Lipids for delivery of therapeutics

Abstract

This disclosure provides a range of amino acid lipid compounds and compositions useful for drug delivery, therapeutics, and the diagnosis and treatment of diseases and conditions. The amino acid lipid compounds and compositions can be used for delivery of various agents such as nucleic acid therapeutics to cells, tissues, organs, and subjects.

What is claimed is: 
     
         1 . A compound comprising the structure shown in Formula I:
   R 3 —(C═O)-Xaa-Z—R 4   Formula I
   wherein
 Xaa is any D- or L-amino acid residue having the formula —NR N —CR 1 R 2 —(C═O)—, or a peptide of n=2-20 amino acid residues having the formula —{NR N —CR 1 R 2 —(C═O)} n —, wherein
 R 1  is independently, for each occurrence, a non-hydrogen, substituted or unsubstituted side chain of an amino acid; 
 R 2  is independently, for each occurrence, hydrogen, or an organic group consisting of carbon, oxygen, nitrogen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms, or C(1-5)alkyl, cycloalkyl, cycloalkylalkyl, C(3-5)alkenyl, C(3-5)alkynyl, C(1-5)alkanoyl, C(1-5)alkanoyloxy, C(1-5)alkoxy, C(1-5)alkoxy-C(1-5)alkyl, C(1-5)alkoxy-C(1-5)alkoxy, C(1-5)alkyl-amino-C(1-5)alkyl-, C(1-5)dialkyl-amino-C(1-5)alkyl-, nitro-C(1-5)alkyl, cyano-C(1-5)alkyl, aryl-C(1-5)alkyl, 4-biphenyl-C(1-5)alkyl, carboxyl, or hydroxyl, 
 R N  is independently, for each occurrence, hydrogen, or an organic group consisting of carbon, oxygen, nitrogen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms, or C(1-5)alkyl, cycloalkyl, cycloalkylalkyl, C(3-5)alkenyl, C(3-5)alkynyl, C(1-5)alkanoyl, C(1-5)alkanoyloxy, C(1-5)alkoxy, C(1-5)alkoxy-C(1-5)alkyl, C(1-5)alkoxy-C(1-5)alkoxy, C(1-5)alkyl-amino-C(1-5)alkyl-, C(1-5)dialkyl-amino-C(1-5)alkyl-, nitro-C(1-5)alkyl, cyano-C(1-5)alkyl, aryl-C(1-5)alkyl, 4-biphenyl-C(1-5)alkyl, carboxyl, or hydroxyl, 
 
 R 3  is independently a lipophilic tail derived from a naturally-occurring or synthetic lipid, phospholipid, glycolipid, triacylglycerol, glycerophospholipid, sphingolipid, ceramide, sphingomyelin, cerebroside, or ganglioside, wherein the tail may contain a steroid; or a substituted or unsubstituted C(3-22)alkyl, C(6-12)cycloalkyl, C(6-12)cycloalkyl-C(3-22)alkyl, C(3-22)alkenyl, C(3-22)alkynyl, C(3-22)alkoxy, or C(6-12)alkoxy-C(3-22)alkyl; 
 R 4  is independently a lipophilic tail derived from a naturally-occurring or synthetic lipid, phospholipid, glycolipid, triacylglycerol, glycerophospholipid, sphingolipid, ceramide, sphingomyelin, cerebroside, or ganglioside, wherein the tail may contain a steroid; or a substituted or unsubstituted C(3-22)alkyl, C(6-12)cycloalkyl, C(6-12)cycloalkyl-C(3-22)alkyl, C(3-22)alkenyl, C(3-22)alkynyl, C(3-22)alkoxy, or C(6-12)alkoxy-C(3-22)alkyl; 
 wherein either one of R 3  and R 4  is a lipophilic tail as defined above and the other is an amino acid terminal group, or both R 3  and R 4  are lipophilic tails; the amino acid terminal group being hydrogen, hydroxyl, amino, or an organic protective group; 
 Z is NH, O, S, —CH 2 S—, —CH 2 S(O)—, or an organic linker consisting of 1-40 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms; 
   and salts thereof.   
     
     
         2 . A compound comprising the structure shown in Formula I:
   R 3 —(C═O)-Xaa-Z—R 4   Formula I
   wherein
 Xaa is a D- or L-amino acid residue having the formula —NR N —CR 1 R 2 —(C═O)—, wherein
 R 1  is a substituted or unsubstituted basic side chain of an amino acid; 
 R 2  is hydrogen, or C(1-5)alkyl, 
 R N  is hydrogen, or C(1-5)alkyl, 
 
 R 3  is independently a substituted or unsubstituted C(6-22)alkyl or C(6-22)alkenyl; 
 R 4  is independently a substituted or unsubstituted C(6-22)alkyl or C(6-22)alkenyl; 
 Z is NH, O, or an organic linker consisting of 1-40 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms; 
   and salts thereof.   
     
     
         3 . The compound of  claim 2 , wherein Xaa is selected from arginine, homoarginine, norarginine, nor-norarginine, ornithine, lysine, homolysine, histidine, 1-methylhistidine, pyridylalanine, asparagine, N-ethylasparagine, glutamine, 4-aminophenylalanine, the N-methylated versions thereof, and side chain modified derivatives thereof. 
     
