Salts of an LSD1 inhibitor

• US 10,329,255 B2
• Filed: 08/11/2016
• Issued: 06/25/2019
• Est. Priority Date: 08/12/2015
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Pan, Yongchun, Han, Wayne, Cao, Ganfeng, Jia, Zhongjiang, Sharief, Vaqar, Zhou, Jiacheng
• Primary Examiner(s): Royds Draper, Leslie A.
• Application Number:
  US15/234,053
• Publication Number:
  US 20170044101A1
• Time in Patent Office: 1,048 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/32 by oxygen atoms

Abstract

The present disclosure relates to tosylate salts 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of the LSD1-associated or mediated diseases such as cancer.

Claims

1. A salt which is a 4-methylbenzenesulfonic acid salt of 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid or a hydrate or solvate thereof, wherein the salt is crystalline.

2. The salt of claim 1, or a hydrate or solvate thereof, wherein the salt is 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid bis(4-methylbenzenesulfonate).

3. The salt of claim 1, which is a hydrate.

4. The salt of claim 1, having Form I.

5. The salt of claim 4, wherein the salt exhibits a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 94.6°

C. and a peak temperature of about 103.1°

C.

6. The salt of claim 4, wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at about 3.6 degrees 2-theta.

7. The salt of claim 4, wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at about 4.9 degrees 2-theta.

8. The salt of claim 4, wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at about 6.2 degrees 2-theta.

9. The salt of claim 4, wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at about 7.7 degrees 2-theta.

10. The salt of claim 4, wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at about 22.7 degrees 2-theta.

11. The salt of claim 4, wherein the salt has an X-ray powder diffraction pattern comprising at least two characteristic peaks selected from the group consisting of about 3.6, about 4.9, about 6.2, about 7.7, and about 22.7 degrees 2-theta.

12. The salt of claim 11, wherein the salt has an X-ray powder diffraction pattern further comprising one or more characteristic peak at a position selected from the group consisting of about 8.9, about 10.0, about 11.5, about 14.3, about 15.0, about 15.5, about 16.3, about 17.8, about 19.1, about 19.8, about 20.9, and about 22.2 degrees 2-theta, and combinations thereof.

13. The salt of claim 4, having an X-ray powder diffraction pattern with characteristic peaks as substantially shown in FIG. 1.

14. The salt of claim 4, having a Differential Scanning calorimetry (DSC) thermogram substantially as depicted in FIG. 2.

15. The salt of claim 4, having a Thermal Gravimetric Analysis (TGA) thermogram substantially as depicted in FIG. 3.

16. The salt of claim 4, wherein the salt exhibits a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 94.6°

C. and a peak temperature of about 103.1°

C.; and

an X-ray powder diffraction pattern comprising a characteristic peak at about 3.6, about 4.9, about 6.2, about 7.7 or about 22.7 degrees 2-theta.

17. The salt of claim 1, wherein the salt has a melting point of about 103.1°

C.

18. The salt of claim 1, having a form selected from the group consisting of Form HI, Form HII, Form HIII and Form DH.

19. The salt of claim 18, wherein the salt has Form HI and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 80°

C.

20. The salt of claim 18, having Form HI and an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 7.0, about 10.4, about 13.6, about 15.5, about 17.3, about 22.2, and about 24.0 degrees 2-theta.

21. The salt of claim 18, having Form HI and an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from the group consisting of about 7.0, about 10.4, about 13.6, about 15.5, about 17.3, about 22.2, and about 24.0 degrees 2-theta.

22. The salt of claim 18, having Form HI and an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from the group consisting of about 7.0, about 10.4, about 13.6, about 15.5, about 17.3, about 22.2, and about 24.0 degrees 2-theta.

23. The salt of claim 18, having Form HI and an X-ray powder diffraction pattern substantially as shown in FIG. 4.

24. The salt of claim 18, having Form HI and a DSC thermogram substantially as depicted in FIG. 5.

25. The salt of claim 18, having Form HI and a TGA thermogram substantially as depicted in FIG. 6.

26. The salt of claim 18, wherein the salt has Form HI and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 80°

C.; and

an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 7.0, about 10.4, about 13.6, about 15.5, about 17.3, about 22.2, and about 24.0 degrees 2-theta.

27. The salt of claim 18, wherein the salt has Form HII and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 52°

C.

28. The salt of claim 18, having Form HII and an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 8.7, about 10.1, about 14.8, about 21.3, about 22.0, about 22.7, and about 24.3 degrees 2-theta.

