Azole compounds used as tuberculostatic and leishmanicide agents

Abstract

This invention refers to new 1,2,3-triazole and imidazole compounds included in the families of compounds represented by general formula VIII. where: X is an atom of “C” or “N;” where X is “N” the radicals do triazole ring are represented by: R 1 =COR 2 , CSR 3 , CN(R 4 )R 5 or CF 2 R 6 ; R 2 =H, NHNH 2 , alkyl, aryl substituted or not, OH, NR 7 R 8 or OR 9 ; R 3 =alkyl or aryl substituted or not; R 4 =H, OH, alkyl or aryl substituted or not; R 5 =R 6 =R 7 =R 8 =R 9 =R 10 =H, alkyl or aryl substituted or not; where X is “C” the radicals do imidazolic ring are represented by: R 1 =COR 2 ; R 2 =NHNH 2 , OH, OR 3 , or NR 4 R 5 ; R 3 =alkyl or aryl substituted or not; =R 5 H, alkyl or aryl substituted or not; R 10 =NHR 6 or NR 6 R 7 ; R 6 =R 7 =COR 8 ; R 8 =aryl substituted or not; while radical R n can be located in any one or in more than one of the carbon atoms of the aromatic ring, and these radicals can be equal or different, represented by hydrogen, alkylic groups with 1 or more carbon atoms in a linear or branched chain alkenes or alkynes, hydroxyl, hydroxyalkyl or oxygenated functions in acyclic or cyclic systems forming an heterocyclic ring, free or substituted amines, thioalkyl, donators and/or removing groupings of electrons or halogens, thus “n” can vary from 1 to 5. This invention also refers to a pharmaceutical composition comprising, as active principle, at least one of the azole compounds represented by the general formula VIII, to the use of such compositions and to method of treatment or inhibition de tuberculosis and leishmaniasis.

1 . AZOLE COMPOUNDS USED AS TUBERCULOSTATIC AND LEISHMANICIDE AGENTS wherein the compounds 1,2,3-triazole and/or imidazole, or one of their salts, are represented by the general formula VIII: 
     
       
         
         
             
             
         
       
       where: 
       X is an atom of “C” or “N” 
       where X is “N” the radicals do triazole ring are represented by: 
       R 1 =COR 2 , CSR 3 , CN(O)R 5  or CF 2 R 6 ; 
       R 2 =H, NHNH 2 , alkyl, aryl substituted or not, OH, NR 7 R 8  or OR 9    
       R 3 =alkyl or aryl substituted or not 
       R 4 =H, OH, alkyl or aryl substituted or not 
       R 5 =R 6 =R 7 =R 8 =R 9 =R 10 =H, alkyl or aryl substituted or not 
       when X is “C” the radicals of the imidazolic ring are represented by: 
       R 1 =COR 2    
       R 2 =NHNH 2 , OH, OR 3 , or NR 4 R 5    
       R 3 =alkyl or aryl substituted or not 
       R 4 =R 5 =H, alkyl or aryl substituted or not 
       R 10 =NHR 6  or NR 6 R 7    
       R 6 =R 7 =COR 8    
       R 8 =aryl substituted or not 
     
     while radical R n  can be located in any one or in more than one of the carbon atoms of the aromatic ring, and these radicals can be equal or different, represented by hydrogen, alkylic groups with 1 or more carbon atoms in a linear or branched chain alkenes or alkynes, hydroxyl, hydroxyalkyl or oxygenated functions in acyclic or cyclic systems forming an heterocyclic ring, free or substituted amines, thioalkyl, donators and/or removing groupings of electrons or halogens, thus “n” can vary from 1 to 5. 
   
   
       2 . AZOLE COMPOUNDS USED AS TUBERCULOSTATIC AND LEISHMANICIDE AGENTS according to  claim 1  wherein the compounds 1,2,3-triazole are selected among: 
     4-carboxaldehyde-1-(4-chlorophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-bromophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-methylphenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-methoxyphenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(3-chlorophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(3,5-dichlorophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(3-cyanophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-cyanophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-nitrophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(2-methoxyphenyl)-1H-1,2,3-triazole; and, 4-carboxaldehyde 1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole, or one of their salts. 
   
   
       3 . AZOLE COMPOUNDS USED AS TUBERCULOSTATIC AND LEISHMANICIDE AGENTS according to  claim 1  wherein the compounds 1,2,3-triazole are selected among: 
     1-(4-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-bromophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-methylphenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(2,5-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(3-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(3,5-dichlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(3-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-nitrophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(2-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole; and, 1-(3,4-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole, or one of their salts. 
   
   
       4 . AZOLE COMPOUNDS USED AS TUBERCULOSTATIC AND LEISHMANICIDE AGENTS according to  claim 1  wherein the compounds 1,2,3-triazole are selected among: 
     (AND)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine; and, 
     (AND)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il)methylene)benzenamine, or one of their salts. 
   
   
       5 . AZOLE COMPOUNDS USED AS TUBERCULOSTATIC AND LEISHMANICIDE AGENTS according to  claim 1  wherein the compounds imidazole are selected among: 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(3,5-dichloridephenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(2,6-difluorophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(3,5-dichloridephenyl)-1H-imidazole-4-carboxylate; and, 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(2,6-difluorophenyl)-1H-imidazole-4-carboxylate. 
   
   
       6 . AZOLE COMPOUNDS USED AS TUBERCULOSTATIC AND LEISHMANICIDE AGENTS according to  claim 1  wherein the compounds imidazole are selected among: 
     Ester ethyl 5-[(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-cyanophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-chlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(3,5-dichlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(2,6-difluorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-cyanophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-chlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(3,5-dichlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; and, 
     Ester ethyl 1-(2,6-difluorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate. 
   
