CN106083763A - 查尔酮衍生物及其制备方法与应用 - Google Patents
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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
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Abstract
本发明公开了一种查尔酮衍生物，包括芳基哌嗪、芳基磺酰基哌嗪类苦参碱衍生物，还公开了该衍生物的制备方法和在药物中的应用。
Description
技术领域
本发明涉及芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物，还涉及该衍生物的制备方法和在制药中的应用。
技术背景
炎症是人体组织受到诸如病原菌、刺激物等的损伤时，维管组织产生的一系列复杂的生理应激反应。无论是急性还是慢性炎症，对人体都会造成不同程度的损伤。如果炎症得不到及时的治疗，它会发展成为一些严重的疾病，如：类风湿性关节炎、肠炎类疾病、银屑病、慢性哮喘等。所以，对炎症的治疗是人们一直关注的问题，新型抗炎药物的开发更是重中之重。
未见兼具查尔酮的抗炎活性和芳基哌嗪、芳基磺酰基哌嗪类药物的抗炎活性的相关药物。
发明内容
本发明要解决的技术问题是提供一种查尔酮和芳基哌嗪、芳基磺酰基哌嗪类抗炎活性协同作用的芳基哌嗪、芳基磺酰基哌嗪类查尔酮衍生物。
本发明要解决的另一技术问题是提供芳基哌嗪、芳基磺酰基哌嗪类查尔酮衍生物的制备方法和在制药中的应用。
解决上述技术问题本发明采用如下技术方案：
芳基哌嗪、芳基磺酰基哌嗪类查尔酮衍生物，该衍生物为以下通式的化合物之一：
通式Ⅰ：
通式Ⅱ：
以上芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物2a-2r和4a-4p的制备方法，以氟代苯乙酮和取代的苯甲醛为起始原料，经过碱性条件下的缩合得到氟代查尔酮，再用芳基哌嗪取代得到芳基哌嗪查尔酮；如果用哌嗪环取代氟代查尔酮得到哌嗪查尔酮中间体，进一步用芳基磺酰基哌嗪取代得到芳基磺酰基哌嗪查尔酮。
上述的芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物在制备抗炎药物中的应用。
本发明基于药物拼合原理，通过化学方法合成了芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物，实验表明这些衍生物能通式发挥苦参碱和芳基哌嗪、芳基磺酰基哌嗪类药物的抗炎活性，具有一定的应用参考意义。
具体实施方式：
以下结合实施例具体说明在查尔酮基础上发明的芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物及其制备方法。
以下为芳基哌嗪查尔酮和芳基磺酰基哌嗪类查尔酮的合成路线：
实施例1 一类含芳基哌嗪查尔酮类化合物的制备方法
(1)4-氟代查尔酮1a的制备
在100 mL圆底烧瓶中加入15 mL乙醇、25 mL 10%的氢氧化钠溶液和5 mL (0.05 mol)苯甲醛，在室温搅拌下，缓慢滴加6 mL (0.05 mol) 氟代苯乙酮，滴加完毕，15-25℃搅拌2-3小时，直至有淡黄色絮状物产生，继续搅拌半小时并在冰浴下静止半小时使更多固体析出。将所得到固体过滤，乙醇重结晶即得中间体1a。1b-1d的合成方法与1a类似。收率为89%~94%。
(2)芳基哌嗪类查尔酮的制备
在50 mL 三口烧瓶中分别加入 0.868g (3.84 mmol) 1a、0.637g (4.6 mmol)碳酸钾、1.065g (4.608 mmol) 1-(3,4-二氯苯基) 哌嗪和5 mL DMF，120℃下加热反应12小时。反应完毕，将反应液冷却至室温，加水搅拌，再加适量的乙酸乙酯，将不溶黄色固体过滤，大量乙醇洗涤，再用少量乙酸乙酯冲洗，即可得产物2a。参考化合物2a的制备方法制备2b-2r。
化合物2a-2r结构鉴定数据如下：
2a: （E）-1-（4-（4-（3,4-二氯苯基）哌嗪-1-基）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 产率：58%；m.p: 185.3-187.1℃; 1H NMR (600 MHz, CDCl3) δ：8.05 (d, J = 8.9Hz, 2H), 7.83 (d, J = 15.6 Hz, 1H), 7.69 – 7.66 (m, 2H), 7.59 (d, J = 15.6Hz, 1H), 7.46 – 7.41 (m, 3H), 7.34 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 2.8 Hz,1H), 6.99 (d, J = 9.0 Hz, 2H), 6.83 – 6.81 (m, 1H), 3.60 – 3.54 (m, 4H), 3.40– 3.34 (m, 4H). 13C NMR (151 MHz, CDCl3) δ：188.14, 153.73, 150.28, 143.40,135.29, 132.97, 130.73, 130.61, 130.19, 128.92, 128.83, 128.32, 122.81,121.96, 117.48, 115.53, 113.82, 48.51, 47.21. ESI-MS m/z: 438.232[M]+。
: （E）-1-（4-（4-（4-硝基苯基）哌嗪-1-基）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 产率：56%；m.p: 225.8-227.4℃; 1H NMR (600 MHz, CDCl3) δ：8.19 (d, J = 9.3Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 15.6 Hz, 1H), 7.67 (d, J =6.1 Hz, 2H), 7.58 (d, J = 15.6 Hz, 1H), 7.43 (d, J = 7.0 Hz, 3H), 6.95 (d, J= 8.8 Hz, 2H), 6.87 (d, J = 9.3 Hz, 2H), 3.69 – 3.61 (m, 8H). ESI-MS m/z:414.332[M+1]+。
: （E）-1-（4-（4-（2-氟苯基）哌嗪-1-基）苯基）-3-苯基-2-烯-1-丙酮；黄色固体;产率: 53%; m.p: 142.8-144.5℃;1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.9 Hz,2H), 7.83 (d, J = 15.6 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.60 (d, J = 15.6 Hz,1H), 7.49 – 7.37 (m, 3H), 7.15 – 7.06 (m, 2H), 7.04 – 6.97 (m, 4H), 3.62 –3.54 (m, 4H), 3.32 – 3.24 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 188.13, 154.12,143.25, 135.34, 130.71, 130.13, 128.89, 128.60, 128.31, 124.56, 123.03,122.98, 122.04, 119.04, 116.35, 116.21, 113.78, 50.35, 47.64. ESI-MS m/z:387.341[M+1]+。
