CN105175360B - 醚类芳基哌嗪衍生物及其盐、制备方法和用途 - Google Patents

醚类芳基哌嗪衍生物及其盐、制备方法和用途 Download PDF

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CN105175360B
CN105175360B CN201510561570.2A CN201510561570A CN105175360B CN 105175360 B CN105175360 B CN 105175360B CN 201510561570 A CN201510561570 A CN 201510561570A CN 105175360 B CN105175360 B CN 105175360B
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陈洪
马录芳
姚景才
冯爱青
孙涛
罗光远
王豹
陈夏雨
俞佳俊
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Luoyang Normal University
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Abstract

本发明公开了醚类芳基哌嗪衍生物（Ⅰ）。其中：m、X、Y、Z、R1– R5 的定义见说明书。本发明还公开了这些醚类芳基哌嗪衍生物的制备方法以及使用这些新型衍生物用于抗肿瘤的用途。本发明所述的化合物经初步药效学研究，体外抗肿瘤实验，结果显示：一些化合物表现较好的抗肿瘤活性，可研制开发为新型的抗肿瘤药物。

Description

醚类芳基哌嗪衍生物及其盐、制备方法和用途
技术领域
本发明涉及药物化学、药物先导化合物的发现领域，具体涉及一类新型醚类芳基哌嗪衍生物、其制备方法和在抗肿瘤药物中的用途。
背景技术
***癌已成为威胁老年男性健康的重要疾病。***癌是西方国家男性发病率最高、死亡率居第二位的实体肿瘤（J. Radiat. Res, 2011, 52, 743-751）。在美国，***癌的发病率已经超过肺癌，成为第一位危害男性健康的肿瘤。据美国癌症协会估计，2013年美国大约有 238590例新发***癌，有29720例将死于此病（CA Cancer J. Clin.2013, 63, 11-30）。在欧洲，每年得到确诊的新发***癌病例大约有416700人，***癌占全部男性癌症的22.8%，占全部男性癌症死亡人数的9.5%（Eur. J. Cancer, 2013, 49,1374-1403）。而在过去发病率较低的亚洲国家，近年来患病人数增长也在加快（中华实验外科杂志。 2005，9，1031-1034）。
临床上，局限性疾病可以通过手术或放射疗法切除或破坏癌细胞来治愈。然而，转移性***癌不能治愈并且雄激素切除疗法成为标准疗法。尽管单独使用各种化学治疗药物或与放射治疗结合来治疗晚期患者，但是对***癌没有任何一种传统的癌症治疗方法是非常成功的。其它研究显示：一旦肿瘤细胞成为激素抵抗性，对于激素不敏感性***癌来说，标准的细胞毒试剂几乎不能提高治疗结果或存活率，尽管它们在一定程度上可以缓解病人的疼痛。因此，发明和开发更有效、安全的抗***癌药物是迫切的。
本发明的目的是提供一种新型的醚类芳基哌嗪衍生物及其盐。
本发明的另一目的是提供上述新型的醚类芳基哌嗪衍生物及其盐的制备方法。
本发明的再一目的是提供新型的醚类芳基哌嗪衍生物在抗肿瘤药物中的用途。
本发明新型的醚类芳基哌嗪衍生物具有下述通式（Ⅰ）的结构：
其中：
m = 0、1；
X = C或N; Y = C或N; Z = C或N;
R1 = H、直连或支链烷基、不饱和的烷基、取代或未取代苯基、芳烷基、直连或支链烷氧基、不饱和的烷氧基、F、Cl、Br、I、CF3、CN、NO2、OH、CHO、SR6、烷基砜基、取代或未取代芳基砜基、氨基、酰基、酯基；
R2 = H、直连或支链烷基、不饱和的烷基、取代或未取代苯基、芳烷基、直连或支链烷氧基、不饱和的烷氧基、F、Cl、Br、I、CF3、CN、NO2、OH、CHO、SR6、烷基砜基、取代或未取代芳基砜基、氨基、酰基、酯基；
R3 = H、直连或支链烷基、不饱和的烷基、取代或未取代苯基、芳烷基、直连或支链烷氧基、不饱和的烷氧基、F、Cl、Br、I、CF3、CN、NO2、OH、CHO、SR6、烷基砜基、取代或未取代芳基砜基、氨基、酰基、酯基；
R4 = H、直连或支链烷基、不饱和的烷基、取代或未取代苯基、芳烷基、直连或支链烷氧基、不饱和的烷氧基、F、Cl、Br、I、CF3、CN、NO2、OH、CHO、SR6、烷基砜基、取代或未取代芳基砜基、氨基、酰基、酯基；
R5 = H、直连或支链烷基、不饱和的烷基、取代或未取代苯基、芳烷基、直连或支链烷氧基、不饱和的烷氧基、F、Cl、Br、I、CF3、CN、NO2、OH、CHO、SR6、烷基砜基、取代或未取代芳基砜基、氨基、酰基、酯基；
R6 = H、直连或支链烷基、不饱和的烷基、取代或未取代苯基、芳烷基。
本发明所述的醚类芳基哌嗪衍生物通过下述方法制备：首先原料4-(溴乙烷)苯乙酸（1）被硼烷二甲基硫醚络合物(BMS)还原成中间体2，其次中间体2在碱催化下与5,6,7,8-四氢-2-萘酚反应得到中间体3，再次中间体3在碱催化下与对甲苯磺酰氯（TsCl）反应生成羟基保护的中间体4。最后中间体4与相应芳基哌嗪类化合物或芳基哌啶类化合物发生亲核取代反应得到相应的化合物5-28。
本发明上述化合物经初步药理学研究，体外抗肿瘤实验，结果显示：一些化合物表现良好的抗肿瘤活性，可研制开发新型的抗肿瘤药物。
本发明的优选化合物具有下述化合物5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28的结构:
本发明中间体2的制备过程如下：
中间体2的制备工艺包括：
4-(溴乙烷)苯乙酸在常温下与硼烷二甲基硫醚络合物(BMS)反应得到2-(4-(bromomethyl)-
phenyl)ethanol（中间体2）。
本发明中间体3的制备过程如下：
中间体3的制备工艺包括：
2-(4-(bromomethyl)phenyl)ethanol（中间体2）在碳酸钾催化下，与5,6,7,8-四氢-2-萘酚反应得到2-(4-((5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)phenyl)ethanol（中间体3）。
本发明中间体4的制备过程如下：
中间体4的制备工艺包括：
2-(4-((5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)phenyl)ethanol（中间体3）在三乙胺催化下，与对甲苯磺酰氯反应得到2-(4-((5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)phenyl)ethyl 4-methylbenzenesulfonate（中间体4）。
本发明化合物5-28的制备过程如下：
化合物5-28的制备工艺包括：
中间体4与相应芳基哌嗪类化合物或芳基哌啶类化合物反应得到化合物5-28
本发明所述醚类芳基哌嗪衍生物的盐由下列Ⅱ表示：
其中HX为生理上可接受的酸
本发明所述的醚类芳基哌嗪衍生物的盐主要包括氢溴酸盐、氢碘酸盐、盐酸盐、高氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、杏仁酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、草酸盐、磷酸盐、琥珀酸盐、墟泊酸盐、乳酸盐中的一种
本发明所述的醚类芳基哌嗪衍生物可药用盐的制备方法，其特征是：将醚类芳基哌嗪衍生物溶于有机溶剂中，然后加入HX酸，常温下搅拌，析出的固体为醚类芳基哌嗪衍生物的无机酸盐或有机酸盐。
本发明所涉及的醚类芳基哌嗪衍生物，初步药理学研究（体外抗肿瘤活性测试），结果显示：一些化合物表现良好的抗肿瘤活性，可进一步研制开发为新型的抗肿瘤药物。
具体实施方式：
下面通过实施例进一步说明本发明。实施例给出了代表性新化合物的合成、相关结构鉴定数据及化合物活性数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
熔点测定用a Fisher Johns hot-stage测定仪(温度计未校正)。
所有目标化合物（盐酸盐）的1HNMR，13C NMR用瑞士Bruker AVANCE AV-400NB测定，TMS做内标。
低分辨质谱（EI）用Thremo DSQ 质谱仪测定。
实施例1：中间体2的制备
在250 mL圆底烧瓶中加入5 g (0.021 mol) 4-(溴乙烷)苯乙酸，100 mL 四氢呋喃，在 0 ℃下缓慢加入21.9 mL 硼烷二甲基硫醚络合物(BMS，2M in THF)。反应混合物在0 ℃下反应1 h后，然后逐渐恢复常温。反应结束后缓慢加入水终止反应，用乙酸乙酯萃取（100 mL × 3），合并有机相，有机相分别用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，浓缩。粗产物没有纯化直接用于下一步反应。
实施例2：中间体3的制备
在250 mL圆底烧瓶中加入4 g（18.7 mmol）中间体2，2.76 g（18.7 mmol）5,6,7,8-四氢-2-萘酚，10.32 g（74.8 mmol）碳酸钾，150 mL 乙腈，在60 ℃下反应16 h。TLC显示原料反应完全。停止反应，过滤，浓缩。粗产物经硅胶柱层析纯化，洗脱剂：V(乙酸乙酯):V(石油醚) = 1:15，得4.14 g 白色固体，收率：70%（以原料4-(溴乙烷)苯乙酸计算）。M.p.: 61-62 oC; 1H NMR (500 MHz, CDCl3) δ in ppm: 7.39 (d, J = 8.0 Hz, 2H), 7.30 (d, J= 8.0 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 8.2, 2.7 Hz, 1H), 6.70(d, J = 2.5 Hz, 1H), 5.00 (s, 2H), 3.87 (t, J = 6.5 Hz, 2H), 2.88 (t, J = 6.5Hz, 2H), 2.75 (br s, 2H), 2.71 (br s, 2H), 1.78 (dt, J = 6.6, 3.4 Hz, 4H),1.48 (s, 1H); MS (EI, m/z): 282 (M+), 251, 182, 147, 135 (100%), 117, 105,91.
实施例3：中间体4的制备
在250 mL圆底烧瓶中加入4 g（14.18 mmol）中间体3，5.73 g（56.72 mmol）三乙胺，0.17 g 4-（N,N-二甲基）氨基吡啶(催化量)，100 mL二氯甲烷，在 0 ℃下缓慢加入4.04g（21.3 mmol）对甲苯磺酰氯（TsCl）的二氯甲烷溶液。反应混合物在0 ℃下反应16 h，TLC显示原料反应完全。缓慢加入水终止反应，用二氯甲烷萃取（100 mL × 3），合并有机相，有机相分别用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，浓缩。粗产物经硅胶柱层析纯化，洗脱剂：V(乙酸乙酯):V(石油醚) = 1:20，得5.87 g 白色固体，收率：95%。M.p.: 92-93 oC;1H NMR (500 MHz, CDCl3) δ in ppm: 7.68 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.2Hz, 1H), 6.73 (dd, J = 8.2, 2.6 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 4.98 (s,2H), 4.21 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H), 2.74
(br s, 2H), 2.70 (br s, 2H), 2.43 (s, 3H), 1.78 (dt, J = 6.6, 3.4 Hz,4H); MS (EI, m/z): 436 (M+), 289, 264, 236, 155, 117 (100%), 104, 91.
实施例4：化合物5的制备
在25mL圆底烧瓶中加入100 mg（0.23 mmol）中间体4，44.5 mg（0.27 mmol）N-苯基哌嗪，190.4 mg（1.38 mmol）碳酸钾，15 mL 乙腈，在85 ℃下反应16 h，TLC显示原料反应完全。停止反应，过滤，浓缩。粗产物经硅胶柱层析纯化，洗脱剂：V(乙酸乙酯):V(石油醚) =1:20，得58.8 mg 白色固体，收率：60%。M.p.: 140-141 oC (HCl salt); MS (ESI, m/z):427.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.54 (s, 1H), 7.39 (d, J =8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.02 (d, J =8.1 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.74 – 6.65(m, 2H), 5.01 (s, 2H), 3.82 (d, J = 10.7 Hz, 2H), 3.62 (d, J = 10.7 Hz, 2H),3.45 – 3.01 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.69 (t, J = 2.8 Hz,4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 149.5, 137.5, 136.6, 135.9,129.6, 129.1, 128.7, 127.9, 120.0, 116.0, 114.5, 112.5, 68.7, 55.9, 50.5,45.4, 29.0, 28.9, 27.9, 22.9, 22.6.
实施例5：化合物6的制备
中间体4与1-(2-吡啶基)哌嗪的反应，合成过程同实施例4。得68.7 mg白色固体，收率：70%。M.p.: 166-167 oC (HCl salt); MS (ESI, m/z): 428.1 [M+1]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 11.84 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.96 (br s,1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 – 7.28 (m, 3H), 6.98 (t, J = 6.3 Hz, 1H),6.94 (d, J = 8.0 Hz, 1H), 6.72 – 6.69 (m, 2H), 5.02 (s, 2H), 4.53 (d, J =10.7 Hz, 2H), 3.93 – 2.97 (m, 10H), 2.67 (br s, 2H), 2.62 (br s, 2H), 1.69(t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 137.5, 136.5,135.9, 129.6, 128.7, 127.9, 114.5, 113.9, 112.5, 68.7, 55.9, 49.9, 42.9,29.0, 28.9, 27.9, 22.9, 22.6.
实施例6：化合物7的制备
中间体4与1-(2-甲基苯基)哌嗪的反应，合成过程同实施例4。得82.9 mg白色固体，收率：82%。M.p.: 183-184 oC (HCl salt); MS (ESI, m/z): 441.1 [M+1]+; 1H NMR(500 MHz, DMSO-d 6) δ in ppm: 10.96 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.32(d, J = 8.0 Hz, 2H), 7.23 – 6.92 (m, 5H), 6.74 – 6.68 (m, 2H), 5.03 (s, 2H),3.63 (d, J = 10.7 Hz, 2H), 3.44 – 3.34 (m, 2H), 3.30 – 3.06 (m, 8H), 2.67 (brs, 2H), 2.63 (br s, 2H), 2.27 (s, 3H), 1.70 (dt, J = 6.4, 3.4 Hz, 4H).
实施例7：化合物8的制备
中间体4与1-(4-甲基苯基)哌嗪的反应，合成过程同实施例4。得75.9 mg白色固体，收率：75%。M.p.: 167-168 oC (HCl salt); MS (ESI, m/z): 441.1 [M+1]+; 1H NMR(400 MHz, DMSO-d 6) δ in ppm: 11.56 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30(d, J = 8.0 Hz, 2H), 7.13 – 6.89 (m, 5H), 6.79 – 6.63 (m, 2H), 5.02 (s, 2H),3.75 (d, J = 10.7 Hz, 2H), 3.62 (d, J = 10.7 Hz, 2H), 3.43 – 3.06 (m, 8H),2.67 (br s, 2H), 2.62 (br s, 2H), 2.22 (s, 3H), 1.69 (br s, 4H); 13C NMR (101MHz, DMSO-d 6) δ in ppm: 156.0, 147.1, 137.5, 136.6, 135.9, 129.6, 129.5,129.3, 128.7, 127.9, 116.4, 114.5, 112.5, 68.7, 55.9, 50.4, 46.0, 29.0, 28.9,27.9, 22.9, 22.6, 20.0.
实施例8：化合物9的制备
中间体4与1-(3-甲基苯基)哌嗪的反应，合成过程同实施例4。得80.9 mg白色固体，收率：80%。M.p.: 178-179 oC (HCl salt); MS (ESI, m/z): 441.1 [M+1]+; 1H NMR(400 MHz, CDCl3) δ in ppm: 13.80 (s, 1H), 7.65 – 7.27 (m, 8H), 6.96 (d, J =8.3 Hz, 1H), 6.74 – 6.63 (m, 2H), 4.98 (s, 2H), 4.66 (t, J = 12.0 Hz, 2H),4.30 (br s, 2H), 3.76 – 3.56 (m, 4H), 3.50 – 3.13 (m, 4H), 2.72 (br s, 2H),2.68 (br s, 2H), 2.40 (s, 3H), 1.76 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101MHz, CDCl3) δ in ppm: 156.8, 141.9, 141.6, 138.7, 137.5, 134.9, 131.6, 130.9,130.3, 130.1, 129.3, 128.7, 121.7, 118.3, 115.2, 112.9, 69.8, 58.6, 51.4,49.4, 30.4, 30.1, 28.9, 23.8, 23.5, 21.9.
实施例9：化合物10的制备
中间体4与1-(2-苯甲腈)哌嗪的反应，合成过程同实施例4。得62.2 mg白色固体，收率：60%。M.p.: 131-132 oC (HCl salt); MS (ESI, m/z): 452.1 [M+1]+; 1H NMR (400MHz, CDCl3) δ in ppm: 13.20 (s, 1H), 7.60 (dd, J = 7.7, 1.2 Hz, 1H), 7.55 (t,J = 7.7 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.20 –7.07 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.76 – 6.64 (m, 2H), 4.99 (s, 2H),3.95 – 2.99 (m, 12H), 2.72 (br s, 2H), 2.69 (br s, 2H), 1.77 (dt, J = 6.4,3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.5, 153.9, 138.3, 136.8,135.4, 134.4, 134.1, 130.0, 129.8, 129.0, 128.3, 124.1, 119.8, 117.8, 114.8,112.6, 107.3, 69.6, 58.8, 52.5, 48.6, 30.0, 29.8, 28.6, 23.5, 23.2.
实施例10：化合物11的制备
中间体4与1-(2-甲氧苯基)哌嗪的反应，合成过程同实施例4。得75.5 mg白色固体，
收率：72%。M.p.: 154-155 oC (HCl salt); MS (ESI, m/z): 457.1 [M+1]+; 1HNMR (400 MHz, CDCl3) δ in ppm: 12.98 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.28(d, J = 8.0 Hz, 2H), 7.12 – 6.85 (m, 5H), 6.75 – 6.65 (m, 2H), 4.99 (s, 2H),3.86 (s, 3H), 3.66 – 3.49 (m, 6H), 3.39 – 3.04 (m, 6H), 2.73 (br s, 2H), 2.69(br s, 2H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm:156.2, 151.7, 138.6, 138.0, 136.4, 135.3, 129.7, 129.5, 128.7, 127.9, 124.3,121.0, 118.8, 114.5, 112.3, 111.1, 69.3, 58.5, 55.2, 52.3, 47.2, 29.6, 29.5,28.3, 23.1, 22.9.
实施例11：化合物12的制备
中间体4与1-(2-乙氧苯基)哌嗪的反应，合成过程同实施例4。得75.6 mg白色固体，
收率：70%。M.p.: 171-172 oC (HCl salt); MS (ESI, m/z): 471.1 [M+1]+; 1HNMR (400 MHz, CDCl3) δ in ppm: 13.97 (s, 1H), 8.17 (d, J = 5.8 Hz, 1H), 7.44-7.32 (m, 5H), 7.16 – 6.90 (m, 3H), 6.84 – 6.66 (m, 2H), 5.03 (s, 2H), 4.95(br s, 2H), 4.48 (br s, 2H), 4.36 (q, J = 6.0 Hz, 2H), 3.69 (d, J = 9.5 Hz,4H), 3.36 (br s, 4H), 2.77 (br s, 2H), 2.73 (br s, 2H), 1.77 (dt, J = 6.4,3.4 Hz, 4H), 1.67 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ in ppm:156.5, 151.9, 138.3, 137.0, 134.9, 131.6, 130.0, 129.8, 129.0, 128.3, 123.8,121.6, 114.8, 114.1, 112.6, 69.6, 65.4, 58.4, 49.3, 48.7, 29.9, 29.8, 28.6,23.4, 23.2, 14.9.
实施例12：化合物13的制备
中间体4与1-(4-甲氧苯基)哌嗪的反应，合成过程同实施例4。得78.6 mg白色固体，收率：75%。M.p.: 146-147 oC (HCl salt); MS (ESI, m/z): 457.1 [M+1]+; 1H NMR(400 MHz, DMSO-d 6) δ in ppm: 11.48 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30(d, J = 8.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.88(d, J = 9.0 Hz, 2H), 6.71 (m, 2H), 5.02 (s, 2H), 3.70 (s, 3H), 3.64 (t, J =12.0 Hz, 4H), 3.40 – 3.10 (m, 8H), 2.66 (br s, 2H), 2.62 (br s, 2H), 1.69 (t,J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 155.8, 153.9, 147.2,142.7, 137.3, 136.3, 135.7, 129.4, 128.5, 127.7, 118.1, 114.3, 114.2, 112.3,68.5, 55.7, 55.0, 50.3, 46.8, 28.8, 28.7, 27.7, 22.7, 22.4.
实施例13：化合物14的制备
中间体4与1-(3-甲氧苯基)哌嗪的反应，合成过程同实施例4。73.4 mg白色固体，收率：70%。M.p.: 181-182 oC (HCl salt); MS (ESI, m/z): 457.1 [M+1]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 11.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J =8.0 Hz, 2H), 7.16 (t, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.74 – 6.52(m, 4H), 6.45 (dd, J = 8.1, 1.9 Hz, 1H), 5.01 (s, 2H), 3.83 (d, J = 10.7 Hz,2H), 3.73 (s, 3H), 3.60 (d, J = 10.7 Hz, 2H), 3.46 – 3.03 (m, 8H), 2.66 (brs, 2H), 2.61 (br s, 2H), 1.69 (br s, 4H); 13C NMR (101 MHz, DMSO) δ in ppm:162.1, 157.9, 152.6, 139.4, 138.4, 137.7, 131.7, 131.5, 130.5, 129.7, 116.3,114.4, 110.2, 107.1, 104.0, 70.6, 57.8, 56.8, 52.3, 47.1, 30.9, 30.7, 29.7,24.8, 24.5.
实施例14：化合物15的制备
中间体4与1-(5-氯-2-甲氧苯基)哌嗪的反应，合成过程同实施例4。得67.6 mg无色油状液体，收率：60%。M.p.: 182-183 oC (HCl salt); MS (ESI, m/z): 491.1 [M+1]+;1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.40 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H),7.29 (d, J = 8.0 Hz, 2H), 7.07 – 6.90 (m, 4H), 6.72 – 6.68 (m, 2H), 5.01 (s,2H), 3.79 (s, 3H), 3.60 (d, J = 10.7 Hz, 2H), 3.54 (d, J = 10.7 Hz, 2H), 3.39– 3.07 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.68 (t, J = 2.8 Hz, 4H);13C NMR (101 MHz, DMSO-d 6) δ in ppm: 155.6, 150.2, 140.2, 137.1, 136.1, 135.5,129.2, 128.3, 127.5, 124.0, 122.1, 117.7, 114.1, 112.8, 112.1, 68.3, 55.6,55.3, 50.4, 46.1, 28.6, 28.5, 27.5, 22.5, 22.2.
实施例15：化合物16的制备
中间体4与1-(2-氟苯基)哌嗪的反应，合成过程同实施例4。得66.3 mg白色固体，收率：65%。M.p.: 157-158 oC (HCl salt); MS (ESI, m/z): 445.1 [M+1]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 11.41 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J =8.0 Hz, 2H), 7.23 – 7.00 (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 10.8Hz, 2H), 5.02 (s, 2H), 3.64 (d, J = 10.7 Hz, 2H), 3.50 (d, J = 10.7 Hz, 2H),3.36 – 3.10(m, 8H), 2.66 (br s, 2H), 2.62 (br s, 2H), 1.69 (br s, 4H); 13C NMR(101 MHz, DMSO-d 6) δ in ppm: 156.4, 154.0, 138.7, 137.9, 136.9, 136.3, 130.0,129.1, 128.3, 125.3, 123.7, 120.0, 116.6, 116.4, 114.9, 112.9, 69.1, 56.5,51.2, 47.3, 29.4, 29.3, 28.3, 23.3, 23.0.
实施例16：化合物17的制备
中间体4与1-(4-氟苯基)哌嗪的反应，合成过程同实施例4。得71.4 mg白色固体，收率：70%。M.p.: 159-160 oC (HCl salt); MS (ESI, m/z): 445.1 [M+1]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 11.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J =8.0 Hz, 2H), 7.16 – 6.90 (m, 5H), 6.71 (m, 2H), 5.02 (s, 2H), 3.75 (d, J =10.7 Hz, 2H), 3.63 (d, J = 10.7 Hz, 2H), 3.41 – 3.07 (m, 8H), 2.67 (br s,2H), 2.62 (br s, 2H), 1.69 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δin ppm: 158.0, 156.2, 155.6, 146.5, 137.8, 136.8, 136.1, 129.9, 128.9, 128.1,118.1, 118.1, 115.8, 115.6, 114.7, 112.7, 68.9, 56.1, 50.7, 46.4, 29.2, 29.1,28.1, 23.1, 22.8.
实施例17：化合物18的制备
中间体4与1-(2,4-二氟苯基)哌嗪的反应，合成过程同实施例4。得69.0 mg白色固体，收率：65%。M.p.: 137-138 oC (HCl salt); MS (ESI, m/z): 463.1 [M+1]+; 1H NMR(400 MHz, CDCl3) δ in ppm: 13.11 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.27 (d,J = 8.0 Hz, 2H), 7.00 – 6.91 (m, 2H), 6.87 – 6.78 (m, 2H), 6.75 – 6.62 (m,2H), 4.98 (s, 2H), 3.67 (t, J = 12.0 Hz, 4H), 3.40 – 3.00 (m, 8H), 2.72 (brs, 2H), 2.69 (br s, 2H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz,CDCl3) δ in ppm: 160.2, 157.7, 157.0, 156.58, 154.5, 138.3, 136.8, 135.5,134.7, 134.6, 130.0, 129.8, 129.0, 128.3, 120.6, 120.5, 114.8, 112.6, 111.4,111.2, 105.3, 105.0, 104.8, 69.6, 58.7, 52.4, 47.8, 29.9, 29.8, 28.6, 23.5,23.2.
实施例18：化合物19的制备
中间体4与1-(2-氯苯基)哌嗪的反应，合成过程同实施例4。得79.3 g白色固体，收率：75%。 M.p.: 159-160 oC (HCl salt); MS (ESI, m/z): 461.1 [M+1]+; 1H NMR (400MHz, CDCl3) δ in ppm: 13.10 (s, 1H), 7.43 – 7.21 (m, 6H), 7.13 – 7.02 (m,2H), 6.96 (d, J = 8.3 Hz, 1H), 6.77 – 6.64 (m, 2H), 4.99 (s, 2H), 3.88 – 2.96(m, 12H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.68 (t, J = 2.8 Hz, 4H); 13C NMR(101 MHz, CDCl3) δ in ppm: 156.6, 147.1, 138.3, 136.8, 135.6, 130.7, 130.0,129.8, 129.0, 128.9, 128.3, 128.1, 125.4, 121.1, 114.8, 112.6, 69.6, 58.8,52.6, 48.1, 30.0, 29.8, 28.6, 23.5, 23.2.
实施例19：化合物20的制备
中间体4与1-(4-氯苯基)哌嗪的反应，合成过程同实施例4。得68.7 mg白色固体，收率：65%。M.p.: 157-158 oC (HCl salt); MS (ESI, m/z): 461.1 [M+1]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 11.56 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J =8.0 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.94 (d, J =8.2 Hz, 1H), 6.71 (m, 2H), 5.02 (s, 2H), 3.83 (d, J = 10.7 Hz, 2H), 3.62 (d,J = 10.7 Hz, 2H), 3.40 – 3.07 (m, 8H), 2.67 (br s, 2H), 2.62 (br s, 2H), 1.69(t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.2, 148.6, 137.8,136.8, 136.1, 129.9, 129.0, 128.9, 128.1, 123.7, 117.7, 114.7, 112.7, 68.9,56.1, 50.5, 45.4, 29.2, 29.1, 28.1, 23.1, 22.8.
实施例20：化合物21的制备
中间体4与1-(3-氯苯基)哌嗪的反应，合成过程同实施例4。得65.5 mg白色固体，收率：62%。M.p.: 146-147 oC (HCl salt); MS (ESI, m/z): 461.1 [M+1]+; 1H NMR (400MHz, CDCl3) δ in ppm: 13.21 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J =8.0 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.00 – 6.90 (m, 3H), 6.80 (d, J = 6.5Hz, 1H), 6.74 – 6.64 (m, 2H), 4.98 (s, 2H), 3.84 – 2.95 (m, 12H), 2.72 (br s,2H), 2.69 (br s, 2H), 1.76 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ inppm: 156.8, 150.6, 138.7, 137.1, 135.8, 135.7, 130.9, 130.3, 130.1, 129.4,128.6, 122.3, 117.9, 115.6, 115.1, 112.9, 69.9, 59.1, 52.2, 47.0, 30.3, 30.1,29.0, 23.8, 23.5.
实施例21：化合物22的制备
中间体4与1-(2,4-二氯苯基)哌嗪的反应，合成过程同实施例4。得63.8 mg白色固体，收率：65%。M.p.: 135-136 oC (HCl salt); MS (ESI, m/z): 495.0 [M+1]+; 1H NMR(400 MHz, CDCl3) δ in ppm: 13.16 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 (d,J = 8.0 Hz, 2H), 7.25 – 7.15 (m, 2H), 7.02 (dd, J = 8.0, 1.4 Hz, 1H), 6.96(d, J = 8.3 Hz, 1H), 6.76 – 6.61 (m, 2H), 4.99 (s, 2H), 3.69 (t, J = 12.0 Hz,4H), 3.50 – 2.97 (m, 8H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.77 (dt, J =6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.9, 149.3, 138.7,137.1, 135.8, 134.6, 130.4, 130.1, 129.3, 128.6, 128.3, 128.0, 126.6, 119.7,115.2, 112.9, 69.9, 59.1, 52.9, 48.4, 30.3, 30.1, 29.0, 23.8, 23.5.
实施例22：化合物23的制备
中间体4与1-(5-氯-2-甲基苯基)哌嗪的反应，合成过程同实施例4。得65.4 mg无色油状液体，收率：60%。M.p.: 147-148 oC (HCl salt); MS (ESI, m/z): 475.1 [M+1]+;1H NMR (400 MHz, CDCl3) δ in ppm: 13.21 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H),7.29 (d, J = 8.0 Hz, 2H), 7.14 – 6.93 (m, 4H), 6.75 – 6.64 (m, 2H), 5.00 (s,2H), 3.66 (br s, 4H), 3.43 – 2.94 (m, 8H), 2.73 (br s, 2H), 2.69 (br s, 2H),2.23 (s, 3H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ inppm: 156.6, 150.2, 138.4, 136.9, 135.6, 132.4, 132.3, 130.8, 130.1, 129.8,129.1, 128.3, 124.9, 120.6, 114.9, 112.6, 69.7, 58.8, 52.8, 48.6, 30.1, 29.8,28.7, 23.5, 23.2, 17.4.
实施例23：化合物24的制备
中间体4与1-(4-溴苯基)哌嗪的反应，合成过程同实施例4。得81.4 mg白色固体，收率：70%。M.p.: 169-170 oC (HCl salt); MS (ESI, m/z): 506.9 [M+2]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 11.48 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.38 (d, J =8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.93 (d, J =8.2 Hz, 1H), 6.70 (m, 2H), 5.01 (s, 2H), 3.83 (d, J = 10.7 Hz, 2H), 3.61 (d,J = 10.7 Hz, 2H), 3.40 – 3.03 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.68(t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 148.7, 137.5,136.5, 135.9, 131.6, 129.6, 128.7, 127.9, 117.9, 114.5, 112.5, 111.2, 68.7,55.9, 50.3, 45.0, 29.0, 28.9, 27.9, 22.9, 22.6.
实施例24：化合物25的制备
中间体4与1-(2-三氟甲基苯基)哌嗪的反应，合成过程同实施例4。得79.5 mg白色固体，收率：70%。M.p.: 159-160 oC (HCl salt); MS (ESI, m/z): 495.1 [M+1]+; 1H NMR(400 MHz, CDCl3) δ in ppm: 13.08 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.62 –7.49 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 – 7.27 (m, 3H), 6.96 (d, J = 8.3Hz, 1H), 6.75 – 6.65 (m, 2H), 4.99 (s, 2H), 3.80 (t, J = 10.7 Hz, 2H), 3.62(d, J = 10.7 Hz, 2H), 3.40 – 2.94 (m, 8H), 2.73 (br s, 2H), 2.69 (br s, 2H),1.76 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.9,150.3, 138.7, 137.1, 135.9, 133.8, 130.3, 130.1, 129.4, 128.6, 127.6, 127.6,126.9, 125.3, 115.2, 112.9, 70.0, 59.1, 53.2, 50.3, 30.3, 30.1, 29.0, 23.8,23.5.
实施例25：化合物26的制备
中间体4与1-(4-三氟甲基苯基)哌嗪的反应，合成过程同实施例4。得68.1 mg白色固体，收率：60%。M.p.: 166-167 oC (HCl salt); MS (ESI, m/z): 495.1 [M+1]+; 1H NMR(400 MHz, CDCl3) δ in ppm: 13.39 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.40 (d,J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 8.0 Hz, 3H), 6.75 –6.65 (m, 2H), 4.99 (s, 2H), 3.90 – 3.60 (m, 6H), 3.33 (br s, 2H), 3.24 (br s,2H), 3.00 (br s, 2H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.77 (dt, J = 6.5,3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.6, 151.6, 138.4, 136.9,135.4, 130.1, 129.9, 129.0, 128.3, 126.9, 116.2, 114.9, 112.6, 69.6, 58.8,51.8, 45.9, 30.0, 29.8, 28.7, 23.5, 23.2.
实施例26：化合物27的制备
中间体4与4-苯基哌啶的反应，合成过程同实施例4。得68.4 mg白色固体，收率：70%。M.p.: 146-147 oC (HCl salt); MS (ESI, m/z): 426.1 [M+1]+; 1H NMR (400 MHz,CDCl3) δ in ppm: 12.55 (s, 1H), 7.38 (d, J = 7.0 Hz, 2H), 7.35 – 7.20 (m,7H), 6.96 (d, J = 8.2 Hz, 1H), 6.78 – 6.60 (m, 2H), 4.98 (s, 2H), 3.74 (br s,2H), 3.32 (br s, 2H), 3.20 (br s, 2H), 2.84 – 2.68 (m, 8H), 2.14 – 1.95 (m,3H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.9,143.2, 138.7, 137.0, 136.1, 130.3, 130.1, 129.4, 129.2, 128.5, 127.6, 127.2,115.2, 112.9, 70.0, 59.3, 54.0, 41.1, 30.6, 30.5, 30.1, 29.0, 23.8, 23.5.
实施例27：化合物28的制备
中间体4与4-苯基-4-羟基哌啶的反应，合成过程同实施例4。得83.1 mg白色固体，收率：82%。M.p.: 194-195 oC (HCl salt); MS (ESI, m/z): 442.1 [M+1]+; 1H NMR (400MHz, DMSO-d 6) δ in ppm: 1H NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 7.52 (d, J =7.0 Hz, 2H), 7.38 (d, J = 7.0 Hz, 2H), 7.33 – 7.19 (m, 5H), 6.96 (d, J = 8.2Hz, 1H), 6.77 – 6.62 (m, 2H), 4.98 (s, 2H), 3.57 – 3.05 (m, 8H), 2.82 (br s,2H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.98 (d, J = 11.6 Hz, 2H), 1.76 (t, J= 2.8 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 156.6, 145.9, 138.3, 136.7, 135.7,130.0, 129.8, 129.0, 128.7, 128.2, 127.8, 124.6, 114.8, 112.6, 69.6, 69.4,58.6, 49.3, 35.4, 30.2, 29.8, 28.6, 23.5, 23.2.
实施例28：体外抗肿瘤细胞活性测试
1. 材料：
1.1 CCK-8试剂盒购于日本同仁化学研究所。
1.2 靶细胞的制备：人***癌细胞系PC-3、LNCaP、DU145以及正常的***上皮细胞WPMY-1的复苏与培养。
a.分别从液氮罐中取出人***癌细胞系PC-3、LNCaP、DU145以及正常的***上皮细胞WPMY-1的冷存管，迅速置入37℃水浴箱中，不停摇动使之迅速溶化，无菌操作移入离心管中;
b.分别加DMEM完全培养液到PC-3细胞及WPMY-1细胞的离心管至10 mL，F12完全培养基到LNCaP细胞的离心管至10 mL，1640完全培养基到DU145细胞的离心管至10 mL，1000rmp离心5 min，弃上清。
c.PC-3、WPMY-1细胞分别加DMEM完全培养基3-4 mL吹打使细胞混匀后移入培养瓶中， LNCaP细胞加3-4 mL的F12完全培养基吹打使细胞混匀后移入培养瓶中，DU145细胞加3-4 mL的1640完全培养基吹打使细胞混匀后移入培养瓶中，5% CO2，37℃ 培养；
d.观察细胞生长情况，及时更换培养液，分瓶。
1.3 细胞计数：
a.选取对数生长期细胞，胰酶消化，分别对应的完全培养基终止，移入离心管中，加相应的完全培养基至10 mL ；
b.取10 μL 细胞悬液滴入计数板一侧凹槽中，显微镜下计数四个大格的细胞总数、除以4，乘104，即为每毫升培养液所含细胞数；
c.调整细胞数至1×105 cells/mL 。
1.4 醚类芳基哌嗪衍生物溶液配置：
取醚类芳基哌嗪衍生物加入DMSO溶剂，调整初浓度为10 mmol，配置浓度为1 mmol待用，4℃保存。
2.试验方法
2.1 96孔板各孔加入人***癌细胞系PC-3、LNCaP、DU145以及正常的***上皮
细胞WPMY-1 100 μL（1×105 cells/mL），37℃培养过夜。
2.2 弃液，加入不同浓度的受试对象100 μL，对照加DMEM完全培养基100 μL，继续培养24 h。.
2.3 各孔加入CCK-8检测试剂10 μL，继续培养20 min至1 h。
2.4 酶标仪450 nm下测定每孔OD值。
2.5 计算抑制率：
肿瘤细胞抑制率% = [(对照组测定的平均OD值—加药组测定的平均OD值)/对照组测定的平均OD值]×100%。
2.6 以抑制率对药物浓度的对数作图，求得IC50值：
以lgc为横坐标，抑制率为纵坐标，求得IC50值。
本发明化合物的体外抗肿瘤细胞活性结果如下表所示：

Claims (4)

1.醚类芳基哌嗪衍生物，其特征在于：为具有下述5-7、9-14、16-19、21-23、25结构的化合物，
。
2.如权利要求1所述的醚类芳基哌嗪衍生物的制备方法，其特征在于：包括如下步骤：首先原料4-(溴乙烷)苯乙酸（1）被硼烷二甲基硫醚络合物还原成中间体2，其次中间体2在碱催化下与5,6,7,8-四氢-2-萘酚反应得到中间体3，再次中间体3在碱催化下与对甲苯磺酰氯反应生成羟基保护的中间体4；最后中间体4与相应芳基哌嗪类化合物发生亲核取代反应得到相应的化合物5-7、9-14、16-19、21-23、25；反应式如下所示：
；
所述中间体2与5,6,7,8-四氢-2-萘酚反应所用到的碱是碳酸钾；中间体3与对甲苯磺酰氯反应所用到的碱是三乙胺。
3.如权利要求1所述醚类芳基哌嗪衍生物的盐，其特征在于：包括氢溴酸盐、氢碘酸盐、盐酸盐、高氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、杏仁酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、草酸盐、磷酸盐、琥珀酸盐或乳酸盐。
4.如权利要求1所述醚类芳基哌嗪衍生物在制备抗***癌药物中的用途。
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