Substituted imidazoles as selective modulators of bradykinin B2 receptors

Abstract

Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7 ′ are variables defined herein, which compounds are modulators of Bradykinin B 2 receptors. These compounds are therefore useful in the diagnosis and treatment of renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility, glaucoma, pain, asthma, and rhinitis, and for the increase of permeability of the blood-brain barrier or the blood-brain-tumor barrier.

What is claimed is:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 1  is arylalkyl (with the proviso that R 1  may not be 3-Fluorobenzyl), heteroarylalkyl, allyl, each of which which is optionally substituted directly or through a O(CH 2 ) n  linker (where n=1, 2, 3 or 4) with up to three substituents independently selected from: 
 (i) halogen (with the proviso that R 1  may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C 1 -C 6 ) alkyl),  
 (ii) C 1 -C 6 alkoxyNR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , CONR 8 R 9 ,  
  wherein R 8  and R 9  are the same or different and represent hydrogen, straight or branched chain lower alkyl, or R 8  and R 9  form a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A  wherein n=1, 2, 3, 4, COR A , and CO 2 R A ,  
  wherein R A  represents hydrogen, or straight or branched chain lower alkyl,  
 (iv) SO 2 R A , NHSO 2 R A , SO 2 NHR A , SO 2 NHCOR A , CONHSO 2 R A ,  
  wherein R A  represents hydrogen, or straight or branched chain lower alkyl,  
 (v) tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;  
 
 R 2  and R 3  are the same or different and represent 
 (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ′R 9 ′, NR 8 ′R 8 ′, CONR 8 ′R 8 ′, NR 8 ′COR 8 ′,  
  wherein R 8 ′ and R 8 ′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ′ and R 8 ′ is a 5, 6, or 7 membered heterocyclic ring, optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ′ where n=1, 2, 3, 4, COR A ′, or CO 2 R A ′,  
  wherein R A ′ represents hydrogen or straight or branched chain lower alkyl; or  
 
 R 2  and R 3  may be taken together to form a carbocyclic or heterocyclic saturated ring;  
 R 4  represents straight or branched chain lower alkyl; 
 R 5  represents halogen or trifluoromethyl;  
 R 6 , R 7  and R 7 ′ are the same or different and represent 
 (i) hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C 1 -C 10  alkyl, C 1 -C 10  alkoxy (with the proviso that R 6 , R 7 , or R 7 ′ may not be C 1 -C 10  alkoxy when located ortho to Y), C 1 -C 6 alkylthio, halogen, aminomethyl, di(C 1 -C 6 )alkylamino, mono or diC 1 -C 6 alkylaminomethyl, or  
 (ii) C 1 -C 6  alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl;  
 (iii) or any two adjacent R 6 , R 7  or R 7 ′ may be joined to form a 5 to 7 membered ring containing 1 or 2 oxygen atoms where the remaining ring members are carbon; or  
 
 R 5  and R 6  are joined to form a 5, 6, or 7 membered carbocyclic or heterocyclic aromatic ring which is optionally substituted with up to four substituents selected from: 
 (i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, alkylaminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ″R 9 ″, NR 8 ″R 9 ″, CONR 8 ″R 9 ″ NR 8 ″COR 9 ″, where R 8 ″ and R 9 ″ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ″ and R 9 ″ can be a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, lower alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ″ where n=1, 2, 3, 4, COR A ″, or CO 2 R A ″, wherein R A ″ represents hydrogen or straight or branched chain lower alkyl; and R 7  and R 7′  are as defined above; and  
 
 
 Y represents a bond or CH 2 , when Y═CH 2  it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.  
 
     
     
         2 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 1  is benzyl, each of which which is optionally substituted directly or through a O(CH 2 ) n  linker (where n=1, 2, 3 or 4) with up to three substituents independently selected from: 
 (i) halogen (with the proviso that R 1  may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C 1 -C 6 ) alkyl),  
 (ii) C 1 -C 6 alkoxyNR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , CONR 8 R 9 ,  
  wherein R 8  and R 9  are the same or different and represent hydrogen, straight or branched chain lower alkyl, or R 8  and R 9  is a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A  wherein n=1, 2, 3, 4, COR A , and CO 2 R A , wherein R A  represents hydrogen, or straight or branched chain lower alkyl,  
 (iv) SO 2 R A , NHSO 2 R A , SO 2 NHR A , SO 2 NHCOR A , CONHSO 2 R A ,  
  wherein R A  represents hydrogen, or straight or branched chain lower alkyl,  
 (v) tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;  
 
 R 2  and R 3  are the same or different and represent 
 (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ′R 9 ′, NR 8 ′R 9 ′, CONR 8 ′R 9 ′, NR 8 ′COR 9 ′, wherein R 8 ′ and R 9 ′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ′ and R 9 ′ is a 5, 6, or 7 membered heterocyclic ring, optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ′ where n=1, 2, 3, 4, COR A ′, or CO 2 R A ′,  
  wherein R A ′ represents hydrogen or straight or branched chain lower alkyl; or  
 
 R 2  and R 3  may be taken together to form a carbocyclic or heterocyclic saturated ring;  
 R 4  represents straight or branched chain lower alkyl;  
 R 5  represents halogen or trifluoromethyl;  
 R 6 , R 7  and R 7 ′ are the same or different and represent 
 (i) hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C 1 -C 10  alkyl, C 1 -C 10  alkoxy (with the proviso that R 6 , R 7 , or R 7 ′ may not be C 1 -C 10  alkoxy when located ortho to Y), C 1 -C 6 alkylthio, halogen, aminomethyl, di(C 1 -C 6 )alkylamino, mono or diC 1 -C 6 alkylaminomethyl, or  
 (ii) C 1 -C 6  alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl;  
 (iii) or any two adjacent R 6 , R 7  or R 7 ′ may be joined to form a 5 to 7 membered ring containing 1 or 2 oxygen atoms where the remaining ring members are carbon; and  
 
 Y represents a bond or CH 2 , when Y═CH 2  it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.  
 
     
     
         3 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 1  is allyl, 2, 3, or 4 picolyl, or quinolinylmethyl, each of which is optionally substituted with up to three substituents independently selected from 
 (i) halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C 1 -C 6 ) alkyl),  
 (ii) C 1 -C 6 alkoxyNR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , CONR 8 R 9 , wherein R 8  and R 9  are the same or different and represent hydrogen, or straight or branched chain lower alkyl, or R 8  and R 9  form a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A  wherein n=1, 2, 3, 4, COR A , and CO 2 R A , wherein R 8  represents hydrogen, or straight or branched chain lower alkyl;  
 
 R 2  and R 3  are the same or different and represent 
 (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 
 (ii) C 1 -C 6 alkoxyNR 8 ′R 9 ′, NR 8 ′R 9 ′, CONR 8 ′R 9 ′, NR 8 ′COR 9 ′, wherein R 8 ′ and R 9 ′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ′ and R 9 ′ is a 5, 6, or 7 membered heterocyclic ring, optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy, 
 (iii) O(CH 2 ) n CO 2 R A ′ where n=1, 2, 3, 4, COR A ′, or CO 2 R A ′,  
  wherein R A ′ represents hydrogen or straight or branched chain lower alkyl; or  
 
 R 2  and R 3  may be taken together to form a carbocyclic or heterocyclic saturated ring,  
 R 4  represents straight or branched chain lower alkyl;  
 R 5  represents halogen or trifluoromethyl; and  
 R 6 , R 7  and R 7 ′ are the same or different and represent 
 hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C 1 -C 10  alkyl, C 1 -C 10  alkoxy (with the proviso that R 6 , R 7 , or R 7 ′ may not be C 1 -C 10  alkoxy when located ortho to Y), C 1 -C 6 alkylthio, halogen, aminomethyl, di(C 1 -C 6 )alkylamino, mono or diC 1 -C 6 alkylaminomethyl, or C 1 -C 6 alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl; and  
 
 Y represents a bond or CH 2 , when Y═CH 2  it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.  
 
     
     
         4 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 1  is benzyl which is optionally substituted directly or through a O(CH 2 ) n  linker (where n=1, 2, 3 or 4) with up to three substituents independently selected from: 
 (i) halogen (with the proviso that R 1  may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C 1 -C 6 ) alkyl),  
 (ii) C 1 -C 6 alkoxyNR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , CONR 8 R 9 , wherein R 8  and R 9  are the same or different and represent hydrogen, straight or branched chain lower alkyl, or R 8  and R 9  form a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A  wherein n=1, 2, 3, 4, COR A , and CO 2 R A , wherein R A  represents hydrogen, or straight or branched chain lower alkyl,  
 (iv) SO 2 R A , NHSO 2 R A , SO 2 NHR A , SO 2 NHCOR A , CONHSO 2 R A , wherein R A  represents hydrogen, or straight or branched chain lower alkyl, and  
 (v) tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;  
 
 R 2  and R 3  are the same or different and represent 
 (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ′R 9 ′, NR 8 ′R 9 ′, CONR 8 ′R 9 ′, NR 8 ′COR 9 ′, wherein R 8 ′ and R 9 ′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ′ and R 9 ′ is a 5, 6, or 7 membered heterocyclic ring, optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ′ where n=1, 2, 3, 4, COR A ′, or CO 2 R A ′, wherein R A ′ represents hydrogen or straight or branched chain lower alkyl; or  
 
 R 2  and R 3  may be taken together to form a carbocyclic or heterocyclic saturated ring;  
 R 4  represents straight or branched chain lower alkyl;  
 R 5  is part of an aromatic ring formed with R 6 ;  
 R 6  is part of a 5, 6, or 7 membered carbocyclic or heterocyclic aromatic ring formed with R 5  which is optionally substituted with up to four substituents selected from: 
 (i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, alkylaminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ″R 9 ″, NR 8 ″R 9 ″, CONR 8 ″R 9 ″ NR 8 ″COR 9 ″, where R 8 ″ and R 9 ″ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ″ and R 9 ″ can be a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, lower alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ″ where n=1, 2, 3, 4, COR A ″, or CO 2 R A ″, wherein R A ″ represents hydrogen or straight or branched chain lower alkyl; and  
 
 R 7  and R 7 ′ represent 
 hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C 1 -C 10  alkyl, C 1 -C 10  alkoxy (with the proviso that R 6 , R 7 , or R 7 ′ may not be C 1 -C 10 alkoxy when located ortho to Y), C 1 -C 6 alkylthio, halogen, aminomethyl, di(C 1 -C 6 )alkylamino, mono or diC 1 -C 6 alkylaminomethyl, or C 1 -C 6 alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl; and  
 
 Y represents a bond or CH 2 , when Y═CH 2  it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.  
 
     
     
         5 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 1  is allyl, 2, 3, or 4 picolyl, or quinolinylmethyl, each of which is optionally substituted with up to three substituents independently selected from 
 (i) halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C 1 -C 6 ) alkyl),  
 (ii) C 1 -C 6 alkoxyNR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , CONR 8 R 9 , wherein R 8  and R 9  are the same or different and represent hydrogen, or straight or branched chain lower alkyl, or R 8  and R 9  form a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy, and  
 (iii) O(CH 2 ) n CO 2 R A  wherein n=1, 2, 3, 4, COR A , and CO 2 R A , wherein R A  represents hydrogen, or straight or branched chain lower alkyl;  
 
 R 2  and R 3  are the same or different and represent 
 (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ′R 9 ′, NR 8 ′R 9 ′, CONR 8 ′R 9 ′, NR 8 ′COR 9 ′, wherein R 8 ′ and R 9 ′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ′ and R 9 ′ form a 5, 6, or 7 membered heterocyclic ring, optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ′ where n=1, 2, 3, 4, COR A ′, or CO 2 R A ′, wherein R A ′ represents hydrogen or straight or branched chain lower alkyl; or  
 
