Use of an N-substituted pyridyl benzisoselazolone compound

Abstract

Disclosed is a use of an N-substituted pyridyl benzisoselazolone compound. The use is particularly a use in the preparation of a medicament for treating and/or preventing a disease caused by coronavirus. The present disclosure surprisingly found that the N-substituted pyridyl benzisoselazolone compound, such as ebselen, can significantly inhibit the activity of the main protease of a coronavirus and the intracellular replication capability of SARS-CoV-2, which can be used for treating a disease caused by coronavirus.

Claims

1. A method for treating a disease caused by coronavirus in an animal suffering from the disease caused by coronavirus, comprising: administering an effective amount of an N-substituted pyridyl benzisoselazolone compound or a pharmaceutical composition comprising the same to the animal, wherein the N-substituted pyridyl benzisoselazolone compound is represented by general formula I as follows: ##STR00017## wherein in the general formula I, R.sub.1 is selected from hydrogen, halogen, linear or branched C.sub.1-C.sub.4 alkyl group or alkoxy; and R1 is substituted at 3-, 4-, 5- or 6-position; R.sub.2 is selected from hydrogen, halogen, linear or branched C.sub.1-C.sub.4 alkyl group or alkoxy; and R.sub.2 is substituted at any carbon atom on 2-pyridine ring; X represents a nitrogen atom with a substitution position at 2-, 3- or 4-.

2. The method of claim 1, wherein the animal is a mammal or an avian; or, the pharmaceutical composition is in an oral dosage form; or, the pharmaceutical composition is a cold medicine or a veterinary medicine.

3. The method of claim 1, wherein the N-substituted pyridyl benzisoselazolone compound is a compound represented by general formula (Ia) as follows: ##STR00018## wherein R1 and R2 are defined as above; a compound represented by general formula (Ib): ##STR00019## R1 and R2 are defined as above; or a compound represented by general formula (Ic): ##STR00020##

4. The method of claim 2, wherein the mammal comprises human, swine and feline; or, the coronavirus belongs to Orthocoronavirinae subfamily.

5. The method of claim 4, wherein the coronavirus belongs to Alpha Coronavirus genus, Beta Coronavirus genus, Gamma Coronavirus genus or Delta Coronavirus genus.

6. The method of claim 5, wherein the coronavirus is selected from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43, HCoV-229E, TGEV, PEDV, PDCoV, FIPV or IBV.

7. A method for treating a disease caused by coronavirus in an animal suffering from the disease caused by coronavirus, comprising: administering an effective amount of a compound or a pharmaceutical composition comprising the same to the animal, wherein the compound is represented by the formula as follows: ##STR00021##

8. The method of claim 6, wherein the animal is a mammal or an avian; or, the pharmaceutical composition is in an oral dosage form; or, the pharmaceutical composition is a cold medicine or a veterinary medicine.

9. The method of claim 8, wherein the mammal comprises human, swine and feline; or, the coronavirus belongs to Orthocoronavirinae subfamily.

10. The method of claim 9, wherein the coronavirus belongs to Alpha Coronavirus genus, Beta Coronavirus genus, Gamma Coronavirus genus or Delta Coronavirus genus.

11. The method of claim 10, wherein the coronavirus is selected from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43, HCoV-229E, TGEV, PEDV, PDCoV, FIPV or IBV.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 shows that ebselen has a strong inhibition activity on the main protease of novel coronavirus (SARS-CoV-2).

[0056] FIG. 2 shows that ebselen is an inhibitor targeting the activity pocket of the main protease of novel coronavirus by molecular docking.

[0057] FIG. 3 showing that ebselen can prevent cytopathy caused by novel coronavirus infection (a: ebselen addition, b: cells infected with novel coronavirus, c: Mock control, added with 0.1% DMSO).

[0058] FIG. 4 shows the antiviral assay at cell level.

[0059] FIG. 5 shows the superimposed structure of the main proteases from different species of coronavirus; indicating that the binding pocket for substrate/inhibitor (green) is very conservative (12 structures of coronavirus including SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, BtCoV-HKU1, MHV-A59, PEDV, FIPV, TGEV, HCoV-NL63, HCoV-229E and IBV are aligned).

DETAILED DESCRIPTION

Example 1

[0060] It can be seen from in vitro enzyme activity assays that ebselen can significantly inhibit the activity of the main protease of novel coronavirus (SARS-CoV-2), with an IC.sub.50 value of 0.48 μM (FIG. 1). Molecular docking shows that ebselen is an inhibitor targeting the active pocket of the main protease of novel coronavirus (FIG. 2).

[0061] It can be seen from in vitro cell-virus assays that ebselen can prevent cytopathy caused by novel coronavirus infection (FIG. 3), and significantly inhibits the replication ability of SARS-CoV-2 in cells (FIG. 4). Meanwhile, clinical trials have confirmed that ebselen has high safety profile and can therefore be used for the treatment of diseases caused by coronavirus.

[0062] See Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, doi: 10.1038/s41422-020-0282-0 (2020) for the detailed experimental methods of in vitro enzyme activity assays and in vitro cell-virus assays.

[0063] Since the substrate binding pocket of coronavirus main protease is highly conserved (FIG. 5), inhibitors (ebselen, etc.) targeting its binding pocket will have a broad-spectrum anti-coronavirus effect. It can be seen that the ebselen of the present disclosure can be used to treat a disease caused by SARS-CoV-2, and should also be able to treat a major infectious disease caused by other coronaviruses such as SARS-CoV and MERS-CoV. It can also be used as a common cold medicine for treating a disease caused by coronavirus such as HCoV-HKU1, HCoV-NL63, HCoV-OC43 and HCoV-229E; in addition, it can also be used as a veterinary medicine to treat an animal disease caused by porcine transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine delta coronavirus (PDCoV), feline infectious peritonitis virus (FIPV), avian infectious bronchitis virus (IBV) or other animal diseases.

[0064] Although the specific embodiments of the present disclosure are described above, those skilled in the art should understand that the embodiments are merely illustrative examples, and various modifications and variations can be made to those embodiments without departing from the spirit or scope of the present disclosure. Thus, the protection scope of the present disclosure is defined by the appended claims.