TW202241430A - A medicament for treating viral respiratory tract infection comprising dp1 antagonist and neuraminidase inhibitor - Google Patents

Abstract

Provided is a pharmaceutical composition for treating viral respiratory tract infection comprising combination of a compound represented by Formula (I):

Description

Medicine for treating viral respiratory tract infection comprising DP1 antagonist and neuraminidase inhibitor

The invention relates to a medicine for treating viral respiratory tract infection. More specifically, the present invention relates to a medicine for treating influenza virus infection and influenza virus infection of subjects with severe influenza state, which is characterized in that it combines a DP1 antagonist and neuraminidase Inhibitors.

It is known that prostaglandin D2 (PGD2), a product of the cyclooxygenase circuit of arachidonic acid metabolism, has a strong bronchoconstriction effect, which can induce vascular hyperpermeability or chemotaxis of inflammatory cells such as eosinophils, so the PGD2 receptor Antagonists are useful in the treatment of allergic diseases (eg, asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, etc.). For example, the applicant of the present application reported a sulfonamide derivative having antagonist activity on DP receptor which is one of PGD2 receptors as a therapeutic agent for allergic diseases (Patent Document 1). In addition, the applicant of the present case reported that the compound represented by formula (I) showed high affinity and selectivity for DP1 receptor in the binding test. It has been reported that in animal models of allergic rhinitis, this agent significantly inhibits antigen-induced nasal resistance, nasal mucus, and cell infiltration of nasal mucosa, and furthermore, the compound represented by formula (I) inhibits asthma caused by antigen exposure Response, respiratory allergic reactivity, cell infiltration and mucin production in the lung (Non-Patent Document 1).

Furthermore, it is suggested that PGD2 is related to the regulation of immune and inflammatory responses to specific viral infections. For example, the concentration of PGD2 in the upper respiratory tract of infants hospitalized due to bronchitis accompanied by RS (Respiratory Syncytial, respiratory fusion) virus infection increased, and it was shown in a mouse model of RS virus infection that by administering a DP1 receptor agonist Or a DP2 receptor antagonist, which can promote virus clearance and inhibit the inflammatory response of lung tissue (Non-Patent Document 2). In addition, it has been reported that in a mouse hepatitis virus infection model, PGD2 regulates the overactivation of inflammasome, suggesting that prostaglandin signaling is related to the regulation of the optimal immune response set point (non-patent literature 3 ).

On the other hand, it has been reported that in aged mice, the concentration of PGD2 in BALF (Bronchoalveolar lavage fluid, bronchoalveolar lavage fluid) increases compared with young mice, followed by induction of dendritic cells after virus infection and The ensuing virus-specific adaptive immune response is reduced. According to the report, the adaptive immune response to viral infection can be improved by administering an antagonist of the DP1 receptor, so by blocking the PGD2 signal mediated by the DP1 receptor, the adaptive immune response accompanying aging The reduction of the protective effect (Non-Patent Document 4).

Influenza is an acute respiratory infection caused by viruses of the Orthomyxoviridae family. Humans are known to be infected with two types of influenza A virus and influenza B virus. After an incubation period of 1 to 4 days, these viruses can cause acute febrile infection of the respiratory tract characterized by severe fever, cough, fatigue, headache, and/or muscle pain. It is considered that the annual influenza pandemic causes 3 to 5 million severe cases and 250,000 to 500,000 deaths worldwide each year (WHO (World Health Organization, World Health Organization) 2017).

Influenza is generally a disease that can be cured as long as it is a healthy adult, but the disease is associated with a higher attack rate and occasionally a higher mortality rate in children, elderly patients, and immunocompromised patients. Hospitalization due to a severe influenza state is likely to result in high mortality (4%-8%), admission to the Intensive Care Unit (ICU) (5%-17%), and long-term hospitalization of 5-9 days. During the epidemic season, up to 34% of patients need ICU care, and the mortality rate is as high as 15%, etc., and the result may become more serious (non-patent document 5). Anti-influenza virus drugs, namely M2 ion channel inhibitors (such as amantadine and rimantadine), RNA (Ribonucleic Acid, ribonucleic acid) polymerase inhibitors (such as favipiravir), neuraminidase (NA ) inhibitors (ie, oseltamivir, zanamivir, peramivir, and laninamivir), and cap-dependent endonuclease inhibitors (baloxavir mapoxil) are currently available in various countries for Treatment of uncomplicated acute influenza virus infection.

Both seasonal and pandemic influenza virus infections are major health problems. It is believed that in severe clinical cases, the mixed infection of bacteria (such as pneumococcus) after influenza virus infection is the decisive factor for severe pneumonia or death One of the reasons (Non-Patent Document 6). However, no antiviral drug has been shown to conclusively reduce hospitalization or mortality in randomized clinical trials. Also, as a symptomatic treatment for severe influenza, the industry is trying to treat it with host-targeted drugs represented by steroids, but there are no clinically proven therapeutic drugs. Therefore, there is an urgent need for novel influenza therapeutics that demonstrate effectiveness beyond current treatments. [Prior Art Literature] [Patent Document]

[Patent Document 1] International Publication No. 2007/037187 [Non-patent literature]

[Non-Patent Document 1] European Journal of Pharmacology. Volume 765, 2015, pages 15-23 [Non-Patent Document 2] Science Translational Medicine. Volume 10, 2018, eaao0052 [Non-Patent Document 3] PNAS. Volume 114, 2017, pages E5444-53 [Non-Patent Document 4] The Journal of Clinical Investigation. Volume 121, 2011, pages 4921-30 [Non-Patent Document 5] Antiviral Therapy. Volume 17, 2012, pages 143-57 [Non-Patent Document 6] Journal of Infectious Diseases. Volume 16, 2012, pages e321～e331

[Problem to be solved by the invention]

The subject of the present invention is to provide a pharmaceutical composition for treating influenza virus infection and influenza virus in subjects with severe influenza status by combining a DP1 antagonist and a neuraminidase inhibitor infectious disease. [Technical means to solve the problem]

The inventors of the present invention have made repeated studies in order to solve the above-mentioned problems, and as a result, have newly found that by combining a specific compound (compound II-74) among the PGD2 receptor antagonists described in Patent Document 1 with a specific neuraminidase inhibitor , Compared with the case of administering each alone, the death rate of mice was reduced, thereby completing the present invention.

