Dimethyl cyclohexene derivative and application thereof in resisting influenza virus
阅读说明：本技术 二甲基环己烯类衍生物及其在抗流感病毒中的应用 (Dimethyl cyclohexene derivative and application thereof in resisting influenza virus ) 是由 张建蒙 于 2020-05-08 设计创作，主要内容包括：本发明属于医药技术领域,提供了一种如下列通式所示的二甲基环己烯类衍生物及其制备方法,本发明还公开了所述二甲基环己烯类衍生物在抗流感病毒中的应用,<Image he="400" wi="681" file="DDA0002481922390000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of medicines, provides a dimethylcyclohexene derivative shown as the following general formula and a preparation method thereof, and also discloses application of the dimethylcyclohexene derivative in resisting influenza viruses,)
1. The dimethyl cyclohexene derivative shown in the general formula I,
said R1Selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) An alkoxy group;
said R2Selected from hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl.
2. The agent of claim 1A cyclohexene derivative, wherein said R is1Selected from hydrogen, halogen, (C)1-C4) Alkoxy group, (C)1-C4) An alkyl group.
3. The dimethylcyclohexene derivative according to claim 1, wherein R is2Is selected from R2Selected from hydrogen, (C)1-C3) An alkyl group.
4. Dimethylcyclohexenes derivatives of formula I selected from:
5. application of the dimethylcyclohexene derivative shown as the general formula I as an anti-influenza virus medicament.
6. The use of the dimethylcyclohexene derivative of claim 5 as a medicament against influenza virus, wherein the anti-influenza virus is H5N1 or H5N 6.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a dimethylcyclohexene derivative and application thereof in resisting influenza viruses.
Background
Influenza, an acute upper respiratory infectious disease caused by influenza virus, has the characteristics of high morbidity and high mortality, and seriously threatens the health and life of human beings. Therefore, the prevention and treatment of influenza has become a very urgent task in the world public health field.
In view of the key role of Neuraminidase (NA) in the life cycle of influenza virus, the neuraminidase has become an important target for designing anti-influenza virus drugs at present. To date, four neuraminidase inhibitors (NAIs) have been marketed, zanamivir, oseltamivir, peramivir, and laninamivir, respectively. However, the wide emergence of drug-resistant strains and the inconvenience of administration still make the current anti-influenza situation severe.
Therefore, the development of novel, highly effective and drug-resistant NA inhibitors is still of great significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a dimethylcyclohexene derivative, a preparation method thereof and application thereof in resisting influenza virus.
In order to achieve the above object, the present invention provides dimethylcyclohexene derivatives represented by the general formula (I):
said R1Selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) An alkoxy group.
Said R2Selected from hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl.
Preferably, said R is1Selected from hydrogen, halogen, (C)1-C4) Alkoxy group, (C)1-C4) An alkyl group.
Preferably, said R is2Selected from hydrogen, (C)1-C3) An alkyl group.
The compounds of the general formula I according to the invention are preferably the following compounds, but these are not intended to limit the invention in any way:
the derivative can be applied to anti-influenza virus medicines.
The derivatives of the invention are useful as medicaments for the treatment and/or prevention of influenza virus infections.
Preferably, the influenza virus infection of the invention is of type H5N1 or H5N 6.
The derivatives of the invention comprising formula I may be synthesized by methods well known in the chemical arts, including, inter alia, the methods according to scheme 1 disclosed herein, specifically: 4, 4-dimethylcyclohexanone is used as a starting material, and an intermediate 2 is prepared by Vilsmeier-Haack-Arnold reaction; then carrying out Suzuki coupling reaction on the intermediate and various substituted phenylboronic acids to prepare an intermediate 3; the intermediate 3 and oseltamivir are subjected to reductive amination to obtain a target compound T1-T4; and then respectively hydrolyzing under alkaline conditions to obtain target compounds T5-T8.
Scheme 1 is as follows:
synthetic scheme 1 reagents and conditions (a) DMF, PBr3,CHCl3,rt；(b)phenylboronic acid, Pd(OAc)2,K2CO3,EtOH,80℃；(c)(d)NaBH(OAc)3,EtOH,rt；(d)NaOH, EtOH/H2O,rt.
The positive progress effects of the invention are as follows: the inventor designs and synthesizes a series of novel dimethylcyclohexene derivatives by means of a computer-aided drug design method. The compound has better activity and novel framework, and the dimethylcyclohexene fragment can extend into the 150-cavity, thereby enhancing the antiviral activity of oseltamivir.
Detailed Description
The examples provided below are intended to illustrate but not limit the scope of the invention. The starting materials may generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described herein. The reagents used are, without particular reference, analytically or chemically pure.