CN104098457B - 四氢姜黄素类似物及其制备和应用 - Google Patents

四氢姜黄素类似物及其制备和应用 Download PDF

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CN104098457B
CN104098457B CN201310126499.6A CN201310126499A CN104098457B CN 104098457 B CN104098457 B CN 104098457B CN 201310126499 A CN201310126499 A CN 201310126499A CN 104098457 B CN104098457 B CN 104098457B
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tetrahydrocurcumin
dibenzyl
ethyl
curcumin
dimethyl tetrahydro
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董金华
刘冰弥
夏明钰
徐莉英
张美慧
吉晓玲
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Shenyang Pharmaceutical University
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Abstract

本发明属于医药技术领域，涉及一系列四氢姜黄素类似物及其制备和应用，具有如式Ⅰ结构特征，其中R1，R，n如说明书所述。所述四氢姜黄素类似物药学上可接受的盐和溶剂化物，以及含有所述四氢姜黄素类似物或其药学上可接受的盐作为活性成分的药物，可用于治疗癌症。本发明所述的四氢姜黄素类似物及其药用盐类具有较好的抗癌活性，其制备方法简单可行，易操作。

Description

四氢姜黄素类似物及其制备和应用
技术领域：
本发明涉及一系列新的四氢姜黄素类似物，该化合物的盐类和以该化合物或其盐类为活性成分的药物组合物，可用于治疗癌症。本发明还涉及一系列四氢姜黄素类似物及合成所述的中间体的制备方法。
背景技术：
姜黄素(Curcumin)是从姜科姜黄属植物姜黄(Curcumalonga L.)根茎中提取的酚类天然产物，具有抗肿瘤、抗氧化、抗菌、抗炎等广泛的生物活性（Anand P , Thomas SG ,Kunnumakkara AB, et al. Biological activities of curcumin and its analogues(Congeners) made by man and Mother Nature[J]. Biochem Pharmacol, 2008, 76:1590–1611.）。近年的研究表明，该化合物无毒副作用、抗瘤谱广且同时具有癌症预防和癌症治疗作用(Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “Curcumin”: fromkitchen to clinic[J]. Biochem Pharmacol, 2008, 75(4): 787–809.)，美国国立癌症研究所(national cancer institute, NCI)已将其列为第三代肿瘤化学预防药物(Chauhan DP. Chemotherapeutic potential of curcumin for colorectal cancer[J].Curr Pharm Des, 2002, 8(19): 1695-1706.)，现已进入临床Ⅰ期和临床Ⅱ期试验。姜黄素选择性差，不溶于水，且由于具有α，β-不饱和β-双酮结构及其与末端苯环形成的长共轭结构，在体内外不稳定，代谢迅速，因而抗肿瘤活性较低。研究发现把内源性小分子氨基酸、醋酸、 葡萄糖和核酸与姜黄素结构末端苯环上的酚羟基进行拼合可以提高生物利用度(Mishra S, Narain U, Mishra R, Misra K. Design, development and synthesis ofmixedbioconjugates of piperic acid-glycine, curcumin-glycine/alanine andcurcumin-glycine-piperic acid and their antibacterial and antifungalproperties[J]. Bioorganic & Medicinal Chemistry, 2005, 13(5): 1477-1486. ;Kumar S, Narain U, Tripathi S, Misra K. Syntheses of curcumin bioconjugatesand study of their antibacterial activities against β-lactamase-producingmicroorganisms[J]. Bioconjugate Chemistry, 2001, 12(4): 464-469. ; Ferrari E,Lazzari S, Marverti, G, et al. Synthesis, cytotoxic and combined cDDPactivity of new stable curcumin derivatives[J]. Bioorganic & MedicinalChemistry, 2009, 17(8): 3043-3052.)。Wichitnithad等在姜黄素的酚羟基上引入琥珀酸，形成酯结构，提高了姜黄素的抗肿瘤活性(Wichitnithad W, Nimmannit U,Wacharasindhu S, et al. Synthesis, Characterization and Biological Evaluationof Succinate Prodrugs of Curcuminoids for Colon Cancer Treatment[J].Molecules, 2011, 16(2): 1888-1900.)。Tamvakopoulos等对姜黄素的酚羟基进行甲基化，提高了姜黄素在体内的代谢稳定性及抗肿瘤活性(Tamvakopoulos C, Dimas K, Sofianos ZD, et al. Metabolism and Anticancer Activity of the Curcumin Analogue,Dimethoxycurcumin[J].Clinical Cancer Research, 2007, 13(4): 1269-1277.)。Ohtsu等在姜黄素的活性亚甲基的碳原子上引入了双丙基并对姜黄素的酚羟基进行丙基化得到的化合物与临床上使用的治疗前列腺癌药物羟基氟他胺有相同的抗雄激素活性(Ohtsu H,Itokawa H, Xiao ZY, et al. Antitumor Agents 222. Synthesis and Anti-androgenActivity of New Diarylheptanoids[J]. Bioorganic& Medicinal Chemistry, 2003,11(23): 5083–5090.)。Han等为了消除不稳定的β-双酮结构，在活性亚甲基碳原子上引入双甲基提高了姜黄素抗肿瘤活性(Han YM, Shin DS, Lee YJ, et al. 2-Hydroxycurcuminoid induces apoptosis of human tumor cells through thereactive oxygen species–mitochondria pathway[J]. Bioorganic & MedicinalChemistry Letters, 2011, 21(2): 747–751.)。Li Pui-Kai实验室对姜黄素的活性亚甲基碳原子上引入了环己基并对双羟基进行甲基化，合成的化合物被命名为FLLL32，是一个JAK2/STAT3抑制剂，在体外和体内实验中都表现出强抗肿瘤活性（Lin L, Hutzen B, ZuoM, et al. Novel STAT3 phosphorylation inhibitors exhibit potentgrowthsuppressive activity in pancreatic and breast cancer cells[J]. CancerResearch, 2010, 70(6):2445–2454；Lin L, Deangelis S, Foust E, et al. A novelsmall molecule inhibits STAT3 phosphorylation and DNA binding activity andexhibits potent growth suppressive activity in human cancer cells[J].Molecular Cancer, 2010, 9(1): 217-227；Bill MA, Fuchs JR, Li C, et al.RTehseaerc hsmall molecule curcumin analog FLLL32 induces apoptosis inmelanoma cells via STAT3 inhibition and retains the cellular response tocytokines with anti-tumor activity[J]. Molecular Cancer, 2010, 9(1): 165-177；Fossey SL, Bear MD, Lin J, et al. The novel curcumin analog FLLL32 decreasesSTAT3 DNA binding activity and expression, and induces apoptosis inosteosarcoma cell lines[J]. BMC Cancer, 2011, 11(112), 1-15； Onimoe GI, LiuA, Lin L, et al. Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibitpotent growth suppressive activity in osteosarcoma cells and tumor growth inmice[J]. Investigational New Drugs, 2012, 30(3):916-926；Wei CC, Ball S, LinL, et al. Two small molecule compounds, LLL12 and FLLL32, exhibit potentinhibitory activity on STAT3 in human rhabdomyosarcoma cells[J].International Journal of oncology, 2011, 38(1):279-85.），并对其合成方法及用途申请了专利（Li PK, Li CL, Lin JY, Fuchs JR. Curcumin Analoges as Dual JAK2/STAT3 Inhibitors and Methods of Making and Using the Same[P].WO2010/121007A1.）。本实验室对姜黄素及其类似物在抗肿瘤活性方面的前期研究表明，改善化合物的稳定性及水溶性有利于提高抗肿瘤活性（殷学志. 姜黄素曼尼希碱衍生物的合成及活性研究. [学位论文]. 沈阳药科大学，2007，05.；陈娜. 姜黄素类衍生物的合成及活性研究.[学位论文]. 沈阳药科大学，2009, 05; 张同波. 姜黄素衍生物的合成及活性研究. [学位论文]. 沈阳药科大学，2010, 05）。因此，本发明首次明确提出同时改造姜黄素的活性亚甲基和苯环上的取代基二个部位，在姜黄素活性亚甲基的碳原子上插入偕双烃基并对碳碳双键进行了加氢饱和，以消除其长共轭结构及活性亚甲基这一反应位点，从而提高稳定性；在此基础上，为增加水溶性、提高抗肿瘤活性，又在姜黄素的酚羟基上引入亲水性的胺代烷基侧链，合成了本发明所述四氢姜黄素类似物，并经药理试验研究了其抗肿瘤活性。
发明内容：
本发明以姜黄素及其类似物为先导化合物，一方面为提高姜黄素的稳定性，在活性亚甲基碳原子上插入偕双烃基基团并对碳碳双键进行了加氢饱和，从而消除其母核的长共轭结构及亚甲基这一反应活性位点；另一方面，为提高化合物的极性或亲水性、增强其抗癌活性，在姜黄素结构两端的酚羟基上引入亲水性的胺烷基类基团，合成了本发明所述四氢姜黄素类似物，并经药理试验证明可抑制多种肿瘤细胞增值，它们的主要作用为抗肿瘤。
本发明的目的在于提供一种结构新颖的四氢姜黄素类似物及其盐类或它们的溶剂化物。
本发明的第二个的是提供该类似物的制备方法。
本发明的第三个目的是提供含有该类似物的药物组合物。
本发明的第四个目的是提供该类似物的用途，本发明所述四氢姜黄素类似物或组合物可以用于制备各种抗肿瘤的药物。
具体地说，本发明提供的四氢姜黄素类似物具有以下结构：
或其药学上可接受的盐或溶剂化物。
其中，n为0～4，R为甲基、苄基。R1为卤素，或带有取代基的氨基，所述取代基选自：C1-C6烃基；或者带有取代基的哌嗪，所述取代基选自：C1-C6烃基，苯基，苄基，苯基烯丙基，羟基乙基，C1-C6烃基选自甲基，乙基，异丙基，异丁基；或者为吗啉基，四氢吡咯基，哌啶基，4-哌啶基哌啶基。
优选地所述四氢姜黄素类似物，R为甲基、苄基，R1为带有取代基的氨基，所述取代基选自：C1-C2烃基；或者带有取代基的哌嗪，所述取代基选自：甲基，乙基，异丙基，异丁基，苯基，苄基，苯基烯丙基，羟基乙基；或者为吗啉基，四氢吡咯基，哌啶基，4-哌啶基哌啶基。
本发明所提供的实施方案中，本发明的化合物含有碱性基团，则可与酸成盐，采用本领域技术人员所熟知的方法可以制备四氢姜黄素类似物的药用盐。
本发明提供了含上述四氢姜黄素类似物及其药用盐类，其特征在于，所述的药用盐为与合适的非毒性有机酸或无机酸成的盐。
本发明还提供了上述四氢姜黄素类似物的制备方法，其特征在于：通过卤代醚类中间体Ⅱ，与脂肪胺类、取代哌嗪、吗啉、四氢吡咯、哌啶、取代哌啶进行组合反应。
本发明中提供了用于合成四氢姜黄素类似物的合成方法。
本发明上述四氢姜黄素类似物及其药用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。
本发明所述四氢姜黄素类似物具有较好的水溶性，通过MTT法对人宫颈癌细胞HeLa，人肝癌细胞HepG2，人纤维肉瘤细胞HT-1080，人结肠癌细胞HCT116，人黑色素瘤细胞A375-S2，人乳腺癌细胞MCF-7，人肺癌细胞A549，人组织细胞淋巴瘤细胞U-937，人慢性髓原白血病细胞K562，人原髓细胞白血病细胞HL60等十类细胞的体外活性测试，与姜黄素相比，活性和选择性都有很大提高，因此，有可能从中找到治疗肿瘤的新型药物。
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。
实施例1 4, 4-二烃基取代姜黄素的通用合成方法
1）将姜黄素10.0 g (27.06mmol)溶于200 mL的二氯甲烷中，加入7.6 mL(81.48mmol)乙酸酐和6.6 mL (81.48mmol)吡啶，搅拌下升温至回流，反应1 h后，冷却至，用水洗，饱和碳酸氢钠水洗涤，无水硫酸钠干燥，减压浓缩，得到黄色固体。用乙酸乙酯和石油醚重结晶，得到O, O’-二乙酰姜黄素黄色晶状固体9.8g，产率95%，mp:168~6170℃。
2）将35.4mmol O，O’-二乙酰姜黄素溶于50 mL的丙酮中置于250 mL茄形瓶中，加入无水碳酸钾 106.2mmol，搅拌下升温至回流，滴加卤代烷106.2mmol，加毕继续反应。待反应完成后，冷却至，过滤除去碳酸钾。将滤液减压浓缩，剩余物用丙酮和乙醇重结晶，得到晶状固体（O, O’-二乙酰-4, 4-二烃基姜黄素）。
3）将0.1 mol O, O’-二乙酰-4, 4-二烃基姜黄素溶于适量的无水甲醇，置于250mL茄形瓶中，加入氢氧化钠0.25mol，搅拌下升温至35℃。待反应完成后，减压蒸出甲醇。将残余物溶于适量二氯甲烷中，用乙酸将溶液调至中性，用大量水洗。将有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，剩余物用乙酸乙酯和石油醚重结晶，得到4, 4-二烃基姜黄素。
按此合成方法得到：
4, 4-二甲基姜黄素(1)；4, 4-二苄基姜黄素(2)
4，4-二甲基姜黄素：黄色固体，熔点 136-138°C。1H-NMR (300 MHz) δ: 1.47(6H, s), 3.91 (6H, s), 6.62 (d, J = 15.6 Hz, 2H), 6.89 (2H, d, J = 8.4 Hz),6.99 (2H, d, J = 1.8 Hz), 7.09 (2H, dd, J = 1.8, 8.4 Hz), 7.66 (2H, d, J =15.6 Hz)。
4, 4-二苄基姜黄素：黄色固体，熔点115-117°C。1H-NMR (600 MHz): δ3.38 (4H,s), 3.86 (6H, s), 6.54 (2H, d, J = 15.6 Hz), 6.86 (4H, m), 7.03 (2H, dd, J =1.8, 7.8 Hz), 7.10 (4H, m), 7.17 (2H, m), 7.21 (4H, m), 7.69 (2H, d, J = 15.6Hz)。
实施例2 4, 4-二甲基四氢姜黄素(3)合成方法
将0.01mol 4, 4-二甲基姜黄素溶于50 ml乙醇中，加入0.5g 10%的Pd/C，室温下常压氢化，反应12小时后处理，得到黄色固体，熔点：55-58°C。1H-NMR (300 MHz) δ: 1.47(6H, s), 2.55 (4H, m), 2.69 (4H, m), 3.83 (6H, s), 6.55 (4H, m), 6.79 (2H, d,J = 8.4 Hz)。
实施例3 4, 4-二苄基四氢姜黄素(4)合成方法
将0.01mol 4, 4-二苄基姜黄素溶于50 ml乙醇中，加入0.5g 10%的Pd/C，室温下常压氢化，反应12小时后处理，得到黄色固体，熔点：73-75°C。1H-NMR (300 MHz) δ: 2.55(4H, m), 2.69 (4H, m), 3.31 (4H, s), 3.83 (6H, s), 6.55 (4H, m), 6.79 (2H, d,J = 8.4 Hz), 6.93 (4H, m), 7.21 (6H, m)。
实施例4 式Ⅱ化合物4, 4-二烃基四氢姜黄素卤代醚类化合物通用合成方法
将12.0mmol 4, 4-二烃基四氢姜黄素溶于适量乙腈中，加入36.0mmol无水碳酸钾，回流反应0.5h后，滴加36.0mmol的二卤代物（用5 mL乙腈稀释），在15 min内滴加完毕，继续反应。待反应完成后，过滤除去碳酸钾，减压浓缩滤液至油状。将油状物溶于适量的DMF中，慢慢滴加到大量的冰水混合物中，并剧烈搅拌过夜。过滤，得到式Ⅱ化合物卤代醚类中间体，用乙酸乙酯和石油醚重结晶，得到晶状固体。
按此合成方法得到：
O, O’-二(2-溴乙基)-4, 4-二甲基四氢姜黄素（Ⅱ-1）；
O, O’-二(3-氯丙基)-4, 4-二甲基四氢姜黄素（Ⅱ-2）；
O, O’-二(2-溴乙基)-4, 4-二苄基四氢姜黄素（Ⅱ-3）；
O, O’-二(3-氯丙基)-4, 4-二苄基四氢姜黄素（Ⅱ-4）
O, O’-二(2-溴乙基)-4, 4-二甲基四氢姜黄素（Ⅱ-1）：白色固体，熔点：85-88°C。1H-NMR (300 MHz) δ: 1.48 (6H, s), 2.56 (8H, m), 2.69 (8H, m), 3.82 (6H, s),6.55 (4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(3-氯丙基)-4, 4-二甲基四氢姜黄素（Ⅱ-2）：白色固体，熔点：76-78°C。1H-NMR (300 MHz) δ: 1.48 (6H, s), 2.25 (4H, m), 2.58 (4H, m), 2.71 (4H, m),3.75 (4H, t, J = 6.3 Hz), 3.82 (6H, s), 4.11 (4H, t, J = 6.3 Hz), 6.55 (4H,m), 6.80 (2H, d, J = 8.4 Hz)。
O, O’-二(2-溴乙基)-4, 4-二苄基四氢姜黄素（Ⅱ-3）：白色固体，熔点：148-150°C。1H-NMR (300 MHz) δ:2.58 (4H, m), 2.71 (4H, m), 3.31 (4H, s), 3.74 (4H, t, J= 6.3 Hz), 3.82 (6H, s), 4.11 (4H, t, J = 6.3 Hz), 6.59 (4H, m), 6.79 (2H, d,J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(3-氯丙基)-4, 4-二苄基四氢姜黄素（Ⅱ-4）：白色固体，熔点：95-97°C。1H-NMR (300 MHz) δ:2.25 (4H, m), 2.58 (4H, m), 2.71 (4H, m), 3.31 (4H, s),3.75 (4H, t, J = 6.3 Hz), 3.82 (6H, s), 4.11 (4H, t, J = 6.3 Hz), 6.59 (4H,m), 6.79 (2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
实施例5 式Ⅰ化合物O, O’-二胺基烷基-4, 4-二烃基四氢姜黄素的通用合成方法
将实施例4中式Ⅱ化合物1.43 mmol、碳酸钾7.15mmol、N-取代哌嗪或取代仲胺7.15 mmol溶于10mL乙腈中，加热回流5 h。过滤除去碳酸钾，减压蒸去乙腈，剩余物溶于30mL二氯甲烷中，用3N盐酸溶液洗涤(30 mL×3)，合并酸液，用碳酸钠中和至pH9.0~10.0，二氯甲烷萃取(30 mL×5)，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，所得油状物经硅胶柱色谱分离纯化(洗脱剂为二氯甲烷-甲醇)，得到式Ⅰ化合物。
按此合成方法得到：
O, O’-二(2-二甲氨基乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-1）；
O, O’-二(2-二乙氨基乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-2）；
O, O’-二(2-(吡咯-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-3）；
O, O’-二(2-(哌啶-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-4）；
O, O’-二(2-吗啉基乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-5）；
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-6）；
O, O’-二(3-二甲氨基丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-7）；
O, O’-二(3-二乙氨基丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-8）；
O, O’-二(3-(吡咯-1-基)丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-9）；
O, O’-二(3-(哌啶-1-基)丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-10）；
