Memantine compounds and their preparation and uses thereof

Abstract

Provided are compounds of formula (I), or a stereoisomer, mixture of stereoisomers, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, compositions, method of making and uses thereof.

1 .- 30 . (canceled) 
     
     
         31 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein:
 R 1  is H, an amino-protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; 
 R 2  is 
 
       
         
           
           
               
               
           
         
         R 3  and R 4  are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl or aryl; and 
         R 5  is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; 
         wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 , and R 4  are each independently optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, hydroxy, mercapto, alkyl, alkylamino, dialkylamino, alkoxy, alkylacyl, alkenylacyl, alkylthio, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkylacylalkyl, alkenylacylalkyl, alkylthioalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R 5  is independently optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, mercapto, alkyl, alkylamino, dialkylamino, alkoxy, alkylacyl, alkenylacyl, alkylthio, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkylacylalkyl, alkenylacylalkyl, alkylthioalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
       
     
     
         32 . The compound of  claim 31 , wherein R 1  is H, an amino-protecting group or C 1-6  alkyl optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, hydroxyl, mercapto, C 1-6  alkoxy, C 6-10  aryl, C 2-10  heterocyclyl and C 1-9  heteroaryl. 
     
     
         33 . The compound of  claim 31 , wherein R 3  and R 4  are each independently H or C 1-9  alkyl. 
     
     
         34 . The compound of  claim 31 , wherein R 5  is C 1-30  alkyl, C 2-30  alkenyl, C 2-30  alkynyl, C 6-14  aryl or C 1-9  heteroaryl, wherein the C 1-30  alkyl, C 2-30  alkenyl, C 2-30  alkynyl, C 6-14  aryl, C 1-9  heteroaryl is optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, mercapto, C 1-30  alkylamino, C 1-30  dialkylamino, C 1-30  alkoxy, C 1-30  alkylacyl, C 2-30  alkenylacyl, C 1-30  alkylthio, C 6-14  aryl and C 1-9  heteroaryl. 
     
     
         35 . The compound of  claim 34 , wherein R 5  is naphthylmethyl, phenyl, benzyl, methyl, propyl, isopropyl, octyl, hendecyl, tridecyl, pentadecyl or heptadecyl. 
     
     
         36 . The compound of  claim 31  represented by formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R 5  is C 1-30  alkyl, C 6-10  aryl or C 1-30  alkyl substituted with C 6-10  aryl. 
     
     
         37 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof. 
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 31  or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         39 . The pharmaceutical composition of  claim 38 , further comprising a cholinesterase inhibitor. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the cholinesterase inhibitor is tacrine, donepezil, huperzine-A, galantamine, rivastigmine, or a combination thereof. 
     
     
         41 . The pharmaceutical composition of  claim 38 , which is a suspension. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the compound or the stereoisomer, the deuterated analog, the tautomer, or the solvate is present in the suspension in a nanocrystalline or a microcrystalline form. 
     
     
         43 . A method for treating or ameliorating the symptoms of a neurodegenerative disease in a human in need thereof, wherein the method comprises administering to the human a compound of  claim 31 , the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, atrophic myelitis, AIDS dementia, vascular dementia or the combinations thereof. 
     
     
         44 . The method of  claim 43 , wherein the human suffers from moderate to severe dementia of the Alzheimer's disease. 
     
     
         45 . A method for inhibiting the activity of N-methyl-D-aspartate (NMDA) receptor in a human in need thereof, wherein the method comprises administering to the human a compound of  claim 31 . 
     
     
         46 . A method for treating or ameliorating the symptoms of diabetes in a human in need thereof, wherein the method comprises administering to the human a compound of  claim 31 .