Processes for the preparation of piperidinic derivatives and pharmaceutic compositions containing the same

Abstract

Production processes for preparing pharmaceutical compositions containing new molecules capable of inhibiting acetylcholinesterase, thus being useful in the treatment of pathologies associated to cholinergic transmission, such as memory related disorders, neurodegenerative disorders such as Alzheimer's Disease, Miastenia Gravis or in the treatment of intoxications induced by chemical agents of central action.

1 . A process for the preparation of piperidinic derivatives of general formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         n corresponds to an integer number from 2 to 16, and 
         R 1  is hydrogen, acyl, alkyl, alkoxyl, cycloalkyl; furyl, tiophenyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, quinazolyl, isoquinolyl or Phenyl-W;
 wherein W is hydrogen, ortho-alkyl, ortho-cycloalkyl, ortho-alkoxyl, ortho-cycloalkoxyl, ortho-thioxy, ortho-aryloxy, ortho-sulfones, ortho-sulfides, ortho-sulfoxides, ortho-sulfonates, ortho-sulfonamides, ortho-amino, ortho-amido, ortho-halo, ortho-carboalkoxy, ortho-carbothioalkoxy, ortho-trihaloalkane, ortho-cyano, ortho-nitro, meta-alkyl, meta-cycloalkyl, meta-alkoxyl, meta-cycloalkoxyl, meta-thioxy, meta-aryloxy, meta-sulfones, meta-sulfides, meta-sulfoxides, meta-sulfonates, meta-sulfonamides, meta-amino, meta-amido, meta-halo, meta-carboalkoxy, meta-carbothioalkoxy, meta-trihaloalkane, meta-cyano, meta-nitro, para-alkyl, para-cycloalkyl, para-alkoxyl, para-cycloalkoxyl, para-thioxy, para-aryloxy, para-sulfones, para-sulfides, para-sulfoxides, para-sulfonates, para-sulfonamides, para-amino, para-amido, para-halo, para-carboalkoxy, para-carbothioalkoxy, para-trihaloalkane, para-cyano or para-nitro; 
 
         or a pharmaceutically acceptable salt thereof, 
         comprising at least one step of alcoholic and/or hydroalcoholic extraction of flowers and/or buds from plants of the  Cassia  genus. 
       
     
     
         2 . The process according to  claim 1 , wherein the referred piperidinic derivatives are obtained from plants of the specie  C. spectabilis.    
     
     
         3 . The process according to  claim 1 , further comprising subjecting the extract to at least one of the following steps:
 concentration;   filtration;   liquid-liquid extraction;   alkalinization;   column chromatography fractioning; and   any combination of the above steps.   
     
     
         4 . A process for the preparation of piperidinic derivatives of general formula (II) 
       
         
           
           
               
               
           
         
         wherein: 
         n corresponds to an integer number from 2 to 16; 
         R 1  is hydrogen, acyl, alkyl, alkoxyl, cycloalkyl; furyl, tiophenyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, quinazolyl, isoquinolyl or Phenyl-W;
 wherein W is hydrogen, ortho-alkyl, ortho-cycloalkyl, ortho-alkoxyl, ortho-cycloalkoxyl, ortho-thioxy, ortho-aryloxy, ortho-sulfones, ortho-sulfides, ortho-sulfoxides, ortho-sulfonates, ortho-sulfonamides, ortho-amino, ortho-amido, ortho-halo, ortho-carboalkoxy, ortho-carbothioalkoxy, ortho-trihaloalkane, ortho-cyano, ortho-nitro, meta-alkyl, meta-cycloalkyl, meta-alkoxyl, meta-cycloalkoxyl, meta-thioxy, meta-aryloxy, meta-sulfones, meta-sulfides, meta-sulfoxides, meta-sulfonates, meta-sulfonamides, meta-amino, meta-amido, meta-halo, meta-carboalkoxy, meta-carbothioalkoxy, meta-trihaloalkane, meta-cyano, meta-nitro, para-alkyl, para-cycloalkyl, para-alkoxyl, para-cycloalkoxyl, para-thioxy, para-aryloxy, para-sulfones, para-sulfides, para-sulfoxides, para-sulfonates, para-sulfonamides, para-amino, para-amido, para-halo, para-carboalkoxy, para-carbothioalkoxy, para-trihaloalkane, para-cyano or para-nitro; 
 
         R 2  is either hydrogen or alkyl with 1 to 9 carbon atoms, and 
         X is halogen; 
         or a pharmaceutically acceptable salt thereof; 
         comprising the step of submitting the respective starting compounds to a reaction of acidification with strong acids. 
       
