Aryl and heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of bradykinin B2 receptors

Abstract

Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein: A, B, C. and D are N or CH; X is a bond or (un)substituted CH 2 ; R 1 is lower alkenyl or (un)substituted lower alkyl; R 3 is lower alkyl; and R 2 , R 4 , R 5 , and R 6 are variables defined herein; which compounds are 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 circulatroy 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 or glaucoma, or for the increase of permeability of blood-brain barrier, pain, asthma, and rhinitis.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof wherein: 
 R 1  is not 3-fluorobenzyl and represents 
 (i) (C 2 -C 6 )alkenyl; or  
 (ii) R 1  represents aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino, mono- or di(C 1 -C 6 )alkylamino, amino (C 1 -C 6 ) alkyl, mono- or di (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxy, or  
 (iii) OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where 
 n=1, 2, 3, or 4; and  
 R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 )alkyl; or  
 R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members in the ring are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C 1 -C 6 )alkyl;  
 
 
 R 2  represents hydrogen, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, amino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 ), or mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxy; or 
 OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where 
 n=1, 2, 3, or 4; and  
 R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 )alkyl; or  
 R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C 1 -C 6 )alkyl;  
 
 
 R 3  represents (C 1 -C 6 )alkyl;  
 R 4  represents halogen or trifluoromethyl;  
 R 5  and R 6  are the same or different and represent hydrogen, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 6 ) alkyl, halogen, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, mono or di(C 1 -C 6 )alkylamino(C 1 -C 6 ), or mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxy; or  
 R 4  and R 5  together with the carbon atoms to which they are attached form a 5 or 6 membered aromatic ring which is optionally substituted with one or two groups independently selected from halogen, nitro, trifluoromethyl, cyano, hydroxy, (C 1 -C 6 )alkyl, amino, or mono- or di(C 1 -C 6 )alkylamino; or 
 OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where 
 n=1, 2, 3, or 4; and  
 R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 )alkyl; or  
 R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C 1 -C 6 )alkyl;  
 
 
 X represents a bond or CH 2 , where the CH 2  is optionally mono- or disubstituted with a (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy; and  
 A, B, C. and D are the same or different and represent CR P  or N where R p  represents hydrogen or C 1 -C 6  alkyl or C 1 -C 6  alkoxy where the alkyl portion of each is optionally substituted with, carboxy, halogen, amino, or mono- or di(C 1 -C 6 )alkylamino, with the proviso that not more than two of A, B, C. and D represent N.  
 
     
     
         2 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable non-toxic salts thereof wherein 
 R 1  is not 3-fluorobenzyl and represents 
 (i) (C 2 -C 6 )alkenyl; or  
 (ii) R 1  represents aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 ) alkyl, hydroxy(C 1 -C 6 )alkyl, amino, mono- or di(C 1 -C 6 )alkylamino, amino (C 1 -C 6 ) alkyl, mono- or di(C 1 -C 6 ) alkylamino (C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxy, or  
 (iii) OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where 
 n=1, 2, 3, or 4; and  
 R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 )alkyl; or  
 R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members in the ring are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C 1 -C 6 ) alkyl;  
 
 
 R 3  is C 3 -C 6  alkyl;  
 R 4  is chloro or fluoro; and  
 R a  and R b  independently represent hydrogen or C 1 -C 6  alkoxy.  
 
     
     
         3 . A compound according to  claim 2 , wherein R 1  is benzyl mono- or disubstituted on the ring portion with 
 (C 1 -C 6 ) alkyl, halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 ) alkyl, hydroxy(C l -C 6 )alkyl, amino, mono- or di(C 1 -C 6 )alkylamino, aminomethyl, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, or mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxy; or    OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where 
 n=1, 2, 3, or 4; and  
 R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 ) alkyl; or  
 R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C 1 -C 6 ) alkyl;  
 except that R 1  is not 3-fluorobenzyl.  
   
     
     
         4 . A compound according to  claim 2 , wherein R 4  is chloro and each of R a  and R b  are C 1 -C 6  alkoxy.  
     
     
         5 . A compound according to  claim 2 , wherein R 3  is isoamyl and R a  and R b  are methoxy.  
     
     
         6 . A compound according to  claim 2 , wherein R 4  is chloro, R 3  is isoamyl and R a  and R b  are methoxy.  
     
     
         7 . A compound according to  claim 2  wherein R 1  is benzyl substituted in the 2- or 3-positions of its phenyl ring with hydroxy, C 1 -C 2  alkyl, C 1 -C 2  alkoxy, ω-[4-((C 1 -C 6 )alkyl)piperazinyl](C 1 -C 4 )alkoxy, methyl sulfonate, 3-halopropoxy, carboxymethoxy, 2-, 3-, or 4-pyridylmethyl, 3-pyrrolidinyl(C 1 -C 6 )alkoxy, tetrazolyl, halogen, preferably bromo, fluoro or chloro, (C 1 -C 6 )alkylamino(C 1 -C 4 )alkoxy, 3-morpholin-4-yl(C 1 -C 6 )alkoxy, ω-piperidyl(C 1 -C 4 )alkoxy, (C 1 -C 3 )alkoxycarbonylmethoxy, [N-(methylsulfonyl)carbamoyl]methoxy, trifluoromethyl, and nitro.  
     
     
         8 . A compound according to  claim 7 , wherein R 1  is a benzyl group substituted in the 2-position of the phenyl ring.  
     
     
         9 . A comopound according to  claim 2 , wherein R 1  is 2-fluoro-, 2-bromo- or 2-chloro-5-nitrobenzyl, 3,5-dihalobenzyl where the halogen is chloro or fluoro, 5-hydroxy(C 1 -C 2 )alkyl-2-(C 1 -C 3 )alkoxybenzyl, 5-(C 2 -C 4 )alkanoyl-2-(C 1 -C 3 )alkoxybenzyl, and 3-amino-5- or 6-(C 1 -C 2 )alkoxybenzyl.  
     
     
         10 . A comopound according to  claim 2 , wherein R 1  is alkenyl groups such as allyl or 1-buten-2- or 3-yl.  
     
     
         11 . A compound according to  claim 1  which is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino, mono- or di (C 1 -C 6 ) alkylamino, aminomethyl, methylamino (C 1 -C 6 ) alkyl, mono- or di(C 1 -C 6 )alkylaminomethyl, mono- or di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkoxy, or OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where n=1, 2, 3, or 4 and R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 )alkyl or R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring up to two of which members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and each member is optionally substituted with (C 1 -C 6 )alkyl, with the proviso that R 1  is not 3-fluorobenzyl.  
 
     
     
         12 . A compound according to  claim 1  which is:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable non-toxic salts thereof wherein: 
 R 1  represents (C 2 -C 6 ) alkenyl; or  
 R 1  represents aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino, mono- or di(C 1 -C 6 )alkylamino, aminomethyl, methylamino(C 1 -C 6 )alkyl, mono- or di(C 1 -C 6 )alkylaminomethyl, mono- or di(C 1 -C 6 ) alkylamino(C 1 -C 6 )alkoxy, or OR 7 , O(CH 2 ) n C(O)R 7 , O(CH 2 ) n NR 7 R 8 , O(CH 2 ) n CO 2 R 7 , NR 7 COR 8 , COR 7 , CONR 7 R 8  or CO 2 R 7  where n=1, 2, 3, or 4 and R 7  and R 8  are the same or different and represent hydrogen, SO 2 Me, or (C 1 -C 6 )alkyl or R 7  and R 8  together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring up to two of which members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and each member is optionally substituted with (C 1 -C 6 )alkyl, with the proviso that R 1  is not 3-fluorobenzyl.  
 
     
     
         13 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         14 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-({2-[3-(4-methylpiperazinyl)propoxy]phenyl}methyl)benzimidazol-2-yl]methyl}carboxamide.  
     
     
         15 . A compound according to  claim 1 , which is 2-{2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}benzimidazolyl)methyl]phenoxy}acetic acid.  
     
     
         16 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[3-(2-pyridylmethyl)imidazolo[5,4-b]pyridin-2-yl]methyl}carboxamide.  
     
     
         17 . A compound according to  claim 1 , which is 2-(2-chlorophenyl)-N-({3-[(2-methoxyphenyl)methyl]imidazolo[5,4-b]pyridin-2-yl}methyl)-N-(3-methylbutyl)acetamide.  
     
     
         18 . A compound according to  claim 1 , which is [2-chloro-4-(methylethoxy)phenyl]-N-({3-[(2-methoxyphenyl)methyl]imidazolo[5,4-b]pyridin-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]imidazolo[4,5-c]pyridin-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         20 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-[(1-{[3-(3-pyrrolidinylpropoxy)phenyl]methyl}benzimidazol-2-yl)methyl]carboxamide.  
     
     
         21 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-[(1-prop-2-enylbenzimidazol-2-yl)methyl]carboxamide.  
     
     
         22 . A compound according to  claim 1 , which is 2-(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-1-[(2-methoxyphenyl)methyl]benzimidazol-4-yloxy)acetic acid.  
     
     
         23 . A compound according to  claim 1 , which is 2-{2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}benzimidazolyl)methyl]phenoxyl}-N-(methylsulfonyl) acetamide.  
     
     
         24 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-({1-[(2-(2H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]benzimidazol-2-yl}methylcarboxamide.  
     
     
         25 . A compound according to  claim 1 , which is 2-(2-chlorophenyl)-N-({1-[(2-chlorophenyl)methyl]benzlmidazol-2-yl}methyl)-N-pentylacetamide.  
     
     
         26 . A compound according to  claim 1 , which is 2-(2-chlorophenyl)-N-({1-[(2-chlorophenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)acetamide.  
     
     
         27 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxy-5-nitrophenyl) methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         28 . A compound according to  claim 1 , which is 2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)-N-pentylcarboxamide.  
     
     
         29 . A compound according to  claim 1 , which is N-({3-[(3,5-dichlorophenyl)methyl]imidazolo[5,4-b]pyridin-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         30 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-hydroxyphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         31 . A compound according to  claim 1 , which is 2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}benzimidazolyl)methyl]phenyl methylsulfonate.  
     
     
         32 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-[(1-{[5-(hydroxyethyl)-2-methoxyphenyl]methyl}benzimidazol-2-yl)methyl]-N-(3-methylbutyl) carboxamide.  
     
     
         33 . A compound according to  claim 1 , which is N-({1-[(5-acetyl-2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide.  
     
     
         34 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-chlorophenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         35 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-{[1-({3-[3-(methylamino)propoxy]phenyl}methyl)benzimidazol-2-yl]methyl}-N-(3-methylbutyl)carboxamide.  
     
     
         36 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-({3-[3-(4-methylpiperazinyl)propoxy]phenyl}methyl)benzimidazol-2-yl]methyl)carboxamide.  
     
     
         37 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-(2-pyridylmethyl)benzimidazol-2-yl]methyl}carboxamide.  
     
     
         38 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-{[1-({3-[2-(ethylamino)ethoxy]phenyl}methyl)benzimidazol-2-yl]methyl}-N-(3-methylbutyl) carboxamide.  
     
     
         39 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-fluorophenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl) carboxamide.  
     
     
         40 . A compound according to  claim 1 , which is N-butyl(2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]benzimidazole-2-yl}methyl)carboxamide.  
     
     
         41 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({3-[(3-chlorophenyl)methyl]imidazolo[5,4-b]pyridin-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         42 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl)carboxamide.  
     
     
         43 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-[(1-{[3-(3-morpholin-4-ylpropoxy)phenyl]methyl}benzimidazol-2-yl)methyl]carboxamide.  
     
     
         44 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-({3-[2-(4-methylpiperazinyl)ethoxy]phenyl}methyl)benzimidazol-2-yl]methyl}carboxamide.  
     
     
         45 . A compound according to  claim 1 , which is 3-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}benzimidazolyl)methyl]phenyl methylsulfonate.  
     
     
         46 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-[(1-{[3-(2-piperidylethoxy)phenyl]methyl}benzimidazol-2-yl)methyl]carboxamide.  
     
     
         47 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(3-hydroxyphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         48 . A compound according to  claim 1 , which is ethyl 2-{2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-carbonylamino]methyl}benzimidazolyl)methyl]phenoxy}acetate.  
     
     
         49 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-({3-[2-methoxyphenyl) methyl]imidazolo [5,4-b]pyridin-2-yl}methyl)-N-(3-methylbutyl)carboxamide.  
     
     
         50 . A compound according to  claim 1 , which is N-({1-[(3-amino-6-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl) carboxamide.  
     
     
         51 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-({2-[2-(4-methylpiperazinyl)ethoxy]phenyl}methyl)benzimidazol-2-yl]methyl}carboxamide.  
     
     
         52 . A compound according to  claim 1 , which is N-butyl(2-chloro-3,4-dimethoxyphenyl)-N-({1-[(3-fluorophenyl)methyl]benzimidazol-2-yl}methyl)carboxamide.  
     
