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Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative as well as preparation method and application thereof

A technology of indolylpyrimidine and its derivatives, which is applied in the field of medicine, can solve the problem of EGFR selectivity reduction, and achieve high activity, increased metabolic stability, and high selectivity

Active Publication Date: 2021-11-02
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Clinical studies have proved that AZ5104 and AZ7550 are the two main active metabolites of osimertinib metabolized by cytochrome P450. The inhibitory effect of del19 / T790M was significantly enhanced, but the selectivity to wild-type EGFR was reduced, and the inhibitory effect on EGFRWT was related to the occurrence of toxic side effects such as skin rash after medication (J .Med.Chem.2014,57,8249)

Method used

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  • Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative as well as preparation method and application thereof
  • Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative as well as preparation method and application thereof
  • Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] This embodiment provides a compound VIII-1, the structural formula of the compound VIII-1 is:

[0028]

[0029] The compound VIII-1 is synthesized according to the following steps:

[0030]

[0031] Specifically, the preparation method of compound VIII-1 comprises the following steps:

[0032] Preparation of Intermediate III Add 5.00g (42.68mmol) indole I and 7.28g (128.04mmol) KOH into 50mL DMF, stir at 0°C for 30min, then slowly add 7.42g (51.22mmol) deuteromethyl iodide II dropwise To the above system, stirred at room temperature for 12h. The reaction was monitored by thin-layer chromatography TLC. After the reaction was completed, the reaction system was extracted with ethyl acetate (3×150mL), the organic phases were combined, and the organic phases were washed with anhydrous MgSO 4 After drying, filter with suction, and concentrate Intermediate III under reduced pressure to obtain 5.121 g of light yellow liquid with a yield of 89%. 1 H NMR (400MHz, DMSO-d ...

Embodiment 2

[0039] This embodiment provides a compound VIII-2, the structural formula of the compound VIII-2 is:

[0040]

[0041] This example also provides a preparation method of compound VIII-2, which is basically the same as the preparation method of compound VIII-1 provided in Example 1, the difference mainly lies in: the intermediate VI-2, intermediate The structural formula of body VII-2 is different from that in Example 1, especially the group R in the structural formula of intermediate VI-2 and intermediate VII-2 1 different, the group R in this example 1 for:

[0042] Compound VIII-2 prepared by the above method is a white solid, and the calculated yield is about 90%; 1 H NMR (400MHz, DMSO-d 6 )δ9.04(s,1H),8.80(s,1H),8.57(s,1H),8.31(d,J=5.3Hz,1H),8.26(d,J=7.7Hz,1H),7.87( s,1H),7.52(d,J=8.1Hz,1H),7.26-7.19(m,2H),7.19-7.14(m,1H),6.84(s,1H),6.71(dd,J=16.9, 10.2Hz, 1H), 6.47(br, 1H), 6.25(d, J=16.9Hz, 1H), 5.75(d, J=10.2Hz, 1H), 3.87(s, 3H), 2.88-2.72(m, 4H), 2.22-2.06 (...

Embodiment 3

[0044] This embodiment provides a compound VIII-3, the structural formula of the compound VIII-3 is:

[0045]

[0046] This example also provides a preparation method of compound VIII-3, which is basically the same as the preparation method of compound VIII-2 provided in Example 2, the main difference being that 0.10 g (0.16 mmol) of compound VIII- 2. Add 0.18g (1.63mmol) trifluoroacetic acid into 2mL dichloromethane, and stir at room temperature for 1h. The reaction was monitored by thin-layer chromatography TLC. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, and the concentrate was extracted with saturated potassium carbonate aqueous solution and ethyl acetate (3×50mL), and the organic phases were combined, anhydrous MgSO 4 Dry, filter with suction, and concentrate under reduced pressure to obtain compound Ⅷ-3. The compound VIII-3 is a white solid, and the calculated yield is about 99%; 1 H NMR (400MHz, DMSO-d 6...

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Abstract

The invention provides a deuterated 2-substituted aniline-4-indolyl pyrimidine derivative which is characterized in that the structural general formula of the deuterated 2-substituted aniline-4-indolyl pyrimidine derivative is shown in the specification, and in the structural general formula, a group R1 is a halogen atom, a chain primary amine group containing C2-C8, a five-membered or six-membered cyclic aliphatic secondary amine group containing C4-C15 and a halogen-substituted cyclobutyl amine group. The invention also provides a preparation method and application of the compound. The compound has the effect of inhibiting EGFR tyrosine kinase, so that a new way is opened up for searching an anti-tumor drug based on an EGFR tyrosine kinase inhibitor as a target spot.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a deuterated 2-substituted aniline-4-indolylpyrimidine derivative and a preparation method and application thereof. Background technique [0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase of the erbB receptor family. Studies have shown that EGFR is highly expressed in a variety of tumor cells, and the signaling pathways mediated by it can regulate a variety of cellular processes such as proliferation and adhesion , migration, differentiation and apoptosis are closely related to the occurrence and development of tumors. Therefore, EGFR is an effective target for the treatment of cancer, especially non-small cell lung cancer (NSCLC). [0003] Osimertinib (Osimertinib, AZD9291), is the third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor developed by AstraZeneca, which was approved by the US Food and Drug...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/04C07D413/14C07D403/14A61P35/00
CPCC07D401/14C07D403/04C07D413/14C07D403/14A61P35/00Y02P20/55
Inventor 余斌常俊标张静雅
Owner ZHENGZHOU UNIV
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