CN1146557C - 用于制备1型钠-氢交换剂抑制剂的方法 - Google Patents
用于制备1型钠-氢交换剂抑制剂的方法 Download PDFInfo
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- CN1146557C CN1146557C CNB001316613A CN00131661A CN1146557C CN 1146557 C CN1146557 C CN 1146557C CN B001316613 A CNB001316613 A CN B001316613A CN 00131661 A CN00131661 A CN 00131661A CN 1146557 C CN1146557 C CN 1146557C
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- cyclopropyl
- quinoline
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- pyrazoles
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- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/10—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by doubly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
公开了制备NHE-1抑制剂的方法。NHE-1抑制剂可用于减少由组织缺血导致的组织损伤。
Description
发明背景
本发明涉及1型钠-氢交换剂(NHE-1)抑制剂和制备该抑制剂的方法。
心肌缺血损伤可发生在门诊以及手术前后的处置中,可导致猝死、心肌梗塞或充血性心衰的形成。预防或减少心肌缺血损伤、特别是手术前后的心肌梗塞的需要在医学上尚没有得到满足。人们期望这疗法对生命是安全的,减少高危患者的住院治疗,提高他们的生命质量,降低他们的总保健成本。
药理学上的心保护作用将减少心肌梗塞和机能障碍的发生和进展,它们可发生在这些手术处置中(手术前后)。除了减少缺血性心脏病患者的心肌损伤和改善缺血后心肌功能以外,心保护作用还将降低由“危险期”患者(例如年龄超过65岁、不耐受运动、冠状动脉疾病、糖尿病、高血压)心肌梗塞和机能障碍引起的心脏疾病的发病率和死亡率,他们需要非心脏手术。
人们还没有充分了解引起缺血和再灌注后所观察到的心肌损伤的机制。
各种公开出版物已经公开了胍衍生物的用途,例如用于心律失常的治疗。
最近出版的专利申请PCT/IB 99/00206于1999年9月2日出版,公开号为WO99/43663,其公开内容引用在此作为参考文献,其中公开了各种NHE-1抑制剂,包括[5-环丙基-1-(喹啉-5-基)-1H-吡唑-4-羰基]胍。
《医药化学杂志》1997,40,2017-2034“(2-甲基-5-(甲磺酰)苯甲酰基)胍Na+/H+对向运输剂抑制剂”和Arzrneim.Forsch(《药物研究》)25,Nr.10(1975)“取代的苯乙酰胍:新一类抗高血压剂”公开了合成酰基胍的方法,除了酰基氯和胍以外,使酯与胍偶联,其中底物是芳族单环结构。
另外,《杂环化学杂志》24,1669(1987)“2-二甲氨基亚甲基-1,3-二酮与二亲核试剂的反应VI:1,5-二取代的1H-吡唑-4-羧酸乙酯或甲酯的合成”公开了5-取代的1-苯基-1H-吡唑-4-羧酸酯的制备方法。
因此,显然目前需要用于手术前后心肌缺血治疗的化合物及其制备方法,本领域也在继续寻找中。
发明概述
本发明在一方面涉及用于制备N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍、N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍与甲磺酸化合而成的单甲磺酸盐的方法。
优选地,该化合作用是在一种极性非质子传递溶剂中、在约40℃至约80℃的温度下进行的。也优选地,该溶剂是丙酮与1-甲基-2-吡咯烷酮的混合物。
本发明在另一方面涉及用于制备N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍的方法,该方法包括:
a.使5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸与亚硫酰氯在甲苯中化合,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯;和
b.使盐酸胍和氢氧化钠与5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯的四氢呋喃悬浮液在约-10℃至约10℃的温度下化合约1小时至约3小时。
优选地,5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸与亚硫酰氯在约60℃至约90℃的温度下化合约一至约三小时。也优选地,5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸是在氢氧化钠的存在下,通过用甲醇在回流下水解而制备的。
本发明在另一方面涉及用于制备5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯的方法,该方法包括:在一种胺碱的存在下,使喹啉-5-基肼与甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯在一种反应惰性溶剂中化合。
优选地,该溶剂是乙醇,该胺碱是三乙胺,该化合作用发生在约50℃至约回流的温度下。
本发明在另一方面涉及用于制备甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯的方法,该方法包括:在洁净条件下,使甲基-3-环丙基-3-氧代丙酸酯与N,N-二甲基甲酰胺二甲基乙缩醛在约50℃至约110℃的温度下化合约一至约五小时。
本发明在另一方面涉及用于制备N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍的单甲磺酸盐的方法,该方法包括:
a.在洁净条件下,使甲基-3-环丙基-3-氧代丙酸酯与N,N-二甲基甲酰胺二甲基乙缩醛在约50℃至约110℃的温度下化合约一至约五小时;
b.在一种胺碱的存在下,使喹啉-5-基肼与甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯在一种反应惰性溶剂中化合,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯;
c.在氢氧化钠的存在下,将5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯与甲醇在回流下水解,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸;
d.使5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸与亚硫酰氯化合,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯;
e.使盐酸胍和氢氧化钠与5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯的四氢呋喃悬浮液在约-10℃至约10℃的温度下化合约1小时至约3小时,生成N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍;和
f.使N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍与甲磺酸化合,生成N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍的单甲磺酸盐。
与1999年9月2日出版的WO99/43663所公开的操作比较,本发明提供了多种优点。例如,优选的是与亚硫酰氯在甲苯中生成酰基氯,这是因为直接从反应中分离出酰基氯的HCl盐,为固体。将酰基氯在四氢呋喃(THF)中用胍HCl和含水氢氧化钠在低温下处理,可提高纯度和产率。高温导致酰基氯水解的增加以及其他副产物的生成。
“药学上可接受的”指载体、稀释剂、赋形剂和/或盐必须与制剂的其他成分是可相容的,对接受者是无害的。
本文所用的表达方式“反应惰性溶剂”和“惰性溶剂”指该溶剂或溶剂的混合物不与原料、试剂、中间体或产物发生不利于所需产物的产出这种方式的相互作用。
具有普通技能的化学工作者会认识到,某些本发明化合物将含有一个或多个具有特定立体化学或几何构型的原子,从而形成立体异构体和构型异构体。所有这样的异构体和它们的混合物也包括在本发明中。还包括本发明化合物的水合物和溶剂化物。
借助于描述本发明的说明书和权利要求书,其他特征和优点将是显而易见的。
发明的详细说明
一般来说,本发明化合物、即[5-环丙基-1-(喹啉-5-基)-1H-吡唑-4-羰基]-胍及其盐(包括单甲磺酸盐)可以按照化学领域已知的方法加以制备,特别是按照本文的说明。本发明化合物的某些制备方法是作为发明的进一步特征加以提供的,通过下列反应流程加以阐述。其他方法描述在实验部分。
