Novel compounds advantageous in the treatment of central nervous system diseases and disorders

Abstract

A series of novel amides showing broad pharmaceutical activity. Compounds described herein are effective as anticonvulsants, chemical countermeasures, and analgesics. Such compounds also show, neuroprotective/neuroreparative effects and activity against spinal muscular atrophy. Such pharmaceutically active compounds show utility in the treatment of central nervous system (“CNS”) diseases and disorders, such as anxiety, depression, insomnia, migraine headaches, schizophrenia, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's, ALS, and Huntington's disease) spasticity, and bipolar disorder. Furthermore, such compounds may additionally find utility as analgesics (e.g., for the treatment of chronic or neuropathic pain) and as neuroprotective agents useful in the treatment of stroke(s), and/or traumatic brain and/or spinal cord injuries.

What is claimed is: 
     
         1 . A compound represented by Formula I 
       
         
           
           
               
               
           
         
         wherein R 1  is one of H, CH 3 , C 2 H 5 , (CH 2 ) 2 SO 3 H, or CHZCOOH; 
         Z is one of H, CH 3 , CH(CH 3 ) 2 , CH 2 Cl 6 H 5 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3 ; 
         R 2  is one of H, CH 3 , CH 2 H 5 , (CH 2 ) 2 OCH 3 , (CH 2 ) 3 OCH 3 , or C 1 -C 5  alkyl; or 
         R 1  and R 2  together are cycloalkyl or heterocycle; 
         R 3  is 
       
       
         
           
           
               
               
           
         
       
       where X is nothing, (—CH 2 —), (—CH 2 -) 2 , or (—CH 2 -) 3 , or 
       
         
           
           
               
               
           
         
       
       where X is one of nothing, (—CH 2 —), (—CH 2 -) 2 , or (—CH 2 —) 3 ,
 R 4  is one of H, Cl, F, CF 3 , CN, C 1 -C 5  alkyl, C 1 -C 5  alkoxy, OCF 3 , CONR 1 R 2 , 
 
       
         
           
           
               
               
           
         
       
       where X is (—CH 2 —) or (—CH 2 -) 2 , 
       
         
           
           
               
               
           
         
       
       where R 5  is one of H, Cl, F, CF 3 , CN, C 1 -C 5  alkyl, C 1 -C 5  alkoxy, OCF 3 , or CONR 1 R 2 ; and
 n of R 4 =1−5 and n of R 5 =1-4. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is an amide derivative of taurine, glycine, alanine, valine, phenylalanine, leucine, or isoleucine. 
     
     
         3 . A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound of Formula I of  claim 1  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         4 . A pharmaceutical composition for treating and/or preventing one or more neurodegenerative disease, comprising a neuroprotective effective amount of at least one compound of Formula I of  claim 1  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the neurodegenerative disease is at least one of Huntington's Disease, Parkinson's Disease, Alzheimer's Disease, or amyotrophic lateral sclerosis (ALS). 
     
     
         6 . A pharmaceutical composition for treating and/or preventing spinal muscular atrophy, comprising a therapeutically effective amount of at least one compound of Formula I of  claim 1  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         7 . A method for treating and/or preventing one or more of a neurodegenerative disease, spinal muscular atrophy, or Duchenne muscular dystrophy, comprising administering to a subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         8 . A compound represented by Formula IIA 
       
         
           
           
               
               
           
         
         wherein Ar is a substituted phenyl or an optionally substituted heterocyclic aryl selected form the group consisting of pyrazine, optionally substituted pyridine, or an optionally substituted quinoxaline, wherein up to 5 substituents may be present, wherein each substituent on Ar is independently selected from the group consisting of
 alkyl, halogen, alkoxy, thioalkyl, sulfoxyalkyl, sulfonylalkyl, haloalkyl, haloalkoxy, OH, CH 2 OH, CONH 2 , CN, acetoxy, N(alkyl) 2 , benzyl, benzyloxy, NO 2 , CHO, CH 3 CH(OH), acetyl, OCH 2 COOH, 
 an optionally substituted aromatic ring system attached to one or two atoms of the Ar, the aromatic rings being selected from the group consisting of phenyl, phenoxy, and heterocyclic aryl, and 
 a bifunctional substituent that forms a ring with the Ar, wherein the bifunctional substituents are selected from the group consisting of a cycloalkyl and an alkylenedioxy; 
 
         R 1  and R 2  are each independently selected from the group consisting of H and optionally substituted alkyl, or R 1  and R 2  together are cycloalkyl or heterocycle, wherein when R 1  is H, R 2  is (CH 2 ) 2 SO 3 H or CHZCOOH, wherein Z is one of the group consisting of H, CH 3 , CH(CH 3 ) 2 , CH 2 Cl 6 H 5 , CH 2 CH(CH 3 ) 2 , and CH(CH 3 )CH 2 CH 3 ; 
         R 3  is selected from the group consisting of OH, optionally substituted alkyl, and together with R 4  cycloalkyl, with the proviso that when R 3  is OH, then R 4  is not an ethyl; 
         R 4  is one of optionally substituted alkyl or together with R 3  cycloalkyl; and 
         X is one of nothing, O, NR 1 , S, sulfone, or sulfoxide. 
       
     
     
         9 . The compound of  claim 8 , wherein the compound is an amide derivative of taurine, glycine, alanine, valine, phenylalanine, leucine, or isoleucine. 
     
     
         10 . A compound as in  claim 8 , the compound being represented by Formula II 
       
         
           
           
               
               
           
         
         wherein Ar is an optionally substituted pyrazine, optionally substituted pyridine, or an optionally substituted quinoxaline, wherein up to 5 substituents are optionally present on Ar and each substituent is independently selected from the group consisting of alkyl, halogen, alkoxy, CH 2 OH, CONH 2 , CN, and OCH 2 COOH. 
       
     
     
         11 . A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound of Formula IIA of  claim 8  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         12 . A pharmaceutical composition for treating and/or preventing one or more neurodegenerative disease, comprising a neuroprotective effective amount of at least one compound of Formula IIA of  claim 8  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the neurodegenerative disease is at least one of Huntington's Disease, Parkinson's Disease, Alzheimer's Disease, or amyotrophic lateral sclerosis (ALS). 
     
     
         14 . A pharmaceutical composition for treating and/or preventing spinal muscular atrophy, comprising a therapeutically effective amount of at least one compound of Formula IIA of  claim 8  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         15 . A method for treating and/or preventing one or more of a neurodegenerative disease, spinal muscular atrophy, or Duchenne muscular dystrophy, comprising administering to a subject a therapeutically effective amount of a compound of Formula IIA of  claim 8 . 
     
     
         16 . A compound represented by Formula III 
       
         
           
           
               
               
           
         
         wherein R 1  is one of H, CH 3 , C 2 H 5 , (CH 2 ) 2 SO 3 H, or CHZCOOH; 
         Z is one of H, CH 3 , CH(CH 3 ) 2 , CH 2 Cl 6 H, CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3 ; 
         R 2  is independently one of H or CH 3 ; or R 1  and R 2  together are cycloalkyl or heterocycle; 
         R 3  is one of H, Cl, F, CF 3 , CN, C 1 -C 5  alkyl, C 1 -C 5  alkoxy, OCF 3  or CONR 1 R 2 ; and 
         n=0-2. 
       
     
     
         17 . The compound of  claim 16 , wherein the compound is an amide derivative of taurine, glycine, alanine, valine, phenylalanine, leucine, or isoleucine. 
     
     
         18 . A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound of Formula III of  claim 16  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         19 . A pharmaceutical composition for treating and/or preventing one or more neurodegenerative disease, comprising a neuroprotective effective amount of at least one compound of Formula III of  claim 16  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the neurodegenerative disease is at least one of Huntington's Disease, Parkinson's Disease, Alzheimer's Disease, or amyotrophic lateral sclerosis (ALS). 
     
     
         21 . A pharmaceutical composition for treating and/or preventing spinal muscular atrophy, comprising a therapeutically effective amount of at least one compound of Formula III of  claim 16  admixed with at least one of a pharmaceutically acceptable carrier or an excipient. 
     
     
         22 . A method for treating and/or preventing one or more of a neurodegenerative disease, spinal muscular atrophy, or Duchenne muscular dystrophy, comprising administering to a subject a therapeutically effective amount of a compound of  claim 16 .