Substituted bis-acridines and related compounds as CCR5 receptor ligands, anti-inflammatory agents and anti-viral agents

Abstract

This invention relates to substituted bis-acridines and related compounds which are ligands, in particular, antagonists of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune disease such as multiple sclerosis, and inflammatory bowel disease, all in mammals, by the use of substituted bis-acridines and related compounds which are CCR5 receptor antagonists. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor ligands may be useful in the treatment of HIV infection.

What is claimed is:  
     
         1 . A method of treating a CCR5-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         X are independently one or more of H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alky, Ar-C 0-4 alkyl, CH 2 NR′ 2 , CH 2 OR′, CN, COR′, CONR′ 2 , CO 2 R′, CF 3 , NR′ 2 , NR′COR′, NR′CONR′R′, NR′CO 2 R″, NR′SO 2 R″, NO 2 , OR′, S(O) 0-2 R″, S(O) 0-2 CF 3 , or halo;  
         R′ is H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkiyl or Ar-C 0-4 alkyl;  
         R″ is C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;  
         D and D′ are independently CX or N;  
         V and V′ are independently C(R) 2 , NR 1 , O, or S(O) 0-2 ;  
         R 1  are independently H, C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl, Ar-C 0-4 alkyl, —C(O)CF 3 , —C(O)R′, or —SO 2 R″, or, when V and V′ are —NR 1 , the two R 1  groups taken together may be (C(R) 2 ) 2-3  to form a heterocyclic ring of five to nine members;  
         n is 0, 1, 2 or 3; and  
         R are independently H, C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl, or, when V and V′ are independently NR 1 , O or S(O) 0-2 , any two R taken together may be (C(R) 2 ) 2-4  to form a carbocyclic ring of three to eight members.  
       
     
     
         2 . The method as claimed in    claim 1    wherein the compound of formula (I) is a compound selected from: 
 N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1 ,2-ethanediarine bis(trifluoroactate);  
 N,N′-di-9-acridinyl-1,2-ethanediamine bis(trifluoroactate);  
 N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1 ,3-propanedi amine bis(trifluoroactate);  
 9,9′-(1,4-piperazinediyl)bis-6-chloro-2-methoxy-acridine bis(trifluoroacetate);  
 N-(6-chloro-2-methoxy-9-acridinyl)-N-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroacetate);  
 N,N′-bis(6-chloro-2-hydroxy-9-acridinyl)- 1 ,2-ethanediamine bis(trifluoroactate);  
 N-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyll-N-(6-chloro-2-hydroxy-9-acridinyl]-1,2-ethanediamine bis(trifluoroactate);  
 N-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl-N-(6-chloro-2-methoxy-9-acridinyl]-1,2-ethanediarnine bis(trifluoroactate);  
 N,N′-bis[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl]- 1 ,2-ethanediamine bis(trifluoroactate);  
 N,N′-Bis[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-1,2-ethanediamine bis(trifluoroactate);  
 N-[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyll-N-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroactate);  
 N-[6-chloro-2-(tert-butoxycarbonyIl)methoxy-9-acridinyl]-N-.(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediamnine bis(trifluoroactate);  
 N,N′-bis(6-chloro-2-carboxymethoxy-9-acridinyl)- 1 ,2-ethanediamine bis(trifluoroactate);  
 N-[6-chloro-2-(2-dimethylamino)ethoxy-9-acridinyll-N-(6-chloro-2-hydroxy-9-acridinyl]- 1.2-ethanediamnine bis(trifluoroactate);  
 N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-dimethyl- 1,2-ethanediamine bis(trifluoroactate);  
 N,N′-bis(6chloro-2-methoxy-9-acridinyl)-N,N′7-bis(trifluoromethylcarbonyl)-1,2-ethanediarrine bis(trifluoroactate);  
 N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N-(trifluoromethylcarbonyl)- 1,2-ethanediamine bis(trifluoroacetate);  
 Bis(6-chloro-2-methoxy-9-acridinyl)- 1,3-propane;  
 Bis(2-methoxy-9-acridinyl)-1,4-butane bis(trifluoroactate);  
 1-(6-chloro-2-methoxy-9-acridinyl)4-(2-methoxy-9-acridinyl)butane,  
 N-(9-acridinyl)-N-(6-chloro-2-methoxy-9-acridinyl)- l ,2-ethanediamine,. bis(trifluoroactate); and  
 N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-bis(acetyl)- 1,2-ethanediamine.  
 
     
     
         3 . The method as claimed in    claim 1   , wherein the disease is selected from asthma and atopic disorders, rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection.  
     
     
         4 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         X are independently one or more of H, optionaly substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl, Ar-C 0-4 alkyl, CH 2 NR′ 2 , CH 2 OR′, CN, COR′, CONR′ 2 , CO 2 R′, CF 3 , N(R′) 2 , NR′COR′, NR′CONR′R′, NR′CO 2 R″, NR′SO 2 R″, NO 2 , OR′, S(O) 0-2 R″, S(O) 0-2 CF 3 , or halo;  
         R′ is H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;  
         R″ is C 1-6 alkl, C 3-7 cycloalkyl-C 0-4 -alkyl or Ar-C 0-4 alkyl;  
         D and D′ are independently CX or N;  
         V and V′ are independently C(R) 2 , NR 1 , O, or S(O) 0-2 ;  
         R 1  are independently H, C 1-6 alkyl, C 3-7 cycloalky-C 0-4 alkyl, Ar-C 0-4 alkyl, —C(O)CF 3 , —C(O)R′, or —SO 2 R″, or, when V and V′ are —NR 1 , the two R 1  groups taken together may be (C(R) 2 ) 2-3  to form a heterocyclic ring of five to nine members;  
         n is 0, 1, 2or 3; and  
         R are independently H, C 1-6 alkyl, C 3-7 cycIoalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl, or, when V and V′ are independently NR 1 , O or S(O) 0-2 , any two R taken together may be (C(R) 2 ) 2-4  to form a carbocyclic ring of three to eight members, with the proviso that the compound of formula (I) is not 9,9′-(1,3-propanediyl)bis-acridine; 9,9′-(1,5-pentanediyl)bis-acridine; N,N′-di-9-acridinyl-1,2-ethanediamine; N,N′-bis(4-ethyl-9-acridinyl)- 1,2-ethanediaamine; N,N′-bis(3-methoxy-9-acridinyl)-1,2-ethanediamine; N,N′-bis(4-butoxy-9-acridinyl)-1,2-ethanediarnine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-ethanediamine; trans-N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-cyc]ohexanediarnine; 9,9′-(1,4-piperazinediyl)bis[6-chloro-2-methoxy-acridine]; N,N′-di-9-acridinyl-1,2-propanediamine; N,N′-di-9-acridinyl-1,3-propanediamine; N,N′-bis(1-nitro-9-acridinyl)-1,3-propanediamine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,3-propanediamine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-2,2-methyl-1,3-propanediamine; N,N′-bis(6-chloro-2-fluoro-9-acridinyl)- 1,3-propanediamine; N,N′-di-9-acridinyl-1,4-butanediamine; N,N′-bis(4-ethyl-9-acridinyl)-1,4-butanediamnine; N,N′-bis(1-nitro-9-acridinyl)- 1,4-butanediamine; N,N′-bis(3-methoxy-9-acridinyl)-1,4-butanediamine; N,N′-bis(4-propoxy-9-acridinyl)-1,4-butanediamine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,4-butanediamine; N,N′-bis(3,6-dichloro-9-acridinyl)-1,4-butanediamine; 6-chloro-N-[2-[(6-chloro-2-methoxy-9-acridinyl)thio]ethyl]-2-methoxy-9-acridinamine; 9,9′-[1,2-ethanediylbis(thio)]bis-acridine; 9,9′-[1,2-ethanediylbis(thio)]bis-3-acridinamine; 9,9′-[1,3-propanediy]bis(thio)3bis-acridine; 9-[1,4-butanediylbis(thio)]bis-acridine; 9,9′-[1,4-butanediylbis(thio)]bis-1-acridinamine; 9,9′-[1,4-butanediylbis(thio)]bis-3-acridinaniine; 9,9′-[1,4-butanediylbis(thio)]bis4-acridinamine; 9,9′-[methylenebis(oxy)]bis-anthracene; 9-[methylenebis(oxy)]bis[10-methoxy-anthracenel; 9,9′-[methylenebis(oxy)]bis[10-propoxy-anthracene]; 9,9′-[methylenebis(oxy)]bis 10-(2-methoxyethoxy)-anthracene]; 9,9′-[1,2-ethanediylbis(oxy)]bis-anthracene; 9,9′-(1,3-propanediyl)bis-anthracene; 9,9′-(1,4-butanediyl)bis-anthracene; 9,9′-(1,4-butanediyl)bis 10-(chloromethyl)-anthracene; 9-13-(9-anthracenyloxy)propyl)anthracene; 9,9′-(1,5-pentanediyl)bis-anthracene; 9,9′-(1,5-pentanediyl)bis 10-(chloromethyl)-anthracene; and 9,9′-(1,6-hexanediyl)bis-anthracene.  
       
     
     
         5 . A compound of formula (IA) or a pharmaceutically acceptable salt thereof: 
 wherein:    X 1 , X 2 , X 3  and X 4  are independently H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl, Ar-C 0-4 alkyl, CH 2 NR′ 2 , CH 2 OR′, CN, COR′, CONR′ 2 , CO 2 R′, CF 3 , N(R′) 2 , NR′COR′, NR′CONR′R′, NR′CO 2 R″, NR′SO 2 R″, NO 2 , OR′, S(O) 0-2 R″, S(O) 0-2 CF 3  or halo;    R′ is H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;    R″ is C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;    R 1  are independently H, C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl, Ar-C 0-4 alkyl, —C(O)CF 3 , —C(O)R′, or —SO 2 R″, or, the two R 1  groups taken together may be (C(R) 2 ) 2-3  to form a heterocyclic ring of five to nine members;    n is 0, 1, 2 or 3; and    R are independently H, C 1-6 alky, C 3-7 cycloalkyI-C 0-4 alkyl or Ar-C 0-4 alkyl, or, any two R taken together may be (C(R) 2 ) 2-4  to form a carbocyclic ring of three to eight members,    provided that when n is 1, 2 or 3, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4  are not all hydrogen; and, provided that when n is 1, R 1  are both H, and one of R is CH 3 , X 1 , X 2 , X 3  and X 4  are not all hydrogen; and, provided that when n is 1, R 1  are both H, R are all H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4-ethyl, 3-methoxy or 4-butoxy; and, provided that when n is 1, and R 1  are both H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when the two R 1  groups taken together are (CH 2 ) 2  and form a 6-membered heterocyclic ring, and R are all H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 1, R 1  are both H, two R are (CH 2 ) 4  to form a six-membered carbocyclic ring, and all other R are H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 2, R 1  are both H, R are all H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 1-NO 2 ; and, provided that when n is2, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4 are not2-methoxy-6-chloro or 2-fluoro-6-chloro; and, provided that when [C(R) 2 ] n C(R) 2 , is CH 2 C(CH 3 ) 2 CH 2 , X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 3, R 1  are both H, R are all H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4-ethyl, 1-nitro, 3-methoxy, or 4-propoxy; and, provided that when n is 3, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4  are not 3,6-dichloro or 2-methoxy-6-chloro.    
     
     
         6 . A compound of formula (IA) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         X 1 , X 2 , X 3  and X4 are independently H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl, Ar-C 0-4 alkyl, CH 2 NR′ 2 , CH 2 OR′, CN, COR′, CONR′ 2 , CO 2 R′, CF 3 , N(R′) 2 , NR′COR′, NR′CONR′R′, NR′CO 2 R″, NR′SO 2 R″, NO 2 , OR′, S(O) 0-2 R″, S(O) 0-2 CF 3 , or halo;  
         R′ is H, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;  
         R″ is C 1-6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;  
         R 1  are independently H, C 1-6 alkyl, or one of R 1  is —C(O)CF 3 ;  
         n is 0, 1, 2 or 3; and  
         R is H or C 1-6 alkyl,  
         provided that when n is 1, 2 or 3, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4  are not all hydrogen; and, provided that when n is 1, R 1  are both H, and one of R is methyl, X 1 , X 2 , X 3  and X 4  are not all hydrogen; and, provided that when n is 1, R 1  are both H, R are all H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4-ethyl, 3-methoxy or 4-butoxy; and, provided that when n is 1, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 2, R 1  are both H, R are all H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 1-NO 2 ; and, provided that n is 2, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro or 2-fluoro-6-chloro; and, provided that when [C(R) 2 ] n C(R) 2  is CH 2 C(CH 3 ) 2 CH 2 , X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 3, R 1  are both H, R are all H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4-ethyl, 1-nitro, 3-methoxy, or 4-propoxy; and, provided that when n is 3, R 1  are both H, and R are all H, X 1 , X 2 , X 3  and X 4  are not 3,6-dichloro or 2-methoxy-6-chloro.  
       
     
     
         7 . A compound of formula (IA) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         X 1 , X 2 , X 3  and X 4  are independently one or more of H, OR′, or halo;  
         R′ is H or optionally substituted C 1-6 alkyl;  
         R 1  is H, C 1-6 alkyl, or one of R 1  is —CO(CF 3 );  
         n is 1 or 2; and  
         R is H or C 1-6 alkyl,  
         provided that when R 1  are both H, X 1 , X 2 , X 3  and X 4  are not all hydrogen; and provided that when n is 1, R 1  are both H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4ethyl, 3-methoxy, 4-butoxy; and, provided that when n is 1, and R 1  are both H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6chloro; and, provided that when n is 2, and R 1  are both H, X 1 , X 2 , X 3 , and X 4  are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.  
       
     
     
         8 . A compound of formula (IA) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         X 1 , X 2 , X 3  and X 4  are independently one or more of H, OR′, or halo;  
         R is H or C 1-6 alkyl optionally substituted with N(C 1-6 alkyl) 2 , or CO 2 C 1-6 alkyl;  
         R 1  is H, CH 3 , or one of R 1  is —CO(CF 3 );  
         n is 1 or 2; and  
         R is H,  
         provided that when R 1  are both H, X 1 , X 2 , X 3  and X 4  are not all hydrogen; and, provided that when n is 1, R 1  are both H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4-ethyl, 3-methoxy, 4-butoxy; and, provided that when n is 1, and R 1  are both H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 2, and R 1  are both H, X 1 , X 2 , X 3 , and X 4  are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.  
       
     
     
         9 . A compound of formula (IA) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         X 1 , X 2 , X 3  and X 4  are independently one or more of H, OR, or halo;  
         R′ is H or C 1-6 alkyl optionally substituted with N(CH 3 ) 2 , or CO 2 C 1-6 alkyl;  
         R 1  is H, CH 3 , or one of R 1  is —CO(CF 3 );  
         n is 1 or 2; and  
         R is H,  
         provided that when R 1  are both H, X 1 , X 2 , X 3  and X 4  are not all hydrogen; and, provided that when n is 1, R 1  are both H, and X 2  and X 3  are each hydrogen, X 1  and X 4  are not each 4-ethyl, 3-methoxy, 4-butoxy; and, provided that when n is 1, and R 1  are both H, X 1 , X 2 , X 3  and X 4  are not 2-methoxy-6-chloro; and, provided that when n is 2, and R 1  are both H, X 1 , X 2 , X 3 , and X 4  are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.