Compounds and methods for treating inflammatory and fibrotic disorders
View Patent ↗Disclosed are compounds and methods for treating inflammatory and fibrotic disorders, including methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the p38 MAPK by the compound. Also disclosed are derivatives and analogs of pirfenidone, useful for modulating a stress activated protein kinase (SAPK) system.
1. A compound of formula II:
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, aryl, alkenylenearyl, and heteroaryl;
R 2 is selected from the group consisting of alkyl; aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , CN, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl;
R 3 is selected from the group consisting of hydrogen, aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy;
R 4 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cyano, alkoxy, alkenyl, and alkenylenearyl;
X 1 , X 2 , X 4 , and X 5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydo, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide; and
X 3 is alkoxy substituted with one or more substituents selected from the group consisting of alkyl; cycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH 2 , NH 2 , oxo (═O), aryl, haloalkyl, halo, and OH; aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl; heterocycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH 2 , NH 2 , oxo (═O), aryl, haloalkyl, halo, and OH; heteroaryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl; hydroxyl; alkoxy; aryloxy; mercapto; alkylthio; arylthio; cyano; halo; carbonyl; thiocarbonyl; alkoxycarbonyl; nitro; silyl; trihalomethanesulfonyl; trifluoromethyl; and amino.
2. The compound of claim 1 , wherein X 3 is substituted with one or more substituents selected from the group consisting of hydroxyl; halo; aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl; heteroaryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl; cycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH 2 , NH 2 , oxo (═O), aryl, haloalkyl, halo, and OH; heterocycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH 2 , NH 2 , oxo (═O), aryl, haloalkyl, halo, and OH; and amino.
3. The compound of claim 2 , wherein X 3 is alkoxy substituted with an aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl.
4. The compound of claim 3 , wherein X 3 is alkoxy substituted with an aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl.
5. The compound of claim 1 , wherein X 3 is alkoxy substituted with a heterocycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH 2 , NH 2 , oxo (═O), aryl, haloalkyl, halo, and OH.
6. The compound of claim 5 , wherein the heterocycloalkyl is optionally substituted with alkyl.
7. The compound of claim 5 , wherein the heterocycloalkyl is a five, six or seven membered ring selected from the group consisting of oxazole, pyrrole, imidazole, pyrazole, pyrrolidine, piperidine, piperazine, morpholine, and azepane.
8. The compound of claim 7 , wherein the heterocycloalkyl is piperidine.
9. The compound of claim 7 , wherein the heterocycloalkyl is N-methyl piperazine.
10. The compound of claim 7 , wherein the heterocycloalkyl is pyrrolidine.
11. The compound of claim 7 , wherein the heterocycloalkyl is morpholine.
12. The compound of claim 1 , wherein X 3 is an alkoxy substituted with amino.
13. The compound of claim 1 , wherein X 3 is an alkoxy substituted with N-alkyl amino or N,N-dialkyl amino.
14. The compound of claim 1 , wherein R 2 is alkyl.
15. The compound of claim 14 , wherein R 2 is methyl.
16. The compound or claim 1 , wherein R 2 is haloalkyl.
17. The compound or claim 1 , wherein R 2 is aryl optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, OH, alkoxy, haloalkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl.
18. The compound of claim 17 , wherein R 2 is phenyl.
19. The compound or claim 1 , wherein R 2 is heteroaryl optionally substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , CN, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl.
20. The compound or claim 1 , wherein R 1 is hydrogen.
21. The compound or claim 1 , wherein R 3 is hydrogen.
22. The compound or claim 1 , wherein R 4 is hydrogen.
23. The compound or claim 1 , wherein each of X 1 , X 2 , X 4 , and X 5 is hydrogen.
24. A method for treating a fibrotic condition, comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.
25. The method of claim 24 , wherein the fibrotic condition is idiopathic pulmonary fibrosis.
26. The method of claim 24 , wherein the compound is administered by inhalation.
27. A pharmaceutical composition comprising a compound of claim 1 , and pharmaceutically acceptable excipients.