CN111867585A - 噁二唑瞬时受体电位通道抑制剂 - Google Patents
噁二唑瞬时受体电位通道抑制剂 Download PDFInfo
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- CN111867585A CN111867585A CN201980020491.7A CN201980020491A CN111867585A CN 111867585 A CN111867585 A CN 111867585A CN 201980020491 A CN201980020491 A CN 201980020491A CN 111867585 A CN111867585 A CN 111867585A
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Abstract
本发明涉及式I化合物及其药学上可接受的盐,其中A、X、R1、R4和n如本文所定义的。此外,本发明涉及式I化合物的制备方法和使用方法以及含有所述化合物的药物组合物。所述化合物可用于治疗由TRPA1介导的疾病和病况,如疼痛。
Description
相关申请的交叉引用
本申请要求2018年03月19日提交的美国临时申请号62/644,987,2018年05月24日提交的美国临时申请号62/676,057,2018年08月31日提交的美国临时申请号62/725,488和2019年03月01日提交的美国临时申请号62/812,806的优先权,其全部内容通过引用在此并入本文。
技术领域
本发明涉及噁二唑化合物、其制备、含有其的药物组合物及其作为瞬时受体电位(TRP)阳离子通道拮抗剂的用途。
背景技术
TRP通道是在人(和其他动物)的各种细胞类型的质膜上发现的一类离子通道。存在至少28种已知的人TRP通道,其基于序列同源性和功能被分成许多家族或组。瞬时受体电位阳离子通道亚家族A成员1(TRPA1)是非选择性阳离子传导通道,其通过钠、钾和钙的通量调节膜电位。已显示TRPA1在人背根神经节神经元和外周感觉神经中高度表达。在人中,TRPA1被许多反应性化合物(如丙烯醛、异硫氰酸烯丙酯、臭氧)以及非反应性化合物(如烟碱和薄荷醇)激活,因此被认为作为化学传感器起作用。
许多已知的TRPA1激动剂是在人和其他动物中引起疼痛、刺激和神经源性炎症的刺激物。因此,预计TRPA1拮抗剂或阻断TRPA1通道激活物的生物学作用的药剂可用于治疗疾病(如哮喘及其恶化、慢性咳嗽和相关疾病),以及可用于治疗急性和慢性疼痛。最近,还显示组织损伤和氧化应激的产物(例如,4-羟基壬烯醛和相关化合物)激活TRPA1通道。这一发现为小分子TRPA1拮抗剂在治疗与组织损伤、氧化应激和支气管平滑肌收缩相关的疾病中的应用提供了另外的理论依据,所述疾病例如哮喘、慢性阻塞性肺病(COPD)、职业性哮喘和病毒诱发的肺炎。此外,最近的研究结果已经将TRPA1通道的激活与疼痛感知增加相关联(Kosugi等,J.Neurosci 27,(2007)4443-4451;Kremayer等,Neuron 66(2010)671-680;Wei等,Pain 152(2011)582-591);Wei等,Neurosci Lett 479(2010)253-256)),从而为小分子TRPA1抑制剂在治疗疼痛病症中的应用提供了另外的理论依据。
发明内容
在一些实施方式中,提供了式(I)化合物、其立体异构体、其互变异构体及其盐:
其中:
A是:取代或未取代的6-6稠合双环杂芳基;取代或未取代的5-6稠合双环杂芳基;或者取代和未取代的6-5稠合双环杂芳基;
X是:键;C1-4亚烷基;-O-;-S-;-SO2-;或-N(Ra)-;
n是:0、1、2或3;
Ra是H或C1-6烷基,其可以是未取代的或被卤素取代一次或多次的;
R1是:H;或C1-6烷基;和
R4是:取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基;
或者R1和R4可以一起形成与取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基稠合的未取代或取代的C3-6环烷基。
在其他实施方式中,提供了下述化合物、其立体异构体及其药学上可接受的盐:
一些其他实施方式提供了药物组合物,其包含上文所述的化合物或其药学上可接受的盐,以及药学上可接受的载体、稀释剂或赋形剂。
一些其他实施方式提供了如上文所述的化合物或其药学上可接受的盐,其用于医学治疗。
一些其他实施方式提供了如上文所述的化合物或其药学上可接受的盐,其用于治疗或预防呼吸病症。
一些其他实施方式提供了如上文所述的化合物或其药学上可接受的盐,其用于制备治疗或预防呼吸病症的药物。
一些其他实施方式提供了在哺乳动物中治疗呼吸病症的方法,其包括向所述哺乳动物施用治疗有效量的如上文所述的化合物或其药学上可接受的盐。
一些其他实施方式提供了如上文所述的化合物或其药学上可接受的盐,其用于调节TRPA1活性。
一些其他实施方式提供了如上文所述的化合物或其药学上可接受的盐,其用于治疗或预防由TRPA1活性介导的疾病或病况。
一些其他实施方式提供了如上文所述的化合物或其药学上可接受的盐用于制备治疗或预防由TRPA1活性介导的疾病或病况的药物的用途。
一些其他实施方式提供了用于调节TRPA1活性的方法,其包括使TRPA1与如上文所述的化合物或其药学上可接受的盐接触。
一些其他实施方式提供了用于在哺乳动物中治疗由TRPA1活性介导的疾病或病况的方法,其包括向所述哺乳动物施用治疗有效量的如上文所述的化合物或其药学上可接受的盐。
具体实施方式
定义
除非另有说明,否则说明书和权利要求书中使用的以下特定术语和短语定义如下:
术语“部分”和“取代基”是指原子或化学键合的一组原子,其通过一个或多个化学键与另一个原子或分子连接,从而形成分子的一部分。
术语“取代的”是指该化合物或部分的至少一个氢原子被另一个取代基或部分替代。此类取代基的实例包括但不限于卤素、-OH、-CN、氧代、烷氧基、烷基、烯基、芳基、杂芳基、卤代烷基、卤代烷氧基、环烷基和杂环基。例如,术语“被卤素取代的烷基”是指烷基(如下文所定义)的一个或多个氢原子被一个或多个卤素原子替代的事实(例如,三氟甲基、二氟甲基、氟甲基、氯甲基等)。
术语“烷基”是指具有1至20个碳原子的脂族直链或支链饱和烃部分。在特定实施方式中,烷基具有1至10个碳原子。在特定实施方式中,烷基具有1至6个碳原子。烷基基团可以任选地被一个或多个本文所述的取代基独立地取代。
本文所用的术语“亚烷基”是指具有1至12个碳原子的,在另一个实施方式中是指具有1至6个碳原子的直链或支链饱和二价烃基,其中所述亚烷基可以任选地独立地被一个或多个本文所述的取代基取代。实例包括但不限于亚甲基、亚乙基、亚丙基、2-甲基亚丙基、亚戊基等。
术语“亚烯基”是指具有至少一个不饱和位点(即,碳-碳双键)的2-8个碳原子(C2-8)的直链或支链二价烃基,其中亚烯基可以是任选的被取代的。实例包括但不限于亚乙烯基(-CH=CH-)、烯丙基(-CH2CH=CH-)等。
术语“烷氧基”表示式-O-R’的基团,其中R’是烷基。烷氧基可以任选地独立地被一个或多个本文所述的取代基取代。烷氧基部分的实例包括甲氧基、乙氧基、异丙氧基和叔丁氧基。
“芳基”指具有5至16个碳环原子的单环、二环或三环芳族环的环状芳烃部分。双环芳环系统包括具有两个稠合的五元芳环(表示为5-5)、具有五元芳基环和稠合的六元芳基环(表示为5-6和6-5)以及具有两个稠合的六元芳基环(表示为6-6)的稠合双环。芳基可以如本文所定义的任选被取代。芳基部分的实例包括但不限于苯基、萘基、菲基、芴基、茚基、并环戊二烯基、薁基等。术语“芳基”还包括环状芳烃基团的部分氢化的衍生物,条件是环状芳烃部分的至少一个环是芳族的,其各自任选地被取代。
术语“杂芳基”表示具有5至16个环原子的芳族杂环单环、二环或三环环系,其包含1、2、3或4个选自N、O和S的杂原子,其余环原子是碳。在一些方面,单环杂芳基环可以是5-6元。双环杂芳基环系统包括具有两个稠合的五元杂芳基环(表示为5-5)、具有五元杂芳基环和稠合的六元杂芳基环(表示为5-6和6-5)以及具有两个稠合的六元杂芳基环(表示为6-6)的稠合双环。该杂芳基可以如本文所定义的任选被取代。杂芳基部分的实例包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基、三嗪基、异噁唑基、苯并呋喃基、异噻唑基、苯并噻吩基、吲哚基、异吲哚基、异苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、异喹啉基、喹唑啉基或喹喔啉基。
术语“卤代”、“卤素”和“卤化物”可以互换使用,其是指取代基氟、氯、溴或碘。
术语“卤代烷基”表示其中烷基的氢原子中的一个或多个已经被相同或不同的卤素原子、特别是氟原子替代的烷基。卤代烷基的实例包括一氟-、二氟-或三氟-甲基、-乙基或-丙基,例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基、二氟甲基或三氟甲基。
术语“杂烷基”是指如本文所定义的直链或支链烷基,其在链中具有2至14个碳、2至10个碳或2至6个碳,其中一个或多个已被选自S、O、P和N的杂原子代替。杂烷基的非限制性实例包括烷基醚、仲和叔烷基胺、酰胺和烷基硫化物。
“环烷基”意指具有单环、二环(包括桥连二环)或三环并且在环中具有3-10个碳原子的饱和或部分不饱和碳环部分。环烷基部分可以任选被一个或多个取代基取代。在具体的实施方式中,环烷基含有3-8个碳原子(即,(C3-C8)环烷基)。在其它的具体的实施方式中,环烷基含有3-6个碳原子(即,(C3-C6)环烷基)。环烷基部分的实例包括、但不限于环丙基、环丁基、环戊基、环己基、环庚基及其部分不饱和(环烯基)衍生物(例如,环戊烯基、环己烯基和环庚烯基)、二环[3.1.0]己基、二环[3.1.0]己烯基、二环[3.1.1]庚基和二环[3.1.1]庚烯基。环烷基部分可以以“螺环烷基”形式连接,如“螺环丙基”:
“杂环”或“杂环基”是指4、5、6和7-元单环、7、8、9和10-元二环(包括桥连二环)或10、11、12、13、14和15-元二环的杂环部分,其是饱和的或部分不饱和的,在环中具有一个或多个(例如,1、2、3或4个)选自氧、氮和硫的杂原子,其余环原子是碳。在一些方面,该杂环是杂环烷基。在特定实施方式中,杂环或杂环基是指4、5、6或7-元杂环。当用于指杂环的环原子时,氮或硫也可以是氧化形式,并且氮可以被一个或多个(C1-C6)烷基取代。杂环可以在任何杂原子或碳原子上与其侧基连接,从而产生稳定的结构。任何杂环环原子都可以任选被一个或多个本文所述的取代基取代。此类饱和或部分不饱和的杂环的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、吡咯烷酮基、哌啶基、吡咯啉基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、噁唑烷基、哌嗪基、二噁烷基、二氧杂环戊烷基、二氮杂基、氧氮基(oxazepinyl)、硫氮杂基(thiazepinyl)、吗啉基和奎宁环基。术语杂环还包括其中杂环与一个或多个芳基、杂芳基或环烷基环稠合的基团,例如二氢吲哚基、3H-吲哚基、苯并二氢吡喃基、氮杂二环[2.2.1]庚基、氮杂二环[3.1.0]己烷基、氮杂二环[3.1.1]庚烷基、八氢吲哚基或四氢喹啉基。
术语“稠合双环”表示包括两个稠合环的环系统,包括如本文其他地方所定义的桥连环烷基和桥连杂环烷基。所述环各自独立地为芳基、杂芳基、环烷基和杂环。在一些方面,所述环各自独立地为C5-6芳基、5-6元杂芳基、C3-6环烷基和4-6元杂环。稠合双环体系的非限制性实例包括C5-6芳基-C5-6芳基、C5-6芳基-4-6元杂芳基和C5-6芳基-C5-6环烷基。
术语“稠合三环”表示包括三个稠合环的环系。所述环各自独立地为芳基、杂芳基、环烷基和杂环。在一些方面,所述环各自独立地为C5-6芳基、5-6元杂芳基、C3-6环烷基和4-6元杂环。稠合三环体系的非限制性实例是C3-6环烷基-C3-6环烷基-C5-6芳基,例如C3环烷基-C5环烷基-C6芳基。
除非另有说明,否则术语“氢”是指氢原子部分(-H),不是H2。
在本文的描述中,如果所描绘的结构与给予该结构的名称之间存在差异,则以所描绘的结构为准。另外,如果结构或结构的一部分的立体化学未用例如粗体楔形或虚线表示,则结构或结构的一部分应解释为包括其所有立体异构体。然而,在某些情况下,当存在多个手性中心时,结构和名称可以表示为单一对映体以帮助描述相对的立体化学。
除非另有说明,否则术语“式……的化合物”是指选自该式所定义的化合物类的任意化合物(包括任意这类化合物的任意药学上可接受的盐或酯,另有说明的除外)。
术语“药学上可接受的盐”是指保留游离碱或游离酸的生物学有效性和性质的那些盐,其在生物学上或其他方面不是不期望的。如本文所用,“药学上可接受的”是指载体、稀释剂或赋形剂,其与制剂的其他成分相容并且对其接受者无害。盐可以用无机酸和有机酸形成,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等,优选盐酸;所述有机酸例如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、水杨酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、N-乙酰半胱氨酸等。另外,可以通过向游离酸中加入无机碱或有机碱来制备盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐和镁盐等。衍生自有机碱的盐包括但不限于以下物质的盐:伯、仲和叔胺,被取代的胺,包括天然存在的被取代的胺,环状胺和碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚胺树脂等。
本发明的化合物可以以药学上可接受的盐的形式存在。另一个实施方式提供了式I化合物的非药学上可接受的盐,其可用作分离或纯化式I化合物的中间体。本发明的化合物也可以以药学上可接受的酯的形式存在(即,用作前药的式I的酸的甲酯和乙酯)。本发明的化合物也可以是溶剂化的,即水合的。溶剂化可以在制备过程中实现,或者可以发生,即,由最初无水的式I化合物的吸湿性质造成。
具有相同的分子式、但其原子键合的性质或顺序不同或其原子空间排列不同的化合物被称为“异构体”。其原子空间排列不同的异构体被称为“立体异构体”。非对映体是在一个或多个手性中心上具有相反构型的不是对映体的立体异构体。具有一个或多个不对称中心的彼此是不可叠加的镜像的立体异构体称为“对映体”。当化合物具有不对称中心时,例如,如果碳原子与四个不同的基团键合,则可能有一对对映体。对映体可以用其一个或多个不对称中心的绝对构型来表征,并且通过Cahn、Ingold和Prelog的R-和S-排序规则或通过分子旋转偏振光平面的方式描述并指定为右旋或左旋(即,分别为(+)或(-)异构体)。手性化合物可以以单独的对映体的形式或以其混合物的形式存在。含有等比例对映体的混合物称为“外消旋混合物”。在某些实施方式中,化合物富含至少约90%重量的单一非对映体或对映体。在其他实施方式中,化合物富含至少约95%、98%或99%重量的单一非对映体或对映体。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋物、非对映体、区域异构体和单独的异构体(例如,单独的对映体)都包括在本发明的范围内。
本发明的化合物可以含有不对称或手性中心,因此以不同的立体异构形式存在。本发明的化合物的所有立体异构形式均构成本发明的一部分,包括但不限于非对映体、对映体和阻转异构体,以及其混合物,例如外消旋混合物。在一些情况下,立体化学尚未确定或已临时分配。许多有机化合物以光学活性形式存在,即,其具有旋转平面偏振光平面的能力。在描述光学活性化合物时,前缀D和L或者R和S用于表示分子关于其手性中心的绝对构型。前缀d和l或者(+)和(-)用于表示化合物旋转平面偏振光的符号,(-)或l表示化合物是左旋的。以(+)或d为前缀的化合物是右旋的。对于给定的化学结构,除了其是彼此的镜像之外,这些立体异构体是相同的。特定的立体异构体也可以称为对映体,这类异构体的混合物通常称为对映体混合物。对映体的50:50混合物被称为外消旋混合物或外消旋物,其可以出现在化学反应或方法中没有立体选择性或立体特异性的情况中。术语“外消旋混合物”和“外消旋物”是指不具有光学活性的两种对映体的等摩尔混合物。可通过手性分离方法例如超临界流体色谱(SFC)将对映体从外消旋混合物中分离出来。分离的对映体中手性中心上的构型的指定可以是暂时性的,出于示例性目的,如化合物(l)、(m)和(n)中描述,而立体化学是确定性的,如来自x射线晶体学数据。
术语化合物的“治疗有效量”指有效预防、缓解或改善疾病的症状或延长所治疗的个体的存活的化合物的量。治疗有效量的确定在本领域的技能范围内。本发明的化合物的治疗有效量或剂量可以在宽范围内变化,并且可以以本领域已知的方式确定。这种剂量将根据每个具体病例中的个体需要进行调整,包括所施用的特定化合物、施用途径、所治疗的病况以及所治疗的患者。一般而言,在对体重约为70Kg的成年人进行口服或肠胃外施用的情况下,约0.1mg至约5,000mg、1mg至约1,000mg或1mg至100mg的日剂量可能是适合的,不过,在适合时可能超过上限或下限。日剂量可以以单剂量或多个分剂量施用,或者对于肠胃外施用,可以以连续输注的方式给予。
术语“药学上可接受的载体”旨在包括与药物施用相容的任何和所有材料,包括溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等张剂和吸收延迟剂,以及与药物施用相容的其他材料和化合物。除非任何常规介质或试剂与活性化合物不相容,否则可考虑将其用于本发明的组合物中。补充的活性化合物也可掺入组合物中。
用于制备本发明的组合物的有用的药物载体可以是固体、液体或气体;因此,组合物可以是片剂、丸剂、胶囊剂、栓剂、散剂、肠溶包衣制剂或其它受保护的制剂(例如,结合在离子交换树脂上或者包在脂质-蛋白囊泡中)、持续释放制剂、溶液、混悬剂、酏剂、气雾剂等。载体可以选自:各种油,包括石油、动物油、植物油或合成来源的油,例如花生油、豆油、矿物油、芝麻油等。水、盐水、葡萄糖水溶液和二醇是优选的液体载体,特别是(当与血液等张时)对于注射溶液而言。例如,用于静脉内施用的制剂包含活性成分的无菌水溶液,其通过将固体活性成分溶解在水中以产生水溶液并使溶液无菌来制备。适合的药用赋形剂包括淀粉、纤维素、滑石粉、葡萄糖、乳糖、滑石粉、明胶、麦芽、大米、面粉、白垩、二氧化硅、硬脂酸镁、硬脂酸钠、甘油单硬脂酸酯、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。可以向组合物中加入常规的药物添加剂,如防腐剂、稳定剂、润湿剂或乳化剂、用于调节渗透压的盐、缓冲剂等。适合的药物载体以及其配制在E.W.Martin的Remington’s PharmaceuticalSciences中有描述。在任何情况下,这些组合物均含有有效量的活性化合物以及适合的载体,以制备适当的剂型用于给接受者适当地施用。
在本发明的方法的实施中,治疗有效量的本发明的任意一种化合物或本发明的任意化合物的组合或其药学上可接受的盐或酯通过本领域已知的任何常规的且可接受的方法单独施用或组合施用。因此,化合物或组合物可以口服(例如,口腔)施用、舌下施用、肠胃外(例如,肌内、静脉内或皮下)施用、直肠(例如,通过栓剂或洗涤剂)施用、透皮(例如,皮肤电致孔)施用或通过吸入(例如,通过气雾剂)施用,施用形式是固体、液体或气体剂型,包括片剂和混悬剂。所述施用可以以单一单位剂型连续治疗或单剂量随意治疗进行。治疗组合物也可以是与亲脂性盐如双羟萘酸联合的油乳剂或分散液的形式,或者是可生物降解的持续释放组合物的形式用于皮下或肌内施用。
化合物
本发明的一个实施方式提供了式I化合物、其立体异构体、其互变异构体及其盐:
或其药学上可接受的盐,
其中:
A是:取代或未取代的6-6稠合双环杂芳基,其可以是部分饱和的;取代或未取代的5-6稠合双环杂芳基,其可以是部分饱和的;或取代和未取代的6-5稠合双环杂芳基,其可以是部分饱和的;
X是:键;C1-4亚烷基;-O-;-S-;-SO2-;或-N(Ra)-;
n是:0、1、2或3;
Ra是H或C1-6烷基,其可以是未取代的或被卤素取代一次或多次;
R1是:H;或C1-6烷基;和
R4是:取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基;
或者R1和R4可以一起形成与取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基稠合的未取代或取代的C3-6环烷基。
在一些方面中,n是0、1或2。在一些方面中,n是0或1。在一些方面中,n是0。在一些方面中,n是1。
在一些方面中,A选自:
其中:
E是五元或六元杂芳基环,其中一个环碳原子任选被氧代取代;
G是具有被氧代取代的一个环碳原子的六元杂芳基环;
Y1、Y2、Y3、Y4、Y5和Y6中的一至三个是氮,Y1、Y2、Y3、Y4、Y5和Y6中的其它是碳,且Y1、Y2、Y3和Y4中的一个可以是–C(O)-或-C(S)-;
Z1、Z2、Z3、Z4和Z5中的一个或两个是氮,和Z1、Z2、Z3、Z4和Z5中的其它是碳;
每个R2独立地为H;-C1-4烷基;-C1-4卤代烷基;-CN;卤素;卤代C1-4烷氧基;C1-4烷氧基;-OH;-SO2-C1-4烷基;-C1-4CN、C1-4醛;C1-4酮;苄基氨基;或NR14R15;
P是0、1或2;
每个R3独立地为:H;-C1-4烷基;-C1-4卤代烷基;-CN;卤素;或NR14R15;
q是0或1;
R14和R15各自独立地为:H;取代或未取代的-C1-4烷基;取代或未取代的-C(O)-C1-4烷基;取代或未取代的C3-6环烷基;取代或未取代的3-至6-元杂环烷基;取代或未取代的3-至6-元-C1-4烷基-杂环烷基;取代或未取代的-C1-4杂烷基;-C(O)NR16R17;取代或未取代的-C1-4烷基-C(O)NR16R17;取代或未取代的苯基;或取代或未取代的苄基;
或者R14和R15与其所连接的原子一起可形成任选地包括一个选自O、N和S的另外的杂原子的4-、5-、6-或7-元环;和
R16和R17各自独立地为H和C1-4烷基。
在一些方面中,A是选自下述的稠合杂芳基部分:
其中:
每个R2独立地为:H;D;-C1-4烷基;-C1-4卤代烷基;C1-4烷氧基;-CN、卤素;-C(O)CH3;-C(O)NR16R17;-NH2;NHC1-4烷基,其中所述C1-4烷基任选地包含氧杂原子或-OH取代基;-NHC(O)-C1-4烷基;-NHCH2C(O)N(C1-4烷基)2;苄基氨基;和包含氧杂原子的-NH-C4-6杂环基;
每个R3独立地为:H;D;-C1-4烷基;-C1-4卤代烷基;-CN;卤素;或NR14R15;
p是0、1或2;和
q是0或1。
在一些方面中,每个R2独立地选自H、-D、-C1-4烷基、-C1-4卤代烷基、-CN、卤素、-C(O)CH3、-NH2、NHC1-4烷基,其中所述C1-4烷基任选地包含氧杂原子或-OH取代基、-NHC(O)-C1-4烷基、-NHCH2C(O)N(C1-4烷基)2、-C(O)-NH2;和包含氧杂原子的-NH-C4-6杂环基。在一些方面中,每个R2独立地选自H、D、-CH3、–CN、-卤素、-NH2、-NHCH3、NHCH2CH3、-NHCH2CH2CH2OH、-NHCH2CH2OCH3、-NHC(O)CH3、-NHCH2C(O)N(CH3)2、 且p为0或1。R3选自H、-D、-C1-4烷基、-C1-4卤代烷基、-CN和卤素。在一些方面中,R3选自H、-D和-CN。
在一些方面中,每个R2独立地选自H、-D、-C1-4烷基或-NH2。
在一些方面中,每个R3独立地选自H、-D、-C1-4烷基或-NH2。
在一些方面中,每个R2独立地选自H、-D或-C1-4烷基。
在一些方面中,每个R3独立地选自H、-D或-C1-4烷基。
在一些方面中,A是选自下述的稠合杂芳基部分:
在一些方面中,A是选自下述的稠合杂芳基部分:
其中R2、R3、p和q如本文其它地方所定义。
在一些方面中,A选自:
其中R2、R3、p和q如本文其他地方所定义。
在一些方面中,A选自:
其中R2、R3、p和q如本文其它地方所定义。
在一些方面中,A是:
在一些方面中,A是:
在一些方面中,A选自:
在一些方面中,A选自:
在一些方面中,A选自:
在一些方面中,A选自:
在一些方面中,A选自:
在一些方面中,A是:
在一些方面中,A是:
在一些方面中,A是:
在一些方面中,A是:
在一些方面中,A是:
在一些方面中,A是:
在一些方面中,X是亚甲基。
R4选自取代或未取代的苯基、取代或未取代的杂芳基和取代或未取代的萘基。在一些方面中,R4是:
其中每个R18独立地选自H、卤素、-OH、-C1-4烷基、-C1-4卤代烷基、-CN、卤素、C1-4卤代烷氧基、C1-4烷氧基、-SO2-C1-4烷基、-C1-4CN、C1-4醛、C1-4酮、五氟硫基、未取代或取代的C3-6环烷基、未取代或取代的苯基、未取代或取代的杂芳基、稠合芳基和稠合杂芳基;和k是0至3。在一些方面中,每个R18独立地选自H、Cl、-OCHF2、-OCF3、-OCH3和-CN。在某些实施方式中,R18是卤素。在某些实施方式中,R18是氯或氟。在某些实施方式中,k是0、1或2。
在一些方面中,R4选自:
在一些方面中,R4选自:
在这样的方面中,每个R10独立地选自H、卤素、-CN、-OH、C1-4烷基、取代或未取代的C3-6环烷基、C1-4卤代烷基、C1-4卤代烷氧基、C1-4烷氧基、-SO2-C1-4烷基、C1-4CN、C1-4醛、C1-4酮、-S-C1-4卤代烷基、五氟硫基、未取代或取代的C3-6环烷基、未取代或取代的苯基、未取代的或取代的或未取代的5-至6-元杂芳基、取代或未取代的4-至6-元杂环烷基、取代或未取代的苯基和取代或未取代的萘基。每个u独立地选自0、1、2和3。在一些方面中,每个R10独立地选自卤素、C1卤代烷氧基和C1烷氧基。在某些实施方式中,每个R10是卤素。
在一些方面中,其中R1和R4一起形成与取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基稠合的未取代或取代的C3-6环烷基,此类组合的R1和R4可以具有下式
其中*表示螺连接点以及u和R10如本文所定义。
在一些方面中,R4选自:
在一些方面中,R4选自:
在一些方面中,式(I)化合物可以是式(II):
其中A、X、R1和R4如本文所定义。
在一些方面中,式(I)化合物可以是式(IIIa)或式(IIIb)
其中E、G、R1、R2、R3、R4、X、Y1、Y2、Y3、Y4、Y5、Y6、fZ1、Z2、Z3、Z4、Z5、p和q如本文所定义。
在一些方面中,X是C1-4亚烷基。
在一些方面中,X是亚甲基。
在一些方面中,R1是H。
在一些方面中,R4是:
在一些方面中,式(I)化合物可以是式(IVa)或式(IVb)
其中E、G、R1、R2、R3、R4、X、Y1、Y2、Y3、Y4、Y5、Y6、fZ1、Z2、Z3、Z4、Z5、p和q如本文所定义。
在一些方面中,式(I)化合物可以是式(Va)
其中R1、R2、R4和p如本文所定义。
在一些方面中,式(I)化合物可以是式(Vb)
其中R1、R2、R3、R4、p和q如本文所定义。
在一些方面中,式(I)化合物可以是式(VIa)或式(VIb)
其中R1、R2、R4和p如本文所定义。
在一些方面中,式(I)化合物可以是式(VIc)或式(VId)
其中R1、R2、R3、R4、p和q如本文所定义。
在一些方面中,式(I)化合物可以是式(VIIa)或式(VIIb)
其中R1、R2、R4、R18、p和k如本文所定义。
在一些方面中,式(I)化合物可以是式(VIIc)或式(VIIc)
其中R1、R2、R3、R18、p、q和k如本文所定义。
在式(I)的某些实施方式中,基团A可以是下式所示的基团:
其中:
B是选自下述的五元杂芳基:吡咯、吡唑、吡唑、咪唑或三唑,其中的每一个可以是未取代的或被Ra取代一次,且其中吡咯、吡唑和咪唑各自可以是部分饱和的;和
Rb是氢、C1-6烷基,其可以是未取代的或被-NR16R17取代一次。
在某些实施方式中,B是咪唑基。
在某些实施方式中,B是1-甲基-咪唑-5-基-。
在某些实施方式中,B是三唑基。
在某些实施方式中,B是5-甲基-1H-1,2,3-三唑-1-基。
在某些实施方式中,A是2-氨基-3-甲基嘧啶-4(3H)-酮-5-基。
在某些实施方式中,Rb是氢。
在一些方面中,式(I)化合物或其药学上可接受的盐及其立体异构体选自下述:
在本发明的另一个实施方式中,式(I)的化合物是同位素标记的,其中一个或多个原子被具有不同原子质量或质量数的原子替代。这类同位素标记的(即,放射性标记的)式I的化合物被视为属于本发明的范围。可以掺入式I化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,分别例如但不限于2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。这些同位素标记的化合物可以用于帮助例如通过表征对离子通道的作用部位或模式或者对离子通道、特别是TRPA1上的药理学重要的作用部位的结合亲和力来确定或测定化合物的有效性。某些同位素标记的式I化合物、例如掺入放射性同位素的那些,可用于药物和/或底物组织分布研究。放射性同位素氚(即3H)和碳-14(即14C)因其易于掺入和方便的检测手段而特别可用于该目的。例如,式I的化合物可以富含1%、2%、5%、10%、25%、50%、75%、90%、95%或99%的指定同位素。
用较重的同位素例如氘(即2H)取代因较大的代谢稳定性而可以提供某些治疗优势,例如增加的体内半衰期或降低的剂量需求。因此,应将如本文所使用的术语“氢”或-H理解为涵盖氘和氚。
用正电子发射同位素例如11C、18F、15O和13N取代可用于正电子发射断层成像术(PET)研究,以检查底物受体占有率。同位素标记的式I化合物通常可通过本领域技术人员已知的常规技术或者通过与下面给出的实施例中所述的方法类似的方法、使用适当的同位素标记的试剂替换以前使用的非同位素标记的试剂来制备。
在另一个实施方式中,本发明提供了药物组合物,其包含治疗有效量的式I的化合物和药学上可接受的载体、稀释剂和/或赋形剂。
除盐形式外,本发明还提供了前药形式的化合物。本文所用的术语“前药”是指在生理条件下易于发生化学变化以提供本发明的化合物的那些化合物。另外,前药可以通过化学或生物化学方法在离体环境中转化为本发明的化合物。例如,当将前药置于具有合适的酶或化学试剂的透皮贴剂储库中时,前药可以被缓慢转化为本发明的化合物。
本发明的前药可以包括磷酸盐、磷酸酯、烷基磷酸盐、烷基磷酸酯、酰基醚或下文所述的其它前药部分。在一些实施方式中,所述前药部分是:
还包括其它类型的前药。例如,其中氨基酸残基或者两个或更多个(例如,两个、三个或四个)氨基酸残基的多肽链通过酰胺或酯键共价连接到本发明的化合物的游离氨基、羟基或羧酸基团上。所述氨基酸残基包括但不限于通常由三个字母符号表示的20种天然存在的氨基酸,还包括磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、4-羟基脯氨酸、羟基赖氨酸、锁链赖氨酸(demosine)、异锁链赖氨酸(isodemosine)、γ-羧基谷氨酸、马尿酸、八氢吲哚-2-甲酸、抑胃酶氨酸、1,2,3,4-四氢异喹啉-3-甲酸、青霉胺、鸟氨酸、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸(homocysteine)、高丝氨酸(homoserine)、甲基丙氨酸、对苯甲酰基苯丙氨酸、苯基甘氨酸、炔丙基甘氨酸、肌氨酸、甲硫氨酸砜(methionine sulfone)和叔丁基甘氨酸。
还包括其它类型的前药。例如,本发明的化合物的游离羧基可以衍生化为酰胺和烷基酯。作为另一个实例,包含游离羟基的本发明的化合物可以通过将羟基转化为例如但不限于磷酸酯、半琥珀酸酯、二甲基氨基乙酸酯或磷酰基氧基甲基氧基羰基等基团而衍生化为前药,如Fleisher,D.等,(1996)Improved oral drug delivery:solubilitylimitations overcome by the use of prodrugs Advanced Drug Delivery Reviews,19:115中所概括的。还包括羟基和氨基的氨基甲酸酯前药,以及羟基的碳酸酯前药、磺酸酯和硫酸酯。还包括将羟基衍生化为(酰基氧基)甲基和(酰基氧基)乙基醚,其中酰基可以是任选被基团取代的烷基酯,所述基团包括但不限于醚、胺和羧酸官能团,或者其中酰基是如上所述的氨基酸酯。这种类型的前药描述于J.Med.Chem.,(1996),39:10中。更具体的实例包括用诸如以下基团替代醇基团的氢原子:(C1-6)烷酰基氧基甲基、1-((C1-6)烷酰基氧基)乙基、1-甲基-1-((C1-6)烷酰基氧基)乙基、(C1-6)烷氧基羰基氧基甲基、N-(C1-6)烷氧基羰基氨基甲基、琥珀酰基、(C1-6)烷酰基、α-氨基(C1-4)烷酰基、芳基酰基和α-氨基酰基、或α-氨基酰基-α-氨基酰基,其中α-氨基酰基各自独立地选自天然存在的L-氨基酸,P(O)(OH)2、-P(O)(O(C1-6)烷基)2或糖基(由除去碳水化合物的半缩醛形式的羟基产生的基团)。
对于前药衍生物的另外的实例,参见例如:a)Design of Prodrugs,H.Bundgaard编辑,(Elsevier,1985)和Methods in Enzymology,Vol.42,p.309-396,K.Widder等编辑(Academic Press,1985);b)A Textbook of Drug Design and Development,Krogsgaard-Larsen和H.Bundgaard编辑,H.Bundgaard编写的第5章"Design and Application ofProdrugs,"p.113-191(1991);c)H.Bundgaard,Advanced Drug Delivery Reviews,8:1-38(1992);d)H.Bundgaard,等,Journal of Pharmaceutical Sciences,77:285(1988);和e)N.Kakeya,等,Chem.Pharm.Bull.,32:692(1984),通过引用将其各自的具体内容合并入本文。
另外,本发明提供了本发明化合物的代谢产物。本文所用的“代谢产物”是指通过在特定化合物或其盐的体内代谢产生的产物。这类产物可由所施用的化合物的例如氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯化、酶促裂解等产生。
代谢产物通常通过如下鉴定:制备本发明的化合物的放射性标记的(例如,14C或3H)同位素,以可检测的剂量(例如,大于约0.5mg/kg)肠胃外施用于动物如大鼠、小鼠、豚鼠、猴,或者施用于人,允许有足够的时间进行代谢(通常约30秒至30小时),从尿液、血液或其他生物样本中分离其转化产物。这些产物可以容易地被分离,因为其是被标记的(其他产物通过使用能够结合在代谢产物中存活的表位的抗体来分离)。代谢产物结构以常规方式测定,例如通过MS、LC/MS或NMR分析测定。通常,代谢产物的分析以与本领域技术人员公知的常规药物代谢研究相同的方式进行。只要其在体内没有被另外发现,代谢产物就可用于本发明的化合物的治疗性给药的诊断测定。
本发明的某些化合物可以以非溶剂化形式和溶剂化形式存在,包括水合形式。通常,溶剂化形式与非溶剂形式是等价的,并且均包括在本发明的范围内。本发明的某些化合物可以以多种结晶形式或无定形形式存在。通常,对于本发明所考虑的用途而言,所有物理形式均是等价的,并且均在本发明的范围内。
在本发明的另一个实施方式中,提供了用于制备标题化合物的方法。参见路线I,显示了用于制备本发明化合物的一般合成步骤,其中Xa是卤素,且在每次出现时可以是相同的或不同的,Ra是芳基或C1-6烷基,且每次出现时可以是相同的或不同的,且R1、R18和k是如本文所定义的。
路线1
在路线1的步骤1中,芳基醛化合物a与烯丙基格氏试剂b反应以提供烯丙基芳基醇化合物c。在某些实施方式中,Xa可以是卤素,且R1可以是氢。步骤1的反应可以使用THF等在极性非质子溶剂条件下进行。
在步骤2中进行氧化以氧化化合物c中的不饱和部分,从而提供环氧芳基醇化合物d。此反应可以使用诸如间氯过苯甲酸的温和氧化剂在极性非质子溶剂(如二氯甲烷)中来实现。
在步骤3中,使用诸如硫酸的强酸处理环氧化合物d来实现重排,以形成芳基羟基四氢呋喃化合物e。此反应可在诸如二噁烷的水溶性极性溶剂中进行。
在步骤4中,化合物e与磺酰基卤化物试剂f反应以提供芳基四氢呋喃磺酸酯化合物g。步骤4的反应可在存在诸如二氯甲烷的极性非质子溶剂的条件下在存在胺催化剂的情况下实现。在某些实施方式中,Ra可以是甲基,且Xa可以是氯。
在步骤5中,将化合物g用诸如氰化钠或氰化钾的氰化物试剂处理,以置换磺酸酯基并提供芳基四氢呋喃腈化合物h。此反应可在诸如二甲亚砜的极性的、水可混溶的溶剂中进行。
在步骤6中,将腈化合物h用羟胺处理以提供芳基四氢呋喃羟基甲脒化合物j。步骤6的反应可在诸如乙醇的醇溶剂中进行。
在步骤7中,通过化合物j与双卤乙酸酐试剂k的反应发生环形成以提供芳基噁二唑基四氢呋喃化合物m。此反应可在诸如二氯乙烷的极性非质子溶剂中进行。在某些实施方式中,Xa是氯。
在步骤8中,通过咪唑并嘧啶酮化合物n与化合物n的反应进行N-烷基化,得到四氢呋喃噁二唑化合物p,其为根据本发明的式I化合物。步骤8的反应可在碳酸钾和三烷基碘化铵的存在下在溶剂(如DMF)中进行。
现参见路线2,显示了另一个制备本发明化合物的方法。
路线2
在路线2的步骤1中,芳基醛化合物a与乙酸烯丙酯试剂q反应以提供芳基烯丙醇化合物c。在步骤1中可以使用诸如(R)或(S)BINAP(2,2'-双(二苯基膦基)-1,1'-联萘)的手性或不对称合成试剂来赋予化合物c所需的立体化学。在这一方面,步骤1的反应可在碳酸铯、4-氯-3-硝基苯甲酸和/或卤代环辛二烯铱(I)二聚体的存在下在醇溶剂(如异丙醇)中进行。
在步骤2中,化合物c经过溴化以提供二溴化合物r。步骤2的反应可以通过直接使用溴在极性非质子溶剂(如二氯甲烷)中处理化合物c来进行。
在步骤3中进行环化以提供芳基溴四氢呋喃化合物s。步骤3的反应可以通过使用碳酸钾在醇溶剂(如甲醇)中处理化合物r来实现。
在步骤4中,将芳基溴四氢呋喃化合物s用氰酸盐处理以形成芳基四氢呋喃腈化合物h。此反应可以使用氰酸钾在二甲亚砜或类似溶剂中实现。
使用化合物h,然后可进行路线1的步骤6、7和8,以提供四氢呋喃噁二唑化合物p,其为根据本发明的式I化合物。
可以在本发明的范围内对上述方法进行很多变化,并且其对本领域技术人员是有启示的。可以使用几种不同的双环杂芳基化合物替代咪唑并嘧啶酮化合物n,这将通过下面的实验实施例变得显而易见。可以在最终化合物p以及某些中间体上使用手性柱分离技术,以提供特定的所需立体异构体,如以下实验实施例中所述。
药物组合物和施用
除了上面提供的一种或多种化合物(包括其立体异构体、互变异构体、溶剂化物、代谢产物、同位素、药学上可接受的盐或前药)之外,本发明还提供了包含式I化合物或其实施方式和至少一种药学上可接受载体的组合物和药物。本发明的组合物可用于选择性地抑制患者(例如,人)的TRPA1。
本文所用的术语“组合物”旨在涵盖包含规定量的规定成分的产品,以及直接或间接由规定量的几种规定成分的组合所产生的任何产品。
在一个实施方式中,本发明提供了包含式I的化合物或其实施方式及其立体异构体、互变异构体、溶剂化物、代谢产物、同位素、药学上可接受的盐、或前药以及药学上可接受的载体、稀释剂或赋形剂的药物组合物或药剂。在另一个实施方式中,本发明提供了制备包含本发明的化合物的组合物(或药剂)的方法。在另一个实施方式中,本发明提供了将式I的化合物或其实施方式和包含式I的化合物或其实施方式的组合物施用于有需要的患者(例如,人患者)。