流程I
按照流程I,式II化合物与过量式III化合物、即N,N-二甲基甲酰胺二甲基乙缩醛化合,可选地在一种酸催化剂、例如对甲苯磺酸的存在下,在洁净条件下,在约50℃至约110℃的温度下反应约一至约五小时,优选地在约70℃至约80℃的温度下反应约一至约两小时,制得式IV化合物。该反应也可以在乙酸乙酯中进行。
式IV化合物与式V化合物在一种惰性溶剂、例如乙醇中环化,优选地在一种胺碱、例如三乙胺的存在下,在约50℃至约回流(78℃)的温度下反应约1小时至约四小时,生成式VI的吡唑化合物。该反应也可以在乙酸乙酯和甲醇中进行。
将式VI吡唑用一种碱、例如氢氧化钠在一种溶剂、例如甲醇中水解,适宜在环境温度或优选在高温(例如回流)下反应约一小时至约五小时,制得式VII的酸。
一般地,式VII酸与胍在一种适当的偶联剂的存在下偶联。适当的偶联剂是可将羧酸转化为反应性基团者,该反应性基团一旦与胺反应,即生成酰胺键。
偶联剂可以是这样一种试剂,当它与羧酸和胍一起混合时,即按照一罐法进行该缩合作用。示范性偶联剂是盐酸1-(3-二甲氨基丙基)-3-乙基碳二亚胺-羟基苯并三唑(EDC/HOBT)、二环己基碳二亚胺/羟基苯并三唑(HOBT)、2-乙氧基-1-乙氧羰基-1,2-二氢喹啉(EEDQ)和二乙基磷酰氰。偶联是在过量胍这种碱的存在下,在一种惰性溶剂、优选为一种非质子传递溶剂中、在约-20℃至约50℃的温度下进行约1至约48小时。示范性溶剂包括乙腈、二氯甲烷、二甲基甲酰胺和氯仿或它们的混合物。
优选地,偶联剂也是这样的试剂,它把羧酸转化为活化的中间体,后者在第一步中分离出来和/或生成,然后在第二步中与胍反应。这样的偶联剂和活化中间体的实例是用于生成酰基氯的亚硫酰氯或草酰氯、用于生成酰基氟或烷基氯甲酸酯(例如异丁基或异丙烯基氯甲酸酯)的氰尿酰氟、用于(与一种叔胺碱)生成羧酸混合酐的丙烷膦酸酐(丙烷膦酸的酸酐,PPA)或用于生成酰基咪唑的羰基二咪唑。如果偶联剂是草酰氯,那么使用少量二甲基甲酰胺作为助溶剂以及另一种溶剂(例如二氯甲烷)是有利的,可催化酰基氯的生成。该活化的酸衍生物可以通过将该中间体在适当的溶剂中与适当的碱混合而进行偶联。适当的溶剂/碱组合例如在过量胍这种碱的存在下的二氯甲烷、二甲基甲酰胺或乙腈或它们的混合物。其他适当的溶剂/碱组合包括水或(C1-C5)醇或它们的混合物以及一种助溶剂、例如二氯甲烷、四氢呋喃或二噁烷,和一种碱、例如氢氧化钠、氢氧化钾或氢氧化锂,碱是足量的,以消耗反应中释放的酸。这些偶联剂的使用和溶剂与温度的适当选择是本领域技术人员已知的,或者按照本说明书可以容易地从文献中加以确定。可用于偶联羧酸的这些和其他示范性条件描述在Houben-Weyl,Vol XV,partII,E.Wunsch,Ed.,G.Theime Verlag,1974,Stuttgart;M.Bodansky,肽合成原理(Principles of Peptide Synthesis),Springer-Verlag,Berlin 1984;肽的分析、合成和生物学(ThePeptides,Analysis,Synthesis and Biology)(ed.E.Gross和J.Meienhofer),vols 1-5(Academic Press,NY 1979-1983)。
在优选的实施方式中,将式VII酸用过量亚硫酰氯(例如3至6当量)在甲苯等非质子传递溶剂中、在约60℃至约90℃的温度下活化约十五分钟至约两小时,优选地在约75℃的温度下活化约一至约两小时。
所得式VIII的活化酰基氯的无水四氢呋喃溶液与过量盐酸胍和一种无机碱(例如氢氧化钠)水溶液在四氢呋喃中、在约-20℃至约10℃的温度下化合约一小时至约三小时,在最后一小时使温度升至环境温度,制得式IX化合物。
式IX化合物与甲磺酸在一种非质子传递溶剂中、在约40℃至约80℃的温度下化合约10分钟至约一小时,溶剂优选为丙酮与1-甲基-2-吡咯烷酮的混合物,优选为约90%至60%丙酮,其余为1-甲基-2-吡咯烷酮,然后在避光条件下,在约20℃至约30℃的温度下搅拌约3小时至约6小时,优选地在约环境温度下搅拌约5小时。优选地,将固体再次在丙酮中拌浆约6至约17小时。盐的生成也可以在四氢呋喃中进行。如果选择了这种溶剂,那么95%乙醇淤浆是优选的。
用于上述化合物的原料和试剂也是易于获得的,或者易为本领域技术人员利用常规的有机合成方法合成。例如,本文所用的一些化合物涉及或者来源于存在巨大科学价值和商业需要的天然化合物,因此,这样的化合物是商业上可得到的,或者是文献中所报道的,或者通过文献中所报道的方法易于从其他普遍可获得的物质制得。
本领域技术人员将认识到,很多用在本文方法中的化合物可以以若干互变异构形式存在。所有这些互变异构形式被认为是本发明的一部分。例如,化合物的羰基胍部分的所有互变异构形式都是包括在本发明中的。
本发明化合物[5-环丙基-1-(喹啉-5-基)-1H-吡唑-4-羰基]-胍是碱性的,它与药学上可接受的阴离子生成盐。所有这样的盐、包括二盐都在本发明的范围之内,它们可以通过常规方法制备。例如,制备方法可以是在含水、不含水或部分含水的介质中,使酸性与碱性反应物简单地接触。回收盐的方法可以是过滤、用一种非溶剂沉淀后过滤、蒸发溶剂,或者在水溶液的情况下,还可以是冷冻干燥,视情况而定。
另外,当本发明化合物生成代谢产物、水合物或溶剂化物时,它们也在本发明的范围之内。
本领域技术人员将认识到,其他心血管剂可以与本发明化合物联合使用,例如β-阻滞剂(如醋丁洛尔、阿替洛尔、波吲洛尔、拉贝洛尔、甲吲洛尔、纳多洛尔、氧烯洛尔、吲哚洛尔、普萘洛尔、索他洛尔)、钙通道阻滞剂(如氨氯地平、硝苯地平、尼索地平、尼群地平、维拉帕米)、ACE抑制剂(如卡托普利、依那普利)、硝酸盐(如硝酸异山梨酯、5-单硝酸异山梨酯、硝酸甘油)、利尿剂(如氢氯噻嗪、吲达帕胺、吡咯他尼、希帕胺)、苷(如地高辛、甲地高辛)、溶血栓剂(如tPA)、血小板抑制剂(如reopro)、阿司匹林、双嘧达莫、氯化钾、可乐定、哌唑嗪、醛糖还原酶抑制剂(如唑泊司他)和腺苷A3受体激动剂。
本发明化合物抑制钠/质子(Na+/H+)交换运输系统,从而可用作由钠/质子(Na+/H+)交换运输系统的加速作用导致的疾病的治疗剂或预防剂,例如心血管疾病(如动脉硬化、高血压、心律失常(如缺血性心律失常、由心肌梗塞引起的心律失常、PTCA后或血栓溶解后的心律失常等)、心绞痛、心肥大、心肌梗塞、心衰(如充血性心衰、急性心衰、心肥大等)、PTCA后再狭窄、休克(如出血性休克、内毒素性休克等))、肾脏疾病(如糖尿病、糖尿病性肾病、缺血性急性肾衰等)、与缺血或缺血再灌注有关的器官病症(如与心肌缺血再灌注有关的病症、急性肾衰或由手术治疗诱发的病症,如冠状动脉旁路搭桥术(CABG)、血管手术、器官移植术、非心脏手术或经皮经腔冠状动脉成形术(PTCA))、脑血管疾病(如缺血性中风、出血性中风等)、脑缺血性病症(如与脑梗塞有关的病症、脑卒中后遗症或脑水肿)。
本发明化合物可用作进行性心肌缺血(急性冠状综合征,例如心肌梗塞或不稳定性绞痛)或脑缺血(例如中风)患者的心肌保护剂。本发明化合物也可用作被诊断为冠状心脏病(例如以前的心肌梗塞或不稳定性绞痛)的患者或心肌梗塞高危(例如年龄超过65岁,具备两个或以上冠状心脏病的危险因素)患者的慢性心肌保护剂。
本发明化合物有效减少由缺血导致的组织损伤(例如基本上防止了组织损伤,包括组织保护作用)。
单个或一组优选的缺血组织是心、脑、肝、肾、肺、肠、骨骼肌、脾、胰腺、神经、脊髓、视网膜组织、脉管系统或肠组织。尤其优选的缺血组织是心组织。缺血损伤可能发生在器官移植术过程中。
除此以外,本发明化合物值得注意的是它对细胞增殖的强抑制作用,例如成纤维细胞的增殖和血管平滑肌细胞的增殖。为此,本发明化合物作为治疗剂是有价值的,用于细胞增殖代表主要或次要病因的疾病,因此可用作抗动脉硬化剂,以及对抗糖尿病晚期并发症、癌症、肺纤维变性、肝纤维变性或肾纤维变性等纤维变性疾病、肾小球硬化、器官肥大或增生,特别是前列腺增生或肥大、肺纤维变性、糖尿病并发症或PTCA后复发的狭窄,或者是由内皮细胞损伤导致的疾病。
本发明化合物作为药剂在哺乳动物(例如人)的如本文所述疾病治疗中的应用例如手术过程中的心肌保护作用、进行性心或脑缺血患者的心肌保护作用或被诊断为冠状心脏病的患者的慢性心保护作用,本发明化合物在常规的临床前期心保护作用测定中的活性证实了这种应用(参见体内测定,Klein,H.等《循环》92:912-917(1995);离体心脏测定,Scholz,W.等《心血管研究》29:260-268(1995);抗心律失常测定,Yasutake M.等《美国生理学杂志》36:H2430-H2440(1994);NMR测定,Kolke等《胸心血管手术杂志》112:765-775(1996))。这些测定也提供了一种可将本发明化合物的活性与其他已知化合物的活性进行比较的手段。这些比较的结果可用于在治疗这些疾病时,确定对包括人在内的哺乳动物的剂量水平。
本发明化合物可以通过任意方法给药,该方法将化合物优选地释放到所需的组织(例如肝和/或心组织)。这些方法包括口服途径、肠胃外、十二指肠内途径等。一般来说,本发明化合物可以是单剂(例如每日一次)或多剂的,或者通过恒定输液给药。
本发明化合物例如可用于减少或减小损伤,它直接作用于任何对缺血/再灌注损伤敏感的组织(例如心、脑、肺、肾、肝、肠、骨骼肌、视网膜),损伤是由缺血引起的(例如心肌梗塞)。活性化合物因此可用于预防性地防止、也就是(前瞻性地或预防性地)减弱或阻止面临缺血(例如心肌缺血)危险的患者的组织损伤(例如心肌组织)。
