Crystal forms of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide

• US 9,796,721 B2
• Filed: 07/01/2016
• Issued: 10/24/2017
• Est. Priority Date: 07/02/2015
• Status: Active Grant

• Current Assignee: Acerta Pharma B.V. (Astrazeneca PLC)
• Original Assignee: Acerta Pharma B.V. (Astrazeneca PLC)
• Inventors: Blatter, Fritz, Ingallinera, Tim, Barf, Tjeerd, Aret, Edwin, Krejsa, Cecile, Evarts, Jerry
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/200,875
• Publication Number:
  US 20170029428A1
• Time in Patent Office: 480 Days
• Field of Search: 514249, 544350
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/13 : Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

In some embodiments, the invention relates to crystalline solid forms, including hydrates, polymorphs, and salt forms, of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide. In some embodiments, the invention relates to amorphous solid forms of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide. In some embodiments, the invention also relates to pharmaceutical compositions containing the solid forms, and methods for treating conditions or disorders by administering to a subject a pharmaceutical composition that includes the forms, including pharmaceutical compositions and methods for overcoming the effects of acid reducing agents.

Claims

1. A crystal form of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide characterized by a reflection X-ray powder diffraction pattern comprising peaks at 6.4°

±

0.2°

2θ

, 8.6°

±

0.2°

2θ

, 10.5°

±

0.2°

2θ

, 11.6°

±

0.2°

2θ and

15.7°

±

0.2°

2θ

.

2. The crystal form of claim 1, wherein the reflection X-ray powder diffraction pattern further comprises peaks at 10.9°

±

0.2°

2θ

, 12.7°

±

0.2°

2θ

, 13.4°

±

0.2°

2θ

, 14.3°

±

0.2°

2θ

, 14.9°

±

0.2°

2θ and

18.2°

±

0.2°

2θ

.

3. The crystal form of claim 2, wherein the reflection X-ray powder diffraction pattern comprises one or more peaks at 11.3°

±

0.2°

2θ

, 15.1°

±

0.2°

2θ

, 16.1°

±

0.2°

2θ

, 17.3°

±

0.2°

2θ

, 19.2°

±

0.2°

2θ

, 19.4°

±

0.2°

2θ

, 19.8°

±

0.2°

2θ

, 20.7°

±

0.2°

2θ

, 21.1°

±

0.2°

2θ

, 21.4°

±

0.2°

2θ

, 21.6°

±

0.2°

2θ

, 21.9°

±

0.2°

2θ

, 22.6°

±

0.2°

2θ

, 23.3°

±

0.2°

2θ

, 23.6°

±

0.2°

2θ

, 24.9°

±

0.2°

2θ

, 25.2°

±

0.2°

2θ

, 25.4°

±

0.2°

2θ

, 25.7°

±

0.2°

2θ

, 26.1°

±

0.2°

2θ

, 26.4°

±

0.2°

2θ

, 26.8°

±

0.2°

2θ

, 26.9°

±

0.2°

2θ

, 27.7°

±

0.2°

2θ

, 28.6°

±

0.2°

2θ

, 29.1°

±

0.2°

2θ

, 29.4°

±

0.2°

2θ

, 30.1°

±

0.2°

2θ

, 30.5°

±

0.2°

2θ

, 31.7°

±

0.2°

2θ

, 31.9°

±

0.2°

2θ

, 32.2°

±

0.2°

2θ

, 32.6°

±

0.2°

2θ

, 33.1°

±

0.2°

2θ

, 33.4°

±

0.2°

2θ

°

±

0.2°

2θ

, 34.5°

±

0.2°

2θ

, 35.9°

±

0.2°

2θ

, 36.1°

±

0.2°

2θ

, 36.8°

±

0.2°

2θ

, 37.4°

±

0.2°

2θ

, 38.1°

±

0.2°

2θ

, 38.9°

±

0.2°

2θ and

39.5°

±

0.2°

2θ

.

