Crystalline polymorphs of Bruton's tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11820760-B2
Application number	US-201917283301-A
Country	US
Kind code	B2
Filing date	Oct 15, 2019
Priority date	Oct 15, 2018
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

Provided are crystalline forms of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, pharmaceutical compositions, methods of use and methods of making thereof.

First claim

The invention claimed is:

1. Crystalline Form B, crystalline Form C, crystalline Form D, crystalline Form E, crystalline Form F, crystalline Form H, crystalline Form J, crystalline Form K, crystalline Form L, crystalline Form M, crystalline Form N, crystalline Form P, or crystalline Form Q of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

2. The crystalline Form B of claim 1 , wherein the crystalline form is
characterized by at least three or at least four powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.1°, 7.0°, 8.1°, 12.1° and 18.3°.

3. The crystalline Form C of claim 1 , wherein the crystalline form is
characterized by at least three, at least four or at least five PXRD peaks at 2θ angles selected from 3.4°, 5.5°, 6.9°, 7.7°, 8.8° and 12.5°.

4. The crystalline Form D of claim 1 , wherein the crystalline form:
is characterized by at least three, at least four or at least five PXRD peaks at 2θ angles selected from 5.4°, 6.3°, 8.3°, 10.9°, 12.5° and 19.1°.

5. The crystalline Form E of claim 1 , wherein the crystalline form
is characterized by at least three, at least four or at least five PXRD peaks at 2θ angles selected from 4.2°, 5.1°, 5.9°, 7.0°, 12.0° and 16.9°.

6. The crystalline Form F of claim 1 , wherein the crystalline form
is characterized by at least three, four or five PXRD peaks at 2θ angles selected from 3.6°, 4.7°, 5.7°, 7.3°, 8.9°, 12.4° and 16.8°.

7. The crystalline Form H of claim 1 , wherein the crystalline form
is characterized by at least three or four PXRD peaks at 2θ angles selected from 4.6°, 6.3°, 8.4°, 13.4° and 18.7°.

8. The crystalline Form J of claim 1 , wherein the crystalline form
is characterized by at least three or at least four PXRD peaks at 2θ angles selected from 4.0°, 7.1°, 7.3°, 12.0°, 12.5°.

9. The crystalline Form K of claim 1 , wherein the crystalline form
is characterized by at least three, at least four or at least five PXRD peaks at 2θ angles selected from 5.7°, 8.0°, 8.7°, 9.7°, 12.0° and 18.0°.

10. The crystalline Form L of claim 1 , wherein the crystalline form
is characterized by at least three, at least four, at least five, at least six, at least seven or at least eight PXRD peaks at 2θ angles selected from 7.1°, 7.9°, 9.1°, 10.0°, 10.4°, 12.8°, 16.1°, 16.8° and 18.4°.

11. The crystalline Form M of claim 1 , wherein the crystalline form
is characterized by at least three, at least four or at least five PXRD peaks at 2θ angles selected from 3.5°, 4.3°, 8.0°, 8.7°, 12.9° and 17.4°.

12. The crystalline Form N of claim 1 , wherein the crystalline form
is characterized by at least three, four, five, six or seven PXRD peaks at 2θ angles selected from 4.8°, 7.1°, 10.4°, 11.5°, 15.2°, 17.7°, 19.8° and 22.8°.

13. The crystalline Form P of claim 1 , wherein the crystalline form
is characterized by at least three, at least four or at least five PXRD peaks at 2θ angles selected from 5.3°, 9.7°, 14.2°, 15.8°, 17.5° and 24.2°.

14. The crystalline Form Q of claim 1 , wherein the crystalline form
is characterized by at least three, at least four, at least five, at least six or at least seven PXRD peaks at 2θ angles selected from 5.2°, 8.5°, 9.6°, 10.5°, 14.0°, 15.7° and 17.3°.

15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and (i) the crystalline Form B, or (ii) the crystalline Form C, or (iii) the crystalline Form D, or (iv) the crystalline Form E, or (v) the crystalline Form F, or (vi) the crystalline Form H, or (vii) the crystalline Form J, or (viii) the crystalline Form K, or (ix) the crystalline Form L, or (x) the crystalline Form M, or (xi) the crystalline Form N, (xii) the crystalline Form P, or (xiii) a crystalline Form Q of claim 1 .

