CN115209919A - 慢性心衰的治疗或预防方法 - Google Patents
慢性心衰的治疗或预防方法 Download PDFInfo
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- CN115209919A CN115209919A CN202180021810.3A CN202180021810A CN115209919A CN 115209919 A CN115209919 A CN 115209919A CN 202180021810 A CN202180021810 A CN 202180021810A CN 115209919 A CN115209919 A CN 115209919A
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- compound
- heart failure
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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Abstract
本发明的目的之一在于,提供慢性心衰的治疗或预防。提供慢性心衰的治疗或预防用药物组合物,其含有抑制SGLT1的化合物或其制药上可接受的盐;和慢性心衰的治疗或预防方法,其特征在于,给与抑制SGLT1的化合物或其制药上可接受的盐。
Description
技术领域
本发明涉及慢性心衰的治疗或预防用药物组合物,其含有抑制SGLT(Na+-葡萄糖协同转运蛋白)1的化合物或其制药上可接受的盐;和慢性心衰的治疗或预防方法,其特征在于,给与抑制SGLT1的化合物或其制药上可接受的盐。
背景技术
心衰是指被定义为某种心脏功能障碍,即心脏中发生器质性和/或功能性异常而导致心泵送功能的代偿机制失效,其结果是出现呼吸困难、疲倦感和/或浮肿,与其相伴运动耐受能力降低的临床综合征,其特征之一在于确认到左室舒张末期压力的上升。慢性心衰是这些状态慢性持续。
慢性心衰中,确认到动作时的疲劳感、咳嗽、浮肿和伴随其的体重增加等。慢性心衰基于左室射血分数,被分类为左室射血分数降低的心衰(以下称为“HFrEF”(heartfailure with reduced ejection fraction))和左室射血分数保持的心衰(以下称为“HFpEF”(heart failure with preserved ejection fraction))。
HFrEF被认为左室收缩能力障碍是主要病因,其特征在于,大多病例中确认到左室扩大。在此,扩大是指心脏的内径、内腔变大。HFrEF中,左室内径缩短率降低。
尽管确立了HFrEF的标准治疗,但任一药剂均无法解决低血压、心动过缓之类的血液动力学关联副作用和高钾血症、肾功能降低等这些药剂中共通的安全性方面的课题。进一步,仍然是预后不良的疾病。
另一方面,HFpEF被认为左室舒张能障碍是主要病因,其特征在于,大多病例中确认到左室肥大。在此,肥大是指心脏的壁厚变大的状态。
作为HFpEF的治疗药,尽管将利尿药、神经体液因子抑制药用于各自解除淤血、背景疾病,但不存在改善生命预后的药剂。
现有技术文献
专利文献
专利文献1:国际公开第2013/031922号
专利文献2:国际公开第2019/168096号
专利文献3:国际公开第2019/194207号。
附图说明
图1示出心肌梗塞后心衰大鼠介质组与假手术组相比,左室舒张末期压力显著增加,心肌梗塞后心衰大鼠中实施例1的化合物(本说明书中记作“化合物1”)与介质相比,左室舒张末期压力示出低值。图中的††表示相对于假手术组的p<0.01。
图2示出心肌梗塞后心衰大鼠介质组与假手术组相比,左室射血分数显著降低,心肌梗塞后心衰大鼠中化合物1(渐增)与介质相比,左室射血分数显著增加,化合物1(3mg/kg)与介质相比,左室射血分数示出高值。图中的††表示相对于假手术组的p<0.01,*表示相对于心肌梗塞后心衰大鼠介质组的p<0.05。
图3示出高血压性心衰大鼠介质组与正常对照组相比,左室舒张末期压力显著增加,高血压性心衰大鼠中化合物1与介质相比,左室舒张末期压力显著降低。图中的††表示相对于正常对照组的p<0.01,*和**表示相对于高血压性心衰大鼠介质组的p<0.05和p<0.01。
图4示出高血压性心衰大鼠介质组与正常对照组相比,舒张末期压力容量关系(本说明书中称为“EDPVR”(end-diastolic pressure-volume relationship))β显著增加,高血压性心衰大鼠中化合物1(渐增)与介质相比,EDPVRβ显著降低,化合物1(3mg/kg)与介质相比,EDPVRβ示出低值。图中的†表示相对于正常对照组的p<0.05,*表示相对于高血压性心衰大鼠介质组的p<0.05。
图5示出在任一组中,左室射血分数均未确认到变化。
图6示出高血压性心衰大鼠介质组与正常对照组相比,收缩期血压显著增加。图中的††表示相对于正常对照组的p<0.01。
图7示出在高血压性心衰大鼠中,化合物1与介质相比,对尿量未造成影响。
具体实施方式
以下,例示出多个具体方式。
[项1]
慢性心衰的治疗或预防用药物组合物,其含有抑制SGLT1的化合物或其制药上可接受的盐。
[项2]
慢性心衰的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐:
[化1]
[式中,
R1为氢或卤素,
R2为C1-6烷基或卤代C1-6烷基,
R3为
(1)C1-6烷基、
(2)卤代C1-6烷基、
(3)被R3A取代的吡啶基、或
(4)任选被R3B取代的吡嗪基、嘧啶基或哒嗪基、
R3A为氰基、卤素或卤代C1-3烷基,
R3B为卤素、羟基、C1-3烷基、卤代C1-3烷基、C1-3烷氧基或-N(R4)(R5),
R4和R5各自独立地为氢或C1-3烷基]。
[项3]
根据项1或2所述的药物组合物,其中,抑制SGLT1的化合物或式[I]的化合物或其制药上可接受的盐为式[II]至[V]中任一者的化合物或其制药上可接受的盐:
[化2]
[项4]
根据项1至3中任一者所述的药物组合物,其中,抑制SGLT1的化合物或式[I]的化合物或其制药上可接受的盐为式[II]的化合物或其制药上可接受的盐:
[化3]
[项5]
根据项1至4中任一者所述的药物组合物,其中,慢性心衰为HFrEF。
[项6]
根据项1至4中任一者所述的药物组合物,其中,慢性心衰为HFpEF。
[项7]
慢性心衰的治疗或预防方法,其特征在于,向对象给与治疗上有效量的抑制SGLT1的化合物或项2所述的式[I]的化合物或其制药上可接受的盐。
[项8]
抑制SGLT1的化合物或项2所述的式[I]的化合物或其制药上可接受的盐,其用于治疗或预防慢性心衰。
[项9]
抑制SGLT1的化合物或项2所述的式[I]的化合物或其制药上可接受的盐在制造用于治疗或预防慢性心衰的药物中的用途。
部分结构中的以下:
[化4]
的双波浪线表示该结构的键合部位。
“卤素”中,包括例如氟、氯、溴和碘。
“C1-3烷基”是指碳原子数1至3的直链状或支链状的饱和烃基。“C1-3烷基”中,包括甲基、乙基、正丙基和异丙基。
“C1-6烷基”是指碳原子数1至6的直链状或支链状的饱和烃基。“C1-6烷基”中,包括例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基和正己基。
“卤代C1-3烷基”是指被独立地选自上述“卤素”中的1至5个卤素取代的上述“C1-3烷基”。“卤代C1-3烷基”中,包括例如单氟甲基、二氟甲基、三氟甲基、2-氟乙基、2-氯乙基、2-溴乙基、1,1-二氟乙基、2,2,2-三氟乙基、五氟乙基、3-氟丙基、3-氯丙基、1,1-二氟丙基和3,3,3-三氟丙基。
“氟C1-3烷基”是指被1个至5个氟取代的上述“C1-3烷基”。“氟C1-3烷基”中,包括例如单氟甲基、二氟甲基、三氟甲基、2-氟乙基、1,1-二氟乙基、2,2,2-三氟乙基、五氟乙基、3-氟丙基、1,1-二氟丙基和3,3,3-三氟丙基。
“卤代C1-6烷基”是指被独立地选自上述“卤素”中的1至5个卤素取代的上述“C1-6烷基”。“卤代C1-6烷基”中,包括例如单氟甲基、二氟甲基、三氟甲基、2-氟乙基、2-氯乙基、2-溴乙基、1,1-二氟乙基、2,2,2-三氟乙基、五氟乙基、3-氟丙基、3-氯丙基、1,1-二氟丙基、3,3,3-三氟丙基、4,4,4-三氟丁基、5,5,5-三氟戊基和6,6,6-三氟己基。
“氟C1-6烷基”是指被1个至5个氟取代的上述“C1-6烷基”。“氟C1-6烷基”中,包括例如单氟甲基、二氟甲基、三氟甲基、2-氟乙基、1,1-二氟乙基、2,2,2-三氟乙基、五氟乙基、3-氟丙基、1,1-二氟丙基、3,3,3-三氟丙基、4,4,4-三氟丁基、5,5,5-三氟戊基和6,6,6-三氟己基。
“C1-3烷氧基”是指上述“C1-3烷基”与氧原子键合的基团。“C1-3烷氧基”中,包括甲氧基、乙氧基、正丙氧基和异丙氧基。
“吡啶基”是指下式中任一者。
[化5]
“吡嗪基”是指下式。
[化6]
“嘧啶基”是指下式中任一者。
[化7]
“哒嗪基”是指下式中任一者。
[化8]
“取代”包括化学上可接受的任意的取代。例如,“被R3A取代的吡啶基”是指下式中任一者。
[化9]
式[I]的化合物的各取代基包括对各自而例示的如下的具体的方式,此外将这些各取代基的具体的方式组合得到的方式也包括在式[I]的化合物中。
某个方式中,R1为卤素。另一方式中,R1为氟。
某个方式中,R2为C1-6烷基或氟C1-6烷基。另一方式中,R2为C1-6烷基。又另一方式中,R2为氟C1-3烷基。
某个方式中,R3为
(1)卤代C1-6烷基、
(2)被R3A取代的吡啶基、或
(3)任选被R3B取代的吡嗪基或嘧啶基。
另一方式中,R3选自卤代C1-6烷基和式[H1]至[H14]。
又另一方式中,R3为卤代C1-6烷基、式[H2]或[H8]。
[化10]
某个方式中,R3A为卤素或卤代C1-3烷基。另一方式中,R3A为氟或氟C1-3烷基。
某个方式中,R3B为卤素或卤代C1-3烷基。另一方式中,R3B为氟C1-3烷基。
某个方式中,R4和R5各自独立地为C1-3烷基。
某个方式中,式[I]的化合物为式[II]或[III]的化合物:
[化11]
另一方式中,式[I]的化合物为式[II]的化合物。又另一方式中,式[I]的化合物为式[III]的化合物的1水合物、即式[VI]的化合物:
[化12]
本说明书中制药上可接受的盐只要是本技术领域中已知的不伴随过度毒性的盐,则可以是任意盐。具体而言,可以举出与无机酸的盐、与有机酸的盐、与无机碱的盐、和与有机碱的盐等。各种方式的制药上可接受的盐是本领域公知的,例如记载于以下的参考文献:
(a)Berge等人,J.Pharm.Sci.,66,p1-19(1977)、
(b)Stahl等人,“Handbook of Pharmaceutical Salt:Properties,Selection,and Use”(Wiley-VCH,Weinheim,Germany,2002)、
(c)Paulekuhn等人,J.Med.Chem.,50,p6665-6672(2007)。
按照本身公知的方法,通过使式[I]的化合物与无机酸、有机酸、无机碱或与有机碱反应,由此能够分别得到其制药上可接受的盐。
作为与无机酸的盐,可以例示出与氢氟酸、盐酸、氢溴酸、氢碘酸、硝酸、磷酸或硫酸的盐。可以优选列举出与盐酸、硝酸、硫酸、磷酸或氢溴酸的盐。
作为与有机酸的盐,可以例示出与乙酸、己二酸、藻酸、4-氨基水杨酸、脱氢亚甲基柠檬酸、苯甲酸、苯磺酸、依地酸钙、樟脑酸、樟脑-10-磺酸、碳酸、柠檬酸、依地酸、乙烷-1,2-二磺酸、十二烷基硫酸、乙磺酸、富马酸、葡庚糖酸、葡萄糖酸、葡萄糖醛酸、葡庚糖酸、羟乙酰基阿散酸、己基间苯二酚、羟基-萘甲酸、2-羟基-1-乙磺酸、乳酸、乳糖酸、苹果酸、马来酸、扁桃酸、甲磺酸、甲基硫酸、甲基硝酸、亚甲基双(水杨酸)、半乳糖二酸、萘-2-磺酸、2-萘甲酸、1,5-萘二磺酸、油酸、草酸、帕莫酸、泛酸、果胶酸、苦味酸、丙酸、聚半乳糖醛酸、水杨酸、硬脂酸、丁二酸、鞣酸、酒石酸、茶氯酸、硫氰酸、三氟乙酸、对甲苯磺酸、十一烷酸、天冬氨酸或谷氨酸的盐。可以优选举出与草酸、马来酸、柠檬酸、富马酸、乳酸、苹果酸、丁二酸、酒石酸、乙酸、三氟乙酸、苯甲酸、葡萄糖醛酸、油酸、帕莫酸、甲磺酸、苯磺酸、对甲苯磺酸或2-羟基-1-乙磺酸的盐。
作为与无机碱的盐,可以例示出与锂、钠、钾、镁、钙、钡、铝、锌、铋或铵的盐。可以优选举出与钠、钾、钙、镁或锌的盐。
作为与有机碱的盐,可以例示出与槟榔碱、甜菜碱、胆碱、克立咪唑、乙二胺、N-甲基葡糖胺、N-苯甲基苯乙基胺、三(羟基甲基)甲基胺、精氨酸或赖氨酸的盐。可以优选举出与三(羟基甲基)甲基胺、N-甲基葡糖胺或赖氨酸的盐。
抑制SGLT1的化合物或其制药上可接受的盐(以下也称为“SGLT1抑制剂”)只要是抑制SGLT1的物质则可以是任意物质,可以为低分子化合物、核酸、多肽、蛋白质、抗体、疫苗等。SGLT1抑制活性可以通过本领域技术人员公知的方法测定,例如可以按照专利文献1至3中任一者所述的评价方法,基于通过SGLT1输送的α-甲基-D-吡喃葡萄糖苷的标记体(14C-AMG)的细胞内摄入量而算出。
某个方式中,SGLT1抑制剂为式[I]的化合物或其制药上可接受的盐:
[化13]
[式中,各标记与前述为相同含义]。
式[I]中包括的化合物可以通过本领域技术人员公知的方法制造,例如可以通过专利文献1至3中记载的任一方法制造。此外,式[I]中包括的化合物的SGLT1抑制活性通过这些文献确认。
本说明书中,SGLT1抑制剂可以与其他药剂、例如抑制SGLT2的化合物或其制药上可接受的盐(以下也称为“SGLT2抑制剂”)组合使用而治疗和/或预防慢性心衰。SGLT2抑制剂只要是抑制SGLT2的物质,即可为任意物质,可以是低分子化合物、核酸、多肽、蛋白质、抗体、疫苗等。某个方式中,SGLT2抑制剂是具有通过抑制葡萄糖从尿的再摄取而增加糖的尿中排泄量,从而能够降低血糖值的功能的物质。
SGLT1抑制剂(例如式[I]的化合物或其制药上可接受的盐)和SGLT2抑制剂有时以溶剂化物的形式存在。溶剂化物是指例如式[I]的化合物或其制药上可接受的盐上配位有溶剂的分子。溶剂化物只要是制药上可接受的溶剂化物即可,可以举出式[I]的化合物或其制药上可接受的盐的水合物、乙醇化物、和二甲基亚砜化物等。具体而言,可以举出式[I]的化合物的半水合物、1水合物、2水合物或1乙醇化物、或者式[I]的化合物的钠盐的1水合物或2盐酸盐的2/3乙醇化物等。这些溶剂化物可以按照公知的方法得到。例如,式[III]的化合物如下式[VI]那样,可以以1水合物形式存在。
[化14]
式[I]的化合物可以被同位素(2H、3H、14C、35S等)标记。
式[I]的化合物或其制药上可接受的盐优选为实质上精制的式[I]的化合物或其制药上可接受的盐。进一步优选为精制为80%以上的纯度的式[I]的化合物或其制药上可接受的盐。
抑制SGLT1是指抑制SGLT1的功能从而使其活性消失或减弱。优选抑制人SGLT1。SGLT1的功能的抑制或活性的消失或者减弱优选在人的临床应用中进行。某个方式中,通过抑制SGLT1,抑制左室舒张末期压力的上升,和/或增加左室射血分数,因此改善HFrEF,具有慢性心衰的预防或治疗效果。另一方式中,通过抑制SGLT1,左室舒张末期压力降低,和/或EDPVRβ降低,因此改善HFpEF,具有慢性心衰的预防或治疗效果。SGLT1抑制剂能够改善HFrEF和HFpEF中任一者或两者。
抑制SGLT2是指抑制SGLT2的功能从而使其活性消失或减弱。优选抑制人SGLT2。SGLT2的功能的抑制或活性的消失或者减弱优选在人的临床应用中进行。
本说明书中SGLT2抑制剂中,包括例如糖苷化合物或者其盐或它们的溶剂化物。在此,糖苷化合物是指糖或糖衍生物与糖苷配基部分通过糖苷键(例如C-糖苷键合或O-糖苷键合)键合的化合物,糖或糖衍生物具有下述结构。
[化15]
[式中,Y为O或S,糖苷键与1位的碳原子形成]
本说明书中SGLT2抑制剂中,包括例如以下的物质。应予说明,为了方便,本说明书整体使用惯用名。
[表1]
[表2]
某个方式中,SGLT1抑制剂可以通过与SGLT2抑制剂组合使用而向对象给与,用于慢性心衰的治疗和/或预防。
另一方式中,提供含有SGLT1抑制剂的慢性心衰的治疗或预防用药物,其特征在于,组合使用SGLT1抑制剂和SGLT2抑制剂。
又另一方式中,提供含有SGLT2抑制剂的慢性心衰的治疗或预防用药物,其特征在于,组合使用SGLT1抑制剂和SGLT2抑制剂。
又另一方式中,提供含有SGLT1抑制剂的慢性心衰的治疗或预防用药物,其特征在于,对正在接受利用SGLT2抑制剂的治疗的对象给与。
又另一方式中,提供含有SGLT2抑制剂的慢性心衰的治疗或预防用药物,其特征在于,对正在接受利用SGLT1抑制剂的治疗的对象给与。
本说明书中组合使用是指以任意的顺序向对象给与例如SGLT1抑制剂和SGLT2抑制剂。各药剂各自具有不同作用机理,因此通过组合使用,能够实现加合的或协同的治疗或预防效果。又另一方式中,组合使用通过使用多种作用机制不同的药剂,与单独给与1种药剂的情况相比,可以减少各药剂的给与量,可以减轻各药剂固有的副作用。在此,作为副作用,可以举出例如低血糖、体重增加、脱水、多尿、尿频等。某个方式中,SGLT1抑制剂与SGLT2抑制剂可以向对象同时、连续、或隔有一定间隔(例如30分钟以内、1小时以内、2小时以内、4小时以内),一起、或分别以任意的顺序给与。一种药剂在将其向对象给与时,可以在最初给与的另一种药剂中包含的有效成分在对象的体内以治疗上有效量存在的期间给与。另一方式中,SGLT1抑制剂与SGLT2抑制剂可以作为将这些药剂组合得到的单一的合剂而向对象给与。这些药剂的给与比和配合比可以根据给与对象、给与途径、对象疾病、症状、疾病的危重度、和它们的组合而适当选择。例如,给与对象为人的情况下,相对于SGLT1抑制剂1重量份,可以使用0.01重量份至1000重量份的SGLT2抑制剂。
某个方式中,SGLT1抑制剂与SGLT2抑制剂的组合使用中,包括式[I]的化合物或其制药上可接受的盐与糖苷化合物或者其盐或它们的溶剂化物的组合使用。
另一方式中,SGLT1抑制剂与SGLT2抑制剂的组合使用中,包括式[II]的化合物或其制药上可接受的盐与糖苷化合物或者其盐或它们的溶剂化物的组合使用。
某个方式中,SGLT1抑制剂与SGLT2抑制剂的组合使用中,包括例如
式[I]的化合物或其制药上可接受的盐与达格列净、
式[I]的化合物或其制药上可接受的盐与依格列净、
式[I]的化合物或其制药上可接受的盐与托格列净、
式[I]的化合物或其制药上可接受的盐与恩格列净、
式[I]的化合物或其制药上可接受的盐与卡格列净、和
式[I]的化合物或其制药上可接受的盐与鲁格列净
的组合使用。
另一方式中,SGLT1抑制剂与SGLT2抑制剂的组合使用中,包括
式[II]的化合物或其制药上可接受的盐与达格列净、
式[II]的化合物或其制药上可接受的盐与依格列净、
式[II]的化合物或其制药上可接受的盐与托格列净、
式[II]的化合物或其制药上可接受的盐与恩格列净、
式[II]的化合物或其制药上可接受的盐与卡格列净、和
式[II]的化合物或其制药上可接受的盐与鲁格列净
的组合使用。
本说明书中组合使用是指包括式[I]的化合物或其制药上可接受的盐与达格列净的组合使用。
本说明书中组合使用是指包括式[I]的化合物或其制药上可接受的盐与恩格列净的组合使用。
本说明书中组合使用是指包括式[II]的化合物或其制药上可接受的盐与达格列净的组合使用。
本说明书中组合使用是指包括式[II]的化合物或其制药上可接受的盐与恩格列净的组合使用。
本说明书中药剂是指SGLT1抑制剂或SGLT2抑制剂。某一药剂对接受基于另一药剂的治疗的对象给与是指组合使用的一个方式,包括例如将某一药剂对对象给与时,在先给与的另一药剂中包含的有效成分在对象的体内以治疗上有效量存在的期间给与该某一药剂。
本说明书中SGLT1抑制剂的治疗上有效量可以根据给与对象、给与途径、对象疾病、症状、疾病的危重度、和它们的组合而适当变更。对人(体重60kg)口服给与的情况,作为治疗上有效量的下限值,可以举出例如每1日约0.01mg、约0.1mg、约0.5mg、约1mg、约10mg、约20mg或约50mg,作为治疗上有效量的上限值,可以举出例如每1日约1mg、约5mg、约10mg、约20mg、约50mg、约100mg、约200mg、约500mg或约1000mg。
作为本说明书中SGLT1抑制剂和药物组合物的给与次数,可以举出各自1日1次、2次、3次或其以上的次数。
本说明书中治疗是指包括症状的改善、重症化的防止、缓解的维持、和复发的防止。例如,慢性心衰的治疗是指包括心功能的恢复和改善,具体而言,包括左室舒张末期压力的降低、左室射血分数的上升、和EDPVR(舒张末期压力容量关系)β的降低。
本说明书中的“预防”是指包括抑制症状的发病。例如,慢性心衰的预防是指包括心功能的维持,具体而言,包括左室舒张末期压力的上升抑制、左室射血分数的维持、和收缩期血压的维持。
本说明书中的“慢性心衰”有时也被称为淤血性心衰,包括HFrEF和HFpEF。“HFrEF”有时也被称为收缩心衰、收缩性心衰、或收缩期心衰,包括例如心肌梗塞后心衰。“HFpEF”有时也被称为舒张心衰、舒张性心衰、或舒张期心衰,包括例如高血压性心衰。
本说明书中的“HFrEF”被定义为左室射血分数降低的心衰,更具体而言,被定义为左室射血分数低于45%的心衰。某个方式中,HFrEF中,包括左室射血分数低于40%的心衰。另一方式中,HFrEF中,包括左室射血分数低于35%的心衰。
某个方式中,HFrEF中,包括因冠状动脉疾病而发生的HFrEF。作为冠状动脉疾病,可以举出例如缺血性心脏病,具体而言心绞痛和心肌梗塞。心绞痛是因动脉硬化等而导致冠状动脉变窄所引起的疾病,例如葡萄糖在血中的过量吸收可能成为一个原因。心肌梗塞是因冠状动脉堵塞而引起的疾病,例如葡萄糖在心肌细胞中的过量吸收可能成为一个原因。
本说明书中的“HFpEF”被定义为左室射血分数保持的心衰,更具体而言,被定义为左室射血分数为45%以上的心衰。某个方式中,HFpEF中,包括左室射血分数为50%以上的心衰。
某个方式中,HFpEF中,包括因高血压而发生的HFpEF。
左室射血分数是每次心跳心脏送出的血液量(泵出量)除以心脏舒张时的左室舒张末期容量得到的值。
左室射血分数可以使用例如超声诊断装置而得到。
EDPVR表示舒张末期容量与舒张末期压力的关系,其关系性可以用指数曲线近似。作为该曲线的斜率的EDPVRβ其值越高,则表示心脏越坚硬而难以舒张。即,EDPVRβ是左室舒张能力的指标之一。例如,EDPVRβ大于0.015的情况下,是左室舒张能力降低的状态。
EDPVR可以使用例如压力容量测量导管系统得到。
某个方式中,本发明是慢性心衰的治疗或预防用药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是因冠状动脉疾病或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有SGLT1抑制剂。另一方式中,本发明是因心绞痛、心肌梗塞或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是用于降低左室舒张末期压力高于正常范围的个体中的左室舒张末期压力的药物组合物,其含有SGLT1抑制剂。某个方式中,左室舒张末期压力的正常范围为4至8mmHg。
某个方式中,本发明是HFrEF的治疗或预防用药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是因冠状动脉疾病而产生的HFrEF的治疗或预防用药物组合物,其含有SGLT1抑制剂。另一方式中,本发明是因心绞痛或心肌梗塞而产生的HFrEF的治疗或预防用药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是用于使左室射血分数降低至低于45%的个体中的左室射血分数上升的药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是HFpEF的治疗或预防用药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是因高血压而产生的HFpEF的治疗或预防用药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是用于降低EDPVR(舒张末期压力容量关系)β高的个体中的EDPVR(舒张末期压力容量关系)β的药物组合物,其含有SGLT1抑制剂。
某个方式中,本发明是慢性心衰的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是因冠状动脉疾病或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。另一方式中,本发明是因心绞痛、心肌梗塞或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是用于降低左室舒张末期压力高于正常范围的个体中的左室舒张末期压力的药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是HFrEF的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是因冠状动脉疾病而产生的HFrEF的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。另一方式中,本发明是因心绞痛或心肌梗塞而产生的HFrEF的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是用于使左室射血分数降低至低于35%的个体中的左室射血分数上升的药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是HFpEF的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是因高血压而产生的HFpEF的治疗或预防用药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是用于降低EDPVR(舒张末期压力容量关系)β高于0.015的个体中的EDPVR(舒张末期压力容量关系)β的药物组合物,其含有式[I]的化合物或其制药上可接受的盐。
某个方式中,本发明是慢性心衰的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是因冠状动脉疾病或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。另一方式中,本发明是因心绞痛、心肌梗塞或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是用于降低左室舒张末期压力高于正常范围的个体中的左室舒张末期压力的药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是HFrEF的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是因冠状动脉疾病而产生的HFrEF的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。另一方式中,本发明是因心绞痛或心肌梗塞而产生的HFrEF的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是用于使左室射血分数降低至低于35%的个体中的左室射血分数上升的药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是HFpEF的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是因高血压而产生的HFpEF的治疗或预防用药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是用于降低EDPVR(舒张末期压力容量关系)β高于0.015的个体中的EDPVR(舒张末期压力容量关系)β的药物组合物,其含有式[II]的化合物或其制药上可接受的盐。
某个方式中,本发明是慢性心衰的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是因冠状动脉疾病或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。另一方式中,本发明是因心绞痛、心肌梗塞或高血压而产生的慢性心衰的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是用于降低左室舒张末期压力高于正常范围的个体中的左室舒张末期压力的药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是HFrEF的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是因冠状动脉疾病而产生的HFrEF的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。另一方式中,本发明是因心绞痛或心肌梗塞而产生的HFrEF的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是用于使左室射血分数降低至低于35%的个体中的左室射血分数上升的药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是HFpEF的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是因高血压而产生的HFpEF的治疗或预防用药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
某个方式中,本发明是用于降低EDPVR(舒张末期压力容量关系)β高于0.015的个体中的EDPVR(舒张末期压力容量关系)β的药物组合物,其含有SGLT1抑制剂和SGLT2抑制剂。
本说明书中的药物组合物可以按照药物制剂的技术领域中公知的方法,通过将SGLT1抑制剂的治疗上有效量与至少1种以上的制药上可接受的载体等和根据需要的SGLT2抑制剂适当混合等而制造。该药物组合物中的SGLT1抑制剂的含量根据剂型、给与量等而不同,例如为组合物整体的0.1至100重量%。
作为本说明书中药物组合物的剂型,可以举出片剂、胶囊剂、颗粒剂、散剂、锭剂、糖浆剂、乳剂、混悬剂等口服剂、和外用剂、栓剂、注射剂、滴眼剂、经鼻剂、经肺剂等非口服剂。
作为制药上可接受的载体,可以举出作为制剂原材料而通用的各种有机或无机载体物质,可以举出固体制剂中的赋形剂、崩解剂、粘结剂、流化剂、润滑剂等、和液状制剂中的溶剂、助溶剂、悬浮剂、等渗剂、缓冲剂、无痛化剂等和半固体制剂中的基质、乳化剂、湿润剂、稳定剂、稳定化剂、分散剂、增塑剂、pH调节剂、吸收促进剂、凝胶化剂、防腐剂、填充剂、溶解剂、助溶剂、悬浮剂等。进一步根据需要,可以追加保存剂、抗氧化剂、着色剂、甜味剂等添加物。
作为赋形剂,可以举出乳糖、白糖、D-甘露醇、D-山梨糖醇、玉米淀粉、糊精、微晶纤维素、结晶纤维素、羧甲基纤维素、羧甲基纤维素钙、羧基甲基淀粉钠、低取代度羟基丙基纤维素和阿拉伯胶等。
作为崩解剂,可以举出羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羧基甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代度羟基丙基纤维素、羟基丙基甲基纤维素和结晶纤维素等。
作为粘结剂,可以举出羟基丙基纤维素、羟基丙基甲基纤维素、聚维酮、结晶纤维素、白糖、糊精、淀粉、明胶、羧甲基纤维素钠和阿拉伯胶等。
作为流化剂,可以举出轻质无水硅酸和硬脂酸镁等。
作为润滑剂,可以举出硬脂酸镁、硬脂酸钙和滑石等。
作为溶剂,可以举出精制水、乙醇、丙二醇、聚乙二醇、芝麻油、玉米油和橄榄油等。
作为助溶剂,可以举出丙二醇、D-甘露醇、苯甲酸苯甲酯、乙醇、三乙醇胺、碳酸钠和柠檬酸钠等。
作为悬浮剂,可以举出苯扎氯铵、羧甲基纤维素、羟基丙基纤维素、丙二醇、聚维酮、甲基纤维素、和单硬脂酸丙三醇酯等。
作为等渗剂,可以举出葡萄糖、D-山梨糖醇、氯化钠和D-甘露醇等。
作为缓冲剂,可以举出磷酸氢钠、乙酸钠、碳酸钠和柠檬酸钠等。
作为无痛化剂,可以举出苯甲醇等。
作为基质,可以举出水、动植物油(橄榄油、玉米油、花生油、芝麻油、蓖麻油等)、低级醇类(乙醇、丙醇、丙二醇、1,3-丁二醇、苯酚等)、高级脂肪酸和其酯、蜡类、高级醇、多元醇、烃类(白色凡士林、液体石蜡、石蜡等)、亲水凡士林、精制羊毛脂、吸水软膏、加水羊毛脂、亲水软膏、淀粉、普鲁兰多糖、阿拉伯胶、黄蓍胶、明胶、葡聚糖、纤维素衍生物(甲基纤维素、羧基甲基纤维素、羟基乙基纤维素、羟基丙基纤维素等)、合成高分子(羧基乙烯基聚合物、聚丙烯酸钠、聚乙烯醇、聚乙烯基吡咯烷酮等)、丙二醇、聚乙二醇(聚乙二醇200~600等)、和它们中2种以上的组合。
作为保存剂,可以举出对羟基苯甲酸乙酯、氯丁醇、苯甲醇、脱氢乙酸钠和山梨酸等。
作为抗氧化剂,可以举出亚硫酸钠和抗坏血酸等。
作为着色剂,可以举出食用色素(食用红色2号或3号、食用黄色4号或5号等)、和β-胡萝卜素等。
作为甜味剂,可以举出糖精钠、甘草酸二钾、和阿斯巴甜等。
本说明书中药物组合物可以对人和除了人之外的哺乳动物(小鼠、大鼠、仓鼠、豚鼠、兔、猫、狗、猪、牛、马、羊、猴等),口服或非口服(局部、直肠、静脉给与、肌肉内、皮下等)给与。给与量根据给与对象、疾病、症状、剂型、给与途径等而不同,例如对成人患者(体重60kg)口服给与的情况的给与量针对有效成分,为每1日、通常约0.01mg至约1g的范围。可以将这些量分为1次至多次给与。某个方式中,SGLT1抑制剂可以与其他药剂制剂化为单独的药物组合物而组合使用给与,也可以以不同给与途径以任意的顺序和时间间隔向对象给与。另一方式中,利用组合使用的各药剂的给与量可以与单独给与各药剂的情况相比减少,向成人患者(体重60kg)口服给与的情况的给与量可以为每1日约0.01mg至1000mg的范围。
某一方式中,SGLT1抑制剂可以以试剂盒(给与、治疗和/或预防试剂盒等)、包装(包装物等)和药剂组(和/或容器)的形态提供,其一起包含SGLT1抑制剂、适当的SGLT2抑制剂、和记载了为治疗和/或预防而是否能够使用或应当使用的记载物。这样的试剂盒、包装和药剂组可以具有填充了SGLT1抑制剂、适当的SGLT2抑制剂、和/或其他药剂或药物(或成分)的1个以上的容器。作为这样的试剂盒、包装和药剂组的例,可以举出适当面向对象疾病的治疗和/或预防的商业用试剂盒、商业用包装和商业用药剂组。作为这样的试剂盒、包装和药剂组中包含的记载物,可以举出根据管制药物或生物学的产品的制造、使用或销售的政府机关所指示的形态的注意事项或随附文件,其为与对人的给与相关的产品的制造、使用或销售所涉及的表示该政府机关的许可的注意事项或随附文件。上述试剂盒、包装和药剂组中,可以包括经包装的产品,此外,也可以包括为了适当的给与步骤(步骤)而构成的结构物,也可以包括包含对象疾病的治疗和/或预防等的以能够实现更优选的医学上的治疗和/或预防的方式而构成的结构物。
实施例
按照专利文献2和3的记载的制造方法,得到实施例1至40的化合物(以下称为化合物1至40)。各化合物的物性值和SGLT1抑制活性数据如这些文献中记载那样。
[表3-1]
[表3-2]
[表3-3]
[表3-4]
[表3-5]
[表3-6]
[表3-7]
[表3-8]
[试验例1]
对心肌梗塞后心衰大鼠中的心功能的评价
对雄性SD大鼠(8周龄、日本SLC株式会社)用戊巴比妥麻醉后,在人工呼吸器管理下开胸,将冠状动脉左前降支永久结扎,制作心肌梗塞后心衰大鼠。设定同样开胸而仅进行心脏露出的假手术组。心肌梗塞制作2周后,对心肌梗塞后心衰大鼠组,各自1日1次口服给与介质(0.5%甲基纤维素液)或化合物1(3mg/kg组或渐增组)。渐增组从3mg/kg开始,2周后增量至6mg/kg,进一步2周后增量至8mg/kg,其以后以8mg/kg给与。假手术组中,将介质1日1次口服给与。给与8周后,使用超声诊断装置(Aplio 300、东芝medical systems株式会社)测定左室射血分数,将Catheter-tipped micromanometer(Model SPR-320、Millar Inc.)从左颈动脉插入左室内,测定左室舒张末期压力。统计分析在假手术介质给与组和心肌梗塞后心衰大鼠介质给与组间实施Aspin-Welch t test。相对于心肌梗塞后心衰大鼠的介质的化合物1的检验进行Steel的多组检验。显著水平设为两侧5%。其结果是,心肌梗塞后心衰大鼠介质给与组与假手术介质给与组相比,左室射血分数降低,左室舒张末期压力上升,因此能够确认HFrEF发病。心肌梗塞后心衰大鼠中,化合物1增加了左室射血分数,抑制左室舒张末期压力的上升,因此改善了HFrEF。结果示于图1和2。
通过试验例1,确认化合物1具有HFrEF改善效果。通过与试验例1同样的方法,可以确认化合物2至40的HFrEF改善效果。通过与试验例1同样的方法,可以确认组合使用化合物1至40(例如化合物1)与SGLT2抑制剂(例如达格列净)的HFrEF改善效果。
[试验例2]
对高血压性心衰大鼠中的心功能的评价
对雄性DIS/Eis(Dahl-Iwai S)大鼠(Dahl大鼠)(7周龄、日本SLC株式会社),喂食高食盐食物(MF 8%氯化钠制备饲料、oriental酵母工业株式会社),制作高血压性心衰大鼠。正常对照喂食通常食物(CRF-1固型、oriental酵母工业株式会社)。3周后,确认病态(高血压或心肥大)的发病后,对高血压性心衰大鼠组,各自1日1次口服给与介质(0.5%甲基纤维素液)或化合物1(3mg/kg组或渐增组)。渐增组从3mg/kg开始,1周后增量至6mg/kg,进一步1周后阶段性增量至8mg/kg,其以后以8mg/kg给与。正常对照组中,将介质1日1次口服给与。给与5周后,使用超声诊断装置(Aplio 300、东芝medical systems株式会社),使用左室射血分数和非观血式自动血压测定装置(BP-98A、株式会社ソフトロン),测定收缩期血压。给与6周后,将ADVantage P-V catheter(Model FTH-1918B-E318、Transonic ScisenseInc.)从心尖部插入左室内,测定左室舒张末期压力。进一步,使用ADVantage P-Vcatheter和Ultrasonic flow probe(Model 2.5PSB1459、Transonic Scisense Inc.),由利用一过性下腔静脉阻塞的压力容量关系,算出EDPVRβ。统计分析在正常对照介质给与组和高血压性心衰大鼠介质给与组间实施Student test或Aspin-Welch t test。相对于高血压性心衰大鼠的介质的化合物1的检验进行Dunnett的多组检验。显著水平设为两侧5%。其结果是,高血压性心衰大鼠与正常对照组相比,EDPVRβ和左室舒张末期压力上升,未确认到左室射血分数的降低,因此可以确认HFpEF发病。进一步,高血压性心衰大鼠中,化合物1降低EDPVRβ和左室舒张末期压力,改善了HFpEF。此时,高血压性心衰大鼠与正常对照组相比,确认到收缩期血压的增加,呈现高血压,但化合物1对收缩期血压不造成影响。此外,高血压性心衰大鼠中化合物1对尿量不造成影响。结果示于图3、4、5、6和7。
通过试验例2,确认化合物1具有HFpEF改善效果。通过与试验例2同样的方法,可以确认化合物2至40的HFpEF改善效果。通过与试验例2同样的方法,可以确认组合使用化合物1至40(例如化合物1)与SGLT2抑制剂(例如达格列净)的HFpEF改善效果。
[制剂例]
作为式[I]的化合物的制剂例,可以举出例如下述的制剂配方,但不因此受到限定。
制剂例1(胶囊的制造)
(1)化合物1 30mg
(2)微晶纤维素 10mg
(3)乳糖 19mg
(4)硬脂酸镁 1mg
将成分(1)、(2)、(3)和(4)混合,填充在明胶胶囊中。
制剂例2(片剂的制造)
(1)化合物1 10g
(2)乳糖 50g
(3)玉米淀粉 15g
(4)羧甲基纤维素钙 44g
(5)硬脂酸镁 1g
将成分(1)、(2)、(3)的全部量和30g的成分(4)用水炼合,真空干燥后,进行整粒。向该整粒末中,混合14g的成分(4)和1g的成分(5),通过压片机压片。以这样的方式,得到平均1片含有10mg化合物1的片剂1000片。
工业实用性
期待抑制SGLT1的化合物或其制药上可接受的盐对慢性心衰的治疗或预防是有用的。
Claims (9)
1.慢性心衰的治疗或预防用药物组合物,其含有抑制SGLT1的化合物或其制药上可接受的盐。
5.根据权利要求1至4中任一项所述的药物组合物,其中,慢性心衰为HFrEF。
6.根据权利要求1至4中任一项所述的药物组合物,其中,慢性心衰为HFpEF。
7.慢性心衰的治疗或预防方法,其特征在于,向对象给与治疗上有效量的抑制SGLT1的化合物或权利要求2所述的式[I]的化合物或其制药上可接受的盐。
8.抑制SGLT1的化合物或权利要求2所述的式[I]的化合物或其制药上可接受的盐,其用于治疗或预防慢性心衰。
9.抑制SGLT1的化合物或权利要求2所述的式[I]的化合物或其制药上可接受的盐在制造用于治疗或预防慢性心衰的药物中的用途。
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EP (1) | EP4122495A4 (zh) |
JP (1) | JPWO2021187548A1 (zh) |
KR (1) | KR20220156574A (zh) |
CN (1) | CN115209919A (zh) |
AU (1) | AU2021237149A1 (zh) |
BR (1) | BR112022018396A2 (zh) |
CA (1) | CA3175131A1 (zh) |
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EP4026562A4 (en) * | 2019-09-04 | 2023-09-13 | Japan Tobacco Inc. | METHOD FOR TREATING OR PREVENTING CHRONIC KIDNEY DISEASE |
WO2023210634A1 (ja) * | 2022-04-28 | 2023-11-02 | 国立大学法人東海国立大学機構 | 拡張障害を伴う心不全の治療用医薬組成物 |
Citations (4)
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CN103917535A (zh) * | 2011-08-31 | 2014-07-09 | 日本烟草产业株式会社 | 吡唑化合物和其药物用途 |
WO2019144864A1 (en) * | 2018-01-23 | 2019-08-01 | Sunshine Lake Pharma Co., Ltd. | Glucopyranosyl derivative and use thereof |
US20190330193A1 (en) * | 2018-04-04 | 2019-10-31 | Japan Tobacco Inc. | Pyrazole compounds substituted with heteroaryl and pharmaceutical use thereof |
US20190352284A1 (en) * | 2018-03-01 | 2019-11-21 | Japan Tobacco Inc. | Methyllactam ring compound and pharmaceutical use thereof |
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- 2021-03-18 JP JP2022508425A patent/JPWO2021187548A1/ja active Pending
- 2021-03-18 KR KR1020227035794A patent/KR20220156574A/ko unknown
- 2021-03-18 EP EP21772065.5A patent/EP4122495A4/en active Pending
- 2021-03-18 US US17/796,606 patent/US20230321044A1/en active Pending
- 2021-03-18 CN CN202180021810.3A patent/CN115209919A/zh active Pending
- 2021-03-18 BR BR112022018396A patent/BR112022018396A2/pt not_active Application Discontinuation
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CN103917535A (zh) * | 2011-08-31 | 2014-07-09 | 日本烟草产业株式会社 | 吡唑化合物和其药物用途 |
WO2019144864A1 (en) * | 2018-01-23 | 2019-08-01 | Sunshine Lake Pharma Co., Ltd. | Glucopyranosyl derivative and use thereof |
US20190352284A1 (en) * | 2018-03-01 | 2019-11-21 | Japan Tobacco Inc. | Methyllactam ring compound and pharmaceutical use thereof |
US20190330193A1 (en) * | 2018-04-04 | 2019-10-31 | Japan Tobacco Inc. | Pyrazole compounds substituted with heteroaryl and pharmaceutical use thereof |
Non-Patent Citations (1)
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YOHEI SAWA 等: "Pretreatment with KGA-2727, a selective SGLT1 inhibitor, is protective against myocardial infarction-induced ventricular remodeling and heart failure in mice", JOURNAL OF PHARMACOLOGICAL SCIENCES, vol. 142, 7 November 2019 (2019-11-07), pages 21 - 22 * |
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MX2022011490A (es) | 2022-10-07 |
CA3175131A1 (en) | 2021-09-23 |
EP4122495A4 (en) | 2024-03-27 |
WO2021187548A1 (ja) | 2021-09-23 |
EP4122495A1 (en) | 2023-01-25 |
US20230321044A1 (en) | 2023-10-12 |
AU2021237149A1 (en) | 2022-10-06 |
JPWO2021187548A1 (zh) | 2021-09-23 |
KR20220156574A (ko) | 2022-11-25 |
BR112022018396A2 (pt) | 2022-11-08 |
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