CN114787155A - 药物化合物 - Google Patents
药物化合物 Download PDFInfo
- Publication number
- CN114787155A CN114787155A CN202080084820.7A CN202080084820A CN114787155A CN 114787155 A CN114787155 A CN 114787155A CN 202080084820 A CN202080084820 A CN 202080084820A CN 114787155 A CN114787155 A CN 114787155A
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- CN
- China
- Prior art keywords
- acid
- compound
- benzodiazepine
- rsv
- pyrazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000011282 treatment Methods 0.000 claims abstract description 16
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- -1 4-chloro-2-fluorophenoxy Chemical group 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
式(I)的苯并二氮衍生物:其中:R1和R2中的每一个独立地是H或卤素;R3是H、C1‑C6烷基或‑NHR8;(i)a、c和e均是键,并且b、d和f不存在;或b、d和f均是键,并且a、c和e不存在;R4是H或选自C1‑C6烷基、C3‑C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的;R5是H或卤素;R6是‑OR8、‑NR8R9或‑R8;R7是H或卤素;R8和R9中的每一个独立地是H或选自C1‑C6烷基、C3‑C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的;n是1或2;并且V、W和X中的一个是N或CH,并且另外两个是CH;及其药学上可接受的盐是RSV的抑制剂,并且因此可用于治疗或预防RSV感染。
Description
技术领域
背景技术
RSV是副黏病毒科的负义单链RNA病毒。RSV容易通过感染者的分泌物经由表面或手对手转移而传播。与流感不同,其不是通过小颗粒气溶胶传播的。在成功接种后,潜育期为4至6天,在此期间病毒通过感染细胞与未感染细胞融合并通过坏死上皮的脱落而从鼻咽传播到下呼吸道。在婴儿中,结合粘液分泌增加和水肿,这可以导致粘液堵塞,引起过度膨胀和远侧肺组织塌陷,指示细支气管炎。常见缺氧,并且通常由于呼吸窘迫而造成进食能力受损。在RSV肺炎中,气道的炎性浸润由单核细胞组成并且更推广为涉及细支气管、支气管和肺泡(alveoli)。已发现病毒脱落的持续时间和程度与疾病的临床症状和严重程度相关。
RSV是全世界婴幼儿严重呼吸道感染的主要原因。早产儿和患有慢性肺病或心脏病的婴儿的发病率和死亡率最高,尽管许多因RSV感染住院的婴儿在其它方面是健康的。婴儿期严重RSV感染可以导致数年复发性气喘,并与后期哮喘发展有关。
RSV也是老年人和免疫受损儿童和成人以及慢性阻塞性肺疾病(COPD)和充血性心力衰竭(CHF)患者发病和死亡的主要原因。
RSV具有季节性发病;其具有高度可预测性并发生在两个半球的冬季,欧洲和北美从9月到5月,在12月和1月达到峰值,而在热带国家可以全年发生。其影响>90%的婴儿和2岁以下幼儿,并且因为天然免疫是短暂的;许多人每年将被重新感染。与流感一样,在老年人中,RSV导致约10%的冬季住院,相关死亡率为10%。
目前的抗RSV治疗包括使用抗RSV单克隆抗体,称为帕利珠单抗(palivizumab)。帕利珠单抗的这种使用是RSV的预防性而非治疗性处理(治疗,treatment)。尽管这种抗体通常是有效的,但其使用限于早产儿和高危婴儿。事实上,其有限的利用性意味着其对于许多需要抗RSV治疗的人是不可用的。因此,迫切需要现有抗RSV治疗的有效替代方案。
小分子也已被提出作为RSV的抑制剂。这些包括苯并咪唑类和苯并二氮类。例如,RSV604——具有亚微摩尔抗RSV活性的苯并二氮化合物——的发现和初步开发被描述于Antimicrobial Agents and Chemotherapy,2007年9月,3346-3353(Chapman et al)中。RSV的苯并二氮抑制剂也被公开在包括下列的出版物中:WO2004/026843和WO2005/089770(Arrow Therapeutics Limited);WO2016/166546和WO2018/033714(DurhamUniversity);和WO2017/015449、WO2018/129287和WO2018/226801(EnantaPharmaceuticals,Inc.)。
需要确定具有抗RSV活性的进一步化合物,具体地具有有效抗病毒活性和有利药代动力学性质的组合的化合物。
发明内容
其中:
R1和R2中的每一个独立地是H或卤素;
R3是H、C1-C6烷基或-NHR8;
R4是H或选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的;
R5是卤素;
R6是H、-OR8、-NR8R9或-R8;
R7是H或卤素;
R8和R9中的每一个独立地是H或选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的;
