TETRASUBSTITUTED ALKENE COMPOUNDS AND THEIR USE

• US 20160347717A1
• Filed: 05/27/2016
• Published: 12/01/2016
• Est. Priority Date: 05/29/2015
• Status: Active Grant

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Inventors: BOCK, Mark, HAO, Ming-Hong, KORPAL, Manav, NYAVANANDI, Vijay Kumar, PUYANG, Xiaoling, SMITH, Peter Gerard, WANG, John, SAMAJDAR, Susanta, ZHENG, Guo Zhu, ZHU, Ping
• Granted Patent: US 9,796,683 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/14 Ortho-condensed systems

Abstract

Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and/or the subject in need of treatment may express a mutant ER-α protein.

Claims

1. A compound given by formula II:

2. The compound or pharmaceutically acceptable salt of claim 1, given by formula I:

3. A compound according to claim 2, wherein R₁ is ethyl.

5. A compound according to claim 2, wherein R₆ and R₇ are both methyl.

6. A compound according to claim 2, wherein R₂ and R₈ are H.

7. A compound according to claim 2, wherein R₂ is F.

11. A compound according to claim 2, wherein m, n, and p are 0.

17. A compound of claim 2, having the following formula:

19. A compound of claim 1 having the following formula:

47. A pharmaceutical composition comprising the compound of claim 17 or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient.

49. A pharmaceutical composition comprising the compound of claim 19 or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient.

4. (canceled)

8-10. -10. (canceled)

12-16. -16. (canceled)

18. A compound having the following formula:

41. A method of treating breast cancer comprising administering to a subject a compound of claim 18.

42. The method of claim 41, wherein said breast cancer is an ER-positive breast cancer.

43. The method of claim 42, where said subject expresses a mutant ER-α

protein.

48. A pharmaceutical composition comprising the compound of claim 18 or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient.

20. A compound given by formula III:

21. The compound according to claim 20, wherein R₁ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and a 4-6 membered heterocyclic ring.

22. The compound according to claim 20, wherein:

R₂ is selected from the group consisting of H, halogen, methyl and ethyl;

R₃ are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl;

R₄ are the same or different and are independently selected from the group consisting of H, halogen, C₁-C₆ alkyl and C₁-C₆ alkoxy;

R₅ are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl;

R₈ and R₁₀ are the same or different and are independently selected from the group consisting of H and methyl;

R₉ is selected from the group consisting of H, methyl and ethyl; and

R₆ and R₇ are the same or different and are independently selected from the group consisting of H and C₁-C₆ alkyl or wherein R₆ and R₇ form a 4-6 atom heterocyclic ring with the N to which they are attached, optionally also containing an O atom.

23. The compound of claim 20, wherein Y is —

C(O)NR₆R₇.

24. The compound of claim 20, wherein R₆ and R₇ are methyl.

25. The compound of claim 23, wherein R₂, R₈, R₉, and R₁₀ are each H.

26. The compound of claim 23, wherein R₁ is ethyl.

27. The compound of claim 23, wherein R₁ is cyclobutyl.

29. The compound of claim 23, wherein R₂ is F.

33. The compound of claim 23, wherein m, n, and p are 0.

38. A method of treating breast cancer comprising administering to a subject a compound of claim 20.

39. The method of claim 38, wherein said breast cancer is an ER-positive breast cancer.

40. The method of claim 39, where said subject expresses a mutant ER-α

protein.

28. (canceled)

30-32. -32. (canceled)

34-37. -37. (canceled)

44-46. -46. (canceled)