IP Library › Granted Patent US 12,365,665
Granted Patent B2
US 12,365,665 · App. 17/607,449 · Granted Jul 22, 2025

Solid form of diaminopyrimidine compound or hydrate thereof, preparation method therefor, and application thereof

Inventors: CheungLing Cheng (Beijing, CN); Yanping Zhao (Beijing, CN); Hongjun Wang (Beijing, CN); Zewang Feng (Beijing, CN); Huai Huang (Beijing, CN); Kai Liu (Beijing, CN); Xuelian Liu (Beijing, CN); Jianmei Pang (Beijing, CN); Nana Tian (Beijing, CN); Xichao Chen (Beijing, CN); Shenzhen Fu (Beijing, CN); Jie Meng (Beijing, CN); Liying Zhou (Beijing, CN); Yanan Liu (Beijing, CN)
Assignee: BEIJING TIDE PHARMACEUTICAL CO., LTD.
C07D401/12C07B2200/13
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Quick Facts
Patent No.
US 12,365,665
App. No.
17/607,449
Granted
Jul 22, 2025
Kind
B2
Abstract

The present invention relates to a solid form of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine or a hydrate thereof, a method for preparing the solid form, a pharmaceutical composition comprising the solid form, and a use of the solid form for the prevention or treatment of a disease modulated by P2X3 and/or P2X2/3 receptor antagonists.

Claims (78)

1. A crystalline form I of compound A anhydrate:

the crystalline form I has an X-Ray Powder Diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 19.8±0.2° and 20.3±0.2°.

2. A method for preparing the crystalline form I of compound A anhydrate according to claim 1 , comprising the following steps:

1) adding compound A to water, followed by addition of an acid, stirring to dissolve compound A and obtain a solution, which is optionally filtered to obtain a filtrate;

2) adding a base to the solution or filtrate obtained in step 1), and collecting the precipitated solid by filtration; and

3) adding the obtained solid to water and stirring, filtering to collect the solid, which is optionally dried to obtain crystalline form I;

alternatively, the method comprising dissolving compound A in a good solvent to form a solution, then adding an anti-solvent thereto, and stirring to allow the precipitation of a solid, which is filtered to obtain the crystalline form.

3. The method according to claim 2 , wherein the acid is acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid.

4. The method according to claim 2 , wherein the base is sodium hydroxide, potassium hydroxide or ammonia.

5. The method according to claim 2 , wherein the good solvent is a cyclic ether having 3-10 carbon atoms; and/or

the anti-solvent is a hydrocarbon having 5-10 carbon atoms or a linear ether having 2-6 carbon atoms.

6. The method according to claim 2 , wherein the good solvent is tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; and/or

the anti-solvent is dichloromethane, trichloromethane, n-hexane, n-heptane, toluene, diethyl ether, diisopropyl ether or methyl tert-butyl ether.

7. The method according to claim 2 , wherein the good solvent is tetrahydrofuran; and

the anti-solvent is n-heptane or methyl tert-butyl ether.

8. The method according to claim 2 , wherein the weight/volume ratio (g/mL) of compound A to the good solvent is 1:(30-120).

9. The method according to claim 2 , wherein the weight/volume ratio (g/mL) of compound A to the good solvent is 1:40 or 1:100.

10. The method according to claim 2 , wherein the volume ratio of the good solvent to the anti-solvent is 1:1 to 1:5.

11. A pharmaceutical composition comprising the crystalline form I of compound A anhydrate according to claim 1 , and one or more pharmaceutically acceptable carriers.

12. A method for the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist, comprising administering to a subject in need thereof the crystalline form I of compound A anhydrate according to claim 1 .

13. The method according to claim 12 , wherein the disease is selected from the group consisting of a urinary tract disease selected from reduced bladder capacity, frequent micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity; a pain disease selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine and cluster headaches, nerve injury, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury and pain associated with irritable bowel syndrome; a cardiovascular system disease; a respiratory disease selected from chronic obstructive pulmonary disease, asthma and bronchospasm; a gastrointestinal disease selected from irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic, and pain associated with gastrointestinal distension.

14. The method according to claim 13 , wherein the cardiovascular system disease is hypertension; and the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome.

15. The crystalline form I of compound A anhydrate according to claim 1 , wherein the crystalline form I has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2° and 20.3±0.2°.

16. The crystalline form I of compound A anhydrate according to claim 1 , wherein the crystalline form I has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 6.2±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 16.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.3±0.2°, 21.8±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1±0.2°, 26.2±0.2°, 26.5±0.2°, 27.8±0.2°, 28.5±0.2°, 29.3±0.2° and 30.6±0.2°.

17. The crystalline form I of compound A anhydrate according to claim 1 , wherein the crystalline form I has a DSC graph comprising endothermic/exothermic peaks at 245/255° C.

18. The crystalline form I of compound A anhydrate according to claim 1 , wherein in a thermogravimetric analysis, the crystalline form I has a weight loss of 0.1% when heated to 100-150° C.

19. A crystalline form,

wherein the crystalline form is selected from the group consisting of:

a crystalline form Il of compound A monohydrate:

wherein the crystalline form II has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 13.0±0.2°, 19.5±0.2°, 19.9±0.2° and 22.7±0.2°;

a crystalline form III of compound A hemihydrate:

wherein the crystalline form III has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 20.5±0.2° and 21.7±0.2°;

a crystalline form IV of compound A sesquihydrate:

wherein the crystalline form IV has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 17.2±0.2°, 21.3±0.2°, 24.1±0.2° and 27.9±0.2°;

a crystalline form V of compound A monohydrate:

wherein the crystalline form V has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 14.1±0.2°, 21.0±0.2° and 29.6±0.2°;

a crystalline form VI of compound A monohydrate:

wherein the crystalline form VI has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.4±0.2°, 12.1±0.2°, 16.6±0.2°, 20.7±0.2°, 22.8±0.2° and 27.3±0.2°;

a crystalline form VII of compound A sesquihydrate:

wherein the crystalline form VII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 13.1±0.2°, 19.9±0.2° and 20.2±0.2°; or

a crystalline form VIII of compound A hemihydrate:

wherein the crystalline form VIII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 13.0±0.2°, 16.8±0.2°, 19.4±0.2°, 21.7±0.2°, 22.9±0.2° and 27.4±0.2°.

20. The crystalline form according to claim 19 ,

wherein the crystalline form is selected from the group consisting of:

a crystalline form Il of compound A monohydrate:

wherein the crystalline form II has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 9.6±0.2°, 13.0±0.2°, 19.5±0.2°, 19.9±0.2° and 22.7±0.2°;

a crystalline form III of compound A hemihydrate:

wherein the crystalline form III has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 19.3±0.2°, 20.5±0.2°, 21.7±0.2° and 26.9±0.2°;

a crystalline form IV of compound A sesquihydrate:

wherein the crystalline form IV has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2° and 27.9±0.2°;

a crystalline form V of compound A monohydrate:

wherein the crystalline form V has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 9.4±0.2°, 11.9±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2° and 29.6±0.2°;

a crystalline form VI of compound A monohydrate:

wherein the crystalline form VI has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 15.4±0.2°, 16.6±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.8±0.2° and 27.3±0.2°;

a crystalline form VII of compound A sesquihydrate:

wherein the crystalline form VII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 13.1±0.2°, 16.9±0.2°, 19.9±0.2°, 20.2±0.2°, 24.9±0.2° and 28.8±0.2°; or

a crystalline form VIII of compound A hemihydrate:

wherein the crystalline form VIII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.3±0.2°, 13.0±0.2°, 16.8±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.9±0.2°, 25.8±0.2° and 27.4±0.2°.

