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Endomorphin analogue and application thereof

A technology of endomorphin and analogues, applied in the field of endomorphin analogues and its application, can solve problems such as withdrawal symptoms, respiratory depression, addiction, etc., achieve improved imbalance, good anti-enzymolysis effect, and improve side effects Effect

Active Publication Date: 2020-09-11
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Acute or excessive administration of opioids such as morphine can cause respiratory depression, nausea, vomiting, constipation and other gastrointestinal side effects. Long-term administration can lead to side effects such as tolerance and addiction. broken symptoms

Method used

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  • Endomorphin analogue and application thereof
  • Endomorphin analogue and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthesis of embodiment 1 anti-N-benzyloxycarbonyl-4-hydroxyl-proline (1)

[0025] 4-Hydroxyproline (10g, 76.4mmol) was dissolved in saturated NaHCO 3 (376mL) and THF (376mL), under ice-cooling conditions, dropwise add benzyl chloroformate (15.4g, 91.6mmol) THF (20mL) solution, remove the ice-bath, and stir overnight. After the reaction is complete, adjust the pH to 3 with 3mol / L hydrochloric acid, extract with EA, collect the organic layer, anhydrous Na 2 SO 4 dry. Rotary evaporation gave 25 g of colorless oily liquid. It was directly used for the next reaction without purification.

Embodiment 2

[0026] Synthesis of embodiment 2 anti-N-benzyloxycarbonyl-4-hydroxyl-proline methyl ester (2)

[0027] Add SOCl to 300 mL of methanol solution under ice bath condition 2 (12.5mL, 164mmol), a small amount of methanol (15mL) dissolved compound 1 (25g, 94mmol), added to the above system, stirred for 10min, removed the ice bath, refluxed overnight. After the reaction stopped, spin dry. Silica gel column chromatography (PE:EA=3:1-1:1) gave 22.5 g of a colorless oily substance, with a yield of 85.7%.

Embodiment 3

[0028] Example 3 Synthesis of N-benzyloxycarbonyl-4-oxo-proline methyl ester (3)

[0029] Compound 2 (10g, 35.8mmol) was dissolved in dichloromethane (200mL), trichloroisocyanic acid (6.3g, 27.3mmol) was added in batches, and stirred for 15min; at 0°C, TEMPO (0.58g, 3.7mmol) was added in batches ), stirred for 2h. After the reaction is complete, use saturated NaHCO 3 , 10% citric acid, water, saturated NaCl washing, anhydrous Na 2 SO 4 dry. After rotary evaporation, the crude product was subjected to silica gel column chromatography (PE:EA=3:1-1:1) to obtain 7.45 g of light yellow oil with a yield of 75.1%. 1 H NMR (400MHz, CDCl 3 )δ7.35–7.32(m,5H),5.24–5.10(m,2H),4.87–4.81(m,1H),3.98–3.90(m,2H),3.76–3.62(m,3H),2.95– 2.89(m,1H),2.63–2.57(m,1H).

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Abstract

The invention discloses an endomorphin analogue and application thereof. The compound disclosed by the invention is a mu-opioid receptor antagonist, and can be used for treating opioid addiction abstinence symptoms, or is used for alleviating respiratory depression and gastrointestinal tract side effects caused by opioid medicines. In addition, the compound disclosed by the invention contains oxidation-resistant 2,6-dimethyl tyrosine (Dmt), and can be used for preventing and treating free-radical-related diseases, including neurodegenerative diseases, diabetic complications, stroke, myocardialinfarction, percutaneous coronary intervention, inflammation, glaucoma, cataract and the like.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a class of endomorphin analogs and applications thereof. Background technique [0002] Morphine, fentanyl, oxycodone, and pethidine are commonly used opioid analgesics in clinical practice, and morphine is the gold standard for analgesics. Morphine is mostly used for severe pain caused by trauma, surgery, burns, cancer, etc. It is also used for angina pectoris caused by myocardial infarction. Although other types of analgesic drugs have been developed, opioid drugs represented by morphine still have an irreplaceable position in the treatment of moderate and severe pain. [0003] Opioids such as morphine exert analgesic effects by acting on opioid receptors. Opioid receptors are widely present in the brain and gastrointestinal tract. Traditionally, opioid receptors can be divided into three types: μ, δ, and κ. Exogenous or endogenous opioids, when they bind to opioid recept...

Claims

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Application Information

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IPC IPC(8): C07K5/107A61K38/07A61P25/04A61P25/00A61P3/10A61P9/10A61P29/00A61P27/06A61P27/12
CPCC07K5/1016A61P25/04A61P25/00A61P3/10A61P9/10A61P29/00A61P27/06A61P27/12A61K38/00Y02A50/30
Inventor 秦亚娟施赛健厉廷有彼得W·席勒陈珍
Owner NANJING MEDICAL UNIV
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