Use of GAL3 receptor antagonists for the treatment of depression and/or anxiety and compounds useful in such methods
This invention is directed to pyrimidine and indolone derivatives which are selective antagonists for the GAL3 receptor. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression and/or anxiety. This invention also provides a method of treating depression and/or anxiety in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist.
1 - 272 . (canceled)
273 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
wherein each of Y 1 , Y 2 , Y 3 , and Y 4 is independently —H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; —F, —Cl, —Br, or —I; —NO 2 ; —N 3 ; —CN; —OR 4 , —SR 4 —OCOR 4 , —COR 4 , —NCOR 4 , —N(R 4 ) 2 , —CON(R 4 ) 2 , or —COOR 4 ; aryl or heteroaryl; or any two of Y 1 , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each R 4 is independently —H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(C 1 -C 6 )alkyl;
wherein A is A′, straight chained or branched C 1 -C 7 alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl;
wherein A′ is
wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ;
wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine
wherein Q 6 is
wherein n is an integer from 1 to 4 inclusive;
wherein each R 22 is independently H, F, Cl, or straight chained or branched C 1 -C 4 alkyl;
or a pharmaceutically acceptable salt thereof.
274 . The pharmaceutical composition of claim 273 , wherein the compound is an enantiomerically and diastereomerically pure compound.
275 . The pharmaceutical composition of claim 273 , wherein the compound is a pure E imine isomer or a pure E alkene isomer.
276 . The pharmaceutical composition of claim 273 , wherein the compound is a pure Z imine isomer or a pure Z alkene isomer.
277 . The pharmaceutical composition of claim 273 , wherein the composition can be administered orally.
278 . The pharmaceutical composition of claim 273 , wherein B is Q 6 .
279 . The pharmaceutical composition of claim 278 , wherein A is aryl.
280 . The pharmaceutical composition of claim 279 , wherein the compound has the structure:
281 . The pharmaceutical composition of claim 280 , wherein the compound is:
282 . A compound having the structure:
wherein each of Y 1 , Y 2 , Y 3 , and Y 4 is independently —H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; —F, —Cl, —Br, or —I; —NO 2 ; —N 3 ; —CN; —OR 4 , —SR 4 —OCOR 4 , —COR 4 , —NCOR 4 , —N(R 4 ) 2 , —CON(R 4 ) 2 , or —COOR 4 ; aryl or heteroaryl; or any two of Y 1 , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each R 4 is independently —H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(C 1 -C 6 )alkyl;
wherein A is A′, straight chained or branched C 1 -C 7 alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl;
wherein A′ is
wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ;
wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine
wherein Q 6 is
wherein n is an integer from 1 to 4 inclusive;
wherein each R 22 is independently H, F, Cl, or straight chained or branched C 1 -C 4 alkyl;
or a pharmaceutically acceptable salt thereof.
283 . An enantiomerically and diastereomerically pure compound of claim 282 .
284 . A pure E imine isomer or a pure E alkene isomer of the compound of claim 282 .
285 . A pure Z imine isomer or a pure Z alkene isomer of the compound of claim 282 .
286 . The compound of claim 282 , wherein B is Q 6 .
287 . The compound of claim 286 , wherein A is aryl.
288 . The compound of claim 287 , wherein the compound has the structure:
289 . The compound of claim 288 , wherein the compound is: