CN1711252A - 4-(苯基-哌嗪基-甲基)苯甲酰胺衍生物及其在治疗疼痛或胃肠疾病中的用途 - Google Patents
4-(苯基-哌嗪基-甲基)苯甲酰胺衍生物及其在治疗疼痛或胃肠疾病中的用途 Download PDFInfo
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- CN1711252A CN1711252A CNA200380102831XA CN200380102831A CN1711252A CN 1711252 A CN1711252 A CN 1711252A CN A200380102831X A CNA200380102831X A CN A200380102831XA CN 200380102831 A CN200380102831 A CN 200380102831A CN 1711252 A CN1711252 A CN 1711252A
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- Prior art keywords
- alkyl
- compound
- phenyl
- methyl
- diethylin
- Prior art date
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
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Abstract
本发明制备了通式(I)化合物及其盐、对映体和包括该化合物的组合物,其中R1、R2和R3如说明书定义。它们可用于治疗,特别是用于治疗疼痛。
Description
发明背景
1.发明领域
本发明涉及新的化合物、其制备方法、其用途及含有该新化合物的药物组合物。该新化合物适用于治疗,特别是用于治疗疼痛、忧虑症和功能性胃肠疾病。
2.相关现有技术讨论
受体已经被确认为在许多身体功能如循环和疼痛系统中具有作用。因此,δ-受体的配体发现可用作止痛剂和/或用作抗高血压药物。δ-受体的配体也显示出了具有免疫调节活性。
至少可以很好地确认三种类型的类鸦片受体(μ、δ和κ),它们在许多动物(包括人)种类中于中枢和周围神经系统中是显然的。当一种或多种这类受体被活化时,在许多动物模型中均观察到了痛觉丧失。
也有一些例外,目前可得到的选择性类鸦片δ配体在自然界为肽类,且不适于通过全身路径给药。一种非肽δ-激动剂的实例为SNC80(Bilsky E.J.et al.,Journal of Pharmacology and ExperimentalTherapeutics,273(1),pp.359-366(1995))。
在现有技术中被确认的许多δ激动剂的药物动力学性能都很差,其在通过全身路径给药时没有止痛作用。此外,据文献介绍,这些δ激动剂化合物中的许多化合物在通过全身给药时,均显示出显著的惊厥作用。
Roberts等人的美国专利US 6,130,222描述了一些δ激动剂。
然而,人们仍需要一些改进的δ-激动剂。
发明描述
定义
除非在本说明书中另外指明,本说明书中使用的命名一般遵循实施例及下述文献中所述的规则:Nomenclature of Organic Chemistry,Sections A,B,C,D,E,F,and H,Pergamon Press,Oxford,1979,对于实例性化学结构名称和命名化学结构的规则,该文献在此引作参考。
单独使用或作为后缀或前缀使用的术语“Cm-n”和“Cm-n基团”是指含m至n个碳原子的任何基团。
单独使用或作为后缀或前缀使用的术语“烃”是指仅包含碳和氢原子的任何结构,其可含多达14个碳原子。
单独使用或作为后缀或前缀使用的术语“烃基团”或“烃基”是指从烃中除去一个或多个氢后所得的任何结构。
单独使用或作为后缀或前缀使用的术语“烷基”是指含1至大约12个碳原子的单价直链或支链烃基团。“烷基”可任意地包含一个或多个不饱和碳-碳键。
单独使用或作为后缀或前缀使用的术语“亚烷基”是指含1至大约12个碳原子的二价直链或支链烃基团,其可用于一起连接两个结构。
单独使用或作为后缀或前缀使用的术语“链烯基”是指带有至少一个碳-碳双键且含至少2至大约12个碳原子的单价直链或支链烃基团。
单独使用或作为后缀或前缀使用的术语“炔基”是指带有至少一个碳-碳三键且含至少2至大约12个碳原子的单价直链或支链烃基团。
单独使用或作为后缀或前缀使用的术语“环烷基”是指含至少3至大约12个碳原子的单价含环烃基团。
单独使用或作为后缀或前缀使用的术语“环链烯基”是指带有至少一个碳-碳双键且含至少3至大约12个碳原子的单价含环烃基团。
单独使用或作为后缀或前缀使用的术语“环炔基”是指带有至少一个碳-碳三键且含至少7至大约12个碳原子的单价含环烃基团。
单独使用或作为后缀或前缀使用的术语“芳基”是指带有一个或多个具有芳族特征(如4n+2个离域电子)的多不饱和碳环且含5至大约14个碳原子的单价烃基团。
单独使用或作为后缀或前缀使用的术语“亚芳基”是指带有一个或多个具有芳族特征(如4n+2个离域电子)的多不饱和碳环且含5至大约14个碳原子的二价烃基团,其可用于一起连接两个结构。
单独使用或作为后缀或前缀使用的术语“杂环”是指包含具有一个或多个多价独立选自作为环结构部分的N、O、P和S的杂原子且在环中包括至少3至大约20个原子的结构或分子的环。杂环可以是饱和或不饱和的,包含一个或多个双键,杂环可包含一个以上的环。当杂环包含一个以上的环时,该环可以是稠合或不稠合的。稠合环一般是指至少两个环在其之间共有两个原子。杂环可具有芳族特征,或不具有芳族特征。
单独使用或作为后缀或前缀使用的术语“杂芳族”是指包含具有一个或多个多价独立选自作为环结构部分的N、O、P和S的杂原子且在环中包括至少3至大约20个原子的结构或分子的环,其中带有环的结构或分子具有芳族特征(如4n+2个离域电子)。
单独使用或作为后缀或前缀使用的术语“杂环基团”、“杂环部分”、“杂环的”或“杂环”是指通过从其中离去一个或多个氢而由杂环衍生的基团。
单独使用或作为后缀或前缀使用的术语“杂环基”是指通过从其中离去一个氢而由杂环衍生的单价基团。
单独使用或作为后缀或前缀使用的术语“亚杂环基”是指通过从其中离去两个氢而由杂环衍生的二价基团,其可用于一起连接两个结构。
单独使用或作为后缀或前缀使用的术语“杂芳基”是指具有芳族特征的杂环基。
单独使用或作为后缀或前缀使用的术语“杂环烷基”是指不具有芳族特征的杂环基。
单独使用或作为后缀或前缀使用的术语“亚杂芳基”是指具有芳族特征的亚杂环基。
单独使用或作为后缀或前缀使用的术语“亚杂环烷基”是指不具有芳族特征的亚杂环基。
单独使用或作为后缀或前缀使用的术语“六元”是指具有含六个原子环的基团。
单独使用或作为后缀或前缀使用的术语“五元”是指具有含五个原子环的基团。
五元环杂芳基为具有含五个环原子的杂芳基,其中1、2或3个环原子独立选自N、O或S。
五元环杂芳基的实例包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、异噻唑基、异噁唑基、1,2,3-三唑基、四唑基、1,2,3噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基和1,3,4-噁二唑基。
六元环杂芳基为具有含六个环原子的杂芳基,其中1、2或3个环原子独立选自N、O或S。
六元环杂芳基的实例包括吡啶基、吡嗪基、嘧啶基、三嗪基和哒嗪基。
作为前缀使用的术语“取代”是指其中一个或多个氢被一个或多个C1-6烃基,或一个或多个含一个或多个选自N、O、S、F、Cl、Br、I和P的杂原子的化学基团替代的结构、分子或基团。含个或多个杂原子的实例性化学基团包括-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R、氧代(=O)、亚氨基(=NR)、硫代(=S)和肟基(=N-OR),其中“R”为C1-6烃基。例如取代苯基可以是指硝基苯基、甲氧基苯基、氯苯基、氨基苯基等,其中硝基、甲氧基、氯和氨基可以替代苯环中的任何适宜的氢。
作为第一结构、分子或基团的后缀使用且其后接着一个或多个化学基团命名的术语“取代”是指第二结构、分子或基团,它(们)是利用一个或多个命名的化学基团替代第一结构、分子或基团的一个或多个氢的结果。例如,“被硝基取代的苯基”是指硝基苯基。
杂环包括如单环杂环,例如氮丙啶、环氧乙烷、硫杂丙环、氮杂环丁烷、环氧乙烯、环硫乙烯(thietane)、吡咯烷、吡咯啉、咪唑烷、吡唑烷、吡唑啉、二氧戊环、环丁砜、2,3-二氢呋喃、2,5-二氢呋喃、四氢呋喃、噻吩烷、哌啶、1,2,3,6-四氢吡啶、哌嗪、吗啉、硫代吗啉、吡喃、硫代吡喃、2,3-二氢吡喃、四氢吡喃、1,4-二氢吡啶、1,4-二噁烷、1,3-二噁烷、二噁烷、高哌啶、2,3,4,7-四氢-1H-吖庚因、高哌嗪、1,3-二氧杂环庚三烷、4,7-二氢-1,3-二氧杂环庚三烯和六亚甲基氧化物。
此外,杂环包括芳族杂环,如吡啶、哌嗪、嘧啶、吡嗪、噻吩、呋喃、呋咱、吡咯、咪唑、噻唑、噁唑、吡唑、异噻唑、异噁唑、1,2,3-三唑、四唑、1,2,3-噻二唑、1,2,3-噁二唑、1,2,4-三唑、1,2,4-噻二唑、1,2,4-噁二唑、1,3,4-三唑、1,3,4-噻二唑和1,3,4-噁二唑。
另外,杂环包括多环杂环,例如吲哚、二氢吲哚、异二氢吲哚、喹啉、四氢喹啉、异喹啉、四氢异喹啉、1,4-苯并二噁烷、香豆素、二氢香豆素、苯并呋喃、2,3-二氢苯并呋喃、异苯并呋喃、苯并吡喃、苯并二氢吡喃、异苯并二氢吡喃、氧杂蒽、吩氧硫杂环己二烯、噻蒽、中氮茚、异吲哚、吲唑、嘌呤、2,3-二氮杂萘、萘啶、喹喔啉、喹唑啉、噌啉、喋啶、菲啶、萘嵌间二氮杂苯、邻二氮杂菲、吩嗪、吩噻嗪、吩噁嗪、1,2-苯并异噻唑、苯并噻吩、苯并噁唑、苯并噻唑、苯并咪唑、苯并三唑、噻吨、咔唑、咔啉、吖啶、pyrolizidine和喹嗪。
除了上面描述的多环杂环外,杂环还包括其中两个或多个环之间的环聚变包含一个以上两个环的键和两个以上两个环的原子的多环杂环。这类桥接杂环的实例包括奎宁环、二氮杂二环并[2.2.1]庚烷和7-氧杂二环并[2.2.1]庚烷。
杂环基包括如单环杂环基,例如氮丙啶基、环氧乙烷基、硫杂丙环基、氮杂环丁烷基、环氧乙烯基、环硫乙烯基(thietanyl)、吡咯烷基、吡咯啉基、咪唑烷基、吡唑烷基、吡唑啉基、二氧戊环基、环丁砜基、2,3-二氢呋喃基、2,5-二氢呋喃基、四氢呋喃基、噻吩烷基、哌啶基、1,2,3,6-四氢吡啶基、哌嗪基、吗啉基、硫代吗啉基、吡喃基、硫代吡喃基、2,3-二氢吡喃基、四氢吡喃基、1,4-二氢吡啶基、1,4-二噁烷基、1,3-二噁烷基、二噁烷基、高哌啶基、2,3,4,7-四氢-1H-吖庚因基、高哌嗪基、1,3-二氧杂环庚三烷基、4,7-二氢-1,3-二氧杂环庚三烯基和六亚甲基氧基。
