Benzimidazole cyclooxygenase-2 inhibitor

Abstract

This invention provides a compound of the following formula: or the pharmaceutically acceptable salts thereof, wherein Ar is heteroaryl; X 1 and X 2 are independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkanoyl, carboxy, carbamoyl, cyano, nitro, mercapto, (C 1 -C 4 alkyl)thio, (C 1 -C 4 alkyl)sulfinyl, (C 1 -C 4 alkyl)sulfonyl, aminosulfonyl, or the like; R 1 is selected from hydrogen, straight or branched C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, phenyl, heteroaryl and the like; R 2 and R 3 are independently selected from hydrogen, halo, C 1 -C 4 alkyl, phenyl and the like; or R 1 and R 2 can form, together with the carbon atom to which they are attached, a C 5 -C 7 cycloalkyl ring; and m and n are independently 0, 1, 2 or 3. These compounds and pharmaceutical compositions containing such compounds are useful as analgesics and anti-inflammatory agents.

1 . A compound of formula I:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein  
         Ar is heteroaryl selected from  
         a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or  
         a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and  
         said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;  
         X 1  is independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, [N-(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, [N, N-di(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, N-(C 1 -C 4  alkanoyl)amino, N-(C 1 -C 4  alkyl)-N-(C 1 -C 4  alkanoyl)amino, N-[(C 1 -C 4  alkyl)sulfonyl]amino, N-[(halo-substituted C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, (C 1 -C 4  alkoxy)carbonyl, carbamoyl, [N-(C 1 -C 4  alkyl)amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, cyano, nitro, mercapto, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, aminosulfonyl, [N-(C 1 -C 4  alkyl)amino]sulfonyl and [N,N-di(C 1 -C 4  alkyl)amino]sulfonyl;  
         X 2  is independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, [N-(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, [N, N-di(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, N-(C 1 -C 4  alkanoyl)amino, N-(C 1 -C 4  alkyl)-N-(C 1 -C 4  alkanoyl)amino, N-[(C 1 -C 4  alkyl)sulfonyl]amino, N-[(halo-substituted C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, (C 1 -C 4  alkoxy)carbonyl, carbamoyl, [N-(C 1 -C 4  alkyl)amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, aminosulfonyl, [N-(C 1 -C 4  alkyl)amino]sulfonyl and [N,N-di(C 1 -C 4  alkyl)amino]sulfonyl;  
         R 1  is selected from  
         hydrogen;  
         straight or branched C 1 -C 4  alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino;  
         C 3 -C 8  cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino;  
         C 4 -C 8  cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino;  
         phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, [N-(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, [N, N-di(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, N-(C 1 -C 4  alkanoyl)amino, N-[(C 1 -C 4  alkyl)(C 1 -C 4  alkanoyl)]amino, N-[(C 1 -C 4  alkyl)sulfonyl]amino, N-[(halo-substituted C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, (C 1 -C 4  alkoxy)carbonyl, carbamoyl, [N-(C 1 -C 4  alkyl)amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, cyano, nitro, mercapto, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, aminosulfonyl, [N-(C 1 -C 4  alkyl)amino]sulfonyl and [N,N-di(C 1 -C 4  alkyl)amino]sulfonyl; and  
         heteroaryl selected from  
         a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or  
         a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and  
         said heteroaryl being optionally substituted with one to three substituent(s) selected from X 1 ;  
         R 2  and R 3  are independently selected from:  
         hydrogen;  
         halo;  
         C 1 -C 4  alkyl;  
         phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino;  
         or R 1  and R 2  can form, together with the carbon atom to which they are attached, a C 3 -C 7  cycloalkyl ring;  
         m is 0, 1, 2, 3, 4 or 5; and  
         n is 0, 1, 2, 3 or 4.  
       
