CN114591267A - 单羰基姜黄素含氮衍生物及其制备方法和应用 - Google Patents
单羰基姜黄素含氮衍生物及其制备方法和应用 Download PDFInfo
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- CN114591267A CN114591267A CN202210328766.7A CN202210328766A CN114591267A CN 114591267 A CN114591267 A CN 114591267A CN 202210328766 A CN202210328766 A CN 202210328766A CN 114591267 A CN114591267 A CN 114591267A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- 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
- C07D295/10—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 doubly bound oxygen or sulphur atoms
- C07D295/112—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 doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
- C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
- C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
一种单羰基姜黄素含氮衍生物及其制备方法和应用，属于医药技术领域，具有如式Ⅰ、Ⅱ、Ⅲ、Ⅳ结构特征。本发明还包括所述单羰基姜黄素含氮衍生物或其药学上可接受的盐类，含有所述单羰基姜黄素含氮衍生物或其药学上可接受的盐类作为活性成分的药物组合物，并用于治疗癌症。该单羰基姜黄素含氮衍生物具有较好的抗癌活性，其制备方法简单可行，易操作。其中，结构通式中的n、R1、R2如权利要求书和说明书所述。
Description
技术领域
本发明属于医药技术领域，具体涉及一种单羰基姜黄素含氮衍生物及其制备方法和应用，更涉及一系列新的单羰基姜黄素含氮衍生物及其药学上可接受的盐类，以及该单羰基姜黄素含氮衍生物或其药学上可接受的盐类和以该单羰基姜黄素含氮衍生物或其药学上可接受的盐类为活性成分的药物，可用于治疗癌症。
背景技术
姜黄素是从姜黄(拉丁学名：Curcuma longa L.)中分离出来的一种多酚类化合物，大量研究表明姜黄素具有多种生物和药理活性，如抗炎、抗氧化、抗病毒、抗菌等(参见文献：Zhou W,Liu Q.F,Zang X.H,et al.Combination use of tolfenamic acid withcurcumin improves anti-inflammatory activity and reduces toxicity in mice[J].J Food Biochem,2020,44(6)13240-13250)。尽管姜黄素已被证明是安全的，并可调节与癌症和其他多种慢性病相关的多个靶点，但其生物利用度低和体内代谢快限制了其临床疗效(参见文献：Garcea G,Jones D,Singh R,et al.Detection of curcumin and itsmetabolites in hepatic tissue and portal blood of patients following oraladministration[J].Brit J Cancer,2004,90(5):1011-1015)。有部分研究认为，姜黄素结构中的β-二酮结构是一系列醛酮还原酶的特定底物，所以导致姜黄素吸收差、代谢快(参见文献：Azzi E,Alberti D,Parisotto S,et al.Design,synthesis and preliminary in-vitro studies of novel boronated monocarbonyl analogues of Curcumin(BMAC)forantitumor and beta-amiloyd disaggregation activity[J].Bioorg Chem,2019,93:103324)。
因此，近年来，许多学者致力于对姜黄素中的β-二酮基团进行修饰改造，其中一部分人用羰基替换姜黄素的β-二酮部分，形成单羰基姜黄素类似物，与姜黄素相比，此类衍生物表现出了比姜黄素更高的代谢稳定性，并具有良好的抗炎和细胞毒性(参见文献：LiangG,Shao L,Wang Y,et al.Exploration and synthesis of curcumin analogues withimproved structural stability both in vitro and in vivo as cytotoxic agents[J].Bioorg Med Chem,2009,17(6):2623-2631.Zhao C,Cai Y,He X,et al.Synthesisand anti-inflammatory evaluation of novel mono-carbonyl analogues of curcuminin LPS-stimulated RAW 264.7macrophages[J].Eur J Med Chem,2010,45(12):5773-5780)。
发明内容
本发明提供了一种单羰基姜黄素含氮衍生物及其制备方法和应用，其以姜黄素为先导化合物，为提高化合物的稳定性和亲水性、增强其抗癌活性，将姜黄素中的β-二酮基团替换为单羰基，并且在姜黄素结构的苯环或苯环的酚羟基上引入亲水性的胺烷基类基团，合成了单羰基姜黄素含氮衍生物，从而改善水溶性，并经药理试验证明可抑制多种肿瘤细胞增殖，能够提高抗肿瘤活性，它们的主要作用为抗肿瘤。
本发明提供单羰基姜黄素含氮衍生物及其药学上可接受的盐类，结构为以下结构通式(I)、结构通式(Ⅱ)、结构通式(Ⅲ)、结构通式(Ⅳ)中的一种或几种：
