Therapeutic compounds
The invention provides compounds of formula I: and salts thereof, as well as pharmaceutical compositions comprising such compounds. The compounds are useful for treating cancers, Alzheimer's disease, and conditions associated with demyelination.
1. A compound of formula I:
wherein:
X 1 is —O— and ring A is phenyl, 6-membered heteroaryl, indenyl, naphthyl or 9-10 membered bicyclic heteroaryl;
L is absent, or —CH═CH—;
R 2 is —COOH, —B(OH) 2 , or —SO 3 H;
each R A is independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);
each R B is independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, or 3;
or a salt thereof.
2. The compound of claim 1 , which is a compound of formula Ia:
or a salt thereof.
3. A compound of formula Ib:
wherein:
X 1 is —CH 2 — or —O—;
R 2 is —COOH, —B(OH) 2 , or —SO 3 H;
R A is selected from the group consisting of halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);
R B is selected from the group consisting of halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);
or a salt thereof.
4. The compound of claim 1 , which is a compound of formula Ic:
wherein:
ring A is phenyl, 6-membered heteroaryl, indenyl, naphthyl or 9-10 membered bicyclic heteroaryl;
R 2 is —COOH, —B(OH) 2 , or —SO 3 H;
each R A is independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);
each R B is independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, and oxo (═O);
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, or 3;
or a salt thereof.
5. The compound of claim 1 , which is a compound of formula Id:
wherein ring A is phenyl or 6-membered heteroaryl;
or a salt thereof.
6. The compound of claim 1 , which is a compound of formula Ie:
wherein Z 1 is N or CH;
or a salt thereof.
7. The compound of claim 1 , wherein R 2 is —COOH.
8. The compound of claim 1 , wherein ring A is naphthyl.
9. The compound of claim 1 , wherein ring A is phenyl.
10. The compound of claim 1 that is selected from the group consisting of:
11. A pharmaceutical composition comprising a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
12. A method for inhibiting cancer cell growth comprising contacting the cell in vitro or in vivo with an effective amount of a compound as described in claim 1 , or a salt thereof.
13. A method for treating cancer in a mammal having the cancer comprising administering to the mammal an effective amount of compound as described in claim 1 , or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 wherein the cancer is glioblastoma multiforme, breast, lung, colon, pancreatic, skin, cutaneous T-cell lymphoma, acute promyelocytic leukemia, ovarian, bladder, kidney, head and neck cancers, or Kaposi's sarcoma.
15. A method for activating RXR in a cell comprising contacting the cell in vitro or in vivo with an effective amount of a compound as described in claim 1 , or a salt thereof.
16. A method for treating Alzheimer's disease in a human having the Alzheimer's disease comprising administering to the human an effective amount of compound of claim 1 , or a pharmaceutically acceptable salt.
17. A method for treating multiple sclerosis in a mammal having multiple sclerosis comprising administering to the mammal an effective amount of compound as described in claim 1 , or a pharmaceutically acceptable salt.
18. A pharmaceutical composition comprising a compound as described in claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
19. A method for inhibiting cancer cell growth comprising contacting the cell in vitro or in vivo with an effective amount of a compound as described in claim 3 , or a salt thereof.
20. A method for treating cancer in a mammal having the cancer comprising administering to the mammal an effective amount of compound as described in claim 3 , or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 wherein the cancer is glioblastoma multiforme, breast, lung, colon, pancreatic, skin, cutaneous T-cell lymphoma, acute promyelocytic leukemia, ovarian, bladder, kidney, head and neck cancers, or Kaposi's sarcoma.
22. A method for activating RXR in a cell comprising contacting the cell in vitro or in vivo with an effective amount of a compound as described in claim 3 , or a salt thereof.
23. A method for treating Alzheimer's disease in a human having the Alzheimer's disease comprising administering to the human an effective amount of compound of claim 3 , or a pharmaceutically acceptable salt.
24. A method for treating multiple sclerosis in a mammal having multiple sclerosis comprising administering to the mammal an effective amount of compound as described in claim 3 , or a pharmaceutically acceptable salt.
25. The compound of claim 3 that is selected from the group consisting of:
or a salt thereof.