Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases

Abstract

The invention relates to BCAT inhibitors and the use thereof for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating anxiety, psychosis, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, chronic pain, neuropathic pain, Parkinson's disease, diabetic retinopathy, glaucoma, CMV retinitis, urinary incontinence, opioid tolerance or withdrawal, and inducing anesthesia, as well as for enhancing cognition.

1 . A compound of the Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 3  is H, halogen, alkyl, carboxy, alkoxy, or substituted alkoxy;  
 R 1 , R 2 , R 4 , and R 5  are independently, H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, NO 2 , halogen, or CF 3 ;  
 R 6  or R 7  is independently H, halogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, C(CH 2 ) n —NHSO 2 -aryl, C(CH 2 ) n —NHSO 2 -substituted aryl, (CH 2 ) n —NHSO 2 -alkyl, (CH 2 ) n —NHSO 2 -substituted alkyl, (CH 2 ) n —NHSO 2 -arylalkyl, (CH 2 ) n —NHSO 2 -substituted arylalkyl, NHSO 2 -aryl, (CH 2 ) n aryl, (CH 2 ) n -substituted aryl, (CH 2 ) n -alkyl, (CH 2 ) n -substituted alkyl, O-alkyl, O-substituted alkyl, (CH 2 ) n —SO 2 NH-aryl, (CH 2 ) n —SO 2 NH-substituted aryl, (CH 2 ) n —SO 2 NH-alkyl, (CH 2 ) n —SO 2 NH-substituted alkyl, (CH 2 ) n —C(O)NH-arylalkyl, (CH 2 ) n —C(O)NH-substituted arylalkyl, (CH 2 ) n —C(O)NH-aryl, (CH 2 ) n —C(O)NH-substituted aryl, (CH 2 ) n —C(O)NH-alkyl, (CH 2 ) n —C(O)NH-substituted alkyl, (CH 2 ) n —SO 2 NH-arylalkyl, (CH 2 ) n —SO 2 NH-substituted arylalkyl, (CH 2 ) n —NH 2 , (CH 2 ) n NH-aryl, (CH 2 ) n —NH-substituted aryl, (CH 2 ) n —NH-alkyl, (CH 2 ) n —NH-substituted alkyl, (CH 2 ) n —NH-arylalkyl, (CH 2 ) n —NH-substituted arylalkyl, (CH 2 ) n —NHSO 2 -aryl, (CH 2 ) n —NHSO 2 -substituted aryl, (CH 2 ) n —NHC(O)-arylalkyl, (CH 2 ) n —NHC(O)-substituted arylalkyl, (C≡C)-alkyl, (C≡C)-substituted alkyl, (C≡C)-arylalkyl, (C≡C)-substituted arylalkyl, (C≡C)-aryl, or (C≡C)-substituted aryl; and  
 n is 0, 1, 2, or 3.  
 or a pharmaceutically acceptable salt, ester, prodrug, or amide thereof.  
 
     
     
         2 . A compound according to  claim 1  where R 1 , R 2 , R 3 , R 4  and R 5  are hydrogen.  
     
     
         3 . A compound according to  claim 1  wherein R 6  or R 7  comprises —NHSO 2 -aryl, —NHSO 2 -substituted aryl, —NHSO 2 -alkyl or —NHSO 2 -substituted alkyl, and R 1 , R 2 , R 3 , R 4  and R 5  are H.  
     
     
         4 . (Cancelled).  
     
     
         5 . A compound according to  claim 1  wherein the compound is: 
 Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(2,4,6-trichlorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[[4-(trifluoromethyl)phenyl]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(3,4-dimethoxyphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[[(4-phenoxy)benzene]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(2-chloro-6-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[(methylsulfonyl)amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-ethylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-propylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-butylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-pentylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-fluorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[phenylsulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    4-Benzylamino-benzoic acid 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(3-methylphenyl)sulfonyl]amino-, 2-(phenylsulfonyl)hydrazide;    4-(1,1-Dimethylethyl)-benzoic acid 2-(phenylsulfonyl)hydrazide;    [1,1′-Biphenyl]-4-carboxylic acid 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-methoxyphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    4-Iodo-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-Phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide;    Phenethyl-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3-Cyclohexyl-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3-Cyclohexyl-3-hydroxy-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3-Cyclohexyl-3-hydroxy-1-propyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3,3-Dimethyl-1-butynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide; and    4-(3,3-Dimethyl-1-butyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide.    
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1  and pharmaceutically acceptable carrier.  
     
