CN113302190A - Fxr(nr1h4)调节化合物 - Google Patents
Fxr(nr1h4)调节化合物 Download PDFInfo
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- CN113302190A CN113302190A CN202080009189.4A CN202080009189A CN113302190A CN 113302190 A CN113302190 A CN 113302190A CN 202080009189 A CN202080009189 A CN 202080009189A CN 113302190 A CN113302190 A CN 113302190A
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- fxr
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Abstract
本公开一般涉及结合FXR并充当FXR激动剂的式(I)化合物。本公开还涉及该化合物用于制备通过所述化合物与所述核受体的结合来治疗疾病和/或病症的药物的用途,并且涉及用于合成所述化合物的方法。
Description
相关申请的交叉引用
本专利申请要求于2019年1月15日提交的标题为“FXR(NR1H4)MODULATINGCOMPOUNDS(FXR(NR1H4)调节化合物)”的美国临时专利申请No.62/792,714的优先权的权益,其内容全文并入本文中。
序列表
与本申请相关的序列表以文本格式提供而代替纸质副本,并且据此以引用方式并入本说明书。包含序列表的文本文件的名称为“1274_SequenceListing”。2018年12月17日创建的文本文件为约1千字节,并经由EFS-Web以电子方式提交。
技术领域
本公开涉及结合法尼醇X受体(FXR,Farnesoid X Receptor)并充当该法尼醇X受体的激动剂或调节剂,以及充当FXR的激动剂或调节剂的化合物。本公开还涉及该化合物用于通过所述化合物治疗和/或预防疾病和/或病症的用途。
背景技术
法尼醇X受体(FXR)是一种核激素受体,当涉及人受体时通常也被称为NR1H4(核受体亚家族1,组H,成员4)。FXR与多种生物功能相关联。FXR主要在肝脏和整个胃肠道中表达,但也存在于肾脏、肾上腺和卵巢中。FXR与控制细胞内基因表达相关联,并且可参与旁分泌和内分泌信号转导。在肠和肝脏中,FXR起到胆汁酸体内平衡和肝脏脂肪生成的调节剂的作用。FXR也与肝脏的库普弗细胞(Kupffer cell)和肝窦内皮细胞相关联,其中据信其具有与炎症、纤维化和门静脉高压相关的功能。
许多FXR激动剂是已知的,并且与许多生理状况(包括肝脏疾病)的关系正处于研究中。FXR激动剂可在脂肪变性、小叶发炎、肝细胞气球样变性和纤维化中具有有益效果。
FXR激动作用可在体内不同区域中导致不同的效应。在远端小肠和影响全身的器官诸如肝脏中,FXR的活化直接导致激素FGF19的表达和分泌。FGF19通过下调胆汁酸合成来调节胆汁酸,这例如在诸如肝脏疾病的病症中可为有益的。FXR激动剂也与有害效应诸如瘙痒相关联。此类有害效应和它们所经历的程度可能取决于FXR激动作用的部位。例如,已经提出瘙痒与非肠FXR激动作用相关联。
仍然需要具有期望的效力、选择性和降低的有害效应的FXR激动剂。
发明内容
本公开提供了结合NR1H4受体(FXR)并充当FXR的激动剂或调节剂的化合物。本公开还涉及该化合物用于通过所述化合物与所述核受体的结合来治疗和/或预防疾病和/或病症的用途。
本公开提供了一种式(I)的化合物:
或其药学上可接受的盐。
一些实施方案提供了包含式(I)的化合物和药学上可接受的赋形剂的药物组合物。
一些实施方案提供了式(I)的化合物或其药学上可接受的盐的固体形式。
本文还提供了治疗患有FXR介导的病症的患者的方法,该方法包括向有此需要的患者给药式(I)的化合物。
附图说明
图1示出了在给予实施例1的化合物之后,食蟹猴中的FGF19血浆浓度随时间推移的图表。
图2示出了在给予比较例1的化合物之后,食蟹猴中的FGF19血浆浓度随时间推移的图表。
图3示出了在给予比较例2的化合物之后,食蟹猴中的FGF19血浆浓度随时间推移的图表。
图4是式(I)甲磺酸盐形式I的X-射线粉末衍射图。
图5是式(I)甲磺酸盐形式I的DSC曲线。
图6是式(I)甲磺酸盐形式I的TGA曲线。
具体实施方式
本公开涉及FXR激动剂。本公开还涉及与FXR激动剂相关的组合物和方法,以及此类化合物用于通过所述化合物与FXR的结合来治疗和/或预防疾病和病症的用途。本公开还涉及治疗和/或预防肝脏疾病的组合物和方法,包括将FXR激动剂与一种或多种额外治疗剂组合。
FXR激动剂在肝脏和整个胃肠道中表达,其中它们的活化或失活可在肝脏的一种或多种疾病,诸如NASH、PSC和/或肝纤维化中起作用。然而,FXR激动剂也在身体的其他区域中被鉴别出,在该情况下它们的功能可能有所不同。FGF19是回肠上皮细胞中FXR的主要靶基因。胆汁酸对回肠FXR的生理活化导致了FGF19的分泌。在肝脏中,FXR激动作用和FGF19信号传导具有重叠和不同的功能。例如,这两种途径均抑制胆汁酸合成。肝细胞中的FXR激动作用间接下调了许多同样由FGF19减少的酶。
FXR激动剂可用于治疗和预防多种病症,包括肝脏疾病。肝脏疾病可包括肝脏的急性或慢性损伤,例如由感染、损伤、血液中正常物质的异常积聚或其他原因所致。虽然许多FXR激动剂和相关类似物是已知的,但是此类FXR激动剂可能存在一些缺点,包括较差功效、代谢问题和/或不良事件。
本文公开了FXR激动剂以及相关的组合物和方法。本文所公开的FXR激动剂可令人惊奇地维持良好的治疗效果,同时使副作用和不良代谢问题最小化。
在一些实施方案中,本文所述的FXR激动剂可具有期望的细胞效力。例如,在一些实施方案中,相对于具有较低细胞效力的化合物,高细胞效力能够在较低剂量的给药药物下提供较高的FXR激动作用。
在一些实施方案中,本公开提供了可在胃肠道中展示出高水平的FXR激动作用且展示出降低的全身FXR激动作用的FXR激动剂。本文所公开的FXR激动剂可在口服给药时导致FGF19分泌增加,而在静脉内给药时导致最小限度的FGF19增加。降低的全身FXR激动作用可为有利的,例如通过降低和/或限制某些不良反应(诸如瘙痒)的可能性,或者通过降低与全身药物的潜在药物-药物相互作用的风险。
在一些实施方案中,本文所述的FXR激动剂具有良好的靶标选择性。例如,本文所述的FXR激动剂激动FXR,并且不显著改变TGR5和/或与FXR相关的其他核激素受体的活性。在一些实施方案中,本文所述的FXR激动剂相对于肝FXR而言优先地激动肠FXR。
有利地,本文所公开的口服给药的FXR激动剂可以产生血浆FGF19水平的剂量依赖性增加和血清C4水平的减小,这指示胆汁酸合成减少。
定义和一般参数
如在本说明书中所用,以下术语和短语通常旨在具有如下阐述的含义,除非使用它们的上下文中另外指明。
本文中提及的“约”一个值或者参数包括(并描述)涉及该值或者参数本身的实施方案。在一些实施方案中,所述术语“约”包括指出的量±10%。在其它实施方案中,所述术语“约”包括指出的量±5%。在一些其它实施方案中,所述术语“约”包括指出的量±1%。此外,所述术语“约X”包括“X”的描述。此外,单数形式"一"和"所述"包括复数指代,除非上下文另有明确规定。因此,例如,提及的“该化合物”包括多个这种化合物,以及提及的“该测定”包括对本领域技术人员已知的一种或多种测定及其等价物的指代。
本文中示例性描述的公开内容可以在不存在本文未具体公开的任何一个或多个要素、一个或多个限制的情况下适当地实践。因此,例如,术语“包含”、“包括”、“含有”等应当被广泛地而非限制性地理解。另外,本文中所用的术语和表达被作为描述而非限制性的术语使用,并且使用的此类术语和表达并非旨在排除所示出和描述的特征的任何等同物或其部分,但是应当认识到,在所要求保护的公开内容的范围之内,各种修改均是可能的。
在一些实施方案中,本公开的化合物可为“前药”的形式。术语“前药”在药学领域中定义为药物的生物无活性衍生物,其在给药于人体时根据一些化学或酶促途径转化为生物活性母体药物。前药的实例包括酯化羧酸。
在人类肝脏中,UDP-葡萄糖苷酸基转移酶作用于具有氨基、氨基甲酰基、硫基(巯基)或羟基的某些化合物,以通过糖苷键将尿苷二磷酸-α-D-葡萄糖醛酸缀合,或者在二期代谢过程中酯化具有羧基或羟基的化合物。本发明的化合物可以是葡糖苷酸化的,也就是说,与葡糖醛酸结合,以形成葡糖苷酸,特别是(β-D)葡糖苷酸。
形成胆汁的一个步骤是单个胆汁酸与氨基酸(特别是甘氨酸或牛磺酸)的缀合。本发明的化合物可以在可取代的位置与甘氨酸或牛磺酸缀合。
本公开的化合物可为药学上可接受的盐的形式。术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸(包括无机碱或酸以及有机碱或酸)制备的盐。本公开的化合物可为药学上可接受的盐的形式。术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸(包括无机碱或酸以及有机碱或酸)制备的盐。在本公开的化合物含有一个或多个酸性或碱性基团的情况下,本公开还包括它们相应的药学上或毒理学上可接受的盐,特别是它们药学上可利用的盐。因此,含有酸性基团的本公开的化合物可以存在这些基团,并且可以根据本公开例如作为碱金属盐、碱土金属盐或铵盐使用。这些盐的更精确的实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺(如乙胺、乙醇胺、三乙醇胺或氨基酸)的盐或本领域的技术人员已知的其他碱所成的盐。含有一个或多个碱性基团(即可被质子化的基团)的本发明化合物可以存在并可根据本发明以其与无机酸或有机酸的加成盐的形式使用。合适的酸的实例包括氯化氢、溴化氢、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡萄糖酸、抗坏血酸、吡啶-4-甲酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。
如果本发明化合物在分子中同时含有酸性基团和碱性基团,那么除了所提及的盐形式外,本发明还包括内盐或内铵盐(betaine)(两性离子)。相应的盐可以通过本领域技术人员已知的常规方法获得,例如通过使其与有机或无机酸或碱在溶剂或分散剂中接触,或通过与其它盐进行阴离子交换或阳离子交换。
在一些实施方案中,式(I)的化合物的药学上可接受的盐包括两性离子。例如,式(I)的化合物可如下形成两性离子:
本公开还包括本公开的化合物的所有这样的盐,其由于低生理相容性而不直接适用于药物,但其可例如用作化学反应或制备药学上可接受的盐的中间体。可用于与基础化合物反应形成药学上可接受的盐(分别为酸加成或碱加成盐)的酸和碱是本领域的技术人员已知的。类似地,由基础化合物(根据本公开)制备药学上可接受的盐的方法是本领域的技术人员已知的,并且公开于例如Berge等人,Journal of Pharmaceutical Science,1977年1月,第66卷,第1期,以及其他来源。
此外,本文所公开的化合物可经受互变异构。在化合物或它们的前药的互变异构(例如酮-烯醇互变异构)可能发生的情况下,单独的形式(例如酮和烯醇形式)以及它们任何比率的混合物各自在本公开的范围之内。这同样适用于立体异构体,例如对映体、顺式/反式异构体、非对映体、构象异构体等。
术语“保护基”是指掩蔽或改变官能团的特性或化合物作为整体的特性的化合物的部分。化学保护基团和用于保护/脱保护的策略是本领域公知的。参见例如ProtectiveGroups in Organic Chemistry,Theodora W.Greene,John Wiley&Sons,Inc.,New York,1991。保护基通常用于掩蔽某些官能团的反应性,以助于期望的化学反应的效率,例如以有序和有计划的方式形成和断裂化学键。术语“脱保护”是指移除保护基。
“离去基团”包括可在化学反应期间带着反应性碳原子的共价键的一对电子离开的分子片段。
本领域的技术人员应理解,当可选取代基的列表包括由于其化合价要求或其他原因而不能用于取代特定基团的成员时,该列表旨在技术人员的知识下理解为仅包括列表中适于取代特定基团的那些成员。
此外,本公开的化合物能够以溶剂化物的形式存在,诸如包括作为水溶剂化物,或药学上可接受的溶剂化物,诸如醇,特别是乙醇的那些。“溶剂化物”通过溶剂和化合物的相互作用形成。
在某些实施方案中,提供了本文所述的化合物的光学异构体、外消旋体或它们的其他混合物或其药学上可接受的盐或其混合物。如果需要,异构体可以通过本领域公知的方法,例如通过液相色谱法进行分离。在那些情况下,可以通过不对称合成或通过拆分来获得单一对映体或非对映体,即光学活性形式。拆分可以例如通过常规方法实现,诸如在拆分剂存在下结晶,或使用例如手性高压液相色谱(HPLC)柱的色谱法。
“立体异构体”是指由相同键所键合的相同原子构成,但具有不可互换的不同三维结构的化合物。本公开设想了各种立体异构体及其混合物,并且包括“对映体”,其是指分子为彼此不可重叠的镜像的两个立体异构体。“非对映体”是具有至少两个不对称原子但彼此不是镜像的立体异构体。
在一些实施方案中,本文所公开的化合物以及它们药学上可接受的盐可以包括不对称中心,并因此可以产生对映体、非对映体和其他立体异构形式,其可以根据绝对立体化学定义为(R)-或(S)-,或对于氨基酸定义为(D)-或(L)-。一些实施方案包括所有此类可能的异构体,以及它们的外消旋和光学纯形式。光学活性的(+)和(-)、(R)-和(S)-,或(D)-和(L)-异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术例如色谱法和分级结晶来拆分。用于制备/分离单个对映体的常规技术包括从合适的光学纯前体进行手性合成,或使用例如手性高压液相色谱法(HPLC)来拆分外消旋体(或盐或衍生物的外消旋体)。当本文所述的化合物含有烯属双键或其他几何不对称中心时,除非另外指明,否则意图化合物包括E和Z几何异构体两者。
包括本文所述的化合物或其药学上可接受的盐、异构体或混合物的本文所提供的组合物可包括外消旋混合物、或含有对映体过量的一种对映体的混合物,或单一非对映体或非对映体混合物。这些化合物的所有此类异构形式均明确地包括在本文中,如同具体和单独地列出了每种和每个异构形式。
本申请中所给出的任何通式或结构也意欲代表为化合物的非标记的形式以及同位素标记的形式。同位素标记的化合物具有由本申请中给出的通式所描述的结构,除了一个或多个原子被具有选择的原子质量或质量数的原子所置换。可以掺入本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如,但不限于2H(氘、D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。本发明包括多种同位素标记的本发明化合物,例如那些放射性同位素如3H、13C和14C掺入其中的化合物。此类同位素标记的化合物可用于代谢研究、反应动力学研究、检测或成像技术,例如正电子发射断层扫描术(PET)或单光子发射计算机断层成像术(SPECT),包括药物或底物组织分布测定或用于患者的放射性治疗。同位素标记的本发明化合物及其前药通常可通过利用下文中描述的合成路线或实施例和制备中描述的步骤来制备,其中将非同位素标记的试剂替换为便利可得的同位素标记的试剂。
本公开还包括其中1至n个(其中n为分子中的氢的数目)连接至碳原子的氢被氘置换的本文公开的化合物的“氘代类似物”。此类化合物可显示出对代谢的抗性增强,因此可用于增加式I任何化合物的半衰期(当给药至哺乳动物,例如人时)。参见例如Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”,TrendsPharmacol.Sci.5(12):524-527(1984)。此类化合物通过本领域中已知的方法合成,例如,通过使用其中一个或多个氢原子已经被氘置换的起始材料。
氘标记的或取代的本发明的治疗性化合物可以具有有益的DMPK(药物代谢和药代动力学)性质,其涉及分布、代谢和排泄(ADME)。使用较重同位素(例如氘)的取代可以基于较大的代谢稳定性提供一些治疗优势,例如体内半衰期增加、降低的剂量需求和/或治疗指数改善。18F标记的化合物可以用于PET或SPECT研究。
此类较重同位素(具体的为氘)的浓度可以由同位素富集因子来定义。在本发明化合物中,任何没有具体指定为特定同位素的原子意味着其代表该原子的任何稳定的同位素。除非另有说明,当某一位置具体指定为"H"或"氢"时,应当理解,该位置为具有其天然丰度同位素组成的氢。相应地,在本发明的化合物中,任何被具体指定为氘(D)的原子意味着代表氘。
此外,本公开提供了药物组合物,该药物组合物包含作为活性成分的本公开的化合物、或其前药化合物、或其药学上可接受的盐或溶剂化物,以及药学上可接受的载体。
“药物组合物”意指一种或多种活性成分和一种或多种构成载体的惰性成分,以及直接或间接地由任何两种或更多种成分的组合、复合或聚集,或由一种或多种成分的解离,或由一种或多种成分的其他类型的反应或相互作用而产生的任何产物。因此,本公开的药物组合物可涵盖通过混合至少一种本公开的化合物和药学上可接受的载体制备的任何组合物。
如本文所用,“药学上可接受的载体”包括对所公开的化合物或其用途无害的赋形剂或试剂,诸如溶剂、稀释剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。使用此类载体和试剂来制备药物活性物质的组合物是本领域公知的(参见例如Remington’s Pharmaceutical Sciences,Mace Publishing Co.,Philadelphia,PA,第17版,(1985);和ModernPharmaceutics,Marcel Dekker,Inc.第3版(G.S.Banker&C.T.Rhodes编辑))。
术语“治疗有效量”和“有效量”互换使用,并且是指当以一个或多个剂量给药于有此类治疗需要的患者(例如人)时足以实现如下所定义的治疗的化合物的量。治疗有效量将根据患者、所治疗的疾病、患者的体重和/或年龄、疾病的严重程度,或由有资格的处方者或护理者确定的给药方式而变化。
术语“治疗”或“处理”意指给药式(I)的化合物或药学上可接受的盐以用于如下目的:(i)延缓疾病发作,即使得疾病的临床症状不发展或延缓其发展;(ii)抑制疾病,即阻止临床症状发展;和/或(iii)减轻疾病,即使得临床症状或其严重程度的消退。
缩写和首字母缩略词的列表
缩写 含义
(±)-BINAP (±)-2,2′-双(二苯基膦基)-1,1′-联萘
2-MeTHF 2-甲基四氢呋喃
ACN或MeCN 乙腈
aq. 水性
Bn 苄基
BOC或Boc 叔丁氧羰基
BSA 牛血清白蛋白
BSS 平衡盐溶液
calcd 计算的
DAST (二乙氨基)三氟化硫
DCM 二氯甲烷
DIBAL-H 二异丁基氢化铝
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EA 乙酸乙酯
EDTA 乙二胺四乙酸
ESI 电喷雾离子化
Et 乙基
Et2O 二乙醚
EtOAc 乙酸乙酯
FBS 胎牛血清
h或hr 小时
HATU 1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
HPLC 高效液相色谱法
IPA 异丙醇
IPTG 异丙基β-D-1-硫代半乳吡喃糖苷
LCMS或LC/MS 液相色谱-质谱
Me 甲基
MEM 最低基础培养基
MeOH 甲醇
MSA 甲磺酸
min 分钟
MS 质谱
m/z 质荷比
NADPH 二氢烟酰胺-腺嘌呤二核苷酸磷酸
NMP N-甲基吡咯烷酮
NMR 核磁共振光谱法
n-BuLi 正丁基锂
PE 石油醚
rpm 每分钟转数
RT或rt 室温
sat. 饱和的
TBAF 四丁基氟化铵
TBDMS 叔丁基二甲基甲硅烷基
TBS 叔丁基二甲基甲硅烷基
TEMPO 2,2,6,6-四甲基哌啶1-氧基
TFA 三氟乙酸
THF 四氢呋喃
TMS 三甲基甲硅烷基
UPLC 超高效液相色谱法
如本文所用,“FXR激动剂”是指能够结合并活化法尼醇X受体(FXR)的任何试剂,其可称为胆汁酸受体(BAR)或NR1H4(核受体亚家族1,组H,成员4)受体。FXR激动剂可以充当FXR的激动剂或部分激动剂。该试剂可为化学化合物或生物分子(例如,蛋白质或抗体)。可以例如在使用荧光共振能量转移(FRET)无细胞测定的体外测定中,通过几种不同的方法来测量FXR激动剂的活性,如Pellicciari等人,Journal of Medicinal Chemistry,2002年,第15卷,第45期:3569-72中所述。
如本文所提及,“ASK1抑制剂”可为能够使凋亡信号调节激酶1(ASK1)蛋白失活的任何试剂。该试剂可为化学化合物或生物分子(例如,蛋白质或抗体)。ASK1蛋白活性可以通过几种不同的方法进行测量。例如,ASK1蛋白的活性可以基于ASK1蛋白磷酸化底物蛋白的能力来测定。用于鉴定ASK1抑制剂的方法是已知的(参见例如US 2007/0276050和US 2011/0009410,这两者全文以引用方式并入本文中)。示例性ASK1底物蛋白包括MAPKK3、MAPKK4、MAPKK6、MAPKK7或它们的片段。ASK1蛋白活性也可通过ASK1蛋白的磷酸化水平来测量,例如,对应于人全长ASK1蛋白的苏氨酸838(T838)或小鼠全长ASK1蛋白的苏氨酸845(T845)的ASK1蛋白中苏氨酸残基的磷酸化水平。例如,在ASK1蛋白包含全长人ASK1蛋白序列的情况下,ASK1抑制剂可使全长人ASK1蛋白序列中的T838的磷酸化减弱。可以使用针对人ASK1T838或小鼠ASK1 T845的位点特异性抗体来检测磷酸化水平。
如本文所用,“ACC抑制剂”是指能够结合并抑制乙酰辅酶A羧化酶(ACC)的任何试剂。ACC抑制剂可以充当ACC的抑制剂或部分抑制剂。该试剂可为化学化合物或生物分子(例如,蛋白质或抗体)。ACC抑制剂的活性可通过本领域已知的方法进行测量,诸如美国专利No.8,969,557和/或美国专利申请公开No.20160108061中所描述和引用的那些。
如本文所用,“甲状腺激素受体β激动剂”或“THRβ激动剂”是指能够结合并活化甲状腺激素受体β(其可称为NR1A2(核受体亚家族1,组A,成员2)受体)的任何试剂。THRβ激动剂可以充当THRβ的激动剂或部分激动剂。该试剂可为化学化合物或生物分子(例如,蛋白质或抗体)。THRβ激动剂的活性可通过已知的方法进行测量。
化合物
本文提供了一种具有下式(I)的化合物:
或其药学上可接受的盐。
在一些实施方案中,药学上可接受的盐为甲磺酸盐。例如,提供了下式的化合物:
固体形式
在一些实施方案中,本公开提供了式(I)的化合物或其药学上可接受的盐的固体形式。固体形式,诸如结晶形式可以提供生物利用度和稳定性的优点,可适于作为药物组合物中的活性成分使用。
药物物质或活性成分的晶体结构的变化可影响药物产品或活性成分的溶解速率(其可影响生物利用度等)、可制造性(例如,易于处理,能够一致地制备已知强度的剂量)以及稳定性(例如,热稳定性、储存期等)。此类变化可以影响不同剂量或递送形式(诸如溶液或固体口服剂型,包括片剂和胶囊)的药物组合物的制备或配制。与其他形式诸如非结晶或无定形形式相比,结晶形式可提供期望或合适的吸湿性、粒度控制、溶解速率、溶解度、纯度、物理和化学稳定性、可制造性、收率和/或工艺控制。
在一些实施方案中,提供了式(I)的化合物的稳定固体形式。例如,式(I)的甲磺酸盐可以作为稳定的结晶形式产生,其在多种制造条件下不转化为其他多晶型并且/或者作为相同的多晶型形成。
因此,式(I)的化合物的结晶形式可以提供诸如改善以下项的优点:化合物的制备方法,化合物的药物产品形式的稳定性或储存性,化合物的药物物质的稳定性或储存性,和/或作为活性剂的化合物的生物利用度和/或稳定性。
在一些实施方案中,固体形式为式(I)甲磺酸盐形式I。
式(I)甲磺酸盐形式I可以通过X-射线粉末衍射图来表征,其中固体形式表现出基本上如图4所示的X-射线粉末衍射(XRPD)图谱。式(I)甲磺酸盐形式I可表现出基本上如图5所示的差示扫描量热法(DSC)热谱图。式(I)甲磺酸盐形式I可表现出基本上如图6所示的热重分析(TGA)热谱图。
在式(I)甲磺酸盐形式I的一些实施方案中,适用以下(a)-(c)中的至少一者、至少两者或全部:(a)式(I)甲磺酸盐形式I具有基本上如图4所示的XRPD图谱;(b)式(I)甲磺酸盐形式I具有基本上如图5所示的DSC热谱图;(c)式(I)甲磺酸盐形式I具有基本上如图6所示的TGA热谱图。
在一些实施方案中,式(I)甲磺酸盐形式I具有以下特性中的至少一者、至少两者、或至少三者:
(a)基本上如图4所示的XRPD图谱
(b)基本上如图5所示的DSC热谱图
(c)基本上如图6所示的TGA热谱图。
在一些实施方案中,式(I)甲磺酸盐形式I具有XRPD图谱,其显示出具有基本上如图4所示的XRPD图谱的最大强度的°2θ-反射中的至少两者、至少三者、至少四者、至少五者、至少六者、至少七者、至少八者、或至少九者。
在某些实施方案中,式(I)甲磺酸盐形式I具有包括9.6、19.3和22.6处的°2θ-反射(±0.2°2θ)的XRPD图谱。在一些实施方案中,式(I)甲磺酸盐形式I具有这样的XRPD图谱,其包括9.6、19.3和22.6处的°2θ-反射(±0.2°2θ),以及3.2、6.4和12.8处的°2θ-反射(±0.2°2θ)中的一者、两者或三者。在一些实施方案中,式(I)甲磺酸盐形式I具有这样的XRPD图谱,其包括9.6、19.3和22.6处的°2θ-反射(±0.2°2θ),以及22.1、25.8和29.1处的°2θ-反射(±0.2°2θ)中的一者、两者或三者。在一些实施方案中,式(I)甲磺酸盐形式I具有包括9.6、19.3、22.6、3.2、6.4、12.8、22.1、25.8和29.1处的°2θ-反射(±0.2°2θ)的XRPD图谱。
在一些实施方案中,式(I)甲磺酸盐形式I具有包括始于约221℃的吸热峰的差示扫描量热法热谱图。
药物组合物和给药模式
此外,本公开提供了药物组合物,该药物组合物包含作为活性成分的至少一种本公开的化合物、或其前药化合物、或其药学上可接受的盐或溶剂化物,以及药学上可接受的载体。
本公开的药物组合物可另外包含一种或多种其他化合物作为活性成分,如前药化合物或其他核受体调节剂。
该组合物适用于口服、直肠、局部、肠胃外(包括皮下、肌内和静脉内)、眼部(眼科)、肺部(鼻或口腔吸入)或鼻给药,尽管在任何给定情况下最合适的途径将取决于所治疗病症的性质和严重程度以及活性成分的性质。它们可方便地以单位剂型提供,并且通过药学领域公知的任何方法进行制备。
在实际应用中,本发明化合物可以根据常规药物复合技术作为活性成分与药物载体紧密混合。取决于给药所需的制剂形式,例如口服或肠胃外(包括静脉内),载体可以采用多种形式。在制备用于口服剂型的组合物时,可以使用任何通常的药物介质,例如在口服液体制剂如悬浮液、酏剂和溶液剂的情况下的水、二醇、油、醇、调味剂、防腐剂、着色剂等;或在口服固体制剂如粉末剂、硬和软胶囊剂和片剂的情况下的载体如淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等,其中固体口服制剂是比液体制剂更优选的。
由于其易于给药,片剂和胶囊剂代表最有利的口服剂量单位形式,在这种情况下,使用固体药物载体。如果需要,片剂可以用标准的水性或非水性技术包衣。这样的组合物和制剂应含有至少0.1%的活性化合物。这些组合物中活性化合物的百分比当然可以变化,并且可以方便地在单位重量的约2%至约60%之间。在这种治疗有用的组合物中的活性化合物的量使得将获得有效的剂量。活性化合物也可以鼻内给药,例如作为液滴或喷雾剂。
片剂、丸剂、胶囊剂等也可以含有粘合剂如黄蓍胶、阿拉伯树胶、玉米淀粉或明胶;赋形剂如磷酸二钙;崩解剂如玉米淀粉、马铃薯淀粉、海藻酸;润滑剂如硬脂酸镁;和甜味剂如蔗糖、乳糖或糖精。当剂量单位形式是胶囊剂时,除了上述类型的材料之外,它可以含有液体载体如脂肪油。
各种其它材料可以作为涂层存在或改变剂量单位的物理形式。例如,片剂可以用虫胶、糖或两者包衣。除了活性成分之外,糖浆或酏剂还可含有作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味剂如樱桃味或橙味调味剂。
在一些实施方案中,本公开的化合物还可作为与各种抗衡阳离子的盐使用以产生口服可用的制剂。
本公开的化合物也可以肠胃外给药。这些活性化合物的溶液或悬浮液可以在与表面活性剂如羟丙基纤维素适当混合的水中制备。分散体也可以在甘油、液体聚乙二醇及其在油中的混合物中制备。在通常的储存和使用条件下,这些制剂含有防腐剂以防止微生物的生长。
适用于可注射用途的药物形式包括无菌水溶液或分散体以及用于临时制备无菌可注射溶液或分散体的无菌粉末。在所有情况下,所述形式必须是无菌的,并且必须是流体,以达到存在易注射性的程度。在制造和储存的条件下必须是稳定的,并且必须防止诸如细菌和真菌等微生物的污染作用。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、其合适的混合物和植物油的溶剂或分散介质。
为了向哺乳动物,尤其是人类提供有效剂量的本公开化合物,可使用任何适合的给药途径。例如,可以使用口服、直肠、局部、肠胃外、眼睛、肺、鼻等。剂型包括片剂、锭剂、分散剂、混悬剂、溶液剂、胶囊剂、霜剂、软膏剂、气雾剂等。在一些实施方案中,本公开化合物口服给药。
试剂盒
本文还提供了试剂盒,其包括本公开的化合物或其药物可接受的盐,互变异构体,立体异构体,立体异构体混合物,前药或氘代类似物以及合适的包装。在一个实施方案中,试剂盒还包括使用说明书。在一个方面,试剂盒包括本公开的化合物或其药物可接受的盐、互变异构体、立体异构体、立体异构体混合物、前药或氘代类似物,和标签和/或使用化合物治疗本文所述的适应症(包括疾病或病症)的说明书。
本文还提供了制品,其在合适容器中包含本文所述的化合物或其药物可接受的盐、互变异构体、立体异构体、立体异构体混合物、前药或氘代类似物。容器可以是小瓶、罐子、安瓿、预装注射器和静脉袋。
治疗方法和用途
“治疗”或“处置”是用于得到有益的或者希望的结果(包括临床结果)的方法。有益的或者希望的临床结果可包括以下中的一个或者多个:a)抑制疾病或者病症(例如,减少疾病或者病症所导致的一个或者多个症状和/或减轻疾病或者病症的严重性);b)减慢或者阻止与疾病或者病症相关联的一个或者多个临床症状的发展(例如,稳定疾病或者病症,防止或者延缓疾病或者病症的恶化或者进展,和/或防止或者延缓疾病或者病症的传播(例如,转移));和/或c)减轻疾病,即,导致临床症状消退(例如,改善疾病状态,提供疾病或者病症的部分或者全部缓解,增强其它药物疗法的效果,延缓疾病进展,提高生命质量和/或延长存活)。
“预防”或“防止”是指对疾病或病症的任何处理,其使得疾病或病症的临床症状不出现。在一些实施方案中,化合物可给药于处于疾病或病症风险或具有疾病或病症家族史的受试者(包括人)。
“受试者”指的是动物,如哺乳动物(包括人),其已经或者将要成为治疗、观察或实验的对象。本文所述方法可用于人类治疗和兽医应用。在一些实施方案中,所述受试者为哺乳动物。在一个实施方案中,受试者为人类。
本文所述化合物或其药物可接受的盐、互变异构体、立体异构体、立体异构体混合物、前药或氘代类似物的术语“治疗有效量”或“有效量”是指当给药受试者时足以实现治疗的量,以提供治疗益处,如改善症状或减缓疾病进展。例如,治疗有效量可为足以减少对FXR激动作用有响应的疾病或病症的症状的量。所述治疗有效量可取决于受试者和治疗的疾病或者病症、受试者的体重和年龄、疾病或者病症的严重性和给药方式而改变,其可由本领域普通技术人员容易地确定。
本公开还涉及本文所公开的化合物用于通过所述化合物与所述核受体的结合来治疗和/或预防疾病和/或病症的用途。另外,本公开涉及所述化合物用于制备通过所述化合物与所述核受体的结合来治疗和/或预防疾病和/或病症的药物的用途。
在一些实施方案中,本公开涉及根据式(I)的化合物在制备药物中的用途,所述药物用于预防和/或治疗慢性肝内或者一些形式的肝外胆汁郁积性病症、肝纤维化、急性肝内胆汁郁积性病症、由胆汁组成不当引起的梗阻性或者慢性炎性障碍、具有减少的膳食脂肪和脂溶性膳食维生素摄入的胃肠病症、炎性肠病、脂质和脂蛋白紊乱、II型糖尿病以及I型和II型糖尿病的临床并发症、由器官的慢性脂肪性和纤维性变性产生的病症和疾病,所述器官的慢性脂肪性和纤维性变性由于强化的脂质并且具体为甘油三酯积累和随后促纤维化途径的活化所导致,肥胖症和代谢综合征(血脂障碍、糖尿病和异常高的体重指数的合并病症)、急性心肌梗塞、急性中风、作为慢性阻塞性动脉粥样硬化的终点出现的血栓形成、细胞内细菌或者寄生原生动物的持续感染、非恶性过度增殖性性障碍、恶性过度增殖性性障碍、结肠腺癌并且具体为肝细胞癌、肝脏脂肪变性和相关综合征、作为慢性肝病或者外科肝切除的结果的肝功能衰竭或者肝功能失常、乙型肝炎感染、丙型肝炎感染和/或与酒精诱发性肝硬化或者与病毒传播型肝炎相关的胆汁郁积性和纤维变性影响。
本文提及的药物可以通过常规方法制备,包括根据本公开的化合物与药物可接受的载体的组合。
FXR可以同时调节肝脏中胆汁酸的合成输出和它们在肠内的再循环(通过调节胆汁酸结合蛋白)。FXR可以参与许多不同的生理过程的调节,这些生理过程与病因相关,并且用于治疗多种疾病,如胆固醇结石、代谢障碍诸如II型糖尿病、血脂异常或肥胖症、慢性炎性疾病诸如炎性肠病、或慢性肝内形式的胆汁淤积。
FXR调节肝脏和胃肠道中应答基因的复杂模式。基因产物影响各种不同的生理过程。例如,FXR经由上调编码SHP(相对于LRH-1具有显性抑制的另一种核受体)的mRNA来抑制Cyp7A1的诱导。由于FXR结合初级胆汁酸即该途径的终产物,这可被视为对基因表达水平的反馈抑制的实例。
FXR配体诱导胆汁流量并使胆汁酸组成朝更亲水的组成变化。随着首次合成的FXR配体GW4064作为工具化合物和半合成人工胆汁酸配体6-α-乙基-CDCA的开发,可以分析有效激动剂对FXR的超刺激效应。示出了两种配体均诱导胆管结扎动物的胆汁流量。此外,除了促胆汁分泌作用之外,还可以展示出肝保护作用。这些肝保护作用包括由基质金属蛋白酶组织抑制因子TIMP-1和2的抑制引起的抗纤维化作用、肝星状细胞中胶原沉积分解基质金属蛋白酶2的诱导,以及α-胶原mRNA和转化生长因子β(TGF-β)mRNA(这两者均为促纤维化因子)的后续减少。
此外,在胆管结扎的动物模型以及雌激素诱导的胆汁淤积的动物模型中展示了抗胆汁淤积活性。遗传研究表明,在遗传形式的胆汁淤积(进行性家族性肝内胆汁淤积症=PFIC,I-IV型)中,FXR自身的核定位由于FIC1基因的突变而降低(在PFIC I型中也称为拜勒氏病(Byler′s Disease))(F.Chen等人,Gastroenterology 2004,126,756;L.Alvarez等人,Hum.Mol.Genet.2004,13,2451),或者编码MDR-3磷脂输出泵的FXR靶基因的水平降低(在PFIC III型中)。有越来越多的证据表明,FXR结合化合物可以在慢性胆汁淤积性病症诸如原发性胆汁性肝硬化(PBC)或原发性硬化性胆管炎(PSC)的治疗方案中展示出实质性的临床效用。
FXR激动剂可用于预防胆固醇结石形成或预防手术切除或震荡波碎石术后胆结石再形成。例如,使用合成的FXR工具化合物GW4064,可以表明FXR的活化导致胆固醇饱和指数(CSI)的改善并且直接导致C57L胆结石易感小鼠中胆结石形成的消除,而FXR敲除小鼠中的药物治疗则示出对胆结石形成没有影响。因此,在本公开的一个实施方案中,根据式(I)的化合物和包含所述化合物的药物组合物用于预防和/或治疗由不当胆汁组成引起的阻塞性或慢性炎性障碍,诸如胆石病,也称为胆固醇结石。
FXR激动剂可用于保护肠免于赘生性转化和息肉发展以及它们在肠中向腺癌的转化。缺乏FXR导致肝细胞癌(HCC)即肝癌的最突出形式的形成高度增加。而功能性FXR防止结肠腺癌和肝细胞癌形成,FXR活化诱导肝切除术后肝的再生。
与FXR活化相关的肝保护、抗肿瘤和肝再生的联合效应可在治疗上被开发为利用FXR激动剂来治疗严重肝脏疾病。在一个实施方案中,根据本公开的化合物和包含所述化合物的药物组合物用于治疗肝脏疾病诸如HCC、刺激肝脏再生长以及改善与大型肝切除术(major liver surgery)相关的副作用、不依赖于病因的肝硬化以及在肝移植或大型肝脏手术过程中预防或治疗肝缺血。
此外,FXR可为血清甘油三酯的关键调节剂。通过合成性激动剂来活化FXR可导致血清甘油三酯显著降低——主要为降低的VLDL的形式,但也导致总血清胆固醇降低。降低血清甘油三酯并非单独的效应。用合成的FXR激动剂GW4064治疗db/db或ob/ob小鼠导致了血清甘油三酯、总胆固醇、游离脂肪酸、酮体诸如3-OH丁酸酯的显著性和组合性下降。此外,FXR活化与肝细胞中的细胞内胰岛素信号传导途径结合,导致来自肝脏糖原异生的葡萄糖输出减少,但伴随着肝糖原增加。FXR治疗对胰岛素敏感性以及葡萄糖耐受性有积极影响。最近在过度进食高脂饮食的小鼠中也观察到对体重减少的影响。该体重减轻效应可能是由FXR诱导FGF-19(已知导致体重减轻和运动表型的成纤维细胞生长因子)引起。已经展示了FXR激动剂对体重减少的影响。
因此,可以以不同的治疗方式开发FXR激动剂:FXR结合化合物被认为是治疗II型糖尿病的良好候选物,因为它们具有胰岛素敏感性、糖原异生(glycogenogenic)作用和降脂作用。
在一个实施方案中,根据本公开的化合物和包含所述化合物的药物组合物用于预防和/或治疗II型糖尿病,该II型糖尿病可以通过FXR介导的全身胰岛素敏感性和肝脏中的细胞内胰岛素信号传导上调、周围葡萄糖摄取和代谢增加、肝脏中的糖原贮积增加、来自肝源性糖原异生的血清中葡萄糖输出的减少来克服。
在另一个实施方案中,所述化合物和药物组合物用于预防和/或治疗慢性肝内胆汁淤积,诸如PBC、PSC、进行性家族性胆汁淤积症(PFIC)、酒精诱发性肝硬化和相关的胆汁淤积,以及一些形式的肝外胆汁淤积病症或肝纤维化。
本公开还涉及式(I)的化合物或包含所述化合物的药物组合物,其用于预防和/或治疗具有降低的膳食脂肪和脂溶性膳食维生素摄取的胃肠病症,该胃肠病症可通过增加胆汁酸和磷脂的肠水平来克服。
在另一个实施方案中,所述化合物或药物组合物用于预防和/或治疗选自脂质和脂蛋白障碍,诸如作为临床表现病症的高胆固醇血症、高甘油三酯血症和动脉粥样硬化的疾病,该疾病可通过FXR对降低总血浆胆固醇、降低血清甘油三酯、增加肝胆固醇向胆汁酸的转化以及增加肝脏中VLDL和其他脂蛋白的清除和代谢转化的有益效果来改善。
在另一个实施方案中,所述化合物和药物组合物用于预防和/或治疗疾病,其中FXR靶向药物的降脂、抗胆汁淤积和抗纤维化的组合效应可用于治疗肝脏脂肪变性和相关综合征,诸如非酒精性脂肪性肝炎(NASH),或用于治疗与酒精诱发性肝硬化或与病毒传播形式的肝炎相关的胆汁淤积和纤维化效应。
结合降血脂效应,已示出功能性FXR的丧失导致了ApoE敲除小鼠中的动脉粥样硬化增加。因此,FXR激动剂可具有作为抗动脉粥样硬化和心脏保护药物的临床效用。血管平滑肌细胞中内皮素-1的下调也可有助于此类有益治疗效果。
本公开还涉及根据式(I)的化合物或包含所述化合物的药物组合物,其用于预防和创伤后治疗心血管障碍,诸如急性心肌梗塞、急性中风、或作为慢性阻塞性动脉粥样硬化的终点出现的血栓形成。
除控制肠和结肠息肉形成外,FXR似乎在乳腺癌组织和细胞系中表达,但在健康乳腺组织中不表达,并且似乎与ER阳性乳腺癌细胞中的雌激素受体相互作用。因此,FXR可以是治疗增殖性疾病,尤其是表达FXR的小分子响应形式的转移癌形式的潜在靶标。
在另一个实施方案中,所述化合物和药物组合物用于预防和/或治疗恶性过度增殖性障碍,诸如不同形式的癌症,特别是某些形式的乳腺、肝或结肠癌,其中干扰FXR配体将具有有益影响。
FXR可能参与肠内抗菌防御的控制。FXR激动剂可在炎性肠病(IBD)的治疗中具有有益影响。例如,在其中肠的上(回肠)部分受侵袭的IBD形式(例如回肠克罗恩氏病)中,FXR激动剂可通过FXR介导的细菌生长控制而具有有益效果。在IBD中,适应性免疫应答的脱敏在肠道免疫系统中以某种方式受损。细菌过度生长则可以是建立慢性炎症反应的触发起因。因此,通过FXR机制抑制细菌生长可能是预防急性炎症发作的关键机制。
因此,本公开还涉及根据式(I)的化合物或包含所述化合物的药物组合物,其用于预防和/或治疗与炎性肠病相关的疾病,诸如克罗恩氏病或溃疡性结肠炎。认为FXR介导的肠屏障功能恢复和非共生细菌负荷的减少有助于减少细菌抗原向肠免疫系统的暴露,并因此可以减少炎症反应。
本公开还涉及用于预防和/或治疗肥胖症和相关障碍诸如代谢综合征(血脂异常、糖尿病和异常高的体重指数(body-mass index)的组合病症)的化合物或药物组合物,该肥胖症和相关障碍可通过FXR介导的降低血清甘油三酯、血糖和增加的胰岛素敏感性以及FXR介导的体重减轻来克服。
在另一个实施方案中,本公开的化合物或药物组合物可用于预防和/或治疗I型和II型糖尿病的临床并发症。此类并发症的实例包括糖尿病性肾病、糖尿病性视网膜病、糖尿病性神经病变或周围动脉闭塞性疾病(PAOD)。本公开还涵盖了糖尿病的其他临床并发症。
此外,还可以通过给药本公开的化合物或药物组合物来预防和/或治疗由于由器官的慢性脂肪性和纤维性变性产生的病症和疾病,所述器官的慢性脂肪性和纤维性变性由于强化的脂质(enforced lipid),特别是甘油三酯积累和随后促纤维化途径的活化所导致。此类病症和疾病涵盖了肝脏中的NASH和慢性胆汁淤积性病症、肾脏中的肾小球硬化症和糖尿病性肾病、眼中的黄斑变性和糖尿病性视网膜病以及神经变性疾病诸如脑中的阿尔茨海默病,或周围神经系统中的糖尿病性神经病变。
在另一个实施方案中,本公开的化合物或药物组合物可用于预防和/或治疗先天性肝纤维化。
剂量
所采用的活性成分的有效剂量可以根据所采用的具体化合物、给药模式、所治疗的病症和所治疗病症的严重程度来变化。所述剂量可以由本领域的技术人员容易地确定。
当治疗或预防本公开的化合物所适用的FXR介导的病症时,当以约0.1毫克至约300毫克/千克动物体重的日剂量给药本公开的化合物时,获得了通常令人满意的结果。在一些实施方案中,本公开的化合物作为单次日剂量或以每日两至六次的分剂量或以缓释形式给予。对于大多数大型哺乳动物,总日剂量为约1毫克至约1000毫克,或约1毫克至约50毫克。在70kg成人的情况下,总日剂量将通常为约7毫克至约350毫克。可以调整该给药方案以提供最佳的治疗反应。在一些实施方案中,总日剂量为约1毫克至约900毫克、约10毫克至约800毫克、约20毫克至约700毫克、约30毫克至约600毫克、约40毫克至约550毫克、约50毫克至约400毫克、约50毫克至约300毫克,或约50毫克至约200毫克。
本申请的化合物或其组合物可以使用上述任何合适的模式每天给药一次、两次、三次或四次。另外,化合物的给药或治疗可持续数天;例如,对于一个治疗周期,通常治疗将持续至少7天、14天或28天。治疗周期在癌症化疗中是公知的,并且经常在周期之间以约1至28天,通常约7天或约14天的休息期交替。在其他实施方案中,治疗周期也可为连续的。
在一个具体实施方案中,本文所提供的方法包括向受试者给药约1至800mg的本文所述化合物的初始日剂量并以增量增加剂量直至实现临床功效。可以使用约5、10、25、50或100mg的增量来增加剂量。剂量可以每天、每隔一天、每周两次或每周一次增加。
组合
在一些实施方案中,将本文所公开的化合物与一种或多种额外治疗剂组合给药,以治疗或预防本文所公开的疾病或病症。在一些实施方案中,一种或多种额外治疗剂是ACE抑制剂、乙酰辅酶A羧化酶抑制剂、腺苷A3受体激动剂、脂联素受体激动剂、AKT蛋白激酶抑制剂、AMP激活蛋白激酶(AMPK)、胰淀素受体激动剂、血管紧张素II AT-1受体拮抗剂、自毒素抑制剂、生物活性脂质、降钙素激动剂、胱天蛋白酶抑制剂、胱天蛋白酶3刺激物、组织蛋白酶抑制剂、小窝蛋白1抑制剂、CCR2趋化因子拮抗剂、CCR3趋化因子拮抗剂、CCR5趋化因子拮抗剂、氯离子通道刺激物、CNR1抑制剂、细胞周期蛋白D1抑制剂、细胞色素P450 7A1抑制剂、DGAT1/2抑制剂、二肽基肽酶IV抑制剂、内皮唾酸蛋白调节剂、嗜酸性粒细胞趋化因子配体抑制剂、细胞外基质蛋白调节剂、法尼醇X受体激动剂、脂肪酸合酶抑制剂、FGF1受体激动剂、成纤维细胞生长因子(FGF-15、FGF-19、FGF-21)配体、半乳糖凝集素-3抑制剂、胰高血糖素受体激动剂、胰高血糖素样肽1激动剂、G蛋白偶联胆汁酸受体1激动剂、Hedgehog(Hh)调节剂、丙型肝炎病毒NS3蛋白酶抑制剂、肝细胞核因子4α调节剂(HNF4A)、肝细胞生长因子调节剂、HMG CoA还原酶抑制剂、IL-10激动剂、IL-17拮抗剂、回肠胆酸钠协同转运蛋白抑制剂、胰岛素增敏剂、整合素调节剂、白介素-1受体-相关激酶4(IRAK4)抑制剂、Jak2酪氨酸激酶抑制剂、己酮糖激酶抑制剂、克洛索β刺激物、5-脂氧合酶抑制剂、脂蛋白脂酶抑制剂、肝脏X受体、LPL基因刺激物、溶血磷脂-1受体拮抗剂、赖氨酰氧化酶同系物2抑制剂、基质金属蛋白酶(MMP)抑制剂、MEKK-5蛋白激酶抑制剂、膜铜胺氧化酶(VAP-1)抑制剂、甲硫氨酸氨肽酶-2抑制剂、甲基CpG结合蛋白2调节剂、微小RNA-21(miR-21)抑制剂、线粒体解偶联剂、髓鞘碱性蛋白刺激物、NACHT LRR PYD结构域蛋白3(NLRP3)抑制剂、NAD-依赖性脱乙酰酶长寿蛋白(Sirtuin)刺激物、NADPH氧化酶抑制剂(NOX)、烟酸受体1激动剂、P2Y13嘌呤受体刺激物、PDE 3抑制剂、PDE 4抑制剂、PDE 5抑制剂、PDGF受体β调节剂、磷脂酶C抑制剂、PPARα激动剂、PPARδ激动剂、PPARγ激动剂、PPARγ调节剂、蛋白酶激活受体-2拮抗剂、蛋白激酶调节剂、Rho相关蛋白激酶抑制剂、钠葡糖转运子-2抑制剂、SREBP转录因子抑制剂、STAT-1抑制剂、硬脂酰CoA去饱和酶-1抑制剂、细胞因子信号传导抑制因子-1刺激物、细胞因子信号传导抑制因子-3刺激物、转化生长因子β(TGF-β)、转化生长因子β活化激酶1(TAK1)、甲状腺激素受体β激动剂、TLR-4拮抗剂、转谷氨酰胺酶抑制剂、酪氨酸激酶受体调节剂、GPCR调节剂、核激素受体调节剂、WNT调节剂或YAP/TAZ调节剂。
一种或多种额外治疗剂的非限制性实例包括:
ACE抑制剂,诸如依那普利;
乙酰辅酶A羧化酶(ACC)抑制剂,诸如DRM-01、吉卡宾、PF-05175157和QLT-091382;
腺苷受体激动剂,诸如CF-102、CF-101、CF-502和CGS21680;
脂联素受体激动剂,诸如ADP-355;
胰淀素/降钙素受体激动剂,诸如KBP-042;
AMP激活蛋白激酶刺激物,诸如O-304;
血管紧张素II AT-1受体拮抗剂,诸如厄贝沙坦;
自毒素抑制剂,诸如PAT-505、PAT-048、GLPG-1690、X-165、PF-8380和AM-063;
生物活性脂质,诸如DS-102;
1型大麻素受体(CNR1)抑制剂,诸如namacizumab和GWP-42004;
胱天蛋白酶抑制剂,诸如恩利卡生;
泛组织蛋白酶B抑制剂,诸如VBY-376;
泛组织蛋白酶抑制剂,诸如VBY-825;
CCR2/CCR5趋化因子拮抗剂,诸如cenicriviroc;
CCR2趋化因子拮抗剂,诸如丙帕锗;
CCR3趋化因子拮抗剂,诸如柏替木单抗;
氯离子通道刺激物,诸如cobiprostone;
二脂酰甘油脂酰基转移酶2(DGAT2)抑制剂,诸如IONIS-DGAT2Rx;
二肽基肽酶IV抑制剂,诸如利拉利汀;
嗜酸性粒细胞趋化因子配体抑制剂,诸如柏替木单抗;
细胞外基质蛋白调节剂,诸如CNX-024;
脂肪酸合酶抑制剂,诸如TVB-2640;
成纤维细胞生长因子19(rhFGF19)/细胞色素P450(CYP)7A1抑制剂,诸如NGM-282;
成纤维细胞生长因子21(FGF-21)配体,诸如BMS-986171、
BMS-986036;
成纤维细胞生长因子21(FGF-21)/胰高血糖素样肽1(GLP-1)激动剂,诸如YH-25723;
半乳糖凝集素-3抑制剂,诸如GR-MD-02;
胰高血糖素样肽1(GLP1R)激动剂,诸如AC-3174、利拉鲁肽、索马鲁肽;
G蛋白偶联胆汁酸受体1(TGR5)激动剂,诸如RDX-009、INT-777;
热休克蛋白47(HSP47)抑制剂,诸如ND-L02-s0201;
HMG CoA还原酶抑制剂,诸如阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀和辛伐他汀;
IL-10激动剂,诸如peg-伊洛白介素;
回肠胆酸钠协同转运蛋白抑制剂,诸如A-4250、volixibat乙醇钾水合物(SHP-262)和GSK2330672;
胰岛素增敏剂,诸如KBP-042、MSDC-0602K、Px-102、RG-125(AZD4076)和VVP-100X;
己酮糖激酶抑制剂,诸如PF-06835919;
β克洛索(KLB)-FGF1c激动剂,诸如NGM-313;
5-脂氧合酶抑制剂,诸如泰鲁司特(MN-001);
脂蛋白脂酶抑制剂,诸如CAT-2003;
LPL基因刺激物,诸如阿利泼金;
肝脏X受体(LXR)调节剂,诸如PX-L603、PX-L493、BMS-852927、T-0901317、GW-3965和SR-9238;
溶血磷脂-1受体拮抗剂,诸如BMT-053011、UD-009、AR-479、ITMN-10534、BMS-986020和KI-16198;
赖氨酰氧化酶同系物2抑制剂,诸如辛妥珠单抗;
氨基脲敏感胺氧化酶/血管黏附蛋白-1(SSAO/VAP-1)抑制剂,诸如PXS-4728A;
甲硫氨酸氨肽酶-2抑制剂,诸如ZGN-839;
甲基CpG结合蛋白2调节剂,诸如巯乙胺;
线粒体解偶联剂,诸如2,4-二硝基酚;
髓鞘碱性蛋白刺激物,诸如奥利索西;
NADPH氧化酶1/4抑制剂,诸如GKT-831;
烟酸受体1激动剂,诸如ARI-3037MO;
硝唑尼特;
NACHT LRR PYD结构域蛋白3(NLRP3)抑制剂,诸如KDDF-201406-03和NBC-6;
核受体调节剂,诸如DUR-928;
P2Y13嘌呤受体刺激物,诸如CER-209;
PDE 3/4抑制剂,诸如泰鲁司特(MN-001);
PDE 5抑制剂,诸如西地那非;
PDGF受体β调节剂,诸如BOT-191、BOT-509;
PPAR激动剂,诸如elafibranor(GFT-505)、MBX-8025、氘代吡格列酮R-对映体、吡格列酮、DRX-065、赛格列扎(saroglitazar)和IVA-337;
蛋白酶激活受体-2拮抗剂,诸如PZ-235;
蛋白激酶调节剂,诸如CNX-014;
Rho相关蛋白激酶(ROCK)抑制剂,诸如KD-025;
钠葡糖转运子-2(SGLT2)抑制剂,诸如依格列净、依碳酸瑞格列净、埃格列净、达格列净和索格列净(sotagliflozin);
SREBP转录因子抑制剂,诸如CAT-2003和MDV-4463;
硬脂酰CoA去饱和酶-1抑制剂,诸如aramchol;
甲状腺激素受体(THR)β激动剂,诸如MGL-3196、MGL-3745、VK-2809;
TLR-4拮抗剂,诸如JKB-121;
酪氨酸激酶受体调节剂,诸如CNX-025;
GPCR调节剂,诸如CNX-023;和
核激素受体调节剂,诸如Px-102。
在某些具体实施方案中,一种或多种额外治疗剂选自A-4250、AC-3174、乙酰水杨酸、AK-20、AKN-083、阿利泼金、aramchol、ARI-3037MO、ASP-8232、阿托伐他汀、柏替木单抗、无水甜菜碱、BAR-704、BI-1467335、BMS-986036、BMS-986171、BMT-053011、BOT-191、BTT-1023、BWD-100、BWL-200、CAT-2003、cenicriviroc、CER-209、CF-102、CGS21680、CNX-014、CNX-023、CNX-024、CNX-025、cobiprostone、考来维仑、达格列净、16-脱氢-孕烯醇酮、氘代吡格列酮R-对映体、2,4-二硝基酚、DRX-065、DS-102、DUR-928、EDP-305、elafibranor(GFT-505)、恩利卡生、依那普利、EP-024297、埃格列净、依格列汀(evogliptin)、EYP-001、F-351、fexaramine、GKT-831、GNF-5120、GR-MD-02、氢氯噻嗪、二十碳五烯酸乙酯、IMM-124-E、INT-767、IONIS-DGAT2Rx、INV-33、依格列净、厄贝沙坦、丙帕锗、IVA-337、JKB-121、KB-GE-001、KBP-042、KD-025、M790、M780、M450、二甲双胍、西地那非、LC-280126、利拉利汀、利拉鲁肽、LJN-452、LMB-763、MBX-8025、MDV-4463、巯乙胺、MET-409、MGL-3196、MGL-3745、MSDC-0602K、namacizumab、NC-101、ND-L02-s0201、NFX-21、NGM-282、NGM-313、NGM-386、NGM-395、NTX-023-1、去甲熊去氧胆酸、O-304、奥贝胆酸、25HC3S、奥利索西、PAT-505、PAT-048、peg-伊洛白介素、吡格列酮、吡非尼酮、PRI-724、PX20606、Px-102、PX-L603、PX-L493、PXS-4728A、PZ-235、RDX-009、RDX-023、依碳酸瑞格列净、新用途三辛酸甘油酯(repurposedtricaprilin)、RG-125(AZD4076)、赛格列扎、索马鲁肽、辛妥珠单抗(simtuzumab)、SIPI-7623、索利霉素、索格列净、他汀类药物(阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀)、TCM-606F、TERN-101、TEV-45478、泰鲁司特(MN-001)、TLY-012、tropifexor、TRX-318、TVB-2640、UD-009、熊去氧胆酸、VBY-376、VBY-825、VK-2809、维莫德吉、volixibat乙醇钾水合物(SHP-626)、VVP-100X、WAV-301、WNT-974和ZGN-839。
在一些实施方案中,方法和组合物包括治疗有效量的凋亡信号调节激酶1(ASK1)抑制剂和治疗有效量的法尼醇X受体(FXR)激动剂,其中FXR激动剂是式(I)的化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物或互变异构体。
在本文所公开的方法和药物组合物的某些实施方案中,ASK1抑制剂是式(II)的化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物或互变异构体。
ASK1抑制剂,诸如式(II)的化合物可使用本领域的技术人员已知的方法合成和表征,诸如US2007/0276050、US2011/0009410和US2013/0197037所述的那些。
在一些实施方案中,方法和组合物包括治疗有效量的乙酰辅酶A羧化酶(ACC)抑制剂和治疗有效量的法尼醇X受体(FXR)激动剂,其中FXR激动剂是式(I)的化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物或互变异构体。
在本文所公开的方法和药物组合物的某些实施方案中,ACC抑制剂是式(III)的化合物:
或其药学上可接受的盐。
ACC抑制剂,诸如式(III)的化合物可使用本领域的技术人员已知的方法合成和表征,诸如PCT国际申请公开No.WO 2013/071169所述的那些。
在一些实施方案中,方法和组合物包括治疗有效量的甲状腺激素受体(THR)β激动剂与治疗有效量的法尼醇X受体(FXR)激动剂的组合,其中FXR激动剂是式(I)的化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物或互变异构体。
在本文所公开的方法和药物组合物的某些实施方案中,THRβ激动剂是式(IV)的化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物或互变异构体。
THRβ激动剂,诸如式(IV)的化合物可使用本领域的技术人员已知的方法合成和表征。
实施例
以下实施例被包括在内以展示本公开的具体实施方案。本领域的技术人员应当理解,以下实施例中公开的技术代表在本公开的实践中良好起作用的技术,并因此可被认为构成用于其实践的具体模式。然而,根据本公开,本领域的技术人员应当理解,这些实施例是示例性而非穷举性的。在不脱离本公开的精神和范围的情况下,可以对所公开的具体实施例作出许多改变并且仍然获得类似或相似的结果。
本文所公开的化合物可以使用适当的材料根据以下方案和实施例的过程进行制备,并且通过以下具体实施例进一步例示。此外,通过利用本文所述的过程,结合本领域的普通技术,可以容易地制备本文要求保护的本公开的额外化合物。实施例进一步说明了用于制备本公开的化合物的细节。本领域的技术人员将容易理解,以下制备过程的条件和方法的已知变型形式可用于制备这些化合物。为了合成本公开所描述的实施方案的化合物,要合成化合物的结构的检测将提供每个取代基的识别。在一些情况下,终产物的识别可以通过本文实施例给出的检测方法而使必要起始材料的识别变得明显。化合物能够以其药学上可接受的盐的形式分离,例如上述的那些。本文所述的化合物通常在室温和压力下是稳定和可分离的。
下文示出了本文所公开的化合物的制备的例示。除非另外指明,变量具有与上述相同的含义。以下给出的实施例旨在说明本公开的具体实施方案。如下所述的合成中所用的合适的起始材料、结构单元和试剂例如可从Sigma-Aldrich或Acros Organics商购获得,或者可通过如下文献中所述的过程常规制备:"March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure",第5版;John Wiley&Sons或T.Eicher,S.Hauptmann"The Chemistry of Heterocycles;Structures,Reactions,Synthesis andApplication",第2版,Wiley-VCH 2003;Fieser等人“Fiesers′Reagents for OrganicSynthesis”John Wiley&Sons 2000。
方法
X-射线粉末衍射(XRPD)
在PANanalytical XPERT-PRO衍射仪上,在以下实验设置下在环境条件下采集XRPD图谱:45KV,40mA,扫描范围2至40°2θ,步长0.0084或0.0167°2θ,测量时间:5min。
差示扫描量热法(DSC)
在配备有50位自动取样器的TA Instruments Q2000系统上采集DSC热谱图。使用合乎标准的铟进行能量和温度校准。典型地,将1-5mg的各样品在带针孔铝盘中以10℃/min从约25℃加热至约300℃。在整个测量中,在样品上维持50mL/min的干燥氮气吹扫。熔融吸热的起始记录为熔点。
热重分析(TGA)
在配备有25位自动取样器的TA Instruments Q5000系统上采集TGA热谱图。将约1-5mg的各样品装载到预配衡的铝盘中并且以10℃/min从约25℃加热至约350℃。在整个测量中,在样品上维持25mL/min的氮气吹扫。
通用合成方案
式(Ia)的化合物(其中Y为N)可根据以下通用合成方案进行合成。
在以上通用合成方案中,A为亚吡啶基或亚苯基,它们各自任选地被一个或两个独立地选自卤素、C1-4-烷氧基、卤代-C1-4-烷氧基、C1-4-烷基和卤代-C1-4-烷基的基团取代;Q为亚苯基或亚吡啶基,它们各自任选地被一个或两个独立地选自卤素、甲基、C1-4-烷氧基、卤代-C1-4-烷氧基、-CH2F、-CHF2和-CF3的取代基取代;X为离去基团,Y为可用于形成有机金属物类诸如格氏试剂的基团诸如卤素,Z为被R1取代的异噁唑或被C1-4-烷基或C3-6-环烷基取代的吡唑,R2和R3独立地选自氢、卤素、甲氧基、-CF3、-CHF2、-CH2F、-OCH2F、-OCHF2、-OCF3和甲基;R4为-CO2R5或-C(O)NR5R6;R5为氢、C1-6-烷基或卤代-C1-6-烷基;并且R6为氢或C1-6-烷基,其中所述C1-6-烷基任选地被1至6个独立地选自卤素、-SO3H和-CO2H的取代基取代。PG为保护基,并且其余变量如本文所提供。式(C)的化合物可通过使式(A)的化合物与式(B)的化合物在碱存在下反应来制备。通过形成有机金属物类诸如格氏试剂,然后与适当保护的3-酮氮杂环丁烷缩合,由式(C)的化合物形成式(D)的化合物。在适当的脱保护条件下,由式(D)的化合物形成式(E)的化合物。可使式(E)的化合物与式(F)的化合物在碱的存在下混合以给出式(Ia)的化合物。
另选地,式(D)的化合物可通过使式(A)的化合物与式(G)的化合物在碱的存在下反应来形成。
适当的结构(A)和(B)的化合物可根据以下实施例中描述的方法或通过本领域已知的方法进行制备。例如,X可为卤素(例如,氟、溴、氯和/或碘),并且PG可为叔丁基羰基保护基(BOC)。
实施例1:式(I)的制备
步骤1:2,6-二氯-4-氟苯甲醛肟的制备
将2,6-二氯-4-氟苯甲醛(20g,100mmol)、盐酸羟胺(14g,210mmol)和碳酸钠(27g,260mmol)在乙醇/水(5:1,170mL)中的悬浮液超声处理约10分钟,然后在室温下搅拌过夜。
用水和乙酸乙酯对混合物进行稀释。将水相用乙酸乙酯萃取两次。将合并的有机层用饱和氯化钠水溶液洗涤,经无水硫酸镁干燥,过滤,并减压浓缩以提供期望的中间体。LCMS-ESI+(m/z):[M+H]+ C7H5Cl2FNO计算值:207.97;实测值:207.99.
步骤2:2,6-二氯-4-氟-N-羟基苯甲亚氨酰氯(2,6-dichloro-4-fluoro-N-hydroxy benzimidoyl chloride)的制备
将2,6-二氯-4-氟苯甲醛肟(21g,99mmol)的N,N-二甲基甲酰胺(200mL)溶液用一份N-氯代琥珀酰亚胺(1.5g,11mmol)处理。向混合物中鼓入氯化氢蒸气(约40mL,从浓盐酸瓶的顶部空间获取)。在添加另一份N-氯代琥珀酰亚胺(1.5g,90mmol)之后,再引入两倍体积的氯化氢气体(40mL×2)。分小份添加额外N-氯代琥珀酰亚胺(12g,11mmol)。在观察放热至25℃之后,将混合物在室温水浴中冷却。允许温度降至约23℃,分批添加剩余的N-氯代琥珀酰亚胺。在添加结束时,LC/MS分析显示出肟起始材料的存留,因此添加最后一部分N-氯代琥珀酰亚胺(1.2g,9.0mmol)。允许混合物在室温下搅拌过夜,并且不经后处理进行至后续合成步骤。LCMS-ESI+(m/z):[M+H]+C7H4Cl3FNO计算值:241.93;实测值:242.20.
步骤3:5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-甲酸乙酯的制备
将环丙基-3-氧代丙酸乙酯(19g,120mmol)的2-甲基四氢呋喃溶液在室温下经由注射器用三乙胺(55mL,400mmol)处理。在搅拌30分钟之后,经由注射器滴加含有2,6-二氯-4-氟-N-羟基苯甲亚氨酰氯(24g,99mmol)的反应混合物。在添加结束时,将混合物在约60℃下加热过夜。使反应混合物减压浓缩。将残余物用10%盐酸溶液和乙酸乙酯稀释。水相用乙酸乙酯萃取三次。将合并的有机萃取物用饱和氯化钠水溶液洗涤一次,经无水硫酸镁干燥,并减压浓缩。残余物通过快速色谱(硅胶)纯化以提供期望的中间体。LCMS-ESI+(m/z):[M+H]+ C15H13Cl2FNO3计算值:344.02;实测值:344.03.
步骤4:(5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲醇的制备
使5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-甲酸乙酯溶液(15g,44mmol)吸收在2-甲基四氢呋喃(220mL)中,并在磁力搅拌下在约-12℃至-10℃湿冰/丙酮浴中冷却。滴加氢化铝锂溶液(2.0M于四氢呋喃中,53mmol)。在浴中搅拌30分钟之后,将在冰水浴中冷却的混合物相继用水(2.0mL,极小心滴加)、15%氢氧化钠水溶液(2.0mL)和水(6.0mL)淬灭。允许悬浮液在室温下搅拌15分钟,然后添加无水硫酸镁,随后再搅拌一小时。过滤浆液;将滤饼用乙酸乙酯洗涤,并将滤液在减压下浓缩至干。残余物通过快速色谱(硅胶)纯化以提供期望的中间体。LCMS-ESI+(m/z):[M+H]+ C13H11Cl2FNO2计算值:302.01;实测值:302.51.
步骤5:4-(氯甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑的制备
在室温下,将亚硫酰氯(6.6mL,90mmol)添加到(5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲醇(9.1g,30mmol)在二氯甲烷(150mL)中的混合物。然后将混合物在约45℃下加热45分钟。使混合物减压浓缩。将残余物吸收在二乙醚中并再浓缩。将此再重复两次以提供期望的中间体,其无需进一步纯化而继续进行。LCMS-ESI+(m/z):[M+H]+C13H10Cl3FNO计算值:319.97;实测值:320.50.
步骤6:4-((4-溴-3-氯苯氧基)甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑的制备
将粗制4-(氯甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑(4.2g,13mmol)的N,N-二甲基甲酰胺(50mL)溶液用4-溴-3-氯酚(2.7g,13mmol)、碘化钠(3.3g,22mmol)和无水碳酸钾(3.6g,26mmol)处理。将混合物在约60℃下加热25分钟。在冷却后,过滤混合物,并减压浓缩滤液。残余物通过快速色谱(硅胶)纯化以提供期望的中间体。LCMS-ESI+(m/z):[M+H]+ C19H13BrCl3FNO2计算值:489.91;实测值:490.10.
步骤7:3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯的制备
在氩气气氛下,经由注射器用异丙基氯化镁/氯化锂溶液(1.3M,12mL,15mmol)处理4-((4-溴-3-氯苯氧基)甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑(5.1g,10mmol)的四氢呋喃(27mL)溶液。将所得混合物搅拌一小时,然后引入额外体积的异丙基氯化镁/氯化锂溶液(1.3M,4.0mL,5.2mmol)。经过45分钟搅拌之后,添加另一份异丙基氯化镁/氯化锂溶液(1.3M,1.0mL,1.3mmol)。在搅拌一小时之后,将一份3-氧代氮杂环丁烷-1-甲酸叔丁酯(3.8g,22mmol)添加到在湿冰/丙酮浴中冷却的格氏混合物中。在搅拌30分钟之后,添加额外份的3-氧代氮杂环丁烷-1-甲酸叔丁酯(0.80g,4.7mmol)。将混合物用10%柠檬酸水溶液(50mL)淬灭。水相用乙酸乙酯萃取三次。将合并的有机物用水和饱和氯化钠水溶液各洗涤一次,经无水硫酸镁干燥,过滤,并减压浓缩。残余物通过快速色谱(硅胶)纯化以提供期望的中间体。LCMS-ESI+(m/z):[M+H]+ C27H27Cl3FN2O5计算值:584.86;实测值:483.19.
步骤8:3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)氮杂环丁烷-3-醇甲苯磺酸盐的制备
将对甲苯璜酸一水合物(3.5g,18mmol)添加到3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(5.3g,9.1mmol)和异丙醇(21mL)的混合物中。将混合物在约50℃下加热过夜,随后在磁力搅拌下在湿冰/丙酮浴中冷却。将所得悬浮液在约50℃下加热到几乎恢复均匀。在混合物冷却之后,添加己烷,并超声处理所得悬浮液,然后温热至约50℃。将固体通过抽滤收集,用己烷洗涤,并在约75℃真空烘箱中干燥,以提供期望中间体的甲苯磺酸盐。LCMS-ESI+(m/z):[M+H]+ C22H19Cl3FN2O3计算值:483.04;实测值:483.19.
步骤9:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸甲酯的制备
将3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)氮杂环丁烷-3-醇甲苯磺酸盐(0.47g,0.71mmol)、6-氯烟酸甲酯(0.15g,0.90mmol)和碳酸钾(0.49g,3.6mmol)在N,N-二甲基甲酰胺(4mL)中的混合物在80℃下加热过夜。使混合物在乙酸乙酯与水之间分配。水相用乙酸乙酯萃取三次。将合并的萃取物相继用水和饱和氯化钠水溶液洗涤,经无水硫酸镁干燥,过滤,并减压浓缩。残余物通过快速色谱(硅胶)纯化以提供期望的中间体。LCMS-ESI+(m/z):[M+H]+ C29H24Cl3FN3O5计算值:618.07;实测值:618.41.
步骤10:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸的制备
将6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)异烟酸甲酯(0.32g,0.51mmol)和氢氧化锂一水合物(43mg,1.0mmol)在四氢呋喃/水(1:1,10mL)中的混合物在室温下搅拌过夜。
将混合物减压浓缩以移除大部分挥发物。将所得的含水混合物进一步用水稀释,用乙酸处理,然后用10%盐酸水溶液处理。将所得的沉淀通过抽滤收集,用水洗涤,并在约50℃真空烘箱中干燥,以提供呈游离酸形式的期望材料。LCMS-ESI+(m/z):[M+H]+C28H22Cl3FN3O5计算值:604.05;实测值:604.41.
步骤11:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸Tris盐的制备
将6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸(0.29g,0.48mmol)作为悬浮液吸收在MeOH/水(95:5,2mL)中,用氨基丁三醇(58mg,0.48mmol)处理,在55℃下加热并浓缩,以提供氨基丁三醇盐形式的期望的酸。1H NMR(400MHz,甲醇-d4)δ8.65(dd,J=2.2,0.8Hz,1H),8.05(dd,J=8.7,2.2Hz,1H),7.38(d,J=8.3Hz,2H),7.35(d,J=8.7Hz,1H),6.87(d,J=2.6Hz,1H),6.78(dd,J=8.6,2.6Hz,1H),6.42(dd,J=8.8,0.8Hz,1H),4.92(s,2H),4.57(dd,J=9.3,1.1Hz,2H),4.29(dd,J=9.2,1.1Hz,2H),3.63(s,7H),2.32(tt,J=8.0,5.5Hz,1H),1.25-1.11(m,4H).
实施例2:比较例1的合成
6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)-5-氟烟酸
中间体A的合成:
在约-78℃和N2下,向(4-溴-3-氯苯氧基)(叔丁基)二甲基硅烷(60g,187mmol)的THF(500mL)溶液中滴加n-BuLi(2.5M,75mL)。将反应在约-78℃下搅拌1小时。接着,在-78℃下,将3-氧代氮杂环丁烷-1-甲酸叔丁酯(27g,155mmol)的THF(500mL)溶液滴加到混合物中。然后将反应在约20℃下搅拌3小时。将反应混合物倾注到H2O(1L)中并用EtOAc(2L)萃取三次。将合并的有机层用水(1L)洗涤,经Na2SO4干燥,过滤并真空浓缩。采用10:1石油醚:EtOAc洗脱,通过硅胶色谱法纯化粗产物,以给出3-(4-((叔丁基二甲基甲硅烷基)氧基)-2-氯苯基)氮杂环丁烷-3-醇(中间体A)。
步骤1:3-(2-氯-4-羟基苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯
在约-10℃下,向3-(4-((叔丁基二甲基甲硅烷基)氧基)-2-氯苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(中间体A,1.27g,3.07mmol)的THF(50.0mL)溶液中滴加含1M TBAF的THF(3.68mL,3.68mmol)。将反应搅拌2小时并浓缩,以得到3-(2-氯-4-羟基苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯,其无需进一步纯化即可使用。
步骤2:4-(氯甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑
将(5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲醇(45mg,2.80mmol)的DCM(28.0mL)溶液冷却至约0℃。添加亚硫酰氯(1.02mL,14.0mmol)并将溶液在约45℃下加热1小时。使反应浓缩至干,并且无需纯化即用于下一步骤。
步骤3:3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯
将3-(2-氯-4-羟基苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(922mg,3.07mmol)的DMF(28.0mL)溶液添加到粗制4-(氯甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑中,然后添加碳酸钾(773mg,5.60mmol)。将混合物在约60℃下加热8小时。将反应浓缩,用水稀释并用EtOAc(3×)萃取。将合并的有机层用水、盐水洗涤,经MgSO4干燥,过滤并浓缩。通过硅胶色谱(DCM/Et2O/MeOH)纯化粗产物,以得到3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯。LCMS-ESI+(m/z):[(M+H)-BOC]+计算值483.04;实测值483.04.
