Crystal forms of acrylic acid derivatives, preparation method therefor and use thereof

Patent metadata

Field	Value
Publication number	US-12522599-B2
Application number	US-202017610167-A
Country	US
Kind code	B2
Filing date	May 21, 2020
Priority date	May 24, 2019
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

Crystal forms A, B, C, D, E, F, G and H of a compound represented by formula I and a preparation method therefor, as well as medical uses for the various crystal forms and advantages thereof in various aspects.

First claim

The invention claimed is:

1 . A crystal form A of a compound of formula I,

wherein its X-ray powder diffraction pattern with Cu-Kα radiation comprises characteristic peaks at 2θ of 10.5±0.2°, 12.3±0.2°, 14.9±0.2°, 16.2±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, and 24.4±0.2° in degrees;
wherein the crystal form A is a monohydrate of the compound of formula I.

2 . A method for preparing the crystal form A according to claim 1 , selected from any one of the following methods:
method (1): adding the compound of formula I to a solvent to obtain a suspension, wherein the solvent is C1-C3 alcohol, water or a mixture thereof, stirring crystal slurry in the suspension at 5-50° C. for 1-7 days, separating solid, and drying it under vacuum at 20-60° C. for 8-24 hours to obtain crystal form A; or method (2): adding the compound of formula I to a C1-C3 alcohol to obtain a clear solution after dissolution, then adding water to precipitate to turbidity, stirring until solidification, separating solid, and drying it under vacuum at 20-60° C. for 8-24 hours to obtain crystal form A.

3 . The method for preparing the crystal form A according to claim 2 , wherein in method (1), the C1-C3 alcohol in the method (1) is one or more of methanol, ethanol, n-propanol, and isopropanol.

4 . The method for preparing the crystal form A according to claim 2 , wherein in method (2), the C1-C3 alcohol in the method (2) is one or more of methanol, ethanol, n-propanol, and isopropanol.

5 . The method for preparing the crystal form A according to claim 2 , wherein weight-volume ratio of the compound of formula I to the solvent in the method (1) is 1:2-1:10 (g/mL).

6 . The method for preparing the crystal form A according to claim 2 , wherein weight-volume ratio of the compound of formula I and the C1-C3 alcohol in the method (2) is 1:5-1:20 (g/mL).

7 . The method for preparing the crystal form A according to claim 2 , wherein weight-volume ratio of the compound of formula I to water in the method (2) is 1:3-1:100 (g/mL).

8 . A pharmaceutical composition, comprising a therapeutically effective amount of the crystal form A according to claim 1 .

9 . A method of treating a disease by downregulating estrogen receptor, comprising administering the crystal form A according to claim 1 to a subject in need thereof, wherein the disease is a cancer, the cancer is breast cancer.

10 . The method of treating a disease by downregulating estrogen receptor according to claim 9 , wherein the estrogen receptor is estrogen receptor α.

11 . A method of downregulating estrogen receptor, comprising administering the crystal form A according to claim 1 to a subject in need thereof.

12 . The method of downregulating estrogen receptor according to claim 11 , wherein the method is for downregulating an estrogen receptor α.

13 . A crystal form B of a compound of formula I,

wherein its X-ray powder diffraction pattern with Cu-Kα radiation comprises characteristic peaks at 2θ of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 16.2±0.2°, 16.7±0.2°, and 23.0±0.2° in degrees;
wherein the crystal form B is a monohydrate of the compound of formula I.

14 . A method for preparing the crystal form B according to claim 13 , comprising:
adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring crystal slurry at 5-40° C. for 0.5-36 hours, separating solid, and drying it under vacuum at 20-40° C. for 8-24 hours to obtain crystal form B.

15 . The method for preparing the crystal form B according to claim 14 , wherein the halogenated hydrocarbon is one or more of dichloromethane, dichloroethane, trichloromethane, and dibromomethane; or
weight-volume ratio of the compound of formula I to the water-saturated halogenated hydrocarbon solution is 1:3-1:4 (g/mL).

16 . A crystal form C of a compound of formula I,

wherein its X-ray powder diffraction pattern with Cu-Kα radiation comprises characteristic peaks at 2θ of 4.5±0.2°, 5.7±0.2°, 8.5±0.2°, 12.2±0.2°, 14.0±0.2°, 16.7±0.2°, 23.0±0.2° in degrees;
wherein the crystal form C is a monohydrate of the compound of formula I.

17 . A method for preparing the crystal form C according to claim 16 , comprising:
adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring crystal slurry at 5-40° C. for 2-7 days, separating solid, and drying it under vacuum at 20-40° C. for 8-24 hours to obtain crystal form C.

18 . The method for preparing the crystal form C according to claim 17 , wherein the halogenated hydrocarbon is one or more of dichloromethane, dichloroethane, trichloromethane, and dibromomethane; or
weight-volume ratio of the compound of formula I to the water-saturated halogenated hydrocarbon solution is 1:15-1:50 (g/mL).

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Zheng Jianfeng
• Zhang Liang
• Zhao Min
• Shi Zhenjuan
• Li Xufei
• Yang Zhiqing

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title