CN110573508A - 稠合咪唑并-哌啶jak抑制剂化合物 - Google Patents
稠合咪唑并-哌啶jak抑制剂化合物 Download PDFInfo
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- CN110573508A CN110573508A CN201880028413.7A CN201880028413A CN110573508A CN 110573508 A CN110573508 A CN 110573508A CN 201880028413 A CN201880028413 A CN 201880028413A CN 110573508 A CN110573508 A CN 110573508A
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Abstract
本发明提供一种用作JAK抑制剂的式1式1化合物
Description
技术领域
本发明涉及一种适用于治疗多种疾病,尤其眼部、皮肤及呼吸道疾病的JAK激酶抑制剂化合物。本发明还关于所述化合物的结晶形式、包括此类化合物的医药组合物、使用此类化合物治疗适合于JAK抑制剂治疗的疾病的方法及适用于制备所述化合物的方法及中间物。
背景技术
细胞因子为细胞间信号传导分子,其包含趋化因子、干扰素、介白素、淋巴介质及肿瘤坏死因子。细胞因子对于正常细胞生长及免疫性调节为关键的且还驱动免疫介导的疾病且有助于恶性细胞生长。许多细胞因子的较高含量已牵涉到大量疾病或病况,确切地说表征为炎症的那些疾病的病变。涉及疾病的多种细胞因子视经由转录因子的信号转导与转录活化因子(STAT)家族传导信号的酪氨酸激酶(JAK)的杰纳斯(Janus)家族而定,经由信号传导路径起作用。
JAK家族包括四个成员JAK1、JAK2、JAK3及酪氨酸激酶2(TYK2)。细胞因子结合至JAK依赖性细胞因子受体诱导受体二聚,其使得JAK激酶上酪氨酸残基磷酸化,影响JAK活化。磷酸化JAK转而结合且使各种STAT蛋白质磷酸化,所述蛋白质在单元细胞核中二聚、内化且直接调节基因转录,在其它作用中,导致与发炎疾病相关的下游作用。JAK通常与细胞因子受体成对缔合作为均二聚体或杂二聚体。特定细胞因子与特定JAK配对相关。JAK家族的四个成员中的每一者涉及与发炎相关的细胞因子中的至少一者的信号传导。
发炎在多种眼部疾病,包含眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞及异位性角膜结膜炎中发挥显著作用。眼色素层炎涵盖多种眼内发炎病况且通常为自体免疫性的,在无已知感染性触发的情况下出现。估计所述病况在美国影响约2百万患者。在一些患者中,与眼色素层炎相关的慢性发炎引起组织破坏,且在美国其为失明的第五个主要原因。在眼色素层炎患者的眼睛中较高的经由JAK-STAT路径传导信号的细胞因子包含IL-2、IL-4、IL-5、IL-6、IL-10、IL-23及IFN-γ。(Horai及Caspi,J Interferon Cytokine Res,2011,31,733-744;Ooi等人,Clinical Medicine and Research,2006,4,294-309)。用于眼色素层炎的现有疗法通常次最优的,且多种患者控制不良。类固醇(尽管通常有效)与白内障及提高的眼内压/青光眼相关。
糖尿病性视网膜病变(DR)由视网膜中的血管损伤引起。在患有糖尿病的人群中其为最常见的视觉丧失的原因。血管生成路径以及发炎路径在疾病中起重要作用。通常,DR将发展为糖尿病性黄斑水肿(DME),患有糖尿病的患者中视觉丧失的最常见原因。估计所述病况仅在美国影响约一百五十万患者,其中约20%患有影响双眼的疾病。据信,经由JAK-STAT路径传导信号的细胞因子(诸如IL-6)以及其产生部分地通过JAK-STAT路径信号传导驱动的其它细胞因子(诸如IP-10及MCP-1(或者称为CCL2))在与DR/DME相关的炎症中起作用(Abcouwer,J Clin Cell Immunol,2013,Suppl 1,1-12;Sohn等人,American Journal ofOpthamology,2011,152,686-694;Owen及Hartnett,Curr Diab Rep,2013,13,476-480;Cheung等人,Molecular Vision,2012,18,830-837;Dong等人,Molecular Vision,2013,19,1734-1746;Funatsu等人,Ophthalmology,2009,116,73-79)。针对DME的现有疗法为次最优的:玻璃体内抗VEGF治疗仅在一部分患者中有效,且类固醇与白内障及增加的眼内压相关。
干眼病(DED)为影响美国约5百万患者的多因素病症。据信眼表面炎症在此疾病的发展及传播中起重要作用。已注意到在患有DED的患者眼液中较高含量的细胞因子,诸如IL-1、IL-2、IL-4、IL-5、IL-6及IFN-γ。(Stevenson等人,Arch Ophthalmol,2012,130,90-100),且含量通常与疾病严重程度有关。还认为年龄相关的黄斑部变性及异位性角膜结膜炎与JAK依赖性细胞因子相关。
视网膜静脉栓塞(RVO)为非常盛行的视觉致残性疾病。视网膜血流堵塞可导致视网膜血管结构损伤、出血及组织局部缺血。虽然RVO的原因系多因素的,但血管以及炎性介质两者皆显示出重要性(Deobhakta等人,International Journal of Inflammation,2013,文章ID 438412)。经由JAK-STAT路径传导信号的细胞因子(诸如IL-6及IL-13)以及其产生部分地通过JAK-STAT路径信号传导驱动的其它细胞因子(诸如MCP-1)已在患有RVO的患者的眼部组织中检测到含量较高(Shchuko等人,Indian Journal of Ophthalmology,2015,63(12),905-911)。虽然患有RVO的许多患者通过光凝治疗,但此为本质上破坏性治疗。还使用抗VEGF剂,但其仅在一部分患者中有效。降低眼部炎症水平的类固醇药品(曲安奈德(Triamcinolone acetonide)及地塞米松(dexamethasone)植入物)还已显示为患有特定形式的RVO的患者提供有益结果,但其还已显示导致白内障及增加的眼内压/青光眼。
异位性皮炎(AD)为仅在美国就影响估计一千四百万人的常见慢性发炎性皮肤病。据估计,AD影响发达国家中10-20%儿童及1-3%成人(Bao等人,JAK-STAT,2013,2,e24137)且发病率逐渐提高。依赖于JAK-STAT路径的促炎性细胞因子,尤其IL-4、IL-5、IL-10、IL-13及IFNγ的提高与AD相关(Bao等人,Leung等人,The Journal of ClinicalInvestigation,2004,113,651-657)。另外,IL-31(经由JAK配对传导信号的另一细胞因子)的上调已展示在与AD的慢性状态相关的瘙痒性皮炎中具有作用。(Sunkoly等人,Journalof Allergy and Clinical Immunology,2006,117,411-417)
哮喘为气管的慢性疾病,其无预防或治愈方法。所述疾病的特征在于气管发炎、纤维化、高反应性及重构,其皆促成气流限制。全世界估计有3亿人罹患哮喘,且据估计,截至2025,患有哮喘的人数将增长超过1亿。虽然大多数患者可用吸入皮质类固醇实现对哮喘症状的控制,所述吸入皮质类固醇可与白三烯修饰剂及/或长效β促效剂组合,但仍有一部分患有重度哮喘的患者的疾病不受常规疗法控制。涉及经由JAK-STAT路径传导信号的哮喘发炎的细胞因子包含IL-2、IL-3、IL-4、IL-5、IL-6、IL-9、IL-11、IL-13、IL-23、IL-31、IL-27、胸腺基质淋巴生成素(TSLP)、干扰素-γ(IFNγ)及粒细胞-巨噬细胞群落刺激因子(GM-CSF)。除哮喘以外,气管发炎为其它呼吸道疾病所特有的。慢性阻塞性肺病(COPD)、囊肿性纤维化(CF)、肺炎、间质肺病(包含特发性肺纤维化)、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿、阻塞性细支气管炎及类肉瘤病还为呼吸道疾病,其中据信病理生理学与JAK信号传导细胞因子相关。
考虑到发炎疾病中的细胞因子的数目提高且各细胞因子与特定JAK配对相关,针对JAK家族的所有成员的泛活性的化学抑制剂可具有用于治疗眼部、皮肤及呼吸道疾病的较宽效用。仍需要有效泛JAK抑制剂。
发明内容
在一个方面中,本发明提供一种适用于治疗发炎疾病的JAK抑制剂化合物。
确切地说,在一个方面中,本发明提供式的1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮
在下文中为化合物1,或其医药学上可接受的盐。
本发明还提供化合物的结晶形式,形式1及形式2。
本发明还提供一种包括化合物1或其医药学上可接受的盐及医药学上可接受的载剂的医药组合物。
在一个方面中,本发明提供一种治疗哺乳动物的眼部疾病的方法,所述方法包括向哺乳动物投与化合物1或本发明的医药组合物。在一个方面中,眼部疾病为眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞及异位性角膜结膜炎。确切地说,眼部疾病为糖尿病性黄斑水肿或眼色素层炎。
在又一方法方面中,本发明提供一种治疗皮肤的发炎疾病,尤其异位性皮炎的方法,所述方法包括向哺乳动物的皮肤施加化合物1或本发明的医药组合物。
在另一方面中,本发明提供一种治疗哺乳动物的呼吸道疾病的方法,所述方法包括向哺乳动物投与化合物1或其医药学上可接受的盐或本发明的医药组合物。
在单独及不同方面中,本发明还提供本文所描述的合成方法及中间物,其适用于制备化合物1。
本发明还提供用于医学疗法的如本文所描述的化合物1以及本发明化合物在制造供治疗哺乳动物的眼部疾病、皮肤病或呼吸道疾病用的调配物或药物中的用途。
附图说明
本发明的各种方面通过参考附图说明。
图1展示化合物1的结晶形式2的粉末x射线衍射(PXRD)图案(在下文中为形式2)。
图2展示结晶形式2的差示扫描热量测定(DSC)热分析图。
图3展示结晶形式2的热解重量分析(TGA)图。
图4展示在约25℃的温度下观测到的结晶形式2的动态湿气吸附(DMS)等温线。
图5展示形式2的偏光显微镜图像。
图6展示化合物1的结晶形式1的粉末x射线衍射(PXRD)图案(在下文中为形式1)。
图7展示结晶形式1的差示扫描热量测定(DSC)热分析图。
图8展示结晶形式1的热解重量分析(TGA)图。
图9展示在约25℃的温度下观测到的结晶形式1的动态湿气吸附(DMS)等温线。
图10展示形式1的偏光显微图像。
具体实施方式
如ChemDraw软件(PerkinElmer,Inc.,Cambridge,MA)中所实施,本文中根据IUPAC公约命名化学结构。
此外,本发明化合物的结构中的四氢咪唑并哌啶部分的咪唑并部分以互变异构形式存在。化合物可相等地表示为
根据IUPAC公约,这些图示产生四氢咪唑并哌啶部分的原子的不同编号。因此,此结构指定为1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮。其还可指定为1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮。应理解,虽然结构以特定形式展示或命名,但本发明还包含其互变异构体。
本发明化合物含有若干碱基,且因此化合物可以自由碱形式或各种盐形式,诸如单质子化盐形式、二质子化盐形式或其混合物存在。除非另外指示,否则所有此类形式均包含在本发明的范围内。
本发明还包含同位素标记的式1化合物,即原子被换成或富含原子数相同但原子质量不同于在自然界中占绝大多数的原子质量的原子的式1化合物。可结合在式1化合物中的同位素的实例包含(但不限于)2H、3H、11C、13C、14C、13N、15N、15O、17O、18O及18F。备受关注的为富含氚或碳14的式1化合物,所述化合物可用于例如组织分布研究中。还备受关注的为尤其在代谢部位富含氘的式1化合物,所述化合物预期具有较高代谢稳定性。另外,备受关注的为富含诸如11C、18F、15O及13N的正电子发射同位素的式1化合物,所述化合物可用于例如正电子发射断层摄影法(PET)研究。
定义
当描述包含其各种方面及实施例的本发明时,以下
术语“治疗有效量”意味着当向需要治疗的患者投与时足以实现治疗的量。
术语“治疗(treating/treatment)”意味着预防、改善或抑制正在治疗的患者(尤其人类)的医学病况、疾病或病症(例如呼吸道疾病);或减轻医学病况、疾病或病症的症状。
术语“医药学上可接受的盐”意味着向患者或哺乳动物,诸如人类投与可接受的盐(例如对于给定剂量方案具有可接受的哺乳动物安全性的盐)。代表性医药学上可接受的盐包含以下的盐:乙酸、抗坏血酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、乙二磺酸、反丁烯二酸、龙胆酸、葡萄糖酸、葡糖醛酸、谷氨酸、马尿酸、氢溴酸、盐酸、羟乙基磺酸、乳酸、乳糖酸、顺丁烯二酸、苹果酸、杏仁酸、甲烷磺酸、粘液酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸、烟碱酸、硝酸、乳清酸、帕莫酸、泛酸、磷酸、丁二酸、硫酸、酒石酸、对甲苯磺酸及羟萘甲酸及其类似酸。
术语“其盐”意味着当酸的氢经阳离子(诸如金属阳离子或有机阳离子及其类似阳离子)置换时所形成的化合物。举例来说,阳离子可为式1化合物的质子化形式,即一或多个氨基由酸质子化的形式。典型地,盐为医药学上可接受的盐,但此对于不意在投与至患者的中间化合物的盐来说不需要。
术语“氨基-保护基”意味着适用于防止在氨基氮处的不当反应的保护基。代表性氨基-保护基包含(但不限于)甲酰基;酰基,例如烷酰基,诸如乙酰基及三氟乙酰基;烷氧基羰基,诸如叔丁氧基羰基(Boc);芳基甲氧基羰基,诸如苯甲氧基羰基(Cbz)及9-茀基甲氧基羰基(Fmoc);芳基甲基,诸如苯甲基(Bn)、三苯甲基(Tr)及1,1-二(4'-甲氧基苯基)甲基;硅烷基,诸如三甲基硅烷基(TMS)、叔丁基二甲基硅烷基(TBDMS)、[2-(三甲基硅烷基)乙氧基]甲基(SEM);及其类似基团。
术语“羟基-保护基”意味着适用于防止在羟基处的不当反应的保护基。代表性羟基-保护基包含(但不限于)烷基,诸如甲基、乙基及叔丁基;酰基,例如烷酰基,诸如乙酰基;芳基甲基,诸如苯甲基(Bn)、对甲氧基苯甲基(PMB)、9-茀基甲基(Fm)及二苯甲基(二苯甲基,DPM);硅烷基,诸如三甲基硅烷基(TMS)及叔丁基二甲基硅烷基(TBS);及其类似基团。
许多保护基及其引入及移除描述于T.W.Greene及P.G.M.Wuts,ProtectingGroups in Organic Synthesis,第三版,Wiley,New York中
一般合成程序
化合物1及其中间物可根据使用市售或常规制备的起始物质及试剂的以下一般方法及程序制备。另外,除非另外指示,否则可使用具有酸性或碱性原子或官能基的化合物或可以盐形式产生(在一些情况下,在特定反应中使用盐将需要在执行反应之前使用常规程序将盐转化为非盐形式,例如自由碱)。
虽然可在以下程序中展示或描述本发明的特定实施例,但本领域的技术人员将认识到本发明的其它实施例或方面还可使用所述程序或通过使用本领域的技术人员已知的其它方法、试剂及起始物质来制备。确切地说,应了解,化合物1可通过多种方法途径制备,其中反应物以不同次序组合以提供不同中间物途径,从而产生最终产物。
1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(化合物1)的制备详细描述于随附实例中。关键步骤概述于流程1中
流程1
其中反应剂7为2-吗啉基乙酸2,5-二氧代吡咯烷-1-酯,即变量RA表示活化剂2,5-二氧代吡咯烷基,如实例1中所描述。或者,在典型的酰胺键形成条件下,吗啉-4-基乙酸(即,RA表示氢)用作反应剂7,如实例4中所描述。
中间物3可如以下制剂1及3中所描述制备。关键受保护中间物5的制备的替代方法在流程2中示出。
流程2
溴吲唑醛8可与苯甲基受保护的亚胺化合物2反应以提供中间物9。反应典型地在亚硫酸氢钠存在下,在约130℃与约140℃之间的温度下进行约1与约6小时之间或直到反应基本上完成为止。化合物9使用诸如硼氢化钠的还原剂还原以提供化合物10,在典型的铃木-宫浦偶合条件下将其与受保护的苯基三氟硼酸盐11组合以提供中间物5。反应典型地在高温下在钯催化剂存在下进行。作为三氟硼酸酯钾盐展示于流程2中的铃木搭配物11可通过使相应的酸酯(以下制剂1中的中间物1-5)与二氟化氢钾反应制备以提供中间物11。或者,可使用硼酸酯中间物替代三氟硼酸酯11。
因此,在一个方法方面中,本发明提供一种制备式1化合物或其医药学上可接受的盐的方法,所述方法包括使式6化合物与式7化合物如流程1中所说明反应,提供式1化合物或其医药学上可接受的盐。
在额外方法方面中,本发明提供一种适用于制备式1化合物的式5化合物及式6化合物。
结晶形式
在另一方面中,本发明提供呈结晶形式的1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)。
形式1
本发明的结晶形式1为化合物1的结晶自由形式。在一个方面中,形式1通过粉末X射线衍射(PXRD)图案表征,所述图案除其它峰以外在以下2θ值处具有显著衍射峰:8.16±0.20、8.97±0.20、15.29±0.20、16.70±0.20、18.00±0.20及20.18±0.20。形式1可进一步通过PXRD图案表征,所述图案在选自以下的2θ值处具有两个或多于两个额外衍射峰,包含三个或多于三个及四个或多于四个额外衍射峰:7.69±0.20、10.66±0.20、11.46±0.20、11.91±0.20、15.80±0.20、17.02±0.20、18.83±0.20、22.39±0.20、22.98±0.20、24.89±0.20及26.54±0.20。在另一方面中,形式1通过PXRD图案表征,所述图案在选自以下的2θ值处具有三个、四个、五个或六个衍射峰:8.16±0.20、8.97±0.20、15.29±0.20、16.70±0.20、18.00±0.20及20.18±0.20。
如粉末X射线衍射的领域中所熟知,与相对峰高度相比,PXRD图案的峰位置对实验细节(诸如样本制备及仪器几何结构的细节)相对更不敏感。因此,在一个方面中,结晶形式1通过粉末x射线衍射图案表征,其中峰位置基本上符合图6中展示的那些峰位置。
在另一方面中,当曝露于高温时,结晶形式1通过其行为表征。如图7中所展现,以10℃/分钟的加热速率记录的差示扫描热量测定(DSC)迹线展现吸热热流的峰,鉴别为约210℃至约234℃范围内或约215℃至约229℃之间的范围内或约220℃至约224℃之间的范围内的熔融转变。结晶形式1通过以10℃/分钟的加热速率记录的差示扫描热量测定迹线表征,其展示在约221.7℃下的峰的吸热热流的最大值。图8的热解重量分析(TGA)迹线展示在低于约293℃的分解起始的温度下,无显著重量损失。
