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Imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor

A kind of naphthalene and compound technology, applied in the field of imidazonaphthalene PI3K and mTOR dual inhibitors

Active Publication Date: 2013-10-23
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no PI3K / mTOR dual inhibitor drug on the market. Therefore, it is necessary to develop more structural types of PI3K / mTOR dual inhibitors, and select compounds with better efficacy and safety for the treatment of cancer.

Method used

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  • Imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor
  • Imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor
  • Imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Example 1 8-(2-methoxypyridin-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2,3-dihydroimidazo[4, 5-c][1,7] Preparation of naphthyridine (compound 1)

[0180] The preparation of embodiment 1-a (6-bromo-2-chloropyridine-3-amino) methylene malonate diethyl ester

[0181]

[0182]Add 20.7g (100mmol) of 6-bromo-3-amino-2-chloropyridine and 21.6g (100mmol) of diethyl ethoxymethylene malonate into 200mL of absolute ethanol, stir and reflux for 5 hours, and cool. A solid was precipitated and filtered to obtain 36.0 g of a white solid with a yield of 95.3%.

Embodiment 1-b

[0183] Example 1-b Preparation of 8-chloro-6-bromo-4-hydroxy[1,7]phthalazine-3-carboxylic acid ethyl ester

[0184]

[0185] 30.2g (80mmol) (6-bromo-2-chloropyridine-3-amino) diethyl methylene malonate was heated to reflux in 200mL diphenyl ether and stirred for 2 hours, then the reaction mixture was poured into petroleum ether, A yellow solid was precipitated, which was filtered and dried to obtain 24.5 g of the product, with a yield of 92.4%.

Embodiment 1-c

[0186] Example 1-c Preparation of 8-chloro-6-(2-methoxypyridin-5-yl)-4-hydroxy[1,7]phthalazine-3-carboxylic acid ethyl ester

[0187]

[0188] 16.6g (50mmol) 8-chloro-6-bromo-4-hydroxy [1,7] ethyl phthalazine-3-carboxylate, 9.18g (60mmol) 2-methoxypyridine-4-boronic acid, 1.6 g of bis(triphenylphosphine)palladium(II) dichloride and 50 mL of 1M Na 2 CO 3 The solution was added in 150mL DMF, stirred at room temperature for 2h, and the mixture was washed with saturated NaHCO 3 quenched with aqueous solution, then extracted with ethyl acetate, washed with brine, washed with Na 2 SO 4 After drying, filtering and evaporating to dryness under reduced pressure, 15.6 g of the product was obtained with a yield of 86.7%.

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PUM

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Abstract

The invention relates to the technical field of medicine, and in particular to an imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor represented by a general formula (I), a pharmaceutically acceptable salt or a stereomer thereof, wherein R1, R2, R3, R3', R4, R5 and X are defined in the description; and the invention further relates to a preparation method of the compounds, a pharmaceutical preparation containing the compounds, a pharmaceutical composition containing the compounds, and application of the compounds in preparation of medicines for treating and / or preventing proliferative diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to imidazodiazine-type PI3K and mTOR dual inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds, Pharmaceutical compositions containing these compounds, and applications of these compounds in the preparation of medicines for treating and / or preventing proliferative diseases. 2. Background technology [0002] Tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in the genetic material of cells, resulting in abnormal gene expression and abnormal proliferation of cells. Tumor cells lose their normal growth regulation function and have the ability to grow independently or relatively independently. When the tumorigenic factors are stopped, they can continue to grow and consume a large amount of nutrients in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14C07D519/00A61K31/4545A61K31/444A61K31/4375A61P35/00A61P17/00A61P13/08
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD