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Novel GABA (gamma-aminobutyric acid) receptor modulator and application thereof

A pharmacy and compound technology, applied in the field of new regulators, can solve the problems of strong lipophilicity and low oral bioavailability, and achieve good biological activity and reduce the effect of metabolic rate.

Inactive Publication Date: 2019-03-22
SUZHOU VINTAGENCE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oral bioavailability is low because these drugs are highly lipophilic and metabolized rapidly in the liver

Method used

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  • Novel GABA (gamma-aminobutyric acid) receptor modulator and application thereof
  • Novel GABA (gamma-aminobutyric acid) receptor modulator and application thereof
  • Novel GABA (gamma-aminobutyric acid) receptor modulator and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1. Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopentyl[a]phenanthrene -17-position)-3-(pyridine-2-position) propyl-1-one (1-1)

[0055]

[0056] Compound 1-1 was prepared according to the following process:

[0057]

[0058] Dissolve commercially available compound A (100mg, 0.31mol) in ethanol (5ml) and water (2ml), add pyridine-2-carboxaldehyde (68mg, 0.62mmol) and sodium hydroxide (18mg, 0.46mmol) successively, room temperature Stirred for 15 hours, concentrated and extracted twice with EA (30mlx2), washed once with brine (30ml), dried over anhydrous sodium sulfate, concentrated and silica gel column chromatography to obtain 72mg of white foamy solid B, yield: 57%. 1 H-NMR (400MHz, CDCl 3 )δ: 8.67(d, 1H, J=3.2Hz), 7.77-7.73(m, 1H), 7.54-7.46(m, 2H), 7.33-7.28(m, 2H), 2.92(t, 1H, J= 8.4Hz),2.37-2.29(m,1H),2.06-1.99(m,3H),1.71-1.56(m,14H),1.46-1.33(m,8H),1.25-1.16(m,10H),1.10 -1.00(m,3H),0.64(s,3H); ESI...

Embodiment 2

[0064] Example 2. Preparation of 1-(3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopentyl[ a] phenanthrene-17-position)-3-oxo)-1H-pyrazole-4-carbonitrile (2-1)

[0065]

[0066] Compound 2-1 was prepared according to the following process:

[0067]

[0068] Compound A (50mg, 0.15mmol) was dissolved in DME (20ml), paraformaldehyde (9mg, 0.29mmol) and dimethylamine hydrochloride (21mg, 0.26mmol) were added successively, and the mixture was refluxed for 48 hours. Adjust the pH to 13-14 with 2M NaOH aqueous solution, extract three times with EA (30mlx3), dry over anhydrous sodium sulfate, concentrate and column chromatography to obtain 19 mg of yellow oily liquid C, yield: 32%. ESI-MS m / z 376.2(M+H) + .

[0069] Dissolve compound C (130mg, 0.34mmol) in THF (10ml), cool in an ice bath to 0-5°C, add iodomethane (246mg, 1.73mmol), continue the reaction at 0-5°C for 1 hour, and Stir overnight. Concentrate to dryness to obtain 145 mg of yellow...

Embodiment 3

[0075] Example 3. Activity Test

[0076] Compounds were tested for modulatory activity using an artificial patch clamp method using ex vivo electrophysiology. Using stable expression of human GABA A HEK293T cell line of the receptor (subunit composition: α1β2γ2). Methods as below:

[0077] with GABA A The receptor subunit α1β2γ2 was stably transfected into HEK293T cells, the cells were passaged, and then inoculated into sterile culture dishes. Confluent populations of cells are electrocoupled and cells are cultured at a density capable of recording single cells. Total cell currents were measured using a HEKA EPC-10 amplifier and using PatchMaster software. Cells were voltage clamped at -80 mV clamping voltage. After pre-incubation with increasing concentrations of the test article, GABA receptors were stimulated with 2uM GABA. The pre-incubation time is 30s, the stimulation time is 2s, and the dilution concentration of the test product is 0.01, 0.1, 1, 10uM.

[0078] D...

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PUM

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Abstract

The invention relates to a neurosteroids type novel GABA (gamma-aminobutyric acid) receptor modulator, pharmaceutically acceptable salt or ester, and application in treating related CNS diseases.The compound provided by the invention has favorable biological activity and an excellent PK property, and the novel compound has a large potential to be used as an CNS disease treatment drug for oraladministration.

Description

technical field [0001] The present invention specifically relates to a kind of GABA A Novel modulators of receptors and uses thereof. Background technique [0002] GABA (γ-aminobutyric acid) is the main neurotransmitter in the central nervous system. GABA, a neurotransmitter, can mediate the downstream ion channel GABA A and GABA C receptor and metabotropic GABA B Receptors, increase the flow of ions inside and outside the nerve cell membrane, and exert physiological functions. Although GABA produces an inhibitory effect on the release of neurotransmitters, GABA itself is not an inhibitory but an stimulatory transmitter because GABA activates the opening of GABA receptors. [0003] Most literatures believe that schizophrenia, epilepsy, mood disorders and autism are all related to abnormal GABA receptors. GABA A Receptors can mediate sedative-hypnotic, anti-anxiety and muscle relaxation effects, and can affect diet, fertility, circadian rhythms, etc.; GABA B The recep...

Claims

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Application Information

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IPC IPC(8): C07J43/00C07J9/00C07J33/00C07J17/00A61K31/58A61P25/08A61P25/24A61P25/18A61P25/20A61P25/22A61P25/00A61P21/02
CPCA61P21/02A61P25/00A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24C07J9/00C07J17/00C07J33/002C07J43/003
Inventor 李本
Owner SUZHOU VINTAGENCE PHARM CO LTD
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