:（E）-1-（4-（4-（苄基）哌嗪-1-基）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率:56%; m.p: 142.9-144.2℃; 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J = 8.9 Hz, 2H),7.81 (d, J = 15.6 Hz, 1H), 7.68 – 7.64 (m, 2H), 7.58 (d, J = 15.6 Hz, 1H),7.46 – 7.39 (m, 3H), 7.39 – 7.34 (m, 4H), 7.31 (d, J = 6.4 Hz, 1H), 6.93 (d,J = 8.9 Hz, 2H), 3.60 (s, 2H), 3.45 – 3.38 (m, 4H), 2.67 – 2.57 (m, 4H). 13CNMR (151 MHz, CDCl3) δ 188.06, 154.19, 143.09, 137.79, 135.39, 130.69,130.08, 129.18, 128.89, 128.35, 128.29, 128.16, 127.27, 122.09, 113.48,63.02, 52.74, 47.32. ESI-MS m/z: 383.225[M]+。
: （E）-1-（4-（4-（2,4-甲基苯基）哌嗪-1-基）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率: 63%；m.p: 134.7-135.1℃; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.9Hz, 2H), 7.83 (d, J = 15.6 Hz, 1H), 7.68 (dd, J = 7.7, 1.4 Hz, 2H), 7.61 (d,J = 15.6 Hz, 1H), 7.47 – 7.40 (m, 3H), 7.07 (s, 1H), 7.04 – 6.96 (m, 4H),3.58 – 3.51 (m, 4H), 3.06 (dd, J = 13.4, 8.5 Hz, 4H), 2.35 (s, 3H), 2.33 (s,3H).13C NMR (151 MHz, CDCl3) δ 188.08, 171.16, 154.33, 148.62, 143.14, 135.38,133.13, 132.63, 131.94, 130.71, 130.10, 128.89, 128.31, 127.21, 122.08,118.94, 113.61, 51.79, 47.95, 21.06, 20.73. ESI-MS m/z: 397.369[M+1]+。
: （E）-1-（4-（4-（3-氯苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率: 51%; m.p: 199.5-201.6℃; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.7 Hz,2H), 7.83 (d, J = 15.6 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 15.6Hz, 1H), 7.48 – 7.39 (m, 3H), 7.23 (t, J = 8.1 Hz, 1H), 6.99 (d, J = 8.7 Hz,2H), 6.94 (d, J = 13.2 Hz, 1H), 6.87 (dd, J = 16.6, 8.1 Hz, 2H), 3.61 – 3.53(m, 4H), 3.42 – 3.34 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 171.16, 153.82,151.94, 143.33, 135.31, 135.10, 130.72, 130.19, 130.16, 128.91, 128.71,128.31, 121.99, 119.85, 116.01, 114.10, 113.75, 48.52, 47.26. ESI-MS m/z:403.282[M+1]+。
: （E）-1-（4-（4-（2,3-二氯苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率: 58%; m.p: 139.8-141.1℃; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.8Hz, 2H), 7.83 (d, J = 15.6 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.60 (d, J = 15.6Hz, 1H), 7.47 – 7.39 (m, 3H), 7.25 – 7.18 (m, 2H), 7.04 – 6.97 (m, 3H), 3.62– 3.56 (m, 4H), 3.26 – 3.20 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 188.15,154.16, 150.79, 143.29, 135.33, 134.24, 130.71, 130.15, 128.91, 128.62,128.35, 127.71, 127.58, 125.10, 122.02, 118.61, 113.80, 51.12, 47.69. ESI-MSm/z: 438.329[M]+。
:（E）-1-（4-（4-（3-甲氧基苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体;收率: 52%; m.p: 127.6-128.3℃; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.9 Hz,2H), 7.82 (d, J = 15.6 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.60 (d, J = 15.6 Hz,1H), 7.47 – 7.39 (m, 3H), 7.26 – 7.21 (m, 1H), 6.99 (d, J = 8.9 Hz, 2H), 6.61(dd, J = 8.2, 2.1 Hz, 1H), 6.53 (t, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.1, 2.2Hz, 1H), 3.83 (d, J = 3.8 Hz, 3H), 3.56 (dd, J = 15.5, 10.2 Hz, 4H), 3.41 –3.36 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 188.11, 160.69, 153.96, 152.32,143.25, 135.34, 130.72, 130.13, 129.97, 128.90, 128.55, 128.31, 122.03,113.68, 109.04, 104.90, 102.83, 55.24, 48.95, 47.36. ESI-MS m/z: 399.338[M+1]+。
