CN101316846A - 用于治疗功能性胃肠疾病、ibs和功能性消化不良的新的氮杂环丁烷化合物 - Google Patents
用于治疗功能性胃肠疾病、ibs和功能性消化不良的新的氮杂环丁烷化合物 Download PDFInfo
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- CN101316846A CN101316846A CNA2006800442320A CN200680044232A CN101316846A CN 101316846 A CN101316846 A CN 101316846A CN A2006800442320 A CNA2006800442320 A CN A2006800442320A CN 200680044232 A CN200680044232 A CN 200680044232A CN 101316846 A CN101316846 A CN 101316846A
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- azetidine
- piperazine
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Abstract
本发明涉及新的氮杂环丁烷化合物,涉及包含所述化合物的药用组合物,以及所述化合物在治疗功能性胃肠疾病、IBS和功能性消化不良中的用途。所述化合物为神经激肽(NK)拮抗剂。本发明还涉及所述化合物的制备方法。
Description
发明领域
本发明涉及式I新化合物,涉及包含所述化合物的药用组合物,并涉及所述化合物在治疗中的用途。本发明还涉及式I化合物及其新中间体的制备方法。
发明背景
神经激肽,也称作速激肽,包含一类肽神经传递素,存在于外周和中枢神经系统中。三种主要的速激肽为物质P(SP)、神经激肽A(NKA)和神经激肽B(NKB)。对于三种主要的速激肽,已知有至少三种受体类型。基于其促进激动剂SP、NKA和NKB的相对选择性,受体被分为神经激肽1(NK1)、神经激肽2(NK2)和神经激肽3(NK3)受体。
需要口服活性的NK受体拮抗剂来治疗,例如呼吸、心血管、神经、疼痛、肿瘤、炎症和/或胃肠疾病。为了提高这些治疗的治疗指数,希望获得无毒性或毒性最小的化合物,并且对所述NK受体有选择性。此外,认为所述药物必须具有良好的药动和代谢性质,以改善治疗和安全性概况,例如较低的肝酶抑制性质。
众所周知,如果一种药物的血浆水平被同时给予的另一种药物所改变,则可能发生严重问题(例如毒性)。如果一种药物的代谢由于同时给予的另一种物质(具有肝酶抑制性质)而发生变化,那么可能会出现这种现象-被称为药物相互作用。CYP(细胞色素P450)3A4是人肝脏中最重要的酶,因为大多数被氧化的药物经由这种酶进行生物转化。因此,不希望使用对这种肝酶具有显著抑制程度的药物。现已发现,本领域已知的许多NK受体拮抗剂,可将CYP3 A4抑制到某一水平,因此,如果那些化合物以高剂量用于治疗,则还是可能存在风险。因而,需要具有改良药动性质的新NK受体拮抗剂。本发明提供了具有低水平CYP3 A4酶抑制性质的化合物,因为在CYP3 A4抑制分析中获得了比较高的IC50值。所述测定CYP3 A4抑制的方法,描述于Bapiro等,Drug Metab.Dispos.29,30-35(2001)。
众所周知,某些化合物可对人的心脏复极化产生不良作用,在心电图(ECG)上可观察到QT间期延长。在极端情况下,这种药物引起的QT间期延长会导致一类心脏心律失常,叫做Torsades de Pointes(TdP;Vandenberg等,hERG K+channels:friend and foe(hERG K+通道:朋友和敌人).Trends Pharmacol Sci 2001;22:240-246),最终导致心室纤维颤动和猝死。这种病症中的主要事件是,通过这些化合物抑制了延迟整流钾电流(IKr)的快组分。这些化合物与负载这种电流的通道蛋白的孔形成的α亚单位相结合。孔形成的α亚单位被人类ether-a-go-go相关基因(hERG)编码。由于IKr在心脏动作电位复极化中起着重要作用,因此它的抑制作用减慢了复极化,并且表现为QT间期延长。虽然QT间期延长本身并不关系到安全性,但其具有心血管不良反应的风险,少数人会出现TdP,并恶化成为心室纤维颤动。
特别地,希望NK受体拮抗剂具有适当的药效和药动性质平衡,使其可用于治疗。除具有足够且选择性的效能之外,NK受体拮抗剂需要与相关的药动性质相平衡。因此,NK拮抗剂的必要条件有:a)对不同的NK受体有足够高的亲和性,b)药动性质(吸收、分布和消除性质),使药物可能作用于外周和中枢神经系统的靶向NK受体。例如,NK受体拮抗剂需要具有足够高的代谢稳定性,c)对不同的离子通道(例如hERG-编码的钾通道)有足够低的亲和性,以获得可耐受的安全性,和d)低水平的肝酶(例如CYP3A4)抑制性,以防药物相互作用。此外,为了增强NK受体拮抗剂的功效,对受体具有长期持久竞争作用模式的NK拮抗剂是有益的。
EP 0625509、EP 0630887、WO 95/05377、WO 95/12577、WO95/15961、WO 96/24582、WO 00/02859、WO 00/20003、WO 00/20389、WO 00/25766、WO 00/34243、WO 02/51807和WO 03/037889公开了哌啶基丁酰胺衍生物,其是速激肽拮抗剂。
“4-Amino-2-(aryl)-butylbenzamides and Their ConformationallyConstrained Analogues.Potent Antagonists of the Human Neurokinin-2(NK2)Receptor(4-氨基-2-(芳基)-丁基苯甲酰胺及其构象限制的同类物,人神经激肽-2(NK2)受体的有效拮抗剂)”,Roderick MacKenzie,A.等,Bioorganic & Medicinal Chemistry Letters(2003),13,2211-2215,公开了化合物N-[2-(3,4-二氯苯基)-4-(3-吗啉-4-基氮杂环丁烷-1-基)丁基]-N-甲基苯甲酰胺,发现其具有功能性的NK2受体拮抗性质。
WO 96/05193、WO 97/27185和EP 0962457公开了具有速激肽拮抗剂活性的氮杂环丁烷基烷基内酰胺衍生物。
EP 0790248公开了氮杂环丁烷基烷基氮杂哌啶酮和氮杂环丁烷基烷基氧杂哌啶酮,作为速激肽拮抗剂。
WO 99/01451和WO 97/25322公开了作为速激肽拮抗剂的氮杂环丁烷基烷基哌啶衍生物。
EP 0791592公开了具有速激肽拮抗性质的氮杂环丁烷基烷基戊二酰亚胺。
WO2004/110344A2公开了双NK1,2拮抗剂及其用途。
本发明的一个目的是提供用于治疗的新神经激肽拮抗剂。另一目的是提供具有良好平衡的药动和药效性质的新化合物。
发明概述
本发明提供了通式(I)化合物及其药学上和药理学上可接受的盐,和式I化合物及其盐的对映体。
其中,
Het为
其中,
R为C1-C4烷基;环丙基;C1-C4甲氧基烷基;C1-C4乙氧基烷基;C1-C4羟基烷基;四氢呋喃-2-基;四氢呋喃-3-基;四氢吡喃-2-基;四氢吡喃-3-基;或四氢吡喃-4-基;
或者Het为
其中,
Y为C1-C3烷基;-CH2-O-CH2-;或-CH2-CH2-O-。
在本发明的一个实施方式中,R为C1-C4烷基;C1-C4甲氧基烷基;C1-C4乙氧基烷基;C1-C4羟基烷基;四氢呋喃-2-基;四氢呋喃-3-基;四氢吡喃-2-基;四氢吡喃-3-基;或四氢吡喃-4-基。在本发明的另一实施方式中,R为C1-C3烷基。在另一个实施方式中,R为C1-C3烷基。在另一个实施方式中,R为环丙基。在本发明的另一个实施方式中,R为C1-C2甲氧基烷基。在本发明的另一个实施方式中,R为C1-C2乙氧基烷基。
在本发明的一个实施方式中,Y为C2-C3烷基。在另一个实施方式中,Y为-CH2-O-CH2-。
在本发明的另一个实施方式中,式I化合物为S-对映体。
本发明涉及如上所述的式I化合物及其盐。用于药用组合物的盐是药学上可接受的盐,但是其它盐可用于生产式I化合物。
本发明化合物能够与各种无机酸和有机酸形成盐,这些盐也在本发明的范围内。这些酸加成盐的例子包括:乙酸盐、己二酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐(camphorate)、樟脑磺酸盐、柠檬酸盐、环己基氨基磺酸盐、乙烷磺酸盐、延胡索酸盐、谷氨酸盐、乙醇酸盐、半硫酸盐、2-羟基乙基磺酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基马来酸盐、乳酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、硝酸盐、草酸盐、棕榈酸盐(palmoate)、过硫酸盐、苯基乙酸盐、磷酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、奎尼酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、氨基磺酸盐、磺胺酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐(对-甲苯磺酸盐)和十一酸盐。
药学上可接受的盐可以用常规方法由相应的酸制得。非药学上可接受的盐可用作中间体,这也是本发明的另一个方面。
酸加成盐也可以是聚合盐,例如聚合磺酸盐。
可通过常规方法形成盐,例如通过游离碱态的产品与一当量或多当量的适当酸在盐难溶于其中的溶剂或媒介中反应,或者在例如水的溶剂中反应,通过真空或冷冻干燥除去溶剂,或者在适当的离子交换树脂上将现有盐的阴离子交换为另一种阴离子。
式I化合物具有一个或多个手性中心,应明白的是,本发明包括所有的光学异构体、对映体和非对映异构体。式(I)化合物的形式可以是单一的立体异构体,也就是说,单一的对映体(R-对映体或S-对映体)和/或非对应异构体。式(I)化合物的形式也可以是外消旋混合物,即,对映体的等摩尔混合物。
化合物可以作为构象异构体的混合物而存在。本发明的化合物包括构象异构体的混合物和单一的构象异构体。
如本文所用的,术语“C1-C4烷基”包括直链和支链的C1-C4烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
如本文所用的,“C1-C4羟基烷基”是含有1至4个碳原子和羟基的羟基烷基。
如本文所用的,术语“C1-C4甲氧基烷基”是包含1至4个碳原子烷基链和甲氧基的甲氧基烷基。
如本文所用的,术语“C1-C4乙氧基烷基”是包含1至4个碳原子烷基链和乙氧基的乙氧基烷基。
药物制剂
本发明的一个方面,提供了包含式I化合物(作为游离碱或其药学上可接受盐的单一对映体、外消旋体或者其混合物)的药物制剂,用于预防和/或治疗呼吸、心血管、神经、疼痛、肿瘤、发炎和/或胃肠疾病。
本发明的药用组合物可用对于需治疗病情而言的标准方式来给予,例如,经由口服、局部、肠胃外、口腔、鼻腔、阴道或直肠给药或者经由吸入或吹入。为了这些目的,本发明化合物可以用本领域周知的方法,制成例如片剂、小丸剂、胶囊剂、水溶液或油溶液、悬浮液、乳剂、霜剂、膏剂、凝胶剂、喷鼻剂、栓剂、吸入用的细粉或气溶胶或气雾剂,以及肠胃外使用(包括静脉内、肌内或输液)的无菌水溶液或油溶液或悬浮液或无菌乳剂。
除了本发明化合物之外,本发明的药用组合物还可包含,或者共同给予(同时地或依次地),一种或多种可治疗这里所述一种或多种病情的药物。
本发明药用组合物人用式I化合物的日用剂量,通常为0.01至25毫克/千克体重。或者,式I化合物的日用给予剂量为0.1至5毫克/千克体重。依照本领域周知的原则,该日用剂量可以根据需要分次给予,给予化合物的精确量和给药途经取决于受治患者的体重、年龄和性别以及受治的特定病情。
通常单位剂型包含约1毫克至500毫克的本发明化合物。例如供口服给药的片剂或胶囊,可含有多达250毫克(通常为5至100毫克)的式(I)化合物或其药学上可接受的盐。在另一个实施例中,对于吸入给药,式(I)化合物或其药学上可接受盐的日给药剂量为5至100毫克,单一剂量或分成两次至四次日用剂量。在其它实施例中,对于静脉内或肌内注射或输液给药,可以使用包含至多10%w/w(通常为5%w/w)式(I)化合物或其药学上可接受盐的无菌溶液或悬浮液。
医疗和药物用途
本发明提供了治疗或预防病情(其中作用于NK受体的对速激肽的拮抗作用是有益的)的方法,所述方法包括:给予患者有效量的式(I)化合物或者其药学上可接受的盐。本发明还提供了式(I)化合物或者其药学上可接受盐在药物制备中的用途,所述药物用于可得益于作用于NK受体的对速激肽的拮抗作用的病情。
式(I)化合物或者其药学上可接受的盐或溶剂化物可用于生产药物,所述药物用于预防或治疗呼吸、心血管、神经、疼痛、肿瘤和/或胃肠疾病。
这些病患的例子包括:哮喘、过敏性鼻炎、肺病、咳嗽、感冒、发炎、慢性阻塞性肺病、气道反应性疾病、风疹、高血压、风湿性关节炎、浮肿、血管新生、疼痛、偏头痛、紧张性头痛、精神病、抑郁症、焦虑、阿尔茨海默症(Alzheimer′s disease)、精神分裂症、亨廷顿氏病(Huntington′s disease)、膀胱运动过强、尿失禁、饮食疾病、躁狂抑郁症、药物依赖、运动障碍、认知障碍、肥胖、应激病症、排尿障碍、躁狂、轻度躁狂和攻击行为、双相障碍、肿瘤、癌、纤维肌痛、非心源性胸痛、胃肠运动过强、胃哮喘、克罗恩氏病(Crohn′s disease)、胃排空障碍、溃疡性结肠炎、肠易激综合症(IBS)、炎性肠病(IBD)、呕吐、胃哮喘、胃动力疾病、胃食管反流病(GERD)或功能性消化不良。
药理学
用于FLIPR和结合分析的细胞转染和培养
用人NK2受体(在pRc/CMV中的hNK2R cDNA,Invitrogen)或人NK3受体(在pcDNA 3.1/Hygro(+)/IRES/CD8中的hNK3R,Invitrogen载体,经AstraZeneca EST-Bio UK,Alderley Park改良(Invitrogen vectormodified at AstraZeneca EST-Bio UK,Alderley Park))稳定转染中国仓鼠卵巢(CHO)K1细胞(来自ATCC)。用阳离子液体试剂LIPOFECTAMINETM(Invitrogen)转染细胞,用1毫克/毫升Geneticin(G418,Invitrogen)挑选hNK2R转染的细胞,用500微克/毫升Hygromycin(Invitrogen)挑选hNK3R转染的细胞。借助于荧光活化细胞分选仪(FACS)来收集单个细胞克隆,测试其在FLIPR分析(见下)中的功能性,在培养基中扩增,冻存起来供以后使用。用人NK1受体稳定转染的CHO细胞来自AstraZeneca R&D,Wilmington USA。将人NK1受体cDNA(得自肺组织的RNA-PCR)亚克隆至pRcCMV(Invitrogen)。用磷酸钙进行转染,用1毫克/毫升G418进行挑选。
用hNK1R、hNK2R和hNK3R稳定转染的CHO细胞,在加湿培养箱中5%CO2下,在含Glutamax 1、10%胎牛血清(FBS)、1%青霉素/链霉素(PEST)的Nut Mix F12(HAM)中进行培养,对于hNK1R和hNK2R表达细胞补充有200微克/毫升的Geneticin,对于hNK3R表达细胞补充有500微克/毫升的Hygromycin。细胞在T175烧瓶中培养,在70至80%铺满时常规传代至20至25代。
评估所选试验化合物抑制人NK
1
/NK
2
/NK
3
受体活化的活性
(FLIPR分析)
用以下方法来评估本发明化合物抑制NK1/NK2/NK3受体活化的活性(测量结果为细胞内Ca2+NK1/NK2/NK3受体介导的增加):
将用人NK1、NK2或NK3受体稳定转染的CHO细胞注入黑壁/透明底的96孔平板(Costar 3904),每孔3.5×104细胞,在37℃的CO2培养箱中的标准生长培养基里培养大约24小时。在FLIPR分析之前,向各96孔平板细胞中加入Ca2+敏感性染料Fluo-3(TEFLABS 0116),其在加载培养基中浓度为4μM,加载培养基由Nut Mix F 12(HAM)及Glutamax I,22mM HEPES,2.5mM Probenicid(Sigma P-8761)和0.04%Pluronic F-127(Sigma P-2443)组成,在37℃的CO2培养箱中暗处保存1小时。然后用多管道吸管在分析缓冲液(Hanks平衡的盐溶液(HBSS):包含20mM HEPES、2.5mM丙磺舒Probenicid和0.1%BSA)中将细胞洗涤三次,在最后洗涤结束时留下150微升。试验化合物在检测缓冲液中的系列稀释液(最终的DMSO浓度保持在1%以下),用FLIPR(荧光成像平板读数器)自动吸取至每个试验孔中,用FLIPRCCD照相机记录2分钟预培养期的荧光强度(激发光488nm,发射光530nm)。然后用FLIPR向已含200微升分析缓冲液(含有试验化合物或载体)的每个孔中加入50微升物质P(NK1特异性)、NKA(NK2特异性)或Pro-7-NKB(NK3特异性)激动剂溶液(最终浓度相当于大约EC60浓度),再连续检测荧光2分钟。测定的响应为激动剂加入后的峰值相对荧光,从每种化合物10个点的浓度-响应曲线计算IC50。然后用下式将IC50转化为pKB值:
KB=IC50/1+(用于分析的激动剂EC60浓度/EC50激动剂)
pKB=-log KB
测定化合物对人NK
1
/NK
2
/NK
3
受体的解离常数(Ki)(结合分析)
依照下面方法,由人NK1、NK2或NK3受体稳定转染的CHO细胞来制备膜:
细胞用溶液分离,通过离心收集在含5%FBS的PBS中,在PBS中洗涤两次,并以1×108细胞/毫升的浓度重新悬浮于Tris-HCl 50mM、KCl 300mM、EDTA-N2 10mM pH7.4(4℃)中。细胞悬浮液用Ultra Turrax以12.000转/分钟(rpm)均匀化30秒。以38.000xg离心均匀混合物(4℃),并将颗粒重新悬浮于Tris-HCl(50mM,pH7.4)中。重复一次均匀化,将均匀混合物在冰上培养45分钟。再次如上所述将均匀混合物离心,并重新悬浮于Tris-HCl(50mM,pH7.4)中。该离心步骤总共重复三次。最后一次离心步骤之后,将颗粒重新悬浮于Tris-HCl(50mM)中,并用Dual Potter,10strokes均匀化形成均匀溶液,取部分供蛋白质测定。将膜等分,于-80℃冷冻至使用。
在培养缓冲液(含有0.1%BSA、40毫克/升枯草杆菌抗生素、完全的不含EDTA的蛋白酶抑制剂鸡尾酒片20片/升(Roche)和3mMMnCl2的50mM Tris缓冲液(pH7.4RT))中,以200微升/孔的最终分析体积,在96孔微量滴定板(非结合表面平板,Corning 3600)中,于室温下,进行进行放射配基结合分析。通过加入递增量的试验化合物,绘制竞争结合曲线。将试验化合物溶解并连续稀释于DMSO中,分析中DMSO的终浓度为1.5%。加入50微升无标记的ZD 6021(非选择性NK拮抗剂,终浓度为10μM)来测定非特异性结合。对于总的结合,使用50微升的1.5%DMSO(终浓度)/培养缓冲液。在对hNK1r的结合实验中,使用[3H-Sar,Met(O2)-物质P](终浓度为4nM)。在对hNK2r的结合实验中,使用[3H-SR48968](终浓度为3nM)。在对hNK3r的结合实验中使用[3H-SR142801](终浓度为3nM)。将50微升放射配基、3微升稀释于DMSO中的实验化合物和47微升培养缓冲液,与5至10微克细胞膜在100微升培养缓冲液中混合,于室温在微板振荡器上培养30分钟。
然后通过在Filtermat B(Wallac)上快速过滤来收集膜(0.1%BSA和0.3%聚乙烯亚胺(Sigma P-3143)中预浸),使用Micro 96收集器(Harvester)(Skatron Instruments,挪威)进行。通过收集器(Harvester)用冰冷的洗涤缓冲液(含3mM MnCl2的50mM Tris-HCl,4℃时pH为7.4)来洗涤过滤器,并在50℃干燥30至60分钟。用微密封器(Microsealer)(Wallac,芬兰)将Meltilex闪烁片(scintillator sheet)融在过滤器上,在β-液体闪烁计数器(1450Microbeta,Wallac,芬兰)上对过滤器计数。
用Cheng-Prusoff等式(Biochem.Pharmacol.22:3099-3108,1973)计算未标记配基的Ki值:其中L为所用放射活性配基的浓度,Kd为放射活性配基对受体的亲和力(通过饱和结合测定)。
使用Excel Fit将数据拟合四参数等式
Ki=IC50/(1+(L/Kd))
结果
总体而言,所测试的本发明化合物,证明在pKB8至9范围内对NK1受体有统计学上显著的拮抗活性。对NK2受体,该pKB范围为7至9。总体上,对NK3受体的拮抗活性在pKB7至9范围。
总体上,所测试的本发明化合物,证明在低浓度下有统计学上显著的CYP3A4抑制作用。依照Bapiro等;Drug Metab.Dispos.29,30-35(2001)测定的IC50值总体大于15μM。
对hERG的活性
式I化合物对hERG编码的钾通道的活性测定,可依照Kiss L等人Assay Drug Dev Technol.1(2003),127-35:“High throughpution-channel pharmacology:planar-array-based voltage clamp(高通量离子通道药理学:基于平面阵列的电压夹)”。
总体上,所测试的本发明化合物,证明在低浓度下具有统计学上显著的hERG活性。如上所述,测定的IC50值总体上大于10μM。
代谢稳定性
式I化合物的代谢稳定性测定如下:
生物转化的速度,可以测定为代谢物的形成速率或者母体化合物的消失速率。实验设计包括用肝微粒体(通常0.5毫克/毫升)培养低浓度底物(通常1.0μM),在不同时间点(通常0、5、10、15、20、30、40分钟)取出部分。试验化合物通常溶于DMSO中。培养混合物中DMSO浓度通常为0.1%或更少,因为更多溶剂会大大降低某些CYP450的活性。在100mM磷酸钾缓冲液中进行培养(pH为7.4,37℃)。用乙腈或甲醇来终止反应。用HPLC-MS分析母体化合物。考虑微粒体蛋白浓度和肝重,由计算的半衰期(t1/2)来估计内在清除率Clint。
总体而言,本发明化合物在高浓度时具有体外代谢稳定性,如上检测的内在清除率值,通常低于40微升/分钟/毫克蛋白。
下表说明本发明化合物的性质:
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(8aR)-6-氧代六氢吡咯并[1,2-a]吡嗪-2(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺二盐酸盐(实施例1)
pKB(NK1) | pKB(NK2) | pKB(NK3) | IC50(hERG) | IC50(CYP3A4) | Clint(HLM) |
8.7 | 7.8 | 8.5 | 12.4μM | >50μM | 14.0μl/min/mg |
生物学评估
沙鼠脚踏(foot tap)(NKl特异性实验模型)
雄性Mongolian沙鼠(60至80克)购自Charles River,德国。一到,就将它们10只一组,随意供给食物和水,养在温湿度控制的储存室里。实验之前至少留7天让动物适应居住条件。每只动物只能使用一次,实验之后立即通过心脏穿刺或服用致死过量戊巴比妥钠处死。
沙鼠用异氟烷麻醉。可能的CNS可渗透NK1受体拮抗剂,经腹膜内、静脉内或皮下给予。用激动剂刺激之前,在各时间点(通常30至120分钟)给予化合物。
用异氟烷使沙鼠轻微麻醉,在前囟上的皮肤作一小切口。使用带4毫米长针的Hamilton注射器,icv给予5微升10pmol的ASMSP(选择性的NK1受体激动剂)。夹住伤口,将动物放在小的塑料笼中,让其醒过来。将笼子放在充满水的塑料管道上,该管道经由压力传感器与电脑相连。记录后脚踏数(number of hind feet taps)。
粪粒产量(NK2特异性实验模型)
式I化合物的体内效果(NK2),可如The Journal of Pharmacologyand Experimental Therapeutics(2001),pp.559-564所述,使用沙鼠,通过测量NK2受体激动剂导致的沙鼠粪粒产量来确定。
