Opiate receptor antagonist conjugates and application thereof

A technology of receptor antagonists and conjugates, applied in the field of conjugates covalently coupled with hydrophilic polymers and opioid receptor antagonists, can solve diarrhea and cramps, unpredictable effects, laxatives non-specific issues

Active Publication Date: 2017-08-11
SHANGHAI HANMAI BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the treatment of constipation, the use of laxatives, the selection of appropriate opioids and opioid antagonists are used to relieve or treat constipation caused by long-term use of opioid analgesics; the use of a single laxative is usually ineffective, and regular use of stimulants is required. Laxatives, but laxatives are nonspecific and unpredictable in action and often cause diarrhea and cramping

Method used

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  • Opiate receptor antagonist conjugates and application thereof
  • Opiate receptor antagonist conjugates and application thereof
  • Opiate receptor antagonist conjugates and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: Preparation of polyethylene glycol mesylate

[0088]

[0089] Add 50ml dichloromethane, 7.18ml triethylamine, 206mg p-dimethylaminopyridine and 10.0g CH in the reaction flask 3 -(OCH 2 CH 2 ) 6 -OH (abbreviated as mPEG6-OH) (Jiaxing Bomei, M006110503). Add 3.28ml methanesulfonyl chloride in 50ml dichloromethane solution dropwise with stirring at 0°C. After the addition, the reaction was stirred overnight at room temperature. The reaction solution was transferred to a separatory funnel and washed with dilute hydrochloric acid and brine successively. The organic layer was separated, dried with 30 g of anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated by rotary evaporation to obtain 13.6 g of crude product. The crude product was purified by chromatography to obtain 13.0g mPEG6-OMs(CH 3 -(OCH 2 CH 2 ) 6 -OSO 2 CH 3 ). 1H-NMR (400MHz, CDCl3), δppm 4.35-4.41 (2H, m), 3.74-3.80 (2H, m), 3.60-3.70 (18H, m), 3.52-3.58 (2H, m), 3.38 (3H) , S...

Embodiment 2

[0100] Example 2: Preparation of 3-MOM-naltrexone and 3-MOM-naloxone

[0101]

[0102] 200ml of dichloromethane, 41.7g of diisopropylethylamine and 19.83g of naltrexone hydrochloride (Jinan Haohua Industrial Co., Ltd., FR00007) were sequentially added to the reaction flask. 17.7 g of chloromethyl methyl ether in 200 ml of dichloromethane was added dropwise with stirring at 0°C. After the addition was completed, the reaction was stirred overnight. The reaction solution was transferred into a separatory funnel and washed with lye (400ml water+40g anhydrous sodium carbonate+10.0g sodium hydroxide+30g sodium chloride and mixed). The organic layer was separated, dried with 30 g of anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated by rotary evaporation to obtain 21.3 g of product 3-MOM-naltrexone. 1H-NMR (400MHz, CDCl3), δppm 6.85-6.92 (1H, d, J=8.0Hz), 6.58-6.65 (1H, d, J=8.4Hz), 5.20-5.30 (2H, m), 4.68 (1H , S), 3.52 (3H, s), 3.15-3.22 (1H, d, J=6.0 Hz),...

Embodiment 3

[0104] Example 3: Preparation of 3-MOM-6-α-naltrexol and 3-MOM-6-α-naloxol

[0105]

[0106] Under the protection of argon, 100ml of tetrahydrofuran and 16.8g of 3-MOM-naltrexone were added to the reaction flask. While stirring at -10°C, add 45ml of a tetrahydrofuran solution of potassium tri-sec-butylborohydride. Use thin layer chromatography (TLC) to check the progress of the reaction. After the reaction is completed, adjust the pH to 2-4 with dilute hydrochloric acid. The reaction solution was transferred to a separatory funnel, and extracted with dichloromethane 4 times (150, 100, 100, 100 ml). Separate the organic layer, add 10.0 g of sodium hydroxide in 150 ml of aqueous solution to the water layer, mix well, and extract 3 times with dichloromethane (100 ml×3). The organic layers were combined, dried with 20 g of anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated by rotary evaporation to obtain 16.5 g of the product 3-MOM-6-α-naltrexol. 1H-NMR ...

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Abstract

The invention relates to opiate receptor antagonist conjugates and an application thereof, in particular to conjugates prepared from hydrophilic polymers and opiate receptor antagonists through covalent coupling and an application of the conjugates.

Description

Technical field [0001] The present invention relates to opioid receptor antagonist conjugates and applications thereof. Specifically, the present invention relates to a conjugate of a hydrophilic polymer covalently coupled with an opioid receptor antagonist and its application. Background technique [0002] Pain is one of the most common human sufferings and one of the most unbearable symptoms for patients. As far as cancer pain is concerned, according to statistics, at least 5 million cancer patients worldwide suffer from pain every day. There are 1.8 million new cancer patients in my country each year, and nearly 1.4 million cancer deaths. Of these patients, 50% have moderate to severe pain, and 30% of them have intolerable severe pain. By 2020, the number of new cancer cases worldwide will reach 20 million each year, and the number of deaths will reach 16 million each year, and 70% of cancer patients will be distributed in developing countries. In developing countries, mos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/08A61K31/485A61K47/60A61P1/00A61P1/10A61P25/04
CPCC07D489/08A61K31/485A61K47/60A61P1/10A61P29/00A61P23/00A61K31/439
Inventor 徐敏
Owner SHANGHAI HANMAI BIO PHARMA CO LTD
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