CN1228337C - 氨基甲酸衍生物及其作为促代谢谷氨酸受体配基的用途 - Google Patents
氨基甲酸衍生物及其作为促代谢谷氨酸受体配基的用途 Download PDFInfo
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- CN1228337C CN1228337C CNB008064652A CN00806465A CN1228337C CN 1228337 C CN1228337 C CN 1228337C CN B008064652 A CNB008064652 A CN B008064652A CN 00806465 A CN00806465 A CN 00806465A CN 1228337 C CN1228337 C CN 1228337C
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- xanthene
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- carboxylic acid
- acid amides
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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- C07C233/00—Carboxylic acid amides
- C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
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Abstract
本发明涉及化学式(I)化合物,其中X代表O、S或不形成桥的两个氢原子;A1/A2分别独立地代表苯基或一个含有1或2个氮原子的六元杂环;B代表式(A)基团,其中Y代表-O-、-S-键或一个化学键;Z代表-O-、-S-;或者B为(a、b、c或d)所示五元杂环基团。在控制或防止急性和/或慢性神经性疾病中,这些化合物可用作促代谢谷氨酸受体配基。
Description
本发明涉及通式所示的氨基甲酸酯类衍生物:
其中
R1代表氢原子或低级烷基;
R2、R2’分别独立代表氢,低级烷基,低级烷氧基,卤素或三氟甲基;
X代表O、S或不形成桥的两个氢原子;
A1/A2分别独立代表苯基或含有1或2个氮原子的六元杂环;
B是下式所示基团,
其中
R3代表低级烷基,低级链烯基,低级链炔基,苄基,低级烷基环烷基,低级烷基-氰基,低级烷基-吡啶基,低级烷基-低级烷氧基-苯基,低级烷基-苯基,其任选地被低级烷氧基所取代,或苯基,其任选地被低级烷氧基所取代,或低级烷基噻吩基,环烷基,低级烷基-三氟甲基或低级烷基-吗啉基;
Y代表-O-、-S-键或一个化学键;
Z代表-O-、-S-键。
或者B是下式所示的五元杂环基团:
其中,R4、R5代表氢、低级烷基、低级烷氧基、环己基、低级烷基-环己基或三氟甲基,前提条件是R4、R5中至少有一个为氢;以及它们可药用的盐。
特别是,本发明涉及下列结构的化合物:
或
或
或
或
其中取代基的定义如上所述。
这些化合物及其盐类是新颖的,具有有价值的治疗特性。
现已令人惊叹地发现,通式(I)化合物是促代谢谷氨酸受体的拮抗剂和/或激动剂。
在中枢神经系统(CNS)中,通过由神经元发出的神经递质与神经受体的相互作用而产生刺激的传递。
CNS中最常见的神经递质L-谷氨酸在许多生理过程中发挥着关键的作用。谷氨酸依赖性刺激受体可分为两个主要组:第一组形成配基控制的离子通道。促代谢谷氨酸受体(mGluR)则属于第二主组,而且属于G-蛋白偶联受体家族。
目前,这些mGLuR中的8个不同成员是已知的,其中某些甚至具有亚型。在结构参数、不同的第二信使信号途径以及对低分子量化合物不同的亲合力的基础上,可将这8个受体再分为3个亚组:mGluR1、mGluR5属于组I;mGluR2、mGluR3属于组II;mGluR4、mGluR6、mGluR7、mGluR8属于组III。
属于第一组的促代谢谷氨酸受体配基可用来治疗或预防急性和/或慢性神经性失调,如精神障碍、精神分裂症、阿尔茨海默病、认知障碍、记忆疾病以及慢性和急性疼痛。
关于这一点,其它可治疗的适应症为由搭桥手术或移植、头部供血不足、脊柱损伤、头部损伤、妊娠缺氧、心搏停止及低血糖等因素引起的有限的脑部功能。进一步的适应症包括亨亭顿氏舞蹈病、肌萎缩侧索综合症(ALS)、由艾滋病引起的痴呆症、眼损伤、视网膜病变、特发性帕金森氏综合症或由药物引起的帕金森氏综合症以及一些可导致谷氨酸缺乏功能的症状,如肌痉挛、惊厥、偏头痛、尿失禁、尼古丁成瘾、鸦片成瘾、焦虑、呕吐、运动障碍以及忧郁等。
本发明的目标是式I化合物及它们可药用的盐类以及作为药用活性物质,它们的制备,基于本发明化合物的药物及它们制备以及本发明化合物在控制或预防前述种类疾病以及相应地用于相应药物生产的用途。
在本发明范围内,优选的式I化合物包括那些化合物,其中A代表苯基,X代表不形成桥的两个氢原子,并且B代表基团:
其中Z代表O,并且R3和Y如上所述。
下面是这类化合物的例子:
二苯乙酰基-氨基甲酸丁酯,
二苯乙酰基-氨基甲酸乙酯或
二苯乙酰基-氨基甲酸-戊-4-炔基酯。
进一步优选的式I化合物,其中A表示苯基,X代表-O-或-S-键,B代表基团:
其中Z代表O,并且R3及Y如上所述。
这些化合物的例子是:
(9H-呫吨-9-羰基)-氨基甲酸乙酯,
(9H-呫吨-9-羰基)-氨基甲酸丁酯,或
(9H-硫代呫吨-9-羰基)-氨基甲酸丁酯。
在本发明范围内,优选的式I化合物是那些化合物,其中A表示苯基、X代表不形成桥的两个氢原子、B代表下式所示杂环基团:
其中R4、R5含义如上所述。
这些化合物的例子是:
N-(5-乙基噁唑-2-基)-2,2-二苯乙酰胺,
N-(5-甲基噁唑-2-基)-2,2-二苯乙酰胺,
2,2-二苯基-N-(5-丙基-[1,3,4]噁二唑-2-基)-乙酰胺,
N-[5-(2-甲氧基-乙基)-[1,3,4]噁二唑-2-基]-2,2-二苯乙酰胺,
N-(3-甲基-[1,2,4]噁二唑-5-基)-2,2-二苯乙酰胺,
N-(3-环丙基-[1,2,4]噁二唑-5-基)-2,2-二苯乙酰胺,或
N-(5-甲基-[1,2,4]噁二唑-3-基)-2,2-二苯乙酰胺。
