Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring
This invention provides, but is not limited to, novel oleanolic acid derivatives having the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds and compositions.
1. A pharmaceutical composition comprising a compound of the formula:
wherein:
Y is cyano, heteroaryl (C≦12) , substituted heteroaryl (C≦12) , or —C(O)R a , further wherein:
R a is:
hydrogen, hydroxy, halo, amino, azido, mercapto or silyl; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , alkoxyamino (C≦12) , dialkylamino (C≦12) , alkenylamino (C≦12) , alkynylamino (C≦12) , arylamino (C≦12) , aralkylamino (C≦12) , heteroarylamino (C≦12) , heteroaralkylamino (C≦12) , amido (C≦12) , or a substituted version of any of these groups; and
X is OR b , or NR b R c , wherein R b and R c are each independently:
hydrogen or hydroxy;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , arylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups; or
provided that R b is absent when the atom to which it is bound is part of a double bond, further provided that when R b is absent the atom to which it is bound is part of a double bond;
or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof; and
a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
wherein R a is:
hydrogen, hydroxy, halo or amino; or
alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heteroaralkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , alkynyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , heteroaralkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , alkoxyamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , alkynylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , heteroaralkylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups;
or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof.
3. The pharmaceutical composition of claim 2 , wherein the compound is further defined as:
wherein R a is alkoxy (C1-4) , alkylamino (C1-4) , alkoxyamino (C1-4) , dialkylamino (C2-4) , or a substituted version or any of these groups; or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof.
4. The pharmaceutical composition of claim 2 , wherein the compound is further defined as:
wherein R a is hydrogen, hydroxy, amino, methoxy, or 2,2,2-trifluoroethylamino; or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof.
5. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
wherein Y is heteroaryl (C≦8) or a substituted heteroaryl (C≦8) ; or a pharmaceutically acceptable salt, tautomer, or optical isomer thereof.
6. The pharmaceutical composition of claim 1 , wherein X is OR b .
7. The pharmaceutical composition of claim 6 , wherein R b is absent.
8. The pharmaceutical composition of claim 6 , wherein R b is hydrogen.
9. The pharmaceutical composition of claim 1 , wherein X is NR b .
10. The pharmaceutical composition of claim 9 , wherein R b is hydroxy.
11. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
12. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
13. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
14. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
15. The composition of claim 1 , wherein the compound is further defined as:
16. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
17. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
18. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
19. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
20. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
21. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
22. The pharmaceutical composition of claim 1 , wherein the compound is further defined as:
23. The pharmaceutical composition of claim 1 , wherein the composition is formulated for oral delivery.
24. A pharmaceutical composition comprising a compound of the formula:
and
a pharmaceutically acceptable carrier.