CN113425720A - Application of iminosugar compound in preparation of medicine for resisting SARS-CoV-2 virus - Google Patents

Application of iminosugar compound in preparation of medicine for resisting SARS-CoV-2 virus Download PDF

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CN113425720A
CN113425720A CN202110353666.5A CN202110353666A CN113425720A CN 113425720 A CN113425720 A CN 113425720A CN 202110353666 A CN202110353666 A CN 202110353666A CN 113425720 A CN113425720 A CN 113425720A
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dnj
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acid
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CN113425720A8 (en
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王侯
雷蒙德.德韦克
杨光
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Shenzhen Qianhai Nobel Prize Scientists Technology Transfer And Transformation Co ltd
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

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Abstract

The invention discloses an application of an imine sugar compound in preparing an anti-coronavirus medicament, in particular to an application of NB-DNJ (meglumine) in preparing an anti-SARS-CoV-2 medicament. The iminosugar compound can be used for preparing broad-spectrum antiviral drugs and has the characteristics of low toxicity and good activity.

Description

Application of iminosugar compound in preparation of medicine for resisting SARS-CoV-2 virus
Technical Field
The invention relates to the field of chemical pharmacy, in particular to application of an imine carbohydrate compound in preparing antiviral drugs.
Background
Iminosugar (DNJ) drug molecules were first natural products discovered and extracted from mulberry leaves in 1987, whose structures mimic the cyclic structure of sugars, in which the oxygen in the ring of cyclic glucose is replaced by nitrogen.
Structural similarity to sugar molecules means that many imine sugar molecules are competitive inhibitors of enzymes that act on sugar substrates. The compounds show excellent therapeutic potential for a variety of diseases including glycosylated fat storage disorder metabolic disease (Gaucher) targeting glucosylceramide synthase and type II diabetes mellitus targeting intestinal α -glucosidase. The action mechanism of inhibiting the virus is to disrupt the normal folding of virus coating glycosylation protein through the activity inhibition of endoplasmic reticulum alpha-glucosidase (ER-glucosidase I/II), so as to interfere the production of new virus in host cells and eliminate the virus. This viral suppression mechanism is also well documented in the clinic, in that two patients with mutated glucosidase genes are not infected by the virus due to the lack of this enzyme activity, and the virus cannot replicate efficiently in cells isolated from the body of these two patients. As a brand new virus inhibiting strategy, aiming at the endoplasmic reticulum alpha-glucosidase target of a host cell, the virus inhibitor can effectively inhibit various 'coating viruses' and variants thereof without depending on the form of the virus, thereby achieving the broad-spectrum antiviral effect.
Disclosure of Invention
The invention mainly solves the technical problem of providing an antiviral compound, preferably a medicament for treating coronavirus, and further preferably a medicament for treating SARS-CoV-2 coronavirus.
In order to solve the technical problems:
the invention firstly provides an imine compound, and the tautomer, the optical isomer, the solvate, the polymorph, the pharmaceutically acceptable salt, the pharmaceutically acceptable ester, the pharmaceutically acceptable prodrug or the derivative of the imine sugar compound refers to a sugar analogue with nitrogen atom substitution on the position of an internal epoxy atom. In a specific embodiment, the iminosugar compound is NB-DNJ or N-7-oxadecenyl-DNJ.
Preferably, the iminosugar compound is of formula 1 NB-DNJ.
Figure BDA0003001207050000021
Further, the present invention provides uses and methods of using the imine sugar compounds for treating viral infections, including coronavirus infections, particularly SARS-CoV-2 coronavirus infections
The imine sugar compound, especially the compounds NB-DNJ and N-7-oxadecenyl-DNJ, has obvious activity of resisting SARS-CoV-2, and has low cytotoxicity and good drug safety.
