Novel dihydroxyhexanoic acid derivatives

Abstract

The present invention relates to methods of making dihydroxyhexanoic acid derivatives of the general formula (I) that are useful to treat inflammation and other immune disorders.

What is claimed is:  
     
         8 . A method of making a compound having a formula (I)  
       
         
           
           
               
               
           
         
       
       wherein said compound of formula (I) is: 
 quinoxaline-2-carboxylic acid 4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 7,8-difluoro-quinoline-3-carboxylic acid (1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl -octyl)-amide;  
 6,7,8-trifluoro-quinoline-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl -octyl)-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl -7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R) -hydroxycarbamoyl-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide; or  
 quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;  
 wherein the method comprises reacting ammonia or a low molecular weight amine with a compound having the formula (II)  
                     
 wherein R 1  is quinoxaline-2-carboxylic acid, 7,8-difluoro-quinoline-3-carboxylic acid, or 6,7,8-trifluoroquinoline-3-carboxylic acid; and  
 R 2  is benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 3-chloro-benzyl, 3-fluoro-benzyl, 3,4-difluoro-benzyl, naphthalen-1-yl-methyl, or thiophen-2-yl-methyl.  
 
     
     
         9 . The method of  claim 8 , wherein the method further comprises forming the compound of formula (II) by coupling a compound of formula (III)  
       
         
           
           
               
               
           
         
       
       with an acid of the formula R 1 CO 2 H or an acid chloride thereof in the presence of a coupling reagent.  
     
     
         10 . The method of  claim 9 , wherein the method further comprises forming the compound of formula (III) by reacting a compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein P is a protecting group with trifluoro acetic acid.  
     
     
         11 . The method of  claim 10 , wherein the method further comprises forming the compound of formula (IV) by reacting a compound of formula (V)  
       
         
           
           
               
               
           
         
       
       with 4-bromo-2-methyl-2-butene in the presence of a strong base.  
     
     
         12 . A compound having the formula (V)  
       
         
           
           
               
               
           
         
         wherein P is a protecting group and  
         R 2  is benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 3-chloro-benzyl, 3-fluoro-benzyl, 3,4-difluoro-benzyl, naphthalen-1-yl-methyl, or thiophen-2-yl-methyl.  
       
     
     
         13 . A compound having the formula (IV)  
       
         
           
           
               
               
           
         
         wherein P is a protecting group and  
         R 2  is benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 3-chloro-benzyl, 3-fluoro-benzyl, 3,4-difluoro-benzyl, naphthalen-1-yl-methyl, or thiophen-2-yl-methyl.  
       
     
     
         14 . A compound having the formula (III)  
       
         
           
           
               
               
           
         
         wherein R 2  is benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 3-chloro-benzyl, 3-fluoro-benzyl, 3,4-difluoro-benzyl, naphthalen-1-yl-methyl, or thiophen-2-yl-methyl.  
       
     
     
         15 . A compound having the formula (II)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is quinoxaline-2-carboxylic acid, 7,8-difluoro-quinoline-3-carboxylic acid, or 6,7,8-trifluoroquinoline-3-carboxylic acid, and  
 R 2  is benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 3-chloro-benzyl, 3-fluoro-benzyl, 3,4-difluoro-benzyl, naphthalen-1-yl-methyl, or thiophen-2-yl-methyl.  
 
     
     
         16 . The compound of  claim 12  or  13 , wherein P is t-butoxycarbonyl.  
     
     
         17 . The compound of  claim 15 , wherein R 1  is quinoxlaine-2-carboxylic acid.  
     
     
         18 . The compound of any of claims  12 - 17 , wherein R 2  is 3-fluoro-benzyl.  
     
     
         19 . A pharmaceutical composition for treating a disorder or condition selected from acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity, and granulomatous in a mammal, comprising an amount of a compound having the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein said compound of formula (I) is: 
 quinoxaline-2-carboxylic acid 4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 7,8-difluoro-quinoline-3-carboxylic acid (1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl -octyl)-amide;  
 6,7,8-trifluoro-quinoline-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl -octyl)-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide; or  
 quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;  
 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
 
     
     
         20 . A method for treating a disorder or condition selected from acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity, and granulomatous in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound having the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein said compound of formula (I) is: 
 quinoxaline-2-carboxylic acid 4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 7,8-difluoro-quinoline-3-carboxylic acid (1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;  
 6,7,8-trifluoro-quinoline-3-carboxylic acid (1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl -7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;  
 quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide; or  
 quinoxaline-2-carboxylic acid (4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;  
 or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.