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Phthalazine derivatives, and preparation method, pharmaceutical composition and application thereof

A technology of compounds and hydrates, applied in the field of thallazine derivatives, can solve problems such as animal fear and anxiety

Active Publication Date: 2017-06-16
SHANGHAI SIMR BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Region-specific knockout of α5GABA in the brain A Receptor expression induces fear and anxiety behavior in animals
Therefore, previously disclosed α5GABA A Inverse agonists entering the brain will produce side effects of fear and anxiety, it is impossible to be directly used in the field of medicine, it must be modified

Method used

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  • Phthalazine derivatives, and preparation method, pharmaceutical composition and application thereof
  • Phthalazine derivatives, and preparation method, pharmaceutical composition and application thereof
  • Phthalazine derivatives, and preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0310] 6-((3-(5-Methylisoxazol-3-yl)-[1,2,4]triazol[3,4-a]phthalazine-6-oxy)methylene)-N - Morpholine Niacinamide (01)

[0311] Compound A4 (100 mg, 0.248 mmol), HOBt (68 mg, 0.496 mmol) and EDCI (95 mg, 0.496 mmol) were sequentially added to 5 mL of DMF, and stirred at room temperature for 10 minutes under argon protection. 4-Aminomorpholine (CAS: 4319-49-7) (30.6 mg, 0.3 mmol) and N,N-diisopropylethylamine (130 mg, 0.992 mmol) were sequentially added to the mixture, followed by stirring at room temperature for 12 hours. TLC (developing solvent: dichloromethane:methanol=10:1, Rf=0.4) showed that the starting material was completely reacted. Add 25 mL of dichloromethane to the reaction solution, then pour the reaction solution into 30 mL of water, and adjust the pH to 5-6 with 2N citric acid. The organic layer was separated and washed with water (20 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by a preparative pl...

Embodiment 2

[0313] (R)-N-(1-hydroxy n-propanol-2-yl)-6-((3-(5-methylisoxazol-3-yl)-[1,2,4]triazole[ 3,4-a]phthalazine-6-oxo)methylene)nicotinamide (02)

[0314] The experimental operation was as described in Example 1: the raw materials were compound A4 and D-aminopropanol (CAS: 35320-23-1) to obtain product (02) (35 mg, 20.5%), which appeared as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.06~9.05(d,1H),8.60~8.58(d,1H),8.37~8.35(d,2H),8.27(d,1H),8.13(t,1H ),8.00(t,1H),7.87~7.85(d,1H),6.93(s,1H),5.77(s,2H),4.77~4.74(t,1H),4.05~4.02(m,1H), 3.45(m,1H),3.37(m,1H),3.33(s,1H),2.58(s,3H),2.01~1.99(m,1H),1.15~1.13(d,3H); LC-MS: m / z(ES+)for C 23 h 21 N 7 o 4 460.14[M+1] + .

Embodiment 3

[0316] N-((1S,2S)-2-hydroxycyclopentyl)-6-((3-(5-methylisoxazol-3-yl)-[1,2,4]triazole[3, 4-a]phthalazine-6-oxo)methylene)nicotinamide (03)

[0317] The experimental operation was as described in Example 1: the raw materials were compound A4 and trans-(1S,2S)-2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) to obtain the product (75mg, 65.8%) Appearance is white solid. 1 H NMR (400MHz, DMSO-d6) δ: 9.04(d,1H), 8.60~8.58(d,1H), 8.48~8.46(d,1H), 8.38~8.36(d,1H), 8.28~8.25(d ,1H),8.15~8.12(t,1H),8.02~8.00(t,1H),7.87~7.85(d,1H),6.93(s,1H),5.78(s,2H),4.81~4.80(d ,1H), 4.02~3.99(m,2H), 2.58(s,3H), 2.02~1.99(m,2H), 1.87~1.46(m,4H); LC-MS: m / z(ES+) for C 25 h 23 N 7 o 4 486.19[M+1] + .

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Abstract

The invention provides compounds as shown in a general formula (I) which is described in the specification and cis-trans-isomers, enantiomers, diastereomers, racemes, solvates, hydrates, pharmaceutically acceptable salt and esters thereof. The invention further provides preparation method for the compounds, pharmaceutical compositions of the compounds and application of the compounds as modulators for an alpha5-GABAA receptor. T, Z, A and Y in the formula (I) are as defined in the specification.

Description

[0001] Technical field: [0002] The present invention relates to α5-GABA A Hazelazine derivatives with receptor modulating function, their preparation, pharmaceutical compositions containing them and their use as medicines. [0003] Background technique: [0004] 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. [0005] GABA with α5 A receptor (α5-GABA A receptor) in the mammali...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5377A61K31/502A61P25/28A61P9/10A61P29/00
CPCC07D487/04A61K31/502A61K31/5377A61P9/10
Inventor 李帅孙勇
Owner SHANGHAI SIMR BIOTECHNOLOGY CO LTD
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