本发明的形式1结晶自由形式的代表性动态湿气吸附(DMS)迹线展示于图9中。结晶形式1展现吸附及解吸附的两次循环之间的轻微滞后。形式1展现在室温下,在5%至70%相对湿度的湿度范围内约0.99%重量增加及在5%至90%相对湿度的湿度范围内约1.32%重量增加,如图9中所示。形式1视为略微吸湿的。
结晶形式1已展示在曝露于升高的温度及湿度后为稳定的。在40℃及75%相对湿度的加速条件下36周后,未观测到化学纯度的统计显著变化。
形式1可通过在加热后使化合物1溶解于乙醇中,继而添加乙腈制备,其中乙腈与乙醇的比率为约1:1或约1:3至3:1。所得混合物随后升温,继而在约20℃与约25℃之间的温度下搅拌约4小时至约30小时,或约16小时。随后过滤固体且干燥以提供形式1。
形式1还可通过使化合物1与乙醇混合且在约50与约80℃之间的温度下搅拌混合物约2至30分钟,或约10分钟,继而在约50与约80℃之间的温度下缓慢添加乙腈来制备,其中乙腈与乙醇的体积比率为约3:1至1:1或约1.5:1。可添加形式1的晶种且在约20℃与约25℃之间的温度下搅拌反应混合物约4小时及约30小时,或约18小时。随后过滤固体且干燥以提供形式1。
形式2
本发明的结晶形式2为化合物1的结晶自由形式。在一个方面中,形式2通过粉末X射线衍射(PXRD)图案表征,所述图案除其它峰以外在以下2θ值处具有显著衍射峰:10.61±0.20、11.84±0.20、14.94±0.20、18.26±0.20及19.06±0.20。形式2可进一步通过PXRD图案表征,所述图案在13.32±0.20、17.69±0.20及21.10±0.20的2θ值处具有额外衍射峰。形式2可进一步通过PXRD图案表征,所述图案在选自以下的2θ值处具有两个或多于两个额外衍射峰,包含三个或多于三个及四个或多于四个额外衍射峰:10.85±0.20、16.14±0.20、16.35±0.20、18.43±0.20、19.20±0.20、19.49±0.20、20.72±0.20、21.94±0.20、22.64±0.20、23.64±0.20、25.19±0.20及28.08±0.20。
在另一方面中,形式2通过PXRD图案表征,所述图案在选自以下的2θ值处具有三个、四个、五个或六个衍射峰:10.61±0.20、11.84±0.20、13.32±0.20、14.94±0.20、17.69±0.20、18.26±0.20、19.06±0.20及21.10±0.20。
如粉末X射线衍射的领域中所熟知,与相对峰高度相比,PXRD图案的峰位置对实验细节(诸如样本制备及仪器几何结构的细节)相对更不敏感。因此,在一个方面中,结晶形式2通过粉末x射线衍射图案表征,其中峰位置基本上符合图1中展示的那些者。
结晶形式2的结构已进一步通过单晶x射线衍射分析表征。结晶属于斜方晶结晶系统及Pbca空间群。单位晶胞尺寸为: α=90°,β=90°,γ=90°,计算密度为1.302g/cm3。结晶每单位晶胞含有八个分子。结构证实结晶不含有水或其它溶剂分子,且分子结构符合如本文所描绘的实例1的化合物的结构。从经导出原子位置预测的粉末X射线衍射峰与观测结果充分一致。
在另一方面中,当曝露于高温时,结晶形式2通过其行为表征。如图2中所展现,以10℃/分钟的加热速率记录的差示扫描热量测定(DSC)迹线展现吸热热流的峰,鉴别为约268℃至约277℃范围内或约270℃至约275℃之间的范围内或约271℃至约274℃之间的范围内的熔融转变。结晶形式2通过以10℃/分钟的加热速率记录的差示扫描热量测定迹线表征,其展示在约272.6±2℃下的峰的吸热热流的最大值。
图3的热解重量分析(TGA)迹线展示在低于约269℃的分解起始的温度下,无显著重量损失。
本发明的形式2结晶自由形式的代表性动态湿气吸附(DMS)迹线展示于图4中。结晶形式2展示吸附及解吸附的两次循环之间无滞后且展现极小的吸湿性倾向。形式2展现在室温下,在5%至90%相对湿度的湿度范围内约0.18%重量增加及在5%至70%相对湿度的湿度范围内约0.12%重量增加,如图4中所示。形式2视为非吸湿性的。
形式2可通过在约45与75℃之间的温度下或在约60℃下使实例1的化合物1溶解于DMSO(例如以1g化合物1(对于1至3mL)或约2mL DMSO的比率)中,继而添加甲醇来制备,其中甲醇与DMSO的体积比率为约1:4至约1:1,或约1:2。随后在约60与约90℃之间或约75℃的温度下将均匀混合物逐滴添加至甲醇及水的预混合溶液中(其中甲醇与DMSO的比率在1.5与3之间至1),其中甲醇与水的预混合溶液的体积比率为约0.5:1至约1:2,或约1:0.9。随后将混合物在约60与约90℃之间或约75℃的温度下搅拌约30分钟至约2小时,或约1小时。可随后在约60与约90℃之间或约75℃的温度下缓慢添加水,其中水与甲醇的体积比率在2与4之间。随后典型地历经约2至约12小时或约6小时,使所得浆料缓慢冷却至室温(典型地,约20与约25℃之间的温度)。随后将浆料保持在室温下,且随后过滤且用水与甲醇的混合物洗涤以提供形式2,其中水占约50至约90%或约70%。
在一个方面中,本发明提供一种制备结晶形式2的方法,其包括:
(a)在极性非质子性溶剂中或在极性水混溶性溶剂中或在极性非质子性溶剂与极性水混溶性溶剂的混合物中,在45与75℃之间的温度下形成1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮的均匀混合物;
(b)在60与90℃之间的温度下将均匀混合物添加至水混溶性溶剂与水的混合物中,得到第二混合物;
(c)在60与90℃之间的温度下将水缓慢添加至第二混合物中以形成浆料;且
(d)从浆料分离结晶形式。
在一些方面中,步骤(a)的极性非质子性溶剂选自由以下组成的群:DMSO、DMF、NMP、DMAc及硝基甲烷,步骤(a)的极性水混溶性溶剂选自由以下组成的群:乙腈、丙酮、甲醇、乙醇及THF,且步骤(b)的水混溶性溶剂选自由以下组成的群:乙腈、丙酮、甲醇、乙醇、正丙醇、异丙醇、正丁醇、THF、DMSO、DMF、NMP、DMAc及硝基甲烷。在一些方面中,步骤(a)的极性非质子性溶剂为DMSO,步骤(a)的极性水混溶性溶剂为甲醇,且步骤(b)的水混溶性溶剂为甲醇。
在一些方面中,在步骤(d)之前,使步骤(c)中所获得的浆料冷却至约20与25℃之间的温度。
或者,形式2可通过在极性水混溶性溶剂与水的混合物中在60与90℃之间的温度下搅拌实例1中所获得的化合物1形成。在一些方面中,溶剂与水的比率为约1:1或2:1至0.5:1。在一些方面中,极性水混溶性溶剂选自由以下组成的群:乙腈、丙酮、甲醇、乙醇、正丙醇、异丙醇、正丁醇、THF、DMSO、DMF、NMP、DMAc及硝基甲烷。
医药组合物
化合物1及其医药学上可接受的盐典型地以医药组合物或调配物形式使用。此类医药组合物可有利地通过任何可接受的投与途径向患者投与,包含(但不限于)经口、吸入、经眼注射、表面(包含经皮)、经直肠、经鼻及非经肠投与模式。
因此,在其组合物方面中的一者中,本发明涉及一种包括医药学上可接受的载剂或赋形剂及化合物1的医药组合物,其中,如上文所定义,“化合物1”意味着化合物1或其医药学上可接受的盐。任选地,必要时此类医药组合物可含有其它治疗剂及/或调配剂。当论述组合物及其用途时,化合物1还可在本文中称为“活性剂”。
在一些方面中,本发明提供一种包括化合物1或其医药学上可接受的盐或形式1或形式2及医药学上可接受的载剂的医药组合物。在一些方面中,医药组合物适用于施加至眼睛。在一些方面中,组合物适用于注射至眼部中。在一些方面中,组合物适用于玻璃体内注射。在一些方面中,组合物为悬浮液。在一些方面中,组合物为结晶悬浮液。在一些方面中,组合物为形式1或形式2的悬浮液。
本发明的医药组合物典型地含有治疗有效量的化合物1。然而,本领域的技术人员将认识到,医药组合物可含有超过治疗有效量(即,主体组合物)或小于治疗有效量(即,经设计用于多次投与以获得治疗有效量的个别单位剂量)。
典型地,此类医药组合物将含有约0.01至约95重量%的活性剂;包含例如约0.05至约30重量%;及约0.1重量%至约10重量%的活性剂。
任何常规载剂或赋形剂可用于本发明的医药组合物中。选择特定载剂或赋形剂,或载剂或赋形剂的组合将视用于治疗特定患者或特定类型的医学病况或疾病病状的投与模式而定。就此来说,对于特定模式模式,适合的医药组合物的制备很好地在熟习医药技术者的范围内。另外,本发明的医药组合物中所使用的载剂或赋形剂市售可得。作为进一步说明,常规调配技术描述于雷明顿:药学科学及实践(The Science and Practice ofPharmacy),第20版,利平科特威廉姆斯&怀特,巴尔的摩,马里兰州(Lippincott Williams&White,Baltimore,Maryland)(2000);及H.C.Ansel等人,医药剂型及药物递送系统(Pharmaceutical Dosage Forms and Drug Delivery Systems),第7版,利平科特威廉姆斯&怀特,巴尔的摩,马里兰州(1999)。
可充当医药学上可接受的载剂的材料的代表性实例包含(但不限于)以下:糖,诸如乳糖、葡萄糖及蔗糖;淀粉,诸如玉米淀粉及马铃薯淀粉;纤维素诸如微晶纤维素,及其衍生物,诸如羧甲基纤维素钠、乙基纤维素钠及乙酸纤维素钠;粉末状黄蓍;麦芽;明胶;滑石;赋形剂,诸如可可脂及栓剂蜡;油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;二醇,诸如丙二醇;多元醇,诸如丙三醇、山梨糖醇、甘露糖醇及聚乙二醇;酯,诸如油酸乙酯及月桂酸乙酯;琼脂;缓冲剂,诸如氢氧化镁及氢氧化铝;褐藻酸;无热原质水;等张生理食盐水;林格氏溶液(Ringer's solution);乙醇;磷酸盐缓冲溶液;及医药组合物中所采用的其它无毒相容物质。
典型地通过将活性剂与医药学上可接受的载剂及一或多种任选的成分充分且紧密地混合或掺合来制备医药组合物。随后可使用常规程序及设备将所得均匀掺合的混合物成形为锭剂、胶囊、丸剂及其类似物或装载至其中。
本发明的医药组合物较佳以单位剂型封装。术语“单位剂型”系指适用于单独或与一或多种额外单位组合向患者给药的物理离散单位,即,各单位含有预定量的计算的活性剂以产生所需治疗效果。举例来说,此类单位剂型可为胶囊、锭剂、丸剂及其类似物,或适合于眼部或肠胃外投与的单位封装。
在一个实施例中,本发明的医药组合物适用于经口投与。用于经口投与的适合的医药组合物可呈胶囊、锭剂、丸剂、锭剂、扁囊剂、糖衣药丸、散剂、粒剂形式;或于水性或非水性液体中的溶液或悬浮液形式;或呈水包油液体乳液或油包水液体乳液形式;或呈酏剂或糖浆形式;及其类似形式;各自含有预定量的化合物1作为活性成分。
当意在用于以固体剂型(即,呈胶囊、锭剂、丸剂及其类似形式)经口投与时,本发明的医药组合物将典型地包括活性剂及一或多种医药学上可接受的载剂。任选地,此类固体剂型可包括:填充剂或延长剂,诸如淀粉、微晶纤维素、乳糖、磷酸二钙、蔗糖、葡萄糖、甘露醇及/或硅酸;粘合剂,诸如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖及/或阿拉伯胶;保湿剂,诸如甘油;崩解剂,诸如交联羧甲基纤维素钠、琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐及/或碳酸钠;溶液阻滞剂,诸如石蜡;吸收促进剂,诸如季铵化合物;湿润剂,诸如十六醇及/或丙三醇单硬脂酸酯;吸附剂,诸如高岭土及/或膨润土;润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及/或其混合物;着色剂;及缓冲剂。
脱模剂、湿润剂、包衣剂、甜味剂、调味剂及芳香剂、防腐剂及抗氧化剂还可存在于本发明的医药组合物中。医药学上可接受的抗氧化剂的实例包含:水溶性抗氧化剂,诸如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸钠、亚硫酸钠及其类似物;油溶性抗氧化剂,诸如抗坏血酸棕榈酸酯、丁基化羟基大茴香醚、丁基化羟基甲苯、卵磷脂、没食子酸丙酯、α生育酚及其类似物;及金属螯合剂,诸如柠檬酸、乙二胺四乙酸、山梨糖醇、酒石酸、磷酸及其类似物。用于锭剂、胶囊、丸剂及其类似物的包衣剂包含用于肠溶衣的那些包衣剂,诸如邻苯二甲酸乙酸纤维素、聚邻苯二甲酸乙酸乙烯酯、邻苯二甲酸羟丙基甲基纤维素、羟丙基甲基纤维素、甲基丙烯酸、甲基丙烯酸酯共聚物、偏苯三甲酸乙酸纤维素、羧甲基乙基纤维素、丁二酸乙酸羟丙基甲基纤维素及其类似物。
本发明的医药组合物还可经调配,以使用(例如)呈不同比例的羟丙基甲基纤维素或其它聚合物基质、脂质体及/或微球体,来提供活性剂的减缓或控制释放。另外,本发明的医药组合物可任选地含有乳浊剂且可经调配,使得其任选地以经延迟方式在胃肠道的某一部分中仅仅或优先释放活性成分。可使用的包埋组合物的实例包含聚合物质及蜡。活性剂还可呈(若适宜)与上文所描述的赋形剂中的一或多者的微囊封形式。
用于经口投与的适合的液体剂型以说明方式包含医药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。液体剂型典型地包括活性剂及惰性稀释剂(诸如水)或其它溶剂、增溶剂及乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(尤其棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油及芝麻油)、油酸、甘油、四氢呋喃醇、聚乙二醇及脱水山梨糖醇的脂肪酸酯,及其混合物。或者,某些液体调配物可例如通过喷雾干燥转变成粉末,所述粉末用以通过常规程序制备固体剂型。
除活性成分以外,悬浮液可含有悬浮剂,诸如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂-琼脂及黄蓍及其混合物。
化合物1还可非经肠(例如通过静脉内、皮下、肌肉内或腹膜内注射)投与。对于非经肠投与,活性剂典型地与用于非经肠投与的适合的媒剂掺合,所述适合的媒剂包含例如无菌水溶液;盐水;低分子量醇,诸如丙二醇、聚乙二醇;植物油;明胶;脂肪酸酯,诸如油酸乙酯及其类似物。非经肠调配物还可含有一或多种抗氧化剂、增溶剂、稳定剂、防腐剂、湿润剂、乳化剂、缓冲剂或分散剂。可通过使用无菌可注射介质、灭菌剂、过滤、照射或加热来使这些调配物无菌。
化合物1还可以用于眼部注射的无菌水性悬浮液或溶液形式调配。此类水性调配物中可包含的适用的赋形剂包含聚山梨醇酯80;纤维素聚合物,诸如羧甲基纤维素、羟丙基甲基纤维素、甲基纤维素;氯化钾;氯化钙;氯化钠;氯化镁;乙酸钠;柠檬酸钠;组氨酸;α-α-二水合海藻糖;蔗糖;聚山梨醇酯20;羟丙基-β-环糊精;苯扎氯铵;安伯来特(Amberlite)IRP-69;聚氧化乙烯二醇醚(月桂基、硬脂酰基及油基);乙烯二胺四乙酸钠盐;牛磺胆酸钠;皂素及十六醇聚氧乙烯醚EL;聚卡波非-半胱氨酸;黄原胶;结兰胶(Gellan gum);玻尿酸;脂质体及磷酸钠。渗透性增强剂、表面活性剂、胆酸、环糊精(诸如2-羟丙基-β-环糊精)及螯合剂可包含在调配物中。具有与活性剂形成复合物的能力的具有亲水性外表面及亲脂性内表面的圆柱形寡核苷酸还可包含于调配物中。苯甲醇可充当防腐剂,且可包含氯化钠以调整张力。另外,可将盐酸及/或氢氧化钠添加至溶液中以供用于pH调节。用于眼部注射的水性调配物可制备成无防腐剂。
眼部调配物可允许活性成分持续释放至眼部。眼部调配物可配制为乳液(水包油或油包水)、悬浮液或软膏。悬浮液调配物可含有结晶形式,例如形式1或形式2或非晶态的化合物1或其医药学上可接受的盐。
化合物1还可经调配适用于滴眼剂给药或玻璃体内植入物。植入物可允许递送持续治疗含量的药物。储槽植入物典型地用被诸如硅、乙烯乙酸乙烯酯(EVA)或聚乙烯醇(PVA)的非反应性物质包围的粒化药物核心制得;这些植入物为生物可降解的且可递送连续量的药物持续数个月至一年。还可使用基质植入物。其典型地在1天至6个月时间段期间用于递送起始剂量,继而逐渐减少的剂量的药物。其最常由共聚物聚乳酸(PLA)及/或聚乳酸乙醇酸(PLGA)制成,其降解成水及二氧化碳。还可使用离子导入。其为非侵入性技术,其中施加较小电流以增强电离药物穿透至组织中。
基于细胞的递送系统的囊封细胞技术(ECT)还可用以将治疗剂递送至眼部。典型地,经基因修饰的细胞已封装于半透膜的中空管中,其妨碍免疫细胞进入且允许养分及治疗分子在膜内自由扩散。密封聚合物部分的两端,且将钛环放置于锚定末端上,其植入在平坦部且锚定至巩膜。
化合物1可调配成任何形式,递送至眼部后部。递送模式的实例为文献中已知的(Kuno等人,Polymers,2011,3,193-221,del Amo等人,Drug Discovery Today,2008,13,135-143,Short,Toxicologic Pathology,2008,36,49-62)。此类递送模式包含(但不限于)脉络膜上腔递送,其允许经由脉络膜上腔空间递送至脉络膜及视网膜;球筋膜囊下递送;眼周递送;隐形眼镜;泪点塞;及巩膜塞。化合物1还可通过眼周、巩膜外、眼球后、眼球周或结膜下注射递送。
化合物1可以乳液、聚合微观或奈米球、脂质体、微观或奈米粒子、微球体、胶束或树状体形式递送。可使用生物可降解且生物相容的聚合物,诸如聚乳酸及PLGA。化合物1可为囊封的。
另外,化合物1可经调配用于以软膏或乳膏形式局部投与至皮肤。软膏调配物为具有典型地清楚的油性或油腻材料的基质的半固体制剂。用于软膏调配物的适合的油性材料包含石蜡脂(石油膏)、蜂蜡、可可脂、牛油树脂及十六醇。必要时,软膏可任选地另外包含润肤剂及渗透增强剂。
乳膏调配物可制备为包括油相及水相,典型地包含纯化水的乳液。乳膏调配物的组分可包含:油性基质,诸如矿脂、矿物油、植物油及动物油;及三酸甘油酯;乳膏基质,诸如羊毛蜡醇、硬脂酸及鲸蜡硬脂醇;凝胶基质,诸如聚乙烯醇;溶剂,诸如丙二醇及聚乙二醇;乳化剂,诸如聚山梨醇酯;硬脂酸酯,诸如硬脂酸甘油酯、辛基羟基硬脂酸酯、硬脂酸聚乙二醇酯、PEG硬脂酰基醚、棕榈异丙酸酯及脱水山梨糖醇单硬脂酸酯;稳定剂,诸如多醣及亚硫酸钠;润肤剂(即,保湿剂),诸如中链三酸甘油酯、肉豆蔻酸异丙酯及二甲聚硅氧烷;硬化剂,诸如十六醇及硬脂醇;抗微生物剂,诸如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯氧基乙醇、山梨酸、重氮利定脲及丁基化羟基大茴香醚;渗透增强剂,诸如N-甲基吡咯烷酮、丙二醇、单月桂酸聚乙二醇酯及其类似物;及螯合剂,诸如乙二胺四乙酸二钠。
或者,本发明的医药组合物经调配以通过吸入来投与。通过吸入投与的适合的医药组合物将典型地呈气溶胶或粉末形式。此类组合物一般使用熟知的递送装置投与,所述递送装置诸如定量给药吸入器、干粉吸入器、喷雾器或类似递送装置。
当使用加压容器通过吸入投与时,本发明的医药组合物将典型地包括活性成分及适合的推进剂,诸如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适合的气体。另外,医药组合物可呈包括化合物1及适用于粉末吸入器的粉末的胶囊或药筒(例如由明胶制得)形式。适合的粉末基质包含例如乳糖或淀粉。
以下非限制性实例说明了本发明的代表性医药组合物。
锭剂经口固体剂型
以4:5:1:1的比率将化合物1或其医药学上可接受的盐与微晶纤维素、聚乙烯吡咯烷酮及交联羧甲基纤维素钠干燥掺合且压缩成锭剂以提供例如每锭5mg、20mg或40mg活性剂的单位剂量。
胶囊经口固体剂型
通过湿式造粒以4:5:1:1的比率将化合物1或其医药学上可接受的盐与微晶纤维素、聚乙烯吡咯烷酮及交联羧甲基纤维素钠组合且装载至明胶或羟丙基甲基纤维素胶囊中以提供例如每胶囊5mg、20mg或40mg活性剂的单位剂量。
液体调配物
通过将本发明化合物添加至水与抗坏血酸的混合物中来形成包括化合物1(0.1%)、水(98.9%)及抗坏血酸(1.0%)的液体调配物。
包覆肠溶包衣的口服剂型
使化合物1溶解于含有聚乙烯吡咯烷酮的水溶液中且以1:5w/w活性剂:珠粒的比率喷雾涂布于微晶纤维素或糖珠粒上,且随后施加包括丙烯酸共聚物的约5%重量增加的包覆肠溶包衣。将包覆肠溶包衣的珠粒装载至明胶或羟丙基甲基纤维素胶囊中,得到例如每胶囊30mg活性剂的单位剂量。
包覆肠溶包衣的口服剂型
将包括及的组合或丁二酸乙酸羟丙基甲基纤维素的包覆肠溶包衣施加至上文所描述的锭剂口服剂型或胶囊口服剂型。
用于眼部注射的水性调配物
每mL无菌水性悬浮液包含5mg至50mg化合物1、用于张力的氯化钠、作为防腐剂的0.99%(w/v)苯甲醇、0.75%羧甲基纤维素钠及0.04%聚山梨醇酯。可包含氢氧化钠或盐酸以将pH调节至5至7.5。
用于眼部注射的水性调配物
无菌无防腐剂水性悬浮液包含含5mg/mL至50mg/mL化合物1的10mM磷酸钠、40mM氯化钠、0.03%聚山梨醇酯20及5%蔗糖。
用于局部投与的软膏调配物
以提供含有0.05重量%至5重量%活性剂的组合物的比率,将化合物1与石蜡脂、C8-C10三酸甘油酯、辛基羟基硬脂酸酯及N-甲基吡咯烷酮组合。
用于局部投与的软膏调配物
以提供含有0.05重量%至5重量%活性剂的组合物的比率,将化合物1与白石蜡脂、丙二醇、单及二甘油酯、石蜡、丁基化羟基甲苯及乙二胺四乙酸钙二钠组合。
用于局部投与的软膏调配物
将化合物1与矿物油、石蜡、碳酸伸丙酯、白石蜡脂及白蜡组合以提供含有0.05重量%至5重量%活性剂的组合物。
用于局部投与的乳膏调配物
将矿物油与化合物1、丙二醇、棕榈异丙酸酯、聚山梨醇酯60、十六醇、脱水山梨糖醇单硬脂酸酯、聚乙二醇40硬脂酸酯、山梨酸、对羟基苯甲酸甲酯及对羟基苯甲酸丙酯组合以形成油相,通过剪切掺合将其与纯化水组合以提供含有0.05重量%至5重量%活性剂的组合物。
用于局部投与的乳膏调配物
包括化合物1、苯甲醇、十六醇、无水柠檬酸、单及二甘油酯、油醇、丙二醇、十六基十八基硫酸钠、氢氧化钠、硬脂醇、三酸甘油酯及水的乳膏调配物含有0.05重量%至5重量%活性剂。
用于局部投与的乳膏调配物
包括化合物1、十六醇硬脂醇、十四烷酸异丙酯、丙二醇、聚西托醇1000、二甲聚硅氧烷360、柠檬酸、柠檬酸钠及纯化水与作为防腐剂的咪唑烷基脲、对羟基苯甲酸甲酯及对羟基苯甲酸丙酯的乳膏调配物含有0.05重量%至5重量%活性剂。
干燥粉末组合物
将微粉化化合物1(1g)与经研磨的乳糖(25g)掺合。随后以足以提供每剂约0.1mg至约4mg之间的化合物1的量将此经掺合的混合物装载至可剥离泡壳封装的个别泡壳中。使用干燥粉末吸入器投与泡壳的内含物。
定量吸入器组合物
使微粉化化合物1(10g)分散于通过使卵磷脂(0.2g)溶解于去矿物质水(200mL)中制备的溶液中。喷雾干燥所得悬浮液,且随后经微粉化以形成包括平均直径小于约1.5μm的粒子的微粉化组合物。随后将微粉化组合物装载至以当通过定量吸入器投与时每剂足以提供约0.1mg至约4mg化合物1的量含有加压1,1,1,2-四氟乙烷的定量吸入器套筒中。
喷雾器组合物
使化合物1(25mg)溶解于含有1.5至2.5当量盐酸的溶液中,继而添加氢氧化钠以将pH调节至3.5至5.5及3重量%甘油。充分搅拌溶液直到所有组分溶解为止。使用每剂提供约0.1mg至约4mg化合物1的喷雾器装置投与溶液。
效用
化合物1已展示为以下JAK酶家族的强力抑制剂:JAK1、JAK2、JAK3及TYK2。
眼部疾病
许多眼部疾病已展示与依赖于JAK-STAT路径的促炎性细胞因子升高有关。由于化合物1在所有四种JAK酶下展现强力抑制,因此预期强力抑制经由JAK传导信号的多种细胞因子(诸如IL-6、IL-2及IFN-γ)的信号传导及致病作用,以及防止其产生通过JAK-STAT路径信号传导驱动的其它细胞因子(诸如MCP-1及IP-10)的增加。
确切地说,化合物1在检定3至6中所描述的细胞检定中展现pIC50值为6.4或更大(IC50值为400nM或更小)以用于抑制IL-6、IL-2及IFNγ信号传导,所述检定包含记录抑制细胞因子升高的下游作用的检定。
检定7的药物动力学研究展现在单一玻璃体内注射之后持续暴露于家兔眼睛中且血浆中的浓度比玻璃体组织中观测到的低至少三个数量级。
此外,化合物1的玻璃体内给药已展现,大鼠视网膜/脉络膜组织中的IL-6诱导的pSTAT3的显著抑制以及家兔玻璃体以及视网膜/脉络膜组织中的IFN-γ诱导的IP-10的显著且持久的抑制。化合物1的玻璃体内给药已展现,家兔中的IFN-γ诱导的pSTAT1的显著且持久的抑制。
预期,在显著全身性含量不存在下,持久眼部JAK抑制将在眼部中产生强效局部抗发炎活性,而无全身性驱动不良作用。因此,化合物1预期有益于多种眼部疾病,包含(但不限于)眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞及异位性角膜结膜炎。
确切地说,眼色素层炎(宝来(Horai)及卡斯皮(Caspi),干扰素细胞因子研究杂质(J Interferon Cytokine Res),2011,31,733-744)、糖尿病性视网膜病变(艾博库韦(Abcouwer),临床细胞免疫学杂质(J Clin Cell Immunol),2013,增刊1,1-12)、糖尿病性黄斑水肿(佐恩(Sohn)等人,美国眼科学杂质(American Journal of Opthamology),2011,152,686-694)、干眼病(史蒂文森(Stevenson)等人,眼科学档案(Arch Ophthalmol),2012,130,90-100)、视网膜静脉栓塞(舒库寇(Shchuko)等人,印度眼科学杂质(Indian Journalof Ophthalmology),2015,63(12),905-911)及年龄相关的黄斑部变性(尼克贝恩(Knickelbein)等人,国际眼科学临床(Int Ophthalmol Clin),2015,55(3),63-78)的特征在于经由JAK-STAT路径传导信号的某些促炎性细胞因子提高。因此,化合物1可能能够缓解相关眼部发炎且逆转疾病进展或缓解这些疾病症状。
因此,在一个方面中,本发明提供一种治疗哺乳动物的眼部疾病的方法,所述方法包括向哺乳动物眼部投与包括1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮或其医药学上可接受的盐及医药载剂的医药组合物。在一个方面中,眼部疾病为眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞或异位性角膜结膜炎。在一个方面中,所述方法包括通过玻璃体内注射投与化合物1。
发炎性皮肤病
举例来说,异位性皮炎与依赖于JAK-STAT路径的促炎性细胞因子,尤其IL-4、IL-5、IL-10、IL-13及IFNγ的提高相关。除了上文所引用的细胞检定中的细胞因子抑制之外,化合物1展现针对IL-13的抑制13nM的IC50值,如检定2中所描述。此外,化合物1的模型乳膏及软膏调配物已展现至少2天(小鼠)及至少7天(小型猪)的持久经皮含量,而无可检测的血浆曝露。
预期在显著全身性含量不存在下化合物1的持久经皮含量将产生有效局部抗炎性及皮肤止痒活动,而无全身驱动的不良作用。因此,预期化合物1有利于大量经皮发炎性或瘙痒病况,包含(但不限于)斑秃、白斑病、皮肤T细胞淋巴瘤、结节性痒疹、扁平苔癣、原发性局部皮肤淀粉样变性、大疱性类天疱疮、移植物抗宿主病的皮肤表现、类天疱疮、盘状狼疮、环状肉芽肿、慢性单纯性苔癣、外阴/阴囊/肛周搔痒病、硬化性苔癣、疱疹后神经痛发痒、扁平毛发苔癣及秃发性毛囊炎。确切地说,斑秃(Xing等人,Nat Med.2014年9月;20(9):1043-9)、白斑病(Craiglow等人,JAMA Dermatol.2015年10月;151(10):1110-2)、皮肤T细胞淋巴瘤(Netchiporouk等人,Cell Cycle.2014;13(21):3331-5)、结节性痒疹(Sonkoly等人,JAllergy Clin Immunol.2006年2月;117(2):411-7)、扁平苔癣(Welz-Kubiak等人,JImmunol Res.2015;2015:854747)、原发性局部皮肤淀粉样变性(Tanaka等人,Br JDermatol.2009年12月;161(6):1217-24)、大疱性类天疱疮(Feliciani等人,Int JImmunopathol Pharmacol.1999年5月至8月;12(2):55-61)及移植物抗宿主病的经皮表现(Okiyama等人,J Invest Dermatol.2014年4月;134(4):992-1000)的特征在于经由JAK活化传导信号的某些细胞因子的提高。因此,化合物1可能能够缓解这些细胞因子所引发的相关经皮发炎或搔痒病。确切地说,化合物1预期适用于治疗异位性皮炎及其它发炎性皮肤病。
因此,在一个方面中,本发明提供一种治疗哺乳动物(例如人类)的发炎性皮肤病的方法,所述方法包括向哺乳动物的皮肤施加包括1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮或其医药学上可接受的盐及医药载剂的医药组合物。在一个方面中,发炎性皮肤病为异位性皮炎。
化合物1还可与革兰氏阳性(gram positive)抗生素,诸如莫匹罗星(mupirocin)及夫西地酸(fusidic acid)组合使用来治疗发炎性皮肤病。因此,在一个方面中,本发明提供一种治疗哺乳动物的发炎性皮肤病的方法,所述方法包括向哺乳动物的皮肤施加化合物1及革兰氏阳性抗生素。在另一方面中,本发明提供一种包括1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮或其医药学上可接受的盐、革兰氏阳性抗生素及医药学上可接受的载剂的医药组合物。
呼吸疾病
经由JAK-STAT路径传导信号的细胞因子,尤其IL-2、IL-3、IL-4、IL-5、IL-6、IL-9、IL-11、IL-13、IL-23、IL-31、IL-27、胸腺基质淋巴生成素(TSLP)、干扰素-γ(IFNγ)及粒细胞-巨噬细胞群落刺激因子(GM-CSF)还涉及哮喘发炎及其它发炎性呼吸道疾病。如上文所描述,化合物1已展示为JAK1、JAK2、JAK3及TYK2酶的强力抑制剂且还已展现细胞检定的促炎性细胞因子的有效抑制。
JAK抑制剂的消炎剂活性已稳固地表明在哮喘的临床前模型中(Malaviya等人,Int Immunopharmacol,2010,10,829,-836;Matsunaga等人,Biochem and Biophys ResCommun,2011,404,261-267;Kudlacz等人,Eur J Pharmacol,2008,582,154-161)。因此,化合物1预期适用于治疗发炎性呼吸道病症,尤其哮喘。肺脏的发炎及纤维化为除哮喘以外的其它呼吸道疾病所特有的,诸如慢性阻塞性肺病(COPD)、囊肿性纤维化(CF)、肺炎、间质肺病(包含特发性肺纤维化)、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿及阻塞性细支气管炎。因此,化合物1还预期适用于治疗慢性阻塞性肺病、囊肿性纤维化、肺炎、间质肺病(包含特发性肺纤维化)、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿、阻塞性细支气管炎及类肉瘤病。
因此,在一个方面中,本发明提供一种治疗哺乳动物(例如人类)的呼吸道疾病的方法,所述方法包括向哺乳动物投与1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮或其医药学上可接受的盐。
在一个方面中,呼吸道疾病为哮喘、慢性阻塞性肺病、囊肿性纤维化、肺炎、慢性阻塞性肺病(COPD)、囊肿性纤维化(CF)、肺炎、间质肺病(包含特发性肺纤维化)、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿、阻塞性细支气管炎或类肉瘤病。在另一方面中,呼吸道疾病为哮喘或慢性阻塞性肺病。
在另一方面中,呼吸道疾病为肺部感染、蠕虫感染、肺部动脉高血压、类肉瘤病、肺淋巴血管平滑肌增生症、支气管扩张或浸润性肺病。在又一方面中,呼吸道疾病为药物诱发的肺炎、真菌诱发的肺炎、过敏性支气管肺曲菌病、过敏性肺炎、嗜酸性球性肉芽肿伴多血管炎、特发性急性嗜酸性球性肺炎、特发性慢性嗜酸性球性肺炎、嗜伊红白血球增多综合症、吕弗勒综合症(syndrome)、阻塞性细支气管炎伴机化性肺炎或免疫检查点抑制剂诱发的肺炎。
本发明进一步提供一种治疗哺乳动物的哮喘的方法,所述方法包括向哺乳动物投与包括1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮或其医药学上可接受的盐及医药学上可接受的载剂的医药组合物。
化合物1或其医药学上可接受的盐还可适用于治疗嗜酸性球性肺病。嗜酸性球性呼吸道炎症为统称为嗜酸性球性肺病的典型特征(Cottin等人,Clin.Chest.Med.,2016,37(3),535-56)。嗜酸性球性疾病与IL-4、IL-13及IL-5信号传导相关。嗜酸性球性肺病包含感染(尤其是蠕虫感染)、药物诱发的肺炎(例如通过诸如抗生素、苯妥英(phenytoin)或l-色氨酸的治疗药物诱发)、真菌诱发的肺炎(例如过敏性支气管肺曲菌病)、过敏性肺炎及嗜酸性球性肉芽肿伴多血管炎(先前已知为彻奇-斯全司综合症(Churg-Strauss syndrome))。未知病因的嗜酸性球性肺病包含特发性急性嗜酸性球性肺炎、特发性慢性嗜酸性球性肺炎、嗜伊红白血球增多综合症及吕弗勒综合症。
化合物1或其医药学上可接受的盐还可适用于治疗PAH。IL-6基因中的多态现象与IL-6含量升高及发生肺动脉高血压(PAH)的风险增加有关(Fang等人,J Am SocHypertens.,2017,11(3),171-177)。确证IL-6于PAH中的作用,IL-6受体链gp130的抑制改善PAH大鼠模型中的疾病(Huang等人,Can J Cardiol.,2016,32(11),1356.e1-1356.e10)。
化合物1或其医药学上可接受的盐还可适用于治疗非过敏性肺病,诸如类肉瘤病及肺淋巴血管平滑肌增生症。诸如IFNγ、IL-12及IL-6的细胞因子已涉及一定范围的非过敏性肺病,诸如类肉瘤病及肺淋巴血管平滑肌增生症(El-Hashemite等人,Am.J.Respir.Cell Mol.Biol.,2005,33,227-230,及El-Hashemite等人,Cancer Res.,2004,64,3436-3443)。
化合物1或其医药学上可接受的盐还可适用于治疗支气管扩张及浸润性肺病,其为与慢性嗜中性白血球发炎相关的疾病。某些细胞因子与嗜中性白血球发炎(例如IL-6、IFNγ)相关。
病理性T细胞活化对于多种呼吸道疾病的病因至关重要。自体反应性T细胞在阻塞性细支气管炎伴机化性肺炎(还称为COS)中起作用。类似于COS,肺移植排斥的病因与受体T细胞因为移植供体肺所致的异常T细胞活化有关。肺移植排斥可早期以原发性移植物功能障碍(PGD)、机化性肺炎(OP)、急性排斥反应(AR)或淋巴细胞性细支气管炎(LB)形式发生,或其可在肺移植后数年以慢性肺同种异体移植物功能障碍(CLAD)形式发生。CLAD先前已知为阻塞性细支气管炎(BO),但现在视为可具有不同病理学表现的综合症,包含BO、限制性CLAD(rCLAD或RAS)及嗜中性球同种异体移植物功能障碍。慢性肺同种异体移植物功能障碍(CLAD)为肺移植受体长期管理中的主要挑战,此系由于其导致移植肺逐渐失去功能(Gauthier等人,Curr Transplant Rep.,2016,3(3),185-191)。CLAD对治疗的反应不佳,且因此,仍需要能够预防或治疗此病况的有效化合物。诸如IFNγ及IL-5的若干JAK依赖性细胞因子在CLAD及肺移植排斥中上调(Berastegui等人,Clin Transplant.2017,31,e12898)。此外,在JAK依赖性IFN信号传导下游的CXCR3趋化激素(诸如CXCL9及CXCL10)的高肺含量与肺移植患者的恶化结果有关(Shino等人,PLOS One,2017,12(7),e0180281)。JAK抑制已展示为在肾脏移植排斥中有效(Vicenti等人,American Journal ofTransplantation,2012,12,2446-56)。因此,化合物1有可能有效治疗或预防肺移植排斥及CLAD。如描述为肺移植排斥的基础的类似T细胞活化事件还视为造血干细胞移植后可能发生的肺移植物抗宿主病(GVHD)的主要驱动因素。类似于CLAD,肺GVHD为一种慢性进行性病况,其结果极其不良且目前尚无经批准的治疗。对95位接受全身性JAK抑制剂卢佐替尼(ruxolitinib)作为补救治疗的患有类固醇难治性急性或慢性GVHD的患者的回溯性多中心调查研究表明,大多数患者(包含患有肺GVHD的患者)对卢佐替尼完全或部分反应(Zeiser等人,Leukemia,2015,29,10,2062-68)。近年来,免疫检查点抑制剂诱发的肺炎是随着免疫检查点抑制剂的使用增加而出现的另一种T细胞介导的肺病。在用这些T细胞刺激剂处理的癌症患者中,可能产生致死性肺炎。化合物1或其医药学上可接受的盐具有提供这些低水平严重的呼吸道疾病的新颖治疗的可能性。
胃肠道疾病
作为JAK抑制剂,化合物1或其医药学上可接受的盐还可适用于多种其它疾病。化合物1或其医药学上可接受的盐可适用于多种胃肠道发炎适应症,包含(但不限于)发炎性肠病、溃疡性结肠炎(直肠乙状结肠炎、全结肠炎、溃疡性直肠炎及左半结肠炎)、克罗恩氏病(Crohn's disease)、胶原性结肠炎、淋巴细胞性结肠炎、白塞氏病(Behcet's disease)、乳糜泻、免疫检查点抑制剂诱发的结肠炎、回肠炎、嗜酸性球性食道炎、移植物抗宿主疾病相关的结肠炎及感染性结肠炎。溃疡性结肠炎(Reimund等人,J Clin Immunology,1996,16,144-150)、克罗恩氏病(Woywodt等人,Eur J Gastroenterology Hepatology,1999,11,267-276)、胶原性结肠炎(Kumawat等人,Mol Immunology,2013,55,355-364)、淋巴细胞性结肠炎(Kumawat等人,2013)、嗜伊红血球食道炎(Weinbrand-Goichberg等人,ImmunolRes,2013,56,249-260)、移植物抗宿主疾病相关的结肠炎(Coghill等人,Blood,2001,117,3268-3276)、感染性结肠炎(Stallmach等人,Int J Colorectal Dis,2004,19,308-315)、白塞氏病(Zhou等人,Autoimmun Rev,2012,11,699-704)、乳糜泻(de Nitto等人,World JGastroenterol,2009,15,4609-4614)、免疫检查点抑制剂诱发的结肠炎(例如CTLA-4抑制剂诱发的结肠炎;(Yano等人,J Translation Med,2014,12,191)、PD-1-或PD-L1-抑制剂诱发的结肠炎)及回肠炎(Yamamoto等人,Dig Liver Dis,2008,40,253-259)的特征在于特定促炎性细胞因子含量升高。作为经由JAK活化传导信号的多种促炎性细胞因子,化合物1或其医药学上可接受的盐可能够缓解发炎且缓解症状。确切地说,化合物1或其医药学上可接受的盐可能适用于诱导及维持溃疡性结肠炎缓解,且适用于治疗克罗恩氏病、免疫检查点抑制剂诱导的结肠炎及移植物抗宿主病中的胃肠道不良作用。因此,在一个方面中,本发明提供一种治疗哺乳动物(例如人类)的胃肠道发炎疾病的方法,所述方法包括向哺乳动物投与化合物1或其医药学上可接受的盐或包括医药学上可接受的载剂及化合物1或其医药学上可接受的盐的医药组合物。
其它疾病
化合物1或其医药学上可接受的盐还可适用于治疗其它疾病,诸如其它发炎疾病、自体免疫疾病或癌症。
化合物1或其医药学上可接受的盐可适用于治疗以下中的一或多者:关节炎、类风湿性关节炎、青少年类风湿性关节炎、移植排斥、干眼症、牛皮癣性关节炎、糖尿病、胰岛素依赖性糖尿病、运动神经元疾病、骨髓发育不良综合症、疼痛、肌肉减少症、恶病质、败血性休克、全身性红斑性狼疮症、白血病、慢性淋巴细胞性白血病,慢性骨髓细胞性白血病、急性淋巴细胞性白血病、急性骨髓性白血病、僵直性脊椎炎、骨髓纤维化、B细胞淋巴瘤、肝细胞癌、霍奇金氏病、乳癌、多发性骨髓瘤、黑素瘤、非霍奇金氏淋巴瘤、非小细胞肺癌、卵巢透明细胞癌、卵巢肿瘤、胰脏肿瘤、真性红细胞增多症、休格连综合症(Sjoegrens syndrome)、软组织肉瘤、肉瘤、脾肿大、T细胞淋巴瘤及重型地中海贫血。
组合疗法
本发明化合物或其医药学上可接受的盐可与通过相同机制或不同机制作用来治疗疾病的一或多种试剂组合使用。不同试剂可在分开的组合物或同一组合物中依序或同时投与。用于组合疗法的适用的试剂类别包含(但不限于)抗血管生成、类固醇、抗炎性、血浆血管舒缓素抑制剂、胎盘生长因子配位体抑制剂、VEGF-A配位体抑制剂、血管生成素配位体-2抑制剂、蛋白质酪氨酸磷酸酶β抑制剂、Tek酪氨酸激酶受体刺激剂、钙调神经磷酸酶抑制剂、VEGF配位体抑制剂、mTOR复合物1抑制剂、mTOR抑制剂、IL-17拮抗剂、钙调蛋白调节剂、FGF受体拮抗剂、PDGF受体拮抗剂、VEGF受体拮抗剂、TNFα配位体抑制剂、TNF粘结剂、蛋白聚糖4刺激剂、VEGF-C配位体抑制剂、VEGF-D配位体抑制剂、CD126拮抗剂、补体级联抑制剂、糖皮质激素促效剂、补体C5因子抑制剂、大麻素受体拮抗剂、神经鞘胺醇-1-磷酸盐受体-1调节剂、神经鞘胺醇-1-磷酸盐受体-3调节剂、神经鞘胺醇-1-磷酸盐受体-4调节剂、神经鞘胺醇-1-磷酸盐受体-5调节剂、乙醛去氢酶抑制剂、Flt3酪氨酸激酶抑制剂、试剂盒酪氨酸激酶抑制剂、蛋白激酶C抑制剂、促肾上腺皮质激素配位体、基质细胞衍生的因子1配位体抑制剂、免疫球蛋白G1促效剂;介白素-1β配位体抑制剂、粘蛋白刺激剂;核因子κB调节剂、细胞毒性T淋巴球蛋白质-4刺激剂、T细胞表面糖蛋白CD28抑制剂、脂蛋白脂肪酶刺激剂;PPARα促效剂、腺苷A3受体促效剂、血管紧张素II受体拮抗剂、VEGF受体拮抗剂、干扰素β配位体、SMAD-2调节剂;TGFβ1配位体抑制剂、生长抑素受体促效剂、IL-2受体α子单元抑制剂、VEGF-B配位体抑制剂、胸腺素β4配位体、血管紧张素II AT-1受体拮抗剂、CCR2趋化激素拮抗剂、膜铜胺氧化酶抑制剂、CD11a拮抗剂、ICAM-1抑制剂、类胰岛素生长因子1拮抗剂、血管舒缓素抑制剂、海藻糖基转移酶6刺激剂、GDP海藻糖合成酶调节剂、GHR基因抑制剂、IGF1基因抑制剂、VEGF-1受体拮抗剂、白蛋白促效剂、IL-2拮抗剂、CSF-1拮抗剂;PDGF受体拮抗剂、VEGF-2受体拮抗剂、mTOR抑制剂、PPARα促效剂、ρGTP酶抑制剂、ρ相关蛋白激酶抑制剂、补体C3抑制剂、EGR-1转录因子抑制剂、核红细胞系2相关因子调节剂、核因子κB抑制剂、整合素α-V/β-3拮抗剂、红血球生成素受体促效剂、类升糖素肽1促效剂、TNFRSF1A基因刺激剂、血管生成素配位体-2抑制剂、α-2抗纤维蛋白溶酶抑制剂、胶原蛋白拮抗剂、纤维结合蛋白抑制剂、层粘连蛋白拮抗剂、纤维蛋白溶酶刺激剂、神经生长因子配位体、FGF1受体拮抗剂、FGF3受体拮抗剂、itk酪氨酸激酶抑制剂、Lck酪氨酸激酶抑制剂、Ltk酪氨酸激酶受体抑制剂、PDGF受体α拮抗剂、PDGF受体β拮抗剂、蛋白质酪氨酸激酶抑制剂、VEGF-3受体拮抗剂、膜铜胺氧化酶抑制剂、生长抑素2受体促效剂、生长抑素4受体促效剂、生长抑素5受体促效剂、蛋白激酶Cα抑制剂、蛋白激酶Cβ抑制剂、蛋白激酶Cδ抑制剂蛋白激酶Cε抑制剂蛋白激酶Cη抑制剂、蛋白激酶Cθ抑制剂、锚蛋白调节剂、粘蛋白刺激剂、P2Y2嘌呤受体促效剂、间隙连接α-1蛋白质抑制剂、CCR3趋化激素拮抗剂;伊红趋素配位体抑制剂、胺氯吡脒敏感性钠通道抑制剂、PDGF受体拮抗剂、蛋白质酪氨酸激酶抑制剂、视网膜色素上皮蛋白质抑制剂、基质金属蛋白酶抑制剂、PDGF受体拮抗剂、PDGF受体β拮抗剂、PDGF-B配位体抑制剂、生长激素受体拮抗剂、细胞粘附分子抑制剂、整合素调节剂、CXCR4趋化激素拮抗剂、含有卷曲-螺旋结构域的蛋白质抑制剂、Hsp 90调节剂、ρ相关蛋白激酶抑制剂、VEGF基因抑制剂、内皮因子抑制剂、CCR3趋化激素拮抗剂、maxi K钾通道调节剂、maxi K钾通道刺激剂、PGF2α促效剂、前列腺素受体促效剂、电压闸控氯化物通道2调节剂、补体C5a受体拮抗剂、肌苷单磷酸去氢酶抑制剂、介白素18配位体抑制剂、TRP阳离子通道M8刺激剂、CNTF受体促效剂、TRPV1基因抑制剂、去氧核糖核酸酶I刺激剂、IRS1基因抑制剂、ρ相关蛋白激酶抑制剂、聚ADP核糖聚合酶1抑制剂、聚ADP核糖聚合酶2抑制剂、聚ADP核糖聚合酶3抑制剂、香草精类VR1促效剂、NFAT5基因刺激剂、粘蛋白刺激剂、Syk酪氨酸激酶抑制剂、α2肾上腺素受体促效剂、环加氧酶抑制剂、淀粉状蛋白沉积抑制剂、肝糖合成酶激酶-3抑制剂、PARP刺激剂、tau沉积抑制剂、DDIT4基因抑制剂、血红蛋白合成调节剂、介白素-1β配位体抑制剂、TNF拮抗剂、KCNQ电压闸控钾通道刺激剂、NMDA受体拮抗剂、环加氧酶1抑制剂、环加氧酶抑制剂、5-HT1a受体促效剂、钙通道抑制剂、FGF-2配位体调节剂、磷酸肌醇3-激酶抑制剂、CD44拮抗剂、玻尿酸酶调节剂、玻尿酸促效剂、IL-1拮抗剂、I型IL-1受体拮抗剂、补体因子P抑制剂、微管蛋白拮抗剂、β淀粉状蛋白拮抗剂、IL2基因刺激剂、I-κB激酶β抑制剂、核因子κB调节剂、纤维蛋白溶酶原活化剂抑制剂1抑制剂、FGF-2配位体、蛋白酶调节剂及促皮质素调节剂。
可与本发明JAK抑制剂化合物组合使用的特定试剂包含(但不限于)拉路单抗(lanadelumab)、阿柏西普(aflibercept)、RG-7716、AKB-9778、环孢菌素(ciclosporin)、贝伐单抗(bevacizumab)、依维莫司(everolimus)、塞库金单抗(secukinumab)、丙酮化氟新龙(fluocinolone acetonide)、RP-101、乳酸角鲨胺(squalamine lactate)、重组人类润滑素、OPT-302、沙瑞卢单抗(sarilumab)、地塞米松(dexamethasone)、艾库组单抗(eculizumab)、芬戈莫德(fingolimod)、阿达木单抗(adalimumab)、雷莎单抗(reproxalap)、米哚妥林(midostaurin)、促皮质素(corticotropin)、聚乙二醇镜像L-寡核苷酸(olaptesed pegol)、康纳单抗(canakinumab)、核黄素(recoflavone)、阿巴西普(abatacept)、非诺贝特(fenofibrate)、皮克尼森(piclidenoson)、OpRegen、坎地沙坦(candesartan)、戈利木单抗(golimumab)、派加替尼(pegaptanib)、干扰素-β、地司特泰(disitertide)、乙酸奥曲肽(octreotide acetate)、阿奈可他(anecortave)、巴利昔单抗(basiliximab)、脉络膜上腔曲安奈德(suprachoroidal triamcinolone acetonide)、RGN-259、二氟泼尼酯(difluprednate)、HL-036、艾维科泰聚乙二醇钠(avacincaptad pegolsodium)、依贝沙坦(irbesartan)、丙帕锗(propagermanium)、曲安奈德(triamcinoloneacetonide)、阿奇霉素(azithromycin)、BI-1467335、立他司特(lifitegrast)、氯替泼诺(loteprednol etabonate)、泰普洛单抗(teprotumumab)、KVD-001、TZ-101、艾特多森(atesidorsen)、Nov-03、贝伐单抗(bevacizumab)、AVA-101、RU-101、伏环孢素(voclosporin)、伏环单抗(vorolanib)、西罗莫司(sirolimus)、胆碱非诺贝特(cholinefenofibrate)、VX-210、APL-2、CPC-551、艾拉米肽(elamipretide)、SF-0166、西滨泰德(cibinetide)、艾拉米肽、利拉鲁肽(liraglutide)、EYS-606、内斯瓦库单抗(nesvacumab)、阿柏西普(aflibercept)、奥克纤溶酶(ocriplasmin)、费戈替尼(filgotinib)、赛尼杰明(cenegermin)、阿迪坡塞(adipocell)、布罗卢西珠单抗(brolucizumab)、兰比珠单抗(ranibizumab)、阿柏西普(aflibercept)、帕利泊芬(padeliporfin)光动力疗法、帕唑帕尼(pazopanib)、ASP-8232、维多利肽(veldoreotide)、索塔妥林(sotrastaurin)、聚乙二醇阿比西巴(abicipar pegol)、四钠地夸磷索(diquafosol tetrasodium)、HCB-1019、康柏西普(conbercept)、柏替木单抗(bertilimumab)、SHP-659、THR-317、ALK-001、PAN-90806、干扰素α-2b、氟新龙(fluocinolone)、苹果酸舒尼替尼(sunitinib malate)、艾米斯塔(emixustat)、hI-con1、TB-403、二甲胺四环素(minocycline)、MA09-hRPE细胞、派勒兰尼钠(pegpleranib sodium)、派格索曼(pegvisomant)、路米内特(luminate)、布利沙福(burixafor)、H-1129、卡妥昔单抗(carotuximab)、AXP-1275、兰比珠单抗(ranibizumab)、异丙基乌诺前列酮(isopropyl unoprostone)、特斯多鲁单抗(tesidolumab)、包覆肠溶包衣霉酚酸钠(enteric-coated mycophenolate sodium)、tadekinigα、曲安奈德(triamcinolone acetonide)、环孢灵(cyclosporine)、ST-266、AVX-012、NT-501-ECT、替维西兰(tivanisiran)、维替泊芬(verteporfin)、链道酶α(dornase alfa)、艾加尼森(aganirsen)、里帕苏地(ripasudil)、磷酸如卡帕瑞(rucaparib phosphate)、珠卡赛辛(zucapsaicin)、四硫钼酸盐(tetrathiomolybdate)、双氯芬酸(diclofenac)、LHA-510、AGN-195263、他克莫司(tacrolimus)、雷巴米特(rebamipide)、R-348、酒石酸溴莫尼定(brimonidine tartrate)、维作米厅(vizomitin)、T-89、LME-636、BI-1026706、利美索龙(rimexolone)、托普霉素(tobramycin)、TOP-1630、他拉泊芬(talaporfin)、溴芬酸钠(bromfenac sodium)、曲安奈德(triamcinolone acetonide)、达尼替德(davunetide)、氯替泼诺(loteprednol etabonate)、XED-60、EG-Mirotin、APD-209、艾得诺韦(adenovir)、PF-04523655、羟基脲(hydroxycarbamide)、那瓦朋特(navamepent)、雷替那明(retinalamin)、CNTO-2476、兰比珠单抗(ranibizumab)、氟鲁匹汀(flupirtine)、B27PD、S-646240、GLY-230、肼酞嗪(hydralazine)、奈帕芬胺(nepafenac)、DexNP、海藻糖(Trehalose)、玻尿酸、地塞米松-Ca持续释放储存物(dexamethasone-Ca sustained-release depot)、那鲁佐坦(naluzotan)、玻尿酸酶(hyaluronidase)、玻尿酸钠(sodiumhyaluronate)、伊苏那金(isunakinra)、生长抑素(somatostatin)、CLG-561、OC-10X、UCA-002、重组人类表皮生长因子、哌罗来斯(pemirolast)、VM-100、MB-11316、单钠α流明诺(monosodium alpha luminol)、兰比珠单抗(ranibizumab)、IMD-1041、LMG-324、HE-10、透明质酸钠(cinhyaluronate sodium)、BDM-E、间质前驱体细胞、二硫龙(disulfiram)、CTC-96、PG-101、贝复舒(Beifushu)、胰凝乳蛋白酶。
本文中还提供一种包括化合物1或其医药学上可接受的盐及一或多种其它治疗剂的医药组合物。治疗剂可选自上文规定的试剂类别及上文所描述的特定试剂的清单。在一些实施例中,医药组合物适用于经眼递送。在一些实施例中,医药组合物为液体或悬浮液组合物。
另外,在一个方法方面中,本发明提供一种治疗哺乳动物的疾病或病症的方法,其包括向哺乳动物投与化合物1或其医药学上可接受的盐及一或多种其它治疗剂。
当用于组合疗法中时,药剂可调配成单一医药组合物,或药剂可提供于单独组合物中,其同时或在不同时间通过相同或不同投与途径投与。此类组合物可分开地封装或可作为试剂盒封装在一起。试剂盒中两种或更多种治疗剂可通过相同投与途径或通过不同投与途径投与。
实例
提供以下合成及生物学实例以说明本发明,且不以任何方式解释为限制本发明的范围。除非另外指示,否则在以下实例中,以下缩写具有以下含义。以下未定义的缩写具有其一般可接受的含义。
CAN=乙腈
DCC=二环己基碳化二亚胺
DIPEA=N,N-二异丙基乙胺
DMAc=二甲基乙酰胺
DMF=N,N-二甲基甲酰胺
DMSO=二甲亚砜
EtOAc=乙酸乙酯
HATU=六氟磷酸N,N,N',N'-四甲基-O-(7-氮杂苯并三唑-1-基)脲盐
LDA=二异丙基氨基锂
Min=分钟
MTBE=甲基叔丁基醚
NBS=N-溴丁二酰亚胺
NMP=N-甲基-2-吡咯烷酮
RT=室温
THF=四氢呋喃
双(频哪醇根基)二硼=4,4,5,5,4',4',5',5'-八甲基-[2,2']双[[1,3,2]二氧杂硼杂环戊基]
Pd(dppf)Cl2-CH2Cl2=二氯(1,1'-双(二苯基膦基)-二茂铁)-二钯(II)错合物与二氯甲烷
试剂及溶剂购自商业供应商(Aldrich、Fluka、Sigma等)且不经进一步纯化即使用。通过薄层层析(TLC)、分析型高效液相层析(anal.HPLC)及质谱分析监测反应混合物的进展。如在各反应中尤其描述来处理反应混合物;通常通过萃取及其它纯化方法(诸如温度依赖性及溶剂依赖性结晶及沈淀)来纯化反应混合物。另外,通过管柱层析或通过制备型HPLC,典型地使用C18或BDS管柱填充物及常规洗脱剂来常规纯化反应混合物。下文描述典型的制备型HPLC条件。
通过质谱及1H-NMR光谱常规地进行反应产物的表征。对于NMR分析,使样本溶解于氘化溶剂(诸如CD3OD、CDCl3或d6-DMSO)中,且在标准观测条件下用瓦里安(Varian)Gemini2000仪器(400MHz)获得1H-NMR光谱。通过电喷雾电离法(ESMS)用耦合至自动纯化系统的Applied Biosystems(Foster City,CA)型号API 150EX仪器或Waters(Milford,MA)3100仪器,来进行化合物的质谱鉴定。
制备型HPLC条件
管柱:C18,5μm.21.2×150mm或C18,5μm 21×250或C14,5μm 21×150mm
管柱温度:室温
流动速率:20.0mL/min
移动相:A=水+0.05%TFA
B=ACN+0.05%TFA,
注射体积:(100-1500μL)
检测器波长:214nm
粗化合物以约50mg/mL溶解于1:1水:乙酸中。使用2.1×50mm C18管柱进行4分钟分析规模的测试操作,继而使用100μL注射液,使用基于分析规模的测试操作的B滞留%,进行15或20分钟制备型规模操作。准确的梯度依赖于样本。用21×250mm C18管柱及/或21×150mm C14管柱检测具有紧密操作杂质的样本以进行最佳分离。通过质谱分析鉴定含有所需产物的馏分。
制剂1:2-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1-5)
(a)2-(苯甲氧基)-4-溴-1-氟苯(1-2)
同时进行两个反应且组合处理。在20℃下搅拌5-溴-2-氟苯酚(1-1)(850g,4.5mol)、溴甲苯(837g,4.9mol)及碳酸钾(923g,6.7mol)于ACN(5L)中的混合物12小时。合并反应物且浓缩,用水(8L)稀释且用EtOAc(3×3L)萃取。分离有机层,用盐水(3L)洗涤,经硫酸钠干燥,且浓缩。经由硅胶垫(用3:1石油醚:EtOAc洗脱)纯化粗产物,得到呈白色固体状的标题中间物(1.83kg,73%产率)。1H NMR(400MHz,CDCl3)δ7.38-7.46(m,5H),7.15(dd,J=7.6,2.0Hz,1H),6.98-7.15(m,1H),5.12(s,2H)。
