A long-acting and low-addiction hnk derivative and its preparation method

A drug and compound technology, applied in the field of long-acting and low-addiction HNK derivatives and their preparation, can solve the problems of limiting the long-acting effect of depression, adverse physical and mental effects of patients, etc.

Active Publication Date: 2021-10-08
SHENZHEN RUIJIAN BIOSCI TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In our experimental study, we found that (2R,6R; 2S,6S)-hydroxynorketamine (HNK) does not last long after administration, and basically has no activity within 1 week, which seriously limits the treatment Desired long-term effect in depression
At the same time, our research also found that the application of HNK will produce a certain degree of addiction, which will cause adverse effects on the patient's body and mind.

Method used

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  • A long-acting and low-addiction hnk derivative and its preparation method
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  • A long-acting and low-addiction hnk derivative and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: the synthesis of (2R,6R)-6-hydroxy demethyl ketamine (HNK)

[0088]

[0089] Step 1: In a two-neck bottle or a three-necked bottle, add 50 grams of magnesium powder, and slowly add a mixed solution of 119.2 grams of bromocyclopentane and THF dropwise after initiation. After the dropwise addition, reflux for 2-4 hours to obtain 1.6mol / L Cyclopentyl Grignard Reagent. Add 840 mg of CuBr to the mixture of THF and o-chlorobenzonitrile (50.0 g), and add cyclopentyl Grignard reagent (1.6 mol / L, 280 ml) dropwise under ice-bath conditions. Reflux for 1 hour after the dropwise addition, cool to room temperature, add 100ml of water, then add 200ml of 15% dilute sulfuric acid solution, stir overnight, spin dry THF, extract with EA, dry, and pass through a silica gel column to obtain compound A 2-chlorophenyl ring Amyl ketone 60g, yield 80%.

[0090] Step 2: According to the reported method (Bioorganic & Medicinal Chemistry 2013, 12, 5098), 20 g (96 mmol) of compo...

Embodiment 2

[0098] Embodiment 2: the synthesis of compound I6

[0099]

[0100] Compound G (170mg, 0.5mmol) was dissolved in 3mL dry THF, dry triethylamine (0.28mL, 2mmol) was added, then 3-furoyl chloride (130mg, 1mmol) was added under ice-bath conditions, and then within 1 hour Slowly rise to room temperature, stir overnight, then add sodium bicarbonate solution, extract with EA, spin the solvent and vacuum dry, pass through a silica gel column to obtain compound H 6 N-Boc-(2R,6R)-6-(3-furyl)formyloxydemethylketamine 173mg, yield 80%. 1 H NMR (400MHz, CDCl 3 ):8.11(br,1H),7.81-7.79(brs,1H),7.42-7.28(m,4H),6.67(brs,1H),6.63(m,1H),5.35-5.31(m,1H), 3.92-3.87(m,1H),2.39-2.33(m,1H),1.94-1.74(m,4H),1.30(brs,9H). 13 CNMR (100MHz, CDCl 3 ): 202.5, 168.5, 161.4, 153.3, 148.4, 143.8, 134.3, 133.7, 131.4, 131.1, 129.8, 126.3, 118.5, 109.1, 79.4, 73.5, 67.2, 38.5, 35.8, 28.2, 19.8.

[0101] Compound H 6 (170mg) was dissolved in 3mL of dry THF, gaseous HCl was introduced to saturation at r...

Embodiment 3

[0102] Embodiment 3: the synthesis of compound C and D

[0103]

[0104] Compounds C and D were prepared by the following preparation methods.

[0105]

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Abstract

The invention relates to the field of medicines, in particular to a long-acting and low-addiction HNK derivative for treating depression, including complex regional pain syndrome (CRPS), and a preparation method thereof. The compound of the present invention has the structure shown in formula I, and has the functions of antidepression, anesthesia, analgesia, improvement of cognitive function, lung protection, prevention or treatment of amyotrophic lateral sclerosis or prevention or treatment of complex regional pain syndrome. Compared with the existing known HNK compounds, the compound of the present invention has a longer drug effect time, and the compound of the present invention basically does not produce addiction.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a long-acting and low-addiction HNK derivative for treating depression, including complex regional pain syndrome (CRPS), and a preparation method thereof. Background technique [0002] Ketamine is a representative of phencyclidine intravenous anesthesia commonly used in clinical practice, and it is one of the anesthetics with rapid development in clinical and basic research in recent years. In clinical practice, it is often used to meet the anesthesia needs of pediatrics, obstetrics, perioperative period and patients with special diseases because of its characteristics of rapid induction, short action time, quick recovery, and less impact on the respiratory and circulatory systems. [0003] Ketamine was first synthesized in 1962, used in humans in 1965, and officially approved by the FDA for clinical use in 1970. Its typical "separated anesthesia" and short-acting exact analgesia made i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/68A61P23/00A61P29/00A61P25/28A61P11/00A61P25/24A61P25/22A61P21/00A61P25/16A61K31/341
CPCA61P11/00A61P21/00A61P23/00A61P25/16A61P25/22A61P25/24A61P25/28A61P29/00C07D307/68
Inventor 李书鹏周强
Owner SHENZHEN RUIJIAN BIOSCI TECH LTD
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