阅读说明：本技术 恩曲替尼在制备病毒抑制剂中的应用 (Application of enretinib in preparation of virus inhibitor ) 是由 岑山 李泉洁 衣岽戎 于 2020-05-12 设计创作，主要内容包括：本发明公开了恩曲替尼在制备病毒抑制剂中的应用。本发明提供了式(Ⅰ)所示化合物或其在药学上可接受的盐的应用：在制备病毒抑制剂中的应用；在抑制病毒中的应用。本发明提供了式(Ⅰ)所示化合物或其在药学上可接受的盐的应用：在制备产品中的应用,所述产品的用途为治疗病毒感染引起的疾病；在治疗病毒感染引起的疾病中的应用。本发明的发明人发现,式(Ⅰ)所示化合物同时与hNV-RdRp和DENV-RdRp具有结合的小分子化合物,进而可以抑制hNV-RdRp和DENV-RdRp活性。式(Ⅰ)所示化合物对多种病毒具有抑制作用,从而可以用作广谱抗病毒制剂。<Image he="344" wi="700" file="DDA0002488265300000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses application of enretinib in preparation of a virus inhibitor. The invention provides a compound shown as a formula (I) or an application of a pharmaceutically acceptable salt thereof: the application in preparing virus inhibitor; the application in inhibiting virus. The invention provides a compound shown as a formula (I) or an application of a pharmaceutically acceptable salt thereof: the application of the product in preparing products for treating diseases caused by virus infection; the application in treating diseases caused by virus infection. The inventor of the invention finds that the compound shown in the formula (I) can be combined with hNV-RdRp and DENV-RdRp simultaneously, and further can inhibit hNV-RdRp and DENV-RdRp activities. The compounds of formula (I) have inhibitory effects on a variety of viruses and are therefore useful as broad-spectrum antiviral agents.)

1. The compound shown in the formula (I) or the application of the pharmaceutically acceptable salt thereof is (a) or (b) as follows:

(a) the application in preparing virus inhibitor;

(b) the application in inhibiting viruses;

2. the use of claim 1, wherein: the virus is a single-stranded positive-stranded RNA virus.

3. The use of a compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1, as (c) or (d):

(c) the application in preparing products; the product is used for treating diseases caused by virus infection;

(d) the application in treating diseases caused by virus infection.

4. Use according to claim 3, characterized in that: the virus is a single-stranded positive-stranded RNA virus.

5. The use of a compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which is (e) or (f) below:

(e) the application in preparing virus RdRp inhibitor;

(f) use in inhibiting the RdRp activity of a virus.

6. The use of claim 5, wherein: the virus is a single-stranded positive-stranded RNA virus.

7. A pharmaceutical compound characterized by: the active ingredient of the pharmaceutical compound is a compound represented by the formula (i) as described in claim 1 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical compound of claim 7, wherein: the pharmaceutical compounds are useful for inhibiting viruses and/or treating diseases caused by viral infections and/or inhibiting the RdRp activity of viruses.

9. A method of inhibiting viral infection in an animal comprising the steps of: administering a compound represented by the formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1 to a recipient animal to inhibit viral infection of the animal.

10. A method of treating a disease caused by a viral infection comprising the steps of: administering a compound represented by the formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1 to a recipient animal to treat a disease caused by a viral infection.

Technical Field

The invention belongs to the technical field of medicines, relates to a new application of enrofloxacin, and particularly relates to an application of enrofloxacin in preparation of a virus inhibitor.

Background

The continuous emergence of various new viral pathogens poses a great threat and challenge to global public health safety. For example, both human norovirus (hNV) and dengue virus (DENV) are highly contagious and are prevalent worldwide each year. Norovirus is a single positive-strand RNA virus belonging to (+) ssrna (iv), and belongs to the family caliciviridae, causing non-bacterial acute gastroenteritis, and norovirus infection can cause severe diarrhea, vomiting, and stomachache, with up to 20 million deaths per year in developing countries due to norovirus infection. Dengue is a single-stranded positive-stranded RNA virus of the flavivirus genus of the Flaviviridae family; is a mosquito-borne infectious disease, which can cause fever, rash, arthralgia and severe hemorrhagic shock; approximately 3.9 million people worldwide infect dengue virus annually, with as many as 9600 million people suffering. To date, there are no effective drugs for treating human norovirus and dengue virus infectious diseases. Currently, most antiviral drugs are usually targeted to one specific virus and are not sufficient to cope with the outbreaks of the various emerging viruses. In order to quickly cope with pandemic threats, the development of broad-spectrum antiviral drugs is urgently required.

RNA-dependent RNA polymerase (RdRp) is a key protein factor involved in the replication of viral genomic RNA and an important target for the study of novel drugs against a broad spectrum of RNA viruses. Despite sequence differences between different virus families, the structure of viral RNA polymerases is relatively conserved. The shape of RNA polymerase is similar to the right hand of human, and is composed mainly of three domains, finger, palm and thumb. There are two major ligand binding sites in RNA polymerase: a catalytically active site and various allosteric binding sites. Nucleoside analogs (NIs), such as BCX4430, favipiravir, ribavirin and remdesivir, exert antiviral effects by targeting the active site of RNA polymerase. However, this inhibition mechanism often leads to side effects such as off-target. Non-nucleoside inhibitors (NNIs) bind to the allosteric site of RNA polymerase and exert antiviral activity by preventing conformational changes required for transcription, often with low toxicity and side effects, and have received extensive attention in drug development. To date, most of the NNIs in clinical use or in clinical trials have been developed against the Hepatitis C Virus (HCV) and are species specific. There is an urgent need to develop a broad spectrum of non-nucleoside inhibitors. HCV is an enveloped single-stranded positive-strand RNA virus, (+) ssRNA virus, belonging to the Flaviviridae family of the genus hepacivirus (Flaviviridae).