进一步优选的式I化合物是,其中A表示苯基、X代表-O-或-S-原子;B代表由下式所示的杂环基团:
例如以下化合物:
9H-呫吨-9-羧酸噁唑-2-基-酰胺,
9H-呫吨-9-羧酸(5-丙基-[1,3,4]噁二唑-2-基)酰胺,
9H-呫吨-9-羧酸(5-乙基-噁唑-2-基)酰胺,
9H-呫吨-9-羧酸(5-甲基-噁唑-2-基)酰胺,
9H-呫吨-9-羧酸(5-丙基-噁唑-2-基)酰胺,
9H-呫吨-9-羧酸(5-乙基-[1,3,4]噁二唑-2-基)酰胺,
9H-呫吨-9-羧酸(5-环丙烷基甲基[1,3,4]噁二唑-2-基)酰胺,
9H-呫吨-9-羧酸(4-甲基-噁唑-2-基)酰胺,
9H-呫吨-9-羧酸(3-甲基-[1,2,4]噁二唑-5-基)酰胺,
9H-呫吨-9-羧酸(5-三氟甲基-[1,3,4]噁二唑-2-基)酰胺,
9H-呫吨-9-羧酸(5-甲氧基甲基-[1,3,4]噁二唑-2-基)酰胺,
9H-呫吨-9-羧酸(3-环丙烷基-[1,2,4]噁二唑-5-基)酰胺,
9H-呫吨-9-羧酸(5-甲基[1,2,4]噁二唑-3-基)酰胺,除外消旋体外,本发明还包括所有立体异构形式。
用于本描述中的术语“低级烷基”表示含有1-7个碳原子、优选含1-4个碳原子的直链或支链饱和烃基,例如甲基、乙基、正丙基、异丙基等。
用于本说明书中的术语“低级烷氧基”代表与一个氧原子成键的前述低级烷基;
术语“卤素”包括氟、氯、溴和碘。
通式I中的化合物及其可药用的盐类可由一系列步骤制备,包括:
a)使下列式所示的化合物
与式
所示的化合物反应,生成下式所示化合物:
其中取代基定义如上所述,或者
b)使下式所示的化合物
与式
所示的化合物反应,生成下式所示的化合物:
其中G为合适的离去基团,如Cl,Br或酰氧基,或碳酰氯等同物,如碳酰吡唑化物、碳酰咪唑、碳酰苯并三唑、羰氧基琥珀酰亚胺,或活化的酯类,如对硝基苯基酯、五氯苯基酯等,其它取代基的定义如上所述,或者
c)使下式所示化合物
与式
所示化合物反应,生成下式所示化合物:
或者
d)使下式所示化合物:
与式
所示的化合物反应,生成下式所示化合物:
其中取代基的定义如上所述,或
e)使下式所示化合物:
与下式杂环化合物
反应,生成下式所示化合物:
其中B是下式所示的五元杂环,
并且其中其余取代基的定义如上所述,
并且,如果需要,
将式I化合物中的一个功能基团转换为另一个功能基团;
并且,如果需要,
将式I化合物转变为可药用的盐。
按照方案(a)将化学式II的化合物,如二苯乙酰基异氰酸酯加入至式III化合物例如醇(1-丁醇、苄醇、烯丙醇、异丙醇)的二氯甲烷溶液中,然后混合物于室温下搅拌。
式IA化合物可由方案(b)制得。使式V化合物,例如相应的脲烷或氨基甲酸烷基酯,与式IV化合物,例如9H-呫吨-9-碳酰氯或溴,或与化学式IV所示的乙酰氧基衍生物,或与式IV碳酰氯等同物,包括羰基吡唑基团、羰基咪唑基团、羰基苯并三唑基团、羰氧基琥珀酰亚胺基基团或如对硝基苯酯、五氯苯酯等活性酯进行反应。在如吡啶的溶剂中,于室温下按本领域内现有技术进行反应。
此外,可按照步骤(c)或(d)制备式IA-1和IA化合物,其中化学式VI化合物与式VII或VIII化合物反应。本反应按照与方案b)类似的方法进行。
在0℃下,在N,N-二甲氨基吡啶存在下,使式IX所示的杂环化合物与式IV所示的化合物反应可以制备式IB所示的化合物。优选的溶剂是二氯甲烷。
可很容易地按照已知的方法制备可药用的盐类,并且考虑待转变成盐化合物的性质。有机或无机酸,包括如盐酸、氢溴酸、硫酸、硝酸、磷酸或柠檬酸、甲酸、顺丁烯二酸、反丁烯二酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等适合用于制备式I所示的碱性化合物可药用的盐类。含有碱金属或碱土金属的化合物,例如钠、钾、钙、镁或类似物以及碱性胺类或碱性氨基酸类适合于形成酸性化合物的可药用盐类。
图1概述了式IA所示化合物的制备。在实例1-30、32及34-43中详细描述了式I所示的代表性化合物的制备方法。图2描述了式IB所示的化合物的制备方法,在实例31、33及44-69中详细描述了这些方法。
图解1
取代基的定义同前所述。
图解2
其中B是下列所示的五元杂环化合物:
相应取代基的定义同上所述。
图1和图2中所用的原料都是已知化合物,或者可按照本领域已知的方法制备。
如前已述及的,式I所示的化合物及其可药用的盐类是促代谢谷氨酸受体激动剂和/或拮抗剂,可用于治疗或预防急性和/或慢性神经性失调,如精神障碍、精神分裂症、阿尔茨海默病、认知障碍、记忆缺陷以及急和慢性疼痛。其它可治疗的适应症为由搭桥手术或移植、脑部供血不足、脊柱损伤、头部损伤、妊娠缺氧、心搏停止及低血糖等因素引起的脑部疾病。可治疗的适应症进一步包括阿尔茨海默病,亨廷顿氏舞蹈病、ALS、艾滋病引起的痴呆症、眼损伤、视网膜病变、特发性帕金森氏综合症或由药物引起的帕金森氏综合症以及一些可导致谷氨酸功能缺乏的症状,如肌痉挛、惊厥、偏头痛、尿失禁、尼古丁成瘾、精神病、鸦片成瘾、焦虑、呕吐、运动障碍以及忧郁等。
本发明的化合物是组I mGlu受体激动剂和/或拮抗剂。例如,实施例1-22及30-69中的化合物已经显示出激动剂活性,而实施例23-29中的化合物则是拮抗剂。按下述方法测定,化合物显示的活性为50μM或更低,典型的是为1μM或更低,但理想的是为0.5μM或更低。
下表显示了一些特定的活性数据:
实施例序号 | 激动剂/拮抗剂 | IC50(μM) |
10 | 激动剂 | 0.22 |
32 | 激动剂 | 0.14 |
65 | 激动剂 | 0.4 |
23 | 拮抗剂 | 6.31 |
24 | 拮抗剂 | 2.79 |
25 | 拮抗剂 | 1.38 |
试验的描述
按照schlaeger et al,New Dev.New Appl.Anim.CellTechn.,Proc.ESACT Meet.,15,(1998),105-112及117-120中描述的方法,将S.Nakani shi教授(东京,日本)提供的编码大鼠mGlu la受体的cDNA瞬时转染至EBNA细胞中。将经mGlu la转染的EBNA细胞在Fluo-3AM(终浓度为0.5μM)中于37℃孵育1小时,并用测定缓冲液(在DMEM中加入Hank‘s盐及20mM HEPES配制而成)试液洗涤4次后,对其进行[Ca2+]i测定。用荧光成像板计数仪(FLIPR,MolecularDevices Corporation,La Jolla,CA,USA.)进行[Ca2+]i的测定。当化合物经测试可对抗作为激动剂的10μM谷氨酸时,则可将其评价为拮抗剂。
使用迭代非线性曲线拟合软件Origin(Microcal Software Inc.,Northampton,MA,USA),将抑制曲线(拮抗剂)或兴奋曲线(激动剂)拟合四参数对数方程求出EC50及Hill系数。
式I化合物及其可药用的盐类可用作药物,例如可制成药物制剂的形式。药物制剂可经口服给药,例如可制成片剂、包衣剂、糖衣剂、硬及软胶囊剂、溶液剂、乳剂或悬浮剂等形式。然而,也可经直肠给药,如可制成栓剂,或经非肠道给药,如制成注射溶液形式。
式I所示的化合物及其可药用的盐类可与药学惰性的有机或无机的载体制成药物制剂。例如,乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐类及类似物等皆可用作片剂、包衣剂、糖衣剂和硬胶囊剂的载体。用于软明胶胶囊的合适载体是,如植物油、蜡、脂肪、半固态或液态的多元醇及类似物等;然而根据活性物质的性质不同,通常在软胶囊剂的情况下不需要载体。用于制备溶液剂和糖浆剂的合适载体是,例如水、多元醇、蔗糖、转化糖、葡萄糖及类似物等。如醇类、多元醇类、甘油、植物油类等佐剂可用作式I所示化合物的水溶性盐类的水性注射溶液,然而,作为常规一般不必要。用作栓剂的合适载体是,例如天然或硬化油类、蜡、脂肪、半液态或液态的多元醇及类似物等。
此外,药物制剂可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、香料、改变渗透压的盐类、缓冲剂、掩蔽剂或抗氧化剂。它们也可以含有治疗上有价值的其它物质。
如前所述,含有式I所示化合物或其可药用盐以及治疗惰性赋形剂的药物也是本发明的一个目标,这些药物的生产方法也是本发明目标之一,其包括将一或多个式I化合物或其可药用的盐类、并且如果需要可包括一或多个治疗上有价值的其它物质与一或多个治疗上可用的惰性载体一起制成盖伦剂型。
这些药物的剂量可在很宽的范围内变化,当然,需要与特定情况的个体相配合。一般来说,口服或非肠道给药的有效剂量是0.01-20毫克/公斤/天,对于前面提及的所有适应症,优选剂量是0.1-10毫克/公斤/天。因此,一个体重70公斤的成年人每天的用药剂量为0.7-1400毫克,优选剂量为每天7-700毫克。
最后,用如前所述,式I所示的化合物及其可药用的盐类在制备控制或预防前面提到类型的急性和/或慢性神经性失调的药物中的用途也是本发明的目标。
实施例1
二苯乙酰基氨基甲酸丁酯:
将二苯乙酰基异氰酸酯(2.33毫升,0.5M二氯甲烷溶液,1.16毫摩尔)加入搅拌状态下的正丁醇(0.32毫升,3.49毫摩尔)的二氯甲烷(4毫升)溶液中,然后将混合溶液于室温搅拌1小时。真空除溶剂得一黄色油状物,油状物以硅胶柱层析纯化(乙酸乙酯/己烷=1∶2)得淡黄色固体的标题化合物(0.3克,83%),m.p.82-84℃,MS:m/e=334(M+Na+)。
实施例2
二苯乙酰基氨基甲酸苄酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和苄醇制备标题化合物,其为白色固体,m.p.100-101℃,MS:m/e=345(M+)。
实施例3
二苯乙酰基氨基甲酸烯丙酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和烯丙醇制备标题化合物,其为白色固体,m.p.118-120℃,MS:m/e=295(M+)。
实施例4
二苯乙酰基氨基甲酸异丙酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和异丙醇制备标题化合物,其为白色固体,m.p.122-124℃,MS:m/e=297(M+)。
实施例5
二苯乙酰基氨基甲酸叔丁酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和叔丁醇制备标题化合物,其为淡黄色固体,m.p.160-162℃,MS:m/e=334(M+Na+)。
实施例6
(9H-呫吨-9-羰基)-氨基甲酸乙酯
于0℃下,将9H-呫吨-9-碳酰氯(1.50克,6.13毫摩尔)加入至搅拌状态下的脲烷(0.82克,9.21毫摩尔)及DMAP(0.05克,0.41毫摩尔)的吡啶溶液中(10毫升)。然后将混合溶液于室温搅拌17小时。蒸发反应混合物,加入水(50毫升)/饱和碳酸氢钠溶液(20毫升)。将固体过滤,先用水结晶,然后再用乙醇/正己烷重结晶,得白色固体产品(1.22克,67%),m.p.228℃(分解),MS:m/e=298.2(M+H+)。
实施例7
(RS)-(2-溴-9H-呫吨-9-羰基)-氨基甲酸乙酯
按照实施例6的通用方法,从脲烷和2-溴-9H-呫吨-9-碳酰氯制备标题化合物,其为淡棕色固体,m.p.203℃,MS:m/e=375(M+)。
实施例8
(9H-呫吨-9-羰基)-氨基甲酸丁酯
按照实施例6的通用方法,从9H-呫吨-9-碳酰氯和氨基甲酸丁酯制备标题化合物,其为白色固体,m.p.180-183℃,MS:m/e=325.4(M+H+)。
实施例9
二苯乙酰基氨基甲酸乙酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和乙醇制备标题化合物,其为白色固体,m.p.133℃,MS:m/e=284.2(M+H+)。
实施例10
二苯乙酰基-氨基甲酸环丙基甲酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和环丙基甲醇制备标题化合物,其为白色固体,m.p.108℃,MS:m/e=309.4(M+H+)。
实施例11
二苯乙酰基-氨基甲酸戊-4-炔基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和戊-4-炔-1-醇制备标题化合物,其为白色固体,m.p.109℃,MS:m/e=321.4(M+H+)。
实施例12
二苯乙酰基-氨基甲酸-(2-氰基)-乙基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和3-羟基丙腈制备标题化合物,其为白色固体,m.p.113℃,MS:m/e=308.3(M+H+)。
实施例13