     
     
         2 . A compound according to  claim 1 , wherein 
 Ar is heteroaryl selected from    a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one or two N atom(s) in addition to said hetero atom, or    a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to three N atom(s) in addition to said N atom; and    X 1  is independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, N-(C 1 -C 4  alkanoyl)amino, C 1 -C 4  alkanoyl, carboxy, carbamoyl, [N-(C 1 -C 4  alkyl)amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, cyano, nitro, mercapto and (C 1 -C 4  alkyl)thio;    X 2  is independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, N-(C 1 -C 4  alkanoyl)amino, [(C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, carbamoyl, N-carbamoylamino, cyano, nitro, mercapto and (C 1 -C 4  alkyl)thio;    R 1  is selected from    hydrogen;    straight or branched C 1 -C 4  alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C 1 -C 4  alkoxy and amino;    C 3 -C 8  cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy and amino;    C 4 -C 8  cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino;    phenyl optionally substituted with one to three substituent(s) wherein the substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, (C 1 -C 4  alkanoyl)amino, C 1 -C 4  alkanoyl, carboxy, carbamoyl, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, and aminosulfonyl; or    heteroaryl selected from    a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one or two N atom(s) in addition to said hetero atom; or    a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to three N atom(s) in addition to said N atom; wherein    said heteroaryl being optionally substituted with one to three substituent(s) selected from X 1  of this claim;    R 2  and R 3  are independently selected from:    hydrogen;    halo;    C 1 -C 4  alkyl;    phenyl optionally substituted with one to three substituent(s) wherein the substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino;    or R 1  and R 2  can form, together with the carbon atom to which they are attached, a C 5 -C 7  cycloalkyl ring;    m is 0, 1, 2, 3 or 4; and    n is 0, 1, 2 or 3.    
     
     
         3 . A compound according to  claim 2 , wherein 
 Ar is selected from    a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one N atom in addition to said hetero atom, or    a 6-membered monocyclic aromatic ring having one N atom and optionally containing one or two N atom(s) in addition to said N atom; and    X 1  is selected from halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkoxy, carbamoyl, [N-(C 1 -C 4  alkyl)amino]carbonyl, [N,N di(C 1 -C 4  alkyl)amino]carbonyl and cyano;    X 2  is selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, N-formylamino, N-(C 1 -C 4  alkanoyl)amino, [(C 1 -C 4  alkyl)sulfonyl]amino, N-carbamoylamino, cyano and nitro; and    R 1  is selected from    C 1 -C 4  alkyl optionally substituted with one to three substituents wherein said substituents are independently selected from halo, hydroxy and amino;    C 5 -C 7  cycloalkyl optionally substituted with one to three substituents wherein said substituents are independently selected from halo, hydroxy and amino;    phenyl optionally substituted with one or two substituent(s), said substituents being independently selected from halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, (C 1 -C 4  alkyl)thio, C 1 -C 4  alkylsulfonyl and amino; or    heteroaryl optionally substituted with one or two C 1 -C 4  alkyl group(s), wherein said heteroaryl being selected from    a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one N atom in addition to said hetero atom, or    a 6-membered monocyclic aromatic ring having one N atom and optionally containing one or two N atom(s) in addition to said N atom;    R 2  and R 3  are independently selected from    hydrogen;    halo;    C 1 -C 4  alkyl; and    phenyl optionally substituted from halo, hydroxy, amino, C 1 -C 4  alkyl and C 1 -C 4  alkoxy;    or R 1  and R 2  can form, together with the carbon atom to which they are attached, a C 5-6  cycloalkyl ring;    m is 0, 1, 2 or 3; and    n is 0, 1 or 2.    
     
     
         4 . A compound according to  claim 3 , wherein 
 Ar is selected from pyridyl, pyrimidinyl, pyrazinyl thiazolyl, furyl, oxazolyl, isooxazolyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl and pyridazinyl;    X 1  is selected from halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy, carbamoyl and cyano;    X 2  is selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, N-formylamino, N-(C 1 -C 4  alkanoyl)amino, [(C 1 -C 4  alkyl)sulfonyl]amino, N-carbamoylamino, cyano and nitro;    R 1  is selected from    (straight or branched) C 1 -C 4  alkyl;    C 5 -C 7  cycloalkyl;    phenyl optionally substituted with one or two substituent(s), said substituents being independently selected from halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkyl)thio and C 1 -C 4  alkylsulfonyl; or    heteroaryl optionally substituted with one or two C 1 -C 4  alkyl group(s), said heteroaryl being selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, furyl, oxazolyl, isooxazolyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl and pyrazolyl;    R 2  is selected from hydrogen, C 1 -C 4  alkyl and phenyl;    R 3  is selected from hydrogen, halo, C 1 -C 4  alkyl and cyano;    or R 1  and R 2  can form, together with the carbon atom to which they are attached, cyclohexyl; and    m is 0, 1 or 2.    
     