Any pharmaceutically acceptable salt of the imine saccharide compounds of the invention may be used for the purposes of the present invention. "pharmaceutically acceptable salt" means an acid salt prepared from pharmaceutically acceptable, non-toxic acids, which are, within the scope of medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; base or organic addition salts of acidic residues such as carboxylic acids; and the like, as well as combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, non-toxic acidic salts include those derived from inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; other acceptable inorganic salts include metal salts such as: sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as: calcium salts, magnesium salts, and the like, as well as combinations comprising one or more of the foregoing salts.
Organic salts of the compounds include salts prepared from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH2) n-COOH (where n is 0 to 4), and the like; organic amine salts, such as: triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, and the like; and amino acid salts, such as: arginine salts, aspartic acid salts, glutamic acid salts, and the like, as well as combinations comprising one or more of the foregoing salts.
Some of the compounds of the present invention may have chiral centers that may give rise to various stereoisomers. The term "stereoisomers" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes the mirror image isomers (enantiomers) and mixtures of mirror image isomers (racemates, racemic mixtures). The present invention relates to each of these stereoisomers, as well as mixtures thereof. Enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be resolved by conventional techniques for optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on the compounds of the invention. Optically pure isomers can also be obtained individually using enantiomer-specific synthesis.
By "pharmaceutically acceptable excipient or carrier" is meant a pharmaceutically acceptable material, composition or vehicle. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
An effective amount of the imine saccharide compound of the invention or a pharmaceutically acceptable salt thereof is preferably administered to a patient in need of such treatment, formulated according to the usual route of administration and according to methods known in the art in conventional pharmaceutical compositions (comprising an effective amount of the active ingredient and a suitable pharmaceutically acceptable carrier) and dosage forms.
By "therapeutically effective amount" is meant an amount of active ingredient which, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disease in question. The specific dose of the compound administered according to the invention will be determined by the specific circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. In particular, a "therapeutically effective amount of a compound" refers to an amount of the compound sufficient to prevent or alleviate to some extent one or more viral-caused diseases.
Individual and daily dosages vary depending on the type and severity of the viral infectious disease to be treated and the response of the particular patient to drug treatment. Thus, the exact individual doses will be determined according to standard medical principles under the direction of a physician.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be used alone or in combination with other active therapeutic agents.
The other therapeutic agents include other antiviral drugs, antimicrobial drugs, immunopotentiators, sterol compounds, biological agents, and the like.
In one embodiment of the invention, the compounds used may be administered orally, topically, parenterally, by inhalation or spraying, sublingually, transdermally, by buccal administration, rectally, intravenously, intramuscularly or by other means in dosage unit formulations containing conventional pharmaceutical carriers. The pharmaceutical composition may be formulated in any pharmaceutical form, such as: tablets, granules, injections, gels, pills, capsules, suppositories, implants, sustained release, controlled release, pellets and combinations. Some dosage forms, such as tablets and capsules, can be subdivided into appropriate dosage unit forms containing appropriate quantities of the active component, such as an effective amount to achieve the desired purpose.
Pharmaceutically acceptable carriers and excipients suitable for use in the oral formulations disclosed herein include, but are not limited to, diluents such as fillers and bulking agents, binders, lubricants, anti-caking agents, disintegrants, sweeteners, buffers, preservatives, solubilizers, isotonic agents, suspending and dispersing agents, wetting or emulsifying agents, flavoring and perfuming agents, thickening agents and vehicles.