另外,杂环基包括芳族杂环基或杂芳基,例如吡啶基、哌嗪基、嘧啶基、吡嗪基、噻吩基、呋喃基、呋咱基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、异噻唑基、异噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基和1,3,4-噁二唑基。
另外,杂环基包括多环杂环基(包括芳族或非芳族),例如吲哚基、二氢吲哚基、异二氢吲哚基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、1,4-苯并二噁烷基、香豆素基、二氢香豆素基、苯并呋喃基、2,3-二氢苯并呋喃基、异苯并呋喃基、苯并吡喃基、苯并二氢吡喃基、异苯并二氢吡喃基、氧杂蒽基、吩氧硫杂环己二烯基、噻蒽基、中氮茚基、异吲哚基、吲唑基、嘌呤基、2,3-二氮杂萘基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、喋啶基、菲啶基、萘嵌间二氮杂苯基、邻二氮杂菲基、吩嗪基、吩噻嗪基、吩噁嗪基、1,2-苯并异噻唑基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并三唑基、噻吨基、咔唑基、咔啉基、吖啶基、pyrolizidinyl和喹嗪基。
除了上面描述的多环杂环基外,杂环基还包括其中两个或多个环之间的环聚变包含一个以上两个环的键和两个以上两个环的原子的多环杂环基。这类桥接杂环基的实例包括奎宁环基、二氮杂二环并[2.2.1]庚基和7-氧杂二环并[2.2.1]庚基。
单独使用或作为后缀或前缀使用的术语“烷氧基”是指通式-O-R基团,其中R选自烃基。烷氧基实例包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、环丙基甲氧基、烯丙氧基和炔丙氧基。
单独使用或作为后缀或前缀使用的术语“胺”或“氨基”是指通式-NRR′基团,其中R和R′独立地选自氢或烃基。
卤素包括氟、氯、溴和碘。
作为基团前缀使用的术语“卤代”是指基团中的一个或多个氢被一个或多个卤素原子替代。
“RT”或“rt”意为室温。
实施方案描述
一方面,本发明提供了式I化合物及其可药用盐、非对映体、对映体及其混合物:
其中
R1选自-H、C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被-个或多个选自-R、-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;
R2选自-H、C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;以及
R3选自C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基。
在另一实施方案中,本发明化合物为下述式I化合物,其中
R1为-CH2-R4,其中R4选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基,其中所述苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基任意地被一个或多个选自C1-6烷基、卤代C1-6烷基、-NO2、-CF3、C1-6烷氧基、氯、氟、溴和碘的基团取代;
R2选自-H和C1-3烷基;以及
R3选自C1-6烷基和C3-6环烷基。
在另一实施方案中,本发明化合物为下述式I化合物,其中R1为-CH2-R4,其中R4选自苯基、吡啶基、呋喃基、咪唑基、吡咯基和噻唑基;
R2选自-H和甲基;以及
R3选自甲基、乙基、丙基和异丙基。
在进一步的实施方案中,本发明化合物为下述式I化合物,其中R1为-H;
R2选自-H和C1-3烷基;以及
R3选自C1-6烷基和C3-6环烷基。
人们应当可以理解,当本发明化合物包含一个或多个手性中心时,本发明化合物可以以对映体或非对映体或以外消旋混合物形式存在并可分离。本发明化合物包括式I化合物的任何可能的对映体、非对映体、外消旋物或其混合物。本发明化合物的旋光活性形式可以通过下述方法制备,例如,通过由旋光活性起始原料合成或通过基于下述的方法非对称合成,经外消旋物的手性色析法分离制得。
人们也非常欣赏,本发明的一些化合物可以以几何异构体形式存在,如烯烃的E和Z异构体。本发明包括式I化合物的任何几何异构体。人们可进一步地理解,本发明包括式I化合物的互变体。
人们还可以理解,本发明化合物可以以溶剂化物(如水合物)或非溶剂化物形式存在。人们可进一步地理解,本发明包括式I化合物的所有溶剂化物形式。
本发明还包括式I化合物的盐。一般地,本发明化合物的可药用盐可通过本领域公知的标准步骤获得,例如将足够的碱性化合物如烷胺于适宜的酸如HCl或乙酸反应,得到生理学可接受的阴离子。人们也可以通过在水合介质中,利用1当量的碱金属或碱土金属氢氧化物或醇盐(如乙醇盐或甲醇盐),或适宜的碱性有机胺(如胆碱或甲葡胺)处理含有适宜酸性质子的本发明化合物,接着通过常规的纯化技术纯化,制得碱金属(如钠、钾或锂)或碱土金属(如钙)盐。
在一个实施方案中,上述式I化合物可转化成可药用盐或其溶剂化物,特别是酸加成盐,如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、甲磺酸盐或对甲苯磺酸盐。
本发明新的化合物可用于治疗,特别是治疗各种疼痛疾病,如慢性疼痛、神经性疼痛、急性疼痛、癌症疼痛、由风湿性关节炎引起的疼痛、偏头痛、内脏疼痛等。但这种罗列不能被解释为是彻底的。
本发明化合物可用作免疫调节剂,特别是用于自体免疫疾病如关节炎,用于皮肤移植、器官移植及类似的手术所需,用于胶原质疾病、各种敏感症,用作抗肿瘤剂和抗病毒剂。
本发明化合物可用于其中出现类鸦片受体恶化或机能不良或在这种范例中暗示着这种情况的病态中。这可涉及在诊断技术和造影应用如正电子发射体层摄影术(PET)中使用同位素标记转化形式的本发明化合物。
本发明化合物可用于治疗腹泻、萎靡不振症、忧郁症及与紧张有关的疾病,如创伤后精神紧张性障碍、急性焦虑症、泛化性焦虑症、社会恐怖症和强迫症,尿失禁、早射、各种精神疾病、咳嗽、肺气肿,各种肠胃疾病如便秘,功能性胃肠疾病如过敏性肠综合症和功能性消化不良,帕金森病及其它运动原疾病、脑外伤、中风、心肌梗塞后的心脏保护、脊髓伤害和药物沉溺,包括治疗酒精、烟碱、类鸦片及其它药物滥用,以及用于交感神经系统疾病,如高血压。
本发明化合物可在一般的感觉缺乏和受监控的麻醉护理中用作止痛剂。为了获得维持麻醉期间所必需的平衡作用(如健忘症、痛觉丧失、肌肉松弛和镇静),经常组合使用具有不同性能药剂。这种组合包括吸入性麻醉剂、催眠药、抗焦虑药、神经肌内阻滞剂和镇静剂。
本发明的范围还包括将上述式I化合物用于制造治疗上文讨论过的任何疾病的药剂中。
本发明进一步的方面涉及治疗患有上文讨论的任何疾病的患者的方法,该方法包括对需要这类治疗的患者服用有效量的式I化合物。
由此,本发明提供了这里所定义的用于治疗的式I化合物或其可药用盐或溶剂化物。
在进一方面,本发明提供了将这里定义的式I化合物或其可药用盐或溶剂化物用于制造用于治疗的药物。
在本说明书的上下文中,除非有相反指明,术语“治疗”也包括“预防”。术语“治疗的”和“治疗地”也应如此。在本发明上下文中,术语“治疗”进一步包括服用有效量的本发明化合物、缓解预先存在的急性或慢性病症或复发病症。该定义也包括预防复发病症的预防性治疗和慢性疾病的持续性治疗。
本发明化合物可用于治疗,特别是用于治疗各种疼痛疾病,其包括但不局限于:慢性疼痛、神经性疼痛、急性疼痛、背痛、癌症疼痛和内脏疼痛。
在热血动物如人的治疗使用中,本发明化合物可通过任何路径包括经口、肌内、皮下、局部、鼻内、腹膜内、胸内、静内、硬脑膜外、膜内、脑心室内或通过注入到关节中,以常规的药物组合物形式服用本发明化合物。
在本发明的一个实施方案中,给药路径为经口、静内或肌内。
当确定特定患者最适宜的个人给药方法和给药剂量水平时,剂量取决于给药路径、疾病的严重性、患者的年龄和体重及主治医生一般考虑的其它因素。
对于由本发明化合物制备药物组合物,惰性可药用载体可以是固体或液体。固体形式的制剂包括粉剂、片剂、可分散颗粒、胶囊、扁胶囊和栓剂。
固体载体可以是一种或多种物质,其也可用作稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、结合剂或崩解剂;它也可以是封在胶囊中的物质。
在粉剂中,载体为细分的固体,其与细分的本发明化合物或活性成分混合。在片剂中,活性成分与具有必要结合性能的载体以适宜的比例混合,压成所需的形状和尺寸。
对于制备栓剂组合物,将低熔点石蜡(如脂肪酸甘油酯和可可脂的混合物)首先熔化,然后可通过如搅拌,将活性成分分散在其中。然后,将熔化的均质混合物注入到方面尺寸的模具中,冷却并固化。
适宜的载体为碳酸镁、硬脂酸镁、滑石、乳糖、蔗糖、胶质、糊精、淀粉、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点石蜡、可可脂等。
术语组合物也可包括活性成分与作为提供胶囊载体的封胶物质,其中活性成分(含有或不含有其它载体)被与其相关的载体包围。类似地,也包括扁胶囊。
片剂、粉剂、扁胶囊和胶囊可以固体剂量形式适用于口服。
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丙二醇水溶液可以是适用于非肠道给药的液体制剂。液体组合物也可在丙二醇水合溶液中制成。
适于口服给药的水溶液可以通过将活性成分溶解在水中并根据需要添加适宜的着色剂、香味剂、稳定剂和增稠剂而制成。适于口服使用的水合悬浮液可通过将细分的活性成分与各种物质如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠及药物制剂领域公知的其它悬浮剂一起分散在水中而制成。
根据给药形式,药物组合物可优选地包括0.05%至99%(重量),更优选0.10至50%(重量)本发明化合物,所有百分比均基于总的组合物重量。
为了实施本发明,治疗有效量可通过本领域普通技术人员使用公知的标准确定,包括个体患者的年龄、体重及对药物的响应,以及本发明上下文解释的待治疗或预防的疾病种类。
本发明的范围包括将上文定义的式I化合物用于制造药物的用途。
本发明的范围还包括将式I化合物用于制造治疗疼痛的药物的用途。
本发明的范围另外还包括将任何式I化合物用于制造治疗各种疼痛的药物的用途,所述疼痛包括但不局限于:慢性疼痛、神经性疼痛、急性疼痛、背痛、癌症疼痛和内脏疼痛。
本发明进一步的方面涉及治疗患有上文讨论的任何疾病的患者的方法,该方法包括对需要这类治疗的患者服用有效量的上述式I化合物。
另外本发明提供了一种药物组合物,该药物组合物包含式I化合物或其可药用盐及可药用载体。
特别地,本发明提供了一种用于治疗,特别是治疗疼痛的药物组合物,该药物组合物包含式I化合物或其可药用盐及可药用载体。
进一步地,本发明提供了一种用于治疗上文讨论过的任何疾病的药物组合物,该药物组合物包含式I化合物或其可药用盐及可药用载体。
在进一步的方面,本发明提供了制备式I化合物的方法。
在一实施方案中,本发明提供了制备式II化合物的方法,该方法包括:
a)将式III化合物
在存在苯并三唑的条件下,与式IV化合物反应,
b)将步骤a)得到的产物与式V化合物反应,得到式II化合物,
其中
R8选自C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述的C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被一个或多个选自C1-6烷基、卤代C1-6烷基、-NO2、-CF3、C1-6烷氧基、氯、氟、溴和碘的基团取代;
M选自Li、Na、K、-ZnX′和-MgX′,其中X′为卤素;以及
R9选自氢、-R、-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR,其中R独立地为氢或C1-6烃基。
在另一实施方案中,本发明提供了制备式VII化合物的方法:
该方法包括:
将式VIII化合物
与C1-6烷基氨基甲酸酯反应,得到式VII化合物,
其中
R8选自C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述的C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2 6杂芳基-C1 4烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;
X选自卤素、三氟磺酸盐和磺胺;以及
R11为C1-6烷基。
在进-步的实施方案中,本发明提供了制备式X化合物的方法,
该方法包括:
将式IX化合物,
与R4-CHO反应,得到式X化合物,
其中
R4选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基,其中所述苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基任意地被一个或多个选自C1-6烷基、卤代C1-6烷基、-NO2、-CF3、C1-6烷氧基、氯、氟、溴和碘的基团取代;
R2选自-H、C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;以及
R3选自C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基。
特别地,本发明化合物可通过下列流程1-7所示的合成路线制备。
流程1
流程2
流程3
流程4
流程5
流程6
流程7
由此,本发明进-步方面涉及式XI化合物及其可药用盐、非对映体、对映体或其混合物:
其中
R1选自-H、C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被一个或多个选自-R、-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基。
生物学评价
我们发现本发明化合物在热血动物如人中,对δ受体具有活性。特别地,本发明化合物对δ受体配体有效。在下文的体外测定中,本发明集中在活性中,特别是涉及在大鼠脑功能测定和/或人δ受体功能测定(低)中确定的拮抗剂潜在性能和效力。该特征与体内活性相关,并不与结合亲合力直接相关。这些体外测定测试了化合物对δ受体的活性,将获得的IC50值用于确定特定化合物对δ受体的选择性活性。在本说明书上下文中,IC50通常是指其中观测到标准放射性δ受体配体转移50%的化合物浓度。
化合物对κ和μ受体的活性也可在类似的测定中测得。
体外模型
细胞培养
A.在含有不含钙的DMEM10%FBS、5%BCS、0.1%聚丙二醇与环氧乙烷的加聚物(聚醚)F-68和600μg/ml geneticin的振荡烧瓶中,于37℃和5%CO2的悬浮液中生长人293S细胞表达克隆人κ、δ和μ受体和新霉素抵抗。
B.称重大鼠大脑,浸渍在冰冷PBS(含2.5mM EDTA,pH 7.4)。在冰冷溶菌缓冲液(50mM Tris,pH 7.0,2.5mM EDTA,含仅在使用前由0.5M储存在DMSO:乙醇中原料加入的0.5MmM苯基甲基磺酰氟)中,利用polytron均质大脑30秒钟(大鼠)。
膜制备
将细胞制成小球状,悬浮在溶菌缓冲液(50mM Tris,pH 7.0,2.5mMEDTA,含仅在使用前由0.1M储存在乙醇中原料加入的0.1M PMSF)中,在冰上孵育15分钟,然后利用polytron均质30秒钟。在4℃下,以1000g(最大)旋转悬浮液10分钟。上清液存放在冰上,如前再悬浮和旋转小球。合并两次旋转的上清液,以46,000g(最大)旋转30分钟。在冰冷Tris缓冲液(50mM Tris/Cl,pH 7.0)中再悬浮小球,并再旋转。最终的小球在膜缓冲液(50mM Tris,0.32M蔗糖,pH 7.0)中再旋转。在干冰/乙醇中冷冻于聚丙烯试管中的等份试样(1ml),在使用前存放在-70℃下。利用十二烷基硫酸钠,通过改进Lowry测定确定蛋白质浓度。
结合测定
在37℃下解冻膜,在冰上冷却,通过25-测量针穿过3次,将其稀释至结合缓冲液(50mM Tris,3mM MgCl2,1mg/ml BSA(Sigma A-7888),pH 7.4,在通过0.22m滤纸过滤后将其存放在4℃下,向其中加入新鲜的5μg/ml抑肽酶、10μM倍司他汀、10μM diprotin A,不含DTT)中。将100μl的等份试样加入到含100μl适宜的放射性配体和100μl各种浓度的被试化合物的冰冷12×75mm聚丙烯试管中。
分别在存在或不存在10μM纳洛酮条件下测定总的结合(TB)和非特定(NS)结合。将试管在25℃下旋流并孵育60-75分钟,之后迅速通过预浸在0.1%聚乙烯亚胺中至少2小时的GF/B滤纸(Whatman)真空过滤内容物,利用大约12ml/试管冰冷清洗缓冲液(50mM Tris,pH7.0,3mM MgCl2)洗涤。在将滤纸浸透在含6-7ml闪烁液的小瓶中至少12小时后,利用β-计数器测定滤纸中保留的放射性(dpm)。如果测定在96-深孔板中进行,则过滤在96-孔PEI-浸湿均匀滤纸上进行,利用3×1ml清洗缓冲液洗涤该滤纸,在55℃下于烤炉干燥2小时。在每孔加入50μl MS-20闪烁液后,在TopCount(Packard)中计数过滤孔板。
功能测定
通过确定化合物受体复合体活化GTP对受体偶合的G-蛋白结合的程度,测定化合物激动剂活性。在GTP结合测定中,GTP[γ]35S于测试化合物结合,由HEK-293S细胞表达克隆人类鸦片受体或由均质大鼠和小鼠大脑成膜。激动剂在这些膜中刺激GTP[γ]35S结合。由剂量响应曲线测定化合物的EC50和Emax值。如果剂量响应曲线通过δ-激动剂naltrindole右移,则证明该化合物通过δ-受体调节了激动剂活性。对于人δ-受体功能测定,当与用于确定EC50(高)时相比,用于该测定的人δ-受体表达为较低水平时,即可测定EC50(低)。测定与标准δ-激动剂SNC80相关的Emax值,亦即,高于100%,表示化合物具有比SNC80更好的效力。
大鼠大脑GTP步骤
在37℃下解冻大鼠大脑膜,通过25-测量针穿过3次,将其稀释至结合缓冲液(50mM Hepes,20mM NaOH,100mM NaCl,1mM EDTA,5mMMgCl2,pH 7.4,Addfresh:1mM DTT,0.1%BSA)。将最终浓度120μMGDP加入到膜稀释液中。借助于适量膜蛋白质(20μg/孔)和每孔100000-130000dmp GTPγ35S(0.11-0.14nM),在300μl剂量中,由10-点剂量响应曲线评价化合物EC50和Emax。在不存在和存在3μM SNC-80条件下确定基本和最大被刺激结合活性。
数据分析
特定结合(SB)计算成TB-NS。将存在各种测试化合物条件下的SB表示成对照SB的百分数。根据分对数图或曲线拟合程序如Ligand、GraphPad Prism、SigmaPlot或ReceptorFit,计算配体在特定替代结合放射性配体中的IC50和Hill系数(nH)值。Ki值可根据Cheng-Prussoff方程计算得到。被试配体的IC50、Ki和nH的平均值±S.E.M.值记载在至少三条替代曲线中。
基于上述试验记录,我们发现本发明化合物和用于其制备中的一些中间体对人δ-受体具有活性。本发明化合物和选择的中间体的生物学活性示于表1和2中。
表1
化合物序号1-11 | 人δ(nM) | 人κ | 人μ | 大鼠大脑(nM) | |||
IC50 | EC50(高) | %EMax(高) | IC50 | IC50 | EC50 | %EMax | |
0.25-0.74 | 0.55-1.93 | 89-102 | 247-1636 | 93-1100 | 0.93-16.7 | 135-170 |
表2
化合物序号12-23, | 人δ(nM) | 人κ | 人μ | ||
IC50 | EC50(低) | %EMax(低) | IC50 | IC50 | |
及中间体4a | 0.18-4.18 | 3.26-484 | 58-106 | 1277-8728 | 92-6560 |
受体浸透饱和度实验
通过利用浓度0.2至5倍于估计Ka(如果所需放射性配体的量是可行的,最高可10倍于Ka)的适当反射线配体,在细胞膜上进行结合测定,从而确定放射性受体Ka值。将特定放射性配体结合表达成pmole/mg膜蛋白。根据一点模型(one-site model),由个体的特定结合(B)与nM游离(F)放射性配体的非线性拟合关系得到个体实验的Kδ和Bmax值。
利用Von Frey试验确定Mechano-异常性疼痛
利用Chaplan等人(1994)描述的方法,在08:00至16:00h之间进行测试。将大鼠置于有机玻璃笼中,该笼具有钢丝筛孔底,其允许鼠爪通过,使大鼠渐渐习惯10-15分钟。测试区域为中脚底左后爪,避免敏感度较低的足垫。利用具有对数增量的硬度的8种(0.41、0.69、1.20、2.04、3.63、5.50、8.51和15.14克,Stoelting,Ill,USA)VonFrey毛发接触脚爪。Von Frey毛发自垂直于脚底面的筛孔地板下方施用,需要使用足够的力量,使其轻轻地扣住脚爪,保持大约6-8秒钟。如果脚爪强烈地缩回,记载正响应。在去掉毛发后立即退缩,也被认为是正响应。步行则被认为是不确定的响应,此时应重新刺激。
试验方法
对于FCA-对照组,在手术后第1天测试动物。利用Dixon(1980)上下法确定50%退缩阈限。利用该系列的中间值2.04g毛发开始测试。不论上升还是衰减,总是以连续的方式进行刺激。在对初始选择的毛发没有爪退缩响应的情况下,需要更强的刺激;在存在爪退缩的情况下,则要选择下次更弱些的刺激。在立即接近50%阈限的条件下,通过该方法计算的最佳阈限需要6次响应;当发生第一次响应变化,即阈限第一次交叉时,开始计数这6次响应。在阈限落在刺激范围之外的情况下,则要分别指派下述数值,即15.14(正常敏感度)或0.41(最大异常性疼痛)。利用规则X=没有退缩,O=退缩,以及50%退缩阈限通过下列公式进行内插:
