CN104945334B - 紫苏醇衍生物及其制备和应用 - Google Patents

紫苏醇衍生物及其制备和应用 Download PDF

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CN104945334B
CN104945334B CN201410119760.4A CN201410119760A CN104945334B CN 104945334 B CN104945334 B CN 104945334B CN 201410119760 A CN201410119760 A CN 201410119760A CN 104945334 B CN104945334 B CN 104945334B
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perilla alcohol
salt
alcohol derivant
cancer
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CN104945334A (zh
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惠子
董金华
张美慧
夏明钰
徐莉英
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Shenyang Pharmaceutical University
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    • 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

Abstract

本发明属于医药技术领域，涉及一系列紫苏醇衍生物及其制备和应用，具有如式Ⅰ结构特征。本发明还包括所述紫苏醇衍生物药学上可接受的盐和溶剂化物，含有所述紫苏醇衍生物或其药学上可接受的盐作为活性成分的药物组合物，并用于治疗癌症。本发明所述的紫苏醇衍生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

紫苏醇衍生物及其制备和应用
技术领域：
本发明涉及一系列新的紫苏醇衍生物，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紫苏醇衍生物的中间体的制备方法。
背景技术：
紫苏醇（perillyl alcohol）为异戊二烯萜类挥发油，广泛存在于紫苏叶、柑桔、樱桃、薄荷等植物中，可以诱导细胞凋亡、抑制肿瘤细胞增殖、诱导肿瘤细胞再分化，是目前已知的少数几个对肿瘤既有化学预防作用又有化学治疗作用的天然产物（胡东,陈燕.食物来源单萜类物质紫苏醇的抗癌作用[J].临床血液杂志，2001,14(3):141-143）。在肿瘤形成初始阶段，紫苏醇不仅能降低动物模型中肿瘤的发生几率，还能减少肿瘤发生种类，对食道癌（Liston B W,Nines R,Carlton P S,et a1.Perillyl alcohol as a chemopreventiveagent in N-nitro-somethylvenzylamine-induced rat esophageal tumorigenesis[J].Cancer Research,2003,63(10):2399-2403）、结肠直肠癌（Meadows S M,Mulkerin D,Berlin J,et al.Phase II trial of perillyl alcohol with metastatic colorectalcancer[J].International Journal of Gastrointestinal Cancer,2002,32(2-3):125-128）、胰腺癌（Lebedeva I V,Suzz,Vozhilla N,et al.Mechanism of in vitropancreatic cancer cell growth inhibition by melanoma differentiation-associated gene7/interleuk in-24and perillyl alcohol[J].Cancer Research,2008,68(18):7439-7447）和乳腺癌（Yuri T,Danbara N,Tsujita-Kyutoku M,et al.Perillylalcohol inhibits human breast cancer cell growth in vitro and in vivo[J].Breast Cancer Research and Treatment,2004,84(3):251-260,）等肿瘤均有预防和治疗作用，效果显著。在国外已作为抗肿瘤药物进入临床Ⅰ期和临床Ⅱ期研究阶段（Liu G,Oettel K,Ummersen L V,et al.Phase II trial of perilly alcohol (NSC641066)administered daily in patients with metastatic androgen independent prostatecancer[J].Investigational New Drugs,2003,21(3):367-372.Bailey H H,Attia S,Love R R,et al.Phase II trial of daily oral perillyl alcohol(NSC641066)intreatment-refractory metastatic breast cancer[J].Cancer Chemother Pharmacol,2008,62(1):149-157.da Fonseca C O,Schwartsmann G,Fischer J,et al.Preliminaryresults from a phase I/II study of perillyl alcohol intranasal administrationin adults with recurrent maligant gliomas[J].Surgical Neurology,2008,70(3):259-266.）。
国内外对紫苏醇衍生物的化学修饰仅限于三方面：①将紫苏醇的环外羟基以维A酸酯化，合成维A酸类衍生物,目前未见该类衍生物的药理活性报道（Das B C,MahalingamS M,Panda L,et al.Design and synthesis of potential new apoptosis agents:hybrid compounds containing perillyl alcohol and new constrained retinoids[J].Tetrahedron Letters,2010,51(11):1462–1466）。②将紫苏醇环外羟基和葡萄糖成苷键，合成葡萄糖类衍生物，该类衍生物对小鼠肺癌细胞的抑制活性较紫苏醇略高（Xanthakis E,Magkouta S,Loutrari H,et al.Enzymatic synthesis of perillylalcohol derivatives and investigation of their antiproliferative activity[J].Biocatalysis and Biotransformation,2009,27(3):170-178.）。③在羟基α-碳原子上引入磷酸酯结构或将羟基用磷酸酯结构取代。该类化合物对法尼基转移酶和小鼠胚胎成纤维细胞NIH-3T3未见明显抑制作用（Eummer J T,Gibbs B S,Zahn T J.et al.Novellimonene phosphonate and farnesyl diphosphate analogues:design,synthesis,andevaluation as potential protein-farnesyl transferase inhibitors[J].Bioorganic&Medicinal Chemistry,1999,7(2):241-250.）。
紫苏醇水溶性差，口服给药生物利用度低，限制了其临床应用（Liu G,Oettel K,Ummersen L V,,et al.Phase II trial of perilly alcohol(NSC641066)administereddaily in patients with metastatic androgen independent prostate cancer[J].Investigational New Drugs,2003,21(3):367-372.Bailey H H,Attia S,Love R R,etal.Phase II trial of daily oral perillyl alcohol(NSC641066)in treatment-refractory metastatic breast cancer[J].Cancer Chemother Pharmacol,2008,62(1):149-157.）。针对以上问题，借鉴本课题组前期对榄香烯、柠檬烯衍生物抗癌构效关系的研究结果，认为增强化合物的极性和水溶性有利于提高抗肿瘤活性（陈娇娇,董金华,景永奎,等.柠檬烯类似物及其制备方法和用途[P].中国专利,200610081622.7,公开号CN101070300.董金华,徐莉英,景永奎,等.一种β-榄香烯含氮衍生物的制备及应用[P].中国专利,200610080037.5,公开号CN1844105.徐莉英,董金华,景永奎,等.β-榄香烯含氮衍生物及其制备方法和用途[P].中国专利,200610081625.0,公开号CN1850779.）。因此，本发明首次明确提出保持紫苏醇的含双键的单环单萜骨架，在环外烯丙位引入亲水性的含氮基团，从而改善水溶性，提高抗肿瘤活性，合成了本发明所述紫苏醇衍生物，并经药理试验研究了其抗肿瘤活性。
发明内容：
本发明以紫苏醇为先导化合物，为提高化合物的极性或亲水性、增强其抗癌活性，在环外烯丙位引入亲水性的胺类基团，合成了紫苏醇衍生物，并经药理试验证明可抑制多种肿瘤细胞增殖，它们的主要作用为抗肿瘤。
本发明提供紫苏醇衍生物结构如下式I：
其中，R1、R2为氢、C1-C12烷基，含有含氮杂环和甲氧甲酰基的C1-C12烷基，含氮原子的5-12元芳基；或NR1R2为5-10元含氮杂环，或NR1R2为带有取代基的哌嗪基，所述取代基选自：C1-C12烷基、C1-C6烷氧基苯基、含有烯键的C1-C6烷基、含有炔键的C1-C6烷基、含有羟基的C1-C6烷基、含有苯基的C1-C6烷基；含氮5-10元杂环；C1-C6烷基、C3-C7环烷基取代的氨基。
优选地，R1、R2为氢、C1-C6烷基，含有含氮杂环和甲氧甲酰基的C1-C6烷基，含氮原子的5-9元芳基；或NR1R2为带有取代基的哌嗪基，所述取代基选自：C1-C6烷基、C1-C4烷氧基苯基、含有烯键的C1-C4烷基、含有炔键的C1-C4烷基、含有羟基的C1-C4烷基、含有苯基的C1-C4烷基；含氮5-10元杂环；C1-C4烷基、C5-C6环烷基取代的氨基。
