Amino ceramide-like compounds and therapeutic methods of use

Abstract

The present invention provides amino ceramide-like compounds which inhibit glucosyl ceramide (GlyCer) formation by inhibiting the enzyme GlyCer synthase, thereby lowering the level of glycosphingolipids. The compounds of the present invention have improved GlcCer synthase inhibition activity and are therefore useful in therapeutic methods for treating various conditions and diseases associated with altered glycosphingolipid levels.

1 . (canceled) 
     
     
         2 . A method for treating a patient with collagen vascular disease, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
       
       a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, wherein
 R 1  is a phenyl, a substituted phenyl group, a branched aliphatic group, or a 7-15 carbons long alkyl chain or a 7-15 carbons long alkenyl chain with a double bond next to the kernel; 
 R 2  is an alkyl group 6, 7, or 8 carbons long; and 
 R 3  is a pyrrolidine, azetidine, morpholine or piperidine, in which the nitrogen atom is attached to the kernel. 
 
     
     
         3 . The method of  claim 2 , wherein R 1  is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxyl, methylenedioxy, ethylenedioxy, trimethylenedioxy and cyclohexyl. 
     
     
         4 . A method for treating a patient with atherosclerosis, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
       
       a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, wherein
 R 1  is a phenyl, a substituted phenyl group, a branched aliphatic group, or a 7-15 carbons long alkyl chain or a 7-15 carbons long alkenyl chain with a double bond next to the kernel; 
 R 2  is an alkyl group 6, 7, or 8 carbons long; and 
 R 3  is a pyrrolidine, azetidine, morpholine or piperidine, in which the nitrogen atom is attached to the kernel. 
 
     
     
         5 . The method of  claim 4 , wherein R 1  is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxyl, methylenedioxy, ethylenedioxy, trimethylenedioxy and cyclohexyl. 
     
     
         6 . A method for treating a diabetic patient with renal hypertrophy, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
       
       a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, wherein
 R 1  is a phenyl, a substituted phenyl group, a branched aliphatic group, or a 7-15 carbons long alkyl chain or a 7-15 carbons long alkenyl chain with a double bond next to the kernel; 
 R 2  is an alkyl group 6, 7, or 8 carbons long; and 
 R 3  is a pyrrolidine, azetidine, morpholine or piperidine, in which the nitrogen atom is attached to the kernel. 
 
     
     
         7 . The method of  claim 6 , wherein R 1  is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxyl, methylenedioxy, ethylenedioxy, trimethylenedioxy and cyclohexyl. 
     
     
         8 . A method for treating patient having a microbial or viral infection, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
       
       a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, wherein
 R 1  is a phenyl, a substituted phenyl group, a branched aliphatic group, or a 7-15 carbons long alkyl chain or a 7-15 carbons long alkenyl chain with a double bond next to the kernel; 
 R 2  is an alkyl group 6, 7, or 8 carbons long; and 
 R 3  is a pyrrolidine, azetidine, morpholine or piperidine, in which the nitrogen atom is attached to the kernel. 
 
     
     
         9 . The method of  claim 8 , wherein R 1  is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxyl, methylenedioxy, ethylenedioxy, trimethylenedioxy and cyclohexyl. 
     
     
         10 . The method of  claim 8 , wherein the patient has an  Escherichia coli  microbial infection or an influenza type A viral infection.