一般来说,本发明化合物可以口服给药或肠胃外给药(例如静脉内、肌内、皮下或髓内)。也可以适用局部给药,例如患者患有胃肠道病症,或者根据医师的判断,药物治疗应用于组织或器官表面是最好的。
化合物的给药量和时间当然将取决于受治疗者、疾病的严重性、给药方式和开方医师的判断。由于患者与患者的差异性,下面给出的剂量是指导性的,医师可以调节药物的剂量,以达到医师认为适合于患者的治疗。在考虑所需的治疗程度时,医师必须权衡各种因素,例如患者的年龄、先前存在的疾病的表现以及其他疾病的表现(例如心血管疾病)。
例如,在一种给药方式中,本发明化合物可以在心手术之前(例如手术前二十四小时内)和/或过程中和/或之后(例如手术后二十四小时内)给药,手术存在心肌缺血的危险。在尤其优选的方式中,将输液在手术前给药,剂量为约1mg至约300mg,时间为约一分钟至约一小时,然后在手术前的其余时间、手术中和手术后的阶段进行恒定输液,剂量为约1mg/kg/天至约100mg/kg/天,例如包括手术治疗后约2至约7天。本发明化合物也可以以长期每日方式给药。
本发明化合物的用量对缺血的保护作用是有效的。优选的本发明化合物的剂量为约0.001至约100mg/kg/天。尤其优选的本发明化合物的剂量为约0.01至约50mg/kg/天。
本发明化合物一般以药物组合物的形式给药,该组合物包含本发明化合物以及药学上可接受的载体、赋形剂或稀释剂。因此,本发明化合物可以单独或与另一种试剂一起以任意常规的口服、肠胃外、直肠或透皮剂型给药。
对口服给药来说,药物组合物可以采取溶液、悬浮液、片剂、丸剂、胶囊、粉末等形式。所用片剂含有各种赋形剂,例如柠檬酸钠、碳酸钙和磷酸钙,以及各种崩解剂,例如淀粉、优选的马铃薯或木薯淀粉和某些复合硅酸盐,以及粘合剂,例如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶。另外,润滑剂、例如硬脂酸镁、月桂基硫酸钠和滑石通常对压片是非常有用的。也使用相似类型的固体组合物作为软胶囊和硬胶囊的填充剂;在这一点上优选的材料也包括乳糖或奶糖以及大分子聚乙二醇。当口服给药需要含水悬浮液和/或酏剂时,可将本发明化合物与各种防腐剂、缓冲剂、甜味剂、矫味剂、着色剂、乳化剂和/或悬浮剂混合,以及稀释剂,例如水、乙醇、丙二醇、甘油及其各种可能的组合。
对肠胃外给药来说,例如可以使用芝麻油或花生油或含水丙二醇的溶液,以及相应水溶性盐的无菌水溶液。如果必要的话,这些水溶液可以是适当缓冲的,并且液体稀释剂首先用足量的盐水或葡萄糖等赋予等渗性。这些水溶液尤其适合于静脉内、肌内、皮下和腹膜内注射。在这一点上,所用无菌的含水介质按照本领域技术人员熟知的标准技术,都是易于得到的。
对透皮(例如局部)给药来说,制备稀的、无菌的、含水或部分含水溶液(浓度通常为约0.1%至约5%)、不含水的溶液,与上述肠胃外溶液类似。
对本领域技术人员来说,制备含有一定量活性成分的各种药物组合物的方法是已知的,或者按照本文所公开的将是显而易见的。例如,制备药物组合物的方法参见《Remington’s PharmaceuticalScience》Mack Publishing Company,Easter,Pa.,15th Edition(1975)。
根据本发明的药物组合物例如可以含有0.0001%-95%的本发明化合物。不论怎样,所要给药的组合物或制剂将含有一定量根据本发明的化合物,其含量对治疗患者的疾病/状态是有效的。
本发明化合物一般将以适宜的制剂给药。下列制剂实例仅供举例说明,并不打算限制本发明的范围。
在下列制剂中,“活性成分”指本发明化合物。
如下制备静脉内制剂:
制剂1:静脉内溶液
成分 含量
活性成分 25mg
等渗盐水 1000ml
将上述成分的溶液对患者静脉内给药。
上述活性成分也可以是试剂的组合。
实施例
实施例1
将甲基-3-环丙基-3-氧代丙酸酯(15g,106mmol,1eq(当量))和N,N-二甲基甲酰胺二甲基乙缩醛(14.7ml,111mmol,1.05eq)在75℃N2下加热1.5小时。然后将所得橙色的油冷却至室温。TLC分析(1∶1 EtOAc/己烷)指示原料消失,出现微小弱极性斑点和明显强极性斑点(甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯)。将粗的混合物用在下面的步骤中。
实施例2
将粗的甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯(20.9g,106mmol,1.07eq)用乙醇(250ml)稀释。按顺序先加入三乙胺(34.4ml,247mmol,2.5eq),再加入喹啉-5-基-肼(22.9g,98.6mmol,1eq)。加入喹啉-5-基-肼后观察到有轻微气体放出。所得不均匀的混合物在N2下加热回流(78℃)2小时。加热3分钟后,混合物变得均匀和非常黑。然后将混合物冷却至室温。TLC分析(1∶1EtOAc/己烷)指示有轻微弱极性斑点(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯)。APCI质谱指示还有所需的产物。然后将反应混合物浓缩。向残余物中加入EtOAc(300ml)和0.1N HCl(400ml)。该乳液在室温下搅拌10分钟,然后通过硅藻土Celite垫过滤以除去固体。分离所得两相混合物。含水层用EtOAc萃取(2×300ml)。合并后的有机层用0.1N HCl洗涤(2×300ml),然后经硫酸钠干燥,浓缩。向残余物中加入热的异丙醚(80ml)。所得浑浊溶液搅拌2分钟。然后加入己烷(125ml)。使固体形成颗粒过夜。过滤收集固体,得到产物5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯,为黄橙色粉末(20.8g,2步产率72%)。
实施例3
向5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯(20g,68.2mmol,1eq)的MeOH(120ml)溶液中加入2N NaOH(54.5ml,109mmol,1.6eq)。将所得溶液在N2下加热回流(65℃)1.5小时,然后冷却至室温。TLC分析(1∶1 EtOAc/己烷)指示原料消失。在真空下的旋转蒸发器上小心地加热(35℃),除去甲醇。碱性含水层然后用EtOAc洗涤(2×100ml)。所得碱性含水层用浓HCl缓慢酸化至pH1至2。产物在酸化过程中沉淀出来。淤浆在室温下搅拌0.5小时,然后过滤收集固体。固体用1N HCl洗涤(2×25ml),干燥,得到酸,为淡棕色固体(18.8g,99%)。
实施例4
向搅拌下的5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸(25g,89.5mmol,1eq)的甲苯(250ml)悬浮液中加入亚硫酰氯(32.6ml,448mmol,5eq)。将所得悬浮液在75℃N2下加热1.5小时。反应混合物始终是不均匀的。过滤收集固体酰基氯。黄褐色固体用甲苯洗涤(3×50ml),在真空下干燥。将酰基氯的THF(250ml)悬浮液冷却至0℃。在N2下,通过滴加漏斗历经5-10分钟加入盐酸胍(17.1g,179mmol,2eq)和2N NaOH(224ml,448mmol,5eq)的水溶液。加入碱性胍的水溶液后反应变得均匀和两相。混合物在0℃下搅拌,同时历经1小时缓慢加热至室温,然后在室温下再搅拌1小时。TLC分析(4∶1二氯甲烷/甲醇)指示出现强极性斑点(N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)-胍)和痕量原料酸。在真空下小心地加热(35℃),除去THF,导致产物沉淀出来。含水层在室温下搅拌1小时,使产物形成颗粒。过滤收集固体,用水洗涤(2×50ml),干燥。产物的颜色从灰白色到中等棕色不等。这一批是中等棕色。在MeOH(125ml)中再次拌浆30分钟,得到所需产物N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)-胍(22.6g,产率79%),为淡黄褐色固体。
实施例5
将N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)-胍(3.08kg,9.61mol,1eq)悬浮在丙酮(30.8kg)中。加入1-甲基-2-吡咯烷酮(12.3kg),得到均匀的溶液。另用4.8kg丙酮清洗前者(具体来说没有过滤)。反应溶液加热至50℃。加入甲磺酸(0.83kg,8.65mol,0.9eq)的丙酮(8.3kg)溶液,同时保持温度低于55℃。将所得淤浆在50℃下搅拌1至2小时,然后冷却,过滤。滤饼用丙酮清洗,然后干燥,得到N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)-胍的单甲磺酸盐(3.24kg,81%),为灰白色固体。
实施例6
向3.165kg实施例5产物中加入123升(3.8体积)丙酮。将淤浆在室温下搅拌20小时。淤浆过滤,固体在50℃下干燥。产物是具有等径形式的无水晶体(3.145kg,99%),熔点(开始)228℃。
Claims (10)
1、用于制备N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)-胍的单甲磺酸盐的方法,该方法包括使N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)-胍与甲磺酸化合的步骤。
2、如权利要求1所述的方法,其中该化合物是在一种极性非质子传递溶剂中、在40℃至80℃的温度下被化合的。
3、如权利要求2所述的方法,其中该溶剂是丙酮与1-甲基-2-吡咯烷酮的混合物。
4、如权利要求1所述的方法,其中N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍是如下制备的:
a.使5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸与亚硫酰氯在甲苯中化合,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯;和
b.使盐酸胍和氢氧化钠与5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯的四氢呋喃悬浮液在-10℃至10℃的温度下化合1小时至3小时。
5、如权利要求4所述的方法,其中5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸与亚硫酰氯在60℃至90℃的温度下化合-至三小时。
6、如权利要求4所述的方法,其中5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸是在氢氧化钠的存在下,通过将5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯用甲醇水溶液在回流下水解而制备的。
7、如权利要求6所述的方法,其中5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯是如下制备的:在一种胺碱的存在下,使喹啉-5-基-肼与甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯在一种反应惰性溶剂中化合。
8、如权利要求7所述的方法,其中该溶剂是乙醇,该胺碱是三乙胺,该化合作用发生在50℃至回流的温度下。
9、如权利要求7所述的方法,其中甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯是如下制备的:在洁净条件下,使甲基-3-环丙基-3-氧代丙酸酯与N,N-二甲基甲酰胺二甲基乙缩醛在50℃至110℃的温度下化合一至五小时。
10、如权利要求1的方法,该方法包括:
a.在洁净条件下,使甲基-3-环丙基-3-氧代丙酸酯与N,N-二甲基甲酰胺二甲基乙缩醛在50℃至110℃的温度下化合一至五小时;
b.在一种胺碱的存在下,使喹啉-5-基肼与甲基-3-环丙基-2-二亚甲氨基-3-氧代丙酸酯在一种反应惰性溶剂中化合,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯;
c.在氢氧化钠的存在下,将5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸甲酯用甲醇水溶液在回流下水解,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸;
d.使5-环丙基-1-喹啉-5-基-1H-吡唑-4-羧酸与亚硫酰氯化合,生成5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯;
e.使盐酸胍和氢氧化钠与5-环丙基-1-喹啉-5-基-1H-吡唑-4-酰基氯的四氢呋喃悬浮液在-10℃至10℃的温度下化合1小时至3小时,生成N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍;和
f.使N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍与甲磺酸化合,生成N-(5-环丙基-1-喹啉-5-基-1H-吡唑-4-羰基)胍的单甲磺酸盐。
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CZ20004018A3 (cs) | 2002-04-17 |
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TWI221152B (en) | 2004-09-21 |
PL343542A1 (en) | 2001-05-07 |
KR20010060211A (ko) | 2001-07-06 |
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