In another embodiment, the compounds for use according to the invention are in the form of injectable preparations to be administered to a patient to be treated, by which is meant injections of the drugs according to the invention, together with suitable solvents or dispersion media, in the form of sterile or sterile solutions, emulsions or suspensions for injection into the human body, as well as sterile preparations of powders for constitution with a solution or suspension before use. The injection comprises injection (wherein the large-volume injection for intravenous drip is also called intravenous transfusion), sterile powder for injection and concentrated solution for injection.
In the present description and claims, the term "comprises or comprising" and variants of this word, are not intended to exclude other technical features, additives, components or steps. The term includes the expression "consisting of and variations thereof. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description of the invention or may be learned by practice of the invention. The following examples are provided by way of illustration and are not intended to limit the present invention. Moreover, the present invention covers all possible combinations of the particular and preferred embodiments described herein.
The terminology convention:
"stereoisomers" or "stereoisomers" are compounds having the same chemical composition but differing arrangements of atoms or groups in space. It includes "diastereomers" and "enantiomers"
"diastereoisomers" are stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example: melting point, boiling point, spectral characteristics and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis, crystallization, using, for example, chiral HPLC columns in the presence of resolving agents or chromatography.
"enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. 50 of enantiomer: 50 is referred to as a racemic mixture or racemate, which may occur already without stereoselectivity or stereospecificity during chemical reaction or processing.
"prodrug" refers to a compound that is metabolized in the host, e.g., hydrolyzed or oxidized, to form a compound of the invention, and typical examples of prodrugs include compounds having a biologically labile protecting group on a functional group of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, de-aminated, hydroxylated, de-hydroxylated, hydrolyzed, dehydrated, alkylated, de-alkylated, acylated, de-acylated, phosphorylated, dephosphorylated to produce the active compound.
"derivative" refers to a more complex product derived from a compound in which a hydrogen atom or group of atoms is replaced with another atom or group of atoms.
Drawings
FIG. 1 shows the 1H NMR spectrum of NB-DNJ and the structure of the compound.
FIG. 2 1H NMR spectrum of N-7-oxadecenyl-DNJ and compound structure.
FIG. 3 1H NMR spectrum of MON-DNJ and compound structure.
FIG. 4 Iminosugar compound cytotoxicity assay.
FIG. 5 Iminosugar compound activity against SARS-CoV-2 virus infection.
FIG. 6N protein gene copy number assay shows that iminosugar compounds are active against SARS-CoV-2 virus.
FIG. 7ORF1 gene copy number assay shows that iminosugar compounds are active against SARS-CoV-2 virus.
Detailed Description
The following detailed description of the preferred embodiments of the present invention, taken in conjunction with the accompanying drawings, will make the advantages and features of the invention easier to understand by those skilled in the art, and thus will clearly and clearly define the scope of the invention.
1) Iminosugar compound cytotoxicity assays
Experimental procedure
1. Vero-E6 cells were plated in 96-well plates and reached a fully confluent state after 1 day.
3. For each iminosugar compound (NB-DNJ, N-7-oxadecenyl-DNJ and MON-DNJ, all obtained from the institute for sugar biology, Oxford university) 1000. mu.M was used as a starting concentration, and diluted in MEM medium in a gradient.
4. The medium in the 96-well plate was aspirated and the cells were washed with 1x PBS.
5. The PBS wash was removed and 200. mu.l of a dilution of the iminosugar compound was added.
6. At 37 ℃ 5% CO2The culture was carried out for 48 hours.
7 after the culture is completed, the cells are removedIn addition to 100ul of medium, 20ul of Promega CellTiter was added
Figure BDA0003001207050000071
AQueous One Solution reagent.
8. The well plate was heated at 37 ℃ with 5% CO2Culturing for 1-4 hours.
9. The absorbance at 490nm was measured in a 96-well plate microplate reader.
Test results
The compounds NB-DNJ, N-7-oxadecenyl-DNJ and MON-DNJ (the specific compound structures are shown in figures 1, 2 and 3) are small in cytotoxicity, and the cell survival rate is over 80% under the drug concentration of up to 1mM (figure 4). The compounds NB-DNJ, N-7-oxadecenyl-DNJ and MON-DNJ were shown to be highly safe.
2) Iminosugar compound activity assay against SARS-CoV-2 virus
Drug-dispensing reservoir
Iminosugar drugs (NB-DNJ, N-7-oxadecenyl-DNJ and MON-DNJ) were dissolved in MilliQ ultrapure water to prepare a 100mM stock solution, which was filtered through a 0.22 μm filter and stored in a refrigerator at-20 ℃. Drug stock was diluted with MEM according to a gradient. 200ul of diluted drug was added to each well.
Experimental procedure
1. Vero-E6 cells were seeded in 96-well plates to reach a cell density of 90-100% confluence after 24 hours.
2. MEM medium was aspirated and cells were washed with PBS.
3. SARS-CoV-2 virus was diluted in MEM and MOI adjusted to 1pfu per cell to a final volume of 100 ul/well.
4. The PBS in the wells was aspirated and the virus/MEM mixture was added. Incubate for 90 minutes at room temperature with gentle shaking.
5. At the end of the virus incubation, the pathogens were removed, the cells were washed 2 times with PBS and diluted drug was added to each well.
6. At 37 ℃ 5% CO2The culture was carried out in an incubator for 48 hours.
7. Aspirating the medium, labelling the cells with anti-S protein antibody, flow cytometry (FACS) analysis of the S protein positive cells (S)+Cells).
8. Extracting RNA of the cell, carrying out RT-PCR quantitative test on the N protein and ORF1 gene of the cell after drug treatment, and detecting the copy number of the gene so as to reflect the virus load.
Test results
FACS analysis results As shown in FIG. 5, compounds NB-DNJ, N-7-oxadecenyl-DNJ and MON-DNJ were all effective in reducing the ratio of S protein positive cells, indicating that these compounds all inhibited infection or replication of SARS-CoV-2 virus. Wherein the inhibitory activity of N-7-oxadecenyl-DNJ at the cellular level is relatively superior.
The results of RT-PCR quantitative test are shown in FIG. 6 and FIG. 7, and compounds NB-DNJ, N-7-oxadecenyl-DNJ and MON-DNJ can effectively reduce the copy number of the N protein and ORF1 genes, wherein the compounds NB-DNJ and N-7-oxadecenyl-DNJ can reduce the copy number of the virus genes by nearly 1000 times at the level of 4uM compared with the group without drug treatment, and show very good antiviral activity. The antiviral activity of the compound MON-DNJ gene level is at least 10 times lower than that of NB-DNJ and N-7-oxadecenyl-DNJ, and the structure-activity relationship of the imine sugar compound against SARS-CoV-2 virus is shown.
NB-DNJ, also known as meglumine, is an active ingredient of the prescription drug zaves, has been marketed for many years for the treatment of gaucher's disease and type II diabetes; while MON-DNJ has completed phase 2a clinical trials for anti-dengue virus. Although there are many documents reporting the antiviral activity of iminosugar compounds, the activity of such compounds against SARS-CoV-2 virus has not been studied at all. Furthermore, it can be seen from the test results of the present invention that the activities of different iminosugar compounds against SARS-CoV-2 virus showed no significant difference. The present invention unexpectedly found and demonstrated that NB-DNJ can be effective against SARS-CoV-2 virus; considering the path of clinical development comprehensively, NB-DNJ is expected to be developed into a first-line preventive and therapeutic drug for new coronavirus.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent changes made by using the contents of the present specification and the drawings, or applied directly or indirectly to other related technical fields, are included in the scope of the present invention.

Claims (4)

1. Use of imine sugar compounds in the preparation of antiviral drugs.
2. Use according to claim 1, wherein the coronavirus is SARS-CoV-2.
3. Use according to claim 1, characterized in that the iminosugar compound is NB-DNJ or N-7-oxadecenyl-DNJ.
4. Use according to claim 1, characterized in that the iminosugar compound is NB-DNJ.
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CN102655746A (en) * 2009-02-23 2012-09-05 联合治疗公司 Iminosugars and methods of treating viral diseases
CN104703597A (en) * 2012-06-06 2015-06-10 尤尼特尔滤过性微生物学有限责任公司 Novel iminosugars and their applications

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CN102655746A (en) * 2009-02-23 2012-09-05 联合治疗公司 Iminosugars and methods of treating viral diseases
CN104703597A (en) * 2012-06-06 2015-06-10 尤尼特尔滤过性微生物学有限责任公司 Novel iminosugars and their applications

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