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Small molecule compound for overcoming EGFR drug resistance mutation as well as preparation method and application of small molecule compound

A technology of small molecule compounds and drug-resistant mutations, applied in drug combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of small quantity and types, poor clinical curative effect, and large toxic and side effects, and achieve low toxicity , good selectivity, and the effect of avoiding compound resistance

Active Publication Date: 2019-03-08
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Existing EGFR-TKI drugs are prone to drug resistance mutations, among which EGFR T790M Mutations are the most difficult class of drug resistance mutations to overcome, and overcoming EGFR T790M The number and types of drug-resistant drugs are small, and many problems such as drug resistance, large toxic and side effects, and poor clinical efficacy have been encountered.

Method used

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  • Small molecule compound for overcoming EGFR drug resistance mutation as well as preparation method and application of small molecule compound
  • Small molecule compound for overcoming EGFR drug resistance mutation as well as preparation method and application of small molecule compound
  • Small molecule compound for overcoming EGFR drug resistance mutation as well as preparation method and application of small molecule compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Compound 1: 4-acryloylamido-N-(1-(4-fluorophenyl)ethyl)benzamide

[0055] Use raw material A as (raw material A1), raw material B is (raw material B1), raw material C is (raw material C1)

[0056] The synthetic route is as follows:

[0057]

[0058] The specific synthesis method is:

[0059] Add raw material A1 (500mg, 3.62mmol), 10ml ethanol and 3mL 50% hydroxylamine aqueous solution into a 50ml sealed tube, seal the reaction at 70°C, and complete the reaction in 5h. Remove the solvent by evaporation under reduced pressure, add 10 mL of distilled water to the residue, extract twice with 50 mL of DCM, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and remove the solvent by evaporation under reduced pressure to obtain intermediate I1 as a white solid, intermediate I1 was directly used in the next reaction without further purification.

[0060] Intermediate I1 (3mmol) was dissolved in 10ml methanol, ammonium acetate (693mg, 9mmol) an...

Embodiment 2

[0070] Compound 2: 4-Acryloylamido-N-(1-phenylethyl)benzamide

[0071] Use raw material A as (raw material A2), raw material B is (raw material B1), raw material C is (raw material C1)

[0072] The synthetic route is as follows:

[0073]

[0074] According to the synthetic route, compared with compound 1, the synthetic raw material A was replaced, and the other synthetic raw materials and dosages, as well as the specific preparation method were the same as those of compound 1, and will not be repeated here.

[0075] The yield of compound 2 was 78%.

[0076] That 1 H NMR data are as follows:

[0077] 1 H NMR (400MHz, DMSO-d 6 )δ10.35(s,1H),8.68(d,J=8.0Hz,1H),7.87(d,J=8.6Hz,2H),7.74(d,J=8.7Hz,2H),7.39(d, J=7.4Hz, 2H), 7.32(t, J=7.6Hz, 2H), 7.22(t, J=7.2Hz, 1H), 6.45(dd, J=17.0, 10.1Hz, 1H), 6.29(dd, J=17.0,1.8Hz,1H),5.79(dd,J=10.1,1.8Hz,1H),5.16(p,J=7.0Hz,1H),1.47(d,J=7.1Hz,3H).

[0078] ESI-ms(m / z):295.1[M+H] +

Embodiment 3

[0080] Compound 3: 4-acryloylamido-N-(1-(3-chlorophenyl)ethyl)benzamide

[0081] Use raw material A as (raw material A3), raw material B is (raw material B1), raw material C is (raw material C1)

[0082] The synthetic route is as follows:

[0083]

[0084] According to the synthetic route, compared with compound 1, the synthetic raw material A was replaced, and the other synthetic raw materials and dosages, as well as the specific preparation method were the same as those of compound 1, and will not be repeated here.

[0085] The yield of compound 3 was 76%.

[0086] That 1 H NMR data are as follows:

[0087] 1H NMR (400MHz, DMSO-d 6 )δ10.37(s,1H),8.73(d,J=7.9Hz,1H),7.88(d,J=8.7Hz,2H),7.75(d,J=8.7Hz,2H),7.45(s, 1H),7.43–7.31(m,2H),7.30–7.18(m,1H),6.46(dd,J=17.0,10.1Hz,1H),6.29(dd,J=17.0,2.0Hz,1H),5.80 (dd,J=10.1,2.0Hz,1H),5.15(p,J=7.1Hz,1H),1.47(d,J=7.0Hz,3H).

[0088] ESI-ms(m / z):329.1[M+H] +

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Abstract

The invention belongs to the field of chemical medicines and specifically relates to a small molecule compound for overcoming EGFR drug resistance mutation. The small molecule compound has a formula as shown in the specification. The small molecule compound provided by the invention has a good inhibition effect on an H1975 cell strain with EGFRT790M mutation in vitro, that is, a part of moleculeshave median inhibitory concentrations up to a nanomole grade level upon H1975, is small in toxicity, has IC50 of 10 [mu]M or greater upon most cell strains except the H1975, has good selectivity, doesnot directly inhibit the activity of the EGFR, is capable of avoiding compound drug resistance caused by drug resistance mutation, provides novel effective options for development and preparation ofa new generation of EGFRT790M drug resistant small molecule target medicines, and has good development prospects.

Description

technical field [0001] The invention relates to the technical field of chemically synthesized drugs, in particular to a small molecule compound for overcoming EGFR drug-resistant mutations and its preparation method and use. Background technique [0002] Lung cancer is one of the most common malignant tumors, and its morbidity and mortality both rank first in the list of malignant tumors. According to the differentiation and morphological characteristics of lung cancer, lung cancer can be divided into two categories, small cell lung cancer (Small Cell Lung Cancer, SCLC) and non-small cell lung cancer (Non Small Cell Lung Cancer, NSCLC), of which NSCLC is the most common type of lung cancer. type, accounting for about 80 to 85% of lung cancer, and the 5-year survival rate is less than 15%. [0003] Surgical resection is generally used in the treatment of early NSCLC, but there are still risks of recurrence and metastasis. Early diagnosis of lung cancer is difficult, and mos...

Claims

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Application Information

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IPC IPC(8): C07C237/30C07C237/32A61K31/166A61P35/00
CPCA61P35/00C07C237/30C07C237/32
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV