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Quindoline derivative, medicine composition thereof, preparation method and application

A derivative and quinoline technology, applied in the field of quinoline derivatives, can solve the problems of large differences in the activity of compounds, no structure-activity relationship, unsatisfactory and other problems

Active Publication Date: 2016-01-27
SHANGHAI HAIJU BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are many selective c-Met inhibitors in different stages of research and development. A series of small molecule compounds developed by Sugen can selectively inhibit c-Met kinase activity at the nanomolar level (W02005004607, W02005004808, W02005005378), Amgen’s Compound AMG-208 is in Phase I clinical research (W02008008539, W02009091374), SGX’s SGX126 has terminated Phase I clinical research due to renal toxicity (W02008051808), Johnson & Johnson’s compound JNJ-38877605 (W02007075567) and Pfizer’s PF-04217903 (US2007265272) have entered the first phase of clinical research; however, there is still no selective c-Met protein kinase inhibitor on the market at this stage
[0006] In WO2008051808, various structurally modified c-Met kinase inhibitors are disclosed, but the research on the structure-activity relationship is still quite lacking, and the activity of the products varies. For example, the IC of the compounds of Examples 28 and 29 50 Not ideal, not only exceeding 100nM, but even reaching the micromolar level
[0007] In WO2013038362, a series of c-Met kinase inhibitors are disclosed, which also does not involve the study of the structure-activity relationship. Examples 18, 26, 28, 34 and 45 all carry nitrogen-containing groups at the 3-position of the quinoline ring Group substitution, but poor activity
[0008] In WO2014180182, the 3-position and 4-position disubstitution on the quinoline ring is disclosed, but it does not involve the study of structure-activity relationship, and the activity of the obtained compounds is very different.

Method used

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  • Quindoline derivative, medicine composition thereof, preparation method and application
  • Quindoline derivative, medicine composition thereof, preparation method and application
  • Quindoline derivative, medicine composition thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: 9-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3- Synthesis of base]methyl}-8-fluoro-4-methyl-2H-[1,4]oxazizo[3,2-c]quinolin-3(4H)-one

[0065] The synthetic route is as follows:

[0066]

[0067] Step 1: Preparation of 3-amino-6-bromo-7-fluoro-quinoline-4-ol (HJ-1)

[0068] Add compound 6-bromo-7-fluoro-3-nitroquinoline-4-ol (2.5g, 9.0mmol) and methanol (15ml) in 100ml one-necked flask, add hydrazine hydrate (2.7g, 46.5ml) under ice bath mmol) and Raney nickel (0.45mmol), stirred at room temperature until the end of the reaction. The reaction solution was filtered, the filter cake was washed three times with methanol, and the organic phase was spin-dried to obtain 2.20 g of compound 3-amino-6-bromo-7-fluoro-quinoline-4-ol (HJ-1), with a yield of 95% ;MSm / z(ESI):258.89([M+l] + ).

[0069] Step 2: Preparation of 9-bromo-8-fluoro-2H-[1,4]oxazino[3,2-c]quinolin-3(4H)-one (HJ-2)

[0070] Add (HJ-1) (2.10g, 8.8mmol) prepared in ...

Embodiment 2

[0082] Example 2: 8-fluoro-4-methyl-9-{[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3- b] Pyridazin-3-yl]sulfanyl}-2H-[1,4]oxazizo[3,2-c]quinolin-3(4H)-one

[0083] The synthetic route is as follows:

[0084]

[0085] Step 1: Preparation of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (HJ-8)

[0086] Add dioxane (67ml) and water (27ml) in the three-necked flask of 250ml as solvent, then add successively 3,6-dichloropyridazine (2.68g, 18mmol), potassium carbonate (6.0g, 43.5mmol), 1-methylpyrazole-4-boronic acid pinacol ester (2.99g, 14.4mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.7g, 0.96mmol ), after replacing with nitrogen, the temperature was raised to 80°C. After reacting for 10 hours, the reaction solution was concentrated and separated by column chromatography to obtain 1.96 g of light yellow solid 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (HJ-8) , yield 70%; MSm / z (ESI): 195.12 ([M+l] + ).

[0087] Step 2: Preparation of 3-h...

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Abstract

The invention discloses a quindoline derivative, a medicine composition thereof, a preparation method and application. The quindoline derivative has c-Met inhibition activity and can be used for treating, alleviating and / or preventing cancerous or similar diseases. (See the specification).

Description

technical field [0001] The invention relates to a quinoline derivative, its pharmaceutical composition, preparation method and application. Background technique [0002] Cellular signaling is a fundamental mechanism of action. Stimulus signals from outside the cell can regulate various physiological responses of cells, such as cell proliferation, differentiation, apoptosis, and motility, after being transmitted to the inside of the cell. Many signaling processes are reversible processes utilizing protein phosphorylation, involving specific protein kinases and phosphorylases. Protein kinases (PKs) can transfer the phosphate group of ATP to specific amino acid residues of functional proteins, and play a very important role in the signal transduction process. [0003] Protein kinases can be classified into serine-threonine kinases (STKs) and tyrosine kinases (PTKs) according to the class of amino acids that serve as substrates in the phosphorylation process. Tyrosine kinases...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/5383A61P35/00
CPCC07D519/00A61K31/5383A61P35/00C07B2200/07C07B2200/09
Inventor 张茹玲
Owner SHANGHAI HAIJU BIOLOGICAL TECH CO LTD