O, O’-二(2-吗啉基丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-11）；
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-12）；
O, O’-二(2-二甲氨基乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-13）；
O, O’-二(2-二乙氨基乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-14）；
O, O’-二(2-(吡咯-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-15）；
O, O’-二(2-(哌啶-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-16）；
O, O’-二(2-吗啉基乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-17）；
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-18）；
O, O’-二(3-二甲氨基丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-19）；
O, O’-二(3-二乙氨基丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-20）；
O, O’-二(3-(吡咯-1-基)丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-21）；
O, O’-二(3-(哌啶-1-基)丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-22）；
O, O’-二(2-吗啉基丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-23）；
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-24）；
O, O’-二(2-二甲氨基乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-1）：黄色油状物，1H-NMR(300 MHz) δ:1.48 (6H, s), 2.26 (12H, s), 2.47 (4H, t, J = 6.6 Hz), 2.59 (4H,m), 2.70 (4H, m), 3.82 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79(2H, d, J = 8.4 Hz)。
O, O’-二(2-二乙氨基乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-2）：黄色油状物，1H-NMR(300 MHz) δ:1.07 (12H, t, J = 7.2 Hz), 1.48 (6H, s), 2.61 (12H, m), 2.68 (8H,m), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J =8.4 Hz)。
O, O’-二(2-(吡咯-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-3）：黄色油状物，1H-NMR (300 MHz) δ:1.48 (6H, s), 1.81 (8H, m), 2.58 (12H, m), 2.68 (8H, m), 3.81(6H, s), 4.04 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(2-(哌啶-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-4）：黄色油状物，1H-NMR (300 MHz) δ:1.45 (4H, m), 1.48 (6H, s), 1.59 (8H, m), 2.40 (8H, m), 2.49(4H, t, J = 7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(2-吗啉基乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-5）：黄色油状物，1H-NMR(300 MHz) δ:1.48 (6H, s), 2.46 (8H, m), 2.51 (4H, t, J = 6.9 Hz), 2.59 (4H,m), 2.71 (4H, m), 3.71 (8H, m), 3.82 (6H, s), 4.03 (4H, t, J = 6.6 Hz), 6.55(4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-6）：黄色油状物，1H-NMR (300 MHz) δ: 1.48 (6H, s), 2.28 (6H, s), 2.52 (20H, m), 2.60 (8H,m), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J =8.4 Hz)。
O, O’-二(3-二甲氨基丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-7）：黄色油状物，1H-NMR(300 MHz) δ:1.48 (6H, s), 1.95-2.04 (4H, m), 2.26 (12H, s), 2.47 (4H, t, J =7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.82 (6H, s), 4.02 (4H, t, J = 6.6 Hz),6.55 (4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(3-二乙氨基丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-8）：黄色油状物，1H-NMR(300 MHz) δ:1.07 (12H, t, J = 7.2 Hz),1.48 (6H, s), 2.61 (12H, m), 2.68 (8H,m), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J =8.4 Hz)。
O, O’-二(3-(吡咯-1-基)丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-9）：黄色油状物，1H-NMR (300 MHz) δ:1.48 (6H, s), 1.81 (8H, m), 2.51 (2H, m), 2.58 (12H, m), 2.68(8H, m), 3.82 (6H, s), 4.04 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J= 8.4 Hz)。
O, O’-二(3-(哌啶-1-基)丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-10）：黄色油状物，1H-NMR (300 MHz) δ:1.45 (4H, m), 1.48 (6H, s), 1.59 (8H, m), 2.01 (4H, m),2.40 (8H, m), 2.49 (4H, t, J = 7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.81 (6H,s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(2-吗啉基丙基)-4, 4-二甲基四氢姜黄素（Ⅰ-11）：黄色油状物，1H-NMR(300 MHz) δ:1.48 (6H, s), 1.99 (4H, m), 2.46 (8H, m), 2.51 (4H, t, J = 6.9Hz), 2.59 (4H, m), 2.71 (4H, m), 3.71 (8H, m), 3.82 (6H, s), 4.03 (4H, t, J =6.6 Hz), 6.55 (4H, m), 6.79 (2H, d, J = 8.4 Hz)。
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二甲基四氢姜黄素（Ⅰ-12）：黄色油状物，1H-NMR (300 MHz) δ: 1.48 (6H, s), 1.99 (4H, m), 2.28 (6H, s), 2.52 (20H,m), 2.60 (8H, m), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.55 (4H, m), 6.79(2H, d, J = 8.4 Hz)。
O, O’-二(2-二甲氨基乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-13）：黄色油状物，1H-NMR (300 MHz) δ:2.26 (12H, s), 2.47 (4H, t, J = 7.2 Hz), 2.59 (4H, m), 2.70(4H, m), 3.31 (4H, s), 3.82 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.58 (4H, m,),6.78 (2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(2-二乙氨基乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-14）：黄色油状物，1H-NMR (300 MHz) δ:1.07 (12H, t, J = 7.2 Hz), 2.61 (12H, m), 2.68 (8H, m), 3.31(4H, s), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.58 (4H, m), 6.77 (2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(2-(吡咯-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-15）：黄色油状物，1H-NMR (300 MHz) δ:1.81 (8H, m), 2.51 (2H, m), 2.58 (12H, m), 2.68 (8H, m),3.31 (4H, s), 3.82 (6H, s), 4.04 (4H, t, J = 6.6 Hz), 6.58 (4H, m), 6.78 (2H,d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(2-(哌啶-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-16）：黄色油状物，1H-NMR (300 MHz) δ:1.45 (4H, m), 1.59 (8H, m), 2.40 (8H, m), 2.49 (4H, t, J =7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t,J = 6.6 Hz), 6.58 (4H, m), 6.78 (2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H,m)。
O, O’-二(2-吗啉基乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-17）：黄色油状物，1H-NMR(300 MHz) δ:2.46 (8H, m), 2.51 (4H, t, J = 6.9 Hz), 2.59 (4H, m), 2.71 (4H,m), 3.31 (4H, s), 3.71 (8H, m), 3.82 (6H, s), 4.03 (4H, t, J = 6.6 Hz), 6.59(4H, m), 6.78 (2H, d, J = 8.7 Hz), 6.93 (4H, m), 7.21 (6H, m)。