将组合物以符合良好医学实践的方式配制、给药和施用。在该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、活性剂的递送部位、施用方法、施用方案、和医生所知的其它因素。待施用的化合物的有效量将由这些考虑因素确定,并且是抑制TRPA1活性以预防或治疗不希望的疾病或病症例如疼痛所必需的最小量。例如,所述量可以是低于对正常细胞或哺乳动物整体而言有毒的量。
在一个实例中,每剂肠胃外施用的本发明的化合物的治疗有效量为约0.01-100mg/kg,或者约例如0.1至20mg/kg患者体重/天,所用的化合物的典型起始范围为0.3至15mg/kg/天。在某些实施方式中,日剂量以单个日剂量给予或者以每日2至6次的分剂量给予或者以持续释放形式给予。在70kg成年人的情况下,总的日剂量通常为约7mg至约1,400mg。可以调整该剂量方案以提供最佳治疗响应。所述化合物可以以每天1至4次、优选每天一次或两次的方案施用。
本发明的化合物可以以任何方便的施用形式进行施用,例如片剂、散剂、胶囊剂、溶液、分散剂、混悬剂、糖浆、喷雾剂、栓剂、凝胶剂、乳剂、贴剂等。这类组合物可含有药物制剂中的常规组分,例如稀释剂、载体、pH调节剂、甜味剂、填充剂和其它活性剂。
本发明的化合物可以通过任何适合的方式施用,包括口服、局部(包括口腔和舌下)、直肠、阴道、透皮、肠胃外、皮下、腹膜内、肺内、皮内、鞘内和硬膜外和鼻内,以及如果需要,对于局部治疗而言,可以病灶内施用。肠胃外输注包括肌内、静脉内、动脉内、腹膜内、脑内、眼内、病灶内或皮下施用。
包含式I的化合物或其实施方式的组合物通常根据标准药学实践配制为药物组合物。通过混合本发明的化合物和稀释剂、载体或赋形剂制备典型的制剂。适合的稀释剂、载体和赋形剂是本领域技术人员公知的,并且例如在以下文献中有详细描述:Ansel,HowardC.,等,Ansel’s Pharmaceutical Dosage Forms and Drug DeliverySystems.Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.等,Remington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&Wilkins,2000;和Rowe,Raymond C.Handbook of PharmaceuticalExcipients.Chicago,Pharmaceutical Press,2005。制剂还可以包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、遮蔽剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、矫味剂、稀释剂和其他已知的添加剂以提供药物(即,本发明的化合物或其药物组合物)的优雅呈现或者帮助制备药物产品(即,药物)。适合的载体、稀释剂和赋形剂是本领域技术人员公知的,包括:缓冲剂,例如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;六甲氯铵;苯扎氯铵;苄索氯铵;苯酚、丁醇或苯甲醇;对羟基苯甲酸烷基酯,例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);低分子量(小于约10个残基的)多肽;蛋白,例如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,例如EDTA;糖,如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子,例如钠;金属络合物(例如,锌-蛋白络合物);和/或非离子表面活性剂,例如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。本发明的活性药物成分(例如,式I化合物或其实施方式)也可以包埋在例如通过凝聚技术或通过界面聚合制备的微囊中,例如,分别在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳、纳米粒和纳米囊)或在粗乳液(macroemulsion)中的羟甲基纤维素或明胶-微囊和聚(甲基丙烯酸甲酯)微囊。这些技术在Remington:The Science and Practice of Pharmacy:Remington the Scienceand Practice of Pharmacy(2005)第21版,Lippincott Williams&Wilkins,Philadelphia,PA中公开。所用的特定载体、稀释剂或赋形剂将取决于应用本发明化合物的方式和目的。通常基于本领域技术人员公认为对哺乳动物施用安全(GRAS)的溶剂来选择溶剂。通常,安全的溶剂是无毒的含水溶剂,例如水和在水中可溶的或可混溶的其它无毒溶剂。适合的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如,PEG 400、PEG 300)等及其混合物。可接受的稀释剂、载体、赋形剂和稳定剂在所采用的剂量和浓度下对接受者是无毒的。
可以制备本发明化合物(例如,式I化合物或其实施方式)的持续释放制剂。持续释放制剂的适合的实例包括含有式I化合物或其实施方式的固体疏水性聚合物的半渗透性基质,所述基质是成型制品的形式,例如薄膜或微囊。持续释放基质的实例包括聚酯、水凝胶(例如,聚(2-羟基乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚丙交酯(美国专利号3,773,919)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物(Sidman等,Biopolymers 22:547,1983)、不可降解的乙烯-醋酸乙烯酯(Langer等,J.Biomed.Mater.Res.15:167,1981)、可降解的乳酸-乙醇酸共聚物例如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林构成的可注射微球)和聚-D-(-)-3-羟基丁酸(EP 133,988A)。持续释放组合物还包括脂质体包埋的化合物,其可以通过本身已知的方法制备(Epstein等,Proc.Natl.Acad.Sci.U.S.A.82:3688,1985;Hwang等,Proc.Natl.Acad.Sci.U.S.A.77:4030,1980;美国专利4,485,045和4,544,545;和EP 102,324A)。通常,脂质体是小的(约200-800埃)单层类型,其中脂质含量大于约30mol%胆固醇,所选择的比例被调整以实现最佳治疗。
在一个实例中,式I的化合物或其实施方式可以通过在环境温度下在适当的pH和所需的纯度下与生理学上可接受的载体(即,在用于盖伦施用形式中的剂量和浓度下对接受者无毒的载体)混合来配制。制剂的pH主要取决于化合物的具体用途和浓度,但优选为约3至约8的范围中的任意值。在一个实例中,将式I的化合物(或其实施方式)配制在pH 5的乙酸盐缓冲液中。在另一个实施方式中,式I的化合物或其实施方式是无菌的。化合物可以例如以固体或无定形组合物的形式、以冻干制剂的形式或以水溶液的形式储存。
适合用于口服施用的本发明的化合物(例如,式I的化合物或其实施方式)的制剂可以制备成离散单元,例如丸剂、胶囊剂、扁囊剂或片剂,其各自含有预定量的本发明的化合物。
压制片剂可以通过在适合的机器中压制自由流动形式的活性成分如粉末或颗粒来制备,所述粉末或颗粒任选地混合有粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂。模制片剂可以通过在适合的机器中模制用惰性液体稀释剂润湿的粉末状活性成分的混合物来制备。片剂可以任选地包衣或刻痕,并任选地配制以提供活性成分从其缓慢的或受控的释放。
可以制备片剂、糖锭(troches)、锭剂、水性或油性混悬剂、可分散的粉末或颗粒、乳剂、硬或软胶囊例如明胶胶囊、糖浆或酏剂用于口服使用。用于口服使用的本发明的化合物(例如,式I的化合物或其实施方式)的制剂可以根据本领域已知的用于制备药物组合物的任何方法来制备,并且所述组合物可以含有一种或多种物质,包括甜味剂、矫味剂、着色剂和防腐剂,以提供适口的制剂。含有与适合用于制备片剂的无毒的药学上可接受的赋形剂混合的活性成分的片剂是可接受的。这些赋形剂可以是例如:惰性稀释剂,例如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,或者可以通过已知技术包衣,所述技术包括微囊化以延迟在胃肠道中的崩解和吸附,从而在更长的时间段中提供持续的作用。例如,可以使用延时材料,例如单独的或与蜡一起使用的单硬脂酸甘油酯或二硬脂酸甘油酯。
适合的口服施用形式的一个实例是片剂,其含有约1mg、5mg、10mg、25mg、30mg、50mg、80mg、100mg、150mg、250mg、300mg和500mg本发明的化合物,以及与其混合的约90-30mg无水乳糖、约5-40mg交联羧甲基纤维素钠、约5-30mg聚乙烯吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁。首先将粉末成分混合在一起,然后与PVP溶液混合。可以将所得组合物干燥、造粒、与硬脂酸镁混合并使用常规设备压制成片剂形式。气雾剂制剂的一个实例可以如下制备:将本发明的化合物、例如5-400mg本发明的化合物溶解在适合的缓冲溶液例如磷酸盐缓冲液中,如果需要,加入张度剂(tonicifer)例如盐如氯化钠。可以将溶液过滤,例如使用0.2微米过滤器过滤,以除去杂质和污染物。
对于眼或其它外部组织例如口腔和皮肤的治疗,制剂优选以含有活性成分的局部软膏或乳膏的形式应用,所含有的活性成分的量为例如0.075-20%w/w。当配制成软膏时,活性成分可与石蜡或与水混溶性软膏基质一起使用。或者,可以将活性成分配制在具有水包油乳膏基质的乳膏中。如果需要,乳膏基质的水相可以包括多元醇,即具有两个或更多个羟基的醇,例如丙二醇、丁烷-1,3-二醇、甘露醇、山梨醇、甘油和聚乙二醇(包括PEG 400)及其混合物。局部制剂可以根据需要包含增强活性成分通过皮肤或其他被侵袭区域的吸收或渗透的化合物。这类皮肤渗透增强剂的实例包括二甲亚砜和相关类似物。
对于局部制剂,需要的是将有效量的根据本发明的药物组合物施用到靶点区域,例如与待治疗的外周神经元相邻的皮肤表面、粘膜等。该量通常为每次应用约0.0001mg至约1g的本发明化合物,取决于待治疗的区域、所述使用是否是诊断性的、预防性的或治疗性的、症状的严重性和所使用的局部介质的性质。优选的局部制剂是软膏,其中每cc软膏基质使用约0.001mg至约50mg活性成分。药物组合物可以被配制成透皮组合物或透皮递送装置(“贴剂”)。此类组合物包括例如背衬、活性化合物储库、控制膜、衬里和接触粘着剂。这类透皮贴剂可用于提供所需的本发明化合物的连续脉冲施用或按需递送。
可以将制剂包装在单位剂量或多剂量容器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,仅需要在使用前即刻添加无菌液体载体例如水即可用于注射。当场配制的注射溶液和悬浮液由前述种类的无菌粉末、颗粒和片剂制备。优选的单位剂量制剂是含有活性成分的上文所述的日剂量或单位每日分剂量的那些,或其适当的部分。
当结合靶点位于脑中时,本发明的某些实施方式提供穿过血脑屏障的式I的化合物(或其实施方式)。某些神经变性疾病与血脑屏障的渗透性增加相关,使得可以容易地将式I的化合物(或其实施方式)导入脑中。当血脑屏障保持完整时,存在多种本领域已知的方法用于跨越血脑屏障运输分子,包括但不限于物理方法、基于脂质的方法和基于受体和通道的方法。
将式I的化合物(或其实施方式)运输跨越血脑屏障的物理方法包括但不限于完全绕过血脑屏障或通过在血脑屏障中产生开口。
绕过方法包括但不限于直接注射入大脑(参见例如,Papanastassiou等,GeneTherapy 9:398-406,2002)、间质输注/对流增强递送(参见例如,Bobo等,Proc.Natl.Acad.Sci.U.S.A.91:2076-2080,1994)和在大脑中植入递送装置(参见例如,Gill等,Nature Med.9:589-595,2003;和Gliadel WafersTM,Guildford)。
在屏障中产生开口的方法包括但不限于超声(参见例如,美国专利公开号2002/0038086)、渗透压(例如,通过施用高张甘露醇(Neuwelt,E.A.,Implication of theBlood-Brain Barrier and its Manipulation,第1和2卷,Plenum Press,N.Y.,1989))和透化作用(permeabilization),例如用缓激肽或通透化剂A-7(参见例如,美国专利号5,112,596、5,268,164、5,506,206和5,686,416)。
将式I的化合物(或其实施方式)跨越血脑屏障运输的基于脂质的方法包括但不限于:将式I的化合物(或其实施方式)包封在与抗体结合片段偶联的脂质体中,所述抗体结合片段与血脑屏障的血管内皮上的受体结合(参见例如,美国专利申请公开号2002/0025313);和将式I的化合物(或其实施方式)在低密度脂蛋白颗粒(参见例如,美国专利申请公开号2004/0204354)或载脂蛋白E(参见例如,美国专利申请公开号2004/0131692)中涂敷。
将式I的化合物(或其实施方式)跨越血脑屏障运输的基于受体和通道的方法包括但不限于使用糖皮质激素阻断剂以增加血脑屏障的渗透性(参见例如,美国专利申请公开号2002/0065259、2003/0162695和2005/0124533)、激活钾通道(参见例如,美国专利申请公开号2005/0089473)、抑制ABC药物转运蛋白(参见例如,美国专利申请公开号2003/0073713)、用转铁蛋白涂覆式I的化合物(或其实施方式)和调节一种或多种转铁蛋白受体的活性(参见例如,美国专利申请公开号2003/0129186)和使抗体阳离子化(参见例如,美国专利号5,004,697)。
对于脑内使用,尽管一次性注射是可接受的,但是在某些实施方式中,化合物可以通过输注到CNS的流体贮池中连续施用。抑制剂可以被施用到脑室中或者在其它情况下被引入CNS或脊髓液中。施用可以通过使用留置导管和连续给药工具如泵进行,或者可以将其通过植入例如脑内植入持续释放载体施用。更具体地,抑制剂可以通过长期植入的套管注射或在渗透性微型泵的帮助下长期输注。皮下泵可用于通过小管将蛋白质递送到脑室。高度复杂的泵可以通过皮肤重新填充,并且可以在无需手术介入的情况下设定其递送速度。涉及皮下泵装置的适合的施用方案和递送系统或通过完全植入的药物递送系统进行连续的脑室内输注的实例是用于给阿尔茨海默病患者和帕金森病动物模型施用多巴胺、多巴胺激动剂和胆碱能激动剂的那些,如Harbaugh,J.Neural Transm.Suppl.24:271,1987;和DeYebenes等,Mov.Disord.2:143,1987中所述。
适应证和治疗方法
已经显示本发明的代表性化合物调节TRPA1活性。因此,本发明的化合物可用于治疗由TRPA1活性介导的疾病和病症。这些疾病和病症包括但不限于:疼痛(急性、慢性、炎症性或神经性疼痛);痒病或各种炎性病症;内耳病症;发热或其它体温调节病症;气管支气管或膈膜功能障碍;胃肠道或泌尿道病症;慢性阻塞性肺病;失禁;和与流向CNS的血流减少或CNS缺氧相关的病症。
在一个具体实施方式中,本发明的化合物可以施用以治疗疼痛,包括但不限于神经性和炎症性疼痛等。某些类型的疼痛可以被认为是疾病或病症,而其它类型的疼痛可以被认为是各种疾病或病症的症状,并且疼痛可以包括各种病因。可用本发明的TRPA1调节剂治疗的示例性的疼痛类型包括与以下事项相关的、由以下事项引起的或由以下事项导致的疼痛:骨关节炎、回旋套病症、关节炎(例如,类风湿性关节炎或炎性关节炎;参见Barton等,Exp.Mol.Pathol.2006,81(2),166-170)、纤维肌痛、偏头痛和头痛(例如,丛集性头痛、窦性头痛或紧张性头痛;参见Goadsby Curr.Pain Headache Reports2004,8,393)、窦炎、口腔粘膜炎、牙痛、牙科创伤(dental trauma)、拔牙、牙科感染、烧伤(Bolcskei等,Pain 2005,117(3),368-376)、晒伤、皮炎、银屑病、湿疹、昆虫叮或咬、肌肉骨骼障碍、骨折、韧带扭伤、足底筋膜炎、肋软骨炎、肌腱炎、滑囊炎、网球肘、投手肘(pitcher’s elbow)、髌腱炎、重复性劳损(repetitive strain injury)、肌筋膜综合征、肌肉劳损、肌炎、颞颌关节病症、切断术、腰痛、脊髓损伤、颈部疼痛、颈椎加速伸展性损伤(whiplash)、膀胱痉挛、胃肠道障碍、膀胱炎、间质性膀胱炎、胆囊炎、泌尿道感染、尿道绞痛、肾绞痛、咽炎、感冒疮、口炎、外耳炎、中耳炎(Chan等,Lancet,2003,361,385)、口腔烧灼综合征、粘膜炎、食道痛、食道痉挛、腹部病症(abdominal disorders)、胃食管反流病、胰腺炎、肠炎、应激性肠病、炎症性肠病、克罗恩病、溃疡性结肠炎、结肠扩张(colon distension)、腹部狭窄(abdominalconstriction)、憩室病、憩室炎、肠积气、痔、肛门裂、肛门直肠障碍、前列腺炎、附睾炎、睾丸疼痛、直肠炎、直肠疼痛、生产(labor)、分娩(childbirth)、子宫内膜异位症、经期痉挛、骨盆痛、外阴痛、阴道炎、口唇和生殖器感染(例如,单纯疱疹)、胸膜炎、心包炎、非心脏性胸痛、挫伤、擦伤、皮肤切口(Honore,P.等,J Pharmacal Exp Ther.,2005,314,410-21)、术后疼痛、周围神经病、中枢神经病、糖尿病性神经病、急性疱疹性神经痛、疱疹后神经痛、三叉神经痛、舌咽神经痛、非典型面部疼痛、神经根病、HIV相关神经病、物理性神经损伤、灼痛、反射交感性营养不良、坐骨神经痛、颈部、胸部或腰部神经根病、臂神经丛病、腰丛病、神经变性障碍、枕神经痛、肋间神经痛、眶上神经痛、腹股沟神经痛、感觉异常性股痛、生殖股神经痛(genitofemoral neuralgia)、腕管综合征、莫顿神经瘤、乳房切除术后综合征(post-mastectomy syndrome)、开胸术后综合征(post-thoracotomy syndrome)、小儿麻痹症后期综合征(post-polio syndrome)、吉-巴综合征、雷诺综合征、冠状动脉痉挛(Printzmetal心绞痛或变异型心绞痛)、内脏痛觉过敏(Pomonis,J.D.等,J.Pharmacal.Exp.Ther.2003,306,387;Walker,K.M.等,J.Pharmacal.Exp.Ther.2003,304(1),56-62)、丘脑痛、癌症(例如,由包括溶骨肉瘤在内的癌症引起的疼痛、由通过放疗或化疗治疗癌症引起的疼痛、或由与癌症相关的神经或骨损伤引起的疼痛(参见,Menendez,L.等,Neurosci.Lett.2005,393(1),70-73;Asai,H.等,Pain 2005,117,19-29)或骨破坏性疼痛(参见,Ghilardi,J.R.等,J.Neurosci.2005,25,3126-31))、感染、或代谢疾病。另外,所述化合物可用于治疗疼痛适应证,例如内脏疼痛、眼痛、热痛(thermal pain)、牙痛、辣椒素诱发的疼痛(以及由辣椒素诱发的其它症状病况,例如咳嗽、流泪和支气管痉挛)。
在另一个具体的实施方式中,本发明的化合物可以施用以治疗痒病,所述痒病可以由各种原因造成,例如皮肤病症或炎性病症。