     
         5 . A compound according to  claim 4 , wherein 
 Ar is heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl and thiazolyl;    X 1  is selected from fluoro, chloro, methyl, methoxy, trifluoromethyl, carbamoyl and cyano;    X 2  is selected from fluoro, methyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-methylsulfonylamino, N-formylamino, N-acetylamino, N-carbamoylamino, cyano and nitro;    R 1  is selected from methyl, isopropyl, cyclohexyl, phenyl, furyl, thienyl, pyridyl, imidazolyl and thiazolyl which are optionally substituted with one to three substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy, fluoro, chloro and hydroxy;    R 2  is selected from hydrogen, methyl and phenyl;    or R 1  and R 2  can form, together with the carbon atom to which they are attached, cyclohexyl;    R 3  is selected from hydrogen, fluoro and cyano; and    m is 0 or 1.    
     
     
         6 . A compound according to  claim 1  selected from 
 (E)-1-(2-Pyridyl)-2-styryl-1H-benzimidazole;  
 (E)-1-(4-Pyridyl)-2-styryl-1H-benzimidazole;  
 (E)-1-(2-Pyrimidyl)-2-styryl-1H-benzimidazole oxalate;  
 (E)-2-(2-Fluorostyryl)-1-(2-pyridyl)-1H-benzimidazole hydrochloride;  
 (E)-2-(2,6-Difluorostyryl)-1-(2-pyridyl)-1H-benzimidazole hydrochloride;  
 (E)-2-[2-(3-Furyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole;  
 (E)-1-(2-Pyridyl)-2-[2-(2-thienyl)ethenyl]-1H-benzimidazole;  
 (E)-5-Methyl-1-(2-pyridyl)-2-styryl-1H-benzimidazole;  
 (E)-5-Fluoro-1-(2-pyridyl)-2-styryl-1H-benzimidazole;  
 (E)-1-(2-Pyridyl)-2-styryl-5-methoxy-1H-benzimidazole oxalate;  
 (E)-2-[2-(Cyclohexyl)ethenyl]-5-methyl-1-(2-pyridyl)-1H-benzimidazole oxalate;  
 (E)-2-[2-(3-Furyl)ethenyl]-5-methyl-1-(2-pyridyl)-1H-benzimidazole oxalate;  
 (E)-5-Methyl-1-(2-pyridyl)-2-[2-(2-thienyl)ethenyl]-1H-benzimidazole oxalate;  
 (E)-2-[2-(Cyclohexyl)ethenyl]-5-fluoro-1-(2-pyridyl)-1H-benzimidazole;  
 (E)-2-[2-(3-Furyl)ethenyl]-1-(2-pyridyl)-5-methoxy-1H-benzimidazole oxalate;  
 (E)-5-Methoxy-2-[2-(2-methyl-3-furyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole.  
 
     
     
         7 . A compound according to  claim 1 , selected from 
 (E)-2-[2-(Cyclohexyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole;    (E)-5-Fluoro-1-(2-pyridyl)-2-styryl-1H-benzimidazole;    (E)-1-(2-Pyridyl)-2-styryl-5-methoxy-1H-benzimidazole oxalate;    (E)-5-Methyl-1-(2-pyridyl)-2-[2-(2-thienyl)ethenyl]-1H-benzimidazole oxalate;    (E)-2-[2-(Cyclohexyl)ethenyl]-5-fluoro-1-(2-pyridyl)-1H-benzimidazole;    (E)-5-Methoxy-2-[2-(2-methyl-3-furyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole.    
     
     
         8 . A pharmaceutical composition useful as anti-inflammatory and analgesic agents, which comprises a compound according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         9 . A pharmaceutical composition for treating a disorder or condition in a mammal, selected from rheumatoid and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer, Alzheimer disease, and other disorders and conditions, in which a pathological role of prostaglandins is implicated, comprising an amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.  
     
     
         10 . A method of treating a disorder or a medical condition in which prostaglandins are implicated as pathogens, in a mammalian subject, which comprises administering to a mammal an amount of compound of  claim 1  or a pharmaceutically acceptable salt thereof, that is effective in treating said disorder or medical condition.  
     
     
         11 . A method of treating a disorder or condition in a mammal, selected from rheumatoid and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer, Alzheimer disease and other disorders and conditions, in which a pathological role of prostaglandins are implicated, comprising administering to a mammal in need of such treatment an amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.