CN117503776A - Pharmaceutical composition and application thereof - Google Patents
Pharmaceutical composition and application thereof Download PDFInfo
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- CN117503776A CN117503776A CN202310080034.5A CN202310080034A CN117503776A CN 117503776 A CN117503776 A CN 117503776A CN 202310080034 A CN202310080034 A CN 202310080034A CN 117503776 A CN117503776 A CN 117503776A
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- 150000001875 compounds Chemical class 0.000 claims abstract description 35
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a pharmaceutical composition and application thereof, in particular to a pharmaceutical composition for preventing and/or treating coronavirus infection and pharmaceutical application thereof. The pharmaceutical composition comprises a) an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; b) a therapeutically effective amount of 3CL protease inhibitors of (c). The pharmaceutical composition of the invention can be used as coronavirusThe inhibitor has obvious synergistic effect, is used for treating and/or preventing and relieving diseases caused by coronaviruses, and has the advantages of good curative effect, high safety, reduced virus resistance, reduced toxic and side effects of the medicines and the like.
Description
The present application claims priority from chinese patent application No. 202210941259.0 filed 5, 8, 2022, the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the field of pharmacy, and relates to a pharmaceutical composition for preventing and/or treating coronavirus infection and application thereof.
Background
Coronaviruses are a class of enveloped positive-stranded single-stranded RNA viruses. Since the record, the world has been subjected to multiple coronavirus attacks. The novel coronavirus (SARS-CoV-2) is a very infectious coronavirus. Since the explosion of SARS-CoV-2, many variant strains have emerged, many of which are more infectious and pathogenic than the original strain. SARS-CoV-2 will also evolve over time, and more infectious, pathogenic or immune-escaping variants will likely appear in the future. Therefore, the development of specific drugs against SARS-CoV-2 is an important problem to be solved internationally at present, and is also a necessity of future strategic reserves.
Currently, the antiviral field of combination is being accepted by more and more doctors and patients. The combined use of antiviral drugs with different targets or different action mechanisms can not only improve the treatment effect of diseases, but also reduce the drug resistance of viruses, reduce the toxic and side effects of the drugs and the like.
VV116 is an orally available anti-SARS-CoV-2 a nucleoside analog triisobutyrate prodrug of (c). The compound is capable of being rapidly metabolized in vivo to the parent nucleoside and converted into its triphosphate-active form in the cell. The VV116 nucleoside triphosphate form can compete with endogenous natural nucleoside triphosphates for binding to the active center of viral RNA-dependent RNA polymerase, thereby inhibiting the transcriptional replication link of the virus and exerting antiviral effects. VV116 has been used in Uzbexastein batches for the treatment of COVID-19 and several clinical trials are actively underway. The structural formula of VV116 is shown below:
nirmatrelvir (PF-07321332) is an orally administered 3CL protease (3C-like protease) inhibitor that is effective in inhibiting the activity of 3CL proteases in various coronaviruses, thereby exerting antiviral effects. The 3CL protease is a cysteine protease whose main function is to cleave the coronavirus polyprotein to produce various functional proteins including RNA-dependent RNA polymerase, helicase, single-stranded RNA binding protein, exoribonuclease, endoribonuclease, 2' -O-ribomethyltransferase, etc., which all play an important role in viral replication. Nirmatrelvir is an active ingredient of the anti-novel coronavirus drug Paxlovid, another ingredient in Paxlovid is ritonavir, which is mainly used to slow down the metabolism of the Nirmatrelvir. Paxlovid has obtained Emergency Use Authority (EUA) for the treatment of COVID-19 in the United states, the United kingdom, the European Union, and Canada, respectively. The structural formula of the Nirmatrelvir is shown as follows:
monnpiravir (EIDD 2801) is the first oral antiviral drug approved for treating patients with new coronapneumonia, and the main plasma metabolite of the oral antiviral drug, beta-D-N4-hydroxycytosine (NHC), is a cytosine nucleoside derivative, and the compound shows remarkable inhibition effect on replication of various viruses (influenza virus, hepatitis C virus, SARS, MERS, SARS-CoV-2 and the like) and is a broad-spectrum antiviral nucleoside analogue. NHCs are converted into their triphosphate-active form in cells, which, when incorporated into the RNA strand of a virus by viral RNA-dependent RNA polymerase, do not cause termination of nucleic acid chain elongation, but rather cause fatal mutation of the virus, thereby exerting antiviral effects. Molnupiravir has been approved in the united kingdom for the treatment of covd-19 and has obtained Emergency Use Authority (EUA) from the united states Food and Drug Administration (FDA). The Molnupiravir has the structural formula shown below:
disclosure of Invention
The inventors of the present invention have unexpectedly found that the use of a pyrrolotriazine base nucleoside analogue (a compound of formula (I)) in combination with a 3CL protease inhibitor is capable of acting synergistically against coronaviruses, whereas there is no synergistic effect in combination with a nucleoside analogue NHC by a mutagenic mechanism of action, and therefore the present invention relates generally to the following aspects.
The first aspect of the present invention relates to a pharmaceutical composition comprising:
a) A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and
b) A therapeutically effective amount of a 3CL protease inhibitor;
in the method, in the process of the invention,
R 1 、R 2 each independently selected from hydrogen, C 1-20 Alkanoyl, C 3-10 Cycloalkyl formyl, amino C 1-20 An alkanoyl group;
or R is 1 、R 2 Are connected to each other to form
R 3 Selected from hydrogen, C 1-20 Alkanoyl, C 3-10 Cycloalkyl formyl, amino C 1-20 An alkanoyl group;
R 4 selected from hydrogen, deuterium, halogen;
x is selected from-CH 2 -、-CD 2 -。
In some embodiments, R 1 、R 2 Each independently selected from hydrogen, C 1-10 Alkanoyl, C 3-7 Cycloalkyl formyl, amino C 1-10 An alkanoyl group;
or R is 1 、R 2 Are connected to each other to form
R 3 Selected from hydrogen, C 1-20 Alkanoyl, C 3-7 Cycloalkyl formyl, amino C 1-10 An alkanoyl group;
R 4 selected from hydrogen, deuterium, halogen;
x is selected from-CH 2 -、-CD 2 -。
In some embodiments, R 1 、R 2 Each independently selected from hydrogen, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, hexanoyl, 2-ethylbutyryl and 3, 3-dimethylbutyryl, cyclopropaneformyl, cyclobutylformyl, cyclopentaformyl, cyclohexanoyl, cycloheptyl, alpha-aminoisovaleryl, or R 1 、R 2 Are connected to each other to form
Preferably, R 1 、R 2 Each independently selected from hydrogen, isobutyryl, cyclopropylcarbonyl, or R 1 、R 2 Are connected to each other to form
In some embodiments, R 3 Selected from the group consisting of hydrogen, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, hexanoyl, 2-ethylbutyryl, 2-methylpentanoyl, 2-propylpentanoyl, 3-dimethylbutyryl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, cyclopropaneyl, cyclobutaneyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, aminoacetyl, alpha-aminopropionyl, alpha-aminoisopentanoyl;
preferably, R 3 Selected from the group consisting of hydrogen, propionyl, isobutyryl, pivaloyl, 2-ethylbutyryl, 2-methylpentanoyl, 2-propylpentanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, cyclopropanecarbonyl, cyclopentanoyl, cyclohexanoyl, α -aminoisopentanoyl.
In some embodiments, R 4 Selected from hydrogen, deuterium, fluorine, chlorine and iodine, preferably hydrogen, deuterium, fluorine.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is any one of the compounds having the structure:
in some embodiments, the compound of formula (I) is selected from compounds 11, 14, 16, 20, 27, 30, 32, 37, 41, 68, and 69, preferably, the compound of formula (I) is compound 69.
In some embodiments, the 3CL protease inhibitor is selected from one or more of the following: nirmatrelvir, S-217622, EDP-235, GC-376, PBI-0451, FB2001, VV993 and SIM0417; preferably, the 3CL protease inhibitor is nirmatrelvir.
In some embodiments, the pharmaceutical composition further comprises:
c) A synergistic agent; and
d) Optionally a pharmaceutically acceptable carrier or excipient.
In some embodiments, the potentiator is ritonavir.
In some embodiments, the mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the 3CL protease inhibitor is 0.01-99.99:1, preferably 0.1-20:1, more preferably 0.5-4:1, even more preferably 0.5:1, 1:1, 1.5:1, 2:1, 2:3, 4:3.
In some embodiments, where the pharmaceutical composition comprises a potentiator, the mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to 3CL protease inhibitor, potentiator in the pharmaceutical composition is 1:0.01-99.99:0.01-99.99, preferably 1:0.1-20:0.1-20, more preferably 1:0.2-5:0.2-5.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the same formulation unit as the 3CL protease inhibitor, or the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a different specification formulation unit than the 3CL protease inhibitor.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with a 3CL protease inhibitor.
A second aspect of the invention relates to the use of a pharmaceutical composition according to the first aspect of the invention for the preparation of a medicament, wherein the medicament is (a) an inhibitor of coronavirus replication; or (b) a medicament for the treatment and/or prophylaxis and/or alleviation of a disease caused by a coronavirus infection.
In some embodiments, the coronavirus is one or more selected from the group consisting of:
(1) Coronavirus infecting humans: for example, severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV), human coronavirus OC43 (Human coronavirus OC 43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKUl (Human coronavirus HKUl);
(2) Coronavirus infecting animals: such as Porcine Epidemic Diarrhea Virus (PEDV), feline infectious peritonitis virus (FIFV).
In some embodiments, the disease caused by coronavirus infection is one or more selected from the group consisting of:
(D1) Common cold, high risk symptom infection, respiratory tract infection, pneumonia and complications thereof caused by human coronavirus infection;
(D2) Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus;
(D3) Infectious peritonitis in cats caused by feline coronavirus;
preferably, the disease caused by coronavirus infection is a disease caused by SARS-CoV-2 infection, in particular, one or more selected from the group consisting of: respiratory tract infection, pneumonia and complications thereof caused by SARS-CoV-2 infection;
preferably, the complications include arrhythmia, myocarditis, respiratory failure, impaired liver function, and impaired kidney function.
The beneficial effects are that:
the in vitro cell experiments of the invention show that: the combination of VV116 (compound 69) and nirmatrelvir can inhibit the proliferation of SARS-CoV-2 and HCoV-OC43 in cells, and the effect is obviously higher than that of single administration, and the combination can achieve good therapeutic effect at low dosage, and has obvious synergistic effect.
The in vivo suckling mouse model drug effect experiment of the invention shows that: the combination of the VV116 and the nirmatrelvir can effectively inhibit the loading of HCoV-OC43 in the brain and the lung, has higher effect than that of single administration, and has obvious synergistic effect.
Therefore, the composition of the VV116 and the nirmatrelvir can be used as a coronavirus inhibitor for treating diseases caused by coronavirus infection, and has the advantages of good curative effect, high safety, reduced virus resistance, reduced toxic and side effects of medicines and the like.
Drawings
FIG. 1 shows the results of in vitro inhibition activity assays and synergy calculations for SARS-CoV-2delta variant using combinations of VV116 and nirmatrelvir at different concentrations as described in example 1.
FIG. 2 shows the results of in vitro inhibition activity assay and synergy calculation of HCoV-OC43 by combination of VV116 and nirmatrelvir at different concentrations in example 2.
FIG. 3 shows the results of in vitro inhibition activity assays of SARS-CoV-2delta variant with various concentrations of the combination VV116 and NHC of example 3 and the results of the additive calculations.
FIG. 4 is the results of in vivo inhibition activity assays for HCoV-OC43 on a milk mouse model of HCoV-OC43 infection of VV116, nirmatrelvir and ritonavir of example 4, alone or in combination.
FIG. 5 shows the results of in vivo inhibitory activity assays for SARS-CoV-2delta variant in a K18-hACE2 mouse model of SARS-CoV-2delta variant infection with VV116, nirmatrelvir and ritonavir as described in example 5, alone or in combination.
Detailed Description
Description of the terminology:
in the present invention, unless explicitly stated otherwise, terms used in the present invention have the meanings defined below. Terms not explicitly defined herein have the general meaning commonly understood by those skilled in the art.
The short dash ("-") that is not between two letters or symbols represents the attachment site for a substituent. For example, "-CH 2 -”、“-CD 2 "means that the group is attached to the remainder of the molecule through a carbon atom. However, "-" may be omitted when the attachment site for the substituent is apparent to those skilled in the art, for example, for a substituent such as halogen.
When the radicals carry wavy linesIn this case, the wavy line indicates the position of attachment of this group to the rest of the molecule.
As used herein, "alkanoyl" refers to a fully saturated straight or branched monovalent hydrocarbon radical linked by an acyl group. The alkanoyl group preferably contains 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, 1-3 or 1-2 carbon atoms. The number preceding the alkanoyl group represents the number of carbon atoms, e.g. "C 1-20 Alkanoyl "means alkanoyl having 1-20 carbon atoms and so on. Representative examples of alkanoyl groups include, but are not limited to, formyl, acetyl, propionyl, butyryl, isobutyryl, 2-ethylbutyryl, 3-dimethylbutyryl, pentanoyl, isopentanoyl, pivaloyl, 2-methylpentanoyl, 2-propylpentanoyl, 2-dimethylpentanoyl, 2, 3-dimethylpentanoyl, hexanoyl, 3-methylhexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, and the like.
As used herein, "cycloalkyl formyl" refers to a saturated, non-aromatic carbocyclic ring linked by a formyl group, including mono-, bi-or tricyclic, preferably monocyclic. Preferably 3 to 10 carbon atoms, more preferably 3 to 8 ring carbon atoms, for example 3 to 7, 3 to 6 ring carbon atoms. "C 3-10 Cycloalkyl formyl "is intended to include C 3 、C 4 、C 5 、C 6 、C 7 And C 8 Cycloalkyl groups and formyl groups, and so on. Representative examples of cycloalkyl formyl include, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexanyl, cycloheptenyl, and cyclo Xin Jiaxian.
As used herein, "aminoalkyl" refers to a group as defined herein that is obtained by substitution of one or more hydrogen atoms in an alkanoyl group with an amino group. Representative examples of aminoalkyl groups include, but are not limited to, aminoacetyl, α -aminopropionyl, α -aminoisovaleryl, and the like.
As used herein, "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds of the invention, and which are not biologically or otherwise undesirable. Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the compounds of the present invention. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, with hydrobromic acid being preferred. Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts may be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, such as, inter alia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods. Generally, the salts can be prepared as follows: the free acid form of the compound is reacted with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.) or the free base form of the compound is reacted with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixed solvent of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred when feasible. Other suitable salts can be found in Remington's pharmaceutical sciences (Remington's Pharmaceutical Sciences), 20 th edition, mack publishing company (Mack Publishing Company), easton, pa., (1985), incorporated herein by reference.
As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, the like, and combinations thereof, which are well known to those of ordinary skill in the art (see, e.g., remington's Pharmaceutical Sciences), 18 th edition, mack publishing company (Mack Printing Company), 1990, pp.1289-1329, incorporated herein by reference). Unless any conventional carrier is not compatible with the active ingredient, it is contemplated that it may be used in therapeutic or pharmaceutical compositions.
As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that can elicit a biological or medical response in an individual or ameliorate symptoms, slow or delay the progression of a disease, or prevent a disease, etc. The "therapeutically effective amount" may be determined by the attending physician or veterinarian practitioner and will vary with factors including the compound, the condition being treated, the severity of the condition being treated, the age and associated health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian practitioner, etc.
As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. Individual also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred embodiment, the individual is a human.
As used herein, "inhibition" refers to the alleviation or inhibition of a particular patient, symptom or condition or disease, or a significant reduction in biological activity or process baseline activity.
As used herein, the term "treating" any disease or disorder in one embodiment refers to ameliorating the disease or disorder (i.e., preventing or slowing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter that may not be perceived by the patient. In another embodiment, "treating" refers to modulating a disease or condition physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both.
As used herein, "preventing" refers to administering one or more pharmaceutical substances, particularly the compounds of the invention and/or pharmaceutically acceptable salts thereof, to an individual having a constitution susceptible to the disease, in order to prevent the individual from suffering from the disease.
Through extensive and intensive studies, the present inventors have unexpectedly found that a pyrrolotriazine base nucleoside analog (an effective amount of a compound represented by formula (I)) can exert a synergistic anti-coronavirus effect in combination with a 3CL protease inhibitor. Experiments show that the pharmaceutical composition of the invention has remarkable anti-coronavirus activity, is expected to have obvious advantages in the treatment of various coronavirus infections such as 2019 novel coronavirus (SARS-CoV-2), human coronavirus OC43 (Human coronavirus OC 43) and the like, and the invention is completed on the basis.
In particular, the invention discloses the use of a class of pharmaceutical compositions in anti-coronavirus, which can be used for the preparation of a medicament for the treatment of a disease, condition or indication caused by coronavirus infection. The virus is severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV), human coronavirus OC43 (Human coronavirus OC), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL), human coronavirus HKUl (Human coronavirus HKU 1), porcine Epidemic Diarrhea Virus (PEDV) or feline infectious peritonitis virus (FIFV).
In particular, the invention provides the use of a pharmaceutical composition in the preparation of a virus inhibitor, for example in the preparation of a medicament for the treatment and/or prevention of diseases caused by severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV), human coronavirus OC43 (Human coronavirus OC 43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirusNL 63), human coronavirus HKUl (Human coronavirusHKUl), porcine Epidemic Diarrhea Virus (PEDV) and/or feline infectious peritonitis virus (FIFV) infection. The pharmaceutical composition can obviously inhibit proliferation of 2019 novel coronaviruses and HCoV-OC43 and other coronaviruses in cells in vitro and in vivo, the effect is obviously higher than that of single administration, and the pharmaceutical composition can achieve good inhibition effect with low dosage, and has obvious synergistic effect and good clinical application prospect.
The present invention will be described in detail with reference to examples. The embodiments of the present invention are limited to the description of the present invention, and are not limited thereto. The experimental methods and other experimental operations are conventional in the art, and those skilled in the art can refer to various common specifications, technical literature or related specifications, manuals, etc. before the filing date of the present application.
