21-substituted progesterone derivatives as new antiprogestational agents
A compound having the general formula: in which: R 1 is a member selected from the group consisting of —OCH 3 , —SCH 3 , —N(CH 3 ) 2 , —NHCH 3 , —CHO, —COCH 3 and —CHOHCH 3 ; R 2 is a member selected from the group consisting of halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkyl carbonate, cypionyloxy, S-alkyl and S-acyl; R 3 is a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; R 4 is a member selected from the group consisting of hydrogen and alkyl; and X is a member selected from the group consisting of ═O and ═N—OR 5 , wherein R 5 is a member selected from the group consisting of hydrogen and alkyl. In addition to providing the compounds of Formula I, the present invention provides methods wherein the compounds of Formula I are advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce labor; and for contraception.
1. A compound having the formula:
in which:
R 1 is a member selected from the group consisting of —N(CH 3 ) 2 and —NHCH 3 ;
R 2 is alkoxy;
R 3 is acyloxy;
R 4 is a member selected from the group consisting of hydrogen and alkyl; and
X is ═O.
2. A compound in accordance with claim 1 , in which:
R 1 is —N(CH 3 ) 2 .
3. A compound in accordance with claim 1 , in which:
R 2 is methoxy.
4. A compound in accordance with claim 1 , in which:
R 2 is ethoxy.
5. A compound in accordance with claim 1 , in which:
R 3 is acetoxy.
6. A compound in accordance with claim 1 , in which:
R 4 is alkyl.
7. A compound in accordance with claim 6 , in which:
R 4 is methyl.
8. A compound in accordance with claim 1 , in which:
R 1 is —N(CH 3 ) 2 ;
R 2 is methoxy;
R 3 is acetoxy;
R 4 is methyl; and
X is ═O.
9. A compound in accordance with claim 1 , in which:
R 1 is —NHCH 3 .
10. A compound in accordance with claim 9 , in which:
R 2 is methoxy;
R 3 is acetoxy;
R 4 is methyl; and
X is ═O.
11. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
12. A pharmaceutical composition comprising an effective amount of a compound of claim 2 and a pharmaceutically acceptable excipient.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 3 and a pharmaceutically acceptable excipient.
14. A pharmaceutical composition comprising an effective amount of a compound of claim 4 and a pharmaceutically acceptable excipient.
15. A pharmaceutical composition comprising an effective amount of a compound of claim 5 and a pharmaceutically acceptable excipient.
16. A pharmaceutical composition comprising an effective amount of a compound of claim 6 and a pharmaceutically acceptable excipient.
17. A pharmaceutical composition comprising an effective amount of a compound of claim 7 and a pharmaceutically acceptable excipient.
18. A pharmaceutical composition comprising an effective amount of a compound of claim 8 and a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising an effective amount of a compound of claim 9 and a pharmaceutically acceptable excipient.
20. A pharmaceutical composition comprising an effective amount of a compound of claim 10 and a pharmaceutically acceptable excipient.
21. A method of producing an antiprogestational effect in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
22. A method of inducing menses in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
23. A method of treating endometriosis in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
24. A method of treating dysmenorrhea in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
25. A method of treating an endocrine hormone-dependent tumor in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
26. The method in accordance with claim 25 , in which said endocrine hormone-dependent tumor is a member selected from the group consisting of kidney, breast, endometrial, ovarian and prostate.
27. A method of treating uterine fibroids in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
28. A method of inhibiting uterine endometrial proliferation in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 .
29. A method of inducing labor, said method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .
30. A method of contraception, said method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .
31. A method of postcoital contraception, said method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .
32. A method of treating fibrocystic disease of the breast, said method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .
33. A method of treating fibrocystic disease of the uterus, said method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .
34. The method in accordance with any of claims 21 , 23 , 25 , and 27 in which:
R 1 is N(CH 3 ) 2 ;
R 2 is alkoxy;
R 3 is acyloxy;
R 4 is alkyl; and
X is ═O.
35. The method in accordance with claim 34 , in which:
R 2 is methoxy or ethoxy.
36. The method in accordance with claim 34 , in which:
R 3 is acetoxy.
37. The method in accordance with claim 34 , in which:
R 4 is methyl.
38. The method in accordance with any of claims 21 - 25 and 27 - 33 , in which:
R 1 is —N(CH 3 ) 2 ;
R 2 is methoxy;
R 3 is acetoxy;
R 4 is methyl; and
X is ═O.