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A class of gabab receptor negative allosteric modulator and its medical application

A technology for receptors and uses, applied in the field of ligand molecules for γ-aminobutyric acid B-type receptors, which can solve the problems of immaturity and lack of GABA negative allosteric regulators

Inactive Publication Date: 2016-09-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, currently the GABA B The study of the negative allosteric regulation function of the receptor is immature, so far there is no GABA B Reports of Negative Allosteric Modulators of Receptors

Method used

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  • A class of gabab receptor negative allosteric modulator and its medical application
  • A class of gabab receptor negative allosteric modulator and its medical application
  • A class of gabab receptor negative allosteric modulator and its medical application

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0067] Preparation Example 1——Preparation of Compound D31

[0068]

[0069] Raw material aldehyde D1 (100mg, 0.427mmol, synthetic reference Chinese Journal of Medicinal Chemistry 2005,15,4) and Ph 3 After mixing P=CH-CHO (156mg, 0.512mmol, purchased from Bailingwei Reagent Company), add toluene (2ml), N 2 Under protection, heat at 100°C overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and subjected to silica gel column chromatography (PE / EA=40 / 1-10 / 1), to obtain D31 (19.2 mg, 17%) as a light reddish-brown solid. 1 H NMR (CDCl 3 ,300MHz):δ9.64(d,J=8.1Hz,1H),7.43(d,J=15.6Hz,1H),7.41(s,2H),6.62(dd,J=7.5Hz,15.6Hz,1H ),5.63(s,1H),1.46(s,18H).

preparation Embodiment 2

[0070] Preparation Example 2——Preparation of Compounds D73 and D60

[0071]

[0072] Preparation of compound D72

[0073] Raw materials aldehyde D1 (1.17g, 5.0mmol), triethyl orthoformate (4.1g, 38.6mmol), NH 4 Cl (0.05g, 0.935mmol) was mixed with MeOH (3ml) and heated to reflux for 3.5h. The reaction solution was gradually cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in DCM (10ml), diluted with PE60-90°C (20ml), a yellow solid precipitated, distilled at atmospheric pressure until the distillate was 60°C, and cooled to room temperature. The raw material was removed by filtration, and the filtrate was concentrated to obtain D72 (0.647 g, 46%) as a yellow solid. 1 H NMR (CDCl 3 ,300MHz): δ7.22(s,2H),5.25(s,1H),5.22(s,1H),3.35(s,6H),1.44(s,18H).

[0074] Preparation of compound E25

[0075] TMSCl (2.049g, 18.9mmol), DMAP (0.089g, 0.727mmol), and ethyl pyruvate (1.690g, 14.55mmol) were successively added to redistille...

preparation Embodiment 3

[0080]Preparation Example 3——Preparation of Compound D51

[0081]

[0082] Preparation of Compound D38

[0083] Raw material aldehyde D1 (0.234g, 1.00mmol) and malonic acid (0.310g, 3.0mmol) were mixed, under N2, redistilled pyridine (0.85ml) and piperidine (0.03ml) were added, and heated at 100°C for 1.5h. The reaction solution was poured into a mixture of 12N HCl (0.5ml) and ice water (0.8ml), stirred for 1h, and a large amount of orange solids precipitated out. Filter and wash the filter cake with water. After the filter cake was dissolved in DCM, PE was added at 60-90°C, and distilled at atmospheric pressure until the distillate was 60°C, and a white solid was precipitated. Cool to room temperature, filter, and wash the filter cake with PE to obtain milky white solid D38 (196 mg, 71%). 1H NMR (CDCl3, 300MHz): δ7.75(d, J=15.6Hz, 1H), 7.40(s, 2H), 6.31(d, J=15.6Hz, 1H), 5.56(s, 1H), 1.46( s,18H).

[0084] Preparation of Compound D53

[0085] D38 (507mg, 1.83mmol) wa...

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Abstract

The present invention relates to the field of pharmaceutical chemistry. In particular, the present invention relates to a γ-aminobutyric acid type-B receptor (Gamma Aminobutyric Acid B Receptor, referred to as a GABABR or GABAB receptor for short) ligand molecule and a medicinal use thereof, wherein the ligand molecule has the structure of formula I. The ligand molecule which the present invention relates to is a GABAB receptor negative allosteric modulator, can non-competitively inhibit GABAB receptor agonist-induced activation of the receptor, and can be used to prepare drugs for the treatment of GABAB receptor hyperexcitability-related diseases, wherein the diseases comprise epilepsy, anxiety, depression or low cognitive ability caused by nerve damage, and so on.

Description

technical field [0001] The invention relates to a class of γ-aminobutyric acid B-type receptors (Gamma Aminobutyric Acid B Receptor, referred to as GABA B R or GABA B receptor) ligand molecules. The ligand molecule involved in the present invention has GABA B Negative allosteric modulation of the receptor, which can non-competitively inhibit GABA B Activation of this receptor caused by agonists of the receptor can be used for GABA B Treatment of related diseases caused by excessive receptor excitability, such as epilepsy, anxiety, depression or cognitive impairment caused by nerve damage. Background technique [0002] γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system. A receptor, GABA C receptor and metabolite of GABA B It exerts physiological functions through receptors (Trends in neurosciences 2001, 24, 277-282). GABA B Receptors mainly exist in the pre-synaptic and post-synaptic parts of neurons, mediat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/245C07C59/90C07C69/738C07C235/80C07C47/27C07D495/04A61K31/12A61K31/192A61K31/216A61K31/165A61K31/11A61K31/4188A61P25/08A61P25/22A61P25/24A61P25/28
CPCC07C47/27C07C49/245C07C59/90C07C69/738C07C235/80C07D495/04A61P25/08A61P25/22A61P25/24A61P25/28C07C235/78
Inventor 南发俊刘剑峰陈林海孙兵
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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