     
     
         5 . The process according to  claim 4 , wherein the referred strong acid is hydrochloric acid. 
     
     
         6 . The process according to  claim 5 , wherein R 1  is acetyl, R 2  is hydrogen, X is chloride and n is equal to 9. 
     
     
         7 . The process according to  claim 5 , wherein R 1  is hydrogen, R 2  is hydrogen, X is chloride and n is equal to 9. 
     
     
         8 . The process according to  claim 5 , wherein R 1  is t-butoxycarbonyl, R 2  is hydrogen, X is chloride and n is equal to 9. 
     
     
         9 . The process according to  claim 5 , wherein R 1  is acetyl, R 2  is methyl, X is iodide and n is equal to 9. 
     
     
         10 . A process for the preparation of piperidinic derivatives of general formula (III) 
       
         
           
           
               
               
           
         
         wherein: 
         n corresponds to an integer number from 2 to 16; 
         R 1  is hydrogen, acyl, alkyl, alkoxyl, cycloalkyl; furyl, tiophenyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, quinazolyl, isoquinolyl or Phenyl-W;
 wherein W is hydrogen, ortho-alkyl, ortho-cycloalkyl, ortho-alkoxyl, ortho-cycloalkoxyl, ortho-thioxy, ortho-aryloxy, ortho-sulfones, ortho-sulfides, ortho-sulfoxides, ortho-sulfonates, ortho-sulfonamides, ortho-amino, ortho-amido, ortho-halo, ortho-carboalkoxy, ortho-carbothioalkoxy, ortho-trihaloalkane, ortho-cyano, ortho-nitro, meta-alkyl, meta-cycloalkyl, meta-alkoxyl, meta-cycloalkoxyl, meta-thioxy, meta-aryloxy, meta-sulfones, meta-sulfides, meta-sulfoxides, meta-sulfonates, meta-sulfonamides, meta-amino, meta-amido, meta-halo, meta-carboalkoxy, meta-carbothioalkoxy, meta-trihaloalkane, meta-cyano, meta-nitro, para-alkyl, para-cycloalkyl, para-alkoxyl, para-cycloalkoxyl, para-thioxy, para-aryloxy, para-sulfones, para-sulfides, para-sulfoxides, para-sulfonates, para-sulfonamides, para-amino, para-amido, para-halo, para-carboalkoxy, para-carbothioalkoxy, para-trihaloalkane, para-cyano or para-nitro; 
 
         R 2  is either hydrogen or alkyl with 1 to 9 carbon atoms, and 
         X is halogen; 
         or a pharmaceutically acceptable salt thereof; 
         comprising the step of submitting the respective starting compounds to a reduction reaction. 
       
     
     
         11 . The process according to  claim 10 , wherein the reducing agent is chosen from NaBH 4 /H 2 O, sodium in ethanol, LiAlH 4 , H 2  and mixtures thereof. 
     
     
         12 . The process according to  claim 11 , wherein R 1  is acetyl, R 2  is hydrogen, X is chloride and n is equal to 9. 
     
     
         13 . The process according to  claim 4 , further comprising subjecting the extract to at least one of the following steps:
 concentration;   filtration;   liquid-liquid extraction;   alkalinization;   column chromatography fractioning; and   any combination of the above steps.   
     
     
         14 . The process according to  claim 10 , further comprising subjecting the extract to at least one of the following steps:
 concentration;   filtration;   liquid-liquid extraction;   alkalinization;   column chromatography fractioning; and   any combination of the above steps.   
     
     
         15 . The process according to  claim 1 , wherein R 1  is acetyl or t-butoxycarbonyl, R 2  is hydrogen or methyl, and X is chloride or iodide. 
     
     
         16 . The process according to  claim 4 , wherein R 1  is acetyl or t-butoxycarbonyl, R 2  is hydrogen or methyl, and X is chloride or iodide. 
     
     
         17 . The process according to  claim 10 , wherein R 1  is acetyl or t-butoxycarbonyl, R 2  is hydrogen or methyl, and X is chloride or iodide