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7Beta-methyl-tetralone derivative and preparation method and application thereof

A technology of methoxyphenyl and trifluoromethylphenyl, which is applied in the field of chemical pharmaceuticals and can solve problems such as analgesia, sedation, and respiratory depression addiction

Inactive Publication Date: 2019-08-13
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Central analgesics such as morphine and pethidine are all of the type of μ agonists, and most of them have side effects such as analgesia, sedation, respiratory depression and addiction

Method used

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  • 7Beta-methyl-tetralone derivative and preparation method and application thereof
  • 7Beta-methyl-tetralone derivative and preparation method and application thereof
  • 7Beta-methyl-tetralone derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1 can prepare the compound with general formula (I) by the same method, wherein,

[0027] 2 preparation

[0028] Under the protection of argon, add thebaine (500mg, 1.6mmol, 1eq) anhydrous acetonitrile 5mL and diisopropyl azodicarboxylate (0.34mL, 1.7mmol, 1.1eq) into the three-necked flask, and reflux for 4h , cooled to room temperature overnight. The reaction solution was spin-dried, the residue was dissolved in 5 mL of methanol, and pyridine hydrochloric acid (185 mg, 1.6 mmol, 1 eq) was added and stirred for two days. Suction filtration, wash the filter cake with methanol and ethyl acetate to obtain 215mg of white solid 1, yield 40%, melting point: 260.3°C (decomposition point);

[0029] 1H-NMR (400MHz, CDCl3) δ6.68(d, J=8.2Hz, 1H), 6.62(d, J=8.2Hz, 1H), 5.50(d, J=6.4Hz, 1H), 5.27(s, 1H), 5.03(d, J=6.4Hz, 1H), 3.85(s, 3H), 3.60(s, 3H), 3.17(ddd, Ja=17.6, Jb=13.8, Jc=4.2Hz, 3H), 2.93 (dd, Ja=13.7Hz, Jb=4.8 Hz, 1H), 2.07(td, Ja=12.5Hz, Jb=5.1Hz, 3H), 1....

Embodiment 2

[0067] Example 2 Radioactive Ligand Binding Experiment

[0068]The compounds used in the pharmacological binding screening were all in free base form. The experiment is divided into total binding tubes and non-specific binding tubes, and several sets of sample tubes are set up to add the compounds to be screened. Add 80uL of cell suspension expressing opioid κ, μ and δ receptors to the total binding tube, add [3H]U69593, [3H]DAMGO, [3H]DPDPE respectively to the three tubes (final concentration is 0.35nM) 10uL; Add U50488, DAMGO, and DPDPE to the corresponding non-specific tubes to make the final concentration 1uM; add 10ul of the same concentration of drugs to the sample tube (final concentration is 1uM), and adjust to a final volume of 100uL with 50mM Tris.HCl (pH 7.4). Incubate at 37°C for 30 min, then place in an ice bath to terminate the reaction. Suction filtration through GF / C (Whatman) glass fiber filter paper on the Millipore sample collector. Rinse three times with...

Embodiment 335

[0072] Example 3[ 35 S] GTPγS binding assay

[0073] Measuring protein concentration with Bradford Protein Concentration Assay Kit: Add standard protein BSA at concentrations of 0, 50, 100, 200, 250 μg / ml and samples to be tested to 96-well plates, add 20 μl to each well; add G250 to each well 200 μl of staining solution was placed at room temperature for 3-5 minutes, and the absorbance at A595 wavelength was measured with a microplate reader. The protein concentration was calculated from the standard curve.

[0074] Table 2

[0075]

[0076] The prepared membrane receptors were diluted with reaction buffer (R.B) to the desired concentration, and samples were added as shown in Table 2 (unit: μl). The reaction tube was incubated in a water bath at 27°C for 1 hour, filtered under reduced pressure with a glass fiber membrane and counted by liquid scintillation. Calculate according to the following formula:

[0077] [ 35 S] GTPγS binding rate=100×(cpm sample -cpm non-sp...

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Abstract

The invention belongs to the field of chemical pharmacy and relates to a 7beta-methyl-tetralone derivative shown in a general formula (I) and a preparation method thereof. According to the compound shown in the general formula (I), with thebaine as a raw material, through related conversion methods such as N-demethylation, N-acylation, a Diels-Alder reaction and reduction, oxidation and Grignard reactions, the compound is synthesized. The compound shown in the general formula (I) belongs to an opioid receptor ligand, a radioactive receptor ligand combination experiment is adopted, the affinityand selectivity of the ligand to three subtypes of an opioid receptor are measured, and a [35S]GTPgammaS combination experiment is adopted for measuring the excitement inhibitory activity of the ligand; it is proved through a result that the compound has the functions of alleviating pain, resisting depression, withdrawing opioid addiction, relieving itching and the like and can be applied to preparation of an opioid receptor treatment medicine and applied to clinical analgesia or depression resistance or opioid addiction withdrawal treatment or itching relieving treatment.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and relates to a 7β-methyl-neperidone derivative compound with general formula (I) and a preparation method thereof, and relates to the use of the derivative in the preparation of drugs for opioid receptor therapy. Background technique [0002] Studies have disclosed that opioid receptors are mainly divided into three receptor subtypes: μ, δ, and κ. Central analgesics such as morphine and pethidine are all of the type of μ agonists, and most of them have side effects such as analgesia, sedation, respiratory depression and addiction. Studies have shown that δ receptors are widely distributed in the central nervous system, which can regulate μ receptors and participate in the formation of tolerance dependence; κ receptors are widely expressed in the brain, and activating κ receptors can antagonize μ receptors. Function, blocking drug addiction, anxiety, diuretic, hallucinogenic and other effects. ...

Claims

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Application Information

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IPC IPC(8): C07D487/10A61K31/485A61P25/20A61P25/24A61P25/36A61P17/04A61P25/04
CPCA61P17/04A61P25/04A61P25/20A61P25/24A61P25/36C07D487/10
Inventor 李炜邵黎明孙惠姣刘景根王瑜珺徐学军孔令辉肖立吴海灏
Owner FUDAN UNIV
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