CN1275981A - 新型药物活性化合物、其制备方法和其用作ece抑制剂的用途 - Google Patents
新型药物活性化合物、其制备方法和其用作ece抑制剂的用途 Download PDFInfo
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Abstract
本发明涉及新型药物活性化合物、其制备方法的用于制备治疗疾病的药物制剂的用途(抑制内皮肽转化酶(=ECE))。
Description
本发明涉及新型药物活性化合物、其制备方法和用于制备治疗疾病的药物制剂的用途。
内皮缩血管肽是一种由21个氨基酸组成并且是由血管内皮合成和释放的肽。内皮缩血管肽以三种同种型存在:ET-1、ET-2和ET-3。下文的“内皮缩血管肽”或“ET”指的是一种或所有的内皮缩血管肽的同种型。内皮缩血管肽是一种有效的血管收缩剂并且对管肌紧张性具有强有力的作用。公知这种血管收缩是由内皮缩血管肽与其受体的结合所导致的(Nature,332,1988,411-415;FEBS Letters,231,1988,440-444和Biochem.Biophys.Res.Commun.,154,1988,868-875)。
内皮缩血管肽的增加或异常释放导致外周、肾和大脑血管中持续的血管收缩,这可导致疾病。正如文献中所报导的,内皮缩血管肽涉及许多疾病,这些疾病包括高血压、急性心肌梗塞、肺动脉高血压、雷诺氏综合征、大脑血管痉挛、中风、良性前列腺肥大、动脉粥样硬化、哮喘和前列腺癌(J.Vascular Med.Biology 2,(1990)207,J.Am.Med.Association 264,(1990)2868,Nature 344,(1990)114,N.Engl.J.Med.322,(1989)205,N.Engl.J.Med.328,(1993)1732,Nephron 66,(1994)373,Stroke 25,(1994)904,Nature 365,(1993)759,J.Mol.Cell.Cardiol.27,(1995)A234;Cancer Research56,(1996)663,Nature Medicine 1,(1995)944)。
目前文献中已经描述了至少两种内皮缩血管肽受体亚型ETA和ETB受体(Nature 348,(1990)730,Nature 348,(1990)732)。因此,抑制内皮缩血管肽与一种或两种受体结合的物质应拮抗内皮缩血管肽的生理作用并由此代表了有价值的药物。
然而,这些受体拮抗剂的缺陷在于内皮缩血管肽已经形成且在其产生后内皮缩血管肽的作用必须被拮抗。防止内皮缩血管肽从其前体(所谓的大内皮缩血管肽)形成的物质在内皮缩血管肽作用的早期阶段介入并由此代表了一种所需的内皮缩血管肽受体拮抗剂的可替代物,因为它们应具有例如通过ACE(ACE=“血管紧张肽转化酶”,Szelke等,Nature,299,555)或ANP(ANP=,Sybertz等,J.Pharmacol.Exp.Ther.250,1989,624)抑制剂所显示的更直接和更好的作用。
本发明的目的是提供内皮缩血管肽转化酶(=ECE)的抑制剂。
其中取代基具有下列含义:
R1和R2彼此独立为取代或非取代的支链或非支链的C1-C8-烷基、C1-C8-烷芳基或C1-C8-烷基杂芳基、取代或非取代的芳基或杂芳基;
R4是取代或非取代的C4-C14-芳基、C4-C14-杂芳基,所具有的一个或多个环中含有一个或多个选自O、S和N的杂原子;
R5是C1-C8-烷基、C1-C8-烷芳基、芳基或杂芳基。
本发明进一步涉及用于制备上述通式I的化合物的方法,该方法包括下列步骤:
并与一种酰化剂R4COC(V)反应并去除保护基SG1,从而得到上述通式I的化合物,其中取代基R1、R2、R3和R4具有上述含义且SG1是一种保护基。
本发明进一步涉及通式I的化合物用于抑制内皮缩血管肽转化酶(=ECE)、用于制备治疗疾病的药物制剂的用途并涉及这些含有至少一种其它降血压活性物质或药物的药物制剂的用途。
上述通式I、II、III和IV中的取代基R1和R2具有下列含义:
R1和R2彼此独立为取代或非取代的支链或非支链的C1-C8-烷基、C1-C8-烷芳基或C1-C8-烷基杂芳基、取代或非取代的芳基或杂芳基;
其中
烷基支链或非支链的C1-C8-烷基链诸如甲基、乙基、正丙基、1-甲基乙基、正丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、1-乙基丙基、正己基、1,1-二甲基丙基、1,2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、正庚基或正辛基;
烷芳基支链或非支链的C1-C8-烷芳基诸如C1-C8-烷基苯基或C1-C8-烷基萘基,诸如甲基苯基、乙基苯基、丙基苯基、1-甲基乙基苯基、丁基苯基、1-甲基丙基苯基、2-甲基丙基苯基、1,1-二甲基乙基苯基、戊基苯基、1-甲基丁基苯基、2-甲基丁基苯基、3-甲基丁基苯基、2,2-二甲基丙基苯基、1-乙基丙基苯基、己基苯基、庚基苯基、辛基苯基、甲基萘基、乙基萘基、丙基萘基、1-甲基乙基萘基、丁基萘基、1-甲基丙基萘基、2-甲基丙基萘基、1,1-二甲基乙基萘基、戊基萘基、1-甲基丁基萘基、2-甲基丁基萘基、3-甲基丁基萘基、2,2-二甲基丙基萘基、1-乙基丙基萘基、己基萘基、庚基萘基或辛基萘基;
烷基杂芳基支链或非支链的C1-C8-烷基杂芳基,其具有一个或多个3-至8-元芳香杂环的单或稠合芳环系,如果需要含有一个或多个杂原子诸如S、N或O;
芳基诸如苯基、萘基、蒽基或菲基;
杂芳基具有一个或多个5-至8-元的芳香杂环的单或稠合的芳环系,如果需要含有一个或多个杂原子诸如S、N或O,诸如噻吩基、吡啶基或吲哚基。
所有所述的基团R1或R2(如果合适)可以被基团-NHp(C1-C8-烷基)2-p、-QHn(C1-C8-烷基)1-n、-SS-叔丁基、-CN、-NO2或诸如氟、氯、溴或碘的卤素中的一个或多个所取代,其中p是0、1或2;Q是硫或氧,n是0或1,且C1-C8-烷基具有上述含义。
R1和R2的优选基团是那些来源于天然或非天然的氨基酸的基团,在这些基团中的官能基能够被保护或不被保护。由于基团R1和R2有利地来源于天然或非天然的氨基酸,所以与所述基团邻接的立构中心可以存在于D和L构型中(=R-或S-型)。R1和R2的另外的优选基团是取代或非取代的支链或非支链的C1-C4-烷基、C1-C4-烷芳基或C1-C4-烷基杂芳基、取代或非取代的芳基或杂芳基,且特别优选的是C1-C4-烷芳基。
在不太优选的形式中,基团R1和R2一般还可以是氢。然而,含有这些基团的化合物仅表现出很小或几乎没有生物作用。
上述通式I、III和IV中的取代基R3具有下列含义:
如果合适,通式a、b或c可以带有其它取代基。通式b中的R5具有下述含义。
上述通式I和V中的取代基R4具有下列含义:
取代基R4是取代或非取代的C4-C14-芳基、C4-C14-杂芳基,该基团带有一个或多个含有一个或多个杂原子的环,所述的杂原子选自O、S和N,其中
C4-C14-芳基诸如苯基、萘基、蒽基或菲基;
C4-C14-杂芳基具有一个或多个5-至8-元芳香杂环的单或稠合芳环系,可以(如果合适)含有一个或多个杂原子诸如S、N或O,诸如噻吩基、吡啶基或吲哚基。
所有所述的基团R4可以(如果合适)被下列基团中的一个或多个所取代:支链或非支链的C1-C4-烷基、C6-C14-芳基、-COOR6、-NHp(C1-C8-烷基)2-p、-QHn(C1-C8-烷基)1-n、-SS-叔丁基、-CN、-NO2或诸如氟、氯、溴或碘的卤素,其中R6是H或C1-C8-烷基,p是0、1或2;Q是硫或氧,n是0或1,且C1-C8-烷基、C1-C4-烷基或C6-C14-芳基具有上述含义。
上述通式b中的取代基R5具有下列含义:
R5是C1-C8-烷基、C1-C8-烷芳基、芳基或杂芳基,
烷基支链或非支链的C1-C8-烷基链诸如甲基、乙基、正丙基、1-甲基乙基、正丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、1-乙基丙基、正己基、1,1-二甲基丙基、1,2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、正庚基或正辛基;
烷芳基支链或非支链的C1-C8-烷芳基诸如C1-C8-烷基苯基或C1-C8-烷基萘基,诸如甲基苯基、乙基苯基、丙基苯基、1-甲基丙基苯基、丁基苯基、1-甲基丙基苯基、2-甲基丙基苯基、1,1-二甲基乙基苯基、戊基苯基、1-甲基丁基苯基、2-甲基丁基苯基、3-甲基丁基苯基、2,2-二甲基丙基苯基、1-乙基丙基苯基、己基苯基、庚基苯基、辛基苯基、甲基萘基、乙基萘基、丙基萘基、1-甲基乙基萘基、丁基萘基、1-甲基丙基萘基、2-甲基丙基萘基、1,1-二甲基乙基萘基、戊基萘基、1-甲基丁基萘基、2-甲基丁基萘基、3-甲基丁基萘基、2,2-二甲基丙基萘基、1-乙基丙基萘基、己基萘基、庚基萘基或辛基萘基;
芳基诸如苯基、萘基、蒽基或菲基;
杂芳基具有一个或多个5-至8-元芳香杂环的单或稠合的芳环系,可以(如果合适)含有一个或多个杂原子诸如S、N或O,诸如噻吩基、吡啶基或吲哚基;
基团R5可以(如果合适)带有另外的取代基。
本发明的化合物可以是游离化合物的形式或其具有生理活性的盐的形式、其互变异构和同分异构形或游离化合物与各种盐的组合物的形式。本发明的化合物还包括对映形的纯化合物或非对映形的纯化合物、其盐或其混合物。
按照一种自身公知的方式例如通过形成非对映形盐、通过手性色谱法或通过立体有择全合成可以纯化或制备本发明的对映形或非对映形化合物。
通过正如例如Hruby等(J.med.Chem.38,1995,3462)、Coy等(J.med.Chem.30,1987,1162)或coy等(Tetrahedron,44,1988,835)所公开的本领域技术人员公知的方法制备本发明的化合物并因此不需要进一步的解释。因此,有利地在羧酸官能上被适当保护的式II的氨基酸衍生物与式III的氨基醛缩合,得到亚胺,然后通过就地添加酸用例如NaBH3CN使后者还原而得到通式IV的胺(反应图解I)。
适合作为保护基SG1的保护基是所有那些在蛋白质合成中本领域技术人员公知的基团,诸如叔丁基、苄基、三苯甲游基、甲基;或者就是商购的聚苯乙烯树脂形式的聚合连接的保护基,诸如2-氯三苯甲基氯或Wang树脂(由Bachem或Nobvabiochem提供)。优选的保护基是叔丁基和2-氯三苯甲基树脂。
如文献中所述进行向亚胺的转化并在原位进行还原(V.J.Hruby等J.med.Chem.38,1995,3462,D.H.Coy等J.med.Chem.,30,1987,1162和D.H.Coy等Tetrahedron 44 1988 835),如Gallop等(J.Am.Chem.Soc.117,1995,7029)所述能够且有利的是添加原甲酸三甲酯以形成亚胺。
IV转化成I优选在有2-10倍过量酰基氯存在下在吡啶和二氯甲烷的混合物(约1∶1)中于0-100℃下进行,优选20-60℃。
在合成完成后,如果需要,通过常规的色谱法例如通过通常在纯化蛋白质和肽中使用的制备型FPLC或HPLC色谱法来纯化通式I的化合物。
在本发明化合物中用CH2NH基团取代肽键导致这些化合物与肽裂解酶相比具有提高的稳定性并由此表现出较长的生物活性。
由于侧链不受这种修饰的影响,所以本发明的化合物与实际的肽非常相似。因此将它们看作天然底物的稳定合成类似物,这是因为所述物质的构象仅因分子中的这一很小的变化而得到了微不足道的改变或者完全没有因此而改变。
本发明的化合物非常有选择性地抑制具有μm范围活性的内皮缩血管肽转化酶并可将其用于该目的。在这一范围内没有检测到对其它金属蛋白酶诸如ACE(=血管紧张肽转化酶)、NEP 24.11(=中性内肽酶24.11)或基质金属蛋白酶(=MMP)、MMP-1、MMP-3或MMP-9的抑制;嗜热菌蛋白酶、木瓜蛋白酶和凝血酶不接受这些化合物为底物,也不被这些化合物所抑制。这类选择性类别的抑制剂的优点是显而易见的:一方面,在其它酶过程中没有干扰,使得也没有不需要的副作用出现;而另一方面,这些化合物对酶降解非常稳定,因为它们不被非特异性反应中的其它蛋白酶所降解。因此,很可能可以以非常低的剂量将它们进行给药,这意味着例如所述化合物降解产物产生副作用的可能性可以进一步得到降低。
本发明的化合物、其立体异构形和/或具有生理活性的盐以及其互变异构形或同分异构形适用于制备治疗疾病的药物制剂,优选用于制备治疗与血管收缩或其它内皮缩血管肽的生物效能相关的疾病的药物。优选将对映异构的纯化合物或非对映异构的纯化合物用作活性物质。
本发明的化合物提供了对下列疾病的新型治疗潜能:高血压、肺动脉高血压、心肌梗塞、慢性心衰、心绞痛、急性/慢性肾衰竭、肾功能不全、脑血管痉挛、大脑局部缺血、蛛网膜下出血、偏头痛、哮喘、动脉粥样硬化、内毒素休克、内毒素诱发的器官衰竭、血管内凝血、血管成形术后再狭窄、良性前列腺增生、局部缺血和中毒诱发的肾衰竭或高血压、环孢素诱发的肾衰竭、间充质瘤转移和生长、癌症、前列腺癌、造影剂诱发的肾衰竭、胰腺炎和胃肠溃疡。
优选以药物制剂的形式将本发明的化合物进行给药,使得药物的释放在这些条件下进行,即其释放绝大部分在身体的特定膈间例如胃、肠、血流或肝中。
本发明进一步涉及由本发明通式I的抑制剂与凝乳酶-血管紧张肽系统的抑制剂组成的组合制剂。所述的凝乳酶-血管紧张肽系统的抑制剂是凝乳酶抑制剂、血管紧张肽II拮抗剂和(特别是)血管紧张肽转化酶(ACE)抑制剂。
可以将所述的组合物以单一药物剂型或时间且空间分离物的形式进行给药。
由于涉及给药的剂量和方式,所以所考虑的因素与对相应的单一物质的所考虑的因素相同。
这些组合型制剂优选适用于治疗和预防高血压及其后遗症并用于治疗心衰。
可以按照一种常规方式通过口服或非肠道(皮下、静脉内、肌内、腹膜内)给予本发明的化合物。还可以使用吸入剂或喷雾剂通过鼻咽空间进行给药。
剂量取决于患者的年龄、疾病情况和体重以及给药方式。
可以将本发明的新型化合物用于常规固体或液体药物剂型,例如作为片剂、薄膜片剂、胶囊、粉剂、颗粒剂、栓剂、悬浮剂、溶液、软膏剂、霜剂或喷雾剂。以常规方式制备它们。将用于该目的的活性物质与常规药物助剂诸如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、湿润剂、分散剂、乳化剂、溶剂、缓释剂、抗氧化剂和/或推进剂气体一起加工处理(参照H.Sucker等:Pharmazeutische Technologie,Thieme-Verlag,Stuttgart,1991)。在这种方式中获得的给药剂型中一般含有0.1-90重量%的活性物质。
可以将钙拮抗剂与本发明抑制剂的组合物用于治疗以血管收缩为主的疾病或与病理性血管收缩相关的疾病。实例是:所有类型的高血压(包括肺动脉高血压)、冠心病、心衰、肾和大脑局部缺血、急性和慢性肾功能不全。
由于单个组分活性的冲淡差现象,所以组合两类活性物质是一种理想的添加过程。另一种优点在于剂量的降低意味着不需要的副作用更不可能出现。
一般通过口服方式给予本发明的组合物,例如通过片剂、包衣片剂、糖衣药丸、硬和软胶囊、溶液、乳剂或悬浮液的形式。然而,还可以通过直肠给药,例如通过栓剂的形式;或通过胃肠外例如注射用溶液的形式给药。可以以含有两种相互混合的活性物质的产物形式诸如片剂或胶囊给予活性物质;或分开的为此组合目的的单一物质可以同时或连续给药。
通过将本发明的组合物与药物上的惰性无机或有机赋形剂一起加工处理可以生产片剂、包衣片剂、糖衣药丸和硬胶囊。可以用于不片剂糖衣药丸和硬胶囊的赋形剂是乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐。适于软胶囊的赋形剂是植物油、蜡、脂肪、半固体和液体多元醇。
用于制备溶液和糖浆的合适的赋形剂的实例是水、多元醇、蔗糖、惰性糖、葡萄糖等。用于注射用溶液的合适赋形剂是水、醇、多元醇、甘油、植物油。用于栓剂的合适的赋形剂是天然硬化油、蜡、脂肪、半液体或液体多元醇等。
药物制剂可以另外含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、增甜剂、着色剂、调味剂、改变渗透压的盐、缓冲剂、包衣剂和/或抗氧化剂。
实施例:实施例1:化合物1a至1k的合成
在9ml 99∶1 DMF/HOAc中,a.在0.4mmol具有被2-Cl-三苯甲基-树脂(2a)保护C-末端的苯基丙氨酸中的加入0.75mmol N-Fmoc-苯基丙氨酸(3a)(R=CH2PH,R3=Fmoc)并一起振摇0.5小时。然后分几部分加入NaBH3CN,直到茚三酮试验显示没有游离伯氨基存在为止。接着通过抽吸过滤、用DMF、异丙醇和二氯甲烷洗涤固体(4a)并在真空中干燥。
在约10ml 1/1吡啶/二氯甲烷中,在0.4mmol的(4a)于中加入催化量的DMAP(=4-二甲氨基吡啶)和2mmol 2-噻吩碳酰氯并一起振摇、直到茚三酮试验显示没有仲氨基存在为止。接着通过抽吸过滤反应物、用DMF和二氯甲烷洗涤,并按如下方式除去聚合保护基:
将(4a)在约10ml的1/1/8乙酸、三氟乙醇和二氯甲烷的混合物中振摇1小时,并过滤和浓缩含有1a的溶液(反应图解II)。
如Schmidt等(FEBS Letters 356,1994:238-243)所述,使用来自CHO细胞的重组人ECE来检测内皮缩血管肽转化酶(ECE)抑制剂。
在膜的分离和溶解后,通过单-Q色谱法和WGA卵磷脂(lectin)色谱法进一步纯化所用的酶制剂。在这种方式中获得的制剂不含干扰异种蛋白酶活性并具有1-20mU/mg范围的特异性活性。将5μl的这种酶溶液用495μl的试验缓冲液(100mM Pi,500mM NaCl,0.1mg/mlBSA pH 7.2)并在每种情况中用5μl在所述试验缓冲液适当浓缩的抑制剂溶液(10-3M、10-4M、10-5M等)预培养10分钟。将50μl的等分试样与溶于0.02%乙酸的5μl 2×10-3 M大ET1溶液(=大内皮缩血管肽1)混合。1小时后,在37℃下,通过添加150μl的0.5%TFA(=三氟乙酸)水溶液终止混合物的反应并以10000×g离心5分钟,且如Takada等(Biochem.Biophys.Res.Comm.176,1991,860)、K.Ohnaka等(Biochem.Biophys.Res.Comm.168,1990,1128)所述通过测定借助于反相HPLC形成的内皮缩血管肽而确定酶反应物。根据不同抑制剂浓度下的抑制值来产生抑制区并读出半数最大抑制量(IC50)作为抑制作用强度的测定值。表I表明了各种物质对ECE、ACE和NEP 24.11的IC50值。表I:各种抑制剂的IC50值
化合物 | IC50(ECE) | IC50(ACE) | IC50(NEP) |
1a | 2μm | >100μm | >100μm |
1b | 3μm | >100μm | >100μm |
1c | 4μm | >100μm | >100μm |
Claims (12)
2.如权利要求1所述的通式I的化合物、其具有生理活性的盐或其组合物,其中取代基R1和R2彼此独立为取代或非取代的支链或非支链的C1-C4-烷基、C1-C4-烷芳基或C1-C4-烷基杂芳基、取代或非取代的芳基或杂芳基。
4.如权利要求1所述的通式I的化合物、其具有生理活性的盐或其组合物用于制备治疗疾病的药物制剂的用途。
5.如权利要求1所述的通式I的化合物、其具有生理活性的盐或其组合物用于制备治疗与血管收缩或其它内皮缩血管肽的生物效能相关的疾病的药物制剂的用途。
6.如权利要求1所述的通式I的化合物、其具有生理活性的盐或其组合物用于制备治疗疾病的药物制剂的用途,所述的疾病选自高血压、肺动脉高血压、心肌梗塞、慢性心衰、心绞痛、急性/慢性肾衰竭、肾功能不全、脑血管痉挛、大脑局部缺血、蛛网膜下出血、偏头痛、哮喘、动脉粥样硬化、内毒素休克、内毒素诱发的器官衰竭、血管内凝血、血管成形术后再狭窄、良性前列腺增生、局部缺血和中毒诱发的肾衰竭或高血压、环孢素诱发的肾衰竭、间充质瘤转移和生长、癌症、前列腺癌、造影剂诱发的肾衰竭、胰腺炎和胃肠溃疡。
7.如权利要求1所述的通式I的化合物用于抑制内皮缩血管肽转化酶的用途。
8.如权利要求7所述的化合物用于选择性抑制内皮缩血管肽转化酶的用途,其中不抑制其它蛋白酶,所述的其它蛋白酶选自ACE、NEP、MMP-1、MMP-3、MMP-9、嗜热菌蛋白酶、木瓜蛋白酶和凝血酶。
9.如权利要求1所述的通式I的化合物与可降血压的其它活性物质一起用于制备治疗疾病的药物制剂的用途。
10.一种含有如权利要求1所述的通式I化合物、其具有生理活性的盐或其组合物的药物制剂。
11.一种如权利要求10所述药物制剂与至少一种其它可降血压的活性物质的组合物。
12.一种如权利要求11所述的组合物,含有ACE抑制剂作为降血压的活性物质。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19745146.2 | 1997-10-14 | ||
DE19745146A DE19745146A1 (de) | 1997-10-14 | 1997-10-14 | Neue pharmazeutisch wirksame Verbindungen, ihre Herstellung und Verwendung |
Publications (1)
Publication Number | Publication Date |
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CN1275981A true CN1275981A (zh) | 2000-12-06 |
Family
ID=7845379
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98810211A Pending CN1275981A (zh) | 1997-10-14 | 1998-09-18 | 新型药物活性化合物、其制备方法和其用作ece抑制剂的用途 |
Country Status (14)
Country | Link |
---|---|
US (1) | US6469056B1 (zh) |
EP (1) | EP1023282A1 (zh) |
JP (1) | JP2001519427A (zh) |
KR (1) | KR20010024480A (zh) |
CN (1) | CN1275981A (zh) |
AU (1) | AU1023599A (zh) |
BR (1) | BR9813037A (zh) |
CA (1) | CA2305499A1 (zh) |
DE (1) | DE19745146A1 (zh) |
HU (1) | HUP0004734A3 (zh) |
IL (1) | IL135168A0 (zh) |
NO (1) | NO20001846D0 (zh) |
WO (1) | WO1999019320A1 (zh) |
ZA (1) | ZA989312B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030176356A1 (en) * | 2001-04-24 | 2003-09-18 | University Of North Texas Health Science Center | Endothelin antagonists and endothelin-converting enzyme inhibitors for the treatment of glaucoma |
JP2005500287A (ja) | 2001-06-11 | 2005-01-06 | シャイアー バイオケム インコーポレイテッド | Flavivirus感染の処置または予防のための化合物および方法 |
CA2510811A1 (en) * | 2002-12-20 | 2004-07-08 | Bayer Healthcare Ag | Use of substituted 2,5-diamidoindoles for the treatment of urological diseases |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9300048D0 (en) | 1993-01-04 | 1993-03-03 | Wellcome Found | Endothelin converting enzyme inhibitors |
WO1994022906A1 (en) * | 1993-03-26 | 1994-10-13 | Warner-Lambert Company | Inhibitors of endothelin converting enzyme |
GB9313330D0 (en) * | 1993-06-28 | 1993-08-11 | Fujisawa Pharmaceutical Co | New compound and its preparation |
BR9407933A (pt) | 1993-11-01 | 1996-11-26 | Japat Ltd | Antagonistas de receptores de endotelina |
US5610177A (en) * | 1994-08-08 | 1997-03-11 | Warner-Lambert Company | Acylated amino acids as endothelin antagonists |
-
1997
- 1997-10-14 DE DE19745146A patent/DE19745146A1/de not_active Withdrawn
-
1998
- 1998-09-18 HU HU0004734A patent/HUP0004734A3/hu unknown
- 1998-09-18 WO PCT/EP1998/005945 patent/WO1999019320A1/de not_active Application Discontinuation
- 1998-09-18 CA CA002305499A patent/CA2305499A1/en not_active Abandoned
- 1998-09-18 KR KR1020007003933A patent/KR20010024480A/ko not_active Application Discontinuation
- 1998-09-18 IL IL13516898A patent/IL135168A0/xx unknown
- 1998-09-18 CN CN98810211A patent/CN1275981A/zh active Pending
- 1998-09-18 BR BR9813037-4A patent/BR9813037A/pt not_active IP Right Cessation
- 1998-09-18 AU AU10235/99A patent/AU1023599A/en not_active Abandoned
- 1998-09-18 US US09/529,181 patent/US6469056B1/en not_active Expired - Fee Related
- 1998-09-18 JP JP2000515892A patent/JP2001519427A/ja active Pending
- 1998-09-18 EP EP98952597A patent/EP1023282A1/de not_active Withdrawn
- 1998-10-13 ZA ZA9809312A patent/ZA989312B/xx unknown
-
2000
- 2000-04-10 NO NO20001846A patent/NO20001846D0/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
NO20001846L (no) | 2000-04-10 |
HUP0004734A1 (hu) | 2001-05-28 |
JP2001519427A (ja) | 2001-10-23 |
US6469056B1 (en) | 2002-10-22 |
EP1023282A1 (de) | 2000-08-02 |
NO20001846D0 (no) | 2000-04-10 |
HUP0004734A3 (en) | 2002-11-28 |
ZA989312B (en) | 2000-04-13 |
IL135168A0 (en) | 2001-05-20 |
BR9813037A (pt) | 2000-08-15 |
DE19745146A1 (de) | 1999-04-15 |
CA2305499A1 (en) | 1999-04-22 |
WO1999019320A1 (de) | 1999-04-22 |
AU1023599A (en) | 1999-05-03 |
KR20010024480A (ko) | 2001-03-26 |
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