Pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as preparation method and application of pyrrolopyrimidine compounds

A compound and hydrate technology, applied in the field of medicine, can solve the problems of reduced curative effect, drug failure, loss of Cys797 covalent binding, etc.

Inactive Publication Date: 2019-12-03
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of inhibitor has inhibitory effects on wild-type and activating mutant EGFR at the same time, and has achieved great clinical success, but the drug resistance of recipient patients after taking it for a period of time, especially the drug resistance caused by the T790M mutation Sex reduces or loses efficacy
The second-generation EGFR inhibitor afatinib (Afatinib) is an irreversible inhibitor that contains a Michael receptor that can covalently bind to the cysteine ​​residue (Cys797) located at the entrance of the ATP binding pocket. The inhibitor shows strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and its inhibitory activity aga

Method used

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  • Pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as preparation method and application of pyrrolopyrimidine compounds
  • Pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as preparation method and application of pyrrolopyrimidine compounds
  • Pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as preparation method and application of pyrrolopyrimidine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Example 1. (2-((2-((5-chloro-4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)-7H-pyrrole Preparation of [2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0150]

[0151] Step 1) (2-((2-((5-chloro-4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)-7-(( Preparation of 2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0152]280 mg (1 mmol) of 1-(4-amino-2-chloro-5-methoxyphenyl)-N,N-dimethylpiperidin-4-amine, (2-((2-chloro-7 -((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine dimethyl 450 mg ( 1 mmol), 17 mg (0.1 mmol) of p-toluenesulfonic acid were placed in a reaction flask, 10 ml of sec-butanol was added, heated and stirred until the reaction was completed, and 350 mg of the product was obtained by column chromatography after rotary evaporation and concentration, with a yield of 50%. MS:698[M+H] + .

[0153] Step 2) (2-((2-((5-chloro-4-(4-(di...

Embodiment 2

[0155] Example 2. (2-((2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0156]

[0157] The preparation of reference example 1, in the starting material with equimolar equivalent of 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Aniline was substituted for 1-(4-amino-2-chloro-5-methoxyphenyl)-N,N-dimethylpiperidin-4-amine. 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.35(s,1H),8.97–8.76(m,1H),8.36(s,1H),7.63–7.48(m,2H), 7.46(s,1H),7.08(t,J=7.7Hz,1H),6.96(t,J=2.8Hz,1H),6.82(s,1H),6.38(d,J=2.7Hz,1H), 3.89(s,3H),3.28–3.23(m,2H),2.68(t,J=11.4Hz,2H),2.59–2.51(m,4H),2.42–2.23(m,5H),2.16(s, 3H),1.91–1.85(m,2H),1.83(d,J=13.4Hz,6H),1.68–1.49(m,2H); MS:623[M+H] + .

Embodiment 3

[0158] Example 3. N-(5-chloro-4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-4-(1-methyl-1H-ind Preparation of Indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0159]

[0160] With reference to the preparation of Example 1, in the starting material, equimolar equivalents of 2-chloro-4-(1-methyl-1H-indol-3-yl)-7-((2-(trimethylsilyl) )ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine instead of (2-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphonium dimethyl. 1 HNMR(400MHz,DMSO-d6)δ11.52(s,1H),8.65(d,J=7.9Hz,1H),8.51(s,1H),8.41(s,1H),7.60(s,1H), 7.53(d, J=8.1Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.20(t, J=6.6Hz, 2H), 6.86(d, J=9.0Hz, 2H), 3.94( d,J=8.1Hz,6H),3.34–3.31(m,2H),2.70(t,J=11.1Hz,2H),2.28–2.25(m,1H),2.24(s,6H),1.94–1.78 (m,2H),1.67–1.51(m,2H); MS:530[M+H] + .

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Abstract

The invention provides pyrrolopyrimidine compounds containing m-chloroaniline substituents as well as a preparation method and application of the pyrrolopyrimidine compounds, and particularly relatesto compounds represented by a formula (I) shown in the specification, and isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs of the compounds, a preparation method of the compounds, and the isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs of the compounds and applications of the compounds, and the isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs of the compounds in preparation of drugs used as a kinase inhibitor. The compounds provided by the invention have good inhibitory activity on mutant EGFR<T790M> and EGFRC<797S> kinases, and shows moderate inhibitory activity on wild EGFR kinase at the same time.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a pyrrolopyrimidine compound containing m-chloroaniline substituents, a preparation method and an application thereof. Background technique [0002] Protein kinase is an important signal messenger for cell life activities, which can catalyze the transfer of the γ-phosphate group at the end of ATP to the hydroxyl receptor in the substrate amino acid residue (serine, threonine, tyrosine), thereby activating the target Protein (Johnson L.N., and Lewis R.J., Structural basis for control by phosphorylation, Cheminform, 2001, 101, 2209.). Protein kinases are involved in numerous physiological processes, including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., Kinetic and catalytic mechanisms of proteinkinases, Chemical reviews, 2001, 101, 2271.). Among the existing drug targets in the human body, members of the protein kinase family...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07D487/04A61K31/675A61K31/519A61P37/02A61P27/02A61P17/06A61P17/00A61P17/14A61P19/02A61P1/00A61P9/10A61P11/00A61P19/08A61P35/00A61P35/02
CPCA61P1/00A61P9/10A61P11/00A61P17/00A61P17/06A61P17/14A61P19/02A61P19/08A61P27/02A61P35/00A61P35/02A61P37/02C07D487/04C07F9/65616
Inventor 张强王中祥冯守业张宏波杨海龙周利凯徐占强
Owner BEIJING SCITECH MQ PHARMA LTD
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