CN103096892A - 含有氨甲酰氧基芳基烷酰基芳基哌嗪化合物的药物组合物 - Google Patents
含有氨甲酰氧基芳基烷酰基芳基哌嗪化合物的药物组合物 Download PDFInfo
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- CN103096892A CN103096892A CN201180043088XA CN201180043088A CN103096892A CN 103096892 A CN103096892 A CN 103096892A CN 201180043088X A CN201180043088X A CN 201180043088XA CN 201180043088 A CN201180043088 A CN 201180043088A CN 103096892 A CN103096892 A CN 103096892A
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- phenyl
- piperazine
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- oxygen
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Abstract
一种包括氨甲酰氧基芳基烷酰基芳基哌嗪化合物并可有效预防或治疗糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的药物组合物。
Description
技术领域
本申请要求2010年7月8日向韩国知识产权局提交的韩国专利申请No.10-2010-0065950的优先权，该申请的公开文本在此以引用方式全文纳入本文。
本发明涉及含有氨甲酰氧基芳基烷酰基芳基哌嗪化合物的药物组合物，及通过使用所述药物组合物治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的方法。
背景技术
脂氧合酶是在植物和动物中存在的、催化特定多不饱和脂肪酸(例如脂质和脂蛋白)氧合的非血红素的含铁酶。已知多种不同的脂氧合酶具有特定的氧化反应。哺乳动物的脂氧合酶是依据它们在将被氧合的花生四烯酸酯中的位置命名的。已知人体内有三种类型的脂氧合酶，它们催化将氧分子加合到花生四烯酸酯中的碳位5、12和15。因此，依据氧分子所加合的碳位的位置将所述酶命名为5-、12-或15-脂氧合酶。5-脂氧合酶将花生四烯酸酯转变为5-过氧化氢二十碳四烯酸(5-HPETE)。这是产生5-羟基二十碳四烯酸(5-HETE)和白细胞三烯(LT)的代谢途径的第一阶段。同样地，12-和15-脂氧合酶分别将花生四烯酸酯转变为12-HPETE和15-HPETE。12-HPETE的生物化学还原产生15-HETE，其是化合物15-HETE脂氧素的前体。多种生物学效应与具有脂氧合酶活性的产物有关，并且已知这些产物中有许多是多种疾病的调节因子。15-脂氧合酶通常在内皮细胞、平滑肌细胞、单核细胞/巨噬细胞、肾小球系膜细胞、肾小管上皮细胞和足细胞中表达，并且催化由花生四烯酸形成15-S-羟基二十碳四烯酸(15-S-HETE)(Natarajan and Nadler，Front.Biosci.(2003)8：s783-795；Reilly et al.，J.Biol.Chem.(2004)279(10)：9440-9450)。
糖尿病慢性并发症包括大血管并发症、糖尿病肾病、糖尿病神经病变等。如果糖尿病持续数年，微血管和大血管缓慢地发生病理改变。微血管并发症的发生直接由高血糖引起。如果山梨糖醇在高血糖的促进下形成，则血管壁的厚度增加并且血流受到影响，以此促进血液凝结。如果持续高血糖诱导的微血管损伤在肾脏、神经元等中发生，则可能发生糖尿病慢性并发症例如糖尿病肾病、糖尿病神经病变。同时，高血糖是大血管并发症的间接诱因，并且由高血糖状态下的脂代谢异常导致的胆固醇增加是高血糖的直接诱因。
现有技术中公开了15-脂氧合酶参与动脉硬化、肾小球肾炎、高脂血症或炎症的发生。而且，KR2008-67364公开了三唑化合物作为15-脂氧合酶抑制剂。但是，目前尚无可市购的用于通过抑制15-脂氧合酶预防或治疗这些疾病的药剂。因此，需要开发可预防或治疗这些疾病的药物组合物。
发明内容
技术问题
本发明提供了一种用于预防或治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的药物组合物。
本发明还提供了一种通过使用所述药物组合物治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的方法。
技术方案
本发明一方面，提供了一种用于预防或治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的药物组合物，其中所述药物组合物包括治疗有效量的选自下式I表示的化合物、其可药用盐、异构体、溶剂合物或水合物及其组合的化合物；以及可药用载体：
式I
其中，X1包括选自氢，直链或支链的C1-C6烷基，包括F、Cl或Br的卤素，直链或支链的C1-C6烷氧基，硝基和三氟甲基的至少一个；
X2包括选自氢、直链或支链的C1-C6烷基、卤素、直链或支链的C1-C6烷氧基、硝基和三氟甲基的至少一个，并且如果X2包含其中的2个或更多个，它们彼此相同或不同并且与相邻的碳原子形成环；并且
Y是氢或甲基，或者与相邻的碳原子形成羰基。
本发明的一个实施方案的药物组合物可包括治疗有效量的选自上式I表示的化合物、其可药用盐、异构体、溶剂合物或水合物及其组合的化合物。
术语“治疗”应解释为在动物中阻止疾病或状况的发展；抑制疾病或状况，即抑制疾病或状况的发展；以及缓解疾病或状况，即导致疾病或状况的消退，所述动物具有选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病或状况，或者尚未被诊断为具有所述疾病或状况、但易于具有所述疾病或状况。因此，术语“治疗有效量”是指足以获得药效即治疗效应的量。
本发明的一个实施方案中的式I表示的化合物可由化合物合成领域的普通技术人员使用已知化合物或者使用容易从已知化合物制备的化合物来制备。具体地，所述化合物的制备方法详细地公开于KR2008-40393中，其由与本发明相同的发明人申请的，所述专利以引用方式纳入本文。本发明的化合物可通过使用上述所引用的参考文献中公开的方法来化学合成。但是，所述方法仅用于说明目的。因此，本文中所用的操作顺序如果需要可被任选地改变，其不限制本发明的范围。
除式I表示的化合物外，所述化合物还可包括其可药用盐，即其酸加成盐或碱加成盐；和本文式I表示的化合物的立体化学异构体，所述可药用盐可以是可使母体化合物在被给予所述化合物的受试者中保持其活性并且不引起副作用的各种盐中的任意一种。所述可药用盐可以是无机盐或有机盐。酸的实例有乙酸、盐酸、硝酸、天冬氨酸、磺酸、硫酸、马来酸、谷氨酸、甲酸、琥珀酸、磷酸、邻苯二甲酸、鞣酸、酒石酸、氢溴酸、丙酸、苯磺酸、苯甲酸、硬脂酸、乙基磺酸、丁酸、二碳酸、二硫酸、二酒石酸、草酸、丁酸、乙二胺四乙酸钙、樟脑磺酸、碳酸、氯苯甲酸、柠檬酸、乙二胺四乙酸(idetic acid)、甲苯磺酸、乙二磺酸(edicylinic acid)、乙磺酸(ecylinic acid)、富马酸、葡庚糖酸、双羟萘酸、葡糖酸、乙醇酰基对氨基苯胂酸(glycolyllarsanylicacid)、甲基硝酸、聚半乳糖醛酸(polygalatronic acid)、己基雷锁辛酸(hexyllisorcynonic acid)、乌索酸、氢溴酸、氢氯酸(hydrochlorinicacid)、氢碘酸、羟基萘酚酸(hydroxylnaphtholic acid)、羟基乙磺酸、乳糖酸、苦杏仁酸、丙酸酯十二烷基硫酸(estolinic acid)、粘酸、萘磺酸(naphcylic acid)、粘康酸、对硝基甲磺酸、环己磺酸、泛酸(、一氢磷酸、二氢磷酸、水杨酸、氨基磺酸(sulpamic acid)、磺胺酸(sulpanylic acid)、甲磺酸和茶氯酸(theoclic acid)。例如，用于加成盐的酸可以是氢氯酸或甲磺酸。同时，碱盐的实例有铵盐以及碱金属或碱土金属例如锂、钠、钾、镁或钙的盐。碱盐的具体实例有含有有机碱例如苄星、N-甲基-D-葡萄糖胺或海巴明的盐和含有氨基酸例如精氨酸或赖氨酸的盐。同时，所述盐通过用适合的碱或酸处理还可转换成自由基形式。术语“加成盐”包括由式I表示的化合物及其盐形成的溶剂化合物。溶剂化合物的实例是水合物或醇化物。
同时，本发明的一个实施方案的式I表示的化合物的立体化学异构体是指可从式I表示的化合物获得的任何化合物。如果没有另外定义，则化合物的化学名称指示任何可能的立体化学异构体类型的混合物，所述混合物的实例是各自具有基本分子结构的非对映异构体和对映异构体。具体地，立体中心可具有R-或S-配位，并且2-价环状(部分)饱和基团的取代基可具有顺式或反式配位。具有双键的化合物在双键中可具有E或Z-立体化学结构。式I表示的化合物的立体化学异构体包含在本发明的范围内。
式I表示的化合物的非限制性实例是氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-氟-苯基)-3-氧-丙酯、氨基甲酸3-(4-苯并[1，3]二氧杂环戊烯-5-基-哌嗪-1-基)-3-氧-1-苯基-丙酯、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-三氟甲基-苯基)-3-氧-丙酯；盐酸盐、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-硝基-苯基)-3-氧-丙酯、(R)-氨基甲酸3-[4-(4-氯-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、(S)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-苯基-丁酯和氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-氯-苯基)-3-氧-丙酯。本发明的一个实施方案中，式I表示的化合物可以是(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯。
本发明的一个实施方案的药物组合物可包括可药用载体。
所述药物组合物的可药用载体可以是制剂中常规使用的多种材料中的任意一种，可药用载体的非限制性实例是乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁和矿物油。所述药物组合物还可包括润滑剂、湿润剂、芳香剂、乳化剂、混悬剂、防腐剂等。适合的可药用载体和制剂在Remington′s Pharmaceutical Sciences(第19版，1995)中详细公开。
本发明的一个实施方案中，所述药物组合物可以口服或肠胃外给药。肠胃外给药可以是静脉注射、皮下注射、肌肉注射、腹膜内注射、内皮给药、局部给药、鼻内给药、阴道内给药、肺内给药或直肠内给药。对于口服，活性材料可以是被包被的或者被制剂以防止在胃中分解。同时，所述药物组合物还可以通过允许活性材料到达靶细胞的任意装置被给药。给药途径可依据整体状况和将被治疗的受试者的年龄、治疗病症的性质和所用的活性材料而不同。
所述药物组合物的适合的给药量可依据制剂方法；给药方法；患者的年龄、体重、性别和疾病状态；食物；给药时间；给药途径；排泄速率；和反应灵敏度而不同。一般而言，熟练的药师可无任何困难地确定和开具有效治疗或预防的给药量。所述药物组合物的给药量可一次全给予、或者可分为数个部分给予，例如所述药物组合物可每天给予1到4次。
所述药物组合物可通过使用本领域普通技术人员熟知的方法以及可药用载体和/或赋形剂而制成单位剂型，或者可通过使用多剂量容器制备。该情况下，所述制剂可以是油介质或水性介质中的溶液、悬液或者乳液、提取物、粉剂、颗粒剂、片剂或胶囊，并且分散剂或稳定剂也可包括在所述药物组合物中。同时，所述药物组合物可以栓剂、喷雾剂、软膏剂、乳膏、凝胶剂、吸入剂或皮肤贴片形式给予。
所述药物组合物可被用于预防或治疗糖尿病肾病、糖尿病神经病变或糖尿病血管并发症。
术语“糖尿病的”是指相应疾病的原因是糖尿病。同时，术语“糖尿病”是指以胰岛素代谢缺陷诱导的慢性高血糖为特征并且由于慢性高血糖而具有多种异常代谢的一组疾病。因此，糖尿病肾病、糖尿病神经病变或糖尿病血管并发症可分别被理解为糖尿病诱导的肾病、糖尿病诱导的神经病变和糖尿病诱导的血管并发症。
糖尿病肾病是指肾脏的微血管受损伤并因此蛋白质不经过滤直接排出的疾病。糖尿病肾病的发展是由于肾小球超渗透(hiperpenentration)、肾小球基膜异常增厚、肾小球膜细胞增生、肾小球增厚以及细胞外基质的合成和增加，并引起逐渐增加的肾小球硬化症和肾衰竭。糖尿病神经病变是糖尿病的神经系统并发症，其中由于糖尿病而产生神经元功能和结构异常，通常发生在外周神经系统。同时，糖尿病血管并发症是指其中由于糖尿病诱导的高血糖和代谢障碍(例如胰岛素耐受性)导致血液流动障碍而产生动脉硬化的疾病。
同时，所述药物组合物被用于预防或治疗高脂血症、冠状动脉疾病或炎症。
高脂血症是指脂肪(例如甘油三酯或胆固醇)代谢异常进行、因此血液中含有大量脂肪，并且当脂肪物质出现在血液中时其可在血管壁上积累引起炎症并引发心血管疾病的状态。同时，冠状动脉疾病是指在供应心脏的血液通过的动脉(冠状动脉或心脏动脉)中脂肪沉积和纤维组织积累，因此供给心肌的血量减少使得心绞痛、心肌坏死和心肌梗塞发生，因此使心脏功能严重受损的状态。依据本发明的实施方案，高脂血症或冠状动脉疾病的病因可以是或不是糖尿病。
炎症被本领域普通技术人员理解为包括以局部或整体防御反应为特征的症状，可被针对身体的外部损伤、感染、上述慢性疾病和/或外部刺激的化学和/或生理反应(例如变应性反应的部分)引起。所述反应引起受伤组织的损坏、错觉或隔离。例如，炎症的发生可归因于发热、肿胀、疼痛、上火、血管舒张和/或血流增加、白血细胞侵入被感染的位点或功能丧失和/或与其他症状相关的炎性状态。因此，炎症可理解为包括炎性疾病、障碍或状态，特别是急性的、慢性的、溃疡性的、特异的、变应性的和坏死性的炎症，以及本领域普通技术人员已知的其他类型的炎症。因此，所述药物组合物可被用于治疗哮喘、慢性阻塞性肺病(COPD)、肺纤维化、变应性疾病、鼻炎、炎性肠病、溃疡、炎性痛、发热、动脉硬化、冠状动脉疾病、血管炎、胰腺炎、关节炎、骨关节炎、类风湿性关节炎、结膜炎、虹膜炎、巩膜炎、葡萄膜炎、伤口愈合、皮炎、湿疹、银屑病、中风、糖尿病、自身免疫性疾病、阿尔茨海默氏病、多发性硬化、结节病、霍奇金病、其他恶性疾病或具有炎性因子的其他类型疾病。
在本发明的一个实施方案中，所述化合物可具有15-脂氧合酶的抑制活性。