29. The salt of claim 18, having Form HII and an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from the group consisting of about 8.7, about 10.1, about 14.8, about 21.3, about 22.0, about 22.7, and about 24.3 degrees 2-theta.

30. The salt of claim 18, having Form HII and an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from the group consisting of about 8.7, about 10.1, about 14.8, about 21.3, about 22.0, about 22.7, and about 24.3 degrees 2-theta.

31. The salt of claim 18, having Form HII and an X-ray powder diffraction pattern substantially as shown in FIG. 7.

32. The salt of claim 18, having Form HII and a DSC thermogram substantially as depicted in FIG. 8.

33. The salt of claim 18, having Form HII and a TGA thermogram substantially as depicted in FIG. 9.

34. The salt of claim 18, wherein the salt has Form HIT and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 52°

C.; and

an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 8.7, about 10.1, about 14.8, about 21.3, about 22.0, about 22.7, and about 24.3 degrees 2-theta.

35. The salt of claim 18, wherein the salt has Form HIII and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 67°

C.

36. The salt of claim 35, wherein the salt has Form HIII and further exhibits an endothermic peak at a temperature of about 98°

C.

37. The salt of claim 18, having Form HIII and an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 7.0, about 9.0, about 9.2, about 10.2, about 17.9, about 20.3, about 22.0, and about 23.8 degrees 2-theta.

38. The salt of claim 18, having Form HIII and an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from the group consisting of about 7.0, about 9.0, about 9.2, about 10.2, about 17.9, about 20.3, about 22.0, and about 23.8 degrees 2-theta.

39. The salt of claim 18, having Form HIII and an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from the group consisting of about 7.0, about 9.0, about 9.2, about 10.2, about 17.9, about 20.3, about 22.0, and about 23.8 degrees 2-theta.

40. The salt of claim 18, having Form HIII and an X-ray powder diffraction pattern substantially as shown in FIG. 10.

41. The salt of claim 18, having Form HIII and a DSC thermogram substantially as depicted in FIG. 11.

42. The salt of claim 18, having Form HIII and a TGA thermogram substantially as depicted in FIG. 12.

43. The salt of claim 18, wherein the salt has Form HIII and exhibits a differential scanning calorimetry thermogram having endothermic peaks at temperatures of about 67°

C. and about 98°

C.; and

an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 7.0, about 9.0, about 9.2, about 10.2, about 17.9, about 20.3, about 22.0, and about 23.8 degrees 2-theta.

44. The salt of claim 18, wherein the salt has Form DH and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 98°

C.

45. The salt of claim 18, having Form DH and an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 7.5, about 9.6, about 10.7, about 14.8, about 20.1, about 20.7, about 21.6, about 22.9, and about 24.7 degrees 2-theta.

46. The salt of claim 18, having Form DH and an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from the group consisting of about 7.5, about 9.6, about 10.7, about 14.8, about 20.1, about 20.7, about 21.6, about 22.9, and about 24.7 degrees 2-theta.

47. The salt of claim 18, having Form DH and an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from the group consisting of about 7.5, about 9.6, about 10.7, about 14.8, about 20.1, about 20.7, about 21.6, about 22.9, and about 24.7 degrees 2-theta.

48. The salt of claim 18, having Form DH and an X-ray powder diffraction pattern substantially as shown in FIG. 13.

49. The salt of claim 18, having Form DH and a DSC thermogram substantially as depicted in FIG. 14.

50. The salt of claim 18, having Form DH and a TGA thermogram substantially as depicted in FIG. 15.

51. The salt of claim 18, wherein the salt has Form DH and exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 98°

C.; and

an X-ray powder diffraction pattern comprising a characteristic peak selected from the group consisting of about 7.5, about 9.6, about 10.7, about 14.8, about 20.1, about 20.7, about 21.6, about 22.9, and about 24.7 degrees 2-theta.

52. A pharmaceutical composition comprising a salt of claim 1, and pharmaceutically acceptable carrier or excipient.

53. A solid oral dosage form comprising the pharmaceutical composition of claim 52.

54. A method for preparing 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid bis(4-methylbenzenesulfonate), said method comprising:

reacting 1-{[4-({(tert-butoxycarbonyl)[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid having the formula;

55. The method of claim 54, further comprising recrystallizing 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid bis(4-methylbenzenesulfonate).

56. The method of claim 54, wherein the reacting is carried out at a temperature between about 50 and 60°

C.

57. The method of claim 54, wherein the solvent is tetrahydrofuran (THF).