Materials and reagents
VV116 and EIDD2801 are provided by schwangshan biomedical limited with purity greater than 98%; the purity of the Nirmatrelvir purchased from Nanjing Zhengji medical research Co., ltd is more than 98%; ritonavir is purchased from korea biotechnology limited with purity greater than 98%. Balb/c rats aged 5-6 days were purchased from K18-hACE2 mice (Male, 7-8 weeks) from Experimental animal technology Co., ltd. In Jiangsu Ji Yikang Biotech Co., ltd., jiangsu, china.
The new coronavirus is obtained from the national virus resource library by applying for ex-warehouse, and the anti-new coronavirus in-vivo and in-vitro activity test is carried out in a biosafety third-level laboratory. Animal experiments meet the use and nursing standards of experimental animals, and are approved by the ethical examination committee of the institute of life science and research of the Chinese academy of sciences of the Chinese martial arts, and antiviral in vivo activity tests are carried out in a biosafety 3-level laboratory.
Example 1:
the test method comprises the following steps:
1) Uniformly spreading African monkey kidney cells (Vero E6) in a 48-well plate, culturing 5-6 ten thousand cells per well in DMEM+10% FBS culture medium, and culturing in a 37 ℃ cell culture incubator for 12 hours;
2) Cell supernatants were discarded, medium containing dmem+2% fbs of drug or combination drug was changed and incubated in a cell incubator at 37 ℃ for 1 hour. Drug concentration combination design scheme: the concentration of each of the VV116 and the nirmatrelvir is designed to be 7, and the concentration is respectively 2.0 mu M, 0.67 mu M, 0.22 mu M, 0.074 mu M, 0.024 mu M, 0.008 mu M and 0 mu M in sequence, and each drug concentration is combined with the concentration of the other drug, and the specific drug concentration combination is shown in figure 1;
3) Adding a novel coronavirus SARS-CoV-2delta variant strain, wherein MOI=0.01 in each hole, mixing by tapping, and incubating in a cell incubator at 37 ℃ for 24 hours;
4) Cell supernatants were collected, viral RNA was extracted from the supernatants and viral copy numbers were detected using qRT-PCR.
Test results:
the results are shown in FIG. 1. Quantitative evaluation of the inhibition of the virus by quantitative real-time polymerase chain reaction (qRT-PCR) determination of viral copy number can reflect the inhibition of SARS-CoV-2 by VV116 and nirmatrelvir. It can be seen from the figure that the VV116 and the nirmatrelvir have a remarkable inhibitory effect on SARS-CoV-2 and are dose-dependent, the effect of the combination is remarkably higher than that of the single administration, and the combination of the VV116 and the nirmatrelvir in the concentration range of 0-0.67 mu M and the nirmatrelvir in the concentration range of 0-0.074 mu M has remarkable synergistic effect, particularly, the combination of the VV116 and the nirmatrelvir in the concentration range of 0.024 mu M and the nirmatrelvir in the molar ratio of the VV116 and the nirmatrelvir in the molar ratio of 1-3:1 is the strongest.
Example 2:
the test method comprises the following steps:
1) Uniformly spreading human malignant embryo rhabdomyoma cells (RD) in 48-well plates, culturing 6-8 ten thousand cells per well in DMEM+10% FBS culture medium, and culturing in a 37 ℃ cell culture incubator for 12 hours;
2) Cell supernatants were discarded, medium containing dmem+2% fbs of drug or combination drug was changed and incubated in a cell incubator at 37 ℃ for 1 hour. Drug concentration combination design scheme: the concentration of VV116 and nirmatrelvir was designed to be 6, the concentration of VV116 was 5.0. Mu.M, 2.5. Mu.M, 2.0. Mu.M, 1.5. Mu.M, 1.0. Mu.M, 0.0. Mu.M, nirmatrelvir was 0.30. Mu.M, 0.25. Mu.M, 0.20. Mu.M, 0.15. Mu.M, 0.10. Mu.M, 0.0. Mu.M, each drug was combined with the concentration of the other drug, and the specific drug concentration combinations are shown in FIG. 2.
3) Adding human coronavirus HCoV-OC43, performing light beating and mixing uniformly, and incubating in a cell incubator at 37 ℃ for 48 hours;
4) Cell supernatants were collected, viral RNA was extracted from the supernatants and viral copy numbers were detected using qRT-PCR.
