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 compound having a general formula: 
     
       
         
         
             
             
         
       
       wherein 
       R f  is selected from a fluorine atom, two fluorine atoms, or a trifluoromethyl group; 
       R 1  is selected from a H, (C 1 -C 6 ) alkyl; hydroxyl (C 2 -C 6 ) alkyl; (hetero) aryl (C 2 -C 6 ) alkyl; (C 3 -C 7 ) cycloalkyl; (C 2 -C 6 ) alkenyl; (C 1 -C 6 ) alkylsulfonyl; (hetero) arylsulfonyl; (C 1 -C 6 ) alkanoyl; (hetero) aroyl, (C 1 -C 6 ) alkoxycarbonyl; (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl; (hetero) aryloxy (C 1 -C 6 ) alkyl; amino (C 1 -C 6 ) alkyl, wherein the amino group may be optionally substituted by alkyl, (hetero) aryl, alkenyl, alkanoyl, (hetero) aroyl and other; or a group CONR 8 R 9  or SO 2 NR 8 N 9 , wherein R 8  and R 9  independently represent hydrogen or (C 1 -C 6 ) alkyl, or R 8  and R 9  together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclic or nitrogen-containing heteroaryl group; 
       R 2  and R 3  are chosen independently from a hydrogen and a methyl group; and 
       R 4 , R 5 , R 6  and R 7  each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (C 1 -C6) alkyl, (C 1 -C 6 ) alkoxy, phenoxy, phenyl or pyridyl group optionally substituted with a halogen atom or a methyl, methoxy, cyano, trifluoromethyl, or hydroxyl group. 
     
   
   
       2 . A compound or a pharmacologically acceptable salt thereof, which is selected from a group consisting of: 
     5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(5-fluoropyridin-3-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-chloro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-bromo-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(5-fluoropyridin-3-yl)ethyl]-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     6,8-difluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-benzyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-ethyl-8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-chloro-2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-methyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2,8-dimethyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-fluoro-2-methyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-chloro-2-methyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-methyl-8-(trifluoromethyl)-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(6-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(6-fluoropyridin-3-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-fluoro-5-[2-(6-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(2-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(2-fluoropyridin-4-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-fluoro-5-[2-(2-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(3-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     5-[2-(3-fluoropyridin-4-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-fluoro-5-[2-(3-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-methyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2,8-dimethyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     8-fluoro-2-methyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; 
     2-{5-[2-(5-fluoropyridin-3-yl)ethyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}ethanol; 
     2-{5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}ethanol; and 
     2-{8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}ethanol. 
   
   
       3 . 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 hydrogentated pyrido[4,3-b]indole having a general formula of compound II to a vinylpyridine having a general formula of compound III.   
     
       
         
         
             
             
         
       
     
   
   
       4 . 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: 
     
       
         
         
             
             
         
       
     
   
   
       5 . A pharmaceutical composition comprising at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof, for treatment of a 5-HT6 receptor, a NMDA receptor and a BuChE enzyme mediated disorder. 
   
   
       6 . The pharmaceutical composition of  claim 5 , wherein the disorder is Alzheimer's disease. 
   
   
       7 . The pharmaceutical composition of  claim 5 , wherein the disorder is Huntington disease. 
   
   
       8 . A method of treating a 5-HT6 receptor, a NMDA receptor, a BuChE enzyme, or a mitochondrial mediated disorder in a mammal, the method comprising:
 administering to the mammal an effective amount of a pharmaceutical composition comprising at least one of the compounds of  claim 2 .   
   
   
       9 . The method of  claim 8 , the method further comprising:
 antagonizing the 5-HT6 receptor.   
   
   
       10 . The method of  claim 8 , the method further comprising:
 antagonizing the NMDA receptor.   
   
   
       11 . The method of  claim 8 , the method further comprising:
 inhibiting the BuChE enzyme.   
   
   
       12 . The method of  claim 8 , the method further comprising:
 alleviating the mitochondrial mediated disorder.   
   
   
       13 . The method of  claim 8 , the method further comprising:
 antagonizing an H 1  histamine receptor in the mammal.   
   
   
       14 . The method of  claim 13 , the method further comprising:
 inhibiting a release of a histamine in the mammal.   
   
   
       15 . The method of  claim 8 , the method further comprising:
 antagonizing an H 3  histamine receptor in the mammal.   
   
   
       16 . The method of  claim 8 , the method further comprising:
 administering an effective amount of an anti-depressant.   
   
   
       17 . The method of  claim 8 , the method further comprising:
 administering an effective amount of a second modulator for treating the 5-HT6 receptor, the NMDA receptor, the BuChE enzyme, or the mitochondrial mediated disorder.   
   
   
       18 . The method of  claim 17 , wherein the second modulator is donepezil. 
   
   
       19 . The method of  claim 17 , wherein the second modulator is memantine. 
   
   
       20 . The method of  claim 8 , the method further comprising:
 enhancing cognitive ability of the mammal.   
   
   
       21 . The method of  claim 8 , wherein the effective amount is between approximately 1 mg to 1 gram of the compound administered to the mammal during a twenty-four hour period. 
   
   
       22 . A method comprising using at least one of the compounds of  claim 2  as a pharmacological tool for an investigation of a mechanism of protection against neurodegeneration disorders in vivo or in vitro. 
   
   
       23 . A method selected from the group consisting of: (1) slowing aging in a mammal, the method comprising administering to a mammal at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof effective to slow aging; (2) slowing the progression of age associated hair loss in a mammal, the method comprising administering to a mammal an amount of a at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof effective to slow the progression of age associated hair loss; (3) slowing the progression of age associated weight loss in a mammal, the method comprising administering to a mammal an amount of at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof effective to slow the progression of age associated weight loss; (4) slowing the onset of an age associated vision disturbance in a mammal, the method comprising administering to a mammal an amount of at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof effective to slow the onset of an age associated vision disturbance; (5) prolonging the lifespan of a mammal, the method comprising administering to a mammal an amount of at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof effective to prolong the lifespan of the mammal; and (6) improving the quality of life of a mammal, the method comprising administering to a mammal an amount of a at least one of the compounds of  claim 2  or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient thereof effective to improve the quality of life of the mammal.