已知15-脂氧合酶与多种疾病的病因有关，所述疾病包括动脉硬化、哮喘、肾小球肾炎、糖尿病慢性并发症等(Harats et al.，Arterioscler.Thromb.Vasc.Biol.，(2000)20(9)：2100-2105；Natarajan et al.，FrontBiosci.，(2003)8：s783-795；Hatley et al.，J.Biol.Chem.，(2003)278(28)：25369-25375；Shannon et al.，Am.Rev.Respir.Dis.，(1993)147(4)：1024-1028；Montero and Badr，Exp.Neph.，(2000)8(1)：14-19；Hatley et al.，J.Biol.Chem.，(2003)278(28)：25369-25375；Natarajan et al.，Arterioscler Thromb.Vasc.Biol.，24，(2004)24(9)：1542-1548；Ma etal.，Prostaglandins Leukot EssentFatty Acids.，(2005)72(1)：13-20；Xu et al.，Kidney Int.，(2006)69(3)：512-9；Dwarakanath et al.，J.Vasc.Res.，(2008)45(2)：132-142)，并且15-脂氧合酶的表达在糖尿病状态或高血糖状态下增强。所述15-脂氧合酶的表达增强影响多种代谢、信号传递网络、转录控制和基因表达，从而增加自由基、脂质过氧化、有丝分裂原激活的蛋白(MAP)激酶和炎性反应的形成。这些结果有助于发生糖尿病并发症，并且通过人工抑制15-脂氧合酶的表达或活性，在糖尿病动物模型中的糖尿病血管并发症、糖尿病肾病和糖尿病神经病变是可预防和可治疗的(Natarajan andNadler，Front.Biosci.(2003)8：s783-795；Reilly et al.，J.Biol.Chem.(2004)279(10)：9440-9450；Obrosova et al.，Diabetes55(Suppl.1)(2006)A188；Xu et al.，Nephrol Dial Transplant.，(2009)24(6)：1744-1752；Yuan et al.，Am J Physiol Renal Physiol.(2008)295(2)：F605-617)。而且，抑制15-脂氧合酶的表达或活性被建议作为预防或治疗糖尿病诱导的或非糖尿病诱导的冠状动脉疾病的方法(Siu，J Cardiovasc Med(Hagerstown)，(2010)11(1)：1-6；Nagelin et al.，J.Biol.Chem.(2009)284(45)：31303-31314；Natarajan et al.，FrontBiosci.(2003)8：s783-95；Hatley et al.，J.Biol.Chem.(2003)278(28)：25369-25375)，此外，由于15-脂氧合酶在哮喘、变态反应、银屑病的生物合成中起到重要作用并且炎症调节因子和所述酶的抑制剂可抑制与所述疾病状态相关的生物化学途径，所以抑制15-脂氧合酶可用于治疗所述炎症相关的疾病(Liu et al.，Am J Physiol Lung Cell MolPhysiol.(2009)297(1)：1196-1203；Jeon et al.，Clin Exp Allergy.(2009)39(6)：908-917；Claesson，Prostaglandins Other Lipid Mediat.(2009)89(3-4)：120-125；Hajek，J Allergy Clin Immunol.，(2008)122(3)：633-639)。
因此，显示抗15-脂氧合酶的抑制活性的化合物可用作用于预防或治疗上述糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的药剂。
本发明另一方面提供了一种用于治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的方法，其中所述方法包括使所述药物组合物与受试者接触。
所述接触可以在体外或体内进行。如果所述接触是在体内进行，所述方法还可包括将所述药物组合物给予所述受试者。
所述受试者可以是细胞、组织、器官或个体。同时，所述给药可包括使所述药物组合物溶解于适合的缓冲液中的溶液与细胞、组织或器官直接接触，或者可以是肠胃外给药。用于治疗的所述药物组合物和给药方法已在上文中进行了描述，因此此处不再详细描述
同时，可给予所述药物组合物的受试者可以是任何类型的动物。例如，所述受试者可以是人或非人的动物例如狗、猫或小鼠。
附图说明
本发明的上述及其他特征和优点将通过参考附图详细描述示例性实施方案而更明显，其中：
图1示出了本发明中一个实施方案的化合物被给予到诱导了糖尿病的小鼠后所得的血清中总胆固醇量的测量结果；
图2示出了本发明中一个实施方案的化合物被给予到诱导了糖尿病的小鼠后所得的血清中甘油三酯量的测量结果；
图3示出了本发明中一个实施方案的化合物被给予到诱导了糖尿病的小鼠后肾皮质组织中纤连蛋白表达水平的测量结果；
图4示出了本发明中一个实施方案的化合物被给予到诱导了糖尿病的小鼠后肾皮质组织中PAI-1基因转录的mRNA量的测量结果；
图5示出了本发明中一个实施方案的化合物被给予到诱导了糖尿病的小鼠后肾皮质组织中MCP-1基因转录的mRNA量的测量结果；和
图6示出了本发明中一个实施方案的化合物被给予到诱导了糖尿病的小鼠后肾皮质组织中TGF-β1基因转录的mRNA量的测量结果。其中图1到6中＊表示对照组和未给予化合物的测试组之间具有统计学显著性，+表示未给予化合物的测试组和给予化合物的测试组之间具有统计学显著性。
