CN102532114B - 烟酸衍生物,其制备方法及其药物组合物 - Google Patents
烟酸衍生物,其制备方法及其药物组合物 Download PDFInfo
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- CN102532114B CN102532114B CN201110430852.0A CN201110430852A CN102532114B CN 102532114 B CN102532114 B CN 102532114B CN 201110430852 A CN201110430852 A CN 201110430852A CN 102532114 B CN102532114 B CN 102532114B
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Abstract
本发明涉及合成一系列烟酸杂联体及衍生物。结构式如式(I)所示。本发明还提供上述药物组合物的制备,并用于降低血脂、防治动脉粥样硬化、降低心脑血管事件风险药物中的应用,及其他氧化应激参与的神经保护药物中的应用。
Description
发明领域
本发明涉及一系列烟酸杂联体,制备方法,含有它们的药物组合物,以及医药应用。主要应用于异常脂肪血症、糖尿病、动脉粥样硬化、代谢综合征以及类似疾病的化合物和组合物,属于医药领域。
发明背景
烟酸学名为吡啶-3-甲酸,又名尼克丁酸(niotinicacid,niacid)、尼克酸或烟碱酸,简称VB5、Vpp或NA,在空气中稳定,不吸潮;毒性很微。烟酸是重要的降血脂药物,其作用为降低血液中三酰甘油(Triglyceride,TG)和游离脂肪酸(Freefattyacid,FFA)的含量,舒张血管、降低血清中脂肪流动性。不仅如此,大剂量时NA可通过阻断脂肪组织的降解和减少血液中FFA,从而减少肝脏极低密度脂蛋白-胆固醇(verylow-densitylipoproteincholesterol,VLDL-C)的分泌;通过减少胆固醇从高密度脂蛋白-胆固醇(High-densitylipoproteincholesterol,HDL-C)到VLDL转运和延迟肾脏HDL清除而升高HDL-C,从而进一步缓解动脉粥样硬化的形成,减少引起许多威胁生命的心、脑血管疾病,如冠状动脉疾病(CAD)、心肌梗死、脑卒中等产生。当前,用于治疗这类血脂异常的药物有胆固醇酯转移蛋白(CETP)抑制剂、可逆性脂肪转移途径(RLTP)激活剂、抗氧化剂/血管保护剂、脂酰-辅酶A胆固醇酰基转移酶(ACAT)抑制剂、过氧化物酶增殖体受体(PPAR)激动剂、微粒体三酰甘油转移蛋白(MTTP)抑制剂、角鲨烯合成酶抑制剂、脂蛋白脂酶(LPL)激活剂、脂蛋白(Lp(a))阻滞剂、胆酸重吸收抑制剂(BARIs)。烟酸与贝特类药物相似,可降低TG达20%-50%,但烟酸能更大程度的升高HDL-C达15%-35%。烟酸做为一种降脂药已应用于临床近50年,已有大量随机、对照临床试验证实,烟酸单用或与其他药物合用均能降低心血管疾病死亡率,但由于烟酸所需的治疗剂量较大(3~6g/d),且易产生面部潮红、瘙痒、诱发溃疡病及痛风等副作用,限制了其临床应用。为了增强药物的活性,减少副作用,近年来烟酸常与某些药物合用提高药效,如烟酸和阿司匹林合用,对大鼠血浆脂质有调节作用,烟酸可抑制由高脂饮食及三硝基甲苯诱发的高脂血症,两药合用对总胆固醇的影响则优于单用烟酸,这为烟酸前体药物的发展提供了临床依据。
近年来研究显示,氧化应激存在于生命过程的始终,它不仅使健康机体走向衰老,而且是许多疾病过程中的致病环节。特别在免疫功能低下的老人中将会诱发和促进许多疾病的发生发展,诸如动脉粥样硬化、脑卒中、冠心病、高血压、老年痴呆症、糖尿病、帕金森病等。随着年龄增长,人体天然抗自由基的能力,亦即抗氧化能力不断下降,加速了人体衰老的过程。当前增强抗氧化能力乃是防治衰老和老年病的根本手段。
国际上以研究协同药物组合为目标的新药开发模式始于2000年。美国哈佛大学与麻省理工学院合作成立了一家专门从事“协同药物组合”的研发公司,并开发了阿奇霉素+氯喹治疗疟疾、氯丙嗪+戊烷脒治疗肺癌等新组方药物,取得了很大成功。为弥补新化合物的研发的不足,美国、欧盟、日本和澳大利亚都相继出台了关于复方药物研发的基本原则,即增效,减毒,提高依从性。2003年,伦敦大学Wald教授也提出了多效药丸(polypill)的概念,即在一粒药丸中混合三种或更多药物来预防心血管疾病,它被英国医学杂志评价为“50年来最重要的发现之一”。如今确实也出现了如烟酸-沙利度胺、烟酸-甘油三酯及烟酸-吗啡等烟酸前体药物,这也同时说明这种二联体形式的新型药物的合成其道路是可行的。
本发明旨在开发针对重大公共卫生问题——心脑血管疾病和神经系统疾病具有更好疗效的药物,并且根据一药多靶的策略,不仅实现连接化合物片段抗氧化活性,而且发挥烟酸降低血脂,改善心血管等的作用。另外烟酸的脂溶性较差,通过改造能使其具有良好的脂溶性,增加生物利用度,减少对肠胃刺激和面部潮红等副作用。在代谢方面增加其半衰期,达到延长药效的目的。从患者角度出发,把烟酸和抗氧化药物两种联合为一种,能适当增加患者的依从性,避免漏服,给患者带来福音。
发明概述
基于以上研究,结合作用于异常脂肪血症、糖尿病等疾病的不同靶点的药物联合使用要比单一靶点药物的治疗效果更好的特点,我们发明了一系列新颖的烟酸杂联体、衍生物。
本发明的化合物其特征在于存在两个主要的单元:抗氧化部分和烟酸部分,它们通过适当的接头连接。一方面可以调整接头的类型和长度以同时与受体的双重位点结合,提高烟酸的降脂作用,降低其副作用;另一方面,同时发挥抗氧化化合物的抗氧化、抗炎作用,提高改善异常脂肪血症、糖尿病的症状和进程,使得它们成为药物开发的候选物。
本发明涉及式(I)的化合物或其互变异构体,药用盐,前药或溶剂化物。
式(I)
其中X=哌嗪,乙二胺,1,3-丙二胺,1,4-丁二胺,1,5-戊二胺,1,6-己二胺;其中R=
除非另外指明,本发明的化合物还意欲包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如,具有本结构的除了用氘或氚替换氢,或者用13C或14C-富集的碳原子替换碳原子,或15N-富集的氮以为的化合物属于本发明的范围内。
属于“药用盐,衍生物,溶剂化物,前药”是指任何药用盐,酯,溶剂化物,或经施用于接受者后能够提供(直接或间接)本文所述化合物的其他化合物。然而,应当理解非药用盐也属于本发明的范围内,因为那些可能用于植被药用盐,盐,前药和衍生物的植被可以通过本领域已知的方法进行。例如,本发明提供的化合物的药用盐可以通过常规方法由母体化合物合成,该母体化合物含有碱或酸部分。通常,该盐例如通过将游离酸或碱形式的这些化合物与化学计算量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中制备。通常,非水性介质如乙醚,乙酸乙酯,乙醇,异丙醇或乙腈是优选的。酸加成盐的实例包括无机酸加成盐例如,盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,硝酸盐,和有机酸加成盐,如例如乙酸盐,马来酸盐,富马酸盐,柠檬酸盐,草酸盐,琥珀酸盐,酒石酸盐,苹果酸盐,扁桃酸盐和对甲苯磺酸盐。碱加成盐的实例包括无机盐如例如钠,钾,钙,铵,镁,铝和锂盐;和有机碱如例如乙二胺,乙醇胺,N,N-二烷基乙醇胺,三乙醇胺,葡糖胺和碱性氨基酸盐。
优选的衍生物或前药是相对于母体物质,当将这些化合物使用于患者时提高本发明化合物的生物利用度(例如通过使得口服给药的化合物更容易被吸收到血液中)或增强母体化合物向生物区室(例如脑或淋巴系统)的传递的那些。
式(I)化合物前药的任何化合物属于本发明的范围内,术语“前药”以其最广泛的意义使用并且包括在体内转化为本发明化合物的那些衍生物。这些衍生物对于本领域技术人员是显而易见的,并且根据分子中存在的官能团,包括不限于本发明化合物的下列衍生物:酯;氨基酸酯;磷酸;金属盐硫酸;氨基甲酸酯和酰胺。
本发明的化合物可以是作为有利化合物或作为溶剂化物的晶体形式,意欲将两种形式都包括在本发明的范围内。溶剂化的方法是本领域公知的。适当的溶剂化物是药用溶剂化物。在一个具体实施方案中,溶剂化物是水合物。
制备方法:
以下是为制备本发明的化合物的方法,采用的是合成通式方法:
合成通式(I):在冰浴条件下,将a系列化合物与α,ω-二氨基烷烃或哌嗪发生缩合反应,所得产物b系列化合物室温下在有催化剂环境下与烟酸发生缩合反应,进行硅胶柱分离得到产物c系列。反应见通式(I)