其中，n为0～4的整数
R1、R2独自表示：H，C1-C6烃基，C1-C6烷氧基，C1-C6烷氧基苯基，含有羟基的C1-C6烷基，含有苯基的C1-C6烷基，C3-C6环烷基，C3-C6环烷氧基，或R1、R2和氮形成5-10元含氮杂环，R1、R2和氮形成取代或未取代的哌嗪基，其中，取代的哌嗪基中的取代基优选为C1-C6烷基、C1-C6烷氧基苯基中的一种或几种；
所述的C1-C6烃基为C1-C6烷基、含有烯键的C1-C6不饱和烃基，含有炔键的C1-C6不饱和烃基中的一种。
更优选地：n为0～2的整数，R1、R2独立表示H，C1-C6烷基，最优选为C1-C4烷基，C1-C4烷氧基；或R1、R2和氮形成取代或未取代的哌嗪基，取代基的哌嗪基中取代基选自：C1-C4烷基，最优选为甲基，乙基，异丙基，苯基，苄基，羟基乙基。
本发明单羰基姜黄素含氮衍生物及其药学上可接受的盐类，更优选结构式如下：
本发明提供单羰基姜黄素含氮衍生物及其药学上可接受的盐类的制备方法，合成路线如下：
NR1R2如权利要求所述。
优选：NR1R2＝四氢吡咯、哌啶、吗啉、N-甲基哌嗪。
本发明所述单羰基姜黄素含氮衍生物及其药学上可接受的盐类的制备过程中所用溶剂为常用的反应溶剂，无特殊要求。
所述的单羰基姜黄素含氮衍生物的药学上可接受的盐类为单羰基姜黄素含氮衍生物和药学上可接受的盐的混合物，药学上可接受的盐指常规的酸加成盐。
所述的酸加成盐中的酸为无机酸或有机酸，选自盐酸，氢溴酸，氢碘酸，硫酸，磷酸，硝酸，乙酸，酒石酸，水杨酸，甲磺酸，丁二酸，柠檬酸，苹果酸，乳酸，富马酸，马来酸中的一种或几种。
本发明提供了一种药物组合物，所述的药物组合物包括上述单羰基姜黄素含氮衍生物及其药学上可接受的盐类作为活性成分，还包括药学上可被接受的赋形剂。发明还提供了所述单羰基姜黄素含氮衍生物及其药学上可接受的盐类及其药物组合物在制备抗肿瘤药物中的应用。
所述的抗肿瘤药物中，肿瘤为宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、淋巴癌、慢性髓原白血病、原髓细胞白血病。
本发明的单羰基姜黄素含氮衍生物及其制备方法和应用，其有益效果在于：
所描述的单羰基姜黄素含氮衍生物，是为改善姜黄素的水溶性和提高抗癌活性，而在其分子中引入含氮基团所合成的化合物，这些衍生物可能具有更强的生理活性和较大极性，其氨基便于和酸成盐来达到改善水溶性的目的。
本发明的单羰基姜黄素含氮衍生物及其药学上可接受的盐类具有较好的抗癌活性，其制备方法简单可行，易操作。
具体实施方式
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围。
以下实施例中，除非特殊说明，均为质量百分比。
以下实施例，除非特殊说明，采用的原料均为市购，采用的测试检测方法均为常规测试检测方法。
实施例1
化合物2(4-(甲氧基甲氧基)苯甲醛)的合成
将0.1mol化合物1(对羟基苯甲醛)和0.12mol N,N-二异丙基乙胺(DIPEA)溶于100mL二氯甲烷中，冰浴下滴加0.11mol MOMBr(溴甲基甲基醚)，加毕后室温反应1h。向反应液中加入100mL水，分离出有机相，水相用二氯甲烷萃取3次，合并有机相，用5％盐酸洗一次，5％NaOH洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物2。
实施例2
化合物3((E)-3-(4-(甲氧基甲氧基)苯基)丙烯酸)的合成
将0.1mol实施例1产物化合物2(4-(甲氧基甲氧基)苯甲醛)溶于30mL甲苯中，并加入丙二酸0.15mol，吡啶0.2mol，苯胺0.01mol，哌啶0.0025mol，90℃反应1h。减压蒸去反应液中的溶剂，向反应瓶中加入100mL水，并用10％盐酸调至pH为1，抽滤，并用水洗3次，烘干得化合物3。
实施例3
化合物4(5-(4-(甲氧基甲氧基)苯基)-2-乙氧羰基-3-羟基-2,4-戊二酸乙酯)的合成
向250ml三口瓶中，加入0.06mol实施例2产物化合物3并溶于100mL二氯甲烷中，加入草酰氯0.12mol，室温反应1h。减压蒸去溶剂和没有反应完的草酰氯，并用四氢呋喃转移到滴液漏斗中。
将丙二酸二乙酯0.12mol溶于80mL四氢呋喃中，加入氢化钠0.12mol，加毕，室温反应30min。滴加上述制好的酰氯。室温下反应30min。减压蒸去溶剂。加入200mL水，用10％盐酸调节溶液pH为5，用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物4。
实施例4
化合物5(5-(4-(甲氧基甲氧基)苯基)-3-羟基-2,4-戊二烯酸乙酯)的合成
将0.2mol实施例3产物化合物4溶于50mL DMSO中，并加入水0.4mol，120℃反应4h，将反应液倒入100mL水中，用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次,饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物5。
实施例5
化合物7((E)-3-(4-甲氧基苯基)丙烯酸)的合成
化合物7采用与实施例2类似的方法进行合成，不同之处在于，采用化合物6(对甲氧基苯甲醛)替代化合物1(对羟基苯甲醛)。
实施例6
化合物8(3-(4-甲氧基苯基)丙酸)的合成
将0.05mol实施例5产物化合物7溶于50mL甲醇中，并加入钯碳0.0025mol，50℃与氢气反应4h，抽滤去钯碳，滤液减压整干，得到化合物8。
实施例7
化合物9(3-(4-甲氧基苯基)丙酰氯)的合成
向250mL三口瓶中，加入0.05mol实施例6产物化合物8并溶于100mL二氯甲烷中，加入草酰氯0.10mol，室温反应1h。减压蒸去溶剂和没有反应完的草酰氯得到化合物9。
实施例8
化合物10(1-(4-甲氧基甲氧基苯基)-7-(4-甲氧基苯基)-3-羟基-4-乙氧羰基-1,3-庚二烯-5-酮)的合成
将0.05mol实施例4产物化合物5溶于50mL四氢呋喃中，冰浴下加入乙醇镁0.05mol，并于室温下反应30min，冰浴下滴加实施例7产物化合物9的四氢呋喃溶液，滴毕，将反应置于室温下反应30min。减压蒸去溶剂，用10％盐酸调节溶液pH 5，用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物10。
实施例9
化合物11(1-(4-甲氧基甲氧基苯基)-7-(4-甲氧基苯基)-3-羟基-1,3-庚二烯-5-酮)的合成
将0.03mol实施例8产物化合物10溶于30ml DMSO中，并加入水0.06mol，120℃反应4h，将反应液倒入100mL水中，用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次,饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物11。
实施例10
化合物12(1-(4-甲氧基甲氧基苯基)-7-(4-甲氧基苯基)-5-羟基-1-庚烯-3-酮)的合成
将0.02mol实施例9产物化合物11溶于20mL四氢呋喃中，冰浴下滴加1mol/L硼烷四氢呋喃溶液20mL，将反应置于室温下反应30min。加入10％NaOH溶液淬灭反应，减压蒸去溶剂，加入60mL水，用10％盐酸调节溶液pH 5，用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物12。
实施例11
化合物13(1-(4-甲氧基甲氧基苯基)-7-(4-甲氧基苯基)-1,4-庚二烯-3-酮)的合成
将0.01mol实施例10产物化合物12溶于30mL乙酸乙酯中，加入0.0005mol对甲苯磺酸，50℃反应6h，向反应液中加入50mL水，分离出有机相，水相用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物13。
实施例12
化合物14(1-(4-羟基苯基)-7-(4-甲氧基苯基)-1,4-庚二烯-3-酮)的合成
将0.01mol实施例11产物化合物13溶于30mL乙酸乙酯中，加入0.05mol 6mol/L盐酸，并于50℃下反应1h，用10％NaOH溶液调至pH 5，加入50mL水，分离出有机相，水相用乙酸乙酯萃取3次，合并有机相，用饱和NaHCO3洗一次，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物14。
实施例13
结构通式Ⅰ化合物(1-(3-(取代仲胺甲基)-4-羟基苯基)-7-(4-甲氧基苯基)-1,4-庚二烯-3-酮)的通用的合成方法
将0.01mol实施例12产物化合物14溶于30mL乙腈中，加入0.025mol 37％甲醛溶液，0.025mol取代仲胺，并于80℃反应1h。将反应液倒入50mL水，用1mol/L盐酸调节pH8，用乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得到结构通式Ⅰ化合物14a-14e。
对得到的化合物进行核磁和质谱检测，其检测结果为：
化合物14a：黄色油状液体。1H-NMR(600MHz,DMSO-d6)δ(ppm):7.46-7.57(m,3H,Ar-Hand 1-CH＝),7.16(d,J＝8.5Hz,2H,Ar-H),7.01-6.93(m,2H,2-CH＝and 5-CH＝),6.86(d,J＝8.5Hz,2H,Ar-H),6.77(d,J＝8.3Hz,1H,Ar-H),6.51(d,J＝15.7Hz,1H,4-CH＝),3.72(s,3H,-OCH3),3.68(s,2H,Ar-CH2-),2.73(t,J＝7.6Hz,2H,7-CH2),2.55-2.51(m,1H,6-CH2),2.47(s,4H,N-CH2×2),1.55(p,J＝5.7Hz,4H,N-CH2 CH2 ×2),1.44(s,2H,N-CH2CH2 CH2 ).ESI-HRMS(m/z):[M+H]+406.2400。
化合物14b：黄色油状液体。1H-NMR(600MHz,DMSO-d6)δ(ppm):7.50-7.57(m,3H,Ar-Hand 1-CH＝),7.16(d,J＝8.5Hz,2H,Ar-H),6.93-7.01(m,2H,2-CH＝and 5-CH＝),6.86(d,J＝8.5Hz,2H,Ar-H),6.82(d,J＝8.2Hz,1H,Ar-H),6.52(d,J＝15.7Hz,1H,4-CH＝),3.72(s,3H,-OCH3),3.66-3.57(m,6H,Ar-CH2-and OCH2×2),2.73(t,J＝7.6Hz,2H,7-CH2),2.57-2.52(m,2H,6-CH2),2.45(s,4H,N-CH2×2).ESI-HRMS(m/z):[M+H]+408.2192。
化合物14c：黄色固体，熔点:85-87℃.1H-NMR(600MHz,CDCl3)δ(ppm):7.54(d,J＝15.8Hz,1H,1-CH＝),7.42(dd,J＝8.5,2.2Hz,1H,Ar-H),7.24(d,J＝2.2Hz,1H,Ar-H),7.12(d,J＝8.6Hz,2H,Ar-H),6.99(dt,J＝15.6,6.8Hz,1H,5-CH＝),6.87-6.82(m,3H,Ar-H),6.78(d,J＝15.9Hz,1H,2-CH＝),6.42(d,J＝15.6Hz,1H,4-CH＝),3.89(s,2H,Ar-CH2-),3.79(s,3H,-OCH3),2.78-2.68(m,6H,7-CH2 and N-CH2×2),2.58-2.54(m,2H,6-CH2),1.90(p,J＝3.4Hz,4H,N-CH2 CH2 ×2).ESI-HRMS(m/z):[M+H]+392.2247。
化合物14d：黄色固体，熔点:97-99℃.1H-NMR(600MHz,DMSO-d6)δ(ppm):7.58-7.49(m,3H,Ar-H and 1-CH＝),7.17(d,J＝8.5Hz,1H,Ar-H),7.02-6.94(m,2H,2-CH＝and5-CH＝),6.86(d,J＝8.5Hz,2H,Ar-H),6.79(d,J＝8.6Hz,1H,Ar-H),6.52(d,J＝15.7Hz,1H,4-CH＝),3.73(s,3H,-OCH3),3.67(s,2H,Ar-CH2-),2.74(t,J＝7.6Hz,2H,7-CH2),2.56-2.51(m,2H,6-CH2),2.48-2.22(m,8H,N-CH2×4),2.18(s,3H,N-CH3).ESI-HRMS(m/z):[M+H]+421.2511。
