Multi-site combination modified endomorphin analogue, synthesis and application thereof

An endomorphin and multi-site technology, which is applied in the field of multi-site combination modified endomorphin analogs and their synthesis and application, can solve the problem of prolonged drug action time, expensive β-proline, high production cost, etc. problems to achieve good pharmacological activity

Active Publication Date: 2017-07-21
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the proline at the second position of endomorphin is the main enzyme cleavage site, and the preparation of the endomorphin-1 analogue into analgesic drugs still has the problem of short action time, and from the perspective of industrial production, ( S / R ) β-proline is expensive and expensive to produce
Based on this, the Chinese invention patent "Endomorphin-1 analogs and their synthesis and application in the preparation of analgesic drugs" with application number 20111089179.9 provides an amino acid at the second position of endomorphin-1 composed of D-type C Amino acid-substituted endomorphin-1 analogs can significantly prolong the drug action time, but its mu opioid receptor affinity is weak, and the analgesic effect is not significant enough

Method used

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  • Multi-site combination modified endomorphin analogue, synthesis and application thereof
  • Multi-site combination modified endomorphin analogue, synthesis and application thereof
  • Multi-site combination modified endomorphin analogue, synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] The synthesis of embodiment 1 MEL-N1601

[0099](1) Synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-phenylpropionic acid amide: 1 mol of N-tert-butoxycarbonyl-3-amino-2-methenyl- Dissolve 3-phenylpropionic acid in anhydrous dichloromethane, add 4.5 mol of N,N-diisopropylethylamine, 1.6 mol of 1-hydroxybenzotriazole and 1.6 mol of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stir well to dissolve, add 1.6 mol of ammonia water, react at room temperature for 16 hours, add dichloromethane to dilute, wash with 5% citric acid solution twice , washed twice with saturated sodium bicarbonate, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the white solid product N-tert-butoxycarbonyl-3-amino-2-methenyl-3-benzene Propionic acid amide, productive rate is 91%;

[0100] (2) Synthesis of 3-amino-2-methenyl-3-phenylpropionamide trifluoroacetate: 1 mol of N-tert-butoxycarbonyl-3-amino-2-methen...

Embodiment 2

[0109] Preparation of Example 2 MEL-N1602

[0110] (1) Synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3(2-furan)propionic acid amide: 1 mol of N-tert-butoxycarbonyl-3-amino-2-methanol Alkenyl-3(2-furan)propionic acid was dissolved in anhydrous dichloromethane, and 4.6 mol of N,N-diisopropylethylamine and 1.65 mol of 1-hydroxybenzene were added successively under stirring at 0°C. Add triazole and 1.65 mol of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stir to fully dissolve, add 1.65 mol of ammonia water, react at room temperature for 16 hours, add dichloromethane to dilute, 5% lemon Washed twice with acid solution, twice with saturated sodium bicarbonate, once with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the white solid product N-tert-butoxycarbonyl-3-amino-2-methane Alkenyl-3 (2-furan) propionic acid amide, the yield was 89%;

[0111] (2) Synthesis of 3-amino-2-methenyl-3(2-furan)propionamide ...

Embodiment 3

[0120] Synthesis of Example 3 MEL-N1603

[0121] (1) Synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-phenylpropionic acid amide: 1 mol of N-tert-butoxycarbonyl-3-amino-2-methenyl- Dissolve 3-phenylpropionic acid in anhydrous dichloromethane, add 4.6 mol of N,N-diisopropylethylamine, 1.65 mol of 1-hydroxybenzotriazole and 1.65 mol of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stir to dissolve fully, add 1.65 mol of ammonia water, react at room temperature for 16 hours, add dichloromethane to dilute, wash with 5% citric acid solution twice , washed twice with saturated sodium bicarbonate, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the white solid product N-tert-butoxycarbonyl-3-amino-2-methenyl-3-benzene Propionic acid amide, productive rate is 91%;

[0122](2) Synthesis of 3-amino-2-methenyl-3-phenylpropionamide trifluoroacetate: 1 mol of N-tert-butoxycarbonyl-3-amino-2-methenyl-...

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Abstract

Belonging to the field of biomedicine, the invention provides an endomorphin analogue with the first position, the second position and fourth position respectively modified by tyrosine or 2, 6-dimethyltyrosine, N-methyl-D alanine and alpha-alkenyl-beta-amino acid and a synthesis method thereof. The endomorphin analogue is obtained by substituting the first position amino acid of endomorphin (EM1 and EM2) with tyrosine or 2, 6-dimethyltyrosine, substituting the second position amino acid with N-methyl-D alanine, and substituting the fourth position amino acid respectively with phenyl or 2-furyl replaced alpha-alkenyl-beta-amino acid, and is named as MEL-N16 series. Radioligand receptor binding experiment, isolated organ bioassay, in-vitro enzymolysis stability and warm bath tail flick analgesic experiment results show that the endomorphin analogue synthesized by the method provided by the invention has higher affinity than an endomorphine matrix, high enzymolysis stability and high analgesic activity, and has very good clinical application value in preparation of analgesic drugs.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a class of endomorphin (including endomorphin-1 and endomorphin-2) analogues modified by multi-site combinations and a synthesis method thereof, in particular to a tyrosine or 2 , 6-dimethyltyrosine, N-methyl-D-alanine and unnatural α-enyl-β-amino acid co-modified endomorphin analogue and its synthesis method, the present invention also relates to the Application of endomorphin analogs in the preparation of analgesic drugs. Background technique [0002] With the continuous increase of people's life and work pressure in modern society and the arrival of the elderly society, the scope of pain continues to expand. How to treat it with drugs has become a major public health issue. Opioids have been used in the treatment of pain for thousands of years. They mainly play a physiological role by binding to a large number of three classic opioid receptors distributed in the central nervous sys...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/02C07K1/02C07K1/06A61K38/07A61P25/04
CPCA61K38/00C07K5/0202
Inventor 王锐王媛刘鑫赵龙
Owner LANZHOU UNIVERSITY
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