Methods for the solid phase synthesis of combinatorial libraries of benzimidazol, benzoxazoles, benzothiazoles, and derivatives thereof

Abstract

The present invention provides an efficient and versatile method for the synthesis and screening of combinatorial libraries of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof. In order to expedite the synthesis of large arrays of compounds possessing these core structures, a general methodology for solid phase synthesis of these derivatives is provided. Arrays of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof useful as peptidomimetics and for the identification of agents having antifungal, antiviral, antimicrobial, anticoagulant, and antiulcer activity, or use in the treatment of inflammation, hypertension, cancer, and other conditions can be prepared by this method.

1 . A process for the SPOS preparation of 2-substituted benzimidazoles, benzoxazoles, or benzothiazoles comprising 
 reacting a resin-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with cyanogen bromide, or    reacting a resin-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with an aldehyde in the presence of an oxidant, or    reacting a support-bound aldehyde with a 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof in the presence of an oxidant    to form a support-bound substituted benzimidazole, benzoxazole, or benzothiazole, respectively.    
     
     
         2 . The method of    claim 1    wherein the reaction is carried out at room temperature or slightly above room temperature.  
     
     
         3 . The method of    claim 1    wherein the reaction is carried out at about 40°-60° C.  
     
     
         4 . The method of    claim 1    wherein the reaction is carried out in a solvent selected from the group consisting of methanol (MeOH), ethanol (EtOH), acetonitrile (MeCN), dimethylformsamide (DMF), dimethylacetamide (DMA), or combinations thereof.  
     
     
         5 . The method of    claim 1    wherein the reaction is carried out for a period of 2 to 48 h.  
     
     
         6 . The method of    claim 1    wherein the oxidant is selected from a group consisting of p-chloranil (CA), 7,7,8,8-tetracyanoquinodimethane (TCNQ), benzylidene-malononitrile (BMCN), tetracyanoethylene (TCNE), 2,3-dicyano-1,4-benzoquinone (DCBQ), or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).  
     
     
         7 . The method of    claim 1    wherein the reaction is carried out at room temperature, with DMA as the solvent, and TCNE as the oxidant.  
     
     
         8 . The method of    claim 1    further comprising cleaving the solid support with a suitable acid, preferably trifluoroacetic acid (TFA) in dichloromethane (DCM), to form substituted benzimidazoles, benzoxazoles, or benzothiazoles.  
     
     
         9 . The method of    claim 1    wherein the support-bound aldehyde is resin-bound 4-carboxybenzaldehyde.  
     
     
         10 . The method of    claim 1    wherein the support-bound 1,2-arylenediamine is resin-bound N,N′-Fmoc-3,4-diaminobenzoic acid.  
     
     
         11 . The method of    claim 1    wherein the benzimidazole is selected from the group consisting of 2-(4-Carboxyphenyl)benzimidazole; 2-(4-Carboxyphenyl)-4-methyl-benzimidazole; 2-(4-Carboxyphenyl)-4-hydroxybenzimidazole; 2-(4-Carboxyphenyl)-4-nitrobenzimidazole; 2-(4-Carboxyphenyl)-5-ethylbenzimidazole; 2-(4-Carboxyphenyl)-5-benzimidazolylcarboxylic acid; 2-Phenyl-4-benzimidazolylcarboxylic acid; and 2-(4-Carboxyphenyl) benzoxazole; 2-(4-Carboxyphenyl) benzothiazole.  
     
     
         12 . The method of    claim 1    wherein the ratio of 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component to cyanogen bromide component will typically range from about 1:1.1 to about 1:100, preferably from about 1:1.1 to about 1:25.  
     
     
         13 . The method of    claim 1    wherein the ratio of 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component to aldehyde component and to oxidant component will typically range from about 1:1.1:1.1 to about 1:100:100, preferably from about 1:1.1:1.1 to about 1:25:25, and most preferably from about 1:1.1:1.1 to about 1:10:10.  
     
     
         14 . In a process for the preparation of benzimidazole, benzoxazole, or benzothiazole libraries wherein the improvement comprises a step selected from the group consisting of 
 reacting a support-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with cyanogen bromide under mild conditions,    reacting a support-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with an aldehyde in the presence of an oxidant,    reacting a resin-bound aldehyde with a 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof in the presence of an oxidant,    to form a support bound substituted benzimidazole, benzoxazole, or benzothiazole, respectively.    
     
     
         15 . The process for the preparation of benzimidazole, benzoxazole, or benzothiazole libraries of    claim 14    wherein the improvement further comprises one or more subsequent reactions manipulated to increase the molecular diversity of the final products selected from the group consisting of acylation with carboxylic acids or their acyl derivatives, sulfonylation with sulfonyl chlorides, reaction with isocyanates or thiocyanates, condensations with α,β-unsaturated caboxylic acid chlorides or esters, and alklations with aldehydes in the presence of a reducing agent.  
     
     
         16 . The process for the preparation of benzimidazole, benzoxazole, or benzothiazole libraries of    claim 14    or    15    wherein the improvement further comprises cleaving the solid support with triflouric acid (TFA) in dichloromethane (DCM) to form the final product.  
     
     
         17 . A library of benzimidazoles, benzoxazoles, or benzothiazoles or derivatives thereof comprising a plurality of different compounds prepared in accordance with the methods of any one of claims  14 ,  15  and  16 .  
     
     
         18 . A library of benzimidazoles, benzoxazoles, or benzothiazoles or derivatives thereof comprising a plurality of different compounds, each compound covalently linked to a solid support, wherein each of said compounds comprises at least one substituted benzimidazole group, benzoxazole group, or benzothiazole group, or a group derived from a substituted benzimidazole, benzoxazole, or benzothiazole group which group is prepared by 
 reacting a support-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with cyanogen bromide under mild conditions,    reacting a support-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with an aldehyde in the presence of an oxidant,    reacting a resin-bound aldehyde with a 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof in the presence of an oxidant,    to form a support bound substituted benzimidazole, benzoxazole, or benzothiazole, respectively.    
     
     
         19 . A library of benzimidazoles, benzoxazoles, or benzothiazoles or derivatives thereof comprising a plurality of different compounds, each compound covalently linked to a solid support, wherein each of said compounds comprises at least one substituted benzimidazole group, benzoxazole group, or benzothiazole group, or a group derived from a substituted benzimidazole, benzoxazole, or benzothiazole group which group is prepared by 
 reacting a support-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with cyanogen bromide under mild conditions,    reacting a support-bound 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof with an aldehyde in the presence of an oxidant,    reacting a resin-bound aldehyde with a 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or substituted derivative thereof in the presence of an oxidant,    to form a support bound substituted benzimidazole, benzoxazole, or benzothiazole, respectively, and    cleaving the support bound substituted benzimidazole, benzoxazole, or benzothiazole, respectively, with a suitable acid, preferably trifluoroacetic acid (TFA) in dichloromethane (DCM), to form the library of benzimidazoles, benzoxazoles, or benzothiazoles or substituted derivatives thereof.