Pyridoquinoxaline antivirals

Abstract

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are as defined in the specification. The compounds are useful for the treatment of viral infections.

What is claimed is:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
 wherein R 1  is F, Cl, Br, CN or NO 2 ;  
 R 2  is C 1-6 alkyl, optionally substituted by one to three OR 3 , NR 3 R 3 , aryl or het;  
 R 3  is H or C 1-4  alkyl;  
 het is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyridyl, imidazolyl, azetidyl, tetrahydrofuranyl or imidazolidinyl;  
 and aryl is a phenyl or pyridyl radical, attached via a carbon atom, optionally substituted by one to three halogen, OR 3  or NR 3 R 3 .  
 
     
     
         2 . A compound of  claim 1  wherein R 1  is Cl.  
     
     
         3 . A compound of  claim 1  wherein R 2  is methyl.  
     
     
         4 . A compound of  claim 1  wherein R 2  is C 1-4  alkyl, optionally substituted by OH or NH 2 .  
     
     
         5 . A compound of  claim 2  or  3  wherein R 2  is C 1-4  alkyl, optionally substituted by OH or NH 2 .  
     
     
         6 . A compound of  claim 1  wherein R 2  is C 1-4  alkyl, optionally substituted by OC 1-3  alkyl.  
     
     
         7 . A compound of  claim 2  or  3  wherein R 2  is C 1-4  alkyl, optionally substituted by OC 1-3  alkyl.  
     
     
         8 . A compound of  claim 1  wherein R 2  is C 1-4  alkyl, optionally substituted by morpholinyl, piperidinyl, piperazinyl, or pyrrolidinyl.  
     
     
         9 . A compound of  claim 2  or  3  wherein R 2  is C 1-4  alkyl, optionally substituted by morpholinyl, piperidinyl, piperazinyl, or pyrrolidinyl.  
     
     
         10 . A compound of  claim 1  which is 
 a). N-(4-chlorobenzyl)-1-methyl-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 b). N-(4-chlorobenzyl)-1-ethyl-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 c). N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 d). N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-1-(2-phenylethyl)-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 e). N-(4-chlorobenzyl)-1-(2-hydroxy-2-phenylethyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 f). N-(4-chlorobenzyl)-1-(2,3-dihydroxypropyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 g). N-(4-chlorobenzyl)-1-(2-methoxyethyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 h). N-(4-chlorobenzyl)-1-(3-hydroxypropyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,  
 i). N-(4-fluorobenzyl)-1-methyl-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide, or  
 j). N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-1-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide.  
 
     
     
         11 . A compound of  claim 1  which is N-(4-chlorobenzyl)-1-methyl-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide.  
     
     
         12  A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         13 . A method of treating or preventing infections by herpesviruses which comprises administering to a mammal in need thereof a compound of  claim 1 .  
     
     
         14  The method of  claim 13  wherein the mammal is a human.  
     
     
         15 . The method of  claim 13  wherein the mammal is an animal.  
     
     
         16 . The method of  claim 13  wherein said herpesviruses is herpes simplex virus types 1, herpes simplex virus types 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes viruses 6, human herpes viruses 7 or human herpes viruses 8.  
     
     
         17 . The method of  claim 13  wherein said herpesviruses is human cytomegalovirus.  
     
     
         18 . The method of  claim 13  wherein the compound of  claim 1  is administered orally, parenterally or topically.  
     
     
         19 . The method of  claim 13  wherein the compound of  claim 1  is in an amount of from about 0.1 to about 300 mg/kg of body weight.  
     
     
         20 . The method of  claim 13  wherein the compound of  claim 1  is in an amount of from about 1 to about 30 mg/kg of body weight.  
     
     
         21 . A method for inhibiting a viral DNA polymerase, comprising contacting the polymerase with an effective inhibitory amount of a compound of  claim 1 .  
     
     
         22 . A method of treating atherosclerosis and restenosis comprising administering to a mammal in thereof a compound of  claim 1 .  
     
     
         23 . The method of  claim 22  wherein the compound of  claim 1  is in an amount of from about 0.1 to about 300 mg/kg of body weight.  
     
     
         24 . The method of  claim 22  wherein the compound of  claim 1  is in an amount of from about 1 to about 30 mg/kg of body weight.  
     
     
         25 . The method of  claim 13  wherein the compound of  claim 1  is administered orally, parenterally or topically.  
     
     
         26 . A method of preparing an intermediate of formula IV or a pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
       
       which comprises reacting a compound of formula m or its pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
       
       with hydroxide or alkoxide in an aqueous solvent;  
       wherein R 2  is C 1-6 alkyl, optionally substituted by one to three OR 3 , NR 3 R 3 , aryl or het; R 3  is H or C 1-4  alkyl; het is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyridyl, imidazolyl, azetidyl, tetrahydrofuranyl or imidazolidinyl; and aryl is a phenyl or pyridyl radical, attached via a carbon atom, optionally substituted by one to three halogen, OR 3  or NR 3 R 3 .