BENZIMIDAZOLE COMPOUNDS FOR MODULATING IgE AND INHIBITING CELLULAR PROLIFERATION

Abstract

The present invention is directed to small molecule inhibitors of the IgE response to allergens, which are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic. This invention also relates to benzimidazole molecules that are cellular proliferation inhibitors and thus are useful as anticancer agents.

1 . A compound or salt thereof having the one of the following formulas:  
     
       
         
         
             
             
         
       
     
     wherein R is selected from the group consisting of H, C 1 -C 5  alkyl, benzyl, p-fluorobenzyl and dialkylamino alkyl, wherein said C 1 -C 5  alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl; 
 wherein R 1  and R 2  are independently selected from the group consisting of H, alkyl, substituted alkyl, C 3 -C 9  cycloalkyl, substituted C 3 -C 9  cycloalkyl, polycyclic aliphatic groups, substituted polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl, substituted naphthyl, five-member ring heteroaryl, and substituted five-member ring heteroaryl, wherein said five-member ring heteroaryl and said substituted five-member ring heteroaryl contain 1-2 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;  
 wherein R 3  and R 4  are independently selected from the group consisting of H, alkyl, aryl, heteroaryl and COR′;  
 wherein R′ is selected from the group consisting of alkyl, substituted alkyl, C 3 -C 9  cycloalkyl, substituted C 3 -C 9  cycloalkyl, polycyclic aliphatic group, substituted polycyclic aliphatic group, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl, and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur; wherein R′ is not haloalkyl and provided that when R′ is pyridyl, substituted pyridyl or pyridyl-N-oxide, R 1  and R 2  are not adamantyl or substituted adamantyl;  
 wherein said substituted alkyl, substituted polycyclic aliphatic groups, substituted phenyl, substituted naphthyl and substituted heteroaryl contain 1-5 substituents, wherein said substituent is selected from the group consisting of H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH 3 , COOH, OCOR′, COOR′, COR′, CN, CF 3 , OCF 3 , NO 2 , NR′R′, NHCOR′ and CONR′R′;  
 wherein the substituent on R 1 , R 2 , and R′ is selected from the group consisting of H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, carbonyl, OH, OCH 3 , COOH, OCOR′, COOR′, COR′, CN, CF 3 , OCF 3 , NO 2 , NR′R′, NHCOR′ and CONR′R′;  
 wherein X and Y are independently selected from the group consisting of H, halogens, alkoxy, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCOR″, OCH 3 , COOH, CN, CF 3 , OCF 3 , NO 2 , COOR″, CHO and COR″;  
 wherein R″ is a C 1 -C 8  alkyl, wherein said C 1 -C 8  alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl;  
 wherein at least one of R 1 , R 2 , R 3 , or R 4  is not H;  
                     
 wherein R is selected from the group consisting of H, C 1 -C 5  alkyl, benzyl, p-fluorobenzyl and di-alkylamino alkyl, wherein said C 1 -C 5  alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl;  
 wherein R 1  and R 2  are independently selected from the group consisting of H, alkyl, substituted alkyl, C 3 -C 9  cycloalkyl, substituted C 3 -C 9  cycloalkyl, polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur; 
 wherein said substituted phenyl, substituted naphthyl and substituted heteroaryl contain 1-5 substituents, wherein said substituent is selected from the group consisting of H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH 3 , COOH, COOR′ COR′, CN, CF 3 , OCF 3 , NO 2 , NR′R′, NHCOR′ and CONR′R′;  
 
 wherein R 3  and R 4  are independently selected from the group consisting of H, alkyl, aryl, heteroaryl and COR′; 
 wherein R′ is selected from the group consisting of H, alkyl, substituted alkyl, C 3 -C 9  cycloalkyl, substituted C 3 -C 9  cycloalkyl, polycyclic aliphatics, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;  
 
 wherein X and Y are independently selected from the group consisting of H, halogens, alkoxy, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCOR″, OCH 3 , COOH, CN, CF 3 , OCF 3 , NO 2 , COOR″, CHO and COR″; and 
 wherein R″ is a C 1 -C 8  alkyl, wherein said C 1 -C 8  alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl.  
 
 
   
   
       2 . The compound of  claim 1 , wherein said polycyclic aliphatic group is selected from the group consisting of adamantyl, bicycloheptyl, camphoryl, bicyclo[2,2,2]octanyl and norbornyl.  
   
   
       3 . The compound or salt thereof of  claim 1 , wherein said heteroaryl and said substituted heteroaryl is selected from the group consisting of pyridines, thiazoles, isothiazoles, oxazoles, pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles, pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines, pyrazoles, imidazoles, indoles, quinolines, isoquinolines, benzothiophines, benzofurans, parathiazines, pyrans and chromenes.  
   
   
       4 . A pharmaceutical composition for treating asthma or an allergic reaction associated with an increase in IgE levels in a mammal comprising at least one compound or salt thereof of  claim 1 .  
   
   
       5 . The pharmaceutical composition of  claim 4 , further comprising at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.  
   
   
       6 . A pharmaceutical composition for inhibiting cell proliferation in a mammal comprising at least one compound or salt thereof of Genus I as defined in  claim 1 .  
   
