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Hypocrellin derivative containing long-chain quaternary ammonium salt, and preparation method and application thereof

A technology of hypocrellin and hypocrellin B, which is applied in the preparation of organic compounds, imino compounds, aminohydroxyl compounds, etc., and can solve problems such as low solubility, weak light absorption ability, and reduced photodynamic activity. question

Inactive Publication Date: 2016-05-04
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the main absorption wavelength range of hypocrellin is 450-550nm, and this wavelength can penetrate less than 1 mm of tissue, and its ability to absorb light in the photodynamic therapy window (600-900nm) is weak
However, hypocrellin is a kind of lipophilic organic molecule with very low solubility in water, and direct intravenous injection will spontaneously accumulate in the blood and cause blood vessel blockage
Sulfonic acid substituted derivatives (J.Photochem.Photobiol.B.Biol., 1993,17,195-201) can solve the problem of water solubility well, but due to its negative charge, and a large amount of negative charge in cells and tissues Mutually exclusive, with low cellular uptake and greatly reduced photodynamic activity

Method used

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  • Hypocrellin derivative containing long-chain quaternary ammonium salt, and preparation method and application thereof
  • Hypocrellin derivative containing long-chain quaternary ammonium salt, and preparation method and application thereof
  • Hypocrellin derivative containing long-chain quaternary ammonium salt, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Extraction of Hypocretin A (HA): The extraction method refers to Zhao Kaihong's organic chemistry reference book on pages 252-254 of Volume 9 in 1989, and appropriate improvements have been made. The specific method is as follows:

[0063] 100g bamboo red fungus is pulverized with a pulverizer, placed in a Soxhlet extractor, continuously extracted for one day with 1000mL acetone as a solvent until the extract is nearly colorless, the extract is filtered to remove a small amount of insoluble solid insolubles, then spin-dried to remove acetone, and use 500mL dichloromethane was dissolved, washed with 4×400mL distilled water, the organic layer was separated and spin-dried, the solid residue was washed with 5×100mL petroleum ether, the solid was spontaneously ignited and dried in air, and then recrystallized twice with chloroform-petroleum ether to obtain The crystal is the target product Hypocretin A (HA), and the purity is above 98%. Thin-layer silica gel plate chromatog...

Embodiment 2

[0065] Preparation of Hypocretin B (HB): Hypocretin B is obtained by dehydrating Hypocretin B under alkaline conditions. The preparation method refers to Zhao Kaihong’s organic chemistry reference book on pages 252-254 of Volume 9 in 1989, and appropriate improvements have been made. . The specific method is as follows:

[0066] 1 gram of hypocrellin A was dissolved in 1000mL of 1.5% KOH aqueous solution, and after 24 hours of reaction with stirring in the dark, it was neutralized with a slight excess of dilute hydrochloric acid, and the product was extracted with chloroform, and 0.98g of hypocrellin B was obtained after separation and purification , yield 98%.

[0067] The long-chain quaternary ammonium salt derivative used in the present invention is prepared by the following similar general method, with X=N, m=2, n=0, R 1 = R 2 = Me,R 3 =C 10 h 21 Description for the column.

Embodiment 3

[0069] Long-chain quaternary ammonium derivatives (X-(CH 2 ) m -(OCH 2 CH 2 ) n -N + (R 1 )(R 2 )(R 3 ); where X=N, m=2, n=0, R 1 = R 2 = Me,R 3 =C 10 h 21 ) of the preparation, its synthetic route diagram as attached image 3 Shown:

[0070] Preparation of Intermediate 1:

[0071] N,N-Dimethylethylenediamine (4.4g, 0.05mol) and diethyl carbonate (7.10g, 0.06mol) were mixed in a 100ml round bottom flask, and the reaction solution was reacted at 70°C for 48h, and then distilled under reduced pressure 7.20 g of light yellow liquid was obtained, the yield was 89%. 1 HNMR (CDCl 3 ,δ,ppm):5.45(s,-NH-,1H),4.10(d,J=6.5Hz,-CH 2 O,2H),3.24(s,-NH-CH 2 -,2H),2.39(m,-CH 2 N,2H),2.22(d,J=1.5Hz,CH 3 NCH 3 ,6H),1.23(t,J=6.5Hz,-CH 2 CH 3 ,3H). The structural formula of the intermediate 1 is shown in formula (5):

[0072]

[0073] Preparation of Intermediate 2:

[0074] Intermediate 1 and 1-bromodecane (15.25g, 0.05mol) were reacted at 100°C for 48h and 72h. The cr...

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Abstract

The invention discloses a hypocrellin derivative containing a long-chain quaternary ammonium salt, and a preparation method and an application thereof. The structural general formula of the derivative is represented by formula (1) or formula (2) shown in the description. In the formula (1) and the formula (2), X is N, O or S; m is not lower than 2 and not greater than 20, n is not lower than 0 and not greater than 10, p is not lower than 1 and not greater than 2, and m, n and p are positive integers; R1, R2 and R3 are C1-C20 alkyl groups respectively; HA is hypocrellin A; and HB is hypocrellin B. Hypocrellin is modified with long-chain quaternary ammonium salt for the first time, so the water solubility and the biocompatibility of the hypocrellin are enhanced; and the derivative has good oil and water amphipathicity, can effectively combine negatively charged species in organisms, and especially has very good nucleophilicity to tumor cells. The hypocrellin derivative containing a long-chain quaternary ammonium salt can be directly dissolved in normal saline to prepare a preparation medicine, so the medicinal effect of the derivative is improved, and development of hypocrellin medicines for treating cancers and preventing cancer viruses is possible.

Description

technical field [0001] The invention relates to the technical field of photosensitizer medicine for photodynamic therapy. More specifically, it relates to a long-chain quaternary ammonium salt-containing hypocretin derivative and its preparation method and application. Background technique [0002] Photodynamic therapy (Photodynamic Therapy, referred to as PDT) is a new technology for the selective treatment of vascular proliferative lesion tissue that has been developed rapidly in recent years. These diseases have a therapeutic effect. Photodynamic therapy has become the fourth special type of tumor treatment after surgery, radiotherapy and chemotherapy. Its advantages lie in its high efficiency and safety. It can continuously produce tens of millions of highly responsive cells under light irradiation. Reactive oxygen species, which lead to damage or necrosis of diseased cells and tissues, are significantly more efficient than traditional drugs that can only kill a single...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/32C07C249/02C07C251/24C07C319/18C07C323/25C07C213/06C07C217/12A61K41/00A61P35/00
CPCA61K41/0057C07C213/06C07C217/12C07C221/00C07C225/32C07C249/02C07C251/18C07C251/24C07C319/18C07C323/25
Inventor 吴加胜汪鹏飞葛介超刘卫敏
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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