50%阈限=10(Xf+kδ)/10,000
其中Xf=所使用的最后Von Frey毛发值(对数单位);k=正/负响应模式的表列值(由Chaplan等人的方法(1994)获得);以及δ=刺激之间的平均差(对数单位);列表表示出所得正/负响应模式。此处δ=0.224。
根据Chaplan等人的方法(1994),将Von Frey阈限转换成最大可能作用的百分数(%MPE)。将下述方程用于计算%MPE:
%MPE=(处理过的药物阈限(g)-异常性疼痛阈限(g))/(对照阈限(g)
-异常性疼痛阈限(g))×100
测试物质的给药
在进行Von Frey测试之前,大鼠接受测试物质注射(皮下、腹膜内、静内或经口),测试化合物给药与Von Frey测试之间的时间取决于测试化合物的性质。
翻腾试验
当小鼠腹模内给用时,乙酸将引起腹部收缩。这将在局部模式中延伸至其身体。当服用止痛药时,所观察到的所述运动的频率下降,所选择的药物可作为潜在的良好候选药物。
当存在下列因素时,仅考虑完整且典型的翻腾反映:动物处于不运动状态;下段后背稍稍被压低;两只爪的脚底均可观察到。在该测定中,在口服剂量为1-100μmol/kg之后,本发明化合物显示出显著抑制翻腾响应。
(i)溶液制备
乙酸(AcOH):将120μl乙酸加入到19.88ml蒸馏水中,得到最终浓度为0.6%AcOH的最终体积20ml。然后混合(旋涡)溶液,准备注射。化合物(药物):制备各种化合物,将其按照标准方法溶解在最适合的载体中。
(ii)溶液给药
在测试前20、30或40分钟(根据化合物类型及其特征),通过经口、腹模内(i.p.)、皮下(s.c.)或静内(i.v.),以10ml/kg(考虑小鼠平均体重)的剂量服用化合物(药物)。当化合物通过中枢输送(心室内(i.c.v.)或膜内(i.t.))时,给药体积为5μl。
在测试前,立即在两个位置以10ml/kg剂量(考虑小鼠平均体重)腹膜内(i.p.)给用AcOH。
(iii)测试
在20分钟内观察动物(小鼠),记录出现(翻腾反映)的次数,在实验最后编辑。将小鼠保持在与被褥接触的单个“鞋盒”笼中。同时观察总共4只小鼠:一只对照小鼠和三只药物剂量小鼠。
对于忧虑和类似忧虑迹象,在大鼠geller-seifter冲突试验中测定功效。
对于功能性肠胃疾病迹象,在如Coutinho SV等人,AmericanJournal of Physiology-Gastrointestinal & Liver Physiology.282(2):G307-16,2002 Feb描述的测定,在大鼠中测定功效。
另外的体内试验方法
对象及安置
将天真活泼的每组5只雄性Sprague Dawley大鼠(175-200g)安置在控制温度(22℃,40-70%湿度,12-小时白/昼)下。在白昼循环的白天进行实验。动物随意进食、进水,在获得数据后立即宰杀。
样品
化合物(药物)测试包括不接受任何处理的大鼠组和经大肠杆菌脂多糖(LPS)处理过的大鼠组。对于LPS-处理实验,4组接受LPS注射,4组中的1组然后接受载体处理,而另外3组利用药物及其载体处理。第2组实验包括5组大鼠;全部不接受LPS处理。天真活泼的大鼠组不接受化合物(药物)或载体处理;其余4组则利用含有或者不含有药物的载体处理。由此测定可能对USV下降具有贡献的药物的抗焦虑或止痛作用。
LPS给药
在处理前允许将大鼠适应实验室环境15-20分钟。通过LPS(革兰阴性大肠杆菌细菌血清型0111:B4内毒素,Sigma)给药诱发炎症。利用异氟烷麻醉法的标准趋触性外科技术,通过大脑室内(i.c.v.)注射体积为10μl的LPS(2.4μg)。将耳朵之间的皮肤向嘴方向推动,纵向切开大约1cm长的切口,暴露出头骨表面。通过坐标确定刺破位置:晚于前囱0.8mm,左侧于λ(矢状缝)1.5mm,低于侧室头骨表面(垂直)5mm。利用聚乙烯针管(PE20;10-15cm),通过与100-μlHamilton注射器相连的5mm长无菌不锈钢针注射LPS(26-G 3/8)。将由切割针(20-G)制得的4mm塞置于其上,通过硅酮胶保护好26-G针,产生所需的5mm深。
在注射LPS后,再将针保留在该位置10秒钟,从而允许分散化合物,然后离去。闭合切口,将大鼠退回至原来的笼子,在试验前至少使其至少休息3.5小时。
空气吹气刺激实验步骤
在注射LPS并服用化合物(药物)后,将大鼠保留在实验室中。在试验期间,取出所有大鼠,并置于实验室外。一次送进实验室一只大鼠,将其置于透明盒(9×9×18cm)中,然后置于声音衰减的通风室(BRS/LVE,Div.Tech-Serv Inc)中,通风室尺寸为62(w)×35(d)×46(h)cm。通过能够在固定时间间隔(0.2s)和频率为每10秒钟1次吹风的固定强度传递吹气,利用指定系统(AirStim,SanDiegoIntruments),经0.32cm的空气输出喷嘴传送吹气气体。送风最多10次,或者直至开始第1次发出声音。第1次传送空气表记为记录开始。
实验步骤和超声记录
利用置于各个通风室内部并通过LMS(LMS CADA-X 3.5B,DataAcquisition Monitor,Troy,Michigan)软件控制的扩音器(G.R.A.S.sound and vibrations,Vedbaek,Denmark)记录发出声音10分钟。记录0至32000Hz之间的频率,通过相同的软件(LMS CADA-X 3.5B,Time Data Processing Monitor and UPA(User Programming andAnalysis))存储并分析。
化合物(药物)
将所有化合物(药物)的pH值调节在6.5至7.5之间,以体积4ml/kg的量给药。在进行化合物(药物)给药后,将动物送回其原来的笼中,直至测试结束。
分析
通过一系列过滤统计和Fourier分析进行记录(在20-24kHz之间),计算所感兴趣的参数。数据表示成平均SEM。利用T-试验评价统计显著性,比较天真幼稚和LPS-处理过的大鼠,在药物效力Dunnett多重比较试验(post-hoc)后进行单程(one way)ANOVA。当最小p值<0.05时,组与组之间的差异被认为显著。实验至少重复两次。
实施例
本发明将通过下述实施例得到更详细的描述,这些实施例描述了了本发明化合物的制备、纯化和生物学测试的方法,它们不是用来限制本发明的范围。
中间体1:N,N-二乙基-4-甲酰苯甲酰胺
在60℃下,向4-羧基苯甲醛(30g,0.2mol)的100ml甲苯悬浮液中加入SOCl2(97ml,1.3mol)。加热反应,直至放出气体,通过利用甲苯(3×50ml)蒸发至干,使反应停止。由此得到残留物,将其溶解在CH2Cl2(200m)中。在冰浴中搅拌冷却,向其中加入二乙胺(50ml),继续搅拌1小时,再回流加热混合物1小时。冷却后,利用H2O、2N HCl、H2O、2N NaOH顺序洗涤混合物,最后利用H2O洗涤。在MgSO4上干燥溶液,过滤并浓缩至干,得到41g油状物。在140-150℃/1.5torr上蒸馏,得到36.9g(90%)中间体1。
中间体2:叔丁基4-((3-溴苯基){4-[(二乙氨基)羰基]苯基}甲基)哌嗪-1-羧酸酯
在Dean-Stark条件下,加热中间体1(6.84g,33.3mmol)、苯并三唑(3.96g,33.3mmol)和N-Boc哌啶(6.19g,33.3mmol)的200ml甲苯溶液过夜。浓缩反应,将其溶解在45ml无水THF中,在冰浴中冷却。在15分钟内,通过移液管加入3-溴苯基碘化锌(0.5M,于THF,100ml,50mmol)。将反应温热至室温,搅拌30分钟,然后在50℃下加热过夜。利用NH4Cl使反应骤冷,搅拌15分钟,利用乙酸乙酯提取4次。在MgSO4上干燥合并的有机层,过滤并浓缩。快速色谱纯化残留油状物,利用乙酸乙酯/庚烷30/70至50/50洗涤。中间体2的收率为5.86g,33%。
中间体3:4-[[4-[(二乙氨基)羰基]苯基][3-[(甲氧基羰基)氨基]苯基]甲基]-1-哌嗪羧酸,1,1-二甲基乙酯
在吹入N2的条件下,向于无水二噁烷中的中间体2(5.39g,10.17mmol)中加入氨基甲酸甲酯(0.99g,13.2mmol)、xantphos(0.47g,0.81mmol)、Cs2CO3(4.63g,14.2mmol)和Pd2(dba)3(0.465g,0.51mmol)。反应在回流下加热7小时,冷却并通过硅藻土过滤。快速色谱纯化(40/60至80/20乙酸乙酯/庚烷)所得油状物,得到中间体3(3.3g,62%)。
中间体4:[3-[[4-[(二乙氨基)羰基]苯基]-1-哌嗪基甲基]苯基]-氨基甲酸,甲酯
在0℃下,向中间体3(0.788g,1.5mmol)的15ml CH2Cl2溶液中加入TFA(1.15ml,15mmol)。搅拌,直至HPLC测得反应完全。浓缩溶液,将其溶解在20ml乙酸乙酯中,利用10ml 2N K2CO3洗涤。分离有机层,利用5×20ml乙酸乙酯洗涤水层。在MgSO4上干燥合并的有机层,过滤并浓缩,得到中间体4(570mg,89%)。在Chiralpak AD上手性HPLC(20%EtOH/80%庚烷)分离中间体4,得到200mg对映体中间体4a和185mg对映体中间体4b。
分析手性HPLC条件:
Chiralpak AD 15%EtOH/85%庚烷
流速1ml/分钟
中间体4a保留时间25.7分钟
中间体4b保留时间17.5分钟
中间体5:4-碘-N,N-二乙基苯甲酰胺
在0℃下,向4-碘-苯甲酰氯(75g)的500ml CH2Cl2混合物中加入Et3N(50ml)和Et2NH(100ml)的混合物。加入后,将所得反应混合物温热至室温1小时,然后利用饱和氯化铵洗涤。干燥(Na2SO4)有机提取液,过滤并浓缩。由热己烷重结晶残留物,得到80g中间体5。
中间体6:4-[羟基-(3-硝基苯基)甲基]-N,N-二乙基苯甲酰胺
在氮气气氛下,将中间体5,N,N-二乙基-4-碘苯甲酰胺(5.0g,16mmol)溶解在(150ml)中,冷却至-78℃。在-65℃至-78℃下,在10分钟内,滴加n-BuLi(15ml,1.07M,己烷溶液,16mmol)。在下-78℃,通过移液管将溶液加入导于甲苯/THF(大约1∶1,100ml)中的3-硝基苯甲醛(2.4g,16mmol)中。30分钟后加入NH4Cl(水溶液)。真空浓缩后,利用EtOAc/水提取,干燥(MgSO4)并蒸发有机相,硅胶色谱纯化(0-75%EtOAc/庚烷)残留物,得到中间体6(2.6g,50%)。
1H NMR(CDCl3)δ1.0-1.3(m,6H),3.2,3.5(2m,4H),5.90(s,1H),7.30-7.40(m,4H),7.50(m,1H),7.70(d,J=8Hz,1H),8.12(m,1H),8.28(m,1H).
中间体7:外消旋N,N-二乙基-4-[(3-硝基苯基)(1-哌嗪基)甲基]苯甲酰胺
向中间体6(10.01g,30.5mmol)的二氯甲烷(200ml)溶液中加入硫酰溴(2.58ml,33.6mmol)。在室温下1小时后,利用饱和碳酸氢钠水溶液(100ml)洗涤反应,分离有机层。利用二氯甲烷(3×100ml)洗涤水层,干燥(Na2SO4)合并的有机提取液,过滤并浓缩。
将有机提取液中的所得产物溶解在乙腈(350ml)中,加入哌嗪(10.5g,122mmol)。在65℃下加热反应1小时后,利用饱和氯化铵/乙酸乙酯洗涤反应,分离有机层。利用乙酸乙酯(3×100ml)提取水层,干燥(Na2SO4)合并的有机提取液,过滤并浓缩,得到外消旋中间体7。
中间体8:(-)-N,N-二乙基-4-[(3-硝基苯基)(1-哌嗪基)甲基]苯甲酰胺
如下拆分外消旋中间体7,得到纯对映体中间体8:
将中间体7溶解在乙醇(150ml)中,加入二-对甲苯酰-D-酒石酸(11.79g,1当量)。在12小时时间内沉淀出产物。过滤收集固体,再溶解在回流乙醇中,直至所有的固体均溶解(大约1200ml乙醇)。在冷却的同时,过滤收集固体,重复第二次重结晶。过滤收集固体,利用氢氧化钠溶液(2M)处理,利用乙酸乙酯提取。然后干燥(Na2SO4)有机提取液,过滤并浓缩,得到1.986g纯对映体中间体8。
1H NMR(CDCl3)δ1.11(br s,3H),1.25(br s,3H),2.37(br s,4H),2.91(t,J=5Hz,4H),3.23(br s,2H),3.52(br s,2H),4.38(s,1H),7.31-7.33(m,2H),7.41-7.43(m,2H),7.47(t,J=8Hz,1H),7.75-7.79(m,1H),8.06-8.09(m,1H),8.30-8.32(m,1H).
利用下述条件,通过HPLC测定手性纯度:
Chiralpack AD柱(Daicel化学工业有限公司)
流速1ml/分钟
在25℃下的操作时间为30分钟
恒溶剂洗脱15%乙醇/85%己烷
分子保留时间=20分钟
中间体9可通过上述步骤获得,只是使用二-对甲苯酰-L-酒石酸替代二-对甲苯酰-D-酒石酸。
中间体10:N,N-二乙基-4-[(3-硝基苯基)[4-(苯基甲基)-1-哌嗪基]甲基]-苯甲酰胺
向中间体8(1.407g,3.55mmol)的1,2-二氯乙烷(30ml)溶液中加入苯甲醛(0.58ml,5.71mmol)和三乙酰氧基硼氢化钠(1.21g,5.71mmol)。在室温下20小时后,利用碳酸氢钠溶液骤冷反应,分离有机层。利用二氯甲烷(3×50ml)提取水层,干燥(Na2SO4)合并的有机提取液,过滤并浓缩。快速色谱纯化残留物,利用与二氯甲烷中的5%甲醇洗脱,得到中间体10,为无色泡沫(1.576g,91%收率)。
中间体11:4-[(3-氨基苯基)[4-(苯基甲基)-1-哌嗪基]甲基]-N,N-二乙基-苯甲酰胺
向中间体10(1.576g,3.24mmol)的乙醇、四氢呋喃、水和饱和氯化铵的混合物(4∶2∶1∶1,v/v)(30ml)中加入铁颗粒(1.80g,32.4mmol)。回流(90℃)4小时后,将反应冷却至室温,通过硅藻土过滤并浓缩。向残留物中加入碳酸氢钠溶液和二氯甲烷。分离有机层,利用二氯甲烷(3×50ml)提取水层,干燥(Na2SO4)合并的有机提取液,过滤并浓缩。硅胶纯化产物,利用于二氯甲烷中的1%至5%甲醇洗脱,得到中间体11(1.310g,88%收率)。
手性HPLC条件:
Chiralpack AD柱(Daicel化学工业公司)
流速:1ml/分钟
在25℃下的操作时间为30分钟
恒溶剂洗脱30%异丙醇/70%己烷
分子保留时间=18.7分钟
中间体14:4-{(S)-(3-氨基苯基)[4-(哌啶-3-基甲基)哌嗪-1-基]甲基}-N,N-二乙基苯甲酰胺
向中间体9(452mg)的1,2-二氯乙烷(10ml)溶液中加入3-吡啶羧醛(215μl,2当量)和三乙酰氧基硼氢化钠(483mg,2当量)。在氮气下,于室温下搅拌反应18小时,并浓缩。加入饱和碳酸氢钠,利用三份二氯甲烷提取水溶液,在无水硫酸钠上干燥合并的有机物,过滤并浓缩得到中间体12。将粗的中间体12溶解在乙醇、四氢呋喃、水和饱和氯化铵的混合物(4ml;4∶2∶1∶1v/v)中。加入铁纳米颗粒(用抹刀尖刮3下),在微波炉中,于150℃下加热10分钟。冷却所得混合物,通过硅藻土过滤并浓缩。硅胶快速色谱纯化残留物,利用于二氯甲烷中的1%至10%MeOH梯度洗脱,得到中间体14(312mg,60%收率),为无色固体。
中间体15:4-{(S)-(3-氨基苯基)[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]甲基}-N,N-二乙基苯甲酰胺
向中间体9(479mg)的1,2-二氯乙烷(13ml)溶液中加入2-噻唑羧醛(212μl,2当量)和三乙酰氧基硼氢化钠(510mg,2当量)。在氮气气氛下,于室温下搅拌反应18小时。加入饱和碳酸氢钠,利用三份二氯甲烷提取水溶液,在无水硫酸钠上干燥合并的有机液,过滤并浓缩,得到中间体13。将粗中间体13溶解在乙醇、四氢呋喃、水和饱和氯化铵的混合物(4ml,4∶2∶1∶1 v/v)中。加入纳米铁(用抹刀尖刮3下),在微波炉中,于50℃下加热溶液10分钟。冷却所得混合物,通过硅藻土过滤并浓缩。反相色谱纯化残留物,利用于含0.1%三氟乙酸的水中的10%至45%乙腈洗脱,得到作为三氟乙酸盐的产物,冻干得到中间体15(372mg,39%收率),为无色固体。
中间体16a或16b:4-((3-氨基苯基){4-[(二乙氨基)羰基]苯基}甲基)哌嗪-1-羧酸叔丁酯
向中间体8或9(300mg)的二噁烷(40ml)溶液中加入二-叔丁基二碳酸酯(247mg,1.5当量)。将碳酸钠(119mg,1.5当量)溶解在水(15ml)中,然后加入到二噁烷溶液中。12小时后浓缩溶液,然后加入饱和碳酸氢钠。利用三份二氯甲烷提取水溶液,在无水硫酸钠上干燥合并的有机液,过滤并浓缩,得到白色泡沫物。在不进一步纯化的条件下,将泡沫物溶解在乙醇、四氢呋喃、水和饱和氯化铵的混合物(15ml,4∶2∶1∶1 v/v)中。加入铁颗粒(422mg,10当量),在90℃下加热溶液1.5小时。冷却所得混合物,通过硅藻土过滤并浓缩。加入饱和碳酸氢钠,利用三份二氯甲烷提取水溶液,在无水硫酸钠上干燥合并的有机液,过滤并浓缩,分别得到白色泡沫物中间体16a或16b。产物可在不进行进一步纯化的条件下使用(92-99%收率)。
1H NMR(400MHz,CDCl3)1.06-1.16(m,3H),1.17-1.26(m,3H),1.44(s,9H),2.28-2.39(m,4H),3.20-3.31(br s,2H),3.37-3.44(br s,2H),3.48-3.58(br s,2H),3.60-3.70(br s,2H),4.12(s,1H),6.51-6.55(m,1H),6.72(t,J=2.13Hz,1H),6.79(d,J=8.17Hz,1H),7.06(t,J=7.46Hz,1H),7.29(d,J=7.82Hz,2H),7.43(d,J=7.82Hz,2H).
化合物1:R-甲基3-[(4-[(二乙氨基)羰基]苯基)(4-苄基-哌嗪-1-基)甲基]苯基氨基甲酸酯
向溶解在5ml二氯乙烷的中间体4a(200mg,0.47mmol)溶液中加入苯甲醛(95.5μl,0.94mmol)和NaBH(OAc)3(200mg,0.94mmol)。在室温下搅拌反应过夜。然后加入5ml饱和NaHCO3,利用CH2Cl2提取水层4次。在MgSO4上干燥合并的有机液,过滤并浓缩。反相色谱纯化,在下列条件下得到188mg化合物1:LUNA C-18,10-50%B梯度洗脱25分钟,流速:40ml/分钟,20℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.31(m,2H),3.04(m,2H),3.24(m,4H),3.39(m,2H),3.51(m,2H),3.72(s,3H),4.34(s,2H),4.43(s,1H),7.09(m,1H),7.20(m,2H),7.32(d,J=8.2Hz,2H),7.48(s,5H),7.55(d,J=8.2Hz,2H),7.70(s,1H).C31H38N4O3×2.10C2HF3O2×0.3H2O分析计算值:C,55.66;H,5.40;N,7.38.实测值:C,55.70;H,5.24;N,7.41.M.S(计算):515.30(MH+),M.S(实测):515.55(MH+).HPLC:k’:2.95;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
条件:Zorbax C-18,30-80%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>90%(215nm),>94%(254nm),>94%(280nm),Rt:8.7分钟;条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=-14.5°(c=0.74,EtOH)。
化合物1:R-[3-[[4-[(二乙氨基)羰基]苯基][4-(苯基甲基)-1-哌嗪基]甲基]苯基]-氨基甲酸甲酯(通过另一种合成路线)
在氮气气氛下,于室温下,在1ml无水甲苯中一起搅拌氯甲酸甲酯(0.008ml,0.11mmol)和锌粉(8mg,0.11mmol)10分钟。然后滴加中间体10(50mg,0.110mmol)的1ml甲苯溶液,在室温下搅拌反应混合物过夜。然后利用二氯甲烷稀释溶液,并过滤。利用饱和NaHCO3溶液、盐水洗涤有机相,在无水Na2SO4上干燥。快速硅胶色谱纯化产物,利用于丙酮中的50%己烷洗脱,得到化合物1(28mg,50%收率)。
1HNMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.31(m,2H),3.04(m,2H),3.24(m,4H),3.39(m,2H),3.51(m,2H),3.72(s,3H),4.34(s,2H),4.43(s,1H),7.09(m,1H),7.20(m,2H),7.32(d,J=8.2Hz,2H),7.48(s,5H),7.55(d,J=8.2Hz,2H),7.70(s,1H).C31H38N4O3×2.10C2HF3O2×0.3H2O分析计算值:C,55.66;H,5.40;N,7.38.实测值:C,55.70;H,5.24;N,7.41.M.S(计算):515.30(MH+),M.S(实测):515.55(MH+).HPLC:k’:2.95;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
条件:Zorbax C-18,30-80%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>90%(215nm),>94%(254nm),>94%(280nm),保留时间:8.7分钟;条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=-14.5°(c=0.74,EtOH)。
化合物2:S-甲基3-[(4-[(二乙氨基)羰基]苯基)(4-苄基-哌嗪-1-基)甲基]苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(185mg,0.43mmol)和苯甲醛(100μl,0.87mmol),得到178mg化合物2。
1H NMR(400MHz,CD3OD):δ1.09(m,3H),1.22(m,3H),2.31(m,2H),3.04(m,2H),3.24(m,4H),3.40(m,2H),3.51(m,2H),3.72(s,3H),4.34(s,2H),4.43(s,1H),7.09(m,1H),7.19(m,2H),7.32(d,J=8.2Hz,2H),7.48(s,5H),7.55(d,J=8.2Hz,2H),7.71(s,1H).C31H38N4O3×1.60C2HF3O2×0.6H2O分析计算值:C,58.47;H,5.77N,7.98.实测值:C,58.50;H,5.70;N,8.06.M.S(计算):515.30(MH+),M.S(实测):515.57(MH+.HPLC:k’:3.00;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,30-80%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:11.2分钟;手性HPLC条件:Chiralpak AD 30% IPA/70%己烷。旋转:[α]17 D=+17.1°(c=0.77,EtOH)。
化合物3:S-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(噻吩-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(200mg,0.47mmol)和2-噻吩羧醛(66μl,0.70mmol),得到213mg化合物3。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.35(br s,2H),3.04(br s,2H),3.32(m,6H),3.51(m,2H),3.72(s,3H),4.44(s,1H),4.58(s,2H),7.09(m,1H),7.13(dd,J=3.7,J=5.1Hz,3H),7.21(m,2H),7.32(m,3H),7.55(d,J=8.2Hz,2H),7.62(m,1H),7.69(br s,1H),C29H36N4O3S×1.40C2HF3O2×0.9H2O 分析计算值:C,54.84;H,5.67;N,8.04.实测值:C,54.76;H,5.65;N,8.09.M.S(计算):521.26(MH+),M.S(实测):521.26(MH+).HPLC:k’:6.51;纯度:>99%(215nm),>99%(254nm),>99%(280nm).HPLC条件:Zorbax C-18,30-80%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>97%(215nm),>96%(254nm),>96%(280nm),保留时间:22.2分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=+11.3°(c=1.14,MeOH)。
化合物4:R-甲基3-{{4-[(二乙氨基)羧基苯基][4-(噻吩-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和2-噻吩羧醛(66μl,0.70mmol),得到197mg化合物4。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.35(br s,2H),3.02(br s,2H),3.32(m,6H),3.51(m,2H),3.72(s,3H),4.44(s,1H),4.58(s,2H),7.09(m,1H),7.13(m,1H),7.21(m,2H),7.32(m,3H),7.55(d,J=8.0Hz,2H),7.62(d,J=5.1Hz,2H),7.69(s,1H).C29H36N4O3S×1.5C2HF3O2×0.9H2O 分析计算值:C,55.13;H,5.51;N,8.04.实测值:C,55.14;H,5.55;N,8.11.M.S.(计算):521.26(MH+),M.S.(实测):521.23(MH+).HPLC:k’:6.59;纯度:>99%(215nm),>99%(254nrn),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:11.8分钟;手性HPLC条件:Chiralpak AD 30% IPA/70%己烷。旋转:[α]17 D=-12.8°(c=0.96,MeOH)。