(b)2-(苯甲氧基)-4-乙基-1-氟苯(1-3)
同时进行六个反应且组合处理。向先前步骤的产物(200g,711mmol)于THF(100mL)中的溶液中添加碳酸钾(197g,1.4mol)。反应混合物用氮气净化3次,继而添加Pd(dppf)Cl2-CH2Cl2(11.6g,14.2mmol)。使反应混合物冷却至0℃,逐滴添加二乙基锌(1M,1.07L),且在70℃下搅拌反应混合物1小时。合并反应物,冷却至20℃且缓慢倒入水(7L)中。向混合物中添加4M HCl水溶液至pH 6。分离有机层,且水相用EtOAc(3×2L)萃取。经合并的有机层用盐水(5L)洗涤,经硫酸钠干燥,浓缩,且经由硅胶垫(用50:1石油醚:EtOAc洗脱)纯化,得到呈淡黄色油状的标题中间物(900g,92%产率)。1H NMR(400MHz,CDCl3)δ7.29-7.43(m,5H),6.94-6.97(m,1H),6.82(d,J=8.0Hz,1H),6.70(m,1H),5.09(s,2H),2.52-2.58(m,2H),1.17(t,J=7.6Hz,3H)。
(c)1-(苯甲氧基)-4-溴-5-乙基-2-氟苯(1-4)
同时进行四个反应且合并。在20℃下向2-(苯甲氧基)-4-乙基-1-氟苯(1-3)(293g,1.3mol)于ACN(1L)中的溶液中逐份添加NBS(249g,1.4mol)。在20℃下搅拌反应混合物2小时。合并反应混合物且浓缩。残余物用水(5L)稀释且用EtOAc(2×5L)萃取。有机相用盐水(4L)洗涤,经无水硫酸钠干燥,过滤并在真空中浓缩。通过硅胶层析(用石油醚:EtOAc100:1-10:1洗脱)纯化粗产物,得到呈淡黄色油状的标题中间物(1.4kg,89%产率)。1H NMR(400MHz,CDCl3)δ7.29-7.38(m,5H),7.2(d,J=10.4Hz,1H),6.8(d,J=8.8Hz,1H),5.06(s,2H),2.6(q,J=7.6Hz,2H),1.1(t,J=7.6Hz,3H)。
(d)2-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1-5)
同时进行七个反应且组合处理。在氮气下在20℃下向先前步骤的产物(200g,647mmol)于二恶烷(2L)中的溶液中添加乙酸钾(190g,1.9mol)、双(频哪醇根基)二硼(181g,712mmol)及Pd(dppf)Cl2-CH2Cl2(10.6g,12.9mmol)。在120℃下搅拌混合物2小时。合并反应混合物,浓缩,用水(5L)稀释且用EtOAc(3×4L)萃取。经合并的有机相用无水硫酸钠干燥,过滤并在真空中浓缩。通过硅胶层析(用石油醚:EtOAc 1:0-5:1洗脱)纯化粗产物,得到呈白色固体状的标题化合物(1.35kg,84%产率)。1H NMR(400MHz,CDCl3)δ7.33-7.51(m,6H),6.82(d,J=7.6Hz,1H),5.17(s,2H),2.85(q,J=7.6Hz,2H),1.33(s,12H),1.15(t,J=7.6Hz,3H)。
制剂2:1-苯甲基-4-亚氨基-1,4-二氢吡啶-3-胺(2)
在0℃下向吡啶-3,4-二胺(400g,3.67mol)于ACN(3L)中的溶液中逐份添加溴甲苯(596g,3.49mol),且搅拌反应混合物30分钟,且随后在20℃下持续12小时,且过滤。滤饼用ACN(500mL)洗涤且干燥,得到呈白色粉末状的标题化合物的HBr盐(600g,2.14mol,58%产率)。1H NMR(400MHz,MeOD)δ7.83(d,J=5.6Hz,1H),7.64(s,1H),7.32-7.40(m,5H),6.76(d,J=6.8Hz,1H),5.28(s,2H)。
制剂3:6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-甲醛(3)
(a)1-(4-溴-2,6-二氟苯基)-2,2-二乙氧基乙-1-酮(3-1)
同时进行九个反应且组合处理。使1-溴-3,5-二氟苯(100g,518mmol)于THF(700mL)中的溶液脱气且用氮气净化三次。随后在-70℃下添加2M LDA(311mL)且在-70℃下在氮气下搅拌反应混合物0.5小时。在-70℃下在氮气下逐滴添加2,2-二乙氧基乙酸乙酯(96g,544mmol)于THF(200mL)中的溶液,且搅拌反应混合物1小时。合并反应物且逐份倒入冰饱和氯化铵(10L)中且用EtOAc(3×3L)萃取。分离有机层,用盐水(5L)洗涤,经硫酸钠干燥,浓缩,且通过硅胶层析(用石油醚EtOAc 1:0-100:1洗脱)来纯化,得到呈黄色油状的标题化合物(1.26kg,84%产率)。1H NMR(400MHz,CDCl3)δ7.12(d,J=7.2Hz,2H),5.15(s,1H),3.61-3.7(m,4H),1.2(t,J=7.2Hz,6H)。
(b)1-(4'-(苯甲氧基)-2'-乙基-3,5,5'-三氟-[1,1'-联苯]-4-基)-2,2-二乙氧基乙-1-酮(3-2)
同时进行五个反应且组合处理。在20℃下向1-(4-溴-2,6-二氟苯基)-2,2-二乙氧基乙-1-酮(3-1)(189g,586mmol)于乙醇(150mL)及甲苯(1.5L)中的混合物中添加水(150mL)、碳酸钠(84.8g,800mmol)及2-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1-5)(190g,533mmol)。悬浮液在真空下脱气且用氮气净化若干次。添加Pd(dppf)Cl2-CH2Cl2(13g,16mmol)且用氮气净化反应混合物若干次且在120℃下搅拌2小时。合并反应物,冷却至20℃,倒入水(5L)中且用EtOAc(3×4L)萃取。经合并的有机层用盐水(5L)洗涤,经硫酸钠干燥,过滤,浓缩,且通过硅胶层析(用石油醚:EtOAc100:1-5:1洗脱)来纯化,得到呈黄色油状的标题中间物(880g,70%产率)。1H NMR(400MHz,CDCl3)δ7.36-7.48(m,5H),6.94-6.96(m,2H),6.86-6.92(m,2H),5.29(s,1H),5.19(s,2H),3.67-3.77(m,4H),2.52(q,J=7.6Hz,2H),1.25(t,J=6.8Hz,6H),1.07(t,J=7.2Hz,3H)。
(c)6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-3-(二乙氧基甲基)-4-氟-1H-吲唑(3-3)
同时进行四个反应且组合处理。在20℃下向先前步骤的产物(220g,466mmol)于THF(2L)中的溶液中添加单水合肼(47.6g,931mmol)。在100℃下搅拌反应混合物12小时。合并四个反应物且冷却至20℃并浓缩。使残余物溶解于EtOAc(5L)中且用0.1M HCl(2×1.5L)洗涤。经合并的有机层用盐水(1.5L)洗涤,经硫酸钠干燥,过滤且浓缩,得到呈黄色胶状的标题中间物(900g,粗物质),其直接用于下一步骤中。1H NMR(400MHz,CDCl3)δ7.36-7.48(m,5H),6.94-6.96(m,2H),6.86-6.92(m,2H),5.29(s,1H),5.19(s,2H),3.67-3.77(m,4H),2.52(q,J=7.6Hz,2H),1.25(t,J=6.8Hz,6H),1.07(t,J=7.2Hz,3H)。
(d)6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-甲醛(3)
同时进行三个反应且组合处理。在20℃下向先前步骤的产物(300g,643mmol)于丙酮(1.5L)中的溶液中逐滴添加4M HCl(16mL)且在20℃下搅拌反应混合物0.17小时。合并反应物,浓缩,用MTBE(1L)稀释,且过滤。滤饼用MTBE(2×300mL)洗涤且在减压下干燥,得到呈黄色固体状的标题中间物(705g,粗物质),其直接用于下一步骤中。(m/z):[M+H]+C23H18F2N2O2的计算值:393.13;实验值:393.1。1H NMR(400MHz,DMSO-d6)δ14.51(s,1H),10.17(d,J=3.6Hz,1H),7.50(d,J=7.2Hz,2H),7.40-7.42(m,4H),7.24(d,J=8.4Hz,1H),7.15(d,J=12.4Hz,1H),7.06(d,J=8.4Hz,1H),5.25(s,2H),2.52-2.53(m,2H),1.03(t,J=7.6Hz,3H)。
制剂4:5-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-基)-5H-咪唑并[4,5-c]吡啶(4)
同时进行四个反应且组合处理。在20℃下向6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-甲醛(3)、制剂3的产物(172g,440mmol)于DMF(1.1L)中的溶液中添加亚硫酸氢钠(68.6g,659mmol)及1-苯甲基-4-亚氨基-1,4-二氢吡啶-3-胺(2)(136g,484mmol),且在150℃下搅拌反应混合物2小时。合并四种反应物且在减压下浓缩反应混合物。将残余物倒入水(10L)中且过滤。在减压下干燥滤饼,得到呈黄色固体状的标题中间物(990g,粗物质),其不经纯化即直接使用。(m/z):[M+H]+C35H27F2N5O的计算值:572.2;实验值:572.3。
制剂5:5-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶(5)
同时进行三个反应且组合处理。在20℃下向5-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-基)-5H-咪唑并[4,5-c]吡啶(4)、制剂4的产物(330g,577mmol)于甲醇(1.5L)及THF(1L)中的混合物中逐份添加硼氢化钠(267g,6.9mol),且在20℃下搅拌反应混合物24小时。合并三种反应物且将反应混合物添加至水(10L)中,搅拌10分钟,且过滤。滤液用EtOAc(2×5L)萃取且经合并的有机相用无水硫酸钠干燥,过滤且真空浓缩。粗产物用EtOAc(2L)稀释,搅拌30分钟,且过滤。滤饼用MTBE(3×200mL)洗涤,得到呈淡黄色固体状的标题中间物(275g,28%产率)。(m/z):[M+H]+C35H31F2N5O的计算值:576.25;实验值:576.3。1H NMR(400MHz,DMSO-d6)δ7.50-7.52(m,2H),7.35-7.43(m,7H),7.23-7.25(m,3H),7.15(d,J=12.0Hz,1H),6.81(d,J=12.0Hz,1H),5.25(s,2H),3.72(s,2H),3.43(br.s,2H),2.78(br.s,2H),2.66(br.s,2H),2.55(q,2H),1.04(t,J=7.6Hz,3H)。
制剂6:5-乙基-2-氟-4-(4-氟-3-(4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-2-基)-1H-吲唑-6-基)苯酚(6)
同时进行五个反应且组合处理。向5-苯甲基-2-(6-(4-(苯甲氧基)-2-乙基-5-氟苯基)-4-氟-1H-吲唑-3-基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶(5)、制剂5的产物(55g,95.5mmol)于THF(500mL)及甲醇(500mL)中的混合物中添加钯/碳(15g,9.6mmol)及12M HCl水溶液(10mL)。在真空下使悬浮液脱气,用氢净化若干次且在氢气(50psi)下在50℃下搅拌12小时。合并反应物且过滤反应混合物。在真空下浓缩滤液以提供呈灰白色固体状的标题中间物的HCl盐(150g,粗物质)。(m/z):[M+H]+C21H19F2N5O的计算值:396.16;实验值:396.2。1H NMR(400MHz,MeOD)δ7.43(s,1H),7.07(d,J=11.6Hz,1H),6.97(d,J=11.6Hz,1H),6.91(d,J=8.8Hz,1H),4.57(s,2H),3.74(s,2H),3.24(s,2H),2.55(q,J=7.6Hz,2H),1.08(t,J=7.6Hz,3H)。
制剂7:2-吗啉基乙酸2,5-二氧代吡咯烷-1-酯(7')
(a)2-吗啉基乙酸叔丁酯(7-1)
在0℃下向吗啉(160g,1.84mol)及碳酸钾(381g,2.76mol)于THF(3L)中的混合物中缓慢添加2-溴乙酸叔丁酯(341g,1.75mol)。搅拌反应混合物30分钟,且随后在20℃下持续12小时,且浓缩。添加水(1.5L)且反应混合物用EtOAc(3×1L)萃取。分离有机层,用盐水(500mL)洗涤,经硫酸钠干燥,且浓缩,得到呈黄色油状的标题中间物(300g,81%产率)。1HNMR(400MHz,CDCl3)δ3.74(t,J=4.8Hz,4H),3.10(s,2H),2.57(t,J=4.8Hz,4H),1.46(s,9H)。
(b)2-吗啉基乙酸(7")
在20℃下搅拌先前步骤的产物(7-1)(300g,1.49mol)于含3M HCl的二恶烷(2.0L)中的混合物12小时且浓缩,得到呈淡固体状的标题化合物的HCl盐(270g,99%产率),其直接用于下一步骤中1H NMR(400MHz,MeOD)δ4.13(s,2H),3.93(br.s,4H),3.64(br.s,4H)。
(c)2-吗啉基乙酸2,5-二氧代吡咯烷-1-酯(7')
在15℃下搅拌先前步骤的产物(150g,826mmol)、1-羟基吡咯烷-2,5-二酮(95g,826mmol)、DCC(256g,1.24mol)及DIPEA(160g,1.24mol)于DCM(2L)中的混合物12小时且过滤。浓缩滤液且用EtOAc(800mL)洗涤。通过过滤来收集固体且浓缩,得到呈白色固体状的标题化合物(150g,75%产率)。1H NMR(400MHz,DMSO-d6)δ3.68(s,2H),3.58(t,J=4.8Hz,4H),2.82(s,4H),2.57(t,J=5.2Hz,4H)。
实例1:1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)
在15℃下搅拌5-乙基-2-氟-4-(4-氟-3-(4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-2-基)-1H-吲唑-6-基)苯酚(6)2HCl(100g,214mmol)、2-吗啉基乙酸2,5-二氧代吡咯烷-1-酯(7')(67.2g,278mmol)及DIPEA(69g,534mmol)于DMF(600mL)中的混合物12小时且过滤。通过反相层析(Agela FLEXATM FS-1L仪器;2kg Agela C18 DAC管柱;200g样本溶解于DMF(900mL)中;流动速率300mL/min;溶剂A水,溶剂B ACN;梯度(B%,时间(分钟):0/15、0-40/45、40/50)纯化溶液,得到呈淡黄色固体状的标题化合物(50.0g,44.8%产率)。(m/z):[M+H]+C27H28F2N6O3的计算值:523.22;实验值:523.0。1H NMR(400MHz,MeOD)δ7.22(s,1H),6.80-6.96(m,3H),4.68-4.78(m,2H),3.96(s,2H),3.65-3.95(m,4H),3.35-3.38(m,2H),2.77-2.92(m,2H),2.52-2.56(m,6H),1.06(t,J=7.6Hz,3H)。
实例2:结晶1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)形式1
向250mL烧瓶中添加1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)、实例1的产物(5g)及乙醇(50mL),且在50-80℃下搅拌反应混合物10分钟,且随后在50-80℃下缓慢添加ACN(75mL),继而实例3的晶种。在20-25℃下搅拌反应混合物18小时。所得固体通过过滤来收集且在50℃下在真空下干燥18小时以提供标题化合物形式1(3.6g,72%产率)
实例3:结晶1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)形式1
将化合物1、实例1的产物(1g)添加至乙醇(10mL)中且加热至溶解。添加乙腈(10mL)且搅拌反应混合物且升温,且随后在室温下搅拌16小时,过滤,且在50℃下在真空下干燥18小时以提供标题化合物形式1(0.23g)。
实例4:1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)
将N,N-二异丙基乙胺(0.298mL,1.707mmol)添加至5-乙基-2-氟-4-(4-氟-3-(4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-2-基)-1H-吲唑-6-基)苯酚(135mg,0.341mmol)(6)、HATU(156mg,0.410mmol)及2-吗啉基乙酸(7")(54.5mg,0.376mmol)于DMF(0.5mL)中的溶液中,且在室温下搅拌反应混合物24小时。添加氢氧化锂(49.1mg,2.049mmol)且在65℃下搅拌反应混合物1小时,且在真空中浓缩以产生澄清黄色液体。经由制备型HPLC纯化粗液体以产生呈米色固体状的标题化合物的TFA盐(142mg,0.223mmol,65.3%产率)。
实例5:结晶1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)形式2
在60℃下使实例1的化合物1(2.5g)溶解于DMSO(5mL)中。在获得均质溶液后,将MeOH(2.5mL)添加至溶液中。历经30分钟,在75℃下将均匀混合物逐滴添加至MeOH(12.75mL)及H2O(11.25mL)的预混合溶液。在全部添加混合物后,在75℃下搅拌经合并的混合物1小时,同时形成结晶浆料。历经2小时,在75℃下逐滴添加H2O(36mL)。在完成H2O装入之后,在75℃下搅拌浆料1小时,随后历经6小时缓慢冷却至20℃。使浆料在20℃下保持额外10小时,之后过滤,用70%H2O/MeOH(10mL)洗涤,在50℃下在真空下干燥18小时以提供标题化合物形式2(2.13g)。
本发明的固体形式的特性
分别通过粉末X射线衍射(PXRD)、差示扫描热量测定(DSC)、热解重量分析(TGA)、动态湿气吸附(DMS)及偏光显微术图像分析实例2及5的1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)的两个无水形式(形式1及形式2)的样本。还通过单晶x射线衍射分析形式2。
实例6:粉末X射线衍射
用Bruker D8-Advance X射线衍射仪,使用Cu-Kα辐射(输出电压为45kV且电流为40mA),获得图1及6的粉末X射线衍射图案。于Bragg-Brentano几何中操作仪器,其中设定入射、发散度及散射狭缝以使样本处的强度最大化。对于测量,将少量粉末(5-25mg)轻缓地按压于样本固持器上以形成光滑表面,且经历X射线曝露。以2θ-2θ模式以2°至35°的2θ扫描样本,其中步长为0.02°且扫描速度为每步0.30°秒。通过BrukerDiffracSuite测量软件控制数据获取且通过Jade软件(7.5.1版)分析。用刚玉标准物在±0.02°2θ角内校准仪器。针对结晶形式1及结晶形式2,经观测PXRD 2θ峰位置及d-间隔分别展示于表1及2中。
表1:结晶形式1的PXRD数据
表2:结晶形式2的PXRD数据
实例7:热分析
使用具有Thermal Analyst控制器的TA Instruments型号Q-100模块进行差示扫描热量测定(DSC)。收集数据且使用TA Instruments热分析(Thermal Analysis)软件分析。将各结晶形式的样本精确称量至带盖铝盘中。在5℃下进行5分钟等温平衡阶段后,使用10℃/min的线性加热匀变从0℃加热样本至300℃。
本发明的形式1结晶自由形式的代表性DSC热分析图展示于图7中。以10℃/分钟的加热速率记录的差示扫描热量测定(DSC)迹线展现吸热热流中的峰,鉴别为约210℃至约234℃范围内或约215℃至约229℃之间的范围内或约220℃至约224℃之间的范围内的熔融转变。结晶形式的特征在于以10℃/分钟的加热速率记录的差示扫描热量测定迹线,其展示峰值在约221.7℃或221.7±3℃处的最大吸热热流。
本发明的形式2结晶自由形式的代表性DSC热分析图展示于图2中。以10℃/分钟的加热速率记录的差示扫描热量测定(DSC)迹线展现吸热热流中的峰,鉴别为约268℃至约277℃范围内或约270℃至约275℃之间的范围内或约271℃至约274℃之间的范围内的熔融转变。结晶形式的特征在于以10℃/分钟的加热速率记录的差示扫描热量测定迹线,其展示峰值在约272.6℃或272.6±2℃处的最大吸热热流。
使用具备高分辨率能力的TA Instruments型号Q-50模块进行热解重量分析(TGA)测量。使用TA Instruments热分析(Thermal Analyst)控制器收集数据且使用TAInstruments通用分析(Universal Analysis)软件分析。将称量的样本置于铂盘上且以10℃的加热速率自环境温度至300-350℃扫描。在使用期间用氮气流吹扫天平及熔炉室。
本发明的形式1结晶自由形式的代表性TGA迹线展示于图8中。图8的热解重量分析(TGA)迹线展示在低于约293℃的分解起始的温度下,无显著重量损失。
本发明的形式2结晶自由形式的代表性TGA迹线展示于图3中。图3的热解重量分析(TGA)迹线展示在低于约269℃的分解起始的温度下,无显著重量损失。
实例8:动态湿气吸附评定
使用VTI常压微量天平SGA-100系统(VTI公司(VTI Corp.),海厄利亚(Hialeah),FL33016)进行动态湿气吸附(DMS)测量。使用称取的样本且在开始分析时湿度为最低可能值(接近0%RH)。DMS分析由以下组成:进行初始干燥步骤(0%RH),持续120分钟,继而在5%RH/步骤的扫描速率下在5%RH至90%RH的湿度范围内,进行两个吸附及解吸附循环。在25℃下以等温方式进行DMS操作。
本发明的形式1结晶自由形式的代表性DMS迹线展示于图9中。
结晶形式1展现吸附及解吸附的两次循环之间的轻微滞后。形式1展现在室温下,在5%至70%相对湿度的湿度范围内约0.99%重量增加及在5%至90%相对湿度的湿度范围内约1.32%重量增加,如图9中所示。形式1视为略微吸湿的。
本发明的形式2结晶自由形式的代表性DMS迹线展示于图4中。结晶形式2展示吸附及解吸附的两次循环之间无滞后且展现极小的吸湿性倾向。形式2展现在室温下,在5%至70%相对湿度的湿度范围内约0.12%重量增加及在5%至90%相对湿度的湿度范围内约0.18%重量增加,如图4中所示。形式2视为非吸湿性的。
实例9:形式2的单晶X射线衍射
在装备有Oxford Cryosystems Cobra冷却装置的Atlas CCD衍射仪的RigakuOxford衍射Supernova双重来源(Cu在零)上收集数据。使用Cu Kα辐射收集数据。解析结构且使用Bruker AXS SHELXTL套件结晶软件优化。全部细节可见于CIF中。除非另外陈述,否则连接至碳的氢原子以几何形式且以安放各向同性置换参数优化。连接至杂原子的氢原子位于差异傅立叶图谱且用各向同性置换参数自由优化。
表3:形式2的单晶X射线衍射分析数据
实例10:形式1的固体状态稳定性评定
在内部放入含有干燥剂的HDPE瓶子的两个组态a)开口玻璃瓶及b)闭合玻璃瓶下,本发明的形式1结晶自由形式的样本储存于25℃及60%相对湿度(RH)下及40℃及75%RH下。感应密封HDPE瓶子。在特定时间间隔下,移除代表性样本的内含物且通过HPLC分析化学纯度(下文展示为HPLC纯度(a/a%))。
表4:结晶形式1稳定性研究
NT:未测试
实例11:形式1及形式2的偏光显微术(PLM)图像
形式1及形式2的样本在具有正交偏光滤波器的光学显微镜(Olympus BX51)下检验。用由PaxIt成像软件(6.4版)控制的PaxCam摄影机收集影像。于玻璃盖玻片上使用轻质矿物油作为浸渍介质制备样本。视粒子尺寸而定,将4×、10×或20×物镜用于放大。
制剂8:2-碘-1-((2-(三甲基硅烷基)乙氧基)甲基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁酯(C-5)
向化合物C-22(25g,135.86mmol)于0.01M HCl(500mL)中的溶液中添加二甲氧甲烷(21.64mL,244.54mmol)。在100℃下搅拌所得溶液18小时。在真空下移除溶剂且残余物用乙醚及乙醇湿磨两次,过滤且干燥以提供化合物C-21(25.2g,94.6%产率)。
向化合物C-21(25.0g,127.55mmol)于甲醇(250mL)中的溶液中添加DIPEA(57.23mL,318.87mmol),继而添加(Boc)2O(68.23mL,318.87mol)且在室温下搅拌反应物18小时。所得反应物用水(150mL)稀释且使用乙酸乙酯(3×200mL)萃取。经合并的有机层经无水硫酸钠干燥,倾析且在减压下浓缩以获得不经进一步纯化即向前用于下一步骤的粗产物C-20。
向此粗化合物C-20(40.0g,123.8mmol)于甲醇(500mL)中的溶液中添加1M NaOH溶液(200mL)且在室温下搅拌所得溶液18小时。在真空下蒸馏出溶剂且所得粗物质用水(200mL)稀释且使用乙酸乙酯(3×300mL)萃取。经合并的有机层经无水硫酸钠干燥且在减压下浓缩以获得经由管柱层析(100-200硅胶)纯化,用5-10%MeOH:DCM洗脱的粗产物以获得所需产物C-19(20g,72.4%产率)。
在室温下向化合物C-19(20g,89.68mmol)于THF(400mL)中的溶液中添加NIS(30.26g,134.52mmol)且在相同温度下搅拌所得溶液2小时。反应混合物用水(200mL)稀释且于乙酸乙酯(2×300mL)中萃取,有机层用10%硫代硫酸钠水溶液(3×100mL),继而盐水洗涤,经无水硫酸钠干燥且在减压下浓缩以获得不经进一步纯化即用于下一步骤中的粗产物C-18。
在0℃下向化合物C-18(15.0g,42.97mmol)于THF(150mL)中的搅拌溶液中逐份添加NaH(1.8g,45.11mmol)且在室温下搅拌反应混合物1小时。随后在0℃下逐滴添加SEM氯化物(8.18mL,45.11mmol)。在室温下搅拌反应物6小时。通过TLC监测反应进展,反应物在0℃下用冰水(200mL)淬灭且用乙酸乙酯(2×200mL)萃取。经合并的有机层用盐水洗涤且经无水硫酸钠干燥。过滤有机层且在减压下浓缩以获得粗产物,其通过管柱层析(100-200)二氧化硅(用10-15%EtOAc:己烷洗脱)纯化,得到呈粘性液体状的所需产物C-5(11g,55%)。
制剂9:2-(2-乙基-5-氟-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(C-12)
历经50分钟,向化合物C-17(347.6g,973.14mmol)于冷却至-40℃的无水THF(1000mL)中的经搅拌悬浮液中添加正丁基锂(2.5M于己烷中,362.6mL,905.02mmol),此时保持含磷偶极体特有的黄色颜色。使反应混合物升温至-10℃且搅拌1小时,随后将混合物冷却至-30℃且历经30分钟添加化合物R-1(50g,324.38mmol)于无水THF(200mL)中的溶液。使所得混合物升温至环境温度且搅拌隔夜。通过TLC监测反应进展。在完成后,通过逐渐添加水(500mL)淬灭反应物且用乙醚(3×500mL)萃取。经合并的有机层用水(2×500mL)、盐水(250mL)洗涤,经(无水Na2SO4)干燥且在减压下浓缩,得到粗化合物。所获得的粗产物C-16不经纯化即用于下一步骤中。
向粗物质C-16(110g,723.39mmol)于乙醇(1000mL)中的溶液中添加10%Pd/C(50g)。安放一气囊氢气且抽空反应物且用氢气回填三次。在氢气氛围下在室温下搅拌反应物隔夜。在室温下搅拌隔夜之后,反应完成。其经由硅藻土垫过滤且在真空中浓缩以提供粗化合物,其经由管柱层析(100-200)硅胶纯化,使用3-5%乙酸乙酯/己烷洗脱以获得呈无色液体状的所需产物C-15(24g,48%,历经2个步骤)。
向化合物C-15(24.0g,155.84mmol)于MeCN(200mL)中的溶液中添加NBS(28.0g,157.40mmol)于MeCN(100mL)中的溶液。在室温下搅拌所得溶液18小时。在真空中移除溶剂且用二乙醚(100mL)稀释残余物。观测到沈淀,其通过过滤移除且滤液用亚硫酸钠水溶液(200mL)及盐水(100mL)洗涤,经无水硫酸钠干燥且在真空中浓缩,得到呈黄色油状的所需产物C-14(35.0g,97%产率)。
向化合物C-14(20g,85.836mmol)于二恶烷(400mL)中的溶液中添加化合物R-2(32.69g,128.755mmol)及KOAc(25.27g,257.508mmol)。反应混合物用氮气脱气15分钟,随后添加钯催化剂(3.5g,4.29mmol)。搅拌反应混合物并在110℃下加热3小时。反应物经由硅藻土垫过滤且用乙酸乙酯洗涤。滤液用乙酸乙酯(200mL)稀释且用水(2×200mL)及盐水(100mL)洗涤,经硫酸钠干燥且在真空下浓缩。经由管柱层析(100-200硅胶),用3-5%EtOAc:己烷洗脱纯化所获得的粗产物,得到所需产物C-12(20g,83%产率)。
制剂10:3-(二甲基-锡烷基)-6-(2-乙基-5-氟-4-甲氧基苯基)-1-(四氢-2H-哌喃-2-基)-1H-吲唑(C-6)
使化合物C-13(25g,126.84mmol)、3,4-二氢-2H-哌喃(134.5mL,1471.5mL)及p-TSA(5.57g,29.18mmol)的混合物溶解于THF(700mL)中且在60℃下加热隔夜。将反应混合物倒入冰水中且用乙酸乙酯萃取水相。有机层经硫酸钠干燥且过滤。在减压下蒸发滤液且经由硅胶(230-400)管柱(用1至2%乙酸乙酯/己烷洗脱)纯化残余物,得到所需化合物C-11(23.5g,67%产率)。
用氮气脱气化合物C-11(13.3g,47.5mmol)、化合物C-12(15.96g,57.0mmol)及K3PO4(30.21g,142.5mmol)于DMF:H2O(396:99mL)中的溶液15分钟,随后添加钯催化剂(1.6g,2.37mmol)且用氮气净化反应混合物5分钟。在100℃下在连续搅拌下加热所得反应混合物12小时。反应混合物经由硅藻土垫过滤且用乙酸乙酯洗涤。滤液用乙酸乙酯(200mL)稀释,用EtOAc(2×100mL)萃取且用冷水(100mL)及盐水(50mL)洗涤,经硫酸钠干燥且在真空下浓缩以获得粗产物,其经由急骤层析(100-200硅胶),用10%EtOAc:己烷洗脱纯化,得到C-10(14g,91.4%)。
向化合物C-10(52g,146.89mmol)于甲醇(600mL)中的溶液中添加浓HCl(50mL)且在60℃下加热所得溶液隔夜。使反应混合物冷却至室温且在真空下浓缩。残余物用EtOAc(200mL)稀释且用NaHCO3饱和水溶液(2×150mL)洗涤。有机层经Na2SO4干燥且浓缩以获得所需产物C-9(35g,88.9%产率)。
向化合物C-9(17.5g,64.81mmol)于DMF(100mL)中的溶液中添加KOH(14.5g,259.54mmol)且搅拌混合物15分钟。在0℃下缓慢添加碘(32.7g,129.62mmol)于DMF(50mL)中的溶液且在室温下搅拌反应混合物30分钟。通过TLC反应进展,随后反应混合物用水(200mL)稀释且用乙酸乙酯(2×200mL)萃取。有机层用焦亚硫酸钠饱和水溶液(2×150mL)及水(3×100mL)洗涤,经Na2SO4干燥且在真空下浓缩以获得粗产物C-8(21g)。
向C-8(21.0g,53.02mmol)于DCM(230mL)中的溶液中添加p-TsOH(1.8g,10.60mmol)且将混合物冷却至0℃。将化合物R-3(7.04mL,79.54mmol)逐滴添加至上述溶液中且在室温下搅拌反应混合物隔夜。TLC监测展示反应完成。反应混合物用DCM(2×150mL)稀释且用NaHCO3饱和水溶液(200mL)及盐水(200mL)洗涤。有机层经无水Na2SO4干燥且在真空中浓缩,得到粗产物,其通过急骤层析纯化,得到C-7。
用氮气使C-7(10.0g,20.83mmol)于甲苯(200mL)中的溶液脱气20分钟,继而添加R-4(4.89mL,22.91mmol)及Pd(PPh3)4(1.2g,1.04mmol)。反应混合物用氮气净化额外5分钟,且随后在100℃下搅拌。在2小时之后,TLC展示反应完成。使反应混合物冷却至室温,经由硅藻土垫过滤且用乙酸乙酯洗涤残余物。经浓缩的滤液通过管柱层析(中性氧化铝),用2-5%EtOAc:己烷洗脱来纯化,得到产物C-6(6.4g,57.6%产率)。
制剂11:2-(6-(2-乙基-5-氟-4-甲氧基苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶(C-3)
向化合物C-6(6.4g,12.37mmol)于甲苯(100mL)中的溶液中添加化合物C-5(5.9g,12.37mmol)。反应混合物用氮气脱气20分钟,继而添加碘化铜(I)(470mg,2.47mmol)及Pd(PPh3)4(714mg,1.237mmol),随后在100℃下搅拌12小时。通过TLC监测反应进展。使反应物冷却至室温且经由硅藻土垫过滤,残余物用乙酸乙酯洗涤。有机层用水稀释,分离且有机部分用盐水洗涤,经Na2SO4干燥且过滤。在减压下浓缩滤液,得到粗产物,其通过管柱层析(100-200筛孔尺寸二氧化硅),用20%EtOAc:己烷洗脱纯化,得到C-4(4g,45.9%)。
向化合物C-4(4.0g,5.6mmol)于二恶烷(30mL)中的溶液中添加浓HCl(30mL)。在70℃下搅拌反应混合物16小时。通过LCMS监测反应进展。使反应物冷却至室温,在真空中浓缩,用二乙醚湿磨且经由制备型HPLC纯化,得到所需化合物C-3(0.65g,29.5%)。
实例12:1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(C-1)
在室温下向C-3(180mg,0.460mmol)于DCM(0.5ml)中的混合物中添加含1m三溴化硼的DCM(100ml)(2.299ml,2.299mmol)。搅拌所得混合物30分钟,之后将其浓缩。所得残余物与MeOH(3×3.0mL)一起共蒸发,再溶解于AcOH:H2O的1:1混合物(3.0mL)中,过滤且通过反相制备型HPLC纯化。合并所需馏分且冷冻干燥,得到呈TFA盐状的C-2((5-乙基-2-氟-4-(3-(4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-2-基)-1H-吲唑-6-基)苯酚)。
在室温下向C-2、TFA(15mg,0.031mmol)及7"(2当量,0.061mmol)于DMF(0.5ml)中的混合物中添加HATU(25.5mg,0.067mmol)及DIEA(0.043ml,0.244mmol)。所得混合物在室温下搅拌隔夜。反应物用MeOH(0.5000ml)及水(0.500ml)稀释。添加LiOH(2.193mg,0.092mmol)。在65℃下加热所得混合物1小时。随后浓缩反应物,在室温下用DCM(0.500ml)与TFA(0.500ml)的混合物处理所得残余物30分钟,浓缩,再溶解于AcOH:H2O的1:1混合物(1.5mL)中,过滤且通过反相制备型HPLC纯化,得到呈TFA盐状的化合物C-1。(m/z):[M+H]+C27H29FN6O3的计算值:504.23;实验值:505.2。
生物检定
化合物1的特征在于以下生物检定中的一或多者。
检定1:生物化学JAK激酶检定
将四种LanthaScreen JAK生物化学检定的组(JAK1、2、3及Tyk2)载于常见激酶反应缓冲液(50mM HEPES,pH 7.5,0.01%Brij-35,10mM MgCl2,及1mM EGTA)中。重组GST标记的JAK酶及GFP标记的STAT1肽受质获自Life Technologies。
在白色384槽微量培养盘(Corning)中在环境温度下,使连续稀释的化合物与四种JAK酶中的每一者及受质一起预培育1小时。随后添加总体积为10μl、具有1%DMSO的ATP以引发激酶反应。JAK1、2、3及Tyk2的最终酶浓度分别为4.2nM、0.1nM、1nM及0.25nM;所使用的相对应Km ATP浓度为25μM、3μM、1.6μM及10μM;而对于所有四种检定,受质浓度为200nM。在环境温度下使激酶反应进行1小时,之后添加于TR-FRET稀释缓冲液(Life Technologies)中的EDTA(10mM最终浓度)及Tb抗pSTAT1(pTyr701)抗体(Life Technologies,2nM最终浓度)的10μl制剂。在环境温度下将培养盘培育1小时,之后在EnVision读取器(PerkinElmer)上读取。记录且利用发射比信号(520nm/495nm),以基于DMSO及背景对照计算抑制百分比值。
对于剂量-反应分析,相较于化合物浓度绘制抑制百分比数据,且用Prism软件(GraphPad Software)从4参数稳固拟合模型测定IC50值。结果表示为pIC50(IC50的负对数),且随后使用Cheng-Prusoff等式变换为pKi(解离常数Ki的负对数)。
化合物1展现以下酶效能。
表5
检定2:细胞JAK效能检定:抑制IL-13