     
         53 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-[(1-{[2-(trifluoromethyl)phenyl]methyl}benzimidazol-2-yl)methyl]carboxamide.  
     
     
         54 . A compound according to  claim 1 , which is [2-chloro-4-(methylethoxy)phenyl]-N-(3-methylbutyl)-N-({1-[(2-nitrophenyl)methyl]benzimidazol-2-yl}methylcarboxamide.  
     
     
         55 . A compound according to  claim 1 , which is (2-chloro-3,4-dimethoxyphenyl)-N-[(4-methyoxy-1-prop-2-enylbenzimidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide.  
     
     
         56 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or excipient.  
     
     
         57 . A method of treatment or diagnosis of a patient suffering from physiological disorders associated with an excess amount of bradykinin comprising administering to the patient a suffienct amount of a compound according to  claim 1  to reduce the effects of excess bradykinin.  
     
     
         58 . A method of treatment or diagnosis of a patient suffering from physiological disorders associated with an insufficient amount of bradykinin comprising administering to the patient a sufficient amount of a compound according to  claim 1  to reduce the effects of insufficient bradykinin.  
     
     
         59 . A method according to  claim 57  wherein the physiological disorders are renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation, 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, increase of permeability of blood-brain barrier, pain, asthma or rhinitis.  
     
     
         60 . A method according to  claim 58  wherein the physiological disorders are renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation, 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, increase of permeability of blood-brain barrier, pain, asthma or rhinitis.  
     
     
         61 . A use of a compound according to  claim 1  in the manufacture of a medicament for the treatment of renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation, 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 or glaucoma, increase of permeability of blood-brain barrier, pain, asthma or rhinitis.  
     
     
         62 . A process for preparing a compound according to  claim 1 .  
     
     
         63 . A method for the treatment or prevention of a disease or disorder associated with pathogenic BK-2 receptor activation, said method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of  claim 1 .  
     
     
         64 . The use of a compound according to  claim 1  for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with pathogenic bradykinin-2 receptor activation.  
     
     
         65 . The use of a compound according to  claim 1  for the manufacture of a medicament for the treatment or prevention of pain, asthma, or rhinitis.  
     
     
         66 . A method according to  claim 63  wherein the disorder associated with pathogenic bradykinin receptor activation is pain, asthma or rhinitis  
     
     
         67 . A method for localizing BK-2 receptors in a tissue sample comprising: 
 contacting the sample with a detectably-labeled compound of  claim 1  under conditions that permit binding of the compound to neurokinin 3 receptors, washing the sample to remove unbound compound, and detecting the bound compound.    
     
     
         68 . A method of inhibiting the binding of a bradykinin to a BK-2 receptor, said method comprising contacting a compound of  claim 1  with cells expressing the BK-2 receptor in the presence of a bradykinin, wherein the compound is present at a concentration sufficient to inhibit bradykinin binding to cells expressing a cloned human BK-2 receptor in vitro.  
     
     
         69 . A method for altering the signal-transducing activity of BK-2 receptors, said method comprising exposing cells expressing BK-2 receptors to a compound according to  claim 1  at a concentration sufficient to inhibit bradykinin binding to cells expressing a cloned human BK-2 receptor in vitro.  
     
     
         70 . A packaged pharmaceutical composition comprising the pharmaceutical composition of  claim 56  in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to BK-2 receptor modulation.  
     
     
         71 . The packaged pharmaceutical composition of claim  70 , wherein said patient is suffering from anxiety, depression, schizoprenia, obesity, chronic pulmonary obstructive disorder, or pain.  
     
     
         72 . A compound according to  claim 1  wherein the compound exhibits an IC 50  of 1 micromolar or less in a standard assay of BK-2 receptor binding.  
     
     
         73 . A compound according to  claim 1  wherein the compound exhibits an IC 50  of 100 nanomolar or less in a standard assay of BK-2 receptor binding.  
     
     
         74 . A compound according to  claim 1  wherein the compound exhibits an IC 50  of 10 nanomolar or less in a standard assay of BK-2 receptor binding.  
     
     
         75 . A method of increasing the permeability of the blood brain barrier comprising administering a compound according to  claim 1  to a patient.  
     
     
         76 . A method of increasing the brain concentration of a CNS active compound comprising administering a compound according to  claim 1  and the CNS active compound to a patient.