WO2016015480A1 - β-榄香烯14位衍生物及其治疗动脉粥样硬化的用途 - Google Patents

β-榄香烯14位衍生物及其治疗动脉粥样硬化的用途 Download PDF

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WO2016015480A1
WO2016015480A1 PCT/CN2015/075326 CN2015075326W WO2016015480A1 WO 2016015480 A1 WO2016015480 A1 WO 2016015480A1 CN 2015075326 W CN2015075326 W CN 2015075326W WO 2016015480 A1 WO2016015480 A1 WO 2016015480A1
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acid
elemenol
ester
group
mmol
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French (fr)
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尚靖
徐进宜
许海
许婷
王若研
段文丽
陈继超
白仁仁
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大连远大医药科技开发有限公司
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Definitions

  • the invention relates to the field of organic synthesis and medicinal chemistry, in particular to a kind of ⁇ -elemene 14-position derivative, and the invention also discloses a preparation method of the ⁇ -elemene 14-position derivative and the anti-atherd The application of hardening.
  • Cardiovascular and cerebrovascular diseases including coronary artery diseases and strokes, are the world's leading fatal diseases.
  • AS is the common pathophysiological basis for cardiovascular and cerebrovascular events and an important factor in cardiovascular and cerebrovascular diseases and death.
  • the risk factors of AS such as hypercholesterolemia, diabetes, hypertension, smoking, etc., induce excessive oxygen free radicals in endothelial cells and vascular smooth muscle cells.
  • ROS ROS
  • scleroderma scleroderma to plaque rupture
  • --elemene is the main active ingredient of elemene. Studies have shown that ⁇ -elemene has anti-oxidative damage and has potential anti-atherosclerotic effects. However, there are few reports on the treatment of atherosclerosis with ⁇ -elemene derivatives. Therefore, by optimizing the structure of ⁇ -elemene, a new type of lead compound with obvious anti-oxidative damage effect is sought for the treatment of arteries. Atherosclerosis-related diseases have important implications.
  • the 13- and 14-position derivatives of monosubstituted ⁇ -elemene are similar in polarity, especially in the 14-position derivative.
  • the material is much lower and is difficult to separate by simple column chromatography. Therefore, previous research by researchers mainly focused on the modification of the 13-derivative of ⁇ -elemene.
  • the 14-position derivative of ⁇ -elemene still has antioxidant activity, thereby exerting anti-atherosclerosis effect, and further analyzing the structure-activity relationship of ⁇ -elemene, we prepared by HPLC.
  • the invention discloses a ⁇ -elemene 14-position carboxylic acid or ester derivative prepared by using ⁇ -elemene as a raw material, and pharmacological studies show that the derivative of the invention is resistant to oxidation and treating atherosclerosis-related diseases. Has a certain effect.
  • the invention provides A process for the preparation of a series of compounds having the structural properties of formula (I) or (II), the general formula (I) or (II) extends the structural characteristics and structural range of such derivatives. Further, there is provided a compound which is excellent in antioxidant damage and has a potential effect of treating atherosclerotic diseases.
  • R 1 represents a carboxyl group, an optionally substituted C 6-10 aryl group or a C 4-9 aromatic heterocyclic group, and the hetero atom is selected from N, O or S, and the substituent is selected from the group consisting of halogen, OH, NO 2 , CF 3 . , C 1-3 alkyl or C 1-3 alkoxy;
  • R 2 represents an optionally substituted 1,2-phenylenediyl, 1,3-phenyldiyl, 1,4-phenyldiyl, 1,8-naphthalenediyl or 2,6-naphthalenediyl group, said substituent Selected from halogen, OH, NO 2 , CF 3 , C 1-3 alkyl, C 1-3 alkoxy;
  • R 1 preferably represents a carboxyl group, an optionally substituted phenyl group, a pyridyl group or a furyl group, and the substituent is selected from the group consisting of Cl, F, OH, NO 2 , CF 3 , CH 3 or OCH 3 .
  • R 1 more preferably represents carboxy, phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-nitrophenyl, 4-nitrophenyl, 2- Hydroxyphenyl, 4-methylphenyl, 4-methoxyphenyl, pyridyl or furyl.
  • the present invention preferably is any one of the following compounds or a pharmaceutically acceptable salt thereof:
  • the preparation of the compounds of formula (I) or (II) requires the passage of a 14-beta-elemena intermediate.
  • the preparation method of 14- ⁇ -elemarin is shown in Reaction 1.
  • ⁇ -elemene is used as a raw material to react with sodium hypochlorite to form 14-chloro- ⁇ -elemene, 14-chloro- ⁇ -elemene and 13,14-dichloro- ⁇ -elemene. mixture.
  • Separation of the monochloro product from the dichloro product can be achieved by silica gel column chromatography using a mixture of all of the chlorinated product and unreacted ⁇ -elemene.
  • the monochloro mixture is then reacted with anhydrous sodium acetate to form a mixture of ethyl esterification products at 13 and 14 and further hydrolyzed under KOH conditions to produce a mixture of 14-beta-elemenol and 14-beta-elemenol.
  • the separation method was prepared by HPLC, and 14- ⁇ -elemenol (about 17%) was successfully isolated.
  • the carboxyl group in the formula (I) and the derivative in (II) can be produced according to the reaction 2. Under the catalysis of DMAP and EDCI, 14- ⁇ -elemenol is reacted with the corresponding cyclic dianhydride to obtain the corresponding product.
  • a pharmaceutically acceptable salt of a compound of the present invention which is characterized by a conventional acid addition salt or a base addition salt which has the same pharmaceutical efficacy as the compound and which is compatible with a suitable non-toxic organic or inorganic acid or organic base. Or a salt of an inorganic base.
  • the invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof, which can be added into a pharmaceutically acceptable carrier, such as a tablet, a capsule, a powder, a syrup. , liquid, suspension, injection, can be added to the common pharmaceutical excipients such as spices, sweeteners, liquid or solid fillers or diluents.
  • the compound of the present invention can be administered in a clinical manner by oral administration or injection.
  • the compound of the present invention is used in a clinical dose of 0.01 mg to 1000 mg/day, and may be deviated from this range depending on the severity of the condition or the dosage form.
  • the logarithmic growth phase of HUVEC cells was inoculated into a 6-well culture plate with a cell suspension of 10 5 /mL. After 24 hours of culture, the culture solution was aspirated, and the blank group and the injury group were added with fresh serum-free DMEM high glucose culture. Base, routine culture. On the basis of this, the drug-administered group was added with various drugs at a concentration of 5 ⁇ mol/L or 50 ⁇ mol/L. After further culture for 24 hours, DMEM serum-free medium containing H 2 O 2 at a final concentration of 0.5 mmol/L was added for 2 h. Thereafter, the levels of intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured.
  • ROS reactive oxygen species
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • ROS reduction rate (injury group - drug group) / injury group ⁇ 100%
  • MDA reduction rate (model group - administration group) / administration group ⁇ 100%.
  • the experimental groups were as follows: 1 normal group; 2 model group; 3 solvent control group; 4 positive drug group: simvastatin (6.5 mg/kg); 5 compound 23 group (100 mg/kg); 6 compound 24 (100 mg/kg) .
  • simvastatin 6.5 mg/kg
  • 5 compound 23 group 100 mg/kg
  • 6 compound 24 100 mg/kg
  • Figure 1 is the effect of compounds 23, 24 on the morphology of atherosclerotic iliac artery wall
  • reaction solution was suction filtered with celite, and filtrate was then applied to 15mL of saturated brine and extracted with petroleum ether three times.

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Abstract

本发明涉及有机合成和药物化学领域，具体涉及一类β-榄香烯14-位衍生物（I）或（II），其中R1和R2的定义同说明书，本发明还公开了这些β-榄香烯14-位衍生物的制备方法及其在抗动脉粥样硬化方面的应用。

Description

β-榄香烯14位衍生物及其治疗动脉粥样硬化的用途 技术领域
本发明涉及有机合成和药物化学领域，具体涉及一类β-榄香烯14-位衍生物，本发明还公开了这些β-榄香烯14-位衍生物的制备方法及其在抗动脉粥样硬化方面的应用。
背景技术
心脑血管疾病包括冠状动脉性疾病和卒中，是全球主要的致死性疾病，近年来随着人们生活水平的不断提高和饮食习惯的改变，其发病率有逐年上升趋势，据报道每年有一亿六千七百万人死于心血管病，AS是心脑血管事件发生的共同的病理生理基础，是引起心脑血管疾病和死亡的一个重要因素。近年来研究表明，AS的发生发展与氧化应激有着密切关系，AS发生的危险因素，如高胆固醇血症、糖尿病、高血压、吸烟等都会诱导内皮细胞、血管平滑肌细胞等产生过量氧自由基(ROS)，而这些ROS参与动脉粥样硬化从脂纹病变到斑块破裂的整个发展过程，并介导了血管内皮细胞、平滑肌细胞及单核巨噬细胞功能改变及损伤，同时又促进了炎症反应。因此寻找新型的针对性强的抗氧化剂仍然是防治动脉粥样硬化的首要任务。
β-榄香烯，是榄香烯的主要活性成分，研究已表明，β-榄香烯具有抗氧化损伤作用，具有潜在的抗动脉粥样硬化作用。但是目前关于β-榄香烯衍生物在治疗动脉粥样硬化方面的研究却鲜有报道，因此通过对β-榄香烯结构进行优化，寻找新型的抗氧化损伤作用明显的先导化合物对治疗动脉粥样硬化相关疾病具有重要的意义。
鉴于β-榄香烯结构的特点，对其衍生化修饰时，单取代β-榄香烯的13位和14位衍生物由于极性相近，特别是14-位衍生物含量较13-位衍生物低得多，通过单纯的柱层析很难分别分离得到，因而科研工作者之前的研究主要集中在β-榄香烯的13位衍生物的修饰。但是，为了探究β-榄香烯的14-位衍生物是否仍然具有抗氧化活性，进而起到抗动脉粥样硬化作用，同时进一步分析β-榄香烯的构效关系，我们通过HPLC制备分离的方法，对13-β-榄香醇和14-β-榄香醇进行了成功分离(所占比例约为5:1)，并以14-β-榄香醇为先导物首次合成制备了系列β-榄香烯14位羧酸和酯类衍生物，并揭示了其在抗氧化损伤，进而在治疗动脉粥样硬化方面的作用。
发明内容
本发明公开了一种用β-榄香烯为原料制备β-榄香烯14位羧酸或酯类衍生物，药理学研究表明本发明的衍生物在抗氧化以及治疗动脉粥样硬化相关疾病中具有一定功效。本发明提供了 一系列具有通式(I)或(II)结构特性的化合物的制备方法，通式(I)或(II)拓展了此类衍生物结构特征和结构范围。并进一步提供其中的抗氧化损伤作用优异，具有潜在治疗动脉粥样硬化疾病效果的化合物。
本发明的化合物结构式如下：
Figure PCTCN2015075326-appb-000001
其中R1表示羧基、任意取代的C6-10芳基或C4-9芳杂环基，杂原子选自N、O或S，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基或C1-3烷氧基；
R2表示任意取代的1,2-苯二基、1,3-苯二基、1,4-苯二基、1,8-萘二基或2,6-萘二基，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基、C1-3烷氧基；
R2还表示-(CH2)n-，其中n＝0-10、-(CH2)a-CHX-(CH2)b-,X选自C1-3直链烷烃、-(CH2)a-(CH＝CH)c-(CH2)b-、-(CH2)a-(CCH3＝CH)c-(CH2)b-、-(CH2)a-(CH＝CCH3)c-(CH2)b-或-(CH2)a-(C≡C)c-(CH2)b-，其中a＝0-10,b＝0-10,c＝0-10。
R2优选表示CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH＝CH、CH＝CHCH2、CH＝CHCH2CH2、CH2CH＝CH、CH2CH＝CHCH2、CH2CH2CH＝CH、CH＝C(CH3)、CH＝C(CH3)CH2CH2或任意取代的1,2-苯二基、1,3-苯二基或1,4-苯二基，所述取代基选自Cl、F、OH、NO2、CF3、CH3或OCH3。
R2更优选表示CH2、CH2CH2、CH＝CH、CH2CH2CH2或1,2-苯二基。
其中R1优选表示羧基、任意取代的的苯基、吡啶基或呋喃基，所述取代基选自Cl、F、OH、NO2、CF3、CH3或OCH3。
R1更优选表示羧基、苯基、2-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、2-硝基苯基、4-硝基苯基、2-羟基苯基、4-甲基苯基、4-甲氧基苯基、吡啶基或呋喃基。
本发明优选下列任一化合物或其药学上可接受的盐：
4-(14-β-榄香烯氧基)-4-氧代丁酸；
5-(14-β-榄香烯氧基)-4-氧代戊酸；
2-(14-β-榄香烯氧基羰基)苯甲酸；
14-(乙酸)-β-榄香醇酯；
14-(丙酸)-β-榄香醇酯；
14-(丁酸)-β-榄香醇酯；
14-(山梨酸)-β-榄香醇酯；
14-(苯甲酸)-β-榄香醇酯；
14-(4-甲基苯甲酸)-β-榄香醇酯；
14-(4-甲氧基苯甲酸)-β-榄香醇酯；
14-(2-氯苯甲酸)-β-榄香醇酯；
14-(4-氯苯甲酸)-β-榄香醇酯；
14-(3-氟苯甲酸)-β-榄香醇酯；
14-(4-氟苯甲酸)-β-榄香醇酯；
14-(4-硝基苯甲酸)-β-榄香醇酯；
14-(肉桂酸)-β-榄香醇酯；
14-(4-氟肉桂酸)-β-榄香醇酯；
14-(水杨酸)-β-榄香醇酯；
14-(烟酸)-β-榄香醇酯；
14-(异烟酸)-β-榄香醇酯；
14-(呋喃甲酸)-β-榄香醇酯；
丁二酸二(14-β-榄香醇)酯；
邻苯二甲酸二(14-β-榄香醇)酯。
下面是本发明中通式(I)或(II)所示化合物的制备方法。
通式(I)或(II)中所示化合物的制备，都需经过14-β-榄香醇中间体。14-β-榄香醇的制备方法如反应一所示。首先以β-榄香烯为原料，与次氯酸钠发生氯代反应，生成14-氯-β-榄香烯、14-氯-β-榄香烯以及13,14-二氯-β-榄香烯混合物。将所有氯代产物和未反应的β-榄香烯的混合物以石油醚为洗脱剂通过硅胶柱层析，可实现单氯代产物与双氯代产物的分离。单氯代混合物接着与无水醋酸钠反应生成13位和14位乙酯化产物混合物，进一步在KOH条件下水解，即可制得14-β-榄香醇和14-β-榄香醇混合物。最终，通过HPLC制备分离的方法，成功分离得到14-β-榄香醇(所占比例约17％)。
反应一：
Figure PCTCN2015075326-appb-000002
通式(I)中含有羧基和(II)中的衍生物可根据反应二制备。在DMAP和EDCI的催化下，14-β-榄香醇与相应的环二酸酐反应，即可制得相应产物。
反应二：
Figure PCTCN2015075326-appb-000003
如反应三所示，在DMAP和EDCI的催化下，14-β-榄香醇与相应的脂肪族羧酸或芳香族羧酸反应，即可制得如通式(II)所示的其他相应衍生物。
反应三：
Figure PCTCN2015075326-appb-000004
本发明化合物药学上可接受的盐，其特征在于：指常规的酸加成盐或碱加成盐，其具有与化合物同样的药学功效，且与合适的非毒性有机酸或无机酸或有机碱或无机碱成的盐。
本发明还公开了一种药物组合物，含本发明的化合物或其药学上可接受的盐，可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填充料或稀释剂等常用的药物辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
下面是本发明化合物的药效学试验及结果，药效学试验中所用化合物代号的化学结构见实施例：
一、体外抗氧化作用评价
取对数生长期的HUVEC细胞，以105个/mL的细胞悬液接种于6孔培养板中，培养24h后，吸弃培养液，空白组和损伤组加入新鲜的无血清DMEM高糖培养基，常规培养。给药组在此基础上分别加入浓度为5μmol/L或50μmol/L的各种药物，继续培养24h后，加入含H2O2终浓度为0.5mmol/L的DMEM无血清培养基，处理2h后，检测细胞内活性氧(ROS)，丙二醛(MDA)和超氧化物歧化酶(SOD)的含量。
ROS降低率＝(损伤组-给药组)/损伤组×100％
SOD增加率＝(给药组-模型组)/给药组×100％
MDA降低率＝(模型组-给药组)/给药组×100％。
实验结果见表1.
