Augmenting Moieties for Anti-Inflammatory Compounds

Abstract

Augmented or synergized anti-inflammatory constructs are disclosed including anti-inflammatory amino acids covalently conjugated with other anti-inflammatory molecules such as nonsteroidal anti-inflammatory drugs, vanilloids and ketone bodies. Further conjugation with a choline bioisostere or an additional anti-inflammatory moiety further augments the anti-inflammatory activity.

What is claimed is: 
     
         1 - 21 . (canceled) 
     
     
         22 . An anti-inflammatory drug-amino acid conjugate, comprising:
 (a) at least one anti-inflammatory compound conjugated with   (b) an augmenting moiety comprising an anti-inflammatory amino acid selected from the group consisting of valine, nor-valine, leucine, iso-leucine, glycine, cysteine, proline and phenylalanine;   
       wherein conjugation is via the nitrogen atom of the amino acid of said augmenting moiety; and 
       wherein the anti-inflammatory activity of the conjugate is greater than the sum of its parts. 
     
     
         23 . (canceled) 
     
     
         24 . The conjugate of  claim 22 , wherein said amino acid is selected from the group consisting of valine, glycine, proline and phenylalanine. 
     
     
         25 . The conjugate of  claim 22 , wherein said augmenting moiety is an amino acid ester of H—OCH 2 CH 2 C(CH 3 ) 3  or H—OCH 2 CH 2 Si(CH 3 ) 3 , or an amino acid amide of H 2 NCH 2 CH 2 C(CH 3 ) 3  or H 2 NCH 2 CH 2 Si(CH 3 ) 3 . 
     
     
         26 . The conjugate of  claim 22 , wherein said anti-inflammatory compound is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), vanilloids and ketone bodies. 
     
     
         27 . The conjugate of  claim 26 , wherein said NSAID is selected from the group consisting of diclofenac, ibuprofen, naproxen, and indomethacin; wherein said vanilloid is selected from the group consisting of vanillyl alcohol, 3-methoxy-4-acetyloxybenzyl alcohol, and vanillylamine; and wherein said ketone body is selected from the group consisting of 3-hydroxybutyrate and homologues thereof. 
     
     
         28 . An anti-inflammatory drug-amino acid conjugate having the structure of Formula (I)
   AI—NH—CHR—C(═O)O-Q 1   Formula (I)
   
       wherein AI represents an anti-inflammatory drug moiety selected from the group consisting of an NSAID-CO— moiety, a vanillyl-CO— moiety and a 3-hydroxybutyroyl moiety; wherein R is selected from the group consisting of hydrogen, isopropyl and benzyl; and wherein Q 1  is selected from the group consisting of alkyl and heteroalkyl. 
     
     
         29 . An anti-inflammatory drug-amino acid conjugate having the structure of Formula (II)
   AI—NH—CHR—C(═O)—NH-Q 2   Formula (II)
   
       wherein AI represents an anti-inflammatory drug moiety selected from the group consisting of an NSAID-CO— moiety, a vanillyl-CO— moiety and a 3-hydroxybutyroyl moiety; wherein R is selected from the group consisting of hydrogen, isopropyl and benzyl; and Q 2  is —CH 2 CH 2 C(CH 3 ) 3 , —CH 2 CH 2 Si(CH 3 ) 3  or 3-methoxy-4-hydroxybenzyl. 
     
     
         30 . (canceled) 
     
     
         31 . The conjugate of  claim 28 , wherein Q 1  is —CH 2 CH 2 C(CH 3 ) 3  or —CH 2 CH 2 Si(CH 3 ) 3 . 
     
     
         32 . (canceled) 
     
     
         33 . A method of increasing the activity of an anti-inflammatory drug, comprising conjugating said anti-inflammatory drug with an amino acid augmenting moiety to provide an amino acid conjugate of  claim 28 . 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of  claim 33 , wherein Q 1  is selected from the group consisting of —CH 2 CH 2 C(CH 3 ) 3  and —CH 2 CH 2 Si(CH 3 ) 3 . 
     
     
         38 - 39 . (canceled) 
     
     
         40 . The amino acid conjugate of  claim 28 , wherein for the NSAID-CO— moiety, the NSAID is selected from the group consisting of diclofenac, naproxen and indomethacin. 
     
     
         41 . The amino acid conjugate of  claim 29 , wherein for the NSAID-CO— moiety, the NSAID is selected from the group consisting of diclofenac, ibuprofen, naproxen and indomethacin. 
     
     
         42 . A method of increasing the activity of an anti-inflammatory drug, comprising conjugating said anti-inflammatory drug with an amino acid augmenting moiety to provide an amino acid conjugate of  claim 29 . 
     
     
         43 . The method of  claim 42 , wherein Q 2  is —CH 2 CH 2 C(CH 3 ) 3  or —CH 2 CH 2 Si(CH 3 ) 3 . 
     
     
         44 . An anti-inflammatory drug-amino acid conjugate selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         45 . An anti-inflammatory drug-amino acid conjugate of  claim 44  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The anti-inflammatory drug-amino acid conjugate of  claim 44 , wherein said conjugate is 
       
         
           
           
               
               
           
         
       
     
     
         47 . The anti-inflammatory drug-amino acid conjugate of  claim 44 , wherein said conjugate is 
       
         
           
           
               
               
           
         
       
     
     
         48 . The anti-inflammatory drug-amino acid conjugate of  claim 44 , wherein said conjugate is 
       
         
           
           
               
               
           
         
       
     
     
         49 . The anti-inflammatory drug-amino acid conjugate of  claim 44 , wherein said conjugate is 
       
         
           
           
               
               
           
         
       
     
     
         50 . The anti-inflammatory drug-amino acid conjugate of  claim 22 , wherein said augmenting moiety is a valine ester or amide. 
     
     
         51 . The anti-inflammatory drug-amino acid conjugate of  claim 22 , wherein said augmenting moiety is a phenylalanine ester or amide. 
     
     
         52 . The anti-inflammatory drug-amino acid conjugate of  claim 22 , wherein said augmenting moiety is a proline ester or amide. 
     
     
         53 . The anti-inflammatory drug-amino acid conjugate of  claim 22 , comprising:
 (a) an anti-inflammatory compound conjugated with   (b) an augmenting moiety comprising an amino acid ester or amide,   wherein conjugation is via the nitrogen atom of the amino acid of said augmenting moiety;   wherein said amino acid ester or amide is selected from the group consisting of esters and amides of valine, glycine, proline and phenylalanine,   wherein said anti-inflammatory compound is selected from the group consisting of
 (1) the non-steroidal anti-inflammatory drugs diclofenac, ibuprofen, naproxen, and indomethacin; 
 (2) the vanilliods vanillyl alcohol, 3-methoxy-4-acetyloxybenzyl alcohol, and vanillylamine; and 
 (3) the ketone bodies 3-hydroxybutyrate and homologues thereof; and 
   wherein the anti-inflammatory activity of the conjugate is greater than the sum of its parts.   
     
     
         54 . The conjugate of  claim 22 , wherein said augmenting moiety is an amino acid ester or amide of a vanilloid. 
     
     
         55 . The conjugate of  claim 54 , wherein said vanilloid is selected from the group consisting of vanillyl alcohol, vanillyl amine and phenol-protected derivatives thereof.