     
         7 . A method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia or surgery, or treating a neurodegenerative disease, or treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, or treating anxiety, psychosis, glaucoma, CMV retinitis, diabetic retinopathy, urinary incontinence, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, Parkinson's disease, chronic pain, neuropathic pain, or inducing anesthesia, opioid tolerance or withdrawal, or enhancing cognition, comprising administering to a patient in need of such treatment an effective amount of a compound of  claim 1 .  
     
     
         8 . The method of  claim 7  wherein R 6  or R 7  comprises —NHSO 2 -aryl, —NHSO 2 -substitued aryl, —NHSO 2 -alkyl or —NHSO 2 -substituted alkyl, and R 1 , R 2 , R 3 , R 4 , and R 5  are H.  
     
     
         9 . The method of  claim 7  wherein R 1 , R 2 , R 3 , R 4 , and R 5  are hydrogen.  
     
     
         10 . (Cancelled).  
     
     
         11 . The method of  claim 7  wherein R 1 , R 2 , R 3 , R 4 , and R 5  are hydrogen.  
     
     
         12 . The method of  claim 7  wherein the compound is: 
 Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide.    
     
     
         13 . A method for inhibiting branched chain amino acid-dependent aminotransferase in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a compound of  claim 1 .  
     
     
         14 . The method of  claim 13 , wherein R 6  or R 7  comprises —NHSO 2 -aryl, —NHSO 2 -substitued aryl, —NHSO 2 -alkyl or —NHSO 2 -substituted alkyl, and R 1 , R 2 , R 3 , R 4 , and R 5  are H.  
     
     
         15 . (Cancelled).  
     
     
         16 . The method of  claim 13 , wherein R 1 , R 2 , R 3 , R 4 , and R 5  are hydrogen.  
     
     
         17 . The method of  claim 13 , wherein the compound is: 
 Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[[4-(trifluoromethyl)phenyl]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(3,4-dimethoxyphenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[[(4-phenoxy)benzene]sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(2-chloro-6-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[(methylsulfonyl)amino]-, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-methylphenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-ethylphenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-propylphenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-butylphenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-n-pentylphenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-fluorophenyl)sulfonyl]amino]-2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[phenylsulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    4-Benzylamino-benzoic acid 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(3-methylphenyl)sulfonyl]amino], -2-(phenylsulfonyl)hydrazide;    4-Phenoxybenzoic acid, 2-[(3-methyl)phenylsulfonyl]hydrazide;    4-Phenoxybenzoic acid, 2-[3-bromophenylsulfonyl]hydrazide;    4-Phenoxybenzoic acid, 2-[2-chlorophenylsulfonyl]hydrazide;    4-Phenoxybenzoic acid, 2-[2-(trifluoromethoxy)phenylsulfonyl]hydrazide;    4-Phenoxybenzoic acid, 2-[(4-methyl-3-nitro)phenylsulfonyl]hydrazide;    4-Phenoxybenzoic acid, 2-[2-trifluorophenylsulfonyl]hydrazide;    4-(1,1-Dimethylethyl)-benzoic acid 2-(phenylsulfonyl)hydrazide;    [1,1′-Biphenyl]-4-carboxylic acid 2-(phenylsulfonyl)hydrazide;    3-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;    2-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;    4-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;    4-Benzyloxybenzoic acid, 2-(phenylsulfonyl)hydrazide;    Benzoic acid, 4-[[(4-methoxyphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;    4-Iodo-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-Phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide;    Phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3-Cyclohexyl-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3-Cyclohexyl-3-hydroxy-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3-Cyclohexyl-3-hydroxy-1-propyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide;    4-(3,3-Dimethyl-1-butynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide; and    4-(3,3-Dimethyl-1-butyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide.