C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
Disclosed herein are novel C17-heteroaryl 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:
n is 0;
X 1 is —O— or —NH—;
X 2 is ═O or ═NH; and
Y is:
hydrogen, hydroxy, halo, amino, or cyano or —NCO; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤8) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤8) , aryloxy (C≤12) , acyloxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , alkylthio (C≤8) , acylthio (C≤8) , alkylsulfonylamino (C≤8) , or substituted versions of any of these groups;
or a salt thereof.
2. The compound of claim 1 , wherein X 1 is —NH— and X 2 is ═O.
3. The compound of claim 1 , wherein X 1 is —O— and X 2 is ═NH.
4. The compound of claim 1 , wherein Y is —H.
5. The compound of claim 1 , wherein Y is alkyl (C≤4) .
6. The compound of claim 5 , wherein Y is methyl, n-propyl, isopropyl or cyclopropyl.
7. The compound of claim 1 , wherein Y is substituted alkyl (C≤4) .
8. The compound of claim 7 , wherein Y is methoxymethyl.
9. The compound of claim 1 , further defined as:
or a salt thereof.
10. A method of making a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
n is 0-3;
Ar is heteroarenediyl (C≤8) or a substituted version thereof; and
Y is:
hydrogen, hydroxy, halo, amino, or cyano or —NCO; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤8) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤8) , aryloxy (C≤12) , acyloxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , alkylthio (C≤8) , acylthio (C≤8) , alkylsulfonylamino (C≤8) , or substituted versions of any of these groups;
comprising obtaining a compound of formula Ia:
or a salt thereof, wherein:
n is 0-3;
X 1 is —O— or —NH—;
X 2 is ═O or ═NH; and
Y is:
hydrogen, hydroxy, halo, amino, or cyano or —NCO; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤8) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤8) , aryloxy (C≤12) , acyloxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , arylamino (C≤8) , aralkylamino (C≤8) , alkylthio (C≤8) , acylthio (C≤8) , alkylsulfonylamino (C≤8) , or substituted versions of any of these groups; and
reacting the compound of formula Ia under conditions suitable to form the compound of formula I, wherein the conditions comprise reacting the compound of formula Ia with an acid.
11. The method of claim 10 , wherein the acid is p-TsOH.
12. The method of claim 10 , wherein the conditions comprise heating the compound of formula I in a solvent.
13. The method of claim 12 , wherein the solvent is toluene.
14. The method of claim 12 , further comprising heating the mixture of the compound of formula I in the solvent to reflux.
15. The method of claim 10 , wherein the conditions comprise applying microwave radiation to a mixture comprising the compound of formula Ia and a solvent.
16. The method of claim 10 , wherein n is 0.
17. The method of claim 10 , wherein n is 1.
18. The method of claim 10 , wherein X 1 is —NH— and X 2 is ═O.
19. The method of claim 10 , wherein X 1 is —O— and X 2 is ═NH.
20. The method of claim 10 , wherein Y is —H.
21. The method of claim 10 , wherein Y is alkyl (C≤4) .
22. The method of claim 21 , wherein Y is methyl, n-propyl, isopropyl or cyclopropyl.
23. The method of claim 10 , wherein Y is substituted alkyl (C≤4) .
24. The method of claim 23 , wherein Y is methoxymethyl.
25. The method of claim 10 , wherein the compound of formula Ia is further defined as:
or a salt thereof.