CN1117738C - 内皮肽拮抗剂 - Google Patents

内皮肽拮抗剂 Download PDF

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CN1117738C
CN1117738C CN98802096A CN98802096A CN1117738C CN 1117738 C CN1117738 C CN 1117738C CN 98802096 A CN98802096 A CN 98802096A CN 98802096 A CN98802096 A CN 98802096A CN 1117738 C CN1117738 C CN 1117738C
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N·姆鲁格桑
J·C·巴里斯
顾正祥
R·A·莫里森
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Abstract

本发明涉及用作内皮肽拮抗剂的化合物N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺和N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺及其盐。

Description

内皮肽拮抗剂
                         发明背景
本发明涉及用作内皮肽(endothelin)拮抗剂的化合物N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺和N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺及其盐。
                         发明简述
内皮肽拮抗剂尤其是能够抑制内皮肽与内皮肽受体相结合的化合物，其在治疗内皮肽相关性疾病，例如高血压和充血性心力衰竭中十分有效。除了提高拮抗剂对抑制内皮肽的能力外，本领域技术人员始终在试图改进这些化合物的与体内综合机能活动有关的参数。
本发明提供了能够取得上述进步的化合物N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺和N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺及其盐。除具有高效能之外，所述内皮肽拮抗剂还具有极佳的口服生物利用度、持续作用时间以及全身性代谢前在胃肠道内的稳定性，所以特别适用于内皮肽相关性疾病的治疗。
                             发明详述
本发明所述化合物N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺具有如下的结构：本发明所述化合物N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺具有如下结构：
本发明也包括N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺和N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺的任意一种和所有的盐，特别是其与有机酸和无机酸所成的盐。尽管其他的盐在譬如所述化合物的分离和纯化中也适用，但优选采用可药用(即无毒、生理可接受的)盐。
本发明优选：碱金属盐，例如钠盐、钾盐和锂盐；碱土金属盐，例如钙盐和镁盐；和，与有机碱类化合物(例如有机胺)形成的盐，例如与二环己胺、叔丁基胺、苄星、N-甲基-D-葡糖酰胺和hydrabamine所成的盐；以及，与氨基酸形成的盐，氨基酸可例如是精氨酸、赖氨酸等。
本发明所述的盐可以通过，例如，在介质(例如可使盐沉淀的介质或随后可冻干的含水介质)内将N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺或N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺与所需的离子(例如采用等量的碱)反应。
本发明上述具有优异全身性代谢前的胃肠道内稳定性的化合物含有3-异噁唑基。由于该基团可以赋予全身性代谢前在胃肠道内的稳定性，所以本发明也提供下列通式所示的新化合物，这些化合物可用作内皮肽拮抗剂并且具有优良的代谢稳定性：
                 Z*-SO2-NH-(3-异噁唑基)
