Phosphonamide ester compound, salt thereof, related crystal form thereof, preparation method therefor and use thereof

Patent metadata

Field	Value
Publication number	US-11186599-B2
Application number	US-201917047000-A
Country	US
Kind code	B2
Filing date	Jun 3, 2019
Priority date	Jun 12, 2018
Publication date	Nov 30, 2021
Grant date	Nov 30, 2021

Abstract

The present invention relates to compounds represented by formula (I) and formula (II) and a chiral synthesis and chiral isolation method therefor, further relating to a salt and crystal form of the compound represented by formula (I), a preparation method therefor, a pharmaceutical composition comprising the same, and use thereof in the preparation of a medicament used for the treatment of a viral infectious disease such as hepatitis B.

First claim

What is claimed is:

1. Crystalline form A of the fumarate salt of the compound of Formula (I),

wherein
the crystalline form A of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 5.1±0.2°, 6.4±0.2°, 16.3±0.2°, 18.7±0.2°, and 28.2±0.2°.

2. A method for preparing the crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 1 , comprising:
suspending the fumarate salt of the compound of Formula (I) in a solvent selected from the group consisting of ethanol, isopropanol, n-butanol, isopropyl acetate, isobutyl acetate, dimethyl carbonate, butanone, isopropyl ether, and propanol, stirring the resulting suspension for 8 hours at room temperature, and collecting the resulting solid; or
completely dissolving the fumarate salt of the compound of Formula (I) in ethanol until the resulting solution is clear, slowly adding dropwise a poor solvent selected from the group consisting of ethyl acetate, isopropyl acetate, petroleum ether, isopropyl ether, anisole, dichloromethane, acetonitrile and water at 20˜25° C., and collecting the resulting solid; or
completely dissolving the fumarate salt of the compound of Formula (I) in tetrahydrofuran until the resulting solution is clear, slowly adding dropwise a poor solvent selected from the group consisting of ethyl acetate, isopropyl acetate, isopropyl ether, anisole, dichloromethane, acetonitrile and water at 20˜25° C., and collecting the resulting solid; or
suspending the fumarate salt of the compound of Formula (I) in a solvent selected from the group consisting of methyl tert-butyl ether, petroleum ether, isopropyl ether, anisole, dichloromethane, n-heptane, n-hexane and cyclohexane, stirring at 60° C. for 6 hours, and collecting the resulting solid; or
completely dissolving the free base of the compound of Formula (I) with a 0.1 M fumaric acid solution in methanol until the resulting solution is clear, stirring at room temperature for 2 hours, removing the solvent, adding acetonitrile, stirring overnight at room temperature, and collecting the resulting solid.

3. Crystalline form B of the fumarate salt of the compound of Formula (I),

wherein
the crystalline form B of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 10.2±0.2°, 10.8±0.2°, 17.1±0.2°, 18.8±0.2°, and 21.7±0.2°.

4. A method for preparing the crystalline form B of the fumarate salt of the compound of Formula (I) according to claim 3 , comprising:
suspending the fumarate salt of the compound of Formula (I) in methanol or tetrahydrofuran, stirring the resulting suspension for 8 hours at room temperature, and collecting the resulting solid.

5. Crystalline form C of the fumarate salt of the compound of Formula (I),

wherein
the crystalline form C of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 4.3±0.2°, 6.8±0.2°, 14.3±0.2°, 18.8±0.2°, and 27.9±0.2°.

6. A method for preparing the crystalline form C of the fumarate salt of the compound of Formula (I) according to claim 5 ,
comprising:
suspending the fumarate salt of the compound of Formula (I) in anisole, stirring the resulting suspension for 8 hours at room temperature, and collecting the resulting solid.

7. A method for prophylaxis or treating viral infectious diseases, comprising administering to a subject in need thereof the crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 1 .

