Oxidized Lipid Compounds and Uses Thereof

Abstract

Novel oxidized lipids are provided herein, as well as methods for producing same, and uses thereof in treating or preventing an inflammation associated with endogenous oxidized lipids and related conditions.

What is claimed is: 
     
         1 . A compound having a formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein:
 (i) A 1 , A 2  and A 3  are each independently selected from the group consisting of O and S; 
 (ii) R 1  is an alkyl chain 2-28 carbons in length; and 
 (iii) R 2  is selected from the group consisting of (4-methylcarboxy)butyl, (3-carboxy)propyl, (6-carboxy)hexanyl, (2-carboxy)ethyl, 5,6-dihydroxyhexanyl, 5,5-diethoxypentyl and 5,5-dimethoxypentyl; and 
 (iv) R 3  is selected from the group consisting of H, acyl, alkyl, phosphate, phosphocholine, phosphoethanolamine, phosphoethanolamine-N-glutaric acid, phosphoserine, and phosphoinositol. 
 
     
     
         2 . A compound having a formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein:
 (i) A 1 , A 2  and A 3  are each independently selected from the group consisting of O and S; 
 (ii) R 1  is an alkyl chain 2-28 carbons in length; 
 (iii) R 2  is 
 
       
         
           
           
               
               
           
         
         wherein X is a C 1-25  chain, Y is selected from the group consisting, of: 
       
       
         
           
           
               
               
           
         
         
           —OH, —H, alkoxy, halogen, acetoxy and aromatic functional groups; and 
           Z is selected from the group consisting of: 
         
       
       
         
           
           
               
               
           
         
         and —OH, 
         whereas R′ is C 1-4  alkyl; and 
         (iv) R 3  is selected from the group consisting of H, phosphate, phosphoethanolamine, phosphoethanolamine-N-glutaric acid and phosphoserine. 
       
     
     
         3 . A compound having a formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein:
 (i) A 1 , A 2  and A 3  are each independently selected from the group consisting of O and S; 
 (ii) R 1  is selected from the group consisting of dodecyl, octadecyl, octyl, eicosanyl, cis-9-hexadecenyl, (2-octyl)dodecyl and (15-carboxy)pentadecyl; 
 (iii) R 2  is selected from the group consisting of an alkyl chain 2-28 carbons in length and 
 
       
         
           
           
               
               
           
         
         
           provided that at if R 1  is other (15-carboxy)pentadecyl, then R 2  is said 
         
       
       
         
           
           
               
               
           
         
         wherein X is a C 1-25  chain, Y is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           —OH, —H, alkyl, alkoxy, halogen, acetoxy and aromatic functional groups; 
           and 
           Z is selected from the group consisting of: 
         
       
       
         
           
           
               
               
           
         
         and —OH, 
         whereas R′ is C 1-4  alkyl; and 
         (iv) R 3  is selected from the group consisting of H, acyl, alkyl, phosphate, phosphocholine, phosphoethanolamine, phosphoethanolamine-N-glutaric acid, phosphoserine, and phosphoinositol. 
       
     
     
         4 . A compound having a formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein:
 (i) A 1  is S and A 2  and A 3  are each O; 
 (ii) R 1  is an alkyl chain 2-28 carbons in length; 
 (iii) R 2  is 
 
       
         
           
           
               
               
           
         
         wherein X is a C 1-25  chain, Y is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           —OH, —H, alkyl, alkoxy, halogen, acetoxy and aromatic functional groups; 
           and 
           Z is selected from the group consisting of: 
         
       
       
         
           
           
               
               
           
         
         and —OH, 
         whereas R′ is C 1-4  alkyl; and 
         (iii) R 3  is selected from the group consisting of H, acyl, alkyl, phosphate, phosphocholine, phosphoethanolamine, phosphoethanolamine-N-glutaric acid, phosphoserine, and phosphoinositol. 
       
     
     
