CN109563087A - sGC刺激剂的固体形式 - Google Patents
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Abstract
本公开涉及可溶性鸟苷酸环化酶(sGC)刺激剂,化合物I的结晶固体形式。本文还提供了制备这些固体形式的方法。本发明还涉及包含这些固体形式的药物制剂和剂型,以及它们单独或与一种或多种另外的药剂组合用于治疗和/或预防各种疾病或病症的用途。这些疾病或病症是可受益于sGC刺激或一氧化氮(NO)和/或环鸟苷酸(cGMP)浓度增加的疾病或病症。
Description
技术领域
本公开涉及可溶性鸟苷酸环化酶(sGC)的刺激物的固体形式。本发明还提供了制备这些固体形式的方法。本发明还涉及包含这些固体形式的药物制剂和剂型,以及它们单独或与一种或多种另外的药剂组合用于治疗和/或预防各种疾病或病症的用途。这些疾病或病症是可受益于sGC刺激或一氧化氮(NO)和/或环鸟苷酸(cGMP)浓度增加的疾病或病症。
背景技术
sGC是体内NO的主要受体。sGC可以通过NO依赖性和NO非依赖性机制激活。响应于这种活化,sGC将鸟苷-5'-三磷酸(GTP)转化为第二信使cGMP。反过来,cGMP水平的增加调节下游效应物的活性,包括蛋白激酶、磷酸二酯酶(PDEs)和离子通道。
在体内,NO由精氨酸和氧通过各种一氧化氮合酶(NOS)和连续还原无机硝酸盐合成。已经鉴定了三种不同的NOS亚型:在活化的巨噬细胞中发现的诱导型NOS(iNOS或NOSII);组成型神经元NOS(nNOS或NOSI),参与神经传递和长时程增强;和组成型内皮NOS(eNOS或NOSIII),调节平滑肌松弛和血压。实验和临床证据表明NO的浓度或生物利用度降低和/或对内源性NO的反应性有助于疾病的发展。
当与NO非依赖性、血红素非依赖性sGC激活剂相比时,NO非依赖性血红素依赖性sGC刺激剂显示出几种重要的分化特征。这些包括对减少的假体血红素部分的活性的存在的重要依赖性,当与NO组合时强烈的协同酶活化,并且不依赖于NO通过直接刺激sGC刺激cGMP的合成。苄基吲唑化合物YC-1是第一个待鉴定的sGC刺激剂。此后,开发了对sGC具有改善的效力和特异性的额外sGC刺激剂。
以NO非依赖性方式刺激sGC的化合物与靶向异常NO途径的其他当前替代疗法相比具有相当大的优势。需要开发新的,充分表征的sGC刺激剂。化合物I是sGC刺激剂,其已经证明在临床前模型中治疗许多NO相关病症的功效。化合物I先前在WO2014144100实施例1中描述为浅橙色固体。化合物I可以以各种结晶形式存在,也可以形成几种药学上可接受的盐。
与其作为药物的功效相关的固体的性质可取决于固体的形式。例如,在药物中,固体形式的变化可导致诸如以下性质的差异:溶解度和溶解速率,表面性质(例如润湿性),粉末性质(流动、内聚力、堆积密度、混合行为、可压缩性、静电等),片剂性质(硬度、均匀性、脆性、崩解、对热和湿度的稳定性等),口服吸收,生物利用度,储存性能(结块、吸湿性),毒理学结果和临床试验结果。
多晶型的表征可用于防止在临床试验和/或药物商业化期间出现某些问题,例如,以避免药物和产品的不一致(例如,批次之间的不一致),水合物的水合或脱水,化学降解,药品中的非晶化或多晶型转化。如果多晶型物与该化合物的另一种多晶型物或其无定形形式相比改善了溶解度和/或生物利用度,则该多晶型物也可能是优选的。它也可能是优选的,因为它赋予增加的物理或化学稳定性,它提供更高的熔点(导致改善的机械性能),其具有更可接受的味道或气味,或更中性的pH,等等。
发明内容
在一个方面,本发明涉及化合物I的结晶固体形式,如下所示:
出于本公开的目的,除非另有明确说明,否则“化合物I”是指游离碱或上述结构的盐酸盐。化合物I作为其结晶游离碱具有高度多晶型,并且已知具有七种结晶形式(形式A、B、D、E、F、G和H)以及多种溶剂化物。化合物I先前在WO2014144100实施例1中描述为浅橙色固体。
在一个实施方案中,本文公开的化合物I的结晶固体形式是游离碱的多晶型物。在另一个实施方案中,化合物I的结晶固体形式是盐酸盐。在一个实施方案中,化合物I的多晶型物是结晶游离碱形式。在另一个实施方案中,它们是溶剂化物。
另一方面,本文还提供了制备上述结晶游离形式和化合物I的盐的方法。
另一方面,本发明涉及药物组合物,其包含一种或多种本文公开的化合物I的多晶型物,或化合物I的盐酸盐,和至少一种药学上可接受的赋形剂或载体。在另一个实施方案中,本发明涉及包含所述药物组合物的药物剂型。
在另一个实施方案中,本发明涉及治疗有此需要的受试者的疾病、健康状况或病症的方法,包括向受试者单独或联合治疗施用治疗有效量的本文公开的化合物I的多晶型物、或多晶型物的混合物或其盐酸盐;其中所述疾病或病症是可受益于sGC刺激或受益于NO和/或cGMP浓度增加的疾病或病症。
附图说明
图1:显示了化合物I的无定形形式的XRPD图
图2:显示了在5至45的2θ刻度范围内的形式A、形式B、形式D和形式E的叠加的XRPD图(从下到上,按比例缩放,具有偏移)。
图3A:显示了在5至45的2θ刻度范围内的形式A的XRPD图。
图3B:显示了在储存14个月之前和之后的形式A的XRPD图。
图3C:显示了在3至40的2θ刻度范围内的形式A的XRPD图。
图4A:显示了在5至45的2θ刻度范围内的形式B的XRPD图。
图4B:显示了在储存14个月之前和之后形式B的XRPD图。
图4C:显示了在3至40的2θ刻度范围内的形式B的XRPD图。
图5A:显示了在5至45的2θ刻度范围内的形式D的XRPD图。
图5B:显示了在储存14个月之前和之后的形式D的XRPD图。
图5C:显示了在5至45的2θ刻度范围内的形式D的XRPD图。
图6:显示了在5至45的2θ刻度范围内的形式E的XRPD图。
图7:显示了在3至40的2θ刻度范围内的形式F的XRPD图。
图8:显示了在3至40的2θ刻度范围内的形式G的XRPD图。
图9:显示了在3至40的2θ刻度范围内的形式H的XRPD图。
图10:显示了在1800至200cm-1的波数范围内的形式A、形式B、形式D和形式E的叠加的FT-拉曼光谱(从底部到顶部,按比例缩放,具有偏移)。
图11:显示了在0至40的2θ刻度范围内的化合物I的HCl盐的XRPD图。
图12:显示了粗化合物I、多晶型形式A、形式B、形式D、形式E、形式F、形式G和形式H之间的关系。
附图是以举例的方式提供的,并不意图限制本发明的范围。
发明详述
现在将详细参考本发明的某些实施方案,其实例在所附结构和分子式中说明。虽然将结合列举的实施例描述本发明,但是应该理解,它们并不旨在将本发明限制于那些实施例。相反,本发明旨在覆盖可以包括在由权利要求限定的本发明的范围内的所有替代、修改和等同物。本发明不限于本文所述的方法和材料,而是包括与本文所述的那些可用于本发明实践的方法和材料相似或等同的任何方法和材料。如果所结合的一篇或多篇参考文献、专利或类似材料与本申请不同或相矛盾,包括但不限于定义的术语、术语用法、所描述的技术等,以本申请为准。
定义及一般术语
出于本公开的目的,化学元素根据CAS版本元素周期表和Handbook of Chemistryand Physics(第75版)进行鉴定。另外,有机化学的一般原理描述于《有机化学》,ThomasSorrell,University Science Books,Sausalito:1999,和《March's Advanced OrganicChemistry》,5th Ed.,Smith,MB和March,J.,eds.John Wiley&Sons,New York:2001,其全部内容通过引用并入本文。
本公开还包括同位素标记的化合物,其与本文所述的那些相同,但是因为一个或多个原子被原子质量或质量数不同于通常在自然界中发现的原子质量或质量数的原子取代。所指出的任何特定原子或元素的所有同位素都涵盖在本发明化合物及其用途的范围内。可掺入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,例如分别2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、12I和125I。某些同位素标记的本发明化合物(例如,用3H和14C标记的那些)可用于化合物和/或底物组织分布测定。氚化(即3H)和碳-14(即14C)同位素因其易于制备和可检测性而有用。此外,用较重的同位素例如氘(即2H)取代可以提供某些治疗优势,这是由于更高的代谢稳定性(例如,体内半衰期延长或剂量需求减少),因此在某些情况下可能是优选的。正电子发射同位素如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以检查底物受体占有率。同位素标记的本发明化合物通常可以通过用同位素标记的试剂取代非同位素标记的试剂,按照与下文方案和/或实施例中公开的那些类似的方法制备。
如本文所用,化合物I的“固体形式”的特征在于或指所述化合物的特定固相晶格结构(以晶胞尺度)。
化合物如化合物I可以其“纯净形式”或“游离碱形式”存在,游离碱形式可以是结晶或无定形的。化合物的游离碱形式仅由所述化合物的分子形成。
如本文所用,“无定形”或“无定形形式”是没有长程分子有序的固体形式,因此缺乏独特的X射线粉末衍射图(XRPD)。
“晶体”或“晶体形式”是均质固体,其由原子、离子或分子的重复三维图案形成,在组成部分之间具有固定的距离。术语“晶体”也可用于表示这种图案的晶胞。
如本文所用,“结晶”是从溶液、熔体、蒸汽、不同固相或更罕见地直接从气体沉积形成固体晶体的过程。结晶可以是天然的或人工的过程。结晶也是化学固液分离技术,其中发生溶质从液体溶液到纯固体结晶相的质量转移。
如本文所用,“多晶型”是化合物(例如化合物I)以多于一种晶形存在或以不同晶体结构结晶的能力。“多晶型物”是化合物(例如化合物I)的不同晶体结构中的每一种。多晶型物是游离形式的化合物(即结晶游离形式)或其溶剂化物(即“多组分结晶形式”)的晶体结构,其中化合物例如化合物I与溶剂结晶。在一些实施方案中,当结晶的溶剂是水时,溶剂化物是水合物。
如本文所用,“溶剂化物”是指一种或多种溶剂分子(在室温下为液体的物质的分子)与结晶形式的化合物(例如,化合物I)的缔合或络合物,给出上升到一个新的特征结晶固体。本公开内容描述了化合物I的游离碱形式的几种“非溶剂化物”(即化合物I的固体形式,其为结晶游离形式且不是溶剂化物)。
可以形成其他类型的固体形式。例如,当多组分结晶形式的两种化合物在室温下存在时将是独立的固体,所得固体形式称为“共晶”。
当固体形式的组分之一已明确地将质子转移至另一组分,并且所得多组分结晶形式的组分是离子时,所得固体形式称为“盐”。
在共晶体中,在固体形式的不同组分之间不发生离子转移,因此所得组分以非离子形式存在。在共晶中,当在室温下彼此独立存在时,多组分结晶形式的两种(或更多种)组分是固体和非离子的。
当两种物质混合时是否形成盐或共晶将取决于两种组分的pKas之间的差异有多大。
本公开描述了化合物I的一种固体形式,其为盐(盐酸盐)。
存在许多可用的结晶技术,其允许本领域技术人员获得结晶材料。为了从溶液中发生结晶,溶液必须是“过饱和的”。这意味着溶液必须含有比在热力学平衡条件下所含的更多的溶质实体(分子或离子)(“饱和溶液”)。这可以通过各种方法实现,例如:1)“冷却结晶”;2)加入第二种溶剂以降低溶质的溶解度(称为“反溶剂结晶”的技术);3)化学反应;4)改变pH值;5)有机和/或水溶剂体系中的浆料转化是工业实践中最常用的方法。也可以使用其他方法,例如“溶剂蒸发结晶”。如本文所用,“过饱和度”是溶液浓度(C)与相同温度下平衡时浓度(C*)之间的差值。其以浓度单位测量。
用于表征化合物I的固体形式(例如,多晶型物或盐)的术语“化学稳定的”表示当经受特定条件(例如,40℃/40℃)时它不会分解成一种或多种新的不同化学化合物。相对湿度为75%,持续一段特定时间,例如1天,2天,3天,1周,2周,1个月,2个月,3个月,6个月,12个月,18个月,24个月,或更长时间。在一些实施方案中,小于25%的化合物I的多晶型物分解;在一些实施方案中,在指定的条件下,小于20%,小于15%,小于10%,小于5%,小于3%,小于1%或小于0.5%的化合物I的多晶型物分解。在一些实施方案中,在一段时间后,在指定条件下(由所用分析技术的最低检测限确定),没有可检测量的化合物I的给定多晶型物分解。
用于表征化合物I的结晶固体形式(例如,多晶型物或盐)的术语“物理稳定的”是指当经受特定条件,例如40℃/75%相对湿度,在特定时间内,例如,1天,2天,3天,1周,2周,1个月,2个月,3个月,6个月,12个月,18个月,24个月或更长时间,结晶固体形式不会变成化合物I的一种或多种不同的结晶固体形式(例如,通过诸如XRPD等分析技术测量,多晶型物变为化合物I的不同多晶型物)或变成无定形形式。在一些实施方案中,当经受特定条件时,少于25%的化合物I的结晶固体形式变成一种或多种不同的固体形式(另一种结晶固体形式或无定形形式)。在一些实施方案中,当经受特定条件时,少于20%,少于15%,少于10%,少于5%,少于3%,少于1%或少于0.5%的化合物I的结晶固体形式变为化合物I的一种或多种不同的结晶固体形式或无定形形式。在一些实施方案中,在指定条件下,没有可检测量的化合物I的给定固体形式变为化合物I的一种或多种不同固体形式。
当提及化合物I的指定结晶固体形式(例如,本文所述的化合物I的多晶型物或盐)时,术语“基本上纯的”是指指定的结晶固体形式含有少于20%(按重量计)的残余组分(例如化合物I的交替多晶型物,或无定形形式或其他溶剂分子或杂质)。在其他实施方案中,化合物I的基本上纯的结晶固体形式含有小于10%(重量)的化合物I的替代多晶型物,或无定形形式或另外的溶剂分子或杂质。在其他实施方案中,其含有少于5%(重量)的化合物I的替代多晶型物,或无定形形式或另外的溶剂分子或杂质。在其他实施方案中,其含有少于1%(重量)的化合物I的替代多晶型物,或无定形形式或另外的溶剂分子或杂质。
当提及化合物I的指定固体形式(例如,本文所述的化合物I的多晶型物或盐)的特征的光谱、迹线、热曲线等时,本文所用的术语“基本相似”意味着所涉及的光谱、迹线、热曲线等包含少于10%的峰与在本说明书中作为图示出,并且分配给所讨论的化合物I的特定固体形式的光谱、迹线或曲线中的峰不同。在其他实施方案中,其含有少于5%的不同峰。在其他实施方案中,其含有少于1%的不同峰。
当比较XRPD光谱时,对于化合物I的特定固体形式,光谱将与本公开中所示的光谱“基本相似”,其中所述光谱中的特征峰在与本公开的附图中所示的相同的°2θ值处测量,或者在与所述图中所示的那些峰相同的+或-0.5单位的°2θ的范围内测量。如果在所述特定条件下所述一段时间之前和之后固体形式的XRPD“基本相似”,化合物I的固体形式的XRPD将被认为在特定条件下,在一定时间后,是“基本不变的”。
本公开通常涉及评估本文公开的化学、物理或生物学参数。本领域技术人员将理解,这些参数可以用其他化学、物理或生物学参数代替,这些参数虽然未在本文中公开,但在鉴定固体形式方面基本相似。
实施方案
在一个方面,本发明涉及化合物I的结晶固体形式,如下所示:
化合物I是sGC刺激剂,其已经证明在临床前模型中治疗许多NO相关病症的功效。化合物I可以以各种晶形或多晶型存在。这些多晶型物中的一些是结晶游离碱形式。其他是溶剂化物。在一些实施方案中,溶剂化物是水合物。化合物I还可以形成几种药学上可接受的盐,包括其盐酸盐。
在一个实施方案中,本文公开的化合物I的固体形式是多晶型物。在另一个实施方案中,化合物I的固体形式是其盐酸盐。化合物I至少以七种纯多晶型物或结晶游离形式存在:形式A、形式B、形式D、形式E、形式F、形式G和形式H。化合物I先前在WO2014144100的实施例1中描述,作为浅橙色固体。
在一个实施方案中,化合物I的结晶固体形式是多晶型形式E。形式E可通过以下步骤形成:将如实施例部分中所述制备的粗化合物I在>60℃(例如,>70℃)下溶解在MeOH中以获得溶液,然后过滤,在>60℃下加热滤液,加水,冷却至室温(rt),然后过滤并在80℃下真空干燥72小时。
在另一个实施方案中,化合物I的结晶固体形式是多晶型形式A。形式A可通过以下步骤形成:将化合物I溶解在乙酸乙酯中,在>70℃下得到溶液,然后过滤,在20至25℃下进一步搅拌滤液16小时,得到浆液,真空浓缩浆液,加入庚烷,进一步浓缩所得浆液,过滤,并在100℃下真空干燥3小时。
在另一个实施方案中,形式A可通过以下步骤形成:将多晶型形式E溶于乙酸乙酯中,在>70℃下得到溶液,然后过滤,在20至25℃下进一步搅拌滤液16小时,得到浆液,,真空浓缩浆液,加入庚烷,进一步浓缩所得浆液,过滤,并在100℃下真空干燥3小时。
在另一个实施方案中,多晶型形式A可以直接从粗化合物I通过在高于60℃的DMSO中加热,然后加入水以形成浆液并过滤浆液而获得。
在另一个实施方案中,当粗化合物I在室温下在溶剂中浆化并搅拌14至30小时时,分离出多晶型形式A。在一些实施方案中,溶剂选自庚烷、乙酸异丙酯(IPAC)、乙醇、乙酸乙酯或癸烷,或其混合物。然后过滤浆液并在真空下干燥。
在另一个实施方案中,化合物I的固体形式是多晶型形式D。形式D可通过以下步骤形成:将如上所述制备的形式E与正癸烷在145-155℃下混合45分钟以获得浆料,然后在1小时内将浆料冷却至20-30℃,过滤并在80℃真空干燥72小时。
在另一个实施方案中,形式D可以通过在180℃下纯净(在没有溶剂存在下)加热形式E、形式B、形式F、形式G或形式H或其混合物的任何多晶型形成。
在另一个实施方案中,化合物I的固体形式是多晶型形式B。形式B可通过以下步骤形成:将如实施例部分所述制备的粗化合物I与乙腈在70-75℃下混合以形成溶液,然后过滤,在70-75℃下额外加热滤液,加水,冷却至52-62℃形成浆液,冷却浆液多于4小时至0-5℃,过滤并在90-100℃下真空干燥至少30小时。
在另一个实施方案中,化合物I的固体形式是多晶型形式F。形式F是如实施例部分中所述制备的形式A在160℃下纯净加热获得的。
在另一个实施方案中,化合物I的固体形式是多晶型形式G。形式G可通过以下步骤形成:将如实施例部分所述制备的粗化合物I在环境温度下在丙酮中浆化2小时,然后过滤并在30-40℃下真空干燥。在另一个实施方案中,多晶型形式G可通过以下步骤形成:将多晶型形式H在室温下在丙酮中搅拌(室温),然后过滤并在30至40℃下真空干燥。
在另一个实施方案中,化合物I的固体形式是多晶型形式H。形式H可通过以下步骤形成:将如实施例部分所述制备的粗化合物I与丙酮在45至50℃下混合以形成溶液,然后过滤,冷却至室温以形成浆液,然后在室温下搅拌5小时,接着过滤并在30至40℃真空干燥。
在一个方面,化合物I的固体形式是多晶型形式A。
在一些实施方案中,形式A的特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
在一些实施方案中,形式A的特征在于其IR光谱在1730cm-1处显示出频带最大值。
在一些实施方案中,形式A的特征在于XRPD光谱基本上类似于图2或图3A中所示的XRPD光谱。
在其他实施方案中,形式A的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.0、18.3、19.3、20.2和22.0。
在其他实施方案中,形式A的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.0、8.5、9.5、12.4-12.9、13.4、17.1、18.3、19.3、20.2、22.0、30.1和34.1。
在其他实施方案中,形式A的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.0、6.7、8.5、9.5、10.9、12.4-12.9、13.4、16.2、17.1、18.3、19.3、20.2、22.0、23.0、24.1至24.8、25.8、30.1和34.1。
在一些实施方案中,形式A的特征在于XRPD光谱基本上类似于图3C中所示的XRPD光谱。
在其他实施方案中,形式A的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.1(80.81%相对强度),18.4(53.57%),19.4(100.00%),20.3(57.01%)和22.0(56.64%)。
在其他实施方案中,形式A的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.1(80.81%相对强度),9.6(40.35%),12.6(41.26%),13.6(43.19%),18.4(53.57%),19.4(100.00%),20.3(57.01%)和22.0(56.64%)。
在其他实施方案中,形式A的特征在于当在40℃和75%相对湿度的稳定性条件下储存14个月时显示基本不变的XRPD迹线。在这些条件下储存之前和之后的形式A的XRPD迹线显示在图3B中。
在一个方面,化合物I的固体形式是多晶型形式B。
在一些实施方案中,形式B的特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
在一些实施方案中,形式B的特征在于其IR光谱在1200cm-1处显示出最大峰值。
在一些实施方案中,形式B的特征在于XRPD光谱基本上类似于图2或图4A中所示的XRPD光谱。
在其他实施方案中,形式B的特征在于在18.8至19.1°2θ的XRPD光谱中的一个或多个峰。
在另一个实施方案中,形式B的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.8、16.4、17.2、18.8-19.1、20.1和21.1-21.6。
在另一个实施方案中,形式B的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.8、10.6、12.6-13.0、14.6、16.4、17.2、18.8-19.1、20.1、21.1-21.6、24.5、25.3、27.0-27.5、28.9、29.8和30.5。
在一些实施方案中,形式B的特征在于XRPD光谱基本上类似于图4C中所示的XRPD光谱。
在其他实施方案中,形式B的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.9(76.55%相对强度),17.4(57.67%),19.1(100.00%)和25.5(52.26)。
