Unlock instant, AI-driven research and patent intelligence for your innovation.

Pyrazol-triazine derivatives as well as preparation method, pharmaceutical compositions and use thereof

A technology of compounds and hydrates, applied in the direction of drug combinations, active ingredients of heterocyclic compounds, antipyretics, etc., can solve problems such as animal fear and anxiety

Active Publication Date: 2017-11-14
SHANGHAI SIMR BIOTECHNOLOGY CO LTD +2
View PDF10 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Region-specific knockout of α5 GABA in the brain A Receptor expression induces fear and anxiety behavior in animals
Therefore, previously disclosed α5 GABA 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Pyrazol-triazine derivatives as well as preparation method, pharmaceutical compositions and use thereof
  • Pyrazol-triazine derivatives as well as preparation method, pharmaceutical compositions and use thereof
  • Pyrazol-triazine derivatives as well as preparation method, pharmaceutical compositions and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0375] 6-[3-tert-butyl-7-(5-hydroxymethyl-isoxazol-3-yl)pyrazolo[1,5-d][1,2,4]triazine-2-oxomethanol base]-N-morpholine nicotinamide (01)

[0376]

[0377] Add raw material A4 (85 mg), 1-hydroxybenzotriazole (54 mg) and 1-ethyl (3-dimethylaminopropyl) carbodiimide hydrochloride (77 mg) successively in 5 mL of DMF, Stir at room temperature for 10 minutes under nitrogen protection. 4-Aminomorpholine (41 mg) and N,N-diisopropylethylamine (130 mg) were added to the reaction solution. The mixture was stirred at room temperature for 16 hours. TLC plate (developing solvent: dichloromethane: methanol = 10: 1, Rf = 0.5) showed that the starting material was completely reacted. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture, and the organic layer was washed with water (50 mL×2 times). The organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain the product (38 mg, ...

Embodiment 2

[0380] (R)-6-((3-tert-butyl-7-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-d][1,2,4]tri Oxyzine-2-oxy)methyl)-N-(1-hydroxypropan-2-yl)nicotinamide (02)

[0381]

[0382] The experimental operation is as described in Example 1: the condensation reaction between intermediate A4 and (R)-2-amino-n-propanol (CAS: 2799-16-8) to obtain the target compound to obtain the product (35 mg, yield: 41%), appearance It is a white solid.

[0383] 1 H NMR (400MHz, DMSO-d6)δ: .9.60(s,1H)9.00(d,1H J=1.6),8.35~8.23(m,2H),7.63(d,1H J=8.0),7.15(s ,1H),5.59(s,2H),4.73(s,2H),4.06~3.97(m,1H),3.48~3.45(m,1H),3.36~3.30(m,1H),1.50(s,9H ) 1.11 (d,3H J=6.8).LC-MS: m / z (ESI+) for C 23 h 27 N 7 o 5 482[M+1] + .

Embodiment 3

[0385] 6-((3-tert-butyl-7-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-d][1,2,4]triazine-2- Oxy)methyl)-N-((1S,2S)-2-hydroxypropan-2-hydroxycyclopentyl)nicotinamide (03)

[0386]

[0387] The experimental operation was as described in Example 1: the condensation reaction between intermediate A4 and trans-(1S,2S)-2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) gave the product (22 mg, yield : 24.5%), the appearance is white solid.

[0388] 1 H NMR (400MHz, DMSO-d6) δ: 9.60(s, 1H), 8.99(d, 1H J=2.4), 8.42(d, 1H J=6.8), 8.25~8.20(m, 1H), 7.65(d ,1H J=8.4),7.15(s,1H),5.87(t,1H J=6.2),5.59(s,2H),4.80(d,1H J=4.4),4.73(d,2H J=6.0) ,4.05~3.95(m,2H),2.05~1.90(m,1H),1.88~1.78(m,1H),1.70~1.60(m,2H),1.51(s,9H),1.40~1.50(m, 2H).LC-MS:m / z(ESI+)for C 25 h 29 N 7 o 5 508[M+1] + .

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
electrical resistanceaaaaaaaaaa
Login to View More

Abstract

The invention relates to pyrazol-triazine derivatives as well as a preparation method, pharmaceutical compositions and use thereof. The invention provides compounds shown in a general formula (I), or cis-trans isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates thereof or pharmacologically acceptable salts and esters of the compounds, a preparation method of the compounds, pharmaceutical compositions containing the compounds, and use of the compounds as an alpha 5-GABAA receptor modulator, wherein Z, A and Y are defined in the description. The general formula (I) is described in the description.

Description

Technical field: [0001] The present invention relates to α5-GABA A Pyrazole-triazine derivatives with receptor regulating function, their preparation, pharmaceutical compositions containing them and their use as medicines. 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 mammalian brain...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5377A61K31/53A61K31/541A61P25/28A61P21/00A61P25/30A61P9/10A61P25/02A61P25/04A61P29/00
CPCC07D487/04A61K31/53A61K31/5377A61K31/541
Inventor 李帅孙勇李扬
Owner SHANGHAI SIMR BIOTECHNOLOGY CO LTD