化合物5:S-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(噻吩-3-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(200mg,0.47mmol)和3-噻吩羧醛(66μl,0.70mmol),得到205mg化合物5。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.36(m,2H),2.99(m,2H),3.28(m,6H),3.51(m,2H),3.72(s,3H),4.36(s,2H),4.42(s,1H),7.09(m,1H),7.21(m,3H),7.32(d,J=8.0Hz,2H),7.55(m,3H),7.67(m,2H).C29H36N4O3S×1.7C2HF3O2X0.3H2O分析计算值:C,54.05;H,5.36;N,7.78.实测值:C,54.08;H,5.36;N,7.70.M.S.(计算):521.26(MH+),M.S.(实测):521.26(MH+).HPLC:k’:6.68;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1% TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:13.3分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=+11.3°(c=1.15,MeOH)。
化合物6:R-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(噻吩-3-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和3-噻吩羧醛(66μl,0.70mmol),得到199mg化合物6。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.31(br s,2H),3.04(br s,2H),3.24(m,4H),3.37(m,2H),3.51(m,2H),3.72(s,3H),4.37(s,2H),4.43(s,1H),7.09(m,1H),7.21(m,3H),7.32(d,J=8.2Hz,2H),7.55(m,3H),7.68(m,2H).C29H36N4O3S×1.4C2HF3O2×1.0H2O分析计算值:C,54.69;H,5.69;N,8.02.实测值:C,54.74;H,5.63;N,8.16.M.S.(计算):521.26(MH+),M.S.(实测):521.25(MH+).HPLC:k’:6.67;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:9.0分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=-12.9°(c=1.13,MeOH)。
化合物7:S-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(2-呋喃甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(200mg,0.47mmol)和2-糠醛(58μl,0.70mmol),得到172mg化合物7。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.22(m,3H),2.36(br s,2H),3.02(br s,2H),3.31(m,6H),3.51(m,2H),3.72(s,3H),4.42(s,2H),4.44(s,1H),6.52(dd,J=1.9,3.1Hz,1H),6.71(d,J=3.3Hz,1H),7.09(m,1H),7.20(m,2H),7.32(d,J=8.4Hz,2H),7.55(d,J=8.2Hz,2H),7.66(m,1H),7.69(s,1H).C29H36N4O4×1.5C2HF3O2×0.6H2O分析计算值:C,55.99;H,5.68;N,8.16.实测值:C,56.02;H,5.74;N,8.22.M.S.(计算):505.28(MH+),M.S.(实测):505.26(MH+).HPLC:k’:5.92;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>95%(215nm),>95%(254nm),>96%(280nm),保留时间:8.3分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=+14.4°(c=1.06,MeOH)。
化合物8:R-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(2-呋喃甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和2-糠醛(58μl,0.70mmol),得到50mg化合物8。
1H NMR(400MHz,CD3OD):δ1.09(m,3H),1.22(m,3H),2.32(br s,2H),3.06(br s,2H),3.24(m,4H),3.40(m,2H),3.51(m,2H),3.72(s,3H),4.42(s,2H),4.44(s,1H),6.53(dd,J=1.8,3.1Hz,1H),6.71(d,J=3.3Hz,1H),7.09(m,1H),7.20(m,2H),7.32(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.67(m,1H),7.70(s,1H).C29H36N4O4×1.6C2HF3O2×0.3H2O分析计算值:C,55.85;H,5.56;N,8.09.实测值:C,55.76;H,5.50;N,8.25.M.S.(计算):505.28(MH+),M.S.(实测):505.27(MH+).HPLC:k’:6.00;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:7.2分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=-13.8°(c=0.97,MeOH)。
化合物9:S-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(3-呋喃甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(200mg,0.47mmol)和3-糠醛(58μl,0.70mmol),得到167mg化合物9。
1H NMR(400MHz,CD3OD):δ1.09(m,3H),1.22(m,3H),2.32(br s,2H),3.06(br s,2H),3.24(m,4H),3.40(m,2H),3.51(m,2H),3.72(s,3H),4.42(s,2H),4.44(s,1H),6.53(dd,J=1.8,3.1Hz,1H),6.71(d,J=3.3Hz,1H),7.09(m,1H),7.20(m,2H),7.32(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.67(m,1H),7.70(s,1H).C29H36N4O4×2.0C2HF3O2×0.5H2O分析计算值:C,53.44;H,5.30;N,7.55.实测值:C,53.42;H,5.28;N,7.68.M.S.(计算):505.28(MH+),M.S.(实测):505.27(MH+).HPLC:k’:5.99;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>97%(215nm),>97%(254nm),>97%(280nm),保留时间:13.8分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=+13.9°(c=0.94,MeOH)。
化合物10:R-甲基3-{{4-[(二乙氨基)羧基苯基][4-(3-呋喃甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和3-糠醛(58μl,0.70mmol),得到119mg化合物10。
1H NMR(400MHz,CD3OD):δ1.09(m,3H),1.22(m,3H),2.32(br s,2H),3.05(br s,2H),3.21(m,4H),3.47(m,4H),3.72(s,3H),4.24(s,2H),4.43(s,1H),6.58(m,1H),7.09(m,1H),7.20(m,2H),7.32(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.63(m,1H),7.70(s,1H),7.76(s,1H).C29H36N4O4×1.5C2HF3O2×0.2H2O 分析计算值:C,56.58;H,5.62;N,8.25.实测值:C,56.50;H,5.56;N,8.31.M.S.(计算):505.28(MH+),M.S.(实测):505.27(MH+).HPLC:k’:6.02;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:8.7分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]17 D=-14.9°(c=1.10,MeOH)。
化合物11:R-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(1H-咪唑-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和2-咪唑羧醛(68mg,0.70mmol),得到141mg化合物11。
1H NMR(400MHz,CD3OD):δ1.09(m,3H),1.23(m,3H),2.82(br s,4H),3.02(brs,4H),3.24(m,2H),3.52(m,2H),3.73(s,3H),3.98(s,2H),5.03(s,1H),7.27(m,3H),7.42(d,J=8.0Hz,2H),7.49(m,2H),7.67(d,J=8.0Hz,2H),7.84(s,1H).C28H36N6O3×2.1C2HF3O2×1.5H2O分析计算值:C,50.16;H,5.37;N,10.90.实测值:C,50.06;H,5.27;N,11.02.M.S.(计算):505.29(MH+),M.S.(实测):505.28(MH+).HPLC:k’:2.55;纯度:>98%(215nm),>97%(254nm),>97%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:12.5分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=-3.33°(c=1.08,MeOH)。
化合物12:S-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(哌啶-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(200mg,0.47mmol)和2-吡啶羧醛(76mg,0.70mmol),得到213mg化合物12。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.22(m,3H),2.74(br s,4H),3.24(m,2H),3.41(m,4H),3.51(m,2H),3.72(s,3H),4.48(s,2H),4.48(s,1H),7.11(m,1H),7.21(m,2H),7.33(d,J=7.7Hz,2H),7.43(m,1H),7.48(m,1H),7.57(d,J=7.7Hz,2H),7.73(s,1H),7.89(s,1H),8.66(m,1H).C30H37N5O31.5C2HF3O2×1.2H2O分析计算值:C,55.96;H,5.82;N,10.01.实测值:C,55.93;H,5.73;N,10.01.M.S.(计算):516.30(MH+),M.S.(实测):516.29(MH+).HPLC:k’:0.88;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,30-80%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:12.9分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=+16.5°(c=1.24,MeOH)。
化合物13:R-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(哌啶-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和2-吡啶羧醛(76mg,0.70mmol),得到187mg化合物13。
1H NMR(400MHz,CD3OD):δ1.08(m,3H),1.21(m,3H),2.75(br s,4H),3.24(m,2H),3.41(m,4H),3.51(m,2H),3.72(s,3H),4.48(s,2H),4.48(s,1H),7.11(m,1H),7.20(m,2H),7.33(d,J=8.0Hz,2H),7.43(m,1H),7.48(m,1H),7.57(d,J=8.0Hz,2H),7.73(s,1H),7.89(s,1H),8.66(m,1H).C30H37N5O3×1.7C2HF3O2×O.8H2O分析计算值:C,55.42;H,5.61;N,9.67.实测值:C,55.40;H,5.62;N,9.83.M.S.(计算):516.30(MH+),M.S.(实测):516.28(MH+).HPLC:k’:3.02;纯度:>97%(215nm),>98%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:11.3分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=-15.4°(c=1.01,MeOH)。
化合物14:S-甲基3-{{4-[(二乙氨基)羧基苯基][4-(哌啶-4-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4b(200mg,0.47mmol)和4-吡啶羧醛(76mg,0.70mmol),得到217mg化合物14。
1H NMR(游离胺,400MHz,CDCl3):δ1.09(br s,3H),1.21br s,3H),2.43(m,8H),3.24(br s,2H),3.50(s,2H),3.51(br s,2H),3.76(s,3H),4.22(s,1H),6.63(s,1H),7.10(m,1H),7.22(m,4H),7.28(d,J=8.2Hz,2H),7.42(m,1H),7.42(d,J=8.2Hz,2H),8.52(s,2H).C30H37N5O3×1.9C2HF3O2×1.8H2O分析计算值:C,53.09;H,5.60;N,9.16.实测值:C,53.04;H,5.60;N,9.18.M.S.(计算):516.30(MH+),M.S.(实测):516.28(MH+).HPLC:k’:2.69;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:12.9分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=+10.3°(c=1.25,MeOH)。
化合物15:R-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(哌啶-4-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(200mg,0.47mmol)和4-吡啶羧醛(76mg,0.70mmol),得到247mg化合物15。
1H NMR(游离胺,400MHz,CDCl3):δ1.09(br s,3H),1.21br s,3H),2.45(m,8H),3.24(br s,2H),3.50(s,2H),3.51(br s,2H),3.76(s,3H),4.22(s,1H),6.64(s,1H),7.10(m,1H),7.22(m,4H),7.28(d,J=8.2Hz,2H),7.42(m,1H),7.42(d,J=8.2Hz,2H),8.52(d,J=5.7Hz,2H).C30H37N5O3×2.6C2HF3O2×1.0H2O分析计算值:C,50.93;H,5.05;N,8.44实测值:C,50.89;H,5.07;N,8.50.M.S.(计算):516.30(MH+),M.S.(实测):516.28(MH+).HPLC:k’:2.69;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:16.3分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=-8.1°(c=1.10,MeOH)。
化合物16:R-甲基3-{{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-2-基甲基)-哌嗪-1-基]甲基}苯基氨基甲酸酯
利用与化合物1相同的方法,由中间体4a(140mg,0.33mmol)和2-噻唑羧醛(45mg,0.39mmol),得到85mg化合物16。
1H NMR(游离胺,400MHz,CDCl3):δ1.09(br s,3H),1.21br s,3H),2.44(br s,4H),2.61(br s,4H),3.23(br s,2H),3.51(br s,2H),3.76(s,3H),3.88(s,2H),4.23(s,1H),6.61(s,1H),7.11(m,1H),7.23(m,3H),7.28(d,J=8.2Hz,2H),7.41(m,1H),7.43(d,J=8.2Hz,2H)7.70(d,J=3.3Hz,1H).M.S.(计算):522.3(MH+),M.S.(实测):522.2(MH+)HPLC:k’:4.09;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
HPLC条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:9.5分钟;手性HPLC条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=-12.08°(c=1.01,MeOH)。
化合物17:[3-[[4-[(二乙氨基)羰基]苯基][4-(苯基甲基)-1-哌嗪基]甲基]苯基]甲基-氨基甲酸甲酯
利用氢化钠/甲基碘甲基化中间体3,利用TFA裂开Boc基团。将仲胺与苯甲醛和三乙酰氧基硼氢化钠反应,得到外消旋化合物17。通过在Chiralpak AD 25%EtOH/75%庚烷上进行手性HPLC纯化该物质,得到纯对映体化合物17。
1H NMR(400MHz,CD3OD):□1.09(m,3H),1.22(m,3H),2.31(m,2H),3.05(m,2H),3.25(m,4H),3.25(s,3H),3.40(m,2H),3.51(m,2H),3.83(s,3H),4.34(s,2H),4.50(s,1H),7.15(m,1H),7.32(m,4H),7.43(s,1H),7.49(s,5H),7.55(d,J=8.2Hz,2H).M.S.(计算):529.3(MH+),M.S.(实测):529.2(MH+).HPLC:k’:2.42;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>98%(254nm),>99%(280nm),保留时间:7.01分钟;条件:Chiralpak AD 30%IPA/70%己烷。旋转:[α]16 D=-15.69°(c=1.06,MeOH)。
化合物18:[3-[(S)-[4-[(二乙氨基)羰基]苯基][4-(3-哌啶基甲基)-1-哌嗪基]甲基]苯基]-氨基甲基甲酯
在氮气气氛下,于室温下,在3ml无水甲苯中一起搅拌氯甲酸甲酯(0.042ml,0.54mmol)和锌粉(35mg,0.54mmol)10分钟。然后滴加中间体14(247mg,0.54mmol)的8ml甲苯溶液,在室温下搅拌反应混合物1小时。然后利用二氯甲烷稀释溶液,并过滤。利用饱和NaHCO3溶液、盐水洗涤有机相,在无水Na2SO4上干燥。快速硅胶色谱纯化产物,利用于丙酮中的30%己烷升至27%己烷、于丙酮中的3%甲醇洗脱,得到化合物18。
1H NMR(400MHz,CDCl3)δ1.09(br s,3H),1.21(br s,3H),2.31-2.54(m,8H),3.23(br s,2H),3.47-3.56(m,4H),3.76(s,3H),4.21(s,1H),6.68(br s,1H),7.08(dt,J=7.21Hz 1.61Hz,1H),7.18-7.25(m,3H),7.27(d,J=7.86Hz,2H),7.41(d,J=8.02Hz,2H),7.64(dt,J=7.69Hz 1.92Hz,1H),8.49(dd,J=4.97Hz,1.60Hz,1H),8.52(d,J=1.76Hz,1H).实测值:C,56.47;H,6.76;N,10.71.C30H37N5O3×1.0H2O×2.9HCl×0.2C4H10O分析计算值:C,56.55;H,6.76;N,10.70%M.S.(计算):516.3(MH+),M.S.(实测):516.2(MH+).HPLC:k’:4.27;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
条件:Zorbax C-18,10-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>98%(254nm),>99%(280nm),保留时间:6.66分钟;手性HPLC条件:Chiralpak AD 50%乙醇/50%己烷。旋转:[α]D=+7.64°(c=0.497,MeOH)。
化合物19:[3-[(S)-[4-[(二乙氨基)羰基]苯基][4-(2-噻唑基甲基)-1-哌嗪基]甲基]苯基]-氨基甲酸甲酯
在氮气气氛下,于室温下,在2ml无水甲苯中一起搅拌氯甲酸甲酯(0.031mL,0.40mmol)和锌粉(26mg,0.40mmol)10分钟。然后滴加中间体15(185mg,0.40mmol)的5ml甲苯溶液,在室温下搅拌反应混合物1小时。然后利用二氯甲烷稀释溶液,并过滤。利用饱和NaHCO3溶液、盐水洗涤有机相,在无水Na2SO4上干燥。快速硅胶色谱纯化产物,利用于丙酮中的30%己烷升至27%己烷、于丙酮中的3%甲醇洗脱,得到化合物19。
1H NMR(400MHz,CD3OD)δ1.06(t,J=6.49Hz,3H),1.19(t,J=6.93Hz,3H),2.90-3.10(m,2H),3.17-3.25(m,2H),3.33-3.42(m,4H),3.45-3.52(m,2H),3.70(s,3H),4.59(s,2H),7.16-7.23(m,1H),7.26(d,J=4.00Hz,2H),7.36(d,J=7.81Hz,2H),7.65(d,J=7.32Hz,2H),7.73-7.8(m,2H),7.88-7.93(m,1H).实测值:C,56.81;H,6.53;N,11.56.C28H35N5O3S×0.90H2O 1.5HCl分析计算值:C,56.75;H,6.51;N,11.82%.M.S.(计算):522.3(MH+),M.S.(实测):522.2(MH+).HPLC:k’:3.99;纯度:>99%(215nm),>99%(254nm),>99%(280nm).
条件:Zorbax C-18,20-50%B梯度洗脱25分钟,流速:1mL/分钟,25℃,A:0.1%TFA,于水中,B:0.1%TFA,于CH3CN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:20.31分钟;手性HPLC条件:Chiralpak AD 30%乙醇/70%己烷。旋转:[α]D=+9.13°(c=1.06,MeOH)。
化合物20:甲基3-{(R)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
向旋光纯中间体4a(0.150g,0.35mmol)的4ml DMF溶液中加入K2CO3(0.122g,0.88mmol)和4-(氯甲基)-1,3-噻唑(0.066g,0.39mmol),混合物在60℃下加热过夜。蒸发溶剂,将粗产物溶解在二氯甲烷中,然后利用盐水洗涤。在Na2SO4上干燥有机提取液,过滤并浓缩,得到粗产物,将其进行反相HPLC纯化(5-50%CH3CN,于水中,含0.1%TFA,梯度洗脱),得到化合物20(0.030g,11.3%收率),为TFA盐。由CH3CN/H2O冻干该物质,得到白色粉末。
1H NMR(400MHz,CD3OD)δ1.09(t,J=6.6Hz,3H),1.22(t,J=6.8Hz,3H),2.36(br s.,2H),3.04(br s.,2H),3.19-3.35(m,4H),3.42(br s.,2H),3.51(q,J=6.6Hz,2H),3.72(s,3H),4.45(s,1H),4.52(s,2H),7.10(dt,J=1.5,7.0Hz,1H),7.16-7.24(m,2H),7.33(d,J=8.4Hz,2H),7.56(d,J=8.2Hz,2H),7.71,(s,1H),7.84(s,1H),9.1(s,1H).纯度(HPLC):>89%(215nm),>99%(254nm),>99%(280nm);
条件:Zorbax C-18,10-95%B梯度洗脱25分钟,流速:1mL/分钟,40℃,A:0.1%甲酸,于水中,B:0.1%甲酸,于MeCN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:6.67分钟;条件:Chiralpak AD 50%IPA/50%己烷。旋转:[α]18 D=-14.7°(c=0.88,MeOH)。
化合物21:甲基3-{(S)-{4-[(二乙氨基)羰基]苯基)[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
向旋光纯中间体4b(0.225g,0.53mmol)的4ml DMF溶液中加入K2CO3(0.183g,1.33mmol)和4-(氯甲基)-1,3-噻唑(0.099g,0.58mmol),在60℃下加热混合物过夜。蒸发溶剂,将粗产物溶解在二氯甲烷中,利用水和盐水洗涤。在Na2SO4上干燥有机提取液,过滤并浓缩,得到粗产物,将其进行反相HPLC纯化(5-50%CH3CN,于H2O中,含0.1%TFA,梯度洗脱),得到化合物21(0.166g,41.7%收率),为TFA盐。由CH3CN/H2O冻干该物质,得到白色粉末。
1H NMR(400MHz,CD3OD)δ0.97(t,J=7.2Hz,3H),1.11(t,J=6.8Hz,3H),2.25(br s.,2H),2.91(br s.,2H),3.07-3.21(m,4H),3.31(br s.,2H),3.41(q,J=6.8Hz,2H),3,61(s,3H),4.34(s,1H),4.41(s,2H),6.99(dt,J=1.6,7.0Hz,1H),7.05-7.13(m,2H)7.22(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.60(s,1H),7.74(d,J=2.0Hz,1H),8.99(d,J=2.0Hz,1H),9.13(s,1H).C28H35N5O3S×1.8TFA×1.1H2O分析计算值:C,50.83;H,5.26;N,9.38实测值:C,50.82;H,5.23;N,9.33.MS(计算):552.2(MH+),MS(实测):552.2(MH+).纯度(HPLC):>99%(215nm),>99%(254nm),>99%(280nm);
条件:Zorbax C-18,10-95%B梯度洗脱25分钟,流速:1mL/分钟,4O℃,A:0.1%甲酸,于水中,B:0.1%甲酸,于MeCN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:6.66分钟;条件:Chiralpak AD 50%IPA/50%己烷。旋转:[α]18 D=+14.5°(c=1.07,MeOH)。
化合物22:甲基3-{(R)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
向中间体4a(0.163g,0.38mmol)的1,2-二氯乙烷(6ml)溶液中加入噻唑-5-羧醛(0.087g,0.77mmol)和NaHB(OAc)3(0.163g,0.77mmol)。在室温下搅拌反应过夜,利用饱和NaHCO3水溶液骤冷。分离层,利用二氯甲烷(2×15mL)提取水层。利用H2O、盐水洗涤合并的有机层,然后在Na2SO4上干燥,过滤并浓缩,进行反相HPLC纯化(5-50%CH3CN,于H2O中,含0.1%TFA,梯度洗脱),得到化合物22(0.205g,71.2%收率),为TFA盐。由CH3CN/H2O冻干该物质,得到浅黄色固体。
