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Benzoporphyrin chlorophyll photosensitizer and its preparation process and use

A technology of benzochloroporphyrin and chloroporphyrin, applied in the field of medicine, can solve the problems of high phototoxicity and complexity of normal tissues, and low photodynamic effect of target lesions

Inactive Publication Date: 2009-06-24
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The first generation of porphyrin photosensitizers such as hematoporphyrin derivative (HpD), photofrin II (Photofrin II, trade name: porfimer sodium, Porfimer Sodium), cancer photophyrin (Photocarcinorin, PSD-007) etc. have the following disadvantages: (1) they are complex mixed porphyrin preparations, and the quality is difficult to control; (2) the absorption coefficient (ε) in the red light region (>600nm) is small, resulting in low photodynamic effect on target lesions, which limits the curative effect (3) The content of photosensitized porphyrin that has no selective localization effect on tumors is high and cleared slowly in the body, resulting in high phototoxicity to normal tissues

Method used

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  • Benzoporphyrin chlorophyll photosensitizer and its preparation process and use
  • Benzoporphyrin chlorophyll photosensitizer and its preparation process and use
  • Benzoporphyrin chlorophyll photosensitizer and its preparation process and use

Examples

Experimental program
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Effect test

Embodiment 1

[0057] Example 1 Chlorin f dimethyl ester (V 1 ) preparation

[0058]Take chlorin f(VI 1 ) 0.65g (1.21mmol) was dissolved in 50mL redistilled tetrahydrofuran (THF), and 10mL (6.67mmol) of freshly prepared 2.8% (w / v) diazomethane ether solution was added at 0°C to react 10mM, and then add 0.2mL Decompose excess diazomethane with glacial acetic acid, recover 2 / 3 of THF under reduced pressure, dilute with 50mL chloroform, wash with water until neutral, dry over anhydrous sodium sulfate, recover solvent, and separate by silica gel H column chromatography after drying to obtain black powder V 1 0.45g, melting point 211-212°C, yield 66.2%. UV lambda max (CH 2 Cl 2 ) nm: 666 (7.1×10 4 ), 610 (7.3×10 3 ), 529 (6.2×10 3 ), 499 (1.7×10 4 ), 401 (1.9×10 5 ) (soret). 1 H NMR (500Hz, CDCl 3 )δ ppm: 9.82, 9.77, 9.63 and 8.75 (each s, each 1H, 4 × meso-H), 8.07 (dd, 1H, J = 17.9 and 11.5Hz, 2a-H x ), 6.33 (d, 1H, J=17.9Hz, 2b-H B ), 6.15 (d, 1H, J=11.5Hz, 2b-H A ), 4.50(m, 2H,...

Embodiment 2

[0059] Example 2 Chlorin p 6 Trimethyl ester (V 2 ) preparation

[0060] 2.0g of purpurin-18 (3.55mmol) was dissolved in 50mL of tetrahydrofuran, 200mL of methanol and 250mL of 20% (w / v) sodium hydroxide aqueous solution were added, and the reaction was stirred at room temperature until the ultraviolet absorption peak at 698nm disappeared, which took about 1h. Then it was diluted with 500 mL of water, neutralized with 10% (w / v) sulfuric acid to pH 5-6, extracted with diethyl ether (200 mL×3), and dried over anhydrous sodium sulfate. Add 30mL (20mmol) of 2.8% (w / v) diazomethane ether solution to the ether solution under ice-salt bath cooling, react for 10mM, then add 0.5mL glacial acetic acid to decompose the excess diazomethane, recover the solvent, dry it through silica gel H Column chromatography separated black powder V 2 1.8g, melting point 232-233°C, yield 81.3%. UV lambda max (CH 2 Cl 2 ) nm: 669 (6.3×10 4 ), 615 (8.2×10 3 ), 530 (9.8×10 3 ), 499 (1.7×10 4 ), ...

Embodiment 3

[0061] Example 3 Chlorin e 6 Trimethyl ester (V 3 ) preparation

[0062] According to the method of embodiment 1, 3.6g (6.04mmol) chlorin e 6 (VI 3 ) reacted with 2.8% (w / v) diazomethane ether solution 40mL (26.67mmol) to obtain a black solid V 3 2.43g, melting point 209-210°C, yield 63.1%. UV lambda max (CH 2 Cl 2 ) nm: 664 (1.3×10 5 ), 608 (1.5×10 4 ), 530 (1.5×10 4 ), 501 (3.8×10 4 ), 402 (3.7×10 5 ) (soret). 1 H NMR (500Hz, CDCl 3 )δ ppm: 9.69, 9.56 and 8.75 (each s, each 1H, 3×meso-H), 8.05 (dd, 1H, J=17.8 and 11.5Hz, 2a-H x ), 6.34 (d, 1H, J=17.8Hz, 2b-H B ), 6.13 (d, 1H, J=11.5Hz, 2b-H A ), 5.34 (d, 1H, J=18.9Hz, 10-H A ), 5.23 (d, 1H, J=18.9Hz, 10-H B ), 4.42(m, 2H, 7, 8-H), 4.25, 3.76, 3.61, 3.57, 3.46 and 3.29(each s, each 3H, 5-, 1-, 3-Me and OMe×3), 3.79( q, 2H, J=7.5Hz, 4a-CH 2 ), 2.54 (m, 2H, 7b-CH 2 ), 2.18 (m, 2H, 7a-CH 2 ), 1.75 (d, 3H, J = 7.0Hz, 8-Me), 1.70 (t, 3H, J = 7.5Hz, 4b-Me), -1.28and-1.46 (each br s, each 1H, NH in the ring ×2...

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Abstract

The invention relates to the technical field of medicine, and relates to a novel chlorphine photosensitizer—benzophyllogreen porphyrin compound, a preparation method and application thereof. The structure of the compound of the present invention is shown in general formula (I), wherein, R1 represents H, CH3, CO2CH3, CH2CO2CH3, CHCO2CH3; R2 represents COOCH3, CO, when R2 is CO, it forms a 5-membered ring with R1 as CHCOOCH3; R3 represents H, lower alkyl, (CH2) mOH, (CH2) mNR4R5, R4 and R5 independently represent lower alkyl, m represents an integer between 2-6, lower alkyl refers to a straight chain containing 1-6 carbon atoms or branched chain alkyl. Compared with the new-generation photosensitizer verteporfin (verteporfin) currently used in clinical practice, the benzochlorophyllin compounds of the present invention have the advantages of high efficiency and low toxicity, and can be used to prepare new photodynamic cancer drugs and photodynamic Drugs used to treat benign vascular diseases such as age-related macular degeneration (a proliferative disorder of retinal microvessels) and port wine stain (a congenital microvascular malformation of the skin).

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to a novel chlorphine photosensitizer—benzophyllogreen porphyrin compound, a preparation method and application thereof. Background technique [0002] Photodynamic therapy (PDT) is a new technology for the treatment of malignant tumors developed in the early 1980s. The basis of its treatment is to irradiate the tumor tissue selectively taken in photosensitizer with light of a certain wavelength, and the photosensitizer induces a photodynamic reaction to produce cytotoxic inactivation effect on tumor cells, leading to tumor tissue necrosis and exerting a therapeutic effect. [0003] The first generation of porphyrin photosensitizers such as hematoporphyrin derivative (HpD), photofrin II (Photofrin II, trade name: porfimer sodium, Porfimer Sodium), cancer photophyrin (Photocarcinorin, PSD-007) etc. have the following disadvantages: (1) they are complex mixed porphyrin preparations, an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/22A61K31/40A61P35/00A61P9/00
Inventor 姚建忠张万年余建鑫盛春泉章玲缪震元杨松宋云龙徐辉张珉
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY