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Pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor

A technology of alkyl and compound, applied in the field of pyridopyrimidine mTOR inhibitors, which can solve the problems of poor solubility and stability, large molecular weight, etc.

Active Publication Date: 2013-01-23
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The known mTOR inhibitor rapamycin can effectively inhibit the proliferation or growth of various tissue types such as smooth muscle cells, T cells and various tumor types of cells, but due to the mTOR macrolide inhibitors such as rapamycin , large molecular weight, poor solubility and stability, so it is necessary to develop small molecule inhibitors of mTOR with better solubility and stability, and select compounds with better efficacy and safety for the treatment of cancer

Method used

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  • Pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor
  • Pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor
  • Pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0214] Example 1 (5-(4-(8-oxa-3-azabicyclo[3.2.1]nonan-3-yl)-2-((S)-3-methylmorpholine)pyrido[ 2,3-d] pyrimidine Preparation of pyridin-7-yl)-2-methoxyphenyl)methanol (compound 1)

[0215]

[0216] (1) 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]nonane

[0217]

[0218] 2,4,7-trichloropyrido[2,3-d]pyrimidine (1g, 4.29mmol) and 8-oxa-3-azabicyclo[3.2.1]nonane hydrochloride (640mg, 4.29 mmol) was dissolved in 20 mL of DCM, and DIEA (0.9 mL, 5.15 mmol) was added dropwise in an ice-water bath. After the reaction was stirred at room temperature for 18 h, the reaction solution was washed with water, the organic layer was dried and concentrated to obtain a solid, which was directly used in the next reaction without purification.

[0219] (2)(5-(4-(8-oxa-3-azabicyclo[3.2.1]nonan-3-yl)-2-chloropyrido[2,3-d]pyrimidin-7-yl )-2-methoxyphenyl)methanol

[0220]

[0221] 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]nonane (310...

Embodiment 2

[0227] Example 2 (5-(4-(3-oxa-8-azabicyclo[3.2.1]nonan-8-yl)-2-((S)-3-methylmorpholine)pyrido[ 2,3-d]pyrimidine-7- base)-2-methoxyphenyl)methanol preparation (compound 3)

[0228]

[0229] (1) 8-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]nonane

[0230]

[0231] Operation is the same as in Example 1(1), and the product is directly used in the next step without purification.

[0232] (2)(5-(4-(3-oxa-8-azabicyclo[3.2.1]nonan-8-yl)-2-chloropyrido[2,3-d]pyrimidin-7-yl )-2-methoxyphenyl)methanol

[0233]

[0234] Operation is the same as in Example 1(2), and the product is directly used in the next step without purification.

[0235] (3) (5-(4-(3-oxa-8-azabicyclo[3.2.1]nonan-8-yl)-2-((S)-3-methylmorpholine)pyridine[2 ,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methanol

[0236]

[0237] Operation is the same as Example 1(3), and the productive rate is 7.5%.

[0238] Molecular formula: C 26 h 31 N 5 o 4 Molecular weight: 477.5 Mass spectr...

Embodiment 3

[0240] Example 3 (5-(4-(2-oxa-5-azabicyclo[2.2.2]nonan-5-yl)-2-((S)-3-methylmorpholine)pyrido[ 2,3-d]pyrimidine-7- base)-2-methoxyphenyl)methanol preparation (compound 4)

[0241]

[0242] (1) 5-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]nonane

[0243]

[0244]Operation is the same as in Example 1(1), and the product is directly used in the next step without purification.

[0245] (2)(5-(4-(2-oxa-5-azabicyclo[2.2.2]nonan-5-yl)-2-chloropyrido[2,3-d]pyrimidin-7-yl )-2-methoxyphenyl)methanol

[0246]

[0247] Operation is the same as in Example 1(2), and the product is directly used in the next step without purification.

[0248] (3) (5-(4-(2-oxa-5-azabicyclo[2.2.2]nonan-5-yl)-2-((S)-3-methylmorpholine)pyrido[ Preparation of 2,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methanol

[0249]

[0250] Operation is the same as Example 1(3), and the productive rate is 29%.

[0251] Molecular formula: C 26 h 31 N 5 o 4 Molecular weight: 477.5 ...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor which is shown as a general formula (I), pharmaceutically acceptable salts and stereoisomers thereof, and deuterated pyridopyrimidine mammalian mTOR inhibitors, wherein Z<1>, Z<2>, Z<3>, R<1>, R<2>, R<3>, X and W are defined in the specifications. The invention also relates to preparation methods for the compounds, medicinal inhibitors and medicinal compositions which contain the compounds, and the application of the compounds to preparation of medicines for treating and / or preventing post-transplant lymphoproliferative diseases which have response to inhibition of mTOR activity.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to pyridopyrimidine mTOR inhibitors, pharmaceutically acceptable salts thereof, stereoisomers or deuterated products thereof, preparation methods of these compounds, pharmaceutical preparations and pharmaceutical combinations containing these compounds compounds, and the use of these compounds in the preparation of medicaments for the treatment and / or prevention of proliferative diseases responsive to the inhibition of mTOR activity. 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 a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D519/00A61K31/5377A61K31/5386A61P35/00A61P35/02
Inventor 吴永谦王爱臣
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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