     
         4 . The compound of  claim 2 , wherein Xaa is arginine, an N-methylated version thereof, or a side chain modified derivative thereof. 
     
     
         5 . The compound of  claim 2 , wherein Xaa is norarginine, an N-methylated version thereof, or a side chain modified derivative thereof. 
     
     
         6 . The compound of  claim 2 , wherein Xaa is lysine, an N-methylated version thereof, or a side chain modified derivative thereof. 
     
     
         7 . The compound of  claim 2 , wherein Xaa is histidine, an N-methylated version thereof, or a side chain modified derivative thereof. 
     
     
         8 . The compound of  claim 2 , wherein Xaa is pyridylalanine, an N-methylated version thereof, or a side chain modified derivative thereof. 
     
     
         9 . The compound of  claim 2 , wherein Xaa is Cysteine or Serine. 
     
     
         10 . The compound of  claim 2 , wherein R 2  is hydrogen. 
     
     
         11 . The compound of  claim 2 , wherein R N  is hydrogen. 
     
     
         12 . The compound of  claim 2 , wherein R 3  and R 4  are C(6-22)alkyl and are the same or different. 
     
     
         13 . The compound of  claim 2 , wherein R 3  and R 4  are C(6-22)alkenyl and are the same or different. 
     
     
         14 . The compound of  claim 2 , wherein R 3  is C(6-22)alkyl and R 4  is C(6-22)alkenyl. 
     
     
         15 . The compound of  claim 2 , wherein R 4  is C(6-22)alkyl and R 3  is C(6-22)alkenyl. 
     
     
         16 . The compound of  claim 2 , wherein Z is NH. 
     
     
         17 . The compound of  claim 2 , wherein Z is O. 
     
     
         18 . The compound of  claim 2 , wherein Xaa is a peptide of 2-20 amino acid residues. 
     
     
         19 . The compound of  claim 2 , wherein Xaa has a side chain containing a functional group having a pKa from 5 to 7.5. 
     
     
         20 . The compound of  claim 2 , wherein Xaa has a side chain containing a releasing functional group selected from 3,5-diiodo-tyrosine, 1-methylhistidine, 2-methylbutanoic acid, 2-o-anisylpropanoic acid, meso-tartaric acid, 4,6-dimethylpyrimidinamine, p-phthalic acid, creatinine, butanoic acid, N,N-dimethyl-1-naphthylamine, pentanoic acid, 4-methylpentanoic acid, N-methylaniline, 1,10-phenanthroline, 3-pyridinecarboxylic acid, hexanoic acid, propanoic acid, 4-animobenzoic acid, 2-methylpropanoic acid, heptanoic acid, octanoic acid, cyclohexanecarboxylic acid, quinoline, 3-quinolinamine, 2-aminobenzoic acid, 4-pyridinecarboxylic acid, nonanic acid, melamine, 8-quinolinol, trimethylacetic acid, 6-methoxyquinoline, 4-(methylamino)benzoic acid, p-methylaniline, 3-(methylamino)benzoic acid, malic acid, N-ethylaniline, 2-benzylpyridine, 3,6-dinitrophenol, N,N-dimethylaniline, 2,5-dimethylpiperazine, p-phenetidine, 5-methylquinoline, 2-phenylbenzimidazole, pyridine, picolinic acid, 3,5-diiodityrosine, p-anisidine, 2-(methylamino)benzoic acid, 2-thiazolamine, glutaric acid, adipic acid, isoquinoline, itaconic acid, o-phthalic acid, benzimidazole, piperazine, heptanedioic acid, acridine, phenanthridine, succinic acid, methylsuccinic acid, 4-methylquinoline, 3-methylpyridine, 7-isoquinolinol, malonic acid, methymalonic acid, 2-methylquinoline, 2-ethylpyridine, 2-methylpyridine, 4-methylpyridine, histamine, histidine, maleic acid, cis-1,2-cyclohexanediamine, 3,5-dimethylpyridine, 2-ethylbenzimidazole, 2-methylbenzimidazole, cacodylic acid, perimidine, citric acid, isocitric acid, 2,5-dimethylpyridine, papaverine, 6-hydroxy-4-methylpteridine, L-thyroxine, 3,4-dimethylpyridine, methoxypyridine, trans-1,2-cyclohexanediamine, 2,5-pyridinediamine, l-1-methylhistidine, l-3-methylhistidine, 2,3-dimethylpyridine, xanthopterin, 1,2-propanediamine, N,N-diethylaniline, alloxanic acid, 2,6-dimethylpyridine, L-carnosine, 2-pyridinamine, N-b-alanylhistidine, pilocarpine, 1-methylimidazol, 1H-imidazole, 2,4-dimethylpyridine, 4-nitrophenol, 2-nitrophenol, tyrosineamide, 5-hydoxxyquinazoline, 1,1-cyclopropanedicarboxylic acid, 2,4,6-trimethylpyridine, veronal, 2,3-dichlorophenol, 1,2-ethanediamine, 1-isoquinolinamine, and combinations thereof.