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Glyoxalase I irreversible inhibitor and preparation method and application thereof

A technology of dichloromethane and compounds, which is applied in the field of glyoxalase I competitive inhibitors and its preparation, can solve the problems of poor affinity of irreversible inhibitors and lack of breakthroughs in research and development, and achieve good application prospects and drug efficacy Long-lasting, good therapeutic effect

Active Publication Date: 2016-11-23
SHENZHEN YONGZE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The research and development of glyoxalase I irreversible inhibitors has not been breakthrough for a long time, and the affinity of the irreversible inhibitors reported in the literature is very poor, and its Ki is around 0.1-0.3mM

Method used

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  • Glyoxalase I irreversible inhibitor and preparation method and application thereof
  • Glyoxalase I irreversible inhibitor and preparation method and application thereof
  • Glyoxalase I irreversible inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] The preparation of embodiment 1 compound 15 of the present invention

[0077] The synthetic route is as follows:

[0078]

[0079] The specific synthesis process is as follows:

[0080] Preparation of Compound 2

[0081] Compound 1 (10.00g, 49.02mmol), potassium carbonate (13.53g, 98.04mmol) and potassium hydroxide (2.75g, 49.02mmol) were dissolved in a mixed solvent of THF (90mL) and water (30mL). Stir and add benzyloxycarbonyl succinimide (18.3 g, 73.53 mmol). After the addition, it was naturally raised to room temperature and reacted for 8 hours. Concentrate under reduced pressure to remove THF, extract the aqueous layer with ether, separate the layers, acidify the aqueous layer with citric acid to pH=4, precipitate out, and extract with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain light yellow oily compound 2 (15.57 g, yield 94%), which was directly used in the next step.

[0082...

Embodiment 2

[0110] Embodiment 2 The preparation of compound 15DE of the present invention

[0111]

[0112] Preparation of compound 16

[0113] Under ice bath, compound 2 (5g, 14.79mmol) and potassium carbonate (3.06g, 22.19mmol) were dissolved in DMF (50mL), magnetically stirred, iodoethane (3.45g, 22.19mmol) was added dropwise to the reaction flask ), after the addition was completed, the reaction was naturally raised to room temperature for 5 h, and the reaction was monitored by TLC to be complete. The reaction solution was added to water (300mL), extracted with ethyl acetate (300mL×2), the organic phases were combined, and the organic phase was washed with saturated aqueous sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. After drying the organic solvent, the mixed solvent of ethyl acetate and petroleum ether was stirred to disperse the residue evenly, and then filtered to obtain light yellow solid 16 (4.8 g, yi...

Embodiment 3

[0132] Embodiment 3. Preparation of glyoxalase I inhibitor freeze-dried powder injection of the present invention

[0133] The preparation process of the glyoxalase I inhibitor freeze-dried powder injection of the present invention comprises the following steps:

[0134] 1) Add lyophilized support agent and co-solvent: adjust the pH value of the medicinal solution to 4-9, and add mannitol, a lyophilized support agent with half the weight of the glyoxalase I inhibitor. The co-solvent is β-hydroxymethylcyclodextrin for injection, and the addition amount is equal to that of the glyoxalase I inhibitor.

[0135] The weight ratio of the glyoxalase I inhibitor to the freeze-dried support agent mannitol is 6:1-3:1.

[0136] The lyophilized support agent is selected from one or a mixture of any two of mannitol, xylitol, sorbitol, sodium chloride and dextran; the weight of glyoxalase I inhibitor and β-hydroxymethyl cyclodextrin The ratio is 10:1 to 1:1.

[0137] 2) Depyrogenation: Ad...

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Abstract

The invention provides a glyoxalase I irreversible inhibitor shown as the formula I (pleases see the formula in the description) and a preparation method and application thereof. The glyoxalase I irreversible inhibitor reacts with glyoxalase I in a covalent bond mode to enable the glyoxalase I to be irreversibly inactivated. The glyoxalase I irreversible inhibitor has good application and development prospects on preparation of drugs for treating malignant tumors such as a prostatic cancer, a lung cancer, an intestinal cancer, a bladder cancer, leukemia, a breast cancer and a skin cancer and various relapsed tumors.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to an inhibitor of glyoxalase system, in particular to a glyoxalase I competitive inhibitor and its preparation method and application. Background technique [0002] At present, many drugs used clinically or under development are aimed at attacking tumor cells by directly or indirectly inhibiting DNA and / or proteins. In this case, rapidly dividing normal cells, such as the intestinal epithelium and bone marrow, are also adversely affected with strong side effects. [0003] A toxic compound called methylglyoxal is inevitably produced in the process of glucose metabolism in the human body, which can cause programmed cell death. The human body has developed a glyoxalase system during the long-term evolution process, which is composed of glyoxalase I (glyoxalase I, GlxI for short) and glyoxalase II (glyoxalase II, GlxII for short), which can detoxify methylglyoxalase The role of aldehyd...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078A61K38/05A61P35/00A61P35/02A61P19/10
Inventor 郑哲彬金天刘潇邓琪山石清黄茂林
Owner SHENZHEN YONGZE PHARM CO LTD
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