Method for the synthesis of compounds of formula I and their uses thereof

Abstract

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer's disease, erectile dysfunction, and tumor invasion and metastasis.

1 . A method for the inhibition of the interaction of RAGE with its physiological ligands, which comprises administering to a subject in need thereof, at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof,  
         wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
       
     
     
         2 . The method of  claim 1 , wherein the ligand(s) is(are) selected from advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin.  
     
     
         3 . The method of  claim 1 , wherein at least on of Aryl 1  or Aryl 2  is further substituted with a lipophilic group selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylaryl, and C 1 -C 6  alkoxyaryl.  
     
     
         4 . A method for treating acute and/or chronic inflammation, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof,  
         wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
       
     
     
         5 . A method for treating vascular permeability, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         6 . A method for treating nephropathy, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         7 . A method for treating atherosclerosis, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         8 . A method for treating retinopathy, which comprises administering to a subject in need thereof a therapeutically effective amount of compound of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         9 . A method for treating Alzheimer's disease, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; 
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         10 . A method for treating erectile dysfunction, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         11 . A method for treating tumor invasion and/or metastasis, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C- 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 )n— bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 .  
 
       
     
     
         12 . A method of treating RAGE mediated diseases, the method comprising administering to a subject in need thereof, a therapeutically effective amount of at least one compound comprising at least one moiety of the formula  
       
         
           
           
               
               
           
         
         wherein L 1  is a C 1 -C 4  alkyl group and L 2  is a direct bond, and Aryl 1  and Aryl 2  are aryl, wherein each of Aryl 1  and Aryl 2  are substituted by at least one lipophilic group selected from the group consisting of 
 a) —Y—C 1-6  alkyl;  
 b) —Y-aryl;  
 c) —Y—C 1-6  alkylaryl;  
 d) —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 e) —Y—C 1-6 -alkyl-W—R 20 ; 
 wherein 
 Y and W are, independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,  
                     
 and  
 
 
 f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; 
 wherein 
 R 18  and R 19  are independently selected from the group consisting of aryl, C 1 -C 6  alkyl, C 1 -C 6  alkylaryl, C 1 -C 6  alkoxy, and C 1 -C 6  alkoxyaryl;  
 R 20  is selected from the group consisting of aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl;  
 R 7 , R 8 , R 9  and R 10  are independently selected from the group consisting of hydrogen, aryl, C 1 -C 6  alkyl, and C 1 -C 6  alkylaryl; and wherein R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -X-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,  
                     
 
 
 
         or a pharmaceutically acceptable salt thereof, 
 wherein at least one of Aryl 1  and Aryl 2  is substituted with a lipophilic group of the formula —Y—C 1-6 -alkyl-NR 7 R 8 ;  
 
         in combination with one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.