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2-arylureido-N-(4-fluorobenzyl)nicotinamide compound and application thereof

A technology of nicotinamide and fluorobenzyl, which is applied in the application field of anti-influenza virus drugs, and achieves the effects of stable yield, extensive therapeutic effect, and simple preparation method

Inactive Publication Date: 2022-01-28
SHENYANG PHARMA UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, A-type H1N1, H5N1, H3N2 subtype influenza viruses have shown resistance to oseltamivir

Method used

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  • 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound and application thereof
  • 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound and application thereof
  • 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of 2-(3-phenylureido)-N-(4-fluorobenzyl)nicotinamide

[0037]

[0038] Step A: Preparation of 2,3-pyridinedicarboxylic anhydride

[0039] Put 16.7g (100mmol) of 2,3-pyridinedicarboxylic acid in a 100mL eggplant-shaped bottle, add 20.0mL of acetic anhydride, heat up and reflux for 30min, cool, crystallize, filter with suction, and dry to obtain 2,3-pyridinedicarboxylic anhydride Pale yellow solid 12.4g, yield 83.2%, m.p.: 132.6-133.8°C. (Literature (GRIBBLE G, FLETCHER G, KETCHA D, et al. Metalated heterocycles in the synthesis of ellipticine analogues: A new route to the 10H-pyrido[2,3-b]carbazole ring system. Journal of Organic Chemistry, 1989, 54( 14): 3264-3269.) Value: 133-134°C).

[0040] Step B: Preparation of 2-carbamoylpyridine-3-carboxylic acid

[0041]Put 13.6g (200mmol) of 25% ammonia water in a 100mL eggplant-shaped bottle, and slowly add 7.46g (50mmol) of 2,3-pyridine dicarboxylic anhydride in an ice-water bath, stir for 2.5h, t...

Embodiment 2

[0049] Example 2: Preparation of 2-[3-(4-methylphenyl)ureido]-N-(4-fluorobenzyl)nicotinamide

[0050]

[0051] According to the preparation method of Example 1, 0.68 g of white solid was obtained with a yield of 45.0%. m.p.:206.1-208.0℃;IR:(KBr,cm -1 ) 3336, 3063, 2906, 1684, 1615, 1544, 1507, 1435, 1405, 737; 1 H-NMR (400MHz, CDCl 3 ):δ2.32(s,3H,CH 3 ), 4.61(d,2H,ArCH 2 NH),6.59(brs,1H,NH),6.89(dd,1H,Ar-H,J 1 =7.6Hz,J 2 =4.8Hz), 7.05(t,2H,Ar-H,J=8.8Hz),7.13(d,2H,Ar-H,J=8.4Hz),7.34(dd,2H,Ar-H,J 1 =8.4Hz,J 2 =6.4Hz), 7.46(d,2H,Ar-H,J=8.4Hz),7.80(dd,1H,Ar-H,J 1 =7.6Hz,J 2 =1.6Hz), 8.34(dd,1H,Ar-H,J 1 =4.8Hz,J 2 =1.2Hz), 10.38(s,1H,NH),11.66(s,1H,NH); ESI-MS(m / z):379.1([M+H] + ).

Embodiment 3

[0052] Example 3: Preparation of 2-[3-(4-methoxyphenyl)ureido]-N-(4-fluorobenzyl)nicotinamide

[0053]

[0054] According to the preparation method of Example 1, 0.52 g of white solid was obtained with a yield of 33.0%. m.p.:199.5-200.3℃;IR:(KBr,cm -1 ) 3363, 3047, 2837, 1673, 1629, 1541, 1512, 1487, 1417, 740; 1 H-NMR (400MHz, CDCl 3 ):δ3.80(s,3H,OCH 3 ),4.60(d,2H,ArCH 2 NH),6.58(brs,1H,NH),6.86-6.91(m,3H,Ar-H),7.05(t,2H,Ar-H,J=8.8Hz),7.34(dd,2H,Ar-H ,J 1 =8.4Hz,J 2 =5.6Hz), 7.48(d,2H,Ar-H,J=8.8Hz),7.80(dd,1H,Ar-H,J 1 =7.6Hz,J 2 =1.2Hz), 8.33(dd,1H,Ar-H,J 1 =5.2Hz,J 2 =1.6Hz), 10.38(s,1H,NH),11.57(s,1H,NH); ESI-MS(m / z):395.2([M+H] + ).

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Abstract

The invention discloses a 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound and an application thereof, belongs to the technical field of medicines, and particularly relates to the 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound, a prodrug, a drug active metabolite and a pharmaceutically acceptable salt thereof, and the application thereof as an anti-influenza virus drug; and particularly, the 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound has a relatively good curative effect on various influenza A. The 2-arylureido-N-(4-fluorobenzyl)nicotinamide compound provided by the invention can also be used in combination with known medicaments which can be used for treating or preventing influenza. Preferred combinations comprise the compound provided by the invention and an M2 ion channel protein inhibitor, the compound provided by the invention and a neuraminidase inhibitor, the compound provided by the invention and an interferon inducer, the compound provided by the invention and an antisense oligonucleotide, and the compound provided by the invention and an inosine monophosphate dehydrogenase inhibitor.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a 2-aryl ureido-N-(4-fluorobenzyl)nicotinamide compound and its application as an anti-influenza virus drug. Background technique [0002] Influenza virus is a single-stranded RNA virus belonging to the genus Influenzavirus in the orthomyxoviridae family. According to their surface matrix protein (matrix protein, MP) and nucleoprotein (nucleoprotein, NP) antigenicity, it can be divided into A, B, C and D (also known as A, B, C and D) four types. According to the antigenic difference between hemagglutinin (Hemagglutinin) and neuraminidase (Neuraminidase, also known as sialidase Sialidase), 16 HA subtypes (H1~H16) and 9 neuraminidases have been identified for influenza A virus Enzyme subtype (N1 ~ N9). Influenza B virus has only one hemagglutinin and neuraminidase, and no other subtypes. Among them, the most prevalent is type A influenza virus, which can infect vario...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82A61P31/16A61K31/455
CPCC07D213/82A61P31/16
Inventor 胡春蒋云莲张富荣薛泽宇金同阳夏新鹏姜麦张超王文彦黄二芳
Owner SHENYANG PHARMA UNIVERSITY
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