   
       7 . The pharmaceutical composition of  claim 6 , further comprising at least one additional ingredient which is active in reducing at least one symptom associated with said cell proliferation.  
   
   
       8 . A method for treating an allergic reaction in a mammal wherein said reaction is caused by an increase in IgE levels comprising administering an IgE-suppressing amount of at least one compound or salt thereof of  claim 1 .  
   
   
       9 . The method of  claim 8  further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.  
   
   
       10 . The method of  claim 9 , wherein said at least one additional ingredient is selected from the group consisting of a short-acting β 2 -adrenergic agonist, a long-acting β 2 -adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.  
   
   
       11 . The method of  claim 9 , wherein said at least one additional ingredient is combined with said at least one IgE-suppressing compound or salt thereof in a pharmaceutically acceptable diluent and co-administered to the mammal.  
   
   
       12 . The method of  claim 11 , wherein said at least one IgE-suppressing compound or salt thereof is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.  
   
   
       13 . The method of  claim 12 , wherein said dose is administered in divided doses at regular periodic intervals.  
   
   
       14 . The method of  claim 13 , wherein said regular periodic intervals occur daily.  
   
   
       15 . A method for treating asthma in a mammal comprising administering an IgE-suppressing amount of at least one compound or salt thereof of  claim 1 .  
   
   
       16 . The method of  claim 15  further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said asthma.  
   
   
       17 . The method of  claim 16 , wherein said additional ingredient is selected from the group consisting of a short-acting β 2 -adrenergic agonist, a long-acting β 2 -adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.  
   
   
       18 . A method for inhibiting cellular proliferation in a mammal comprising administering an amount of at least one compound or salt thereof of Genus I as defined in  claim 1 .  
   
   
       19 . The method of  claim 18  further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said cellular proliferation.  
   
   
       20 . The method of  claim 19 , wherein said at least one additional ingredient is selected from the group consisting of antifungals, antivirals, antibiotics, anti-inflammatories, and anticancer agents.  
   
   
       21 . The method of  claim 19 , wherein said at least one additional ingredient is selected from the group consisting of alkylating agent, antimetabolite, DNA cutter, topoisomerase I poison, topoisomerase II poison, DNA binder, and spindle poison.  
   
   
       22 . The method of  claim 19 , wherein said at least one additional ingredient is combined with said at least one compound or salt thereof in a pharmaceutically acceptable diluent and co-administered to the mammal.  
   
   
       23 . The method of  claim 22 , wherein said at least one compound or salt thereof is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.  
   
   
       24 . The method of  claim 23 , wherein said dose is administered in divided doses at regular periodic intervals.  
   
   
       25 . The method of  claim 24 , wherein said regular periodic intervals occur daily.  
   
   
       26 . The method of  claim 18  further comprising administering at least one other therapy which is effective in ameliorating at least one symptom associated with cellular proliferation.  
   
   
       27 . The method of  claim 26 , wherein said therapy is an anti-cancer therapy.  
   
   
       28 . The method of  claim 26 , wherein said therapy is selected from the group consisting of radiation, immunotherapy, gene therapy, and surgery.  
   
   
       29 . A method of preparing a compound or salt thereof of  claim 1  comprising: 
 reacting a 3,4-diaminobenzoic acid with a 4-nitrobenzaldehyde to yield a first intermediate or salt thereof,    aminating said first intermediate or salt thereof to yield a second intermediate or salt thereof,    reducing said second intermediate or salt thereof to yield a third intermediate or salt thereof, and    acylating said third intermediate or salt thereof to obtain said compound or salt thereof.    
   
   
       30 . A method of preparing a compound or salt thereof of Genus II as defined in  claim 1  comprising: 
 reacting a 4-nitro-1,2,-phenylenediamine with an alkyl 4-formylbenzoate to yield a first intermediate or salt thereof,    treating said first intermediate or salt thereof with an aqueous base to yield a second intermediate or salt thereof,    aminating said second intermediate or salt thereof to yield a third intermediate or salt thereof,    reducing said third intermediate or salt thereof to yield a fourth intermediate or salt thereof, and    acylating said fourth intermediate or salt thereof to obtain said compound or salt thereof.    
   
   
       31 . A method of preparing a compound or salt thereof of Genus III as defined in  claim 1  comprising: 
 reacting a 3,4-diaminobenzoic acid with a 4-alkoxycarbonyl benzaldehyde to yield a first intermediate or salt thereof,    treating said first intermediate or salt thereof with an agent selected from the following group: inorganic acid halide, organic acid chlorides and mixed anhydrides, to yield a second intermediate or salt thereof,    aminating said second intermediate or salt thereof to yield a third intermediate or salt thereof,    treating said third intermediate or salt thereof with an aqueous base to yield a fourth intermediate or salt thereof, and    aminating said fourth intermediate or salt thereof to obtain said compound or salt thereof.    
   
   
       32 . A compound or salt thereof selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       33 . A compound or salt thereof selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       34 . A compound or salt thereof selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       35 . A compound or salt thereof selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       36 . A compound or salt thereof selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       37 . A compound or salt thereof selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       38 . A compound or salt thereof selected from the group consisting of: