CN101287722A - 作为代谢型谷氨酸受体拮抗剂的取代的哌嗪 - Google Patents
作为代谢型谷氨酸受体拮抗剂的取代的哌嗪 Download PDFInfo
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- CN101287722A CN101287722A CNA2006800289759A CN200680028975A CN101287722A CN 101287722 A CN101287722 A CN 101287722A CN A2006800289759 A CNA2006800289759 A CN A2006800289759A CN 200680028975 A CN200680028975 A CN 200680028975A CN 101287722 A CN101287722 A CN 101287722A
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- chloro
- piperazine
- phenyl
- ethyl
- compound
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Abstract
本发明涉及式I的化合物或其可药用盐或溶剂化物,其中Ar1、Ar2、Hy、L、R1、m和n为如在说明书中定义的。本发明也包括药物组合物及其用途、制备该化合物的方法以及医学治疗mGluR5-介导的病症的方法。
Description
发明领域
本发明涉及新类型的化合物、包含所述化合物的药物制剂及所述化合物在治疗中的用途。本发明进一步涉及制备所述化合物的方法和在其中制备的新的中间体。
背景技术
谷氨酸为哺乳动物中枢神经系统(CNS)中主要的兴奋性神经递质。谷氨酸通过结合并从而活化细胞表面受体而产生其对中枢神经元的作用。这些受体已经根据受体蛋白质的结构特点、受体将信号转导到细胞内的手段和药理学特征被分为二个主要类型,离子型谷氨酸受体(ionotropic glutamate receptor)和代谢型谷氨酸受体(metabotropicglutamate receptor)。
代谢型谷氨酸受体(mGluRs)为与G蛋白质偶联的受体,其在结合谷氨酸之后活化多种细胞内第二信使系统。在完整的哺乳动物神经元中的mGluRs的活化引起一种或多种以下响应:磷脂酶C活化;磷酸肌醇(PI)水解增加;细胞内钙释放;磷脂酶D活化;腺苷酸环化酶的活化或抑制;环腺苷酸(cAMP)的形成增加或减少;鸟苷酰环化酶的活化;环单磷酸鸟苷(cGMP)的形成增加;磷脂酶A2的活化;花生四烯酸释放增加;电压控制的和配体控制的离子通道活性的增加或降低。Schoepp等人,TrendsPharmacol.Sci.,14:13(1993);Schoepp,Neurochem.Int.,24:439(1994);Pin等人,Neuropharmacology,34:1(1995);Bordi和Ugolini,Prog.Neurobiol.,59:55(1999)。
已经通过分子克隆鉴定了八种不同的mGluR亚型,称mGluR1到mGluR8。Nakanishi,Neuron,13:1031(1994);Pin等人,Neuropharmacology,34:1(1995);Knopfel等人,J.Med.Chem.,38:1417(1995)。另外的受体多样性通过某些mGluR亚型的可变剪接形式的表达而发生。Pin等人,PNAS,89:10331(1992);Minakami等人,BBRC,199:1136(1994);Joly等人,J.Neurosci.,15:3970(1995)。
代谢型谷氨酸受体亚型可根据氨基酸序列同源性、受体利用的第二信使系统和它们的药理学特征被再分成三组,第I组、第II组、和第III组mGluRs。第I组mGluR包括mGluR1、mGluR5及其可变剪接变体。激动剂与这些受体的结合引起磷脂酶C活化和随后的细胞内钙的转移。
神经病症、精神病症和疼痛病症
阐明第I组mGluRs的生理学作用的努力表明,这些受体的活化引起神经元的兴奋。不同的研究证明,第I组mGluRs激动剂可以在施用于海马、大脑皮质、小脑和丘脑以及其它CNS区域中的神经元时产生突触后兴奋。证据表明这种兴奋是由于突触后mGluRs的直接活化,但是还已表明存在有突触前mGluRs的活化,引起神经递质的释放增加。Baskys,Trends Pharmacol.Sci.,15:92(1992);Schoepp,Neurochem.Int.,24:439(1994);Pin等人,Neuropharmacology,34:1(1995);Watkins等人,Trends pharmacol.Sci.,15:33(1994)。
代谢型谷氨酸受体参与在哺乳动物CNS中的许多正常过程中。mGluRs的活化已被证明是诱导海马长时增强和小脑长时抑制所需要的。Bashir等人,Nature,363:347(1993);Bortolotto等人,Nature,368:740(1994);Aiba等人,Cell,79:365(1994);Aiba等人,Cell,79:377(1994)。此外,已经证明了mGluR的活化在伤害感受和痛觉丧失中的作用,Meller等人,Neuroreport,4:879(1993);Bordi和Ugolini,Brain Res.,871:223(1999)。另外,mGluR活化已经表现出在多种其它正常过程中起调节作用,所述过程包括突触传递、神经元发育、细胞凋亡性神经元死亡、突触可塑性、空间学习、嗅觉记忆、心搏动的中枢控制、觉醒、运动控制和前庭眼球反射的控制。Nakanishi,Neuron,13:1031(1994);Pin等人,Neuropharmacology,34:1;Knopfel等人,J.Med.Chem.,38:1417(1995)。
另外,第I组代谢型谷氨酸受体,特别是mGluR5,已经表现出在多种病理生理学过程和影响CNS的病症中起作用。这些病症包括中风、头创伤、缺氧和缺血损伤、低血糖、癫痫症、神经变性病症比如阿尔茨海默氏病和疼痛。Schoepp等人,Trends Pharmacol.Sci.,14:13(1993);Cunningham等人,Life Sci.,54:135(1994);Hollman等人,Ann.Rev.Neurosci.,17:31(1994);Pin等人,Neuropharmacology,34:1(1995);Knopfel等人,J.Med.Chem.,38:1417(1995);Spooren等人,TrendsPharmacol.Sci.,22:331(2001);Gasparini等人,Curr.Opin.Pharmacol.,2:43(2002);Neugebauer,Pain 98:1(2002)。这些病症的大部分病理学被认为是由于谷氨酸诱导的CNS神经元过度兴奋。因为第I组mGluRs看起来通过突触后的机制和增强的突触前谷氨酸释放来增加谷氨酸介导的神经元兴奋,它们的活化可能对所述病理学有责任。因此,第I组mGluR受体的选择性拮抗剂可能在治疗上是有利的,特别是作为神经保护剂、镇痛药或抗惊厥药。
在阐明代谢型谷氨酸受体(特别是第I组)的神经生理学作用方面的新进展已经确定了这些受体在治疗急性和慢性神经病和精神障碍和慢性及急性疼痛病中是有前途的药物靶标。
胃肠道病症
下食道括约肌(LES)易于间歇性松弛。结果,因为机械屏障在这时暂时丧失,来自胃的流体可以进入食道,这种情况以下简称为“返流”现象。
胃-食管返流病(GERD)是最常见的上胃肠道疾病。当前的药物疗法针对减少胃酸分泌,或针对中和食道中的酸。返流的主要机制已被认为是取决于张力减退的下食道括约肌。然而,例如,Holloway&Dent (1990)Gastroenterol.Clin.N.Amer.,19,PP.517-535中表明,大多数的返流急性发作在暂时性下食道括约肌松弛(TLESR)过程中发生,即不是由吞咽引起的松弛。还表明,在患有GERD的患者中,胃酸分泌通常是正常的。
根据本发明的新的化合物被认为可用于抑制暂时性下食道括约肌松弛(TLESR)并由此用于治疗胃-食管返流病(GERD)。
本文中的单词“TLESR”,暂时性下食道括约肌松弛,根据Mittal,R.K,Holloway,R.H.,Penagini,R.,Blackshaw,L.A.,Dent,J.,1995;Transientlower esophageal sphincter relaxation.Gastroenterology,109,PP.601-610定义。
本文中的术语“返流”是指因为机械屏障在这时暂时丧失,来自胃的流体能够进入食道。
本文中的术语“GERD”,胃食管返流病,根据van Heerwarden,M.A.,Smout A.J.P.M.,2000;Diagnosis of reflux disease.Baillière’sClin.Gastroenterol.14,pp.759-774定义。
因为它们的生理学和病理生理学的重要性,需要表现出对于mGluR亚型,特别是对第一组受体亚型,最特别是对mGluR5,具有高选择性的新的有效的mGluR激动剂和拮抗剂。
本发明的目的是提供在代谢型谷氨酸受体(mGluRs),特别是在mGluR5受体,表现出活性的化合物。
发明概述
本发明的一个实施方案涉及式I的化合物或其可药用盐、水合物、溶剂化物、同工型、互变异构体、旋光异构体或其组合:
其中:
Ar1和Ar2为独立选择的、任选取代的芳基或杂芳基,其中所述取代基选自F、Cl、Br、I、OH、硝基、C1-6-烷基、C1-6烷基卤、OC1-6-烷基、OC1-6-烷基卤、C2-6-链烯基、C2-6-炔基、CN、CO2R2、SR2、S(O)R2、SO2R2、芳基、杂芳基、环烷基和杂环烷基,其中任一个环基可以进一步被至少一个选自下述的取代基取代:F、Cl、Br、I、OH、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤、C2-6-链烯基、C2-6-炔基、CN、CO2R2、SR2、S(O)R2、SO2R2;
R1,在每种情况下独立地选自F、Cl、Br、I、OH、CN、硝基、C1-6-烷基、OC1-6-烷基、C1-6-烷基卤、OC1-6-烷基卤、(CO)R2、O(CO)R2、O(CO)OR2、CO2R2、-CONR2R3、C1-6-亚烷基OR2、OC2-6-亚烷基OR2和C1-6-亚烷基氰基;
R2和R3独立地选自H、C1-6-烷基、C1-6-烷基卤、C2-6-链烯基、C2-6-炔基和环烷基;
Hy为包含二或三个杂原子的5元杂环,所述杂原子独立地选自N、O和S,其中所述环任选地被一个或多个选自下述的取代基取代:F、Cl、Br、I、OH、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤、CN、CO2R2、CONR2R3、SR2、S(O)R2、SO2R2;
L选自-CR4R5-、-C(O)-、-C(NR4)-和-C(S)-;
R4和R5独立地选自H、C1-6-烷基、C1-6-烷基卤、C2-6-链烯基和C2-6-炔基;
m为选自0、1、2、3和4的整数;和
n为选自1和2的整数。
另一个实施方案为药物组合物,其包括作为活性成分的治疗有效量的根据式I的化合物与一种或多种可药用稀释剂、赋形剂和/或惰性载体。
如下述更详细描述的其它实施方案涉及用于治疗、用于治疗mGluR5介导的病症、用于制备治疗mGluR5介导的病症的药物的根据式I的化合物。
其它的实施方案涉及治疗mGluR5介导的病症的方法,包括给药哺乳动物治疗有效量的根据式I的化合物。
在另一实施方案中,提供用于抑制mGlurR5受体活化的方法,其包括用有效量的根据式I的化合物处理包含所述受体的细胞。
优选实施方案的详细说明
本发明是基于发现了显示出作为药物,特别是作为代谢型谷氨酸受体拮抗剂的活性的化合物。更特别地,本发明的化合物显示出作为mGluR5受体拮抗剂的活性,因此,其可用于治疗,特别是用于治疗与谷氨酸功能障碍相关的神经病学、精神病学、疼痛和胃肠道病症。
定义
除非在本说明书中另有规定,在本说明书中使用的命名法通常遵循在Nomenclature of Organic Chemistry,部分A、B、C、D、E、F和H,Pergamon Press,Oxford,1 979中规定的实例和规则,将其中示例性的化学结构名称和命名化学结构的规则引入本文作为参考。任选地,化合物的名称可以使用化学命名程序:ACD/ChemSketch,5.09版/2001年9月,Advanced Chemistry Development,Inc.,Toronto,Canada产生。
如本文使用的术语“烷基”指具有一个至六个碳原子的直链或支链烃基,包括甲基、乙基、丙基、异丙基、叔丁基等。
如本文使用的术语“链烯基”指具有二个至六个碳原子的直链或支链链烯基,包括乙烯基、1-丙烯基、1-丁烯基等。
如本文使用的术语“炔基”指具有二个至六个碳原子的直链或支链炔基,包括1-丙炔基(炔丙基)、1-丁炔基等。
如本文使用的术语“环烷基”指具有三个至七个碳原子的环基(其可以是不饱和的),包括环丙基、环己基、环己烯基等。
如本文使用的术语“杂环烷基”指具有至少一个选自N、S和O的杂原子的三元至七元环基(其可以是不饱和的),包括哌啶基、哌嗪基、吡咯烷基、四氢呋喃基等。
如本文使用的术语“烷氧基”指具有一个至六个碳原子的直链或支链烷氧基,包括甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基等。
如本文使用的术语“卤代(halo)”指卤素,包括氟、氯、溴、碘等,放射性的和非放射性的。
如本文使用的术语“亚烷基”指具有一个至六个碳原子的双官能的支链的或无支链的饱和烃基,包括亚甲基、亚乙基、亚正丙基、亚正丁基等。
如本文使用的术语“亚链烯基”指具有二个至六个碳原子且具有至少一个双键的双官能的支链的或无支链的烃基,包括亚乙烯基、亚正丙烯基、亚正丁烯基等。
如本文使用的术语“亚炔基”指具有二个至六个碳原子且具有至少一个三键的双官能的支链的或无支链的烃基,包括亚乙炔基、亚正丙炔基、亚正丁炔基等。
如本文使用的术语“芳基”指具有五个至十二个原子的芳香基,包括苯基、萘基等。
术语“杂芳基”指包括至少一个选自N、S和O的杂原子的芳香基,其包括吡啶基、吲哚基、呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、喹啉基、噁唑基等。
术语“烷芳基”、 “烷基杂芳基”和“烷基环烷基”指被芳基、杂芳基或环烷基取代的烷基,包括2-苯乙基、3-环己基丙基等。
术语“包含两个或三个独立地选自N、O和S的杂原子的5-元杂环”包括芳香环和杂芳香环,以及可以是饱和的或不饱和的环,其包括异噁唑基、噁唑基、噁二唑基、吡唑基、噻唑基、咪唑基、三唑基等。
术语“可药用盐”指适合治疗患者的酸加成盐或碱加成盐。
“可药用酸加成盐”指式I表示的碱性化合物或任意其中间体的任何无毒的有机酸或无机酸加成盐。形成适宜的盐的示例性无机酸包括盐酸、氢溴酸、硫酸和磷酸及酸金属盐(acid metal salts)比如正磷酸一氢钠和硫酸氢钾。形成适宜的盐的示例性有机酸包括单羧酸、二羧酸和三羧酸。这样的酸的示例为,例如乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、2-苯氧基苯甲酸、对-甲苯磺酸及其它磺酸比如甲烷磺酸和2-羟基乙烷磺酸。可以形成单酸盐或二酸盐,并且这样的盐可以以水合的、溶剂化的或基本上无水的形式存在。通常,与这些化合物的游离碱形式相比,这些化合物的酸加成盐更溶于水和多种亲水性有机溶剂,并且证实了更高的熔点。适宜的盐的选择标准是本领域技术人员已知的。其它非可药用盐例如草酸盐,可以用于例如分离式子I的化合物以供实验室使用或用于随后转化成可药用酸加成盐。
“可药用碱加成盐”指式I表示的酸性化合物或任意其中间体的任何无毒的有机碱或无机碱加成盐。形成适宜的盐的示例性的无机碱包括氢氧化锂、钠、钾、钙、镁或钡。形成适宜的盐的示例性的有机碱包括脂肪的、脂环的或芳香的有机胺,比如甲胺、三甲胺和甲基吡啶或氨。适宜的盐的选择可能很重要,以便在该分子中其它位置的酯官能性(如果存在)不被水解。适宜的盐的选择标准是本领域技术人员已知的。
“溶剂化物”指式I的化合物或式I的化合物的可药用盐,其中适宜的溶剂分子并入晶格中。适宜的溶剂为在作为溶剂化物给药剂量是生理学容许的。适宜的溶剂的实例为乙醇、水等。当水为溶剂时,所述分子称为水合物。
术语“立体异构体”为各个分子的仅仅在原子空间取向上不同的所有异构体的通称。其包括镜象异构体(对映异构体)、几何(顺式/反式)异构体和具有多于一个手性中心且彼此不成镜像的化合物的异构体(非对映异构体)。
术语“治疗”指减轻症状、临时或永久性消除症状的起因,或预防或减慢所述障碍或病症的症状的出现。
术语“治疗有效量”指化合物的在治疗所述障碍或病症中有效的量。
术语“可药用载体”指与活性成分混合以便可以形成药物组合物的无毒溶剂、分散剂、赋形剂、助剂或其它物质,所述药物组合物即能给药至患者的剂型。这样的载体的一个实例为用于非肠道给药通常使用的可药用油。
化合物
本发明的化合物通常符合式I:
其中Ar、Hy、L、R1、m和n为上文定义的。
在一个实施方案中,Ar1为任选取代的苯基;示例性的取代基可选自F、Cl、Br、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤和CN。
在另一个实施方案中,Ar2为任选取代的吡啶基,例如2-吡啶基;示例性的取代基可选自F、Cl、Br、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤和CN。
在一个实施方案中,Hy为噁唑基;在另一个实施方案中,其为异噁唑;在其它实施方案中,其为噁二唑基或三唑基。
在一个实施方案中,L为-CH2-基;在另一个中,其为-CH(Me)-基;在还一个中,其为C(O)基。
在还一个实施方案中,R1为H或C1-6-烷基。
在一个实施方案中,n为1;在另一个中,n为2。
在还一个实施方案中,m为0;在其它中,m为1或2。
本领域技术人员应当理解,当本发明的化合物包含一个或多个手性中心时,本发明的化合物可以以对映体形式或非对映体形式,或作为外消旋混合物存在和分离。本发明包括式I化合物的任何可能的对映异构体、非对映体、外消旋体或其混合物。本发明的化合物的光学活性形式可以通过例如如下方法制备:手性色谱分离外消旋体或化学方法或酶拆分方法(enzymatic resolution methodology)、从光学活性的原料合成或通过基于随后描述的步骤的不对称合成。
本领域技术人员也应当理解本发明的某些化合物可以以几何异构体例如链烯的E和Z异构体存在。本发明包括式I化合物的任何几何异构体。进一步理解本发明包括式I化合物的互变异构体。
本领域技术人员也应当理解本发明的某些化合物可以以溶剂化的,例如水合的,以及未溶剂化的形式存在。将进一步理解本发明包括式I化合物的所有这些溶剂化的形式。
式I的化合物的盐也在本发明的范围内。通常,本发明的化合物的可药用盐是使用本领域众所周知的标准方法获得的,例如,通过使充分碱性的化合物,例如烷基胺,与适宜的酸,例如HCl或乙酸,反应以得到具有生理学可接受的阴离子的盐。通过在水性介质中用一当量碱金属或碱土金属氢氧化物或醇盐(比如乙醇盐或甲醇盐),或适宜的碱性有机胺(比如胆碱或葡甲胺)处理具有适宜的酸性质子比如羧酸或酚的本发明的化合物,然后通过常规纯化技术制备相应的碱金属(比如钠、钾或锂)或碱土金属(比如钙)盐也是可能的。另外,季铵盐可以通过例如向中性胺中加入烷基化剂来制备。
在本发明的一个实施方案中,式I的化合物可以转化成其可药用盐或溶剂化物,特别是酸加成盐比如氢氯化物、氢溴化物、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、甲烷磺酸盐或对甲苯磺酸盐。
本发明的具体实例包括下述化合物、其可药用盐、水合物、溶剂化物、旋光异构体及其组合:
药物组合物
