CN107098946B - Cetp抑制剂的合成与用途 - Google Patents
Cetp抑制剂的合成与用途 Download PDFInfo
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- CN107098946B CN107098946B CN201610102917.1A CN201610102917A CN107098946B CN 107098946 B CN107098946 B CN 107098946B CN 201610102917 A CN201610102917 A CN 201610102917A CN 107098946 B CN107098946 B CN 107098946B
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Abstract
本发明公开了CETP抑制剂的合成与用途;所述衍生物如式I的化合物。药效学实验表明,本发明式I化合物对CETP具有较好的抑制效果,已达到纳摩尔级别;其次,式I化合物的基本母核来源于天然产物中的五环三萜,原料价廉易得,在成药的安全性上较普通的小分子化合物风险更小,具有更高的应用开发价值。因此,本发明式I化合物可以用于制备抗高脂血症、动脉粥样硬化等心脑血管疾病药物。本发明还提供了式I化合物的制备方法。
Description
技术领域
本发明涉及药物化学领域,具体涉及新型五环三萜类衍生物及其制备方法与在制药中的用途,尤其涉及五环三萜类衍生物作为CETP抑制剂在预防和治疗动脉粥样硬化及高脂血症中的用途。
背景技术
动脉粥样硬化(Atherosclerosis,AS)易发生在大、中动脉,如心脏血管,引起供血组织缺血缺氧,出现如冠心病、心肌梗塞以及外周血管病等临床症状和体征,它是产生心血管疾病的主要病理基础。高脂血症是促进动脉粥样硬化和危及人类健康的冠状动脉粥样硬化性心脏病(CHD)的主要危险因素之一,降低血脂可以降低冠状动脉粥样硬化性心脏病的发生率。
大量流行病学研究表明,AS的发生与血浆中高密度脂蛋白胆固醇(HDL-C)水平呈负相关,而与血浆中低密度脂蛋白胆固醇(LDL-C)以及极低密度脂蛋白胆固醇(VLDL-C)水平呈正相关(N.Engl.J.Med..1989,321:1311;Circulation 1992,85:2025)。HDL一方面可以抑制胆固醇酯在巨噬细胞内累积,阻止其转化为泡沫细胞;另一方面它可以将动脉粥样硬化斑块内泡沫细胞里胆固醇转运至肝脏分解,从而促进胆固醇逆转运(RCT)过程,防止AS的形成。
1985年,Koizumi等发现一个因基因突变至胆固醇酯转移蛋白(CETP)缺乏的家系,HDL水平升高,同时冠心病发病率明显下降,并且发现如果抑制CETP活性,能有效提高血浆内HDL-C的水平,因此抑制CETP活性成为治疗动脉粥样硬化的新靶点。CETP是由476个氨基酸组成的一种疏水性的血浆糖蛋白,它是RCT过程中的关键酶之一,将胆固醇酯(CE)由抗动脉粥样硬化作用的HDL颗粒转运至促动脉粥样硬化形成的LDL及VLDL颗粒,同时将甘油三酯从LDL及VLDL逆向转运给HDL,净效应是提高了LDL-C水平,降低了HDL-C水平(J.LipidRes.1993,34:1225)。此外,CETP也介导胆固醇酯转运至巨噬细胞形成泡沫细胞,因此是一个致动脉粥样硬化的重要因子。所以当CETP受到抑制时,apoA-I和apoA-II的分解代谢受阻,HDL水平升高,加速了胆固醇通过HDL向肝脏转运,降低了As及高脂血症形成的风险。
自上20世纪90年代至今,辉瑞、罗氏、默克和礼来等大型制药公司在开发以CETP为靶标的降脂药物领域展开了激烈竞争,并报道了大量不同结构类型的小分子CETP抑制剂,但到目前为止世界范围内还没有一种CETP抑制剂成功上市,Pfizer公司的Torcetrapib由于严重的不良反应,如头痛、血压升高及心血管毒性,且致死率高于对照组,其III期临床试验在2006年底被迫终止。而Roche的Dalcetrapib由于“缺乏有意义的临床疗效”,其III期临床试验在2012年终止。Eli Lilly公司的Evacetrapib由于仍旧不能有效减少心脑血管不良事件发生于2015年10月终止III期临床试验。目前处在临床三期试验阶段的CETP抑制剂只有Merck公司的Anacetrapib,其结果预计在2017年内完成,但其是否能真正改善的胆固醇水平、降低心血管疾病的风险仍然未知。因此,临床上迫切需要开发安全、有效、可控的新型CETP小分子抑制剂。
综上所述,CETP是高脂血症及动脉粥样硬化等心血管疾病的重要治疗靶点,其抑制剂具有重要的开发价值。
发明内容
本发明所要解决的技术问题在于设计、合成新型的含有五环三萜骨架的CETP抑制剂,以开发疗效好、副作用小的抗高脂血症及动脉粥样硬化药物。
本发明公开了一系列齐墩果酸或熊果酸衍生物或其药学上可接受的盐或溶剂化物,所述衍生物如通式I的化合物:
其中R1为甲基或氢;R2为甲基或氢;R3为甲基或氢;
R4为氟、氯、溴、碘、三氟甲基或甲基;
R5为甲基、乙基、异丙基、环丙基、环丁基或甲氧甲基;
R6为甲基、乙基、丙基、异丙基或叔丁基;
n=1,2,3,4;
本发明通式I的化合物优选R1为甲基或氢;R2为甲基或氢;R3为甲基或氢;
R4为三氟甲基或甲基;R5为甲基、乙基、环丙基或甲氧甲基;R6为甲基、乙基、丙基或异丙基;n=1,2,3,4;
本发明通式I的化合物更优选R1为甲基或氢;R2为甲基或氢;R3为甲基或氢;
本发明通式I的化合物优选R4为三氟甲基;
本发明通式I的化合物更优选R5为乙基;
本发明通式I的化合物更优选R6为乙基;
本发明通式I的化合物更优选n=1,2,3。
本发明优选的化合物如下:
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-齐墩果烷-12-烯-28-酸;
3β-(4-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-齐墩果烷-12-烯-28-酸;
3β-(5-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-齐墩果烷-12-烯-28-酸;
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-12-熊果烯-28-酸;
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉4-基)氨基)-4-氧代丁酰基)氧基-12-熊果烯-28-酸;
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-12-熊果烯-28-酸。
本发明的另一目的是提供了一系列齐墩果酸或熊果酸衍生物式I化合物的制备方法,如下反应式:
具体包括下列步骤
(1)式II化合物与式V化合物在碱性条件下加热,发生亲核取代反应,制得式III化合物;所采用的碱性溶剂选自吡啶、哌啶、N-甲基吗啉、二异丙基乙胺、四甲基乙二胺,优选吡啶;采用的温度选自于60℃~200℃,优选110℃~160℃;
(2)式III化合物与式VI化合物缩合生成化合物IV;所采用的活化试剂选自草酰氯、氯化亚砜、羰基二咪唑、氯甲酸酯,优选氯化亚砜;采用的溶剂选自二氯甲烷、氯仿、四氢呋喃、甲苯、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺或二甲亚砜中的一种或多种的混合溶剂,优选二氯甲烷;采用的温度选自-20℃~60℃,优选0℃~30℃;
(3)式IV化合物在适当的条件下脱除保护基;R7为羟基保护基,适当的羟基保护基对于本领域技术人员是已知的,包括苄基、对甲氧基苄基、苄氧羰基、苯甲酰基、甲基苯甲酰基、对氯苯甲酰基、乙酰基、异丁酰基、甲磺酰基、对甲苯磺酰基、三甲基甲硅烷基、三乙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、三苯甲基等,优选R6为苄基;采用的温度选自20℃~100℃,优选温度为25℃~50℃。
在上述反应式中,R1、R2、R3、R4、R5、R6如上述式I化合物中所定义。
本发明的又一目的是提供了一系列齐墩果酸或熊果酸衍生物式I化合物在制药中的用途。
药效学实验结果表明,本发明式I化合物对CETP具有较好的抑制效果,已达到纳摩尔级别;其次,式I化合物的基本母核来源于天然产物中的五环三萜,原料价廉易得,在成药的安全性上较普通的小分子化合物风险更小,具有更高的应用开发价值。上述实验结果提示,本发明化合物或其药学上可接受的盐可以用于制备抗动脉粥样硬化或治疗高脂血症药物。
本发明还提供了一种预防或治疗高脂血症、动脉粥样硬化等心脑血管疾病的药物组合物,其中含有治疗有效量的式I化合物或其药学上可接受的盐和药学上可接受的载体。所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、颗粒剂、散剂、糖浆剂、口服液、注射剂等制剂学上常规的制剂形式。
附图说明
图1化合物I-5的核磁共振氢谱;
图2所述衍生物通式I。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。
实施例1
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-齐墩果烷-12-烯-28-酸(I-1)
步骤一
室温下,将齐墩果酸苄酯II-1(200mg)溶于无水甲苯(3mL)中,加入丙二酸环(亚)异丙酯V-1(78mg),升温至120℃,回流8小时;将反应液降至室温,倒入水(20mL)中,乙酸乙酯(10mL x 3)萃取水相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=6∶1)得淡黄色粘稠液体丙二酸齐墩果酸苄酯单酯(III-1)106mg,收率46%。
步骤二
将化合物III-1(100mg)溶于干燥的氯化亚砜(2mL)中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷(1mL)备用;将中间体VI(58mg)溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺(44mg),再将上述制得的化合物III-1的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌6小时;向反应液中加入5mL二氯甲烷,依次用1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=4∶1)得淡黄色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-齐墩果烷-12-烯-28-酸苄酯(IV-1)78mg,收率50%。
步骤三
将化合物IV-1(60mg)溶于甲醇(2mL)与四氢呋喃(2mL)的混合溶剂中,加入20%氢氧化钯/碳(12mg),通入氢气,室温搅拌9小时;硅藻土过滤,滤饼分别用乙酸乙酯(5mL)与二氯甲烷(5mL)洗涤,蒸干滤液得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得无色粘稠液体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-齐墩果烷-12-烯-28-酸(I-1)33mg,收率61%;1HNMR(300MHz,CDCl3)δ7.67-7.64(m,1H),7.61(s,1H),7.51-7.49(m,1H),7.43(s,1H),5.28(s,1H),5.13-5.11(m,1H),4.62-4.59(m,1H),4.53-4.49(m,1H),4.27-4.22(m,2H),3.53-3.40(m,2H),2.84-2.80(m,1H),2.54-2.48(s,1H),1.14(s,3H),0.95(s,3H),0.93(s,3H),0.91(s,3H),0.91(s,3H),0.88(s,3H)。
实施例2
3β-(4-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-齐墩果烷-12-烯-28-酸(I-2)
步骤一
室温下,将齐墩果酸苄酯II-1(200mg)溶于无水吡啶(3mL)中,先后加入丁二酸酐V-2(180mg)与4-二甲氨基吡啶(45mg),升温至130℃,回流7小时;将反应液降至室温,分别加水(20mL)与二氯甲烷(10mL),先用1.0M盐酸(10mL x 2)洗涤,然后有机相依次用水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=6∶1)得白色固体丁二酸齐墩果酸苄酯单酯(III-2)230mg,收率98%。
步骤二
将化合物III-2(100mg)溶于干燥的氯化亚砜(2mL)中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷(1mL)备用;将中间体VI(63mg)溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺(45mg),再将上述制得的化合物III-1的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌5小时;向反应液中加入5mL二氯甲烷,依次用1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=4∶1)得淡黄色固体3β-(4-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-齐墩果烷-12-烯-28-酸苄酯(IV-2)103mg,收率67%。
步骤三
将化合物IV-2(100mg)溶于甲醇(2mL)与四氢呋喃(2mL)的混合溶剂中,加入20%氢氧化钯/碳(20mg),通入氢气,室温搅拌12小时;硅藻土过滤,滤饼分别用甲醇(5mL)与二氯甲烷(5mL)洗涤,蒸干滤液得粗品,经硅胶柱层析(二氯甲烷∶甲醇=80∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-齐墩果烷-12-烯-28-酸(I-2)(55mg),收率60%;1HNMR(300MHz,CDCl3)δ7.59-7.56(m,1H),7.49-7.48(m,2H),6.17(d,J=8.7Hz,1H),5.27(s,1H),5.08-5.01(m,1H),4.56-4.43(m,2H),4.29-4.16(m,2H),2.84-2.45(m,6H),1.14(s,3H),0.93(s,3H),0.90(s,3H),0.88(s,3H),0.86(s,3H),0.84(s,3H),0.75(s,3H)。
实施例3
3β-(5-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-齐墩果烷-12-烯-28-酸(I-3)
步骤一
室温下,将齐墩果酸苄酯II-1(200mg)溶于无水吡啶(3mL)中,先后加入戊二酸酐V-3(208mg)与4-二甲氨基吡啶(45mg),升温至130℃,回流15小时;将反应液降至室温,分别加水(20mL)与二氯甲烷(10mL),先用1.0M盐酸(10mL x 2)洗涤,然后有机相依次用水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=10∶1)得白色固体戊二酸齐墩果酸苄酯单酯(III-3)222mg,收率92%。
步骤二
将化合物III-3(82mg)溶于干燥的氯化亚砜(2mL)中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷(1mL)备用;将中间体VI(50mg)溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺(36mg),再将上述制得的化合物III-3的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌8小时;向反应液中加入5mL二氯甲烷,依次用1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-齐墩果烷-12-烯-28-酸苄酯(IV-3)74mg,收率60%。
步骤三
将化合物IV-3(75mg)溶于甲醇(2mL)与四氢呋喃(1mL)的混合溶剂中,加入湿重10%钯碳(15mg),通入氢气,室温搅拌20小时;硅藻土过滤,滤饼分别用甲醇(5mL)与二氯甲烷(5mL)洗涤,蒸干滤液得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=10∶1)得3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-齐墩果烷-12-烯-28-酸(I-3)50mg,收率74%;1HNMR(300MHz,CDCl3)δ7.60-7.58(m,1H),7.49-7.46(m,1H),7.40(s,1H),5.98(d,J=6.0Hz,1H),5.26(s,1H),5.11-5.03(m,1H),4.54-4.46(m,2H),4.28-4.16(m,2H),2.84-2.78(m,1H),2.53-2.30(m,6H),1.12(s,3H),0.93(s,3H),0.92(s,3H),0.89(s,3H),0.87(s,3H),0.86(s,3H),0.74(s,3H)。
实施例4
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-12-熊果烯-28-酸(I-4)
步骤一
室温下,将熊果酸苄酯II-2(500mg)溶于无水甲苯(6mL)中,加入丙二酸环(亚)异丙酯V-1(263mg),升温至120℃,回流8小时;将反应液降至室温,倒入水(20mL)中,乙酸乙酯(10mL x 3)萃取水相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=5∶1)得淡黄色粘稠液体丙二酸熊果酸苄酯单酯(III-4)520mg,收率89%。
步骤二
将化合物III-4(185mg)溶于干燥的氯化亚砜(2mL)中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷(2mL)备用;将中间体VI(102mg)溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺(74mg),再将上述制得的化合物III-4的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌12小时;向反应液中加入5mL二氯甲烷,依次用1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=4∶1)得淡黄色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-12-熊果烯-28-酸苄酯(IV-4)109mg,收率40%。
步骤三
将化合物IV-4(90mg)溶于甲醇(2mL)与四氢呋喃(2mL)的混合溶剂中,加入20%氢氧化钯/碳(15mg),通入氢气,室温搅拌12小时;硅藻土过滤,滤饼分别用甲醇(5mL)与二氯甲烷(5mL)洗涤,蒸干滤液得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-3-氧代丙酰基)氧基-齐墩果烷-12-烯-28-酸(I-4)48mg,收率59%;1HNMR(300MHz,CDCl3)δ7.68-7.64(m,1H),7.61(s,1H),7.52-7.49(m,1H),7.44(s,1H),5.25(s,1H),5.17-5.09(m,1H),4.65-4.60(m,1H),4.54-4.47(m,1H),4.31-4.19(m,2H),3.54-3.41(m,2H),2.58-2.49(m,1H),2.22-2.18(m,1H),1.09(s,3H),0.97(s,3H),0.91(s,3H),0.88(s,6H),0.86(s,3H),0.79(s,3H)。
实施例5
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-12-熊果烯-28-酸(I-5)
步骤一
室温下,将熊果酸苄酯II-2(200mg)溶于无水吡啶(3mL)中,先后加入丁二酸酐V-2(180mg)与4-二甲氨基吡啶(45mg),升温至130℃,回流7小时;将反应液降至室温,分别加水(20mL)与二氯甲烷(10mL),先用1.0M盐酸(10mL x 2)洗涤,然后有机相依次用水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=5∶1)得白色固体丁二酸齐墩果酸苄酯单酯(III-5)226mg,收率97%。
步骤二
