Crystalline sulfamide compound

Patent metadata

Field	Value
Publication number	US-11254665-B2
Application number	US-201816649120-A
Country	US
Kind code	B2
Filing date	Sep 21, 2018
Priority date	Sep 22, 2017
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

The present application relates to a crystalline sulfamide compound, and in particular relates to a crystalline (S)—N—((S)-1-(2-chlorphenyl)-2-((3,3-difluorocyclobutyl)amido)-2oxoethyl)-2-(4-cyanopyridin-2-base)-N-(3-fluorophenyl)-isothiazolidine-3-formamide 1,1-dioxide, and a preparation method therefor, a crystalline composition, a pharmaceutical composition and uses thereof. An X-ray powder diffraction spectrum of a crystalline hydrate of formula II of the present application has diffraction peaks at positions of about 14.40°, 20.28°, 20.94°, 22.02°, and 24.46°, represented by 2θ. The crystalline hydrate of formula II of the present application has good IDH1 inhibitory activity and performs high stability, and therefore has advantages in physical property, safety and metabolic stability, and has high medicine value.

First claim

What is claimed is:

1. A crystalline form of a monohydrate of (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1,1-dioxide represented by formula II,

wherein the X-ray powder diffraction spectrum thereof has diffraction peaks at 14.40°±0.2°, 20.28°±0.2°, 20.94°±0.2°, 22.02°±0.2° and 24.46°±0.2°, represented by 2θ values.

2. The crystalline form of the monohydrate of formula II according to claim 1 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks at 9.12°±0.2°, 13.32°±0.2°, 14.40°±0.2°, 15.64°±0.2°, 16.46°±0.2°, 20.28°±0.2°, 20.94°±0.2°, 22.02°±0.2°, 22.98°±0.2°, 24.46°±0.2° and 29.34°±0.2°, represented by 2θ values.

3. The crystalline form of the monohydrate of formula II according to claim 2 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks at 5.52°±0.2°, 9.12°±0.2°, 10.30°±0.2°, 10.48°±0.2°, 11.96°±0.2°, 13.32°±0.2°, 14.40°±0.2°, 14.90°±0.2°, 15.64°±0.2°, 16.46°±0.2°, 17.28°±0.2°, 17.58°±0.2°, 18.60°±0.2°, 19.14°±0.2°, 19.32°±0.2°, 20.28°±0.2°, 20.94°±0.2°, 21.20°±0.2°, 22.02°±0.2°, 22.98°±0.2°, 23.52°±0.2°, 24.46°±0.2°, 25.74°±0.2°, 26.06°±0.2°, 26.74°±0.2°, 27.32°±0.2°, 27.98°±0.2°, 28.40°±0.2°, 28.90°±0.2°, 29.34°±0.2°, 30.36°±0.2°, 31.00°±0.2°, 31.74°±0.2°, 32.22°±0.2°, 32.82°±0.2°, 33.32°±0.2° and 37.84°±0.2°, represented by 2θ values.

4. The crystalline form of the monohydrate of formula II according to claim 1 , wherein the differential scanning calorimetry (DSC) measurement pattern thereof has an onset point at 186° C.±5° C.

5. A crystal composition, characterized in that the crystalline form of the monohydrate of formula II according to claim 1 represents 50% or more of the weight of the crystal composition.

6. A pharmaceutical composition, comprising the crystalline form of the monohydrate of formula II according to claim 1 .

7. A method for treating IDH1 mutation-induced cancer, comprising administering a therapeutically effective amount of the crystalline form of the monohydrate of formula II according to claim 1 to a subject in need thereof.

8. A method of preparing the crystalline form of the monohydrate of formula II according to claim 1 , comprising: (1) dissolving a compound of formula I in an organic solvent, and stirring till the solution is clear, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, acetone, tetrahydrofuran, acetonitrile, dichloromethane, or ethyl acetate; (2) adding water to the solution obtained in step (1); and (3) cooling down the solution to crystallization, filtering and drying,

9. The method according to claim 8 , wherein in step (1), the organic solvent is selected from one or more mixed solvents of methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, acetone, tetrahydrofuran, acetonitrile, dichloromethane, or ethyl acetate.

10. The method according to claim 8 , wherein in step (1), the molar volume ratio of the compound of formula I to the organic solvent is 1 mmol: 2-20 mL.

11. The method according to claim 8 , wherein in step (1), the temperature for dissolving the compound of formula I in the organic solvent is 20° C. to 100° C.

12. The method according to claim 8 , wherein the molar volume ratio of the compound of formula I in step (1) to the water in step (2) is 1 mmol: 0.01-5 mL.

13. A crystalline form of (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1,1-dioxide represented by formula I,

wherein the X-ray powder diffraction spectrum thereof has diffraction peaks at 8.64°±0.2°, 9.34°±0.2°, 20.72°±0.2°, 21.30°±0.2° and 24.02°±0.2°, represented by 2θ values.

14. The crystalline form of the compound of formula I according to claim 13 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks at 8.64°±0.2°, 9.34°±0.2°, 14.62°±0.2°, 19.66°±0.2°, 20.04°±0.2°, 20.46°±0.2°, 20.72°±0.2°, 21.30°±0.2°, 22.46°±0.2°, 24.02°±0.2° and 27.42°±0.2°, represented by 2θ values.

15. The crystalline form of the compound of formula I according to claim 14 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks at 8.64°±0.2°, 9.34°±0.2°, 11.18°±0.2°, 12.80°±0.2°, 13.68°±0.2°, 14.62°±0.2°, 15.18°±0.2°, 15.58°±0.2°, 16.36°±0.2°, 17.04°±0.2°, 17.60°±0.2°, 18.14°±0.2°, 18.40°±0.2°, 18.88°±0.2°, 19.66°±0.2°, 20.04°±0.2°, 20.46°±0.2°, 20.72°±0.2°, 21.30°±0.2°, 22.16°±0.2°, 22.46°±0.2°, 22.92°±0.2°, 23.16°±0.2°, 24.02°±0.2°, 24.32°±0.2°, 24.92°±0.2°, 25.14°±0.2°, 25.48°±0.2°, 25.92°±0.2°, 26.30°±0.2°, 27.42°±0.2°, 27.84°±0.2°, 28.46°±0.2° 30.16°±0.2°, 30.98°±0.2° and 33.18°±0.2°, represented by 2θ values.

16. The crystalline form of the compound of formula I according to claim 13 , wherein the differential scanning calorimetry (DSC) measurement pattern thereof has an onset point at 103° C.±5° C.

17. A method for preparing the crystalline form of the (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1,1-dioxide of formula I according to claim 13 , comprising: (1) dissolving the (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1,1-dioxide of formula I in an anhydrous organic solvent, stirring till the solution is clear, and added with 4A molecular sieve to drying, wherein the anhydrous organic solvent is selected from one or more of dichloromethane, isopropanol, n-hexane, ethyl acetate, or methyl tert-butyl ether; (2) filtering under nitrogen protection, and cooling down the filtrate to crystallization; and (3) filtering under nitrogen protection and drying

18. A crystal composition, wherein the crystalline form of the compound of formula I according to claim 13 represents 50% or more of the weight of the crystal composition.

19. A pharmaceutical composition comprising the crystalline form of the compound of formula I according to claim 13 .

20. A method for treating IDH1 mutation-induced cancer, comprising administering a therapeutically effective amount of the crystalline form of the compound of formula I according to claim 13 to a subject in need thereof.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Lianyungang Runzhong Pharmaceutical Co Ltd
• Centaurus Biopharma Co Ltd

Inventors

• Zhang Xiquan
• Xu Wenwei
• Li Mingming
• Kong Minmin
• Wu Shufeng
• Zhang Aiming

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/04 Primary

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

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/425

  Thiazoles · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title