[go: up one dir, main page]

WO2021047437A1 - Composition pharmaceutique pour le traitement de la grippe virale et sa préparation - Google Patents

Composition pharmaceutique pour le traitement de la grippe virale et sa préparation Download PDF

Info

Publication number
WO2021047437A1
WO2021047437A1 PCT/CN2020/113105 CN2020113105W WO2021047437A1 WO 2021047437 A1 WO2021047437 A1 WO 2021047437A1 CN 2020113105 W CN2020113105 W CN 2020113105W WO 2021047437 A1 WO2021047437 A1 WO 2021047437A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
active ingredient
pharmaceutical composition
oseltamivir
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2020/113105
Other languages
English (en)
Chinese (zh)
Inventor
陈小新
李海军
刘卓伟
刘志强
万春喜
龙超峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Raynovent Biotech Co Ltd
Original Assignee
Guangdong Raynovent Biotech Co Ltd
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 Guangdong Raynovent Biotech Co Ltd filed Critical Guangdong Raynovent Biotech Co Ltd
Priority to CN202080062567.5A priority Critical patent/CN114502150B/zh
Publication of WO2021047437A1 publication Critical patent/WO2021047437A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/13—Amines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition for treating viral influenza and a preparation containing the pharmaceutical composition.
  • Influenza virus known as influenza virus (IFV)
  • IVF Influenza virus
  • WHO World Health Organization
  • influenza pandemic Every influenza pandemic has a huge impact on global public health and the economy. Devastation.
  • the current clinical plan for influenza includes vaccination and antiviral drugs for chemotherapy and chemoprevention.
  • One of the important antiviral drugs is neuraminidase inhibitors, such as Oseltamivir (OSE), Zana Zanamivir, Peramivir, etc., such antiviral drugs have obvious effects on influenza A virus, and are commonly used clinical drugs for the treatment of viral influenza.
  • Oseltamivir OSE
  • Zana Zanamivir Zana Zanamivir
  • Peramivir Peramivir
  • antiviral drugs have obvious effects on influenza A virus, and are commonly used clinical drugs for the treatment of viral influenza.
  • the resulting drug resistance has become increasingly serious.
  • the proportion of oseltamivir-resistant strains of the seasonal A H1N1 influenza virus in China from 2008 to 2009 has reached 28%, and the resistance of influenza viruses affects existing anti-influenza viruses. The therapeutic effect of the drug.
  • oseltamivir is metabolized into its active metabolite oseltamivir carboxylic acid to exert its drug effect.
  • By competitively binding with the active site of influenza virus neuraminidase it interferes with the virus from the infected host cell. During the release process, thereby reducing the spread of influenza A or B viruses.
  • Patent WO2018041263 discloses a series of pyrimidine derivatives. In vitro activity data showed that some compounds showed positive effects in the test of inhibiting influenza virus replication. In further animal experiments, some compounds also showed significant therapeutic effects on influenza A virus H1N1 mouse infection model. Among them, compound 1 The comprehensive performance of (Example 4, WX-216) is relatively outstanding, and it is considered to have a better prospect of preparing medicines.
  • influenza virus has the characteristics of high mutation rate and multiple inter-virus recombination phenomena. Although 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 effective in a short time. Inhibiting/reducing the concentration of the virus in the body and curing the defects of the viral cold, the corresponding increase in the dosage and the lengthening of the treatment time also bring a greater risk of medication to the patient. Finberg RW et al., J Infect Dis, 2019 Mar 15; 219(7): 1026-1034. A combination experiment of Pimodivir and oseltamivir was published, and the results showed that the combination of 600 mg Pimodivir and 75 mg oseltamivir Use can minimize the load of influenza A virus.
  • the first object of the present invention is to overcome at least one of the above-mentioned shortcomings of the prior art and provide a pharmaceutical composition for the treatment of viral influenza, which utilizes the synergistic effect between the active ingredients to solve the problem of influenza Technical problems such as the drug resistance of the virus can effectively reduce the risk of clinical medication. After comprehensive evaluation, it is believed that the pharmaceutical composition has a better prospect for preparing a medicine.
  • a pharmaceutical composition comprising 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 thereof
  • the second effective ingredient is a neuraminidase inhibitor; the mass ratio of the first effective ingredient to the second effective ingredient is 1-8:1.
  • the first active ingredient refers to a mixture obtained by mixing one or more of the compound 1, the ester corresponding to the compound 1, the salt of the compound 1, and the salt of the ester corresponding to the compound 1, in any ratio.
  • the compound 1, the ester corresponding to the compound 1, the salt of the compound 1, and the salt of the ester corresponding to the compound 1 each include the subordinate anhydrate, ansolvate, hydrate, and solvate thereof.
  • the ester corresponding to compound 1 refers to the ester formed by compound 1 and organic acid, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and the like of compound 1.
  • the salt of compound 1 is the salt formed by compound 1 and organic acid and/or inorganic acid, or the salt formed by compound 1 and organic base and/or inorganic base, including but not limited to the hydrochloride and hydrobromic acid of compound 1.
  • the salt of the corresponding ester of compound 1 refers to the salt of the ester formed by the aforementioned compound 1 with 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 salt of the methyl ester of compound 1 Acid salt, compound 1 methyl ester sulfate, compound 1 ethyl ester hydrochloride, compound 1 ethyl ester sulfate, etc.
  • the neuraminidase inhibitor referred to by the second active ingredient is oseltamivir (Oseltamivir) or its derivatives, zanamivir (zanamivir) or its derivatives, peramivir (Peramivir) or its derivatives
  • Oseltamivir Oseltamivir
  • zanamivir zanamivir
  • Peramivir peramivir
  • Acids and/or bases can also be esters, amides, or other derivatives such as carboxylic acids and their salts obtained after hydrolysis, and each includes its subordinate anhydrates, ansolvates, hydrates and solvents
  • oseltamivir or its derivatives can be selected as oseltamivir free state, or oseltamivir phosphate, oseltamivir carboxylic acid, oseltamivir carboxylate, and the like.
  • the mass ratio of the first effective ingredient to the second effective ingredient is 1 to 8:1, preferably, the mass ratio of the first effective ingredient to the second effective ingredient is 100 to 600:75; specifically, the The mass ratio of the first active ingredient to the second active ingredient is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75.
  • the quality of the salt in the present invention refers to the mass based on free base/acid equivalent, and the hydrate/solvate refers to the mass based on dry matter (on an equivalent basis).
  • Anhydrous basis the mass of metabolites (such as ester hydrolysis to obtain carboxylic acid) refers to the mass of the compound before metabolism.
  • the first active ingredient in the pharmaceutical composition is compound 1, and the second active ingredient is oseltamivir phosphate; the combination of compound 1 and oseltamivir phosphate in the pharmaceutical composition
  • the mass ratio is 100-600:75; specifically, the mass ratio of the compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75.
  • the first active ingredient in the pharmaceutical composition is the sodium salt of compound 1, and the second active ingredient is oseltamivir phosphate; the sodium salt of compound 1 in the pharmaceutical composition is combined with oseltamivir phosphate.
  • the mass ratio of setavir phosphate is 100-600:75; specifically, the mass ratio of the sodium salt of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75 .
  • the first active ingredient in the pharmaceutical composition is compound 1 hydrochloride
  • the second active ingredient is oseltamivir phosphate
  • in the pharmaceutical composition compound 1 hydrochloride
  • the mass ratio with oseltamivir phosphate is 100-600:75; specifically, the mass ratio of the hydrochloride of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500: 75,600:75.
  • the first active ingredient in the pharmaceutical composition is the potassium salt of compound 1, and the second active ingredient is oseltamivir phosphate;
  • the mass ratio of setavir phosphate is 100-600:75; specifically, the mass ratio of the potassium salt of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75 .
  • the first active ingredient in the pharmaceutical composition is the calcium salt of compound 1, and the second active ingredient is oseltamivir phosphate;
  • the mass ratio of setavir phosphate is 100-600:75; specifically, the mass ratio of the calcium salt of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75 .
  • the first active ingredient in the pharmaceutical composition is p-toluenesulfonate of compound 1
  • the second active ingredient is oseltamivir phosphate
  • the mass ratio of tosylate to oseltamivir phosphate is 100-600:75; specifically, the mass ratio of p-toluenesulfonate to oseltamivir phosphate of the compound 1 is about 100:75,200: 75,300:75,400:75,500:75,600:75.
  • the drug composition of inhibitor has a better drug synergistic effect, showing a significantly better anti-influenza virus effect than a single component, and also showing a better anti-influenza virus effect than the aforementioned specific range.
  • the pharmaceutical composition with the external mass ratio has significantly better anti-influenza virus effect. It can be known that when the mass ratio of the first active ingredient and the second active ingredient in the unit preparation is within the specific range, it has better anti-influenza virus effect. Effect: After comprehensive evaluation of other pharmaceutical properties (such as mixture stability, fluidity, etc.), it is believed that the pharmaceutical composition has a better prospect for pharmaceutical preparation.
  • Another object of the present invention is to disclose a preparation method of the aforementioned pharmaceutical composition, which can ensure the stable preparation of the aforementioned pharmaceutical composition.
  • the preparation method adopts a conventional mixing method in the art; more specifically, the preparation method may be a direct mixing method, an equal incremental method, etc., and the mixing equipment used may be a common mixing method in the field, depending on the preparation scale.
  • Equipment, such as V-type mixer, double cone mixer, rotary mixer, etc., can also be prepared by manual mixing in small-scale preparation.
  • the third object of the present invention is to disclose a preparation containing the aforementioned pharmaceutical composition.
  • the preparation includes the aforementioned pharmaceutical composition and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is selected from any one or two or more of fillers, binders, disintegrants, glidants, lubricants, and flavoring agents.
  • the filler is selected from calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sucrose, lactose, fructose, xylitol, mannitol , Starch or its derivatives, dextrin, microcrystalline cellulose, etc., a mixture obtained by mixing any one or two or more of them in any ratio.
  • the binder is selected from gum arabic, gelatin, tragacanth, dextrin, polyvinylpyrrolidone, starch and its derivatives, sodium alginate, sorbitol, syrup, hydroxypropyl methylcellulose, methyl cellulose Any one or two of cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose and polymethacrylate, etc. The mixture obtained by mixing more than one species in any ratio.
  • the disintegrant is selected from starch, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl methyl A mixture obtained by mixing any one or two or more of base cellulose, microcrystalline cellulose, and methyl cellulose in an arbitrary ratio.
  • the glidant is a mixture obtained by mixing any one or more of colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc in any ratio.
  • the lubricant is selected from calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, and lauryl sulfate A mixture obtained by mixing any one or two or more of sodium, sodium stearyl fumarate, talc, zinc stearate, and polyethylene glycol in an arbitrary ratio.
  • the flavoring agent is selected from any one or a mixture of two or more of stevioside, aspartame, and other flavors and sweeteners commonly used in the art in any ratio.
  • the preparation containing the aforementioned pharmaceutical composition is an oral preparation, specifically a powder, granule, pellet, capsule, tablet, solution or lozenge.
  • the preparations containing the aforementioned pharmaceutical composition also exhibit significantly better anti-influenza virus effects than those containing single-component preparations, and also show greater anti-influenza virus effects than those containing the aforementioned specific range.
  • the pharmaceutical composition preparations with other mass ratios have significantly better anti-influenza virus effects, and have a better market prospect.
  • the present invention has the following outstanding advantages and beneficial effects:
  • a pharmaceutical composition which comprises a first active ingredient (compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt or a combination thereof) with a mass ratio in a specific range, and
  • the second active ingredient (neuraminidase inhibitor), which has a better drug synergistic effect, in which the neuraminidase inhibitor is hydrolyzed with oseltamivir and/or oseltamivir salt and/or oseltamivir
  • the oseltamivir carboxylic acid or oseltamivir carboxylate obtained later has the best effect, and after comprehensive evaluation, it is believed that the pharmaceutical composition has a better prospect for preparing medicines.
  • a preparation method of the pharmaceutical composition is provided, which can ensure the stable preparation of the aforementioned pharmaceutical composition.
  • a preparation containing the aforementioned pharmaceutical composition is provided, which correspondingly shows a significantly better anti-influenza virus effect than a preparation containing a single component, and is also shown to be more effective than a pharmaceutical combination containing a mass ratio outside the aforementioned specific range
  • the drug preparation has significantly better anti-influenza virus effect and has a better market prospect.
  • the contribution of the present invention lies in the discovery that a combination of drugs within a specific range has a synergistic effect. Therefore, those skilled in the art can understand that when the combination of drugs in a unit dosing unit is within the scope of the present invention, it can be considered to be used.
  • the technical solution protected by the present invention specifically, the aforementioned unit administration unit refers to the smallest unit for clinical use, such as: unit tablet, unit capsule, unit bottle of oral liquid, unit package of granules, etc. .
  • the oseltamivir phosphate used in the examples is the bulk drug of the commercially available Tamiflu, CAS: 204255-11-8, with a purity of >99%; the oseltamivir used is the free substance of the commercially available Tamiflu bulk drug, CAS :196618-13-0, purity>99%; the oseltamivir carboxylic acid used is a commercially available intermediate, CAS: 187227-45-8, purity>99%.
  • zanamivir CAS: 139110-80-8
  • peramivir CAS: 229614-55-5
  • the compound 1 was prepared by the method disclosed in Example 4 of WO2018041263, and the structure characterization proved that the obtained product was compound 1.
  • the mass ratios of the salt of compound 1 prepared in Examples 2-6 and oseltamivir or oseltamivir phosphate were 50:75 and 100:75, respectively. , 200:75, 300:75, 400:75, 500:75, 600:75, 700:75 pharmaceutical composition, the mass of the salt refers to the mass of the free substance (free base/acid equivalent) .
  • compound 1 and oseltamivir carboxylic acid active metabolite
  • H3N2 A/Aichi/2/1968 (H3N2), purchased from ATCC.
  • Dog kidney epithelial cell line (Madin-Darby Canine Kidney Cells, MDCK).
  • Drug dissolution method Compound 1 and the active metabolite of oseltamivir (oseltamivir carboxylic acid, calculated as oseltamivir) were dissolved in dimethyl sulfoxide (DMSO), prepared as a 100mM/L mother liquor, and stored for later use; Dilute with Medium Essential Medium (MEM) as a working solution (Note: the final concentration of DMSO is 1%).
  • DMSO dimethyl sulfoxide
  • MEM Medium Essential Medium
  • nM 0.25 ⁇ M (1:62.5 ⁇ 16000)
  • the specific manifestation is that the virus inhibition rate after the combination is higher than the single-agent virus inhibition rate; in view of compound 1 After entering the human body, the plasma protein binding rate can reach 99.9%. It can be seen that the compound 1 in the free state in the body accounts for about 0.1%, and the binding rate of oseltamivir carboxylic acid in the human plasma protein is 0.3%, which shows that the body is in a free state.
  • Oseltamivir carboxylic acid accounts for about 99.7%; after conversion, that is, in the body, the molar ratio of compound 1 to oseltamivir carboxylic acid should be about 1:16 to 16:1 when there is a good synergistic effect. That is, when the mass ratio of compound 1 to oseltamivir is approximately in the range of 1:11.3 to 22.5:1 (440:4992 to 7040:312), there is a good synergistic effect.
  • compound 1 has a synergistic effect with oseltamivir, zanamivir and peramivir, but compared with other groups, the oseltamivir group has a synergistic performance significantly better than other groups.
  • Mortality rate (%) number of dead mice in each group (only)/total number before infection (only) ⁇ 100%
  • mice developed symptoms such as shortness of breath, curled up and trembling, weight loss, and died; after 14 days of continuous observation, the mice in the blank group were in good condition and no death was observed, while the mortality of the mice in the virus group reached 100%; compound 1:30mg/kg group has a complete protective effect on infected mice, and its mortality rate is 0%; compound 1:20mg/kg group has obvious protective effect on infected mice, and its mortality rate is 20%; compound The mortality of mice in the 1:5 mg/kg administration group was 80%; the mortality of mice in the oseltamivir phosphate: 10 mg/kg administration group and the compound 1:1.5 mg/kg administration group was 100%. After compound 1 was used in combination with oseltamivir phosphate at the doses of 5 mg/kg and 20 mg/kg, the mortality rate was significantly reduced, and the synergistic effect was obvious.
  • Table 2 The results are shown in Table 2:
  • the synergistic effect of the composition of the present invention is inconsistent in vivo and in vitro; specifically, the composition exhibits inconsistent in vivo and in vitro regardless of the range of drug synergistic effects and the more effective range.
  • the specific performance is that the mass ratio of oseltamivir and compound 1 is about 1:22.5 to 11.3:1 according to the range of drug synergy in vitro, and the range of drug synergy is surprisingly large in in vivo experiments.
  • the mass ratio of compound 1 and oseltamivir phosphate is 75 ⁇ 600:75 (1 ⁇ 8:1), which is synergistic; further, the mass ratio of compound 1 and oseltamivir phosphate is 75: 75,100:75,200:75,300:75,400:75,500:75,600:75, it shows a good synergy of drugs in the body;
  • Example 7 The pharmaceutical composition obtained in Example 7 was mixed with an appropriate amount of filler, binder, and disintegrant, and then directly compressed to prepare a tablet (200mg+75mg).

Landscapes

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

Abstract

L'invention concerne une composition pharmaceutique et une préparation de celle-ci, la composition pharmaceutique contenant deux ingrédients efficaces ayant un rapport massique compris dans une certaine plage. La composition pharmaceutique présente un effet anti-virus de la grippe significativement meilleur, et après une évaluation complète, la composition pharmaceutique est considérée comme ayant de bonnes perspectives pour la préparation de médicaments.
PCT/CN2020/113105 2019-09-10 2020-09-02 Composition pharmaceutique pour le traitement de la grippe virale et sa préparation Ceased WO2021047437A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080062567.5A CN114502150B (zh) 2019-09-10 2020-09-02 一种用于治疗病毒性感冒的药物组合物及其制剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910851759 2019-09-10
CN201910851759.3 2019-09-10

Publications (1)

Publication Number Publication Date
WO2021047437A1 true WO2021047437A1 (fr) 2021-03-18

Family

ID=74866856

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/113105 Ceased WO2021047437A1 (fr) 2019-09-10 2020-09-02 Composition pharmaceutique pour le traitement de la grippe virale et sa préparation

Country Status (2)

Country Link
CN (1) CN114502150B (fr)
WO (1) WO2021047437A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022089261A1 (fr) * 2020-10-29 2022-05-05 广东众生睿创生物科技有限公司 Forme cristalline d'un dérivé de pyrimidine et son procédé de préparation
WO2025237212A1 (fr) * 2024-05-11 2025-11-20 广东众生睿创生物科技有限公司 Sel de méglumine dérivé de pyrimidine et formes cristallines de celui-ci

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492381A (zh) * 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 流感病毒复制的抑制剂
CN104151312A (zh) * 2009-06-17 2014-11-19 沃泰克斯药物股份有限公司 流感病毒复制抑制剂
WO2018041263A1 (fr) * 2016-09-05 2018-03-08 广东众生药业股份有限公司 Dérivé de pyrimidine du virus de la grippe
CN108276401A (zh) * 2017-01-05 2018-07-13 广东东阳光药业有限公司 流感病毒复制抑制剂及其用途
WO2019170067A1 (fr) * 2018-03-05 2019-09-12 广东众生睿创生物科技有限公司 Forme cristalline et forme saline de composé pyridoimidazole et son procédé de préparation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017133670A1 (fr) * 2016-02-05 2017-08-10 Savira Pharmaceuticals Gmbh Dérivés de pyridine et de pyrimidine et leur utilisation dans le traitement, l'atténuation des symptômes ou la prévention de la grippe
CN107759571B (zh) * 2016-08-16 2021-03-02 广东东阳光药业有限公司 流感病毒复制抑制剂及其使用方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151312A (zh) * 2009-06-17 2014-11-19 沃泰克斯药物股份有限公司 流感病毒复制抑制剂
CN103492381A (zh) * 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 流感病毒复制的抑制剂
WO2018041263A1 (fr) * 2016-09-05 2018-03-08 广东众生药业股份有限公司 Dérivé de pyrimidine du virus de la grippe
CN108276401A (zh) * 2017-01-05 2018-07-13 广东东阳光药业有限公司 流感病毒复制抑制剂及其用途
WO2019170067A1 (fr) * 2018-03-05 2019-09-12 广东众生睿创生物科技有限公司 Forme cristalline et forme saline de composé pyridoimidazole et son procédé de préparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DONALD F. SMEE, DALE L. BARNARD, STEVEN M. JONES: "Activities of JNJ63623872 and oseltamivir against influenza A H1N1pdm and H3N2 virus infections in mice", ANTIVIRAL RESEARCH, ELSEVIER BV, NL, vol. 136, 19 October 2016 (2016-10-19), NL, pages 45 - 50, XP055485753, ISSN: 0166-3542, DOI: 10.1016/j.antiviral.2016.10.009 *
FINBERG ROBERT W, LANNO RIIN, ANDERSON DAVID, FLEISCHHACKL ROMAN, VAN DUIJNHOVEN WILBERT, KAUFFMAN ROBERT S, KOSOGLOU TEDDY, VINGE: "Phase 2b Study of Pimodivir (JNJ-63623872) as Monotherapy or in Combination With Oseltamivir for Treatment of Acute Uncomplicated Seasonal Influenza A: TOPAZ Trial", JOURNAL OF INFECTIOUS DISEASES, UNIVERSITY OF CHICAGO PRESS, US, vol. 219, no. 7, 15 March 2019 (2019-03-15), US, pages 1026 - 1034, XP055791527, ISSN: 0022-1899, DOI: 10.1093/infdis/jiy547 *
RANDAL A. BYRN, JONES STEVEN M., BENNETT HAMILTON B., BRAL CHRIS, CLARK MICHAEL P., JACOBS MARC D., KWONG ANN D., LEDEBOER MARK W.: "PRECLINICAL ACTIVITY OF VX-787, A FIRST-IN-CLASS, ORALLY BIOAVAILABLE INHIBITOR OF THE INFLUENZA VIRUS POLYMERASE PB2 SUBUNIT", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 59, no. 3, 1 March 2015 (2015-03-01), US, pages 1569 - 1582, XP055485823, ISSN: 0066-4804, DOI: 10.1128/AAC.04623-14 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022089261A1 (fr) * 2020-10-29 2022-05-05 广东众生睿创生物科技有限公司 Forme cristalline d'un dérivé de pyrimidine et son procédé de préparation
WO2025237212A1 (fr) * 2024-05-11 2025-11-20 广东众生睿创生物科技有限公司 Sel de méglumine dérivé de pyrimidine et formes cristallines de celui-ci

Also Published As

Publication number Publication date
CN114502150A (zh) 2022-05-13
CN114502150B (zh) 2023-03-24

Similar Documents

Publication Publication Date Title
US20210008072A1 (en) Formulations of azaindole compounds
CN105849100A (zh) 流感病毒复制抑制剂
AU2012276114B2 (en) Substituted cinnamamide derivative, preparation method and use thereof
BRPI0702875A2 (pt) formas cristalinas de tigeciclina e seus processos de preparação
TW201629004A (zh) 酚系ｔｒｐｖ１促效劑之前藥
EP3609502A1 (fr) Polythérapies pour le traitement d'infection par le virus de la grippe
WO2021047437A1 (fr) Composition pharmaceutique pour le traitement de la grippe virale et sa préparation
CN106957315B (zh) N-取代苯磺酰基-氮杂吲哚氧基苯甲酰胺类化合物及其制备药物的用途
WO2017041680A1 (fr) Composition pharmaceutique à base de vortioxétine ou d'un sel de celle-ci, et son procédé de préparation
CN104490909A (zh) 一种咖啡酸衍生物在制备具有抗rsv病毒作用的药物中的应用
KR101902567B1 (ko) 플루오로치환된 (3r,4r,5s)-5-구아니디노-4-아세트아미도-3-(펜탄-3-일옥시)사이클로헥센-1-카복실릭 엑시드, 이의 에스테르 및 이의 용도
CN107530342A (zh) 口服给药用医药组合物
CN106551946B (zh) 一种含三氟胸苷和盐酸替比嘧啶的药物组合物及制备方法
CN113116899B (zh) 一种用于治疗流感的药物组合物及含有该药物组合物的制剂
CN101665449B (zh) 他米巴罗汀的水溶性前药及其制备方法与应用
WO2015192672A1 (fr) Dérivé de benzofurane, son procédé de préparation, et son utilisation
WO2022142731A1 (fr) Composé antiviral et son procédé de préparation
CN101993417A (zh) 磷酸二甲啡烷的稳定新晶型
CN108938580B (zh) 盐酸帕罗西汀口崩片
WO2008144956A1 (fr) Nouveaux composés ambroxol, leurs procédés de préparation et leurs utilisations
JP2016504358A (ja) オキシブチニンを投与するための方法および組成物
CN116390908A (zh) 抗病毒治疗
CN111920794A (zh) 一种环己烯基-dl-天门冬氨酸衍生物在神经氨酸酶抑制剂药物制剂质量控制中的用途
JP2009533428A (ja) 筋肉内抗ウイルス処置
WO2024131615A1 (fr) Composition pharmaceutique pour le traitement ou l'atténuation de la covid-19 et formulation la comprenant

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: 20863118

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20863118

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 26/08/2022)

122 Ep: pct application non-entry in european phase

Ref document number: 20863118

Country of ref document: EP

Kind code of ref document: A1