CN109415372B - 螺-内酰胺nmda受体调节剂及其用途 - Google Patents
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Abstract
本文公开化合物,其具有调节NMDA受体活性的增强的效能。所述化合物能够用于治疗病症比如抑郁和有关的障碍。本文还公开该化合物的可口服获得的配制剂和其它药学上可接受的递送形式,包括静脉内配制剂。
Description
与有关申请的交叉引用
本申请要求于2016年5月19日提交的U.S.临时专利申请No.62/338,767的优先权和益处;通过援引将其内容全部并入本文。
背景技术
N-甲基-d-天冬氨酸("NMDA")受体是突触后、离子型受体,其响应尤其是兴奋性氨基酸谷氨酸和甘氨酸和合成的化合物NMDA。NMDA受体控制二价和一价离子通过与受体有关联的通道进入突触后神经细胞的流动(Foster等人,Nature 1987,329:395-396;Mayer等人,Trends in Pharmacol.Sci.1990,11:254-260)。NMDA受体已牵涉于指定神经元建构和突触连接性的发展期间,并且可以牵涉于经验依赖性的突触修饰中。此外,NMDA受体也被认为牵涉于长时程增强和中枢神经系统障碍中。
NMDA受体在支撑许多高级认知功能比如记忆获得、保留和学习的突触可塑性中,以及某些认知途径中和疼痛知觉中发挥主要作用(Collingridge等人,The NMDAReceptor,Oxford University Press,1994)。此外,NMDA受体的某些特性表明它们可以牵涉于支撑意识本身的脑部信息处理中。
NMDA受体吸引特别的兴趣,原因是其显得牵涉于广谱CNS障碍中。例如,在由卒中或跌打损伤引起的脑缺血期间,过量兴奋性氨基酸谷氨酸从受损或缺氧的神经元释放出来。该过量谷氨酸结合至NMDA受体,其打开其配体-门控离子通道;钙内流又产生高水平的细胞内钙,其活化生物化学级联,引起蛋白质降解和细胞死亡。该现象称为兴奋性中毒,其也被认为负责与其它障碍有关的神经损害,所述其它障碍的范围是低血糖症和心脏停搏直至癫痫。此外,有初步报告指出在亨廷顿病症、帕金森氏病症和帕金森氏有关病症比如运动障碍和L-多巴诱导的运动障碍和阿尔茨海默病的慢性神经变性中的相似牵涉。NMDA受体的活化已显示负责卒中后痉挛,而在癫痫某些模型中,NMDA受体的活化已显示对癫痫发作的产生是必需的。NMDA受体的神经精神牵涉也被认识到,原因是动物麻醉剂PCP(苯环利定)阻断NMDA受体Ca++通道在人中产生类似精神分裂症的精神病状态(综述于Johnson,K.andJones,S.,1990)。此外,NMDA受体也牵涉于某些类型空间学习中。
NMDA受体据信由包埋在突触后膜中的数个蛋白质链组成。目前发现的前两种类型的亚单位形成可能含有绝大多数变构的结合位点的大细胞外区域,成环和折叠以形成可渗透Ca++的孔或通道的数个跨膜区域,和羧基末端区域。通道的打开和关闭受各种配体与位于细胞外表面上的蛋白质区域(变构位点)结合的调节。配体的结合被认为影响蛋白质总体结构的构象变化,其最终反映在通道的打开、部分打开、部分关闭或关闭。
NMDA受体化合物可以通过变构位点对NMDA受体发挥双重(激动剂/拮抗剂)效果。这些化合物一般称为"功能性部分激动剂"。在主要位点配体的存在下,部分激动剂将替代某些配体和从而降低Ca++流动通过受体。在不存在主要位点配体或主要位点配体的水平降低的情况下,部分激动剂的作用则是增加Ca++流动通过受体通道。
本领域一直需要新的和特异性更高的/更有效的化合物,其能够结合NMDA受体的甘氨酸结合位点并提供药物益处。此外,医学领域一直需要所述化合物的可口服递送形式。
发明概要
本公开提供化合物,其能够是NMDA调节剂例如NMDA的部分激动剂。更特别地,本公开提供具有下式的化合物:
或其立体异构体、N-氧化物和/或药学上可接受的盐,其中Rb选自氢,卤素,羟基,氰基,和C1-C6烷基;R1选自氢,卤素,和C1-C6烷基;和R2选自氢,卤素,和C1-C6烷基。
本文也提供药物组合物,包括所公开的化合物;和药学上可接受的赋形剂。上述组合物能够适于向患者口服或静脉内给药。
在某些实施方式中,本文描述的化合物结合至NMDA受体亚型。在某些实施方式中,本文描述的化合物结合至一种亚型而不结合至另一种。
在又一方面,提供在有需要的患者中治疗选自下述的病症的方法:孤独症,焦虑,抑郁,双相情感障碍,注意涣散障碍,注意力缺陷伴多动障碍(ADHD),精神分裂症,精神障碍,精神病症状,回避社交,强迫性障碍,恐怖症,创伤后应激综合征,行为障碍,冲动控制障碍,物质滥用障碍,睡眠障碍,记忆障碍,学习障碍,尿失禁,多系统萎缩症,进行性上核性麻痹,Friedrich共济失调,Down综合征,脆性X染色体综合征,结节性硬化,橄榄体脑桥小脑萎缩,大脑性瘫痪,药物诱导性视神经炎,缺血性视网膜病,糖尿病性视网膜病,青光眼,痴呆,AIDS痴呆,阿尔茨海默氏病,亨廷顿舞蹈病,痉挛状态,肌阵挛,肌肉痉挛,Tourette综合征,癫痫,大脑缺血,卒中,脑肿瘤,外伤性脑损伤,心脏停搏,脊髓病,脊髓损伤,外周神经病,纤维肌痛,急性神经性疼痛,和慢性神经性疼痛。所述方法能够包括向患者给予药学有效量的所公开的化合物,或其药学上可接受的盐、立体异构体、N-氧化物和/或水合物。
在某些实施方式中,方法包括治疗抑郁。例如,抑郁能够包括一种或多种严重抑郁障碍,情绪恶劣性精神障碍,精神病性抑郁,产后抑郁症,季节性情感障碍,双相情感障碍,情感障碍,或由慢性医学病症引起的抑郁。在某些实施方式中,方法能够治疗精神分裂症。所述精神分裂症能够是妄想狂样型精神分裂症,错乱型精神分裂症,紧张型精神分裂症,未分型精神分裂症,残留型精神分裂症,精神分裂后抑郁,或简单型精神分裂症。
附图说明
图1描述化合物A在积极情绪学习(PEL)模型中的平均50-kHz USV数据。
图2描述化合物A对野生型NMDAR2亚型[3H]MK-801结合的增强。
图3描述在雄性Sprague Dawley大鼠中单次静脉内(2mg/kg)和口服(10mg/kg)剂量给药之后化合物A的平均血浆浓度-时间曲线。
图4描述在雄性Sprague Dawley大鼠中单次口服(10mg/kg)剂量给药之后化合物A的平均血浆、脑和CSF浓度-时间曲线。
图5描述化合物B在PEL模型中的平均50-kHz USV数据。
图6描述化合物B对野生型NMDAR2亚型[3H]MK-801结合的增强。
图7描述在雄性Sprague Dawley大鼠中单次静脉内(2mg/kg)和口服(10mg/kg)剂量给药之后化合物B的平均血浆浓度-时间曲线。
图8描述在雄性Sprague Dawley大鼠中单次口服(10mg/kg)剂量给药之后化合物B的平均血浆、脑和CSF浓度-时间曲线。
图9描述化合物A体外MN、Ames和hERG测试的结果。
图10描述化合物B体外MN、Ames和hERG测试的结果。
图11描述对于化合物A的PEL测量的反转冲击波诱导的认知低下。
图12描述对于化合物B的PEL测量的反转冲击波诱导的认知低下。
图13描述对于化合物A在大鼠中新鲜感诱导的食欲减少(NIH)试验的结果。
图14描述对于化合物B在大鼠中新鲜感诱导的食欲减少(NIH)试验的结果。
图15描述化合物A的镇痛效果。
图16描述化合物B的镇痛效果。
图17描述对于化合物A的Porsolt强迫游泳试验的结果。
图18描述对于化合物B的Porsolt强迫游泳试验的结果。
发明详述
本公开一般地涉及能够调节NMDA的化合物例如NMDA拮抗剂或部分激动剂,和使用所公开的化合物的组合物和/或方法。应认识到所公开的化合物可以调节其它蛋白质靶标和/或NMDA受体亚型。
术语"烷基"如本文所用是指饱和的直链或支化的烃,比如1-6、1-4、或1-3个碳原子的直链或支化的基团,本文分别称为C1-C6烷基、C1-C4烷基和C1-C3烷基。例如,"C1-C6烷基"是指含有1-6个碳原子的直链或支化的饱和烃。C1-C6烷基的实例包括但不限于甲基,乙基,丙基,丁基,戊基,己基,异丙基,异丁基,仲丁基,叔丁基,异戊基,和新戊基。示范性烷基包括但不限于甲基,乙基,丙基,异丙基,2-甲基-1-丙基,2-甲基-2-丙基,2-甲基-1-丁基,3-甲基-1-丁基,3-甲基-2-丁基,2,2-二甲基-1-丙基,2-甲基-1-戊基,3-甲基-1-戊基,4-甲基-1-戊基,2-甲基-2-戊基,3-甲基-2-戊基,4-甲基-2-戊基,2,2-二甲基-1-丁基,3,3-二甲基-1-丁基,2-乙基-1-丁基,丁基,异丁基,叔丁基,戊基,异戊基,新戊基,和己基。
术语"氰基"如本文所用是指残基-CN。
术语"卤代"或"卤素"如本文所用是指氟(F),氯(Cl),溴(Br),和/或碘(I)。
术语"羟基"和"羟基"如本文所用是指残基-OH。
术语"化合物"如本文所用是指化合物本身及其药学上可接受的盐、水合物、酯和N-氧化物,包括其各种立体异构体及其同位素标记形式,除非从说明书上下文另有理解或明确地局限于化合物的一种特别形式即化合物本身、特定的立体异构体和/或同位素标记的化合物,或其药学上可接受的盐、水合物、酯或N-氧化物。应理解,化合物能够指同位素标记的化合物和/或化合物的立体异构体的药学上可接受的盐或水合物、酯或N-氧化物。
术语"部分"如本文所用是指化合物或分子的一部分。
本公开化合物能够含有一个或多个手性中心和/或双键,和因此能够作为立体异构体比如几何异构体和对映体或非对映体存在。术语"立体异构体"如本文所用由化合物的全部几何异构体,对映体和/或非对映体组成。例如,在化合物显示特定手性中心的情况下,未用化合物的该手性中心和其它手性中心的所述手性描述的化合物也属于本公开范围,也即以二维"平"或"直"键而不是以三维例如粗线或虚线楔形键描述的化合物。立体特异性化合物可以通过符号"R"或"S"指定,取决于致立体异构碳原子周围的取代基构型。本公开涵盖这些化合物的全部各种立体异构体及其混合物。对映体或非对映体的混合物可以在命名中指定为"(±)",但是本领域技术人员应认识到某一结构可以隐含地表示手性中心。应理解的是,化学结构的图解描述例如通式化学结构涵盖所指化合物的全部立体异构形式,除非另有指定。
如本文讨论,本公开化合物能够具有多个手性中心。各手性中心可以独立地是R、S或R和S的任何混合物。例如,在某些实施方式中,手性中心可以具有的R:S比率是约100:0至约50:50("外消旋体"),约100:0至约75:25,约100:0至约85:15,约100:0至约90:10,约100:0至约95:5,约100:0至约98:2,约100:0至约99:1,约0:100至50:50,约0:100至约25:75,约0:100至约15:85,约0:100至约10:90,约0:100至约5:95,约0:100至约2:98,约0:100至约1:99,约75:25至25:75,或约50:50。与所公开的化合物或化合物的混合物的外消旋配制剂相比,包含更高比率的一种或多种异构体(即R和/或S)的所公开的化合物的配制剂可以具有增强的治疗特征。
本公开化合物的单独对映体和非对映异构体能够合成地制备自含不对称或立构中心的可商购原料,或者通过制备外消旋混合物随后进行本领域普通技术人员熟知的拆分方法来制备。这些拆分方法是诸如(1)将对映体混合物连接至手性辅剂,通过重结晶或色谱法分离所得的非对映体的混合物,从辅剂释放光学纯产品,(2)采用旋光拆分剂成盐,(3)在手性液体色谱柱上直接分离光学对映体的混合物,或者(4)用立体选择性的化学或酶促试剂进行动力学拆分。外消旋混合物还能够通过熟知方法比如手性相气体色谱法或在手性溶剂中结晶化合物拆分为它们的组分对映体。在构成新立构中心期间或在转化事先存在的立构中心期间单个反应物形成立体异构体的不相等混合物的立体选择性合成,化学或酶反应是本领域熟知的。立体选择性合成涵盖对映和非对映选择性转化两者。参见例如Carreira和Kvaerno,Classics in Stereoselective Synthesis,Wiley-VCH:Weinheim,2009。
本公开化合物还能够存在几何异构体,其来自取代基在碳-碳双键周围的排列或取代基在环烷基或杂环周围的排列。符号表示键,其如本文描述可以是单键、双键或三键。碳-碳双键周围的取代基指定为"Z"或"E"构型,其中术语"Z"和"E"按照IUPAC标准使用。除非另有指定,描述双键的结构涵盖"E"和"Z"异构体。
另选地,碳-碳双键周围的取代基能够称为"顺式"或"反式",其中"顺式"代表取代基在双键的同侧和"反式"代表取代基在双键的对侧。取代基在碳环周围的排列还能够指定为"顺式"或"反式。"术语"顺式"代表取代基在环平面的同侧和术语"反式"代表取代基在环平面的对侧。化合物的混合物,其中取代基位于环平面的相同和对侧,指定为"顺式/反式。"
本公开也包涵同位素标记的化合物,其等同与本文描述的那些化合物,例外是一个或多个原子用这样的原子替换,其具有与自然界通常存在的原子质量或质量数不同的原子质量或质量数。能够掺入本文描述的化合物同位素的实例包括氢,碳,氮,氧,磷氟和氯的同位素,比如分别是2H("D"),3H,13C,14C,15N,18O,17O,31P,32P,35S,18F和36Cl。例如,本文描述的化合物能够将一个或多个H原子用氘替换。
某些同位素标记的化合物(例如用3H和14C标记的那些)能够用于化合物和/或底物组织分布测试。由于制备容易和可检测性,氚化(也即3H)和碳-14(也即14C)同位素可以是特别优选的。此外,用更重的同位素比如氘(也即2H)取代可以提供更高的代谢稳定性所导致的某些治疗优势(例如增加的体内半衰期或减少的剂量需求),于是在某些情况下可以是优选的。同位素标记的化合物能够一般地制备如下:按照类似于本文公开的那些例如在实施例部分中的程序,用同位素标记的试剂取代非同位素标记的试剂。
短语"药学上可接受的"或"药理学上可接受的"如本文所用是指化合物、分子个体、组合物、物质和/或剂型,其在适当给予动物或人类的情况下不产生不利、变应性或其它不希望的反应。对于人类给药,制剂应符合FDA的Office of Biologics standards所要求的无菌、致热原性、一般安全和纯度标准。
短语"药学上可接受的载体"和"药学上可接受的赋形剂"如本文所用是指与药物给药相容的任何各种溶剂、分散媒介、包衣、等渗剂和吸收延缓剂等。药物可接受的载体能够包括磷酸缓冲的盐水溶液,水,乳液(例如油/水或水/油乳液),和各种类型的润湿剂。组合物也能够包括稳定剂和防腐剂。
