FLUORO-CONTAINING DERIVATIVES OF HYDROGENATED PYRIDO[4,3-b]INDOLES WITH NEUROPROTECTIVE AND COGNITION ENHANCING PROPERTIES, PROCESS FOR PREPARING, AND USE

Abstract

Some exemplary embodiments comprise fluoro-containing derivatives of pyrido[4,3-b]indoles (and exemplary methods of making the same) that may be administered to a mammal (including a human) in an effective amount for potential use in the treatment or prophylaxis of neurological disorders including AD, mild cognitive impairment, senile and vascular dementia, HD, ALS, Parkinson's disease, AIDS-related dementia, ischaemic cerebral pathologies, neuropathic pain, ADHD (attention deficit disorder/hyperactivity syndrome), eating disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia (in particular the cognitive deficit of schizophrenia), stroke and also disorders associated with spinal trauma and/or head injury. These derivatives may also be useful for the treatment of borderline personality disorder, obesity, and for use as geroprotectors. The compounds may also be used as “pharmacological tools” for an investigation of the mechanism of protection against neurodegeneration disorders in vivo or in vitro.

1 . A method for synthesis of a fluoro-containing pyrido[4,3-b]indole derivative having a general formula of compound I, the method comprising:
 adding a hydrogenated pyrido[4,3-b]indole having a general formula of compound II to a vinylpyridine having a general formula of compound III:   
     
       
         
         
             
             
         
       
       wherein the reaction of a gamma-carboline of formula II with a vinylpyridine of formula III is preferably carried out in a solvent (e.g., DMF, DMSO, HMPTA, NMP, ethanol, etc.) and in the presence of a base (e.g., MeONa, t-BuOK, NaOH, DABCO, tributylamine, CsF, etc.). 
     
   
   
       2 . A method for synthesis of compounds of formula I according to  claim 1  by nucleophilic addition of a hydrogenated pyrido[4,3-b]indole of formula II to a reactive vinylpyridine of formula III: 
     
       
         
         
             
             
         
       
       wherein compound III is fluoro or di-fluoro substituted vinylpyridine. 
     
   
   
       3 . A method for synthesis of compounds of formula I according to  claim 1  by nucleophilic addition of a hydrogenated pyrido[4,3-b]indole of formula II to a reactive vinylpyridine of formula III: 
     
       
         
         
             
             
         
       
       wherein compound III is trifluoromethyl substituted vinylpyridine. 
     
   
   
       4 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       5 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       6 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-8-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       7 . The method of  claim 1 , wherein compound I is:
 8-chloro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       8 . The method of  claim 1 , wherein compound I is:
 8-bromo-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       9 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       10 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-6,8-difluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       11 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-8-trifluoromethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       12 . The method of  claim 1 , wherein compound I is:
 5-[2-(5-fluoropyridin-3-yl)ethyl]-8-trifluoromethoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       13 . The method of  claim 1 , wherein compound I is:
 2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       14 . The method of  claim 1 , wherein compound I is:
 2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       15 . The method of  claim 1 , wherein compound I is:
 2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       16 . The method of  claim 1 , wherein compound I is:
 2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       17 . The method of  claim 1 , wherein compound I is:
 2,8-dimethyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       18 . The method of  claim 1 , wherein compound I is:
 8-chloro-2-methyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
   
   
       19 . A method for synthesis of a fluoro-containing pyrido[4,3-b]indole derivative having a general formula of compound I, the method comprising:
 adding a hydrogenated pyrido[4,3-b]indole having a general formula of compound II to a vinylpyridine having a general formula of compound III:   
     
       
         
         
             
             
         
       
       wherein the reaction of a gamma-carboline of formula II with a vinylpyridine of formula III is preferably carried out in a solvent (e.g., DMF, DMSO, HMPTA, NMP, ethanol, etc.) and in the presence of a base (e.g., MeONa, t-BuOK, NaOH, DABCO, tributylamine, CsF, etc.); and 
       wherein compound III is 2-Fluoro-5-vinylpyridine is formed by a mixture of 2-fluoro-5-bromopyridine, tributyl(vinyl)stannane, and tetrakis(triphenyl-phosphine)palladium. 
     
   
   
       20 . A method for synthesis of a fluoro-containing pyrido[4,3-b]indole derivative having a general formula of compound I, the method comprising:
 adding a hydrogenated pyrido[4,3-b]indole having a general formula of compound II to a vinylpyridine having a general formula of compound III:   
     
       
         
         
             
             
         
       
       wherein the reaction of a gamma-carboline of formula II with a vinylpyridine of formula III is preferably carried out in a solvent (e.g., DMF, DMSO, HMPTA, NMP, ethanol, etc.) and in the presence of a base (e.g., MeONa, t-BuOK, NaOH, DABCO, tributylamine, CsF, etc.); and 
       wherein compound III is 3-Fluoro-5-vinylpyridine formed by a mixture of 3-fluoro-5-bromopyridine, tributyl(vinyl)stannane, and tetrakis(triphenylphosphine)palladium.