Photosensitizer prodrug compound, and preparation method and application thereof

A technology of compounds and photosensitizers, applied in the field of medicine, can solve problems such as poor stability, restricting curative effect, dimerization and inactivation, etc., and achieve the effects of avoiding inactivation, promoting curative effect, and enhancing lipophilicity

Active Publication Date: 2019-09-20
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Therefore, the technical problem to be solved by the present invention is to overcome the defects of 5-ALA and its ester derivatives in the prior art that are prone to dimerization and inactivation, poor stability, and restricting its curative effect, thereby providing a photosensitizer precursor Pharmaceutical compound and its preparation method and application

Method used

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  • Photosensitizer prodrug compound, and preparation method and application thereof
  • Photosensitizer prodrug compound, and preparation method and application thereof
  • Photosensitizer prodrug compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] This embodiment provides a photosensitizer prodrug compound (dimethyl 4,7,16,19-tetraoxo-8,15-dioxa-11,12-dithia-6,17-diazadocosanedioate), which has the following formula (P-1 ) shows the structure:

[0059]

[0060] The synthetic route of compound shown in formula (P-1) is as follows:

[0061]

[0062] The preparation method of the compound shown in formula (P-1) specifically comprises the following steps:

[0063] (1) Synthesis of Intermediate 1-1

[0064] 2-Hydroxyethyl disulfide (1.3mmol) was dissolved in ultra-dry acetonitrile (5mL), and under nitrogen protection, DSC (5.2mmol) and Et3N (7.8mmol) were added in sequence, and after 6 hours of reaction at room temperature, the solvent was spin-dried , the residue was dissolved in dichloromethane (20mL), and washed once with saturated sodium bicarbonate, saturated ammonium chloride and saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, spin-dried to obtain intermediate 1-1; ...

Embodiment 2

[0071] This embodiment provides a photosensitizer prodrug compound, which has a structure shown in the following formula (P-2):

[0072]

[0073] The synthetic route of the compound shown in the formula (P-2) is the same as in Example 1, the difference is that the compound A-1 is replaced by 5-ALA, and the compound B-1 is replaced by a compound shown in the following formula (B-2) .

[0074]

[0075] The preparation method of the compound shown in formula (P-2) specifically comprises the following steps:

[0076] The steps of synthesizing intermediate 1-1 are the same as in Example 1;

[0077] The intermediate 1-1 (1.3mmol), the hydrochloride (1.3mmol) of 5-ALA and the hydrochloride (1.3mmol) of compound B-2 were dispersed in ultra-dry THF, and under nitrogen protection, DIPEA ( 3.9 mmol), after overnight reaction at room temperature, the solvent was spin-dried, the residue was dissolved in dichloromethane (20 mL), and washed once with saturated ammonium chloride, satu...

Embodiment 3

[0082] This embodiment provides a photosensitizer prodrug compound, which has a structure shown in the following formula (P-3):

[0083]

[0084] The synthetic route of the compound shown in formula (P-3) is the same as in Example 1, and the difference is that the compound A-1 is replaced by the compound shown in the following formula (A-3), and compound A-1 is replaced by the compound shown in the following formula (B-3). The compound shown is substituted for compound B-1.

[0085]

[0086] The preparation method of the compound shown in formula (P-3) specifically comprises the following steps:

[0087] The steps of synthesizing intermediate 1-1 are the same as in Example 1;

[0088] Disperse intermediate 1-1 (1.3mmol), compound A-3 hydrochloride (1.3mmol) and compound B-3 hydrochloride (1.3mmol) in ultra-dry THF, under nitrogen protection, slowly drop DIPEA (3.9mmol), after overnight reaction at room temperature, the solvent was spin-dried, the residue was dissolved ...

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Abstract

The invention provides a photosensitizer prodrug compound, and a preparation method and an application thereof. The compound has a structure represented by formula (I). A disulfide bond is introduced at the N end of 5-ALA or its ester derivative, the disulfide bond is a GSH responsive group, the group containing the disulfide bond undergoes self-immolative reaction under the condition of linking urethane to the beta position of the disulfide bond in order to release the connected 5-ALA or its ester derivative, protoporphyrin is generated in an intracellular metabolism manner, and the photosensitizer plays a role in photodynamic diagnosis, so dimerization induced inactivation of the 5-ALA is avoided, and the drug stability is increased; and the overexpression of the GSH in various tumor cells and the response of the prodrug compound to the GSH enhance the tumor targeting property of the drug. The invention also provides the application of the photosensitizer prodrug compound in the preparation of the drug for photodynamic diagnosis and treatment.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a photosensitizer prodrug compound and its preparation method and application. Background technique [0002] Photodynamic therapy (Photodynamic Therapy, PDT) is a new method of treating tumor diseases by using photosensitizing drugs and laser activation. The process is to irradiate the tumor with a specific wavelength, which can activate the photosensitive drug selectively gathered in the tumor tissue, triggering a photochemical reaction to destroy the tumor. The photosensitive drugs in the new generation of photodynamic therapy (PDT) will transfer energy to the surrounding oxygen to generate highly active singlet oxygen, which can oxidize with nearby biomacromolecules, resulting in cytotoxicity and killing tumors cell. Compared with traditional tumor therapy, the advantage of PDT is that it can perform precise and effective treatment with less side effects. [0003] A photos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/12C07C319/22A61K41/00A61P35/00
CPCA61K41/0061A61P35/00C07C323/12
Inventor 李珂林建国邱玲刘清竹吕高超彭莹谢敏浩
Owner JIANGSU INST OF NUCLEAR MEDICINE
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