WO2024131615A1 - 一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂 - Google Patents

一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂 Download PDF

Info

Publication number
WO2024131615A1
WO2024131615A1 PCT/CN2023/138496 CN2023138496W WO2024131615A1 WO 2024131615 A1 WO2024131615 A1 WO 2024131615A1 CN 2023138496 W CN2023138496 W CN 2023138496W WO 2024131615 A1 WO2024131615 A1 WO 2024131615A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
compound
pharmaceutical composition
salt
atv014
Prior art date
Application number
PCT/CN2023/138496
Other languages
English (en)
French (fr)
Inventor
陈小新
李官官
曹流
黄建洲
龙超峰
杨斯迪
李坤
Original Assignee
广东众生睿创生物科技有限公司
深圳安泰维生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东众生睿创生物科技有限公司, 深圳安泰维生物医药有限公司 filed Critical 广东众生睿创生物科技有限公司
Publication of WO2024131615A1 publication Critical patent/WO2024131615A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/53—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition for treating or alleviating COVID-19 and a preparation containing the pharmaceutical composition.
  • Novel coronavirus pneumonia has become one of the most serious infectious diseases in human history. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has infected more than 650 million people. It is the most urgent public health issue that needs to be addressed worldwide.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • Patent PCT/CN2022/117124 records a series of ketoamide derivatives with 3CL protease binding inhibition. In vitro activity data showed that some compounds showed positive effects in experiments to inhibit the activity of the new coronavirus Mpro (3CL) protease. In further mouse pharmacokinetic tests, some compounds also showed longer half-lives and better pharmacokinetic properties. Among them, compound 1 (PCT/CN2022/117124 Example 1) has a relatively outstanding overall performance and is considered to have good drug development prospects.
  • ATV014, CAS: 2691076-98-7 developed by Zhang Xumu's team at Southern University of Science and Technology, is a nucleoside compound that can inhibit RNA polymerase (RdRp). It has good in vitro antiviral activity, pharmacokinetic properties, in vivo antiviral effects and broad-spectrum anti-coronavirus activity.
  • the genetic material RNA genome of the new coronavirus may mutate automatically at any time during its proliferation, and the enzymes that repair errors in the replication process of the genetic material RNA of the new coronavirus are less active and cannot correct errors in time, it may mutate in a short period of time.
  • the new coronavirus continues to enhance its adaptability to the environment in order to adapt to the new environment, increasing the possibility of genetic mutations in the new coronavirus replicon virus, thereby causing the new coronavirus to mutate in a short period of time.
  • clinical antiviral drugs are used for symptomatic treatment. In order to survive, the new coronavirus may also mutate in a short period of time, and even become more toxic and enhance drug resistance.
  • the new coronavirus has the characteristics of high mutation rate and frequent inter-virus recombination, which affect the therapeutic effect of drugs.
  • new structures and new mechanisms of active compounds are constantly being discovered, in the long run, the use of a single antiviral drug may not be able to effectively inhibit/reduce the concentration of the virus in the body and cure COVID-19 in a short period of time. The corresponding increase in dosage and prolonged treatment time also bring greater medication risks to patients.
  • Combination therapy is one of the effective solutions.
  • Paxlovid is the world's first oral 3CL protease inhibitor for the new coronavirus launched by Pfizer. It contains two ingredients, one of which is PF-07321332 (nematevir) and the other is ritonavir. PF-07321332 inhibits the activity of 3CL, the main protease required for the replication of the new coronavirus, and ritonavir slows down the decomposition of the first ingredient PF-07321332 in the body, allowing PF-07321332 to increase its concentration and maintain a lasting effect, thereby improving its effectiveness.
  • PF-07321332 nematevir
  • ritonavir slows down the decomposition of the first ingredient PF-07321332 in the body, allowing PF-07321332 to increase its concentration and maintain a lasting effect, thereby improving its effectiveness.
  • the first purpose of the present invention is to overcome the shortcomings of the prior art and provide a pharmaceutical composition for the treatment of new coronary pneumonia.
  • the pharmaceutical composition utilizes the synergistic effect between the active ingredients to solve technical problems such as the drug resistance of the new coronavirus and reduce the risk of clinical drug use.
  • the first aspect of the present invention provides a pharmaceutical composition, which comprises a first active ingredient and a second active ingredient, wherein the first active ingredient is compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt or a combination of said substances, and the second active ingredient is ATV014 or a pharmaceutically acceptable salt, hydrate, solvate thereof, specifically, the molar ratio of the first active ingredient to the second active ingredient is 50:1 to 1:50.
  • the first active ingredient refers to compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt or a combination of the above substances, which can be a mixture of one or more of compound 1, the ester corresponding to compound 1, the salt of compound 1, and the salt of the ester corresponding to compound 1 in any proportion.
  • the corresponding esters, salts of compound 1, and salts of the esters corresponding to compound 1 each include their lower anhydrates, ansolvates, hydrates, and solvates; the esters corresponding to compound 1 refer to esters formed between compound 1 and organic acids, including but not limited to formate, acetate, propionate, isopropionate, n-butyrate, tert-butyrate, etc.
  • the salts of compound 1 are salts formed between compound 1 and organic acids and/or inorganic acids, or salts formed between compound 1 and organic bases and/or inorganic bases, including but not limited to hydrochlorides, Hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, tartrate, camphorsulfonate, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, ethylenediamine salt, triethylamine salt, etc.; the salt of the ester corresponding to compound 1 refers to the salt formed by the ester formed by the aforementioned compound 1 and an organic acid and an organic base and/or an inorganic base and/or an organic acid and/or an inorganic acid, including but not limited to the hydrochloride of the methyl ester of compound 1, the sulfate of the methyl ester of compound 1, the hydrochloride
  • the second active ingredient is ATV014 or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the molar ratio of the first active ingredient to the second active ingredient is 50:1 to 1:50, preferably, the molar ratio of the first active ingredient to the second active ingredient is 20:1 to 1:20, more preferably, the molar ratio of the first active ingredient to the second active ingredient is 10:1 to 1:10, more preferably, the molar ratio of the first active ingredient to the second active ingredient is 5:1 to 1:10. Most preferably, the molar ratio of the first active ingredient to the second active ingredient is 1:1.
  • the molar ratio of the first active ingredient to the second active ingredient is 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:10, 1:20, 1:30, 1:40 or 1:50.
  • the mass of the salts of the present invention refers to the mass on a free basis (free base/acid equivalent), and the mass of hydrates/solvates refers to the mass on an anhydrous basis.
  • the aforementioned pharmaceutical composition comprising the first active ingredient (compound 1 or its corresponding ester or its corresponding salt or its corresponding ester salt or a combination of the substances) and the second active ingredient (ATV014 or its pharmaceutically acceptable salt, hydrate, solvate), when the molar ratio of the two active ingredients is within a specific range, has a better drug synergistic effect, which is manifested as a significantly better anti-new coronavirus effect than a single ingredient, and also manifested as a significantly better anti-new coronavirus effect than a pharmaceutical composition with a molar ratio outside the aforementioned specific range.
  • the molar ratio of the first active ingredient and the second active ingredient in the unit preparation is within the specific range, it has a better anti-new coronavirus effect; after comprehensively evaluating the other drug properties (such as mixture stability, fluidity, etc.), it is believed that the pharmaceutical composition has a better drug prospect.
  • the present scheme can also be used in combination drug administration, such as taking the first active ingredient and the second active ingredient simultaneously or successively.
  • the molar ratio of the two active ingredients is within a specific range, it has a better drug synergistic effect, which is manifested as a significantly better anti-new coronavirus effect than a single ingredient, and also manifested as a significantly better anti-new coronavirus effect than a drug combination with a molar ratio outside the aforementioned specific range.
  • the pharmaceutical composition in the first object of the present invention in addition to comprising the first active ingredient and the second active ingredient, further comprises a third active ingredient, wherein the third active ingredient is an antiretroviral drug; the definitions and corresponding scopes of the first active ingredient and the second active ingredient are the same as those of the pharmaceutical composition in the first object of the present invention.
  • the antiretroviral drug referred to by the third active ingredient is ritonavir.
  • the first active ingredient is compound 1 or its corresponding ester or its corresponding salt, its corresponding ester salt or a combination of the substances
  • the second active ingredient is ATV014 or a pharmaceutically acceptable salt thereof
  • the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 50:1:0.1-5 to 1:50:0.1-5; preferably, the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is 20:1:0.3-2 to 1:20:0.3-2; preferably, the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is 10:1:0.3-2 to 1:10:0.3-2; More preferably, the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is 5:1:0.3-2 to 1:10:0.3-2; more preferably, the molar ratio of the first active ingredient, the second active ingredient and
  • the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 50:1:1, 40:1:1, 30:1:1, 24:1:1, 20:1:1, 10:1:1, 6:1:1, 5:1:1, 3:1:1, 2:1:1, 1.5:1:1, 1:1:1, 1:1.5:1, 1:2:1, 1:3:1, 1:5:1, 1:6:1, 1:10:1, 1:20:1, 1:24:1, 1:30:1, 1:40:1 or 1:50:1.
  • the pharmaceutical composition containing the first active ingredient, the second active ingredient and the third active ingredient is a combination of Compound 1, ATV014 and ritonavir.
  • the first active ingredient and the second active ingredient are respectively present in separate preparation units.
  • the first active ingredient and the second active ingredient are administered simultaneously or sequentially.
  • Another object of the present invention is to provide a method for preparing the aforementioned pharmaceutical composition, which can ensure the stable preparation of the aforementioned pharmaceutical composition.
  • the preparation method is prepared by a conventional mixing method in the art, and more specifically, the preparation method can be prepared by a direct mixing method, an equal amount incremental method, and the like.
  • the equipment used in the mixing can be a common mixing equipment in the art, such as a V-type mixer, a double cone mixer, a rotary mixer, etc., depending on the scale of preparation. Manual mixing can also be used for small-scale preparation.
  • the third object of the present invention is to provide a preparation containing the aforementioned pharmaceutical composition.
  • the preparation comprises the aforementioned pharmaceutical composition and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from any one or more of a filler, a binder, a disintegrant, a glidant, a lubricant, a flavoring agent, and the like.
  • the filler is selected from any one of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, sucrose, lactose, fructose, xylitol, mannitol, starch or its derivatives, dextrin and microcrystalline cellulose, or a mixture of two or more thereof in any proportion.
  • the binder is selected from gum arabic, gelatin, tragacanth, dextrin, polyvinyl pyrrolidone, starch and its derivatives, sodium alginate, sorbitol, syrup, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose and polymethacrylic acid.
  • the disintegrant is selected from any one of starch, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl methylcellulose, microcrystalline cellulose and methylcellulose, or a mixture of two or more thereof in any proportion.
  • the glidant is selected from any one of colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, etc., or a mixture of two or more thereof in any proportion.
  • the lubricant is selected from any one of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, zinc stearate and polyethylene glycol, or a mixture of two or more thereof in any proportion.
  • the flavoring agent is selected from any one of stevioside, aspartame and other commonly used flavors and sweeteners in the art, or a mixture of two or more of them in any proportion.
  • the preparation containing the aforementioned pharmaceutical composition is an oral preparation, which may be a powder, granules, pellets, capsules, tablets, lozenges or oral liquids.
  • the specification of compound 1 or its corresponding ester or its corresponding salt or its corresponding salt of an ester or a combination of the substances in the preparation can be 50-1500 mg; preferably, the specification of the preparation is 100-1000 mg; specifically, the specification of compound 1 or its corresponding ester or its corresponding salt or its corresponding salt of an ester or a combination of the substances in the preparation is 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.
  • the first active ingredient and the second active ingredient may be present in separate preparation units, respectively.
  • the first active ingredient and the second active ingredient may be administered simultaneously or sequentially.
  • preparations containing the aforementioned pharmaceutical composition also show significantly better anti-new coronavirus effects than preparations containing single ingredients, and also show significantly better anti-new coronavirus effects than pharmaceutical composition preparations containing a molar ratio outside the aforementioned specific range, and have good market prospects.
  • the fourth object of the present invention is to provide a pharmaceutical use, that is, the use of the pharmaceutical composition described in the first object of the present invention and/or the preparation described in the third object of the present invention in the preparation of a drug for alleviating or treating novel coronavirus infection.
  • a fifth object of the present invention is to provide a use, wherein the first active ingredient and the second active ingredient are formulated to be administered once a day, twice a day or three times a day on the same day.
  • the first active ingredient and the second active ingredient are formulated to be co-delivered in a common oral administration dosage unit or the first active ingredient and the second active ingredient are formulated to be administered in separate oral administration dosage units.
  • the new coronavirus infection targeted by the pharmaceutical use is the new coronavirus infection caused by the common type of the new coronavirus and its variants.
  • the new coronavirus targeted by the pharmaceutical use is the new coronavirus infection caused by the Alpha variant, Beta variant, Gamma variant, Delta variant, Lambda variant and/or Omicron variant.
  • the infection includes fever, cough, sore throat, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.
  • the first active ingredient and the second active ingredient are each formulated and each is administered once a day, twice a day, or three times a day.
  • the first active ingredient and the second active ingredient are formulated for co-delivery in an oral administration dosage unit.
  • the first active ingredient and the second active ingredient are formulated for administration in separate oral dosage units.
  • the present invention has the following outstanding advantages and beneficial effects:
  • a pharmaceutical composition which comprises a first active ingredient (compound 1 or its corresponding ester or its corresponding salt or its corresponding ester salt or a combination of said substances) and a second active ingredient (ATV014 or its pharmaceutically acceptable salt) in a specific molar ratio, and may optionally further contain a third active ingredient (antiretroviral drug).
  • the pharmaceutical composition has good drug synergy and is considered to have good drug development prospects after comprehensive evaluation.
  • a method for preparing a pharmaceutical composition is provided, which can ensure stable preparation of the aforementioned pharmaceutical composition.
  • a preparation containing the aforementioned pharmaceutical combination which also exhibits significantly better anti-new coronavirus effects than preparations containing a single ingredient, and also exhibits significantly better anti-new coronavirus effects than preparations containing pharmaceutical combinations with a molar ratio outside the aforementioned specific range, and has good market prospects.
  • the contribution of the present invention lies in the discovery that drugs within a specific range have synergistic effects. Therefore, those skilled in the art can understand that when the types and proportions of active ingredients in a unit dosing unit are within the range described in the present invention, or the types and proportions of unit dosing units of different active ingredients in the same sales unit are within the range described in the present invention, it can be considered that the technical scheme protected by the present invention is used; specifically, the aforementioned unit dosing unit refers to the smallest unit for clinical use, such as: a unit tablet, a unit capsule, a unit bottle of oral liquid, a unit package of granules, etc.; the aforementioned unit dosing units of different active ingredients in the same sales unit refer to different unit dosing units put into the same package for sale in a specific proportion, and different unit dosing units are taken and administered in combination according to a specific proportion during clinical use, such as: tablets of different active ingredients (Paxlovid) are placed in a unit box, etc.
  • the "pharmaceutically acceptable salt” used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • salts formed by non-toxic acids include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates or perchlorates; and organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates or malonates; or these salts are obtained by other methods described in books and literature, such as ion exchange methods.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate
  • Salts obtained by reaction with an appropriate base include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed by compounds of any N-containing group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium or magnesium salts, etc.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol.
  • hydrate refers to an association formed by one or more water molecules and a compound of the present invention.
  • “Combination” means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compound disclosed herein and the combination partner can be administered separately at the same time or can be administered at certain time intervals.
  • pharmaceutical composition or “combination administration” or the like as used herein is intended to encompass administration of the selected combination partners to a single individual (e.g., a patient) in need thereof, and is intended to include treatment regimens in which the substances are not necessarily administered by the same route of administration or at the same time.
  • Figure 1 is the body weight change curve of infected mice after administration.
  • Figure 2 shows the lung viral load after different times of administration.
  • the ATV014 described in the present invention can be prepared by referring to the methods disclosed in the prior art, such as referring to the methods disclosed in Examples 9 and 17 of CN202111083730.9 and Examples 1 to 3 of CN202110621245.6.
  • the ATV014 used in the examples listed in the present invention is a homemade raw material drug according to the above method, and the purity is >99%.
  • the ritonavir used in the examples is the raw material of the commercially available ritonavir tablets, CAS: 155213-67-5, purity> 99%.
  • compositions with molar ratios of free compound 1 to ATV014 of 40:1, 30:1, 20:1, 1:20, 1:30 and 1:40 were prepared respectively.
  • Example 17 Testing the anti-new coronavirus activity of the composition of compound 1 and ATV014
  • SARS-CoV-2 (B.1, hCoV-19/CHN/SYSU-IHV/2020 strain, Accession ID on GISAID:EPI_ISL_444969).
  • Two 24-well plates of A549-hACE2 were plated, with 5 ⁇ 10 4 cells in each well. After 24 hours, the cells were attached to the wall, and SARS-CoV-2 infected the cells at an MOI of 0.05. After infection at 37°C for 1 hour, the cells were washed twice with a preheated PBS solution, and the compound 1 and ATV014 composition prepared in Examples 2 to 16 were prepared into different concentrations, and the infected cells were added to the culture medium containing different concentrations of the drug to be tested or DMSO. After 48 hours, the supernatant was collected, and the intracellular virus was detected by fluorescent quantitative PCR, and the drug inhibition rate was calculated (see Table 1).
  • the anti-new coronavirus effect of compound 1 or its corresponding ester or its corresponding salt or its corresponding ester salt or the combination of the substances, and ATV014 or its pharmaceutically acceptable salt when the molar ratio is 10:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5 or 1:10 is significantly better than the effect of using compound 1 or its corresponding ester or its corresponding salt or its corresponding ester salt or the combination of the substances alone, and the effect of using ATV014 or its pharmaceutically acceptable salt alone, and is also significantly better than the anti-new coronavirus effect of the pharmaceutical composition whose molar ratio is not within the specific range.
  • the activity experiment further showed that when the molar ratio of compound 1 or its corresponding ester or its corresponding salt or its corresponding ester salt or a combination of the substances, and ATV014 or its pharmaceutically acceptable salt, and ritonavir is 50:1:0.1-5 to 1:50:0.1-5, the pharmaceutical composition has a good anti-new coronavirus effect; when the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 20:1:0.3-2 to 1:20:0.3-2, the pharmaceutical composition has a better anti-new coronavirus effect; and when the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 10:1:0.3-2 to 1:10:0.3-2, the anti-new coronavirus effect of the pharmaceutical composition is optimal.
  • Example 2 The pharmaceutical composition obtained in Example 2 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 1.00 mg + 0.94 mg).
  • Example 3 The pharmaceutical composition obtained in Example 3 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 1.00 mg + 1.25 mg).
  • Example 4 The pharmaceutical composition obtained in Example 4 was mixed with an appropriate amount of filler, binder, and disintegrant and then directly compressed to prepare tablets. (The combined mass of compound 1 and ATV014 is: 1.00 mg + 1.88 mg).
  • Example 5 The pharmaceutical composition obtained in Example 5 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 0.50 mg + 1.57 mg).
  • Example 6 The pharmaceutical composition obtained in Example 6 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 0.50 mg + 3.14 mg).
  • Example 7 The pharmaceutical composition obtained in Example 7 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 0.10 mg + 3.14 mg).
  • Example 8 The pharmaceutical composition obtained in Example 8 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 1.00 mg + 0.63 mg).
  • Example 9 The pharmaceutical composition obtained in Example 9 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 1.00 mg + 0.42 mg).
  • Example 10 The pharmaceutical composition obtained in Example 10 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the combined mass of compound 1 and ATV014 was: 2.00 mg + 0.63 mg).
  • Example 11 The pharmaceutical composition obtained in Example 11 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 2.00 mg + 0.42 mg).
  • Example 12 The pharmaceutical composition obtained in Example 12 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 2.00 mg + 0.25 mg).
  • Example 13 The pharmaceutical composition obtained in Example 13 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 2.00 mg + 0.13 mg).
  • Example 14 The pharmaceutical composition obtained in Example 14 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets (the mass combination of compound 1 and ATV014 was: 5.00 mg + 0.06 mg).
  • Example 16 The pharmaceutical composition obtained in Example 16 was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets (the mass combination of compound 1, ATV014 and ritonavir was: 2.00 mg + 0.42 mg + 0.75 mg).
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets.
  • 188 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets. 376 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets. 628 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets.
  • 126 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets.
  • 84 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets.
  • 63 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets.
  • 42 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and then directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets.
  • 25 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets and placed in the same package.
  • compound 1 200 mg was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets. 13 mg of ATV014 was mixed with appropriate amounts of fillers, binders and disintegrants and directly compressed into tablets and placed in the same package.
  • compound 1 266 mg was mixed with appropriate amounts of fillers, binders, and disintegrants and directly compressed into tablets.
  • 56 mg of ATV014 was mixed with appropriate amounts of fillers, binders, and disintegrants and directly compressed into tablets.
  • 100 mg of ritonavir tablets were placed in the same package.
  • Example 17 The test was carried out in the same manner as in Example 17.
  • the experimental data showed that the combined use of Compound 1, ATV014 and ritonavir had a higher virus inhibition rate, indicating that Compound 1, ATV014 and ritonavir had obvious drug synergy; when the molar ratio of Compound 1 to the second active ingredient ATV014 and the third active ingredient ritonavir was about 50:1:0.1-5 to 1:50:0.1-5, the pharmaceutical composition had a better effect of inhibiting the new coronavirus; when the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition was about 20:1:0.3-2 to 1:20:0.3-2, the pharmaceutical composition had a better effect of inhibiting the new coronavirus.
  • the pharmaceutical composition when the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 20:1:0.3-2 to 1:20:0.3-2, the pharmaceutical composition has a better effect of inhibiting the new coronavirus; when the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 10:1:0.3-2 to 1:10:0.3-2, the pharmaceutical composition has a further effect of inhibiting the new coronavirus; and when the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient in the pharmaceutical composition is about 5:1:0.3-2 to 1:10:0.3-2, the pharmaceutical composition of 1:1:0.3-2 has the best effect of inhibiting the new coronavirus.
  • the molar ratio of the first active ingredient, the second active ingredient and the third active ingredient may be 50:1:1, 40:1:1, 30:1:1, 24:1:1, 20:1:1, 10:1:1, 6:1:1, 5:1:1, 3:1:1, 2:1:1, 1.5:1:1, 1:1:1, 1:1.5:1, 1:2:1, 1:3:1, 1:5:1, 1:6:1, 1:10:1, 1:20:1, 1:24:1, 1:30:1, 1:40:1 or 1:50:1.
  • Example 21 Testing the in vivo anti-new coronavirus activity of the composition of compound 1 and ATV014
  • This experiment used GraphPad Prism 8.0.1 software for graphing, summarizing and statistics of result data.
  • the Delta strain of the new coronavirus was isolated and preserved by the biosafety level 3 laboratory of Guangdong CDC.
  • the K18-hACE2 transgenic mice were provided by the School of Medicine of Sun Yat-sen University and purchased from Jackson Laboratory in the United States.
  • the strain is C57BL/6 (B6.Cg-Tg(K18-ACE2)2Prlmn/J).
  • mice C57BL/6(B6.Cg-Tg(K18-ACE2)2Prlmn/J) mice were randomly divided into 4 groups according to their body weight before the experiment, with 10 mice in each group.
  • the group settings are as follows:
  • mice 40 C57BL/6 (B6.Cg-Tg(K18-ACE2)2Prlmn/J) mice were anesthetized with isoflurane and infected with the Delta strain of the new coronavirus via intranasal drops.
  • the intranasal dose of the strain was 500 PFU/mouse, and the infection volume was 50 ⁇ L.
  • mice were infected by intranasal drip on D0, and the solvent was given 2 hours after the challenge, with a volume of 0.2 mL/mouse, once a day until the 3rd and 5th days after the challenge.
  • ATV014 (100 mg/kg) dose group 3 mL of 10 mg/mL ATV014 stock solution was taken; mice were infected by intranasal drip on D0, and drug administration began 2 hours after challenge, with a volume of 0.2 mL/mouse, once a day until the 3rd and 5th days after challenge.
  • Compound 1 (150 mg/kg) dose group 3 mL of 15 mg/mL Compound 1 stock solution was drawn; mice D0 were infected by intranasal drip, and drug administration began 2 hours after challenge, with a volume of 0.2 mL/mouse, once a day until the 3rd and 5th days after challenge.
  • ATV014 (100 mg/kg) + Compound 1 (150 mg/kg) dose group 3 mL of the original solution with a concentration of 10 mg/mL ATV014 and 15 mg/mL Compound 1 was drawn; mice D0 were infected by intranasal drip, and the drug was administered 2 h after the challenge, with a volume of 0.2 mL/mouse. Once a day, until the 3rd and 5th days after the challenge.
  • mice The weight of mice was recorded on the day of infection (recorded as Day 0), and the weight of mice and the death of mice were observed and recorded every day.
  • General clinical observations were performed once a day, including: the mobility and survival status of mice; eyes and hair; death and any observable clinical manifestations.
  • mice were killed on the third day (Day 3) and the fifth day (Day 5) after infection.
  • the mice were dissected, the left lungs of the mice were taken, weighed, and put into 1 mL DPBS buffer for tissue grinding, and the ground tissue fluid was tested for the titer of the new coronavirus.
  • qPCR used the Daan Gene Novel Coronavirus 2019-nCoV Nucleic Acid Detection Kit (Cat. No. A0930, primer sequences are DAAN-N-F: AAGAAATTCAACTCCAGGCAGC (SEQ ID NO: 1); DAAN-N-R: GCTGGTTCAATCTGTCAAGCAG (SEQ ID NO: 2); DAAN-N-P: TCACCGCCATTGCCAGCCA (SEQ ID NO: 3)).
  • DAAN-N-F AAGAAATTCAACTCCAGGCAGC
  • DAAN-N-P TCACCGCCATTGCCAGCCA
  • mice after infection was tested, and the results are shown in FIG1 . There was no statistical difference in the body weight changes of different drug-administered groups compared with the vehicle control group.
  • mice On the third and fifth days after infection, mice were killed, lungs and multi-lobe lung tissues were homogenized, tissue RNA was extracted, and the results of qPCR detection of lung viral load are shown in Figure 2.
  • the new coronavirus RNA can be detected in the lung tissue of each group of mice, and each mouse in the solvent control group (Mock) has a higher viral load, indicating that the mouse infection modeling of this experiment was successful.
  • the viral loads of the other drug treatment groups were not significantly different from those of the control group.
  • ATV014 and ATV014 + compound 1 to K18-ACE2 mice can reduce the viral load to varying degrees.
  • ATV014 (100 mg/kg) and ATV014 (100 mg/kg) + compound 1 (150 mg/kg) have significant anti-new coronavirus effects in the mouse model, and the antiviral effect of the drug combination group is better than that of the single drug group, indicating that ATV014 and compound 1 have a synergistic antiviral effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

涉及一种药物组合物，所述药物组合物包含第一有效成分和第二有效成分，其中第一有效成分为化合物1、其对应的酯、其对应的盐、其对应的酯的盐或所述物质的组合，第二有效成分为ATV014或其药学上可接受的盐、水合物、溶剂合物，所述第一有效成分与第二有效成分的摩尔比为50:1～1:50，该组合物具有较好的成药前景。

Description

一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂 技术领域
本发明属于药物制剂领域，特别涉及一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂。
背景技术
新型冠状病毒肺炎(COVID-19)已成为人类历史上最严重的传染性疾病之一，它是由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)引起的，目前已造成超累计6.5亿人感染，是世界范围内当前最为迫切急需解决的公共卫生问题。
目前虽然已有包括疫苗接种和抗病毒药物进行治疗，但是由于变异毒株的出现造成疫情反复出现，因此开发新型安全有效的抗病毒药物对于遏制疫情具有重要意义。专利PCT/CN2022/117124记载了一系列具有3CL蛋白酶结合抑制作用的酮酰胺衍生物。体外活性数据表明，部分化合物在抑制新型冠状病毒Mpro(3CL)蛋白酶活性实验中表现出积极效应，在进一步的小鼠药代动力学试验中，部分化合物亦表现出半衰期更长，更好的药代动力学性质，其中化合物1(PCT/CN2022/117124实施例1)的综合表现相对突出，被认为具有较好的成药前景。
ATV014，CAS：2691076-98-7，由南方科技大学张绪穆团队开发，是一款可以抑制RNA聚合酶(RdRp)的核苷类化合物，其具有良好的体外抗病毒活性、药代动力学特性、体内抗病毒效果以及广谱抗冠状病毒活性。
由于新冠病毒的遗传物质RNA基因组在其增殖过程中，时刻都可能自动地发生突变，并且新冠病毒遗传物质RNA在复制过程中修复错误机制的酶，活性较低，无法及时纠正错误，因此导致其在短时间内可能出现变异。另外，由于外界环境在不断变化，新冠病毒为了适应新环境，不断地增强自身对环境的适应程度，增加了新冠病毒复制子病毒发生基因突变的可能性，从而导致新冠病毒短时间内出现变异。同时临床使用抗病毒药物对症治疗，新冠病毒为了存活，也可能在短时间内出现基因突变，甚至毒性变强，增强耐药性。
可以看出，新冠病毒具有突变率高、病毒间重组现象多等特点，影响药物的治疗效果。尽管新结构、新机制活性化合物不断被发现，但在长远看来，使用单一抗病毒药物可能存在无法在短时间内有效抑制/降低体内病毒浓度，治愈新冠肺炎的缺陷，其对应的使用剂量增大及治疗时间拉长也给患者带来了较大的用药风险，联合用药是有效的解决方案之一。
Paxlovid是辉瑞公司推出的全球首款针对新冠病毒的口服3CL蛋白酶抑制剂，其包含两个成分，其中之一是PF-07321332(奈玛特韦)，另一是利托那韦。PF-07321332抑制新冠病毒复制所需的主要蛋白酶3CL的活性，利托那韦减缓体内第一种成分PF-07321332的分解，使得PF-07321332提高浓度，维持持久的效果，从而提高其有效性。
寻找新的解决方案，增强3CL蛋白酶抑制剂的活性，克服病毒耐药性，延长有临床应用前景的抗新冠肺炎药物使用寿命，是现有技术亟待解决的技术问题。
发明内容
本发明的第一个目的在于克服现有技术的不足，提供一种用于治疗新冠肺炎的药物组合物，该药物组合物利用有效成分之间的协同作用，解决了的新冠病毒的耐药性等技术问题，降低临床用药风险。
本发明的目的通过下述技术方案实现：
本发明的第一个方面提供一种药物组合物，所述药物组合物包含第一有效成分和第二有效成分，其中第一有效成分为化合物1、其对应的酯、其对应的盐、其对应的酯的盐或所述物质的组合，第二有效成分为ATV014或其药学可接受的盐、水合物、溶剂合物，具体的，所述第一有效成分与第二有效成分的摩尔比为50:1～1:50。
所述第一有效成分指代的化合物1、其对应的酯、其对应的盐、其对应的酯的盐或所述物质的组合，具体可为化合物1、化合物1对应的酯、化合物1的盐、化合物1对应的酯的盐中一种或两种以上以任意比例混合所得的混合物，前述化合物1、化合物1 对应的酯、化合物1的盐、化合物1对应的酯的盐各自包含其下位的无水合物、无溶剂合物、水合物及溶剂合物；所述化合物1对应的酯指代化合物1与有机酸形成的酯，包括但不限于化合物1的甲酸酯、乙酸酯、丙酸酯、异丙酸酯、正丁酸酯、叔丁酸酯等；所述化合物1的盐为化合物1与有机酸和/或无机酸形成的盐、或化合物1与有机碱和/或无机碱形成的盐，包括但不限于化合物1的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、酒石酸盐、樟脑磺酸盐、锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、氨盐、乙二胺盐、三乙胺盐等；化合物1对应的酯的盐指代前述化合物1与有机酸形成的酯与有机碱和/或无机碱和/或有机酸和/或无机酸形成的盐，包括但不限于化合物1甲酯的盐酸盐、化合物1甲酯的硫酸盐、化合物1乙酯的盐酸盐、化合物1乙酯的硫酸盐等。
第二有效成分为ATV014或其药学可接受的盐、水合物、溶剂合物。
第二有效成分指ATV014或其药学可接受的盐，亦包含其下位的无水合物、无溶剂合物、水合物及溶剂合物，比如ATV014可以是ATV014的无水合物，也可以是ATV014的水合物、ATV014的溶剂合物等。
第一有效成分与第二有效成分的摩尔比为50:1～1:50，优选的，第一有效成分与第二有效成分的摩尔比为20:1～1:20，更优选的，第一有效成分与第二有效成分的摩尔比为10:1～1:10，更优选的，第一有效成分与第二有效成分的摩尔比为5:1～1:10。最优选的，第一有效成分与第二有效成分的摩尔比为1:1。
在一些具体的案例中，第一有效成分与第二有效成分的摩尔比为50:1、40:1、30:1、 20:1、10:1、5:1、3:1、2:1、1.5:1、1:1、1:1.5、1:2、1:3、1:5、1:10、1:20、1:30、1:40或1:50。
如无特别说明，本发明盐的质量均指代以游离物计的质量(free base/acid equivalent)，水合物/溶剂合物均指代以折干折纯计的质量(on an anhydrous basis)。
发明人在实验中令人吃惊的发现：前述包含第一有效成分(化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合)，和第二有效成分(ATV014或其药学可接受的盐、水合物、溶剂合物)的药物组合物，当两种有效成分摩尔比在特定范围时，其具有较好的药物协同作用，表现为较单一成分明显更好的抗新冠病毒的效果，也表现为较前述特定范围之外摩尔比的药物组合物明显更优的抗新冠病毒的效果，可知当单位制剂中第一有效成分和第二有效成分的摩尔比在该特定范围内时，其具有更优的抗新冠病毒的效果；综合其余成药性能(如：混合物稳定性、流动性等)评价后认为该药物组合物具有更好的成药前景。
此外，本方案亦可用于联合用药情况，如同时或先后服用第一有效成分和第二有效成分，当两种有效成分摩尔比在特定范围时，其具有较好的药物协同作用，表现为较单一成分明显更好的抗新冠病毒的效果，也表现为较前述特定范围之外摩尔比的药物组合物明显更优的抗新冠病毒的效果。
进一步的，前述本发明第一个目的中的药物组合物，其在包含第一有效成分和第二有效成分的基础上，还进一步包含第三有效成分，所述第三有效成分为抗逆转录病毒药物；对其中第一有效成分和第二有效成分的定义及对应范围均与前述本发明第一个目的中的药物组合物相同。具体的，所述第三有效成分指代的抗逆转录病毒药物为利托那韦。
具体的，所述含有第三有效成分的药物组合物中，如前所述，其第一有效成分为化合物1或其对应的酯或其对应的盐其对应的酯的盐或所述物质的组合，第二有效成分为ATV014或其药学可接受的盐，该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为50:1:0.1～5至1:50:0.1～5；优选的，该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比为20:1:0.3～2至1:20:0.3～2；优选的，该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比为10:1:0.3～2至1:10:0.3～2； 更优选的，该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比为5:1:0.3～2至1:10:0.3～2；更优选的，该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比为1:1:0.3～2。
具体的，该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为50:1:1、40:1:1、30:1:1、24:1:1、20:1:1、10:1:1、6:1:1、5:1:1、3:1:1、2:1:1、1.5:1:1、1:1:1、1:1.5:1、1:2:1、1:3:1、1:5:1、1:6:1、1:10:1、1:20:1、1:24:1、1:30:1、1:40:1或1:50:1。
本发明的一个优选的实施方式，前述含有第一有效成分、第二有效成分与第三有效成分的药物组合物为化合物1、ATV014、利托那韦的组合。
在一些优选的实施方式中，所述第一有效成分和第二有效成分分别存在于单独的制剂单位中。
在一些优选的实施方式中，所述第一有效成分和第二有效成分同时或先后施用。
本发明的另一目的在于提供一种前述药物组合物的制备方法，该制备方法可以保证稳定制备前述药物组合物。具体的，所述制备方法采用本领域常规的混合方法制备得到，更具体的，所述制备方法可以通过直接混合法、等量递增法等方法制备得到。所用混合中使用的设备视其制备规模可以是本领域常见的混合设备，如V型混合机、双锥混合机、旋转混合机等，小规模制备时亦可采用手动混合方式制备。
本发明的第三个目的在于提供一种含有前述药物组合物的制剂。具体的，该制剂包含前述药物组合物及药学上可接受的辅料，所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、助流剂、润滑剂、矫味剂等中的任意一种或两种以上。
具体的，所述填充剂选自碳酸钙、碳酸镁、磷酸钙、硫酸钙、氧化镁、羧甲基纤维素钙、羧甲基纤维素钠、蔗糖、乳糖、果糖、木糖醇、甘露醇、淀粉或其衍生物、糊精和微晶纤维素等中的任意一种或两种以上以任意比例混合所得混合物。
具体的，所述粘合剂选自阿拉伯胶、明胶、黄蓍胶、糊精、聚乙烯吡咯烷酮、淀粉及其衍生物、藻酸钠、山梨醇、糖浆、羟丙基甲基纤维素、甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、葡萄糖和聚甲基丙烯 酸酯等中的任意一种或两种以上以任意比例混合所得混合物。
具体的，所述崩解剂选自淀粉、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素、微晶纤维素和甲基纤维素等中的任意一种或两种以上以任意比例混合所得混合物。
具体的，所述助流剂选自胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉等中的任意一种或两种以上以任意比例混合所得混合物。
具体的，所述润滑剂选自硬脂酸钙、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、硬脂酸镁、微晶纤维素、苯甲酸钠、氯化钠、十二烷基硫酸钠、硬脂酸镁、硬脂基富马酸钠、滑石粉、硬脂酸锌和聚乙二醇等中的任意一种或两种以上以任意比例混合所得混合物。
具体的，所述矫味剂选自甜叶菊甙、阿司巴甜和本领域常用的其它香精及甜味剂等中的任意一种或两种以上以任意比例混合所得混合物。
在一些优选的实施方式中，所述含有前述药物组合物的制剂为口服制剂，可为散剂、颗粒剂、微丸、胶囊、片剂、锭剂或口服液体剂。
前述制剂中，所述制剂中化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合的规格，即，单位制剂中含有化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合的量，可以为50-1500mg；优选的，所述制剂的规格为100-1000mg；具体的，所述制剂中化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合的规格为100mg、150mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg或1000mg。
本发明的组合物，所述第一有效成分和第二有效成分可以分别存在于单独的制剂单位中。第一有效成分和第二有效成分可同时或先后施用。
基于前述药物组合物的有益效果，如：药物协同作用等，含有前述药物组合物的制剂也对应表现为较含有单一成分制剂明显更好的抗新冠病毒的效果，也表现为较含有前述特定范围之外摩尔比的药物组合物制剂明显更优的抗新冠病毒的效果，具有较好的市场前景。
本发明的第四个目的在于提供一种制药用途，即本发明前述第一个目的所述之药物组合物和/或本发明前述第三个目的所述之制剂在制备缓解或治疗新型冠状病毒感染的药物中的应用。
本发明的第五个目的在于提供一种用途，所述第一有效成分和第二有效成分配制成各自在相同天以每日一次、每日两次或每日三次每日施用。第一有效成分和第二有效成分配制成以共同的经口施用剂量单位共递送或第一有效成分和第二有效成分配制成以分开的经口施用剂量单位施用。
本发明人惊人地发现，基于药物之间的协同作用，本发明所述之药物组合物及含有该药物组合物的制剂表现为较单独使用较好的抗新冠治疗效果，可以有效减低使用剂量，并有利于避免耐药现象出现。进一步的，所述制药用途所针对的新型冠状病毒感染为新型冠状病毒的普通型及其变异株引起的新冠感染，更进一步的，所述制药用途所针对的新冠为由Alpha变异株，Beta变异株，Gamma变异株，Delta变异株、Lambda变异株和/或Omicron变异株引起的新型冠状病毒感染。所述感染包括发热、咳嗽、咽痛、肺炎、急性呼吸道感染、严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克。
在一些优选的实施方式中，所述第一有效成分和第二有效成分各自配制，各自以每日一次、每日两次或每日三次的频率施用。
在一些优选的实施方式中，所述第一有效成分和第二有效成分配制成经口施用剂量单位共递送。
在一些优选的实施方式中，所述第一有效成分和第二有效成分配制成以分开的经口施用剂量单位施用。
本发明与现有技术相比具有如下突出的优点及有益效果：
1、提供了一种药物组合物，该药物组合物包含摩尔比在特定范围的第一有效成分(化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合)，和第二有效成分(ATV014或其药学可接受的盐)，并可选择进一步含有第三有效成分(抗逆转录病毒药物)其具有较好的药物协同作用，综合评价后认为具有较好的成药前景。
2、提供了一种药物组合物的制备方法，该制备方法可以保证稳定制备前述药物组合物。
3、提供了一种含有前述药物组合物的制剂，该制剂也对应表现为较含有单一成分制剂明显更好的抗新冠病毒的效果，也表现为较含有前述特定范围之外摩尔比的药物组合物制剂明显更优的抗新冠病毒的效果，具有较好的市场前景。
4、提供了一种制药用途，该制药用途利用药物之间的协同作用，达到更好的治疗效果。
本发明的贡献在于发现了特定范围内的药物之间具有协同作用，因此本领域的技术人员可以理解，当单位给药单元中有效成分的种类及比例在本发明所述的范围内，或同一销售单元中不同有效成分的单位给药单元的种类及比例在本发明所述的范围内，均可认为是使用了本发明所保护的技术方案；具体的，前述单位给药单元指代用于临床使用的最小单元，如：单位片的片剂、单位粒的胶囊、单位瓶的口服液、单位包的颗粒剂等；前述同一销售单元中不同有效成分的单位给药单元指代不同单位给药单元按特定比例放入同一包装中销售，临床使用时按照特定比例取用不同单位给药单元搭配施用，如：单位盒中置入不同有效成分的片剂(Paxlovid)等。
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的 内容。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐或高氯酸盐；和有机酸盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐或丙二酸盐；或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐或戊酸盐，等等。通过与适当的碱反应得到的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠、锂、钾、钙或镁盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和氨基乙醇。
术语“水合物”是指一个或多个水分子与本发明的化合物所所形成的缔合物。
“联合”表示在单个剂量单位形式中的固定组合或用于组合施用的部分的药盒，其中本发明公开化合物和组合伴侣可以在同一时间独立施用或者可以在一定的时间间隔 内分别施用，特别是使联合和伴侣表现出合作、例如协同作用。如本文所用的术语“药物组合物”或“联合给药”等意欲囊括将所选的组合伙伴施用于需要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同施用途径或同时施用的治疗方案。
附图说明
图1为感染小鼠给药后体重变化曲线。
图2为给药不同时间后肺部病毒载量图。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。
本发明所述ATV014可参照现有技术公开的方法制备，如参照CN202111083730.9实施例9和实施例17及CN202110621245.6实施例1至实施例3公开的方法分别制备。
具体的，本发明所列举实施例所用ATV014为根据上述方法自制的原料药，纯度>99％。
实施例所用的利托那韦为市售制剂利托那韦片的原料药，CAS：155213-67-5，纯度>99％。
实施例1制备化合物1
合成路线：
步骤1：化合物1-2的盐酸盐的合成
将化合物1-1(500mg，1.75mmol)溶解于乙酸乙酯(5mL)中，加入氯化氢的乙酸乙酯溶液(10mL，4N)，反应在20℃搅拌2小时。减压浓缩，未经纯化，得到化合物1-2的盐酸盐。1H NMR(400MHz,CD3OD)δ＝4.28-4.20(m,1H),3.91-3.81(m,3H),3.45-3.35(m,2H),2.86-2.74(m,1H),2.48-2.36(m,1H),2.29-2.19(m,1H),2.02-1.94(m,1H),1.93-1.80(m,1H)。
步骤2：化合物1-4的合成
将化合物Boc-L-环己基甘氨酸(1g，3.89mmol)加入至N,N-二甲基甲酰胺(10mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(1.77g，4.66mmol)，反应搅拌0.5hr，加入二异丙基乙胺(1.26g，9.72mmol)，化合物1-3的盐酸盐(1.02g，4.66mmol)， 反应在20℃搅拌16小时。反应液中加入甲基叔丁基醚(50mL)，水(20mL)洗，3％柠檬酸(20mL×2)洗，饱和氯化钠溶液(20mL)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。经硅胶柱层析纯化(石油醚：乙酸乙酯＝3:1)，得到化合物1-4。1H NMR(400MHz,CDCl3)δ＝5.22-5.11(m,1H),4.36(d,J＝3.9Hz,1H),4.27(dd,J＝6.9,9.3Hz,1H),4.21-4.12(m,2H),3.83(dd,J＝7.8,10.4Hz,1H),3.70(br dd,J＝3.6,10.4Hz,1H),2.81-2.61(m,2H),1.82-1.70(m,6H),1.68-1.61(m,4H),1.56-1.48(m,2H),1.46-1.38(m,9H),1.29-1.22(m,4H),1.21-0.98(m,4H)。
步骤3：化合物1-5的合成
化合物1-4(1.41g，3.34mmol)加入至四氢呋喃(14mL)中，加入一水合氢氧化锂LiOH.H2O(280.03mg，6.67mmol)的水(5mL)溶液，反应在20℃搅拌16小时。3％柠檬酸溶液(50mL)中和粗品，乙酸乙酯(50mL)萃取，有机相经饱和氯化钠溶液(30mL)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。未经纯化。得到化合物1-5。1H NMR(400MHz,DMSO-d6)δ＝12.58-12.23(m,1H),6.92-6.82(m,1H),4.11-3.94(m,2H),3.82-3.76(m,1H),3.72-3.62(m,1H),2.73-2.64(m,1H),2.62-2.55(m,1H),1.92-1.42(m,12H),1.40-1.32(m,9H),1.18-1.06(m,3H),1.00-0.81(m,2H)。
步骤4：化合物1-6的合成
将化合物1-5(650mg，1.65mmol)加入至2-丁酮(7mL)中，加入1-羟基苯并三唑(222.63mg，1.65mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(379.03mg，1.98mmol)，二异丙基乙胺(638.84mg，4.94mmol)，反应在20℃搅拌0.5hr，加入化合物1-2的盐酸盐(366.88mg，1.65mmol)，反应在20℃搅拌16小时。反应液中加入水(20mL)，二氯甲烷：甲醇(30mL×2，10:1)萃取，合并有机相，有机相经3％柠檬酸(20mL×2)洗，饱和氯化钠溶液(20mL)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。经硅胶柱层析纯化(二氯甲烷：甲醇＝20:1)，得到化合物1-6。1H NMR(400MHz,CDCl3)δ＝7.49-7.42(m,1H),6.23-6.05(m,1H),5.28-5.17(m,1H),4.64-4.51(m,1H),4.43-4.24(m,2H),3.92-3.81(m,1H),3.78-3.70(m,3H),3.39-3.27(m,2H),2.94-2.75(m,2H),2.57-2.36(m,2H),2.24-2.07(m,1H),1.94-1.50(m,14H),1.49-1.41(m,9H),1.27- 0.95(m,6H)。
步骤5：化合物1-7的合成
将化合物1-6(3.10g，5.51mmol)溶于四氢呋喃(31mL)中，在0℃加入硼氢化锂(240.02mg，11.02mmol)，缓慢升温至20℃反应2h。反应液中加入水(10mL)和乙酸乙酯(20mL)搅拌10min，有白色固体析出过滤，得到滤饼，即为目标产物1-7粗品。[M+1]+＝535.4。
步骤6：化合物1-8的合成
将化合物1-7(0.5g，935.13μmol)溶于二氯甲烷(10mL)，然后将戴斯-马丁氧化剂(594.94mg，1.40mmol)加入到反应体系，反应在25℃搅拌16h。向反应体系中加入饱和硫代硫酸钠(15mL)和饱和碳酸氢钠溶液(15mL)搅拌10min，用二氯甲烷(50mL×2)萃取，有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，浓缩，得到化合物1-8粗品。[M+1]+＝533.4。
步骤7：化合物1-9的合成
将化合物1-8(436mg，818.52μmol)溶于二氯甲烷(5mL)，并把冰乙酸(58.98mg，982.22mmol)，环戊基异氰(94.44mg，982.22μmol)加入到反应体系中，反应在25℃下搅拌2h。向反应体系中加入饱和氯化铵溶液(10mL)搅拌10min，加入二氯甲烷(20mL)萃取，有机相用水(10mL)洗后，无水硫酸钠干燥，过滤，减压浓缩。经硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到化合物1-9。[M+1]+＝688.4。
步骤8：化合物1-10的合成
将化合物1-9(190mg，276.22μmol)溶于甲醇(3mL)，然后加入碳酸钾(95.44mg，690.54μmol)的水(2mL)溶液。反应在20℃搅拌16h。向反应体系中加入3％柠檬酸(20mL)，用二氯甲烷(40mL)萃取3次，有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。得到1-10粗品。[M+1]+＝646.5。
步骤9：化合物1-11的合成
将化合物1-10(238.00mg，368.52μmol)溶于二氯甲烷(24mL)，然后将戴斯-马丁氧 化剂(203.19mg，479.08μmol)加入。反应在20℃搅拌18h。向反应体系中加入硫代硫酸钠(15mL)和碳酸氢钠溶液(15mL)搅拌10min，用二氯甲烷萃取(50mL×2)萃取，有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，浓缩。经硅胶柱层析纯化(二氯甲烷:甲醇＝20:1)，得到产物1-11。[M+1]+＝644.5。
步骤10：化合物1-12的合成
将化合物1-11(125mg，194.16μmol)溶于四氢呋喃(3mL)，然后将盐酸乙酸乙酯(4M，2.91mL)加入。反应在20℃搅拌1h。反应液直接用油泵旋蒸，用少量二氯甲烷重复旋蒸，得到化合物1-12。[M+1]+＝544.4。
步骤11：化合物1的合成
将化合物1-12(125mg，229.91μmol)溶于四氢呋喃(2.5mL)，0℃，将三氟乙酸酐(193.15mg，919.63μmol)，吡啶(127.30mg，1.61mmol)加入。反应在20℃搅拌16h。向反应体系中加入水(20mL)，用二氯甲烷萃取(40mL×2)，有机相用依次用3％柠檬酸(40mL)和饱和氯化钠溶液(40mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品用制备HPLC分离得到化合物1。[M+1]+＝640.0，1H NMR(400MHz,CD3OD)δppm 0.94-1.10(m,2H),1.13-1.32(m,3H)1.32-1.46(m,1H),1.47-1.57(m,3H),1.59-1.68(m,4H),1.69-1.81(m,6H),1.83-2.00(m,5H),2.01-2.17(m,1H),2.19-2.38(m,1H),2.49-2.57(m,1H),2.58-2.70(m,1H),2.73-2.89(m,1H),3.20-3.26(m,1H),3.37-3.45(m,1H),3.73-3.86(m,1H),3.88-3.97(m,1H),4.03-4.10(m,1H),4.11-4.18(m,1H),4.19-4.29(m,1H),4.29-4.37(m,1H),4.39-4.47(m,1H),4.57-4.60(m,2H)。
