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 other wise delivered to the brain.

1 . A method for treatment of neurodegenerative disease, comprising the step of administering to an individual in need of such treatment a therapeutically effective amount of a purine scaffold compound that inhibits Hsp90, wherein the compound and the mode of administration are selected such that the compound is delivered to the brain. 
     
     
         2 . The method of  claim 1 , wherein the compound crosses the blood brain barrier. 
     
     
         3 . The method of  claim 1  or  2 , wherein the purine scaffold compound is a compound comprising a purine moiety to which is bonded an additional aryl or heteroaryl ring at the 8- or 9-position via a linker, wherein the compound as a whole possesses the necessary flexibility and substituent groups to be received within the N-terminal pocket of Hsp90. 
     
     
         4 . The method of  claim 3 , wherein the additional aryl or heteroaryl ring is affixed at the 9-position and is substituted at the 4′ and 5′ positions only. 
     
     
         5 . The method of  claim 3 , in which the purine scaffold compound has the general structure: 
       
         
           
           
               
               
           
         
         wherein R is hydrogen, a C 1  to C 10  alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms such as N or O; 
         Y 1  and Y 2  are independently C, N, S or O, with the proviso that when Y 1  and/or Y 2  is O the double bonds are missing or rearranged to retain the aryl nature of the ring 
         X 4  is hydrogen, halogen, for example F or Cl, or Br; 
         X 3  is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2  is alkyl; and 
         X 2  is halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 , alkyl, COO-alkyl, NH 2 , OH 2 , or CN; and 
         X 1  represents one more substituents on the aryl group, with the proviso that X 1  represents at least one substituent in the 5′-position said substituent in the 5′-position being selected from the same choices as X 2 : C 1  to C 6  alkyl or alkoxy; or wherein X 1  has the formula —X—Y—Z— wherein X, Y and Z are independently C, N, S or O, connected by single or double bonds and with appropriate hydrogen substitution to satisfy valence, and Y may be (CH 2 ) 2 , and one of X and Z is bonded at the 5′-position of the aryl ring and the other is bonded to the 4′ position. 
       
     
     
         6 . The method of  claim 5 , wherein the right-side aryl group is substituted at the 2′ and 5′ position only. 
     
     
         7 . The method of  claim 5 , wherein the right side aryl group is substituted at the 2′, 4′, and 5′ positions. 
     
     
         8 . The method of  claim 5 , wherein at least one of X, Y and Z is a carbon atom. 
     
     
         9 . The method of  claim 8 , wherein X 1  is —O—(CH 2 ) n —O—, wherein n is 1 or 2. 
     
     
         10 . The method of  claim 9 , wherein X 2  is halogen. 
     
     
         11 . The method of  claim 10 , wherein X 2  is Br or I. 
     
     
         12 . The method of  claim 9 , wherein R is an alkyl group containing a nitrogen heteroatom. 
     
     
         13 . The method of  claim 12 , wherein R is 3-isopropylaminopropyl,
 3-(isopropyl(methyl)amino)propyl, 3-(isopropyl(ethyl)amino)propyl,   3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl,   3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)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.   
     
     
         14 . The method of  claim 13 , wherein R is 3-isopropylaminopropyl. 
     
     
         15 . The method of  claim 13 , wherein X 2  is halogen. 
     
     
         16 . The method of  claim 15 , wherein X 2  is Br or I. 
     
     
         17 . The method of  claim 9 , wherein X 4  is halogen. 
     
     
         18 . The method of  claim 17 , wherein X 2  is halogen. 
     
     
         19 . The method of  claim 18 , wherein X 2  is Br or I. 
     
     
         20 . The method of  claim 17 , wherein R is an alkyl group containing a nitrogen heteroatom. 
     
     
         21 . The method of  claim 20 , wherein R is 3-isopropylaminopropyl,
 3-(isopropyl(methyl)amino)propyl, 3-(isopropyl(ethyl)amino)propyl,   3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl,   3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)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.   
     
     
         22 . The method of  claim 21 , wherein R is 3-isopropylaminopropyl. 
     
     
         23 . The method of  claim 21 , wherein X 2  is halogen. 
     
     
         24 . The method of  claim 23 , wherein X 2  is Br or I. 
     
     
         25 . The method of  claim 9 , wherein R is a terminal alkyne. 
     
     
         26 . The method of  claim 25 , wherein R is propynyl. 
     
     
         27 . The method of  claim 26 , wherein X 2  is halogen. 
     
     
         28 . The method of  claim 1 , wherein the purine scaffold compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 1  or  2 , wherein the purine scaffold compound has the formula: 
       
         
           
           
               
               
           
         
         wherein R is an alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms such as N or O connected to the 2′ position to form an 8 or 10 membered ring ring; 
         Y 1  and Y 2  are independently C, N, S or O, with the proviso that when Y 1  and/or Y 2  is O the double bonds are missing or rearranged to retain the aryl nature of the ring 
         X 4  is hydrogen, halogen, for example F or Cl, or Br; 
         X 3  is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2  is alkyl; and 
         X 2  is part of R; and 
         X 1  represents one more substituents on the aryl group, with the proviso that X 1  represents at least one substituent in the 5′-position said substituent in the 5′-position being selected from the same choices as X 2 : C 1  to C 6  alkyl or alkoxy; or wherein X 1  has the formula —X—Y—Z— wherein X, Y and Z are independently C, N, S or O, connected by single or double bonds and with appropriate hydrogen substitution to satisfy valence, and Y may be (CH 2 ) 2 , and one of X and Z is bonded at the 5′-position of the aryl ring and the other is bonded to the 4′ position. 
       
     
     
         30 . The method of  claim 1 , wherein the purine scaffold compound has the formula