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-18）：黄色油状物，1H-NMR (300 MHz) δ: 2.28 (6H, s), 2.52 (20H, m), 2.60 (8H, m), 3.31 (4H,s), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.58 (4H, m), 6.78 (2H, d, J =8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(3-二甲氨基丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-19）：黄色油状物，1H-NMR (300 MHz) δ:1.95-2.04 (4H, m), 2.26 (12H, s), 2.47 (4H, t, J = 7.2 Hz),2.59 (4H, m), 2.70 (4H, m), 3.31 (4H, s), 3.82 (6H, s), 4.02 (4H, t, J = 6.6Hz), 6.58 (4H, m,), 6.78 (2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(3-二乙氨基丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-20）：黄色油状物，1H-NMR (300 MHz) δ:1.07 (12H, t, J = 7.2 Hz), 2.00 (4H, m), 2.61 (12H, m), 2.68(8H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.58 (4H, m),6.77 (2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(3-(吡咯-1-基)丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-21）：黄色油状物，1H-NMR (300 MHz) δ:1.81 (8H, m), 2.51 (4H, m), 2.58 (12H, m), 2.68 (8H, m),3.31 (4H, s), 3.82 (6H, s), 4.04 (4H, t, J = 6.6 Hz), 6.58 (4H, m), 6.78 (2H,d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
O, O’-二(3-(哌啶-1-基)丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-22）：黄色油状物，1H-NMR (300 MHz) δ:1.45 (4H, m), 1.59 (8H, m), 2.01 (4H, m), 2.40 (8H, m),2.49 (4H, t, J = 7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.31 (4H, s), 3.81 (6H,s), 4.02 (4H, t, J = 6.6 Hz), 6.58 (4H, m), 6.78 (2H, d, J = 8.7 Hz), 6.94(4H, m), 7.21 (6H, m)。
O, O’-二(2-吗啉基丙基)-4, 4-二苄基四氢姜黄素（Ⅰ-23）：黄色油状物，1H-NMR(300 MHz) δ:1.99 (4H, m), 2.46 (8H, m), 2.51 (4H, t, J = 6.9 Hz), 2.59 (4H,m), 2.71 (4H, m), 3.31 (4H, s), 3.71 (8H, m), 3.82 (6H, s), 4.03 (4H, t, J =6.6 Hz), 6.59 (4H, m), 6.78 (2H, d, J = 8.7 Hz), 6.93 (4H, m), 7.21 (6H, m)。
O, O’-二(2-(4-甲基哌嗪-1-基)乙基)-4, 4-二苄基四氢姜黄素（Ⅰ-24）：黄色油状物，1H-NMR (300 MHz) δ: 1.99 (4H, m), 2.28 (6H, s), 2.52 (20H, m), 2.60 (8H,m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t, J = 6.6 Hz), 6.58 (4H, m), 6.78(2H, d, J = 8.7 Hz), 6.94 (4H, m), 7.21 (6H, m)。
实施例6 式Ⅰ化合物O, O’-二胺基烷基-4, 4-二烃基四氢姜黄素盐酸盐的通用合成方法
将实施例5中得到的式Ⅰ化合物溶于适量的丙酮中，搅拌下，滴加氯化氢乙醚溶液，析出白色的固体产物，抽滤，用少量丙酮洗涤，干燥，得到O, O’-二胺基烷基-4, 4-二烃基四氢姜黄素盐酸盐。
实施例7
用MTT法测定了目标化合物对对人宫颈癌细胞HeLa，人肝癌细胞HepG2，人纤维肉瘤细胞HT-1080，人结肠癌细胞HCT116，人黑色素瘤细胞A375-S2，人乳腺癌细胞MCF-7，人肺癌细胞A549，人组织细胞淋巴瘤细胞U-937，人慢性髓原白血病细胞K562，人原髓细胞白血病细胞HL60等十类肿瘤细胞的增殖抑制作用。
1）贴壁细胞 选用对数生长期的贴壁肿瘤细胞，用胰酶消化后，用含10％小牛血清的RPMI l640培养基配成5×104/ml的细胞悬液，接种在96孔培养板中，每孔100 μl，37℃，5％CO2 培养24 h。实验组更换新的含不同浓度被测样品（10~100 μmol•L-1）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 培养48 h。弃去上清液，用PBS小心洗2次，每孔加入100 μl新鲜配制的含0.5 mg/ml MTT的培养基，37℃继续培养4 h。小心弃去上清，并加入150 μl DMSO，用微型振荡器混匀10 min后，用酶标仪在492nm处测定光密度值(OD)。
2）悬浮细胞 选用对数生长期的细胞，用含10％小牛血清的RPMI l640培养基配成1×104/ml的细胞悬液，接种在96孔培养板中，每孔50 μl，37℃，5％CO2 培养24 h。实验组加入含不同浓度被测样品（10~100 μmol•L-1）的培养液50 μl，对照组则加入含等体积溶剂的培养液，每组设3个平行孔，37℃，5％CO2 培养48 h，每孔加入10 μl新鲜配制的含5 mg/mlMTT的培养基，37℃继续培养4 h。用三联液（SDS 10 g ，10 M HCl 0.1 mL，异丁醇 5 mL，用蒸馏水稀释至100 mL）100μl溶解结晶， 37℃孵育12 h。用酶标仪在492 nm处测定光密度值(OD)。
按以下公式计算药物对肿瘤细胞体外增殖的抑制率（Inhibition Rate，IR%）：
IR%=（1-ODsample/ODcontrol）´ 100%
用ICP1.0.0软件计算药物的半数抑制浓度（IC50）。
结果见下表，表明与姜黄素比较，这些目标化合物抑制肿瘤细胞株的IC50值有所提高，因此这类化合物有望开发成为治疗抗肿瘤的药物。
。

Claims (9)

1.具有式Ⅰ结构的四氢姜黄素类似物或其盐：
其中，n为0～4，R为甲基、苄基，R1为吗啉基，四氢吡咯基，哌啶基，4-哌啶基哌啶基或带有取代基的氨基，所述取代基选自：C1-C6烃基；或者带有取代基的哌嗪，所述取代基选自：C1-C6烃基，苯基，苄基，苯基烯丙基，羟基乙基。
2.权利要求1所述的四氢姜黄素类似物或其盐：
其中，R1为带有取代基的氨基，所述取代基选自：C1-C2烃基。
3.权利要求1所述的四氢姜黄素类似物或其盐：
其中，C1-C6烃基为甲基，乙基，异丙基，异丁基。
4.四氢姜黄素类似物或其盐，选自：
O,O’-二(2-二甲氨基乙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-二乙氨基乙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-(吡咯-1-基)乙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-(哌啶-1-基)乙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-吗啉基乙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-(4-甲基哌嗪-1-基)乙基)-4,4-二甲基四氢姜黄素
O,O’-二(3-二甲氨基丙基)-4,4-二甲基四氢姜黄素
O,O’-二(3-二乙氨基丙基)-4,4-二甲基四氢姜黄素
O,O’-二(3-(吡咯-1-基)丙基)-4,4-二甲基四氢姜黄素
O,O’-二(3-(哌啶-1-基)丙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-吗啉基丙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-(4-甲基哌嗪-1-基)乙基)-4,4-二甲基四氢姜黄素
O,O’-二(2-二甲氨基乙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-二乙氨基乙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-(吡咯-1-基)乙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-(哌啶-1-基)乙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-吗啉基乙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-(4-甲基哌嗪-1-基)乙基)-4,4-二苄基四氢姜黄素
O,O’-二(3-二甲氨基丙基)-4,4-二苄基四氢姜黄素
O,O’-二(3-二乙氨基丙基)-4,4-二苄基四氢姜黄素
O,O’-二(3-(吡咯-1-基)丙基)-4,4-二苄基四氢姜黄素
O,O’-二(3-(哌啶-1-基)丙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-吗啉基丙基)-4,4-二苄基四氢姜黄素
O,O’-二(2-(4-甲基哌嗪-1-基)乙基)-4,4-二苄基四氢姜黄素。
5.权利要求1所述有四氢姜黄素类似物或其盐，其中，所述的盐为与合适的非毒性有机酸或无机酸成的盐。
6.一种药物组合物，包含权利要求1所述的四氢姜黄素类似物或其盐为活性成分和药学上可接受的赋形剂。
7.一种权利要求1所述式Ⅰ化合物的合成方法，该方法包括：4,4-二烃基四氢姜黄素(Ⅲ)与卤代烷反应，生成中间体4,4-二烃基四氢姜黄素卤代醚(Ⅱ)，再与脂肪仲胺或杂环胺反应，得到式Ⅰ化合物；
其中，n为0～4，R为甲基、苄基，X为Cl、Br，R1为吗啉基，四氢吡咯基，哌啶基，4-哌啶基哌啶基或带有取代基的氨基，所述取代基选自：C1-C6烃基；或者带有取代基的哌嗪，所述取代基选自：C1-C6烃基，苯基，苄基，苯基烯丙基，羟基乙基。
8.权利要求1-5任何一项所述四氢姜黄素类似物或其盐或权利要求6所述的药物组合物在在制备抗肿瘤药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的肿瘤为宫颈癌、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。
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