在其他实施方案中,形式B的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:7.0(44.44%相对强度),8.9(76.55%),17.4(57.67%),19.1(100.00%),20.3(49.78%),21.8(36.16%)和25.5(52.26)。
在其他实施方案中,形式B的特征在于当在40℃和75%相对湿度的稳定性条件下储存14个月时显示基本不变的XRPD迹线。在这些条件下储存之前和之后的形式B的XRPD迹线显示在图4B中。
在一个方面,化合物I的固体形式是多晶型形式D。
在一些实施方案中,形式D的特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
在一些实施方案中,形式D的特征在于其IR光谱显示在1665、1639和968cm-1处的谱带最大值。在一些实施方案中,形式D的特征在于其IR光谱在1665cm-1处显示谱带最大值。在其他实施方案中,形式D的特征在于其IR光谱在1639cm-1处显示谱带最大值。在其它实施方案中,形式D的特征在于其IR光谱在968cm-1处显示谱带最大值。
在一些实施方案中,形式D的特征在于XRPD光谱基本上类似于图2或图5A中所示的XRPD光谱。
在其他实施方案中,形式D的特征在于当在40℃和75%相对湿度的稳定性条件下储存14个月时显示基本不变的XRPD迹线。在这些条件下储存之前和之后的形式D的XRPD迹线显示在图5B中。
在其他实施方案中,形式D的特征在于在18.8°2θ的XRPD光谱中的峰。
在另一个实施方案中,形式D的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:17.1、18.1、18.8和25.0。
在另一个实施方案中,形式D的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.8、17.1、18.1、18.8和25.0。
在一些实施方案中,形式D的特征在于XRPD光谱基本上类似于图5C中所示的XRPD光谱。
在其他实施方案中,形式D的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:4.7(97.11%相对强度),18.1(80.97%),18.6(100.00%)和26.8(65.25)。
在其他实施方案中,形式D的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:4.7(97.11%相对强度),8.3(64.04%),18.1(80.97%),18.6(100.00%)和26.8(65.25)。
在一个方面,化合物I的固体形式是多晶型形式E。
在一些实施方案中,形式E的特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
在一些实施方案中,形式E的特征在于其IR光谱在1690和1515cm-1处显示出带的最大值。在一些实施方案中,形式E的特征在于其IR光谱在1690cm-1处显示出最大峰。在一些实施方案中,形式E的特征在于其IR光谱在1515cm-1处显示出最大峰。
在一些实施方案中,形式E的特征在于XRPD光谱基本上类似于图2或图6中所示的XRPD光谱。
在其他实施方案中,形式E的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:7.4、18.8-19.3、21.1、24.8和25.5。
在其他实施方案中,形式E的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:7.4、13.9、15.1、16.3、17.6、18.8-19.3、21.1、22.3-22.5、24.8、25.5和27.1。
在一个方面,化合物I的固体形式是多晶型形式F。
在一些实施方案中,形式F的特征在于XRPD光谱基本上类似于图7中所示的XRPD光谱。
在其他实施方案中,形式F的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.3(100.00%相对强度),8.6(58.80%)和16.4(62.95%)。
在另一个实施方案中,形式F的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.3(100.00%相对强度),8.6(58.80%),16.4(62.95%)和19.0(48.51%)。
在一个方面,化合物I的固体形式是多晶型形式G。
在一些实施方案中,形式G的特征在于XRPD光谱基本上类似于图8中所示的XRPD光谱。
在其他实施方案中,形式G的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:10.7(55.47%相对强度)和18.33(100.00%)。
在另一个实施方案中,形式G的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:10.7(55.47%相对强度),13.9(42.47%),18.33(100.00%)和21.6(40.73%)。
在一个方面,化合物I的固体形式是多晶型形式H。
在一些实施方案中,形式H的特征在于XRPD光谱基本上类似于图9中所示的XRPD光谱。
在其他实施方案中,形式H的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.77(89.22%相对强度),6.39(100.00%),9.1(84.17%)和18.5(67.04%)。
在另一个实施方案中,形式H的特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.77(89.22%rel int),6.39(100.00%),9.1(84.17%),18.5(67.04%)和18.83(67.04%)。
本发明的药学上可接受的盐。
本文所用的短语“药学上可接受的盐”是指化合物I的药学上可接受的有机或无机盐。化合物I的药学上可接受的盐可用于医药中。然而,非药学上可接受的盐可用作制备化合物I的其他固体形式的中间体。
药学上可接受的盐包括包含另一个充当抗衡离子的原子或分子。抗衡离子可以是稳定母体化合物上的电荷的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电荷的原子。多个带电原子是药学上可接受的盐的一部分的实例可具有多个抗衡离子。在某些情况下,抗衡离子可以是相同的。在其他情况下,它们对于每个带电原子可能是不同的。因此,药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
本文所述的药学上可接受的盐和其它典型的药学上可接受的盐的制备由Berg等人,《Pharmaceutical Salts》,J.Pharm.Sci.,1977:66:1-19,通过引用整体并入本文。
在一个实施方案中,化合物I的药学上可接受的盐是化合物I的盐酸盐。
化合物I的盐酸盐可以通过将化合物I以如上所述制备的多晶型D在1M HCl中悬浮,与i-PrOH混合,在20至40℃的温度循环下搅拌来制备,加热速率为40℃/h,冷却速度为5℃/h。
化合物I的盐酸盐的特征在于熔点为256℃。
化合物I的盐酸盐的特征在于在pH1.4下的水溶解度为0.5mg/mL。在饱和溶液的pH下测定水溶解度。将盐在25℃下在水中振荡24小时。过滤后,通过HPLC测定浓度为0.5mg/mL,pH为1.4。
化合物I的盐酸盐的特征在于XRPD图案基本上类似于图11中所示的XRPD图案。
药物组合物和给药方法。
本文公开的结晶固体形式可以配制成药物组合物或“制剂”。
通过将结晶固体形式的化合物I与载体、稀释剂或赋形剂混合来制备典型的制剂。合适的载体、稀释剂和赋形剂是本领域技术人员公知的,包括诸如碳水化合物,蜡,水溶性和/或可溶胀聚合物,亲水或疏水材料,明胶,油,溶剂,水等材料。所用的特定载体,稀释剂或赋形剂将取决于配制化合物I的多晶型物或药学上可接受的盐的方式和目的。溶剂通常基于本领域技术人员公认的安全(GRAS-通常认为是安全的)给予哺乳动物的溶剂来选择。通常,安全溶剂是无毒的含水溶剂,例如水和其它在水中可溶或可混溶的无毒溶剂。合适的含水溶剂包括水,乙醇,丙二醇,聚乙二醇(例如PEG400,PEG300)等,以及它们的混合物。制剂还可包括其他类型的赋形剂,例如一种或多种缓冲剂,稳定剂,抗粘附剂,表面活性剂,润湿剂,润滑剂,乳化剂,粘合剂,悬浮剂,崩解剂,填充剂,吸附剂,包衣(例如肠溶或缓释),防腐剂,抗氧化剂,不透明剂,助流剂,加工助剂,着色剂,甜味剂,芳香剂,调味剂和其它已知的添加剂,以提供药物的优雅呈现或帮助制造药物产品(即药物)。
可以使用常规的溶解和混合程序制备制剂。例如,在一种或多种上述赋形剂的存在下,将原料药物(即化合物I的多晶型物或药学上可接受的盐)溶解在合适的溶剂中。具有所需纯度的化合物任选地与药学上可接受的稀释剂、载体、赋形剂或稳定剂混合,形成冻干制剂、研磨粉末或水溶液形式。制剂可以通过在环境温度下在适当的pH下和所需的纯度下与生理学上可接受的载体混合来进行。制剂的pH主要取决于具体用途和化合物的浓度,但可以在约3至约8的范围内。当本文所述的制剂是通过溶剂法形成的固体无定形分散体时,当形成混合物时可以将添加剂直接添加到喷雾干燥溶液,例如将添加剂作为浆料溶解或悬浮在溶液中,然后喷雾干燥。或者,可以在喷雾干燥过程之后添加添加剂以帮助形成最终配制的产品。
通常将化合物I的多晶型物或药学上可接受的盐配制成药物剂型,以提供易于控制的药物剂量并使患者符合规定的方案。可以制备多晶型物或化合物I的药学上可接受的盐的药物制剂用于各种途径和类型的给药。对于相同化合物可存在各种剂型,因为不同的医学条件可能需要不同的给药途径。
可以与载体材料组合以产生单一剂型的活性成分的量将根据所治疗的受试者和特定的给药方式而变化。例如,用于口服给予人的时间释放制剂可含有约1至1000mg活性物质,其与适当且方便量的载体物质混合,其可占总组合物的约5至约95%(重量比)。可以制备药物组合物以提供易于测量的给药量。例如,用于静脉内输注的水溶液可以含有每毫升溶液约3至500μg的活性成分,以便可以以约30mL/hr的速率输注合适的体积。作为一般提议,所施用的抑制剂的初始药学有效量将在约0.01-100mg/kg每剂量的范围内,即每天约0.1至20mg/kg患者体重,所用化合物的典型初始范围为0.3至15mg/kg/天。
本文所用的术语“治疗有效量”是指在研究人员、兽医、医生或其他临床医生正在寻求的组织、系统、动物或人体中引发生物或药物反应的活性化合物或药剂的量。待施用的化合物的治疗或药学有效量将受这些考虑因素控制,并且是改善、治愈或治疗疾病或病症或其一种或多种症状所需的最小量。
化化合物I的多晶型物或药学上可接受的盐的药物组合物将以符合良好医学实践的方式配制、给药和施用,即量、浓度、时间表、疗程、载体和给药途径。在此背景下考虑的因素包括所治疗的特定疾病,所治疗的特定哺乳动物,个体患者的临床状况,疾病的原因,药剂的递送部位,给药方法,给药方案,以及医疗从业者已知的其他因素,例如个体患者的年龄、体重和反应。
“预防有效量”一词是指在疾病或病症获得前有效预防或大幅度降低其获得疾病或障碍的机会,或在疾病或病症获得前降低其严重程度,或在症状出现前降低其一个或多个症状的严重程度的量。大致上,预防措施分为初级预防(预防疾病的发展)和二级预防(即疾病已经发展,并且保护患者不受此过程恶化的影响)。
可接受的稀释剂、载体、赋形剂和稳定剂是在所用剂量和浓度下对接受者无毒的那些,包括缓冲剂,如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂(如十八烷基二甲基苄基氯化铵;六甲基氯化铵;苯扎氯铵,苄索氯铵;苯酚,丁基或苄醇;对羟基苯甲酸烷基酯,如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);血清白蛋白、明胶或免疫球蛋白等蛋白质;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂如EDTA;糖,如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐抗衡离子如钠;金属配合物(例如锌-蛋白质配合物);和/或非离子表面活性剂,例如TWEENTM,PLURONICSTM或聚乙二醇(PEG)。活性药物成分也可以包埋在微胶囊中,例如,通过凝聚技术或通过界面聚合制备,例如分别为羟甲基纤维素或明胶-微胶囊和聚-(甲基丙烯酸甲酯)微胶囊;在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)或在粗乳液中。这些技术在Remington's:The Science and Practiceof Pharmacy,第21版,University of the Sciences in Philadelphia,Eds.,2005(以下称“Remington's”)中公开。
术语“施用”、“给予”或“给药”涉及本发明的固体形式、组成或调配物,是指将所述化合物引入需要治疗的动物的系统中。当本发明化合物与一种或多种其他活性剂组合提供时,“施用”及其变体应理解为包括同时和/或连续引入所述化合物和其他活性剂。
取决于所治疗疾病的严重程度和类型,本文所述的组合物可以全身或局部给药,例如经口(例如,使用胶囊、粉末、溶液、悬浮液、片剂、舌下片剂等),通过吸入(例如,使用气溶胶、气体、吸入器、雾化器等),经耳(例如,使用滴耳液),局部(例如,使用乳膏、凝胶、搽剂、乳液、软膏、糊剂、透皮贴剂等),经眼(例如,用滴眼液、眼用凝胶、眼科软膏),经直肠(例如,使用灌肠剂或栓剂),经鼻,经颊,经阴道(例如,使用冲洗液、宫内避孕器、阴道栓剂、阴道环或片剂等),通过植入的储库等,或肠胃外。
本文所用的术语“肠胃外”包括但不限于皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。优选地,组合物通过口服、腹膜内或静脉内给药。
本文所述的药物组合物可以以任何口服可接受的剂型口服给药,包括但不限于胶囊、片剂、水悬浮液或溶液。用于口服给药的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物外,液体剂型可含有本领域常用的惰性稀释剂,例如水或其它溶剂,增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及其混合物。除惰性稀释剂外,口服组合物还可包括助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这种固体剂型中,活性化合物与以下成分混合:至少一种惰性的药学上可接受的赋形剂或载体,例如柠檬酸钠或磷酸二钙,和/或a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)保湿剂如甘油,d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂如石蜡,f)吸收促进剂如季铵化合物,g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯,h)吸收剂如高岭土和膨润土,和i)润滑剂如滑石,硬脂酸钙,硬脂酸镁,固体聚乙二醇,十二烷基硫酸钠及其混合物。片剂可以是未包衣的,或者可以通过已知技术包衣,包括微囊化以掩盖令人不愉快的味道或延迟胃肠道中的崩解和吸附,从而在较长时期内提供持续作用。例如,可以使用延时材料,例如单独的甘油单硬脂酸酯或二硬脂酸甘油酯或与蜡一起使用。可以使用水溶性掩味材料,例如羟丙基甲基纤维素或羟丙基纤维素。
适于口服给药的化合物I的多晶型物或化合物I的药学上可接受的盐的制剂可以制备成离散的单位,例如片剂、丸剂、锭剂(troche)、锭剂(lozenge)、水性或油性悬浮液、可分散的粉末或颗粒、乳液、硬胶囊或软胶囊(例如明胶胶囊)、糖浆或酏剂。用于口服使用的化合物的制剂可根据本领域已知的任何制备药物组合物的方法制备。
口服使用的制剂也可以作为硬明胶胶囊提供,其中活性成分与惰性固体稀释剂混合,例如碳酸钙、磷酸钙或高岭土,或作为软明胶胶囊,其中活性成分与水溶性载体混合,例如聚乙二醇或油介质,例如花生油、液体石蜡或橄榄油。
活性固体形式也可以是具有一种或多种上述赋形剂的微胶囊形式。
当口服使用需要含水悬浮液时,将活性成分与乳化剂和悬浮剂混合。如果需要,可以加入某些甜味剂和/或调味剂。糖浆和酏剂可以用甜味剂配制,例如甘油、丙二醇、山梨糖醇或蔗糖。此类制剂还可含有缓和剂、防腐剂、调味剂和着色剂和抗氧化剂。
本文所述组合物的无菌可注射形式(例如,用于肠胃外给药)可以是水性或油性悬浮液。可以根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂配制这些悬浮液。无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如在1,3-丁二醇或PEG400中的溶液。可以使用的可接受的载体和溶剂包括水,林格氏溶液和等渗氯化钠溶液。另外,无菌的固定油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。脂肪酸,例如油酸及其甘油酯衍生物可用于制备注射剂,液可以是天然的药学上可接受的油,例如橄榄油或蓖麻油,尤其是它们的聚氧乙基化形式。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂,例如羧甲基纤维素或类似的分散剂,它们通常用于配制药学上可接受的剂型,包括乳剂和混悬剂。其他常用的表面活性剂,例如吐温、司盘和其它乳化剂或生物利用度增强剂,其通常用于制备药学上可接受的固体、液体或其它剂型,也可用于可注射制剂的目的。
油性悬浮液可以通过将化合物I的多晶型物或其药学上可接受的盐悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可加入如上所述的甜味剂和调味剂以提供适口的口服制剂。这些组合物可以通过加入抗氧化剂如丁基化羟基茴香醚或α-生育酚来保存。
化合物I的多晶型物的水性悬浮液或化合物I的药学上可接受的盐含有活性物质与适于制备水性悬浮液的赋形剂的混合物。这些赋形剂包括悬浮剂,例如羧甲基纤维素钠、交联羧甲基纤维素、聚维酮、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶,以及分散或润湿剂,例如天然存在的磷脂(例如,卵磷脂),环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯),环氧乙烷与长链脂族醇的缩合产物(例如十七烷氧基乙醇),环氧乙烷与衍生自脂肪酸的偏酯和己糖醇酐的缩合产物(例如,聚氧乙烯脱水山梨糖醇单油酸酯)。含水悬浮液还可含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂和一种或多种甜味剂,例如蔗糖或糖精。
可注射制剂可以灭菌,例如,通过细菌截留过滤器过滤,或通过掺入无菌固体组合物形式的灭菌剂,其可以在使用前溶解或分散在无菌水或其它无菌可注射介质中。
可通过局部推注注射将可注射溶液或微乳液引入患者的血流中。或者,以保持本发明化合物的恒定循环浓度的方式给予溶液或微乳液可能是有利的。为了保持这种恒定的浓度,可以使用连续的静脉内输送装置。这种装置的一个例子是Deltec CADD-PLUSTM5400型静脉泵。
用于直肠或阴道给药的组合物优选是栓剂,其可以通过将本文所述的固体形式与合适的无刺激性赋形剂或载体如可可脂、蜂蜡、聚乙二醇或栓剂蜡混合来制备,所述赋形剂或载体在环境温度下为固体,但在体温下为液体,因此在直肠或阴道腔内融化并释放活性化合物。适用于阴道给药的其他制剂可以呈现为阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾剂。
本文所述的药物组合物还可以局部给药,特别是当治疗目标包括局部施用易于接近的区域或器官时,包括眼、耳、皮肤或下肠道疾病。对于这些区域或器官中的每一个,容易制备合适的局部制剂。
用于局部或透皮施用本文所述化合物的剂型包括软膏、糊剂、乳膏、洗剂、凝胶、粉末、溶液、喷雾剂、吸入剂或贴剂。在无菌条件下将活性成分与药学上可接受的载体和任何所需的防腐剂或缓冲剂混合。眼科制剂、滴耳剂和滴眼剂也包括在本发明的范围内。另外,本发明考虑使用透皮贴剂,其具有提供化合物控制递送至身体的附加优点。这种剂型可以通过将化合物溶解或分散在适当的介质中来制备。吸收促进剂也可用于增加化合物在皮肤上的通量。可以通过提供速率控制膜或通过将化合物分散在聚合物基质或凝胶中来控制速率。用于下肠道的局部施用可以以直肠栓剂制剂(参见上文)或以合适的灌肠剂制剂实现。也可以使用局部透皮贴剂。
对于局部应用,药物组合物可以配制成合适的软膏,其含有悬浮或溶解在一种或多种载体中的活性组分。用于局部施用本发明固体形式的载体包括但不限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,可以将药物组合物配制成合适的洗剂或乳膏,其中含有悬浮或溶解在一种或多种药学上可接受的载体中的活性组分。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。
对于眼科用途,药物组合物可以配制成等渗的、pH调节的无菌盐水中的微粉化悬浮液,或优选地,作为等渗的、pH调节的无菌盐水中的溶液,含有或不含防腐剂如苄基氯化铵。或者,对于眼科用途,可以将药物组合物配制成软膏例如凡士林。对于眼睛或其他外部组织(例如口腔和皮肤)的治疗,制剂可以作为局部软膏或乳膏施用,其含有活性成分,其量为例如0.075至20%w/w。当配制成软膏时,活性成分可以与油基、石蜡基或水混溶性软膏基质一起使用。
或者,可以将活性成分配制成具有水包油乳膏基质的乳膏。如果需要,乳膏基质的水相可包括多元醇,即具有两个或更多个羟基的醇,例如丙二醇、1,3-丁二醇、甘露醇、山梨糖醇、甘油和聚乙二醇(包括PEG 400)及其混合物。局部制剂可以理想地包括增强活性成分通过皮肤或其他受影响区域的吸收或渗透的化合物。这种皮肤渗透促进剂的实例包括二甲基亚砜和相关的类似物。
