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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 increased affinity and decreased affinity of adenosine triphosphate

Active Publication Date: 2014-10-22
ASTRAZENECA AB
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  • Summary
  • 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

[0495] Example 1: N-{4-methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(5-methyl-4-pyrazole A[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

[0496] at -10°C in N 2 Acryloyl chloride (0.331 mL, 1 M in THF, 0.33 mmol) was added 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, then concentrated in vacuo. Dissolve the residue in CH 2 Cl 2 (5mL) plus a small amount of CH 3 OH. Then, with saturated NaHCO 3 (2 mL) wash the solution, dry (MgSO 4 ), and then concentrated in vacuo. Purified by FCC with CH 2 Cl 2 5-25% CH in 3 OH, the appropriate fractions were concentrated in vacuo, and the obtained material was dissolved in CH 2 Cl 2 :7N methanol-ammonia 100:8 (1 mL), filter through a 1 g plug of silica gel. Conc...

Embodiment 2

[0497] 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

[0498] at -5°C in N 2 Acryloyl chloride (0.217 mL, 1 M in THF, 0.22 mmol) was added dropwise to N'-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl] in 1 min -4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 7, 100 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.33 mmol) in THF (3 mL). The resulting mixture was stirred at 0 °C for 15 minutes, then concentrated in vacuo. Dissolve the residue in CH 2 Cl 2 (5mL) add a few drops of CH 3 OH, with saturated NaHCO 3 solution (2 mL) for washing. Then, the organic solution was dried (MgSO 4 ), loaded onto silica gel under vacuum. Purified by FCC, used in CH 2 Cl 2 5-25% CH in 3 OH, and the appropriate fractions were concentrated in vacuo to obtain a residue, which was washed with CH 3 OH (0.3 mL) and dried in air. The title compound (37 mg, 31%) was obtain...

Embodiment 3

[0500] 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

[0501] at 0°C in N 2 , acryloyl chloride (0.025 mL, 0.30 mmol) 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, 135 mg, 0.30 mmol) and DIPEA (0.090 mL, 0.33 mmol) in CH 2 Cl 2 (10 mL) and DMF (2 mL). The resulting suspension was stirred at 0°C for 2 hours. Then warm to room temperature. The mixture was then diluted with water (15 mL) and washed with CH 2 Cl 2 (40 mL) for extraction. The resulting organic solution was washed with saturated Na 2 CO 3 (20 mL) and washed with saturated brine (20 mL). The solution was then dried (MgSO 4 ), concentrated in vacuo. Purified by FCC, used in CH 2 Cl 2 Elution with 1-5% 7M Methanol-Ammonia in Ethanol afforded the crude product. Further purification was carried out by preparative HPLC (Waters SunF...

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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 201280033773.9 (PCT / GB2012 / 051783 ) of a divisional application for a patent application for invention. 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 activation of epidermal growth factor receptors by certain variant forms (such as L858R activating mutants, Exon19 Treatment or prevention of diseases or conditions mediated by deletion activating mutants, and T790M resistance mutants). Such compounds and their salts are useful in the treatment or prevention of many different cancers. The present invention also relates to pharmaceutical compositions comprising said compounds and their salts (especially useful polymorphic forms of these compounds and salts), to intermediates useful in the preparation of said compounds, and to the use of said compounds and their salts. Methods of treati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D401/14C07D403/04C07D519/00A61K31/506A61K31/5377A61P35/00A61P35/02
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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