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
wherein R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, alkenylenearyl, and heteroaryl;
R 2 is selected from the group consisting of aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl; haloalkylcarbonyl; cycloalkyl; hydroxylalkyl; sulfonamide; unsubstituted cycloheteroalkyl and cycloheteroarlkyl substituted with one to three substituents independently selected from alkyleneOH, C(O)NH 2 , NH 2 , aryl, haloalkyl, halo, and OH; or R 2 and R 1 together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring;
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, haloalkyl, alkoxy, alkenyl, and alkenylenearyl;
X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydro, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X 2 and X 3 together form a 5- or 6-membered ring comprising —O(CH 2 ) n O—, wherein n is 1 or 2, wherein at least one of X 1 , X 2 , X 3 , and X 4 is not hydrogen; and
X 5 is hydrogen,
with the proviso that (a) at least one of X 1 , X 2 , X 3 , and X 4 is not selected from the group consisting of hydrogen, halo, alkoxy, and hydroxy or (b) at least one of R 1 , R 2 , R 3 , or R 4 is not selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, halo, hydroxy, and alkoxyalkyl,
or a pharmaceutically acceptable salt, or ester thereof.
2. The compound of claim 1 , wherein one of X 1 , X 2 , and X 3 is not hydrogen.
3. A compound having a structure of formula (III) or formula (IV)
wherein
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, haloalkyl, alkoxy, alkenyl, and alkenylenearyl;
X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydro, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X 2 and X 3 together form a 5- or 6-membered ring comprising —O(CH 2 ) n O—, wherein n is 1 or 2, wherein at least one of X 1 , X 2 , X 3 , and X 4 is not hydrogen;
X 5 is hydrogen; and
X 8 is hydrogen or alkyl; and
X 6 and X 7 are independently selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X 6 and X 7 together form an optionally substituted 5 or 6 membered heterocyclic ring,
or a pharmaceutically acceptable salt, or ester thereof.
4. The compound of claim 3 , wherein X 7 is hydrogen.
5. The compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, 4-pyridyl, cyclopropanyl, 2-furanyl, cyano, H 2 NSO 2 , (CH 3 ) 2 NSO 2 , fluoro, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl.
6. The compound of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is alkyl or cycloalkyl.
7. The compound of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is haloalkyl.
8. The compound of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is alkenyl.
9. The compound of claim 1 , wherein at least one of X 1 , X 2 , or X 3 is amino.
10. The compound of claim 1 having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound exhibits an IC 50 in a range of about 100 μM to about 1000 μM for inhibition of p38 MAPK.
12. The compound of claim 11 , wherein the compound exhibits an IC 50 is in the range of about 200 μM to about 800 μM.
13. The compound of claim 1 , wherein the compound exhibits an EC 50 in the range of about 0.1 μM to about 1000 μM for inhibition of TNFα secretion in a bodily fluid in vivo.
14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
15. The compound of claim 2 , wherein R 2 is selected from the group consisting of aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl; haloalkylcarbonyl; cycloalkyl; hydroxylalkyl; sulfonamido; and unsubstituted cycloheteroalkyl; or R 2 and R 1 together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring.
16. The compound of claim 15 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 3 having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A compound selected from the group consisting of:
and, or a pharmaceutically acceptable salt thereof.