技术领域Technical Field
本发明涉及含有三嗪衍生物的口服给与的制剂。详细而言，涉及含有示出冠状病毒3CL蛋白酶抑制活性的三嗪衍生物、其制药上可接受的盐或它们的复合体作为有效成分的口服给与的制剂。The present invention relates to an oral preparation containing a triazine derivative, and more particularly, to an oral preparation containing a triazine derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a complex thereof as an active ingredient.
背景技术Background Art
属于套式病毒目冠状病毒科正冠状病毒亚科的冠状病毒具有约30千碱基的基因组大小，是已知的RNA病毒中最大级别的单链正链RNA病毒。冠状病毒被分类为α冠状病毒属、β冠状病毒属、γ冠状病毒属和δ冠状病毒属的4种，作为对人感染的冠状病毒，已知α冠状病毒属的2种(HCoV-229E、HCoV-NL63)和β冠状病毒属的5种(HCoV-HKU1、HCoV-OC43、SARS-CoV、MERS-CoV、SARS-CoV-2)，总计7种。其中，4种(HCoV-229E、HCoV-NL63、HCoV-HKU1、HCoV-OC43)是感冒的病原体，其余是新型冠状病毒(SARS-CoV-2)，以及引起重症肺炎的重症急性呼吸道综合征(SARS)冠状病毒(SARS-CoV)和中东呼吸道综合征(MERS)冠状病毒(MERS-CoV)。The coronavirus belonging to the subfamily Orthocoronavirus of the family Coronaviridae in the order Nidovirales has a genome size of about 30 kilobases and is the largest single-stranded positive-strand RNA virus among the known RNA viruses. Coronaviruses are classified into four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. As coronaviruses that infect humans, two species of the alphacoronavirus genus (HCoV-229E, HCoV-NL63) and five species of the betacoronavirus genus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2) are known, for a total of seven species. Among them, four species (HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43) are pathogens of colds, and the rest are the new coronavirus (SARS-CoV-2), as well as the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and the Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) that cause severe pneumonia.
在2022年9月21日时点所确认的新型冠状病毒感染症(COVID-19)感染人数为6.1亿人以上，死亡数达到650万人以上(非专利文献1)。作为SARS-CoV-2的主要感染途径，报告了飞沫感染、接触感染和气溶胶感染，SARS-CoV-2确认到与气溶胶一起在空气中持续漂浮3小时左右，维持感染力(非专利文献2)。潜伏期间为2～14天左右，典型而言为发热(87.9％)、干咳(67.7％)、疲倦感(38.1％)、痰(33.4％)等感冒样症状(非专利文献3)。重症例中，引起急性呼吸窘迫综合征、因急性肺损伤、间质性肺炎等而导致的呼吸道衰竭。此外，还报告了肾衰竭、肝衰竭等多器官衰竭。As of September 21, 2022, the number of confirmed COVID-19 infections is over 610 million, and the death toll is over 6.5 million (Non-Patent Document 1). As the main infection routes of SARS-CoV-2, droplet infection, contact infection, and aerosol infection have been reported. SARS-CoV-2 has been confirmed to float in the air with aerosols for about 3 hours and maintain infectivity (Non-Patent Document 2). The incubation period is about 2 to 14 days, typically with cold-like symptoms such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and sputum (33.4%) (Non-Patent Document 3). In severe cases, acute respiratory distress syndrome, respiratory failure caused by acute lung injury, interstitial pneumonia, etc. are caused. In addition, multiple organ failure such as renal failure and liver failure has also been reported.
在日本，根据现有药物的药物重定位，作为抗病毒药的瑞德西韦、作为抗炎症药的地塞米松、作为类风湿性关节炎药的巴瑞替尼被批准作为针对COVID-19的治疗药，在2022年1月，追加批准了作为抗IL-6受体抗体的托珠单抗。此外，于2021年7月，特例批准了作为抗体鸡尾酒疗法的RONAPREVE(Casirivimab/Imdevimab)，于2021年9月，特例批准了Sotrovimab，于2021年12月，特例批准了莫匹拉韦(molnupiravir)。针对关于这些药剂的有效性、安全性，没有得到充分的证据。因此，急迫的是研发针对COVID-19的治疗药。In Japan, based on the drug repositioning of existing drugs, remdesivir as an antiviral drug, dexamethasone as an anti-inflammatory drug, and baricitinib as a rheumatoid arthritis drug were approved as treatment drugs for COVID-19, and in January 2022, tocilizumab as an anti-IL-6 receptor antibody was additionally approved. In addition, RONAPREVE (Casirivimab/Imdevimab) was approved as an antibody cocktail therapy in July 2021, sotrovimab was approved as a special case in September 2021, and mopilavir (molnupiravir) was approved as a special case in December 2021. There is no sufficient evidence for the effectiveness and safety of these drugs. Therefore, it is urgent to develop treatment drugs for COVID-19.
冠状病毒如果对细胞感染，则合成2个多聚蛋白。在该2个多聚蛋白中，包含制作病毒基因组的复制复合体、2个蛋白酶。蛋白酶为了剪切由病毒合成的多聚蛋白、使各个蛋白质发挥功能而发挥不可缺少的作用。2个蛋白酶之中，几乎承担了多聚蛋白的剪切的是3CL蛋白酶(主蛋白酶)(非专利文献4)。If coronavirus infects cells, it synthesizes two polyproteins. The two polyproteins contain a replication complex that makes the viral genome and two proteases. Proteases play an indispensable role in cleaving polyproteins synthesized by the virus and allowing each protein to function. Among the two proteases, 3CL protease (main protease) is almost responsible for the cleavage of polyproteins (Non-patent Document 4).
作为以3CL蛋白酶为靶标的COVID-19治疗药，2021年6月，在ClinicalTrials.gov上公开了由Pfizer公司进行的作为PF-00835231的前药的Lufotrelvir(PF-07304814)的Phase1b试验结束(NCT04535167)。此外，2021年3月，Pfizer公司发表开始针对新型冠状病毒感染症的治疗药PF-07321332的Phase1试验。PF-00835231、Lufotrelvir和PF-07321332的结构式如以下所示，与本发明化合物化学结构不同(非专利文献5、12和13、以及专利文献6和7)。As a COVID-19 therapeutic drug targeting 3CL protease, in June 2021, the Phase 1b trial of Lufotrelvir (PF-07304814), a prodrug of PF-00835231, conducted by Pfizer was announced on ClinicalTrials.gov (NCT04535167). In addition, in March 2021, Pfizer announced the start of Phase 1 trials for PF-07321332, a therapeutic drug for novel coronavirus infection. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, which are different from the chemical structures of the compounds of the present invention (Non-patent Documents 5, 12, and 13, and Patent Documents 6 and 7).
PF-00835231：PF-00835231:
【化1】【Chemistry 1】
Lufotrelvir(PF-07304814)：Lufotrelvir (PF-07304814):
【化2】【Chemistry 2】
PF-07321332：PF-07321332:
【化3】【Chemistry 3】
进一步，2021年7月，在ClinicalTrials.gov上公开了开始以具有高危因子的COVID-19患者作为对象的PF-07321332和利托那韦联用的Phase2/3试验(NCT04960202)。此外，2021年11月，在Pfizer公司的主页上，报告了PAXLOVID(TM)(PF-07321332；利托那韦)在成人的高危患者中，与安慰剂相比使入院或死亡的风险减少89％(非专利文献14)。进一步，2021年12月，PAXLOVID(TM)在美国被批准紧急使用许可，2022年2月10日在日本特例批准了PAXLOID(注册商标)包装。Furthermore, in July 2021, a Phase 2/3 trial (NCT04960202) of the combination of PF-07321332 and ritonavir, which began targeting COVID-19 patients with high-risk factors, was disclosed on ClinicalTrials.gov. In addition, in November 2021, on the homepage of Pfizer, it was reported that PAXLOVID(TM) (PF-07321332; ritonavir) reduced the risk of hospitalization or death by 89% compared with placebo in high-risk adult patients (Non-Patent Literature 14). Furthermore, in December 2021, PAXLOVID(TM) was approved for emergency use in the United States, and on February 10, 2022, PAXLOID (registered trademark) packaging was approved as a special case in Japan.
非专利文献5～8中公开了具有3CL蛋白酶抑制活性的化合物，但任一文献中均没有记载或暗示与本发明相关的化合物、制造方法和合成中间体。Non-patent documents 5 to 8 disclose compounds having 3CL protease inhibitory activity, but none of the documents describes or suggests the compounds, production methods, and synthetic intermediates related to the present invention.
专利文献1～4和8～12中公开了具有P2X3和/或P2X2/3受体拮抗作用的三嗪衍生物和尿嘧啶衍生物，但任一文献中，均没有针对3CL蛋白酶抑制活性和抗病毒效果进行记载或暗示。此外，也没有记载或暗示本发明所涉及的制造方法和合成中间体。Patent documents 1 to 4 and 8 to 12 disclose triazine derivatives and uracil derivatives havingP2X3 and/or P2X2/3 receptor antagonism, but none of the documents describes or suggests 3CL protease inhibitory activity and antiviral effects. In addition, the production method and synthetic intermediates involved in the present invention are not described or suggested.
非专利文献9～11中公开了具有抗肿瘤效果的三嗪衍生物，但任一文献中，均没有针对冠状病毒3CL蛋白酶抑制活性和抗病毒效果进行记载，此外，也没有记载或暗示与本发明相关联的化合物、制造方法和合成中间体。Non-patent documents 9 to 11 disclose triazine derivatives having antitumor effects, but none of the documents describes coronavirus 3CL protease inhibitory activity and antiviral effects, and further, no compounds, production methods, or synthetic intermediates related to the present invention are described or suggested.
专利文献5中公开了具有甘丙肽受体调节作用的三嗪衍生物，但任一文献中均没有针对3CL蛋白酶抑制活性和抗病毒效果进行记载或暗示。此外，也没有记载或暗示本发明所涉及的制造方法和合成中间体。Patent Document 5 discloses triazine derivatives having galanin receptor modulating effects, but neither document describes nor suggests 3CL protease inhibitory activity nor antiviral effects. In addition, neither document describes nor suggests the production method and synthetic intermediates involved in the present invention.
现有技术文献Prior art literature
专利文献Patent Literature
专利文献1：国际公开第2012/020749号Patent Document 1: International Publication No. 2012/020749
专利文献2：国际公开第2013/089212号Patent Document 2: International Publication No. 2013/089212
专利文献3：国际公开第2010/092966号Patent Document 3: International Publication No. 2010/092966
专利文献4：国际公开第2014/200078号Patent Document 4: International Publication No. 2014/200078
专利文献5：国际公开第2012/009258号Patent Document 5: International Publication No. 2012/009258
专利文献6：国际公开第2021/205298号Patent Document 6: International Publication No. 2021/205298
专利文献7：国际公开第2021/250648号Patent Document 7: International Publication No. 2021/250648
专利文献8：中国专利申请公开第113620888号说明书Patent Document 8: Chinese Patent Application Publication No. 113620888
专利文献9：中国专利申请公开第113666914号说明书Patent Document 9: Chinese Patent Application Publication No. 113666914
专利文献10：中国专利申请公开第113735838号说明书Patent Document 10: Chinese Patent Application Publication No. 113735838
专利文献11：中国专利申请公开第113773300号说明书Patent Document 11: Chinese Patent Application Publication No. 113773300
专利文献12：中国专利申请公开第113801097号说明书Patent Document 12: Chinese Patent Application Publication No. 113801097
非专利文献Non-patent literature
非专利文献1：“COVID-19Dashboard by the Center for Systems Science andEngineering at Johns Hopkins University”、[online]、Johns Hopkins University、[2022年3月14日检索]、互联网<URL：https://coronavirus.jhu.edu/map.html>Non-Patent Literature 1: “COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University”, [online], Johns Hopkins University, [retrieved on March 14, 2022], Internet <URL: https://coronavirus.jhu.edu/map.html>
非专利文献2：The NEW ENGLAND JOURNAL of MEDICINE(2020年)、382卷、1564～1567页Non-patent document 2: The New England Journal of Medicine (2020), Vol. 382, pp. 1564-1567
非专利文献3：“Report of the WHO-China Joint Mission on CoronavirusDisease 2019(COVID-19)”、[online]、2020年2月28日、WHO、[2021年2月8日检索]、互联网<URL：https://www.who.int/docs/default-source/coronaviruse/wh邻china-joint-missio正o正covid-19-final-report.pdf>Non-Patent Document 3: “Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)”, [online], February 28, 2020, WHO, [retrieved on February 8, 2021], Internet <URL: https://www.who.int/docs/default-source/coronaviruse/wh邻china-joint-missionio正o正covid-19-final-report.pdf>
非专利文献4：Science(2003年)、300卷、1763～1767页Non-patent document 4: Science (2003), Vol. 300, pp. 1763-1767
非专利文献5：“A comparative analysis of SARS-CoV-2antiviralscharacterizes 3CLpro inhibitor PF-00835231as a potential new treatment forCOVID-19”、Journal of Virology、2021年4月26日、[2022年2月15日检索]、互联网<URL：https://journals.asm.org/doi/10.1128/JVI.01819-20><doi：10.1128/JVI.01819-20>Non-patent literature 5: “A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19”, Journal of Virology, April 26, 2021, [retrieved February 15, 2022], Internet <URL: https://journals.asm.org/doi/10.1128/JVI.01819-20><doi: 10.1128/JVI.01819-20>
非专利文献6：Cell Research(2020年)、30卷、678～692页Non-patent document 6: Cell Research (2020), Vol. 30, pp. 678-692
非专利文献7：Science(2020年)、368卷、409～412页Non-patent document 7: Science (2020), Vol. 368, pp. 409-412
非专利文献8：ACS Central Science(2021年)、7卷、3号、467～475页Non-patent literature 8: ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475
非专利文献9：Cancer Treatment Reviews(1984年)、11卷、Supplement 1、99～110页Non-patent document 9: Cancer Treatment Reviews (1984), Vol. 11, Supplement 1, pp. 99-110
非专利文献10：Contributions to Oncology(1984年)、18卷、221～234页Non-patent document 10: Contributions to Oncology (1984), Vol. 18, pp. 221-234
非专利文献11：Arzneimittel-Forschung(1984年)、11卷、6号、663～668页Non-patent document 11: Arzneimittel-Forschung (1984), Vol. 11, No. 6, pp. 663-668
非专利文献12：261st Am Chem Soc(ACS)Natl Meet·2021-04-05/2021-04-16·Virtual,N/A·Abst 243Non-patent literature 12: 261st Am Chem Soc (ACS) Natl Meet·2021-04-05/2021-04-16·Virtual, N/A·Abst 243
非专利文献13：Science(2021年)、374卷、1586～1593页Non-patent literature 13: Science (2021), Vol. 374, pp. 1586-1593
非专利文献14："Pfizer's Novel COVID-19Oral Antiviral TreatmentCandidate Reduced Risk Of Hospitalization Or Death By 89％In Interim AnalysisOf Phase 2/3EPIC-HR Study"、[online]、2021年11月5日、Pfizer Press Release、[2022年2月15日检索]、互联网＜URL：https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate＞Non-Patent Literature 14: "Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk Of Hospitalization Or Death By 89% In Interim Analysis Of Phase 2/3 EPIC-HR Study", [online], November 5, 2021, Pfizer Press Release, [retrieved on February 15, 2022], Internet <URL: https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate>
非专利文献15：AIMECS 2021(AFMC International Medicinal ChemistrySymposium 2021)、在线研讨会、2021年11月29日-12月2日Non-patent literature 15: AIMECS 2021 (AFMC International Medicinal Chemistry Symposium 2021), online seminar, November 29-December 2, 2021
非专利文献16：bioRxiv preprint doi：https：//doi.org/10.1101/2022.01.26.477782、“Discovery of S-217622,aNon-Covalent Oral SARS-CoV-2 3CLProtease Inhibitor Clinical Candidate for Treating COVID-19”Non-patent literature 16: bioRxiv preprint doi: https://doi.org/10.1101/2022.01.26.477782, "Discovery of S-217622, aNon-Covalent Oral SARS-CoV-2 3CLProtease Inhibitor Clinical Candidate for Treating COVID-19"
非专利文献17：J.Med.Chem.(2022年)、65卷、6499～6512页、“Discovery of S-217622,a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor ClinicalCandidate for Treating COVID-19”Non-patent literature 17: J. Med. Chem. (2022), Vol. 65, pp. 6499-6512, “Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”
发明内容Summary of the invention
发明要解决的课题Problems to be solved by the invention
本发明的目的在于，提供一种示出冠状病毒3CL蛋白酶抑制活性的三嗪衍生物、其制药上可接受的盐或它们的复合体的制造方法。An object of the present invention is to provide a method for producing a triazine derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a complex thereof.
此外，本发明的目的在于，提供一种含有示出冠状病毒3CL蛋白酶抑制活性的三嗪衍生物、其制药上可接受的盐或它们的复合体作为有效成的口服给与的制剂。Another object of the present invention is to provide an oral preparation containing a triazine derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a complex thereof as an active ingredient.
用于解决问题的手段Means used to solve problems
本发明涉及以下。The present invention relates to the following.
(1)式(III)所示的化合物或其盐的制造方法，其特征在于，使式(I)所示的化合物或其盐、和式(II)所示的化合物或其盐在酸存在下反应(1) A method for producing a compound represented by formula (III) or a salt thereof, characterized in that a compound represented by formula (I) or a salt thereof and a compound represented by formula (II) or a salt thereof are reacted in the presence of an acid.
【化4】【Chemistry 4】
(式中，R1为取代或未取代的C1-C4烷基，R2各自独立地为卤素、氰基或甲基，n为1～5的整数)(wherein,R1 is a substituted or unsubstituted C1-C4 alkyl group,R2 is independently a halogen, a cyano group or a methyl group, and n is an integer of 1 to 5)
【化5】【Chemistry 5】
(式中，R3各自独立地为取代或未取代的C1-C4烷基，m为0～5的整数)(wherein, R3 is each independently a substituted or unsubstituted C1-C4 alkyl group, and m is an integer of 0 to 5)
【化6】【Chemistry 6】
(2)根据上述(1)所述的制造方法，其中，酸为三氟乙酸。(2) The production method according to (1) above, wherein the acid is trifluoroacetic acid.
(3)根据上述(1)或(2)所述的制造方法，其中，式(III)所示的化合物为式(III-1)：(3) The production method according to (1) or (2) above, wherein the compound represented by formula (III) is formula (III-1):
【化7】【Chemistry 7】
(4)式(VI)所示的化合物或其盐或它们的溶剂化物的制造方法，其特征在于，使式(IV)所示的化合物或其盐、与式(V)所示的化合物或其盐在酸存在下反应(4) A method for producing a compound represented by formula (VI) or a salt thereof or a solvate thereof, characterized in that a compound represented by formula (IV) or a salt thereof and a compound represented by formula (V) or a salt thereof are reacted in the presence of an acid.
【化8】【Chemistry 8】
(式中，R4为取代或未取代的芳族杂环式基、或取代或未取代的芳族碳环式基，p为0或1，其他标记为与上述(1)相同含义)(wherein,R4 is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic group, p is 0 or 1, and other symbols have the same meanings as in (1) above)
【化9】【Chemistry 9】
(式中，R5各自独立地为卤素、或取代或未取代的烷基，q为0～5的整数)(wherein, R5 is independently halogen, or substituted or unsubstituted alkyl, and q is an integer of 0 to 5)
【化10】【Chemistry 10】
(式中的标记为与上述相同含义)。(The symbols in the formula have the same meanings as above).
(5)根据上述(4)所述的制造方法，其中，酸为乙酸。(5) The production method according to (4) above, wherein the acid is acetic acid.
(6)根据上述(4)或(5)所述的制造方法，其中，式(VI)所示的化合物为式(VII)：(6) The production method according to (4) or (5) above, wherein the compound represented by formula (VI) is formula (VII):
【化11】【Chemistry 11】
(7)式(VII)所示的化合物、或其盐或它们的溶剂化物的制造方法，其包括：由上述(1)～(3)中任一项所述的制造方法，得到式(III)所示的化合物或其盐的步骤(7) A method for producing a compound represented by formula (VII), a salt thereof, or a solvate thereof, comprising: obtaining a compound represented by formula (III) or a salt thereof by the method described in any one of (1) to (3) above;
【化12】【Chemistry 12】
【化13】【Chemistry 13】
(8)式(VII)所示的化合物的富马酸共晶体I形的制造方法，其特征在于，将式(VII)所示的化合物或其盐在富马酸、丙酮和水存在下结晶化(8) A method for producing a fumaric acid cocrystal of a compound represented by formula (VII) in form I, characterized in that the compound represented by formula (VII) or a salt thereof is crystallized in the presence of fumaric acid, acetone and water.
【化14】【Chemistry 14】
(9)根据上述(8)所述的制造方法，其特征在于，使通过使用上述(1)～(7)中任一项所述的制造方法得到的式(VII)所示的化合物或其盐结晶化(9) The production method according to (8) above, characterized in that the compound represented by formula (VII) or a salt thereof obtained by using the production method described in any one of (1) to (7) above is crystallized.
【化15】【Chemistry 15】
(10)根据上述(8)或(9)所述的制造方法，其中，结晶化温度为40～60℃，结晶化时间为120分钟以上。(10) The production method according to (8) or (9) above, wherein the crystallization temperature is 40 to 60°C and the crystallization time is 120 minutes or longer.
(11)式(VIII)：(11) Formula (VIII):
【化16】【Chemistry 16】
所示的化合物、或其盐。The compound shown, or a salt thereof.
(12)式(IX)：(12) Formula (IX):
【化17】【Chemistry 17】
所示的化合物、或其盐。The compound shown, or a salt thereof.
(13)式(X)：(13) Formula (X):
【化18】【Chemistry 18】
所示的化合物、或其盐。The compound shown, or a salt thereof.
(14)式(XI)：(14) Formula (XI):
【化19】【Chemistry 19】
所示的化合物、或其盐。The compound shown, or a salt thereof.
(15)式(VII)：(15) Formula (VII):
【化20】【Chemistry 20】
所示的化合物的甲苯化物。Toluylate of the indicated compound.
(16)式(VII)所示的化合物的富马酸共晶体I形，其实质上不含式(VII)所示的化合物的游离体(16) Fumaric acid cocrystal form I of the compound represented by formula (VII), which does not substantially contain the free form of the compound represented by formula (VII)
【化21】【Chemistry 21】
(17)以下的式：(17) The following formula:
【化22】【化22】
所示的化合物的甲磺酸盐。The mesylate salt of the indicated compound.
(18)以下的式：(18) The following formula:
【化23】【Chemistry 23】
所示的化合物的甲磺酸盐。The mesylate salt of the indicated compound.
(19)以下的式：(19) The following formula:
【化24】【Chemistry 24】
所示的化合物、或其盐。The compound shown, or a salt thereof.
(20)以下的式：(20) The following formula:
【化25】【Chemistry 25】
所示的化合物、或其盐。The compound shown, or a salt thereof.
(21)根据上述项目(20)所述的盐，其为以下的式：(21) The salt according to item (20) above, which is of the following formula:
【化26】【Chemistry 26】
所示的化合物的1,8-二氮杂双环[5.4.0]-7-十一碳烯盐。The 1,8-diazabicyclo[5.4.0]-7-undecene salt of the compound shown.
(22)口服给与的制剂(药物组合物)，其含有式(VII)：(22) A preparation (pharmaceutical composition) for oral administration, comprising formula (VII):
【化27】【Chemistry 27】
所示的化合物、其制药上可接受的盐或它们的复合体作为有效成分。The compound shown, its pharmaceutically acceptable salt or a complex thereof is used as an active ingredient.
(23)根据上述(22)所述的制剂(药物组合物)，其中，有效成分为式(VII)所示的化合物的复合体，该复合体为包含富马酸的复合体。(23) The preparation (pharmaceutical composition) according to (22) above, wherein the active ingredient is a complex of the compound represented by formula (VII), and the complex is a complex containing fumaric acid.
(24)根据上述(23)所述的制剂(药物组合物)，其中，该复合体是式(VII)所示的化合物和富马酸为1:1的摩尔比的共晶体。(24) The preparation (pharmaceutical composition) according to (23) above, wherein the complex is a co-crystal of the compound represented by formula (VII) and fumaric acid in a molar ratio of 1:1.
(25)根据上述(22)～(24)中任一项所述的制剂(药物组合物)，其中，在制剂中含有高分子。(25) The preparation (pharmaceutical composition) according to any one of (22) to (24) above, wherein the preparation contains a polymer.
(26)根据上述(25)所述的制剂(药物组合物)，其中，高分子为选自纤维素系高分子、丙烯酸系高分子、乙烯基系高分子中的1种以上。(26) The preparation (pharmaceutical composition) according to (25) above, wherein the polymer is one or more selected from the group consisting of cellulose-based polymers, acrylic polymers, and vinyl-based polymers.
(27)根据上述(22)～(26)中任一项所述的制剂(药物组合物)，其中，有效成分为通过上述(4)～(10)中任一项所述的方法得到的化合物、其制药上可接受的盐或它们的复合体。(27) A preparation (pharmaceutical composition) according to any one of (22) to (26) above, wherein the active ingredient is a compound obtained by the method according to any one of (4) to (10) above, a pharmaceutically acceptable salt thereof, or a complex thereof.
(28)根据上述(22)～(27)中任一项所述的制剂(药物组合物)，其用于治疗和/或预防冠状病毒感染症。(28) The preparation (pharmaceutical composition) according to any one of (22) to (27) above, which is used for treating and/or preventing coronavirus infection.
(29)根据上述(28)所述的制剂(药物组合物)，其中，冠状病毒感染症为新型冠状病毒感染症(COVID-19)。(29) The preparation (pharmaceutical composition) according to (28) above, wherein the coronavirus infection is the new coronavirus infection (COVID-19).
(30)根据上述(22)所述的制剂，其含有125.0mg的式(VII)所示的化合物作为有效成分。(30) The preparation according to (22) above, comprising 125.0 mg of the compound represented by formula (VII) as an active ingredient.
(31)根据上述(23)所述的制剂，其中所述制剂包含152.3mg的式(VII)所示的化合物和富马酸的摩尔比为1：1的复合体。(31) The preparation according to (23) above, wherein the preparation comprises 152.3 mg of a complex of the compound represented by formula (VII) and fumaric acid in a molar ratio of 1:1.
(32)根据上述(22)所述的制剂，其含有250.0mg的式(VII)所示的化合物作为有效成分。(32) The preparation according to (22) above, comprising 250.0 mg of the compound represented by formula (VII) as an active ingredient.
(33)根据上述(23)所述的制剂，其中所述制剂包含304.6mg的式(VII)所示的化合物和富马酸的摩尔比为1：1的复合体。(33) The preparation according to (23) above, wherein the preparation comprises 304.6 mg of a complex of the compound represented by formula (VII) and fumaric acid in a molar ratio of 1:1.
(34)根据上述(22)所述的制剂，其含有25.0mg的式(VII)所示的化合物作为有效成分。(34) The preparation according to (22) above, comprising 25.0 mg of the compound represented by formula (VII) as an active ingredient.
(35)根据上述(23)所述的制剂，其中所述制剂包含30.46mg的式(VII)所示的化合物和富马酸的摩尔比为1：1的复合体。(35) The preparation according to (23) above, wherein the preparation comprises 30.46 mg of a complex of the compound represented by formula (VII) and fumaric acid in a molar ratio of 1:1.
(36)根据上述(22)～(35)中任一项所述的制剂，其用于12岁以上儿童及成人。(36) The preparation according to any one of (22) to (35) above, which is for children aged 12 years or older and adults.
(37)根据上述(22)～(35)中任一项所述的制剂，其用于6岁以上且未满12岁的儿童。(37) The preparation according to any one of (22) to (35) above, which is for children aged 6 to 12 years old.
发明效果Effects of the Invention
通过本发明所涉及的制造方法制造的化合物具有针对冠状病毒3CL蛋白酶的抑制活性，作为冠状病毒感染症的治疗剂和/或预防剂是有用的。The compound produced by the production method of the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic agent and/or preventive agent for coronavirus infection.
此外，通过本发明所涉及的制造方法制造的化合物作为医药原料是有用的。Furthermore, the compound produced by the production method according to the present invention is useful as a pharmaceutical raw material.
进一步，含有通过本发明所涉及的制造方法制造的化合物(I-0005)的富马酸共晶体的药物组合物作为新型冠状病毒感染症(COVID-19)的治疗剂是非常有用的。本发明所涉及的制造方法是能够以高收率制造本发明所涉及的化合物的方法。Furthermore, a pharmaceutical composition containing a fumaric acid cocrystal of the compound (I-0005) produced by the production method of the present invention is very useful as a therapeutic agent for novel coronavirus infection (COVID-19). The production method of the present invention is a method that can produce the compound of the present invention in high yield.
本发明所涉及的口服给与的制剂(药物组合物)具有针对冠状病毒3CL蛋白酶的抑制活性，作为冠状病毒感染症的治疗剂和/或预防剂是有用的。The oral preparation (pharmaceutical composition) of the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and/or preventive agent for coronavirus infection.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1示出实施例a中的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的粉末X射线衍射图案。横轴为2θ(°)，纵轴表示强度(计数)。Figure 1 shows the powder X-ray diffraction pattern of the fumaric acid cocrystal form I (crystal form I) of the compound represented by formula (VII) in Example a. The horizontal axis represents 2θ (°) and the vertical axis represents intensity (counts).
图2示出图1的粉末X射线分析图案的峰列表。FIG. 2 shows a peak list of the powder X-ray analysis pattern of FIG. 1 .
图3示出式(VII)所示的化合物的富马酸共晶体I形(晶型I)的非对称单元中的结构。FIG3 shows the structure of the asymmetric unit of the fumaric acid cocrystal Form I (Form I) of the compound represented by Formula (VII).
图4示出显示出图1的粉末X射线分析图案的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的DSC分析结果。横轴表示温度(℃)，纵轴表示热量(W/g)。Figure 4 shows the DSC analysis results of the fumaric acid cocrystal Form I (Crystal Form I) of the compound represented by Formula (VII) showing the powder X-ray analysis pattern of Figure 1. The horizontal axis represents temperature (°C) and the vertical axis represents heat (W/g).
图5示出显示出图1的粉末X射线分析图案的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的TG/DTA分析结果。纵轴表示热量(μV)或重量变化(％)，横轴表示温度(℃)。图中的Cel是指摄氏度(℃)。FIG5 shows the TG/DTA analysis results of the fumaric acid cocrystal form I (crystal form I) of the compound represented by formula (VII) showing the powder X-ray analysis pattern of FIG1 . The vertical axis represents heat (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure means Celsius (°C).
图6示出显示出图1的粉末X射线分析图案的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的DVS分析结果。即使改变湿度，也未观察到实质性的重量变化，该晶体对水分是稳定的。Figure 6 shows the DVS analysis results of the fumaric acid cocrystal Form I (Form I) of the compound represented by Formula (VII) showing the powder X-ray analysis pattern of Figure 1. Even when the humidity was changed, no substantial weight change was observed, and the crystals were stable to moisture.
图7示出实施例1a的步骤4中得到的化合物I-005的HPLC测定结果。式(VII)所示的化合物(化合物I-005)的pa％(峰面积)为约95pa％。7 shows the results of HPLC analysis of compound I-005 obtained in step 4 of Example 1a. The pa% (peak area) of the compound represented by formula (VII) (compound I-005) was about 95 pa%.
图8示出步骤4'中得到的化合物I-005的HPLC测定结果。式(VII)所示的化合物(化合物I-005)的pa％为约99pa％。8 shows the results of HPLC analysis of compound I-005 obtained in step 4'. The pa% of the compound represented by formula (VII) (compound I-005) was about 99 pa%.
图9示出实施例b中的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的粉末X射线衍射图案。横轴为2θ(°)，纵轴表示强度(计数)。Figure 9 shows the powder X-ray diffraction pattern of the fumaric acid cocrystal form I (crystal form I) of the compound represented by formula (VII) in Example b. The horizontal axis represents 2θ (°) and the vertical axis represents intensity (counts).
图10示出图9的粉末X射线分析图案的峰表格。FIG. 10 is a peak table showing the powder X-ray analysis pattern of FIG. 9 .
图11示出式(VII)所示的化合物的富马酸共晶体I形(晶型I)的非对称单元中的结构图。FIG. 11 shows a structural diagram of the asymmetric unit of the fumaric acid cocrystal Form I (Form I) of the compound represented by Formula (VII).
图12示出实施例1b的步骤5-1中得到的式(VII)所示的化合物的未干晶体的HPLC的结果。式(VII)所示的化合物的pa％为约99pa％。12 shows the results of HPLC of the undried crystals of the compound represented by formula (VII) obtained in step 5-1 of Example 1b. The pa% of the compound represented by formula (VII) was about 99 pa%.
图13示出图12中排除了甲苯来源的峰(RT＝约9.8min)的分析结果。式(VII)所示的化合物的pa％为约99.7pa％，各杂质为约0.1pa％以下。Fig. 13 shows the analysis results excluding the peak derived from toluene (RT = about 9.8 min) in Fig. 12. The pa% of the compound represented by formula (VII) was about 99.7 pa%, and each impurity was about 0.1 pa% or less.
图14示出实施例1b的步骤5-2中得到的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的DSC分析结果。FIG. 14 shows the DSC analysis results of the fumaric acid cocrystal Form I (Form I) of the compound represented by Formula (VII) obtained in Step 5-2 of Example 1b.
图15示出实施例1b的步骤5-2中得到的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的TG/DTA分析结果。至150℃的重量减少为0.28％。Figure 15 shows the results of TG/DTA analysis of the fumaric acid cocrystal Form I (Form I) of the compound represented by Formula (VII) obtained in Step 5-2 of Example 1b. The weight loss at 150°C was 0.28%.
图16示出实施例1b的步骤5-2中得到的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的HPLC的结果。FIG. 16 shows the results of HPLC of the fumaric acid cocrystal Form I (Form I) of the compound represented by Formula (VII) obtained in Step 5-2 of Example 1b.
图17示出实施例1b的步骤5-2中得到的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的粒度分布。D50为25.35μm，D90为73.56μm。Figure 17 shows the particle size distribution of the fumaric acid cocrystal Form I (Crystal Form I) of the compound represented by Formula (VII) obtained in Step 5-2 of Example 1b. D50 is 25.35 μm, and D90 is 73.56 μm.
图18示出实施例1b的步骤5-2中得到的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的DVS分析结果。即使改变湿度，也未观察到实质性的重量变化，该晶体对水分是稳定的。Figure 18 shows the DVS analysis results of the fumaric acid cocrystal Form I (Crystal Form I) of the compound represented by Formula (VII) obtained in Step 5-2 of Example 1b. Even when the humidity was changed, no substantial weight change was observed, and the crystals were stable to moisture.
图19示出图18的DVS测定前后的粉末X射线分析图案的比较。DVS测定的前后，晶型不发生变化，是稳定的。Fig. 19 shows a comparison of the powder X-ray analysis patterns before and after the DVS measurement of Fig. 18. Before and after the DVS measurement, the crystal form did not change and was stable.
图20示出式(VII)所示的化合物的甲苯化物的粉末X射线衍射图案。横轴为2θ(°)，纵轴表示强度(计数)。20 shows the powder X-ray diffraction pattern of the toluene compound represented by formula (VII). The horizontal axis represents 2θ (°) and the vertical axis represents intensity (counts).
图21示出实施例6的溶出行为。横轴表示时间(分钟)，纵轴表示溶出率(％)。Fig. 21 shows the dissolution behavior of Example 6. The horizontal axis represents time (minutes), and the vertical axis represents the dissolution rate (%).
图22示出实施例6A和6B的制剂中使用的有效成分(式(VII)所示的化合物的富马酸共晶体I形晶体)的粒度分布。FIG. 22 shows the particle size distribution of the active ingredient (form I crystal of the fumaric acid cocrystal of the compound represented by formula (VII)) used in the preparations of Examples 6A and 6B.
图23示出实施例6C和6D的制剂中使用的有效成分(式(VII)所示的化合物的富马酸共晶体I形晶体)的粒度分布。FIG. 23 shows the particle size distribution of the active ingredient (form I crystal of the fumaric acid cocrystal of the compound represented by formula (VII)) used in the preparations of Examples 6C and 6D.
图24示出Phase 2a Part的SARS-CoV-2的病毒滴度的基线起算的变化量。纵轴表示病毒滴度的基线起算的变化量(log10(TCID50/mL))，横轴示出评价时点。Figure 24 shows the change in the viral titer of SARS-CoV-2 from the baseline in Phase 2a Part. The vertical axis represents the change in the viral titer from the baseline (log10 (TCID50 /mL)), and the horizontal axis represents the evaluation time point.
图25示出最初确认到病毒滴度阴性为止的时间。纵轴表示SARS-CoV-2病毒滴度阴性者的比例(单位：％)。横轴示出治疗开始起算的时间(单位：小时)。Figure 25 shows the time until the virus titer was initially confirmed to be negative. The vertical axis shows the proportion of patients with negative SARS-CoV-2 virus titer (unit: %). The horizontal axis shows the time from the start of treatment (unit: hours).
图26示出各时点处的COVID-19的12症状总计分数的基线起算的变化量。纵轴表示COVID-19的12症状总计分数的基线起算的变化量。横轴表示评价时点。Figure 26 shows the change from the baseline of the total score of 12 symptoms of COVID-19 at each time point. The vertical axis represents the change from the baseline of the total score of 12 symptoms of COVID-19. The horizontal axis represents the evaluation time point.
图27示出实施例10的溶出行为。横轴表示时间(分钟)，纵轴表示含量校正后的溶出率(％)。Fig. 27 shows the dissolution behavior of Example 10. The horizontal axis represents time (minutes), and the vertical axis represents the content-corrected dissolution rate (%).
具体实施方式DETAILED DESCRIPTION
以下，说明本说明书中使用的各术语的含义。各术语只要没有特别说明，在单独使用的情况或与其他术语组合使用的情况下，均以相同含义使用。The meanings of the terms used in this specification are described below. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.
“由……组成”这一术语是指仅具有构成要件。The term "consisting of" means having only the constituent elements.
“包含”或“含有”这一术语是指不限于构成要件，不排除未记载的要素。The term "include" or "comprising" does not limit the constituent elements and does not exclude undescribed elements.
此外，遍及本说明书的整体，单数形式的表达在没有特别说明的情况下，应当理解为也包括其复数形式的概念。因此，单数形式的冠词(例如英语的情况中“a”、“an”、“the”等)在没有特别说明的情况下，应当理解为也包括其复数形式的概念。In addition, throughout the entirety of this specification, expressions in the singular form should be understood to include the concept of its plural form unless otherwise specified. Therefore, articles in the singular form (such as "a", "an", "the", etc. in English) should be understood to include the concept of its plural form unless otherwise specified.
此外，本说明书中使用的术语在没有特别说明的情况下，应当理解以该上述领域中通常使用的含义使用。因此，在没有另外定义的情况下，本说明书中使用的全部专业术语和科学技术术语具有与由本发明所述领域的本领域技术人员所通常理解的相同含义。在矛盾的情况下，本说明书(包括定义)优先。In addition, the terms used in this specification should be understood to be used with the meaning commonly used in the above-mentioned fields unless otherwise specified. Therefore, all technical terms and scientific and technical terms used in this specification have the same meanings as those commonly understood by those skilled in the art in the field of the present invention unless otherwise defined. In the event of a conflict, this specification (including definitions) takes precedence.
“卤素”是指包括氟原子、氯原子、溴原子、和碘原子。特别优选为氟原子和氯原子。The "halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and particularly preferably a fluorine atom and a chlorine atom.
“烷基”是指包括碳原子数1～15、优选为碳原子数1～10、更优选为碳原子数1～6、进一步优选为碳原子数1～4的直链或支链状的烃基。例如，可以举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、正庚基、异庚基、正辛基、异辛基、正壬基、正癸基等。The "alkyl group" refers to a linear or branched hydrocarbon group 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, and n-decyl.
作为“烷基”的优选的方式，可以举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基。作为进一步优选方式，可以举出甲基、乙基、正丙基、异丙基、叔丁基。Preferred embodiments of the "alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
“C1-C4烷基”是指包括碳原子数1～4的直链或支链状的烃基。例如，可以举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。The "C1-C4 alkyl group" refers to a linear or branched hydrocarbon group having 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
“芳族碳环式基”是指单环或2环以上的环状芳族烃基。例如，可以举出苯基、萘基、蒽基、菲基等。作为6元芳族碳环式基，可以举出例如苯基。作为10元芳族碳环式基，可以举出例如萘基等。作为14元芳族碳环式基，可以举出例如蒽基、菲基等。"Aromatic carbocyclic group" refers to a monocyclic or cyclic aromatic hydrocarbon group with more than two rings. For example, phenyl, naphthyl, anthracenyl, phenanthryl, etc. can be mentioned. As a 6-membered aromatic carbocyclic group, for example, phenyl can be mentioned. As a 10-membered aromatic carbocyclic group, for example, naphthyl, etc. can be mentioned. As a 14-membered aromatic carbocyclic group, for example, anthracenyl, phenanthryl, etc. can be mentioned.
作为“芳族碳环式基”的优选的方式，可以举出苯基。A preferred embodiment of the "aromatic carbocyclic group" includes a phenyl group.
“芳族碳环”是指由上述“芳族碳环式基”导出的环。The "aromatic carbocyclic ring" means a ring derived from the above-mentioned "aromatic carbocyclic group".
“芳族杂环式基”是指在环内具有1个以上的任意选自O、S和N中的相同或不同的杂原子的单环或2环以上的芳族环式基。The "aromatic heterocyclic group" refers to a monocyclic or bicyclic aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N which are the same or different in the ring.
2环以上的芳族杂环式基也包括在单环或2环以上的芳族杂环式基上稠合有上述“芳族碳环式基”中的环得到的基团，该键合位可以在任一环上具有。The aromatic heterocyclic group having two or more rings also includes a group in which a ring in the above-mentioned "aromatic carbocyclic group" is fused to a monocyclic or bicyclic aromatic heterocyclic group, and the bonding position may be in any ring.
作为单环的芳族杂环式基，优选为5～8元、更优选为5元或6元。作为5元芳族杂环式基，可以举出例如吡咯基、嘧啶基、吡唑基、三唑基、四唑基、呋喃基、噻吩基、异噁唑基、噁唑基、噁二唑基、异噻唑基、噻唑基、噻二唑基等。作为6元芳族杂环式基，可以举出例如吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等。The monocyclic aromatic heterocyclic group is preferably 5-8-membered, more preferably 5-membered or 6-membered. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of the 6-membered aromatic heterocyclic group include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
作为2环的芳族杂环式基，优选为8～10元、更优选为9元或10元。例如，可以举出吲哚基、异吲哚基、吲唑基、吲嗪基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、萘啶基、喹喔啉基、嘌呤基、蝶啶基、苯并嘧啶基、苯并异噁唑基、苯并噁唑基、苯并噁二唑基、苯并异噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、三唑并吡啶基、咪唑并噻唑基、吡唑并哒嗪基、噁唑并吡啶基、噻唑并吡啶基等。作为9元芳族杂环式基，可以举出吲哚基、异吲哚基、吲唑基、吲嗪基、嘌呤基、苯并嘧啶基、苯并异噁唑基、苯并噁唑基、苯并噁二唑基、苯并异噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基、苯并呋喃基、咪唑并吡啶基、三唑并吡啶基、噁唑并吡啶基、噻唑并吡啶基等。作为10元芳族杂环式基，可以举出喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、萘啶基、喹喔啉基、蝶啶基、吡唑并哒嗪基等。The bicyclic aromatic heterocyclic group is preferably 8-10-membered, more preferably 9-membered or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyrimidinyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, imidazopyridinyl, triazolopyridinyl, imidazothiazolyl, pyrazolopyridazinyl, oxazolopyridinyl, and thiazolopyridinyl. Examples of the 9-membered aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzopyrimidinyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranyl, imidazopyridinyl, triazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, etc. Examples of the 10-membered aromatic heterocyclic group include quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazolopyridazinyl, etc.
作为3环以上的芳族杂环式基，优选为13～15元。例如，可以举出咔唑基、吖啶基、氧杂蒽基、吩噻嗪基、吩噁噻基、吩噁嗪基、二苯并呋喃基等。The aromatic heterocyclic group having three or more rings is preferably a 13- to 15-membered group, and examples thereof include a carbazolyl group, an acridinyl group, a xanthenyl group, a phenothiazinyl group, a phenoxathiyl group, a phenoxazinyl group, and a dibenzofuranyl group.
作为“芳族杂环式基”的优选的方式，可以举出三唑基。A preferred embodiment of the "aromatic heterocyclic group" is a triazolyl group.
“芳族杂环”是指由上述“芳族杂环式基”导出的环。The "aromatic heterocyclic ring" means a ring derived from the above-mentioned "aromatic heterocyclic group".
作为“取代烷基”的取代基，可以举出下述取代基组A。任意的位置的碳原子可以与选自下述取代基组A中的1个以上的基团键合。Examples of the substituent of the "substituted alkyl group" include the following substituent group A. One or more groups selected from the following substituent group A may be bonded to a carbon atom at any position.
取代基组A：卤素、氰基和硝基。Substituent Group A: halogen, cyano and nitro.
作为“取代C1-C4烷基”的取代基，可以举出下述取代基组B。任意的位置的碳原子可以与选自下述取代基组B中的1个以上的基团键合。Examples of the substituent of the "substituted C1-C4 alkyl group" include the following substituent group B. One or more groups selected from the following substituent group B may be bonded to a carbon atom at any position.
取代基组B：卤素、氰基和硝基。Substituent Group B: halogen, cyano and nitro.
作为“取代芳族碳环式基”和“取代芳族杂环式基”等“芳族碳环”和“芳族杂环”的环上的取代基，可以举出下述取代基组C。环上的任意的位置的原子可以与选自下述取代基组C中的1个以上的基团键合。Examples of substituents on the "aromatic carbocyclic ring" and "aromatic heterocyclic ring" such as "substituted aromatic carbocyclic group" and "substituted aromatic heterocyclic group" include the following substituent group C. Atoms at any position on the ring may be bonded to one or more groups selected from the following substituent group C.
取代基组C：卤素、氰基、硝基和烷基。Substituent Group C: halogen, cyano, nitro and alkyl.
式(VI)和式(VII)所示的化合物不限于特定的异构体，包括全部可能的异构体(例如酮-烯醇异构体、亚胺-烯胺异构体、非对映异构体、光学异构体、旋转异构体等)、外消旋体或它们的混合物。The compounds represented by formula (VI) and formula (VII) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
【化28】【Chemistry 28】
例如，式(VII)所示的化合物、化合物I-005包括以下那样的互变异构体。For example, the compound represented by formula (VII), compound I-005, includes the following tautomers.
【化29】【化29】
实质不含式(VII)：Substantially free of formula (VII):
【化30】【Chemistry 30】
所示的化合物的游离体的式(VII)所示的化合物的富马酸共晶体I形是指通过粉末X射线衍射测定等测定仪器，未检测到式(VII)所示的化合物的游离体来源的峰(检测限以下)的式(VII)所示的化合物的富马酸共晶体I形。The fumaric acid cocrystal form I of the compound represented by formula (VII) which is a free form of the compound represented by formula (VII) refers to the fumaric acid cocrystal form I of the compound represented by formula (VII) in which no peak derived from the free form of the compound represented by formula (VII) is detected (below the detection limit) by measuring instruments such as powder X-ray diffraction measurement.
进一步，式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、和式(XI)(以下记作式(VII)等)所示的化合物中的一个以上的氢、碳和/或其他原子可以各自被氢、碳和/或其他原子的同位素替代。作为这样的同位素的例子，各自如2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、123I和36Cl那样，包括氢、碳、氮、氧、磷、硫、氟、碘和氯。式(VII)等所示的化合物也包括被这样的同位素替代的化合物。被该同位素替代的化合物作为医药品也是有用的，包括式(VII)等所示的化合物的所有放射性标记体。此外，用于制造该“放射性标记体”的“放射性标记化方法”也包括在本发明中，该“放射性标记体”作为药物代谢动力学研究、结合测定中的研究和/或诊断的工具是有用的。Furthermore, one or more hydrogen, carbon and/or other atoms in the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), and formula (XI) (hereinafter referred to as formula (VII) etc.) may be replaced by isotopes of hydrogen, carbon and/or other atoms. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as2 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 and36 Cl. The compounds represented by formula (VII) etc. also include compounds replaced by such isotopes. The compounds replaced by such isotopes are also useful as pharmaceuticals, including all radiolabeled forms of the compounds represented by formula (VII) etc. Furthermore, the present invention also includes a "radiolabeling method" for producing the "radiolabeled substance", which is useful as a tool for research in pharmacokinetic studies, binding assays and/or diagnosis.
此外，本发明的晶体可以是氘变换体。本发明的晶体可以被同位素(例如3H、14C、35S、125I等)标记。Furthermore, the crystal of the present invention may be a deuterated form. The crystal of the present invention may be labeled with an isotope (eg,3 H,14 C,35 S,125 I, etc.).
式(VII)等所示的化合物的放射性标记体可以通过本技术领域中公知的方法制备。例如，式(VII)等所示的氚标记化合物可以通过使用氚的催化剂的脱卤化反应，向式(VII)等所示的特定的化合物中导入氚，由此制备。该方法包括在适当的催化剂、例如Pd/C的存在下，在碱的存在下或不存在下，使式(VII)等所示的化合物被适当卤素取代的前体与氚气反应。用于制备氚标记化合物的其他适当的方法可以参照“Isotopes in thePhysical and Biomedical Sciences,Vol.1,Labeled Compounds(Part A),Chapter 6(1987年)”。14C-标记化合物可以通过使用具有14C碳的原料而制备。The radiolabeled form of the compound represented by formula (VII) etc. can be prepared by a method known in the art. For example, the tritium-labeled compound represented by formula (VII) etc. can be prepared by introducing tritium into a specific compound represented by formula (VII) etc. through a dehalogenation reaction using a tritium catalyst. The method comprises reacting a precursor of the compound represented by formula (VII) etc. substituted with a suitable halogen with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. 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 C-labeled compounds can be prepared by using a raw material having14 C carbon.
本发明的制剂中，可以使用式(VII)等所示的化合物的制药上可接受的盐。作为式(VII)等所示的化合物的制药上可接受的盐，可以举出例如式(VII)等所示的化合物与碱金属(例如锂、钠、钾等)、碱土金属(例如钙、钡等)、镁、过渡金属(例如锌、铁等)、氨、有机碱(例如三甲基胺、三乙基胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、乙二胺、吡啶、甲基吡啶、喹啉等)和氨基酸と的盐、或无机酸(例如盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸等)、和有机酸(例如甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、丁二酸、扁桃酸、戊二酸、苹果酸、苯甲酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲磺酸、乙磺酸、三氟乙酸等)的盐。这些盐可以通过通常进行的方法而形成。In the preparation of the present invention, a pharmaceutically acceptable salt of the compound represented by formula (VII) or the like can be used. As the pharmaceutically acceptable salt of the compound represented by formula (VII) etc., for example, salts of the compound represented by formula (VII) etc. 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 commonly performed methods.
作为式(VII)所示的化合物的制药上可接受的盐，例如由式(VII)所示的化合物和抗衡分子或抗衡离子组成，可以包含任意数量的抗衡分子或抗衡离子。式(VII)所示的化合物的制药上可接受的盐是指通过在化合物与抗衡分子或抗衡原子之间进行质子移动，经由离子键而形成的物质。As a pharmaceutically acceptable salt of the compound represented by formula (VII), for example, it is composed of the compound represented by formula (VII) and a counter molecule or counter ion, and may contain any number of counter molecules or counter ions. The pharmaceutically acceptable salt of the compound represented by formula (VII) refers to a substance formed by proton transfer between the compound and the counter molecule or counter atom via an ionic bond.
本发明的制剂中，可以使用式(VII)所示的化合物或其制药上可接受的盐的复合体。式(VII)所示的化合物或其制药上可接受的盐有时形成溶剂化物(例如水合物等)、共晶体和/或包合化合物，本说明书中将它们记载为“复合体”。In the preparation of the present invention, a complex of the compound represented by formula (VII) or a pharmaceutically acceptable salt thereof can be used. The compound represented by formula (VII) or a pharmaceutically acceptable salt thereof sometimes forms a solvate (e.g., a hydrate), a co-crystal and/or an inclusion compound, which are described as "complexes" in this specification.
本说明书中使用的“溶剂化物”是指可以例如使式(VII)等所示的化合物与任意数量的溶剂分子(例如水分子等)配位。通过将式(VII)等所示的化合物或其制药上可接受的盐在大气中放置，吸收水分，有时吸附水附着，有时形成水合物。The term "solvate" as used in this specification means that, for example, a compound represented by formula (VII) or the like can be coordinated with any number of solvent molecules (e.g., water molecules). When a compound represented by formula (VII) or the like or a pharmaceutically acceptable salt thereof is placed in the atmosphere, moisture is absorbed, water is adsorbed, and a hydrate is formed.
作为溶剂分子，可以举出例如乙腈、氯苯、氯仿、环己烷、1,2-二氯乙烯、二氯甲烷、1,2-二甲氧基乙烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、1,4-二氧杂环己烷、2-乙氧基乙醇、乙二醇、甲酰胺、己烷、甲醇、2-甲氧基乙醇、甲基丁基酮、甲基环己烷、N-甲基吡咯烷酮、硝基甲烷、吡啶、环丁砜、四氢萘、甲苯、1,1,2-三氯乙烯、二甲苯、乙酸、苯甲醚、1-丁醇、2-丁醇、乙酸正丁酯、叔丁基甲基醚、异丙苯、二甲基亚砜、乙酸乙酯、二乙基醚、甲酸乙酯、甲酸、庚烷、乙酸异丁酯、乙酸异丙酯、乙酸甲酯、3-甲基-1-丁醇、甲基乙基酮、甲基异丁基酮、2-甲基-1-丙醇、戊烷、1-戊醇、1-丙醇、2-丙醇、乙酸丙酯、四氢呋喃、水(即水合物)、乙醇、丙酮、1,1-二乙氧基丙烷、1,1-二甲氧基甲烷、2,2-二甲氧基丙烷、异辛烷、异丙基醚、甲基异丙基酮、甲基四氢呋喃、石油醚、三氯乙酸和三氟乙酸、优选为、乙酸、苯甲醚、1-丁醇、2-丁醇、乙酸正丁酯、叔丁基甲基醚、异丙苯、二甲基亚砜、乙酸乙酯、二乙基醚、甲酸乙酯、甲酸、庚烷、乙酸异丁酯、乙酸异丙酯、乙酸甲酯、3-甲基-1-丁醇、甲基乙基酮、甲基异丁基酮、2-甲基-1-丙醇、戊烷、1-戊醇、1-丙醇、2-丙醇、乙酸丙酯、四氢呋喃、水(即水合物)、乙醇、丙酮、1,1-二乙氧基丙烷、1,1-二甲氧基甲烷、2,2-二甲氧基丙烷、异辛烷、异丙基醚、甲基异丙基酮、甲基四氢呋喃、石油醚、三氯乙酸和三氟乙酸、更优选为、水(即水合物)、乙醇、丙酮、1,1-二乙氧基丙烷、1,1-二甲氧基甲烷、2,2-二甲氧基丙烷、异辛烷、异丙基醚、甲基异丙基酮、甲基四氢呋喃、石油醚、三氯乙酸和三氟乙酸等。Examples of the solvent molecule include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, xylene, acetic acid, anisole, 1 -Butanol, 2-Butanol, n-butyl acetate, tert-butyl methyl ether, isopropylbenzene, 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, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane , isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, preferably, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, tert-butyl methyl ether, isopropylbenzene, 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, tetramethylene glycol, Hydrofuran, water (i.e. hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, more preferably, water (i.e. hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, etc.
本说明书中使用的“共晶体”是指抗衡分子在同一晶格内规则性排列，可以包含任意数量的抗衡分子。此外，共晶体是指化合物与抗衡分子的分子间相互作用经由氢键、范德华力等、非共价键性且非离子性的化学的相互作用。The term "co-crystal" as used herein refers to a regular arrangement of counter molecules in the same crystal lattice, and may include any number of counter molecules. In addition, a co-crystal refers to a non-covalent and non-ionic chemical interaction between the intermolecular interaction between the compound and the counter molecule via hydrogen bonding, van der Waals forces, etc.
例如，作为式(VII)所示的化合物的共晶体，由式(VII)所示的化合物和抗衡分子组成，可以包含任意数量的抗衡分子。优选由式(VII)所示的化合物和富马酸组成，可以包含任意数量的富马酸。进一步优选式(VII)所示的化合物和富马酸为1:1的摩尔比的共晶体。For example, as a co-crystal of the compound represented by formula (VII), it is composed of the compound represented by formula (VII) and a counter molecule, and may contain any number of counter molecules. Preferably, it is composed of the compound represented by formula (VII) and fumaric acid, and may contain any number of fumaric acids. Further preferably, the co-crystal is a 1:1 molar ratio of the compound represented by formula (VII) and fumaric acid.
共晶体在化合物本质上保持无电荷或中性的方面与盐相区分。Co-crystals are distinguished from salts in that the compound remains essentially uncharged or neutral.
共晶体在抗衡分子不在水或溶剂中的方面与水合物或溶剂化物相区分。Co-crystals are distinguished from hydrates or solvates in that the countermolecule is not in water or solvent.
本发明的式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、和式(XI)所示的化合物或其盐有时形成溶剂化物(例如水合物等)、共晶体和/或多晶型，本发明也包括这样的各种的溶剂化物、共晶体和多晶型。“溶剂化物”可以使式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、和式(XI)所示的化合物与任意数量的溶剂分子(例如水分子等)配位。此外，有时通过将式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、和式(XI)所示的化合物或其盐重结晶，形成多晶型。The compounds represented by Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), and Formula (XI) of the present invention or their salts may form solvates (e.g., hydrates), co-crystals and/or polymorphs, and the present invention also includes such various solvates, co-crystals and polymorphs. "Solvates" can coordinate the compounds represented by Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), and Formula (XI) with any number of solvent molecules (e.g., water molecules). In addition, polymorphs may be formed by recrystallizing the compounds represented by Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), and Formula (XI) or their salts.
本说明书中使用的“晶体”是指所构成的原子、离子、分子等三维规则排列的固体，与不具有这样的规则的内部结构的非晶质固体相区分。本发明的晶体可以为单晶、孪晶、多晶体等。As used herein, "crystal" refers to a solid whose constituent atoms, ions, molecules, etc. are arranged in a three-dimensional regular pattern, and is distinguished from an amorphous solid that does not have such a regular internal structure. The crystal of the present invention may be a single crystal, a twin crystal, a polycrystal, or the like.
进一步，“晶体”中，有时存在组成相同同时晶体中的排列不同的“多晶型”，包括这些在内称为“晶态”。Furthermore, in a "crystal", there may be "polymorphs" having the same composition but different arrangements in the crystal, and all of these are referred to as "crystalline states".
除此之外，式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、和式(XI)所示的化合物也可以变换为这些盐或这些制药上可接受的溶剂化物。本发明的晶体可以是这些盐、水合物、溶剂化物、多晶型中任一者，即使是二种以上的混合物，也意图包括在发明的范围内。In addition, the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), and formula (XI) may also be converted into these salts or these pharmaceutically acceptable solvates. The crystal of the present invention may be any of these salts, hydrates, solvates, and polymorphs, and even a mixture of two or more thereof is intended to be included in the scope of the invention.
晶态和结晶化度可以通过包括例如粉末X射线衍射测定、拉曼分光法、红外吸收光谱测定法、水分吸脱附测定、差示扫描量热测定、溶解特性在内的多种技术测定。The crystalline state and degree of crystallinity can be determined by a variety of techniques including, for example, powder X-ray diffraction measurement, Raman spectroscopy, infrared absorption spectroscopy, water adsorption and desorption measurement, differential scanning calorimetry, and dissolution characteristics.
此外，通过将式(VII)等所示的化合物、其制药上可接受的盐或它们的复合体进行重结晶，有时形成“多晶型”。Furthermore, by recrystallizing the compound represented by formula (VII) or the like, a pharmaceutically acceptable salt thereof, or a complex thereof, "polymorphs" may be formed.
本发明制剂中，可以使用这样的各种的盐、复合体(水合物、溶剂化物、共晶体、包合化合物)、多晶型，此外，即使是它们中的二种以上的混合物也可以使用。In the preparation of the present invention, various salts, complexes (hydrates, solvates, co-crystals, inclusion compounds), and polymorphs can be used, and even a mixture of two or more of them can be used.
(粉末X射线衍射(XRPD))(X-ray powder diffraction (XRPD))
粉末X射线衍射(XRPD)是用于测定固体的晶态和结晶性的灵敏度最良好的分析法之一。如果对晶体照射X射线，则被晶面反射，彼此相互干涉，示出与结构的周期对应的存在秩序的衍射线。另一方面，针对非晶质固体，通常在其结构中不具有存在秩序的重复周期，因此不引起衍射现象，示出特征性的宽XRPD图案(也被称为光晕图案)。Powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystalline state and crystallinity of solids. If X-rays are irradiated on a crystal, they are reflected by the crystal planes and interfere with each other, showing diffraction lines with order corresponding to the period of the structure. On the other hand, amorphous solids generally do not have an ordered repetitive period in their structure, so they do not cause diffraction phenomena and show a characteristic wide XRPD pattern (also called a halo pattern).
式(VII)等所示的化合物的晶态可以通过粉末X射线衍射图案和特征性衍射峰识别。式(VII)等所示的化合物的晶态可以通过特征性衍射峰的存在而与其他晶态相区分。The crystalline state of the compound represented by formula (VII) etc. can be identified by the powder X-ray diffraction pattern and characteristic diffraction peaks. The crystalline state of the compound represented by formula (VII) etc. can be distinguished from other crystalline states by the presence of characteristic diffraction peaks.
本说明书中使用的特征性衍射峰是由观测的衍射图案选择的峰。特征性衍射峰优选为选自衍射图案中的约10根、更优选为约5根、进一步优选为约3根。The characteristic diffraction peak used in this specification is a peak selected from an observed diffraction pattern. The characteristic diffraction peak is preferably about 10 peaks selected from the diffraction pattern, more preferably about 5 peaks, and even more preferably about 3 peaks.
在区分多个晶体的基础上，与峰的强度相比，在该晶体确认而在其他晶体中未确认的峰在鉴定其晶体的基础上，成为优选的特征性峰。只要是这样的特征性峰，即使是一个或二个峰，也能够对该晶体标记特征。将测定得到的图表进行比较，如果这些特征性峰一致，则可以说粉末X射线衍射图案实质上一致。On the basis of distinguishing multiple crystals, the peak confirmed in the crystal but not confirmed in other crystals becomes the preferred characteristic peak on the basis of identifying the crystal compared with the intensity of the peak. As long as it is such a characteristic peak, even if it is one or two peaks, it is possible to mark the characteristics of the crystal. The charts obtained by the measurement are compared. If these characteristic peaks are consistent, it can be said that the powder X-ray diffraction patterns are substantially consistent.
一般而言，粉末X射线衍射中的衍射角度(2θ)可以在±0.2°的范围内产生误差，因此需要理解为粉末X射线衍射的衍射角度的值也包括±0.2°左右的范围内的数值。因此，本发明中也不仅包括粉末X射线衍射中的峰的衍射角度完全一致的晶体，也包括峰的衍射角度在±0.2°左右的误差内一致的晶体。Generally speaking, the diffraction angle (2θ) in powder X-ray diffraction can have an error within the range of ±0.2°, so it is necessary to understand that the value of the diffraction angle of powder X-ray diffraction also includes a value within the range of about ±0.2°. Therefore, the present invention also includes not only crystals whose peak diffraction angles in powder X-ray diffraction are completely consistent, but also crystals whose peak diffraction angles are consistent within an error of about ±0.2°.
以下的表和图中表示的峰的强度一般而言已知可能因多种因子、例如相对于X射线波束的晶体的选择取向的效果、粗大颗粒的影响、所分析的物质的纯度或样品的结晶化度而发生变动。此外，针对峰位置，也可能基于样品高度的变动而发生位移。进一步，如果使用不同波长测定，则按照布拉格公式(nλ＝2dsinθ)得到不同位移，但通过使用这样的另外波长而得到的另外的XRPD图案也包括在本发明的范围内。The intensity of the peaks shown in the following tables and figures is generally known to vary due to various factors, such as the effect of the selective orientation of the crystal relative 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 also be shifted based on the change in sample height. Further, if different wavelengths are used for measurement, different shifts are obtained according to the Bragg formula (nλ=2dsinθ), but other XRPD patterns obtained by using such other wavelengths are also included in the scope of the present invention.
(单晶结构分析)(Single crystal structure analysis)
鉴定晶体的方法之一中，可以得到该晶体中的晶体学的参数、进一步原子坐标(表示各原子的空间位置关系的值)和三维结构模型。参照樱井敏雄著“X射线结构分析的指引”裳华房发行(1983年)、Stout&Jensen著X-Ray Structure Determination：A PracticalGuide,MacmillanCo.,New York(1968)等。鉴定本发明那样的复合体、盐、光学异构体、互变异构体、几何异构体的晶体的结构时，单晶结构分析是有用的。One of the methods for identifying a crystal is to obtain the crystallographic parameters, atomic coordinates (values indicating the spatial positional relationship of each atom) and a three-dimensional structural model of the crystal. See Toshio Sakurai's "Guide to X-ray Structure Analysis" published by Shokabo (1983), Stout & Jensen's "X-Ray Structure Determination: A Practical Guide", Macmillan Co., New York (1968), etc. Single crystal structure analysis is useful for identifying the structure of a crystal of a complex, salt, optical isomer, tautomer, or geometric isomer as in the present invention.
式(VII)等所示的化合物具有冠状病毒3CL蛋白酶抑制活性，因此作为冠状病毒3CL蛋白酶所参与的疾病的治疗和/或预防剂是有用的。本发明中“治疗剂和/或预防剂”这一情况下，也包括症状改善剂。作为冠状病毒3CL蛋白酶所参与的疾病，可以举出病毒感染症，可以优选举出冠状病毒感染症。The compounds represented by formula (VII) and the like have coronavirus 3CL protease inhibitory activity and are therefore useful as therapeutic and/or preventive agents for diseases in which coronavirus 3CL protease is involved. In the present invention, the term "therapeutic and/or preventive agent" also includes symptom-improving agents. Diseases in which coronavirus 3CL protease is involved include viral infections, and preferably coronavirus infections.
作为一个方式，作为冠状病毒，可以举出对人感染的冠状病毒。作为对人感染的冠状病毒，可以举出HCoV-229E、HCoV-NL63、HCoV-HKU1、HCoV-OC43、SARS-CoV、MERS-CoV、和/或SARS-CoV-2。In one embodiment, coronaviruses that infect humans include coronaviruses that infect humans, and coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
作为一个方式，作为冠状病毒，可以举出α冠状病毒和/或β冠状病毒、更优选为β冠状病毒、进一步优选为乙型冠状病毒(Sarbecovirus)。In one embodiment, examples of the coronavirus include alpha coronavirus and/or beta coronavirus, more preferably beta coronavirus, and even more preferably beta coronavirus (Sarbecovirus).
作为一个方式，作为α冠状病毒，可以举出HCoV-229E和HCoV-NL63。可以特别优选举出HCoV-229E。In one embodiment, as alpha coronavirus, HCoV-229E and HCoV-NL63 can be mentioned. HCoV-229E can be particularly preferably mentioned.
作为一个方式，作为β冠状病毒，可以举出HCoV-HKU1、HCoV-OC43、SARS-CoV、MERS-CoV、和/或SARS-CoV-2。可以举出优选为HCoV-OC43或SARS-CoV-2、特别优选为SARS-CoV-2。In one embodiment, beta coronaviruses include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. HCoV-OC43 or SARS-CoV-2 is preferred, and SARS-CoV-2 is particularly preferred.
作为一个方式，作为β冠状病毒，可以举出β冠状病毒A谱系(β-coronaviruslineage A)、β冠状病毒B谱系(β-coronavirus lineage B)、和β冠状病毒C谱系(β-coronavirus lineage C)。可以举出更优选为β冠状病毒A谱系(β-coronavirus lineageA)、和β冠状病毒B谱系(β-coronavirus lineage B)、特别优选为β冠状病毒B谱系(β-coronavirus lineage B)。As one embodiment, as β-coronavirus, β-coronavirus A lineage, β-coronavirus B lineage, and β-coronavirus C lineage can be mentioned. More preferably, β-coronavirus A lineage and β-coronavirus B lineage can be mentioned, and β-coronavirus B lineage is particularly preferred.
作为β冠状病毒A谱系(β-coronavirus lineage A)，可以举出例如HCoV-HKU1和HCoV-OC43、优选为、HCoV-OC43。作为β冠状病毒B谱系(β-coronavirus lineage B)，可以举出例如SARS-CoV和SARS-CoV-2、优选为SARS-CoV-2。作为β冠状病毒C谱系(β-coronaviruslineage B)，可以举出优选为MERS-CoV。As the β-coronavirus A lineage (β-coronavirus lineage A), for example, HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43, can be mentioned. As the β-coronavirus B lineage (β-coronavirus lineage B), for example, SARS-CoV and SARS-CoV-2 can be mentioned, preferably SARS-CoV-2. As the β-coronavirus C lineage (β-coronavirus lineage B), preferably MERS-CoV can be mentioned.
作为一个方式，作为冠状病毒，可以举出HCoV-229E、HCoV-OC43、和/或SARS-CoV-2、特别优选为SARS-CoV-2。In one embodiment, examples of coronavirus include HCoV-229E, HCoV-OC43, and/or SARS-CoV-2, and SARS-CoV-2 is particularly preferred.
作为冠状病毒感染症，可以举出因HCoV-229E、HCoV-NL63、HCoV-OC43、HCoV-HKU1、SARS-CoV、MERS-CoV、和/或SARS-CoV-2而导致的感染症。可以举出优选为因HCoV-229E、HCoV-OC43、和/或SARS-CoV-2而导致的感染症、特别优选为因SARS-CoV-2而导致的感染症。Examples of coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. Examples include infections caused by HCoV-229E, HCoV-OC43, and/or SARS-CoV-2, and particularly infections caused by SARS-CoV-2.
作为冠状病毒感染症，可以举出特别优选为新型冠状病毒感染症(COVID-19)。As the coronavirus infection, the novel coronavirus infection (COVID-19) is particularly preferred.
以下，针对本发明所涉及的制造方法进行说明。Hereinafter, the manufacturing method according to the present invention will be described.
步骤1式(III)所示的化合物的制造方法Step 1: Method for producing a compound represented by formula (III)
【化31】【Chemistry 31】
式中的标记与上述为相同含义。The symbols in the formula have the same meanings as described above.
本步骤是式(III)所示的化合物的制造方法，其特征在于，使式(I)所示的化合物与式(II)所示的化合物在酸存在下反应。This step is a method for producing a compound represented by formula (III), characterized in that a compound represented by formula (I) and a compound represented by formula (II) are reacted in the presence of an acid.
相对于式(I)所示的化合物，式(II)所示的化合物通常可以使用1.0～5.0当量、例如1.0～3.0当量。The compound represented by formula (II) can be used usually in an amount of 1.0 to 5.0 equivalents, for example, 1.0 to 3.0 equivalents, based on the compound represented by formula (I).
作为溶剂，只要是高效率地进行上述步骤的溶剂，则没有特别限制，也可以利用酸作为溶剂。可以举出酸、甲苯、二氯甲烷、二氯乙烷等，可以单独或混合使用。优选地，可以举出酸。The solvent is not particularly limited as long as it is a solvent that can efficiently carry out the above steps, and an acid may be used as the solvent. Examples thereof include acid, toluene, dichloromethane, and dichloroethane, which may be used alone or in combination. Preferably, an acid may be used.
