CN100415709C - β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途 - Google Patents

β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途 Download PDF

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CN100415709C
CN100415709C CNB2006100427873A CN200610042787A CN100415709C CN 100415709 C CN100415709 C CN 100415709C CN B2006100427873 A CNB2006100427873 A CN B2006100427873A CN 200610042787 A CN200610042787 A CN 200610042787A CN 100415709 C CN100415709 C CN 100415709C
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borneol
dihydroxy phenyl
propionate
alpha
alpha hydroxy
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CN1868998A (zh
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郑晓晖
张群正
王世祥
赵新锋
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Northwest University
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Northwest University
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Priority to NZ572958A priority patent/NZ572958A/en
Priority to SI200731105T priority patent/SI2019090T1/sl
Priority to DK07721123.3T priority patent/DK2019090T3/da
Priority to ES12002538.2T priority patent/ES2618677T3/es
Priority to HUE12002538A priority patent/HUE032505T2/en
Priority to KR1020087030201A priority patent/KR101059639B1/ko
Priority to MYPI20084629A priority patent/MY148134A/en
Priority to SI200731907A priority patent/SI2514739T1/sl
Priority to PL12002538T priority patent/PL2514739T3/pl
Priority to EP12002538.2A priority patent/EP2514739B1/en
Priority to AU2007250364A priority patent/AU2007250364B8/en
Priority to PL07721123T priority patent/PL2019090T3/pl
Priority to PCT/CN2007/001550 priority patent/WO2007131446A1/zh
Priority to US12/301,069 priority patent/US8017786B2/en
Priority to CA2652299A priority patent/CA2652299C/en
Priority to EP07721123A priority patent/EP2019090B1/en
Priority to DK12002538.2T priority patent/DK2514739T3/en
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Abstract

