Cardiolipin molecules and method of synthesis

A technology of cardiolipin and phospholipid, applied in the field of cardiolipin molecule and synthesis

Inactive Publication Date: 2005-12-28
NEOPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the use of phosphotriesters and phosphoramidites in the preparation of phospholipids such as cardiolipin, especially cardiolipin substances with different fatty acid chain lengths, is not well established.

Method used

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  • Cardiolipin molecules and method of synthesis
  • Cardiolipin molecules and method of synthesis
  • Cardiolipin molecules and method of synthesis

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Experimental program
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Effect test

Embodiment 1 4

[0071] The synthesis of embodiment 1 tetramyristoyl cardiolipin

[0072] 1A. 2-Benzyl-1,3-bis[(1,2-dimyristoyl-sn-propanetriyl-3)-phosphoryl]glycerol dibenzyl ester

[0073]

[0074] R 1 , R 2 = myristoyl (C 14:0 chain)

[0075] 1,2-Dimyristoyl-sn-glycerol (10 g, 19.53 mmol), benzyl N,N-tetraisopropylphosphoramidite (9.87 g, 29.29 mmol) and 1H - Tetrazole (65mL 0.45M acetonitrile sol, 29.29mmol) in CH 2 Cl 2 (125 mL) was stirred for 3 hours. Add 2-benzyloxy 1,3-propanediol (1.18 g, 6.47 mmol) in CH 2 Cl 2 (20 mL) followed by 1H-tetrazole (37.7 mL of 0.45M acetonitrile sol, 16.85 mmol) and stirred for 3 hours. The reaction mixture was cooled to -40°C, and tert-butyl hydroperoxide (TBHP, 6.4 mL of 5-6M decane sol, 32.35 mmol) was added. After stirring at -40 °C for 30 min, the reaction mixture was warmed to room temperature and washed with CH 2 Cl 2 (250mL) diluted, washed {saturated Na 2 SO 3 Aqueous solution (2×50 mL), saturated NaHCO 3 Aqueous...

Embodiment 2 4

[0080] The synthesis of embodiment 2 tetralauroyl cardiolipin

[0081] 2A. 2-Benzyl-1,3-bis[(1,2-dilauroyl-sn-propanetriyl-3)-phosphoryl]glycerol dibenzyl ester

[0082]

[0083] R 1 ,R 2 = Lauroyl (C 12:0 chain)

[0084] Method 1: 1,2-dilauroyl-sn-glycerol (2.2g, 4.82mmol), benzyl N,N-tetraisopropyl phosphoramidite (1.95g, 5.78mmol) and 1H-tetrazole (12.84 mL 0.45M acetonitrile sol, 5.78mmol) in CH 2 Cl 2 (25 mL) was stirred at room temperature under argon for 3 hours. Add 2-benzyloxy 1,3-propanediol (352 mg, 1.92 mmol) in CH 2 Cl 2 (10 mL) followed by 1H-tetrazole (12.84 mL of 0.45M acetonitrile sol, 5.78 mmol) and stirred for 3 hours. The reaction mixture was cooled to -40°C, and 3-chloroperoxyperbenzoic acid (m-CPBA, 2.77 g, 9.64 mmol) was added in portions. After stirring at -40 °C for 30 min, the reaction mixture was warmed to room temperature and washed with CH 2 Cl 2 (150mL) diluted, washed {saturated Na 2 SO 3 Aqueous solution (2×50 mL)...

Embodiment 3 4

[0090] The synthesis of embodiment 3 tetralauroyl cardiolipin

[0091] In this method, tetralauroyl cardiolipin was synthesized via 2-cyanoethylphosphoramidite.

[0092] 3A. 2-Benzyl-1,3-bis[(1,2-dilauroyl-sn-propanetriyl-3)-phosphoryl]glycerol dicyanoethyl ester

[0093]

[0094] R 1 ,R 2 = Lauroyl (C 12:0 chain)

[0095] 1,2-Dilauroyl-sn-glycerol (1.74 g, 3.79 mmol) and N,N-diisopropylethylamine (545 mg, 4.22 mmol) in anhydrous ether (20 mL) were dissolved under argon atmosphere To the mixture of 2-cyanoethyldiisopropylchlorophosphoramidite (1 g, 4.22 mmol) was added. The mixture was stirred at room temperature for 1 hour, the separated diisopropylamine hydrochloride was filtered and the filtrate was concentrated in vacuo. The residue was thus used in the phosphorylation reaction.

[0096] Phosphoramidite and 1H-tetrazole (9.4mL 0.45M acetonitrile sol, 4.22mmol) in anhydrous CH 2 Cl 2 (30 mL), add 2-benzyloxy 1,3-propanediol (312 mg, 1.71 mmol) in ...

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Abstract

The present invention provides a new synthesis route for cardiolipin, especially short-chain cardiolipin, having different fatty acids and / or alkyl chains of different chain lengths, with or without unsaturation. The method comprises: reacting 1,2-O-sn-diacyl / 1,2-O-sn-dialkylglycerol or 2-O-protected glycerol with phosphoramidite reagent or phosphotriester to generate protected Cardiolipin, which is deprotected to prepare short-chain cardiolipin. This reaction scheme can be used to generate new variants of cardiolipin. Cardiolipin prepared by this method may be contained in liposomes, which may also contain active agents, such as hydrophobic or hydrophilic drugs. Such liposomes may be used in the treatment of diseases or in diagnostic and / or analytical assays. Liposomes can also contain ligands for targeting to specific cell types or specific tissues.

Description

field of invention [0001] The present invention relates to novel synthetic methods for the preparation of cardiolipin analogs / variants and compositions containing them. The invention also relates to liposomal formulations or complexes or emulsions containing active agents or drugs and their use in the treatment of human and animal diseases. Background of the invention [0002] Liposome formulations have the ability to increase the solubility of hydrophobic drugs in aqueous solutions. They often reduce side effects associated with drug therapy and provide a resilient tool for developing new formulations of active agents. [0003] Liposomes are generally prepared from natural phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid and phosphatidylinositol. Anionic phospholipids, such as phosphatidylglycerol and cardiolipin, can be added to create a net negative surface charge which provides colloidal s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/10
Inventor M·U·艾哈迈德M·K·乌科拉姆I·艾哈迈德
Owner NEOPHARM CO LTD
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