短语"药物组合物"如本文所用是指组合物,其包含与一种或多种药学上可接受的载体一起配制的本文公开的至少一种化合物。药物组合物还能够含有提供补充、额外或增强的治疗功能的其它活性化合物。
术语"个体"、"患者"和"受试者"如本文所用可互换地使用且包括任何动物,包括哺乳动物,优选小鼠、大鼠、其它啮齿类、兔子、犬、猫、猪、牛、羊、马或灵长类,和更优选人类。本公开描述的化合物能够给予至哺乳动物比如人类,但是还能够给予至其它哺乳动物比如需要兽医学治疗的动物例如家养动物(例如狗、猫等),农业动物(例如牛、羊、猪、马等)和实验室动物(例如大鼠、小鼠、豚鼠等)。在本公开描述的方法中治疗的哺乳动物优选是哺乳动物,其中希望治疗例如疼痛或抑郁。
术语"治疗"如本文所用包括任何效果,例如减少、降低、调节、改善或消除,其引起病症、疾病、障碍等(包括其一种或多种症状)的改善。治疗能够治愈,改善或至少部分改善障碍。
术语"障碍"是指术语"疾病"、"病症"或"疾病"且与它们可互换地使用,除非另有指定。
术语"调节"如本文所用是指和包括拮抗(例如抑制),激动,部分拮抗,和/或部分激动。
短语"药学有效量"和"治疗有效量"如本文所用是指化合物(例如所公开的化合物)的量,其将引起研究者、兽医、医生或其它临床医师所寻求的组织、系统、动物或人类的生物学或医学应答。本公开描述的化合物能够以治疗有效量给予以治疗疾病。化合物的治疗有效量能够是实现希望的治疗和/或预防性效果所需要的量,比如引起疾病或障碍比如抑郁症状减少的量。
短语"药学上可接受的盐"如本文所用是指具有酸性或碱性基团的盐,其能够存在于本公开化合物中和/或用于本公开的组合物中。本公开化合物的药学上可接受的盐(例如酸或碱),在给药至患者的情况下,能够提供本发明化合物或其活性代谢物或残余物。
在本发明组合物中包括的碱性化合物能够与各种无机和有机酸形成各式各样的盐。可以用来制备所述碱性化合物的药学上可接受的酸加成盐的酸是形成非毒性酸加成盐即含药理学可接受的阴离子的盐的那些,所述盐包括但不限于苹果酸盐,草酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,硝酸盐,硫酸盐,硫酸氢盐,磷酸盐,酸式磷酸盐,异烟酸盐,乙酸盐,乳酸盐,水杨酸盐,柠檬酸盐,酒石酸盐,油酸盐,单宁酸盐,泛酸盐,酒石酸氢盐,抗坏血酸盐,琥珀酸盐,马来酸盐,龙胆酸盐,富马酸盐,葡糖酸盐,葡萄糖醛酸盐,糖质酸盐,甲酸盐,苯甲酸盐,谷氨酸盐,甲磺酸盐,乙烷磺酸盐,苯磺酸盐,对-甲苯磺酸盐和双羟萘酸盐(即1.1'-亚甲基-二-(2-羟基-3-萘甲酸盐))。在本发明组合物中包括的酸性化合物能够与各种药理学可接受的阳离子形成碱盐。所述盐的实例包括碱金属或碱土金属盐,和特别是钙、镁、钠、锂、锌、钾和铁盐。在本发明组合物中包括的具有碱性或酸性部分的化合物还可以与各种氨基酸形成药学上可接受的盐。本发明化合物可以同时含有酸性和碱性基团;例如1个氨基和1个羧酸基团。在上述情况下,化合物能够作为酸加成盐、两性离子或碱盐存在。
用药学上可接受的溶剂比如水、乙醇等,本文公开的化合物能够以溶剂化形式以及未溶剂化形式存在,并且期望本公开包涵溶剂化形式和未溶剂化形式两者。在某些实施方式中,化合物是无定形的。在某些实施方式中,化合物是单一的多晶型物。在各种实施方式中,化合物是多晶型物的混合物。在特别的实施方式中,化合物是晶型。
术语"前药"如本文所用是指化合物,其在体内转化以产生所公开的化合物或该化合物的药学上可接受的盐、水合物或溶剂化物。转化可以通过各种机理(比如通过酯酶、酰胺酶、磷酸酶、氧化和或还原性代谢)发生在各种位置(比如肠腔中或通过肠、血液或肝)。前药是本领域熟知的(参见例如Rautio,Kumpulainen等人,Nature Reviews DrugDiscovery2008,7,255)。例如,如果本文描述的化合物或该化合物的药学上可接受的盐、水合物或溶剂化物含有羧酸官能团,前药能够是将羧酸基团氢原子替换为比如下述基团而形成的酯:(C1-C8)烷基、(C2-C12)烷酰基氧基甲基、具有4至9个碳原子的1-(烷酰基氧基)乙基,具有5至10个碳原子的1-甲基-1-(烷酰基氧基)-乙基,具有3至6个碳原子的烷氧羰基氧基甲基,具有4至7个碳原子的1-(烷氧羰基氧基)乙基,具有5至8个碳原子的1-甲基-1-(烷氧羰基氧基)乙基,具有3至9个碳原子的N-(烷氧羰基)氨基甲基,4至10个碳原子的1-(N-(烷氧羰基)氨基)乙基,3-邻羟甲基苯甲酸内酯基,4-巴豆酸内酯基,γ-丁内酯-4-基,二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(比如β-二甲基氨基乙基),氨基甲酰基-(C1-C2)烷基,N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基,哌啶子基-(C2-C3)烷基,吡咯烷子基-(C2-C3)烷基,或吗啉代-(C2-C3)烷基。
类似地,如果本文描述的化合物含有醇官能团,前药能够通过将醇基团氢原子替换为比如下述基团形成:(C1-C6)烷酰基氧基甲基,1-((C1-C6)烷酰基氧基)乙基,1-甲基-1-((C1-C6)烷酰基氧基)乙基(C1-C6)烷氧羰基氧基甲基,N-(C1-C6)烷氧羰基氨基甲基,琥珀酰基,(C1-C6)烷酰基,α-氨基(C1-C4)烷酰基,芳基酰基和α-氨基酰基,或α-氨基酰基-α-氨基酰基,其中各α-氨基酰基独立地选自天然L-氨基酸,P(O)(OH)2,-P(O)(O(C1-C6)烷基)2或糖基(除去碳水化合物半缩醛形式羟基得到的残基)。
如果本公开描述的化合物具有胺官能团,则前药能够形成如下:例如形成酰胺或氨基甲酸酯,N-酰基氧基烷基衍生物,(氧代二氧杂环戊烯基)甲基衍生物,N-曼尼希碱,亚胺或烯胺。此外,仲胺能够代谢裂解以产生生物学活性的伯胺,或者叔胺能够代谢裂解以产生生物学活性的伯胺或仲胺。参见例如Simplício等人,Molecules 2008,13,519及其参考文献。
除非另有定义,本文所用的全部技术和科学术语具有与本公开所涉领域普通技术人员一般理解相同的含义。
在说明书通篇当中,在组合物和试剂盒描述为具有、包括或包含特定组分或者过程和方法描述为具有、包括或包含特定步骤的情况下预期的是,额外存在本公开组合物和试剂盒,其基本上由所述组分组成或由所述组分组成,且存在根据本公开的过程和方法,其基本上由所述处理步骤组成或由所述处理步骤组成。
在本申请当中,在一个要素或组分据称包括在和/或选自所述的要素或组分列表当中的情况下,应理解的是该要素或组分能够是所述要素或组分中任一种,或者所述要素或组分能够选自由所述要素或组分中的两种或更多种组成的组。
此外,应理解本文描述的组合物或方法的要素和/或特征能够以各种形式组合而不背离本公开的主旨和范围,无论在本文中明确还是蕴含指出。例如,在提及具体化合物的情况下,该化合物能够用于本公开组合物的各种实施方式中和/或本公开方法中,除非从上下文另有理解。换言之,在本申请中,实施方式的描述和描绘方式使得撰写和描画清楚和简明的申请成为可能,但期望的是且将认识到的是实施方式能够进行各种组合或拆分而不背离本申请的教导和公开。例如,应认识到的是本文描述和描绘的全部特征能够应用于本文描述和描绘的公开的全部方面。
冠词"一个"和"一种"如本公开所用是指一个或多于一个(即至少一个)该冠词的语法目的,除非上下文不适用。举例来说,"一个要素"意指一个要素或多于一个要素。
术语"和/或"如本公开所用是指"和"或者"或",除非另有指定。
应理解的是,措辞"至少一个"包括在该措辞之后的每一个单独的所描述目标和所描述目标中两种或更多种的各种组合,除非从上下文和应用另有理解。针对三个或更多所描述目标的措辞"和/或"应理解为具有相同含义,除非从上下文另有理解。
术语"包括"、"包含"、"包涵"、"具有"、"拥有"、"涵盖"、"含有"、"涵有"或"蕴含"包括其语法等价物的使用应一般理解为开放式和非限制性的,例如不排除额外的未描述的要素或步骤,除非上下文另有特别描述或理解。
在术语"约"用于定量值前的情况下,本公开也包括特定的定量值本身,除非另有具体描述。如本文所用,术语"约"是指从标称值±10%的变化,除非另有指定或推断。
在关于组合物中组分或物质的量提供百分比的情况下,该百分比应理解为是基于重量的百分比,除非上下文另有说明或理解。
在提供例如聚合物的分子量而非绝对值的情况下,该分子量则应理解为是平均分子重量,除非上下文另有说明或理解。
应理解步骤顺序或进行某些动作的顺序是不重要的,只要本公开仍然可行。此外,两个或更多个步骤或动作能够同时进行。
在本说明书各处,取代基按组或按范围公开。特别期望的是,该描述包括所述组和范围的成员的各自每个单独子组合。例如,术语"C1-6烷基"特别期望单独地公开C1,C2,C3,C4,C5,C6,C1-C6,C1-C5,C1-C4,C1-C3,C1-C2,C2-C6,C2-C5,C2-C4,C2-C3,C3-C6,C3-C5,C3-C4,C4-C6,C4-C5和C5-C6烷基。另外比如说,范围0至40的整数特别期望单独地公开0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39和40,和范围1至20的整数特别期望单独地公开1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19和20。额外的例子包括,短语"任选用1-5个取代基取代"特别期望单独地公开能够包括0,1,2,3,4,5,0-5,0-4,0-3,0-2,0-1,1-5,1-4,1-3,1-2,2-5,2-4,2-3,3-5,3-4和4-5个取代基的化学基团。
本文使用任何各种实例或示范性语言,例如"比如"或"包括"仅期望更佳地说明本公开而并不是对本公开范围进行限制,除非是在权利要求书中。说明书中并无语言应解释为指出任何未要求保护的要素对实施本公开是必需的。
此外,如果变量并未定义,那么该变量的定义正如本公开其它部分的描述,除非上下文有不同理解。此外,各变量和/或取代基的定义例如C1-C6烷基、R2、Rb、w等在任何结构或化合物中出现多于一次的情况下,能够独立于其在相同结构或化合物中的其余定义。
本文式和/或化合物中变量和/或取代基的定义涵盖多个化学基团。本公开包括实施方式,其中例如i)变量和/或取代基的定义是选自本文描述的那些化学基团的单个化学基团,ii)定义是选自本文描述的那些的化学基团中两个或更多个的集合,和iii)化合物由变量和/或取代基的组合定义,其中变量和/或取代基通过(i)或(ii)定义。
出于清楚起见,本文所描述公开的各方面有标题和/或分为各部分;然而,应理解在一个特定部分描述的本公开的全部方面、实施方式或特征并不局限于该特定部分,而是能够适用于本公开的任何方面、实施方式或特征。
化合物
所公开的化合物包括具有下式的化合物:
或其立体异构体、N-氧化物和/或药学上可接受的盐,其中Rb选自氢,卤素,羟基,氰基和C1-C6烷基;R1选自氢,卤素和C1-C6烷基;而R2选自氢,卤素和C1-C烷基。
在某些实施方式中,R1是氢。在某些实施方式中,R1是C1-C6烷基,例如甲基(CH3)。
在某些实施方式中,R2是氢。在某些实施方式中,R2是C1-C6烷基,例如甲基(CH3)。
在某些实施方式(包括本文描述的任何实施方式)中,Rb是氢。在某些实施方式中,Rb是C1-C6烷基,例如甲基(CH3)。
在各种实施方式中,所公开的化合物具有下式:
或其立体异构体、N-氧化物和/或药学上可接受的盐。
在某些实施方式中,化合物选自实施例中刻划的化合物。
在某些实施方式中,所公开的化合物具有下式:
或其N-氧化物和/或药学上可接受的盐。
在某些实施方式中,所公开的化合物具有下式:
或其N-氧化物和/或药学上可接受的盐。
所公开的化合物可以提供在NMDA受体处打开的有效阳离子通道,例如可以结合或连接NMDA受体的谷氨酸位点以帮助阳离子通道打开。所公开的化合物可以通过充当激动剂用来调节(打开或关闭)NMDA受体。
在某些实施方式中,本文描述的化合物结合至特定的NMDA受体亚型。例如,所公开的化合物可以结合至一种NMDA亚型而非另一种。在某些实施方式中,所公开的化合物可以结合至一种、或多于一种NMDA亚型,和/或例如可以具有与某些其它NMDA亚型的实质上更少的结合活性(或实质无活性)。例如,在某些实施方式中,所公开的化合物(例如化合物A)结合至NR2A但实质上不结合至NR2D。在某些实施方式中,所公开的化合物(例如化合物B)结合至NR2B和NR2D但实质上更弱地结合至NR2A和NR2C。
如本文描述的化合物可以是甘氨酸位点NMDA受体部分激动剂。部分激动剂在该上下文中所用应理解为意指,在低浓度该类似物充当激动剂而在高浓度该类似物则充当拮抗剂。甘氨酸结合并不被谷氨酸抑制或被竞争性抑制剂谷氨酸抑制,并且在NMDA受体上并不结合于与谷氨酸相同的位点。NMDA受体上存在甘氨酸的第二和分开的结合位点。从而,NMDA受体的配体-门控离子通道受至少这两种不同的变构位点控制。所公开的化合物可以能够结合或连接NMDA受体的甘氨酸结合位点。在某些实施方式中,所公开的化合物可以具有的效能是现有NMDA受体甘氨酸位点部分激动剂的活性的10-倍或更高。
所公开的化合物可以展示高治疗指数。治疗指数如本文所用是指在50%群体中产生毒性的剂量(即TD50)与对50%群体的最小有效剂量(即ED50)的比率。从而,治疗指数=(TD50):(ED50)。在某些实施方式中,所公开的化合物可以具有的治疗指数是至少约10:1,至少约50:1,至少约100:1,至少约200:1,至少约500:1,或至少约1000:1。
组合物
在其它方面,提供配制剂和组合物,其包含所公开的化合物和任选的药学上可接受的赋形剂。在某些实施方式中,配制剂包括一种或多种所公开的化合物的外消旋混合物。
配制剂能够制备为任何各种形式使用。举例来说但不受限制,化合物能够制备于适于口服给药、皮下注射或其它方法的配制剂中,从而向可以有需要的患者给予活性剂,正如药物领域已知。例如,本公开药物组合物能够适于向眼递送。有关方法能够包括向有需要的患者例如向患者眼部给予药学有效量的所公开的化合物或包括所公开的化合物的药物组合物,其中给予能够局部、结膜下、肌腱下、玻璃体内、眼球后、眼球周、前房内和/或全身地进行。
如本文描述所公开的化合物在配制剂中的量可以根据因素比如个体疾病状态、年龄、性别和体重而变化。给药方案可以调节以提供最佳治疗反应。例如,可以给予单个药丸,可以随时间给予数个分开的剂量或可以按治疗情况的急迫性所需成比例地减少或增加剂量。特别有利的是配制剂量单元形式的肠胃外组合物,从而利于给药和剂量均匀性。剂量单元形式如本文所用是指物理上离散的单元,其适于用作待治疗的哺乳动物受试者的单元式剂量;各单元含有经计算以产生希望治疗效果的预先确定量的活性化合物以及需要的药物载体。
剂量单元形式的规格取决于和直接依赖(a)所选化合物的独特特征和待实现的特别治疗效果,和(b)本领域配制所述活性化合物以治疗个体敏感性的固有局限。
治疗组合物一般必须在制备和贮藏条件下无菌和稳定。组合物能够配制为溶液、微乳剂、脂质体或对高药物浓度适宜的其它有序结构。载体能够是溶剂或分散体介质,含有例如水,乙醇,多元醇(例如甘油、丙二醇和液体聚乙二醇等),及其适宜的混合物。合适的流动性能够如下保持:例如使用包衣比如卵磷脂,在分散体的情况下保持需要的颗粒尺寸和使用表面活性剂。在许多情况中,优选在组合物中包括等渗剂,例如糖类、多元醇比如甘露醇、山梨醇或氯化钠。可注射组合物的延长吸收能够如下引起:在组合物中包括延缓吸收的试剂例如单硬脂酸盐和明胶。
化合物能够在时间释放配制剂中给予,例如包括缓释聚合物的组合物。化合物能够用保护化合物防止快速释放的载体制备,比如受控释放配制剂,包括植入物和微囊化的递送系统。能够使用生物可降解、生物可相容的聚合物,比如乙烯乙酸乙烯酯,聚酐,聚乙醇酸,胶原,聚原酸酯,聚乳酸和聚乳酸,聚乙醇酸共聚物(PLG)。制备所述配制剂的许多方法是本领域技术人员一般已知的。
无菌可注射溶液能够制备如下:将化合物以需要量与上文列举的成分之一或组合按需要掺入适当溶剂中,随后过滤灭菌。一般来说,分散体制备如下:将活性化合物掺入无菌媒介物,其含有基础分散体介质和来自上文列举那些的所需的其它成分。在无菌粉末制备无菌可注射溶液的情况下,优选制备方法是真空干燥和冷冻干燥,其产生活性成分粉末和来自其预先无菌过滤的溶液的任何额外希望成分。
按照备择方面,化合物可以用增强该化合物溶解度的一种或多种额外化合物配制。
方法
提供用于在有需要的患者中治疗病症的方法,其是通过给予治疗有效量或剂量的本文描述的化合物。在某些实施方式中,病症能够是精神病症。比如说,能够治疗精神疾病。在又一方面,能够治疗神经系统病症。比如说,能够治疗影响中枢神经系统、周围神经系统和/或眼的病症。在某些实施方式中,能够治疗神经变性疾病。
在某些实施方式中,方法包括给予化合物以治疗罹患下述的患者:孤独症,焦虑,抑郁,双相情感障碍,注意涣散障碍,注意力缺陷伴多动障碍(ADHD),精神分裂症,精神障碍,精神病症状,回避社交,强迫性障碍(OCD),恐怖症,创伤后应激综合征,行为障碍,冲动控制障碍,物质滥用障碍(例如戒断症状、鸦片成瘾、尼古丁成瘾和乙醇成瘾),睡眠障碍,记忆障碍(例如不足、损失或降低的产生新记忆的能力),学习障碍,尿失禁,多系统萎缩症,进行性上核性麻痹,Friedrich共济失调,Down综合征,脆性X染色体综合征,结节性硬化,橄榄体脑桥小脑萎缩,大脑性瘫痪,药物诱导性视神经炎,缺血性视网膜病,糖尿病性视网膜病,青光眼,痴呆,AIDS痴呆,阿尔茨海默氏病,亨廷顿舞蹈病,痉挛状态,肌阵挛,肌肉痉挛,婴儿痉挛,Tourette综合征,癫痫,大脑缺血,卒中,脑肿瘤,外伤性脑损伤,心脏停搏,脊髓病,脊髓损伤,外周神经病,急性神经性疼痛,和慢性神经性疼痛。
在某些实施方式中,提供方法治疗与衰老有关的记忆障碍,精神分裂症,特殊学习障碍,癫痫发作,卒中后痉挛,脑缺血,低血糖症,心脏停搏,癫痫,Lewy体痴呆,偏头痛,AIDS痴呆,亨廷顿舞蹈病,帕金森病,早期阿尔茨海默氏病,和阿尔茨海默氏病。
在某些实施方式中,提供方法用于治疗精神分裂症。例如,妄想狂样型精神分裂症,错乱型精神分裂症(即青春期痴呆型精神分裂症),紧张型精神分裂症,未分型精神分裂症,残留型精神分裂症,精神分裂后抑郁,和简单型精神分裂症可以用本文描述的方法和组合物治疗。精神障碍比如情感性分裂症,妄想性障碍,短暂精神障碍,分享性精神障碍和具妄想或幻觉的精神障碍还可以用本文描述的组合物治疗。
偏执型精神分裂症可以表征为存在妄想或听觉幻觉,但是不存在思维障碍、错乱行为或情感冷淡。妄想可以是迫害性和/或夸大性的,但除了这些之外还可以存在其它情况比如嫉妒、笃信或躯体化。错乱型精神分裂症可以表征为思维障碍和情感冷淡同时存在。紧张型精神分裂症可以表征为患者可以几乎不运动或展示激动的、无目的的运动。症状能够包括紧张性木僵和蜡样屈曲。未分型精神分裂症可以表征为存在精神病症状但是并不符合妄想狂样、错乱或紧张型精神分裂症的标准。残留型精神分裂症可以表征为阳性症状仅以低强度存在。精神分裂后抑郁可以表征为在精神分裂性疾病后果中出现抑郁发作,其中仍可以存在某些低水平的精神分裂性症状。简单型精神分裂症可以表征为显著阴性症状的隐伏性和进行性发展,而无精神病发作病史。
在某些实施方式中,提供方法用于治疗可以存在于其它精神障碍中的精神病症状,包括但不限于双相情感障碍,边缘型人格障碍,药物中毒,和药物诱导性精神病。在某些实施方式中,提供方法用于治疗可以存在于例如妄想性障碍中的妄想(例如"非古怪")。
在各种实施方式中,提供方法用于治疗在包括但不限于社会焦虑障碍、回避型人格障碍和分裂型人格障碍的病症中的回避社交。
在某些实施方式中,本公开提供方法用于在有需要的患者中治疗涉及突触功能障碍的神经发育障碍,其中该方法一般包括向患者给予治疗有效量的所公开的化合物或包括所公开的化合物的药物组合物。在某些实施方式中,涉及突触功能障碍的神经发育障碍能够是Rett综合征也称为大脑萎缩性血氨过多,MECP2复制综合征(例如MECP2障碍),CDKL5综合征,脆性X染色体综合征(例如FMR1障碍),结节性硬化(例如TSC1障碍和/或TSC2障碍),神经纤维瘤病(例如NF1障碍),Angelman综合征(例如UBE3A障碍),PTEN错构瘤肿瘤综合征,Phelan-McDermid综合征(例如SHANK3障碍),或婴儿痉挛。在特别的实施方式中,神经发育障碍能够由神经连接素(例如NLGN3障碍和/或NLGN2障碍)和/或神经连接蛋白(例如NRXN1障碍)中的突变引起。
在某些实施方式中,提供方法用于治疗神经性疼痛。神经性疼痛可以是急性或慢性的。在某些情况下,神经性疼痛可以与比如下述病症有关:疱疹,HIV,创伤性神经伤害,卒中,缺血后,慢性背痛,疱疹后神经痛,纤维肌痛,反射交感性营养不良,复杂性局部疼痛综合征,脊髓损伤,坐骨神经痛,幻肢疼痛,糖尿病性神经病比如糖尿病性周围神经病变(DPN),和癌症化疗药物诱导性神经性疼痛。也提供方法增强疼痛缓解和向患者提供止痛。
在各种实施方式中,本公开方法包括在有需要的患者中治疗孤独症和/或孤独症谱系障碍的方法,包括向患者给药有效量的所公开的化合物。在某些实施方式中,提供方法在有需要的患者中减少孤独症症状,其中该方法包括向患者给予有效量的所公开的化合物。例如在给药之后,化合物可以降低孤独症的一种或多种症状的发生率,比如避免眼神接触,社会化失败,注意涣散,恶劣情绪,机能亢进,异常声音敏感性,说话不适当,干扰的睡眠和持续动作。所述降低的发生率可以相对未治疗的同一个体或未治疗的其它个体的发生率进行度量。
本文也提供方法调节细胞中的孤独症靶标基因表达,包括将细胞与有效量的本文描述的化合物接触。孤独症基因表达可以例如选自ABAT,APOE,CHRNA4,GABRA5,GFAP,GRIN2A,PDYN和PENK。在某些实施方式中,提供方法调节罹患突触可塑性相关障碍的患者中的突触可塑性,包括向患者给药有效量的化合物。
在某些实施方式中,提供方法在有需要的患者中治疗阿尔茨海默氏病或例如治疗例如伴随早期阿尔茨海默氏病的遗忘症,包括给药化合物。本文也提供方法体外或体内(例如在细胞中)调节阿尔茨海默氏淀粉样蛋白(例如β淀粉样蛋白肽,例如同种型Aβ1-42),包括将所述蛋白质与有效量的本公开化合物接触。例如,在某些实施方式中,化合物可以阻断所述淀粉样蛋白在海马脑片中抑制长时程增强以及凋亡性神经元细胞死亡的能力。在某些实施方式中,所公开的化合物能够为有需要的阿尔茨海默氏患者提供神经保护性特性,例如对晚期阿尔茨海默氏相关的神经元细胞死亡的治疗效果。
在某些实施方式中,所公开的方法包括治疗由另一病症比如卒中、肌萎缩性侧索硬化(ALS或Lou Gehrig病)、多发性硬化、外伤性脑损伤、阿尔茨海默氏病、痴呆和/或帕金森病诱导的假延髓病性影响("PBA")或精神病。所述方法与本公开的其它方法一样包括向有需要的患者给药药学有效量的所公开的化合物。
在各种实施方式中,提供治疗抑郁的方法,包括给药本文描述的化合物。在某些实施方式中,治疗可以缓解抑郁或抑郁症状而不影响行为或肢体协调和不诱导或促进癫痫发作活性。根据该方面期望治疗的示范性抑郁病症包括但不限于严重抑郁障碍,情绪恶劣性精神障碍,精神病性抑郁,产后抑郁症,经前期综合征,经前情绪障碍,季节性情感障碍(SAD),双相情感障碍(或躁狂性抑郁障碍),情感障碍,和由慢性医学病症比如癌症或慢性痛、化学疗法、慢性应激和创伤后应激障碍引起的抑郁症。此外,罹患任何形式抑郁的患者常常体验焦虑。与焦虑有关的各种症状包括恐惧,惊慌,心悸,呼吸浅促,疲劳,恶心和头痛等。焦虑或其任何症状可以通过给予如本文描述的化合物治疗。
本文也提供方法在对治疗有抗性的患者中治疗病症,所述患者是例如罹患精神或中枢神经系统病症的患者,其并未和/或仍未响应至少一种或至少两种其它化合物或治疗剂的充分疗程。例如,本文提供方法在治疗抗性患者中治疗抑郁,包含a)任选鉴定治疗抗性的患者和b)向所述患者给予有效剂量的化合物。
在某些实施方式中,本文描述的化合物可以用于患者的急性护理。例如,能够向患者给予化合物以治疗本文描述的病症的特别发作(例如严重发作)。
本文也包括组合治疗,其包含所公开的化合物和与之组合的一种或多种其它活性剂。例如,所公开的化合物可以与一种或多种抗抑郁药比如三环抗抑郁药,MAO-I's,SSRI's,和双重和三重摄取抑制剂和/或抗焦虑药相组合。可以与化合物组合使用的示范性药物包括安拿芬尼,Adapin,多虑平,Elavil,盐酸地昔帕明,派莫乐,盐酸地昔帕明,多虑平,三甲丙咪嗪,丙咪嗪,盐酸普鲁替林,Parnate,Nardil,异唑肼,依他普仑,Luvox,Paxil,Prozac,Zoloft,Wellbutrin,郁复伸,瑞美隆,欣百达,曲拉唑酮(曲唑酮),和路滴美。在其它实例中,化合物可以与抗精神病药组合。抗精神病药的非限制性实例包括丁酰苯类,吩噻嗪,噻吨,氯氮平,奥氮平,利培酮,喹硫平,齐拉西酮,氨磺必利,阿塞那平,帕利哌酮,伊潘立酮,佐替平,舍吲哚,鲁拉西酮,和阿立哌唑。应理解化合物和一种或多种上述治疗剂的组合可以用于治疗任何适宜病症和并不局限于用作抗抑郁药或抗精神病药。
实施例
下述实施例仅出于示例性意图提供,而并不期望限制本公开的范围。
本文可以使用下述缩写和具有所指出的定义:Ac是乙酰基(-C(O)CH3),AIDS是获得性免疫缺陷综合征,Boc和BOC是叔丁氧基羰基,Boc2O是二碳酸二叔丁酯,Bn是苄基,BOM-Cl是苄氧基甲烷氯化物,CAN是硝酸铈铵,Cbz是羧基苄基,DCM是二氯甲烷,DIAD是偶氮二羧酸二异丙基酯,DIPEA是N,N-二异丙基乙胺,DMAP是4-二甲基氨基吡啶,DMF是N,N-二甲基甲酰胺,DMSO是二甲亚砜,EDC和EDCI是1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐,ESI是电喷雾离子化,EtOAc是乙酸乙酯,Gly是甘氨酸,h是小时,HATU是2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐,HIV是人类免疫缺陷病毒,HOBt是羟基苯并三唑,HPLC是高效液相色谱,LCMS是液相色谱/质谱,LDA是二异丙基氨基锂,LiHMDS是六甲基二硅氮烷化锂,MTBE是甲基叔丁基醚,NMDAR是N-甲基-d-天冬氨酸受体,NMP是N-甲基-2-吡咯烷酮,NMR是核磁共振,Pd/C是钯/碳,PMB是对-甲氧基苄基,RT是室温(例如约20℃至约25℃),TBS和TBDMS是叔丁基二甲基甲硅烷基,TEA是三乙胺,TLC是薄层色谱法,TFA是三氟乙酸,THF是四氢呋喃,TMS是三甲基甲硅烷基,TMSCN是三甲基甲硅烷基氰化物,和TPP是三苯基膦。
实施例1-合成化合物A和化合物A马来酸盐
合成(3R,7aS)-3-(三氯甲基)四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(1):
在RT向L-脯氨酸(2.0kg,0.017mol)的氯仿(50L)悬浮液加入水合氯醛(5.7kg,0.034mol)。在反向Dean-Stark装置中将反应混合物加热至60℃和收集获得的水。在16小时之后,减压蒸发挥发物。粗制固体用冷乙醇洗涤,过滤和干燥,提供化合物1(2.2kg,57%),是白色固体。1H-NMR:(500MHz,DMSO-d6):δ5.82(s,1H),4.11-4.08(m,1H),3.33-3.27(m,2H),3.19-3.14(m,1H),2.15-2.10(m,1H),1.96-1.91(m,1H),1.80-1.74(m,1H),1.65-1.58(m,1H)。
合成(3R,7aR)-7a-((苄氧基)甲基)-3-(三氯甲基)四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(2):
在-78℃在氮气氛下向二异丙胺(221.2mL,1.533mol)的THF(870mL)溶液滴加正-BuLi(1.6M,在己烷中)(958.5mL,1.533mol)。在加入完成之后,将反应混合物的温度提高至-20℃和搅拌1小时。再次冷却至-78℃,加入THF(1L)中的化合物1(250g,1.022mol)和搅拌30分钟。然后滴加苄基氯甲基醚(208mL,1.329mol)和继续搅拌1小时。在原料消耗之后(TLC监测),反应混合物用冰冷水淬灭(100mL)和用Et2O萃取(2x 100mL)。合并的有机层用盐水洗涤(100mL),在无水Na2SO4上干燥和减压浓缩,获得粗制化合物,将其通过柱色谱法纯化用10%EtOAc/正-己烷洗脱,获得化合物2(220g,粗制),是褐色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ7.42-7.26(m,5H),5.60(s,1H),4.59-4.53(d,2H),3.67-3.61(m,2H),3.37-3.33(m,1H),3.31-3.10(m,1H),2.12-1.99(m,2H),1.87-1.75(m,2H);LCMS(ESI):m/z363.9[M++1]。