使用化合物I的多晶型物或化合物I的药学上可接受的盐制备的乳液的油相可以以已知方式由已知成分构成。虽然该相可仅包含乳化剂(也称为乳化剂),但它理想地包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。亲水性乳化剂可与亲脂性乳化剂一起包含,所述亲脂性乳化剂用作稳定剂。在一些实施方案中,乳化剂包括油和脂肪。有或没有稳定剂的乳化剂一起构成所谓的乳化蜡,并且蜡与油脂一起构成所谓的乳化软膏基质,其形成乳膏配方的油性分散相。适用于配制化合物I的多晶型物或化合物I的药学上可接受的盐的乳化剂和乳液稳定剂包括TweenTM-60、SpanTM-80、十八十六醇、苯甲醇、肉豆蔻醇、单硬脂酸甘油酯和月桂基硫酸钠。
药物组合物还可以通过鼻气雾剂或通过吸入给药。此类组合物根据药物制剂领域熟知的技术制备,并且可以使用苯甲醇或其他合适的防腐剂,用以提高生物利用度的吸收促进剂,碳氟化合物和/或其他常规增溶剂或分散剂制备成盐水溶液。
使用的药物组合物(或制剂)可以以各种方式包装,这取决于用于施用药物的方法。通常,用于分配的制品包括其中以适当的形式沉积药物制剂的容器。合适的容器是本领域技术人员公知的,包括诸如瓶子(塑料和玻璃)、小袋、安瓿、塑料袋、金属圆筒等材料。容器还可以包括防篡改组件,以防止轻易获取包装内容物。另外,容器上附有描述容器内容物的标签。标签还可能包含适当的警告。
制剂可以包装在单位剂量或多剂量容器中,例如密封的安瓿和小瓶中,并且可以在冷冻干燥(冻干)条件下储存,仅需要在使用前添加无菌液体载体(例如水)以供注射。临时注射溶液和悬浮液由前述类型的无菌粉末、颗粒和片剂制备。优选的单位剂量制剂是含有如上所述的每日剂量或单位每日亚剂量或其适当部分的活性成分的那些。
在另一个方面,化合物I的多晶型物或化合物I的药学上可接受的盐可以配制在包含兽医载体的兽医用组合物中。兽用载体是可用于施用组合物的材料,并且可以是固体,液体或气体材料,其在惰性或兽医领域中是可接受的并且与活性成分相容。这些兽医用组合物可以肠胃外、口服或通过任何其他所需途径给药。
治疗方法
另一方面,本发明涉及通过在有此需要的患者中单独或组合使用本文公开的化合物I的结晶固体形式或包含它们的药物组合物治疗某些病症。
本公开涉及化合物I的结晶固体形式,及其药物制剂及其单独或与一种或多种另外的药剂组合用于治疗和/或预防各种疾病的用途,其中浓度增加优选为NO或cGMP浓度的增加。
增加NO的产生或增加组织中cGMP的浓度导致血管舒张、抑制血小板聚集和粘附、抗高血压效果、抗重塑效果、抗纤维化、抗细胞凋亡效果、抗炎效果和神经元信号传递效果,以及其他效果。
在其他实施方案中,本文公开的化合物I的结晶固体形式可用于预防和/或治疗特征在于生物系统(例如,在人体中)中NO的不期望的降低的生物利用度和/或敏感性的疾病和病症,例如与氧化应激或亚硝化应激条件有关的那些。
本文所用的术语“心血管疾病”(或“心血管病症”)是指基于循环器官例如心脏、血管(动脉,毛细血管和静脉)或两者的异常症状的疾病。该术语还包括一般影响心血管系统的任何疾病,包括心脏病,脑血管疾病,肾脏、肝脏和相关器官,或肺的血管疾病,以及外周动脉疾病等。
“sGC相关的心血管疾病”是已知或怀疑涉及NO/sGC/cGMP系统的心血管疾病,并且是可通过激活NO合酶而被sGC激活/刺激治疗或预防的心血管疾病,或通过添加NO或NO供体或NO前体如L-精氨酸或L-瓜氨酸,或通过抑制负责cGMP分解的PDE(磷酸二酯酶),或上述任何一种的组合方法。
本文所用的术语“血管舒张”是指血管扩张。它是由血管壁内的平滑肌细胞松弛引起的,特别是在大静脉、大动脉和较小的小动脉中。实质上,该过程与“血管收缩”相反,“血管收缩”是血管变窄。当血管扩张时,由于血管阻力降低,血液流动增加。因此,动脉血管(主要是小动脉)的扩张会降低血压。反应可能是内在的(由于周围组织中的局部过程)或外在的(由于激素或神经系统)。此外,响应可以定位于特定器官(取决于特定组织的代谢需要,如在剧烈运动期间),或者它可以是全身性的(在整个体循环中看到)。
如本文所用的术语“血管收缩”是指由于肌肉收缩导致的血管变窄。血管收缩是身体调节和维持平均动脉压(MAP)的一种机制。广泛性血管收缩通常导致全身血压升高,但也可能在特定组织中发生,导致血流局部减少。
如本文所用,术语“支气管收缩”用于限定由于周围平滑肌收紧导致的肺部气道收缩,随之发生咳嗽,喘息和呼吸短促。这种情况有很多原因,最常见的是哮喘。运动和过敏可以在无症状的个体中引起症状。其他病症如慢性阻塞性肺病(COPD)也可伴有支气管收缩。
在整个公开内容中,术语“高血压(hypertension)”、“动脉高血压”或“高血压(HBP)”可互换使用,并且指的是极其常见且高度可预防的慢性病症,其中动脉中的血压(BP)高于正常的或期望的。如果控制不当,它是几种严重心血管和肾脏疾病的重要危险因素。高血压可能是一种原发性疾病,称为“原发性高血压”或“特发性高血压”,或者可能由其他疾病引起或与之相关,在这种情况下,它被归类为“继发性高血压”。原发性高血压占所有病例的90-95%。
如本文所用,术语“顽固性高血压”是指高于目标血压的高血压(通常低于140/90mmHg,但对于患有合并糖尿病或肾病的患者,建议低于130/80mmHg的低目标)尽管同时使用三种属于不同抗高血压药物类别的抗高血压药物。需要四种或更多药物来控制血压的人也被认为患有顽固性高血压。高血压是糖尿病中极为常见的合并症,取决于肥胖、种族和年龄,影响约20-60%的糖尿病患者。这种类型的高血压在本文中称为“糖尿病性高血压”。在2型糖尿病中,高血压通常作为胰岛素抵抗的代谢综合征的一部分存在,还包括中心性肥胖和血脂异常。在1型糖尿病中,高血压可能反映了糖尿病肾病的发病。
如本文所用,“肺动脉高压(PH)”是一种疾病,其特征在于肺血管(肺动脉,肺静脉和肺毛细血管)中的血压持续升高,其导致右心肥大,最终导致右心衰竭和死亡。PH的常见症状包括呼吸短促、头晕和昏厥,所有这些症状都会因劳累加剧而恶化。如果不进行治疗,诊断后的预期寿命中位数为2.8年。PH以许多不同的形式存在,根据其病因分类。类别包括肺动脉高压(PAH),患有左心疾病的PH,与肺病和/或低氧血症相关的PH,由于慢性血栓形成和/或栓塞性疾病引起的PH和各种PH。PAH在一般人群中很少见,但与某些常见病症如HIV感染、硬皮病和镰状细胞病相关的患病率增加。其他形式的PH通常比PAH更常见,例如,PH与慢性阻塞性肺病(COPD)的关联是特别令人关注的。目前对肺动脉高压的治疗取决于疾病的阶段和机制。
术语“冠状动脉疾病”是指对心肌的血液供应部分或完全阻断(心肌或心肌缺血)的病症。这种心肌供血减少可能导致一些“急性心肌综合征”:胸痛(“心绞痛”,稳定或不稳定)和不同类型的心脏病(“心肌梗塞”或MI)。冠状动脉疾病的一个常见原因是“动脉粥样硬化”,这是指动脉硬化,由于动脉壁中的脂肪沉积,然后可能通过形成动脉粥样硬化斑块进展,缩小并最终阻塞血液流向动脉。这种动脉粥样硬化过程也可能影响其他动脉,而不仅仅是心脏的动脉。血栓是导致动脉阻塞的最常见原因,因为动脉通常由于动脉粥样硬化斑块(动脉粥样硬化斑块)而部分阻塞;动脉粥样硬化可能破裂或撕裂,导致凝块形成。偶尔,冠状动脉疾病是由冠状动脉痉挛引起的,冠状动脉痉挛可以自发发生或由于使用某些药物(例如可卡因,尼古丁)而发生。很少,冠状动脉疾病的原因是出生缺陷,病毒感染(例如,川崎病),系统性红斑狼疮(狼疮),动脉炎症(动脉炎),从心室进入其中一个的血凝块冠状动脉或物理损伤(例如,受伤或放射治疗)。
如本文所用,“不稳定性心绞痛”是指心绞痛症状模式的变化,包括心绞痛延长或恶化和严重症状的新发作。
MI(心肌梗塞)可分为两种类型:“非ST段抬高”MI和“ST段抬高”MI。急性冠状动脉综合征的并发症取决于冠状动脉阻塞的程度、时间和位置。如果阻塞影响大量的心肌,心脏将无法有效泵送。如果阻塞阻断了流向心脏电气系统的血流,心律可能会受到影响。当心脏病发作时,部分心肌会死亡。死的组织和取代它的疤痕组织不会收缩。当其余的心脏试图收缩时,疤痕组织有时甚至会扩张或凸出。因此,抽血的肌肉较少。如果足够多的肌肉死亡,心脏的抽吸能力可能会降低,心脏无法满足身体对氧气和血液的需求。然后发生心力衰竭、低血压或两者兼而有之。如果超过一半的心肌受损或死亡,心脏通常不能发挥功能,严重残疾或死亡。
如本文所用,“心力衰竭”(HF)是左心室(LV)心肌重塑的进行性病症,其最终导致复杂的临床综合征,其中心脏功能受损和循环充血是定义的特征,并且导致血液输送不足和营养到身体组织。当心脏受损或过度劳累并且无法抽出从体循环返回的所有血液时,就会发生这种情况。由于抽出较少的血液,返回心脏的血液会回流,并且身体的其他部位会积聚液体。心力衰竭还会损害肾脏处理钠和水的能力,从而进一步加剧了液体的滞留。心力衰竭的特征在于自主神经功能障碍,神经激素激活和细胞因子的过度产生,其导致进行性循环衰竭。心力衰竭的症状包括:运动或休息时呼吸困难(呼吸短促),夜间因突然呼吸困难而醒来,均表明肺水肿;一般疲劳或虚弱;脚、脚踝和腿部水肿;体重迅速增加;或慢性咳嗽,包括产生粘液或血液的咳嗽。根据其临床表现,心力衰竭被分类为从头、短暂、急性、急性后或慢性。急性心力衰竭,即需要紧急治疗的症状的快速或逐渐发作,可能从头开始或由于慢性心力衰竭而失代偿。术语“心力衰竭”通常用于表示“慢性心力衰竭”。术语“充血性心力衰竭(CHF)”或“充血性心力衰竭(CCF)”通常与慢性心力衰竭互换使用。心力衰竭的常见原因包括冠状动脉疾病,包括先前的心肌梗塞(心脏病发作)、高血压、心房颤动、心脏瓣膜病和心肌病。这些通过改变心脏的结构或功能导致心力衰竭。
心力衰竭有两种主要类型:“由于射血分数降低引起的心力衰竭(HFREF)”,也称为“由于左心室收缩功能障碍引起的心力衰竭”或“收缩性心力衰竭”,以及“射血分数保持不变的心力衰竭(HFPEF)”,也称为“舒张性心力衰竭”或“射血分数正常的心力衰竭(HFNEF)”。射血分数是在单次收缩期间从心脏泵出的心脏中的血液的比例。它是正常的百分比,介于50%和75%之间。
术语“急性”(如在“急性HF”中)用于表示快速发作,“慢性”表示长持续时间。慢性心力衰竭是一种长期的情况,通常具有稳定的治疗症状。“急性失代偿性”心力衰竭是恶化或失代偿性心力衰竭,指的是一个人的特征是心力衰竭体征和症状改变导致需要紧急治疗或住院治疗。在高输出的情况下也可能发生心力衰竭(然后它被称为“高输出心力衰竭”),其中心室收缩功能正常但心脏不能处理重要的血容量增加。
在心血管生理学中,术语“射血分数(EF)”定义为左心室和右心室中随每次心跳或心动周期抽出的血液分数。在医学成像允许的有限数学中,EF应用于右心室,其通过肺动脉瓣将血液喷射到肺循环中,或左心室,其通过主动脉瓣将血液喷射到脑和体循环中。
术语“具有保留的射血分数(HFPEF)的心力衰竭”通常被理解为表示心力衰竭的体征和症状的表现,射血分数大于55%。其特征在于左心室顺应性降低,导致左心室压力增加。由于左心室功能差,HFPEF常见左心房大小增加。充血性心力衰竭、心房颤动和肺动脉高压的风险增加。风险因素是高血压、高脂血症、糖尿病、吸烟和阻塞性睡眠呼吸暂停。在这种类型的心力衰竭中,心肌收缩良好但心室在松弛阶段不能充满血液。
术语“射血分数降低(HFREF)的心力衰竭”是指射血分数小于40%的心力衰竭。
糖尿病是心力衰竭患者的常见合并症,并且与较差的结果相关,并且可能损害治疗的功效。其他重要的合并症包括系统性高血压、慢性气流阻塞、睡眠呼吸暂停、认知功能障碍、贫血、慢性肾病和关节炎。慢性左心衰竭通常与肺动脉高压的发展有关。某些合并症的发生频率因性别而异:在女性中,高血压和甲状腺疾病更常见,而男性更常患慢性阻塞性肺病(COPD)、外周血管疾病、冠状动脉疾病和肾功能不全。抑郁症是心力衰竭的常见并发症,这两种情况往往会相互复杂化。恶病质一直被认为是心力衰竭的严重且常见的并发症,影响所有心力衰竭患者的高达15%并且预后不良。心脏恶病质定义为在六个月内非体重,非自愿性丧失至少6%的体重。
如本文所用,术语“心律失常”是指在超过90%的心脏病发作的人中发生的异常心律。有时问题在于心脏部分引发心跳并且心率可能太慢,其他时候问题可能导致心脏过快或不规律地跳动。有时,心跳的信号不是从心脏的一部分传导到另一部分,心跳可能会减慢或停止。此外,未死但血流不畅的心肌区域可能易受刺激。这会引起心律问题,如室性心动过速或心室颤动。如果心脏完全停止泵送,这可能导致心脏停搏。
“心包”是围绕心脏的袋或膜。“心包炎”或该膜的炎症可能由于心脏病发作而发展,并且可能导致发热、心包积液、覆盖肺部(胸膜)的膜的炎症、胸腔积液和关节疼痛。心脏病发作后的其他并发症可能包括二尖瓣功能障碍、心肌破裂、心室壁凸出(心室动脉瘤)、血栓和低血压。
术语“心肌病”是指心室肌壁的结构和功能的进行性损害。心肌病的主要类型是扩张的、肥大的和限制性的。心肌病通常会导致心力衰竭的症状,并且还可能导致胸痛、昏厥和猝死。
术语“二尖瓣反流”或“二尖瓣功能不全”是指心脏的二尖瓣不紧密闭合,允许血液在心脏中向后流动的情况。结果,血液不能有效地通过心脏或身体的其他部分移动,导致疲劳或呼吸短促。
术语“睡眠呼吸暂停”是指最常见的睡眠呼吸障碍。这是一种特征为间歇性,周期性减少或完全停止气流的病症,其可能或可能不涉及阻塞上呼吸道。睡眠呼吸暂停有三种类型:阻塞性睡眠呼吸暂停,最常见的形式,中枢性睡眠呼吸暂停和混合性睡眠呼吸暂停。
“中枢性睡眠呼吸暂停(CSA)”是由大脑正常呼吸信号故障引起的,而不是气道的物理阻塞。呼吸努力的缺乏导致血液中二氧化碳的增加,这可能引起患者的注意。CSA在一般人群中很少见,但在收缩性心力衰竭患者中相对常见。
如本文所用,术语“代谢综合征”、“胰岛素抵抗综合征”或“综合征X”是指代谢病症的组或聚类(腹部肥胖,升高的空腹血糖,“血脂异常”(即,血脂水平升高)和升高的血压(HBP),其一起发生的频率高于单独偶然发生,并且共同促进2型糖尿病和心血管疾病的发展。代谢综合征的特征在于甘油三酯增加、高密度脂蛋白胆固醇(HDL-胆固醇)降低及在一些情况下低密度脂蛋白胆固醇(LDL-胆固醇)水平中度升高的特定脂质特征,以及由于组分危险因素的压力加速的“动脉粥样硬化疾病”的进展。有几种类型的血脂异常:“高胆固醇血症”是指胆固醇水平升高。家族性高胆固醇血症是一种由于19号染色体(19p13.1-13.3)上的缺陷的特殊形式的高胆固醇血症。“高甘油三酯血症”是指甘油酯水平升高(例如,“高甘油三酯血症”涉及升高的甘油三酯水平)。“高脂蛋白血症”是指脂蛋白水平升高(除非另有说明,通常为LDL)。
术语“脂肪变性”是指细胞内脂质的异常保留。它通常反映了合成和消除甘油三酯的正常过程的损害。多余的脂肪积聚在囊泡中,从而取代细胞的细胞质。在严重的情况下,细胞可能会破裂。通常在肝脏中观察到脂肪变性,因为它是主要与脂肪代谢相关的器官。它也可以在心脏、肾脏和肌肉组织中观察到。
如本文所用,术语“外周血管疾病(PVD)”,通常也称为“外周动脉疾病(PAD)”或“外周动脉闭塞性疾病(PAOD)”,是指不在冠状动脉、主动脉弓血管系统或大脑内的大动脉阻塞。PVD可由动脉粥样硬化、导致狭窄的炎症过程、栓塞、血栓形成或其他类型的闭塞引起。它引起急性或慢性“缺血(缺乏血液供应)”。PVD通常用于指下肢发现的动脉粥样硬化阻塞。PVD还包括归因于动脉的间歇性狭窄(例如,“雷诺氏现象”)或其扩大(红斑性肢痛),即血管痉挛引起的微血管疾病的一部分疾病。外周动脉疾病包括闭塞性血栓性血管炎、外周动脉闭塞性疾病、雷诺氏病和雷诺氏综合症。常见的症状是腿冷或脚冷、间歇性跛行、下肢疼痛和严重的肢体缺血(下肢溃疡和坏死)。外周动脉疾病的诊断和治疗指南可见于Eur.J.Vasco Endovasc.Surg,2007,33(1),S1中。
本文所用的术语“狭窄”是指血管或其他管状器官或结构中的异常变窄。它有时也被称为“狭窄(stricture)”(如在尿道狭窄中)。术语“缩窄”是同义词,但通常仅在主动脉缩窄的情况下使用。术语“再狭窄”是指手术后狭窄的复发。
术语“血栓形成”是指在血管内形成血凝块(“血栓”),阻碍血液流过循环系统。当血管受伤时,身体使用血小板(血小板)和纤维蛋白形成血凝块以防止失血。或者,即使血管未受伤,如果适当的条件存在,也可能在体内形成血凝块。如果凝血过于严重并且凝块脱落,那么移动的凝块现在被称为“栓子”。术语“血栓栓塞”是指血栓形成及其主要并发症“栓塞”的组合。当血栓占据动脉腔表面积的75%以上时,供给组织的血流量减少到足以引起症状,因为氧气减少(缺氧)和代谢产物如乳酸(“痛风”)的积累。超过90%的阻塞可导致缺氧,完全剥夺氧气和“梗塞”,这是一种细胞死亡模式。
“栓塞”(多次栓塞)是栓子(一个能够在远离其原点的位置堵塞动脉毛细血管床的分离的血管内肿块)进入动脉床的狭窄毛细血管而引起阻塞的事件(血管栓塞)闭塞)在身体的一个遥远的部分。不要将其与原产地阻塞的血栓相混淆。形成栓塞的材料可以有许多不同的来源:如果材料是血液,“栓子”被称为“血栓”;固体物质也可能包含脂肪、细菌残留物、感染组织等。
“缺血”是对组织血液供应的限制,导致细胞代谢所需的氧和葡萄糖短缺(以保持组织存活)。缺血通常由血管问题引起,导致组织损伤或功能障碍。它还意味着身体某一部分的局部贫血症有时是由于充血(如血管收缩、血栓形成或栓塞)引起的。如果在心肌(或“心肌”)中发生“缺血”,则缺血被称为心肌缺血。其他类型的局部缺血例如是脑缺血、严重肢体缺血等。
当缺血一段时间后血液供应返回组织时,发生“再灌注”。在恢复到组织的循环后,可能发展炎症和氧化应激过程。这一系列事件的一个例子是与器官移植相关的缺血再灌注。
“再灌注损伤”是在缺血一段时间后血液供应返回组织并且随后发生炎症和氧化损伤而不是恢复正常功能时引起的组织损伤。缺血问题的再灌注通常与微血管损伤有关,特别是由于毛细血管和小动脉的渗透性增加导致组织中扩散和流体过滤的增加。活化的内皮细胞在再灌注后产生更多的活性氧物质但NO更少,并且不平衡导致炎症反应。通过新返回的血流携带到该区域的白细胞释放大量炎性因子和自由基以响应组织损伤。恢复的血液流动会带来氧气,破坏细胞蛋白质、DNA和质膜。这种缺血-再灌注过程也被认为是导致慢性伤口愈合(例如,压疮或糖尿病性溃疡)的原因。
本文使用的术语“血管病”是血管疾病(动脉,静脉和毛细血管)的总称。最常见和最普遍的血管病是“糖尿病性血管病”,慢性糖尿病的常见并发症。另一种常见类型的血管病是“脑淀粉样血管病”(CAA),也称为嗜刚性血管病,其中淀粉样沉积物形成在中枢神经系统的血管壁中。使用术语congophilic是因为淀粉样蛋白的异常聚集的存在可以通过在应用称为刚果红的特殊染色剂后对脑组织进行显微镜检查来证明。淀粉样物质仅存在于脑中,因此该疾病与其他形式的淀粉样变性无关。
“中风”或脑血管意外(CVA)是由于对大脑的血液供应的干扰而导致的脑功能的快速丧失。这可能是由于阻塞(血栓形成、动脉栓塞、脂肪堆积或痉挛)或出血(血液渗漏)引起的“缺血”(缺乏血流,导致组织缺氧和葡萄糖供应不足)。结果,大脑的受影响区域不能发挥作用,这可能导致无法在身体的一侧移动一个或多个肢体,无法理解或制定语言,或者无法看到视野的一侧。中风的危险因素包括老年、高血压、既往卒中或短暂性脑缺血发作(TIA)、糖尿病、高胆固醇、吸烟和心房颤动。高血压是中风最重要的可改变的危险因素。“缺血性中风”偶尔在医院接受溶栓治疗(也称为“凝块破坏者”),一些出血性中风可从神经外科手术中获益。预防复发可能涉及给予抗血小板药物,如阿司匹林和双嘧达莫,控制和减少高血压,以及使用他汀类药物。选定的患者可能受益于颈动脉内膜切除术和抗凝血剂的使用。
“血管性痴呆”是老年人痴呆症的第二大常见原因。它在男性中更常见,并且通常在70岁以后开始。在患有血管危险因素(例如,高血压、糖尿病、高脂血症、吸烟)和有几次中风的人中更常发生。许多人患有血管性痴呆和阿尔茨海默病。血管性痴呆通常发生在多个小脑梗塞(或有时是出血)导致足够的神经元或轴突丧失以损害脑功能时。血管性痴呆包括以下类型:多发性腔隙性梗死(其中小血管受到影响,梗塞发生在半球白色和灰质内深处);多发梗塞性痴呆(其中中型血管受影响);战略性单梗塞性痴呆(其中单个梗塞发生在大脑的关键区域,如角回或丘脑;Binswanger痴呆或皮质下动脉硬化性脑病(其中小血管性痴呆与严重,控制不良的高血压和全身血管相关)疾病并导致轴突和髓鞘的弥漫性和不规则性丧失伴有广泛的神经胶质增生,由于梗塞导致的组织死亡或脑部白质的血液供应丧失。
术语“神经胶质瘤”是指从脑或脊柱开始的一种肿瘤。它被称为神经胶质瘤,因为它来自神经胶质细胞。胶质瘤最常见的部位是大脑。胶质瘤占所有脑和中枢神经系统肿瘤的约30%,占所有恶性脑肿瘤的80%。
根据美国精神病学协会的精神疾病诊断和统计手册第四版(DSM-IV),术语“性功能障碍”包括一系列“性欲紊乱和与性反应周期相关的心理生理变化”的特征。虽然这种类型的问题很常见,但只有在问题导致患者痛苦时,才会认为存在性功能障碍。性功能障碍可以是身体上的,也可以是心理上的。它可以作为主要病症存在,通常是激素性的,尽管大多数情况下它是继发于其他医学病症或对所述病症的药物治疗。所有类型的性功能障碍可以进一步分类为终身、获得性、情境性或全身性(或其组合)。
DSM-IV-TR规定了“女性性功能障碍”的五大类:性欲/兴趣障碍;“性唤起障碍(包括生殖器,主观和合并)”;性高潮障碍;性交困难和阴道痉挛;和持续的性唤起障碍。
“女性性唤起障碍(FSAD)”被定义为持续或反复无法达到或维持足够程度的性兴奋,导致个人痛苦。FSAD包括缺乏主观兴奋感(即主观性唤起障碍)和缺乏诸如润滑和肿胀(即生殖器/身体性唤起障碍)的体感反应。FSAD可能是严格的心理起源,尽管它通常由医学或生理因素引起或复杂化。低雌激素是与FSAD相关的最常见的生理状况,导致泌尿生殖器萎缩和阴道润滑减少。
如本文所用,“勃起功能障碍(ED)”是男性性功能障碍,其特征在于在性表现期间不能发展或维持阴茎的勃起。阴茎勃起是血液进入并保留在阴茎内的海绵状体内的水力效应。当信号从大脑传递到阴茎神经时,该过程通常由性唤起引发。当勃起难以产生时,表明勃起功能障碍。最重要的有机原因是心血管疾病和糖尿病、神经系统疾病(例如,前列腺切除手术造成的创伤)、激素不足(性腺机能减退)和药物副作用。
在一个实施方案中,本文所述的化合物I的多晶型物和药学上可接受的盐因此可用于预防和/或治疗与循环相关的以下类型的心脏、肺、外周、肝、肾或脑血管/内皮病症、状况和疾病:
·与高血压和冠状动脉血流减少有关的疾病;急性和慢性冠状动脉血压升高;动脉高血压;心脏和肾脏并发症引起的血管疾病;由心脏病、中风、脑缺血或肾衰竭引起的血管疾病;顽固性高血压(resistant hypertension);糖尿病高血压;原发性高血压;继发性高血压;妊娠期高血压;先兆子痫;门静脉高压;心肌梗死;
·心力衰竭,HFPEF,HFREF;急性和慢性心力衰竭;心力衰竭的更具体形式:急性失代偿性心力衰竭,右心室衰竭,左心室衰竭,全心衰,缺血性心肌病,扩张型心肌病,先天性心脏病,心室瓣缺陷性心力衰竭,二尖瓣狭窄,二尖瓣关闭不全,主动脉瓣狭窄,主动脉瓣不足,三尖瓣狭窄,三尖瓣关闭不全,肺动脉瓣狭窄,肺动脉瓣关闭不全,合并瓣膜缺损;糖尿病心衰;酒精性心肌病或储存心肌病;舒张期心力衰竭,收缩期心力衰竭;现有慢性心力衰竭的急性期(心力衰竭恶化);舒张期或收缩期功能障碍;冠状动脉供血不足心律失常;心室前负荷减少;心脏肥大;心力衰竭/心肾综合征;门静脉高压;内皮功能障碍或损伤;心房和心室节律和传导障碍的紊乱:I-III级房室传导阻滞(AVB I-III),室上性快速性心律失常,心房颤动,心房扑动,心室颤动,心室扑动,室性快速性心律失常,扭转性室性心动过速,心房颤动和室性期前收缩,AV结外期收缩,病态窦房结综合征,晕厥,房室结再入性心动过速;Wolff-Parkinson-White综合征或急性冠状动脉综合征;拳击手心肌病(Boxercardiomyopathy);室性早搏;心肌病;癌症诱发的心肌病;化疗引起的心脏毒性;
·血栓栓塞性疾病和缺血;心肌缺血;梗死;心肌梗死;心脏病发作;心肌功能不全;内皮功能障碍;脑卒中;短暂性脑缺血发作(TIAs);阻塞性血栓性血管炎;稳定或不稳定型心绞痛;冠状动脉痉挛或外周动脉痉挛;变异型心绞痛;Prinzmetal心绞痛;心脏肥大;先兆子痫;血栓形成疾病;缺血再灌注损伤;器官移植相关的缺血再灌注;肺移植、心脏移植、静脉移植失败相关的缺血再灌注;创伤患者血液替代物的保存;
·外周血管疾病;外周动脉疾病;外周闭塞性动脉疾病;肌张力增高;雷诺综合症或现象(原发性和继发性);雷诺氏病;严重肢体缺血;外周栓塞;间歇性跛行;血管闭塞性风险;肌营养不良症,Duchenne肌营养不良症,Becker肌营养不良症;微循环异常;血管渗漏或渗透的控制;腰椎管狭窄症;闭塞性血栓性血管炎;血栓性血管炎;外周灌注障碍;动脉和静脉血栓形成;微量白蛋白尿;外周和自主神经病;糖尿病神经性疼痛;糖尿病微血管病变;肝血管闭塞性疾病;镰状细胞病的血管闭塞性风险;高血压风险;
·水肿;心力衰竭引起的肾水肿;
·阿尔茨海默氏病;帕金森病;血管性痴呆;血管性认知障碍;脑血管痉挛;先天性肌无力综合征;蛛网膜下腔出血;创伤性脑损伤;认知障碍(如轻度认知功能障碍、年龄相关学习和记忆障碍、年龄相关性记忆丧失、血管性痴呆、颅脑损伤、脑卒中、脑卒中后痴呆、创伤后头部损伤、一般性注意力障碍、和学习记忆障碍儿童的注意力障碍)后的感知、注意能力、学习能力或记忆表现的改善;路易体痴呆;患有额叶变性的痴呆,包括Pick's综合征;进行性核麻痹;伴有皮质基底节变性的痴呆;肌萎缩侧索硬化症(ALS);亨廷顿氏病;脱髓鞘;多发性硬化症;丘脑退化;Creutzfeldt-Jakob痴呆;艾滋病痴呆;伴痴呆精神分裂症或柯萨科夫精神病;多系统萎缩和其他形式的帕金森综合症;运动障碍;神经保护;焦虑,紧张和抑郁或创伤后应激障碍(PTSD);双相情感障碍;精神分裂症;CNS相关的性功能障碍和睡眠障碍;病理性饮食失调和使用昂贵食品和成瘾药物;控制脑灌注;偏头痛;脑梗塞(脑卒中)后果的预防和控制;中风后果的预防和控制,脑缺血和头部损伤;与CNS疾病相关的神经病变;与MS相关的神经性疼痛;化疗引起的神经性疼痛;与带状疱疹相关的神经性疼痛;与脊柱手术相关的神经性疼痛;
·休克;心源性休克;败血症;感染性休克;过敏性休克;动脉瘤;控制白细胞活化;抑制或调节血小板聚集;多器官功能障碍综合征(MODS);多器官功能衰竭(MOF);
·肺/呼吸系统疾病:肺动脉高压(PH);肺动脉高压(PAH)和相关的肺血管重塑;以局部血栓形成和右心肥大形式的血管重塑;肺性高血压;原发性肺动脉高压;继发性肺动脉高压;家族性肺动脉高压;散发性肺动脉高压;毛细血管前肺动脉高压;特发性肺动脉高压;其他形式的PH;与左心室疾病、HIV、SCD、血栓栓塞(CTEPH)、结节病、慢性阻塞性肺病、肺纤维化、急性呼吸窘迫综合征(ARDS)、急性肺损伤、α-1抗胰蛋白酶缺乏症(AATD)、肺气肿、吸烟诱发肺气肿和囊性纤维化(CF)有关的PH;血栓性肺动脉病;丛生性肺动脉病;囊性纤维化;支气管收缩或肺支气管收缩;急性呼吸综合症;肺纤维化,肺移植;哮喘病;
·与以下关联或相关的肺动脉高血压:左心室功能障碍,低氧血症,WHO组I、II、III、IV和V高血压病,二尖瓣瓣膜病,缩窄性心包炎,主动脉瓣狭窄,心肌病,纵隔纤维化,肺纤维化,肺静脉畸形引流,肺静脉闭塞性疾病,肺血管炎,胶原性血管疾病,先天性心脏病,肺静脉高压,间质性肺病,睡眠呼吸紊乱,睡眠呼吸暂停,肺泡通气不足,长期暴露于高原,新生儿肺部疾病,肺泡-毛细血管发育不良,镰状细胞病,其他凝血功能障碍,慢性血栓栓塞,肺栓塞;肿瘤,寄生虫或异物引起的肺栓塞;结缔组织病,狼疮,狼疮性肾炎,血吸虫病,肉状瘤病,慢性阻塞性肺病,哮喘,肺气肿,慢性支气管炎,肺毛细血管瘤,组织细胞增多症X,淋巴管,压缩肺血管;由于腺病,肿瘤或纤维性纵隔炎引起的压缩肺血管;
·动脉硬化疾病或病症:动脉粥样硬化;与内皮损伤、血小板和单核细胞粘附和聚集、平滑肌增殖或迁移有关的动脉粥样硬化;再狭窄;血栓溶解治疗、经皮腔内血管成形术(PTA)、经腔冠状动脉成形术(PTCAs)、心脏移植、旁路手术或炎症过程后发生的再狭窄;
·微血管和大血管损伤(血管炎);纤维蛋白原水平升高和低密度DLD;纤溶酶原激活物抑制剂1(PA-1)的浓度增加;
·代谢综合征;与代谢综合征相关的代谢疾病或疾病:肥胖症;皮下脂肪过多;过度肥胖;糖尿病;高血压;脂质相关疾病,高脂血症,血脂异常,高胆固醇血症,高密度脂蛋白胆固醇(HDL-胆固醇)降低,低密度脂蛋白胆固醇(LDL-胆固醇)水平中度升高,高甘油三酯血症,高甘油酯血症,低脂蛋白血症,谷甾醇血症,脂肪肝疾病,酒精性脂肪肝病(AFLD),非酒精性脂肪性肝病(NAFLD),肝炎;先兆子痫;多囊肾病进展;肝脏脂肪变性或肝脏脂质积聚异常;非酒精性脂肪性肝炎(NASH);心脏、肾脏或肌肉的脂肪变性;alphabeta脂蛋白血症;谷固醇血症;黄瘤病;丹吉尔病;高氨血症及相关疾病;肝性脑病;其他中毒性脑病;雷氏综合症;
·性、妇科和泌尿系统疾病:勃起功能障碍;阳痿;早泄;女性性功能障碍;女性性唤起功能障碍;性欲减退性唤起症;阴道萎缩;性交困难;萎缩性阴道炎;良性前列腺增生(BPH),前列腺肥大,前列腺增生;膀胱出口梗阻;膀胱疼痛综合征(BPS);间质性膀胱炎(IC);膀胱过度活动;神经源性膀胱和尿失禁;糖尿病肾病;原发性和继发性痛经;下尿路综合征(LUTS);子宫内膜异位症;骨盆疼痛;男性和女性泌尿生殖系统器官的良性和恶性疾病;
·慢性肾病;急慢性肾功能不全;急慢性肾功能衰竭;狼疮性肾炎;潜在或相关的肾脏疾病:低灌注,透析低血压,阻塞性尿路病,肾小球病,肾小球肾炎,急性肾小球肾炎,肾小球硬化症,肾小管间质疾病,肾病,原发性和先天性肾病,肾炎;以肌酐和/或水排泄异常减少为特征的疾病;以尿素、氮、钾和/或肌酸酐血浓度异常升高为特征的疾病;以肾酶活性改变为特征的疾病,以谷氨酰合成酶活性改变为特征的疾病;以尿渗透压或尿量改变为特征的疾病;以微量白蛋白尿增加为特征的疾病,以大量白蛋白尿为特征的疾病;以肾小球和小动脉损伤、肾小管扩张、高磷血症和/或透析需要为特征的疾病;肾功能不全后遗症;与肺灌肠有关的肾功能不全;与HF有关的肾功能不全;与尿毒症或贫血有关的肾功能不全;电解质紊乱(高钾血症,低钠血症);骨和碳水化合物代谢紊乱;急性肾损伤;
·眼部疾病或病症,如青光眼、视网膜病变和糖尿病视网膜病变。
术语“炎症”是指血管组织对有害刺激(例如病原体、受损细胞或刺激物)的复杂生物反应。急性炎症的典型症状是疼痛、发热、发红、肿胀和功能丧失。炎症是有机体去除有害刺激并启动愈合过程的保护性尝试。炎症不是感染的同义词,即使两者经常相关(前者通常是后者的结果)。炎症也可以在没有感染的情况下发生,尽管这种类型的炎症通常是适应不良的(例如在动脉粥样硬化中)。炎症是一种刻板的反应,因此与适应性免疫相比,它被认为是先天免疫的机制,适应性免疫对每种病原体都是特异性的。在没有炎症的情况下逐渐破坏组织会损害生物体的存活。另一方面,慢性炎症可能导致许多疾病,例如枯草热、牙周炎、动脉粥样硬化、类风湿性关节炎、甚至癌症(例如胆囊癌)。因此,炎症通常受到身体的严密调节。炎症可分为急性或慢性。“急性炎症”是身体对有害刺激的初始反应,并且通过血浆和白细胞(尤其是粒细胞)从血液到受损组织的增加的运动来实现。一系列生化事件传播并成熟炎症反应,涉及局部血管系统,免疫系统和受损组织内的各种细胞。被称为“慢性炎症”的延长的炎症导致炎症部位存在的细胞类型的进行性转变,其特征在于炎症过程中组织的同时破坏和愈合。
在另一个实施方案中,本文所述的化合物I的多晶型物和药学上可接受的盐因此可用于预防和/或治疗以下类型的心脏、肺、外周、肝、肾、消化或中枢神经系统状况、病症和疾病。这可能涉及炎症或炎症过程:
·心肌炎症(心肌炎);慢性心肌炎;急性心肌炎;病毒性心肌炎;
·血管炎;胰腺炎;腹膜炎;类风湿病;
·肾脏炎症性疾病;免疫性肾病:肾移植排斥反应,免疫复合物诱发的肾病,毒素引起的肾病,造影剂诱发的肾病;糖尿病和非糖尿病肾病,肾盂肾炎,肾囊肿,肾硬化,高血压性肾硬化和肾病综合征;
·慢性间质性炎症,炎症性肠病(IBD),克罗恩病,溃疡性结肠炎(UC);
·炎症性皮肤病;
·眼部炎症性疾病,睑缘炎,干眼症和修格兰氏症候群;眼睛纤维化。
术语“伤口愈合”是指复杂的过程,其中皮肤(或另一器官或组织)在受伤后自我修复。例如,在正常皮肤中,表皮(最外层)和真皮(内层或更深层)以稳态平衡存在,形成对外部环境的保护屏障。一旦保护屏障被破坏,伤口愈合的正常(生理)过程立即开始运动。经典的伤口愈合模型分为三个或四个连续但重叠的阶段:(1)止血(一些作者不认为是一个阶段),(2)炎症,(3)增殖和(4)重塑。在皮肤受伤时,一系列复杂的生化事件发生在密切协调的级联中,以修复损伤。在损伤后的最初几分钟内,血小板粘附到损伤部位,被激活,聚集(连接在一起),然后激活凝血级联,在交联的纤维蛋白蛋白网中形成聚集的血小板凝块。该凝块阻止活动性出血(“止血”)。在炎症阶段,细菌和细胞碎片被白细胞吞噬并从伤口中除去。血小板衍生的生长因子(储存在血小板的α颗粒中)释放到伤口中,引起增殖期细胞的迁移和分裂。增殖期的特征在于血管生成,胶原沉积,肉芽组织形成,上皮形成和伤口收缩。在“血管生成”中,血管内皮细胞形成新血管。在“纤维组织形成”和肉芽组织形成中,成纤维细胞通过排泄胶原蛋白和纤连蛋白而生长并形成新的临时细胞外基质(ECM)。同时,发生表皮的“再上皮化”,其中上皮细胞在伤口床上增殖和“爬行”,为新组织提供覆盖。在伤口收缩期间,肌成纤维细胞通过抓住伤口边缘并使用类似于平滑肌细胞中的机制收缩来减小伤口的大小。当细胞的作用接近完成时,不需要的细胞会发生细胞凋亡。在成熟和重塑过程中,胶原蛋白被重塑并沿着张力线重新排列,不再需要的细胞被细胞凋亡除去。然而,该过程不仅复杂而且易碎,并且易于中断或失败,导致形成不愈合的慢性伤口(一个例子包括糖尿病伤口或溃疡,特别是糖尿病足溃疡)。导致不愈合的慢性伤口的因素是糖尿病、静脉或动脉疾病、感染和老年代谢缺陷。
术语“骨愈合”或“骨折愈合”是指增殖性生理过程,其中身体促进骨折的修复。在骨折愈合过程中,几个恢复阶段促进了骨折和脱位周围区域的增殖和保护。该过程的长度取决于损伤的程度,并且对于大多数上部身体骨折的修复给出了通常的两到三周的边缘;给予较低的身体伤害四周以上的任何地方。愈合过程主要由“骨膜”(覆盖骨骼的结缔组织膜)决定。骨膜是前体细胞的一种来源,其发育成“成软骨细胞”和成骨细胞,其对于骨的愈合是必需的。骨髓(当存在时)、骨内膜、小血管和成纤维细胞是前体细胞的其他来源。
在另一个实施方案中,本文所述的化合物I的多晶型物和药学上可接受的盐因此可用于治疗以下类型的疾病、病症或状况,其中需要刺激伤口或骨愈合过程:
·糖尿病患者的伤口或溃疡愈合;微血管灌注改善;损伤后微血管灌注改善或抵消围手术期护理中的炎症反应;肛裂;糖尿病溃疡;糖尿病足溃疡;骨愈合;破骨细胞骨吸收和重塑;和新骨形成。
术语“结缔组织”(CT)是指一种支持,连接或分离身体的不同类型的组织和器官的动物组织。它是动物组织的四大类之一,其他是上皮、肌肉和神经组织。到处都可以找到结缔组织,包括中枢神经系统。它位于其他组织之间。所有CT都有三种主要成分-基础物质、纤维和细胞-所有这些成分都浸没在体液中。
术语“结缔组织病症或病症”是指涉及身体的一个或多个部分中的结缔组织异常的任何病症。某些病症的特征在于免疫系统的过度活动,导致对组织的炎症和全身性损伤,通常用结缔组织替换正常组织(例如,某些器官的正常组织)。其他疾病涉及结缔组织本身的生化异常或结构缺陷。其中一些疾病是遗传性的,有些是病因不明。
当结缔组织疾病具有自身免疫起源时,它们被归类为“风湿性疾病”、“自身免疫性风湿性疾病”或“自身免疫性胶原-血管疾病”。
在“自身免疫性疾病”中,身体产生的抗体或其他细胞攻击身体自身的组织。许多自身免疫性疾病影响各种器官中的结缔组织。在自身免疫性疾病中,炎症和免疫应答可导致结缔组织周围以及其他组织(包括重要器官,例如肾脏或胃肠道器官)的结缔组织损伤。围绕心脏的囊(心包膜)、覆盖肺部的膜(胸膜)、纵隔(胸腔中的一组未定的结构,被疏松的结缔组织包围,包含心脏、心脏的大血管、食道、气管、膈神经、心脏神经、胸导管、胸腺和中央胸部的淋巴结)甚至大脑都可能受到影响。
如本文所用的术语“纤维化”是指结缔组织或纤维组织(瘢痕组织、胶原)在身体的某个器官或部分中的累积。如果纤维化由单一细胞系产生,则称为“纤维瘤”。当身体试图修复和替换受损细胞时发生纤维化,因此可以是反应性、良性或病理状态。生理性纤维化与瘢痕形成过程相似。当所讨论的组织反复且连续地受损时,病理状态发展。即使严重,单次发作的伤害通常也不会引起纤维化。如果重复或连续受伤(例如在慢性肝炎中发生),身体会尝试修复损伤,但这些尝试反而导致疤痕组织的过度积聚。瘢痕组织开始取代器官的规则组织,其执行瘢痕组织不能执行的某些功能;它还可以干扰血液流动并限制其他细胞的血液供应。结果,这些其他功能性细胞开始死亡并形成更多的瘢痕组织。当这种情况发生在肝脏时,静脉中的血液从肠道到肝脏(门静脉)的血压增加,从而引起称为“门静脉高压症”的病症。
术语“硬化”是指通常通过用结缔组织替换正常器官特异性组织而通常是柔性的组织或结构或器官的硬化或硬化。
有许多类型的纤维化或纤维化疾病,包括但不限于肺纤维化(特发性肺纤维化、囊性纤维化),肝纤维化(或“肝硬化”),心内膜心肌纤维化,陈旧性心肌梗死,心房纤维化,纵隔纤维化,骨髓纤维化(影响骨髓),腹膜后纤维化,进行性大量纤维化(影响肺部),肾性纤维化(影响皮肤),克罗恩病,关节纤维化,佩罗尼氏病(影响阴茎),杜普征氏掌挛缩(影响手和手指),某些形式的粘连性囊炎(影响肩部)。
存在许多类型的硬化或“硬化疾病”,包括但不限于肌萎缩侧索硬化症(ALS);动脉粥样硬化;局灶性节段性肾小球硬化和肾病综合征;海马硬化(影响大脑);硬化性苔癣(一种硬化阴道和阴茎结缔组织的疾病);肝硬化(肝硬化);多发性硬化症或局灶性硬化症(影响协调的疾病);骨硬化(骨密度显着降低的疾病);耳硬化症(影响耳朵的疾病);结节性硬化症(影响多种系统的罕见遗传病);原发性硬化性胆管炎(胆管硬化);原发性侧索硬化(随意肌肉进行性肌无力);和瘢痕疙瘩。
术语“硬皮病”或“系统性硬化症”或“进行性系统性硬皮病”是指涉及关节,皮肤和内脏器官的瘢痕形成以及血管异常的病症。系统性硬化症有时可以以有限的形式发生,例如有时仅影响皮肤或主要仅影响皮肤的某些部分或作为CREST综合征(其中涉及皮肤的外围区域而不涉及躯干)。系统性硬化症的通常初始症状是肿胀,然后在手指末端增厚和收紧皮肤。“雷诺现象”,其中手指突然和暂时变得非常苍白、刺痛或变得麻木,疼痛或两者兼而有之,这种情况很常见。
术语“多发性肌炎”是指肌肉炎症。术语“皮肌炎”是指伴有皮肤炎症的肌肉炎症。术语“多软骨炎”是指软骨炎症。
术语“嗜酸性粒细胞性筋膜炎”是指一种罕见的疾病,其中嗜酸性粒细胞免疫细胞被释放并导致“筋膜”的炎症和硬化,“筋膜”是皮肤下面、肌肉顶部和肌肉之间的坚韧纤维组织层。筋膜疼痛发炎、肿胀、手臂和腿部逐渐变硬。随着手臂和腿部的皮肤逐渐变硬,它们变得难以移动。最终他们陷入了不寻常的位置。有时,如果涉及手臂,该人可能会发展为腕管综合症。
在另一个实施方案中,可通过施用本文所述的化合物I的多晶型物或药学上可接受的盐治疗和/或预防的特定疾病,包括但不限于涉及炎症、自身免疫或纤维化的以下类型的疾病(即,纤维化疾病):
·泌尿生殖系统和肾脏疾病:糖尿病肾病;慢性肾脏疾病或功能不全引起的肾纤维化和肾功能衰竭;由于积聚/沉积和组织损伤引起的肾纤维化和肾衰竭;肾硬化;进行性硬化症;肾小球肾炎;局灶性节段性肾小球硬化;肾病综合征;前列腺肥大;肾纤维化;间质性肾纤维化;
·肺系统疾病:肺纤维化;特发性肺纤维化;囊性纤维化;进行性大块纤维化;影响肺部的进行性大块纤维化;
·影响心脏的疾病:心内膜心肌纤维化;老年心肌梗死;心房纤维化;心脏间质纤维化;心脏重塑和纤维化;心脏肥大;
·肝脏和相关器官紊乱:肝硬化或肝硬化;肝硬化伴慢性肝病;肝纤维化;肝星状细胞活化;NASH;肝纤维胶原和总胶原蛋白积聚;坏死性和/或免疫性肝病;原发性胆汁性肝硬化;原发性硬化性胆管炎;其他胆汁淤积性肝病:与肉芽肿性肝病、肝脏恶性肿瘤、妊娠期肝内胆汁淤积、肝炎、败血症、药物或毒素、移植物抗宿主病、肝移植后、胆总管结石、胆管肿瘤、胰腺癌、Mirizzi相关综合征、艾滋病胆管病或寄生虫相关的那些;血吸虫病;肝细胞癌;
·消化系统疾病或病症:克罗恩病;溃疡性结肠炎;胃肠道硬化;贲门失弛缓症;
·皮肤或眼睛疾病:肾源性纤维化;增殖性玻璃体视网膜病变;糖尿病性视网膜病变;眼睛纤维化;
·纤维化局部或皮肤病或病症;皮肤纤维化;硬皮病,皮肤纤维化;硬斑病;肥厚性疤痕;痣;瘢痕疙瘩;肉瘤;肉芽肿;
·影响神经系统的疾病:肌萎缩性脊髓侧索硬化症(ALS);海马硬化,多发性硬化症(MS);局灶性硬化;原发性侧索硬化;
·骨骼疾病;骨硬化;
·耳硬化症;其他听力疾病或紊乱;听力损伤,部分或全部听力损失;部分或全部耳聋;耳鸣;噪音引起的听力损失;
·其他涉及自身免疫、炎症或纤维化的疾病:硬皮病;局限性硬皮病或阿狄森氏瘢痕瘤;纵隔纤维化;纤维化纵隔炎;骨髓纤维化;腹膜后纤维化;关节纤维化;阴茎硬结症;杜普伊特伦氏挛缩;硬化性苔藓;某些形式的粘连性囊炎;动脉粥样硬化;结节性硬化症;系统性硬化症;多发性肌炎;皮肌炎;多软骨炎;嗜酸性筋膜炎;系统性红斑狼疮或狼疮;骨髓纤维化,骨髓纤维化或骨髓纤维化;结节病;子宫肌瘤;子宫内膜异位症。
在另一个实施方案中,可通过施用本文所述的化合物I的多晶型物或药学上可接受的盐来治疗和/或预防的特定疾病疾病包括但不限于:某些类型的癌症;镰状细胞病;镰状细胞性贫血;癌转移;骨质疏松症;胃轻瘫;功能性消化不良;糖尿病并发症;脱发;与内皮功能障碍有关的疾病;与一氧化氮生成减少有关的神经系统疾病;精胺丁二酸酶缺乏症;神经肌肉疾病;杜兴肌营养不良症(DMD);Becker肌营养不良症(BMD);肢带肌肉营养不良;远端肌病;I型和II型肌强直性营养不良;面部-肩胛-腓骨肌营养不良;常染色体和X连锁的Emery-Dreifuss肌营养不良症;眼咽肌营养不良症;肌萎缩侧索硬化症;和脊髓肌肉萎缩(SMA)。
在一些实施方案中,本发明涉及治疗受试者的疾病、健康状况或病症的方法,包括向需要治疗的受试者施用治疗有效量的本文所述的化合物I的多晶型物或药学上可接受的盐。其中疾病、健康状况或病症选自上面列出的疾病之一。
在另一个实施方案中,本发明的固体形式可以以植入装置的形式递送,例如支架。支架是插入体内天然通道/导管中的网状管,以防止或抵消疾病引起的局部流动收缩。该术语还可以指用于暂时保持这种天然导管打开以允许进行手术的管。
药物洗脱支架(DES)是置于狭窄的患病外周或冠状动脉中的外周或冠状动脉支架(支架),其缓慢释放药物以阻断细胞增殖,通常是平滑肌细胞增殖。这可以防止纤维化,再加上凝块(血栓),否则会阻塞支架动脉,这个过程称为再狭窄。在血管成形术过程中,介入心脏病专家或介入放射科医师通常将支架置于外周或冠状动脉内。DES中常用于阻断细胞增殖的药物包括紫杉醇或雷帕霉素类似物。
在本发明的一些实施方案中,本发明化合物I的多晶型物或药学上可接受的盐或其药物组合物可通过涂有固体形式或药物组合物的药物洗脱支架递送。涂有固体形式的本发明化合物I(或药物组合物)的药物洗脱支架可用于预防经皮冠状动脉介入治疗期间的支架再狭窄和血栓形成。涂有固体形式的本发明化合物I(或药物组合物)的药物洗脱支架可能能够阻止平滑细胞增殖以及辅助血管再生和插入支架的动脉的内皮组织再生。
用于治疗由冠状动脉闭塞性疾病引起的难治性心绞痛的经皮冠状动脉介入治疗的替代方案是称为冠状动脉旁路移植术(CABG)的手术。CABG仅提供对持续过程的缓解,该过程由于移植物动脉粥样硬化的快速发展而进一步复杂化。隐静脉移植物是CABG手术中最常用的导管。静脉CABG的长期临床成功受到三个主要原因的阻碍:加速移植物动脉粥样硬化、内皮化不完全和血栓形成。
在一些实施方案中,本发明化合物I的固体形式可用于预防CABG期间的隐静脉移植物衰竭。本发明的固体形式可有助于内皮化过程并有助于预防血栓形成。在该适应症中,化合物I的固体形式以凝胶形式局部递送。
术语“疾病”、“病症”和“状况”在本文中可互换使用,指sGC、cGMP和/或NO介导的医学或病理学病症。
如本文所用,术语“受试者”和“患者”可互换使用。术语“受试者”和“患者”是指动物(例如,诸如鸡、鹌鹑或火鸡的鸟,或哺乳动物),特别是包括非灵长类动物(例如,牛、猪、马、绵羊、兔子、豚鼠、大鼠、猫、狗和小鼠)和灵长类动物(例如,猴子、黑猩猩和人类),更具体地说是人类的“哺乳动物”。在一些实施方案中,受试者是非人动物,例如农场动物(例如,马、牛、猪或绵羊),或宠物(例如,狗、猫、豚鼠或兔)。在一些实施方案中,受试者是人。
本发明还提供了治疗受试者的上述疾病、状况和病症之一的方法,包括给予需要治疗的受试者治疗有效量的化合物I的多晶型物或药学上可接受的盐。或者,本发明提供化合物I的多晶型物或药学上可接受的盐在治疗需要治疗的受试者中的这些疾病、状况和病症之一中的用途。本发明进一步提供制备或制备用于治疗这些疾病、状况和病症之一的药物的方法,包括使用化合物I的多晶型物或药学上可接受的盐。
如本文所用,术语“生物样品”是指体外或离体样品,并且包括但不限于细胞培养物或其提取物;从哺乳动物或其提取物中获得的活检材料;血液、唾液、尿液、粪便、精液、眼泪、淋巴液、眼液、玻璃体液或其他体液或其提取物。
如本文所用,术语“治疗”或“治疗”可互换使用。这些术语是指用于获得有益或期望结果的方法,包括但不限于治疗益处。治疗益处包括根除或改善所治疗的潜在疾病;它还包括根除或改善与潜在病症相关的一种或多种症状,使得在患者中观察到改善,尽管患者可能仍然患有潜在病症。
如本文所用,术语“治疗”和“处理”是指减少或改善sGC、cGMP和/或NO介导的病症的进展、严重性和/或持续时间,或改善一种或所述病症的更多症状(优选地,一种或多种可辨别的症状)(即,“管理”而不是“治愈”该病症),由一种或多种疗法的施用(例如,一种或多种治疗剂,例如多晶型物或化合物I的药学上可接受的盐或其本发明的组合物)。在具体实施方案中,术语“治疗”和“处理”是指改善sGC、cGMP和/或NO介导的病症的至少一种可测量的物理参数。在其他实施方案中,术语“治疗”和“处理”是指通过物理上例如稳定可辨别的症状,或通过生理上稳定物理参数,或全部两者,抑制sGC、cGMP和/或NO介导的病症的进展。
如本文所用的术语“预防”是指预先施用药物以避免或预防疾病或病症的一种或多种症状的出现。医学领域的普通技术人员认识到术语“预防”不是绝对术语。在医学领域中,应理解为预防性施用药物以基本上减少病症的可能性或严重性或病症的症状,这是本公开内容中意图的意义。医师案头参考(Physician's Desk Reference),该领域的标准文本,使用了数百次术语“预防”。如其中所使用的,关于病症或疾病的术语“预防”是指在疾病或病症完全表现出来之前避免疾病或病症的原因、作用、症状或进展。
在一个实施方案中,本发明的方法是对患者,特别是人的预防性或“先发制人”措施,其具有发展sGC、cGMP和/或NO相关疾病、障碍或症状的倾向(例如,遗传倾向)。
在其他实施方案中,本发明的方法是对患有疾病、病症或状况的患者,特别是人的预防性或“先发制人”措施,使得其有发展sGC、cGMP和/或NO相关疾病、障碍或症状的风险。
本文所述的化合物和药物组合物可单独使用或组合使用,用于治疗或预防由sGC、cGMP和/或NO介导、调节或影响的疾病或病症。
本文公开的化合物和组合物还可用于兽医治疗伴侣动物、外来动物和农场动物,包括但不限于狗、猫、小鼠、大鼠、仓鼠、沙鼠、豚鼠、兔、马、猪和牛。
在其他实施方案中,本发明提供刺激生物样品中sGC活性的方法,包括使所述生物样品与本发明的化合物或组合物接触。在生物样品中使用sGC刺激剂可用于本领域技术人员已知的各种目的。此类目的的实例包括但不限于生物测定和生物样本储存。
联合疗法
本文所述的固体形式和药物组合物可与一种或多种另外的治疗剂联合使用。对于与一种以上活性剂的组合治疗,其中活性剂在分开的剂量制剂中,活性剂可以单独给药或联合给药。另外,一种元素的给药可以在施用另一种药剂之前、同时或之后进行。
当与其他药剂共同给药时,例如当与另一种止痛药共同给药时,第二药剂的“有效量”将取决于所用药物的类型。合适的剂量对于批准的药剂是已知的,并且可以由技术人员根据受试者的状况,所治疗的病症的类型和本文所述的化合物的剂量进行调整。如果没有明确说明剂量,则应假定有效剂量。例如,本文所述的化合物可以以约0.01至约10000mg/kg体重/天,约0.01至约5000mg/kg体重/天,约0.01至约3000mg/kg体重/天,约0.01至约1000mg/kg体重/天,约0.01至约500mg/kg体重/天,约0.01至约300mg/kg体重/天,约0.01至约100mg/kg体重/天的剂量范围给予受试者。
当使用“组合疗法”时,可以使用第一剂量的式I或表I的化合物或其药学上可接受的盐和第二剂量的另外的合适的治疗剂来实现有效剂量。
在本发明的一个实施方案中,式I或表I的化合物或其药学上可接受的盐和另外的治疗剂各自以有效剂量施用(即,各自以治疗有效的量施用,如果单独使用)。在另一个实施方案中,式I或表I的化合物或其药学上可接受的盐和另外的治疗剂各自以单独不提供治疗效果(亚治疗剂量)的剂量施用。在另一个实施方案中,式I或表I的化合物或其药学上可接受的盐可以以有效剂量施用,而另外的治疗剂以亚治疗剂量施用。在另一个实施方案中,式I或表I的化合物或其药学上可接受的盐可以亚治疗剂量施用,而另外的治疗剂,例如合适的癌症治疗剂,以有效剂量施用。
如本文所用,术语“组合”或“共同施用”可互换使用,指使用一种以上疗法(例如,一种或多种预防和/或治疗剂)。术语的使用不限制向受试者施用治疗(例如,预防和/或治疗剂)的顺序。
共同施用包括以基本上同时的方式施用第一和第二量的化合物,例如在单一药物组合物中,例如,具有固定比率的第一和第二量的胶囊或片剂,或多个,每个单独的胶囊或片剂。此外,这种共同给药还包括以任何顺序以顺序方式使用每种化合物。当共同施用涉及单独施用第一量的式I或表I的化合物或其药学上可接受的盐和第二量的另外的治疗剂时,所述化合物在足够接近的时间内施用以具有理想的治疗效果。例如,每次给药之间可以产生所需治疗效果的时间可以是几分钟到几小时,并且可以考虑每种化合物的性质如效力、溶解度、生物利用度、血浆半衰期和动力学曲线。例如,式I或表I的化合物或其药学上可接受的盐和第二治疗剂可以在彼此约24小时内,彼此在约16小时内,彼此在约8小时内,彼此在约4小时内,彼此在约1小时内,或彼此在约30分钟内以任何顺序施用。
更具体地,可以在(例如,5分钟,15分钟,30分钟,45分钟,1小时,2小时,4小时,6小时,12小时,24小时,48小时,72小时,96小时,1周,2周,3周,4周,5周,6周,8周或12周前)之前施用第一疗法(例如,预防或治疗剂,例如本文所述的化合物),同时或(例如,5分钟,15分钟,30分钟,45分钟,1小时,2小时,4小时,6小时,12小时,24小时,48小时,72小时,96小时,1周,2周,3周,4周,5周,6周,8周或12周)之后给受试者施用第二疗法(例如,预防或治疗剂,例如抗癌剂)。
可以与式I或表I的化合物或其药学上可接受的盐组合单独给药或者在相同的药物组合物中给药的其他治疗剂的实例,包括但不限于:
(1)内皮衍生释放因子(EDRF);
(2)NO供体,如亚硝基硫醇,亚硝酸盐,悉尼酮亚胺(sydnonimine),NONOate,N-亚硝基胺,N-羟基亚硝胺,亚硝基亚胺,硝基酪氨酸,二氮杂二胺,氧杂三唑5-亚胺,肟,羟胺,N-羟基胍,羟基脲或呋咱。这些类型化合物的一些实例包括:三硝酸甘油酯(也称为GTN,硝酸甘油,硝化甘油和三硝基甘油),甘油的硝酸酯;硝普钠(SNP),其中一氧化氮分子与铁金属配位,形成方形双锥体复合物;3-吗啉代壬亚胺(SIN-1),一种由吗啉和悉尼酮亚胺组合形成的两性离子化合物;S-亚硝基-N-乙酰基青霉胺(SNAP),具有亚硝基硫醇官能团的N-乙酰化氨基酸衍生物;二亚乙基三胺/NO(DETA/NO),一种与二亚乙基三胺共价连接的一氧化氮化合物;和NCX 4016,乙酰水杨酸的间硝基氧基甲基苯基酯。这些类型的NO供体中的一些的更具体的实例包括:经典的硝基类扩张剂,例如有机硝酸盐和亚硝酸酯,包括硝酸甘油,亚硝酸戊酯,硝酸异山梨酯异山梨酯,5-单硝酸异山梨酯和尼可地尔;异山梨醇FK 409(NOR-3);FR144420(NOR-4);3-吗啉悉尼酮亚胺;林西多明氯水合物(“SIN-1”);S-亚硝基-N-乙酰基青霉胺(“SNAP”);AZD3582(CINOD先导化合物),NCX 4016,NCX 701,NCX 1022,HCT 1026,NCX1015,NCX 950,NCX 1000,NCX 1020,AZD 4717,NCX 1510/NCX 1512,NCX 2216和NCX 4040(均可从NicOx SA获得),S-亚硝基谷胱甘肽(GSNO),硝普钠,V-Pyrro-NO,S-亚硝基谷胱甘肽单乙酯(GSNO-酯),6-(2-羟基-1-甲基-亚硝基肼基)-N-甲基-1-己胺(NOC-9)或二乙胺NONOate。一氧化氮供体也如美国专利No.5,199,080、美国专利5,155,137、5,366,997、5,405,919、5,650,442、5,700,830、5,632,981、6,290,981、5,691,423、5,721,365、5,714,511、6,511,911和5,814,666,Chrysselis等(2002)J Med Chem.45:5406-9(例如NO供体14和17),以及《一氧化氮供体:药学和生物学研究(Nitric Oxide Donors forPharmaceutical and Biological Research)》,编辑:Peng George Wang,Tingwei BillCai,Naoyuki Taniguchi,Wiley,2005中所公开。
(3)增强cGMP浓度的其他物质,如原卟啉IX、花生四烯酸和苯肼衍生物;
(4)一氧化氮合酶底物:例如,基于n-羟基胍的类似物,如N[G]-羟基-L-精氨酸(NOHA),1-(3,4-二甲氧基-2-氯亚苄基氨基)-3-羟基胍和PR5(1-(3,4-二甲氧基-2-氯亚苄基氨基)-3-羟基胍);L-精氨酸衍生物(如homo-Arg,homo-NOHA,N-叔丁氧基-和N-(3-甲基-2-丁烯基)氧-L-精氨酸,刀豆氨酸,ε-胍-己酸,胍丁胺,羟基-胍丁胺和L-酪氨酰-L-精氨酸);N-烷基-N'-羟基胍(如N-环丙基-N'-羟基胍和N-丁基-N'-羟基胍),N-芳基-N'-羟基胍(如N-苯基-N'-羟基胍和其对位取代的衍生物分别带有-F,-Cl,-甲基,-OH取代基);胍衍生物如3-(三氟甲基)丙基胍;和其他人在Cali等人(2005,Current Topics in MedicinalChemistry 5:721-736)的评论,以及在其中引用的参考文献中公开;
(5)增强eNOS转录的化合物:例如WO02/064146,WO02/064545,WO02/064546和WO02/064565,和相应的专利文献,例如US2003/0008915,US2003/0022935,US2003/0022939和US2003/0055093中描述的化合物。其他eNOS转录增强子,包括US20050101599中描述的那些(例如,2,2-二氟苯并[1,3]二氧杂环戊烯-5-羧酸茚-2-基酰胺和4-氟-N-(茚满-2-基)-苯甲酰胺)和Sanofi-Aventis化合物AVE3085和AVE9488(CA登记号916514-70-0;等,Journal of Thrombosiis and Homeostasis 2005;Volume 3,Supplement 1:abstractnumber P1487);
(6)没有独立的血红素独立的sGC激活剂,包括但不限于:BAY 58-2667(参见专利公开DE19943635)
HMR-1766(ataciguat sodium,参见专利公开WO2000002851)
S 3448(2-(4-氯-苯磺酰基氨基)-4,5-二甲氧基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺(参见专利公开DE19830430和WO2000002851)
HMR-1069(Sanofi-Aventis)。
(7)血红素依赖性sGC刺激剂,包括但不限于:
YC-1(参见专利公开EP667345和DE19744026)
Riociguat(BAY 63-2521,Adempas,商品,描述于DE19834044)
Neliciguat(BAY 60-4552,描述于WO 2003095451)
Vericiguat(BAY 1021189,Riociguat的临床备份),
BAY 41-2272(描述于DE19834047和DE19942809)
BAY 41-8543(描述于DE19834044)
Etriciguat(描述于WO 2003086407)
CFM-1571(参见专利公开WO2000027394)
A-344905,其丙烯酰胺类似物A-350619和氨基嘧啶类似物A-778935。
化合物在以下公开申请之一中公开:US20090209556,US8455638,US20110118282(WO2009032249),US20100292192,US20110201621,US7947664,US8053455(WO2009094242),US20100216764,US8507512,(WO2010099054)US20110218202(WO2010065275),US20130012511(WO2011119518),US20130072492(WO2011149921),US20130210798(WO2012058132),Tetrahedron Letters(2003),44(48):8661-8663中公开的其他化合物。
(8)抑制cGMP降解的化合物,例如:
PDE5抑制剂,例如西地那非(Viagra)和其他相关药剂,例如Avanafil,Lodenafil,Mirodenafil,枸橼酸西地那非(Revatio),他达拉非(Cialisfil)或伐地那非(Udenafil)和乌地那非;前列地尔;和双嘧达莫;PF-00489791
PDE9抑制剂,例如PF-04447943;
(9)钙通道阻滞剂,例如:
二氢吡啶类钙通道阻滞剂:氨氯地平(Norvasc),阿雷地平(Sapresta),阿折地平(Calblock),巴尼地平(HypoCa),贝尼地平(Coniel),西尼地平(Atelec,Cinalong,Siscard),氯维地平(Cleviprex),地尔硫卓,依福地平(Landel),非洛地平(Plendil),拉西地平(Motens,Lacipil),乐卡地平(Zanidip),马尼地平(Calslot,Madipine),尼卡地平(Cardene,Carden SR),硝苯地平(Procardia,Adalat),尼伐地平(Nivadil),尼莫地平(Nimotop),尼索地平(Baymycard,Sular,Syscor),尼群地平(Cardif,Nitrepin,Baylotensin),普拉地平(Acalas),伊拉地平(Lomir);
苯丙氨酰胺钙通道阻滞剂:维拉帕米(Calan,Isoptin)
加洛帕米(Procorum,D600);
苯并硫氮杂卓:地尔硫卓(Cardizem);
非选择性钙通道抑制剂,如:咪拉地尔,苄普地尔和氟司必林,芬地林;
(10)内皮素受体拮抗剂(ERAs):例如双重(ETA和ETB)内皮素受体拮抗剂波生坦(以销售);西他生坦,以的名称销售;安贝生坦在美国以销售;双/非选择性内皮素拮抗剂Actelion-1,于2008年进入临床试验;
(11)前列环素衍生物或类似物:例如前列环素(前列腺素I2),依前列醇(合成前列环素,以销售);曲前列环素IloprostIloprost(以销售);口服和吸入形式的正在开发中;Beraprost是一种口服前列腺素,可在日本和韩国使用;
(12)抗高脂血症,例如:胆汁酸螯合剂(例如,考来烯胺,考来替泊,考来替兰和考来维仑);他汀类药物如阿托伐他汀,辛伐他汀,洛伐他汀,氟伐他汀,匹伐他汀,瑞舒伐他汀和普伐他汀;伊折麦布等胆固醇吸收抑制剂;其他降脂剂如二十碳五烯酸乙酯,Omega-3-酸乙酯,Reducol;纤维酸衍生物如氯贝特,苯扎贝特,克利贝特,吉非贝齐,氯烟贝特,比尼贝特,非诺贝特,环丙贝特,非诺贝特胆碱;烟酸衍生物,如阿西莫司和烟酸;他汀类药物,烟酸,肠道胆固醇吸收抑制补充剂(依泽替米贝等)和贝特类药物的组合;抗血小板治疗,如氯吡格雷硫酸氢盐;
(13)抗凝剂,如下列类型:
·香豆素(维生素K拮抗剂):(香豆素)主要用于美国和英国;和主要用于其他国家;
·肝素和衍生物质,如:肝素;低分子量肝素,磺达肝素和艾卓肝素;
·直接凝血酶抑制剂,如:阿加曲班,来匹卢定,比伐卢定和达比加群酯;希美加群未在美国获得批准;
·组织纤溶酶原激活剂,用于溶解凝块和解除阻塞动脉,如阿替普酶;
(14)抗血小板药物:例如噻吩并吡啶类,例如氯吡格雷和噻氯匹定;潘生丁;阿司匹林;
(15)ACE抑制剂,例如以下类型:
·含巯基的试剂,如甲巯丙脯酸(商品名),第一种ACE抑制剂和佐芬普利;
·含有二羧酸盐的药物,如依那普利雷米普利喹那普利培哚普利赖诺普利和贝那普利
·含膦酸盐的药剂,如:福辛普利;
·天然存在的ACE抑制剂,如:Casokinins和lactokinins,是摄入乳制品,尤其是培养乳后天然存在的酪蛋白和乳清的分解产物;由益生菌瑞士乳杆菌或酪蛋白衍生的乳酸三肽Val-Pro-Pro和Ile-Pro-Pro也具有ACE抑制和抗高血压功能;
·其他ACE抑制剂,如阿拉普利,地拉普利,西拉普利,咪达普利,群多普利,替莫普利,莫昔普利,螺普利,
(16)补充氧疗;
(17)β受体阻滞剂,如下列类型:
·非选择性药物:(具有额外的α-阻断活性),(具有额外的α-阻断活性),(具有内在的拟交感神经活性), (具有内在的拟交感神经活性),Oxprenonol,Acebutolol,Sotalol,Mepindolol,Celiprolol,Arotinolol,Tertatolol,Amosulalol,Nipradilol,和
·β1-选择性药物:(具有内在的拟交感神经活性), 盐酸多巴酚丁胺,马来酸伊索拉定,卡维地洛,他林洛尔,和
·β2-选择性药物:(弱α-肾上腺素能激动剂活性);
(18)抗心律失常药如下列类型:
·I型(钠通道阻滞剂):奎尼丁,利多卡因,苯妥英,普罗帕酮
·III型(钾通道阻滞剂):胺碘酮,多非利特,索他洛尔
·V型:腺苷,地高辛
(19)利尿剂如:噻嗪类利尿剂,例如氯噻嗪,氯噻酮和氢氯噻嗪,苄氟甲噻嗪,环噻嗪,甲基噻嗪,聚噻嗪,喹吖啶,西咪酰胺,甲氧苄啶,吲达帕胺,辛可兰;袢利尿剂,如呋塞米和Toresamide;保钾利尿剂如阿米洛利,螺内酯,坎利酸钾,依普利酮和氨苯喋呤;这些药剂的组合;其他利尿剂如乙酰唑胺和卡培立肽
(20a)直接作用的血管扩张剂,例如盐酸肼苯哒嗪,二氮嗪,硝普钠,卡拉嗪;其他血管扩张剂,如硝酸异山梨酯和5-硝酸异山梨酯;
(20b)外源性血管扩张剂,例如:
·腺苷激动剂主要用作抗心律失常药;
·阿尔法阻滞剂(阻断肾上腺素的血管收缩作用):
α-1-肾上腺素能受体拮抗剂如哌唑嗪,吲哚拉明,乌拉地尔,布那唑嗪,特拉唑嗪,多沙唑嗪
·心房利钠肽(ANP);
·乙醇;
·组胺诱导剂,补充蛋白质C3a,C4a和C5a通过触发肥大细胞和嗜碱性粒细胞释放组胺起作用;
·四氢大麻酚(THC),大麻中的主要活性化学物质,具有轻微的血管舒张作用;
·罂粟碱,一种在罂粟罂粟中发现的生物碱;
(21)支气管扩张剂:有两种主要类型的支气管扩张剂,β2激动剂和抗胆碱能药,示例如下:
·β2受体激动剂:或沙丁胺醇(常用品牌名称:Ventolin)和是短效β2受体激动剂,可迅速缓解COPD症状。长效β2受体激动剂(LABAs),如和
·抗胆碱能药:是最广泛使用的短效抗胆碱能药物。噻托溴铵是COPD中最常用的长效抗胆碱能药物;
·支气管扩张剂和磷酸二酯酶抑制剂;
(22)皮质类固醇:如倍氯米松,甲基强的松龙,倍他米松,泼尼松,泼尼松龙,曲安奈德,地塞米松,氟替卡松,氟尼缩松和氢化可的松,以及布地奈德等皮质类固醇类似物
(23)膳食补充剂,例如:ω-3油;叶酸,烟酸,锌,铜,韩国红参,银杏,松树皮,蒺藜(Tribulus terrestris),精氨酸,燕麦,角质山羊杂草,马卡根,巴西榥榥木(muirapuama),锯棕榈和瑞典花粉;维生素C,维生素E,维生素K2;睾酮补充剂,睾酮透皮贴剂;Zoraxel,Naltrexone,Bremelanotide(前身为PT-141),Melanotan II,hMaxi-K;Prelox:天然成分,L-精氨酸天冬氨酸和碧萝芷的专有混合物/组合;
(24)PGD2受体拮抗剂,包括但不限于,在美国公开申请US20020022218,US20010051624和US20030055077,PCT公开申请W09700853,W09825919,WO03066046,WO03066047,WO03101961,WO03101981,WO04007451,WO0178697,WO04032848,WO03097042,WO03097598,WO03022814,WO03022813和WO04058164,欧洲专利申请EP945450和EP944614中描述为具有PGD2拮抗活性的化合物,以及在Torisu等人2004 Bioorg Med Chem Lett 14:4557,Torisu等2004 Bioorg Med Chem Lett 2004 14:4891,和Torisu等2004 Bioorg&Med Chem 200412:4685中列出的那些;
(25)免疫抑制剂诸如环孢素(环孢素A,),他克莫司(FK-506,),雷帕霉素(西罗莫司,)和其他FK-506型免疫抑制剂,和麦考酚酯,例如,麦考酚酸吗乙酯
(26)非甾体抗哮喘诸如β2激动剂(例如,特布他林,奥西那林,非诺特罗,乙基异丙肾上腺素,沙丁胺醇,沙美特罗,比托特罗和吡布特罗),β2激动剂,皮质类固醇的组合(例如,沙美特罗,氟替卡松福莫特罗-布地奈德),茶碱,色甘酸,色甘酸钠,奈多罗米,阿托品,异丙托溴铵,异丙托溴铵,白三烯生物合成抑制剂(zileuton,BAY1005);
(27)非甾体抗炎剂(NSAIDS),诸如丙酸衍生物(例如,阿明洛芬,苯恶洛芬,布氯酸,卡洛芬,芬布芬,非诺洛芬,氟洛芬,氟比洛芬,布洛芬,吲哚洛芬,酮洛芬,咪洛芬,萘普生,奥沙普秦,吡罗芬,普拉洛芬,舒洛芬,噻洛芬酸和硫噁洛芬),醋酸衍生物(如吲哚美辛,阿西美辛,阿洛芬,环氯茚酸,双氯芬酸,芬氯酸,芬克洛酸,芬替酸,乙基二氢苯并呋喃乙酸,异丁芬酸,伊索克酸,奥西平酸,舒林酸,二氢氧二苯并硫杂,托麦汀,齐多美辛和佐美酸),芬那酸衍生物(例如,氟芬那酸,甲氯芬那酸,甲芬那酸,尼氟酸和托芬那酸),联苯羧酸衍生物(例如,二氟尼柳和氟苯柳),昔康类(例如,伊索昔康,吡罗昔康,舒多昔康和替诺昔康),水杨酸盐(如乙酰水杨酸和柳氮磺胺吡啶)和吡唑啉酮(如阿帕酮,苯并吡咯烷,芬吡酯,保守霉素,羟基保泰松和保泰松);
(28)环氧合酶-2(COX-2)抑制剂,例如塞来昔布罗非考昔伐地考昔,艾托考昔,帕瑞昔布和罗美昔布;(阿片类镇痛药,如可待因,芬太尼,氢吗啡酮,左啡烷,哌替啶,美沙酮,吗啡,羟考酮,羟吗啡酮,丙氧芬,丁丙诺啡,布托啡诺,地佐辛,纳布啡和喷他佐辛;和
(29)抗糖尿病药,如胰岛素和胰岛素模拟物,磺脲类(如格列本脲,格列本脲,格列吡嗪,格列齐特,格列喹酮,格列美脲,Meglinatide,甲苯磺丁脲,氯磺丙脲,乙酰苯磺酰环己脲,甲磺氮草脲),双胍类,例如二甲双胍α-葡萄糖苷酶抑制剂(如阿卡波糖,依帕司他,伏格列波糖,米格列醇),噻唑烷酮类化合物,如罗格列酮(文迪雅),曲格列酮环格列酮,吡格列酮和恩格列酮;胰岛素敏化剂,如吡格列酮和罗格列酮;胰岛素促分泌素如瑞格列奈,那格列奈和米格列奈;包括Exanatide和利拉鲁肽在内的肠促胰岛素模拟物;Amylin类似物如普兰林肽;葡萄糖降低剂如吡啶甲酸铬(任选与生物素结合);二肽基肽酶IV抑制剂,例如西他列汀,维达列汀,沙格列汀,阿格列汀和利格列汀;目前正在开发用于治疗糖尿病的疫苗;AVE-0277,Alum-GAD,BHT-3021,IBC-VS01;用于治疗糖尿病的发展中的细胞因子靶向疗法,例如阿那白滞素,那可马单抗,双醋瑞因,Gevokizumab,LY-2189102,MABP-1,GIT-027;
(30)HDL胆固醇增加剂,例如Anacetrapib,MK-524A,CER-001,DRL-17822,Dalcetrapib,JTT-302,RVX-000222,TA-8995;
(31)抗肥胖药物,如盐酸甲基苯丙胺,盐酸安非拉酮芬特明盐酸苯并噻嗪酒石酸苯二甲吗啉马吲哚奥利司他西布曲明盐酸盐一水合物利莫那班安非泼拉酮,吡啶甲酸铬,RM-493,TZP-301;苯丁胺/托吡酯,安非他酮,西布曲明/二甲双胍,安非他酮SR/唑尼沙胺SR,沙美特罗,昔萘酸盐/丙酸氟替卡松等组合物;盐酸氯卡色林,芬特明/托吡酯,安非他酮,头孢曲坦,艾塞那肽,KI-0803,利拉鲁肽,盐酸二甲双胍,西布曲明/二甲双胍,876167,ALS-L-1023,安非他酮SR/唑尼沙胺SR,CORT-108297,Canagliflozin,吡啶甲酸铬,GSK-1521498,LY-377604,Metreleptin,Obinepitide,P-57AS3,PSN-821,沙美特罗昔萘酸盐/丙酸氟替卡松,钨酸钠,生长激素(重组),TM-30339,TTP-435,替莫瑞林,特索芬辛,韦利贝特,唑尼沙胺,BMS-830216,ALB-127158,AP-1030,ATHX-105,AZD-2820,AZD-8329,Beloranib hemiocaalate,CP-404,HPP-404,ISIS-FGFR4Rx,胰高血糖素,KD-3010PF,05212389,PP-1420,PSN-842,肽YY3-36,白藜芦醇,S-234462;S-234462,Sobetirome,TM-38837,四氢大麻酚,ZYO-1,β-拉帕醌;
(32)血管紧张素受体阻滞剂,如氯沙坦,缬沙坦,坎地沙坦西酯,依普罗沙坦,厄贝沙坦,替米沙坦,奥美沙坦酯,阿齐沙坦酯;
(33)肾上腺素抑制剂,如阿利吉仑半氟双胍;
(34)中枢作用的α-2-肾上腺素能受体激动剂,例如甲基多巴,可乐定,胍法辛;
(35)肾上腺素能神经元阻滞剂,如胍乙啶,胍那决尔;
(36)咪唑啉I-1受体激动剂,例如磷酸二氢嘧啶核苷和盐酸莫索尼定水合物;
(37)醛固酮拮抗剂,如螺内酯和依普利酮
(38)钾通道活化剂,如吡那地尔
(39)多巴胺D1激动剂,例如甲磺酸非诺多泮;其他多巴胺激动剂,如异波帕胺,多培沙明和多卡巴胺;
(40)5-HT2拮抗剂,如酮色林;
(42)加压素拮抗剂,例如托伐普坦;
(43)钙通道敏化剂如左西孟旦或活化剂如尼可地尔;
(44)PDE-3抑制剂,例如氨力农,米力农,依诺莫酮,维纳啉酮,匹莫苯,奥普力农;
(45)腺苷酸环化酶活化剂,例如盐酸柯福辛达洛比;
(46)正性肌力药,如地高辛和甲地高辛;代谢性强心剂,如泛癸利酮;脑神经肽如奈西立肽;
(47)用于治疗勃起功能障碍的药物,如前列地尔,阿肽地尔,甲磺酸酚妥拉明,维格,前列地尔;
(48)抗肥胖药物:
(49)用于治疗阿尔茨海默病的药物:例如,用于轻度至中度阿尔茨海默病的胆碱酯酶抑制剂,包括(加兰他敏),(利凡斯的明)和(多奈哌齐),(他克林);(美金刚),一种N-甲基D-天冬氨酸(NMD A)拮抗剂和用于治疗中度至重度阿尔茨海默病;维生素E(一种抗氧化剂)。
(50)抗抑郁药:三环类抗抑郁药,如阿米替林地昔帕明丙咪嗪阿莫沙平去甲替林;选择性5-羟色胺再摄取抑制剂(SSRI),如帕罗西汀氟西汀舍曲林和柠檬醛其他如多塞平和曲唑酮SNRIs(例如文拉法辛和瑞波西汀);多巴胺能抗抑郁药(例如安非他酮和安咪奈汀)。
(51)神经保护剂:例如,美金刚,左旋多巴,溴隐亭,培高利特,利克索,普拉克索,卡麦角林,目前正在研究的神经保护剂,包括抗凋亡药物(CEP 1347和CTCT346),拉扎洛依,生物能量学,抗谷氨酸能药物和多巴胺受体。其他临床评价的神经保护剂是例如单胺氧化酶B抑制剂司来吉兰和雷沙吉兰,多巴胺激动剂和复合物I线粒体强化剂辅酶Q10。
(52)抗精神病药物:例如齐拉西酮(GeodonTM),利培酮(RisperdalTM)和奥氮平(ZyprexaTM)。
(53)NEP抑制剂,例如沙卡布曲,奥马曲拉。
(54)亚甲基蓝(MB)。
试剂盒
本文所述的化合物和药物制剂可以包含在试剂盒中。所述试剂盒可包括单剂量或多剂量的两种或更多种药剂,每种药剂单独包装或配制,或单剂量或多剂量的两种或更多种药剂组合包装或配制。因此,一种或多种试剂可以存在于第一容器中,并且试剂盒可以任选地在第二容器中包含一种或多种试剂。一个或多个容器放置在包装内,并且包装可任选地包括给药或剂量说明。试剂盒可以包括其他组分,例如注射器或用于施用药剂的其他装置以及稀释剂或其他配制方法。因此,试剂盒可包含:a)药物组合物,其包含本文所述的化合物和药学上可接受的载体、媒介物或稀释剂;b)容器或包装。试剂盒可任选地包含描述在本文所述的一种或多种方法中使用药物组合物的方法的说明书(例如,预防或治疗本文所述的一种或多种疾病和病症)。所述试剂盒可任选地包含第二药物组合物,其包含一种或多种本文所述的用于共同治疗的其他药剂,药学上可接受的载体、媒介物或稀释剂。包含本文所述化合物和试剂盒中包含的第二药物组合物的药物组合物可任选地组合在同一药物组合物中。
试剂盒包括用于容纳药物组合物的容器或包装,并且还可以包括分开的容器,例如分开的瓶子或分开的箔包。容器可以是例如纸或纸板盒,玻璃或塑料瓶或罐,可重复密封的袋(例如,用于容纳片剂的“再填充物”以放置到不同的容器中)或泡罩包装。根据治疗方案,用个别剂量按压包装。可以在单个包装中一起使用多于一个容器以销售单一剂型。例如,片剂可以包含在瓶子中,瓶子又包含在盒子中。
试剂盒的实例是所谓的泡罩包装。泡罩包装在包装工业中是众所周知的,并且广泛用于药物单位剂型(片剂,胶囊等)的包装。泡罩包装通常由一片相对硬的材料构成,该材料覆盖有优选透明的塑料材料的箔。在包装过程中,在塑料箔中形成凹槽。凹槽具有待包装的单个片剂或胶囊的尺寸和形状,或者可具有尺寸和形状以容纳待包装的多个片剂和/或胶囊。接下来,将片剂或胶囊相应地放置在凹槽中,并且在箔的与形成凹槽的方向相反的面上将相对硬的材料片密封在塑料箔上。结果,片剂或胶囊根据需要单独密封或共同密封在塑料箔和片材之间的凹槽中。优选地,片材的强度使得片剂或胶囊可以通过在凹槽上手动施加压力从泡罩包装中取出,由此在凹槽的位置处在片材中形成开口。然后可以通过所述开口除去片剂或胶囊。
可能需要提供书面记忆辅助,其包含关于何时服用药物的医生,药剂师或受试者的信息和/或指令。“每日剂量”可以是单个片剂或胶囊或在给定的一天服用的几个片剂或胶囊。当试剂盒包含单独的组合物时,试剂盒的一种或多种组合物的日剂量可以由一种片剂或胶囊组成,而试剂盒的另一种或多种组合物的日剂量可以由几种片剂或胶囊组成。试剂盒可以采用分配器的形式,该分配器设计成按照其预期用途的顺序一次一个地分配每日剂量。分配器可以配备记忆辅助装置,以便进一步促进对方案的依从性。这种记忆辅助器的一个例子是机械计数器,它指示已经分配的每日剂量的数量。这种记忆辅助的另一个例子是电池供电的微芯片存储器,其与液晶读出器或听觉提醒信号耦合,例如,读出最后一次每日剂量的日期和/或提醒一个何时服用下一剂。
实施例
实施例1:粗化合物I的制备
i):化合物(1')和N,O-二甲基羟胺的偶联,得到N-甲氧基-N-甲基异噁唑-3-甲酰胺(2')
将异噁唑-3-羧酸((1'),241.6g,2137mmol,1.0当量)、甲苯(1450mL)和DMF(7.8g,107mmol,0.05当量)加入到配备有机械搅拌器和数字温度计的适当的反应容器中。将所得浆液加热至45-50℃。然后通过加料漏斗在2小时内加入草酰氯(325g,2559mmol,1.2当量),同时保持反应温度在45至50℃之间,并观察到剧烈的气体逸出。加入后得到棕色混合物。将棕色混合物在1小时内加热至87至92℃并在87至92℃下搅拌1小时。如HPLC所示完成反应。在加热过程中,棕色混合物变成深色溶液。通过将一部分反应混合物骤冷成哌啶并通过HPLC监测哌啶酰胺来监测反应。将深色混合物冷却至20-25℃,然后通过烧结玻璃漏斗过滤以除去任何不溶物。将黑色滤液减压浓缩至体积为400mL深色油状物。
将碳酸钾(413g,2988mmol,1.4当量)和水(1000mL)加入到配备有机械搅拌器和数字温度计的合适反应容器中。将反应溶液冷却至-10至-5℃。将N,O-二甲基羟胺盐酸盐(229g,2348mmol,1.1当量)加入合适的反应容器中并溶于水(1000mL)中。然后将N,O-二甲基羟胺溶液和二氯甲烷(2500mL)加入到碳酸钾溶液中。
然后通过加料漏斗缓慢加入上述深色油状物(400mL),同时保持反应温度-10至0℃。加入略微放热,加入后得到棕色混合物。将混合物在0至5℃下搅拌20分钟。然后升温至20至25℃。收集底部有机层并且用二氯甲烷(400mL)萃取顶部水层。将合并的有机层用15%氯化钠溶液(1200mL)洗涤。用硫酸镁干燥有机层,然后过滤。减压浓缩滤液,得到中间体(2'),为深色油状物(261.9g,97wt%,76%收率,3wt%甲苯,由1H-NMR获得,0.04wt%含水量,由KF获得)。1H-NMR(500MHz,CDCl3)δppm8.48(s,1H);6.71(s,1H);3.78(s,3H);3.38(s,3H)。
ii):化合物(2')和丙炔酸乙酯的烷基化反应得到(E)-4-(异噁唑-3-基)-2-(甲氧基甲基)氨基)-4-氧代丁-2-烯酸乙酯(3')
将中间体(2')(72.2g,96wt%,444mmol,1.0当量)、丙炔酸乙酯(65.7g,670mmol,1.5当量)和无水THF(650mL)加入到配备有机械搅拌器和数字温度计的适当的反应容器中。将溶液冷却至-65至-55℃。然后通过加料漏斗缓慢加入双(三甲基甲硅烷基)酰胺的THF溶液(1M,650mL,650毫摩尔,1.46当量),同时保持反应温度-65至-55℃。添加完成后,将混合物在-55℃以下搅拌10分钟。然后加入1N HCl(650mL,650毫摩尔,1.46当量)以淬灭反应,同时保持反应温度低于-20℃,然后立即加入乙酸乙酯(1500mL)和水(650mL)。收集顶部乙酸乙酯层,底部水层用乙酸乙酯(800mL)萃取。将合并的有机层用10%柠檬酸(1000mL)和饱和氯化钠溶液(650mL)洗涤。减压浓缩有机层,得到深色油状物。
将深色油状物溶于二氯甲烷/乙酸乙酯/庚烷的溶液(150毫升/100毫升/100毫升)中。将溶液上样到硅胶垫(410g)上,用乙酸乙酯/庚烷(1/1v/v)洗脱硅胶垫。收集滤液(~3000mL),然后减压浓缩至150mL体积,静置后得到浆液。然后将庚烷(200mL)加入到浆料中,并将浆液在减压下浓缩至150mL的体积。过滤得到的浆液,将滤饼用庚烷(150mL)洗涤。然后将滤饼空气干燥过夜,得到中间体(3'),为棕色固体(63.4g,56%收率,HPLC纯度>99%)。。1H-NMR(500MHz,CDCl3)δppm8.42(d,J=1.53Hz,1H);6.76(d,J=1.53Hz,1H);6.18(s,1H);4.47(q,J=7.07Hz,2H);3.75(s,3H);3.21(s,3H);1.41(t,J=7.17Hz,3H)。
iii):化合物3'和2-氟苄基肼的环化,得到1-(2-氟苯甲基)-5-(异噁唑-3-基)-1H-吡唑-3-羧酸乙酯(4')
将中间体(3')(72.9g,287mmol,1.0当量)和无水乙醇(730mL)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将混合物冷却至0至5℃。然后将2-氟苄基肼(48.2g,344毫摩尔,1.2当量)加入混合物中。将混合物在0至10℃下搅拌1小时,然后温热至20至25℃并在20至25℃下搅拌16小时。通过HPLC完成反应。在1分钟内将浓HCl(33.9g,37wt%,344mmol,1.2当量)加入到反应混合物中,并且批料温度从20℃放热至38℃。获得浆料。将混合物在1小时内冷却至0至10℃并在0-10℃下搅拌1小时。过滤所得浆液,并用乙醇(200mL)洗涤滤饼。将滤饼在真空下在30至40℃下经16小时干燥,得到中间体(4'),为灰白色固体(81.3g,90%收率,HPLC纯度>99%)。1H-NMR(500MHz,CDCl3)δppm8.47(d,J=1.68Hz,1H);7.15-7.26(m,2H);6.94-7.08(m,2H);6.77-6.87(m,1H);6.55(d,J=1.68Hz,1H);5.95(s,2H);;4.43(q,J=7.02Hz,2H);1.41(t,J=7.17Hz,3H)。
iv):化合物(4')的胺化,得到1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-甲脒盐酸盐(5'B)
将无水氯化铵(267g,4991mmol,5.0当量)和甲苯(5400mL)加入到配备有机械搅拌器和数字温度计的合适反应容器中。通过加料漏斗缓慢加入甲苯中的三甲基铝(2M,2400mL,4800mmol,4.8当量),同时保持反应温度在20至40℃(注意:在加入期间观察到甲烷气体逸出)。然后在30分钟内将混合物加热至75至80℃。得到澄清的白色溶液。在75至90℃下在1小时内将中间体(4')(315g,999毫摩尔,1.0当量)以4等份加入反应混合物中。将反应在80至90℃下搅拌30分钟。然后加热至100至110℃并在100至110℃下搅拌3小时。通过HPLC完成反应。将反应混合物冷却至10至20℃,通过加料漏斗缓慢加入甲醇(461g,14.4摩尔,14.4当量),同时保持反应温度10-40℃。注意,淬火是非常放热(very exothermic)的,并且观察到很多气体逸出。获得稠浆料。然后通过加料漏斗缓慢加入3N HQ(6400mL,3N,19.2摩尔,19.2当量),同时保持反应温度在20至45℃。将混合物加热至80至85℃并在80至85℃下搅拌10分钟。获得清晰的双相混合物。将混合物在3小时内冷却至0至5℃并在0至5℃下搅拌1小时。过滤所得浆液,滤饼用水(3000mL)洗涤。将滤饼在40至50℃下在24小时内真空干燥,得到中间体(5'B),为灰白色固体(292g,91%收率,HPLC纯度>99%)。1H-NMR(500MHz,DMSO-6)δppm9.52(s,2H);9.33(s,2H);9.18(d,J=1.53Hz,1H);7.88(s,1H);7.29-7.38(m,1H);7.19-7.25(m,1H);7.10-7.16(m,1H);7.03(d,J=1.53Hz,1H);6.92-6.98(m,1H);5.91(s,2H)。熔点1180-185℃。
v):化合物(5'B)和氟代丙二酸二乙酯环化,得到5-氟-2-(1-(2-氟苯甲基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4,6-二醇(6')
将中间体(5'B)(224.6g,698mmol,1.0当量),甲醇(2250mL)和氟代丙二酸二乙酯(187g,1050mmol,1.5当量)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。然后通过加料漏斗加入甲醇钠的甲醇溶液(567g,30wt%,3149mmol,4.5当量),同时保持反应温度为20至35℃。将混合物在20至35℃下搅拌30分钟。并获得轻质悬浮液。通过HPLC完成反应。通过加料漏斗在1小时内加入1.5N HQ溶液(2300mL,3450mmol,4.9当量),同时保持反应温度为20至30℃。获得白色悬浮液。通过pH试纸,反应混合物的pH为~1。将浆液在20至30℃下搅拌30分钟。过滤所得浆液,用预先混合的甲醇和水(500mL/500mL)溶液洗涤滤饼,然后用水(1000mL)洗涤。将滤饼在50至60℃下在16小时内真空干燥,得到中间体(6'),为灰白色固体(264g,97%收率,HPLC纯度>99%)。1H-NMR(500MHz,DMSO-s)δppm12.82(br.s.,1H);12.31(br.s.,1H);9.14(d,J=1.53Hz,1H);7.55(s,1H);7.31-7.37(m,1H);7.18-7.25(m,1H);7.10-7.15(m,2H);6.97-7.02(t,J=7.55Hz,1H);5.88(s,2H)。
vi):氯化化合物(6'),得到3-(3-(4,6-二氯-5-氟嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)异噁唑(7)
将中间体(6')(264g,71mmol,1.0当量),乙腈(4000mL)和N,N-二甲基苯胺(138g,11 137mmol,1.6当量)加入到配备有适当的反应容器中。机械搅拌器和数字温度计。将浆料混合物加热至70-80℃。然后通过加料漏斗在1小时内加入三氯氧磷(655g,4270毫摩尔,6.0当量),同时保持反应温度为70至80℃。将混合物在75至80℃下搅拌22小时,得到棕色溶液。通过HPLC完成反应。然后将混合物冷却至0至5℃,并在25℃下沉淀出类似固体的棉。通过加料漏斗缓慢加入水(3000mL),同时将反应温度保持在0至10℃。将浆液在0至10℃下搅拌30分钟。过滤所得浆液,并用预混合的乙腈和水(500mL/500mL)溶液洗涤滤饼。将滤饼在35至45℃下在16小时内真空干燥,得到中间体(7'),为灰白色固体(283g,98%收率,HPLC纯度>99%)。1H-NMR(500MHz,CDCl3)δppm8.48(d,J=1.68Hz,1H);7.44(s,1H);7.19-7.25(m,1H);;6.96-7.08(m,2H);6.81-6.88(m,1H);6.60(d,J=1.68Hz,1H);6.03(s,2H)。
vii):用甲氧基取代化合物(7'),得到3-(3-(4-氯-5-氟-6-甲氧基嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)异噁唑(8')
将甲醇(3400mL)和甲醇中的甲醇钠(154mL,5.4M,832mmol,1.2当量)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将反应混合物加热至23至27℃。在40分钟内将中间体(7')(283g,693毫摩尔,1.0当量)以小份(每份5-10g)加入混合物中,同时保持反应温度23至27℃。将浆液在23至27℃下搅拌30分钟。通过HPLC完成反应。过滤所得浆液,滤饼用甲醇(850mL)洗涤,然后用水(850mL)洗涤。将滤饼在35至45℃下真空干燥16小时,得到中间体(8'),为灰白色固体(277g,99%收率,HPLC纯度97%)。1H-NMR(500MHz,CDCl3)5ppm 8.47(d,J=1.83Hz,1H);7.38(s,1H);7.18-7.25(m,1H);7.01-7.08(m,1H);6.94-7.00(m,1H);6.81-6.88(m,1H);6.60(d,J=1.68Hz,1H);6.00(s,2H);4.21(s,3H)。
viii):氢化化合物(8'),得到3-(3-(5-氟-4-甲氧基嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)异噁唑(9')
中间体(8')(226克,560毫摩尔,1.0当量)、钯(活性炭上10%,标称50%水湿,22.6克,0.01摩尔,0.018当量)、四氢呋喃(3400毫升)和三乙胺(91g,897毫摩尔,1.6当量)加入装有机械搅拌器和数字温度计的合适反应容器中。在20至30℃下,通过特氟隆管在10分钟内将氮气鼓入反应混合物中。然后将混合物加热至40至50℃并在6小时内通过特氟隆管将氢气鼓入反应混合物中,同时保持反应温度为40至50℃。通过HPLC完成反应。然后在10分钟内通过特氟隆管将氮气鼓入反应混合物中。在40至50℃下,将反应混合物通过HypoSupercelTM热过滤,并将滤饼用四氢呋喃(2000mL)洗涤。将滤液减压浓缩至~1300mL的体积,得到浆液。然后通过连续加入甲醇(3000mL)将四氢呋喃在减压下溶剂交换为甲醇。溶剂交换后的最终体积为1300mL。过滤所得浆液,滤饼用甲醇(500mL)洗涤。将滤饼在20至25℃下在16小时内真空干燥,得到中间体(9'),为白色固体(192g,93%收率,HPLC纯度98%)。1H-NMR(500MHz,CDCl3)δppm8.47(d,J=1.68Hz,1H);8.41(d,J=2.59Hz,1H);7.36(s,1H);7.17-7.24(m,1H);6.95-7.07(m,2H);6.83-6.90(m,1H);6.60(d,J=1.68Hz,1H);5.99(s,2H);4.19(s,3H)。
ix):将化合物(9')去甲基化,得到5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-醇(10')
中间体(9')(230g,623毫摩尔,1.0当量),MeOH(3450mL)和锥形。将HCl(307g,37wt%,3117mmol,5.0当量)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将混合物加热至60至65℃并获得溶液。然后将混合物在60至65℃下搅拌17小时,得到浆液。通过HPLC完成反应。将浆液在2小时内冷却至20至25℃并在20至25℃下搅拌30分钟。过滤所得浆液,并用甲醇(1000mL)洗涤滤饼。将滤饼在35至45℃下在16小时内真空干燥,得到中间体(10'),为白色固体(214g,97%收率,HPLC纯度>99%)。1H-NMR(500MHz,DMSO-d6)δppm12.90-13.61(br.s.,1H);9.11(d,J=1.68Hz,1H);8.16(s,1H);7.64(s,1H);7.29-7.42(m,1H);7.17-7.28(m,2H);7.08-7.15(m,1H);6.97(s,1H);5.91(s,3H)。
x):将化合物(10')氯化,得到3-(3-(4-氯-5-氟嘧啶-2-基)-1-(2-氟苄基)-1H-吡唑-5-基)异噁唑(式IV)
将中间体(10')(214g,602mmol,1.0当量),乙腈(3000mL)和N,N-二甲基苯胺(109g,899mmol,1.5当量)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将浆料混合物加热至70至80℃。然后通过加料漏斗在30分钟内加入三氯氧磷(276g,1802mmol,3.0当量)。同时保持反应温度70-80℃。将混合物在75至80℃下搅拌2小时,得到绿色溶液。通过HPLC完成反应。然后将混合物冷却至0至5℃。通过加料漏斗缓慢加入水(1500mL),同时将反应温度保持在0至10℃。将浆液在0至10℃下搅拌30分钟。过滤所得浆液,并用预混合的乙腈和水(500mL/500mL)和水(500mL)溶液洗涤滤饼。将滤饼在真空下在30至40℃下经16小时干燥,得到式IV的中间体,为灰白色至粉红色固体(214g,95%收率,HPLC纯度>99%)。1HNMR(500MHz,CDCl3)5ppm 8.65(s,1H);8.48(d,J=1.68Hz,1H);7.44(s,1H);7.21-7.25(m,11H);6.97-7.06(m,2H);6.83-6.87(m,1H);6.61(d,J=1.68Hz,1H);6.03(s,2H)。
a):将中间体(15)氰化以提供2-(溴甲基)-3,3,3-三氟-2-((三甲基甲硅烷基)氧基)丙腈(16)
将三甲基硅烷甲腈(153g,1.54摩尔,0.97当量)和三乙胺(4.44mL,3.22g,0.032mol,0.02当量)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将混合物冷却至5℃。通过加料漏斗在35分钟内加入3-溴-1,1,1-三氟丙-2-酮((15),304g,1.59摩尔,1.0当量),同时保持反应温度在10至20℃之间。加入后3小时内将混合物在20-30℃下搅拌,得到中间体(16),为稠油状物,将其直接用于下一步骤。1H-NMR(500MHz,CDCl3)δppm3.68(d,J=11.14Hz,1H);3.57(d,J=11.14Hz,1H),0.34-0.37(m,9H)。
b):将腈化合物(16)转化为酰胺,得到2-(溴甲基)-3,3,3-三氟-2-羟基丙酰胺(17)
将浓硫酸(339mL,6.37摩尔,4.0当量)在配备有机械搅拌器、数字温度计和加料漏斗的合适反应容器中搅拌。将硫酸加热至45℃。通过加料漏斗在50分钟内加入上述中间体(16),同时保持温度低于75℃。将反应混合物在75℃下搅拌2小时,然后冷却至室温。1H-NMR表明反应完成。将反应混合物冷却至-15℃并通过加料漏斗用乙酸乙酯(1824mL)在45分钟内稀释(非常放热),同时保持温度在-15至5℃之间。在-10至0℃之间通过加料漏斗缓慢加入水(1520mL)1小时20分钟(非常放热)。分离各层,有机层用15%氯化钠水溶液(1520mL)、25%碳酸钠水溶液(911mL)洗涤,然后用15%氯化钠水溶液(911mL)洗涤。过滤有机层并减压浓缩,得到348g中间体(17),为浅黄色油状物。将该油状物溶于甲醇(1200mL)中并浓缩,得到380g中间体(17)。(296g调整重量,79%产率)。1H-NMR(500MHz,CDCl3)δ6.61-6.94(m,1H);5.92-6.26(m,1H);3.93-4.00(m,1H);3.68(d,J=l 1.14Hz,1H)。
c):化合物(17)的N-烷基化反应得到2-(氨基甲基)-3,3,3-三氟-2-羟基丙酰胺(14)
将7N氨的甲醇溶液(600mL,4.28mol,10当量)加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将溶液冷却至0至5℃。然后通过加料漏斗在0至5℃下经30分钟加入中间体(17)(102g,0.432摩尔,1当量)。将反应混合物在1小时内温热至20至25℃并保持72小时。通过HPLC完成反应。将反应混合物冷却至0至5℃并在2分钟内加入甲醇钠(78mL,5.4M,0.421摩尔,0.97当量)。然后将反应混合物减压浓缩至300mL的体积。加入2L乙酸乙酯,在减压下继续浓缩至体积至700mL,得到浆液。向浆液中加入700mL乙酸乙酯,使最终体积达到1400mL。加入102mL水并搅拌2分钟以得到两相溶液。分层。减压浓缩乙酸乙酯层至600mL体积。然后将乙酸乙酯层加热至>60℃并在55至60℃之间缓慢加入庚烷(600mL)。将混合物冷却至15至20℃,得到浆液。将浆液在15至20℃下搅拌2小时并过滤。将固体在25℃下真空干燥16小时,得到胺(14),为白色固体(48g,64%收率)。1H-NMR(500MHz,MeOH-d4)δppm2.94(d,J=13.73Hz,1H);3.24(d,J=13.58Hz,1H)。
d):胺(14)的手性拆分为(R)-2,2-二甲基-5-(三氟甲基)噁唑烷-5-甲酰胺(R)-2-羟基琥珀酸盐(18A)和(D)-苹果酸的1:1盐。
将胺(14)(105g,0.608摩尔,1.0当量),(D)-马来酸(82g,0.608摩尔,1.0当量)和丙酮(1571mL)加入到配备有机械搅拌器和数字温度计的合适反应容器中。将反应混合物在20至25℃下搅拌16小时。过滤所得浆液,并用丙酮(300mL)洗涤湿滤饼。将湿滤饼装回反应容器中,并加入丙酮(625mL)。将浆料加热至53℃并保持6小时。将浆液冷却至20至25℃并在该温度下保持16小时。过滤浆液,用丙酮(200mL)洗涤湿滤饼。将湿滤饼在40℃下真空干燥4小时,得到82.4g的(18A)和(D)-苹果酸的1:1盐,其为白色固体(82.4g,39%收率,97%ee)。1H-NMR(500MHz,D20)δppm4.33(br,s,1H);3.61(br,d,J=13.58Hz,1H);3.40-3.47(m,1H);2.76(br,d,J=15.87Hz,1H);2.53-2.63(m,1H);2.16(br,s,4H)。
e):中间体(18A)和式IV的1:1(D)-苹果酸盐的偶合,得到(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺(化合物I)
将中间体(18A)和(D)-苹果酸(74.1g,0.214摩尔,2.5当量)和水(44.8mL)的1:1盐加入到配备有机械搅拌器和数字温度计的合适的反应容器中。将反应混合物加热至70℃并搅拌20分钟。通过吹氮气除去反应过程中产生的丙酮。将反应混合物冷却至30至40℃,并加入式IV(32g,0.086摩尔,1.0当量),DMSO(448mL)和Hunig碱(44.7mL,0.257mol,3.0当量)。将反应混合物加热至90℃并在90℃下搅拌17小时。通过HPLC完成反应。然后将混合物冷却至60℃。在55至62℃下加入另一部分Hunig碱(104mL,0.599摩尔,7.0当量),然后加入水(224mL)。将反应混合物在55至60℃下搅拌15分钟以形成种床。通过加料漏斗在55至62℃下在30分钟内加入水(320mL),并将所得浆液在55至60℃下搅拌1小时。过滤所得浆液,并将滤饼用预先混合的甲醇和水(320mL/320mL)溶液洗涤,然后用水(640mL)洗涤。然后将滤饼在40℃下真空干燥16小时,得到化合物I,为灰白色固体(40g,92%收率,HPLC纯度99%,ee98%)。1H-NMR(500MHz,DMSO-d6)δppm9.10(s,1H);8.33(d,J=2.90Hz,1H);7.93(s,br,1H);7.90(s,1H);7.78(s,br,1H);7.69(s,br,1H);7.52(s,1H);7.33(q,J=7.02Hz,1H);7.17-7.25(m,1H);7.17-7.25(m,1H);7.10(t,J=7.48Hz,1H);6.98(t,J=7.55Hz,1H);5.90(s,2H);3.92-4.05(m,2H)。
原油化合物I及其多晶型形式A、形式B、形式D、形式E、形式F、形式G和形式H之间的相互关系示于图12中。
实施例2:粗品(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯基-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)氨基)甲基-2-羟基丙酰胺(粗化合物I)至多晶型形式B
将粗化合物I(0.68kg,1.33mol)和乙腈(20.4L)加入30L夹套反应容器中。将反应混合物低速搅拌并加热至70至75℃直至大部分固体溶解。将30L夹套反应容器中的溶液通过气体分散管(粗玻璃料)在线过滤到100L夹套反应容器中。然后将反应混合物加热至70-75℃并加入水(20.4L),同时在1小时内保持批料温度>65℃。将反应混合物冷却至52-62℃并在52-62℃下搅拌最少1小时以形成种床。将所得浆液在最少4小时内冷却至0-5℃并在0-5℃保持最少1小时。过滤浆液,滤饼用预先混合的乙腈和水(3.4L/3.4L)溶液洗涤。然后将滤饼在90-100℃下真空干燥最少30小时,得到化合物I,为白色固体形式B的多晶型物(0.58kg,85%收率)。1H-NMR(500MHz,DMSO-d6)δppm9.10(s,1H);8.33(d,J=2.90Hz,1H);7.93(s,br,1H);7.90(s,1H);7.78(s,br,1H);7.69(s,br,1H);7.52(s,1H);7.33(q,J=7.02Hz,1H);7.17-7.25(m,1H);7.17-7.25(m,1H);7.10(t,J=7.48Hz,1H);6.98(t,J=7.55Hz,1H);5.90(s,2H);3.92-4.05(m,2H)。
实施例3:重结晶粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-)吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺(化合物I)得到多晶型形式E
向装有机械搅拌器、冷凝器、滴液漏斗、氮气入口、热电偶和加热-冷却容量的5L四颈圆底烧瓶中加入粗化合物I(67.4g,132mmol)和甲醇(2500mL)。将混合物加热至>60℃(例如,高于70℃)以获得溶液。过滤溶液,将滤液加热至>60℃。将水(1500mL)加入混合物中,同时保持温度>60℃。使混合物在1小时内冷却至室温并在该温度下保持1小时。过滤浆液,滤饼用甲醇/水(600mL,体积比1/1)冲洗。收集滤饼并在80℃下真空干燥72小时,得到化合物I的多晶型形式E,为白色固体(59.5g,88%收率)。
实施例4A:重结晶(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基))-lH-吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺的多晶型形式E获得多晶型形式A
向装有机械搅拌器、冷凝器、滴液漏斗、氮气入口、热电偶和加热-冷却能力的1L四颈圆底烧瓶中加入化合物I作为多晶型E(19.3g,38mmol)和乙酸乙酯(600mL)。将混合物加热至>70℃以获得溶液。过滤溶液,滤液在20至25℃下搅拌16小时,得到浆液。将浆液在真空下浓缩至最终体积-150mL。在20分钟内将庚烷(300mL)加入到浆液中,并将混合物在真空下浓缩至最终体积为~350mL。过滤浆液,滤饼用庚烷(50mL)冲洗。收集滤饼并在100℃下真空干燥3小时,得到多晶型形式A,为白色固体(19.1g,99%收率)。
实施例4B:重结晶粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-)吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺(化合物I)获得多晶型形式A
通过类似于实施例4A中所述的方法,用粗制化合物I代替形式E作为起始原料,通过从乙酸乙酯中分离,直接从粗化合物I获得多晶型形式A。
通过在高于60℃加热后从DMSO/水中分离,也直接从粗化合物I获得多晶型A。
当将粗制Compoud I在任何溶剂庚烷、(乙酸异丙酯)、IPAC、乙醇、乙酸乙酯或癸烷中在室温下浆化并搅拌14至30小时时,也分离出多晶型形式A。过滤样品并通过XRPD分析残留的固体。
实施例5A:重结晶(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺的多晶型形式E获得多晶型形式D
向装有机械搅拌器、冷凝器、滴液漏斗、氮气入口、热电偶和加热-冷却容量的2L四颈圆底烧瓶中加入多晶型形式E的化合物I(14.0g,28mmol)和正癸烷(560毫升)。将混合物加热至145至155℃并在145至155℃下保持45分钟。将所得浆液在1小时内冷却至20至30℃,然后过滤。将滤饼用庚烷(280mL)冲洗。收集滤饼并在80℃下真空干燥72小时,得到形式D的化合物I,为白色固体(12.9g,92%收率)。
实施例5B:获得多晶型D的其他方法
如图12中概述和下面描述,多晶型形式D也通过在180℃下加热许多其他多晶型形式(纯)而获得。在一些实施方案中,加热化合物I以获得多晶型形式D。在一些实施方案中,加热多晶型形式F以获得多晶型形式D。在一些实施方案中,加热多晶型形式B以获得多晶型形式D。在一些实施方案中,加热多晶型形式E以获得多晶型形式D。在一些实施方案中,加热多晶型形式G以获得多晶型形式D。在一些实施方案中,加热多晶型形式H以获得多晶型形式D。
向100mL圆底烧瓶中加入化合物I、形式F、形式B、形式E、形式G或形式H(5g)。将固体加热至180℃并在5分钟内保持在180℃。将所有化合物I固体缓慢熔化并再固化,得到固体。用研钵和研杵研磨固体,得到~4.8g粉末。HPLC显示99.8%的纯度。XRPD显示它是D型.DSC在196℃下显示出尖锐的峰。
实施例6:形式F的制备
当形式A在160℃下纯净加热时,获得新的多晶型形式F。这种形式在室温时看起来不稳定,并且没有被分离纯净。
实施例7:重结晶粗品(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺(化合物I)获得多晶型形式G
向装有搅拌器的烧瓶中加入粗化合物I(2.0g)和丙酮(15.0mL)。将混合物在室温(22至25℃)下搅拌2小时。然后过滤所得浆液。将滤饼用丙酮(5mL)冲洗。收集滤饼并在40℃下真空干燥超过15小时,得到多晶形形式G,为白色固体。
通过在室温下在丙酮中搅拌如下所述获得的多晶型H,然后过滤并在30至40℃下真空干燥,获得多晶型形式G。
实施例8:重结晶粗品(R)-3,3-三氟-2-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)氨基)甲基)-2-羟基丙酰胺获得多晶型形式H
向装有搅拌器的烧瓶中加入粗化合物I(2.0g)和丙酮(15.0mL)。将混合物加热至45-50℃并搅拌直至形成溶液。然后过滤热溶液并在搅拌下缓慢冷却至室温。再搅拌15小时,然后过滤所得浆液。将滤饼用丙酮(5mL)冲洗。收集滤饼并在40℃下真空干燥15小时,得到多晶型形式H,为白色固体。
实施例9:多晶型特征
X射线粉末衍射(XRPD):
使用D8 Advance,Bruker装置获得X射线粉末衍射迹线;使用两种方法中的一个:
扫描5-45°2θ,0.02°步长,每步1秒;要么
扫描3-40°2θ,0.037°步长,每步1.5秒
傅里叶变换红外光谱(FTIR):
使用来自ThermoFisher Scientific的Nicolet iS 10 FTIR装置获得FTIR迹线
方法:通过32次扫描衰减全反射分析,在525-4000cm-1的波数范围内分辨率为4,每次测量前获得
背景
实施例10:HCl盐制备
方案1:将50.5mg化合物I(其多晶型D)和98.2mL 1M HCl悬浮于2mL i-PrOH中。将该悬浮液在20℃至40℃之间的温度下搅拌。使用40℃/h的加热速率和5℃/h的冷却速率。8天后,过滤悬浮液,并将固体在真空下干燥(约5毫巴,1小时)。
方案2:将299.9mg化合物I作为其多晶型D和少量上述获得的盐酸盐(来自方案1)的晶体悬浮在5mL的i-PrOH中。然后加入589mL 1M HCl和5mL i-PrOH,并将该悬浮液在20℃至40℃的温度下循环加热,使用加热速率为40℃/h,冷却速率为5℃/h。6天后,过滤悬浮液,并将固体在真空下干燥(约5毫巴,1小时)。
实施例11:HCl盐特征化合物I的HCl盐的特征在于图11的XRPD图。
通过元素分析表征化合物I的HCl盐,给出下表中显示的1:1比例(形式D:HCl)的测量值和计算值:
本文使用的术语仅用于描述特定实施方案的目的,并不意图限制本发明。如这里所使用的,单数形式“一”,“一个”和“该”也旨在包括复数形式,除非上下文另有明确说明。将进一步理解,术语“包含”(和任何形式的包括,例如“包含”),“具有”(和任何形式的具有,例如“有”),“包括”(以及任何形式的包括,例如“包括”),“含有”(以及任何形式含有,例如“含有”),以及其他任何语法变体,都是开放的-连接动词。结果,“包含”,“具有”,“包括”或“含有”一个或多个步骤或元素的方法或设备拥有那些一个或多个步骤或元素,但不限于仅拥有那些一个或多个步骤或元素。同样地,“包括”,“具有”,“包含”或“含有”一个或多个特征的设备的方法或元素的步骤拥有那些一个或多个特征,但不限于仅拥有那些特征或者一个或多个特征。更多功能。此外,以某种方式配置的设备或结构至少以这种方式配置,但是也可以以未列出的方式配置。
如本文所用,术语“包含”、“具有”、“包括”、“含有”及其他语法变体包括术语“由......组成”和“基本上由......组成”。
当在本文中使用时,短语“基本上由......组成”或其语法变体应被视为指定所述特征、整数、步骤或组件,但不排除添加一个或多个附加特征、整数、步骤、组件或其组,但仅在其附加特征、整数、步骤、组分或组不会实质上改变所要求保护的组合物、装置或方法的基本和新颖特征时。
本说明书中引用的所有出版物均通过引用并入本文,如同每个单独的出版物被具体和单独地指出通过引用并入本文,如同完全阐述一样。
除非另外明确指出,否则通过引用并入的主题不被认为是任何权利要求限制的替代。
在整个说明书中引用一个或多个范围的情况下,每个范围旨在是用于呈现信息的简写格式,其中该范围被理解为包含该范围内的每个离散点,如同其在本文中完全阐述一样。
虽然本文已经描述和描绘了本发明的若干方面和实施例,但是本领域技术人员可以影响替代方面和实施例以实现相同的目的。因此,本公开和所附权利要求旨在覆盖落入本发明的真实精神和范围内的所有这些进一步和替代方面和实施例。
Claims (70)
1.化合物I的结晶固体形式:
2.权利要求1的结晶固体形式,其是选自形式A、形式B、形式D、形式E、形式F、形式H或形式G的结晶游离形式。
3.权利要求1的结晶固体形式,其是盐酸盐。
4.根据权利要求2的化合物I的结晶游离形式E,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:7.4、18.8-19.3、21.1、24.8和25.5。
5.根据权利要求4的化合物I的结晶游离形式E,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:7.4、13.9、15.1、16.3、17.6、18.8-19.3、21.1、22.3-22.5、24.8、25.5和27.1。
6.根据权利要求2的化合物I的结晶游离形式E,其特征在于XRPD谱基本上类似于图2或图6中所示的XRPD光谱。
7.根据权利要求2的化合物I的结晶游离形式E,其特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
8.根据权利要求2的化合物I的结晶游离形式E,其特征在于IR光谱在1690cm-1处显示出最大峰。
9.根据权利要求2的化合物I的结晶游离形式E,其特征在于IR光谱在1515cm-1处显示最大峰。
10.根据权利要求2的化合物I的结晶游离形式E,其特征在于IR光谱显示在1690和1515cm-1处的频带最大值。
11.根据权利要求2的化合物I的结晶游离形式A,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.0、18.3、19.3、20.2和22.0。
12.根据权利要求11的化合物I的结晶游离形式A,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.0、8.5、9.5、12.4-12.9、13.4、17.1、18.3、19.3、20.2、22.0、30.1和34.1。
13.根据权利要求12的化合物I的结晶游离形式A,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.0、6.7、8.5、9.5、10.9、12.4-12.9、13.4、16.2、17.1、18.3、19.3、20.2、22.0、23.0、24.1至24.8、25.8、30.1和34.1。
14.根据权利要求2的化合物I的结晶游离形式A,其特征在于XRPD光谱基本上类似于图2或图3A中所示的XRPD光谱。
15.根据权利要求2的化合物I的结晶游离形式A,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:6.1(80.81%相对强度),9.6(40.35%),12.6(41.26%),13.6(43.19%),18.4(53.57%),19.4(100.00%),20.3(57.01%)和22.0(56.64)。
16.根据权利要求2的化合物I的结晶游离形式A,其特征在于XRPD光谱基本上类似于图3C中所示的XRPD光谱。
17.根据权利要求2的化合物I的结晶游离形式,其特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
18.根据权利要求2的化合物I的结晶游离形式,其特征在于IR光谱在1730cm-1处显示出频带最大值。
19.根据权利要求2的化合物I的结晶游离形式A,其特征在于,当在40℃和75%相对湿度的稳定性条件下储存14个月时,显示基本不变的XRPD迹线。
20.根据权利要求2的化合物I的结晶游离形式D,其特征在于XRPD光谱中的峰的°2θ在18.8。
21.根据权利要求20的化合物I的结晶游离形式D,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:17.1、18.1、18.8和25.0。
22.根据权利要求21的化合物I的结晶游离形式D,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.8、17.1、18.1、18.8和25.0。
23.根据权利要求2的化合物I的结晶游离形式D,其特征在于XRPD光谱基本上类似于图2或图5A中所示的XRPD光谱。
24.根据权利要求2的化合物I的结晶游离形式D,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:4.7(97.11%相对强度),8.3(64.04%),18.1(80.97%),18.6(100.00%)和26.8(65.25)。
25.根据权利要求2的化合物I的结晶游离形式D,其特征在于XRPD光谱基本上类似于图5C中所示的XRPD光谱。
26.根据权利要求2的化合物I的结晶游离形式D,其特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
27.根据权利要求2的化合物I的结晶游离形式D,其特征在于IR光谱在1665cm-1处显示出频带最大值。
28.根据权利要求2的化合物I的结晶游离形式D,其特征在于IR光谱在1639cm-1处显示出频带最大值。
29.根据权利要求2的化合物I的结晶游离形式D,其特征在于IR光谱在968cm-1处显示出频带最大值。
30.根据权利要求2的化合物I的结晶游离形式D,其特征在于IR光谱显示在1665、1639和968cm-1处的频带最大值。
31.根据权利要求2所述的化合物I的结晶游离形式D,其特征在于,当在40℃和75%相对湿度的稳定条件下储存14个月时,显示基本不变的XRPD迹线。
32.根据权利要求2的化合物I的结晶游离形式B,其特征在于XRPD光谱中的一个或多个峰在以下°2θ:18.8至19.1。
33.根据权利要求32的化合物I的结晶游离形式B,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.8、16.4、17.2、18.8-19.1、20.1和21.1-21.6。
34.根据权利要求33的化合物I的结晶游离形式B,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:8.8、10.6、12.6-13.0、14.6、16.4、17.2、18.8-19.1、20.1、21.1-21.6、24.5、25.3、27.0-27.5、28.9、29.8和30.5。
35.根据权利要求2的化合物I的结晶游离形式B,其特征在于XRPD光谱基本上类似于图2或图4A所示的XRPD光谱。
36.根据权利要求2的化合物I的结晶游离形式B,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:7.0(44.44%相对强度),8.9(76.55%),17.4(57.67%),19.1(100.00%),20.3(49.78%),21.8(36.16%)和25.5(52.26%)。
37.根据权利要求2的化合物I的结晶游离形式B,其特征在于XRPD光谱基本上类似于图4C中所示的XRPD光谱。
38.根据权利要求2的化合物I的结晶游离形式B,其特征在于FT-拉曼光谱基本上类似于图10中所示的光谱。
39.根据权利要求2的化合物I的结晶游离形式B,其特征在于IR光谱在1200cm-1处显示出最大峰值。
40.根据权利要求2的化合物I的结晶游离形式B,其特征在于,当在40℃和75%相对湿度的稳定性条件下储存14个月时,显示基本不变的XRPD迹线。
41.根据权利要求2的化合物I的结晶游离形式F,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.3(100.00%相对强度),8.6(58.80%),16.4(62.95%),和19.0(48.51%)。
42.根据权利要求2的化合物I的结晶游离形式F,其特征在于XRPD光谱基本上类似于图7中所示的XRPD光谱。
43.根据权利要求2的化合物I的结晶游离形式G,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:10.7(55.47%相对强度),13.9(42.47%),18.33(100.00%),和21.6(40.73%)。
44.根据权利要求2的化合物I的结晶游离形式G,其特征在于XRPD光谱基本上类似于图8中所示的XRPD光谱。
45.根据权利要求2的化合物I的结晶游离形式H,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.77(89.22%相对强度),6.39(100.00%%),9.1(84.17%),和18.5(67.04%)。
46.根据权利要求2的化合物I的结晶游离形式H,其特征在于XRPD光谱中的一个或多个峰选自以下°2θ:5.77(89.22%相对强度),6.39(100.00%),9.1(84.17%),18.5(67.04%)和18.83(67.04%)。
47.根据权利要求2的化合物I的结晶游离形式H,其特征在于XRPD光谱基本上类似于图9中所示的XRPD光谱。
48.权利要求3的盐酸盐,其特征在于熔点为256℃。
49.权利要求3的盐酸盐,其特征在于在pH1.4下水溶解度为0.5mg/mL。
50.权利要求3的盐酸盐,其特征在于XRPD图案基本上类似于图11中所示的XRPD图案。
51.一种制备化合物I的结晶游离形式E的方法,包括:
a.将化合物I在MeOH中溶解在最低60℃下,得到溶液;
b.过滤所述溶液并在至少60℃下加热滤液;
c.向所述滤液中加水,形成水溶液,将所述水溶液冷却至室温(rt);
d.过滤所述水溶液并在真空下干燥滤液。
52.一种制备化合物I的结晶游离形式A的方法,包括:
a.将结晶游离形式E在最低70℃下溶解在乙酸乙酯中,得到溶液;
b.过滤所述溶液并在20至25℃下搅拌所得滤液16小时以形成浆液;
c.浓缩并过滤,并在真空下干燥所述浆料。
53.一种制备化合物I的结晶游离形式A的方法,包括:
a.将粗化合物I在最低70℃溶解在乙酸乙酯中,得到溶液;
b.过滤所述溶液并在20至25℃下搅拌所得滤液16小时以形成浆液;
c.浓缩并过滤,并在真空下干燥所述浆料。
54.一种制备化合物I的结晶游离形式A的方法,包括:
a.将化合物I在DMSO中加热至少60℃,形成溶液;
b.加水形成浆液;和
c.过滤所述浆液以分离结晶游离形式A。
55.一种制备化合物I的结晶游离形式A的方法,包括:
a.将粗制化合物I在选自庚烷、IPAC、乙醇、乙酸乙酯或癸烷或其混合物的溶剂中制浆;
b.在室温下搅拌14至30小时;和
c.过滤至所述浆液并在真空下干燥。
56.一种制备化合物I的结晶游离形式D的方法,包括:
a.将结晶游离形式E与正癸烷在145-155℃下混合,得到浆液;
b.用1小时将浆液冷却至20至30℃;和
c.过滤所述浆液并在真空下干燥。
57.一种制备化合物I的结晶游离形式D的方法,包括加热形式F、形式B、形式E、形式G或形式H的任何一种结晶游离形式或其混合物,在180℃下纯化。
58.一种制备化合物I的结晶游离形式B的方法,包括:
a.将粗化合物I与乙腈混合,形成溶液;
b.过滤所述溶液,形成滤液,并在70至75℃加热所述滤液;
c.向所述加热的滤液中加水;
d.冷却至52-62℃形成浆液;
e.进一步将所述浆料冷却至0-5℃至少4小时;和
f.过滤冷却的浆液并在真空下干燥所得滤液。
59.一种制备化合物I的结晶游离形式F的方法,包括在160℃下纯化形式A。
60.一种制备化合物I的结晶游离形式G的方法,包括:
a.将粗化合物I在丙酮中在室温下混合约2小时,形成浆液;和
b.过滤所述浆液并在真空下干燥。
61.一种制备化合物I的结晶游离形式G的方法,包括:
a.在室温下在丙酮中搅拌形式H约2小时,形成浆液;和
b.过滤所述浆液并在真空下干燥。
62.一种制备化合物I的结晶形式H的方法,包括:
a.将粗化合物I与丙酮在45-50℃下混合,得到溶液;
b.过滤和冷却形成浆液;和
c.搅拌并过滤所述浆液并在真空下干燥。
63.一种药物组合物,其包含根据权利要求2的结晶游离形式的化合物I或权利要求3的盐酸盐,和至少一种药学上可接受的赋形剂或载体。
64.一种药物剂型,其包含根据权利要求1、2或3中任一项的化合物I的结晶固体形式。
65.一种治疗需要治疗的受试者的疾病、健康状况或病症的方法,包括向需要治疗的受试者施用治疗有效量的权利要求1至50中任一项的化合物I的结晶固体形式,或权利要求63的药物组合物,或权利要求64的药物剂型,其中所述疾病,健康状况或病症选自:
·与高血压和冠状动脉血流减少有关的疾病;急性和慢性冠状动脉血压升高;动脉高血压;心脏和肾脏并发症引起的血管疾病;由心脏病、中风、脑缺血或肾衰竭引起的血管疾病;顽固性高血压(resistant hypertension);糖尿病高血压;原发性高血压;继发性高血压;妊娠期高血压;先兆子痫;门静脉高压;心肌梗死;
·心力衰竭,HFPEF,HFREF;急性和慢性心力衰竭;心力衰竭的更具体形式:急性失代偿性心力衰竭,右心室衰竭,左心室衰竭,全心衰,缺血性心肌病,扩张型心肌病,先天性心脏病,心室瓣缺陷性心力衰竭,二尖瓣狭窄,二尖瓣关闭不全,主动脉瓣狭窄,主动脉瓣不足,三尖瓣狭窄,三尖瓣关闭不全,肺动脉瓣狭窄,肺动脉瓣关闭不全,合并瓣膜缺损;糖尿病心衰;酒精性心肌病或储存心肌病;舒张期心力衰竭,收缩期心力衰竭;现有慢性心力衰竭的急性期(心力衰竭恶化);舒张期或收缩期功能障碍;冠状动脉供血不足心律失常;心室前负荷减少;心脏肥大;心力衰竭/心肾综合征;门静脉高压;内皮功能障碍或损伤;心房和心室节律和传导障碍的紊乱:I-III级房室传导阻滞(AVB I-III),室上性快速性心律失常,心房颤动,心房扑动,心室颤动,心室扑动,室性快速性心律失常,扭转性室性心动过速,心房颤动和室性期前收缩,AV结外期收缩,病态窦房结综合征,晕厥,房室结再入性心动过速;Wolff-Parkinson-White综合征或急性冠状动脉综合征;拳击手心肌病(Boxercardiomyopathy);室性早搏;心肌病;癌症诱发的心肌病;化疗引起的心脏毒性;
·血栓栓塞性疾病和缺血;心肌缺血;梗死;心肌梗死;心脏病发作;心肌功能不全;内皮功能障碍;脑卒中;短暂性脑缺血发作(TIAs);阻塞性血栓性血管炎;稳定或不稳定型心绞痛;冠状动脉痉挛或外周动脉痉挛;变异型心绞痛;Prinzmetal心绞痛;心脏肥大;先兆子痫;血栓形成疾病;缺血再灌注损伤;器官移植相关的缺血再灌注;肺移植、心脏移植、静脉移植失败相关的缺血再灌注;创伤患者血液替代物的保存;
·外周血管疾病;外周动脉疾病;外周闭塞性动脉疾病;肌张力增高;雷诺综合症或现象(原发性和继发性);雷诺氏病;严重肢体缺血;外周栓塞;间歇性跛行;血管闭塞性风险;肌营养不良症,Duchenne肌营养不良症,Becker肌营养不良症;微循环异常;血管渗漏或渗透的控制;腰椎管狭窄症;闭塞性血栓性血管炎;血栓性血管炎;外周灌注障碍;动脉和静脉血栓形成;微量白蛋白尿;外周和自主神经病;糖尿病神经性疼痛;糖尿病微血管病变;肝血管闭塞性疾病;镰状细胞病的血管闭塞性风险;高血压风险;
·水肿;心力衰竭引起的肾水肿;
·阿尔茨海默氏病;帕金森病;血管性痴呆;血管性认知障碍;脑血管痉挛;先天性肌无力综合征;蛛网膜下腔出血;创伤性脑损伤;认知障碍(如轻度认知功能障碍、年龄相关学习和记忆障碍、年龄相关性记忆丧失、血管性痴呆、颅脑损伤、脑卒中、脑卒中后痴呆、创伤后头部损伤、一般性注意力障碍、和学习记忆障碍儿童的注意力障碍)后的感知、注意能力、学习能力或记忆表现的改善;路易体痴呆;患有额叶变性的痴呆,包括Pick's综合征;进行性核麻痹;伴有皮质基底节变性的痴呆;肌萎缩侧索硬化症(ALS);亨廷顿氏病;脱髓鞘;多发性硬化症;丘脑退化;Creutzfeldt-Jakob痴呆;艾滋病痴呆;伴痴呆精神分裂症或柯萨科夫精神病;多系统萎缩和其他形式的帕金森综合症;运动障碍;神经保护;焦虑,紧张和抑郁或创伤后应激障碍(PTSD);双相情感障碍;精神分裂症;CNS相关的性功能障碍和睡眠障碍;病理性饮食失调和使用昂贵食品和成瘾药物;控制脑灌注;偏头痛;脑梗塞(脑卒中)后果的预防和控制;中风后果的预防和控制,脑缺血和头部损伤;与CNS疾病相关的神经病变;与MS相关的神经性疼痛;化疗引起的神经性疼痛;与带状疱疹相关的神经性疼痛;与脊柱手术相关的神经性疼痛;
·休克;心源性休克;败血症;感染性休克;过敏性休克;动脉瘤;控制白细胞活化;抑制或调节血小板聚集;多器官功能障碍综合征(MODS);多器官功能衰竭(MOF);
·肺/呼吸系统疾病:肺动脉高压(PH);肺动脉高压(PAH)和相关的肺血管重塑;以局部血栓形成和右心肥大形式的血管重塑;肺性高血压;原发性肺动脉高压;继发性肺动脉高压;家族性肺动脉高压;散发性肺动脉高压;毛细血管前肺动脉高压;特发性肺动脉高压;其他形式的PH;与左心室疾病、HIV、SCD、血栓栓塞(CTEPH)、结节病、慢性阻塞性肺病、肺纤维化、急性呼吸窘迫综合征(ARDS)、急性肺损伤、α-1抗胰蛋白酶缺乏症(AATD)、肺气肿、吸烟诱发肺气肿和囊性纤维化(CF)有关的PH;血栓性肺动脉病;丛生性肺动脉病;囊性纤维化;支气管收缩或肺支气管收缩;急性呼吸综合症;肺纤维化,肺移植;哮喘病;
·与以下关联或相关的肺动脉高血压:左心室功能障碍,低氧血症,WHO组I、II、III、IV和V高血压病,二尖瓣瓣膜病,缩窄性心包炎,主动脉瓣狭窄,心肌病,纵隔纤维化,肺纤维化,肺静脉畸形引流,肺静脉闭塞性疾病,肺血管炎,胶原性血管疾病,先天性心脏病,肺静脉高压,间质性肺病,睡眠呼吸紊乱,睡眠呼吸暂停,肺泡通气不足,长期暴露于高原,新生儿肺部疾病,肺泡-毛细血管发育不良,镰状细胞病,其他凝血功能障碍,慢性血栓栓塞,肺栓塞;肿瘤,寄生虫或异物引起的肺栓塞;结缔组织病,狼疮,狼疮性肾炎,血吸虫病,肉状瘤病,慢性阻塞性肺病,哮喘,肺气肿,慢性支气管炎,肺毛细血管瘤,组织细胞增多症X,淋巴管,压缩肺血管;由于腺病,肿瘤或纤维性纵隔炎引起的压缩肺血管;
·动脉硬化疾病或病症:动脉粥样硬化;与内皮损伤、血小板和单核细胞粘附和聚集、平滑肌增殖或迁移有关的动脉粥样硬化;再狭窄;血栓溶解治疗、经皮腔内血管成形术(PTA)、经腔冠状动脉成形术(PTCAs)、心脏移植、旁路手术或炎症过程后发生的再狭窄;
·微血管和大血管损伤(血管炎);纤维蛋白原水平升高和低密度DLD;纤溶酶原激活物抑制剂1(PA-1)的浓度增加;
·代谢综合征;与代谢综合征相关的代谢疾病或疾病:肥胖症;皮下脂肪过多;过度肥胖;糖尿病;高血压;脂质相关疾病,高脂血症,血脂异常,高胆固醇血症,高密度脂蛋白胆固醇(HDL-胆固醇)降低,低密度脂蛋白胆固醇(LDL-胆固醇)水平中度升高,高甘油三酯血症,高甘油酯血症,低脂蛋白血症,谷甾醇血症,脂肪肝疾病,酒精性脂肪肝病(AFLD),非酒精性脂肪性肝病(NAFLD),肝炎;先兆子痫;多囊肾病进展;肝脏脂肪变性或肝脏脂质积聚异常;非酒精性脂肪性肝炎(NASH);心脏、肾脏或肌肉的脂肪变性;alphabeta脂蛋白血症;谷固醇血症;黄瘤病;丹吉尔病;高氨血症及相关疾病;肝性脑病;其他中毒性脑病;雷氏综合症;
·性、妇科和泌尿系统疾病:勃起功能障碍;阳痿;早泄;女性性功能障碍;女性性唤起功能障碍;性欲减退性唤起症;阴道萎缩;性交困难;萎缩性阴道炎;良性前列腺增生(BPH),前列腺肥大,前列腺增生;膀胱出口梗阻;膀胱疼痛综合征(BPS);间质性膀胱炎(IC);膀胱过度活动;神经源性膀胱和尿失禁;糖尿病肾病;原发性和继发性痛经;下尿路综合征(LUTS);子宫内膜异位症;骨盆疼痛;男性和女性泌尿生殖系统器官的良性和恶性疾病;
·慢性肾病;急慢性肾功能不全;急慢性肾功能衰竭;狼疮性肾炎;潜在或相关的肾脏疾病:低灌注,透析低血压,阻塞性尿路病,肾小球病,肾小球肾炎,急性肾小球肾炎,肾小球硬化症,肾小管间质疾病,肾病,原发性和先天性肾病,肾炎;以肌酐和/或水排泄异常减少为特征的疾病;以尿素、氮、钾和/或肌酸酐血浓度异常升高为特征的疾病;以肾酶活性改变为特征的疾病,以谷氨酰合成酶活性改变为特征的疾病;以尿渗透压或尿量改变为特征的疾病;以微量白蛋白尿增加为特征的疾病,以大量白蛋白尿为特征的疾病;以肾小球和小动脉损伤、肾小管扩张、高磷血症和/或透析需要为特征的疾病;肾功能不全后遗症;与肺灌肠有关的肾功能不全;与HF有关的肾功能不全;与尿毒症或贫血有关的肾功能不全;电解质紊乱(高钾血症,低钠血症);骨和碳水化合物代谢紊乱;急性肾损伤;
·眼部疾病或病症,如青光眼、视网膜病变和糖尿病视网膜病变。
66.一种治疗需要治疗的个体的疾病、健康状况或病症的方法,包括向需要治疗的个体施用治疗有效量的根据权利要求1到50中任一权利要求所述化合物I的结晶固体形式、根据权利要求63所述的药物组合物或根据权利要求64所述的药物剂型,其中所述疾病、健康状况或病症选自:
·心肌炎症(心肌炎);慢性心肌炎;急性心肌炎;病毒性心肌炎;
·血管炎;胰腺炎;腹膜炎;类风湿病;
·肾脏炎症性疾病;免疫性肾病:肾移植排斥反应,免疫复合物诱发的肾病,毒素引起的肾病,造影剂诱发的肾病;糖尿病和非糖尿病肾病,肾盂肾炎,肾囊肿,肾硬化,高血压性肾硬化和肾病综合征;
·慢性间质性炎症,炎症性肠病(IBD),克罗恩病,溃疡性结肠炎(UC);
·炎症性皮肤病;
·眼部炎症性疾病,睑缘炎,干眼症和修格兰氏症候群;眼睛纤维化。
67.一种治疗需要治疗的个体的疾病、健康状况或病症的方法,包括向需要治疗的个体施用治疗有效量的根据权利要求1到50中任一权利要求所述化合物I的结晶固体形式、根据权利要求63所述的药物组合物或根据权利要求64所述的药物剂型,其中所述疾病、健康状况或病症选自糖尿病患者的伤口或溃疡愈合;微血管灌注改善;损伤后微血管灌注改善或抵消围手术期护理中的炎症反应;肛裂;糖尿病溃疡;糖尿病足溃疡;骨愈合;破骨细胞骨吸收和重塑;和新骨形成。
68.一种治疗需要治疗的个体的疾病、健康状况或病症的方法,包括向需要治疗的个体施用治疗有效量的根据权利要求1到50中任一权利要求所述化合物I的结晶固体形式、根据权利要求63所述的药物组合物或根据权利要求64所述的药物剂型,其中所述疾病、健康状况或病症选自:
·泌尿生殖系统和肾脏疾病:糖尿病肾病;慢性肾脏疾病或功能不全引起的肾纤维化和肾功能衰竭;由于积聚/沉积和组织损伤引起的肾纤维化和肾衰竭;肾硬化;进行性硬化症;肾小球肾炎;局灶性节段性肾小球硬化;肾病综合征;前列腺肥大;肾纤维化;间质性肾纤维化;
·肺系统疾病:肺纤维化;特发性肺纤维化;囊性纤维化;进行性大块纤维化;影响肺部的进行性大块纤维化;
·影响心脏的疾病:心内膜心肌纤维化;老年心肌梗死;心房纤维化;心脏间质纤维化;心脏重塑和纤维化;心脏肥大;
·肝脏和相关器官紊乱:肝硬化或肝硬化;肝硬化伴慢性肝病;肝纤维化;肝星状细胞活化;NASH;肝纤维胶原和总胶原蛋白积聚;坏死性和/或免疫性肝病;原发性胆汁性肝硬化;原发性硬化性胆管炎;其他胆汁淤积性肝病:与肉芽肿性肝病、肝脏恶性肿瘤、妊娠期肝内胆汁淤积、肝炎、败血症、药物或毒素、移植物抗宿主病、肝移植后、胆总管结石、胆管肿瘤、胰腺癌、Mirizzi相关综合征、艾滋病胆管病或寄生虫相关的那些;血吸虫病;肝细胞癌;
·消化系统疾病或病症:克罗恩病;溃疡性结肠炎;胃肠道硬化;贲门失弛缓症;
·皮肤或眼睛疾病:肾源性纤维化;增殖性玻璃体视网膜病变;糖尿病性视网膜病变;眼睛纤维化;
·纤维化局部或皮肤病或病症;皮肤纤维化;硬皮病,皮肤纤维化;硬斑病;肥厚性疤痕;痣;瘢痕疙瘩;肉瘤;肉芽肿;
·影响神经系统的疾病:肌萎缩性脊髓侧索硬化症(ALS);海马硬化,多发性硬化症(MS);局灶性硬化;原发性侧索硬化;
·骨骼疾病;骨硬化;
·耳硬化症;其他听力疾病或紊乱;听力损伤,部分或全部听力损失;部分或全部耳聋;耳鸣;噪音引起的听力损失;
·其他涉及自身免疫、炎症或纤维化的疾病:硬皮病;局限性硬皮病或阿狄森氏瘢痕瘤;纵隔纤维化;纤维化纵隔炎;骨髓纤维化;腹膜后纤维化;关节纤维化;阴茎硬结症;杜普伊特伦氏挛缩;硬化性苔藓;某些形式的粘连性囊炎;动脉粥样硬化;结节性硬化症;系统性硬化症;多发性肌炎;皮肌炎;多软骨炎;嗜酸性筋膜炎;系统性红斑狼疮或狼疮;骨髓纤维化,骨髓纤维化或骨髓纤维化;结节病;子宫肌瘤;子宫内膜异位症。
69.一种治疗需要治疗的个体的疾病、健康状况或病症的方法,包括向需要治疗的个体施用治疗有效量的根据权利要求1到50中任一权利要求所述化合物I的结晶固体形式、根据权利要求63所述的药物组合物或根据权利要求64所述的药物剂型,其中所述疾病、健康状况或病症选自某些类型的癌症;镰状细胞病;镰状细胞性贫血;癌转移;骨质疏松症;胃轻瘫;功能性消化不良;糖尿病并发症;脱发;与内皮功能障碍有关的疾病;与一氧化氮生成减少有关的神经系统疾病;精胺丁二酸酶缺乏症;神经肌肉疾病;杜兴肌营养不良症(DMD);Becker肌营养不良症(BMD);肢带肌肉营养不良;远端肌病;I型和II型肌强直性营养不良;面部-肩胛-腓骨肌营养不良;常染色体和X连锁的Emery-Dreifuss肌营养不良症;眼咽肌营养不良症;肌萎缩侧索硬化症;和脊髓肌肉萎缩(SMA)。
70.一种治疗或预防有此需要的受试者的疾病,健康状况或病症的方法,包括单独或联合治疗给予该受试者治疗有效量的权利要求1至50中任一项的化合物I的结晶固体形式,其中所述疾病或病症是可受益于sGC刺激或受益于NO和/或cGMP浓度增加的疾病或病症。
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MA45603A (fr) * | 2016-07-07 | 2019-05-15 | Ironwood Pharmaceuticals Inc | Nouveaux procédés de préparation de stimulateurs de la guanylate cyclase soluble |
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CN110862424A (zh) * | 2019-12-03 | 2020-03-06 | 海南顿斯医药科技有限公司 | 一种硫酸阿米卡星化合物 |
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CN114199812A (zh) * | 2021-12-28 | 2022-03-18 | 南通联亚药业有限公司 | 一种盐酸美金刚缓释制剂中盐酸美金刚的检测方法 |
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