将化合物III-5(100mg)溶于干燥的氯化亚砜(2mL)中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷(1mL)备用;将中间体VI(63mg)溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺(45mg),再将上述制得的化合物III-5的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌5小时;向反应液中加入5mL二氯甲烷,依次用1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=4∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-12-熊果烯-28-酸苄酯(IV-5)108mg,收率70%。
步骤三
将化合物IV-5(100mg)溶于甲醇(2mL)与四氢呋喃(2mL)的混合溶剂中,加入20%氢氧化钯/碳(20mg),通入氢气,室温搅拌16小时;硅藻土过滤,滤饼分别用甲醇(5mL)与二氯甲烷(5mL)洗涤,蒸干滤液得粗品,经硅胶柱层析(二氯甲烷∶甲醇=100∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-12-熊果烯-28-酸(I-5)66mg,收率73%;1HNMR(300MHz,CDCl3)δ7.60-7.58(m,1H),7.50-7.48(m,2H),6.23(d,J=9.0Hz,1H,),5.24(s,1H),5.06-5.04(m,1H),4.56-4.46(m,2H),4.29-4.13(m,2H),2.76-2.60(m,4H),2.54-2.45(m,1H),2.20-2.17(m,1H)1.08(s,3H),0.95(s,3H),0.88(s,3H),0.86(s,6H),0.84(s,3H),0.77(s,3H)。
实施例6
3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-12-熊果烯-28-酸(I-6)
步骤一
室温下,将熊果酸苄酯II-2(300mg)溶于无水吡啶(4mL)中,先后加入戊二酸酐V-3(310mg)与4-二甲氨基吡啶(67mg),升温至130℃,回流13小时;将反应液降至室温,分别加水(20mL)与二氯甲烷(10mL),先用1.0M盐酸(10mL x 2)洗涤,然后有机相依次用水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=7∶1)得白色固体戊二酸熊果酸苄酯单酯(III-6)300mg,收率83%。
步骤二
将化合物III-6(82mg)溶于干燥的氯化亚砜(2mL)中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷(1mL)备用;将中间体VI(50mg)溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺(36mg),再将上述制得的化合物III-6的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌9小时;向反应液中加入5mL二氯甲烷,依次用1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-12-熊果烯-28-酸苄酯(IV-6)86mg,收率70%。
步骤三
将化合物IV-6(80mg)溶于甲醇(2mL)与四氢呋喃(1mL)的混合溶剂中,加入湿重10%钯碳(15mg),通入氢气,室温搅拌20小时;硅藻土过滤,滤饼分别用甲醇(5mL)与二氯甲烷(5mL)洗涤,蒸干滤液得粗品,经硅胶柱层析(石油醚∶乙酸乙酯=2∶1)得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-5-氧代戊酰基)氧基-12-熊果烯-28-酸(I-6)56mg,收率77%;1HNMR(300MHz,CDCl3)δ7.61-7.58(m,1H),7.50-7.47(m,1H),7.41(s,1H),6.02(d,J=9.0Hz,1H),5.23(s,1H),5.11-5.04(m,1H),4.54-4.47(m,2H),4.28-4.16(m,2H),2.50-2.37(m,6H),2.19-2.16(m,1H),1.07(s,3H),0.94(s,6H),0.86(s,3H),0.85(s,6H),0.76(s,3H)。
实施例7
体外CETP抑制活性药效学试验
药品:受试化合物(上述实施例制备)、对照药MK-0859(4S,5R)-5-(3,5-二(三氟甲基)苯基)-3-((4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)-[1,1′-二苯基]-2-基)甲基)-4-甲基恶唑烷-2-酮。
实验材料:胆固醇酯转移蛋白活性检测试剂盒(Roar CETP RP Activity AssayKit,Catalog#RB-RPAK),重组人胆固醇酯转移蛋白(Roar Recombinant CETP,rCETP,Catalog#R8899),96孔板(Nunc-442587),96孔微滴定透明板(Greiner-655090)。
实验方法:CETP存在于正常人群的血浆和血清中,它将中性脂质从HDL转移至LDL以及VLDL中,胆固醇酯转移蛋白活性检测试剂盒中包含有一种带有荧光自淬灭功能的中性脂质分子;该脂质分子可以被重组人胆固醇酯转移蛋白转移至试剂盒中所包含的另一种受体分子上,这种受CETP介导的带有荧光的脂质分子的转移过程导致了荧光强度的增加(ExEm=465/535nm);CETP抑制剂将使试剂盒中脂质分子转移到受体分子的过程受到抑制,因而荧光强度会减弱,通过检测荧光强度,运用GraphPad软件拟合出待测化合物对CETP的抑制率。
实验步骤:
1.重组人胆固醇酯转移蛋白准备:将rCETP用1X测试缓冲液调至蛋白浓度为80μg/mL;
2.化合物准备:将所测化合物用100%DMSO溶解配制成10mM的母液储存,然后在96孔板上用DMSO稀释成8个滴定点;
3.测试方法按照CETP抑制剂筛选试剂盒与重组CETP蛋白使用指导说明进行;
空白对照:4μl脂质分子与4μl受体分子溶解在200μl的测试缓冲液中;
阳性对照:4μl脂质分子、4μl受体分子以及30ng人重组CETP蛋白溶解在200μl的测试缓冲液中;
测试板:4μl脂质分子、4μl受体分子、30ng人重组CETP蛋白以及1μl待测化合物溶解在200μl的测试缓冲液中;
4.将测试的96孔板在37℃的培养箱中孵育3个小时;
5.用荧光计检测每个样品的荧光增加的强度(激发波长:465nm;发射波长:535nm),通过扣除每组样品中的空白组的荧光强度来确定测试组中的因转移而增加的荧光强度。
6.通过GraphPad软件拟合出脂质分子的浓度与荧光信号强度线性图。对数据进行拟合,计算待测化合物对CETP的IC50。
结果:通过化学发光检测系统检测受试化合物对CETP的抑制活性,部分实验结果如表1所示。结果表明,受试化合物中部分化合物对CETP具有较好的抑制效果。
表1化合物抑制CETP作用
实施例8
片剂
将实施例14中制得的化合物I-5(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合,制粒,压片。
Claims (5)
2.如权利要求1所述衍生物的制备方法,如下反应式:
具体包括下列步骤:
步骤一:
室温下,将熊果酸苄酯II-2 200mg溶于无水吡啶3mL中,先后加入丁二酸酐V-2 180mg与4-二甲氨基吡啶45mg,升温至130℃,回流7小时;将反应液降至室温,分别加水20mL与二氯甲烷10mL,先用1.0M盐酸10mL x 2洗涤,然后有机相依次用水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析得白色固体丁二酸齐墩果酸苄酯单酯III-5;所述硅胶柱的流动相为石油醚∶乙酸乙酯=5∶1;
步骤二:
将化合物III-5 100mg溶于干燥的氯化亚砜2mL中,室温搅拌2小时,蒸除反应液中剩余的氯化亚砜,再溶于无水二氯甲烷1mL备用;将中间体VI63mg溶于无水二氯甲烷,将反应液降至0℃,先加入三乙胺45mg,再将上述制得的化合物III-5的酰氯溶液慢慢滴入反应液,滴毕,移至室温搅拌5小时;向反应液中加入5mL二氯甲烷,依次用 1.0M盐酸、饱和碳酸氢钠、水以及饱和食盐水洗涤,无水硫酸钠干燥,蒸干有机相得粗品,经硅胶柱层析得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代丁酰基)氧基-12-熊果烯-28-酸苄酯IV-5;所述硅胶柱的流动相为石油醚∶乙酸乙酯=4∶1
步骤三:
将化合物IV-5 100mg溶于甲醇2mL与四氢呋喃2mL的混合溶剂中,加入20%氢氧化钯/碳 20mg,通入氢气,室温搅拌16小时;硅藻土过滤,滤饼分别用甲醇5mL与二氯甲烷5mL洗涤,蒸干滤液得粗品,经硅胶柱层析得白色固体3β-(3-(((2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)氨基)-4-氧代 丁酰基)氧基-12-熊果烯-28-酸I-5;所述硅胶柱的流动相为二氯甲烷∶甲醇=100∶1。
3.如权利要求1所述熊果酸衍生物在制备CETP抑制剂治疗高血脂、动脉粥样硬化代谢性疾病中的用途。
4.一种预防或治疗高血脂、动脉粥样硬化代谢性疾病的药物组合物,其特征在于,所述药物组合物中含有如权利要求1所述式I-5化合物。
5.如权利要求4的药物组合物,其特征在于,所述药物组合物为片剂、胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂。
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CN101607979A (zh) * | 2009-03-02 | 2009-12-23 | 中国药科大学 | 五环三萜-维生素c缀合物、其制备方法及其医药用途 |
CN102399254A (zh) * | 2010-09-07 | 2012-04-04 | 中国药科大学 | 新型五环三萜衍生物、其制备方法及用途 |
CN104725456A (zh) * | 2013-12-24 | 2015-06-24 | 中国药科大学 | 五环三萜类胆固醇酯转运蛋白抑制剂、其药物组合物及医药用途 |
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CN102399254A (zh) * | 2010-09-07 | 2012-04-04 | 中国药科大学 | 新型五环三萜衍生物、其制备方法及用途 |
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