合成(R)-2-((苄氧基)甲基)吡咯烷-2-羧酸甲酯盐酸盐(3):
在RT向化合物2(400g,1.096mol)的甲醇(1L)溶液加入2N HCl/MeOH(1.64L,3.29mol)和在80℃搅拌16小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粗制品用己烷洗涤(3x750mL)和减压干燥,提供化合物3(358g,粗制),是红色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ10.40(br s,1H),7.40-7.21(m,5H),4.64-4.50(d,2H),4.49-4.3(d,2H),3.76(s,3H),3.33-3.22(m,2H),2.22-2.15(s,1H),2.02-1.9(m,2H),1.95-1.83(m,1H)。
合成(R)-2-((苄氧基)甲基)吡咯烷-1,2-二羧酸1-(叔丁基)2-甲基酯(4):
在0℃在氮气氛下向搅拌的化合物3(313g,粗制1.096mol)的DCM(2.19L)悬浮液滴加Et3N(458.4mL,3.288mol)和搅拌10分钟。然后在0℃滴加Boc酸酐(358.4g,1.644mol)。反应混合物达到RT和搅拌16小时。在原料消耗之后(TLC监测),反应用水稀释(2x1L)和用CH2Cl2萃取(2x 500mL)。经合并的有机层用10%柠檬酸(pH~7)和盐水溶液(1L)洗涤。有机层在Na2SO4上干燥和减压浓缩,提供粗制化合物,将其通过柱色谱法纯化用20%EtOAc/正-己烷洗脱,获得化合物4(215g,56%),是无色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ7.37-7.26(m,5H),4.56-4.48(m,2H),4.03-3.87(dd,1H),3.69-3.67(d,1H),3.62(s,3H),3.53-3.47(m,1H),3.33-3.30(m,1H),2.27-2.20(m,1H),2.03-1.89(m,2H),1.88-1.79(m,1H),1.46-1.24(2s,9H);LCMS(ESI):m/z 250.1[(M++1)-Boc]。
合成(R)-2-((苄氧基)甲基)-1-(叔丁氧基羰基)吡咯烷-2-羧酸(5):
向化合物4(215g,0.616mol)的MeOH:THF:H2O(3L,5:5:3)溶液加入NaOH(73.9g,1.848mol)和在RT搅拌10分钟。反应混合物加热至80℃和搅拌16小时。在原料消耗之后(TLC监测),反应混合物达到RT,蒸发挥发物。粗制物质用水稀释(1L)和用Et2O萃取(2x 500mL)。分开的水层用2N HCl溶液酸化(pH~3)和用DCM萃取(2x 750mL)。合并的有机层用盐水溶液洗涤,在Na2SO4上干燥和浓缩,提供化合物5(170g,82.4%),是米白色固体。1H-NMR:(500MHz,DMSO-d6):δ12.66(br s,1H),7.36-7.26(m,5H),4.54-4.47(m,2H),4.05-3.90(dd,1H),3.88-3.63(d,1H),3.63-3.44(m,1H),3.34-3.27(m,1H),2.27-2.01(m,1H),2.02-1.8(m,2H),1.79-1.76(m,1H),1.17-1.14(2s,9H);LCMS(ESI):m/z 235.1[(M++1)-Boc]。
合成(R)-1-(叔丁氧基羰基)-2-(羟基甲基)吡咯烷-2-羧酸(6):
在RT向搅拌的化合物5(170g,0.507mol)的CH3OH(1L)溶液加入50%润湿的10%Pd-C(68g)和在H2气氛下搅拌16小时。在原料消耗之后(TLC监测),反应混合物过滤通过C盐垫和垫用CH3OH洗涤(1L)。获得的滤液减压浓缩,提供化合物6(110g,88%),是白色固体。1H-NMR:(400MHz,DMSO-d6):δ12.66(br s,1H),3.96-3.83(dd,1H),3.63-3.60(m,1H),3.49-3.46(m,1H),3.34-3.25(m,2H),2.30-2.15(m,1H),1.95-1.72(m,3H),1.38-1.33(2s,9H);LCMS(ESI):m/z 244[M+-1];手性HPLC:95.88%。
合成(R)-2-(((2S,3R)-1,3-二(苄氧基)-1-氧代丁烷-2-基)氨基甲酰基)-2-(羟基甲基)吡咯烷-1-羧酸叔丁酯(7):
在N2气氛下向冷却至0℃的搅拌的化合物6(110g,0.448mol)的DCM(20mL)溶液加入二异丙基乙胺(206mL,1.12mol),中间体D1(150g,0.448mol)和HATU(204g,0.537mol)。反应混合物达到RT和搅拌4小时。在原料消耗之后(TLC监测),反应混合物用DCM稀释(1L)和用水(2x500mL)、10%柠檬酸溶液(500mL)和盐水溶液(500mL)洗涤。有机层在无水Na2SO4上干燥和减压浓缩,提供粗制化合物,将其通过柱色谱法纯化用30%EtOAc/正-己烷洗脱,获得化合物7(143g,60%),是无色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ8.20-8.12(d,1H),7.29-7.18(m,10H),5.83-5.59(m,1H),5.08(s,2H),4.50-4.44(m,2H),4.30-4.26(m,1H),4.08-4.00(m,2H),3.42-3.40(m,2H),3.39-3.29(m,1H),2.19-2.08(m,1H),1.96-1.87(m,1H),1.68-1.63(m,2H),1.23-1.15(2s,9H),1.14-1.13(d,3H);LCMS(m/z):525.2[M+-1];HPLC:76.2%;手性HPLC:69.47%。
合成(R)-2-((2S,3R)-1,3-二(苄氧基)-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(8):
在RT在氮气氛下向三苯基膦(161.4g,0.612mol)的THF(430mL)溶液滴加DIAD(123.8g,0.612mol)和搅拌15分钟。向其滴加化合物7(215g,0.408mol)的THF(860mL)溶液,RT搅拌4小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粗制物质通过硅胶柱色谱法纯化用20%EtOAc/己烷洗脱,提供化合物8(180g,与副产品DIAD的混合物),是黄色浆液。1H-NMR:(400MHz,DMSO-d6):δ7.31-7.18(m,10H),5.18-5.10(m,2H),4.61-4.54(m,2H),4.27-4.18(m,2H),3.78-3.77(d,1H),3.45-3.43(d,1H),3.35-3.31(d,1H),3.27-3.23(m,1H),2.03-1.98(m,2H),1.78-1.76(m,2H),1.39-1.31(2s,9H),1.23-1.22(d,3H)(DIAD副产品峰未捕获);LCMS(ESI):m/z 509.4[M++1]。
合成(2S,3R)-2-((R)-5-(叔丁氧基羰基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)-3-羟基丁酸(9):
在N2气氛下将化合物8(85g,0.167mol)的甲醇(850mL)溶液脱气。然后在RT加入50%润湿的10%Pd-C(40g)和在H2气氛下搅拌24小时。在原料消耗之后(TLC监测),反应混合物过滤通过C盐垫和减压浓缩滤液。获得的粗制固体用Et2O稀释(1L)和在RT激烈搅拌1小时。将获得的固体物质滤出和干燥,提供化合物9(75g,68%),是白色固体。1H-NMR:(400MHz,DMSO-d6):δ12.86(br s,1H),5.24(br s 1H),4.06-4.00(m,2H),3.88-3.82(m,1H),3.51-3.50(m,1H),3.43-3.34(m,1H),3.31-3.23(m,1H),2.15-2.09(m,2H),1.82-1.78(m,2H),1.39-1.31(2s,9H),1.10-1.08(d,3H);LCMS(m/z):329.1[M++1];HPLC:93.97%。
合成(R)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(A4):
于0℃在氮气氛下向搅拌的化合物9(150g,0.457mol)的CH2Cl2(2L)溶液加入二异丙基乙胺(176.85g,1.37mol),NH4Cl(48.8g,0.914mol)和HATU(208.3g 0.548mol)。反应混合物达到RT和搅拌12小时。在原料消耗之后(TLC监测),反应混合物用水稀释(2x750mL)和用CH2Cl2萃取(2x 1L)。合并的有机层用2N HCl溶液和饱和氯化钠溶液(750mL)洗涤。有机层在无水Na2SO4上干燥和减压浓缩。粗制化合物通过柱色谱法纯化,纯化合物用3%MeOH/CH2Cl2洗脱。获得的物质用DCM稀释(2L)和用饱和柠檬酸洗涤(5x 500mL),饱和碳酸氢盐洗涤、随后盐水洗涤和在Na2SO4上干燥。物质与乙醚研磨(2x 500mL),提供化合物A4(80g,53%),是白色固体。1H-NMR:(400MHz,D2O):δ4.36-4.21(m,2H),4.03-3.98(m,1H),3.76-3.67(m,1H),3.56-.3.37(m,2H),2.32-2.23(m,2H),1.97-1.93(m,2H),1.49-1.47(2s,9H),1.33-1.32(d,3H);LCMS(ESI):m/z 328.3[M++1];HPLC:99.30%;手性HPLC:98.97%;SOR(c=1,CH3OH):-11.08。
合成(2S,3R)-3-羟基-2-((R)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(10):
在0℃在氮气氛下向搅拌的化合物A4(10g,0.030mol)的CH2Cl2(50mL)溶液加入TFA(24mL,0.3058mol)。反应混合物达到RT和搅拌4小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粘稠浆液物质用醚(2x 100mL)和己烷(1x 100mL)洗涤,减压干燥,提供化合物10(3.5g,TFA盐),是粘稠浆液,将其用于后续步骤。粗制RM不加纯化地原样使用。LCMS(ESI):m/z 228.1[M++1]。
合成(2S,3R)-3-羟基-2-((R)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(化合物A):
在RT在氮气氛下向搅拌的化合物10(10g,TFA盐,0.028mol)的甲醇(50mL)溶液加入异丁醛(10mL,0.115mmol)随后AcOH(12mL)和搅拌10分钟。然后,分批加入NaCNBH3(7.2g,11.5mmol)和继续搅拌16小时。在原料消耗之后(TLC监测),反应混合物用CH2Cl2稀释(10mL)和减压浓缩。用5g批料进行相似反应。将两个批次合并,获得的粗制物质通过硅胶柱色谱法纯化用4%MeOH/DCM洗脱,提供(2S,3R)-3-羟基-2-((R)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺的混合物。获得的混合物再进行柱色谱,纯化合物在100%乙酸乙酯中洗脱,提供(2S,3R)-3-羟基-2-((R)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(8g),是粘稠浆液。1H-NMR:(500MHz,CD3OD):δ4.16-4.12(m,1H),4.09(d,J=7.0Hz,1H),3.60(d,J=6.0Hz,1H),3.54(d,J=6.0Hz,1H),2.97-2.93(m,1H),2.75(q,J=8.0Hz,1H),2.47-2.45(m,2H),2.22-2.18(m,1H),2.16-2.10(m,1H),1.92-1.83(m,2H),1.76-1.73(m,1H),1.24(d,J=6.0Hz,3H),0.92-0.89(m,6H);LCMS(ESI):m/z 284.1[M++1];HPLC:97.65%;手性HPLC:98.25%;SOR(c=1,CH3OH):1.6。
合成(4R)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-鎓(Z)-3-羧基丙烯酸盐(化合物A马来酸盐):
在室温下向(2S,3R)-3-羟基-2-((R)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(400mg,1.41mmol)的H2O(4mL)溶液加入马来酸(148mg,1.27mmol)和搅拌16小时。在原料消耗之后(TLC监测),减压除水。获得的粗制物质与戊烷和己烷研磨,减压干燥,提供(4R)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-鎓(Z)-3-羧基丙烯酸盐(530mg,94%),是白色固体。1H NMR(500MHz,CD3OD)δ6.29(s,2H),4.21-4.12(m,2H),3.91-3.85(m,1H),3.83-3.79(m,1H),3.61-3.51(m,1H),3.29-3.19(m,1H),3.04(dd,J=9.0,12.5Hz,1H),2.90(dd,J=5.8,12.2Hz,1H),2.52-2.43(m,1H),2.40-2.31(m,1H),2.25-1.97(m,3H),1.28(d,J=5.8Hz,3H),1.04(dd,J=6.4,9.9Hz,6H);LCMS(ESI):m/z 284.3[M++1-马来酸];HPLC:96.83%;熔点:113.4℃-117.5℃。
