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Hypocrellin derivative as well as preparation method and application thereof

A technology of oleocanthal and derivatives, which is applied in the directions of pharmaceutical formulations, drug combinations, photodynamic therapy, etc., can solve the problems of low yield of synthetic derivatives, reduced quantum yield, increased drug cost, etc., and achieves high conversion rate and high efficiency. Productivity, ease of operation, the effect of solving the problem of scar-free treatment

Pending Publication Date: 2022-06-21
INST OF CHEM CHINESE ACAD OF SCI
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  • 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 derivative as well as preparation method and application thereof
  • Hypocrellin derivative as well as preparation method and application thereof
  • Hypocrellin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Preparation of Compound H498

[0066] Bamboo Rhododendron A (HA) 31mg (5.7×10 -5 mol), solid potassium hydroxide 130mg (2.3×10 -3 mole) was added to 20 mL of dimethylformamide, mixed thoroughly, heated to 130°C under the protection of argon, and reacted with electromagnetic stirring for 3.5 hours. was extracted with chloroform for three times, combined, and drained to obtain a black powder, which was recrystallized from dichloromethane / petroleum ether to obtain a brown powder, 25.3 mg of oleocanthin 498 (H498), with a yield of 89.5%.

[0067] The structural detection data of this product are shown below:

[0068] UV spectrum λ max (CHCl 3 ): 455.5, 530.5, 571.5nm;

[0069] Fluorescence Spectrumλ max (CHCl 3 ): 587.6nm, 624nm (shoulder peak);

[0070] Infrared spectrumν max : 3433cm -1 ,2541cm -1 ,1727cm -1 ,1623cm -1 ,1395cm -1 ,;

[0071] NMR: δ(1H): 16.69, 16.61(2H), 6.81(s), 6.67(2H), 4.77, 4.62, 4.30(6H), 4.17(s)-3.15(9H), 1.12(3H);

[007...

Embodiment 2

[0074] Example 2: Preparation of compound H496

[0075] Bamboo Rhododendron A (HA) 44mg (8.05×10 -5 mol), with solid potassium hydroxide 0.9g (1.6×10 -2 mol) was added to 25 mL of dimethylformamide, fully mixed, heated to 137° C. under nitrogen protection, and reacted with electromagnetic stirring for 5 hours. After 24 hours, neutralize with an appropriate amount of dilute aqueous hydrochloric acid, extract with chloroform three times, combine, wash with water until neutral, and drain to obtain brown powder. Dichloromethane / petroleum ether was recrystallized to obtain 32.9 mg of brown-red powder, which was oleocorthin 496 (H496), and the yield was 82.4%.

[0076] The structural detection data of the product are shown below:

[0077] UV spectrum λ max (CHCl 3 ): 438.5nm, 528.5nm, 569.5nm;

[0078] Fluorescence Spectrumλ max (CHCl 3 ): 581.2nm, 624nm (shoulder peak);

[0079] Infrared spectrumν max : 3431cm -1 ,2942cm -1 ,1730cm -1 ,1609cm -1 ,1458cm - ;

[0080]...

Embodiment 3

[0087] Example 3: Preparation of Compound H436

[0088] Bamboo Rhododendron B (HB) 41.0mg (7.76×10 -5 mol), solid potassium carbonate 1.1g (1.96×10 -2 mole) was added to 40 mL of dimethylformamide solution, heated to 135°C under nitrogen protection, and reacted with electromagnetic stirring for 4.5 hours. Hour, extracted with dichloromethane 3 times and combined, washed with water until neutral, and drained to obtain a brown-red solid, which was recrystallized from dichloromethane / petroleum ether to obtain 24.1 mg of a brown-red solid, which was oleocanthin 436 (H436), and the yield was 24.1 mg. was 71.1%.

[0089] The structural detection data of this product are shown below:

[0090] UV spectrum λ max (CHCl 3 ): 326.0nm, 450.5nm, 560.5nm;

[0091] Fluorescence Spectrumλ max (CHCl 3 ): 583.6nm;

[0092] Infrared spectrumν max : 2917cm -1 , 1720cm-1 , 1622cm -1 ,1458cm -1 ,1223cm -1 ;

[0093] NMR: δ(1H): 16.87, 16.63(2H), 7.79, 7.58, 7.29(3H) 6.99, 6.44(2H), 4....

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Abstract

The invention belongs to the technical field of photodynamic phototherapy photosensitizer medicines for microvascular diseases. In particular to a hypocrellin derivative as shown in a formula I, and a stereoisomer, a position isomer, an isotope label, a solvate, a polymorphic substance, a prodrug or a pharmaceutically acceptable salt thereof. The maximum light absorption wavelength of the hypocrellin derivative as shown in the formula I is 400-600nm, and the depth of penetrating tissues conforms to the focus depth of microvascular diseases. The problem of scar-free treatment can be solved, absorption of visual pigments can be avoided as far as possible, and teratogenic new blood of a focus is selectively destroyed without damaging normal tissues or visual pigments, so that the effect of photodynamic phototherapy is exerted to the greatest extent.

Description

technical field [0001] The invention belongs to the technical field of photodynamic phototherapy photosensitizers for microvascular diseases, and particularly relates to a oleocanthal derivative and a preparation method and application thereof. Background technique [0002] Hypocrellin is a kind of natural photosensitizer extracted from Hypocrella bambuase, a parasitic fungus parasitic on arrow bamboo in Yunnan and other places in my country. It belongs to 3,10-dihydroxy-4, 9-Perylenequinone compounds. There are two main types of naturally extracted rhodopsin: Hypocrellin A (Hypocrellin A, referred to as "HA") and Hypocrellin B (Hypocrellin B, referred to as "HB") (Jiang Lijin, the structure of rhodopsin , Properties, Photochemical Reactions and Mechanisms (I), Scientific Bulletin, 1990, 35(21): 1608-1616; Jiang Lijin, Structure, Properties, Photochemical Reactions and Mechanisms of Bamboo Rhododendron (II), Scientific Bulletin, 1990, ( 22): 1681-1690), of which more than 9...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/93A61K41/00A61P9/00
CPCC07D307/93A61K41/0057A61P9/00
Inventor 谢杰
Owner INST OF CHEM CHINESE ACAD OF SCI
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