二苯乙酰基-氨基甲酸-3-(4-吡啶)-丙基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和3-吡啶-4-基-丙-1-醇制备标题化合物,其为棕色固体,m.p.147-150℃,MS:m/e=374.4(M+H+)。
实施例14
二苯乙酰基-氨基甲酸3-苄氧基-丙基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和3-苄氧基-1-丙醇制备标题化合物,其为无色油,MS:m/e=403.5(M+H+)。
实施例15
二苯乙酰基-氨基甲酸-2-(3,4-二甲氧基苯基)-乙基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和2-(3,4-二甲氧基-苯基)-乙醇制备标题化合物,其为白色固体,m.p.144℃,MS:m/e=419.5(M+H+)。
实施例16
二苯乙酰基-氨基甲酸-(RS)-2-苯基-丙酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和(RS)-2-苯基-1-丙醇制备标题化合物,其为白色固体,m.p.131℃,MS:m/e=373.5(M+H+)。
实施例17
二苯乙酰基-氨基甲酸噻吩-2-基-甲酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和2-噻吩-甲醇制备标题化合物,其为白色固体,m.p.116℃,MS:m/e=351.4(M+H+)。
实施例18
二苯乙酰基-氨基甲酸环戊酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和环戊醇制备标题化合物,其为白色固体,m.p.120-123℃,MS:m/e=323.4(M+H+)。
实施例19
二苯乙酰基-氨基甲酸环己酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和环己醇制备标题化合物,其为白色固体,m.p.117-119℃,MS:m/e=337.4(M+H+)。
实施例20
二苯乙酰基-氨基甲酸-4-苯基-丁酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和4-苯基-丁-1-醇制备标题化合物,其为淡黄色固体,m.p.118℃,MS:m/e=387.5(M+H+)。
实施例21
二苯乙酰基-氨基甲酸-3,5-二甲氧基苯基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和3,5-二甲氧基苯酚制备标题化合物,其为白色固体,m.p.150-152℃,MS:m/e=391.4(M+H+)。
实施例22
二苯乙酰基-氨基甲酸-2,2,2-三氟乙基酯
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和2,2,2-三氟乙醇制备标题化合物,其为白色固体,m.p.125-127℃,MS:m/e=337.3(M+H+)。
实施例23
2,2-二苯基丙酰氨基甲酸乙酯
按照实施例1的通用方法,从2,2-二苯基丙酰异氰酸酯的粗品与乙醇反应制备标题化合物,为无色胶状物,MS:m/e=297.4(M+H+)。
实施例24
(2,2-二苯基丙酰基)-氨基甲酸烯丙酯
按照实施例1的通用方法,从2,2-二苯基丙酰基异氰酸酯和丙-2-烯-1-醇制备标题化合物,其为白色固体,m.p.89℃,MS:m/e=309.4(M+H+)。
实施例25
(2,2-二苯基丙酰基)-氨基甲酸丁酯
按照实施例1的通用方法,从2,2-二苯基丙酰基异氰酸酯和丁-1-醇制备标题化合物,其为白色固体,m.p.83℃,MS:m/e=325.4(M+H+)。
实施例26
(2,2-二苯基丙酰基)-氨基甲酸环丙基甲酯
按照实施例1的通用方法,从2,2-二苯基丙酰基异氰酸酯和环丙基甲醇制备标题化合物,其为白色固体,m.p.125℃,MS:m/e=323.4(M+H+)。
实施例27
(2,2-二苯基丙酰基)氨基甲酸环己酯
按照实施例1的通用方法,从2,2-二苯基丙酰基异氰酸酯和环己醇反应制备标题化合物,其为白色固体,m.p.126℃,MS:m/e=351.4(M+H+)。
实施例28
(2,2-二苯基丙酰基)氨基甲酸-4-苯基-丁酯:
按照实施例1的通用方法,从2,2-二苯基丙酰基异氰酸酯和4-苯基-丁-1-醇制备标题化合物,为黄色油状物,MS:m/e=401.5(M+H+)。
实施例29
(2,2-二苯基丙酰基)氨基甲酸-2,2,2-三氟乙基酯:
按照实施例1的通用方法,从2,2-二苯基丙酰异氰酸酯和2,2,2-三氟乙醇制备标题化合物,其为白色固体,m.p.143-145℃,MS:m/e=351.3(M+H+)。
实施例30
(9H-硫代呫吨-9-羰基)氨基甲酸乙酯
按照实施例6的通用方法,从9H-硫代呫吨-9-碳酰氯[U.S.专利3,284,449]与脲烷制备标题化合物,其为白色固体,m.p.179-182℃,MS:m/e=314.2(M+H+)。
实施例31
9H-硫代呫吨-9-羧酸-噁唑-2-基-酰胺
于0℃下,将(0.100克,0.384毫摩尔)9H-硫代呫吨-9-碳酰氯加入搅拌状态下的2-氨基噁唑(0.048克,0.575毫摩尔)[Cockerill& al.,Sythesis 591(1976)]和DMAP(0.003克,0.03毫摩尔)的吡啶溶液(2毫升)中。继续于室温搅拌16小时,蒸发反应溶剂后加水(5毫升)/饱和碳酸氢钠溶液(2毫升)。过滤得到固体,将其溶解于二氯甲烷,干燥(无水硫酸镁)后真空浓缩。粗品以硅胶柱层析纯化(二氯甲烷/甲醇=40∶1),得到白色固体产品(0.022克,18%),m.p.188-191℃,MS:m/e=309.1(M+H+)。
实施例32
(9H-硫代呫吨-9-羰基)-氨基甲酸丁酯
按照实施例6的通用方法,从9H-硫代呫吨-9-碳酰氯和氨基甲酸丁酯制备标题化合物,其为白色固体,m.p.151-154℃,MS:m/e=342.2(M+H+)。
实施例33
9H-呫吨-9-羧酸-噁唑-2-基-酰胺
按照实施例31的通用方法,从9H-呫吨-9-碳酰氯和2-氨基噁唑制备标题化合物,其为白色固体,m.p.232-235℃,MS:m/e=292(M+)。
实施例34
二苯乙酰基-氨基甲酸-2-吗啉-4-基-乙酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和2-吗啉-4-基-乙醇制备标题化合物,其为白色固体,m.p.135-137℃,MS:m/e=369.3(M+H+)。
实施例35
二苯乙酰基硫代氨基甲酸S-丁酯:
按照实施例1的通用方法,从二苯乙酰基异氰酸酯和硫代丁醇制备标题化合物,其为白色固体,m.p.99℃,MS:m/e=327(M+)。
实施例36
[(3-氯-5-三氟甲基)-吡啶-2-基]-间-甲苯基-乙酰基]-氨基甲酸
乙酯
将97μl(95毫克,0.80毫摩尔)的碳酸二乙酯及38μl(30毫克,0.50毫摩尔)异丙醇溶解于2毫升无水四氢呋喃中。所得的溶液冷至0℃后,加入29毫克(0.67毫摩尔)氢化钠分散体(于矿物油中,含量为55%)。然后于0℃下分次加入164毫克(0.50毫摩尔)的3-氯-5-三氟甲基2-吡啶基-3-甲基苯乙酰胺。于0℃搅拌反应1小时后,升至室温,搅拌过夜。采用常规方法,以氯化铵溶液及乙酸乙酯处理反应液后,得到一黄色油状物,用硅胶闪式层析纯化,洗脱剂为正己烷∶乙酸乙酯=5∶1。得到14.1毫克(0.035毫摩尔,7%)白色固体状的[(3-氯-5-三氟甲基-吡啶-2-基)-间-甲苯基-乙酰基]-氨基甲酸乙酯,m.p.146-147℃,MS:m/e=401.3(M+H)。
实施例37
(9H-呫吨-9-羰基)-氨基甲酸环丙基甲基酯
按照实施例36的通用方法,从9H-呫吨-9-碳酰氯和氨基甲酸环丙基甲酯制备标题化合物,其为白色固体,m.p.183-185℃,MS:m/e=323(M+)。
实施例38
(4-三氟甲基-9H-呫吨-9-羰基)-氨基甲酸乙基酯
按照实施例36的通用方法,从4-三氟甲基-9H-呫吨-9-碳酰氯和氨基甲酸乙酯制备标题化合物,其为白色固体,m.p.196-198℃,MS:m/e=365(M+)。
实施例39
环丙羧酸二苯基乙酰基-酰胺
将氢化钠(95毫克,2.36毫摩尔;60%)加入冷却的(0℃)搅拌状态的2,2-二苯乙酰胺(500毫克,2.36毫摩尔)的四氢呋喃(20毫升)溶液中,混合物于室温搅拌反应0.5小时。然后于室温滴加入环丙烷甲酰氯(247毫克,2.36毫摩尔)的四氢呋喃(5毫升)溶液,并继续于室温搅拌20小时。然后将反应液倾入饱和碳酸氢钠溶液(50毫升)中,以乙酸乙酯萃取(2×70毫升)。合并有机层,以饱和盐水(50毫升)洗涤后,干燥(无水硫酸镁)并蒸发。进一步以柱层析(甲苯∶乙酸乙酯=19∶1)纯化。得到的产品以乙酸乙酯/正己烷重结晶,得到白色固体(133毫克,20%)。m.p.178℃,MS:m/e=279(M+)。
实施例40
9H-呫吨-9-羧酸丁酰基-酰胺
按照实施例39的通用方法,从9H-呫吨-9-甲酰胺(carboxylicacid amide)和丙烷甲酰氯(propanecarboxylic acid chloride)制备标题化合物,其为白色固体,m.p.222℃,MS:m/e=295(M+)。
实施例41
N-二苯乙酰基-丁酰胺
按照实施例39的通用方法,从2,2-二苯乙酰胺和丙烷甲酰氯制备标题化合物,其为白色固体,m.p.205℃,MS:m/e=281(M+)。
实施例42
戊烷羧酸二苯乙酰基-酰胺
按照实施例39的通用方法,从2,2-二苯乙酰胺和戊烷甲酰氯制备标题化合物,其为白色固体,m.p.87℃,MS:m/e=309(M+)。
实施例43
戊酸二苯乙酰基-酰胺
按照实施例39的通用方法,从2,2-二苯乙酰胺和丁烷甲酰氯制备标题化合物,其为白色固体,m.p.83℃,MS:m/e=296.3(M+)。
实施例44
9H-呫吨-9-羧酸(5-丙基[1,3,4]噁二唑-2-基)酰胺
44a)于0℃下,将122毫克(0.5毫摩尔)9-呫吨-甲酰氯的1.22毫升二氯甲烷溶液滴加至76毫克(0.60毫摩尔,1.2当量)5-丙基-[1,3,4]噁二唑-2-基胺和6毫克(0.05毫摩尔,0.1当量)N,N-二甲氨基吡啶的2毫升无水吡啶中。混合物于0℃搅拌反应3-4小时,然后于室温搅拌过夜。再将反应液倾入搅拌良好的50毫升乙酸乙酯与50毫升水的混合液中。分离有机相。水相以25毫升乙酸乙酯萃取二次。合并的有机相用25毫升水洗两次,浓缩。用约25毫升乙酸乙酯处理残留物并蒸发至干。得粗品(167毫克,淡黄色固体)。粗品以乙醇重结晶后得到62毫克(0.185毫摩尔,37%)白色结晶状9H-呫吨-9-羧酸(5-丙基[1,3,4]噁二唑-2-基)酰胺,m.p.215-216℃,MS:m/e=335(M+)。
44b)上述反应中使用的5-丙基-[1,3,4]噁二唑-2-基胺的合成方法如下:
于30分钟内,将4.80克(47.0毫摩尔)丁酰肼的(50毫升)甲醇溶液滴加至5.0克(47.0毫摩尔)溴化氰的50毫升甲醇溶液中。将混合物回流15分钟,然后真空浓缩直至出现晶体。过滤得晶体(9克),用60毫升乙醇处理。然后加入5克粉状碳酸钾,所成悬浮液于室温搅拌5分钟。过滤生成的橙色悬浮液,真空浓缩滤液。将得到的橙色粉末(5.5克)用硅胶闪式层析纯化,洗脱剂:二氯甲烷/甲醇/28%的氨水=80∶10∶1,得到3.95克(31.1毫摩尔,66%)呈白色结晶状的5-丙基-[1,3,4]噁二唑-2-基胺。MS:m/e=127(M+)。
实施例45
2,2-二苯基-N-(5-丙基-[1,3,4]噁二唑-2-基)-乙酰胺
按照实施例44a)的通用方法,从5-丙基[1,3,4]噁二唑-2-基胺和2,2-二苯基乙酰氯制备标题化合物,其为粘稠状油,MS:m/e=322.4(M+H+)。
实施例46
9H-呫吨-9-羧酸[1,3,4]噁二唑-2-基酰胺
按照实施例44a)的通用方法,从[1,3,4]噁二唑-2-基胺和9H-呫吨-甲酰氯制备标题化合物,其为白色固体,m.p.239-240℃,MS:m/e=293(M+)。
按照44b)方法,可以从甲酰肼和溴化氰制备上述反应所用的[1,3,4]噁二唑-2-基胺,其为白色固体,MS:m/e=85(M+)。
实施例47
N-[1,3,4]噁二唑-2-基-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从[1,3,4]噁二唑-2-基胺和2,2-二苯乙酰氯制备标题化合物,为淡黄色固体产物,m.p.131-132℃,MS:m/e=279.2(M+)。
实施例48