在另一个具体的实施方式中,本发明的化合物可以施用以治疗炎性病症,包括选自以下的病症:肾或肝胆病症、免疫学病症、药物反应和未知/特发性病况。可用本发明的活性剂治疗的炎性病症包括例如炎性肠病(IBO)、克罗恩病和溃疡性结肠炎(Geppetti,P.等,Br.J.Pharmacal.2004,141,1313-20;Yiangou,Y.等,Lancet2001,357,1338-39;Kimball,E.S.等,Neurogastroenterol.Motif.,2004,16,811)、骨关节炎(Szabo,A.等,J.Pharmacal.Exp.Ther.2005,314,111-119)、银屑病、银屑病关节炎、类风湿性关节炎、重症肌无力、多发性硬化、硬皮病、肾小球肾炎、胰腺炎、炎症性肝炎、哮喘、慢性阻塞性肺病、变应性鼻炎、眼色素层炎和炎症的心血管表现,包括动脉粥样硬化、心肌炎、心包炎和血管炎。
在另一个具体的实施方式中,本发明的化合物可以施用以治疗内耳病症。这类病症包括例如听觉过敏、耳鸣、前庭超敏反应(vestibular hypersensitivity)和发作性眩晕。
例如,本发明的化合物可以施用以治疗气管支气管或膈膜功能障碍,包括例如哮喘和与变态反应有关的免疫应答(Agopyan,N.等,Am.J.Physiol.Lung CellMol.Physiol.2004,286,L563-72;Agopyan,N.等,Toxicol.Appl.Pharmacal.2003,192,21-35)、咳嗽(例如,急性或慢性咳嗽、或者因胃食管反流疾病的刺激导致的咳嗽;参见Lalloo,U.G.等,J.Appl.Physiol.1995,79(4),1082-7)、支气管痉挛、慢性阻塞性肺病、慢性支气管炎、肺气肿和呃逆(打呃、打嗝)。
在另一个具体的实施方式中,本发明的化合物可以施用以治疗胃肠道和泌尿道病症,例如膀胱过度活动、炎症性痛觉过敏、膀胱的内脏反射亢进、出血性膀胱炎(Dinis,P.等,J Neurosci.,2004,24,11253-11263)、间质性膀胱炎(Sculptoreanu,A.等,NeurosciLett.,2005,381,42-46)、炎症性前列腺疾病、前列腺炎(Sanchez,M.等,Eur JPharmacal.,2005,515,20-27)、恶心、呕吐、肠痉挛、肠胀气、膀胱痉挛、尿急、排便急迫和紧迫性失禁。
在另一个具体的实施方式中,本发明的化合物可以施用以治疗与流向CNS的血流减少或CNS缺氧相关的病症。这类病症包括例如头部创伤、脊髓损伤、血栓栓塞性卒中或出血性卒中、短暂性脑缺血发作(transient ischaemic attack)、脑血管痉挛、低血糖、心脏停搏、癫痫持续状态、围产期窒息、阿尔茨海默病和亨廷顿舞蹈病。
在其他实施方式中,本发明的化合物可以施用以治疗通过TRPA1活性介导的其它疾病、病症或病况,例如焦虑;学习或记忆病症;与眼相关的病症(例如,青光眼、视力丧失、眼内压升高和结膜炎);秃发(例如,通过刺激毛发生长);糖尿病(包括胰岛素抗性糖尿病或由胰岛素敏感或分泌介导的糖尿病病况);肥胖(例如,通过抑制食欲);消化不良;胆石绞痛;肾绞痛;膀胱疼痛综合征;发炎的食道;上呼吸道疾病;尿失禁;急性膀胱炎;和蛰刺毒作用(envenomations)(如海洋生物、蛇或昆虫叮或咬,包括水母、蜘蛛或黄貂鱼的蛰刺毒作用)。
在一个具体的实施方式中,本发明的化合物可以施用以治疗疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、关节炎、痒病、咳嗽、哮喘或炎症性肠病。
在另一个实施方式中,本发明提供了治疗神经性疼痛或炎症性疼痛的方法,所述方法包括给有需要的个体施用治疗有效量的本文所述的化合物的步骤。
在另一个实施方式中,本发明提供了用于调节TRPA1活性的本文所述的化合物或其药学上可接受的盐。
在另一个实施方式中,本发明提供了用于医学治疗的本文所述的化合物或其药学上可接受的盐。
在另一个实施方式中,本发明提供了治疗选自慢性阻塞性肺病(COPD)、哮喘、变应性鼻炎和支气管痉挛的呼吸病症的方法,所述方法包括给有需要的个体施用治疗有效量的本文所述的化合物。
在另一个实施方式中,本发明提供了用于治疗或预防呼吸病症的本文所述的化合物或其药学上可接受的盐。
在另一个实施方式中,本发明提供了本文所述的化合物或其药学上可接受的盐在制备用于治疗或预防呼吸病症的药物中的用途。
在另一个实施方式中,本发明提供了治疗哺乳动物(例如,人)的呼吸病症的方法,所述方法包括给所述哺乳动物施用本文所述的化合物或其药学上可接受的盐。
在另一个实施方式中,本发明提供了调节TRPA1活性的方法,所述方法包括使TRPA1与本文所述的化合物或其药学上可接受的盐接触。
在另一个实施方式中,本发明提供了用于治疗或预防由TRPA1活性介导的疾病或病况的本文所述的化合物或其药学上可接受的盐。在该实施方式的方面内,所述疾病或病况是疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、痒病、炎性病症、内耳病症、发热或其它体温调节病症、气管支气管或膈膜功能障碍、胃肠道或泌尿道病症、慢性阻塞性肺病、失禁或与流向CNS的血流减少或CNS缺氧相关的病症。在该实施方式的某些方面内,其中所述疾病或病况是疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、关节炎、痒病、咳嗽、哮喘、炎症性肠病或内耳病症。
在另一个实施方式中,本发明提供了本文所述的化合物或其药学上可接受的盐在制备用于治疗或预防由TRPA1活性介导的疾病或病况的药物中的用途。在该实施方式的方面内,所述疾病或病况是疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、痒病、炎性病症、内耳病症、发热或其它体温调节病症、气管支气管或膈膜功能障碍、胃肠道或泌尿道病症、慢性阻塞性肺病、失禁、或者与流向CNS的血流减少或CNS缺氧相关的病症。在该实施方式的方面内,所述疾病或病况是疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、关节炎、痒病、咳嗽、哮喘、炎症性肠病或内耳病症。
在另一个实施方式中,本发明提供了用于治疗哺乳动物(例如,人)的由TRPA1活性介导的疾病或病况的方法,所述方法包括给所述哺乳动物施用本文所述的化合物或其药学上可接受的盐。在该实施方式的某些方面内,所述疾病或病况是疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、痒病、炎性病症、内耳病症、发热或其它体温调节病症、气管支气管或膈膜功能障碍、胃肠道或泌尿道病症、慢性阻塞性肺病、失禁、或者与流向CNS的血流减少或CNS缺氧相关的病症。在该实施方式的方面内,所述疾病或病况是疼痛(包括但不限于急性、慢性、神经性和炎症性疼痛)、关节炎、痒病、咳嗽、哮喘、炎症性肠病或内耳病症。在一些实施方式中,所述疾病或病况是哮喘。
组合疗法
在治疗离子通道介导的疾病和病况中,本发明的化合物可以与一种或多种其它本发明的化合物或一种或多种其它治疗剂或其任何组合组合使用。例如,本发明的化合物可以与其它治疗剂组合同时、顺序或分开施用,所述其它治疗剂包括但不限于以下那些。
阿片类镇痛药,例如吗啡、海洛因、可卡因、氧化吗啡、左啡诺、左洛啡烷、羟考酮、可待因、二氢可待因、丙氧芬、纳美芬、芬太尼、氢可酮、氢吗啡酮、meripidine、美沙酮、纳洛芬、纳洛酮、纳曲酮、丁丙诺啡、布托啡诺、纳布啡和喷他佐辛。
非阿片类镇痛药,例如,对乙酰氨基酚和水杨酸盐(例如,阿司匹林)。
非甾体抗炎药(NSAID),例如布洛芬、萘普生、非诺洛芬、酮洛芬、塞来考昔、双氯芬酸、二氟尼柳(diflusinal)、依托度酸、芬布芬、非诺洛芬、氟苯柳、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、甲氯芬那酸、甲芬那酸、美洛昔康、萘丁美酮、萘普生、尼美舒利、硝基氟吡洛芬、奥沙拉秦、奥沙普秦、保泰松、吡罗昔康、柳氮磺胺吡啶、舒林酸、托美汀和佐美酸。
抗惊厥药,例如卡马西平、奥卡西平、拉莫三嗪、丙戊酸盐、托吡酯、加巴喷丁和普瑞巴林。
抗抑郁药,例如三环抗抑郁药,例如阿米替林、氯米帕明、去甲丙咪嗪(despramine)、丙咪嗪和去甲替林。
COX-2选择性抑制剂,例如塞来考昔、罗非考昔、帕瑞考昔、伐地考昔、地拉考昔、艾托考昔和芦米考昔。
α-肾上腺素能药,例如多沙唑嗪、坦洛新、可乐定、胍法辛、右美托咪定(dexmetatomidine)、莫达非尼和4-氨基-6,7-二甲氧基-2-(5-甲磺酰氨基-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉。
巴比妥类镇静剂,例如异戊巴比妥、阿普比妥、仲丁比妥、布他比妥(butabital)、甲苯比妥、美沙比妥、美索比妥、戊巴比妥、苯巴比妥、司可巴比妥、他布比妥、西美拉(theamylal)和硫喷妥。
速激肽(NK)拮抗剂,特别是NK-3、NK-2或NK-1拮抗剂,例如(aR,9R)-7-[3,5-双(三氟甲基)苄基)]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮芳辛并[2,1-g][1,7]-萘啶-6-13-二酮(TAK-637)、5-[[2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基苯基]乙氧基-3-(4-氟苯基)-4-吗啉基]-甲基]-1,2-二氢-3H-1,2,4-三唑-3-酮(MK-869)、阿瑞吡坦(aprepitant)、拉奈匹坦、达匹坦或3-[[2-甲氧基5-(三氟甲氧基)苯基]-甲基氨基]-2-苯基哌啶(2S,3S)。
煤焦油镇痛药,例如对乙酰氨基酚。
血清素再摄取抑制剂,例如帕罗西汀、舍曲林、诺氟西汀(氟西汀去甲基代谢产物)、代谢产物去甲基舍曲林、’3氟伏沙明、帕罗西汀、西酞普兰、西酞普兰代谢产物去甲基西酞普兰、依他普仑、d,l-芬氟拉明、非莫西汀、伊福西汀、氰基度硫平(cyanodothiepin)、利托西汀、达泊西汀、奈法唑酮、西立氯胺、曲唑酮和氟西汀。
去甲肾上腺素(降肾上腺素)再摄取抑制剂,例如马普替林、洛非帕明、米氮平(mirtazepine)、羟丙替林、非唑拉明、托莫西汀、米安舍林、安非他酮、安非他酮代谢物羟基安非他酮、诺米芬辛和维洛沙秦尤其是选择性去甲肾上腺素再摄取抑制剂,如瑞波西汀、特别是(S,S)-瑞波西汀、和文拉法辛、度洛西汀、精神安定药、镇静药/抗焦虑药。
双重血清素-去甲肾上腺素再摄取抑制剂,例如文拉法辛、文拉法辛代谢物O-去甲基文拉法辛、氯米帕明、氯米帕明代谢物去甲基氯米帕明、度洛西汀、米那普仑和丙咪嗪。
乙酰胆碱酯酶抑制剂,例如多奈哌齐。
5-HT3拮抗剂,例如昂丹司琼。
亲代谢型谷氨酸受体(metabotropic glutamate receptor)(mGluR)拮抗剂。
局麻药,例如美西律和利多卡因。
皮质类固醇,例如地塞米松。
抗心律失常药,例如美西律和苯妥英。
毒蕈碱拮抗剂,例如托特罗定、丙哌维林、曲司氯铵(tropsium chloride)、达非那新、索利那新、替米维林和异丙托铵。
大麻素类。
Vanilloid受体激动剂(例如,树脂毒素)或拮抗剂(例如,辣椒平(capsazepine))。
镇静药,例如格鲁米特、甲丙氨酯、甲喹酮和氯醛比林。
抗抑郁药,例如米氮平。
局部用药物,例如利多卡因、辣椒素和树脂毒素。
抗组胺药或H1拮抗剂。
NMDA受体拮抗剂。
5-HT受体激动剂/拮抗剂。
PDEV抑制剂。
胆碱能(烟碱)镇痛药。
α-2-δ配体。
前列腺素E2亚型拮抗剂。
白三烯B4拮抗剂。
5-脂氧合酶抑制剂。
5-HT3拮抗剂。
本文所用的“组合”是指一种或多种本发明的化合物与一种或多种其它本发明的化合物或一种或多种另外的治疗剂的任何混合物或组合方式(permutation)。除非上下文另有说明,否则“组合”可包括本发明的化合物与一种或多种治疗剂同时或顺序递送。除非上下文另有说明,否则“组合”可包括本发明的化合物与另一种治疗剂的剂型。除非上下文另有说明,否则“组合”可包括本发明的化合物与另一种治疗剂的施用途径。除非上下文另有说明,否则“组合”可包括本发明的化合物与另一种治疗剂的制剂。剂型、施用途径和药物组合物包括但不限于本文所述的那些。
实施例
式I化合物的通用制备
用于制备这些化合物的起始材料和试剂通常可以从商业供应商例如AldrichChemical公司获得,或者是通过本领域技术人员已知的方法按照参考文献中提出的步骤制备,所述参考文献例如Fieser and Fieser’s Reagents for Organic Synthesis;Wiley&Sons:New York,1991,第1-15卷;Rodd’s Chemistry of Carbon Compounds,ElsevierScience Publishers,1989,第1-5卷和增刊;以及Organic Reactions,Wiley&Sons:NewYork,1991,第1-40卷。
以下合成反应方案仅举例说明了一些可以合成本发明的化合物的方法,可以对这些合成反应方案进行各种修改,并推荐给参考本申请的公开内容的本领域技术人员。
如果需要,可以使用常规技术分离和纯化合成反应方案的起始材料和中间体,所述常规技术包括但不限于过滤、蒸馏、结晶、色谱法等。可以使用常规手段表征这些材料,所述常规手段包括物理常数和光谱数据。
尽管本文描绘并描述了某些示例性实施方式,但是本发明的化合物可以使用适宜的起始材料根据本文概括描述的方法和/或通过本领域技术人员可获得的方法制备。
将中间体和最终化合物通过快速色谱法和/或通过反相制备型HPLC(高效液相色谱法)和/或通过超临界流体色谱法进行纯化。除非另有说明,否则快速色谱是使用来自ISCO或SiliCycle的预填充硅胶柱在ISCO色谱仪(来自Teledyne Isco,Inc.)上进行。反相制备型HPLC是使用(1)Polaris C-18 5μM柱(50x 21mm)或(2)XBridgePrep C-18OBD 5μM柱(19x 150mm)进行。超临界流体色谱法是使用Chiral Technologies、Chiralpak AD、Chiralpak AS、Chiralpak IA、Chiralpak IB、Chiralpak IC、Chiralcel OD或Chiralcel OJ的填充柱进行,柱尺寸例如是:(1)4.6cm x 5cm,3μM,(2)4.6cm x 5cm,5μM或(3)15cm x 21.2mm,5μM。
质谱(MS)可使用(1)Sciex 15质谱仪(ES+模式)或(2)Shimadzu LCMS 2020质谱仪(ESI+模式)进行。除非另有说明,否则质谱数据通常仅给出母体离子。在指明时,针对特定的中间体或化合物提供MS或HRMS数据。
核磁共振光谱法(NMR)可以使用(1)Bruker AV III 300NMR光谱仪、(2)Bruker AVIII 400NMR光谱仪或(3)Bruker AV III 500NMR光谱仪进行,并且参照是四甲基硅烷。在指明时,针对特定的中间体或化合物提供NMR数据。
涉及对空气敏感的试剂的所有反应均是在惰性气氛下进行的。试剂以从商业供应商处接收的形式使用,另有说明的除外。
以下实施例中可以使用下述缩写:
BuOH 正丁醇
DMF 二甲基甲酰胺
DMSO 二甲亚砜
EtONa 乙醇钠
LCMS 液相色谱质谱法
LDA 二异丙基氨基锂
LiHMDS 双(三甲基硅基)氨基锂
m-CPBA 间氯过氧苯甲酸
MeMgCl 甲基氯化镁
MeONa 甲醇钠
n-BLi 正丁基锂
PCMCl 对甲氧基苄基氯
SEMCl (2-氯甲氧基乙基)三甲基硅烷
TEA 三乙胺
TMSCHN2 三甲基硅基重氮甲烷
制备1:7-甲基-1H-嘌呤-6(7H)-酮
制备1反应路线如下:
步骤1:6-氯-7-甲基-7H-嘌呤的制备
在0℃下向用氮气吹扫且维持氮气惰性氛围的1L 3-颈圆底烧瓶中放置6-氯-9H-嘌呤(15.4g,0.1mol,1当量)和四氢呋喃(155mL),随后在搅拌下逐滴添加MeMgCl(36.6mL,1.0M THF溶液,1.1当量)。将混合物在0℃下搅拌30min。在搅拌下向其中逐滴添加碘甲烷(42.6g,3当量)。将所得溶液在50℃下在油浴中搅拌5h,通过添加50mL NH4Cl水溶液淬灭反应且用二氯甲烷(3x 50mL)萃取。将合并的有机层用盐水(2x 50mL)洗涤并在真空下浓缩。由比例为1:10的CH2Cl2/石油醚对粗产物进行重结晶,得到呈浅绿色固体状的所需产物(7g,42%)。
步骤2:7-甲基-1H-嘌呤-6(7H)-酮的制备
向1L 3-颈圆底烧瓶中放置6-氯-7-甲基-7H-嘌呤(100g,590mmol,1eq)和甲酸(1L)。将所得溶液在70℃下搅拌3h。将所得混合物在真空下浓缩,并将残留物用500mL水稀释。将所得溶液用3x 250mL的乙醚/乙酸乙酯(20:1)萃取并将水层用甲苯在真空下浓缩以除去水和甲酸。将残留物溶解在水中。用NH3.H2O(25%)将溶液的pH值调节至9,并将水层在真空下浓缩。通过过滤收集固体,用水洗涤两次并干燥,得到呈黄色固体状的所需产物(55g,62%)。
制备2:5-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮
制备2的反应路线如下:
步骤1:3-溴-5-氟异烟酸的制备
在0℃下在氮气下将n-BuLi(250mL,0.62mol,2.5当量)逐滴添加至双(丙-2-基)胺(76g,0.75mmol,3当量)和四氢呋喃(1L)的溶液中。将混合物在0℃下搅拌30min。在搅拌下在-70℃下向其中逐滴添加3-溴-5-氟吡啶(44g,0.25mol,1当量)。将所得溶液在-70℃下搅拌1h。接着将反应混合物倾入干冰在500mL THF中的混合物中。将所得混合物搅拌30min,并且接着在真空下浓缩。将残留物溶解在水中。用氯化氢(1mol/L)将溶液的pH值调节至3。将混合物用乙酸乙酯萃取,用无水硫酸钠干燥并在真空下浓缩,得到呈黄色固体状的产物(40g,72%)。
步骤2:3-溴-5-氟异烟酸甲酯的制备
在搅拌下在0℃下在氮气下将TMSCHN2(180mL,360mmol,2当量)逐滴添加至3-溴-5-氟异烟酸(40g,182mmol,1当量)、THF(240mL)和MeOH(80mL)的溶液中。将所得溶液在室温下搅拌3h。将所得混合物在真空下浓缩。将残留物通过硅胶柱纯化,用乙酸乙酯/石油醚(1/9)洗脱,得到呈黄色油状物的标题化合物(35g,83%)。
步骤3:3-氟-5-甲基异烟酸甲酯的制备
在室温下在氮气下将Zn(CH3)2(225mL,0.22mol,1.5当量)添加至3-溴-5-氟异烟酸酯(35g,0.15mol,1当量)、二噁烷(1L)和Pd(dppf)Cl2(11g,15mmol,0.1当量)的混合物中。将所得溶液在50℃下搅拌3h。然后通过添加甲醇淬灭反应。过滤出固体。将所得混合物在真空下浓缩。将残留物溶解在乙酸乙酯中,用盐水洗涤,用无水硫酸钠干燥并在真空下浓缩。将残留物通过硅胶柱色谱纯化,得到产物(17g,69%)。
步骤4:3-氟-4-(甲氧基羰基)-5-甲基吡啶1-氧化物的制备
在0℃下在氮气下将m-CPBA(96g,0.56mol,1.5当量)添加到5-氟-3-甲基吡啶-4-甲酸甲酯(63g,0.37mol,1当量)在二氯甲烷(1.7L)的溶液中。将所得混合物在室温下搅拌15h。通过添加饱和碳酸氢钠溶液淬灭反应,用乙酸乙酯萃取,用饱和Na2S2O3溶液和盐水洗涤,用无水硫酸钠干燥,并在真空下浓缩。将残留物通过硅胶柱纯化,用乙酸乙酯/庚烷(9/1)洗脱,得到呈黄色固体状的标题化合物(62g,89%)。
步骤5:3-氨基-4-(甲氧基羰基)-5-甲基吡啶1-氧化物的制备
向3-氟-4-(甲氧基羰基)-5-甲基吡啶1-氧化物(62g,0.34mol,1当量)在DMSO(600mL)的混合物中通入NH3(g),并将混合物在80℃下搅拌12h。在完成之后,将混合物用水(1500mL)稀释,并用EA(800mL×3)萃取。将合并的有机层用盐水洗涤两次。将所得混合物在真空下浓缩,得到呈黄色固体状的标题化合物(62g,粗品),其未经进一步纯化即用于下一步骤。
步骤6:3-氨基-5-甲基异烟酸甲酯的制备
将3-氨基-4-(甲氧基羰基)-5-甲基吡啶1-氧化物(62g,0.34mol,1当量)、甲醇(400mL)和雷尼镍(10g)的混合物在室温下在氢气氛围下搅拌30min。过滤出固体。将所得溶液在真空下浓缩,得到呈黄色固体状的标题化合物(40g,两步共71%)。
