2 -(2,4,5-substituted -anilino) Pyrimidine Derivatives As Egfr Modulators Useful For Treating Cancer

A pyrimidine and 5-a technology, applied in the field of 2-pyrimidine compounds and their pharmaceutically acceptable salts, can solve the problems of decreased affinity and increased affinity of adenosine triphosphate

Active Publication Date: 2014-10-22
ASTRAZENECA AB
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The most prevalent EGFR activating mutations (L858R and delE746_A750) result in increased affinity for small molecule tyrosine kinase inhibitors (e.g., gefitinib and erlotinib) relative to wild-type (WT) EGFR, as well as increased affinity for Decreased affinity for adenosine triphosphate (ATP)

Method used

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  • 2 -(2,4,5-substituted -anilino) Pyrimidine Derivatives As Egfr Modulators Useful For Treating Cancer
  • 2 -(2,4,5-substituted -anilino) Pyrimidine Derivatives As Egfr Modulators Useful For Treating Cancer
  • 2 -(2,4,5-substituted -anilino) Pyrimidine Derivatives As Egfr Modulators Useful For Treating Cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0493] Example 1: N-{4-methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(5-methyl-4-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

[0494] At -10℃ in N 2 In 1 minute, add acryloyl chloride (0.331mL, 1M in THF, 0.33mmol) dropwise to 6-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridine- 4-yl)-N1-[5-methyl-4-(pyrazolo[1,5-a]-pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (intermediate 1,146 mg, 0.33 mmol) and DIPEA (0.086 mL, 0.50 mmol) in THF (4 mL). The resulting mixture was stirred at 0°C for 15 minutes and then concentrated in vacuo. Dissolve the residue in CH 2 Cl 2 (5mL) add a small amount of CH 3 OH. Then, use saturated NaHCO 3 (2mL) Wash the solution, dry (MgSO 4 ), and then concentrated in vacuo. Purification using FCC, using CH 2 Cl 2 5-25% CH in 3 OH is eluted, the appropriate fraction is vacuum concentrated, and the obtained material is dissolved in CH 2 Cl 2 : 7N methanol-ammonia 100:8 (1mL), filtered through a 1g silica gel plug. Conc...

Embodiment 2

[0495] Example 2: N-(5-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-[1-methyl- 3,6-Dihydro-2H-pyridin-4-yl)phenyl)prop-2-enamide

[0496] At -5℃ in N 2 Within 1 minute, add acryloyl chloride (0.217mL, 1M in THF, 0.22mmol) dropwise to N'-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl] -4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 7, 100mg, 0.22mmol) and DIPEA (0.057 mL, 0.33 mmol) in a slurry in THF (3 mL). The resulting mixture was stirred at 0°C for 15 minutes and then concentrated in vacuo. Dissolve the residue in CH 2 Cl 2 (5mL) Add a few drops of CH 3 OH, use saturated NaHCO 3 Solution (2mL) wash. Then, the organic solution was dried (MgSO 4 ), loaded onto silica gel under vacuum. Purification by FCC, used in CH 2 Cl 2 5-25% CH in 3 OH was eluted, and the appropriate fractions were concentrated in vacuo to obtain the residue, which was used in CH 3 Wash with OH (0.3 mL) and dry in air. The title compound (37 mg, 31%) wa...

Embodiment 3

[0498] Example 3: N-(5-{[4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl]amino}-4-methoxy-2-[4-methyl Piperazin-1-yl]phenyl)prop-2-enamide

[0499] At 0℃ in N 2 In, acryloyl chloride (0.025mL, 0.30mmol) was added dropwise to N'-[4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl]-4-methoxy- 6-(4-Methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 12, 135mg, 0.30mmol) and DIPEA (0.090mL, 0.33mmol) in CH 2 Cl 2 (10mL) and DMF (2mL) in solution. The resulting suspension was stirred at 0°C for 2 hours. Then warm to room temperature. Then dilute the mixture with water (15mL) and use CH 2 Cl 2 (40 mL) extraction. Use saturated Na 2 CO 3 (20 mL) and then washed with saturated brine (20 mL). Then the solution is dried (MgSO 4 ), concentrated in vacuo. Purification by FCC, used in CH 2 Cl 2 The 1-5% 7M methanol-ammonia in the elution was carried out to obtain a crude product. Use preparative HPLC (Waters SunFire column, 5μ silica gel, diameter 19mm, length 100mm) for further purification, water ...

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Abstract

The present invention relates to certain 2-(2,4,5-substituted-anilino)pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exon19 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.

Description

[0001] This application is a national application number of 201280033773.9 (PCT / GB2012 / 051783) entitled "2-(2,4,5-substituted aniline) pyrimidine derivatives as EGFR tuner for the treatment of cancer" filed on July 25, 2012 ) Divisional application of invention patent application. Technical field [0002] The present invention relates to certain 2-(2,4,5-substituted aniline) pyrimidine compounds and pharmaceutically acceptable salts thereof, which can be used for certain variant forms of epidermal growth factor receptor (such as L858R activation mutant, Exon19 The treatment or prevention of diseases or conditions mediated by deletion activating mutants and T790M resistance mutants. Such compounds and their salts can be used in the treatment or prevention of many different cancers. The present invention also relates to pharmaceutical compositions comprising the compounds and their salts (especially useful polymorphs of these compounds and salts), intermediates useful in the prepa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61P35/00A61P35/02
CPCC07D401/02C07D471/04C07D401/14C07D403/04C07D403/14C07D487/10C07D519/00A61P35/00C07D401/04A61K31/437
Inventor S.布特沃思M.R.V.芬莱R.A.瓦德V.K.卡达姆巴C.R.钦塔昆特拉A.穆鲁干H.M.雷德费尔恩C.E.楚亚奎
Owner ASTRAZENECA AB
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