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Dual PI3K and mTOR inhibitor compounds

A compound, CH2 technology, used in organic chemistry, pharmaceutical combinations, medical preparations containing active ingredients, etc.

Active Publication Date: 2012-04-04
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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  • Dual PI3K and mTOR inhibitor compounds
  • Dual PI3K and mTOR inhibitor compounds
  • Dual PI3K and mTOR inhibitor compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1 8-(6-methoxypyridin-3-yl)-3-methyl-1-piperidin-4-yl-3,4-dihydrothieno[3′,2′:5,6 ]pyrido[4,3-d] Preparation of pyrimidin-2(1H)-one (compound 1)

[0158] 1. Preparation of tert-butyl thiophen-2-ylcarbamate

[0159]

[0160] 2-thiophene formic acid (10g, 78mmol), DPPA (20.2mL, 93.6mmol) and triethylamine (17.4mL, 125mmol) were dissolved in tert-butanol (150mL), the reaction was refluxed for 6h, cooled, concentrated, and the residue was decanted into saturated NaHCO 3 In the aqueous solution, a pale yellow solid precipitated out, washed three times with water, dried in vacuum at 45°C for 8 hours, and the product was directly used in the next step.

[0161] 2. Preparation of Thiophene-2-amine

[0162]

[0163] The product from the previous step (12 g, 60 mmol) was dissolved in dichloromethane (200 mL), and hydrogen chloride gas was introduced into the mixture for 2 h under ice-bath conditions. TLC (petroleum ether: ethyl acetate = 5: 1) showed that the...

Embodiment 2

[0199] Example 2 (R)-1-[1-(2-hydroxypropionyl)piperidin-4-yl]-8-(6-methoxypyridin-3-yl)-3-methyl-3,4 - dihydrothiazide Preparation of pheno[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one (compound 2)

[0200]

[0201] 8-(6-methoxypyridin-3-yl)-3-methyl-1-piperidin-4-yl-3,4-dihydrothieno[3′,2′:5,6]pyridine And[4,3-d]pyrimidin-2(1H)-one hydrochloride (compound 1) (102mg, 0.23mmol) was dissolved in dichloromethane (20mL), triethylamine (0.05mL) was added respectively, (R )-lactic acid (26.7mg, 0.296mmol), 1-hydroxybenzotriazole (37.8mg, 0.280mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (70.8mg, 0.37mmol), the reaction was stirred at room temperature for 2 hours, TLC (dichloromethane:methanol=10:1) showed that the reaction was complete, the reaction solution was washed with saturated sodium carbonate solution, water, and saturated brine successively, and the organic layer was It was dried with anhydrous sodium sulfate, concentrated, separated and purified...

Embodiment 3

[0204] Example 3 8-(6-methoxypyridin-3-yl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]-3,4 - Dihydrothiophene Preparation of [3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one (compound 3)

[0205] 1.2-Bromo-4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(trifluoromethyl)aniline)thieno[2,3-b]pyridine-5-carboxylic acid Preparation of ethyl ester

[0206]

[0207] 2-Bromo-4-chlorothieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (see (6) in Example 1) (4.5g, 14mmol) and 4-(4-amino-2 -(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (4.0g, 11.6mmol) was dissolved in ethanol (10mL), triethylamine (4.68g, 46.3mmol) was added to the system, and reflux Stir for 48 hours. Cooling, concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate = 3: 1) gave 2.1 g of light yellow solid, yield 23.8%.

[0208] 2.4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(trifluoromethyl)phenylamino)-2-(6-methoxypyridin-3-yl)thiophene ...

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PUM

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Abstract

The invention which belongs to the technical field of medicines concretely relates to dual PI3K and mTOR inhibitor compounds with a general formula represented by formula (I), pharmaceutically acceptable salts thereof, or stereoisomers thereof. In the formula (I), R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, X and Y are defined in the specification. The invention also relates to a preparation method of the compounds, medicinal preparations containing the compounds, medicinal compositions containing the compounds, and an application of the compounds in the preparation of medicines for treating and / or preventing proliferative diseases.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to PI3K and mTOR dual inhibitor compounds, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds, and drugs containing these compounds Compositions, and the application of these compounds in the preparation of medicines for treating and / or preventing proliferative diseases. Background technique [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 the human body. If...

Claims

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Application Information

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IPC IPC(8): C07D495/14C07D519/00A61K31/519A61P35/00A61P17/00A61P13/08
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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