实施例2
取1.00g实施例1制备所得化合物1游离物，将其与0.94g ATV014混合均匀，得到摩尔比为1:1.5的药物组合物。
实施例3
取1.00g实施例1制备所得化合物1游离物，将其与1.25g ATV014混合均匀，得到摩尔比为1:2的药物组合物。
实施例4
取1.00g实施例1制备所得化合物1游离物，将其与1.88g ATV014混合均匀，得到摩尔比为1:3的药物组合物。
实施例5
取0.50g实施例1制备所得化合物1游离物，将其与1.57g ATV014混合均匀，得到摩尔比为1:5的药物组合物。
实施例6
取0.50g实施例1制备所得化合物1游离物，将其与3.14g ATV014混合均匀，得到摩尔比为1:10的药物组合物。
实施例7
取0.10g实施例1制备所得化合物1游离物，将其与3.14g ATV014混合均匀，得到摩尔比为1:50的药物组合物。
实施例8
取1.00g实施例1制备所得化合物1游离物，将其与0.63g ATV014混合均匀，得到摩尔比为1:1的药物组合物。
实施例9
取1.00g实施例1制备所得化合物1游离物，将其与0.42g ATV014混合均匀，得到摩尔比为1.5:1的药物组合物。
实施例10
取2.00g实施例1制备所得化合物1游离物，将其与0.63g ATV014混合均匀，得到摩尔比为2:1的药物组合物。
实施例11
取2.00g实施例1制备所得化合物1游离物，将其与0.42g ATV014混合均匀，得到摩尔比为3:1的药物组合物。
实施例12
取2.00g实施例1制备所得化合物1游离物，将其与0.25g ATV014混合均匀，得到摩尔比为5:1的药物组合物。
实施例13
取2.00g实施例1制备所得化合物1游离物，将其与0.13g ATV014混合均匀，得到摩尔比为10:1的药物组合物。
实施例14
取5.00g实施例1制备所得化合物1游离物，将其与0.06g ATV014混合均匀，得到摩尔比为50:1的药物组合物。
实施例15
采用与实施例2相同的方法，分别制备得到化合物1游离物与ATV014摩尔比为40:1,30:1,20:1,1:20,1:30和1:40的药物组合物。
实施例16
取2.00g实施例1制备所得化合物1游离物，将其与0.42g ATV014和0.75g利托那韦混合均匀，得到摩尔比为3:1:1的药物组合物。
实施例17测试化合物1和ATV014组合物的抗新冠病毒活性
实验目的：通过细胞实验，测试化合物1和ATV014组合物的抗新冠病毒活性。
实验用病毒株：SARS-CoV-2(B.1,hCoV-19/CHN/SYSU-IHV/2020 strain,Accession ID on GISAID:EPI_ISL_444969)。
实验条件：全部实验在中山大学生物安全3级实验室完成。
实验方案：
铺2个A549-hACE2的24孔板细胞，每孔种5×104个细胞，24小时后细胞贴壁后，SARS-CoV-2以MOI 0.05感染细胞，37℃感染1h后，用预热的PBS溶液洗细胞2次，将由实施例2至16制备而得的化合物1和ATV014组合物配置成不同浓度，再将感染细胞加入含有不同浓度待测药物或DMSO的培养基。48h后，收取上清，通过荧光定量PCR的方式检测细胞内病毒，计算出药物抑制率(见表1)。
表1各组药物处理浓度与抑制率
备注：“-”意指实验数据已无法反映联用效果，因此此处不再赘述。
结果显示：
单用化合物1 0.1μM时，抑制率达99.91％，随着化合物1浓度的增加，并不能再带来明显的抑制率增加，而单用ATV014 0.5μM时，抑制率达99.98％，随着ATV014浓度的增加，并不能再带来明显的抑制率增加；
单用化合物1 0.01μM浓度时，没有抗病毒效果，单用ATV014 0.1μM的抑制率为62.40％，但是当化合物1 0.01μM与ATV014 0.1μM联用时，抑制病毒率提升至79.80％，抑制效果呈现为随ATV014浓度不断增加而显著提升的趋势，体现出明显的联用增效作用；
单用化合物1 0.05μM浓度时，抑制率达87.39％，而单用ATV014 0.01μM浓度时，几乎没有抗病毒效果，但是当化合物1 0.05μM与ATV014 0.01μM联用时，抑制病毒率可提升至99.45％，体现出明显的联用增效作用；
其他组别亦对照体现出明显的联用增效作用。
综上可以看出，在细胞水平上，化合物1和ATV014联用，抗病毒效果有所提升。体外活性实验表明，化合物1与ATV014在体外具有一定协同作用，较单一使用化合物 1和单一使用ATV014实验组具有更优的抗新冠病毒的效果。
进一步体内活性实验表明，当化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合，和ATV014或其药学可接受的盐均具有一定协同作用，表现为二者联合使用时较单一使用具有更优的抗新冠病毒的效果。
综上活性实验结果可知，当化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合，和ATV014或其药学可接受的盐的摩尔比为1:50～50:1时，有效成分之间具有较好的药物协同作用，表现为较单一成分明显更好的抗新冠病毒的效果，也表现为较前述特定范围之外摩尔比的药物组合物明显更优的抗新冠病毒的效果。具体的，化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合，和ATV014或其药学可接受的盐摩尔比为10:1、5:1、3:1、2:1、1.5:1、1:1、1:1.5、1:2、1:3、1:5或1:10时的抗新冠病毒效果明显优于单独使用化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合，及单独使用ATV014或其药学可接受的盐的效果，也明显优于摩尔比不在该特定范围内的药物组合物的抗新冠病毒效果。
活性实验进一步表明，化合物1或其对应的酯或其对应的盐或其对应的酯的盐或所述物质的组合，和ATV014或其药学可接受的盐，和利托那韦摩尔比为50:1:0.1～5至1:50:0.1～5时，药物组合物具有较好的抗新冠病毒效果，当药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为20:1:0.3～2至1:20:0.3～2时，药物组合物具有更好的抗新冠病毒效果；而当该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为10:1:0.3～2至1:10:0.3～2时，药物组合物的抗新冠病毒效果最优。
实施例18
将实施例2所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：1.00mg+0.94mg)。
将实施例3所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：1.00mg+1.25mg)。
将实施例4所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂 (化合物1与ATV014的质量组合为：1.00mg+1.88mg)。
将实施例5所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：0.50mg+1.57mg)。
将实施例6所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：0.50mg+3.14mg)。
将实施例7所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：0.10mg+3.14mg)。
将实施例8所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：1.00mg+0.63mg)。
将实施例9所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：1.00mg+0.42mg)。
将实施例10所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：2.00mg+0.63mg)。
将实施例11所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：2.00mg+0.42mg)。
将实施例12所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：2.00mg+0.25mg)。
将实施例13所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：2.00mg+0.13mg)。
将实施例14所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1与ATV014的质量组合为：5.00mg+0.06mg)。
将实施例16所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(化合物1、ATV014、利托那韦的质量组合为：2.00mg+0.42mg+0.75mg)。
实施例19
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，188mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，250mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，376mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，628mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，126mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，84mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，63mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，42mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，25mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将200mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，13mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，置于同一包装中。
将266mg化合物1与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，56mg ATV014与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂，100mg利托那韦片置于同一包装中。
实施例20
按照实施例17同样的方法进行测试，实验数据表明，化合物1、ATV014和利托那韦联合使用具有较高的抑制病毒率，显示化合物1、ATV014和利托那韦三者具有明显的药物协同作用；当化合物1，与第二有效成分为ATV014，及第三有效成分利托那韦的摩尔比约为50:1:0.1～5至1:50:0.1～5时，药物组合物具有较好的抑制新冠病毒效果；当药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为20:1:0.3～2至1:20:0.3～2时，药物组合物具有更好的抑制新冠病毒效果；当药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为20:1:0.3～2至1:20:0.3～2时，药物组合物具有更好的抑制新冠病毒效果；当药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为10:1:0.3～2至1:10:0.3～2时，药物组合物具有更进一步的抑制新冠病毒效果；而当该药物组合物中第一有效成分、第二有效成分与第三有效成分的摩尔比约为5:1:0.3～2至1:10:0.3～2时，优选1:1:0.3～2药物组合物的抑制新冠病毒效果最优。
具体的，以上第一有效成分、第二有效成分和第三有效成分的摩尔比可为50:1:1、40:1:1、30:1:1、24:1:1、20:1:1、10:1:1、6:1:1、5:1:1、3:1:1、2:1:1、1.5:1:1、1:1:1、1:1.5:1、1:2:1、1:3:1、1:5:1、1:6:1、1:10:1、1:20:1、1:24:1、1:30:1、1:40:1或1:50:1。
实施例21测试化合物1和ATV014组合物的体内抗新冠病毒活性
实验目的：通过小鼠感染新冠病毒造模，测试化合物1和ATV014组合物的体内抗新冠病毒活性。
实验方案：
1.材料和方法
1.1主要仪器设备
本实验所使用的主要仪器设备如下：
表2主要仪器