(2)如上述項目(1)所記載之醫藥組合物，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 (3)如上述項目(1)或(2)所記載之醫藥組合物，其中病毒性呼吸道感染症係由選自流行性感冒病毒、冠狀病毒、RS(Respiratory Syncytial，呼吸道融合)病毒、副流行性感冒病毒、腺病毒、鼻病毒、波卡病毒及間質肺炎病毒中之至少一種病毒所引起之感染症。 (4)如上述項目(1)至(3)中任一項所記載之醫藥組合物，其中病毒性呼吸道感染症係由A型流行性感冒病毒或B型流行性感冒病毒所引起之感染症。 (5)如上述項目(1)至(3)中任一項所記載之醫藥組合物，其中病毒性呼吸道感染症係由SARS(Severe Acute Respiratory Syndrome，嚴重急性呼吸道症候群)冠狀病毒(SARS-CoV)、SARS冠狀病毒2(SARS-CoV2)或MERS(Middle East Respiratory Syndrome，中東呼吸道症候群)冠狀病毒(MERS-CoV)所引起之感染症。 (6)如上述項目(1)至(5)中任一項所記載之醫藥組合物，其中病毒性呼吸道感染症係伴有病毒感染時之細菌之重複感染及/或二次感染之感染症。 (7)如上述項目(1)至(6)中任一項所記載之醫藥組合物，其為經口投予劑。 (8)如上述項目(1)至(7)中任一項所記載之醫藥組合物，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～200 mg。 (8-a)如上述項目(1)至(7)中任一項所記載之醫藥組合物，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～100 mg。 (8-b)如上述項目(1)至(7)中任一項所記載之醫藥組合物，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg。 (8-c)如上述項目(1)至(7)中任一項所記載之醫藥組合物，其包含式(I)所表示之化合物或其製藥上所容許之鹽100 mg。 (8-d)如上述項目(1)至(7)中任一項所記載之醫藥組合物，其包含式(I)所表示之化合物或其製藥上所容許之鹽150 mg。 (8-e)如上述項目(1)至(7)中任一項所記載之醫藥組合物，其包含式(I)所表示之化合物或其製藥上所容許之鹽200 mg。 (9)一種醫藥組合物，其包含用以與神經胺酸酶抑制劑併用之式(I)所表示之化合物或製藥上所容許之鹽。 [化2]

(10)如上述項目(9)所記載之醫藥組合物，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 (11)一種神經胺酸酶抑制劑，其用以與式(I)所表示之化合物或製藥上所容許之鹽併用。 [化3]

(12)一種醫藥組合物，其包含用以與式(I)所表示之化合物或製藥上所容許之鹽併用的選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 [化4]

The present invention relates to the following items (1)～(8), (8-a)～(8-e), (9)～(20), (20-a)～(20-e), (21)～ (28), (28-a)～(28-e), (29)～(36), (36-a)～(36-e), (37)～(44), (44-a)～ (44-e), (45)-(52) and (52-a)-(52-e). (1) A pharmaceutical composition for treating viral respiratory infections, characterized by combining a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a neuraminidase inhibitor. [chemical 1]

(2) The pharmaceutical composition as described in the above item (1), wherein the neuraminidase inhibitor is selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir at least one compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (3) The pharmaceutical composition as described in the above item (1) or (2), wherein the viral respiratory infection is selected from influenza virus, coronavirus, RS (Respiratory Syncytial, respiratory fusion) virus, paraepidemic Infectious disease caused by at least one virus among influenza virus, adenovirus, rhinovirus, pocavirus and metapneumovirus. (4) The pharmaceutical composition as described in any one of the above items (1) to (3), wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus . (5) The pharmaceutical composition as described in any one of the above items (1) to (3), wherein the viral respiratory infection is caused by SARS (Severe Acute Respiratory Syndrome, Severe Acute Respiratory Syndrome) coronavirus (SARS-CoV) ), SARS coronavirus 2 (SARS-CoV2) or MERS (Middle East Respiratory Syndrome, Middle East Respiratory Syndrome) coronavirus (MERS-CoV). (6) The pharmaceutical composition as described in any one of the above items (1) to (5), wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection . (7) The pharmaceutical composition according to any one of the above items (1) to (6), which is an oral administration agent. (8) The pharmaceutical composition according to any one of the above items (1) to (7), comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (8-a) The pharmaceutical composition according to any one of the above items (1) to (7), comprising 50 mg to 100 mg of the compound represented by 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 formula (I) or a pharmaceutically acceptable salt thereof. (8-c) The pharmaceutical composition according to any one of the items (1) to (7) above, comprising 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (8-d) The pharmaceutical composition according to any one of the above items (1) to (7), comprising 150 mg of the compound represented by 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 formula (I) or a pharmaceutically acceptable salt thereof. (9) A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a neuraminidase inhibitor. [Chem 2]

(10) The pharmaceutical composition as described in the above item (9), wherein the neuraminidase inhibitor is selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir at least one compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (11) A neuraminidase inhibitor used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt. [Chem 3]

(12) A pharmaceutical composition comprising a compound selected from the group consisting of oseltamivir, zanamivir, peramivir and lanimide for use in combination with the compound represented by formula (I) or a pharmaceutically acceptable salt. At least one compound in the group consisting of Wei, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [chemical 4]

(14)如上述項目(13)所記載之合劑，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物或其製藥上所容許之鹽、或者其等之溶劑合物。 (15)如上述項目(13)或(14)所記載之合劑，其中病毒性呼吸道感染症係由選自流行性感冒病毒、冠狀病毒、RS病毒、副流行性感冒病毒、腺病毒、鼻病毒、波卡病毒及間質肺炎病毒中之至少一種病毒所引起之感染症。 (16)如上述項目(13)至(15)中任一項所記載之合劑，其中病毒性呼吸道感染症係由A型流行性感冒病毒或B型流行性感冒病毒所引起之感染症。 (17)如上述項目(13)至(15)中任一項所記載之合劑，其中病毒性呼吸道感染症係由SARS冠狀病毒(SARS-CoV)、SARS冠狀病毒2(SARS-CoV2)或MERS冠狀病毒(MERS-CoV)所引起之感染症。 (18)如上述項目(13)至(17)中任一項所記載之合劑，其中病毒性呼吸道感染症係伴有病毒感染時之細菌之重複感染及/或二次感染之感染症。 (19)如上述項目(13)至(18)中任一項所記載之合劑，其為經口投予劑。 (20)如上述項目(13)至(19)中任一項所記載之合劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～200 mg。 (20-a)如上述項目(13)至(19)中任一項所記載之合劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～100 mg。 (20-b)如上述項目(13)至(19)中任一項所記載之合劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg。 (20-c)如上述項目(13)至(19)中任一項所記載之合劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽100 mg。 (20-d)如上述項目(13)至(19)中任一項所記載之合劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽150 mg。 (20-e)如上述項目(13)至(19)中任一項所記載之合劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽200 mg。 (13) A mixture for treating viral respiratory tract infection, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a neuraminidase inhibitor. [chemical 5]

(14) The mixture as described in the above item (13), wherein the neuraminidase inhibitor is at least one selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof. (15) The mixture as described in the above item (13) or (14), wherein the viral respiratory infection is selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus Infectious disease caused by at least one virus among , Polkadot virus and metapneumovirus. (16) The mixture as described in any one of the above items (13) to (15), wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. (17) The mixture as described in any one of the above items (13) to (15), wherein the viral respiratory infection is caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS Infectious disease caused by coronavirus (MERS-CoV). (18) The mixture as described in any one of the above items (13) to (17), wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. (19) The mixture described in any one of the above items (13) to (18), which is an oral administration preparation. (20) The mixture as described in any one of the above items (13) to (19), which contains 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (20-a) The mixture as described in any one of the above items (13) to (19), which contains 50 mg to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (20-b) The mixture described in any one of the above items (13) to (19), which contains 50 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (20-c) The mixture according to any one of the above items (13) to (19), which contains 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (20-d) The mixture described in any one of the above items (13) to (19), which contains 150 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (20-e) The mixture described in any one of the above items (13) to (19), which contains 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

(22)如上述項目(21)所記載之治療方法，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 (23)如上述項目(21)或(22)所記載之治療方法，其中病毒性呼吸道感染症係由選自流行性感冒病毒、冠狀病毒、RS病毒、副流行性感冒病毒、腺病毒、鼻病毒、波卡病毒及間質肺炎病毒中之至少一種病毒所引起之感染症。 (24)如上述項目(21)至(23)中任一項所記載之治療方法，其中病毒性呼吸道感染症係由A型流行性感冒病毒或B型流行性感冒病毒所引起之感染症。 (25)如上述項目(21)至(23)中任一項所記載之治療方法，其中病毒性呼吸道感染症係由SARS冠狀病毒(SARS-CoV)、SARS冠狀病毒2(SARS-CoV2)或MERS冠狀病毒(MERS-CoV)所引起之感染症。 (26)如上述項目(21)至(25)中任一項所記載之治療方法，其中病毒性呼吸道感染症係伴有病毒感染時之細菌之重複感染及/或二次感染之感染症。 (27)如上述項目(21)至(26)中任一項所記載之治療方法，其為經口投予劑。 (28)如上述項目(21)至(27)中任一項所記載之治療方法，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～200 mg。 (28-a)如上述項目(21)至(27)中任一項所記載之治療方法，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～100 mg。 (28-b)如上述項目(21)至(27)中任一項所記載之治療方法，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg。 (28-c)如上述項目(21)至(27)中任一項所記載之治療方法，其包含式(I)所表示之化合物或其製藥上所容許之鹽100 mg。 (28-d)如上述項目(21)至(27)中任一項所記載之治療方法，其包含式(I)所表示之化合物或其製藥上所容許之鹽150 mg。 (28-e)如上述項目(21)至(27)中任一項所記載之治療方法，其包含式(I)所表示之化合物或其製藥上所容許之鹽200 mg。 (21) A treatment method for viral respiratory tract infection, comprising the steps of: combining a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and a neuraminidase inhibitor; Administration to individuals in need of treatment for viral respiratory infections. [chemical 6]

(22) The treatment method as described in the above item (21), wherein the neuraminidase inhibitor is selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir At least one compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (23) The treatment method as described in the above item (21) or (22), wherein the viral respiratory infection is selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, nasal Infectious disease caused by at least one virus among virus, pocavirus and metapneumovirus. (24) The treatment method described in any one of the above items (21) to (23), wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. (25) The treatment method described in any one of the above items (21) to (23), wherein the viral respiratory infection is caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or Infectious disease caused by MERS coronavirus (MERS-CoV). (26) The treatment method described in any one of the above items (21) to (25), wherein the viral respiratory infection is an infection accompanied by bacterial superinfection and/or secondary infection during viral infection. (27) The treatment method described in any one of the above items (21) to (26), which is an oral administration agent. (28) The treatment method described in any one of the above items (21) to (27), comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (28-a) The treatment method described in any one of the above items (21) to (27), which comprises 50 mg to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (28-b) The treatment method described in any one of the above items (21) to (27), comprising 50 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (28-c) The treatment method described in any one of the above items (21) to (27), comprising 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (28-d) The treatment method described in any one of the above items (21) to (27), comprising 150 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (28-e) The treatment method described in any one of the above items (21) to (27), comprising 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

(30)如上述項目(29)所記載之用途，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 (31)如上述項目(29)或(30)所記載之用途，其中病毒性呼吸道感染症係由選自流行性感冒病毒、冠狀病毒、RS病毒、副流行性感冒病毒、腺病毒、鼻病毒、波卡病毒及間質肺炎病毒中之至少一種病毒所引起之感染症。 (32)如上述項目(29)至(31)中任一項所記載之用途，其中病毒性呼吸道感染症係由A型流行性感冒病毒或B型流行性感冒病毒所引起之感染症。 (33)如上述項目(29)至(32)中任一項所記載之用途，其中病毒性呼吸道感染症係由SARS冠狀病毒(SARS-CoV)、SARS冠狀病毒2(SARS-CoV2)或MERS冠狀病毒(MERS-CoV)所引起之感染症。 (34)如上述項目(29)至(33)中任一項所記載之用途，其中病毒性呼吸道感染症係伴有病毒感染時之細菌之重複感染及/或二次感染之感染症。 (35)如上述項目(29)至(34)中任一項所記載之用途，其為經口投予劑。 (36)如上述項目(29)至(35)中任一項所記載之用途，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～200 mg。 (36-a)如上述項目(29)至(35)中任一項所記載之用途，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～100 mg。 (36-b)如上述項目(29)至(35)中任一項所記載之用途，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg。 (36-c)如上述項目(29)至(35)中任一項所記載之用途，其包含式(I)所表示之化合物或其製藥上所容許之鹽100 mg。 (36-d)如上述項目(29)至(35)中任一項所記載之用途，其包含式(I)所表示之化合物或其製藥上所容許之鹽150 mg。 (36-e)如上述項目(29)至(35)中任一項所記載之用途，其包含式(I)所表示之化合物或其製藥上所容許之鹽200 mg。 (29) Use of a pharmaceutical composition for the manufacture of a medicine for the treatment of viral respiratory tract infections, the composition being a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a neuraminidase inhibitor combination. [chemical 7]

(30) The use as described in the above item (29), wherein the neuraminidase inhibitor is at least one selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir A compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (31) The use as described in the above item (29) or (30), wherein the viral respiratory infection is selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus Infectious disease caused by at least one virus among , Polkadot virus and metapneumovirus. (32) The use as described in any one of the above items (29) to (31), wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. (33) The use as described in any one of the above items (29) to (32), wherein the viral respiratory infection is caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS Infectious disease caused by coronavirus (MERS-CoV). (34) The use as described in any one of the above items (29) to (33), wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. (35) The use described in any one of the above items (29) to (34), which is an oral administration agent. (36) The use as described in any one of the above items (29) to (35), comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (36-a) The use as described in any one of the above items (29) to (35), comprising 50 mg to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (36-b) The use as described in any one of the above items (29) to (35), comprising 50 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (36-c) The use as described in any one of the above items (29) to (35), comprising 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (36-d) The use as described in any one of the above items (29) to (35), comprising 150 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (36-e) The use described in any one of the above items (29) to (35), comprising 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

(38)如上述項目(37)所記載之醫藥，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 (39)如上述項目(37)或(38)所記載之醫藥，其中病毒性呼吸道感染症係由選自流行性感冒病毒、冠狀病毒、RS病毒、副流行性感冒病毒、腺病毒、鼻病毒、波卡病毒及間質肺炎病毒中之至少一種病毒所引起之感染症。 (40)如上述項目(37)至(39)中任一項所記載之醫藥，其中病毒性呼吸道感染症係由A型流行性感冒病毒或B型流行性感冒病毒所引起之感染症。 (41)如上述項目(37)至(39)中任一項所記載之醫藥，其中病毒性呼吸道感染症係由SARS冠狀病毒(SARS-CoV)、SARS冠狀病毒2(SARS-CoV2)或MERS冠狀病毒(MERS-CoV)所引起之感染症。 (42)如上述項目(37)至(41)中任一項所記載之醫藥，其中病毒性呼吸道感染症係伴有病毒感染時之細菌之重複感染及/或二次感染之感染症。 (43)如上述項目(37)至(42)中任一項所記載之醫藥，其為經口投予劑。 (44)如上述項目(37)至(43)中任一項所記載之醫藥，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～200 mg。 (44-a)如上述項目(37)至(43)中任一項所記載之醫藥，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～100 mg。 (44-b)如上述項目(37)至(43)中任一項所記載之醫藥，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg。 (44-c)如上述項目(37)至(43)中任一項所記載之醫藥，其包含式(I)所表示之化合物或其製藥上所容許之鹽100 mg。 (44-d)如上述項目(37)至(43)中任一項所記載之醫藥，其包含式(I)所表示之化合物或其製藥上所容許之鹽150 mg。 (44-e)如上述項目(37)至(43)中任一項所記載之醫藥，其包含式(I)所表示之化合物或其製藥上所容許之鹽200 mg。 (37) A medicine for treating viral respiratory tract infection, which is obtained by combining a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a neuraminidase inhibitor. [chemical 8]