步骤4:3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)氮杂环丁烷-3-醇
向3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(1.52g,2.60mmol)的DCM(130mL)溶液中添加含4N HCl的1,4-二噁烷(26.0mL,104mmol)。将该溶液在室温下搅拌2.5小时并浓缩至干,以得到盐酸盐形式的3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)氮杂环丁烷-3-醇,其无需进一步纯化即可使用。LCMS-ESI+(m/z):[M+H]+计算值483.04;实测值483.03.
步骤5:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)-5-氟烟酸甲酯
将甲基6-氯-5-氟吡啶(235mg,1.24mmol)、盐酸盐形式的3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)氮杂环丁烷-3-醇(495mg,0.952mmol)和碳酸钾(1.05g,7.61mmol)在DMF(30.0mL)中的混合物在约60℃下加热1小时。将反应浓缩,用水稀释并用EtOAc(3×)萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过硅胶色谱(DCM/Et2O/MeOH)纯化粗制混合物,以得到6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)-5-氟烟酸甲酯。LCMS-ESI+(m/z):[M+H]+计算值636.07;实测值635.96.
步骤6:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)-5-氟烟酸(比较例1)
向6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)-5-氟烟酸甲酯(364mg,0.571mmol)的THF/水(1:1,20.0mL)溶液中添加氢氧化锂一水合物(41.3mg,0.984mmol)。将溶液搅拌18小时,浓缩以移除THF,并用水(10.0mL)稀释。使用1N HCl将pH调节至3。将固体过滤,用水洗涤,溶解于ACN/水中并冻干,以得到6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)-5-氟烟酸(比较例1)。LCMS-ESI+(m/z):[M+H]+计算值622.05;实测值622.12.1H NMR(400MHz,DMSO-d6)δ12.84(bs,1H),8.44(t,J=1.7Hz,1H),7.79-7.63(m,3H),7.39(d,J=8.7Hz,1H),6.95(d,J=2.5Hz,1H),6.77(dd,J=8.6,2.6Hz,1H),6.28(s,1H),4.93(s,2H),4.70(d,J=9.8Hz,2H),4.34(d,J=9.5Hz,2H),2.50-2.43(m,1H),1.22-1.08(m,4H).
实施例3:FRET活性测定
如下执行配体介导的辅因子肽相互作用的测定,以定量配体与核受体FXR的结合。
人FXRα配体结合结构域(LBD)的制备:人FXRαLBD在大肠杆菌(E.coli)菌株BL21(DE3)中表达为N-末端GST标记的融合蛋白。将编码FXR配体结合结构域的DNA克隆到载体pDEST15(Invitrogen)中。表达受IPTG诱导型T7启动子的控制。配体结合结构域的氨基酸边界是数据库条目NM_005123(RefSeq)的氨基酸187-472。FXR-LBD的表达和纯化:将转化的大肠杆菌菌株的过夜预培养物在LB-氨苄青霉素培养基中以1:20稀释并在30℃下生长至OD600=0.4-0.6的光密度。然后通过添加0.5mM IPTG诱导基因表达。将细胞在30℃和180rpm下再孵育6h。通过离心(7000×g,7分钟,室温)收集细胞。对于每升原始细胞培养物,使细胞重悬于10mL裂解缓冲液(50mM葡萄糖,50mM Tris pH 7.9,1mM EDTA和4mg/mL溶菌酶)中,并在冰上放置30min。然后使细胞经受超声处理,并经由离心(22000×g,30min,4℃)移除细胞碎片。每10mL上清液添加0.5mL预洗谷胱甘肽4B琼脂糖浆液(Qiagen),并使悬浮液在4℃下保持缓慢旋转1小时。通过离心(2000×g,15秒,4℃)沉淀谷胱甘肽4B琼脂糖珠并在洗涤缓冲液(25mM Tris,50mM KCl,4mM MgCl2和1M NaCl)中洗涤两次。将沉淀重悬于3mL洗脱缓冲液/升原始培养物(洗脱缓冲液:20mM Tris,60mM KCl,5mM MgCl2和80mM谷胱甘肽,在作为粉末使用之前立即加入)。使悬浮液在4℃下保持旋转15min,沉淀珠粒并且用比第一次洗脱缓冲液减半的体积再次洗脱。合并洗脱液,并在含有60mM KCl、5mM MgCl2以及1mM二硫苏糖醇和10%(v/v)甘油的20mM Hepes缓冲液(pH 7.5)中透析过夜。通过SDS-Page分析蛋白质。
该方法测量了推定的配体调节纯化细菌表达的FXR配体结合结构域(LBD)与基于SRC-1的残基676-700(LCD2,676-700)的合成生物素化肽之间相互作用的能力。使用的肽序列为B-CPSSHSSLTERHKILHRLLQEGSPS-COOH(SEQ ID NO:1),其中N-末端是生物素化的(B)。FXR的配体结合结构域(LBD)利用载体pDEST15在BL-21细胞中表达为与GST的融合蛋白。通过超声处理裂解细胞,并根据制造商的说明书用谷胱甘肽琼脂糖(Pharmacia)纯化融合蛋白。为了筛选对FXR-肽相互作用有影响的化合物,应用Perkin Elmer LANCE技术。该方法依赖于从供体到连接至所关注结合伴侣的受体荧光团的结合依赖性能量转移。为了便于处理并减少来自化合物荧光的背景,LANCE技术利用通用荧光团标记和时间分辨检测。在含有20-60ng/孔的融合至GST的重组表达的FXR-LBD、200-600nM N-末端生物素化肽(代表SRC1氨基酸676-700)、200ng/孔链霉亲和素-xlAPC缀合物(Prozyme)和6-10ng/孔Eu W1024-抗GST(Perkin Elmer)的基于Tris的缓冲液(20mM Tris-HCl pH 7.5;60mM KCl,5mM MgCl2;35ng/μL BSA)中,在384孔板中以25μL的最终体积进行测定。样品的DMSO含量保持在1%。在生成测定混合物并稀释潜在的FXR调节配体之后,使测定在暗处于室温在FIA-板黑色384孔(Greiner)中平衡1小时。LANCE信号通过Perkin Elmer VICTOR2VTM多标计数仪进行检测。通过绘制在665nm和615nm处的发射光之间的比率来使结果可视化。在没有添加配体的情况下,观察到基础水平的FXR-肽形成。促进复合物形成的配体诱导时间分辨荧光信号的浓度依赖性增加。预期与单体FXR和FXR-肽复合物两者同样良好结合的化合物不产生信号变化,而预期优先与单体受体结合的配体诱导了所观察信号的浓度依赖性降低。
为了评估化合物的激动潜能,测定了实施例化合物的EC50值,并在下表1中列出(FRET EC50)。如表1中所示,将实施例1的化合物与比较例1和比较例2(美国专利申请公开No.2017/0355685的实施例3)一起评估,它们的化学结构示出于下表中。
实施例4:哺乳动物单杂交(Mammalian one hybrid,M1H)测定
如下执行配体介导的Gal4启动子驱动的反式激活的测定,以定量配体结合介导的FXR的活化。
将编码FXR配体结合结构域的cDNA部分在CMV启动子控制下作为与酵母GAL4DNA结合结构域的融合物克隆到载体pCMV-BD(Stratagene)中。配体结合结构域的氨基酸边界是数据库条目NM_005123(RefSeq)的氨基酸187-472。将质粒pFR-Luc(Stratagene)用作报告质粒,其含有具有酵母GAL4结合位点的五个串联重复序列的合成启动子,从而驱动作为报告基因的萤火虫(Photinus pyralis,北美萤火虫)荧光素酶基因的表达。为了改善实验的准确性,将质粒pRL-CMV(Promega)共转染。pRL-CMV含有组成型CMV启动子,从而控制海肾荧光素酶(Renilla reniformis luciferase)的表达。在约37℃下5%CO2中,在具有L-谷氨酰胺和补充有10%胎牛血清、0.1mM非必需氨基酸、1mM丙酮酸钠和每mL100单位青霉素/链霉亲和素的Earle's BSS的MEM中生长的HEK293细胞(获自DSMZ,Braunschweig,Germany)中进行所有的Gal4报告基因测定。培养基和补充剂获自Invitrogen。对于该测定,在每孔100μL不含酚红和L-谷氨酰胺而含有补充有10%活性炭/葡聚糖处理的FBS(HyClone,SouthLogan,Utah)、0.1mM非必需氨基酸、2mM谷氨酰胺、1mM丙酮酸钠和每mL100单位青霉素/链霉亲和素的Earle's BSS的MEM中,将5×105个细胞铺板到96孔板的每个孔中,在约37℃下5%CO2中孵育。第二天,细胞为>90%融合度。移除培养基并将细胞用20μL/孔的基于OptiMEM-聚乙烯-亚胺的转染试剂(OptiMEM,Invitrogen;Polyethyleneimine,Aldrich目录号40,827-7)瞬时转染,包括上述三种质粒。在添加转染混合物后2-4小时,添加具有与用于铺板细胞相同的组成的MEM。然后添加在MEM中预稀释的化合物储备液(最终媒介物浓度不超过0.1%)。将细胞再孵育16小时,然后使用Dual-Light荧光素酶测定系统在相同的细胞提取物中相继测量萤火虫和海肾荧光素酶活性(Dyer等人,Anal.Biochem.2000,282,158-161)。所有实验一式三份进行。
为了评估实施例化合物的FXR激动效力,在M1H测定中测定效力并在下表1中列出(M1H EC50)。
表1
实施例5:食蟹猴(Cynomolgus Monkey)体内药效学评估
如下测定实施例1的式(I)、比较例1和比较例2的体内药效学。
供试品和制剂
口服混悬液剂量
在pH 2的1%十二烷基硫酸钠(SLS)、1%乙醇和98%水的水性悬浮液中,以1mg/mL的浓度配制式(I)(实施例1)的口服溶液剂量。在1%羟丙基甲基纤维素(HPMC)、0.5%Tween80和98.5%水中,以2.5mg/mL的浓度配制比较例1和比较例2的口服混悬液剂量。
静脉剂量
在包含5%DMSO、15%NMP、60%PEG 300和具有1.1当量NaOH的水的媒介物中,以0.5mg/mL的浓度配制式(I)的化合物(实施例1)、比较例1和比较例2的静脉剂量。
动物
每个给药组由三至六只雄性食蟹猴组成。在给药时,动物体重在2.4至4.4kg之间。
给药
口服供试品经由口服灌胃以2mL/kg或经由鼻饲插管以5mL/kg给药于食蟹猴,剂量为5mg/kg。将静脉内供试品以大约2mL/kg的剂量经由隐静脉或头静脉中的留置导管以大约30分钟输注给药,剂量为1mg/kg。
样品采集
在给药后的指定时间点从各动物采集静脉血样。采集血样,并转移至含有EDTA钾(K2)抗凝血剂的管中。
血浆中FGF19浓度的测定
使用来自BioVendor的FGF19 ELISA测定试剂盒(产品编号RD191107200R)来测定所采集血样中的FGF19浓度。
血浆中药物浓度的测定
对于在API 5000 LC/MS/MS系统上的分析,用200μL含有内标物的乙腈(ACN)处理50μL等分试样的各血浆样本。将以上溶液以5000RPM离心10分钟,并且将50μL的上清液转移至干净的96孔板中,随后添加200μL的水。将10μL的等分试样注射到API 5000 LC/MS/MS系统中。
对于在Applied Biosystems API 5500 LC/MS/MS系统上的分析,用120μL含有内标物的乙腈(ACN)处理20μL等分试样的各血浆样本。将以上溶液离心,并且将100μL的上清液转移至干净的96孔板中,随后添加100μL的水。将7-10μL的等分试样注射到API 5500 LC/MS/MS系统中。
HPLC条件
使用来自Agilent Technologies(Part#735700-902)的Zorbax Extend C18 HPLC柱(50×2.1mm,3.5μm)(比较例1和比较例2)或Waters BEH C18柱(50×2.1mm,1.7μm)(实施例1)。对于Zorbax Extend C18 HPLC柱,流动相A含有经甲酸调节至pH 3.0的1%乙腈的10mM甲酸铵水溶液,并且流动相B含有经甲酸调节至pH 4.6的乙腈中的10%10mM甲酸铵。对于Waters BEH C18柱,流动相A含有95%水、5%乙腈和0.1%甲酸,并且流动相B含有50%甲醇、50%乙腈和0.1%甲酸。具有两个相同Agilent 1200系列二元泵(P/N G1312A Bin泵)的Thermo Aria多路复用器用于洗脱和分离。所用的洗脱程序对于Zorbax Extend C18 HPLC列于下表2中,且对于Waters BEH C18柱列于表3中。
表2.
表3.
将来自AB Sciex,Foster City,CA的API 5000三重四极质谱仪以多反应监测模式使用来定量化合物。所用的质谱参数列于下表4中。
表4.
食蟹猴中的口服与IV给药
在远端小肠以及影响全身的器官诸如肝脏中,法尼醇X受体的活化直接导致FGF19的表达和分泌。在口服和静脉内给药实施例1、比较例1或比较例2的剂量的给药之后,将血浆FGF19水平评价为雄性食蟹猴中FXR活化的药效学指标。口服给药(PO)与静脉给药(IV)后FGF19水平之间的差异被用于比较所给药各化合物的肠FXR激动作用(经由PO数据分析)和全身FXR激动作用(经由IV数据分析)的程度。在24小时时段内的不同时间点测量药物和FGF19的血浆水平以生成药代动力学和药效学曲线。
图1示出了在给予实施例1的化合物之后,食蟹猴中的FGF19血浆浓度随时间推移的图表。
图2示出了在给予比较例1的化合物之后,食蟹猴中的FGF19血浆浓度随时间推移的图表。
图3示出了在给予比较例2的化合物之后,食蟹猴中的FGF19血浆浓度随时间推移的图表。
药代动力学数据汇总于下表5中。
表5.
如结果所反映,与给药前的FGF19基线水平相比,实施例1、比较例1和比较例2的口服给药都导致了给药间隔内血浆FGF19的增加。这指示肠FXR受体的激动作用。实施例1的IV给药未导致FGF19增加,这指示缺乏全身FXR激动作用。相比之下,与给药前的FGF19基线水平相比,比较例1和2的IV给药增加了FGF19水平,这指示发生全身FXR激动作用。
这些数据表明实施例1和比较例2的回肠暴露导致了肠上皮中的FXR活化。该数据进一步表明,相对于实施例1而言,通过IV给药,比较例1和比较例2的全身暴露导致了较大的全身性非肠FXR活化。
实施例6:UGT1A1抑制
测试式(I)的化合物(实施例1)对UGT1A1的抑制,并与比较例1进行比较。为了执行该测定,将样品化合物与人UGT1A1表达的SupersomesTM(0.25mg/mL)、丙甲菌素(25μg/mg)和UDPGA(5mM)在探针底物雌二醇(10μM)的存在下在37℃下一起孵育30分钟。将选择性UGT1A1抑制剂阿扎那韦作为阳性对照与测试化合物一起进行筛选。反应通过将等分试样在两体积的甲醇中淬灭来终止。将样品在4℃下以2500rpm离心30分钟,并将上清液的等分试样用含甲酸的去离子水(最终甲酸浓度0.1%)和内标物稀释。Cyprotex通用LC-MS/MS条件用于监测雌二醇3-葡糖苷酸的形成。与媒介物对照相比,代谢物形成的减少用于计算IC50值。
数据示出实施例1的化合物显示了所比较化合物之间的最有效UGT1A1抑制。实施例1具有0.44μM的IC50。
实施例7:CYP2C8、CYP3A4和CYP2B6抑制
评估式(I)的化合物(实施例1)对CYP2C8、CYP3A4和CYP2B6的抑制,并与比较例1进行比较。
CYP2C8
将六种样品化合物浓度(0.1、0.25、1、2.5、10、25μM于DMSO中;最终DMSO浓度0.25%)与人肝微粒体(1mg/mL)和NADPH(1mM)在探针底物甲苯磺丁脲(120μM)的存在下在37℃下一起孵育60分钟。将选择性CYP2C9抑制剂磺胺苯吡唑作为阳性对照与测试化合物一起进行筛选。
CYP3A4
将六种样品化合物浓度(0.1、0.25、1、2.5、10、25μM于DMSO中;最终DMSO浓度0.26%)与人肝微粒体(0.1mg/mL)和NADPH(1mM)在探针底物咪达唑仑(2.5μM)的存在下在37℃下一起孵育5分钟。将选择性CYP3A4抑制剂酮康唑作为阳性对照与测试化合物一起进行筛选。或者,将六种样品化合物浓度(0.1、0.25、1、2.5、10、25μM于DMSO中;最终DMSO浓度0.275%)与人肝微粒体(0.5mg/mL)和NADPH(1mM)在探针底物睾酮(50μM)的存在下在37℃下一起孵育5分钟。将选择性CYP3A4抑制剂酮康唑作为阳性对照与测试化合物一起进行筛选。
CYP2B6
将六种测试化合物浓度(0.1、0.25、1、2.5、10、25μM于DMSO中;最终DMSO浓度0.3%)与人肝微粒体(0.1mg/mL)和NADPH(1mM)在探针底物安非他酮(110μM)的存在下在37℃下一起孵育5分钟。将选择性CYP2B6抑制剂噻氯匹定作为阳性对照与测试化合物一起进行筛选。
对于CYP2B6、CYP2C8和CYP3A4孵育中的每者,通过添加甲醇来终止反应。然后离心样品并通过LC-MS/MS分析。在分析之前,将包含内标物的含甲酸去离子水(最终浓度0.1%)添加到最终样品中。与媒介物对照相比,代谢物形成的减少用于计算IC50。
数据示出实施例I的化合物不抑制CYP2B6,而比较例1抑制CYP2B6。
实施例8:式(I)甲磺酸盐形式I的制备
式(I)甲磺酸盐形式I通过将6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸(0.050g,0.0827mmol)与甲磺酸(8uL,0.123mmol)在具有异丙醇(1mL)的小瓶中混合来制备,得到浆液。将浆液加热至约50℃保持约30分钟,然后缓慢冷却至室温并使浆液保持约16小时。然后过滤浆液,并且分离的固体通过图4所示的XRPD来表征。然后将固体在约50℃的真空烘箱中干燥,并且以得到相同图谱的XRPD来表征。式(I)甲磺酸盐形式I XRPD峰包括以下位置处的峰:3.2、6.4、9.6、12.8、19.3、22.1、22.6、25.8、29.1°2θ。所获得的XRPD峰列于下表1中。
表1.
执行DSC和TGA分析。式(I)甲磺酸盐形式I的DSC热谱图示出约221℃处的吸热事件,随后是放热事件,如图5所示。式(I)甲磺酸盐形式I的TGA热谱图示出在加热至约200℃时约0.6%的重量损失,如图6所示。
式(I)甲磺酸盐形式I也通过如下方式形成:将6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸(3.00g,4.96mmol)作为悬浮液吸收在MeCN/水(1.5:1v/v,15mL)中,并且用氢氧化钠水溶液(30重量%,0.56mL,5.95mmol)处理。然后,将所得溶液在数小时内装入第二容器中,该第二容器包含预热至约50℃的甲磺酸(1.0mL,15.9mmol)在MeCN(15mL)中的搅拌溶液。将所得浆液在约50℃下老化数小时,然后冷却至约20℃。将浆液在真空下过滤,并将所得固体在达约60℃的升高温度下真空干燥,以提供式(I)甲磺酸盐形式I。
式(I)甲磺酸盐形式I的形成也通过将6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)苯基)-3-羟基氮杂环丁烷-1-基)烟酸(0.5g,0.83mmol)作为悬浮液吸收在丙酮/水(97:3v/v,10mL)中,并加热至约55℃。向浆液中加入甲磺酸(60μL,0.91mmol),并将混合物在约55℃下老化数小时。将浆液冷却至约20℃并真空过滤。将所得固体用丙酮洗涤并在达约60℃的升高温度下真空干燥,以提供式(I)甲磺酸盐形式I。
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序列表
<110> 吉利德科学公司
<120> FXR(NR1H4)调节化合物
<130> 1274.PF
<150>
<151> 2018-12-18
<160> 1
<170> PatentIn版本3.5
<210> 1
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 1
Cys Pro Ser Ser His Ser Ser Leu Thr Glu Arg His Lys Ile Leu His
1 5 10 15
Arg Leu Leu Gln Glu Gly Ser Pro Ser
20 25
Claims (49)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其用于治疗法尼醇X受体(FXR)介导的病症。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其中所述FXR介导的病症是肝脏疾病。
4.根据权利要求2至3中任一项所述的化合物或其药学上可接受的盐,其中所述FXR介导的病症是非酒精性脂肪性肝炎(NASH)。
5.根据权利要求2至3中任一项所述的化合物或其药学上可接受的盐,其中所述FXR介导的病症是原发性硬化性胆管炎(PSC)。
6.根据权利要求2至3中任一项所述的化合物或其药学上可接受的盐,其中所述FXR介导的病症是原发性胆汁性胆管炎(PBC)。
7.根据权利要求2至3中任一项所述的化合物或其药学上可接受的盐,其中所述FXR介导的病症是肝纤维化。
9.根据权利要求8所述的药物组合物,其还包含药学上可接受的载体。
10.一种治疗患有法尼醇X受体(FXR)介导的病症的患者的方法,其包括向有此需要的患者给药根据权利要求1所述的化合物或药学上可接受的盐或者根据权利要求8所述的药物组合物。
11.根据权利要求10所述的方法,其中所述FXR介导的病症选自:
慢性肝内或肝外胆汁淤积性病症;
肝纤维化;
慢性或阻塞性肝脏炎性障碍;
肝硬化;
肝脏脂肪变性或相关综合征;
与酒精诱发性肝硬化或与病毒传播形式的肝炎相关的胆汁淤积或纤维化效应;
急性或慢性肝衰竭;
大型肝切除术后肝缺血;
化疗相关脂肪性肝炎(CASH);
原发性胆汁性肝硬化(PBC);
原发性硬化性胆管炎(PSC);
胃肠道或肝脏的赘生物疾病;以及
炎性肠病(IBD);
血脂障碍或脂蛋白障碍;
I型糖尿病;
II型糖尿病;
选自糖尿病性肾病、糖尿病性神经病变、糖尿病性视网膜病的I型和II型糖尿病的临床并发症,以及其他观察到的临床显现出长期糖尿病的效应;
非酒精性脂肪性肝病(NAFLD);
非酒精性脂肪性肝炎(NASH);
肥胖症;
选自血脂异常、糖尿病和异常高的体重指数的组合病症的代谢综合征;
急性心肌梗死;
急性中风;和
作为慢性阻塞性动脉粥样硬化的终点出现的血栓形成;
非恶性过度增殖性障碍;
选自肝细胞癌、结肠腺瘤和息肉病的恶性过度增殖性障碍;
结肠腺癌;
乳腺癌;
胰腺腺癌;以及
巴雷特食管。
12.根据权利要求1所述的化合物或其药学上可接受的盐用于制备治疗法尼醇X受体(FXR)介导的病症的药物的用途。
15.根据权利要求13至14中任一项所述的方法,其中FXR激动剂和所述ASK1抑制剂分开给药。
16.根据权利要求13至15中任一项所述的方法,其中所述肝脏疾病是非酒精性脂肪性肝炎(NASH)。
17.根据权利要求13至15中任一项所述的方法,其中所述肝脏疾病是原发性硬化性胆管炎(PSC)。
18.根据权利要求13至15中任一项所述的方法,其中所述肝脏疾病是原发性胆汁性肝硬化(PBC)。
21.根据权利要求19至20中任一项所述的药物组合物,其还包含药学上可接受的载体。
24.根据权利要求22至23中任一项所述的方法,其中所述ACC抑制剂和所述FXR激动剂分开给药。
25.根据权利要求22至24中任一项所述的方法,其中所述肝脏疾病是非酒精性脂肪性肝炎(NASH)。
26.根据权利要求22至24中任一项所述的方法,其中所述肝脏疾病是原发性硬化性胆管炎(PSC)。
27.根据权利要求22至24中任一项所述的方法,其中所述肝脏疾病是原发性胆汁性肝硬化(PBC)。
30.根据权利要求28至29中任一项所述的药物组合物,其还包含药学上可接受的载体。
33.根据权利要求31至32中任一项所述的方法,其中所述THRβ激动剂和所述FXR激动剂分开给药。
34.根据权利要求31至33中任一项所述的方法,其中所述肝脏疾病是非酒精性脂肪性肝炎(NASH)。
35.根据权利要求31至33中任一项所述的方法,其中所述肝脏疾病是原发性硬化性胆管炎(PSC)。
36.根据权利要求31至33中任一项所述的方法,其中所述肝脏疾病是原发性胆汁性肝硬化(PBC)。
39.根据权利要求37至38中任一项所述的药物组合物,其还包含药学上可接受的载体。
42.根据权利要求41所述的结晶形式,其中所述结晶形式为形式I。
43.根据权利要求42所述的结晶形式,其特征在于X射线衍射图具有9.6°、19.3°和22.6°2θ(±0.2°2θ)处的2θ-反射。
44.根据权利要求42-43中任一项所述的结晶形式,其特征在于X射线衍射图还包括3.2°、6.4°和12.8°2θ(±0.2°2θ)处的2θ-反射。
45.根据权利要求42-44中任一项所述的结晶形式,其特征在于X射线衍射图还包括22.1°、25.8°和29.1°2θ(±0.2°2θ)处的2θ-反射。
46.根据权利要求42-45中任一项所述的结晶形式,其具有基本上如图4所示的X射线衍射图。
47.根据权利要求42-46中任一项所述的结晶形式,其具有包括始于约221℃的吸热的差示扫描量热法热谱图。
48.根据权利要求42-47中任一项所述的结晶形式,其具有基本上如图5所示的差示扫描量热法热谱图。
49.根据权利要求42-48中任一项所述的结晶形式,其具有基本上如图6所示的热重分析。
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