本发明公开了结构式(I)表示的化合物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯及其合成方法和用途。其合成方法如下：将β-(3，4-二羟基苯基)-α-羟基丙酸与冰片在催化量的催化剂存在下反应得到，催化剂为路易斯酸催化剂，如对甲基苯磺酸、S2O8 2-/ZrO2、三氯化铝或氯化锌，反应在溶剂四氢呋喃、甲苯、1，4-二氧六环或N，N-二甲基甲酰胺中进行，反应温度控制在65℃～150℃，反应8h～12h即可。本发明在丹参素的结构中增加了冰片的化学结构，其改性物用于心脑血管疾病的预防和治疗，效果将十分显著。

Description

β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途
技术领域
本发明涉及一种防治心脑血管疾病的药物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯及其合成方法和用途。
背景技术
丹参是一种疗效明确的治疗心脑血管疾病的中药，目前普遍认为丹参素(其化学名称为：β-(3，4-二羟基苯基)-α-羟基丙酸)是丹参水溶性组分的主要活性成分，药理试验表明，丹参素的疗效不显著。因此，对丹参素的结构进行改造，有可能提高其在防治心脑血管疾病方面的疗效。
中国专利申请200410026205中提供一种β-(3，4-二羟基苯基)-α-羟基丙酸异丙酯及其制备方法。该方法从丹参在人血清中的主要代谢产物中发现并筛选出具有治疗效果的β-(3，4-二羟基苯基)-α-羟基丙酸异丙酯，设计了它的合成路线，并合成出了此化合物。
冰片可以通过心脑屏障，而丹参不易通过心脑屏障，因此在丹参素的结构中，增加冰片的化学结构对丹参素进行结构改造，其改性物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯用于心脑血管疾病的预防和治疗，效果将可能十分显著。
发明内容
本发明的目的在于提供一种β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成路线，并合成出了β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯，将其用于心脑血管疾病的预防和治疗。
化合物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯，其结构式为：
Figure C20061004278700031
上述化合物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法如下：将β-(3，4-二羟基苯基)-α-羟基丙酸与冰片在催化量的催化剂存在下反应得到。
所述的催化剂为路易斯酸催化剂，如甲基苯磺酸、S2O8 2-/ZrO2、三氯化铝或氯化锌；
β-(3，4-二羟基苯基)-α-羟基丙酸与冰片反应摩尔比为：1∶1～1∶1.5，反应在溶剂四氢呋喃、甲苯、1，4-二氧六环或N，N-二甲基甲酰胺中进行，反应温度根据选择溶剂的不同而变化，控制在65℃～150℃，反应8h～12h。
催化剂S2O8 2/ZrO2的制备方法如下：在0-10℃下，将氨水加至ZrOCl2溶液中，至pH值9-12，陈化，洗涤沉淀至无Cl-，烘干、研磨后置于(NH4)2S2O8溶液中浸泡，过滤、干燥、研磨，于500-700℃培烧2-5h制得S2O8 2-/ZrO2。
上述化合物用于制备预防和治疗心脑血管疾病的药品。
附图说明
图1β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成路线图
图2β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的质谱图
图3β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯红外光谱图
具体实施方式
以下结合合成实例及药效学试验报告对本发明作进一步的详细说明。
实施例1：β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯合成路线如附图1所示。
(1)乙酰甘氨酸的合成
在250mL三口瓶中加入0.33mol甘氨酸和100mL蒸馏水，剧烈搅拌至溶解，搅拌下缓慢滴加0.67mol醋酸酐，继续剧烈搅拌50min。抽滤、洗涤、干燥，得白色晶体，收率860％。
(2)2-甲基-4-(3，4-二乙酰氧基苄叉基)噁唑酮的合成