9H-呫吨-9-羧酸-(5-乙基-[1,3,4]噁二唑-2-基)-酰胺
48a)将500.5毫克(1.64毫摩尔)(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)甲酮和186.8毫克(1.64毫摩尔)5-乙基[1,3,4]噁二唑-2-基胺悬浮于1.5毫升DMF中,并于130℃搅拌反应6小时。再将反应混合物冷至室温,加入5毫升丙酮。然后继续搅拌5分钟,过滤反应物,用丙酮洗涤所得产物并真空干燥,得到219.5毫克白色固体状的9H-呫吨-9-羧酸(5-乙基-[1,3,4]噁二唑-2-基)酰胺,m.p.256-257℃,MS:m/e=321.2(M+)。
48b)上述反应中使用的5-乙基-[1,3,4]噁二唑-2-基胺的合成方法如下:
将34克的饱和碳酸氢钾溶液(75毫摩尔)及7.7克(72毫摩尔)溴化氰的60毫升水溶液加入至6.3克丙酰肼(72毫摩尔)的50毫升水溶液中。将反应温度由22℃升至32℃,二氧化碳开始逸出,30分钟后出现白色晶体。将白色的反应悬浮液继续搅拌3小时后静置过夜。然后将反应液真空蒸发至干,所得粗晶以20毫升水重结晶,滤集产品并以少量冰水洗涤后,真空干燥。得到6.1克(54毫摩尔,75%)白色固体状的5-乙基-[1,3,4]噁二唑-2-基胺。m.p.174-175℃,MS:m/e=113.1(M+)。
48c)上述反应中使用的(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)甲酮的合成方法如下:
将2.6克(11毫摩尔)9-呫吨羧酸酰肼悬浮于2.5毫升水中,加入10毫升的2N盐酸溶液。再将30毫升乙醇加入至上述粘稠的白色悬浮液中,升温至65℃,然后冷却至室温。在剧烈搅拌下,将1.1克(11毫摩尔)乙酰丙酮加入至上述淡黄色溶液中。约2分钟后,当温度升至30℃时开始出现白色晶体。于室温继续搅拌15分钟,再于0℃搅拌15分钟,过滤所得产物,并用-20℃的乙醇洗涤。粗产品用15毫升乙醇重结晶,得2.80克(9.2毫摩尔,84%)白色晶体状(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)甲酮。m.p.114-115℃,MS:m/e=304.1(M+)。
实施例49
N-(5-乙基-[1,3,4]噁二唑-2-基)-2,2-二苯乙酰胺
按照实施例48a)的通用方法,从1-(3,5-二甲基吡唑-1-基)-2,2-二苯乙酮和5-乙基-[1,3,4]-噁二唑-2-基胺制备标题化合物,其为白色固体,m.p.123-125℃,MS:m/e=308.2(M+H+)。
按照实例48c)的通用方法,从2,2-二苯乙酰肼[Chem.Zentralblatt.
100,2414(1929)]和乙酰丙酮制备上述反应中使用的1-(3,5-二甲基吡唑-1-基)-2,2-二苯乙酮,其为白色固体,m.p.91-92℃,MS:m/e=291.2(M+H+)。
实施例50
9H-呫吨-9-羧酸(5-甲基-[1,3,4]噁二唑-2-基)-酰胺
按照实施例44a)的通用方法,从5-甲基[1,3,4]噁二唑-2-基胺和9-呫吨甲酰氯制备标题化合物,其为白色固体产物,m.p.261-263℃,MS:m/e=307.1(M+)。
按照实例48b)的通用方法,从乙酰肼与溴化氰反应制备上述反应中使用的5-甲基[1,3,4]噁二唑-2-基胺,其为白色固体,MS:m/e=99(M+)。
实施例51
N-(5-甲基-[1,3,4]-噁二唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从5-甲基-[1,3,4]-噁二唑-2-基胺和2,2-二苯乙酰氯制备标题化合物,其为白色固体产物,m.p.160-161℃,MS:m/e=293.1(M+)。
实施例52
9H-呫吨-9羧酸(5-甲氧基甲基[1,3,4]噁二唑-2-基)酰胺
按照实施例48a)的通用方法,从(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)甲酮和5-甲氧基甲基-[1,3,4]噁二唑-2-基胺制备标题化合物,其为白色固体,m.p.233-234℃,MS:m/e=337.1(M+H+)。
按照实例48b)的通用方法,从甲氧基乙酰肼[J.Org.Chem.USSR,6(1),93(1970)]和溴化氰反应制备上述反应中使用的5-甲氧基甲基-[1,3,4]噁二唑-2-基胺,其为白色固体,m.p.113-114℃,MS:m/e=129.2(M+)。
实施例53
]N-(5-甲氧基甲基-[1,3,4]噁二唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从2,2-二苯乙酰氯和5-甲氧基甲基-[1,3,4]-噁二唑-2-基胺制备标题化合物,其为白色固体,m.p.138-140℃,MS:m/e=324.3(M+H+)。
实施例54
9H-呫吨-9羧酸[5-(2-甲氧基乙基)-[1,3,4]噁二唑-2-基]酰胺
按照实施例44a)的通用方法,从(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)-甲酮和[5-(2-甲氧基乙基)-[1,3,4]噁二唑-2-基]胺制备标题化合物,其为白色固体,m.p.204℃,MS:m/e=351.1(M+H+)。
按照实例48b)的通用方法,从3-甲氧基丙酰肼[US 3441606]与溴化氰制备上述反应中所使用的[5-(2-甲氧基乙基)-[1,3,4]噁二唑-2-基]胺,其为白色固体,m.p.105-106℃,MS:m/e=143.1(M+)。
实施例55
N-[5-(2-甲氧基乙基)-[1,3,4]-噁二唑-2-基]-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从2,2-二苯乙酰氯和[5-(2-甲氧基乙基)-[1,3,4]-噁二唑-2-基]胺制备标题化合物,其为白色固体,m.p.114-115℃,MS:m/e=338.2(M+H+)。
实施例56
9H-呫吨-9羧酸(5-环丙基-[1,3,4]噁二唑-2-基)酰胺
按照实施例48a)的通用方法,从(3,5-二甲基吡唑-1-基)-(9H-呫吨-9-基)甲酮和5-环丙基-[1,3,4]噁二唑-2-基]胺[J.Med.Pharm.Chem.
