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Hypocrellin derivatives, and preparation method and application thereof

A technology of oleocanthal and derivatives, applied in the field of oleocanthin derivatives and preparation thereof, can solve the problems of reduced quantum yield, increased drug cost, low yield of synthetic derivatives and the like

Inactive Publication Date: 2019-03-05
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among the hypocretin derivatives that have been reported so far, the water-soluble derivatives are all at the cost of loss of biological activity; while many derivatives are still fat-soluble, and some are even more lipophilic than the parent. Obviously, it is difficult to directly Medication; Hypocretin derivatives have some defects as phototherapy reagents compared with the parent: for example, the quantum yields of the singlet oxygen of the aminated derivatives are all lower than the parent, so this is very important for them in PDT (light application in dynamic therapy) is very detrimental
In addition, the yield of synthetic derivatives is low, and these factors will greatly increase the cost of drug application
[0008] Although hypocretin compounds do not have advantages in the treatment of solid tumors, since the tissue penetration depth of hypocreline photosensitizers that absorb light coincides with the depth of microvascular disease lesions, it may be a class that is more suitable for such superficial tumors. Targeted photodynamic drugs for phenotypic diseases

Method used

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  • Hypocrellin derivatives, and preparation method and application thereof
  • Hypocrellin derivatives, and preparation method and application thereof
  • Hypocrellin derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1, the preparation of hypocrellin

[0066] Hypocretin A (HA) 55mg (1.0×10 -4 mol), solid potassium carbonate 120mg (8.7×10 -4 mol) into 15ml of dimethylformamide, mixed thoroughly, heated to 125°C under the protection of nitrogen, reacted with electromagnetic stirring for 4 hours, dried the solvent under reduced pressure, dissolved the residue with an appropriate amount of dilute hydrochloric acid aqueous solution, washed with water until neutral , extracted 3 times with dichloromethane and combined, drained to obtain a black powder, the reaction product was separated and purified on a silica gel thin-layer chromatography plate with 1% citric acid aqueous solution, and the developing solvent was chloroform: ethyl acetate: methanol (V: V: V) = 2:1:1, collect R f =0.84 product, black powder was obtained, which was hypocretin 32 mg, and the yield was 62%.

[0067] The structure detection data of this product are as follows:

[0068] UV spectrum λ max (CHCl ...

Embodiment 2

[0076] Embodiment 2, the preparation of hypocrellin

[0077] Hypocretin A (HA) 50mg (9.2×10 -5 mol), solid sodium carbonate 300mg (2.8×10 -3 mol) into 10ml of dimethylformamide, mixed thoroughly, heated to 130°C under the protection of argon, and reacted with electromagnetic stirring for 4.5 hours. The solvent was dried under reduced pressure, and the residue was dissolved with an appropriate amount of dilute hydrochloric acid aqueous solution, washed with water until medium property, chloroform extraction was combined for 3 times, drained to obtain a black powder, and the reaction product was separated and purified on a silica gel thin-layer chromatography plate with 1% citric acid aqueous solution, and the developing solvent was chloroform: ethyl acetate: methanol (V: V: V) = 2:1:1, collect R f =0.84, the black powder was finally obtained, which was 24 mg of hypocrellin, and the yield was 51%.

[0078] The structure detection data of this product are as follows:

[0079]...

Embodiment 3

[0087] Embodiment 3, the preparation of hypocrellin

[0088] Hypocretin A (HA) 88mg (1.61×10 -4 mol), with solid sodium hydroxide 300mg (5.35×10 -3 mol) into 15ml of dimethylformamide, mixed thoroughly, heated to 130°C under the protection of nitrogen, and reacted with electromagnetic stirring for 4 hours, vacuumed the solvent to dry up, dissolved the residue with an appropriate amount of dilute hydrochloric acid aqueous solution, washed with water until neutral , extracted three times with dichloromethane and combined, and dried to obtain a black powder. The reaction product was separated and purified on a silica gel thin-layer chromatography plate with 1% citric acid aqueous solution, and the developing solvent was dichloromethane:methanol (V:V)=5:1, and R f =0.58 component, 44 mg of black powder was obtained, which was hypocrellin, and the yield was 55%.

[0089] The structural detection data of the product are as follows:

[0090] UV spectrum λ max : 367.0nm, 511.5nm,...

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Abstract

The invention belongs to the technical field of photodynamic phototherapy photosensitizer drugs for microvascular diseases, and specifically relates to hypocrellin derivatives of formulas I and II shown in the specification, and stereoisomers, isotopic labels, solvates, polymorphs, prodrugs, or pharmaceutically acceptable salts of the two types of hypocrellin derivatives. The maximum light absorption wavelength of the hypocrellin derivatives represented by the formula I and the formula II is located at 460 to 570 nm, and the depth of penetrating tissue is consistent with the depth of a lesionof a microvascular disease. The problem of scar-free treatment can be solved, also absorption of visual pigments is avoided as much as possible, and teratogenic new blood vessels at the lesion are selectively destroyed without damaging normal tissues or visual pigment, so that the effect of photodynamic phototherapy is played to a maximum extent.

Description

technical field [0001] The invention belongs to the technical field of photosensitizer medicine for photodynamic phototherapy for microvascular diseases, and specifically relates to hypocretin derivatives and their preparation methods and applications. Background technique [0002] Hypocrellin (Hypocrellin) is a natural photosensitizer extracted from a parasitic fungus-Hypocrella bambuase that parasitizes Arrow bamboo in Yunnan and other places in my country. It belongs to 3,10-dihydroxy-4, 9-perylenequinones. There are two main types of naturally extracted hypocrellin: Hypocrellin A (Hypocrellin A, referred to as "HA") and Hypocrellin B (Hypocrellin B, referred to as "HB") (Jiang Lijin, Hypocrellin structure , Properties, Photochemical Reaction and Mechanism (I), Science Bulletin, 1990,35(21):1608-1616; Jiang Lijin, Structure, Properties, Photochemical Reaction and Mechanism of Hypocretin (II), Science Bulletin, 1990, ( 22):1681-1690), of which more than 95% are HA. Under...

Claims

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Application Information

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IPC IPC(8): C07C50/36C07C46/00A61K31/122A61K41/00A61P9/14A61P9/00A61P27/02
CPCA61K41/0057C07C50/36
Inventor 谢杰
Owner INST OF CHEM CHINESE ACAD OF SCI
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