CN100338055C - 2－杂环－1,2－乙二醇的氨基甲酸酯 - Google Patents

2－杂环－1,2－乙二醇的氨基甲酸酯 Download PDF

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CN100338055C
CN100338055C CNB028124472A CN02812447A CN100338055C CN 100338055 C CN100338055 C CN 100338055C CN B028124472 A CNB028124472 A CN B028124472A CN 02812447 A CN02812447 A CN 02812447A CN 100338055 C CN100338055 C CN 100338055C
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thienyl
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methane amide
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崔溶文
李基好
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Abstract

说明2-杂环-1，2-乙二醇的氨基甲酸酯化合物。所述化合物能有效地治疗中枢神经系统症状，尤其是作为抗惊厥剂或者抗癫痫药。

Description

2-杂环-1，2-乙二醇的氨基甲酸酯
技术领域
本发明涉及用于治疗中枢神经系统症状的药用化合物，尤其是用作抗惊厥剂、抗癫痫药、神经保护剂和肌肉松弛剂。更特别的是，本发明涉及2-杂环-1，2-乙二醇的氨基甲酸酯。
技术背景
已知芳基链烷醇的手性或外消旋氨基甲酸酯化合物可以用作抗癫痫药和肌肉松弛剂。在美国专利No.5,854,283中，已经发现卤化的2-苯基-1，2-乙二醇的单氨基甲酸酯以及2-苯基-1，2-乙二醇的二氨基甲酸酯的光学纯的形式能有效治疗中枢神经系统症状，尤其是作为抗惊厥剂或抗癫痫药。
在Toxicol.和Appl.Pharm.2，397-402(1960)中提到(2-苯基-2-乙氧基)氧代甲酰胺能有效地作为抗癫痫药。在J.Pharmacol.Exp.Ther.，104，229(1952)中已经说明了2-甲基-3-丙基-1，3-丙二醇的二氨基甲酸酯及其药效。
在美国专利No.2,884,444中，已经揭示了2-苯基-1，3-丙二醇的二氨基甲酸酯。在美国专利No.2,937,119中，也揭示了氨基甲酸酯，如异丙基2-甲基-2丙基-1，3丙二醇二(氨基甲酸酯)。
目前，在治疗中枢神经系统症状中已经使用上述的一些氨基甲酸酯。
本发明中，提供了2-杂环-1，2-乙二醇的氨基甲酸酯，包括含有上述氨基甲酸酯活性成分的药物组合物，以及使用所述药物组合物治疗中枢神经系统症状的方法。
发明内容
本发明涉及通式I所示的化合物及其医药上可接受的盐，以及它们的对映体，以及对映体混合物。
Figure C0281244700041
式中，A是杂环部分，它任选地被一个或多个选自烷基、芳基、卤素、三卤代甲基、三卤代甲氧基、三烷基甲硅烷基、S(O)R、SO2R、SO2NRR’、SO3R、SR、NO2、NRR’、OR、CN、C(O)R、OC(O)R、NHC(O)R、CO2R和CONRR’的取代基取代；其中，R和R’各自为氢、烷基或芳基；B1和B2各自为羟基或OCONR1R2，其前提是B1和B2不同时为羟基，且R1和R2分别选自氢、羟基、烷基、烷氧基、烷芳基、芳烷基、芳基和芳氧基。
使用通式I所示化合物、其对映体以及对映体混合物及其医药上可接受的盐来治疗中枢神经系统症状，尤其是作为抗惊厥剂、抗癫痫药、神经保护剂和中枢活性肌肉松弛剂。
具体实施方式
本发明涉及通式I所示的化合物及其医药上可接受的盐，
Figure C0281244700051
式中，A是杂环部分，它任选地被一个或多个选自烷基、芳基、卤素、三卤代甲基、三卤代甲氧基、三烷基甲硅烷基、S(O)R、SO2R、SO2NRR’、SO3R、SR、NO2、NRR’、OR、CN、C(O)R、OC(O)R、NHC(O)R、CO2R和CONRR’的取代基取代；其中，R和R’各自为氢、烷基或芳基；B1和B2各自为氢或OCONR1R2，其前提是B1和B2不同时为羟基，且R1和R2分别选自氢、羟基、烷基、烷氧基、烷芳基、芳烷基、芳基和芳氧基和它们的对映体，以及对映体混合物。
