Crystal form of tenofovir prodrug, preparation method thereof, and method of use thereof

Patent metadata

Field	Value
Publication number	US-9840525-B2
Application number	US-201515326126-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Jul 21, 2014
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

A crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate of formula (I) is provided. Also provided is a preparation method and method of using the crystal form. Specifically, a crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate of formula (I) having an X-ray powder diffraction (XRPD) spectrum including diffraction peaks at 2θ±0.20° of 5.08, 12.44, 13.18, 22.37, 23.37 and 28.56 is provided. The crystal form provided herein has high bioavailability, significant efficacy, good stability, high yield and high purity, and contributes to the selection and design of a drug administration route and the determination of process parameters of a pharmaceutical preparation, thereby improving drug production quality.

First claim

What is claimed is:

1. A crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I):

the crystal form having a characteristic X-ray powder diffraction (XRPD) spectrum comprising diffraction peaks at 2θ±0.20° of 5.08, 12.44, 13.18, 22.37, 23.37, and 28.56.

2. The crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 1 , wherein the XRPD spectrum comprises diffraction peaks at 2θ±0.20° of 5.08, 7.42, 10.15, 12.44, 13.18, 22.37, 23.37, and 28.56.

3. The crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 1 , wherein the crystal form has a differential scanning calorimetry (DSC) spectrum comprising an endothermic melting peak at 110.9 ° C.

4. The crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 1 , having an XRPD spectrum as shown in FIG. 1 .

5. A preparation method of the crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 1 , wherein the preparation method comprises:
(a) dissolving any form of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate in an organic solvent under heating to obtain a solution of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate;
(b) cooling the solution of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate to precipitate a crystal; and
(c) filtering the crystal to obtain the target crystal form.

6. The preparation method according to claim 5 , wherein the organic solvent is selected from the group consisting of acetonitrile, anhydrous methanol, anhydrous ethanol, isopropanol, anhydrous methanol/n-heptane, anhydrous ethanol/n-heptane, isopropanol/n-heptane, anhydrous methanol/methyl tert-butyl ether, anhydrous ethanol/methyl tert-butyl ether, isopropanol/methyl tert-butyl ether, anhydrous methanol/isopropyl ether, anhydrous ethanol/isopropyl ether, isopropanol/isopropyl ether, anhydrous methanol/diethyl ether, anhydrous ethanol/diethyl ether and isopropanol/diethyl ether.

7. The preparation method according to claim 5 , wherein the 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate is dissolved in the organic solvent at a temperature of 30° C. to a reflux temperature.

8. The preparation method according to claim 5 , wherein the solution of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate is cooled to a temperature of −40° C. to 40° C.

9. A pharmaceutical composition comprising the crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 1 , optionally further comprising a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9 , wherein the composition is formulated for oral administration or injection.

11. The pharmaceutical composition according to claim 9 , wherein the composition is formulated as a tablet, capsule, dispersion or suspension.

12. The crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 2 , wherein the XRPD spectrum further comprises diffraction peaks at 2θ±0.20° of 16.35, 18.23, 21.36, 25.00, and 31.68.

13. The preparation method according to claim 6 , wherein the organic solvent is anhydrous methanol/n-heptane.

14. The preparation method according to claim 7 , wherein the temperature is the reflux temperature.

15. The preparation method according to claim 8 , wherein the temperature is 0° C. to 10° C.

16. The pharmaceutical composition according to claim 10 , being formulated for oral administration.

17. The pharmaceutical composition according to claim 11 , being formulated as a tablet.

18. A pharmaceutical composition comprising the crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate of formula (I) according to claim 4 , optionally further comprising a pharmaceutically acceptable carrier.

19. A method of treating acquired immune deficiency syndrome (AIDS) or hepatitis B virus (HBV) in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 9 .

20. A method of treating acquired immune deficiency syndrome (AIDS) or hepatitis B virus (HBV) in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 18 .

Assignees

• Jiangsu Hansoh Pharmaceutical Group Co Ltd

Inventors

• Chen Ming
• Tian Chengyao
• Zhao Mingli
• Yu Jun
• Yang Baohai
• Lu Aifeng

Classifications

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61P31/18

  for HIV · CPC title

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61P31/20

  for DNA viruses · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title