 R 2  and R 3  may be taken together to form a carbocyclic or heterocyclic saturated ring;  
 R 4  represents straight or branched chain lower alkyl;  
 R 5  is part of an aromatic ring formed with R 6 ;  
 R 6  is part of a 5, 6, or 7 membered carbocyclic or heterocyclic aromatic ring formed with R 5  which is optionally substituted with up to four substituents selected from: 
 (i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C 1 -C 6  alkyl, amino, C 1 -C 6  alkoxy, aminomethyl, alkylaminomethyl, mono or di(C 1 -C 6 )alkylamino, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C 1 -C 6 ) alkyl,  
 (ii) C 1 -C 6 alkoxyNR 8 ″R 9 ″, NR 8 ″R 9 ″, CONR 8 ″R 9 ″ NR 8 ″COR 9 ″, where R 8 ″ and R 9 ″ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R 8 ″ and R 9 ″ can be a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, lower alkyl, amino, mono or di(C 1 -C 6 )alkylamino, or C 1 -C 6  alkoxy,  
 (iii) O(CH 2 ) n CO 2 R A ″ where n=1, 2, 3, 4, COR A ″, or CO 2 R A ″, wherein R A ″ represents hydrogen or straight or branched chain lower alkyl;  
 
 R 7  and R 7 ′ represent  
 hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C 1 -C 10  alkyl, C 1 -C 10  alkoxy (with the proviso that R 6 , R 7 , or R 7 ′ may not be C 1 -C 10  alkoxy when located ortho to Y), C 1 -C 6 alkylthio, halogen, aminomethyl, di(C 1 -C 6 )alkylamino, mono or diC 1 -C 6 alkylaminomethyl, or C 1 -C 6 alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl; and  
 Y represents a bond or CH 2 , when Y═CH 2  it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.  
 
     
     
         6 . A compound according to  claim 2  where R 2  and R 3  do not form a carbocyclic or heterocyclic ring.  
     
     
         7 . A compound according to  claim 3  where R 2  and R 3  do not form a carbocyclic or heterocyclic ring.  
     
     
         8 . A compound according to  claim 4  where R 2  and R 3  do not form a carbocyclic or heterocyclic ring.  
     
     
         9 . A compound according to  claim 5  where R 2  and R 3  do not form a carbocyclic or heterocyclic ring.  
     
     
         10 . A compound according to  claim 2  of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 4  are as defined in  claim 2 .  
     
     
         11 . A compound according to  claim 10  wherein R 4  is isoamyl or n-pentyl.  
     
     
         12 . A compound according to  claim 3  of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 4  are as defined in  claim 3 .  
     
     
         13 . A compound according to  claim 12  wherein R 4  is isoamyl or n-pentyl.  
     
     
         14 . A compound according to  claim 2  of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 4  are as defined in  claim 2 .  
     
     
         15 . A compound according to  claim 14  wherein R 4  is isoamyl or n-pentyl.  
     
     
         16 . A compound according to  claim 3  of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 4  are as defined in  claim 3 .  
     
     
         17 . A compound according to  claim 16  wherein R 4  is isoamyl or n-pentyl.  
     
     
         18 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-chlorophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         19 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         20 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         21 . A compound according to  claim 1 , which is Ethyl {2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetate.  
     
     
         22 . A compound according to  claim 1 , which is {2-[(2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetic acid.  
     
     
         23 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-cyanophenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         24 . A compound according to  claim 1 , which is 2-{2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino}methyl]-4,5-dimethylimidazol-1-yl)methyl}benzoic acid.  
     
     
         25 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-[cyanomethoxy]-phenyl)methyl]imidazol-2yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         26 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{[1-benzyl-4,5-dimethylimidazol-2-yl]methyl}-N-(3-methylbutyl)carboxamide.  
     
     
         27 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl-N-({4,5-dimethyl-1-[(2-methylphenyl)methyl]}imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         28 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl-N-[(4,5-dimethyl-1-{[2-(trifluoromethyl)phenyl]methyl}imidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide.  
     
     
         29 . A compound according to  claim 1 , which is N-{[4,5-Dichloro-1-benzylimidazol-2-yl]methyl}(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         30 . A compound according to  claim 1 , which is N-({4,5-Dichloro-1-[(2-chlorophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         31 . A compound according to  claim 1 , which is N-({4,5-Dichloro-1-[(2-methylphenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         32 . A compound according to  claim 3 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-diethyl-1-[(pyridin-2-yl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl) carboxamide.  
     
     
         33 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(quinolin-2-yl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl) carboxamide.  
     
     
         34 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{4,5-diethyl-1-[(5-ethyl-2-methoxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         35 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(5-bromo-2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         36 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(5-chloro-2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide.  
     
     
         37 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-({3-[(2-chlorophenyl)methyl](3,4,5,6,7-pentahydrobenzimidazol-2-yl)}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         38 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-carboxamidophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         39 . A compound according to  claim 1 , which is N-({4,5-Dichloro-1-[(2-carboxamidophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         40 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-sulfonamidophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         41 . A compound according to  claim 1 , which is N-({4,5-Dichloro-1-[(2-sulfonamidophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         42 . A compound according to  claim 1 , which is (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         43 . A compound according to  claim 1 , which is N-({4,5-Dichloro-1-[(2-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         44 . A pharmaceutical composition comprising a compound according to  claim 1 , together with at least one pharmaceutically acceptable carrier or excipient.  
     
     
         45 . A packaged pharmaceutical composition comprising a pharmaceutical composition of  claim 44  in a container and instructions for using the composition to treat a patient in need thereof.  
     
     
         46 . The packaged pharmaceutical composition of  claim 45 , wherein said patient is suffering from renal disease, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility, glaucoma, asthma, rhinitis, brain cancer, or a brain tumor.  
     
     
         47 . A method for the treatment of physiological disorders associated with excess of or insufficient amount of bradykinin, which method comprises administration to a patient in need thereof a bradykinin reducing amount of a compound according to 1 or a bradykinin enhancing amount of a compound according to  claim 1 .  
     
     
         48 . A method for the treatment of a patient suffering from renal disease, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes,. diabetic complications, male infertility, glaucoma, asthma, or rhinitis, which comprises administering a sufficient amount of a compound according to  claim 1  to alter the symptoms of such disease.  
     
     
         49 . A method of increasing the permeability of the blood brain barrier which comprises administering a compound according to  claim 1  to a patient.  
     
     
         50 . A method of increasing the brain concentration of a CNS active compound which comprises administering a compound according to any one of  claim 1  and the CNS active compound to a patient.  
     
     
         51 . A method for localizing bradykinin receptors in tissue section samples comprising: 
 contacting with a sample of tissue a detectably-labeled compound of  claim 1 , under conditions that permit binding of the compound to the sample of tissue; washing the tissue sample to remove unbound compound; and detecting the bound compound.    
     
     
         52 . The method of  claim 51 , wherein the compound is radiolabeled.  
     
     
         53 . A method of inhibiting the binding of bradykinin to the BK-2 receptor, which method comprises contacting, in the presence of bradykinin, a solution comprising a compound of  claim 1 , with cells expressing the BK-2 receptor, wherein the compound is present in the solution at a concentration sufficient to reduce levels of bradykinin binding to cells expressing the BK-2 receptor in vitro.  
     
     
         54 . A method for altering the signal-transducing activity of a cell surface BK-2 receptor, said method comprising contacting cells expressing such a receptor with a solution comprising a compound according to  claim 1 , wherein the compound is present in the solution at a concentration sufficient to reduce levels of NPY binding to cells expressing the NPY 5  receptor in vitro.  
     
     
         55 . A compound according to any one of  claim 1 , wherein in an assay of BK-2 binding the compound exhibits an K 1  of 1 micromolar or less.  
     
     
         56 . A compound according to any one of  claim 1 , wherein in an assay of BK-2 binding the compound exhibits an K 1  of 100 nanomolar or less.  
     
     
         57 . A compound according to any one of  claim 1 , wherein in an assay of BK-2 binding the compound exhibits an K 1  of 10 nanomolar or less.