Dihydroindene and tetrahydronaphthalene 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 Ia:
wherein:
D is
R N is (C 3 -C 6 )cycloalkyl, or (C 2 -C 6 )alkynyl, wherein the (C 3 -C 6 )cycloalkyl, and (C 2 -C 6 )alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, and cyano;
R 2 is —COOH, —B(OH) 2 , or —SO 3 H;
ring A is phenyl or 6-membered heteroaryl;
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, and (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, and (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. A compound of formula I:
wherein:
p is 0 and D is
or p is 1 and D is
R N is (C 3 -C 6 )cycloalkyl, or (C 2 -C 6 )alkynyl, wherein the (C 3 -C 6 )cycloalkyl, and (C 2 -C 6 )alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, nitro, and cyano;
R 2 is —COOH, —B(OH) 2 , or —SO 3 H;
ring A is
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, and (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, and (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.
3. The compound of claim 2 that is selected from the group consisting of:
and salts thereof.
4. A compound selected from the group consisting of:
and salts thereof.
5. A pharmaceutical composition comprising a compound as described in claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
6. 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 2 , or a salt thereof.
7. A method for treating cancer in a mammal having cancer comprising administering to the mammal an effective amount of compound as described in claim 2 , or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 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.
9. 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 2 , or a salt thereof.
10. A method for treating Alzheimer's disease in a human having Alzheimer's disease comprising administering to the human an effective amount of compound as described in claim 2 , or a pharmaceutically acceptable salt.
11. A method for treating multiple sclerosis, a disease associated with demyelination, in a human having multiple sclerosis comprising administering to the human an effective amount of compound as described in claim 2 , or a pharmaceutically acceptable salt.