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2-Arylaminopyridine, pyrimidine or triazine derivatives and their preparation and use

A pyridine and pyrimidine technology, used in drug combinations, pharmaceutical formulations, active ingredients of heterocyclic compounds, etc., can solve problems such as inability to achieve patient drug concentration

Active Publication Date: 2018-06-12
WUXI SHUANGLIANG BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, the clinical experimental results of these irreversible inhibitors mentioned above show that these inhibitors still have certain limitations, such as toxic effects due to off-target effects, side effects caused by low selectivity, and inability to achieve sufficient drug concentrations in patients.

Method used

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  • 2-Arylaminopyridine, pyrimidine or triazine derivatives and their preparation and use
  • 2-Arylaminopyridine, pyrimidine or triazine derivatives and their preparation and use
  • 2-Arylaminopyridine, pyrimidine or triazine derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1: N-(5-((4-(benzo[d]isoxazol-3-yl)pyrimidin-2-yl)amino)-4-(methoxy)-2-((2- (Dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide (compound 14a)

[0144]

[0145] Compound 13a (40 mg, 0.14 mmol) was dissolved in dichloromethane (10 mL) and tert-butanol (1 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbadiene was added under ice-salt bath cooling Imine hydrochloride (EDCI, 35mg, 0.28mmol), triethylamine (19mg, 0.28mmol) and acrylic acid (13mg, 0.28mmol) were added, and the mixture was heated to room temperature for 2h. A saturated potassium carbonate solution was added to the reaction solution, stirred for 10 min, and separated, the organic phase was dried, evaporated to dryness, and purified by preparative chromatography to obtain 8 mg of a light yellow solid. 1 H NMR (400MHz, CDCl 3 ):δ10.23(s,1H),9.50(s,1H),8.69(d,J=5.0Hz,1H),8.57(d,J=8.0Hz,1H),7.68-7.57(m,4H) ,7.38-7.29(m,1H),6.85(s,1H),6.45-6.28(m,2H),5.71(m,1H),3.93(s,3H),2.96-2.88(m,2H),2.75 (s,3H),2....

Embodiment 2

[0155] Example 2: N-(5-((4-(benzo[d]isoxazol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiper (oxin-1-yl)phenyl)acrylamide (compound 14b)

[0156]

[0157] Compound 14b was prepared in the same manner as compound 14a, except that compound 13a was replaced with compound 13b. 1 HNMR (400MHz, CDCl 3 ):δ9.45(s,1H),8.68(d,J=5.0Hz,1H),8.56-8.54(m,2H),7.68-7.58(m,4H),7.39-7.35(m,1H), 6.85(s,1H),6.44-6.23(m,2H),5.78(d,J=9.1Hz,1H),3.93(s,3H),2.99-2.98(m,4H),2.69(m,4H) ,2.45(s,3H); MS(ESI)(m / z):[M+H] + 486.2.

[0158] 1-(4-bromo-5-methoxy-2-nitrophenyl)-N,N-dimethylpiperidin-4-amine (compound 11c)

[0159]

[0160] Compound 11c was prepared in the same manner as compound 11a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylpiperidin-4-amine. 1 H NMR (400MHz, CDCl 3 )δ8.22(s,1H),6.51(s,1H),3.97(s,3H),3.38(d,J=12.4Hz,2H),2.93-2.87(m,2H),2.45-2.31(m ,7H),1.95-1.92(m,2H),1.84-1.74(m,2H); MS(ESI)(m / z):[M+H] + 358.1.

[0161] 4-(Benzo[d]isoxazol-3-y...

Embodiment 3

[0167] Example 3: N-(5-((4-(benzo[d]isoxazol-3-yl)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidine-1 -yl)-4-methoxyphenyl)acrylamide (compound 14c)

[0168]

[0169] Compound 14c was prepared in the same manner as compound 14a, except that compound 13a was replaced by compound 13c. 1 HNMR (400MHz, CDCl 3 ):δ9.39(s,1H),8.65(d,J=5.0Hz,1H),8.52(d,J=7.9Hz,1H),8.41(s,1H),7.75-7.53(m,4H) ,7.36(t,J=7.4Hz,1H),6.76(s,1H),6.37-6.36(m,2H),5.78-5.77(m,1H),3.92(s,3H),3.18-3.15(m ,2H),2.81-2.76(m,3H),2.67(s,6H),2.25-2.22(m,2H),1.98-1.96(m,2H); MS(ESI)(m / z):[M +H] + 514.3.

[0170] (S)-1-(1-(4-bromo-5-methoxy-2-nitrophenyl)pyrrolidin-2-yl)-N,N-dimethylmethylamine (compound 11d)

[0171]

[0172] Except for replacing N,N,N'-trimethylethylenediamine with (S)-N,N-dimethyl-1-(pyrrolidin-2-yl)-methanamine, the same as compound 11a Preparation of compound 11d. 1 H NMR (400MHz, CDCl 3 ):δ8.12(s,1H),6.71(s,1H),3.95(s,3H),3.62-3.55(m,1H),2.72-2.61(m,2H),2.49-2.23(m,8H ),2.09-1.71(...

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PUM

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Abstract

The present invention relates to 2-arylaminopyridine, pyrimidine or triazine derivatives and their preparation method and application. The 2-arylaminopyridine, pyrimidine or triazine derivatives can act on certain mutant forms of epidermal growth factor receptors, such as L858R activation mutants, delE746_A750 mutants, Exon19 deletion activation mutants and T790M drug-resistant mutants , and thus be used in the treatment and prevention of diseases and conditions. The 2-arylaminopyridine, pyrimidine or triazine derivatives can be used for the treatment and prevention of cancer. The present invention also relates to pharmaceutical compositions comprising 2-arylaminopyridine, pyrimidine or triazine derivatives, intermediates for the preparation of 2-arylaminopyridine, pyrimidine or triazine derivatives, and the use of 2-arylamino Methods of pyridine, pyrimidine or triazine derivatives for the treatment of diseases mediated by various forms of EGFR.

Description

technical field [0001] The present invention belongs to the field of new medical technology, and particularly relates to 2-arylaminopyridine, pyrimidine or triazine derivatives or pharmaceutically acceptable salts or solvates thereof, which can be used for certain types of epidermal growth caused by certain variant forms Treatment or prevention of diseases or conditions mediated by factor receptors (eg L858R activating mutant, delE746_A750 mutant, Exonl9 deletion activating mutant and T790M drug resistant mutant). Such compounds or salts thereof, or solvates thereof, are useful in the treatment or prevention of many different cancers. The invention also relates to processes for the preparation of intermediates useful in the preparation of said compounds. Background technique [0002] The main treatments for cancer patients are radiotherapy, chemotherapy and surgery. Clinically, about 80% of lung cancers are non-small-cell lung cancer (NSCLC). According to statistics from t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04C07D413/14C07D487/10C07D471/04C07D519/00C07D495/04C07D403/04C07D403/14C07D487/04A61K31/506A61K31/53A61K31/519A61K31/4439A61K31/444A61P35/00A61P35/02
CPCC07D403/04C07D403/14C07D413/04C07D413/14C07D471/04C07D487/04C07D487/10C07D495/04C07D519/00A61K31/403A61K31/437A61K31/506A61K31/519C07D401/04C07D405/04A61P35/00A61K31/44A61K31/505A61K31/53C07D213/73C07D239/42C07D251/42
Inventor 吴家权张海军曹焕岩金深霜张帅陆政华董健王赪晨谈秋
Owner WUXI SHUANGLIANG BIOTECH CO LTD
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