制备Int-D:
合成(叔丁氧基羰基)-L-苏氨酸(A1):
在RT向SM-2(50g,0.420mol)的1,4-二噁烷:水(500mL,1:1)溶液滴加NaHCO3(133g,1.255mol)和搅拌15分钟。然后将Boc-酸酐(144mL,0.629mol)滴加至反应混合物和在RT继续搅拌16小时。在原料消耗之后(TLC监测),减压浓缩反应混合物,获得的残余物用水稀释(200mL)和用1N HCl酸化(pH~2)。水层用EtOAc萃取(2x 300mL)。经合并的有机层用盐水洗涤(1x 200mL),在无水Na2SO4上干燥,过滤和减压浓缩,提供A1(80g,87%),是无色浆液。1H-NMR:(500MHz,DMSO-d6):δ12.5(br s,1H),6.30(d,J=8.5Hz,1H),4.50(br s,1H),4.05-4.02(m,1H),3.88-3.86(m,1H),1.39(s,9H),1.08(d,J=6.0Hz,3H);
LCMS(m/z):218.1[M+-1]
合成O-苄基-N-(叔丁氧基羰基)-L-苏氨酸(B1):
在-20℃在N2气氛下向搅拌的化合物A1(80g,0.365mol)的DMF(800mL)溶液滴加60%NaH(22g,0.913mol)和搅拌2小时。向其滴加苄基溴(52mL,0.438mol)和在0℃搅拌反应混合物4小时。在原料消耗之后(TLC监测),反应混合物用冰冷水淬灭和用二乙醚萃取(2x500mL)。含水层用1N HCl酸化(pH~2)。水层用EtOAc萃取(2x 1L)。分开的有机层用盐水溶液洗涤,在无水Na2SO4上干燥和减压浓缩,提供化合物B1(84g,粗制),是粘稠浆液。
1H-NMR:(500MHz,DMSO-d6):δ12.64(br s,1H),7.34-7.25(m,5H),6.46(d,J=8.5Hz,1H),4.53(d,J=11.5Hz,1H),4.39(d,J=12.0Hz,1H),4.00-3.98(m,2H),1.39(s,9H),1.15(d,J=6.0Hz,3H)。
合成O-苄基-N-(叔丁氧基羰基)-L-苏氨酸苄酯(C1):
在RT在N2气氛下向搅拌的化合物B1(78g,0.252mol)的DMF(780mL)溶液加入K2CO3(87g,0.631mol)和搅拌30分钟。在RT向其滴加苄基溴(45mL,0.378mol)和搅拌16小时。反应混合物用水淬灭(2L)和用二乙醚萃取(2x 1L)。分开的有机层用盐水洗涤,在无水Na2SO4上干燥和减压浓缩。粗制物质通过硅胶柱色谱法纯化用10%EtOAc/正-己烷洗脱,提供化合物C1(68g,68%),是黄色浆液。1H-NMR:(500MHz,DMSO-d6):δ7.37-7.18(m,10H),6.81(d,J=9.0Hz,1H),5.08(s,2H),4.49(d,J=12.0Hz,1H),4.32(d,J=12.0Hz,1H),4.25-4.22(m,1H),4.01-3.98(m,1H),1.38(s,9H),1.15(d,J=6.0Hz,3H);质量(ESI):m/z 399.4[M+]。
合成O-苄基-L-苏氨酸苄酯盐酸盐(D1):
向化合物C1(68g,0.170mol)的二乙醚(500mL)溶液加入4N HCl/1,4-二噁烷(130mL,0.511mol)和在RT搅拌16小时。在原料消耗之后(TLC监测),减压浓缩反应混合物。粗制物质溶于二乙醚(1L)和在RT激烈搅拌1h。将获得的固体滤出和减压干燥,提供化合物D1(50g,87%),是白色固体(HCl盐)。1H-NMR:(400MHz,DMSO-d6):δ8.59(s,2H),7.50-7.25(m,10H),5.23(d,J=12.5Hz,1H),5.16(d,J=12.5Hz,1H),4.54(d,J=12.0Hz,1H),4.36(d,J=12.0Hz,1H),4.12-4.09(m,1H),4.09-3.99(m,1H),1.29(d,J=6.5Hz,3H);质量(ESI):m/z 336.4[M++1]。
实施例2-合成化合物B和化合物B马来酸盐
合成(3S,7aR)-3-(三氯甲基)四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(1):
在RT向D-脯氨酸(3kg,26.057mol)的氯仿(60L)悬浮液加入水合氯醛(8.62kg,52.115mol)。反应混合物在反向Dean-Stark装置中加热至80℃和收集获得的水。在搅拌24小时之后,将反应混合物冷却至室温和加入盐水溶液(25L)。反应混合物搅拌30分钟和沉降30分钟。分开的有机层在Na2SO4上干燥和减压浓缩,减压蒸发挥发物。获得的粗制固体与冷乙醇(5L)制浆液,过滤和干燥,提供化合物1(4.7kg,74%),是米白色固体。1H-NMR:(500MHz,DMSO-d6):δ5.82(s,1H),4.11-4.09(m,1H),3.33-3.28(m,1H),3.19-3.14(m,1H),2.17-2.10(m,1H),1.97-1.91(m,1H),1.80-1.74(m,1H),1.65-1.58(m,1H)。
合成(3S,7aS)-7a-((苄氧基)甲基)-3-(三氯甲基)四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(2):
在-78℃在氮气氛下向二异丙胺(442mL,3.067mol)的THF(1L)溶液滴加正-BuLi(1.6M,在己烷中)(1.91L,3.067mol)。在加入完成之后,将反应混合物的温度提高至-20℃和搅拌45分钟。再次冷却至-78℃,滴加THF(2L)中的化合物1(500g,2.044mol)和搅拌45分钟。然后滴加苄基氯甲基醚(425mL,3.067mol)和继续搅拌2小时。在原料消耗之后(TLC监测),反应混合物用冰冷水淬灭(2L)和用Et2O萃取(2x 1L)。合并的有机层用盐水洗涤(3L),在Na2SO4上干燥和减压浓缩,提供粗制化合物,将其通过柱色谱法纯化用10%EtOAc/正-己烷洗脱,获得化合物2(425g,57%),是黄色液体。1H-NMR:(500MHz,DMSO-d6):δ7.35-7.26(m,5H),5.60(s,1H),4.59-4.53(d,2H),3.67-3.62(m,2H),3.71-3.31(m,1H),3.16-3.11(m,1H),2.12-1.99(m,2H),1.86-1.72(m,2H);LCMS(ESI):m/z 363.8[M+-1]。
合成(S)-2-((苄氧基)甲基)吡咯烷-2-羧酸甲酯盐酸盐(3):
在RT向化合物2(1kg,2.742mol)的甲醇(2L)溶液加入2N HCl/甲醇(4.1L,8.227mol)和搅拌30分钟。在60℃搅拌反应混合物16小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粗制糖浆用DM水稀释(3L)和用EtOAc洗涤(2x1L)。含水层pH(8-9)用NaHCO3溶液调节。含水层用5%MeOH/DCM萃取(2x2L)。合并的有机层用盐水溶液洗涤,在Na2SO4上干燥和减压浓缩,提供化合物3(600g,88%),是褐色浆液。重复又一1kg批次和获得600g的化合物3。1H-NMR:(500MHz,DMSO-d6):δ10.54(br s,1H),9.44(br s,1H),7.40-7.30(m,5H),4.68-4.62(d,1H),4.51-4.46(d,1H),4.00-3.90(m,2H),3.76(s,3H),3.33-3.16(m,2H),2.20-2.14(s,1H),2.01-1.85(m,3H)。
合成(S)-2-((苄氧基)甲基)吡咯烷-1,2-二羧酸1-(叔丁基)2-甲基酯(4):
在0℃在氮气氛下向搅拌的化合物3(1.2kg,4.819mol)的DCM(6L)悬浮液滴加Et3N(1.35L,9.638mol)和搅拌20分钟。然后在0℃滴加Boc-酸酐(1.65L,7.228mol)。反应混合物达到RT和搅拌8小时。在原料消耗之后(TLC监测),反应用DM水稀释(3L)和用DCM萃取(2L)。合并的有机层用10%柠檬酸(2L)溶液和盐水溶液(2L)洗涤。有机层在Na2SO4上干燥和减压浓缩,提供化合物4(2kg,粗制),是褐色浆液。1H-NMR:(500MHz,DMSO-d6):δ7.37-7.28(m,5H),4.57-4.50(m,2H),4.03-3.88(dd,1H),3.71-3.69(d,1H),3.63(s,3H),3.52-3.47(m,1H),3.36-3.31(m,1H),2.32-2.23(m,1H),2.05-1.88(m,2H),1.82-1.77(m,1H),1.38-1.26(s,9H);LCMS(ESI):m/z 350.2[(M++1)]。
合成(S)-2-((苄氧基)甲基)-1-(叔丁氧基羰基)吡咯烷-2-羧酸(5):
在RT向化合物4(1kg,2.865mol)的MeOH:THF(3L,1:1)溶液加入NaOH(343.84g,8.595mol)/H2O(1.5L),在70℃搅拌6小时。在原料消耗之后(TLC监测),反应混合物达到RT,减压蒸发挥发物。粗制物质用水稀释(5L)和用EtOAc萃取(2x 2L)。分开的水层用6N HCl溶液酸化(pH~2)和用DCM萃取(3x 2L)。合并的有机层用盐水溶液洗涤,在Na2SO4上干燥和浓缩,提供化合物5(550g,58%),是褐色浆液。重复又一1kg批次和获得550g的化合物5。1H-NMR:(500MHz,DMSO-d6):δ12.68(br s,1H),7.36-7.28(m,5H),4.56-4.49(m,2H),4.07-3.90(dd,1H),3.66-3.64(d,1H),3.50-3.44(m,1H),2.29-2.20(m,1H),2.03-1.75(m,3H),1.39-1.28(2s,9H)。LCMS(ESI):m/z 236.0[M++1-Boc];HPLC:76.79%;手性HPLC:96.26%
合成(S)-1-(叔丁氧基羰基)-2-(羟基甲基)吡咯烷-2-羧酸(6):
在RT向搅拌的化合物5(1.1kg,32.835mol)的甲醇(10L)溶液加入50%润湿的10%Pd-C(500g)和在H2气氛下(3kg)搅拌8小时。在原料消耗之后(TLC监测),反应混合物过滤通过C盐垫,垫用甲醇洗涤(50mL)。获得的滤液减压浓缩,获得粗制,将其与Et2O研磨,提供化合物6(650g,81%),是米白色固体。1H-NMR:(500MHz,DMSO-d6):δ3.92-3.80(dd,1H),3.64-3.61(m,1H),3.49-3.34(m,1H),3.32-3.26(m,1H),2.29-2.16(m,1H),1.95-1.71(m,3H),1.38-1.33(s,9H);LCMS(ESI):m/z 243.8[M+-1]。
合成(S)-2-(((2S,3R)-1,3-二(苄氧基)-1-氧代丁烷-2-基)氨基甲酰基)-2-(羟基甲基)吡咯烷-1-羧酸叔丁酯(7):
在0-5℃在氮气氛下向化合物6(450g,0.836mol)的DCM(4.5L)溶液加入N,N-二异丙基乙胺(846mL,4.591mol)。在搅拌10分钟之后,加入中间体D1(615g,1.836mol)。在搅拌10分钟之后,加入HATU(701g,2.204mol)。反应混合物达到RT和搅拌6小时。在原料消耗之后(TLC监测),反应混合物用DCM稀释(1L)和用水(2x2L)、10%柠檬酸溶液(2L)和盐水溶液(2L)洗涤。有机层在无水Na2SO4上干燥和减压浓缩,提供粗制化合物,将其通过柱色谱法纯化用40%EtOAc/正-己烷洗脱,获得化合物7,将其溶于Et2O(1.5L)和搅拌1h。获得的沉淀过滤和减压干燥,提供化合物7(630g,65%),是白色固体。1H-NMR:(400MHz,DMSO-d6):δ7.91-7.89(d,0.5H),7.53-7.51(d,0.5H),7.32-7.19(m,10H),5.64(br s,1H),5.16-5.04(m,2H),4.62-4.49(m,2H),4.31-4.28(m,1H),4.09-4.02(m,1.5H),3.87(br s,1H),3.57-3.56(m,0.5H),3.43-3.37(m,1H),3.29-3.25(m,1H),2.32-2.14(m,1H),1.98-1.90(m,1H),1.75-1.69(m,2H),1.33-1.26(2s,9H),1.14-1.12(d,3H);LCMS(m/z):527.6[M++1];HPLC:96.60%。
合成(S)-2-((2S,3R)-1,3-二(苄氧基)-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(8):
在RT在氮气氛下向三苯基膦(295g,1.125mol)的THF(846mL)溶液滴加DIAD(227g,1.125mol)和搅拌30分钟。反应混合物冷却至15℃,滴加化合物7(423g,0.804mol)的THF(1.2L)溶液和在RT搅拌4小时。获得的粗制物质用己烷洗涤,随后与50%Et2O/己烷搅拌30分钟。滤出形成的沉淀和减压浓缩滤液。获得的粗制品通过硅胶柱色谱法纯化用40%EtOAc/己烷洗脱,提供化合物8(425g,粗制),是褐色浆液。1H-NMR:(400MHz,DMSO-d6):δ7.38-7.21(m,10H),5.17-5.10(m,2H),4.56-4.50(m,2H),4.31-4.28(d,1H),4.06-3.99(m,2H),3.89-3.88(d,0.5H),3.48-3.47(d,0.5H),3.36-3.34(m,1H),3.25-3.19(m,1H),2.10-2.02(m,2H),1.79-1.77(m,2H),1.40-1.25(s,9H),1.15-1.12(d,3H)。LCMS(ESI):m/z509.4[M++1];HPLC:92.31%;手性HPLC:86.47%。
合成(2S,3R)-2-((S)-5-(叔丁氧基羰基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)-3-羟基丁酸(9):
在N2气氛下将化合物8(283g,0.557mol)的甲醇(1.2L)溶液脱气。然后在RT加入50%润湿的10%Pd-C(140g)和在H2气氛下搅拌24小时。在原料消耗之后(TLC监测),反应混合物过滤通过C盐垫和减压浓缩滤液。获得的粗制固体用Et2O稀释(500mL)和在0℃激烈搅拌1小时。滤出获得的固体物质和干燥,提供化合物9(140g,76%),是白色固体。1H-NMR:(500MHz,DMSO-d6):δ12.86(br s,1H),5.24(br s 1H),4.06-4.00(m,2H),3.88-3.82(m,1H),3.51-3.50(m,1H),3.43-3.34(m,1H),3.31-3.23(m,1H),2.15-2.09(m,2H),1.82-1.78(m,2H),1.39-1.31(2s,9H),1.10-1.08(d,3H);LCMS(m/z):327.1[M+-1];HPLC:95.44%;手性HPLC:100.00%。
合成(S)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(B4):
在0℃在氮气氛下向搅拌的化合物9(420g,1.28mol)的CH2Cl2(4.2L)溶液加入HATU(584g,1.536mol),NH4Cl(137g,2.56mol)和二异丙基乙胺(708mL,3.841mol)。反应混合物达到RT和搅拌8小时。在原料消耗之后(TLC监测),反应混合物在水(2L)和CH2Cl2(2L)之间分配和搅拌15分钟。有机层分开,用2N HCl溶液(2x1L)和饱和NaHCO3溶液(2L)和盐水溶液(2L)洗涤。有机层在无水Na2SO4上干燥和减压浓缩。获得的粗制通过硅胶柱色谱法纯化用5%MeOH/CH2Cl2洗脱,提供化合物B4(320g,混合物),是米白色固体。混合物化合物B4(87g)溶于DCM和用Et2O再沉淀,在RT下激烈搅拌1h。过滤产品和减压干燥,获得化合物B4(82g),是白色固体。1H-NMR:(400MHz,D2O):δ4.53-4.10(m,2H),4.08-3.96(m,1H),3.80-3.72(m,1H),3.60-3.39(m,2H),2.53-2.31(m,2H),2.02-1.93(m,2H),1.51-1.45(s,9H),1.31-1.29(d,3H);LCMS(ESI):m/z 326.1[M+-1];HPLC:99.66%;手性HPLC:99.76%;SOR(c=1,MeOH):-49.61。
合成(2S,3R)-3-羟基-2-((S)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(10):
在0℃在氮气氛下向搅拌的化合物B4(10g,0.031mol)的CH2Cl2(40mL)溶液加入TFA(23mL,0.305mol)。反应混合物达到RT和搅拌3小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粘稠浆液物质用醚洗涤(2x 50mL)和减压干燥,提供化合物10(10g,TFA盐,粗制),是粘稠浆液,将其用于后续步骤。1H-NMR:(400MHz,D2O):δ4.38-4.10(m,2H),4.11-3.94(m,2H),3.56-3.44(m,2H),2.52-2.38(m,2H),2.24-2.16(m,2H),1.39-1.27(d,3H);LCMS(ESI):m/z 228.2[M++1]。
合成(2S,3R)-3-羟基-2-((S)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(化合物B):
在RT在氮气氛下向搅拌的粗制化合物10(10g,TFA盐,0.029mol)的甲醇(50mL)溶液加入异丁醛(6.5mL,0.073mol)、随后AcOH(2.5mL),搅拌10分钟。然后,分批加入NaCNBH3(5.4g,0.087mol)和继续搅拌16小时。原料并未完全消耗(TLC监测)。再次加入异丁醛(3.2mL,0.036mol)和AcOH(1mL)和继续搅拌2小时。在原料消耗之后(TLC监测),反应混合物用CH2Cl2稀释(20mL)和减压浓缩。获得的粗制物质通过硅胶柱色谱法纯化用4%MeOH/DCM洗脱,提供(2S,3R)-3-羟基-2-((S)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(6g),是粘稠浆液。1H-NMR:(500MHz,CD3OD):δ4.10-4.07(m,2H),3.63(d,J=5.5Hz,1H),3.49(d,J=6.0Hz,1H),2.97-2.93(m,1H),2.74(q,J=8.0Hz,1H),2.41-2.34(m,2H),2.26-2.20(m,1H),2.17-2.11(m,1H),1.94-1.81(m,2H),1.73-1.69(m,1H),1.21(d,J=6.0Hz,3H),0.91-0.89(m,6H);LCMS(ESI):m/z 284.1[M++1];HPLC:99.53%;手性HPLC:100.00%;SOR(c=0.5,MeOH):-60.25。
合成(4S)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-鎓(Z)-3-羧基丙烯酸盐(化合物B马来酸盐):
在室温下向(2S,3R)-3-羟基-2-((S)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(180mg,0.636mmol)的H2O(2mL)溶液加入马来酸(59mg,0.508mmol)和搅拌16小时。在原料消耗之后(TLC监测),减压除水。获得的粗制物质与戊烷和己烷研磨,减压干燥,提供(4S)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-5-异丁基-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-鎓(Z)-3-羧基丙烯酸盐(210mg,86%),是淡黄色固体。1H NMR(400MHz,CD3OD)δ6.28(s,2H),4.21-4.11(m,2H),3.90(d,J=7.0Hz,1H),3.71(d,J=7.0Hz,1H),3.47-3.36(m,1H),3.20-3.09(m,1H),2.92-2.82(m,1H),2.81-2.71(m,1H),2.48-2.38(m,1H),2.36-2.26(m,1H),2.20-1.88(m,3H),1.24(d,J=6.0Hz,3H),1.00(t,J=7.0Hz,6H);LCMS(ESI):m/z 284.2[M++1-马来酸];HPLC:97.98%;熔点:114.8℃-118.3℃。
实施例3-合成化合物C
合成(3R,7aS)-3-(三氯甲基)四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(1):
在RT向L-脯氨酸(2.0kg,0.017mol)的氯仿(50L)悬浮液加入水合氯醛(5.7kg,0.034mol)。反应混合物在反向Dean-Stark装置中加热至60℃和收集获得的水。在16小时之后,减压浓缩挥发物。粗制固体用冷乙醇洗涤,过滤和干燥,提供化合物1(2.2kg,57%),是白色固体。1H-NMR:(500MHz,DMSO-d6):δ5.82(s,1H),4.11-4.08(m,1H),3.33-3.27(m,2H),3.19-3.14(m,1H),2.15-2.10(m,1H),1.96-1.91(m,1H),1.80-1.74(m,1H),1.65-1.58(m,1H)。
合成(3R,7aR)-7a-((苄氧基)甲基)-3-(三氯甲基)四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(2):
在-78℃在氮气氛下向二异丙胺(221.2mL,1.533mol)的THF(870mL)溶液滴加正-BuLi(1.6M,在己烷中)(958.5mL,1.533mol)。在加入完成之后,反应混合物的温度提高至-20℃和搅拌1小时。再次冷却至-78℃,加入THF(1L)中的化合物1(250g,1.022mol)和搅拌30分钟。然后滴加苄基氯甲基醚(208mL,1.329mol)和继续搅拌1小时。在原料消耗之后(TLC监测),反应混合物用冰冷水淬灭(100mL)和用Et2O萃取(2x 100mL)。合并的有机层用盐水洗涤(100mL),在无水Na2SO4上干燥和减压浓缩,将其通过柱色谱法纯化用10%EtOAc/正-己烷洗脱,获得化合物2(220g,粗制),是褐色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ7.42-7.26(m,5H),5.60(s,1H),4.59-4.53(d,2H),3.67-3.61(m,2H),3.37-3.33(m,1H),3.31-3.10(m,1H),2.12-1.99(m,2H),1.87-1.75(m,2H);LCMS(ESI):m/z 363.9[M++1]。
合成(R)-2-((苄氧基)甲基)吡咯烷-2-羧酸甲酯盐酸盐(3):
在RT向化合物2(400g,1.096mol)的甲醇(1L)溶液加入2N HCl/MeOH(1.64L,3.29mol)和在80℃搅拌16小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粗制品用己烷洗涤(3x750mL)和减压干燥,提供化合物3(358g,粗制),是红色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ10.40(br s,1H),7.40-7.21(m,5H),4.64-4.50(d,2H),4.49-4.3(d,2H),3.76(s,3H),3.33-3.22(m,2H),2.22-2.15(s,1H),2.02-1.9(m,2H),1.95-1.83(m,1H)。
合成(R)-2-((苄氧基)甲基)吡咯烷-1,2-二羧酸1-(叔丁基)2-甲基酯(4):
在0℃在氮气氛下向搅拌的化合物3(313g,粗制1.096mol)的DCM(2.19L)悬浮液滴加Et3N(458.4mL,3.288mol)和搅拌10分钟。然后在0℃滴加Boc-酸酐(358.4g,1.644mol)。反应混合物达到RT和搅拌16小时。在原料消耗之后(TLC监测),反应用水稀释(2x1L)和用CH2Cl2萃取(2x 500mL)。经合并的有机层用10%柠檬酸(pH~7)和盐水溶液(1L)洗涤。有机层在Na2SO4上干燥和减压浓缩,提供粗制化合物,将其通过柱色谱法纯化用20%EtOAc/正-己烷洗脱,获得化合物4(215g,56%),是无色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ7.37-7.26(m,5H),4.56-4.48(m,2H),4.03-3.87(dd,1H),3.69-3.67(d,1H),3.62(s,3H),3.53-3.47(m,1H),3.33-3.30(m,1H),2.27-2.20(m,1H),2.03-1.89(m,2H),1.88-1.79(m,1H),1.46-1.24(2s,9H);LCMS(ESI):m/z 250.1[(M++1)-Boc]。
合成(R)-2-((苄氧基)甲基)-1-(叔丁氧基羰基)吡咯烷-2-羧酸(5):
向化合物4(215g,0.616mol)的MeOH:THF:H2O(3L,5:5:3)溶液加入NaOH(73.9g,1.848mol)和在RT搅拌10分钟。反应混合物加热至80℃和搅拌16小时。在原料消耗之后(TLC监测),反应混合物达到RT,蒸发挥发物。粗制物质用水稀释(1L)和用Et2O萃取(2x 500mL)。分开的水层用2N HCl溶液酸化(pH~3)和用DCM萃取(2x 750mL)。合并的有机层用盐水溶液洗涤,在Na2SO4上干燥和浓缩,提供化合物5(170g,82.4%),是米白色固体。1H-NMR:(500MHz,DMSO-d6):δ12.66(br s,1H),7.36-7.26(m,5H),4.54-4.47(m,2H),4.05-3.90(dd,1H),3.88-3.63(d,1H),3.63-3.44(m,1H),3.34-3.27(m,1H),2.27-2.01(m,1H),2.02-1.8(m,2H),1.79-1.76(m,1H),1.17-1.14(2s,9H);LCMS(ESI):m/z 235.1[(M++1)-Boc]。
合成(R)-1-(叔丁氧基羰基)-2-(羟基甲基)吡咯烷-2-羧酸(6):
在RT向搅拌的化合物5(170g,0.507mol)的CH3OH(1L)溶液加入50%润湿的10%Pd-C(68g)和在H2气氛下搅拌16小时。在原料消耗之后(TLC监测),反应混合物过滤通过C盐垫,垫用CH3OH洗涤(1L)。减压浓缩获得的滤液,提供化合物6(110g,88%),是白色固体。1H-NMR:(400MHz,DMSO-d6):δ12.66(br s,1H),3.96-3.83(dd,1H),3.63-3.60(m,1H),3.49-3.46(m,1H),3.34-3.25(m,2H),2.30-2.15(m,1H),1.95-1.72(m,3H),1.38-1.33(2s,9H);LCMS(ESI):m/z 244[M+-1];手性HPLC:95.88%。
合成(R)-2-(((2S,3R)-1,3-二(苄氧基)-1-氧代丁烷-2-基)氨基甲酰基)-2-(羟基甲基)吡咯烷-1-羧酸叔丁酯(7):
