CN1738801A - 二芳基亚甲基哌啶衍生物、其制备及其用途 - Google Patents
二芳基亚甲基哌啶衍生物、其制备及其用途 Download PDFInfo
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- CN1738801A CN1738801A CNA2004800022753A CN200480002275A CN1738801A CN 1738801 A CN1738801 A CN 1738801A CN A2004800022753 A CNA2004800022753 A CN A2004800022753A CN 200480002275 A CN200480002275 A CN 200480002275A CN 1738801 A CN1738801 A CN 1738801A
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Classifications
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
制备了通式(I)的化合物,式中R1、R2、R3、R4、和R5如说明书中所定义,以及盐,其对映体,和包括该化合物的医药组合物。它们可用于治疗、尤其疼痛的控制。
Description
技术领域
本发明涉及新型化合物、其制备方法、其用途和包含该新型化合物的医药组合物。该新型化合物可用于治疗,具体地说,可用于治疗疼痛、焦虑和功能性胃肠紊乱。
背景技术
受体已被确认在很多身体功能例如循环系统和疼痛系统中有作用。因此,δ受体的配体可以找到作为止痛药和/或作为抗高血压剂的潜在用途。也已经有人显示δ受体的配体具有免疫调节活性。
鸦片类受体的至少三个不同种群(μ、δ和κ)的确认现已得到普遍认可,所有三种在包括人在内的很多物种的中枢神经系统和末梢神经系统中都是显而易见的。在各种动物模型中,当这些受体中一种或多种受到活化时,已观察到痛觉缺失。
除少数例外,目前可供利用的选择性鸦片类δ配体在性质上是肽的,不适用于经由全身性途径给药。非肽δ兴奋剂的一个实例是SNC80(Bilsky E.J.等人,Journal of Pharmacology and ExperimentalTherapeutics,273(1),pp.359-366(1995))。
先有技术上已经确认的很多δ兴奋剂化合物的很多缺点在于它们因药物动力学不良而受损害,而且当经由全身性途径给药时不止痛。此外,文献也已记载,其中很多δ兴奋剂化合物当全身性给药时显示出显著的惊厥效应。
Delorme等人的美国专利No.6,187,792描述了一些δ兴奋剂。
然而,目前仍然需要改进的δ兴奋剂。
发明内容
除非本说明书内另有说明,否则本说明书中使用的命名法一般遵循Nomenclature of Organic Chemistry,Sections A,B,C,D,E,F,and H,Pergamon Press,Oxford 1979中所述的实例和规则,该书因其实例性化学结构名称和化学结构命名规则而列为本文参考文献。任选地,化合物名称也可以使用如下化学命名程序产生:ACD/Chem Sketch,Version5.09/September 2001,Advanced Chemistry Development,Inc.,Toronto,Canada.单独或作为前缀使用的“Cm-n”或“Cm-n基团”这一术语系指有m~n个碳原子的任何基团。
单独或者作为后缀或前缀使用的“烃”这一术语系指只包含碳原子和氢原子且可多达14个碳原子的任何结构。
单独或者作为后缀或前缀使用的“烃基”这一术语系指作为从烃去除一个或多个氢的结果的任何结构。
单独或者作为后缀或前缀使用的“烷基”这一术语系指包含1~约12个碳原子的一价直链或支化链烃基。除非另有说明,否则一般的“烷基”既包括饱和烷基也包括不饱和烷基。
单独或者作为后缀或前缀使用的“亚烷基”这一术语系指用来将两种结构连接在一起的、包含1~约12个碳原子的二价直链或支化链烃基。
单独或者作为后缀或前缀使用的“链烯基”这一术语系指一种有至少一个碳-碳双键且包含至少2~约12个碳原子的一价直链或支化链烃基。
单独或者作为后缀或前缀使用的“链炔基”这一术语系指一种有至少一个碳-碳叁键且包含至少2~约12个碳原子的一价直链或支化链烃基。
单独或者作为后缀或前缀使用的“环烷基”这一术语系指包含至少3~约12个碳原子的一价含环烃基。
单独或者作为后缀或前缀使用的“环烯基”这一术语系指有至少一个碳-碳双键且包含至少3~约12个碳原子的一价含环烃基。
单独或者作为后缀或前缀使用的“环炔基”这一术语系指有至少一个碳-碳叁键且包含约7~约12个碳原子的一价含环烃基。
单独或者作为后缀或前缀使用的“芳基”这一术语系指有一个或多个有芳香性(例如4n+2离域电子)且包含5~约14个碳原子的多不饱和碳环的一价烃基。
单独或者作为后缀或前缀使用的“亚芳基”这一术语系指有一个或多个有芳香性(例如4n+2离域电子)且包含5~约14个碳原子的多不饱和碳环、用来将两种结构连接在一起的二价烃基。
单独或者作为后缀或前缀使用的“杂环”这一术语系指有一个或多个独立地选自N、O和S的多价杂原子作为环结构的一部分且该环中包括至少3~约20个原子的含环结构或分子。杂环可以是饱和的或不饱和的、含有一个或多个双键的、且杂环可以含有不止一个环。当杂环含有不止一个环时,这些环可以是稠合的或非稠合的。稠合环一般系指至少2个环共享其间的2个原子。杂环可以有芳香性,也可以没有芳香性。
单独或者作为后缀或前缀使用的“杂烷基”这一术语系指一种作为有一个或多个选自N、O和S的杂原子置换烷基中一个或多个碳原子的结果而生成的基团。
单独或者作为后缀或前缀使用“杂芳香族”这一术语系指有一个或多个独立地选自N、O和S的多价杂原子作为环结构的一部分并在该环中包括至少3~约20个原子的含环结构或分子,其中该含环结构或分子有芳香性(例如4n+2离域电子)。
单独或者作为后缀或前缀使用的“杂环基”、“杂环片断”、“杂环的”或“杂环”这一术语系指一种从杂环通过脱除其上的一个或多个氢而衍生的基团。
单独或者作为后缀或前缀使用的“杂环基”这一术语系指一种从杂环通过脱除其上的一个氢而衍生的一价基团。
单独或者作为后缀或前缀使用的“亚杂环基”这一术语系指一种从杂环通过脱除其上的两个氢而衍生的、用来将两种结构连接在一起的二价基团。
单独或者作为后缀或前缀使用的“杂芳基”这一术语系指一种有芳香性的杂环基。
单独或者作为后缀或前缀使用的“杂环烷基”这一术语系指没有芳香性的杂环基。
单独或者作为后缀或前缀使用的“亚杂芳基”这一术语系指一种有芳香性的亚杂环基。
单独或者作为后缀或前缀使用的“亚杂环烷基”这一术语系指一种没有芳香性的亚杂环基。
作为前缀使用的“六员”这一术语系指一种有一个含有六个环原子的环的基团。
作为前缀使用的“五员”这一术语系指一种有一个含有五个环原子的环的基团。
五员环杂芳基是一种有一个含5个环原子的环的杂芳基,其中1、2或3个环原子独立地选自N、O和S。
五员环杂芳基的实例是噻吩基、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。
六员环杂芳基系指一种有一个含6个环原子的环的杂芳基,其中1、2或3个环原子独立地选自N、O和S。
六员环杂芳基的实例是吡啶基、吡嗪基、嘧啶基、三嗪基和哒嗪基。
作为前缀使用的“有取代”这一术语系指一种结构、分子或基团,其中一个或多个氢置换成一个或多个C1-12烃基,或者一个或多个含有一个或多个选自N、O、S、F、Cl、Br、I、和P的杂原子的化学基团。含有一个或多个杂原子的化学基团的实例包括杂环基、-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)、亚胺基(=NR)、硫代(=S)、和肟基(=N-OR),其中每个“R”都是C1-12烃基。例如,有取代苯基可以指硝基苯基、吡啶基苯基、甲氧基苯基、氯苯基、氨基苯基等,其中该硝基、吡啶基、甲氧基、氯、和氨基可以置换该苯环上任何一个适用的氢。
作为第一结构、分子或基团的前缀使用并跟随一个或多个化学基团名称的“有取代”这一术语系指一种是用一个或多个所列举化学基团置换第一结构、分子或基团的一个或多个氢的结果的第二结构、分子或基团。例如,“有硝基取代的苯基”系指硝基苯基。
“任选地有取代”这一术语系指有取代的基团、结构、或分子和无取代的基团、结构或分子两者。
杂环包括,例如,单环式杂环,如氮丙啶、环氧乙烷、硫杂丙环、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、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、四氢噻吩、哌啶、1,2,3,6-四氢吡啶、哌嗪、吗啉、硫代吗啉、吡喃、噻喃、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-氮杂、高哌嗪、1,3-二氧杂环庚烷、4,7-二氢-1,3-dioxepin、和氧杂环庚烷。
此外,杂环包括芳香族杂环,例如吡啶、吡嗪、嘧啶、哒嗪、噻吩、呋喃、呋咱、呲咯、咪唑、噻唑、噁唑、呲唑、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。
此外,杂环还涵盖多环式杂环,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、色烯、苯并二氢吡喃、异苯并二氢吡喃、咕吨、phenoxathiin、噻蒽、中氮茚、异吲哚、吲唑、嘌呤、2,3-二氮杂萘、1,5-二氮杂萘、喹喔啉、喹唑啉、噌啉、蝶啶、菲啶、啶、菲咯啉、吩嗪、吩噻嗪、吩噁嗪、1,2-苯并异噁唑、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、吡咯烷士定、和quinolizidine。
除以上所述的多环式杂环外,杂环还包括多环式杂环,其中两个或多个环之间的环稠合包括不止一个键归两个环共有、且不止两个原子归两个环共有。这样的桥联杂环的实例包括奎宁环、二氮杂双环[2.2.1]庚烷和7-氧杂双环[2.2.1]庚烷。
杂环基包括,例如,单环式杂环基,如氮丙啶基、环氧乙烷基、硫杂丙环基、氮杂环丁基、氧杂环丁基、硫杂环丁基、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、四氢噻吩基、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、噻喃基、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、l,3-二噁烷基、二噁烷基、高哌啶基、2,3,4,7-四氢-1H-氮杂基、高哌嗪基、l,3-二氧杂环庚基、4,7-二氢-1,3-dioxepinyl、和氧杂环庚基。
此外,杂环基还包括芳香族杂环基或杂芳基,例如,吡啶基、吡嗪基、嘧啶基、哒嗪基、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。
此外,杂环基还涵盖多环式杂环基(包括芳香族的和非芳香族的两种),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、色烯基、苯并二氢吡喃基、异苯并二氢吡喃基、咕吨基、phenoxathiinyl、噻蒽基、中氮茚基、异吲哚基、吲唑基、嘌呤基、2,3-二氮杂萘基、1,5-二氮杂萘基、喹喔啉基、喹唑啉基、噌啉基、蝶啶基、菲啶基、啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁嗪基、1,2-苯并异噁唑基、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、吡咯烷士定基、和quinolizidinyl。
除以上所述的多环式杂环基外,杂环基还包括多环式杂环基,其中,两个或多个环之间的环稠合包括不止一个键归两个环共有,且不止两个原子归两个环共有。这样的桥联杂环的实例包括奎宁环基、二氮杂双环[2.2.1]庚基、和7-氧杂双环[2.2.1]庚基。
单独或者作为后缀或前缀使用的“烷氧基”这一术语系指通式-O-R的基团,式中R选自烃基。烷氧基的实例包括甲氧基、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。
单独或者作为后缀或前缀使用的“胺”或“氨基”这一术语系指通式-NRR’的基团,式中R和R’独立地选自氢或烃基。
单独或者作为前缀或后缀使用的“酰基”这一术语系指-C(=O)-R,式中R是任选地有取代的烃基、氢、氨基或烷氧基。酰基包括,例如,乙酰基、丙酰基、苯甲酰基、苯乙酰基、羰乙氧基、和二甲基氨基甲酰基。
卤素包括氟、氯、溴和碘。
作为某一基团的前缀使用的“卤代”这一术语系指该基团上的一个或多个氢置换成一个或多个卤素。
“RT”或“rt”系指室温。
第一环基与第二环基“稠合”系指第一环与第二环共享其间的至少两个原子。
除非另有说明,否则“连接”这一术语系指共价连接或键合。
这里提供的是式I的一种化合物,其医药上可接受的盐、其非对映异构体、其对映异构体、及其混合物:
式中
R1选自C6-10芳基和C2-6杂芳基,其中所述C6-10芳基和C2-6杂芳基任选地有一个或多个选自-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独立地是氢或C1-6烷基;和
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基、其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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独立地是氢或C1-6烷基。
在一种实施方案中,本发明的化合物是式I的化合物,式中R1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-氧化吡啶基,其中R1任选地有一个或多个选自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、R3、和R4独立地是C1-3烷基或卤代C1-3烷基;
R5选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自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。
在另一种实施方案中,本发明的化合物是式I的化合物,式中R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、吡咯基、和噻唑基,其中R1任选地有一个或多个选自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、R3、R4独立地是C1-3烷基、卤代C1-3烷基;和
R5是氢。
在一种进一步的实施方案中,本发明的化合物是式I的化合物,式中R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、吡咯基、和噻唑基;
R2和R3是乙基;
R4是C1-3烷基;和
R5是氢。
要理解的是,当本发明的化合物含有一个或多个手性中心时,本发明的化合物可以以对映异构体形式或非对映异构体形式存在,而且可以分离成为这些形式,或作为外消旋混合物存在。本发明包括式I化合物的任何可能对映异构体、非对映异构体、外消旋体或其混合物。本发明化合物的光学活性形式可以,例如,通过外消旋体的手性色谱分离、通过从光学活性起始原料的合成、或通过基于后面所述程序的不对称合成来制备。
也要知道的是,本发明的某些化合物可以作为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。要进一步理解的是,本发明涵盖式I化合物的互变异构体。
也要理解的是,本发明的某些化合物可以以溶剂化形式例如水合形式以及未溶剂化形式存在。要进一步理解的是,本发明涵盖式I化合物的所有这样的溶剂化形式。
在本发明范围内也有式I化合物的盐。一般来说,本发明化合物的医药上可接受盐可以使用业内众所周知的标准程序得到,例如通过使足够碱性的化合物例如烷基胺与适用酸例如HCl或乙酸反应,提供生理上可接受阴离子。也可以通过在水性介质中用1当量碱金属或碱土金属氢氧化物或醇盐(例如乙醇盐或甲醇盐)或适用碱性有机胺(例如胆碱或麦格鲁明)处理有适用酸性质子例如羧酸或苯酚的本发明化合物随后用惯常精制技术,来制造对应的碱金属(例如钠、钾、或锂)盐或碱土金属(例如如钙)盐。
在一种实施方案中,可以将以上式I化合物转化成其医药上可接受盐或溶剂合物、尤其酸加成盐例如盐酸盐、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。
本发明的新型化合物可用于治疗,尤其用于治疗各种疼痛病症,例如慢性疼痛、神经病性疼痛、急性疼痛、癌痛、类风湿性关节炎引起的疼痛、偏头痛、内脏疼痛等。然而,这份清单不应解读为是穷尽的。
本发明的化合物可用来作为免疫调节剂,尤其用于自免疫疾病例如关节炎,用于皮移植、器官移植和类似外科需要,用于胶原疾病、各种变应性,用来作为抗肿瘤剂和抗病毒剂。
本发明的化合物可用于这样的疾病状态,其中,鸦片类受体的退化或机能障碍存在或隐含于该范例中。这可以涉及本发明化合物的同位素标记版本在诊断技术和成像应用例如正电子发射断层扫描(PET)中的用途。
本发明化合物可用于治疗腹泻、抑郁、焦虑和与压力有关的紊乱例如后创伤压力紊乱、恐慌性紊乱、一般化焦虑紊乱、社会恐怖、和强迫观念与行为紊乱、尿失禁、早泄、各种精神性疾患、咳嗽、肺水肿、各种胃肠紊乱例如便秘、功能性胃肠紊乱例如刺激性肠综合征和功能性消化不良、帕金森病及其它运动紊乱、创伤性脑受伤、中风、心肌梗塞后心脏保护、脊柱受伤和药瘾,包括治疗酒精、尼古丁、鸦片类及其它药物滥用,和用于交感神经系统紊乱例如高血压。
本发明化合物可作为止痛剂供全身麻醉和监控麻醉护理期间使用。往往使用不同性能的药剂组合来达到维持麻醉状态所需要的效果的平衡(例如记忆缺失、痛觉缺失、肌肉松驰和镇静作用)。这种组合中包括的是吸入性麻醉剂、安眠药、抗焦虑药、神经肌肉阻断剂和鸦片类药物。
在本发明范围内也包括按照以上式I的任何一种化合物用于制造以上所讨论的任何一种病症的治疗用药剂的用途。
本发明的一个进一步方面是患有以上所讨论的任何一种病症的受治疗者的治疗方法,从而对需要这样一种治疗的患者给药有效量的按照以上式I的化合物。
因此,本发明提供一种如此前所定义的、用于治疗的式I化合物或其医药上可接受盐或溶剂合物。
在一个进一步方面,本发明提供一种如此前所定义的式I化合物或其医药上可接受盐或溶剂合物用于制造一种治疗用药剂的用途。
在本说明书范畴内,“治疗”这一术语也包括“预防”,除非有相反的具体指示。对“治疗的”和“治疗地”这一术语应当有相应理解。在本发明范畴内,“治疗”这一术语进一步涵盖给药有效量的本发明化合物,以缓解要么先存在的疾病状态、急性或慢性的病症,要么复发的病症。这个定义也涵盖用于防止复发性病症的预防性治疗和慢性病症的继续治疗。
本发明化合物可用于治疗,尤其用于治疗各种疼痛病症,包括但不限于急性疼痛、慢性疼痛、神经性疼痛、急性疼痛、背痛、癌痛、和内脏痛。
在用于温血动物例如人的治疗方面,本发明的化合物可以以惯常医药组合物的形式经由任何途径给药,包括经口、经肌内、经皮下、经局部、经鼻内、经腹膜内、经胸内、经静脉内、经硬膜外、经膜内、经脑室内和注射到关节内。
在本发明的一种实施方案中,给药途径可以是经口、经静脉内或经肌内的。
剂量将取决于给药途径、疾病的严重性、患者的年龄和体重、以及主治医生在确定最适合于特定患者的个体治疗方案和剂量水平时通常考虑的其它因素。
为了从本发明化合物制备医药组合物,惰性医药上可接受载体可以是要么固体要么液体。固体形式制剂包括散剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂、和栓剂。
固体载体可以是一种或多种物质,这些物质也可以充当稀释剂、矫味矫臭剂、增溶剂、润滑剂、悬浮剂、粘结剂、或药片崩解剂;它也可以是一种包囊材料。
在散剂中,载体是一种微细固体,该固体呈一种与本发明的微细化合物或有效成分的混合物。在片剂中,该有效成分与具有必要粘结性能的载体以适当比例混合并以所希望的形状和尺寸压紧。
为了制备栓剂组合物,先将一种低熔点蜡例如甘油脂肪酸酯和可可脂的混合物熔融,通过诸如搅拌将有效成分分散于其中。然后将熔融均匀混合物倾入方便尺寸的模型中,并使之冷却、凝固。
适用的载体是碳酸镁、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、低熔点蜡、可可脂等。
组合物这一术语也意在包括该有效成分和作为提供胶囊的载体的包囊材料的配方,在胶囊中该有效成分(有或无其它载体)被一种因此而与其缔合在一起的载体包围。类似地包括偏囊剂。
片剂、散剂、扁囊剂、和胶囊剂可以用来作为适合于经口给药的固体剂型。
液体形式组合物包括溶液、悬浮液、和乳状液。例如,该有效化合物的无菌水溶液或水-丙二醇溶液可以是适用于非经肠给药的液体制剂。液体组合物也可以用聚乙二醇水溶液配制成溶液剂。
经口给药的水溶液可以制备如下:将有效成分溶于水中,并添加适当着色剂、矫味矫臭剂、稳定剂、和增稠剂,依希望而定。经口用途的水性悬浮液剂可以这样制作:将微细有效成分连同粘性材料例如天然的和合成的胶、树脂、甲基纤维素、羧甲基纤维素钠、和医药配方业内已知的其它悬浮剂一起分散在水中。
因给药方式而异,该医药组合物较好包括0.05~99wt%(重量百分率)、更好0.10~50wt%本发明化合物,所有重量百分率均以总组合物为基准。
本发明实施用的治疗有效量,可以由业内技术人员通过使用已知基准包括个体患者的年龄、体重和反应来确定,并在要治疗或要预防的疾病的范畴内予以解读。
在本发明范围内的,有如以上所定义的式I的任何一种化合物用于制造一种药剂的用途。
在本发明范围内的,也有式I的任何一种化合物用于制造一种疼痛治疗用药剂的用途。
还提供的是按照式I的任何一种化合物用于制造各种疼痛病症治疗用药剂的用途,该疼痛病症包括但不限于:急性疼痛,慢性疼痛,神经性疼痛,急性疼痛,背痛,癌痛,和内脏痛。
本发明的一个进一步方面是患有以上所讨论的任何一种病症的患者的治疗方法,因而对需要这样的治疗的患者给药有效量的按照以上式I的化合物。
此外,还提供一种医药组合物,包含与医药上可接受载体配合的式I的化合物或其医药上可接受盐。
具体地说,提供的是一种用于治疗、更具体地用于疼痛治疗的医药组合物,包含与医药上可接受载体配合的式I化合物或其医药上可接受盐。
进而,提供的是一种用于以上所讨论的任何一种病症的医药组合物,包含与医药上可接受载体配合的式I化合物或其医药上可接受盐。
这里也提供的是式I化合物的制备方法。
在一种实施方案中,本发明提供一种式I化合物制备方法,
包含使式II化合物与X-C(=O)-R4或R4C(=O)-OC(=O)R4反应,
式中
R1选自C6-10芳基和C2-6杂芳基,其中所述C6-10芳基和C2-6杂芳基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基;
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基,和
X是Cl、Br或I。
在另一种实施方案中,本发明提供一种式I化合物制备方法,
包含使式III化合物与R1-CHO或R1-CH2X反应,
式中
R1选自C6-10芳基和C2-6杂芳基,其中所述C6-10芳基和C2-6杂芳基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基;
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基;和
X是Cl、Br或I。
具体地说,本发明化合物和用于其制备的中间体可以按照方案1~3中列举的合成路线制备。
方案1
方案2
因此,在另一个方面,本发明提供式III化合物:
式中
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基。
生物学评估
已发现本发明化合物对温血动物例如人体中的δ受体有活性。具体地说,已发现本发明化合物是有效的δ受体配体。以下的离体试验证实了这些令人惊讶的活性,尤其关于兴奋剂药效和功效,如同大鼠脑功能试验和/或人δ受体功能试验(低)中所证实的。这一特色可能与活体活性有关,而且可能与粘结亲和力不是线性相关的。在这些离体试验中,试验了一种化合物对δ受体的活性并得到了IC50,以确定一种特定化合物对δ受体的选择性活性。在本文中,IC50一般地系指观察到标准放射性δ受体的50%置换的该化合物的浓度。
该化合物对κ受体和μ受体的活性也用类似试验进行测定。
离体模型
细胞培养
表达克隆的人κ、δ和μ受体以及新霉素抗性的人293S细胞在含有无钙DMEM 10%FBS、5%BCS、0.1%Pluronic F-68、和600μg/mlgeneticin的悬浮液中、在摇床烧瓶中、在37℃和5%CO2下生长。
将大鼠大脑称重、用冰冷PBS(含有2.5mM EDTA,pH7.4)漂洗。该大脑在冰冷溶胞缓冲剂(50mM Tris,pH7.0,2.5mM EDTA,临使用前添加来自DMSO:乙醇中的0.5M储备溶液的苯甲磺酰氟0.5MmM)中用一台polytron匀化30秒(大鼠)。
膜制备
细胞造粒并再悬浮于溶胞缓冲剂(50mM Tris,pH7.0,2.5mMEDTA,临使用前添加来自乙醇中0.1M储备溶液的PMSF0.1mM)中,在冰上培养15分钟,然后用一台polytron匀化30秒。该悬浮液在4℃以1000g(最大)旋转10分钟。上清液在冰上保存,片状沉淀物像以前一样再悬浮和旋转。将两次旋转的上清液合并,以46,000g(最大)旋转30分钟。该片状沉淀物再悬浮于冷Tris缓冲剂(50mMTris/Cl,pH7.0)中,再次旋转。最终片状沉淀物再悬浮于膜缓冲剂(50mM Tris,0.32M蔗糖,pH7.0)中。将聚丙烯管中的等分样品(1ml)在干冰/乙醇中冷冻,并于-70℃贮存直至使用。蛋白质浓度是用改进的Lowry试验以硫酸十二烷酯钠测定的。
结合试验
将膜在37℃解冻、用冰冷却(或当不立即使用时保持在冰上)、3次通过25号针、并稀释到结合缓冲剂(50mM Tris,3mM MgCl2,1mg/ml BSA(Sigma A-7888,pH7.4)中,经由0.22m过滤器过滤后在4℃贮存,而且若该膜是从组织(大鼠、小鼠、猴子、无DTT)衍生的时则新鲜添加5μg/ml aprotinin、10μM bestatin、10μM diprotin A。将100μl等分试样添加到含有100μl适当放射性配体和100μl各种浓度的试验化合物的冰冷12×75mm聚丙烯管中。在10μM纳洛酮的存在和不存在下,分别测定总结合(TB)和非特异性结合(NS)。将这些管旋转、在25℃培养60~75分钟,然后将内容物迅速经由用0.1%聚乙烯亚胺预浸渍至少2小时的GF/B过滤器(Whatman公司)真空过滤,并以约12ml/试管冰冷洗涤缓冲剂(50mM Tris,pH7.0,3mMMgCl2)洗涤。该过滤器在含有6~7ml闪烁流体的微管形瓶中浸渍至少12小时之后,用β计数器测定该过滤器上保留的放射性(dpm)。若该试验是在96眼深孔平皿上进行,则过滤用96眼PEI浸渍的unifilter进行,用3×1ml洗涤缓冲剂洗涤、在55℃烘箱中干燥2小时。该过滤器板在添加50μlMS-20闪烁流体/孔之后用一台TopCount(Packard公司)计数。在用96眼深孔平皿进行试验的情况下,化合物的IC50在δ的情况下是从10点排代曲线评估的,而在μ和κ的情况下是从5点排代曲线评估的。该试验是用300μl以适量膜蛋白(在δ、μ、和κ的情况下分别为2μg、35μg、和1μg)和50000~80000dpm/孔适当示踪剂(在δ、μ、和κ的情况下分别为125I-DeltorphinII,125I-FK33824、和125I-DPDYN)进行的。总结合和非特异性结合是10μM纳洛酮的不存在和存在下进行的。
功能试验
该化合物的兴奋剂活性是通过确定该化合物受体络合物使GTP与该受体与之偶合的G-蛋白结合活化的程度来测定的。在GTP结合试验中,GTP[γ]35S是与试验化合物和来自表达克隆人鸦片类受体的HEK-293S或来自匀化大鼠或小鼠大脑的膜结合的。兴奋剂刺激这些膜中的GTP[γ]35S结合。从剂量响应曲线确定化合物的EC50和Emax值。进行了δ拮抗剂naltrindole引起的剂量响应曲线右移,以验证兴奋剂活性是经由δ受体传递的。对于人δ受体功能试验来说,EC50(低)是当用于该试验的人δ受体以比用于测定EC50(高)的那些更低的水平表达时测定的。Emax值是相对于标准δ兴奋剂SNC80而言确定的,即高于100%的是其功效优于SNC80的化合物。
大鼠大脑GTP的程序
大鼠大脑膜在37℃解冻、3次通过25号钝端针、用GTPγS结合液(50mM Hepes、20mM NaOH、100mM NaCl、1mM EDTA、5mMMgCl2、pH7.4,现添加:1mM DTT、0.1%BSA)稀释。添加膜稀释液达到最终120μM GDP。化合物的EC50和Emax是从用300μl以适量膜蛋白(20μl/孔)和100000~130000dpm GTRγ35S/孔(0.11~0.14nM)得到的10点剂量-响应曲线评估的。基础的和最大的刺激结合是在3μM SNC-80不存在和存在下测定的。在稳定地表达克隆的δ受体的HEK293S细胞上进行的试验是以稍微不同的缓冲剂(50mM Hepes、20mMNaOH、200mM NaCl、1mM EDTA、5mM MgCl2、pH7.4,现添加:0.5%BSA、无DTT)和3μM GDP最终浓度进行的。
数据分析
特异性结合(SB)是作为TB-NS计算的,各种试验化合物存在下的SB表示为对照SB的百分率。IC50和配体在置换特异性结合的放射性配体方面的希尔系数(nH)的数值是从对数图或曲线拟合程序例如Ligand、GraphPad Prism、SigmaPlot、或ReceptoFit计算的。Ki值是从Cheng-Prussoff方程计算的。对于在至少3条排代曲线中试验的配体,报告了IC50、Ki和nH的平均±S.E.M.值。本发明化合物的生物学活性列于表1和2中。
表1
化合物号 | 人δ(nM) | 人κ(nM) | 人μ(nM) | 大鼠大脑(nM) | |||
IC50 | EC50(高) | %EMax(高) | IC50 | IC50 | EC50 | %EMax | |
3-4 | 0.34-0.59 | 1.46-2.65 | 95-98 | 2470-8000 | 344-368 | 7.2-15.8 | 126-137 |
表2
化合物号 | 人δ(nM) | 人κ(nM) | 人μ(nM) | ||
IC50 | EC50(低) | %EMax(低) | IC50 | IC50 | |
1-2,5-9 | 0.19-149 | 15.7-274 | 80-112 | 5828-9074 | 106-4441 |
受体饱和实验
放射性配体Kδ值是通过用适当放射性配体以0.2~5倍估计Kδ(若所需要的放射性配体量是可行的,则可多达10倍)范围内的浓度进行细胞膜上的结合试验来确定的。特异性放射性配体结合表达为pmol/mg膜蛋白。来自个别实验的Kδ和Bmax数值是从特异性结合(B)对nM游离(F)放射性配体的个体非线性拟合按照单点模式得到的。
使用Von Frey试验的机械-Allodynia测定
使用Chaplan等人(1994年)描述的方法,在08:00~16:00之间进行试验。将大鼠放进置于金属丝网底部上面、使得能够着爪子的有机玻璃笼中,并使之习惯10~15分钟。试验区是中跖左后爪,避免不太敏感的爪垫。使爪子与一系列8根有对数增量劲度的Von Frey毛(0.41,0.69,1.20,2.04,3.63,5.50,8.51,和15.14克;美国伊利诺州Stoelting)接触。该Von Frey毛是从金属丝网地板下面垂直于跖表面以足够的力施用的,以引起爪子稍微弯曲并保持大约6~8秒。若爪子敏捷回缩,测视为阳性反应。在该毛撤除时立即退缩也视为阳性反应。移动视为不确定的反应,在这样的情况下重复刺激。
试验方案
FCA处理组的动物在手术后第1天进行试验。用Dixon(1980年)的自上而下方法确定50%回缩阈值。试验用该系列中部的2.04g毛开始。刺激总是以无论上升还是下降的相继方式提供的。在对最初选择的毛的爪回缩反应不存在时,提供更强烈的刺激;在爪子回缩的情况下,选择下一个更弱的刺激。用这种方法的最佳阈值计算要求6次反应紧挨着50%阈值,而且这6次反应的计数始于反应第一次变化发生时,例如第一次跨越阈限。在阈限落在刺激范围以外的情况下,分别指定15.14(正常灵敏度)或0.41(最大allodynic)的数值。所得到的阳性反应和阴性反应的模式按惯例列表:X=无回缩,O=回缩;且50%回缩阈限用下式插入
50%g阈限=10(Xf+Kδ)/10000式中Xf=所使用的最后一根von Frey毛的值(对数单位);k=阳性/阴性反应模式的表格值(来自Chaplan等(1994));且δ=刺激之间的平均差(对数单位)。在此,δ=0.224。
按照Chaplan等人(1994),将von Frey阈限值转化成最大可能效果的百分率(%MPE)。使用以下方程计算%MPE:
试验物质的给药
在von Frey试验之前给大鼠(经皮下、经腹膜内、经静脉内或经口)注射试验化合物,试验化合物与von Frey试验之间的时间因试验化合物的性质而异。
Writhing试验
当对小鼠经腹膜内给药时,乙酸会引起腹部收缩。然后,这些将以典型的方式使其身体伸展。当给药止痛药时,就不太经常观察到这种所描述的运动,该药物是作为潜在良好候选者选择的。
只有当存在下列要素时才认为是完全的和典型的Writhing反射:动物不处于运动中,较低的背部稍微凹陷,双爪的跖形态是可观察的。在这种试验中,本发明的化合物证实经口给药1~100μmol/kg之后Writhing反应的显著抑制。
(i)溶液制备
乙酸(AcOH):将120μL乙酸添加到19.88mL蒸馏水中,以期得到最终体积为20mL且最终浓度为0.6%AcOH。然后,将该溶液混合(旋转)并准备好用于注射。
化合物(药物):每一种化合物都按照标准程序制备和溶解于最适用的载体中。
(ii)溶液给药
在试验前20、30或40分钟(按照化合物的类别及其特征),以10mL/kg(考虑平均小鼠体重)经口、经腹膜内(i.p.)、经皮下(s.c.)或经静脉内(i.v.)给药该化合物(药物)。当该化合物经中枢例如经脑室内(i.c.v.)或经鞘内(i.t.)输送时,给药5μL的体积。
AcOH是在临试验前以10mL/kg(考虑平均小鼠体重)在2个部位经腹膜内(i.p.)给药的。
(iii)试验
对动物(小鼠)观察为期20分钟,注意并在实验结束时汇总发生(Writhing反射)的次数。将小鼠保持在有触断层的单个“鞋盒式”笼子里。通常同时观察总共4只小鼠:一只对照和三种药物剂量。
为了焦虑和类焦虑指示,已经在大鼠的geller-seifter冲突试验中确定了功效。
为了功能性胃肠紊乱指示,可以在Coutinho SV等人,AmericanJournal of Physiology-Gastrointestinal & Liver Physiology,282(2):G307-16,2002Feb.所述的试验中确定对大鼠的功效。
追加的活体试验方案
对象和居所
将纯朴的雄性Sprague Dawley大鼠(175-200g)以5只一组关在控温室(22℃,40~70%湿度,12小时亮/暗)中。实验在该循环的亮期期间进行。动物有食物和水供随意取食和饮用,并在采集数据后立即宰杀。
样品
化合物(药物)试验包括不接受任何处理的大鼠组和用大肠杆菌脂多糖(LPS)处理的其它组。为了LPS处理实验,给4个组注射LPS,然后这4个组之一进行载体处理、其余3个组注射该药物及其载体。进行第二套实验,涉及5组大鼠,这些全部不接受LPS处理。纯朴组不接受化合物(药物)或载体;其余4个组用有或无药物的载体处理。进行这些实验是要确定药物的抗焦虑或镇静效果,这些效果会有助于USV减少。
LPS的给药
处理前让大鼠在该实验室中习惯15~20分种。通过LPS(革兰氏阴性大肠菌血清型0111:B4的内毒素,Sigma公司)的给药诱发炎症。在异呋喃麻醉下,使用标准定向外科技术,以10μL的体积经脑室内(i.c.v.)注射LPS(2.4μg)。将两耳之间的皮肤推向嘴侧,做约1cm的纵向切口以使头颅骨表面露出。打孔部位由坐标确定:前囟向后0.8mm,λ(矢状骨缝)左侧1.5mm,和侧脑室头颅骨表面以下(垂直)5mm。LPS是经由用聚乙烯管(PE20;10~15cm)连接到100μL Hamilton注射器上的5mm长无菌不锈钢针(26-G3/8)注射的。将一个从切针(20-G)制成的4mm阻挡器放上去、用硅胶固定到26-G针上,以造成所希望的5mm深度。
在LPS注射后,该针在那个位置上再停留10秒钟以使该化合物得以扩散,然后取出。将该切口缝合、并将该大鼠放回它原来的笼中,并使之在试验前休息至少3.5小时。
吹气刺激的实验装置
在LPS注射和化合物(药物)给药后,这些大鼠仍留在该实验室中。试验时,将大鼠全部取出、放置在该实验室外。一次将一只大鼠带进该试验室、放进一个透明盒子(9×9×18cm)中,然后将后者放进一个尺寸为62(w)×35(d)×46(h)cm的消音通风室(BRS/LVE,Div.Tech-Serv Inc.)中。吹气经由0.32cm的空气输出喷嘴的输送是由一个能以每10秒一吹的频率输送固定持续时间(0.2秒)和固定强度的吹气的系统(AirStim,San Diego Instruments公司)控制的。给予最多10次吹气,或直至总是首先出现的发声开始为止。第一次吹气标志着记录开始。
超声记录实验装置和超声记录
使用放置在每个(消音通风)室内并由LMS(LMS CADA-X 3.5B,Data Acquisition Monitor公司,密歇根州特洛伊)软件控制的麦克风(G.R.A.S.声音和振动公司,丹麦韦德巴克)记录发声10分钟。将0~32000Hz的频率记录、存储并以同一软件(LMS CADA-X 3.5B,TimeData Processing Monitor and UPA(用户编程与分析))分析。
化合物(药物)
所有化合物(药物)都调至pH6.5~7.5之间,并以4mL/kg的体积给药。化合物(药物)给药之后,让动物返回其原来的笼中直至试验时。
分析
该记录进行一系列统计分析和傅里叶分析,以过滤(20~24KHz之间)和计算有兴趣的参数。数据表达为平均值±SEM。统计显著性,对于纯朴大鼠与LPS处理大鼠之间的比较来说用T试验予以评价,而对于药物有效性来说则先用单通道ANOVA随后用Dunnett多比较试验(post-hoc)予以评价。当最小p值≤0.05时,认为组与组之间的差异是显著的。实验重复至少2次。
使用Hargreaves跖试验确定热痛觉过敏
FCA或角叉菜聚糖的给药
弗洛因德完全佐剂(FCA):SIGMA cat.#F 5881,结核分支杆菌(H37Ra,ATCC 25177),1mg/mL,热灭活,干燥,0.85mL石蜡,0.15mL二缩甘露醇单油酸酯。或角叉菜聚糖λ型IV(Cg):SIGMA cat.#C-3889(植物性明胶;爱尔兰苔藓),NaCl中的(1.0%溶液)。
注射是用Hamilton注射器以无菌针尺寸26G5/8”进行的。将大鼠捉住并放进异呋喃麻醉室中。当达到所希望的效果时,将大鼠取出并以腹侧卧(胸骨位置)放置。抓住左后爪并将针导入#2指与#3指的足垫之间的皮下腹侧,以期达到爪的中部(跖骨区)。最后,将100μL FCA或100μL角叉菜聚糖溶液的体积缓慢注射到该爪中,并在拔出针之后施加一个小的压力3~4秒种。
