CN1272313C - 20－羟基二十碳四烯酸生成抑制剂 - Google Patents

20－羟基二十碳四烯酸生成抑制剂 Download PDF

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CN1272313C
CN1272313C CNB028089855A CN02808985A CN1272313C CN 1272313 C CN1272313 C CN 1272313C CN B028089855 A CNB028089855 A CN B028089855A CN 02808985 A CN02808985 A CN 02808985A CN 1272313 C CN1272313 C CN 1272313C
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alkyl
base
carbonyl
replaces
alkylamino
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CN1633413A (zh
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佐藤正和
宫田则之
石井孝明
松永结子
天田英明
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

下式代表的羟基甲眯化合物和其可药用盐，式中R1代表取代的吗啉代、取代的哌啶子基、哌嗪-1-基、取代的哌嗪-1-基、硫代吗啉-1-基、全氢化吖庚因-1-基、全氢化吖辛因-1-基、四氢吡啶-1-基、吡咯啉-1-基等；X代表氮原子或CR5代表的基团；R2到R5相同或不同，分别代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基或卤原子。本发明提供了一种药物，它抑制参与微血管收缩或扩张以及在主要器官如肾脏和脑血管中诱导细胞增殖的20-HETE形成酶。

Description

20-羟基二十碳四烯酸生成抑制剂
技术领域
本发明涉及抑制由花生四烯酸生成20-羟基二十碳四烯酸(20-HETE)的羟基亚胺甲基氨基苯或羟脒基吡啶衍生物。
背景技术
关于由花生四烯酸生成的生理活性物质，为人们所熟知的是通过环加氧酶生成的前列腺素类，和通过脂肪氧化酶生成的白三烯类。但近年来，人们逐渐认识到通过属于细胞色素p450族的酶由花生四烯酸产生的20-HETE在体内有多种作用(J.Vascular Research，volume32，page 79(1995))。到目前为止，已经阐明20-HETE收缩或扩张微血管，还在主要器官如肾和脑血管中诱导细胞增殖，还有人提出20-HETE在体内发挥重要生理活性的同时，还深入参与多种肾脏疾病、脑血管疾病、循环疾病等的病理过程(J.Vascular Research，volume 32，page 79(1995)；Am.J.Physiol.，volume 277，page R607(1999)；Physiol.Rev.，volume 82，page 131(2002)，等)。
本发明的目的是提供一种药物，其抑制20-HETE的生成，后者参与微血管的收缩或扩张、在主要器官如肾脏和脑血管中诱导细胞增殖等。
发明内容
为了解决上述问题，经过大量的探索和研究，本发明的发明人现发现几种抑制20-HETE生成的芳香族化合物，从而完成了本发明。
即，本发明涉及下式代表的羟基甲眯化合物或其可药用盐。
[其中R1代表取代的吗啉代、取代的哌啶子基、哌嗪-1-基、取代的哌嗪-1-基、硫代吗啉-1-基、全氢化吖庚因-1-基、全氢化吖辛因-1-基、四氢吡啶-1-基、吡咯啉-1-基、1，4-二氧杂-8-氮杂螺[4，5]癸烷-8-基或十氢喹啉-1-基；X代表氮原子或CR5代表的基团；R2到R5相同或不同，分别代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基或卤原子。]
本发明所用的术语定义如下。取代的吗啉代指1到3个C1-4烷基取代的吗啉代，其实例是2-甲基吗啉代、2-乙基吗啉代、3-甲基吗啉代、2，6-二甲基吗啉代、2，3，5-三甲基吗啉代，其中更优选2，6-二甲基吗啉代。
取代的哌啶子基指C1-4烷基取代的哌啶子基、C1-4烷氧基取代的哌啶子基、羟基取代的哌啶子基、C2-5烷氧羰基取代的哌啶子基、单C2-7烷基氨基羰基或二C2-7烷基氨基羰基取代的哌啶子基、C1-4烷氧基-C1-6烷基取代的哌啶子基、C1-6羟烷基取代的哌啶子基、单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基取代的哌啶子基，其实例有2-甲基哌啶子基、3-甲基哌啶子基、4-甲基哌啶子基、4-乙基哌啶子基、4-甲氧基哌啶子基、4-羟基哌啶子基、4-甲氧羰基哌啶子基、4-乙氧羰基哌啶子基、4-二甲基氨基羰基哌啶子基、3-二乙基氨基羰基哌啶子基、4-(2-甲氧乙基)哌啶子基、4-(2-羟乙基)哌啶子基、4-(2-二甲基氨基乙基)哌啶子基，其中更优选4-羟基哌啶子基、4-(2-羟乙基)哌啶子基、4-乙氧羰基哌啶子基和3-二乙基氨基羰基哌啶子基。
取代的哌嗪-1-基指哌嗪-1-基、C1-4烷基取代的哌嗪-1-基、含4-8个环原子的环烷基取代的哌嗪-1-基、C1-4烷氧基-C1-4烷基取代的哌嗪-1-基、C1-6羟烷基取代的哌嗪-1-基、单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基取代的哌嗪-1-基、吡咯烷-1-基-C1-6烷基取代的哌嗪-1-基、吗啉代羰基-C1-6烷基取代的哌嗪-1-基、C2-6烷酰基取代的哌嗪-1-基、苯基取代的哌嗪-1-基、吡啶基取代的哌嗪-1-基，其实例有2-甲基哌嗪-1-基、3-甲基哌嗪-1-基、4-甲基哌嗪-1-基、4-乙基哌嗪-1-基、4-环己基哌嗪-1-基、4-(2-甲氧乙基)哌嗪-1-基、4-(2-羟乙基)哌嗪-1-基、4-(2-二甲基氨基乙基)哌嗪-1-基、4-(2-吡咯烷-1-基-乙基)哌嗪-1-基、4-(1-吗啉代羰基甲基)哌嗪-1-基、4-苯基哌嗪-1-基，其中更优选4-甲基哌嗪-1-基、4-乙基哌嗪-1-基、4-环己基哌嗪-1-基、4-(2-羟乙基)哌嗪-1-基、4-(2-二甲基氨基乙基)哌嗪-1-基、4-(2-吡咯烷-1-基-乙基)哌嗪-1-基、4-(吗啉代羰基甲基)哌嗪-1-基、4-乙酰基哌嗪-1-基、4-苯基哌嗪-1-基和4-(2-吡啶基)哌嗪-1-基。
本发明中，“Cx-y”指含有x到y个碳原子的基团。
卤原子是氟原子、氯原子、溴原子或碘原子。
C1-4和C1-6烷基指分别含有1-4和1-6个碳原子的直链或支链烷基。C1-4烷基的实例有甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基，其中更优选甲基。C1-6烷基的实例是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基和异己基，其中更优选甲基和乙基。
C1-4烷氧基指含有1到4个碳原子的直链或支链烷氧基，其实例有甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和叔丁氧基。
C2-5烷氧羰基指含有1到4个碳原子的直链或支链烷氧基与羰基结合组成的取代基，其实例有甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基和丁氧羰基。
单C2-7烷基氨基羰基或二C2-7烷基氨基羰基指一或二个含有1到6个碳原子的直链或支链烷基取代的氨基与羰基结合组成的取代基，其实例有甲基氨基羰基、乙基氨基羰基、二甲基氨基羰基、二乙基氨基羰基和二异丁基氨基羰基，其中更优选二乙基氨基羰基。
C1-4烷氧基-C1-4烷基指含有1到4个碳原子的直链或支链烷氧基与含有1-4个碳原子的直链或支链烷基结合组成的取代基，其实例有甲氧甲基、乙氧甲基、甲氧乙基、乙氧乙基、丙氧乙基、异丙氧乙基、丁氧乙基和叔丁氧乙基。
C1-6羟烷基指羟基取代的含有1-6个碳原子的直链或支链烷基，其实例有羟甲基、1-羟乙基、2-羟乙基、3-羟丙基和5-羟戊基，其中更优选2-羟乙基。
单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基指一或二个含有1到4个碳原子的直链或支链烷基取代的氨基与含有1到6个碳原子的直链或支链烷基结合组成的取代基，其实例有甲基氨基甲基、1-甲基氨基乙基、2-甲基氨基乙基、3-甲基氨基丙基、4-二甲基氨基丁基、二甲基氨基甲基、1-二甲基氨基乙基、2-二甲基氨基乙基和3-二甲基氨基丙基，其中更优选2-二甲基氨基乙基。
含有4到8个环原子的环烷基指环丁基、环戊基、环己基、环庚基和环辛基，其中更优选环己基。
吡咯烷-1-基-C1-6烷基指吡咯烷-1-基取代的含有1到6个碳原子的直链或支链烷基，其实例有吡咯烷-1-基-甲基、2-(吡咯烷-1-基)乙基、3-(吡咯烷-1-基)丙基和5-(吡咯烷-1-基)戊基，其中更优选2-(吡咯烷-1-基)乙基。
吗啉代羰基-C1-6烷基指吗啉代羰基取代的含有1-6个碳原子的直链或支链烷基，其实例有吗啉代羰基甲基、2-吗啉代羰基乙基、3-吗啉代羰基丙基和5-吗啉代羰基戊基，其中更优选吗啉代羰基甲基。
这些化合物的熔点、测定的MASS值、TLC的Rf值和展开剂列于表1。在TLC测定中，使用Fuji Silysia Chemical Ltd.制造的SiO2(NH)。
可药用盐是与碱金属、碱土金属、铵、烷基铵等的盐，与无机酸或有机酸的盐。其实例有钠盐、钾盐、钙盐、铵盐、铝盐、三乙基铵盐、乙酸盐、丙酸盐、丁酸盐、甲酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡糖酸盐、葡庚糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、2-羟乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、月桂基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、与半胱氨酸的盐、与N-乙酰基半胱氨酸的盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、氢碘酸盐、烟酸盐、草酸盐、苦味酸盐、硫代氰酸盐、十一酸盐、与丙烯酸聚合物的盐和与羧乙烯基聚合物的盐。
本发明的化合物可用例如下列所示的方法合成。即，下式(a)代表的化合物：
Figure C0280898500081
(其中，Y是卤原子，R2、R3、R4和X与上述定义的意义相同)与下式(b)代表的化合物在有或无合适的溶剂存在下反应：
         R1H                    (b)
(其中R1与上述定义的意义相同)
得到下式(c)代表的化合物。(其中R1、R2、R3、R4和X与上述定义的意义相同。)
然后，在合适的溶剂中(例如甲醇、乙醇、丙醇、四氢呋喃、二噁烷、甲苯、二氯甲烷、氯仿、乙腈和乙酸乙酯)，用还原剂(例如，氢气气氛中的钯-活性碳、钯-活性碳/水合肼、钯-活性碳/甲酸铵、氯化锡(II)一水合物、铁/氯化铵和阮内镍/水合肼)将化合物(c)的硝基还原，制得苯胺衍生物(d)。(其中R1、R2、R3、R4和X与上述定义的意义相同。)
然后，化合物(d)与二甲基甲酰胺二甲基缩醛在合适的溶剂(例如，甲醇、乙醇、丙醇、四氢呋喃、二噁烷、甲苯、二氯甲烷、氯仿、乙腈和乙酸乙酯)中反应2到72小时，反应温度为室温到150℃，优选70℃到100℃。上文中制备的中间体在合适的溶剂(例如，甲醇、乙醇、丙醇、四氢呋喃、二噁烷、甲苯、二氯甲烷、氯仿、乙腈和乙酸乙酯)中用羟胺盐酸盐处理，制得式(1)代表的本发明的化合物。或者，式(d)的化合物与原甲酸酯如原甲酸三甲酯或原甲酸三乙酯在有或无催化剂量的有机酸如乙酸、无机酸如盐酸或胺与无机酸的盐如吡啶盐酸盐存在下反应得到一中间体。反应温度是从室温到150℃，优选70℃到100℃，反应时间是2到72小时。将其分离或不分离，然后在合适的溶剂(例如，甲醇、乙醇、丙醇、四氢呋喃、二噁烷、甲苯、二氯甲烷、氯仿、乙腈和乙酸乙酯)中用羟胺处理，制得式(1)代表的本发明的化合物。
本发明的药物含式(1)所代表的化合物或其可药用盐作为有效成份。这样的药物特别用来作为肾脏疾病、脑血管疾病或循环疾病的治疗剂。根据本发明的20-HETE生成抑制剂含式(1)代表的化合物或其可药用盐作为有效成份，它有效抑制20-HETE的生成。