1H NMR(400MHz,CD3OD)δ1.09(t,J=6.8Hz,3H),1.22(t,J=6.8Hz,3H),2.77(br s.,4H),3.18-3.40(m,6H),3.51(q,J=7.0Hz,2H),3.72(s,3H),4.56(s,1H),4.63(s,2H),7.12(dt,J=1.9,8.4Hz,1H),7.19(dt,J=1.95,8.4Hz,1H),7.21-7.26(m,1H),7.34(d,J=8.4Hz,2H),7.57(d,J=8.2Hz,2H),7.74(s,1H),8.05(s,1H),9.17(s,1H).C28H35N5O3S×2.6TFA×0.3H2O分析计算值:C,48.42;H,4.68;N,8.50.实测值:C,48.49;H,4.83;N,8.30.MS(计算):552.2(MH+),MS(实测):552.2(MH+).纯度(HPLC):>99%(215nm),>99%(254nm),>99%(280nm);
条件:Zorbax C-18,10-95%B梯度洗脱25分钟,流速:1mL/分钟,40℃,A:0.1%甲酸,于水中,B:0.1%甲酸,于MeCN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:9.92分钟;条件:Chiralpak AD 50%IPA/50%己烷。旋转:[α]18 D=-12.4°(c=1.01,MeOH)。
化合物23:甲基3-{(S)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸酯
向中间体4b(0.223g,0.53mmol)的1,2-二氯乙烷(8ml)溶液中加入噻唑-5-羧醛(0.119g,1.05mmol)和NaHB(OAc)3(0.223g,1.05mmol)。搅拌反应过夜,利用饱和NaHCO3水溶液骤冷。分离层,利用二氯甲烷(2×15mL)提取水层。利用H2O、盐水洗涤合并的有机层,然后在Na2SO4上干燥,过滤并浓缩,进行反相HPLC纯化(5-50%CH3CN,于H2O中,含0.1%TFA,梯度洗脱),得到化合物23(0.214g,54.2%收率),为TFA盐。由CH3CN/H2O冻干该物质,得到黄色固体。
1H NMR(400MHz,CD3OD)δ1.09(t,J=6.3Hz,3H),1.22(t,J=6.6Hz,3H),2.52(br s.,2H),2.97(brs.,2H),3.18-3.40(m,6H),3.51(q,J=6.8Hz,2H),3.72(s,3H),4.56(s,1H),4.64(s,2H),7.11(dt,J=1.56,7.4Hz,1H),7.17-7.21(m,1H),7.21-7.26(m,1H),7.35(d,J=8.2Hz,2H),7.57(d,J=8.4Hz),7.74(s,1H),8.05(s,1H),9.17(s,1H).纯度(HPLC):>98%(215nm),>99%(254nm),>99%(280nm);
条件:Zorbax C-18,10-95%B梯度洗脱25分钟,流速:1mL/分钟,40℃,A:0.1%甲酸,于水中,B:0.1%甲酸,于MeCN中;手性纯度:>99%(215nm),>99%(254nm),>99%(280nm),保留时间:13.26分钟;条件:Chiralpak AD 50%IPA/50%己烷。旋转:[α]18 D=+12.7°(c=0.97,MeOH)。
Claims (15)
1.式I化合物及其可药用盐、非对映体、对映体及其混合物:
其中
R1选自-H、C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被一个或多个选自-R、-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;
R2选自-H、C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;以及
R3选自C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基。
2.根据权利要求1的化合物,其中
R1为-CH2-R4,其中R4选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基,其中所述苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基任意地被一个或多个选自C1-6烷基、卤代C1-6烷基、-NO2、-CF3、C1-6烷氧基、氯、氟、溴和碘的基团取代;
R2选自-H和C1-3烷基;以及
R3选自C1-6烷基和C3-6环烷基。
3.根据权利要求2的化合物,其中
R4选自苯基、吡啶基、呋喃基、咪唑基、吡咯基和噻唑基;
R2选自-H和甲基;以及
R3选自甲基、乙基、丙基和异丙基。
4.根据权利要求1的化合物,其中
R1为-H;
R2选自-H和C1-3烷基;以及
R3选自C1-6烷基和C3-6环烷基。
5.根据权利要求1的化合物,其中该化合物选自下列化合物及其对映体和可药用盐:
3-[(4-[(二乙氨基)羰基]苯基)(4-苄基-哌嗪-1-基)甲基]苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(噻吩-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(噻吩-3-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(2-呋喃基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(3-呋喃基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(1H-咪唑-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(吡啶-2-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(吡啶-4-基-甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-2-基甲基)-哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
[3-[[4-[(二乙氨基)羰基]苯基][4-(苯基甲基)-1-哌嗪基]甲基]苯基]氨基甲酸甲酯;
[3-[(S)-[4-[(二乙氨基)羰基]苯基][4-(3-吡啶基甲基)-1-哌嗪基]甲基]苯基]氨基甲酸甲酯;
[3-[(S)-[4-[(二乙氨基)羰基]苯基][4-(2-噻唑基甲基)-1-哌嗪基]甲基]苯基]氨基甲酸甲酯;
3-{(R)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{(S)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{(R)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
3-{(S)-{4-[(二乙氨基)羰基]苯基}[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]甲基}苯基氨基甲酸甲酯;
[3-[[4-[(二乙氨基)羰基]苯基]-1-哌嗪基甲基]苯基]氨基甲酸甲酯。
6.权利要求1至5任一的化合物用作药物。
7.权利要求1至5任一的化合物在制备用于治疗疼痛、忧虑症或功能性肠胃疾病的药物中的用途。
8.一种药物组合物,该组合物包括权利要求1至5任一的化合物及可药用载体。
9.一种治疗热血动物疼痛的方法,该方法包括对需要这种治疗的动物服用治疗有效量的权利要求1至5任一化合物。
10.一种治疗热血动物功能性胃肠疾病的方法,该方法包括对需要这种治疗的动物服用治疗有效量的权利要求1至5任一化合物。
11.一种治疗热血动物忧虑症的方法,该方法包括对需要这种治疗的动物服用治疗有效量的权利要求1至5任一化合物。
12.一种制备式II化合物的方法,该方法包括:
a)将式III化合物
在存在苯并三唑的条件下,与式IV化合物反应,
b)将步骤a)得到的产物与式V化合物反应,得到式II化合物,
其中
R8选自C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述的C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被一个或多个选自C1-6烷基、卤代C1-6烷基、-NO2、-CF3、C1-6烷氧基、氯、氟、溴和碘的基团取代;
M选自Li、Na、K、-ZnX′和-MgX′,其中X′为卤素;以及
R9选自氢、-R、-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR,其中R独立地为氢或C1-6烃基。
13.一种制备式VII化合物的方法:
该方法包括:
将式VIII化合物
与C1-6烷基氨基甲酸酯反应,得到式VII化合物,
其中
R8选自C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述的C1-6烷基-O-C(=O)-、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;
X选自卤素、三氟磺酸盐和磺胺;以及
R11为C1-6烷基。
14.一种制备式X化合物的方法,
该方法包括:
将式IX化合物,
与R4-CHO反应,得到式X化合物,
其中
R4选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基,其中所述苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基和N-环氧-吡啶基任意地被一个或多个选自C1-6烷基、卤代C1-6烷基、-NO2、-CF3、C1-6烷氧基、氯、氟、溴和碘的基团取代;
R2选自-H、C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基;以及
R3选自C1-6烷基和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任意地被一个或多个选自-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基。
15.式XI化合物及其可药用盐、非对映体、对映体或其混合物:
其中
R1选自-H、C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基,其中所述C6-10芳基、C2-6杂芳基、C6-10芳基-C1-4烷基和C2-6杂芳基-C1-4烷基任意地被一个或多个选自-R、-NO2、-OR、-Cl、-Br、-I、-F、-CF3、-C(=O)R、-C(=O)OH、-NH2、-SH、-NHR、-NR2、-SR、-SO3H、-SO2R、-S(=O)R、-CN、-OH、-C(=O)OR、-C(=O)NR2、-NRC(=O)R和-NRC(=O)-OR的基团取代,其中R独立地为氢或C1-6烷基。
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SE0203302D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
SE0203301D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
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2002
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2003
- 2003-05-11 UA UAA200503862A patent/UA80988C2/uk unknown
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- 2003-11-05 AU AU2003278665A patent/AU2003278665B2/en not_active Ceased
- 2003-11-05 AR ARP030104053A patent/AR041895A1/es unknown
- 2003-11-05 JP JP2004549776A patent/JP4528128B2/ja not_active Expired - Fee Related
- 2003-11-05 KR KR1020057008061A patent/KR20050072482A/ko not_active Application Discontinuation
- 2003-11-05 WO PCT/SE2003/001707 patent/WO2004041802A1/en active Application Filing
- 2003-11-05 CA CA002502732A patent/CA2502732A1/en not_active Abandoned
- 2003-11-05 CN CNB200380102831XA patent/CN100415729C/zh not_active Expired - Fee Related
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KR20050072482A (ko) | 2005-07-11 |
ZA200503556B (en) | 2006-08-30 |
US20060122193A1 (en) | 2006-06-08 |
BR0315995A (pt) | 2005-09-27 |
IS7863A (is) | 2005-05-25 |
AR041895A1 (es) | 2005-06-01 |
US7960389B2 (en) | 2011-06-14 |
UA80988C2 (en) | 2007-11-26 |
AU2003278665A1 (en) | 2004-06-07 |
NZ539484A (en) | 2007-05-31 |
US20070254890A1 (en) | 2007-11-01 |
WO2004041802A1 (en) | 2004-05-21 |
PL376894A1 (pl) | 2006-01-09 |
TW200418822A (en) | 2004-10-01 |
JP2006514002A (ja) | 2006-04-27 |
US7253173B2 (en) | 2007-08-07 |
WO2004041802A8 (en) | 2005-03-10 |
EP1562924A1 (en) | 2005-08-17 |
MXPA05004708A (es) | 2005-08-03 |
NO20052698L (no) | 2005-06-06 |
CN100415729C (zh) | 2008-09-03 |
JP4528128B2 (ja) | 2010-08-18 |
AU2003278665B2 (en) | 2008-05-22 |
NO20052698D0 (no) | 2005-06-06 |
CA2502732A1 (en) | 2004-05-21 |
SE0203303D0 (sv) | 2002-11-07 |
RU2005111985A (ru) | 2006-01-20 |
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