Inhibitors of matrix metallaproteinases
View Patent ↗The present invention provides novel compounds of formulas I-IX, as described herein. Also provided are compositions of compounds of formulas I-IX, methods of making compounds of formulas I-IX, and methods of using compounds of formulas I-IX. The compounds of the invention can be used to inhibit matrix metalloproteinases, and are useful to treat conditions and diseases associated therewith.
1. A compound of formula I:
wherein
R 1 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkoxy, aryl, heteroaryl, hydroxy, SR 5 , NR 5 R 5 , or absent;
R 2 is CH 2 , carbonyl, SO 2 , or OH;
L is CH 2 , NR 5 , or O;
R 3 and R 4 are each independently hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, carboxy, cyano, nitro, halo, trifluoromethyl, trifluoromethoxy, SR 5 , SO 2 N(R 5 ) 2 , NR 5 R 5 , or CO 2 R 5 ;
each n is independently 0 to 4;
each R 5 is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 6 -C 10 )aroyl, aryl, aryl(C 1 -C 6 )alkyl, heteroaryl, heteroaryl(C 1 -C 6 )alkyl, or a nitrogen protecting group;
X is O;
D is S, SO, SO 2 , C═N—OH, or carbonyl;
E is a direct bond, or (C 1 -C 6 )alkyl;
J is S, O, or NR 5 ;
G, T, and Q are each independently H, (C 1 -C 6 )alkyl, or cyano;
any alkyl, amino, aryl, heteroaryl, or cycloalkyl is optionally substituted with 1 to about 5 (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, nitro, halo, amino, or hydroxy groups;
or a pharmaceutically acceptable salt thereof;
provided that when L is CH 2 or O, and R 2 is CH 2 , R 1 is not (C 1 -C 6 )alkyl;
when L is O and R 2 is carbonyl, R 1 is not (C 1 -C 6 )alkyl; and
when L is NR 5 , R 2 is not CH 2 .
2. The compound of claim 1 wherein R 1 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, or aryl; and R 2 is CH 2 , carbonyl, or SO 2 .
3. The compound of claim 1 wherein L is CH 2 , O, or NR 5 wherein R 5 is H, (C 1 -C 6 )alkyl, or a nitrogen protecting group.
4. The compound of claim 1 wherein R 3 is hydroxy, halo, amino, hydroxyphenyl, halophenyl, or SO 2 N(R 5 ) 2 wherein each R 5 of R 3 is H.
5. The compound of claim 1 wherein R 4 is hydroxy, halo, amino, or SO 2 N(R 5 ) 2 wherein each R 5 of R 4 is H.
6. The compound of claim 1 wherein D is SO 2 , or carbonyl.
7. The compound of claim 1 wherein E is a direct bond, CH 2 , or (C 1 -C 6 )alkyl, optionally substituted with 1 to 5 halo groups.
8. The compound of claim 1 wherein J is S, O, or NH.
9. The compound of claim 1 wherein G, T, and Q are each H.
10. The compound of claim 1 wherein the compound of formula I is a compound of the formula:
11. The compound of claim 10 wherein J is S or O; the groups G, T, and Q are each H; and each n is 0.
12. The compound of claim 10 wherein L is CH 2 , R 2 is carbonyl, and R 1 is (C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkoxy, or hydroxy.
13. The compound of claim 10 wherein L is NR 5 wherein R 5 is H, R 2 is SO 2 or carbonyl, and R 1 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy.
14. The compound of claim 10 wherein L is O, R 2 is SO 2 or carbonyl, and R 1 is (C 1 -C 6 )alkyl or optionally substituted aryl.
15. The compound
16. The compound
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
18. A composition comprising a compound of claim 1 and a chemotherapeutic agent.
19. A method of inhibiting a matrix metalloproteinase in a cell comprising contacting a cell with an amount of a compound of claim 1 that is effective to inhibit a matrix metalloproteinase.
20. The method of claim 19 wherein the contacting is in vitro or in vivo.