4. The crystal form of claim 2, wherein the reflection X-ray powder diffraction pattern further comprises peaks at 11.3°

±

0.2°

2θ

, 15.1°

±

0.2°

2θ

, 16.1°

±

0.2°

2θ

, 17.3°

±

0.2°

2θ

, 19.2°

±

0.2°

2θ

, 19.4°

±

0.2°

2θ

, 19.8°

±

0.2°

2θ

, 20.7°

±

0.2°

2θ

, 21.1°

±

0.2°

2θ

, 21.4°

±

0.2°

2θ

, 21.6°

±

0.2°

2θ

, 21.9°

±

0.2°

2θ

, 22.6°

±

0.2°

2θ

, 23.3°

±

0.2°

2θ

, 23.6°

±

0.2°

2θ

, 24.9°

±

0.2°

2θ

, 25.2°

±

0.2°

2θ

, 25.4°

±

0.2°

2θ

, 25.7°

±

0.2°

2θ

, 26.1°

±

0.2°

2θ

, 26.4°

±

0.2°

2θ

, 26.8°

±

0.2°

2θ

, 26.9°

±

0.2°

2θ

, 27.7°

±

0.2°

2θ

, 28.6°

±

0.2°

2θ

, 29.1°

±

0.2°

2θ

, 29.4°

±

0.2°

2θ

, 30.1°

±

0.2°

2θ

, 30.5°

±

0.2°

2θ

, 31.7°

±

0.2°

2θ

, 31.9°

±

0.2°

2θ

, 32.2°

±

0.2°

2θ

, 32.6°

±

0.2°

2θ

, 33.1°

±

0.2°

2θ

, 33.4°

±

0.2°

2θ

°

±

0.2°

2θ

, 34.5°

±

0.2°

2θ

, 35.9°

±

0.2°

2θ

, 36.1°

±

0.2°

2θ

, 36.8°

±

0.2°

2θ

, 37.4°

±

0.2°

2θ

, 38.1°

±

0.2°

2θ

, 38.9°

±

0.2°

2θ and

39.5°

±

0.2°

2θ

.

5. The crystal form of claim 2, wherein the crystal form is a crystalline anhydrate.

6. The crystal form of claim 1, 2, 3, 4 or 5, wherein the peaks are present when the reflection x-ray powder diffraction is carried out using Cu—

K_α

radiation.

7. The crystal form of claim 1, 2, 3, 4 or 5, wherein the peaks are present when the reflection x-ray powder diffraction is carried out using a Bruker D8 Advance powder X-ray diffractometer equipped with a LynxEye detector and operating in Bragg-Brentano reflection geometry, a tube voltage of 40 kV and current of 40 mA, a variable divergence slit with a 3°

window, a step size of 0.02°

2θ

, sample rotation of 0.5 rps, and a step time of 37 seconds.

8. A pharmaceutical composition comprising the crystal form of any of claim 1, 2, 3, 4 or 5 and at least one pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition further comprises an extragranular acidulant.

10. The pharmaceutical composition of claim 9, wherein the extragranular acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, (±

)-tartaric acid, ascorbic acid, isoascorbic acid, alginic acid, a salt of alginic acid, Protacid F 120 NM, Protacid AR 1112 and Carbopol 971P, or a combination thereof.

11. The pharmaceutical composition of claim 9, wherein the extragranular acidulant is selected from the group consisting of alginic acid, a sodium salt of alginic acid and a potassium salt of alginic acid.

12. A method of inhibiting Bruton'"'"'s tyrosine kinase activity in a human, comprising administering to said human a therapeutically effective amount of the pharmaceutical composition of claim 8.

13. The method of claim 12, wherein the human suffers from a hyperproliferative disease.

14. The method of claim 13, wherein the hyperproliferative disease is chronic lymphocytic leukemia.

15. The method of claim 13, wherein the hyperproliferative disease is small lymphocytic lymphoma.

16. The method of claim 13, wherein the hyperproliferative disease is mantle cell lymphoma.

17. The method of claim 13, wherein the hyperproliferative disease is Waldenstrom'"'"'s macroglobulinemia.