如果动物在该程序期间醒来,则将其送回吸入室中直至达到所希望的效果。在跖内注射之后,让这些运动在它们的笼中在观察下醒来。
对于FCA处理来说,让大鼠的炎症过程发展48小时。对于角叉菜聚糖处理来说,让大鼠的炎症过程发展3小时。在该试验的那个早晨,将大鼠放进该实验室(它们的笼中)。让它们对该房间习惯至少30分钟。
试验部位
将热刺激施加于足垫之间的跖表面中心。试验部位必须与该玻璃接触,且其间无尿或粪便,以期保持玻璃对皮肤的正确传热性能。
跖装置由一个有玻璃顶部/平台的盒子组成,玻璃表面由内部反馈机制保持在30℃。这个玻璃平台下面有一个安装在可移动臂上的灯泡,一面镜子放在下面以使该光线能配置在大鼠的爪子之下。当该光线被激活时,它通过一个~2mm直径的小孔闪耀。实验者将该光线激活,且当该爪子移开时自动传感器将该光线切断;20.48秒的切断确保一旦该大鼠不将其爪子移开也不会发生组织损害。实验者也可以在任何一点上切断该光线。一个计时器会记录该光线被激活的持续时间。
通量计:测量该光线被激活时的通量/cm2。这应当保持在~97-98;该通量可以通过调整跖器件来改变,但一定不要在实验中间改变。
时间历程
该实验可以在改变炎症诱发后的时间长度之后进行。痛觉过敏是FCA注射后48小时或角叉菜聚糖注射后3小时测定的。
试验程序
纯朴大鼠:对于剂量响应曲线的确定程序来说,使用7只大鼠一组作为对照组;它们与其余28只大鼠一起麻醉,但不给予任何注射。纯朴组的试验可以要么在该实验开始前进行,要么在该实验之后立即进行,为了尽可能减少压力,将大鼠置于放在跖器件上面的单个有机玻璃盒(14×21×9cm)中;让它们习惯为期30分钟。当这些动物准备进行试验时,将光线直接放在试验部位之下并予以激活,记录回缩的潜伏期。在为期5~8分钟之后,让皮肤温度恢复正常,取第二次读数,然后取出该大鼠并重新放回它们的笼子中。
基线值:将其余28只已经注射了FCA(或角叉菜聚糖)的大鼠(分成4组)放进该机器上的单个盒子中并使之习惯30分钟。实验者应验证爪子发炎的程度并核对是否变色。将热刺激置于试验部位之下,记录回缩的潜伏期;像以上一样取2次读数。正是这些基线值与纯朴动物的那些值的比较确定了痛觉过敏是否存在。
后药物试验:一旦确定了痛觉过敏,就给大鼠注射有兴趣的化合物。每一种化合物都按照标准程序制备和溶解于最适用的载体中。给药途径、剂量、体积、和注射后的试验时间对该化合物(或该类化合物)是特异性的。当在注射例如i.v.或s.c.注射后20~30分钟试验化合物时,将大鼠放在跖装置上并使之习惯,同时药物产生其效果。当在注射后60分钟或更长时间试验化合物时,将大鼠连同其笼友一起放回其原来的笼中。大鼠总是与其原来的笼友一起重新放进它们原来的笼中,最大限度减少在一群大鼠内部重新建立社会结构的压力。30分钟后,将大鼠放在跖机上,并使之对该跖机习惯30分钟。试验像以上所述那样进行。取2次读数。
试验基准:
该动物必须是平和、安静但警觉的,处于正确位置上,在爪的皮肤与该机器的玻璃表面之间无尿或粪便。当有下列情况时不应对动物进行试验:
-该动物处于运动中,包括用鼻吸气(嗅)、清洁身体和探查;
-该动物正在睡觉;
-该动物显示出明显的压力征兆(强直性不动、发声、耳朵偏平),除非这些是化合物副作用的可能结果而且无法避免;
-该动物以这样一种方式配置:爪子不与该玻璃直接接触(爪子放在尾上面);
-该动物的爪子由于注射不良的结果而显示蓝色。在这种情况下,该动物(在开始时)就完全从该实验中排除出去。
当尿和粪便存在时,将该动物取出,并将玻璃表面擦试干净,然后将该动物重新放回。当该动物正在睡觉、或显示强直性不动时,实验者可以轻轻移动该盒子或将其于移至该盒子前面,以引起短期注意行为。在整个试验中应进行动物行为的密切观察。
再试验
在该实验期间的任何时候,若实验者不能肯定爪回缩反应不是对热刺激的反应,则可以在5~8分钟后重新试验该动物。这可以是由于该动物突然移动的缘故,也可以是施加该刺激时有尿或粪便的缘故。
可接受反应
将下列任何一种视为对热刺激的反应:
-爪子离开玻璃的回缩移动(往往随后舔爪子):
-身体侧向移动(受刺激爪子的对侧),
-趾从玻璃上移开;
-发炎爪子的中央平面(爪子中部)从该玻璃上移开。
分析
数据表达为平均值±SEM。统计显著性,对于纯朴大鼠与发炎大鼠之间的比较来说是用T试验评价的,而对于药物有效性来说是先用单通道ANOVA随后用Dunnett多比较试验(post-hoc)评价的。当最小p值≤0.05时,就认为组与组之间的差异是显著的。
实施例
以下实施例将更详细地进一步描述本发明,这些实施例描述可以用来制备、精制、分析和生物学测试本发明化合物方法,不要将其理解为对本发明的限制。
中间体1:4-[(二甲氢基氢膦基)甲基]苯甲酸甲酯
4-(溴甲基)苯甲酸甲酯(11.2g,49mmol)和亚磷酸三甲酯(25mL)的混合物在N2下回流5小时。通过与甲苯共蒸馏脱除过量亚磷酸三甲酯,以定量产率给出中间体1。
1H NMR(CDCl3)δ3.20(d,2H,J=22Hz,CH2),3.68(d,3H 10.8Hz,OCH3),3.78(d,3H,11.2Hz,OCH3),3.91(s,3H,OCH3),7.38(m,2H,Ar-H),8.00(d,2H,J=8Hz,Ar-H).
中间体2:4-(4-甲氧羰基偏亚苄基)哌啶-1-羧酸叔丁酯
在-78℃,向中间体1在干燥THF(200mL)中的溶液中滴加二异丙基亚胺化锂(32.7mL,己烷中1.5M,49mmol)。然后,在添加N-叔丁氧羰基-4-哌啶酮(9.76g,49mmol,在100mL干燥THF中)之前使反应混合物回升到室温。12小时后,反应混合物用水(300mL)熄灭、用乙酸乙酯(3×300mL)萃取。合并的有机相用MgSO4干燥、蒸发,给出一种产物,后者用闪急色谱法精制,提供白色固体状中间体2(5.64g,35%)。
IR(NaCl)3424,2974,2855,1718,1688,1606,1427,1362,1276cm-1;1H NMR(CDCl3)δ1.44(s,9H),2.31(t,J=5.5Hz,2H),2.42(t,J=5.5Hz,2H),3.37(t,J=5.5Hz,2H),3.48(t,J=5.5Hz,2H),3.87(s,3H,OCH3),6.33(s,1H,CH),7.20(dJ=6.7Hz,2H,Ar-H),7.94(d,J,=6.7Hz,2H,Ar-H);13C NMR(CDCl3)δ28.3,29.2,36.19,51.9,123.7,127.8,128.7,129.4,140.5,142.1,154.6,166.8.
中间体3:4-溴-4-[溴-(4-甲氧羰基苯基)甲基]哌啶-1-羧酸叔丁酯
向中间体2(5.2g,16mmol)和K2CO3(1.0g)在干燥二氯甲烷(200mL)中的混合物中添加溴(2.9g,18mmol)在30mL CH2Cl2中的0℃溶液。在室温下1.5小时后,K2CO3过滤后的溶液浓缩。然后,将残渣溶于乙酸乙酯(200mL)中,用水(200mL)、0.5M HCl(200mL)和食盐水(200mL)洗涤,用MgSO4干燥。脱除溶剂提供一种产物,再用甲醇重结晶,给出白色固体状中间体3(6.07g,78%)。
IR(NaCl)3425,2969,1725,1669,1426,1365,1279,1243cm-1;1H NMR(CDCl3)δ1.28(s,9H),1.75(m,1H),1.90(m,1H),2.1(m,2H),3.08(br,2H),3.90(s,3H,OCH3),4.08(br,3H),7.57(d,J=8.4Hz,2H,Ar-H)7.98(d,J=8.4Hz,2H,Ar-H);13C NMR(CDCl3)δ28.3,36.6,38.3,40.3,52.1,63.2,72.9,129.0,130.3,130.4,141.9,154.4,166.3.
中间体4:4-[溴-(4-羧基苯基)亚甲基]哌啶-1-羧酸叔丁酯
将中间体3(5.4g,11mmol)在甲醇(300mL)和2.0M NaOH(100mL)中的溶液在40℃加热3小时。该固体过滤收集、真空干燥过夜。将干燥的盐溶解于40%乙腈/水中,用浓HCl调整到pH2。过滤分离出白色粉末状中间体4(3.8g,87%):1H NMR(CDCl3)δ1.45(s,9H,tBu),2.22(dd,J=5.5Hz,6.1Hz,2H),2.64(dd,J=5.5Hz,6.1Hz,2H),3.34(dd,J=5.5Hz,6.1Hz,2H),3.54(dd,J=5.5Hz,6.1Hz,2H),7.35(d,J=6.7Hz,2H,Ar-H),8.08(d,J=6.7Hz,2H,Ar-H);13C NMR(CDCl3)δ28.3,31.5,34.2,44.0,115.3,128.7,129.4,130.2,137.7,145.2,154.6,170.3.
中间体5:4-[溴-(4-二乙基氨基甲酰基苯基)亚甲基]哌啶-1-羧酸
叔丁酯
向中间体4(1.0g,2.5mmol)在干燥二氯甲烷(10mL)中的-20℃溶液中添加氯甲酸异丁酯(450mg,3.3mmol)。在-20℃20分钟后,添加二乙胺(4mL),让反应物回升到室温。1.5小时后蒸发溶剂,残渣在乙酸乙酯与水之间分配。有机相用食盐水洗涤、用MgSO4干燥。去除溶剂提供一种产物,后者用闪急色谱法精制,给出白色针状中间体5(800mg,73%):
IR(NaCl)3051,2975,1694,1633,1416,1281,1168,1115cm-1;1H NMR(CDCl3)δ1.13(br,3H,CH3),1.22(br,3H,CH3),1.44(s,9H,tBu),2.22(t,J=5.5Hz,2H),2.62(t,J=5.5Hz,2H),3.33(m,4H),3.55(m,4H),7.31(d,J=8.0Hz,2H,Ar-H),7.36(d,J=8.0Hz,2H,Ar-H);13C NMR(CDCl3)δ12.71,14.13,28.3,31.5,34.2,39.1,43.2,79.7,115.9,126.3,129.3,136.8,137.1,140.6,154.6,170.5.
中间体6:4-[溴(哌啶-4-亚基)甲基]-N,N-二乙基苯甲酰胺
向中间体5(15.6g,34.6mmol)在二氯甲烷(200mL)中的溶液中添加三氟乙酸(30mL,311mmol)。该溶液在室温下搅拌16小时。然后该溶液用饱和NaHCO3中和,水层用二氯甲烷(3×100mL)萃取,合并的有机萃取物干燥(Na2SO4)、过滤、浓缩,给出淡黄色固体状中间体6(12.05g,99%)。
中间体7a:4-{溴[1-(噻吩-2-基甲基)哌啶-4-亚基]甲基}-N,N-二
乙基苯甲酰胺
向中间体6(1.4g,3.99mmol)在1,2-二氯乙烷(30mL)中的溶液中添加2-噻吩甲醛(746μL,7.99mmol)和三乙酰氧基硼氢化钠(1.694g,7.99mmol)。反应物在氮气下在室温搅拌。18小时后,反应物用二氯甲烷稀释、用饱和碳酸氢钠水溶液洗涤。水层用2份二氯甲烷萃取,合并的有机萃取物用无水硫酸钠干燥、过滤和浓缩。所得到的材料用闪急色谱法精制、用乙酸乙酯/己烷(7∶3)洗脱,得到粘稠无色油状的中间体7a(1.702g,95%)。
中间体8a:4-{(3-氨基苯基)[1-(噻吩-2-基甲基)哌啶-4-亚基]
甲基}-N,N-二乙基苯甲酰胺
向中间体7a(1.702g,3.81mmol)在甲苯(40mL)和乙醇(8mL)的混合物中的溶液中添加间氨基苯硼酸一水合物(0.886g,5.71mmol)和碳酸钠水溶液(2M,4.76mL,9.52mmol)。然后,让氮气在该溶液中鼓泡25分钟后添加四(三苯膦)钯(0.439g,0.38mmol)。该溶液在90℃加热5小时、然后冷却、添加饱和氯化铵(40mL)和乙酸乙酯。水层用2份乙酸乙酯萃取,合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用5%甲醇/二氯甲烷洗脱,得到黄色泡沫状中间体8a(1.605g,91%)。
化合物1:4-{[3-(乙酰胺基)苯基][1-(噻吩-2-基甲基)哌啶-4-
亚基]甲基}-N,N-二乙基苯甲酰胺
向中间体8a(370mg,0.8mmol)在二氯甲烷(10mL)中的溶液中添加三乙胺(345μL,.248mmol)、随后添加乙酰氯(63μL,0.89mmol)。该溶液搅拌1小时,添加饱和碳酸氢钠(10mL)。水层用2份二氯甲烷萃取,合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用逆相色谱法精制、用含有0.1%三氟乙酸的10%~40%乙腈/水洗脱。得到三氟乙酸盐形式的化合物1,将其冻干,给出一种白色粉末(278mg;52%产率)。
HPLC纯度:>99%(215nm);>99%(254nm);>99%(280m).实测:C,57.87;H,5.48;N,6.26.C30H35N3O2Sx1.5CF3CO2Hx0.7H2O有C,57.83;H,5.57;N,6.13%.1H NMR(400MHz,CDCl3)δ1.11-1.16(m,3H),1.20-1.29(m,3H),2.14(s,3H),2.66-2.75(m,6H),3.25-3.30(m,2H),3.52-3.60(m,4H),4.42(s,2H),6.77(d,J=7.06Hz,lH),7.04-7.10(m,3H),7.18-7.22(m,lH),7.23(br s,1H),7.24-7.28(m,2H),7.29(s,1H),7.40(d,J=8.16Hz,1H),7.44(d,J=5.98Hz,1H),7.83(brs,1H).
中间体7b:4-{溴[1-(2-呋喃基甲基)哌啶-4-亚基]甲基}-N,N-二乙
基苯甲酰胺
向中间体6(1.4g,3.99mmol)在1,2-二氯乙烷(30mL)中的溶液中添加2-糠醛(62μL,7.99mmol)和三乙酰氧基硼氢化钠(1.694g,7.99mmol)。反应物在氮气下在室温搅拌。18小时后,反应物用二氯甲烷稀释,用饱和碳酸氢钠水溶液洗涤。水层用2份二氯甲烷萃取,合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用乙酸乙酯/己烷(7∶3)洗脱,得到淡黄色油状中间体7b(1.503g,87%)。
中间体8b:4-{(3-氨基苯基)[1-(2-呋喃基甲基)哌啶-4-亚基]
甲基}-N,N-二乙基苯甲酰胺
向中间体7b(2.120g,4.93mmol)在甲苯(50mL)和乙醇(10mL)的混合物中的溶液中添加间氨基苯硼酸一水合物(1.145g,7.39mmol)和碳酸钠水溶液(2M,6.15mL,12.31mmol)。然后,让氮气在该溶液中鼓泡25分钟,随即添加四(三苯膦)钯(0.569,0.49mmol)。该溶液在90℃加热5小时、然后冷却、添加饱和氯化铵(40mL)和乙酸乙酯。水层用2份乙酸乙酯萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用5%甲醇/二氯甲烷洗脱,得到黄色泡沫状中间体8b(1.967g,90%)。
化合物2:4-{[3-(乙酰胺基)苯基][1-(2-呋喃基甲基)哌啶-4-
亚基]甲基}-N,N-二乙基苯甲酰胺
向中间体8b(442mg,0.99mmol)在二氯甲烷(10mL)中的溶液中添加三乙胺(431μL,3.08mmol),随后添加乙酸酐(103μL,1.09mmol)。该溶液搅拌1小时,添加饱和碳酸氢钠(10mL)。水层用2份二氯甲烷萃取,合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用逆相色谱法精制、用含有0.1%三氟乙酸的10%~40%乙腈/水洗脱。得到作为三氟乙酸盐的化合物2,冷冻干燥给出白色粉末(264mg,44%产率)。
HPLC纯度:>99%(215nm);>99%(254nm);>99%(280m).实测:C,61.19;H,5.75;N,6.71.C30H35N3O3x1.3CF3CO2Hx0.3H2O有C,61.25;H,5.82;N,6.57%.1H NMR(400MHz,CDCl3)δ1.12(brs,3H),1.24(brs,3H),2.12(s,3H),2.64-2.75(m,6H),3.27(br s,2H),3.53(br s,4H),4.25(s,2H),6.43-6.47(m,1H,6.57-6.62(m,1H),6.77(d,J=7.74Hz,lH),7.05(d,J=8.71Hz,2H),7.21-7.29(m,4H),7.43(d,J=9.06Hz,lH),7.48br s,1H),7.88(br s,1H).
中间体7c:4-{溴[1-(苯甲基)哌啶-4-亚基]甲基}-N,N-二乙基苯甲
酰胺
向中间体6(7.783g,22.2mmol)在二氯甲烷(160mL)中的溶液中添加三乙胺(9.3mL,66.8mmol)和苄基溴(3.2mL,26.9mmol)。反应物在氮气下在室温搅拌。24小时后,反应物用水洗涤、水层用二氯甲烷萃取。合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用乙酸乙酯/己烷(7∶3)洗脱,得到无色固体状中间体7c(6.89g,70%)。
中间体8c:4-{(3-氨基苯基)[1-(苯甲基)哌啶-4-亚基]甲基}-N,N-
二乙基苯甲酰胺
向中间体7c(8.50g,19.3mmol)在二甲苯(120mL)和乙醇(80mL)的混合物中的溶液中添加间氨基苯硼酸一水合物(3.96g,28.9mmol)和碳酸钠水溶液(2M,29.0mL,58mmol)。然后,让氮气在该溶液中鼓泡25分钟,随即添加四(三苯膦)钯(1.67g,1.4mmol)。该溶液在90℃加热18小时,然后冷却、添加水(60mL)和乙酸乙酯。水层用2份乙酸乙酯萃取,合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用2%~4%甲醇/二氯甲烷洗脱,得到橙色泡沫状中间体8c(8.14g,93%)。
化合物3:4-[[3-(乙酰胺基)苯基][1-(苯甲基)-4-哌啶亚基]甲
基]-N,N-二乙基苯甲酰胺
向中间体8c(500mg,1.1mmol)在二氯甲烷(10mL)中的溶液中添加吡啶(262mg,3.32mmol)、随后添加乙酰氯(82μL,1.15mmol)。该溶液搅拌18小时、然后添加水(10mL)。水层用2份二氯甲烷萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用闪急色谱法精制、用2%~10%甲醇/二氯甲烷洗脱。产物用1N HCl醚溶液转化成对应的盐酸盐,给出无色固体状化合物3(540mg,92%产率)。
HPLC纯度:>99%(215nm);>98%(254nm);>98%(280nm).1H NMR(400MHz,CD3OD)δ1.11(t,J=6.7Hz,3H),1.23(t,J=6.7Hz,3H),2.06-2.14(m,2H),2.44-2.59(m,2H),3.11(t,J=12.3Hz,2H),3.25-3.30(m,2H),3.43-3.58(m,4H),4.35(s,2H),6.80-6.91(m,1H),7.22-7.31(m,3H),7.32-7.40(m,3H),7.42-7.58(m,6H).
中间体7d:4-[溴[1-(3-噻吩基甲基)-4-哌啶亚基]甲基]-N,N-二乙
基苯甲酰胺
向中间体6(5.58g,15.9mmol)在1,2-二氯乙烷(100mL)中的溶液中添加3-噻吩甲醛(1.8mL,20.6mmol)和三乙酰氧基硼氢化钠(4.72g,22.3mmol)。反应物在氮气下在室温搅拌。18小时后,反应物用二氯甲烷稀释、用饱和碳酸氢钠水溶液洗涤。水层用2份二氯甲烷萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用5%甲醇/二氯甲烷洗脱,给出橙色油状中间体7d(6.863g,97%产率)。
中间体8d:4-[(3-氨基苯基)[1-(3-噻吩基甲基)-4-哌啶亚基]
甲基]-N,N-二乙基苯甲酰胺
向中间体7d(6.86g,15.3mmol)在甲苯(150mL)和乙醇(30mL)的混合物中的溶液中添加间氨基苯硼酸-水合物(3.6g,23.2mmol)和碳酸钠水溶液(2M,19.0mL,38mmol)。然后,让氮气在该溶液中鼓泡25分钟,随即添加四(三苯膦)钯(1.8g,1.6mmol)。该溶液在90℃加热18小时,然后冷却、添加水(60mL)和乙酸乙酯。水层用2份乙酸乙酯萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用3%~5%甲醇/二氯甲烷洗脱,得到无色泡沫状中间体8d(6.453g,92%)。
化合物4:4-[[3-(乙酰胺基)苯基][1-(3-噻吩基甲基)-4-哌啶亚
基]甲基]-N,N-二乙基苯甲酰胺
向中间体8d(1.05g,2.1mmol)在二氯甲烷(25mL)中的溶液中添加三乙胺(450μL,3.23mmol)、随后添加乙酰氯(210μL,2.95mmol)。该溶液在室温搅拌3天,添加饱和碳酸氢钠溶液(20mL)水层用2份二氯甲烷萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用闪急色谱法精制、用5%~8%甲醇/乙酸乙酯洗脱,给出黄色泡沫状化合物4(324.6mg,28%产率)。化合物4用1M HCl醚溶液转化成对应的盐酸盐。
HPLC纯度:>97%(215nm);>97%(254nm);>97%(280nm).实测:C,63.54;H,6.69;N,7.38.C30H35N3O2Sx1.5HClx0.6H2O有C,63.53;H,6.70;N,7.41%.1H NMR(400MHz,CD3OD)δ1.09(t,J=13.7Hz,3H),1.18-1.25(m,3H),2.07(s,3H),2.43-2.56(m,2H),2.69-2.85(m,2H),3.01-3.12(m,2H),3.21-3.31(m,2H),3.46-3.57(m,4H),4.36(s,2H),6.81-6.87(m,1H),7.19-7.28(m,4H),7.29-7.35(m,3H),7.50(t,J=1.7Hz,1H),7.55(dd,J=2.9,4.9Hz,1H),7.66-7.71(m,1H).
中间体7e:4-[溴[1-(3-吡啶基甲基)-4-哌啶亚基]甲基]-N,N-二乙
基苯甲酰胺
向中间体6(0.5g,1.42mmol)在1,2-二氯乙烷(15mL)中的溶液中添加3-吡啶甲醛(160μL,1.71mmol)和三乙酰氧基硼氢化钠(392mg,1.85mmol)。反应物在氮气下在室温搅拌。18小时后,反应物用二氯甲烷稀释、用饱和碳酸氢钠水溶液洗涤。水层用2份二氯甲烷萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用5%甲醇/二氯甲烷洗脱,得到黄色油状中间体7e(630mg,100%)。
中间体8e:4-[(3-氨基苯基)[1-(3-吡啶基甲基)-4-哌啶亚基]
甲基]-N,N-二乙基苯甲酰胺
向中间体7e(630mg,1.42mmol)在甲苯(9mL)和乙醇(2mL)的混合物中的溶液中添加间氨基苯硼酸-水合物(264mg,1.70mmol)和碳酸钠水溶液(2M,1.8mL,3.55mmol)。然后让氮气在该溶液中鼓泡25分钟,随即添加四(三苯膦)钯(98mg,0.09mmol)。该溶液在90℃加热5小时、然后冷却、添加饱和氯化铵(40mL)和乙酸乙酯。水层用2份乙酸乙酯萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用闪急色谱法精制、用3%~5%甲醇/二氯甲烷洗脱,得到无色泡沫状中间体8e(559mg,84%)。
化合物5:4-[[3-(乙酰胺基)苯基][1-(3-吡啶基甲基)-4-哌啶亚
基]甲基]-N,N-二乙基苯甲酰胺
向中间体8e(240mg,0.53mmol)在二氯甲烷(10mL)中的溶液中添加三乙胺(256μL,1.86mmol)、随后添加乙酰氯(50μL,0.71mmol)。该溶液在室温下搅拌4天,添加饱和碳酸氢钠(20mL)。水层用2份二氯甲烷萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用逆相色谱法精制、用含有0.1%三氟乙酸的10%~40%乙腈/水洗脱。得到作为三氟乙酸盐的化合物5,冷冻干燥,给出一种白色粉末(148mg,39%产率)。
HPLC纯度:>99%(215nm);>99%(254nm);>99%(280nm).实测:C,52.38;H,4.84;N,6.79.C31H36N4O2x0.9H2Ox2.9TFA有C,52.40;H,4.86;N,6.64%.1H NMR(400MHz,CD3OD)δ1.11(t,J=6.7Hz,3H),1.23(t,J=6.8Hz,3H),2.09(s,3H),2.65(br s,4H),3.26-3.55(m,8H),4.47(s,2H),6.81-6.91(m,1H),7.24-7.36(m,6H),7.55-7.56(m,1H),7.69(dd,J=5.0,7.9Hz,1H),8.16(d,J=7.8Hz,1H),8.66-8.82(m,2H)
中间体7f:4-[溴[1-(4-吡啶基甲基)-4-哌啶亚基]甲基]-N,N-二乙
基苯甲酰胺
像对中间体7e所示的那样合成,但使用4-吡啶甲醛作为该醛。
中间体8f:4-[(3-氨基苯基)[1-(4-吡啶基甲基)-4-哌啶亚基]甲
基]-N,N-二乙基苯甲酰胺
像对中间体8e所示的那样合成,但使用中间体7f作为溴乙烯。
化合物6:4-[[3-(乙酰胺基)苯基][1-(4-吡啶基甲基)-4-哌啶亚
基]甲基]-N,N-二乙基苯甲酰胺
向中间体8f(255mg,0.56mmol)在二氯甲烷(10mL)中的溶液中添加三乙胺(272μL,1.86mmol)、随后添加乙酰氯(51μL,0.72mmol)。该溶液在室温搅拌3天,添加饱和碳酸氢钠(20mL)。水层用2份二氯甲烷萃取、合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用逆相色谱法精制、用含有0.1%三氟乙酸的10%~35%乙腈/水洗脱。化合物6是作为三氟乙酸盐得到的,冷冻干燥,给出一种黄色粉末(48mg,12%产率)。
HPLC纯度:>99%(215nm);>99%(254nm);>99%(280nm).实测:C,53.16;H,5.14;N,6.74.C31H36N4O2x2.6TFAx1.4H2O有C,53.13;H,5.10;N,6.85%1H NMR(400MHz,CD3OD)δ1.11(t,J=6.6Hz,3H),1.23(t,J=6.8Hz,3H),2.09(s,3H),2.57-2.73(m,4H),3.27-3.43(m,6H),3.50-3.53(m,2H),4.44(s,2H),6.85-6.88(m,1H),7.20-7.31(m,4H),7.32-7.38(m,2H),7.57(s,1H),7.69(d,J=6.1Hz,2H),8.74(d,J=5.5Hz,2H).
中间体9:4-[[3-(乙酰胺基)苯基](哌啶-4-亚基)甲基]-N,N-二
乙基苯甲酰胺
向中间体5(5.00g,11.1mmol)在甲基(100mL)和乙醇(100mL)的混合物中的溶液中添加3-乙酰胺基苯硼酸(2.95g,16.5mmol)和碳酸钠水溶液(2M,35mL,70mmol)。然后,让氮气通过该溶液鼓泡20分钟,随即添加四(三苯膦)钯(1.28g,1.10mg)。该溶液在90℃加热18小时,然后真空浓缩。残渣用食盐水稀释、用2份乙酸乙酯萃取。合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。残渣用闪急色谱法精制、用5%甲醇/二氯甲烷洗脱。然后,将该材料溶解于二氯甲烷(80mL)中、添加三氟乙酸(10mL)。反应物在室温搅拌18小时,然后添加饱和碳酸氢钠水溶液。分层、有机层用另一份饱和碳酸氢钠水溶液和一份食盐水洗涤。有机层干燥(Na2SO4)、过滤、浓缩,得到褐色固体状中间体9(4.38g,97%)。1H NMR(400MHz,CDCl3)δ1.12(t,J=7.03Hz,3H),1.24(t,J=6.05Hz,3H),2.11(s,3H),2.37-2.47(m,4H),2.89-2.99(m,4H),3.22-3.33(m,2H),3.48-3.59(m,2H),6.73-6.78(m,1H),7.05-7.10(m,3H),7.19(t,J=8.01Hz,1H),7.25(d,J=8.20Hz,2H),7.58-7.63(m,1H).
化合物7:4-{[3-(乙酰胺基)苯基][1-(吡啶-2-基甲基)哌啶-4-
亚基]甲基}-N,N二乙基]苯甲酰胺
向中间体9(0.550g,1.36mmol)在1,2-二氯乙烷(50mL)中的溶液中添加2-吡啶甲醛(0.21mL,2.18mmol)和三乙酰氧基硼氢化钠(0.489g,2.31mmol)。反应物在氮气下在室温搅拌。18小时后,反应物用饱和碳酸氢钠水溶液洗涤。水层用2份二氯甲烷萃取,合并的有机萃取物用无水硫酸钠干燥、过滤、浓缩。所得到的材料用逆相色谱法精制,用含有0.1%三氟乙酸的10%~45%乙腈/水洗脱。得到作为三氟乙酸盐的化合物7,冷冻干燥,给出一种无色固体(0.339g,41%)。
HPLC纯度:>99%(215nm);>99%(254nm);>99%(280nm).实测:C,59.46;H,5.74;N,8.06.C31H36N4O2x1.6CF3CO2Hx0.7H2O有C,59.39;H,5.68;N,8.10%.1H NMR(400MHz,CD3OD)δ1.11(br t,J=7.03Hz,3H),1.24(br t,J=6.64Hz,3H),2.09(s,3H),2.64-2.77(m,4H),3.24-3.34(m,2H),3.35-3.47(m,4H),3.48-3.60(m,2H),4.51(s,2H),6.88(ddd,J=6.64,1.95,1.56Hz,1H),7.24-7.30(m,4H),7.36(d,J=8.40Hz,2H),7.45(ddd,J=7.62,4.88,0.98Hz,1H),7.47-7.50(m,1H),7.56-7.58(m,1H),7.89(td,J=7.81,1.76Hz,1H),8.68(ddd,J=4.88,1.76,0.98Hz,1H).
化合物8:4-{[3-(乙酰胺基)苯基][1-(1,3-噻唑-4-基甲基)哌啶
-4-亚基]甲基}-N,N-二乙基苯甲酰胺
向中间体9(0.421g,1.04mmol)在干燥DMF(10mL)中的溶液中添加4-氯甲基三唑盐酸盐(0.354g,2.08mmol)和碳酸钾(0.287g,2.08mmol)。反应物在室温下搅拌2天,然后真空浓缩。残渣用二氯甲烷稀释、用一份饱和碳酸氢钠水溶液洗涤。水层用2份二氯甲烷萃取、合并的有机萃取物干燥(Na2SO4)、过滤和浓缩。所得到的材料用逆相色谱法精制,用含有0.1%三氟乙酸的10%~40%乙腈/水洗脱。得到作为三氟乙酸盐的化合物8、冷冻干燥、给出一种无色固体(0.114g,18%)。
HPLC纯度:>99%(215nm);>99%(254nm);>99%(280nm).实测:C,56.13;H,5.26;N,8.41.C29H34N4O2Sx1.5CF3CO2Hx0.6H2O有C,5615;H,5.40;N,8.18%.1H NMR(400MHz,CD3OD)δ1.12(brt,J=7.23Hz,3H),1.23(br t,J=7.62Hz,3H),2.09(s,3H),2.40-2.94(m,4H),3.08-3.24(m,2H),3.24-3.34(m,2H),3.48-3.68(m,4H),4.53(s,2H),6.87(d,t,J=7.03,1.56Hz,1H),7.25(d,J=8.20Hz,2H),7.27-7.33(m,2H),7.36(d,J=8.40Hz,2H),7.53-7.56(m,1H),7.86(d,J=1.95Hz,1H),9.11(d,J=1.95Hz,1H).
