Nitrogen mustard phospholipid compound and preparation method thereof

A nitrogen mustard phospholipid and compound technology, which is applied in the field of nitrogen mustard phospholipid compounds and preparation, can solve the problems of short half-life, poor selectivity, high toxicity and the like, and achieve the effects of low toxic side effects and prolonged release half-life

Inactive Publication Date: 2013-07-10
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The alkylation part (that is, the double β-chloroethylamine group in the general formula, also known as the nitrogen mustard group) is a functional group with anti-tumor activity. It forms a highly active ethyleneiminium ion through intramolecular ring formation. Under neutral or weak base conditions, it quickly combines with nucleophilic groups of various organic substances to carry out alkylation; the carrier part mainly affects the pharmacokinetic properties such as the absorption and distribution of drugs in the body, but the current nitrogen mustards Drugs generally have disadvantages such as poor selectivity, high toxicity, and short half-life, and this type of drug is very unstable in the aqueous phase, and the residence time in the blood is only 0.5-1min

Method used

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  • Nitrogen mustard phospholipid compound and preparation method thereof
  • Nitrogen mustard phospholipid compound and preparation method thereof
  • Nitrogen mustard phospholipid compound and preparation method thereof

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preparation example Construction

[0032] The preparation method of formula (1) proposed by the present invention uses nitrogen mustardic anhydride or nitrogen mustard acid chloride and glycerophospholipid derivatives as reaction reagents, and organic bases in organic solvents are used as catalysts to realize the reaction. The reaction formula is expressed as follows:

[0033]

[0034] R 1 Represents one or several groups such as hydrogen atom or hydrocarbon group, R 2 Representative (ClCH 2 CH 2 ) 2 NR 3 , R 3 Represents one or several groups such as hydrocarbon group, aryl group, aromatic hydrocarbon group, etc.

[0035] - "hydrocarbyl" is defined as C 1 -C 18 straight-chain or branched-chain alkanes or alkenes

[0036] - "Aromatic group" is defined as a hydrocarbyl group connected to an aryl group; the meaning of the hydrocarbyl group here is as defined above

[0037] In the preparation method of the compound of formula (1), the organic solvent is one or a mixture of dichloromethane, chloroform, ...

Embodiment 1

[0040] Preparation of compound I

[0041]

[0042] The synthetic route of compound I is as the above formula. Add nitrogen mustard benzoyl chloride (2mmol), glycerol phosphatidylcholine (1mmol), and 10ml of chloroform as solvent into the round bottom flask. After stirring, add 4-dimethylaminopyridine (DMAP ), heated for 24 hours. Thin-layer liquid chromatography showed that after the reaction was completed, the reaction system was washed three times with water, chloroform was removed by vacuum rotary evaporation, and a white or yellowish product was obtained by separation on a silica gel column with a yield of 80%.

Embodiment 2

[0044] Preparation of Compound II

[0045]

[0046] The synthetic route of compound II is as above formula. Add nitrogen mustard benzenebutyryl chloride (1mmol), glycerol phosphatidylcholine (1mmol) and 10ml of chloroform as solvent into a round bottom flask. After stirring, add DMAP and react at room temperature for 5 hours. Thin-layer liquid chromatography showed that after the reaction was completed, the reaction system was washed three times with water, chloroform was removed by vacuum rotary evaporation, and a white or yellowish product was obtained by separation on a silica gel column with a yield of 75%.

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Abstract

The invention discloses a nitrogen mustard phospholipid compound and a preparation method thereof. The compound expressed as the following formula in the specification and salts of pharmaceutically acceptable acids formed by the compounds are obtained through a chemical synthesis method, wherein R1 represents either -H or -CH3, R2 represents (ClCH2CH2)2NR3, R3 represents one or more of alkylene, aryl, aromatic alkylene and the like, and R1 and R2 can be identical or different; and the acids include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, carbonic acid and the like, as well as organic acids such as formic acid, acetic acid, citric acid, lactic acid, fumaric acid, tartaric acid, gluconic acid and the like. The compounds can be used as a liquid preparation, a solid preparation, a semisolid preparation, a sterilizing preparation and a sterile preparation.

Description

technical field [0001] The invention relates to a nitrogen mustard phospholipid compound with an antitumor effect and a preparation method thereof, and relates to the technical field of medicine. Background technique [0002] Nitrogen mustard is a commonly used alkylating antitumor drug, which has a good killing effect on tumor cells. At present, nitrogen mustard hydrochloride, chlorambucil, nitrogen mustard, cyclophosphamide, etc. have been used clinically. It can be divided into two parts: the alkylation part and the carrier part. The alkylation part (that is, the double β-chloroethylamine group in the general formula, also known as the nitrogen mustard group) is a functional group with anti-tumor activity. It forms a highly active ethyleneiminium ion through intramolecular ring formation. Under neutral or weak base conditions, it quickly combines with nucleophilic groups of various organic substances to carry out alkylation; the carrier part mainly affects the pharmacoki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09A61K31/685A61K9/127A61P35/00
Inventor 李新松方硕
Owner SOUTHEAST UNIV
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