(38) The medicine as described in the above item (37), wherein the neuraminidase inhibitor is at least one selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir A compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (39) The medicine as described in the above item (37) or (38), wherein the viral respiratory infection is selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, rhinovirus Infectious disease caused by at least one virus among , Polkadot virus and metapneumovirus. (40) The medicine described in any one of items (37) to (39) above, wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. (41) The medicine as described in any one of the above items (37) to (39), wherein the viral respiratory infection is caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or MERS Infectious disease caused by coronavirus (MERS-CoV). (42) The medicine described in any one of items (37) to (41) above, wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. (43) The medicine described in any one of the above items (37) to (42), which is an oral administration agent. (44) The medicine according to any one of the above items (37) to (43), comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (44-a) The medicine according to any one of the above items (37) to (43), which contains 50 mg to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (44-b) The medicine according to any one of the above items (37) to (43), comprising 50 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (44-c) The medicine according to any one of the above items (37) to (43), comprising 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (44-d) The medicine according to any one of the above items (37) to (43), comprising 150 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (44-e) The medicine according to any one of the above items (37) to (43), which contains 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

(46)如上述項目(45)所記載之醫藥製劑，其中神經胺酸酶抑制劑係選自由奧司他韋、紮那米韋、帕拉米韋及拉尼米韋所組成之群中之至少一種化合物、或其製藥上所容許之鹽、或者其等之溶劑合物。 (47)如上述項目(45)或(46)所記載之醫藥製劑，其中病毒性呼吸道感染症係由選自流行性感冒病毒、冠狀病毒、RS病毒、副流行性感冒病毒、腺病毒、鼻病毒、波卡病毒及間質肺炎病毒中之至少一種病毒所引起之感染症。 (48)如上述項目(45)至(47)中任一項所記載之醫藥製劑，其中病毒性呼吸道感染症係由A型流行性感冒病毒或B型流行性感冒病毒所引起之感染症。 (49)如上述項目(45)至(47)中任一項所記載之醫藥製劑，其中病毒性呼吸道感染症係由SARS冠狀病毒(SARS-CoV)、SARS冠狀病毒2(SARS-CoV2)或MERS冠狀病毒(MERS-CoV)所引起之感染症。 (50)如上述項目(45)至(49)中任一項所記載之醫藥製劑，其中病毒性呼吸道感染症係伴有病毒感染時之細菌之重複感染及/或二次感染之感染症。 (51)如上述項目(45)至(50)中任一項所記載之醫藥製劑，其為經口投予劑。 (52)如上述項目(45)至(51)中任一項所記載之醫藥製劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～200 mg。 (52-a)如上述項目(45)至(51)中任一項所記載之醫藥製劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg～100 mg。 (52-b)如上述項目(45)至(51)中任一項所記載之醫藥製劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽50 mg。 (52-c)如上述項目(45)至(51)中任一項所記載之醫藥製劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽100 mg。 (52-d)如上述項目(45)至(51)中任一項所記載之醫藥製劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽150 mg。 (52-e)如上述項目(45)至(51)中任一項所記載之醫藥製劑，其包含式(I)所表示之化合物或其製藥上所容許之鹽200 mg。 (45) A pharmaceutical preparation for treating viral respiratory tract infection, comprising a single dosage form or different dosage forms of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a neuraminidase inhibitor. [chemical 9]

(46) The pharmaceutical preparation as described in the above item (45), wherein the neuraminidase inhibitor is selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir At least one compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (47) The pharmaceutical preparation as described in the above item (45) or (46), wherein the viral respiratory infection is selected from influenza virus, coronavirus, RS virus, parainfluenza virus, adenovirus, nasal Infectious disease caused by at least one virus among virus, pocavirus and metapneumovirus. (48) The pharmaceutical preparation as described in any one of the above items (45) to (47), wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. (49) The pharmaceutical preparation as described in any one of the above items (45) to (47), wherein the viral respiratory infection is caused by SARS coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV2) or Infectious disease caused by MERS coronavirus (MERS-CoV). (50) The pharmaceutical preparation as described in any one of the above items (45) to (49), wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. (51) The pharmaceutical preparation described in any one of the above items (45) to (50), which is an oral administration preparation. (52) The pharmaceutical preparation according to any one of the above items (45) to (51), which contains 50 mg to 200 mg of the compound represented by 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 contains 50 mg to 100 mg of the compound represented by 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 contains 50 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (52-c) The pharmaceutical preparation according to any one of the above items (45) to (51), comprising 100 mg of the compound represented by 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 contains 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 contains 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

As an embodiment, it includes alleviating the symptoms of pneumonia caused by viral respiratory infections such as the above items (1) to (8), (8-a) to (8-e) and (9), (10) and (12) The pharmaceutical composition described in (12). As one embodiment, it includes the mixture described in the above items (13) to (20) and (20-a) to (20-e) for reducing the symptoms of pneumonia caused by viral respiratory infection. One embodiment includes the treatment methods described in the above items (21) to (28) and (28-a) to (28-e) for alleviating the symptoms of pneumonia caused by viral respiratory infections. One embodiment includes the uses described in the above items (29) to (36) and (36-a) to (36-e) for alleviating the symptoms of pneumonia caused by viral respiratory tract infection. One embodiment includes the medicines described in the above items (37) to (44) and (44-a) to (44-e) for alleviating the symptoms of pneumonia caused by viral respiratory infections. As one embodiment, it includes a pharmaceutical preparation as described in the above items (45) to (52) and (52-a) to (52-e) for alleviating the symptoms of pneumonia caused by viral respiratory tract infection. [Effect of Invention]

The medicine for the treatment of viral respiratory tract infection of the present invention exhibits the following excellent effects: the compound represented by the formula (I) as a PGD2 receptor antagonist, or its pharmaceutically acceptable salt, or neuroamine is administered alone. Compared with acidase inhibitors, the mortality caused by influenza virus infection, and the mortality caused by superinfection and/or secondary infection of bacteria during influenza virus infection were improved.

The phrase "consisting of" means having only the constituent elements. The term "comprising" means not being limited to constituent elements, and not excluding elements not described.

Hereinafter, the present invention will be described by showing the embodiments. Throughout this specification, expressions in the singular form should be understood to include concepts in the plural form unless otherwise specified. Therefore, articles in the singular form (for example, "a", "an", "the", etc. in the case of English) should be understood as including the concepts in the plural form unless otherwise specified. In addition, unless otherwise specified, the terms used in this specification should be understood to be used in the meanings commonly used in the relevant field. Therefore, as long as there is no other definition, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In case of conflict, the present specification, including definitions, will control.

