C13-hydroxy derivatives of oleanolic acid and methods of use thereof
Disclosed herein are novel C13-hydroxy derivatives of oleanolic acid, including those of 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, for example, as antioxidant inflammation modulators, and compositions thereof are also provided.
1. A compound of the formula:
wherein:
R 1 is hydrogen, alkyl (C≦6) , acyl (C≦6) , or absent when the oxygen atom to which it is bound forms part of a double bond;
R 2 is hydrogen, alkyl (C≦6) , acyl (C≦6) , a substituted version of either of the two latter two groups, or as provide for below; and
Y is:
hydrogen, hydroxy, halo, amino, cyano or mercapto;
alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , amido (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkyl-sulfonylamino (C≦8) , or substituted versions of any of these groups;
-alkanediyl (C≦8) -R a , -alkenediyl (C≦8) -R a , or a substituted version of any of these groups, wherein R a is:
hydrogen, hydroxy, halo, amino, cyano or mercapto;
heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O— alkyl (C≦8) , —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups; or
R a and R 2 , taken together, are a covalent bond between one end of the -alkanediyl (C≦8) - or -alkenediyl (C≦8) - group and the oxygen atom attached to the carbon atom labeled 13; or
—(CH 2 ) m C(O)R b , wherein m is 0-6 and R b is:
hydrogen, hydroxy, halo, amino, hydroxyamino, or mercapto;
alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkyl-sulfonylamino (C≦8) , amido (C≦8) , —NH-heterocycloalkyl (C≦8) , or a substituted version of any of these groups; or
R b and R 2 , taken together, are a covalent bond between the carbonyl of the —(CH 2 ) m C(O)— group and the oxygen atom attached to the carbon atom labeled 13, wherein m is 1;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , further defined as:
wherein Y is:
hydrogen, hydroxy, halo, amino, cyano or mercapto;
alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , amido (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkylsulfonyl-amino (C≦8) , or substituted versions of any of these groups;
-alkanediyl (C≦8) -R a , -alkenediyl (C≦8) -R a , or a substituted version of any of these groups, wherein R a is:
hydrogen, hydroxy, halo, amino, cyano or mercapto; or
heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , alkenyloxy (C≦8) aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) —OC(O)CH 2 NHC(O)O-alkyl (C≦8) , —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups; or
—(CH 2 ) m C(O)R b , wherein m is 0-6 and R b is:
hydrogen, hydroxy, halo, amino, hydroxyamino, or mercapto; or alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —NH-heterocycloalkyl (C≦8) , or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 1 is hydrogen.
4. The compound of claim 1 , wherein R 1 is acyl (C≦6) .
5. The compound of claim 4 , wherein R 1 is acetyl.
6. The compound of claim 1 , wherein R 1 is absent and the oxygen atom to which it is bound forms part of a double bond, thereby resulting in an oxo group at the carbon atom labeled 12.
7. The compound of claim 1 , wherein R 2 is hydrogen.
8. The compound of claim 1 , wherein Y is substituted alkyl (C≦8) .
9. The compound of claim 8 , wherein Y is hydroxymethyl.
10. The compound of claim 1 , wherein Y is -alkanediyl (C≦8) -R a .
11. The compound of claim 10 , wherein Y is —CH 2 —R a .
12. The compound of claim 1 , wherein R a is hydroxy.
13. The compound of claim 1 , wherein R a is acyloxy (C≦8) .
14. The compound of claim 13 , wherein R a is acetyloxy.
15. The compound of claim 1 , wherein Y is —(CH 2 ) m C(O)R b .
16. The compound of claim 15 , wherein m=0.
17. The compound of claim 15 , wherein R b is alkoxy (C≦8) .
18. The compound of claim 17 , wherein R b is methoxy.
19. The compound of claim 17 , wherein R b is ethoxy.
20. The compound of claim 15 , wherein R b is amino.
21. The compound of claim 15 , wherein R b is alkylamino (C≦8) .
22. The compound of claim 21 , wherein R b is ethylamino.
23. The compound of claim 1 , further defined as:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising:
a) the compound of claim 1 ; and
b) an excipient.