Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
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 compound of the formula:
wherein:
X 1 and X 2 are independently:
hydrogen, OR b , NR b R c , or SR b , 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
a substituent convertible in vivo to hydrogen;
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;
Y is hydroxy, alkoxy (C≦8) , aryloxy (C≦8) , acyloxy (C≦8) , substituted alkoxy (C≦8) , substituted alkoxy (C≦8) , substituted aryloxy (C≦8) , substituted acyloxy (C≦8) , or
NR 1 R 2 , wherein R 1 and R 2 are independently:
hydrogen or hydroxy; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , or heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups;
R 1 ′ is:
hydrogen, cyano, 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) , 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;
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , heteroaryl (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;
R 3 is:
absent or hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
provided that R 3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R 3 is absent the oxygen atom to which it is bound is part of a double bond;
R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ;
R 6 is hydrogen, hydroxy or oxo;
R 7 is hydrogen or hydroxy; and
R 8 , R 9 , R 10 and R 11 are each independently hydrogen, hydroxy, alkyl (C≦8) , substituted alkyl (C≦8) , alkoxy (C≦8) or substituted alkoxy (C≦8) ;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
2. The compound of claim 1 , further defined as:
wherein:
X 1 and X 2 are independently:
hydrogen, OR b , NR b R c , or SR b , wherein R b and R c are each independently:
hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
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;
Y is hydroxy or NR 1 R 2 , wherein:
R 1 and R 2 are independently:
hydrogen or hydroxy; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦2) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦2) , alkenylsulfonyl (C≦2) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , or heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups;
R 1 ′ is:
hydrogen, cyano, 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) , 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;
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , heteroaryl (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;
R 3 is:
absent or hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
provided that R 3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R 3 is absent the oxygen atom to which it is bound is part of a double bond;
R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ; and
R 6 and R 7 are each independently hydrogen or hydroxy;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
3. The compound of claim 2 , further defined as:
wherein:
X 1 is:
hydrogen, OR b , NR b R c , or SR b , wherein R b and R c are each independently:
hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
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;
R 1 and R 2 are independently:
hydrogen or hydroxy; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦2) , heteroaralkoxy (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , or heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups;
R 1 ′ is:
hydrogen, cyano, 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) , 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;
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , heteroaryl (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;
R 3 is:
absent or hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
provided that R 3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R 3 is absent the oxygen atom to which it is bound is part of a double bond; and
R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
4. The compound of claim 2 , further defined as:
wherein:
X 1 and X 2 are independently:
hydrogen, OR b , NR b R c , or SR b , wherein R b and R c are each independently:
hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
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;
R 1 and R 2 are independently:
hydrogen or hydroxy; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , or heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups;
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , heteroaryl (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;
R 6 and R 7 are each independently hydrogen or hydroxy;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
5. The compound of claim 2 , further defined as:
wherein:
X 1 is:
hydrogen, OR b , NR b R c , or SR b , wherein R b and R c are each independently:
hydrogen;
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , acyl (C≦8) , or a substituted version of any of these groups; or
a substituent convertible in vivo to hydrogen;
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;
Y is hydroxy or NR 1 R 2 , wherein:
R 1 and R 2 are independently:
hydrogen or hydroxy; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , alkenyloxy (C≦12) , alkynyloxy (C≦12) , aryloxy (C≦12) , aralkoxy (C≦12) , heteroaryloxy (C≦12) , heteroaralkoxy (C≦12) , thioacyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , or heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups;
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (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; and
R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
6. The compound of claim 1 , further defined as:
wherein:
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (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;
R 1 and R 2 are independently:
hydrogen; or
alkyl (C≦2) , alkenyl (C≦2) , alkynyl (C≦12) , aryl (C≦2) , aralkyl (C≦2) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups; and
R 8 , R 9 , R 10 and R 11 are each independently hydrogen, hydroxy, alkyl (C≦6) , substituted alkyl (C≦6) , alkoxy (C≦6) or substituted alkoxy (C≦6) ;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
7. The compound of claim 2 , further defined as:
wherein:
R 2 ′ is:
cyano, hydroxy, halo or amino; or
fluoroalkyl (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; and
R 1 and R 2 are independently:
hydrogen; or
alkyl (C≦12) , alkenyl (C≦12) , alkynyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , heteroaralkyl (C≦12) , acyl (C≦12) , alkylsulfonyl (C≦12) , alkenylsulfonyl (C≦12) , alkynylsulfonyl (C≦12) , arylsulfonyl (C≦12) , aralkylsulfonyl (C≦12) , heteroarylsulfonyl (C≦12) , heteroaralkylsulfonyl (C≦12) , or a substituted version of any of these groups;
or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, prodrugs, or optical isomers thereof.
8. The compound of claim 1 , wherein X 1 is OR b and R b is absent.
9. The compound of claim 1 , wherein X 2 is hydrogen.
10. The compound of claim 1 , wherein Y is NR 1 R 2 .
11. The compound of claim 1 , wherein R 1 or R 2 is hydrogen.
12. The compound of claim 1 , wherein R 1 or R 2 comprises a fluoro group.
13. The compound of claim 1 , wherein R 2 is acyl (C≦10) .
14. The compound of claim 1 , wherein R 2 is substituted acyl (C≦10) .
15. The compound of claim 1 , wherein R 1 ′ is hydrogen.
16. The compound of claim 1 , wherein R 2 ′ is cyano.
17. The compound of claim 1 , wherein R 3 is absent.
18. The compound of claim 1 , wherein R 4 and R 5 are each methyl.
19. The compound of claim 1 , wherein R 6 and R 7 are each hydrogen.
20. The compound of claim 1 , wherein the bond joining carbon 1 and carbon 2 is a double bond.
21. The compound of claim 1 , wherein the bond joining carbon 9 and carbon 11 is a double bond.
22. The compound of claim 1 , wherein the bond joining carbon 12 and carbon 13 is a single bond.
23. The compound of claim 1 , wherein the bond joining carbon 13 and carbon 18 is a single bond.