Treatment of neurodegenerative diseases through inhibition of hsp90

Abstract

Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are otherwise delivered to the brain.

1 - 30 . (canceled) 
     
     
         31 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein X 4  is hydrogen or halogen; 
         X 6  is amino; 
         X 3  is C, O, N, or S with hydrogens as necessary to satisfy valence, or CF 2 , SO, SO 2  or NR 3  where R 3  is alkyl; 
         R 1  is hydrogen, a C 1  to C 10  alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms; 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein the squiggly line represents the attachment point to X 3 ; 
         X 2  is halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, NH 2 , OH, or CN; 
         and wherein the compound is optionally in the form of an acid addition salt. 
       
     
     
         32 . The compound of  claim 31  wherein the variable atoms in the ring are both N. 
     
     
         33 . The compound of  claim 32 , wherein X 3  is S. 
     
     
         34 . The compound of  claim 32 , wherein X 3  is CH 2 . 
     
     
         35 . The compound of  claim 32 , wherein X 2  is I. 
     
     
         36 . The compound of  claim 32 , wherein R 1  is selected from the group consisting of 3-isopropylaminopropyl, 3-(isopropyl(methypamino)propyl, 3-(isopropyl(ethypamino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methypamino)propyl, 3-(ethyl(methypamino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, or 2-(methyl(prop-2-ynyl)amino)ethyl. 
     
     
         37 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein X 4  is hydrogen or halogen; 
         X 6  is amino; 
         X 3  is C, O, N, or S with hydrogens as necessary to satisfy valence, or CF 2 , SO, SO 2  or NR 3  where R 3  is alkyl; 
         R 1  is hydrogen, a C 1  to C 10  alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms; and 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein X 2  is selected from the group consisting of ethylene or 2-propylene, and wherein the compound is optionally in the form of an acid addition salt. 
       
     
     
         38 . The compound of  claim 37 , wherein the variable atoms in the ring are both N. 
     
     
         39 . The compound of  claim 38 , wherein X 3  is S. 
     
     
         40 . The compound of  claim 38 , wherein X 3  is CH 2 . 
     
     
         41 . The compound of  claim 38 , wherein the compound is PU-HT64, PU-HT65, PU-HT70 or PU-HT78 or an acid addition salt thereof. 
     
     
         42 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein X 4  is hydrogen or halogen; 
         X 6  is amino; 
         X 3  is C, O, N, or S with hydrogens as necessary to satisfy valence, or CF 2 , SO, SO 2  or NR 3  where R 3  is alkyl; 
         R 1  is hydrogen, a C 1  to C 10  alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein X 2  is selected from the group consisting of NH 2 , alkylamino and dialkylamino; and 
         wherein the compound is optionally in the form of an acid addition salt. 
       
     
     
         43 . The compound of  claim 42 , wherein R 1  is selected from the group consisting of 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methypamino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, and 2-(methyl(prop-2-ynyl)amino)ethyl. 
     
     
         44 . A method for treatment of neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of  claim 31 ; wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease. 
     
     
         45 . A method for treatment of neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of  claim 37 ; wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease. 
     
     
         46 . A method for treatment of neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of  claim 42 ; wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease. 
     
     
         47 . A compound: 
       
         
           
           
               
               
           
         
         or an acid addition salt thereof. 
       
     
     
         48 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein X 4  is hydrogen or halogen;
 X 6  is amino; 
 X 3  is C, O, N, or S with hydrogens as necessary to satisfy valence, or CF 2 , SO, SO 2  or NR 3  where R 3  is alkyl; 
 R 1  is selected from the group consisting of 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethylamino)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, and 2-(methyl(prop-2-ynyl)amino)ethyl, or an acid addition salt thereof; and 
 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein X 2  is halogen. 
       
     
     
         49 . A method for treatment of a neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of  claim 48 ; wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease.