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Cell necrosis inhibitor, and preparation method and application thereof

A compound, unsubstituted technology, used in anti-inflammatory agents, antibacterial drugs, pharmaceutical formulations, etc., can solve problems such as limited research and clinical applications, inability to enter the central nervous system through the blood-brain barrier, and poor pharmacokinetic properties.

Active Publication Date: 2020-01-03
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, existing cell necrosis inhibitors all have defects in varying degrees, such as unsatisfactory activity, poor pharmacokinetic properties or low oral bioavailability, and some cannot enter the central nervous system through the blood-brain barrier. The disadvantages limit its further research and clinical application

Method used

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  • Cell necrosis inhibitor, and preparation method and application thereof
  • Cell necrosis inhibitor, and preparation method and application thereof
  • Cell necrosis inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0148] The preparation of formula I compound

[0149] 1. The compound of formula I can be prepared by the following methods:

[0150] 1) Amide condensation: Fragment II first removes the protective agent on the amino group under acidic conditions, and then condenses with Fragment III to obtain the target compound

[0151]

[0152] Some examples are as follows:

[0153]

[0154] (a) in an inert solvent, in the presence of a condensation reagent and a base, react with a compound of formula II and a compound of formula III to obtain a compound of formula I; wherein R is H;

[0155] Wherein, solvent can be: DMF, DMSO, acetonitrile, THF, DCM or its combination

[0156] The condensation reagent can be: HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, PyBOP or combinations thereof

[0157] The base can be: DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine or combinations thereof

[0158] (b) Under acidic conditions, the compound of formula II removes the ...

Embodiment 1

[0219] Embodiment 1, the preparation of condensation reaction synthetic compound I (RIP1-001-017, 019-0116)

[0220] method 1:

[0221]

[0222] Compound II-1 (27.8mg, 0.08mmol) was placed in a 25mL one-mouth bottle, 1mL TFA and 4mL DCM were added thereto, and the reaction was carried out at room temperature for 30min. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, dried in vacuo and redissolved in 4mL DMF. Add HATU (38mg, 0.1mmol), DIEA (51.7mg, 0.4mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid III-1 (20.3mg, 0.1mmol) to it, room temperature Reacted overnight, TLC monitored the end of the reaction, extracted with EA, washed with deionized water, washed with saturated NaCl, Na 2 SO 4 Dry, remove solvent under reduced pressure, reverse phase column separation and lyophilize to give RIP1-001: white solid 14.0 mg (40.4%)

[0223] By changing compound II and compound III (both known compounds, prepared by methods reported in the...

Embodiment 2

[0471] Embodiment 2, the synthesis of compound RIP1-018

[0472]

[0473] Compound RIP1-015 (13mg, 0.03mmol) was placed in a 25mL single-necked bottle, and 5mL of DCM, one drop of acetic anhydride, and two drops of TEA were added to it, and the reaction was carried out at room temperature for 30min. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, extracted with EA, and deionized. Washed with water, washed with saturated NaCl, Na 2 SO 4 Drying, removal of solvent under reduced pressure, reverse phase column separation and lyophilization gave RIP1-018: white solid 10 mg (70.7%).

[0474] RIP1-018: 1 H NMR (400MHz, CDCl 3 )δ8.87(s, 1H), 8.17(s, 1H), 7.86(d, J=7.5Hz, 1H), 7.70(s, 1H), 7.38-7.29(m, 3H), 7.27-7.23(m , 2H), 6.32(s, 1H), 4.82-4.72(m, 1H), 4.12(s, 2H), 3.86(dd, J=11.1, 6.8Hz, 1H), 3.51(s, 3H), 3.01- 2.94(m, 1H), 2.85(s, 3H); 13 CNMR (100MHz, CDCl 3 )δ 174.1, 171.0, 169.7, 158.2, 158.1, 142.3, 139.1, 137.4, 135.3, 129.8...

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PUM

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Abstract

The invention provides a cell necrosis inhibitor, and a preparation method and application thereof. Particularly, the invention provides an inhibitor for inhibiting cell necrosis and / or human receptorinteracting protein 1 kinase (RIP1). The inhibitor has a structure shown as in a following formula I. The compound and a composition comprising the compound are useful in the prevention and / or treatment of diseases involving cell death and / or inflammation.

Description

technical field [0001] The invention relates to an inhibitor for inhibiting cell necrosis and / or human receptor-interacting protein 1 kinase (RIP1), a preparation method and application thereof. The compounds and compositions comprising them can be used in methods for the prevention and / or treatment of diseases involving cell death and / or inflammation. Background technique [0002] Programmed necrosis cell death, also known as programmed necrosis, is a new type of cell death discovered in recent years. Necroptosis, a highly inflammatory form of cell death, is considered an important pathological factor in a variety of degenerative and inflammatory diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and various other related diseases. [0003] Tumor necrosis factor alpha (TNF-α)-induced activation of NF-κB plays a central ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07D498/04A61K31/554A61K31/553A61P1/00A61P1/04A61P17/06A61P27/02A61P17/00A61P1/18A61P19/02A61P29/00A61P19/06A61P19/08A61P1/16A61P37/02A61P13/12A61P15/14A61P37/06A61P9/10A61P31/04A61P25/14A61P25/28A61P25/16A61P37/08A61P11/06A61P3/10A61P11/00A61P1/02
CPCC07D513/04C07D498/04A61P1/00A61P1/04A61P17/06A61P27/02A61P17/00A61P1/18A61P19/02A61P29/00A61P19/06A61P19/08A61P1/16A61P37/02A61P13/12A61P15/14A61P37/06A61P9/10A61P31/04A61P25/14A61P25/28A61P25/16A61P37/08A61P11/06A61P3/10A61P11/00A61P1/02Y02P20/55
Inventor 马大为王开亮夏尚华李征赵金龙李盈
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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