其中Z*是一个有机基团，例如未取代的或取代的萘基、苯基、联苯基或杂环(例如硫苯基)，同时，其中的“3-异噁唑基”是通过其3位与基团-NH-相连的未取代的或取代的异噁唑基。优选的“3-异噁唑基”是未取代的或由烷基(尤其是含有1-12个碳原子的饱和碳链，如甲基)和/或卤素(例如氟、氯、碘和溴)取代的3-异噁唑。在下列文献中描述了多种内皮肽拮抗剂，这些文献的全文而不仅是其中所公开的有关具体化合物均在此引入作为参考：美国专利5,378,715；美国专利5,514,696；美国专利5,420,123；美国专利申请流水号114,251(提交于1993.8.30)；美国专利申请流水号08/728,238(提交于1996.10.8)；欧洲专利申请702,012；美国专利申请流水号08/754,715(提交于1996.11.21)；美国专利申请流水号08/692,869(提交于1996.7.25)；美国专利申请流水号60/011,974(提交于1996.2.20)；美国专利申请流水号60/013,491)(提交于1996.3.12)；美国专利申请流水号60/015,072(提交于1996.4.9)；国际专利申请94/27929；美国专利5,464,853；美国专利5,514,691；EP601386；EP633259；US5,292,740；EP510526；EP526708；EP658548；US5,541,186；WO96/19459；WO96/19455；EP713875；WO96/20177；EP733626；JP8059635；EP682016；GB2295616；WO95/26957；美国专利5,571,821；EP743307；和WO96/31492；；公开的化合物例如是(在此引入作为参考)：波生坦(Ro 47-0203，Clozel，M.，等人，“一种新的口服有效的活性壬肽内皮肽受体拮抗剂-玻生坦的药理学特性”，药理学和试验治疗学杂志，第270(1)卷，228-235(1994))；和TBC-11251，即
Figure C9880209600071
(有关内皮肽抑制剂的IBC国际会议，克罗拉多，CA(1996.2)和第211届美国化学会国内会议，New Orleans，LA(1996.3))。这些化合物含有磺酰基-SO2-NH-，其中有机基团通过磺酰基与分子的其它部分相连。在本发明上述通式Z*-SO2-NH-(3-异噁唑基)中优选的Z*基团是那些在上述文献中描述的通过磺酰基连接化合物的有机基团。除了提供这种代谢稳定的化合物外，本发明还提供这些化合物的应用方法，其中这些化合物适合在内皮肽相关性疾病的治疗中给药。
本发明所述化合物是ET-1、ET-2和/或ET-3拮抗剂，并在治疗与高水平ET有关(例如透析、外伤和手术)的以及所有内皮肽依赖型疾病的情况中均有效。所以这些化合物适合作为抗高血压药。通过含有一种本发明所述化合物的组合物的给药，患高血压的哺乳动物(例如人)宿主的血压可以得到降低。所述化合物也适用于妊娠诱发型高血压和昏迷(惊厥前期和惊厥)、急性门静脉高血压以及由红细胞生成素治疗所继发的高血压。
本发明所述化合物在肾脏、肾小球和肾小球膜细胞功能相关性疾病的治疗中也有效，包括急性和慢性肾衰竭、肾小球损伤、高龄或透析继发性肾损害、肾硬化(尤其是高血压继发性肾硬化)、肾中毒(包括与显影剂和造影剂以及环孢菌素有关的肾中毒)、肾脏局部缺血、原发型膀胱输尿管回流、肾小球硬化症等等。本发明所述化合物同样适合治疗旁分泌和内分泌功能性疾病。
本发明所述化合物也适合治疗内毒素血症或内毒素休克以及出血性休克。
本发明化合物在低氧症和局部缺血症中也有效，它们可作为治疗例如心脏、肾脏和脑部局部缺血和再灌注(例如出现在心肺分流术后)的抗局部缺血药。
此外，本发明的化合物还适合用作抗心律失常药；抗绞痛药；抗纤性颤动药；抗气哮喘药；抗动脉粥样硬化和动脉硬化药；用作心肺分流术麻醉液的添加剂；溶血栓疗法添加剂；和抗腹泻药。本发明所述化合物也适用于：心肌梗塞的治疗；外周血管疾病(例如雷诺氏病和高安氏病)的治疗；心脏肥大(例如心肌肥大症)的治疗；成人和新生儿的原发型肺高血压(例如从原性、栓塞性)以及由心衰、放射和化疗损伤或其他创伤继发的肺部高血压的治疗；中枢神经系统血管疾病(例如休克、偏头痛和蛛网膜下出血)的治疗；中枢神经系统行为疾病的治疗；胃肠道疾病(例如溃疡性结膜炎、节段性回肠炎、胃粘膜损害、溃疡和局部缺血性肠炎)的治疗；胆囊或胆管型疾病(例如胆管炎)的治疗；胰腺炎的治疗；调节细胞生长；良性前列腺肥大的治疗；血管成形术后或移植术后的再狭窄；包括抑制纤维变性在内的对充血性心衰的治疗；抑制心室的扩张、变形和机能障碍；和治疗肝中毒和突发性死亡。本发明所述化合物可用于治疗：包括该病疼痛危象开始和/或进化的镰状红细胞病；产生ET的肿瘤的有害后果(例如血管外皮细胞瘤所致的高血压)；早期和晚期肝脏疾病和损伤，其中包括协同并发症(例如肝中毒、纤维变性和肝硬变)；尿道和或膀胱痉挛症；肝肾综合征；包含结节性脉管炎在内的免疫学疾病，例如狼疮、全身硬化、混合型冷沉球蛋白血症；和与肾机能障碍和肝中毒有关的纤维变性。本发明的化合物在下列疾病的治疗中也有效：代谢和神经性疾病；癌症；胰岛素依赖型和非胰岛素依赖型糖尿病；神经病；视网膜病；母体呼吸窘迫综合征；痛经；癫痫；出血性和局部缺血性休克；骨变形；牛皮癣；和慢性炎症，例如类风湿关节炎、骨关节炎、肉样瘤病和湿疹性皮炎(所有类型的皮炎)。
可以和本发明所述化合物联合配制的有：内皮肽转化酶(ECE)抑制剂，例如磷酰美沙酮(phosphoramidon)；血栓烷受体拮抗剂；钾通道开启剂；凝血酶抑制剂(例如水蛭素及类似物)；生长因子抑制剂，例如PDGF活性调节剂；血小板活化因子(PAF)拮抗剂；血管紧张素II(AII)受体拮抗剂；肾素抑制剂；血管紧张素转化酶(ACE)抑制剂，例如卡托普利、佐芬普利、福辛普利、西那普利、阿拉普利、依那普利、地拉普利、喷托普利、喹那普利、雷米普利、赖诺普利以及这些化合物的盐；中性肽链内断酶(NEP)抑制剂；NEP-ACE双重抑制剂；HMGCoA还原酶抑制剂，例如普伐他汀和洛伐他汀；角鲨烯合成酶抑制剂；胆汁酸螯合剂，例如消胆胺；钙通道阻断剂；钾通道激活剂；β-肾上腺素能剂；抗心律失常药；利尿剂类化合物，例如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟噻嗪、苄氟噻嗪、甲氯噻嗪、三氯噻嗪、泊利噻嗪或苄硫噻嗪以及依他尼酸、tricrynafen、氯噻酮、氟塞米、musolimine、布美他尼、氯苯喋啶、阿米洛利和螺内酯以及这些化合物的盐；强心甙，例如地高辛；和溶血栓剂，例如组织纤溶酶原激活物(tPA)、重组tPA、链激酶、尿激酶、尿激酶原和甲氧苯甲酰化纤溶酶原链激酶激活物复合物(APSAC)。若配制成固定剂量，这种结合产物优选采用如下所述剂量范围内的本发明化合物以及许可剂量范围内的其它药理学活性试剂。本发明化合物还可以与抗真菌药和免疫抑制剂(例如两性霉素B、环孢菌素类等)共同配制或联合，用于抵抗肾小秋挛缩以及此类化合物继发的肾毒性。在血液透析中也可以联合使用本发明所述化合物。
本发明化合物可以通过任何适当的方式(例如口服或非肠道)以有效量对不同种类的患有上述疾病的哺乳动物(例如人)给药，给药可每天1次或均分为2至4次，所述有效量例如是在约0.1-约100mg/kg，优选约0.2-约50mg/kg，更优选约0.5-约25mg/kg(或约1-约2500mg，优选约5-约2000mg)。
所述活性物质可以以组合物形式应用，例如片剂、胶囊、溶液或悬浮液，每单位剂量中含有例如约5-约500mg的本发明化合物或其混合物；也可以以适合创伤愈合的局部形式应用(例如含有0.01-5％(重量)的本发明化合物，每天治疗1-5次)。本发明化合物可以以常规方式与生理可接受赋形剂或载体、辅料、粘合剂、防腐剂、稳定剂、矫味剂等物质相化合，或与可药用的局部用载体例如Plastibase(与聚乙烯胶凝的矿物油)复合。
本发明化合物也可以通过局部给药来治疗外周血管疾病，并且可以配制为霜剂或软膏。
可以将本发明化合物配制为组合物，例如非肠道给药用的灭菌溶液或混悬液。例如，将约0.1-500mg的本发明化合物与生理可接受辅料、载体、赋形剂、粘合剂、防腐剂、稳定剂等复合在满足药学实践要求的单位剂型中。活性物质在这些组合物或制剂中的含量优选是介于能够获得适当剂量的用量范围内。
所以，本发明提供含有本发明所述新化合物的药物组合物和新的使用方法。本发明尤其涉及了在哺乳动物中治疗内皮肽相关性疾病的方法，其中包括给予哺乳动物以治疗内皮肽相关性疾病有效量的本发明化合物。本发明也特别涉及用于治疗内皮肽相关性疾病的药用组合物，所述组合物含有有效量的本发明化合物和生理可接受的赋形剂或载体。一种本发明化合物可以以譬如上述的方法或药物组合物单独使用，或者与一种或多种其它本发明所述化合物和/或至少一种其他的活性剂联合使用，所述的其他活性剂可例如是血管紧张素II(AII)受体拮抗剂、肾素抑制剂、血管紧张素转化酶(ACE)抑制剂、中性肽链内断酶(NEP)-ACE双重抑制剂、利尿剂、强心甙或上文所述的其它活性剂。
在本发明所述方法中，所述的其他活性剂可以在本发明化合物给药之前、同时或之后施用。在本发明所述药物组合物中，该其他活性剂可以与本发明化合物共同配制，或按照本发明所述的方法分别给药。
特别优选的方法和组合物是那些用于治疗：高血压，尤其是低肾素高血压(例如美国专利申请流水号60/035,825，由J.E.Bird提交于1997.1.30，题目为“通过内皮肽拮抗剂给药对低肾素高血压进行预防或治疗的方法”(Attorney Docket No.HA700*)，在此全文引入作为参考)，或肺部高血压，尤其是原发型肺部高血压；良性前列腺肥大；偏头痛；肾、肾小球或肾小球膜细胞疾病；内毒血症；局部缺血；动脉粥样硬化；再狭窄；蛛网膜下出血；和充血性心力衰竭的方法和组合物。