1.2软件
本实验采用GraphPad Prism 8.0.1软件用于结果数据绘图、汇总、统计。
1.3主要实验试剂
表3待测化合物信息
表4主要试剂信息
1.4实验毒株、细胞、小鼠
新冠病毒Delta毒株由广东省CDC生物安全三级实验室分离并保存，K18-hACE2转基因小鼠由中山大学医学院提供，从美国Jackson Laboratory购买获得，品系为C57BL/6(B6.Cg-Tg(K18-ACE2)2Prlmn/J)。
2.测试内容及方法
2.1动物分组
待受试小鼠(C57BL/6(B6.Cg-Tg(K18-ACE2)2Prlmn/J))总共40只，实验前根据体重随机分组，共设4组，每组10只。组别设置如下表：
表5动物组别设置

2.2小鼠感染新冠病毒造模
40只C57BL/6(B6.Cg-Tg(K18-ACE2)2Prlmn/J)小鼠进行异氟烷麻醉，滴鼻感染新冠病毒Delta株，毒株滴鼻剂量均为500PFU/只，感染体积50μL。
2.3小鼠药物处理
空白溶媒组：
处方组成：20％[40％SBE-β-CD]+20％HS15+60％水、pH＝4
小鼠D0进行滴鼻感染，攻毒2h后开始给溶媒，容积为0.2mL/只。每天一次，直至攻毒后第3和第5天。
配制5mL化合物1溶液，化合物1浓度为30mg/mL，
配制15mL ATV014溶液，ATV014浓度为10mg/mL。
表6供试品剂量组配制物料表

配制步骤：
1、取化合物1(150mg)至研钵中，加入HS15(5mL)，研磨至体系为溶清溶液；
2、缓慢加入40％SBE-β-CD水溶液(5mL)研磨至体系为溶清溶液；
3、加入1M盐酸(1mL)，搅拌均匀后，加入ATV014(150mg)，研磨搅拌直至ATV014固体全部溶解；
4、缓慢加入水(13mL)，研磨搅拌至澄清溶液；
5、缓慢分批滴加1M氢氧化钠溶液，用pH计测量pH，调节pH至4。
(2)ATV014(100mg/kg)剂量组：吸取3mL浓度为10mg/mL的ATV014原液；小鼠D0进行滴鼻感染，攻毒2h后开始给药，容积为0.2mL/只。每天一次，直至攻毒后第3和第5天。
(3)化合物1(150mg/kg)剂量组：吸取3mL浓度为15mg/mL的化合物1原液；小鼠D0进行滴鼻感染，攻毒2h后开始给药，容积为0.2mL/只。每天一次，直至攻毒后第3天和第5天。
(4)ATV014(100mg/kg)+化合物1(150mg/kg)剂量组：吸取3mL浓度为10mg/mL ATV014，15mg/mL化合物1的原液；小鼠D0进行滴鼻感染，攻毒2h后开始给药，容积为0.2mL/只。每天一次，直至攻毒后第3天和第5天。
2.4小鼠体重和生存等监测
感染当日(记为Day 0)记录小鼠体重，之后每日定时称取小鼠体重和观察小鼠死亡情况并进行记录。每天进行1次一般临床观察，内容包括：小鼠行动能力和生存状态；眼睛和毛发；死亡和任何可观察到的临床表现。
称重，每天一次。
2.5小鼠肺部病毒载量和活病毒滴度检测
感染后第三天(记为Day 3)及第五天(记为Day 5)处死小鼠。对小鼠进行解剖，取小鼠左肺部，称取重量，放入1mL DPBS缓冲液中进行组织研磨，将研磨好的组织液进行新冠病毒滴度检测。
2.5.1病毒载量测定方法
操作如下：提取肺组织RNA，使用qPCR测定病毒载量。qPCR使用达安基因新型冠状病毒2019-nCoV核酸检测试剂盒(货号：A0930，引物序列为DAAN-N-F：AAGAAATTCAACTCCAGGCAGC(SEQ ID NO:1)；DAAN-N-R：GCTGGTTCAATCTGTCAAGCAG(SEQ ID NO:2)；DAAN-N-P：TCACCGCCATTGCCAGCCA(SEQ ID NO:3))，具体操作步骤见说明书。
3.结果
3.1体重检测
对感染后小鼠体重进行检测，结果如图1显示，不同给药组体重变化幅度与溶媒对照组相比无统计学差异。
3.2肺部病毒载量qPCR检测
攻毒后第三天和第五天，处死小鼠，取肺，多叶肺组织匀浆，提取组织RNA，qPCR检测肺病毒载量结果如图2所示。
从检测结果看，各组小鼠均可以在肺部组织检测到新冠病毒RNA，其中溶媒对照组(Mock)每只小鼠均有较高的病毒载量，说明本次实验的小鼠感染造模成功。感染后第三天，除ATV014(100mg/kg)+化合物1(150mg/kg)药物联用处理组有显著抗病毒效果外，其余药物处理组病毒载量均与对照组无显著差异。感染后第五天ATV014(100mg/kg)，ATV014(100mg/kg)+化合物1(150mg/kg)均有显著抗病毒效果，且ATV014(100mg/kg)+化合物1(150mg/kg)药物联用组抗病毒效果较药物单用组有显著抑制活性。
4结论
本实验条件下，K18-ACE2小鼠灌胃给药ATV014和ATV014+化合物1可不同程度降低病毒载量，其中ATV014(100mg/kg)、ATV014(100mg/kg)+化合物1(150mg/kg)剂量下在小鼠模型中具有显著的抗新冠病毒效果，且药物联用组较药物单用组抗病毒效果更优，提示ATV014与化合物1具有协同抗病毒的作用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (34)