本发明的化合物可以配制成包括式I的化合物或其可药用盐或其溶剂化物与可药用载体或赋形剂的常规药物组合物。可药用载体可以是固体或液体。固体形式的制剂包括,但不限于粉剂、片剂、可分散的颗粒、胶囊、扁囊剂和栓剂。
固体载体可以是一种或多种物质,其也可充当稀释剂、调味剂、增溶剂、润滑剂、混悬剂、粘合剂或片剂崩解剂。固体载体也可以是包封物质。
在粉剂中,载体为细碎的固体,其与本发明的细碎的化合物或活性组分成混合物形式。在片剂中,活性组分与具有所需结合性质的载体以适宜的比例混合,并且被压制成所需的形状和尺寸。
为了制备栓剂组合物,首先熔化低熔点的蜡比如脂肪酸甘油酯和可可脂的混合物,并通过例如搅拌将活性成分分散在其中。然后,将熔融均相混合物倒入适宜尺寸的模具中,并使其冷却和凝固。
适宜的载体包括,但不限于碳酸镁、硬脂酸镁、滑石、乳糖、糖、果胶、糊精、淀粉、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点的蜡、可可脂等。
术语组合物也意在包括活性成分和用作载体的包封物质的制剂,得到其中所述活性组分(有或者没有其它的载体)被因此与其相关的载体包围的胶囊。同样地,包括扁囊剂。
片剂、粉末、扁囊剂和胶囊可用作适于口服给药的固体剂型。
液体形式的组合物包括溶液、悬浮液和乳液。例如,活性化合物的无菌水或水丙二醇溶液可以是适于非肠道给药的液体制剂。液体组合物也可以配制成在含水聚乙二醇溶液中的溶液。
用于口服给药的水溶液可以通过将活性组分溶于水中并根据需要加入适宜的着色剂、调味剂、稳定剂和增稠剂来制备。用于口服使用的含水悬浮液可以通过将细碎的活性组分与粘性物质分散在水中来制备,所述粘性物质比如天然合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠和药物制剂领域已知的其它混悬剂。旨在用于口服使用的示例性的组合物可包含一种或多种着色剂、甜味剂、调味剂和/或防腐剂。
根据给药方式,所述药物组合物包括约0.05%w(重量百分数)至约99%w,更特别是从约0.10%w至50%w的本发明的化合物,所有的重量百分数基于所述组合物的总重量。
用于实施本发明的治疗有效量可以由本领域普通技术人员使用已知的标准(所属标准包括个体患者的年龄、体重和反应)确定,并结合正治疗或正预防的疾病来理解。
医疗用途
已经发现根据本发明的化合物表现对于单独的代谢型谷氨酸受体(mGluR)亚型的高水平的效力和选择性。因此,预期本发明的化合物可用于治疗与mGluR5的兴奋性活化有关的病症,和用于抑制由mGluR5的兴奋性活化引起的神经元损伤。所述化合物可用于在包括人的哺乳动物中产生mGluR5的抑制作用。
包括mGluR5的第一组mGluR受体在中枢和周围神经系统及其它组织中高度表达。因此,期望本发明的化合物非常适合用于治疗mGluR5介导的病症,比如急性和慢性神经病症和精神病症、胃肠道病症和慢性和急性疼痛病症。
本发明涉及用于治疗的如上定义的式I的化合物。
本发明涉及用于治疗mGluR5介导的病症的如上定义的式I的化合物。
本发明涉及用于治疗下述病症的如上定义的式I的化合物:阿尔茨海默病老年性痴呆、AIDS诱导的痴呆、帕金森症、肌萎缩性脊髓侧索硬化症、亨廷顿氏舞蹈病、偏头痛、癫痫症、精神分裂症、抑郁症、焦虑症、急性焦虑症、眼科病症比如视网膜病、糖尿病性视网膜病、青光眼、听觉神经病症比如耳鸣、化疗诱导的神经病症、疱疹后神经痛和三叉神经痛、耐受性、依赖性、脆X综合症、孤独症、精神发育阻滞、精神分裂症和唐氏综合征。
本发明涉及用于治疗疼痛的如上定义的式I的化合物:与偏头痛有关的疼痛、炎性疼痛、神经性疼痛病症比如糖尿病性神经病、关节炎和类风湿性疾病、腰痛(low back pain)、术后疼痛和与多种包括癌症的病症有关的疼痛、心绞痛、肾或胆绞痛、月经痛、偏头痛和痛风。
本发明涉及用于治疗中风、头部创伤、缺氧和缺血性损伤、低血糖症、心血管疾病和癫痫症的如上定义的式I的化合物。
本发明还涉及如上定义的式I的化合物在制备治疗第I组mGluR受体介导的病症和任一种上述病症的药物中的用途。
本发明的一个实施方案涉及根据式I的化合物在治疗胃肠道病症中的用途。
本发明的另一个实施方案涉及式I的化合物在制备如下应用的药物中的用途:用于抑制暂时性下食道括约肌松弛、用于治疗GERD、用于预防G.I.返流、用于治疗回流、用于治疗哮喘、用于治疗喉炎、用于治疗肺病、用于处理发育停滞、用于治疗易激性肠疾病(IBS)和用于治疗功能性消化不良(FD)。
本发明也提供用于治疗患有mGluR5-介导的病症和任意上述病症或具有患所述病症风险的患者的所述病症的方法,其包括给药所述患者如上定义的有效量的式I的化合物。
用于治疗性或预防性处理特定病症所需的剂量将根据治疗的主体、给药途径和正治疗的疾病的严重程度而进行必要的变化。
在本说明书中,术语“治疗”和“疗法”包括预防或者防止,除非特定地指出相反的意思。术语“治疗的”应当作相应的理解。
在该说明书里,除非另有说明,术语“拮抗剂″和“抑制剂”是指通过任何方式部分地或完全地阻断引起配体产生响应的转导通道的化合物。
除非另有说明,术语“病症”指与代谢型谷氨酸受体活性有关的任何病症和疾病。
非医疗用途
除了它们在治疗药物中的用途之外,式I的化合物、其盐和水合物还可在用于体外和体内试验系统的开发和标准化中用作药理学工具,所述试验系统用于在实验动物如猫、狗、兔、猴、大鼠和小鼠中评价mGluR相关活性的抑制剂的作用,作为寻找新的治疗剂的研究的一部分。
制备方法
本发明的另一个方面提供用于制备式I的化合物、或其盐或水合物的方法。制备在本发明中的化合物的方法在此进行描述。某些杂环Hy(例如噁唑、异噁唑和1,2,4-噁二唑)的合成描述在公布的PCT申请WO04014881、WO04014370和WO05080379中,其中重要的细节显示如下。
在下述对这些方法的整个说明中,应当理解,在适当的时候,以有机合成领域技术人员容易理解的方式对各种反应物和中间体加上适宜的保护基并随后将其除去。使用这样的保护基的常规方法以及适宜的保护基的实例在例如″Protective Groups in Organic Synthesis″,T.W.Green,P.G.M.Wuts,Wiley-Interscience,New York,(1999)中描述。还应当理解,通过化学操作将基团或取代基转化为另外的基团或取代基可以在朝向最终产物的合成途径的任何中间体或最终产物上进行,其中可能的转化类型仅仅受限于分子在该阶段载有的其它官能团对所述转化所采用的条件或试剂的固有不相容性。这种固有的不相容性、和通过以合适的次序执行适当的转化和合成步骤绕过这些固有不相容性的方法,是有机合成领域技术人员容易理解的。如下给出了转化的实例,应当理解,所述的转化不仅仅限于举例说明转化的一般性基团或取代基。关于其它适宜的转化的参考和说明在″Comprehensive Organic Transformations-AGuide to Functional Group Preparations″R.C.Larock,VHC Publishers,Inc.(1989)中给出。对其它适宜的反应的参考和说明在有机化学教科书中描述,例如″Advanced Organic Chemistry″,March,第4版,McGrawHill(1992)或″Organic Synthesis″,Smith,McGraw Hill,(1994)。用于纯化中间体和最终产物的技术包括例如在柱或旋转板上的正相和反相色谱法、重结晶、蒸馏和液-液或固-液萃取,其可由本领域技术人员容易理解。取代基和基团的定义如式I中所述,除非另有不同的定义。除非另有说明,术语“室温”和“环境温度”指在16至25℃之间的温度。
中间体的制备
a)式(iv)的噁二唑的形成
如方案1所示,其中A和A’独立地选自Ar1和L-LG2(其中LG2为离去基团比如氯或甲磺酰基(mesylate))的式(iv)的化合物可以通过环化式(iii)的化合物制备,其进而由适当活化的式(ii)的化合物与式(i)的化合物形成。
式(i)的化合物可以在适宜的溶剂中使用适当的碱通过加入羟胺从适宜的腈或从适宜取代的腈胺制备,所述羟胺例如盐酸盐,所述溶剂比如甲醇、乙醇、水、二噁烷或其混合物,所述碱比如氢氧化物、碳酸盐、乙酸盐或吡啶。
式(ii)的化合物可以通过以下述非限定性方法活化:i)当是酰基氯时,使用适宜的试剂比如草酰氯或亚硫酰二氯由酸形成;ii)当是酸酐或混合酸酐时,用试剂比如氯甲酸烷基酯处理形成;iii)使用常规方法在酰胺偶联反应比如EDCI和HOBt或脲鎓盐如HBTU中活化酸;iv)当是烷基酯时,在升高的温度(80-110℃)下,在溶剂比如乙醇或甲苯中使用强碱如叔丁醇钠或氢化钠去质子化羟脒形成。
化合物(i)和(ii)转化成类型(iv)的化合物的转化可以以两个连续步骤经由分离出的如上所述的类型(iii)的中间体进行,或经由在酯形成期间可在原位自发形成的中间体环化进行。酯(iii)的形成可以使用适宜的非质子溶剂比如DCM、四氢呋喃、N,N--二甲基甲酰胺或甲苯与任选适宜的有机碱比如三乙胺、二异丙基乙胺等或无机碱如碳酸氢钠或碳酸钾来完成。式(iii)的化合物形成噁二唑的环化可以在粗酯上进行,通过蒸发溶剂和替换为具有较高沸点的溶剂比如DMF或通过水提取以提供半纯化的物质,或通过用标准层析法纯化物质。所述环化可以如下进行:通过在适宜的溶剂比如吡啶或N,N-二甲基甲酰胺中常规加热或者微波照射(100-180℃),或使用采用试剂比如在四氢呋喃中的四丁铵氟化物的较低温度法,或通过任意其他适宜已知的文献方法。
上述反应的进一步的实施例可以在Poulain等人,TetrahedronLett.,(2001),42,1495-98,Ganglott等人.,Tetrahedron Lett.,(2001),42,1441-43和Mathvink等人,Bioorg.Med.Chem.Lett.(1999),9,1 869-74中找到,在此将其引入作为参考。
b)式(ix)的异噁唑的形成
如方案2所示,其中A和A’独立地选自Ar1和L-LG2(其中LG2为离去基团比如氯或甲磺酰基)的式(ix)的化合物可以通过在溶剂比如甲苯中,在适宜的温度(0℃-100℃)下,在使用适宜的碱比如碳酸氢钠或三乙胺的碱性条件下,式(v)和(vi)的化合物进行1,3-偶极环加成制备。类型(v)的化合物的合成之前已经在文献比如Kim,Jae Nyoung;Ryu,Eung K;J.Org.Chem.(1992),57,6649-50中描述。与类型(vi)的乙炔的1,3-偶极环加成也可以在升高的温度(50-100℃)下,在碱比如三乙胺的存在下,使用类型(vii)的取代的硝基甲烷经由用亲电子试剂比如PhNCO活化来进行。Li,C-S.;Lacasse,E.;Tetrahedron Lett.(2002)43;3565-3568。某些类型(vi)的化合物为市售获得的,或可以通过如本领域技术人员已知的标准方法合成。
可选地,式(viii)的化合物,其由甲基酮和酯使用利用这样的碱如氢化钠或叔丁醇钾的碱性条件的Claisen缩合获得,可经由缩聚和随后在升高的温度(60-120℃)下使用例如盐酸盐形式的羟胺环化生成式(ix)的化合物。
应当理解,对于两种方法而言,随后的功能团转化可能都是必需的。在酯基的情况下,这些转化可包括,但不限于下述三个方法中的任一个:a)使用适宜的还原剂比如LAH在溶剂比如THF中完全还原。b)使用适宜的选择性还原剂比如DIBAL部分还原,随后用卤代烷烷基化。c)使用烷基金属试剂比如烷基镁化卤在溶剂比如甲苯或THF中烷基化,随后用例如硼氢化钠在甲醇中还原。
c)式(xii)和(xv)的1,3-噁唑的形成
如方案3所示,其中A和A’独立地选自Ar1和L-LG2(其中LG2为离去基团比如氯或甲磺酰基)的式(XII)的化合物,可以根据Lee和Hong;Tetrahedron Lett.,(1997),38,8959-60的方法在酸性条件下在原位产生的Tl(OTf)3的存在下由式(x)和(xi)的化合物反应制备。
可选地,异构体(xv)可以由如下的发应获得:式(ii)和(xiii)的化合物如同上面对于式(V)所描述那样进行反应,得到式(xiv)中间体。这样的中间体可通过与Deoxo-Fluor环化脱水作用产生噁唑啉,随后在同一反应锅中使用BrCCl3脱氢作用得到所需的噁唑。Phillips,A.J.;Uto,Y.;Wipf,P.;Reno,M.J.and Williams,D.R.,Organic Letters,(2000)2,1165-8。
d)1,2,3-三唑的形成
根据方案4,1-芳基-1H-1,2,3-三唑衍生物(xviii)可以通过最初重氮化随后使用NaN3将重氮盐转化成相应的叠氮化物(xvii),从市售获得的苯胺(xvi)制备。然后,可以使用催化剂CuSO4以区域专一性方式将所述芳基叠氮化物用炔丙醇环化,得到[1,2,3]三唑醇中间体(xviii)(参见Rostovtsev,V.V.,Green,L.G.,Fokin,V.V.,Sharpless,K.B.:Angew.,Chem.Intl.Ed.2002,41,14,2596-2599。)。所述叠氮化物也可以根据OrganicLetters 2004,第6卷,第22期,3897-3899页的方法通过在65℃加热在9:1 DMSO∶H2O中的芳基碘化物或溴化物(xix)、炔丙醇、L-脯氨酸、碳酸钠、叠氮化钠、抗坏血酸钠和硫酸铜五水合物的混合物从芳基碘化物或溴化物(xix)原位形成。
最终化合物的制备
式I的化合物可以通过在Sn2条件下用亲核试剂处理上述中间体制备。典型地,在温和的碱性条件下,用例如适当取代的芳基哌嗪处理其中离去基团LG为甲磺酰基或氯化物的中间体。
可选地,式I的化合物可以通过例如适当取代的芳基哌嗪与其中L-LG2表示醛基的中间体进行还原性氨基化制备。
式I的化合物也可以通过例如适当取代的芳基哌嗪与其中L-LG2表示CO2H基的中间体进行EDCI偶合制备。
* * * * *
本发明进一步通过下述实施例来阐述,其用于详细说明本发明的一些实施方案。这些实施例并不试图,它们也不能被解释为,限制本发明的范围。显然,本发明可以按除了本文特定描述的之外方式来实施。根据本文的教导,本发明的许多改变和变化是可能的,因此其也在本发明的范围之内。
一般方法
缩写
BOC 叔丁氧基羰基
BSA 牛血清白蛋白
CCD 电荷耦合装置
DBU 1,8-二氮杂二环[5.4.0]十一碳-7-烯
DCM 二氯甲烷
DHPG 3,5-二羟基苯基甘氨酸
DIBAL 二异丁基铝氢化物
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
FLIPR 荧光成像板阅读器
GC/MS 气相色谱偶合质谱
GHEK 表达谷氨酸转运体的人类胚肾
HEPES 4-(2-羟乙基)-1-哌嗪乙烷磺酸(缓冲液)
IP3 肌醇三磷酸
MCPBA 3-氯过苯甲酸(3-chloroperbenzoic acid)
MeOH 甲醇
NMP N-甲基吡咯烷酮
NMR 核磁共振
PCC 氯铬酸吡啶鎓
ppm 百万分率
RT 室温
SPE 固相萃取法
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
所有的起始原料为市售获得的或以前在文献中所描述的。某些杂环Hy的合成描述在公布的PCT申请WO04014881、WO04014370和WO05080379中。
1H和13C NMR谱在Bruker 300、Bruker DPX400或Varian+400光谱仪上记录,1H NMR分别以300、400和400 MHz操作,除非另有说明,在作为溶剂的氘代氯仿中使用TMS或残留溶剂的信号作为参照。所有报告的化学位移为以ppm表示的δ标度,并且信号的精细分裂出现在报告中(s:单峰,br s:宽的单峰,d:双峰,t:三峰,q:四峰,m:多峰)。除非另有说明,在下述表中的1H NMR数据为在300 MHz,使用CDCl3作为溶剂获得的。
分析性在线液相色谱分离随后质谱检测纪录在Waters LCMS上,其由Alliance 2795(LC)和ZQ单四极质谱仪组成。所述质谱仪装有以正离子和/或负离子模式操作的电雾化离子源。离子喷雾电压为±3 kV,质谱仪从m/z 100-700扫描,扫描时间0.8s。对于柱X-Terra MS,Waters,C8,2.1×50mm,3.5 mm,施用从在10mM乙酸铵(aq.)或在0.1%TFA(aq.)中5%至100%乙腈的线性梯度。
产物纯化也使用 Chem Elut Extraction Columns(Varian,cat#1219-8002)、Mega BE-SI(Bond Elut Silica)SPE柱(Varian,cat #12256018;12256026;12256034)或通过在二氧化硅填充的玻璃柱中的急骤层析法进行。
微波加热在来自Biotage/Personal Chemistry的Emrys Optimizer或产生2450 MHz连续照射的Smith Synthesizer Single-mode微波腔(PersonalChemistry AB,Uppsala,Sweden)中进行。
可以使用用于功能活性的标准测定来分析本发明的化合物的药理学性质。谷氨酸受体测定的实例是本领域众所周知的,如在例如Aramori等人,Neuron 8:757(1992),Tanabe等人,Neuron 8:169(1992),Miller等人,J.Neuroscience 15:6103(1995),Balazs,等人,J.Neurochemistry69:151(1997)中所描述的。将在这些出版物中描述的方法引入本文作为参考。方便地,本发明化合物可利用测量表达mGluR5的细胞中的细胞内钙[Ca2+]i转移的测定进行研究。
细胞内钙转移是通过检测装载有荧光指示剂fluo-3的细胞中荧光的变化来测量。使用FLIPR系统(Molecular Devices)测量荧光信号。使用可以检测或者激活或拮抗所述受体的化合物的两种加成(addition)试验。
对于FLIPR分析,将表达人类mGluR5d的细胞接种在涂有胶原蛋白的具有透明底部和黑色侧面的96孔板上,并且在接种后24小时分析[Ca2+]i转移。
使用0.800 W和0.4秒CCD摄像机快门速度的激光设置进行FLIPR试验。用存在于细胞板每孔中的160μL的缓冲液引发每个FLIPR试验。在每次加入所述化合物后,以1秒间隔采样荧光信号50次,随后以5秒间隔采样3次。响应是以采样期间所述响应的峰高度来测量的。
从得自一式两份进行的8点浓度响应曲线(CRC)获得的数据测定EC50和IC50。通过将所有的响应相对于观察到的板的最大响应进行换算产生激动剂CRC。将激动剂攻击的拮抗剂阻断相对于向同一板上的14个对照孔内的激动剂攻击的平均响应归一化。
我们基于肌醇磷酸(IP3)的更新验证了用于mGluR5d的二次功能测定(secondary functional assay)。测定IP3积聚作为受体介导的磷脂酶C更新的指数。将稳定地表达人类mGluR5d受体的GHEK细胞用[3H]肌醇培养过夜,在HEPES缓冲盐水中洗涤3次,用10mM的LiCl预培养10分钟。加入化合物(激动剂),并在37℃培养30分钟。通过预培养测试化合物15分钟,然后在谷氨酸(80μM)或DHPG(30μM)存在下培养30分钟来测定拮抗剂活性。通过加入高氯酸(5%)终止反应。收集样品并中和,使用重力给料式(Gravity-Fed)离子交换柱分离肌醇磷酸。
测试本发明化合物的详细试验设计在下述药物实施例中提供。
实施例1:5-溴嘧啶-4-腈
i)将5-溴嘧啶(50mmol)和MCPBA(57.5mmol)在氯仿(100mL)中加热回流8小时。将该反应混合物在下降的真空下浓缩至干。将固体收集在饱和的碳酸氢盐(100mL)中,并用DCM(3×100mL)萃取。用硫酸镁干燥有机层,过滤并在下降的真空下蒸干。研磨该固体与二乙醚(30mL加10mL洗涤),得到5-溴嘧啶-1-氧化物(23%)。
ii)在环境温度下,用在乙腈(50mL)中的三甲基甲硅烷基氰化物(0.92mmol)和三乙胺(1.84mmol)处理5-溴嘧啶-1-氧化物(0.46mmol)。将粗产物浓缩并通过色谱法(硅胶,己烷/乙酸乙酯)纯化,得到标题化合物(0.46g,20%)。1H NMR(CDCl3)δ(ppm):9.27(s,1H);9.09(s,1H).
