EP-4735421-A1 - CRYSTALLINE FORMS OF (E)-N-HYDROXY-3-(1-(PHENYLSULFONYL)INDOLIN-5-YL)ACRYLAMIDE

Abstract

Disclosed herein is a specific crystalline forms of (E)-N-hydroxy-3-(1-(phenylsulfonyl)indolin-5-yl)acrylamide (ABT-301), the pharmaceutical composition and capsule comprising the same, the intermediate and the medical application thereof. Said crystalline forms of ABT-301 can exhibit unexpected stability and improved pharmacokinetic properties compared to other forms or salt thereof, thereby allowing said compound more suitable for drug development and satisfying the requirements for bioavailability and drug efficacy.

Inventors

• HSU, TSU-AN
• CHANG, SUE-MING

Assignees

• Shih, Chuan
• Anbogen Therapeutics Inc.

Dates

Publication Date

20260506

Application Date

20240626

Claims (1)

1. Attorney Docket No.4929/0489PWO3 CLAIMS What is claimed is: 1. A crystalline form of (E)-N-hydroxy-3-(1-(phenylsulfonyl)indolin-5-yl)acrylamide (ABT-301), wherein the crystalline form comprises Type A form or Type B form; wherein Type A form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of 9.6°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2° and 20.4°±0.2°; and wherein Type B form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of 15.7°±0.2°, 16.6°±0.2°, 20.1°±0.2° and 24.1°±0.2°. 2. The crystalline form of claim 1, wherein Type A form is characterized by an X-ray powder diffraction pattern further comprising peaks at 2θ value of 10.2°±0.2°, 11.8±0.2°, 17.4°±0.2°, 21.3°±0.2° and 21.9°±0.2°. 3. The crystalline form of claim 1, wherein Type A form is hydrate. 4. The crystalline form of claim 1, wherein Type B form is characterized by an X-ray powder diffraction pattern further comprising peaks at 2θ value of 12.5°±0.2° and 21.7±0.2°. 5. The crystalline form of claim 1, wherein Type B form is anhydrate. 6. The crystalline form of claim 1, having a melting point temperature of 125 to 132℃. 7. The crystalline form of claim 1, wherein Type A form has a TGA weight loss of 2 to 4% when heated to a temperature of 100 to 150℃. 8. The crystalline form of claim 1, wherein Type A form has a water uptake of 0.13 to 0.14% at 25℃/ 80%RH. 9. The crystalline form of claim 1, wherein Type B form has a TGA weight loss of 0.7 to 0.8% when heated to a temperature of 150 to 170℃. 10. The crystalline form of claim 1, wherein Type B form has a water uptake of 0.103 to 0.109% at 25℃/80%RH. 11. An intermediate for preparing Type A form or Type B form, wherein the intermediate is a solvate of ABT-301. 12. The intermediate of claim 11, wherein the solvate comprises IPA solvate, acetone solvate, ACN solvate, MeOH solvate, NMP solvate, THF solvate, EtOAc solvate, DMAc solvate, EtOH solvate, DCM solvate, DMSO solvate, 1-4-Dioxane solvate or MIBK solvate. 13. A pharmaceutical composition comprising the crystalline form of claim 1, a surfactant and an oil. 14. The pharmaceutical composition of claim 13, wherein the surfactant is polysrobate 80. Attorney Docket No.4929/0489PWO3 15. The pharmaceutical composition of claim 13, wherein the oil is castor oil. 16. The pharmaceutical composition of claim 13, which is a HDAC inhibitor. 17. The pharmaceutical composition of claim 13, which is in a form of a capsule. 18. The pharmaceutical composition of claim 17, comprising from 25 to 100 mg of the crystalline form of claim 1. 19. The pharmaceutical composition of claim 17, which is encapsulated in a gelatin shell. 20. The pharmaceutical composition of claim 13, which further comprises a plasticizer. 21. The pharmaceutical composition of claim 20, wherein the plasticizer is propylene glycol. 22. A method of treating cancer or fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form of any one of claims 1 to 10. 23. The method of Claim 22, wherein the crystalline form of any one of claims 1 to 10 is a HDAC inhibitor. 24. The method of Claim 22, wherein the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, cervix cancer, gastric cancer, esophageal cancer, neuroendocrine cancer, bone cancer or head and neck cancer. 25. The method of Claim 22, wherein the fibrosis is lung fibrosis, liver fibrosis, skin fibrosis or renal fibrosis.

