Salts of an LSD1 inhibitor and processes for preparing the same

Patent metadata

Field	Value
Publication number	US-10968200-B2
Application number	US-201916555907-A
Country	US
Kind code	B2
Filing date	Aug 29, 2019
Priority date	Aug 31, 2018
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

The present invention relates to processes and intermediates for preparing 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and salts and solid forms thereof, which selectively modulate demethylase. Particular embodiments contemplate compounds and disease indications amenable to treatment by modulation of lysine specific demethylase-1 (LSD1).

First claim

What is claimed is:

1. A salt which is a hydrochloric acid salt of a compound having the structure:

2. The salt of claim 1 , wherein the salt is a solid form.

3. The salt of claim 1 , wherein the salt is crystalline.

4. The salt of claim 1 , wherein the hydrochloric acid salt is a mono-hydrochloric acid salt.

5. The salt of claim 1 , wherein the hydrochloric acid salt is a di-hydrochloric acid salt.

6. The salt of claim 5 , wherein the di-hydrochloric acid salt is a solid form, which is Form I.

7. The salt of claim 6 , wherein Form I has an X-ray diffraction pattern comprising at least one characteristic peak in degrees 2θ selected from about 5.9°, about 7.1°, and about 9.9°.

8. The salt of claim 6 , wherein Form I has an X-ray diffraction pattern comprising at least four characteristic peaks in degrees 2θ selected from about 5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, and about 18.2°.

9. The salt of claim 6 , wherein Form I has an XRPD pattern with characteristic peaks substantially shown in FIG. 1 .

10. The salt of claim 6 , having a DSC thermogram characterized by endotherm peaks at temperatures of about 80° C. and about 175° C.

11. The salt of claim 6 , having a DSC thermogram substantially as shown in FIG. 2 .

12. The salt of claim 6 , having a TGA thermogram substantially as shown in FIG. 3 .

13. The salt of claim 5 , wherein the di-hydrochloric acid salt is a solid form, which is Form II.

14. The salt of claim 13 , wherein Form II has an X-ray diffraction pattern comprising at least one characteristic peak in degrees 2θ selected from about 5.8°, about 13.2°, and about 15.1°.

15. The salt of claim 13 , wherein Form II has an X-ray diffraction pattern comprising at least four characteristic peaks in degrees 2θ selected from about 5.8°, about 13.2°, about 15.1°, about 17.1°, about 20.1° and about 20.8°.

16. The salt of claim 13 , wherein Form II has an XRPD pattern with characteristic peaks substantially shown in FIG. 4 .

17. The salt of claim 13 , having a DSC thermogram having an exotherm peak at a temperature of about 198° C.

18. The salt of claim 13 , having a DSC thermogram substantially as shown in FIG. 5 .

19. The salt of claim 13 , having a TGA thermogram substantially as shown in FIG. 6 .

20. The salt of claim 5 , wherein the di-hydrochloric acid salt is a solid form, which is Form III.

21. The salt of claim 20 , wherein Form III has an X-ray diffraction pattern comprising at least four characteristic peaks in degrees 2θ selected from about 5.4°, about 16.8°, about 21.9°, about 27.7°, and about 28.6°.

22. The salt of claim 5 , wherein the di-hydrochloric acid salt is a solid form, which is Form IV.

23. The salt of claim 22 , wherein Form IV has an X-ray diffraction pattern comprising at least four characteristic peaks in degrees 2θ selected from about 5.8°, about 17.4°, about 18.3°, about 20.9°, about 22.5°, and about 26.9°.

24. The salt of claim 5 , wherein the di-hydrochloric acid salt is a solid form, which is Form V.

25. The salt of claim 24 , wherein Form V has an X-ray diffraction pattern comprising at least four characteristic peaks in degrees 2θ selected from about 5.4°, about 6.8°, about 13.1°, about 15.2, and about 21.7°.

26. The salt of claim 4 , wherein the mono-hydrochloric acid salt is crystalline.

27. The salt of claim 26 , wherein the mono-hydrochloric acid salt has an X-ray diffraction pattern comprising at least four characteristic peaks in degrees 2θ selected from about 10.3°, about 12.8°, about 15.6°, about 16.4°, about 21.5°, and about 25.7°.

28. A salt selected from:
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-methanesulfonic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide di-methanesulfonic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-malonic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-ethanesulfonic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-maleic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-camphorsulfonic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-isethionic acid salt;
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide mono-1,2-ethanedisulfonic acid salt; and
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide sulfuric acid salt, or a hydrate or solvate thereof.

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

30. A pharmaceutical composition comprising a salt of claim 28 or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

31. A solid oral dosage form comprising the pharmaceutical composition of claim 29 .

32. A solid oral dosage form comprising the pharmaceutical composition of claim 31 .

33. A method of inhibiting LSD1, said method comprising: contacting LSD1 with a salt of claim 1 .

34. A method of inhibiting LSD1, said method comprising: contacting LSD1 with a salt of claim 28 or a hydrate or solvate thereof.

Assignees

• Incyte Corp

Inventors

• Jia Zhongjiang
• Han Wayne
• Pan Yongchun
• Martin Timothy
• Zhou Jiacheng
• Li Qun

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D205/06

  having one double bond between ring members or between a ring member and a non-ring member · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title