5,617(1962)]制备标题化合物,其为白色固体,m.p.246-248℃,MS:m/e=333.1(M+H+)。
实施例57
N-(5-环丙基-[1,3,4]-噁二唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从2,2-二苯乙酰氯和5-环丙基-[1,3,4]-噁二唑-2-基胺制备标题化合物,其为白色固体,m.p.159-160℃,MS:m/e=320.3(M+H+)。
实施例58
9H-呫吨-9-羧酸(5-环丙基甲基-[1,3,4]噁二唑-2-基)酰胺
按照实施例48a)的通用方法,从(3,5-二甲基吡唑-1-基)-(9H-呫吨-9-基)甲酮及5-环丙基甲基-[1,3,4]噁二唑-2-基胺制备标题化合物,其为白色固体产物,m.p.234-236℃,MS:m/e=347.1(M+H+)。
按照实例48b)的通用方法,从环丙基酰肼[J.Chem.Soc.PerkinTrans.2,1844(1974)]和溴化氰制备得上述反应使用的5-环丙基甲基-[1,3,4]噁二唑-2-基胺,其为白色固体,m.p.140-141℃,MS:m/e=139(M+)。
实施例59
N-(5-环丙基甲基-[1,3,4]-噁二唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从2,2-二苯乙酰氯和5-环丙基甲基-[1,3,4]-噁二唑-2-基胺制备标题化合物,其为白色固体,m.p.158-159℃,MS:m/e=334.3(M+H+)。
实施例60
9H-呫吨-9-羧酸(5-三氟甲基-[1,3,4]噁二唑-2-基)酰胺
按照实施例48a)的通用方法,从(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)甲酮和5-三氟甲基-[1,3,4]噁二唑-2-基胺[US 2883391]制备标题化合物,其为白色固体,m.p.220-223℃(分解),MS:m/e=362.2(M+H+)。
实施例61
N-(5-三氟甲基-[1,3,4]-噁二唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从2,2-二苯乙酰氯和5-三氟甲基-[1,3,4]-噁二唑-2-基胺制备标题化合物,其为白色固体,m.p.149-150℃,MS:m/e=347.2(M+)。
实施例62
9H-呫吨-9-羧酸(5-乙基-噁唑-2-基)酰胺
按照实施例44a)的通用方法,从5-乙基-噁唑-2-基胺[Ber.95,2419(1962)]和9-呫吨-甲酰氯制备标题化合物,其为白色固体产物,m.p.212-213℃,MS:m/e=320.1(M+)。
实施例63
N-(5-乙基-噁唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从5-乙基-噁唑-2-基胺和2,2-二苯乙酰氯制备标题化合物,其为白色固体产物,m.p.148-149℃,MS:m/e=307.3(M+H+)。
实施例64
9H-呫吨-9-羧酸(5-甲基-噁唑-2-基)酰胺,
按照实施例44a)的通用方法,从5-甲基-噁唑-2-基胺[Be r.95,2419(1962)]及9H-呫吨-甲酰氯制备标题化合物,其为白色固体产物,m.p.217-220℃,MS:m/e=306.1(M+)。
实施例65
N-(5-甲基-噁唑-2-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从5-甲基-噁唑-2-基胺和2,2-二苯乙酰氯制备标题化合物,其为白色固体,m.p.166-168℃,MS:m/e=292.2(M+)。
实施例66
9H-呫吨-9-羧酸(5-丙基-噁唑-2-基)-酰胺,
66a)按照实施例44a)的通用方法,从5-丙基-噁唑-2-基胺[Ber.