Test results:
the results are shown in FIG. 2. Quantitative assessment of the inhibition of the virus by quantitative real-time polymerase chain reaction (qRT-PCR) determination of viral copy number reflects the inhibition of HCoV-OC43 by VV116 and nirmatrelvir. From the graph, it can be seen that the VV116 and the nirmatrelvir have a remarkable inhibitory effect on HCoV-OC43 and are dose-dependent, and the effect of the combined administration is remarkably higher than that of the single administration, and the combination of the VV116 in the concentration range of 0-2.5 μm and the nirmatrelvir in the concentration range of 0-0.15 μm has a remarkable synergistic effect.
Example 3:
the test method comprises the following steps:
1) Uniformly spreading African monkey kidney cells (Vero E6) in a 48-well plate, culturing 5-6 ten thousand cells per well in DMEM+10% FBS culture medium, and culturing in a 37 ℃ cell culture incubator for 12 hours;
2) Cell supernatants were discarded, medium containing dmem+2% fbs of drug or combination drug was changed and incubated in a cell incubator at 37 ℃ for 1 hour. Drug concentration combination design scheme: the concentration of VV116 was set to 2.0. Mu.M, 1.0. Mu.M, 0.5. Mu.M, 0.2. Mu.M, 0.1. Mu.M, 0.0. Mu.M, and NHC was set to 10.0. Mu.M, 5.0. Mu.M, 2.5. Mu.M, 1.2. Mu.M, 0.6. Mu.M, 0.3. Mu.M, 0.0. Mu.M in this order, the concentration of each drug was combined with the concentration of the other drug, and the specific drug concentration combinations are shown in Table 3;
3) Adding a novel coronavirus SARS-CoV-2delta variant strain, wherein MOI=0.01 in each hole, mixing by tapping, and incubating in a cell incubator at 37 ℃ for 24 hours;
4) Cell supernatants were collected, viral RNA was extracted from the supernatants and viral copy numbers were detected using qRT-PCR.
Test results:
the results are shown in FIG. 3. Quantitative evaluation of the inhibition of the virus by quantitative real-time polymerase chain reaction (qRT-PCR) to determine the viral copy number can reflect the inhibition of SARS-CoV-2 by VV116 and NHC. From the graph, the VV116 and NHC have obvious inhibition effect on SARS-CoV-2 and are dose-dependent, and the combined medicament has a certain superposition effect and no synergistic effect.
Example 4:
the test method comprises the following steps: balb/c rats of 5-6 days old were divided into six groups of seven, each with HCoV-OC43 virus (1X 104TCID 50/one), and 1 hour later were given a gavage regimen (day 0) of each group of Balb/c rats, respectively, EIDD2801 250mpk, VV116 50mpk, nirmatrelvir 50mpk+ritonavir 50mpk, VV116 50mpk+nirmatrelvir 50mpk+ritonavir 50mpk, vehicle control (Vehicle group, 40% PEG400+10% HS15+50% ultrapure water) and blank control (Mock group), after which animals of each group were given a single gavage daily except for the blank control group, and observed for changes in behavior and weight, dissected on day 5, and brains and lungs were taken for qPCR detection of viral copy numbers (viral load; vehicle copes; mpk=mg/kg).
Test results:
the results are shown in FIG. 4. In a mouse model infected by HCoV-OC43, quantitative evaluation of the inhibition rate of viruses by measuring the viral copy numbers of the brain and lung of the mouse by real-time quantitative polymerase chain reaction (qRT-PCR) can reflect the inhibition effect of VV116, nirmatrelvir and ritonavir on HCoV-OC 43. As can be seen, VV116 alone reduced brain and lung viral load by 4log10 and 3log10, respectively, compared to vehicle control; the use of nirmatrelvir and ritonavir alone reduced the loading by 6log10 and 3log10, respectively; the combination of VV116, nirmatrelvir and ritonavir reduced brain and lung viral load by 6log10 and 4log10, respectively; the results show that the combined use of the VV116, the nirmatrelvir and the ritonavir has obvious inhibition effect on HCoV-OC43 in a milk rat body, and the combined use effect is obviously higher than that of the single use, so that the combined use has obvious synergistic effect (note: PF-07321332 is nirmatrelvir and ritonavir).
Example 5:
this example is a test of the activity of anti-SARS-CoV-2 delta variant in mice.