所表示之化合物、或其製藥上所容許之鹽；及 (B)神經胺酸酶抑制劑(包括套組)作為有效成分。 或者，本發明之病毒性呼吸道感染症治療用醫藥之特徵在於：作為有效成分，其為 (A)式(I)所表示之化合物、或其製藥上所容許之鹽與 (B)神經胺酸酶抑制劑之合劑。 [化11]

再者，於本說明書中，亦將本發明之病毒性呼吸道感染症治療用醫藥稱為病毒性呼吸道感染症治療劑。又，亦將本發明之病毒性呼吸道感染症治療用醫藥稱為病毒性呼吸道感染症重症化抑制用醫藥或病毒性呼吸道感染症重症化抑制劑。 The medicine for the treatment of viral respiratory tract infection of the present invention is characterized in that: (A) formula (I) [Chemical 10] is used in combination

The indicated compound, or a pharmaceutically acceptable salt thereof; and (B) neuraminidase inhibitors (including sets) as active ingredients. Alternatively, the medicine for treating viral respiratory infection of the present invention is characterized in that: as active ingredients, it is (A) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and (B) neuraminic acid Mixture of enzyme inhibitors. [chemical 11]

In addition, in this specification, the medicine for treating viral respiratory tract infection of the present invention is also referred to as a therapeutic agent for viral respiratory tract infection. In addition, the medicine for treating viral respiratory infection of the present invention is also referred to as a medicine for suppressing aggravation of viral respiratory infection or an inhibitor of aggravation of viral respiratory infection.

(A) PGD2 receptor antagonist The PGD2 receptor antagonist used in the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

The compound represented by formula (I) is [2-(zol-2-yl)-5-(4-{4-[(propane-2-yl)oxy]benzenesulfonyl}piperazol-1- base) phenoxy] acetic acid, and has antagonist activity on DP receptor which is a kind of PGD2 receptor.

The compound represented by formula (I) can be synthesized according to known methods, for example, the methods described in WO2007/037187, WO2008/123349 and WO2013/147118.

(B) Neuraminidase inhibitors As the neuraminidase inhibitor used in the present invention, for example: at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir, and laninamivir, or Its pharmaceutically acceptable salt, or its solvate.

Oseltamivir can form pharmaceutically acceptable salts. As a preferable pharmaceutically acceptable salt, oseltamivir phosphate, (-)-(3R,4R,5S)-4-acetamido-5-amino-3-(1-ethane Ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate. The dosage of oseltamivir alone is 150 mg per day for adults based on oseltamivir.

Zanamivir may form solvates. As a preferred solvate, for example: zanamivir hydrate, (+)-(4S,5R,6R)-5-acetamido-4-guanidino-6-[(1R,2R) -1,2,3-Trihydroxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid hydrate. The dosage of zanamivir alone is 20 mg per day for adults based on zanamivir.

Peramivir may form solvates. As a preferred solvate, for example: peramivir hydrate, (1S,2S,3R,4R)-3-[(1S)-1-acetamido-2-ethylbutyl]- 4-[(aminoiminomethyl)amino]-2-hydroxycyclopentanecarboxylic acid trihydrate. The dosage of peramivir alone is 300 mg or 600 mg per day for adults based on peramivir.

Laninamivir may form solvates. As a preferred solvate, for example: lanimvir octanoate hydrate, 3-caprylate: (2R,3R,4S)-3-acetamido-4-guanidino-2-[ (1R,2R)-2-Hydroxy-1-methoxy-3-(octyloxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate, 2- Octanoate: (2R,3R,4S)-3-Acetamido-4-guanidino-2-[(1S,2R)-3-Hydroxy-1-methoxy-2-(octyloxy )Propyl]-3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate. The dosage of laninamivir alone is 40 mg (inhalation powder) or 160 mg (inhalation suspension) per day for adults based on laninamivir octanoate.

These neuraminidase inhibitors can be synthesized according to known methods, and commercial products can also be used.

In this specification, examples of "pharmaceutically acceptable salts" include alkali metals (such as lithium, sodium, potassium, etc.), alkaline earth metals (such as calcium, barium, etc.), magnesium, transition metals (such as zinc, Iron, etc.), ammonia, organic bases (such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc. ) and amino acid salts; or with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (such as 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- Salts of toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). Such salts can be formed by commonly practiced methods.

The above-mentioned (A) component or the above-mentioned (B) component may form a solvate (eg, hydrate, etc.), and the present invention also includes such various solvates. A "solvate" may coordinate any number of solvent molecules (for example, water molecules, etc.) to the above-mentioned (A) component or the above-mentioned (B) component. By leaving the above-mentioned (A) component or the above-mentioned (B) component in the air, moisture may be absorbed and adsorbed water may adhere, or a hydrate may be formed.

The term "solvate" in this specification means a solvate of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of oseltamivir, zanamivir, and paramilk. A solvate of at least one compound in the group consisting of vir and laninamivir, or a pharmaceutically acceptable salt thereof, for example: monosolvate, disolvate, monohydrate, dihydrate things etc. In addition, pharmaceutically acceptable salts and solvates can be synthesized according to known methods.

As (A) component in this invention, the compound represented by said (I) or its sodium salt, calcium salt, magnesium salt, potassium salt etc. are mentioned. In addition, as the component (B) in the present invention, for example, oseltamivir, oseltamivir phosphate, zanamivir, zanamivir hydrate, peramivir, peramivir hydrate laninamivir, laninamivir caprylate hydrate. As a combination of said (A) component and (B) component, the following combinations are mentioned, for example. The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt, etc. and oseltamivir, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt, etc. and oseltamivir phosphate, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt etc. and zanamivir, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt, etc. and zanamivir hydrate, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt etc. and peramivir, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt etc. and peramivir hydrate, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt etc. and laninamivir, The compound represented by formula (I) or its sodium salt, calcium salt, magnesium salt, potassium salt, etc. and lanimirvir octanoate hydrate. Moreover, as an aspect, the combination of the compound represented by formula (I) and oseltamivir phosphate can be mentioned.

The influenza virus infection of the present invention and the medicine for treating influenza virus infection of the subject with severe influenza state are not particularly special as long as it is a combination of the above-mentioned (A) component and (B) component. However, other active ingredients can be combined within the scope of not impairing the effect of the present invention.

The medicine for treating influenza virus infection and influenza virus infection of a subject with severe influenza status according to the present invention can also be administered by any method of oral or parenteral administration. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, and vaginal administration.

In the case of oral administration, it can be prepared as solid preparations for internal use (such as tablets, powders, granules, capsules, pills, films, etc.), liquids for internal use (such as suspensions, emulsions, etc.) , elixirs, syrups, lemonades, alcoholic preparations, aromatic water preparations, extracts, decoctions, tinctures, etc.) can be administered in any of the commonly used dosage forms. Tablets can be sugar-coated pills, film-coated tablets, enteric-coated tablets, sustained-release tablets, buccal tablets, sublingual tablets, buccal tablets, chewable tablets or oral disintegrating tablets, powders and granules can be dry syrup, capsules It can be soft capsules, microcapsules or slow-release capsules.

In the case of parenteral administration, injections, drips, external preparations (such as eye drops, nasal drops, ear drops, sprays, inhalants, lotions, injections, liniments, containing Gargles, intestinal lotions, ointments, plasters, gels, creams, patches, compresses, powders for external use, suppositories, etc.) are suitably administered in any of the commonly used dosage forms. Injections can also be O/W (Oil in Water, oil in water), W/O (Water in Oil, water in oil), O/W/O (Oil-in-Water-in-Oil, water in oil Oil), W/O/W (Water-in-Oil-in-Water, water-in-oil-in-water) type emulsions.

The influenza virus infection of the present invention and the medicine for treating influenza virus infection of the subject with severe influenza state are not particularly special as long as it is a combination of the above-mentioned (A) component and (B) component. It can be prepared according to methods known to the industry. Also, the shape and size of the therapeutic agent are not particularly limited, and examples of oral preparations include solid preparations, and examples of parenteral preparations include injections, drips, inhalants, and the like.

As a specific example of the pharmaceutical dosage form which consists of the said (A) component and the said (B) component of this invention, the following are mentioned, for example. A mixture comprising a compound represented by formula (I) and oseltamivir or oseltamivir phosphate, Combination of tablets or granules containing the compound represented by formula (I) and capsules or dry syrup of oseltamivir or oseltamivir phosphate (including sets), A mixture comprising a compound represented by formula (I) and zanamivir or zanamivir hydrate, Combination of lozenges or granules containing the compound represented by formula (I) and blister packs of zanamivir or zanamivir hydrate (including sets), A mixture comprising a compound represented by formula (I) and peramivir or peramivir hydrate, Combination of tablets or granules containing the compound represented by formula (I) and intravenous drip of peramivir or peramivir hydrate (including sets), A mixture comprising a compound represented by formula (I) and laninamivir or laninamivir octanoate hydrate, Combination of lozenges or granules containing the compound represented by formula (I) and inhalation powder of laninamivir or laninamivir caprylate hydrate (including sets).

The effective amount of the above-mentioned (A) component and the above-mentioned (B) component can be mixed with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., to prepare a pharmaceutical composition. Furthermore, the pharmaceutical composition can also be prepared for children, the elderly, severe patients or surgery by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the above-mentioned (A) component and the above-mentioned (B) component. A pharmaceutical composition for use. For example, the pharmaceutical composition for children can be used for neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old), infants (over 1 year old and under 7 years old), children (over 7 years old) and less than 15 years old) or patients aged 15 to 18 years old. For example, the pharmaceutical composition for the elderly can be administered to patients over 65 years old.

The dosage of the medicine for treating influenza virus infection and influenza virus infection of the subject of the present invention and a subject with severe influenza condition is preferably in consideration of the patient's age, body weight, type or degree of disease, The route of administration and the like are determined later, and in the case of oral administration, it is usually within the range of 0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day. In the case of parenteral administration, although it varies greatly depending on the route of administration, it is usually within the range of 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day. What is necessary is just to divide and administer once a day to several times.

The medicine for treating influenza virus infection and influenza virus infection of the target person with severe influenza state according to the present invention is characterized in that component (A) and component (B) are combined as active ingredients, as its use form , for example: the form of using separately prepared single doses of (A) and (B) components at the same time, and the use of separately prepared single doses of (A) and (B) components An aspect and an aspect to use in the form of a preparation (mixture) prepared by preparing (A) component and (B) component together.

The doses of (A) component and (B) component when using the influenza virus infection of the present invention and the subject of severe influenza state as a medicine for treating influenza virus infection are based on the dosage forms , The patient's symptoms, age, weight, gender, or other concomitant drugs (if any) are different, and finally entrusted to the doctor's judgment. For example, when (B) component is oseltamivir, the following aspects can be mentioned. For example, for an adult, 50 to 200 mg of the component (A) and 75 mg to 150 mg of the component (B) are administered per day. For example, for an adult, 50 to 100 mg of the component (A) and 75 mg to 150 mg of the component (B) are administered per day. For example, for an adult, 50 mg of the component (A) and 75 mg to 150 mg of the component (B) are administered per day. For example, for an adult, 100 mg of component (A) and 75 mg to 150 mg of component (B) are administered per day. For example, for an adult, 150 mg of the (A) component and 75 mg to 150 mg of the (B) component are administered per day. For example, for an adult, 200 mg of component (A) and 75 mg to 150 mg of component (B) are administered per day. For example, for an adult, 50 to 200 mg of the (A) component and 75 mg of the (B) component are administered per day. For example, for adults, 50 to 100 mg of component (A) and 75 mg of component (B) are administered per day. For example, for an adult, 50 mg of the (A) component and 75 mg of the (B) component are administered per day. For example, for an adult, 100 mg of the (A) component and 75 mg of the (B) component are administered per day. For example, for an adult, 150 mg of the (A) component and 75 mg of the (B) component are administered per day. For example, for an adult, 200 mg of the (A) component and 75 mg of the (B) component are administered per day. For example, for an adult, 50 to 200 mg of the (A) component and 150 mg of the (B) component are administered per day. For example, for an adult, 50 to 100 mg of component (A) and 150 mg of component (B) are administered per day. For example, for an adult, 50 mg of the (A) component and 150 mg of the (B) component are administered per day. For example, for an adult, 100 mg of the (A) component and 150 mg of the (B) component are administered per day. For example, for an adult, 150 mg of the (A) component and 150 mg of the (B) component are administered per day. For example, for an adult, 200 mg of the (A) component and 150 mg of the (B) component are administered per day.

For example, when the (B) component is zanamivir, the following aspects can be mentioned. For example, for adults, 50 to 200 mg of component (A) and 20 mg of component (B) are administered per day. For example, for adults, 50 to 100 mg of component (A) and 20 mg of component (B) are administered per day. For example, for an adult, 50 mg of the (A) component and 20 mg of the (B) component are administered per day. For example, for an adult, 100 mg of the (A) component and 20 mg of the (B) component are administered per day. For example, for an adult, 150 mg of the (A) component and 20 mg of the (B) component are administered per day. For example, for an adult, 200 mg of the (A) component and 20 mg of the (B) component are administered per day.

For example, when the component (B) is peramivir, the following aspects can be mentioned. For example, for adults, 50 to 200 mg of component (A) and 300 mg of component (B) are administered per day. For example, for adults, 50 to 100 mg of component (A) and 300 mg of component (B) are administered per day. For example, for an adult, 50 mg of the (A) component and 300 mg of the (B) component are administered per day. For example, for an adult, 100 mg of the (A) component and 300 mg of the (B) component are administered per day. For example, for an adult, 150 mg of the (A) component and 300 mg of the (B) component are administered per day. For example, for an adult, 200 mg of the (A) component and 300 mg of the (B) component are administered per day.

For example, when (B) component is laninamivir octanoate, the following aspects are mentioned. For example, for adults, 50 to 200 mg of component (A) and 40 mg of component (B) are administered per day. For example, for adults, 50 to 100 mg of component (A) and 40 mg of component (B) are administered per day. For example, for an adult, 50 mg of the (A) component and 40 mg of the (B) component are administered per day. For example, for an adult, 100 mg of the (A) component and 40 mg of the (B) component are administered per day. For example, for an adult, 150 mg of the (A) component and 40 mg of the (B) component are administered per day. For example, for an adult, 200 mg of the (A) component and 40 mg of the (B) component are administered per day.

In addition, regarding this dosage, it may be administered at one time or may be administered in divided doses.

In this specification, the "super-additive effect" means that the survival rate when two or more drugs are used in combination is greater than the sum of the survival rates when each drug is administered alone.

In addition, the present invention provides a treatment method for influenza virus infection and a treatment method for influenza virus infection of a subject with severe influenza status, which includes: combining (A) component and (B) component, A therapeutically effective amount is administered to individuals in need of treatment for influenza virus infection and to subjects with influenza virus infection in subjects with severe influenza status.

Also, in this specification, the so-called therapeutically effective dose refers to the combination of (A) component and (B) component, when administering to an individual in need of treatment, and the combination of (A) component and (B) component. The amount that suppresses the symptoms or fatality rate caused by influenza compared to an individual. A specific effective amount is appropriately set according to the form of administration, the method of administration, the purpose of use, and the age, body weight, symptoms, etc. of the individual, and is not fixed.

In this specification, as a symptom caused by influenza virus, there is at least one systemic symptom, and examples include one or more of headache, fever, chills, muscle pain, arthralgia, and fatigue.

In this specification, as a symptom caused by influenza virus, there is at least one respiratory system symptom, and examples include one or more of cough, sore throat, and nasal congestion.

In this specification, the so-called severe influenza status may include more than one of the following: (a) hospitalization due to influenza virus infection; (b) suffering from influenza virus infection during hospitalization, so need Prolonged hospital stay; (c) National Early Warning Score 2 of 4 or more; (d) Respiratory assistance; (e) At least one complication caused by influenza virus infection requiring hospitalization.

In this specification, the state of severe influenza includes a state requiring respiratory assistance. As an example, the breathing aid is at least one of an artificial respirator, oxygen inhalation from a non-atmospheric oxygen source, and an oxygen concentrator for concentrating atmospheric oxygen.

In this specification, the so-called severe influenza state includes at least one complication caused by influenza virus infection. As an example, the complication caused by influenza virus infection is one or more of heart, brain, or muscle tissue inflammation, and multiple organ failure. As an example, complications caused by influenza virus infection are pneumonia, central nervous system disorder, myositis, rhabdomyolysis, encephalitis, encephalopathy, severe dehydration myocarditis, pericarditis, otitis media, sinusitis, ischemia Exacerbation of chronic heart disease, sepsis, acute lung injury, or acute respiratory distress syndrome, and one or more of acute exacerbations of chronic kidney disease or respiratory disease, such as asthma or chronic obstructive pulmonary disease. [Example]

Hereinafter, although this invention is demonstrated based on an Example, this invention is not limited to these Examples etc. at all.

Test Example 1: Bacterial Mixed Infection Mouse Model for Evaluating the Effectiveness of Concomitant Administration of Compounds Represented by Formula (I) and Oseltamivir Phosphate (1) Materials and methods (1.1) Compounds The compound represented by formula (I) as a DP1 antagonist was synthesized by Shionogi & Co., Ltd. (Osaka Prefecture, Japan) (references: WO2007/037187, WO2008/123349, WO2013/147118). A commercially available product was used as oseltamivir phosphate ("OSP"). The compound represented by formula (I) and the OSP solution were prepared using 0.5% methylcellulose 400 (MC) solution. The administration volume was set at 0.2 mL per mouse, the administration amount of the compound represented by formula (I) was selected based on the non-clinical test results recorded in Non-Patent Document 1, and the administration amount of OSP was based on human clinical administration Quantity selection. (1.2) Viruses and bacteria The A/Osaka/129/2009 strain of influenza virus and the SR1326 strain of pneumococcus isolated clinically in Japan were adapted to mice. (1.3) Animals Specific pathogen-free 7-week-old female BALB/c mice (Charles River Laboratories Japan, Inc.) were used in this study. Body weight and survival rate were monitored once a day. When the body weight decreased by more than 30% compared with that before virus infection, the mice were immediately euthanized according to humane endpoints, and they were considered dead in the analysis of survival time. When inoculating viruses and bacteria, by intramuscularly administering 100 mg/mL of medetomidine hydrochloride, 0.4 mg/mL of midazolam, and 0.5 mg/mL of butorphanol tartrate in normal saline Anesthetize the mouse with μL of anesthesia solution.

(2) Verification of antiviral effect in mouse model Under anesthesia, mice were inoculated nasally with 100 μL of A/Osaka/129/2009 (mouse-adapted strain, 1.00×10 ³ TCID ₅₀ ). On the second day after virus infection, 100 μL of pneumococcal SR1326 (mouse-adapted strain, 1.00×10 ⁴ CFU (Colony Forming Unit)) was nasally inoculated into the mouse under anesthesia. Starting from the first day before virus infection, mice (n=10/group) were orally administered a compound represented by formula (I) at a dose of 30 mg/kg (twice a day, 12 days), or OSP was orally administered at a dose of 10 mg/kg (twice a day, for 12 days). In order to investigate the effect of combination therapy of these compounds, the compound represented by the formula (I) was orally administered at a dose of 30 mg/kg (twice a day, for 12 days) and 10 mg/kg was orally administered. (twice a day, 12 days) doses of OSP to treat mice. 0.5% MC was orally administered to control mice (twice a day for 12 days). The survival rate of the mice was investigated once a day until the 16th day after virus infection.

(3) Statistical analysis Differences between groups in survival time after virus infection were analyzed by log rank test. Statistical analysis was performed using statistical analysis software SAS version 9.2 for Windows (SAS Institute (Cary, NC)). Adjusted two-sided P value less than 0.05 was considered statistically significant.

(4) Results (4-1) Combined effect of the compound represented by formula (I) and OSP Using lethal mixed infection of type A influenza virus and pneumococcus in mice, verify the compound represented by formula (I) and Combined use of OSP for administration effect. All media inoculated with A/Osaka/129/2009 (mouse-adapted strain, 1.00×10 ³ TCID ₅₀ ) and pneumococcus SR1326 (mouse-adapted strain, 1.00×10 ⁴ CFU) were administered to mice until the second day after virus infection. All died within 10 days. In the case of treatment with individual administration of each compound, 10% of the mice treated with the compound represented by formula (I) survived and 20% of the mice in the OSP-treated group survived ( FIG. 1 ). As a result, it was found that in the treatment with individual administration of each compound, no significant effect of prolonging the survival time was observed for the vehicle-administered group. On the other hand, 70% of the mice treated with the combined administration of the compound represented by formula (I) and OSP survived, showing a significantly stronger effect of prolonging the survival time than those administered alone. Based on these results, it is considered that the combined administration of the compound represented by formula (I) and OSP has a more than additive effect compared to the effect of each compound administered alone. Based on the above hints, the influenza virus-bacteria mixed infection mouse model may be useful for estimating the effect of the combined administration of the compound represented by formula (I) and OSP in severe cases.

(4-2) Evaluation of Survival Time of Mice by Combined Administration of Compound Represented by Formula (I) and OSP In this non-clinical study, the present inventors evaluated the effect on the survival time of mice of combined administration of a compound represented by formula (I) and OSP in a mouse model of mixed infection with influenza virus and bacteria. The present inventors have previously confirmed that in the allergic rhinitis mouse model, the compound represented by formula (I) exhibited the maximum effect based on the mechanism of DP-1 inhibition at the dose of 3-30 mg/kg (not Patent Document 1). Therefore, in this study, 30 mg/kg was administered to mice twice a day for 12 days. The dosage of OSP is calculated based on the human pharmacokinetic data of mice (in mice, 5 mg/kg administered twice a day is equivalent to the human clinical dose, and the high dose recommended for the treatment of severe patients is twice as high) . Therefore, in this study, OSP10 mg/kg (2-fold higher dose) was administered to mice as a control drug twice a day for 12 days (Ward et al., J. Antimicrob Chemother., Feb55 Suppl 1: i5～ i21 (2005)). In humans, bacterial co-infection occurs immediately after viral infection or during viral shedding (Chertow et al., JAMA, 2013: 309 (3): 275-282). The inventors of the present invention have previously confirmed that within 2 days after inoculating mice with A/Osaka/129/2009 (a mouse-adapted strain), the virus titer in the lungs reaches a peak level (Onishi et al., Antiviral Research 117 (2015) 52 ~59). Therefore, in this study, the mice were inoculated with pneumococci on day 2 after viral infection. In mice infected with pneumococcus on day 2 after influenza A virus infection, single administration of either the compound represented by formula (I) or OSP was ineffective, but the compound represented by formula (I) The combined administration of compound + OSP significantly prolongs the survival time and improves the survival rate of each single-administered group or medium-administered group (p<0.05). These insights support the usefulness of combination therapy of a compound represented by formula (I) and OSP as a treatment option for patients with severe influenza.

Test Example 2: Influenza A virus-infected mouse model for evaluating the effectiveness of combined administration of a compound represented by formula (I) and OSP (1) Materials and methods (1.1) Compounds The compound represented by formula (I) as a DP1 antagonist was synthesized by Shionogi & Co., Ltd. (Osaka Prefecture, Japan) (references: WO2007/037187, WO2008/123349, WO2013/147118). OSP used a commercial item. The compound suspension and OSP suspension represented by formula (I) were prepared using 0.5% MC solution. The administration volume was set at 0.2 mL per mouse. (1.2) Viruses Use A-H1N1 subtype seasonal influenza virus (laboratory strain or clinical isolate). When a virus strain is not easy to infect and proliferate in mice, a strain adapted to mice is used as the inoculation virus. (1.3) Animals Specific pathogen-free C57BL/6J mice or BALB/c mice were used in this study. Body weight and survival rate were monitored once a day. When the body weight decreased to less than 70% compared with that before virus infection, the mice were immediately euthanized according to humane endpoints, and were considered as dead cases in the analysis of survival time.

(2) Verification of antiviral effect in mouse model Mice were inoculated nasally with 50-100 μL of virus preparation solution under anesthesia. Starting from before or after virus infection, the compound represented by formula (I) was orally administered to mice at a dose of 3 to 30 mg/kg (once a day or twice a day), or Give OSP at a dose of 5-50 mg/kg (twice a day). In order to investigate the effect of combination therapy of these compounds, the compound represented by the formula (I) at a dose of 3 to 30 mg/kg (once a day or twice a day) and orally administered The mice were treated with OSP at a dose of 5-50 mg/kg (once a day or twice a day). A 0.5% MC solution was orally administered to control mice (once a day or twice a day). The administration time is about 5 to 10 days. The number of cases in each group was set at about 5 to 10, and the survival rate and body weight of the mice were investigated once a day about 14 days after virus infection.

(3) Statistical analysis Differences between groups in survival time after virus infection were analyzed by log rank test. Statistical analysis was performed using the statistical analysis software SAS (SAS Institute, Cary, NC, USA). When the adjusted P value of both sides does not reach 0.05, it is considered statistically significant.

Preparation example The formulation examples shown below are merely illustrations and are not intended to limit the scope of the invention in any way. (Preparation example 1) Suspending agent For example, water for injection is added to the original drug of the compound represented by formula (I) to prepare a suspension. (Preparation Example 2) Tablet For example, lactose and magnesium stearate are added to the original drug of the compound represented by formula (I) as additives to make lozenges. [Industrial availability]

It is considered that the medicine for treating viral respiratory tract infection of the present invention is effective against influenza virus infection by combining the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a neuraminidase inhibitor as an active ingredient. And the influenza virus infection of the subjects with severe influenza state showed excellent therapeutic effect.

Figure 1 shows experimental results of the therapeutic effect of compound (I) administration on lethal mixed infection of influenza A virus (inoculation: day 0) and pneumococcus (inoculation: day 2) in mice chart.

Claims (39)

A pharmaceutical composition for treating viral respiratory tract infection, characterized in that the compound represented by formula (I) or its pharmaceutically acceptable salt and neuraminidase inhibitor are combined: [Chem. 1]

. The pharmaceutical composition according to claim 1, wherein the neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir or its pharmaceutical composition salt as above allows. The pharmaceutical composition according to claim 1 or 2, wherein the viral respiratory infection is an infection caused by influenza virus. The pharmaceutical composition according to claim 1 or 2, wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. The pharmaceutical composition according to claim 1 or 2, wherein the viral respiratory tract infection is an infection accompanied by bacterial superinfection and/or secondary infection during viral infection. The pharmaceutical composition according to claim 1 or 2, which is an oral administration agent. The pharmaceutical composition according to claim 1 or 2, comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt used in combination with a neuraminidase inhibitor: [Chem. 2]

. The pharmaceutical composition according to claim 8, wherein the neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir or its pharmaceutical composition salt as above allows. A neuraminidase inhibitor used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt: [Chem. 3]

. A pharmaceutical composition comprising a compound selected from oseltamivir, zanamivir, peramivir and laninamivir for use in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt At least one compound or its pharmaceutically acceptable salt in the group: [Chem. 4]

. A mixture for the treatment of viral respiratory infection, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a neuraminidase inhibitor: [Chem. 5]

. As the combination of claim 12, wherein the neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir or its pharmaceutical name The salt of tolerance. As the mixture of claim 12 or 13, wherein the viral respiratory infection is an infection caused by influenza virus. The mixture as claimed in item 12 or 13, wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. As the mixture of claim 12 or 13, wherein the viral respiratory tract infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. The mixture according to claim 12 or 13, which is an oral administration agent. The mixture according to claim 12 or 13, which contains 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. A use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in combination with a neuraminidase inhibitor for the manufacture of a drug administered to an individual in need of treatment of viral respiratory tract infection for the treatment of A pharmaceutical composition for viral respiratory infection, [Chemical 6]

. Such as the use of claim 19, wherein the neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir or its pharmaceutically The salt of tolerance. As the use of claim 19 or 20, wherein the viral respiratory infection is an infection caused by influenza virus. As the use of claim 19 or 20, wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. Such as the use of claim 19 or 20, wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. As used in claim 19 or 20, it is an oral administration agent. The use according to claim 19 or 20, comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. A kind of medicine, it is used for treating viral respiratory tract infection, and is formed by combining the compound represented by formula (I) or its pharmaceutically acceptable salt and neuraminidase inhibitor: [Chemical 7]

. Such as the medicine of claim 26, wherein the neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir or its pharmaceutical The salt of tolerance. The medicine according to claim 26 or 27, wherein the viral respiratory infection is an infection caused by influenza virus. The medicine according to claim 26 or 27, wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. The medicine according to claim 26 or 27, wherein the viral respiratory infection is an infectious disease accompanied by bacterial superinfection and/or secondary infection during viral infection. The medicine according to claim 26 or 27, which is an oral administration agent. The medicine according to claim 26 or 27, comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. A pharmaceutical preparation for the treatment of viral respiratory tract infections, which is a single dosage form or different dosage forms comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a neuraminidase inhibitor: ]

. The pharmaceutical preparation according to claim 33, wherein the neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir and laninamivir or its pharmaceutical Allowed salt. The pharmaceutical preparation according to claim 33 or 34, wherein the viral respiratory infection is an infection caused by influenza virus. The pharmaceutical preparation according to claim 33 or 34, wherein the viral respiratory infection is an infection caused by type A influenza virus or type B influenza virus. The pharmaceutical preparation according to claim 33 or 34, wherein the viral respiratory tract infection is an infection accompanied by bacterial superinfection and/or secondary infection during viral infection. The pharmaceutical preparation according to claim 33 or 34, which is an oral administration preparation. The pharmaceutical preparation according to claim 33 or 34, comprising 50 mg to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

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