Pyridonyl guanidine F
View Patent ↗The invention provides pyridonyl guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using pyridonyl guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.
1. A method of treating a disorder selected from the group consisting of an immune disorder and inflammatory disorder comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of Formula I in order to ameliorate a symptom of the disorder, wherein Formula I is represented by:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenylene or a six-membered heteroarylene;
A 2 is
X is —OP(O)(OR 11 ) 2 ;
R 1 represents independently for each occurrence halogen, alkyl, haloalkyl, hydroxyl, C 1 -C 6 alkoxy, or cyano;
R 2 is hydrogen;
R 3 is aryl, aralkyl, cycloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl, wherein said aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, C 1 -C 6 alkoxy, and cyano;
R 4 is hydrogen;
R 5 is hydrogen, halogen, alkyl, alkoxyl, or —C(O)R 7 ;
R 6 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl;
R 7 represents independently for each occurrence alkyl or cycloalkyl;
R 8 is hydrogen or alkyl;
R 9 is alkyl, cycloalkyl, haloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, —C(R 6 ) 2 ) m —CN, aryl, aralkyl heteroaryl, or heteroaralkyl;
R 10 is alkyl, cycloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, haloalkyl, or C 1 -C 6 alkoxy;
R 11 represents independently for each occurrence hydrogen or an alkali metal;
n is 1 or 2; and
m is 1, 2, 3, 4, or 5.
2. The method of claim 1 , wherein the disorder is rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, uveitis, or epidermal hyperplasia.
3. The method of claim 1 , wherein the disorder is inflammatory bowel disease.
4. The method of claim 1 , wherein the disorder is Crohn's disease or ulcerative colitis.
5. The method of claim 3 , wherein A 1 is phenylene; and A 2 is
6. The method of claim 5 , wherein A 2 is
7. The method of claim 3 , wherein A 1 is phenylene; and A 2 is
8. The method of claim 7 , wherein A 2 is
9. The method of claim 6 , wherein R 3 is benzyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
10. The method of claim 8 , wherein R 3 is benzyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
11. The method of claim 9 , wherein R 1 is halogen or haloalkyl.
12. The method of claim 10 , wherein R 1 is halogen or haloalkyl.
13. The method of claim 11 , wherein R 2 and R 4 are hydrogen.
14. The method of claim 12 , wherein R 2 and R 4 are hydrogen.
15. The method of claim 13 , wherein R 5 is hydrogen; and n is 1.
16. The method of claim 14 , wherein R 5 is hydrogen; and n is 1.
17. The method of claim 1 , wherein said compound is represented by Formula I-A:
including all stereoisomers, geometric isomers, tautomers, or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
R 1 and R 2 each represent independently for each occurrence hydrogen, chloro, fluoro, or —CF 3 ; and
R 3 is aralkyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, C 1 -C 6 alkoxy, and cyano.
18. The method of claim 17 , wherein R 1 is —CF 3 .
19. The method of claim 18 , wherein R 3 is benzyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
20. The method of claim 2 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. The method of claim 3 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The method of claim 4 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. The method of claim 3 , wherein the compound is
24. The method of claim 4 , wherein the compound is
25. A method of treating inflammatory bowel disease in a human patient, comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical composition to treat the inflammatory bowel disease, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and
26. A method of inhibiting a F 1 F 0 -ATPase, comprising exposing a F 1 F 0 -ATPase to a compound of Formula I-A to inhibit said F 1 F 0 -ATPase, wherein Formula I-A is represented by:
including all stereoisomers, geometric isomers, tautomers, or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
R 1 and R 2 each represent independently for each occurrence hydrogen, chloro, fluoro, or —CF 3 ; and
R 3 is aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein said aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, C 1 -C 6 alkoxy, and cyano.
27. The method of claim 26 , wherein the compound is
or a pharmaceutically acceptable salt thereof.