Bradykinin receptor agonists and uses thereof to treat ocular hypertension and glaucoma

Abstract

The invention provides compositions and methods for treating and/or preventing ocular disorders associated with increased intraocular pressure. In particular, the compounds are bradykinin agonists.

1 . A compound of Formula 1: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1 , R 2  independently=—CH 3  or —Cl; 
         R 3 ═C 1 -C 3 alkyl; 
         A is: 
       
       
         
           
           
               
               
           
         
         R 4 =—OR 5 , —NR 7 R 10  or —R 5 ; 
         R 5 ═C 1 -C 3  alkyl; 
         X=—(CH 2 ) n —, —CF 2 CH 2 —; 
         n=1-3; 
         Y is: 
       
       
         
           
           
               
               
           
         
         D 1 =N, CH, CR 5 , or COR 5 ; 
         R 6 =—C(O)OR 10 , —N(R 10 )C(O)R 11 , —N(R 10 )S(O 2 )R 11 , —C(O)N(R 10 )(R 11 ), —N(R 10 )C(O)OR 11 , —N(R 10 )C(O)NR 7 R 11 , NR 10 R 12 , or —(CH 2 ) m NR 10 R 12 ; 
         R 7 ═H or C 1 -C 3  alkyl; 
         R 8 ═O, NC(O)R 11 , NS(O 2 )R 11 , NC(O)OR 11 , NC(O)NR 7 R 11 , or NR 11 ; 
         R 9 ═NC(O)R 11 , NS(O 2 )R 11 , NC(O)OR 11 , NC(O)NR 7 R 11 , or NR 11 ; 
         R 10 ═H or C 1 -C 3  alkyl; 
         R 11 ═H, C 1 -C 4  alkyl, or —(CH 2 ) p —Z; 
         R 12 ═H, C 1 -C 3  alkyl, or —C(O)R 7 ; m=1-3; 
         p=2-4; 
         Z=—OH or —OR 12 ; 
         R 13 =—N(R 10 )C(O)R 11 , —N(R 10 )S(O 2 )R 11 , —C(O)N(R 10 )(R 11 ), —N(R 10 )C(O)OR 11 , or —N(R 10 )C(O)NR 7 R 11 ; 
         R 14 =—H, —CH 3 , or -cyclopropyl 
         R 15 =—H, C 1 -C 4  alkyl, C(O)OR 11 , —C(O)N(R 10 )(R 11 ) or —(CH 2 ) m NR 10 R 12 ; 
         W=—O— or —NH—; 
         B 1  is: 
       
       
         
           
           
               
               
           
         
         D 2 =N, CH or CF; 
         ; and 
         B 2  is: 
       
       
         
           
           
               
               
           
         
         D 2 =N, CH or CF; 
         or a prodrug thereof. 
       
     
     
         2 . A compound of  claim 1 , wherein:
 R 1 , R 2  independently=—CH 3  or —Cl;   R 3 ═C 1 -C 3  alkyl;   A is:   
       
         
           
           
               
               
           
         
         R 4 =—OR 5  or —NR 7 R 10 ; 
         R 5 ═C 1 -C 3  alkyl; 
         X=—(CH 2 ) n —; 
         n=1-3; 
         Y is: 
       
       
         
           
           
               
               
           
         
         D 1 ═N, CH, CR 5 , or COR 5 ; 
         R 6 ═—N(R 10 )C(O)R 11 , —C(O)N(R 10 )(R 11 ), or —N(R 10 )C(O)OR 11 ; 
         R 7 =—H or C 1 -C 3  alkyl; 
         R 8 =—O—, —NC(O)R 11 , —NC(O)OR 11 , or —NC(O)NR 7 R 11 ; 
         R 9 ═NC(O)R 11  or NC(O)OR 11 ; 
         R 10 =—H or C 1 -C 3  alkyl; 
         R 11 =—H, —C 1 -C 4  alkyl or —(CH 2 ) p —Z; 
         R 14 =—H, —CH 3 , or -cyclopropyl; 
         p=2-4; 
         Z=—OH or —OR 12 ; 
         W=—O— or —NH—; 
         B 1  is: 
       
       
         
           
           
               
               
           
         
       
       and
 B 2 ═B 1 ; 
 or a prodrug thereof. 
 
