Drug compound and purification methods thereof

Patent metadata

Field	Value
Publication number	US-10858386-B2
Application number	US-201916674786-A
Country	US
Kind code	B2
Filing date	Nov 5, 2019
Priority date	Aug 3, 2017
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

The invention provides a method of preparing a lyophilized pharmaceutical composition containing a compound described herein or a pharmaceutically-acceptable salt thereof. The process comprises dissolving the compound in a solvent comprising dimethylsulfoxide and optionally one or more co-solvents to form a solution, and then removing the solvent and any co-solvents by a freeze-drying process. Also provided by the invention are lyophilized pharmaceutical compositions and their use in medicine and in particular in the treatment of cancer.

First claim

What is claimed is:

1. A method of preparing a lyophilized pharmaceutical product, the method comprising removing a portion of a solvent by a freeze-drying process from a solution, thereby generating the lyophilized pharmaceutical product, wherein the solution comprises:
a) a compound of formula (1)

or a pharmaceutically acceptable salt thereof; and
b) the solvent, wherein the solvent comprises DMSO,

wherein the lyophilized pharmaceutical product comprises a compound of formula (2):

or a pharmaceutically-acceptable salt thereof, wherein:
R 1 is a 4-amino-2H-1λ 2 ,3,5-triazin-2-one or a carbamide, each of which is independently substituted or unsubstituted;
each R 2 and R 3 is independently alkyl, which is substituted or unsubstituted; or hydrogen; and
R 4 is hydrogen or an acyl group, each of which is independently substituted or unsubstituted.

2. The method of claim 1 , wherein the compound of formula (2) is

3. The method of claim 1 , wherein the compound of formula (2) is

4. The method of claim 1 , wherein the compound of formula (2) is

5. The method of claim 1 , wherein the compound of formula (2) is

6. The method of claim 1 , wherein the freeze-drying process comprises:
(a) a first freezing stage in which the solution is frozen by reducing a temperature of the solution to about −45° C. to form a frozen solution.

7. The method of claim 6 , wherein the freeze-drying process further comprises:
(b) a first warming stage in which the temperature of the solution is raised from about −45° C. to about 0° C., wherein the solution remains frozen when the temperature of the solution is about 0° C.

8. The method of claim 7 , wherein the freeze-drying process further comprises:
(c) a second freezing stage in which the temperature of the solution is lowered from about 0° C. to about −45° C.

9. The method of claim 8 , wherein the freeze-drying process further comprises:
(d) a primary drying stage in which the temperature of the solution is raised from about −45° C. to about −6° C., wherein the primary drying stage comprises a sublimation step in which the DMSO is removed by sublimation from the solution in a frozen state of the solution under reduced pressure to give a partially dried product.

10. The method of claim 9 , wherein the freeze-drying process further comprises:
(e) a secondary drying stage in which the temperature of the solution is raised from about −6° C. to about 40° C., wherein in the secondary drying stage the DMSO is removed by evaporation from the partially dried product in a non-frozen state under reduced pressure to give the lyophilized pharmaceutical product.

11. A method of preparing a lyophilized pharmaceutical product, the method comprising removing a portion of a solvent by a freeze-drying process from a solution, thereby generating the lyophilized pharmaceutical product, wherein the solution comprises:
a) a compound of formula (1)

or a pharmaceutically acceptable salt thereof; and
b) the solvent, wherein the solvent comprises DMSO,

wherein the lyophilized pharmaceutical product comprises a compound of formula (3):

or a pharmaceutically acceptable salt thereof, wherein R 1 is 4-amino-2H-1λ 2 ,3,5-triazin-2-one or a carbamide, each of which is independently substituted or unsubstituted.

12. The method of claim 11 , wherein the compound of formula (3) is

13. The method of claim 11 , wherein the compound of formula (3) is

14. The method of claim 11 , wherein the freeze-drying process comprises:
(a) a first freezing stage in which the solution is frozen by reducing a temperature of the solution to about −45° C. to form a frozen solution.

15. The method of claim 14 , wherein the freeze-drying process further comprises:
(b) a first warming stage in which the temperature of the solution is raised from about −45° C. to about 0° C., wherein the solution remains frozen when the temperature of the solution is about 0° C.

16. The method of claim 15 , wherein the freeze-drying process further comprises:
(c) a second freezing stage in which the temperature of the solution is lowered from about 0° C. to about −45° C.

17. The method of claim 16 , wherein the freeze-drying process further comprises:
(d) a primary drying stage in which the temperature of the solution is raised from about −45° C. to about −6° C., wherein the primary drying stage comprises a sublimation step in which the DMSO is removed by sublimation from the solution in a frozen state of the solution under reduced pressure to give a partially dried product.

18. The method of claim 17 , wherein the freeze-drying process further comprises:
(e) a secondary drying stage in which the temperature of the solution is raised from about −6° C. to about 40° C., wherein in the secondary drying stage the DMSO is removed by evaporation from the partially dried product in a non-frozen state under reduced pressure to give the lyophilized pharmaceutical product.

19. A method of preparing a lyophilized pharmaceutical product, the method comprising removing a portion of a solvent by a freeze-drying process from a solution, thereby generating the lyophilized pharmaceutical product, wherein the solution comprises:
a) a compound of formula (1)

or a pharmaceutically acceptable salt thereof; and
b) the solvent, wherein the solvent comprises DMSO,

wherein the lyophilized pharmaceutical product comprises a compound of formula (4):

or a pharmaceutically acceptable salt thereof, wherein R 1 is 4-amino-2H-1λ 2 ,3,5-triazin-2-one, which is substituted or unsubstituted; and R 5 is hydroxy or a nucleotide.

20. The method of claim 19 , wherein the nucleotide has the formula:

21. The method of claim 19 , wherein the compound of formula (4) is

22. The method of claim 19 , wherein the freeze-drying process comprises:
(a) a first freezing stage in which the solution is frozen by reducing a temperature of the solution to about −45° C. to form a frozen solution.

23. The method of claim 22 , where

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Joshi-Hangal Rajashree
• Davar Nipun
• Priebe Stephen R

Classifications

• C07H21/04 Primary

  with deoxyribosyl as saccharide radical · CPC title

• C07H19/173

  with 2-deoxyribosyl as the saccharide radical · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/7084 Primary

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title