Description

Attorney Docket No.4929/0489PWO3 CRYSTALLINE FORMS OF (E)-N-HYDROXY-3-(1-(PHENYLSULFONYL)INDOLIN-5- YL)ACRYLAMIDE CROSS REFERENCE This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/523,377 and No.63/523,378, filed on June 27, 2023, the content thereof is incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to new crystalline forms of (E)-N-hydroxy-3-(1- (phenylsulfonyl)indolin-5-yl)acrylamide (ABT-301), to pharmaceutical compositions and capsules comprising the same, and to methods of using the crystalline forms in the treatment of cancer. BACKGROUND OF THE INVENTION Histone deacetylases (HDACs) are a class of enzymes that regulate histone acetylation and thus regulate gene expression to inhibit tumor progression. HDACs are classified according to four categories: class I (HDAC1, 2, 3, and 8); class IIa (HDAC4, 5, 7 and 9) and class IIb (HDAC6 and 10); class III (SIRT1-7); and class IV (HDAC11). They are involved in the post-translational modifications of core histone and nonhistone proteins. These are involved in the post-translational modifications of core histone and nonhistone proteins. U.S. Pat. No. 8,846,748 discloses certain indolyl or indolinyl hydroxamate compounds as HDAC inhibitors having potent anticancer activity. Masahiro Yoshikawa et al. indicate that HDAC inhibitors prevent fibrosis in the liver, skin and lung, U.S. Pat. No. 11,278,523 B2 discloses effect of the HDAC inhibitors on treating lung fibrosis, liver fibrosis or renal fibrosis, but most of their underlying mechanisms remain to be elucidated, and suggests that TSA, an HDAC inhibitor, induces several inhibitory factors of TGF-beta 1 signals, such as Id2 and BMP-7, in human RPTEC (Masahiro Yoshikawa et al., J Am Soc Nephrol 18: 58-65, 2007). Maoyin Pang and Shougang Zhuang indicate that development and progression of some chronic diseases are characterized by fibrosis, including chronic kidney disease, cardic hypertrophy and idiopathic pulmonary fibrosis (Maoyin Pang and Shougang Zhuang, The Journal of Pharmacology and Experimental Therapeutics, Vol.355, No.2, pp. 266-272, 2010). As such, HDAC inhibitors (HDACi) have emerged as a promising class of drugs for treatment of cancers. Some HDACi, such as SAHA, LBH589, PXD101, MS-275, and FK228, are being examined in clinical trials for their ability to treat various solid and hematological malignancies. On the Attorney Docket No.4929/0489PWO3 other hand, SAHA and FK228 have been approved by the U.S. Food and Drug Administration (FDA) to apply for the treatment of cutaneous T-cell lymphoma. Certain indolyl or indolinyl hydroxamate compounds as HDAC inhibitors are disclosed in U.S. Patent Application No. 8,846,748B2. Nevertheless, the differences in various aspects between crystalline forms of said compounds have barely been discussed. SUMMARY OF THE INVENTION The invention is based on the discovery that certain crystalline forms of (E)-N-hydroxy-3-(1- (phenylsulfonyl)indolin-5-yl)acrylamide (ABT-301), which exhibit unexpected stability and improved pharmacokinetic properties. Accordingly, the present invention provides a crystalline form of (E)-N-hydroxy-3-(1- (phenylsulfonyl)indolin-5-yl)acrylamide (ABT-301), wherein the crystalline form comprises Type A form or Type B form; wherein Type A form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of 9.6°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2° and 20.4°±0.2°; and wherein Type B form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of 15.7°±0.2° , 16.6°±0.2°, 20.1°±0.2° and 24.1°±0.2°. Further, Type A form is characterized by an X-ray powder diffraction pattern further comprising peaks at 2θ value of 10.2°±0.2°, 11.8±0.2°, 17.4°±0.2°, 21.3°±0.2° and 21.9°±0.2°. Further, Type A form is hydrate. Further, Type B form is characterized by an X-ray powder diffraction pattern further comprising peaks at 2θ value of 12.5°±0.2° and 21.7±0.2°. Further, Type B form is anhydrate. Further, the crystalline form provided herein has a melting point temperature of 125 to 132℃. Further, Type A form has a TGA weight loss of 2 to 4% when heated to a temperature of 100 to 150℃. Further, Type A form has a water uptake of 0.13 to 0.14% at 25℃/80%RH. Further, Type B form has a TGA weight loss of 0.7 to 0.8% when heated to a temperature of 150 to 170℃. Further, Type B form has a water uptake of 0.103 to 0.109% at 25℃/80%RH. The present invention provides an intermediate for preparing Type A form or Type B form, wherein the intermediate is a solvate of ABT-301, and the solvate comprises IPA solvate, acetone solvate, ACN solvate, MeOH solvate, NMP solvate, THF solvate, EtOAc solvate, DMAc solvate, EtOH solvate, DCM solvate, DMSO solvate, 1-4-Dioxane solvate or MIBK solvate. Attorney Docket No.4929/0489PWO3 The present invention provides a pharmaceutical composition comprising the crystalline for