CN1158568A - 2，3-二氢-1(2，2，2-三氟乙基)-2-氧代-5-苯基-1h-1，4-苯并二氮杂䓬 - Google Patents
2，3-二氢-1(2，2，2-三氟乙基)-2-氧代-5-苯基-1h-1，4-苯并二氮杂䓬 Download PDFInfo
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- CN1158568A CN1158568A CN95195291A CN95195291A CN1158568A CN 1158568 A CN1158568 A CN 1158568A CN 95195291 A CN95195291 A CN 95195291A CN 95195291 A CN95195291 A CN 95195291A CN 1158568 A CN1158568 A CN 1158568A
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- China
- Prior art keywords
- trifluoroethyl
- dihydro
- oxo
- phenyl
- benzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及结构式(I)表示的作为抗心律失常药的新化合物和其所有各种异构形式的消旋物、对映体混合物、个别非对映体或个别对映体，以及它们的可药用盐、水合物或结晶形式其中X和Y各自独立地代表氢、氯、氟、溴、碘或三氟甲基，n是0、1或2，R是氢、氟、氯、溴、碘或三氟甲基、甲基或甲氧基。
Description
发明背景
心律失常经常作为诸如心肌梗塞形成和心力衰竭等心脏疾病的并发症发生。在严重的情形，心律失常会造成心室纤维性颤动并且能引起突然死亡。
虽然现在市场上已有各种抗心律失常药供应，但是还没有得到既有令人满意的效果、又是高度安全的药物。例如，根据Vaughan-Williams分类的第I类抗心律失常药会造成动作电位上向冲程最大速度(Vmax)的选择性抑制，不适合防止心室纤颤。另外，它们在安全性方面有问题，即，会引起心肌收缩力下降并且由于抑制了搏动传导而有诱发心律失常的倾向。β-肾上腺素能受体阻断剂和钙拮抗剂分属第II和第IV类，它们的缺点是其作用或是局限于一定类型的心律失常，或是因为它们的心抑制剂性能而不能用于患心血管疾病的某些病人。但是它们的安全性比第I类抗心律失常药要高。
第III类抗心律失常药是使动作电位的持续时间选择性延长而又不显著减少Vmax的药物。属于这一类的药物有限。诸如索他洛尔和胺碘酮等实例已显示出具有第III类性质。索他洛尔还具有第II类的作用，它可能引起心的抑郁，因此不能用于某些敏感的患者。另外，胺碘酮由于副作用而受到严重限制。这类药物预期在防止心室纤维性颤动方面有效。根据定义，纯的第III类药物不会象第I类抗心律失常药那样由于抑制动作电位传导而引起心肌收缩力下降或诱发心律失常。
发明概要
本发明涉及作为抗心律失常药的结构式(I)表示的新化合物及其所有各种异构形式的消旋物、对映体混合物、个别非对映体或个别对映体，以及它们的可药用的盐、水合物或结晶形式其中X和Y各自独立地是氢、氯、氟、溴、碘或三氟甲基，n是0、1或2；R是氢、氟、氯、溴、碘或三氟甲基、甲基或甲氧基。本发明还涉及含有一种这类新化合物作为活性组分的药物制剂。
本发明的化合物可以有不对称中心并以包括在本发明中的所有各种异构体形式的消旋物、对映体混合物、个别非对映体或个别对映体的形式存在。
本发明还涉及一种治疗心律失常的方法，其作法是使需要这种治疗的患者服用一种上述的新化合物或其制剂。发明详述
本发明的新化合物是作为抗心律失常药的用结构式I表示的化合物和所有各种异构体形式的消旋物、对映体混合物、个别非对映体或个别对映体，以及它们的可药用盐、水合物或结晶形式
其中X和Y各自独立地代表氢、氯、氟、溴、碘，或是三氟甲基，n是0、1或2，R是氢、氟、氯、溴、碘或三氟甲基、甲基或甲氧基。本发明的化合物可以有不对称中心并以包括在本发明中的所有各种异构体形式的消旋物、对映体混合物、个别非对映体或个别对映体的形式存在。
本发明还涉及一种治疗心律失常的方法，其作法是使需要治疗的患者服用一种这类新化合物或其制剂。
本发明的最优选的实施方案是(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
本发明新化合物的另一实施方案是(+)-3，5-二氯-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕苯甲酰胺
本发明新化合物的又一实施方案是(-)-2-(3，4-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
本发明新化合物的另一实施方案是(-)-2-(3，5-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
本发明实施方案的其它实例是：3-环己基-N-〔5-(2-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕丙酰胺3，4-二氯-N-〔5-(2-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕苯甲酰胺
(-)-2-〔3，5-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(4-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(3-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(2-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(2，4-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(3-氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
(-)-2-(4-氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4 〕二氮杂-3-基〕乙酰胺(+)-2-(3，5-二氯苯基)-N-〔2，3-二氢-2-氧代-5-(4-氟苯基)-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(2，4-二氯苯基)-N-〔2-氧代-5-(4-氟苯基)-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
(+)-2-〔3，5-双(三氟甲基)苯基〕-N-〔2-氧代-5-(4-氟苯基)-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔2-氧代-5-(4-氟苯基)-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺2-(3，5-二氯苯基)-N-〔2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
在下面的方案I中示意举例说明了一种制备本发明化合物的新方法，这些步骤在工艺上是众所周知的，并且/或者在随后的实施例中说明。
方案1
方案1续
本发明的新化合物具有第III类抗心律失常药所要求的药理性质，即，它们显示出QTc间期延长和与剂量有关的心室不应期增大。同时对心率、平均动脉血压以及PR和QPS间期无影响。观察到LV+dp/dt(左心室的压力随时间变化)有适度的变化。另外，这些化合物抑制由PVS(程序化心室刺激)诱发的快速性心律失常的发生。
这些化合物在治疗和预防所有各类心律失常方面有效，包括心室和动脉(室上)心律失常。本发明化合物特别适用于控制再发性心律失常和防止由于心室纤维性颤动导致的猝死。这些化合物在治疗和预防受损的心泵功能方面也有效。
在本发明治疗心律失常的新方法中，上述一种化合物或其可药用盐的服用量是每kg体重每天约0.0001至约10mg，优选每kg体重每天约0.0001至约2mg，最好是每kg体重每天经静脉内注入约0.0003至约0.3mg，或者在口服时每Kg体重每天约0.03至约1mg，一次服用或分成2-4次服用。
这些化合物或其可药用的盐按所述的剂量以口服、腹膜内、皮下、肌内、经皮、舌下或静脉内等方式用药。它们最好是静脉内或口服用药，例如以片剂、锭剂、胶囊、酏剂、悬浮液、乳剂、糖浆、糯米纸囊剂、咀嚼胶剂或者经工艺上认可的步骤制备的其它类似形式。在这类适用于治疗的组合物或制剂中，活性化合物应该有能得到合适剂量的数量。
这些化合物可以作为唯一的活性组分服用，或是与其它的抗心律失常药或其它的心血管药物结合服用，例如第I、II或IV类抗心律失常药、血管舒张药、血管紧张肽转化酶抑制剂、血管紧张肽II拮抗剂、利尿药或洋地黄。
可以与使用去纤维性颤动器(包括可植入的去纤维性颤动器)相配合服用这些化合物作为治疗心律失常和受损的心泵功能的一种方法。这些化合物减小去纤维性颤动器起动的频率。
第一类抗心律失常药是指这些药物对钠通道提供阻断作用，这包括具有膜稳定作用的那些化合物。这类化合物的实例是奎尼丁、普鲁卡因酰胺、双异丙吡胺、利多卡因、妥卡尼、氟卡尼和普罗帕酮。第二类抗心律失常化合物是阻断交感神经活性的药物。这类化合物的实例是普萘洛尔和醋丁洛尔。第III类抗心律失常药是延长有效不应期而又不改变静息膜电位或去极化速度的化合物。除了本发明的新化合物之外，诸如乙胺碘酮、溴苄铵和索他洛尔等化合物也被认为属于此类。第IV类抗心律失常药在阻断钙通道方面有效。这类化合物的实例是地尔硫卓和维拉帕米。在药物规划(Pharma Project)C1B，1993年5月号中可以找到对这些类别的进一步定义，该文献在这里引用作为参考。
血管舒张药的实例是例如罂粟碱和硝酸异山梨酯等化合物。血管紧张肽转化酶抑制剂的实例包括依那普利、赖诺普利和卡托普利。利尿剂的实例包括氢氯噻嗪和乙酰唑胺。这里列出的药剂只是实例，不代表本发明所考虑的许多这类化合物的完整名单。
这里提到的各种化合物作为抗心律失常药的活性按照以下实验方案通过测定它们阻断IKs和IKr电流的能力来确定。
外向钾电流是用在另文中详述〔Sanguinetti和Jurkiewicz，1990，心脏延迟整流器K+电流的两个组分：对于第III类抗心律失常药阻断作用的微分灵敏度。普通生理杂志(J.Gen.Physiol)，96：195-215〕的全细胞电压箱技术在单个豚鼠心室肌细胞中测定。肌细胞是用酶(胶原酶和蛋白酶)切消化法由兰根道尔夫法灌注的心脏分离。然后用充满0.5M葡萄糖酸钾、25mM KCl、5mM腺苷三磷酸二钾盐的1mm方孔移液吸管对单个细胞进行电压箱制。细胞浸泡在以下成分的溶液中：132mN NaCl，4mN KCl，1.2mN MgCl2，10mN HEPES，10mN葡萄糖，pH为7.2，温度35℃。
各细胞保持吸持电位-50mV。当电压由-85mV滑升到-50mV以及跃升到-10mV(0.5秒)和+50mV(1.0秒)时施加试验去极化作用。IKI是作为电压滑升期间的峰值外向电流测量。IKr是作为从-10mV到-50mV复极化时的尾电流测量。在调控期间测定电流，然后在暴露于两种不同浓度的药物之后再测定电流。
采用这种试验方法，本文所述的化合物作为IKs阻断剂的IC50小于100nM。本发明的化合物阻断IKs的能力比阻断IKr至少强10倍。
实施例
实施例1(+)-3，5-二氯-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂草-3-基〕苯甲酰胺
步骤A：2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)
-1H-苯并〔e〕〔1，4〕二氮杂的制备
将5-苯基-1，4-苯并二氮杂-2-酮〔J.Org.Chen.(有机化学杂志)，1962，27，3788〕(50g，0.211mole)在二甲基甲酰胺(100ml)中的溶液用碳酸铯(103.5g，0.317mole)和三氟乙基碘(109.7g，0.525mole)处理。将混合物在50℃搅拌过夜。然后将反应混合物倒入2L水中，用乙酸乙酯萃取(3×1L)。合并的乙酸乙酯级分用无水硫酸镁干燥，过滤，减压浓缩。残余物自乙醚中重结晶，得到45g(68％)产物。熔点130-131℃；1H NMR(CDCl3，300MHz)δ7.65-7.60(m，2H)，7.60-7.45(m，5H)，7.40-7.20(m，2H)，5.25(dp，J＝14，8.6Hz，1H)，4.82(d，J＝10.5Hz，1H)，4.15(近似六重峰，J＝8.6Hz，1H)，3.81(d，J＝10.5Hz，1H)步骤B：3-叠氮基-5-苯基-1-(2，2，2-三氟乙基)-1H-苯
并[e][1，4]二氮杂的制备
在搅拌下于15分钟内向冷却到-70℃的5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂(70g，0.22mol)在四氢呋喃(1500ml)中的溶液里逐滴加入叔丁醇钾(1.1当量，0.24mol，240ml在1N四氢呋喃中的溶液)。5分钟内加入2，4，6-三异丙基苯磺酰叠氮(74.8g，0.24mol)在四氢呋喃(250ml)中的溶液。搅拌10分钟，加入乙酸(40ml，0.63mol)，使反应物温热至环境温度。将反应物倒入饱和的NaHCO3(1500ml)和乙酸乙酯(11)中。分离出各相，水相用乙酸乙酯(500ml)萃取。合并的有机层依次用水(500ml)和盐水(300ml)洗。有机层用Na2SO4干燥，蒸发成褐色泡沫状物。将它用乙醚研制，得到65g白色粉末。将滤液浓缩，在硅胶上层析，用30％的乙酸乙酯/己烷洗脱，得到另外的8.9g。合并的产量为74g(93％)。熔点＝159-160℃；1H NMR(CDCl3，300MHz)δ7.70-7.26(m，9H)，5.28-5.12(m，1H)，4.63(s，1H)，4.35-4.10(m，1H)。步骤C：消旋的3-氨基-5-苯基-1-(2，2，2-三氟乙基)-1H
-苯并〔e〕〔1，4〕二氮杂的制备
在搅拌下向3-叠氮基-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并[e][1，4]二氮杂(83.4mmol，30g)在300ml乙醇和150ml四氢呋喃中的溶液里加入10％Pd/C(10％重量，3.0g)。向溶液中鼓入氢气8小时。将反应物过滤，减压蒸发。残余物自乙醚中结晶，得到20.0g白色晶体。从滤液蒸发和重结晶中得到另外的4g。总产率为86.7％。熔点＝141-143℃；1H NMR(CDCl3，300MHz)δ7.70-7.26(m，9H)，5.28-5.12(m，1H)，4.57(s，1H)，4.35-4.10(m，1H)。步骤D：2-氨基-N-〔2-氧代-5-苯基-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕-3-苯基丙酰胺的制备
在搅拌下向3-氨基-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂(92.2mmol，30.74g)在二甲基甲酰胺(300ml)中的溶液里加入N-苄氧基-D-苯基丙氨酸(92.2mmol，27.6g)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.12mol，22.95g)和1-羟基苯并三唑水合物(46.1mmol，6.23g)。在室温下搅拌2小时。然后用1L 10％KHSO4稀释，用乙酸乙酯(2×600ml)萃取。将有机层合并，用饱和的碳酸氢钠溶液(600ml)洗。将其用盐水和硫酸钠干燥，减压蒸发。得到66.58g橙色泡沫状物，根据NMR其中含有乙酸乙酯。NMR1H(CDCl3)δ7.75-7.18(m，20H)，5.62-5.55(m，1H)，5.48-5.00(m，4H)，4.72-4.60(m，1H)，4.25-4.05(m，1H)，3.32-3.05(m，2H)。此物质不经进一步纯化直接用于下一步骤。
在搅拌下向2-(N-苄氧基氨基)-N-〔2-氧代-5-苯基-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂草-3-基〕-3-苯基丙酰胺1L乙醇中的溶液里加入10％Pd/C(15％重量)，向反应物中鼓入氢气2小时，然后在1个大气压的氢气下搅拌过夜。次日上午再向反应物中鼓入氢气3小时。然后将反应物过滤，催化剂用1L二氯甲烷洗，减压蒸发。所得的固体真空干燥过夜，得到44.46g白色固体。将其在硅胶上层析，用1％MeOH∶EtOAc洗脱。收集较高Rf的纯级分并减压蒸发。收集混合级分，蒸发并再层析。收集纯的级分，与上述的纯级分合并，得到较高Rf非对映体的总产量为18.11g，产率83.5％。1H NMR(CDCl3，300MHz)δ8.94(d，J＝8.6Hz，1H)，7.65-7.10(m，9H)，5.64(d，J＝8.6Hz，1H)，5.28-5.12(m，1H)，4.57(s，1H)，4.35-4.10(m，1H)，3.71(dd，J＝9.8和3.9Hz，1H)，3.34(dd，J＝13.9和3.9Hz，1H)，2.79(dd，J＝13.9和10.0Hz，1H)。用X-射线分析确定，在苯并二氮杂的C-3上绝对立体化学构型为(R)。
相应于C-3(S)的低Rf的物质也同样分离。步骤E：3(R)-(+)-3-氨基-5-苯基-1-(2，2，2-三
氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂的制备
在搅拌下向2-氨基-N-〔2-氧代-5-苯基-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕-3-苯基丙酰胺(13.6g，28.3mmol)在二氯甲烷(136ml)中的溶液里加入异硫氰酸苯酯(3.87ml，34.0mmol)。在环境温度下搅拌过夜。然后将反应物在冰中冷却；加入三氟乙酸(2.73ml，0.283mol)，令反应物温热至环境温度。在环境温度下搅拌2.5小时后，将反应物减压蒸发，用90∶10∶1∶1的二氯甲烷∶甲醇∶乙酸∶水进行层析。收集低Rf点，不加热减压蒸发。将残余物溶在600ml二氯甲烷中，用300ml饱和NaHCO3溶液和300ml水洗。溶液用Na2SO4干燥，减压蒸发。残余物自乙酸乙酯∶己烷中结晶，得到6.65g白色粉末。熔点162-164℃；1H NMR(CDCl3，300MHz)δ7.70-7.26(m，9H)，5.28-5.12(m，1H)，4.57(s，1H)，4.35-4.10(m，1H)。[α]D＝+72.9°(c＝0.7，MeOH)
按同样方式由步骤D的较低Rf的产物制备(-)-3S对映体。熔点156-158℃；1H NMR(CDCl3，300MHz)δ7.70-7.26(m，9H)，5.28-5.12(m，1H)，4.57(s，1H)，4.35-4.10(m，1H)。[α]D＝-71.2°(c＝0.66，MeOH)步骤F：(+)-3，5-二氯-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂草-3-基〕苯甲酰胺的制备
在搅拌下向(+)-3R-3-氨基-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂(5.6g，16.8mmol)在二甲基甲酰胺(50ml)中的溶液里加入1-(3-二甲氨基丙基-3-乙基碳化二亚胺盐酸盐(4.44g，23.0mmol)、1-羟基苯并三唑水合物(3.11g，23.0mmol)和3，5-二氯苯甲酸(3.21g，16.8mmol)。在环境温度下搅拌2小时。将反应物用500ml饱和NaHCO3溶液稀释，用2×300ml乙酸乙酯萃取。合并的有机物用10％KHSO4(200ml)、盐水(200ml)洗，在Na2SO4上干燥，蒸发成白色泡沫状物。将其在75×200mm的硅胶柱上层析，用20％的乙酸乙酯∶己烷洗脱。收集纯级分，减压蒸发，得到8.5g白色泡沫状物，将其自15％的乙酸乙酯∶己烷中结晶，得到5.3g白色粉末。熔点140-143℃[α]D＝+47.9°1H NMR(CDCl3，300MHz)δ7.85-7.75(m，2H)，7.70-7.20(m，9H)，5.78(d，J＝8.1Hz、1H)，5.30-5.15(m，1H)，4.30-4.15(m，1H)。C24H16Cl2F3N3O2分析计算值：C，56.93；H，3.19；N，8.30；实验值：C，56.81；H，3.17；N，8.17。
利用与实施例1步骤F基本上相同的步骤制备以下实施例化合物。
实施例2(-)-2-(3，4-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
mp＝219-221℃；[α]D＝-10.8°；1H NMR(CDCl3，300MHz)δ7.65-7.15(m，12H)，5.78(d，J＝8.1Hz，1H)，5.25-5.10(m，1H)，4.254.05(m，1H)，3.56(s，2H)；C25H18Cl2F3N3O2·0.85H2O分析计算值：C，56.06；H，3.71；N，7.84；实验值：C，56.03；H，3.53；N，7.82。
实施例3(-)-2-(3，5-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺mp＝93-100℃，[α]D＝-5.7°；1H NMR(CDCl3，300MHz)δ7.65-7.15(m，12H)，5.78(d，J＝8.1Hz，1H)，5.25-5.10(m，1H)，4.25-4.05(m，1H)，3.65(s，2H)；C25H18Cl2F3N3O2分析计算值：C，57.71；H，3.49；N，8.08；实验值：C，57.41；H，3.48；N，8.12。
实施例4(-)-2-〔3，5-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
m.p.成泡沫体，[α]D＝-9.7°(c＝0.59，MeOH)C27H18F9N3O2·0.75H2O分析计算值：C，53.96；H，3.27；N，6.99；实验值：C，53.96；H，3.1；N，6.98％
实施例5(-)-2-(4-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.253-255℃[α]D＝-9.2°(c＝0.25，MeOH)C26H19F6N3O2·0.05乙醚0.55H2O分析计算值：C，59.03；H，3.9；N，7.88.实验值：C，59.05；H，3.82；N，7.78％.
实施例62-(3-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺熔点172-173℃[α]D＝+5.9°(c＝0.56，CHCl3)C26H19F6N3O2·0.60H2O分析计算值：C，58.89；H，3.84；N，7.92实验值：C，58.92；H，3.71；N，7.98％
实施例7(+)-2-(2-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.170-171℃[α]D＝+9.0°(c＝0.48，CHCl3)C26H19F6N3O2·0.25H2O分析计算值：C，59.6；H，3.75；N，8.02；实验值：C，59.64；H，3.68；N，7.97％
实施例8(-)-2-(2，4-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.143-145℃[α]D＝-22.6°(c＝0.73，MeOH)C25H18N3O2Cl2F3分析计算值：C，57.71；H，3.49；N，8.08；实验值：C，57.75；H，3.52；N，8.09％
实施例9(-)-2-(3-氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
