# US 12,215,098 B2 · Solid form, crystalline form, and crystal form a of FXR agonist, and preparation method and application thereof

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- Number: US 12,215,098 B2
- Document ID: US12215098B2
- Status: Granted
- Kind: B2
- Application number: 17/297,271
- Filed: 2019-11-26
- Published: 2022-02-03
- Granted: 2025-02-04
- Earliest claimed: 2018-11-26
- Assignees: Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
- Applicants: Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
- Inventors: Xiaolin Li; Peng Li; Haiying He
- Web page: https://patentgrep.com/patent/US12215098B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

Disclosed are a solid form, a crystalline form, and crystal form A of a compound of formula (I) used as an FXR agonist, and a preparation method therefor. Also comprised is an application of the compound of formula (I) in preparation of a medication for treating nonalcoholic steatohepatitis (NASH).

## Claims

### Claim 1

A crystalline form of a compound of formula (I), which is crystal form A, characterized by X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles of 12.72±0.2°, and 25.27±0.2°;

### Claim 2 (depends on 1)

The crystal form A of the compound of formula (I) according to claim 1, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles of 11.86±0.2°, 12.72±0.2°, 16.15±0.2°, 17.40±0.2°, 19.72±0.2°, 24.18±0.2°, and 25.27±0.2°.

### Claim 3 (depends on 2)

The crystal form A of the compound of formula (I) according to claim 2, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles of 11.86±0.2°, 12.72±0.2°, 16.15±0.2°, 17.40±0.2°, 19.72±0.2°, 20.38±0.2°, 22.60±0.2°, 23.80±0.2°, 24.18±0.2°, and 25.27±0.2°.

### Claim 4 (depends on 3)

The crystal form A of the compound of formula (I) according to claim 3, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles of 11.86±0.2°, 12.72±0.2°, 13.67±0.2°, 16.15±0.2°, 17.40±0.2°, 19.72±0.2°, 20.38±0.2°, 22.60±0.2°, 23.80±0.2°, 24.18±0.2°, 25.27±0.2°, and 26.57±0.2°.

### Claim 5 (depends on 4)

The crystal form A of the compound of formula (I) according to claim 4, wherein the X-ray powder diffraction pattern is as shown in FIG. 1.

### Claim 6 (depends on 1)

The crystal form A of the compound of formula (I) according to claim 1, wherein the X-ray powder diffraction pattern is as shown in FIG. 5.

### Claim 7 (depends on 1)

The crystal form A of the compound of formula (I) according to claim 1, characterized by a differential scanning calorimetry curve having a starting point of the endothermic peak at 223.58° C.±3° C.

### Claim 8 (depends on 7)

The crystal form A of the compound of formula (I) according to claim 7, wherein the differential scanning calorimetry curve is as shown in FIG. 2.

### Claim 9 (depends on 1)

The crystal form A of the compound of formula (I) according to claim 1, characterized by a thermogravimetric analysis curve having a weight loss of up to 0.7427%±0.2% at 111.29° C.±3° C. and up to 3.6977%±0.2% at 202.79° C.±3° C.

### Claim 10 (depends on 9)

The crystal form A of the compound of formula (I) according to claim 9, wherein the thermogravimetric analysis curve is as shown in FIG. 3.

### Claim 11 (depends on 1)

A method for preparing the crystal form A of the compound of formula (I) according to claim 1, comprising:
(a) adding the compound of formula (I) to a solvent;
(b) stirring at 30 to 50° C. for 40 to 55 hours; and
(c) centrifugating, and then volatilizing the solvent to give the crystal form A of the compound of formula (I);
wherein the solvent is alcohol, tetrahydrofuran, water, acetone, acetonitrile, ethyl acetate, a mixed solvent of alcohol and water, or a mixed solvent of acetone and water.

### Claim 12 (depends on 11)

The preparation method according to claim 11, wherein the alcohol is selected from methanol, ethanol, isopropanol and n-propanol.

### Claim 13 (depends on 11)

The preparation method according to claim 11, wherein the solvent is a mixed solvent of alcohol and water, wherein the volume ratio of alcohol to water is 1:0.6 to 1:1.5.

### Claim 14 (depends on 11)

The preparation method according to claim 11, wherein the solvent is a mixed solvent of acetone and water, wherein the volume ratio of acetone to water is 1:1.5 to 1:2.5.

### Claim 15 (depends on 1)

A method of treating a FXR-related disease selected from metabolic syndrome, hepatobiliary disease, type 2 diabetes, and non-alcoholic fatty liver disease in a subject, comprising administering to the subject the crystal form A of the compound of formula (I) according to claim 1.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the FXR-related disease is non-alcoholic fatty liver disease.

### Claim 17 (depends on 1)

A method of improving hepatic steatosis, improving hepatic function, reducing hepatic damage, or improving hepatic fibrosis in a subject, comprising administering to the subject the crystal form A of the compound of formula (I) according to claim 1.