5-sulfanylhistidines and their disulfides and method of preparation thereof

Abstract

The invention relates to a compound of the 5-acylsulfanyl-histidine type and the derivatives thereof, of general formula (I), wherein R1 to R3=H, alkyl, especially CH3; R4=H, alkyl, especially CH3, alkyle(C=0), substituted alkyl (C═O), aryl (C═O); β-alanyl (H2NCH2CH2 (C═O); α-amino-acyl; R5=alkyl, especially methyl, phenyl. The invention also relates to the use of said compound for producing compounds of the 5-sulfanyl-histidine type and the derivatives thereof, in addition to corresponding disulfides; and to the various methods for the production thereof.

1 - 20 . (canceled) 
     
     
         21 . A compound of the 5-sulfanylhistidine of formula (II): 
       
         
           
           
               
               
           
         
         where: 
         R1=H, or alkyl; 
         R2=R3=H, or alkyl; 
         R4=H, alkyl, alkyl (C═O), substituted alkyl (C═O), aryl (C═O), β-alanyl (H2NCH2CH2 (C═O), or α-amino-acyl; 
         R 1  to R 4  being as defined above; it being understood that when R 1 ═H then R 2 , R 3  and R 4  cannot simultaneously be H. 
         As well as all the stereoisomers, diastereoisomers and enantiomers, in particular in terms of the carbon atom bearing the COOH group, as well as all the corresponding disulfides, taken separately or in a mixture; all the salts of pharmaceutically acceptable acids of said compounds of general formula (II). 
       
     
     
         22 . The compound of  claim 21 , characterized in that R 4  represents hydrogen, methyl, acetyl, benzoyl, or β-alanyl (H 2 NCH 2 CH 2  (C═O). 
     
     
         23 . The compound of  claim 21 , characterized in that it is selected from the group consisting of:
 the disulfide of L-5-sulfanyl-α,N(methyl)-histidine (Compound 22);   L-5-sulfanyl-α,N(methyl)-histidine (Compound 23);   the disulfide of L-5-sulfanyl-α,N,N(dimethyl)-histidine (Compound 24);   L-5-sulfanyl-α,N,N(dimethyl)-histidine (Compound 25);   L-5-sulfanyl-α,N,N,N(trimethyl)-histidine (Compound 26);   the disulfide of L-5-sulfanyl-α,N,N,N(trimethyl)-histidine (Compound 27);   the disulfide of L-5-sulfanyl-α,N(acetyl)-histidine (Compound 28);   L-5-sulfanyl-α,N(acetyl)-histidine (Compound 29);   L-5-sulfanylcarnosine (Compound 30);   the disulfide of iso-ovothiol A (Compound 31);   iso-ovothiol A (Compound 32);   the disulfide of L-5-sulfanyl-α,N,N(dimethyl)-1-methylhistidine (Compound 33);   L-5-sulfanyl-α,N,N,N(trimethyl)-1-methylhistidine (Compound 34);   L-5-sulfanyl-α,N(L-alanyl)-histidine (Compound 35);   and   the disulfide of 5-sulfanyl-α,N(pentanoyl)-histidine (Compound 36).   
     
     
         24 . The compound of  claim 21 , characterized in that the pharmaceutically acceptable acid is selected from a mineral acid, an organic acid, an alkanesulfonic acid or an arylsulfonic acid such as benzene- and paratoluenesulfonic acids. 
     
     
         25 . The compound of  claim 24 , wherein the mineral acid is selected from the group consisting of hydrochloric, hydrobromic, hydroiodic, sulfuric, tartaric, and phosphoric acid. 
     
     
         26 . The compound of  claim 24 , wherein the organic acid is selected from the group consisting of formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, citric, oxalic, glyoxylic, and aspartic acid. 
     
     
         27 . The compound of  claim 24 , wherein the alkanesulfonic acid is selected from the group consisting of methanesulfonic, trifluoromethanesulfonic, and ethanesulfonic acid. 
     
     
         28 . The compound of  claim 24 , wherein the arylsulfonic acid is selected from the group consisting of benzenesulfonic acid and paratoluenesulfonic acid. 
     