具体实施方式
本发明将参考下述实施例进行更详细地描述。这些实施例仅用于说明性目的，不意图限制本发明的范围。
实施例1：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯的合成
将554mg(2.887mmole)苯甲酰基乙酸乙酯和641mg(2.887mmole)3，4-二甲氧基苯基哌嗪溶解于甲苯中，回流24小时。将在降低的压力下浓缩获得的736mg(1.99mmole)化合物溶解于甲醇中，并冷却至0℃，缓慢加入109mg(2.887mmole)硼氢化钠。将所得溶液在室温搅拌2小时，然后在降低的压力下浓缩溶剂并用水溶解，用乙酸乙酯萃取数次。然后，用硫酸镁将所得有机层干燥并且过滤，在降低的压力下浓缩。通过柱色谱法(己烷∶乙酸乙酯＝1∶1)将所得剩余物纯化，从而获得1.592mmole(589mg)化合物。将所得的化合物溶解于四氢呋喃(10mL)中，然后加入820mg(5mmole)1，1′-碳化二咪唑(1，1′-carbomidiazol)并在室温搅拌1小时，加入过量的氨水并在室温搅拌1小时。将反应混合物用水稀释，并用乙酸乙酯萃取数次，用硫酸镁将所得有机层干燥并且过滤，并在降低的压力下浓缩。通过柱色谱法(乙酸乙酯)纯化所得剩余物，产生目标化合物(产量：329mg，收率·28％)
1H NMR(200MHz，CDC13)d：2.82(dd，1H)，3.04(m，5H)，3.61(m，2H)，3.77(m，2H)，3.88(d，6H)，4.77(br，2H)，6.15(t，1H)，6.42(d，1H)，6.57(s，1H)，6.82(d，1H)，7.41(m，5H)
实施例2：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-氟-苯基)-3-氧-丙酯的合成
除使用4-氟-苯甲酰基乙酸和3，4-二甲氧基苯基哌嗪作为起始材料外，以与实施例1相同的方式获得目标化合物(产量：542mg，收率：37％)
1H NMR(200MHz，CDCl3)d：2.82(dd，1H)，3.01(m，5H)，3.60(m，2H)，3.75(m，2H)，3.86(d，6H)，4.92(br，2H)，6.15(t，1H)，6.42(d，1H)，6.56(d，1H)，6.80(d，1H)，7.04(t，2H)，7.38(t，2H)
实施例3：氨基甲酸3-(4-苯并[1，3]二氧杂环戊烯-5-基-哌嗪-1-基)-3-氧-1-苯基-丙酯的合成
除使用苯甲酰基乙酸乙酯和3，4-亚甲基二氧苯基哌嗪作为起始材料外，以与实施例1相同的方式获得目标化合物(产量：190mg，收率·48％)
1H NMR(200MHz，CDCl3)d：2.98(m，6H)，3.59(m，2H)，3.76(m，2H)，4.71(br，2H)，5.94(s，2H)，6.15(t，1H)，6.36(dd，1H)，6.55(s，1H)，6.74(d，1H)，3.40(m，5H)
实施例4：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-三氟甲基-苯基)-3-氧-丙酯；盐酸盐的合成
除使用4-三氟甲基-苯甲酰基乙酸乙酯和3，4-二甲氧基苯基哌嗪作为起始材料外，以与实施例1相同的方式获得目标化合物(产量：250mg，收率：52％)。将产物溶于二氯甲烷并加入饱和的HCl/醚溶液产生其盐酸盐。
1H NMR(200MHz，DMSO)d：2.90(dd，1H)，3.12(dd，1H)，3.34(m，4H)，3.75(s，3H)，3.78(s，3H)，3.85(m，4H)，6.00(m，1H)，6.60(br，2H)，7.01(m，2H)，7.20(m，1H)，7.60(d，2H)，7.75(d，2H)
实施例5：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-硝基-苯基)-3-氧-丙酯的合成
除使用4-硝基-苯甲酰基乙酸乙酯和3，4-二甲氧基苯基哌嗪作为起始材料外，以与实施例1相同的方式获得目标化合物(产量：261mg，收率：57％)。
1H NMR(200MHz，DMSO)d：2.96(dd，1H)，3.16(dd，1H)，3.42(m，4H)，3.76(s，3H)，3.78(s，3H)，3.92(m，4H)，6.05(m，1H)，6.64(br，2H)，7.02(m，1H)，7.24(m，2H)，7.65(d，2H)，8.24(d，2H)
实施例6：(R)-氨基甲酸3-[4-(4-氯-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯的合成
将1.0g(6.0mmole)(R)-3-羟基-3-苯基丙酸和1.18g(6.0mmole)4-氯苯基哌嗪在室温溶解于50mL四氢呋喃(作为溶剂)中，滴加1.24g(6.0mmole)EDC和0.81g(6mmole)HOBt，25℃搅拌5小时。通过在降低的压力下蒸馏除去过量的溶剂，将所得产物用20mL1N氯化钠水溶液中和，加入25mL乙酸乙酯，分离所得的有机层并用15mL乙酸乙酯萃取2次。将所得有机层用2g无水硫酸镁干燥并过滤，将滤液在降低的压力下浓缩并通过柱色谱法(己烷∶乙酸乙酯＝1∶1到1∶10)分离纯化。将0.345g(1mmole)所得产物溶于15mL四氢呋喃中，然后加入0.325g(2mmole)1，1′-碳化二咪唑并在室温搅拌1小时，然后加入过量的氨水并在室温搅拌2小时。将反应混合物用水稀释，并用乙酸乙酯萃取数次，将所得有机层用硫酸镁干燥并在降低的压力下浓缩。将所得剩余物用柱色谱法(己烷∶乙酸乙酯＝1∶1)纯化，从而产生目标化合物(产量：1.2g，收率：52.5％)。
1H NMR(200MHz，CDCl3)d：2.82(dd，1H)，3.07(m，5H)，3.58(m，2H)，3.74(m，2H)，4.81(br，2H)，6.13(t，1H)，6.84(d，2H)，7.38(m，7H)
实施例7：(S)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯的合成
除使用(S)-3-羟基-3-苯基丙酸(6mmole)和3，4-二甲氧基苯基哌嗪(6mmole)作为起始材料外，以与实施例6相同的方式获得目标化合物(产量：1.38g，收率：56％)。
1H NMR(200MHz，CDCl3)d：2.82(dd，1H)，3.04(m，5H)，3.61(m，2H)，3.77(m，2H)，3.88(d，6H)，4.77(br，2H)，6.15(t，1H)，6.42(d，1H)，6.57(s，1H)，6.82(d，1H)，7.41(m，5H)
实施例8：(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯的合成
除使用(R)-3-羟基-3-苯基丙酸和3，4-二甲氧基苯基哌嗪作为起始材料外，以与实施例6相同的方式获得目标化合物(产量：1.040g，收率：42％)。
1H NMR(200MHz，CDCl3)d：2.82(dd，1H)，3.04(m，5H)，3.61(m，2H)，3.77(m，2H)，3.88(d，6H)，4.77(br，2H)，6.15(t，1H)，
实施例9：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-苯基-丁酯的合成
将苯基-1-丙烯基(prophenyl)-酮(4.1mmole)和3，4-二甲氧基苯基哌嗪(4.9mmole)溶于30mL乙醇(作为溶剂)中，并在72℃搅拌48小时。将溶剂在降低的压力下蒸馏，并将所得混合物用水稀释，用水提取两次，用乙酸乙酯提取2次。将有机层在降低的压力下蒸馏，然后用硫酸镁干燥并过滤，将滤液在降低的压力下浓缩并通过柱色谱法(己烷∶乙酸乙酯＝4∶1)纯化，从而产生化合物。将所述化合物(2.9mmole)溶解于20mL甲醇中，缓慢加入NaBH4(3.8mmole)。将所得产物在室温搅拌2小时，将溶剂在降低的压力下浓缩，将黄色剩余物用柱色谱法(己烷∶乙酸乙酯＝1∶1)纯化。将所纯化的化合物(2mmole)溶于15ml四氢呋喃中，然后加入1，1′-碳化二咪唑(4mmole)并在室温搅拌1小时，加入过量的氨水并在室温搅拌2小时。将反应混合物用水稀释，并用乙酸乙酯萃取数次，将所得有机层用硫酸镁干燥并在降低的压力下浓缩。将所得剩余物用柱色谱法(己烷∶乙酸乙酯＝1∶1)纯化，从而产生终产物，(产量：909mg，收率：22％)
1H NMR(200MHz，CDCl3)d1.81(m，1H)，2.32(m，1H)，2.5(m，3H)，2.8(m，2H)，3.14(m，4H)，3.80(s，6H)，4.80(br，2H)，6.02(t，1H)，6.92(m，4H)，7.36(m，5H)
实施例10：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-氯-苯基-3-氧-丙酯的合成
除使用4-氯-苯甲酰基乙酸乙酯和3，4-二甲氧基苯基哌嗪作为起始材料外，以与实施例1相同的方式获得目标化合物(产量：543mg，收率：42％)。
1H NMR(200MHz，CDCl3)d：2.82(dd，1H)，3.01(m，5H)，3.61(m，2H)，3.77(m，2H)，3.86(d，6H)，4.84(br，2H)，6.]5(t，]H)，6.42(d，1H)，6.57(s，1H)，6.82(d，1H)，7.35(s，4H)
实施例11：对15-脂氧合酶的抑制效应的体外测试
为确定实施例1到10所制备的化合物仅特异性地抑制15-脂氧合酶，以人血小板诱导的12-脂氧合酶作为阴性对照，兔网织红细胞诱导的15-脂氧合酶作为测试组用于鉴定所述化合物对12-脂氧合酶的抑制效应。
12-脂氧合酶与作为底物的花生四烯酸酯反应以产生作为产物的12-羟基二十碳四烯酸(12-HETE)。因此，通过以光谱法测量产生的12-HETE的量来评估12-脂氧合酶的活性。同时，15-脂氧合酶与作为底物的亚麻酸发生反应产生13-氢过氧化-9，11-十八碳二烯酸(13-HPODE)作为产物。因此，通过以光谱法测量产生的13-HPODE的量来评估15-脂氧合酶的活性。
当每种化合物的浓度为10μM时测量12-脂氧合酶的活性。将每种样品通过使用缓冲液(50mM Tris-HCl，0.1％Triton X-100，pH7.4)在25℃下预处理15分钟，然后加入30μM花生四烯酸酯(反应过程中将其浓度控制在30μM)，在25℃下反应15分钟，通过在波长570nm下的吸光度测量作为所产生产物的12-HETE的量。
当每种化合物的浓度为10μM时测定15-脂氧合酶的活性。将每个样品通过使用缓冲液(磷酸缓冲的盐水缓冲液，pH7.4)在4℃下预处理15分钟，然后加入260μM亚麻酸(反应过程中将其浓度控制在260μM)，在4℃下反应10分钟，通过在波长660nm下的吸光度测量作为所产生产物的13-HPODE的量。
通过测量所述化合物对12-脂氧合酶和15-脂氧合酶活性的抑制效应得到的结果显示于表1。
[表1]
实施例12：对糖尿病动物模型的糖尿病高脂血症的药效测试
Sprague-Dawley大鼠(n＝21，4周龄，雄性)被用作实验室模型(Central Lab.Animal Inc.)。具有通过腹膜内给予50mg/kg链脲佐菌素诱导的糖尿病的大鼠(n＝14)被用作测试组，通过腹膜内仅给予溶剂(100mM柠檬酸缓冲液，pH4.5)的大鼠(n＝7)被用作对照。一般而言，链脲佐菌素会破坏胰脏的β细胞从而诱导糖尿病，因此血糖会增加并且血清中胆固醇和甘油三酯的量会增加。给予链脲佐菌素后2天，所述测试组被诱导糖尿病。将所述测试组分为2组，一组大鼠每天口服200mg/kg(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯，持续4周。另一组口服30％聚乙二醇(PEG)代替所述化合物。
给予所述化合物和PEG4周后，测定每组的血清中总胆固醇和甘油三酯的量，结果示于图1和2。为测量总胆固醇和甘油三酯的量，从所述大鼠中分离血清，使用了Hitachi7600自动分析仪。结果确认，由于给予(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯，由链脲佐菌素引起的总胆固醇浓度的增加(120±13mg/dl)被减小到66±9mg/dl，与对照的62±5mg/dl相近，同时由链脲佐菌素引起的甘油三酯浓度的增加(760±162mg/dl)被大大减小到126±44mg/dl。即，由于给予所述化合物血清中胆固醇和甘油三酯的增加被显著减少。由此结果，确认了所述化合物可用于预防或治疗高脂血症。
实施例13：对糖尿病肾病的药效测试
Sprague-Dawley大鼠(n＝21，4周龄，雄性)被用作实验室模型(Central Lab.Animal Inc.)。具有通过腹膜内给予50mg/kg链脲佐菌素诱导的糖尿病的大鼠(n＝14)被用作测试组，通过腹膜内仅给予溶剂(100mM柠檬酸缓冲液，pH4.5)的大鼠(n＝7)被用作对照。一般而言，具有链脲佐菌素诱导的糖尿病的大鼠中，糖尿病肾病受高血糖诱导，症状之一是肾纤维化，并且细胞外基质蛋白例如纤连蛋白的基因表达增加。给予链脲佐菌素后2天，所述测试组被诱导糖尿病。将所述测试组分为2组，一组大鼠每天口服200mg/kg(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯，持续4周。另一组口服30％聚乙二醇(PEG)代替所述化合物。
给予所述化合物和PEG4周后，从每组中提取肾皮质组织，然后通过实时反转录聚合酶链式反应测量纤连蛋白的表达水平(即从纤连蛋白转录的mRNA的量)(见图3)。使用正向引物(5′-GCCACACCTACAACCAGTAT-3′；SEQ ID NO：1)和反向引物(5′-ATGACCACTCAGAAATGGAG-3′；SEQ ID NO：2)测量纤连蛋白的表达水平。在所述RT-PCR中，退火在60℃的温度下进行1分钟，SYBRgreen(Applied Biosystem)被用作荧光材料，并且使用AppliedBiosystem公司制造的7300Real-time PCR仪。所述退火之外的反应依据制造商提供的方案使用本领域已知的方法进行。对于对照，使用由β肌动蛋白基因转录的mRNA，测定结果用由所述RT-PCR的结果定量的纤连蛋白mRNA的量除以β肌动蛋白mRNA的量表示。结果，由于给予链脲佐菌素，肾皮质的纤连蛋白的表达水平是所述对照的1.4±0.1倍，并且由于给予(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯，肾皮质的纤连蛋白的表达水平减少至所述对照1.2±0.1倍。由此结果，确认所述化合物对于抑制糖尿病诱导的肾纤维化有效。
实施例14：对具有诱导的糖尿病肾病的动物模型中炎性反应的药效测试
当通过链脲佐菌素诱导糖尿病肾病时，肾脏中的炎性反应增加，因此多种炎症相关的基因(例如PAI-1、MCP-1和TGF-β1)的表达增加。因此，为确认所述化合物对炎症反应的药效，通过实施例13中所用的RT-PCR，测量了由来自实施例13中所用各组的肾皮质组织的PAI-1、MCP-1和TGF-β1基因转录的mRNA的量(见图4、5和6)。使用下述引物序列扩展所述基因：正向引物(5′-TCCGCCATCACCATTTT-3′；SEQ ID NO：3)和反向引物(5′-GTCAGTCATGCCCAGCTTCTC-3′；SEQ ID NO：4)用于扩增PAI-1；正向引物(5′-CCTCCACCACTATGCAGGTCTCC-3′；SEQ ID NO：5)和反向引物(5′-GCACGTGGATGCTACAGGC-3′；SEQ ID NO：6)用于扩增MCP-1；正向引物(5′-CCAACTACTGCTTCAGCTCCA-3′；SEQ IDNO：7)和反向引物(5′-GTCTCCAGGCTCCAAATGT-3′；SEQ ID NO：8)用于扩增TGF-β1。
结果，肾皮质中炎症相关基因PAI-1、MCP-1和TGF-β1的表达分别是对照的1.8±0.1、3.4±1.0和1.6±0.2倍，并且由于给予(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯，肾皮质中PAI-1、MCP-1和TGF-β1基因的表达分别减小至对照的1.1±0.2、1.6±0.3和1.3±0.2倍。由此结果，可确定所述化合物对于抑制糖尿病诱导的炎症相关基因的表达有效。
由实施例13和14的结果可以确认，由于所述化合物可抑制引起糖尿病肾病的纤维化和炎症相关基因的表达，所述化合物可用于预防或治疗糖尿病肾病。
实施例15：给予(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯和制备含有其的片剂(预期)
本发明的化合物被用于预防或治疗糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病或炎症。临床上适合的给药量(口服)是每个成年人300mg。
基于所述的给药量，含有下表2中所示组分的片剂可通过使用常规方法制备。Avicel102(微晶纤维素)被用作赋形剂。
[表2]
所述化合物适合的给药量是每个成年人60kg，这相当于1片或2片含有所述化合物的片剂。
当使用本发明的药物组合物时，糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病或炎症可被有效地预防或治疗。
虽然本发明参考其中的示例性实施方案进行了具体地显示和说明，但是本领域技术人员应理解，可以在不偏离由下述权利要求书所定义的本发明的精神和范围的情况下对其中的形式和细节作出多种改变。
SEQ ID NO：1到SEQ ID NO：8的核苷酸序列或多肽序列作为序列表文本提交，并且所述序列表中的内容全文纳入本申请。
Claims (4)
1.一种用于预防或治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的药物组合物，所述药物组合物包括治疗有效量的选自下式I的化合物、其可药用盐、异构体、溶剂合物或水合物及其组合的化合物以及可药用载体
式I
其中，X1包括选自氢，直链或支链的C1-C6烷基，包括F、Cl或Br的卤素，直链或支链的C1-C6烷氧基，硝基和三氟甲基的至少一个；X2包括选自氢、直链或支链的C1-C6烷基、卤素、直链或支链的C1-C6烷氧基、硝基和三氟甲基的至少一个，并且如果X2包含其中的2个或更多个，它们彼此相同或不同并且与相邻的碳原子形成环；并且
Y是氢或甲基，或者与相邻的碳原子形成羰基。
2.权利要求1的药物组合物，其中所述化合物选自：氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-氟-苯基)-3-氧-丙酯、氨基甲酸3-(4-苯并[1，3]二氧杂环戊烯-5-基-哌嗪-1-基)-3-氧-1-苯基-丙酯、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-三氟甲基-苯基)-3-氧-丙酯；盐酸盐、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-硝基-苯基)-3-氧-丙酯、(R)-氨基甲酸3-[4-(4-氯-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、(S)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、(R)-氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-3-氧-1-苯基-丙酯、氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-苯基-丁酯和氨基甲酸3-[4-(3，4-二甲氧基-苯基)-哌嗪-1-基]-1-(4-氯-苯基)-3-氧-丙酯。
3.权利要求1的药物组合物，其中所述化合物具有15-脂氧合酶的抑制活性。
4.一种治疗选自糖尿病肾病、糖尿病神经病变、糖尿病血管并发症、高脂血症、冠状动脉疾病和炎症的疾病的方法，所述方法包括使权利要求1-3任一项的药物组合物与要治疗的受试者接触。
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