结肠直肠扩张模型
对沙鼠进行结肠直肠扩张(CRD)试验,如前对大鼠和小鼠的描述(Tammpere A,Brusberg M,Axenborg J,Hirsch I,Larsson H,E.Evaluation of pseudo-affective responses to noxious colorectaldistension in rats by manometric recordings(通过压力计记录来评估大鼠对有毒结肠直肠扩张的假情感反应).Pain 2005;116:220-226;Arvidsson S,Larsson M,Larsson H,Lindstrom E,Martinez V.Assessment of visceral pain-related pseudo-affective responses tocolorectal distension in mice by intracolonic manometric recordings(通过结肠内压力计记录来评估小鼠对结肠直肠扩张的内脏疼痛相关假情感的反应).J Pain 2006;7:108-118),稍作修改。简而言之,实验之前让沙鼠每天适应Bollmann笼30至60分钟,连续三天,以降低由于约束应力的运动假象。在轻微异氟烷(Abbott Scandinavia AB,Solna,瑞典)麻醉期间,将具有连接导管的2厘米聚乙烯气球(自制)插入远端结肠,气球底部距离肛门2厘米。用胶带将导管固定在尾巴上。使气球与压力传感器(P-602,CFM-k33,100mmHg,BronkhorstHI-TEC,Veenendal,荷兰)相连。实验开始前至少15分钟,让沙鼠在Bollmann笼子中从镇静状态恢复。
用定制恒压器(AstraZeneca,瑞典)来操纵充气和气球压力控制。使用标准计算机上运行的定制计算机软件(PharmLab on-line4.0)来控制恒压器并收集数据。所用的扩张范例包括80mmHg 12次重复的阶段性扩张(phasic distension)。脉冲持续时间为每隔5分钟30秒。在CRD范例之前腹膜内(i.p.)注射给予化合物或其各自的载体。每只沙鼠在不同时候接受载体和化合物(试验之间至少相隔两天)。因此,每只沙鼠作为其自身的载体对照。
用单独的采样速率对模拟输入通道进行采样,对信号进行数字滤波。以50个样品/秒的速率,对气球压力信号进行采样。使用1Hz高通量滤波器,分离收缩导致的压力变化与恒压器产生的慢变化压力。压力发生器和压力传感器之间的气流阻力进一步增强了动物腹部收缩所产生的压力变化。使用定制计算机软件(PharmLab off-line 4.0)来确定高通量过滤的气球压力信号大小。计算脉冲前30秒(即,基线响应)和脉冲期间的高通量过滤的气球压力信号的平均整流值(ARV)。在计算高通量过滤的气球压力信号大小时,每次脉冲第一秒和最后一秒的信号不计,因为这些反映的是充气和放气期间恒压器产生的假信号,而不是来自动物的信号。
制备方法
在另一方面,本发明提供了制备式(I)化合物或其盐的方法,所述方法包括:
a)式(III)化合物与式(IV)化合物反应:
其中Het如前所述;且条件是将式(III)化合物还原性烷基化,在式(III)化合物氮杂环丁烷基的氮原子和式(IV)化合物醛基的碳原子之间形成N-C键;或者
b)式(III)化合物与式(V)化合物反应:
其中Het如前所述;且L基团使得通过式(III)化合物烷基化,在式(III)化合物氮杂环丁烷基的氮原子和式(V)化合物与L基相邻的碳原子之间形成N-C键;或者
c)式(VI)化合物与式(VII)化合物反应:
其中Het如前所述;L′是离去基;
其中,如有必要,任何其它官能团被保护,并:
i)除去任何保护基;
ii)任选形成药学上可接受的盐。
保护基通常选自文献上或熟练化学家周知的适用于保护所述基团的任何基团,可通过常规方法引入或除去;例如见Protecting Groupsin Organic Chemistry(有机化学中的保护基);Theodora W.Greene。选择除去方法,以便在除去保护基的同时对分子中其它基团的影响最小。
式(III)和(IV)化合物在还原性烷基化条件下进行反应。反应通常在非极端温度下(例如0至40℃),在基本惰性的溶剂中(例如二氯甲烷)进行。典型的还原剂包括硼氢化物(例如氰基硼氢化钠)。
式(III)和(V)化合物在烷基化条件下进行反应。通常在式(V)化合物中L是离去基,例如卤素或烷基磺酰氧基。反应通常在升高的温度(例如30至130℃)下,在基本惰性的溶剂(例如DMF)中进行。
式(III)化合物为已知的,或者可以用常规方法来制备。式(IV)化合物的制备方法例如,式(VII)化合物与式(VIII)化合物在常规酰化条件下进行反应:
式(V)化合物的制备方法例如,式(VII)化合物与式(IX)化合物在常规酰化条件下反应:
其中L为前所述。
式(VI)化合物与式(VII)化合物可以在常规酰化条件下反应,其中
是酸或活化的酸衍生物。这种活化的酸衍生物是文献中周知的。它们可以由酸原位形成,或者经制备、分离随后反应。通常L′是氯,以形成酰基氯。酰化反应通常于非极限温度下,在非亲核碱(例如N,N-二异丙基乙胺)存在下,在基本惰性溶剂(例如二氯甲烷)中进行。
式(VIII)化合物和式(IX)化合物是已知的,或者可用常规方法制备。
实施例
工作实施例
应强调的是,由于构象异构体的存在,本发明化合物的NMR光谱通常非常复杂。认为这是由于围绕酰胺键和/或芳基键缓慢旋转的结果。以下缩写用于化合物NMR数据的表达:s-单峰;d-双峰;t-三峰;qt-四峰;qn-五峰;m-多峰;b-宽的;cm-复杂多峰(可包括宽峰)。
以下实施例将描述(但不限制)本发明。
以下缩写用于实验中:Boc(叔丁氧基羰基),DIPEA(N,N-二异丙基乙胺),DMF(N,N-二甲基甲酰胺),TBTU(N,N,N′,N′-四甲基-O-(苯并三唑-1-基)脲四氟硼酸盐),THF(四氢呋喃),IPA(2-丙醇)和RT(室温)。
实施例1
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(8aR)-6-氧代六氢吡咯并[1,2-a]
吡嗪-2(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺
二盐酸盐
向3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(见方法3;106毫克,0.24毫摩尔)和(8aR)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(见方法1;35毫克,0.18毫摩尔)的甲醇(7毫升)溶液中,加入氰基硼氢化钠(73毫克,1.2毫摩尔)、氯化锌(77毫克,0.56毫摩尔)在少量甲醇中的混合物。室温下搅拌反应混合物15分钟,然后蒸发除去溶剂。残余物在乙酸乙酯和NaHCO3水溶液之间分配,然后分离水溶液,再用乙酸乙酯萃取一次。蒸发除去溶剂。用乙腈和0.1M乙酸铵水溶液的混合物通过反相色谱法来纯化产物。将适当的部分合并,旋转蒸发浓缩。水性残余物用乙酸乙酯萃取,有机溶液经MgSO4干燥。蒸发除去溶剂后将残余物溶于少量水中。加入几滴稀盐酸,冷冻干燥除去溶剂。获得白色粉末的标题化合物68毫克(54%)。1H NMR(500MHz,CDCl3):1.7-4.8(cm,26H),7.0-8.0(cm,7H);LCMS:m/z 626(M+1)+。
实施例2
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(8aS)-6-氧代六氢吡咯并[1,2-a]
吡嗪-2(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺
二盐酸盐
通过使用实施例1中所述同样的还原性烷基化方案来制备标题化合物,但是使用(8aR)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(见方法2)作为胺(产率,37%)。1H NMR(500MHz,CDCl3):1.7-4.9(cm,26H),7.0-8.0(cm,7H);LCMS:m/z 626(M+1)+。
实施例3
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(6-氧代八氢-2H-吡啶并[1,2-a]吡
嗪-2-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺二盐
酸盐
向3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(见方法3;100毫克,0.22毫摩尔)和2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮(见方法4;58毫克,0.28毫摩尔)的二氯甲烷(3毫升)溶液中,加入DIPEA(116毫克,0.90毫摩尔)和三乙酰氧基硼氢化钠(66毫克,0.31毫摩尔)。氮气下于室温搅拌反应混合物2小时。溶液用NaHCO3水溶液洗涤两次,有机溶剂经相分离柱干燥。蒸发除去溶剂,产物经硅胶色谱法(氨饱和的甲醇-二氯甲烷1%至10%)纯化。将恰当的部分合并,旋转蒸发浓缩,然后将残余物溶于少量乙腈/水中。加入几滴稀盐酸,冷冻干燥除去水。获得白色固体的标题化合物114毫克(70%)。1H NMR(500MHz,CDCl3):1.4-3.8(cm,27H),4.6(d,1H),6.8-7.4(cm,6H),7.7(s,1H);LCMS:m/z 640(M+1)+。
实施例4
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aR或9aS)-6-氧代八氢-2H-吡
啶并[1,2-a]吡嗪-2-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯
甲酰胺
向3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(见方法3;267毫克,0.30毫摩尔)和方法5中所述2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮的对映体之一(74毫克,0.35毫摩尔)的二氯甲烷(3毫升)溶液中,加入DIPEA(150毫克,1.15毫摩尔)和三乙酰氧基硼氢化钠(86毫克,0.41毫摩尔)。在氮气下室温搅拌反应混合物2.5小时。溶液用NaHCO3水溶液洗涤两次,有机溶剂经相分离柱干燥。蒸发除去溶剂,产物经硅胶色谱法(氨饱和的甲醇-二氯甲烷1%至10%)纯化。将恰当的部分合并,蒸发除去溶剂。获得白色泡沫的标题化合物133毫克(68%)。1H NMR(400MHz,CDCl3):1.2-3.8(cm,27H),4.6(d,1H),6.7-7.4(cm,6H),7.7(s,1H);LCMS:m/z 640(M+1)+。
实施例5
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aR或9aS)-6-氧代八氢-2H-吡
啶并[1,2-a]吡嗪-2-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯
甲酰胺
通过使用实施例4中所述同样的还原性烷基化方案来制备标题化合物,但是使用方法6中所述2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮的相反对映体作为胺(产率,67%)。1H NMR(400MHz,CDCl3):1.2-3.8(cm,27H),4.5-4.6(d,1H),6.7-7.4(cm,6H),7.7(s,1H);LCMS:m/z 640(M+1)+。
实施例6
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷
-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺
将3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(见方法3;11.2克,25毫摩尔)溶于甲醇(50毫升)和三乙胺(3.5毫升,25毫摩尔)中。将溶液和另一部分三乙胺(3.5毫升,25毫摩尔)一起转移至装有1-乙酰基-4-氮杂环丁烷-3-基哌嗪二盐酸盐的烧瓶中(见WO 96/05193;8.4克,32.6毫摩尔)。室温搅拌混合物45分钟,然后用1小时分次加入三乙酰氧基硼氢化钠(8.0克,37.6毫摩尔)。室温搅拌反应混合物45分钟。加入水(0.45毫升),然后蒸发除去大部分溶剂。将残余物溶于甲苯(56毫升)中,然后在加热至40℃的同时,加入10%NaOH水溶液(55毫升)。在45℃剧烈搅拌该混合物5分钟。分离除去水层,有机溶液留在通风橱中过夜。在尝试几次从不同溶剂中使产物结晶之后,经硅胶色谱法纯化化合物(氨饱和的甲醇-二氯甲烷1%至10%)。获得白色泡沫的标题化合物8.3克(54%)。1HNMR(500MHz,CDCl3):1.4-1.8(cm,2H),2.0(s,3H),2.1-3.8(cm,21H),6.8-7.4(cm,6H),7.7(s,1H);LCMS:m/z 614(M+1)+。
实施例7
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-丙酰基哌嗪-1-基)氮杂环丁烷
-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺二盐酸盐
将3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(见方法3;165毫克,0.4毫摩尔)和1-氮杂环丁烷-3-基-4-丙酰基哌嗪(见方法7;80毫克,0.41毫摩尔)溶于二氯甲烷(10毫升)和少量无水甲醇(0.2毫升)中。加入三乙酰氧基硼氢化钠(157毫克,0.74毫摩尔)和DIPEA(143毫克,1.11毫摩尔)。室温搅拌反应混合物2.5小时,然后用二氯甲烷稀释。溶液用NaHCO3水溶液洗涤两次,然后用盐水洗涤两次。通过相分离柱分离有机相后,蒸发除去溶剂。产物经硅胶色谱法纯化(甲醇-二氯甲烷5∶95)。将油状产物溶于2M的盐酸中,然后冷冻干燥除去溶剂。获得白色固体的标题化合物120毫克(48%)。1H NMR(500MHz,CDCl3):1.2-3.8(cm,28H),6.8-7.8(cm,7H);LCMS:m/z 628(M+1)+。
实施例8
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-氧代六氢吡嗪并[2,1-c][1,4]噁
嗪-8(1H)-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺
将8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐(见方法8;43毫克,0.17毫摩尔)溶于甲醇(3毫升)和几滴水与乙酸(0.2毫升)中。向前面溶液中加入3-溴-N-[(2S)-2(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(见方法3;80毫克,0.18毫摩尔)的甲醇(1毫升)溶液和(聚苯乙烯基甲基)-三甲基铵氰基硼氢化物(4.2毫摩尔/克,47毫克,0.25毫摩尔)。用微波单节加热将反应混合物于120℃加热5分钟。过滤除去树脂,并用甲醇洗涤。蒸发浓缩滤出液。用反相色谱法纯化产物(乙腈-0.1M甲酸铵和0.1M甲酸的水溶液,10%至50%)。蒸发后冷冻干燥,除去收集部分的溶剂。残余物在二氯甲烷和NaHCO3水溶液之间分配。通过相分离柱分离两相,然后蒸发除去有机溶液的溶剂。得到标题化合物50毫克(44%)。1H NMR(500MHz,CD3OD):1.5-1.7(b,IH),1.7-2.0(cm,3H),2.2-4.2(cm,21H),4.5(d,1H),7.0-7.6(cm,6H),7.9(d,1H);LCMS:m/z 642(M+1)+。
实施例9
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[4-(四氢呋喃-2-基羰基)哌嗪-1-基]
氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺
使用实施例8所述同样的还原性烷基化方案来制备标题化合物,但是使用1-氮杂环丁烷-3-基-4-(四氢呋喃-2-基羰基)哌嗪(见方法9)作为胺(产率,60%)。1H NMR(500MHz,CD3OD):1.5-4.9(cm,30H),7.0-8.0(cm,7H);LCMS:m/z 670(M+1)+。
实施例10
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[4-(甲氧基乙酰基)哌嗪-1-基]氮
杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺
使用实施例8所述同样的还原性烷基化方案来制备标题化合物,但是使用1-氮杂环丁烷-3-基-4-(甲氧基乙酰基)哌嗪(见方法10)作为胺(产率,68%)。1H NMR(500MHz,CD3OD):1.5-1.9(cm,2H),2.2-3.6(cm,22H),3.7(m,1H),3.9(t,1H),4.2(s,2H),7.0(d,2H),7.1(t,1H),7.2-7.3(d,1H),7.3-7.6(m,2H),7.9(d,1H);LCMS:m/z 644(M+1)+。
实施例11
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙醇酰基哌嗪-1-基)氮杂环丁
烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺
使用实施例8所述同样的还原性烷基化方案来制备标题化合物,但是使用2-(4-氮杂环丁烷-3-基哌嗪-1-基)-2-氧代乙醇(见方法11)作为胺(产率,50%)。1HNMR(500MHz,CD3OD):1.6-1.9(cm,2H),2.2-3.6(cm,19H),3.7(m,1H),3.9(m,IH),4.2(s,2H),7.0-7.6(m,6H),7.9(d,1H);LCMS:m/z 630(M+1)+。
实施例12
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aS)-4-氧代六氢吡嗪并
[2,1-c][1,4]噁嗪-8(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲
基)苯甲酰胺
向3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(方法3;100毫克,0.22毫摩尔)和(9aS)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮(见方法12;约0.20毫摩尔)的乙醇(20毫升)溶液中,加入氰基硼氢化钠(125毫克,2.0毫摩尔)和氯化锌(135毫克,0.99毫摩尔)的甲醇(10毫升)溶液。室温搅拌反应混合物10分钟,然后蒸发除去溶剂。残余物在乙酸乙酯(50毫升)和水(20毫升)中分配。有机溶液用盐水洗涤,然后经Na2SO4干燥。蒸发除去溶剂,将残余物溶于乙腈(10毫升)、乙酸(100毫克)和水(20毫升)的混合物中。用乙腈和0.1M乙酸铵水溶液的混合物通过反相色谱法来纯化产物。将适当的部分合并,旋转蒸发浓缩。水性残余物用乙酸乙酯萃取,有机溶液经Na2SO4干燥。蒸发除去溶剂。获得标题化合物80毫克(55%)。1H NMR(400MHz,CDCl3):0.9-3.8(cm,21.5H),3.9(d,1H),4.1-4.2(qt,2H),4.4(b,0.5H),4.5-4.6(d,1H),6.6-7.5(cm,6H),7.8(s,1H);LCMS:m/z 642(M+1)+。
实施例13
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aR)-4-氧代六氢吡嗪并
[2,1-c][1,4]噁嗪-8(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲
基)苯甲酰胺
使用实施例12所述同样的还原性烷基化方案来制备标题化合物,但是使用(9aR)-8-氮杂环丁烷-3-基六氢-吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮(见方法13)作为胺(产率,40%)。1H NMR(400MHz,CDCl3):0.9-3.8(cm,21.7H),3.9(dd,1H),4.0-4.2(qt,2H),4.3-4.4(b,0.3H),4.5-4.6(d,1H),6.8-7.4(cm,6H),7.7(s,1H);LCMS:m/z 642(M+1)+。
实施例14
3-溴-N-[(2S)-4-{3-[4-(环丙基羰基)哌嗪-1-基]氮杂环丁烷-1-
基}-2-(4-氟苯基)丁基]-N-甲基-5-(三氟甲基)苯甲酰胺二盐酸盐
向3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(方法3;450毫克,1.0毫摩尔)和1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪(见方法14;约0.9毫摩尔)的甲醇(50毫升)溶液中,加入氰基硼氢化钠(250毫克,4.0毫摩尔)和氯化锌(270毫克,2.0毫摩尔)的甲醇(30毫升)溶液。室温搅拌反应混合物15分钟,然后蒸发除去溶剂。残余物在乙酸乙酯(50毫升)和水(20毫升)中分配。有机溶液用盐水洗涤,然后经Na2SO4干燥。蒸发除去溶剂,将残余物溶于乙酸乙酯中。通过硅胶色谱法来纯化产物,先用乙酸乙酯洗脱,然后用乙酸乙酯、甲醇和三乙胺的(9∶1∶1)混合物洗脱。将适当的部分合并,旋转蒸发浓缩,然后残余物用二氯甲烷共蒸发两次。将残余物溶于二氯甲烷中,向该溶液中加入HCl饱和的二乙醚(1毫升)。蒸发除去溶剂,然后残余物与二氯甲烷共蒸发两次。获得标题化合物220毫克(30%)。1H NMR(400MHz,CDCl3):0.8-1.0(cm,4H),1.2-4.7(cm,24H),6.9-8.0(cm,7H):m/z 640(M+1)+。
实施例15
3-溴-N-[(2S)-4-[3-(4-丁酰基哌嗪-1-基)氮杂环丁烷-1-基]-2-(4-氟
苯基)丁基]-N-甲基-5-(三氟甲基)苯甲酰胺二盐酸盐
向3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(方法3;450毫克,1.0毫摩尔)和1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪(见方法15;约0.9毫摩尔)的甲醇(50毫升)溶液中,加入氰基硼氢化钠(250毫克,4.0毫摩尔)和氯化锌(270毫克,2.0毫摩尔)的甲醇(30毫升)溶液。室温搅拌反应混合物15分钟,然后蒸发除去溶剂。残余物在乙酸乙酯(50毫升)和水(20毫升)中分配。有机溶液用盐水洗涤,然后经Na2SO4干燥。蒸发除去溶剂,将残余物溶于乙酸乙酯中。通过硅胶色谱法来纯化产物,先用乙酸乙酯洗脱,然后用乙酸乙酯、甲醇和三乙胺的(9∶1∶1)混合物洗脱。将适当的部分合并,旋转蒸发浓缩,然后残余物用二氯甲烷共蒸发两次。将残余物溶于二氯甲烷中,向该溶液中加入HCl饱和的二乙醚(1毫升)。蒸发除去溶剂,然后残余物与二氯甲烷共蒸发两次。获得标题化合物220毫克(30%)。1H NMR(400MHz,CD3OD):0.8-1.0(t,3H),1.5-1.6(qt,2H),1.8-2.2(cm,3H),2.4(t,2H),2.6-4.6(cm,20H),7.0-7.6(cm,6H),7.9(d,1H);LCMS:m/z 642(M+1)+。
实施例16
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-异丁酰基哌嗪-1-基)氮杂环丁
烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺二盐酸盐
使用实施例15所述同样的还原性烷基化方案来制备标题化合物,但是使用1-氮杂环丁烷-3-基-4-异丁酰基哌嗪(见方法16)作为胺(产率,29%)。1H NMR(400MHz,CD3OD):1.1(d,6H),1.8-2.2(cm,3H),2.6-4.6(cm,21H),6.8-7.6(cm,6H),7.9(d,1H);LCMS:m/z 642(M+1)+。