n是1、2或3;
V、W和X中的一个是N或CH,并且另外两个是CH;
或其药学上可接受的盐。
具体实施方式
当本文定义的任何基团、环、取代基或部分是取代的时,其一般被如下定义的Q取代。
C1-6烷基或部分是直链或支链的。C1-6烷基一般是C1-4烷基或C4-6烷基。C1-6烷基和部分的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基(即3-甲基丁-1-基)、叔戊基(即2-甲基丁-2-基)、新戊基(即2,2-二甲基丙-1-基)、正己基、异己基(即4-甲基戊-1-基)、叔己基(即3-甲基戊-3-基)和新戊基(即3,3-二甲基丁-1-基)。为避免疑义,当两个烷基部分存在于一个基团中时,烷基部分可以相同或不同。C1-6烷基是未取代的或取代的——一般被一个或多个如下定义的基团Q取代。例如,C1-6烷基是未取代的或被如下定义的1、2或3个基团Q取代。
Q是卤素、硝基、-CN、OH、C1-6烷氧基、C1-6羟烷基、C1-6烷硫基、C1-6烷基、C1-6卤代烷基、C1-4卤代烷氧基、-CO2R'、-NR'2、-SR'、-S(=O)R'、-S(=O)2R'、C3-C10环烷基、5元至10元杂环基、5元至12元芳基或5元至10元杂芳基,其中每个R'独立地选自H、C1-6烷基、C3-10环烷基、5元至10元杂环基、C6-C10芳基和5元至10元杂芳基。为避免疑义,这些定义中的烷基、烷氧基、烷硫基、环烷基、杂环基、芳基和杂芳基部分本身一般是未取代的。
C1-6烷氧基是直链或支链的。其一般是C1-4烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、正丙氧基、正丁氧基、仲丁氧基或叔丁氧基。C1-6烷氧基是未取代的或取代的——一般被一个或多个如上定义的基团Q取代。
C1-6烷硫基是直链或支链的。其一般是C1-4烷硫基,例如甲硫基、乙硫基、丙硫基、异丙硫基、正丙硫基、正丁硫基、仲丁硫基或叔丁硫基。C1-6烷硫基是未取代的或取代的——一般被一个或多个如上定义的基团Q取代。
卤素或卤基团是F、Cl、Br或I。一般,其是F或Cl。被卤素取代的C1-6烷基可以表示为“C1-6卤代烷基”,其意为其中一个或多个氢被卤素取代的如上定义的C1-6烷基。同样,被卤素取代的C1-6烷氧基可以表示为“C1-6卤代烷氧基”,其意为其中一个或多个氢被卤素取代的如上定义的C1-6烷氧基。一般,C1-6卤代烷基或C1-6卤代烷氧基被1、2或3个所述卤素原子取代。卤代烷基和卤代烷氧基包括全卤代烷基和全卤代烷氧基,如-CX3和-OCX3,其中X是卤素,例如-CF3、-CCl3、-OCF3和-OCCl3。
C1-6羟烷基是被一个或多个OH基团取代的如上定义的C1-6烷基。一般,其被一个、两个或三个OH基团取代。优选地,其被单个OH基团取代。
C6-C10芳基是含有6至10个碳原子的芳族碳环基团。其是单环或稠合双环系统,其中芳族环与另一芳族碳环稠合。C6-C10芳基的实例包括苯基和萘基。当被取代时,芳基一般被如上定义的基团Q取代,例如被1、2或3个选自如上定义的基团Q的基团取代。更具体地,取代的芳基如取代的苯基被选自C1-C6烷基、卤素、-OR8和-N(R8)2的1或2个基团取代,其中R8是H或C1-C6烷基,当存在两个时各R8相同或不同。
C3-10环烷基是具有3至10个碳原子的饱和烃环。C3-10环烷基可以是例如C3-C7环烷基,如环丙基、环丁基、环戊基、环己基或环庚基。一般,其是C3-C6环烷基,或C4-C6环烷基,例如环丁基、环戊基或环己基。在一个实施方式中,其是环丁基。C3-10环烷基是未取代的或取代的——一般被一个或多个如上定义的基团Q取代。
4元至10元杂芳基或部分是含有选自O、N和S的1、2、3或4个杂原子的4元至10元芳族杂环基。其是单环或双环的。一般,其含有1个N原子和选自O、S和N的0、1、2或3个另外的杂原子。其可以是例如单环的5元至7元杂芳基,例如5元或6元含N杂芳基。实例包括吡啶基、吡嗪基、嘧啶基、哒嗪基、呋喃基、噻吩基、吡唑烷基、吡咯基、二唑基、唑基、异唑基、噻唑基、噻二唑基、咪唑基和吡唑基。呋喃基、噻吩基、咪唑基、吡啶基和嘧啶基是优选的。其可以可选地是双环杂芳基,例如8元至10元双环杂芳基。实例包括喹啉基、异喹啉基、喹唑基、喹喔啉基、吲哚基、异吲哚基、吲唑基、咪唑并哒嗪基、吡咯并吡啶基、吡唑并嘧啶基和吡咯并嘧啶基。当被取代时,杂芳基(单环或双环)一般被一个或多个,例如1、2或3个,选自C1-4烷基和如上定义的基团Q的基团取代。
4元至10元杂环基是含有5至10个碳原子和至少一个选自N、O、S、SO、SO2和CO(更一般地N或O)的原子或基团的单环或双环非芳族饱和或不饱和环系统。当环系统为双环时,一个环可以是饱和的并且一个环可以是不饱和的。一般,其是C4-10环系统,其中环中的1、2或3个碳原子被选自O、S、SO2、CO和NH的原子或基团取代。更一般地,其是单环的环,优选地单环的C4-C6环。实例包括哌啶基、哌啶-2,6-二酮基、哌啶-2-酮基、哌嗪基、吗啉基、硫代吗啉基、S,S-二氧硫代吗啉基、1,3-二氧戊环基、吡咯烷基、咪唑-2-酮基、吡咯烷-2-酮基、氧杂环丁基、四氢呋喃基和四氢吡喃基部分。
为避免疑义,尽管杂芳基和杂环基的上述定义涉及可以存在于环中的“N”原子,但对于化学技术人员而言显而易见的是,任何这种N原子将被质子化(或将携带如上定义的取代基)——如果其通过单键附接至其相邻各环原子。这种质子化形式被包含在当前对杂芳基和杂环基的定义内。
其中R1是H或卤素,R2是H或卤素,并且其余基团和变量如上文关于式(I)所定义。一般,R1是H或F,并且R2是H或F。例如,R1是H或F,并且R2是F。
其中所有基团和变量如上文关于式(I)或(I’)所定义。
其中所有基团和变量如上文关于式(I)或(I’)所定义。
在上式(Ia’)和(Ib’)中,R1至R7和n中的每一个如上文关于式(I)或(I’)所定义。
在式(Ia″)和(Ib″)中,R1至R7和n中的每一个如上文关于式(I)或(I’)所定义。
其中基团和变量中的每一个如上文关于式(I)或(I')所定义,或其药学上可接受的盐。
其中基团和变量中的每一个如上文关于式(I)或(I')所定义,并且m是0、1或2。
在具有如上定义的结构式(I)、(Ia)、(Ib)、(Ia')、(Ib')、(Ia″)、(Ib″)、(IIa)或(IIb)中的任一种的本发明化合物的一个实施方式中,R2在苯并二氮基环系统的9位。在这种实施方式中,一般,R2是卤素取代基,具体地F。更一般地,在这种实施方式中,R1是H或F,并且R2是H或F。例如,R1是H或F,并且R2是F。
其中R1是H或卤素,R2是H或卤素,并且其余基团和变量如上文关于式(IIa)所定义。一般,R1是H或F,并且R2是H或F。例如,R1是H,并且R2是F。
其中R1是H或卤素,R2是H或卤素,并且其余基团和变量如上文关于式(IIb)所定义。一般,R1是H或F,并且R2是H或F。例如,R1是H,并且R2是F。
在具有上文定义的结构式中的任一种的本发明化合物中,R3是选自H、C1-C6烷基和-NR8R9的基团,其中R8和R9中的每一个独立地是H或选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的。一般,R8是H,并且R9是H或选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的。在一个实施方式中,R8是H,并且R9是H或C1-C6烷基。
在具有上文定义的结构式中的任一种的本发明化合物中,R4是H或选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的。在一个实施方式中,R4是选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的。一般,R4是选自C1-C6烷基(如C1-C3烷基)、C3-C6环烷基(如环丙基)和4元至10元杂环基(例如,含O杂环基,如氧杂环丁基、四氢呋喃基或四氢吡喃基)的基团。
在具有上文定义的结构式中的任一种的本发明化合物中,R5是H或卤素,具体地F。
在具有上文定义的结构式(I)、(I')、(Ia)、(Ib)、(Ia')、(Ib')、(Ia″)或(Ib″)中的任一种的本发明的化合物中,可以存在一个、两个或三个基团R5,当多于一个存在时,其相同或不同。至少一个基团R5一般是F。R5或每个R5键合至其所附接的六元环的任何可用的环碳原子。
在一个实施方式中,R6是H,n是2,一个R5是F,另一个R5是F或Cl。在另一实施方式中,R6是H,n是3,两个基团R5各自是F,并且另一个R5是Cl。
在一个实施方式中,至少一个R5键合至负载将六元环连接至相邻O原子的键的环碳的邻位,即一个R5键合在环位2或6处。例如,n是1,并且R5键合在环位2或6处;或n是2,并且两个基团R5键合在环位2和4处、或2和6处、或4和6处。在这种实施方式中,邻位键合的基团R5或各邻位键合的基团R5一般是F。
在具有上文定义的结构式(I)、(I')、(Ia)、(Ib)、(Ia')、(Ib')、(Ia″)、(Ib″)、(IIb)或(IIb')中的任一种的本发明化合物中,R6键合在未被R5占据的任何可用的环碳原子处。例如,其键合在环位4(即负载将六元环连接至相邻O原子的键的环碳的对位);或其键合在环位3或5处,即负载将六元环连接至相邻O原子的键的环碳的间位。
在以上结构式(I)、(I')、(Ia)、(Ib)、(Ia')、(Ib')、(Ia″)和(Ib″)的化合物中通过基团R5和R6键合的六元环的实例包括下列结构(i)至(v):
在具有上文定义的结构式中的任一种的本发明化合物中,R6是-OR8、-NR8R9或-R8,其中R8和R9中的每一个是H或选自C1-C6烷基、C3-C6环烷基和4元至10元杂环基的基团,该基团是未取代的或取代的。一般,R6是H、C1-C6烷基、-OR8或-NR8R9,其中R8是C1-C6烷基(如C1-C3烷基)、C3-C6环烷基(如环丙基或环丁基),并且R9是H或C1-C6烷基,该烷基和环烷基是未取代的或取代的。更一般地,R6是C1-C6烷基、-OR8或-NR8R9,其中R8是未取代的C1-C6烷基(如甲基、乙基或异丙基)或C3-C6环烷基(如环丙基或环丁基),该环烷基是未取代的或被未取代的C1-C3烷基(如甲基)取代的,并且R9是C1-C6烷基或H。
在一个实施方式中,R6是C1-C6烷基或基团-NR8R9,其中R8和R9相同或不同并且各自是H或C1-C6烷基,n是1或2,并且各R5是F。这些实施方式中的C1-C6一般是甲基或乙基。
本发明的具体化合物包括下列:
和其药学上可接受的盐。
本发明的化合物可以含有不对称或手性中心,因此以不同立体异构形式存在。意图本发明化合物的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体,以及其混合物如外消旋混合物,构成本发明的部分。含有一个或多个手性中心的式(I)化合物可以以对映异构体或非对映异构体纯形式或以异构体混合物形式使用。
本发明包括如上定义的本发明化合物的所有几何和位置异构体。例如,如果本发明的化合物包含双键或稠环,则顺式和反式形式以及其混合物均被包含在本发明的范围内。单一位置异构体和位置异构体混合物也在本发明的范围内。
本发明的化合物可以以非溶剂化以及溶剂化形式与药学上可接受的溶剂如水、乙醇等一起存在,并且意图本发明包含溶剂化和非溶剂化形式。