可以按照，例如，在欧洲专利申请702,012或提交于1996年11月21日的美国专利申请08/754,715(Attorney Docket No.HA662e)中公开的方法或本申请实施例所述的方法来制备N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺和N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1-联苯基]-2-磺酰胺及其盐，上述文献的全文在此引入作为参考。
本发明现将通过下列实施例进一步地加以说明，这些实施例是本发明的优选实施方案。这些实施例只是说明而不是限定本发明。
                          实施例1 N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯
           基]-2-基]甲基]-N，3，3-三甲基丁酰胺的制备
               A. 4，5-二甲基-3-异噁唑胺盐酸盐
向置于烧瓶内的(4，5-二甲基-异噁唑基)氨基甲酸1，1-二甲基乙酯(25.0g，117.79mmol，按照Konoike，T.等人在Tet.Lett.，37，3339-3342(1996)公开的方法制得)中加入100ml 4N HCl的二氧六环溶液。将混合物在室温下搅拌5小时并浓缩，得到本步反应的标题产物，该产物为固体，并且不需纯化就可用于下步反应。
      B. 2-溴-N-(4，5-二甲基-3-异噁唑基)苯磺酰胺
在10分钟内于0℃下分次将溴代苯磺酰氯(28.59g，111.90mmol)加入到A步的全部固体物和4-二甲基胺吡啶(1.44g，11.78mmol)在79ml吡啶内的混合物中。将混合物在40℃下搅拌6.5小时并浓缩。将残余物溶于300ml甲醇(“MeOH”)中，加入1000ml碳酸氢钠水溶液，在真空下浓缩该混合物以除去大部分甲醇。滤出固体，用6N盐酸在0℃下将含水滤液酸化至pH1，用乙酸乙酯(“EtOAc”，2×400ml)提取。提取液用100ml1N盐酸、100ml水和100ml盐水洗涤，干燥并浓缩，得到本步反应的产物(34.32g，纯度～95％，两步的收率为84％)。Rf＝0.57，硅胶，己烷/乙酸乙酯1∶1。
          C. 2-溴-N-(4，5-二甲基-3-异噁唑基)
           -N-[(2-甲氧基乙氧基)甲基]苯磺酰胺
在0℃下，将氢化钠(60％，在矿物油内，4.93g，123.34mmol)分次加入到于343ml二甲基甲酰胺(“DMF”)内的B步标题产物(32.60g，102.78mmol)中。在室温下搅拌30分钟后，在冰盐浴(-15℃)中冷却该混合物并在20分钟内滴加入2-甲氧基乙氧基甲基氯(16.00g，128.48mmol)。搅拌下，该反应在冰盐浴内进行20分钟并进而在室温下进行1.5小时。向反应混合物中加入1400ml1∶1己烷/乙酸乙酯。分离出有机层并用2×800ml水、400ml盐水洗涤，干燥并浓缩。将残余物在硅胶上进行层析，用2.5∶1的己烷/乙酸乙酯洗脱，得到本步反应的标题产物(32.12g，75％)，该产物为油状物。D. N-(4，5-二甲基-3-异噁唑基)-2’-甲酰基-N-[(2-甲氧基乙氧基)甲基]
          -4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺
在-95℃下，将正丁基锂(“n-BuLi”，2M的戊烷溶液，29.07ml，58.14mmol)加入到于264ml四氢呋喃(“THF”)内的C步标题产物(22.16g，52，85mmol)中。将混合物在-95℃下搅拌10分钟，加入三甲基硼酸盐(trimethylborate，6.59g，63.42mmol)并在-78℃下搅拌15分钟。移去冷却浴并在室温下搅拌0.5小时。随后将混合物冷却至0℃并向其中滴加100ml3N盐酸。搅拌30分钟后，混合物用二氯甲烷(300ml，100ml)提取。将合并的有机提取液用30ml盐水洗涤、干燥并浓缩，得到2-二羟硼基-N-(4，5-二甲基-3-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺，该产物为树胶状。
向处于264ml甲苯和132ml 95％乙醇(“EtOH”)内的2-二羟硼基-N-(4，5-二甲基-3-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺和2-溴-5-(2-噁唑基)苯甲醛(13.32g，58.14mmol，按照欧洲专利申请702,012中实施例21所述的方法制得)中加入106ml 2M碳酸钠水溶液和四(三苯基膦)钯(O)(6.11g，5.29mmol)，将反应混合物在氩气和85℃下加热4小时，冷却并用250ml乙酸乙酯稀释。分离出有机层并用100ml水和50ml盐水洗涤，干燥并浓缩。将残余物在硅胶上进行层析，用1∶1的己烷/乙酸乙酯洗脱，得到本步反应的标题产物(16.95g，两步的收率为62.7％)，该产物为无色树胶。1H NMR(CDCl3)δ1.89(s，3H)，2.28(s，3H)，3.28(s，3H)，3.43(m，2H)，3.60-3.76(m，2H)，4.40-4.59(m，2H)，7.28-8.68(m，9H)，9.76(s，1H)。E. N-(4，5-二甲基-3-异噁唑基)-2’-甲酰基-4’-(2-噁唑基)[1，1’-联苯基]-2-
                             磺酰胺
将414ml 6N盐酸加入到处于414ml 95％乙醇内的D步骤标题产物(16.95g，33.14mmol)中。将该混合物回流55分钟并倾入800g冰中。放置2小时后，过滤收集白色沉淀，得到本步反应的标题产物(13.17g，收率92％)。Rf(硅胶)＝0.31(含有5％甲醇的二氯甲烷)。F. N-(4，5-二甲基-3-异噁唑基)-2’-[(甲基氨基)甲基]-4-(2-噁唑基)[1，1’-
                           联苯基]-2-磺酰胺
向处于305ml二氯甲烷内的E步标题产物(12.91g，30.48mmol)和3A分子筛中依次加入乙酸(“AcOH”，4.58g，76.20mmol)和甲胺(8.03M，在乙醇中，13.29ml，106.68mmol)。将混合物搅拌15分钟并加入三乙酰氧基氢硼化钠(19.38g，91.44mmol)。在室温下将反应混合物搅拌2小时，用700ml二氯甲烷和100ml甲醇稀释并经硅藻土过滤。滤液用150ml水洗涤，干燥并浓缩。在残余物用乙醚研制(50ml，30ml，30ml)。用二氯甲烷-庚烷共沸蒸发数次，得到本步反应的标题产物，该产物为灰色固体，该产物不需进一步纯化就可用于下步反应。1H NMR(CDCl3/CD3OD 3∶1)δ 1.83(s，3H)，2.13(s，3H)，2.71(s，3H)，3.87-4.27(m，2H)，7.11-8.09(m，9H)。G. N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联
              苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺
向0℃的处于300ml二氯甲烷中的F步标题化合物中加入三乙胺(6.17g，60.96mmol)并搅拌5分钟。在10分钟内向该混合物中滴加叔丁基乙酰氯(3.98g，29，57mmol)。将反应混合物在0℃下搅拌10分钟并在室温下搅拌1小时。加100ml 10％NaHSO4水溶液。用100ml二氯甲烷提取水层。合并的有机提取液用100ml水、50ml盐水洗涤，干燥并浓缩。将残余物在硅胶上进行层析，用60∶40∶1己烷/乙酸乙酯/乙酸洗脱，得到本实施例的标题产物(13.10g，两步的收率为80％)，该产物为白色固体。熔点＝120-128℃(无定形)。
本发明还提供制备本实施例第D、E和F步的标题产物的新中间体。我们发现，步骤E和F的标题产物本身也是用作治疗内皮肽相关性疾病的内皮肽拮抗剂。
                          实施例2 N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯
    基]-2-基]甲基]-N，3，3-三甲基丁酰胺在体内的功能活性
下列方法将证实本标题化合物在体内的优异的功能活性(包括生物利用度、效能和作用时间，以及代谢稳定性)。
(A) 生物利用度
给禁食雄性大鼠(n＝3)静脉内(10μmol/kg，10分钟滴注)或利用管饲法口服施用(20μmol/kg)单剂量的本标题化合物。静脉内给药采用丙二醇作为赋形剂，口服给药所用的赋形剂为PEG-400。给药后，随时间测定本标题化合物的平均血浆浓度，计算出曲线AUC∞(μM×小时)下的面积，静脉内给药和口服给药的结果分别为31.3±2.9和72.8±17.3。由于静脉内给药和口服给药的剂量-标准化AUC∞值无显著性差异，可认为本标题化合物的生物利用度接近100％。
(B) 升压试验
(i)将大量ET-1静脉内注射到清醒的血压正常的大鼠内，以使平均动脉血压暂时升高，ETA受体拮抗剂可减弱这种血压升高。
在将一定量本标题化合物(0.01μmol/kg(n＝10)，0.03μmol/kg(n＝10)，和0.1μmol/kg(n＝3))静脉内注射给药之前和5分钟后，给Sprague-Dawley大鼠快速浓注大量人ET-1(1nmol/kg，静脉内；赋形剂：含有1％吐温80的5％碳酸氢钠溶液)。比较峰升压反应以判断本标题化合物引起的抑制作用的用量。标题化合物对大量ET-1所致升压反应产生50％的抑制作用(ED50)所需的剂量为0.03μmol/kg。
(ii)采用类似试验方式口服给药标题化合物，以便证实其作用持续时间及效力。在将3μmol/kg本标题化合物给药之前及给药15、105和195分钟之后，给Sprague-Dawley大鼠(n＝3)浓注大量人的ET-1(1nmol/kg，静脉内给药；赋形剂：含有1％吐温80的5％碳酸氢钠溶液)。比较峰升加压反应以判断标题化合物在这些时间间隔内产生的抑制作用的用量。所得结果如表1所示，下列结果证实标题化合物的效力和作用时间很长。
              表1
     给药后的时间 (分钟)      ％抑制
    15     57±7
    105     65±13
    195     74±8
(C) 在胃肠道内全身代谢前的稳定性体外试验
将大鼠盲肠内容物迅速置于冷的脱气磷酸钾缓冲液(50mM，pH7.4，至少吹入30分钟的氮气以达到净化)中。各培养物中含有约0.1g盲肠内容物/ml。将标题化合物加入到作为碳酸氢盐缓冲溶液的培养物中。用200μM的本标题化合物培养并与乙腈1∶1的混合，分析前进行离心。用HPLC-UV和LC-MS在YMC-ODS AQ柱(4.6×150mm，3μ)上进行分析，用醋酸铵/乙腈梯度洗脱并在270nm下检测。在以大鼠盲肠匀浆一起培养1小时后为100％，本标题化合物仍保持不变的百分比(即无法观测到代谢产物)。体内试验
令胆管插套管的大鼠禁食过夜。利用管饲法将本标题混合物以5％的碳酸氢钠溶液(约8mg/ml，29mg/kg)口服给药。在3倍体积的水中得到胃肠道匀浆并加入等体积的乙腈。采用LC-MS/MS定性并用LC-UV在YMC-ODS AQ柱(4.6×150mm，3μ)上定量分析本标题化合物，用乙酸铵/乙腈梯度洗脱并在270nm下检测。口服给药9小时后在胃肠道内仍保持完整的本标题化合物的百分比为100％(即未测出代谢产物)。
                        实施例3 N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-
             (2-噁唑基)[1，1′-联苯基]-2-磺酰胺的制备A. N-(4，5-二甲基-3-异噁唑基)-2’-(羟甲基)-N-[(2-甲氧基乙氧基)
             甲基]-4’-(2-噁唑基)[1，1′-联苯基]-2-磺酰胺
室温下，向溶于10mL甲醇中的实施例1步骤D的标题产物(0.37g，0.76mmol)的溶液中加入硼氢化钠(0.035g，0.93mmol)并将混合物搅拌2小时。随后将澄清的溶液浓缩至5mL，用100ml水稀释，用3×100ml乙酸乙酯提取该水溶液。进而将合并的有机提取液用水洗涤1次并干燥并蒸发，得到0.36g(95％)本步骤标题产物，该产物为无色树胶。Rf(硅胶)＝0.32(含有5％甲醇的二氯甲烷)。B. 2’-(溴甲基)-N-(4，5-二甲基-3-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-
             4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺
在5℃下，将三苯基膦(0.283g，1.08mmol)和四溴化碳(0.358g，1.08mmol)加入到溶于5mlDMF内的A步标题产物(0.37g，0.72mmol)的溶液中，并且将混合物搅拌5小时。随后将该溶液用100ml水稀释并用3×100ml乙酸乙酯提取该水溶液。合并有机提取液，水洗一次，干燥并蒸发。所得残余物在20g硅胶上层析，用2∶1的己烷∶乙酸乙酯洗脱，得到0.285g(69％)本步的标题产物。Rf(硅胶)＝0.34(含有5％甲醇的二氯甲烷)。
                   C. 3，3-二甲基-2-吡咯烷酮
在装有3，3-二甲基-2-氧-1-吡咯烷甲酸1，1-二甲基乙酯·氢氯化物(0.5g，2.34mmol，按照化学研究杂志(摘要)，414-415(1993))的烧瓶内加入1N盐酸的醚(15ml)溶液并将混合物搅拌过夜。随后蒸发该溶液并将残余物真空干燥，得到0.26g(98％)本步反应的标题产物，该产物为浅黄色树胶并且静置后固化。D. N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]- N-[(2-甲氧基乙氧基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺
向溶于3ml DMF中的C步标题产物(0.055g，0.49mmol)的溶液中加入氢化钠(60％在矿物油中的悬浮液，0.019g，0.49mmol)并将混合物在室温和氩气氛下搅拌5分钟。加入B步骤的标题产物(0.14g，0.24mmol)，在室温下将混合物搅拌过夜。在另一个烧瓶内，将另外0.0275(0.25mmol)C步的标题产物和0.01g(0.25mmol)氢化钠在1mlDMF中搅拌10分钟，并且进而将混合物加入到上述溶液中，将反应混合物再搅拌3小时。随后将混合物加入到100ml水中，用3×50ml乙酸乙酯提取该溶液。合并的有机提取液用水洗涤并干燥并蒸发，得到0.16g(100％)本步骤的标题产物，该产物为无色树胶。Rf(硅胶)＝0.24(含有5％甲醇的二氯甲烷)。E. N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-
             4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺的制备
将氯化三甲基硅烷(0.157g，1.45mmol)和碘化钠(0.15g，1.45mmol)加入到溶于2ml乙腈内的D步标题产物(0.157g，0.25mmol)的溶液中，并且将混合物在室温下搅拌1小时。加入另外部分的氯化三甲基硅烷(0.078g，0.726mmol)和碘化钠(0.075g，0.726mmol)。再搅拌混合物1小时。用20ml 1％硫代硫酸钠水溶液稀释该混合物并用3×12ml乙酸乙酯提取。随后将合并的有机提取液用水洗涤1次并干燥并蒸发。残余物通过反相制备HPLC在30×500mmODS 10柱上纯化，用70％溶剂B(90％甲醇，10％水，0.1％三氟乙酸(“TFA”))和30％溶剂A(10％甲醇，90％水，0.1％TFA)洗脱。收集适当的馏分，用碳酸氢钠水溶液中和至pH7，并且浓缩至10ml。进而以硫酸氢钠水溶液将该溶液酸化至pH4，滤出白色固体并干燥，得到0.036g(28％)本实施例的标题产物，该产物为白色固体，熔点110-117℃(无定型)。
本发明同时也提供了制备作为本实施例步骤A、B和D的标题产物的新中间体。
                       实施例4 N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-
       (2-噁唑基)[1，1’-联苯基]-2-磺酰胺的另一种制备方法A. 4-[[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联
             苯基]-2-基]甲基]氨基]-2，2-二甲基丁酸
向处于47ml二氯甲烷中的实施例1步骤E的标题产物(2.00g，4.72mmol)、  3-羧基-3-甲基丁基氯化铵(1.58g，9.45mmol，按照化学研究杂志，414-415(1993)所述方法制得)和3A分子筛中加入乙酸(0.85g，14.17mmol)，随后加入乙酸钠(0.775g，9.45mmol)。将混合物搅拌10分钟并加入三乙酸基硼氢化钠(3.00g，14.17mmol)。在室温下将反应混合物搅拌1小时40分钟，用100ml二氯甲烷稀释并经硅藻土过滤。滤液用2×30ml水、30ml盐水洗涤，干燥并浓缩得到含有标题产物的残余物。Rf(硅胶)＝0.06(二氯甲烷∶甲醇10∶1)。B. N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-
                 4’(2-噁唑基)[1，1’-联苯基]-2-磺酰胺
将步骤A所得的全部残余物溶于50ml二氯甲烷中并加入1，3-二异丙基碳二亚胺(775mg，6.14mmol)。在室温下将反应混合物搅拌1小时并用50ml二氯甲烷稀释，用30ml水和30ml盐水洗涤，干燥并浓缩。将残余物在硅胶上层析，用50∶50∶1的己烷/乙酸乙酯/乙酸洗脱，得到本实施例的标题产物(1.47g，两步的收率为60％)，该产物为白色固体，熔点206-208℃(乙醇/水)。
本发明还提供制备本实施例步骤A的标题产物的新中间体。我们发现，该中间体本身也是用于治疗内皮肽相关性疾病的内皮肽拮抗剂。
                                实施例5 N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-
