WO2022145405A1 - Produit pharmaceutique pour le traitement d'infection virale des voies respiratoires comprenant un antagoniste de dp1 et un inhibiteur d'endonucléase dépendante de la coiffe - Google Patents

Produit pharmaceutique pour le traitement d'infection virale des voies respiratoires comprenant un antagoniste de dp1 et un inhibiteur d'endonucléase dépendante de la coiffe Download PDF

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WO2022145405A1
WO2022145405A1 PCT/JP2021/048473 JP2021048473W WO2022145405A1 WO 2022145405 A1 WO2022145405 A1 WO 2022145405A1 JP 2021048473 W JP2021048473 W JP 2021048473W WO 2022145405 A1 WO2022145405 A1 WO 2022145405A1
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infection
pharmaceutically acceptable
viral
acceptable salt
virus
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PCT/JP2021/048473
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English (en)
Japanese (ja)
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聡一 東福寺
圭太 深尾
伸治 日下部
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塩野義製薬株式会社
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical for treating viral respiratory tract infections. More specifically, the present invention relates to a pharmaceutical for treating influenza virus infection in a subject having an influenza virus infection and a severe influenza condition, which comprises a combination of a DP1 antagonist and a cap-dependent endonuclease inhibitor.
  • Prostaglandin D2 (PGD2), which is a product of the cyclooxygenase circuit of arachidonic acid metabolism, has a strong bronchial contractile effect and induces enhanced vascular permeability and migration of inflammatory cells such as eosinophils, and thus PGD2.
  • Receptor antagonists are known to be useful in the treatment of allergic diseases (eg, asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, etc.).
  • the applicant reports a sulfonamide derivative having an antagonistic activity on the DP receptor, which is one of the PGD2 receptors, as a therapeutic agent for allergic diseases (Patent Document 1).
  • Non-Patent Document 1 the compound represented by the formula (I) exhibits high affinity and selectivity for the DP1 receptor in the binding test.
  • this drug significantly suppresses antigen-induced nasal resistance, nasal juice, and cell infiltration of the nasal mucosa, and the compound represented by the formula (I) is an asthma reaction due to antigen exposure and the airway. It has been reported that hypersensitivity, cell infiltration in the lung and mutin production were suppressed (Non-Patent Document 1).
  • PGD2 is involved in the regulation of immune and inflammatory responses to specific viral infections.
  • PGD2 levels are elevated in the upper airway of infants hospitalized for bronchitis associated with RS virus infection, and in a mouse RS virus infection model, administration of DP1 receptor agonist or DP2 receptor antagonist promotes viral clearance.
  • DP1 receptor agonist or DP2 receptor antagonist promotes viral clearance.
  • the inflammatory response of lung tissue is suppressed (Non-Patent Document 2).
  • PGD2 has been reported to regulate excessive inflammasome activation, suggesting that prostaglandin signaling is involved in the regulation of optimal immune response setpoints. (Non-Patent Document 3).
  • Non-Patent Document 4 PGD2 levels in BALF (bronchial alveolar lavage fluid) are elevated compared to young mice, which is accompanied by induction of dendritic cells after virus infection and subsequent virus-specific adaptive immune response. has been reported to decrease. According to this report, DP1 receptor antagonist administration improved the acquired immune response to viral infections, and blocking the DP1 receptor-mediated PGD2 signal protects against the decline in acquired immune response associated with aging. It is suggested that it acts in a positive manner (Non-Patent Document 4).
  • Influenza is an acute respiratory infection caused by a virus of the Orthomyxoviridae family. Two types of influenza A virus and influenza B virus are known to infect humans. These viruses cause acute febrile infections of the respiratory tract, characterized by rapid fever, cough, malaise, headache, and / or myalgia, after an incubation period of 1-4 days. The annual influenza pandemic is believed to result in 3-5 million severe cases and 250,000-500,000 deaths worldwide each year (WHO 2017). ).
  • Influenza is generally a disease that can be cured by healthy adults, but the disease is associated with high morbidity and occasional high mortality in pediatric, elderly, and immunocompromised patients. Hospitalization for severe influenza conditions can lead to high mortality (4% -8%), intensive care unit (ICU) admission (5% -17%), and long-term hospitalization for 5-9 days. Results can be more severe, with up to 34% of patients requiring ICU care and mortality as high as 15% during the epidemic season (Non-Patent Document 5). Anti-influenza virus agents, i.e.
  • M2 ion channel inhibitors eg, amantazine and limantazine
  • RNA polymerase inhibitors eg, favipyrabil
  • NA neurominidase
  • CEN cap dependence Sexual endonuclease inhibitors
  • Non-Patent Document 6 Non-Patent Document 6
  • host-targeted drugs such as steroids
  • PROBLEM TO BE SOLVED To provide a pharmaceutical composition for treating influenza virus infection in a subject having an influenza virus infection and a severe influenza condition by combining a DP1 antagonist and a cap-dependent endonuclease inhibitor. To provide.
  • the present invention relates to the following items (1) to (8), (8-a) to (8-e), (9) to (20), (20-a) to (20-e), (21). -(28), (28-a)-(28-e), (29)-(36), (36-a)-(36-e), (37)-(44), (44-a) (44-e), (45) to (52) and (52-a) to (52-e).
  • Cap-dependent endonuclease inhibitors are baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01.
  • the above item (1) which is at least one compound selected from the group consisting of -2019-121, AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the viral airway infection is an infection caused by at least one virus selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus, bocavirus and metapneumovirus, as described above.
  • the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV).
  • SARS-CoV SARS coronavirus
  • SARS-CoV2 SARS coronavirus 2
  • MERS coronavirus MERS coronavirus
  • Cap-dependent endonuclease inhibitors are GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01-2019-121,
  • Equation (11) A cap-dependent endonuclease inhibitor for use with the compounds indicated by or pharmaceutically acceptable salts.
  • Cap-dependent endonuclease inhibitors are baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01.
  • the described mixture is an infection caused by at least one virus selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus, bocavirus and metapneumovirus.
  • SARS-CoV SARS coronavirus
  • SARS-CoV2 SARS coronavirus 2
  • MERS coronavirus MERS coronavirus
  • Equation (21) (I): Includes the combination of the compound indicated by, or a pharmaceutically acceptable salt thereof, with a cap-dependent endonuclease inhibitor, and administering a therapeutically effective amount thereof to an individual in need of treatment for a viral airway infection. , How to treat viral airway infections.
  • Cap-dependent endonuclease inhibitors are GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01-2019-121,
  • the viral airway infection is an infection caused by at least one virus selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus, bocavirus and metapneumovirus.
  • SARS-CoV SARS coronavirus
  • SARS-CoV2 SARS coronavirus 2
  • MERS coronavirus MERS coronavirus
  • Cap-dependent endonuclease inhibitors are baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01.
  • the viral airway infection is an infection caused by at least one virus selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus, bocavirus and metapneumovirus.
  • Formula (I) for treating viral respiratory tract infections A drug comprising a combination of the compound indicated by the above, or a pharmaceutically acceptable salt thereof, and a cap-dependent endonuclease inhibitor.
  • Cap-dependent endonuclease inhibitors are baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01.
  • the above item (37) which is at least one compound selected from the group consisting of -2019-121, AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the listed drug is at least one compound selected from the group consisting of -2019-121, AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the viral airway infection is an infection caused by at least one virus selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus, bocavirus and metapneumovirus.
  • the above items (37) to (41), wherein the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV).
  • SARS coronavirus SARS coronavirus
  • SARS-CoV2 SARS coronavirus 2
  • MERS coronavirus MERS coronavirus
  • Cap-dependent endonuclease inhibitors are baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01.
  • the above item (45) which is at least one compound selected from the group consisting of -2019-121, AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the viral airway infection is an infection caused by at least one virus selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus, bocavirus and metapneumovirus.
  • the above items (45) to (49), wherein the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV).
  • SARS coronavirus SARS coronavirus
  • SARS-CoV2 SARS coronavirus 2
  • MERS coronavirus MERS coronavirus
  • the pharmaceutical preparation according to any one of. (50) The pharmaceutical preparation according to any one of the above items (45) to (49), wherein the viral airway infection is an infectious disease accompanied by coinfection and / or secondary infection of bacteria at the time of viral infection.
  • the pharmaceutical preparation according to any one of the above items (45) to (50) which is an orally administered agent.
  • the pharmaceutical preparation according to any one of the above items (45) to (51) which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • 52-a The pharmaceutical preparation according to any one of the above items (45) to (51), which comprises 50 mg to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • the above items (1) to (8), (8-a) to (8-e) and (9), (10) alleviate the symptoms of pneumonia caused by a viral respiratory tract infection.
  • One embodiment comprises the combination according to items (13)-(20) and (20-a)-(20-e) above, which alleviate the symptoms of pneumonia caused by a viral respiratory tract infection.
  • One embodiment includes the therapeutic methods according to items (21)-(28) and (28-a)-(28-e) above, which alleviate the symptoms of pneumonia caused by a viral respiratory tract infection.
  • One embodiment comprises the use according to items (29)-(36) and (36-a)-(36-e) above, which alleviate the symptoms of pneumonia caused by a viral respiratory tract infection.
  • One embodiment comprises the pharmaceuticals according to items (37)-(44) and (44-a)-(44-e) above, which alleviate the symptoms of pneumonia caused by a viral respiratory tract infection.
  • One embodiment comprises the pharmaceutical formulations according to items (45)-(52) and (52-a)-(52-e) above, which alleviate the symptoms of pneumonia caused by a viral respiratory tract infection.
  • the pharmaceutical agent for treating viral airway infections of the present invention contains a compound represented by the formula (I), which is a PGD2 receptor antagonist, a pharmaceutically acceptable salt thereof, or a cap-dependent endonuclease inhibitor, respectively. It has an excellent effect of improving the mortality caused by influenza virus infection and the mortality caused by double infection and / or secondary infection of bacteria at the time of influenza virus infection as compared with the case of administration. ..
  • the pharmaceutical agent for treating a viral respiratory tract infection of the present invention has (A) formula (I): as an active ingredient. With the compound indicated by, or its pharmaceutically acceptable salt, (B) It is characterized by the combined use of a cap-dependent endonuclease inhibitor (including a kit). Alternatively, the pharmaceutical agent for treating a viral respiratory tract infection of the present invention has the formula (A) formula (I): as an active ingredient. With the compound indicated by, or its pharmaceutically acceptable salt, (B) It is a mixture of cap-dependent endonuclease inhibitors.
  • the pharmaceutical agent for treating a viral respiratory tract infection of the present invention is also referred to as a therapeutic agent for a viral respiratory tract infection.
  • the pharmaceutical for treating viral respiratory tract infections of the present invention is also referred to as a pharmaceutical for suppressing the aggravation of viral respiratory tract infections or an agent for suppressing the aggravation of viral respiratory tract infections.
  • PGD2 receptor antagonist used in the present invention is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) is [2- (Oxazole-2-yl) -5- (4- ⁇ 4-[(propan-2-yl) oxy] phenylsulfonyl ⁇ piperazin-1-yl) acetic acid] acetic. It is an acid and has antagonistic activity on the DP receptor, which is one of the PGD2 receptors.
  • the compound represented by the formula (I) can be synthesized according to a known method, for example, the method described in WO2007 / 037187 pamphlet, WO2008 / 123349 pamphlet and WO2013 / 147118 pamphlet.
  • Cap-Dependent Endonuclease Inhibitor examples include baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-036, and the like. At least one compound selected from the group consisting of H-015, ZX-7101A, IFV-PA, KYAH01-2019-121, AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof. Alternatively, solvates thereof may be mentioned.
  • Baloxavir marboxil may form a pharmaceutically acceptable salt.
  • the dose of baloxavir marboxil alone is 80 mg or 40 mg per adult per day as baloxavir marboxil.
  • Examples of GP-681 include the compounds described in WO2019141179 or WO2020224208.
  • Examples of the TG-1000 include the compounds described in WO2019144089.
  • L-742001 examples include the compounds described in US5475109 or Antiviral Research 183 (2020) 104947.
  • AL-794 includes, for example, WO2017223231 or J. Infect. Dis. Examples thereof include the compounds described in 2019 Jan 7 219 (2) 177-185.
  • Examples of KW-036 include the compounds described in WO2021181047 and CN112920202.
  • H-015 examples include the compound described in CN111233891.
  • AV-5124 for example, J. Antimiclob. Chemother. , 2021,76, No. Examples include the compounds described in 4, 1010-8.
  • AV-5116 for example, J. Antimiclob. Chemother. , 2021,76, No. Examples include the compounds described in 4, 1010-8.
  • NX-2016 examples include the compounds described in CN112174956, CN1113578773, and CN112174955.
  • WO2021195278 WO2021191872, WO2021180174, WO20211175173, WO2021007506, CN111233891, CN112778330, CN112876510, CN112754534, CN1121744956, WO20211297999, WO201012716, WO2020015669, CN112174955, CN112217202, J. Antimiclob. Chemother. , 2021,76, No. 4,1010-8, CN1113587773.
  • cap-dependent endonuclease inhibitors may be synthesized according to known methods or commercially available products may be used.
  • the "pharmaceutically acceptable salt” includes alkali metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, etc.).
  • Salts with amino acids, or inorganic acids eg, iron, etc.
  • ammonia organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumin, ethylenediamine, pyridine, picolin, quinoline, etc.)
  • Hydrochloride sulfuric acid, nitrate, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.
  • organic acids eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, Maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanes
  • the above-mentioned component (A) or the above-mentioned component (B) may form a solvate (for example, a hydrate or the like), and the present invention also includes such various solvates.
  • the "solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the component (A) or the component (B).
  • solvent molecules for example, water molecules
  • solvate in the present specification, a solvate of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, valoxavir malboxyl, GP-681, TG-1000, L- Means a solvate of at least one compound selected from the group consisting of 742001 and AL-794, or a pharmaceutically acceptable salt thereof, eg, monosolvate, disolvate, monohydrate, etc. Examples include dihydrate and the like.
  • the pharmaceutically acceptable salt and solvate can be synthesized according to a known method.
  • Examples of the component (A) in the present invention include the compound represented by the above (I) or a sodium salt, a calcium salt, a magnesium salt, a potassium salt and the like thereof.
  • examples of the component (B) in the present invention include baloxavir marboxil, GP-681, TG-1000, L-742001 and AL-794, or pharmaceutically acceptable salts thereof.
  • Examples of the combination of the component (A) and the component (B) include the following combinations.
  • the compound represented by the formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt and the like and baroxavir malboxyl The compound represented by the formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt and the like and GP-681, The compound represented by the formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt and the like and TG-1000, The compound represented by the formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt and the like and L-742001, AL-794 with the compound represented by the formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt and the like. Further, as one embodiment, a combination of the compound represented by the formula (I) and baloxavir marboxil can be mentioned.
  • the pharmaceutical for treating influenza virus infection in a subject having an influenza virus infection and a serious influenza state of the present invention is not particularly limited as long as it is a combination of the above components (A) and (B).
  • Other active ingredients can be further combined as long as the effects of the invention are not impaired.
  • the pharmaceutical agent for treating influenza virus infection in a subject having an influenza virus infection and a serious influenza state of the present invention can be administered by either an oral method or a parenteral method.
  • parenteral administration method include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, instillation, ear instillation, and intravaginal administration.
  • internal solid preparations eg tablets, powders, granules, capsules, rounds, film preparations, etc.
  • internal liquid preparations eg suspensions, emulsions, elixirs, syrups, etc.
  • the tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules may be dry syrup.
  • Capsules may be soft capsules, microcapsules or sustained release capsules.
  • injections, infusions, external preparations eg, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargling agents, enema agents, etc.
  • Any commonly used dosage form such as ointment, plaster, jelly, cream, patch, pap, external powder, suppository, etc. can be suitably administered.
  • the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type or the like.
  • the pharmaceutical for treating influenza virus infection in a subject having an influenza virus infection and a serious influenza state of the present invention is not particularly limited as long as it is a combination of the above components (A) and (B). It can be prepared according to a method known to the vendor.
  • the shape and size of the therapeutic agent are not particularly limited, but examples of the oral preparation include solid preparations, and examples of the parenteral preparation include injections, infusions, and inhalants.
  • a combination drug containing the compound represented by the formula (I) and baloxavir marboxil A combination of a tablet or granule containing the compound represented by the formula (I) and a tablet or granule containing baloxavir marboxil (including a kit).
  • a combination drug containing the compound represented by the formula (I) and GP-681 A combination of a tablet or granule containing the compound represented by the formula (I) and GP-681 (including any dosage form) (including a kit).
  • a combination drug containing the compound represented by the formula (I) and TG-1000 A combination (including kit) of TG-1000 (including any dosage form) with a tablet or granule containing the compound represented by the formula (I).
  • a combination drug containing the compound represented by the formula (I) and L-742001 A combination (including kit) of L-742001 (including any dosage form) with a tablet or granule containing the compound represented by the formula (I).
  • a combination drug containing the compound represented by the formula (I) and AL-794 A combination (including kit) of AL-794 (including any dosage form) with a tablet or granule containing the compound represented by the formula (I).
  • отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form are mixed with the effective amounts of the above-mentioned component (A) and the above-mentioned component (B) as necessary.
  • It can be a composition.
  • the pharmaceutical composition can be used for children, the elderly, and severely ill patients by appropriately changing the effective amounts, dosage forms and / or various pharmaceutical additives of the component (A) and the component (B). Alternatively, it can be a pharmaceutical composition for surgery.
  • pediatric pharmaceutical compositions include newborns (4 weeks to less than 1 year old), infants (4 weeks to less than 1 year old), infants (1 to 7 years old), children (7 to less than 15 years old) or 15 It can be administered to patients aged 18 to 18 years.
  • a pharmaceutical composition for the elderly can be administered to a patient aged 65 years or older.
  • the dose of the drug for treating influenza virus infection in a subject having an influenza virus infection and a serious influenza state of the present invention shall be determined in consideration of the age, weight, type and degree of disease, administration route, etc. of the patient. Although it is desirable to set it, when it is orally administered, it is usually in the range of 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, it is usually 0.005 to 10 mg / kg / day, preferably in the range of 0.01 to 1 mg / kg / day, although it varies greatly depending on the administration route. This may be administered once to several times a day.
  • the pharmaceutical product for treating influenza virus infection in a subject having an influenza virus infection and a serious influenza state of the present invention is characterized by combining the component (A) and the component (B) as an active ingredient.
  • the doses of the components (A) and (B) are the dosage form, the patient's symptoms, and the like. It depends on age, weight, gender, or other concomitant medications (if any) and is ultimately left to the discretion of the doctor.
  • the component (B) is baloxavir marboxil
  • the following aspects can be mentioned. Examples thereof include an embodiment in which 50 to 200 mg of the component (A) and 40 mg to 80 mg of the component (B) are administered per day for an adult. Examples thereof include an embodiment in which 50 to 100 mg of the component (A) and 40 mg to 80 mg of the component (B) are administered per day for an adult.
  • Examples thereof include an embodiment in which 50 mg of the component (A) and 40 mg to 80 mg of the component (B) are administered per day for an adult. Examples thereof include an embodiment in which 100 mg of the component (A) and 40 mg to 80 mg of the component (B) are administered per day for an adult. Examples thereof include an embodiment in which 150 mg of the component (A) and 40 mg to 80 mg of the component (B) are administered per day for an adult. Examples thereof include an embodiment in which 200 mg of the component (A) and 40 mg to 80 mg of the component (B) are administered per day for an adult. Examples thereof include an embodiment in which 50 to 200 mg of the component (A) and 40 mg of the component (B) are administered per day for an adult.
  • Examples thereof include an embodiment in which 50 to 100 mg of the component (A) and 40 mg of the component (B) are administered per day for an adult. An embodiment in which 50 mg of the component (A) and 40 mg of the component (B) are administered per day for an adult can be mentioned. An embodiment in which 100 mg of the component (A) and 40 mg of the component (B) are administered per day for an adult can be mentioned. An embodiment in which 150 mg of the component (A) and 40 mg of the component (B) are administered per day for an adult can be mentioned. An embodiment in which 200 mg of the component (A) and 40 mg of the component (B) are administered per day for an adult can be mentioned.
  • Examples thereof include an embodiment in which 50 to 200 mg of the component (A) and 80 mg of the component (B) are administered per day for an adult.
  • Examples thereof include an embodiment in which 50 to 100 mg of the component (A) and 80 mg of the component (B) are administered per day for an adult.
  • An embodiment in which 50 mg of the component (A) and 80 mg of the component (B) are administered per day for an adult can be mentioned.
  • An embodiment in which 100 mg of the component (A) and 80 mg of the component (B) are administered per day for an adult can be mentioned.
  • An embodiment in which 150 mg of the component (A) and 80 mg of the component (B) are administered per day for an adult can be mentioned.
  • An embodiment in which 200 mg of the component (A) and 80 mg of the component (B) are administered per day for an adult can be mentioned.
  • the dose may be administered at once or in divided doses.
  • effect exceeding addition means a case where the survival rate when two or more kinds of drugs are used in combination is larger than the sum of the survival rates when each drug is administered alone.
  • the present invention also administers a therapeutically effective amount of a combination of component (A) and component (B) to an individual in need of treatment for influenza virus infection in a subject with influenza virus infection and severe influenza status.
  • a method for treating an influenza virus infection and a method for treating an influenza virus infection in a subject having a serious influenza condition.
  • the therapeutically effective amount means that when the component (A) and the component (B) are combined and administered to an individual in need of treatment, the component (A) and the component (B) are combined and administered. It is the amount that suppresses the symptoms or case fatality rate caused by influenza compared to individuals who do not.
  • the specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, body weight, symptom, etc. of the individual, and is not constant.
  • the symptom caused by the influenza virus includes at least one systemic symptom, and includes one or more of headache, fever, chills, myalgia, joint pain and malaise.
  • the symptoms caused by influenza virus include at least one respiratory symptom, and one or more of cough, sore throat, and nasal congestion.
  • a serious influenza condition means (a) hospitalization due to an influenza virus infection, and (b) an extension of hospitalization due to an influenza virus infection during hospitalization. (C) National early warning score 2 of 4 or higher, (d) Respiratory assistance, (e) Having at least one complication due to an influenza virus infection requiring hospitalization. One or more of them can be included.
  • a serious influenza condition includes a condition requiring respiratory assistance.
  • respiratory assistance is at least one of ventilators and oxygen inhalers from non-atmospheric oxygen sources, as well as oxygen concentrators that concentrate atmospheric oxygen.
  • a serious influenza state includes at least one complication caused by an influenza virus infection.
  • the complications resulting from an influenza virus infection are one or more of inflammation of the heart, brain, or muscle tissue, as well as multiple organ failure.
  • complications resulting from influenza virus infections include pneumonia, central nervous system disorders, myitis, rhabdomyolysis, encephalitis, encephalopathy, severe dehydration myocarditis, pericarditis, otitis media, sinusitis, One or more of exacerbations of ischemic heart disease, septicemia, acute lung injury, or acute respiratory urgency syndrome, and acute exacerbations of chronic renal or respiratory disease, such as asthma or chronic obstructive pulmonary disease.
  • Test Example 1 Bacterial mixed infection mouse model for evaluation of efficacy by combined administration of the compound represented by the formula (I) and baloxavir (1)
  • Materials and methods (1.1) Compound DP1 antagonist Formula (I) The compounds indicated by are described in Shionogi & Co. , Ltd. Synthesized in (Osaka, Japan) (References: WO2007 / 037187, WO2008 / 123349, WO2013 / 147118).
  • Baloxavir marboxil (BXA) the active form of baloxavir marboxil, is described by Shionogi & Co., Ltd. , Ltd. Synthesized in (Osaka, Japan).
  • the compound suspension and BXA suspension represented by the formula (I) were prepared using a 0.5% methylcellulose 400 (MC) solution. The dose was 0.2 mL per mouse.
  • MC methylcellulose 400
  • mice When body weight was reduced to less than 70% compared to before virus infection, mice were immediately euthanized according to humane endpoints and considered dead in survival analysis. During viral and bacterial inoculation, mice were administered intramuscularly with 100 ⁇ L of anesthetic solution containing 0.03 mg / mL medetomidine hydrochloride, 0.4 mg / mL midazolam, and 0.5 mg / mL butorphanol tartrate in physiological saline. I was anesthetized.
  • mice were nasally inoculated with 100 ⁇ L of A / Osaka / 129/2009 (mouse acclimatized strain, 1.00 ⁇ 10 3 TCID 50 ) under anesthesia.
  • the mice were nasally inoculated with 100 ⁇ L of Streptococcus pneumoniae SR1326 (mouse-conditioned strain, 1.00 ⁇ 105 CFU) under anesthesia.
  • Test Example 2 Influenza A virus-infected mouse model for efficacy evaluation by combined administration of the compound represented by the formula (I) and BXA
  • Materials and methods (1.1) Compound DP1 antagonist formula (I) ) Is a compound represented by Shionogi & Co. , Ltd. Synthesized in (Osaka, Japan) (References: WO2007 / 037187, WO2008 / 123349, WO2013 / 147118).
  • BXA the active form of baloxavir marboxil, is described in Shionogi & Co., Ltd. , Ltd. Synthesized in (Osaka, Japan).
  • the compound suspension and BXA suspension represented by the formula (I) were prepared using a 0.5% MC solution.
  • Virus A / PR / 8/34 strain which is a seasonal influenza virus laboratory strain of type A H1N1 subtype, was used.
  • Animal 6-week-old male C57BL / 6J mice (Charles River Laboratories Japan, Inc.) in the absence of specific pathogens were used in this study. Body weight and survival were monitored once daily. When body weight was reduced to less than 70% compared to before virus infection, mice were immediately euthanized according to humane endpoints and considered dead in survival analysis.
  • mice Upon virus inoculation, mice were anesthetized by intramuscular administration of 100 ⁇ L of anesthetic solution containing 0.03 mg / mL medetomidine hydrochloride, 0.4 mg / mL midazolam, and 0.5 mg / mL butorphanol tartrate in physiological saline.
  • the compound was orally administered, or BXA at a dose of 1 mg / kg (single dose) was administered subcutaneously.
  • mice were treated with both subcutaneous doses of BXA (FIG. 3).
  • Control mice were orally administered a 0.5% MC solution (administered twice daily for 8 days).
  • the survival rate and body weight of the mice were examined once a day until the 14th day after the virus infection.
  • mice were administered 3 mg / kg or 30 mg / kg twice daily for 8-9 days.
  • the present inventors have compared the time course of plasma concentration of mice subcutaneously injected with a suspension of BXA, which is the active substance thereof, as compared with mice to which baloxavir marboxil (prodrug) was orally administered. I have previously confirmed that it imitates. Therefore, in this study, the BXA suspension was subcutaneously administered to mice. Subcutaneous administration of a 10 mg / kg BXA suspension to mice can maintain the BXA plasma concentration as seen in humans, but in this mouse model, a very strong survival of BXA alone at a dose of 10 mg / kg.
  • mice were inoculated with Streptococcus pneumoniae 2 days after viral infection.
  • mice infected with Streptococcus pneumoniae 2 days after influenza A virus infection single administration of either the compound represented by the formula (I) or BXA was not effective, but the compound represented by the formula (I) + BXA.
  • Test Example 3 Influenza A virus-infected mouse model for evaluation of efficacy by combined administration of the compound represented by the formula (I) and BXA (intrapulmonary virus inhibitory effect)
  • Materials and Methods (1.1) Compounds The compounds represented by the formula (I), which are DP1 antagonists, are described in Shionogi & Co., Ltd. , Ltd. (Osaka Prefecture, Japan) is used (references: WO2007 / 037187, WO2008 / 123349, WO2013 / 147118).
  • BXA the active form of baloxavir marboxil, is described in Shionogi & Co., Ltd. , Ltd. Use the one synthesized in (Osaka, Japan).
  • the compound suspension and BXA suspension represented by the formula (I) are prepared using a 0.5% MC solution.
  • the dosing volume is 0.2 mL per mouse.
  • Virus A type H1N1 subtype seasonal influenza virus (laboratory strain or clinical isolate) is used. If the virus strain is difficult to infect and propagate in mice, the virus acclimatized to mice is used as the inoculum virus.
  • Animal C57BL / 6J mice or BALB / c mice in the absence of specific pathogens are used in this study. If the body weight is reduced to less than 70% compared to before the virus infection, the mice are immediately euthanized according to humane endpoints.
  • mice are nasally inoculated with 100 ⁇ L of virus preparation solution under anesthesia. Starting from before or after virus infection, mice are orally administered with the compound represented by the formula (I) at a dose of 3 to 30 mg / kg (once a day or twice a day), or 0.1 to 0.1. BXA at a dose of 1 mg / kg (single dose) is administered subcutaneously. To investigate the effect of combination therapy with these compounds, oral administration of the compound represented by the formula (I) and 0.1 to 1 mg / kg at a dose of 3 to 30 mg / kg (once a day or twice a day). Mice are treated with both subcutaneous doses of BXA in kg (single dose) doses.
  • Control mice are orally administered with a 0.5% MC solution (once daily or twice daily).
  • the administration period is about 1 to 10 days.
  • the number of cases in each group is about 3 to 10, and the lung virus titer for a period of about 1 to 10 days after virus infection is examined.
  • compositions are merely examples and are not intended to limit the scope of the invention.
  • Suspension Agent For example, water for injection was added to the drug substance of the compound represented by the formula (I) to prepare a suspension agent.
  • Tablets For example, lactose and magnesium stearate were added as additives to the drug substance of the compound represented by the formula (I) to form tablets.
  • the pharmaceutical agent for treating viral airway infections of the present invention comprises a compound represented by the formula (I) of the active ingredient or a pharmaceutically acceptable salt thereof in combination with a cap-dependent endonuclease inhibitor for influenza virus infection. It is considered to show excellent therapeutic effect against influenza virus infection in subjects with severe influenza status.

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Abstract

L'invention concerne une composition pharmaceutique pour le traitement d'une infection virale des voies respiratoires, caractérisée par la combinaison d'un composé représenté par la formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci et d'un inhibiteur d'endonucléase dépendante de la coiffe.
PCT/JP2021/048473 2020-12-28 2021-12-27 Produit pharmaceutique pour le traitement d'infection virale des voies respiratoires comprenant un antagoniste de dp1 et un inhibiteur d'endonucléase dépendante de la coiffe WO2022145405A1 (fr)

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JP2020219007A JP2024054430A (ja) 2020-12-28 2020-12-28 Ｄｐ１アンタゴニストおよびキャップ依存性エンドヌクレアーゼ阻害剤からなるウイルス性気道感染症治療用医薬

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Citations (6)

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WO2007037187A1 (fr) * 2005-09-27 2007-04-05 Shionogi & Co., Ltd. Dérivé sulfonamide ayant une activité antagoniste de récepteur pgd2
WO2013047725A1 (fr) * 2011-09-29 2013-04-04 塩野義製薬株式会社 Produit pharmaceutique thérapeutique contre la rhinite allergique comportant un antagoniste de pgd2 et un antagoniste d'histamine
JP2013177351A (ja) * 2012-02-29 2013-09-09 Shionogi & Co Ltd Ｐｇｄ２拮抗剤及びロイコトリエン拮抗剤からなる喘息治療剤
WO2016006621A1 (fr) * 2014-07-09 2016-01-14 塩野義製薬株式会社 Médicament contenant un antagoniste de pgd2 pour le traitement des symptômes associés aux maladies allergiques
WO2016175224A1 (fr) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci
WO2017104691A1 (fr) * 2015-12-15 2017-06-22 塩野義製薬株式会社 Médicament pour traiter la grippe caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'endonucléase coiffe-dépendante avec un médicament antigrippal

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Publication number Priority date Publication date Assignee Title
WO2007037187A1 (fr) * 2005-09-27 2007-04-05 Shionogi & Co., Ltd. Dérivé sulfonamide ayant une activité antagoniste de récepteur pgd2
WO2013047725A1 (fr) * 2011-09-29 2013-04-04 塩野義製薬株式会社 Produit pharmaceutique thérapeutique contre la rhinite allergique comportant un antagoniste de pgd2 et un antagoniste d'histamine
JP2013177351A (ja) * 2012-02-29 2013-09-09 Shionogi & Co Ltd Ｐｇｄ２拮抗剤及びロイコトリエン拮抗剤からなる喘息治療剤
WO2016006621A1 (fr) * 2014-07-09 2016-01-14 塩野義製薬株式会社 Médicament contenant un antagoniste de pgd2 pour le traitement des symptômes associés aux maladies allergiques
WO2016175224A1 (fr) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci
WO2017104691A1 (fr) * 2015-12-15 2017-06-22 塩野義製薬株式会社 Médicament pour traiter la grippe caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'endonucléase coiffe-dépendante avec un médicament antigrippal

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KAWAI MAKOTO: "Discovery of an Anti-influenza Agent with a Novel Mechanism", MEDCHEM NEWS, JP, vol. 29, no. 2, 1 May 2019 (2019-05-01), JP, pages 75 - 81, XP055948573, ISSN: 2432-8618, DOI: 10.14894/medchem.29.2_75 *
SUNAGAWA, SATOKO; FUJITA, JIRO; NAKAMURA, KATSUNORI: "Anti-Influenza Agents Available in Japan and Pharmacological Properties Thereof", FARUMASHIA, vol. 55, no. 12, 1 December 2019 (2019-12-01), JP , pages 1116 - 1119, XP009537994, ISSN: 0014-8601, DOI: 10.14894/faruawpsj.55.12_1116 *

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