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A kind of chlorin e6 derivative and its pharmaceutically acceptable salt, its preparation method and application

A technology of chlorin and its derivatives, which is applied in the field of medicine, can solve the problems of reduced toxicity, high residual phototoxicity, short laser penetration and killing tumor depth, etc., and achieves reduced toxicity, improved therapeutic effect, and excellent photodynamic killing effect Effect

Active Publication Date: 2019-12-06
SHANGHAI BIOPHY BIOLOGICAL PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first generation of porphyrin photosensitizers such as porfimer sodium (porfimer sodium) have been successfully used in the clinical treatment of tumors, and have achieved remarkable curative effect, but there are also obvious defects: 1) the maximum absorption wavelength in the red light region is short (630nm), making the wavelength The matching laser penetrates and kills the tumor deeply enough and the molar absorption coefficient (ε) is small, resulting in low photosensitivity; 2) It is a multi-component porphyrin mixture; 3) The slow clearance in the body leads to high residual phototoxicity, and the patient receives treatment It needs to be protected from light for 4 to 8 weeks afterwards, causing great psychological pain to the patient.
Nevertheless, there are still few types of drugs for the treatment of tumors, and the options for patients are limited, and the therapeutic effect also has great room for improvement, and its toxicity needs to be further reduced

Method used

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  • A kind of chlorin e6 derivative and its pharmaceutically acceptable salt, its preparation method and application
  • A kind of chlorin e6 derivative and its pharmaceutically acceptable salt, its preparation method and application
  • A kind of chlorin e6 derivative and its pharmaceutically acceptable salt, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: N-[3-(1-methoxy)ethyl-3-desvinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I 1 ) preparation

[0053] S1: Preparation of 3-(1-bromoethyl)-3-desvinylchlorin e6(IV)

[0054] Compound Ⅴ (5.0g), add 200mL of 33% HBr glacial acetic acid solution, seal and stir at room temperature for 24h, evaporate glacial acetic acid and excess HBr under reduced pressure to obtain 5.6g dark green solid compound Ⅳ, namely 3-(1-bromoethyl base)-3-desvinyl chlorin e6, which was directly used in the next reaction without further purification.

[0055] S2: 3-(1-methoxy)ethyl-3-desvinylchlorin e6(Ⅲ 1 ) preparation

[0056] Compound IV (1.12g), dissolved in 25mL of anhydrous acetone, added 2g K 2 CO 3 and 2 mL of dry methanol, stirred and refluxed for 2 h, cooled to room temperature, added 10 times the volume of water, and washed with 10% H 2 SO 4 Neutralize excess K 2 CO 3 And adjust the pH to 5-6, filter, P 2 o 5 After vacuum drying, it was separated by silica gel H column c...

Embodiment 2

[0064] Example 2: N-[3-(1-n-propoxy)ethyl-3-desvinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I 2 ) preparation

[0065] S1: The preparation of 3-(1-bromoethyl)-3-desvinyl chlorin e6(IV) is the same as the preparation method of step S1 in Example 1;

[0066] S2: 3-(1-propoxy)ethyl-3-desvinylchlorin e6(Ⅲ 2 ) preparation: according to the method of step S2 of Example 1, compound IV (1.12g) was reacted with 2mL dry n-propanol to obtain 0.56g black solid III 2 , yield 50.9%.

[0067] 3-(1-propoxy)ethyl-3-desvinyl chlorin e6(Ⅲ 2 ) spectrum data is: MS(ESI + ) m / z:657.78[M+H] + (100%).

[0068] S3: N-[3-(1-n-propoxy)ethyl-3-desvinylchlorin e6-15 2 -Acyl]-L-aspartic acid di-tert-butyl ester (Ⅱ 2 ) preparation

[0069] According to the method of embodiment 1 step S3, compound III 2 (140mg, 0.213mmol) was reacted with equivalent EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl hydrochloride and 2.4 equivalents of DIPEA in dry DMF to obtain black powder II 2 125 mg, yie...

Embodiment 3

[0074] Example 3: N-[3-(1-n-hexyloxy)ethyl-3-desvinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I 3 ) preparation

[0075] S1: The preparation of 3-(1-bromoethyl)-3-desvinyl chlorin e6(IV) is the same as the preparation method of step S1 in Example 1;

[0076] S2: 3-(1-n-hexyloxy)ethyl-3-desvinylchlorin e6(Ⅲ 3 ) preparation: according to the method of step S2 of Example 1, compound IV (1.12g) was reacted with 2mL dry n-hexanol to obtain 0.48g black solid III 3 , yield 41.0%.

[0077] Compound III 3 The spectrogram data is: MS(ESI + )m / z:699.68[M+H] + (100%).

[0078] S3: N-[3-(1-n-hexyloxy)ethyl-3-desvinylchlorin e6-15 2 -Acyl]-L-aspartic acid di-tert-butyl ester (Ⅱ 3 ) preparation: according to the method of embodiment 1 step S3, compound III 3 (150mg, 0.215 mmol) was reacted with equivalent EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl hydrochloride and 2.4 equivalents of DIPEA in dry DMF to obtain black powder Ⅱ 3 120 mg, yield 60.4%.

[0079] Compound II...

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Abstract

The invention relates to a chlorin e6 derivative and a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and belongs to the technical field of medicine. The chlorin e6 ether amino acid derivative includes general structural formula I and The optical isomer of the general structural formula I; its preparation method is to etherify the 3-vinyl group in chlorin e6, and form a peptide with the 15-ethyl carboxyl group and amino acid. The chlorin e6 ether amino acid derivatives and pharmaceutically acceptable salts thereof can be used as photodynamic antitumor drugs. Compared with the similar photosensitizer taraporfin in the existing clinical application, the chlorin e6 ether amino acid derivatives of the present invention have the advantages of strong photodynamic anti-tumor activity and high dark toxicity-phototoxicity ratio, and can be used to prepare new The photodynamic anti-tumor drugs include photodynamic cancer drugs, photodynamic therapy drugs for benign vascular diseases such as age-related macular degeneration and port wine stains, and photodynamic therapy drugs for condyloma acuminatum.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a new class of chlorin photosensitizers - chlorin e6 ether amino acid derivatives and pharmaceutically acceptable salts thereof, their preparation methods and their use in the preparation of anti-tumor and other drugs in the application. Background technique [0002] Photodynamic therapy (PDT) is a new technology for tumor treatment developed in the early 1980s. The principle of treatment is to irradiate the lesion (tumor) tissue that takes in the photosensitizer with a specific wavelength of laser light, and the photosensitizer induces matrix oxygen (O 2 ) excited to produce singlet oxygen ( 1 o 2 ) and other reactive oxygen species (ROS), leading to apoptosis or necrosis of tumor cells and playing a role in tumor therapy. The so-called specific wavelength refers to the maximum absorption wavelength of the photosensitizer in the red light region (>600nm). Since ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/409A61P35/00A61P17/00A61P27/02A61P31/20A61K41/00
CPCA61K41/0071C07D487/04A61K31/409A61K41/00A61P17/00A61P27/02A61P31/20A61P35/00C07D487/22
Inventor 尚华
Owner SHANGHAI BIOPHY BIOLOGICAL PHARM CO LTD
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