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Pyridino five-membered heterocyclic derivative as well as preparation method and applications thereof

A five-membered heterocycle and derivative technology, applied in the field of c-Met inhibitors, can solve the problems of low oral bioavailability, unsatisfactory clinical therapeutic effect and pharmacokinetic parameters, etc.

Inactive Publication Date: 2012-12-19
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are mainly the following problems in the research of C-Met inhibitors: the clinical treatment effect and pharmacokinetic parameters are not ideal, and the oral bioavailability is not high, etc.

Method used

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  • Pyridino five-membered heterocyclic derivative as well as preparation method and applications thereof
  • Pyridino five-membered heterocyclic derivative as well as preparation method and applications thereof
  • Pyridino five-membered heterocyclic derivative as well as preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 1-(4-fluorophenyl)-N-4-((2-(4-fluorophenyl)oxazolo[4,5-b]pyridin-7-yl)oxy)benzene base)-2-oxo-1, the preparation of 2-dihydropyridine-3-amide (compound 1)

[0060] Step 1: Preparation of 2-(4-fluorophenyl)oxazolo[4,5-b]pyridine (1-3)

[0061]

[0062] 1.1g 2-amino-3-hydroxypyridine (1-1) (purchased from Acros Company, Belgium) and 1.4g 4-fluorobenzoic acid (1-2) (purchased from Acros Company, Belgium) in 80g polyphosphoric acid Heat at 250°C for 4 hours. Then, it was poured into a mixture of ice and NaOH, and a precipitate precipitated out. Filter, wash with 1N NaOH, wash with water until neutral, and dry to obtain 1.55 g of light brown solid 1-3 with a yield of 72%.

[0063] LCMS(ESI): 215[M+H]

[0064] 1 H NMR (300MHz, d 6 -DMSO) 8.57 (d, 1H, J = 3.4 Hz), 8.3 (m, 3H), 7.52 (m, 3H).

[0065] Step 2: Preparation of 7-chloro-2-(4-fluorophenyl)oxazolo[4,5-b]pyridine (1-5)

[0066]

[0067] Dissolve 1.2 g of compound 1-3 in 15 mL of dichloromethan...

Embodiment 2

[0088] Example 2 N-((4-((2-(4-fluorophenyl)oxazolo[4,5-b]pyridin-7-yl)oxy)phenyl)aminomethyl Preparation of sulfonyl) 2-2-phenylacetamide (compound 2)

[0089]

[0090] Dissolve 9mg NaSCN in 0.5mL acetone, under argon, add 15μL phenylacetyl chloride (purchased from Acros, Belgium), stir at room temperature for 5 minutes, add 0.5mL acetone, add 1-8 32mg prepared in Example 1, insoluble . Reflux overnight. Evaporate acetone, add water, and filter. The solid was prepared and purified using dichloromethane:methanol (50:1) as the developing solvent to obtain 20 mg of yellow solid 2 with a yield of 40%.

[0091] LCMS(ESI): 499[M+H]

[0092] 1 H NMR (300MHz, d 6 -DMSO) 8.42 (d, 1H, J = 5.5Hz), 8.2 (m, 2H), 7.74 (d, 2H, J = 8.4Hz), 7.4 (m, 8H), 6.94 (d, 1H, J =5.5Hz), 5.74(s, 1H), 3.82(s, 2H).

Embodiment 3

[0093] Example 3 2-Phenyl-N-((4-((2-p-tolyl)-3H-imidazo[4,5]pyridin-7-yl)oxy)phenyl) Carbamoyl)phenylacetamide (compound 3) and 2-phenyl-N-(4-((2-p-tolyl)-3H-imidazo Preparation of [4,5]pyridin-7-yl)oxy)phenyl)phenylacetamide (compound 8)

[0094] Step 1: Preparation of 4-(4-aminophenoxy)-3-nitropyridin-2-amine (3-3)

[0095]

[0096] 8 g of 4-aminophenol (purchased from Acros, Belgium) was dissolved in 80 mL of dry dimethylformamide, degassed with argon for 10 min, added 5.6 g of potassium tert-butoxide, and continued to stir and degas for 1 h. 8g of compound 3-1 was dissolved in 40mL of dimethylformamide, added to the reaction liquid, and protected by argon at 70°C for 20 hours. The solvent was evaporated, and the residue was purified by column, eluent, petroleum ether: ethyl acetate (1:1), to obtain 8.8 g of orange-yellow solid 3-3, with a yield of 80%.

[0097] LCMS (ESI): 246[M+1]

[0098] 1 H NMR (300MHz, d 6 -DMSO) δ7.94 (d, 1H, J = 5.9Hz), 7.06 (br s, 2H),...

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Abstract

The invention discloses a pyridino five-membered heterocyclic derivative or a pharmaceutically acceptable salt of the pyridino five-membered heterocyclic derivative, a structure of which is shown in general formula I. The invention also relates to a preparation method and applications of the pyridino five-membered heterocyclic derivative or the pharmaceutically acceptable salt of the pyridino five-membered heterocyclic derivative in the preparation of drugs used as a c-Met inhibitor.

Description

technical field [0001] The present invention relates to c-Met inhibitor and its synthesis and application. More specifically, it relates to a class of pyrido five-membered heterocyclic derivatives or pharmaceutically acceptable salts thereof and their preparation methods and uses. Background technique [0002] c-Met is a receptor tyrosine kinase that is expressed in both normal cells and tumor cells. The gene, first discovered in George Vande Woude's lab in 1984, is capable of causing tumors in nude mice. Since this gene was discovered after treatment with N-Methyl-N'-nitro-N-nitrosoguanidine, it was named 'c-Met '(Stellrecht CM, Gandhi V. MET receptor tyrosine kinase as a therapeutic anticancer target. Cancer Lett, 2009, 280(1): 1-14). c-Met is the cell surface receptor of hepatocyte growth factor (HGF, also known as scatter factor), and is a kind of pleiotropic cytokine, which can transmit pro-migration, anti-apoptosis and pro- mitotic signal. Activation of c-Met by H...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07D471/04A61K31/444A61K31/437A61P35/04A61P35/00
Inventor 沈竞康陈丹琦熊兵耿美玉艾菁王英
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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