1,3-propane diol esters and ethers and methods for their use in drug delivery

Abstract

The invention relates to compounds of formula: wherein R 1 is selected from the group consisting of fatty acid acyl groups of 12 to 30 carbon atoms and fatty alcohol groups of 12 to 30 carbon atoms, and wherein R 2 is selected from the group consisting of H, fatty acid acyl of 12 to 30 carbon atoms and fatty alcohol groups of 12 to 30 carbon atoms, the same as or different from R 1 , and the residue of a nutrient, drug, or other bioactive compound, and to the use of these compounds to deliver drugs and other bioactive compounds.

1. A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of fatty acid acyl groups of 12 to 30 carbon atoms and fatty alcohol groups of 12 to 30 carbon atoms, and wherein R 2  is selected from the group consisting of fatty acid acyl groups of 12 to 30 carbon atoms and fatty alcohol groups of 12 to 30 carbon atoms, the same as or different from R 1 , the fatty acid acyl or alcohol groups R 2  being selected from the group consisting of γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), adrenic acid, stearidonic acid (SA), eicosapentaenoic acid (EPA), docosapentaenoic acid n-3, docosahexaenoic acid (DHA), columbinic acid (CA), parinaric acid and conjugated linoleic acid (cLA) groups. 
     
     
       2. The compound according to  claim 1 , wherein each said fatty acid or fatty alcohol group has 16 to 30 carbon atoms. 
     
     
       3. The compound according to  claim 1 , having a phosphate, succinate, or other difunctional-acid linking moiety between R 1  and the corresponding diol oxygen, between R 2  and the corresponding diol oxygen, or both. 
     
     
       4. The compound according to  claim 1 , wherein one of R 1  and R 2  is an acyl moiety corresponding to an acid selected from the group consisting of γ-linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA), and the other of R 1  and R 2  is an acyl moiety corresponding to an acid selected from the group consisting of γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), stearidonic acid (SA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (cLA), and columbinic acid (CA). 
     
     
       5. The compound according to  claim 1 , wherein one of R 1  and R 2  is an acyl moiety corresponding to an acid selected from the group consisting of arachidonic acid (AA), and the other is an acyl moiety corresponding to an acid selected from the group consisting of arachidonic acid (AA), γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). 
     
     
       6. The compound according to  claim 1 , wherein one of the R 1  and R 2  is an acyl moiety corresponding to eicosapentaenoic acid (EPA) and the other is an acyl moiety corresponding to an acid selected from the group consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 
     
     
       7. A pharmaceutical composition comprising an effective amount of the compound of  claim 1  and a suitable diluent or carrier. 
     
     
       8. A compound according to  claim 1  having the following 1,3-propane diol linked structure: 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are pairs of fatty acids selected from the group of pairs of fatty acids consisting of:
 γ-linolenic acid and oleic acid; γ-linolenic acid and γ-linolenic acid; eicosapentaenoic acid and eicosapentaenoic acid;, γ-linolenic acid and eicosapentaenoic acid; γ-linolenic acid and docosahexaenoic acid; arachidonic acid and docosahexaenoic acid; arachidonic acid and eicosapentaenoic acid; γ-linolenic acid and arachidonic acid; γ-linolenic acid and stearidonic acid; stearidonic acid and docosahexaenoic acid; arachidonic acid and stearidonic acid; dihomo-γ-linolenic acid and dihomo-γ-linolenic acid; dihomo-γ-linolenic acid and γ-linolenic acid; dihomo-γ-linolenic acid and stearidonic acid; dihomo-γ-linolenic acid and arachidonic acid; dihomo-γ-linolenic acid and eicosapentaenoic acid; dihomo-γ-linolenic acid and docosahexaenoic acid; arachidonic acid and arachidonic acid; eicosapentaenoic acid and stearidonic acid; eicosapentaenoic acid and docosahexaenoic acid; docosahexaenoic acid and docosahexaenoic acid; conjugated linoleic acid and conjugated inoleic acid, conjugated linoleic acid and γ-linolenic acid; conjugated linoleic acid and dihomo-γ-linolenic acid; conjugated linoleic acid and arachidonic acid; conjugated hinoleic acid and stearidonic acid; conjugated linoleic acid and eicosapentaenoic acid; conjugated linoleic acid and docosahexaenoic acid; columbinic acid and columbinic acid; columbinic acid and γ-linolenic acid; columbinic acid and dihomo-γ-linolenic acid; columbinic acid and arachidonic acid; columbinic acid and stearidonic acid; columbinic acid and eicosapentaenoic acid; and columbinic acid and docosahexaenoic acid. 
 
     
     
       9. The compound according to  claim 8 , wherein R 1  and R 2  are both docosahexaenoic acid moieties. 
     
     
       10. The compound according to  claim 8 , wherein R 1  and R 2  are both eicosapentaenoic acid moieties. 
     
     
       11. A pharmaceutical composition comprising an effective amount of the compound of 8, 9 or 10 and a suitable diluent or carrier. 
     
     
       12. A compound having the formula:
   R 1 OCH 2 —CH 2 —CH 2 OR 2  
   
       wherein R 1  is selected from the group consisting of γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), stearidonic add (SA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) groups, and 
       wherein R 2  is selected from the group consisting of:
 a drug used for the treatment of cardiovascular disease; 
 a calcium antagonist; 
 a beta-blocker; 
 a hypolipidaemic agent; 
 an antioxidant; 
 an angiotensin converting enzyme inhibitor; and 
 an angiotensin antagonist. 
 
     
     
       13. A compound according to claim 12, wherein R 2  is a fibrate or statin. 
     
     
       14. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.