Compositions and methods for treating cancer
View Patent ↗Provided herein are compounds used to inhibit the deamination enzyme responsible for the inactivation of therapeutic compounds, and methods of using them.
1. A method of inhibiting the activity of cytidine deaminase (CDA) in a subject in need thereof, comprising administering an effective amount of a compound of formula I:
wherein:
one of R 1 and R 2 is F, and the other is selected from H and F;
one of R 3 and R 4 is H, and the other is selected from H and OH;
where - - - - - - - is a covalent bond or absent, and R 4 is absent when - - - - - - - is a covalent bond;
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
2. The method of claim 1 , wherein the compound is a compound of formula VIII:
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
3. A method of inhibiting the deamination of a CDA substrate by CDA in a subject in need thereof, comprising administering an effective amount of a compound of formula I:
wherein:
one of R 1 and R 2 is F, and the other is selected from H and F;
one of R 3 and R 4 is H, and the other is selected from H and OH;
where - - - - - - - is a covalent bond or absent, and R 4 is absent when - - - - - - - is a covalent bond;
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
4. The method of claim 3 , wherein the compound is a compound of formula VIII:
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
5. The method of claim 3 , wherein the CDA substrate is decitabine.
6. The method of claim 3 , wherein the CDA substrate is a non-decitabine CDA substrate.
7. The method of claim 6 , wherein the CDA substrate is selected from the group consisting of gemcitabine, 5-azacytidine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
8. A method of treating sickle cell anemia in a subject in need thereof, comprising administering to the subject an effective amount of decitabine and a compound of formula I:
wherein:
one of R 1 and R 2 is F, and the other is selected from H and F;
one of R 3 and R 4 is H, and the other is selected from H and OH;
where - - - - - - - is a covalent bond or absent, and R 4 is absent when - - - - - - - is a covalent bond;
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
9. The method of claim 8 , wherein the compound is a compound of formula VIII:
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
10. A method of treating a cancer being treated with a CDA substrate used for treating cancer, comprising:
administering to a subject a CDA substrate used for treating cancer;
administering to the subject a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof; and
administering to the subject a pharmaceutical agent selected from an anti-emetic agent, an agent that increases appetite, a cytotoxic or chemotherapeutic agent, or an agent that relieves pain.
11. The method of claim 10 , wherein the compound is a compound of formula VIII:
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
12. The method of claim 10 , wherein the CDA substrate is decitabine.
13. The method of claim 10 , wherein the CDA substrate is a non-decitabine CDA substrate.
14. The method of claim 13 , wherein the CDA substrate is selected from the group consisting of gemcitabine, 5-azacytidine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
15. A packaged cancer treatment for treatment of a cancer to be treated with a CDA substrate, the packaged cancer treatment comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof; and
instructions for using an effective amount of the compound for treating cancer.
16. The packaged cancer treatment of claim 15 , wherein the compound is a compound of formula VIII:
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.
17. The packaged cancer treatment of claim 15 , further comprising a CDA substrate.
18. The packaged cancer treatment of claim 17 , wherein the CDA substrate is decitabine.
19. The packaged cancer treatment of claim 17 , wherein the CDA substrate is a non-decitabine CDA substrate.
20. The packaged cancer treatment of claim 19 , wherein the CDA substrate is selected from the group consisting of gemcitabine, 5-azacytidine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
21. An in vitro method of inhibiting the activity of CDA, comprising contacting CDA with an effective amount of a compound of formula I:
wherein:
one of R 1 and R 2 is F, and the other is selected from H and F;
one of R 3 and R 4 is H, and the other is selected from H and OH;
where - - - - - - - is a covalent bond or absent, and R 4 is absent when - - - - - - - is a covalent bond;
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester, or a C 2-6 alkenyl ester thereof.