: （E）-1-（4-（4-（4-甲氧基苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率: 55%; m.p : 215.3-217.1℃; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.7Hz, 2H), 7.82 (d, J = 15.6 Hz, 1H), 7.67 (d, J = 7.0 Hz, 2H), 7.60 (d, J =15.6 Hz, 1H), 7.47 – 7.38 (m, 3H), 7.04 – 6.95 (m, 4H), 6.90 (d, J = 8.9 Hz,2H), 3.81 (s, 3H), 3.60 – 3.52 (m, 4H), 3.31 – 3.20 (m, 4H). 13C NMR (151 MHz,CDCl3) δ 188.15, 154.31, 154.07, 145.36, 143.26, 135.34, 130.72, 130.13,128.90, 128.52, 128.31, 122.04, 118.69, 114.57, 113.75, 55.60, 50.69, 47.61.ESI-MS m/z: 399.352[M+1]+。
: （E）-1-（4-（4-（2-氯苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率: 51%; m.p: 119.8-122.1℃; 1H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz,2H), 7.83 (d, J = 15.6 Hz, 1H), 7.68 (d, J = 6.6 Hz, 2H), 7.61 (d, J = 15.6Hz, 1H), 7.43 (p, J = 6.2 Hz, 4H), 7.32 – 7.25 (overlap, 1H), 7.10 (d, J =7.8 Hz, 1H), 7.06 – 6.99 (m, 3H), 3.63 – 3.57 (m, 4H), 3.28 – 3.23 (m, 4H).13C NMR (151 MHz, CDCl3) δ 188.11, 154.23, 148.85, 143.22, 135.36, 130.79,130.72, 130.14, 128.93, 128.91, 128.49, 128.33, 127.73, 124.18, 122.06,120.40, 113.74, 51.03, 47.70. ESI-MS m/z: 403.302[M+1]+。
: （E）-1-（4-（4-（3-三氟甲基苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率: 57%; m.p: 200.9-202.5℃; 1H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 8.9Hz, 2H), 7.83 (d, J = 15.6 Hz, 1H), 7.67 (dd, J = 7.6, 1.6 Hz, 2H), 7.59 (d,J = 15.6 Hz, 1H), 7.47 – 7.40 (m, 4H), 7.19 – 7.11 (m, 3H), 7.00 (d, J = 9.0Hz, 2H), 3.59 (dd, J = 6.2, 4.2 Hz, 4H), 3.47 – 3.42 (m, 4H). 13C NMR (151MHz, CDCl3) δ 188.14, 153.79, 151.02, 143.37, 135.31, 131.71, 131.50, 130.74,130.18, 129.74, 128.92, 128.77, 128.32, 121.99, 118.96, 116.38, 113.79,112.36, 48.51, 47.28. ESI-MS m/z: 437.292[M+1]+。
: （E）-1-（4-（4-苯基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮；黄色固体; 收率:60%; m.p: 208.3-210.1℃; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H),7.83 (d, J = 15.6 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.60 (d, J = 15.6 Hz, 1H),7.49 – 7.40 (m, 3H), 7.33 (t, J = 7.9 Hz, 2H), 7.00 (dd, J = 8.3, 5.3 Hz,4H), 6.93 (dd, J = 15.4, 8.1 Hz, 1H), 3.63 – 3.52 (m, 4H), 3.41 – 3.35 (m,4H). 13C NMR (151 MHz, CDCl3) δ 188.12, 153.99, 150.97, 143.26, 135.35,130.73, 130.14, 129.29, 128.91, 128.57, 128.32, 122.04, 120.33, 116.37,113.72, 49.10, 47.45. ESI-MS m/z: 369.280[M+1]+。
: （E）-1-（4-（4-（3,4-二氯苯基）-1-哌嗪）苯基）-3-（3,4-二甲氧基苯基）-2-烯-1-丙酮；黄色固体; 收率: 57%; m.p: 196.8-198.5℃; 1H NMR (600 MHz, CDCl3) δ 7.79(t, J = 11.3 Hz, 1H), 7.45 (d, J = 15.5 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H),7.26 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1H), 7.01 (dd, J = 23.8, 5.8Hz, 3H), 6.93 (d, J = 8.3 Hz, 1H), 6.81 (dd, J = 8.9, 2.8 Hz, 1H), 3.97 (d, J= 14.3 Hz, 6H), 3.58 – 3.53 (m, 4H), 3.40 – 3.33 (m, 4H). 13C NMR (151 MHz,CDCl3) δ 188.21, 153.63, 151.16, 150.29, 149.23, 143.56, 132.97, 130.62,130.61, 129.10, 128.27, 122.82, 122.79, 119.91, 117.48, 115.53, 113.86,111.16, 110.17, 56.02, 56.00, 48.52, 47.27. ESI-MS m/z: 497.292[M]+。