     
         29 . “One-pot” method (D) for preparing the 5-sulfanyl-histidine compounds of formula (II) as defined in  claim 21 , and their corresponding disulfides from the corresponding histidine compounds, by combining the following methods:
 (A) a method_(A) for preparing the 5-acylsulfanyl-histidine compounds of formula (I), 
 
       
         
           
           
               
               
           
         
         Where R1 to R4 are as defined for the compounds of formula (II) and R5 is alkyl or phenyl;
 as well as all the stereoisomers, diastereoisomers and enantiomers, in particular in terms of the carbon atom bearing the COOH group, taken separately or in a mixture; and all the salts of pharmaceutically acceptable acids of said compound of general formula (I), characterized in that said method is comprising the following steps: 
 1) The reaction of the histidine, racemic (DL) or one of the enantiomers thereof (D or L), or 
 one of their compounds alkylated on the nitrogen in position 1 of the imidazole ring, racemic (DL) or one of the enantiomers thereof (D or L), or 
 one of their compounds alkylated or acylated on the nitrogen of the α-amine function, racemic (DL) or one of the enantiomers thereof (D or L), or 
 one of their compounds alkylated on the nitrogen in position 1 of the imidazole ring and alkylated or acylated on the nitrogen of the α-amine function, racemic (DL) or one of the enantiomers thereof (D or L), 
 in the presence of 1 to 2 equivalents of mineral or organic acid, with 
 a) an agent generating halogenium ions X+ in a polar protic solvent, at temperatures of 0-25° C., then with 
 b) a sulfur-containing reagent of the carbothioic acid type of formula alkyl or phenyl C(═O)SH or one of the salts thereof in a polar protic solvent, 
 then, 
 2) optionally, the purification by column liquid chromatography or any other purification method well known to the person skilled in the art. with 
 
         (B) a method (B) for preparing the 5-sulfanylhistidine compounds of formula (II) obtained from the 5-acylsulfanyl-histidine compounds of formula (I) described in method (A), characterized in that said method comprising the following steps:
 1) Either directly (method B1): 
 e) by hydrolysis of the 5-acylsulfanyl-histidine compound obtained in a polar protic solvent by stirring at a temperature above 20° C. in the presence of a thiol, 
 f) then, optionally, purification by column liquid chromatography or any other purification method well known to the person skilled in the art. 
 2) Or indirectly (method B2): 
 f) by hydrolysis of the 5-acylsulfanyl-histidine compound obtained in a polar protic solvent by stirring at a temperature above 20° C. in order to obtain the corresponding disulfide, 
 g) then reduction of the disulfide by reaction with a thiol, 
 h) then, optionally, purification by column liquid chromatography or any other purification method well known to the person skilled in the art; 
 
         or with 
         (C) a method (C) characterized in that said method comprises the following steps:
 in the presence of 1 to 2 equivalents of mineral or organic acid, the reaction with: 
 c) an agent generating halogenium ions X + in a polar protic solvent, at a temperature of 0-25° C., then with 
 d) a sulfur-containing reagent of the carbothioic acid of formula alkyl or phenyl C(═O)SH or one of the salts thereof in a polar protic solvent, 
 followed by 
 1) Either: 
 
         g) the hydrolysis of the 5-acylsulfanyl-histidine compound obtained in a polar protic solvent by stirring at a temperature between 70 and 130° C. in the presence of a thiol,
 h) then, optionally, the purification by column liquid chromatography or any other purification method well known to the person skilled in the art. 
 2) Or: 
 j) by hydrolysis of the 5-acylsulfanyl-histidine compound obtained in a polar protic solvent by stirring at a temperature between 70 and 130° C. in order to obtain the corresponding disulfide, 
 k) then, optionally, purification by column liquid chromatography or any other purification method well known to the person skilled in the art. 
 
       
     
     
         30 . The method of  claim 29 , wherein the agent generating halogenium ions X + is selected from:
 bromine Br 2 , as commercial reagent or prepared in situ; or   NBS or any N-bromo-imide and N-bromo-amide compound.   
     
     
         31 . The method of  claim 29 , wherein the polar protic solvent is water or an aqueous solution. 
     
     
         32 . The method of  claim 29 , wherein the sulfur-containing reagent of the carbothioic acid is selected from thioacetic acid, thiobenzoic acid, potassium thioacetate, or mixtures thereof. 
     
     
         33 . The method of  claim 29 , wherein the temperature in method (A) is 0-5° C. 
     
     
         34 . The method of  claim 29 , wherein the thiol is selected from mercaptopropionic acid, dithiothreitol or mixtures thereof. 
     
     
         35 . The method of  claim 29 , wherein the temperature in method (B) is between 20 and 130° C.