作为酸，可以举出质子酸、路易斯酸，优选地，可以举出三氟乙酸。Examples of the acid include protonic acids and Lewis acids, and preferably trifluoroacetic acid.
相对于式(I)所示的化合物，酸的使用量通常可以使用1.0当量～大过剩、例如5.0当量～大过剩。The acid can be used in an amount of usually 1.0 equivalent to a large excess, for example 5.0 equivalent to a large excess, relative to the compound represented by formula (I).
反应温度没有特别限制，通常可以在约0℃～约50℃、优选为室温～40℃下进行。The reaction temperature is not particularly limited, and the reaction can be generally carried out at about 0°C to about 50°C, preferably room temperature to 40°C.
反应时间没有特别限制，为0.1小时～12小时、优选为0.1～5小时。The reaction time is not particularly limited, but is 0.1 to 12 hours, preferably 0.1 to 5 hours.
步骤2式(VI)所示的化合物的制造方法Step 2: Method for producing the compound represented by formula (VI)
【化32】【Chemistry 32】
式中的标记与上述为相同含义。The symbols in the formula have the same meanings as described above.
本步骤是式(VI)所示的化合物的制造方法，其特征在于，使式(IV)所示的化合物与式(V)所示的化合物在酸存在下反应。This step is a method for producing a compound represented by formula (VI), characterized in that a compound represented by formula (IV) and a compound represented by formula (V) are reacted in the presence of an acid.
相对于式(IV)所示的化合物，式(V)所示的化合物通常可以使用1.0～5.0当量、例如1.0～1.5当量。The compound represented by formula (V) can be used usually in an amount of 1.0 to 5.0 equivalents, for example, 1.0 to 1.5 equivalents, based on the compound represented by formula (IV).
作为溶剂，只要是高效率地进行上述步骤的溶剂，则没有特别限制，也可以利用酸作为溶剂。可以举出甲苯、叔丁醇、叔戊醇等，可以单独或混合使用。优选地，可以举出甲苯。As a solvent, there is no particular limitation as long as it is a solvent that can efficiently carry out the above steps, and an acid can also be used as a solvent. Examples of the solvent include toluene, tert-butyl alcohol, tert-amyl alcohol, etc., which can be used alone or in combination. Preferably, toluene can be used.
作为酸，可以举出乙酸、2,2-二甲基丁酸等。优选地，可以举出乙酸。Examples of the acid include acetic acid, 2,2-dimethylbutyric acid, etc. Preferably, acetic acid is used.
相对于式(IV)所示的化合物，酸的使用量通常可以使用1.0当量～10当量、例如3.0当量～10当量。The acid can be used in an amount of usually 1.0 to 10 equivalents, for example 3.0 to 10 equivalents, relative to the compound represented by formula (IV).
反应温度没有特别限制，可以通常在室温～约150℃或微波照射下、优选为、50～150℃或微波照射下进行。The reaction temperature is not particularly limited, and the reaction can be generally carried out at room temperature to about 150°C or under microwave irradiation, preferably at 50 to 150°C or under microwave irradiation.
反应时间没有特别限制，为0.1小时～12小时、优选为3～10小时。The reaction time is not particularly limited, but is 0.1 to 12 hours, preferably 3 to 10 hours.
步骤3式(VII)所示的化合物的富马酸共晶体I形的制造方法Step 3: Method for preparing fumaric acid cocrystal form I of the compound represented by formula (VII)
本步骤是式(VII)所示的化合物的富马酸共晶体I形的制造方法，其特征在于，将式(VII)所示的化合物在富马酸、丙酮和水存在下进行结晶化。This step is a method for preparing fumaric acid cocrystal form I of the compound represented by formula (VII), characterized in that the compound represented by formula (VII) is crystallized in the presence of fumaric acid, acetone and water.
相对于式(VII)所示的化合物，富马酸的使用量通常可以使用1.0当量～3.0当量、例如1.0当量～1.5当量。The amount of fumaric acid used can generally be 1.0 to 3.0 equivalents, for example 1.0 to 1.5 equivalents, relative to the compound represented by formula (VII).
结晶化温度没有特别限制，可以通常在40～80℃、优选为40～60℃下进行。The crystallization temperature is not particularly limited, and can be generally 40 to 80°C, preferably 40 to 60°C.
结晶化时间没有特别限制，通常为1小时以上、优选为2小时以上、进一步优选为2～12小时。The crystallization time is not particularly limited, but is usually 1 hour or longer, preferably 2 hours or longer, and more preferably 2 to 12 hours.
只要在丙酮和水存在下即可，优选作为丙酮和水的比例，可以在85:15～50:50下进行。The reaction may be carried out in the presence of acetone and water, and the ratio of acetone to water is preferably 85:15 to 50:50.
式(VII)所示的化合物、其制药上可接受的盐或它们的复合体(以下记作式(VII)所示的化合物等)、和通过本发明所涉及的制造方法制造的化合物(式(VII)所示的化合物等)具有冠状病毒3CL蛋白酶抑制活性，因此作为病毒感染症的治疗和/或预防剂是有用的。The compound represented by formula (VII), its pharmaceutically acceptable salt or a complex thereof (hereinafter referred to as the compound represented by formula (VII) etc.), and the compound produced by the production method involved in the present invention (the compound represented by formula (VII) etc.) have coronavirus 3CL protease inhibitory activity and are therefore useful as a therapeutic and/or preventive agent for viral infections.
进一步，通过本发明所涉及的制造方法制造的化合物具有作为医药的有用性，优选具有下述中任一个或多个优异特征。Furthermore, the compound produced by the production method according to the present invention has usefulness as a medicine, and preferably has any one or more of the following excellent characteristics.
a)对CYP酶(例如CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4等)的抑制作用弱。a) The inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b)示出高生物利用度、适度的清除率等良好的药代动力学。b) It exhibits good pharmacokinetics such as high bioavailability and moderate clearance.
c)代谢稳定性高。c) High metabolic stability.
d)对CYP酶(例如CYP3A4)，在本说明书中记载的测定条件的浓度范围内不示出不可逆的抑制作用。d) No irreversible inhibitory action is shown on CYP enzymes (eg, CYP3A4) within the concentration range of the assay conditions described in the present specification.
e)不具有变异原性。e) Not mutagenic.
f)心血管系统的风险低。f) Low risk to the cardiovascular system.
g)示出高溶解性。g) Shows high solubility.
h)蛋白质非结合率(fu值)高。h) The protein non-binding rate (fu value) is high.
i)具有高冠状病毒3CL蛋白酶选择性。i) High selectivity for coronavirus 3CL protease.
j)具有高冠状病毒增殖抑制活性。例如，在添加人血清(HS)或人血清白蛋白(HSA)的情况下，具有高冠状病毒增殖抑制活性。j) It has high coronavirus proliferation inhibitory activity. For example, when human serum (HS) or human serum albumin (HSA) is added, it has high coronavirus proliferation inhibitory activity.
作为冠状病毒增殖抑制剂，例如后述的CPE抑制效果确认试验(SARS-CoV-2)中，可以举出例如EC50为10μM以下、优选为1μM以下、更优选为100nM以下的方式。As the coronavirus proliferation inhibitor, for example, in the CPE inhibitory effect confirmation test (SARS-CoV-2) described below, an embodiment in which EC50 is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less can be mentioned.
此外，本发明所涉及的化合物的盐·晶体·复合体·共晶体具有作为医药的有用性，优选具有下述中任一个或多个优异特征。In addition, the salt, crystal, complex, or co-crystal of the compound involved in the present invention has usefulness as a medicine, and preferably has any one or more of the following excellent characteristics.
bb)示出高生物利用度、适度的清除率、高AUC、高最高血中浓度等、良好的药代动力学。bb) It shows high bioavailability, moderate clearance, high AUC, high maximum blood concentration, etc., and good pharmacokinetics.
gg)示出高溶解性、高化学稳定性、低吸湿性。gg) shows high solubility, high chemical stability and low hygroscopicity.
含有式(VII)所示的化合物等(例如通过本发明所涉及的制造方法制造的化合物)的药物组合物也可以通过口服的、非口服中任一方法给与。作为非口服给与的方法，可以举出经皮、皮下、静脉内、动脉内、肌肉内、腹腔内、经粘膜、吸入、经鼻、滴眼、滴耳、阴道内给与等。The pharmaceutical composition containing the compound represented by formula (VII) or the like (e.g., the compound produced by the production method of the present invention) can also be administered by any method of oral or parenteral administration. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, vaginal administration, etc.
口服给与的情况下，按照常规方法，制备为内服用固体制剂(例如片剂、散剂、颗粒剂、胶囊剂、丸剂、膜剂等)、内服用液剂(例如混悬剂、乳剂、酏剂、糖浆剂、汽水(Limonade)剂、酒精剂、芳香水剂、浸膏剂、煎剂、酊剂等)等通常使用的任一剂型而给与即可。片剂可以是糖衣片、膜包衣片、腸溶性包衣片、缓释片、锭片、舌下片、口含片、咀嚼片或口腔内崩解片，散剂和颗粒剂可以为干糖浆，胶囊剂可以为软胶囊剂、微胶囊剂或缓释性胶囊剂。In the case of oral administration, it can be prepared into any commonly used dosage form such as solid preparations for internal use (such as tablets, powders, granules, capsules, pills, films, etc.), liquid preparations for internal use (such as suspensions, emulsions, elixirs, syrups, limonades, alcohols, aromatic waters, extracts, decoctions, tinctures, etc.) according to conventional methods and administered. Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, powders and granules can be dry syrups, and capsules can be soft capsules, microcapsules or sustained-release capsules.
非口服给与的情况下，也可以以注射剂、点滴剂、外用剂(例如滴眼剂、点鼻剂、滴耳剂、气溶胶剂、吸入剂、洗剂、注入剂、涂布剂、含漱剂、灌肠剂、軟膏剂、硬膏剂、冻胶剂、霜剂、贴剂、泥敷剂、外用散剂、栓剂等)等通常使用的任一剂型适合地给与。注射剂可以是O/W、W/O、O/W/O、W/O/W型等乳液。In the case of parenteral administration, it can be appropriately administered in any commonly used dosage form such as injection, drip, external preparation (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.). Injections may be emulsions such as O/W, W/O, O/W/O, and W/O/W types.
在式(VII)所示的化合物等(例如通过本发明所涉及的制造方法制造的化合物)的有效量中根据需要混合适合于其剂型的赋形剂、粘结剂、崩解剂、润滑剂等各种医药用添加剂，可以制成药物组合物。进一步，该药物组合物通过适当变更本发明化合物的有效量、剂型和/或各种医药用添加剂，也可以制成儿童用、老人用、重症患者用或手术用的药物组合物。例如，儿童用药物组合物可以对新生儿(出生后未满4周)、乳儿(出生后4周～未满1岁)、幼儿(1岁以上且未满7岁)、小儿(7岁以上且未满15岁)或15岁～18岁的患者给与。例如，老人用药物组合物可以对65岁以上的患者给与。In the effective amount of the compound represented by formula (VII) or the like (for example, the compound manufactured by the manufacturing method involved in the present invention), various pharmaceutical additives such as excipients, binders, disintegrants, lubricants suitable for its dosage form can be mixed as needed to prepare a pharmaceutical composition. Furthermore, the pharmaceutical composition can also be prepared into a pharmaceutical composition for children, the elderly, critically ill patients or surgery by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention. For example, a pharmaceutical composition for children can be given to newborns (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old), infants (over 1 year old and less than 7 years old), children (over 7 years old and less than 15 years old) or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be given to patients over 65 years old.
含有式(VII)所示的化合物等(例如通过本发明所涉及的制造方法制造的化合物)的药物组合物(例如包含式(VII)所示的化合物的富马酸共晶体I形的药物组合物)的给与量期望在考虑患者的年龄、体重、疾病的种类、程度、给与途径等的基础上设定，在口服给与的情况下，通常为0.05～200mg/kg/天、优选为0.1～100mg/kg/天的范围内。非口服给与的情况下，根据给与途径而显著不同，通常为0.005～200mg/kg/天、优选为0.01～100mg/kg/天的范围内。将其分为1天1次～多次给与即可。The dosage of a pharmaceutical composition (e.g., a pharmaceutical composition of fumaric acid cocrystal I form containing a compound represented by formula (VII)) containing a compound represented by formula (VII) or the like (e.g., a compound manufactured by the manufacturing method of the present invention) is preferably set based on the patient's age, weight, type and degree of the disease, administration route, etc., and is generally within the range of 0.05 to 200 mg/kg/day, preferably 0.1 to 100 mg/kg/day in the case of oral administration. In the case of parenteral administration, it varies significantly depending on the administration route, and is generally within the range of 0.005 to 200 mg/kg/day, preferably 0.01 to 100 mg/kg/day. It can be divided into once to multiple administrations per day.
式(VII)所示的化合物等(例如通过本发明所涉及的制造方法制造的化合物))以增强该化合物的作用或减少该化合物的给与量等为目的，可以与例如其他新型冠状病毒感染症(COVID-19)的治疗药(作为该治疗药，包括获得批准的药剂、和开发中或今后开发的药剂)(以下称为组合使用药剂)组合使用。此时，本发明化合物与组合使用的药剂的给与时期不受限定，可以将它们对给与对象同时给与，也可以隔有时间差给与。进一步，本发明化合物与组合使用药剂可以制成包含各自的活性成分的2种以上的制剂而给与，也可以制成包含这些活性成分的单一的制剂而给与。The compound shown in formula (VII) etc. (for example, a compound manufactured by the manufacturing method involved in the present invention)) can be used in combination with, for example, other novel coronavirus infection (COVID-19) therapeutic drugs (as the therapeutic drug, including approved drugs and drugs under development or to be developed in the future) (hereinafter referred to as combined use drugs) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. At this time, the administration period of the compound of the present invention and the combined use drug is not limited, and they can be administered to the administration object at the same time, or they can be administered with a time difference. Further, the compound of the present invention and the combined use drug can be prepared into two or more preparations containing each active ingredient and administered, or a single preparation containing these active ingredients can be prepared and administered.
组合使用药剂的给与量可以适当选择临床上使用的剂量作为基准。此外，本发明化合物与组合使用药剂的配合比可以根据给与对象、给与途径、对象疾病、症状、组合等而适当选择。例如，给与对象为人的情况下，相对于本发明化合物1重量份，使用0.01～100重量份组合使用药剂即可。The dosage of the combined drug can be appropriately selected from the clinically used dosage as a reference. In addition, the ratio of the compound of the present invention and the combined drug can be appropriately selected according to the subject, route of administration, target disease, symptoms, combination, etc. For example, when the subject is human, 0.01 to 100 parts by weight of the combined drug can be used relative to 1 part by weight of the compound of the present invention.
在式(VII)所示的化合物等有效量中根据需要混合适合于其剂型的赋形剂、粘结剂、崩解剂、润滑剂等各种医药用添加剂，可以制成制剂。A preparation can be prepared by mixing an effective amount of the compound represented by formula (VII) or the like with various pharmaceutical additives suitable for the dosage form, such as an excipient, a binder, a disintegrant, and a lubricant, as required.
本发明制剂为口服给与的制剂即可。口服给与的情况下，按照常规方法，制备为内服用固体制剂(例如片剂、散剂、颗粒剂、干糖浆剂、胶囊剂、丸剂、膜剂等)、内服用液剂(例如混悬剂、乳剂、酏剂、糖浆剂、汽水(Limonade)剂、酒精剂、芳香水剂、浸膏剂、煎剂、酊剂等)等通常使用的任一剂型而给与即可。片剂可以是糖衣片、膜包衣片、腸溶性包衣片、缓释片、锭片、舌下片、口含片、咀嚼片或口腔内崩解片，散剂和颗粒剂可以为干糖浆，胶囊剂可以为软胶囊剂、微胶囊剂或缓释性胶囊剂。优选为口服给与的固体制剂或混悬剂，更优选为口服给与的固体制剂，特别优选为片剂、颗粒剂。The preparation of the present invention can be an oral preparation. In the case of oral administration, it can be prepared into any commonly used dosage form such as solid preparations for oral administration (such as tablets, powders, granules, dry syrups, capsules, pills, films, etc.), liquid preparations for oral administration (such as suspensions, emulsions, elixirs, syrups, limonades, alcohols, aromatic waters, extracts, decoctions, tinctures, etc.) according to conventional methods and administered. Tablets can be sugar-coated tablets, film-coated tablets, enteric-soluble coated tablets, sustained-release tablets, tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, powders and granules can be dry syrups, and capsules can be soft capsules, microcapsules or sustained-release capsules. It is preferably a solid preparation or suspension for oral administration, more preferably a solid preparation for oral administration, and particularly preferably a tablet or granule.
作为片剂的形状，也可以采用任一形状，具体而言，可以制成圆形、椭圆形、球形、棒状型、甜甜圈型的形状的片剂。此外，可以为层叠片、有核片等，优选为制造方法简便的单层片。进一步，也可以标记用于提高识别性的符号、文字等刻印，进一步可以标记分割用的割线。The tablet may be in any shape, specifically, a round, oval, spherical, rod-shaped, or donut-shaped tablet. In addition, a laminated tablet or a core-containing tablet may be used, preferably a single-layer tablet with a simple manufacturing method. Furthermore, a symbol or text mark may be marked to improve recognition, and a cutting line for segmentation may be marked.
进一步，本发明制剂通过适当变更式(VII)所示的化合物等有效量、剂型和/或各种医药用添加剂，也可以儿童用、老人用、重症患者用或手术用的制剂。例如，儿童用药物组合物可以对新生儿(出生后未满4周)、乳儿(出生后4周～未满1岁)、幼儿(1岁以上且未满7岁)、小儿(7岁以上且未满15岁)或15岁～18岁的患者给与。例如，老人用制剂可以对65岁以上的患者给与。Furthermore, the preparation of the present invention can also be a preparation for children, the elderly, critically ill patients or surgery by appropriately changing the effective amount of the compound represented by formula (VII), dosage form and/or various pharmaceutical additives. For example, the pharmaceutical composition for children can be given to newborns (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old), infants (over 1 year old and under 7 years old), children (over 7 years old and under 15 years old) or patients aged 15 to 18 years. For example, the preparation for the elderly can be given to patients over 65 years old.
本发明制剂(例如包含式(VII)所示的化合物的富马酸共晶体I形的制剂)的给与量期望在考虑患者的年龄、体重、疾病的种类、程度、给与途径等的基础上设定，在口服给与的情况下，通常为0.05～200mg/kg/天、优选为0.1～100mg/kg/天的范围内。非口服给与的情况下，根据给与途径而显著不同，通常为0.005～200mg/kg/天、优选为0.01～100mg/kg/天的范围内。将其分为1天1次～多次给与即可。The dosage of the preparation of the present invention (e.g., a preparation of fumaric acid cocrystal form I of a compound represented by formula (VII)) is preferably set based on the patient's age, weight, type and degree of the disease, administration route, etc., and is generally within the range of 0.05 to 200 mg/kg/day, preferably 0.1 to 100 mg/kg/day in the case of oral administration. In the case of parenteral administration, it varies significantly depending on the administration route, and is generally within the range of 0.005 to 200 mg/kg/day, preferably 0.01 to 100 mg/kg/day. It can be divided into once a day to multiple administrations.
本发明制剂中含有的式(VII)所示的化合物等重量只要是患者容易服用、能够进行制剂制造的含量，则没有特别限制，为1～450mg、优选为5～350mg、更优选为25～250mg。The weight of the compound represented by formula (VII) and the like contained in the preparation of the present invention is not particularly limited as long as it is a content that is easy for patients to take and can be manufactured as a preparation, and is 1 to 450 mg, preferably 5 to 350 mg, and more preferably 25 to 250 mg.
具体而言，平均1片、1胶囊或1包含有的式(VII)所示的化合物等重量为25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg或250mg。Specifically, the average weight of the compound represented by formula (VII) contained in one tablet, one capsule or one package is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg.
该情况下，25mg是指表示22.5mg～27.5mg、优选为23.7mg～26.3mg的范围的范围，50mg是指表示45.0mg～55.0mg、优选为47.5mg～52.5mg的范围，75mg是指表示67.5mg～82.5mg的范围，优选表示71.2mg～78.8mg的范围，100mg是指表示90.0mg～110.0mg、优选为95.0mg～105.0mg的范围，125mg是指表示112.5mg～137.5mg、优选为118.7mg～131.3mg的范围，150mg是指表示135.0mg～165.0mg、优选为142.5mg～157.5mg的范围，175mg是指表示157.5mg～192.5mg、优选为166.2～183.8mg的范围，200mg是指表示180.0mg～220.0mg、优选为190.0mg～210.0mg的范围，225mg是指表示202.5mg～247.5mg、优选为213.7mg～236.3mg的范围，250mg是指表示225.0mg～275.0mg、优选为237.5mg～262.5mg的范围。In this case, 25 mg means a range of 22.5 mg to 27.5 mg, preferably 23.7 mg to 26.3 mg, 50 mg means a range of 45.0 mg to 55.0 mg, preferably 47.5 mg to 52.5 mg, 75 mg means a range of 67.5 mg to 82.5 mg, preferably 71.2 mg to 78.8 mg, 100 mg means a range of 90.0 mg to 110.0 mg, preferably 95.0 mg to 105.0 mg, 125 mg means a range of 112.5 mg to 137.5 mg, preferably 118.7 mg to 131.3 mg, 1 50 mg means a range of 135.0 mg to 165.0 mg, preferably 142.5 mg to 157.5 mg, 175 mg means a range of 157.5 mg to 192.5 mg, preferably 166.2 to 183.8 mg, 200 mg means a range of 180.0 mg to 220.0 mg, preferably 190.0 mg to 210.0 mg, 225 mg means a range of 202.5 mg to 247.5 mg, preferably 213.7 mg to 236.3 mg, and 250 mg means a range of 225.0 mg to 275.0 mg, preferably 237.5 mg to 262.5 mg.
式(VII)所示的化合物等以增强该化合物的作用或减少该化合物的给与量等为目的，可以与例如其他新型冠状病毒感染症(COVID-19)的治疗药(作为该治疗药，包括获得批准的药剂、和开发中或今后开发的药剂)(以下称为组合使用药剂)组合使用。此时，式(VII)所示的化合物等与组合使用的药剂的给与时期不受限定，可以将它们对给与对象同时给与，也可以隔有时间差给与。进一步，式(VII)所示的化合物等与组合使用药剂可以制成包含各自的活性成分的2种以上的制剂而给与，也可以制成包含这些活性成分的单一的制剂而给与。The compound shown in formula (VII) etc. can be used in combination with, for example, other novel coronavirus infection (COVID-19) therapeutic drugs (including approved drugs and drugs under development or to be developed in the future) (hereinafter referred to as combined drugs) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. At this time, the administration period of the compound shown in formula (VII) etc. and the combined drug is not limited, and they can be administered to the subject at the same time, or they can be administered with a time difference. Further, the compound shown in formula (VII) etc. and the combined drug can be prepared into two or more preparations containing their respective active ingredients and administered, or they can be prepared into a single preparation containing these active ingredients and administered.
组合使用药剂的给与量可以适当选择临床上使用的剂量作为基准。此外，式(VII)所示的化合物等所示的化合物与组合使用药剂的配合比可以根据给与对象、给与途径、对象疾病、症状、组合等而适当选择。例如，给与对象为人的情况下，相对于式(VII)所示的化合物等所示的化合物1重量份，使用0.01～100重量份组合使用药剂即可。The dosage of the combined drug can be appropriately selected from the clinically used dosage as a reference. In addition, the compound shown in the compound shown in formula (VII) and the combined drug can be appropriately selected according to the subject, route of administration, target disease, symptoms, combination, etc. For example, when the subject is human, 0.01 to 100 parts by weight of the combined drug can be used relative to 1 part by weight of the compound shown in the compound shown in formula (VII).
本发明制剂可以含有高分子，作为高分子，可以使用日本药典、日本药典外医药品标准、医药品添加物标准或食品添加物公定书等中收载的高分子。The preparation of the present invention may contain a polymer, and as the polymer, a polymer listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Pharmacopoeia Drug Standards, the Pharmaceutical Additive Standards, the Food Additives Standards, etc. may be used.
含有式(VII)所示的化合物、其制药上可接受的盐或它们的复合体、和高分子的制剂可以提高制剂中的式(VII)所示的化合物的溶解度。A preparation containing the compound represented by formula (VII), a pharmaceutically acceptable salt thereof, or a complex thereof, and a polymer can improve the solubility of the compound represented by formula (VII) in the preparation.
作为高分子，可以举出例如纤维素系高分子、丙烯酸系高分子、乙烯基系高分子、多糖类等。Examples of the polymer include cellulose-based polymers, acrylic-based polymers, vinyl-based polymers, and polysaccharides.
作为纤维素系高分子，可以举出羟基丙基纤维素(HPC)、羟丙甲基纤维素(羟基丙基甲基纤维素)(HPMC)、羟基乙基纤维素、羟基乙基甲基纤维素、羟基丙基甲基纤维素乙酸酯丁二酸酯、羟基丙基甲基纤维素、丁酸酯、甲基纤维素(MC)、甲基羟基乙基纤维素、羧基甲基乙基纤维素、乙基纤维素、结晶纤维素、微晶纤维素、结晶纤维素·羧甲基纤维素钠、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、粉末纤维素、低取代度羟基丙基纤维素、富马酸·硬脂酸·聚乙烯醇缩醛二乙基氨基乙酸酯·羟基丙基甲基纤维素混合物等。Examples of cellulose-based polymers include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose) (HPMC), hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, butyrate, methylcellulose (MC), methyl hydroxyethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose·sodium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, and a mixture of fumaric acid·stearic acid·polyvinyl acetal diethylaminoacetate·hydroxypropyl methylcellulose.
作为丙烯酸系高分子，可以举出氨基烷基丙烯酸酯共聚物E、聚乙烯醇缩醛二乙基氨基乙酸酯、丙烯酸乙酯·甲基丙烯酸甲酯共聚物分散液、氨基烷基甲基丙烯酸酯共聚物、甲基丙烯酸共聚物、2-甲基-5-乙烯基吡啶甲基丙烯酸酯·甲基丙烯酸共聚物、干燥甲基丙烯酸共聚物、甲基丙烯酸二甲基氨基乙基酯·甲基丙烯酸甲酯共聚物等。Examples of acrylic polymers include aminoalkyl acrylate copolymer E, polyvinyl acetal diethylaminoacetate, ethyl acrylate·methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methacrylate·methacrylic acid copolymer, dry methacrylic acid copolymer, and dimethylaminoethyl methacrylate·methyl methacrylate copolymer.
作为乙烯基系高分子，可以举出聚乙烯基吡咯烷酮、聚乙烯醇、聚乙烯醇·甲基丙烯酸甲酯·丙烯酸共聚物、交聚维酮、羧基乙烯基聚合物、聚乙烯醇缩醛二乙基氨基乙酸酯、和聚乙烯醇共聚物等。Examples of the vinyl polymer include polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer, crospovidone, carboxyvinyl polymer, polyvinyl acetal diethylaminoacetate, and polyvinyl alcohol copolymer.
此外，作为多糖类，可以举出普鲁兰多糖等。In addition, examples of polysaccharides include pullulan and the like.
优选为纤维素系高分子、丙烯酸系高分子和/或乙烯基系高分子，更优选为纤维素系高分子，进一步优选为羟丙甲基纤维素(羟基丙基甲基纤维素)。Cellulose-based polymers, acrylic-based polymers and/or vinyl-based polymers are preferred, cellulose-based polymers are more preferred, and hydroxypropylmethylcellulose (hydroxypropylmethylcellulose) is further preferred.
作为另一方式，优选为含有式(VII)所示的化合物、其制药上可接受的盐或它们的复合体作为有效成分、和纤维素系高分子的口服给与的片剂。As another embodiment, a tablet for oral administration containing, as an active ingredient, the compound represented by formula (VII), a pharmaceutically acceptable salt thereof, or a complex thereof, and a cellulose-based polymer is preferred.
本发明制剂中，可以使用选自赋形剂、粘结剂、崩解剂和润滑剂中的1种以上的添加剂。In the preparation of the present invention, one or more additives selected from the group consisting of excipients, binders, disintegrants and lubricants may be used.
本发明制剂中，可以使用赋形剂(也有时为填充剂)。作为赋形剂，可以使用日本药典、日本药典外医药品标准、医药品添加物标准或食品添加物公定书等中收载的赋形剂。例如，作为赋形剂，可以举出糖衍生物、淀粉衍生物、纤维素衍生物、无机系赋形剂、β-环糊精、硬脂酸镁、硬脂酸钙、蔗糖脂肪酸酯、交聚维酮、大豆卵磷脂、黄蓍胶粉末、阿拉伯胶、葡聚糖、普鲁兰多糖等。In the preparation of the present invention, an excipient (sometimes a filler) can be used. As an excipient, an excipient recorded in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Extra-Pharmacopoeia Standard, the Pharmaceutical Additive Standard or the Food Additive Public Book can be used. For example, as an excipient, sugar derivatives, starch derivatives, cellulose derivatives, inorganic excipients, β-cyclodextrin, magnesium stearate, calcium stearate, sucrose fatty acid esters, crospovidone, soybean lecithin, tragacanth powder, gum arabic, dextran, pullulan, etc. can be cited.
作为糖衍生物，有糖类、糖醇，作为糖类，可以举出乳糖、白糖、葡萄糖、果糖、蔗糖等，此外，作为糖醇，可以举出甘露醇、山梨糖醇、赤藓糖醇、木糖醇、粉末麦芽糖水饴、麦芽糖醇等。Sugar derivatives include sugars and sugar alcohols. Examples of sugars include lactose, sucrose, glucose, fructose, and sucrose. Examples of sugar alcohols include mannitol, sorbitol, erythritol, xylitol, powdered maltose syrup, and maltitol.
作为淀粉衍生物，可以举出淀粉、马铃薯淀粉、玉米淀粉(玉米淀粉)、大米淀粉、部分α-化淀粉、α-化淀粉、有孔淀粉、羧基淀粉钠、羟基丙基淀粉、低取代度羧基甲基淀粉钠等。Examples of starch derivatives include starch, potato starch, corn starch (maize starch), rice starch, partially α-starch, α-starch, porous starch, sodium carboxystarch, hydroxypropyl starch, and low-substituted sodium carboxymethyl starch.
作为纤维素衍生物，可以举出结晶纤维素、粉末纤维素、羧甲基纤维素钠、羧甲基纤维素、交联羧甲基纤维素钠、羧甲基纤维素钙、羧基甲基乙基纤维素、低取代度羟基丙基纤维素等。Examples of the cellulose derivatives include crystalline cellulose, powdered cellulose, sodium carboxymethylcellulose, carboxymethylcellulose, croscarmellose sodium, carboxymethylcellulose calcium, carboxymethylethylcellulose, and low-substituted hydroxypropylcellulose.
作为无机系赋形剂，可以举出硅酸盐衍生物、磷酸盐、碳酸盐、硫酸盐、氧化镁、氧化钛、乳酸钙、合成水滑石、滑石、高岭土、干燥氢氧化铝、氧化镁、膨润土等。Examples of the inorganic excipient include silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, and bentonite.
作为硅酸盐衍生物，可以举出含水二氧化硅、轻质无水硅酸等二氧化硅、偏硅酸铝酸镁、合成硅酸铝、硅酸钙等。Examples of silicate derivatives include hydrous silicon dioxide, silicon dioxide such as light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, and calcium silicate.
作为磷酸盐，可以举出无水磷酸氢钙、磷酸一氢钙、磷酸氢钙、磷酸氢钠、磷酸二钾、磷酸二氢钾、磷酸二氢钙、磷酸二氢钠等。Examples of the phosphate include anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate.
作为碳酸盐，可以举出沉降碳酸钙、碳酸钙、碳酸镁等。作为硫酸盐，可以举出硫酸钙等。Examples of carbonates include precipitated calcium carbonate, calcium carbonate, and magnesium carbonate, and examples of sulfates include calcium sulfate.
这些赋形剂可以以适当的比例混合使用2种以上。These excipients may be used by mixing two or more of them at an appropriate ratio.
本发明制剂中的赋形剂优选为甘露醇和/或交联羧甲基纤维素钠。The excipients in the preparation of the present invention are preferably mannitol and/or cross-linked carboxymethylcellulose sodium.
本发明制剂中，可以使用粘结剂，可以使用日本药典、日本药典外医药品标准、医药品添加物标准或食品添加物公定书等中收载的粘结剂。例如，作为粘结剂，可以举出纤维素系粘结剂、淀粉系粘结剂、乙烯基系粘结剂、聚醚、阿拉伯胶、阿拉伯胶粉末、阿拉伯胶末、藻酸、藻酸钠、蔗糖、明胶、糊精、普鲁兰多糖、黄蓍胶、黄蓍胶粉末、黄原胶、果胶、聚丙烯酸钠、琼脂、黄柏粉末、瓜尔胶、轻质无水硅酸、氢化油等。In the preparation of the present invention, a binder can be used, and the binders recorded in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Extra-Pharmacopoeia Standards, the Pharmaceutical Additives Standards or the Food Additives Public Book can be used. For example, as the binder, cellulose-based binders, starch-based binders, vinyl-based binders, polyethers, gum arabic, gum arabic powder, gum arabic powder, alginic acid, sodium alginate, sucrose, gelatin, dextrin, pullulan, tragacanth, tragacanth powder, xanthan gum, pectin, sodium polyacrylate, agar, Phellodendron chinense powder, guar gum, light anhydrous silicic acid, hydrogenated oil, etc. can be cited.
作为纤维素系粘结剂，可以举出羧基甲基纤维素(羧甲基纤维素、CMC)、羧基甲基纤维素钠(羧甲基纤维素钠)、羟基乙基纤维素(HEC)、羟基丙基纤维素(HPC)、羟基丙基甲基纤维素(羟丙甲基纤维素)(HPMC)、甲基纤维素(MC)、结晶纤维素、微晶纤维素、乙基纤维素、结晶纤维素·羧甲基纤维素钠、羧甲基纤维素钙、粉末纤维素、低取代度羟基丙基纤维素等。Examples of the cellulose-based binder include carboxymethylcellulose (carboxymethylcellulose, CMC), sodium carboxymethylcellulose (sodium carboxymethylcellulose), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (hydroxypropylmethylcellulose) (HPMC), methylcellulose (MC), crystalline cellulose, microcrystalline cellulose, ethyl cellulose, crystalline cellulose·sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, and low-substituted hydroxypropyl cellulose.
作为淀粉系粘结剂，可以举出淀粉、α化淀粉、部分α化淀粉、马铃薯淀粉、小麦淀粉、大米淀粉、有孔淀粉、玉米淀粉、羟基丙基淀粉、淀粉乙醇酸钠(羧基甲基淀粉钠)等。Examples of the starch-based binder include starch, pregelatinized starch, partially pregelatinized starch, potato starch, wheat starch, rice starch, porous starch, corn starch, hydroxypropyl starch, sodium starch glycolate (sodium carboxymethyl starch), and the like.
作为乙烯基系粘结剂，可以举出聚乙烯醇(PVA)、聚乙烯基吡咯烷酮(聚维酮)(PVP)、羧基乙烯基聚合物、共聚维酮等。Examples of the vinyl-based binder include polyvinyl alcohol (PVA), polyvinyl pyrrolidone (povidone) (PVP), carboxyvinyl polymer, and copovidone.
作为聚醚，可以举出聚乙二醇(聚乙二醇)200、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇1000、聚乙二醇1500、聚乙二醇1540、聚乙二醇4000、聚乙二醇6000、聚乙二醇20000、丙三醇、聚氧乙烯[105]聚氧丙烯[5]二醇、丙二醇等。Examples of the polyether include polyethylene glycol (PEG) 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, glycerol, polyoxyethylene [105] polyoxypropylene [5] glycol, and propylene glycol.
这些粘结剂可以以适当的比例混合使用2种以上。These binders may be used by mixing two or more kinds at an appropriate ratio.
本发明制剂中的粘结剂优选为羟基丙基纤维素(HPC)。The binder in the formulation of the present invention is preferably hydroxypropylcellulose (HPC).
本发明制剂中，可以使用崩解剂，可以使用日本药典、日本药典外医药品标准、医药品添加物标准或食品添加物公定书等中收载的崩解剂。例如，作为崩解剂，可以举出纤维素系崩解剂、淀粉系崩解剂、乙烯基系崩解剂、偏硅酸铝酸镁等。In the preparation of the present invention, a disintegrant may be used, and a disintegrant listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia External Drug Standards, the Drug Additive Standards, or the Food Additives Public Book may be used. For example, examples of the disintegrant include cellulose-based disintegrants, starch-based disintegrants, vinyl-based disintegrants, and magnesium aluminometasilicate.
作为纤维素系崩解剂，可以举出羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羟基丙基纤维素、低取代度羟基丙基纤维素、交联羧甲基纤维素钠(Ac-Di-Sol)、结晶纤维素、粉末纤维素等。Examples of the cellulose-based disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), crystalline cellulose, and powdered cellulose.
作为淀粉系崩解剂，可以举出部分α-化淀粉、马铃薯淀粉、玉米淀粉、羟基丙基淀粉、羧基甲基淀粉钠、低取代度羧基甲基淀粉钠、淀粉乙醇酸钠、α化淀粉、淀粉等。Examples of the starch-based disintegrant include partially α-starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, α-starch, and starch.
作为乙烯基系崩解剂，可以举出交聚维酮、聚乙烯醇等。Examples of the vinyl-based disintegrant include crospovidone and polyvinyl alcohol.
这些崩解剂可以以适当的比例混合使用2种以上。These disintegrants may be used by mixing two or more kinds at an appropriate ratio.
崩解剂之中，溶胀率非常大的溶胀型崩解剂已知为“超级崩解剂”。作为超级崩解剂，可以举出羧甲基纤维素钙、低取代度羟基丙基纤维素、交联羧甲基纤维素钠、交聚维酮、淀粉乙醇酸钠等。Among disintegrants, swelling type disintegrants with a very large swelling ratio are known as “super disintegrants.” Examples of super disintegrants include carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, cross-linked carboxymethylcellulose sodium, crospovidone, and sodium starch glycolate.
这些超级崩解剂可以以适当的比例混合使用2种以上。此外，可以组合崩解剂和超级崩解剂。These super disintegrants may be used in combination of two or more kinds at an appropriate ratio.
本发明制剂中的崩解剂优选为交联羧甲基纤维素钠。The disintegrant in the preparation of the present invention is preferably croscarmellose sodium.
本发明制剂中，可以含有润滑剂，可以使用日本药典、日本药典外医药品标准、医药品添加物标准或食品添加物公定书等中收载的润滑剂。例如，作为润滑剂，可以举出硬脂酸和硬脂酸金属盐、无机系润滑剂、疏水性润滑剂、亲水性润滑剂、富马酸硬脂基酯钠等。The preparation of the present invention may contain a lubricant, and lubricants listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Pharmacopoeia Drug Standards, the Drug Additive Standards, or the Food Additives Codex, etc., may be used. For example, lubricants include stearic acid and stearic acid metal salts, inorganic lubricants, hydrophobic lubricants, hydrophilic lubricants, sodium stearyl fumarate, etc.
作为硬脂酸和硬脂酸金属盐，可以举出硬脂酸镁、硬脂酸钙、硬脂酸、硬脂醇、硬脂酸聚乙二醇40等。Examples of stearic acid and stearic acid metal salts include magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, and polyethylene glycol 40 stearate.
作为无机系润滑剂，可以举出滑石、轻质无水硅酸、含水二氧化硅、碳酸镁、沉降碳酸钙、干燥氢氧化铝凝胶、偏硅酸铝酸镁、硅酸镁、合成硅酸铝、氧化镁、硫酸镁等。Examples of the inorganic lubricant include talc, light anhydrous silicic acid, hydrous silicon dioxide, magnesium carbonate, precipitated calcium carbonate, dry aluminum hydroxide gel, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, and magnesium sulfate.
作为疏水性润滑剂，可以举出可可脂、巴西棕榈蜡、丙三醇脂肪酸酯、氢化油、白蜂蜡、大豆氢化油、蜂蜡、鲸蜡醇、月桂酸钠等。Examples of the hydrophobic lubricant include cocoa butter, carnauba wax, glycerin fatty acid esters, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetyl alcohol, and sodium laurate.
作为亲水性润滑剂，可以举出蔗糖脂肪酸酯、聚乙二醇(聚乙二醇)等。Examples of the hydrophilic lubricant include sucrose fatty acid esters and polyethylene glycol (PEG).
这些润滑剂可以以适当的比例混合使用2种以上。These lubricants may be used by mixing two or more kinds at an appropriate ratio.
本发明制剂中的粘结剂优选为硬脂酸镁。The binder in the formulation of the present invention is preferably magnesium stearate.
本发明制剂中，可以含有流动化剂，可以使用日本药典、日本药典外医药品标准、医药品添加物标准或食品添加物公定书等中收载的流动化剂。例如，作为流动化剂，可以举出二氧化硅、硬脂酸和其金属盐、结晶纤维素、合成硅酸铝、氧化钛、重质无水硅酸、氢氧化氧化铝镁、磷酸钙、滑石、玉米淀粉、偏硅酸铝酸镁、磷酸氢钙造粒物、硅酸钙、无水磷酸氢钙、合成水滑石等。The preparation of the present invention may contain a fluidizing agent, and fluidizing agents recorded in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia External Pharmaceutical Standards, the Pharmaceutical Additive Standards, or the Food Additives Public Book can be used. For example, as a fluidizing agent, silicon dioxide, stearic acid and its metal salt, crystalline cellulose, synthetic aluminum silicate, titanium oxide, heavy anhydrous silicic acid, magnesium aluminum hydroxide, calcium phosphate, talc, corn starch, magnesium aluminosilicate, calcium hydrogen phosphate granules, calcium silicate, anhydrous calcium hydrogen phosphate, synthetic hydrotalcite, etc. can be cited.
作为二氧化硅，可以举出含水二氧化硅、轻质无水硅酸等。作为硬脂酸和其金属盐，可以举出硬脂酸、硬脂酸钙、硬脂酸镁等。Examples of silicon dioxide include hydrous silicon dioxide and light anhydrous silicic acid. Examples of stearic acid and metal salts thereof include stearic acid, calcium stearate, and magnesium stearate.
这些流动化剂可以以适当的比例混合使用2种以上。These fluidizing agents may be used by mixing two or more of them at an appropriate ratio.
本发明制剂中的粘结剂优选为结晶纤维素。The binder in the preparation of the present invention is preferably crystalline cellulose.
本发明制剂之中，颗粒剂的制造方法没有特别限制，具体而言，为将有效成分、崩解剂、赋形剂等添加剂混合、制造混合粉末后，对该混合粉末造粒的方法；优选为添加水、含有粘结剂的水、溶剂而造粒的湿式造粒法、压缩成型而不使用水的干式造粒法、熔融造粒法。In the preparation of the present invention, the method for producing granules is not particularly limited. Specifically, it is a method of mixing active ingredients, disintegrants, excipients and other additives to produce a mixed powder, and then granulating the mixed powder; preferably, a wet granulation method in which water, water containing a binder, or a solvent is added to granulate, a dry granulation method in which compression molding is performed without using water, or a melt granulation method.
本发明制剂之中，片剂的制造方法没有特别限制，具体而言，为通过上述方法制造颗粒，进一步，对该颗粒混合崩解剂和润滑剂，将该混合颗粒用压片机压片的压片法。The method for producing tablets in the preparation of the present invention is not particularly limited, and specifically, it is a tableting method in which granules are produced by the above method, a disintegrant and a lubricant are further mixed with the granules, and the mixed granules are tableted using a tablet press.
本发明制剂在制造上述的颗粒剂、片剂后，有时将该颗粒剂、片剂用被覆层被覆。在颗粒剂上形成被覆层时，可以使用流化床造粒包衣机、流化床转动包衣机等。在片剂上形成被覆层时，可以使用锅包衣机、通气式包衣机等。包衣机中，在使颗粒剂、片剂流动的同时，对该颗粒剂、片剂喷雾该包衣液，干燥，形成被覆层。After the above-mentioned granules and tablets are prepared, the preparation of the present invention may be coated with a coating layer. When forming the coating layer on the granules, a fluidized bed granulation coating machine, a fluidized bed tumbling coating machine, etc. may be used. When forming the coating layer on the tablets, a pan coating machine, a ventilated coating machine, etc. may be used. In the coating machine, the granules and tablets are fluidized while the coating liquid is sprayed on the granules and tablets, and dried to form the coating layer.
(实施例)(Example)
以下，举出实施例和参考例、以及试验例，进一步详细说明本发明，但本发明不因它们而受到限定。Hereinafter, the present invention will be described in further detail with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto.
此外，本说明书中使用的缩写表示以下的含义。In addition, the abbreviations used in this specification have the following meanings.
Boc：叔丁氧基羰基Boc: tert-Butyloxycarbonyl
CDI：羰基二咪唑CDI: Carbonyldiimidazole
DBU：1,8-二氮杂双环[5.4.0]-7-十一碳烯DBU: 1,8-diazabicyclo[5.4.0]-7-undecene
DIEA：N,N-二异丙基乙基胺DIEA: N,N-diisopropylethylamine
DMA：N,N-二甲基乙酰胺DMA: N,N-dimethylacetamide
DMF：N,N-二甲基甲酰胺DMF: N,N-dimethylformamide
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
DTT：二硫代苏糖醇DTT: dithiothreitol
EDC：1-乙基-3-(3-二甲基氨基丙基)碳二亚胺EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EDT：1,2-乙烷二硫醇EDT: 1,2-Ethanedithiol
EDTA：乙二胺四乙酸EDTA: Ethylenediaminetetraacetic acid
FBS：胎牛血清FBS: Fetal bovine serum
HOBT：1-羟基苯并三唑HOBT: 1-Hydroxybenzotriazole
LHMDS：双(三甲基甲硅烷基)酰胺锂LHMDS: Lithium bis(trimethylsilyl)amide
MEM：伊格尔最小必要培养基MEM: Eagle's Minimum Essential Medium
NMP：N-甲基吡咯烷酮NMP: N-methylpyrrolidone
Pd(OAc)2：乙酸钯Pd(OAc)2 : Palladium acetate
TFA：三氟乙酸TFA: trifluoroacetic acid
TMSCl：氯三甲基硅烷TMSCl: Chlorotrimethylsilane
Xantphos：4,5'-双(二苯基膦基)-9,9'-二甲基氧杂蒽Xantphos: 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene
mM：mmol/LmM：mmol/L
μM：μmol/LμM: μmol/L
nM：nmol/LnM: nmol/L
(实施例a)(Example a)
(化合物的鉴定方法)(Method for identification of compounds)
各实施例中得到的NMR分析以400MHz进行，使用DMSO-d6、CDCl3、Methanol-d4测定。此外，示出NMR数据的情况下，存在未记载所测定的全部峰的情况。The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d6 , CDCl3 , and Methanol-d4. In addition, when NMR data are shown, all the peaks measured may not be described.
RT表示LC/MS：液相色谱/质谱中的保留时间，在以下的条件下测定。RT stands for retention time in LC/MS: liquid chromatography/mass spectrometry, and is measured under the following conditions.
(测定条件1')(Measurement Condition 1')
柱：ACQUITY UPLC(注册商标)BEH C18(1.7μm i.d.2.1x50mm)(Waters)Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters)
流速：0.8mL/分钟Flow rate: 0.8 mL/min
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为含0.1％甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid
梯度：以3.5分钟进行5％-100％溶剂[B]的线性梯度后，维持0.5分钟100％溶剂[B]。Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B].
(测定条件2')(Measurement Condition 2')
柱：Shim-pack XR-ODS(2.2μm、i.d.3.0x50mm)(Shimadzu)Column: Shim-pack XR-ODS (2.2μm, i.d.3.0x50mm) (Shimadzu)
流速：1.6mL/分钟Flow rate: 1.6mL/min
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为含0.1％甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid
梯度：以3分钟进行10％-100％溶剂[B]的线性梯度，维持0.5分钟100％溶剂[B]。Gradient: Linear gradient from 10% to 100% solvent [B] in 3 min, hold at 100% solvent [B] for 0.5 min.
应予说明，说明书中，MS(m/z)这一记载表示通过质谱观测的值。In addition, in this specification, the description "MS (m/z)" means a value observed by mass spectrometry.
(HPLC测定条件)(HPLC measurement conditions)
柱：Xselect CSH Fluoro-Phenyl(3.5μm i.d.4.6x150mm)(Waters)Column: Xselect CSH Fluoro-Phenyl (3.5μm i.d.4.6x150mm) (Waters)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：255nmUV detection wavelength: 255nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为液相色谱用乙腈Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography
梯度：维持2分钟20％溶剂[B]，以6分钟进行20％-37％溶剂[B]的线性梯度，以10分钟进行37％-50％溶剂[B]的线性梯度，以2分钟进行50％-95％溶剂[B]的线性梯度。Gradient: 20% solvent [B] for 2 minutes, linear gradient from 20% to 37% solvent [B] in 6 minutes, linear gradient from 37% to 50% solvent [B] in 10 minutes, linear gradient from 50% to 95% solvent [B] in 2 minutes.
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：10μLInjection volume: 10 μL
(粉末X射线衍射图案的测定)(Measurement of powder X-ray diffraction pattern)
按照日本药典的一般试验法中记载的粉末X射线衍射测定法，进行各实施例中得到的晶体的粉末X射线衍射测定。测定条件示于以下。The powder X-ray diffraction measurement of the crystals obtained in each example was performed according to the powder X-ray diffraction measurement method described in the General Test Methods of the Japanese Pharmacopoeia. The measurement conditions are shown below.
(装置)(Device)
リガク公司制SmartLabSmartLab manufactured by Rigaku Corporation
(操作方法)(Operation method)
测定方法：反射法Measurement method: Reflection method
使用波长：CuKα线Use wavelength: CuKα line
管电流：200mATube current: 200mA
管电压：45kVTube voltage: 45kV
试样板：铝Sample plate: Aluminum
X射线的入射角：2.5°X-ray incident angle: 2.5°
取样宽度：0.02°Sampling width: 0.02°
检测器：HyPix-3000(二维检测模式)Detector: HyPix-3000 (2D detection mode)
(差示扫描量热(DSC)的测定)(Differential Scanning Calorimetry (DSC) Measurement)
进行实施例中得到的晶体的DSC的测定。在铝坩埚中称量试样约3mg，压平测定。测定条件示于以下。应予说明，利用差示扫描量热(DSC)的测定可能在±2℃的范围内产生误差。The crystal obtained in the example was measured by DSC. About 3 mg of the sample was weighed in an aluminum crucible and flattened for measurement. The measurement conditions are shown below. It should be noted that the measurement using differential scanning calorimetry (DSC) may have an error within the range of ±2°C.
装置：TA Instrument Q1000/TA InstrumentDevice: TA Instrument Q1000/TA Instrument
测定温度范围：0℃-295℃Measuring temperature range: 0℃-295℃
升温速度：10℃/分钟Heating rate: 10℃/min
氛围：N2 50mL/分钟Atmosphere:N2 50mL/min
(TG/DTA数据的测定)(TG/DTA data measurement)
称量实施例中得到的晶体约3mg，填充在铝坩埚中，在开放系统中测定。测定条件如下所述。About 3 mg of the crystal obtained in Example was weighed, filled in an aluminum crucible, and measured in an open system. The measurement conditions are as follows.
装置：日立ハイテクノロジーズTG/DTA STA7200RVDevice: Hitachi Haikou TG/DTA STA7200RV
测定温度范围：室温-350℃Measurement temperature range: room temperature-350℃
升温速度：10℃/分钟Heating rate: 10℃/min
(水分吸脱附等温线测定)(Water adsorption and desorption isotherm measurement)
在样品坩埚中称取试样约15～25mg，进行测定。测定条件示于以下。About 15 to 25 mg of a sample was weighed into a sample crucible and measured. The measurement conditions are shown below.
装置：Surface Measurement Systems Ltd.公司制DVS AdventureDevice: DVS Adventure, manufactured by Surface Measurement Systems Ltd.
测定点：0％起每5％至95％RH，和95％RH起每5％至0％Measuring point: 0% every 5% to 95% RH, and 95% every 5% to 0% RH
温度：25℃Temperature: 25℃
(单晶结构分析的测定和分析方法)(Determination and analysis methods of single crystal structure analysis)
单晶结构分析的测定条件和分析方法示于以下。The measurement conditions and analysis method of the single crystal structure analysis are shown below.
(装置)(Device)
リガク公司制XtaLAB P200 MM007XtaLAB P200 MM007 manufactured by Rigaku Corporation
(测定条件)(Measurement conditions)
测定温度：25℃Measurement temperature: 25℃
使用波长：CuKα线Use wavelength: CuKα line
软件：CrysAlisPro 1.171.39.46e(Rigaku Oxford Diffraction,2018)Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
(数据处理)(Data Processing)
软件：CrysAlisPro 1.171.39.46e(Rigaku Oxford Diffraction,2018)Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
数据进行洛伦兹和偏振校正、吸收校正。The data were Lorentz and polarization corrected, and absorption corrected.
(晶体结构分析)(Crystal Structure Analysis)
使用直接法程序ShelXT(Sheldrick,G.M.,2015)进行相位确定，精修使用ShelXL(Sheldrick,G.M.,2015)，实施full-matrix最小二乘法。非氢原子的温度因子均以各向异性进行精修。氢原子使用ShelXL的默认参数通过计算导入，作为riding atom处理。全部氢原子以各向同性参数进行精修。Phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using ShelXL (Sheldrick, G.M., 2015), using the full-matrix least squares method. The temperature factors of non-hydrogen atoms were refined anisotropically. Hydrogen atoms were imported by calculation using the default parameters of ShelXL and treated as riding atoms. All hydrogen atoms were refined using isotropic parameters.
作图使用PLATON(Spek,1991)/ORTEP(Johnson,1976)。The graphics were constructed using PLATON (Spek, 1991)/ORTEP (Johnson, 1976).
(实施例1a)(Example 1a)
化合物(I-005)的合成Synthesis of compound (I-005)
【化33】【化33】
步骤1化合物18的合成Step 1 Synthesis of compound 18
将化合物4a(926mg、4.04mmol)、乙腈(7.41mL)、碳酸钾(726mg、5.25mmol)和2,4,5-三氟苯甲基溴(1000mg、4.44mmol)混合。将反应溶液在80℃下进行40分钟搅拌，放置冷却后，用乙酸乙酯稀释。滤除不溶物后，将滤液浓缩，得到化合物18的粗产物(1.51g、4.04mmol、收率：定量)。Compound 4a (926 mg, 4.04 mmol), 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°C for 40 minutes, left to cool, and then diluted with ethyl acetate. After filtering out the insoluble matter, the filtrate was concentrated to obtain a crude product of compound 18 (1.51 g, 4.04 mmol, yield: quantitative).
LC/MS(ESI)：m/z＝374、RT＝2.54min、LC/MS测定条件1'LC/MS (ESI): m/z = 374, RT = 2.54 min, LC/MS measurement conditions 1'
步骤2化合物19的合成Step 2 Synthesis of compound 19
将化合物18(1.51g、4.04mmol)和TFA(3.02mL)混合。将反应溶液在室温下进行4小时搅拌，静置过夜。将TFA减压馏去，向残渣添加甲苯，共沸。向残渣添加异丙基醚，悬浮后，滤取，得到化合物19(1.22g、3.84mmol、收率95％)。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, and toluene was added to the residue for azeotropy. Isopropyl ether was added to the residue, and after suspension, the residue was filtered to obtain compound 19 (1.22 g, 3.84 mmol, yield 95%).
LC/MS(ESI)：m/z＝318、RT＝1.68min、LC/MS测定条件1'LC/MS (ESI): m/z = 318, RT = 1.68 min, LC/MS measurement conditions 1'
步骤3化合物20的合成Step 3 Synthesis of compound 20
将化合物19(200mg、0.63mmol)、DMF(1.8mL)、碳酸钾(261mg、1.89mmol)和3-(氯甲基)-1-甲基-1H-1,2,4-三唑盐酸盐(159mg、0.946mmol)混合。将反应溶液在60℃下进行2小时搅拌，添加饱和氯化铵水溶液。将水层用乙酸乙酯萃取，将有机层用饱和食盐水洗涤。将有机层用硫酸镁干燥，过滤浓缩。将残渣用异丙基醚、己烷、乙酸乙酯和氯仿的混合溶剂悬浮，滤取。将残渣、DMF(1.8mL)、碳酸钾(261mg、1.89mmol)和3-(氯甲基)-1-甲基-1H-1,2,4-三唑盐酸盐(159mg、0.946mmol)混合。将反应溶液在60℃下进行6小时搅拌，添加饱和氯化铵水溶液。将水层用乙酸乙酯萃取，将有机层用饱和食盐水洗涤。将有机层用硫酸镁干燥，过滤浓缩。将残渣用异丙基醚、己烷、乙酸乙酯和氯仿的混合溶剂悬浮，滤取，得到化合物20(116mg、0.281mmol、收率45％)。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 (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60°C for 2 hours, and a saturated aqueous solution of ammonium chloride 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, DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol) and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60°C for 6 hours, and a saturated aqueous solution of ammonium chloride 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 obtain Compound 20 (116 mg, 0.281 mmol, yield 45%).
LC/MS(ESI)：m/z＝413、RT＝1.84min、LC/MS测定条件1'LC/MS (ESI): m/z = 413, RT = 1.84 min, LC/MS measurement conditions 1'
步骤4化合物(I-005)的合成Step 4 Synthesis of Compound (I-005)
将化合物20(115mg、0.279mmol)、THF(2.30mL)和6-氯-2-甲基-2H-吲唑-5-胺(60.8mg、0.335mmol)混合。向反应溶液中，在0℃下滴加LHMDS(558μL、0.558mmol)。将反应溶液在0℃下进行2.5小时、室温下进行40分钟搅拌，添加饱和氯化铵水溶液。用氯仿萃取，浓缩有机层。将残渣用硅胶柱色谱(氯仿/甲醇)纯化，得到化合物(I-005)(61.8mg、0.116mmol、收率42％)。所得化合物I-005的HPLC测定结果示于图7。Compound 20 (115 mg, 0.279 mmol), THF (2.30 mL) and 6-chloro-2-methyl-2H-indazole-5-amine (60.8 mg, 0.335 mmol) were mixed. LHMDS (558 μL, 0.558 mmol) was added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 2.5 hours and at room temperature for 40 minutes, and a saturated aqueous solution of ammonium chloride was added. The organic layer was concentrated after extraction with chloroform. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain compound (I-005) (61.8 mg, 0.116 mmol, yield 42%). The HPLC measurement results of the obtained compound I-005 are shown in Figure 7.
1H-NMR(CDCl3)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).1 H-NMR (CDCl3 ) 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＝1.70min、LC/MS测定条件1'LC/MS (ESI): m/z = 532, RT = 1.70 min, LC/MS measurement conditions 1'
(实施例2a)(Example 2a)
向化合物(I-005)1170mg中添加富马酸278mg(1.1eq)和乙酸乙酯5.85mL，在室温下进行45分钟搅拌。滤取固体，干燥，由此得到式(VII)所示的化合物的富马酸共晶体I形晶体(1369.4mg、94.6％)。To 1170 mg of compound (I-005) were added 278 mg (1.1 eq) of fumaric acid and 5.85 mL of ethyl acetate, and the mixture was stirred at room temperature for 45 minutes. The solid was filtered and dried to obtain fumaric acid cocrystal I form of the compound represented by formula (VII) (1369.4 mg, 94.6%).
式(VII)所示的化合物的富马酸共晶体I形的单晶结构分析的结果示于以下。The results of single crystal structural analysis of the fumaric acid cocrystal Form I of the compound represented by formula (VII) are shown below.
R1(I＞2.00s(I))为0.0470，由最终的差分傅里叶确认没有电子密度的缺失或误置。R1 (I＞2.00s(I)) was 0.0470, and the final difference Fourier analysis confirmed that there was no loss or misplacement of electron density.
晶体学的数据示于表1。The crystallographic data are shown in Table 1.
【表1】【Table 1】
在此，体积是指单位格子体积，Z是指单位晶格中的分子数。Here, volume refers to the unit lattice volume, and Z refers to the number of molecules in the unit lattice.
式(VII)所示的化合物的富马酸共晶体I形的非对称单元中的结构示于图3。The structure of the asymmetric unit of the fumaric acid cocrystal form I of the compound represented by formula (VII) is shown in FIG3 .
非对称单元中，式(VII)所示的化合物、富马酸各自存在1分子。未确认到离子性的化学相互作用，确认为1:1的摩尔比的共晶体。In the asymmetric unit, the compound represented by formula (VII) and fumaric acid were present in one molecule each. No ionic chemical interaction was confirmed, and a eutectic with a molar ratio of 1:1 was confirmed.
N10-C9的键距离为约N16-C9的键距离为约由该键距离，富马酸共晶体I形的式(VII)所示的化合物鉴定为亚氨基结构：The bond distance between N10 and C9 is about The bond distance between N16 and C9 is about Based on this bond distance, the compound represented by formula (VII) of fumaric acid cocrystal form I was identified as an imino structure:
【化34】【化34】
此外，示出式(VII)所示的化合物的富马酸共晶体I形晶体的粉末X射线衍射的结果。In addition, the results of powder X-ray diffraction of the fumaric acid cocrystal type I crystal of the compound represented by formula (VII) are shown.
图1中，示出式(VII)所示的化合物的富马酸共晶体I形(晶型I)的粉末X射线衍射图案。图1的粉末X射线衍射图案的峰表格示于图2。FIG1 shows a powder X-ray diffraction pattern of fumaric acid cocrystal form I (crystal form I) of the compound represented by formula (VII). FIG2 shows a peak table of the powder X-ray diffraction pattern of FIG1 .
粉末X射线衍射图案中，衍射角度(2θ)：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°和24.6±0.2°处确认到峰。In the powder X-ray diffraction pattern, peaks were confirmed at diffraction angles (2θ) of 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°.
上述粉末X射线衍射峰中，衍射角度(2θ)：9.5±0.2°、10.9±0.2°、18.6±0.2°、23.5±0.2°和24.6±0.2°的峰作为式(VII)所示的化合物的富马酸共晶体I形晶体是特别特征性的。Among the above-mentioned powder X-ray diffraction peaks, the peaks with diffraction angles (2θ): 9.5±0.2°, 10.9±0.2°, 18.6±0.2°, 23.5±0.2° and 24.6±0.2° are particularly characteristic of the fumaric acid cocrystal type I crystal of the compound represented by formula (VII).
示出图1的粉末X射线分析图案的式(VII)所示的化合物的富马酸共晶体I形晶体的DSC分析结果示于图4。吸热峰的起始温度示出约272℃。The DSC analysis results of the fumaric acid cocrystal I-form crystal of the compound represented by formula (VII) showing the powder X-ray analysis pattern of Fig. 1 are shown in Fig. 4. The onset temperature of the endothermic peak was about 272°C.
示出图1的粉末X射线分析图案的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的TG/DTA分析结果示于图5。FIG5 shows the TG/DTA analysis results of the fumaric acid cocrystal Form I (Crystal Form I) of the compound represented by Formula (VII), which shows the powder X-ray analysis pattern of FIG1 .
示出图1的粉末X射线分析图案的式(VII)所示的化合物的富马酸共晶体I形(晶型I)的DVS分析结果示于图6。FIG6 shows the DVS analysis results of the fumaric acid cocrystal Form I (Crystal Form I) of the compound represented by Formula (VII), which shows the powder X-ray analysis pattern of FIG1 .
应予说明，式(VII)所示的化合物(I-005)的合成也可以如下进行。In addition, the synthesis of the compound (I-005) represented by formula (VII) can also be carried out as follows.
步骤4'Step 4'
THF(6mL)中，在化合物20(300mg、0.727mmol)、6-氯-2-甲基-2H-吲唑-5-胺(172mg、0.946mmol)中，在0℃下滴加LHMDS(1M in THF；1.46mL、1.46mmol)。将反应液在0℃下进行2.5小时、室温下进行40分钟搅拌，添加饱和氯化铵水溶液。将水层用EtOAc萃取。将有机层用饱和食盐水洗涤，用硫酸镁干燥，在减压下浓缩。将残渣通过硅胶柱色谱(CHCl3/MeOH、梯度0-20％ MeOH)纯化。将所得固体从丙酮/H2O中固化，得到化合物I-005(95.3mg、收率25％、茶色固体)。所得化合物I-005的HPLC测定结果示于图8(约99pa％)。In THF (6 mL), LHMDS (1M in THF; 1.46 mL, 1.46 mmol) was added dropwise to compound 20 (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) at 0°C. The reaction solution was stirred at 0°C for 2.5 hours and at room temperature for 40 minutes, and a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with EtOAc. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH, gradient 0-20% MeOH). The obtained solid was solidified from acetone/H2O to obtain compound I-005 (95.3 mg, yield 25%, brown solid). The HPLC measurement results of the obtained compound I-005 are shown in Figure 8 (about 99 pa%).
此外，本说明书中使用的缩写表示以下的含义。In addition, the abbreviations used in this specification have the following meanings.
BINAP：2,2'-双(二苯基膦基)-1,1'-联萘BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
CPME：环戊基甲基醚CPME: Cyclopentyl Methyl Ether
CbzCl：氯甲酸苯甲酯CbzCl: Benzyl chloroformate
DME：二甲基醚DME: dimethyl ether
MEK：甲基乙基酮MEK: Methyl Ethyl Ketone
(实施例b)(Example b)
(化合物的鉴定方法)(Method for identification of compounds)
各实施例和参考例中得到的NMR分析以400MHz进行，使用DMSO-d6、CDCl3测定。此外，示出NMR数据的情况下，存在未记载所测定的全部峰的情况。The NMR analysis obtained in each of the Examples and Reference Examples was performed at 400 MHz using DMSO-d6 and CDCl3. When NMR data are shown, all the peaks measured may not be shown.
“RT”或“保持时间”是指表示LC/MS：液相色谱/质谱或液相色谱(HPLC)中的保留时间，在以下的条件下测定。"RT" or "retention time" refers to the retention time in LC/MS: liquid chromatography/mass spectrometry or liquid chromatography (HPLC), and is measured under the following conditions.
应予说明，MS(m/z)这一记载表示通过质谱观测的值。In addition, the description of MS (m/z) indicates the value observed by mass spectrometry.
(测定条件1)(Measurement Condition 1)
柱：ACQUITY UPLC(注册商标)BEH C18(1.7μm i.d.2.1x50mm)(Waters)Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters)
流速：0.8mL/分钟Flow rate: 0.8 mL/min
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为含0.1％甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid
梯度：以3.5分钟进行5％-100％溶剂[B]的线性梯度后，维持0.5分钟100％溶剂[B]。Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B].
(测定条件2)(Measurement Condition 2)
柱：ACQUITY UPLC(注册商标)BEH C18(1.7μm i.d.2.1x50mm)(Waters)Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters)
流速：0.8mL/分钟Flow rate: 0.8 mL/min
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含10mM碳酸铵的水溶液，[B]为含0.1％甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is an acetonitrile solution containing 0.1% formic acid
梯度：以3.5分钟进行5％-100％溶剂[B]的线性梯度后，维持0.5分钟100％溶剂[B]。Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B].
(测定条件4)(Measurement Condition 4)
柱：Xselect CSH C18(3.5μm i.d.4.6x150mm)(Waters)Column: Xselect CSH C18 (3.5μm i.d.4.6x150mm) (Waters)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为液相色谱用乙腈Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography
梯度：以17分钟进行5％-95％溶剂[B]的线性梯度后，维持3分钟95％溶剂[B]。Gradient: A linear gradient from 5% to 95% solvent [B] in 17 minutes, followed by a 3-minute hold at 95% solvent [B].
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：5μLInjection volume: 5μL
(测定条件5)(Measurement Condition 5)
柱：Xselect CSH C18(3.5μm i.d.4.6x150mm)(Waters)Column: Xselect CSH C18 (3.5μm i.d.4.6x150mm) (Waters)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为液相色谱用乙腈Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography
梯度：以17分钟进行5％-95％溶剂[B]的线性梯度后，维持3分钟95％溶剂[B]。Gradient: A linear gradient from 5% to 95% solvent [B] in 17 minutes, followed by a 3-minute hold at 95% solvent [B].
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：10μLInjection volume: 10 μL
(测定条件7)(Measurement Condition 7)
柱：Xselect CSH Fluoro-Phenyl(3.5μm i.d.4.6x150mm)(Waters)Column: Xselect CSH Fluoro-Phenyl (3.5μm i.d.4.6x150mm) (Waters)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：255nmUV detection wavelength: 255nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为液相色谱用乙腈Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography
梯度：维持6分钟20％溶剂[B]，以21分钟进行20％-42％溶剂[B]的线性梯度，以4分钟进行42％-50％溶剂[B]的线性梯度，最后以3分钟进行50％-95％溶剂[B]的线性梯度。Gradient: 20% solvent [B] for 6 minutes, a linear gradient from 20% to 42% solvent [B] in 21 minutes, a linear gradient from 42% to 50% solvent [B] in 4 minutes, and finally a linear gradient from 50% to 95% solvent [B] in 3 minutes.
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：10μLInjection volume: 10 μL
(测定条件8)(Measurement Condition 8)
柱：Xselect CSH Fluoro-Phenyl(3.5μm i.d.4.6x150mm)(Waters)Column: Xselect CSH Fluoro-Phenyl (3.5μm i.d.4.6x150mm) (Waters)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：255nmUV detection wavelength: 255nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为液相色谱用乙腈Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography
梯度：维持2分钟20％溶剂[B]，以6分钟进行20％-37％溶剂[B]的线性梯度，以10分钟进行37％-50％溶剂[B]的线性梯度，以2分钟进行50％-95％溶剂[B]的线性梯度。Gradient: 20% solvent [B] for 2 minutes, linear gradient from 20% to 37% solvent [B] in 6 minutes, linear gradient from 37% to 50% solvent [B] in 10 minutes, linear gradient from 50% to 95% solvent [B] in 2 minutes.
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：10μLInjection volume: 10 μL
(测定条件9)(Measurement Condition 9)
柱：YMC Jsphere ODS-H80(4μm i.d.4.6x250mm)Column: YMC Jsphere ODS-H80 (4μm i.d.4.6x250mm)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：250nmUV detection wavelength: 250nm
流动相：[A]为含0.2％三氟乙酸的水溶液，[B]为液相色谱用甲醇Mobile phase: [A] is an aqueous solution containing 0.2% trifluoroacetic acid, [B] is methanol for liquid chromatography
梯度：以6分钟进行10％-70％溶剂[B]的线性梯度后，维持3分钟70％溶剂[B]，其后以3分钟进行70％-90％的线性梯度，其后维持5分钟90％溶剂[B]，其后以1分钟进行90％-95％的线性梯度，其后维持5分钟95％溶剂[B]Gradient: 10%-70% solvent [B] linear gradient in 6 minutes, then 70% solvent [B] for 3 minutes, then 70% solvent [B] linear gradient in 3 minutes, then 90% solvent [B] for 5 minutes, then 90%-95% linear gradient in 1 minute, then 95% solvent [B] for 5 minutes
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：5μLInjection volume: 5μL
(测定条件10)(Measurement Condition 10)
柱：Xselect CSH C18(3.5μm i.d.4.6x150mm)Column: Xselect CSH C18 (3.5 μm i.d. 4.6 x 150 mm)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：254nmUV detection wavelength: 254nm
流动相：[A]为含0.1％甲酸的水溶液，[B]为液相色谱用乙腈Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography
梯度：以17分钟进行5％-95％溶剂[B]的线性梯度后，维持3分钟95％溶剂[B]。Gradient: A linear gradient from 5% to 95% solvent [B] in 17 minutes, followed by a 3-minute hold at 95% solvent [B].
流量：1.0mL/分钟Flow rate: 1.0mL/min
注入量：10μLInjection volume: 10 μL
(测定条件11)(Measurement Condition 11)
柱：XBridge C18(3.5μm i.d.4.6x150mm)Column: XBridge C18 (3.5μm i.d. 4.6x150mm)
柱温度：40℃附近的恒定温度Column temperature: Constant temperature around 40°C
UV检测波长：210nmUV detection wavelength: 210nm
流动相：[A]为含10mM氨的水溶液，[B]为液相色谱用甲醇Mobile phase: [A] is an aqueous solution containing 10 mM ammonia, [B] is methanol for liquid chromatography
梯度：以5分钟维持5％溶剂[B]，以10分钟进行5％-38％溶剂[B]的线性梯度，以5分钟进行38％-95％溶剂[B]的线性梯度。Gradient: 5% solvent [B] was maintained for 5 minutes, a linear gradient from 5% to 38% solvent [B] was performed in 10 minutes, and a linear gradient from 38% to 95% solvent [B] was performed in 5 minutes.
流量：0.8mL/分钟Flow rate: 0.8mL/min
注入量：10μLInjection volume: 10 μL
(测定条件12)(Measurement Condition 12)
柱：C18柱Column: C18 column
柱温度：40℃Column temperature: 40°C
UV检测波长：255nmUV detection wavelength: 255nm
流动相：[A]为含10mM甲酸氨的水溶液，[B]为液相色谱用甲醇Mobile phase: [A] is an aqueous solution containing 10 mM ammonium formate, [B] is methanol for liquid chromatography
梯度将流动相B的混合比从9:1缓慢提高至1:9，以28分钟进行测定。The mixing ratio of mobile phase B was gradually increased from 9:1 to 1:9 in the gradient, and the measurement was performed over 28 minutes.
流量：0.3mL/分钟Flow rate: 0.3mL/min
注入量：4μLInjection volume: 4 μL
(粉末X射线衍射图案的测定)(Measurement of powder X-ray diffraction pattern)
按照日本药典的一般试验法中记载的粉末X射线衍射测定法，进行各实施例中得到的晶体的粉末X射线衍射测定。测定条件示于以下。(装置)The powder X-ray diffraction measurement of the crystals obtained in each example was performed according to the powder X-ray diffraction measurement method described in the General Test Methods of the Japanese Pharmacopoeia. The measurement conditions are shown below. (Apparatus)
リガク公司制MiniFlex600MiniFlex600 manufactured by Rigaku Corporation
(操作方法)(Operation method)
检测器：高速一维检测器(D/TecUltra2)Detector: High-speed one-dimensional detector (D/TecUltra2)
光源的种类：Cu管球Type of light source: Cu tube ball
使用波长：CuKα线Use wavelength: CuKα line
管电流：15mATube current: 15mA
管电压：40KvTube voltage: 40Kv
试样板：无反射试样板Sample plate: non-reflective sample plate
(单晶结构分析的测定和分析方法)(Determination and analysis methods of single crystal structure analysis)
单晶结构分析的测定条件和分析方法示于以下。The measurement conditions and analysis method of the single crystal structure analysis are shown below.
(装置)(Device)
リガク公司制XtaLAB P200 MM007XtaLAB P200 MM007 manufactured by Rigaku Corporation
(测定条件)(Measurement conditions)
测定温度：25℃Measurement temperature: 25℃
使用波长：CuKα线Use wavelength: CuKα line
软件：CrysAlisPro 1.171.39.46e(Rigaku Oxford Diffraction,2018)Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
(数据处理)(Data Processing)
软件：CrysAlisPro 1.171.39.46e(Rigaku Oxford Diffraction,2018)Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
数据进行洛伦兹和偏振校正、吸收校正。The data were Lorentz and polarization corrected, and absorption corrected.
(晶体结构分析)(Crystal Structure Analysis)
使用直接法程序ShelXT(Sheldrick,G.M.,2015)进行相位确定，精修使用ShelXL(Sheldrick,G.M.,2015)，实施full-matrix最小二乘法。非氢原子的温度因子均以各向异性进行精修。氢原子使用ShelXL的默认参数通过计算导入，作为riding atom处理。全部氢原子以各向同性参数进行精修。Phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using ShelXL (Sheldrick, G.M., 2015), using the full-matrix least squares method. The temperature factors of non-hydrogen atoms were refined anisotropically. Hydrogen atoms were imported by calculation using the default parameters of ShelXL and treated as riding atoms. All hydrogen atoms were refined using isotropic parameters.
作图使用PLATON(Spek,1991)/ORTEP(Johnson,1976)。The graphics were constructed using PLATON (Spek, 1991)/ORTEP (Johnson, 1976).
(差示扫描量热(DSC)的测定)(Differential Scanning Calorimetry (DSC) Measurement)
进行实施例中得到的晶体的DSC的测定。在SUS制坩埚中称量试样约2mg，压平测定。测定条件示于以下。应予说明，利用差示扫描量热(DSC)的测定可能在±2℃的范围内产生误差。The crystal obtained in the example was measured by DSC. About 2 mg of the sample was weighed in a SUS crucible and flattened for measurement. The measurement conditions are shown below. It should be noted that the measurement by differential scanning calorimetry (DSC) may have an error within the range of ±2°C.
装置：DSC 3+Device:DSC 3+
测定温度范围：30℃-300℃Measuring temperature range: 30℃-300℃
升温速度：10℃/分钟Heating rate: 10℃/min
氛围：N2 40mL/分钟Atmosphere: N2 40mL/min
(TG/DTA数据的测定)(TG/DTA data measurement)
称量实施例中得到的晶体约3mg，填充在铝坩埚中，在开放系统中测定。测定条件如下所述。About 3 mg of the crystal obtained in Example was weighed, filled in an aluminum crucible, and measured in an open system. The measurement conditions are as follows.
装置：日立ハイテクサイエンスTG/DTA7200Device: Hitachi Hakashi TG/DTA7200
测定温度范围：30-350℃Measuring temperature range: 30-350℃
升温速度：10℃/分钟Heating rate: 10℃/min
(水分吸脱附等温线测定)(Water adsorption and desorption isotherm measurement)
在样品坩埚中称取试样约15～25mg，进行测定。测定条件示于以下。About 15 to 25 mg of a sample was weighed into a sample crucible and measured. The measurement conditions are shown below.
装置：Surface Measurement Systems Ltd.公司制DVS AdventureDevice: DVS Adventure, manufactured by Surface Measurement Systems Ltd.
测定点：0％起每5％至95％RH，和95％RH起每5％至0％Measuring point: 0% every 5% to 95% RH, and 95% every 5% to 0% RH
温度：25℃Temperature: 25℃
应予说明，DVS测定的前后的粉末X射线分析图案的比较通过以下的方法测定。In addition, the comparison of the powder X-ray analysis patterns before and after the DVS measurement was measured by the following method.
(装置)(Device)
リガク公司制SmartLabSmartLab manufactured by Rigaku Corporation
(操作方法)(Operation method)
测定方法：反射法Measurement method: Reflection method
使用波长：CuKα线Use wavelength: CuKα line
管电流：200mATube current: 200mA
管电压：45kVTube voltage: 45kV
试样板：铝Sample plate: Aluminum
X射线的入射角：2.5°X-ray incident angle: 2.5°
取样宽度：0.02°Sampling width: 0.02°
检测器：HyPix-3000(二维检测模式)Detector: HyPix-3000 (2D detection mode)
(粒度分布的测定)(Determination of particle size distribution)
测定条件如下所述。The measurement conditions are as follows.
制造商：シンパテックManufacturer: シンパテック
装置：激光衍射式HELOS&RODOS粒度分布测定装置Device: Laser diffraction HELOS & RODOS particle size distribution measuring device
范围：R4Range: R4
分散压力：3barDispersion pressure: 3 bar
触发条件：截止2s测定浓度≤1％或10s实际时间Trigger condition: Cut-off 2s measured concentration ≤ 1% or 10s actual time
(实施例1b)(Example 1b)
式(VII)所示的化合物的富马酸共晶体I形的合成Synthesis of Fumaric Acid Cocrystal Form I of the Compound Represented by Formula (VII)
【化35】【Chemistry 35】
步骤1：化合物3的合成Step 1: Synthesis of compound 3
将化合物1(35.0kg、238.8mol、盐酸盐)、N,N-二甲基乙酰胺(273L)、1,8-二氮杂双环[5,4,0]-7-十一碳烯(87.2kg、573.1mol)和化合物2(26.0kg、262.7mol)混合，在25℃下进行10分钟搅拌。在反应溶液中缓和N,N'-羰基二咪唑(50.3kg、310.4mol)、N,N-二甲基乙酰胺(7L)，在50℃下进行90分钟搅拌。在反应溶液中添加甲醇(18.4kg、573.1mol)，冷却至25℃，用10％硫酸将pH调整至2.5。将浆料冷却至5℃，滤取固体，用20％甲醇水洗涤后，干燥，由此得到化合物3(38.12kg、162.0mol、收率：67.9％)。Compound 1 (35.0 kg, 238.8 mol, hydrochloride), N,N-dimethylacetamide (273 L), 1,8-diazabicyclo[5,4,0]-7-undecene (87.2 kg, 573.1 mol) and compound 2 (26.0 kg, 262.7 mol) were mixed and stirred at 25°C for 10 minutes. N,N'-carbonyldiimidazole (50.3 kg, 310.4 mol) and N,N-dimethylacetamide (7 L) were added to the reaction solution and stirred at 50°C for 90 minutes. Methanol (18.4 kg, 573.1 mol) was added to the reaction solution, cooled to 25°C, and the pH was adjusted to 2.5 with 10% sulfuric acid. The slurry was cooled to 5°C, the solid was filtered, washed with 20% methanol water, and dried to obtain compound 3 (38.12 kg, 162.0 mol, yield: 67.9%).
HPLC(UV＝254nm)：RT＝8.9min、HPLC测定条件4HPLC (UV = 254 nm): RT = 8.9 min, HPLC determination conditions 4
步骤2：化合物5的合成Step 2: Synthesis of compound 5
将化合物3(34.5kg、146.7mol)、乙腈(345L)、二异丙基乙基胺(26.5kg、205.4mol)和化合物4(39.6kg、176.0mol)混合，在60℃下进行300分钟搅拌。将反应溶液冷却至25℃，添加水(172.5L)。将浆料冷却至0℃，滤取固体，用66％乙腈水洗涤后，干燥，由此得到化合物5(46.10kg、121.5mol、收率：82.9％)。Compound 3 (34.5 kg, 146.7 mol), acetonitrile (345 L), diisopropylethylamine (26.5 kg, 205.4 mol) and compound 4 (39.6 kg, 176.0 mol) were mixed and stirred at 60°C for 300 minutes. The reaction solution was cooled to 25°C and water (172.5 L) was added. The slurry was cooled to 0°C, the solid was filtered, washed with 66% acetonitrile water, and dried to obtain compound 5 (46.10 kg, 121.5 mol, yield: 82.9%).
HPLC(UV＝254nm)：RT＝14.7min、HPLC测定条件4HPLC (UV = 254 nm): RT = 14.7 min, HPLC determination conditions 4
步骤3：化合物7的合成Step 3: Synthesis of compound 7
将化合物5(29.0kg、76.4mol)、三氟乙酸(72.5L)、化合物6(16.5kg、152.9mol)混合，在35℃下进行180分钟搅拌。将反应溶液冷却，添加乙酸乙酯(348L)，用38％磷酸三钾水溶液、2.3％食盐水、水洗涤。将乙酸乙酯溶液浓缩至203L，添加庚烷(261L)。将浆料冷却至0℃，滤取固体，用乙酸乙酯和庚烷的混合溶剂洗涤后，干燥，由此得到化合物7(23.60kg、65.0mol、收率：85.0％)。Compound 5 (29.0 kg, 76.4 mol), trifluoroacetic acid (72.5 L), and compound 6 (16.5 kg, 152.9 mol) were mixed and stirred at 35 ° C for 180 minutes. The reaction solution was cooled, ethyl acetate (348 L) was added, and washed with 38% tripotassium phosphate aqueous solution, 2.3% saline, and water. The ethyl acetate solution was concentrated to 203 L, and heptane (261 L) was added. The slurry was cooled to 0 ° C, the solid was filtered, washed with a mixed solvent of ethyl acetate and heptane, and dried to obtain compound 7 (23.60 kg, 65.0 mol, yield: 85.0%).
HPLC(UV＝254nm)：RT＝12.5min、HPLC测定条件5HPLC (UV = 254 nm): RT = 12.5 min, HPLC determination conditions 5
步骤4：化合物9的合成Step 4: Synthesis of compound 9
将化合物7(23.3kg、64.1mol)、化合物8(14.0kg、83.4mol、盐酸盐)、碘化钾(6.4kg、38.5mol)、碳酸铯(31.3kg、96.2mol)和N,N-二甲基乙酰胺(139.8L)混合，在40℃下进行360分钟搅拌。将反应溶液冷却至25℃，添加乙酸(34.6kg、577.2mol)。滤取不溶物，在滤液中添加乙腈(93.2L)、水(326.2L)。将浆料冷却至0℃，滤取固体，用20％乙腈水溶液洗涤后，干燥，由此得到化合物9(20.35kg、44.4mol、收率：69.2％)。Compound 7 (23.3 kg, 64.1 mol), compound 8 (14.0 kg, 83.4 mol, hydrochloride), potassium iodide (6.4 kg, 38.5 mol), cesium carbonate (31.3 kg, 96.2 mol) and N, N-dimethylacetamide (139.8 L) were mixed and stirred at 40 ° C for 360 minutes. The reaction solution was cooled to 25 ° C, and acetic acid (34.6 kg, 577.2 mol) was added. The insoluble matter was filtered out, and acetonitrile (93.2 L) and water (326.2 L) were added to the filtrate. The slurry was cooled to 0 ° C, the solid was filtered out, washed with 20% acetonitrile aqueous solution, and dried to obtain compound 9 (20.35 kg, 44.4 mol, yield: 69.2%).
HPLC(UV＝255nm)：RT＝25.1min、HPLC测定条件7HPLC (UV = 255 nm): RT = 25.1 min, HPLC determination conditions 7
针对步骤1～4，进行2次同样的操作。Repeat steps 1 to 4 twice.
步骤5-1：式(VII)所示的化合物的富马酸共晶体I形的合成Step 5-1: Synthesis of Fumaric Acid Cocrystal Form I of the Compound Represented by Formula (VII)
将步骤1～4中得到的化合物9(39.0kg、80.7mol)、化合物10(16.2kg、84.8mol)、乙酸(30.7kg、484.3mol)和甲苯(234L)混合，在100℃下进行360分钟搅拌。添加甲苯(390L)，将所得浆料冷却至25℃。滤取固体，用丙酮洗涤，得到式(VII)所示的化合物的未干晶体(在此得到的未干晶体通过HPLC测定条件8测定的结果示于图12和图13。RT＝9.8min的峰为甲苯)。Compound 9 (39.0 kg, 80.7 mol), compound 10 (16.2 kg, 84.8 mol), acetic acid (30.7 kg, 484.3 mol) and toluene (234 L) obtained in steps 1 to 4 were mixed and stirred at 100° C. for 360 minutes. Toluene (390 L) was added and the resulting slurry was cooled to 25° C. The solid was filtered and washed with acetone to obtain undried crystals of the compound represented by formula (VII) (the undried crystals obtained here were measured by HPLC under condition 8 and the results are shown in Figures 12 and 13. The peak at RT=9.8 min is toluene).
步骤5-2：在所得式(VII)所示的化合物的一半量的未干晶体中添加丙酮(613.5L)和水(109.2L)，在50℃下溶解。将所得溶解液进行活性炭处理，在处理液中添加丙酮(150.2L)和水(5.9L)，浓缩至702L。将浓缩液温度调节至50℃，添加富马酸(4.6kg、72.6mol)、丙酮(150.2L)、水(5.9L)，浓缩至464L。在浓缩液中添加丙酮(78L)，浓缩至265L，添加丙酮(19.5L)。将浆料温度调节至55℃，进行120分钟以上搅拌。将浆料冷却至0℃，滤取固体，用丙酮洗涤后，干燥(在此得到的干燥晶体的DSC、TG/DTA、HPLC、粒度分布、DVS测定的结果示于图14～18。HPLC通过测定条件12测定。图19示出该DVS测定的前后的粉末X射线分析图案的比较)。Step 5-2: Acetone (613.5 L) and water (109.2 L) were added to half the amount of the undried crystals of the compound represented by the obtained formula (VII), and dissolved at 50°C. The obtained solution was treated with activated carbon, and acetone (150.2 L) and water (5.9 L) were added to the treated solution, and concentrated to 702 L. The temperature of the concentrated solution was adjusted to 50°C, and fumaric acid (4.6 kg, 72.6 mol), acetone (150.2 L), and water (5.9 L) were added, and concentrated to 464 L. Acetone (78 L) was added to the concentrated solution, concentrated to 265 L, and acetone (19.5 L) was added. The slurry temperature was adjusted to 55°C, and stirred for more than 120 minutes. The slurry was cooled to 0°C, the solid was filtered out, washed with acetone, and then dried (the results of DSC, TG/DTA, HPLC, particle size distribution, and DVS measurements of the dried crystals obtained are shown in Figures 14 to 18. HPLC was measured under measurement condition 12. Figure 19 shows a comparison of the powder X-ray analysis patterns before and after the DVS measurement).
同样的操作针对其余一半量也反复进行，由此得到式(VII)所示的化合物的富马酸共晶体I形(41.68kg、64.3mol、收率：75.6％)。The same operation was repeated for the remaining half amount, thereby obtaining fumaric acid cocrystal Form I of the compound represented by formula (VII) (41.68 kg, 64.3 mol, yield: 75.6%).
HPLC(UV＝255nm)：RT＝12.8min、HPLC测定条件8HPLC (UV = 255 nm): RT = 12.8 min, HPLC determination conditions 8
(实施例2b)(Example 2b)
式(VII)所示的化合物的甲苯化物的合成Synthesis of toluene compounds represented by formula (VII)
步骤1Step 1
将化合物9(150mg,0.327mmol)和化合物10(65.4mg,0.360mmol)与甲苯(1.5mL)和乙酸(0.187ml,3.27mmol)混合，在100℃下进行9小时搅拌。冷却至室温后，添加庚烷(1.5mL,10V)并过滤，将所得晶体用庚烷(0.7mL)洗涤3次。进行减压干燥，得到式(VII)所示的化合物的晶体(168mg、收率87％)。所得晶体中，包含0.5至0.6分子当量的甲苯作为溶剂化物，在通常操作范围的减压干燥下，未去除甲苯。确认到获得品质良好的式(VII)所示的化合物的甲苯化物。Compound 9 (150 mg, 0.327 mmol) and compound 10 (65.4 mg, 0.360 mmol) were mixed with toluene (1.5 mL) and acetic acid (0.187 ml, 3.27 mmol) and stirred at 100 ° C for 9 hours. After cooling to room temperature, heptane (1.5 mL, 10 V) was added and filtered, and the resulting crystals were washed 3 times with heptane (0.7 mL). The crystals were dried under reduced pressure to obtain crystals of the compound shown in formula (VII) (168 mg, yield 87%). The resulting crystals contained 0.5 to 0.6 molecular equivalents of toluene as a solvate, and toluene was not removed under reduced pressure drying within the normal operating range. It was confirmed that a toluene compound of the compound shown in formula (VII) with good quality was obtained.
1H-NMR(400MHz,CDCl3)δppm：7.93(s,1H),7.70(d,J＝2.57Hz,2H),7.62(brs,1H),7.35-7,45(m,1H),7.07(m,1H),6.92-6.97(td,J＝9.63,6.42,1H),5.34(s,2H),5.14(s,2H),4.20(s,3H),3.87(s,2H).1H-NMR (400MHz, CDCl3 ) δppm: 7.93 (s, 1H), 7.70 (d, J = 2.57Hz, 2H), 7.62 (brs, 1H), 7.35-7, 45 (m, 1H), 7.07 ( m,1H),6.92-6.97(td,J=9.63,6.42,1H),5.34(s,2H),5.14(s,2H),4.20(s,3H),3.87(s,2H).
7.14-7.27ppm,2.35ppm处，确认到相当于甲苯0.5分子至0.6分子的峰。At 7.14-7.27 ppm and 2.35 ppm, peaks corresponding to 0.5 to 0.6 molecules of toluene were confirmed.
参考例1化合物S-4的合成Reference Example 1 Synthesis of Compound S-4
【化36】【化36】
步骤1：化合物S-2的合成Step 1: Synthesis of compound S-2
将化合物S-1(5.50kg、29.5mol)、乙腈(21.7kg)和冰醋酸(115.00kg)混合，冷却至5℃。添加17％亚硝酸钠水溶液(13.03kg)，进行1小时搅拌，升温至25℃后，进行1.5小时搅拌。滤取不溶物，用乙腈(21.7kg)、四氢呋喃(49.0kg)洗涤不溶物。在收集的滤液中添加水(460L)。将浆料冷却至0℃，滤取固体，用水洗涤后，干燥，由此得到化合物S-2(3.75kg、19.0mol、收率：64.4％)。Compound S-1 (5.50 kg, 29.5 mol), acetonitrile (21.7 kg) and glacial acetic acid (115.00 kg) were mixed and cooled to 5°C. A 17% aqueous sodium nitrite solution (13.03 kg) was added, stirred for 1 hour, and after the temperature was raised to 25°C, stirred for 1.5 hours. The insoluble matter was filtered out and washed with acetonitrile (21.7 kg) and tetrahydrofuran (49.0 kg). Water (460 L) was added to the collected filtrate. The slurry was cooled to 0°C, the solid was filtered out, washed with water, and dried to obtain compound S-2 (3.75 kg, 19.0 mol, yield: 64.4%).
LC/MS(ESI)：m/z＝196(M-H)、RT＝11.8min、LC/MS测定条件4LC/MS (ESI): m/z = 196 (M-H), RT = 11.8 min, LC/MS measurement conditions 4
步骤2：化合物S-3的合成Step 2: Synthesis of compound S-3
将化合物S-2(3.25kg、16.4mol)和乙酸乙酯(58.7kg)混合，添加三甲基氧鎓四氟硼酸盐(2.09kg、14.1mol)，在25℃下进行7小时搅拌。在该反应液中，添加乙酸乙酯(29.5kg)、甲醇(10.3kg)的混合液。将该混合液添加至5％碳酸钠水溶液(66.3kg)，分离为有机层与水层。将有机层用5％氯化钠水溶液(65.8kg)洗涤2次，活性炭处理，浓缩至42kg。添加四氢呋喃(87.0kg)，浓缩至23kg，将上述操作反复进行2次，进一步添加四氢呋喃(87.0kg)，浓缩至18.9kg，升温至33℃。在该混合液中添加庚烷(47.0kg)。将浆料冷却至0℃，滤取固体，用四氢呋喃、庚烷的混合液洗涤后，干燥，由此得到化合物S-3(1.68kg、7.9mol,收率：48.2％)。Compound S-2 (3.25 kg, 16.4 mol) and ethyl acetate (58.7 kg) were mixed, trimethyloxonium tetrafluoroborate (2.09 kg, 14.1 mol) was added, and the mixture was stirred at 25°C for 7 hours. A mixed solution of ethyl acetate (29.5 kg) and methanol (10.3 kg) was added to the reaction solution. The mixed solution was added to a 5% aqueous sodium carbonate solution (66.3 kg) and separated into an organic layer and an aqueous layer. The organic layer was washed twice with a 5% aqueous sodium chloride solution (65.8 kg), treated with activated carbon, and concentrated to 42 kg. Tetrahydrofuran (87.0 kg) was added and concentrated to 23 kg. The above operation was repeated twice, and tetrahydrofuran (87.0 kg) was further added, concentrated to 18.9 kg, and the temperature was raised to 33°C. Heptane (47.0 kg) was added to the mixed solution. The slurry was cooled to 0°C, and the solid was collected by filtration, washed with a mixed solution of tetrahydrofuran and heptane, and then dried to obtain compound S-3 (1.68 kg, 7.9 mol, yield: 48.2%).
LC/MS(ESI)：m/z＝212(M+H)、253(M+CH3CN+H)RT＝12.4min、LC/MS测定条件4LC/MS (ESI): m/z = 212 (M+H), 253 (M+CH3 CN+H) RT = 12.4 min, LC/MS measurement conditions 4
步骤3：化合物S-4的合成Step 3: Synthesis of compound S-4
将化合物S-3(1040g、4.9mol)、10％钯碳(PE型、含水)(523g、0.25mol)和乙酸乙酯(8.99kg)混合，添加肼一水合物(504g、10.1mol)，在35℃下进行3小时搅拌。滤取10％钯碳，用水(1560g)、乙酸乙酯(9.00kg)洗涤10％钯碳。在收集的滤液中添加2mol/L盐酸(750g)，分离为有机层和水层。将所得水层用乙酸乙酯(4.69kg)萃取。将有机层合并，进行活性炭处理，浓缩至11.09kg。在该浓缩液中添加4mol/L氯化氢·乙酸乙酯溶液(1124g)。滤取固体，用乙酸乙酯洗涤后，干燥，由此得到化合物S-4(0.84kg、3.9mol、收率：78.5％)。Compound S-3 (1040 g, 4.9 mol), 10% palladium carbon (PE type, containing water) (523 g, 0.25 mol) and ethyl acetate (8.99 kg) were mixed, hydrazine monohydrate (504 g, 10.1 mol) was added, and the mixture was stirred at 35°C for 3 hours. 10% palladium carbon was filtered out, and the 10% palladium carbon was washed with water (1560 g) and ethyl acetate (9.00 kg). 2 mol/L hydrochloric acid (750 g) was added to the collected filtrate, and the mixture was separated into an organic layer and an aqueous layer. The obtained aqueous layer was extracted with ethyl acetate (4.69 kg). The organic layers were combined, treated with activated carbon, and concentrated to 11.09 kg. 4 mol/L hydrogen chloride·ethyl acetate solution (1124 g) was added to the concentrated solution. The solid was filtered out, washed with ethyl acetate, and dried to obtain compound S-4 (0.84 kg, 3.9 mol, yield: 78.5%).
LC/MS(ESI)：m/z＝182(M+H)、223(M+CH3CN+H)RT＝6.6min、LC/MS(ESI): m/z=182(M+H), 223(M+CH3 CN+H) RT=6.6min,
LC/MS测定条件4LC/MS assay conditions 4
氯浓度(离子色谱)：16.74％Chlorine concentration (ion chromatography): 16.74%
参考例2化合物A-3的合成Reference Example 2 Synthesis of Compound A-3
【化37】【化37】
步骤1：化合物A-2的二氯甲烷溶液的合成Step 1: Synthesis of dichloromethane solution of compound A-2
将化合物A-1(9.2kg,65.1mol)和四氢呋喃(64L)混合，冷却至0℃，制成浆料。在其中，在内温保持为8℃以下的同时，耗费60分钟滴加氢化双(2-甲氧基)铝钠(Red-AL)/甲苯溶液(65wt％)(26.4kg,84.9mol)和四氢呋喃(28L)混合得到的Red-AL/四氢呋喃溶液。其后，在0℃～5℃下进行30分钟搅拌。对该反应液，耗费30分钟滴加丙酮(4.9kg,84.3mol)，升温至25℃。在另一反应器中，准备酒石酸钾钠·4水合物(46kg,163mol)和四氢呋喃(138L)混合得到的浆料，耗费30分钟滴加先前的Red-AL还原用丙酮淬灭得到的反应液(该过程中内温达到40℃附近)。以2小时在40℃下持续搅拌后，冷却至25℃。添加水(2.5kg)并搅拌后，进行抽滤，将所得滤液减压浓缩至35kg(28L)。将滤液(28L)3等分，针对第一份添加甲苯(2.6kg)，进行减压浓缩，将上述操作反复进行8次后，最终浓缩干固。在浓缩干固的产物中添加二氯甲烷(13.5kg)，制成产物A-2的二氯甲烷溶液。同样的操作针对第二份、第三份也实施，制备由A-2(5.53kg)和二氯甲烷(42.7kg)构成的A-2/二氯甲烷溶液(收率：74.8％)。Compound A-1 (9.2 kg, 65.1 mol) and tetrahydrofuran (64 L) were mixed and cooled to 0°C to prepare a slurry. While the internal temperature was kept below 8°C, a Red-AL/tetrahydrofuran solution obtained by mixing sodium bis(2-methoxy)aluminum hydroxide (Red-AL)/toluene solution (65 wt%) (26.4 kg, 84.9 mol) and tetrahydrofuran (28 L) was added dropwise over 60 minutes. Thereafter, stirring was performed at 0°C to 5°C for 30 minutes. Acetone (4.9 kg, 84.3 mol) was added dropwise to the reaction solution over 30 minutes, and the temperature was raised to 25°C. In another reactor, a slurry obtained by mixing potassium sodium tartrate · 4 hydrate (46 kg, 163 mol) and tetrahydrofuran (138 L) was prepared, and the reaction solution obtained by quenching the previous Red-AL reduction with acetone was added dropwise over 30 minutes (the internal temperature reached around 40°C during this process). After continuous stirring at 40°C for 2 hours, cool to 25°C. After adding water (2.5kg) and stirring, filter and concentrate the obtained filtrate under reduced pressure to 35kg (28L). Divide the filtrate (28L) into three equal parts, add toluene (2.6kg) to the first part, and concentrate under reduced pressure. Repeat the above operation 8 times and finally concentrate to dryness. Add dichloromethane (13.5kg) to the concentrated product to prepare a dichloromethane solution of product A-2. The same operation is also carried out for the second and third parts to prepare A-2/dichloromethane solution composed of A-2 (5.53kg) and dichloromethane (42.7kg) (yield: 74.8%).
1H-NMR(400MHz,CDCl3,30℃)δppm：8.00(s,1H),4.74(s,2H),3.90(s,3H).1H-NMR (400MHz, CDCl3, 30℃) δppm: 8.00 (s, 1H), 4.74 (s, 2H), 3.90 (s, 3H).
步骤2：化合物8的合成Step 2: Synthesis of compound 8
在步骤1中制造的A-2/二氯甲烷溶液(包含5.53kg的A-2(48.8mol)的二氯甲烷溶液49.8kg)中添加二氯甲烷(44L)，温度调整至25℃。耗费30分钟滴加亚硫酰氯(7.8kg,65.5mol)和二氯甲烷(27L)的混合溶液，使用二氯甲烷(8.2L)，进行线洗涤，制成洗液流入后，在室温下进行7小时搅拌。另外，由乙酸钠(36.2kg,436mol)和水道水(143L)制备20％乙酸钠水溶液(179kg)。20％乙酸钠(119kg)滴加至先前的反应液中。滴加结束时点的pH为4.6附近。将该操作中得到的有机层用由氯化钠(5.5kg)和自来水(49L)制备的10％氯化钠水溶液洗涤，针对水层，也用二氯甲烷(55L)萃取。将合并有机层(二氯甲烷溶液)浓缩至33L后，添加乙酸乙酯(27.5L)，浓缩。浓缩至33L后，另外添加乙酸乙酯(47.5L)，在套温度60℃下进行常压浓缩，将生成的无机盐过滤。在滤液中添加盐酸·乙酸乙酯溶液(4mol/L,12.6kg)，进行盐酸盐化，在25℃下进行30分钟搅拌后，冷却至5℃附近。进行30分钟搅拌，晶析熟成后，过滤所得晶析浆料，用冷却的乙酸乙酯(55L)洗涤，减压干燥，得到化合物8(5.25kg)(淡黄色粉末,收率：64.8％)。Dichloromethane (44 L) was added to the A-2/dichloromethane solution (49.8 kg of dichloromethane solution containing 5.53 kg of A-2 (48.8 mol)) prepared in step 1, and the temperature was adjusted to 25°C. A mixed solution of thionyl chloride (7.8 kg, 65.5 mol) and dichloromethane (27 L) was added dropwise over 30 minutes, and dichloromethane (8.2 L) was used to perform line washing, and after the washing liquid was made to flow in, it was stirred at room temperature for 7 hours. In addition, a 20% sodium acetate aqueous solution (179 kg) was prepared from sodium acetate (36.2 kg, 436 mol) and tap water (143 L). 20% sodium acetate (119 kg) was added dropwise to the previous reaction solution. The pH at the end of the addition was around 4.6. The organic layer obtained in this operation was washed with a 10% sodium chloride aqueous solution prepared from sodium chloride (5.5 kg) and tap water (49 L), and the aqueous layer was also extracted with dichloromethane (55 L). After the combined organic layer (dichloromethane solution) was concentrated to 33 L, ethyl acetate (27.5 L) was added and concentrated. After concentrating to 33 L, ethyl acetate (47.5 L) was added, and the mixture was concentrated under normal pressure at a jacket temperature of 60 ° C, and the generated inorganic salt was filtered. Hydrochloric acid ethyl acetate solution (4 mol/L, 12.6 kg) was added to the filtrate to hydrochloride, and after stirring at 25 ° C for 30 minutes, it was cooled to about 5 ° C. After stirring for 30 minutes and crystallization aging, the resulting crystallization slurry was filtered, washed with cooled ethyl acetate (55 L), and dried under reduced pressure to obtain compound 8 (5.25 kg) (light yellow powder, yield: 64.8%).
1H-NMR(400MHz,DMSO-D6,30℃)δppm：8.54(s,1H),4.70(s,2H),3.86(s,3H).1H-NMR (400MHz, DMSO-D6, 30℃) δppm: 8.54 (s, 1H), 4.70 (s, 2H), 3.86 (s, 3H).
参考例3化合物10的合成Reference Example 3 Synthesis of Compound 10
【化38】【化38】
步骤1：化合物B-2的合成Step 1: Synthesis of compound B-2
在氮气氛围下，对在0℃～5℃下冷却的98％硫酸(395.7L)，将化合物B-1(79.1kg,499mol)分批添加(内温保持为0℃～5℃)。将硝酸钾(55.5kg)保持为内温0℃～12℃，分15次(隔20分钟以上的间隔)分批投入。在内温0℃～5℃下进行5小时搅拌。在冷却至0℃～5℃的水(791L)中，在保持为内温0℃～5℃的同时，缓慢流入先前的反应液，用98％硫酸(39.6L)进行彻底洗涤后，在内温0℃下进行5小时搅拌。将浆料通过离心分离机过滤，用水(791L)洗涤。将所得粗固体在水(791L)中悬浮，在20℃～30℃下进行30分钟搅拌后，过滤固体，用水(791L)洗涤3次后，减压干燥，得到化合物B-2(99.61kg)。Under a nitrogen atmosphere, compound B-1 (79.1 kg, 499 mol) was added in batches to 98% sulfuric acid (395.7 L) cooled at 0°C to 5°C (the internal temperature was maintained at 0°C to 5°C). Potassium nitrate (55.5 kg) was maintained at an internal temperature of 0°C to 12°C and added in batches in 15 times (at intervals of more than 20 minutes). Stirring was performed at an internal temperature of 0°C to 5°C for 5 hours. In water (791 L) cooled to 0°C to 5°C, the previous reaction solution was slowly flowed in while maintaining the internal temperature of 0°C to 5°C, and after thorough washing with 98% sulfuric acid (39.6 L), stirring was performed at an internal temperature of 0°C for 5 hours. The slurry was filtered through a centrifuge and washed with water (791 L). The obtained crude solid was suspended in water (791 L), stirred at 20°C to 30°C for 30 minutes, and then the solid was filtered, washed three times with water (791 L), and dried under reduced pressure to obtain compound B-2 (99.61 kg).
