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7alpha-methyl fused ring morphine derivative as well as preparation method and application thereof

A technology of fused ring and morphine, applied in the field of 7α-methyl fused ring morphine derivatives and its preparation

Pending Publication Date: 2022-03-18
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported in the literature that κ receptor ligands have opioid drugs, which are the most widely used narcotic analgesic drugs in clinical practice. Opioid μ receptor agonists represented by morphine and codeine have obvious respiratory depression, Adverse reactions such as addiction
In contrast, selective opioid κ receptor agonists also have analgesic activity, but there are no problems such as tolerance and addiction of μ receptor agonists, and they do not cause side effects such as respiratory depression and constipation. κ receptor agonists can induce hallucinations, sedation, restlessness and other central side effects, which limit the development and application of this type of compounds to a certain extent

Method used

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  • 7alpha-methyl fused ring morphine derivative as well as preparation method and application thereof
  • 7alpha-methyl fused ring morphine derivative as well as preparation method and application thereof
  • 7alpha-methyl fused ring morphine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] N-cyclopropylmethyl-7α-methyl-7β-hydroxymethyl-6α,14α-endo-ethylene-tetrahydronorthebaine

[0032]

[0033] Reaction route:

[0034]

[0035] Reaction conditions: (a) DIAD / acetonitrile, reflux, 4h; pyridine hydrochloride, methanol, room temperature, 2 days; (b) cyclopropanoyl chloride, triethylamine, dichloromethane, room temperature, 12h; (c) formaldehyde acrolein, lithium tetrafluoroborate, room temperature, 28h; (d) hydrogen, palladium carbon, ethanol, room temperature, 8h; (e) lithium aluminum hydride, tetrahydrofuran, room temperature, 2h.

[0036] Reaction steps:

[0037] a) Add thebaine (1g, 3.2mmol, 1eq) into a 50mL three-neck flask, then add anhydrous acetonitrile (10mL) to dissolve it, replace it with argon three times, and slowly drop it into the above solution using a dropping funnel Diisopropyl azodicarboxylate (0.68mL, 3.5mmol, 1.1eq) was added, and after the dropwise addition, the mixture was refluxed for 4h and cooled to room temperature. The solv...

Embodiment 2

[0043] N-Cyclopropylmethyl-7α-methyl-7β-aldehyde-6α,14α-endo-ethylene-tetrahydronorthebaine

[0044]

[0045] synthetic route:

[0046]

[0047] Reaction conditions: (f) oxalyl chloride, dimethyl sulfoxide, dichloromethane, triethylamine, -78°C to room temperature, 2h.

[0048] Reaction steps:

[0049] f) Add oxalyl chloride (0.06mL, 0.74mmol, 1.25eq) and anhydrous dichloromethane (3mL) into an eggplant-shaped flask, cool to -78°C, add anhydrous dimethyl sulfoxide (0.11mL, 1.53 mmol, 2.6eq) was dissolved in anhydrous dichloromethane (2mL), stirred for 5min; to the above mixture was added a solution of compound 6 (250mg, 0.59mmol, 1eq) dissolved in anhydrous dichloromethane (1mL), Stir for 20min; then add triethylamine (0.41mL, 2.94mmol, 5eq), remove the -78°C dry ice-acetone bath, and react at room temperature for 2h. The reaction solution was washed successively with saturated ammonium chloride solution (5mL x 3) and saturated sodium bicarbonate solution (5mL x 3), t...

Embodiment 3

[0051] (20R)-N-Cyclopropylmethyl-7α-methyl-7β-(1-phenyl-hydroxymethyl)-6α,14α-endo-ethylene-tetrahydronorthebaine

[0052]

[0053] synthetic route:

[0054]

[0055] Reaction conditions: (g) halides, n-butyllithium, tetrahydrofuran, -78°C, 0.25h.

[0056] Reaction steps:

[0057] g) Add bromobenzene (188mg, 1.2mmol, 10eq) and anhydrous tetrahydrofuran (2.5mL) into a Schlenk tube, cool to -78°C, replace argon three times, and add dropwise to the above reaction solution under the protection of argon Add n-butyllithium (2.4M in n-hexane, 0.5mL, 1.2mmol, 10eq), stir for 10min, then slowly inject compound 7 (50mg, 0.12mmol, 1eq) into anhydrous tetrahydrofuran solution (1mL), keep Reaction at -78°C for 0.25h. Remove the dry ice-acetone bath, quench with saturated ammonium chloride solution, add ethyl acetate (10mL x 3) and water (10mL) for extraction, combine the organic phases, wash with saturated brine (15mL), and add anhydrous sodium sulfate After drying and filtering,...

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Abstract

The invention belongs to the field of pharmacy, and relates to a 7alpha-methyl fused ring morphine compound with a formula I and a formula II as well as a preparation method and an application of the 7alpha-methyl fused ring morphine compound. The compounds are prepared through a reaction of thebaine and a substituted styrene reagent and through a series of conversion methods, have opioid receptor binding activity, and multiple compounds including SLL-604, SLL-627 and SLL-631 are selective kappa receptor ligands or mu / kappa dual ligands. The method can be applied to research and development in the treatment fields of pain easing, depression resisting, opioid drug addiction withdrawal, itching relieving and the like.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to 7α-methyl condensed ring morphine derivatives and their preparation method and application. Background technique [0002] Opioid receptors are widely involved in various physiological and pathological activities such as pain modulation and addiction, and are mainly divided into μ, δ, κ and ORL1 receptors. Among them, μ receptors mainly mediate analgesia, apathy, euphoria, heart rate slowing, respiratory depression, intestinal motility inhibition and addiction, and morphine is its classic agonist. The distribution of δ receptors in the brain is related to motor integration, olfaction and recognition functions, and has a regulatory effect on μ receptors, participating in the formation of tolerance dependence. κ receptors are widely distributed in areas of the brain involved in mediating reward, emotion, and cognitive functions, and are also expressed in peripheral tissues, nerv...

Claims

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Application Information

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IPC IPC(8): C07D491/08A61P25/04A61P25/24A61P25/36A61P17/04A61P29/00
CPCC07D491/08A61P25/04A61P25/24A61P25/36A61P17/04A61P29/00Y02A50/30
Inventor 邵黎明刘景根李炜王瑜珺孔令辉叶荣荣孙惠姣柴景蕊
Owner FUDAN UNIV
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