表1β-榄香烯14位羧酸或酯类衍生物对氧化损伤内皮细胞氧化指标的影响(n＝3)
Figure PCTCN2015075326-appb-000005
Figure PCTCN2015075326-appb-000006
体外抗氧化活性评价显示，通过对β-榄香烯14位进行酯化修饰，所得衍生物对损伤后HUVEC表现出了较好的抗氧化活性。实验数据也进一步证实本发明提供了一种制备榄香烯衍生物抗氧化药物的有效方法。
二、本发明化合物对鹌鹑动脉粥样硬化模型动物的作用研究
1.鹌鹑动脉粥样硬化模型的建立与分组
健康雄性鹌鹑120只，重量110±20g/只，分笼饲养。定量给食(20g/只/天)，自由饮水，室温20℃-25℃，光照12小时/天。普通饲料喂养一周后，正常对照组饲以普通鹌鹑专用饲料，其余喂以高脂饲料(1％胆固醇、6％花生油、14％猪油和79％基础饲料)。建立鹌鹑动脉粥样硬化模型。鹌鹑高脂动脉粥样硬化造模3周后，喂以高脂饲料的鹌鹑按血清总胆固醇(TC)水平随机分为7组，每组15只。实验分组如下：①正常组；②模型组；③溶剂对照组；④阳性药组：辛伐他汀(6.5mg/kg)；⑤化合物23组(100mg/kg)；⑥化合物24(100mg/kg)。在喂以饲料的同时，每天上午分别灌胃给予相应药物，正常组和模型组给予等量的生理盐水。每周按体重调整给药剂量，给药7周。
在饲养过程中注意对动物精神状态、饮食、活动、粪便颜色及性状等一般情况的观察，并每周称量动物体重，检查饲喂高脂饲料及药物灌胃对动物身体状况的影响。
2.化合物23,24对动脉粥样硬化鹌鹑动脉壁形态学的影响
2.1采集样本
末次给药后，禁食(不禁水)16h，鹌鹑处死，取出主动脉，用生理盐水冲洗血液以滤纸吸干。主动脉编号后用10％中性甲醛固定，进行HE染色，后观察动脉内膜的病变情况，按动脉粥样硬化病变分型法进行动脉病变程度分析。
2.2实验结果见图1，由图可见，正常对照组动脉内膜光滑。模型组斑块融合成片，几乎覆盖整个管腔。溶剂对照组可见斑块明显凸起，融合成片。阳性药辛伐他汀及化合物23,24组动脉内膜增厚，但未见明显凸向管腔的AS斑块。对斑块形成有明显改善作用。提示化合物23,24 对动脉粥样硬化疾病有良好的治疗作用。
附图说明
图1是化合物23、24对动脉粥样硬化鹌鹑动脉壁形态学的影响
具体实施方式
实施例1
中间体14-β-榄香醇(化合物1)的制备方法
将100mmolβ-榄香烯溶于20mL二氯甲烷和乙酸混合溶液中(V:V＝2:1)，冰浴条件下缓慢滴入含有180mmol活性氯的次氯酸钠溶液，冰浴反应4h。分出二氯甲烷层，水层以二氯甲烷萃取3次，合并二氯甲烷浓缩得淡黄色液体粗品，未经进一步纯化处理，该液体粗品溶于15mL无水N,N-二甲基甲酰胺(DMF)中,搅拌下加入200mmol无水醋酸钠,于100℃反应7h。反应液以硅藻土抽滤,滤液加入15mL饱和食盐水,并以石油醚萃取3次。浓缩石油醚得黄色液体，以石油醚：乙酸乙酯＝30:1(V:V)柱层析分离得到13位和14位乙酯化产物混合物。然后以8mL甲醇和8mL氯仿的混合溶液溶解，加入200mmol氢氧化钾回流反应2h。过滤，滤液浓缩，以石油醚：乙酸乙酯＝5:1(V:V)柱层析，得到无色液体产物，此时总产率为20％。最后，采用HPLC制备方法分离13-β-榄香醇和14-β-榄香醇混合物，手性柱型号为CHIRALPAK AD-H，流动相为正己烷：乙醇＝98：2(V:V)，流速为1mL/min，检测波长为UV 214nm，室温条件下分离混合物，分离得到14-β-榄香醇(所占比例约为17％)。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.44-1.68(m,6H),1.76(s,3H),1.94-2.08(m,2H),4.02(q,J＝13.4Hz,2H),4.73(s,2H),4.86(s,1H),4.91(s,1H),4.95(d,J＝5.5Hz,1H),5.17(s,1H),5.79(dd,J1＝17.8Hz,J2＝10.5Hz,1H).
13C NMR(CDCl3,300MHz)δ:151.4,150.0,149.6,111.0,110.6,108.3,67.4,47.9,45.6,39.6,33.3,26.6,20.9,15.9.
实施例2
4-(14-β-榄香烯氧基)-4-氧代丁酸(化合物2)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和3.3mmol丁二酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝8:1(V:V)柱层析，得到无色液体产物，产率为67％。
1H NMR(CDCl3,300MHz)δ:0.99(s,3H),1.40-1.65(m,6H),1.74(s,3H),1.92-1.97(m,1H), 2.01-2.06(m,1H),2.63-2.73(m,4H),4.51(s,2H),4.72(s,2H),4.89-4.95(m,3H),5.13(s,1H),5.75(dd,J1＝17.8Hz,J2＝10.4Hz,1H).
13C NMR(CDCl3,300MHz)δ:177.9,171.7,150.0,149.3,145.9,113.6,111.0,108.4,68.6,48.3,45.6,39.7,33.0,28.9,26.7,21.0,16.0.
实施例3
5-(14-β-榄香烯氧基)-5-氧代戊酸(化合物3)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和3.3mmol戊二酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝8:1(V:V)柱层析，得到无色液体产物，产率为74％。
1H NMR(CDCl3,300MHz)δ:1.00(s,3H),1.41-1.65(m,6H),1.74(s,3H),1.92-2.06(m,4H),2.44(t,J＝7.3Hz,4H),4.49(s,2H),4.71(s,2H),4.88(s,1H),4.90(d,J＝4.7Hz,1H),4.95(s,1H),5.13(s,1H),5.75(dd,J1＝17.8Hz,J2＝10.4Hz,1H).
13C NMR(CDCl3,300MHz)δ:178.8,172.5,150.0,149.2,146.0,113.5,111.0,108.4,68.3,48.4,45.6,39.6,33.2,33.0,32.9,26.7,21.0,19.8,16.0.
实施例4
2-(14-β-榄香烯氧基羰基)苯甲酸(化合物4)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和3.3mmol邻苯二甲酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝8:1(V:V)柱层析，得到无色液体产物，产率为70％。
1H NMR(CDCl3,300MHz)δ:0.93(s,3H),1.33-1.62(m,6H),1.65(s,3H),1.85-1.90(m,1H),2.02-2.07(m,1H),4.62(s,2H),4.65(s,2H),4.85(d,J＝4.5Hz,1H),4.86(s,1H),4.90(s,1H),5.17(s,1H),5.73(dd,J1＝17.0Hz,J2＝11.2Hz,1H),7.47-7.56(m,2H),7.63-7.66(m,1H),7.83-7.85(m,1H).13C NMR(CDCl3,300MHz)δ:170.7,166.7,149.0,148.2,144.6,132.2,131.1,129.9,129.3,128.9,127.9,113.3,110.1,107.4,68.8,47.5,44.6,38.7,38.6,32.0,25.6,20.0,15.0.
实施例5
14-(乙酸)-β-榄香醇酯(化合物5)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol冰醋酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色 液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为78％。
1H NMR(CDCl3,300MHz)δ:1.00(s,3H),1.41-1.65(m,6H),1.75(s,3H),1.92-2.04(m,2H),2.08(s,3H),4.48(s,2H),4.72(s,2H),4.89-4.91(m,2H),4.95(s,1H),5.14(s,1H),5.76(dd,J1＝17.8Hz,J2＝10.4Hz,1H).
13C NMR(CDCl3,300MHz)δ:170.6,150.0,149.3,146.1,113.3,110.9,108.4,68.2,48.4,45.6,39.7,33.0,26.7,21.0,20.9,16.0.
实施例6
14-(丙酸)-β-榄香醇酯(化合物6)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol丙酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为82％。
1H NMR(CDCl3,300MHz)δ:0.89(t,J＝7.4Hz,3H),0.93(s,3H),1.34-1.67(m,6H),1.70(s,3H),1.84-1.91(m,1H),1.94-2.00(m,1H),2.25(t,J＝7.4Hz,2H),4.41(s,2H),4.64(s,2H),4.80(s,1H),4.83(d,J＝3.9Hz,1H),4.88(s,1H),5.06(s,1H),5.70(dd,J1＝17.8Hz,J2＝10.4Hz,1H).
13C NMR(CDCl3,300MHz)δ:174.0,150.0,149.3,146.2,113.1,111.0,108.4,68.0,48.5,45.7,39.7,33.0,27.6,26.7,21.0,16.1,9.1.
实施例7
14-(丁酸)-β-榄香醇酯(化合物7)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol丁酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为60％。
1H NMR(CDCl3,300MHz)δ:0.86(q,J＝7.5Hz,2H),1.00(s,3H),1.16(t,J＝7.5Hz,3H),1.41-1.65(m,6H),1.74(s,3H),1.91-2.06(m,2H),2.36(q,J＝7.6Hz,2H),4.48(s,2H),4.72(s,2H),4.88(s,1H),4.90(d,J＝3.4Hz,1H),4.95(d,J＝1.4Hz,1H),5.13(s,1H),5.76(dd,J1＝17.8Hz,J2＝10.4Hz,1H).
13C NMR(CDCl3,300MHz)δ:172.2,149.0,148.3,145.2,112.3,110.0,107.4,66.9,47.4,44.7,38.7,35.3,32.0,25.6,20.0,17.4,15.0,12.7.
实施例8
14-(山梨酸)-β-榄香醇酯(化合物8)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol山梨酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为89％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.37-1.65(m,6H),1.74(s,3H),1.85(d,J＝5.6Hz,3H),1.89-2.00(m,1H),2.03-2.08(m,1H),4.55(s,2H),4.71(s,2H),4.88(s,1H),4.90(d,J＝3.3Hz,1H),4.95(s,1H),5.15(s,1H),5.73-5.59(m,2H),6.07-6.25(m,2H),7.23-7.31(m,1H).
13C NMR(CDCl3,300MHz)δ:166.9,150.0,149.3,145.2,139.4,129.8,127.4,118.9,113.2,110.9,108.4,67.9,48.5,45.7,39.7,33.1,26.7,21.0,18.6,16.1.
实施例9
14-(苯甲酸)-β-榄香醇酯(化合物9)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为90％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.38-1.71(m,6H),1.75(s,3H),1.94-2.02(m,1H),2.11-2.16(m,1H),4.73(s,4H),4.93(s,1H),4.94(s,1H),4.98(d,J＝3.8Hz,1H),5.25(s,1H),5.82(dd,J1＝17.0Hz,J2＝10.5Hz,1H),7.42-7.47(m,2H),7.53-7.58(m,1H),8.05-8.08(m,2H).