95,2419(1962)]和9H-呫吨-甲酰氯制备标题化合物,其为白色固体产物,m.p.203-205℃,MS:m/e=334.1(M+)。
66b)上述反应中使用的5-丙基-噁唑-2-基胺的制备方法如下:将21.8克(0.132mol)的2-溴丁醛[Chem.Ber.,
70,1898(1937)]溶于67.5毫升4∶3的DMF和水的混合溶液中。然后于搅拌下加入8.77克(0.145mol)的尿素。将澄清的无色溶液于105℃继续搅拌16小时。生成的淡黄色的溶液冷却至0℃,加入10毫升45%氢氧化钠溶液,溶液变为深黄色(pH12)。然后向反应液加入100毫升盐水并用100毫升9∶1的二氯甲烷:甲醇混合溶液萃取5次。浓缩合并的有机层,得到15.62克红棕色油状物,其经闪式硅胶色谱柱洗脱纯化,洗脱剂:二氯甲烷∶甲醇∶=9∶1,得到6.2克(0.049mol,37%)5-丙基-噁唑-2-基胺,其为黄色油状物,无需进一步纯化即可直接使用。MS:m/e=126.1(M+)。
实施例67
2,2--二苯基-N-(5-丙基-噁唑-2-基)-乙酰胺
按照实施例44a)的通用方法,从5-丙基-噁唑-2-基胺和2,2-二苯乙酰氯制备标题化合物,其为白色固体,m.p.122℃,MS:m/e=320.2(M+)。
实施例68
9H-呫吨-9-羧酸(4-甲基-噁唑-2-基)酰胺
按照实施例48a)的通用方法,从(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)甲酮和5-甲基-噁唑-2-基胺(DE2459380)制备标题化合物,为淡黄色固体,m.p.219-222℃,MS:m/e=306.1(M+)。
实施例69
N-(4-甲基)-噁唑-2-基)-2,2-二苯乙酰胺
按照实施例48a)的通用方法,从(3,5-二甲基-吡唑-1-基)-(9H-呫吨-9-基)-甲酮和5-甲基-噁唑-2-基胺制备标题化合物,其为白色固体,m.p.209-211℃,MS:m/e=306.1(M+)。
实施例70
N-(3-甲基-[1,2,4]噁二唑-5-基)2,2-二苯乙酰胺
按照实施例44a)的通用方法,从3-甲基-[1,2,4]-噁二唑-5-基胺(Helv.Chim.Acta,49(1966),1430-1432)和2,2-二苯乙酰氯制备标题化合物,其为白色固体,m.p.215℃,MS:m/e=293(M+)。
实施例71
9H-呫吨-9-羧酸(3-甲基-[1,2,4]噁二唑-5-基)酰胺
按照实施例44a)的通用方法,从3-甲基-[1,2,4]-噁二唑-5-基胺和9H-呫吨-甲酰氯制备标题化合物,其为白色固体,m.p.208℃,MS:m/e=307(M+)。
实施例72
N-(3-环丙基)-[1,2,4]噁二唑-5-基]-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从3-环丙基-[1,2,4]-噁二唑-5-基胺(Helv.Chim.Act,49(1966),1430-1432)和2,2-二苯乙酰氯制备标题化合物,其为白色固体,m.p.163℃,MS:m/e=219(M+)。
实施例73
9H-呫吨-9-羧酸(3-环丙基-[1,2,4]-噁二唑-5-基)酰胺
按照实施例44a)的通用方法,从3-环丙基-[1,2,4]-噁二唑-5-基胺和9H-呫吨-甲酰氯制备标题化合物,其为白色固体,m.p.275℃,MS:m/e=333(M+)。
实施例74
N-(5-甲基-[1,2,4]噁二唑-3-基)-2,2-二苯乙酰胺
按照实施例44a)的通用方法,从5-甲基-[1,2,4]-噁二唑-3-基胺[EP 413545]与2,2-二苯乙酰氯制备标题化合物,其为白色固体,m.p.153℃,MS:m/e=293(M+)。
实施例75
9H-呫吨-9-羧酸(5-甲基-[1,2,4]-噁二唑-3-基)酰胺
按照实施例44a)的通用方法,从5-甲基-[1,2,4]噁二唑-3-基胺及9H-呫吨-甲酰氯制备标题化合物,其为白色固体,m.p.186℃,MS:m/e=307(M+)。
实施例A
按常规方法制备下列组合物的片剂:
毫克/片
活性成分 100
粉末状乳糖 95
白色玉米淀粉 35
聚乙烯吡咯烷酮 8
羧甲基淀粉钠 10
硬脂酸镁 2
片重:250
实施例B
按常规方法制备下列组合物的片剂:
毫克/片
活性成分 200
粉末状乳糖 100
白色玉米淀粉 64
聚乙烯吡咯烷酮 12
羧甲基淀粉钠 20
硬脂酸镁 4
片重:400
实施例C
制备下列组合物的胶囊:
毫克/片
活性成分 50
晶状乳糖 60
微晶纤维素 34
滑石粉 5
硬脂酸镁 1
胶囊填重:150
先将粒度大小适合的活性成分、晶状乳糖以及微晶纤维素彼此混匀,过筛,然后再将滑石粉和硬脂酸镁与其混合。将最终的混合物装填入大小合适的硬胶囊中。
Claims (6)
2、权利要求1中所述的式I化合物,其中A1和A2代表苯基,并且X代表-O-。
3、按照权利要求2所述的化学式I表示的化合物,它们是:
9H-呫吨-9-羧酸噁唑-2-基酰胺,
9H-呫吨-9-羧酸(5-丙基-[1,3,4]噁二唑-2-基)-酰胺,
9H-呫吨-9-羧酸(5-乙基-噁唑-2-基)-酰胺,
9H-呫吨-9-羧酸(5-甲基-噁唑-2-基)-酰胺,
9H-呫吨-9-羧酸(5-丙基-噁唑-2-基)-酰胺,
9H-呫吨-9-羧酸(5-乙基-[1,3,4]噁二唑-2-基)-酰胺,
9H-呫吨-9-羧酸(4-甲基-噁唑-2-基)-酰胺,
9H-呫吨-9-羧酸(3-甲基-[1,2,4]噁二唑-5-基)-酰胺,
9H-呫吨-9-羧酸(5-三氟甲基-[1,3,4]噁二唑-2-基)-酰胺,
或者
9H-呫吨-9-羧酸(5-甲基[1,2,4]噁二唑-3-基)-酰胺。
4、用于控制或预防急性和/或慢性神经性失调的药物,该药物包含权利要求1-3中任一项所述化合物或其可药用盐和可药用赋形剂。
5、权利要求1-3中任一项所述的式I化合物在制备用于控制或预防急性和/或慢性神经性失调的药物中的用途。
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TW200715993A (en) | 2005-06-15 | 2007-05-01 | Senomyx Inc | Bis-aromatic amides and their uses as sweet flavor modifiers, tastants, and taste enhancers |
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PL2083811T3 (pl) | 2006-11-22 | 2017-05-31 | Clinical Research Associates, Llc | Sposoby leczenia zespołu downa, zespołu łamliwego chromosomu x oraz autyzmu |
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EP2093234A1 (en) | 2008-02-08 | 2009-08-26 | Nutrinova Nutrition Specialties & Food Ingredients GmbH | Oligopeptides for use as taste modulators |
TWI429404B (zh) | 2008-03-03 | 2014-03-11 | Senomyx Inc | 異山梨醇衍生物及彼等作為風味改良劑、促味劑及促味增強劑之用途 |
WO2010089119A1 (en) | 2009-02-04 | 2010-08-12 | Recordati Ireland Limited | Heterocyclic derivatives as m-glu5 antagonists |
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