16. A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject comprising administering to the subject an effective amount of (i) the crystalline Form B, or (ii) the crystalline Form C, or (iii) the crystalline Form D, or (iv) the crystalline Form E, or (v) the crystalline Form F, or (vi) the crystalline Form H, or (vii) the crystalline Form J, or (viii) the crystalline Form K, or (ix) the crystalline Form L, or (x) the crystalline Form M, or (xi) the crystalline Form N, (xii) the crystalline Form P, or (xiii) a crystalline Form Q of claim 1 .

17. The method of claim 16 , wherein the disorder is an autoimmune disorder.

18. The method of claim 17 , wherein the autoimmune disorder is multiple sclerosis.

19. The crystalline Form B of claim 2 , wherein the crystalline form is:
(i) characterized by PXRD peaks at 2θ angles selected from 4.1°, 7.0°, 8.1°, 12.1° and 18.3°;
(ii) characterized by PXRD peaks at 2θ angles selected from 4.1°, 7.0°, 8.1°, 12.1°, 13.0°, 14.7°, 17.6°, 18.3° and 20.7°;
(iii) characterized by a melting temperature of 158.5° C.±2° C. determined by differential scanning calorimetry (DSC) analysis;
(iv) a hygroscopic anhydrate; or
(v) is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

20. The crystalline Form C of claim 3 , wherein the crystalline form is:
(i) characterized by PXRD peaks at 2θ angles selected from 3.4°, 5.5°, 6.9°, 7.7°, 8.8° and 12. 5° ;
(ii) characterized by PXRD peaks at 2θ angles selected from 3.4°, 5.5°, 6.9°, 7.7°, 8.8°, 9.8°, 12.5°, 14.2°, 15.6°, 17.6°, 18.6°, 20.2° and 25.3°;
(iii) characterized by a melting temperature of 164.3° C.±2° C. determined by differential scanning calorimetry (DSC) analysis;
(iv) a hydrate; or
(v) is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

21. The crystalline Form D of claim 4 , wherein the crystalline form:
(i) is characterized by PXRD peaks at 2θ angles selected from 5.4°, 6.3°, 8.3°, 10.9°, 12.5°and 19.1;
(ii) is characterized by PXRD peaks at 2θ angles selected from 5.4°, 6.3°, 8.3°, 10.9°, 12.5°, 13.7°, 14.4°, 15.7°, 16.3°, 17.5°, 18.9°, 19.1°, 19.6°, 22.7°, 23.8°, 24.6°, 25.0°, 25.9°, 28.4°, 29.0°and 30.4°;
(iii) has a melting temperature of 173.2° C.±2° C. determined by differential scanning calorimetry (DSC) analysis;
(iv) is an acetic acid solvate; or
(v) is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

22. The crystalline Form E of claim 5 , wherein the crystalline form:
(i) is characterized by PXRD peaks at 2θ angles selected from 4.2°, 5.1°, 5.9°, 7.0°, 12.0°and 16.9°;
(ii) is characterized by PXRD peaks at 2θ angles selected from 4.2°, 5.1°, 5.9°, 7.0°, 8.5°, 8.7°, 9.8°, 10.2°, 12.0°, 12.4°, 13.7°, 16.9°, 18.1°, 18.7°, 20.7° and 26.6°; o
(iii) has a melting temperature of 167.8° C.±2° C. determined by differential scanning calorimetry (DSC) analysis;
(iv) is an anhydrate; or
(v) is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

23. The crystalline Form F of claim 6 , wherein the crystalline form:
(i) is characterized by PXRD peaks at 2θ angles selected from 3.6°, 4.7°, 5.7°, 7.3°, 8.9°, 12.4° and 16.8°;
(ii) is characterized by PXRD peaks at 2θ angles selected from 3.6°, 4.7°, 5.7°, 7.3°, 8.9°, 9.7°, 12.4°, 13.2°, 14.2°, 14.6°, 16.8°, 18.1°, 19.1°, 20.6°, 22.5°, 23.7°, 24.3°, 25.5° and 29.1°;
(iii) has a melting temperature of 174.7° C.±2° C. determined by differential scanning calorimetry (DSC) analysis;
(iv) is an anhydrate; or
(v) is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

24. The crystalline Form H of c

Assignees

• Biogen Ma Inc

Inventors

• Zheng Fengmei
• Peterson Anton
• Vasudevan Kalyan
• Li Chaomin
• Patience Daniel B
• Lin Yiqing

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title