Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents

1. A compound of the general formula:

wherein:

R 1 is a member selected from the group consisting of —CHO, —CH(OH)CH 3 , and —C(O)CH 3 ;

R 2 is a member selected from the group consisting of —SAc, alkoxy, vinyloxy, —SCN, and —OC(O)R 6 , wherein R 6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, alkoxy, vinyloxy and ethynyloxy;

R 3 is a member selected from the group consisting of alkyl, substituted alkyl, 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;

wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and

with the proviso that if R 2 is —OC(O)R 6 , wherein R 6 is alkyl, and R 1 is —CHO or —C(O)CH 3 , then R 3 is other than C 1-4 alkyl or —OC(O)C 1-6 alkyl.

2. The compound in accordance with claim 1 , wherein R 1 is —C(O)CH 3 .

3. The compound in accordance with claim 1 , wherein R 2 is a member selected from the group consisting of —SCN and —OC(O)R 6 , wherein R 6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, and alkoxy.

4. A compound of general formula I:

wherein:

R 1 is a member selected from the group consisting of —CHO, —CH(OH)CH 3 , and —C(O)CH 3 ;

R 2 is —OC(O)R 6 and R 6 is a member selected from the group consisting of —CH 2 CH 3 , —CH 2 OCH 3 and —OCH 3 ;

R 3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;

R 4 is a member selected from the group consisting of hydrogen and alkyl;

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;

wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and

with the proviso that if R 6 is —CH 2 CH 3 and R 1 is —CHO or —C(O)CH 3 , then R 3 is other than C 1-4 alkyl or —OC(O)C 1-6 alkyl.

5. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 1 and a pharmaceutically acceptable excipient.

6. A compound of the general formula I:

wherein:

R 1 is a member selected from the group consisting of —CHO, —CH(OH)CH 3 , and —C(O)CH 3 ;

R 2 is —OC(O)R 6 wherein R 6 is alkyl or alkoxyalkyl;

R 3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;

R 4 is a member selected from the group consisting of hydrogen and alkyl;

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;

wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and

with the proviso that if R 6 is alkyl and R 1 is —CHO or —C(O)CH 3 , then R 3 is other than C 1-4 alkyl or —OC(O)C 1-6 alkyl.

7. The compound of claim 6 , wherein R 3 is alkoxy or acyloxy.

8. The compound of claim 6 , wherein R 4 is alkyl.

9. The compound of claim 6 , wherein X is ═O.

10. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 2 and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 3 and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 4 and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 6 and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 7 and a pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 8 and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 9 and a pharmaceutically acceptable excipient.

17. A compound of the general formula:

wherein:

R 1 is a member selected from the group consisting of —OCH 3 , —SCH 3 , —CHO, —CH(OH)CH 3 and —C(O)CH 3 ;

R 2 is a member selected from the group consisting of alkoxy, SAc, vinyloxy, —SCN, and —OC(O)R 6 , wherein R 6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, alkoxy, vinyloxy and ethynyloxy;

R 3 is selected from the group consisting of methoxymethoxy, methoxyethoxy, aryloxy, arylalkoxy, 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;

wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and

with the proviso that if R 2 is —OC(O)R 6 , wherein R 6 is alkyl, and R 1 is —CHO or —C(O)CH 3 , then R 3 is other than —OC(O)C 1-6 alkyl.

18. A compound of the general formula:

wherein:

R 1 is —C(O)CH 3 :

R 2 is a member selected from the group consisting of —SAc, alkoxy, vinyloxy, —SCN, and —OC(O)R 6 , wherein R 6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, alkoxy, vinyloxy and ethynyloxy;

R 3 is a member selected from the group consisting of alkyl, substituted alkyl, 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;

wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and

with the proviso that if R 2 is —OC(O)R 6 . wherein R 6 is alkyl, then R 3 is other than C 1-4 alkyl or —OC(O)C 1-6 alkyl.

19. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 18 and a pharmaceutically acceptable excipient.

20. A compound of the general formula:

wherein:

R 1 is a member selected from the group consisting of —OCH 3 , —SCH 3 , —CHO, —CH(OH)CH 3 , and —C(O)CH 3 ;

R 2 is —OC(O)R 6 , wherein R 6 is a member selected from the group consisting of alkyl and alkoxyalkyl;

R 3 is a member selected from the group consisting of alkyl, substituted alkyl, 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;

wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and

with the proviso that if R 2 is —OC(O)R 6 , wherein R 6 is alkyl, and R 1 is —CHO or —C(O)CH 3 , then R 3 is other than C 1-4 alkyl or —OC(O)C 1-6 alkyl.

21. The compound of claim 20 , wherein:

R 2 is —OC(O)R 6 , wherein R 6 is a member selected from the group consisting of —CH 2 CH 3 , —CH 2 OCH 3 and —OCH 3 .

22. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 17 and a pharmaceutically acceptable excipient.

23. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 21 and a pharmaceutically acceptable excipient.

24. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 1 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

25. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 17 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

26. A method of treating a patient in need thereof comprising administering an effective amount of a compound of claim 18 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating, endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

27. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 20 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

28. The compound of claim 20 , wherein R 4 is alkyl.

29. The compound of claim 20 , wherein X is ═O.

30. The compound of claim 20 , wherein R 1 is CHO.

31. The compound of claim 20 , wherein R 1 is —CH(OH)CH 3 .

32. The compound of claim 20 , wherein R 1 is —SCH 3 .

33. The compound of claim 20 , wherein R 1 is —C(O)CH 3 .

34. The compound of claim 20 , wherein R 3 is alkoxy.

35. The compound of claim 20 , wherein R 6 is alkoxyalkyl.

36. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 28 and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 29 and a pharmaceutically acceptable excipient.

38. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 30 and a pharmaceutically acceptable excipient.

39. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 31 and a pharmaceutically acceptable excipient.

40. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 32 and a pharmaceutically acceptable excipient.

41. The compound of claim 1 , wherein R 2 is alkoxy.

42. The compound of claim 41 , wherein R 1 is —C(O)CH 3 , R 2 is methoxy, R 3 is acetoxy, R 4 is methyl, and X is ═O.

43. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 41 and a pharmaceutically acceptable excipient.

44. A pharmaceutical composition comprising an effective amount of the compound in accordance with claim 42 and a pharmaceutically acceptable excipient.

45. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 41 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

46. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 42 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

47. The compound of claim 1 , wherein R 2 is —SAc.

48. The compound of claim 47 , wherein R 1 is —C(O)CH 3 , R 2 is —SAc, R 3 is acetoxy, R 4 is methyl, and X is ═O.

49. A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 47 and a pharmaceutically acceptable excipient.

50. A pharmaceutical composition comprising an effective amount of the compound in accordance with claim 48 and a pharmaceutically acceptable excipient.

51. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 47 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

52. A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 48 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.