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Pyridazine-3-carboxamide compound and preparation method and application thereof in medicine

A technology of compounds and mixtures, applied in the fields of active ingredients of heterocyclic compounds, organic chemistry, pharmaceutical formulations, etc., can solve problems such as difficulties in research and development

Active Publication Date: 2020-02-21
BEIJING INNOCARE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high sequence similarity of the active sites of the JAK kinase family, it is quite difficult to develop a highly selective TYK2 inhibitor

Method used

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  • Pyridazine-3-carboxamide compound and preparation method and application thereof in medicine
  • Pyridazine-3-carboxamide compound and preparation method and application thereof in medicine
  • Pyridazine-3-carboxamide compound and preparation method and application thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] 6-(2,6-Difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxamide

[0222]

[0223] first step

[0224] Methyl 6-chloro-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylate

[0225] Compound 4,6-dichloropyridazine-3-carboxylic acid methyl ester 1a (206mg, 1.00mmol), 4-ethoxyaniline (205mg, 1.50mmol) and diisopropylethylamine (387mg, 3.00mmol ) was dissolved in acetonitrile (3 mL), then heated to 85° C. and stirred for 2 hours in a microwave reactor. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1 to 10 / 1) to obtain the target product 6-chloro-4-((4-ethoxy Phenyl)amino)pyridazine-3-carboxylic acid methyl ester 1b (240 mg, yellow oil), yield: 78%.

[0226] MS m / z(ESI): 308[M+1]

[0227] second step

[0228] 6-(2,6-Difluorophenyl)-4-((4-ethoxyphenyl)amino)pyridazine-3-carboxylic acid methyl ester

[0229] Compound 6-chloro-4-(...

Embodiment 8

[0244] 6-(2,6-Difluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxamide

[0245]

[0246] first step

[0247] Methyl 6-chloro-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxylate

[0248] The compound 4,6-dichloropyridazine-3-carboxylate methyl ester 1a (206 mg, 1.00 mmol) and 4-methanesulfonylaniline (342 mg, 2.00 mmol) were dissolved in ethanol (3 mL), and then dissolved in a microwave reactor Heat to 80°C and stir for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to obtain the target product 6-chloro-4-((4-(methyl Methylsulfonyl)phenyl)amino)pyridazine-3-carboxylate 8a (220 mg, yellow solid), yield: 64%.

[0249] MS m / z(ESI): 342[M+1]

[0250] Step 2 to Step 4

[0251] 6-(2,6-Difluorophenyl)-4-((4-(methylsulfonyl)phenyl)amino)pyridazine-3-carboxamide

[0252] Synthesize the target product ...

Embodiment 9

[0256] 4-((4-cyanophenyl)amino)-6-(2,6-difluorophenyl)pyridazine-3-carboxamide

[0257]

[0258] Example 9 was synthesized according to the synthesis steps of Example 8, but in the first step, 4-cyanoaniline was used instead of 4-methylsulfonylaniline.

[0259] MS m / z(ESI): 352[M+1]

[0260] 1 H NMR (400MHz, DMSO-d 6 )δ11.24(s, 1H), 8.87(s, 1H), 8.15(s, 1H), 7.84(d, J=7.8Hz, 2H), 7.67-7.42(m, 4H), 7.30(d, J = 7.6Hz, 2H).

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Abstract

The invention relates to a pyridazine-3-carboxamide compound suitable for inhibiting or regulating Janus kinase (JAK), especially tyrosine kinase 2 (TYK2), a preparation method of the pyridazine-3-carboxamide compound and an application of the pyridazine-3-carboxamide compound in medicine. Specifically, the invention relates to a compound represented by a general formula (I) and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salts thereof, and a method for treating and / or preventing Janus kinase-mediated related diseases, especially autoimmune diseases, inflammatory diseases and cancer by applying the compound or the pharmaceutically acceptable salts thereof, and a preparation method of the compound or thepharmaceutically acceptable salts thereof. Each substituent of the general formula (I) has the same definition as in the specification.

Description

technical field [0001] The present invention relates to a novel pyridazine-3-carboxamide compound or a pharmaceutically acceptable salt thereof which regulates or inhibits the activity of Janus kinase (JAK), especially tyrosine kinase 2 (TYK2), and contains the compound A pharmaceutical composition or a pharmaceutically acceptable salt thereof, a preparation method of the compound or a pharmaceutically acceptable salt thereof, and a drug containing the compound or a pharmaceutically acceptable salt thereof or the compound or a pharmaceutically acceptable salt thereof The use of the composition in the preparation of medicines for treating and / or preventing related diseases mediated by the kinase, especially autoimmune diseases, inflammatory diseases and cancers, and its use method. Background technique [0002] Janus kinase (JAK) is a non-receptor tyrosine protein kinase consisting of four family members, namely, JAK1, JAK2, JAK3 and TYK2. JAK has 7 homologous domains (JAK H...

Claims

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Application Information

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IPC IPC(8): C07D237/24C07D401/12C07D405/12C07D403/12C07D409/12C07D403/14C07D401/14C07D405/14C07D413/14A61K31/50A61K31/501A61K31/5377A61K31/541A61P37/02A61P29/00A61P35/00A61P17/00A61P3/10A61P27/02A61P25/28A61P37/08A61P37/06A61P11/06A61P19/02A61P5/14A61P7/06A61P1/00A61P15/00A61P21/04A61P1/16A61P1/04A61P13/12A61P17/06A61P17/14A61P35/02A61P17/04A61P25/16A61P25/14A61P9/10
CPCC07D237/24C07D401/12C07D405/12C07D403/12C07D409/12C07D403/14C07D401/14C07D405/14C07D413/14A61P37/02A61P29/00A61P35/00A61P17/00A61P3/10A61P27/02A61P25/28A61P37/08A61P37/06A61P11/06A61P19/02A61P5/14A61P7/06A61P1/00A61P15/00A61P21/04A61P1/16A61P1/04A61P13/12A61P17/06A61P17/14A61P35/02A61P17/04A61P25/16A61P25/14A61P9/10
Inventor 陈向阳庞育成
Owner BEIJING INNOCARE PHARMA TECH CO LTD
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