13C NMR(CDCl3,300MHz)δ:166.2,150.0,149.3,146.2,132.9,130.4,129.6,128.4,113.5,111.1,108.5,68.6,48.7,45.7,39.7,33.1,26.7,21.0,16.2.
实施例10
14-(4-甲基苯甲酸)-β-榄香醇酯(化合物10)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 4-甲基苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为62％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.42-1.69(m,6H),1.75(s,3H),1.93-2.08(m,1H),2.10-2.16(m,1H),2.41(s,3H),4.71(s,4H),4.93(s,2H),4.97(d,J＝4.1Hz,1H),5.24(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.23(d,J＝8.3Hz,2H),7.95(d,J＝8.3Hz,2H).
13C NMR(CDCl3,300MHz)δ:166.2,150.0,149.3,146.3,143.6,129.6,129.1,113.3,111.0,108.5,68.4,48.6,45.7,39.7,33.1,26.7,21.6,21.1,16.2.
实施例11
14-(4-甲氧基苯甲酸)-β-榄香醇酯(化合物11)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 4-甲氧基苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为60％。
1H NMR(CDCl3,300MHz)δ:0.96(s,3H),1.34-1.63(m,6H),1.67(s,3H),1.85-1.95(m,1H),2.02-2.07(m,1H),3.78(s,3H),4.62(s,3H),4.64(s,1H),4.85(s,2H),4.90(d,J＝3.8Hz,1H),5.16(s,1H),5.74(dd,J1＝17.7Hz,J2＝10.5Hz,1H),6.84(d,J＝8.8Hz,2H),7.94(d,J＝8.8Hz,2H).
13C NMR(CDCl3,300MHz)δ:162.4,149.0,148.3,145.3,130.6,112.6,112.2,110.0,107.4,67.3,54.4,47.6,44.7,38.7,32.1,25.7,20.0,15.2.
实施例12
14-(2-氯苯甲酸)-β-榄香醇酯(化合物12)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 2-氯苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为80％。
1H NMR(CDCl3,300MHz)δ:1.03(s,3H),1.43-1.69(m,6H),1.75(s,3H),1.93-2.00(m,1H),2.16-2.21(m,1H),4.69-4.80(m,4H),4.93-4.99(m,3H),5.28(s,1H),5.82(dd,J1＝17.8Hz,J2＝10.5Hz,1H),7.28-7.34(m,1H),7.38-7.47(m,2H),7.84(dd,J1＝7.6Hz,J2＝1.0Hz,1H).
13C NMR(CDCl3,300MHz)δ:165.4,150.0,149.3,145.8,132.5,131.5,131.1,126.6,114.5,111.1,108.4,69.6,48.4,45.7,39.8,39.7,33.1,26.7,21.1,16.0.
实施例13
14-(4-氯苯甲酸)-β-榄香醇酯(化合物13)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 4-氯苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为77％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.32-1.70(m,6H),1.75(s,3H),1.94-2.02(m,1H),2.09-2.14(m,1H),4.72(s,4H),4.94(d,J＝4.4Hz,2H),4.98(d,J＝4.4Hz,1H),5.23(s,1H),5.81 (dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.41(d,J＝8.4Hz,2H),7.99(d,J＝8.4Hz,2H).
13C NMR(CDCl3,300MHz)δ:165.3,150.0,149.2,146.0,139.4,131.0,128.7,113.6,111.1,108.5,68.8,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
实施例14
14-(3-氟苯甲酸)-β-榄香醇酯(化合物14)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 3-氟苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为90％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.43-1.71(m,6H),1.75(s,3H),1.90-2.15(m,2H),4.73(s,4H),4.94-5.00(m,3H),5.24(s,1H),5.81(dd,J1＝17.8Hz,J2＝10.4Hz,1H),7.23-7.29(m,1H),7.39-7.46(m,1H),7.71-7.75(m,1H),7.84-7.87(m,1H).
13C NMR(CDCl3,300MHz)δ:164.2,150.0,149.2,145.9,130.1,130.0,125.4,125.3,120.1,119.8,116.7,116.3,113.7,111.1,108.5,68.9,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
实施例15
14-(4-氟苯甲酸)-β-榄香醇酯(化合物15)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 4-氟苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为70％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.43-1.70(m,6H),1.75(s,3H),1.92-2.17(m,2H),4.72(s,4H),4.94(s,1H),4.95(s,1H),4.98(d,J＝4.1Hz,1H),5.23(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.08-7.14(m,2H),8.05-8.10(m,2H).
13C NMR(CDCl3,300MHz)δ:165.2,150.0,149.2,146.2,132.2,132.1,115.7,115.4,113.5,111.1,108.5,68.7,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
实施例16
14-(4-硝基苯甲酸)-β-榄香醇酯(化合物16)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 4-硝基苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为80％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.41-1.71(m,6H),1.75(s,3H),1.94-2.00(m,1H), 2.10-2.17(m,1H),4.73(s,2H),4.78(s,2H),4.95(s,1H),4.98(s,1H),4.99(d,J＝4.1Hz,1H),5.25(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.5Hz,1H),8.23(d,J＝8.9Hz,2H),8.30(d,J＝8.9Hz,2H).
13C NMR(CDCl3,300MHz)δ:164.3,150.6,149.8,149.2,145.6,135.7,130.7,123.6,114.0,111.3,108.6,69.4,48.7,45.7,39.8,39.7,33.1,26.7,21.0,16.1.
实施例17
14-(肉桂酸)-β-榄香醇酯(化合物17)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol肉桂酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为69％。
1H NMR(CDCl3,300MHz)δ:1.03(s,3H),1.44-1.66(m,6H),1.75(s,3H),1.97-2.13(m,2H),4.62(s,2H),4.73(s,2H),4.92(s,1H),4.94(s,1H),4.98(s,1H),5.21(s,1H),5.81(dd,J1＝17.8Hz,J2＝10.4Hz,1H),6.47(d,J＝16.0Hz,1H),7.37-7.39(m,3H),7.52-7.53(m,2H),7.70(d,J＝16.0Hz,1H).
13C NMR(CDCl3,300MHz)δ:166.6,150.0,149.3,146.2,144.9,134.5,130.3,128.9,128.1,118.1,113.4,111.0,108.5,68.4,48.5,45.7,39.7,33.1,29.7,26.7,21.1,16.1.
实施例18
14-(4-氟肉桂酸)-β-榄香醇酯(化合物18)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol 4-氟肉桂酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为65％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.42-1.65(m,6H),1.75(s,3H),1.93-2.03(m,1H),2.07-2.12(m,1H),4.62(s,2H),4.73(s,2H),4.92(s,1H),4.93(s,1H),4.97(d,J＝1.4Hz,1H),5.20(s,1H),5.80(dd,J1＝17.8Hz,J2＝10.4Hz,1H),6.40(d,J＝16.0Hz,1H),7.05-7.10(m,2H),7.50-7.54(m,2H),7.66(d,J＝16.0Hz,1H).
13C NMR(CDCl3,300MHz)δ:165.6,150.0,149.3,146.2,143.6,130.0,129.9,117.8,116.2,115.9,113.4,111.0,110.0,68.3,48.5,45.7,39.7,33.1,26.7,21.0,16.1.
实施例19
14-(水杨酸)-β-榄香醇酯(化合物19)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol水杨酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为73％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.42-1.67(m,6H),1.75(s,3H),1.94-2.03(m,1H),2.10-2.16(m,1H),4.73(s,2H),4.75(s,2H),4.94-5.00(m,3H),5.25(s,1H),5.85(dd,J1＝17.7Hz,J2＝10.6Hz,1H),6.89(t,J＝8.4Hz,1H),6.98(d,J＝8.0Hz,1H),7.43-7.78(m,1H),7.87(dd,J1＝8.0Hz,J2＝1.6Hz,1H),10.77(s,1H).
13C NMR(CDCl3,300MHz)δ:169.7,161.8,150.0,149.2,145.6,135.7,129.8,119.2,117.6,114.1,112.6,111.2,108.5,68.8,48.6,45.7,39.8,39.7,33.1,26.7,21.0,16.1.
实施例20
14-(烟酸)-β-榄香醇酯(化合物20)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol烟酸，常温反应20h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为58％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.43-1.67(m,6H),1.75(s,3H),1.95-2.03(m,1H),2.11-2.17(m,1H),4.73(s,2H),4.77(s,2H),4.94(s,1H),4.97(s,1H),4.99(d,J＝4.8Hz,1H),5.25(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.4Hz,1H),7.40(dd,J1＝7.9Hz,J2＝4.9Hz,1H),8.30-8.34(m,1H),8.79(dd,J1＝4.7Hz,J2＝1.3Hz,1H),9.26(s,1H).
13C NMR(CDCl3,300MHz)δ:164.8,153.4,150.9,149.9,149.2,145.7,137.1,126.2,123.3,113.9,111.2,108.5,69.0,48.6,45.7,39.7,39.6,33.1,26.7,21.0,16.0.
实施例21
14-(异烟酸)-β-榄香醇酯(化合物21)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol异烟酸，常温反应20h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为85％。
1H NMR(CDCl3,300MHz)δ:1.04(s,3H),1.43-1.71(m,6H),1.75(s,3H),1.94-2.03(m,1H),2.10-2.17(m,1H),4.73(s,2H),4.76(s,2H),4.94(s,1H),4.97(s,1H),4.98(d,J＝4.5Hz,1H),5.24(s,1H),5.80(dd,J1＝17.7Hz,J2＝10.4Hz,1H),7.86(d,J＝5.6Hz,2H),8.79(d,J＝5.6Hz, 2H).
13C NMR(CDCl3,300MHz)δ:164.7,150.6,149.9,149.2,145.6,137.5,122.6,114.0,111.2,108.5,69.3,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
实施例22
14-(呋喃甲酸)-β-榄香醇酯(化合物22)的制备方法
将3mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol呋喃甲酸，常温反应15h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝100:1(V:V)柱层析，得到无色液体产物，产率为83％。
1H NMR(CDCl3,300MHz)δ:0.95(s,3H),1.39-1.58(m,6H),1.67(s,3H),1.84-1.94(m,1H),2.01-2.06(m,1H),4.63(s,3H),4.64(s,1H),4.85(s,2H),4.90(d,J＝3.2Hz,1H),5.16(s,1H),5.73(dd,J1＝17.7Hz,J2＝10.5Hz,1H),6.44(q,J＝1.7Hz,1H),7.11(dd,J1＝3.5Hz,J2＝0.8Hz,1H),7.51(q,J＝0.8Hz,1H).
13C NMR(CDCl3,300MHz)δ:157.3,149.0,148.2,145.3,144.8,116.8,112.7,110.8,110.1,107.4,67.3,47.5,44.7,38.7,32.0,25.6,20.0,15.1.
实施例23
丁二酸二(14-β-榄香醇)酯(化合物23)的制备方法
将6mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.6mmol EDCI和3mmol丁二酸酐，常温反应8h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝100:1(V:V)柱层析，得到无色液体产物，产率为75％。
1H NMR(CDCl3,300MHz)δ:0.92(s,6H),1.33-1.65(m,12H),1.67(s,6H),1.85-1.99(m,4H),2.61(s,4H),4.43(s,4H),4.64(s,4H),4.81(s,2H),4.82(d,J＝3.5Hz,2H),4.87(s,2H),5.06(s,2H),5.68(dd,J1＝17.8Hz,J2＝10.5Hz,2H).
13C NMR(CDCl3,300MHz)δ:170.8,149.0,148.3,144.9,112.5110.0,107.5,67.4,47.4,44.6,38.7,32.0,28.2,25.7,20.0,15.0.
实施例24
邻苯二甲酸二(14-β-榄香醇)酯(化合物24)的制备方法
将6mmol 14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.6mmol EDCI和3mmol邻苯二甲酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄 色液体。以石油醚：乙酸乙酯＝100:1(V:V)柱层析，得到无色液体产物，产率为70％.
1H NMR(CDCl3,300MHz)δ:0.94(s,6H),1.34-1.56(m,12H),1.67(s,6H),1.80-2.07(m,4H),4.60(s,2H),4.64(s,6H),4.85(s,4H),4.90(s,2H),5.14(s,2H),5.73(dd,J1＝17.8Hz,J2＝10.4Hz,2H),7.46-7.48(m,2H),7.65-7.68(m,2H).
13C NMR(CDCl3,300MHz)δ:166.1,149.0,148.3,144.8,130.0,127.9,113.0,110.1,107.4,68.4,47.5,44.6,38.7,32.0,25.7,20.0,15.0。

Claims (8)

  1. 通式(I)或(II)的化合物或其药学上可药用盐：
    Figure PCTCN2015075326-appb-100001
    其中R1表示羧基、任意取代的C6-10芳基或C4-9芳杂环基，杂原子选自N、O或S，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基或C1-3烷氧基；
    R2表示任意取代的1,2-苯二基、1,3-苯二基、1,4-苯二基、1,8-萘二基或2,6-萘二基，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基、C1-3烷氧基；
    R2还表示-(CH2)n-，其中n＝0-10、-(CH2)a-CHX-(CH2)b-,X选自C1-3直链烷烃、-(CH2)a-(CH＝CH)c-(CH2)b-、-(CH2)a-(CCH3＝CH)c-(CH2)b-、-(CH2)a-(CH＝CCH3)c-(CH2)b-或-(CH2)a-(C≡C)c-(CH2)b-，其中a＝0-10,b＝0-10,c＝0-10。
  2. 权利要求1的化合物或其药学上可接受的盐，其中R2表示CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH＝CH、CH＝CHCH2、CH＝CHCH2CH2、CH2CH＝CH、CH2CH＝CHCH2、CH2CH2CH＝CH、CH＝C(CH3)、CH＝C(CH3)CH2CH2或任意取代的1,2-苯二基、1,3-苯二基或1,4-苯二基，所述取代基选自Cl、F、OH、NO2、CF3、CH3或OCH3。
  3. 权利要求2的化合物或其药学上可接受的盐，其中R2表示CH2、CH2CH2、CH＝CH、CH2CH2CH2或1,2-苯二基。
  4. 权利要求1的化合物或其药学上可接受的盐，其中R1表示羧基、任意取代的的苯基、吡啶基或呋喃基，所述取代基选自Cl、F、OH、NO2、CF3、CH3或OCH3。
  5. 权利要求4的化合物或其药学上可接受的盐，其中R1表示羧基、苯基、2-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、2-硝基苯基、4-硝基苯基、2-羟基苯基、4-甲基苯基、4-甲氧基苯基、吡啶基或呋喃基。
  6. 权利要求1的化合物或其药学上可接受的盐，是下列任一化合物或其药学上可接受的盐：
    4-(14-β-榄香烯氧基)-4-氧代丁酸；
    5-(14-β-榄香烯氧基)-4-氧代戊酸；
    2-(14-β-榄香烯氧基羰基)苯甲酸；
    14-(乙酸)-β-榄香醇酯；
    14-(丙酸)-β-榄香醇酯；
    14-(丁酸)-β-榄香醇酯；
    14-(山梨酸)-β-榄香醇酯；
    14-(苯甲酸)-β-榄香醇酯；
    14-(4-甲基苯甲酸)-β-榄香醇酯；
    14-(4-甲氧基苯甲酸)-β-榄香醇酯；
    14-(2-氯苯甲酸)-β-榄香醇酯；
    14-(4-氯苯甲酸)-β-榄香醇酯；
    14-(3-氟苯甲酸)-β-榄香醇酯；
    14-(4-氟苯甲酸)-β-榄香醇酯；
    14-(4-硝基苯甲酸)-β-榄香醇酯；
    14-(肉桂酸)-β-榄香醇酯；
    14-(4-氟肉桂酸)-β-榄香醇酯；
    14-(水杨酸)-β-榄香醇酯；
    14-(烟酸)-β-榄香醇酯；
    14-(异烟酸)-β-榄香醇酯；
    14-(呋喃甲酸)-β-榄香醇酯；
    丁二酸二(14-β-榄香醇)酯；
    邻苯二甲酸二(14-β-榄香醇)酯。
  7. 药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
  8. 权利要求1至6中任一项的化合物或其药学上可接受的盐用于制备治疗动脉粥样硬化的疾病的药物的用途。
PCT/CN2015/075326 2014-08-01 2015-03-27 β-榄香烯14位衍生物及其治疗动脉粥样硬化的用途 WO2016015480A1 (zh)

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