本发明优选的化合物是通式I所示的化合物，其中，A选自
Figure C0281244700052
式中，R3、R4和R5分别选自氢、烷基和芳基，X选自硫、氧和氮。
本发明更加优选的化合物是通式I所示的化合物，其中，A是
Figure C0281244700061
式中，R3、R4和R5如上所述。
通式I所示说明性化合物如下：
(±)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(+)-(2R)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(-)-(2S)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(5-三氟甲基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(5-溴-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
N-甲基-(2-(5-氯-2-噻吩基)-2-N-甲基氨基甲酰氧乙基)氧代甲酰胺，
(2-(5-苯基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(3，4，5-三氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(5-甲基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(2，5-二氯-3-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，
(2-(2-苯并噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，和
(2-(5-叔丁基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺。
在本文中，术语“低级烷基”是指具有1-6个碳原子的直链或支链烷基，如甲基、乙基、异丙基、丁基、戊基、己基等，优选甲基。术语“卤素”是指所用的卤素即溴、氯、氟和碘，优选溴和氯。术语“低级烷氧基”是指低级烷基醚的基团，其中，所述低级烷基部分如上所述，如甲氧基、乙氧基、丙氧基、丁氧基等，优选甲氧基。
通式I中A所示杂环基团的其它例子包括如下：
Figure C0281244700062
Figure C0281244700071
其中，R10可以相同或不同，表示选自氢、烷基、芳基、卤素、三卤代甲基、三卤代甲氧基、三烷基甲硅烷基、S(O)R、SO2R、SO2NRR’、SO3R、SR、NO2、NRR’、OR、CN、C(O)R、OC(O)R、NHC(O)R、CO2R和CONRR’的取代基，m＝1-3，且R和R’分别选自氢、烷基和芳基。
本发明化合物用的原料由以下通式表示：
Figure C0281244700072
式中，A是上述的杂环。这些2-杂环-1，2-乙二醇，其本身是已知的，或者可以通过相应苯乙烯化合物进行双羟基化反应来制备。按照K.Sharpless等在J.Org.Chem 56：4585-8(1991)中所述的步骤可以制备光学活性二醇。
以上通式I所示B1和B2中仅有一个是氨基甲酸酯基团的化合物可以通过反应途径1中所述的合成方法制备，其详细说明如下。在催化量甲醇钠的存在下，使2-杂环-1，2-乙二醇原料和碳酸二甲酯反应。通过真空蒸馏除去所形成的副产物，并在真空中干燥所残留的产物。之后，将所述反应粗产物溶解在低级链烷醇如甲醇中，并在室温下往所述反应溶液中加入过量的胺，提供2-杂环-1，2-乙二醇的单氨基甲酸酯的位置异构形式。
反应途径1
Figure C0281244700081
本发明化合物其中的B1和B2均为氨基甲酸酯基团且所述氨基甲酸酯基团相同的化合物可以按照以下反应途径2所述的反应直接从2-杂环-1，2-乙二醇原料制备。所述2-杂环-1，2-乙二醇溶解在二氯甲烷中，并用约2当量的羰基二咪唑处理。搅拌所得混合物，直到通过薄层色谱分析不能观察到所述原料为止，然后用过量的胺(R1R2NH，其中，R1和R2如上所述)处理所述混合物。所述反应进行24小时完成。用水性溶液进行常规洗涤之后，通过快速色谱柱或者重结晶纯化所述反应粗产物，提供通式I所需的化合物。
反应途径2
Figure C0281244700091
按反应途径3由通式I所示的相应单氨基甲酸酯化合物可以制备本发明其中B1和B2均为氨基甲酸酯基团，且所述氨基甲酸酯基团不同的化合物。用约1当量羰基二咪唑处理所述2-杂环-1，2-乙二醇单氨基甲酸酯。搅拌所得混合物，直到通过薄层色谱分析不能观察到所述原料为止，然后用过量的胺(R1R2NH，其中，R1和R2如上所述，但是至少其中一个和原料的那些不同)处理所述混合物。
反应途径3
Figure C0281244700092
本发明中2-杂环-1，2-乙二醇原料的例子如下：
1-(2-噻吩基)-1，2-乙二醇，
1-(5-氯-2-噻吩基)-1，2-乙二醇，
1-(5-苯基-2-噻吩基)-1，2-乙二醇，
1-(3，4，5-三氯-2-噻吩基)-1，2-乙二醇，
1-(2-苯并噻吩基)-1，2-乙二醇，
1-(5-氰基-2-噻吩基)-1，2-乙二醇，
1-(2-呋喃基)-1，2-乙二醇等。
本发明的化合物包含手性中心。通式(I)所示的化合物在其位置上包含不对称碳原子，它是邻近杂芳环的脂族碳原子。本发明的范围包括纯对映体形式和对映体混合物，其中，一种对映体在通式I所示化合物中占多数。较好是，一种对映体约占90％或更多，最好是约98％或更多。
本发明通式I所示具有碱性胺官能团如氨基、吡啶基或咪唑基的化合物可以和无机酸和有机酸一起形成盐，所述酸包括盐酸、氢溴酸、甲磺酸等。这些盐可以按本领域那些技术人员已知的步骤制备。
在利用本发明化合物治疗中枢神经系统症状，尤其是治疗惊厥、癫痫、神经性疼痛、中风和肌肉痉挛时，优选口服所述化合物。此外，由于通式I所示的化合物可以口服吸收，就不必进行肠道外给药。对于口服给药，通式I所示的化合物较好和药物载体混合。所述载体和通式I所示化合物的比例对需要这种治疗的患者中枢神经系统产生所需效果来说并不重要，并且根据所述组合物是加入胶囊中或者形成药片，所述比例可以改变。在药片中，通常要求使用至少和药物载体一样多的医药活性成分。可以使用各种药物载体或混合物。合适的载体包括乳糖、二代磷酸钙和玉米淀粉。也可以加入其它药物可接受的合适成分，包括润滑剂如硬脂酸镁。
使用常规惰性药物辅助物质将通式I所示的化合物配制成适于口服或肠道外给药的剂型。这种剂型包括药片、悬浮液、溶液等。而且，本发明的化合物可以以硬胶囊或软胶囊的形式给药。在将通式I所示化合物配制成口服和肠道外剂型中所用惰性辅助物质的合适例子对本领域的技术人员来说是显而易见的。这些辅助物质包括水、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、树胶、聚亚烷基二醇等。此外，若需要的话，可以将防腐剂、稳定剂、润湿剂、乳化剂、用于改变渗透压的盐、缓冲剂等加入这种制剂中。
通过“最大电激疗法(MES)”试验已经确定了通式I所示的化合物作为抗惊厥剂的治疗用途，所述试验是熟知的抗局部惊厥的抗惊厥剂用的药理筛选法，其结果列于表I中。在抗惊厥剂用MES试验中使用的步骤如下。在盐水中制备待测化合物的药剂溶液。对试验对象即小鼠(ICR属)通过腹膜内注射给药。在经过规定时间后，使用IITC Life Science 11A型Shocker以50mA-60Hz通过角膜电极将最大电激导入小鼠中0.2秒。通过消除导入最大电激时后肢激励延迟来证实抗惊厥活性。使用三种不同剂量水平以每组至少6只小鼠测定中等功效剂量(ED50)水平。ED50值较小的化合物更加具有作为抗惊厥剂的潜力。
也可以进行用于抗惊厥活性的“戊四唑(PTZ)”试验。已知对抗皮下PTZ诱发惊厥的化合物能提高惊厥的极限，由此它们通常用于防止这种惊厥。在抗惊厥剂的PTZ试验中使用的步骤如下。在盐水中制备所述化合物药剂溶液，通过腹膜内注射对小鼠(ICR属)给药。指定时间后，将100mg/kg PTZ(CD70药剂)通过皮下注射到各动物中，并观察最多30分钟，确定是否存在持续2秒或更长的极限痉挛惊厥。使用三种不同剂量水平以每组至少8只小鼠测定中等功效剂量(ED50)水平。ED50值较小的化合物更加具有作为抗惊厥剂的潜力。
表I中列出了本发明通式I所示化合物的试验结果。
                                 表I
  实施例的化合物   MES ED50(mg/kg)   PTZ ED50(mg/kg)   小时
  4   16.9   31.3   2
  5   8.4   47.2   2
  6   36.9   42.7   2
  7   37.4   -   1
  14   12.6   -   1
  17   14.9   50   1
  18   19.6   -   1
表I中的数据证实了本发明通式I所述的化合物通过防止电激痉挛出现而具有抗惊厥活性，也防止患者出现戊四唑产生的惊厥。
以上述任何一种剂型存在的通式I所示化合物的量是可变的。在用通式I所示活性量的化合物综合治疗CNS症状时，不论给药的途径，以单剂量或分剂量形式，所述剂量通常约为0.02-250mg/kg/天(对体重为50kg的普通人来说为0.001-12.5g/天)。更加优选的剂量范围约为0.15-250mg/kg/天。当然，根据具体化合物和个症的具体性状，主治医师可以开出超过这一范围的剂量。
以下通过实施例进一步说明本发明。除另有说明外，所有的份数均以重量计，且所有的温度均以摄氏度表示。此外，除非另有说明，NMR光谱在200MHz下获得，熔点均未修正，并使用自动旋光计测量旋光性。
实施例1
制备(±)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
在5℃下，将1，1’-羰基二咪唑(4.5g)加入1-(2-噻吩基)-1，2-乙二醇(1.0g，6.9mmol)在二氯甲烷(15ml)的溶液中。在搅拌过程中，使所述反应混合物在1小时内达到室温。在5℃下加入10ml氢氧化铵水溶液(28％氨水)。在室温下搅拌所述反应混合物1小时，用乙酸乙酯萃取，并用0.5N盐酸水溶液、饱和碳酸氢钠和盐水洗涤。经过硫酸钠干燥所述萃取物，过滤，浓缩并由二氯甲烷进行重结晶来纯化，由此制得呈白色固体的标题化合物(1.2g，产率74％)。熔点158-159℃(由二氯甲烷结晶)。[α]D 24’＝0’(c＝0.005，甲醇)。
实施例2
制备(+)-(2R)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了使用(+)-(1R)-1-(2-噻吩基)-1，2-乙二醇(熔点48-50℃，由四氯化碳结晶)代替(±)1-(2-噻吩基)-1，2-乙二醇外，按实施例1所述的步骤制备标题化合物。(熔点184-185℃，由二氯甲烷结晶)[α]D 24’＝+63(c＝0.005，甲醇)。
实施例3
制备(-)-(2S)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了使用(-)-(1S)-1-(2-噻吩基)-1，2-乙二醇(熔点48-50℃，由四氯化碳结晶)代替(±)1-(2-噻吩基)-1，2-乙二醇外，按实施例1所述的步骤制备标题化合物。(熔点184-185℃，由二氯甲烷结晶)[α]D 24’＝-56(c＝0.005，甲醇)。
实施例4
制备(±)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了使用(±)-1-(5-氯-2-噻吩基)-1，2-乙二醇(熔点50-51℃，由四氯化碳结晶)代替(±)-1-(2-噻吩基)-1，1-乙二醇外，按实施例1所述的步骤制备标题化合物。(熔点154-156℃，由二氯甲烷结晶)[α]D 24’＝0’(c＝0.005，甲醇)。
实施例5
制备(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了使用(+)-(1R)-1-(5-氯-2-噻吩基)-1，2-乙二醇(熔点78-80℃，由四氯化碳结晶)代替(±)-1-(2-噻吩基)-1，1-乙二醇外，按实施例1所述的步骤制备标题化合物。(熔点185-186℃，由二氯甲烷结晶)[α]D 24’＝+55(c＝0.005，甲醇)。
实施例6
制备(-)-(2S)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了使用(-)-(1S)-1-(5-氯-2-噻吩基)-1，2-乙二醇(熔点77-78℃，由四氯化碳结晶)代替(±)-1-(2-噻吩基)-1，1-乙二醇外，按实施例1所述的步骤制备标题化合物。(熔点185-186℃，由二氯甲烷结晶)[α]D 24’＝-52(c＝0.005，甲醇)。
实施例7
制备N-甲基-(2-(5-氯-2-噻吩基)-2-N-甲基氨基甲酰氧乙基)氧代甲酰胺
除了使用甲胺代替氢氧化铵外，按实施例1所述的步骤制备标题化合物(熔点104-106℃，由己烷∶乙酸乙酯＝5∶1结晶)。
实施例8
制备(2-(5-苯基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了使用1-(5-氯-2-噻吩基)-1，2-乙二醇(熔点77-78℃，由四氯化碳结晶)代替(±)-1-(2-噻吩基)-1，1-乙二醇外，按实施例1所述的步骤制备标题化合物(熔点202-203℃，由二氯甲烷结晶)。
实施例9
制备(2-(3，4，5-三氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(3，4，5-三氯-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物(熔点193-197℃，由二氯甲烷结晶)。
实施例10
制备(2-(5-甲基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(5-甲基-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物(熔点172-173℃，由二氯甲烷结晶)。
实施例11
制备(2-(2，5-二氯-3-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(2，5-二氯-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物(熔点137-138℃，由乙醚结晶)。
实施例12
制备(2-(3-三氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(3-三氯-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物(熔点153-155℃，由二氯甲烷结晶)。
实施例13
制备(2-(2-苯并噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(2-苯并噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物熔点195℃，(由二氯甲烷结晶)。
实施例14
制备(2-(5-三氟甲基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(5-三氟甲基-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物熔点159-160℃，(由二氯甲烷结晶)。
实施例15
制备(2-(5-叔丁基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(5-叔丁基-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物熔点132-155℃，(由四氢化碳结晶)。
实施例16
制备(2-(5-氰基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(5-氰基-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物熔点149-151℃，(由二氯甲烷结晶)。
实施例17
制备(±)-(2-(5-溴-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
将N-溴琥珀酰亚胺(1.79g)一次加入(±)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺(2.2g，9.5mmol)在40ml氯仿和乙酸1∶1的混合物中的溶液中。搅拌所得悬浮液24小时。然后，用相等体积的水稀释所述反应混合物，并回收分离的有机层，之后用氢氧化钾溶液和水洗涤。经过硫酸钠干燥所述萃取物，过滤，浓缩并由二氯甲烷进行重结晶来纯化，由此制得呈白色固体的标题化合物(2.2g)。熔点160-161℃(由二氯甲烷结晶)。
实施例18
制备(+)-(2R)-(2-(5-溴-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用(+)-(2R)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺作为原料，按实施例17所述的步骤制备所述标题化合物。熔点181-182℃(来自二氯甲烷)。[α]D 24’＝+46’(c＝0.005，甲醇)。
实施例19
制备(-)-(2S)-(2-(5-溴-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
除了所述原料是(-)-(2S)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺，代替(±)-(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺外，按实施例17所述的步骤制备所述标题化合物。熔点181-182℃(来自二氯甲烷)。[α]D 24’＝-46’(c＝0.005，甲醇)。
实施例20
制备(2-(5-硝基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
将(2-(2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺(0.50g)悬浮在4ml乙酸酐中，并将所得混合物冷却至0℃。滴加硝酸(在水中60％，0.37g)在1ml乙酸的混合物，并在室温下搅拌所述混合物1.5小时，将其倒入100ml冰水中，用乙酸乙酯萃取，并用饱和盐水洗涤。经过硫酸钠干燥所述萃取物，过滤，浓缩并由醚进行重结晶来纯化，由此制得呈黄色固体的标题化合物(0.07g，产率12％)。熔点145-147℃(来自醚)。
实施例21
制备(2-(2-噻吩基)-2-羟乙基)氧代甲酰胺
在5℃下，将1，1’-羰基二咪唑(1.13g)加入1-(2-噻吩基)-1，2-乙二醇(1.0g)在20ml二氯甲烷的溶液中。将所述反应混合物升至室温，搅拌1小时，然后，在真空中浓缩，经色谱纯化之后制得呈无色油状的碳酸1-(2-噻吩基)-2-羟乙基)-1，2-乙二醇酯(1.07g，产率90.7％)。将所述产物溶解在20ml四氢呋喃中，并在0℃下往其中加入2g氢氧化铵(相当于28％的氨水)。将所述反应混合物缓慢升至室温，并再搅拌1小时，然后真空中浓缩，经色谱纯化之后制得呈白色固体的(2-(2-噻吩基)-2-羟乙基)氧代甲酰胺(0.30g，产率25％)。熔点71-73℃(来自二氯甲烷)。
实施例22
制备(2-(5-氯-2-噻吩基)-2-羟乙基)氧代甲酰胺
使用1-(5-氯-2-噻吩基)-1，2-乙二醇作为原料，按实施例21所述的步骤制备标题化合物。熔点68-72℃(来自苯)。
实施例23
制备(2-(5-氯-2-噻吩基)-2-氨基甲酰基氧基)乙-1-醇
在5℃下，将咪唑(0.45g)加入1-(5-氯-2-噻吩基)-1，2-乙二醇(1.0g，5.6mmol)和氯化叔丁基二甲基甲硅烷(0.80g)在N，N-二甲基甲酰胺(5ml)的溶液中。使所述反应混合物升至室温，并搅拌1小时，用乙酸乙酯萃取，并用0.5N盐酸水溶液、饱和碳酸氢钠和盐水洗涤。经过硫酸钠干燥所述萃取物，过滤并在真空中浓缩。经过色谱纯化之后制得无色油状物1-叔丁基二甲基甲硅烷氧基-2-(5-氯-2-噻吩基)乙-1-醇(1.14g)。在5℃下将1，1’-羰基二咪唑(0.95g)加入上述醇(1.14g，3.9mmol)在二氯甲烷(20ml)的溶液中。使所述反应混合物升至室温，并搅拌1小时。在5℃下加入氢氧化铵(相当于28％的氨水，10ml)。在室温下搅拌反应混合物1小时，用乙酸乙酯萃取，用0.5N盐酸水溶液、饱和碳酸氢钠和盐水洗涤。经过硫酸钠干燥所述萃取物，过滤并在真空中浓缩。经过色谱纯化之后制得无色油状物1-叔丁基二甲基甲硅烷氧基-2-(5-氯-2-噻吩基)-2-氨基甲酰氧基乙烷(0.47g)。
在5℃下将氟化四丁基铵(在2ml四氢呋喃中的0.1M溶液)加入以上形成的甲酰胺(0.47g，1.6mmol)在四氢呋喃(10ml)的溶液中。搅拌反应混合物1小时，用乙酸乙酯萃取，用0.5N盐酸水溶液、饱和碳酸氢钠和盐水洗涤。经过硫酸钠干燥所述萃取物，过滤并在真空中浓缩。经过色谱纯化之后制得白色固体(2-(5-氯-2-噻吩基)-2-氨基甲酰氧基)乙-1-醇(0.14g)。熔点，117-120℃(来自二氯甲烷)。
实施例24
制备(2-(2-吡啶基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(2-吡啶基)-1，2-乙二醇代替1-(2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物。熔点173-174℃(来自二氯甲烷)。
实施例25
制备(2-(2-吡啶基)-2-羟乙基)氧代甲酰胺
使用1-(2-吡啶基)-1，2-乙二醇作为原料，按实施例21所述的步骤制备标题化合物。熔点116-120℃(来自二氯甲烷)。
实施例26
制备(2-(2-吡啶基)-2-氨基甲酰氧)乙-1-醇
使用1-(2-吡啶基)-1，2-乙二醇作为原料，按实施例23所述的步骤制备标题化合物。熔点123-124℃(来自二氯甲烷)。
实施例27
制备N-甲基-(2-(2-吡啶基)-2-(N-甲基氨基甲酰氧乙基)氧代甲酰胺
使用甲胺代替氢氧化铵，按实施例1所述的步骤制备标题化合物。熔点114-115℃，(来自氯仿/醚)。
实施例28
制备(2-(2-呋喃基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(2-呋喃基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物。熔点155-156℃(来自二氯甲烷)。
实施例29
制备(2-(4-甲基-5-噻唑基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(4-甲基-5-噻唑基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物。熔点166-168℃(来自二氯甲烷)。
实施例30
制备(2-(2-吲哚基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(2-吲哚基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物。熔点145-146℃(来自二氯甲烷)。
实施例31
制备(2-(5-三甲基甲硅烷基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
使用1-(5-三甲基甲硅烷基-2-噻吩基)-1，2-乙二醇作为原料，按实施例1所述的步骤制备标题化合物。熔点138-140℃(来自二氯甲烷)。

Claims (12)

1.通式I所示的化合物及其医药上可接受的盐，和它们的对映体，以及对映体混合物，
Figure C028124470002C1
其特征在于，A是选自如下一组的杂环部分，
Figure C028124470002C2
R3、R4和R5分别选自氢、Cl、Br、CF3、烷基和芳基；B1和B2各自为羟基或OCONR1R2，其前提是B1和B2不同时为羟基，R1和R2分别选自氢和烷基。
2.权利要求1所述的化合物，其特征在于，所述化合物是纯对映体，或者是其中一种对映体占主要部分的对映体混合物。
3.权利要求1所述的化合物，其特征在于，B1和B2为OCONH2。
4.权利要求1所述的化合物，其特征在于，B1和B2中只有一个是OCONH2。
5.权利要求1所述的化合物，其特征在于，R3、R4和R5分别选自氢、烷基和芳基。
6.权利要求1所述的化合物，其特征在于，所述化合物是(±)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺。
7.权利要求1所述的化合物，其特征在于，所述化合物是(+)-(2R)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺。
8.权利要求1所述的化合物，其特征在于，所述化合物是(-)-(2S)-(2-(5-氯-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺。
9.权利要求1所述的化合物，其特征在于，所述化合物是(2-(5-三氟甲基-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺
10.权利要求1所述的化合物，其特征在于，所述化合物是(2-(5-溴-2-噻吩基)-2-氨基甲酰氧乙基)氧代甲酰胺。
11.一种用于治疗惊厥的药物组合物，所述组合物包含有效量的下式表示的化合物及其医药上可接受的盐，和它们的对映体，以及对映体混合物，
Figure C028124470003C1
其特征在于，A是选自如下一组的杂环部分，
Figure C028124470003C2
R3、R4和R5分别选自氢、Cl、Br、CF3、烷基和芳基；B1和B2各自为羟基或OCONR1R2，其前提是B1和B2不同时为羟基，且R1和R2分别选自氢、和烷基。
12.权利要求11所述的药物组合物，其特征在于，所述化合物是纯对映体，或者是其中一种对映体占主要部分的对映体混合物。
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