The experimental method comprises the following steps: male K18-hACE2 mice were randomly divided into 5 groups of 9 mice each, and after anesthesia with isoflurane, SARS-CoV-2delta variant (50 μl 1×10) 3 PFU/ml), 2 hours later, and 2 times daily for each group of K18-hACE2 mice were given VV116 100mpk, VV116 50mpk, nirmatrelvir 100mpk+ritonavir 50mpk, VV116 50mpk+nirmatrelvir 100mpk+ritonavir 50mpk, vehicle control (5%DMSO+5%Solutol HS-15+5% PEG400+85% Saline), respectively. On day 2, a portion of the mice were dissected (5 mice per group) and on day 4, the remaining mice of each group were treated identically. Viral RNA was extracted from lung tissue using the RNeasy Mini Kit (Qiagen Kit) and reverse transcribed according to the protocol of the reverse transcription Kit (PrimeScript Reverse Transcriptase, takara), and then the viral copy number of the mouse lung was determined by real-time quantitative polymerase chain reaction (qRT-PCR) and calculated by standard plasmid concentration. Tissue milling solution was diluted in gradient and incubated with Vero E6 cells, followed by culturing in carboxymethyl cellulose medium for 4-5 hours, and the number of plaques was obtained by crystal violet cell staining, and the virus titer (PFU is plaque forming unit) of the mouse lung tissue was calculated.
Experimental results:
the results are shown in FIG. 5. In a mouse model infected by SARS-CoV-2delta variant, quantitative evaluation of the inhibition rate of the virus by determining the viral copy number of the mouse lung by real-time quantitative polymerase chain reaction (qRT-PCR) and the viral titer of the mouse lung tissue by plaque assay reflects the inhibition effect of VV116, nirmatrelvir+ritonavir, VVV116+nirmatrelvir+ritonavir on SARS-CoV-2delta variant. As can be seen from the figure, on days 2 and 4, mice had lung viral loads reduced by 1.0-2.0log10 with VV116 (100 mpk or 50 mpk) or nirmatrelvir+ritonavir (100 mpk+50mpk, nmt group) alone, as compared to vehicle control; the combination of VV116, nirmatrelvir and ritonavir (50 mpk+100mpk+50mpk, combo) resulted in a higher reduction in pulmonary viral load in mice than the alone group, with a reduction of 3.0-4.0log10 on days 2 and 4. As can be seen from the magnitude of the drop in pulmonary viral titer in mice, VV116 alone (50 mpk) was more potent than nirmatrelvir+ritonavir alone (100 mpk+50 mpk) on day 4; the high dose VV116 (100 mpk) and drug combination (VV 116 50mpk+nirmatrelvir 100mpk+ritonavir 50mpk) can reduce viral titers below the detection limit on both day 2 and day 4. The results show that the combination of VV116, nirmatrelvir and ritonavir has obvious inhibition effect on SARS-CoV-2delta variant strain in mice, and the effect of the combined administration is obviously higher than that of the single administration.
Claims (10)
1. A pharmaceutical composition comprising:
a) A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and
b) A therapeutically effective amount of a 3CL protease inhibitor;
in the case of the formula (I),
R 1 、R 2 each independently selected from hydrogen, C 1-20 Alkanoyl, C 3-10 Cycloalkyl formyl, amino C 1-20 An alkanoyl group;
or R is 1 、R 2 Are connected to each other to form
R 3 Selected from hydrogen、C 1-20 Alkanoyl, C 3-10 Cycloalkyl formyl, amino C 1-20 An alkanoyl group;
R 4 selected from hydrogen, deuterium, halogen;
x is selected from-CH 2 -、-CD 2 -。
2. The pharmaceutical composition according to claim 1, wherein in formula (I),
R 1 、R 2 each independently selected from hydrogen, C 1-10 Alkanoyl, C 3-7 Cycloalkyl formyl, amino C 1-10 An alkanoyl group;
or R is 1 、R 2 Are connected to each other to form
R 3 Selected from hydrogen, C 1-10 Alkanoyl, C 3-7 Cycloalkyl formyl, amino C 1-10 An alkanoyl group;
R 4 selected from hydrogen, deuterium, halogen;
x is selected from-CH 2 -、-CD 2 -。
3. The pharmaceutical composition according to claim 1 or 2, wherein in formula (I),
R 1 、R 2 each independently selected from hydrogen, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, hexanoyl, 2-ethylbutyryl and 3, 3-dimethylbutyryl, cyclopropaneformyl, cyclobutylformyl, cyclopentaformyl, cyclohexanoyl, cycloheptyl, alpha-aminoisovaleryl, or R 1 、R 2 Are connected to each other to form
Preferably, R 1 、R 2 Each independently selected from hydrogen, isobutyryl, cyclopropylcarbonyl, or R 1 、R 2 Are connected to each other to form
R 3 Selected from the group consisting of hydrogen, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, hexanoyl, 2-ethylbutyryl, 2-methylpentanoyl, 2-propylpentanoyl, 3-dimethylbutyryl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, cyclopropaneyl, cyclobutaneyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, aminoacetyl, alpha-aminopropionyl, alpha-aminoisopentanoyl;
preferably, R 3 Selected from the group consisting of hydrogen, propionyl, isobutyryl, pivaloyl, 2-ethylbutyryl, 2-methylpentanoyl, 2-propylpentanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, cyclopropanecarbonyl, cyclopentanoyl, and cyclohexanoyl
Formyl, alpha-amino isovaleryl;
R 4 selected from hydrogen, deuterium, fluorine, chlorine and iodine, preferably hydrogen, deuterium, fluorine;
x is selected from-CH 2 -、-CD 2 -。
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is any one of the compounds having the following structure:
5. the pharmaceutical composition according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from compounds 11, 14, 16, 20, 27, 30, 32, 37, 41, 68 and 69; preferably, the compound of formula (I) is compound 69.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the compound of formula (I) is compound 69 and the 3CL protease inhibitor is selected from one or more of the following: nirmatrelvir, S-217622, EDP-235, GC-376, PBI-0451, FB2001, VV993 and SIM0417; preferably, the 3CL protease inhibitor is nirmatrelvir.