本发明的化合物可以以不同的互变异构体形式存在,并且所有这些形式均被包含在本发明的范围内。术语“互变异构体”或“互变异构体形式”指代可通过低能量屏障(能垒,low energy barrier)相互转化的不同能量的结构异构体。例如,质子互变异构体(也称为质子移变互变异构体)包括通过质子迁移进行的相互转化,例如酮-烯醇互变异构。价键互变异构体(valence tautomers)包括通过一些键合电子的重新组织而进行的相互转化。
本发明的化合物可以通过以下实施例中描述的合成方法制备,或者通过用这种方法的类推法利用化学技术人员熟知的适当起始材料和方法制备。
通过常规方法,式(I)的苯并二氮衍生物可以被转化为其药学上可接受的盐,并且盐可以被转化为游离化合物。例如,式(I)的苯并二氮衍生物可以与药学上可接受的酸接触以形成药学上可接受的盐。药学上可接受的盐是与药学上可接受的酸或碱(形成)的盐。
药学上可接受的酸包括无机酸,如盐酸、硫酸、磷酸、焦磷酸、氢溴酸或硝酸;和有机酸,如柠檬酸、富马酸、马来酸、苹果酸、抗坏血酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。药学上可接受的碱包括碱金属(例如钠或钾)和碱土金属(例如钙或镁)氢氧化物;和有机碱,如烷基胺、芳烷基胺和杂环胺。
已在生物学试验中发现本发明的化合物是呼吸道合胞病毒(RSV)的抑制剂。其具有有效的抗RSV活性以及良好的生物利用度和良好的理化性质的组合。这种性质组合使该化合物在治疗上是有用的并且作为候选药物优于在前讨论的现有技术参考文献中公开的许多化合物。
本发明还提供了如上定义的本发明化合物,用于治疗或预防RSV感染的方法。仍进一步,本发明提供了如上定义的本发明化合物在制备用于治疗或预防RSV感染的药物中的用途。遭受或易受RSV感染的对象因此可以通过包括向其给予如上定义的本发明化合物的方法来治疗。该对象的状况可以从而被改善或缓解。
RSV感染一般是呼吸道感染。RSV感染可以是儿童(例如十岁以下的儿童或两岁以下的婴儿)的感染。在一个实施方式中,本发明提供了如上定义的化合物,用于治疗或预防儿科患者的RSV感染。可选地,感染可以是成熟或老年成人(例如60岁以上的成人、70岁以上的成人或80岁以上的成人)的感染。本发明进一步提供了化合物,用于治疗或预防老年患者的RSV感染。
RSV感染可以是免疫受损个体或遭受COPD或CHF的个体的感染。在另一实施方式中,RSV感染是未受损个体(例如其它方面健康的个体)的感染。
本发明的化合物可以以各种剂型被给予,例如口服,如以片剂、胶囊、糖包衣或膜包衣片剂、液态溶液或悬浮液的形式;或肠胃外,例如肌内、静脉内或皮下。化合物因此可以通过注射、输注或通过吸入或雾化而被给予。化合物优选通过口服给予而被给予。
剂量取决于各种因素,包括患者的年龄、体重和状况以及给予途径。每日剂量可以在宽界限内变化,并将在各具体情况中根据个体要求而被调整。然而,一般,化合物被单独给予成年人时的各给予途径所采用的剂量为0.0001至650mg/kg,最常在0.001至10mg/kg体重范围内,例如0.01至1mg/kg。这种剂量可以被给予例如每天1至5次。对于静脉内注射,合适的每日剂量为0.0001至1mg/kg体重,优选0.0001至0.1mg/kg体重。每日剂量可以作为单一剂量或按照分剂量计划被给予。
单位剂型如片剂或胶囊将通常含有1-250mg活性成分。例如,式(I)的化合物可以以100-250mg的剂量一天1次、一天2次或3次被给予人类患者。例如,式(I)的化合物可以以100-250mg的剂量一天1次、一天2次或3次被给予人类患者。
式(I)的化合物及其药学上可接受的盐可以独自被使用。可选地,其可以以药物组合物的形式被给予。因此,本发明还提供药物组合物,其包括如上文定义的式(I)的化合物或其药学上可接受的盐,以及药学上可接受的佐剂、稀释剂或载体。用于选择和制备适当药物制剂的常规程序被描述于例如"Pharmaceuticals-The Science of Dosage FormDesigns",M.E.Aulton,Churchill Livingstone,1988。
根据给予模式,药物组合物将优选地包括0.05至99%w(重量百分比),更优选0.05至80%w,还更优选0.10至70%w,甚至更优选0.10至50%w的活性成分,所有重量百分比均基于组合物总量。
本发明进一步提供了用于制备本发明的药物组合物的方法,其包括将如上文定义的式(I)的化合物或其药学上可接受的盐与药学上可接受的佐剂、稀释剂或载体混合。
本发明的化合物可以以各种剂型被给予。因此,其可以被口服给予,例如作为片剂、锭剂、糖锭、水性或油性悬浮液、溶液、可分散粉末或颗粒。本发明的化合物还可以被肠胃外给予,无论皮下、静脉内、肌内、胸骨内、经皮,通过输注技术或通过吸入或雾化。该化合物还可以作为栓剂被给予。
本发明的药物组合物的固体口服形式可以含有(连同活性化合物)稀释剂,例如乳糖、右旋糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙、和/或聚乙二醇;粘合剂;例如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;解聚剂(disaggregating agents),例如淀粉、海藻酸、海藻酸盐或乙醇酸淀粉钠;泡腾化混合物;染料;甜味剂;润湿剂,如卵磷脂、聚山梨醇酯、月桂基硫酸盐(酯);以及总体上,药物制剂中使用的无毒且无药理活性的物质。这种药物制剂可以以已知的方式例如通过混合、造粒、压片、糖包衣或膜包衣工艺制备。
用于口服给予的液体分散体可以是糖浆、乳液和悬浮液。糖浆可以含有例如蔗糖或带有甘油和/或甘露醇和/或山梨糖醇的蔗糖,作为载体。
