[go: up one dir, main page]

WO1993023056A1 - Agent preventif ou therapeutique des maladies infectieuses, renfermant de la mizoribine en tant qu'ingredient actif - Google Patents

Agent preventif ou therapeutique des maladies infectieuses, renfermant de la mizoribine en tant qu'ingredient actif Download PDF

Info

Publication number
WO1993023056A1
WO1993023056A1 PCT/JP1993/000615 JP9300615W WO9323056A1 WO 1993023056 A1 WO1993023056 A1 WO 1993023056A1 JP 9300615 W JP9300615 W JP 9300615W WO 9323056 A1 WO9323056 A1 WO 9323056A1
Authority
WO
WIPO (PCT)
Prior art keywords
mizoribine
virus
therapeutic agent
infectious diseases
preventive
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/JP1993/000615
Other languages
English (en)
Japanese (ja)
Inventor
Yoshinori Kosugi
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.)
Asahi Kasei Corp
Asahi Chemical Industry Co Ltd
Original Assignee
Asahi Chemical Industry Co Ltd
Asahi Kasei Kogyo KK
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 Asahi Chemical Industry Co Ltd, Asahi Kasei Kogyo KK filed Critical Asahi Chemical Industry Co Ltd
Publication of WO1993023056A1 publication Critical patent/WO1993023056A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals

Definitions

  • the present invention relates to a virus belonging to the family Orthomyxoviridae or Paramyxoviridae, which comprises Mizoribine (Miz 0 ribine: chemical name; 4 1-Rubamoyl-1 1-D-ribofuranosyl-Imidazolium-5-year-old) as an active ingredient. And a prophylactic or therapeutic agent for infectious diseases caused by Conventional technology
  • Mizoribine is a nucleic acid-related substance that was found in the culture solution of Euvenicillium breff Eldianum M-2166 (FERM P-114) belonging to the genus Euvenicillium. It is a weakly acidic substance that decomposes brown in the vicinity of C.
  • Various methods for its production are known, such as the fermentation method and the chemical synthesis method using the above strains (J. Antibiotics, 27 , (10), 775 (1974), Chem. Pharm. B ⁇ 11.1, 23, 245 (1975). JP-A-48-56894, JP-A-50-12 No. 1275, Japanese Patent Application Laid-Open No. 50-121276, and Japanese Patent Publication No. 51-1693).
  • Mizoribine has an immunosuppressive effect, for example, it is useful for suppressing rejection in renal transplantation.
  • the initial dose per kg of body weight is 2 to 3 mg
  • the maintenance dose is 1 to 2 mg.
  • Anhydrous crystals are used as tablets of Bredinin (registered trademark: manufactured by Asahi Kasei Kogyo Co., Ltd.), which are orally administered in an equivalent amount per day.
  • Mizoribine is known to exhibit strong anti-viral activity against vaccinia virus, a DNA virus (Japanese Patent Application Laid-Open No. 48-56894). It has been reported that it has no effect on the infectious type 1 parainfluenza HVJ virus ⁇ poliovirus (J. Antibiotics, 27, (10), 775 (1974)). Issues to be solved
  • chemotherapeutic agents for herpes virus and lys virus has made it possible to provide causal therapy for viral diseases.
  • Orthomyxoviridae for example, influenza A, B, and C influenza viruses
  • Paramyxoviridae for example, measles virus, mumbus virus, parainfluenza virils or respiratory virus.
  • RNA viruses such as RS virus
  • Clinical differentiation of the pathogenic viruses of these two viral families is limited to measles with characteristic rashes, mumps with typical parotid swelling and influenza in extreme epidemics Difficult. Therefore, antiviral agents having a broad spectrum for these viruses are eagerly awaited (chemotherapy, Vol. 7, No. 10 1991).
  • Ribavirin is Has broad antiviral activity and is approved as the only antiviral agent against RS virus in the United States, but has various restrictions such as strong cytotoxicity and necessitating long-term treatment by aerosol inhalation . Therefore, a safer preparation with stronger antiviral activity has been desired.
  • mizoribine is effective against some DNA viruses, but not against RNA viruses! : J. Antibiotics, 27, (10), 775 (1974)] surprisingly, against the virus belonging to the myzoribine-powered, human-infectious Balamixoviridae or orthomyxoviridae family. As a result, they have found that they show stronger antiviral activity than the conventionally used rivapirin and have low cytotoxicity. As a result, it has become possible to provide a better prophylactic or therapeutic agent than ribavirin.
  • the present invention has been completed based on the above findings, and is an agent for preventing or treating an infectious disease caused by a virus belonging to the human infectious orthomyxoviridae or paramyxoviridae family containing mizoribine as an effective component.
  • Mizoribine of the present invention already filed by the immunosuppressive agent commercially available, acute toxicity (LD 5.)
  • D-MEM medium Derbecco Minimum Essential Medium
  • fetal bovine serum 10% fetal bovine serum
  • D-MEM medium Derbecco Minimum Essential Medium
  • MDCK cells above, manufactured by Omoto Pharmaceutical Co., Ltd.
  • G—HeLa cells Anti-mi-crobial Agentsent C hemother apy Vol. 36, No 2., 4 35-4 39.1 992
  • the cells were cultured using a medium supplemented with 6 gZl.
  • G—He La cells (cells derived from human cervix)> 500 fig / m 1 Ver0 cells (cells derived from african green monkey kidney)> 500 gZm1 MDCK cells (cells derived from canine kidney cell)> 50 Ojug / ml
  • This mizoribine is easy to use as an oral preparation (registered trade name: Bredinin tablet), and is appropriately administered in oral preparations such as capsules and granules, suppositories, and aerosol inhalation It can be formulated as a preparation, transdermal absorption preparation or injection by a conventional formulation technique.
  • Formulations for oral administration include, for example, anhydrous lactose, crystalline cellulose, dextran, starch, etc. as excipients, carboxymethylcellulose sodium, methylcellulose, ethylcellulose, etc. before conjugation, and disintegrants such as ruboxymethylcellulose, calcium carbonate, etc.
  • Lubricants such as methylcellulose and stearic acid, magnesium stearate, talc, etc.
  • Oral preparations such as tablets and capsules can be prepared by a selective combination or a conventional method.
  • a solution for aerosol and a preparation for injection administration can be produced by dissolving mizoribine in an aqueous solvent, and the concentration of mizoribine in the solution is 0.1 to 10 WZV based on the aqueous solvent. %, Preferably about 1 to 10%.
  • the preparations may be prepared by sterilizing or removing bacteria after adjustment. Examples of the aqueous solvent include distilled water for injection and sterilized purified water.
  • additives which are usually appropriately selected and used in liquid preparations, such as buffer for pH adjustment (for example, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, etc.), etc.
  • Tonicity agents eg, sorbitol, glycerin, polyethylene glycol, propylene glycol, glucose, sodium chloride, etc.
  • stabilizers eg, sulfites, bisulfites, metabisulfites, etc.
  • preservatives / disinfectants For example, benzalkonium chloride, paraoxybenzoic acid esters, benzyl alcohol, parachloromethaxinol, chlorcresol, phenethyl alcohol, sorbic acid or its salts, thimerosal, chlorobutanol, etc.
  • chelating agents For example, sodium edetate, sodium citrate, condensed sodium phosphate Etc.
  • viscosity formulations such as polyvinylpyrrolidone, methylcellulose
  • Examples of the human infectious virus belonging to the orthomyxoviridae family include viruses belonging to the genus Influenza virus, such as influenza A, B, and C viruses belonging to the genus influenza virus.
  • Viruses belonging to the human infectious paramyxoviridae family include those belonging to the genus Paramyxovirus, the genus Morbidillus, and the genus Newvirus.
  • type 2 and 3 parainfluenza virus belonging to the genus Paramyxovirus mumps virus, measles virus belonging to the genus Morbivirus, and RS virus belonging to the genus Pneumovirus.
  • Infectious diseases caused by these viruses are defined as diseases caused by these viruses such as common cold symptoms, bronchial inflammation, lung inflammation, measles-like rash, parotid swelling, meningeal inflammation, encephalitis, etc.
  • the names of the onset diseases include influenza, measles, respiratory tract infections, respiratory infections, subacute sclerosing panencephalitis, aseptic meningitis, parotitis, and common cold.
  • the amount of mizoribine used in the present invention is, for example, 1 to 20 mg / kg (body) as an adult 1 B dose in 1 to 3 divided doses a day, or 5 to 50 mg mg as appropriate. It may be administered by inhalation as a contained aerosol preparation.
  • the antiviral activity was measured according to a plaque reduction method (Plaquere duction method: Antimi crobial Agegents and Chemopheral Vol. 36, No. 2, 435-439.1992). Specifically, D-M was prepared by adding Vero cells to 24-well plastic plates (Falcon 3702) and adding 10% fetal bovine serum.
  • a D-MEM medium containing a prescribed concentration of anhydrous crystalline mizoribine, 2% fetal bovine serum, and 0.75% methacel (Methocel A-4M premium: manufactured by Dow Chemical Company, hereinafter abbreviated to metcell). After 0 ml was added and the cells were cultured in a 35 ° 5% carbon dioxide gas culture apparatus for 2 days, the cells were fixed with formalin, stained with crystal violet, and the number of plaques was measured under a microscope. The antiviral effect (EC 5 ) was calculated from the measured number of plaques according to the following equation.
  • Antiviral activity was measured as described in the previous section. Specifically, Vero cells were cultured for 18 hours at 37 ° C and 5% CO 2 in a D-MEM medium containing 10% fetal bovine serum on a 24-well plastic plate. (4) After the formation of the culture cells, remove the culture medium and remove 20 to 10 PFU of the PFU type 3 paraline bruenza virus C243 strain (P arainf 1 uenzatye 3C243H-1 strain; Antimicrobia 1 Agentsand 36, No 2., 435-439.19.92) was inoculated.
  • Antiviral activity against RS virus belonging to Paramyxoviridae The antiviral activity was measured in the same manner as in the previous section. Specifically, G-HeLa cells were placed in a 24-well plastic plate at 37 ° C and 5% CO 2 in a D-MEM medium containing 10% fetal bovine serum and 16 g / 1 glucose. After culturing for 18 hours to form 80% monolayer cultured cells, remove the culture solution and remove 20 to 100 PFU of RS virus long strain (Anti micr obial Agen tsa nd Ch emo theray Vo l) . 36, No 2., 435-439. 1 992).
  • D-MEM medium containing the specified concentration of mizoribine, 2% fetal bovine serum, 0.75% methocel and 16 g / 1 glucose 1. Add Oml, and incubate at 35 ° C and 5% CO2 After culturing for 4 days, the cells were fixed with formalin, stained with crystal violet, and the number of plaques was measured under a microscope. The antiviral effect (EC 5 ) was calculated from the measured number of plaques in the same manner as in the previous section.
  • the antiviral activity was measured according to the MTT-microplate method (MTT-Microplate method, metabolism, Vol. 28,. No. 12, see page 333, 1991).
  • MDCK cells were cultured in a 96-well plastic plate (Falcon 3402) in D-MEM medium supplemented with 8% fetal bovine serum in a 5% CO2 incubator at 37 ° C for 36 hours, and 80% After the culture of the monolayer column, the culture solution is removed and 2 Q 0 xTC ID 50 (Tis sue Cu l tur e e n f ect on dose 50) of influenza B virus strains of Singapore (i ⁇ ⁇ 1 enza enzavirus ⁇ / Singap orestrai ⁇ ; Ant im icror obial Agents and Chemo t he rapy Vo l.
  • D-MEM medium 1001 containing the specified concentrations of mizolipin, 2% bovine albumin, and 0. OS SmgZm1 tribcine, and incubate for 5 days in a 5% CO2 culture device at 35 ° C and 5 mg / ml.
  • Mizoribine has about 10 times stronger antiviral activity against measles virus belonging to Paramyxoinfluenzae family and type 3 parainfluenzaviras than Ribavirin as shown in Tables 1 and 2 above. As shown in Tables 3 and 4, among the various RNA viruses, It also has strong antiviral activity against viruses belonging to the family members of the viridae and orthomyxoviridae. Therefore, based on these results, mizoribine is a drug exhibiting strong antiviral activity in a very small amount against a specific RNA virus belonging to the family Orthomyxoviridae or Paramyxoviridae, and has low cytotoxicity. It is useful as a prophylactic or therapeutic agent for infectious diseases such as influenza, measles, respiratory infection, subacute sclerosing panencephalitis, aseptic meningitis, parotitis, and common cold caused by the virus.
  • infectious diseases such as influenza, measles, respiratory infection, subacute sclerosing panencephalitis

Landscapes

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

Abstract

Agent préventif ou thérapeutique des maladies infectieuses causées par des virus appartenant à la famille des agents infectieux de l'homme des Orthomyxoviridae ou Paramyxoviridae, cet agent contenant de la mizoribine (désignation chimique: 4-carbamoyle-1-β-D-ribofuranosylimidazolium 5-oléate) en tant qu'ingrédient actif. La mizoribine ayant une puissante activité antivirale contre certains virus d'ARN appartenant aux familles susmentionnées, même administrée en quantité minime, elle constitue un agent utile de prévention ou de thérapeutique contre les maladies infectieuses causées par ces virus.
PCT/JP1993/000615 1992-05-15 1993-05-11 Agent preventif ou therapeutique des maladies infectieuses, renfermant de la mizoribine en tant qu'ingredient actif Ceased WO1993023056A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4123386A JPH05310578A (ja) 1992-05-15 1992-05-15 ミゾリビンを有効成分とする感染疾患の予防または治療剤
JP4/123386 1992-05-15

Publications (1)

Publication Number Publication Date
WO1993023056A1 true WO1993023056A1 (fr) 1993-11-25

Family

ID=14859296

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/000615 Ceased WO1993023056A1 (fr) 1992-05-15 1993-05-11 Agent preventif ou therapeutique des maladies infectieuses, renfermant de la mizoribine en tant qu'ingredient actif

Country Status (2)

Country Link
JP (1) JPH05310578A (fr)
WO (1) WO1993023056A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004155777A (ja) * 2002-10-16 2004-06-03 Asahi Kasei Pharma Kk Ｃ型慢性肝炎治療剤
US20040208833A1 (en) * 2003-02-04 2004-10-21 Elan Pharma International Ltd. Novel fluticasone formulations
JP2005104852A (ja) * 2003-09-29 2005-04-21 Kyowa Hakko Kogyo Co Ltd モービリウィルス感染症の予防または治療用組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4856894A (fr) * 1971-11-15 1973-08-09

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4856894A (fr) * 1971-11-15 1973-08-09

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 113, (No. 25), p. 36, 17 December 1990, Abstract No. 224288q; & TRANSPLANT. PROC., Abstract for Vol. 22, No. 4, pages 1682-5. *
JOURNAL OF ANTIBIOTICS, Vol. 27, No. 10, p. 775-782, (1974), K. MIZUNO et al., "Studies of Bredinin. 1". *

Also Published As

Publication number Publication date
JPH05310578A (ja) 1993-11-22

Similar Documents

Publication Publication Date Title
WO2021195211A1 (fr) Composés de quinoléine pour le traitement de troubles respiratoires et d'infections virales
US20170281603A1 (en) Thiazolide compounds for treating viral infections
CN112076262A (zh) 一种中药组合物在制备预防和治疗新型冠状病毒感染肺炎药物中的应用
US20250099474A1 (en) Pharmaceutical for treatment of novel coronavirus infection
US20240002332A1 (en) Small Molecule Inhibitors of SARS-CoV-2 Infections
US20030045577A1 (en) Method for preventing infectious respiratory diseases
WO1993023056A1 (fr) Agent preventif ou therapeutique des maladies infectieuses, renfermant de la mizoribine en tant qu'ingredient actif
RU2738885C1 (ru) Противо-SARS-CoV-2 вирусное средство Антипровир
RU2737086C2 (ru) Жидкая лекарственная форма для лечения и профилактики гриппа и орви
JPH02275821A (ja) 薬剤組成物
CN100475209C (zh) 抗冠状病毒剂
WO2023085979A1 (fr) Nouveaux dérivés de favipiravine
EP0476391B1 (fr) Composition anti-SIDA contenant cépharanthine comme agent thérapeutique
CN104940185B (zh) 刺芒柄花素的医药用途
AU2005291603B2 (en) Novel use of alpha-sympathomimetics having a 2-imidazoline structure
RU2770518C2 (ru) Жидкая лекарственная форма для лечения и профилактики гриппа и орви
RU2770521C2 (ru) Жидкая лекарственная форма для лечения и профилактики гриппа и орви
WO2021049980A1 (fr) Nouvelles formulations pour le traitement et la prévention de maladies virales
RU2744854C1 (ru) Жидкая лекарственная форма для лечения и профилактики гриппа и орви
CN100364975C (zh) 一种抗呼吸道病毒的药物及用途
RU2828875C1 (ru) Способ получения новых производных фавипиравира
CN115697313B (zh) 用于治疗rna病毒诱导的疾病的方法和组合物
RU2832326C1 (ru) Фармацевтическая композиция и лекарственное средство, содержащие новые производные фавипиравира
US20250049733A1 (en) Pharmaceutical composition for the treatment of infectious respiratory diseases caused by influenza and sars-cov-2, among others
RU2744429C1 (ru) Противо-РНК вирусное, в том числе противокоронавирусное средство - замещенный хиноксалин, фармацевтическая композиция и применения

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BE DE DK ES FR GB IT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA