# US 2020/0399272 A1 · Crystal form of 2-(6-methyl-pyridin-2-yl)-3-yl-[6-amido-quinolin-4-yl]-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazole, preparation method therefor and pharmaceutical composition thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2020/0399272 A1 - Document ID: US20200399272A1 - Status: Published application - Kind: A1 - Application number: 16/495,037 - Filed: 2017-03-17 - Published: 2020-12-24 - Earliest claimed: 2017-03-17 - Assignees: Hangzhou SoliPharma Co., Ltd. - Applicants: Hangzhou SoliPharma Co., Ltd. - Inventors: Xiaohong SHENG; Xiaoxia SHENG; Jing WANG - Web page: https://patentgrep.com/patent/US20200399272A1 ## CPC - C07D 487/04: Ortho-condensed systems - A61K 31/4162: condensed with heterocyclic ring systems - A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings - A61P 35/00: Antineoplastic agents - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract The present invention relates to a crystal form of 2-(6-methyl-pyridin-2-yl)-3-(6-amido-quinolin-4-yl)-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazole (Galunisertib or LY2157299), represented by formula (I). Compared with the known solid form of Galunisertib, the crystal form of the present invention has advantages in terms of solubility, hygroscopicity, crystal stability, morphology and the like. The present invention also relates to a process of preparing the crystal forms of Galunisertib, a pharmaceutical composition thereof and a use thereof in the preparation of a medicament for the prevention and/or treatment of diseases associated with TGF-beta. ## Claims ### Claim at position 1 -24. (canceled) ### Claim 25 Galunisertib Form 1 having the structure shown in formula (I) below, wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the galunisertib Form 1, has the following characteristic peaks: 10.2°±0.2°, 14.6°±0.2°, 15.8°±0.2°, 19.0°±0.2°, 19.4°±0.2°, and 21.9°±0.2°. ### Claim 26 (depends on 25) The galunisertib Form 1 according to claim 25, wherein the X-ray powder diffraction pattern of the galunisertib Form 1, expressed as 2θ angles, has the following characteristic peaks: 10.2°±0.2°, 11.2°±0.2°, 12.4°±0.2°, 14.6°±0.2°, 15.8°±0.2°, 16.8°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.9°±0.2°, 23.2°±0.2°, and 25.1°±0.2°. ### Claim 27 (depends on 25) The galunisertib Form 1 according to claim 25, wherein the X-ray powder diffraction pattern of Form 1 is substantially as shown in FIG. 6. ### Claim 28 (depends on 25) A method of preparing the galunisertib Form 1 according to claim 25, the method comprising any one of the following methods: (1) forming a solution of galunisertib in a co-solvent, adding the solution dropwise to an anti-solvent, stirring for crystallization, separating crystals, and drying to obtain the galunisertib Form 1; wherein: the co-solvent is a C3 to C4 ketone; the weight to volume ratio of galunisertib to the co-solvent is from 5 mg:1 mL to 40 mg:1 mL; the anti-solvent is selected from the group consisting of a C4 to C6 ether, n-heptane, and any mixture thereof, the stirring time is 0.5 to 2 hours; and the stirring is at 0° C. to 5° C.; or (2) heating galunisertib monohydrate, and then cooling to room temperature to obtained the galunisertib Form 1; the heating is up to 130° C. to 180° C.; the heating is at a rate of 1° C./min to 50° C./min, more preferably 1° C./min to 10° C./min; and the cooling is at a rate of 1° C./min to 50° C./min. ### Claim 29 Galunisertib Form 2 having the structure shown in formula (I) below, wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the galunisertib Form 1, has the following characteristic peaks: 7.9°±0.2°, 11.7°±0.2°, 12.9°±0.2°, 14.7°±0.2°, 20.5°±0.2°, and 21.9°±0.2°. ### Claim 30 (depends on 29) The galunisertib Form 2 according to claim 29, wherein the X-ray powder diffraction pattern of the galunisertib Form 2, expressed as 2θ angles, has the following characteristic peaks: 7.9°±0.2°, 11.7°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 16.0°±0.2°, 18.5°±0.2°, 20.5°±0.2°, 21.9°±0.2°, 22.3°±0.2°, and 25.6°±0.2°. ### Claim 31 (depends on 29) The galunisertib Form 2 according to claim 29, wherein the X-ray powder diffraction pattern of the galunisertib Form 2 is substantially as shown in FIG. 10. ### Claim 32 (depends on 29) A method of preparing the galunisertib Form 2 according to claim 29, the method comprising any one of the following methods: (1) forming a solution of galunisertib in a solvent, evaporating to dryness to obtain the galunisertib Form 2; wherein: the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, n-propanol, isopropyl acetate, and any mixture thereof; the weight to volume ratio of galunisertib to the solvent is from 2.5 mg:1 mL to 12.5 mg:1 mL; the evaporation is at 25° C. to 40° C.; and the evaporation is atmospheric evaporation or reduced-pressure evaporation; (2) forming a suspension of the galunisertib Form 1 in a solvent, stirring for crystallization, separating crystals and drying to obtain the galunisertib Form 2; wherein: the solvent is tetrahydrofuran or a mixture of isopropyl acetate and toluene; the weight to volume ratio of the galunisertib Form 1 to the solvent is from 10 mg:1 mL to 100 mg:1 mL; the stirring is for 3 to 7 days; the stirring is under 25° C. to 60° C.; or (3) forming a solution of galunisertib in tetrahydrofuran, stirring and cooling for crystallization, separating crystals and drying to obtain the galunisertib Form 2; the solution is formed at 50° C. to 55° C.; the weight to volume ratio of galunisertib to tetrahydrofuran is from 20 mg:1 mL to 30 mg:1 mL; the stirring is at 0° C. to 25° C.; and the stirring time is 0.5 to 5 hours. ### Claim 33 Galunisertib Form 3 having the structure shown in formula (I) below, wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the galunisertib Form 3, has the following characteristic peaks: 8.6°±0.2°, 12.3°±0.2°, 14.5°±0.2°, 17.9°±0.2°, 19.4°±0.2°, and 21.0°±0.2°. ### Claim 34 (depends on 33) The galunisertib Form 3 according to claim 33, wherein the X-ray powder diffraction pattern of the galunisertib Form 3, expressed as 2θ angles, has the following characteristic peaks: 8.6°±0.2°, 10.0°±0.2°, 11.9°±0.2°, 12.3°±0.2°, 14.5°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 19.4°±0.2°, 20.4°±0.2°, 21.0°±0.2°, and 21.9°±0.2°. ### Claim 35 (depends on 33) The Form 3 according to claim 33, wherein the X-ray powder diffraction pattern of the galunisertib Form 3 is substantially as shown in FIG. 14. ### Claim 36 (depends on 33) A method of preparing the galunisertib Form 3 according to claim 33, the method comprising any one of the following methods: (1) forming a solution of galunisertib in acetonitrile, evaporating to dryness to obtain the galunisertib Form 3; wherein: the weight to volume ratio of galunisertib to acetonitrile is from 2.5 mg:1 mL to 20 mg:1 mL; and the evaporation is reduced-pressure evaporation, at 30° C. to 40° C.; (2) forming a suspension of the galunisertib Form 1 in a solvent, stirring for crystallization, separating crystals and drying to obtain the galunisertib Form 3; wherein: the solvent is selected from the group consisting of a C3 to C4 ester, acetonitrile, a C3 to C4 ketone, a C4 to C6 ether, and any mixture thereof, the weight to volume ratio of the galunisertib Form 1 to the solvent is from 10 mg:1 mL to 100 mg:1 mL; the stirring time is 3 to 7 days; and the stirring is at 4° C. to 40° C.; (3) forming a solution of galunisertib in a solvent, stirring and cooling for crystallization, separating crystals and drying to obtain the galunisertib Form 3; wherein: the solvent is selected from the group consisting acetonitrile, a mixture of acetonitrile and ethyl acetate, and a mixture of acetonitrile and methyl tert-butyl ether; the solution is formed at 50° C. to 60° C.; the weight to volume ratio of galunisertib to the solvent is from 10 mg:1 mL to 50 mg:1 mL; the stirring is at 0° C. to 5° C.; and the stirring is for 1 to 3 hr; or (4) forming a solution of galunisertib in a co-solvent, adding an anti-solvent, stirring for crystallization, separating crystals and drying to obtain the galunisertib Form 3; wherein: the co-solvent is acetonitrile or ethyl acetate; the weight to volume ratio of galunisertib to the co-solvent is from 5 mg:1 mL to 20 mg:1 mL; the anti-solvent is a C4 to C6 ether; the stirring time is 0.5 to 2 hours; and the stirring time is at 0° C. to 5° C. ### Claim 37 Galunisertib Form 4 having the structure shown in formula (I) below, wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the galunisertib Form 4, has the following characteristic peaks: 5.9°±0.2°, 11.7°±0.2°, 12.2°±0.2°, 14.1°±0.2°, 16.4°±0.2°, and 21.8°±0.2°. ### Claim 38 (depends on 37) The galunisertib Form 4 according to claim 37, wherein the X-ray powder diffraction pattern of the galunisertib Form 4, expressed as 2θ angles, has the following characteristic peaks: 5.9°±0.2°, 11.7°±0.2°, 12.2°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 16.4°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 20.0°±0.2°, 21.8°±0.2°, 22.4°±0.2°, and 26.1°±0.2°. ### Claim 39 (depends on 37) The Form 4 according to claim 37, wherein the X-ray powder diffraction pattern of the galunisertib Form 4 is substantially as shown in FIG. 18. ### Claim 40 (depends on 37) A method of preparing the galunisertib Form 4 according to claim 37, the method comprising any one of the following methods: (1) forming a suspension of the galunisertib Form 1 in a solvent, stirring for crystallization, separating crystals and drying to obtain the galunisertib Form 4; wherein: the solvent is selected from the group consisting methanol, a mixture of methanol and ethyl acetate, and a mixture of ethanol and n-heptane; the weight to volume ratio of the galunisertib Form 1 to the solvent is from 10 mg:1 mL to 100 mg:1 mL; the stirring is for 3 to 7 days; and the stirring is under 4° C. to 60° C.; (2) forming a solution of galunisertib in a solvent, stirring and cooling for crystallization, separating crystals and drying to obtain the galunisertib Form 4; wherein: the solvent is selected from the group consisting of methanol, a mixture of methanol and methyl tert-butyl ether, and a mixture of methanol and isopropyl acetate; the