实施例2:5-溴吡嗪-2-腈
i)在氮气氛下,将四(三苯膦)钯(O)(10mg)加入到在螺帽反应容器中5-溴吡嗪-2-胺(0.575mmol)、氰化钾(1.15mmol)、碘化铜(I)(0.575mmol)和18-冠-6(20mg)在无水DMF(1mL)中的混合物中,在200℃加热搅拌该混合物1小时。冷却后,加入水(5mL),用氯仿(2x)萃取产物,通过色谱法(二氧化硅,己烷:乙酸乙酯)(0.208 mmol,36%)纯化,得到5-氨基吡嗪-2-腈。
ii)将在乙腈(1mL)中的5-氨基吡嗪-2-腈(0.208mmol)分部分加至溴化铜(II)(0.25mmol)和叔丁基腈(0.31mmol)在乙腈(2mL)中的搅拌溶液中,将该反应混合物保持在60℃1小时。用乙酸乙酯(15mL)稀释反应,并用1N HCl(含水)洗涤两次。通过色谱法(二氧化硅,己烷;乙酸乙酯)进行纯化,得到标题化合物(49%)。1H NMR(CDCl3)δ(ppm):8.83(s,1H);8.71(s,1H)。
实施例3:哌嗪中间体的制备
一般方法A:在RT下氯-杂芳基的亲核取代(硝基活化基团)
将哌嗪(2-5mmol)和2-氯-3-硝基吡啶(1mmol)溶于DMF或乙腈(2-3mL)中,在室温下搅拌5分钟。在加入溶剂后不久观察到少量放热。当TLC分析显示出反应完成时,用DCM稀释该混合物,并用水洗涤。干燥有机层,过滤并浓缩,然后在DCM中的10%MeOH中进行色谱法,得到期望的产物。
一般方法B:杂芳基卤化物的氨基化
i)将BOC-哌嗪(2.4mmol)、5-溴嘧啶-4-腈(2mmol)、碳酸钾(2.8mmol)、2-二环己基膦基-2’,4’,6’-三异丙基联苯(0.16mmol)、三(双亚苄基丙酮)二钯(O)(tris(dibenzylideneacetone)dipalladium)(0.04mmol)溶于NMP(N-甲基吡咯烷酮)(5mL)中,在200℃搅拌10分钟。用乙酸乙酯稀释该冷却的混合物,并用水洗涤。干燥有机层,过滤并浓缩,然后在己烷中的20-50%乙酸乙酯中进行色谱法,得到期望的BOC-保护的中间体。注意:使用相同的步骤由5-溴吡嗪-2-腈制备4-(5-氰基吡嗪-2-基)哌嗪-1-羧酸叔丁基酯,不同在于在85℃下,在DMF中进行该反应4小时。
ii)在标准的条件(50%TFA/DCM)下完成BOC保护基的除去,之后立即与甲磺酸酯(mesylate)反应。
实施例4:5-(5-氯-2-氟苯基)异噁唑-3-甲醛
(i)氯(羟基亚氨基)乙酸乙基酯
在0℃,将浓盐酸(5.9ml,71.65mmol)滴加到甘氨酸乙酯盐酸盐(10g,71.65mmol)在水(15ml)中的溶液中。然后,将在水(7.5ml)中的亚硝酸钠(4.94g,71.65mmol)滴加到得到的混合物中,保持温度低于5℃。10分钟后,滴加另一份等量的盐酸(5.9ml,71.65mmol),然后加入在水中(7.5ml)的亚硝酸钠(4.94g,71.65mmol),再次保持温度低于5℃。在0℃搅拌该反应混合物45分钟,然后用醚洗涤。用无水硫酸钠干燥有机相并真空浓缩,得到黄色固体。从己烷中重结晶该固体,过滤并用己烷洗涤,分离白色的结晶固体(5.4153g,49.9%)。1H NMR(300MHz,CDCl3):δ(ppm)9.01(s,1H);4.42(q,2H);1.41(t,3H)。
(ii)4-氯-2-乙炔基-1-氟苯
在100℃,搅拌2-溴-4-氯-1-氟苯(2.91ml,23.9mmol)、乙炔基-三甲硅烷(5.2ml,36.5mmol)、乙酸钯(II)(108mg,0.478mmol)和三苯膦(250mg,0.965mmol)在三乙胺(30ml)中的溶液过夜。当通过GC/MS完成反应时,用乙酸乙酯稀释混合物,并通过过滤。在真空中浓缩该滤液,并将残余物吸收在硅胶上。使用己烷洗脱产物。真空浓缩,得到定量收率的棕色油,将其用于下一步中无需进一步纯化。1H NMR(300MHz,CDCl3):δ(ppm)7.45(m,1H);7.28(m,1H);7.02(t,1H);0.281(s,9H)。
在室温下,搅拌(5-氯-2-氟-苯基乙炔基)-三甲硅烷(预期5.4196g,23.9mmol)和碳酸钾(16.50g,138.21mmol)在MeOH(60ml)中的混合物1小时。使用GC/MS完成检查(checked)反应混合物,然后用己烷稀释,并用水洗涤。用己烷(2x)萃取水相。用盐水洗涤组合的有机相,用无水硫酸钠干燥,过滤。真空浓缩,得到标题化合物(棕色油,定量收率,3.74g)。1H NMR(300MHz,CDCl3):δ(ppm)7.47(m,1H);7.30(m,1H);7.05(t,1H);3.63(s,1H).
(iii)5-(5-氯-2-氟苯基)异噁唑-3-羧酸乙基酯
将氯(羟基亚氨基)乙酸乙基酯(3.9271g,25.9mmol)和碳酸氢钠(7.00g,84.1mmol)加入到4-氯-2-乙炔基-1-氟苯(2.0019g,12.9mmol)在甲苯(50ml)中的溶液中。在室温下搅拌该反应混合物过夜,然后过滤,并在真空中浓缩滤液。将残余物收集在乙酸乙酯中,并用水洗涤。用盐水洗涤有机相,用硫酸钠干燥并真空浓缩。色谱法(硅胶,0-2%丙酮/己烷),得到黄色固体(1.4794g,42.5%)。1H NMR(300MHz,CDCl3):δ(ppm)8.00(m,1H);7.44(m,1H);7.19(m,2H);4.50(q,2H);1.45(t,3H).
(iv)[5-(5-氯-2-氟苯基)异噁唑-3-基]甲醇
将氢化铝锂(95%,0.2082g,5.486mmol)慢慢地加入到5-(5-氯-2-氟苯基)异噁唑-3-羧酸乙基酯(1.4794g,5.486mmol)在THF(20ml)中的溶液中。在室温下搅拌该反应混合物1小时。加入硫酸钠十水合物猝灭,并在63℃搅拌该混合物15分钟,通过使用DCM的衬垫过滤。真空浓缩滤液,得到棕色固体(600mg,48%,使用而无需进一步纯化)。1HNMR(300MHz,CDCl3):δ(ppm)7.96(m,1H);7.40(m,1H);7.17(t,1H);6.83(s,1H);4.86(d,2H)。
(v)5-(5-氯-2-氟苯基)异噁唑-3-甲醛
将[5-(5-氯-2-氟苯基)异噁唑-3-基]甲醇(600mg,2.636mmol)在DCM中的溶液滴加到氯铬酸吡啶鎓(852.32mg,3.953mmol)在DCM(20ml)中的溶液中。在室温下,搅拌该反应混合物过夜,并通过二氧化硅过滤,真空浓缩滤液。色谱法(硅胶,乙酸乙酯/己烷(0-10%),得到白色固体(310mg,52.1%)。1H NMR(300MHz,CDCl3):δ(ppm)10.24(s,1H);8.05(m,1H);7.43(m,1H);7.07(m,2H)。
实施例5:1-[5-(3-氯苯基)异噁唑-3-基]乙醇
(i)4-(3-氯苯基)-2,4-二氧丁酸乙基酯
在0℃,将氢化钠(60%的油分散液,1.24g,31.1mmol)分批加入3-氯苯乙酮(4.0g,25.9mmol)和草酸二乙酯(4.54g,31.1mmol)在DMF(32mL)的溶液中。在室温下,搅拌该混合物1小时,然后在80℃加热30分钟。冷却后,用3N HCl处理该混合物,然后用乙酸乙酯稀释。用水(3X)和饱和盐水洗涤有机层,用无水硫酸钠干燥,过滤并浓缩。色谱法(二氧化硅,在己烷中0-10%的乙酸乙酯)得到标题化合物(4.43g,67%,黄色固体)。1H NMR(CDCl3)δ(ppm):15.12(br s,1H),7.98(s,1H),7.88(d,1H),7.58(d,1H),7.47(t,1H),7.05(s,1H),4.39(m,2H),1.41(m,3H)。
(ii)5-(3-氯苯基)异噁唑-3-羧酸乙基酯
在80℃,加热4-(3-氯苯基)-2,4-二氧丁酸乙基酯(3.0g,11.8mmol)和盐酸羟胺(2.46g,35.4mmol)在MeOH(60mL)中的溶液4小时。冷却后,过滤该混合物,并用冷的MeOH洗涤,得到5-(3-氯-苯基)-异噁唑-3-羧酸乙酯(2.0g,71%,白色固体)。1H NMR(CDCl3)δ(ppm):7.82(s,1H),7.72(m,1H),7.47(m,2H),4.03(s,3H)。甲酯和乙酯(主要是甲酯)的混合物。
(iii)1-[5-(3-氯苯基)异噁唑-3-基]乙酮
在0℃,将5-(3-氯苯基)异噁唑-3-羧酸乙基酯(300mg,1.19mmol)在甲苯(5ml)中的溶液加入到碘化甲基镁(在二乙醚中,3M)(0.79ml,2.38mmol)、甲苯(1ml)、四氢呋喃(0.39ml,4.77mmol)和三乙胺(1ml,7.15mmol)的混合物中。在0℃,搅拌得到的混合物5小时,然后用1N盐酸(含水,6.5ml,6.5mmol)猝灭,用甲苯(35ml)稀释,连续用水(50ml)、饱和的碳酸氢钠(含水,30ml)、水(50ml)和盐水(30ml)洗涤。真空浓缩有机相。将分离的残余物溶于MeOH(8ml)和20%的氢氧化钾(含水,1ml)中。在45℃搅拌该混合物30分钟,并真空浓缩。将该残余物溶于甲苯(60ml)中,连续用水(50ml)、饱和的碳酸氢钠(含水,50ml)和水(50ml)洗涤。真空浓缩有机相。色谱法(硅胶,在己烷中2%的乙酸乙酯),得到标题化合物(白色固体,156mg,60%)。1H-NMR(CDCl3),δ(ppm):7.77(m,1H),7.66(m,1H),7.42(m,2H),6.90(s,1H),2.69(s,3H).
