Claims for Patent: 6,015,819

Summary for Patent: 6,015,819

Title:	Use of alpha-1C specific compounds to treat benign prostatic hyperplasia
Abstract:	PCT No. PCT/US93/10950 Sec. 371 Date Apr. 1, 1997 Sec. 102(e) Date Apr. 1, 1997 PCT Filed Nov. 12, 1993 PCT Pub. No. WO94/10989 PCT Pub. Date May 26, 1994A 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 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 1A adrenergic receptor, a human alpha 1B adrenergic receptor, and a human histamine H1 receptor, and, binds to a human alpha 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 1C adrenergic receptor. Compounds meeting these criteria are provided.
Inventor(s):	Charles Gluchowski, Carlos C. Forray, George Chiu, Theresa A. Branchek, John M. Wetzel, Paul R. Hartig
Assignee:	H Lundbeck AS
Application Number:	US08/244,354
Patent Claims:	1. A method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of an antagonist which binds to a human α1C adrenergic receptor with a binding affinity at least 48-fold higher than the binding affinity with which the antagonist binds to a human α1B adrenergic receptor, and wherein administration of the antagonist does not cause an orthostatic fall in blood pressure. 2. The method of claim 1, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor or a human α2 adrenergic receptor. 3. The method of claim 1, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 4. The method of claim 1, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a calcium channel. 5. The method of claim 1, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human dopamine D2 receptor. 6. The method of claim 1, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human serotonin receptor. 7. The method of claim 1, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human dopamine D3, D4, or D5 receptor. 8. The method of claim 1, wherein the binding affinity of the antagonist is at least 200-fold higher for the human α1C adrenergic receptor than it is for a human α1B adrenergic receptor. 9. The method of claim 8, wherein the binding affinity of the antagonist is at least 51-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 10. A method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of an antagonist which binds to a human α1C adrenergic receptor with a binding affinity at least 26-fold higher than the binding affinity with which the antagonist binds to a human α1B adrenergic receptor, and wherein administration of the antagonist does not cause an orthostatic fall in blood pressure. 11. The method of claim 3, wherein the binding affinity of the antagonist is at least 65-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 12. The method of claim 3, wherein the binding affinity of the antagonist is at least 93-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 13. A method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of an antagonist which binds to a human α1C adrenergic receptor with a binding affinity at least 35-fold higher than the binding affinity with which the antagonist binds to a human α1A adrenergic receptor and at least 417-fold higher than it is for a human histamine H1 receptor, and wherein administration of the antagonist does not cause an orthostatic fall in blood pressure. 14. The method of claim 10, wherein the binding affinity of the antagonist is at least 91-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor. 15. The method of claim 2, wherein the binding affinity of the antagonist is at least 107-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor. 16. The method of claim 8, wherein the binding affinity of the antagonist is at least 776-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor. 17. The method of claim 13, wherein the binding affinity of the antagonist is at least 28-fold higher for the human α1C adrenergic receptor than it is for a human α2 adrenergic receptor. 18. The method of claim 10, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is (i) at least 91-fold higher than it is for the human α1A adrenergic receptor, (ii) at least 65-fold higher than it is for the human histamine H1 receptor, and (iii) at least 229-fold higher than it is for the human α2 adrenergic receptor. 19. The method of claim 1, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is (i) at least 107-fold higher than it is for the human α1A adrenergic receptor, (ii) at least 93-fold higher than it is for the human histamine H1 receptor, and (iii) at least 209-fold higher than it is for the human α2 adrenergic receptor. 20. The method of claim 1, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is (i) at least 776-fold higher than it is for the human α1A adrenergic receptor, (ii) at least 200-fold higher than it is for the human α1B adrenergic receptor, (iii) at least 51-fold higher than it is for the human histamine H1 receptor, and (iv) at least 871-fold higher than it is for the human α2 adrenergic receptor. 21. The method of claim 10, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 41-fold higher than it is for the calcium channel. 22. The method of claim 8, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 550-fold higher than it is for the calcium channel. 23. The method of claim 8, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 25-fold higher than it is for a human histamine H2 receptor. 24. The method of claim 10, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 234-fold higher than it is for a human histamine H2 receptor. 25. The method of claim 3, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 324-fold higher than it is for a human histamine H2 receptor. 26. The method of claim 10, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 30-fold higher than it is for a human serotonin receptor. 27. The method of claim 6, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 56-fold higher than it is for a human serotonin receptor. 28. The method of claim 8, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 74-fold higher than it is for a human serotonin receptor. 29. A method of claim 1, 10, or 13, wherein the antagonist additionally does not cause an orthostatic fall in blood pressure in rats at a dosage of 10 micrograms of antagonist per kilogram of rat. 30. A method of inhibiting contraction of prostatic tissue which comprises contacting the prostate tissue with an effective contraction-inhibiting amount of an antagonist which binds to a human α1C adrenergic receptor with a binding affinity at least 48-fold higher than the binding affinity with which the antagonist binds to a human α1B adrenergic receptor, and wherein administration of the antagonist does not cause an orthostatic fall in blood pressure. 31. The method of claim 30, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor or a human α2 adrenergic receptor. 32. The method of claim 30, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 33. The method of claim 30, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a calcium channel. 34. The method of claim 30, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human dopamine D2 receptor. 35. The method of claim 30, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human serotonin receptor. 36. The method of claim 30, wherein the binding affinity of the antagonist is at least 10-fold higher for the human α1C adrenergic receptor than it is for a human dopamine D3, D4, or D5 receptor. 37. The method of claim 30, wherein the binding affinity of the antagonist is at least 200-fold higher for the human α1C adrenergic receptor than it is for a human α1B adrenergic receptor. 38. The method of claim 37, wherein the binding affinity of the antagonist is at least 51-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 39. A method of inhibiting contraction of prostatic tissue which comprises contacting the prostate tissue with an effective contraction-inhibiting amount of an antagonist which binds to a human α1C adrenergic receptor with a binding affinity at least 26-fold higher than the binding affinity with which the antagonist binds to a human α1B adrenergic receptor, and wherein administration of the antagonist does not cause an orthostatic fall in blood pressure. 40. The method of claim 39, wherein the binding affinity of the antagonist is at least 65-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 41. The method of claim 32, wherein the binding affinity of the antagonist is at least 93-fold higher for the human α1C adrenergic receptor than it is for a human histamine H1 receptor. 42. A method of inhibiting contraction of prostatic tissue which comprises contacting the prostate tissue with an effective contraction-inhibiting amount of an antagonist which binds to a human α1C adrenergic receptor with a binding affinity at least 35-fold higher than the binding affinity with which the antagonist binds to a human α1A adrenergic receptor and at least 417-fold higher than it is for a human histamine H1 receptor, and wherein administration of the antagonist does not cause an orthostatic fall in blood pressure. 43. The method of claim 39, wherein the binding affinity of the antagonist is at least 91-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor. 44. The method of claim 31, wherein the binding affinity of the antagonist is at least 107-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor. 45. The method of claim 37, wherein the binding affinity of the antagonist is at least 776-fold higher for the human α1C adrenergic receptor than it is for a human α1A adrenergic receptor. 46. The method of claim 42, wherein the binding affinity of the antagonist is at least 28-fold higher for the human α1C adrenergic receptor than it is for a human α2 adrenergic receptor. 47. The method of claim 39, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is (i) at least 91-fold higher than it is for the human α1A adrenergic receptor, (ii) at least 65-fold higher than it is for the human histamine H1 receptor, and (iii) at least 229-fold higher than it is for the human α2 adrenergic receptor. 48. The method of claim 30, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is (i) at least 107-fold higher than it is for the human α1A adrenergic receptor, (ii) at least 93-fold higher than it is for the human histamine H1 receptor, and (iii) at least 209-fold higher than it is for the human α2 adrenergic receptor. 49. The method of claim 30, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is (i) at least 776-fold higher than it is for the human α1A adrenergic receptor, (ii) at least 200-fold higher than it is for the human α1B adrenergic receptor, (iii) at least 51-fold higher than it is for the human histamine H1 receptor, and (iv) at least 871-fold higher than it is for the human α2 adrenergic receptor. 50. The method of claim 39, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 41-fold higher than it is for the calcium channel. 51. The method of claim 37, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 550-fold higher than it is for the calcium channel. 52. The method of claim 37, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 25-fold higher than it is for a human histamine H2 receptor. 53. The method of claim 39, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 234-fold higher than it is for a human histamine H2 receptor. 54. The method of claim 32, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 324-fold higher than it is for a human histamine H2 receptor. 55. The method of claim 39, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 30-fold higher than it is for a human serotonin receptor. 56. The method of claim 35, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 56-fold higher than it is for a human serotonin receptor. 57. The method of claim 37, wherein the binding affinity of the antagonist for the human α1C adrenergic receptor is at least 74-fold higher than it is for a human serotonin receptor. 58. A method of claim 30, 39 or 42, wherein the antagonist additionally does not cause an orthostatic fall in blood pressure in rats at a dosage of 10 micrograms of antagonist per kilogram of rat.