solution is formed at 50° C. to 55° C.; the weight to volume ratio of galunisertib to the solvent is from 10 mg:1 mL to 50 mg:1 mL; the stirring is at 0° C. to 5° C.; and the stirring time is 0.5 to 3 hours; or (3) forming a solution of galunisertib in a co-solvent, adding an anti-solvent, stirring for crystallization, separating crystals and drying to obtain the galunisertib Form 4; wherein: the co-solvent is a C1 to C4 alcohol; the weight to volume ratio of galunisertib to the co-solvent is from 5 mg:1 mL to 30 mg:1 mL; the anti-solvent is diisopropyl ether or n-heptane; the stirring time is 0.5 to 2 hours; and the stirring time is at 0° C. to 5° C. ### Claim 41 Galunisertib Form 7 having the structure shown in formula (I) below, wherein the galunisertib Form 7 has 0.5 to 1.0 mole of water, and wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the galunisertib Form 7, has the following characteristic peaks: 7.0°±0.2°, 8.6°±0.2°, 14.2°±0.2°, 16.7°±0.2°, 21.4°±0.2°, and 23.4°±0.2°. ### Claim 42 (depends on 41) The galunisertib Form 7 according to claim 41, wherein the X-ray powder diffraction pattern of the galunisertib Form 7, expressed as 2θ angles, has the following characteristic peaks: 7.0°±0.2°, 8.6°±0.2°, 12.1°±0.2°, 14.2°±0.2°, 16.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 21.0°±0.2°, 21.4°±0.2°, 22.4°±0.2°, 23.4°±0.2°, and 25.5°±0.2°. ### Claim 43 (depends on 41) The galunisertib Form 7 according to claim 41, wherein the X-ray powder diffraction pattern of the galunisertib Form 7 is substantially as shown in FIG. 25. ### Claim 44 (depends on 41) A method of preparing the galunisertib Form 7 according to claim 41, the method comprising: forming a solution of galunisertib in water-saturated trichloromethane, evaporating to dryness to obtain the galunisertib Form 7; wherein: the weight to volume ratio of galunisertib to water-saturated trichloromethane is from 10 mg:1 mL to 25 mg:1 mL; the evaporation is atmospheric pressure evaporation or reduced-pressure evaporation; and the evaporation is at 25° C. to 40° C. ### Claim 45 (depends on 25) A pharmaceutical composition comprises a therapeutically effective amount of the galunisertib Form 1 according to claim 25, and at least one pharmaceutically acceptable carrier or additive. ### Claim 46 (depends on 25) A method of treating one or more diseases caused by abnormal TGF-β activity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the galunisertib Form 1 according to claim 25, or a pharmaceutical composition thereof, wherein the one or more diseases caused by abnormal TGF-β activity comprises a disease selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease. ### Claim 47 (depends on 29) A pharmaceutical composition comprises a therapeutically effective amount of the galunisertib Form 2 according to claim 29, and at least one pharmaceutically acceptable carrier or additive. ### Claim 48 (depends on 29) A method of treating one or more diseases caused by abnormal TGF-β activity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the galunisertib Form 2 according to claim 29, or a pharmaceutical composition thereof, wherein the one or more diseases caused by abnormal TGF-β activity comprises a disease selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease. ### Claim 49 (depends on 33) A pharmaceutical composition comprises a therapeutically effective amount of the galunisertib Form 3 according to claim 33, and at least one pharmaceutically acceptable carrier or additive. ### Claim 50 (depends on 33) A method of treating one or more diseases caused by abnormal TGF-β activity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the galunisertib Form 3 according to claim 33, or a pharmaceutical composition thereof, wherein the one or more diseases caused by abnormal TGF-β activity comprises a disease selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease. ### Claim 51 (depends on 37) A pharmaceutical composition comprises a therapeutically effective amount of the galunisertib Form 4 according to claim 37, and at least one pharmaceutically acceptable carrier or additive. ### Claim 52 (depends on 37) A method of treating one or more diseases caused by abnormal TGF-β activity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the galunisertib Form 4 according to claim 37, or a pharmaceutical composition thereof, wherein the one or more diseases caused by abnormal TGF-β activity comprises a disease selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease. ### Claim 53 (depends on 41) A pharmaceutical composition comprises a therapeutically effective amount of the galunisertib Form 7 according to claim 41, and at least one pharmaceutically acceptable carrier or additive. ### Claim 54 (depends on 41) A method of treating one or more diseases caused by abnormal TGF-β activity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the galunisertib Form 7 according to claim 41, or a pharmaceutical composition thereof, wherein the one or more diseases caused by abnormal TGF-β activity comprises a disease selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease.