CN1450996A - 2－胍基－4－芳基喹唑啉 - Google Patents

2－胍基－4－芳基喹唑啉 Download PDF

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CN1450996A
CN1450996A CN01815093A CN01815093A CN1450996A CN 1450996 A CN1450996 A CN 1450996A CN 01815093 A CN01815093 A CN 01815093A CN 01815093 A CN01815093 A CN 01815093A CN 1450996 A CN1450996 A CN 1450996A
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R·格里克
N·贝尔
C·维尔姆
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Abstract

本发明涉及式I化合物及其盐和溶剂化物，其中Y是(II)或(III)，Ar：R1、R2、R5、R6、R7和R8定义同上，以及它们作为NHE－3抑制剂的用途。

Description

2-胍基-4-芳基喹唑啉
本发明涉及式I化合物及其盐和溶剂化物：
Figure A0181509300061
其中：Y    是或 Ar    是苯基或萘基，它们各自为未取代的或被R3和/或R4一取代，R1、R2、R3和R4彼此独立，各自为H、A、OA、Hal、CF3、OH、NO2、
NH2、NHA、NA2、NH-CO-A、NH-CO-Ph、SA、SO-A、SO2-A
、SO2-Ph、CN、OCF3、CO-A、CO2H、CO2A、CO-NH2、CO-NHA、
CO-NA2、SO2NH2、SO2NHA、SO2NA2或为未取代的或被A、
OA、Hal或CF3一取代或多取代的苯基，A    是具有1、2、3、4、5或6个碳原子的烷基，Hal  是F、Cl、Br或I，R5、R6、R7和R8彼此独立，各自为H、A或为未取代的或被A、OA、
Hal或CF3一取代或多取代的苯基，其中R5和R7、R5和R6以
及R7和R8能够形成5-7元环，条件是不包括其中R5、R6、R7和R8同时为氢，并且基团R1、R2、R3和R4均不为OH、NO2、NH2、NHA、NA2、NH-CO-A、NH-CO-Ph、SA、SO-A、SO2-A、SO2-Ph、CN、OCF3、CO-A、CO2H、CO2A、CO-NH2、CO-NHA、CO-NA2、SO2NH2、SO2NHA、SO2NA2或者未取代的或被A、OA、Hal或CF3一取代或多取代的苯基的化合物。
本发明同样涉及式I化合物及其盐和溶剂化物作为NHE-3抑制剂的用途。
所述钠/质子交换剂亚型3的其它抑制剂已有报道，例如见EP 0825 178。在US3,131,187中已报道除前提条件外的所述化合物具有其它目的的用途。V.I.Shvedov等在Pharm.Chem.J.(Engl.transl.)1980，14，532-538中或者Khim.Farm.Zh.1980，14，38-43中以及S.C.Bell等在J.Med.Pharm.Chem.1962，5，63-69中报道喹唑啉基胍衍生物。
本发明目的在于发现具有有价值的新化合物，尤其是那些可用于制备药物的化合物。
令人惊奇地是，已发现式I化合物及其盐具有良好的耐受性，并能抑制钠/质子交换剂亚型3。
式I化合物可用作人用或兽用药物中的药物活性成分。
已知Na+/H+交换剂代表具有至少6种不同同工型(NHE-1至NHE-6)的一族，所有这些同工型已被克隆。当亚型NHE-1分布在体内的所有组织中时，其它NHE亚型就选择性地表达在特定的器官，如肾或小肠的腔壁和对腔壁中。这种分布反应了各种同工型的特定功能，即一方面可通过亚型NHE-1调节胞内pH和细胞体积，另一方面通过同工型NHE-2和NHE-3调节小肠和肾中Na+的吸收和再吸收。已发现同工型NHE-4主要存在于胃中。NHE-5的表达被限制在脑和神经组织。NHE-6是在线粒体中形成钠/质子交换剂的同工型。
同工型NHE-3尤其表达在肾小管近端的顶端膜中；因此NHE-3抑制剂特别呈现出肾保护作用。
NHE-3同工型的选择性抑制剂的医疗用途是多种多样的。在可导致激活NHE活性的病理生理性低氧和局部缺血发生后，如在肾局部缺血过程中或者在肾移植的肾摘除、转运或再灌注过程中，NHE-3抑制剂抑制或降低组织损伤和细胞坏死。式I化合物具有细胞保护作用，原因是在供氧不足的情况下，所述化合物能预防钠和水过量吸收至器官的细胞中。
式I化合物具有降血压作用，适于用作治疗高血压的药物的活性组分。它们还适用作利尿剂。当单独或与其它亚型特异性的NHE抑制剂联合使用时，式I化合物具有抗局部缺血作用，可用于治疗血栓形成、动脉粥样硬化、血管痉挛，在手术之前或手术期间保护器官，例如肾和肝，以及用于治疗慢性或急性肾功能衰竭。
式I化合物还可用于治疗休克、脑水肿、神经系统局部缺血、各种形式的休克，例如过敏性、心源性、血容量过低性或细菌性休克，并可用于改善如以下状态下的呼吸运动：中枢睡眠窒息、卧床死亡、术后低氧和其它呼吸疾病。还可与羰基脱水酶(carboanhydrase)抑制剂合用，进一步改善呼吸活性。
式I化合物具有抑制细胞增殖的作用，例如成纤维细胞增殖和平滑肌细胞增殖，因此可用于治疗其中细胞增殖是主要或次要病因的疾病。
式I化合物可用于延缓糖尿病并发症、癌症、纤维样变性疾病、内皮功能衰退、器官肥大和增生，尤其是前列腺增生或前列腺肥大。它们还适于用作某种形式的压力过高、动脉粥样硬化、糖尿病和增殖性疾病的确定和鉴别的诊断剂。由于式I化合物还具有降低血浆脂蛋白水平的优点，因此它可单独或与其它药物合用以治疗血脂水平的升高。
本发明涉及根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗血栓形成、心脏局部缺血状态、外周和中枢神经系统局部缺血状态以及休克缺血状态、外周器官和末梢的局部缺血状态以及在治疗休克状态的药物中的用途。
本发明还涉及根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于手术和器官移植以及手术移植物的防腐和储存的药物中的用途。
本发明还涉及根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗其中细胞增殖为主要或次要病因的疾病、治疗或预防脂肪代谢紊乱或呼吸运动障碍的药物中的用途。
本发明还涉及根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗肾局部缺血、肠局部缺血疾病或用于预防急性或慢性肾病的药物中的用途。
鉴别可抑制钠/质子交换剂亚型3的物质的方法参见例如US5,871,919中的描述。
另外，式I化合物适于治疗细菌和寄生虫疾病。
对于在式I化合物中出现一次以上的所有基团，如A，其意义彼此独立。
用术语水合物表示如半-、一-或二水合物，用术语溶剂化物表示如醇加成化合物，如甲醇或乙醇化物。
在上述式中，A为直链或支链烷基，具有1、2、3、4、5或6个碳原子。A优选为甲基，以及乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基，还可以是戊基、1-、2-或3-甲基丁基、1，1-、1，2-或2，2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1，1-、1，2-、1，3-、2，2-、2，3-或3，3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基或1，1，2-或1，2，2-三甲基丙基。
OA优选是甲氧基、乙氧基、丙氧基、异丙氧基或丁氧基。
Hal优选是F、Cl或Br，也 可以是I，更优选为F、Cl或Br。
除另有说明，在以上或以下所述中，Ph为未取代的苯基。
Ar优选是未取代的苯基或萘基，还优选是被例如A、氟、氯、溴、碘、甲氧基、乙氧基、丙氧基、丁氧基或CF3一取代的苯基或萘基。Ar特别优选是未取代的或被A、氟、氯、溴、碘、甲氧基、乙氧基、丙氧基、丁氧基或CF3一取代的苯基。
R5、R6、R7和R8优选同时是H或彼此独立为H或A，A定义同上。
如果R5和R7一起形成一个环，Y优选采用下列结构之一：
Figure A0181509300101
或
Figure A0181509300102
其中R6和R8定义同上，n是1、2或3，优选为1或2。
如果R7和R8一起形成一个环，Y优选采用下列结构之一：或 其中R5和R6定义同上，n是1、2或3，优选为1或2。
如果R5知R6一起形成一个环，Y优选采用下列结构之一：或
Figure A0181509300106
其中R7和R8定义同上，n是1、2或3，优选为1或2。
因此，本发明特别涉及其中至少一个所述基团具有以上所述优选意义之一的式I化合物的用途及其用法。可通过以下符合式I的亚式1a-1e表示某些优选的化合物类，其中未详细表述的基团具有式I中指明的意义，但其中：在1a中  R1   是H、OH、OA、SA或Hal，尤其是H、OH、OCH3
          或CH3；在1b中  R1   是H、OH、OA、SA或Hal，尤其是H、OH、OCH3
          或CH3；
    R2   是H、Hal、OH、A、NH2、NO2或CN，尤其是H、
          Cl、OH、CH3或NH2；在1c中  R1   是H、OH、OA、SA或Hal，尤其是H、OH、OCH3
          或CH3；
    R2   是H、Hal、OH、A、NH2、NO2或CN，尤其是H、
          Cl、OH、CH3或NH2；
    Ar    是苯基；在1d中  R1   是H、OH、OA、SA或Hal，尤其是H、OH、OCH3
          或CH3；
    R2   是H、Hal、OH、A、NH2、NO2或CN，尤其是H、
          Cl、OH、CH3或NH2；
    Ar    是苯基；
    R3   是H、A、NH2或SA，尤其是H或CH3；在1e中  R1   是H、OH、OA、SA或Hal，尤其是H、OH、OCH3
          或CH3；
    R2   是H、Hal、OH、A、NH2、NO2或CN，尤其是H、
          Cl、OH、CH3或NH2；
    Ar    是苯基；
    R3   是H、A、NH2或SA，尤其是H或CH3；
    R4   是H、Hal、NH2或NO2，尤其是H或NH2。
优选的式I化合物及其盐和溶剂化物还包括那些其中R同时为氢，Ar为苯基，并且基团R1、R2、R3和R4中至少一个具有以下意义之一的化合物：OH、NO2、NH2、NHA、NA2、NH-CO-A、NH-CO-Ph、SA、SO-A、SO2-A、SO2-Ph、CN、OCF3、CO-A、CO2H、CO2A、CO-NH2、CO-NHA、CO-NA2、SO2NH2、SO2NHA、SO2NA2或为未取代的或被A、OA、Hal或CF3一取代或多取代的苯基。在这些化合物中，特别优选那些其中R1基团是Cl，尤其是在6-位上的化合物，以及那些其中R3基团是甲基，尤其是在4’位上的化合物。
优选的式I化合物及其盐和溶剂化物还包括那些其中基团R5、R6、R7和R8同时为氢的化合物。在这些化合物中，特别优选那些其中基团R1是Cl，尤其是在6-位上的化合物，以及那些其中R3基团是甲基，尤其是在4’位上的化合物，和那些其中R4基团是NH2，尤其是在2’位上的化合物。
其中R3基团是甲基，尤其是在4’位上的式I化合物具有对NHE-3受体特别明显的结合选择性。
其中R4基团是NH2，尤其是在2’位上的式I化合物在水溶液中呈现出特别好的溶解性。
优选其中R1是H，R2是6-位上的Cl和R3是4’位上的甲基的式I化合物。此外，特别优选其中R4基团是2’位上的NH2的式I化合物。特别优选的式1f-1k的化合物为：其中R1、R2、R3、R4和Y定义同上，R1优选是H、OH、OA、SA或F，尤其是H、OH、OCH3或CH3。式1f-1k中的R1特别优选是H。
R2优选是H、Cl、A、NH2、NO2、SCH3、SOCH3、SO2CH3、OCH3、OH、CN、CF3、OCF3或F，尤其是H、Cl、F、Br、OH、CH3、NO2或NH2。式1f-1k中的R2特别优选是Cl。
R3优选是H、Cl、A、NH2、NO2、SCH3、CN、C2H5、OCF3或C6H5，尤其是H、A或CH3。式1f-1k中的R3特别优选是CH3。
R4优选是H、F、NH2或NO2，尤其是H或NH2。式1f-1k中的R4特别优选是NH2。
式1f-1k中的Y定义同上。其中Y优选采用以下意义之一：
Figure A0181509300141
或
Figure A0181509300142
Figure A0181509300143
或
Figure A0181509300145
或
Figure A0181509300147
或 或
Figure A01815093001410
Y特别优选具有以下意义之一：或
Figure A0181509300153
或
还特别优选下列化合物11-110及其盐和溶剂化物：N-(6-氯-4-苯基喹唑啉-2-基)-N’-甲基胍                   11N-(6-氯-4-对甲苯基喹唑啉-2-基)-N’-甲基胍               12N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]-N’-甲基胍           13N-[4-(2-氨基苯基)-6-氯喹唑啉-2-基]-N’-甲基胍           14N-[6-氯-4-(4-甲基-2-硝基苯基)喹唑啉-2-基]-N’-甲基胍    15N-[4-(2-氨基-4-甲基苯基)-6-氯喹唑啉-2-基]-N’-甲基胍    16N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]胍                    17N-[4-(2-氨基苯基)-6-氯喹唑啉-2-基]胍                    18N-[6-氯-4-(4-甲基-2-硝基苯基)喹唑啉-2-基]胍             19N-[4-(2-氨基-4-甲基苯基)-6-氯喹唑啉-2-基]胍            110
特别优选式11-110化合物的盐酸盐和对甲苯磺酸盐。
另外，式I化合物及原料的制备可按本领域已知的方法如在文献中说明的方法(如在标准处理中，如Houben-Weyl，Methoden derorganischen Chemie[Methods of Organic Chemistry]，Georg-Thieme-Verlag，Stuttgart)，在已知的适于该反应的条件下进行。在此合成中，也可采用本领域已知的改变，在此不再详述。
如果需要，也可在原位形成原料，这样可不从反应混合物中进行分离，但应立即进一步转化为式I化合物。
式I的2-胍基-4-芳基喹唑啉优选通过使式II的邻-氨基苯基酮、邻氨基萘基酮：
Figure A0181509300161
其中R1、R2和Ar如权利要求1中定义，与1-氰基胍或式NC-Y的对应的N-烷基化或N-芳基化的1-氰基胍反应制备，其中Y定义同上。
该反应可在惰性溶剂中进行。
适当的惰性溶剂的实例为烃，如己烷、石油醚、苯、甲苯或二甲苯；氯化烃，如三氯乙烯、1，2-二氯乙烷、四氯甲烷、氯仿或二氯甲烷；醇如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇；醚如乙醚、二异丙基醚、四氢呋喃(THF)或二氧六环；乙二醇醚类，如乙二醇一甲醚或一乙醚、乙二醇二甲醚(二甘醇二甲醚)；酮如丙酮或丁酮；酰胺如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮(NMP)或二甲基甲酰胺(DMF)；腈如乙腈；亚砜如二甲亚砜(DMSO)；二硫化碳；羧酸如甲酸或乙酸；硝基化合物，如硝基甲烷或硝基苯；酯，如乙酸乙酯以及所述溶剂的混合物。
优选使用DMF、水或醇。
该反应特别优选在无溶剂下进行，例如在100-200℃温度下，在熔融状态下进行。
优选在酸性催化剂，如AlCl3、TiCl4、对甲苯磺酸、BF3、乙酸、硫酸、草酸、POCl3或五氧化二磷存在下进行。
优选的改变包括采用其中一个反应物的盐(如盐酸盐)作为反应物。
制备式I化合物的另一有用的方法包括用式III化合物替代式NC-Y化合物：
               HN＝CX-Y        III其中X是-S-烷基、-S-芳基、O-烷基或O-芳基，且烷基优选如以上对A的定义，芳基优选如以上对Ar的定义，与式II化合物反应。
最后，式I化合物可通过使式IV的2-氯-4-芳基喹唑啉：其中Ar、R1和R2定义同上，与式HY化合物反应制备，其中Y定义同上。HY特别优选是胍。
可采用酸，如通过在惰性溶剂(如乙醇)中，使等当量的碱和酸反应，接着蒸发，将式I的碱转化为相关的酸加成盐。用于该反应的适合的酸为尤其是产生生理学上可接受的酸的那些酸。因此，可使用无机酸，如硫酸、硝酸、氢卤酸(例如盐酸或氢溴酸)、磷酸(例如正磷酸)或者氨基磺酸，还可使用有机酸，尤其是脂族、脂环族、芳脂族、芳族或杂环一元或多元羧酸、磺酸或硫酸，例如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸、乙二磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘一-和二磺酸以及十二烷基硫酸。可利用生理上不接受的盐(如苦味酸盐)分离和/或纯化式I化合物。
本发明还涉及作为NHE-3抑制剂的式I化合物和/或其生理学上可接受的盐在制备(尤其是通过非化学方法)药用制剂上的用途。在该种情况下，可与至少一种固体、液体和/或半液体赋形剂或辅助剂一起，并且如果需要，还结合一或多种其它的活性成分，将所述本发明化合物转化成适当的剂型。
本发明还涉及包含至少一种式I的NHE-3抑制剂和/或一种其生理学上可接受的盐和溶剂化物的药用制剂。
这些制剂可用作人用或兽医方面的药物。适当的赋形剂为适于肠道(例如口服)、非肠道或局部给药并且不与所述新化合物反应的有机或无机物质，如水、植物油、苄醇、亚烷基二醇、聚乙二醇、甘油三乙酸酯、明胶、碳水化合物，如乳糖或淀粉、硬脂酸镁、滑石粉或凡士林。适于口服给药的剂型优选片剂、丸剂、包衣片剂、胶囊剂、粉末剂、颗粒剂、糖浆剂、果汁剂或滴剂，适于直肠给药的剂型为栓剂，适于非肠道给药的为溶液剂，优选油基质或水溶液，还可为混悬剂、乳剂或植入剂，适合局部应用的为软膏剂、霜剂或粉末剂，或者经皮贴剂。
还可将所述新化合物冷冻干燥并将得到的冷冻干燥品例如用于注射剂的制备。可将所提的该制剂灭菌和/或该制剂可包含辅助剂，如润滑剂、防腐剂、稳定剂和/或湿润剂、乳化剂、改善渗透压的盐类、缓冲物质、着色剂和矫味剂和/或多种其它活性组分，例如一或多种维生素。
用于气雾剂或喷雾剂形式给药的适当的药用剂型为，例如式I活性组分在药学上可接受的溶剂中的溶液、混悬液或乳液。
式I化合物及其生理学上可接受的盐和溶剂化物可用于治疗和/或预防上述疾病或疾病状态。
通常，本发明物质优选的给药剂量在每剂量单位约0.1-500mg之间，尤其是1-10mg之间。日剂量优选在每kg体重约0.001-10mg之间。但是，各患者的具体剂量依据多种因素而定，如所用具体化合物的药效、年龄、体重、健康状况、性别、饮食、给药次数和方法、排泄率、联合使用的药物以及所治疗的具体疾病的严重程度。优选口服给药。
实施例：实施例1：
在150℃下，将1.00g2-氨基-5-氯-2’-硝基二苯酮、0.60g1-氰基胍和2.00g对甲苯磺酸一水合物的混合物熔融2小时。向冷却的熔融物中加入甲醇，在65℃下，将该混合物搅拌30分钟。弃去过滤后得到的残留物，向滤液中加入水。然后使该溶液呈碱性，并用乙酸乙酯提取。蒸发提取物，用乙腈结晶，得到游离碱N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]胍鎓。
为形成酸加成盐，将该碱溶解于甲醇中，将该混合物用含有HCl的异丙醇酸化，然后除去溶剂。从乙腈中得到氯化N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]胍鎓的晶体。实施例2：
在170℃下，将1.20g氯化N-(5-甲氧基-4-苯基喹唑啉-2-基)胍鎓与8.00g氯化吡啶鎓一起搅拌6小时。然后将冷却的熔融物用20ml的Na2S2O4溶液处理，分离产生的沉淀物并使之溶于甲醇中，将该溶液用含HCl的异丙醇酸化。除去溶剂，然后将残留物从乙腈中结晶，得到氯化N-(5-羟基-4-苯基喹唑啉-2-基)胍鎓(m.p.310℃)。实施例3：
在150-160℃熔融状态下，将3.01g2-氨基-5-氯二苯酮、2.55gN-氰基-N’-甲基胍和7.42g对甲苯磺酸一水合物的混合物搅拌2小时。向冷却的熔融物中加入甲醇，在65℃下，将该混合物搅拌30分钟。弃去过滤后得到的残留物，向滤液中加入水和乙酸乙酯，再在65℃下将该混合物搅拌30分钟。然后在冰浴中，搅拌下使产物结晶，得到对甲苯磺酸N-(6-氯-4-苯基喹唑啉-2-基)-N’-甲基胍鎓(m.p.268-269℃)。实施例4：
将300mg对甲苯磺酸N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]胍鎓溶解于50ml甲醇中，并在大气压力下，在300mgRaney镍存在下，于室温下氢化21小时。过滤，除去溶剂，从滤液中得到对甲苯磺酸N-[6-氯-4-(2-氨基苯基)喹唑啉-2-基]胍鎓(m.p.250℃)。实施例5：
在80℃下，将0.350g氯化N-(6-甲基硫基(sulfanyl)-4-苯基喹唑啉-2-基)胍鎓与0.140g过硼酸钠三水合物在5ml乙酸中的混合物搅拌30分钟。然后将该溶液蒸发，加入水。将该水溶液调节至pH12，用乙酸乙酯提取。蒸发提取物，得到结晶形式的N-(6-甲亚磺酰基-4-苯基喹唑啉-2-基)胍(m.p.175-180℃)。实施例6：
在80℃下，将1.200g氯化N-(6-甲基硫基-4-苯基喹唑啉-2-基)胍鎓与0.154g过硼酸钠三水合物在5ml乙酸中的混合物搅拌1小时。然后将该反应混合物蒸发，加入水。将得到的溶液调节至pH12，用乙酸乙酯提取。蒸发提取液，得到结晶形式的N-(6-甲磺酰基-4-苯基喹唑啉-2-基)胍(m.p.180-185℃)。
为形成酸加成盐，将0.80g的N-(6-甲磺酰基-4-苯基喹唑啉-2-基)胍用1NHCl水溶液处理，将得到的结晶从乙醇中重结晶。实施例7：
将2.70g的2-氨基-5-氯二苯酮盐酸盐和1.70g的N-氰基-N’，N”-二甲基胍混合，然后在150℃下加热3小时。将反应产物吸收至甲醇中，过滤。蒸发滤液。使残留物从异丙醇和乙醚的混合液中重结晶，得到氯化N-(6-氯-4-苯基喹唑啉-2-基)-N’，N”-二甲基胍鎓(m.p.264-267℃)。实施例8：
在150-160℃熔融状态下，将500mg的2-氨基-5-氯-2’-硝基二苯酮、406mg的N-氰基-N’-乙基胍和1.03g的对甲苯磺酸一水合物的混合物搅拌2小时，然后如实施例3处理，得到对甲苯磺酸N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]-N’-乙基胍鎓(m.p.298-300℃)。实施例9：
在150-160℃熔融状态下，将500mg的2-氨基-5-氯-2’-硝基二苯酮、580mg的N-氰基-N-苯基胍和1.03g的对甲苯磺酸一水合物的混合物搅拌2小时，然后按实施例3处理，得到对甲苯磺酸N-[6-氯化-4-(2-硝基苯基)喹唑啉-2-基]-N’-苯基胍鎓(m.p.261-263℃)。
通过类似于上述的方法，采用相应的前体，获得下列优选作为NHE-3抑制剂的酸加成盐。
pTsOH表示对甲苯磺酸。实施例10-101：
    R1   R2   R3      R4       HX(10)    H     Cl    H         SO2CH3  pTsOH(11)    H     Cl    CH3      SO2CH3  HCl(12)    H     Cl    C2H5    SO2CH3  HCl(13)    H     Cl    OCH3     SO2CH3  HCl(14)    H     Cl    NO2      H          pTsOH(15)    H     Cl    NH2      H          pTsOH  (m.p.260-266℃)(16)    H     Cl    N(CH3)2 H          pTsOH(17)    H     Cl    H         NH2       HCl(18)    H     Cl    CH3      NH2       pTsOH  (m.p.211-214℃)(19)    H     Cl    C2H5    NH2       HCl(20)    H     Cl    OCH3     NH2       HCl(21)    H     Cl    NO2      NH2       HCl(22)    H     Cl    NH2      NH2       HCl(23)    H     Cl    N(CH3)2 NH2       HCl(24)    H     Cl    H         NHCH3      HCl(25)    H     Cl    CH3      NHCH3      HCl(26)    H     Cl    C2H5    NHCH3      HCl(27)    H     Cl    OCH3     NHCH3      HCl(28)    H     Cl    NO2      NHCH3    HCl(29)    H     Cl    NH2      NHCH3    HCl(30)    H     Cl    N(CH3)2 NHCH3    HCl(31)    H     Cl    H         N(CH3)2 HCl(32)    H     Cl    CH3      N(CH3)2 HCl(33)    H     Cl    C2H5    N(CH3)2 HCl(34)    H     Cl    OCH3     N(CH3)2 HCl(35)    H     Cl    NO2      N(CH3)2 HCl(36)    H     Cl    NH2      N(CH3)2 HCl(37)    H     Cl    N(CH3)2 N(CH3)2 HCl(38)    H     Cl    H         OH         HCl(39)    H     Cl    CH3      OH         HCl(40)    H     Cl    C2H5    OH         HCl(41)    H     Cl    OCH3     OH         HCl(42)    H     Cl    NO2      OH         HCl(43)    H     Cl    NH2      OH         HCl(44)    H     Cl    N(CH3)2 OH         HCl(45)    H     Cl    SO2CH3  CH3       HCl(46)    H     Cl    H          CN         HCl      (m.p.＞350°，
                                                  分解)(47)    H     Cl    C2H5    SO2NH2   HCl(48)    H     Cl    OCF3     CH3        HCl(49)    H     Cl    NO2      CH3        HCl(50)    H     Cl    NH2      CH3        HCl(51)    H     Cl    N(CH3)2 CH3        HCl(52)    H     Cl    H          NO2        pTsOH  (m.p.313-315℃)(53)    H     Cl    NO2       H           HCl    (m.p.346℃)(54)    H     H     NH2       H           HCl(55)    H     H     NH2       CH3        HCl(56)    H     Cl    CH3       CO-NH2     HCl(57)    H     H     CH3       SO2CH3    pTsOH(58)    H     Cl    OH          F           pTsOH(59)    H     Cl    F           SCH3       HCl(60)    H     Br    H           CONH2      pTsOH(61)    H     Br    CO-NH2     F           pTsOH(62)    H     NO2  H           H           pTsOH  (m.p.317-320℃)(63)    H      OCH3     H      OCF3     pTsOH(64)    H      OH        H      H         HCl     (m.p.333℃)(65)    H      NH2      H      H         HCl     (m.p.290-296℃)(66)    H      SCH3     H      H         HCl     (m.p.234-238℃)(67)    H      CH3      CN     CO-NH2   pTsOH(68)    H      C6H5    H      H         pTsOH   (m.p.188℃)(69)    H      CF3      SOCH3 H         HCl(70)    H      OCF3     H      H         HCl     (m.p.255-259℃)(71)    H      CN        H      H         HCl     (m.p.330℃)(72)    H      F         H      SOC2H5 pTsOH(73)    H      SOCH3    H      H         pTsOH(74)    H      SO2CH3 H      H          pTsOH(75)    H      Cl        CN     H         HCl     (m.p.344℃)(76)    NH2   Cl        Cl     Cl        HCl(77)    H      Cl        H      OCF3     pTsOH   (m.p.274-277℃)(78)    H      Cl        OCF3  H         HCl     (m.p.310-315℃)(79)    Cl     Cl        CH3   OH        HCl(80)    Cl     H         NH2   H         HCl(81)    Cl     H         NH2   CH3      HCl(82)    CH3   Cl        CH3   CO2H     HCl(83)    C6H5 Cl        CH3   F         HCl(84)    OH     CO-NH2   H      H          pTsOH(85)    Cl     H         H      SCH3      pTsOH(86)    H      Cl        Cl     SCH3      pTsOH(87)    SCH3  H         H      H          HCl    (m.p.303-306℃)(88)    H      F         CH3   CN         HCl(89)    H      Cl        SCH3  H          HCl    (m.p.324-327℃)(90)    CH3   H         CN     H          HCl(91)    H      Cl        C6H5 H          HCl    (m.p.200℃)(92)    H      Cl        CH3   NO2       pTsOH  (m.p.210-214℃)(93)    H      H         Br     SO2CH3   pTsOH(94)    H      H         OCH3  OCF3      pTsOH(95)    H      Cl        H      CN          HCl    (m.p.＞350℃，
                                                    分解)(96)    H      Cl        C2H5 NH2       pTsOH  (m.p.＞257℃，
                                                    分解)(97)    H     Cl    CF3        NO2   pTsOH  (m.p.304-308℃)(98)    H     Cl    C2H5      NO2   pTsOH  (m.p.286-287℃)(99)    H     Cl    SOCH3      H       HCl    (m.p.322-324℃)(1O0)   H     Cl    CF3        NH2    pTsOH  (m.p.＞232℃)(101)   H     Cl    N(C2H5)2 H       HCl    (m.p.200℃)实施例102-154：
   R1  R2   R3       R4      HX(102)  H    Cl    H         SO2CH3 pTsOH(103)  H    Cl    CH3      SO2CH3 HCl(104)  H    Cl    C2H5    SO2CH3 HCl(105)  H    Cl    OCH3     SO2CH3 HCl(106)  H    Cl    NO2      H         HCl(107)  H    Cl    NH2      H         HCl(108)  H    Cl    N(CH3)2 H         HCl(109)  H    Cl    H         NH2      HCl(110)  H    Cl    CH3      NH2      HCl(111)  H    Cl    C2H5    NH2      HCl(112)  H    Cl    OCH3     NH2      HCl(113)  H    Cl    NO2      NH2      HCl(114)  H    Cl    NH2      NH2      HCl(115)  H    Cl    N(CH3)2 NH2      HCl(116)  H    Cl    H         NHCH3     HCl(117)  H    Cl    CH3      NHCH3     HCl(118)  H    Cl    C2H5    NHCH3     HCl(119)  H    Cl    OCH3     NHCH3     HCl(120)  H    Cl    NO2      NHCH3     HCl(121)  H     Cl    NH2         NHCH3    HCl(122)  H     Cl    N(CH3)2    NHCH3    HCl(123)  H     Cl    H            N(CH3)2 HCl(124)  H     Cl    CH3         N(CH3)2 HCl(125)  H     Cl    C2H5       N(CH3)2 HCl(126)  H     Cl    OCH3        N(CH3)2 HCl(127)  H     Cl    NO2         N(CH3)2 HCl(128)  H     Cl    NH2         N(CH3)2 HCl(129)  H     Cl    N(CH3)2    N(CH3)2 HCl(130)  H     Cl    H            OH         HCl(131)  H     Cl    CH3         OH         HCl(132)  H     Cl    C2H5       OH         HCl(133)  H     Cl    OCH3        OH         HCl(134)  H     Cl    NO2         OH         HCl(135)  H     Cl    NH2         OH         HCl(136)  H     Cl    N(CH3)2    OH         HCl(137)  H     Cl    SCH3        CH3       HCl(138)  H     Cl    CH3         CH3       HCl(139)  H     Cl    C2H5       CH3       HCl(140)  H     Cl    OCH3        CH3       HCl(141)  H     Cl    NO2         CH3       HCl(142)  H     Cl    NH2         CH3       HCl(143)  H     Cl    N(CH3)2    CH3       HCl(144)  H     OCF3 NH2         H          HCl(145)  H     OCF3 NH2         CH3       HCl(146)  H     OCH3 SO2CH3     SO2CH3  pTsOH(147)  H     OH    H             H          pTsOH(148)  Cl    OCH3 NH2         H          HCl(149)  Cl    Cl    NH2         CH3       HCl(150)  OCH3 SCH3 H            H          pTsOH(151)  OH    H     H             H          HCl    (m.p.326℃)(152)  Cl    F     H             CONH2     pTsOH(153)  H     CH3  n-SC5H11   H           pTsOH(154)  H     Cl    SO2NH2     F           pTsOH实施例155-205：
   R1   R2   R3       R4      HX(155)  OH    Cl    H         SO2CH3 HCl(156)  OH    Cl    CH3      SO2CH3 HCl(157)  OH    Cl    C2H5    SO2CH3 HCl(158)  OH    Cl    OCH3     SO2CH3 HCl(159)  OH    Cl    NO2      H         HCl(160)  OH    Cl    NH2      H         HCl(161)  OH    Cl    N(CH3)2 H         HCl(162)  OH    Cl    H         NH2      HCl(163)  OH    Cl    CH3      NH2      HCl(164)  OH    Cl    C2H5    NH2      HCl(165)  OH    Cl    OCH3     NH2      HCl(166)  OH    Cl    NO2      NH2      HCl(167)  OH    Cl    NH2      NH2      HCl(168)  OH    Cl    N(CH3)2 NH2      HCl(169)  OH    Cl    H         NHCH3    HCl(170)  OH    Cl    CH3      NHCH3    HCl(171)  OH    Cl    C2H5    NHCH3    HCl(172)  OH    Cl    OCH3     NHCH3    HCl(173)  OH    Cl    NO2      NHCH3    HCl(174)  OH    Cl    NH2      NHCH3    HCl(175)  OH    Cl    N(CH3)2 NHCH3    HCl(176)  OH    Cl    H         N(CH3)2 HCl(177)  OH    Cl    CH3      N(CH3)2 HCl(178)  OH    Cl    C2H5    N(CH3)2 HCl(179)  OH    Cl     OCH3     N(CH3)2 HCl(180)  OH    Cl     NO2      N(CH3)2 HCl(181)  OH    Cl     NH2      N(CH3)2 HCl(182)  OH    Cl     N(CH3)2 N(CH3)2 HCl(183)  OH    Cl     H         OH         OH(184)  OH    Cl     CH3      OH         OH(185)  OH    Cl     C2H5    OH         OH(186)  OH    Cl     OCH3     OH         OH(187)  OH    Cl     NO2      OH         OH(188)  OH    Cl     NH2      OH         OH(189)  OH    Cl     N(CH3)2 OH         OH(190)  OH    Cl     COCH3    CH3       HCl(191)  OH    Cl     CH3      CH3       HCl(192)  OH    Cl     C2H5    CH3       HCl(193)  OH    Cl     OCH3     CH3       HCl(194)  OH    Cl     NO2      CH3       HCl(195)  OH    Cl     NH2      CH3       HCl(196)  OH    Cl     N(CH3)2 CH3       HCl(197)  OH    F      NH2      H          HCl(198)  OH    F      NH2      CH3       HCl(199)  OH    F      NH2      H          HCl(200)  OH    F      NH2      CH3       HCl(201)  OH    OH     H         H           HCl    (m.p.290℃)(202)  OCH3 OCH3 H          CO2CH3  pTsOH(203)  Cl    Cl     CO2H     H          HCl(204)  CH3  Cl     CH3      SCH3      HCl(205)  Cl    Cl     SO2NH2  H          HCl实施例206-292：
   R1  R2   R3      R4       HX(206)  H    Cl    H         NO2      HCl    (m.p.342℃)(207)  H    Cl    CH3      NO2      HCl(208)  H    Cl    C2H5    NO2      HCl(209)  H    Cl    OCH3     NO2      HCl(210)  H    Cl    NO2      NO2      HCl(211)  H    Cl    NH2      NO2      HCl(212)  H    Cl    N(CH3)2 NO2      HCl(213)  H    Cl    H         NH2      HCl    (m.p.300-340℃)(214)  H    Cl    CH3      NH2      HCl(215)  H    Cl    C2H5    NH2      HCl(216)  H    Cl    OCH3     NH2      HCl(217)  H    Cl    NO2      NH2      HCl(218)  H    Cl    NH2      NH2      HCl(219)  H    Cl    N(CH3)2 NH2      HCl(220)  H    Cl    H         NHCH3    HCl(221)  H    Cl    CH3      NHCH3    HCl(222)  H    Cl    C2H5    NHCH3    HCl(223)  H    Cl    OCH3     NHCH3    HCl(224)  H    Cl    NO2      NHCH3    HCl(225)  H    Cl    NH2      NHCH3    HCl(226)  H    Cl    N(CH3)2 NHCH3    HCl(227)  H    Cl    H         N(CH3)2 HCl(228)  H    Cl    CH3      N(CH3)2 HCl(229)  H       Cl     C2H5     N(CH3)2 HCl(230)  H       Cl     OCH3      N(CH3)2 HCl(231)  H       Cl     NO2       N(CH3)2 HCl(232)  H       Cl     NH2       N(CH3)2 HCl(233)  H       Cl     N(CH3)2  N(CH3)2 HCl(234)  H       Cl     H           OH         pTsOH  (m.p.252-254℃)(235)  H       Cl     CH3       OH         HCl(236)  H       Cl     C2H5     OH         HCl(237)  H       Cl     OCH3      OH         HCl(238)  H       Cl     NO2       OH         HCl(239)  H       Cl     NH2       OH         HCl(240)  H       Cl     N(CH3)2  OH         HCl(241)  H       Cl     CN          CH3      HCl(242)  H       Cl     CH3       CH3       HCl(243)  H       Cl     C2H5     CH3       HCl(244)  H       Cl     OCH3      CH3       HCl(245)  H       Cl     NO2       CH3       HCl(246)  H       Cl     NH2       CH3       HCl(247)  H       Cl     N(CH3)2  CH3       HCl(248)  H       Cl     CONH2     F          HCl(249)  H       Cl     NO2       F          HCl(250)  H       H      NH2       F          HCl(251)  H       H      NH2       CH3       HCl(252)  H       Cl     SCH3      Cl         HCl(253)  C6H5 H      CH3       F          HCl(254)  CN      Cl     F          F          HCl(255)  H       Cl     H          CN         HCl    (m.p.350℃)(256)  H       Br     H          CN         HCl(257)  H       Br     SOCH3     F          HCl(258)  H       NO2   H          F          HCl(259)  H       OCH3  CN         F          HCl(260)  H       OH     H          F          HCl(261)  H       NH2   H          F          HCl(262)  H       SCH3  H          F          HCl(263)  H       CH3   CONH2     F          HCl(264)  H       C6H5 H          F          HCl(265)  H     CF3      SOCH3    F          HCl(266)  H     OCF3     H         F          HCl(267)  H     CN        H         F          HCl(268)  H     F         SOCH3    F          HCl(269)  H     SOCH3    H         F          HCl(270)  H     SO2CH3  H         F          HCl(271)  H     Cl        CN        F          HCl(272)  H     Cl        CONH2    Cl         HCl(273)  H     Cl        H         OCF3      pTSOH  (m.p.260-264℃)(274)  H     Cl        OCF3     F          HCl(275)  Cl    Cl        SO2NH2  F          HCl(276)  Cl    H         NH2      F          HCl(277)  Cl    H         NH2      CH3       HCl(278)  CH3  Cl        NHCH3    F          HCl(279)  F     Cl        CH3      NHCH3     HCl(280)  H     H         C6H5    F          HCl(281)  Cl    NH2      F         F          HCl(282)  NH2  Cl        Cl        F          HCl(283)  SCH3 H         H         F          HCl(284)  H     F         N(CH3)2 F          HCl(285)  H     Cl        SCH3     F          HCl(286)  H     H         OCF3     CH3       HCl(287)  H     Cl        SOCH3    H          HCl    (m.p.240℃)(288)  H     Cl        CH3      NH2       pTsOH  (m.p.217-218℃)(289)  H     Cl        H         OCF3      HCl    (m.p.260-264℃)(290)  H     Cl        H         CO2CH3   HCl    (m.p.275-277℃)(291)  H     Cl        CH3      NO2       pTsOH  (m.p.218-220℃)(292)  H     Cl        H         NHCOCH3   HCl    (m.p.317-320℃)实施例293-379：
Figure A0181509300321
   R1  R2   R3       R4      HX(293)  H    Cl    H         H         pTsOH  (m.p.268-296℃)(294)  H    Cl    CH3      H         HCl    (m.p.291-293℃)(295)  H    Cl    C2H5    H         HCl(296)  H    Cl    OCH3     H         HCl(297)  H    Cl    NO2      H         HCl(298)  H    Cl    NH2      H         HCl(299)  H    Cl    N(CH3)2 H         HCl(300)  H    Cl    H         NH2      HCl(301)  H    Cl    CH3      NH2      HCl(302)  H    H     H         NH2      pTsOH   (m.p.231-233℃)(303)  H    Cl    OCH3     NH2      HCl(304)  H    Cl    NO2      NH2      HCl(305)  H    Cl    NH2      NH2      HCl(306)  H    Cl    N(CH3)2 NH2      HCl(307)  H    Cl    H         NHCH3    HCl(308)  H    Cl    CH3      NHCH3    HCl(309)  H    Cl    C2H5    NHCH3    HCl(310)  H    Cl    OCH3     NHCH3    HCl(311)  H    Cl    NO2      NHCH3    HCl(312)  H    Cl    NH2      NHCH3    HCl(313)  H    Cl    N(CH3)2 NHCH3    HCl(314)  H    Cl    H         N(CH3)2 HCl(315)  H    Cl    CH3      N(CH3)2 HCl(316)  H    Cl     C2H5    N(CH3)2 HCl(317)  H    Cl     OCH3     N(CH3)2 HCl(318)  H    Cl     NO2      N(CH3)2 HCl(319)  H    Cl     NH2      N(CH3)2 HCl(320)  H    Cl     N(CH3)2 N(CH3)2 HCl(321)  H    Cl     H         OH        HCl(322)  H    Cl     CH3      OH        HCl(323)  H    Cl     C2H5    OH        HCl(324)  H    Cl     OCH3     OH        HCl(325)  H    Cl     NO2      OH        HCl(326)  H    Cl     NH2      OH        HCl(327)  H    Cl     N(CH3)2 OH        HCl(328)  H    Cl     H         CH3      HCl(329)  H    Cl     CH3      CH3      HCl(330)  H    Cl     C2H5    CH3      HCl(331)  H    Cl     OCH3     CH3      HCl(332)  H    Cl     NO2      CH3      HCl(333)  H    Cl     NH2      CH3      HCl(334)  H    Cl     N(CH3)2 CH3      HCl(335)  H    Cl     H         NO2      pTsOH    (m.p.278-279℃)(336)  H    Cl     NO2      H         HCl(337)  H    H      NH2      H         HCl(338)  H    H      NH2      CH3      HCl(339)  H    Cl     CH3      Cl        HCl(340)  H    H      CH3      H         HCl(341)  H    Cl     H         F         HCl(342)  H    Cl     F         H         HCl(343)  H    Br     H         H         HCl(344)  H    Br     H         F         HCl(345)  H    NO2   H         H         HCl(346)  H    OCH3  H         H         HCl(347)  H    OH     H         H         HCl(348)  H    NH2   H         H         HCl(349)  H    SCH3  H         H         HCl(350)  H    CH3   H         H         HCl(351)  H    C6H5 H         H         HCl(352)  H     CF3     H      H      HCl(353)  H     OCF3    H      H      HCl(354)  H     CN       H      H      HCl(355)  H     F        H      H      HCl(356)  H     SOCH3   H      H      HCl(357)  H     SO2CH3H      H      HCl(358)  H     Cl       CN     H      HCl(359)  H     Cl       H      Cl     HCl(360)  H     Cl       H      OCF3  HCl(361)  H     Cl       OCF3  H      HCl(362)  Cl    Cl       H      H      HCl(363)  Cl    H        NH2   H      HCl(364)  Cl    H        NH2   CH3   HCl(365)  CH3  Cl       CH3   H      HCl(366)  F     Cl       CH3   H      HCl(367)  H     H        H      H      pTsOH    (m.p.225-226℃)(368)  Cl    H        H      H      HCl(369)  H     Cl       Cl     H      HCl(370)  SCH3 H        H      H      HCl(371)  H     F        CH3   H      HCl(372)  H     Cl       SCH3  H      HCl(373)  CH3  H        H      H      HCl(374)  H     Cl       C6H5 H      HCl(375)  H     Cl       CH3   NO2   HCl(376)  H     H        Br     H       HCl(377)  H     H        OCH3  H       HCl(378)  H     H        H      NH2    HCl(379)  H     Cl       H      NH2    pTsOH   (m.p.252-254℃)实施例380-465：
   R1  R2   R3      R4       HX(380)  H    Cl    H         H         pTsOH  (m.p.216-217℃)(381)  H    Cl    CH3      H         pTSOH  (m.p.176-177℃)(382)  H    Cl    C2H5    H         HCl(383)  H    Cl    OCH3     H         HCl(384)  H    Cl    NO2      H         HCl(385)  H    Cl    NH2      H         HCl(386)  H    Cl    N(CH3)2 H         HCl(387)  H    Cl    H         NH2      HCl(388)  H    Cl    CH3      NH2      HCl(389)  H    H     H         NH2      pTsOH   (m.p.＞200℃，
                                              分解)(390)  H    Cl    OCH3     NH2      HCl(391)  H    Cl    NO2      NH2      HCl(392)  H    Cl    NH2      NH2      HCl(393)  H    Cl    N(CH3)2 NH2      HCl(394)  H    Cl    H         NHCH3    HCl(395)  H    Cl    CH3      NHCH3    HCl(396)  H    Cl    C2H5    NHCH3    HCl(397)  H    Cl    OCH3     NHCH3    HCl(398)  H    Cl    NO2      NHCH3    HCl(399)  H    Cl    NH2      NHCH3    HCl(400)  H    Cl    N(CH3)2 NHCH3    HCl(401)  H    Cl    H         N(CH3)2 HCl(402)  H    Cl    CH3      N(CH3)2 HCl(403)  H    Cl    C2H5    N(CH3)2 HCl(404)  H    Cl    OCH3     N(CH3)2 HCl(405)  H    Cl    NO2      N(CH3)2 HCl(406)  H    Cl    NH2      N(CH3)2 HCl(407)  H    Cl    N(CH3)2 N(CH3)2 HCl(408)  H    Cl    H          OH        HCl(409)  H    Cl    CH3       OH        HCl(410)  H    Cl    C2H5     OH        HCl(411)  H    Cl    OCH3      OH        HCl(412)  H    Cl    NO2       OH        HCl(413)  H    Cl    NH2       OH        HCl(414)  H    Cl    N(CH3)2  OH        HCl(415)  H    Cl    H          CH3      HCl(416)  H    Cl    CH3       CH3      HCl(417)  H    Cl    C2H5     CH3      HCl(418)  H    Cl    OCH3      CH3      HCl(419)  H    Cl    NO2       CH3      HCl(420)  H    Cl    NH2       CH3      HCl(421)  H    Cl    N(CH3)2  CH3      HCl(422)  H    Cl    H          NO2      pTsOH  (m.p.233-235℃)(423)  H    Cl    NO2       H         HCl(424)  H    H     NH2       H         HCl(425)  H    H     NH2       CH3      HCl(426)  H    Cl    CH3       Cl        HCl(427)  H    H     CH3       H         HCl(428)  H    Cl    H          F         HCl(429)  H    Cl    F          H         HCl(430)  H    Br    H          H         HCl(431)  H    Br    H          F         HCl(432)  H    NO2  H          H         HCl(433)  H    OCH3 H          H         HCl(434)  H    OH    H          H         HCl(435)  H    NH2  H          H         HCl(436)  H    SCH3 H          H         HCl(437)  H    CH3  H          H         HCl(438)  H     C6H5   H      H      HCl(439)  H     CF3     H      H      HCl(440)  H     OCF3    H      H      HCl(441)  H     CN       H      H      HCl(442)  H     F        H      H      HCl(443)  H     SOCH3   H      H      HCl(444)  H     SO2CH3 H      H     HCl(445)  H     Cl       CN     H      HCl(446)  H     Cl       H      Cl     HCl(447)  H     Cl       H      OCF3  HCl(448)  H     Cl       OCF3  H      HCl(449)  Cl    Cl       H      H      HCl(450)  Cl    H        NH2   H      HCl(451)  Cl    H        NH2   CH3   HCl(452)  CH3  Cl       CH3   H      HCl(453)  F     Cl       CH3   H      HCl(454)  H     H        H      H      HCl(455)  Cl    H        H      H      HCl(456)  H     Cl       Cl     H      HCl(457)  SCH3 H        H      H      HCl(458)  H     F        CH3   H      HCl(459)  H     Cl       SCH3  H      HCl(460)  CH3  H        H      H      HCl(461)  H     Cl       C6H5 H      HCl(462)  H     Cl       CH3   NO2   HCl(463)  H     H        Br     H       HCl(464)  H     H        OCH3  H       HCl(465)  H     H        H      NH2    HCl实施例466-552：
Figure A0181509300381
   R1  R2   R3      R4       HX(466)  H    Cl    H         H         pTsOH    (m.p.236-238℃)(467)  H    Cl    CH3      H         pTsOH    (m.p.244-246℃)(468)  H    Cl    C2H5    H         HCl(469)  H    Cl    OCH3     H         HCl(470)  H    Cl    NO2      H         HCl(471)  H    Cl    NH2      H         HCl(472)  H    Cl    N(CH3)2 H         HCl(473)  H    Cl    H         NH2      HCl(474)  H    Cl    CH3      NH2      HCl(475)  H    H     H         NH2      lTsOH    (m.p.＞200℃，
                                              分解)(476)  H    Cl    OCH3     NH2      HCl(477)  H    Cl    NO2      NH2      HCl(478)  H    Cl    NH2      NH2      HCl(479)  H    Cl    N(CH3)2 NH2      HCl(480)  H    Cl    H         NHCH3    HCl(481)  H    Cl    CH3      NHCH3    HCl(482)  H    Cl    C2H5    NHCH3    HCl(483)  H    Cl    OCH3     NHCH3    HCl(484)  H    Cl    NO2      NHCH3    HCl(485)  H    Cl    NH2      NHCH3    HCl(486)  H    Cl    N(CH3)2 NHCH3    HCl(487)  H    Cl    H         N(CH3)2 HCl(488)  H    Cl    CH3      N(CH3)2 HCl(489)  H    Cl     C2H5    N(CH3)2 HCl(490)  H    Cl     OCH3     N(CH3)2 HCl(491)  H    Cl     NO2      N(CH3)2 HCl(492)  H    Cl     NH2      N(CH3)2 HCl(493)  H    Cl     N(CH3)2 N(CH3)2 HCl(494)  H    Cl     H         OH         HCl(495)  H    Cl     CH3      OH         HCl(496)  H    Cl     C2H5    OH         HCl(497)  H    Cl     OCH3     OH         HCl(498)  H    Cl     NO2      OH         HCl(499)  H    Cl     NH2      OH         HCl(500)  H    Cl     N(CH3)2 OH         HCl(501)  H    Cl     H         CH3       HCl(502)  H    Cl     CH3      CH3       HCl(503)  H    Cl     C2H5    CH3       HCl(504)  H    Cl     OCH3     CH3       HCl(505)  H    Cl     NO2      CH3       HCl(506)  H    Cl     NH2      CH3       HCl(507)  H    Cl     N(CH3)2 CH3       HCl(508)  H    Cl     H         NO2       HCl(509)  H    Cl     NO2      H          HCl(51O)  H    H      NH2      H          HCl(511)  H    H      NH2      CH3       HCl(512)  H    Cl     CH3      Cl         HCl(513)  H    H      CH3      H          HCl(514)  H    Cl     H         F          HCl(515)  H    Cl     F         H          HCl(516)  H    Br     H         H          HCl(517)  H    Br     H         F          HCl(518)  H    NO2   H         H          HCl(519)  H    OCH3  H         H          HCl(520)  H    OH     H         H          HCl(521)  H    NH2   H         H          HCl(522)  H    SCH3  H         H          HCl(523)  H    CH3   H         H          HCl(524)  H    C6H5 H         H          HCl(525)  H     CF3     H      H       HCl(526)  H     OCF3    H      H       HCl(527)  H     CN       H      H       HCl(528)  H     F        H      H       HCl(529)  H     SOCH3   H      H       HCl(530)  H     SO2CH3 H      H       HCl(531)  H     Cl       CN     H       HCl(532)  H     Cl       H      Cl      HCl(533)  H     Cl       H      OCF3   HCl(534)  H     Cl       OCF3  H       HCl(535)  Cl    Cl       H      H       HCl(536)  Cl    H        NH2   H       HCl(537)  Cl    H        NH2   CH3    HCl(538)  CH3  Cl       CH3   H       HCl(539)  F     Cl       CH3   H       HCl(540)  H     H        H      H       HCl(541)  Cl    H        H      H       HCl(542)  H     Cl       Cl     H       HCl(543)  SCH3 H        H      H       HCl(544)  H     F        CH3   H       HCl(545)  H     Cl       SCH3  H       HCl(546)  CH3  H        H      H       HCl(547)  H     Cl       C6H5 H       HCl(548)  H     Cl       CH3   NO2    HCl(549)  H     H        Br     H       HCl(550)  H     H        OCH3  H       HCl(551)  H     H        H      NH2    HCl(552)  H     Cl       H      NH2    pTsOH    (m.p.231-232℃)实施例553-639：
Figure A0181509300411
   R1  R2   R3      R4       HX(553)  H    Cl    H         H         lprsOH(554)  H    Cl    CH3      H         HCl(555)  H    Cl    C2H5    H         HCl(556)  H    Cl    OCH3     H         HCl(557)  H    Cl    NO2      H         HCl(558)  H    Cl    NH2      H         HCl(559)  H    Cl    N(CH3)2 H         HCl(560)  H    Cl    H          NH2     HCl    (m.p.298-301℃)(561)  H    Cl    CH3      NH2      HCl(562)  H    Cl    C2H5    NH2      HCl(563)  H    Cl    OCH3     NH2      HCl(564)  H    Cl    NO2      NH2      HCl(565)  H    Cl    NH2      NH2      HCl(566)  H    Cl    N(CH3)2 NH2      HCl(567)  H    Cl    H         NHCH3    HCl(568)  H    Cl    CH3      NHCH3    HCl(569)  H    Cl    C2H5    NHCH3    HCl(570)  H    Cl    OCH3     NHCH3    HCl(571)  H    Cl    NO2      NHCH3    HCl(572)  H    Cl    NH2      NHCH3    HCl(573)  H    Cl    N(CH3)2 NHCH3    HCl(574)  H    Cl    H         N(CH3)2 HCl(575)  H    Cl    CH3      N(CH3)2 HCl(576)  H    Cl      C2H5    N(CH3)2 HCl(577)  H    Cl      OCH3     N(CH3)2 HCl(578)  H    Cl      NO2      N(CH3)2 HCl(579)  H    Cl      NH2      N(CH3)2 HCl(580)  H    Cl      N(CH3)2 N(CH3)2 HCl(581)  H    Cl      H         OH         HCl(582)  H    Cl      CH3      OH         HCl(583)  H    Cl      C2H5    OH         HCl(584)  H    Cl      OCH3     OH         HCl(585)  H    Cl      NO2      OH         HCl(586)  H    Cl      NH2      OH         HCl(587)  H    Cl      N(CH3)2 OH         HCl(588)  H    Cl      H         CH3       HCl(589)  H    Cl      CH3      CH3       HCl(590)  H    Cl      C2H5    CH3       HCl(591)  H    Cl      OCH3     CH3       HCl(592)  H    Cl      NO2      CH3       HCl(593)  H    Cl      NH2      CH3       HCl(594)  H    Cl      N(CH3)2 CH3       HCl(595)  H    Cl      H          NO2       pTsOH  (m.p.217-220℃)(596)  H    Cl      NO2       H          HCl(597)  H    H       NH2       H          HCl(598)  H    H       NH2       CH3       HCl(599)  H    Cl      CH3       Cl         HCl(600)  H    H       CH3       H          HCl(601)  H    Cl      H          F          HCl(602)  H    Cl      F          H          HCl(603)  H    Br      H          H          HCl(604)  H    Br      H          F          HCl(605)  H    NO2    H          H          HCl(606)  H    OCH3   H          H          HCl(607)  H    OH      H          H          HCl(608)  H    NH2    H          H          HCl(609)  H    SCH3   H          H          HCl(610)  H    CH3    H          H          HCl(611)  H    C6H5  H          H          HCl(612)  H     CF3     H      H      HCl(613)  H     OCF3    H      H      HCl(614)  H     CN       H      H      HCl(615)  H     F        H      H      HCl(616)  H     SOCH3   H      H      HCl(617)  H     SO2CH3 H      H      HCl(618)  H     Cl       CN     H      HCl(619)  H     Cl       H      Cl     HCl(620)  H     Cl       H      OCF3  HCl(621)  H     Cl       OCF3  H      HCl(622)  Cl    Cl       H      H      HCl(623)  Cl    H        NH2   H      HCl(624)  Cl    H        NH2   CH3   HCl(625)  CH3  Cl       CH3   H      HCl(626)  F     Cl       CH3   H      HCl(627)  H     H        H      H      HCl(628)  Cl    H        H      H      HCl(629)  H     Cl       Cl     H      HCl(630)  SCH3 H        H      H      HCl(631)  H     F        CH3   H      HCl(632)  H     Cl       SCH3  H      HCl(633)  CH3  H        H      H      HCl(634)  H     Cl       C6H5 H      HCl(635)  H     Cl       CH3   NO2   HCl(636)  H     H        Br     H      HCl(637)  H     H        OCH3  H      HCl(638)  H     Cl       H      NH2   pTsOH(639)  H     Cl       H      NO2   HCl实施例640-726：
Figure A0181509300441
   R1  R2   R3      R4       HX(640)  H    Cl    H         H         HCl(641)  H    Cl    CH3      H         HCl(642)  H    Cl    C2H5    H         HCl(643)  H    Cl    OCH3     H         HCl(644)  H    Cl    NO2      H         HCl(645)  H    Cl    NH2      H         HCl(646)  H    Cl    N(CH3)2 H         HCl(647)  H    Cl    H         NH2      pTsOH    (m.p.178-180℃)(648)  H    Cl    CH3      NH2      HCl(649)  H    Cl    C2H5    NH2      HCl(650)  H    Cl    OCH3     NH2      HCl(651)  H    Cl    NO2      NH2      HCl(652)  H    Cl    NH2      NH2      HCl(653)  H    Cl    N(CH3)2 NH2      HCl(654)  H    Cl    H         NHCH3    HCl(655)  H    Cl    CH3      NHCH3    HCl(656)  H    Cl    C2H5    NHCH3    HCl(657)  H    Cl    OCH3     NHCH3    HCl(658)  H    Cl    NO2      NHCH3    HCl(659)  H    Cl    NH2      NHCH3    HCl(660)  H    Cl    N(CH3)2 NHCH3    HCl(661)  H    Cl    H         N(CH3)2 HCl(662)  H    Cl    CH3      N(CH3)2 HCl(663)  H     Cl    C2H5    N(CH3)2 HCl(664)  H    Cl     OCH3     N(CH3)2 HCl(665)  H    Cl     NO2      N(CH3)2 HCl(666)  H    Cl     NH2      N(CH3)2 HCl(667)  H    Cl     N(CH3)2 N(CH3)2 HCl(668)  H    Cl     H         OH         HCl(669)  H    Cl     CH3      OH         HCl(670)  H    Cl     C2H5    OH         HCl(671)  H    Cl     OCH3     OH         HCl(672)  H    Cl     NO2      OH         HCl(673)  H    Cl     NH2      OH         HCl(674)  H    Cl     N(CH3)2 OH         HCl(675)  H    Cl     H         CH3       HCl(676)  H    Cl     CH3      CH3       HCl(677)  H    Cl     C2H5    CH3       HCl(678)  H    Cl     OCH3     CH3       HCl(679)  H    Cl     NO2      CH3       HCl(680)  H    Cl     NH2      CH3       HCl(681)  H    Cl     N(CH3)2 CH3       HCl(682)  H    Cl     H         NO2       HCl(683)  H    Cl     NO2      H          HCl(684)  H    H      NH2      H          HCl(685)  H    H      NH2      CH3       HCl(686)  H    Cl     CH3      Cl         HCl(687)  H    H      CH3      H          HCl(688)  H    Cl     H         F          HCl(689)  H    Cl     F         H          HCl(690)  H    Br     H         H          HCl(691)  H    Br     H         F          HCl(692)  H    NO2   H         H          HCl(693)  H    OCH3  H         H          HCl(694)  H    OH     H         H          HCl(695)  H    NH2   H         H          HCl(696)  H    SCH3  H         H          HCl(697)  H    CH3   H         H          HCl(698)  H    C6H5 H         H          HCl(699)  H     CF3     H      H      HCl(700)  H     OCF3    H      H      HCl(701)  H     CN       H      H      HCl(702)  H     F        H      H      HCl(703)  H     SOCH3   H      H      HCl(704)  H     SO2CH3 H      H      HCl(705)  H     Cl       CN     H      HCl(706)  H     Cl       H      Cl     HCl(707)  H     Cl       H      OCF3  HCl(708)  H     Cl       OCF3  H      HCl(709)  Cl    Cl       H      H      HCl(71O)  Cl    H        NH2   H      HCl(711)  Cl    H        NH2   CH3   HCl(712)  CH3  Cl       CH3   H      HCl(713)  F     Cl       CH3   H      HCl(714)  H     H        H      H      HCl(715)  Cl    H        H      H      HCl(716)  H     Cl       Cl     H      HCl(717)  SCH3 H        H      H      HCl(718)  H     F        CH3   H      HCl(719)  H     Cl       SCH3  H      HCl(720)  CH3  H        H      H      HCl(721)  H     Cl       C6H5 H      HCl(722)  H     Cl       CH3   NO2   HCl(723)  H     H        Br     H      HCl(724)  H     H        OCH3  H      HCl(725)  H     Cl       H      NH2   pTsOH  (m.p.178-180℃)(726)  H     Cl       H      H      pTsOH  (m.p.219-220℃)实施例727-813：
Figure A0181509300471
   R1  R2   R3      R4       HX(727)  H    Cl    H         H         HCl    (m.p.250-252℃)(728)  H    Cl    CH3      H         HCl(729)  H    Cl    C2H5    H         HCl(730)  H    Cl    OCH3     H         HCl(731)  H    Cl    NO2      H         HCl(732)  H    Cl    NH2      H         HCl(733)  H    Cl    N(CH3)2 H         HCl(734)  H    Cl    H         NH2      pTsOH(735)  H    Cl    CH3      NH2      HCl(736)  H    Cl    C2H5    NH2      HCl(737)  H    Cl    OCH3     NH2      HCl(738)  H    Cl    NO2      NH2      HCl(739)  H    Cl    NH2      NH2      HCl(740)  H    Cl    N(CH3)2 NH2      HCl(741)  H    Cl    H         NHCH3    HCl(742)  H    Cl    CH3      NHCH3    HCl(743)  H    Cl    C2H5    NHCH3    HCl(744)  H    Cl    OCH3     NHCH3    HCl(745)  H    Cl    NO2      NHCH3    HCl(746)  H    Cl    NH2      NHCH3    HCl(747)  H    Cl    N(CH3)2 NHCH3    HCl(748)  H    Cl    H         N(CH3)2 HCl(749)  H    Cl    CH3      N(CH3)2 HCl(750)  H    Cl     C2H5    N(CH3)2 HCl(751)  H    Cl     OCH3     N(CH3)2 HCl(752)  H    Cl     NO2      N(CH3)2 HCl(753)  H    Cl     NH2      N(CH3)2 HCl(754)  H    Cl     N(CH3)2 N(CH3)2 HCl(755)  H    Cl     H         OH         HCl(756)  H    Cl     CH3      OH         HCl(757)  H    Cl     C2H5    OH         HCl(758)  H    Cl     OCH3     OH         HCl(759)  H    Cl     NO2      OH         HCl(760)  H    Cl     NH2      OH         HCl(761)  H    Cl     N(CH3)2 OH         HCl(762)  H    Cl     H         CH3       HCl(763)  H    Cl     CH3      CH3       HCl(764)  H    Cl     C2H5    CH3       HCl(765)  H    Cl     OCH3     CH3       HCl(766)  H    Cl     NO2      CH3       HCl(767)  H    Cl     NH2      CH3       HCl(768)  H    Cl     N(CH3)2 CH3       HCl(769)  H    Cl     H         NO2       pTsOH  (m.p.221-224℃)(770)  H    Cl     NO2      H          HCl(771)  H    H      NH2      H          HCl(772)  H    H      NH2      CH3       HCl(773)  H    Cl     CH3      Cl         HCl(774)  H    H      CH3      H          HCl(775)  H    Cl     H         F          HCl(776)  H    Cl     F         H          HCl(777)  H    Br     H         H          HCl(778)  H    Br     H         F          HCl(779)  H    NO2   H         H          HCl(780)  H    OCH3  H         H          HCl(781)  H    OH     H         H          HCl(782)  H    NH2   H         H          HCl(783)  H    SCH3  H         H          HCl(784)  H    CH3   H         H          HCl(785)  H    C6H5 H         H          HCl(786)  H     CF3     H      H      HCl(787)  H     OCF3    H      H      HCl(788)  H     CN       H      H      HCl(789)  H     F        H      H      HCl(790)  H     SOCH3   H      H      HCl(791)  H     SO2CH3 H     H      HCl(792)  H     Cl       CN     H      HCl(793)  H     Cl       H      Cl     HCl(794)  H     Cl       H      OCF3  HCl(795)  H     Cl       OCF3  H      HCl(796)  Cl    Cl       H      H      HCl(797)  Cl    H        NH2   H      HCl(798)  Cl    H        NH2   CH3   HCl(799)  CH3  Cl       CH3   H      HCl(800)  F     Cl       CH3   H      HCl(801)  H     H        H      H      HCl(802)  Cl    H        H      H      HCl(803)  H     Cl       Cl     H      HCl(804)  SCH3 H        H      H      HCl(805)  H     F        CH3   H      HCl(806)  H     Cl       SCH3  H      HCl(807)  CH3  H        H      H      HCl(808)  H     Cl       C6H5 H      HCl(809)  H     Cl       CH3   NO2   HCl(810)  H     H        Br     H       HCl(811)  H     H        OCH3  H       HCl(812)  H     Cl       H      NO2    HCl(813)  H     Cl       H      H       pTsOH实施例814-900：
Figure A0181509300501
   R1  R2   R3       R4       HX(814)  H    Cl    H          H         HCl(815)  H    Cl    CH3       H         HCl(816)  H    Cl    C2H5     H         HCl(817)  H    Cl    OCH3      H         HCl(818)  H    Cl    NO2       H         HCl(819)  H    Cl    NH2       H         HCl(820)  H    Cl    N(CH3)2  H         HCl(821)  H    Cl    H          NH2      pTsOH(822)  H    Cl    CH3       NH2      HCl(823)  H    Cl    C2H5     NH2      HCl(824)  H    Cl    OCH3      NH2      HCl(825)  H    Cl    NO2       NH2      HCl(826)  H    Cl    NH2       NH2      HCl(827)  H    Cl    N(CH3)2  NH2      HCl(828)  H    Cl    H          NHCH3    HCl(829)  H    Cl    CH3       NHCH3    HCl(830)  H    Cl    C2H5     NHCH3    HCl(831)  H    Cl    OCH3      NHCH3    HCl(832)  H    Cl    NO2       NHCH3    HCl(833)  H    Cl    NH2       NHCH3    HCl(834)  H    Cl    N(CH3)2  NHCH3    HCl(835)  H    Cl    H          N(CH3)2 HCl(836)  H    Cl    CH3       N(CH3)2 HCl(837)  H    Cl     C2H5    N(CH3)2 HCl(838)  H    Cl     OCH3     N(CH3)2 HCl(839)  H    Cl     NO2      N(CH3)2 HCl(840)  H    Cl     NH2      N(CH3)2 HCl(841)  H    Cl     N(CH3)2 N(CH3)2 HCl(842)  H    Cl     H         OH         HCl(843)  H    Cl     CH3      OH         HCl(844)  H    Cl     C2H5    OH         HCl(845)  H    Cl     OCH3     OH         HCl(846)  H    Cl     NO2      OH         HCl(847)  H    Cl     NH2      OH         HCl(848)  H    Cl     N(CH3)2 OH         HCl(849)  H    Cl     H         CH3       HCl(850)  H    Cl     CH3      CH3       HCl(851)  H    Cl     C2H5    CH3       HCl(852)  H    Cl     OCH3     CH3       HCl(853)  H    Cl     NO2      CH3       HCl(854)  H    Cl     NH2      CH3       HCl(855)  H    Cl     N(CH3)2 CH3       HCl(856)  H    Cl     H         NO2       HCl    (m.p.118-120℃)(857)  H    Cl     NO2      H          HCl(858)  H    H      NH2      H          HCl(859)  H    H      NH2      CH3       HCl(860)  H    Cl     CH3      Cl         HCl(861)  H    H      CH3      H          HCl(862)  H    Cl     H         F          HCl(863)  H    Cl     F         H          HCl(864)  H    Br     H         H          HCl(865)  H    Br     H         F          HCl(866)  H    NO2   H         H          HCl(867)  H    OCH3  H         H          HCl(868)  H    OH     H         H          HCl(869)  H    NH2   H         H          HCl(870)  H    SCH3  H         H          HCl(871)  H    CH3   H         H          HCl(872)  H    C6H5 H         H          HCl(873)  H     CF3     H       H      HCl(874)  H     OCF3    H       H      HCl(875)  H     CN       H       H      HCl(876)  H     F        H       H      HCl(877)  H     SOCH3   H       H      HCl(878)  H     SO2CH3H        H      HCl(879)  H     Cl       CN      H      HCl(880)  H     Cl       H       Cl     HCl(881)  H     Cl       H       OCF3  HCl(882)  H     Cl       OCF3   H      HCl(883)  Cl    Cl       H       H      HCl(884)  Cl    H        NH2    H      HCl(885)  Cl    H        NH2    CH3   HCl(886)  CH3  Cl       CH3    H      HCl(887)  F     Cl       CH3    H      HCl(888)  H     H        H       H      HCl(889)  Cl    H        H       H      HCl(890)  H     Cl       Cl      H      HCl(891)  SCH3 H        H       H      HCl(892)  H     F        CH3    H      HCl(893)  H     Cl       SCH3   H      HCl(894)  CH3  H        H       H      HCl(895)  H     Cl       C6H5  H      HCl(896)  H     Cl       CH3    NO2   HCl(897)  H     H        Br      H      HCl(898)  H     H        OCH3   H      HCl(899)  H     Cl       H       NO2   HCl    (m.p.118-120℃)(900)  H     Cl       H       H      pTsOH  (m.p.＞242℃，
                                             分解)实施例901-961：
   R1  R2   R3      R4        HX(901)  H    Cl    Cl        NH2       pTsOH    (m.p.322-325℃)(902)  H    Cl    Cl        NO2       pTsOH    (m.p.220-222℃)(903)  H    Cl    H         SO2CH3   pTsOH(904)  H    Cl    CH3      SO2CH3   HCl(905)  H    Cl    C2H5    SO2CH3   HCl(906)  H    Cl    OCH3     SO2CH3   HCl(907)  H    Cl    NO2      H           HCl(908)  H    Cl    NH2      H           pTsOH(909)  H    Cl    N(CH3)2 H           pTsOH(910)  H    Cl    H         NH2        HCl(911)  H    Cl    CH3      NH2        pTsOH(912)  H    Cl    C2H5    NH2        HCl(913)  H    Cl    OCH3     NH2        HCl(914)  H    Cl    NO2      NH2        HCl(915)  H    Cl    NH2      NH2        HCl(916)  H    Cl    N(CH3)2 NH2        HCl(917)  H    Cl    H         NHCH3      HCl(918)  H    Cl    CH3      NHCH3      HCl(919)  H    Cl    C2H5    NHCH3      HCl(920)  H    Cl    OCH3     NHCH3      HCl(921)  H    Cl    NO2      NHCH3      HCl(922)  H    Cl    NH2      NHCH3    HCl(923)  H    Cl    N(CH3)2 NHCH3    HCl(924)  H    Cl    N(CH3)2 NHCH3    HCl(925)  H    Cl    H         N(CH3)2 HCl(926)  H    Cl    CH3      N(CH3)2 HCl(927)  H    Cl    C2H5    N(CH3)2 HCl(928)  H    Cl    OCH3     N(CH3)2 HCl(929)  H    Cl    NO2      N(CH3)2 HCl(930)  H    Cl    NH2      N(CH3)2 HCl(931)  H    Cl    N(CH3)2 N(CH3)2 HCl(932)  H    Cl    H         OH         HCl(933)  H    Cl    CH3      OH         HCl(934)  H    Cl    C2H5    OH         HCl(935)  H    Cl    OCH3     OH         HCl(936)  H    Cl    NO2      OH         HCl(937)  H    Cl    NH2      OH         HCl(938)  H    Cl    N(CH3)2 OH         HCl(939)  H    Cl    SO2CH3  CH3       HCl(940)  H    Cl    H          CN         HCl(941)  H    Cl    C2H5    SO2NH2   HCl(942)  H    Cl    OCF3     CH3       HCl(943)  H    Cl    NO2      CH3       HCl(944)  H    Cl    NH2      CH3       HCl(945)  H    Cl    N(CH3)2 CH3       HCl(946)  H    Cl    H         NO2        pTsOH(947)  H    Cl    NO2      H           HCl(948)  H    H     NH2      H           HCl(949)  H    H     NH2      CH3        HCl(950)  H    Cl    CH3      CO-NH2     HCl(951)  H    H     CH3      SO2CH3   pTsOH(952)  H    Cl    OH        F           pTsOH(953)  H    Cl    F         SCH3       HCl(954)  H    Br    H         CONH2      pTsOH(955)  H    Br    CO-NH2   F           pTsOH(956)  H    NO2  H         H           pTsOH(957)  H    OCH3 H         OCF3       pTsOH(958)  H    OH     H     H       HCl(959)  H    NH2   H     H       HCl(960)  H    SCH3  H     H       HCl(961)  H    CH3   CN    CO-NH2 pTsOH药理试验
以下描述用于鉴定作为NHE-3抑制剂的式I化合物的方法。
根据式I化合物对NHE-1至NHE-3同工型的选择性对式I化合物进行特征鉴定。这三种同工型以稳定形式表达在小鼠成纤维细胞系中。可通过对胞内酸中毒后22Na+的EIPA-敏感吸收入细胞内的测定，评价所述化合物的抑制作用。材料和方法表达不同NHE同工型的LAP1细胞系
表达NHE-1、-2和-3同工型的LAP1细胞系(小鼠成纤维细胞系)由ProfJ.Pouyssegur(Nice，法国)处获得。根据Franchi等(1986)的方法，进行转染。细胞培养在含有10％失活胎牛血清(FCS)的Dulbeccos改良eagle培养基(DMEM)中进行。为进行表达NHE的细胞的选择，采用Sardet等(1989)的所谓“酸杀死方法”。首先在不含碳酸氢根和钠离子的NH4Cl缓冲液中，将细胞培养30分钟。然后通过用不含碳酸氢根、NH4Cl和钠离子的缓冲液洗涤，除去细胞外NH4Cl。然后将细胞在不含碳酸氢根的、含NaCl的缓冲液中培养。只有那些功能性表达NHE的细胞能够在胞内酸化作用中存活，这些细胞可经受这种酸化作用。NHE抑制剂对其同工型选择性的特征鉴定
根据Counillon等(1993)和Scholz等(1995)说明的方法，用上述表达NHE-1、NHE-2和NHE-3同工型的小鼠成纤维细胞系测定化合物对所述同工型的选择性。通过NH4Cl前脉冲(prepulse)方法，将细胞进行胞内酸化，然后在不含碳酸氢根的含22Na+的缓冲液中培养。由于该胞外酸化作用，NHE被激活，钠被吸收至细胞中。待测化合物的作用以抑制EIPA(乙基异丙基阿米洛利)-敏感的22Na+的吸收表示。将表达NHE-1、NHE-2和NHE-3的细胞以5-7.5×104个细胞/孔的密度接种于24-孔微量滴定板中，培养至汇合24-48小时。抽吸除去培养基，在37℃下，在NH4Cl缓冲液(50mM NH4Cl、70mM氯化胆碱、15mM MOPS，pH 7.0)中，将细胞培养60分钟。然后除去缓冲液，将所述细胞用氯化胆碱洗涤缓冲液(120mM 氯化胆碱、15mMPIPES/tris、0.1mM G毒毛旋花苷、1mM MgCl2、2mM CaCl2，pH 7.4)快速覆盖2次，然后抽吸过滤。然后在将所述细胞用氯化胆碱带电缓冲液(charging buffer)(120mM 氯化胆碱、15mM PIPES/tris、0.1mMPIPES/tris、0.1mM G毒毛旋花苷、1mM MgCl2、2mM CaCl2，pH 7.4，22Na+(0.925kBg/100ml带电缓冲液)覆盖，然后在该缓冲液中培养6分钟。孵育结束后，抽吸除去孵育缓冲液。为除去胞外放射活性，将该细胞迅速用冰冷的磷酸盐缓冲盐水溶液(PBS)洗涤4次。然后通过在每孔中加入0.3ml 0.1N NaOH，将细胞溶解。将含有细胞片段的溶液转移至闪烁管中。然后将每孔用0.3ml 0.1N NaOH洗涤2次，将该洗涤液同样加入至对应的闪烁管中。向装有该细胞溶解产物的管中加入闪烁合剂，通过测定β放射性确定吸收入细胞中的放射活性。参考文献：Counillon et al.(1993)Mol.Pharmacol.44：1041-1045J.Membrane Biol.120，41-49Franchi et al.(1986)Proc.Natl.Acad.Sci.USA 83：9388-9392J.Membrane Biol.118，193-214Sardet et al.(1989)Cell 56：271-280Scholz et al.(1995)Cardiovasc.Res.29：260-268
以下实施例涉及药用制剂：实施例A：注射玻瓶
用2N盐酸，将100g式I的NHE-3抑制剂和5g磷酸氢二钠的3升双蒸水的溶液调节至pH 6.5，无菌过滤，转移至注射小瓶中，在无菌条件下冷冻干燥，然后在无菌条件下密封。每注射小瓶中含5mg活性成分。
实施例B：栓剂
将20g式I的NHE-3抑制剂与100g大豆卵磷脂和1400g可可脂的混合物熔融，倒入模具中，冷却。每颗栓剂含20mg活性成分。
实施例C：溶液剂
由1g式I的NHE-3抑制剂、9.38gNaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940ml双蒸水中制备溶液。将pH调节至6.8，使溶液体积至1升，经辐照灭菌。该溶液可以以滴眼剂的形式使用。
实施例D：软膏剂
在无菌条件下，将500mg式I的NHE-3抑制剂与99.5g凡士林混合。
实施例E：片剂
按常用方式，将1kg式I的NHE-3抑制剂、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁混合物压制成片，由此得到每片含10mg活性成分的片剂。
实施例F：包衣片剂
按类似于实施例E的方法压片，然后按常用方式，用蔗糖、马铃薯淀粉、滑石粉、黄耆胶和染料的包衣物包衣。实施例G：胶囊剂
按常用方式，将2kg式I的NHE-3抑制剂加入到硬明胶胶囊中，由此得到每颗胶囊含20mg活性成分的胶囊剂。
实施例H：安瓿剂
将1kg式I的NHE-3抑制剂的60升双蒸水的溶液无菌过滤，转移至安瓿中，在无菌条件下冷冻干燥，然后在无菌条件下密封。每个安瓿装有10mg活性成分。

Claims (13)

1.一种式I化合物及其盐和溶剂化物：其中：Y    是或
Figure A0181509300023
Ar    是苯基或萘基，它们各自为未取代的或被R3和/或R4一取代，R1、R2、R3和R4彼此独立，各自为H、A、OA、Hal、CF3、OH、NO2、
NH2、NHA、NA2、NH-CO-A、NH-CO-Ph、SA、SO-A、SO2-A
、SO2-Ph、CN、OCF3、CO-A、CO2H、CO2A、CO-NH2、CO-NHA、
CO-NA2、SO2NH2、SO2NHA、SO2NA2或为未取代的或被A、
OA、Hal或CF3一取代或多取代的苯基，A    是具有1、2、3、4、5或6个碳原子的烷基，Hal  是F、Cl、Br或I，R5、R6、R7和R8彼此独立，各自为H、A或为未取代的或被A、OA、
Hal或CF3一取代或多取代的苯基，其中R5和R7、R5和R6以
及R7和R8能够形成5-7元环，条件是不包括其中R5、R6、R7和R8同时为氢，并且基团R1、R2、R3和R4均不为OH、NO2、NH2、NHA、NA2、NH-CO-A、NH-CO-Ph、SA、SO-A、SO2-A、SO2-Ph、CN、OCF3、CO-A、CO2H、CO2A、CO-NH2、CO-NHA、CO-NA2、SO2NH2、SO2NHA、SO2NA2或者未取代的或被A、OA、Hal或CF3一取代或多取代的苯基的化合物。
2.作为NHE-3抑制剂的根据权利要求1的式I化合物及其盐和溶剂化物。
3.用作对抗疾病的根据权利要求1的式I化合物及其生理学上可接受的盐和溶剂化物。
4.根据权利要求1的式I化合物和/或生理学上可接受的盐和溶剂化物在制备药物中的用途。
5.根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗渗透压力过高、血栓形成、心脏局部缺血状态、外周和中枢神经系统局部缺血状态以及休克缺血状态、外周器官和末梢的局部缺血状态以及在治疗休克状态的药物中的用途。
6.根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于手术和器官移植以及手术移植物的防腐和储存的药物中的用途。
7.根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗其中细胞增殖代表主要或次要病因的疾病、治疗或预防脂肪代谢紊乱或呼吸运动障碍的药物中的用途。
8.根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗肾局部缺血、肠局部缺血疾病以及预防急性或慢性肾病的药物中的用途。
9.根据权利要求1的式I化合物及其生理学上可接受的盐和/或溶剂化物在制备用于治疗细菌和寄生虫疾病的药物中的用途。
10.一种药物制剂，其特征在于包含至少一种根据权利要求1的NHE-3抑制剂和/或它的生理学上可接受的盐和/或溶剂化物中的一种。
11.选自化合物11-110的化合物及其盐和溶剂化物：N-(6-氯-4-苯基喹唑啉-2-基)-N’-甲基胍                11N-(6-氯-4-对甲苯基喹唑啉-2-基)-N’-甲基胍            12N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]-N’-甲基胍        13N-[4-(2-氨基苯基)-6-氯喹唑啉-2-基]-N’-甲基胍           14N-[6-氯-4-(4-甲基-2-硝基苯基)喹唑啉-2-基]-N’-甲基胍    15N-[4-(2-氨基-4-甲基苯基)-6-氯喹唑啉-2-基]-N’-甲基胍    16N-[6-氯-4-(2-硝基苯基)喹唑啉-2-基]胍                    17N-[4-(2-氨基苯基)-6-氯喹唑啉-2-基]胍                    18N-[6-氯-4-(4-甲基-2-硝基苯基)喹唑啉-2-基]胍             19N-[4-(2-氨基-4-甲基苯基)-6-氯喹唑啉-2-基]胍            110。
12.用作药物活性组分的根据权利要求1的化合物。
13.制备式I的2-胍基-4-芳基喹唑啉及其盐和溶剂化物的方法，其特征在于包括以下步骤：
(a)使式II化合物：
Figure A0181509300041
其中R1、R2和Ar定义同上，与1-氰基胍或式NC-Y相应的N-烷基化或N-芳基化的氰基胍反应，其中Y如权利要求1中定义，或者
(b)使式III化合物：
               HN＝CX-Y       III其中X是-S-烷基、-S-芳基、-O-烷基或-O-芳基，替代式NC-Y化合物，与式II化合物反应，或者
(c)使式IV的2-氯-4-芳基喹唑啉：其中Ar、R1和R2如权利要求1中定义，与式HY化合物反应，其中Y如权利要求1中定义，在步骤(a)、(b)或(c)后，任选通过用酸或碱处理，将式I的碱性或酸性化合物转化为它的一种盐或溶剂化物。
CN01815093A 2000-09-05 2001-08-13 2－胍基－4－芳基喹唑啉 Pending CN1450996A (zh)

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DE10304374A1 (de) 2003-02-04 2004-08-05 Aventis Pharma Deutschland Gmbh Neue substituierte 2-Aminoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
GB2467670B (en) * 2007-10-04 2012-08-01 Intellikine Inc Chemical entities and therapeutic uses thereof
WO2018129556A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
HUE036405T2 (hu) 2008-12-31 2018-07-30 Ardelyx Inc Vegyületek és módszerek az NHE-közvetített (Na+/H+ cserével mûködõ) antiport gátlására folyadékretencióval vagy túlzott sómennyiség jelenlétével és a gyomor-bél traktus zavaraival összefüggõ rendellenességek kezelésében
US20120088737A2 (en) * 2009-10-02 2012-04-12 Ajinomoto Co., Inc Novel acyl guanidine derivatives
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US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
CA2880338A1 (en) 2012-08-21 2014-02-27 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
SI2983667T1 (sl) 2013-04-12 2019-09-30 Ardelyx, Inc. Spojine za vezavo NHE3 in metode za zaviranje transporta fosfata
US11147884B2 (en) 2017-01-09 2021-10-19 Ardelyx, Inc. Inhibitors of NHE-mediated antiport
EP3565808A1 (en) 2017-01-09 2019-11-13 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders
AU2018335130B2 (en) 2017-08-04 2023-02-16 Ardelyx, Inc. Glycyrrhetinic acid derivatives for treating hyperkalemia
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DE10163992A1 (de) * 2001-12-24 2003-07-03 Merck Patent Gmbh 4-Aryl-chinazoline

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DE10043667A1 (de) 2002-03-14
PL360391A1 (en) 2004-09-06
MXPA03001877A (es) 2003-06-24
CZ2003858A3 (cs) 2003-06-18
US20040039001A1 (en) 2004-02-26
EP1315704A1 (de) 2003-06-04
AU2001285886A1 (en) 2002-03-22
JP2004508360A (ja) 2004-03-18
KR20030062404A (ko) 2003-07-25
NO20030999D0 (no) 2003-03-04
RU2003108861A (ru) 2004-09-20
WO2002020496A1 (de) 2002-03-14
ZA200302633B (en) 2004-09-08
CA2421222A1 (en) 2003-03-03

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