 17-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

12. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 26-fold higher than the binding affinity with which the compound binds to a human .alpha.B adrenergic receptor.

13. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 48-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

14. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 200-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

15. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 51-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

16. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 65-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

17. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 93-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

18. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 417-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

19. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 35-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.A1 adrenergic receptor, and (ii) at least 17-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

20. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 91-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 26-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

21. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 107-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 48-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

22. The method of claim 1, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 776-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 200-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

23. The method of claim 1, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 35-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 17-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 417-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 28-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

24. The method of claim 1, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 91-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 26-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 65-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 229-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

25. The method of claim 1, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 107-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 48-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 93-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 209-fold lower than the binding affinity with which the compound binds to such adrenergic receptor.

26. The method of claim 1, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 776-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 200-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 51-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 871-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

27. The method of claim 2, wherein the compound binds to a calcium channel with a binding affinity which is at least 41-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

28. The method of claim 2, wherein the compound binds to a calcium channel with a binding affinity which is at least 550-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

29. The method of claim 2, wherein the compound binds to a calcium channel with a binding affinity which is at least 1514-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

30. The method of claim 3, wherein the compound binds to a human H.sub.2 receptor with a binding affinity which is at least 25-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

31. The method of claim 3, wherein the compound binds to a human H.sub.2 receptor with a binding affinity which is at least 234-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

32. The method of claim 3, wherein the compound binds to a human H.sub.2 receptor with a binding affinity which is at least 324-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

33. The method of claim 4, wherein the compound binds to any serotonin receptor with a binding affinity which is at least 23-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

34. The method of claim 4, wherein the compound binds to any serotonin receptor with a binding affinity which is at least 30-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

35. The method of claim 4, wherein the compound binds to the 5HT2 serotonin receptor with a binding affinity which is at least 56-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

36. The method of claim 4, wherein the compound binds to any serotonin receptor with a binding affinity which is at least 74-fold lower than the binding affinity with which the compound binds to the .alpha..sub.1C adrenergic receptor.

37. The method of claim 10, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 17-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

38. The method of claim 10, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 26-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

39. The method of claim 10, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 48-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

40. The method of claim 10, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 200-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

41. The method of claim 10, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 51-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

42. The method of claim 10, wherein the compound binds to a human .alpha.hd 1C adrenergic receptor with a binding affinity at least 65-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

43. The method of claim 10, wherein the compound binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 93-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

44. The method of claim 10, wherein the compound bands to a human .alpha..sub.1C adrenergic receptor with a binding affinity at least 417-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor.

45. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 35-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 17-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

46. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 91-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 26-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

47. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 107-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 48-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

48. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 776-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, and (ii) at least 200-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor.

49. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 35-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 17-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 417-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 28-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

50. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 91-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 26-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 65-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 229-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

51. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 107-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 48-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 93-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 209-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.

52. The method of claim 10, wherein the compound (a) binds to a human .alpha..sub.1C adrenergic receptor with a binding affinity (i) at least 776-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1A adrenergic receptor, (ii) at least 200-fold higher than the binding affinity with which the compound binds to a human .alpha..sub.1B adrenergic receptor, and (iii) at least 51-fold higher than the binding affinity with which the compound binds to a human histamine H.sub.1 receptor, and (b) binds to a human .alpha..sub.2 adrenergic receptor with a binding affinity which is at least 871-fold lower than the binding affinity with which the compound binds to such .alpha..sub.1C adrenergic receptor.
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