取3，4-二羟基苯甲醛0.20mol、乙酰甘氨酸0.24mol和无水醋酸钠0.26mol于250mL三口瓶中，加入醋酸酐189mL，搅拌混匀，在80℃水浴中搅拌反应4h，然后升温至100℃继续搅拌反应1h，冷至室温后将其放入冰箱中冷却。向其中加入100ml水并搅拌，底部有黄色晶体析出，抽滤、洗涤、干燥，得黄色晶体，收率75.0％。
(3)β-(3，4-二乙酰氧基苯基)-α-乙酰氨基丙烯酸的合成
在烧瓶中加入0.15mol 2-甲基-4-(3，4-二乙酰氧基苄叉基)噁唑酮、166mL丙酮和166mL蒸馏水，缓慢加热至沸，加热回流3h。活性炭脱色，滤液放置结晶。抽滤、洗涤、干燥，得米黄色结晶性粉末，收率72.9％。
(4)β-(3，4-二羟基苯基)-α-羟基丙酮酸的合成
取0.25molβ-(3，4-二乙酰氧基苯基)-α-乙酰氨基丙烯酸，加入1mol·L-1盐酸1500mL，搅拌下加热回流8h。活性炭脱色，抽滤，滤液浓缩至有晶体析出。抽滤、洗涤、干燥，得白色疏松状晶体，收率48.1％。
(5)β-(3，4-二羟基苯基)-α-羟基丙酸的合成
取0.17molβ-(3，4-二羟基苯基)丙酮酸，加入112g锌汞齐和1808mL1.4 mol·L-1盐酸溶液，加热回流反应8h。过滤后，滤液用乙酸乙酯反复萃取，并用无水Na2SO4干燥，除去乙酸乙酯，得β-(3，4-二羟基苯基)-α-羟基丙酸。
(6)β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成
在三口瓶中加入0.12molβ-(3，4-二羟基苯基)-α-羟基丙酸和0.18mol冰片，然后加入催化剂对甲基苯磺酸0.86g，四氢呋喃500mL，65℃下反应8h。反应结束后除去催化剂、溶剂和未反应的冰片，得棕色粘稠物，柱色谱分离得淡黄色油状物。
(7)β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的质谱和红外光谱
图2为化合物质谱图，可以看出351.7是(M+H2O)的分子离子峰，它的分子量为333.69，与β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯相符合。图3红外光谱(υ/cm-1)表明：3363.61(OH)，2953.12(CH3)，2913.90(CH2)，1725.51(C＝O)，1608.20、1521.53、1450.32(苯环骨架)，1281.36(酯的C＝O)，1114.39(仲羟基C-O)，885.71和805.68(1，2，4-苯环三取代)。上述表征证明合成得到了β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯。
实施例2：
在三口瓶中加入0.12molβ-(3，4-二羟基苯基)-α-羟基丙酸和0.15mol冰片，然后加入催化剂对甲基苯磺酸0.86g，四氢呋喃500mL，65℃下反应12h。反应结束后减压蒸馏除去反应溶剂，所得粘稠状物质在沸水浴下由油泵(1.3×10-3Pa)抽除冰片，然后加入200mL乙酸乙酯，所得溶液用饱和NaHCO3洗涤以除去未反应的β-(3，4-二羟基苯基)-α-羟基丙酸和对甲基苯磺酸，减压浓缩所得乙酸乙酯层，得棕色粘稠物，柱色谱分离得淡黄色油状物。产品的质谱与红外光谱如附图2和3所示。
实施例3：
催化剂S2O8 2-/ZrO2的制备方法如下：
取0.025mol ZrOCl2·8H2O配制成1mol·L-1的ZrOCl2溶液，在冰水浴中搅拌，慢慢滴入6mol·L-1的氨水，直至pH值至10，陈化12h，抽滤，用蒸馏水洗涤沉淀至无Cl-为止(用0.1mol·L-1AgNO3检验)。将沉淀在110℃下烘10h，研细，然后用0.5mol·L-1(NH4)2S2O8溶液浸泡12h，抽滤，干燥，研细，在马弗炉中600℃下培烧3h即制得S2O8 2-/ZrO2。
在三口瓶中加入0.1molβ-(3，4-二羟基苯基)-α-羟基丙酸和0.12mol冰片，然后加入1.33g催化剂S2O8 2-/ZrO2，1，4-二氧六环400ml，于100℃下反应8h。反应结束后抽滤除去催化剂S2O8 2-/ZrO2，然后减压蒸馏除去溶剂，所得粘稠状物质在沸水浴下由油泵(1.3×10-3Pa)抽除冰片，得黑棕色粘稠物，柱色谱分离得淡黄色油状物。产品的质谱与红外光谱与实施例1相同。
实施例4：
在三口瓶中加入0.06molβ-(3，4-二羟基苯基)-α-羟基丙酸和0.09mol冰片，然后加入催化剂三氯化铝0.60g，溶剂N，N-二甲基甲酰胺200ml，于150℃下反应10h。反应结束后减压蒸馏除去溶剂，所得粘稠状物质在沸水浴下由油泵(1.3×10-3Pa)抽除冰片，得黑棕色物质，再经柱色谱分离得淡黄色油状物。产品的质谱与红外光谱与实施例1相同。
实施例5：药效学试验
(1)对大脑中动脉阻断大鼠脑微循环血流量的影响
SD大鼠60只，体重220±20g。随机分为正常对照组、模型对照组、丹参素注射液组(ip1mL/kg)和β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯小、中、大剂量组(ip 5、15、35mg/kg)。正常对照组和模型对照组ip等体积生理盐水。动物腹腔注射1％戊巴比妥钠40mg/kg麻醉，仰卧位，头部固定，延颈中线切口皮肤，行气管插管，自主呼吸。分离右侧颈总静脉及颈总动脉，穿线备用。将动物固定于大鼠立体定位仪上，于右侧颞顶部用牙科钻钻开一直径为6×8mm大小的颅窗，止血后剪开硬脑膜，暴露软脑膜，玻璃及牙科水泥覆盖密闭，将激光多普勒微循环血流计的激光探头固定于颅窗上。之后动物取侧卧位固定，将右侧颈总动脉提起，结扎近心端，小心剪开颈总动脉，将一直径约0.3mm的尼龙线，穿入动脉，穿线前标记从动脉切口到眼外眦的距离，将尼龙线穿入至接近标记位置时，应减慢穿线速度，并同时观察激光多普勒微循环血流分析仪所显示的脑微循环血流量，穿到大脑中动脉时可出现微循环灌流量的突然下降，出现微循环血流量下降后，再向内穿入约1mm，然后将切口的远心端及动脉内的丝线牢固结扎，剪去多余的丝线。实验结束后，查看尼龙线是否阻塞大脑中动脉的起始部，未阻塞动脉者实验数据作废；对照组不做处理。颅窗制备完毕后，将JI2200型激光多普勒微循环血流仪探头固定于颅窗处，并维持探头在整个实验过程中无位移及转动，记录该区结扎前及结扎后5、15、30、45和60min时的微循环血流量，用药组记录时间相同。以观测时间1min内的平均微循环灌流量为该观察时间的微循环灌流量。
表1对大脑中动脉阻断大鼠脑微循环血流量的影响(n＝10)
Figure C20061004278700071
与模型组比较*P＜0.05，**P＜0.01
本实验显示，阻断大脑中动脉后，供血区(额顶叶)脑微循环血流量迅速下降，并维护一较低水平，至阻断后30min脑微循环血流量才有所增加，但增加幅度较低，说明脑缺血模型成功；β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯15mg/kg 30min和35mg/kg 15min后脑微循环血流量均明显增加。提示扩张微动脉，增加微循环的血流量，缺血性脑血管疾病可能具有较好的的作用，但作用机理有待进一步研究。
(2)对心脏缺血再灌注损伤(I/R)的保护作用
SD大鼠52只，体重220±20 g。随机分为模型对照组、丹参素注射液组(im 1mL/kg)和β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯小、中、大剂量组(ip 5、15、35mg/kg)。正常对照组和模型对照组ip等体积生理盐水。各组连续给药5d。末次给药的同时，用1.5％戊巴比妥钠麻醉大鼠(ip 45mg/kg)，右颈动脉插管，经换能器连接八导生理记录仪，气管插管，通气频率60次/min，开胸，以6/0线，在距冠状动脉前降支根部1mm～2mm系一个袢，其间穿过一塑料管，拉紧袢，观察心电图变化，ST抬高或降低均为结扎成功，结扎线以下心肌组织颜色变暗。30min后拔出塑料管，使冠状动脉血流再通，再灌时局部组织充血。对于缺血30min再灌注30min组，分别记录实验前、缺血1min和30min、再灌30min测定心肌梗死面积；对于缺血30min再灌注2h组，取心脏组织，用10％福尔马林固定后，石蜡包埋，4μm厚连续切片，分别行免疫组化检测；假手术组只穿线，但不结扎冠脉。
对心肌I/R心肌梗死范围的影响  大鼠经30min缺血和30min再灌注后重先结扎冠脉前降支，处死动物，迅速取下心脏，将1％伊文思蓝0.5mL经主动脉注入心腔，以区分缺血区和非缺血区。剪去心房和右室，-20℃冷藏30min，将心脏放入特制的切片槽内，沿长轴切成2mm的薄片，切片浸入1％的TTC磷酸缓冲液中(pH值7.4)，37℃孵育30min，以区分危险区和坏死区。然后用10％的甲醛固定24h，以增强染色颜色对比照相。经处理后，心肌组织被分为：兰色为正常心肌，浅红色为缺血心肌，灰白色为坏死心肌。通过计算机图像分析软件计算梗死心肌(nec)占危险区心肌(即缺血心肌，包括缺血梗死区和缺血未梗死区心肌，aar)的面积百分比(nec/aar)及梗死心肌占整个心肌面积百分比(nec/lv)来表示梗死程度，同时计算危险区心肌占左室面积百分比(aar/lv)。
表2对心肌I/R心肌梗死面积的影响
Figure C20061004278700081
与模型对照组比较*P＜0.05
结果表明，与模型组比较，大剂量组aar/lv、nec/lv和nec/aar分别下降22.5％、20.4％和22％(P＜0.01)，提示可减少心肌I/R心肌梗死面积。
对Bax、Bcl-2、caspase-3、MMP-2和PPARγ蛋白质表达的影响采用标准免疫组化ABC和SP法染色。Bax：抗兔多克隆抗体(Santa CruzBio.Inc.)，稀释度为1∶200；Bcl22：抗兔多克隆抗体(TBD天津生物技术中心)，稀释度为1100；caspase-3：抗兔多克隆抗体(Normarkers Fromont，CA)，稀释度为1∶200；MMP-2：抗小鼠单克隆抗体(NormarkersFromont，CA)，稀释度为1∶200；PPARγ：抗羊多克隆抗体(Santa Cruz Bio Inc.)，稀释度为1∶500。具体步骤按ABC和SP试剂盒说明书操作，DAB显色，中性树脂封片。用PBS代替一抗作为阴性对照。检测内容阳性表达的细胞为棕黄色，MMP-2蛋白在胞浆内，Bcl-2为核膜和胞浆表达，Bax主要存在胞浆，部分在胞核表达，caspase-3主要在胞核表达，部分在胞浆表达。用CMIAS图像分析系统对切片进行随机选场、自动采点分析，以所得心肌组织切片平均光密度值或积分光密度进行统计处理。
表3对Bax、Bcl-2、caspase-3、MMP-2、和PPARγ蛋白质表达的影响(n＝10)
Figure C20061004278700091
与模型对照组比较*P＜0.05，**P＜0.01
本实验表明心肌细胞I/R确实存在Bcl-2和Bax表达的变化，说明它们参与了细胞凋亡的调节。β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯能减少Bax、caspase-3蛋白质的表达，增加Bcl-2蛋白质表达，提示β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯能够通过诱导Bcl-2表达和减少Bax、caspase-3来调动细胞对抗损伤的自我保护机制，逆转心肌I/R所启动的细胞凋亡和坏死过程，而对心肌细胞起保护作用。
MMP-2与心肌I/R损伤有关，且是通过裂解肌钙蛋白I实现的，而肌钙蛋白I的裂解可直接导致细胞凋亡。特异性MMP-2抑制剂可使大鼠心肌I/R心脏功能得以改善，本实验结果显示β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯作用后减少MMP-2蛋白质，这可能为β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯抗心肌I/R损伤的另一机制。

Claims (8)

1. 结构式(I)表示的化合物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯：
Figure C2006100427870002C1
2. 权利要求1所述化合物β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法，其特征在于：将β-(3，4-二羟基苯基)-α-羟基丙酸与冰片在催化量的催化剂存在下反应得到。
3. 根据权利要求2所述β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法，其特征在于：所述的催化剂为路易斯酸催化剂。
4. 根据权利要求3所述β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法，其特征在于：所述的路易斯酸催化剂为对甲基苯磺酸、S2O8 2-/ZrO2、三氯化铝或氯化锌。
5. 根据权利要求2所述β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法，其特征在于：β-(3，4-二羟基苯基)-α-羟基丙酸与冰片摩尔比为：1∶1～1∶1.5。
6. 根据权利要求2所述β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法，其特征在于：反应在溶剂四氢呋喃、甲苯、1，4-二氧六环或N，N-二甲基甲酰胺中进行。
7. 根据权利要求2所述β-(3，4-二羟基苯基)-α-羟基丙酸冰片酯的合成方法，其特征在于：反应在65℃～150℃反应8h～12h。
8. 权利要求1所述化合物在用于制备预防和治疗心脑血管疾病的药品中的应用。
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