在N2气氛下向冷却至0℃的搅拌的化合物6(110g,0.448mol)的DCM(20mL)反应混合物溶液加入二异丙基乙胺(206mL,1.12mol),中间体D1(150g,0.448mol),HATU(204g,0.537mol),在氮气氛下进行。反应混合物达到RT和搅拌4小时。在原料消耗之后(TLC监测),反应混合物用DCM稀释(1L)和用水(2x500mL)、10%柠檬酸溶液(500mL)和盐水溶液(500mL)洗涤。有机层在无水Na2SO4上干燥和减压浓缩,提供粗制化合物,将其通过柱色谱法纯化用30%EtOAc/正-己烷洗脱,获得化合物7(143g,60%),是无色粘稠浆液。1H-NMR:(500MHz,DMSO-d6):δ8.20-8.12(d,1H),7.29-7.18(m,10H),5.83-5.59(m,1H),5.08(s,2H),4.50-4.44(m,2H),4.30-4.26(m,1H),4.08-4.00(m,2H),3.42-3.40(m,2H),3.39-3.29(m,1H),2.19-2.08(m,1H),1.96-1.87(m,1H),1.68-1.63(m,2H),1.23-1.15(2s,9H),1.14-1.13(d,3H);LCMS(m/z):525.2[M+-1];HPLC:76.2%;手性HPLC:69.47%。
合成(R)-2-((2S,3R)-1,3-二(苄氧基)-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(8):
在RT在氮气氛下向三苯基膦(161.4g,0.612mol)的THF(430mL)溶液滴加DIAD(123.8g,0.612mol)和搅拌15分钟。向其滴加化合物7(215g,0.408mol)的THF(860mL)溶液,在RT搅拌4小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粗制物质通过硅胶柱色谱法纯化用20%EtOAc/己烷洗脱,提供化合物8(180g,与DIAD副产品的混合物),是黄色浆液。1H-NMR:(400MHz,DMSO-d6):δ7.31-7.18(m,10H),5.18-5.10(m,2H),4.61-4.54(m,2H),4.27-4.18(m,2H),3.78-3.77(d,1H),3.45-3.43(d,1H),3.35-3.31(d,1H),3.27-3.23(m,1H),2.03-1.98(m,2H),1.78-1.76(m,2H),1.39-1.31(2s,9H),1.23-1.22(d,3H)(未捕获DIAD副产品峰);LCMS(ESI):m/z 509.4[M++1]。
合成(2S,3R)-2-((R)-5-(叔丁氧基羰基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)-3-羟基丁酸(9):
在N2气氛下将化合物8(85g,0.167mol)的甲醇(850mL)溶液脱气。然后在RT加入50%润湿的10%Pd-C(40g)和在H2气氛下搅拌24小时。在原料消耗之后(TLC监测),反应混合物过滤通过C盐垫和减压浓缩滤液。获得的粗制固体用Et2O稀释(1L)和在RT激烈搅拌1小时。滤出获得的固体物质和干燥,提供化合物9(75g,68%),是白色固体。1H-NMR:(400MHz,DMSO-d6):δ12.86(br s,1H),5.24(br s 1H),4.06-4.00(m,2H),3.88-3.82(m,1H),3.51-3.50(m,1H),3.43-3.34(m,1H),3.31-3.23(m,1H),2.15-2.09(m,2H),1.82-1.78(m,2H),1.39-1.31(2s,9H),1.10-1.08(d,3H);LCMS(m/z):329.1[M++1];HPLC:93.97%。
合成(R)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(A4):
将反应混合物冷却至0℃,在氮气氛下向搅拌的化合物9(150g,0.457mol)的CH2Cl2(2L)溶液加入二异丙基乙胺(176.85g,1.37mol),NH4Cl(48.8g,0.914mol)和HATU(208.3g0.548mols)。反应混合物达到RT和搅拌12小时。在原料消耗之后(TLC监测),反应混合物用水稀释(2x750mL)和用CH2Cl2萃取(2x 1L)。合并的有机层用2N HCl溶液和饱和氯化钠溶液(750mL)洗涤。有机层在无水Na2SO4上干燥和减压浓缩。粗制化合物通过柱色谱法纯化,纯化合物用3%MeOH/CH2Cl2洗脱。所获得的物质用DCM(2L)稀释,用饱和柠檬酸(5x 500mL)洗涤、饱和碳酸氢盐洗涤、随后盐水洗涤,在Na2SO4上干燥。物质与醚研磨(2x 500mL),提供化合物A4(80g,53%),是白色固体。1H-NMR:(400MHz,D2O):δ4.36-4.21(m,2H),4.03-3.98(m,1H),3.76-3.67(m,1H),3.56-.3.37(m,2H),2.32-2.23(m,2H),1.97-1.93(m,2H),1.49-1.47(2s,9H),1.33-1.32(d,3H);LCMS(ESI):m/z 328.3[M++1];HPLC:99.30%;手性HPLC:98.97%;SOR(c=1,CH3OH):-11.08。
合成(2S,3R)-3-羟基-2-((R)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(10):
在0℃在氮气氛下向搅拌的化合物A4(2g,6.16mmol)的CH2Cl2(10mL)溶液加入TFA(1.0mL,12.2mmol)。反应混合物达到RT和搅拌2小时。在原料消耗之后(TLC监测),减压蒸发挥发物。获得的粘稠浆液物质用醚洗涤(2x 50mL)和减压干燥,提供粗制化合物10(2.5g,TFA盐),是粘稠浆液,将其用于后续步骤。1H NMR(500MHz,CD3OD):δ4.24-4.17(m,2H),3.99-3.89(m,2H),3.52-3.39(m,2H),2.46-2.32(m,2H),2.26-2.10(m,2H),1.28(d,J=6.1Hz,3H);LCMS(ESI):m/z228.1[M++1]。
合成(2S,3R)-3-羟基-2-((R)-5-((S)-2-羟基丙基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(化合物C):
在RT在氮气氛下向搅拌的化合物10(TFA盐,2g,5.86mmol)的甲醇(10mL)溶液加入NaOMe(630mg,11.7mmol)、随后(S)-2-甲基环氧乙烷(510mg,8.79mmol)。在RT搅拌反应混合物24小时。在原料消耗之后(TLC监测),反应混合物用CH2Cl2稀释(10mL)和减压浓缩。获得的粗制物质通过硅胶柱色谱法纯化用5%MeOH/DCM洗脱,提供(2S,3R)-3-羟基-2-((R)-5-((S)-2-羟基丙基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(185mg,12%),是粘稠浆液。1H NMR(400MHz,CD3OD):δ4.18-4.07(m,2H),3.90-3.81(m,1H),3.63(d,J=6.1Hz,1H),3.58(d,J=6.1Hz,1H),3.11(dt,J=4.2,8.2Hz,1H),2.83-2.67(m,2H),2.62-2.54(m,1H),2.26-2.12(m,2H),1.98-1.83(m,2H),1.24(d,J=6.1Hz,3H),1.14(d,J=6.3Hz,3H);LCMS(ESI):m/z 285.9[M++1];HPLC:97.20%。
实施例4
该实施例展示积极情绪学习(PEL)试验。实验按Burgdorf等人,"The effect ofselective breeding for differential rates of 50-kHz ultrasonic vocalizationson emotional behavior in rats,"Devel.Psychobiol.,51:34-46(2009)的描述进行。大鼠50-kHz超声发声(快乐USVs)是研究积极情感状态的确证模型和最佳地通过冲撞摔打玩耍(rough-and-tumble play)引起。50-kHz超声发声已预先显示与大鼠的奖励和食欲社会行为正相关,并且反映积极情感状态。
PEL测试测量响应社会刺激的积极(快乐)50-kHz超声发声(USVs)的获得,所述社会刺激是异种特异性的冲撞摔打玩耍刺激。异种特异性的冲撞摔打玩耍刺激通过实验者右手给予。动物接受3分钟异种特异性的冲撞摔打玩耍,其由15秒的异种特异性玩耍时段和15秒无刺激时段交替组成。高频率超声发声(USVs)使用Avasoft SASlab Pro(德国)通过声像图来记录和分析,如Burgdorf等人,"Positive emotional learning is regulated inthe medial prefrontal cortex by GluN2B-NMDA receptors,"Neuroscience,192:515-523(2011)的预先描述。对各个无刺激时间段期间发生的频率调制的50-kHz USVs定量从而度量PEL。在测试之前动物并不用玩耍刺激驯化。积极情绪学习在条件刺激(CS)试验期间测量,随后进行轻触非条件刺激(UCS)试验。动物接受由6次CS和6次UCS试验组成的各15秒的试验(共3分钟)。在3分钟时段结束时动物自身给予轻触的奔跑速度也加以测量。
图1显示大鼠PEL试验的结果。结果展示,在PEL测试之前一小时给予的情况下,化合物A增加通过大鼠USVs测量的积极情绪学习,由此指出抗抑郁效果。
实施例5
研究化合物A的微粒体和血浆稳定性。下表指出在60分钟之后剩余的化合物A百分比。
还研究了脑中未结合的药物浓度,并进行了血浆蛋白质结合测试。下表(%结合)指出化合物A的结果。
人类 | 大鼠 |
25.9% | 29.95% |
化合物A的生物可利用度在PO给药之后研究。在剂量给药化合物A(10mg/kg)之后分析CSF、脑和血浆样品。下表指出生物可利用度和CSF/血浆和脑/血浆比率。
生物可利用度(%F) | 42 |
CSF/血浆比率 | 0.65 |
脑/血浆比率 | 0.19 |
实施例6
测试按Moskal等人,"GLYX-13:a monoclonal antibody-derived peptide thatacts as an N-methyl-D-aspartate receptor modulator,"Neuropharmacology,49,1077-87,2005的描述进行。在非平衡条件(15分钟@25℃)下、在增加浓度的化合物A存在下测量与充分洗涤的大鼠皮质膜(200μg)的[3H]MK-801结合(5nM;22.5Ci/mmol)的增强。
图2描述化合物A对野生型NMDAR2亚型[3H]MK-801结合的增强。如图2所示,化合物A是高度NR2A优先的,其不结合至NR2D。
实施例7
对Sprague Dawley大鼠经静脉内给药2mg/kg化合物A。对第二组Sprague Dawley大鼠经口给药10mg/kg化合物A。在24小时时间段抽取血浆样品和分析化合物A。
图3展示在雄性Sprague Dawley大鼠中单次静脉内(2mg/kg)和口服(10mg/kg)剂量给药之后24小时时间段的化合物A的平均血浆浓度-时间曲线。
在又一实验中,Sprague Dawley大鼠经口给药10mg/kg化合物A。在24小时时间段的各时间点分析血浆、脑和CSF样品。
图4显示在雄性Sprague Dawley大鼠中单次口服(10mg/kg)剂量给药之后24小时时间段的化合物A的平均血浆、脑和CSF浓度-时间曲线。
实施例8
该实施例涉及PEL实验,如上文实施例3所述。大鼠超声发声(USVs)试验。
积极情绪学习在条件刺激(CS)试验期间测量,随后进行轻触非条件刺激(UCS)试验。动物接受由6次CS和6次UCS试验组成的各15秒的试验(共3分钟)。
图5显示大鼠USVs试验的结果。结果展示化合物B在大鼠USVs试验中增加积极情绪学习,由此指出抗抑郁效果。
实施例9
研究化合物B的微粒体和血浆稳定性。下表指出在60分钟之后剩余的化合物B百分比。
人类 | 大鼠 | |
微粒体 | 87% | 81% |
血浆 | 100% | 89% |
还研究脑中未结合的药物浓度,和进行血浆蛋白质结合测试。下表(%结合)指出化合物B的结果。
人类 | 大鼠 |
28.8% | 19.8% |
研究化合物B的生物可利用度。在剂量给药化合物B之后分析CSF、脑和血浆样品。下表指出生物可利用度和CSF/血浆和脑/血浆比率。
生物可利用度(%F) | 38 |
CSF/血浆比率 | 0.70 |
脑/血浆比率 | 0.18 |
化合物A和化合物B均具有较低的口服生物利用度,但较高比例能够到达CSF和脑。
实施例10
测试如上文实施例5进行,参见Moskal等人(2005)。在非平衡条件(15分钟@25℃)下、在增加浓度的化合物B存在下测量与充分洗涤的大鼠皮质膜(200μg)的[3H]MK-801结合(5nM;22.5Ci/mmol)的增强。图6描述化合物B对野生型NMDAR2亚型[3H]MK-801结合的增强。化合物B是高度NR2B和NR2D优先的,其在NR2A和NR2C中效能较低。
实施例11
对Sprague Dawley大鼠经静脉内给药2mg/kg化合物B。对第二组Sprague Dawley大鼠经口给药10mg/kg化合物B。在24小时时间段抽取血浆样品和分析化合物B。
图7描述在雄性Sprague Dawley大鼠中单次静脉内(2mg/kg)和口服(10mg/kg)剂量给药之后24小时时间段的化合物B的平均血浆浓度-时间曲线。
在又一实验中,Sprague Dawley大鼠经口给药10mg/kg化合物B。在24小时时间段的各时间点分析血浆、脑和CSF样品。
图8描述在雄性Sprague Dawley大鼠中单次口服(10mg/kg)剂量给药之后24小时时间段的化合物B的平均血浆、脑和CSF浓度-时间曲线。
实施例12
对化合物A进行体外MN(小核)测试。该测试也对化合物B进行。细胞毒性表示为%的对照生长。标记小于60%的细胞毒性值,且化合物在各自浓度被认为是毒性的。化合物A体外MN测试的结果示于图9。化合物B体外MN测试的结果示于图10。
对化合物A和化合物B各自进行Ames测试。对于Ames测试结果,连字符(-)指出阴性结果。弱阳性,如果p<0.05,表示为"+"。强阳性,如果p<0.01,表示为"++"。很强的阳性,如果p<0.001,表示为"+++"。化合物A的Ames测试的结果示于图9。化合物B的Ames测试的结果示于图10。
用化合物A进行hERG测试以鉴定潜在的hERG通道相互作用。另外,用化合物B进行hERG测试。对于hERG来说,显示高于50%的抑制或刺激的结果被视为代表对试验化合物的显著效果。化合物A的hERG测试的结果示于图9而化合物B的hERG测试的结果示于图10。
实施例13
对单次冲击波-诱导的外伤性脑损伤/认知低下进行诱导、修饰以用于大鼠中,根据Goldstein等人,"Chronic traumatic encephalopathy in blast-exposed militaryveterans and a blast neurotrauma mouse model,"Science Translational Medicine,Vol.4,Issue 134,pp.134ra60,2012的方案进行。使用雄性2-3月龄Sprague Dawley大鼠。大鼠安放在具有白杨木片垫子的Lucite笼中,保持12:12的光:暗循环(于5AM开灯),和在整个研究中可以随意获得Purina实验用食物(USA)和自来水。大鼠首先用3.5-4%异氟烷麻醉,然后用1.5x 1.5mm泡沫塞(Pura-Moldex-Metric Inc.,Culver City,California)保护耳部,并且将大鼠置入头部访问型啮齿动物胸部限制器(Stoelting,USA)以保护身体同时允许头部自由活动。将铝激波管(183x 61cm;L-3Applied Technologies,USA)置于离大鼠头部10cm的距离。大鼠接受单次~42PSI氦冲击波,其是穿刺0.014英寸聚酯膜产生的。假对照置于冲击半径以外。冲击之后1小时,向动物给药化合物A(10mg/kgPO)、化合物B(10mg/kg PO)或0.5%Na-CMC/0.9%无菌盐水媒介物(1ml/kg PO)。
冲击之后48小时进行PEL(积极情绪学习)。异种特异性的冲撞摔打玩耍按Burgdorf等人,"The long-lasting antidepressant effects of rapastinel(GLYX-13)are associated with a metaplasticity process in the medial prefrontal cortexand hippocampus,"Neuroscience 308:202-211,2015的预先描述进行。异种特异性的冲撞摔打玩耍刺激通过实验者右手给予。动物接受3分钟异种特异性的冲撞摔打玩耍,其由交替的15秒异种特异性的玩耍时段和15秒无刺激时段组成。高频率超声发声(USVs)用AvasoftSASlab Pro(德国)通过声像图记录和分析,如Burgdorf等人,"Positive emotionallearning is regulated in the medial prefrontal cortex by GluN2B-containingNMDA receptors,"Neuroscience,192:515-523,2011的预先描述。对在各无刺激时间段期间发生的频率调制的50-kHz USVs定量以度量PEL。动物在测试之前并未用玩耍刺激驯化。
化合物A和B的PEL研究结果报告于图11和12。
实施例14
该实施例涉及在应激-诱导的焦虑模型(新鲜感诱导的食欲减少)中评价治疗的抗焦虑效果。该测试也对快速起效的抗抑郁药氯胺酮和GLYX-13敏感(Li等人,"mTOR-dependent synapse formation underlies the rapid antidepressant effects ofNMDA antagonists,"Science329:959-964,2010;和Burgdorf等人,2013)。还参见Bodnoff等人,"A comparison of the effects of diazepam versus several typical andatypical anti-depressant drugs in an animal model of anxiety,"Psychopharmacology,97:277-279,1989。
测试按(Burgdorf等人,2013)的描述进行。使用新鲜感诱导的食欲减少(NIH)试验的一种形式,其已预先显示检测氯胺酮的急性抗焦虑类效果(Li等人,2010)。动物在测试前禁食过夜,在弱红光照明下将实验用食物置于开放区域(40x40x20cm)的中心室,持续10分钟。在测试各动物之间,从设备除去粪便和尿液。在NIH测试之后,确定动物在笼中的进食延迟以充当对照,从而确保对进食的效果是新环境特异性的。对动物录像,为动物首次啃食食物的延迟(秒)离线手工打分。
离平均值2个或更多个标准偏差的单点/剂量组被视为异常值且从数据分析中排除。ED50定义为剂量(或剂量的log线性内插),其展示得自log(剂量)线性(NIH值)图的半最大效果(媒介物和最大有效剂量的平均值)。最大有效剂量定义为统计学上不同于媒介物但是统计学上与更高剂量相当的最低剂量(根据Fisher’s PLSD;α设为0.05)。
结果示于图13和14。如图13所示,化合物A在新鲜感-诱导的食欲减少(NIH)试验中在大鼠中产生抗焦虑效果。平均值±SEM进食延迟:在新鲜感-诱导的食欲减少(NIH)试验中在2-3月龄雄性SD大鼠中用化合物A(10-1000μg/kg PO;蓝色圆圈)或无菌盐水+0.5%Na-CMC媒介物(1ml/kg PO;黑色圆圈)处理,在1小时后进行单次10-min的试验期。动物在测试之前禁食过夜,并且在测试期间将实验用食物置入开放区域的中心室。
如图14所示,化合物B在新鲜感-诱导的食欲减少(NIH)试验中在大鼠中产生抗焦虑效果。平均值±SEM进食延迟:在新鲜感-诱导的食欲减少(NIH)试验中在2-3月龄雄性SD大鼠中用化合物B(0.0001-1μg/kg PO;蓝色圆圈)或无菌盐水+0.5%Na-CMC媒介物(1ml/kgPO;黑色圆圈)处理,在1小时之后进行单次10-min的试验期。动物在测试之前禁食过夜,并且在测试期间将实验用食物置入开放区域的中心室。
实施例15
用机械止痛的Bennett模型来评价化合物的镇痛效果,通过爪回收阈值度量。Bennett GJ,Xie YK,"A peripheral mononeuropathy in rat that produces disordersof pain sensation like those seen in man,"Pain33:87-107,1988。对动物进行保留性神经伤害手术,一旦动物从手术恢复但在施用von frey长丝之后仍展示爪回收低阈值则测试镇痛应答。媒介物动物接受手术然后接受媒介物而不是试验化合物。在试验化合物或媒介物给药后,动物测试1小时、24小时和1周。
使用雄性2-3月龄Sprague Dawley大鼠。Harlan是全部研究的供应商。大鼠安放于具有白杨木片垫的Lucite笼中,保持12:12光:暗循环(于5AM开灯),并且在整个研究期间可以随意获得Purina实验用食物(USA)和自来水。
大鼠用吸入的异氟烷(2.5%)麻醉。保守性神经伤害手术按预先描述进行(Bennett和Xie,1988)。用解剖刀穿过皮肤在右后肢(与股骨平行的后侧)背侧划出切口(~1.5cm长)。用小尖止血钳将股二头肌和浅臀肌分开。用弯钝镊分离并暴露坐骨总神经。为了机械止痛研究,结扎整个坐骨神经。使用止血钳/镊子和铬肠线(5-0),用水手结将神经松散结扎;在神经上进行相距1mm的3次结扎。将结扎带绷紧直至缝合线不沿神经上下滑动。该方案引起神经的部分功能损失。为了热止痛研究,将坐骨神经的腓侧和胫骨分支结扎并切割,留下腓肠分支。参见Decosterd I,Woolf CJ,"Spared nerve injury:an animal model ofpersistent peripheral neuropathic pain,"Pain 87:149-158,2000。术后1-2周进行测试。
在测试期间,使大鼠适应悬吊的金属丝编织网(1cm X 1cm,金属丝直径0.3cm)表面15-20分钟。从最小的开始,将各Von Frey丝垂直挤压受影响(同侧)的后爪足底表面直至稍弯曲,然后保持6秒。如果在撤回长丝之后并未立即观察到明显的后爪回收或回缩行为,则以相同方式使用更大的Von Frey丝。在应答的情况下,则使用更小的Von Frey丝。将其重复直至收集六次应答。
剂量给药化合物A和化合物B(0.1-10mg/kg PO)、加巴喷丁(150mg/kg PO)或0.5%Na-CMC/0.9%无菌盐水之后1小时进行测试。动物在剂量给药之后再测试24小时和1周。化合物A的结果示于图15而化合物B的结果示于图16。对于两种化合物,在Bennett模型中在剂量给药之后1小时、24小时和1周的情况下单次给药10mg/kg PO产生机械镇痛效果,而加巴喷丁仅在剂量给药之后1小时产生镇痛效果。
实施例16
进行非临床体内药理学研究(Porsolt测试)以测量抗抑郁类效果。用阴性对照(0.5%羧甲基纤维素钠/0.9%无菌盐水媒介物)和阳性对照(化合物D)来与化合物A和化合物B比较。该研究允许对Porsolt强迫游泳试验构造各化合物效果的剂量-应答曲线,通过在5-分钟游泳试验期间的大鼠应答(减少的飘浮时间)来评价。
使用雄性2-3月龄Sprague Dawley大鼠(Harlan,Indianapolis,IN)。大鼠安放在具有白杨木片垫的Lucite笼中,保持12:12光:暗循环(于5AM开灯),并且在整个研究期间可以随意获得Purina实验用食物(USA)和自来水。
Porsolt强迫游泳试验经调节用于在大鼠中,按Burgdorf等人,(The long-lasting antidepressant effects of rapastinel(GLYX-13)are associated with ametaplasticity process in the medial prefrontal cortex andhippocampus.Neuroscience 308:202-211,2015)的描述进行。动物置于46cm高×20cm直径的透明玻璃管,在第一天(驯化)用自来水(23±1℃)填充至30cm持续15分钟而在随后的试验日则持续5分钟。动物在剂量给药化合物(化合物A和化合物B),阳性对照(化合物D,10μg/kg),或媒介物(0.5%羧甲基纤维素钠(Na-CMC)/0.9%无菌盐水)之后1小时测试。每隔一只动物换水。给动物录像,飘浮时间定义为将动物头部保持在水面上所需要的努力的最少量,由盲态实验者离线打分,具有高评价者间的可靠性(Pearson’s r>.9)。
EC50定义为剂量(或剂量的log线性内插),其展示半最大效果(媒介物和最大有效剂量的平均),得自log(剂量)线性图。最大有效剂量定义为统计学上不同于媒介物但统计学上与更高剂量相当的最低剂量(根据Fisher’s PLSD)。
化合物A的结果示于图17。向成年雄性Sprague Dawley大鼠给药化合物A(10-1000μg/kg PO;蓝色圆圈或由线连接的数据点),阳性对照化合物D(10μg/kg PO;绿色圆圈或数据点,于10μg/kg PO),或Na-CMC/0.9%盐水(1ml/kg PO;黑色圆圈或数据点,于1ml/kgPO),在1小时后测试。显示在大鼠Porsolt试验中的平均值±SEM飘浮时间。动物在第1天接受15分钟驯化期,随后是5分钟试验。N=6-18每组。如显示,化合物A产生抗抑郁类效果,如在Porsolt试验中在剂量给药之后1小时测量的与媒介物组相比减少的飘浮时间。
化合物B的结果示于图18。向成年雄性Sprague Dawley大鼠给药化合物B(0.1-10μg/kg PO;蓝色圆圈或由线连接的数据点),阳性对照化合物D(10μg/kg PO;绿色圆圈或数据点,于10μg/kg PO),或Na-CMC/0.9%盐水(1ml/kg PO;黑色圆圈或数据点,于1ml/kg PO),在1小时后测试。显示在大鼠Porsolt试验中的平均值±SEM飘浮时间。动物在第1天接受15分钟驯化期,随后是5分钟试验。N=6-18每组。如显示,化合物B产生抗抑郁类效果,如在Porsolt试验中在剂量给药之后1小时测量的与媒介物组相比减少的飘浮时间。
实施例17
下表显示在化合物A,化合物B,(R)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(化合物W),(S)-2-((2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基)-1-氧代-2,5-二氮杂螺[3.4]辛烷-5-羧酸叔丁酯(化合物X),(2S,3R)-3-羟基-2-((R)-5-异丁酰-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(化合物Y),或(2S,3R)-3-羟基-2-((S)-5-异丁酰-1-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)丁酰胺(化合物Z)存在下野生型NMDAR2亚型的比较性体内结合数据。
等价方式
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US20170334922A1 (en) | 2017-11-23 |
JP2019516735A (ja) | 2019-06-20 |
KR20190010613A (ko) | 2019-01-30 |
CL2018003265A1 (es) | 2019-01-25 |
CA3024606C (en) | 2019-09-03 |
US10196401B2 (en) | 2019-02-05 |
EP3458458B1 (en) | 2020-11-04 |
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US20180093994A1 (en) | 2018-04-05 |
AU2017267708B2 (en) | 2020-02-20 |
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