: （E）-1-（4-（4-（2,4-二甲基苯基）-1-哌嗪）苯基）-3-（3,4-二甲氧基苯基）-2-烯-1-丙酮；黄色固体;收率: 61%; m.p: 191.2-193.5℃; 1H NMR (600 MHz, CDCl3) δ8.05 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 15.5 Hz, 1H), 7.46 (d, J = 15.5 Hz,1H), 7.26 (dd, J = 8.3, 1.8 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.07 (s, 1H),7.04 – 6.96 (m, 4H), 6.93 (d, J = 8.3 Hz, 1H), 3.97 (d, J = 16.0 Hz, 6H),3.58 – 3.52 (m, 4H), 3.09 – 3.04(m, 4H), 2.38 – 2.29 (d, 6H). 13C NMR (151MHz, CDCl3) δ 188.20, 154.24, 151.08, 149.22, 148.62, 143.33, 133.13, 132.63,131.94, 130.61, 128.58, 128.37, 127.14, 122.76, 120.04, 118.94, 113.64,111.15, 110.17, 56.01, 56.00, 51.80, 48.01, 20.73, 17.71. ESI-MS m/z:457.325[M+1]+。
:（E）-1-（4-（4-（2,4-二氯苯基）-1-哌嗪）苯基）-3-（4-氯苯基）-2-烯-1-丙酮；黄色固体; 收率:56%; m.p: 189.5-191.7℃; 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J =9.0 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 7.59 (dd, J = 17.4, 12.0 Hz, 3H),7.44 – 7.39 (m, 2H), 7.07 (s, 1H), 7.00 (tt, J = 10.8, 5.4 Hz, 4H), 3.59 –3.53 (m, 4H), 3.10 – 3.05 (m, 4H), 2.35 (s, 3H), 2.31 (d, J = 3.9 Hz, 3H).13CNMR (151 MHz, CDCl3) δ 187.74, 154.40, 148.59, 141.63, 135.92, 133.89,133.17, 132.64, 131.95, 130.73, 129.45, 129.16, 128.11, 127.15, 122.51,118.94, 113.57, 51.78, 47.91, 20.73, 17.71。
:（E）-1-（4-（4-（3,4-二氯苯基）-1-哌嗪）苯基）-3-（3,4-二甲氧基苯基）-2-烯-1-丙酮；黄色固体; 收率: 54%; m.p: 234.6-236.4℃; 1H NMR (600 MHz, CDCl3) δ 8.04(d, J = 9.0 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 7.59 (dd, J = 20.1, 12.0 Hz,3H), 7.43 – 7.39 (m, 2H), 7.25 – 7.19 (m, 2H), 7.03 – 6.99 (m, 3H), 3.62 –3.58 (m, 4H), 3.26 – 3.21 (m, 4H).13C NMR (151 MHz, CDCl3) δ 187.77, 154.22,150.77, 141.75, 135.97, 134.26, 133.84, 130.73, 129.46, 129.17, 128.41,127.71, 127.59, 125.12, 122.45, 118.60, 113.77, 51.11, 47.65.
2q: （E）-1-（4-（4-（4-甲氧基苯基）-1-哌嗪）苯基）-3-（4-氯苯基）-2-烯-1-丙酮；黄色固体; 收率: 58%; m.p: 234.2-236.8℃;1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 9.0Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 7.58 (dd, J = 21.3, 12.0 Hz, 3H), 7.41(d, J = 8.5 Hz, 2H), 7.02 – 6.97 (m, 4H), 6.92 – 6.88 (m, 2H), 3.81 (s, 3H),3.60 – 3.54 (m, 4H), 3.28 – 3.22 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 187.75,154.33, 154.13, 145.34, 141.72, 135.95, 133.86, 130.74, 129.45, 129.17,128.31, 122.47, 118.69, 114.58, 113.72, 55.60, 50.68, 47.57. ESI-MS m/z:433.391[M+1]+。
: （E）-1-（4-（4-（2-甲氧基苯基）-1-哌嗪）苯基）-3-（4-氯苯基）-2-烯-1-丙酮；黄色固体; 收率: 57%; m.p: 139.8-141.5℃;1H NMR (600 MHz, CDCl3) δ 8.04 (d, J =9.0 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 7.58 (dd, J = 21.3, 12.0 Hz, 3H),7.41 (d, J = 8.5 Hz, 2H), 7.02 – 6.97 (m, 4H), 6.92 – 6.88 (m, 2H), 3.81 (s,3H), 3.60 – 3.54 (m, 4H), 3.28 – 3.22 (m, 4H). 13C NMR (151 MHz, CDCl3) δ187.73, 154.33, 152.33, 141.62, 140.83, 135.91, 133.89, 130.74, 129.45,129.16, 128.13, 123.48, 122.51, 121.10, 118.29, 113.58, 111.38, 55.48, 50.47,47.62. ESI-MS m/z: 433.343[M+1]+。
实施例2：一类含芳基磺酰基哌嗪类查尔酮制备方法
（1）哌嗪查尔酮3a的制备：
在50 ml 三口烧瓶中分别加入1.732g (7.68 mmol) 1a,1.274g (9.2 mmol) 碳酸钾,0.794g哌嗪, 5 mL DMF, 120℃反应6小时。将反应液冷却至室温，加水搅拌，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥半小时，将滤液浓缩，柱色谱纯化，洗脱剂梯度依次为：乙酸乙酯：石油醚：10:1，乙酸乙酯，甲醇。收率为58%；
参考化合物3a的制备方法制备3b、3c；
（2）芳基磺酰基哌嗪类查尔酮的制备：
将0.24g (0.8 mmol) 3a 溶于20 mL丙酮中，加入0.133g (1.2 equiv) 碳酸钾, 室温搅拌下加入(1.2 equiv) 4-氯苯基磺酰氯, 常温反应12小时。反应完毕，将反应液旋干，得到的固体产物依次用水和乙醇洗涤，然后乙醇和二氯甲烷重结晶即可得到目标产物4a。参考化合物4a的制备方法制备4b-4p.收率：67%~82%。
化合物4a-4p结构鉴定数据如下:
4a:（E）-1-（4-（4-（4-氯苯磺酰基）-1-哌嗪）苯基）-3-（4-氯苯基）-2-烯-1-丙酮; 黄色固体; 收率:78%；m.p:175.5-177.3℃1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.9 Hz,2H), 7.74 (ddd, J = 12.1, 8.3, 4.1 Hz, 3H), 7.56 (ddd, J = 8.8, 7.5, 5.8 Hz,4H), 7.53 – 7.49 (m, 1H), 7.40 (dd, J = 8.4, 4.1 Hz, 2H), 6.89 (d, J = 9.0Hz, 2H), 3.51 – 3.46 (m, 4H), 3.20 (dd, J = 12.7, 7.7 Hz, 4H).13C NMR (151MHz, CDCl3) δ 187.81, 153.37, 142.12, 139.88, 136.12, 133.92, 133.68, 130.67,129.59, 129.47, 129.29, 129.20, 122.22, 114.41, 47.29, 45.65. ESI-MS m/z:501.142[M]+。
（E）-1-（4-（4-（4-三氟甲氧基苯磺酰基）-1-哌嗪）苯基）-3-（4-氯苯基）-2-烯-1-丙酮; 黄色固体; 收率:77%；m.p:201.4-203.5℃1H NMR (600 MHz, CDCl3) δ 7.99 (d, J= 8.9 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.78 –7.73 (m, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 15.6 Hz, 1H), 7.40 (d, J= 8.4 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 3.53 – 3.47 (m, 4H), 3.27 – 3.23 (m,4H). 13C NMR (151 MHz, CDCl3) δ 187.82, 153.34, 142.16, 139.21, 136.13,133.66, 130.67, 129.47, 129.38, 129.20, 128.29, 126.44, 122.19, 114.48,47.35, 45.66. ESI-MS m/z: 558.492[M+Na]+。
（E）-1-（4-（4-（4-甲基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体; 收率:81%；m.p: 223.1-225.5℃1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.9 Hz,2H), 7.80 (d, J = 15.6 Hz, 1H), 7.73 – 7.62 (m, 4H), 7.54 (d, J = 15.6 Hz,1H), 7.47 – 7.41 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H),3.51 – 3.43 (m, 4H), 3.21 – 3.13 (m, 4H), 2.46 (s, 3H).13C NMR (151 MHz,CDCl3) δ 188.14, 153.37, 144.08, 143.56, 135.20, 132.26, 130.65, 130.24,129.84, 129.29, 128.92, 128.32, 127.88, 121.84, 114.29, 47.26, 45.70, 21.56.ESI-MS m/z: 447.262[M+1]+。
（E）-1-（4-（4-（4-氯苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体;收率:68%；m.p: 191.8-193.7℃1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.9 Hz, 2H),7.81 (d, J = 15.6 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.65 (dd, J = 7.4, 1.9 Hz,2H), 7.60 – 7.51 (m, 3H), 7.47 – 7.40 (m, 3H), 6.91 (t, J = 14.0 Hz, 2H),3.53 – 3.43 (m, 4H), 3.25 – 3.16 (m, 4H).13C NMR (151 MHz, CDCl3) δ 188.17,153.30, 143.65, 139.87, 135.18, 133.93, 130.65, 130.27, 129.59, 129.52,129.20, 128.92, 128.33, 121.82, 114.45, 47.34, 45.67. ESI-MS m/z: 467.235[M+1]+。
（E）-1-（4-（4-（2-萘磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体;收率:71%；m.p:168.5-170.6℃1H NMR (600 MHz, CDCl3) δ 8.39 (t, J = 4.7 Hz, 1H),8.02 (d, J = 8.4 Hz, 2H), 7.96 (t, J = 9.0 Hz, 3H), 7.83 – 7.76 (m, 2H), 7.71– 7.62 (m, 4H), 7.52 (d, J = 15.6 Hz, 1H), 7.45 – 7.39 (m, 3H), 6.87 (d, J =9.0 Hz, 2H), 3.51 – 3.44 (m, 4H), 3.26 (dd, J = 13.7, 8.8 Hz, 4H). 13C NMR(151 MHz, CDCl3) δ 188.15, 153.34, 143.56, 135.19, 135.03, 132.46, 132.23,130.63, 130.23, 129.44, 129.26, 129.08, 128.90, 128.31, 127.99, 127.76,122.88, 121.83, 114.33, 47.34, 45.78. ESI-MS m/z:483.220[M+1]+。
（E）-1-（4-（4-（4-溴苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体;收率:79% m.p: 203.6-205.2℃1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.9 Hz, 2H),7.81 (d, J = 15.6 Hz, 1H), 7.72 (t, J = 7.1 Hz, 2H), 7.70 – 7.61 (m, 4H),7.55 (d, J = 15.6 Hz, 1H), 7.46 – 7.39 (m, 3H), 6.90 (t, J = 7.8 Hz, 2H),3.52 – 3.45 (m, 4H), 3.24 – 3.17 (m, 4H).13C NMR (151 MHz, CDCl3) δ 188.17,153.29, 143.65, 135.18, 134.45, 132.58, 130.65, 130.27, 129.52, 129.27,128.92, 128.36, 128.33, 121.82, 114.45, 47.39, 45.66. ESI-MS m/z: 511.255[M]+。
（E）-1-（4-（4-（4-甲氧基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体; 收率:80% m.p: 194.2-196.5℃ 1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.9Hz, 2H), 7.80 (d, J = 15.6 Hz, 1H), 7.74 (t, J = 9.3 Hz, 2H), 7.69 – 7.61 (m,2H), 7.55 (d, J = 15.6 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.04 (d, J = 8.9 Hz,2H), 6.89 (d, J = 8.9 Hz, 2H), 3.53 – 3.43 (m, 4H), 3.22 – 3.13 (m, 4H).13CNMR (151 MHz, CDCl3) δ 188.16, 163.31, 153.38, 143.57, 135.21, 130.65,130.24, 129.98, 129.29, 128.91, 128.32, 126.80, 121.84, 114.39, 114.29,55.66, 47.25, 45.71. ESI-MS m/z: 463.215[M+1]+。
（E）-1-（4-（4-（2，4，6-三甲基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮;黄色固体; 收率:81%; m.p: 198.7-200.4℃ 1H NMR (600 MHz, CDCl3) δ 8.00 (d, J =8.9 Hz, 2H), 7.79 (d, J = 15.6 Hz, 1H), 7.66 – 7.61 (m, 2H), 7.54 (d, J =15.6 Hz, 1H), 7.44 – 7.38 (m, 3H), 6.98 (d, J = 5.8 Hz, 2H), 6.91 (d, J = 8.9Hz, 2H), 3.44 – 3.37 (m, 4H), 3.36 – 3.31 (m, 4H), 2.65 (d, J = 9.7 Hz, 6H),2.32 (d, J = 3.7 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 188.19, 153.65, 143.53,143.03, 140.65, 135.24, 132.09, 130.98, 130.65, 130.22, 129.28, 128.91,128.32, 121.90, 114.33, 47.33, 43.97, 22.97, 21.01. ESI-MS m/z: 475.298[M+1]+。
（E）-1-（4-（4-（苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮;黄色固体; 收率:75%; m.p: 206.208.4℃1H NMR (600 MHz, CDCl3) δ 7.98 (t, J = 9.4 Hz, 2H),7.85 – 7.77 (m, 3H), 7.68 – 7.63 (m, 3H), 7.61 – 7.51 (m, 3H), 7.46 – 7.40(m, 3H), 6.89 (d, J = 9.0 Hz, 2H), 3.53 – 3.45 (m, 4H), 3.20 (dd, J = 13.6,8.7 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 188.16, 153.37, 143.59, 135.35,135.20, 133.18, 130.64, 130.25, 129.39, 129.23, 128.92, 128.32, 127.82,121.83, 114.35, 47.31, 45.71. ESI-MS m/z: 433.251[M+1]+。
（E）-1-（4-（4-（4-三氟甲氧基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮;黄色固体; 收率:76%; m.p: 181.6-183.1℃1H NMR (600 MHz, CDCl3) δ 8.03 – 7.97(m, 2H), 7.89 – 7.85 (m, 2H), 7.81 (d, J = 15.6 Hz, 1H), 7.65 (dd, J = 7.4,2.0 Hz, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.46 – 7.38 (m, 5H), 6.91 (d, J = 9.0Hz, 2H), 3.49 (dd, J = 11.2, 6.3 Hz, 4H), 3.22 (dd, J = 13.2, 8.3 Hz, 4H). 13CNMR (151 MHz, CDCl3) δ 188.17, 153.31, 152.55, 143.67, 135.17, 133.83,130.65, 130.28, 129.95, 129.57, 128.92, 128.33, 121.80, 121.02, 119.35,114.48, 47.37, 45.69. ESI-MS m/z: 517.235[M+1]+。
（E）-1-（4-（4-（2,4,6-三异丙基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮;黄色固体; 收率:78%; m.p:197.8-199.8℃ 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J =9.0 Hz, 2H), 7.82 (d, J = 15.6 Hz, 1H), 7.66 (dd, J = 7.6, 1.8 Hz, 2H), 7.57(d, J = 15.6 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.21 (d, J = 5.8 Hz, 2H), 6.95 (d,J = 9.0 Hz, 2H), 3.43 (dd, J = 6.5, 3.4 Hz, 4H), 3.40 – 3.36 (m, 4H), 1.30 –1.28 (m, 21H).13C NMR (151 MHz, CDCl3) δ 188.20, 153.68, 153.61, 151.97,143.55, 135.24, 130.66, 130.23, 129.30, 129.19, 128.91, 128.33, 124.06,121.90, 114.30, 47.35, 43.88, 34.22, 29.40, 24.92, 23.56. ESI-MS m/z: 559.292[M+1]+。
（E）-1-（4-（4-（4-叔丁基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体; 收率:69%；m.p: 221.4-223.1℃1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.9Hz, 2H), 7.80 (d, J = 15.6 Hz, 1H), 7.72 (t, J = 9.2 Hz, 2H), 7.65 (dd, J =7.4, 1.8 Hz, 2H), 7.56 (dd, J = 20.1, 12.1 Hz, 3H), 7.46 – 7.39 (m, 3H), 6.90(d, J = 8.9 Hz, 2H), 3.47 (dd, J = 16.3, 11.1 Hz, 4H), 3.24 – 3.17 (m, 4H),1.37 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 193.27, 157.00, 153.55, 137.62,135.38, 132.18, 131.22, 130.65, 129.30, 128.91, 128.52, 128.32, 128.22,127.75, 127.25, 126.18, 114.06, 47.14, 45.70, 35.23, 31.07. ESI-MS m/z:489.400[M+1]+。
（E）-1-（4-（4-（4-三氟甲基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮; 黄色固体; 收率:66%；m.p: 203.5-206.8℃1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.9Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.81 (d, J =15.6 Hz, 1H), 7.70 – 7.62 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.47 – 7.40 (m,3H), 6.90 (d, J = 8.9 Hz, 2H), 3.54 – 3.45 (m, 4H), 3.30 – 3.19 (m, 4H). 13CNMR (151 MHz, CDCl3) δ 193.26, 153.41, 137.74, 135.36, 131.22, 130.65,129.31, 128.93, 128.55, 128.49, 128.27, 128.23, 127.17, 126.43, 114.53,114.29, 47.26, 45.63. ESI-MS m/z: 501.757[M+1]+。
（E）-1-（4-（4-（3，4,二甲氧基苯磺酰基）-1-哌嗪）苯基）-3-苯基-2-烯-1-丙酮;黄色固体; 收率:73%; m.p:176.3-178.8℃ 1H NMR (600 MHz, CDCl3) δ 8.00 (d, J =9.0 Hz, 2H), 7.81 (d, J = 15.6 Hz, 1H), 7.65 (dd, J = 7.4, 1.9 Hz, 2H), 7.55(d, J = 15.6 Hz, 1H), 7.47 – 7.38 (m, 4H), 7.26 (d, J = 2.1 Hz, 1H), 6.99 (t,J = 7.1 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 3.96 (t, J = 4.1 Hz, 6H), 3.47(dd, J = 16.9, 11.7 Hz, 4H), 3.19 (dd, J = 13.5, 8.6 Hz, 4H). 13C NMR (151MHz, CDCl3) δ 188.16, 153.38, 153.01, 149.22, 143.59, 135.20, 130.65, 130.25,129.35, 128.92, 128.32, 126.96, 121.84, 121.81, 114.33, 110.74, 110.30,56.34, 56.23, 47.30, 45.73. ESI-MS m/z: 493.240[M+Na]+。
（E）-1-（4-（4-（4-溴苯磺酰基）-1-哌嗪）苯基）-3-（3,4-二甲氧基苯基）-2-烯-1-丙酮; 黄色固体; 收率:76%; m.p: 209.6-211.3℃1H NMR (600 MHz, CDCl3) δ 7.99 (d,J = 8.9 Hz, 2H), 7.80 – 7.70 (m, 3H), 7.70 – 7.64 (m, 2H), 7.40 (d, J = 15.5Hz, 1H), 7.24 (dd, J = 8.3, 1.8 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.94 –6.86 (m, 3H), 3.96 (d, J = 10.6 Hz, 6H), 3.46 (dd, J = 14.2, 9.0 Hz, 4H),3.24 – 3.16 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 188.26, 153.21, 151.23,149.24, 143.83, 134.45, 132.57, 130.56, 129.80, 129.27, 128.36, 128.16,122.87, 119.77, 114.50, 111.15, 110.17, 56.02, 56.00, 47.41, 45.67. ESI-MS m/z: 572.473[M+1]+。
（E）-1-（4-（4-（4-甲氧基苯磺酰基）-1-哌嗪）苯基）-3-（3,4-二甲氧基苯基）-2-烯-1-丙酮; 黄色固体; 收率:72%; m.p: 198.5-200.1℃ 1H NMR (600 MHz, CDCl3) δ7.99 (d, J = 8.9 Hz, 2H), 7.75 (dd, J = 12.3, 5.8 Hz, 3H), 7.40 (d, J = 15.5Hz, 1H), 7.24 (dd, J = 8.3, 1.8 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.03 (d, J= 8.9 Hz, 2H), 6.95 – 6.85 (m, 3H), 3.96 (d, J = 10.9 Hz, 6H), 3.90 (s, 3H),3.46 (dd, J = 16.8, 11.6 Hz, 4H), 3.21 – 3.11 (m, 4H). 13C NMR (151 MHz,CDCl3) δ 188.25, 163.31, 153.29, 151.21, 149.23, 143.75, 130.55, 129.98,129.56, 128.18, 126.79, 122.86, 119.80, 114.39, 114.33, 111.15, 110.16,56.02, 55.99, 55.67, 47.31, 45.72. ESI-MS m/z:523.298[M+1]+。
通过本发明制备的上述芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物，其纯度在99%以上。
以下表给出了实施例1和实施例2制备的目标化合物的结构式：
| 编号 | 结构 | 编号 | 结构 |
| 2a | 2b | ||
| 2c | 2d | ||
| 2e | 2f | ||
| 2g | 2h | ||
| 2i | 2j | ||
| 2k | 2l | ||
| 2m | 2n | ||
| 2o | 2p | ||
| 2q | 2r | ||
| 4a | 4b | ||
| 4c | 4d | ||
| 4e | 4f | ||
| 4g | 4h | ||
| 4i | 4j | ||
| 4k | 4l | ||
| 4m | 4n | ||
| 4o | 4p |
药理实验
体内抗炎活性研究。
实验材料
实验动物：SPF级昆明种系小鼠，雄性，体重18-22g，均为广西医科大学实验动物中心提供。实验动物生产许可证号为：SCXKG桂2014-0002，实验动物使用许可证：XYKG桂2014-0003。；动物饲料是由广西医科大学实验动物中心生产（标准饲料）。药品和试剂：醋酸地塞米松片，浙江仙琚制药股份有限公司，批号：141002；
阿司匹林肠溶片，沈阳奥吉娜药业有限公司，批号：141019；
受试药，由广西大学提供。统计学处理：所有数据均以±s表示，两组间比较采用t检验。
试验方法：
小鼠二甲苯致耳廓肿胀实验
所有受试药分成三批实验，每次取小鼠，18-22g，雌雄各半，10只/组，给药组灌胃给予（i.g.）。组别分别为：空白对照组、地塞米松对照组、阿司匹林组、各受试药组。空白对照组给予等体积的生理盐水，给药后1h，于小鼠右耳正反面均匀涂抹二甲苯50μl/只，1h后脱颈椎处死，用9mm打孔器在左右相同的部位打下耳片，精确称重，计算肿胀度（mg）及肿胀抑制率（%）；
肿胀度（mg）=右耳耳片重（mg）-左耳耳片重（mg）
抑制率=（空白组平均肿胀度-给药组平均肿胀度）/空白组平均肿胀度×100%
角叉菜胶致小鼠足趾肿胀的影响
动物分组及给药方法同前（2.1），末次给药后1h，在每鼠右侧足趾皮下注射1%角叉菜胶0.05ml，5h后沿踝关节剪下左右两足，称重，计算肿胀度及肿胀抑制率；
肿胀度（mg）=右足重量（mg）-左足重量(mg)
抑制率=（空白组平均肿胀度-给药组平均肿胀度）/空白组平均肿胀度×100%。
实验结果：
对二甲苯致小鼠耳肿胀的影响
与空白组相比，A15、A20、0号化合物和1号化合物无消肿作用。但地塞米松组、阿司匹林组及其他各给药组耳肿胀度均有下降。见表1；
表1 受试药物对小鼠耳肿胀度的影响（±s） n=10
| 组别 | 剂量(mg/kg) | 耳肿胀度（mg） | 肿胀抑制率（%） |
| 空白 | 2.29±1.60 | ||
| 地塞米松 | 5 | 0.47±0.23* | 79.5 |
| 阿司匹林 | 100 | 0.74±0.68* | 67.7 |
| 2a | 40 | 0.87±0.49* | 62.01 |
| 2b | 40 | 0.99±1.12 | 56.77 |
| 2c | 40 | 1.48±1.56 | 35.37 |
| 2d | 40 | 0.67±0.51* | 70.74 |
| 2e | 40 | 0.63±0.45* | 72.49 |
| 2f | 40 | 0.86±0.52* | 62.45 |
| 2g | 40 | 0.95±0.78* | 58.52 |
| 2h | 40 | 1.49±1.13 | 34.93 |
| 2i | 40 | 0.88±0.95* | 61.57 |
| 2j | 40 | 0.51±0.47* | 77.73 |
| 2k | 40 | 0.96±1.21 | 58.08 |
| 2l | 40 | 1.63±1.25 | 28.82 |
| 2m | 40 | 1.21±1.24 | 47.16 |
| 2n | 40 | 1.92±1.74 | 16.16 |
| 2o | 40 | 1.26±0.91 | 44.98 |
| 2p | 40 | 1.53±0.79 | 33.19 |
| 2q | 40 | 0.85±0.81* | 62.88 |
| 2r | 40 | 2.00±1.55 | 12.66 |
| 4a | 40 | 1.91±1.44 | 16.59 |
| 4b | 40 | 0.93±0.93* | 59.39 |
| 4c | 40 | 0.52±0.71* | 77.29 |
| 4d | 40 | 1.82±1.12 | 20.52 |
| 4e | 40 | 1.87±1.92 | 18.34 |
| 4f | 40 | 1.32±1.19 | 42.36 |
| 4g | 40 | 1.45±0.85 | 36.68 |
| 4h | 40 | 1.64±1.36 | 28.38 |
| 4i | 40 | 0.97±1.06* | 57.64 |
| 4j | 40 | 0.76±0.71* | 66.81 |
| 4k | 40 | 1.35±0.98 | 41.05 |
| 4l | 40 | 1.80±1.50 | 21.40 |
| 4m | 40 | 1.07±0.66* | 53.28 |
| 4n | 40 | 1.96±1.24 | 14.41 |
| 4o | 40 | 1.54±1.08 | 32.75 |
| 4p | 40 | 1.36±0.89 | 40.61 |
注：与正常组比较，*P<0.05。
活性实验表明，合成的查尔酮衍生物均有明显的抗炎活性，2d、2e在40 mg/kg剂量下的抗炎活性与阿司匹林（100 mg/kg）相当。而2j、4c在40 mg/kg剂量下的抗炎活性明显优于阿司匹林（100 mg/kg）并与地塞米松（5mg/kg）相当。
Claims (3)
1.芳基哌嗪查尔酮衍生物，其结构特征如下：
通式Ⅰ：
通式Ⅱ：
。
2.根据权利要求1所述的芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物2a-2r和4a-4p的制备方法，其特征在于以氟代苯乙酮和取代的苯甲醛为起始原料，经过碱性条件下的缩合得到氟代查尔酮，再用芳基哌嗪取代得到芳基哌嗪查尔酮；如果用哌嗪环取代氟代查尔酮得到哌嗪查尔酮中间体，进一步用芳基磺酰基哌嗪取代得到芳基磺酰基哌嗪查尔酮。
3.根据权利要求1所述的芳基哌嗪和芳基磺酰基哌嗪类查尔酮衍生物在制备抗炎药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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