8. A method for prophylaxis or treating viral infectious diseases, comprising administering to a subject in need thereof the crystalline form B of the fumarate salt of the compound of Formula (I) according to claim 3 .

9. A method for prophylaxis or treating viral infectious diseases, comprising administering to a subject in need thereof the crystalline form C of the fumarate salt of the compound of Formula (I) according to claim 5 .

10. A pharmaceutical composition, comprising:
i) the crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 1 ; and
ii) one or more pharmaceutically acceptable carriers.

11. A pharmaceutical composition, comprising:
i) the crystalline form B of the fumarate salt of the compound of Formula (I) according to claim 3 ; and
ii) one or more pharmaceutically acceptable carriers.

12. A pharmaceutical composition, comprising:
i) the crystalline form C of the fumarate salt of the compound of Formula (I) according to claim 5 ; and
ii) one or more pharmaceutically acceptable carriers.

13. The crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 1 , wherein the crystalline form A of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 5.1±0.2°, 6.4±0.2°, 14.7±0.2°, 15.3±0.2°, 16.3±0.2°, 18.0±0.2°, 18.7±0.2°, 19.2±0.2°, 28.2±0.2°, and 29.6±0.2°.

14. The crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 13 , wherein the crystalline form A of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 5.1±0.2, 6.4±0.2°, 12.9±0.2°, 14.7±0.2°, 15.3±0.2°, 16.3±0.2°, 18.0±0.2°, 18.7±0.2°, 18.9±0.2°, 19.2±0.2°, 20.0±0.2°, 20.7±0.2°, 22.2±0.2°, 24.0±0.2°, 24.9±0.2°, 25.3±0.2°, 27.8±0.2°, 28.2±0.2°, and 29.6±0.2°.

15. The crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 14 , wherein the crystalline form A of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks as shown in FIG. 1 .

16. The crystalline form A of the fumarate salt of the compound of Formula (I) according to claim 15 , wherein the crystalline form A of the fumarate salt of the compound of Formula (I) has the following cell parameters:
Cell size:
a=13.6818(8) Å
b=6.3963(4) Å
c=17.2967(13) Å
α/°=90
β/°=96.113(6)
γ/°=90
Cell volume: 1505.06 (17) Å 3
Crystal system: monoclinic system
Space group: P2 1
Number of intramolecular asymmetric units: Z=2.

17. The crystalline form B of the fumarate salt of the compound of Formula (I) according to claim 3 , wherein the crystalline form B of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of 9.7±0.2°, 10.2±0.2°, 10.8±0.2°, 14.7±0.2°, 17.1±0.2°, 18.1±0.2°, 18.8±0.2°, 19.2±0.2°, 20.6±0.2°, and 21.7±0.2°.

18. The crystalline form B of the fumarate salt of the compound of Formula (I) according to claim 17 , wherein the crystalline form B of the fumarate salt of the compound of Formula (I) has an XRPD pattern comprising characteristic peaks at diffraction angles (20) of 9.7±0.2°, 10.2±0.2°, 10.8±0.2°, 11.8±0.2°, 13.2±0.2°, 13.8±0.2°, 14.7±0.2°, 16.1±0.2°, 17.1±0.2°, 18.1±0.2°, 18.8±0.2°, 19.2±0.2, 20.6±0.2°, 21.7±0.2°, 22.3±0.2°, 23.8±0.2°, 26.7±0.2°, 27.0±0.2°, 27.5±0.2°, and 29.3±0.2°.

19. The crystalline form B of the fumarate salt of the compound of Formula (I) according to claim 1

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Tian Qiang
• Wang Tianming
• Liu Wei
• Zhang Baolei
• Zhao Mingliang
• Liang Yufeng
• Cai Jiaqiang
• Wang Lichun
• Wang Jingyi

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07F9/65616 Primary

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• C07F9/025

  Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds (of natural phosphatides C07F9/103; phosphines C07F9/5095) · CPC title

• A61P31/18

  for HIV · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title