N-heterocyclic compounds, their intermediates, preparation methods, pharmaceutical compositions and applications

A compound and heterocyclic technology, applied in the field of N-heterocyclic compounds, can solve problems such as poor selectivity and poor cell permeability

Active Publication Date: 2020-07-07
ETERN BIOPHARMA SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the problems of poor selectivity and poor cell membrane permeability of SHP2 inhibitors to SHP2 in the prior art; and provide a kind of N-heterocyclic compound, its intermediate, preparation method, drug Composition and Application

Method used

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  • N-heterocyclic compounds, their intermediates, preparation methods, pharmaceutical compositions and applications
  • N-heterocyclic compounds, their intermediates, preparation methods, pharmaceutical compositions and applications
  • N-heterocyclic compounds, their intermediates, preparation methods, pharmaceutical compositions and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] The synthesis of embodiment 1SHP2-28

[0124] Synthesis of S1

[0125]

[0126] Add 6-bromo-2-naphthoic acid (251.1mg, 1.0mmol) into a 25mL dry egg-shaped bottle, replace the nitrogen three times to make the system in a nitrogen atmosphere, add 5mL of freshly distilled dichloromethane to dissolve it, and then slowly Thionyl chloride (0.36mL, 5.0mmol) was added dropwise, and after the dropwise addition, a catalytic amount of ultra-dry N,N-dimethylamide was added to promote the reaction. After heating to reflux for 30 minutes, stop the heating, spin the solvent dry, pump it with an oil pump for half an hour, and directly put it into the next reaction. In the second step, N, O-dimethylhydroxylamine hydrochloride (107.3mg, 1.1mmol) and triethylamine (0.42mL, 3.0mmol) were added to a 25mL dry egg-shaped bottle, and 5mL of dichloromethane was added to make the raw material completely Dissolve, cool the system to 0°C in an ice-water bath, slowly add the acid chloride newl...

Embodiment 2

[0153] The synthesis of embodiment 2 compound SHP2-30

[0154] Synthesis of S7

[0155]

[0156] Add 6-bromo-2-naphthoic acid (2.4996g, 10.0mmol) into a 50mL dry egg-shaped flask, add 20mL of anhydrous methanol to dissolve it, then slowly add 1mL of concentrated sulfuric acid dropwise, and reflux the system overnight. TLC tracked until the conversion of the raw materials was completed, the heating was stopped, and after cooling to room temperature, saturated aqueous sodium carbonate solution was added to quench the reaction. The reaction system was adjusted to be neutral, extracted with ethyl acetate, and the organic phase was washed three times with water and dried with anhydrous sodium sulfate. Concentration under reduced pressure gave white solid S7 (2.63 g, yield 100%).

[0157] 1 H NMR (300MHz, CDCl 3 )δ8.57(s,1H),8.11–8.03(m,2H),7.81(t,J=8.3Hz,2H),7.62(dd,J=8.4,1.5Hz,1H),3.98(s,3H ).

[0158] Synthesis of S8

[0159]

[0160] Compound S7 (265.1mg, 1.0mmol), ...

Embodiment 3

[0175] The synthesis of embodiment 3 compound SHP2-31

[0176] Synthesis of S11

[0177]

[0178] 2-Chloronaphthalene (325.2mg, 2.0mmol) and aluminum trichloride (320mg, 2.4mmol) were dissolved in 4mL of carbon disulfide solution, the system was cooled to 0°C in an ice-water bath, and acetyl chloride (0.16mL, 2.2 mmol), after the dropwise addition, it was incubated at 0° C. for 10 minutes, and then returned to room temperature and stirred overnight. TLC tracked until the conversion of the raw materials was completed, the reaction solution was poured into ice water, and concentrated hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 2.0. Then it was extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium bicarbonate until neutral. The organic phase was washed several times with water and dried over anhydrous sodium sulfate. Concentration under reduced pressure to obtain the crude product was separated a...

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PUM

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Abstract

The invention discloses an N-heterocyclic ring compound, and an intermediate, a preparation method, a medicine composition and application thereof. The N-heterocyclic ring compound has high selectivity on SHP2, can be used for effectively inhibiting the phosphorylation level of SHP2 downstream signal path ERK in cells, has good inhibition activity on tumor cells, and has wide medicine development prospects. The preparation method is simple; the reaction conditions are mild; the yield and the purity are high; the post treatment is simple; green and environment-friendly effects are achieved; the industrial production is facilitated. The formula I is shown in the specification.

Description

technical field [0001] The present invention relates to an N-heterocyclic compound, its intermediate, preparation method, pharmaceutical composition and application. Background technique [0002] SHP2 (Src homology 2 domain containing protein tyrosine phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by the proto-oncogene PTPN11. It consists of two SH2 domains (N-SH2 and C-SH2), a protein tyrosine phosphatase catalytic domain (PTP) and a hydrophobic carboxyl tail (-COOH). Under normal conditions, N-SH2 of SHP2 forms a ring structure with the catalytic domain of phosphatase, and self-inhibition occurs, resulting in low enzyme activity. Under the trigger of growth factors, cytokines and hormones, N-SH2 binds to phosphorylated tyramine, exposing the catalytic domain of phosphatase, and the activity of SHP2 phosphatase is significantly enhanced. Existing studies have found that SHP2 can regulate cell growth, migration, adhesion and cytoskeleton formation by...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12C07D417/04C07D417/14C07D277/46C07D277/32C07D277/36C07D401/12A61K31/454A61K31/426A61K31/496A61K31/427A61K31/5377A61K31/506A61P35/00
CPCC07D277/32C07D277/36C07D277/46C07D401/12C07D417/04C07D417/12C07D417/14
Inventor 朱继东顾守来思晓佳谢菁菁沈剑
Owner ETERN BIOPHARMA SHANGHAI CO LTD
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