     
     
         3 . A compound of  claim 2 , wherein the compound is selected from the group consisting of:
 Compound 7, 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpiperazine-1-carboxamide   Compound 8, 3-(4-acetamidopiperidin-1-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide;   Compound 28, 3-(4-acetamidophenyl)-N-(2-((2,4-dichloro-3-(((2-methyl-4-(pyridin-2-ylmethoxy)quinolin-8-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide;   Compound 32, 3-(6-acetamidopyridin-3-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide;   Compound 33, 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide;   Compound 34, (S)-tert-butyl 3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)carbamoyl)pyrrolidine-1-carboxylate;   Compound 44, 4-(2-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-methylmorpholine-2-carboxamide;   Compound 56, 4-(3-((2-((3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)-2,4-dimethylphenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide;   Compound 64, 5-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide;   Compound 74, 3-(6-(2-aminoacetamido)pyridin-3-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide; and   Compound 78, 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide.   
     
     
         4 . A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
         5 . A topical ophthalmic formulation comprising a therapeutically effective amount of a compound of  claim 1 , and one or more ingredients selected from the group consisting of surfactants, tonicity agents, buffers, preservatives, co-solvents, and viscosity building agents. 
     
     
         6 . The formulation of  claim 5 , wherein the therapeutically effect amount of the compound is between 0.001-1.0%. 
     
     
         7 . The formulation of  claim 6 , wherein the therapeutically effect amount of the compound is 0.005%. 
     
     
         8 . A method for controlling intraocular pressure in a patient comprising administering to the patient a composition comprising a pharmaceutically acceptable ophthalmic carrier and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein:
 R 1 , R 2  independently=—CH 3  or —Cl;   R 3 ═C 1 -C 3  alkyl;   A is:   
       
         
           
           
               
               
           
         
         R 4 =—OR 5  or —NR 7 R 10 ; 
         R 5 ═C 1 -C 3  alkyl; 
         X=—(CH 2 ) n —; 
         n=1-3; 
         Y is: 
       
       
         
           
           
               
               
           
         
         D 1 =N, CH, CR 5 , or COR 5 ; 
         R 6 =—N(R 10 )C(O)R 11 , —C(O)N(R 10 )(R 11 ), or —N(R 10 )C(O)OR 11 ; 
         R 7 =—H or C 1 -C 3  alkyl; 
         R 8 =—O—, —NC(O)R 11 , —NC(O)OR 11 , or —NC(O)NR 7 R 11 ; 
         R 9 ═NC(O)R 11  or NC(O)OR 11 ; 
         R 10 =—H or C 1 -C 3  alkyl; 
         R 11 =—H, —C 1 -C 4  alkyl or —(CH 2 ) p —Z; 
         R 14 =—H, —CH 3 , or -cyclopropyl; 
         p=2-4; 
         Z=—OH or —OR 12 ; 
         W=—O— or —NH—; 
         B 1  is: 
       
       
         
           
           
               
               
           
         
       
       and
 B 2 ═B 1 ; 
 or a prodrug thereof. 
 
     
     
         10 . The method of  claim 9 , wherein the compound is selected from the group consisting of:
 Compound 7, 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpiperazine-1-carboxamide;   Compound 8, 3-(4-acetamidopiperidin-1-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide;   Compound 28, 3-(4-acetamidophenyl)-N-(2-((2,4-dichloro-3-(((2-methyl-4-(pyridin-2-ylmethoxy)quinolin-8-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide;   Compound 32, 3-(6-acetamidopyridin-3-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide;   Compound 33, 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide;   Compound 34, (S)-tert-butyl 3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)carbamoyl)pyrrolidine-1-carboxylate;   Compound 44, 4-(2-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-methylmorpholine-2-carboxamide;   Compound 56, 4-(3-((2-((3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)-2,4-dimethylphenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide;   Compound 64, 5-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide; and   Compound 78, 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide.   
     
     
         11 . The method of  claim 8 , wherein the patient has glaucoma. 
     
     
         12 . The method of  claim 8 , wherein the patient has ocular hypertension. 
     
     
         13 . The method of  claim 8 , further comprising administering to the patient a therapeutically effective amount of an intraocular (IOP)-lowering agent in combination with a non-peptidic BK agonist. 
     
     
         14 . The method of  claim 13 , wherein the IOP-lowering agent is an aqueous humor production (inflow) inhibitor. 
     
     
         15 . The method of  claim 8 , wherein the composition comprises one or more ingredients selected from the group consisting of surfactants, tonicity agents, buffers, preservatives, co-solvents, and viscosity building agents. 
     
     
         16 . The method of  claim 8 , wherein the therapeutically effect amount of a non-peptidic BK agonist is between 0.001-1.0%. 
     
     
         17 . The method of  claim 16 , wherein the therapeutically effect amount of the non-peptidic BK agonist is 0.005%.