Esters of l-carnitine of alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds
A technology of compounds, drugs, applied in the field of cationic lipids, which can solve the problems of failure to produce encouraging, failure of polynucleotide complexes, etc.
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example 1
[0115] Ester of propionyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoylglycerol (ST772)
[0116] a) Preparation of 1,3-dihydroxypropan-2-one 1,3-dipalmitate (1)
[0117] Dihydroxyacetone (7 g; 0.078 mol) was dissolved in 300 mL of dry chloroform at 0°C (external temperature) under a stream of dry nitrogen.
[0118] To the resulting solution were added palmitoyl chloride (44 g; 0.16 mol) and anhydrous pyridine (15 mL) dropwise.
[0119] The resulting mixture, which had been warmed to ambient temperature, was stirred for 24 hours.
[0120] The mixture was extracted in the following order: 300 mL of 0.5% aqueous hydrochloric acid, 300 mL of 5% aqueous sodium bicarbonate, and finally 300 mL of water.
[0121] The separated organic phase was dehydrated with anhydrous sodium sulfate, filtered through a cellulose filter and concentrated to dryness to give crude product (1).
[0122] Crystallization from 500mL ethanol gave pure product.
[0123] 30.4 g of product (1) ar...
example 2-7
[0161] Prepare the following compounds in the same manner as in the above examples:
[0162] - Esters of L-carnitine bromide and 2-hydroxyacetyl-1,3-dipalmitoylglycerol (ST770);
[0163] - Esters of acetyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoylglycerol (ST 771);
[0164] - Esters of isobutyryl L-carnitine bromide and 2-hydroxyacetyl-1,3 dipalmitoylglycerol (ST 773);
[0165] - Ester of isovaleryl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoylglycerol (ST 774);
[0166] - Ester of L-carnitine bromide with 1,3-dihexanoyl-2-hydroxyacetylglycerol (ST810);
[0167] - Esters of acetyl L-carnitine bromide with 1,3-dihexanoyl-2-hydroxyacetylglycerol (ST 809);
[0168] - ester of propionyl L-carnitine bromide with 1,3-dihexanoyl-2-hydroxyacetylglycerol (ST 808);
[0169] A preferred embodiment of the invention described here involves the preparation of liposomes with anticancer drugs, especially liposomes as carriers for camptothecin, as described in WO ...
example 8
[0194] 7-Benzyloxyiminomethylcamptothecin (CPT 172)
[0195] 500 mg (1.33 mmol) of 7-formylcamptothecin were dissolved in 100 ml of ethanol. 15 ml of pyridine and 638 mg (4 mmol) of O-benzylhydroxylamine hydrochloride were added. The solution was refluxed for 5 hours. The solvent was evaporated in vacuo and the resulting residue was purified by flash chromatography on silica gel with a 4:6 mixture of hexane and ethyl acetate as eluent.
[0196] Yield: 65%
[0197] Melting point: 200-205°C.
[0198] The product obtained contained a mixture of cis and trans isomers in a ratio of 8:2 (isomer A: Rf 0.32; isomer B, Rf 0.19, using Merck 60 F254 silica gel;
[0199] Eluent: hexane:ethyl acetate 3:7).
[0200] HPLC: The analysis was performed with an instrument equipped with a quaternary pump (HP1050), using a Rheodyne syringe (20 μl loop) and a diode array detector (HP 1050), driven using the HPLC-Chem Station program. Spectra were obtained in the range 200-600 nm and chromatog...
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