化合物14e：黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.54(d,J＝15.8Hz,1H,1-CH＝),7.40(d,J＝8.3Hz,1H,Ar-H),7.20(s,1H,Ar-H),7.12(d,J＝8.2Hz,2H,Ar-H),6.98(dt,J＝14.6,6.8Hz,1H,5-CH＝),6.84(d,J＝8.2Hz,2H,Ar-H),6.81(d,J＝8.5Hz,1H,Ar-H),6.77(d,J＝15.9Hz,1H,2-CH＝),6.42(d,J＝15.6Hz,1H,4-CH＝),3.80(s,2H,Ar-CH2-),3.79(s,3H,-OCH3),2.77(t,J＝7.7Hz,2H,7-CH2),2.65(q,J＝7.1Hz,4H,N-CH2×2),2.58-2.53(m,2H,6-CH2),1.13(t,J＝7.1Hz,6H,N-CH2 CH3 ×2).ESI-HRMS(m/z):[M+H]+394.2407。
对比例
一种单羰基姜黄素类似物，其结构式为：
实施例14
卤代醚类姜黄素中间体15通用合成方法
将0.01mol实施例12产物化合物14溶于50mL乙腈中，加入0.01mol二溴代物，0.011mol无水碳酸钾，回流反应5h，减压蒸去溶剂，加入100mL水，用乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得到化合物15。
实施例15
结构通式Ⅱ化合物(1-(取代仲胺基烷氧基苯基)-7-(4-甲氧基苯基)-1,4-庚二烯-3-酮)的通用的合成方法
将0.01mol实施例14产物化合物15溶于50mL乙腈中，加入0.01mol取代仲胺，0.011mol无水碳酸钾，回流反应5h，减压蒸去溶剂，加入100mL水，用乙酸乙酯萃取3次，合并有机相，将有机相用饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得到结构通式(Ⅱ)的化合物15a-15h。
对得到的化合物进行核磁和质谱检测，其检测结果为：
化合物15a：黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.50(d,J＝8.4Hz,2H,Ar-H),7.12(d,J＝8.3Hz,2H,Ar-H),6.99(dt,J＝15.5,6.8Hz,1H,5-CH＝),6.90(d,J＝8.6Hz,2H,Ar-H),6.84(d,J＝8.4Hz,2H,Ar-H),6.81(d,J＝16.0Hz,1H,2-CH＝),6.42(d,J＝15.8Hz,1H,4-CH＝),4.07(t,J＝6.3Hz,2H,-OCH2),3.79(s,3H,-OCH3),2.77(t,J＝7.7Hz,2H,7-CH2),2.67(t,J＝7.4Hz,2H,N-CH2),2.60-2.55(m,6H,6-CH2 and N-CH2×2),2.07-2.02(m,2H,CH2 CH2 CH2),1.83-1.80(m,4H,N-CH2 CH2 ×2).ESI-HRMS(m/z):[M+H]+420.2564。
化合物15b：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.50(d,J＝8.6Hz,2H,Ar-H),7.12(d,J＝8.5Hz,2H,Ar-H),6.99(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.90(d,J＝8.7Hz,2H,Ar-H),6.85(d,J＝8.6Hz,2H,Ar-H),6.81(d,J＝15.9Hz,1H,2-CH＝),6.43(d,J＝15.6Hz,1H,4-CH＝),4.06(t,J＝6.2Hz,2H,-OCH2),3.79(s,3H,-OCH3),2.77(t,J＝7.7Hz,2H,7-CH2),2.67-2.40(m,8H,6-CH2 and N-CH2×3),2.08(s,2H,CH2CH 2 CH2),1.69(s,4H,N-CH2 CH2 ×2),1.49(s,2H,N-CH2CH2 CH2 ).ESI-HRMS(m/z):[M+H]+434.2721。
化合物15c：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.58(d,J＝15.9Hz,1H,1-CH＝),7.51(d,J＝8.7Hz,2H,Ar-H),7.12(d,J＝8.5Hz,2H,Ar-H),6.99(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.91(d,J＝8.7Hz,2H,Ar-H),6.84(d,J＝8.5Hz,2H,Ar-H),6.81(d,J＝15.9Hz,1H,2-CH＝),6.43(d,J＝15.6Hz,1H,4-CH＝),4.07(t,J＝6.3Hz,2H,-OCH2),3.79(s,3H,-OCH3),3.75(s,4H,OCH2×2),2.77(t,J＝7.7Hz,2H,7-CH2),2.59-2.50(m,8H,6-CH2and N-CH2×3),2.03-2.00(m,2H,CH2CH 2 CH2).ESI-HRMS(m/z):[M+H]+436.2521。
化合物15d：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.50(d,J＝8.8Hz,2H,Ar-H),7.12(d,J＝8.6Hz,2H,Ar-H),7.01-6.95(m,1H,5-CH＝),6.90(d,J＝8.8Hz,2H,Ar-H),6.84(d,J＝8.8Hz,2H,Ar-H),6.81(d,J＝15.9Hz,1H,2-CH＝),6.42(d,J＝15.6Hz,1H,4-CH＝),4.05(t,J＝6.4Hz,2H,-OCH2),3.79(s,3H,-OCH3),2.77(t,J＝7.8Hz,2H,7-CH2),2.58-2.47(m,12H,6-CH2 and N-CH2×5),2.33(s,3H,N-CH3),2.01-1.96(m,2H,CH2 CH2 CH2).ESI-HRMS(m/z):[M+H]+449.2841。
化合物15e：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.51(d,J＝8.5Hz,2H,Ar-H),7.12(d,J＝8.5Hz,2H,Ar-H),6.99(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.91(d,J＝8.7Hz,2H,Ar-H),6.84(d,J＝8.6Hz,2H,Ar-H),6.82(d,J＝15.8Hz,1H,2-CH＝),6.42(d,J＝15.7Hz,1H,4-CH＝),4.21(s,2H,-OCH2),3.79(s,3H,-OCH3),2.88(s,2H,N-CH2),2.77(t,J＝7.7Hz,2H,7-CH2),2.67-2.60(m,4H,N-CH2×2),2.58-2.55(m,2H,6-CH2),1.68(s,4H,N-CH2 CH2 ×2),1.48(s,2H,N-CH2CH2 CH2 ).ESI-HRMS(m/z):[M+H]+420.2559。
化合物15f：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.51(d,J＝8.7Hz,2H,Ar-H),7.12(d,J＝8.5Hz,2H,Ar-H),7.00(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.92(d,J＝8.8Hz,2H,Ar-H),6.84(d,J＝8.6Hz,2H,Ar-H),6.82(d,J＝15.8Hz,1H,2-CH＝),6.42(d,J＝15.7Hz,1H,4-CH＝),4.19(s,2H,-OCH2),3.79(s,3H,-OCH3),3.77(s,4H,O-CH2×2),2.87(s,2H,N-CH2),2.77(t,J＝7.7Hz,2H,7-CH2),2.64(s,4H,N-CH2×2),2.58-2.55(m,2H,6-CH2).ESI-HRMS(m/z):[M+H]+422.2351。
化合物15g：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.50(d,J＝8.8Hz,2H,Ar-H),7.11(d,J＝8.5Hz,2H,Ar-H),6.99(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.92(d,J＝8.8Hz,2H,Ar-H),6.84(d,J＝8.6Hz,2H,Ar-H),6.81(d,J＝15.9Hz,1H,2-CH＝),6.42(d,J＝15.6Hz,1H,4-CH＝),4.16(t,J＝5.8Hz,2H,-OCH2),3.79(s,3H,-OCH3),2.95(t,J＝5.7Hz,2H,N-CH2),2.77(t,J＝7.7Hz,2H,7-CH2),2.68(s,4H,N-CH2×2),2.58-2.54(m,2H,6-CH2),1.86-1.80(m,4H,N-CH2 CH2 ×2).ESI-HRMS(m/z):[M+H]+406.2407。
化合物15h：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.51(d,J＝8.6Hz,2H,Ar-H),7.12(d,J＝8.4Hz,2H,Ar-H),6.99(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.91(d,J＝8.7Hz,2H,Ar-H),6.84(d,J＝8.4Hz,2H,Ar-H),6.82(d,J＝15.9Hz,1H,2-CH＝),6.42(d,J＝15.7Hz,1H,4-CH＝),4.14(t,J＝5.8Hz,2H,-OCH2),3.79(s,3H,-OCH3),2.84(t,J＝5.8Hz,2H,N-CH2),2.77(t,J＝7.7Hz,2H,7-CH2),2.64-2.43(m,10H,6-CH2 and N-CH2×4),2.31(s,3H,N-CH3).ESI-HRMS(m/z):[M+H]+435.2677。
实施例16
化合物17((E)-3-(4-乙酰氧基)丙烯酸)的合成
化合物17采用与实施例2类似的方法进行合成，不同之处在于：采用化合物16(4-乙酰氧基苯甲醛)替代化合物1(对羟基苯甲醛)。
实施例17
化合物18(3-(4-乙酰氧基)丙酸)的合成
化合物18采用与实施例6类似的方法进行合成，不同之处在于，采用化合物17替代化合物7。
实施例18
化合物19(3-(4-乙酰氧基)丙酰氯)的合成
化合物19采用与实施例7类似的方法进行合成，不同之处在于，采用化合物18替代化合物8。
实施例19
化合物20(1-(4-甲氧基甲氧基苯基)-7-(4-乙酰氧基苯基)-3-羟基-4-乙氧羰基-1,3-庚二烯-5-酮)的合成
化合物20采用与实施例8类似的方法进行合成，不同之处在于，用化合物19替代化合物9。
实施例20
化合物21(1-(4-甲氧基甲氧基苯基)-7-(4-乙酰氧基苯基)-3-羟基-1,3-庚二烯-5-酮)的合成
化合物21采用与实施例9类似的方法进行合成，不同之处在于，采用化合物20替代化合物10。
实施例21
化合物22(1-(4-甲氧基甲氧基苯基)-7-(4-乙酰氧基苯基)-5-羟基-1-庚烯-3-酮)的合成
化合物22采用与实施例10类似的方法进行合成，不同之处在于：采用化合物21替代化合物11。
实施例22
化合物23(1-(4-甲氧基甲氧基苯基)-7-(4-乙酰氧基苯基)-1,4-庚二烯-3-酮)的合成
化合物23采用与实施例11类似的方法进行合成，不同之处在于：采用化合物22替代化合物12。
实施例23
化合物24(1-(4-甲氧基甲氧基苯基)-7-(4-羟基苯基)-1,4-庚二烯-3-酮)的合成
将0.01mol实施例22产物化合物23溶于30mL甲醇中，室温下加入甲醇钠0.011mol，室温反应1h，减压蒸去溶剂，向反应液中加入100mL水，用1mol/L盐酸调节溶液pH 5，用乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得化合物24。