在治疗成人时，本发明的药物、肾脏疾病、脑血管疾病和循环疾病的治疗剂、以及20-HETE生成抑制剂的剂量优选为每天1到2000mg式(1)所代表的化合物或其可药用盐，可以每天一次性给药或分几次给药。剂量可以根据用途和患者的年龄、体重、症状等适当增加或减少。
本发明的药物、肾脏疾病、脑血管疾病和循环疾病的治疗剂和20-HETE生成抑制剂可以口服或胃肠外给药。其剂型是片剂、胶囊剂、颗粒剂、稀释性粉剂、粉剂、锭剂、软膏剂、霜剂、乳液剂、混悬剂、注射剂等，所有这些都可以通过常规制备方法制备(例如，根据日本药典第1 2版修订本规定的方法)。可以根据患者的症状、年龄和治疗目的挑选适宜的剂型。在各种剂型的制备过程中，可以使用常用的赋形剂(例如，结晶纤维素、淀粉、乳糖和甘露醇)、粘合剂(例如，羟丙基纤维素和聚乙烯吡咯烷酮)、润滑剂(例如，硬脂酸镁和滑石)、崩解剂(例如，羧甲基纤维素钙)等。
本发明的最佳实施方式
通过下列实施例将更详细地阐明本发明。
实施例1：
N-羟基-N’-(3-氯-4-硫代吗啉代苯基)甲眯的合成
将3-氯-4-氟硝基苯(0.070g，0.4mmol)和硫代吗啉(0.1 65g，1.6mmol)的混合物在70℃搅拌1 6小时。将反应混合物冷却至室温，减压浓缩并用硅胶柱色谱(展开剂；氯仿∶甲醇＝9∶1)纯化，得到黄色粉状晶体。向其中加入铁粉(0.27g，4.83mmol)、异丙醇(0.5ml)和1当量的氯化铵水溶液(0.12ml，0.12mol)，随后在70℃搅拌16小时。将反应混合物冷却至室温，向其中加入四氢呋喃(0.4ml)，用硅藻土滤除不溶物后，用乙酸乙酯(0.4ml)洗涤4次。减压浓缩滤液并向其中加入甲醇(0.4ml)和二甲基甲酰胺二甲基缩醛(0.095g，0.8mmol)，随后在70℃搅拌64小时。将反应混合物冷却至室温并减压浓缩，向其中加入甲醇(0.4ml)和羟胺盐酸盐(0.033g，0.48mmol)，随后在室温搅拌6小时。将反应混合物减压浓缩并向其中加入饱和碳酸氢钠水溶液(0.4ml)，随后用乙酸乙酯萃取。减压浓缩有机层，用NH型硅胶柱色谱(展开剂：正己烷∶乙酸乙酯＝1∶1)纯化，并从乙酸乙酯/正己烷中重结晶得到无色粉末状的标题化合物(0.026g)(在下文表1中的化合物3)。
熔点：137.0到138.5℃。
实施例2：
N-[2-(吗啉代)吡啶-5-基]-N’-羟基甲眯的合成
将2-氯-5-硝基吡啶(2g，12.6mmol)和吗啉(4.4g，55.5mmol)的混合物在室温搅拌1小时。向反应混合物中加入水，将从其中析出的结晶过滤得到黄色粉状晶体。向其中加入甲醇(30ml)和钯碳(0.25g)，将混合物在氢气气氛中室温搅拌4小时。用硅藻土滤除不溶物并减压浓缩滤液。向所得残余物中加入甲醇(20ml)和二甲基甲酰胺二甲基缩醛(1.81g，15.2mmol)，随后搅拌回流2小时。将反应混合物冷却至室温，减压浓缩并向其中加入甲醇(20ml)和羟胺盐酸盐(1.05g，15.2mmol)，随后在室温搅拌4小时。将反应混合物减压浓缩并向其中加入饱和碳酸氢钠水溶液(10ml)，随后用乙酸乙酯萃取。有机层经MgSO4干燥，减压浓缩后，用NH型硅胶柱色谱(展开剂：正己烷∶乙酸乙酯＝1∶1)纯化并从乙酸乙酯中重结晶得到无色粉末状标题化合物(0.985g)(下文表1中的化合物127)。
熔点：172.0到174.0℃。
下表列出的化合物是用相应的起始原料按照实施例1或2相同的反应操作合成的。实施例1和2得到的化合物作为化合物3和化合物127也列于其中。
Figure C0280898500151
Figure C0280898500161
Figure C0280898500171
Figure C0280898500191
Figure C0280898500201
Figure C0280898500231
Figure C0280898500241
Figure C0280898500251
Figure C0280898500301
Figure C0280898500302
试验实施例：[对来源于人类肾脏微粒体的20-HETE-生成酶的抑制作用]
对上表所列的化合物，检测了它们对20-HETE生成的抑制作用。
该实验是根据J.Pharmacol.Exp.Ther.，volume 268，page 474(1994)所述方法进行的。
用DMSO将试验化合物溶液调至1μM，加入到含5mM氯化镁和1mM乙二胺四乙酸(EDTA)钠的50mM3-吗啉代丙磺酸缓冲液(MOPS)(pH7.4)中，然后将人类肾脏微粒体提取物(Human CellCulture Center Anatomic Gift Foundation)、[5，6，8，9，11，12，15]氚-花生四烯酸和NADPH加入其中分别作为酶源、底物和辅酶，反应在37℃进行1.5小时。向反应溶液中加入甲酸中止反应，然后将乙腈加入其中(终浓度：50％)。用装有带ODS柱的放射活性物质探测器的高效液相色谱仪(Biosil C18；Biorad制造)测量这样生成的20-HETE的量。
不加入化合物时生成的20-HETE的量被定义为100％，计算加入化合物后20-HETE的生成被抑制50％时化合物的浓度(IC50值)。结果也显示在上表中。
工业实用性
式(1)代表的化合物或其可药用盐可用作20-HETE生成抑制剂。它还可以作为药物，特别是作为治疗肾脏疾病、脑血管疾病和循环疾病的药物。

Claims (3)

1.下式代表的羟基甲眯化合物或其可药用盐：
Figure C028089850002C1
其中R1代表1到3个C1-4烷基取代的吗啉代；取代的哌啶子基，其中取代基选自C1-4烷基、C1-4烷氧基、羟基、C2-5烷氧羰基、单C2-7烷基氨基羰基或二C2-7烷基氨基羰基、C1-4烷氧基-C1-6烷基、C1-6羟烷基、单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基；哌嗪-1-基；取代的哌嗪-1-基，其中取代基选自C1-4烷基、含4-8个环原子的环烷基、C1-4烷氧基-C1-4烷基、C1-6羟烷基、单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基、吡咯烷-1-基-C1-6烷基、吗啉代羰基-C1-6烷基、C2-6烷酰基、苯基、吡啶基；硫代吗啉-1-基；全氢化吖庚因-1-基；全氢化吖辛因-1-基；四氢吡啶-1-基；吡咯啉-1-基；1，4-二氧杂-8-氮杂螺[4，5]癸烷-8-基；十氢喹啉-1-基；单或二(C1-4烷氧基-C1-6烷基)氨基；或单或二(C1-6羟烷基)氨基；X是氮原子或CR5代表的基团；R2到R5相同或不同，分别代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基或卤原子。
2.20-羟基二十碳四烯酸生成抑制剂，其含有下式代表的羟基甲眯化合物或其可药用盐作为有效成分
Figure C028089850002C2
其中R1代表1到3个C1-4烷基取代的吗啉代；取代的哌啶子基，其中取代基选自C1-4烷基、C1-4烷氧基、羟基、C2-5烷氧羰基、单C2-7烷基氨基羰基或二C2-7烷基氨基羰基、C1-4烷氧基-C1-6烷基、C1-6羟烷基、单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基；哌嗪-1-基；取代的哌嗪-1-基，其中取代基选自C1-4烷基、含4-8个环原子的环烷基、C1-4烷氧基-C1-4烷基、C1-6羟烷基、单C1-4烷基氨基-C1-6烷基或二C1-4烷基氨基-C1-6烷基、吡咯烷-1-基-C1-6烷基、吗啉代羰基-C1-6烷基、C2-6烷酰基、苯基、吡啶基；硫代吗啉-1-基；全氢化吖庚因-1-基；全氢化吖辛因-1-基；四氢吡啶-1-基；吡咯啉-1-基；1，4-二氧杂-8-氮杂螺[4，5]癸烷-8-基；十氢喹啉-1-基；单或二(C1-4烷氧基-C1-6烷基)氨基；或单或二(C1-6羟烷基)氨基；X是氮原子或CR5代表的基团；R2到R5相同或不同，分别代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基或卤原子。
3.根据权利要求2的20-羟基二十碳四烯酸生成抑制剂，它是治疗肾脏疾病、脑血管疾病和循环疾病的药物。
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