Nitrogenatd trans-stilbene analogs, method for the obtention and medical applications thereof

Abstract

This invention is related to new nitrogenated trans-stilbene analog compounds, more specifically, imine, pyrrol and Indole derivatives, with procedures for the preparation and use thereof as pharmaceutical compositions for the treatment and/or chemoprevention of those mammalian diseases such as cancer, fibrosclerosis and acute/chronic inflammation, graft-versus-host reaction, ischemic-reperfusion tissue injury in stroke and heart attack, neurodegeneration, and during organ transplantation, whose pathogenic and pathophysiological mechanisms depend on or are significantly contributed by undesirable oxidative stress, angiogenic and proliferative responses.

1 - 25 . (canceled) 
   
   
       26 . A nitrogenated trans-stilbene analog compound of the following general formula (I): 
     
       
         
         
             
             
         
       
       and salts thereof, wherein: 
       (X) is chosen from imine and pyrrole groups, wherein the pyrrole group may be bonded to the aromatic ring (A) by one or two of the pyrrole ring carbons; 
       R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  may be the same or different and are chosen from a hydrogen atom, —OH, and alkoxy groups, wherein at least three of these substituents are chosen from alkoxy-OH and alkoxy groups; and 
       R 5  is absent when the pyrrole ring is bonded to the ring (A) by two carbon atoms. 
     
   
   
       27 . A compound according to  claim 26 , wherein the compound is of the following general formula (II): 
     
       
         
         
             
             
         
       
       and salts thereof. 
     
   
   
       28 . A compound according to  claim 26 , wherein (X) is a pyrrole group which may be bonded to the aromatic ring (A) by one or two of the pyrrole ring carbons. 
   
   
       29 . A compound according to  claim 28 , wherein the compound is of the following general formula (III): 
     
       
         
         
             
             
         
       
       and salts thereof, wherein: 
       (Y) is chosen from a hydrogen atom; nitro, amino, linear and branched alkoxycarbonyl, and amide groups; and organic and inorganic quaternary ammonium salts; 
       (W) is chosen from a hydrogen atom, carboxyl, alkoxycarbonyl and aminocarbonyl groups; 
       (Z) is chosen from a hydrogen atom, linear and branched alkyl, benzyl, carboxyl, arylmethyl, heteroarylmethyl, O-alkyl(aryl)carbamoyl and N-alkyl(aryl)semicarbazide groups. 
     
   
   
       30 . A compound according to  claim 28 , wherein the compound is of the following general formula (IV): 
     
       
         
         
             
             
         
       
       and salts thereof, wherein: 
       (Z) is chosen from a hydrogen atom, linear and branched alkyl, benzyl, carboxyl, arylmethyl, heteroarylmethyl, O-alkyl(aryl)carbamoyl and N-alkyl(aryl)semicarbazide groups; and 
       (U) is chosen from a hydrogen atom and linear and branched alkyl groups. 
     
   
   
       31 . A compound according to  claim 26 , wherein the alkoxy group is a methoxy. 
   
   
       32 . A compound according to  claim 27 , wherein the compound is 5-((E)-(4-Hydroxyphenylimine) methyl)benzene-1,3-diol. 
   
   
       33 . A compound according to  claim 26 , wherein (Z) is a hydrogen atom; (W) is chosen from —COOCH 3  and —COOH; (Y) is chosen from a hydrogen atom, —NH 2  and —NO 2 ; R 1 , R 5 , R 6  and R 10  are hydrogen atoms; and R 2 , R 3 , R 4 , R 7 , R 8  and R 9  are the same or different and are chosen from a hydrogen atom, —OCH 3  and —OH. 
   
   
       34 . A compound according to  claim 33 , wherein (Z) and (Y) are hydrogen atoms. 
   