更为优选地：R1、R2为氢、C1-C4烷基，含有含氮杂环和甲氧甲酰基的C1-C2烷基，含氮原子的5-6元芳基；或NR1R2为带有取代基的哌嗪基，所述取代基选自：C1-C4烷基、C1-C4烷氧基苯基、含有苯基的C1-C4烷基；含氮的5-6元杂环。
本发明优选如下化合物：
本发明提供紫苏醇衍生物及其药用盐的制备方法，合成路线如下：
NR1R2如权利要求所述。
优选：
本发明所述紫苏醇衍生物及其盐的制备过程中所用溶剂为常用的反应溶剂，无特殊要求。
所述的盐指常规的酸加成盐，所述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，马来酸等。
本发明提供了一种药物组合物，所述组合物由上述的紫苏醇衍生物及其盐类和药学上可被接受的赋形剂组成。发明还提供了所述紫苏醇衍生物及其药用盐类及其组合物在制备抗癌药物中的用途。
本发明所描述的紫苏醇衍生物，是为改善紫苏醇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。
本发明的紫苏醇衍生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。
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紫苏醇的合成
将0.1mol紫苏醛溶于100mL无水乙醇中，冰浴下分批加入0.2molNaBH4，加毕后室温反应3h。减压蒸除乙醇，加入30mL水和30mL二氯甲烷，转移至分液漏斗中，分出有机相，水相用二氯甲烷萃取，合并有机相，用水和饱和盐水洗涤，无水硫酸钠干燥。浓缩后得紫苏醇无色透明液体，收率86.8%。
实施例2的合成
将25mL醋酸酐滴加至0.08mol实施例1产物的25mL吡啶溶液中，室温反应4h。加入2mL甲醇，50mL乙酸乙酯，转移至分液漏斗中，分出有机相，用饱和碳酸氢钠和饱和盐水洗涤，无水硫酸钠干燥。浓缩得无色透明液体，收率95.4%。
实施例3的合成
将0.06mol实施例2产物和0.09mol冰醋酸溶于150mL二氯甲烷中，冰浴下缓慢滴加0.24mol次氯酸钠水溶液（含有效氯10%）。加毕继续反应30min。加50mLNa2SO3水溶液，分出有机层，水层用二氯甲烷萃取，合并有机相，用水和饱和NaCl溶液洗涤，无水硫酸钠干燥。浓缩得淡黄色液体，收率85.9%。
实施例4紫苏醇衍生物的合成通法
将4mmol实施例3产物和8mmol碳酸钾溶于10mL丙酮中。搅拌下滴加4.4mmol胺类化合物，加热回流反应8h-12h。减压蒸除丙酮，加入10mL饱和盐水，转移至分液漏斗中，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥。浓缩后得化合物1-11。
按此合成方法得到：
化合物1：淡黄色固体。熔点106-109℃。MS(EI)[M+H]+m/z:265.2274.1H NMR(300MHz,CDCl3)δ(ppm)：5.70(1H,br s),4.95,4.89(2H,s,s),4.00(2H,s),3.05-2.85(4H,m),2.81-2.70(2H,m),2.32-2.17(2H,m),2.15-1.83(4H,m),1.69-1.43(3H,m),1.12(6H,d,J=6.4Hz).
化合物2：白色固体。熔点58-59℃。MS(EI)[M+H]+m/z:343.2381.1H NMR(300MHz,CDCl3)δ(ppm)：6.93–6.79(4H,m),5.70(1H,br s),5.00,4.92(2H,s,s),4.00(2H,s),3.76(3H,s),3.18-2.93(6H,m),2.65-2.45(4H,m),2.37-1.86(6H,m),1.60-1.49(1H,m).
化合物3：淡黄色油状物。MS(EI)[M+H]+m/z:343.2380.1H NMR(300MHz,CDCl3)δ(ppm)7.04–6.79(4H,m),5.71(1H,br s),5.01,4.92(2H,s,s),4.01(2H,s),3.86(3H,s),3.19–2.89(6H,m),2.79–2.40(4H,m),2.38–1.84(6H,m),1.61–1.48(1H,m).
化合物4：粉白色固体。熔点54-55℃。MS(EI)[M+H]+m/z:251.2118.1H NMR(300MHz,CDCl3)δ(ppm)：5.70(1H,br s),4.96,4.88(2H,s,s),4.01(2H,s),2.94(2H,s),2.56-2.33(6H,m),2.30(3H,s),2.29–2.17(3H,m),2.15–2.08(2H,m),2.03-1.84(3H,m),1.56–1.47(1H,m).
化合物5：淡黄色固体。熔点52-53℃。MS(EI)[M+H]+m/z:279.2430.1H NMR(300MHz,CDCl3)δ(ppm)：5.71(1H,br s),4.97,4.89(2H,s,s),4.02(2H,s),2.95(2H,s),2.76–2.30(9H,m),2.27–2.22(1H,m),2.17–2.09(2H,m),2.05–1.84(3H,m),1.57–1.50(1H,m),1.09(6H,d,J=6.5Hz).
化合物6：淡黄色油状物。MS(EI)[M+H]+m/z:327.2431.1H NMR(300MHz,CDCl3)δ(ppm):7.34–7.21(5H,m),5.69(1H,br s),4.94,4.88(2H,s,s),4.00(2H,s),3.51(2H,s),2.98–2.88(2H,m),2.63–2.31(8H,m),2.30-2.07(4H,m),2.01–1.83(2H,m),1.56–1.44(1H,m).
化合物7：淡黄色油状物。MS(EI)[M+H]+m/z:196.1697.1H NMR(300MHz,CDCl3)δ(ppm):5.70(1H,br s),4.95,4.88(2H,s,s),3.99(2H,s),2.93–2.80(2H,m),2.35–2.21(2H,m),2.19(6H,s),2.16–2.08(2H,m),2.02–1.84(2H,m),1.56–1.44(1H,m).
化合物8：淡黄色油状物。MS(EI)[M+H]+m/z:196.1697.236.2009.1H NMR(300MHz,CDCl3)δ(ppm):5.70(1H,br s),4.96,4.87(2H,s,s),4.00(2H,s),2.90(2H,s),2.41–2.08(8H,m),2.01–1.84(2H,m),1.59–1.41(7H,m).
化合物9:淡黄色油状物。MS(EI)[M+H]+m/z:245.1648.1H NMR(300MHz,CDCl3)δ(ppm):8.07(1H,d,J=3.9Hz),7.46–7.39(1H,m),6.65–6.49(1H,m),6.36(1H,d,J=8.4Hz),5.71(1H,br s),5.03,4.92(2H,s,s),4.01(2H,s),3.95-3.85(2H,m),2.34–1.88(6H,m),1.62–1.51(1H,m).
化合物10:淡黄色固体。熔点58-60℃。MS(EI)[M+H]+m/z:246.1601.1H NMR(300MHz,CDCl3)δ(ppm):8.28(2H,d,J=4.8Hz),6.55(1H,t,J=4.8Hz),5.71(1H,br s),5.02,4.91(2H,s,s),4.18–4.05(2H,m),4.01(2H,s),2.31–1.95(6H,m),1.59–1.51(1H,m).
化合物11:淡黄色油状物。MS(EI)[M+H]+m/z:369.2173.1H NMR(300MHz,CDCl3)δ(ppm):7.61(1H,d,J=7.8Hz,),7.34(1H,d,J=7.9Hz),7.21–7.05(3H,m),5.62(1H,br s),4.88,4.80(2H,s,s),3.97(2H,s),3.65(3H,s),3.28–3.20(1H,m),3.15–3.04(2H,m),2.14–1.65(8H,m),1.46-1.34(1H,m,).
实施例5
用MTT法测定了目标化合物对人肺癌细胞A549，人黑色素瘤细胞A375-S2和人纤维肉瘤细胞HT-1080三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100μl，37℃，5％CO2培养24h。实验组更换新的含不同浓度被测样品（10～100μmol·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48h。弃去上清液，用PBS小心洗2次，每孔加入100μl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150μl DMSO，用微型振荡器混匀10min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50μl，37℃，5％CO2培养24h。实验组加入含不同浓度被测样品（10～100μmol·L-1）的培养液50μl，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48h，每孔加入10μl新鲜配制的含5mg/ml MTT的培养基，37℃继续培养4h。用三联液（SDS10g，10M HCl0.1mL，异丁醇5mL，用蒸馏水稀释至100mL）100μl溶解结晶，37℃孵育12h。用酶标仪在492nm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，与紫苏醇比较，除化合物4、5、7和8外，目标化合物抑制三种肿瘤细胞株的IC50值均有所降低，因此在紫苏醇结构中引入含氮基团可以提高紫苏醇的体外抗肿瘤活性。
表1式Ⅰ化合物和紫苏醇对肿瘤细胞的IC50值

Claims (6)

1.如下的紫苏醇衍生物及其盐：
2.一种如权利要求1所述的紫苏醇衍生物及其盐的制备方法，其特征在于：合成路线如下：
3.按照权利要求1所述紫苏醇衍生物及其盐，其特征在于，所述的盐指常规的酸加成盐，所述的酸为有机酸或无机酸，为盐酸，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，富马酸或马来酸。
4.一种药物组合物，其特征在于，包含权利要求1所述的紫苏醇衍生物及其盐和药学上可被接受的赋形剂。
5.权利要求1或3所述紫苏醇衍生物及其盐或权利要求4所述的组合物在制备抗肿瘤药物中的应用。
6.根据权利要求5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、原髓细胞白血病。
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