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Preparation method for long-acting compound

A compound and compound structural formula technology, applied in the preparation of organic compounds, chemical instruments and methods, medical preparations containing active ingredients, etc., can solve problems such as limiting the long-term effect of depression, and achieve the effect of long drug effect time

Active Publication Date: 2019-12-06
PEKING UNIV SHENZHEN GRADUATE SCHOOL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] We found in animal experiments that (2R,6R; 2S,6S)-hydroxynorketamine (HNK) does not last long after administration, and loses its efficacy within 1 week, which seriously limits the treatment Desired long-term effect in depression

Method used

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  • Preparation method for long-acting compound
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  • Preparation method for long-acting compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Embodiment 1: compound preparation method

[0097]

[0098] Step 1: Starting from o-trifluoromethylbenzonitrile, according to the classic ketamine drug synthesis method Calvin Stevens method (preparation route as shown above) to obtain compound D 1 ;

[0099] Step 2: compound D 1 (2.57g, 10mmol) was added into 60ml THF, triethylamine (2.7mL, 20mmol) and Boc 2 O (3.32g, 15mmol), reflux 6h, cooling, spin dry, cross silica gel column to obtain compound E 1 3.25 g, 91% yield. 1 H NMR (300MHz, CDCl 3 ): δ7.80(d, J=8.1Hz, 1H), 7.66(d, J=7.8Hz, 1H), 7.49(t, J=7.5Hz, 1H), 7.22(t, J=7.5Hz, 1H ),5.76(s, 1H),4.30(s,1H),3.46-3.42(m,1H),2.45–2.36(m,1H),2.35-2.22(m,1H),1.76– 1.60(m,6H ),1.21(s,9H). 13 C NMR (75MHz, CDCl 3 ): δ208.9, 151.7, 149.0, 148.6, 136.1, 133.8, 132.6, 130.5, 129.0, 128.1, 128.0, 127.9, 127.8, 121.8, 121.7, 88.9, 80.8, 73.7, 40.0, 29.4, 28.2, 3

[0100] Step 3: Compound E 1 (2.14g, 6mmol) was added to dry 50ml THF, under argon protection, cooled to ...

Embodiment 2

[0103] Embodiment 2: activity test method:

[0104] 1. Forced swimming experiment

[0105] Transfer mice to the laboratory 1 h before the forced swim test (FST). Tests were performed under normal lighting conditions and monitored by a digital video camera. During the test, the mice were individually placed in transparent glass cylinders (28.5 cm high, 14 cm in diameter) containing 20 cm of water (23±1°C). On the first day, mice were trained for 6 min before being removed from the cylinder. On the second day, the mice were administered solvent (physiological saline) control group, HNK, CF3, and then tested their immobility time after 1 hour and 7 days, wherein the immobility time refers to passive floating without other actions. During the last 4 min of the entire 6-min swim test, immobility time was recorded by the Nodus system's EthoVision XT (Noldus, Netherlands) (Castagné et al., 2011, Hajmirzaian et al., 2014, Porsolt et al., 1977). After every two to three trials, the...

Embodiment 3

[0118] Embodiment 3: experimental result

[0119] 1. Depression-like behavior test results in mice:

[0120] Such as figure 1 Shown:

[0121] Depression-like behaviors were measured by the forced swim test. Mice received 10 mg of HNK, CF3 by intragastric administration, and immobility time was measured after 1 hour and 7 days. Percentage of immobility time is expressed as mean ± SEM *p<0.05, **p<0.0 compared to preactivity. N=8 per group Saline: saline mice; HNK: 2R,6R-hydroxynorchloramine-treated mice; CF3, CF3-treated mice.

[0122] 2. Differential protein analysis:

[0123] Such as figure 2 Shown:

[0124]A, with 0.833>Abundance Ratio>1.2 as the critical point, a Ratio value higher than 1.2 is defined as an up-regulated protein, and a Ratio value lower than 0.833 is defined as a down-regulated protein. Compared with the control group, there were 101 differentially expressed proteins in the CF3 treatment group, of which 39 differentially expressed proteins were co-...

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PUM

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Abstract

The invention provides a preparation method for a compound with a long-acting treatment effect. The compound can be used for preparing medicines having anti-depression, anesthetic or analgesic effectsor capable of improving cognitive functions, protecting the lungs, treating amyotrophic lateral sclerosis or treating complex regional pain syndrome.

Description

technical field [0001] The application relates to the field of medicine, in particular to a method for preparing a compound for treating depression, neurological and chronic pain, including complex regional pain syndrome (CRPS). 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 analgesia made it once extremel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C225/20C07C221/00A61K31/133A61P23/00A61P29/00A61P25/28A61P11/00A61P25/24A61P21/00A61P25/16A61P25/04
CPCA61P11/00A61P21/00A61P23/00A61P25/04A61P25/16A61P25/24A61P25/28A61P29/00C07C225/20C07C2601/14
Inventor 周强叶涛李书鹏
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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