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Endomorphin-1 analogue modified by alpha-alkenyl-beta-amino acid and composition and application thereof

An endomorphin and amino acid technology, applied in the field of synthetic methods, can solve the problems such as inability to obtain better effects, and achieve the effects of good pharmacological activity, improved bioavailability, and increased resistance to enzymatic hydrolysis

Active Publication Date: 2012-07-11
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] studies have shown that using unnatural amino acids, especially β-amino acids to modify endomorphin-1 can have a greater impact on its overall affinity, and the 2-position β- The replacement of Pro analogs can improve its affinity and physiological activity, but the replacement of other sites can not get better results(Bioorg. Med. Chem. Lett. 2009,19,4115;J. Med. Chem. 2008, 51, 4270; Eur. J. Pharmacol. 2003, 469, 89)

Method used

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  • Endomorphin-1 analogue modified by alpha-alkenyl-beta-amino acid and composition and application thereof
  • Endomorphin-1 analogue modified by alpha-alkenyl-beta-amino acid and composition and application thereof
  • Endomorphin-1 analogue modified by alpha-alkenyl-beta-amino acid and composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Embodiment one, [Amp 4 ] Synthesis of EM-1

[0101] 1. Synthesis of 3-amino-2-methenyl-3-phenylpropionic acid

[0102] (1) Dimethyl 2-(N-acylpyrrole)ethylphosphonate 1.5 moles and 1-(3,5-bistrifluoromethyl)-3-((1S,2S)-2(1-pyrrole Dissolve 0.2 moles of alkane)cyclohexyl)thiourea catalyst in toluene, stir at 0°C, add 1 mole of N-tert-butoxycarbonylbenzenesulfonylphenylimine and 0.8 liter of potassium carbonate solution, and react at 0°C for 24 Hour, after TLC detection reaction finishes, silica gel column chromatography separates and purifies (PE:EA=1:1, R f =0.4), to obtain colorless oily product (2-(dimethoxyphosphoryl)-3-carbonyl-1-phenyl-3-(1-pyrrole) propyl) tert-butyl carbamate, yield 81% .

[0103](2) Dissolve 0.8 moles of the compound (2-(dimethoxyphosphoryl)-3-carbonyl-1-phenyl-3-(1-pyrrole) propyl) tert-butyl carbamate in anhydrous tetrahydrofuran at minus Add 1.76 moles of sodium methoxide solution dissolved in methanol at 18°C, add 4 moles of paraformald...

Embodiment 2

[0126] Embodiment two, [Amf 4 ] Preparation of EM-1

[0127] 1. Synthesis of 3-amino-2-methenyl-3-(2-furan)propionic acid

[0128] (1) Dimethyl 2-(N-acylpyrrole)ethylphosphonate 1.5 moles and 1-(3,5-bistrifluoromethyl)-3-((1S,2S)-2(1-pyrrole Dissolve 0.2 moles of alkane) cyclohexyl) thiourea catalyst in toluene, stir at 0°C, add 1 mole of N-tert-butoxycarbonylbenzenesulfonyl 2-furimide and 0.8 liter of potassium carbonate solution, and react at 0°C After 24 hours, after the reaction was detected by thin plate chromatography, silica gel column chromatography was used to separate and purify (PE:EA=1:1, R f =0.4), a colorless oily product (tert-butyl 2-(dimethoxyphosphoryl)-3-carbonyl-1-furan-3-(1-pyrrole)propyl)carbamate was obtained with a yield of 85%.

[0129] (2) The compound (2-(dimethoxyphosphoryl)-3-carbonyl-1-furan-3-(1-pyrrole)propyl) tert-butyl carbamate 0.8 mol dissolved in anhydrous tetrahydrofuran, minus 18°C Add 1.76 moles of sodium methoxide solution dissolve...

Embodiment 3

[0153] Embodiment three, [Amc 4 Synthesis of ]EM-1

[0154] 1. Synthesis of 3-amino-2-methenyl-3-(3-chlorophenyl)propionic acid:

[0155] (1) Dimethyl 2-(N-acylpyrrole)ethylphosphonate 1.5 moles and 1-(3,5-bistrifluoromethyl)-3-((1S,2S)-2(1-pyrrole Dissolve 0.2 moles of alkane)cyclohexyl)thiourea catalyst in toluene, stir at 0°C, add 1 mole of N-tert-butoxycarbonylbenzenesulfonyl 3-chlorophenylimine and 0.8 liters of potassium carbonate solution, at 0°C The reaction was carried out for 24 hours, and after the reaction was detected by thin plate chromatography, silica gel column chromatography was used for separation and purification (PE:EA=1:1, R f =0.4), a colorless oily product—(2-(dimethoxyphosphoryl)-3-carbonyl-1-(3-chlorophenyl)-3-(1-pyrrole) propyl) carbamic acid tert Butyl ester, yield 91%.

[0156] (2) The compound (2-(dimethoxyphosphoryl)-3-carbonyl-1-(3-chlorophenyl)-3-(1-pyrrole)propyl) tert-butyl carbamate 0.8 mole dissolved in Water tetrahydrofuran, add 1.76...

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Abstract

The invention provides endomorphin-1 modified by unnatural alpha-alkenyl-beta-amino acid, which is characterized in that fourth amino acid of the endomorphin-1 is respectively formed by replacing the alpha-alkenyl-beta-amino acid replaced by phenyl, 2-furan, 3-chlorphenyl, 1, 3-dioxophenyl. Pharmacological activity identity is conducted on the endomorphin-1 modified by the unnatural alpha-alkenyl-beta-amino acid by radiation ligand receptor combination experiments, isolated organ biological assays, cAMP accumulation experiments, separation enzymolysis stability and analgesic tests with water baths. As the results show, the novel analogue has the advantages of high affinity, high enzymolysis stability and high analgesic activity compared with endomorphin-1, thereby having high application value in preparation of polypeptide analgesic medicine.

Description

Technical field [0001] The present invention belongs to the field of biomedicine, involving one type of internal morphin-1 (EM-1) analog and synthetic method that uses non-natural amino acid modification, especially involved a alpha-olene-β-amino acid modificationThe inner morphine -1 analog and its synthesis method, the present invention also involves the application of the internal morphine -1 analog in preparation of analgesic drugs. Background technique [0002] Oed analgesic drugs mainly play an analgesic effect through binding with μ opioid receptors.After the internal lids of the endogenous lumps of the μ opioid receptor in 1997 were discovered, scientists conducted extensive research on it.Studies have shown that inner morphin is combined with the μ opioid receptor with G protein, and participates in the regulation of many functions including pain, respiratory, cardiovascular, gastrointestinal, endocrine, behavior, etc.EssenceAmong them, the inner morphine-1 (Tyr-Pro-TRP-...

Claims

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Application Information

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IPC IPC(8): C07K5/037C07D307/54C07D317/60C07C229/34C07C227/20A61K38/07A61P25/04
Inventor 王锐王媛赵德鹏刘鑫邢燕红
Owner LANZHOU UNIVERSITY
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