步骤7:3-氨基-5-甲基异烟酸的制备
将3-氨基-5-甲基吡啶-4-甲酸甲酯(40g,0.24mol,1当量)、甲醇(450mL)、水(90mL)和氢氧化钠(38g,0.96mol,4当量)的混合物在室温下搅拌12h。用氯化氢(1mol/L)将溶液的pH值调节至3。将所得混合物在真空下浓缩。将残留物溶解在乙醇中。过滤出固体。将所得滤液在真空下浓缩,得到呈黄色固体状的标题化合物(35g,95%)。
步骤8:5-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮的制备
将3-氨基-5-甲基吡啶-4-甲酸(35g,0.23mol,1当量)、乙醇(450mL)和乙酸,甲脒(35g,0.34mol,1.5当量)的混合物在80℃下搅拌3h。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,用二氯甲烷/甲醇(5/1)洗脱,得到呈黄色固体状的标题化合物(22g,59%)。
制备3:5-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮
制备3的反应路线如下文所示。
步骤1:2-氨基-4-甲基烟酸的制备
向2-L圆底烧瓶中放置2-氨基-4-甲基吡啶-3-甲腈(50g,375.51mmol,1.00当量)和氢氧化钾水溶液(20%,700mL)。将所得溶液在110℃下在油浴中搅拌过夜,并冷却至室温。用HCl水溶液(2N)将混合物的pH值调节至3。将混合物在真空下浓缩。将残留物用2x400mL乙醇洗涤。过滤出固体。将滤液在真空下浓缩,得到40g(粗)的呈黄色固体状的2-氨基-4-甲基吡啶-3-甲酸,其直接用于下一步骤。
步骤2:5-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮的制备
向1-L圆底烧瓶中放置2-氨基-4-甲基吡啶-3-甲酸(40g,262.90mmol,1.00当量)在乙醇(500mL)中的溶液和乙酸甲脒(82.11g,788.69mmol,3.00当量)。将所得溶液在100℃下在油浴中搅拌过夜,并冷却至室温。通过过滤收集固体,用3x 100mL的MeOH洗涤,并在真空下干燥,得到21g(50%)的呈白色固体状的5-甲基-3H,4H-吡啶并[2,3-d]嘧啶-4-酮。
制备4:5,7-二甲基-3H,4H-咪唑并[4,3-f][1,2,4]三嗪-4-酮
制备4的反应路线如下文所示。
步骤1:2-(肟基)-3-氧代丁酸乙酯的制备
在搅拌下在0℃下将NaNO2(3.6g,52.18mmol)在水(6mL)中的溶液逐滴添加到3-氧代丁酸乙酯(5.2g,39.96mmol)和AcOH(6mL)的混合物中。将所得溶液在室温下搅拌12h。用碳酸氢钠(饱和溶液)将溶液的pH值调节至7至8。将所得溶液用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,并在真空下浓缩。此产生呈无色油状物的标题化合物(5.2g,82%),其不经任何进一步纯化即用于下一步骤。LCMS[M+H+]160。
步骤2:2-氨基-3-氧代丁酸乙酯盐酸盐的制备
将2-(肟基)-3-氧代丁酸乙酯(5.2g,32.68mmol)、乙醇(50mL)、浓氯化氢(5mL)和Pd/C(1g,10%)的混合物在室温下在氢气氛围下搅拌48h。过滤出固体。将所得混合物在真空下浓缩。此产生呈灰白色固体状的标题化合物(5g,84%),其不经任何进一步纯化即用于下一步骤。LCMS[M+H+]146。
步骤3:2,4-二甲基-1H-咪唑-5-甲酸乙酯的制备
在室温下在搅拌下将2-氨基-3-氧代丁酸乙酯盐酸盐(4.6g,25.33mmol)在乙醇(10mL)中的溶液逐滴添加至乙烷甲亚胺酸乙酯盐酸盐(8.1g,65.54mmol)、乙醇(100mL)和TEA(8.4g,83.01mmol)的混合物中。将所得溶液在室温下搅拌12h。将所得溶液用乙酸乙酯稀释,用盐水洗涤,用无水硫酸钠干燥,并在真空下浓缩。将残留物在硅胶柱上纯化,用二氯甲烷/甲醇(10/1)洗脱,得到呈浅黄色固体状的标题化合物(1.3g,31%)。LCMS[M+H+]169。
步骤4:1-氨基-2,4-二甲基-1H-咪唑-5-甲酸乙酯的制备
在-10℃下在干冰浴中在氮气下在搅拌下将LiHMDS(8.5mL,1M的THF溶液)逐滴添加至2,4-二甲基-1H-咪唑-5-甲酸乙酯(1.3g,7.73mmol)和N,N-二甲基甲酰胺(200mL)的混合物中。将所得溶液在-10℃下搅拌30min。在0℃下向其中分批添加二苯基亚膦酸胺基酯(2.2g,9.43mmol)。将所得溶液在室温下在搅拌下再反应12h。将所得溶液用水稀释,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥并在真空下浓缩。通过硅胶柱纯化残留物,用二氯甲烷/甲醇(10/1)洗脱,得到呈浅黄色固体状的标题化合物(1.0g,71%)。LCMS[M+H+]184。
步骤5:5,7-二甲基-3H,4H-咪唑并[4,3-f][1,2,4]三嗪-4-酮的制备
将1-氨基-2,4-二甲基-1H-咪唑-5-甲酸乙酯(1.0g,5.46mmol)、甲酰胺(10mL)和MeONa(3.0mL,5.4M的MeOH溶液)的混合物在100℃下在油浴中搅拌1h。将所得溶液用水稀释。用氯化氢(1N)将溶液的pH值调节至5。通过过滤收集固体,并在真空下干燥,得到130mg白色固体。将滤液在C18硅胶柱上纯化,用在30min内由5%增加至95%的CH3CN/H2O(10mmol/L的NH4HCO3)洗脱。收集组分并浓缩,得到370mg白色固体。此产生呈白色固体状的标题化合物(共计500mg,56%)。LCMS[M+H+]165。
制备5:6-甲基-7-氧代-1H,6H,7H-吡唑并[4,3-d]嘧啶-3-甲腈的制备
制备5的反应流程如下文所示。
步骤1:3-碘-1-[[2-(三甲基硅基)乙氧基]甲基]-1H,6H,7H-吡唑并[4,3-d]嘧啶-
7-酮的制备
在0℃下将氢化钠(687mg,28.62mmol)分批添加至3-碘-1H,6H,7H-吡唑并[4,3-d]嘧啶-7-酮(1.5g,5.72mmol)在N,N-二甲基甲酰胺(50mL)中的溶液中。在20min之后,将SEM-Cl(950mg,6.22mmol)逐滴添加至以上溶液中。将所得溶液在室温下搅拌12h,并且不经任何进一步纯化即用于下一步骤。LCMS[M+H+]393。
步骤2:3-碘-6-甲基-1-[[2-(三甲基硅基)乙氧基]甲基]-1H,6H,7H-吡唑并[4,3-
d]嘧啶-7-酮的制备
在0℃下将氢化钠(60mg 2.50mmol)添加至3-碘-1-[[2-(三甲基硅基)乙氧基]甲基]-1H,6H,7H-吡唑并[4,3-d]嘧啶-7-酮的溶液(约0.11M的DMF溶液,50mL,由步骤1制备)中。在20min之后,逐滴添加CH3I(430mg,3.02mmol),并将所得混合物在室温下搅拌3h。将反应溶液在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(250mg,24%)。LCMS[M+H+]407。
步骤3:6-甲基-7-氧代-1-[[2-(三甲基硅基)乙氧基]甲基]-1H,6H,7H-吡唑并[4,
3-d]嘧啶-3-甲腈的制备
在100℃下在氮气下将3-碘-6-甲基-1-[[2-(三甲基硅基)乙氧基]甲基]-1H,6H,7H-吡唑并[4,3-d]嘧啶-7-酮(260mg,0.64mmol)、Zn(CN)2(148mg,1.26mmol)、Pd2(dba)3.CHCl3(66mg,0.06mmol)、dppf(71mg,0.13mmol)和N,N-二甲基甲酰胺(5mL)的混合物用微波辐射照射1h。过滤出固体。将滤液在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(150mg,77%)。LCMS[M+H+]306。
步骤4:6-甲基-7-氧代-1H,6H,7H-吡唑并[4,3-d]嘧啶-3-甲腈的制备
将6-甲基-7-氧代-1-[[2-(三甲基硅基)乙氧基]甲基]-1H,6H,7H-吡唑并[4,3-d]嘧啶-3-甲腈(120mg,0.39mmol)与三氟乙酸(3mL)的混合物在60℃下搅拌18h。将所得混合物在真空下浓缩。此产生呈白色固体状的标题化合物(60mg,87%)。LCMS[M+H+]176。制备6: 1-甲基-6,7-二氢-1H-嘌呤-6-酮
制备6的总体反应路线如下所示:
步骤1:6-氯-7-[(4-甲氧基苯基)甲基]-7H-嘌呤的制备
将氢化钠(858mg,35.75mmol)分批添加至6-氯-7H-嘌呤(3g,19.41mmol)在N,N-二甲基甲酰胺(30mL)中的溶液中。在20min之后,将PMBCl(6.1g,38.81mmol)逐滴添加至以上混合物中。将所得溶液在室温下搅拌4h,用乙酸乙酯稀释,用盐水洗涤,用无水硫酸钠干燥,并在真空下浓缩。将残留物在硅胶柱上纯化,用乙酸乙酯/石油醚(1:1)洗脱,得到呈浅黄色油状物的标题化合物(2.3g,43%)。LCMS[M+H+]275。
步骤2:7-[(4-甲氧基苯基)甲基]-6,7-二氢-1H-嘌呤-6-酮的制备
将6-氯-7-[(4-甲氧基苯基)甲基]-7H-嘌呤(2.3g,8.37mmol)、1,4-二噁烷(3mL)、氢氧化钠(1g,25.00mmol)和水(25mL)的混合物在90℃下搅拌1.5h。用HCl(2M)将溶液的pH值调节至7。通过过滤收集固体,得到呈白色固体状的标题化合物(1.95g,91%)。LCMS[M+H+]257。
步骤3:7-[(4-甲氧基苯基)甲基]-1-甲基-6,7-二氢-1H-嘌呤-6-酮的制备
将7-[(4-甲氧基苯基)甲基]-6,7-二氢-1H-嘌呤-6-酮(1g,3.90mmol)、碳酸钾(1.1g,7.80mmol)、N,N-二甲基甲酰胺(12mL)和CH3I(666mg,4.69mmol)的混合物在室温下搅拌1.5h。过滤出固体。将反应混合物在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/LNH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(700mg,66%)。LCMS[M+H+]271。
步骤4:1-甲基-6,7-二氢-1H-嘌呤-6-酮的制备
将7-[(4-甲氧基苯基)甲基]-1-甲基-6,7-二氢-1H-嘌呤-6-酮(700mg,2.590mmol)与三氟乙酸(10mL)的混合物在70℃下搅拌15h。将所得混合物在真空下浓缩。此产生呈白色固体状的标题化合物(700mg,粗品)。LCMS[M+H+]151。
制备7:4-甲基嘧啶并[4,5-c]哒嗪-5(6H)-酮
制备7的总体反应路线如下所示:
步骤1:4,6-二溴-5-甲基哒嗪-3-胺的制备
在0℃下将Br2(9.6g,60.07mmol)在甲醇(30mL)中的溶液逐滴添加至5-甲基哒嗪-3-胺(3g,27.49mmol)、甲醇(100mL)和碳酸氢钠(11.5g,136.89mmol)的混合物中。将所得溶液在室温下搅拌2h,用水稀释,用乙酸乙酯萃取,用硫酸钠干燥,并在真空下浓缩。通过硅胶柱纯化残留物,使用乙酸乙酯/石油醚(1/4)洗脱,得到呈棕色固体状的标题化合物(4.0g,55%)。LCMS[M+H+]266。
步骤2:4-溴-5-甲基哒嗪-3-胺的制备
在0-10℃下在氮气下将EtMgBr(2mL,15.15mmol,3M的THF溶液)逐滴添加至4,6-二溴-5-甲基哒嗪-3-胺(400mg,1.49mmol)在四氢呋喃(8mL)中的溶液中。将所得溶液在63℃下搅拌35min。用水淬灭反应并在真空下浓缩。将残留物在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(36mg,13%)。LCMS[M+H+]188。
步骤3:3-氨基-5-甲基哒嗪-4-甲酰胺的制备
将4-溴-5-甲基哒嗪-3-胺(80mg,425.47mmol)、NH3/MeOH(7M)(4mL)、Pd(dppf)Cl2(31mg,0.04mmol)、TEA(128mg,1.26mmol)和一氧化碳的混合物在100℃下在10atm压力下搅拌过夜。将反应溶液在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈浅黄色固体状的标题化合物(85mg,粗品)。LCMS[M+H+]153。
步骤4:4-甲基嘧啶并[4,5-c]哒嗪-5(6H)-酮的制备
将3-氨基-5-甲基哒嗪-4-甲酰胺(150mg,0.98mmol)、乙醇(3mL)、EtONa(21%)(3.2g,0.04mmol)、甲酸乙酯(360mg,4.86mmol)在80℃下在氮气下搅拌1h。将所得混合物在真空下浓缩。用氯化氢/H2O(5%)将溶液的pH值调节至8。将所得混合物在真空下浓缩,并用乙醇稀释。过滤出固体,并将滤液在真空下浓缩,得到呈棕色固体状的标题化合物(120mg,75%)。LCMS[M+H+]163。
制备8:5-甲基-4-氧代-3,4-二氢吡啶并[2,3-d]嘧啶-7-甲腈
制备8的总体反应路线如下所示:
步骤1:2,6-二氯-4-甲基烟酰氯的制备
在0℃下将草酰氯(5.5g,43.33mmol)逐滴添加至2,6-二氯-4-甲基吡啶-3-甲酸(3g,14.56mmol)、N,N-二甲基甲酰胺(50mg,0.68mmol)和二氯甲烷(100mL)的溶液中。将所得溶液在室温下搅拌过夜,并在真空下浓缩。此产生呈浅黄色液体状的标题化合物(3.1g,粗品)。
步骤2:26-二氯-4-甲基烟酰胺的制备
在25℃下将2,6-二氯-4-甲基吡啶-3-羰基酰氯(3.1g,13.81mmol)在二氯甲烷(15mL)中的溶液逐滴添加至经搅拌的NH3/THF溶液(0.5M)(42mL)中。在室温下搅拌1h后,将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用乙酸乙酯/石油醚(1/1)洗脱,得到呈白色固体状的标题化合物(1.5g,53%)。LCMS[M+H+]205。
步骤3:2-氨基-6-氯-4-甲基烟酰胺的制备
将2,6-二氯-4-甲基吡啶-3-甲酰胺(50mg,0.24mmol)、二噁烷(2mL,23.60mmol)和氨水(30%,0.5mL)的混合物在130℃下搅拌过夜。将所得混合物在真空下浓缩。将粗产物在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(25mg,55%)。LCMS[M+H+]186。
步骤4:7-氯-5-甲基吡啶并[2,3-d]嘧啶-4(3H)-的制备
将2-氨基-6-氯-4-甲基吡啶-3-甲酰胺(320mg,1.72mmol)与(二乙氧基甲氧基)乙烷(5mL)的混合物在140℃下搅拌过夜。通过过滤收集固体。此产生呈灰色固体状的标题化合物(180mg,53%)。LCMS[M+H+]211。
步骤5:5-甲基-4-氧代-3,4-二氢吡啶并[2,3-d]嘧啶-7-甲腈的制备
将7-氯-5-甲基-3H,4H-吡啶并[2,3-d]嘧啶-4-酮(170mg,0.86mmol)、N,N-二甲基甲酰胺(5mL)、Zn(CN)2(151mg,1.28mmol)、Pd2(dba)3.CHCl3(90mg,0.08mmol)和dppf(96mg,0.17mmol)的混合物在100℃下在氮气下搅拌3h。过滤出固体。将粗产物在C18硅胶柱上纯化,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(100mg,62%)。LCMS[M+H+]187。
制备9:1-[(4-甲氧基苯基)甲基]-1H,6H,7H-咪唑并[4,5-d]哒嗪-7-酮
制备9的总体反应路线如下所示:
步骤1:4-(羟甲基)-1-(4-甲氧基苄基)-1H-咪唑-5-甲酸甲酯的制备
将4-(羟甲基)-1H-咪唑-5-甲酸甲酯(500mg,3.20mmol)、N,N-二甲基甲酰胺(10mL)、碳酸钾(885mg,6.40mmol)、PMBCl(对甲氧基苄基氯,550mg,3.51mmol)的混合物在室温下搅拌过夜。过滤出固体。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用二氯甲烷/甲醇(10/1)洗脱,得到呈浅绿色固体状的标题化合物(600mg,68%)。LCMS[M+H+]277。
步骤2:4-甲酰基-1-(4-甲氧基苄基)-1H-咪唑-5-甲酸甲酯的制备
将4-(羟甲基)-1-[(4-甲氧基苯基)甲基]-1H-咪唑-5-甲酸甲酯(580mg,2.10mmol)、二氯甲烷(20mL)和Dess-Martin(888mg,2.09mmol)的混合物在室温下搅拌1h。过滤出固体。将所得混合物在真空下浓缩,得到呈浅绿色油状物的标题化合物(460mg,80%)。LCMS[M+H+]275。
步骤3:1-[(4-甲氧基苯基)甲基]-1H,6H,7H-咪唑并[4,5-d]哒嗪-7-酮的制备
将4-甲酰基-1-[(4-甲氧基苯基)甲基]-1H-咪唑-5-甲酸甲酯(460mg,1.68mmol)、乙醇(20mL)和NH2NH2.H2O(1.045g,20.88mmol)的混合物在80℃下搅拌1h。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用二氯甲烷/甲醇(20/1)洗脱,得到呈白色固体的标题化合物(400mg,93%)。LCMS[M+H+]257。
制备10:5-甲基-4-氧代-3,4-二氢吡啶并[3,4-d]嘧啶-8-甲腈
制备10的总体反应路线如下所示:
步骤1:5-溴-2-氯-3-氟异烟酸的制备
在-78℃下在氮气下将LDA(47.5mL,2.0moL在THF中的溶液)逐滴添加至5-溴-2-氯-3-氟吡啶(10g,47.52mmol)在四氢呋喃(300mL)中的溶液中。将所得溶液在-78℃下搅拌2h。将所得混合物倾入含CO2(固体)的THF中。将反应混合物在真空下浓缩。用氯化氢(2M)将残留物的pH值调节至<7。将所得混合物用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,并在真空下浓缩。此产生呈白色固体状的标题化合物(15g,粗品)。LCMS[M-H+]254。
步骤2:5-溴-3-氟-2-甲基异烟酸甲酯的制备
将5-溴-2-氯-3-氟吡啶-4-甲酸(15g,59.0mmol)、四氢呋喃(100mL)、甲醇(20mL)、TMSCHN2(60mL,2M的己烷溶液)的混合物在室温下搅拌2h。将所得混合物在真空下浓缩。此产生呈油状物的标题化合物(12g,粗品),其不经任何进一步纯化即用于下一步骤。LCMS[M+H+]248。
步骤3:2-氯-3-氟-5-甲基异烟酸甲酯的制备
将5-溴-2-氯-3-氟吡啶-4-甲酸甲酯(5g,18.62mmol)、三环己基磷烷(1.3g,4.60mmol)、乙酸钯(147mg,0.66mmol)和甲苯(60mL)的混合物在100℃下在氮气下搅拌12h。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用乙酸乙酯/石油醚(1:5)洗脱,得到呈白色固体状的标题化合物(2.5g,66%)。LCMS[M+H+]204。
步骤4:3-氨基-2-氯-5-甲基异烟酸甲酯的制备
将NH3(g)(17.5mL,7M的CH3OH溶液)逐滴添加至2-氯-3-氟-5-甲基吡啶-4-甲酸甲酯(2.5g,12.28mmol)在CH3OH(50mL)中的溶液中。将所得溶液在100℃下搅拌12h,并在真空下浓缩。通过硅胶柱纯化残留物,使用乙酸乙酯/石油醚(1:5)洗脱,得到呈白色固体状的标题化合物(300mg,12%)。LCMS[M+H+]201。
步骤5:3-氨基-2-氯-5-甲基异烟酸的制备
将3-氨基-2-氯-5-甲基吡啶-4-甲酸甲酯(300mg,1.5mmol)、水(2mL)、氢氧化钠(200mg,5.00mmol)和甲醇(10mL)的混合物在50℃下搅拌2h。将所得混合物在真空下浓缩。此产生呈白色固体状的标题化合物(250mg,粗品),其不经任何进一步纯化即用于下一步骤。LCMS[M+H+]187。
步骤6:8-氯-5-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮的制备
将3-氨基-2-氯-5-甲基吡啶-4-甲酸(252mg,1.35mmol)、乙酸甲脒(600mg,5.80mmol)和BuOH(15mL)的混合物在120℃下搅拌12h。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用二氯甲烷/甲醇(20:1)洗脱,得到呈白色固体状的标题化合物(140mg,53%)。LCMS[M+H+]196。
步骤7:5-甲基-4-氧代-3,4-二氢吡啶并[3,4-d]嘧啶-8-甲腈的制备
在130℃下在氮气下将8-氯-5-甲基-3H,4H-吡啶并[3,4-d]嘧啶-4-酮(200mg,1.02mmol)、Pd2(dba)3(100mg,0.10mmol)、dppf(200mg,0.36mmol)、氰化锌(120mg,1.00mmol)和N,N-二甲基甲酰胺(5mL)的混合物用微波辐射照射1h。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用二氯甲烷/甲醇(10/1)洗脱,得到呈白色固体状的标题化合物(140mg,74%)。LCMS[M+H+]187。
制备11:5-甲基嘧啶并[4,5-d]嘧啶-4(3H)-酮
制备11的总体反应路线如下所示:
步骤1:4-氨基-6-甲基嘧啶-5-甲酸乙酯的制备
将NH3(g)(8mL,约14%的乙醇溶液)逐滴添加至4-氯-6-甲基嘧啶-5-甲酸乙酯(800mg,4.00mmol)在乙醇(10mL)中的溶液中。将所得溶液在120℃下搅拌16h。将所得混合物在真空下浓缩。通过硅胶柱纯化残留物,使用乙酸乙酯/石油醚(1:5)洗脱,得到呈白色固体状的标题化合物(700mg,97%)。LCMS[M+H+]182。
步骤2:4-氨基-6-甲基嘧啶-5-甲酸的制备
将4-氨基-6-甲基嘧啶-5-甲酸乙酯(700mg,3.90mmol)、氢氧化钠(464.4mg,11.60mmol)、水(6mL)和甲醇(30mL)的混合物在50℃下搅拌3h。用氯化氢(2M)将溶液的pH调节至3。将所得混合物在真空下浓缩,得到呈白色固体状的标题化合物(700mg,粗品)。LCMS[M+H+]154。
步骤3:5-甲基嘧啶并[4,5-d]嘧啶-4(3H)-酮的制备
将4-氨基-6-甲基嘧啶-5-甲酸(700mg,4.6mmol)、乙酸甲脒(2g,19.40mmol)和丁-1-醇(35mL)的混合物在130℃下搅拌3天。将反应物用水稀释,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,并在真空下浓缩。通过硅胶柱纯化残留物,使用二氯甲烷/甲醇(20/1)洗脱,得到呈浅黄色固体状的标题化合物(300mg)。LCMS[M+H+]163。
制备12:5-(氯甲基)-3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑
制备12的总体反应路线如下所示:
步骤1:(R)-1-(4-氯苯基)丁-3-烯-1-醇的制备
平行进行四个反应:在压力容器中添加4-氟苯甲醛(100.0g,711.4mmol,1.00eq)、(1Z,5Z)-环辛-1,5-二烯氯化铱(14.3g,21.3mmol,0.03eq)、Cs2CO3(46.3g,142.2mmol,0.2eq)和4-氯-3-硝基-苯甲酸(14.3g,71.4mmol,0.1eq)、(R)-BINAP(22.1g,35.5mmol,0.05eq)。将烧瓶用氮气吹扫,然后添加1,4-二噁烷(700.0mL)、乙酸烯丙酯(712.2g,7.11mol,10.0eq)和i-PrOH(85.5g,1.42mol,108.9mL,2.00eq)。使反应混合物在112℃油浴中搅拌20h。TLC(石油醚:乙酸乙酯=5:1,Rf=0.34)显示出现了一个新的主要斑点。使反应混合物冷却、合并,然后过滤以除去固体。将固体用EtOAc(2x 400.0mL)洗涤,并将滤液在减压下浓缩。通过柱色谱(SiO2,石油醚/乙酸乙酯=5/1)纯化粗残留物。提供呈棕色油状物的(R)-1-(4-氯苯基)丁-3-烯-1-醇(414.0g,2.27mol,收率79.6%)。
步骤2:(1R)-3,4-二溴-1-(4-氯苯基)丁-1-醇的制备
平行进行三个反应:在-30℃下将Br2(126.7g,793.3mmol,40.9mL,1.05eq)在DCM(480.0mL)中的溶液逐滴添加至(R)-1-(4-氯苯基)丁-3-烯-1-醇(138.0g,755.5mmol,1.00eq)在DCM(480.0mL)中的溶液中。将所得混合物在-30℃下搅拌1h。TLC(石油醚:乙酸乙酯=5:1,Rf1=0.42,Rf2=0.31)显示起始原料的耗尽和两个新的斑点。然后将三个反应组合在一起进行后处理。通过添加饱和Na2S2O3水溶液(3.00L)和水(3.00L)淬灭反应。将烧瓶自浴槽中移出,并使其在20℃下剧烈搅拌(橙色迅速消失)。将所得混合物用DCM(2x 2.50L)萃取,并将合并的有机相用盐水(2.00L x 2)洗涤,用Na2SO4干燥,并在减压下浓缩。反应物未经进一步纯化即用于下一步骤。获得呈棕色油状物的(1R)-3,4-二溴-1-(4-氯苯基)丁-1-醇(743.0g,粗品)。
步骤3:(2R)-4-溴-2-(4-氯苯基)四氢呋喃的制备
平行进行三个反应:在20℃下向(1R)-3,4-二溴-1-(4-氯苯基)丁-1-醇(247.0g,721.2mmol,1.00eq)在MeOH(1.70L)中的溶液中添加K2CO3(398.7g,2.89mol,4.00eq)。然后将反应混合物在20℃下搅拌12h。TLC(石油醚:乙酸乙酯=5:1,Rf1=0.72,Rf2=0.56)显示起始原料耗尽。然后将三个反应组合以进行后处理。将反应混合物冷却,并依次添加饱和NH4Cl水溶液(1.50L)和水(1.50L)。将混合物转移至分液漏斗中,并用EtOAc(2x 3.0L)萃取。然后将合并的有机层用水(3.00L)和盐水(3.00L)的混合物洗涤并将合并的有机层用无水Na2SO4干燥,过滤并在减压下浓缩。反应物未进一步纯化即用于下一步骤。获得呈棕色油状物的(2R)-4-溴-2-(4-氯苯基)四氢呋喃(555.0g,粗品)。
步骤4:(3R,5R)-5-(4-氯苯基)四氢呋喃-3-甲腈的制备
平行进行三个反应:将(2R)-4-溴-2-(4-氯苯基)四氢呋喃(170.0g,649.9mmol,1.00eq)和KCN(112.3g,1.62mol,2.50eq)在DMSO(1.20mL)中的混合物脱气并用氮气吹扫三次,此时将混合物在60℃下在氮气氛围下搅拌20小时。TLC(石油醚:乙酸乙酯=5/1,Rf1=0.51,Rf2=0.21)显示两个新的斑点。通过从油浴中移出终止反应,并将三个反应物一起后处理并合并。在冷却至20℃后,将混合物用EtOAc(200.0mL)稀释,并在烧结漏斗上过滤固体并用额外的EtOAc(140.0mL)洗涤。将滤液转移至10.0L分液漏斗,随后添加水(4.00L)和盐水(800.0mL)。将各层分离并将水层用额外的EtOAc(2x 800.0mL)萃取。然后将合并的有机层用水(800.0mL)和盐水(800.0mL)的混合物洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,得到橙色油状物。通过柱层析(SiO2,石油醚/乙酸乙酯=50/1至5:1)纯化残留物。获得呈黄色固体状的(3R,5R)-5-(4-氯苯基)四氢呋喃-3-甲腈(102.0g,392.9mmol,收率20.1%,纯度80.0%)以及呈黄色固体状的非对映异构体(120.0g,577.8mmol,收率29.6%)。
步骤5:(3R,5R,Z)-5-(4-氯苯基)-N'-羟基四氢呋喃-3-甲脒的制备
将(3R,5R)-5-(4-氯苯基)四氢呋喃-3-甲腈(102.0g,491.2mmol,1.00eq)和羟胺(40.5g,1.23mol,2.50eq)在EtOH(600.0mL)中的混合物脱气,并用N2吹扫三次,然后将混合物在83℃下在N2氛围下搅拌2hr,此时HPLC显示反应完成。将反应混合物在减压下浓缩,得到粗残留物,将其用100.0mL MTBE处理并搅拌1hr,此时出现白色固体。将混合物过滤并将滤液浓缩,得到呈白色固体状的(3R,5R,Z)-5-(4-氯苯基)-N'-羟基四氢呋喃-3-甲脒(107.0g,444.5mmol,收率90.5%)。
步骤6:(3R,5R)-N'-(2-氯乙酰氧基)-5-(4-氯苯基)四氢呋喃-3-甲脒的制备
在0℃下向(3R,5R,Z)-5-(4-氯苯基)-N'-羟基四氢呋喃-3-甲脒(89.8g,525.5mmol,21.0mL,1.10eq)在MTBE(800.0mL)中的混合物中添加2-氯乙酸酐(115.0g,477.8mmol,1eq),并用N2吹扫三次,然后将混合物在25℃下在N2氛围下搅拌0.5hr。HPLC显示反应完成。将反应混合物添加至500.0mL饱和NaHCO3水溶液中。将所得混合物用EtOAc(3x250.0mL)萃取,并将合并的有机层用无水Na2SO4干燥,过滤并在减压下浓缩。向黄色油状物中添加300.0mL MTBE,将混合物搅拌5min,然后在-20℃下冷却。在布氏漏斗上收集所得固体,然后用150.0mL冷MTBE(-20℃)冲洗,得到呈白色固体状的所需产物(3R,5R)-N'-(2-氯乙酰氧基)-5-(4-氯苯基)四氢呋喃-3-甲脒(120.0g,378.3mmol,收率79.1%)。
步骤7:5-(氯甲基)-3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑的
制备
将(3R,5R)-N'-(2-氯乙酰氧基)-5-(4-氯苯基)四氢呋喃-3-甲脒(135.0g,425.6mmol,1.00eq)和活化的分子筛(135.0g)在甲苯(675.0mL)中的混合物脱气并用N2吹扫三次,然后将混合物在120℃下在N2氛围下搅拌2hr。HPLC和TLC(石油醚:乙酸乙酯=1/1,Rf=0.60)显示反应完成。将反应混合物过滤,并将滤液浓缩。通过柱层析(SiO2,石油醚/乙酸乙酯=25/1至5:1)纯化粗残留物,得到呈黄色油状物的5-(氯甲基)-3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑(82.0g,274.1mmol,收率64.4%)。
实施例1:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-7-甲基-1H-嘌呤-6(7H)-酮的制备
实施例1的总体反应路线如下所示:
步骤1:1-(4-氯苯基)丁-3-烯-1-醇的制备
在0℃下历时30min将烯丙基氯化镁(2.0M的THF溶液,15.5mL,31.0mmol)添加到4-氯苯甲醛(3.43mL,28.2mmol)在THF(28mL)中的溶液中。将所得混合物在0℃下搅拌30min,用乙醚(25mL)稀释,并用饱和NH4Cl水溶液(25mL)和H2O(25mL)淬灭反应。将各层分离,并将水层用乙醚(3x 50mL)萃取。将合并的有机层用盐水(50mL)洗涤,用硫酸镁干燥,过滤并在减压下浓缩。将所得的残留物通过SiO2层析(5至20%梯度的EtOAc/己烷)纯化,得到呈无色油状物的标题化合物(2.71g,53%)。1H NMR(500MHz,CDCl3)δ7.34–7.27(m,4H),5.84–5.73(m,1H),5.21–5.16(m,1H),5.16–5.14(m,1H),4.75–4.71(m,1H),2.57–2.40(m,2H),2.03(d,J=3.3Hz,1H)。
步骤2:1-(4-氯苯基)-2-(环氧乙烷-2-基)乙醇的制备
在0℃下将m-CPBA(77%,3.31g,14.8mmol)分批添加至1-(4-氯苯基)丁-3-烯-1-醇(2.71g,14.8mmol)在DCM(48mL)中的溶液中。允许所得混合物升温至20℃,并搅拌18h。将反应混合物冷却至0℃,用DCM稀释,并以分批添加Ca(OH)2(2.6g,29.6mmol)来淬灭反应。将所得混合物在20℃下搅拌2h,过滤出固体并将滤液在减压下浓缩,得到呈无色油状物的标题化合物(2.79g,95%)。1H NMR(500MHz,CDCl3,非对映异构体的混合物)δ7.35–7.29(m,4H),4.96(dd,J=8.3,5.0Hz,0.5H),4.92(dd,J=9.0,3.4Hz,0.5H),3.19–3.13(m,0.5H),3.05–2.99(m,0.5H),2.83(dd,J=4.7,4.1Hz,0.5H),2.77(dd,J=4.8,4.1Hz,0.5H),2.62(dd,J=4.8,2.8Hz,0.5H),2.54–2.46(m,1.5H),2.14(ddd,J=14.6,9.0,3.8Hz,0.5H),2.06(ddd,J=14.3,4.9,4.0Hz,0.5H),1.85–1.74(m,1H)。
步骤3:5-(4-氯苯基)四氢呋喃-3-醇的制备
将硫酸(98%,0.68mL,12.5mmol)添加至1-(4-氯苯基)-2-(环氧乙烷-2-基)乙醇(2.59g,13.0mmol)在1,4-二噁烷(130mL)的混合物中。将所得混合物在50℃下搅拌16h。将反应混合物倾至碎冰上,通过添加饱和NaHCO3水溶液中和,并用DCM(3x 150mL)萃取。将合并的有机层用硫酸镁干燥,过滤并在减压下浓缩。将所获得的残留物通过SiO2层析(10至50%梯度的EtOAc/己烷)纯化,得到呈黄色油状物的标题化合物(1.38g,53%)。1H NMR(500MHz,CDCl3,非对映异构体的混合物)δ7.37–7.26(m,4H),5.13(dd,J=10.2,5.7Hz,0.56H),4.91–4.86(m,0.44H),4.67–4.55(m,1H),4.24(dd,J=9.9,4.4Hz,0.56H),4.07–4.03(m,0.44H),3.93–3.87(m,1H),2.70–2.62(m,0.44H),2.35–2.29(m,0.56H),1.93–1.84(m,1H),1.75(d,J=4.1Hz,0.56H),1.63(d,J=5.7Hz,0.44H)
步骤4:5-(4-氯苯基)四氢呋喃-3-基甲烷磺酸酯的制备
在0℃下将甲磺酰氯(0.50mL,6.41mmol)添加至5-(4-氯苯基)四氢呋喃-3-醇(980mg,4.93mmol)和三乙胺(2.06mL,14.8mmol)在DCM(25mL)中的溶液中。将所得混合物搅拌15min,然后添加饱和NaHCO3水溶液(25mL)。将各层分离,并将水层用DCM(25mL)萃取。将合并的有机层用盐水(25mL)洗涤,用硫酸镁干燥,过滤并在减压下浓缩,得到呈无色油状物的标题化合物(1.36g,99%)。1H NMR(500MHz,CDCl3,非对映异构体的混合物)δ7.35–7.24(m,4H),5.44–5.36(m,1H),5.10(dd,J=10.3,5.5Hz,0.56H),4.88(t,J=7.5Hz,0.44H),4.38–4.33(m,1H),4.16–4.13(m,0.56H),3.97(dd,J=11.1,4.5Hz,0.44H),3.09(s,1.68H),2.98(s,1.32H),2.84–2.75(m,0.44H),2.68–2.63(m,0.56H),2.20–2.14(m,0.44H),2.08–2.00(m,0.56H)。
步骤5:(3R,5R)-5-(4-氯苯基)四氢呋喃-3-甲腈的制备
将5-(4-氯苯基)四氢呋喃-3-基甲烷磺酸酯(1.36g,4.91mmol)和氰化钾(1.60g,24.6mmol)在DMSO(12mL)中的混合物在105℃下搅拌1h。将反应混合物用EtOAc稀释,并用饱和NaHCO3水溶液、水和盐水洗涤。将有机相用硫酸镁干燥,过滤并在减压下浓缩。将所获得的残留物用SiO2层析(0至40%梯度的EtOAc/己烷)纯化,得到呈黄色油状物的标题化合物(213mg,21%)(第一洗脱非对映异构体)和呈黄色油状物的不希望的顺式非对映异构体(224mg,22%)(第二洗脱非对映异构体)。标题化合物:1H NMR(500MHz,CDCl3)δ7.35–7.32(m,2H),7.26–7.23(m,2H),5.09–5.02(m,1H),4.38(dd,J=8.9,7.6Hz,1H),4.09–4.03(m,1H),3.28–3.19(m,1H),2.68–2.61(m,1H),2.18–2.11(m,1H)。顺式非对映异构体:1H NMR(500MHz,CDCl3)δ7.37–7.33(m,2H),7.33–7.28(m,2H),4.86(dd,J=8.7,6.7Hz,1H),4.29(dd,J=9.0,5.4Hz,1H),4.12(dd,J=9.0,7.7Hz,1H),3.31–3.22(m,1H),2.80-2.72(m,1H),2.17–2.08(m,1H)。
步骤6:(3R,5R)-5-(4-氯苯基)-N'-羟基四氢呋喃-3-甲脒的制备
将羟胺(50%水溶液,0.31mL,5.13mmol)添加至(3R,5R)-5-(4-氯苯基)四氢呋喃-3-甲腈(213.mg,1.03mmol)在EtOH(5.1mL)中的溶液中,并将所得混合物在80℃下搅拌1h。将溶剂在减压下蒸发,并将残留物与EtOH(2x)并与DCM(1x)共蒸发,得到呈浓稠无色油状物的标题化合物(231mg,94%)。LCMS[M+H+]241。步骤7:5-(氯甲基)-3-((3R,5R)-5-(4-氯苯 基)四氢呋喃-3-基)-1,2,4-噁二唑的制备
在20℃下将氯乙酸酐(212mg,1.24mmol)添加至(3R,5R)-5-(4-氯苯基)-N'-羟基四氢呋喃-3-甲脒(231mg,0.960mmol)在DCE(5mL)中的溶液中。将所得混合物搅拌15min,添加二异丙基乙胺(0.25mL,1.44mmol),并将反应混合物在减压下浓缩。将残留物用甲苯(5mL)稀释,并将反应混合物在100℃下搅拌1h。将反应混合物用EtOAc(25mL)稀释,并用饱和NaHCO3水溶液、水和盐水洗涤。将有机相用硫酸镁干燥,过滤并在减压下浓缩。将所获得的残留物用SiO2层析(0至25%梯度的EtOAc/己烷)纯化,得到呈黄色油状物的标题化合物(235mg,82%)。LCMS[M+H+]299。1H NMR(500MHz,CDCl3)δ7.35–7.29(m,4H),5.14(t,J=7.3Hz,1H),4.69(s,2H),4.47(dd,J=8.8,7.6Hz,1H),4.10(dd,J=8.8,6.6Hz,1H),3.79–3.73(m,1H),2.72(ddd,J=12.5,7.0,5.3Hz,1H),2.23(ddd,J=12.8,9.0,7.6Hz,1H)。
步骤8:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1H-嘌呤-6(7H)-酮的制备
将外消旋5-(氯甲基)-3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑(130.mg,0.430mmol)、7-甲基-1H-嘌呤-6-酮(98mg,0.650mmol)、四丁基碘化铵(4mg,0.010mmol)和碳酸钾(180mg,1.30mmol)在DMF(2mL)中的混合物在20℃下搅拌2h。将水(2mL)添加至反应混合物中,通过过滤收集固体,用水洗涤并在真空下干燥,得到呈外消旋混合物形式的标题化合物(152mg,85%)。将对映异构体通过SFC(柱:Lux Cel-3,10x250mm,5μm,40%MeOH,10mL/min,150bar,柱温:40C,运行时间16min)分离,得到呈白色固体状的标题化合物(43mg,24%)(第一洗脱对映异构体,RT=11.5min)和呈白色固体状的标题化合物的对映异构体(43mg,24%)(第二洗脱对映异构体,RT=13.5min)。标题化合物:LCMS[M+H+]413。1H NMR(500MHz,DMSO-d6)δ8.46(s,1H),8.24(s,1H),7.42–7.36(m,4H),5.57(s,2H),5.01(t,J=7.3Hz,1H),4.35(dd,J=8.6,7.4Hz,1H),3.96(s,3H),3.90(dd,J=8.6,6.3Hz,1H),3.80–3.71(m,1H),,2.60–2.54(m,1H),2.17–2.10(m,1H)。
实施例2:1-((3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-7-甲基-1H-嘌呤-6(7H)-酮的合成
实施例2的总体反应路线如下所示:
步骤1:(R)-1-(4-氟苯基)丁-3-烯-1-醇的制备
将(R)-(+)-BINAP(12.9g,20.1mmol)、4-氯-3-硝基苯甲酸(8.12g,40.3mmol)和Cs2CO3(26.3g,80.6mmol)装入2L两颈烧瓶中。添加1,4-二噁烷(671mL)、乙酸烯丙酯(435mL,4028mmol)、异丙醇(62mL,806mmol)和4-氟苯甲醛(43.2mL,4023mmol)。在烧瓶顶部装上冷凝器和翻口塞。将氮气鼓泡通过反应混合物。在鼓泡的同时将氯(1,5-环辛二烯)铱(i)二聚体(6.83g,10.1mmol)添加至溶液中,并对反应物再鼓泡通气10min。将反应物在112℃下在油浴中搅拌27h。将反应物冷却至室温,并过滤出固体。将滤液在旋转蒸发仪(rotavap)上浓缩。
将粗混合物与甲苯(2x)共蒸发。将粗物质在硅胶柱(15W x 15H)上纯化。将产物加载到最小量的甲苯中并用各2L的3%、4%、6%、8%、10%、15%、20%iPrOAc/庚烷洗脱。将23g混合组分用硅胶柱使用5%iPrOAc/庚烷,然后使用20%iPrOAc/庚烷进行再纯化。使用相同条件将另外的7.3g的混合组分再纯化,得到呈橙色油状物的标题化合物(58.3g,收率87%)。
步骤2:(R)-3,4-二溴-1-(4-氟苯基)丁-1-醇的制备
在-30℃--40℃下历时1h30将溴(16.3mL,317mmol)在DCM(302mL)中的溶液逐滴添加至(1R)-1-(4-氟苯基)丁-3-烯-1-醇(50.2g,302mmol)在DCM(755mL)中的溶液中。将反应物在-30℃下搅拌30min。用饱和Na2S2O3(300mL)和水(300mL)淬灭反应,并将反应物在室温下搅拌30min。将各相分离,并将水层用DCM(2x)萃取。将合并的有机层用MgSO4干燥,过滤并浓缩,得到呈粗棕色油状物的标题化合物(96.9g,收率98%)。
步骤3:(R)-4-溴-2-(4-氟苯基)四氢呋喃的制备
将K2CO3(166g,1189mmol)添加至(1R)-3,4-二溴-1-(4-氟苯基)丁-1-醇(96.9g,297mmol)在MeOH(743mL)中的溶液中。使用20℃下的水浴来控制放热。将反应物在室温下搅拌过夜。将反应物冷却至10℃,并依次添加饱和NH4Cl(500mL)和水(500mL)。将混合物用iPrOAc(3x)萃取,用水和盐水洗涤。将合并的有机层用MgSO4干燥、过滤并浓缩,得到呈粗棕色油状物的标题化合物(69.8g,收率96%)。
步骤4:(3R,5R)-5-(4-氟苯基)四氢呋喃-3-甲腈的制备
将氰化钾(57.4g,855mmol)添加至(2R)-4-溴-2-(4-氟苯基)四氢呋喃(69.8g,285mmol)在DMSO(570mL)中的溶液中。将反应混合物在105℃下搅拌15h。使反应物冷却至室温。通过过滤除去过量的KCN,并将固体用iPrOAc洗涤。将反应混合物分配于水/iPrOAc中,并用iPrOAc(3x)萃取。将合并的有机萃取物用水(2x)和盐水洗涤,并将其用MgSO4干燥、过滤并浓缩。将粗混合物用硅胶层析纯化,使用15cm(宽度)x 18cm(高度)的柱,用5%、7%、10%、12%、15%、20%、25%、30%、35%、40%iPrOAc/庚烷洗脱,得到呈透明黄色油状物的标题反式腈(18.4g,收率34%)。获得呈透明黄色油状物的顺式腈(3S,5R)-5-(4-氟苯基)四氢呋喃-3-甲腈(15.7g,收率29%)。
步骤5:(3R,5R,Z)-5-(4-氟苯基)-N'-羟基四氢呋喃-3-甲脒的制备
将羟胺(50质量%的水溶液)(49.5mL,808mmol)添加至(3R,5R)-5-(4-氟苯基)四氢呋喃-3-甲腈(48.3g,202mmol)在EtOH(505mL)中的溶液中。将混合物在80℃下搅拌2h。将反应混合物在旋转蒸发仪上浓缩。将混合物在硅胶垫(10cm宽x 7cm高)上纯化,使用100%DCM(1.5L)洗脱杂质,然后使用10%MeOH/DCM(2L)洗脱产物。一些产物在第一级分中出来,其它级分是干净的。将第一级分在一旁浓缩并再纯化。通过硅胶柱将19.6g的混合级分再纯化,使用100%DCM,然后使用10%MeOH/DCM,得到呈蓝灰色胶状物的标题化合物(36.4g,收率80%)。
步骤6:(3R,5R,Z)-N'-(2-氯乙酰氧基)-5-(4-氟苯基)四氢呋喃-3-甲脒的制备
在0℃下将氯乙酸酐(10.8g,60.1mmol)分批添加至(3R,5R)-5-(4-氟苯基)-N'-羟基-四氢呋喃-3-甲脒(12.3g,54.6mmol)在MTBE(137mL)中的溶液中。将反应物在室温下搅拌20min。将反应混合物冷却至0℃,用iPrOAc稀释,并使用饱和NaHCO3进行分配。将水层用iPrOAc(3x)萃取。将合并的有机层再次用饱和NaHCO3和盐水洗涤,用MgSO4干燥、过滤并浓缩,但不进行完全。将溶剂换为MTBE并浓缩直至获得油性残留物。将产物用150mL的MTBE湿磨。将溶液冷却至-20℃,通过过滤回收并在-20℃下用MTBE洗涤。将产物在真空下干燥,得到呈白色固体状的标题产物(11.9g,收率73%)。
步骤7:5-(氯甲基)-3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二唑的
制备
将[(Z)-[氨基-[(3R,5R)-5-(4-氟苯基)四氢呋喃-3-基]亚甲基]氨基]2-氯乙酸酯(36.0g,120mmol)和分子筛粉末(40g,在烘箱中预活化)在甲苯(479mL)中的混合物在115℃下搅拌8h。将反应混合物冷却至室温。通过过滤除去分子筛,并使用iPrOAc洗涤。将滤液在旋转蒸发仪上浓缩。通过硅胶柱纯化粗混合物,使用0-50%iPrOAc/庚烷,得到呈透明油状物的标题化合物(32.1g,收率95%)。
步骤8:1-((3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1H-嘌呤-6(7H)-酮的制备
在0℃下将7-甲基-1H-嘌呤-6-酮(23.9g,159mmol)和K2CO3(47.6g,341mmol)添加至5-(氯甲基)-3-[(3R,5R)-5-(4-氟苯基)四氢呋喃-3-基]-1,2,4-噁二唑(32.1g,114mmol)在DMF(227mL)中的溶液中。将混合物在0℃下搅拌6h。使反应物升温至室温过夜。在0℃下依次添加EtOH(95mL)和水(950mL)。通过在烧结漏斗上过滤回收固体,并在0℃下用水洗涤。将固体在真空下干燥15min。将固体溶解在DCM中,使用MgSO4干燥,过滤并浓缩。一旦在旋转蒸发仪上获得糊状物,立即将DCM换成iPrOAc,并与约100mL的iPrOAc共蒸发2次。将残留物用415mL的iPrOAc湿磨,冷却至0℃,通过过滤回收并用冷iPrOAc洗涤并在真空下干燥,得到呈灰白色固体状的标题化合物(40.5g,收率90%)。
步骤9:1-((3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1H-嘌呤-6(7H)-酮的重结晶
将1-((3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲基)-7-甲基-1H-嘌呤-6(7H)-酮(40g,101mmol)放置在1L反应器中,并添加EtOH/水(7:3,720mL)(18体积)。将混合物加热至75℃。历时40min将材料缓慢溶解。此时,使用粗物质的混悬液(1g混悬在EtOH/水1:1中,20mL)对该材料种晶。将所获得的混悬液静置,以在75℃下陈化30min。此时,历时2h将混悬液缓慢冷却至25℃,然后在25℃下再静置1h。将材料通过过滤漏斗过滤;将固体用EtOH/水(1:1,100mL)洗涤。将固体在空气中干燥,然后在轻微氮气流存在下将材料在真空炉中静置(60℃过夜),得到呈白色结晶固体状的标题化合物(36.2g,收率91%)。
实施例3:2-氨基-3-((3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二
唑-5-基)甲基)-5-甲基吡唑并[5,1-f][1,2,4]三嗪-4(3H)-酮
步骤1:1-氨基-4-甲基-1H-吡唑-5-甲酸甲酯的制备
在-20℃下历时5min将LiHMDS(1M的THF溶液)(14.3mL,14.3mmol)添加至4-甲基-1H-吡唑-5-甲酸乙酯(2.00g,13.0mmol)在DMF(130mL)中的溶液中。将所得混合物中0℃下搅拌15min,然后一次性添加o-(二苯基氧膦基)羟胺(3.63g,15.6mmol)。在出现白色沉淀之后,反应混合物迅速变得非常浓,并在室温下偶尔手动搅拌持续1h。将反应物用水稀释,直至沉淀完全溶解,并在室温下搅拌15min。将反应混合物浓缩至干,并用约150mL的2:1DCM/EtOAc稀释。通过过滤除去固体,进一步用2:1DCM/EtOAc洗涤滤饼,将滤液在减压下浓缩并与庚烷共蒸发2次。将残留物用快速柱层析(DCM装载,100g biotage SiO2,在DCM中0-4%的MeOH梯度,超过17个CV)纯化,得到呈浅黄色油状物的2-氨基-4-甲基-吡唑-3-甲酸乙酯(1.54g,9.10mmol,收率70%)。LCMS:纯度=98%,MH+=169.8。1H NMR(400MHz,CDCl3)δ7.14(d,J=0.4Hz,1H),5.62(br s,2H),4.39(q,J=7.1Hz,2H),2.23(d,J=0.6Hz,3H),1.40(t,J=7.1Hz,3H)。
步骤2:2-氨基-5-甲基吡唑并[5,1-f][1,2,4]三嗪-4(3H)-酮的制备
将N,N-二异丙基乙胺(1.16mL,6.65mmol)添加至2-氨基-4-甲基-吡唑-3-甲酸乙酯(450.mg,2.66mmol)和氯甲脒盐酸盐(611mg,5.32mmol)在DCM(10mL)中的混合物中。将反应混合物在MW照射下在150℃下加热2h。将溶液冷却至室温并过滤出沉淀,并用DCM洗涤,得到呈米色粉末状的2-氨基-5-甲基-3H-吡唑并[5,1-f][1,2,4]三嗪-4-酮(432mg,2.62mmol,收率98%)。LCMS:纯度=85%,MH+=166.3。1H NMR(400MHz,DMSO-D6)11.25(s,1H),7.32(s,1H),6.13(s,1H),2.26(t,4H)
步骤3:2-氨基-3-((3-((3R,5R)-5-(4-氟苯基)四氢呋喃-3-基)-1,2,4-噁二唑-
5-基)甲基)-5-甲基吡唑并[5,1-f][1,2,4]三嗪-4(3H)-酮的制备
向5-(氯甲基)-3-[5-(4-氟苯基)四氢呋喃-3-基]-1,2,4-噁二唑(40.0mg,0.140mmol,由实施例6制备)在DMF(0.42mL)中的溶液中依次添加2-氨基-5-甲基-3H-吡唑并[5,1-f][1,2,4]三嗪-4-酮(28.0mg,0.170mmol)和碳酸钾(39.1mg,0.280mmol)。将反应混合物在室温下搅拌2h。用水稀释,用EtOAc萃取,用NH4Cl、盐水洗涤,用MgSO4干燥,过滤并浓缩。将残留物用正相快速色谱(12g,SiO2,0-10%MeOH/DCM)纯化。将含有产物的级分合并,并在真空中蒸发。将化合物溶解在乙腈与水的混合物中,冷冻干燥并冻干,得到呈白色固体状的2-氨基-3-[[3-[5-(4-氟苯基)四氢呋喃-3-基]-1,2,4-噁二唑-5-基]甲基]-5-甲基-吡唑并[5,1-f][1,2,4]三嗪-4-酮(16.2mg,0.039mmol,收率28%)。LCMS:纯度=96%,MH+=412.0。1H NMR(400MHz,dmso)7.44-7.35(m,3H),7.21-7.11(m,2H),6.88(s,2H),5.48(s,2H),5.00(t,J=7.4Hz,1H),4.36(dd,J=8.5,7.4Hz,1H),3.89(dd,J=8.5,6.3Hz,1H),3.77(dt,J=13.9,6.9Hz,1H),2.56(ddd,J=12.4,7.0,5.1Hz,1H),2.29(d,J=0.4Hz,3H),2.15(ddd,J=12.7,8.9,7.8Hz,1H)。
实施例4:2-氨基-3-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二
唑-5-基)甲基)-5-甲基吡唑并[5,1-f][1,2,4]三嗪-4(3H)-酮的制备
向5-(氯甲基)-3-[5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑(40.0mg,0.130mmol,在实施例1中制备)在DMF(0.42mL)中的溶液中依次添加2-氨基-5-甲基-3H-吡唑并[5,1-f][1,2,4]三嗪-4-酮(26.5mg,0.160mmol,在实施例105中制备)和碳酸钾(37.0mg,0.270mmol)。将反应混合物在室温下搅拌2h。用水稀释,用EtOAc萃取,用NH4Cl、盐水洗涤,用MgSO4干燥,过滤并浓缩。将残留物用快速层析(SiO2,12g,0-10%MeOH/DCM)纯化。将含有产物的级分合并,并在真空中蒸发。将化合物溶解在乙腈与水的混合物中,冷冻干燥并冻干,得到呈白色固体状的2-氨基-3-[[3-[5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑-5-基]甲基]-5-甲基-吡唑并[5,1-f][1,2,4]三嗪-4-酮(21.7mg,0.051mmol,收率38%)。LCMS:纯度=95%,MH+=428.1。1H NMR(400MHz,dmso)7.44-7.35(m,5H),6.87(s,2H),5.48(s,2H),5.01(t,J=7.5Hz,1H),4.36(dd,J=8.5,7.4Hz,1H),3.90(dd,J=8.6,6.3Hz,1H),3.77(dd,J=14.9,6.3Hz,1H),2.57(ddd,J=7.3,6.2,3.3Hz,1H),2.29(s,3H),2.20-2.08(m,1H)。
实施例5:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-7-甲基-1,7-二氢-6H-嘌呤-6-酮-2-d
步骤1:2-氯-7-甲基-1,7-二氢-6H-嘌呤-6-酮的制备
将2,6-二氯-7-甲基嘌呤(1.0g,4.93mmol)和NaOH(0.99g,24.63mmol)在水(10mL)中的溶液在90℃下搅拌1小时。用HCl(10%)将反应混合物调节至pH 2。通过过滤收集固体,得到呈白色固体状的标题化合物。
步骤2:7-甲基-1,7-二氢-6H-嘌呤-6-酮-2-d的制备
将2-氯-7-甲基-1H-嘌呤-6-酮(700.0mg,3.79mmol)、Zn(2465.06mg,37.92mmol)和DCOOD(1820.35mg,37.92mmol)在CD3OD(10.0g,277.78mmol)和D2O(5.0g,250mmol)中的混合物在60℃下搅拌16小时。将反应混合物用MeOH(100mL)稀释。过滤固体并将滤液在减压下浓缩。通过C18硅胶柱纯化残留物,用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱。此产生呈白色固体状的标题化合物(370mg)。
步骤3:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1,7-二氢-6H-嘌呤-6-酮-2-d的制备
向5-(氯甲基)-3-[5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑(20.0mg,0.070mmol,根据类似于实施例2的步骤制备)在DMF(0.5mL)中的溶液中依次添加2-氘-7-甲基-1H-嘌呤-6-酮(12.1mg,0.080mmol)和碳酸钾(18.5mg,0.130mmol)。将反应混合物在室温下搅拌16h。然后将混合物用水稀释,用EtOAc萃取,用NH4Cl、盐水洗涤,用MgSO4干燥,过滤并浓缩。将残留物用快速层析(SiO2,12g,0-10%MeOH/DCM)纯化。将含有产物的级分合并,并在真空中蒸发。将化合物溶解在乙腈与水的混合物中,冷冻干燥并冻干,得到呈白色固体状的1-[[3-[5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑-5-基]甲基]-2-氘-7-甲基-嘌呤-6-酮(18.0mg,0.044mmol,收率65%)。LCMS:纯度=96%,MH+=414.0。1H NMR(400MHz,dmso)8.22(s,1H),7.42–7.28(m,4H),5.55(s,2H),4.99(t,J=7.4Hz,1H),4.33(dd,J=8.5,7.4Hz,1H),3.93(s,3H),3.88(dd,J=8.6,6.3Hz,1H),3.80-3.70(m,1H),2.61-2.52(m,1H),2.19-2.08(m,1H)。
实施例6:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-7-甲基-1,7-二氢-6H-嘌呤-6-酮-8-d
步骤1:8-溴-7-甲基-1,7-二氢-6H-嘌呤-6-酮的制备
将7-甲基-1H-嘌呤-6-酮(200.0mg,1.33mmol)和NBS(284.53mg,1.6mmol)在乙腈(8mL)中的混合物在80℃下搅拌过夜。将溶剂在真空下浓缩。通过在硅胶上快速层析将残留物纯化,使用CH2Cl2/MeOH(10:1)洗脱,得到呈白色固体的标题化合物。
步骤2:7-甲基-1,7-二氢-6H-嘌呤-6-酮-8-d的制备
将8-溴-7-甲基-1H-嘌呤-6-酮(1.4g,6.11mmol)、D2O(5.mL,mmol)、CD3OD(10.mL,mmol)、Zn(3.91g,61.13mmol)和DCOOD(2.93g,61.13mmol)的混合物在室温下搅拌一小时。过滤出固体,通过C18硅胶柱纯化滤液,使用CH3CN/H2O(10mmol/L NH4HCO3,5%至95%,历时30min)洗脱,此产生呈白色固体状的标题化合物(510mg)。
步骤3:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1,7-二氢-6H-嘌呤-6-酮-8-d的制备
向5-(氯甲基)-3-[5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑(20.0mg,0.070mmol,根据类似于实施例2的步骤制备)在DMF(0.5mL)中的溶液中依次添加8-氘-7-甲基-1H-嘌呤-6-酮(12.1mg,0.080mmol)和碳酸钾(18.5mg,0.130mmol)。将反应混合物在室温下搅拌16h。用水稀释,用EtOAc萃取,用盐水洗涤,用MgSO4干燥,过滤并浓缩。用快速层析(SiO2,12g,0-10%MeOH/DC)纯化残留物。将含有产物的级分合并,并在真空中蒸发。将化合物溶解在乙腈与水的混合物中,冷冻干燥并冻干,得到呈白色固体状的1-[[3-[5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑-5-基]甲基]-8-氘-7-甲基-嘌呤-6-酮(12.0mg,0.029mmol,收率43%)。LCMS:纯度=99%,MH+=414.0。1H NMR(400MHz,dmso)8.44(s,1H),7.47-7.28(m,4H),5.56(s,2H),4.99(t,J=7.3Hz,1H),4.33(t,J=7.9Hz,1H),3.93(s,3H),3.88(dd,J=8.5,6.3Hz,1H),3.79-3.70(m,1H),2.61-2.51(m,1H),2.19-2.08(m,1H)。
实施例7:1-((3-((3R,5R)-5-(4-氯苯基)-四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-7-甲基-1H-嘌呤-2,6(3H,7H)-二酮
实施例7的反应路线如下所示:
步骤1:2-氯-1-((3-((3R,5R)-5-(4-氯苯基)-四氢呋喃-3-基)-1,2,4-噁二唑-5-
基)甲基)-7-甲基-1H-嘌呤-6(7H)-酮的制备
在室温下在氮气下将NaH(60%)(39.0mg,0.65mmol)分批添加至2-氯-7-甲基-1H-嘌呤-6-酮(100.0mg,0.54mmol)在DMF(3mL)中的溶液中,并搅拌1小时。然后,添加5-(氯甲基)-3-[(3R,5R)-5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑(194.0mg,0.65mmol,根据类似于实施例1的步骤制备)在DMF(3mL)中的溶液。将所得溶液在50℃下搅拌过夜。将所得溶液通过RP-HPLC进一步纯化,得到呈白色固体状的标题化合物(91mg,38%)。
步骤2:1-((3-((3R,5R)-5-(4-氯苯基)-四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1H-嘌呤-2,6(3H,7H)-二酮的制备
将2-氯-1-[[3-[(3R,5R)-5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑-5-基]甲基]-7-甲基-嘌呤-6-酮(300.0mg,0.67mmol)和HCl(36%)(0.5mL,0.67mmol)在1,4-二噁烷(10mL)中的溶液在95℃下搅拌4小时。通过RP-HPLC纯化残留物,得到呈白色固体状的标题化合物(145mg,50%)。LCMS[M+H+]:429.1。1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.03(s,1H),7.40(d,J=1.3Hz,4H),5.31(s,2H),5.02(t,J=7.3Hz,1H),4.36(dd,J=8.6,7.4Hz,1H),3.91(dd,J=8.6,6.3Hz,1H),3.87(s,3H),3.77–3.73(m,1H),2.1–2.56(m,1H),2.20–2.06(m,1H)。
实施例8:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-2,7-二甲基-1H-嘌呤-6(7H)-酮
实施例8的总体反应路线如下所示:
步骤1:46-二氯-N2-二甲基嘧啶-5-胺的制备
在氮气下向1L RBF中添加NaHMDS(1M的THF溶液,126mL,126mmol)和THF(120mL)。将溶液在冰浴中冷却,并当内部探针指示2℃时,历时40min加入(canulated)4,6-二氯-2-甲基嘧啶-5-胺(20.0g,112mmol)在THF(120mL)中的溶液,以使内部温度保持在2至4℃之间。使得反应混合物在2℃下搅拌1小时,并历时5min添加碘甲烷(8.2mL,131mmol)。将反应混合物在20℃下搅拌2小时,并通过添加饱和NH4Cl水溶液(350mL)、水(50mL)和盐水(50mL)来终止反应。将所得混合物用EtOAc(3x 200mL)萃取。将合并的有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,得到呈棕色油状物的粗4,6-二氯-N,2-二甲基嘧啶-5-胺(假定21.6g,粗产率100%),其在室温下静置后发生固化。LCMS显示纯度为88%,并将粗物质按照原样用于下一反应中。
步骤2:6-氯-N5,2-二甲基嘧啶-4,5-二胺的制备
向500mL压力容器中转移含粗4,6-二氯-N,2-二甲基嘧啶-5-胺(21.6g,112mmol)的乙醇(70mL)。添加28%NH4OH水溶液(130mL,1924mmol),将烧瓶密封,并将混合物在80℃油浴中搅拌18小时。使得反应混合物在20℃下冷却,并将其在冰浴中冷却。缓慢形成金色固体,并将混合物在0℃下搅拌2小时。将混悬液过滤,并将固体用冷EtOH(30mL)和水(60mL)的混合物洗涤,得到呈金色固体状的6-氯-N5,2-二甲基-嘧啶-4,5-二胺(12.2g,70.7mmol,收率63%,根据LCMS纯度为91%)。将母液浓缩,并将所得固体混悬于MeOH和水(~5:1)中。将混合物加热至70℃,并使得其在20℃下冷却。将所得混悬液过滤,并将固体用最少的冷MeOH洗涤,得到第二次收获的呈米色固体状的6-氯-N5,2-二甲基嘧啶-4,5-二胺(1.40g,8.11mmol,收率7%,根据LCMS纯度为97%)。
步骤3:2,7-二甲基-1H-嘌呤-6(7H)-酮的制备
向6-氯-2,N5-二甲基嘧啶-4,5-二胺(3.50g,20.3mmol)在原甲酸三乙酯(15mL)中的溶液中添加甲酸(2.80g,60.8mmol)。将所得混合物在100℃下搅拌过夜。将所得混合物浓缩。将粗产物用乙酸乙酯洗涤,得到呈黄色固体状的2,7-二甲基-1H-嘌呤-6(7H)-酮(2.00g,收率60%)。1H NMR(300MHz,DMSO-d6)δ12.14(s,1H),8.07(s,1H),3.93(s,3H),2.32(s,3H)。
步骤4:1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-2,7-二甲基-1H-嘌呤-6(7H)-酮的制备
将5-(氯甲基)-3-[(3R,5R)-5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑(8.40g,28.1mmol,根据类似于实施例1的步骤制备)、2,7-二甲基-1H-嘌呤-6(7H)-酮(5.07g,30.9mmol)和碳酸钾(11.6g,84.2mmol)装入200mL RBF中。添加DMF(56mL),并将混合物在40℃油浴中搅拌2小时。移除热源,并将反应混合物转移至含有EtOAc(100mL)和水(500mL)的分液漏斗中。将混合物用EtOAc(3x 100mL)萃取。将合并的有机层用水(40mL)与盐水(40mL)的混合物洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,得到粗产物(根据LCMS纯度为77%)。将粗棕色油状物溶解在EtOAc(100mL)中,并逐滴添加庚烷(60mL),这使得缓慢形成固体。将混合物在0℃下搅拌30min,并在布氏漏斗上收集固体,用庚烷冲洗,并空气干燥15min,得到第一批呈黄色固体状的1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲基)-2,7-二甲基-1H-嘌呤-6(7H)-酮(8.0g,18.7mmol,收率67%,根据LCMS纯度为92%)。将滤液浓缩,并将其通过反相层析(C18,MeCN/10mM NH4HCO2/H2O,pH3.8,0至60%梯度)纯化,得到第二批呈白色固体状的1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲基)-2,7-二甲基-1H-嘌呤-6(7H)-酮(950mg,2.23mmol,收率8%,根据LCMS纯度>99%)。
将第一批所需产物(8.0g,根据LCMS纯度为92%)与从前一批获得的第三批(1.3g,根据LCMS纯度为96%)合并。将材料溶解在EtOAc(250mL)中,并在旋转蒸发仪上将溶剂换成iPrOH(3个循环的iPrOH添加(50mL)/蒸发50mL溶剂)。在该过程中,析出固体,并在旋转蒸发仪上使溶剂减少至约100mL。将混悬液冷却至0℃,并在布氏漏斗上收集固体,用冷iPrOH冲洗,并空气干燥15min,得到第四批呈浅米色固体状的1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲基)-2,7-二甲基-1H-嘌呤-6(7H)-酮(8.50g,根据LCMS纯度为99%)。对经纯化材料的颜色仍不满意,将其溶解在EtOAc(500mL)中,并将棕色溶液用8g活性炭处理。使得混合物搅拌15min。将混悬液在硅藻土上过滤,并将滤饼用EtOAc冲洗。将无色滤液在减压下蒸发,得到第五批呈白色固体状的1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲基)-2,7-二甲基-1H-嘌呤-6(7H)-酮(7.50g,根据LCMS纯度为99%)。最后,将第二批(950mg,根据LCMS纯度>99%)和第五批(7.50g,根据LCMS纯度为99%)合并在200mL RBF中,并添加iPrOH(100mL)。将混悬液在100℃油浴中搅拌,直至完全溶解,并添加水(3mL)。将烧瓶从油浴中移出,并使得浅黄色透明溶液在室温下冷却。将混悬液在冰浴中冷却,并在布氏漏斗上收集固体,用冷iPrOH(20mL)冲洗,并空气干燥24小时,得到呈白色固体状的标题化合物1-((3-((3R,5R)-5-(4-氯苯基)四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲基)-2,7-二甲基-1H-嘌呤-6(7H)-酮(7.3g)。LCMS:纯度=99.4%,MH+=427.2/429.2。1H NMR(400MHz,DMSO-d6)d 8.18(s,1H),7.46-7.33(m,4H),5.63(s,2H),5.00(t,J=7.4Hz,1H),4.35(dd,J=8.4,7.5Hz,1H),3.93(s,3H),3.95-3.88(m,1H),3.79-3.70(m,1H),2.60(s,3H),2.63-2.53(m,1H),2.13(ddd,J=12.7,8.9,7.8Hz,1H)。
实施例9:1-((3-((3R,5R)-5-(4-氯苯基)-四氢呋喃-3-基)-1,2,4-噁二唑-5-基)
甲基)-7-甲基-1H-嘌呤-6,8(7H,9H)-二酮
实施例9的总体反应路线如下所示:
步骤1:8-氯-7-甲基-1H-嘌呤-6(7H)-酮的制备
将NCS(6.0g,44.93mmol)和7-甲基-1H-嘌呤-6-酮(8.7g,57.95mmol)在DMF(70mL)中的溶液在室温下搅拌过夜。将所得溶液通过RP-HPLC进一步纯化,得到呈灰白色固体状的标题化合物(4.7g,65%)。
步骤2:8-氯-1-((3-((3R,5R)-5-(4-氯苯基)-四氢呋喃-3-基)-1,2,4-噁二唑-5-
基)甲基)-7-甲基-1H-嘌呤-6(7H)-酮的制备
将5-(氯甲基)-3-[(3R,5R)-5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑(55.0mg,0.18mmol,根据类似于实施例1的步骤制备)、8-氯-7-甲基-1H-嘌呤-6(7H)-酮(30.0mg,0.19mmol)、K2CO3(51.0mg,0.37mmol)和TBAI(3.4mg,0.01mmol)在DMF(3mL)中的溶液在室温下搅拌2小时。将残留物通过RP-HPLC纯化,得到呈白色固体状的标题化合物(48mg,67%)。
步骤3:1-((3-((3R,5R)-5-(4-氯苯基)-四氢呋喃-3-基)-1,2,4-噁二唑-5-基)甲
基)-7-甲基-1H-嘌呤-6,8(7H,9H)-二酮的制备
将8-氯-1-[[3-[(3R,5R)-5-(4-氯苯基)四氢呋喃-3-基]-1,2,4-噁二唑-5-基]甲基]-7-甲基-嘌呤-6-酮(230.0mg,0.51mmol)在甲酸(5mL)中的溶液在95℃下搅拌2小时。将所得溶液通过RP-HPLC进一步纯化,得到呈白色固体状的标题化合物(51mg,23%)。LCMS[M+H+]:429.1。
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),7.39(d,J=2.1Hz,4H),5.53(s,2H),5.01(t,J=7.3Hz,1H),4.36(t,J=8.0Hz,1H),3.90(dd,J=8.5,6.2Hz,1H),3.81–3.75(m,1H),2.61–2.56(m,1H),2.20–2.06(m,1H)。
上述化合物以及使用上述步骤用适当的起始原料制备的其它化合物与各化合物的hTRPA1 IC50值一起显示在表1中。
下表2提供了表1的化合物的质子NMR数据。
表2
示例性化合物的IC50确定
使用FLIPR Tetra仪器确定化合物对人TRPA1通道的IC50(有效浓度)。将表达TRPA1的CHO细胞接种在384孔板中,在37℃下孵育过夜,且在37℃下用BD钙指示染料加载1小时,随后在室温下加载15分钟。测定缓冲液为含有20mM HEPES(pH再调整为7.4)以及0.02%BSA的Hank平衡盐溶液(HBSS)。
在染料加载和板冷却之后,使用FLIPR Tetra将化合物添加至细胞。然后,将板与化合物在室温下孵育10分钟或90分钟,随后添加激动剂。在此孵育之后,添加约EC80浓度的肉桂醛(75)以活化通道并测量肉桂醛诱导的钙流入的阻断。
将IC50结果用标准希尔函数拟合,保持希尔系数(n)固定在1.5。固定希尔系数通常将降低IC50确定的变异性。分别检查IC50结果,以确保在验证结果之前正确设置MIN和MAX点。
本文公开的化合物的IC50(hTRPA1 IC50(微摩尔))结果如上表1中所示,其中“hTRPA1”指hTRPA1 CHO Ca2+MAX EVO(IC50)。
本书面说明书使用实例来公开本发明,包括最佳方式,并且还使本领域技术人员能够实施本发明,包括制备和使用任何装置或系统以及实施任何引入的方法。本发明的专利范围由权利要求限定,可以包括本领域技术人员可以想到的其它实例。如果这些另外的实例具有与权利要求的字面语言没有区别的结构要素,或者如果其包括与权利要求的字面语言无实质性区别的等价结构要素,则所述另外的实例涵盖在权利要求的范围内。
Claims (39)
1.式(I)化合物:
或其药学上可接受的盐,其中:
A是:取代或未取代的6-6稠合双环杂芳基,其可以是部分饱和的;取代或未取代的5-6稠合双环杂芳基,其可以是部分饱和的;或者取代和未取代的6-5稠合双环杂芳基,其可以是部分饱和的;
X是:键;C1-4亚烷基;-O-;-S-;-SO2-;或-N(Ra)-;
n是:0、1、2或3;
Ra是H或C1-6烷基,其可以是未取代的或被卤素取代一次或多次;
R1是:H;或C1-6烷基;和
R4是:取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基;
或者R1和R4可以一起形成与取代或未取代的苯基;取代或未取代的杂芳基;或取代或未取代的萘基稠合的未取代或取代的C3-6环烷基。
2.根据权利要求1所述的化合物,其中A是:
其中:
E是五元或六元杂芳基环,其中一个环碳原子任选被氧代取代;
G是具有被氧代取代的一个环碳原子的六元杂芳基环;
Y1、Y2、Y3、Y4、Y5和Y6中的一至三个是氮,其它的Y1、Y2、Y3、Y4、Y5和Y6是碳,且Y1、Y2、Y3和Y4中的一个可以是–C(O)-或-C(S)-;
Z1、Z2、Z3、Z4和Z5中的一个或两个是氮,且其它的Z1、Z2、Z3、Z4和Z5是碳;
每个R2独立地为H、D;-C1-4烷基;-C1-4卤代烷基;-CN;卤素;卤代C1-4烷氧基;C1-4烷氧基;-OH;-SO2-C1-4烷基;-C1-4CN、C1-4醛;C1-4酮;苄基氨基;或NR14R15;
p是0、1或2;
每个R3独立地为:H;D;-C1-4烷基;-C1-4卤代烷基;-CN;卤素;或NR14R15;
q是0或1;
R14和R15各自独立地为:H;取代或未取代的-C1-4烷基;取代或未取代的-C(O)-C1-4烷基;取代或未取代的C3-6环烷基;取代或未取代的3-至6-元杂环烷基;取代或未取代的-C1-4杂烷基;-C(O)NR16R17;取代或未取代的-C1-4烷基-C(O)NR16R17;取代或未取代的苯基;或取代或未取代的苄基;
或者R14和R15与其所连接的原子一起可形成任选地包括一个选自O、N和S的另外的杂原子的4-、5-、6-或7-元环;和
R16和R17各自独立地为H和C1-4烷基。
11.根据权利要求1-10中任一项所述的化合物,其中X是亚甲基。
13.根据权利要求12所述的化合物,其中每个R18独立地为:H;Cl;-OCHF2;-OCF;-OCH3;或-CN。
14.根据权利要求12或13所述的化合物,其中每个R18独立地为氟或氯。
24.药物组合物,其包含如权利要求1至23中任一项所述的化合物或其药学上可接受的盐,和药学上可接受的载体、稀释剂或赋形剂。
25.如权利要求1至24中任一项所述的化合物或其药学上可接受的盐,其用于医学治疗。
26.如权利要求1至24中任一项所述的化合物或其药学上可接受的盐,其用于治疗或预防呼吸病症。
27.如权利要求1至24中任一项所述的化合物或其药学上可接受的盐,其用于制备治疗或预防呼吸病症的药物。
28.治疗哺乳动物呼吸病症的方法,包括向所述哺乳动物施用如权利要求1至24中任一项所述的化合物或其药学上可接受的盐。
29.如权利要求1至24中任一项所述的化合物或其药学上可接受的盐,其用于调节TRPA1活性。
30.如权利要求1至24中任一项所述的化合物或其药学上可接受的盐,其用于治疗或预防由TRPA1活性介导的疾病或病况。
31.根据权利要求30所述的化合物,其中所述疾病或病况是疼痛、痒病、炎性病症、内耳病症、发热或其它体温调节病症、气管支气管或膈膜功能障碍、胃肠道或泌尿道病症、慢性阻塞性肺病、失禁、或者与流向CNS的血流减少或CNS缺氧相关的病症。
32.根据权利要求31所述的化合物,其中所述疾病或病况是疼痛、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳病症。
33.如权利要求1至24中任一项所述的化合物或其药学上可接受的盐用于制备治疗或预防由TRPA1活性介导的疾病或病况的药物的用途。
34.根据权利要求33所述的用途,其中所述疾病或病况是疼痛、痒病、炎性病症、内耳病症、发热或其它体温调节病症、气管支气管或膈膜功能障碍、胃肠道或泌尿道病症、慢性阻塞性肺病、失禁、或者与流向CNS的血流减少或CNS缺氧相关的病症。
35.根据权利要求34所述的用途,其中所述疾病或病况是疼痛、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳病症。
36.调节TRPA1活性的方法,包括使TRPA1与如权利要求1-24中任一项所述的化合物或其药学上可接受的盐接触。
37.治疗哺乳动物由TRPA1活性介导的疾病或病况的方法,包括向所述哺乳动物施用如权利要求1至24中任一项所述的化合物或其药学上可接受的盐。
38.根据权利要求37所述的方法,其中所述疾病或病况是疼痛、痒病、炎性病症、内耳病症、发热或其它体温调节病症、气管支气管或膈膜功能障碍、胃肠道或泌尿道病症、慢性阻塞性肺病、失禁、或者与流向CNS的血流减少或CNS缺氧相关的病症。
39.根据权利要求38所述的方法,其中所述疾病或病况是疼痛、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳病症。
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