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Substituted butenamide-N-oxide and preparation method and application thereof

A crotyl amide and oxide technology, applied in organic chemistry, drug combination, pharmaceutical formulations, etc., can solve the problems of low survival rate and poor patient prognosis, and achieve the effects of short reaction time, less three wastes, and environmentally friendly process.

Pending Publication Date: 2021-10-12
JIANGSU SUZHONG PHARM GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Non-small cell lung cancer (NSCLC) is a malignant tumor that seriously threatens human health. Despite the continuous improvement of surgery and chemotherapy techniques, the prognosis of patients is still poor, and the 5-year survival rate is less than 20%.

Method used

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  • Substituted butenamide-N-oxide and preparation method and application thereof
  • Substituted butenamide-N-oxide and preparation method and application thereof
  • Substituted butenamide-N-oxide and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] In a 100mL reaction flask, add 30mL of dichloromethane, and add 2.0g of (E)-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxyquinoline-6 -yl]-4-(dimethylamino)but-2-enamide (4.55mmol) was dissolved in dichloromethane, cooled to 0°C, and 2.0g (11.59mmol) of m-chloroperoxybenzoic acid was added, Stir the reaction for 20 minutes, after the reaction is complete as detected by TLC, add 20 mL of saturated sodium bicarbonate solution under stirring, a large amount of solids precipitate out, filter with suction, wash the filter cake with 10 mL of water, then wash with 10 mL of dichloromethane, and dry at 25°C for 24 hours to obtain (E )-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide N -Oxide 1.7g, yield 82.0%, moisture 13%, purity 98.87% (area normalization method).

[0050] To the obtained product (E)-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)butane- 2-enamide-N-oxide is detected, and its hydrogen spectr...

Embodiment 2

[0052] In a 250mL beaker, add 100mL dichloromethane, 50mL purified water, add 5.7g (E)-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxyquinoline- 6-yl]-4-(dimethylamino)but-2-enamide maleate (10mmol), stirred at room temperature, slowly added 5.5g of potassium carbonate, the solution gradually dissolved, left to stand, liquid separation , the aqueous phase was extracted with 20 mL of dichloromethane, combined with dichloromethane, washed with 30 mL of water, allowed to stand, separated, and dried overnight with 20.0 g of anhydrous sodium sulfate. Suction filtration, transfer the filtrate to a 250mL flask, cool down to -10°C, add m-chloroperoxybenzoic acid 2.0g (11.6mmol), stir below 0°C for 0.5h, naturally heat up, the reaction solution is white and turbid.

[0053] The reaction solution was poured into potassium carbonate 1.65g / 200mL aqueous solution, stirred for 10min, a large amount of white insoluble matter was filtered, washed with 300mL of water, beaten, filtered with suctio...

Embodiment 3

[0054] Embodiment 3: Drug efficacy test

[0055] 1. Purpose: To detect the ATP concentration when the compound of Example 1 inhibits four kinases to reach km by using Mobility shift assay; use staurosporine E as a positive control, the initial concentration is 10 μM, 4-fold dilution, 10 gradients , two parallel.

[0056] 2. Experimental materials:

[0057] EGFR (Camna, Cat.No 08-115, Lot.No 13CBS-0005M)

[0058] EGFR L858R (eurofins, Cat.No 14-626M, Lot.No 31001U)

[0059] EGFR (d746-750) (Carna, Cat.No 08-527, Lot.No 11CBS-1129F)

[0060] EGFR T790M (Invitrogen, Cat.No PV4804, Lot.No 1691293B)

[0061] Peptide FAM-P22 (GL Biochem, Cat.No.112393, Lot.No.P1801 16-MJ112393)

[0062] ATP (Sigma, Cat. No. A7699-1G, CAS No. 987-65-5)

[0063] DMSO (Sigma, Cat. No. D2650, Lot. No. 474382)

[0064] EDTA (Sigma, Cat. No. E5134, CAS No. 60-00-4)

[0065] 96-well plate (Coming, Cat.No.3365, Lot.No.22008026)

[0066]384-well plate (Cormning, Cat.No.3573, Lot.No.12608008)

[006...

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Abstract

The invention discloses a substituted butenamide-N-oxide as well as a preparation method and application thereof. The compound is prepared by carrying out oxidation reaction on a compound (E)-N-[4-(3-ethynylphenyl) amino-3-cyano-7-ethoxyquinoline-6-yl]-4-(dimethylamino) butyl-2-alkenyl amide or a salt thereof in a solvent. A pharmaceutical composition containing the compound can be used as a targeted drug for treating patients with tumors. Compared with the prior art, the N-oxide has a good anti-cancer effect, the application prospect of an anti-cancer treatment drug is increased, the process preparation and operation are relatively simple, the reaction time is short, few three wastes are generated, and the process is environmentally friendly.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a substituted crotonamide-N-oxide and its preparation method and application. Background technique [0002] Non-small cell lung cancer (NSCLC) is a malignant tumor that seriously threatens human health. Despite the continuous improvement of surgery and chemotherapy techniques, the prognosis of patients is still poor, and the 5-year survival rate is less than 20%. At present, molecular targeted therapy targeting human epidermal growth factor receptor (EGFR) has become the most important way to treat NSCLC. [0003] EGFR is the expression product of the proto-oncogene C-erbB-1. The gene is located on chromosome 7 and belongs to the transmembrane receptor tyrosine kinase. After EGFR binds to its ligand, it can activate downstream signaling pathways, regulate tumor cell proliferation, differentiation, angiogenesis and apoptosis inhibition, thereby regulating a series of tumor biological beh...

Claims

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Application Information

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IPC IPC(8): C07D215/54A61P35/00A61K31/4706
CPCC07D215/54A61P35/00
Inventor 唐海涛岳永力葛海涛王正俊赵耕先刘美香夏崇亮许华宏朱钦权
Owner JIANGSU SUZHONG PHARM GRP CO LTD
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