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Triazolopyridazine derivative as well as preparation method, pharmaceutical composition and application thereof

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

Pending Publication Date: 2021-06-18
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 α5-GABA in the brain A Receptor expression causes 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 directly apply to the field of medicine, it must be modified

Method used

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  • Triazolopyridazine derivative as well as preparation method, pharmaceutical composition and application thereof
  • Triazolopyridazine derivative as well as preparation method, pharmaceutical composition and application thereof
  • Triazolopyridazine derivative as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0235] 2) Compound 3 can be prepared by step c, directly heating the corresponding hydrazide and compound 1 in acid catalysis, such as p-toluenesulfonic acid, etc., in various ethers or alcohol solvents, and there will be different Regioisomers arise and require separation. Alternatively, for substrates with weaker reactivity, compound 2 can be obtained by separating and obtaining compound 2 after reacting hydrazide with compound 1 under similar conditions as in step b, and then heating the ring closure in alcohols, acetic acid and other solvents through step d, Compound 3 was obtained after separation of the isomers.

[0236] 3) Compound 7 can be obtained from the corresponding ester compound 6 by reduction of step i by sodium borohydride, lithium aluminum hydride in solvents such as ethers and alcohols. In addition, for the ester compound 6 with a complex structure, it can be obtained from the corresponding halogenated heteroaryl ester, or the heteroaryl ester substituted b...

Embodiment 1

[1102] Embodiment 1 (method A)

[1103] 3-(7-methoxy-6-((1-methyl-1H-1,2,4-triazol-5-yl)methoxy)-[1,2,4]triazolo[4 ,3- b] pyridazin-3-yl)-5-methylisoxazole

[1104]

[1105] 3-(6-Chloro-7-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-5-methylisoxazole (60mg, 0.23 mmol), (1-methyl-1H-1,2,4-triazol-5-yl)methanol (26mg, 0.23mmol) and cesium carbonate (147mg, 0.45mmol) were added to acetonitrile (3mL) successively, and the reaction mixture Stir at 50°C for 16 hours. The mixture was poured into ice water, and the precipitated solid was collected by filtration and dried to obtain 51.0 mg of the title compound as a white solid, with a yield of 66% 1 H NMR (400MHz, DMSO-d 6 )δ7.98(s,1H),7.77(s,1H),7.09(s,1H),5.66(s,2H), 3.98(s,3H),3.94(s,3H),2.56(s,3H )LC-MS: m / z[M+H] + =343

Embodiment 11

[1107] 6-(((7-methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl )oxygen base)methyl)-N-(2,2,2-trifluoroethyl)nicotinamide

[1108]

[1109]6-[7-methoxy-3-(5-methyl-isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl Oxymethyl]-nicotinic acid (200mg, 0.52mmol), HOBT (210mg, 1.56mmol) and EDCI (210mg, 1.56mmol) were added to 5mL of DMF successively, 2,2,2-trifluoroethylamine ( 1410mg, 1.0mmol) and triethylamine (0.5ml) were sequentially added to the mixture, followed by stirring at room temperature overnight. The mixture was diluted with ethyl acetate (10 mL), washed once with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 15 / 1) to obtain 8 mg of the target compound as a white solid with a yield of 3%. The appearance was a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ9.37-9.29 (m, 1H), 9.06 (d, J = 2.0Hz, 1H), 8.29 (dd, J = 2.2, 8.1Hz, 1H), 7.77 (s, 1H), 7.7...

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Abstract

The invention relates to triazolopyridazine derivatives as well as a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound shown in a general formula (I), cis-trans isomers, enantiomers, diastereoisomers, racemes, solvates, hydrates or pharmaceutically acceptable salts or prodrugs of the compound, and a preparation method of the compound, the cis-trans isomers, the enantiomers, the diastereoisomers, the racemes, the solvates, the hydrates or the pharmaceutically acceptable salts or the prodrugs of the compound; preparation method thereof; pharmaceutical compositions containing the compounds, and the use of the compounds as alpha 5-GABAA receptor modulators, wherein R 1, R 2, and Z are as defined in the specification. pharmaceutical compositions containing the compounds and application of the compounds as alpha-5-GABAA receptor modulators, wherein R1, R2 and Z are as defined in the specification.

Description

Technical field: [0001] The present invention relates to α5-GABA A Triazolopyridazine derivatives with receptor modulating 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, the other is GABA B receptors, which are members of the G protein-coupled receptor superfamily. GABA in mammals A Receptor subunits are 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 for GABA...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/5025A61K31/5383A61K31/519A61K31/5377A61P29/00A61P25/28A61P9/10A61P19/06A61P19/02A61P25/00
CPCC07D487/04C07D519/00A61P29/00A61P25/28A61P9/10A61P19/06A61P19/02A61P25/00A61P25/30A61P21/00A61K31/5025A61K31/541A61K31/5383A61K31/519A61K31/5377A61K31/4375A61K31/4439C07D471/04
Inventor 金赟王非吴金华陈南阳孙勇李帅
Owner SHANGHAI SIMR BIOTECHNOLOGY CO LTD
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