   
       7 . PHARMACEUTICAL COMPOSITIONS wherein at least one of the 1,2,3-triazole and/or imidazole compounds, or one of their salts, represented by the general formula VIII: 
     
       
         
         
             
             
         
       
       where: 
       X is an atom of “C” or “N” 
       where X is “N” the radicals do triazole ring are represented by: 
       R 1 =COR 2 , CSR 3 , CN(O)R 5  or CF 2 R 6 ; 
       R 2 =H, NHNH 2 , alkyl, aryl substituted or not, OH, NR 7 R 8  or OR 9    
       R 3 =alkyl or aryl substituted or not 
       R 4 =H, OH, alkyl or aryl substituted or not 
       R 5 =R 6 =R 7 =R 8 =R 9 =R 10 =H, alkyl or aryl substituted or not 
       where X is “C” the radicals of the imidazolic ring are represented by: 
       R 1 =COR 2    
       R 2 =NHNH 2 , OH, OR 3 , or NR 4 R 5    
       R 3 =alkyl or aryl substituted or not 
       R 4 =R 5 =H, alkyl or aryl substituted or not 
       R 10 =NHR 6  or NR 6 R 7    
       R 6 =R 7 =COR 8    
       R 8 =aryl substituted or not 
     
     while radical R n  can be located in any one or in more than one of the carbon atoms of the aromatic ring, and these radicals can be equal or different, represented by hydrogen, alkylic groups with 1 or more carbon atoms in a linear or branched chain alkenes or alkynes, hydroxyl, hydroxyalkyl or oxygenated functions in acyclic or cyclic systems forming an heterocyclic ring, free or substituted amines, thioalkyl, donators and/or removing groupings of electrons or halogens, thus “n” can vary from 1 to 5. 
   
   
       8 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the compounds 1,2,3-triazole are selected among: 
     4-carboxaldehyde-1-(4-chlorophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-bromophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-methylphenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-methoxyphenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(3-chlorophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(3,5-dichlorophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(3-cyanophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-cyanophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(4-nitrophenyl)-1H-1,2,3-triazole; 
     4-carboxaldehyde-1-(2-methoxyphenyl)-1H-1,2,3-triazole; and, 
     4-carboxaldehyde 1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole, or one of their salts. 
   
   
       9 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the compounds 1,2,3-triazole are selected among: 
     1-(4-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-bromophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-methylphenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(2,5-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(3-chlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(3,5-dichlorophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(3-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-cyanophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(4-nitrophenyl)-4-difluoromethyl-1H-1,2,3-triazole; 
     1-(2-methoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole; and, 
     1-(3,4-dimethoxyphenyl)-4-difluoromethyl-1H-1,2,3-triazole, or one of their salts. 
   
   
       10 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the compounds 1,2,3-triazole are selected among: 
     (AND)-4-chloride-N-((1-(4-chlorophenyl)-1H-1,2,3-triazole-4-il) methylene)benzenamine; and, 
     (AND)-4-bromo-N-((1-(4-bromophenyl)-1H-1,2,3-triazole-4-il) methylene)benzenamine, or one of their salts. 
   
   
       11 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the compounds imidazole are selected among: 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(3,5-dichloridephenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(4-fluorobenzoic)amino]-1-(2,6-difluorophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(3,5-dichloridephenyl)-1H-imidazole-4-carboxylate; and, 
     Ester ethyl 5-[(bis(2-fluorobenzoic)amino]-1-(2,6-difluorophenyl)-1H-imidazole-4-carboxylate. 
   
   
       12 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the compounds imidazole are selected among: 
     Ester ethyl 5-[(4-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-cyanophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-chlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(3,5-dichlorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester 1-(2,6-difluorophenyl)-5-[(4-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 5-[(2-fluorobenzoic)amino]-1-(4-methylphenyl)-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-cyanophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(4-chlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate; 
     Ester ethyl 1-(3,5-dichlorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate de ethyl; and, 
     Ester ethyl 1-(2,6-difluorophenyl)-5-[(2-fluorobenzoic)amino]-1H-imidazole-4-carboxylate. 
   
   
       13 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the composition is in the pharmaceutical form of solution, suspension, emulsion, ointment, cream, gel, tablet and/or capsule. 
   
   
       14 . PHARMACEUTICAL COMPOUNDS according to  claim 7  wherein the composition is in the pharmaceutical formulation for oral, topic and/or injection form. 
   
   
       15 . USE OF PHARMACEUTICAL COMPOUNDS IN THE TREATMENT OR INHIBITION OF DISEASES as described in  claim 7  wherein it is employed as drug in the treatment or inhibition of tuberculosis and leishmaniasis. 
   
   
       16 . METHOD OF TREATMENT OR INHIBITION OF DISEASES wherein the pharmaceutical composition of  claim 7  is employed as a drug in the treatment or inhibition of tuberculosis and leishmaniasis. 
   
   
       17 . METHOD OF TREATMENT OR INHIBITION OF DISEASES according to  claim 16  wherein the pharmaceutical composition is employed in the pharmaceutical form of solution, suspension, emulsion, ointment, cream, gel, tablet and/or capsule. 
   
   
       18 . METHOD OF TREATMENT OR INHIBITION OF DISEASES according to  claim 17  wherein the pharmaceutical composition is employed in the pharmaceutical form for oral, topic and/or injectable use.