通过测量诱导BEAS-2B人类肺上皮细胞(ATCC)中的STAT6磷酸化的介白素-13(IL-13,R&D Systems),来进行AlphaScreen JAKI细胞效能检定。将抗STAT6抗体(CellSignaling Technologies)结合至AlphaScreen受体珠粒(Perkin Elmer),而使用EZ-LinkSulfo-NHS-生物素(Thermo Scientific)对抗pSTAT6(pTyr641)抗体(Cell SignalingTechnologies)进行生物素标记。
在5%CO2含湿气培育箱中在37℃下,在补充有10%FBS(Hyclone)、100U/mL青霉素、100μg/mL链霉素(Life Technologies)及2mM GlutaMAX(Life Technologies)的50%DMEM/50%F-12培养基(Life Technologies)中,使BEAS-2B细胞生长。在检定第1天,在具有25μL培养基的白色聚D赖氨酸涂布的384孔培养盘(Corning)中,以7,500个细胞/孔密度接种细胞,且在培育箱中使其黏附隔夜。在检定第2天,将培养基移除,且用含有测试化合物的剂量反应的12μL检定缓冲液(汉克氏(Hank's)平衡盐溶液/HBSS,25mM HEPES及1mg/mL牛血清白蛋白/BSA)替换。将化合物连续稀释于DMSO中,且随后在培养基中再稀释1000倍,以使最终DMSO浓度达到0.1%。在37℃下使细胞与测试化合物一起培育1小时,且继而添加12μl预温热的IL-13(80ng/ml于检定缓冲液中)以用于刺激。在37℃下培育30分钟后,移除检定缓冲液(含有化合物及IL-13),及10μL细胞溶解缓冲液(25mM HEPES、0.1%SDS、1%NP-40、5mM MgCl2、1.3mM EDTA、1mM EGTA,且补充有Complete Ultra mini蛋白酶抑制剂及来自Roche Diagnostics的PhosSTOP)。在环境温度下震荡培养盘30分钟,之后添加检测试剂。首先添加生物素抗pSTAT6及抗STAT6结合的受体珠粒的混合物且在环境温度下培育2小时,继而添加抗生蛋白链菌素结合的供体珠粒(Perkin Elmer)。培育最少2小时后,在EnVision盘式读取器上读取检定培养盘。记录且利用AlphaScreen发光信号,以基于DMSO及背景对照计算抑制百分比值。
对于剂量-反应分析,相较于化合物浓度绘制抑制百分比数据,且用Prism软件从4参数稳固拟合模型测定IC50值。结果还可表示为IC50值的负对数,pIC50。化合物1在此检定中展现7.9的pIC50值。
检定3:细胞JAK效能检定:抑制人类PBMC中的IL-2/抗CD3刺激IFNγ
在从人类全血分离的人类外周血液单核细胞(PBMC)(Stanford Blood Center)中测量测试化合物用于抑制介白素-2(IL-2)/抗CD3刺激的干扰素γ(IFNγ)的效能。因为IL-2经由JAK传导信号,此检定提供JAK细胞效能的测量。
(1)使用ficoll梯度从健康供体的人类全血分离人类外周血液单核细胞(PBMC)。在37℃,5%CO2含湿气培育箱中在补充有10%热不活化的胎牛血清(FBS,LifeTechnologies)、2mM Glutamax(Life Technologies)、25mM HEPES(Life Technologies)及1X Pen/Strep(Life Technologies)的RPMI(Life Technologies)中培养细胞。细胞以200,000个细胞/孔接种于培养基(50μL)中且培养1小时。将化合物连续稀释于DMSO中,且随后在培养基中再稀释500倍(达到2×最终检定浓度)。将测试化合物稀释液(100μL/孔)添加至细胞中,且在37℃、5%CO2下培育1小时,继而于预温热检定培养基(50μL)中添加IL-2(R&DSystems;最终浓度100ng/mL)及抗CD3(BD Biosciences;最终浓度1μg/mL)持续24小时。
(2)细胞因子刺激之后,细胞在500g下离心5分钟且移除上清液且在-80℃下冷冻。为了测定测试化合物回应于IL-2/抗CD3的抑制效能,经由ELISA(R&D Systems)测量上清液IFNγ浓度。通过分析IFNγ浓度与化合物浓度的抑制曲线来测定IC50值。数据表示为pIC50(负十进制对数IC50)值。化合物1在此检定中展现约6.7的pIC50值。
检定4:细胞JAK效能检定:抑制CD4+T细胞中IL-2刺激的pSTAT5
使用流式细胞测量术在自人类全血分离的人类外周血液单核细胞(PBMC)(Stanford Blood Center)中在CD4-阳性(CD4+)T细胞中测量测试化合物抑制介白素-2(IL-2)/抗CD3刺激的STAT5磷酸化的效能。因为IL-2经由JAK传导信号,此检定提供JAK细胞效能的测量。
使用藻红素(PE)结合的抗CD4抗体(Clone RPA-T4,BD Biosciences)鉴别CD4+T细胞,同时使用Alexa Fluor 647结合的抗pSTAT5抗体(pY694,Clone 47,BD Biosciences)检测STAT5磷酸化。
(1)遵循检定3段落(1)的方案,不同之处在于用IL-2/抗CD3刺激细胞因子30分钟而非24小时。
(2)细胞因子刺激之后,将细胞用预温热的固定溶液(200μL;BD Biosciences)在37℃,5%CO2下固定10分钟,用DPBS缓冲液(1mL,Life Technologies)洗涤两次,且在4℃下再悬浮于冰冷的Perm Buffer III(1000μL,BD Biosciences)中30分钟。细胞用含2%FBS的DPBS(FACS缓冲液)洗涤两次,接着在室温下在暗处再悬浮于含有抗CD4PE(1:50倍稀释)及抗CD3抗CD3Alexa Fluor 647(1:5倍稀释)的FACS缓冲液(100μL)中持续60分钟。培育之后,细胞在FACS缓冲液中洗涤两次,之后使用LSRII流式细胞仪(BD Biosciences)分析。为了测定测试化合物回应于IL-2/抗CD3的抑制效能,在CD4+T细胞中测量pSTAT5的中位荧光强度(MFI)。通过分析MFI与化合物浓度的抑制曲线测定IC50值。数据表示为pIC50(负十进制对数IC50)值。化合物1在此检定中展现约7.7的pIC50值。
检定5:细胞JAK效能检定:抑制人类PBMC中的IL-6刺激的CCL2(MCP-1)
在从人类全血分离的人类外周血液单核细胞(PBMC)(Stanford Blood Center)中测量测试化合物用于抑制介白素-6(IL-6)刺激的CCL2(MCP-1)生产的效能。因为IL-6经由JAK传导信号,此检定提供JAK细胞效能的远端测量。
(1)遵循检定3段落(1)的方案直到与测试化合物一起培育。在本发明检定中,在将测试化合物添加至孔中且培育之后,于预温热检定培养基(50μL)中添加IL-6(R&DSystems;最终浓度10ng/ml)。
(2)细胞因子刺激48小时之后,细胞在500g下离心5分钟且移除上清液且在-80℃下冷冻。为了测定测试化合物回应于IL-6的抑制效能,经由ELISA(R&D Systems)测量上清液CCL2(MCP-1)浓度。通过分析CCL2/MCP-1浓度与化合物浓度的抑制曲线来测定IC50值。数据表示为pIC50(负十进制对数IC50)值。化合物1在此检定中展现约6.4的pIC50值。
检定6:细胞JAK效能检定:抑制IFNγ诱导的pSTAT1
使用流式细胞测量术在衍生自人类全血(Stanford Blood Center)的CD14阳性(CD14+)单核球中测量测试化合物用于抑制干扰素γ(IFNγ)刺激的STAT1磷酸化的效能。因为IFNγ经由JAK传导信号,此检定提供JAK细胞效能的测量。
使用异硫氰酸荧光素(FITC)结合的抗CD14抗体(Clone RM052,Beckman Coulter)鉴别单核球,且使用Alexa Fluor 647结合的抗pSTAT1抗体(pY701,Clone 4a,BDBiosciences)检测STAT1磷酸化。
使用ficoll梯度从健康供体的人类全血分离人类外周血液单核细胞(PBMC)。在37℃,5%CO2含湿气培育箱中在补充有10%胎牛血清(FBS,Life Technologies)、2mMGlutamax(Life Technologies)、25mM HEPES(Life Technologies)及1×Pen/Strep(LifeTechnologies)的RPMI(Life Technologies)中培养细胞。将细胞以250,000个细胞/孔接种于培养基(200μL)中,培养2小时,且随后再悬浮于含有各种浓度的测试化合物的分析培养基(50μL)(补充有0.1%牛血清白蛋白(Sigma)、2mM Glutamax、25mM HEPES及1×Penstrep的RPMI)中。将化合物连续稀释于DMSO中,且随后在培养基中再稀释1000倍,以使最终DMSO浓度达到0.1%。在37℃,5%CO2下将测试化合物稀释液与细胞一起培育1小时,继而在培养基(50μL)中以0.6ng/mL的最终浓度添加预温热的IFNγ(R&D Systems)持续30分钟。细胞因子刺激之后,将细胞用预温热的固定溶液(100μL)(BD Biosciences)在37℃,5%CO2下固定10分钟,用FACS缓冲液(1mL)(含1%BSA的PBS)洗涤两次,再悬浮于1:10抗CD14 FITC:FACS缓冲液(100μL)中,且在4℃下培育15分钟。将细胞洗涤一次,且随后在4℃下再悬浮于冰冷的Perm Buffer III(BD Biosciences)(100μL)中30分钟。细胞用FACS缓冲液洗涤两次,且随后在室温下在暗处再悬浮于1:10抗pSTAT1 Alexa氟647:FACS缓冲液(100μL)中30分钟,在FACS缓冲液中洗涤两次,且使用LSRII流式细胞仪(BD Biosciences)分析。
为了测定测试化合物的抑制效能,在CD14+单核球中测量pSTAT1的中位荧光强度(MFI)。通过分析MFI与化合物浓度的抑制曲线测定IC50值。数据表示为pIC50(负十进制对数IC50)值。化合物1在此检定中展现约7.1的pIC50值。
检定7:家兔眼睛中的眼部药物动力学
此检定的目标为测定测试化合物在家兔眼部组织中的药物动力学。
溶液调配物
使实例2中制备的1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)溶解于2%2-羟丙基-β-环糊精中以获得1mg/mL的目标浓度。向纽西兰白色家兔(50μg/眼)投与测试化合物的溶液的双侧玻璃体内注射(50μL/眼)。在注射后预定时间点(30分钟、4小时、1天、3天、7天、14天)在以下眼部组织中测量测试化合物浓度:玻璃体、房水、视网膜/脉络膜及虹膜-睫状体。在各时间点给药两个家兔(四只眼睛)。在玻璃体组织中,化合物1展现浓度的二相降低,表征为半衰期为约9小时的浓度的初始降低及终半衰期为约2天的最终降低。还发现化合物快速分布于视网膜及脉络膜区域中且展示与玻璃体组织中类似的药物动力学概况。
悬浮液调配物
通过在生理盐水中将实例2的化合物1(形式1)与0.5%羟丙基甲基纤维素(HPMCE5)+0.02%Tween 80组合制备悬浮液调配物以获得5mg/mL、20mg/mL及80mg/mL的目标浓度,分别用于0.25mg/眼、1mg/眼及4mg/眼剂量。向纽西兰白色家兔投与测试化合物的悬浮液的双侧玻璃体内注射(50μL/眼)。在注射后30分钟、4小时、24小时、72小时、7天、14天、28天、56天及84天在如溶液调配物检定中的眼部组织中测量测试化合物浓度。对于4mg/眼剂量组,还在注射后168天额外时间点收集。所有剂量组在眼中均展现可测量的药物浓度直到此研究中测试的最后时间点。在12周(84天)所有剂量均观测到稳固持久曝露。对于4mg/眼组,在24周(84天)观测到持久曝露。化合物展示从30分钟到24周玻璃体组织中的药物浓度的线性降低,其中药物清除率为约5至10μg/mL/天。清除率与媒剂中的化合物1的溶解度及溶液调配物中的眼部药物动力学行为一致。所有剂量组在眼中均展现可测量的药物浓度直到此研究中测试的最后时间点。因此,药物曝露长于此研究中观测到的结果似乎合理。在所有三个浓度下,测量血浆中的药物浓度且发现比玻璃体组织中的浓度低至少3个数量级。即在非对数尺标3个数量级相当于对数尺标为1000。
通过在生理盐水中将实例5的化合物1(形式2)与0.5%羟丙基甲基纤维素(HPMCE5)+0.02%Tween 80组合制备悬浮液调配物以获得0.4mg/mL、1mg/mL、2mg/mL及20mg/mL的目标浓度,分别用于0.02mg/眼、0.05mg/眼、0.1mg/眼及1mg/眼剂量。向荷兰黑带兔投与测试化合物的悬浮液的双侧玻璃体内注射(50μL/眼)。在注射后30分钟、7天、14天、28天、42天及56天,在以下眼部组织中测量测试化合物浓度:玻璃体液、房水、虹膜-睫状体、视网膜、视网膜色素上皮/脉络膜细胞及血浆。化合物展示从30分钟到最后测试时间点(28天(对于0.02mg/眼剂量)、42天(对于0.05mg/眼及1mg/眼剂量)及56天(对于0.1mg/眼剂量))玻璃体组织中的药物浓度非常缓慢地降低。所有剂量组在眼中均展现可测量的药物浓度直到此研究中测试的最后时间点。因此,药物曝露长于此研究中观测到的结果似乎合理。在所有三个浓度下,测量血浆中的药物浓度且发现比玻璃体组织中的浓度低至少3个数量级。(3个数量级相当于对数即在非对数尺标(non-logarithmic scale)为1000)。
检定8:药效动力学检定:抑制大鼠中IL6诱导的pSTAT3
在大鼠视网膜/脉络膜匀浆中测量测试化合物的单次玻璃体内投与抑制IL-6诱导的pSTAT3的能力。
通过使实例2的化合物1与0.5%羟丙基甲基纤维素(HPMC E5 LV)、0.02%Tween80及含9mg/mL氯化钠的纯化水组合以获得10mg/mL的目标浓度来制备悬浮液调配物。
向雌性路易斯大鼠玻璃体内(IVT)给药(每眼5μL)悬浮液调配物。三天后,玻璃体内投与IL-6(Peprotech;0.1mg/mL;每眼5μL)或媒剂以诱发pSTAT3。用IL-6第二次IVT注射一小时后剥离眼部组织。使视网膜/脉络膜组织均质化且使用ELISA(Cell SignalingTechnology)来测量pSTAT3水准。相较于媒剂/媒剂组及媒剂/IL-6组计算IL-6诱导的pSTAT3的抑制百分比。大于100%的抑制反映pSTAT3水准降低至低于媒剂/媒剂组中所观测到的那些水准。
在IL-6挑战之后预处理3天的情况下,通过悬浮液调配物投与50μg剂量化合物1将视网膜/脉络膜组织中的IL-6诱导的pSTAT3抑制116%。
检定9:药效动力学检定:抑制家兔眼睛中IFNγ诱导的IP-10
在家兔玻璃体及视网膜/脉络膜组织中测量单次玻璃体内投与测试化合物抑制干扰素γ(IFNγ)诱导的IP-10蛋白质水准的能力。
通过使实例2的化合物1(形式1)与0.5%羟丙基甲基纤维素(HPMC E5)、0.02%Tween 80及含9mg/mL氯化钠的纯化水组合以获得20mg/mL的目标浓度来制备悬浮液调配物。
将雄性纽西兰白色家兔(Liveon Biolabs,印度)用于研究。在到达研究机构(Jubilant Biosys Ltd.,印度)后使动物适应环境。为每只家兔提供具有每眼50μL的总剂量体积的总共两次玻璃体内(IVT)注射。第一次IVT注射(每眼45μL)递送0.9mg测试化合物或媒剂。一周后,第二次IVT注射(每眼5μL)递送用于诱导IP-10的IFNγ(1μg/眼;储备溶液1mg/mL;Kingfisher Biotech)或媒剂。在注射当天,通过肌肉内注射氯胺酮(35mg/kg)及甲苯噻嗪(5mg/kg)麻醉家兔。一旦深入麻醉,则用无菌盐水冲洗各眼,且使用具有31号规格的针的0.5mL胰岛素注射器(50单位=0.5mL)在双眼的鼻侧上通过标记距直肌3.5mm及距角膜缘4mm的Braunstein固定卡尺(2 3/4")的位置进行IVT注射。
用IFNγ进行第二次IVT注射后24小时收集组织。收集玻璃体液(VH)及视网膜/脉络膜组织(R/C)并均质化,且使用家兔CXCL10(IP-10)ELISA试剂盒(Kingfisher Biotech)来测量IP-10蛋白质水准。相较于媒剂/媒剂组及媒剂/IFNγ组计算IFNγ诱导的IP-10的抑制百分比。
在IFNγ刺激之前进行1周预处理的情况下,化合物1的悬浮液调配物分别在玻璃体液及视网膜/脉络膜组织两者中皆将IFNγ诱导的IP-10抑制81%及80%。在IFNγ刺激之前进行1个月预处理的情况下,还观测到类似功效。
检定10:小鼠及小型猪皮肤中的经皮药物动力学
此检定的目标为在曝露于完整小鼠或小型猪皮肤之后24小时测定测试化合物的表皮、经皮及血浆药物动力学。
将1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮(1)调配为如所描述的乳膏或软膏中的0.5%(w/w),分别作为表6中的调配物A或调配物B。
在给药之前二十四小时,从25g雄性Balb/c小鼠背部刮毛,曝露至少6cm2的面积(约身体表面的10%),及单独实验中,从10kg Gottingen小型猪的背部刮毛,曝露至少450cm2的面积(约身体表面的10%)。在时间零点,在异氟醚麻醉之后,以25μL/cm2的剂量将测试化合物施加至小鼠或小型猪的背部。皮肤覆盖有接着剂覆盖层以预防化合物流失至笼子或垫褥。
在24小时曝露之后,轻轻地用肥皂及水洗涤背部以移除未吸收药物且拍干。此洗涤后紧接着,通过心脏穿刺从小鼠抽取血液且经由静脉穿刺从小型猪抽取血液。随后通过胶带汽提移除外部皮肤(角质层)。在表层曝露后,获取0.5cm穿孔活检。快速地分离表层及真皮,称重且快速冷冻。在给药后48小时于小鼠中获得类似样本且在给药后48小时、94小时及168小时(7天)于小型猪中获得类似样本。
使用Covaris超声波均质器使表层及真皮样本于1:10(w/v)水中均质化。样本于3个体积乙腈中萃取且经由LC-MS分析针对标准曲线进行定量。如通过药物动力学参数AUC0-t所证明,对于以下表7中所展示的血浆、表层及真皮,显著化合物曝露展现于表层及真皮层中,同时血浆曝露为小鼠中于调配物A中可忽略的且在调配物B中于小鼠中及两种调配物中于小型猪中低于定量限值。
表6
表7
检定11:小鼠中的肺脏及血浆药物动力学
以下文方式测定化合物1的血浆及肺脏浓度及其比率。在检定中使用来自CharlesRiver Laboratories的BALB/c小鼠。实例2的化合物1形式1以0.1mg/mL的浓度调配于含0.01%Tween 80的生理盐水(0.9%氯化钠水溶液)中作为悬浮液。通过经口抽吸将50μL悬浮液调配物引入小鼠气管中。在各个时间点(0.083、1、4、24、48、72及96小时)。给药后,经由心脏穿刺移除血液样本且从小鼠切除完整肺脏。在4℃下以约12,000rpm使血液样本离心(Eppendorf离心机,5804R)4分钟以收集血浆。肺脏经填塞干燥、称取且以1:3的稀释液于无菌水中均质化。通过LC-MS分析,对照在测试矩阵中构建成标准曲线的分析型标准品,来确定化合物1的血浆及肺脏浓度。充分曝露于肺脏中发现360μg hr/g的肺脏AUC(0-96小时)。在约40小时计算肺脏半衰期。肺脏与血浆比率测定为肺脏AUC(以μg hr/g为单位)与血浆AUC(以μg hr/mL为单位)的比率(其中AUC常规地定义为测试化合物浓度与时间的曲线下面积)。肺脏与血浆AUC比率为1780,展示血浆中的极低曝露。
检定12:药效动力学检定:抑制家兔眼睛中IFNγ诱导的pSTAT1
在家兔视网膜/脉络膜组织中测量单次玻璃体内投与测试化合物抑制干扰素γ(IFNγ)诱导的STAT1蛋白质(pSTAT1)的磷酸化的能力。
通过使实例2的化合物1(形式1)与0.5%羟丙基甲基纤维素(HPMC E5)、0.02%Tween 80及含9mg/mL氯化钠的纯化水组合以获得20mg/mL的目标浓度来制备悬浮液调配物。
将雄性纽西兰白色家兔(Liveon Biolabs,印度)用于研究。在到达研究机构(Jubilant Biosys Ltd.,印度)后使动物适应环境。为每只家兔提供具有每眼50μL的总剂量体积的总共两次玻璃体内(IVT)注射。第一次IVT注射(每眼45μL)递送0.9mg测试化合物或媒剂。一周后,第二次IVT注射(每眼5μL)递送用于诱导IP-10的IFNγ(1μg/眼;储备溶液1mg/mL;Kingfisher Biotech)或媒剂。在注射当天,通过肌肉内注射氯胺酮(35mg/kg)及甲苯噻嗪(5mg/kg)麻醉家兔。一旦深入麻醉,则用无菌盐水冲洗各眼,且使用具有31号规格的针的0.5mL胰岛素注射器(50单位=0.5mL)在双眼的鼻侧上通过标记距直肌3.5mm及距角膜缘4mm的Braunstein固定卡尺(2 3/4")的位置进行IVT注射。
用IFNγ进行第二次IVT注射后2小时收集组织。收集视网膜/脉络膜组织(R/C)并均质化,且在ProteinSimple WES仪器上通过定量蛋白质印迹法测量pSTAT1水准。相较于媒剂/媒剂组及媒剂/IFNγ组,计算IFNγ诱导的pSTAT1的抑制百分比。
在IFNγ刺激之前进行1周预处理的情况下,化合物1的悬浮液调配物将IFNγ诱导的pSTAT1抑制85%。在IFNγ刺激之前用单次给药悬浮液调配物3个月预处理之后,化合物1的悬浮液调配物将IFNγ诱导的pSTAT1抑制76%。
通过在生理盐水中使实例5的化合物1(形式2)与0.5%羟丙基甲基纤维素(HPMCE5)+0.02%Tween 80组合制备悬浮液调配物以获得11.1、3.3及1.1mg/mL的目标浓度。
将雄性纽西兰白色家兔(Liveon Biolabs,印度)用于研究。在到达研究机构(Jubilant Biosys Ltd.,印度)后使动物适应环境。为每只家兔提供具有每眼50μL的总剂量体积的总共两次玻璃体内(IVT)注射。第一次IVT注射(每眼45μL)递送500μg、150μg或50μg测试化合物或媒剂。两周后,第二次IVT注射(每眼5μL)递送用于诱导IP-10的IFNγ(1μg/眼;储备溶液1mg/mL;Kingfisher Biotech)或媒剂。在注射当天,通过肌肉内注射氯胺酮(35mg/kg)及甲苯噻嗪(5mg/kg)麻醉家兔。一旦深入麻醉,则用无菌盐水冲洗各眼,且使用具有31号规格的针的0.5mL胰岛素注射器(50单位=0.5mL)在双眼的鼻侧上通过标记距直肌3.5mm及距角膜缘4mm的Braunstein固定卡尺(2 3/4")的位置进行IVT注射。
用IFNγ进行第二次IVT注射后2小时收集组织。收集视网膜/脉络膜组织(R/C)并均质化,且在ProteinSimple WES仪器上通过定量蛋白质印迹法测量pSTAT1水准。相较于媒剂/媒剂组及媒剂/IFNγ组,计算IFNγ诱导的pSTAT1的抑制百分比。
在IFNγ刺激之前进行2周预处理的情况下,化合物1的悬浮液调配物将IFNγ诱导的pSTAT1抑制79%(对于500μg剂量)、58%(对于150μg剂量)及61%(50μg剂量)。
检定13:激酶组筛检及GINI系数
针对其它激酶筛选化合物1及C-1以评估其选择率特征。
在来源于BL21菌株的大肠杆菌(E.coli)宿主中同时于24孔方框中生长激酶标记的T7噬菌体病毒株。E.大肠杆菌生长至对数期并自冷冻储备液用T7相感染(感染倍率=0.4)并通过在32℃下振荡培育直到裂解(90至150分钟)。将裂解物离心(6,000×g)并过滤(0.2μm)以移除细胞残渣。在HEK-293细胞中产生剩余激酶且随后标记有DNA以供qPCR检测。
在室温下用生物素化小分子配位体处理经抗生蛋白链菌素涂布的磁性珠粒持续30分钟,以生成用于激酶分析的亲和树脂。用过量生物素阻断经配位的珠粒,且用阻断缓冲液(SeaBlock(Pierce),1%BSA、0.05%Tween 20、1mM DTT)洗涤以移除未结合的配位体及减少非特异性噬菌体结合。结合反应通过在1×结合缓冲剂(20%SeaBlock、0.17×PBS、0.05%Tween 20、6mM DTT)中组合激酶、经配位的亲和珠粒及测试化合物来组装。将测试化合物制备为含40×原料的100%DMSO并直接稀释至检定中。所有反应均在聚丙烯384孔培养盘中以0.04ml的最终体积进行。将分析板在室温下在震荡下培育1小时,且用洗涤缓冲液(1×PBS、0.05%Tween 20)洗涤亲和珠粒。随后将珠粒再悬浮于洗脱缓冲液(1×PBS、0.05%吐温20、0.5μM非生物素化亲和配位体)中,且在室温下在震荡下培育30分钟。洗脱液中的激酶浓度通过qPCR来测量。
在1μM下筛选化合物,且表8及9中的初始结合相互作用的结果报导为“抑制%”(=100-((测试化合物信号-阳性对照信号)/((阴性对照信号)-(阳性对照信号))×100),其中阴性对照为DMSO且阳性对照为对照化合物。
表8
化合物/激酶 | ALK | AURKA | CDK2 | CDK7 | CDK9 | CSF1R | EPHB6 | GSK3B |
1 | 75 | 11 | 6 | 74 | 9 | 98 | 88 | 31 |
C-1 | 81 | 57 | 53 | 99 | 95 | 100 | 98 | 68 |
表9
化合物/激酶 | KIT | PAK4 | PKAC-ALPHA | PLK4 | SLK | SRC | SYK | VEGFR2 |
1 | 87 | 93 | 20 | 58 | 100 | 93 | 46 | 42 |
C-1 | 99 | 99 | 70 | 68 | 100 | 100 | 78 | 63 |
发现化合物1展现与化合物C-1相比明显更低的CDK7及CDK9结合抑制。化合物1还具有较低若干其它激酶结合抑制。
针对35种不同激酶筛选化合物1及C-1两者。测定两种化合物的Gini系数。化合物1具有0.62的GINI系数且化合物C-1具有0.46的GINI系数。Gini系数用于表示针对一组激酶的化合物的选择率(Graczyk,J.Med.Chem.,2007,50,5773-5779)。较高数值对应于更高选择性化合物。
化合物1与化合物C-1之间的唯一结构差异为核心上存在氟基。此结构差异已展示对化合物的激酶组选择率具有重要作用。
检定14:细胞毒性检定
在BEAS-2B人类肺上皮细胞(ATCC)中在普通生长条件下,进行CellTiter-Glo发光细胞活力/细胞毒性分析。
在5%CO2含湿气培育箱中在37℃下,在补充有10%FBS(Hyclone)、100U/mL青霉素、100μg/mL链霉素(Life Technologies)及2mM GlutaMAX(Life Technologies)的50%DMEM/50%F-12培养基(Life Technologies)中,使细胞生长。在分析第1天,在具有25μL培养基的白色384孔组织培养培养盘(Corning)中,以500个细胞/孔密度接种细胞,且在培育箱中使其粘附隔夜。在检定第2天,添加5μL含有测试化合物的剂量反应的培养基,且在37℃下培育48小时。随后添加30μL CellTiter-Glo检测溶液(Promega),在定轨震荡器上混合5分钟,且再培育10分钟,之后在EnVision读取器上读取。记录发光信号且计算DMSO对照百分比值。
对于剂量反应分析,相较于化合物浓度绘制DMSO对照百分比数据,以通过连接各数据点的线导出剂量反应曲线。将各曲线超过15%抑制阈值的浓度定义为CC15。
预期在此检定中展现更高CC15值的测试化合物具有产生细胞毒性的更小的可能性。
化合物1展现3.16μM的CC15,而化合物C-1展现630nM的CC15。因此,与化合物C-1相比,基于此检定,化合物1明显不大可能以产生细胞毒性。
化合物1与化合物C-1之间的唯一结构差异为核心上存在氟基。此结构差异已展示对化合物的细胞毒性具有重要作用。
虽然本发明已参考其特定方面或实施例进行描述,但本领域的一般技术人员应了解,可进行各种变化或可代入等效物,而不偏离本发明的真实精神及范围。另外,在由适用的专利状况及规定允许的程度上,本文中所引用的所有公开案、专利及专利申请案以全文引用的方式并入本文中,所述引用的程度如同将各文件单独地以引用的方式并入本文中一般。
Claims (45)
1.一种下式化合物,
或其医药学上可接受的盐。
2.一种下式化合物,
3.一种下式化合物的结晶形式,
其中所述结晶形式的特征在于,粉末X射线衍射图案包括在10.61±0.20、11.84±0.20、14.94±0.20、18.26±0.20及19.06±0.20的2θ值处的衍射峰。
4.根据权利要求3所述的结晶形式,其中所述粉末X射线衍射图案的特征进一步在于在13.32±0.20、17.69±0.20及21.10±0.20的2θ值处具有额外衍射峰。
5.根据权利要求4所述的结晶形式,其中所述粉末X射线衍射图案的特征进一步在于在选自以下的2θ值处具有两个或多于两个额外衍射峰:10.85±0.20、16.14±0.20、16.35±0.20、18.43±0.20、19.20±0.20、19.49±0.20、20.72±0.20、21.94±0.20、22.64±0.20、23.64±0.20、25.19±0.20及28.08±0.20。
6.根据权利要求3所述的结晶形式,其中所述结晶形式的特征在于,粉末X射线衍射图案的峰位置基本上与图1中所展示的图案的峰位置一致。
7.根据权利要求3所述的结晶形式,其中所述结晶形式的特征在于在10℃/分钟的加热速率下记录的差示扫描热量测定迹线,所述迹线展示在268℃与277℃之间的温度下具有吸热热流的最大值。
8.根据权利要求3所述的结晶形式,其中所述结晶形式的特征在于在10℃/分钟的加热速率下记录的差示扫描热量测定迹线,所述迹线展示在272.6±2℃处具有峰的吸热热流的最大值。
9.根据权利要求3所述的结晶形式,其中所述结晶形式的特征在于基本上与图2中所展示者一致的差示扫描热量测定迹线。
10.一种下式化合物的结晶形式,
其中所述结晶形式的特征在于,粉末X射线衍射图案包括在8.16±0.20、8.97±0.20、15.29±0.20、16.70±0.20、18.00±0.20及20.18±0.20的2θ值处的衍射峰。
11.根据权利要求10所述的结晶形式,其中所述粉末X射线衍射图案的特征进一步在于在选自以下的2θ值处具有两个或多于两个额外衍射峰:7.69±0.20、10.66±0.20、11.46±0.20、11.91±0.20、15.80±0.20、17.02±0.20、18.83±0.20、22.39±0.20、22.98±0.20、24.89±0.20及26.54±0.20。
12.根据权利要求10所述的结晶形式,其中所述结晶形式的特征在于,粉末X射线衍射图案的峰位置基本上与图6中所展示的图案的峰位置一致。
13.根据权利要求10所述的结晶形式,其中所述结晶形式的特征在于在10℃/分钟的加热速率下记录的差示扫描热量测定迹线,所述迹线展示在215℃与229℃之间的温度下具有吸热热流的最大值。
14.根据权利要求10所述的结晶形式,其中所述结晶形式的特征在于在10℃/分钟的加热速率下记录的差示扫描热量测定迹线,所述迹线展示在221.7±3℃处具有峰的吸热热流的最大值。
15.根据权利要求10所述的结晶形式,其中所述结晶形式的特征在于基本上与图7中所展示者一致的差示扫描热量测定迹线。
16.一种医药组合物,其包括根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式及医药学上可接受的载剂。
17.根据权利要求16所述的医药组合物,其中所述组合物适用于施加至眼部。
18.根据权利要求17所述的医药组合物,其中所述组合物适用于玻璃体内注射。
19.根据权利要求18所述的医药组合物,其中所述组合物为悬浮液。
20.一种用于制备式1化合物或其医药学上可接受的盐的方法,
所述方法包括:
(a)使式6化合物:
与式7化合物反应:
其中RA为氢或2,5-二氧代吡咯烷基,及
(b)任选地制备医药学上可接受的盐
以提供式1化合物或其医药学上可接受的盐。
21.一种式6化合物,
或其盐。
22.一种制备根据权利要求3所述的结晶形式的方法,其包括:
(a)在极性非质子性溶剂中或在极性水混溶性溶剂中或在极性非质子性溶剂与极性水混溶性溶剂的混合物中,在45与75℃之间的温度下形成1-(2-(6-(2-乙基-5-氟-4-羟基苯基)-4-氟-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-基)-2-吗啉基乙-1-酮的均匀混合物;
(b)在60与90℃之间的温度下将所述均匀混合物添加至水混溶性溶剂与水的混合物中,得到第二混合物;
(c)在60与90℃之间的温度下将水缓慢添加至所述第二混合物中以形成浆料;及
(d)从所述浆料分离所述结晶形式。
23.根据权利要求22所述的方法,其中步骤(a)的所述极性非质子性溶剂选自由以下组成的群组:DMSO、DMF、NMP、DMAc及硝基甲烷,步骤(a)的所述极性水混溶性溶剂选自由以下组成的群组:乙腈、丙酮、甲醇、乙醇及THF,且步骤(b)的所述水混溶性溶剂选自由以下组成的群组:乙腈、丙酮、甲醇、乙醇、正丙醇、异丙醇、正丁醇、THF、DMSO、DMF、NMP、DMAc及硝基甲烷。
24.根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式,其用于治疗哺乳动物的眼部疾病。
25.根据权利要求24所述的化合物或结晶形式,其中所述眼部疾病为眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞或异位性角膜结膜炎。
26.根据权利要求25所述的化合物或结晶形式,其中所述眼部疾病为糖尿病性黄斑水肿或眼色素层炎。
27.一种根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式的用途,其用于制造供治疗哺乳动物的眼部疾病用的药物。
28.根据权利要求27所述的用途,其中所述眼部疾病为眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞或异位性角膜结膜炎。
29.一种治疗哺乳动物的眼部疾病的方法,所述方法包括向所述哺乳动物的眼睛投与包括根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式及医药学上可接受的载剂的医药组合物。
30.根据权利要求29所述的方法,其中所述眼部疾病为眼色素层炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、干眼病、年龄相关的黄斑部变性、视网膜静脉栓塞或异位性角膜结膜炎。
31.根据权利要求30所述的方法,其中所述眼部疾病为眼色素层炎或糖尿病性黄斑水肿。
32.根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式,其用于治疗哺乳动物的皮肤的发炎疾病。
33.根据权利要求32所述的化合物或结晶形式,其中所述皮肤的发炎疾病为异位性皮炎。
34.一种根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式的用途,其用于制造供治疗哺乳动物的皮肤的发炎疾病用的药物。
35.根据权利要求34所述的用途,其中所述皮肤的发炎疾病为异位性皮炎。
36.一种治疗哺乳动物的皮肤的发炎疾病的方法,所述方法包括向所述哺乳动物的所述皮肤施加包括根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式及医药学上可接受的载剂的医药组合物。
37.根据权利要求36所述的方法,其中所述皮肤的发炎疾病为异位性皮炎。
38.根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式,其用于治疗哺乳动物的呼吸道疾病。
39.根据权利要求38所述的化合物或结晶形式,其中所述呼吸道疾病为哮喘、慢性阻塞性肺病、囊肿性纤维化、肺炎、特发性肺纤维化、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿、肺脏移植排斥、原发性移植功能障碍、机化性肺炎、急性肺脏移植排斥、淋巴细胞细支气管炎、慢性肺脏同种异体移植功能障碍、限制性慢性肺脏同种异体移植功能障碍、嗜中性白血球同种异体移植功能障碍或阻塞性细支气管炎。
40.根据权利要求39所述的化合物或结晶形式,其中所述呼吸道疾病为哮喘、慢性肺脏同种异体移植功能障碍或慢性阻塞性肺病。
41.一种根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式的用途,其用于制造供治疗哺乳动物的呼吸道疾病用的药物。
42.根据权利要求41所述的用途,其中所述呼吸道疾病为哮喘、慢性阻塞性肺病、囊肿性纤维化、肺炎、特发性肺纤维化、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿、肺脏移植排斥、原发性移植功能障碍、机化性肺炎、急性肺脏移植排斥、淋巴细胞细支气管炎、慢性肺脏同种异体移植功能障碍、限制性慢性肺脏同种异体移植功能障碍、嗜中性白血球同种异体移植功能障碍或阻塞性细支气管炎。
43.一种治疗哺乳动物的呼吸道疾病的方法,所述方法包括向所述哺乳动物投与包括根据权利要求1或2所述的化合物或根据权利要求3至15中任一权利要求所述的结晶形式及医药学上可接受的载剂的医药组合物。
44.根据权利要求43所述的方法,其中所述呼吸道疾病为哮喘、慢性阻塞性肺病、囊肿性纤维化、肺炎、特发性肺纤维化、急性肺损伤、急性呼吸窘迫综合症、支气管炎、气肿、肺脏移植排斥、原发性移植功能障碍、机化性肺炎、急性肺脏移植排斥、淋巴细胞细支气管炎、慢性肺脏同种异体移植功能障碍、限制性慢性肺脏同种异体移植功能障碍、嗜中性白血球同种异体移植功能障碍或阻塞性细支气管炎。
45.根据权利要求44所述的方法,其中所述呼吸道疾病为哮喘、慢性肺脏同种异体移植功能障碍或慢性阻塞性肺病。
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