Resolvins: bioemplates for novel therapeutic interventions

Abstract

The present invention is generally drawn to novel isolated therapeutic agents, termed resolvins, generated from the interaction between a dietary omega-3 polyunsaturated fatty acid (PUFA) such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), cyclooxygenase-II (COX-2) and an analgesic, such as aspirin (ASA). Surprisingly, careful isolation of compounds generated from the combination of components in an appropriate environment provide di- and tri-hydroxy EPA or DHA compounds having unique structural and physiological properties. The present invention therefore provides for many new useful therapeutic di- or tri-hydroxy derivatives of EPA or DHA (resolvins) that diminish, prevent, or eliminate inflammation or PMN migration, for example. The present invention also provides methods of use, methods of preparation, and packaged pharmaceuticals for use as medicaments for the compounds disclosed throughout the specification.

What is claimed is: 
     
         1 . A method of treating or preventing inflammation in a subject, comprising administering to the subject a compound having a structure of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         P 1 , P 2  and P 3 , if present, each individually is a hydroxyl-protecting group or hydrogen atom; 
         R 1 , R 2  and R 3 , if present, each individually is a hydrogen atom, substituted or unsubstituted, branched or unbranched alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted, branched or unbranched alkylaryl group, or halogen atom; 
         Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN; 
         each R a  is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl, and 6-16 membered heteroarylalkyl; 
         each R b  is a suitable group independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] 7 ,NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  and —[NR a C(NR a )] n NR c R c ; 
         each R c  is independently a protecting group or R a , or, alternatively, each R c  is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  or suitable R b  groups; 
         each R d  independently is a protecting group or R a ; 
         X, if present, is a substituted or unsubstituted methylene, an oxygen atom, a substituted or unsubstituted nitrogen atom, or a sulfur atom; 
         Q represents one or more substituents and each Q individually, if present, is a halogen atom or a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy, or aminocarbonyl group; 
         U, if present, is a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonyloxy, or aryloxycarbonyloxy group; and 
         each n independently is an integer from 0 to 3, 
         wherein any carbon-carbon double bond may be either cis or trans; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A method of  claim 1 , wherein the compound has a structure of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A method of  claim 1 , wherein the compound has a structure of the formula: 
       
         
           
           
               
               
           
         
         wherein any carbon-carbon double bond may be either cis or trans, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A method of  claim 1 , wherein the compound has a structure of the formula: 
       
         
           
           
               
               
           
         
         wherein any carbon-carbon double bond may be either cis or trans, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . A method of  claim 4 , wherein the compound has a structure of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         Z is —C(O)OR d , 
         R d  is a protecting group or R a , 
         R a  is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl, and 
         P 1  and P 2  each individually are a hydrogen atom or a hydroxyl-protecting group, and 
         wherein any carbon-carbon double bond may be either cis or trans, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The method of  claim 5 , wherein the carbon atom at C-17 has an R configuration. 
     
     
         7 . The method of  claim 5 , wherein the C-10 carbon atom has an S configuration and the carbon atom at C-17 has an S configuration. 
     
     
         8 . The method of  claim 5 , wherein the C-10 carbon atom has an R configuration and the carbon atom at C-17 has an S configuration. 
     
     
         9 . The method of any of  claims 4 - 8 , wherein P 1  and P 2  each are hydrogen atoms, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 9 , wherein Z is a carboxylic acid or a carboxylic ester, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 10 , wherein Z is a carboxylic acid salt. 
     
     
         12 . The method of any of  claims 4 - 8 , wherein Z is COOR a , wherein R a  is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, or (C6-C16) arylalkyl, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof.