C4 monomethyl triterpenoid derivatives and methods of use thereof

摘要

Disclosed herein are novel C4-monomethyl triterpenoid compounds and derivatives thereof, 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.

主权项

1. A compound of the formula:wherein:
X1 and X2 are independently hydrogen, halo, hydroxy, amino or oxo, provided that X1 is not oxo when carbon atoms 12 and 13 are connected to one another with a double bond, further provided that X2 is not oxo when carbon atoms 9 and 11 are connected to one another with a double bond; R1 is —CN, iodo, —CF3, or —C(O)Ra, wherein Ra is —OH, alkoxy(C1-4), —NH2, alkylamino(C1-4), or —NH—S(O)2-alkyl(C1-4); R2 is hydrogen or R2 is absent when the atom to which it is bound forms part of a double bond; R2′ is hydrogen, ═CH2, alkyl(C≦8), or substituted alkyl(C≦8); R3 and R4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group Rc; and Y is:
—H, —OH, —SH, —CN, —F, —CF3, —NH2 or —NCO;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), alkylamino(C≦8), dialkylamino(C≦8), alkenylamino(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;-alkanediyl(C≦8)-Rb, -alkenediyl(C≦8)-Rb, or a substituted version of any of these groups, wherein Rb is:
hydrogen, hydroxy, halo, amino or thio; orheteroaryl(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), 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)CH2NHC(O)O-t-butyl, —OCH2-alkylthio(C≦8), or a substituted version of any of these groups;—(CH2)mC(O)Rc, wherein m is 0-6 and Rc is:
hydrogen, hydroxy, halo, amino, —NHOH,  or thio; oralkyl(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-alkoxy(C≦8), —NH-heterocycloalkyl(C≦8), —NHC(NOH)-alkyl(C≦8), —NH-amido(C≦8), or a substituted version of any of these groups;Rc and R3, taken together, are —O— or —NRd—, wherein Rd is hydrogen or alkyl(C≦4); orRc and R4, taken together, are —O— or —NRd—, wherein Rd is hydrogen or alkyl(C≦4); or—NHC(O)Re, wherein Re is:
hydrogen, hydroxy, amino; oralkyl(C≦8), alkenyl(C≦8), alkynyl(C≦8), aryl(C≦8), aralkyl(C≦8), heteroaryl(C≦8), heterocycloalkyl(C≦8), alkoxy(C≦8), aryloxy(C≦8), aralkoxy(C≦8), heteroaryloxy(C≦8), acyloxy(C≦8), alkylamino(C≦8), dialkylamino(C≦8), arylamino(C≦8), or a substituted version of any of these groups;or a pharmaceutically acceptable salt or tautomer thereof.