悬浮液和乳液可以含有例如天然胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇作为载体。用于肌内注射的悬浮液或溶液可以含有(连同活性化合物)药学上可接受的载体,例如无菌水、橄榄油、油酸乙酯、二醇——例如丙二醇,以及如需,合适量的盐酸利多卡因。进一步的适于悬浮液的载体包括无菌水、羟丙基甲基纤维素(HPMC)、聚山梨醇酯80、聚乙烯吡咯烷酮(PVP)、气溶胶AOT(即1,2-双(2-乙基己氧基羰基)乙磺酸钠)、pluronic F127和/或captisol(即磺丁基醚-β-环糊精)。
本发明的化合物可以例如被配制成在选自下列的载体中的水性悬浮液:
(i)0.5%w/v羟丙基甲基纤维素(HPMC)/0.1%w/v聚山梨醇酯80;
(ii)0.67%w/v聚乙烯吡咯烷酮(PVP)/0.33%w/v气溶胶AOT(1,2-双(2-乙基己氧基羰基)乙磺酸钠);
(iii)1%w/v pluronic F 127;和
(iv)0.5%w/v聚山梨醇酯80。
载体可以通过本领域技术人员已知的标准程序制备。例如,载体(i)至(iv)中的每一种可以通过以下制备:将所需量的赋形剂称重到合适的容器中,添加大约80%最终体积的水,和磁力搅拌直至形成溶液。然后将载体用水补足体积。式I的化合物的水悬浮液可以通过以下制备:将所需量的式I化合物称重到合适的容器中,添加100%所需体积的载体,和磁力搅拌。
用于注射或输注的溶液可以含有例如无菌水作为载体,或者优选地其可以是无菌水性等渗盐水溶液的形式。
本发明的化合物还可以与用于治疗病毒感染的其他化合物组合给予。因此,本发明进一步涉及组合疗法,其中本发明化合物或其药学上可接受的盐或包括本发明化合物的药物组合物或制剂与其他一种或多种治疗剂被同步或顺序或作为组合制剂被给予,用于治疗或预防病毒感染,具体地RSV感染。
在本文中,在使用术语“组合”的情况下,要理解这指代同时、分开或顺序的给予。在本发明的一个方面,“组合”指代同时给予。在本发明的另一方面,“组合”指代分开给予。在本发明的进一步方面,“组合”指代顺序给予。在给予是顺序的或分开的情况下,给予第二组分的延迟不应使该组合的有益效果损失。
用于组合疗法的合适治疗剂包括
(i)RSV融合抑制剂;
(ii)其它RSV核衣壳(N)蛋白抑制剂;
(iii)其它RSV蛋白抑制剂,如抑制磷蛋白(P)蛋白和大(L)蛋白的那些;
(iv)抑制L蛋白的核苷或聚合酶抑制剂;
(v)抗RSV单克隆抗体,如F蛋白抗体;
(vi)免疫调节toll样受体化合物;
(vii)其它呼吸道病毒抗病毒剂,如抗流感和抗鼻病毒化合物;和/或
(viii)抗炎化合物。
RSV核衣壳(N)蛋白在病毒转录和复制中起关键作用,介导基因组RNA和病毒编码的RNA依赖性RNA聚合酶之间的相互作用。RSV P蛋白和L蛋白是RSV的病毒编码的RNA依赖性RNA聚合酶的组分。
根据本发明的进一步方面,提供了如上文定义的式(I)化合物或其药学上可接受的盐与如上文(i)至(vi)列出的治疗剂中的一种或多种组合用于治疗RSV。
以下实施例用于进一步示例本发明。制备实施例涉及用于制备实施例的化合物的起始材料和中间体的制备。实施例和制备实施例均不以任何方式限制本发明。
实施例
试剂获自商业来源,并且不经进一步纯化而使用。所有温度均以℃表示。TLC在铝载硅胶板(aluminium backed silica gel plates)上以254nM荧光指示剂(中值孔径)进行。除非另有说明,快速柱层析利用Biotage Isolera One系统、使用KP-Sil或Ultra硅胶柱进行。NMR光谱在环境探针温度(标称295K)下,在400MHz光谱仪上被记录。化学位移(δ)以ppm给出,并通过利用溶剂的残留峰作为内标(CDCl3,δH=7.26ppm,δC=77.16ppm;DMSO-d6,δH=2.50ppm,δC=39.52ppm)校准。偶合常数以赫兹(Hz)给出。LRMS利用配备有APCI离子源的Advion Plate Express expressionL紧凑型质谱仪来记录。
制备实施例(3S)-3-氨基-5-苯基-1,3-二氢-1,4-苯并二氮-2-酮和(3S)-3-氨基-9-氟-5-苯基-1,3-二氢-1,4-苯并二氮-2-酮利用WO/2004/026843、WO/2005/090319和WO/2017/015449中描述的方法制备。
缩写词
制备实施例
1A 5-氨基-1-乙基吡唑-4-羧酸乙酯
制备(乙氧基亚甲基)氰基乙酸乙酯(10.50g,62.06mmol)在无水EtOH(120mL)中的悬浮液,并且添加草酸乙基肼(9.32g,62.06mmol),然后通过注射器经15min添加NEt3(17.3mL,124.1mmol)。将反应在50℃下加热5h,然后在rt下搅拌16h。在减压下去除挥发物,并将残留物溶解在EtOAc(100mL)中。将粗产物用水(2×60mL)和盐水(60mL)洗涤,干燥(MgSO4)并在减压下去除溶剂。通过快速色谱法(30%EtOAc:庚烷)纯化残留物以得到黄色固体(5.16g,45%)。LRMS:184.0[M+H]+;TLC(EtOAc)Rf=0.63。
2A 5-氯-1-乙基吡唑-4-羧酸乙酯
在氮气下,将亚硝酸叔丁酯(5.19mL,43.7mmol)添加至氯化亚铜(I)(3.24g,32.7mmol)在MeCN(90mL)中的冷(0℃)溶液中。经30min逐部分添加中间体1A(5.00g,27.3mmol),将反应在0℃下搅拌1h,然后在65℃下加热40min。将反应冷却至rt并倒入6M aqHCl(100mL)中,并用CH2Cl2(100mL,然后3×50mL)萃取。将合并的有机相干燥(MgSO4),在减压下去除溶剂并通过快速色谱法(0-10%EtOAc:庚烷)纯化残留物以得到无色油状物(2.87g,52%)。1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),4.23(q,J=7.1Hz,2H),4.19(q,J=7.3Hz,2H)1.33(t,J=7.2Hz,3H),1.27(t,J=7.1Hz,3H).LRMS:202.9[M+H]+。