7. The pharmaceutical composition of any one of claims 1-6, wherein the pharmaceutical composition further comprises:
c) A synergistic agent; and
d) Optionally a pharmaceutically acceptable carrier or excipient;
preferably, the potentiator is ritonavir.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the 3CL protease inhibitor is 0.01-99.99:1, preferably 0.1-20:1, more preferably 0.5-4:1, even more preferably 0.5:1, 1:1, 1.5:1, 2:1, 2:3, 4:3;
in the case where the pharmaceutical composition contains a potentiator, the mass ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the 3CL protease inhibitor, the potentiator in the pharmaceutical composition is 1:0.01-99.99:0.01-99.99, preferably 1:0.1-20:0.1-20, further preferably 1:0.2-5:0.2-5.
9. Use of a pharmaceutical composition according to any one of claims 1-8 in the manufacture of a medicament, wherein the medicament is (a) an inhibitor of coronavirus replication; or (b) a medicament for the treatment and/or prophylaxis and/or alleviation of a disease caused by a coronavirus infection.
10. The use according to claim 9, characterized in that,
the coronavirus is one or more selected from the group consisting of:
(1) Coronavirus infecting humans: such as severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV), human coronavirus OC43 (Human coronavirus OC), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKU1 (Human coronavirus HKUl);
(2) Coronavirus infecting animals: such as Porcine Epidemic Diarrhea Virus (PEDV), feline infectious peritonitis virus (FIFV);
the disease caused by coronavirus infection is one or more selected from the group consisting of:
(D1) Common cold, high risk symptom infection, respiratory tract infection, pneumonia and complications thereof caused by human coronavirus infection;
(D2) Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus;
(D3) Infectious peritonitis in cats caused by feline coronavirus;
preferably, the disease caused by coronavirus infection is a disease caused by SARS-CoV-2 infection, in particular, one or more selected from the group consisting of: respiratory tract infection, pneumonia and complications thereof caused by SARS-CoV-2 infection;
preferably, the complications include arrhythmia, myocarditis, respiratory failure, impaired liver function, and impaired kidney function.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2023/111419 WO2024027844A1 (en) | 2022-08-05 | 2023-08-07 | Pharmaceutical composition and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210941259 | 2022-08-05 | ||
| CN2022109412590 | 2022-08-05 |
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|---|---|
| CN117503776A true CN117503776A (en) | 2024-02-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202310080034.5A Pending CN117503776A (en) | 2022-08-05 | 2023-01-17 | Pharmaceutical composition and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN117503776A (en) |
| WO (1) | WO2024027844A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110215456A (en) * | 2019-06-25 | 2019-09-10 | 华中农业大学 | A kind of cat coronavirus inhibitor combination being made of GC376 and GS-441524 |
| CN111135166A (en) * | 2020-03-05 | 2020-05-12 | 华中农业大学 | Pharmaceutical composition consisting of GC376 and GS-441524 and application thereof in inhibiting new coronavirus |
| CN112778310A (en) * | 2020-04-20 | 2021-05-11 | 中国科学院上海药物研究所 | Application of nucleoside analogue or combination preparation containing nucleoside analogue in resisting virus |
| KR102169476B1 (en) * | 2020-05-20 | 2020-10-23 | (주)신테카바이오 | Composition for preventing or treating sars coronavirus 2 infection disease |
| US11351149B2 (en) * | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| US20230372381A1 (en) * | 2020-10-05 | 2023-11-23 | Rensselaer Polytechnic Institute | COMPOSITIONS AND METHODS UTILIZING PROTEIN INHIBITORS FOR SYNERGISTIC INHIBITION AND TREATMENT OF SARS-CoV-2 |
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2023
- 2023-01-17 CN CN202310080034.5A patent/CN117503776A/en active Pending
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