Esters of L-carnitine or alkanoyl L-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds

Abstract

Esters of L-carnitine and alkanoyl L-carnitines are described which can be used as cationic lipids for the intracellular delivery of pharmacologically active compounds. New esters of L-carnitine and alkanoyl L-carnitines of formula (I) are also disclosed wherein the R groups are as defined in the description.

1 . Compounds of formula (I)  
       
         
           
           
               
               
           
         
       
       where: 
 n is an integer from 1 to 3;  
 R is hydrogen or alkanoyl, straight or branched, with 2-6 carbon atoms;  
 R 1  and R 2 , which may be the same or different, represent a saturated or unsaturated straight acyl chain, with 3-20 carbon atoms; and  
 X −  is the anion of a pharmacologically acceptable acid.  
 
     
     
         2 . Compound according to  claim 1 , in which R is selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl.  
     
     
         3 . Compound according to  claim 1  in which R 1  and R 2  are selected from the group consisting of hexanoyl, undecanoyl, myristoyl, palmitoyl or oleoyl.  
     
     
         4 . Compound according to  claim 1 , in which X −  is selected from the group consisting of chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate; acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate; acid maleate; mucate; orotate; oxalate; acid oxalate; sulphate; acid sulphate; trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.  
     
     
         5 . Compound according to  claim 1 , selected from the group consisting of: 
 ester of L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;    ester of acetyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;    ester of propionyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;    ester of isobutyryl L-carnitine bromide with 2-hydroxyacetyl-1,3 dipalmitoyl glycerol;    ester of isovaleryl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;    ester of L-carnitine bromide with 1,3-dihexanoyl-2-hydroxycetyl glycerol;    ester of acetyl L-carnitine bromide with 1,3-dihexanoyl-2-hydroxyacetyl glycerol;    ester of propionyl L-carnitine bromide with 1,3-dihexnoyl-2-hydroxyacetyl glycerol.    
     
     
         6 . Use of a compound according to any of claims  1 - 5  for the preparation of liposomes.  
     
     
         7 . Liposome comprising a compound of anyone of claims  1 - 5 .  
     
     
         8 . Liposome according to  claim 7 , further containing helper lipids.  
     
     
         9 . Liposome according to  claim 8 , in which said helper lipid is selected from the group consisting of cholesterol, 1-palmitoyl-2-oleoyl phosphatidyl choline or dioleyl phosphatidyl choline.  
     
     
         10 . Use of a liposome according to any one of claims  7 - 9 , for the preparation of a composition useful for the transport of pharmacologically active compounds.  
     
     
         11 . Use according to  claim 10 , in which the pharmacologically active compound is a naturally occurring or modified plasmid or polynucleotide.  
     
     
         12 . Use according to  claim 11 , in which the plasmid or polynucleotide is useful in gene therapy.  
     
     
         13 . Use according to  claim 11 , in which the plasmid or polynucleotide codes for a peptide or protein useful as a vaccine.  
     
     
         14 . Use according to  claim 10 , in which the active compound is a drug.  
     
     
         15 . Use according to  claim 14 , in which said drug is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.  
     
     
         16 . Use according to  claim 15 , in which said drug is an anticancer or antiangiogenic agent.  
     
     
         17 . Use according to  claim 16 , in which said anticancer agent is selected from the group consisting of taxol or a camptothecin derivative.  
     
     
         18 . Use according to  claim 17 , in which said derivative of camptothecin is selected from the group consisting of 
 7-carbonitrilecamptothecin;    7-benzyloxyiminomethylcamptothecin, and    7-butoxyiminomethylcamptothecin.    
     
     
         19 . Use of a liposome according to claims  7 - 9  for the preparation of a cosmetic composition.  
     
     
         20 . Pharmaceutical composition comprising a liposome according to claims  7 ,  8 , or  9 .  
     
     
         21 . Composition according to  claim 20 , in which said liposome contains a pharmacologically active compound.  
     
     
         22 . Composition according to  claim 21 , in which the active compound is a naturally occurring or modified plasmid or polynucleotide  
     
     
         23 . Composition according to  claim 22 , in which the plasmid or polynucleotide is useful in gene therapy.  
     
     
         24 . Composition according to  claim 22 , in which the plasmid or polynucleotide codes for a peptide or protein useful as a vaccine  
     
     
         25 . Cosmetic composition comprising a liposome according to any one of claims  7 - 9 .  
     
     
         26 . Composition according to  claim 25 , in which said liposome contains a substance with cosmetic activity.  
     
     
         27 . Composition according to  claim 21 , in which said compound is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.  
     
     
         28 . Composition according to claims  20 - 27 , which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of a nasal or mouth spray.  
     
     
         29 . Use of the liposome comprising a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       where: 
 R 3  is a saturated or unsaturated, straight or branched acyl chain, with 4-26 carbon atoms;  
 R 4  is a saturated or unsaturated, straight or branched alkyl chain, with 4-26 carbon atoms; and  
 X −  is the anion of a pharmacologically acceptable acid for the transport of drugs or of substances with cosmetic activity.  
 
     
     
         30 . Use according to  claim 29 , in which R 3  is preferably selected from the group consisting of nonanoyl, dodecanoyl, myristoyl, palmitoyl, stearoyl or oleoyl.  
     
     
         31 . Use according to  claim 29 , in which R 4  is preferably selected from the group consisting of nonyl, undecyl, tetradecyl, hexadecyl or oleyl.  
     
     
         32 . Use according to  claim 30 , in which X −  is selected from the group consisting of chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate; acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate; acid maleate; mucate; orotate; oxalate; acid oxalate; sulphate; acid sulphate; trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.  
     
     
         33 . Use according to claims  29 - 32 , in which the compound is selected from the group consisting of: 
 palmitoyl L-carnitine chloride undecyl ester;    stearoyl L-carnitine chloride undecyl ester;    stearoyl L-carnitine chloride tetradecyl ester;    palmitoyl L-carnitine chloride tetradecyl ester;    myristoyl L-carnitine chloride tetradecyl ester;    palmitoyl L-carnitine bromide hexadecyl ester;    oleoyl L-carnitine chloride oleyl ester.    
     
     
         34 . Use according to according to  claim 29 , in which the drug is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.  
     
     
         35 . Use according to  claim 34 , in which said drug is an anticancer or antiangiogenic agent.  
     
     
         36 . Use according to  claim 35 , in which said anticancer agent is selected from the group consisting of taxol or a derivative of camptothecin.  
     
     
         37 . Use according to  claim 36 , in which said derivative of camptothecin is selected from the group consisting of 
 7-benzylooxyiminomethylcamptothecin or    7-butoxyiminomethylcamptothecin.    
     
     
         38 . Use according to  claim 29 , in which the liposome additionally contains helper lipids.  
     
     
         39 . Use according to  claim 38 , in which said helper lipid is selected from the group consisting of cholesterol, 1-palmitoyl-2-oleoyl phosphatidyl choline or dioleyl phosphatidyl choline.  
     
     
         40 . Composition comprising a liposome according to  claim 29 , for the transport of drugs or of a substance with cosmetic activity.  
     
     
         41 . Composition according to  claim 40 , in which the drug is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.  
     
     
         42 . Composition according to claims  40 - 41 , which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of a nasal or mouth spray.  
     
     
         43 . Use of a liposome comprising a compound of formula (III):  
       
         
           
           
               
               
           
         
       
       where: 
 R 5  is a saturated or unsaturated, straight or branched acyl chain, with 4-26 carbon atoms;  
 R 6  is a saturated or unsaturated, straight or branched alkyl chain, with 4-26 carbon atoms; and  
 X −  is the anion of a pharmacologically acceptable acid;  
 with the proviso that:  
 when R 5  is stearoyl, R 6  is not stearyl,  
 when R 5  is oleoyl, R 6  is not stearyl,  
 when R 5  is palmitoyl, R 6  is not palmitoyl,  
 when R 5  is myristoyl, R 6  is not myristoyl,  
 when R 5  is lauroyl, R 6  is not lauryl,  
 when R 5  is oleoyl, R 6  is not oleyl  
 for the transport of a naturally occurring or modified plasmid or polynucleotide.  
 
     
     
         44 . Use according to  claim 43 , in which R 5  is preferably selected from the group consisting of nonanoyl, dodecanoyl, myristoyl, palmitoyl, stearoyl or oleoyl.  
     
     
         45 . Use according to  claim 43 , in which R 6  is preferably selected from the group consisting of nonyl, undecyl, tetradecyl, hexadecyl or oleyl.  
     
     
         46 . Use according to  claim 43 , in which X −  is selected from the group consisting of chloride; bromide; iodide; aspartate; acid aspartate; citrate;. acid citrate; tartrate; acid tartrate; phosphate; acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate; acid maleate; mucate; orotate; oxalate; acid oxalate; sulphate; acid sulphate; trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.  
     
     
         47 . Use according to claims  43 - 46 , in which the compound is selected from the group consisting of: 
 palmitoyl L-carnitine chloride undecyl ester;    stearoyl L-carnitine chloride undecyl ester;    stearoyl L-carnitine chloride tetradecyl ester;    palmitoyl L-carnitine chloride tetradecyl ester.    
     
     
         48 . Use according to  claim 43 , in which the plasmid or polynucleotide codes for a peptide or protein useful as a vaccine.  
     
     
         49 . Use according to  claim 43 , in which the liposome additionally contains helper lipids.  
     
     
         50 . Use according to  claim 49 , in which said helper lipid is selected from the group consisting of cholesterol, 1-palmitoyl-2-oleoyl phosphatidyl choline or dioleyl phosphatidyl choline.  
     
     
         51 . Composition comprising a liposome according to  claim 43 , for the transport of a naturally occurring or modified plasmid or polynucleotide.  
     
     
         52 . Composition according to  claim 51 , in which the polynucleotide or plasmid codes for a peptide or protein useful as a vaccine.  
     
     
         53 . Composition according to claims  51 - 52 , which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of nasal or mouth sprays.