CN116782904A - Pharmaceutical composition containing triazine derivative - Google Patents
Pharmaceutical composition containing triazine derivative Download PDFInfo
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- CN116782904A CN116782904A CN202280007447.4A CN202280007447A CN116782904A CN 116782904 A CN116782904 A CN 116782904A CN 202280007447 A CN202280007447 A CN 202280007447A CN 116782904 A CN116782904 A CN 116782904A
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- 150000003918 triazines Chemical class 0.000 title description 4
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- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 151
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 68
- 125000003118 aryl group Chemical group 0.000 claims abstract description 67
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- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 125000001424 substituent group Chemical group 0.000 claims description 192
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Abstract
The present invention provides a pharmaceutical composition containing a compound exhibiting coronavirus proliferation inhibitory activity. A pharmaceutical composition comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof. (wherein Y is N; R) 1 Is a substituted or unsubstituted aromatic heterocyclic group; r is R 2 Is a substituted or unsubstituted 6 membered aromatic carbon ring group; r is R 3 Is a substituted or unsubstituted aromatic heterocyclic group; -X-is-NH-; m is 0 or 1; r is R 5a Is a hydrogen atom; r is R 5b Is a hydrogen atom; n is 1; r is R 4a Is a hydrogen atom; r is R 4b Is a hydrogen atom)
Description
Technical Field
The present invention relates to pharmaceutical compositions containing compounds that exhibit coronavirus 3CL protease inhibitory activity.
Background
Coronaviruses belonging to the order coronaviridae, the order coronaviridae (nidoviruses), have a genome size of about 30kb, being the largest class of single-stranded +strand RNA viruses among the known RNA viruses. Coronaviruses can be classified into 4 kinds of coronaviruses, namely, alpha coronavirus, beta coronavirus, gamma coronavirus and delta coronavirus, and 2 kinds of coronaviruses (HCoV-229E, HCoV-NL 63) of alpha coronavirus and 5 kinds of beta coronavirus (HCoV-HKU 1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2) are known as coronaviruses for infecting humans, and 7 kinds of coronaviruses are known in total. Of these, 4 (HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC 43) are causative agents of the common cold, and the remaining 3 are Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV) and novel coronavirus (SARS-CoV-2) that cause severe pneumonia.
The new coronavirus infectious disease (covd-19) was declared epidemic by WHO at day 3 and 11 of 2020. The number of infections confirmed at 2022, 9 and 21 is 6.1 million or more, and the number of deaths is 650 ten thousand or more (non-patent document 1). As a main infection route of SARS-CoV-2, droplet infection, contact infection and aerosol infection have been reported, and it has been confirmed that SARS-CoV-2 floats in the air for about 3 hours together with aerosol and maintains infectivity (non-patent document 2). The incubation period is about 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), tiredness (38.1%), sputum (33.4%) are typical (non-patent document 3). In severe cases, respiratory failure may occur due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, and the like. In addition, multi-organ failure such as renal failure and liver failure has been reported.
In japan, drug repositioning based on existing drugs, adefovir as an antiviral drug, dexamethasone as an anti-inflammatory drug, and baratinib as a rheumatic drug have been approved as therapeutic drugs for covd-19, and tolizumab as an anti-IL-6 receptor antibody was additionally approved at month 1 of 2022. In addition, ronaprve (casirizumab)/idevemab (idevemab)) as an antibody cocktail therapy was given as a specialty batch at month 2021, sonovimab (sotrovimab) was given as a specialty batch at month 2021, 12 months 2021, mo Nupi pyrvir (molnupirvir) was given as a specialty batch at month 2021. There is no adequate evidence for the effectiveness, safety, or both of these agents. Therefore, there is an urgent need to create therapeutic agents, particularly oral agents, for covd-19.
Coronaviruses synthesize various proteins required for self-replication when they infect cells. There are 2 multimeric proteins comprising replication complexes that make the viral genome, 2 proteases. Proteases cleave multimeric proteins synthesized by viruses and serve an indispensable role for the functioning of the various proteins. Among the 2 proteases, 3CL protease (main protease) plays a role in cleavage of most of the multimeric proteins (non-patent document 4).
Completion of phase 1b clinical trials of Lufotrelvir (PF-07304814), a prodrug of PF-00835231, carried out by Pfizer, 2021, as a 3CL protease-targeted covd-19 therapeutic was carried out on clinical trimals. In addition, at month 3 of 2021, pfizer corporation announced the initiation of phase 1 clinical trials of therapeutic agent PF-07321332 for a novel coronavirus infectious disease. The structural formulae of PF-00835231, lufotrelvir and PF-07321332 are shown below, and the chemical structures are different from those of the compounds according to the present invention (non-patent documents 5, 12 and 13 and patent documents 5 and 6).
PF-00835231:
[ chemical formula 1]
Lufotrelvir(PF-07304814):
[ chemical formula 2]
PF-07321332:
[ chemical formula 3]
Furthermore, clinical Trials.gov was subjected to a 2/3 phase clinical trial (NCT 04960202) of PF-07321332 and ritonavir combined on a patient with COVID-19 having a high risk factor starting at month 7 of 2021. In addition, at month 11 of 2021, PAXLOVID (TM) (PF-07321332; ritonavir) was reported on the homepage of Pfizer corporation to reduce the risk of hospitalization or death by 89% in high-risk patients of adults compared with placebo (non-patent document 14). In addition, PAXLOVID (TM) was licensed for emergency use in the united states at month 12 of 2021, and PAXLOVID (registered trademark) combination package was licensed for special use in japan at month 2 of 2022.
Although non-patent documents 5 to 8 disclose compounds having 3CL protease inhibitory activity, no pharmaceutical composition containing the compounds of the present invention is described or suggested in any document.
Although patent documents 1 to 4 disclose having a p 2X 3 And/or p 2X 2/3 Triazine derivatives with receptor antagonism, but in any literatureThere is no description or suggestion of a pharmaceutical composition comprising a compound having 3CL protease inhibitory activity and antiviral effect.
Although non-patent documents 9 to 11 disclose triazine derivatives having antitumor effects, none of the documents describes coronavirus 3CL protease inhibitory activity and antiviral effects, nor does any document describe or suggest pharmaceutical compositions containing the compounds according to the present invention.
Prior art literature
Patent literature
Patent document 1: international publication No. 2012/020749
Patent document 2: international publication No. 2013/089212
Patent document 3: international publication No. 2010/092966
Patent document 4: international publication No. 2014/200078
Patent document 5: international publication No. 2021/205298
Patent document 6: international publication No. 2021/250648
Non-patent literature
Non-patent document 1: "COVID-19Dashboard by the Center for Syst ems Science and Engineering at Johns Hopkins University", [ onlie ne ], johns Hopkins University, [2022, 9, 21-day check out ], website < UR L: https:// corenavir, jhu.edu/map.html >
Non-patent document 2: the NEW ENGLAND JOURNAL of MEDICIN E (2020), volume 382, pages 1564-1567
Non-patent document 3: "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [ online ], 28, 2020, WHO, [2022, 9, 21, website, ", website < URL: https:// www.wh o.int/docs/default-source/coronavir/WHO-child-joint-transmission-on-covi d-19-final-report. Pdf >
Non-patent document 4: science (2003), volume 300, pages 1763-1767
Non-patent document 5: "A comparative analysis of SARS-CoV-2anti virals characterizes 3CLpro inhibitor PF-00835231as a potential new treatment for COVID-19", journal of Virology, [ online ], 23 nd of 2021, 23 nd of 2022 nd of 9 th of 21 st of the year, website < URL: https:// jvi.as m.org/content/early/2021/02/19/JVi.01819-20> < doi:10.1128/JVi.01819-20>
Non-patent document 6: cell Research (2020), volume 30, pages 678-692
Non-patent document 7: science (2020), volume 368, pages 409-412
Non-patent document 8: ACS Central Science (2021), volume 7, 3, pages 467-475)
Non-patent document 9: cancer Treatment Reviews (1984), volume 11, supplement 1, pages 99 to 110
Non-patent document 10: contributions to Oncology (1984), vol.18, pages 221-234
Non-patent document 11: arzneimittel-Forschung (1984), vol.11, 6, pages 663-668
Non-patent document 12:261st Am Chem Soc (ACS) Natl Meet 2021-04-05/2021-04-16. Virtual, N/A. Abst 243
Non-patent document 13: science (2021), volume 374, pages 1586 to 1593
Non-patent document 14: "Pfizer's Novel COVID-19Oral Antiviral Tr eatment Candidate Reduced Risk Of Hospitalization Or Death By89%In Interim Analysis Of Phase 2/3EPIC-HR Study", [ online ], month 11, 5, pfizer Press Release, month 9, 21, 2022, website < URL: https:// www.pfizer.com/news/press-release/press-release-de tail/pfizer-novel-covid-19-oral-anti-therapeutic-treatment-truck ]
Disclosure of Invention
Problems to be solved by the invention
The purpose of the present invention is to provide a pharmaceutical composition containing a compound having coronavirus 3CL protease inhibitory activity. Preferably, the present invention provides a medicament containing a compound having an antiviral effect, particularly, a proliferation inhibitory effect of coronavirus.
Means for solving the problems
The present invention relates to the following.
(1)
A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[ chemical formula 4]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(2) The pharmaceutical composition according to item (1) above, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(3) The pharmaceutical composition according to item (1) or (2) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and alkyl.
(4) The pharmaceutical composition according to any one of the above items (1) to (3), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(5) A pharmaceutical composition comprising the compound according to item (1) above or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(6) The pharmaceutical composition according to any one of the above items (1) to (5), which is a 3CL protease inhibitor.
(7) The pharmaceutical composition according to any one of the above items (1) to (6), which is used for inhibiting the viral proliferation of SARS-CoV-2.
(8) The pharmaceutical composition according to any one of the above items (1) to (7), which is a novel therapeutic and/or prophylactic agent for coronavirus infectious disease (covd-19).
(9) The pharmaceutical composition according to any one of the above items (1) to (8), which is used for inhibiting the severity of an infectious disease caused by SARS-CoV-2.
(10) The pharmaceutical composition according to any one of the above items (1) to (9), which is used in the following manner: administration begins after manifestation of symptoms of the infectious disease caused by SARS-CoV-2, or within 72 hours from the determination of SARS-CoV-2 positive.
(11) The pharmaceutical composition according to any one of the above items (1) to (9), which is used in the following manner: administration begins after manifestation of symptoms of the infectious disease caused by SARS-CoV-2, or within 24 hours from the determination of SARS-CoV-2 positive.
(12) The pharmaceutical composition according to any one of the above items (1) to (9), which is used in the following manner: administration begins after manifestation of symptoms of the infectious disease caused by SARS-CoV-2, or within 120 hours from the determination of SARS-CoV-2 positive.
(13) The pharmaceutical composition according to any one of the above items (1) to (12), wherein the symptom of the infectious disease caused by SARS-CoV-2 is 1 or more of 12 kinds of symptoms of COVID-19, which is a moderate or more.
(14) The pharmaceutical composition according to any one of the above items (1) to (9), which is used for inhibiting the viral transmission of SARS-CoV-2.
(15) A method for inhibiting viral proliferation of SARS-CoV-2, comprising the step of administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment and/or prevention of a novel coronavirus infectious disease (covd-19).
[ chemical formula 5]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(16) The method for inhibiting viral proliferation of SARS-CoV-2 as described in item (15) above, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(17) The method for inhibiting viral proliferation of SARS-CoV-2 as described in item (15) or (16) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(18) The method for inhibiting the proliferation of SARS-CoV-2 virus as described in any one of the above items (15) to (17), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(19) The method for inhibiting viral proliferation of SARS-CoV-2 as described in item (15) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(20) A method of treatment and/or prophylaxis of a novel coronavirus infectious disease (covd-19), comprising the step of administering to a subject in need of treatment and/or prophylaxis of a novel coronavirus infectious disease (covd-19) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
[ chemical formula 6]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a Is a hydrogen atom;
R 4b is a hydrogen atom)
(21) The method for treating and/or preventing a novel coronavirus infectious disease (COVID-19) as set forth in item (20) above, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(22) The method for treating and/or preventing a novel coronavirus infectious disease (COVID-19) as set forth in item (20) or (21) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(23) The method for treating and/or preventing a novel coronavirus infectious disease (COVID-19) as set forth in any one of the above items (20) to (22), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(24) The method for treating and/or preventing a novel coronavirus infectious disease (COVID-19) as set forth in item (20) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(25) A method for inhibiting the severity of an infectious disease caused by SARS-CoV-2, comprising the step of administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment and/or prevention of a novel coronavirus infectious disease (covd-19).
[ chemical formula 7]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(26) A method for inhibiting the severity of an infectious disease caused by SARS-CoV-2 as described in item (25) above, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(27) A method for inhibiting the severity of an infectious disease caused by SARS-CoV-2 as described in the above item (25) or (26), wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(28) The method for inhibiting severe infectious diseases caused by SARS-CoV-2 as described in any one of the above items (25) to (27), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(29) The method for inhibiting the severe infectious disease caused by SARS-CoV-2 as described in item (25) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(30) A method of treatment of a novel coronavirus infectious disease (covd-19), which is a method of treatment and/or prophylaxis of a novel coronavirus infectious disease (covd-19), the method comprising the steps of: for an individual in need of treatment and/or prevention of a novel coronavirus infectious disease (covd-19), the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered after manifestation of symptoms of the infectious disease caused by SARS-CoV-2 or within 72 hours from the judgment of positive SARS-CoV-2.
[ chemical formula 8]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(31) Novel coronavirus infectious disease (C) as set forth in item (30) aboveOVID-19), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(32) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in item (30) or (31) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
Wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(33) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in any one of the above items (30) to (32), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(34) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in item (30) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(35) A method of treatment of a novel coronavirus infectious disease (covd-19), which is a method of treatment and/or prophylaxis of a novel coronavirus infectious disease (covd-19), the method comprising the steps of: for an individual in need of treatment and/or prevention of a novel coronavirus infectious disease (covd-19), the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered after manifestation of symptoms of the infectious disease caused by SARS-CoV-2 or within 24 hours from the judgment of positive SARS-CoV-2.
[ chemical formula 9]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(36) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in item (35) above, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(37) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in item (35) or (36) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(38) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in any one of the above items (35) to (37), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(39) The method for treating a novel coronavirus infectious disease (COVID-19) as set forth in item (35) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(40) A method of inhibiting viral transmission of SARS-CoV-2, comprising the step of administering to a subject in need of treatment and/or prevention of a novel coronavirus infectious disease (covd-19) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
[ chemical formula 10]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(41) The method for inhibiting viral propagation of SARS-CoV-2 as described in item (40) above, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(42) The method for inhibiting viral propagation of SARS-CoV-2 as described in item (40) or (41) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(43) The method for inhibiting viral propagation of SARS-CoV-2 as described in any of the above items (40) - (42), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(44) The method for inhibiting viral propagation of SARS-CoV-2 as described in item (40) above, wherein the compound of formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(45) Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting viral proliferation of SARS-CoV-2.
[ chemical formula 11]
(wherein Y is N;
R 1 is substituted or unsubstitutedA substituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(46) The use as described in the above item (45), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(47) The use as described in item (45) or (46) above, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(48) The use according to any one of the above items (45) to (47), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(49) The use as described in item (45) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(50) The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of novel coronavirus infectious disease (COVID-19).
[ chemical formula 12]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromaticA heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(51) The use as described in the above item (50), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(52) The use as described in the above item (50) or (51), wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(53) The use according to any one of the above items (50) to (52), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(54) The use as described in the above item (50), wherein the compound represented by the formula (I) is selected from the group consisting of Compound I-003, compound I-005, compound I-017 and Compound I-023.
(55) Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting the criticality of an infectious disease caused by SARS-CoV-2.
[ chemical formula 13]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(56) The use as described in the above item (55), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(57) The use as described in the above item (55) or (56), wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(58) The use according to any one of the above items (55) to (57), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(59) The use as described in the above item (55), wherein the compound represented by the formula (I) is selected from the group consisting of Compound I-003, compound I-005, compound I-017 and Compound I-023.
(60) Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for administration after manifestation of symptoms of an infectious disease caused by SARS-CoV-2, or within 72 hours from the determination of SARS-CoV-2 positive.
[ chemical formula 14]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(61) The use as described in the above item (60), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(62) The use as described in the above item (60) or (61), wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(63) The use according to any one of the above items (60) to (62), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(64) The use as set forth in item (60) above, wherein the compound represented by formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
(65) Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for administration after manifestation of symptoms of an infectious disease caused by SARS-CoV-2, or within 24 hours from the determination of SARS-CoV-2 positive.
[ chemical formula 15]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromaticA group of heterocyclic groups;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(66) The use as described in the above item (65), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(67) The use as described in the above item (65) or (66), wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(68) The use according to any one of the above items (65) to (67), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(69) The use as described in the above item (65), wherein the compound represented by the formula (I) is selected from the group consisting of Compound I-003, compound I-005, compound I-017 and Compound I-023.
(70) Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting viral transmission of SARS-CoV-2.
[ chemical formula 16]
(wherein Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom)
(71) The use as described in the above item (70), wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
(72) The use as described in the above item (70) or (71), wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
(73) The use according to any one of the above items (70) to (72), wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
(74) The use as described in the above item (70), wherein the compound represented by the formula (I) is selected from the group consisting of Compound I-003, compound I-005, compound I-017 and Compound I-023.
Effects of the invention
The compound of the present invention has an inhibitory activity against coronavirus 3CL protease, and a pharmaceutical composition containing the compound of the present invention is useful as a therapeutic and/or prophylactic agent for infectious diseases caused by coronaviruses.
Further, the compound of the present invention is useful as a pharmaceutical agent in a pharmaceutical composition containing the compound (I-003) or the compound (I-005).
In addition, a pharmaceutical composition containing the p-toluenesulfonate crystal of the compound (I-003) or the fumaric acid co-crystal of the compound (I-005) is very useful as a therapeutic agent for novel coronavirus infectious disease (COVID-19).