1H-NMR(400MHz,CDCl3)δppm：10.31(s,1H),8.46(d,J＝6.60Hz,1H),7.47(d,J＝9.17Hz,1H).1H-NMR (400MHz, CDCl3) δppm: 10.31 (s, 1H), 8.46 (d, J = 6.60Hz, 1H), 7.47 (d, J = 9.17Hz, 1H).
HPLC(UV＝250nm)：RT＝10.9min、HPLC测定条件9HPLC (UV = 250nm): RT = 10.9min, HPLC determination conditions 9
步骤2：化合物S-2的合成Step 2: Synthesis of compound S-2
将乙醇(697L)、水(697L)和肼1水合物(73.5kg,1468mol)混合，加热至45℃。在其中，耗费60分钟滴加化合物B-2(99.6kg,489mol)和乙醇(299L)的混合溶液，进一步以8小时在45℃至50℃下进行9小时搅拌。将内温保持为40℃～50℃的同时，耗费30分钟以上滴加由碳酸氢钾(53.9kg,538mol)和水(1295L)制备的水溶液。冷却至0℃～5℃，进行1小时搅拌后，进行过滤。将水(1335L)和乙醇(657L)混合，使用冷却至0℃～5℃的乙醇水溶液，将先前的固体洗涤。进行减压干燥，得到化合物S-2(83.25kg)(收率：86.9％)。Ethanol (697L), water (697L) and hydrazine monohydrate (73.5kg, 1468mol) were mixed and heated to 45°C. A mixed solution of compound B-2 (99.6kg, 489mol) and ethanol (299L) was added dropwise over 60 minutes, and further stirred at 45°C to 50°C for 9 hours over 8 hours. While maintaining the internal temperature at 40°C to 50°C, an aqueous solution prepared from potassium bicarbonate (53.9kg, 538mol) and water (1295L) was added dropwise over 30 minutes. After cooling to 0°C to 5°C and stirring for 1 hour, the mixture was filtered. Water (1335L) and ethanol (657L) were mixed, and the previous solid was washed with an ethanol aqueous solution cooled to 0°C to 5°C. Drying under reduced pressure gave compound S-2 (83.25kg) (yield: 86.9%).
1H-NMR(400MHz,DMSO-d6)δppm：13.56-13.98(m,1H),8.67(s,1H),8.37(d,J＝0.98Hz,1H),7.92(d,J＝0.61,1H).1H-NMR (400MHz, DMSO-d6) δppm: 13.56-13.98 (m, 1H), 8.67 (s, 1H), 8.37 (d, J = 0.98Hz, 1H), 7.92 (d, J = 0.61, 1H) .
HPLC(UV＝250nm)：RT＝10.4min、HPLC测定条件9HPLC (UV = 250nm): RT = 10.4min, HPLC determination conditions 9
步骤3：化合物S-3的合成Step 3: Synthesis of compound S-3
将化合物S-2(84kg,430mol)和乙酸乙酯(1596L)混合，在20℃～30℃下进行搅拌。分多次投入三甲基氧鎓四氟硼酸盐(77.6kg,525mol)，添加乙酸乙酯(84L)，在25℃下进行6小时搅拌。耗费2小时在先前的反应液中滴加甲醇(252L)和乙酸乙酯(420L)的混合溶液，进行过剩的三甲基氧鎓四氟硼酸盐的淬灭。在碳酸钠(84kg)和水(1596L)混合得到的碳酸钠水溶液中，耗费1小时滴加先前的淬灭后的反应液，添加乙酸乙酯(420L)和甲醇(84L)。将通过分液操作得到的有机层用饱和食盐水(1680kg)洗涤2次，对所得有机层进行活性炭过滤处理。其后，将有机层减压浓缩后，流入四氢呋喃(2520L)，进一步进行减压浓缩。再次实施四氢呋喃的追加流入和减压浓缩的操作后，滴加庚烷(2139L)，冷却至-5℃～5℃后，在0℃附近进行1小时搅拌，晶析熟成。过滤晶析浆料，用冷却的四氢呋喃(224L)和庚烷(912L)的混合溶液洗涤。进行减压干燥，得到化合物S-3(65.73kg)(收率：74.1％)。Compound S-2 (84 kg, 430 mol) and ethyl acetate (1596 L) were mixed and stirred at 20°C to 30°C. Trimethyloxonium tetrafluoroborate (77.6 kg, 525 mol) was added in several portions, ethyl acetate (84 L) was added, and the mixture was stirred at 25°C for 6 hours. A mixed solution of methanol (252 L) and ethyl acetate (420 L) was added dropwise to the previous reaction solution over 2 hours to quench the excess trimethyloxonium tetrafluoroborate. The previously quenched reaction solution was added dropwise to an aqueous sodium carbonate solution obtained by mixing sodium carbonate (84 kg) and water (1596 L) over 1 hour, and ethyl acetate (420 L) and methanol (84 L) were added. The organic layer obtained by the liquid separation operation was washed twice with saturated brine (1680 kg), and the obtained organic layer was filtered with activated carbon. Thereafter, the organic layer was concentrated under reduced pressure, and tetrahydrofuran (2520 L) was flowed in, and further concentrated under reduced pressure. After the additional inflow of tetrahydrofuran and the operation of vacuum concentration were performed again, heptane (2139 L) was added dropwise, and after cooling to -5°C to 5°C, stirring was performed at about 0°C for 1 hour to crystallize and mature. The crystallized slurry was filtered and washed with a mixed solution of cooled tetrahydrofuran (224 L) and heptane (912 L). It was dried under reduced pressure to obtain compound S-3 (65.73 kg) (yield: 74.1%).
1H-NMR(400MHz,CDCl3)δppm：8.31(s,1H),8.13(s,1H),7.81(s,1H),4.27(s,3H).1H-NMR (400MHz, CDCl3) δppm: 8.31 (s, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 4.27 (s, 3H).
HPLC(UV＝254nm)：RT＝10.3min、HPLC测定条件10HPLC (UV = 254 nm): RT = 10.3 min, HPLC determination conditions 10
步骤4：化合物10的合成Step 4: Synthesis of compound 10
将化合物S-3(65.7kg,310mol)和乙酸乙酯(657L)混合，在室温下搅拌后，冷却至10℃附近，进行氮气置换。添加5％的铂-碳(57.7kg,53％水分含有)。氢气置换后，将内温调节至25℃附近的同时，进行4小时搅拌。确认原料消失后，进行氮气置换，实施过滤操作，去除铂-碳催化剂。实施分液操作后，浓缩有机层，在乙酸乙酯溶液中滴加庚烷，形成晶析浆料。过滤，用庚烷/乙酸乙酯洗涤后，实施减压干燥，得到化合物10(37.24kg)(收率：66.2％)。Compound S-3 (65.7 kg, 310 mol) and ethyl acetate (657 L) were mixed, stirred at room temperature, cooled to about 10 ° C, and replaced with nitrogen. Add 5% platinum-carbon (57.7 kg, 53% water content). After hydrogen replacement, adjust the internal temperature to about 25 ° C and stir for 4 hours. After confirming that the raw materials disappear, nitrogen replacement is performed, and filtering operation is performed to remove the platinum-carbon catalyst. After the liquid separation operation is performed, the organic layer is concentrated, and heptane is added dropwise to the ethyl acetate solution to form a crystallization slurry. After filtering, washing with heptane/ethyl acetate, and drying under reduced pressure, compound 10 (37.24 kg) (yield: 66.2%) is obtained.
1H-NMR(400MHz,CDCl3)δppm：7.70(s,1H),7.64(s,1H),6.89(s,1H),4.15(s,3H).1H-NMR (400MHz, CDCl3) δppm: 7.70 (s, 1H), 7.64 (s, 1H), 6.89 (s, 1H), 4.15 (s, 3H).
HPLC(UV＝254nm)：RT＝4.8min、HPLC测定条件10HPLC (UV = 254 nm): RT = 4.8 min, HPLC determination conditions 10
参考例4化合物9的合成Reference Example 4 Synthesis of Compound 9
【化39】【化39】
步骤1：化合物C-2的合成Step 1: Synthesis of compound C-2
将化合物C-1(10.00g、48.0mmol、甲磺酸盐)、N,N'-羰基二咪唑(8.18g、50.4mmol)、乙腈(60.00mL)、和二异丙基乙基胺(6.83g、52.8mmol)混合，在10℃下进行60分钟搅拌。在反应液中，将化合物1(8.09g、55.2mmol、盐酸盐)、二异丙基乙基胺(7.14g、55.2mmol)混合，在50℃下进行210分钟搅拌。冷却反应液，浓缩至45g。添加2-丙醇(100mL)，浓缩至60g后，添加2-丙醇(100mL)。将浆料冷却至0℃，滤取固体，用2-丙醇洗涤后，干燥，由此得到化合物C-2(10.48g、42.2mmol、收率：88％)。Compound C-1 (10.00 g, 48.0 mmol, methanesulfonate), N,N'-carbonyldiimidazole (8.18 g, 50.4 mmol), acetonitrile (60.00 mL), and diisopropylethylamine (6.83 g, 52.8 mmol) were mixed and stirred at 10°C for 60 minutes. In the reaction solution, compound 1 (8.09 g, 55.2 mmol, hydrochloride) and diisopropylethylamine (7.14 g, 55.2 mmol) were mixed and stirred at 50°C for 210 minutes. The reaction solution was cooled and concentrated to 45 g. 2-Propanol (100 mL) was added, and after concentrating to 60 g, 2-Propanol (100 mL) was added. The slurry was cooled to 0°C, the solid was filtered, washed with 2-propanol, and dried to obtain compound C-2 (10.48 g, 42.2 mmol, yield: 88%).
HPLC(UV＝210nm)：RT＝14.5min、HPLC测定条件11HPLC (UV = 210 nm): RT = 14.5 min, HPLC measurement conditions 11
步骤2：化合物C-3的合成Step 2: Synthesis of compound C-3
将化合物C-2(8.00g、32.2mmol)、N,N'-羰基二咪唑(6.79g、41.9mmol)、四氢呋喃(80.0mL)、和1,8-二氮杂双环[5,4,0]-7-十一碳烯(5.40g,35.4mmol)混合，在25℃下进行120分钟搅拌。滴加四氢呋喃(80.0mL)，将反应液冷却至0℃，形成晶析浆料。滤取固体，用四氢呋喃洗涤后，加热干燥，由此得到化合物C-3的晶体(12.6g、29.6mmol、1,8-二氮杂双环[5.4.0]-7-十一碳烯盐、收率：92％)。Compound C-2 (8.00 g, 32.2 mmol), N,N'-carbonyldiimidazole (6.79 g, 41.9 mmol), tetrahydrofuran (80.0 mL), and 1,8-diazabicyclo[5,4,0]-7-undecene (5.40 g, 35.4 mmol) were mixed and stirred at 25°C for 120 minutes. Tetrahydrofuran (80.0 mL) was added dropwise, and the reaction solution was cooled to 0°C to form a crystallization slurry. The solid was filtered, washed with tetrahydrofuran, and dried by heating to obtain crystals of compound C-3 (12.6 g, 29.6 mmol, 1,8-diazabicyclo[5.4.0]-7-undecene salt, yield: 92%).
HPLC(UV＝210nm)：RT＝1.9min、HPLC测定条件11HPLC (UV = 210 nm): RT = 1.9 min, HPLC measurement conditions 11
步骤3：化合物9的合成Step 3: Synthesis of compound 9
将化合物C-3(1.00g、2.3mmol、1,8-二氮杂双环[5.4.0]-7-十一碳烯盐)、N,N-二甲基乙酰胺(5.0mL)、和化合物4(579.2mg、2.6mmol)混合，在70℃下进行300分钟搅拌。冷却反应液，添加乙腈(10mL)，浓缩至9.4g，将上述操作反复进行2次。在浓缩液中添加化合物6(461mg、4.7mmol)和二异丙基乙基胺(456mg、3.5mmol)，在60℃下进行160分钟搅拌。将反应液冷却至25℃，添加乙酸(703mg、11.7mmol)、水(8.0mL)和种晶，将所得晶析浆料冷却至0℃。在浆料中添加水(12.0mL)，滤取固体，用20％乙腈水溶液洗涤后，干燥，由此得到化合物9(0.86g、1.9mmol,收率：79.5％)。Compound C-3 (1.00 g, 2.3 mmol, 1,8-diazabicyclo[5.4.0]-7-undecene salt), N,N-dimethylacetamide (5.0 mL), and compound 4 (579.2 mg, 2.6 mmol) were mixed and stirred at 70°C for 300 minutes. The reaction solution was cooled, acetonitrile (10 mL) was added, and concentrated to 9.4 g, and the above operation was repeated twice. Compound 6 (461 mg, 4.7 mmol) and diisopropylethylamine (456 mg, 3.5 mmol) were added to the concentrated solution and stirred at 60°C for 160 minutes. The reaction solution was cooled to 25°C, acetic acid (703 mg, 11.7 mmol), water (8.0 mL) and seed crystals were added, and the resulting crystallization slurry was cooled to 0°C. Water (12.0 mL) was added to the slurry, and the solid was collected by filtration, washed with a 20% acetonitrile aqueous solution, and then dried to obtain Compound 9 (0.86 g, 1.9 mmol, yield: 79.5%).
HPLC(UV＝255nm)：RT＝14.5min、HPLC测定条件8HPLC (UV = 255 nm): RT = 14.5 min, HPLC determination conditions 8
参考例5化合物S-3的合成Reference Example 5 Synthesis of Compound S-3
【化40】【Chemistry 40】
步骤1：化合物S-3的合成Step 1: Synthesis of compound S-3
与参考例3的步骤1同样地，得到化合物B-2。接着，将化合物B-2(30g、147mmol)和NMP(120mL)混合，在冰冷下添加Boc-羧酸盐(56g、383mmol)，在室温下进行30分钟搅拌。在反应液中，添加二异丙基乙基胺(38.6mL、221mmol)，在90℃下进行20小时搅拌。将反应液设为80℃，添加水(240mL)后，冷却至室温，滤除析出的不溶物。将所得固体用NMP/水＝1/2(15mL)的混合液洗涤3次，进一步用水(30mL)洗涤3次。使所得固体悬浮在乙酸异丙酯(60mL)、庚烷(240mL)中，在室温下搅拌后，用乙酸异丙酯/庚烷＝1/4(30mL)洗涤3次，由此得到化合物D-3。使所得固体悬浮在乙酸异丙酯(100mL)中。将所得悬浮液在55℃下添加至甲磺酸(96mL、1474mmol)和乙酸异丙酯(100mL)的混合液，用乙酸异丙酯(60mL)彻底洗涤，在该温度下进行25分钟搅拌。在冰冷下，将水(240mL)、氢氧化钠水溶液(239mL、1916mmol)和乙酸异丙酯(150mL)添加至反应液中，在40℃下搅拌。在所得反应液中，添加乙酸异丙酯(150mL)。将所得有机层用水(90mL)洗涤3次，浓缩至45g。添加乙酸异丙酯(12g)、庚烷(210mL)，滤取所得不溶物，将固体用乙酸异丙酯/庚烷＝1/7(30ml)洗涤3次，干燥，由此得到化合物S-3(25.3g、120mmol、收率：81.1％)。Compound B-2 was obtained in the same manner as in step 1 of reference example 3. Next, compound B-2 (30 g, 147 mmol) and NMP (120 mL) were mixed, Boc-carboxylate (56 g, 383 mmol) was added under ice cooling, and stirred at room temperature for 30 minutes. Diisopropylethylamine (38.6 mL, 221 mmol) was added to the reaction solution, and stirred at 90°C for 20 hours. The reaction solution was set to 80°C, and after adding water (240 mL), it was cooled to room temperature and the precipitated insoluble matter was filtered out. The obtained solid was washed 3 times with a mixed solution of NMP/water = 1/2 (15 mL), and further washed 3 times with water (30 mL). The obtained solid was suspended in isopropyl acetate (60 mL) and heptane (240 mL), stirred at room temperature, and washed 3 times with isopropyl acetate/heptane = 1/4 (30 mL), thereby obtaining compound D-3. The obtained solid was suspended in isopropyl acetate (100 mL). The obtained suspension was added to a mixed solution of methanesulfonic acid (96 mL, 1474 mmol) and isopropyl acetate (100 mL) at 55°C, washed thoroughly with isopropyl acetate (60 mL), and stirred at this temperature for 25 minutes. Under ice cooling, water (240 mL), an aqueous sodium hydroxide solution (239 mL, 1916 mmol) and isopropyl acetate (150 mL) were added to the reaction solution and stirred at 40°C. Isopropyl acetate (150 mL) was added to the obtained reaction solution. The obtained organic layer was washed 3 times with water (90 mL) and concentrated to 45 g. Isopropyl acetate (12 g) and heptane (210 mL) were added, the obtained insoluble matter was filtered out, and the solid was washed three times with isopropyl acetate/heptane = 1/7 (30 ml) and dried to obtain compound S-3 (25.3 g, 120 mmol, yield: 81.1%).
1H-NMR(400MHz,CDCl3)δppm：8.34(s,1H),8.13(s,1H),7.84(s,1H),4.28(s,3H).1H-NMR (400MHz, CDCl3) δppm: 8.34 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 4.28 (s, 3H).
参考例6化合物10的合成Reference Example 6 Synthesis of Compound 10
【化41】【Chemistry 41】
步骤1：化合物T-2、T-3的合成Step 1: Synthesis of compounds T-2 and T-3
在冰冷下，将化合物T-1(40g、182mmol)、浓硫酸(200mL、3677mmol)和69％硝酸(23.3g、255mmol)混合，在冰冷至室温下进行3小时搅拌，其后静置过夜。在冰水520mL中注入其混合液，添加二氯甲烷(200mL)，进行分液操作。将所得二氯甲烷溶液用5％碳酸氢钠水溶液(400mL)洗涤2次，浓缩干固。在所得固体中添加甲醇(120mL)后，浓缩至内容量达到116g。在所得浆料中添加甲醇至内容量达到333g后，添加水(240mL)，滤取所得不溶物，将固体用甲醇/水＝1/1(200mL)洗涤，干燥，由此得到化合物T-2/T-3＝1/2.78的混合物(30.67g、收率：58.5％)。Under ice cooling, compound T-1 (40 g, 182 mmol), concentrated sulfuric acid (200 mL, 3677 mmol) and 69% nitric acid (23.3 g, 255 mmol) were mixed, stirred for 3 hours under ice cooling to room temperature, and then allowed to stand overnight. The mixed solution was injected into 520 mL of ice water, and dichloromethane (200 mL) was added to perform a liquid separation operation. The obtained dichloromethane solution was washed twice with a 5% aqueous sodium bicarbonate solution (400 mL) and concentrated to dryness. After adding methanol (120 mL) to the obtained solid, it was concentrated to a content of 116 g. After adding methanol to the obtained slurry until the content reached 333 g, water (240 mL) was added, the obtained insoluble matter was filtered out, and the solid was washed with methanol/water = 1/1 (200 mL) and dried to obtain a mixture of compound T-2/T-3 = 1/2.78 (30.67 g, yield: 58.5%).
LC/MS(ESI)：作为m/z，未进行MS检测，RT＝2.04min、LC/MS测定条件1LC/MS (ESI): as m/z, without MS detection, RT = 2.04 min, LC/MS measurement condition 1
步骤2：化合物T-4的合成Step 2: Synthesis of compound T-4
在氮气气流下，在T-2/T-3＝1/2.78的混合物(200mg)中添加2-丙醇(1.4mL)，升温至60℃，添加三乙基胺(0.289mL、2.07mmol)，进行1.5小时搅拌。其后，在60℃下在反应液中添加将甲基胺盐酸盐(94mg、1.39mmol)溶解在水(0.4mL)中的溶液，进行3小时搅拌。在所得反应液中在60℃下添加水(8mL)后，冷却至室温，进行30分钟搅拌。滤取析出的不溶物，将所得固体用水(5mL)洗涤，干燥，由此得到化合物T-4(194mg、0.699mmol、收率：100％)。Under nitrogen flow, 2-propanol (1.4 mL) was added to a mixture (200 mg) of T-2/T-3 = 1/2.78, the temperature was raised to 60°C, triethylamine (0.289 mL, 2.07 mmol) was added, and the mixture was stirred for 1.5 hours. Thereafter, a solution of methylamine hydrochloride (94 mg, 1.39 mmol) dissolved in water (0.4 mL) was added to the reaction solution at 60°C, and the mixture was stirred for 3 hours. After adding water (8 mL) to the obtained reaction solution at 60°C, the mixture was cooled to room temperature and stirred for 30 minutes. The precipitated insoluble matter was filtered out, and the obtained solid was washed with water (5 mL) and dried to obtain compound T-4 (194 mg, 0.699 mmol, yield: 100%).
LC/MS(ESI)：m/z＝277(M+H)、RT＝2.46min、LC/MS测定条件2LC/MS (ESI): m/z = 277 (M+H), RT = 2.46 min, LC/MS measurement conditions 2
步骤3：化合物T-5的合成Step 3: Synthesis of compound T-5
在氮气气流下，将化合物T-4(500mg,1.80mmol)和2-丙醇(2.5mL)和三丁基膦(802mg、3.96mmol)混合，在80℃下进行1.5小时搅拌。冷却至室温后，用甲苯(3mL)进行3次溶剂置换，进行浓缩至浓缩后的残渣达到5g。其后，将反应液冰冷至4℃，添加4mol/L盐酸-乙酸乙酯溶液(1.5mL)，进行20分钟搅拌。滤取所得晶析浆料，用甲苯(2.5mL)洗涤，干燥，由此得到固体。在水(4.3mL)和碳酸氢钠(0.192g、2.29mmol)的混合液中，逐渐少量添加所得固体，将pH调整至7～8，进行30分钟搅拌，得到晶析浆料。滤取，用水(8.6mL)洗涤，干燥，由此得到化合物T-5(351mg、1.43mmol、收率：79.4％)。Under a nitrogen stream, compound T-4 (500 mg, 1.80 mmol), 2-propanol (2.5 mL) and tributylphosphine (802 mg, 3.96 mmol) were mixed and stirred at 80 ° C for 1.5 hours. After cooling to room temperature, the solvent was replaced with toluene (3 mL) three times and concentrated until the residue after concentration reached 5 g. Thereafter, the reaction solution was ice-cooled to 4 ° C, 4 mol/L hydrochloric acid-ethyl acetate solution (1.5 mL) was added, and stirred for 20 minutes. The obtained crystallization slurry was filtered, washed with toluene (2.5 mL), and dried to obtain a solid. In a mixed solution of water (4.3 mL) and sodium bicarbonate (0.192 g, 2.29 mmol), the obtained solid was gradually added in small amounts, the pH was adjusted to 7-8, and stirred for 30 minutes to obtain a crystallization slurry. The residue was collected by filtration, washed with water (8.6 mL), and dried to obtain compound T-5 (351 mg, 1.43 mmol, yield: 79.4%).
LC/MS(ESI)：m/z＝245(M+H)、RT＝1.90min、LC/MS测定条件1LC/MS (ESI): m/z = 245 (M+H), RT = 1.90 min, LC/MS measurement conditions 1
步骤4：化合物10的合成Step 4: Synthesis of compound 10
在氮气气流下，将化合物T-5(2.015g、8.21mmol)、DME(20mL)、叔丁醇钠(1.104g、11.49mmol)、二苯甲酮亚胺(1.645mL、9.80mmol)、BINAP(0.153g、0.246mmol)、和二乙酰氧基钯(0.036g、0.160mmol)混合，在80℃下进行9小时搅拌，静置过夜。在所得悬浮液中添加乙醇(10mL)，冷却至5℃。在悬浮液中少量逐渐添加30％硫酸(20mL)，在室温下搅拌过夜。在所得反应液中添加乙酸乙酯(40mL)、水(20mL)，实施分液操作。将所得水层用乙酸乙酯(10mL)洗涤，将有机层用10％硫酸(10mL)洗涤。合并所得水层，冰冷后，使用48％氢氧化钠水溶液，中和至pH达到8。添加乙酸乙酯(20mL)，滤取析出的硫酸钠，实施分液操作。在所得水层中添加乙酸乙酯(20mL)，实施分液操作。合并所得有机层，浓缩，进一步用乙酸乙酯(10mL)反复进行4次溶剂置换。添加庚烷(12mL)，将所得晶析浆料在冰冷下进行1小时搅拌。滤取，用乙酸乙酯/庚烷＝1/3(6mL)洗涤，干燥，由此得到化合物10(1.18g、6.5mmol、收率：79.2％)。Under a nitrogen stream, compound T-5 (2.015 g, 8.21 mmol), DME (20 mL), sodium tert-butoxide (1.104 g, 11.49 mmol), benzophenone imine (1.645 mL, 9.80 mmol), BINAP (0.153 g, 0.246 mmol), and diacetoxypalladium (0.036 g, 0.160 mmol) were mixed, stirred at 80°C for 9 hours, and allowed to stand overnight. Ethanol (10 mL) was added to the resulting suspension, and the mixture was cooled to 5°C. 30% sulfuric acid (20 mL) was gradually added to the suspension in small amounts, and the mixture was stirred at room temperature overnight. Ethyl acetate (40 mL) and water (20 mL) were added to the resulting reaction solution, and a liquid separation operation was performed. The resulting aqueous layer was washed with ethyl acetate (10 mL), and the organic layer was washed with 10% sulfuric acid (10 mL). The resulting aqueous layers were combined, cooled on ice, and neutralized to pH 8 using a 48% aqueous sodium hydroxide solution. Ethyl acetate (20 mL) was added, the precipitated sodium sulfate was filtered out, and a liquid separation operation was performed. Ethyl acetate (20 mL) was added to the obtained aqueous layer, and a liquid separation operation was performed. The obtained organic layers were combined, concentrated, and the solvent replacement was repeated 4 times with ethyl acetate (10 mL). Heptane (12 mL) was added, and the obtained crystallization slurry was stirred under ice-cooling for 1 hour. Filtered, washed with ethyl acetate/heptane = 1/3 (6 mL), and dried to obtain compound 10 (1.18 g, 6.5 mmol, yield: 79.2%).
LC/MS(ESI)：m/z＝182(M+H)、RT＝0.88min、LC/MS测定条件1LC/MS (ESI): m/z = 182 (M+H), RT = 0.88 min, LC/MS measurement conditions 1
参考例7化合物U-4的合成Reference Example 7 Synthesis of Compound U-4
【化42】【Chemistry 42】
步骤1：化合物U-2的合成Step 1: Synthesis of compound U-2
将化合物U-1(2.09g、22.6mmol、盐酸盐)和CPME(12.04g)和水(7g)混合，缓慢添加将碳酸钾(4.25g、30.8mmol)溶解在水(7g)中得到的溶液，以使得反应液的温度达到20～30℃。将所得混合溶液剧烈搅拌，缓慢添加CbzCl(3.50g、20.5mmol)以使得反应液的温度达到20～30℃，在室温下进行1小时搅拌。对所得溶液实施分液操作，将有机层用水(14g)洗涤后，浓缩。在残渣中添加CPME(15.05g)，进一步浓缩至残渣达到10.5g。将所得溶液升温至45℃，维持温度同时耗费30分钟添加庚烷(9.58g)，其后进一步进行30分钟搅拌。添加庚烷(19.15g)后，将所得晶析浆料在冰冷下进行30分钟搅拌。滤取，将所得固体用CPME-庚烷(3g-9.58g)的混合液洗涤，干燥，由此得到化合物U-2(3.41g、17.93mmol、收率：86％)。Compound U-1 (2.09 g, 22.6 mmol, hydrochloride) was mixed with CPME (12.04 g) and water (7 g), and a solution obtained by dissolving potassium carbonate (4.25 g, 30.8 mmol) in water (7 g) was slowly added so that the temperature of the reaction solution reached 20 to 30°C. The obtained mixed solution was vigorously stirred, and CbzCl (3.50 g, 20.5 mmol) was slowly added so that the temperature of the reaction solution reached 20 to 30°C, and stirred at room temperature for 1 hour. The obtained solution was subjected to a liquid separation operation, and the organic layer was washed with water (14 g) and concentrated. CPME (15.05 g) was added to the residue, and the residue was further concentrated to 10.5 g. The obtained solution was heated to 45°C, and heptane (9.58 g) was added over 30 minutes while maintaining the temperature, and then stirred for a further 30 minutes. After adding heptane (19.15 g), the obtained crystallization slurry was stirred for 30 minutes under ice cooling. The solid obtained was collected by filtration, washed with a mixed solution of CPME-heptane (3 g - 9.58 g), and dried to obtain compound U-2 (3.41 g, 17.93 mmol, yield: 86%).
HPLC(UV＝254nm)：RT＝9.51min、HPLC测定条件5HPLC (UV = 254 nm): RT = 9.51 min, HPLC determination conditions 5
步骤2：化合物U-3的合成Step 2: Synthesis of compound U-3
在化合物U-2(8.00g、42.1mmol)中添加甲醇(31.66g)，冷却至0℃后，添加甲醇钠的28％甲醇溶液(2.43g、12.6mmol)，在该温度下进行4小时搅拌。在所得溶液中，在0～5℃下添加N-甲基甲酰肼(3.74g、50.5mmol)溶解在甲醇(19g)中得到的溶液，进一步在该温度下添加乙酸(2.53g、42.1mmol)，在0℃下进行2小时搅拌。将所得溶液升温至60℃，在该温度下进行4小时搅拌。将反应液浓缩至32g后，添加乙酸乙酯(57.73g)、5％碳酸氢钠水溶液(67.53g)。将所得混合溶液进行10分钟搅拌，进行分液操作。针对所得水层，也用乙酸乙酯(57.73g)萃取。将合并的有机层浓缩至40g。添加MEK(64.4g)，进一步浓缩至40g，将上述操作反复进行2次。在所得浓缩液中在20～30℃下添加甲磺酸(4.04g、42.0mmol)溶解在MEK(32.2g)中得到的溶液，在室温下进行30分钟搅拌。滤取析出的晶析浆料，将所得固体用MEK(25.76g)洗涤，干燥，由此得到化合物U-3(10.1g、29.5mmol、甲磺酸盐、收率：70％)。Methanol (31.66 g) was added to compound U-2 (8.00 g, 42.1 mmol), and after cooling to 0°C, a 28% methanol solution of sodium methoxide (2.43 g, 12.6 mmol) was added, and the mixture was stirred at the same temperature for 4 hours. To the resulting solution, a solution of N-methylformylhydrazide (3.74 g, 50.5 mmol) dissolved in methanol (19 g) was added at 0 to 5°C, and acetic acid (2.53 g, 42.1 mmol) was further added at the same temperature, and the mixture was stirred at 0°C for 2 hours. The resulting solution was heated to 60°C and stirred at the same temperature for 4 hours. After the reaction solution was concentrated to 32 g, ethyl acetate (57.73 g) and a 5% aqueous sodium bicarbonate solution (67.53 g) were added. The resulting mixed solution was stirred for 10 minutes and a liquid separation operation was performed. The resulting aqueous layer was also extracted with ethyl acetate (57.73 g). The combined organic layers were concentrated to 40 g. MEK (64.4 g) was added, and the mixture was further concentrated to 40 g. The above operation was repeated twice. A solution of methanesulfonic acid (4.04 g, 42.0 mmol) dissolved in MEK (32.2 g) was added to the obtained concentrated solution at 20-30°C, and stirred at room temperature for 30 minutes. The precipitated crystallization slurry was filtered out, and the obtained solid was washed with MEK (25.76 g) and dried to obtain compound U-3 (10.1 g, 29.5 mmol, mesylate, yield: 70%).
HPLC(UV＝254nm)：RT＝7.90min、HPLC测定条件5HPLC (UV = 254 nm): RT = 7.90 min, HPLC determination conditions 5
步骤3：化合物C-1的合成Step 3: Synthesis of compound C-1
将化合物U-3(10g、29.2mol、甲磺酸盐)和甲醇(79.15g)混合，在室温下搅拌后，进行氮气置换。添加钯-碳(钯10％)(0.5g、5重量％)，氢气置换后，在室温下进行7小时搅拌。氮气置换后，用硅藻土(注册商标)过滤操作去除钯-碳催化剂。将所得滤液浓缩至50g。添加MEK(40.25g)，浓缩至40g，将上述操作反复进行2次。滤取所得晶析浆料，用MEK(25.76g)洗涤，干燥，由此得到化合物C-1(5.3g、25.5mmol、甲磺酸盐、收率：87％)。Compound U-3 (10 g, 29.2 mol, methanesulfonate) and methanol (79.15 g) were mixed, stirred at room temperature, and then replaced with nitrogen. Palladium-carbon (palladium 10%) (0.5 g, 5 wt%) was added, and after hydrogen replacement, stirring was carried out at room temperature for 7 hours. After nitrogen replacement, the palladium-carbon catalyst was removed by filtration using diatomaceous earth (registered trademark). The obtained filtrate was concentrated to 50 g. MEK (40.25 g) was added and concentrated to 40 g, and the above operation was repeated twice. The obtained crystallization slurry was filtered, washed with MEK (25.76 g), and dried to obtain compound C-1 (5.3 g, 25.5 mmol, methanesulfonate, yield: 87%).
HPLC(UV＝254nm)：RT＝2.75min、HPLC测定条件11HPLC (UV = 254 nm): RT = 2.75 min, HPLC measurement conditions 11
式(VII)所示的化合物的富马酸共晶体I形的单晶结构分析的结果示于以下。The results of single crystal structural analysis of the fumaric acid cocrystal Form I of the compound represented by formula (VII) are shown below.
R1(I＞2.00s(I))为0.0470，由最终的差分傅里叶确认没有电子密度的确实或误置。R1 (I>2.00s(I)) was 0.0470, and the final differential Fourier analysis confirmed that there was no accuracy or misplacement of the electron density.
晶体学的数据示于表2。The crystallographic data are shown in Table 2.
【表2】【Table 2】
在此，体积是指单位格子体积，Z是指单位晶格中的分子数。Here, volume refers to the unit lattice volume, and Z refers to the number of molecules in the unit lattice.
此外，非氢原子的原子坐标示于表3～表4。在此，U(eq)是指等价各向同性温度因子。In addition, the atomic coordinates of non-hydrogen atoms are shown in Tables 3 and 4. Here, U(eq) means an equivalent isotropic temperature factor.
【表3】【Table 3】
【表4】【Table 4】
接着，氢原子的原子坐标示于表5。在此，U(iso)是指各向同性温度因子。此外，表5的氢原子的编号与所键合的非氢原子的编号关联。Next, the atomic coordinates of the hydrogen atoms are shown in Table 5. Here, U(iso) means isotropic temperature factor. In addition, the numbers of the hydrogen atoms in Table 5 are associated with the numbers of the non-hydrogen atoms to which they are bonded.
【表5】【Table 5】
进一步，原子间键距离(单位：埃)示于表6。Furthermore, the interatomic bond distances (unit: angstrom) are shown in Table 6.
【表6】【Table 6】
式(VII)所示的化合物的富马酸共晶体I形在非对称单元中，存在1分子的式(VII)所示的化合物。式(VII)所示的化合物的富马酸共晶体I形的非对称单元中的结构示于图11。Fumaric acid cocrystal form I of the compound represented by formula (VII) contains one molecule of the compound represented by formula (VII) in the asymmetric unit. The structure of the fumaric acid cocrystal form I of the compound represented by formula (VII) in the asymmetric unit is shown in FIG11 .
应予说明，表3～表4和表6中的非氢原子的编号各自与图11中记载的编号对应。It should be noted that the numbers of the non-hydrogen atoms in Tables 3 to 4 and Table 6 correspond to the numbers described in FIG. 11 .
如表6所述那样，N10-C9的键距离示出约N16-C9的键距离示出约As shown in Table 6, the bond distance between N10 and C9 is about The bond distance of N16-C9 is shown to be approximately
N10-C9的键距离(约)短于N16-C9的键距离(约)，因此富马酸共晶体I形的式(VII)所示的化合物鉴定为亚氨基结构：The bond distance between N10 and C9 (approx. ) is shorter than the bond distance of N16-C9 (approx. ), so the compound represented by formula (VII) of fumaric acid cocrystal form I was identified as an imino structure:
【化43】【Chemistry 43】
即，即使是同一化合物，也根据结晶化条件等，存在采取亚氨基结构的情况和采取氨基结构的情况，即使在形成盐、复合体的情况下，也根据其盐、复合体的抗衡分子的种类，存在采取亚氨基结构的情况和采取氨基结构的情况，即使是同一抗衡分子，也根据结晶化条件等，存在采取亚氨基结构的情况和采取氨基结构的情况。此外，也存在采取亚氨基结构的化合物、其盐或它们的复合体与采取氨基结构的化合物、其盐或它们的复合体的混合物。That is, even for the same compound, there are cases where an imino structure is adopted and cases where an amino structure is adopted, depending on the crystallization conditions, etc., and even when a salt or a complex is formed, there are cases where an imino structure is adopted and cases where an amino structure is adopted, depending on the type of countermolecule of the salt or the complex, and even for the same countermolecule, there are cases where an imino structure is adopted and cases where an amino structure is adopted, depending on the crystallization conditions, etc. In addition, there is also 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.
示出通过与实施例1b的步骤5-2同样的制造方法得到的式(VII)所示的化合物的富马酸共晶体I形的粉末X射线衍射的结果。The results of powder X-ray diffraction of the fumaric acid cocrystal form I of the compound represented by formula (VII) obtained by the same production method as step 5-2 of Example 1b are shown.
粉末X射线衍射图案中，衍射角度(2θ)：7.7±0.2°、9.5±0.2°、10.0±0.2°、10.9±0.2°、13.8±0.2°、14.6±0.2°、18.6±0.2°、22.6±0.2°、23.4±0.2°和24.6±0.2°处确认到峰。In the powder X-ray diffraction pattern, peaks were confirmed at diffraction angles (2θ) of 7.7±0.2°, 9.5±0.2°, 10.0±0.2°, 10.9±0.2°, 13.8±0.2°, 14.6±0.2°, 18.6±0.2°, 22.6±0.2°, 23.4±0.2°, and 24.6±0.2°.
式(VII)所示的化合物的富马酸共晶体I形(晶型I)的粉末X射线衍射图案示于图9。横轴为2θ(°)，纵轴表示强度(计数)。The powder X-ray diffraction pattern of the fumaric acid cocrystal form I (crystal form I) of the compound represented by formula (VII) is shown in Figure 9. The horizontal axis represents 2θ (°) and the vertical axis represents intensity (counts).
图9的粉末X射线衍射图案中的峰表格示于图10。FIG10 shows a peak table in the powder X-ray diffraction pattern of FIG9 .
此外，示出式(VII)所示的化合物的甲苯化物的粉末X射线衍射的结果。In addition, the results of powder X-ray diffraction of the toluene compound of the compound represented by formula (VII) are shown.
粉末X射线衍射图案中，在衍射角度(2θ)：7.4±0.2°、8.1±0.2°、13.7±0.2°、15.1±0.2°、16.3±0.2°、19.3±0.2°、21.4±0.2°、22.6±0.2°、24.6±0.2°、26.6±0.2°、27.8±0.2°和29.5±0.2°处确认到峰。In the powder X-ray diffraction pattern, peaks were confirmed at diffraction angles (2θ) of 7.4±0.2°, 8.1±0.2°, 13.7±0.2°, 15.1±0.2°, 16.3±0.2°, 19.3±0.2°, 21.4±0.2°, 22.6±0.2°, 24.6±0.2°, 26.6±0.2°, 27.8±0.2°, and 29.5±0.2°.
式(VII)所示的化合物的甲苯化物的粉末X射线衍射图案示出图20。横轴为2θ(°)，纵轴表示强度(计数)。The powder X-ray diffraction pattern of the toluene compound represented by formula (VII) is shown in Fig. 20. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (counts).
针对式(VII)所示的化合物的甲苯化物，未鉴定分子结构(氨基体/亚氨基体)。The molecular structure (amino form/imino form) of the toluene compound represented by formula (VII) was not identified.
以下，记载本发明化合物的生物试验例。The following are biological test examples of the compounds of the present invention.
本发明所涉及的式(VII)所示的化合物具有冠状病毒3CL蛋白酶抑制作用，只要抑制冠状病毒3CL蛋白酶即可。The compound represented by formula (VII) involved in the present invention has a coronavirus 3CL protease inhibitory effect, and it only needs to inhibit the coronavirus 3CL protease.
具体而言，以下记载的评价方法中，IC50优选为50μM以下、更优选为1μM以下、进一步更优选为100nM以下。Specifically, in the evaluation method described below, IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.
试验例1：使用人TMPRSS2表达Vero E6细胞(Vero E6/TMPRSS2细胞)的致细胞病变效应(CPE)抑制效果确认试验Test Example 1: Cytopathic effect (CPE) inhibition test using human TMPRSS2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells)
＜操作流程＞＜Operation Flow＞
·受试试样的稀释、分注Dilution and injection of test samples
预先将受试试样用DMSO稀释至适度的浓度，制作2～5倍阶梯稀释系列后，分注至384孔板中。The test sample was diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold step dilution series was prepared and then dispensed into a 384-well plate.
·细胞和SARS-CoV-2的稀释、分注Dilution and aliquoting of cells and SARS-CoV-2
将VeroE6/TMPRSS2细胞(JCRB1819、5×103细胞/孔)和SARS-CoV-2(100TCID50/孔)在培养基(MEM、2％FBS、青霉素-链霉素)中混合，分注至加入了受试试样的孔中后，用CO2培养箱培养3天。VeroE6/TMPRSS2 cells (JCRB1819, 5×103 cells/well) and SARS-CoV-2 (100 TCID50 /well) were mixed in culture medium (MEM, 2% FBS, penicillin-streptomycin), dispensed into wells containing test samples, and cultured in a CO2 incubator for 3 days.
·CellTiter-Glo(注册商标)2.0的分注和发光信号的测定· CellTiter-Glo (registered trademark) 2.0 dispensing and luminescence signal measurement
将3天培养的板恢复至室温后，将CellTiter-Glo(注册商标)2.0分注至各孔中，用板混合机混合。放置一定时间后，用读板仪测定发光信号(Lum)。After the 3-day cultured plate was returned to room temperature, CellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed using a plate mixer. After standing for a certain period of time, the luminescent signal (Lum) was measured using a plate reader.
＜各测定项目值的算出＞<Calculation of each measurement item value>
·50％ SARS-CoV-2感染细胞死亡抑制浓度(EC50)算出· Calculation of 50% SARS-CoV-2 infected cell death inhibition concentration (EC50 )
x记作化合物浓度的对数值、y记作％效能时，用以下的Logistic回归式拟合抑制曲线，算出代入y＝50(％)时的x的值作为EC50。When x is the logarithmic value of the compound concentration and y is the % efficacy, the inhibition curve was fitted using the following logistic regression equation, and the value of x when y=50(%) was substituted and calculated asEC50 .
y＝min+(max-min)/{1+(X50/x)^Hill}y＝min+(max-min)/{1+(X50/x)^Hill}
％效能＝{(样品-病毒对照)/(细胞对照-病毒对照)}*100％% efficacy = {(sample - virus control) / (cell control - virus control)} * 100%
细胞对照：细胞对照孔的Lum的平均Cell control: Average Lum of cell control wells
病毒对照：病毒对照孔的Lum的平均Virus control: Average Lum of virus control wells
min：y轴下限值，max：y轴上限值，X50：拐点的x坐标，Hill：min与max的中点处的曲线斜率min: y-axis lower limit, max: y-axis upper limit, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max
本发明化合物本质上如上所述试验。结果示于以下。The compounds of the invention were tested essentially as described above. The results are shown below.
化合物I-005：0.328μMCompound I-005: 0.328 μM
试验例2：对SARS-CoV-2 3CL蛋白酶的抑制活性试验Test Example 2: Inhibitory activity test on SARS-CoV-2 3CL protease
＜材料＞＜Materials＞
·市售的重组SARS-CoV-2 3CL蛋白酶Commercially available recombinant SARS-CoV-2 3CL protease
·市售的底物肽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)Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1)
·内部标准肽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(SEQ ID NO:2)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln可以参照文献(Atherton,E.；Sheppard,R.C.、“In Solid Phase Peptide Synthesis,APractical Approach”、IRLPress at Oxford University Pres、1989.和Bioorg.Med.Chem.、5卷、9号、1997年、1883-1891页等)合成。以下示出一例。Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be synthesized with reference to the literature (Atherton, E.; Sheppard, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989. and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below.
使用Rink酰胺树脂，通过Fmoc固相合成，合成H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu(Lys侧链被Boc保护，Thr侧链被叔丁基保护，Ser侧链被叔丁基保护，Glu的C末端OH被叔丁基保护，Glu侧链的羧酸与树脂缩合)。N末端Dabcyl基的修飾使用EDC/HOBT在树脂上缩合4-二甲基氨基偶氮苯-4'-羧酸(Dabcyl-OH)。最终脱保护、和从树脂裂解通过用TFA/EDT＝95:5处理来进行。其后，通过反相HPLC纯化。H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain is protected by Boc, Thr side chain is protected by tert-butyl, Ser side chain is protected by tert-butyl, C-terminal OH of Glu is protected by tert-butyl, and the carboxylic acid of Glu side chain is condensed with resin) was synthesized by Fmoc solid phase synthesis using Rink amide resin. The N-terminal Dabcyl group was modified by condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC/HOBT. The final deprotection and cleavage from the resin were carried out by treatment with TFA/EDT=95:5. Thereafter, it was purified by reverse phase HPLC.
·RapidFire Cartridge C4 typeA·RapidFire Cartridge C4 typeA
＜操作流程＞＜Operation Flow＞
·测定缓冲液的制备Preparation of assay buffer
本试验中，使用由20mM Tris-HCl、100mM氯化钠、1mM EDTA、10mM DTT、0.01％ BSA组成的测定缓冲液。针对IC50值为10nM以下的化合物，使用由20mM Tris-HCl、1mM EDTA、10mM DTT、0.01％BSA组成的测定缓冲液。In this test, an assay buffer composed of 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT, and 0.01% BSA was used. For compounds withIC50 values of 10 nM or less, an assay buffer composed of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA was used.
·受试试样的稀释、分注Dilution and injection of test samples
预先将受试试样用DMSO稀释至适度的浓度，制作2～5倍阶梯稀释系列后，分注至384孔板中。The test sample was diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold step dilution series was prepared and then dispensed into a 384-well plate.
·酶与底物的添加、酶反应Enzyme and substrate addition, enzyme reaction
在准备的化合物板中，添加8μM的底物、和6或0.6nM的酶溶液，在室温下进行3～5小时温育。其后，添加反应停止液(0.067μM内部标准、0.1％甲酸、10或25％乙腈)，停止酶反应。8 μM substrate and 6 or 0.6 nM enzyme solution were added to the prepared compound plate and incubated at room temperature for 3 to 5 hours. Then, a reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile) was added to stop the enzyme reaction.
·反应产物的测定Determination of reaction products
反应结束的板使用RapidFire System 360和质谱仪(Agilent、6550iFunnel Q-TOF)、或Rapid Fire System 365和质谱仪(Agilent、6495CTriple Quadrupole)测定。作为测定时的流动相，使用A溶液(75％异丙醇、15％乙腈、5mM甲酸铵)和B溶液(0.01％三氟乙酸、0.09％甲酸)。The plate after the reaction was completed was measured using RapidFire System 360 and mass spectrometer (Agilent, 6550iFunnel Q-TOF), or Rapid Fire System 365 and mass spectrometer (Agilent, 6495CTriple Quadrupole). As the mobile phase for the measurement, A solution (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and B solution (0.01% trifluoroacetic acid, 0.09% formic acid) were used.
通过质谱仪检测的反应产物记作使用RapidFire Integrator或能够进行同等分析的程序算出的产物面积(Product area)值。此外，也算出同时检测的内部标准，，记作内部标准面积(Internal Standard area)值。The reaction product detected by mass spectrometry is recorded as the product area value calculated using RapidFire Integrator or a program capable of performing equivalent analysis. In addition, the internal standard detected simultaneously is also calculated and recorded as the internal standard area value.
＜各测定项目值的算出＞<Calculation of each measurement item value>
·P/IS的算出Calculation of P/IS
在签署项目中得到的面积(area)值通过下述的式计算，算出P/IS。The area value obtained in the signed project is calculated using the following formula to calculate P/IS.
P/IS＝产物面积值/内部标准面积值P/IS = product area value / internal standard area value
·50％ SARS-CoV-2 3CL蛋白酶抑制浓度(IC50)算出·Calculation of 50% SARS-CoV-2 3CL protease inhibition concentration (IC50 )
x记作化合物浓度的对数值、y记作％抑制时，用以下的Logistic回归式拟合抑制曲线，算出代入y＝50(％)时的x的值作为IC50。When x is expressed as the logarithm of the compound concentration and y is expressed as % inhibition, the inhibition curve was fitted using the following logistic regression equation, and the value of x when y=50(%) was substituted and calculated asIC50 .
y＝min+(max-min)/{1+(X50/x)^Hill}y＝min+(max-min)/{1+(X50/x)^Hill}
％抑制＝{1-(样品-对照(-))/对照(+)-对照(-))}*100% inhibition = {1-(sample-control (-))/control (+)-control (-))}*100
对照(-)：酶抑制条件孔的P/IS的平均Control (-): Average P/IS of wells with enzyme inhibition
对照(+)：DMSO对照孔的P/IS的平均Control (+): Average P/IS of DMSO control wells
min：y轴下限值，max：y轴上限值，X50：拐点的x坐标，Hill：min与max的中点处的曲线斜率min: y-axis lower limit, max: y-axis upper limit, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max
本发明化合物本质上如上所述试验。结果示于以下。The compounds of the invention were tested essentially as described above. The results are shown below.
化合物I-005：0.010μMCompound I-005: 0.010 μM
试验例1-2：使用人TMPRSS2表达Vero E6细胞(Vero E6/TMPRSS2细胞)的致细胞病变效应(CPE)抑制效果确认试验Test Example 1-2: Cytopathic effect (CPE) inhibition test using human TMPRSS2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells)
＜操作流程＞＜Operation Flow＞
·受试试样的稀释、分注Dilution and injection of test samples
预先将受试试样用DMSO稀释至适度的浓度，制作3倍阶梯稀释系列后，分注至96孔板中。The test sample was diluted in advance with DMSO to an appropriate concentration, and a 3-fold step dilution series was prepared and then dispensed into a 96-well plate.
·细胞和SARS-CoV-2的稀释、分注Dilution and aliquoting of cells and SARS-CoV-2
将VeroE6/TMPRSS2细胞(JCRB1819、1.5×10细胞/孔)和SARS-CoV-2hCoV-19/Japan/TY/WK-521/2020、hCoV-19/Japan/QK002/2020、hCoV-19/Japan/QHN001/2020、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(30-1000TCID50/孔)在培养基(MEM、2％FBS、青霉素-链霉素)中混合，分注至加入了受试试样的孔中后，用CO2培养箱培养3天。VeroE6/TMPRSS2 cells (JCRB1819, 1.5 × 10 cells/well) and SARS-CoV-2 hCoV-19/Japan/TY/WK-521/2020, hCoV-19/Japan/QK002/2020, hCoV-19/Japan/QHN001/2020, 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 (30-1000 TCID50 /well) was mixed with a culture medium (MEM, 2% FBS, penicillin-streptomycin), dispensed into the wells containing the test samples, and cultured in a CO2 incubator for 3 days.
·CellTiter-Glo(注册商标)2.0的分注和发光信号的测定· CellTiter-Glo (registered trademark) 2.0 dispensing and luminescence signal measurement
将3天培养的板恢复至室温后，将CellTiter-Glo(注册商标)2.0分注至各孔中，用板混合机混合。放置一定时间后，用读板仪测定发光信号(Lum)。After the 3-day cultured plate was returned to room temperature, CellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed using a plate mixer. After standing for a certain period of time, the luminescent signal (Lum) was measured using a plate reader.
＜各测定项目值的算出＞<Calculation of each measurement item value>
·50％ SARS-CoV-2感染细胞死亡抑制浓度(EC50)算出· Calculation of 50% SARS-CoV-2 infected cell death inhibition concentration (EC50 )
x记作化合物浓度的对数值、y记作％效能时，用以下的Logistic回归式拟合抑制曲线，算出代入y＝50(％)时的x的值作为EC50。When x is the logarithmic value of the compound concentration and y is the % efficacy, the inhibition curve was fitted using the following logistic regression equation, and the value of x when y=50(%) was substituted and calculated asEC50 .
y＝min+(max-min)/{1+(X50/x)^Hill}y＝min+(max-min)/{1+(X50/x)^Hill}
％效能＝{(样品-病毒对照)/(细胞对照-病毒对照)}*100％% efficacy = {(sample - virus control) / (cell control - virus control)} * 100%
细胞对照：细胞对照孔的Lum的平均Cell control: Average Lum of cell control wells
病毒对照：病毒对照孔的Lum的平均Virus control: Average Lum of virus control wells
min：y轴下限值，max：y轴上限值，X50：拐点的x坐标，Hill：min与max的中点处的曲线斜率min: y-axis lower limit, max: y-axis upper limit, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max
本发明化合物本质上如上所述试验。结果示于以下。The compounds of the invention were tested essentially as described above. The results are shown below.
(SARS-CoV-2hCoV-19/Japan/TY/WK-521/2020)(SARS-CoV-2hCoV-19/Japan/TY/WK-521/2020)
式(VII)所示的化合物的富马酸共晶体I形：0.37μMFumaric acid cocrystal form I of the compound represented by formula (VII): 0.37 μM
试验例2-2：对SARS-CoV-2 3CL蛋白酶的抑制活性试验Test Example 2-2: Inhibitory Activity Test on SARS-CoV-2 3CL Protease
＜材料＞＜Materials＞
·市售的重组SARS-CoV-2 3CL蛋白酶Commercially available recombinant SARS-CoV-2 3CL protease
·市售的底物肽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)Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1)
·内部标准肽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(SEQ ID NO:2)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln可以参照文献(Atherton,E.；Sheppard,R.C.、“In Solid Phase Peptide Synthesis,APractical Approach”、IRLPress at Oxford University Pres、1989.和Bioorg.Med.Chem.、5卷、9号、1997年、1883-1891页、等)合成。以下示出一例。Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be synthesized with reference to the literature (Atherton, E.; Sheppard, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989. and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below.
使用Rink酰胺树脂，通过Fmoc固相合成，合成H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu(Lys侧链被Boc保护，Thr侧链被叔丁基保护，Ser侧链被叔丁基保护，Glu的C末端OH被叔丁基保护，Glu侧链的羧酸与树脂缩合)。N末端Dabcyl基的修飾使用EDC/HOBT在树脂上缩合4-二甲基氨基偶氮苯-4'-羧酸(Dabcyl-OH)。最终脱保护、和从树脂裂解通过用TFA/EDT＝95:5处理来进行。其后，通过反相HPLC纯化。H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain is protected by Boc, Thr side chain is protected by tert-butyl, Ser side chain is protected by tert-butyl, C-terminal OH of Glu is protected by tert-butyl, and the carboxylic acid of Glu side chain is condensed with resin) was synthesized by Fmoc solid phase synthesis using Rink amide resin. The N-terminal Dabcyl group was modified by condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC/HOBT. The final deprotection and cleavage from the resin were carried out by treatment with TFA/EDT=95:5. Thereafter, it was purified by reverse phase HPLC.
·RapidFire Cartridge C4 typeA·RapidFire Cartridge C4 typeA
＜操作流程＞＜Operation Flow＞
·测定缓冲液的制备Preparation of assay buffer
本试验中，使用由20mM Tris-HCl、1mM EDTA、10mM DTT、0.01％ BSA组成的测定缓冲液。In this test, an assay buffer composed of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA was used.
·受试试样的稀释、分注Dilution and injection of test samples
预先将受试试样用DMSO稀释至适度的浓度，制作3倍阶梯稀释系列后，分注至384孔板中。The test sample was diluted in advance with DMSO to an appropriate concentration, and a 3-fold step dilution series was prepared and dispensed into a 384-well plate.
·酶与底物的添加、酶反应Enzyme and substrate addition, enzyme reaction
在准备的化合物板中，添加8μM的底物、和6nM的酶溶液，在室温下进行3小时温育。其后，添加反应停止液(0.072μM内部标准、0.1％甲酸、10％乙腈)，停止酶反应。8 μM substrate and 6 nM enzyme solution were added to the prepared compound plate and incubated at room temperature for 3 hours. Then, a reaction stop solution (0.072 μM internal standard, 0.1% formic acid, 10% acetonitrile) was added to stop the enzyme reaction.
·反应产物的测定Determination of reaction products
反应结束的板使用RapidFire System 360和质谱仪(Agilent、6550iFunnel Q-TOF)测定。作为测定时的流动相，使用A溶液(75％异丙醇、15％乙腈、5mM甲酸铵)和B溶液(0.01％三氟乙酸、0.09％甲酸)。The reaction-completed plate was measured using RapidFire System 360 and a mass spectrometer (Agilent, 6550iFunnel Q-TOF). As mobile phases for the measurement, solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid) were used.
通过质谱仪检测的反应产物记作使用RapidFire Integrator算出的产物面积(Product area)值。此外，也算出同时检测的内部标准，，记作内部标准面积(InternalStandard area)值。The reaction product detected by the mass spectrometer was recorded as the product area value calculated using RapidFire Integrator. In addition, the internal standard detected simultaneously was also calculated and recorded as the internal standard area value.
＜各测定项目值的算出＞<Calculation of each measurement item value>
·P/IS的算出Calculation of P/IS
在签署项目中得到的面积(area)值通过下述的式计算，算出P/IS。The area value obtained in the signed project is calculated using the following formula to calculate P/IS.
P/IS＝产物面积值/内部标准面积值P/IS = product area value / internal standard area value
·50％ SARS-CoV-2 3CL蛋白酶抑制浓度(IC50)算出·Calculation of 50% SARS-CoV-2 3CL protease inhibition concentration (IC50 )
x记作化合物浓度的对数值、y记作％抑制时，用以下的Logistic回归式拟合抑制曲线，算出代入y＝50(％)时的x的值作为IC50。When x is expressed as the logarithm of the compound concentration and y is expressed as % inhibition, the inhibition curve was fitted using the following logistic regression equation, and the value of x when y=50(%) was substituted and calculated asIC50 .
y＝min+(max-min)/{1+(X50/x)＾Hill}y＝min+(max-min)/{1+(X50/x)＾Hill}
％抑制＝{1-(样品-对照(-))/对照(+)-对照(-))*100% inhibition = {1-(sample-control(-))/control(+)-control(-))*100
对照(-)：不含SARS-CoV-2 3CL蛋白酶和受试物质的孔中的P/IS比的平均Control (-): Average of the P/IS ratios in wells without SARS-CoV-2 3CL protease and test substances
对照(+)：含有SARS-CoV-2 3CL蛋白酶且不含受试物质的孔中的P/IS比的平均Control (+): Average of the P/IS ratios in wells containing SARS-CoV-2 3CL protease and no test substance
min：y轴下限值，max：y轴上限值，X50：拐点的x坐标，Hill：min与max的中点处的曲线斜率min: y-axis lower limit, max: y-axis upper limit, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max
本发明化合物本质上如上所述试验。结果示于以下。The compounds of the invention were tested essentially as described above. The results are shown below.
式(VII)所示的化合物的富马酸共晶体I形：0.0132μMFumaric acid cocrystal form I of the compound represented by formula (VII): 0.0132 μM
(实施例5)(Example 5)
以式(VII)所示的化合物的量达到约1.8(w/v)％的方式，称量式(VII)所示的化合物的富马酸共晶体I形晶体，在溶解有0.3(w/v)％的高分子的水溶液中添加分散。Fumaric acid cocrystal type I crystals of the compound represented by formula (VII) are weighed so that the amount of the compound represented by formula (VII) becomes about 1.8 (w/v)%, and are added and dispersed in an aqueous solution in which a polymer is dissolved at 0.3 (w/v)%.
作为添加剂，使用氨基烷基甲基丙烯酸酯共聚物E(Evonik公司制)、羟基丙基纤维素(日本曹达公司制)、羟丙甲基纤维素(信越化学工业公司制)、聚乙烯醇(Merck公司制)、聚乙烯基吡咯烷酮(BASF公司制)、聚乙烯醇·甲基丙烯酸甲酯·丙烯酸共聚物(日新化成公司制)。As additives, aminoalkyl methacrylate copolymer E (manufactured by Evonik), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), hydroxypropyl methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), polyvinyl alcohol (manufactured by Merck), polyvinyl pyrrolidone (manufactured by BASF), and polyvinyl alcohol, methyl methacrylate, and acrylic acid copolymer (manufactured by Nissin Chemical Co., Ltd.) were used.
【表7】【Table 7】
试验例3：溶解度评价Test Example 3: Solubility Evaluation
将实施例5的各分散液1mL添加至空腹时模拟人工肠液(FaSSIF)14mL中，用恒温搅拌器在37℃、400rpm下进行1小时搅拌。1小时搅拌后，将样本用0.45μm过滤器过滤，通过液相色谱法测定滤液中的式(VII)所示的化合物的浓度。1 mL of each dispersion of Example 5 was added to 14 mL of simulated artificial intestinal fluid (FaSSIF) at fasting time, and stirred for 1 hour at 37°C and 400 rpm using a thermostatic stirrer. After 1 hour of stirring, the sample was filtered with a 0.45 μm filter, and the concentration of the compound represented by formula (VII) in the filtrate was measured by liquid chromatography.
(测定法)(Measurement method)
·检测器：紫外吸光光度计(测定波长222nm)Detector: UV spectrophotometer (measurement wavelength 222nm)
·柱：ACQUITY UPLC BEH C18 2.1×50mm、1.7μm·Column: ACQUITY UPLC BEH C18 2.1×50mm, 1.7μm
·柱温度：40℃附近的一定温度Column temperature: Constant temperature around 40°C
·流动相A：0.1M甲酸铵溶液、流动相B：乙腈Mobile phase A: 0.1M ammonium formate solution, mobile phase B: acetonitrile
·流动相的送液：将流动相A和流动相B的混合比改变为7:3或如以下的表那样，控制浓度梯度。· Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed to 7:3 or as shown in the following table to control the concentration gradient.
【表8】【Table 8】
·流量：约0.6mL/minFlow rate: about 0.6mL/min
·注入量：1μL或1.5μLInjection volume: 1μL or 1.5μL
·样品冷却剂温度：约10℃Sample coolant temperature: about 10°C
·自动注射器洗涤液：水/甲醇混合液(7:3)Automatic syringe washing solution: water/methanol mixture (7:3)
·面积测定范围：试样溶液注入后4分钟或7.5分钟Area measurement range: 4 minutes or 7.5 minutes after sample solution injection
·式(VII)所示的化合物的量的计算式· Calculation formula for the amount of the compound represented by formula (VII)
式(VII)所示的化合物的量(％)＝ATII/ΣAT×100The amount of the compound represented by formula (VII) (%) = ATII/ΣAT×100
ATII：试样溶液的式(VII)所示的化合物的峰面积ATII: Peak area of the compound represented by formula (VII) in the sample solution
ΣAT：试样溶液的峰面积的总计(空白和系统峰除外)ΣAT: Total peak area of sample solution (excluding blank and system peaks)
(结果)(result)
式(VII)所示的化合物的溶解度试验结果示于以下的表。其结果是，式(VII)所示的化合物通过添加高分子，溶解度大幅提高。The results of the solubility test of the compound represented by formula (VII) are shown in the following table. As a result, the solubility of the compound represented by formula (VII) was significantly improved by adding a polymer.
【表9】【Table 9】
本实验中使用的式(VII)所示的化合物的富马酸共晶体I形晶体的粒径是D50为3.44μm、D90为8.33μm。The particle sizes of the fumaric acid cocrystal type I crystals of the compound represented by formula (VII) used in this experiment were D50 of 3.44 μm and D90 of 8.33 μm.
(实施例6)(Example 6)
(片剂的制造方法)(Method for producing tablets)
制造含有式(VII)所示的化合物的富马酸共晶体I形晶体的片剂。A tablet containing form I crystals of the fumaric acid cocrystal of the compound represented by formula (VII) was produced.
以下的表中，示出平均1个片剂的配方。将式(VII)所示的化合物的富马酸共晶体I形晶体、D-甘露醇(Roquette公司制)、交联羧甲基纤维素钠(DuPont公司制)、羟基丙基纤维素(日本曹达公司制)、轻质无水硅酸(Cabot公司制)和硬脂酸镁(Mallinckrodt公司制)过30目筛而筛分混合后，造粒。The following table shows the formulation of an average tablet. Fumaric acid eutectic I-type crystals of the compound represented by formula (VII), D-mannitol (manufactured by Roquette), cross-linked carboxymethyl cellulose sodium (manufactured by DuPont), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), light anhydrous silicic acid (manufactured by Cabot Corporation) and magnesium stearate (manufactured by Mallinckrodt Corporation) were sieved and mixed through a 30-mesh sieve, and then granulated.
添加经造粒和整粒的颗粒、结晶纤维素(旭化成公司制)和硬脂酸镁(Mallinckrodt公司制)、或轻质无水硅酸(Cabot公司制)并混合后，用静态压缩机或旋转式压片机，压缩成型为直径9.0mm，得到下述组成的片剂。After adding and mixing the granulated and sized particles, crystalline cellulose (manufactured by Asahi Kasei Corporation) and magnesium stearate (manufactured by Mallinckrodt Co., Ltd.), or light anhydrous silicic acid (manufactured by Cabot Corporation), the mixture is compressed into a diameter of 9.0 mm using a static compressor or a rotary tablet press to obtain tablets of the following composition.
【表10】【Table 10】
试验例4：片剂的溶出试验Test Example 4: Dissolution test of tablets
(溶出试验法)(Dissolution test method)
溶出试验通过第18修订日本药典溶出试验法第2法(含有表面活性剂的溶出试验第1液、桨法、桨转速：50rpm，结果：2片的平均值)而进行。The dissolution test was conducted according to the 18th revised Japanese Pharmacopoeia dissolution test method 2 (dissolution test liquid 1 containing surfactant, paddle method, paddle rotation speed: 50 rpm, result: average value of 2 tablets).
(实验结果)(Experimental results)
实施例6A、6B、6C和6D的溶出试验结果示于图21。其结果是，任一实施例中，均示出快速溶出性。The dissolution test results of Examples 6A, 6B, 6C and 6D are shown in Fig. 21. As a result, all Examples showed rapid dissolution.
试验例4中使用的实施例6A和6B的制剂中使用的有效成分(式(VII)所示的化合物的富马酸共晶体I形晶体)的粒度分布示于图22。10％粒径为0.69μm，50％粒径为4.00μm，90％粒径为10.80μm。The particle size distribution of the active ingredient (fumaric acid cocrystal type I crystal of the compound represented by formula (VII)) used in the preparations of Examples 6A and 6B used in Test Example 4 is shown in Figure 22. The 10% particle size is 0.69 μm, the 50% particle size is 4.00 μm, and the 90% particle size is 10.80 μm.
试验例4中使用的实施例6C和6D的制剂中使用的有效成分(式(VII)所示的化合物的富马酸共晶体I形晶体)的粒度分布示于图23。10％粒径为0.67μm，50％粒径为3.63μm，90％粒径为10.98μm。The particle size distribution of the active ingredient (fumaric acid cocrystal type I crystal of the compound represented by formula (VII)) used in the preparations of Examples 6C and 6D used in Test Example 4 is shown in Figure 23. The 10% particle size is 0.67 μm, the 50% particle size is 3.63 μm, and the 90% particle size is 10.98 μm.
粒度分布的测定条件示于以下。The measurement conditions of the particle size distribution are shown below.
制造商：シンパテックManufacturer: シンパテック
装置：激光衍射式HELOS&RODOS粒度分布测定装置Device: Laser diffraction HELOS & RODOS particle size distribution measuring device
范围：R2Range: R2
分散压力：3barDispersion pressure: 3 bar
触发条件：截止2s测定浓度≤1％或10s实际时间Trigger condition: Cut-off 2s measured concentration ≤ 1% or 10s actual time
试验例5：随时间稳定性试验中的制剂中的稳定化剂的影响Test Example 5: Effect of stabilizers in formulations during stability test over time
示出确认与试验例4中使用的相同批次的实施例6A的制剂的随时间稳定性的结果。Results of confirming the stability over time of the preparation of Example 6A of the same batch as used in Test Example 4 are shown.
a.稳定性试验法a. Stability test method
将实施例6A的制剂1)在褐色玻璃瓶闭塞状态下在60℃下保管两周，或2)在褐色玻璃瓶开盖状态下在40℃、75％相对湿度下保管一个月。其后，测定本发明制剂中的式(VII)所示的化合物的相关物质量。The preparation of Example 6A was stored 1) at 60°C for two weeks in a closed brown glass bottle or 2) at 40°C and 75% relative humidity for one month in an open brown glass bottle. Thereafter, the amount of the compound represented by formula (VII) in the preparation of the present invention was measured.
(试样液制备方法)(Sample solution preparation method)
(测定方法)(Measurement method)
通过以下的方法、条件，用液相色谱，测定本发明制剂中的式(VII)所示的化合物的相关物质量。The amount of the relevant substance of the compound represented by formula (VII) in the preparation of the present invention was measured by liquid chromatography according to the following method and conditions.
·检测器：紫外吸光光度计(测定波长：222nm)Detector: UV spectrophotometer (measurement wavelength: 222nm)
·柱：C18柱Column: C18 column
·柱温度：40℃附近的一定温度Column temperature: Constant temperature around 40°C
·流动相A：0.01mol/L甲酸铵溶液、流动相B：乙腈Mobile phase A: 0.01 mol/L ammonium formate solution, mobile phase B: acetonitrile
·流动相A和流动相B的混合比将流动相B的混合比从9:1缓慢提高至1:9，以32分钟进行测定。Mixing Ratio of Mobile Phase A and Mobile Phase B The mixing ratio of mobile phase B was gradually increased from 9:1 to 1:9, and the measurement was performed over 32 minutes.
·流量：0.6mL/分钟Flow rate: 0.6mL/min
相关物质量将HPLC图表的色谱图的峰面积的总计记作100％，算出相对于其量的比例(％)。The amount of the related substance was calculated based on the total of the peak areas of the chromatogram of the HPLC chart being taken as 100%, and the ratio (%) to the amount was calculated.
b.结果b. Results
稳定性试验的结果示于以下的表。实施例6A的制剂的总相关物质量1)在褐色玻璃瓶闭塞状态下在60℃下保管两周，或2)在褐色玻璃瓶开盖状态下在40℃、75％相对湿度下保管一个月后，未增加，是稳定的。The results of the stability test are shown in the table below. The total amount of related substances in the preparation of Example 6A did not increase after 1) storage at 60°C for two weeks in a closed brown glass bottle or 2) storage at 40°C and 75% relative humidity for one month in an open brown glass bottle, indicating that the preparation is stable.
【表11】【Table 11】
根据以上，本发明制剂对湿度和温度稳定性高。As described above, the preparation of the present invention has high stability to humidity and temperature.
实施例7Example 7
试验例6临床试验(Ph2a)Test Example 6 Clinical Trial (Ph2a)
对仅具有轻症/中等症和无症状/轻度症状的SARS-CoV-2感染者，反复口服给与受试药(有效成分：式(VII)所示的化合物的富马酸共晶体I形晶体)时的有效性和安全性的评价通过以安慰剂作为比较对象的基于随机分配的双盲比较试验实施。The efficacy and safety of repeated oral administration of the test drug (active ingredient: fumaric acid cocrystal form I of the compound represented by formula (VII)) to SARS-CoV-2 infected patients with only mild/moderate symptoms and asymptomatic/mild symptoms was evaluated by a double-blind comparative trial based on random allocation with placebo as the comparator.
Phase 2a Part的主要评价项目在轻症/中等症和无症状的SARS-CoV-2感染者中共通，是各时点处的SARS-CoV-2的病毒滴度的基线起算的变化量，确认受试药的抗病毒效果。The main evaluation items of Phase 2a Part are common to those with mild/moderate symptoms and asymptomatic SARS-CoV-2 infection, and are the changes in the baseline SARS-CoV-2 viral titer at each time point to confirm the antiviral effect of the test drug.
轻症/中等症的SARS-CoV-2感染者选择符合下述的全部基准的患者。Patients with mild/moderate SARS-CoV-2 infection are selected if they meet all the following criteria.
(a)12岁以上且未满70岁的男性或女性患者。(a) Male or female patients aged 12 years or older and under 70 years old.
(b)登记前120小时以内被诊断为SARS-CoV-2阳性。(b) Diagnosed as SARS-CoV-2 positive within 120 hours before registration.
(c)COVID-19发病至登记为止的时间为120小时以内。(c) The time from COVID-19 onset to registration is within 120 hours.
(d)登记时因COVID-19而导致的以下的症状(COVID-19的12种症状)之中任一者中，具有1个项目以上(COVID-19发病前起存在的症状除外)的中等度(COVID-19症状分数：2)以上的症状。(d) At the time of registration, the applicant has one or more of the following symptoms (12 symptoms of COVID-19) due to COVID-19 (excluding symptoms that existed before the onset of COVID-19) of moderate severity (COVID-19 symptom score: 2) or higher.
全身症状：疲劳感、肌肉或身体疼痛、头疼、恶寒、发烧General symptoms: fatigue, muscle or body aches, headache, chills, fever
呼吸道症状：鼻水或鼻塞、喉咙痛、咳嗽、气喘Respiratory symptoms: runny or stuffy nose, sore throat, cough, wheezing
消化器症状：恶心、呕吐、腹泻Digestive symptoms: nausea, vomiting, diarrhea
无症状的SARS-CoV-2感染者选择符合下述的全部基准的患者。Asymptomatic SARS-CoV-2 infected patients were selected if they met all the following criteria.
(a)12岁以上且未满70岁的男性或女性患者。(a) Male or female patients aged 12 years or older and under 70 years old.
(b)登记前120小时以内被诊断为SARS-CoV-2阳性。(b) Diagnosed as SARS-CoV-2 positive within 120 hours before registration.
(c)无症状：登记前2周以内，未确认到以下的COVID-19症状(SARS-CoV-2感染前存在的症状除外)。(c) Asymptomatic: No symptoms of COVID-19 (excluding symptoms that existed before SARS-CoV-2 infection) were confirmed within 2 weeks prior to registration.
全身症状：疲劳感、肌肉或身体疼痛、头疼、恶寒、发烧、味觉异常、嗅觉异常Systemic symptoms: fatigue, muscle or body aches, headache, chills, fever, abnormal taste, abnormal smell
呼吸道症状：鼻水或鼻塞、喉咙痛、咳嗽、气喘Respiratory symptoms: runny or stuffy nose, sore throat, cough, wheezing
消化器症状：恶心、呕吐、腹泻Digestive symptoms: nausea, vomiting, diarrhea
无症状/仅轻度症状：随机分配前2周以内，因COVID-19而导致的以下的症状(COVID-19的12种症状)中任一者中，均不具有中等度(COVID-19症状分数：2)以上的症状(COVID-19发病前存在的症状除外)。Asymptomatic/mild symptoms only: None of the following symptoms (COVID-19 symptom score: 2) due to COVID-19 were moderate or above within 2 weeks before randomization (excluding symptoms that existed before the onset of COVID-19).
全身症状：倦怠感(疲劳感)、肌肉痛或身体疼痛、头痛、恶寒/出汗、发烧或发热Systemic symptoms: fatigue, muscle pain or body aches, headache, chills/sweating, fever or heat
呼吸道症状：鼻水或鼻塞、喉咙痛、咳嗽、气喘(呼吸困难)Respiratory symptoms: runny or stuffy nose, sore throat, cough, wheezing (difficulty breathing)
消化器症状：恶心、呕吐、腹泻Digestive symptoms: nausea, vomiting, diarrhea
临床试验药的给与方法Administration of Clinical Trial Drugs
(i)受试药(i) Drug under investigation
250mg片：片剂中包含式(VII)所示的化合物的富马酸共晶体I形晶体，作为式(VII)所示的化合物包含250mg。本250mg片是将与实施例6C同样的各组成2倍而制成的片剂。250 mg tablet: The tablet contains 250 mg of the compound represented by formula (VII) as the fumaric acid cocrystal I crystal. This 250 mg tablet is a tablet prepared by doubling the same composition as in Example 6C.
125mg片：片剂中包含式(VII)所示的化合物的富马酸共晶体I形晶体，作为式(VII)所示的化合物包含125mg。本125mg片是与实施例6C同样的组成的片剂。125 mg tablet: The tablet contains the fumaric acid cocrystal I-form crystal of the compound represented by formula (VII), and contains 125 mg of the compound represented by formula (VII). This 125 mg tablet has the same composition as Example 6C.
(ii)安慰剂(ii) Placebo
安慰剂-D片：是与上述250mg片外观无法区分的片剂，不含式(VII)所示的化合物的富马酸共晶体I形晶体。Placebo-D tablet: a tablet that is indistinguishable in appearance from the above-mentioned 250 mg tablet, and does not contain form I crystals of the fumaric acid cocrystal of the compound represented by formula (VII).
安慰剂-B片：是与上述125mg片外观无法区分的片剂，不含式(VII)所示的化合物的富马酸共晶体I形晶体。Placebo-B tablet: a tablet that is indistinguishable in appearance from the above-mentioned 125 mg tablet, and does not contain form I crystals of the fumaric acid cocrystal of the compound represented by formula (VII).
给与量和给与方法Dosage and method of administration
Phase 2a Part中，作为轻症/中等症或无症状的SARS-CoV-2感染者而判断为适格的受试者，以1:1:1的比率，随机分配为受试药的375/125mg组、受试药的750/250mg组、安慰剂组中任一者。In Phase 2a Part, eligible subjects who were judged as mild/moderately ill or asymptomatic SARS-CoV-2 infected persons were randomly assigned in a 1:1:1 ratio to either the 375/125 mg group of the investigational drug, the 750/250 mg group of the investigational drug, or the placebo group.
每个给与组的临床试验药Clinical trial drug for each administration group
375/125mg组375/125 mg group
在第1天各自给与125mg片和安慰剂-D片，在第2～5天各自每1天给与1片125mg片和安慰剂-D片。On day 1, a 125 mg tablet and a placebo-D tablet were each administered, and on days 2 to 5, one 125 mg tablet and one placebo-D tablet were each administered once a day.
750/250mg组750/250mg group
在第1天各自给与250mg片和安慰剂-B片，在第2～5天各自每1天给与1片250mg片和安慰剂-B片。On day 1, a 250 mg tablet and a placebo-B tablet were each administered, and on days 2 to 5, one 250 mg tablet and one placebo-B tablet were each administered once a day.
安慰剂组Placebo group
在第1天各自给与安慰剂-D片和安慰剂-B片，在第2～5天各自每1天给与1片安慰剂-D片和安慰剂-B片。On day 1, one tablet of placebo-D and one tablet of placebo-B were administered, and on days 2 to 5, one tablet of placebo-D and one tablet of placebo-B were administered every other day.
应予说明，“第1天”表示给与首日，“第2天～第5天”表示从给与首日起算的第2天～第5天。It should be noted that “the first day” means the first day of payment, and “the second to fifth day” means the second to fifth days from the first day of payment.
有效性的主要评价项目(Phase 2a Part)Main evaluation items for effectiveness (Phase 2a Part)
Phase 2a Part的有效性的主要评价项目在轻症/中等症和无症状的SARS-CoV-2感染者中共通，是各时点处的SARS-CoV-2的病毒滴度的基线起算的变化量。定义为各时点处的SARS-CoV-2病毒滴度的观测值的基线起算的绝对变化量。The main evaluation items for the effectiveness of Phase 2a Part are common to those with mild/moderate symptoms and asymptomatic SARS-CoV-2 infection, and are the changes in the SARS-CoV-2 viral titer at each time point from the baseline. It is defined as the absolute change in the observed SARS-CoV-2 viral titer at each time point from the baseline.
主要评价项目的分析(Phase 2a Part)Analysis of main evaluation items (Phase 2a Part)
针对轻症/中等症的SARS-CoV-2感染者群体、无症状的SARS-CoV-2感染者群体、和它们的合并群体各自，以mITT群体为对象，算出各时点处的SARS-CoV-2的病毒滴度的基线起算的变化量的概要统计量。进一步，针对将轻症/中等症和无症状的SARS-CoV-2感染者合并的群体，应用van Elteren检验，在两侧显著水准5％针对各时点处的SARS-CoV-2的病毒滴度，在受试药的各用量组与安慰剂组间进行对比。van Elteren检验中使用的层中，使用轻症/中等症的SARS-CoV-2感染者群体、和无症状的SARS-CoV-2感染者群体。For each of the mild/moderate SARS-CoV-2 infected group, the asymptomatic SARS-CoV-2 infected group, and their combined group, the summary statistics of the change in the SARS-CoV-2 viral titer at each time point from the baseline were calculated with the mITT group as the object. Furthermore, for the combined group of mild/moderate and asymptomatic SARS-CoV-2 infected people, the van Elteren test was applied to compare the SARS-CoV-2 viral titer at each time point between each dose group of the test drug and the placebo group at a two-sided significance level of 5%. In the stratum used in the van Elteren test, the mild/moderate SARS-CoV-2 infected group and the asymptomatic SARS-CoV-2 infected group were used.
主要评价项目的结果Results of the main evaluation items
(1)各时点处的SARS-CoV-2的病毒滴度的基线起算的变化量(Phase 2a Part)(1) Changes in SARS-CoV-2 viral titers from baseline at each time point (Phase 2a Part)
Phase 2a Part中，将69例随机化，375/125mg组中分配22例(其中1例为未给与例)，750/250mg组中分配23例，安慰剂组中分配24例。69例之中，基线的RT-PCR为阳性的病例数为44例，其中基线的病毒滴度被检测到的病例数为40例。该40例的构成在375/125mg组中为14例，750/250mg组中为13例，安慰剂组中为13例。应予说明，这些群体的例数和其内容基于至2022年1月17日时点为止能够获取的RT-PCR测定结果、和病毒滴度测定结果而算出。In Phase 2a Part, 69 cases were randomized, 22 cases were assigned to the 375/125mg group (1 of which was not given), 23 cases were assigned to the 750/250mg group, and 24 cases were assigned to the placebo group. Among the 69 cases, 44 cases were positive for RT-PCR at baseline, and 40 cases had detected baseline viral titers. The 40 cases consisted of 14 cases in the 375/125mg group, 13 cases in the 750/250mg group, and 13 cases in the placebo group. It should be noted that the number of cases and their contents in these groups are calculated based on the RT-PCR measurement results and viral titer measurement results that can be obtained as of January 17, 2022.
作为Phase 2a Part的最终结果，69例之中，基线的RT-PCR为阳性的病例数为47例，其中基线的病毒滴度被检测到的病例数为43例。该43例的构成在375/125mg组中为15例，750/250mg组中为14例，安慰剂组中为14例。As the final result of Phase 2a Part, among the 69 cases, 47 cases were positive for RT-PCR at baseline, and 43 cases had detectable viral titers at baseline. The 43 cases consisted of 15 cases in the 375/125mg group, 14 cases in the 750/250mg group, and 14 cases in the placebo group.
临床试验方案中规定的入院日用随访表示，与给药日(Day)的对应关系和允许宽度如下所述。Op V是指任选随访，表示任选入院日。The hospitalization day specified in the clinical trial protocol is represented by follow-up, and the correspondence and allowable width with the dosing day (Day) are as follows. Op V means optional follow-up, which means an optional hospitalization day.
【表12】【Table 12】
以Modified intention-to-treat population(修正的意向性治疗，随机化且基线的RT-PCR与病毒滴度均为阳性的全部受试者)为对象，SARS-CoV-2病毒滴度的基线起算的变化量的各组的平均值的推移示于图24。本分析在分析中包括轻症/中等症的SARS-CoV-2感染者、和无症状的SARS-CoV-2感染者，仅表示必要入院日的随访。此外，病毒滴度低于检测下限(0.8log10(TCID50/mL))的情况下，其病毒滴度的值作为0.8log10(TCID50/mL)处理。375/125mg组中随访3(给药开始后第4天)、750/250mg组中随访2(给药开始后第2天)和随访3(给药开始后第4天)的时点处，以显著水平0.05与安慰剂组相比，病毒滴度统计学显著减少。应予说明，至2022年1月17日时点能够获取的RT-PCR测定结果、和病毒滴度测定结果中，375/125mg组中随访3(给药开始后第4天)以后、750/250mg组中随访2(给药开始后第2天)以后的全部时点处，与安慰剂组相比，病毒滴度也存在减少的倾向。The mean change of each group of the change in the baseline of the SARS-CoV-2 virus titer is shown in Figure 24 for the modified intention-to-treat population (modified intention-to-treat, randomized and all subjects with positive RT-PCR and viral titer at baseline). This analysis includes mild/moderate SARS-CoV-2 infected persons and asymptomatic SARS-CoV-2 infected persons in the analysis, and only represents the follow-up of the necessary hospitalization day. In addition, when the viral titer is lower than the lower limit of detection (0.8log10 (TCID50 /mL)), the value of the viral titer is treated as 0.8log10 (TCID50 /mL). At the time points of follow-up 3 (4th day after the start of administration) in the 375/125mg group, follow-up 2 (2nd day after the start of administration) and follow-up 3 (4th day after the start of administration) in the 750/250mg group, the viral titer was statistically significantly reduced compared with the placebo group at a significant level of 0.05. It should be noted that among the RT-PCR assay results and viral titer assay results available as of January 17, 2022, viral titers tended to decrease compared with the placebo group at all time points after follow-up 3 (4th day after the start of administration) in the 375/125 mg group and after follow-up 2 (2nd day after the start of administration) in the 750/250 mg group.
此外，针对各时点处的病毒滴度的阳性患者的比例，示于以下。In addition, the proportion of positive patients with respect to the virus titer at each time point is shown below.
第4天的时点处，相对于安慰剂组中的病毒滴度为0.8以上的阳性者的比例，750/250mg组中减少80％，375/125mg组中减少63％。第6天的时点处，相对于安慰剂组中的病毒滴度为0.8以上的阳性者的比例，750/250mg组中减少54％，375/125mg组中减少100％。At the 4th day, the proportion of positive patients with a viral titer of 0.8 or more in the placebo group was reduced by 80% in the 750/250 mg group and 63% in the 375/125 mg group. At the 6th day, the proportion of positive patients with a viral titer of 0.8 or more in the placebo group was reduced by 54% in the 750/250 mg group and 100% in the 375/125 mg group.
第4天和第6天的时点处，750/250mg组和375/125mg组两者中，与安慰剂组相比，发现病毒滴度为阳性的患者比例低的倾向。因此，暗示了通过服用本发明的药物组合物，能够迅速减少排出具有感染性的病毒的患者。At the time points of day 4 and day 6, a tendency was found that the proportion of patients with positive virus titers was lower in both the 750/250 mg group and the 375/125 mg group compared with the placebo group. Therefore, it is suggested that the number of patients excreting infectious viruses can be rapidly reduced by taking the pharmaceutical composition of the present invention.
次要评价项目的结果Results of secondary evaluation items
(1)最初确认病毒滴度阴性为止的时间(Phase 2a Part)(1) Time until the virus titer is initially confirmed to be negative (Phase 2a Part)
最初确认SARS-CoV-2的病毒滴度阴性为止的时间示于以下的表13和图25。The time until the SARS-CoV-2 virus titer was initially confirmed to be negative is shown in the following Table 13 and Figure 25.
Phase 2a Part的69例之中，375/125mg组中示出15例，750/250mg组中示出13例，安慰剂组中示出14例中的结果。Among the 69 cases in Phase 2a Part, the results were shown for 15 cases in the 375/125 mg group, 13 cases in the 750/250 mg group, and 14 cases in the placebo group.
【表13】【Table 13】
[分层对数秩检验中，仅受试者层(轻症/中等症,无症状/轻度)记作分层因子][In the stratified log-rank test, only the subject layer (mild/moderate, asymptomatic/mild) was recorded as the stratification factor]
如表13所示那样，375/125mg组中，与安慰剂组相比，中央值短至49.8小时，针对最初确认病毒滴度阴性为止的时间，也未观察到显著区别(p＝0.0159)。750/250mg组中，与安慰剂组相比，中央值短至48.4小时，针对最初确认病毒滴度阴性为止的时间，也未观察到显著区别(p＝0.0205)。As shown in Table 13, in the 375/125 mg group, the median value was as short as 49.8 hours compared with the placebo group, and no significant difference was observed in the time until the initial confirmation of negative viral titer (p = 0.0159). In the 750/250 mg group, the median value was as short as 48.4 hours compared with the placebo group, and no significant difference was observed in the time until the initial confirmation of negative viral titer (p = 0.0205).
此外，如图25所示那样，安慰剂组中，50％的患者的病毒滴度达到阴性为止的时间为在治疗开始起大约经过4.6天后。与此相对地，750/250mg组和375/125mg组中，50％的患者的病毒滴度达到阴性为止的时间为在治疗开始起大约经过2.6天。因此，确认最初确认50％的患者的病毒滴度为止的时间缩短约2天。In addition, as shown in FIG25 , in the placebo group, the time until the viral titer of 50% of the patients became negative was about 4.6 days after the start of treatment. In contrast, in the 750/250 mg group and the 375/125 mg group, the time until the viral titer of 50% of the patients became negative was about 2.6 days after the start of treatment. Therefore, the time until the viral titer of 50% of the patients was initially confirmed was shortened by about 2 days.
(2)各时点处的COVID-19的12症状总计分数的基线起算的变化量(Phase 2aPart)(2) Changes from baseline in the total score of 12 COVID-19 symptoms at each time point (Phase 2aPart)
各时点处的COVID-19的12症状总计分数的基线起算的变化量示于图6。The changes from baseline in the total score of the 12 symptoms of COVID-19 at each time point are shown in FIG6 .
Phase 2a Part的69例之中，以轻症/中等症的受试者为对象的375/125mg组中示出13例、750/250mg组中示出12例、安慰剂组中示出14例中的结果。Among the 69 cases in Phase 2a Part, results were shown for 13 cases in the 375/125 mg group, 12 cases in the 750/250 mg group, and 14 cases in the placebo group, which were subjects with mild/moderate symptoms.
如图26所示那样，375/125mg组和750/250mg组中，第2天(1次给与后)以后的全部时点处，与安慰剂组相比，COVID-19的12症状总计分数存在数值上改善的倾向。As shown in FIG26 , in the 375/125 mg group and the 750/250 mg group, at all time points after the second day (after the first administration), the total scores of the 12 symptoms of COVID-19 tended to be numerically improved compared with the placebo group.
(3)重症化抑制效果(Phase 2a Part)(3) Effect of suppressing the progression of symptoms (Phase 2a Part)
Phase 2a Part的69例之中，以轻症/中等症的受试者为对象，在给与开始后的任一时点顺序量表(以8阶段分类临床重症度的顺序尺度，表14)的分数首次恶化至3以上的受试者的比例示于表15。Among the 69 cases in Phase 2a Part, for subjects with mild/moderate symptoms, the proportion of subjects whose scores on the ordinal scale (an ordinal scale for clinical severity classified into 8 stages, Table 14) first deteriorated to 3 or more at any time point after the start of administration is shown in Table 15.
【表14】【Table 14】
【表15】【Table 15】
如表15所示那样，375/125mg组和750/250mg组中，未确认到给与开始后顺序量表首次恶化为3以上的病例。As shown in Table 15, in the 375/125 mg group and the 750/250 mg group, no case was observed in which the ordinal scale deteriorated to 3 or more for the first time after the start of administration.
有害事件的发现频度Frequency of harmful incidents
Phase 2a Part中，不存在死亡、危重的有害事件和导致给与中止的有害事件。There were no deaths, serious adverse events, or adverse events leading to discontinuation of administration in the Phase 2a Part.
本发明的制剂可用于12岁以上儿童及成人。The preparation of the present invention can be used for children over 12 years old and adults.
(实施例8)(Example 8)
(片剂的制造方法)(Method for producing tablets)
制造含有式(VII)所示的化合物的富马酸共晶体I形晶体的片剂。A tablet containing form I crystals of the fumaric acid cocrystal of the compound represented by formula (VII) was produced.
以下的表中，示出平均1个片剂的配方。将式(VII)所示的化合物的富马酸共晶体I形晶体、D-甘露醇(Roquette公司制)、交联羧甲基纤维素钠(DuPont公司制)、羟基丙基纤维素(日本曹达公司制)、轻质无水硅酸(Cabot公司制)和硬脂酸镁(Mallinckrodt公司制)过30目筛而筛分混合后，造粒。The following table shows the formulation of an average tablet. Fumaric acid eutectic I-type crystals of the compound represented by formula (VII), D-mannitol (manufactured by Roquette), cross-linked carboxymethyl cellulose sodium (manufactured by DuPont), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), light anhydrous silicic acid (manufactured by Cabot Corporation) and magnesium stearate (manufactured by Mallinckrodt Corporation) were sieved and mixed through a 30-mesh sieve, and then granulated.
添加经造粒和整粒的颗粒、结晶纤维素(旭化成公司制)和硬脂酸镁(Mallinckrodt公司制)、或轻质无水硅酸(Cabot公司制)并混合后，用静态压缩机或旋转式压片机，压缩成型为长径15.4mm×短径8mm，得到下述组成的片剂。After adding and mixing the granulated and sized particles, crystalline cellulose (produced by Asahi Kasei Corporation) and magnesium stearate (produced by Mallinckrodt Co., Ltd.), or light anhydrous silicic acid (produced by Cabot Corporation), the mixture is compressed using a static compressor or a rotary tablet press to form a tablet having a long diameter of 15.4 mm x short diameter of 8 mm to obtain a tablet of the following composition.
【表16】【Table 16】
试验例7：片剂的溶出试验Test Example 7: Dissolution test of tablets
(溶出试验法)(Dissolution test method)
对于实施例8A、8B、8C和8D，溶出试验通过第18修订日本药典溶出试验法第2法(含有表面活性剂的溶出试验第1液、桨法、桨转速：50rpm，结果：2片的平均值)而进行。For Examples 8A, 8B, 8C and 8D, the dissolution test was conducted by the 18th Revised Japanese Pharmacopoeia Dissolution Test Method 2 (dissolution test solution 1 containing surfactant, paddle method, paddle rotation speed: 50 rpm, result: average value of 2 tablets).
(实验结果)(Experimental results)
任一实施例中，均示出快速溶出性。In any of the examples, rapid dissolution was shown.
(实施例9)(Example 9)
(片剂的制造方法)(Method for producing tablets)
制造含有式(VII)所示的化合物的富马酸共晶体I形晶体的片剂。A tablet containing form I crystals of the fumaric acid cocrystal of the compound represented by formula (VII) was produced.
以下的表中，示出平均1个片剂的配方。将式(VII)所示的化合物的富马酸共晶体I形晶体、D-甘露醇(Roquette公司制)、交联羧甲基纤维素钠(DuPont公司制)、羟基丙基纤维素(日本曹达公司制)、轻质无水硅酸(Cabot公司制)和硬脂酸镁(Mallinckrodt公司制)过30目筛而筛分混合后，造粒。The following table shows the formulation of an average tablet. Fumaric acid eutectic I-type crystals of the compound represented by formula (VII), D-mannitol (manufactured by Roquette), cross-linked carboxymethyl cellulose sodium (manufactured by DuPont), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), light anhydrous silicic acid (manufactured by Cabot Corporation) and magnesium stearate (manufactured by Mallinckrodt Corporation) were sieved and mixed through a 30-mesh sieve, and then granulated.
添加经造粒和整粒的颗粒、结晶纤维素(旭化成公司制)和硬脂酸镁(Mallinckrodt公司制)、或轻质无水硅酸(Cabot公司制)并混合后，用静态压缩机或旋转式压片机，压缩成型为直径5mm或5.5mm，得到下述组成的片剂。After adding and mixing the granulated and sized particles, crystalline cellulose (manufactured by Asahi Kasei Corporation) and magnesium stearate (manufactured by Mallinckrodt Co., Ltd.), or light anhydrous silicic acid (manufactured by Cabot Corporation), the mixture is compressed into a diameter of 5 mm or 5.5 mm using a static compressor or a rotary tablet press to obtain tablets of the following composition.
【表17】【Table 17】
试验例8：片剂的溶出试验Test Example 8: Dissolution test of tablets
(溶出试验法)(Dissolution test method)
对于实施例9中的2个配方，溶出试验通过第18修订日本药典溶出试验法第2法(含有表面活性剂的溶出试验第1液、桨法、桨转速：50rpm，结果：2片的平均值)而进行。For the two formulations in Example 9, dissolution tests were conducted according to the 18th Revised Japanese Pharmacopoeia Dissolution Test Method 2 (dissolution test liquid 1 containing surfactant, paddle method, paddle speed: 50 rpm, result: average value of 2 tablets).
(实验结果)(Experimental results)
任一实施例中，均示出快速溶出性。In any of the examples, rapid dissolution was shown.
本发明的制剂可用于12岁以上儿童及成人。The preparation of the present invention can be used for children over 12 years old and adults.
(实施例10)(Example 10)
(颗粒剂的制造方法)(Method for producing granules)
制造含有式(VII)所示的化合物的富马酸共晶体I形晶体的颗粒剂。A granule containing form I crystals of the fumaric acid cocrystal of the compound represented by formula (VII) is produced.
以下的表中，示出平均1份颗粒剂的配方。将式(VII)所示的化合物的富马酸共晶体I形晶体、D-甘露醇(Roquette公司制)、氢化麦芽糖淀粉糖浆(麦芽糖醇，Roquette公司制)、交联羧甲基纤维素钠(DuPont公司制)、羟基丙基纤维素(日本曹达公司制)、轻质无水硅酸(Cabot公司制)、硬脂酸镁(Mallinckrodt公司制)和三氯蔗糖(三荣源ffi公司制)过30目筛而筛分混合后，造粒。The following table shows the formulation of the granules per part. Fumaric acid eutectic I-type crystals of the compound represented by formula (VII), D-mannitol (manufactured by Roquette), hydrogenated maltose starch syrup (maltitol, manufactured by Roquette), cross-linked sodium carboxymethylcellulose (manufactured by DuPont), hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.), light anhydrous silicic acid (manufactured by Cabot Co., Ltd.), magnesium stearate (manufactured by Mallinckrodt Co., Ltd.) and sucralose (manufactured by Sanyogen Co., Ltd.) were sieved and mixed through a 30-mesh sieve, and then granulated.
添加经造粒和整粒的颗粒、轻质无水硅酸(Cabot公司制)和三氯蔗糖(三荣源ffi公司制)并混合后，得到下述组成的颗粒剂。The granulated and sized particles, light anhydrous silicic acid (manufactured by Cabot Corporation) and sucralose (manufactured by Sanei Gen Co., Ltd.) were added and mixed to obtain granules having the following composition.
【表18】【Table 18】
试验例9：颗粒剂的溶出试验Test Example 9: Dissolution test of granules
(溶出试验法)(Dissolution test method)
对于实施例10中的2个配方，溶出试验通过第18修订日本药典溶出试验法第2法(含有表面活性剂的溶出试验第1液、桨法、桨转速：50rpm，结果：2颗粒剂的平均值)而进行。For the two formulations in Example 10, dissolution tests were conducted according to the 18th Revised Japanese Pharmacopoeia Dissolution Test Method 2 (dissolution test solution 1 containing surfactant, paddle method, paddle speed: 50 rpm, result: average value of 2 granules).
(实验结果)(Experimental results)
含量校正后的溶出试验结果示于图27，其结果是，任一实施例中，均示出快速溶出性。The results of the dissolution test after content correction are shown in FIG27 , and the results show that rapid dissolution was observed in all Examples.
试验例10：颗粒剂的随时间稳定性试验Test Example 10: Time-dependent stability test of granules
对于实施例10中的2个配方，示出确认随时间稳定性的结果。For the two formulations in Example 10, results of confirming stability over time are shown.
a.稳定性试验法a. Stability test method
将实施例10的制剂1)在DUMA瓶(塑料容器，GERRESHEIMER)闭塞状态在40℃、75％相对湿度下保管三周，或2)在加入了硅胶的DUMA瓶闭塞状态在40℃、75％相对湿度下保管三周，或3)在DUMA瓶闭塞状态在40℃、75％相对湿度下保管一个月，或4)在加入了硅胶的DUMA瓶闭塞状态在40℃、75％相对湿度下保管一个月。其后，测定本发明制剂中的式(VII)所示的化合物的相关物质量。The preparation of Example 10 was stored 1) in a DUMA bottle (plastic container, GERRESHEIMER) in a closed state at 40°C and 75% relative humidity for three weeks, 2) in a DUMA bottle with silica gel added in a closed state at 40°C and 75% relative humidity for three weeks, 3) in a DUMA bottle in a closed state at 40°C and 75% relative humidity for one month, or 4) in a DUMA bottle with silica gel added in a closed state at 40°C and 75% relative humidity for one month. Thereafter, the amount of the related substance of the compound represented by formula (VII) in the preparation of the present invention was measured.
(试样液制备方法)(Sample solution preparation method)
(测定方法)(Measurement method)
通过以下的方法、条件，用液相色谱，测定本发明制剂中的式(VII)所示的化合物的相关物质量。The amount of the relevant substance of the compound represented by formula (VII) in the preparation of the present invention was measured by liquid chromatography according to the following method and conditions.
·检测器：紫外吸光光度计(测定波长：222nm)Detector: UV spectrophotometer (measurement wavelength: 222nm)
·柱：C18柱Column: C18 column
·柱温度：40℃附近的一定温度Column temperature: Constant temperature around 40°C
·流动相A：0.01mol/L甲酸铵溶液、流动相B：乙腈Mobile phase A: 0.01 mol/L ammonium formate solution, mobile phase B: acetonitrile
·流动相A和流动相B的混合比将流动相B的混合比从9:1缓慢提高至1:9，以32分钟进行测定。Mixing Ratio of Mobile Phase A and Mobile Phase B The mixing ratio of mobile phase B was gradually increased from 9:1 to 1:9, and the measurement was performed over 32 minutes.
·流量：0.3mL/分钟Flow rate: 0.3mL/min
相关物质量将HPLC图表的色谱图的峰面积的总计记作100％，算出相对于其量的比例(％)。The amount of the related substance was calculated based on the total of the peak areas of the chromatogram of the HPLC chart being taken as 100%, and the ratio (%) to the amount was calculated.
b.结果b. Results
稳定性试验的结果示于以下的表19和20。实施例10的制剂的总相关物质量在任一条件下均未增加，是稳定的。The results of the stability test are shown in the following Tables 19 and 20. The total amount of related substances in the preparation of Example 10 did not increase under any conditions and was stable.
【表19】【Table 19】
【表20】【Table 20】
根据以上，本发明制剂对湿度和温度稳定性高。As described above, the preparation of the present invention has high stability to humidity and temperature.
以下所示的制剂例仅为例示，不意图以任何方式限定发明的范围。The preparation examples shown below are for illustrative purposes only and are not intended to limit the scope of the invention in any way.
本发明的化合物可以通过任意的以往的途径，特别是经肠、例如口服、例如以片剂、颗粒剂或胶囊剂的形态，或非口服、例如以注射液剂或混悬剂的形态，局部、例如以洗剂、凝胶剂、软膏剂或霜剂的形态，或以经鼻形态或栓剂形态作为药物组合物给与。与至少1种药学上可接受的载体或稀释剂一起，包含游离形态或药学上可接受的盐的形态的本发明的化合物的药物组合物可以通过以往的方法，利用混合、造粒或包衣法而制造。例如，作为口服用组合物，可以直肠含有赋形剂、崩解剂、粘结剂、润滑剂等和有效成分等的片剂、颗粒剂、胶囊剂。此外，作为注射用组合物，可以制成溶液剂或混悬剂，也可以被灭菌，此外，可以含有保存剂、稳定化剂、缓冲化剂等。The compounds of the present invention can be administered as a pharmaceutical composition by any conventional route, in particular enteral, for example, oral, for example, in the form of tablets, granules or capsules, or parenteral, for example, in the form of injection solutions or suspensions, topically, for example, in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories. Together with at least one pharmaceutically acceptable carrier or diluent, the pharmaceutical composition of the compound of the present invention in the form of a free form or a pharmaceutically acceptable salt can be manufactured by conventional methods, using mixing, granulation or coating methods. For example, as an oral composition, tablets, granules, and capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients can be administered rectally. In addition, as an injectable composition, it can be made into a solution or suspension, and can also be sterilized. In addition, it can contain a preservative, a stabilizer, a buffering agent, etc.
(制剂例1)混悬剂(Preparation Example 1) Suspension
在式(VII)所示的化合物的原药中，添加例如注射用水，制成混悬剂。The original drug of the compound represented by formula (VII) is added with water for injection, for example, to prepare a suspension.
(制剂例2)片剂(Preparation Example 2) Tablet
在式(VII)所示的化合物的原药中，作为添加剂，添加例如D-甘露醇、硬脂酸镁，制成片剂。The original drug of the compound represented by formula (VII) is prepared into tablets by adding, as additives, for example, D-mannitol and magnesium stearate.
(制剂例3)颗粒剂(Preparation Example 3) Granules
在式(VII)所示的化合物的原药中，作为添加剂，添加例如D-甘露醇、硬脂酸镁，制成颗粒剂。The original drug of the compound represented by formula (VII) is added with, for example, D-mannitol and magnesium stearate as additives to prepare granules.
工业实用性Industrial Applicability
通过本发明所涉及的制造方法制造的化合物具有对冠状病毒3CL蛋白酶的抑制作用，可以认为作为冠状病毒3CL蛋白酶所参与的疾病或状态的治疗剂和/或预防剂是有用的。本发明所涉及的新型的合成中间体或它们的盐、和本发明所涉及的制造方法对医药品制造是有用的。The compound produced by the production method of the present invention has an inhibitory effect on coronavirus 3CL protease, and is considered to be useful as a therapeutic agent and/or preventive agent for diseases or conditions in which coronavirus 3CL protease is involved. The novel synthetic intermediate or salt thereof and the production method of the present invention are useful for the production of pharmaceuticals.
本发明制剂具有对冠状病毒3CL蛋白酶的抑制作用，可以认为作为冠状病毒3CL蛋白酶所参与的疾病或状态的治疗剂和/或预防剂是有用的。The preparation of the present invention has an inhibitory effect on coronavirus 3CL protease and is considered to be useful as a therapeutic and/or preventive agent for diseases or conditions in which coronavirus 3CL protease is involved.
| Application Number | Priority Date | Filing Date | Title |
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| JP2021-189932 | 2021-11-24 | ||
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| Publication Number | Publication Date |
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| CN117255680Atrue CN117255680A (en) | 2023-12-19 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211151791.9APendingCN116514734A (en) | 2021-11-24 | 2022-09-21 | Method for producing triazine derivatives and preparations for oral administration containing triazine derivatives |
| CN202280007992.3APendingCN117255680A (en) | 2021-11-24 | 2022-11-22 | Formulations for oral administration containing triazine derivatives |
| Application Number | Title | Priority Date | Filing Date |
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| CN202211151791.9APendingCN116514734A (en) | 2021-11-24 | 2022-09-21 | Method for producing triazine derivatives and preparations for oral administration containing triazine derivatives |
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| CN (2) | CN116514734A (en) |
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| Date | Code | Title | Description |
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| PB01 | Publication | ||
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| WD01 | Invention patent application deemed withdrawn after publication | Application publication date:20231219 |