Feruloyl amide derivative as well as medical application and crystal structure thereof

A technology of ferulamide and its derivatives, which is applied in the field of new compounds and can solve problems such as the reduction of NA inhibitory activity

Active Publication Date: 2021-01-12
湖南先施制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In 2016, Harionol et al [Scientific Reports, 2016,6(1):38692-38701] studied the NA inhibitory activity of ferulic acid derivatives, and found that ferulic acid itself has a certain NA inhibitory activity IC 50 The value is 140 μ M, wherein the compound F1 (IC 50 =127μM) activity was slightly improved, and the ferulic acid derivative F2 (IC 50 =191μM) and F3 (IC 50 =1000μM) the inhibitory activity of NA was significantly reduced

Method used

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  • Feruloyl amide derivative as well as medical application and crystal structure thereof
  • Feruloyl amide derivative as well as medical application and crystal structure thereof
  • Feruloyl amide derivative as well as medical application and crystal structure thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of (E)-N-(4-tert-butyl-5-nitrothiazol-2-yl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide

[0057]

[0058] 0.23g (1.2mmol) ferulic acid, 0.16g (1.2mmol) 1-hydroxybenzotriazole, 0.23g (1.2mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Dissolve hydrochloride in 10 mL of N,N dimethylformamide and stir for 30 min, add 0.20 g (1 mmol) of 2-amino-4-tert-butyl-5-nitrothiazole, heat up to 115°C and react for 16 h (monitored by TLC). The reaction solution was cooled to room temperature, poured into ice water, and the precipitated solid was filtered by suction, washed with saturated sodium bicarbonate solution, dilute hydrochloric acid, and water successively, and the crude product was recrystallized from ethanol to obtain red powder (E)-N-(4-tert-butyl -5-nitrothiazol-2-yl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide, yield 36.8%, m.p.262~263°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 1.50(s, 9H, 3×CH 3 ), 3.88 (s, 3H, CH 3 ), 6.82 (d, J=15.6Hz, 1H, =CH), 6.91 (d, J=8.0Hz, ...

Embodiment 2

[0060]Preparation of (E)-N-(4-tert-butyl-5-(imidazol-1-yl)thiazol-2-yl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide

[0061]

[0062] According to the method of Example 1, 0.23g (1.2mmol) ferulic acid and 0.20g (1mmol) 2-amino-4-tert-butyl-5-imidazolhiazole were reacted at 115°C for 10h (monitored by TLC), and the crude product was washed with ethanol Recrystallized to give light yellow powder (E)-N-(4-tert-butyl-5-(imidazol-1-yl)thiazol-2-yl)-3-(4-hydroxy-3-methoxyphenyl) Acrylamide, yield 38.2%, m.p.244~246°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 1.15(s, 9H, 3×CH 3 ), 3.85(s, 3H, OCH 3 ), 6.77 (d, J=15.6Hz, 1H, =CH), 6.88 (d, J=7.6Hz, 1H, C 6 h 3 ), 7.12~7.14(m, 2H, imidazole ring-H+C 6 h 3 ), 7.21(s, 1H, C 6 h 3 ) 7.47 (s, 1H, imidazole ring-H), 7.67 (d, J=15.6Hz, 1H, =CH), 7.94 (s, 1H, imidazole ring-H), 9.71 (s, 1H, OH), 12.40 (s, 1H, NH).

Embodiment 3

[0064] (E)-N-(4-tert-butyl-5-(1,2,4-triazol-1-yl)thiazol-2-yl)-3-(4-hydroxy-3-methoxyphenyl ) Preparation of acrylamide

[0065]

[0066] According to the method of Example 1, 0.23g (1.2mmol) ferulic acid was reacted with 0.22g (1mmol) 2-amino-4-tert-butyl-5-(1,2,4-triazole)thiazole at 115°C 10h (monitored by TLC), the crude product was recrystallized from ethanol to obtain beige powder (E)-N-(4-tert-butyl-5-(1,2,4-triazol-1-yl)thiazol-2-yl) -3-(4-Hydroxy-3-methoxyphenyl)acrylamide, yield 41.5%, m.p.196~198°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 1.14(s, 9H, 3×CH 3 ), 3.85(s, 3H, OCH 3 ), 6.78 (d, J=15.6Hz, 1H, =CH), 6.88 (d, J=8.0Hz, 1H, C 6 h 3 ), 7.14 (d, J=8.0Hz, 1H, C 6 h 3 ), 7.22(s, 1H, C 6 h 3 ), 7.69 (d, J=15.6Hz, 1H, =CH), 8.28 (s, 1H, triazole ring-H), 8.98 (s, 1H, triazole ring-H), 9.74 (s, 1H, OH ), 12.53 (s, 1H, NH).

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Abstract

The invention relates to a feruloyl amide derivative as shown in a formula I and pharmaceutically acceptable salt thereof, a pharmaceutical composition and a crystal structure thereof, and applicationof the feruloyl amide derivative and the pharmaceutically acceptable salt thereof in preparation of an influenza virus neuraminidase inhibitor. In the formula I, R and R1 are selected from hydrogen,C1-C2 alkyl, C3-C4 linear alkyl or C3-C4 branched alkyl; R2 is selected from hydrogen, a C1-C2 alkyl group, a C3-C4 linear alkyl group or a C3-C4 branched alkyl group, carboxymethyl and a C1-C4 alkoxycarbonyl methyl group; and R3 is selected from hydrogen, C1-C2 alkyl, C3-C4 straight-chain alkyl or C3-C4 branched-chain alkyl, nitro, alkoxy carbonyl, alkanoyl, 1-imidazolyl, 1, 2, 4-triazole-1-yl or 1-(methoxy imino)alkyl.

Description

technical field [0001] The invention relates to a class of novel compounds, their crystal structures and applications, in particular to ferulamide derivatives, their crystal structures and their applications in the preparation of influenza virus neuraminidase inhibitors. Background technique [0002] In 2012, Li et al [Bioorganic & Medicinal Chemistry Letters, 2012,22(19):6085-6088] designed and synthesized multiple series of ferulic acid derivatives by introducing different heterocyclic fragments after esterification of the carboxyl end of ferulic acid, and tested their activity As a result, ferulic acid derivatives were found to have general growth inhibitory effects on a broad spectrum of cancer cell lines including lung cancer, melanoma, and breast cancer. According to the structure-activity relationship, the compound A introduced with the nitrate fragment of benzenesulfonyl fluoride has a better inhibitory effect, and it has a better growth inhibitory effect on the abov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04C07D277/58C07D277/46A61P31/16A61K31/427A61K31/426
CPCC07D417/04C07D277/58C07D277/46A61P31/16C07B2200/13
Inventor 胡艾希崔满营叶姣
Owner 湖南先施制药有限公司
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