CN110204511A - 一种麝香草酚氨基醇及其制备方法与应用 - Google Patents

一种麝香草酚氨基醇及其制备方法与应用 Download PDF

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CN110204511A
CN110204511A CN201910569957.0A CN201910569957A CN110204511A CN 110204511 A CN110204511 A CN 110204511A CN 201910569957 A CN201910569957 A CN 201910569957A CN 110204511 A CN110204511 A CN 110204511A
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蔡友良
高嫄
强浩
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Shenqi Science & Technology Development Co Ltd Nanjing
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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Abstract

本发明公开了一类麝香草酚氨基醇及其制备方法与应用，所述的制备方法是以麝香草酚为起始原料在碱性条件下与环氧氯丙烷反应，得到环氧化物中间体；中间体再与相应仲胺反应得产物。本发明的麝香草酚氨基醇经药理实验证明具有良好抗肿瘤活性，可用于制备抗肿瘤药物。

Description

一种麝香草酚氨基醇及其制备方法与应用
技术领域
本发明涉及化学合成领域，具体涉及为麝香草酚氨基醇及其制备方法和应用。
背景技术
麝香草酚(Thymol)又名百里酚，最初是从唇形科中草药植物百里香(Thymusserpyllum)，同时广泛分布于麝香草、牛至、香青兰等药用植物中，是一种有代表性的氢醌类化合物。研究发现，麝香草酚具有广谱抗菌效果，亦可用作驱蛔虫剂和防腐剂。中药活性成分在药效学和药物代谢动力学方面或多或少的存在一定的缺陷，主要有药效不高、毒副作用太大或在体内代谢速度过快及过慢等缺陷。因此，为了延长麝香草酚的作用时间，对其结构进行修饰，使其具备抗肿瘤活性，显示出良好的新药开发前景。
发明内容
本发明是针对上述存在的技术问题提供一种麝香草酚氨基醇及其制备方法和应用
本发明的目的可以通过以下技术方案实现：
一种麝香草酚氨基醇，其结构式如下所示：
式A中，为化合物1，为化合物2。
一种上述麝香草酚氨基醇的制备方法，该方法包括以下步骤：
(1)有机溶剂中，麝香草酚为起始原料在碱性条件下与环氧氯丙烷反应，得式B所示的环氧化物中间体；
(2)有机溶剂中，所述的中间体B与仲胺反应，得所述的麝香草酚氨基醇；
上述方法中：步骤(1)中的反应时间为16～20h，反应温度为0～50℃；有机溶剂为DMF或THF，碱为氢化钠。
上述方法中：步骤(1)中麝香草酚与环氧氯丙烷的摩尔比为1：2.5～3。
上述方法中：步骤(2)中反应时间为16～20h，反应温度为60～70℃；有机溶剂为C1～C4直链或支链的低级醇。
上述方法中：步骤(2)中有机溶剂为甲醇、乙醇或异丙醇。
上述方法中：中间体B与仲胺的摩尔比为1：1～1.3。优选：仲胺为7-氯-4-(1-哌嗪基)喹啉或1-(2-乙氧基苯基)哌嗪。
本发明技术方案中，上述的麝香草酚氨基醇类衍生物在制备抗肿瘤药物中的应用。本发明的有益效果：
本发明的麝香草酚氨基醇经药理实验证明具有良好抗肿瘤活性，可用于制备抗肿瘤药物。
具体实施方式
下面结合实施例对本发明做进一步说明，但本发明的保护范围不限于此：
实施例1化合物1的合成
化合物1结构为：
步骤1：0℃氮气保护下将环氧氯丙烷(2.5mmol)加入含有氢化钠(1.9mmol)、麝香草酚(1mmol)的DMF溶液(3ml)中加热至50℃搅拌反应16h，TLC监测；反应结束后，产物用乙酸乙酯萃取，水溶液多次洗涤，减压干燥，得环氧化物中间体。
步骤2：将步骤1中所得的环氧化物中间体和等物质的量的1-(2-乙氧基苯基)哌嗪加入到甲醇中65℃搅拌反应16h，TLC监测；反应结束后，产物经减压脱溶及进一步纯化，得到化合物1，产率76％，纯度98.7％。1H NMR(500MHz,6d-DMSO)δ7.30(s,1H),6.96(s,1H),6.87–6.79(m,3H),6.71(d,2H),5.15(s,1H),4.26(s,1H),4.12(s,3H),3.93(s,1H),3.81(s,1H),3.44(s,3H),3.05(s,1H),2.84(s,3H),2.79(s,2H),2.30(d,4H),2.26–2.01(m,1H),1.34(s,2H),1.14(s,6H).
实施例2化合物2的制备
化合物2结构为：
步骤1：0℃氮气保护下将环氧氯丙烷(2.5mmol)加入含有氢化钠(1.9mmol)、麝香草酚(1mmol)的DMF溶液(3ml)中加热至50℃搅拌反应16h，TLC监测；反应结束后，产物用乙酸乙酯萃取，水溶液多次洗涤，减压干燥，得环氧化物中间体。
步骤2：将步骤1中所得的环氧化物中间体和等物质的量的7-氯-4-(1-哌嗪基)喹啉加入到甲醇中65℃搅拌反应16h，TLC监测；反应结束后，产物经减压脱溶及进一步纯化，得到化合物2，产率81％，纯度99.0％。1H NMR(500MHz,6d-DMSO)δ8.70(d,J＝15.0Hz,1H),8.45(d,J＝15.0Hz,1H),7.74(d,J＝3.1Hz,1H),7.38(dd,J＝15.0,2.9Hz,1H),7.26(t,J＝31.1Hz,1H),6.96(dd,J＝15.0,2.9Hz,1H),6.79(dd,J＝54.9,9.0Hz,2H),5.15(s,1H),4.52–4.00(m,1H),3.95(t,J＝3.2Hz,1H),3.80(d,J＝3.1Hz,1H),3.15(s,3H),3.05(s,1H),2.86–2.79(m,4H),2.52–1.99(m,4H),2.26–1.99(m,1H),1.14(d,J＝12.7Hz,6H).
实施例3麝香草酚氨基醇对KB(人口腔表皮样癌细胞)肿瘤细胞株的抑制作用。
对KB细胞株的体外抗肿瘤活性测定，采用磺酰罗丹明B(SRB)法。步骤如下：将KB肿瘤细胞(处于对数生长期)按一定密度接种至96孔板(每孔90μL)，过夜培养后，依次加入一定浓度的麝香草酚氨基醇作用72小时，每个浓度均设三复孔，并设无细胞调零孔和相应浓度的对照组(阿霉素)。作用结束后，贴壁细胞倾去培养液，加入10％(w/v)三氯乙酸(100μL/孔)于4℃固定1h，随后用蒸馏水冲洗五次，室温干燥后，每孔加入SRB溶液(Sigma，St.Louis，MO，U.S.A)(4mg/mL，溶于1％冰乙酸)100μL，室温下孵育染色15min后，用1％冰乙酸冲洗五次洗去未结合的SRB，室温干燥后，每孔加入10mM Tris溶液100μL，使用SpectraMax 190酶标仪测定560nm波长下的光密度(OD值)。
所合成的麝香草酚氨基醇1、2对KB肿瘤细胞株均有良好的抑制作用。抗肿瘤活性测试结果见表1中所示。
表1化合物对KB细胞增殖抑制的IC50(μM/L)

Claims (9)

1.一种麝香草酚氨基醇，其特征在于：其结构式如下所示：
式A中，为化合物1，为化合物2。
2.根据权利要求1所述的麝香草酚氨基醇的制备方法，其特征在于：该方法包括以下步骤：
(1)有机溶剂中，麝香草酚为起始原料在碱性条件下与环氧氯丙烷反应，得式B所示的环氧化物中间体；
(2)有机溶剂中，所述的中间体B与仲胺反应，得所述的麝香草酚氨基醇；
3.根据权利要求2所述的制备方法，其特征在于：步骤(1)中的反应时间为16～20h，反应温度为0～50℃；有机溶剂为DMF或THF，碱为氢化钠。
4.根据权利要求2所述的制备方法，其特征在于：步骤(1)中麝香草酚与环氧氯丙烷的摩尔比为1：2.5～3。
5.根据权利要求2所述的制备方法，其特征在于：步骤(2)中反应时间为16～20h，反应温度为60～70℃；有机溶剂为C1～C4直链或支链的低级醇。
6.根据权利要求5所述的制备方法，其特征在于：步骤(2)中有机溶剂为甲醇、乙醇或异丙醇。
7.根据权利要求2所述的制备方法，其特征在于：中间体B与仲胺的摩尔比为1：1～1.3。
8.根据权利要求2所述的制备方法，其特征在于：仲胺为7-氯-4-(1-哌嗪基)喹啉或1-(2-乙氧基苯基)哌嗪。
9.根据权利要求1所述的麝香草酚氨基醇类衍生物在制备抗肿瘤药物中的应用。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147864A2 (en) * 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Methods of using piperazine compounds in treating sodium channel-mediated diseases or conditions
US20110218155A1 (en) * 2008-10-10 2011-09-08 Dana-Farber Cancer Institute, Inc. Chemical modulators of pro-apoptotic bax and bcl-2 polypeptides
US20150353473A1 (en) * 2014-06-06 2015-12-10 Ktn Biotec, Inc. Novel anticancer agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147864A2 (en) * 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Methods of using piperazine compounds in treating sodium channel-mediated diseases or conditions
US20110218155A1 (en) * 2008-10-10 2011-09-08 Dana-Farber Cancer Institute, Inc. Chemical modulators of pro-apoptotic bax and bcl-2 polypeptides
US20150353473A1 (en) * 2014-06-06 2015-12-10 Ktn Biotec, Inc. Novel anticancer agent

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MACIEJEWSKI, M.等: "Regioselective Cleavage of 2-Aryloxymethyloxiranes to 3-Aryloxy-1-halogeno- propan-2-ols", 《CHEMINFORM》 *
栗进才等: "麝香草酚衍生物的设计、合成及抗菌活性", 《化学世界》 *

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