(iv)1-[5-(3-氯苯基)异噁唑-3-基]乙醇
在室温下,搅拌1-[5-(3-氯苯基)异噁唑-3-基]乙酮(100mg,0.45mmol)、硼氢化钠(34mg,0.90mmol)和MeOH(3ml)的混合物3小时。用水(30ml)和盐水(30ml)猝灭该反应,用DCM(3×30ml)萃取产物。干燥有机层(,硫酸钠),过滤并真空浓缩,得到标题化合物(白色固体,110mg)。1H-NMR(CDCl3),δ(ppm):7.69(m,1H),7.59(m,1H),7.37(m,2H),6.59(s,1H),5.07(q,1H),3.45(bs,1H),1.58(d,3H)。
实施例6:1-[5-(5-氯-2-氟苯基)异噁唑-3-基]乙醇
在0℃,将碘化甲基镁(3M,二乙醚)(0.766ml,2.298mmol)滴加到5-(5-氯-2-氟苯基)异噁唑-3-甲醛(259.3mg,1.149mmol)在THF(5ml)中的溶液中。在0℃搅拌该混合物1.5小时,然后加入乙酸乙酯和氯化铵。分离有机相,用盐水洗涤,用无水硫酸钠干燥并真空浓缩。色谱法(硅胶,0-20%乙酸乙酯/己烷),得到标题化合物(透明油,190mg,68.3%)。1HNMR(300MHz,CDCl3):δ(ppm)7.95(m,1H);7.40(m,1H);7.17(t,1H);6.80(s,1H);5.12(m,1H);2.22(d,1H);1.64(d,3H)。
实施例7:3-[3-(1-羟乙基)异噁唑-5-基]苯基氰
(i)5-(3-碘苯基)异噁唑-3-羧酸甲基酯
在0℃,将氢化钠(60%的油分散体,4.9g,122.8mmol)分批加入3-碘苯乙酮(25.18g,102.3mmol)和草酸二乙酯(14.5g,122.8mmol)在DMF(125mL)的溶液中。在室温下,搅拌该混合物1小时,然后在115℃加热1小时。冷却后,用3N HCl处理该混合物,然后用乙酸乙酯稀释。用水(3X)和饱和盐水洗涤有机层,用无水硫酸钠干燥,过滤并浓缩。色谱法(二氧化硅,在己烷中0-10%的乙酸乙酯)得到中间体(24.21g,71.3%,黄色固体)。
加热回流该中间体(33.87g,102mmol)和盐酸羟胺(21.3g,306mmol)在MeOH(450mL)中的溶液4小时。冷却后,过滤该混合物,并用冷的MeOH洗涤,得到标题化合物(24.10g,72%,棕色固体)。1HNMR(CDCl3)δ(ppm):8.18(m,1H),7.82(t,2H),7.26(t,1H),6.97(s,1H),4.03(s,3H)。
(ii)[5-(3-碘苯基)异噁唑-3-基]甲醇
在-78℃,将DIBAL(55.8mL,在甲苯中1.5M,83.7mmol)慢慢地加入到5-(3-碘苯基)异噁唑-3-羧酸甲基酯(12g,36.5mmol)在甲苯(60ml)和THF(60mL)中的溶液中。在-78℃,搅拌得到的混合物过夜,然后使其慢慢地加热至室温。用冰和饱和的氯化铵(含水)猝灭该反应。用乙酸乙酯萃取产物,并用盐水洗涤有机层,用硫酸钠干燥并真空浓缩,得到标题化合物(灰白色固体,10.5g,95.6%)。1H-NMR(CDCl3),δ(ppm):8.12(m,1H),7.76(ddm,2H),7.21(t,1H),6.62(s,1H),4.83(s,2H),2.45(br s,1H)。
(iii)5-(3-碘苯基)异噁唑-3-甲醛
在室温下,搅拌[5-(3-碘苯基)异噁唑-3-基]甲醇(8.5g,28.23mmol)和氯铬酸吡啶鎓(9.13g,42.35mmol)在DCM(150ml)中的混合物过夜。用在己烷中的15%的乙酸乙酯稀释该混合物,并穿过少量硅胶填料,用另外的在己烷中的15%的乙酸乙酯洗脱。真空浓缩该洗脱液,得到标题化合物(浅黄色固体,7.0g,83%)。1H-NMR(CDCl3),δ(ppm):10.21(s,1H),8.19(m,1H),7.83(ddm,2H),7.27(m,1H),6.93(s,1H)。
(iv)3-[3-(1-羟乙基)异噁唑-5-基]苯基氰
将碘化甲基镁(33mL,在二乙醚中3M,99mmol)加入到冷的(0℃)5-(3-碘苯基)异噁唑-3-甲醛(7.5g,25mmol)在THF(100mL)中的溶液中。在0℃搅拌该反应混合物1小时,并用饱和的氯化铵猝灭。用乙酸乙酯萃取产物,并用盐水洗涤有机层,用硫酸钠和硅胶的混合物干燥。真空浓缩滤液,色谱法(二氧化硅,在己烷中15-50%的乙酸乙酯)得到粗的碘-异噁唑-醇(浅黄色油,6.5g,含有大约33%的1-(5-苯基异噁唑-3-基)乙醇)。
将叔丁基二甲基氯硅烷(2.5g,2.3mmol)加入到粗的1-[5-(3-碘苯基)-异噁唑-3-基]乙醇(4.9g,15.55mmol)和DBU(2.53g,2.13mmol)在DCM(60mL)的溶液中,并在室温下搅拌该反应3小时。加入叔丁基二甲基氯硅烷(2.5g,2.3mmol)和DBU(2.53g,2.13mmol),继续搅拌15分钟,直到TLC显示出醇被耗尽。将产物在饱和的氯化铵和DCM之间分配,干燥并真空浓缩有机层,得到碘-异噁唑-甲硅烷基醚(浅黄色固体,8.4g粗品)。
在82℃,搅拌粗的甲硅烷基醚、氰化锌(1.6g,13.69mmol)、四(三苯基膦)钯(O)(1.58g,1.37mmol)在DMF(100mL)中的混合物10分钟。用乙酸乙酯稀释该混合物,并通过过滤。真空浓缩滤液,并用DCM稀释。用水洗涤该溶液,用硫酸钠干燥并过滤。色谱法(预吸附在二氧化硅上,在己烷中1-5%的乙酸乙酯)得到纯的氰基-异噁唑-甲硅烷基醚(灰白色固体,3.83g,经3步,46.5%)。1H-NMR(CDCl3),δ(ppm):8.07(m,1H),8.04(dm,1H),7.73(dm,1H),7.62(t,1H),6.66(s,1H),5.09(q,1H),1.54(d,3H),0.93(s,9H),0.13(s,3H),0.06(s,3H)。
在0℃,将TBAF(20mL,在THF中1M,20mmol)加入到纯的氰基-异噁唑-甲硅烷基醚(3.83g,11.66mmol)在THF(40mL)中的溶液中,在室温下搅拌该混合物过夜。将产物在DCM和水之间分配。用盐水洗涤有机层,并用硫酸镁干燥。加入硅胶,使混合物通过使用在己烷中的50%乙酸乙酯的硅胶填料。真空浓缩该洗脱液,并将残余物与己烷研磨,得到标题化合物(灰白色固体,2.5g,100%)。1H-NMR(CDCl3),δ(ppm):8.07(m,1H),8.03(dm,1H),7.75(dm,1H),7.62(t,1H),6.7(s,1H),5.13(q,1H),1.64(d,3H)
实施例8:5-(3-氯苯基))异噁唑-3-羧酸
i)[5-(3-氯苯基)异噁唑-3-基]甲醇
在室温下,将氢化铝锂(320mg,8.4mmol)慢慢地加入5-(3-氯苯基)异噁唑-3-羧酸乙基酯(2.0g,8.4)在THF(100ml)中的溶液中。在1小时后,用水猝灭反应混合物,然后用乙酸乙酯萃取。用水和饱和盐水洗涤有机层,用无水硫酸钠干燥,过滤并浓缩。然后通过使用在己烷中15-40%的乙酸乙酯的急骤柱层析法纯化得到的残余物,得到标题化合物(1.32g,75%,黄色固体)。1H NMR(CDCl3)δ(ppm):7.78(s,1H),7.68(m,1H),7.43(m,2H),6.63(s,1H),4.84(d,2H),2.23(t,1H).
ii)5-(3-氯苯基))异噁唑-3-羧酸
将高锰酸钾(4.1g,26.23mmol)加入到冷的(10℃)[5-(3-氯苯基)异噁唑-3-基]甲醇(1.1g,5.25mmol)在丙酮(20mL)中的溶液中。在2小时后,将反应混合物通过过滤,用丙酮和水洗涤。真空除去丙酮,用1N HCl(aq)酸化水层。用乙酸乙酯(2x)萃取该产物,并干燥有机层,过滤并真空浓缩。用己烷研磨,得到标题化合物(286mg,24%,灰白色固体)。
实施例9:1,3-噁唑中间体-2-(3-氯苯基)-1,3-噁唑-4-羧酸的制备
i)2-[(3-氯苯甲酰基)氨基]-3-羟基丙酸甲基酯
在0℃,将N-甲基吗啉(7.0ml,63.8mmol)和EDCI(4.97g,31.9mmol)加入到3-氯苯甲酸(5.0g,31.9mmol)、丝氨酸甲酯盐酸化物(6.1g,31.9mmol)和HOBt(4.31g,31.9mmol)在DMF(100ml)中的混合物中。将该混合物加热至室温,并搅拌18小时。用乙酸乙酯(300ml)稀释该混合物,然后用水(3×250ml)洗涤,之后用盐水洗涤。用Na2SO4(无水)干燥有机提取物,然后真空浓缩,得到标题化合物(7.2g,93%,浅黄色固体)。1HNMR(CDCl3)δ(ppm):7.78(s,1H),7.66(d,1H),7.45,(dd,1H),7.34(t,1H),7.25(br,d,1H),4.82(m,1H),4.08(m,2H),3.79(s,3H),3.19(br,t,1H)。
ii)2-(3-氯苯基)-1,3-噁唑-4-羧酸甲基酯
在-20℃,将Deoxo-氟/二(2-甲氧基乙基)氨基-三氟化硫(7.2g,32.6mmol)滴加到2-[(3-氯苯甲酰基)氨基]-3-羟基丙酸甲基酯(7.2g,29.6mmol)在DCM中的溶液中。在该温度搅拌30分钟后,滴加BrCCl3(3.6g,18.1mmol),随后滴加DBU(2.79g,18.1mmol)。然后,在2-3℃搅拌该混合物8小时,之后用饱和的NaHCO3(aq)猝灭,随后用乙酸乙酯萃取。然后,用盐水洗涤有机萃取物,并用Na2SO4(无水)干燥。通过在硅胶上使用在己烷中的乙酸乙酯作为洗脱液的急骤柱层析进行纯化,得到2-(3-氯苯基)-1,3-噁唑-4-羧酸甲基酯(4.1g,59%,黄色固体)。.1HNMR(CDCl3)δ(ppm):8.30(s,1H),8.12(d,1H),7.98(dd,1H),7.45(m,2H),3.96(s,3H)。
iii)2-(3-氯苯基)-1,3-噁唑-4-羧酸
将氢氧化钠(10mL,1M,10mmol)加入到2-(3-氯苯基)-1,3-噁唑-4-羧酸甲基酯(1.0g,54.21mmol)在MeOH(20mL)中的悬浮液中。在60℃加热得到的混合物15分钟,然后用冰水混合物稀释。用1N HCl(aq)酸化得到的混合物直到pH为3。通过过滤收集固体产物,用水洗涤,并在真空下干燥,得到标题化合物(789mg,84%)。
实施例10:1-[5-(3-氯苯基)-1,2,4-噁二唑-3-基]乙醇
(i)N′,2-二羟基丙亚氨酰胺(dihydroxypropanimidamide)
在室温下,搅拌氢氧化钠(3.09g,77.37mmol)和盐酸羟胺(5.38g,77.37mmol)在乙醇(40mL)中的溶液30分钟。过滤该溶液,并将滤液慢慢加入到2-羟基-丙腈(5.05ml,70.34mmol)中。在室温下,搅拌该混合物过夜,然后浓缩,得到标题化合物(白色固体,6.3728g,87%)。1HNMR(300MHz,DMSO):δ(ppm)8.91(s,1H);5.23(s,2H);5.11(s,1H);4.01(q,1H);1.21(d,3H)。
(ii)1-[5-(3-氯苯基)-1,2,4-噁二唑-3-基]乙醇
在0℃,将3-氯-苯甲酰氯(2.71ml,21.13mmol)加入到2,N-二羟基-丙亚氨酰胺(2.0g,19.21mmol)在吡啶(25mL)中的溶液中。搅拌该反应混合物2.5小时,同时将其加热至室温,然后,在140℃加热1小时(密封的小瓶)。将该反应混合物倾入冰水中,并用DCM(×2)萃取。用盐水洗涤有机层,用无水硫酸钠干燥并真空浓缩。从在己烷中10%的乙酸乙酯重结晶得到的棕色固体,得到标题化合物(浅棕色固体,2.1828g,46.8%)。1H NMR(300MHz,CDCl3):δ(ppm)8.16(m,1H);8.04(m,1H);7.58(m,1H);7.50(m,1H);5.12(q,1H);2.71(s,1H);1.70(d,3H)。
实施例11:1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙醇
(i)1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙酸乙酯
在0℃,将几滴DMF加入到2-乙酰氧基丙酸(540mg,4.1mmol)和草酰氯(4mL,在DCM中2M,8mmol)在DCM(4mL)中的混合物中,观察起泡。在0℃搅拌该混合物30分钟,然后加热至室温1.5小时。加入甲苯(5mL)以确保除去在真空中浓缩期间过量的草酰氯。将3-氯-N′-羟基苯甲亚氨酰胺(599mg,3.51mmol)加入到酰基氯在乙酸乙酯(30mL)的溶液中。加入饱和的碳酸氢钠水溶液,强力搅拌该反应混合物30分钟。层分离,用盐水洗涤有机层,用硫酸钠干燥并真空浓缩。将DMF(5mL)加入到残余物中,在135℃搅拌得到的混合物1.5小时。真空除去溶剂,并用色谱法(手产物预吸附在二氧化硅上,在己烷中5-10%的乙酸乙酯)得到产物(452mg,48.3%)。1H NMR(300MHz,CDCl3):δ(ppm)8.11(m,1H),7.99(dm,1H),7.51(dm,1H),7.46(t,1H),6.11(q,1H),2.21(s,3H),1.77(d,3H)。
(ii)1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙醇
将氢氧化锂(3.7mL,0.5M的水溶液,1.85mmol)加入到1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙酸乙酯(451.6mg,1.69mmol)在THF(6mL)和MeOH(2.5mL)中的溶液中。搅拌该混合物2小时,然后在乙酸乙酯和水之间分配。用盐水洗涤有机层,用硫酸钠干燥并真空除去溶剂。色谱法(二氧化硅,在己烷中15-20%的乙酸乙酯)得到标题化合物(白色固体,382.9mg,100%)。1H NMR(300MHz,CDCl3):δ(ppm)8.11(m,1H),7.99(dm,1H),7.51(dd,1H),7.47(t,1H),5.19(m,1H),2.73(d,1H),1.75(d,3H)。
实施例12:一般方法:从乙炔形成三唑环
在65℃,搅拌芳基碘或芳基溴(1mmol)、炔丙醇(1mmol)、L-脯氨酸(0.2mmol)、碳酸钠(00.2mmol)、叠氮化钠(1.2mmol)、抗坏血酸钠(0.1mmol)和硫酸铜五水合物(0.05mmol)在2ml的9∶1DMSO∶H2O中的混合物过夜。用乙酸乙酯稀释该混合物,连续用水和稀氢氧化铵(3x)洗涤。通过SPE柱色谱法(二氧化硅,在DCM中7-10%的MeOH)纯化得到三唑。参考:Organic Letters.2004,Vol.6,No.22,3897-3899。
以这种方式制备下述化合物:
实施例13:5-(1-氯乙基)-3-(3-氯苯基)-1,2,4-噁二唑
(i)3-氯-N′-羟基苯甲亚氨酰胺
将氢氧化钠(8.2g,在50mL水中)和盐酸羟胺(16g,在20mL水中)加入到3-氯-苯基氰(28g,203.5mmol)在80℃的乙醇(50mL)中的溶液中。在80℃,搅拌得到的混合物2小时。真空除去溶剂,得到标题化合物(29.82g,85.9%)。1H NMR(300MHz,CDCl3):δ(ppm)7.65(s,1H),7.52(d,1H),7.41(d,1H),7.35(t,1H),4.86(br,2H),1.68(br,1H)。
(ii)5-(1-氯乙基)-3-(3-氯苯基)-1,2,4-噁二唑
将2-氯丙酰基氯化物(8.94g,70.4mmol)滴加到3-氯-N′-羟基苯甲亚氨酰胺(10.0g,58.7mmol)在10℃(冰浴)的乙酸乙酯(200mL)中的溶液中。加入饱和的碳酸氢钠水溶液,强力搅拌该反应混合物10分钟。层分离,连续用水和盐水洗涤有机层,用硫酸钠干燥并真空浓缩。将DMF(60mL)加入到残余物中,在135℃搅拌得到的混合物1.5小时。用水和DCM稀释该混合物,层分离。用水和盐水洗涤有机层,用硫酸钠干燥,过滤并真空浓缩。色谱法(产物预吸附在二氧化硅上,在己烷中5%的乙酸乙酯)得到产物(7.5g,52.6%)。1H NMR(300MHz,CDCl3):δ(ppm)8.11(s,1H),7.99(d,1H),7.52(d,1H),7.45(t,1H),5.28(q,1H),2.05(d,3H).
实施例14:一般方法:醇的甲磺酰化
在0℃,将甲磺酰氯(1.5mmol)和三乙胺(2mmol)加入到杂芳基醇(1mmol)在DCM(10-15ml)中的溶液中。在0℃搅拌该反应混合物30分钟,然后用冷的饱和的碳酸氢钠洗涤。用盐水洗涤有机层,用硫酸钠干燥并真空浓缩,得到标题化合物,使用其而无需进一步纯化。
使用上述方法合成下述甲磺酸酯。
实施例15:一般方法:甲磺酸酯的哌嗪置换
在80℃,搅拌适宜的甲磺酸酯(1mmol)、芳基哌嗪(1.5mmol)和碳酸钾(2mmol)在乙腈(15ml)中的混合物过夜。用乙酸乙酯和水稀释该反应混合物。用饱和的碳酸氢钠和盐水洗涤有机层,用无水硫酸钠干燥,并真空浓缩。SPE柱色谱法(硅胶,在己烷中0-70%的乙酸乙酯)得到期望的化合物。
使用上述方法合成下述化合物。
以相同的方法由相应的氯化物代替甲磺酸酯制备下述化合物。
实施例16:一般方法:用醛进行还原性氨基化
将氰基硼氢钠(1M THF)(1mmol)加入到芳基哌嗪(1mmol)、乙酸(0.09ml)和杂环醛(1mmol)在MeOH(4.5ml)中的溶液中。在室温下搅拌该反应混合物过夜。加入饱和的碳酸氢钠,并用DCM萃取产物。分离有机相,用水和盐水洗涤,用无水硫酸钠干燥并真空浓缩。SPE柱色谱法(硅胶,在己烷中0-50%的乙酸乙酯)得到期望的化合物。
使用上述方法合成下述化合物。
实施例17.1:经由EDCI偶合酸到芳基哌嗪上得到酰胺
1-{[5-(3-氯苯基)异噁唑-3-基]羰基}-4-(3-硝基吡啶-2-基)哌嗪
在室温下,搅拌1-(3-硝基吡啶-2-基)哌嗪(43.7mg,0.2mmol)、5-(3-氯苯基)异噁唑-3-羧酸(44.7mg,0.21mmol)、EDCI(38.3mg,0.2mmol)和HOBt(27.0mg,0.2mmol)在DMF(1mL)中的混合物过夜。用水稀释该混合物,并萃取到DCM中。干燥有机提取物,过滤并真空浓缩。将得到的固体与醚研磨,得到标题化合物(75.7mg,91.4%,黄色固体)。1HNMR(CDCl3)δ(ppm):8.41(dd,1H),8.22(dd,1H),7.82(t,1H),7.70(dd,1H),7.47(m,2H),6.92(s,1H),6.88(dd,1H),4.15(m,2H),3.99(m,2H),3.60(m,4H)。
以这种方式制备下述化合物:
实施例18:药物实施例
在表达mGluR5D的细胞系中的mGluR5拮抗作用的功能性评价
可以使用用于药理学活性的标准测定来分析本发明的化合物的性质。谷氨酸受体测定的实例是本领域众所周知的,如在例如Aramori等人,Neuron 8:757(1992),Tanabe等人,Neuron 8:169(1992),Miller等人,J.Neuroscience 15:6103(1995),Balazs,等人,J.Neurochemistry 69:151(1997)中所描述的。将在这些出版物中描述的方法引入本文作为参考。方便地,本发明化合物可利用测量表达mGluR5的细胞中的细胞内钙[Ca2+]i转移的测定(FLIPR)或测定肌醇磷酸更新的另一种测定(IP3)进行研究。
FLIPR测定
将如在WO97/05252中所述的表达人类mGluR5d的细胞以100,000个细胞每孔的密度接种在带有胶原涂层的、具有透明底部和黑色侧面的96孔板上,并且在接种24小时后进行试验。所有的测定在包含127mM的NaCl、5mM的KCl、2mM的MgCl2、0.7mM的NaH2PO4、2mM的CaCl2、0.422mg/ml的NaHCO3、2.4mg/ml的HEPES、1.8mg/ml的葡萄糖和1mg/ml的BSA Fraction IV(pH 7.4)的缓冲液中进行。将96孔板中的细胞培养物加载在上述缓冲液中60分钟,所述缓冲液含有在0.01%聚氧丙烯酸(pluronic acid)(自有的(proprietary)非离子型表面活性剂多元醇-CAS编号9003-11-6)中的4μM发荧光的钙指示剂fluo-3(Molecular Probes,Eugene,Oregon)的乙酰氧基甲基酯形式。在装载期后,除去fluo-3缓冲液,并用新鲜的测定缓冲液替换。使用0.800W和0.4秒CCD摄像机快门速度和激发波长和发射波长分别为488nm和562nm的激光装置进行FLIPR试验。用存在于每个细胞板的孔中的160μl的缓冲液引发每个试验。加入来自拮抗剂板的40μl,随后加入来自激动剂板的50μl。以90秒的间隔分开拮抗剂加入和激动剂加入。在所述两次加入的每次之后,立即以1秒间隔采样荧光信号50次并随后以5秒间隔采样3次。响应是以采样期间对激动剂响应的峰高度与本底荧光之间的差异来测量。使用线性最小二乘法拟合程序确定IC50。
IP3测定
另一个对mGluR5d的功能测定描述在WO97/05252中,其是基于磷脂酰肌醇更新。受体活化刺激磷脂酶C活性,并导致肌醇1,4,5-三磷酸(IP3)的形成增加。
将稳定地表达人类mGluR5d的GHEK以40×104细胞/孔接种在包含1μCi/孔[3H]肌醇的介质中的24孔聚-1-赖氨酸涂层板上。培养细胞过夜(16小时),然后,洗涤三次,在37℃在补充有1单位/ml的谷丙转氨酶和2mM的丙酮酸盐的HEPES缓冲盐水(146mM NaCl、4.2mMKCl、0.5mM MgCl2、0.1%葡萄糖、20mM HEPES、pH 7.4)中培养1小时。将细胞在HEPES缓冲盐水中洗涤一次,并在包含10mM LiCl的HEPES缓冲盐水中预培养10分钟。在37℃培养化合物两份15分钟,然后加入谷氨酸(80μM)或DHPG(30μM),并且再培养30分钟。通过加入在冰上的0.5ml的高氯酸(5%)终止该反应,并在4℃培养至少30分钟。将样品收集在15ml的聚丙烯管中,并使用离子交换树脂(DowexAGl-X8甲酸盐晶型,200-400目,BIORAD)柱分离肌醇磷酸。首先通过用8ml的30mM甲酸铵洗脱甘油基磷脂酰肌醇来进行肌醇磷酸分离。接着,用8ml的700mM甲酸铵/100mM甲酸洗脱所有的肌醇磷酸,并收集在闪烁瓶中。然后,将该洗脱液与8ml的闪烁剂混合,通过闪烁计数测定[3H]肌醇的结合。将来自两份样品的dpm计数绘成图,使用线性最小二乘法拟合程序确定IC50。
通常,本发明的化合物以少于10μM的浓度(或用IC50值)在本文描述的测定中有活性。本发明的优选化合物具有的EC50值少于1μM;更优选的化合物少于约100nM。例如,实施例16.1、15.11、15.16和15.17的化合物分别具有的IC50值为199、101、1082和159nM。
Claims (19)
1.式I的化合物或其可药用盐、水合物、溶剂化物、同工型、互变异构体、旋光异构体或其组合:
其中
Ar1和Ar2为独立选择的、任选取代的芳基或杂芳基,其中所述取代基选自F、Cl、Br、I、OH、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤、C2-6-链烯基、C2-6-炔基、CN、CO2R2、SR2、S(O)R2、SO2R2、芳基、杂芳基、环烷基和杂环烷基,其中任一个环取代基都可以进一步被至少一个选自下述的取代基取代:F、Cl、Br、I、OH、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤、C2-6-链烯基、C2-6-炔基、CN、CO2R2、SR2、S(O)R2、SO2R2;
R1,在每种情况下独立地选自F、Cl、Br、I、OH、CN、硝基、C1-6-烷基、OC1-6-烷基、C1-6-烷基卤、OC1-6-烷基卤、(CO)R2、O(CO)R2、O(CO)OR2、CO2R2、CONR2R3、C1-6-亚烷基OR2、OC2-6亚烷基OR2和C1-6亚烷基氰基;
R2和R3独立地选自H、C1-6-烷基、C1-6-烷基卤、C2-6-链烯基、C2-6-炔基和环烷基;
Hy为包含二或三个杂原子的5元杂环,所述杂原子独立地选自N、O和S,其中所述环任选地被一个或多个选自下述的取代基取代:F、Cl、Br、I、OH、硝基、C1-6-烷基、C1-6-烷基卤、OC1-6-烷基、OC1-6-烷基卤、CN、CO2R2、CONR2R3、SR2、S(O)R2、SO2R2;
L选自-CR4R5-、-C(O)-、-C(NR4)-和-C(S)-;
R4和R5独立地选自H、C1-6-烷基、C1-6-烷基卤、C2-6-链烯基和C2-6-炔基;
m为选自0、1、2、3和4的整数;和
n为选自1和2的整数。
2.根据权利要求1的化合物,其中Ar1为任选取代的苯基。
3.根据权利要求2的化合物,其中Ar2选自任选取代的吡啶基和任选取代的吡嗪基。
4.根据权利要求3的化合物,其中Ar2是任选取代的2-吡啶基。
5.根据权利要求4的化合物,其中L选自CH2和CH(Me)。
6.根据权利要求5的化合物,其中Hy选自异噁唑、1,2,4-噁二唑和1,2,3-三唑。
7.选自下述的化合物:
3-(4-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}哌嗪-1-基)吡嗪-2-腈,
2-(4-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}哌嗪-1-基)烟腈,
6-(4-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}哌嗪-1-基)烟腈,
1-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}-4-吡啶-2-基哌嗪,
2-(4-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}哌嗪-1-基)吡嗪,
3-(4-{1-[5-(3-氰基苯基)异噁唑-3-基]乙基}哌嗪-1-基)吡嗪-2-腈,
3-(4-{1-[5-(5-氯-2-氟苯基)异噁唑-3-基]乙基}哌嗪-1-基)吡嗪-2-腈,
6-(4-{1-[5-(5-氯-2-氟苯基)异噁唑-3-基]乙基}哌嗪-1-基)烟腈,
3-(3-{1-[4-(3-硝基吡啶-2-基)哌嗪-1-基]乙基}异噁唑-5-基)苯基氰,
1-{1 -[5-(3-氯苯基)异噁唑-3-基]乙基}-4-(3-硝基吡啶-2-基)哌嗪,
3-(4-{1-[5-(3-氯苯基)-1,2,4-噁二唑-3-基]乙基}哌嗪-1-基)吡嗪-2-腈,
6-(4-{1-[5-(3-氯苯基)-1,2,4-噁二唑-3-基]乙基}哌嗪-1-基)烟腈,
2-(4-{1-[5-(3-氯苯基)-1,2,4-噁二唑-3-基]乙基}哌嗪-1-基)烟腈,
6-(4-{1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙基}哌嗪-1-基)烟腈,
3-(4-{1-[1-(3-氯苯基)-1H-1,2,3-三唑-4-基]乙基}哌嗪-1-基)吡嗪-2-腈,
2-(4-{1-[1-(3-氯苯基)-1H-1,2,3-三唑-4-基]乙基}哌嗪-1-基)烟腈,
6-(4-{1-[1-(3-氯苯基)-1H-1,2,3-三唑-4-基]乙基}哌嗪-1-基)烟腈,
6-(4-{1-[1-(5-氯-2-氟苯基)-1H-1,2,3-三唑-4-基]乙基}哌嗪-1-基)烟腈,
5-(4-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}哌嗪-1-基)嘧啶-4-腈,
5-(4-{1-[5-(3-氯苯基)异噁唑-3-基]乙基}哌嗪-1-基)吡嗪-2-腈,
2-(4-{1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙基}哌嗪-1-基)烟腈,
3-(4-{1-[3-(3-氯苯基)-1,2,4-噁二唑-5-基]乙基}哌嗪-1-基)吡嗪-2-腈,
6-(4-{[5-(5-氯-2-氟苯基)异噁唑-3-基]甲基}哌嗪-1-基)烟腈,
3-(4-{[5-(5-氯-2-氟苯基)异噁唑-3-基]甲基}哌嗪-1-基)吡嗪-2-腈,
1-{[5-(3-氯苯基)异噁唑-3-基]羰基}-4-(3-硝基吡啶-2-基)哌嗪,和
1-{[2-(3-氯苯基)-1,3-噁唑-5-基]羰基}-4-(3-硝基吡啶-2-基)哌嗪。
8.药物组合物,其包括作为活性成分的治疗有效量的根据权利要求1的化合物与一种或多种可药用稀释剂、赋形剂和/或惰性载体。
9.根据权利要求8的药物组合物,用于治疗mGluR5介导的病症。
10.根据权利要求1的化合物用于治疗。
11.根据权利要求1的化合物用于治疗mGluR5介导的病症。
12.根据权利要求1的化合物在制备用于治疗mGluR5介导的病症的药物中的用途。
13.一种治疗mGluR5介导的病症的方法,包括给药哺乳动物治疗有效量的根据权利要求1的化合物。
14.根据权利要求13的方法,其中所述哺乳动物为人类。
15.根据权利要求14的方法,其中所述病症为神经病症。
16.根据权利要求14的方法,其中所述病症为精神病症。
17.根据权利要求14的方法,其中所述病症为慢性和急性疼痛病症。
18.根据权利要求14的方法,其中所述病症为胃肠道病症。
19.用于抑制mGlur5受体活化的方法,其包括用有效量的根据权利要求1的化合物处理包含所述受体的细胞。
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CN113087669A (zh) * | 2019-12-23 | 2021-07-09 | 南京药石科技股份有限公司 | 一种4-氰基-5-溴嘧啶的制备方法 |
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GB0711521D0 (en) * | 2007-06-14 | 2007-07-25 | Glaxo Group Ltd | Novel compounds |
JP2011515359A (ja) * | 2008-03-18 | 2011-05-19 | グラクソ グループ リミテッド | 治療用トリアゾールアミド誘導体 |
EP2300437B1 (en) | 2008-06-05 | 2013-11-20 | Glaxo Group Limited | Benzpyrazol derivatives as inhibitors of pi3 kinases |
JP5502077B2 (ja) * | 2008-06-05 | 2014-05-28 | グラクソ グループ リミテッド | 新規な化合物 |
WO2009147189A1 (en) | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | Novel compounds |
JP5656880B2 (ja) | 2009-03-09 | 2015-01-21 | グラクソ グループ リミテッドGlaxo Group Limited | Pi3キナーゼの阻害剤としての4−オキサジアゾール−2−イル−インダゾール |
DK2899191T3 (da) | 2009-04-30 | 2017-11-13 | Glaxo Group Ltd | Oxazol-substituerede indazoler som pi3-kinaseinhibitorer |
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GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
US8822464B2 (en) | 2011-11-28 | 2014-09-02 | Boehringer Ingelheim International Gmbh | N-aryl-piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors |
US8741892B2 (en) | 2011-12-05 | 2014-06-03 | Boehringer Ingelheim International Gmbh | Compounds |
US8642774B2 (en) | 2011-12-08 | 2014-02-04 | Boehringer Ingelheim International Gmbh | Compounds |
US8796467B2 (en) * | 2011-12-13 | 2014-08-05 | Boehringer Ingelheim International Gmbh | Compounds |
US8846948B2 (en) | 2011-12-13 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Compounds |
US8716277B2 (en) * | 2011-12-14 | 2014-05-06 | Boehringer Ingelheim International Gmbh | Substituted imidazole compounds useful as positive allosteric modulators of mGlu5 receptor activity |
US8883789B2 (en) | 2011-12-14 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors |
US8937176B2 (en) * | 2011-12-14 | 2015-01-20 | Boehringer Ingelheim International Gmbh | Compounds |
US8889677B2 (en) | 2012-01-17 | 2014-11-18 | Boehringer Ingellheim International GmbH | Substituted triazoles useful as mGlu5 receptor modulators |
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US5681956A (en) * | 1990-12-28 | 1997-10-28 | Neurogen Corporation | 4-aryl substituted piperazinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands |
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CN113087669B (zh) * | 2019-12-23 | 2023-11-17 | 南京药石科技股份有限公司 | 一种4-氰基-5-溴嘧啶的制备方法 |
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IL188806A0 (en) | 2008-08-07 |
CA2616307A1 (en) | 2007-02-22 |
US20080312246A1 (en) | 2008-12-18 |
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TW200800946A (en) | 2008-01-01 |
MX2008001606A (es) | 2008-04-14 |
US20070037820A1 (en) | 2007-02-15 |
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AR057728A1 (es) | 2007-12-12 |
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