化合物9:4-{[3-(乙酰胺基)苯基][1-(1,3-噻唑-5-基甲基)哌啶
-4-亚基]甲基}-N,N-二乙基苯甲酰胺
使用与化合物7相同的方法,并使用中间体9(0.440g,1.08mmol)和噻唑-5-甲醛(0.196g,1.73mmol),得到作为其TFA盐的化合物9(0.272g,41%)。这种材料冷冻干燥,产生一种浅黄色固体。
HPLC纯度:>95%(215nm);>97%(254nm);>99%(280nm).实测:C,55.04;H,5.33;N,7.83.C29H34N4O2Sx1.7CF3CO2Hx0.6H2O有C,55.02;H,5.26;N,7.92%.1H NMR(400MHz,CD3OD)δ1.12(br t,J=6.25Hz,3H),1.23(br t,J=6.64Hz,3H),2.10(s,3H),2.46-2.90(m,4H),3.23-3.35(m,4H),3.37-3.65(m,4H),4.73(s,2H),6.87(dt,J=6.83,1.76Hz,1H),7.23-7.33(m,4H),7.36(d,J=8.40Hz,2H),7.55-7.58(m,1H),8.09(s,1H),9.20(s,1H).
Claims (13)
1.式I化合物、其医药上可接受的盐、其非对映异构体、对映异构体、或其混合物:
式中
R1选自C6-10芳基和C2-6杂芳基,其中所述C6-10芳基和C2-6杂芳基任选地有一个或多个选自-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独立地是氢或C1-6烷基;和
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基、其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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独立地是氢或C1-6烷基。
2.按照权利要求1的化合物,
式中R1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-氧化吡啶基,其中R1任选地有一个或多个选自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、R3、和R4独立地是C1-3烷基或卤代C1-3烷基;
R5选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自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。
3.按权利要求1的化合物,
式中R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、吡咯基、和噻唑基,其中R1任选地有一个或多个选自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、R3、R4独立地是C1-3烷基、卤代C1-3烷基;和
R5是氢。
4.按照权利要求1的化合物,
式中R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、吡咯基、和噻唑基;
R2和R3是乙基;
R4是C1-3烷基;和
R5是氢。
5.按照权利要求1的化合物,其中该化合物选自:
4-{[3-(乙酰胺基)苯基][1-(噻吩-2-基甲基)哌啶-4-亚基]甲基}-N,N-二乙基苯甲酰胺;
4-{[3-(乙酰胺基)苯基][1-(2-呋喃基甲基)哌啶-4-亚基]甲基}-N,N-二乙基苯甲酰胺;
4-[[3-(乙酰胺基)苯基][1-(苯甲基)-4-哌啶亚基]甲基]-N,N-二乙基苯甲酰胺;
4-[[3-(乙酰胺基)苯基][1-(3-噻吩基甲基)-4-哌啶亚基]甲基]-N,N-二乙基苯甲酰胺;
4-[[3-(乙酰胺基)苯基][1-(3-吡啶基甲基)-4-哌啶亚基]甲基]-N,N-二乙基苯甲酰胺;
4-[[3-(乙酰胺基)苯基][1-(4-吡啶基甲基)-4-哌啶亚基]甲基]-N,N-二乙基苯甲酰胺;
4-{[3-(乙酰胺基)苯基][1-(吡啶-2-基甲基)哌啶-4-亚基]甲基}-N,N-二乙基苯甲酰胺;
4-{[3-(乙酰胺基)苯基][1-(1,3-噻唑-4-基甲基)哌啶-4-亚基]甲基}-N,N-二乙基苯甲酰胺;
4-{[3-(乙酰胺基)苯基][1-(1,3-噻唑-5-基甲基)哌啶-4-亚基]甲基}-N,N-二乙基苯甲酰胺;及其医药上可接受的盐。
6.按照权利要求1~5中任何一项的化合物用来作为一种药剂。
7.按照权利要求1~5中任何一项的化合物的用途,用于制造疼痛、焦虑或功能性胃肠紊乱治疗用药剂。
8.一种医药组合物,包含按照权利要求1~5中任何一项的化合物和医药上可接受的载体。
9.温血动物中疼痛的治疗方法,包含对所述需要此类治疗的动物给药治疗有效量的按照权利要求1~5中任何一项的化合物的步骤。
10.温血动物中功能性胃肠紊乱的治疗方法,包含对所述需要此类治疗的动物给药治疗有效量的按照权利要求1~5中任何一项的化合物的步骤。
11.一种式I化合物制备方法,
包含使式II化合物与X-C(=O)-R4或R4C(=O)-OC(=O)R4反应,
式中
R1选自C6-10芳基和C2-6杂芳基,其中所述C6-10芳基和C2-6杂芳基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基;
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基,和
X是Cl、Br或I。
12.一种式I化合物的制备方法,
包含使式III化合物与R1-CHO或R1-CH2X反应,
式中
R1选自C6-10芳基和C2-6杂芳基,其中所述C6-10芳基和C2-6杂芳基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基;
R2、R3、R4和R5独立地选自氢、C1-6烷基、和C3-6环烷基,其中所述C1-6烷基和C3-6环烷基任选地有一个或多个选自-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,式中R独立地是氢或C1-6烷基;和
X是Cl、Br或I。
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WO2020211836A1 (zh) * | 2019-04-19 | 2020-10-22 | 北京酷瓴生物技术有限公司 | 苯甲烯哌啶衍生物及其制备方法、中间体和用途 |
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JP4549024B2 (ja) | 2001-05-18 | 2010-09-22 | アストラゼネカ・アクチエボラーグ | 4(フェニル−ピペラジニル−メチル)ベンズアミド誘導体及び疼痛、不安症又は胃腸障害の治療のためのその使用 |
SE0203300D0 (sv) | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
SE0203301D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
SE0203303D0 (sv) | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
CA2525860A1 (en) * | 2003-05-16 | 2004-11-25 | Astrazeneca Ab | Diarylmethylidene piperidine derivatives, preparations thereof and uses thereof |
KR20140015122A (ko) | 2003-10-01 | 2014-02-06 | 아돌로 코포레이션 | 스피로시클릭 헤테로시클릭 유도체 및 이의 사용 방법 |
DK1781631T3 (da) | 2004-08-02 | 2012-05-14 | Astrazeneca Ab | Diarylmethylpiperazinderivater, præparater dermed og anvendelser deraf |
WO2006091160A1 (en) * | 2005-02-28 | 2006-08-31 | Astrazeneca Ab | Diarylmethyl piperazine derivatives, preparations thereof and uses thereof |
US7598261B2 (en) | 2005-03-31 | 2009-10-06 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
US7576207B2 (en) | 2006-04-06 | 2009-08-18 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
MY148880A (en) * | 2006-10-20 | 2013-06-14 | Astrazeneca Ab | N-(2-hydroxyethyl)-n-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide, the process of making it as well as its use for the treatment of pain, anxiety and depression |
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US2898339A (en) * | 1957-07-29 | 1959-08-04 | Wm S Merrell Co | N-substituted benzhydrol, benzhydryl, and benzhydrylidene piperidine |
US4581171A (en) * | 1983-07-27 | 1986-04-08 | Janssen Pharmaceutica, N.V. | [[Bis(aryl)methylene]-1-piperidinyl]alkyl-pyrimidinones useful for treating psychotropic disorders |
US4816586A (en) * | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
US5140029A (en) * | 1989-01-09 | 1992-08-18 | Janssen Pharmaceutica N.V. | 2-aminopyrimidinone derivatives |
US4939137A (en) * | 1989-06-28 | 1990-07-03 | Ortho Pharmaceutical Corporation | Ring-fused thienopyrimidinedione derivatives |
US5683998A (en) * | 1991-04-23 | 1997-11-04 | Toray Industries, Inc. | Tricyclic triazolo derivatives, processes for producing the same and the uses of the same |
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IL151550A0 (en) * | 2000-03-03 | 2003-04-10 | Ortho Mcneil Pharm Inc | 3-(diarylmethylene)-8-azabicyclo [3.2.1] octane derivatives |
US6556387B1 (en) * | 2000-03-31 | 2003-04-29 | Seagate Technology Llc | Controlling mechanical response characteristics of a disc drive actuator by adjusting a fastener engaging the actuator shaft to vary axial force on the bearing assembly |
SE0001207D0 (sv) * | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
SE0101766D0 (sv) * | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
WO2005003131A1 (en) * | 2003-06-27 | 2005-01-13 | Janssen Pharmaceutica N.V. | Tricyclic delta opioid modulators |
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WO2020211836A1 (zh) * | 2019-04-19 | 2020-10-22 | 北京酷瓴生物技术有限公司 | 苯甲烯哌啶衍生物及其制备方法、中间体和用途 |
CN111825654A (zh) * | 2019-04-19 | 2020-10-27 | 北京酷瓴生物技术有限公司 | 苯甲烯哌啶衍生物及其制备方法、中间体和用途 |
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AU2004204390A1 (en) | 2004-07-29 |
JP2006516559A (ja) | 2006-07-06 |
BRPI0406614A (pt) | 2005-12-06 |
IS7980A (is) | 2005-08-12 |
CA2510382A1 (en) | 2004-07-29 |
IL169366A0 (en) | 2007-07-04 |
MXPA05007484A (es) | 2005-09-21 |
WO2004062562A2 (en) | 2004-07-29 |
AR042887A1 (es) | 2005-07-06 |
NO20053809D0 (no) | 2005-08-12 |
PL378336A1 (pl) | 2006-03-20 |
TW200504059A (en) | 2005-02-01 |
NZ540758A (en) | 2008-03-28 |
US20060154964A1 (en) | 2006-07-13 |
WO2004062562A3 (en) | 2004-09-16 |
UA80012C2 (en) | 2007-08-10 |
NO20053809L (no) | 2005-10-17 |
EP1587790A2 (en) | 2005-10-26 |
ZA200505186B (en) | 2006-04-26 |
RU2324680C2 (ru) | 2008-05-20 |
AU2004204390B2 (en) | 2007-09-06 |
RU2005121491A (ru) | 2006-02-10 |
CN100422151C (zh) | 2008-10-01 |
SE0300105D0 (sv) | 2003-01-16 |
KR20050096137A (ko) | 2005-10-05 |
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