Indole-1-carbonate compound and preparation method and application thereof

A technology of carbonates and compounds, applied in the field of drug synthesis, can solve problems such as poor oral exposure

Active Publication Date: 2018-07-06
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its important metabolite AZ5104 has better activity (nearly 10-fold difference), and also has more than 10-fold significant selectivity difference for EGFRWT and mutations, but itself has poor oral exposure

Method used

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  • Indole-1-carbonate compound and preparation method and application thereof
  • Indole-1-carbonate compound and preparation method and application thereof
  • Indole-1-carbonate compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] 2-(2-((5-acrylamide-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-indole-1-methyl carbonate (I-1)

[0102] Synthesis method 1:

[0103] N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) -4-Methoxyphenyl)acrylamide (ie AZ5104, 3.0g, 6.18mmol) was dissolved in 200mL of anhydrous tetrahydrofuran, and sodium hydride (packed in mineral oil, 60%, 740mg, 18.53mmol) was added slowly under ice-bath conditions , after stirring for 2min, methyl chloroformate (1.75g, 18.53mmol) dissolved in 50mL of tetrahydrofuran was slowly added dropwise, the ice bath was removed, and after 10min, the reaction solution was slowly poured into 200mL of saturated ammonium chloride solution, and 200mL of ethyl acetate was added to extract the organic phase, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin-dried solvent, and purified by column chromatography to obtain 2-(2-((5-acrylamide-4-((2...

Embodiment 2

[0111] 2-(2-((5-acrylamide-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-ethyl carbonate (I-2)

[0112] Except that methyl chloroformate is replaced by ethyl chloroformate, the synthetic method is the same as synthetic method 1 in Example 1.

[0113] 1 H NMR (400MHz, CDCl 3 )δ10.08(s,1H),9.64(s,1H),8.53(d,J=5.2Hz,1H),8.42(s,1H),8.38(d,J=7.5Hz,1H),8.26( d,J=8.1Hz,1H),7.64(s,1H),7.37(ddd,J=15.1,14.0,6.7Hz,2H),7.14(d,J=5.2Hz,1H),6.81(s,1H ),6.41(d,J=2.8Hz,2H),5.72–5.64(m,1H),4.53(q,J=7.1Hz,2H),3.90(s,3H),2.94–2.86(m,2H) , 2.72 (s, 4H), 2.36 (s, 2H), 2.31 (s, 8H), 1.49 (d, J=7.1Hz, 3H).

[0114] LR-Mass (ESI): 558.8 (M+1, C 30 h 36 N 7 o 4 ).

Embodiment 3

[0116] 2-(2-((5-acrylamide-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-propyl carbonate (I-3)

[0117] Except that methyl chloroformate is replaced by propyl chloroformate, the synthetic method is the same as synthetic method 1 in Example 1.

[0118] 1 H NMR (500MHz, CDCl 3 )δ9.91(s,1H),9.50(s,1H),8.73(d,J=14.8Hz,1H),8.55(dd,J=14.8,3.1Hz,1H),8.11(dd,J=14.9 ,3.1Hz,1H),7.43–7.06(m,4H),6.43(s,1H),6.17(ddd,J=26.6,24.4,12.2Hz,2H),5.69(dd,J=33.3,4.6Hz, 1H), 4.69(s, 1H), 4.21(t, J=14.7Hz, 2H), 3.86(s, 3H), 3.53(dt, J=21.9, 14.6Hz, 2H), 2.75(s, 3H), 2.50 (t, J = 14.6Hz, 2H), 2.21 (s, 6H), 1.91–1.49 (m, 2H), 1.01 (t, J = 13.4Hz, 3H).

[0119] LR-Mass (ESI): 572.8 (M+1, C 31 h 38 N 7 o 4 ).

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Abstract

The invention belongs to the field of medicine synthesis and specifically relates to indole-1-carbonate compound shown in a general formula (I), a pharmaceutically acceptable salt, a deuterium compound or a solvate of the indole-1-carbonate compound, a preparation method thereof and application thereof in preparing medicine for selectively inhibiting active EGFR resistance mutation T790M and activated mutation. The formula (I) is shown in the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a class of indole-1-carbonate compounds and their preparation methods, as well as their use in the preparation of antitumor drugs. Background technique [0002] Epidermal Growth Factor Receptor (EGFR), also known as ErbB1 or HER1, is an important member of the ErbB receptor family. After binding to endogenous ligands such as Epidermal Growth Factor (EGF), homologous two Polymerize or heterodimerize with other members of the ErbB family (such as HER2, HER3, HER4), activate downstream pathways through phosphorylation of key tyrosine residues in the intracellular end, and regulate cell proliferation and survival. [0003] Epidemiology has found that the overexpression or overactivation of EGFR is closely related to the occurrence and development of many tumors, such as 40-80% of non-small cell lung cancer (NSCLC) overexpression of EGFR (Fujino, S.; Enokibori, T. ; Tezuka, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCC07D403/04
Inventor 胡有洪陈笑艳丁健任文明钟大放陈奕谢华
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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