WO2022145405A1

WO2022145405A1 - Pharmaceutical for treatment of viral respiratory tract infection comprising dp1 antagonist and cap-dependent endonuclease inhibitor

Info

Publication number: WO2022145405A1
Application number: PCT/JP2021/048473
Authority: WO
Inventors: 聡一東福寺; 圭太深尾; 伸治日下部
Original assignee: 塩野義製薬株式会社
Priority date: 2020-12-28
Filing date: 2021-12-27
Publication date: 2022-07-07
Also published as: TW202241431A; JP2024054430A

Abstract

Provided is pharmaceutical composition for treating a viral respiratory tract infection, characterized by combining a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a cap-dependent endonuclease inhibitor.

Description

A drug for the treatment of viral respiratory tract infections consisting of a DP1 antagonist and a cap-dependent endonuclease inhibitor.

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.).
For example, 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).
The applicant also reports that the compound represented by the formula (I) exhibits high affinity and selectivity for the DP1 receptor in the binding test. In an animal model of allergic rhinitis, 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).

Furthermore, it has been suggested that PGD2 is involved in the regulation of immune and inflammatory responses to specific viral infections. For example, 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. , It has been shown that the inflammatory response of lung tissue is suppressed (Non-Patent Document 2). In addition, in a mouse hepatitis virus infection model, 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).

On the other hand, in aged mice, 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), neurominidase (NA) inhibitors (ie, oseltamivir, zanamivir, peramivir and laninavir), and cap dependence Sexual endonuclease (CEN) inhibitors (baloxavir marboxil) are currently available for the treatment of uncomplicated acute influenza virus infections in various countries.
As cap-dependent endonucleases, GP-681 Phase I trials and TG-1000 Phase I trials are under clinical trials.

Both seasonal and pandemic influenza virus infections are serious health problems, and in critical clinical cases, mixed infections with bacteria (eg, pneumococcal) after influenza virus infection can cause severe pneumonia or lethality. It is considered to be one of the decisive causes of the virus (Non-Patent Document 6). However, no antiviral drug has been shown to decisively reduce hospitalization or mortality in randomized clinical trials. In addition, as a symptomatic treatment for the aggravation of influenza, treatment with host-targeted drugs such as steroids has been attempted, but there is no clinically established therapeutic drug. Therefore, there is an urgent need for new influenza drugs that are more effective than current therapies.

International Publication No. 2007/037187

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.

As a result of repeated studies to solve the above problems, the present inventors have found that a specific compound (Compound II-74) among the PGD2 receptor antagonists described in Patent Document 1 and a specific cap-dependent endonuclease inhibition. We have newly found that the mortality rate of mice is reduced by combining them with the agents as compared with the case where they are administered alone, and have completed the present invention.

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).
(1) Equation (I):

A pharmaceutical composition for treating a viral respiratory tract infection, characterized in combination with a compound represented by, or a pharmaceutically acceptable salt thereof, and a cap-dependent endonuclease inhibitor.
(2) 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 pharmaceutical composition described.
(3) 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 pharmaceutical composition according to item (1) or (2).
(4) The pharmaceutical composition according to any one of the above items (1) to (3), wherein the viral airway infection is an infection caused by influenza A virus or influenza B virus.
(5) The above items (1) to (5) the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV). The pharmaceutical composition according to any one of 3).
(6) The pharmaceutical composition according to any one of the above items (1) to (5), wherein the viral airway infection is an infectious disease accompanied by double infection and / or secondary infection of bacteria at the time of viral infection.
(7) The pharmaceutical composition according to any one of the above items (1) to (6), which is an orally administered agent.
(8) The pharmaceutical composition according to any one of the above items (1) to (7), which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(8-a) The pharmaceutical composition according to any one of the above items (1) to (7), which comprises 50 mg to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(8-b) The pharmaceutical composition according to any one of the above items (1) to (7), which contains 50 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(8-c) The pharmaceutical composition according to any one of the above items (1) to (7), which contains 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(8-d) The pharmaceutical composition according to any one of the above items (1) to (7), which comprises 150 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(8-e) The pharmaceutical composition according to any one of the above items (1) to (7), which contains 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(9) Formula (I) for use in combination with a cap-dependent endonuclease inhibitor:

A pharmaceutical composition comprising the compound indicated by or a pharmaceutically acceptable salt.
(10) 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 pharmaceutical composition according to the above item (9), which is at least one compound selected from the group consisting of AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof, or a solvate thereof. thing.
Equation (11):

A cap-dependent endonuclease inhibitor for use with the compounds indicated by or pharmaceutically acceptable salts.
Equation (12): (I):

Baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-036, H-015, ZX-7101A, for use in combination with the compounds indicated by or pharmaceutically acceptable salts. Includes at least one compound selected from the group consisting of IFV-PA, KYAH01-2019-121, AV-5124, AV-5116 and NX-2016, or pharmaceutically acceptable salts thereof, or solvates thereof. Pharmaceutical composition.
Equation (13): (I):

With the compound indicated by, or its pharmaceutically acceptable salt,
A combination drug for the treatment of viral respiratory tract infections, including a cap-dependent endonuclease inhibitor.
(14) 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 (13), 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 described mixture.
(15) 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 mixture according to item (13) or (14).
(16) The mixture according to any one of the above items (13) to (15), wherein the viral airway infection is an influenza A virus or an influenza B virus infection.
(17) The above items (13) to (17), wherein the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV). The mixture according to any one of 15).
(18) The combination according to any one of the above items (13) to (17), wherein the viral airway infection is an infectious disease accompanied by double infection and / or secondary infection of bacteria at the time of viral infection.
(19) The combination drug according to any one of the above items (13) to (18), which is an orally administered agent.
(20) The combination drug according to any one of the above items (13) to (19), which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(20-a) The combination according to any one of the above items (13) to (19), which comprises 50 mg to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(20-b) The combination according to any one of the above items (13) to (19), which comprises 50 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(20-c) The combination according to any one of the above items (13) to (19), which comprises 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(20-d) The combination according to any one of the above items (13) to (19), which comprises 150 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(20-e) The combination according to any one of the above items (13) to (19), which comprises 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
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.
(22) 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 therapeutic method according to the above item (21), which is at least one compound selected from the group consisting of AV-5124, AV-5116 and NX-2016, or a pharmaceutically acceptable salt thereof, or a solvate thereof. ..
(23) 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 treatment method according to item (21) or (22).
(24) The treatment method according to any one of the above items (21) to (23), wherein the viral airway infection is an influenza A virus or an influenza B virus infection.
(25) The above items (21) to (25), wherein the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV). The treatment method according to any one of 23).
(26) The treatment method according to any one of the above items (21) to (25), wherein the viral airway infection is an infectious disease accompanied by double infection and / or secondary infection of bacteria at the time of viral infection.
(27) The treatment method according to any one of the above items (21) to (26), which is an orally administered agent.
(28) The therapeutic method according to any one of the above items (21) to (27), which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(28-a) The therapeutic method according to any one of the above items (21) to (27), which comprises 50 mg to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(28-b) The therapeutic method according to any one of the above items (21) to (27), which comprises 50 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(28-c) The therapeutic method according to any one of the above items (21) to (27), which comprises 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(28-d) The therapeutic method according to any one of the above items (21) to (27), which comprises 150 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(28-e) The therapeutic method according to any one of the above items (21) to (27), which comprises 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(29) Use of a pharmaceutical composition for producing a pharmaceutical for treating a viral respiratory tract infection, wherein the composition is of formula (I) :.

Use, which is a combination of the compound indicated by, or a pharmaceutically acceptable salt thereof, and a cap-dependent endonuclease inhibitor.
(30) 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 (29), 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. ) Use of description.
(31) 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. Use of item (29) or (30).
(32) The use according to any one of the above items (29) to (31), wherein the viral airway infection is an influenza A virus or an influenza B virus infection.
(33) The above items (29) to (33), wherein the viral airway infection is an infection caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS coronavirus (MERS-CoV). 32) Use according to any one of.
(34) The use according to any one of the above items (29) to (33), wherein the viral airway infection is an infectious disease accompanied by coinfection and / or secondary infection of bacteria at the time of viral infection.
(35) The use according to any one of the above items (29) to (34), which is an orally administered agent.
(36) The use according to any one of the above items (29) to (35), which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(36-a) The use according to any one of the above items (29) to (35), which comprises 50 mg to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(36-b) The use according to any one of the above items (29) to (35), which comprises 50 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(36-c) The use according to any one of the above items (29) to (35), which comprises 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(36-d) The use according to any one of the above items (29) to (35), which comprises 150 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(36-e) The use according to any one of the above items (29) to (35), which comprises 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

(37) 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.
(38) 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.
(39) 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 medicine according to item (37) or (38).
(40) The drug according to any one of the above items (37) to (39), wherein the viral airway infection is an infection caused by influenza A virus or influenza B virus.
(41) 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). 39) The pharmaceutical according to any one of.
(42) The drug according to any one of the above items (37) to (41), wherein the viral airway infection is an infectious disease accompanied by coinfection and / or secondary infection of bacteria at the time of viral infection.
(43) The drug according to any one of the above items (37) to (42), which is an orally administered agent.
(44) The drug according to any one of the above items (37) to (43), which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(44-a) The drug according to any one of the above items (37) to (43), which comprises 50 mg to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(44-b) The pharmaceutical according to any one of the above items (37) to (43), which comprises 50 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(44-c) The drug according to any one of the above items (37) to (43), which comprises 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(44-d) The pharmaceutical according to any one of the above items (37) to (43), which comprises 150 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(44-e) The pharmaceutical according to any one of the above items (37) to (43), which comprises 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

Equation (45): (I):

A pharmaceutical preparation for treating a viral respiratory tract infection, which is a single dosage form or a separate dosage form, which comprises a compound represented by the above, or a pharmaceutically acceptable salt thereof, and a cap-dependent endonuclease inhibitor.
(46) 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 pharmaceutical product described.
(47) 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 pharmaceutical preparation according to item (45) or (46).
(48) The pharmaceutical preparation according to any one of the above items (45) to (47), wherein the viral airway infection is an influenza A virus or an influenza B virus infection.
(49) 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). 47) 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.
(51) The pharmaceutical preparation according to any one of the above items (45) to (50), which is an orally administered agent.
(52) 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.
(52-b) The pharmaceutical preparation according to any one of the above items (45) to (51), which comprises 50 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(52-c) The pharmaceutical preparation according to any one of the above items (45) to (51), which comprises 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(52-d) The pharmaceutical preparation according to any one of the above items (45) to (51), which comprises 150 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(52-e) The pharmaceutical preparation according to any one of the above items (45) to (51), which comprises 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

As one embodiment, 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. And the pharmaceutical composition according to (12).
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. ..

It is a graph of the experimental result which shows the therapeutic effect of administration of compound (I) with respect to the lethal mixed infection of influenza A virus (inoculation: day 0) and Streptococcus pneumoniae (inoculation: day 2) in a mouse. It is a graph of the experimental result which shows the therapeutic effect of administration of compound (I) with respect to the lethal infection of influenza A virus in a mouse. It is a graph of the experimental result which shows the therapeutic effect of administration of compound (I) with respect to the lethal infection of influenza A virus in a mouse.

The term "consisting of" means having only constituent requirements. The term "contains" is not limited to the constituents and means does not exclude elements not described.

Hereinafter, the present invention will be described with reference to embodiments. Throughout the specification, it should be understood that the singular representation also includes its plural concept, unless otherwise noted. Therefore, it should be understood that singular articles (eg, "a", "an", "the", etc. in English) also include the plural concept, unless otherwise noted.
It should also be understood that the terms used herein are used in the sense commonly used in the art of the invention, unless otherwise noted. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, this specification (including definitions) takes precedence.

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.
In the present specification, 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. In addition, 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.

(A) PGD2 receptor antagonist The 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.

(B) Cap-Dependent Endonuclease Inhibitor Examples of the cap-dependent endonuclease inhibitor used in the present invention 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.

Examples of L-742001 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.

Examples of H-015 include the compound described in CN111233891.

As AV-5124, for example, J. Antimiclob. Chemother. , 2021,76, No. Examples include the compounds described in 4, 1010-8.

As AV-5116, for example, J. Antimiclob. Chemother. , 2021,76, No. Examples include the compounds described in 4, 1010-8.

Examples of NX-2016 include the compounds described in CN112174956, CN1113578773, and CN112174955.

As the cap-dependent endonuclease inhibitor, the compounds described in the following documents can be used.
ＷＯ２０１７２２３２３１、ＷＯ２０１８０４２３０３、ＷＯ２０１４０４３２５２、ＷＯ２０１７０７２３４１、ＷＯ２０１５０３８６６０、ＷＯ２０１６００５３３１、ＷＯ２０１７１０９０８８、ＷＯ２０１７１５６１９４、ＷＯ２０１７１５３９５０、ＷＯ２０１７１５３９１９、ＷＯ２０１７１５８１５１、ＷＯ２０１７１５８１４７、ＷＯ２０１４１０８４０８、ＷＯ２０１３１７４９３０、ＷＯ２０１３１７４９３１、ＷＯ２０１６００５３３０、ＷＯ２０１７０４６３６２、ＷＯ２０１７０４６３１８、ＷＯ２０１９０５２５６５、ＷＯ２０１９１９６８９１、ＣＮ１０９５０３６２５、ＣＮ１１０３１７２１１、ＷＯ２０２００７８４０１、ＣＮ１１１３７７９４４、ＣＮ１１１４１０６６１、 WO2010226532, J. Mol. Med. Chem. 2020 63 9403-9420, WO201010231, WO2010147068, WO2012039414, WO2016175224, JP2017-137291, JP2019-059697, GB2280435, US2013090300, WO201307251, WO2014023791, WO2014074926, WO2014108406 WO201777715. 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.

These cap-dependent endonuclease inhibitors may be synthesized according to known methods or commercially available products may be used.

As used herein, 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.), and 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, ethanesulfonic acid, trifluoroacetic acid, etc.) And salt can be mentioned. These salts can be formed by conventional methods.

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). When the component (A) or the component (B) is left in the atmosphere, it may absorb water and adsorbed water may adhere to it or form a hydrate.

As the "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.
In addition, 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. Examples of the parenteral administration method include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, instillation, ear instillation, and intravaginal administration.

For oral administration, follow the conventional method for internal solid preparations (eg tablets, powders, granules, capsules, rounds, film preparations, etc.), internal liquid preparations (eg suspensions, emulsions, elixirs, syrups, etc.). It may be prepared and administered in any of the commonly used dosage forms such as an agent, a limonade agent, a liquor agent, an aromatic water agent, an extract agent, a decoction agent, a tincture agent, 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.

In the case of parenteral administration, 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.

Specific examples of the dosage form of the pharmaceutical product comprising the above-mentioned component (A) and the above-mentioned component (B) of the present invention include the following.
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).

Various medicinal additives 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. Further, 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. For example, 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. For example, 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. As the usage mode, a mode in which a single agent separately prepared for each of the component (A) and (B) is used at the same time, and a single agent separately prepared for each of the component (A) and the component (B) are separately used. Examples thereof include a mode in which the component (A) and the component (B) are formulated together and used as a preparation (mixture) prepared by prescribing the component (A) and the component (B) together.

When used as a therapeutic agent for influenza virus infection in a subject having an influenza virus infection and a serious influenza state of the present invention, 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. For example, when 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.

In the present specification, "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. Provided are 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.

Further, in the present specification, 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.

In the present specification, 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.

In the present specification, the symptoms caused by influenza virus include at least one respiratory symptom, and one or more of cough, sore throat, and nasal congestion.

In the present specification, 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.

In the present specification, a serious influenza condition includes a condition requiring respiratory assistance. As an example, 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.

In the present specification, a serious influenza state includes at least one complication caused by an influenza virus infection. As an example, 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. As one example, 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.

Hereinafter, the present invention will be described based on examples, but the present invention is not limited to these examples.

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.
(1.2) Viruses and Fungi A / Osaka / 129/2009 strains of influenza virus and SR1326 strain of Streptococcus pneumoniae, which were clinically isolated in Japan, were acclimated to mice.
(1.3) Animal A 6-week-old female BALB / c mouse (Charles River Laboratories Japan, Inc.) in the absence of a specific pathogen was 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. During viral and bacterial inoculation, mice were administered intramuscularly with 100 μL 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.

(2) Verification of antiviral effect in mouse model Mice were nasally inoculated with 100 μL of A / Osaka / 129/2009 (mouse acclimatized strain, 1.00 × 10 ³ TCID ₅₀ ) under anesthesia. On the second day after virus infection, the mice were nasally inoculated with 100 μL of Streptococcus pneumoniae ^SR1326 (mouse-conditioned strain, 1.00 × 105 CFU) under anesthesia. Starting from the second day after virus infection, mice (n = 9 to 10 / group) were orally administered with the compound represented by the formula (I) at a dose of 30 mg / kg (administered twice a day for 9 days). , Or a dose of 0.2 mg / kg (single dose) of BXA was administered subcutaneously. To investigate the effect of combination therapy with these compounds, oral administration and 0.2 mg / kg (single dose) of the compound represented by the formula (I) at a dose of 30 mg / kg (twice daily for 9 days). ) Was treated with both subcutaneous doses of BXA. Control mice were subcutaneously administered with a 0.5% MC solution (single dose). The survival rate and body weight of the mice were examined once a day until the 14th day after the virus infection.

(3) Statistical analysis The difference in survival time after virus infection between groups was analyzed by logrank test. Statistical analysis was performed using statistical analysis software SAS version 9.4 (SAS Institute, Cary, NC, USA). Adjusted bilateral P-values below 0.05 were considered statistically significant.

(4) Result Effect of combined administration of the compound represented by the formula (I) and BXA The effect of the combined administration of the compound represented by the formula (I) and BXA was performed using a lethal mixed-infected mouse of influenza A virus and Streptococcus pneumoniae. And verified. 20% of vehicle-treated mice inoculated with A / Osaka / 129/2009 (mouse acclimatized strain, 1.00 × 10 ³ TCID ₅₀ ) and Streptococcus pneumoniae SR1326 (mouse acclimatized strain, 1.00 × 10 ⁵ CFU) survived. .. In the case of treatment by single administration of each compound, all the mice treated with the compound represented by the formula (I) died, and 20% of the mice in the BXA treatment group survived (Fig. 1). As a result, no significant effect of prolonging the survival time was observed in the vehicle-administered group in the treatment by the single administration of each compound. In contrast, 60% of the mice treated with the combined administration of the compound represented by the formula (I) and BXA survived, showing a significantly stronger survival time-prolonging effect than the single administration of each. From this result, it is considered that the effect of the combined administration of the compound represented by the formula (I) and BXA is higher than the effect of the single administration of each compound.
From the above, it is suggested that a mouse model of a mixed infection of influenza virus and bacteria may be useful for estimating the effect of the combined administration of the compound represented by the formula (I) and BXA in a serious case.

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 (1) 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. The dose was 0.2 mL per mouse.
(1.2) Virus A / PR / 8/34 strain, which is a seasonal influenza virus laboratory strain of type A H1N1 subtype, was used.
(1.3) 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. Upon virus inoculation, mice were anesthetized by intramuscular administration of 100 μL 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.

(2) Verification of antiviral effect in mouse model Mice were nasally inoculated with 100 μL of A / PR / 8/34 strain (3.00 × 10 ³ TCID ₅₀ ) under anesthesia. It is represented by the formula (I) of a dose of 3 mg / kg or 30 mg / kg (administered twice a day for 8 days) to mice (n = 5 to 10 / group) starting from the 3rd day after virus infection. The compound was orally administered, or BXA at a dose of 1 mg / kg (single dose) was administered subcutaneously. To investigate the effect of combination therapy with these compounds, oral administration of the compound represented by the formula (I) and 1 mg / kg (single) at a dose of 3 mg / kg or 30 mg / kg (administered twice daily for 8 days). Mice were treated with both subcutaneous doses of BXA (dose) (FIG. 2). Similarly, starting from the 3rd day after virus infection, the compound represented by the formula (I) was orally administered to mice (n = 10 / group) at a dose of 30 mg / kg (administered twice a day for 8 days). Alternatively, BXA at a dose of 0.5 mg / kg (single dose) was subcutaneously administered. To investigate the effect of combination therapy with these compounds, oral administration and 0.5 mg / kg (single dose) of the compound represented by the formula (I) at a dose of 30 mg / kg (twice daily for 8 days). 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.

(4) Concomitant effect of the compound represented by the formula (I) and BXA The effect of the combined administration of the compound represented by the formula (I) and BXA was verified using a lethal infected mouse of influenza A virus. In the study shown in FIG. 2, all vehicle-treated mice inoculated with the A / PR / 8/34 strain died by 9 days after virus infection. In the case of treatment by single administration of each compound, 10% of the mice treated with the compound represented by the formula (I) at the doses of 3 mg / kg and 30 mg / kg survived, and 40 mice in the BXA treatment group survived. % Survived (Fig. 2). As a result, a significant effect of prolonging the survival time was observed in the treatment by monoadministration of BXA, but in the treatment by monoadministration of the compound represented by the formula (I), it was in the vehicle administration group. On the other hand, no significant effect of prolonging the survival period was observed. In contrast, 50% and 70% of the mice treated by the combined administration of the compound represented by the formula (I) at the doses of 3 mg / kg and 30 mg / kg and BXA survived, respectively, and the compound represented by the formula (I). The combined administration of BXA and BXA showed a significantly stronger survival-prolonging effect than the single administration of the compound represented by the formula (I).
Next, in the test shown in FIG. 3, 9 out of 10 medium-administered mice inoculated with the A / PR / 8/34 strain died by 9 days after virus infection, and the survival rate was 10%. Met. In the case of treatment by single administration of each compound, 10% of the mice treated with the compound represented by the formula (I) at a dose of 30 mg / kg survived, and 20% of the mice in the BXA treatment group survived (FIG. 3). ). As a result, no significant prolongation effect on survival was observed in the vehicle-administered group in the treatment with BXA or the compound represented by the formula (I) alone. In contrast, 90% of the mice treated with the combination administration of the compound represented by the formula (I) and BXA at a dose of 30 mg / kg survived, and the combination administration treatment of the compound represented by the formula (I) and BXA resulted in survival. It showed a significantly stronger survival time-prolonging effect than the single administration of each compound. From these results, it is considered that the effect of the combined administration of the compound represented by the formula (I) and BXA is higher than the effect of the single administration of each compound.
From the above, it is suggested that the influenza virus-infected mouse model may be useful for estimating the effect of the combined administration of the compound represented by the formula (I) and BXA in a serious case.

Evaluation of mouse survival time by combined administration of the compound represented by the formula (I) and BXA (Test Example 1 and Test Example 2)
In this non-clinical study, we evaluated the effect of combined administration of the compound represented by formula (I) with BXA in a mouse model infected with influenza virus and a mouse model infected with influenza virus and bacteria on the survival time of mice. .. The present inventors have previously confirmed that the compound represented by the formula (I) exhibits the maximum effect based on the DP-1 inhibition mechanism at a dose of 3 to 30 mg / kg in a mouse model of allergic rhinitis. (Non-Patent Document 1). Therefore, in this study, 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. Since it is difficult to detect the effect of concomitant use with other drugs because it shows an effect, the concomitant use of the compound represented by the formula (I) with respect to BXA at a dose of 0.2 mg / kg, 0.5 mg / kg or 1 mg / kg. (WO20200194024, WO20200194042, Fukao et al., J Antimicrov Chemother, 2019: 74: 654-662).
In this study, in addition to the influenza virus infection model, a model that imitates a mixed bacterial infection (a mixed infection model of influenza virus and Streptococcus pneumoniae), which is one of the factors that make influenza more severe in humans, is used. The effect of the combined treatment of the compound shown in (I) and BXA was examined. In humans, mixed bacterial infections occur immediately after viral infection or during viral shedding (Cherto et al., JAMA, 2013: 309 (3): 275-282). We have previously confirmed that lung viral titers reach peak levels within 2 days after inoculating mice with A / Osaka / 129/2009 (mouse conditioned strain) (Onishi et al.). , Inventoral Research 117 (2015) 52-59). Therefore, in this study, mice were inoculated with Streptococcus pneumoniae 2 days after viral infection. In 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. The combined administration of the virus significantly prolonged the survival period and improved the survival rate (p <0.05) with respect to each single administration group or vehicle administration group. These findings support the usefulness of the combination therapy of the compound represented by formula (I) and BXA as a treatment option in patients with severe influenza.

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)
(1) 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.
(1.2) 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.
(1.3) 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.

(2) Verification of antiviral effect in mouse model Mice are nasally inoculated with 100 μL 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.

(3) Statistical analysis The difference between groups of virus titers at the time of each evaluation is analyzed by Dunnett's method or t-test. Statistical analysis is performed using statistical analysis software SAS (SAS Institute, Cary, NC, USA). Adjusted bilateral P-values below 0.05 are considered statistically significant.

Pharmaceutical Examples The following pharmaceutical examples are merely examples and are not intended to limit the scope of the invention.
(Pharmaceutical Example 1) 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.
(Pharmaceutical Example 2) 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.

Claims

Equation (I):

A pharmaceutical composition for treating a viral respiratory tract infection, characterized in combination with a compound represented by, 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, KYAH01-2019- The pharmaceutical composition according to claim 1, which is at least one compound selected from the group consisting of 121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 1 or 2, wherein the viral respiratory tract infection is an infection caused by influenza virus.
The pharmaceutical composition according to any one of claims 1 to 3, wherein the viral airway infection is an infection caused by influenza A virus or influenza B virus.
The pharmaceutical composition according to any one of claims 1 to 4, 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 composition according to any one of claims 1 to 5, which is an orally administered agent.
The pharmaceutical composition according to any one of claims 1 to 6, comprising 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
Formula (I) for use with cap-dependent endonuclease inhibitors:

A pharmaceutical composition comprising the compound indicated by or a pharmaceutically acceptable salt.
Cap-dependent endonuclease inhibitors are baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01-2019- The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is at least one compound selected from the group consisting of 121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
Equation (I):

A cap-dependent endonuclease inhibitor for use with the compounds indicated by or pharmaceutically acceptable salts.
Equation (I):

Baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-036, H-015, ZX-7101A, for use in combination with the compounds indicated by or pharmaceutically acceptable salts. A pharmaceutical composition comprising at least one compound selected from the group consisting of IFV-PA, KYAH01-2019-121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
Equation (I):

With the compound indicated by, or its pharmaceutically acceptable salt,
A combination drug for the treatment of viral respiratory tract infections, including 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, KYAH01-2019- 12. The combination according to claim 12, which is at least one compound selected from the group consisting of 121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
The combination according to claim 12 or 13, wherein the viral respiratory tract infection is an infection caused by influenza virus.
The combination according to any one of claims 12 to 14, wherein the viral airway infection is an influenza A virus or an influenza B virus infection.
The combination according to any one of claims 12 to 15, wherein the viral airway infection is an infectious disease associated with double infection and / or secondary infection of bacteria at the time of viral infection.
The combination drug according to any one of claims 12 to 16, which is an orally administered agent.
The combination according to any one of claims 12 to 17, comprising 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
Equation (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 baloxavir marboxil, GP-681, TG-1000, L-742001, AL-794, KW-066, H-015, ZX-7101A, IFV-PA, KYAH01-2019- 19. The therapeutic method of claim 19, wherein at least one compound selected from the group consisting of 121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
The treatment method according to claim 19 or 20, wherein the viral respiratory tract infection is an infection caused by influenza virus.
The treatment method according to any one of claims 19 to 21, wherein the viral airway infection is an infection caused by influenza A virus or influenza B virus.
The treatment method according to any one of claims 19 to 22, wherein the viral airway infection is an infection accompanied by coinfection and / or secondary infection of bacteria at the time of viral infection.
The treatment method according to any one of claims 19 to 23, which is an orally administered agent.
The therapeutic method according to any one of claims 19 to 24, comprising 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
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, KYAH01-2019- 26. The pharmaceutical agent of claim 26, which is at least one compound selected from the group consisting of 121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
The medicine according to claim 26 or 27, wherein the viral respiratory tract infection is an infection caused by influenza virus.
The medicine according to any one of claims 26 to 28, wherein the viral airway infection is an infection caused by influenza A virus or influenza B virus.
The pharmaceutical according to any one of claims 26 to 29, 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 medicine according to any one of claims 26 to 30, which is an orally administered agent.
The pharmaceutical according to any one of claims 26 to 31, which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
Equation (I):

A pharmaceutical preparation for treating a viral respiratory tract infection, which is a single dosage form or a separate dosage form, comprising the compound indicated by, 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, KYAH01-2019- 33. The pharmaceutical preparation according to claim 33, which is at least one compound selected from the group consisting of 121, AV-5124, AV-5116 and NX-2016 or a pharmaceutically acceptable salt thereof.
The pharmaceutical preparation according to claim 33 or 34, wherein the viral respiratory tract infection is an infection caused by influenza virus.
The pharmaceutical preparation according to any one of claims 33 to 35, wherein the viral airway infection is an infection caused by influenza A virus or influenza B virus.
The pharmaceutical preparation according to any one of claims 33 to 36, wherein the viral airway infection is an infection accompanied by coinfection and / or secondary infection of bacteria at the time of viral infection.
The pharmaceutical preparation according to any one of claims 33 to 37, which is an orally administered agent.
The pharmaceutical preparation according to any one of claims 33 to 38, which comprises 50 mg to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.