起始物料的制备
上述实施例的起始物料,或者外购,或者使用标准方法由已知材料而容易制得。例如,以下反应是一些起始物料的例子(而非限制)。
方法1
(8aR)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮
(a)(8aR)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮
将(8aR)-六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(见WO 03/066635;0.17克,1.2毫摩尔)、1-(二苯基甲基)氮杂环丁烷-3-基甲烷磺酸酯(见J.Org.Chem.;56;1991;6729;0.40克,1.3毫摩尔)和三乙胺(0.20毫升,1.4毫摩尔)溶于乙腈中。用微波单节加热将混合物在150℃加热15分钟,然后蒸发除去溶剂。残余物在乙酸乙酯和NaHCO3水溶液之间分配,水相进一步用乙酸乙酯萃取。有机相干燥后,蒸发除去溶剂。产物经硅胶色谱法纯化(甲醇-二氯甲烷5∶95)。获得浅黄色油状的(8aR)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮0.23克(54%)。1HNMR(500MHz,CDCl3):1.5-1.6(m,2H),1.7-1.8(m,1H),2.1-2.2(m,1H),2.3-2.4(m,2H),2.6-2.7(d,1H),2.8(m,1H),2.8-2.9(m,3H),3.0(qn,1H),3.4(t,2H),3.6(m,1H),4.0(d,1H),4.4(s,1H),7.2(m,2H),7.2-7.3(m,4H),7.4(m,4H);LCMS:m/z 362(M+1)+。
(b)(8aR)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮
将(8aR)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(0.23克,0.64毫摩尔)溶于乙酸(20毫升)中,向所得溶液中加入氢氧化钯/碳(0.33克)。于室温氢气下(5巴)搅拌混合物48小时,然后用过滤除去催化剂。蒸发除去溶剂,将残余物溶于乙醇中。溶液经阳离子交换柱(Isolute SCX-2,10克)过滤。柱子用乙醇洗涤,然后产物用氨饱和的甲醇洗脱。蒸发除去溶剂,得到标题混合物0.10克(84%)。1H NMR(500MHz,CDCl3):1.5-1.6(m,2H),1.8(m,1H),2.1-2.2(m,1H),2.3-2.4(m,2H),2.7(d,1H),2.8-2.9(m,2H),3.2(qn,1H),3.5-3.7(m,4H),4.0(dd,1H)。
方法2
(8aS)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮
(a)(8aS)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮
使用方法1a中所述的N-烷基化反应方案来制备标题化合物,但是使用(8aS)-六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(见WO 03/066635)作为胺(产率,56%)。1H NMR(500MHz,CDCl3):1.5-1.6(qn,2H),1.7-1.8(m,2H),2.1-2.2(m,1H),2.3-2.4(m,2H),2.6-2.7(d,1H),2.8(d,1H),2.8-2.9(m,2H),3.0(qn,1H),3.4(t,2H),3.6(m,1H),4.0(d,1H),4.4(s,1H),7.1-7.2(t,2H),7.2-7.3(t,4H),7.4(t,4H);LCMS:m/z 362(M+1)+。
(b)(8aS)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮
使用方法1b中所述的氢化反应方案来制备标题化合物,但是使用(8aS)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮作为底物(产率,73%)。1H NMR(500MHz,CDCl3):1.5-1.6(m,2H),1.8(m,1H),2.1-2.2(m,1H),2.3-2.4(m,2H),2.6-2.8(d,1H),2.8-3.0(m,2H),3.2-3.4(m,2H),3.5-3.7(m,4H),4.0(dd,1H)。
方法3
3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲
酰胺
(a)3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺
向[(2S)-2-(4-氟苯基)戊-4-烯-1-基]甲基胺(见Bioorg.Med.Chem.Lett;2001;265-270;0.54克,2.8毫摩尔)和3-溴-5-三氟甲基苯甲酸(0.81克,3.0毫摩尔)的DMF(7毫升)溶液中,加入TBTU(0.96克,3.0毫摩尔)和DIPEA(1.41克,10.9毫摩尔)。于室温氮气下搅拌反应混合物过夜,然后在乙酸乙酯和NaHCO3水溶液中分配。水相用乙酸乙酯萃取三次。合并的有机溶液用水洗涤三次,然后经相分离柱干燥。蒸发除去溶剂,产物经硅胶色谱法纯化(乙酸乙酯-庚烷10%至17%)。获得3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺0.86克(68%)。1H NMR(500MHz,CDCl3):2.1-3.8(cm,8H),4.9-5.1(m,2H),5.5-5.8(m,1H),6.8-7.4(cm,6H),7.8(s,1H)。
(b)3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺
向3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺(0.86克,1.9毫摩尔)的丙酮(45毫升)溶液中,加入OsO4(2.5%/叔丁基醇,0.49毫升,0.039毫摩尔)和4-甲基吗啉-4-氧化物(0.41克,3.5毫摩尔)。于室温氮气下搅拌溶液过夜,然后加入NaHSO3(39%,45毫升)水溶液。搅拌混合物2小时,用水稀释,然后用二氯甲烷萃取两次。合并的有机溶液用相分离柱分离,蒸发除去溶剂。将残余物(1.08克)溶于THF(18毫升)和水(4.5毫升)中,向所得溶液中加入NaIO4(0.73克,3.4毫摩尔)。室温氮气下搅拌混合物过夜。混合物在二氯甲烷和水之间分配。水相用二氯甲烷萃取,然后合并的有机溶液用盐水洗涤,并用相分离柱分离。蒸发除去溶剂,获得标题化合物0.78克(90%)。1HNMR(500MHz,CDCl3):2.4-4.4(cm,8H),6.8-7.8(cm,7H),9.8(s,1H);LCMS:m/z 447(M-1)+。
方法4
2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮
(a)2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮
向1-(二苯基甲基)氮杂环丁烷-3-酮(见Bioorg.Med.Chem.Lett.;13;2003;2191-2194,1.32克,5.6毫摩尔)和八氢-6H-吡啶并[1,2-a]吡嗪-6-酮盐酸盐(Bioorg.Med.Chem.;2004;71-86;1.30克,6.8毫摩尔)的甲醇(10毫升)溶液中,加入乙酸(1毫升)。该溶液与(聚苯乙烯基甲基)三甲基铵氰基硼氢化物(4.2毫摩尔/克,1.67克,8.8毫摩尔)混合,用微波单节加热将混合物于120℃加热5分钟。过滤除去树脂后,蒸发除去溶剂。产物用氨饱和的甲醇(2%)和二氯甲烷的混合物通过硅胶色谱法纯化。获得油状的2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮0.58克(28%)。1H NMR(500MHz,CDCl3):1.4(q,1H),1.7(t,2H),1.8-2.0(m,3H),2.3-2.4(m,1H),2.4-2.5(d,1H),2.7-2.8(t,3H),3.0(m,3H),3.4-3.6(m,3H),4.5(s,1H),4.6(d,1H),7.2(m,2H),7.3(m,4H),7.4(m,4H);LCMS:m/z 376(M+1)+。
(b)2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮
使用方法1b所述的氢化反应方案来制备标题化合物,但是使用2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮作为底物(产率,99%)。LCMS:m/z 210(M+1)+。
方法5
2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮的对映体之
(a)(+)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮
2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮(见方法4a)的两种对映体,通过手性色谱法用OD柱(250×20毫米)分离。流动相为庚烷/异丙醇/三乙胺(70/30/0.1),进样量为160毫克。样品在异丙醇中的浓度为20毫克/毫升。从448毫克外消旋化合物中得到134毫克的(+)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮,光学纯度超过99.9%e.e。通过在线测量来确定旋光(+)的信号。LCMS:m/z 376(M+1)+。
(b)(+)-2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮
将(+)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮(138毫克,0.37毫摩尔)和甲酸铵(70毫克,1.1毫摩尔)溶于乙醇(3毫升)中。加入氢氧化钯/碳(52毫克),用微波单节加热将反应混合物于120℃加热2分钟。过滤除去催化剂,蒸发除去溶剂。获得标题化合物77毫克(100%)。LCMS:m/z 210(M+1)+。
方法6
2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮的相反对映
体
(a)(-)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮
使用方法5中所述的条件,通过手性色谱法分离2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮(见方法4a)的(-)-对映体。从448毫克外消旋化合物中得到138毫克的(-)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮,光学纯度超过99.9%e.e。通过在线测量来确定旋光(-)的信号。LCMS:m/z 376(M+1)+。
(b)2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮的相反对映体
使用方法5b中所述的氢化反应方案来制备标题化合物,但是使用(-)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮作为底物(产率,100%)。LCMS:m/z 210(M+1)+。
方法7
1-氮杂环丁烷-3-基-4-丙酰基哌嗪
(a)1-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪
于60℃氮气下搅拌1-(二苯基甲基)氮杂环丁烷-3-基甲烷磺酸酯(见J.Org.Chem.;56;1991;6729;25克,78.6毫摩尔)、哌嗪(67.7克,0.79摩尔)和无水乙腈的混合物过夜。冷却混合物,在水和二氯甲烷之间分配。有机层用水和盐水洗涤。溶液经Na2SO4干燥,然后蒸发除去溶剂。残余物经硅胶柱色谱法纯化(甲醇-二氯甲烷5∶95)。获得黄色油状的1-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪17.5克(72%)。1HNMR(400MHz,CDCl3):2.1-2.4(m,4H),2.8-2.9(m,2H),3.0(m,4H),3.4-3.5(m,2H),3.7-3.9(m,1H),4.4(s,1H),7.2-7.4(m,10H);LCMS:m/z 308(M+1)+。
(b)1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-丙酰基哌嗪
室温下搅拌1-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪(250毫克,0.81毫摩尔)、K2CO3(146毫克,1.1毫摩尔)、丙酰基氯(98毫克,1.1毫摩尔)和乙腈(6毫升)的混合物16小时。混合物经相分离柱过滤,蒸发除去溶剂。将残余物溶于二氯甲烷,溶液用NaHCO3水溶液洗涤。有机相用相分离柱分离,然后蒸发除去溶剂。获得油状的1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-丙酰基哌嗪216毫克(73%)。1HNMR(500MHz,CDCl3):1.1-1.2(t,3H),2.2-2.4(m,6H),2.9(t,2H),3.0(m,1H),3.4-3.5(m,4H),3.6(b,2H),4.4(s,1H),7.2(m,2H),7.3(m,4H),7.4(m,4H);LCMS:m/z 364(M+1)+。
(c)1-氮杂环丁烷-3-基-4-丙酰基哌嗪
将1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-丙酰基哌嗪(0.22克,0.59毫摩尔)溶于乙醇(9毫升)和乙酸(0.2毫升)的混合物中,向所得溶液加入氢氧化钯/碳(83毫克)。于室温氢气下(5巴)搅拌混合物23小时,然后通过相分离柱过滤催化剂,再用乙醇洗涤。蒸发除去溶剂,将残余物溶于甲醇(1毫升)中。溶液经阳离子交换柱(Isolute SCX-2,10克)过滤。柱子用THF洗涤,然后产物用氨饱和的甲醇洗脱。蒸发除去溶剂,得到油状的标题化合物0.13克(100%)。1H NMR(500MHz,CD3OD):1.1(t,3H),2.3-2.5(m,6H),3.4(m,1H),3.6(m,4H),3.9-4.0(m,4H)。
方法8
8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐
(a)4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸叔丁酯
在0℃向3-(羟甲基)哌嗪-1-羧酸叔丁酯(360毫克,1.7毫摩尔)的二氯甲烷(10毫升)溶液中,加入三乙胺(505毫克,5.0毫摩尔)。将氯乙酰氯(282毫克,2.5毫摩尔)溶于二氯甲烷(5毫升)中,在0℃将该溶液逐滴加入前面的溶液中。在0℃下搅拌反应混合物1小时,然后在室温下搅拌3小时。加入KHSO4水溶液(1M,5毫升),然后经相分离柱分离有机相。蒸发除去溶剂,将经硅胶色谱法纯化过的中间体酰胺溶于DMF(2毫升)中。冷却的同时,在氮气下,将该溶液逐滴加入到NaH(60毫克,2.5毫摩尔)的DMF悬浮液中。室温搅拌混合物48小时,然后用乙酸乙酯稀释,然后加入(pored over)HCl(0.5M)水溶液。用NaOH调整至pH12,然后分离有机相。蒸发除去溶剂,产物经硅胶色谱法纯化。获得4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸叔丁酯90毫克(21%)。1H NMR(500MHz,sCDCl3):1.4(s,9H),2.5-2.7(m,2H),2.8(m,1H),3.4-3.5(m,2H),3.9-4.2(m,5H),4.5(d,1H);LCMS:m/z 257(M+1)+。
(b)六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐
向4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸叔丁酯(90毫克,0.35毫摩尔)的乙腈(10毫升)溶液中,加入浓HCl水溶液(3滴)。室温搅拌混合物30分钟,然后蒸发除去溶剂。获得六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐74毫克(100%)。1H NMR(500MHz,CD3OD):3.0-3.2(m,3H),3.4-3.5(m,2H),3.7-3.8(m,1H),4.0(m,1H),4.1(m,1H),4.2(s,2H),4.7-4.8(m,1H);LCMS:m/z 157(M+1)+。
(c)8-[1-(二苯基甲基)]氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
用实施例4a中所述的还原性烷基化方案来制备标题化合物,但是使用六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐作为胺(产率,54%)。1H NMR(500MHz,CDCl3):1.7(t,1H),1.8-1.9(m,1H),2.6(d,1H),2.7-2.8(m,2H),2.9(m,2H),3.0(m,1H),3.4(m,2H),3.5(m,1H),3.6(m,1H),3.9(dd,1H),4.1-4.2(m,2H),4.4(s,1H),4.5-4.6(d,1H);LCMS:m/z 378(M+1)+。
(d)8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐
将8-[1-(二苯基甲基)]氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮(84毫克,0.22毫摩尔)溶于乙醇(4毫升)和乙酸(0.4毫升)的混合物,向所得溶液加入少量氢氧化钯/碳。于室温氢气下(5巴)搅拌混合物24小时,然后用过滤除去催化剂。蒸发除去溶剂,残余物在甲苯和HCl(0.1M)水溶液之间分配。分离水溶液,冷冻干燥除去溶剂。获得标题化合物53毫克(96%)。1H NMR(500MHz,D2O):3.0-3.3(m,3H),3.6(t,2H),3.8(m,1H),4.1(m,1H),4.2(dd,1H),4.3(s,2H),4.5-4.7(m,4H),4.7-4.8(m,2H);LCMS:m/z 212(M+1)+。
方法9
1-氮杂环丁烷-3-基-4-(四氢呋喃-2-基羰基)哌嗪
(a)1-[1-(二苯基甲基)]氮杂环丁烷-3-基]-4-(四氢呋喃-2-基羰基)哌嗪
用方法4a中所述的还原性烷基化方案来制备标题化合物,但是使用1-(四氢呋喃-2-基羰基)哌嗪作为胺(产率,82%)。1H NMR(500MHz,CD3OD):1.9-2.0(m,3H),2.0-2.1(m,1H),2.2(m,1H),2.3-2.4(m,3H),3.0(m,3H),3.4(t,2H),3.5-3.6(m,1H),3.6-3.7(m,1H),3.8(qt,1H),3.9(qt,1H),4.5(s,1H),4.7(t,1H),7.2(t,2H),7.3(t,4H),7.4(t,4H);LCMS:m/z 406(M+1)+。
(b)1-氮杂环丁烷-3-基-4-(四氢呋喃-2-基羰基)哌嗪
将氢氧化钯/碳(0.15克)置于5毫升试管中,然后加入1-[1-(二苯基甲基)]氮杂环丁烷-3-基]-4-(四氢呋喃-2-基羰基)哌嗪(0.66克,1.6毫摩尔)、甲醇(4毫升)和乙酸(0.3毫升)的溶液。于室温氢气下(1.6巴)搅拌混合物60小时,然后用过滤除去催化剂。蒸发除去溶剂,粗品无需定量而用于下一步骤。LCMS:m/z 240(M+1)+。
方法10
1-氮杂环丁烷-3-基-4-(甲氧基乙酰基)哌嗪
(a)1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-(甲氧基乙酰基)哌嗪
向1-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪(见方法7a;615毫克,2.0毫摩尔)的DMF(8毫升)溶液中,加入甲氧基乙酸(272毫克,3.0毫摩尔)、DIPEA(310毫克,2.4毫摩尔)和TBTU(770毫克,2.4毫摩尔)。室温搅拌反应混合物12小时,然后在二氯甲烷和NaHCO3水溶液之间分配。水相用二氯甲烷萃取两次,然后合并的有机溶液用盐水洗涤,并经MgSO4干燥。蒸发除去溶剂,产物经反相色谱法纯化,用乙腈和0.1M乙酸铵水溶液的混合物作为流动相。获得1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-(甲氧基乙酰基)哌嗪610毫克(80%)。1HNMR(500MHz,CD3OD):2.3-2.4(m,4H),3.0(m,3H),3.4(s,3H),3.4m,2H),3.5(m,2H),3.6(m,2H),4.1(s,2H),4.5(s,1H),7.2(t,2H),7.3(t,4H),7.4(d,4H);LCMS:m/z 380(M+1)+。
(b)1-氮杂环丁烷-3-基-4-(甲氧基乙酰基)哌嗪
用方法9b中所述的氢化反应方案来制备标题化合物,但是使用1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-(甲氧基乙酰基)哌嗪作为底物。粗品无需定量而用于下一步骤。LCMS:m/z 214(M+1)+。
方法11
2-(4-氮杂环丁烷-3-基哌嗪-1-基)-2-氧代乙醇
(a)2-{4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪-1-基}-2-氧代乙醇
用方法10a中所述的酰胺生成反应方案来制备标题化合物,但是使用2-羟基乙酸作为羧酸(产率,54%)。1H NMR(500MHz,CD3OD):2.3-2.4(m,4H),3.0(m,3H),3.4(m,4H),3.6m,2H),4.1(s,2H),4.5(s,1H),7.2(t,2H),7.3(t,4H),7.4(d,4H);LCMS:m/z 366(M+1)+。
(b)2-(4-氮杂环丁烷-3-基哌嗪-1-基)-2-氧代乙醇
用方法9b中所述的氢化反应方案来制备标题化合物,但是使用2-{4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪-1-基}-2-氧代乙醇作为底物。粗品无需定量而用于下一步骤。LCMS:m/z 200(M+1)+。
方法12
(9aS)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
(a)(3S)-3-(羟甲基)哌嗪-1-羧酸苯甲酯盐酸盐
将(2S)-2-(羟基甲基)哌嗪-1,4-二羧酸4-苯甲酯1-叔丁酯(见WO02/000631;1.6克,4.6毫摩尔)溶于乙腈(25毫升)中,向所得溶液中加入浓HCl(1毫升)。室温搅拌混合物过夜,然后蒸发除去溶剂。获得无色油状的(3S)-3-(羟基甲基)哌嗪-1-羧酸苯甲酯盐酸盐1.3克(100%)。1H NMR(500MHz,CD3OD):3.1-3.4(m,5H),3.7(m,1H),3.8(m,1H),4.2(m,2H),5.2(m,2H),7.2-7.4(m,5H);LCMS:m/z 251(M+1)+。
(b)(3S)-4-(溴乙酰基)-3-(羟基甲基)哌嗪-1-羧酸苯甲酯
将(3S)-3-(羟基甲基)哌嗪-1-羧酸苯甲酯盐酸盐(0.83克,2.9毫摩尔)溶于二氯甲烷(10毫升)和DIPEA(1.5毫升,8.6毫摩尔)中。于0℃逐滴加入溴乙酰氯(0.48克,3.0毫摩尔)。室温搅拌混合物1小时,然后加入水(10毫升)。通过相分离柱来分离相。收集有机溶液,蒸发除去溶剂。获得棕色油状的(3S)-4-(溴乙酰基)-3-(羟甲基)哌嗪-1-羧酸苯甲酯1.1克(100%)。LCMS:m/z 370(M-1)-。
(c)(9aS)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯
将(3S)-4-(溴乙酰基)-3-(羟基甲基)哌嗪-1-羧酸苯甲酯(1.1克,2.9毫摩尔)溶于甲苯(25毫升)中,向所得溶液中加入碳酸钾(4.0克,28.8毫摩尔)。将混合物加热至回流过夜,冷却至室温,然后过滤除去固体。蒸发除去溶剂,产物经硅胶色谱法纯化(甲醇-二氯甲烷1%至10%)。获得无色油状的(9aS)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯0.19克(23%)。1H NMR(500MHz,CDCl3):2.6-3.0(m,3H),3.4-3.6(m,2H),4.0(d,1H),4.1-4.3(m,4H),4.5(d,1H),5.1(s,2H),7.2-7.4(m,5H)。
(d)(9aS)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
将(9aS)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯(0.19克,0.65毫摩尔)溶于乙醇(20毫升)中。将溶液转移至装有10%钯碳(0.1克)、甲酸(0.1克,2.2毫摩尔)和甲酸铵(0.2克,3.17毫摩尔)的25毫升小瓶中。用微波单节加热将混合物于120℃加热5分钟。过滤除去催化剂,(9aS)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮的粗品溶液无需纯化和定量而用于下一步骤。
(e)(9aS)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
向1-(二苯基甲基)氮杂环丁烷-3-酮(见Bioorg.Med.Chem.Lett.;13;5 2003;2191-2194,约0.65毫摩尔)和(9aS)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮(0.65毫摩尔)的甲醇(10毫升)溶液中,加入氰基硼氢化钠(125毫克,2.0毫摩尔)和氯化锌(135毫克,1.0毫摩尔)的甲醇(20毫升)溶液。室温搅拌反应混合物15分钟,然后蒸发除去溶剂。残余物在乙酸乙酯(50毫升)和水(20毫升)之间分配。有机溶液用盐水洗涤,然后经Na2SO4干燥。蒸发除去溶剂,将残余物溶于乙腈(10毫升)、乙酸(100毫克)和水(10毫升)的混合物中。产物用乙腈和0.1M乙酸铵水溶液的混合物经反相色谱法纯化。合并适当的部分,旋转蒸发浓缩。水性残余物用乙酸乙酯萃取,有机溶液经Na2SO4干燥。蒸发除去溶剂,获得(9aS)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮170毫克(69%)。1H NMR(400MHz,CDCl3):1.6-1.7(m,1H),1.8-1.9(m,1H),2.6(d,1H),2.7-2.8(m,2H),2.8-2.9(m,2H),3.0(qn,1H),3.3-3.7(m,4H),3.9(dd,1H),4.0-4.2(qt,2H),4.4(s,1H),4.5(dd,1H),7.2(t,2H),7.3(m,4H),7.4(m,4H);LCMS:m/z 378(M+1)+。
(f)(9aS)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
将(9aS)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮(85毫克,0.22毫摩尔)溶于乙醇(18毫升)中。将溶液转移至装有乙醇(2毫升)、10%钯碳(0.1克)、甲酸(0.1克,2.2毫摩尔)和甲酸铵(0.2克,3.17毫摩尔)的25毫升小瓶中。用微波单节加热将混合物于120℃加热5分钟。过滤除去催化剂,(9aS)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮的粗品溶液无需纯化和定量而用于下一步骤。
方法13
(9aR)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
(a)(2R)-2-(羟基甲基)哌嗪-1,4-二羧酸4-苯甲酯1-叔丁酯
将(2R)-4-[(苯甲氧基)羰基]-1-(叔丁氧基羰基)哌嗪-2-羧酸(1.4克,3.9毫摩尔)溶于二甲氧基乙烷(10毫升)中,向冷却的所得溶液中加入N-甲基吗啉(0.4克,3.9毫摩尔),然后逐滴加入氯甲酸异丁酯(0.54克,3.9毫摩尔)。于0℃搅拌混合物20分钟,然后过滤混合物。将滤出液转移至500毫升烧瓶中,然后再次冷却。加入溶于水(5毫升)中的硼氢化钠(0.22克,5.9毫摩尔),移除外部的冷却浴。搅拌反应混合物直至其温度达到室温,这时加入水(120毫升)。混合物用乙酸乙酯萃取三次,合并的有机溶液干燥后蒸发。产物经硅胶柱色谱法(乙酸乙酯-庚烷10%至70%)纯化。获得无色油状的(2R)-2-(羟基甲基)哌嗪-1,4-二羧酸4-苯甲酯1-叔丁酯1.2克(84%)。1HNMR(500MHz,CDCl3):1.4(s,9H),2.7-3.2(b,4H),3.5(b,2H),3.8-4.2(m,4H),5.1(m,2H),7.2-7.4(m,5H);LCMS:m/z 349(M-1)+。
(b)(3R)-3-(羟基甲基)哌嗪-1-羧酸苯甲酯盐酸盐
用实施例12a中所述的水解反应方案来制备标题化合物,但是使用(2R)-2-(羟基甲基)哌嗪-1,4-二羧酸4-苯甲酯1-叔丁酯作为底物(产率,100%)。1HNMR(500MHz,CD3OD):3.1-3.4(m,5H),3.7(m,1H),3.8(m,1H),4.2(m,2H),5.2(m,2H),7.2-7.4(m,5H);LCMS:m/z 251(M+1)+。
(c)(3R)-4-(溴乙酰基)-3-(羟基甲基)哌嗪-1-羧酸苯甲酯
用实施例12b中所述的酰化反应方案来制备标题化合物,但是使用(3R)-3-(羟甲基)哌嗪-1-羧酸苯甲酯盐酸盐作为胺(产率,100%)。LCMS:m/z 370(M-1)+。
(d)(9aR)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯
用实施例12c中所述的环化反应方案来制备标题化合物,但是使用(3R)-4-(溴乙酰基)-3-(羟甲基)哌嗪-1-羧酸苯甲酯作为底物(产率,17%)。1H NMR(500MHz5 CDCl3):2.6-3.0(m,3H),3.4-3.6(m,2H),4.0-4.3(m,5H),4.6(d,1H),5.1-5.2(s,2H),7.2-7.4(m,5H);LCMS:m/z291(M+1)+。
(e)(9aR)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
用实施例12d中所述的还原性去保护反应方案来制备标题化合物,但是使用(9aR)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯作为底物。(9aR)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮的粗品溶液无需纯化和定量而用于下一步骤。
(f)(9aR)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
用实施例12e中所述的还原性烷基化反应方案来制备标题化合物,但是使用(9aR)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮作为胺(产率,71%)。1HNMR(400MHz,CDCl3):1.6-1.7(t,1H),1.8(dt,1H),2.5-2.6(d,1H),2.7-2.8(m,2H),2.8-2.9(m,2H),2.9-3.0(qn,1H),3.3-3.4(m,2H),3.5(m,1H),3.8-3.9(dd,1H),4.0-4.2(qt,2H),4.2-4.3(s,1H),4.4-4.5(m,1H),7.1(m,2H),7.2(m,4H),7.4(m,4H);LCMS:m/z 378(M+1)+。
(g)(9aR)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮
用实施例12f中所述的还原性去保护反应方案来制备标题化合物,但是使用(9aR)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮作为底物。(9aR)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮的粗品溶液无需纯化和定量而用于下一步骤。LCMS:m/z 212(M+1)+。
方法14
1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪
(1)1-(环丙基羰基)-4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪
用实施例7b中所述的酰化反应方案来制备标题化合物,但是使用环丙基羰基氯作为酰化剂(产率,60%)。1H NMR(400MHz,CDCl3):0.7(m,2H),0.9(m,2H),1.6-1.7(m,1H)2.2-2.4(b,4H),2.8-3.0(m,3H),3.4(t,2H),3.6(b,4H),4.4(s,1H),7.2(t,2H),7.2-7.3(m,4H),7.4(d,4H);LCMS:m/z 376(M+1)+。
(b)1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪
用方法12f中所述的还原性去保护反应方案来制备标题化合物,但是使用1-(环丙基羰基)-4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪作为底物。1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪的粗品溶液无需纯化和定量而用于下一步骤。LCMS:m/z 210(M+1)+。
方法15
1-氮杂环丁烷-3-基-4-丁酰基哌嗪
(a)1-丁酰基-4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪
用实施例7b中所述的酰化反应方案来制备标题化合物,但是使用丁酰氯作为酰化剂(产率,50%)。1H NMR(400MHz,CDCl3):0.9(t,3H),1.5-1.7(m,4H),2.2-2.3(m,4H),2.8-3.0(m,3H),3.3(b,2H),3.5(b,2H),3.6(b,2H),4.4(s,1H),7.1-7.2(t,2H),7.3(m,4H),7.4(d,4H);LCMS:m/z 378(M+1)+。
(b)1-氮杂环丁烷-3-基-4-丁酰基哌嗪
用方法12f中所述的还原性去保护反应方案来制备标题化合物,但是使用1-丁酰基-4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪作为底物。1-氮杂环丁烷-3-基-4-丁酰基哌嗪的粗品溶液无需纯化和定量而用于下一步骤。LCMS:m/z 212(M+1)+。
方法16
1-氮杂环丁烷-3-基-4-异丁酰基哌嗪
(a)1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-异丁酰基哌嗪
用实施例7b中所述的酰化反应方案来制备标题化合物,但是使用异丁酰氯作为酰化剂(产率,59%)。1H NMR(400MHz,CDCl3):1.1(d,6H),2.3(m,4H),2.8(qn,1H),2.9(t,2H),3.0(qn,1H),3.4(t,2H),3.5(b,2H),3.6(b,2H),4.4(s,1H),7.2(t,2H),7.3(m,4H),7.4(d,4H);LCMS:m/z 378(M+1)+。
(b)1-氮杂环丁烷-3-基-4-异丁酰基哌嗪
用方法12f中所述的还原性去保护反应方案来制备标题化合物,但是使用1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-异丁酰基哌嗪作为底物。1-氮杂环丁烷-3-基-4-异丁酰基哌嗪的粗品溶液无需纯化和定量而用于下一步骤。LCMS:m/z 212(M+1)+。
Claims (18)
4.权利要求2的化合物,其中R为C1-C3烷基。
5.权利要求4的化合物,其中R为C1-C2烷基。
6.权利要求2的化合物,其中R为C1-C2甲氧基烷基。
7.权利要求2的化合物,其中R为C1-C2乙氧基烷基。
8.权利要求3的化合物,其中Y为C2-C3烷基。
9.权利要求3的化合物,其中Y为-CH2-O-CH2-。
10.权利要求1至9中任一项的化合物,其中所述化合物为S-对映体。
11.权利要求1的化合物,选自
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(8aR)-6-氧代六氢吡咯并[1,2-a]吡嗪-2(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(8aS)-6-氧代六氢吡咯并[1,2-a]吡嗪-2(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(6-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aR)-6-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aS)-6-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-丙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-氧代六氢吡嗪并[2,1-c][1,4]嗪-8(1H)-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[4-(四氢呋喃-2-基羰基)哌嗪-1-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[4-(甲氧基乙酰基)哌嗪-1-基]氮杂环丁烷-1-基}丁基]-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙醇酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aS)-4-氧代六氢吡嗪并[2,1-c][1,4]嗪-8(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-((2S)-2-(4-氟苯基)-4-{3-[(9aR)-4-氧代六氢吡嗪并[2,1-c][1,4]嗪-8(1H)-基]氮杂环丁烷-1-基}丁基)-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-[(2S)-4-{3-[4-(环丙基羰基)哌嗪-1-基]氮杂环丁烷-1-基}-2-(4-氟苯基)丁基]-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-[(2S)-4-[3-(4-丁酰基哌嗪-1-基)氮杂环丁烷-1-基]-2-(4-氟苯基)丁基]-N-甲基-5-(三氟甲基)苯甲酰胺;和
3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-异丁酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺。
12.权利要求1至11中任一项的化合物,其用于治疗。
13.权利要求1至11中任一项化合物用于生产治疗功能性胃肠疾病的药物的用途。
14.权利要求1至11中任一项化合物用于生产治疗IBS的药物的用途。
15.权利要求1至11中任一项化合物用于生产治疗功能性消化不良的药物的用途。
16.一种药物制剂,其包含用作活性成分的权利要求1至11中任一项的化合物和药学上可接受的载体或稀释剂。
17.制备式(I)化合物的方法,其包括以下步骤:
a)式(III)化合物与式(IV)化合物反应:
其中Het如权利要求1所述;且条件是将式(III)化合物还原烷基化,在式(III)化合物氮杂环丁烷基的氮原子和式(IV)化合物醛基的碳原子之间形成N-C键;或者
b)式(III)化合物与式(V)化合物反应:
其中Het如权利要求1所述;且L基团使得通过式(III)化合物烷基化,在式(III)化合物氮杂环丁烷基的氮原子和式(V)化合物与L基相邻的碳原子之间形成N-C键;或者
c)式(VI)化合物与式(VII)化合物反应:
其中Het如权利要求1所述;L′是离去基;其中,如有必要,任何其它的官能团被保护,并:
i)除去任何保护基;
ii)任选形成药学上可接受的盐。
18.一种化合物,其选自:
(8aR)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮;
(8aR)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮;
(8aS)-2-氮杂环丁烷-3-基六氢吡咯并[1,2-a]吡嗪-6(2H)-酮;
(8aS)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡咯并[1,2-a]吡嗪-6(2H)-酮;
3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺;
3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺;
2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮;
2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮;
(+)-2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮;
(+)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮;
(-)-2-氮杂环丁烷-3-基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮;
(-)-2-[1-(二苯基甲基)氮杂环丁烷-3-基]八氢-6H-吡啶并[1,2-a]吡嗪-6-酮;
1-氮杂环丁烷-3-基-4-丙酰基哌嗪;
1-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪;
1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-丙酰基哌嗪;
8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐;
4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸叔丁酯;
六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮盐酸盐;
8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
1-氮杂环丁烷-3-基-4-(四氢呋喃-2-基羰基)哌嗪;
1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-(四氢呋喃-2-基羰基)哌嗪;
1-氮杂环丁烷-3-基-4-(甲氧基乙酰基)哌嗪;
1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-(甲氧基乙酰基)哌嗪;
2-(4-氮杂环丁烷-3-基哌嗪-1-基)-2-氧代乙醇;
2-{4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪-1-基}-2-氧代乙醇;
(9aS)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(3S)-3-(羟甲基)哌嗪-1-羧酸苯甲酯盐酸盐;
(3S)-4-(溴乙酰基)-3-(羟甲基)哌嗪-1-羧酸苯甲酯;
(9aS)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯;
(9aS)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(9aS)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(9aS)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(9aR)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(2R)-2-(羟甲基)哌嗪-1,4-二羧酸4-苯甲酯1-叔丁酯;
(3R)-3-(羟甲基)哌嗪-1-羧酸苯甲酯盐酸盐;
(3R)-4-(溴乙酰基)-3-(羟甲基)哌嗪-1-羧酸苯甲酯;
(9aR)-4-氧代六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-羧酸苯甲酯;
(9aR)-六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(9aR)-8-[1-(二苯基甲基)氮杂环丁烷-3-基]六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
(9aR)-8-氮杂环丁烷-3-基六氢吡嗪并[2,1-c][1,4]噁嗪-4(3H)-酮;
1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪;
1-(环丙基羰基)-4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪;
1-氮杂环丁烷-3-基-4-(环丙基羰基)哌嗪;
1-氮杂环丁烷-3-基-4-丁酰基哌嗪;
1-丁酰基-4-[1-(二苯基甲基)氮杂环丁烷-3-基]哌嗪;
1-氮杂环丁烷-3-基-4-丁酰基哌嗪;
1-氮杂环丁烷-3-基-4-异丁酰基哌嗪;
1-[1-(二苯基甲基)氮杂环丁烷-3-基]-4-异丁酰基哌嗪;和
1-氮杂环丁烷-3-基-4-异丁酰基哌嗪。
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CN104906106A (zh) * | 2015-04-23 | 2015-09-16 | 谭作华 | 一种抗肿瘤细胞增殖的药物组合物及其应用 |
CN104873482A (zh) * | 2015-05-05 | 2015-09-02 | 青岛市市立医院 | 一种抗慢性心力衰竭的药物组合物 |
CN104958297A (zh) * | 2015-06-03 | 2015-10-07 | 周玉梅 | 一种用于麻醉镇静催眠的药物组合物及其应用 |
CN105663133A (zh) * | 2016-03-07 | 2016-06-15 | 青岛市肿瘤医院 | 一种抑制淋巴瘤细胞增殖的药物组合物及其应用 |
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US8288370B2 (en) | 2012-10-16 |
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CA2624491A1 (en) | 2007-04-05 |
WO2007037743A1 (en) | 2007-04-05 |
ZA200802645B (en) | 2008-12-31 |
EP1940845A4 (en) | 2010-11-17 |
HK1121142A1 (en) | 2009-04-17 |
TW200745122A (en) | 2007-12-16 |
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