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Pyridazinone compounds, preparation method thereof, medicinal composition and application thereof

A compound, pyridazinone technology, applied in the field of medicinal chemistry, can solve the problems of large difference in activity level at the cellular level, poor physical and chemical properties, etc.

Active Publication Date: 2014-03-26
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

However, due to the poor physical and chemical properties of amide and carbamate groups, the activity of this type of compound at the cell level is quite different from that at the enzyme level.

Method used

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  • Pyridazinone compounds, preparation method thereof, medicinal composition and application thereof
  • Pyridazinone compounds, preparation method thereof, medicinal composition and application thereof
  • Pyridazinone compounds, preparation method thereof, medicinal composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0124] Preparation Example 1: Preparation of Intermediate I-1:

[0125]

[0126] Put 40ml of DMF in a round bottom flask, slowly add 6.89ml of POCl under ice-cooling 3 (Phosphorus oxychloride), after the dropwise addition, after stirring in an ice bath for 35min, slowly add a DMF solution of 5g of 6-fluoroindole in a constant pressure dropping funnel, and stir for 40min at 35°C. The reaction solution gradually changed from colorless to red. After TLC showed that the reaction was complete, 100 ml of 19.3 mmol / L NaOH aqueous solution was added, and vigorously stirred at 80° C. for 30 min. The reaction solution was cooled, and ethyl acetate was added for extraction, 30 ml each time, for a total of three extractions. The organic layers were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to silica gel column chromatography to obtain 4.5 g of intermediate I-1 (white solid, yield 75%).

[0127] 1 H NMR (300MHz,D 2 O)δ10.01(s,1H),8.24(dd,J=...

preparation Embodiment 2

[0128] Preparation Example 2: Preparation of Intermediate I-2:

[0129]

[0130]Dissolve 1.5g of 3-formyl-6-fluoroindole (ie intermediate I-1) in isopropanol, add 150mg of palladium carbon and 3.2g of sodium borohydride, and reflux overnight at 80°C. After TLC showed that the substrate disappeared, the palladium carbon was removed by filtration. After the filtrate was concentrated, the excess sodium borohydride was quenched by adding water, and extracted with ethyl acetate, 15 ml each time, three times. The organic layers were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and silica gel column chromatography to obtain intermediate I-2 (white solid, quantitative yield).

[0131] 1 H NMR (300MHz, CDCl 3 )δ7.60(s,1H),7.56(dd,J=7.5,5.1Hz,1H),7.03(dd,J=8.0,1.4Hz,1H),6.98–6.90(m,2H),2.34(s ,3H).

preparation Embodiment 3

[0132] Preparation Example 3: Preparation of Intermediate I-3:

[0133]

[0134] 1 g of 3-methyl-6-fluoroindole (ie intermediate I-2) and 1 g of dichloropyridazine were dissolved in reevaporated and dried THF under nitrogen protection. Add 270 mg NaH under ice cooling and stir rapidly. After the reaction was stable, the ice bath was removed and stirred at room temperature. After the complete conversion of the substrate was detected by TLC, excess water was added to quench the unreacted NaH, and extracted with ethyl acetate, 20 ml each time, twice. The combined organic layers were dried and concentrated. The crude product was dissolved in glacial acetic acid and refluxed at 120 °C overnight. After stopping the reaction, the glacial acetic acid was distilled off under reduced pressure, and the crude product was dissolved in 100ml of ethyl acetate, washed 5 times with 50ml of water each time. The organic layer was dried, concentrated, and subjected to silica gel column chr...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to pyridazinone compounds as shown in general formula I or isomers thereof or pharmaceutically acceptable salt, ester prodrug or solvate thereof, a preparation method thereof, a medicinal composition and application thereof in preparation of a tyrosine kinase inhibitor (especially c-Met inhibitor). The compounds or the medicinal composition thereof serving as a tyrosine kinase inhibitor (especially c-Met inhibitor) can be used for preventing and / or treating neoplastic diseases related to c-Met abnormality.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a new class of pyridazinone compounds or their isomers or pharmaceutically acceptable salts, esters, prodrugs or solvates, their preparation methods, pharmaceutical compositions and their use in the preparation of phenolic compounds. Use in amino acid kinase inhibitors, especially c-Met inhibitors. The compound or its pharmaceutical composition can be used as a tyrosine kinase inhibitor, especially as a c-Met inhibitor, to prevent and / or treat tumor diseases related to c-Met abnormality. Background technique [0002] Malignant tumors seriously threaten human survival and health, and the prevention and / or treatment of malignant tumors is a worldwide problem. At present, a large number of anti-tumor targets have been discovered, among which protein tyrosine kinases have become a class of anti-tumor targets with good prospects. [0003] The recepto...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D471/04A61K31/5377A61K31/501A61P11/00A61P35/02A61P35/00A61P27/02A61P37/06A61P27/06A61P1/04A61P15/00A61P7/10
CPCC07D401/14C07D471/04A61K31/50A61K31/501A61K31/5377A61P1/04A61P7/10A61P11/00A61P15/00A61P27/02A61P27/06A61P35/00A61P35/02A61P37/06
Inventor 胡有洪耿美玉邢唯强丁健艾菁
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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