21. The crystalline form according to claim 19 ,

wherein the crystalline form is selected from the group consisting of:

a crystalline form Il of compound A monohydrate:

wherein the crystalline form II has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 9.6±0.2°, 10.9±0.2°, 13.0±0.2°, 14.9±0.2°, 15.8±0.2°, 16.8±0.2°, 19.5±0.2°, 19.9±0.2°, 22.7±0.2°, 23.7±0.2°, 25.2±0.2°, 26.0±0.2°, 28.5±0.2°, 29.0±0.2°, 30.0±0.2° and 32.5±0.2°;

a crystalline form III of compound A hemihydrate:

wherein the crystalline form III has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 13.0±0.2°, 15.0±0.2°, 15.4±0.2°, 16.5±0.2°, 17.3±0.2°, 19.3±0.2°, 19.9±0.2°, 20.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.1±0.2°, 26.5±0.2°, 26.9±0.2°, 28.7±0.2° and 32.2±0.2°;

a crystalline form IV of compound A sesquihydrate:

wherein the crystalline form IV has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 14.3±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.2±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 27.9±0.2°, 31.2±0.2° and 31.7±0.2°;

a crystalline form V of compound A monohydrate:

wherein the crystalline form V has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 9.4±0.2°, 11.6±0.2°, 11.9±0.2°, 12.4±0.2°, 14.1±0.2°, 14.5±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.6±0.2°, 18.2±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 25.2±0.2°, 27.0±0.2° and 29.6±0.2°;

a crystalline form VI of compound A monohydrate:

wherein the crystalline form VI has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 13.4±0.2°, 14.7±0.2°, 15.4±0.2°, 16.6±0.2°, 17.4±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.1±0.2°, 22.8±0.2°, 23.6±0.2°, 26.0±0.2°, 27.3±0.2°, 28.0±0.2° and 30.4±0.2°;

a crystalline form VII of compound A sesquihydrate:

wherein the crystalline form VII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 9.4±0.2°, 10.8±0.2°, 13.1±0.2°, 15.4±0.2°, 16.9±0.2°, 18.8±0.2°, 19.9±0.2°, 20.2±0.2°, 22.2±0.2°, 23.2±0.2°, 24.9±0.2°, 26.4±0.2° and 28.8±0.2°; or

a crystalline form VIII of compound A hemihydrate:

wherein the crystalline form VIII has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 8.7±0.2°, 10.3±0.2°, 10.8±0.2°, 13.0±0.2°, 14.1±0.2°, 14.8±0.2°, 16.8±0.2°, 17.5±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.3±0.2°, 22.9±0.2°, 25.8±0.2°, 27.4±0.2°, 27.8±0.2°, 30.4±0.2° and 31.6±0.2°.

22. A pharmaceutical composition comprising any one of the crystalline forms of claim 19 , and one or more pharmaceutically acceptable carriers.

23. A method for the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist, comprising administering to a subject in need thereof any one of the crystalline forms according to claim 19 .

24. The method according to claim 23 , wherein the disease is selected from the group consisting of a urinary tract disease selected from reduced bladder capacity, frequent micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity; a pain disease selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine and cluster headaches, nerve injury, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury and pain associated with irritable bowel syndrome; a cardiovascular system disease; a respiratory disease selected from chronic obstructive pulmonary disease, asthma and bronchospasm; a gastrointestinal disease selected from irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic, and pain associated with gastrointestinal distension.

25. The method according to claim 24 , wherein the cardiovascular system disease is hypertension; and the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 29, 2021
From: CHENG, CHEUNGLING; ZHAO, YANPING; WANG, HONGJUN; FENG, ZEWANG; HUANG, HUAI; LIU, KAI; LIU, XUELIAN; PANG, JIANMEI; TIAN, NANA; CHEN, XICHAO; FU, SHENZHEN; MENG, JIE; ZHOU, LIYING; LIU, YANAN
To: BEIJING TIDE PHARMACEUTICAL CO., LTD.
Reel/Frame 057975/0406 →
Continuity (1)
Related Publication 20220204475A1 · Jun 30, 2022
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