m.p.188-189℃[α]D＝-5.4°(c＝1.03，MeOH)C25H19ClF3N3O2·0.10乙醚分析计算值：C，61.84；H，4.09；N，8.52；实验值：C，61.84；H，4.05；N，8.5％
实施例10(-)-2-(4-氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1 H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.246-247℃，[α]D＝-10.1 °(c＝0.45，MeOH).C25H19ClF3N3O2·0.20H2O 0.15乙醚分析计算值：C，61.42；H，4.21；N，8.39；实验值：C，61.46；H，4.15；N，8.39％
实施例11(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
步骤A：2，4-双(三氟甲基)苄腈
在搅拌下于30分钟内向加热到60℃的100ml乙醇和250ml磷酸盐缓冲液(每5ml水1g NaH2PO4·H2O，用50％NaOH调节到pH＝7.0)及NaCN(81.3mmol，4.0g)的两相混合物中逐滴加入2，4-双(三氟甲基)苄基溴(32.5mmol，10g)在50ml乙醇中的溶液。将反应混合物在60℃加热24小时。然后减压蒸发。剩余的水相用2×150ml乙酸乙酯萃取。将有机层合并，用盐水和Ba2SO4干燥。将有机相减压蒸发，残余物在硅胶上层析，用10％乙酸乙酯∶己烷洗脱。收集纯级分，蒸发，得到7.0g浅黄色油状物，产率85.1％，NMR1H(CDCl3)δ 8.0-7.85(m，3H)，4.03(s，2H)。步骤B：2，4-双(三氟甲基)苯乙酸
将2，4-双(三氟甲基)苄腈(41.5mmol，10.51g)溶在100ml乙酸、50ml浓硫酸和20ml水中。加热至120℃保持3小时。然后用1L冰水冲稀反应物，用2×300ml乙酸乙酯萃取。将合并的有机物用2×200ml水洗，用盐水和Na2SO4干燥，减压蒸发。残余物溶在最少量的乙醚中，加入足量的己烷使产物结晶沉淀。收集固体，得到7.74g白色晶体状的2，4-双(三氟甲基)苯乙酸，产率68.5％NMR1H(CDCl3)δ7.93(s，1H)，7.80(d，J＝7.9Hz，1H)，7.55(d，J＝7.9Hz，1H)3.94(s，2H)。步骤C：(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
在搅拌下向3R-3-氨基-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-2，3-二氢-1H-苯并〔e〕〔1，4〕二氮杂(28.4mmol，9.47g)在二甲基甲酰胺(100ml)中的溶液里加入2，4-双(三氟甲基)苯乙酸(28.4mmol，7.74g)，1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(42.6mmol，8.16g)和1-羟基苯并三唑水合物(14.2mmol，1.92g)。在室温下搅拌1小时。然后用750ml的10％KHSO4将反应物稀释，用乙酸乙酯萃取(2×300ml)。将有机层合并，用饱和的碳酸氢钠溶液洗(1×600ml)。然后用盐水和硫酸钠将有机物干燥，减压蒸发。残余物在硅胶上层析，用20％的乙酸乙酯∶己烷洗脱。收集纯级分并蒸发之。残余物溶在100ml温热的75％异丙醇∶水中。令其缓慢冷却，在室温下搅拌过夜(16小时)。将此悬浮液短暂地冷却到5℃并过滤。将白色固体在60℃干燥过夜，得到10.5g物质，其熔点为132-134℃。X射线衍射证实其结晶性。NMR1H(CDCl3)δ7.95-7.25(m，13H)，5.60(d，J＝8.1Hz，1H)，5.30-5.10(m，1H)，4.25-4.06(m，1H)，3.96(s，2H)C27H18F9N3O2分析计算值：C，55.20；H，3.09；N，7.15；实验值：C，55.03；H，3.14；N，7.10％
实施例12(±)-2-(3，5-二氯苯基)-N-〔2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
m.p.219-220℃.外消旋C25H18N3O2Cl2F3分析计算值：C，57.71；H，3.49；N，8.08；实验值：C，57.94；H，3.48；N，8.02％
实施例132-(3，5-二氯-4-甲氧基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
m.p.100-104℃，[α]D＝-8.9°(c＝0.55，MeOH).C26H20Cl2F3N3O3分析计算值：C，56.74；H，3.66；N，7.63；实验值：C，55.67；H，3.47；N，7.41％
以下实施例是用与实施例1中所述基本上相同的步骤制备，但是在步骤A中用合适的氟代氨基苯酮代替。
实施例14(+)-2-(3，5-二氯苯基)-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.成泡沫体，[α]D＝+3.4°(c＝0.55，MeOH)C25H17N3O2Cl2F4分析计算值：C，55.78；H，3.18；N，7.81；实验值：C，55.73；H，3.25；N，7.72％
实施例15(-)-2-(2，4-二氯苯基)-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.成泡沫体，[α]D＝-1.1°(c＝0.68，MeOH)C25H17N3O2F4分析计算值：C，55.78；H，3.18；N，7.81；实验值：C，55.82；H，3.41；N，7.42％
实施例16(+)-2-〔3，5-双(三氟甲基)苯基〕-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺m.p.成泡沫体，[α]D＝+2.8°(c＝0.67，MeOH)C27H17N3O2F10分析计算值：C，53.56；H，2.83；N，6.94；实验值：C，53.56；H，2.93；N，6.91％
实施例17(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺[α]D＝-14°(c＝0.63；MeOH).C27H17N3O2F10分析计算值：C，53.56；H，2.83；N，6.94；实验值：C，53.3；H，2.89；N，7.05％
实施例183-环己基-N-〔2，3-二氢-5-(2-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕丙酰胺m.p.202-204℃1H NMRδ(CDCl3，)7.72(m，8H)，5.65(d，J＝8.3Hz，1H)，5.35-5.08(m，1H)，4.32-4.15(m，1H)2.37(t，J＝7.8Hz，2H)，1.80-1.55(m，7H)，1.45-C26H27F4N3O2分析计算值：C，63.8；H，5.56；N，8.58；实验值：C，63.82；H，5.54；N，8.56％
实施例193，4-二氯-N-〔2，3-二氢-5-(2-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕苯甲酰胺
m.p.168-170℃.1H NMRδ(CDCl3)8.03(d，J＝2.0，1H)，7.86(d，J＝7.8Hz，1H)，7.78-7.05(m，9H)，5.80(d，J＝7.8Hz，1H)，5.27-5.15(m，1H)，4.35-4.20(m，1H)C24H15Cl2F4N3O2分析计算值：C，54.98；H，2.88；N，8.01，实验值：C，54.96；H，2.89；N，8.12％
Claims (14)
1.作为抗心律失常药的结构式I化合物和其所有各种异构形式的消旋物、对映体混合物、个别非对映体或个别对映体，以及它们的可药用盐、水合物或结晶形式其中X和Y各自独立地是氢、氯、氟、溴、碘或三氟甲基，n是0、1或2，R是氢、氟、氯、溴、碘或三氟甲基、甲基或甲氧基。
2.权利要求1的化合物，选自：(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(+)-3，5-二氯-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕苯甲酰胺(-)-3，4-二氯苯基-1-基-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
(-)-2-(3，5-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺3-环己基-N-〔2，3-二氢-5-(2-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕丙酰胺
3，4-二氯-N-〔2，3-二氢-5-(2-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕苯甲酰胺
(-)-2-〔3，5-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(4-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(3-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(2-三氟甲基苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
(-)-2-(2，4-二氯苯基)-N-〔3R-2，3-二氢-1-(2，2，2-三氟乙基)-2-氧代-5-苯基-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(3-氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(4-氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(+)-2-(3，5-二氯苯基)-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-(2，4-二氯苯基)-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
(+)-2-〔3，5-双(三氟甲基)苯基〕-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔2，3-二氢-5-(4-氟苯基)-2-氧代-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺(±)-2-(3，5-二氯苯基)-N-〔2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
2-(3，5-二氯-4-甲氧基苯基)-N-〔2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
3.权利要求1的化合物(+)-3，5-二氯-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕苯甲酰胺
4.权利要求1的化合物(-)-2-(3，4-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
5.权利要求1的化合物(-)-2-(3，5-二氯苯基)-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
6.权利要求1的化合物(-)-2-〔2，4-双(三氟甲基)苯基〕-N-〔3R-2，3-二氢-2-氧代-5-苯基-1-(2，2，2-三氟乙基)-1H-苯并〔e〕〔1，4〕二氮杂-3-基〕乙酰胺
7.一种药物制剂，其中含有一种可药用的载体和治疗上有效数量的一种权利要求1的化合物或其可药用的盐、结晶形式或水合物。
8.权利要求7的药物制剂，其中还含有另一种抗心律失常药或其它的心血管药物。
9.一种预防或治疗心律失常的方法，该方法包括使需要这种治疗的患者服用对于抗心律失常是有效数量的权利要求1化合物。
10.权利要求9的方法，其中包括同时服用另一种抗心律失常药或其它的心血管药物。
11.一种药物制剂，其中含有一种可药用的载体和治疗上有效数量的权利要求6化合物或其可药用的盐、结晶形式或水合物。
12.权利要求11的药物制剂，其中还含有另一种抗心律失常药或其它的心血管药物。
13.一种预防或治疗心律失常的方法，该方法包括使需要这种治疗的患者服用对于抗心律失常是有效数量的权利要求6的化合物。
14.权利要求13的方法，其中包括同时服用另一种抗心律失常药或其它的心血管药物。
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| US5428031A (en) * | 1991-12-03 | 1995-06-27 | Merck & Co., Inc. | Methods of treating cardiac arrhythmia |
| DE69204040T2 (de) * | 1991-12-20 | 1996-03-28 | Merck Sharp & Dohme | 3-Phenylureido-1,4-Benzodiazepinone und ihre Verwendung als Cholecystokinin- oder Gastrinantagonisten. |
| ZA93436B (en) * | 1992-01-24 | 1993-08-25 | Chugai Pharmaceutical Co Ltd | Benzopyran derivatives |
| GB9203790D0 (en) * | 1992-02-21 | 1992-04-08 | Merck Sharp & Dohme | Therapeutic agents |
| WO1993019063A1 (en) * | 1992-03-16 | 1993-09-30 | Merck Sharp & Dohme Limited | Benzodiazepine derivatives, compositions containing them and their use in therapy |
| IT1254558B (it) * | 1992-03-26 | 1995-09-25 | Mini Ricerca Scient Tecnolog | Composti a base di 3,4-diaril-(5h)-furan-2-one ad attivita' fungicida 3 |
| GB9209518D0 (en) * | 1992-05-01 | 1992-06-17 | Merck Sharp & Dohme | Therapeutic agents |
| US5360802A (en) * | 1992-05-11 | 1994-11-01 | Merck Sharpe & Dohme Ltd. | Benzodiazepine derivatives, compositions containing them and their use in therapy |
| GB9218412D0 (en) * | 1992-08-28 | 1992-10-14 | Merck Sharp & Dohme | Therapeutic agents |
| US5426185A (en) * | 1993-11-22 | 1995-06-20 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
| US5428157A (en) * | 1993-11-22 | 1995-06-27 | Merck & Co., Inc. | 3-acylaminobenzodiazepines |
| US5438055A (en) * | 1993-11-22 | 1995-08-01 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
| US5439906A (en) * | 1993-11-22 | 1995-08-08 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
| US5441950A (en) * | 1994-06-09 | 1995-08-15 | G. D. Searle & Co. | Substituted dibenzoxazepine and dibenzthiazepine carbamate compounds, pharmaceutical compositions and methods of use |
-
1995
- 1995-08-17 DE DE69513295T patent/DE69513295T2/de not_active Expired - Fee Related
- 1995-08-17 JP JP8508203A patent/JPH10504570A/ja active Pending
- 1995-08-17 CA CA002195974A patent/CA2195974C/en not_active Expired - Fee Related
- 1995-08-17 AU AU33667/95A patent/AU692300B2/en not_active Ceased
- 1995-08-17 HU HU9701275A patent/HU220635B1/hu not_active IP Right Cessation
- 1995-08-17 MX MX9701195A patent/MX9701195A/es unknown
- 1995-08-17 NZ NZ291988A patent/NZ291988A/en unknown
- 1995-08-17 RU RU97104124A patent/RU2149161C1/ru active
- 1995-08-17 CZ CZ97485A patent/CZ285008B6/cs not_active IP Right Cessation
- 1995-08-17 SK SK222-97A patent/SK282019B6/sk unknown
- 1995-08-17 EP EP95930197A patent/EP0776208B1/en not_active Expired - Lifetime
- 1995-08-17 KR KR1019970701009A patent/KR970705395A/ko not_active Ceased
- 1995-08-17 US US08/516,226 patent/US5658901A/en not_active Expired - Fee Related
- 1995-08-17 PL PL95319104A patent/PL319104A1/xx unknown
- 1995-08-17 BR BR9508608A patent/BR9508608A/pt not_active Application Discontinuation
- 1995-08-17 DK DK95930197T patent/DK0776208T3/da active
- 1995-08-17 AT AT95930197T patent/ATE186463T1/de not_active IP Right Cessation
- 1995-08-17 WO PCT/US1995/010500 patent/WO1996005839A1/en not_active Application Discontinuation
- 1995-08-17 ES ES95930197T patent/ES2139933T3/es not_active Expired - Lifetime
- 1995-08-17 CN CN95195291A patent/CN1158568A/zh active Pending
-
1997
- 1997-02-12 BG BG101227A patent/BG63032B1/bg unknown
- 1997-02-17 FI FI970668A patent/FI970668A0/fi unknown
- 1997-02-17 NO NO970731A patent/NO970731L/no not_active Application Discontinuation
-
2000
- 2000-02-04 GR GR20000400287T patent/GR3032592T3/el not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694874B (zh) * | 2002-09-20 | 2010-06-09 | 阿罗治疗有限公司 | 苯并二氮杂*衍生物以及包含它们的药用组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| GR3032592T3 (en) | 2000-05-31 |
| FI970668L (fi) | 1997-02-17 |
| CZ48597A3 (en) | 1997-09-17 |
| NO970731D0 (no) | 1997-02-17 |
| US5658901A (en) | 1997-08-19 |
| RU2149161C1 (ru) | 2000-05-20 |
| DK0776208T3 (da) | 2000-05-01 |
| MX9701195A (es) | 1997-05-31 |
| EP0776208A4 (en) | 1997-12-29 |
| BR9508608A (pt) | 1997-12-30 |
| DE69513295T2 (de) | 2000-06-08 |
| AU3366795A (en) | 1996-03-14 |
| SK22297A3 (en) | 1997-09-10 |
| EP0776208A1 (en) | 1997-06-04 |
| HU220635B1 (hu) | 2002-03-28 |
| CA2195974A1 (en) | 1996-02-29 |
| PL319104A1 (en) | 1997-07-21 |
| NO970731L (no) | 1997-02-17 |
| FI970668A0 (fi) | 1997-02-17 |
| KR970705395A (ko) | 1997-10-09 |
| BG63032B1 (bg) | 2001-02-28 |
| SK282019B6 (sk) | 2001-10-08 |
| ATE186463T1 (de) | 1999-11-15 |
| BG101227A (en) | 1998-03-31 |
| JPH10504570A (ja) | 1998-05-06 |
| EP0776208B1 (en) | 1999-11-10 |
| DE69513295D1 (de) | 1999-12-16 |
| CZ285008B6 (cs) | 1999-04-14 |
| AU692300B2 (en) | 1998-06-04 |
| HUT76811A (en) | 1997-11-28 |
| ES2139933T3 (es) | 2000-02-16 |
| WO1996005839A1 (en) | 1996-02-29 |
| CA2195974C (en) | 2000-12-05 |
| NZ291988A (en) | 1998-11-25 |
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