         5 . A compound selected from the group consisting of:
 1-hexadecyl-2-(4-carboxy)butyl-glycero-3-phosphate (CI-201-PA);   1-hexadecyl-2-(4-methylcarboxy)butyl-glycero-3-phosphoethanolamine;   1-hexadecyl-2-(4-methylcarboxy)butyl-glycero-3-phosphocholine (CI-208);   1-hexadecyl-2-(4-carboxy)butyl-glycero-3-phosphoethanolamine (CI-202);   1-hexadecyl-2-(3-carboxy)propyl-glycero-3-phosphoethanolamine (CI-206);   1-hexadecyl-2-(3-carboxy)propyl-glycero-3-phosphocholine (CI-205);   1-hexadecyl-2-(6-carboxy)hexanyl-glycero-3-phosphocholine (CI-203);   1-dodecyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (CI-209);   1-hexadecyl-2-(4-carboxy)butyl-glycero-3-phosphoethanolamine-N-glutaric acid (CI-210);   1-(15′-carboxy)pentadecyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (CI-213);   1-(15′-carboxy)pentadecyl-2-(4-carboxy)butyl-glycero-3-phosphoethanolamine (CI-214);   1-octadecyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (CI-215);   1-octadecyl-2-(4 carboxy)butyl-glycero-3-phosphoethanolamine (CI-216);   1-hexadecyl-2-(2-carboxy)ethyl-glycero-3-phosphocholine (CI-217);   1-S-hexadecyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (1-S-CI-201);   1-S-hexadecyl-2-(4-carboxy)butyl-glycero-3-phosphoethanolamine (1-S-CI-202);   1-hexadecyl-2-(5,6-dihydroxy)hexanyl-glycero-3-phosphocholine (di-OH);   1-(cis-9-hexadecenyl)-2-(4-carboxy)butyl-glycero-3-phosphocholine;   1-hexadecyl-2-(4-carboxy)butyl-glycerol;   1-hexadecyl-2-(5′,5′-diethoxypentyl)-glycero-3-phosphocholine (diEtAc);   1-hexadecyl-2-(5′,5′-dimethoxypentyl)-glycero-3-phosphocholine (diMeAc);   1-octyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (CI-207);   1-octyl-2-(4-carboxy)butyl-glycero-3 phosphoethanolamine;   1-eicosanyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (CI-219);   1-eicosanyl-2-(4-carboxy)butyl-glycero-3-phosphoethanolamine (CI-220);   1-(2-octyl)dodecyl-2-(4-carboxy)butyl-glycero-3-phosphocholine (VB-221);   1-(2-octyl)dodecyl-2-(4-carboxy)butyl-glycero-3-phosphoethanolamine (VB-222); and   1-hexadecyl-2-(4-carboxy)butyl-glycero-3-phosphoserine (VB-223).   
     
     
         6 . The compound of any of  claims 1 - 5 , being identified for use in a method of treating or preventing an inflammation associated with an endogenous oxidized lipid. 
     
     
         7 . The compound of any of  claims 1 - 5 , being identified for use in a method for decreasing of a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23. 
     
     
         8 . The compound of any of  claims 1 - 5 , being identified for use in a method of treating a disease or disorder in which decreasing of a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23 is beneficial. 
     
     
         9 . A pharmaceutical composition comprising, as an active ingredient, the compound of any of  claims 1  to  5 , and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9 , packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment or prevention of an inflammation associated with an endogenous oxidized lipid. 
     
     
         11 . The pharmaceutical composition of  claim 9 , packaged in a packaging material and identified in print, in or on said packaging material, for decreasing of a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23. 
     
     
         12 . The pharmaceutical composition of  claim 9 , packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a disease or disorder in which decreasing of a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23 is beneficial. 
     
     
         13 . A method of treating or preventing an inflammation associated with an endogenous oxidized lipid, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of  claims 1  to  5 , thereby treating or preventing the inflammation associated with an endogenous oxidized lipid in said subject. 
     
     
         14 . A method of decreasing a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23 in a subject, the method comprising administering to the subject an effective amount of a compound of any of  claims 1  to  5 . 
     
     
         15 . A method of treating a disease or disorder in which decreasing a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound of any of  claims 1  to  5 . 
     
     
         16 . A use of the compound of any of  claims 1  to  5  in the manufacture of a medicament for treating or preventing an inflammation associated with an endogenous oxidized lipid. 
     
     
         17 . A use of the compound of any of  claims 1  to  5  in the manufacture of a medicament for decreasing a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23 in a subject. 
     
     
         18 . A use of the compound of any of  claims 1  to  5  in the manufacture of a medicament for treating a disease or disorder in which decreasing a level of a cytokine selected from the group consisting of interleukin-12 and interleukin-23 is beneficial. 
     
     
         19 . The compound, composition, method or use of any of  claims 6 ,  9 ,  13  and  16 , wherein said inflammation is associated with a disease or disorder selected from the group consisting of an idiopathic inflammatory disease or disorder, a chronic inflammatory disease or disorder, an acute inflammatory disease or disorder, an autoimmune disease or disorder, an infectious disease or disorder, an inflammatory malignant: disease or disorder, an inflammatory transplantation-related disease or disorder, an inflammatory degenerative disease or disorder, a disease or disorder associated with a hypersensitivity, an inflammatory cardiovascular disease or disorder, an inflammatory cerebrovascular disease or disorder, a peripheral vascular disease or disorder, an inflammatory glandular disease or disorder, an inflammatory gastrointestinal disease or disorder; an inflammatory cutaneous disease or disorder, an inflammatory hepatic disease or disorder, an inflammatory neurological disease or disorder, an inflammatory musculo-skeletal disease or disorder, an inflammatory renal disease or disorder, an inflammatory reproductive disease or disorder, an inflammatory systemic disease or disorder, an inflammatory connective tissue disease or disorder, an inflammatory tumor, necrosis, an inflammatory implant-related disease or disorder, an inflammatory aging process, an immunodeficiency disease or disorder and an inflammatory pulmonary disease or disorder.