Claims for Patent: 9,670,147

Summary for Patent: 9,670,147

Title:	Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
Abstract:	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.
Inventor(s):	Eric Anderson, Xin Jiang, Melean Visnick
Assignee:	Reata Pharmaceuticals Holdings LLC
Application Number:	US14/753,297
Patent Claims:	1. A compound of the formula: wherein: X1 and X2 are independently: hydrogen, ORb, NRbRc, or SRb, wherein Rb and Rc 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 Rb is absent when the atom to which it is bound is part of a double bond, further provided that when Rb 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 NR1R2, wherein R1 and R2 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; R1′ 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; R2′ 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; R3 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 R3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R3 is absent the oxygen atom to which it is bound is part of a double bond; R4 and R5 are each independently alkyl(C≦8) or substituted alkyl(C≦8); R6 is hydrogen, hydroxy or oxo; R7 is hydrogen or hydroxy; and R8, R9, R10 and R11 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: X1 and X2 are independently: hydrogen, ORb, NRbRc, or SRb, wherein Rb and Rc 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 Rb is absent when the atom to which it is bound is part of a double bond, further provided that when Rb is absent the atom to which it is bound is part of a double bond; Y is hydroxy or NR1R2, wherein: R1 and R2 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; R1′ 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; R2′ 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; R3 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 R3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R3 is absent the oxygen atom to which it is bound is part of a double bond; R4 and R5 are each independently alkyl(C≦8) or substituted alkyl(C≦8); and R6 and R7 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: X1 is: hydrogen, ORb, NRbRc, or SRb, wherein Rb and Rc 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 Rb is absent when the atom to which it is bound is part of a double bond, further provided that when Rb is absent the atom to which it is bound is part of a double bond; R1 and R2 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; R1′ 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; R2′ 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; R3 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 R3 is absent when the oxygen atom to which it is bound is part of a double bond, further provided that when R3 is absent the oxygen atom to which it is bound is part of a double bond; and R4 and R5 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: X1 and X2 are independently: hydrogen, ORb, NRbRc, or SRb, wherein Rb and Rc 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 Rb is absent when the atom to which it is bound is part of a double bond, further provided that when Rb is absent the atom to which it is bound is part of a double bond; R1 and R2 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; R2′ 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; R6 and R7 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: X1 is: hydrogen, ORb, NRbRc, or SRb, wherein Rb and Rc 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 Rb is absent when the atom to which it is bound is part of a double bond, further provided that when Rb is absent the atom to which it is bound is part of a double bond; Y is hydroxy or NR1R2, wherein: R1 and R2 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; R2′ 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 R4 and R5 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: R2′ 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; R1 and R2 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 R8, R9, R10 and R11 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: R2′ 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 R1 and R2 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 X1 is ORb and Rb is absent. 9. The compound of claim 1, wherein X2 is hydrogen. 10. The compound of claim 1, wherein Y is NR1R2. 11. The compound of claim 1, wherein R1 or R2 is hydrogen. 12. The compound of claim 1, wherein R1 or R2 comprises a fluoro group. 13. The compound of claim 1, wherein R2 is acyl(C≦10). 14. The compound of claim 1, wherein R2 is substituted acyl(C≦10). 15. The compound of claim 1, wherein R1′ is hydrogen. 16. The compound of claim 1, wherein R2′ is cyano. 17. The compound of claim 1, wherein R3 is absent. 18. The compound of claim 1, wherein R4 and R5 are each methyl. 19. The compound of claim 1, wherein R6 and R7 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.