Certain compounds, compositions and methods
View Patent ↗The present invention provides certain tetrahydrouridine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of making and using such compounds.
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration;
and wherein R 1 and R 2 are fluoro.
2. The compound of claim 1 , wherein the compound is represented by Compound 1a or a pharmaceutically acceptable salt thereof:
3. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable excipient.
4. A method for inhibiting cytidine deaminase, comprising administering to a subject in need a composition consisting essentially of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration;
and wherein R 1 and R 2 are fluoro;
and a pharmaceutically acceptable excipient.
5. The method of claim 4 , wherein the compound is represented by Compound 1a or a pharmaceutically acceptable salt thereof:
6. A composition comprising:
(i) a compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration; and
wherein R 1 and R 2 are fluoro; and
(ii) a CDA substrate drug;
wherein the CDA substrate drug is not decitabine.
7. The composition of claim 6 , wherein the CDA substrate drug is selected from 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
8. The composition of claim 7 , wherein the CDA substrate drug is 5-azacytidine.
9. The composition of claim 7 , wherein the CDA substrate drug is gemcitabine.
10. The composition of claim 7 , wherein the CDA substrate drug is ara-C.
11. The composition of claim 6 , wherein the compound is represented by Compound 1a or a pharmaceutically acceptable salt thereof:
12. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable excipient.
13. A composition comprising:
(i) a compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration; and
wherein R 1 and R 2 are fluoro; and
(ii) a CDA substrate drug;
wherein the CDA substrate drug is decitabine.
14. The composition of claim 13 , wherein the compound is represented by Compound 1a or a pharmaceutically acceptable salt thereof:
15. A pharmaceutical composition comprising the composition of claim 14 and a pharmaceutically acceptable excipient.
16. A method for treating cancer, comprising:
(i) administering to a mammal in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration;
and wherein R 1 and R 2 are fluoro; and
(ii) administering to a mammal in need thereof a CDA substrate drug;
wherein the CDA substrate drug is not decitabine.
17. The method of claim 16 , wherein the CDA substrate drug is selected from 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
18. The method of claim 17 , wherein the CDA substrate drug is 5-azacytidine.
19. The method of claim 17 , wherein the CDA substrate drug is gemcitabine.
20. The method of claim 17 , wherein the CDA substrate drug is ara-C.
21. The method of claim 17 , wherein the cancer is selected from hematological cancers and solid cancers.
22. The method of claim 17 , wherein the cancer is a myelodysplastic syndrome.
23. The method of claim 17 , wherein the cancer is a hematological cancer selected from leukemia, acute myeloid leukemia and chronic myeloid leukemia.
24. The method of claim 17 , wherein the cancer is a solid cancer selected from pancreatic cancer, ovarian cancer, peritoneal cancer, non small cell lung cancer, metastatic breast cancer, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, gynecological cancer, fallopian tube carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, cervical carcinoma, genitourinary tract cancer, and gastrointestinal cancer.
25. The method of claim 16 , wherein the compound is represented by Compound 1a or a pharmaceutically acceptable salt thereof:
26. The method of claim 17 , wherein the compound is administered at substantially the same time with the CDA substrate drug.
27. The method of claim 17 , wherein the compound is administered prior to the CDA substrate drug.
28. The method of claim 17 , wherein the compound is administered after the CDA substrate drug.
29. The method of claim 17 , wherein the compound and the CDA substrate drug are administered in a single unit dosage form.
30. The method of claim 17 , wherein the compound and the CDA substrate drug are administered in multiple, separate unit dosage forms.
31. A method for treating cancer, comprising:
(i) administering to a mammal in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration;
and wherein R 1 and R 2 are fluoro; and
(ii) administering to a mammal in need thereof a CDA substrate drug;
wherein the CDA substrate drug is decitabine.
32. The method of claim 31 , wherein the cancer is selected from hematological cancers and solid cancers.
33. The method of claim 31 , wherein the cancer is a myelodysplastic syndrome.
34. The method of claim 31 , wherein the cancer is a hematological cancer selected from leukemia, acute myeloid leukemia and chronic myeloid leukemia.
35. The method of claim 31 , wherein the cancer is a solid cancer selected from pancreatic cancer, ovarian cancer, peritoneal cancer, non small cell lung cancer, metastatic breast cancer, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, gynecological cancer, fallopian tube carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, cervical carcinoma, genitourinary tract cancer, and gastrointestinal cancer.
36. The method of claim 31 , wherein the compound is represented by Compound 1a or a pharmaceutically acceptable salt thereof:
37. The method of claim 31 , wherein the compound is administered at substantially the same time with the CDA substrate drug.
38. The method of claim 31 , wherein the compound is administered prior to the CDA substrate drug.
39. The method of claim 31 , wherein the compound is administered after the CDA substrate drug.
40. The method of claim 31 , wherein the compound and the CDA substrate drug are administered in a single unit dosage form.
41. The method of claim 31 , wherein the compound and the CDA substrate drug are administered in multiple, separate unit dosage forms.
42. The compound of claim 2 , wherein the compound is represented by Compound 1a:
43. A pharmaceutical composition comprising the compound of claim 42 and a pharmaceutically acceptable excipient.
44. The composition of claim 11 , wherein the compound is represented by Compound 1a:
45. A pharmaceutical composition comprising the composition of claim 44 and a pharmaceutically acceptable excipient.
46. The composition of claim 14 , wherein the compound is represented by Compound 1a:
47. A pharmaceutical composition comprising the composition of claim 46 and a pharmaceutically acceptable excipient.
48. The method of claim 25 , wherein the compound is represented by Compound 1a:
49. The method of claim 36 , wherein the compound is represented by Compound 1a:
50. The method of claim 5 , wherein the compound is represented by Compound 1a:
51. A method for inhibiting degradation of a CDA substrate drug by cytidine deaminase, comprising administering to a subject that is undergoing treatment with the CDA substrate drug a composition consisting essentially of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein the carbon marked by an asterisk may have an (R) or an (S) configuration;
and wherein R 1 and R 2 are fluoro;
and a pharmaceutically acceptable excipient.
52. The method of claim 51 , wherein the compound is represented by Compound 1a: