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Application of long-acting low-addiction HNK derivative in preparation of medicines

A technology of drugs and compounds, applied in the field of drugs, can solve problems such as limiting the long-term effect of depression and adverse physical and mental effects of patients, and achieve the effect of long-term drug effect

Active Publication Date: 2021-03-19
SHENZHEN RUIJIAN BIOSCI TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] We found in experimental research that (2R,6R; 2S,6S)-hydroxynorketamine (HNK) does not last long after administration, and basically has no activity within 1 week, which severely limits the treatment Expected long-term effects 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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  • Application of long-acting low-addiction HNK derivative in preparation of medicines
  • Application of long-acting low-addiction HNK derivative in preparation of medicines
  • Application of long-acting low-addiction HNK derivative in preparation of medicines

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, and 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, the yield was 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 C NMR (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 s...

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, relates to application of a low-addiction HNK derivative in preparation of medicines, and in particular relates to application of the low-addiction HNKderivative in preparation of medicines for treating or preventing depression, including diseases such as complex regional pain syndrome (CRPS) and the like. The compound disclosed by the invention has a structure as shown in a formula I, and can be used for preparing medicines for preventing or treating depression, anesthesia, analgesia, cognitive function improvement, lung protection, amyotrophic lateral sclerosis or complex regional pain syndrome. Compared with the existing known HNK compounds, the compound provided by the invention has longer drug effect time, and the compound provided bythe invention basically does not generate addiction.

Description

technical field [0001] The invention relates to the field of medicines, in particular to the application of a low-addiction HNK derivative in the treatment or prevention of depression, including complex regional pain syndrome (CRPS) and other diseases. Background technique [0002] Ketamine is a representative of phencyclidine intravenous anesthesia commonly used in clinical practice, and 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 "separation anesthesia" and short-term definite analges...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/68A61K31/341A61P23/00A61P29/00A61P25/04A61P25/28A61P11/00A61P25/24A61P25/22A61P21/00A61P25/16
CPCA61P11/00A61P21/00A61P23/00A61P25/04A61P25/16A61P25/22A61P25/24A61P25/28A61P29/00C07D307/68
Inventor 李书鹏周强
Owner SHENZHEN RUIJIAN BIOSCI TECH LTD
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