   
       35 . A compound according to  claim 33 , selected from the following group: 3,5-bis(3,5-Dihydroxyphenyl)-1H-pyrrole-2-methyl carboxylate; 3,5-bis(3,5-Dimethoxyphenyl)-1H-pyrrole-2-methyl carboxylate; 5-(3,5-Dihydroxyphenyl)-3-(4-hydroxyphenyl)-1H-pyrrole-2-methyl carboxylate; 3-(4-methoxyphenyl)-5-(dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid; 5-(3,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrrole-2-methyl carboxylate; 5-(3,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrrole-2-methyl carboxylate; 5-(3,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxylate; 4-amino-3,5-bis(3,5-dimethoxyphenyl)-1H-pyrrole-2-methyl carboxylate; 5-(3,5-dimethoxyphenyl)-3-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-methyl carboxylate; 3,5-bis(3,5-dimethoxyphenyl)-4-nitro-1H-pyrrole-2methyl carboxylate; 3,5-bis(3,5-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid; and 3-(3,5-Dihydroxyphenyl)-5-(4-hydroxyphenyl)-1H-pyrrole-2-methyl carboxylate. 
   
   
       36 . A compound according to  claim 26 , wherein (Z) is chosen from a hydrogen atom and —COOC(CH 3 ) 3  group; (U) is a hydrogen atom; and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9  are R 10  the same or different and are chosen from a hydrogen atom, —OCH 3  and —OH. 
   
   
       37 . A compound according to  claim 36 , selected from among the following group: 2-(2,5-dihydroxyphenyl)-1H-indole-4,6-diol; 4,6-Dimethoxy-2-(3,5-dimethoxyphenyl)-1H-indole; 4,6-Dimethoxy-2-(2,5-dimethoxyphenyl)-1H-indole-1-tert-butyl carboxylate; 4,6-Dimethoxy-2-(2,5-dimethoxyphenyl)-1H-indole; and 4,6-Dimethoxy-2-(3,5-dimethoxyphenyl)-1H-indole-1-tert-butylcarboxylate. 
   
   
       38 . A method for obtaining the compound according to  claim 27 , comprising the following steps:
 i) reacting an aromatic aldehyde with an aniline in the presence or absence of an organic solvent;   ii) purification by crystallization in a suitable solvent.   
   
   
       39 . A method according to  claim 38 , wherein a drying agent is added to the reaction mixture. 
   
   
       40 . A method for obtaining a compound according to  claim 29 , comprising the following steps:
 i) reacting an imine, a nitroalkene, a metallic salt and a tertiary organic base;   ii) conducting said reaction in conditions selected from a) in the presence of microwave radiation and b) in the presence of an organic solvent, at a temperature ranging from −25° C. to +25° C.;   iii) obtaining a mixture of 2-alkoxycarbonyl pyrrolidines and dissolving said mixture in cyclic ether with an oxidizing agent at a temperature ranging from 60° C. to 250° C.;   iv) obtaining a mixture of 2-alkoxycarbonyl-NH-pyrrole and 2-alkoxycarbonyl-4-nitro-NH-pyrrole and separating said mixture by fractioned crystallization or chromatography;   v) obtaining compound of general formula (III) by means of chemical transformations of compounds obtained by iv).   
   
   
       41 . A method for obtaining the compound according to  claim 30 , comprising the following steps:
 i) reacting an amine, an alpha-haloketone and a tertiary amine;   ii) conducting said reaction in the presence of microwave radiation at a temperature ranging from 90° C. to 180° C., with a radiation power ranging from 25 W to 200 W, for a time period ranging from 5 minutes to 30 minutes, at a pressure ranging from 50 psi to 200 psi.   iii) obtaining 2-aryl-1H-indoles from ii);   iv) obtaining compounds of general formula (IV) by means of chemical transformations of the 2-aryl-1H-indoles from iii).   
   
   
       42 . A method according to  claim 41 , wherein the temperature at point (ii) ranges from 130° C. to 170° C., the radiation power ranges from 80 W to 120 W, in a time ranging from 7 to 15 minutes. 
   
   
       43 . A pharmaceutically-acceptable composition comprising at least one compound according to  claim 26 . 
   
   
       44 . A method of treatment and prophylaxis of carcinogenic and inflammatory diseases comprising administering a composition according to  claim 43 . 
   
   
       45 . A method of treatment according to  claim 44  wherein the carcinogenic disease is hepatic metastasis. 
   
   
       46 . A pharmaceutical composition according to  claim 43 , in conjunction with at least one pharmaceutically-acceptable vehicle. 
   
   
       47 . A pharmaceutical composition according to  claim 43  comprising at least one additional therapeutically active substance. 
   
   
       48 . A pharmaceutical composition according to  claim 47  wherein the additional therapeutically active substance is quercetin.