实施例24
结构通式Ⅲ化合物中间体26(7-(3-(取代仲胺甲基)-4-羟基苯基)-1-(4-甲氧基甲氧基苯基)-1,4-庚二烯-3-酮)的通用的合成方法
化合物26采用与实施例13类似的方法进行合成，不同之处在于，采用化合物24替代化合物14。
实施例25
结构通式Ⅲ化合物(7-(3-(取代仲胺甲基)-4-羟基苯基)-1-(4-羟基苯基)-1,4-庚二烯-3-酮)的通用的合成方法
将0.01mol实施例24产物中间体26溶于30mL乙酸乙酯中，加入0.05mol 6mol/L盐酸，并于50℃下反应1h，用10％NaOH溶液调至pH 8～9，加入50mL水，分离出有机相，水相用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥。浓缩后得结构通式Ⅲ化合物26a-26e。
对得到的化合物进行核磁和质谱检测，其检测结果为：
化合物26a：淡黄色固体。熔点：133-135℃。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.46(d,J＝8.6Hz,2H,Ar-H),7.02-6.96(m,2H,Ar-H and 5-CH＝),6.86(d,J＝8.6Hz,2H,Ar-H),6.82-6.78(m,2H,Ar-H and 2-CH＝),6.76(d,J＝8.2Hz,1H,Ar-H),6.41(d,J＝15.6Hz,1H,4-CH＝),3.79(s,2H,Ar-CH2-),2.71(t,J＝7.6Hz,2H,7-CH2),2.62(s,4H,N-CH2×2),2.57-2.53(m,2H,6-CH2),1.83(p,J＝3.3Hz,4H,N-CH2 CH2 ×2).ESI-HRMS(m/z):[M+H]+378.2093。
化合物26b：淡黄色固体。熔点：140-142℃。1H-NMR(600MHz,CDCl3)δ(ppm):7.56(d,J＝15.9Hz,1H,1-CH＝),7.48(d,J＝8.6Hz,2H,Ar-H),7.03-6.95(m,2H,Ar-H and 5-CH＝),6.85(d,J＝8.6Hz,2H,Ar-H),6.81(d,J＝15.9Hz,1H,2-CH＝),6.77(d,J＝2.2Hz,1H,Ar-H),6.76(d,J＝8.2Hz,1H,Ar-H),6.41(d,J＝15.6Hz,1H,4-CH＝),3.64(s,2H,Ar-CH2-),2.81-2.36(m,8H,6-CH2 and 7-CH2 and N-CH2×2),1.65-1.58(m,4H,N-CH2 CH2 ×2),1.54-1.40(m,2H,N-CH2CH2 CH2 ).ESI-HRMS(m/z):[M+H]+392.2242。
化合物26c：淡黄色固体。熔点：152-154℃。1H-NMR(600MHz,CDCl3)δ(ppm):7.56(d,J＝15.9Hz,1H,1-CH＝),7.46(d,J＝8.7Hz,2H,Ar-H),7.01(dd,J＝8.2,2.2Hz,1H,Ar-H),6.96(dt,J＝15.7,6.8Hz,1H,5-CH＝),6.85(d,J＝8.5Hz,2H,Ar-H),6.81-6.77(m,2H,Ar-Hand 2-CH＝),6.76(d,J＝8.2Hz,1H,Ar-H),6.39(d,J＝15.6Hz,1H,4-CH＝),3.67(s,2H,Ar-CH2-),2.93-2.38(m,12H,6-CH2 and 7-CH2 and N-CH2×4),2.36(s,3H,N-CH3).ESI-HRMS(m/z):[M+H]+407.2361。
化合物26d：淡黄色固体。熔点：149-151℃。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.46(d,J＝8.6Hz,2H,Ar-H),7.03-6.96(m,2H and 5-CH＝),6.87(d,J＝8.5Hz,2H,Ar-H),6.82-6.76(m,3H,Ar-H and 2-CH＝),6.41(d,J＝15.6Hz,1H,4-CH＝),3.74(s,4H,OCH2×2),3.68(s,2H,Ar-CH2-),2.72(t,J＝7.6Hz,2H,7-CH2),2.62-2.47(m,6H,6-CH2 and N-CH2×2).ESI-HRMS(m/z):[M+H]+394.2041。
化合物26e：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.57(d,J＝15.9Hz,1H,1-CH＝),7.47(d,J＝8.6Hz,2H,Ar-H),7.03-6.96(m,2H,2H and 5-CH＝),6.86(d,J＝8.6Hz,2H,Ar-H),6.83-6.77(m,2H,Ar-H and 2-CH＝),6.76(d,J＝8.2Hz,1H,Ar-H),6.41(d,J＝15.6Hz,1H,4-CH＝),3.75(s,2H,Ar-CH2-),2.71(t,J＝7.7Hz,2H,7-CH2),2.62(q,J＝7.2Hz,4H,N-CH2×2),2.57-2.52(m,2H,6-CH2),1.10(t,J＝7.2Hz,6H,N-CH2 CH3 ×2).ESI-HRMS(m/z):[M+H]+380.2250。
实施例26
结构通式Ⅳ化合物中间体25卤代醚类单羰基姜黄素的通用的合成方法
化合物25采用与实施例14类似的方法进行合成，不同之处在于，采用化合物24替代化合物14。
实施例27
结构通式Ⅳ化合物中间体27((1E，4E)-7-(取代仲胺基烷氧基苯基)-1-(4-(甲氧基甲氧基)苯基)-1,4-庚二烯-3-酮)的合成
化合物27采用与实施例15类似的方法进行合成，不同之处在于，采用化合物25替代化合物15。
实施例28
结构通式Ⅳ化合物((1E，4E)-7-(取代仲胺基烷氧基苯基)-1-(4-羟基苯基)-1,4-庚二烯-3-酮)的合成
结构通式Ⅳ化合物(27a-27h)采用与实施例25类似的方法进行合成，不同之处在于：采用化合物27替代中间体26。
对得到的化合物进行核磁和质谱检测，其检测结果为：
化合物27a：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.42(d,J＝16.0Hz,1H,1-CH＝),7.39(d,J＝8.6Hz,2H,Ar-H),7.06(d,J＝8.6Hz,2H,Ar-H),6.88-6.83(m,3H,Ar-H and 5-CH＝),6.77(d,J＝8.5Hz,2H,Ar-H),6.71(d,J＝15.9Hz,1H,2-CH＝),6.35(d,J＝15.7Hz,1H,4-CH＝),3.92(t,J＝6.1Hz,2H,-OCH2),2.76(t,J＝7.3Hz,2H,7-CH2),2.67(s,4H,N-CH2×2),2.56-2.52(m,2H,6-CH2),2.10(p,J＝6.4Hz,2H,-OCH2 CH2 CH2),1.76(p,J＝5.8Hz,4H,N-CH2 CH2 ×2),1.52(s,2H,N-CH2 CH2 CH2 ).ESI-HRMS(m/z):[M+H]+420.2567。
化合物27b：淡黄色油状液体。1H-NMR(600MHz,DMSO-d6)δ(ppm):7.59(d,J＝8.3Hz,2H,Ar-H),7.54(d,J＝15.9Hz,1H,1-CH＝),7.16(d,J＝8.2Hz,2H,Ar-H),7.01-6.94(m,2H,2-CH＝and 5-CH＝),6.86(d,J＝8.4Hz,2H,Ar-H),6.82(d,J＝8.4Hz,2H,Ar-H),6.50(d,J＝15.7Hz,1H,4-CH＝),4.00(t,J＝6.1Hz,2H,-OCH2),3.01(s,6H,N-CH2×3),2.73(t,J＝7.6Hz,2H,7-CH2),2.56-2.51(m,2H,6-CH2),2.03-1.98(m,2H,-OCH2 CH2 CH2),1.83(s,4H,N-CH2 CH2 ×2).ESI-HRMS(m/z):[M+H]+406.2387。
化合物27c：淡黄色固体。熔点：62-64℃。1H-NMR(600MHz,CDCl3)δ(ppm):7.51(d,J＝16.1Hz,1H,1-CH＝),7.45(d,J＝8.2Hz,2H,Ar-H),7.10(d,J＝8.2Hz,2H,Ar-H),6.94(dt,J＝14.4,6.8Hz,1H,5-CH＝),6.86(d,J＝8.1Hz,2H,Ar-H),6.82(d,J＝8.1Hz,2H,Ar-H),6.78(d,J＝16.0Hz,1H,2-CH＝),6.39(d,J＝15.7Hz,1H,4-CH＝),3.98(t,J＝6.3Hz,2H,-OCH2),3.77(s,4H,-OCH2×2),2.77(t,J＝7.6Hz,2H,7-CH2),2.64-2.51(m,8H,6-CH2and N-CH2×3),2.01(s,2H,-OCH2 CH2 CH2).ESI-HRMS(m/z):[M+H]+422.2355。
化合物27d：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.54(d,J＝16.1Hz,1H,1-CH＝),7.44(d,J＝8.3Hz,2H,Ar-H),7.08(d,J＝8.2Hz,2H,Ar-H),6.95(dt,J＝15.9,6.9Hz,1H,5-CH＝),6.82-6.79(m,4H,Ar-H),6.77(d,J＝16.0Hz,2H,2-CH＝),6.39(d,J＝15.7Hz,1H,4-CH＝),3.96(t,J＝6.2Hz,2H,-OCH2),2.76(t,J＝7.6Hz,2H,7-CH2),2.60-2.53(m,12H,6-CH2 and N-CH2×5),2.34(s,3H,N-CH3),1.96(p,J＝6.6Hz,2H,-OCH2 CH2 CH2).ESI-HRMS(m/z):[M+H]+435.2673。
化合物27e：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.52(d,J＝15.8Hz,1H,1-CH＝),7.40(d,J＝8.6Hz,2H,Ar-H),7.07(d,J＝8.6Hz,2H,Ar-H),6.92(dt,J＝15.6,7.0Hz,1H,5-CH＝),6.85(d,J＝8.6Hz,2H,Ar-H),6.78(d,J＝8.6Hz,2H,Ar-H),6.76(d,J＝16.0Hz,1H,2-CH＝),6.39(d,J＝15.6Hz,1H,4-CH＝),4.18(t,J＝5.5Hz,2H,-OCH2),3.09(s,2H,-OCH2 CH2 ),2.90(s,4H,N-CH2×2),2.75(t,J＝7.6Hz,2H,7-CH2),2.57-2.52(m,2H,6-CH2),1.92(s,4H,-NCH2 CH2 ×2).ESI-HRMS(m/z):[M+H]+392.2247。
化合物27f：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.54(d,J＝15.9Hz,1H,1-CH＝),7.41(d,J＝8.6Hz,2H,Ar-H),7.06(d,J＝8.6Hz,2H,Ar-H),6.93(dt,J＝15.6,6.9Hz,1H,5-CH＝),6.84(d,J＝8.6Hz,2H,Ar-H),6.78-6.74(m,3H,Ar-H and 2-CH＝),6.40(d,J＝15.6Hz,1H,4-CH＝),4.15(t,J＝5.5Hz,2H,-OCH2),2.94(t,J＝5.6Hz,2H,-OCH2 CH2 ),2.78-2.68(m,6H,7-CH2 and N-CH2×2),2.56-2.51(m,2H,6-CH2),1.73-1.70(m,4H,-NCH2 CH2 ×2),1.50(s,2H,-NCH2CH2 CH2 ).ESI-HRMS(m/z):[M+H]+406.2406。
化合物27g：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.55(d,J＝16.3Hz,1H,1-CH＝),7.45(d,J＝8.6Hz,2H,Ar-H),7.10(d,J＝8.5Hz,2H,Ar-H),6.96(dt,J＝15.7,6.9Hz,1H,5-CH＝),6.86(d,J＝8.6Hz,2H,Ar-H),6.82(d,J＝8.6Hz,2H,Ar-H),6.79(d,J＝15.9Hz,1H,2-CH＝),6.41(d,J＝15.6Hz,1H,4-CH＝),4.14(t,J＝5.6Hz,2H,-OCH2),3.78(t,J＝4.8Hz,4H,-OCH2×2),2.89(t,J＝5.6Hz,2H,-OCH2 CH2 N-),2.77(t,J＝7.6Hz,2H,7-CH2),2.68(s,4H,-NCH2×2),2.58-2.54(m,2H,6-CH2).ESI-HRMS(m/z):[M+H]+408.2199。
化合物27h：淡黄色油状液体。1H-NMR(600MHz,CDCl3)δ(ppm):7.52(d,J＝15.6Hz,1H,1-CH＝),7.42(d,J＝8.5Hz,2H,Ar-H),7.08(d,J＝8.3Hz,2H,Ar-H),6.93(dt,J＝15.5,6.9Hz,1H,5-CH＝),6.85-6.80(m,4H,Ar-H),6.76(d,J＝16.0Hz,1H,2-CH＝),6.38(d,J＝15.6Hz,1H,4-CH＝),4.08(t,J＝5.6Hz,2H,-OCH2),2.84(t,J＝5.6Hz,2H,-OCH2 CH2 N-),2.76(t,J＝7.5Hz,2H,7-CH2),2.71(s,4H,-NCH2×2),2.63(s,4H,-NCH2×2),2.58-2.51(m,2H,6-CH2),2.37(s,3H,N-CH3).ESI-HRMS(m/z):[M+H]+421.2516。
实施例29
用MTT法测定了目标化合物对人乳腺癌细胞MCF-7，人黑色素瘤细胞A375，人结肠癌细胞的增殖抑制作用。
选用对数生长期的贴壁肿瘤细胞，用胰酶消化后，MCF7、A375、HCT116用含10％胎牛血清的培养基配成5×104/mL(后续药物处理48h)的细胞悬液，接种在96孔培养板中，每孔100ml，37℃，5％CO2培养24h。实验组更换新的含不同浓度被测样品的培养液，对照组则更换含等体积溶剂的培养液，每组设3个平行孔，37℃，5％CO2分别培养48h。弃去上清液，用PBS小心洗2次，每孔加入100mL新鲜配制的含0.5mg/mL MTT的培养基，37℃继续培养4h。小心弃去上清，并加入150mLDMSO，用微型振荡器混匀10min后，用酶标仪在492nm处测定光密度值(OD)。
按下式计算药物对肿瘤细胞生长的抑制率(Inhibition Rate，IR％)：
＝[A492(阴性对照)-A492(加药组)]/A492(阴性对照)×100％
用Graphpad Prism 6.02软件求出样品的半数抑制浓度(IC50)。
结果见下表，对于MCF7、A375、HCT116细胞，大部分目标化合物抑制肿瘤细胞株的IC50值均小于姜黄素，并且，根据14a-14e的结构的化合物和对比例的结构化合物相比，14a-14e的结构的化合物抑制肿瘤细胞株的IC50值大部分小于对比例的结构化合物，因此，将姜黄素结构中的β-二酮替换为单羰基并在苯环引入胺基可提高化合物的体外抗肿瘤活性。
表1式Ⅰ化合物和姜黄素对肿瘤细胞的IC50值
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (10)
1.一种单羰基姜黄素含氮衍生物及其药学上可接受的盐类，结构为以下结构通式(I)、结构通式(Ⅱ)、结构通式(Ⅲ)、结构通式(Ⅳ)中的一种或几种：
其中，n为0～4的整数
R1、R2独自表示：H，C1-C6烃基，C1-C6烷氧基，C1-C6烷氧基苯基，含有羟基的C1-C6烷基，含有苯基的C1-C6烷基，C3-C6环烷基，C3-C6环烷氧基，或R1、R2和氮形成5-10元含氮杂环，R1、R2和氮形成取代或未取代的哌嗪基，其中，取代的哌嗪基中的取代基为C1-C6烷基、C1-C6烷氧基苯基中的一种或几种。
2.根据权利要求1所述的单羰基姜黄素含氮衍生物及其药学上可接受的盐类，其特征在于，R1、R2独立选自：H，C1-C4烷基，C1-C4烷氧基，或R1、R2和氮形成取代或未取代的哌嗪基，取代的哌嗪基中的取代基为甲基，乙基，异丙基，苯基，苄基，羟基乙基。
3.根据权利要求1所述的单羰基姜黄素含氮衍生物及其药学上可接受的盐类，其特征在于，选自以下结构中的一种：
4.根据权利要求1所述的单羰基姜黄素含氮衍生物及其药学上可接受的盐类，其特征在于，单羰基姜黄素含氮衍生物的药学上可接受的盐类为单羰基姜黄素含氮衍生物和药学上可接受的盐的混合物，药学上可接受的盐为常规的酸加成盐。
5.根据权利要求4所述的单羰基姜黄素含氮衍生物及其药学上可接受的盐类，其特征在于，所述的酸加成盐中的酸为有机酸或无机酸，选自：盐酸，溴酸，氢碘酸，硫酸，磷酸，硝酸，乙酸，酒石酸，水杨酸，甲磺酸，丁二酸，柠檬酸，苹果酸，乳酸，富马酸，马来酸中的一种或几种。
6.权利要求1-5任意一项所述的单羰基姜黄素含氮衍生物及其药学上可接受的盐类的制备方法，其特征在于，包括以下合成路线：
其中，结构通式(I)、结构通式(Ⅱ)合成路线如下：
结构通式(Ⅲ)、结构通式(Ⅳ)合成路线如下：
其中，n为0～4的整数
R1、R2独自表示：H，C1-C6烃基，C1-C6烷氧基，C1-C6烷氧基苯基，含有羟基的C1-C6烷基，含有苯基的C1-C6烷基，C3-C6环烷基，C3-C6环烷氧基，或R1、R2和氮形成5-10元含氮杂环，R1、R2和氮形成取代或未取代的哌嗪基，其中，取代的哌嗪基中的取代基为C1-C6烷基、C1-C6烷氧基苯基中的一种或几种。
7.一种药物组合物，其特征在于，包含权利要求1-5任意一项所述的单羰基姜黄素含氮衍生物及其药学上可接受的盐类作为活性成分。
8.根据权利要求7所述的药物组合物，其特征在于，还包括药学上可被接受的赋形剂。
9.权利要求1-5任意一项所述单羰基姜黄素含氮衍生物及其药学上可接受的盐类或权利要求7或8所述的药物组合物在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用，其特征在于：所述的抗肿瘤药物中，肿瘤选自宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、淋巴癌、慢性髓原白血病、原髓细胞白血病。
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