Polymorophs of 5-aza-4′-thio-2′-deoxycytidine

Patent metadata

Field	Value
Publication number	US-11447472-B2
Application number	US-202117384345-A
Country	US
Kind code	B2
Filing date	Jul 23, 2021
Priority date	Jul 23, 2020
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

The present disclosure provides crystalline polymorphs of 5-aza-4′-thio-2′-deoxycytidine. The crystalline polymorphs may be formulated in a pharmaceutical composition, optionally in combination with an additional chemotherapeutic agent. The crystalline polymorphs are useful to treat various diseases including blood cancers, such as myelodysplastic syndrome and leukemia. A process for preparing the crystalline polymorphs of 5-aza-4′-thio-2′-deoxycytidine is also disclosed. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A crystalline polymorph of 5-aza-4′-thio-2′-deoxycytidine, wherein the crystalline polymorph has a powder X-ray diffraction pattern that contains peaks at about 8°, about 13°, about 15°, about 17°, about 19°, about 22°, about 23° about 26°, about 28°, about 29°, about 31°, about 33°, and about 37° 2θ.

2. The crystalline polymorph of claim 1 , wherein the crystalline polymorph has an X-ray powder diffraction pattern that is substantially similar to, or the same as, the X-ray powder diffraction pattern shown in FIG. 11 .

3. A pharmaceutical composition comprising an effective amount of the crystalline polymorph of claim 1 and a pharmaceutically acceptable carrier.

4. An 5-aza-4′-thio-2′-deoxycytidine compound consisting of the crystalline polymorph of claim 1 .

5. A crystalline polymorph of 5-aza-4′-thio-2′-deoxycytidine, wherein the crystalline polymorph has a powder X-ray diffraction pattern that contains peaks at about 6°, about 12°, about 13°, about 14°, about 16°, about 18°, about 20°, about 21°, about 22°, about 26°, about 27°, about 29°, about 30°, about 33°, about 35°, about 36°, about 39°, and about 41° 2θ.

6. The crystalline polymorph of claim 5 , which exhibits an X-ray powder diffraction pattern substantially similar to, or the same as, the X-ray powder diffraction pattern shown in FIG. 16 .

7. A pharmaceutical composition comprising an effective amount of the crystalline polymorph of claim 5 and a pharmaceutically acceptable carrier.

8. An 5-aza-4′-thio-2′-deoxycytidine compound consisting of the crystalline polymorph of claim 5 .

9. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the crystalline polymorph of claim 1 .

10. The method of claim 9 , wherein the cancer is a blood cancer.

11. The method of claim 10 , wherein the blood cancer is selected from the group consisting of non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and solitary myeloma.

12. The method of claim 9 , wherein the cancer is a solid cancer.

13. The method of claim 9 , wherein administering is via a treatment cycle.

14. The method of claim 13 , wherein each treatment cycle includes administering the effective amount of the compound for a time period of from about 4 days to about 6 days.

15. The method of claim 9 , wherein the administering is via a course of treatment comprising:
a first treatment cycle that includes administering the effective amount of the crystalline polymorph for a time period of from about 4 days to about 6 days;
a first rest period that includes abstaining from administering the crystalline polymorph for a time period of about 1 day to about 3 days;
a second treatment cycle that includes administering the effective amount of the crystalline polymorph for a time period of from about 4 days to about 6 days; and
a second rest period that includes abstaining from administering the crystalline polymorph for a time period of at least about 8 days.

16. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the crystalline polymorph of claim 5 .

17. The method of claim 16 , wherein the cancer is a blood cancer.

18. The method of claim 17 , wherein the blood cancer is selected from the group consisting of non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and solitary myeloma.

19. The method of claim 16 , wherein the cancer is a solid cancer.

20. The method of claim 16 , wherein administering is via a treatment cycle.

21. The method of claim 20 , wherein each treatment cycle includes administering the effective amount of the compound for a time period of from about 4 days to about 6 days.

22. The method of claim 16 , wherein the administering is via a course of treatment comprising:
a first treatment cycle that includes administering the effective amount of the crystalline polymorph for a time period of from about 4 days to about 6 days;
a first rest period that includes abstaining from administering the crystalline polymorph for a time period of about 1 day to about 3 days;
a second treatment cycle that includes administering the effective amount of the crystalline polymorph for a time period of from about 4 days to about 6 days; and
a second rest period that includes abstaining from administering the crystalline polymorph for a time period of at least about 8 days.

Assignees

• Southern Res Inst
• Pinotbio Inc

Inventors

• Suto Mark J
• Jung Doo Young
• Lee Jin Soo
• Cho Hyunyong

Classifications

• C07D409/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07H19/12 Primary

  Triazine radicals · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title