Disclosure of Invention

The technical problem to be solved by the invention is how to inhibit the virus and correspondingly how to treat diseases caused by virus infection.

In order to solve the technical problems, the invention provides a new application of the enretinib.

The structural formula of the enrotinib is shown in formula (I), and the CAS number of the enrotinib is 1108743-60-7.

The invention provides a compound shown in formula (I) or an application of a pharmaceutically acceptable salt thereof, which is (a) or (b) as follows:

(a) the application in preparing virus inhibitor;

(b) the application in inhibiting virus.

The invention provides a compound shown in formula (I) or an application of a pharmaceutically acceptable salt thereof, which is (c) or (d) as follows:

(c) the application in preparing products; the product is used for treating diseases caused by virus infection;

(d) the application in treating diseases caused by virus infection.

Illustratively, the product may be a medicament, vaccine or pharmaceutical formulation.

The product may contain, in addition to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a suitable carrier or excipient. The carrier material herein includes, but is not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, carboxymethyl cellulose, etc.). Among these, water-soluble carrier materials are preferred. The materials can be prepared into various dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, freeze-dried powder injections and the like. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. In order to prepare the dosage form for unit administration into a pill, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. In order to prepare the unit dosage form into suppositories, various carriers known in the art can be widely used. As examples of the carrier, there may be mentioned, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. In order to prepare the unit dosage form into preparations for injection, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, etc., can be used. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired. The preparation can be used for injection administration, including subcutaneous injection, intravenous injection, intramuscular injection, intracavity injection and the like; for luminal administration, such as rectally and vaginally; administration to the respiratory tract, e.g., nasally; administration to the mucosa.

The invention provides a compound shown in formula (I) or an application of a pharmaceutically acceptable salt thereof, which is (e) or (f) as follows:

(e) the application in preparing virus RdRp inhibitor;

(f) use in inhibiting the RdRp activity of a virus.

The present invention also provides a pharmaceutical compound characterized in that: the active ingredient of the medicinal compound is a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutical compounds are useful for inhibiting viruses and/or treating diseases caused by viral infections and/or inhibiting the RdRp activity of viruses.

The present invention also provides a method of inhibiting viral infection in an animal comprising the steps of: a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is administered to a recipient animal to inhibit viral infection of the animal.

The present invention also provides a method of treating a disease caused by a viral infection, comprising the steps of: a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a recipient animal to treat a disease caused by a viral infection.

Any of the viruses described above is a single-stranded positive-stranded RNA virus.

Any of the viruses described above is a virus having an RdRp.

Any of the above viruses is a virus of the Caliciviridae family or a virus of the Flaviviridae family.

The virus of the Caliciviridae family is a norovirus, such as a human norovirus or a murine norovirus.

The virus of the Flaviviridae family is a virus of the genus Flaviviridae or a virus of the genus hepatitis C virus.

Any one of the above viruses is a norovirus (e.g., a human norovirus or a murine norovirus), a dengue virus, or a hepatitis c virus.

In the present invention, the inhibitory virus may also be referred to as an antiviral.

The totality of RdRp is known as RNA-dependent RNA polymerase.

hNV-RdRp is shown as a sequence 1 in the sequence table.

The DNEV-RdRp is shown as a sequence 3 in a sequence table.

Emtrictinib exerts a broad spectrum antiviral effect by targeting RNA-dependent RNA polymerase.

In the present invention, the animal may be a mammal, such as a human; the animal may also be other than a mammal, such as a mouse, infected with the virus.

In the present invention, the term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in s.m. berge, et al, j.pharmaceutical Sciences,1977,66: 1.

The inventors of the present invention found that a small molecule compound having both hNV-RdRp and DENV-RdRp binding to the compound of formula (I) (the binding site is located at hNV-RdRp and the common allosteric site of DENV-RdRp) can inhibit hNV-RdRp and DENV-RdRp activities. The compounds of formula (I) have inhibitory effects on a variety of viruses and are therefore useful as broad-spectrum antiviral agents. The invention has important application value for resisting virus.

Drawings

FIG. 1 is an electrophoretogram of the protein in example 2.

FIG. 2 is a graph showing the results of example 3.

FIG. 3is a graph showing the results of example 4.

FIG. 4 is a graph showing the results of example 5.

FIG. 5 is a graph showing the results of example 6.

FIG. 6 is a graph showing the results of the RNA inhibition ratio in example 7.

FIG. 7 is a graph showing the results of the relative abundances of positive-strand RNA and negative-strand RNA in example 7.

FIG. 8 is a graph showing the results of example 8.

FIG. 9 is a graph showing the results of example 9.

FIG. 10 is a graph showing the results of example 10.

Detailed Description

The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. Unless otherwise specified, the experimental procedures in the following examples are conventional procedures known to those skilled in the art or as suggested by the manufacturers. Unless otherwise specified, the test materials used in the following examples were purchased from conventional biochemical stores. Unless otherwise stated, the quantitative tests in the following examples were performed in triplicate, and the results were averaged. Protein concentration was measured by BCA protein assay kit (Pierce).

The compound RAI-13 has a CAS number of 1108743-60-7, a Chinese name of Entricinib and an English name of Entretinib, has a structural formula shown as a formula (I), and belongs to a small molecular compound.

RdRp of human norovirus, denoted by hNV-RdRp.

RdRp of dengue virus, expressed as DENV-RdRp.