# US 11,111,248 B2 · 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

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- Number: US 11,111,248 B2
- Document ID: US11111248B2
- Status: Granted
- Kind: B2
- Application number: 16/495,037
- Filed: 2017-03-17
- Published: 2020-12-24
- Granted: 2021-09-07
- 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/US11111248B2

## 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 1

Crystalline Form 1 of galunisertib of formula (I):
wherein the crystalline Form 1 is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at angles (° 2θ) of 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 2 (depends on 1)

The crystalline Form 1 according to claim 1, wherein the crystalline Form 1 is further characterized by a powder X-ray diffraction pattern comprising additional diffraction peaks at angles (° 2θ) of 11.2°±0.2°, 12.4°±0.2°, 16.8°±0.2°, 19.8°±0.2°, 23.2°±0.2°, and 25.1°±0.2°.

### Claim 3 (depends on 1)

The crystalline Form 1 according to claim 1, wherein the crystalline Form 1 is further characterized by a powder X-ray diffraction pattern as shown in FIG. 6.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or additive and a therapeutically effective amount of the crystalline Form 1 according to claim 1.

### Claim 5 (depends on 4)

The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a dosage form selected from the group consisting of an aerosol, a capsule, a cream, an injectable solution, an ointment, a powder, a suppository, a suspension, a syrup, and a tablet.

### Claim 6 (depends on 1)

A method for treating a disease in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the crystalline Form 1 according to claim 1;
wherein the disease is caused by abnormal transforming growth factor beta activity in the subject; and
wherein the disease is selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease.

### Claim 7 (depends on 4)

A method for treating a disease in a subject, wherein the method comprises administering to the subject in need thereof the pharmaceutical composition according to claim 4;
wherein the disease is caused by abnormal transforming growth factor beta activity in the subject; and
wherein the disease is selected from the group consisting of a cancer, a pre-cancer, a kidney disease, fibrosis, and an eye disease.

### Claim 8 (depends on 1, 7)

The method according to claim 7, wherein the pharmaceutical composition comprises 0.5 mg to 500 mg of the crystalline Form 1 according to claim 1.

### Claim 9 (depends on 1, 8)

The method according to claim 8, wherein the pharmaceutical composition comprises 150 mg of the crystalline Form 1 according to claim 1.

### Claim 10 (depends on 1, 8)

The method according to claim 8, wherein the pharmaceutical composition comprises 20 mg of the crystalline Form 1 according to claim 1.

### Claim 11 (depends on 7)

The method according to claim 7, wherein the disease is a cancer.

### Claim 12 (depends on 7)

The method according to claim 7, wherein the disease is a pre-cancer.

### Claim 13 (depends on 7)

The method according to claim 7, wherein the disease is a kidney disease.

### Claim 14 (depends on 7)

The method according to claim 7, wherein the disease is fibrosis.

### Claim 15 (depends on 7)

The method according to claim 7, wherein the disease is an eye disease.

### Claim 16 (depends on 7)

The method according to claim 7, wherein the subject is a human.

### Claim 17 (depends on 1)

A process for preparing the crystalline Form 1 according to claim 1, wherein the process comprises the following steps:
(1) forming a solution of galunisertib dissolved in a co-solvent selected from the group consisting of acetone and methyl ethyl ketone, or a mixture thereof;
(2) adding the solution provided in step (1) dropwise to an anti-solvent selected from the group consisting of n-heptane, methyl tert-butyl ether, diethyl ether, and diisopropyl ether, or a mixture thereof, to provide a suspension;
(3) stirring the suspension provided in step (2) at a temperature in the range of 0° C. to 5° C. for a period of 0.5 hour to 2 hours, to afford a precipitate;
(4) crystallizing the precipitate provided in step (3); and
(5) drying the crystal provided in step (4) to obtain the crystalline Form 1 according to claim 1.

### Claim 18 (depends on 17)

The process according to claim 17, wherein the mass to volume ratio of galunisertib to the co-solvent is in the range of 5 mg:1 mL to 40 mg:1 mL.

### Claim 19 (depends on 1)

A process for preparing the crystalline Form 1 according to claim 1, wherein the process comprises the following steps:
(1) heating galunisertib monohydrate to a temperature in the range of 130° C. to 180° C. at a rate in the range of 1° C./minute to 50° C./minute; and
(2) cooling to room temperature at a rate in the range of 1° C./minute to 50° C./minute, to obtain the crystalline Form 1 according to claim 1.

### Claim 20 (depends on 19)

The process according to claim 19, wherein the heating galunisertib monohydrate to a temperature in the range of 130° C. to 180° C. in step (1) is performed at a rate in the range of 1° C./minute to 10° C./minute.