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Phthalazine isoxazole alkoxy derivative, preparation method, pharmaceutical composition and uses thereof

An alkoxy and alkyl technology, which can be used in drug combinations, antipyretics, pharmaceutical formulations, etc., and can solve the problem of single inverse agonist structure.

Active Publication Date: 2019-09-20
SHANGHAI SIMR BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is that existing α5-GABA A The structure of the inverse agonist is too single, therefore, the present invention provides phthalazine isoxazolidinyloxy derivatives, its preparation method, pharmaceutical composition and application, and this type of compound is effective to α5-GABA A better inverse agonism

Method used

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  • Phthalazine isoxazole alkoxy derivative, preparation method, pharmaceutical composition and uses thereof
  • Phthalazine isoxazole alkoxy derivative, preparation method, pharmaceutical composition and uses thereof
  • Phthalazine isoxazole alkoxy derivative, preparation method, pharmaceutical composition and uses thereof

Examples

Experimental program
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Effect test

preparation example 1

[0483]

[0484] 3-(6-Chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-5-(methoxymethyl)isoxazole (B-2)

[0485] Mix B-1 (0.8 g, 4 mmol) (CAS: 4752-10-7) and A-1 (0.75 g CAS: 625120-12-9) in DMF (10 mL), and stir at 90° C. for 1 hour. TLC showed that the starting material was completely reacted, and the mixture was cooled to room temperature and poured into ice water (100 mL). The resulting precipitate was collected by filtration, washed with water three times, and dried to obtain product B-2 (1 g crude) as a pale yellow solid.

preparation example 2

[0487] 6-[3-(5-Methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl ]-Nicotinic acid methyl ester (B-3)

[0488]Mix B-2 (1g crude), A-2 (CAS: 56026-36-9) (0.53g, 3.2mmol) and cesium carbonate (2.1g, 6.4mmol) in DMF (20mL), stir at room temperature for 16 Hour. TLC showed that the reaction of the starting material was complete, and the mixture was poured into ice water (200 mL). The resulting precipitate was collected by filtration, washed with water three times, and dried to obtain the light brown solid product B-3 (0.93 gcrude).

Embodiment 1

[0490] 6-[3-(5-Methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl ]-Niacin (01)

[0491] Lithium hydroxide (4.96g, 95.29mmol) was dissolved in 60ml of water, then added to a suspension of B-3 (8.5g, 19.06mmol) in methanol (150mL), and stirred for 3 hours. The reaction solution was poured into water, the pH was adjusted to 4, and a yellow solid was obtained by suction filtration, which was then slurried with ethanol and then with methyl tert-butyl ether, and dried by an oil pump to obtain a light yellow powder (5.3 g, 64%). 1 H NMR (400MHz, DMSO-d 6 ):δ13.42(s,1H),9.10(s,1H),8.58(d,J=8.0Hz,1H),8.38(d,J=8.4Hz,1H),8.34-8.32(m,1H) ,8.15-8.11(m,1H),8.00-7.98(m,1H),7.87(d,J=8.0Hz,1H),7.15(s,1H),5.80(s,2H),4.71(s,2H ), 3.39(s,3H).LCMS: Rt=3.059min, [M+H] + =432.

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Abstract

The present invention discloses a phthalazine isoxazole alkoxy derivative, a preparation method, a pharmaceutical composition and uses thereof, and provides a compound represented by a formula I, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a pharmaceutically acceptable salt or a prodrug thereof. According to the present invention, the compound has good inverse agonistic effect on alpga5-GABAA.

Description

technical field [0001] The present invention relates to α5-GABA A Phthalazine isoxazolidinyloxy derivatives with receptor regulating function, their preparation method, pharmaceutical composition and their application as medicine. Background technique [0002] γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system. There are two types of GABA receptors in nature, one is GABA A Receptors, which are members of the ligand-gated ion channel superfamily, and the other is GABA B Receptors, which are members of the G protein-coupled receptor superfamily. GABA in mammals A Receptor subunits have been found to include α1-6, β1-4, γ1-3, δ, ε, θ and ρ1-2 subunits, among which the α subunit, β subunit and γ subunit pair form a complete functional GABA A receptor is essential, and the alpha subunit p-benzodiazepine and GABA A Receptor binding is critical. [0003] GABA with α5 A receptor (α5-GABA A receptor) in the mammalia...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5025A61P25/28A61P21/00A61P25/30A61P25/00A61P25/04A61P29/00A61P25/06
CPCC07D487/04A61P25/28A61P21/00A61P25/30A61P25/00A61P25/04A61P29/00A61P25/06C07D519/00
Inventor 王非吴金华金赟孙勇李帅
Owner SHANGHAI SIMR BIOTECHNOLOGY CO LTD
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