     (2-噁唑基)[1，1’-联苯基]-2-磺酰胺在体内的功能活性
以下将证实本标题化合物在体内的优异的功能活性(包括生物利用度、效力和作用时间，以及代谢稳定性)。
(A) 生物利用度
利用实施例2(A)所述方法，测得本标题化合物的口服生物利用度约为78％。
(B) 升压试验
利用实施例2(B)(i)所述方法，标题化合物对大量ET-1所致升压反应产生50％抑制作用(ED50)所需的剂量约为0.01μmol/kg。
表2中所列结果证实本标题化合物的效力和可长时间的作用，这些结果是利用实施例2(B)(ii)所述方法测定的。
            表1
     给药后的时间 (分钟)      ％抑制
    15     62±5
    105     50±7
    195     38±7
(C) 在胃肠道内的全身代谢前稳定性
采用实施例2(C)所述方法获得以下本标题化合物的稳定性数据。体外试验
在与大鼠盲肠匀浆一起培养1小时后，本标题化合物仍保持完整的百分比为100％。体内试验
口服给药9小时后在胃肠道内仍保持完整的本标题化合物的百分比为100％。

Claims (23)

1.化合物N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺或其盐。
2.权利要求1所述的化合物为N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺或其可药用盐。
3.权利要求1所述的化合物为N-[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]-N，3，3-三甲基丁酰胺。
4.权利要求1所述的化合物的盐为该化合物的可药用盐，其中所述盐为锂盐、钠盐或钾盐，或者是与碱性有机胺形成的盐。
5.权利要求2的化合物在制备用于治疗内皮肽相关性疾病的药物中的用途。
6.权利要求5的用途，其中所述药物是治疗高血压的药物。
7.权利要求5的用途，其中所述药物是治疗肺部高血压的药物。
8.权利要求5的用途，其中所述药物是治疗原发型肺部高血压的药物。
9.用于治疗内皮肽相关性疾病的药物组合物，该组合物含有有效量的权利要求2所述的化合物和生理可接受的赋形剂或载体。
10.权利要求9所述的药物组合物，该组合物还含有至少一种血管紧张素II(AII)受体拮抗剂、肾素抑制剂、血管紧张素转化酶(ACE)抑制剂、中性肽链内断酶(NEP)-ACE双重抑制剂、利尿剂或强心甙。
11.化合物N-(4，5-二甲基-3-异噁唑基)-2’-[(甲基氨基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺。
12.N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺或其盐。
13.权利要求12所述的化合物或其盐，是N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺或其可药用盐。
14.权利要求12所述的化合物，所述化合物为N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺。
15.权利要求12所述的化合物的盐为该化合物的可药用盐，其中所述盐为锂盐、钠盐或钾盐，或者是与碱性有机胺形成的盐。
16.权利要求13的化合物在制备用于治疗内皮肽相关性疾病的药物中的用途。
17.权利要求13的化合物在制备用于治疗高血压的药物中的用途。
18.权利要求13的化合物在制备用于治疗肺部高血压的药物中的用途。
19.权利要求13的化合物在制备用于治疗原发型肺部高血压的药物中的用途。
20.用于治疗内皮肽相关性疾病的药物组合物，该组合物含有有效量的权利要求13所述的化合物和生理可接受的赋形剂或载体。
21.权利要求20所述的药物组合物，该组合物还含有至少一种血管紧张素II(AII)受体拮抗剂、肾素抑制剂、血管紧张素转化酶(ACE)抑制剂、中性肽链内断酶(NEP)-ACE双重抑制剂、利尿剂或强心甙。
22.化合物N-(4，5-二甲基-3-异噁唑基)-2’-[(3，3-二甲基-2-氧-1-吡咯烷基)甲基]-N-[(2-甲氧基乙氧基)甲基]-4’-(2-噁唑基)[1，1’-联苯基]-2-磺酰胺。
23.化合物4-[[[2’-[[(4，5-二甲基-3-异噁唑基)氨基]磺酰基]-4-(2-噁唑基)[1，1’-联苯基]-2-基]甲基]氨基]-2，2-二甲基丁酸。
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