其中X=哌嗪,乙二胺,1,3-丙二胺,1,4-丁二胺,1,5-戊二胺,1,6-己二胺
通式(I)
合成通式(II):在冰浴条件下,将烟酸与α,ω-二氨基烷烃或哌嗪发生缩合反应,所得产物d化合物室温下在有催化剂环境下与e系列化合物发生缩合反应,进行硅胶柱分离得到产物f系列。反应见通式(H)
其中X=哌嗪,乙二胺,1,3-丙二胺,1,4-丁二胺,1,5-戊二胺,1,6-己二胺
通式(II)
对于接头中含有胺,酯或其他单元的化合物的备选方法对于本领域技术人员是显而易见的。
如果需要,可以通过常规方法如结晶法或色谱法纯化反应产物。当用于制备本发明化合物的上述方法产生立体异构体的混合物时,这些异构体可以通过常规技术如制备色谱法分离。如果存在手性中心,化合物可能以外消旋形式制备,或者可以通过对映特异性合成或通过拆分来制备单个的对映异构体。
一种优选的药用形式是结晶形式,包括药物组合物中的这种形式。如果是盐和溶剂化物,另外的离子或溶剂部分也应当是非毒性。本发明的化合物可以存在不同的多晶型物,意欲本发明包括所有这些形式。
发明另一方面涉及硫辛酸-烟酸以及它们活性成分的药物组合物,具有较高的药理作用及安全性。可用于预防及协同治疗各种脑血管和心血管疾病的药物,如高血压、心绞痛、动脉粥样硬化、偏头痛、心或脑梗塞、脑血栓或脑卒中。异常血脂症、糖尿病、氧化应激参与的神经系统疾病。
上文所述药学上可接受的载体、辅剂或赋形剂,是指药学领域常规的药物载体,例如:稀释剂,赋形剂如水等,填充剂如淀粉、蔗糖等;黏合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解剂如琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季胺化合物;表面活性剂如滑石粉、硬脂酸镁和钙和聚乙二醇。另外还可以以组合物中加入其它辅料如香味剂、甜味剂等。
本发明硫辛酸-烟酸杂联体或其互变异构体、药用盐类、前药或溶剂化物可以给病人口服或、皮下或静脉注射、或用植入体内的方法给药,因此可以制备成常规的口服制剂、注射剂。所述的硫辛酸-烟酸室温溶于水或部分溶于水,可以制备水溶液或悬浮剂型。药物学上也可以液体或固型剂来口服,例如水性悬浮液、乙醇溶液,片剂或胶囊。如果需要,也可以将其制成缓释剂型或控释剂型。
本发明的化合物和组合物可以与其它药物一起使用以提供联合治疗。其它药物可以形成相同组合物的一部分,或者可以作为同时或不同时给药的分开的组合物提供。
提供下列实施例进一步举例说明本发明,它们不应当认为是对本发明范围的限定。
附图说明
附图1是烟酸衍生物结构式的图;附图2是化合物1药效量IC50为0.22μM的图;附图3是化合物3药效量IC50为0.33μM的图;附图4是小鼠体内自由脂肪酸含量测定的图;附图5是血管扩张作用的观察的图。
实施例
以上已经描述了用于制备本发明化合物的通用方法。
实施例1:
N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)nicotinamide
将硫辛酸(6.18g,30mmol)和BOP(15.9g,36mmol)溶于48ml二氯甲烷中,并在冰浴环境下滴入乙二胺(120mmol,8.01ml)中,搅拌60分钟,然后室温反应30分钟,体系每次用20ml饱和食盐水萃取三次,水萃取一次,无水硫酸镁干燥,减压蒸馏得到产物,溶解于60ml二氯甲烷,加入4.2mlTEA、烟酸(1.11g,9mmol)和BOP(4.38g,9.9mmol),室温搅拌反应,用TLC监控直到反应完全,而后每次用60ml饱和食盐水水萃取三次,水萃取一次,无水硫酸镁干燥,浓缩得到粗产物,硅胶柱层析分离,洗脱剂甲醇∶二氯甲烷=1∶30,得到1.02g黄色固体,产率20.9%。1HNMR(400MHz,CDCl3)δ9.09(s,1H),8.74(d,J=3.2Hz,1H),8.15(d,J=8.0Hz,1H),7.56(br,1H),7.41(dd,J=7.5,5.3Hz,1H),6.11(br,1H),3.66-3.46(m,5H),3.22-3.01(m,2H),2.47-2.33(m,1H),2.23(t,J=7.2Hz,2H),1.92-1.79(m,1H),1.74-1.56(m,4H),1.49-1.37(m,2H).
实施例2:
N-(3-(5-(1,2-dithiolan-3-yl)pentanamido)propyl)nicotinamide
将硫辛酸(1.03g,5mmol)和BOP(2.65g,6mmol)溶于16ml二氯甲烷中,并在冰浴环境下滴入1,3-丙二胺(3.40ml,40mmol)中,搅拌60分钟,然后室温反应30分钟,体系每次用20ml饱和食盐水萃取三次,水萃取一次,无水硫酸镁干燥,减压蒸馏得到产物,溶解于20ml二氯甲烷,加入1.4mlTEA、烟酸(0.37g,3mmol)和BOP(1.46g,3.3mmol),室温搅拌反应,用TLC监控直到反应完全,而后每次用20ml饱和食盐水水萃取三次,水萃取一次,无水硫酸镁干燥,浓缩得到粗产物,硅胶柱层析分离,洗脱剂甲醇∶二氯甲烷=(1∶100-5∶100),得到0.047g黄色固体,产率4.2%。1HNMR(400MHz,CDCl3)δ9.12(s,1H),8.71(d,J=4.5Hz,1H),8.21(d,J=7.8Hz,1H),7.76(br,1H),7.44-7.37(m,1H),6.19(br,1H),3.59-3.32(m,5H),3.23-3.06(m,2H),2.51-2.39(m,1H),2.25(t,J=7.4Hz,2H),1.96-1.84(m,1H),1.78-1.62(m,6H),1.54-1.40(m,2H).
实施例3:
N-(6-(5-(1,2-dithiolan-3-yl)pentanamido)hexyl)nicotinamide
将硫辛酸(1.03g,5mmol)和BOP(2.65g,6mmol)溶于16ml二氯甲烷中,并在冰浴环境下滴入1,6-己二胺(5.27ml,40mmol)中,搅拌60分钟,然后室温反应30分钟,体系每次用20ml饱和食盐水萃取三次,水萃取一次,无水硫酸镁干燥,减压蒸馏得到产物,溶解于20ml二氯甲烷,加入1.4mlTEA、烟酸(0.37g,3mmol)和BOP(1.46g,3.3mmol),室温搅拌反应,用TLC监控直到反应完全,而后每次用20ml饱和食盐水水萃取三次,水萃取一次,无水硫酸镁干燥,浓缩得到粗产物,硅胶柱层析分离,洗脱剂甲醇∶二氯甲烷=(1∶100-5∶100),得到0.511g黄色固体,产率41.6%。1HNMR(400MHz,CDCl3)δ9.04(d,J=1.7Hz,1H),8.72(dd,J=4.8,1.5Hz,1H),8.18(dt,J=8.0,1.8Hz,1H),7.46-7.34(m,1H),6.69(br,1H),5.60(br,1H),3.60-3.50(m,1H),3.47(dd,J=12.8,6.8Hz,2H),3.27(dd,J=12.9,6.7Hz,2H),3.20-3.06(m,2H),2.49-2.38(m,1H),2.18(t,J=7.3Hz,2H),1.95-1.83(m,1H),1.74-1.58(m,6H),1.55-1.33(m,8H).
实施例4:
5-(1,2-dithiolan-3-yl)-1-(4-nicotinoylpiperazin-1-yl)pentan-1-one
将硫辛酸(1.03g,5mmol)和BOP(2.65g,6mmol)溶于16ml二氯甲烷中,并在冰浴环境下滴入已用二氯甲烷40ml溶解好的哌嗪(3.45g,40mmol)中,搅拌60分钟,然后室温反应30分钟,体系每次用20ml饱和食盐水萃取三次,水萃取一次,无水硫酸镁干燥,减压蒸馏得到产物,溶解于20ml二氯甲烷,加入1.4mlTEA、烟酸(0.37g,3mmol)和BOP(1.46g,3.3mmol),室温搅拌反应,用TLC监控直到反应完全,而后每次用20ml饱和食盐水水萃取三次,水萃取一次,无水硫酸镁干燥,浓缩得到粗产物,硅胶柱层析分离,洗脱剂甲醇∶二氯甲烷=(1∶100-5∶100),得到0.047g黄色固体,产率4.1%。
1HNMR(400MHz,CDCl3)δ8.73-8.64(m,2H),7.80-7.75(m,1H),7.42-7.36(m,1H),3.82-3.38(m,9H),3.28-3.00(m,2H),2.52-2.28(m,3H),1.97-1.86(m,1H),1.78-1.60(m,4H),1.56-1.42(m,2H).
实施例5:比较例
烟酸作为比较药物,购买于Sigma公司(产品号:72309)
实施例6:比较例
硫辛酸作为比较药物,购买于Sigma公司(产品号:62320)
实施例7:生物学评估
GPR109A受体激动作用
受试化合物配制低、中、高三个浓度,分别为10-7M、10-6M、10-5M。384孔板中每孔加入5μl受试化合物/福斯高林溶液,然后加入含抗体的细胞悬液5μL,37℃孵育45min;加入10μL的检测复合物,37℃孵育3h检测。每次试验设立阴性、阳性对照孔,阴性对照以细胞stimulationbuffer代替受试化合物/福斯高林溶液,阳性对照孔以福斯高林-细胞stimulationbuffer作为刺激药物。把阳性孔中的cAMP浓度定义为100%,阴性孔中cAMP浓度定义为0%。按照以下公式计算受试化合物对福斯高林诱导的cAMP积累的抑制率。
Cm:阳性孔cAMP浓度即福斯高林诱导的细胞内累积的cAMP水平;
Co:阴性孔cAMP浓度即细胞内基础cAMP水平;
Cs:5μM的福斯高林与受试化合物共刺激细胞时,细胞内的cAMP浓度;
活性化合物IC50确定。
结果见附表1
用福斯高林-细胞stimulationbuffer按3倍浓度梯度稀释受试化合物。选取11个浓度受试化合物(浓度分别为10-11、10-10、10-9、3x10-9、10-8、3x10-8、10-7、3x10-7、10-6、10-5、10-4M)制作其抑制福斯高林诱导的cAMP累积的量效曲线。TECAN酶标仪软件可以绘制量效曲线,并计算IC50。结果见附图2、3。
实施例8:生物学评估
抑制L-glutamate诱导细胞毒性作用
小鼠海马神经元细胞株HT22,用含10%胎牛血清的DMEM完全培养基,在37℃,饱和湿度,含体积分数为5%CO2、95%空气的二氧化碳培养箱中常规培养。取对数生长期细胞,以0.25%胰酶消化后,完全培养基重悬,显微镜下细胞计数板计数并调整细胞浓度为10×104个/ml,接种96孔细胞培养板,100μL/孔,培养过夜,使细胞贴壁。将96孔板中培养基吸走,待测化合物用DMSO溶解,用完全培养基稀释1000倍成30μM,加入到96孔板中,100μL/孔。预孵育30min后,加入5μL100mML-glutamate。模型组不加待测化合物,直接加入5μL100mML-glutamate。孵育24h后,每孔加入10μL5mg/mLMTT,孵育1h,弃去上清,加DMSO100μL/孔,振荡使生成物formazan充分溶解,在酶标仪上测定各孔吸光度值,测定波长570nm。采用公式化合物促进细胞的存活率(%)=100%*(A待测化合物-A模型组)/(A正常对照组-A模型组)计算细胞存活率。结果见附表2
实施例9:生物学评估
在小鼠体内抑制非酯化游离脂肪酸(NEFA)
实验前将雄性C57/BL小鼠随机分成4组(n=7),给予不禁食小鼠腹腔注射生理盐水和1%DMSO,30mg/kg烟酸,30mg/kg受试化合物,30min后摘取眼球取血0.5ml,离心(3000r/min×10min),取血清。NEFA测定试验是按照厂商说明书(南京建成生物工程研究所)进行。结果见附图4
实施例10:生物学评估
血管扩张实验
取豚鼠,腹腔注射烟酸30mg/kg,受试化合物30mg/kg,实时拍照观察.附图5
结果见附表3
附表1受试化合物对福斯高林诱导的cAMP累积的抑制效应
附表2受试化合物抑制L-glutamate诱导细胞毒性作用
Claims (3)
1.一种具有下述结构式的化合物或其药用盐:
其中X=哌嗪基、乙二胺基、1,3-丙二胺基、1,4-丁二胺基、1,5-戊二胺基或1,6-己二胺基;其中条件是:
当X为乙二胺基时,R不为
2.一种药物组合物,包括如权利要求1所述的任一化合物或其药用盐以及药用载体或赋形剂。
3.式(I)的化合物或其药用盐在制备治疗以下疾病的药物中的应用:
其中X=哌嗪基、乙二胺基、1,3-丙二胺基、1,4-丁二胺基、1,5-戊二胺基或1,6-己二胺基;其中
其中所述疾病选自:异常脂肪血症、糖尿病、动脉粥样硬化、氧化应激参与的神经系统疾病。
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