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Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors

A compound, C1-C3 technology, used in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as unclear activation mechanism

Inactive Publication Date: 2010-03-17
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The mechanism of activation of class III PI3Ks is unclear

Method used

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  • Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors
  • Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors
  • Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[1366] general method

[1367] The following general procedures will outline the synthesis of the pyrazolopyrimidine analogs for each example.

[1368] Summary: Preparative HPLC using a Gilson instrument

[1369] The crude material was dissolved in 1.5 ml DMSO and 0.5 ml MeOH, filtered through 0.45 μm GMF, and purified by Gilson HPLC using Phenomenex LUNA C 18 Column: 60mm×21.20mm I.D., 5μm particle size, using ACN / water (containing 0.2% TFA or ammonium hydroxide) gradient elution. Appropriate fractions were subsequently analyzed by LC / MS.

[1370] Analytical HPLC conditions: instrument - Agilent 1100; column: Thermo Aquasil C18, 50×2.1mm, 5μm; mobile phase: A: water containing 0.1% formic acid; B: containing 0.1% formic acid ACN for formic acid; flow rate: 0.800 mL / min; column temperature: 40 °C; injection volume: 5 mL; UV: monitors 215 nm, 230 nm, 254 nm, 280 nm and 300 nm;

[1371] Gradient table:

[1372] time (minutes) B％

[1373] 0 5

[1374] 2.5 95

[1375] 4...

example 1

[1379] Example 1: 2,4,6-Trichloro-pyrimidine-5-carbaldehyde (Scheme 1)

[1380] After 1.5 hours, to POCl cooled to 0°C 3 (200 mL) in DMF (42 mL) was slowly added barbituric acid (30 g). The mixture was then heated to reflux for 16 hours and then evaporated (disintegrated carefully by pouring the distillate slowly into a stirred slurry of ice methanol). The residue was cooled to 0 °C and added very slowly to the ice-water solution, at which point a beige solid formed. The solid was filtered, dissolved in DCM, washed with water, washed with saturated NaHCO 3 solution washed, dried (MgSO 4 ) and concentrated in vacuo to give white crystals (24g).

example 2

[1381] Example 2: 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (Scheme 1)

[1382] To a solution of chloroacetaldehyde (3.7 g, 17.5 mmol) dissolved in EtOH (50 mL) and cooled to -78 °C was added methylhydrazine (0.93 mL, 17.5 mmol) and TEA (8 mL). The mixture was stirred at -78°C for 30 minutes, then at 0°C for 2 hours. The solution was then concentrated in vacuo without heating. To the reduced volume solution was added EtOAc and washed with saturated NaHCO 3 Solution The solution was washed and concentrated in vacuo without heating. Filtration through a small plug of silica gel (2:1 EtOAc:Hex) and concentration gave the desired product as a yellow solid.

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Abstract

The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR -related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K -related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.

Description

technical field [0001] The present invention relates to pyrazolopyrimidine analogs; compositions comprising pyrazolopyrimidine analogs; and methods for treating or preventing mTOR-related diseases, comprising administering an effective amount of pyrazolopyrimidine analogs. The present invention also relates to a method for treating or preventing PI3K-related diseases, which comprises administering an effective amount of pyrazolopyrimidine analogs. Background technique [0002] The mammalian target of rapamycin (Rapamycin), mTOR, is a cell signal transduction protein, which regulates the response of tumor cells to nutrients and growth factors, and through the effect on vascular endothelial growth factor (VEGF), Controls blood supply to tumors. mTOR inhibitors starve cancer cells and, by inhibiting the action of mTOR, shrink tumors. All mTOR inhibitors bind mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K / Akt pathway. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P29/00A61P35/00A61P3/10
CPCC07D487/04A61P1/18A61P13/08A61P13/12A61P17/06A61P19/00A61P19/02A61P19/08A61P27/02A61P29/00A61P3/10A61P35/00A61P35/02A61P37/06A61P43/00A61P9/00A61P9/10
Inventor 阿里·扎什克帕维尔·沃伊切赫·诺瓦克叶罗恩·费尔海耶恩凯文·J·柯伦约书亚·卡普兰戴维·马尔维茨马修·格雷戈里·比尔萨维奇德雷克·塞西尔·科尔塞米拉米斯·艾拉尔-卡劳斯蒂安柯尔·于戴维·詹姆斯·理查德马克·勒菲弗
Owner WYETH LLC
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