Indolone compounds useful to treat cognitive impairment

Abstract

This invention provides a method of treating a subject suffering from a cognitive impairment or a cognitive disorder which comprises administering to the subject an amount of an indolone compound effective to treat the subject's cognitive impairment or disorder.

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         21 . A method comprising administering a therapeutically effective amount of a compound to a subject suffering from a cognitive impairment, the 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; —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 C1-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 R 1  and R 2  are each independently —H, straight chained or branched C 1 -C 7  alkyl, —F, —Cl, —Br, —I, —NO 2 , or —CN; 
         wherein R 3  is —H, straight chained or branched C 1 -C 7  alkyl, —F, —Cl, —Br, —I, —NO 2 , —CN, —OR 6  aryl or heteroaryl; 
         wherein R 5  is straight chained or branched C 1 -C 7  alkyl, —N(R 4 ) 2 , —OR6, or aryl; 
         wherein R 6  is straight chained or branched C 1 -C 7  alkyl or aryl; 
         wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following: —H, —F, —Cl, —Br, —I, —CN, methyl, ethyl or methoxy; 
         wherein each n is independently an integer from 1 to 4 inclusive; 
         wherein the compound is a pure Z imine isomer, a pure E imine isomer, or a mixture of Z and E imine isomers; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method of  claim 21 , wherein the compound is enantiomerically and diastereomerically pure. 
     
     
         23 . The method of  claim 21 , wherein the compound is enantiomerically or diastereomerically pure. 
     
     
         24 . The method of  claim 21 , wherein the compound is a pure Z imine isomer. 
     
     
         25 . The method of  claim 21 , wherein the compound is a pure E imine isomer. 
     
     
         26 . The method of  claim 21 , wherein the compound is a mixture of Z and E imine isomers. 
     
     
         27 . The method of  claim 21 , wherein the compound has 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, —CF 3 , —F, —Cl, —Br, —I, —OR 4 , —N(R 4 ) 2 , or —CON(R 4 ) 2 ; 
         wherein each R 4  is independently —H, straight chained or branched C 1 -C 7  alkyl, —CF 3 , or phenyl; 
         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; and 
         wherein A′ is 
       
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 27 , wherein B is aryl. 
     
     
         29 . The method of  claim 28 , wherein B is phenyl and the phenyl is optionally substituted with one or more of the following: —H; —F, —Cl, —Br, —CF3, straight chained or branched C 1 -C 7  alkyl, —N(R 4 ) 2 , —OR 4 , —COR 4 , —NCOR 4 , —CO 2 R 4 , or —CON(R 4 ) 2 . 
     
     
         30 . The method of  claim 29 , wherein A is aryl. 
     
     
         31 . The method of  claim 29 , wherein A is heteroaryl. 
     
     
         32 . A method comprising administering a therapeutically effective amount of a compound to a subject suffering from a cognitive impairment, the compound having the structure: 
       
         
           
           
               
               
           
         
         wherein each R 24  is independently one or more of the following: H, F, Cl, Br, I, CF 3  or OCH 3 ; 
         wherein R 25  is methyl, ethyl, allyl, or phenyl and the phenyl is optionally substituted with F, Cl, Br, CF 3 , or OR 4 ; and 
         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. 
       
     
     
         33 . The method of  claim 21 , wherein the cognitive impairment is associated with a psychiatric disorder, a psychotic disorder, a neurological disorder or a neurotic disorder. 
     
     
         34 . The method of  claim 21 , wherein the cognitive impairment is associated with a disorder of the central nervous system. 
     
     
         35 . The method of  claim 21 , wherein the cognitive impairment is associated with head trauma, brain trauma or cerebrovascular disease. 
     
     
         36 . The method of  claim 21 , wherein the cognitive impairment is associated with attention deficit disorder. 
     
     
         37 . The method of  claim 21 , wherein the cognitive impairment is associated with an affective disorder. 
     
     
         38 . The method of  claim 33 , wherein the psychotic disorder is schizophrenia. 
     
     
         39 . The method of  claim 34 , wherein the disorder of the central nervous system is age-associated memory impairment, mild cognitive impairment, Alzheimer's disease or Parkinson's disease. 
     
     
         40 . The method of  claim 35 , wherein the cerebrovascular disease is vascular dementia.