A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9556222-B2
Application number	US-201314406854-A
Country	US
Kind code	B2
Filing date	Jun 14, 2013
Priority date	Jun 15, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

Disclosed herein are novel A-ring epoxidized triterpenoid compounds and derivatives thereof, including those of the formula (I), 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.

First claim

The invention claimed is:

1. A compound of the formula:

wherein:
R 1 is cyano, halo, or —C(O)R a , wherein R a is hydroxy, amino, alkoxy (C1-4) , alkylamino (C1-4) , dialkylamino (C≦8) , or alkylsulfonylamino (C1-4) ;
R 2 and R 2 ′ are each independently hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) ;
R 3 and R 4 are each independently hydrogen, methyl or as defined below when either of these groups is taken together with group R c ; and
Y is:
hydrogen, hydroxy, amino, cyano, halo, 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) , 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) -R b , wherein the alkanediyl (C≦8) group is either substituted or unsubstituted and R b is:
hydroxy, halo, or amino; or
heteroaryl (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) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R C , wherein m is 0-6 and R c is:
hydrogen, hydroxy, halo, amino, or mercapto;
alkyl (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) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;
R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl(c); or
R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl(c); or

—NHC(O)R e , wherein R e is:
hydrogen, hydroxy, amino; 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) , 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 thereof.

2. The compound of claim 1 , further defined by the formula:

wherein:
R 2 and R 2 ′ are each independently hydrogen or methyl;
Y is:
hydrogen, hydroxy, amino, cyano, or halo,
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) , arylamino (C≦8) , aralkylamino (C≦8) , or substituted versions of any of these groups;
-alkanediyl (C≦8) -R b , wherein R b is:
hydroxy, halo, or amino; or
heteroaryl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , amido (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:
hydrogen, hydroxy, halo, amino, 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) , aryloxy (C≦8) , aralkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups; or

—NHC(O)R e , wherein R e is:
hydrogen, hydroxy, amino; or
alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the bond between carbon atoms 9 and 11 is a double bond.

4. The compound of claim 1 , wherein R 2 is methyl.

5. The compound of claim 1 , wherein R 2 ′ is methyl.

6. The compound of claim 1 , wherein Y is —(CH 2 ) m C(O)R c , wherein m is 0 and R c is hydrogen, hydroxy, amino, alkyl (C≦8) , heteroaryl (C≦8) , alkoxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or a substituted version of any of these groups other than hydrogen, hydroxy, and amino.

7. The compound of claim 6 , wherein R c is alkoxy (C≦8) .

8. The compound of claim 6 , wherein R c is hydroxy.

9. The compound of claim 6 , wherein R c is alkylamino (C≦8) .

10. The compound of claim 6 , wherein R c is heteroaryl (C≦8) .

11. The compound of claim 1 , wherein Y is —(CH 2 ) m C(O)R c , wherein m is 2 and R c is hydroxy, amino, alkoxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or a substituted version of any of these groups other than hydroxy and amino.

12. The compound of claim 11 , wherein R c is alkylamino (C≦8) .

13. The compound of claim 1 , wherein Y is -alkanediyl (C≦8) -R b .

14. The compound of claim 1 , wherein Y is alkyl (C≦8) .

15. The compound of claim 1 , wherein Y is heteroaryl (C≦8) .

16. The compound of claim 1 , wherein Y is —NHC(O)R e , wherein R e is alkyl (C≦8) , alkoxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or substituted version of any of these groups.

17. The compound of claim 1 , further defined as:

or a pharmaceutically acceptable salt of any of the above listed formulas.

18. A pharmaceutical composition comprising:
a) a compound of claim 1 ; and
b) a pharmaceutically acceptable carrier.

19. A method of treating a disease or disorder selected from the group consisting of atherosclerosis, diabetes, rheumatoid arthritis, lupus, psoriasis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, liver failure, chronic obstructive pulmonary disease, cardiovascular disease, chronic kidney disease, inflammatory bowel disease, dermatitis, mucositis, uveitis, glaucoma, macular degeneration, retinopathy, osteoarthritis, osteoporosis, asthma, cystic fibrosis, schizophrenia, depression, bipolar disorder, attention deficit disorder, cachexia, muscular dystrophy, obesity, stroke, septic shock, anaphylaxis, graft-versus-host disease, and ischemia-reperfusion injury in a patient in need thereof, comprising administering to the patient a compound of claim 1 in an amount sufficient to treat the disease or disorder.

Assignees

• Reata Pharmaceuticals Inc

Inventors

• Anderson Eric
• Bender Christopher F
• Jiang Xin
• Liu Xiaofeng
• Sun Haizhou
• Visnick Melean

Classifications

• C07J63/008

  Expansion of ring D by one atom, e.g. D homo steroids · CPC title

• C07D493/22

  in which the condensed system contains four or more hetero rings · CPC title

• A61K31/336

  having three-membered rings, e.g. oxirane, fumagillin · CPC title

• C07J71/001 Primary

  Oxiranes · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title