Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative and application thereof

A compound and hydrate technology, applied in the field of 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivatives and anti-influenza drugs, can solve the problems of low immunity and low efficacy in children

Active Publication Date: 2021-01-05
GUANGZHOU NUCIEN PHARM CO LTD
View PDF4 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Influenza vaccination is the main preventive method and is highly effective, but it has the disadvantage that it must be injected once a year and is less effective for immunocompromised and high-risk adults and young children
[0011] There are still some deficiencies in the druggability of the above-mentioned compounds. Therefore, it is still very urgent for scientists to research and develop new anti-influenza drugs with CEN inhibitory effects.

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
  • 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative and application thereof
  • 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative and application thereof
  • 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Example 1: N-ethyl-1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazepine-11-yl)-5-hydroxyl-4,6- Dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-b]pyridazine-3-carboxamide

[0164] Obtained by the following reaction formula:

[0165] Step 1) Synthesis of compound 1-2

[0166]

[0167] Add isobutyl chloroformate ( 92.9mg, 680.0umol, 89.3uL, 1.10eq). The mixture was stirred at 0-5°C for 30 mins. Add ethylamine (27.9mg, 618.2umol, 40.5uL, 1.00eq) to the mixture at 0~5°C. The mixture was stirred at 20-30°C for 60 mins. TLC (EtOAc:MeOH=10:1, R f (R1)=0.50) showed complete consumption of Compound 1 and formation of multiple spots. The reaction solution was concentrated to dryness, the residue was washed successively with 2-MeTHF (1 mL) and saturated brine, and the organic layer was concentrated to dryness. The crude product was purified by prep-TLC (EtOAc:MeOH=10:1), and LCMS showed the expected m / z to obtain compound 1-2 (0.100g, 231.8umol, 37.5%yield) as a yellow oil, which ...

Embodiment 2

[0174] Example 2: 1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazin-11-yl)-5-hydroxy-4,6-dioxo-2 ,3,4,6-tetrahydro-1H-pyrido[1,2-b]pyridazine-3-carboxamide

[0175] Obtained by the following reaction formula:

[0176] Step 1) synthesis of compound 2-2

[0177]

[0178] Compound 2-1 (200.0g, 812.3mmol, 1.00eq), EtI (228.0g, 1.46mol, 116.9mL, 1.80eq), DBU (185.5 g, 1.22mol, 183.7mL, 1.50eq) in DMF (1000mL) Stir at 20~30℃ for 1hrs.TLC (PE:EA=1:1,R f = 0.60) showed that the reaction was complete. The mixture was introduced into 4L of water and extracted with EA (1000mL*3). The organic layer was washed with saturated brine (1000 mL*2) and concentrated to dryness to obtain compound 2-2 (190.0 g, 692.8 mmol, yield 85.3%) as a yellow oil. HNMR conforms to the expected structure. 1 H NMR: (400MHz, CHLOROFORM-d) δ7.74(d, J=5.6Hz, 1H), 7.51-7.44(m, 2H), 7.39-7.29(m, 3H), 6.46(d, J=5.6Hz ,1H),5.36-5.23(m,2H),4.33(q,J=7.2Hz,2H),1.31(t,J=7.1Hz,3H)

[0179] Step 2) Synthesis of ...

Embodiment 3

[0206] Example 3: N-isopropyl-1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepine-11-yl)-5-hydroxy-4,6 -Dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-b]pyridazine-3-carboxamide

[0207] Obtained by the following reaction formula:

[0208] Step 1) Synthesis of compound 3-1

[0209]

[0210] Compound 1-1 (0.300g, 741.81umol, 1.00eq), DMF (3mL), i-PrNH 2 (219.2mg, 3.71mmol, 318.7uL, 5.00eq), HATU (338.5mg, 890.2umol, 1.20eq) were stirred at 20~30°C for 1hr. LCMS showed the expected m / z. The mixture was diluted with 2-MeTHF (3mL) , saturated saline nd washed with sat.aq.NaCl (2mL*3). The organic layer was concentrated to dryness to obtain compound 3-1 (0.300 g, 673.4 umol, 90.8% yield) as a yellow oil, which was used for the next reaction. MS(ESI, m / z): 446.2[(M+H) + ].

[0211] Step 2) Synthesis of Compound 3-2

[0212]

[0213] Compound 3-1 (300mg, 673.34umol, 1.00eq), A (178.0mg, 673.4umol, 1.00eq), T 3 A solution of P (3.21 g, 5.04 mmol, 3.00 mL, purity.0% purity, 7.49...

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
diameteraaaaaaaaaa
Login to View More

Abstract

The invention belongs to the field of medicines, and particularly relates to a 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative, a compound thereof, and pharmaceutically acceptable salts and solvates thereof, comprising hydrates, polycrystals, prodrugs, eutectic crystals, tautomers and stereoisomers. More specifically, the compound provided by the invention can be used as an anti-influenza drug with a CEN inhibition effect.

Description

[0001] field of invention [0002] The invention belongs to the field of medicines, and in particular relates to a 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative and its application. More specifically, the compounds described in the present invention can be used as anti-influenza drugs with CEN inhibitory effect. Background technique [0003] Influenza is a highly contagious respiratory disease caused by influenza viruses. Among them, influenza A virus has the widest host range, which can infect both poultry and mammals, and can easily cause a worldwide pandemic. There have been four major influenza outbreaks (1918, 1957, 1968, 2009) in the past century. Among them, the "Spanish flu" (H1N1) that broke out in 1918 directly caused about 50 million deaths, which was the flu outbreak with the largest number of deaths in human history. The most recent "Mexican flu" (A / 2009 / H1N1) that broke out in 2009 spread rapidly to 214 countries around the world, kil...

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): C07D471/04A61K31/5025A61K45/06A61P31/16
CPCC07D471/04A61P31/16
Inventor 胡双华林寨伟崔柏成
Owner GUANGZHOU NUCIEN PHARM CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com