Drawings
FIG. 1 shows a powder X-ray diffraction pattern of a p-toluenesulfonate Form I crystal (Form I) of the compound represented by formula (I-A). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).
FIG. 2 shows the structure in an asymmetric unit of a p-toluenesulfonate form I crystal of the compound of formula (I-A).
FIG. 3 shows powder X-ray diffraction patterns of fumaric acid co-crystal Form I (Form I) of the compound represented by the formula (I-B). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).
FIG. 4 shows the structure in an asymmetric unit of fumaric acid eutectic type I (Form I) of the compound represented by the formula (I-B).
[ FIG. 5A]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 Nasal inoculation of mice), medium twice a day from just after infection, or intrapulmonary viral titers 1 day after infection when the fumaric acid co-crystal form I crystals of the compound shown in (I-B) were administered in a single dose. The vertical axis represents intrapulmonary viral titers and the horizontal axis represents each administration group.
[ FIG. 5B ]]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 Nasal inoculation of mice), and administration of medium twice a day from just after infection, and intrapulmonary viral titers after 1 day of infection when the fumaric acid co-crystal form I crystals of the compound shown in (I-B). The vertical axis represents intrapulmonary viral titers and the horizontal axis represents each administration group.
[ FIG. 6A]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 Nasal inoculation of mice), administration of medium twice a day from 1 day after infection, and intrapulmonary viral titers 1-3 days after infection when fumaric acid co-crystal form I crystals of the compound shown in (I-B) are administered for 2 days. The vertical axis represents the intrapulmonary viral titers and the horizontal axis represents the number of days since infection.
[ FIG. 6B ]]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 Nasal inoculation of mice), administration of medium twice a day from 3 days after infection, and intrapulmonary viral titers 1-5 days after infection at 2 days of fumaric acid co-crystal form I crystals of the compound shown in (I-B). The vertical axis represents the intrapulmonary viral titers and the horizontal axis represents the number of days since infection.
[ FIG. 7 ]]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 Nasal inoculation of mice), administration of medium three times a day from 1 day after infection, and intrapulmonary viral titers 1-3 days after infection when fumaric acid co-crystal form I crystals of the compound shown in (I-B) were administered for 2 days. The vertical axis represents the intrapulmonary viral titers and the horizontal axis represents the number of days since infection.
[ FIG. 8A]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 5 TCID 50 Mice were vaccinated nasally, with senior retired mice of 35-45 weeks old), and medium was administered twice a day from 1 day after infection, and body weight was changed from 7 days after infection until 5 days for fumaric acid cocrystal form I crystals of the compound shown in (I-B). The vertical axis represents the weight change (%) when the body weight on the day of infection is 100%, and the horizontal axis represents the number of days since infection.
[ FIG. 8B ]]Shows that mice were infected against hCoV-19/Japan/TY7-501/2021 (1.00X 10) 5 TCID 50 Nasal inoculation of mice, senior retired mice of 35-45 weeks old), administration of medium twice a day from 1 day after infection, survival rate of fumaric acid co-crystal form I crystals of the compound shown in (I-B) for 5 days until 7 days after infection. The vertical axis represents survival (%), and the horizontal axis represents days since infection.
[ FIG. 8C]Shows that mice are infected with the domesticated strain MA-P10 for hCoV19/Japan/TY/WK-521/2020 (1.00X 10) 3 Or 1.00×10 4 TCID 50 Nasal inoculation of mice, 15-week-old mice), administration of vehicle twice a day from 1 day after infection, and weight fluctuation of fumaric acid co-crystal form I crystals of the compound shown in (I-B) for 5 days up to 7 days after infection. The vertical axis represents the weight fluctuation (%) when the weight on the day of infection is 100%, and the horizontal axis represents the self-inductanceDays after dyeing.
[ FIG. 8D]Shows that mice are infected with the domesticated strain MA-P10 for hCoV19/Japan/TY/WK-521/2020 (1.00X 10) 3 Or 1.00×10 4 TCID 50 Nasal inoculation of mice, 15 week old), survival of the fumaric acid co-crystal form I crystals of the compound shown in (I-B) for 5 days, up to 7 days after infection, twice a day from 1 day after infection. The vertical axis represents survival (%), and the horizontal axis represents days since infection.
FIG. 8E]Shows that mice are infected with the domesticated strain MA-P10 for hCoV19/Japan/TY/WK-521/2020 (1.00X 10) 3 TCID 50 Mice were vaccinated nasally, with senior retired mice of 35-45 weeks old), and medium was administered twice a day from 1 day after infection, and body weight was changed from 7 days after infection until 5 days for fumaric acid cocrystal form I crystals of the compound shown in (I-B). The vertical axis represents the weight change (%) when the body weight on the day of infection is 100%, and the horizontal axis represents the number of days since infection.
[ FIG. 8F]Shows that mice are infected with the domesticated strain MA-P10 for hCoV19/Japan/TY/WK-521/2020 (1.00X 10) 3 TCID 50 Nasal inoculation of mice, senior retired mice of 35-45 weeks old), administration of medium twice a day from 1 day after infection, survival rate of fumaric acid co-crystal form I crystals of the compound shown in (I-B) for 5 days until 7 days after infection. The vertical axis represents survival (%), and the horizontal axis represents days since infection.
FIG. 9]Shows that hCoV19/Japan/TY11-927/2021 was infected with hamsters (at 5.00X 10 3 PFU/hamster vaccinated nasally) and the pulmonary viral titer of the administered hamster 6 days after infection at the same time as the administered hamster without vaccinating. Hamsters were administered with fumaric acid co-crystal form I crystals of the compound shown in (I-B) twice a day from immediately after infection. The vertical axis represents intrapulmonary viral titers and the horizontal axis represents each administration group.
[ FIG. 10 ]]Shows administration of the Compounds to hCoV19/Japan/TY11-927/2021 infected hamsters (per 5.00X 10) 3 PFU/hamster nasal inoculation), since just after infectionInfected (Infected) hamsters and non-Infected (Contact) hamsters were Infected 6 days later to the same time as the non-Infected hamsters that were not vaccinated with the virus. Hamsters were administered with fumaric acid co-crystal form I crystals of the compound shown in (I-B) twice a day from immediately after infection. The vertical axis represents intrapulmonary viral titers and the horizontal axis represents each administration group.
FIG. 11A]Shows administration of the Compounds to hCoV19/Japan/TY11-927/2021 infected hamsters (1.00X 10) 2 TCID 50 Nasal inoculation of hamsters), infection (Infected) after 5 days of infection with non-Infected hamsters that were not vaccinated with virus at the same time since 2 days of infection, and intrapulmonary viral titers of non-Infected (Contact) hamsters. Hamsters were administered with fumaric acid co-crystal form I crystals of the compound shown in (I-B) twice a day from 1 day after infection. The vertical axis represents intrapulmonary viral titers and the horizontal axis represents each administration group.
FIG. 11B]Shows administration of the Compounds to hCoV19/Japan/TY11-927/2021 infected hamsters (1.00X 10) 2 TCID 50 Nasal inoculation of hamsters), infection (Infected) after 5 days of infection with non-Infected hamsters that were not vaccinated with virus at the same time since 2 days of infection, and intrapulmonary viral titers of non-Infected (Contact) hamsters. Hamsters were administered with fumaric acid co-crystal form I crystals of the compound shown in (I-B) twice a day from 1 day after infection. The vertical axis represents viral titers in the turbinates and the horizontal axis represents each administration group.
FIG. 12A]Shows that mice are infected with the domesticated strain MA-P10 for hCoV19/Japan/TY/WK-521/2020 (3.00X 10) 2 TCID 50 Nasal inoculation of mice, 37-57 week old), subcutaneous administration of vehicle 24 hours prior to infection, and weight change until 14 days after infection with the compound shown in (I-B). The vertical axis represents the weight change (%) when the body weight on the day of infection is 100%, and the horizontal axis represents the number of days since infection.
FIG. 12B]Shows that mice are infected with the domesticated strain MA-P10 for hCoV19/Japan/TY/WK-521/2020 (3.00X 10) 2 TCID 50 Nasal inoculation of mice, 37-57 week old mice), subcutaneous administration of medium 24 hours prior to infection (I-B)) Survival rate of the indicated compounds up to 14 days after infection. The vertical axis represents survival (%), and the horizontal axis represents days since infection.
Detailed Description
Hereinafter, the meaning of each term used in the present specification will be described. Unless specifically stated otherwise, each term is used in the same sense, either alone or in combination with other terms.
The term "consisting of … …" means having only the constituent elements.
The term "comprising" means not limited to the constituent elements, and does not exclude the elements not described.
Hereinafter, the present invention will be described with reference to the embodiments. Throughout this specification, unless specifically stated otherwise, the expression in the singular is to be understood as also encompassing the plural concepts thereof. Accordingly, unless specifically indicated otherwise, singular forms (e.g., "a," "an," "the," etc., in the context of English) are to be construed to also include plural forms of the concepts thereof.
In addition, in the present specification, unless specifically stated otherwise, terms used should be understood to be used in the meaning commonly used in the art. 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, the present specification, including definitions, will control.
The term "halogen" includes fluorine atom, chlorine atom, bromine atom and iodine atom. Fluorine atoms and chlorine atoms are particularly preferred.
The term "alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
Preferable examples of the "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferable examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
The "alkenyl group" includes a straight-chain or branched hydrocarbon group having 1 or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms. Examples thereof include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl (prenyl), butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, methacenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.
Preferred examples of the "alkenyl group" include vinyl, allyl, propenyl, isopropenyl, and butenyl. Further preferable examples include vinyl and n-propenyl.
The term "alkynyl" includes straight-chain or branched hydrocarbon groups having 1 or more triple bonds at any position and having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. The resin may further have a double bond at any position. For example, acetylene, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like are included.
Preferable examples of the "alkynyl" include ethynyl, propynyl, butynyl and pentynyl. Further preferable examples include an ethynyl group and propynyl group.
The term "aromatic carbocyclic group" means a monocyclic or 2-or more-ring cyclic aromatic hydrocarbon group. Examples thereof include phenyl, naphthyl, anthryl and phenanthryl.
As a preferred embodiment of the "aromatic carbocyclic group" a phenyl group is mentioned.
The term "6-membered aromatic carbocyclic group" means a monocyclic cyclic aromatic hydrocarbon group. For example, phenyl is mentioned.
The term "non-aromatic carbocyclic group" refers to a monocyclic or 2-or more cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. "non-aromatic carbocyclic group of 2 or more rings" also includes those obtained by fusing a ring in the above "aromatic carbocyclic group" to a monocyclic or 2 or more non-aromatic carbocyclic group.
In addition, "non-aromatic carbocyclic group" also includes a group bridged as follows, or a group forming a spiro ring.
[ chemical formula 17]
The monocyclic non-aromatic carbocyclic group is preferably a group having 3 to 16 carbon atoms, more preferably a group having 3 to 12 carbon atoms, and still more preferably a group having 4 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
The non-aromatic carbocyclic group having 2 or more rings is preferably a group having 8 to 20 carbon atoms, more preferably a group having 8 to 16 carbon atoms. Examples thereof include indanyl, indenyl, acenaphthylenyl, tetrahydronaphthyl and fluorenyl.
The term "aromatic heterocyclic group" refers to a monocyclic or 2-ring or more aromatic ring group having 1 or more heteroatoms selected from O, S and N optionally in the ring.
The 2-ring or more aromatic heterocyclic group also includes a group obtained by condensing a ring in the above "aromatic carbocyclic group" on a single ring or a 2-ring or more aromatic heterocyclic group, and may have the bond at any ring.
The monocyclic aromatic heterocyclic group is preferably 5 to 8-membered, more preferably 5-membered or 6-membered. Examples of the 5-membered aromatic heterocyclic group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a furanyl group, a thienyl group, an isoxazolyl group, an oxazolyl group, an oxadiazolyl group, an isothiazolyl group, a thiazolyl group, and a thiadiazolyl group. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
The 2-ring aromatic heterocyclic group is preferably 8 to 10-membered, more preferably 9-membered or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazole, imidazopyridinyl, triazolopyridinyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridinyl, thiazolopyridinyl, and the like. Examples of the 9-membered aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazole, benzofuranyl, imidazopyridinyl, triazolopyridinyl, oxazolopyridinyl, and thiazolopyridinyl. Examples of the 10-membered aromatic heterocyclic group include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, and the like.
The aromatic heterocyclic group having 3 or more rings is preferably 13 to 15 membered. Examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiazinyl, phenoxazinyl, dibenzofuranyl and the like.
The term "5-to 6-membered aromatic heterocyclic group" means a 5-or 6-membered aromatic heterocyclic group in the above-mentioned "aromatic heterocyclic group".
The term "9-to 10-membered aromatic heterocyclic group" means a 9-or 10-membered aromatic heterocyclic group in the above-mentioned "aromatic heterocyclic group".
The term "non-aromatic heterocyclic group" refers to a monocyclic or 2-ring or more non-aromatic ring group having 1 or more heteroatoms selected from O, S and N optionally in the ring. The 2-ring or more non-aromatic heterocyclic group also includes a group obtained by condensing each ring of the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", and/or "aromatic heterocyclic group" on a single ring or 2-ring or more non-aromatic heterocyclic group, and a group obtained by condensing a ring of the above-mentioned "aromatic heterocyclic group" on a single ring or 2-ring or more non-aromatic heterocyclic group, and may have such a bond at any ring.
In addition, the "non-aromatic heterocyclic group" includes a group which is bridged as described below, or a group which forms a spiro ring.
[ chemical formula 18]
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8-membered, more preferably 5-membered or 6-membered.
Examples of the 3-membered non-aromatic heterocyclic group include a thiiranyl group, an oxetanyl group, and an aziridinyl group. Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclic group include oxathiamyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxacyclopentyl, dioxolyl, tetrahydrothienyl, and the like. Examples of the 6-membered non-aromatic heterocyclic group include dioxanyl, thialkyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholino, dihydropyridinyl, tetrahydropyridinylTetrahydropyranyl, dihydro oxazinyl, tetrahydro pyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiaynyl, thiazinyl and the like. Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepine Radical, tetrahydrodiaza->A radical, an oxetanyl radical.
The non-aromatic heterocyclic group having 2 or more rings is preferably 8 to 20 membered, more preferably 8 to 13 membered, and still more preferably 8 to 10 membered. Examples thereof include indolinyl, isoindolinyl, chromanyl, and isochromanyl.
In the present specification, the term "optionally substituted with a substituent group α" means "optionally substituted with 1 or more groups selected from the substituent group α". The same applies to the substituent groups β, γ and γ'.
Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
Substituent group beta: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted by substituent group alpha, alkenyl which may be substituted by substituent group alpha, alkynyl which may be substituted by substituent group alpha, alkylcarbonyl which may be substituted by substituent group alpha, alkenylcarbonyl which may be substituted by substituent group alpha, alkynylcarbonyl which may be substituted by substituent group alpha, alkylsulfanyl which may be substituted by substituent group alpha, alkenylsulfanyl which may be substituted by substituent group alpha, alkynylsulfinyl which may be substituted by substituent group alpha, alkenylsulfinyl which may be substituted by substituent group alpha, alkynylsulfinyl which may be substituted by substituent group alpha, alkylsulfonyl which may be substituted by substituent group alpha, alkenylsulfonyl which may be substituted by substituent group alpha, alkynylsulfonyl which may be substituted by substituent group alpha,
An aromatic carbocyclic group which may be substituted with a substituent group gamma, a non-aromatic carbocyclic group which may be substituted with a substituent group gamma ', an aromatic heterocyclic group which may be substituted with a substituent group gamma', a non-aromatic heterocyclic group which may be substituted with a substituent group gamma ', an aromatic carbocyclic alkyl group which may be substituted with a substituent group gamma', a non-aromatic carbocyclic alkyl group which may be substituted with a substituent group gamma ', an aromatic heterocyclic alkyl group which may be substituted with a substituent group gamma, a non-aromatic heterocyclic alkyl group which may be substituted with a substituent group gamma', an aromatic carbocyclic carbonyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclic carbonyl group which may be substituted with a substituent group gamma', an aromatic heterocyclic carbonyl group which may be substituted with a substituent group gamma ', a non-aromatic heterocyclic carbonyl group which may be substituted with a substituent group gamma', an aromatic carbocyclic oxycarbonyl group which may be substituted with a substituent group gamma 'a non-aromatic carbocyclic oxycarbonyl group which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic oxycarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclic thio group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic thio group which may be substituted with a substituent group γ', an aromatic heterocyclic thio group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic thio group which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ', a heterocyclic sulfonyl group which may be substituted with a substituent group γ, an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ'.
Substituent group γ: substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl.
Substituent group γ': substituent group gamma and oxo group.
Examples of the substituents on the rings of the "aromatic carbocycle" and "aromatic heterocycle" of the "substituted aromatic carbocycle group" and "substituted aromatic heterocycle group" include the following substituent group B. The atom at any position on the ring may be bonded to 1 or more groups selected from the following substituent group B.
Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfinyl, sulfo, thiocarbonyl, thiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl,
an alkyl group which may be substituted with a substituent group α, an alkenyl group which may be substituted with a substituent group α, an alkynyl group which may be substituted with a substituent group α, an alkyloxycarbonyl group which may be substituted with a substituent group α, an alkenyloxy group which may be substituted with a substituent group α, an alkynyloxy group which may be substituted with a substituent group α, an alkylcarbonyloxy group which may be substituted with a substituent group α, an alkenylcarbonyloxy group which may be substituted with a substituent group α, an alkylcarbonyl group which may be substituted with a substituent group α, an alkenylcarbonyl group which may be substituted with a substituent group α, an alkenyloxycarbonyl group which may be substituted with a substituent group α, an alkynyloxycarbonyl group which may be substituted with a substituent group α, an alkylsulfanyl group which may be substituted with a substituent group α, an alkenylsulfanyl group which may be substituted with a substituent group α, an alkynylsulfinyl group which may be substituted with a substituent group α, an alkylsulfinyl group which may be substituted with a substituent group α, an alkenylsulfinyl group which may be substituted with a substituent group α, an alkynylsulfonyl group which may be substituted with a substituent group α,
Amino group which may be substituted with substituent group beta, imino group which may be substituted with substituent group beta, carbamoyl group which may be substituted with substituent group beta, sulfamoyl group which may be substituted with substituent group beta,
an aromatic carbocyclic group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic group which may be substituted with a substituent group γ ', an aromatic heterocyclic group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic group which may be substituted with a substituent group γ ', an aromatic carbocyclic oxy which may be substituted with a substituent group γ ', a non-aromatic carbocyclic oxy which may be substituted with a substituent group γ ', an aromatic heterocyclic oxy which may be substituted with a substituent group γ ', a non-aromatic heterocyclic oxy which may be substituted with a substituent group γ ', an aromatic carbocyclic carbonyl oxy which may be substituted with a substituent group γ ', a non-aromatic carbocyclic carbonyl oxy which may be substituted with a substituent group γ ', an aromatic heterocyclic carbonyl oxy which may be substituted with a substituent group γ ', a non-aromatic heterocyclic carbonyl oxy which may be substituted with a substituent group γ ', an aromatic carbocyclic carbonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic carbonyl group which may be substituted with a substituent group γ a non-aromatic carbocyclic carbonyl group which may be substituted with a substituent group gamma ', an aromatic heterocyclic carbonyl group which may be substituted with a substituent group gamma ', a non-aromatic heterocyclic carbonyl group which may be substituted with a substituent group gamma ', an aromatic carbocyclic oxycarbonyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclic oxycarbonyl group which may be substituted with a substituent group gamma ', an aromatic heterocyclic oxycarbonyl group which may be substituted with a substituent group gamma ', a non-aromatic heterocyclic oxycarbonyl group which may be substituted with a substituent group gamma ', an aromatic carbocyclic alkyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclic alkyl group which may be substituted with a substituent group gamma ', an aromatic heterocyclic alkyl group which may be substituted with a substituent group gamma ', a non-aromatic heterocyclic alkyl group which may be substituted with a substituent group gamma ', an aromatic carbocyclic alkyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclic alkyl group which may be substituted with a substituent group gamma An aromatic heterocycloalkyloxy group which may be substituted with a substituent group γ ', a non-aromatic heterocycloalkyloxy group which may be substituted with a substituent group γ ', an aromatic carbocyclic alkyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic alkyloxycarbonyl group which may be substituted with a substituent group γ ', an aromatic heterocycloalkyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic heterocycloalkyloxycarbonyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic alkyloxyalkyl group which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxyalkyl group which may be substituted with a substituent group γ ', an aromatic heterocycloalkyloxyalkyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic thioalkyl group which may be substituted with a substituent group γ ' a non-aromatic carbocyclic sulfanyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfanyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic sulfanyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ ', and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ '.
The substituents on the rings of the "non-aromatic carbocyclic ring" and the "non-aromatic heterocyclic ring" of the "substituted non-aromatic carbocyclic group" and the "substituted non-aromatic heterocyclic group" include the following substituent group C. The atom at any position on the ring may be bonded to 1 or more groups selected from the following substituent group C.
Substituent group C: substituent group B and oxo.
When the "non-aromatic carbocyclic ring" and the "non-aromatic heterocyclic ring" are substituted with the "oxo group", the "non-aromatic carbocyclic ring" refers to a ring in which 2 hydrogen atoms on carbon atoms are substituted as described below.
[ chemical formula 19]
As R 1 The substituent of the "substituted or unsubstituted aromatic heterocyclic group" or "substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group" in (a) may be exemplified by:
halogen;
substituted or unsubstituted alkyl.
May be substituted with 1 or more groups selected from them.
As R 1 In the formula, "substituted or unsubstituted aromatic heterocyclic group" or "substituted or unsubstituted 5-to 6-membered aromatic heterocyclic ringExamples of the substituent of the group "of the formula include:
halogen;
substituted alkyl (hydroxy as substituent); unsubstituted alkyl.
May be substituted with 1 or more groups selected from them.
As R 2 Examples of the substituent of the "substituted or unsubstituted 6-membered aromatic carbocyclic group" in (a) include:
halogen; cyano group;
substituted or unsubstituted alkyl.
May be substituted with 1 or more groups selected from them.
As R 2 Examples of the substituent of the "substituted or unsubstituted 6-membered aromatic carbocyclic group" in (a) include:
halogen; cyano group;
substituted alkyl (halogen as a substituent); unsubstituted alkyl.
May be substituted with 1 or more groups selected from them.
As R 3 The substituent of the "substituted or unsubstituted aromatic heterocyclic group" or "substituted or unsubstituted 9-10 membered aromatic heterocyclic group" in (a) may be exemplified by:
halogen;
substituted or unsubstituted alkyl;
a substituted or unsubstituted non-aromatic heterocyclic group.
May be substituted with 1 or more groups selected from them.
As R 3 The substituent of the "substituted or unsubstituted aromatic heterocyclic group" or "substituted or unsubstituted 9-10 membered aromatic heterocyclic group" in (a) may be exemplified by:
halogen;
substituted alkyl (halogen, hydroxy, alkylcarbonylamino, non-aromatic heterocyclic group as substituents); unsubstituted alkyl;
Substituted non-aromatic heterocyclic group (alkylcarbonyl as substituent); unsubstituted non-aromatic heterocyclic groups.
May be substituted with 1 or more groups selected from them.
R in the compound represented by the following formula (I) 1 、R 2 、R 3 And m. Examples of the compound represented by the formula (I) include all combinations of specific examples shown below. Y, -X-, R 5a 、R 5b 、n、R 4a R is R 4b As shown in item (1) above.
[ chemical formula 20]
R 1 Examples thereof include a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-1).
R 1 Examples thereof include a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group (hereinafter referred to as A-2).
R 1 Examples thereof include an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-3) substituted with halogen, a substituted alkyl group (substituent: hydroxy group) or an unsubstituted alkyl group.
R 1 Examples thereof include a 5-to 6-membered aromatic heterocyclic group substituted with halogen, a substituted alkyl group (substituent: hydroxy group) or an unsubstituted alkyl group, and an unsubstituted 5-to 6-membered aromatic heterocyclic group (hereinafter referred to as A-4).
R 1 Examples thereof include an aromatic heterocyclic group substituted with an unsubstituted alkyl group or halogen, and an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-5).
R 1 Examples thereof include a 5-to 6-membered aromatic heterocyclic group substituted with an unsubstituted alkyl group or halogen, and an unsubstituted 5-to 6-membered aromatic heterocyclic group (hereinafter referred to as A-6).
R 1 Examples thereof include an aromatic heterocyclic group substituted with an unsubstituted alkyl group or halogen (hereinafter referred to as A-7).
R 1 Examples thereof include a 5-to 6-membered aromatic heterocyclic group substituted with an unsubstituted alkyl group or halogen (hereinafter referred to as "heterocyclic group")A-8)。
R 1 Examples thereof include an aromatic heterocyclic group substituted with an unsubstituted alkyl group and an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-9).
R 1 Examples thereof include a 5-to 6-membered aromatic heterocyclic group substituted with an unsubstituted alkyl group and an unsubstituted 5-to 6-membered aromatic heterocyclic group (hereinafter referred to as A-10).
R 1 An aromatic heterocyclic group substituted with an unsubstituted alkyl group (hereinafter referred to as A-11) may be mentioned.
R 1 Examples thereof include a 5-to 6-membered aromatic heterocyclic group substituted with an unsubstituted alkyl group (hereinafter referred to as A-12).
R 2 Examples thereof include a substituted or unsubstituted 6-membered aromatic carbon ring group (hereinafter referred to as B-1).
R 2 Examples thereof include a 6-membered aromatic carbon ring group substituted with halogen, cyano, substituted alkyl (substituent: halogen) or unsubstituted alkyl (hereinafter referred to as B-2).
R 2 Examples thereof include a 6-membered aromatic carbon ring group substituted with halogen, cyano or unsubstituted alkyl (hereinafter referred to as B-3).
R 2 Examples thereof include a 6-membered aromatic carbon ring group (hereinafter referred to as B-4) substituted with 2 to 4 substituents selected from substituent group G (substituent group G: halogen, cyano and unsubstituted alkyl).
R 2 Examples thereof include a 6-membered aromatic carbon ring group (hereinafter referred to as B-5) substituted with 2 to 3 substituents selected from substituent group G (substituent group G: halogen, cyano and unsubstituted alkyl).
R 2 Examples thereof include a 6-membered aromatic carbon ring group (hereinafter referred to as B-6) substituted with 3 to 4 substituents selected from the substituent group G (substituent group G: halogen, cyano and unsubstituted alkyl).
R 2 Examples thereof include a 6-membered aromatic carbon ring group substituted with 3 halogens (hereinafter referred to as B-7).
R 3 Examples thereof include a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-1).
R 3 Can be substituted or unsubstituted9-to 10-membered aromatic heterocyclic group (hereinafter referred to as C-2).
R 3 Examples thereof include an aromatic heterocyclic group substituted with halogen or a substituted or unsubstituted alkyl group (hereinafter referred to as C-3).
R 3 Examples thereof include a 9-to 10-membered aromatic heterocyclic group (hereinafter referred to as C-4) substituted with halogen or a substituted or unsubstituted alkyl group.
R 3 Examples thereof include an aromatic heterocyclic group substituted with halogen or unsubstituted alkyl (hereinafter referred to as C-5).
R 3 Examples thereof include 9-to 10-membered aromatic heterocyclic groups substituted with halogen or unsubstituted alkyl groups (hereinafter referred to as C-6).
R 3 An indazolyl group substituted with a halogen or an unsubstituted alkyl group (hereinafter referred to as C-7) may be mentioned.
R 3 Examples thereof include indazolyl groups substituted with halogen and unsubstituted alkyl groups (hereinafter referred to as C-8).
m is 0 or 1 (hereinafter referred to as D-1).
m is 0 (hereinafter referred to as D-2).
m is 1 (hereinafter referred to as D-3).
The compounds represented by the formula (I) can be exemplified by the following modes.
(a-1)
R 1 Is (A-12);
R 2 is (B-7);
R 3 is (C-8);
m is (D-2).
(a-2)
R 1 Is (A-12);
R 2 is (B-7);
R 3 is (C-8);
m is (D-3).
(a-3)
R 1 Is (A-12);
R 2 is (B-7);
R 3 is (C-8);
m is (D-1).
(a-4)
R 1 Is (A-4);
R 2 is (B-4);
R 3 is (C-4);
m is (D-1).
The compound represented by the formula (I) is preferably a compound represented by the formula (I-A) or a compound represented by the formula (I-B).
The chemical structural formulas shown in the formula (I), the formula (I-A) and the formula (I-B) are also used in a unified manner in the formulas.
The compounds of formula (I) are not limited to a particular isomer, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof. For example, the compounds represented by formula (I) include such tautomers as follows.
[ chemical formula 21]
For example, the compounds represented by the formula (I-A), the compounds (I-003) include the following tautomers and mixtures thereof.
[ chemical formula 22]
For example, the compound represented by the formula (I-B), the compound (I-005) include the following tautomers and mixtures thereof.
[ chemical formula 23]
More than one hydrogen, carbon and/or other atoms of the compound represented by formula (I) may each be replaced with isotopes of hydrogen, carbon and/or other atoms. As such isotopesExamples of (a) are respectively as follows 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F、 123 I, I 36 Cl thus contains hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. The compounds represented by formula (I) also include compounds substituted with such isotopes. The isotopically substituted compounds are also useful as pharmaceuticals, including all radiolabels of compounds represented by formula (I). In addition, a "radiolabeling method" for making the "radiolabel" is also included in the present invention, which is useful as a tool for metabolic drug kinetic studies, studies in binding assays, and/or diagnostics.
The crystal of the present invention may be a deuterium transformant. The crystals of the present invention may also be modified with co-located elements (e.g., 3 H、 14 C、 35 S、 125 I), etc.).
Radiolabeled bodies of compounds of formula (I) may be prepared using methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by: tritium is introduced into a specific compound represented by the formula (I) by catalytic dehalogenation using tritium. The method comprises the following steps: a precursor obtained by appropriately subjecting a compound represented by formula (I) to halogen substitution in the presence or absence of a base in the presence of an appropriate catalyst, for example, pd/C, is reacted with tritium gas. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, vol.1, labeled Compounds (Part a), chapter 6 (1987)". 14 The C-labelled compound may be prepared by using a compound having the following properties 14 C carbon raw material.
Examples of pharmaceutically acceptable salts of the compound represented by the formula (I) include salts of the compound represented by the formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.), and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., 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.). These salts can be formed by a conventionally practiced method.
As pharmaceutically acceptable salts of the compounds of formula (I-A), for example, those formed from the compounds of formula (I-A) and a counter-molecule or counter-ion, any number of counter-molecules or counter-ions may be included. Pharmaceutically acceptable salts of the compounds of formula (I-A) refer to salts that mediate ionic bonding by proton transfer between the compound and the counter molecule or counter atom.
The pharmaceutically acceptable salt of the compound of formula (I-A) is preferably p-toluenesulfonate of the compound of formula (I-A).
In the preparation of the present invention, a complex of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be used. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may sometimes form solvates (e.g., hydrates, etc.), co-crystals, and/or clathrates, and these are referred to as "complexes" in this specification.
As used herein, "solvate" means that any number of solvent molecules (e.g., water molecules, etc.) can be coordinated to, for example, a compound of formula (I). The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is allowed to stand in the atmosphere to absorb moisture, and water is adsorbed or a hydrate is formed.
Examples of the solvent molecule include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1, 2-dichloroethylene, methylene chloride, 1, 2-dimethoxyethane, N-dimethylacetamide and N, N-dimethylformamide, 1, 4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydronaphthalene, toluene, 1, 2-trichloroethylene, xylene, acetic acid, anisole, 1-butanol, 2-butanol, N-butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, water (i.e., hydrates), ethanol, acetone, 1-diethoxypropane, 1-dimethoxymethane, 2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, preferable examples include acetic acid, anisole, 1-butanol, 2-butanol, N-butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, water (i.e., hydrate), ethanol, acetone, 1-diethoxypropane, 1-dimethoxymethane, 2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, more preferably, water (i.e., hydrate), ethanol, acetone, 1-diethoxypropane, 1-dimethoxymethane, 2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, and the like are mentioned.
As used herein, "co-crystal" refers to a regular arrangement of counter molecules within the same lattice, and may include any number of counter molecules. The co-crystal means: the intermolecular interaction between the compound and the counter molecule is a substance that chemically interacts non-covalently and non-ionically, such as hydrogen bonds and van der waals forces.
For example, as a co-crystal of the compound represented by the formula (I-B), composed of the compound represented by the formula (I-B) and a counter molecule, any number of counter molecules may be contained. Preferably consisting of a compound of formula (I-B) and fumaric acid, any number of fumaric acids may be included. It is further preferable that the molar ratio of the compound represented by the formula (I-B) to fumaric acid is 1: 1.
The co-crystal is distinguished from salt in the following ways: the compound remains essentially charge-free or neutral.
The co-crystal is distinguished from the hydrate or solvate in the following ways: the counter molecule is not water or solvent.
As used herein, "crystal" refers to a solid in which constituent atoms, ions, molecules, and the like are regularly arranged in three dimensions, and is distinguished from an amorphous solid that does not have such a regular internal structure. The crystals of the present invention may be single crystal, bicrystal, polycrystal, etc.
In addition, "crystals" sometimes exist in "polymorphs" which are identical in composition but differ in arrangement in the crystals, and they are collectively referred to as "crystal forms".
The crystal form and crystallinity can be measured by various techniques including powder X-ray diffraction measurement, raman spectroscopy, infrared absorption spectrometry, moisture absorption/desorption measurement, differential scanning calorimetry measurement, and dissolution characteristics, for example.
In addition, a "polymorph" may be formed by recrystallizing a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a complex thereof.
In the preparation of the present invention, various salts, complexes (hydrates, solvates, co-crystals, clathrates) and polymorphs thereof may be used, and a mixture of two or more of them may be used.
(powder X-ray diffraction (XRPD))
Powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for determining the crystalline form and crystallinity of solids. When the crystal is irradiated with X-rays, reflection occurs at the lattice plane, and mutual interference occurs, and ordered diffraction lines corresponding to the period of the structure are displayed. On the other hand, amorphous solids generally do not have an ordered repetition period in their structure, and therefore, do not undergo diffraction phenomena, exhibiting a broad XRPD pattern without features (also known as a halo pattern).
The crystal forms of the compounds represented by the formulas (I-A) and (I-B) can be identified by powder X-ray diffraction patterns and characteristic diffraction peaks. The crystalline forms of the compounds of formula (I-A) and formula (I-B) can be distinguished from other crystalline forms by the presence of characteristic diffraction peaks.
The characteristic diffraction peak used in the present specification is a peak selected from the observed diffraction patterns. The characteristic diffraction peaks are preferably selected from about 10, more preferably about 5, and even more preferably about 3 of the diffraction patterns.
In distinguishing a plurality of crystals, a peak that is confirmed in the crystal and is not confirmed in other crystals becomes a characteristic peak preferable for determining the crystal, compared with the intensity of the peak. If such characteristic peaks are present, one or both peaks may also characterize the crystal. Comparing the measured images, it can be said that the powder X-ray diffraction patterns are substantially identical if the characteristic peaks are identical.
In general, since an error may occur in the diffraction angle (2θ) in powder X-ray diffraction in the range of ±0.2°, it is to be understood that the value of the diffraction angle in powder X-ray diffraction also includes a value in the range of about ±0.2°. Therefore, not only crystals in which diffraction angles of peaks in powder X-ray diffraction are completely uniform, but also crystals in which diffraction angles of peaks are uniform with an error of about ±0.2° are included in the present invention.
It is known that the intensities of the peaks shown in the following tables and figures may generally vary depending on various factors, such as the effect of the preferred orientation of the crystal with respect to the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. In addition, the peak position may be shifted based on the variation in the sample height. In addition, when measurements are made using different wavelengths, different offsets can be obtained according to the bragg equation (nλ=2dsinθ), but other XRPD patterns obtained by using other wavelengths are also included within the scope of the present invention.
(analysis of Single Crystal Structure)
By one of the methods for specifying a crystal, parameters of crystallography, atomic coordinates (values indicating spatial positional relationships of atoms) and a three-dimensional structure model in the crystal can be obtained. Reference is made to sakura's guidelines for X-ray structural analysis "skirt chinese house release (1983), stout & Jensen, X-Ray Structure Determination: a Practical Guide, macmillan co., new York (1968), etc. Single crystal structure analysis is useful in identifying the structure of crystals of such complexes, salts, optical isomers, tautomers, geometric isomers of the present invention.
The compound of the present invention has coronavirus 3CL protease inhibitory activity and is therefore useful as a therapeutic and/or prophylactic agent for diseases in which coronavirus 3CL protease participates. In the present invention, the term "therapeutic agent and/or prophylactic agent" also includes a symptom-improving agent. The disease in which coronavirus 3CL protease participates may be a viral infectious disease, and preferably a coronavirus infectious disease.
As one embodiment, coronaviruses that infect humans are exemplified. As coronaviruses infecting humans, HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2 can be mentioned.
In one embodiment, the coronavirus may be an α coronavirus and/or a β coronavirus, more preferably a β coronavirus, and still more preferably sarbecovirus.
As one embodiment, examples of the alpha coronavirus include HCoV-229E and HCoV-NL63. HCoV-229E is particularly preferred.
As one embodiment, examples of the beta coronavirus include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. Preferably, HCoV-OC43 or SARS-CoV-2, and particularly preferably SARS-CoV-2.
As one embodiment, as the beta coronavirus, there may be mentioned beta coronavirus lineage A (beta-coronavirus lineage A), beta coronavirus lineage B (beta-coronavirus lineage B), and beta coronavirus lineage C (beta-coronavirus lineage C). More preferably, the beta coronavirus lineage A (beta-coronavirus lineage A) and the beta coronavirus lineage B (beta-coronavirus lineage B), and particularly preferably, the beta coronavirus lineage B (beta-coronavirus lineage B) are exemplified.
As the beta coronavirus lineage A (. Beta. -coronavirus lineage A), for example, HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43, can be mentioned. As the beta coronavirus spectrum B (. Beta. -coronavirus lineage B), for example, SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2, can be mentioned. As the beta coronavirus lineage C (. Beta. -coronavirus lineage C), MERS-CoV is preferably mentioned.
As one embodiment, the coronavirus may be HCoV-229E, HCoV-OC43 and/or SARS-CoV-2, and particularly preferably SARS-CoV-2.
It is generally known that viruses mutate during repeated multiplication and infection. The coronavirus may be any strain in which the compound of the present invention can exhibit the coronavirus 3CL protease inhibitory activity, and includes not only known variants in the art but also variants which will appear in the future. As a known variant of SARS-CoV-2, there can be mentioned, for example, a variant used in the examples of the present specification.
Examples of infectious diseases caused by coronaviruses include HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. The infectious disease caused by HCoV-229E, HCoV-OC43 and/or SARS-CoV-2 is preferable, and the infectious disease caused by SARS-CoV-2 is particularly preferable.
As coronavirus infectious diseases, a novel coronavirus infectious disease (COVID-19) is particularly preferred.
Examples of the classification of the severity of disease in patients infected with the novel coronavirus are as follows. ( Reference is made to: new coronavirus infectious disease COVID-19 diagnosis and treatment guide version 5.2 (Japanese Ministry of thick students) )
(light symptoms)
The oxygen saturation is 96% or more. The clinical state is: no symptoms of respiratory organs, or cough alone, no dyspnea, and in any case no manifestations of pneumonia were found.
(middle-aged condition I)
Oxygen saturation is less than 96% and greater than 93%. Dyspnea and pneumonia are manifested.
(middle disease II)
Oxygen saturation was less than 93%. There is respiratory failure, requiring oxygen administration.
(severe cases)
Into the ICU or requires a respirator.
The above classification is a definition of the severity classification in japan, and for example, the severity classification in NIH in china and usa can be cited.
In addition, the asymptomatic SARS-CoV-2 infected person refers to an asymptomatic pathogen carrier. For example, 14 kinds of people whose symptoms of COVID-19 are not recognized can be mentioned.
( 14 symptoms of covd-19: tiredness, muscle or body pain, headache, chills, fever, abnormal taste, abnormal smell, runny nose or stuffy nose, sore throat, cough, shortness of breath, nausea, vomiting, diarrhea )
In the present specification, the 12 symptoms of covd-19 include tiredness, muscle or body pain, headache, chills, fever, runny nose or nasal obstruction, sore throat, cough, shortness of breath, nausea, vomiting, and diarrhea.
In the present specification, severe inhibition means: inhibiting asymptomatic SARS-CoV-2 infection increases to a point where the condition is classified as mild, moderate I, moderate II or severe.
In the present specification, severe inhibition means: inhibiting asymptomatic SARS-CoV-2 infection or mild SARS-CoV-2 infection is increased to a degree that is classified as moderate I, moderate II or severe.
In the present specification, severe inhibition means: inhibiting the asymptomatic SARS-CoV-2 infected person, the mild SARS-CoV-2 infected person or the moderate SARS-CoV-2 infected person of moderate disease I, to a mild degree classified as moderate disease II or severe disease.
In the present specification, severe inhibition means: inhibiting the increase of asymptomatic SARS-CoV-2 infected patients, mild SARS-CoV-2 infected patients, moderate SARS-CoV-2 infected patients of moderate disease I or moderate SARS-CoV-2 infected patients of moderate disease II to the extent of mild illness classified as severe.
In the present specification, severe inhibition means: by virtue of the viral proliferation inhibitory effect of the agent of the present invention, the risk of hospitalization and death of SARS-CoV-2 infected patients is reduced.
In the present specification, severe inhibition means: the virus proliferation inhibition effect of the agent of the present invention reduces inflammation in the lung of SARS-CoV-2 infected patients.
In the present specification, severe inhibition means: the virus proliferation inhibitory effect of the agent of the present invention inhibits pneumonia caused by viral infection of SARS-CoV-2.
In the present specification, severe inhibition means: by the virus proliferation inhibition effect of the agent of the present invention, the host immune excessive response caused by the virus infection of SARS-CoV-2 is inhibited.
One embodiment of the present invention is to administer the pharmaceutical composition of the present invention to an infected patient having at least one of the following severe risk factors among SARS-CoV-2 infected patients.
Over 50 years old
Obesity (BMI of 30 kg/m) 2 Above, the method comprises
Cardiovascular diseases (including diseases of the cardiovascular system including hypertension and congenital heart disease)
Chronic lung disease (including asthma, interstitial lung disease)
Type 1 or type 2 diabetes
Chronic kidney injury (including dialysis patients)
Chronic liver disease
Immunosuppressed state (e.g., malignancy treatment, bone marrow or organ transplantation, immunodeficiency, poorly controlled HIV, AIDS, sickle cell anemia, thalassemia, long-term administration of immunosuppressant)
Chronic Obstructive Pulmonary Disease (COPD)
Dyslipidemia (He)
Smoke-absorbing
Immunodeficiency after solid organ transplantation
Pregnancy (gestation)
Patients suffering from a neurological disease or complex condition (e.g., cerebral palsy, congenital disease)
Patients with high medical dependence (e.g. tracheotomy, gastrostomy, positive pressure ventilation)
As one embodiment, the pharmaceutical composition of the present invention may be used to inhibit the severity of a symptom of covd-19 by administering to an infected person having at least one risk factor for severity.
As one embodiment, the pharmaceutical composition of the present invention can be used in patients suffering from pneumonia caused by SARS-CoV-2.
One embodiment of the present invention is to administer the pharmaceutical composition of the present invention to an infected patient having at least one of the following severe risk factors among SARS-CoV-2 infected patients.
Patients fitted with ECMO (extracorporeal membrane type artificial lung)
Patient fitted with artificial respirator
Patient entering ICU
Oxygen saturation (SpO) 2 ) Patients with less than 93% (indoor air) or requiring oxygen inhalation
One embodiment of the present invention is to administer the pharmaceutical composition of the present invention to an infected patient having at least one of the following severe risk factors among SARS-CoV-2 infected patients.
Oxygen saturation (SpO 2) less than 94% (indoor air, sea level)
PaO2/FiO2 of less than 300mmHg
Respiratory rate of 30 times/min or more
Lung infiltration of 50% or more
(Process for producing Compound of formula (I))
The compound represented by the formula (I) can be produced, for example, by a general synthesis method shown below. The extraction, purification, and the like may be performed by performing a treatment performed in a usual organic chemistry experiment. Reference may be made to methods known in the art for synthesis. The extraction, purification, and the like may be performed by performing a treatment performed in a usual organic chemistry experiment.
The compounds of formula (I) may be prepared by methods known in the art. For example, reference may be made to WO2010092966, WO2012020749, WO2013089212, WO2014200078, WO2012020742, WO2013118855 and the like.
(A method)
[ chemical formula 24]
(wherein Alk is a C1-C3 alkyl group, lg 1 R is a leaving group 6 The other symbols are synonymous with the foregoing, and are hydrogen atoms. )
(step 1)
In a solvent such as N, N-dimethylformamide, N-dimethylacetamide, N '-dimethylimidazolidinone, dimethylsulfoxide, or THF, in the presence of a base such as DBU, triethylamine, N-diisopropylethylamine, or pyridine (preferably DBU), under cooling conditions of-20 to 50 ℃, preferably-10 to ice, the compound (A-1) or its hydrochloride or bromate is reacted with the isocyanate (A-2) or 1-carbamoyl imidazole (A-2'). Then, the reaction mixture is reacted with a carbonylation agent such as 1,1' -carbonyldiimidazole, phosgene or triphosgene, and a base such as DBU, triethylamine, N-diisopropylethylamine or pyridine (preferably DBU) at-20℃to 50℃and preferably-10℃to ice-cool, whereby the compound (A-3) can be produced.
(step 2)
Compound (A-5) can be produced by reacting compound (A-3) with compound (A-4) in a solvent such as acetonitrile, acetone, DMF, or DMSO in the presence of a base such as potassium carbonate, sodium carbonate, N-diisopropylethylamine, or the like, under a heating reflux, preferably a heating reflux, of 50℃to 50 ℃.
Examples of the leaving group include halogen and-OSO 2 (C t F 2t+1 ) (wherein t is an integer of 1 to 4), and the like. As halogen, preference is given to chlorine, iodine and bromine, as-OSO 2 (C t F 2t+1 ) Base grouppreferably-OTf group (triflate).
(step 3)
The compound represented by the formula (I) can be produced by reacting the compound (A-5) with the compound (A-6) or the compound (A-6') in a solvent such as NMP, DMF, DMA, DMSO, t-butanol or 2-methyl-2-butanol in the presence or absence of an acid such as acetic acid at 60℃to 150℃and preferably 80℃to 120 ℃.
By using the optically active isocyanate (A-2), a compound represented by the optically active compound (I) can be produced.
(method B)
[ chemical formula 25]
(wherein Alk is a C1-C3 alkyl group, pro is a C1-C4 alkyl group or a tert-butoxycarbonyl group, lg 2 R is a leaving group 6 The other symbols are synonymous with the foregoing, and are hydrogen atoms. )
(step 1)
The compound (B-2) can be produced from the compound (B-1) in the same manner as in the step 2 of the above-mentioned A method.
(step 2)
Compound (B-3) can be produced by treating compound (B-2) with a strong acid such as TFA at-20℃to room temperature, preferably at room temperature, in the presence or absence of an organic solvent.
(step 3)
The compound (B-4) can be produced from the compound (B-3) in the same manner as in the step 3 of the above-mentioned method A.
(step 4)
The compound (I-X) can be produced by Goldberg amination using the compound (B-4) and the compound (B-5).
The leaving group includes the leaving group described in step 1 of the method A.
As the catalyst, for example, commercially available copper catalysts such as copper iodide, copper cyanide, copper bromide and the like can be used.
As the ligand, 1, 2-dimethylethylenediamine, trans-N, N' -dimethylcyclohexane-1, 2-diamine, and the like can be used.
As the base, potassium carbonate, potassium phosphate, or the like can be used.
As the solvent, NMP, dioxane, DMSO, or the like can be used.
The reaction temperature may be any temperature from room temperature to the reflux temperature of the solvent, and it is preferable to carry out the reaction under reflux by heating.
(method C)
[ chemical formula 26]
(wherein Alk is a C1-C3 alkyl group, lg 3 Other symbols are synonymous with the foregoing as leaving groups. )
(step 1)
The compound (C-2) can be produced in the same manner as in the step 2 of the above-mentioned A method.
The leaving group includes the leaving group described in step 1 of the method A.
(step 2)
The compound represented by the compound (I) can be produced in the same manner as in the step 3 of the above-mentioned method a.
The compounds of the present invention have coronavirus 3CL protease inhibitory activity and are therefore useful as therapeutic and/or prophylactic agents for viral infectious diseases.
The compound according to the present invention is useful as a medicine, and preferably has any one or more of the following excellent characteristics.
a) The inhibition of CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Shows good pharmacokinetics with high bioavailability, moderate clearance rate and the like.
c) High metabolic stability.
d) The CYP enzyme (e.g., CYP3 A4) does not exhibit an irreversible inhibitory effect in the concentration range of the measurement conditions described in the present specification.
e) Has no mutagenicity.
f) The risk of cardiovascular system is low.
g) Showing high solubility.
h) The protein unbound fraction (fu value) was high.
i) Has high selectivity of coronavirus 3CL protease.
j) Has high coronavirus proliferation inhibiting activity. For example, it has high coronavirus proliferation inhibitory activity when added to Human Serum (HS) or Human Serum Albumin (HSA).
Examples of the coronavirus proliferation inhibitor include, for example, EC in the CPE inhibition effect confirmation test (SARS-CoV-2) described later 50 Is 10. Mu.M or less, preferably 1. Mu.M or less, more preferably 100nM or less.
The salt, crystal and complex (co-crystal) of the compound represented by formula (I) is useful as a medicine, and preferably has any one or more of the following excellent characteristics.
A) Shows high bioavailability, moderate clearance, high AUC, high maximum blood concentration, etc., and good pharmacokinetics.
B) Shows high solubility, high chemical stability and low hygroscopicity.
The pharmaceutical composition of the present invention may be administered by any method orally, parenterally. Examples of the parenteral administration include percutaneous, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
In the case of oral administration, the composition may be formulated into any of commonly used dosage forms such as solid preparations for internal use (for example, tablets, powders, granules, capsules, pills, films, etc.), solutions for internal use (for example, suspensions, emulsions, elixirs, syrups, lemonades, alcoholic solutions, aromatic solutions, extracts, decoction, tinctures, etc.), and the like, according to a conventional method. The tablet can be sugar-coated tablet, film coated tablet, enteric coated tablet, delayed release tablet, buccal tablet, sublingual tablet, buccal tablet, chewable tablet or orally disintegrating tablet, the powder and granule can be dry syrup, and the capsule can be soft capsule, microcapsule or delayed release capsule.
In the case of parenteral administration, it can be suitably administered by any of commonly used dosage forms such as injections, drops, external preparations (e.g., eye drops, nose drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, cough-containing agents, enemas, ointments, plasters, jellies, creams, patches, cataplasms, external powders, suppositories, etc.). The injection can be O/W, W/O, O/W/O, W/O/W emulsion.
The compound of the present invention can be mixed with various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form thereof, if necessary, in an effective amount to prepare a pharmaceutical composition. The pharmaceutical composition can be prepared into a pharmaceutical composition for children, the elderly, patients with severe symptoms or for surgery by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention. For example, the pharmaceutical composition for children may be administered to a newborn (less than 4 weeks after birth), an infant (4 weeks after birth and less than 1 year old), a young child (more than 1 year old and less than 7 years old), a child (more than 7 years old and less than 15 years old), or a patient between 15 and 18 years old. For example, a pharmaceutical composition for elderly people may be administered to patients over 65 years old.
The administration amount of the pharmaceutical composition of the present invention (for example, a pharmaceutical composition comprising a p-toluenesulfonate form I crystal of the compound represented by the formula (I-a) or a pharmaceutical composition comprising a fumaric acid co-crystal form I of the compound represented by the formula (I-B)) is preferably set on the basis of considering the age, weight, kind of disease, degree, administration route, etc. of the patient, and in the case of oral administration, is usually in the range of 0.05 to 200 mg/kg/day, preferably 0.1 to 100 mg/kg/day. In the case of parenteral administration, although there are large differences depending on the route of administration, it is usually in the range of 0.005 to 200 mg/kg/day, preferably 0.01 to 100 mg/kg/day. It is administered 1 to 1 time a day to several times.
For example, the compound according to the present invention may be used in combination with other novel therapeutic agents for coronavirus infectious disease (covd-19) (including agents that have been approved as such therapeutic agents, and agents that are in development or later developed) (hereinafter, referred to as combination agents) for the purpose of enhancing the action of the compound or reducing the amount of the compound to be administered. In this case, the timing of administration of the compound and the combination agent according to the present invention is not limited, and they may be administered simultaneously to the administration subject or may be administered with a time difference therebetween. The compound and the combination agent according to the present invention may be administered in the form of a preparation containing 2 or more kinds of each active ingredient, or may be administered in the form of a single preparation containing the active ingredients.
The administration amount of the combination agent may be appropriately selected based on the clinically used amount. In addition, the mixing ratio of the compound according to the present invention and the combination agent may be appropriately selected according to the administration subject, the administration route, the disease, the symptoms, the combination, and the like of the subject. For example, when the subject is a human, 0.01 to 100 parts by weight of the combination agent may be used per 1 part by weight of the compound according to the present invention.
Examples
The present invention will be described in more detail below with reference to examples and reference examples, but the present invention is not limited thereto.
The abbreviations used in the present specification mean the following meanings.
Boc: t-Butoxycarbonyl group
CDI: carbonyl diimidazoles
DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene
DIEA: n, N-diisopropylethylamine
DMA: n, N-dimethylacetamide
DMF: n, N-dimethylformamide
DMSO: dimethyl sulfoxide
DTT: dithiothreitol
EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
EDT:1, 2-ethanedithiol
EDTA: ethylenediamine tetraacetic acid
FBS: fetal bovine serum
HOBT: 1-hydroxybenzotriazoles
LHMDS: lithium bis (trimethylsilyl) amide
MEM: eagle minimum essential medium
NMP: n-methylpyrrolidone
Pd(OAc) 2 : palladium acetate
TFA: trifluoroacetic acid
TMSCL: trimethylchlorosilane
Xantphos:4,5 '-bis (diphenylphosphino) -9,9' -dimethylxanthene
mM:mmol/L
μM:μmol/L
nM:nmol/L
(method for identifying Compound)
NMR analyses obtained in the examples were carried out at 400MHz using DMSO-d 6 、CDCl 3 、MeOH-d 4 The measurement was performed. In addition, when NMR data is expressed, all peaks measured may not be described.
In the specification, RT represents LC/MS: retention time in liquid chromatography/mass spectrometry was measured under the following conditions.
(measurement condition 1)
Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7. Mu. Mi. D.2.1X10 mm) (Waters)
Flow rate: 0.8 mL/min
UV detection wavelength: 254nm
Mobile phase: [A] an aqueous solution containing 0.1% formic acid, and [ B ] an acetonitrile solution containing 0.1% formic acid
Gradient: after a linear gradient of 5% to 100% solvent [ B ] was performed for 3.5 minutes, 100% solvent [ B ] was maintained for 0.5 minutes.
(measurement condition 2)
Column: shim-pack XR-ODS (2.2 μm, i.d. 3.0x50mm) (Shimadzu)
Flow rate: 1.6 mL/min
UV detection wavelength: 254nm
Mobile phase: [A] an aqueous solution containing 0.1% formic acid, and [ B ] an acetonitrile solution containing 0.1% formic acid
Gradient: a linear gradient of 10% to 100% solvent [ B ] was performed over 3 minutes, with 100% solvent [ B ] maintained for 0.5 minutes.
In the specification, the term MS (m/z) refers to a value observed by mass spectrometry.
(measurement of powder X-ray diffraction Pattern)
Powder X-ray diffraction measurement of the crystals obtained in each example was carried out according to the powder X-ray diffraction measurement method described in the general test method of the Japanese drug administration. The measurement conditions are as follows.
(apparatus)
Rigaku Corporation SmartLab
(method of operation)
The measuring method comprises the following steps: reflection method
The wavelength is used: cuK alpha line
Tube current: 200mA
Tube voltage: 45kV
Sample plate: aluminum (Al)
Incidence angle of X-rays: 2.5 degree
Sampling width: 0.02 degree
A detector: hyPix-3000 (two-dimensional detection mode)
(determination and analysis method for analysis of Single Crystal Structure)
The measurement conditions and the analysis method of the single crystal structure analysis are as follows.
(apparatus)
Rigaku Corporation XtaLAB P200 MM007
(measurement conditions)
Measuring temperature: 25 DEG C
The wavelength is used: cuK alpha line
Software: crysalisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
(data processing)
Software: crysalisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
And carrying out Lorentz and polarization correction and absorption correction on the data.
(analysis of Crystal Structure)
Phase determination was performed using the direct method program sheldxt (sheldlick, g.m., 2015), and refinement was performed using the full-matrix least squares method using sheldxl (sheldlick, g.m., 2015). The shift parameters of non-hydrogen atoms were all refined with anisotropy. The hydrogen atom was introduced by calculation using the default parameters of ShellXL, treated as riding atom. All hydrogen atoms were refined with isotropic parameters.
PLATON (Spek, 1991)/ORTEP (Johnson, 1976) was used in the charts of FIGS. 2 and 4.
Example 1
Synthesis of Compound (I-003)
[ chemical formula 27]
Process 1 Synthesis of Compound 14
3,4, 5-Trifluorobenzylamine (3.34 g,20.7 mmol) was dissolved in dichloromethane (33.4 mL) and cooled in a water bath. Benzoyl isothiocyanate (2.93 mL,21.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes.
The solvent was distilled off, and the residue was diluted with methanol, and 1mol/L aqueous sodium hydroxide solution (7.45 mL,7.45 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes, and 2mol/L aqueous hydrochloric acid was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (8.3 g) of compound 14. The crude product was used in the next step in 100% yield without further purification.
LC/MS (ESI): m/z=221, rt=1.45 min, lc/MS assay condition 2
Process 2 Synthesis of Compound 15
The crude product of compound 14 (8.3 g), DMF (85 mL), methyl iodide (4.84 mL,77 mmol) were mixed and the reaction solution stirred at 50℃for 40 min. To the reaction solution was added water, which was extracted with ethyl acetate, followed by washing with water. To the aqueous layer was added a 2mol/L aqueous sodium hydroxide solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give a crude product of compound 15 (3.86 g,16.5mmol, yield 80%).
LC/MS (ESI): m/z=235, rt=0.84 min, lc/MS assay condition 2
Process 3 Synthesis of Compound 16
Triphosgene (0.507 g,1.71 mmol) and THF (6 mL) were mixed and the reaction solution was cooled in an ice bath. 3-amino-5-methylpyridine (0.460 g,4.27 mmol) and triethylamine (1.48 mL,10.7 mmol) were mixed in THF (6 mL), and the resulting solution was added dropwise to the reaction solution. After stirring the reaction solution at room temperature for 40 minutes, it was cooled in an ice bath. Compound 15 (1 g,4.27 mmol) was added to the reaction solution and stirred at room temperature for 55 minutes. Water was added, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product of compound 16 (1.57 g,4.26mmol, yield: quantitative).
LC/MS (ESI): m/z=369, rt=1.52 min, lc/MS assay condition 1
Process 4 Synthesis of Compound 17
CDI (2.78 g,17.2 mmol), compound 16 (1.58 g,4.29 mmol) and DMF (12.6 mL) were mixed. Diisopropylethylamine (3.00 mL,17.2 mmol) was added to the reaction solution, and the mixture was irradiated with microwaves for 30 minutes while stirring at 110 ℃. The reaction solution was poured into ice, and the precipitate formed was filtered off and washed with water. The resulting residue was dried under reduced pressure to give a crude product of compound 17 (649 mg,1.51mmol, yield 35%). LC/MS (ESI): m/z=395, rt=1.74 min, lc/MS assay condition 1
Process 5 Synthesis of Compound (I-003)
6-chloro-2-methyl-2H-indazol-5-amine (55.3 mg,0.304 mmol), compound 17 (100 mg,0.254 mmol) and THF (1 mL) were mixed. The reaction solution was cooled in an ice bath and LHMDS (0.761 mL,0.761 mmol) was added. The reaction solution was stirred in an ice bath for 40 minutes, and a saturated aqueous ammonium chloride solution was added. The organic layer was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to give compound (I-003) (80 mg,0.145mmol, yield 57.4%).
1 H-NMR(Methanol-d4)δ:8.43(d,J=1.0Hz,1H),8.36(d,J=2.0Hz,1H),8.18(s,1H),7.74(s,1H),7.72(br s,1H),7.48-7.35(m,3H),5.32(s,2H),4.20(s,3H),2.42(s,3H).
LC/MS (ESI): m/z=528, rt=1.93 min, lc/MS assay condition 1
Example 2
Synthesis of Compound (I-005)
[ chemical formula 28]
Process 1 Synthesis of Compound 18
Compound 4 (926 mg,4.04 mmol) (synthesis see WO2012020749, WO2013089212 and WO 2014200078), acetonitrile (7.41 mL), potassium carbonate (726 mg,5.25 mmol) and 2,4, 5-trifluorobenzyl bromide (1000 mg,4.44 mmol) were mixed. The reaction solution was stirred at 80℃for 40 minutes, allowed to stand for cooling, and then diluted with ethyl acetate. After insoluble matter was filtered off, the filtrate was concentrated to give a crude product of compound 18 (1.51 g,4.04mmol, yield: quantitative).
LC/MS (ESI): m/z=374, rt=2.54 min, lc/MS assay condition 1
Process 2 Synthesis of Compound 19
Compound 18 (1.51 g,4.04 mmol) and TFA (3.02 mL) were mixed. The reaction solution was stirred at room temperature for 4 hours and allowed to stand overnight. TFA was distilled off under reduced pressure, toluene was added to the residue, and azeotropy was performed. Isopropyl ether was added to the residue, which was then suspended and filtered to give compound 19 (1.22 g,3.84mmol, yield 95%). LC/MS (ESI): m/z=318, rt=1.68 min, lc/MS assay condition 1
Process 3 Synthesis of Compound 20
Compound 19 (200 mg,0.63 mmol), DMF (1.8 mL), potassium carbonate (261 mg,1.89 mmol) and 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride (1599 mg,0.946 mmol) were mixed. The reaction solution was stirred at 60℃for 2 hours, and a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate and chloroform and filtered. The residue was mixed with DMF (1.8 mL), potassium carbonate (261 mg,1.89 mmol) and 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride (1599 mg,0.946 mmol). The reaction solution was stirred at 60℃for 6 hours, and a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate and chloroform, and filtered to give compound 20 (116 mg,0.281mmol, yield 45%).
LC/MS (ESI): m/z=413, rt=1.84 min, lc/MS measurement conditions: 1 Process 4 Synthesis of Compound (I-005)
Compound 20 (115 mg,0.279 mmol), THF (2.30 mL) and 6-chloro-2-methyl-2H-indazol-5-amine (60.8 mg,0.335 mmol) were mixed. LHMDS (558. Mu.L, 0.558 mmol) was added dropwise to the reaction solution at 0deg.C. The reaction solution was stirred at 0℃for 2.5 hours, at room temperature for 40 minutes, and a saturated aqueous ammonium chloride solution was added. The organic layer was concentrated by extraction with chloroform. The residue was purified by silica gel column chromatography (chloroform/methanol) to give compound (I-005) (61.8 mg,0.116mmol, yield 42%).
1 H-NMR(CDCl 3 )δ:7.96(s,1H),7.82(d,J=2.5Hz,2H),7.48(br s,1H),7.45-7.37(m,1H),7.08(s,1H),6.97-6.88(m,1H),5.35(s,2H),5.17(s,2H),4.21(s,3H),3.89(s,3H).
LC/MS (ESI): m/z=532, rt=1.70 min, lc/MS assay condition 1
The compounds usable in the present invention were synthesized according to the above-described general synthesis methods and the methods described in examples 1 and 2. The structures and physical properties (LC/MS data) of the respective compounds, including the compounds produced in examples 1 and 2, are shown in the following table. The compounds described as amino structures in the tables may have an imino structure, and the compounds shown as imino structures may have an amino structure. That is, even the same compound may have an imino structure or an amino structure depending on crystallization conditions or the like, and even when a salt or a complex is formed, there may be an imino structure or an amino structure depending on the kind of a counter molecule of the salt or the complex, and even if the same counter molecule, there may be an imino structure or an amino structure depending on crystallization conditions or the like. In addition, a mixture of a compound having an imino structure, a salt thereof, or a complex thereof and a compound having an amino structure, a salt thereof, or a complex thereof may be used.
TABLE 1
TABLE 2
TABLE 3
TABLE 4
TABLE 5
TABLE 6
TABLE 7
TABLE 8
TABLE 9
Example 3
To 1400mg of compound (I-003), 557. Mu.L (1.05 eq) of an aqueous solution of 5mol/L of p-toluenesulfonic acid in 7mL of ethyl acetate was added. After stirring at 60℃for 15 minutes, stirring was carried out at 25℃for 2 hours. The solid was filtered and dried, whereby p-toluenesulfonate form I crystals (1289.6 mg, 69%) of the compound represented by formula (I-a) were obtained.
The results of single crystal structure analysis of the p-toluenesulfonate form I crystal of the compound represented by the formula (I-A) are shown below.
R1 (I >2.00s (I)) was 0.0444, and it was confirmed by the final difference Fourier that there was neither a loss of electron density nor a misplacement.
The crystallographic data are shown in table 10.
TABLE 10
Here, the volume represents the unit cell volume, and Z represents the number of molecules in the unit cell.
The structure in the asymmetric unit of the p-toluenesulfonate form I crystal of the compound of formula (I-A) is shown in FIG. 2.
In the asymmetric unit, 1 molecule exists in each of the compound represented by the formula (I-A) and p-toluenesulfonic acid. The formation of a salt was confirmed by bonding no hydrogen atom to the oxygen atom represented by O3, O4 and O5 of p-toluenesulfonic acid and bonding a hydrogen atom to the nitrogen atom of N7 of the compound represented by the formula (I-a).
The bond length of N3-C9 is aboutThe bond length of N4-C9 is about +.>The bond length identifies that the compound shown as the formula (I-A) in the p-toluenesulfonate I type crystal is of imino structure:
[ chemical formula 29]
In addition, the results of powder X-ray diffraction of the p-toluenesulfonate form I crystals of the compound represented by formula (I-A) are shown.
In the powder X-ray diffraction pattern, at the diffraction angle (2θ): peaks were confirmed at 9.1±0.2°, 11.5±0.2°, 14.6±0.2°, 15.2±0.2°, 18.8±0.2°, 20.2±0.2°, 23.6±0.2°, 24.2±0.2°, 24.9±0.2° and 26.9±0.2°.
In the powder X-ray diffraction pattern, diffraction angle (2θ): peaks of 9.1.+ -. 0.2 °, 15.2.+ -. 0.2 °, 18.8.+ -. 0.2 °, 23.6.+ -. 0.2 ° and 24.9.+ -. 0.2 ° are particular characteristics of the p-toluenesulfonate salt form I crystal as the compound represented by formula (I-A).
Example 4
To 1170mg of compound (I-005) were added 278mg (1.1 eq) of fumaric acid and 5.85mL of ethyl acetate, and the mixture was stirred at room temperature for 45 minutes. The solid was filtered and dried, whereby fumaric acid co-crystal form I crystals (1369.4 mg, 94.6%) of the compound represented by the formula (I-B) were obtained.
The results of the single crystal structure analysis of fumaric acid co-crystal form I of the compound represented by the formula (I-B) are shown below.
R1 (I >2.00s (I)) was 0.0470, and no loss of electron density nor misplacement was confirmed by final difference Fourier.
The crystallographic data are shown in table 11.
TABLE 11
Here, the volume represents the unit cell volume, and Z represents the number of molecules in the unit cell.
The structure in the asymmetric unit of fumaric acid co-crystal form I of the compound of formula (I-B) is shown in FIG. 4.
In the asymmetric unit, 1 molecule exists in each of the compound represented by the formula (I-B) and fumaric acid. No ionic chemical interaction was confirmed, which was confirmed to be 1:1 in molar ratio.
The bond length of N10-C9 is aboutThe bond length of N16-C9 is approximately +.>The bond length identifies that the compound shown in the formula (I-B) of the fumaric acid eutectic I is of an imino structure:
[ chemical formula 30]
In addition, the results of powder X-ray diffraction of fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) are shown.
In the powder X-ray diffraction pattern, at the diffraction angle (2θ): peaks were confirmed at 7.8.+ -. 0.2 °, 9.5.+ -. 0.2 °, 10.1.+ -. 0.2 °, 10.9.+ -. 0.2 °, 13.8.+ -. 0.2 °, 14.7.+ -. 0.2 °, 18.6.+ -. 0.2 °, 22.6.+ -. 0.2 °, 23.5.+ -. 0.2 ° and 24.6.+ -. 0.2 °.
In the powder X-ray diffraction pattern, diffraction angle (2θ): peaks of 9.5.+ -. 0.2 °, 10.9.+ -. 0.2 °, 18.6.+ -. 0.2 °, 23.5.+ -. 0.2 ° and 24.6.+ -. 0.2 ° are particular characteristics of the fumaric acid co-crystal form I crystals as the compound represented by the formula (I-B).
Biological test examples of the compounds according to the present invention are described below. The compounds of the present invention can be essentially tested as in the following test examples.
The compound represented by the formula (I) according to the present invention may be any compound having a coronavirus 3CL protease inhibitory activity and inhibiting a coronavirus 3CL protease.
Specifically, in the evaluation method described below, the IC50 is preferably 50. Mu.M or less, more preferably 1. Mu.M or less, and still more preferably 100nM or less.
Test example 1: cytopathic Effect (Cytopathic effect) (CPE) inhibition Effect confirmation assay Using human TMPRSS 2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells)
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 2-5-fold gradient dilution series were prepared, they were dispensed into 384-well plates.
Dilution and dispensing of cells and SARS-CoV-2
VeroE6/TMPRSS2 cells (JCRB 1819, 5X 10) 3 Individual cells/well) and SARS-CoV-2 (100-300 TCID 50 Well) in a culture medium (MEM, 2% FBS, penicillin-streptomycin), and after dispensing into wells containing test samples, the mixture was subjected to CO 2 Culturing in an incubator for 3 days.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 3 days of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% concentration of inhibition of death of SARS-CoV-2 infected cells (EC 50 ) Calculation of
Let x be the logarithmic value of the compound concentration, and let y be the% Efficacy (efficiency), the inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
(%Efficacy={(Sample-virus control)/(cell control-virus control)}*100%)
Cell control (cell control): average Lum (the average of Lum of cell control wells) of cell control wells
Virus control (virus control): average Lum (the average of Lum of virus control wells) of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown in the table below.
Incidentally, EC 50 A value of less than 1. Mu.M is referred to as "A", and a value of 1. Mu.M or more and less than 10. Mu.M is referred to as "B".
Compound I-003:0.177 mu M
Compound I-005:0.328 mu M
Compound I-006: 0.747. Mu.M
Compound I-010:0.306 mu M
Compound I-012:0.131 mu M
Compound I-017:0.0960 mu M
Compound I-023:1.03 mu M
Compound I-035: 0.395. Mu.M
TABLE 12
Test examples 1-2: cytopathic Effect (CPE) inhibition assay Using human TMPRSS 2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells)
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 3-fold gradient dilution series were prepared, they were dispensed into 96-well plates.
Dilution and dispensing of cells and SARS-CoV-2
VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 4 Individual cells/well) and SARS-CoV-2hCoV-19/Japan/TY/WK-521/2020, hCoV-19/Japan/QK002/2020, hCoV-19/Japan/QHN/2020, hCoV-19/Japan/QHN002/2020, hCoV-19/Japan/TY7-501/2021, hCoV-19/Japan/TY7-503/2021, hCoV-19/Japan/TY8-612/2021, hCoV-19/Japan/TY11-927-P1/2021, hCoV-19/Japan/TY 33-456/2021, hCoV-19/Japan/28-444/2021, hCoV-19/Japan/TY26-717/2021 (30-3000 TCID) 50 Well) in a culture medium (MEM, 2% FBS, penicillin-streptomycin), and after dispensing into wells containing test samples, the mixture was subjected to CO 2 Culturing in an incubator for 3 days or 4 days.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 3 days of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% concentration of inhibition of death of SARS-CoV-2 infected cells (EC 50 ) Calculation of
Let x be the logarithmic value of compound concentration, let y be% efficacy, the inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Cell control: mean Lum of cell control wells
Virus control: average Lum of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown below.
TABLE 13-1
Test examples 1 to 3: cytopathic Effect (CPE) inhibition assay Using human TMPRSS 2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells)
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 3-fold gradient dilution series were prepared, they were dispensed into 96-well plates.
Dilution and dispensing of cells and SARS-CoV-2
VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 4 Individual cells/well) and SARS-CoV-2hCoV-19/Japan/TY38-873/2021, hCoV-19/Japan/TY38-871/2021, hCoV-19/Japan/TY40-385/2022, hCoV-19/Japan/TY41-716/2022, hCoV-19/Japan/TY41-703/2022, hCoV-19/Japan/TY41-702/2022, hCoV-19/Japan/TY41-686/2022 (300-3000 TCID) 50 Well) in a culture medium (MEM, 2% FBS, penicillin-streptomycin), and after dispensing into wells containing test samples, the mixture was subjected to CO 2 Culturing in an incubator for 4 days.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 3 days of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% concentration of inhibition of death of SARS-CoV-2 infected cells (EC 50 ) Calculation of
Let x be the logarithmic value of compound concentration, let y be% efficacy, the inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Cell control: mean Lum of cell control wells
Virus control: average Lum of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown below.
[ Table 13-2]
Test example 2: inhibition Activity assay for SARS-CoV-2 3CL protease
< Material >
Commercially available recombinant SARS-CoV-2 3CL protease
Commercially available substrate peptides
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu (Edans) -NH2 (SEQ ID NO: 1)
Internal standard peptide (Internal Standard peptide)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu (13C6,15N) -Gln (SEQ ID NO: 2)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu (13C6,15N) -Gln can be synthesized by reference (Athereton, E.; sheppard, R.C., "In Solid Phase Peptide Synthesis, APractical Approach", IRL Press from oxford university (IRL Press at Oxford University Pres), 1989, and Bioorg. Med. Chem., vol.5, 9 th, 1997, pages 1883-1891, etc.). An example is shown below.
H-Lys-Thr-Ser-Ala-Val-Leu (13C6,15N) -Glu (resin) -OαOtBu (Lys side chain protected by Boc, thr side chain protected by tert-butyl, ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, carboxylic acid of Glu side chain condensed with resin) was synthesized by Fmoc solid phase synthesis using Rink amide resin. Modification of the N-terminal Dabcyl group is the condensation of 4-dimethylaminoazobenzene-4' -carboxylic acid (Dabcyl-OH) on the resin with EDC/HOBT. Final deprotection and cleavage from resin was achieved by using TFA/edt=95: 5, performing treatment. Then, purification was performed by reverse phase HPLC.
·RapidFire Cartridge C4 typeA
< procedure >
Preparation of detection buffer
In this test, a detection buffer consisting of 20mM Tris-HCl, 100mM sodium chloride, 1mM EDTA, 10mM DTT, 0.01% BSA was used. For IC 50 As a compound having a value of 10nM or less, a detection buffer composed of 20mM Tris-HCl, 1mM EDTA, 10mM DTT, and 0.01% BSA was used.
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 2-5-fold gradient dilution series were prepared, they were dispensed into 384-well plates.
Addition of enzyme and substrate, enzymatic reaction
To the prepared compound plate, 8. Mu.M of a substrate and 6 or 0.6nM of an enzyme solution were added, and incubation was performed at room temperature for 3 to 5 hours. Then, a reaction stop solution (0.067. Mu.M internal standard (Internal Standard), 0.1% formic acid, 10 or 25% acetonitrile) was added to stop the enzyme reaction.
Determination of the reaction products
The plates after completion of the reaction were measured using a Rapid FireSystem 360 and a mass spectrometer (Agilent, 6550iFunnel Q-TOF), or Rapid Fire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadrupole). As mobile phases for the measurement, a solution A (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and a solution B (0.01% trifluoroacetic acid, 0.09% formic acid) were used.
The reaction Product detected by the mass spectrometer was calculated as a Product area (Product area) value using RapidFire Integrator or a program capable of performing equivalent analysis. In addition, the internal standard detected at the same time is also calculated as an internal standard area (Internal Standard area) value.
< calculation of measurement item values >
Calculation of P/IS
The area value obtained in the previous item was calculated by the following equation, and P/IS was calculated.
P/IS = product area value/internal standard area value
50% SARS-CoV-2 3CL protease inhibition concentration (IC 50 ) Calculation of
Let x be the logarithmic value of the compound concentration, let y be% Inhibition (Inhibition), the Inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as IC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% inhibition = {1- (sample-control (-))/control (+) -control (-)) } 100
(%Inhibition={1-(Sample-Control(-))/Control(+)-Control(-))}*100)
Control (-): average P/IS of enzyme inhibition conditioned wells
(Control(-):the average of P/IS of enzyme inhibited condition wells)
Control (+): mean P/IS of DMSO control wells
(Control(+):the average of P/IS of DMSO control wells)
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown in the table below.
Note that IC 50 The value of "A" is defined as "B" when the value is less than 0.1. Mu.M, and "B" when the value is 0.1. Mu.M or more and less than 1. Mu.M, and "C" when the value is 1. Mu.M or more and less than 10. Mu.M.
Compound I-003: 0.014. Mu.M
Compound I-005: 0.010. Mu.M
Compound I-006: 0.0058. Mu.M
Compound I-010: 0.0054. Mu.M
Compound I-012:0.0091 mu M
Compound I-017:0.0034 mu M
Compound I-023: 0.0063. Mu.M
Compound I-035: 0.0098. Mu.M
TABLE 14-1
Test example 2-2: inhibition Activity assay for SARS-CoV-2 3CL protease
< Material >
Commercially available recombinant SARS-CoV-2 3CL protease
Variants of SARS-CoV-2 3CL protease (G15S, T21I, T24I, K88R, L89F, K90R, P108S, P132H, A193V, H246Y, A255V)
Commercially available substrate peptides
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu (Edans) -NH2 (SEQ ID NO: 1)
Internal standard peptide
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu (13C6,15N) -Gln (SEQ ID NO: 2)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu (13C6,15N) -Gln can be synthesized by reference (Athereton, E.; sheppard, R.C., "In Solid Phase Peptide Synthesis, APractical Approach", IRL Press from oxford university (IRL Press at Oxford University Pres), 1989, and Bioorg. Med. Chem., vol.5, 9 th, 1997, pages 1883-1891, etc.). An example is shown below.
H-Lys-Thr-Ser-Ala-Val-Leu (13C6,15N) -Glu (resin) -OαOtBu (Lys side chain protected by Boc, thr side chain protected by tert-butyl, ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, carboxylic acid of Glu side chain condensed with resin) was synthesized by Fmoc solid phase synthesis using Rink amide resin. Modification of the N-terminal Dabcyl group is the condensation of 4-dimethylaminoazobenzene-4' -carboxylic acid (Dabcyl-OH) on the resin with EDC/HOBT. Final deprotection and cleavage from resin was achieved by using TFA/edt=95: 5, performing treatment. Then, purification was performed by reverse phase HPLC.
·RapidFire Cartridge C4 typeA
< procedure >
Preparation of detection buffer
In this test, a detection buffer consisting of 20mM Tris-HCl, 1mM EDTA, 10mM DTT, 0.01% BSA was used.
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and 3-fold gradient dilution series were prepared and dispensed into 384-well plates.
Addition of enzyme and substrate, enzymatic reaction
To the prepared compound plate, a substrate having a final concentration of 2 to 4. Mu.M and an enzyme solution having a final concentration of 2 to 6nM were added, and incubation was performed at room temperature for 2 to 3 hours. Then, a reaction stop solution (0.072. Mu.M internal standard, 0.1% formic acid, 10% acetonitrile) was added to stop the enzyme reaction.
Determination of the reaction products
For the plates after completion of the reaction, the measurement was performed using a Rapid FireSystem 360 and a mass spectrometer (Agilent, 6550iFunnel Q-TOF). As mobile phases for the measurement, a solution A (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and a solution B (0.01% trifluoroacetic acid, 0.09% formic acid) were used.
The reaction product detected by the mass spectrometer was calculated as a product area value using RapidFire Integrator. In addition, the internal standard detected at the same time is also calculated as an internal standard area value.
< calculation of measurement item values >
Calculation of P/IS
The area value obtained in the previous item was calculated by the following equation, and P/IS was calculated.
P/IS = product area value/internal standard area value
50% SARS-CoV-2 3CL protease inhibition concentration (IC 50 ) Calculation of
Let x be the logarithmic value of the compound concentration, let y be% inhibition, the inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as IC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% inhibition = {1- (sample-control (-))/control (+) -control (-)) } 100
Control (-): average P/IS ratio of wells without SARS-CoV-2 3CL protease and test substrate
(Control(-):the average of P/IS ratio in the wells without SARS-CoV-2 3CL protease and test substance)
Control (+): average P/IS ratio of wells with SARS-CoV-2 3CL protease and no test substrate
(Control(+):the average of P/IS ratio in the wells with SARS-CoV-2 3CL protease and without test substance)
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown below.
TABLE 14-2
Test example 3: test of inhibition of proliferation of pulmonary viral titers in SARS-CoV-2-infected mice by administration of fumaric acid co-crystal form I crystals of Compound of formula (I-B)
< materials and methods >
Compounds
Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
SARS-CoV-2hCoV19/Jap an/TY7-501/2021 strain isolated from national institute of infectious disease was used.
Pulmonary infection, drug administration and pulmonary recovery in mice
Female BALB/c mice (CLEA Japan, inc.) of 5 weeks old without specific pathogen were used in this study. At the time of virus inoculation, mice were anesthetized by intramuscular administration of 100 μl of anesthetic solution containing 0.03mg/mL medetomidine hydrochloride, 0.4mg/mL midazolam, 0.5mg/mL buprenorphine tartrate in PBS. Mice were vaccinated nasally under anesthesia with 50. Mu.L of hCoV19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 ). Immediately after infection with the virus, as a starting point, fumaric acid cocrystal form I crystals of the compound represented by the formula (I-B) were orally administered to mice in an amount of 2mg/kg, 4mg/kg, 8mg/kg, 16mg/kg, 32mg/kg, 64mg/kg, singly or in an amount of 1mg/kg, 2mg/kg, 4mg/kg, 8mg/kg, 16mg/kg, 32mg/kg for 1 day 2 times (n=5-10/group). For control mice, 0.5% mc was orally administered 2 times a day 1. The lungs of the mice were recovered 1 day after virus infection, 2mL of PBS was added and homogenized, and the supernatant after centrifugation was recovered.
Determination of the Lung Virus titre
Lung homogenates were serially diluted 10-fold with medium (MEM, 2% FBS, penicillin-streptomycin) and then incubated with VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 4 Individual cells/well) were mixed and seeded into 96-well plates. In CO 2 After 4 days of culture in the incubator, cytopathic effect (CPE) was observed, and the virus titer contained in the lung homogenate was calculated.
Statistical analysis
The differences between groups of virus titers in lung homogenates were analyzed by the Dunnett assay. Statistical analysis was performed using statistical analysis software SAS version 9.4Windows (SAS Institute (Ca ry, NC)). The adjusted double sided P value was considered statistically significant at less than 0.05.
The compounds of the present invention were tested essentially as described above. The results are shown below.
For the group of administration of fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B), the administration was carried out in a dose-dependent manner at any of single administration or 1 day 2The intrapulmonary viral titers after 1 day of infection were reduced, and at all administration amounts of 2mg/kg or more, significantly lower viral titers were shown compared to the 0.5% mc administration group (fig. 5A and 5B). In the 32, 64mg/kg administration group at single administration, and the 16, 32mg/kg administration group at 2 times of 1 day, the intrapulmonary viral titer substantially reached the lower limit of quantification (1.80-log 10 TCID 50 /mL)。
Test example 4: test of inhibition of proliferation of pulmonary viral titers in SARS-CoV-2-infected mice by delayed administration of fumaric acid co-crystal form I crystals of Compound represented by formula (I-B)
< materials and methods >
Compounds
The compound of the present invention (fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B)) was prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
SARS-CoV-2hCoV19/Jap an/TY7-501/2021 strain isolated by national institute of infectious disease was used.
Pulmonary infection, drug administration and pulmonary recovery in mice
Female BALB/c mice (CLEA Japan, inc.) of 5 weeks old without specific pathogen were used in this study. At the time of virus inoculation, mice were anesthetized by intramuscular administration of 100 μl of anesthetic solution containing 0.03mg/mL medetomidine hydrochloride, 0.4mg/mL midazolam, 0.5mg/mL buprenorphine tartrate in PBS. Mice were vaccinated nasally under anesthesia with 50. Mu.L of hCoV19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 ). The fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) were orally administered to mice at an amount of 30mg/kg, 150mg/kg for 1 day 2 times, using 1 day or 3 days after virus infection as a starting point (n=5/group). For control mice, 0.5% mc was orally administered 1 day 1. Compound administration was set to 2 days from the start of administration. The lungs of the mice were recovered 2 days after the start of administration, 2mL of PBS was added and homogenized, and the supernatant after centrifugation was recovered.
Determination of the Lung Virus titre
Lung homogenates were serially diluted 10-fold with medium (MEM, 2% FBS, penicillin-streptomycin) and then incubated with VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 4 Individual cells/well) were mixed and seeded into 96-well plates. In CO 2 After 4 days of culture in the incubator, cytopathic effect (CPE) was observed, and the virus titer contained in the lung homogenate was calculated.
The compounds of the present invention were tested essentially as described above. The results are shown below.
In the group administered 1 day from the start of infection, the intrapulmonary virus titers 2 days after the start of administration were shown to be 6.47-log in the 0.5% MC-administered group 10 TCID 50 Each of the fumaric acid cocrystal form I crystals 30 of the compound of formula (I-B) was shown to be 4.47-log in the administration group of 150mg/kg per mL 10 TCID 50 /mL、2.90-log 10 TCID 50 /mL (FIG. 6A). In the group administered 3 days from the start of infection, the intrapulmonary virus titers 2 days after the start of administration were shown to be 4.83-log in the 0.5% MC-administered group 10 TCID 50 Per mL, shown as 3.63-log in the fumaric acid co-crystal form I crystal 30, 150mg/kg administration group, respectively, of the compound represented by the formula (I-B) 10 TCID 50 /mL、3.35-log 10 TCID 50 /mL (FIG. 6B).
In any case where administration was started 1 day after and 3 days after infection, in the fumaric acid co-crystal form I crystal administration group of the compound represented by formula (I-B), the intrapulmonary viral titer was shown to be low compared with the 0.5% mc administration group, thereby suggesting that the effect of reducing the intrapulmonary viral titer was exhibited even if the period from infection to administration was vacated.
Test example 4-2: test of inhibition of proliferation of pulmonary viral titers in SARS-CoV-2-infected mice by delayed administration of fumaric acid co-crystal form I crystals of Compound represented by formula (I-B)
< materials and methods >
Compounds
Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
SARS-CoV-2hCoV19/Jap an/TY7-501/2021 strain isolated by national institute of infectious disease was used.
Pulmonary infection, drug administration and pulmonary recovery in mice
Female BALB/c mice (CLEA Japan, inc.) of 5 weeks old without specific pathogen were used in this study. At the time of virus inoculation, mice were anesthetized by intramuscular administration of 100 μl of anesthetic solution containing 0.03mg/mL medetomidine hydrochloride, 0.4mg/mL midazolam, 0.5mg/mL buprenorphine tartrate in PBS. Mice were vaccinated nasally under anesthesia with 50. Mu.L of hCoV19/Japan/TY7-501/2021 (1.00X 10) 4 TCID 50 ). Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were orally administered to mice 1 day 3 times at an amount of 8, 16, 32, 64mg/kg, using as a starting point 1 day after virus infection (n=5/group). For control mice, 0.5% mc was orally administered 1 day 1. Compound administration was set to 2 days from the start of administration. The lungs of the mice were recovered 2 days after the start of administration, 2mL of PBS was added and homogenized, and the supernatant after centrifugation was recovered.
Determination of the Lung Virus titre
Lung homogenates were serially diluted 10-fold with medium (MEM, 2% FBS, penicillin-streptomycin) and then incubated with VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 4 Individual cells/well) were mixed and seeded into 96-well plates. In CO 2 After 4 days of culture in the incubator, cytopathic effect (CPE) was observed, and the virus titer contained in the lung homogenate was calculated.
The compounds of the present invention were tested essentially as described above. The results are shown below.
In the group administered 1 day from the start of infection, the intrapulmonary virus titers 2 days after the start of administration were shown to be 6.57-log in the 0.5% MC-administered group 10 TCID 50 Per mL, shown as 5.55, 4.66, 2.85, 2.40-log in the fumaric acid co-crystal form I crystals 8, 16, 32, 64mg/kg administration group of the compound represented by formula (I-B), respectively 10 TCID 50 /mL. Fumaric acid of the Compound represented by the formula (I-B)In the co-crystal type I crystal administration group, the intrapulmonary viral titer was shown to be low compared to the 0.5% mc administration group, thereby suggesting that even if the period from infection to administration was vacated, there was an effect of reducing the intrapulmonary viral titer (fig. 7).
Test example 5: death and weight loss inhibition test of SARS-CoV-2 infected mice by administration of fumaric acid Co-crystal type I Crystal of Compound of formula (I-B)
< materials and methods >
Compounds
The compound of the present invention (fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B)) was prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
A strain of SARS-CoV-2hCoV19/Jap an/TY7-501/2021 isolated by the national institute of infectious diseases (TY 7-501) and a strain of SARS-Co V-2hCoV19/Japan/TY/WK-521/2020 domesticated mouse strain MA-P10 isolated by the university of North sea were used.
Pulmonary infection, drug administration and weight measurement in mice
Retired female BALB/c mice (CLEA Japan, inc.) of 15 weeks old or 35-45 weeks old without specific pathogens were used in this study. At the time of virus inoculation, mice were anesthetized by intramuscular administration of 100 μl of anesthetic solution containing 0.03mg/mL medetomidine hydrochloride, 0.4mg/mL midazolam, 0.5mg/mL buprenorphine tartrate in PB S. Mice were vaccinated nasally under anesthesia with 50. Mu.L TY7-501 (1.00X 10) 5 TCID 50 )、MA-P10(1.00×10 3 TCID 50 Or 1.00×10 4 TCID 50 ). TY7-501 was used only for 35-45 week old retired mice. Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were orally administered to mice in an amount of 50mg/kg 1 day 2 times from 1 day after virus infection (n=4/group). For control mice, 0.5% mc was orally administered 2 times a day 1. Body weight was monitored 1 day 1, and in the evaluation of survival rate, death was considered when the body weight immediately before infection became less than 80% based on the body weight.
The compounds of the present invention were tested essentially as described above. The results are shown below.
Infection of TY7-501 1.00×10 in 35-45 week old senior retired mice 5 TCID 50 In (2) the body weight was reduced from 3 days after infection, and after 5 days of infection, all the test cases died. At this time, in the fumaric acid co-crystal form I crystal of the compound represented by the formula (I-B) 50mg/kg administration group, all test cases survived until 7 days after the observed infection, and weight loss was suppressed (FIGS. 8A and 8B). At 15 weeks of age mice were infected with MA-P10 1.00X 10 3 TCID 50 In the case of (2), weight loss was observed 3 days after infection, but no death was observed. On the other hand, when 15-week-old mice were infected with MA-P10.00X 10 4 TCID 50 In (2) the body weight was reduced from 3 days after infection, and after 4 days of infection, death was observed in some individuals, and after 6 days of infection, all the test cases were dead. At this time, in the fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) 50mg/kg administration group, all test cases survived until 7 days after the observed infection, and no weight loss was observed (FIG. 8C and FIG. 8D).
Next, MA-P10.00×10 mice were infected with a 35-45 week old, high-week old retired mouse 3 TCID 50 In the case of (3) days after infection, the weight was reduced, and after 5 days of infection, death was observed in some individuals, and after 6 days of infection, all the test cases died, and therefore, it was considered that even in the case of the Gao Zhouling-35-45 week old retired mice, the weight was liable to be severe even at a low infection amount. At this time, in the fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) 50mg/kg administration group, all test cases survived until 7 days after the observed infection, inhibiting weight loss (FIGS. 8E and 8F).
From the above results, it was suggested that the administration of fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) has an effect of suppressing mortality and weight loss in any of 15-week-old mice and 35-45-week-old, high-week-old retired mice.
It is known that, in old mice, as in humans, the expression level of ACE2 receptor known as the receptor for SA RS-CoV-2 is increased compared to young mice (references Sc ientific Reports (2020) 10:22401 and Molecular Therapy Methods & Clinical Development, vol.18, P1-6,2020), and normal immune responses against and excluding the body from the infection source are reduced, and therefore, it is estimated that the mice are fatal due to viral infection. However, as shown above, in the SAR S-CoV-2 infected mice model using aged mice, the survival of the mice after 7 days of infection was shown to be 100% by administration of fumaric acid co-crystal type I crystals of the compound represented by formula (I-B). The non-clinical trial using aged mice was positioned as one of non-clinical evaluation systems that imitate the process of achieving criticality in high-risk patients with underlying diseases, and thus, supported the usefulness of fumaric acid co-crystal form I crystals of the compound represented by formula (I-B) as a treatment option for patients at high risk of criticality.
In addition, the above test results suggest that the compound of formula (I-B) has suppressed the severe cases caused by viral infection in the group to which the fumaric acid co-crystal form I crystals are administered, and that the fumaric acid co-crystal form I crystals of the compound of formula (I-B) are useful as medicines for suppressing the severe cases of infectious diseases caused by SARS-CoV-2, in addition to supporting the antiviral effect against SARS-CoV-2.
Test example 6: antiviral effects against SARS-CoV
< Material >
Maintenance Medium (MEM containing 2% FBS)
To 1000mL of minimal essential medium (Minimum Essential Medium) was added 8.5% NaHCO 3 10mL, 20mL of FBS, and 10mL of L-glutamine.
MTT solution
3- (4, 5-dimethyl-2-thiazole) -2,5-diphenyl-2H-tetrazolium bromide (3- (4, 5-dimethyl-2-thiazol) -2,5-diphenyl-2H-tetrazolium bromide) was dissolved in PBS so as to be 5. Mu.g/mL, and then filtered through a 0.45 μm or 0.22 μm filter.
Cell lysis solution (virus inactivating solution)
To 500mL of isopropanol was added 50mL of Triton X, 4mL of hydrochloric acid (12 mol/L).
Dimethyl sulfoxide (Dimethyl sulfoxide, DMSO)
ELISA (Thermo Fisher, perkin Elmer, etc.)
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in advance with DMSO to make a 3-fold gradient dilution series. Further diluted with a maintenance medium, and dispensed into a 96-well plate at 50. Mu.L/well.
Dilution and dispensing of cells and viruses
Virus (SARS-CoV Hanoi strain (1000 TCID) 50 Per well) were each diluted with a maintenance medium and 50 μl/well each was dispensed into a 96-well plate containing the test sample.
VeroE6/TMPRSS2 cells (1.5X10) 4 Individual cells/well) were dispensed 100 μl/well each into 96-well plates containing test samples and viruses. Mixing with plate mixer, mixing with CO 2 Culturing in an incubator for 3 days.
MTT solution and cell lysis solution
The 96-well plate after 3 days of culture was observed with naked eyes under a microscope, and the morphology of cells, the presence or absence of crystals, and the like were confirmed. MTT solution (30. Mu.L each) was dispensed into each well and mixed with CO 2 Culturing in an incubator for 4-6 hours. 150. Mu.L of supernatant was removed from each plate without sucking in cells. The cell lysis solution (virus inactivation solution) was dispensed into each well at 150. Mu.L each. The plate was wrapped with a preservative film in a manner that it did not dry, and left overnight at room temperature.
Measurement of absorbance (96 well plate)
Next day, the plates were mixed with a plate mixer. For 96-well plates, absorbance at 2 wavelengths of 570nm and 630nm was measured using a microplate reader.
< calculation of measurement item values >
50% inhibition of viral infection cell death (EC 50 ) Calculation of
Let x be the logarithmic value of the compound concentration, let y be the% efficacy, the inhibition curve was fitted by the following logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Sample (Sample): average of sample wells OD (the average of ODs of Sample wells)
Cell control (cell control): average OD (the average of ODs of cell control wells) of cell control wells
Virus control (virus control): average OD (the averag e of ODs of virus control wells) of virus control wells
OD:OD(570nm)-OD(630nm)
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. EC (EC) 50 As shown below.
Fumaric acid co-crystal form I crystals of a compound represented by the formula (I-B): SARS-CoV0.209. Mu.M
Test example 7: antiviral Effect against HCoV-OC43
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after preparing a 3-fold gradient dilution series, the samples were dispensed into 96-well plates and diluted with a maintenance medium (MEM, 2% fbs, penicillin-streptomycin).
Dilution and dispensing of cells and HCoV-OC43
MRC-5 cells (2X 10) suspended in subculture medium (DMEM, 10% FBS, penicillin-streptomycin) were plated one day before infection 4 Individual cells/well) were seeded into 96-well plates, and on the next day, they were infected with HCoV-OC43 (100 TCID) suspended in maintenance medium (MEM, 2% FBS, penicillin-streptomycin) for 1 hour 50 /hole). Then, after washing 1 time with the maintenance medium, the addedMaintenance Medium with test agent in CO 2 Culturing in an incubator for 42 hours. In order to investigate cytotoxicity of the test agent, the same procedure was performed in the absence of virus.
Quantification of viral load
The supernatant of the plates after 42 hours of culture was recovered and RNA was extracted using the Quick-RNA visual Kit (ZYMO RESEARCH, #R1041). The extracted RNA solution was quantified by real-time PCR (Applied BioSystems QuantStudio 3). Primer reference (Journal of Clinical microbiology 2005, jun 43 (11), 5452-5456).
< calculation of measurement item values >
90% HCoV-OC43 Virus replication inhibition concentration (EC 90 ) Calculation of
In the concentration-dependent curve where x is the logarithmic value of the compound concentration and y is the copy number of virus (Log copies/mL), a value corresponding to 1Log reduction relative to the virus control was calculated by the two-point method from the copy numbers of the concentrations before and after that. That is to say,
X=log10(high conc.)
x=log10(low conc.)
Y=log10(low copies/mL)-log10(control copies/mL)
y=log10(high copies/mL)-log10(control copies/mL)
EC is calculated by 90 Values.
EC 90 =10[x+(-1-y)×(X-x)/(Y-y)]
The compounds of the present invention were tested essentially as described above. The results are shown below.
Fumaric acid co-crystal form I crystals of a compound represented by the formula (I-B): EC (EC) 90 0.074μM
Test example 8: antiviral Effect against HCoV-229E
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after preparing a 3-fold gradient dilution series, the samples were dispensed into 96-well plates and diluted with a maintenance medium (MEM, 2% fbs, penicillin-streptomycin).
Dilution and dispensing of cells and HCoV-229E
MRC-5 cells (2X 10) suspended in subculture medium (DMEM, 10% FBS, penicillin-streptomycin) were plated one day before infection 4 Individual cells/well) were inoculated into 96-well plates, and on the next day, they were infected with HCoV-229E (1000 TCID) suspended in maintenance medium (MEM, 2% FBS, penicillin-streptomycin) for 1 hour 50 /hole). Then, the virus solution is removed, and a maintenance medium to which a test agent has been added is added to CO 2 Culturing in an incubator for 72 hours. In order to investigate cytotoxicity of the test agent, the same procedure was performed in the absence of virus.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 72 hours of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% HCoV-229E infected cell death inhibition concentration (EC 50 ) Calculation of
Let x be the logarithmic value of compound concentration, let y be% efficacy, the inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Cell control: mean Lum of cell control wells
Virus control: average Lum of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
Calculation of 50% cytotoxicity concentration
Let x be the logarithmic value of the compound concentration and let y be% cytotoxicity (cytotoxinty), a suppression curve is fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) is calculated as CC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% cytotoxicity = { (sample-medium control)/(cell control-medium control) } 100%
(%Cytotoxicity={(Sample-medium control)/(cell con trol-medium control)}*100%)
Cell control: mean Lum of cell control wells
Medium control (medium control): average Lum (th e average of Lum of medium control wells) of Medium control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown below.
Fumaric acid co-crystal form I crystals of a compound represented by the formula (I-B): EC (EC) 50 5.53μM,CC 50 >200μM
Test example 9: effect of human serum and mouse serum on anti-SARS-CoV-2 Activity
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 3-fold gradient dilution series were prepared, they were dispensed into 96-well plates.
Addition of serum-supplemented Medium
The samples were prepared with medium (MEM, 2% fbs, penicillin-streptomycin) so as to be 0, 6.25%, 12.5, 25, 50% human serum or 0, 3.125, 6.25, 12.5, 25% mouse serum, and then dispensed into wells containing test samples, and incubated at room temperature for 1 hour.
Dilution and dispensing of cells and SARS-CoV-2
VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 3 Individual cells/well) and SARS-CoV-2hCoV-19/Japan/TY7-501/2021 (1000 TCID in human serum) 50 Well 10000TCID in mouse serum 50 Well) in a culture medium (MEM, 2% FBS, penicillin-streptomycin), and after an equal amount of the mixture was dispensed into wells containing a test sample and human serum, mouse serum, the mixture was subjected to CO 2 Culturing in an incubator for 3 days.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 3 days of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% concentration of inhibition of death of SARS-CoV-2 infected cells (EC 50 ) Calculation of
Let x be the logarithmic value of the compound concentration, let y be the% efficacy, the inhibition curve was fitted by the following logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Cell control: mean Lum of cell control wells
Virus control: average Lum of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
Protein-regulated (EC) 50 (PA-EC 50 ) Calculation of (2)
EC at each serum concentration was calculated 50 After that, PA-EC was calculated by linear regression under serum 100% conditions 50 Values.
The compounds of the present invention were tested essentially as described above. The results are shown below.
Fumaric acid co-crystal form I crystals of a compound represented by the formula (I-B): human serum PA-EC 50 3.02 mu.M, mouse serum PA-EC 50 3.93μM
Test example 10-1: cytopathic effect (CPE) inhibition assay Using human ACE2, TMPRSS2 expressing HEK293T cells (HEK 293T/ACE2-TMPRSS2 cells)
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 3-fold gradient dilution series were prepared, they were dispensed into 96-well plates.
Dilution and dispensing of cells and SARS-CoV-2
HEK293T/ACE2-TMPRSS2 cells (SL 222, 1.5X10) 4 Individual cells/well) and SARS-CoV-2hCoV-19/Japan/TY/WK-521/2020, hCoV-19/Japan/QK002/2020, hCoV-19/Japan/TY7-501/2021, hCoV-19/Japan/TY8-612/2021, hCoV-19/Japan/TY11-927-P1/2021 (3000-9000 TCID) 50 Well) in a culture medium (MEM, 2% FBS, penicillin-streptomycin), and after dispensing into wells containing test samples, the mixture was subjected to CO 2 Culturing in an incubator for 3 days.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 3 days of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% concentration of inhibition of death of SARS-CoV-2 infected cells (EC 50 ) Calculation of
Let x be the logarithmic value of compound concentration, let y be% efficacy, the inhibition curve was fitted by the following Logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Cell control: mean Lum of cell control wells
Virus control: average Lum of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown below.
Fumaric acid co-crystal form I crystals of a compound represented by the formula (I-B): 0.026-0.058. Mu.M
Test example 10-2: cytopathic effect (CPE) inhibition assay Using human ACE2, TMPRSS2 expressing HEK293T cells (HEK 293T/ACE2-TMPRSS2 cells)
< procedure >
Dilution and dispensing of the test sample
Test samples were diluted to appropriate concentrations in DMSO in advance, and after 3-fold gradient dilution series were prepared, they were dispensed into 96-well plates.
Dilution and dispensing of cells and SARS-CoV-2
HEK293T/ACE2-TMPRSS2 cells (SL 222, 1.5X10) 4 Individual cells/well) and SARS-CoV-2hCoV-19/Japan/TY38-873/2021 (9000 TCID) 50 Well) in a culture medium (MEM, 2% FBS, penicillin-streptomycin), and after dispensing into wells containing test samples, the mixture was subjected to CO 2 Culturing in an incubator for 3 days.
Measurement of a light-emitting Signal by dispensing CellTiter-Glo (registered trademark) 2.0
After plates after 3 days of incubation were returned to room temperature, cellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed with a plate mixer. After a certain time, the luminescence signal (Lum) was measured with an enzyme-labeled instrument.
< calculation of measurement item values >
50% concentration of inhibition of death of SARS-CoV-2 infected cells (EC 50 ) Calculation of
Let x be the logarithmic value of the compound concentration, let y be the% efficacy, the inhibition curve was fitted by the following logistic regression equation, and the value of x substituted into y=50 (%) was calculated as EC 50 。
y=min+(max-min)/{1+(X50/x)^Hill}
% potency = { (sample-virus control)/(cell control-virus control) } 100%
Cell control: mean Lum of cell control wells
Virus control: average Lum of virus control wells
min: y-axis lower limit, max: y-axis upper limit, X50: the x-coordinate of the inflection point, hill: slope of curve at midpoint of min and max
The compounds of the present invention were tested essentially as described above. The results are shown below.
Fumaric acid co-crystal form I crystals of a compound represented by the formula (I-B): 0.083 mu M
Test example 11: virus transmission inhibition test from SARS-CoV-2 infected animal to non-infected animal by preventive administration of fumaric acid co-crystal type I crystal of compound represented by formula (I-B)
< materials and methods >
Compounds
Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
The SARS-CoV-2hCoV19/Jap an/TY11-927/2021 strain isolated by the national institute of infectious disease was used.
Hamster lung infection, administration, lung recovery
Male syrian hamsters (japan SLC, inc.) of 5 weeks of age without specific pathogens were used in this study. The infected hamster 1 inoculated with the virus was housed in the same cage as the administered hamster 3 not inoculated with the virus, and the transmission of the virus to the administered hamster living with the infected hamster was tested. In vaccinating the virus, hamsters were anesthetized by inhaled administration of isoflurane. 200. Mu.L of hCoV19/Japan/TY11-927/2021 (5.00X 10) were subjected to anesthesia 3 PFU) was inoculated nasally into hamsters. For hamsters to be administered without virus inoculation, fumaric acid cocrystal form I crystals of the compound represented by formula (I-B) were orally administered at an amount of 30,200 mg/kg for 1 day 2 times, taking the time of virus inoculation into hamsters as a starting point. For control hamsters, 0.5% mc was orally administered 2 times a day 1. Compound administration was set to 6 days from the start of administration. At the position ofHamster lungs were recovered 6 days after the start of administration, 5mL of PBS was added and homogenized, and the supernatant after centrifugation was recovered.
Determination of the Lung Virus titre
Lung homogenates were serially diluted 10-fold with medium (MEM, 2% fbs, penicillin-streptomycin) and inoculated into VeroE6/TMPRSS2 cells (JCRB 1819, 2.0x10) previously cultured in 24-well plates 5 Individual cells/well). In CO 2 After 2 days of culture in the incubator, the virus plaques were observed, and the virus titers contained in the lung homogenates were calculated.
The compounds of the present invention were tested essentially as described above. The results are shown below.
The intrapulmonary viral titers of the administered hamsters were shown to be 6.12-log in the 0.5% MC administration group 6 days after onset of homonymy with infected hamsters 10 PFU/mL, shown as 3.48-log in the co-crystal form I crystals 30, 200mg/kg administration group, respectively, of the compound represented by formula (I-B) 10 PFU 50 /mL, detection limit or less (FIG. 9). In the fumaric acid co-crystal type I crystal administration group of the compound represented by the formula (I-B), the intrapulmonary virus titer was shown to be low compared to the 0.5% mc administration group, thereby suggesting an effect of reducing the transmission of virus from hamsters infected.
Test example 12: virus transmission inhibition test from SARS-CoV-2 infected animals to non-infected animals by administering fumaric acid co-crystal form I crystals of the Compound represented by the formula (I-B) immediately after infection
< materials and methods >
Compounds
Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
The SARS-CoV-2hCoV19/Jap an/TY11-927/2021 strain isolated by the national institute of infectious disease was used.
Hamster lung infection, administration, lung recovery
This studyMale syrian hamsters (japan SLC, inc.) of 5 weeks old without specific pathogens were used. The infected hamster 1 inoculated with the virus was housed in the same cage as the non-infected hamster 2 not inoculated with the virus, and the transmission of the virus to the non-infected hamster living with the infected hamster was examined. In the case of virus inoculation, hamsters were anesthetized by inhalation administration of isoflurane, and 200. Mu.L of hCoV-19/Japan/TY11-927/2021 (5.00X 10) were nasally inoculated 3 PF U). For hamster infection, fumaric acid cocrystal form I crystals of the compound of formula (I-B) were orally administered at an amount of 200mg/kg for 1 day 2 times as a starting point at the time of virus inoculation. For control infected hamsters, 0.5% mc was orally administered 2 times a day 1. Compound administration was set to 4 days from the start of administration. The non-infected hamster lung was recovered 6 days after infection, 5mL of PBS was added and homogenized, and the supernatant after centrifugation was recovered.
Determination of the Lung Virus titre
Lung homogenates were serially diluted 10-fold with medium (MEM, 2% fbs, penicillin-streptomycin) and inoculated into VeroE6/TMPRSS2 cells (JCRB 1819, 2.0x10) previously cultured in 24-well plates 5 Individual cells/well). In CO 2 After 2 days of culture in the incubator, the virus plaques were observed, and the virus titers contained in the lung homogenates were calculated.
The compounds of the present invention were tested essentially as described above. The results are shown below.
The intrapulmonary viral titers of non-infected hamsters were shown to be 6.36-log in the 0.5% MC administration group 6 days after onset of homonymy with infected hamsters 10 PFU/mL, in the 200mg/kg administration group of the fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B), was shown to be below the detection limit (FIG. 10). In the fumaric acid co-crystal type I crystal administration group of the compound represented by the formula (I-B), the intrapulmonary virus titer was shown to be low compared to the 0.5% mc administration group, thereby suggesting an effect of reducing the transmission of virus from hamsters infected.
Test example 13: virus transmission inhibition test from SARS-CoV-2 infected animals to non-infected animals by post-infection delayed administration of fumaric acid co-crystal type I crystals of the compound represented by formula (I-B)
< materials and methods >
Compounds
Fumaric acid cocrystal form I crystals of the compound of formula (I-B) were prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 5mL/kg. The administration amount represents an amount obtained by conversion in the form of a free body.
Virus
The SARS-CoV-2hCoV19/Jap an/TY11-927/2021 strain isolated by the national institute of infectious disease was used.
Hamster lung infection, administration, lung and turbinate recovery
In this study, 6 week old male syrian hamsters (Jap an SLC, inc.) without specific pathogens were used. 1 infected hamster inoculated with the virus was kept in the same cage as 1 non-infected hamster not inoculated with the virus, and 2 days after infection, the transmission of the virus to the non-infected hamster living with the infected hamster was examined. Implemented with each set n=3. In vaccinating the virus, hamsters were anesthetized by subcutaneous administration of 200. Mu.L of anesthetic solution containing 0.07mg/mL of medetomidine hydrochloride, 6.98mg/mL of alfasin, 1.16mg/mL of buprenorphine tartrate, and 100. Mu.L of hCoV-19/Japan/TY11-927/2021 (1.00X10) 2 TCID 50 ). For hamster infection, fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) were orally administered at an amount of 50mg/kg for 1 day 2 times as a starting point after 1 day of virus inoculation. For control infected hamsters, 0.5% mc was orally administered 2 times a day 1. Compound administration was set to 4 days from the start of administration. After 5 days of infection, infected and non-infected hamster lungs and turbinates were recovered, 5mL or 1mL of PBS was added, and homogenized, and the supernatant after centrifugation was recovered.
Determination of viral titers in the Lung and nasal turbinates
Lung or turbinate homogenates were serially diluted 10-fold with medium (MEM, 2% fbs, penicillin-streptomycin) and inoculated into Ve roE6/TMPRSS2 cells (JCRB 1819, 1.5x10) previously cultured in 96-well plates 4 Individual cells/well). In CO 2 After 5 days of culture in the incubator, cytopathic effect (CPE) was observedThe viral titers contained in the lung or nasal concha homogenates were calculated.
The compounds of the present invention were tested essentially as described above. The results are shown below.
The intrapulmonary viral titers of non-infected hamsters were shown to be 5.30-log in the 0.5% MC administration group 3 days after onset of homonymy with infected hamsters 10 TCID 50 Per mL, shown as 2.97-lo g in the 50mg/kg administration group of fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) 10 TCID 50 /mL (FIG. 11A). In addition, the intranasal viral titers of non-infected hamsters were shown to be 6.06-log in the 0.5% MC administration group 3 days after onset of homonymy with infected hamsters 10 TCID 50 Per mL, shown as 2.89-log in the 50mg/kg administration group of fumaric acid co-crystal form I crystals of the compound represented by the formula (I-B) 10 TCID 50 /mL (FIG. 11B). In the fumaric acid co-crystal type I crystal administration group of the compound represented by the formula (I-B), the virus titers in the lung and the nasal turbinates were shown to be low compared with the 0.5% MC administration group, thereby suggesting an effect of reducing the transmission of viruses from hamsters infected.
Test example 14: death and weight loss inhibition test of SA RS-CoV-2 infected mice by prophylactic administration of the Compound represented by formula (I-B)
< materials and methods >
Compounds
The compound of the present invention (compound represented by the formula (I-B)) was prepared using a 0.5% methylcellulose (0.5% MC) solution. The administration volume was set at 10mL/kg×2.
Virus
A domesticated strain MA-P10 of SARS-CoV-2hCoV19/Japan/TY/WK-521/2020 strain isolated from Hokkaido university was used.
Pulmonary infection, drug administration and weight measurement in mice
Retired female BAL B/c mice 37-57 weeks old (CLEA Japan, inc.) without specific pathogens were used in this study. Intramuscular administration of 100. Mu.L of anesthetic solution comprising 0.03mg/mL medetomidine hydrochloride, 0.4mg/mL midazolam, 0.5mg/mL buprenorphine tartrate in PBS at the time of virus inoculation Mice were anesthetized. Mice were vaccinated nasally under anesthesia with 50. Mu.L of MA-P10 (3.00X 10) 2 TCID 50 ). The compounds of formula (I-B) were subcutaneously administered to mice in an amount of 32, 64, 96, 128mg/kg once (n=15/group) 1 day prior to viral infection. For control mice, 0.5% mc was subcutaneously administered in a single pass. Body weight was monitored 1 day 1, and in the evaluation of survival rate, death was considered when the body weight immediately before infection became less than 80% based on the body weight.
The compounds of the present invention were tested essentially as described above. The results are shown below.
Infection of MA-P10.00×10 in 37-57 week old senior retired mice 2 TCID 50 In (2) the weight was reduced from the next day of infection, and after 4 days of infection, death was observed in some individuals, and after 8 days of infection, all test cases were dead. At this time, the survival rates up to 14 days after infection were 6.7%, 60%, 80%, and 100% in the administration groups of compounds 32, 64, 96, and 128mg/kg represented by the formula (I-B), and weight loss was suppressed in the administration groups of 32mg/kg or more (FIGS. 12A and B). The concentrations in plasma immediately before infection, i.e., after administration for 1 day, were measured and found to be 1740, 2990, 3110 and 3370. Mu.g/mL, respectively.
From the above results, it was found that, in the case of 37-57-week-old high-week-old retired mice, 64mg/kg or more of the compound of formula (I-B) was subcutaneously administered 1 day before infection, and the effect of suppressing death and weight loss was exhibited when the concentration of the compound in plasma at the time of viral infection was 2990. Mu.g/mL or more.
The above test results show that the compound of formula (I-B) is useful as a prophylactic agent for infectious diseases caused by SARS-CoV-2, while suppressing the occurrence of severe cases caused by viral infection when the compound of formula (I-B) is administered subcutaneously.
Test example 15: test for confirming inhibition effect of viral proliferation using human airway epithelial cells (human airway epithelial cells)
< procedure >
Dilution and dispensing of the test sample
Diluting test sample with DMSO to proper concentration, making 3-fold gradient dilution series, and using Mucilair TM The culture broth was diluted 200-fold and dispensed into 24-well plates.
SARS-CoV-2 infection
Mucilair inoculated in Transwell TM (Nasal cavity), about 5.0X10 5 Individual cells/well) infection with SARS-CoV-2 hCoV-19/Japan/TY11-927-P1/2021, hCoV-19/Japan/TY38-873/2021 (5000 TCID) 50 Hole), in CO 2 Culturing in an incubator for 2 hours. Then use Mucilair TM Washing the culture solution, placing transwell in a well containing test sample, and adding CO 2 Culturing in an incubator. For hCoV-19/Japan/TY11-927-P1/2021, mucilair was added to the transwell 2, 3 days after infection TM Culture medium, for hCoV-19/Japan/TY38-873/2021, was supplemented with Mucilair to transwell 1, 2 days after infection TM The culture broth was recovered as a supernatant.
Determination of viral titers in supernatants
The recovered supernatant was serially diluted 10-fold with medium (MEM, 2% FBS, penicillin-streptomycin) and then was subjected to a dilution series with VeroE6/TMPRSS2 cells (JCRB 1819, 1.5X10) 4 Individual cells/well) were mixed and seeded into 96-well plates. In CO 2 After 4 days of culture in the incubator, cytopathic effect (CPE) was observed, and the virus titer contained in the supernatant was calculated.
< calculation of measurement item values >
90% SARS-CoV-2 Virus production inhibitory concentration (EC 90 ) Calculation of
In the case where x is the logarithmic value of the compound concentration and y is the viral titer (Log 10 TCID 50 Concentration-dependent curve of/mL) will be 1log relative to the virus control 10 The equivalent value of reduction was calculated by the two-point method based on the virus titers at the 2 concentrations before and after the reduction.
[ mathematics 1]
X = lowest concentration at which the mean value of the decrease relative to control virus titer is less than-1 (the low cont. At the average of reduction from control viral titer of < -1)
x=highest concentration at average value of decrease of-1 or more relative to control virus titer (the high control. At the average of reduction from controlviral titer of. Gtoreq. -1)
Average of the decrease in y=x relative to control virus titers (the average of reduction from control viral titer at x)
Average of the decrease in y=x relative to control virus titers (the average of reduction from control viral titer at X)
EC is calculated by 90 Values.
EC 90 =10 [log(x) +(-1-Y)×(log(x)-log(X))/(Y-y)]
The compounds of the present invention were tested essentially as described above. The results are shown below.
TABLE 15
The following formulation examples are merely examples and are not intended to limit the scope of the invention in any way.
The compounds according to the invention can be administered as pharmaceutical compositions by any of the conventional routes, in particular enterally, e.g. orally (in the form of, for example, tablets or capsules), or parenterally (in the form of, for example, injectable solutions or suspensions), locally in the form of, for example, lotions, gels, ointments or creams, or in the form of nasal or suppository formulations. The pharmaceutical composition of the compound of the present invention comprising the compound in a free form or a pharmaceutically acceptable salt form together with at least 1 pharmaceutically acceptable carrier or diluent can be produced by mixing, granulating or coating methods by conventional methods. For example, as the composition for oral administration, tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients, etc. can be prepared. The injectable composition may be formulated into a solution or suspension, may be sterilized, and may contain a preservative, a stabilizer, a buffer, or the like.
Industrial applicability
The compound of the present invention has an inhibitory activity against coronavirus 3CL protease, and a pharmaceutical composition containing the compound of the present invention is useful as a therapeutic and/or prophylactic agent for infectious diseases caused by coronaviruses.
Claims (12)
1. A pharmaceutical composition comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
[ chemical formula 1]
In the formula (I), Y is N;
R 1 is a substituted or unsubstituted aromatic heterocyclic group;
R 2 is a substituted or unsubstituted 6 membered aromatic carbon ring group;
R 3 is a substituted or unsubstituted aromatic heterocyclic group;
-X-is-NH-;
m is 0 or 1;
R 5a is a hydrogen atom;
R 5b is a hydrogen atom;
n is 1;
R 4a is a hydrogen atom;
R 4b is a hydrogen atom.
2. The pharmaceutical composition of claim 1, wherein R 1 Is a substituted or unsubstituted 5-to 6-membered aromatic heterocyclic group.
3. The pharmaceutical composition of claim 1 or 2, wherein R 2 A 6 membered aromatic carbon ring group substituted with 1, 2 or 3 substituents selected from substituent group G;
wherein the substituent group G is a group consisting of halogen, cyano and unsubstituted alkyl.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein R 3 Is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.
5. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of compound I-003, compound I-005, compound I-017 and compound I-023.
6. The pharmaceutical composition of any one of claims 1-5, which is a 3CL protease inhibitor.
7. The pharmaceutical composition according to any one of claims 1 to 6, for inhibiting viral proliferation of SARS-CoV-2.
8. The pharmaceutical composition according to any one of claims 1 to 7, which is a therapeutic and/or prophylactic agent for a novel coronavirus infectious disease (covd-19).
9. The pharmaceutical composition according to any one of claims 1 to 8, for inhibiting the severity of infectious diseases caused by SARS-CoV-2.
10. The pharmaceutical composition according to any one of claims 1 to 9 for use in the following manner: administration begins after manifestation of symptoms of the infectious disease caused by SARS-CoV-2, or within 72 hours from the determination of SARS-CoV-2 positive.
11. The pharmaceutical composition according to any one of claims 1 to 9 for use in the following manner: administration begins after manifestation of symptoms of the infectious disease caused by SARS-CoV-2, or within 24 hours from the determination of SARS-CoV-2 positive.
12. The pharmaceutical composition of any one of claims 1-9 for inhibiting viral transmission of SARS-CoV-2.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021-157929 | 2021-09-28 | ||
JP2021-171725 | 2021-10-20 | ||
JP2022-000723 | 2022-01-05 | ||
JP2022-015035 | 2022-02-02 | ||
JP2022-131590 | 2022-08-22 | ||
JP2022131590 | 2022-08-22 | ||
PCT/JP2022/035803 WO2023054292A1 (en) | 2021-09-28 | 2022-09-27 | Pharmaceutical composition containing triazine derivative |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115038696A (en) * | 2021-04-14 | 2022-09-09 | 盐野义制药株式会社 | Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same |
CN116284133A (en) * | 2022-03-24 | 2023-06-23 | 南京知和医药科技有限公司 | Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999036410A1 (en) * | 1998-01-13 | 1999-07-22 | Scriptgen Pharmaceuticals, Inc. | Triazine antiviral compounds |
WO2019087884A1 (en) * | 2017-10-31 | 2019-05-09 | 富士フイルム株式会社 | Composition, antimicrobial composition, antiviral composition, anti-norovirus composition, spray and wiper |
WO2022158528A1 (en) * | 2021-01-20 | 2022-07-28 | 国立大学法人北海道大学 | Anti-viral agent |
CN115038696A (en) * | 2021-04-14 | 2022-09-09 | 盐野义制药株式会社 | Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999036410A1 (en) * | 1998-01-13 | 1999-07-22 | Scriptgen Pharmaceuticals, Inc. | Triazine antiviral compounds |
WO2019087884A1 (en) * | 2017-10-31 | 2019-05-09 | 富士フイルム株式会社 | Composition, antimicrobial composition, antiviral composition, anti-norovirus composition, spray and wiper |
WO2022158528A1 (en) * | 2021-01-20 | 2022-07-28 | 国立大学法人北海道大学 | Anti-viral agent |
CN115038696A (en) * | 2021-04-14 | 2022-09-09 | 盐野义制药株式会社 | Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115038696A (en) * | 2021-04-14 | 2022-09-09 | 盐野义制药株式会社 | Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same |
CN116284133A (en) * | 2022-03-24 | 2023-06-23 | 南京知和医药科技有限公司 | Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof |
CN116284133B (en) * | 2022-03-24 | 2024-03-29 | 南京知和医药科技有限公司 | Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof |
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