3A 5-溴-1-(氧杂环己-4-基)吡唑-4-羧酸乙酯
4A 3-溴-1-(氧杂环己-4-基)吡唑-4-羧酸乙酯
将4-甲基苯磺酸氧杂环己-4-酯(1.67g,6.53mmol)添加至3-溴-1H-吡唑-4-羧酸乙酯(1.30g,5.93mmol)和Cs2CO3(2.63g,8.01mmol)在DMF(10mL)中的溶液中,并在80℃下加热16h。冷却至rt后,添加水(40mL)并将混合物用EtOAc(3×20mL)萃取。将有机相用水和盐水(各20mL)洗涤,干燥(Na2SO4)并在减压下去除溶剂。通过快速色谱法(10-80%EtOAc:庚烷)纯化得到中间体3A,为白色固体(445mg,25%)。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),4.66(tt,J=11.3,4.3Hz,1H),4.24(q,J=7.1Hz,2H),4.01–3.91(m,2H),3.50(td,J=12.0,2.1Hz,2H),2.08–1.94(m,2H)1.83(ddd,J=12.6,4.4,2.0Hz,2H),1.27(t,J=7.1Hz,3H)。LRMS:303.0/305.0[M+H]+。获得中间体4A(第二洗脱区域异构体),为白色固体(1.02g,57%)。1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),4.45(dd,J=10.5,5.0Hz,1H),4.22(q,J=7.1Hz,2H),4.00–3.88(m,2H),3.48–3.36(m,2H),2.04–1.83(m,4H),1.27(t,J=7.1Hz,3H)。LRMS:303.4/305.4[M+H]+。
5A 5-溴-1-(氧杂环丁-3-基)吡唑-4-羧酸乙酯
6A 3-溴-1-(氧杂环丁-3-基)吡唑-4-羧酸乙酯
通过与关于中间体3A所述类似的程序,用3-溴-1H-吡唑-4-羧酸乙酯(1.70g,7.76mmol)、4-甲基苯磺酸氧杂环丁-3-酯(1.95g,8.50mmol)和Cs2CO3(3.43g,10.48mmol)并在90℃下加热22h来制备。通过快速色谱法(10-100%EtOAc:庚烷)纯化得到中间体5A(第一洗脱区域异构体),为白色固体(640mg,30%)。1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),5.75(tt,J=7.4,6.2Hz,1H),4.98–4.85(m,4H),4.24(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H)。LRMS:275.5/277.5[M+H]+。中间体6A:第二洗脱区域异构体,白色固体(1.06g,50%)。1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),5.60(tt,J=7.5,6.1Hz,1H),4.94–4.77(m,4H),4.23(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H)。LRMS:275.5/277.5[M+H]+。
7A 5-(2-氟-4-甲基苯氧基)-1-(氧杂环己-4-基)吡唑-4-羧酸乙酯
将中间体3A(150mg,0.49mmol)、2-氟-4-甲基苯酚(68.7mg,0.54mmol)和Cs2CO3(324mg,0.99mmol)在1-甲基-2-吡咯烷酮(2mL)中的溶液在密封小瓶中在135℃下加热21h。将反应冷却至rt,用水(10mL)稀释并用EtOAc(3×15mL)萃取。将合并的有机相用水(2×15mL)和盐水(15mL)洗涤,干燥(Na2SO4),并在减压下去除溶剂。通过快速色谱法(0-30%EtOAc:庚烷)纯化残留物以得到白色固体(100mg,58%)。1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.28–7.15(m,1H),6.98–6.86(m,1H),6.74(t,J=8.6Hz,1H),4.54–4.40(m,1H),4.04–3.86(m,4H),3.51–3.39(m,2H),2.27(s,3H),2.10–1.95(m,2H),1.84–1.72(m,2H),0.96(t,J=7.1Hz,3H)。LRMS:349.1[M+H]+。
通过关于中间体7A所述的相同一般程序制备下列中间体化合物。
13A 5-(4-氯-2,6-二氟苯氧基)-1-(氧杂环丁-3-基)吡唑-4-羧酸乙酯
通过与中间体2A类似的程序,利用MeCN(8mL)中的氯化铜(II)(25.0mg,0.19mmol)、亚硝酸叔丁酯(0.03mL,0.22mmol)、中间体11A(63mg,0.15mmol)并在0℃下搅拌20min,然后在rt下搅拌4h制备。黄色油状物(20mg,38%)。LRMS:359.1[M+H]+;TLC(1:1EtOAc:庚烷)Rf=0.65。
14A 5-(4-氯-2,6-二氟苯氧基)-1-(氧杂环己-4-基)吡唑-4-羧酸乙酯
通过与中间体2A类似的程序,利用MeCN(16mL)中的氯化铜(II)(76.4mg,0.57mmol)、亚硝酸叔丁酯(0.08mL,0.68mmol)和中间体12A(167mg,0.45mmol)并在0℃下搅拌30min,然后在rt下搅拌3h制备。白色固体(27mg,15%)。LRMS:387.3[M+H]+;TLC(1:1EtOAc:庚烷)Rf=0.83。
15A 5-(2,6-二氟-4-甲基苯氧基)-1-乙基吡唑-4-羧酸
将中间体8A(70mg,0.230mmol)和LiOH(1M aq;1.8mL,1.8mmol)在THF:MeOH(1:1;6mL)中的溶液在55℃下加热3h。在减压下去除挥发物,用HCl(1M aq.)将残留物酸化至pH≈2,然后用EtOAc(3×10mL)萃取。将合并的有机萃取物用水和盐水(各10mL)洗涤,干燥(MgSO4),并在减压下去除溶剂以得到白色固体(58mg,91%)。1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.02(d,J=9.8Hz,2H),4.12(q,J=7.3Hz,2H),2.27(s,3H),1.34(t,J=7.2Hz,3H)。LRMS:283.0[M+H]+。
以与中间体15A类似的方式制备下列中间体化合物。
实施例
将NEt3(0.04mL,0.32mmol)和HATU(66.6mg,0.18mmol)添加至中间体15A(49.4mg,0.18mmol)和(3S)-3-氨基-5-苯基-1,3-二氢-1,4-苯并二氮-2-酮(40.0mg,0.16mmol)在DMF(1mL)中的溶液中,并将反应在rt下搅拌2小时45分钟。添加水(20mL),导致形成沉淀,通过过滤收集沉淀,用水(5mL)洗涤。将沉淀溶解在EtOAc(20mL)中,干燥(MgSO4),在减压下浓缩并通过快速色谱法(50-100%EtOAc:庚烷)纯化以得到白色固体(66mg,80%)。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.02(d,J=8.2Hz,1H),8.34(s,1H),7.65–7.59(m,1H),7.55–7.37(m,5H),7.31–7.16(m,3H),6.93(d,J=9.8Hz,2H),5.23(d,J=8.2Hz,1H),4.12(q,J=7.2Hz,2H),2.21(s,3H),1.35(t,J=7.2Hz,3H)。LRMS:516.5[M+H]+。
通过关于实施例1的化合物描述的程序,用(3S)-3-氨基-5-苯基-1,3-二氢-1,4-苯并二氮-2-酮或(3S)-3-氨基-9-氟-5-苯基-1,3-二氢-1,4-苯并二氮-2-酮制备本发明的下列化合物。
实施例7:体外效力
按照以下方案对化合物进行RSV斑块(plaque)减少测定。
斑块减少测定:
使Hep-G2细胞(ECACC,85011430)在烧瓶中传代并将其接种在24孔板中的含有抗生素和补充10%FBS的DMEM中。在接种和随后的培育期间,将细胞在含有2%FBS的DMEM中培养。将RSV(RSV A2 ECACC,0709161v)的100个斑块形成单位/孔与化合物的八个连续稀释液混合。随后,将100μL病毒/化合物混合物添加至汇合的Hep-G2细胞单层中。将细胞和病毒/化合物混合物在湿润的5%CO2培养箱中于37℃下培养2h,然后去除接种物并添加1mL含有化合物稀释液的覆盖物(含有2%FBS和0.8%CMC的DMEM)。将细胞在湿润的5%CO2培养箱中于37℃下培养2天。
将细胞在添加75/25%v/v EtOH/MeOH之前用PBS洗涤3min。去除固定剂(Fixative)并用PBS洗涤平板。将预先滴定量的一抗添加至200μL PBS/2%奶粉中,并将平板在37℃下培育90min。将平板用PBS/0.05%Tween20洗涤3次,然后添加在200μL PBS/2%奶粉中的兔抗山羊辣根过氧化物酶,并在37℃下培育1h。在使用PBS/0.05%Tween20进行三个洗涤步骤后,添加200μL即用的TrueBlue并将平板在rt下培育10-15min,然后用水洗涤。在去除水后,将平板在黑暗中风干。
利用Immunospot S6 Macro分析仪对平板进行扫描和分析,其配备有BioSpot分析软件以计数免疫染色斑块(virospots)。斑块计数用于计算相对于RSV病毒对照孔中斑块计数平均值的感染%。通过在Dotmatics中可变斜率的4参数非线性回归拟合的抑制曲线的内插(interpolation),分别以50%信号减少计算EC50值。斑块EC50和细胞毒性CC50值是至少两次实验的平均值,并且数字四舍五入为整单位。
结果
实施例7:体外药代动力学
对化合物进行以下测定以研究肝微粒体稳定性。
微粒体培育:实验程序
汇集的肝微粒体购自信誉良好的商业供应商,并在使用前储存在-80℃下。将微粒体(最终蛋白质浓度0.5mg/mL)、0.1M磷酸盐缓冲液pH 7.4和测试化合物(最终底物浓度1μM;最终DMSO浓度0.25%)在37℃下预培育,然后添加NADPH(最终浓度1mM)以开始反应。最终培育体积为50μL。每种测试的化合物包括对照培育,其中添加0.1M磷酸盐缓冲液pH 7.4,代替NADPH(NADPH-)。各物种包括两种对照化合物。对每种测试化合物单独进行所有培育。将每种化合物培育0、5、15、30和45min。对照(NADPH-)培育仅45min。通过在适当时间点以1:3的比将培育物转移到乙腈中来停止反应。将终止平板在4℃下以3,000rpm离心20min以沉淀蛋白质。蛋白质沉淀后,将样品上清液在上至4种化合物的盒中合并,添加内标,并通过LC-MS/MS分析样品。根据ln峰面积比(化合物峰面积/内标峰面积)vs时间的作图,确定线的梯度。随后,计算半衰期(t1/2)和内在清除率(CLint)。
结果
实施例8:水性制剂
按照以下程序,将实施例1的化合物配制成pH4的在30%w/v captisol(即磺丁基醚-β-环糊精)中的溶液。
载体30%w/v captisol(即磺丁基醚-β-环糊精)通过以下制备:将所需量的captisol称重到合适的容器中,添加最终体积的大约80%的水并磁力搅拌直至溶液形成。然后将载体用水补足体积。
实施例1的化合物的水溶液通过将175mg化合物称重到合适的容器中并添加所需体积的大约80%的载体来制备。利用盐酸水溶液,将pH调节至pH2,并将所得混合物磁力搅拌直至溶液形成。然后用载体将制剂补足体积,并利用氢氧化钠水溶液将pH调节至pH4。
实施例9:片剂组合物
如下制造片剂,每个片剂重0.15g并含有25mg本发明的化合物:
10,000个片剂的组成
本发明的化合物(250g)
乳糖(800g)
玉米淀粉(415g)
滑石粉(30g)
硬脂酸镁(5g)
将本发明的化合物、乳糖和一半玉米淀粉混合。然后迫使混合物通过0.5mm网孔尺寸的筛。将玉米淀粉(10g)悬浮在温水(90mL)中。利用所得糊状物将粉末造粒。将颗粒干燥并在1.4mm网孔尺寸的筛上破碎成小碎块。添加剩余量的淀粉、滑石和镁,仔细混合并加工成片剂。
实施例10:可注射制剂
本发明的化合物 200mg
盐酸溶液0.1M或
氢氧化钠溶液0.1M q.s.,至pH 4.0至7.0
无菌水q.s.至 10mL
将本发明的化合物溶解在大部分水(35℃-40℃)中,并酌情用盐酸或氢氧化钠将pH调节至4.0至7.0。然后将该批次用水补足体积,并通过无菌微孔过滤器过滤到无菌10mL琥珀色玻璃小瓶(1型)中,并用无菌封盖和密封件密封。
实施例11:肌内注射
将本发明的化合物溶解在glycofurol中。然后添加苯甲醇并溶解,并添加水至3mL。然后将混合物通过无菌微孔过滤器过滤,并密封在无菌3mL玻璃小瓶(1型)中。
实施例12:糖浆制剂
将本发明的化合物溶解在甘油和大部分纯净水的混合物中。然后将苯甲酸钠水溶液添加至溶液中,然后添加山梨糖醇溶液,最后调味剂。用纯净水补足体积并充分混合。
Claims (18)
5.根据前述权利要求中任一项所述的化合物,其中V和W均是CH,并且X是N或CH。
7.根据前述权利要求中任一项所述的化合物,其中n是1,R5处于R5和R6所键合的六元环的环位2,并且R6处于R6和R5所键合的六元环的环位4。
8.根据权利要求1所述的化合物,其选自:
和其药学上可接受的盐。
9.药物组合物,其包括根据权利要求1-8中任一项限定的化合物和药学上可接受的载体或稀释剂。
10.根据权利要求1-8中任一项限定的化合物,用于通过疗法治疗人体或动物体。
11.根据权利要求1-8中任一项限定的化合物,用于治疗或预防RSV感染。
12.根据权利要求1-8中任一项限定的化合物在制备用于治疗或预防RSV感染的药物中的用途。
13.治疗遭受或易受RSV感染的对象的方法,所述方法包括向所述对象给予有效量的根据权利要求1-8中任一项限定的化合物。
14.产品,含有:
(a)根据权利要求1-8中任一项限定的化合物;和
(b)一种或多种进一步的治疗剂;
用于在遭受或易受RSV感染的对象的治疗中同时、分开或顺序应用。
15.根据权利要求14所述的产品,其中所述进一步的治疗剂是:
(i)RSV核衣壳(N)蛋白抑制剂;
(ii)蛋白抑制剂,如抑制磷蛋白(P)和/或大(L)蛋白的蛋白抑制剂;
(iii)抗RSV单克隆抗体,如F蛋白抗体;
(iv)免疫调节toll样受体化合物;
(v)呼吸道病毒抗病毒剂,如抗流感和/或抗鼻病毒化合物;和/或
(vi)抗炎化合物。
16.药物组合物,其包括:(a)根据权利要求1-8中任一项限定的化合物,和(b)一种或多种根据权利要求15限定的治疗剂,以及药学上可接受的载体或稀释剂。
18.根据权利要求16所述的方法,其中所述酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、甲磺酸、苯磺酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、乙磺酸、天冬氨酸和谷氨酸。
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PCT/GB2020/052769 WO2021084280A1 (en) | 2019-11-01 | 2020-11-02 | Pharmaceutical compounds |
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- 2020-11-02 JP JP2022525559A patent/JP2023513866A/ja active Pending
- 2020-11-02 EP EP20801391.2A patent/EP4051675A1/en active Pending
- 2020-11-02 WO PCT/GB2020/052769 patent/WO2021084280A1/en unknown
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GB201915932D0 (en) | 2019-12-18 |
EP4051675A1 (en) | 2022-09-07 |
JP2023513866A (ja) | 2023-04-04 |
CA3159032A1 (en) | 2021-05-06 |
KR20220097446A (ko) | 2022-07-07 |
US20220380349A1 (en) | 2022-12-01 |
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