  1. 一种药物组合物，其特征在于，所述药物组合物包含第一有效成分和第二有效成分，其中第一有效成分为化合物1、其对应的酯、其对应的盐、其对应的酯的盐或所述物质的组合，第二有效成分为ATV014或其药学可接受的盐、水合物、溶剂合物，所述第一有效成分与第二有效成分的摩尔比为50:1～1:50，
  2. 根据权利要求1所述的药物组合物，其中，所述第一有效成分为化合物1、化合物1对应的酯、化合物1对应的盐、化合物1对应的酯的盐中一种或两种以上以任意比例混合所得的混合物。
  3. 根据权利要求1或2所述的药物组合物，其中，所述化合物1对应的酯是指化合物1与有机酸形成的酯，选自化合物1的甲酸酯、乙酸酯、丙酸酯、异丙酸酯、正丁酸酯或叔丁酸酯；所述化合物1的盐是指化合物1与有机酸和/或无机酸形成的盐、或化合物1与有机碱和/或无机碱形成的盐，选自化合物1的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、酒石酸盐、樟脑磺酸盐、锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、氨盐、乙二胺盐或三乙胺盐；化合物1对应的酯的盐是指化合物1与有机酸形成的酯与有机碱和/或无机碱和/或有机酸和/或无机酸形成的盐，选自化合物 1甲酸酯的盐酸盐、化合物1甲酸酯的硫酸盐、化合物1乙酸酯的盐酸盐或化合物1乙酸酯的硫酸盐。
  4. 根据权利要求1所述的药物组合物，其中，所述第二有效成分选自ATV014或其水合物、溶剂合物。
  5. 根据权利要求1所述的药物组合物，其中，所述第一有效成分与第二有效成分的摩尔比为20:1～1:20。
  6. 根据权利要求1-5任意一项所述的药物组合物，其中，所述第一有效成分与第二有效成分的摩尔比为10:1～1:10，优选5:1～1:10，更优选1:1。
  7. 根据权利要求1至4任意一项所述的药物组合物，其中，所述第一有效成分与第二有效成分的摩尔比为50:1、40:1、30:1、20:1、10:1、5:1、3:1、2:1、1.5:1、1:1、1:1.5、1:2、1:3、1:5、1:10、1:20、1:30、1:40或1:50。
  8. 根据权利要求1所述的药物组合物，其中，所述药物组合物中第一有效成分为化合物1和/或化合物1的钠盐和/或化合物1的钾盐和/或化合物1的盐酸盐和/或化合物1的钙盐和/或化合物1的对甲苯磺酸盐，第二有效成分为ATV014，第一有效成分与第二有效成分的摩尔比为50:1～1:50。
  9. 根据权利要求1或8所述的药物组合物，其中，所述药物组合物中第一有效成分为化合物1和/或化合物1的钠盐和/或化合物1的钾盐和/或化合物1的盐酸盐和/或化合物1的钙盐和/或化合物1的对甲苯磺酸盐，第二有效成分为ATV014，第一有效成分与第二有效成分的摩尔比为20:1～1:20。
  10. 根据权利要求1或8所述的药物组合物，所述药物组合物中第一有效成分为化合物1和/或化合物1的钠盐和/或化合物1的钾盐和/或化合物1的盐酸盐和/或化合物1的钙盐和/或化合物1的对甲苯磺酸盐，第二有效成分为ATV014，第一有效成分与ATV014的摩尔比为50:1、40:1、30:1、20:1、10:1、5:1、3:1、2:1、1.5:1、1:1、1:1.5、1:2、1:3、1:5、1:10、1:20、1:30、1:40或1:50。
  11. 根据权利要求1-10任意一项所述的药物组合物，其中，所述药物组合物中还进一步包含第三有效成分，所述第三有效成分为抗逆转录病毒药物。
  12. 根据权利要求11所述的药物组合物，所述第三有效成分为利托那韦。
  13. 根据权利要求11或12所述的药物组合物，所述第一有效成分、第二有效成分和第三有效成分的摩尔比为50:1:0.1～5至1:50:0.1～5。
  14. 根据权利要求11至13任意一项所述的药物组合物，所述第一有效成分、第二有效成分和第三有效成分的摩尔比为20:1:0.3～2至1:20:0.3～2。
  15. 根据权利要求11至14任意一项所述的药物组合物，所述第一有效成分、第二有效成分和第三有效成分的摩尔比为10:1:0.3～2至1:10:0.3～2，优选5:1:0.3～2至1:10:0.3～2，更优选1:1:0.3～2。
  16. 根据权利要求11至13任意一项所述的药物组合物，所述第一有效成分、第二有效成分和第三有效成分的摩尔比为50:1:1、40:1:1、30:1:1、24:1:1、20:1:1、10:1:1、6:1:1、5:1:1、3:1:1、2:1:1、1.5:1:1、1:1:1、1:1.5:1、1:2:1、1:3:1、1:5:1、1:6:1、1:10:1、1:20:1、1:24:1、1:30:1、1:40:1或1:50:1。
  17. 根据权利要求1至16任意一项所述的药物组合物，其特征在于，所述第一有效成分和第二有效成分分别存在于单独的制剂单位中。
  18. 根据权利要求1至17任意一项所述的药物组合物，其特征在于，所述第一有效成分和第二有效成分同时或先后施用。
  19. 一种制剂，其特征在于，所述制剂包含如权利要求1-18任意一项所述的药物组合物及药学上可接受的辅料。
  20. 根据权利要求19所述的制剂，其特征在于，所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、助流剂、润滑剂、矫味剂中的任意一种或两种以上。
  21. 根据权利要求20所述的制剂，其特征在于，所述填充剂选自碳酸钙、碳酸镁、磷酸钙、硫酸钙、氧化镁、羧甲基纤维素钙、羧甲基纤维素钠、蔗糖、乳糖、果糖、木糖醇、甘露醇、淀粉或其衍生物、糊精、微晶纤维素中的任意一种或两种以上以任意比例混合所得混合物。
  22. 根据权利要求20所述的制剂，其特征在于，所述粘合剂选自阿拉伯胶、明胶、 黄蓍胶、糊精、聚乙烯吡咯烷酮、淀粉及其衍生物、藻酸钠、山梨醇、糖浆、羟丙基甲基纤维素、甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、葡萄糖和聚甲基丙烯酸酯中的任意一种或两种以上以任意比例混合所得的混合物。
  23. 根据权利要求20所述的制剂，其特征在于，所述崩解剂选自淀粉、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素、微晶纤维素和甲基纤维素中的任意一种或两种以上以任意比例混合所得混合物。
  24. 根据权利要求20所述的制剂，其特征在于，所述助流剂选自胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉中的任意一种或两种以上以任意比例混合所得混合物。
  25. 根据权利要求20所述的制剂，其特征在于，所述润滑剂选自硬脂酸钙、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、硬脂酸镁、微晶纤维素、苯甲酸钠、氯化钠、十二烷基硫酸钠、硬脂酸镁、硬脂基富马酸钠、滑石粉、硬脂酸锌和聚乙二醇中的任意一种或两种以上以任意比例混合所得混合物。
  26. 根据权利要求20所述的制剂，其特征在于，所述矫味剂选自甜叶菊甙、阿司巴甜和本领域常用的其它香精及甜味剂中的任意一种或两种以上以任意比例混合所得混合物。
  27. 根据权利要求19-26任意一项所述的制剂，其特征在于，所述制剂为口服制剂，剂型为散剂、颗粒剂、微丸、胶囊、片剂、锭剂或口服液体剂。
  28. 根据权利要求1-18任意一项所述的药物组合物或权利要求19-27任意一项所述的制剂在制备缓解或治疗新型冠状病毒感染的药物中的应用。
  29. 根据权利要求28所述的应用，其特征在于，所述新型冠状病毒感染为新型冠状病毒的普通型及其变异株引起的新冠感染。
  30. 根据权利要求28或29所述的应用，其特征在于，所述新型冠状病毒感染为由Alpha变异株、Beta变异株、Gamma变异株、Delta变异株、Lambda变异株和/或Omicron 变异株引起的新型冠状病毒感染。
  31. 根据权利要求28-30所述的应用，其中，所述感染包括发热、咳嗽、咽痛、肺炎、急性呼吸道感染、严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克。
  32. 根据权利要求28至31中任一项所述的用途，其中，所述第一有效成分和第二有效成分各自配制，各自以每日一次、每日两次或每日三次的频率施用。
  33. 根据权利要求28至31中任一项所述的用途，其中，所述第一有效成分和第二有效成分配制成经口施用剂量单位共递送。
  34. 根据权利要求28至31中任一项所述的用途，其中第一有效成分和第二有效成分配制成以分开的经口施用剂量单位施用。
PCT/CN2023/138496 2022-12-23 2023-12-13 一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂 WO2024131615A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211662655 2022-12-23
CN202211662655.6 2022-12-23

Publications (1)

Publication Number Publication Date
WO2024131615A1 true WO2024131615A1 (zh) 2024-06-27

Family

ID=91587697

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/138496 WO2024131615A1 (zh) 2022-12-23 2023-12-13 一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂

Country Status (1)

Country Link
WO (1) WO2024131615A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018042343A2 (en) * 2016-08-30 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Compounds that inhibit 3c and 3cl proteases and methods of use thereof
CN113262224A (zh) * 2020-02-17 2021-08-17 中国科学院上海药物研究所 奈非那韦在制备防治新冠肺炎药物中的应用
WO2021226546A1 (en) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Protease inhibitors for treatment or prevention of coronavirus disease
CN113735862A (zh) * 2020-12-30 2021-12-03 南方科技大学 一种治疗病毒感染的核苷类化合物及其用途
WO2022217155A2 (en) * 2021-04-09 2022-10-13 Emory University Thionucleosides as antiviral agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018042343A2 (en) * 2016-08-30 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Compounds that inhibit 3c and 3cl proteases and methods of use thereof
CN113262224A (zh) * 2020-02-17 2021-08-17 中国科学院上海药物研究所 奈非那韦在制备防治新冠肺炎药物中的应用
WO2021226546A1 (en) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Protease inhibitors for treatment or prevention of coronavirus disease
CN113735862A (zh) * 2020-12-30 2021-12-03 南方科技大学 一种治疗病毒感染的核苷类化合物及其用途
WO2022217155A2 (en) * 2021-04-09 2022-10-13 Emory University Thionucleosides as antiviral agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PEIPEI ZHAO, ZHENG WENHUI, BU MIN, HE WANLIN, CAI YAN: "Progress in Development of Coronavirus Inhibitors", CHEMISTRY, vol. 83, no. 8, 18 August 2020 (2020-08-18), pages 674 - 689, XP093183217, DOI: 10.14159/j.cnki.0441-3776.2020.08.001 *
XU HANG-XIAN: "Review on Synthesis of α-Ketoamides", SYNTHETIC MATERIALS AGING AND APPLICATION, vol. 48, no. 2, 24 April 2019 (2019-04-24), pages 148 - 151, XP093183214, DOI: 10.16584/j.cnki.issn1671-5381.2019.02.033 *

Similar Documents

Publication Publication Date Title
JP7026152B2 (ja) フェノール性ｔｒｐｖ１アゴニストのプロドラッグ
ES2208453T3 (es) Agonistas de los receptores adrenergicos beta 2.
EP1935892B1 (en) Glycyrrhetinic acid-30-amide derivatives and the uses thereof
CA2661166A1 (en) Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
TWI579277B (zh) 取代桂皮醯胺衍生物、其製備方法、其應用及醫藥組成物
EP2558087A1 (en) AMIDO COMPOUNDS AS RORyt MODULATORS AND USES THEREOF
US20080234323A1 (en) Amorphous and Three Crystalline Forms of Rimonabant Hydrochloride
WO2018171816A1 (zh) 一种氘代的二肽硼酸或其酯类化合物及其合成方法与用途
WO2023065606A1 (zh) 新型氘代氰基类化合物、其制备方法、组合物及应用
KR20110017452A (ko) 무스칼린 수용체 길항제로서 활성인 신규한 화합물
WO2022089562A1 (zh) 抑制基因缺陷的hiv病毒的用途
CN101597272B (zh) 艾拉莫德的钾盐化合物,其制备方法和药物应用
WO2024131615A1 (zh) 一种用于治疗或缓解新冠肺炎的药物组合物及含有该药物组合物的制剂
WO2024016640A1 (zh) 抗组胺类化合物及其制备方法和用途
WO2019205812A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2022194252A1 (zh) 一种化合物的多晶型及其制备方法和应用
WO2022161205A1 (zh) 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用
WO2021047437A1 (zh) 一种用于治疗病毒性感冒的药物组合物及其制剂
JP7266676B2 (ja) チエノピリドン誘導体のカリウム塩一水和物及びその調製方法
TW201811769A (zh) 哌嗪（ｐｉｐｅｒａｚｉｎｅ）衍生物
WO2021233133A1 (zh) 用作ret激酶抑制剂的化合物及其应用
WO2021155781A1 (zh) 含五元杂环的苯磺酰胺类化合物及其制备方法和用途
CN104892449B (zh) 一种精胺类似物及其药用盐的制备方法和用途
JP5621037B2 (ja) アルキルジアミン類誘導体及びその抗うつ薬としての使用
CN111825608A (zh) 四氢喹啉类与四氢异喹啉类化合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23905781

Country of ref document: EP

Kind code of ref document: A1