CN110117288A - 7β-甲基-奈培酮衍生物及其制备方法和用途 - Google Patents

7β-甲基-奈培酮衍生物及其制备方法和用途 Download PDF

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CN110117288A
CN110117288A CN201810123729.6A CN201810123729A CN110117288A CN 110117288 A CN110117288 A CN 110117288A CN 201810123729 A CN201810123729 A CN 201810123729A CN 110117288 A CN110117288 A CN 110117288A
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李炜
邵黎明
孙惠姣
刘景根
王瑜珺
徐学军
孔令辉
肖立
吴海灏
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Abstract

本发明属于化学制药领域，涉及具有通式(I)的7β‑甲基‑奈培酮衍生物化合物及其制备方法，本发明的具有通式(I)的化合物；以蒂巴因为原料，通过N‑脱甲基、N‑酰化、Diels‑Alder反应、还原、氧化、格氏反应等相关转化方法合成，所述通式(I)的化合物属于阿片受体配基，采用放射性受体配体结合实验，测定配基对于阿片受体三种亚型的亲和力以及选择性，采用[35S]GTPγS结合实验测定配基的激动抑制活性，结果显示，所述化合物具有镇痛、抗抑郁、阿片成瘾性戒断、止痒等作用，可用于制备阿片受体治疗药物，用于临床镇痛、抗抑郁、阿片成瘾性戒断治疗或止痒治疗。

Description

7β-甲基-奈培酮衍生物及其制备方法和用途
技术领域
本发明属于化学制药领域，涉及具有通式(I)的7β-甲基-奈培酮衍生物化合物及其制备方法，并涉及所述衍生物在制备阿片受体治疗药物中的用途。
背景技术
研究公开了阿片受体主要分为μ、δ、κ等三种受体亚型。吗啡、哌替啶等临床上所用的中枢镇痛药物均属于μ激动剂类型，且大多存在镇痛、镇静、呼吸抑制以及成瘾等副作用。研究显示，δ受体在中枢神经系统广泛分布，它对μ受体具有调节作用，参与耐受性依赖性的形成；κ受体在脑内广泛表达，激动κ受体产生拮抗μ受体激动作用、阻断药物成瘾性、焦虑、利尿、致幻等作用。有文献报道κ配基具有多种药理活性，如镇痛(见Dykstra LA等，J.Pharmacol.Exp.Ther.1987, 242,413-420)、止痒(见Husbands SM等，J.Pharmacol.Exp.Ther.2009,328, 193-200)、抗抑郁(见Portoghese PS等,Life Sci,1987,40,1287-92)。μ/κ等多重作用配基在临床上也具有广泛应用，如镇痛、可卡因成瘾戒断治疗(Neumeyer JL 等，J.Med.Chem.2000,43,114–122)等，代表药物有布托啡诺、丁丙诺啡；布托啡诺用于治疗癌性疼痛、手术后疼痛，副作用弱于吗啡；丁丙诺啡(buprenorphine)是奥维醇类化合物，临床上用于镇痛和对阿片类成瘾患者的戒断治疗。此外， Alkermes公司开发的抗抑郁药物ALKS 5461(丁丙诺啡与ALKS 33组成的复方) 已完成临床III期试验，证实对现有抗抑郁药物治疗无效的难治性抑郁症有疗效。因此κ配基及κ/μ双重配基在制备疼痛、抑郁、阿片成瘾性、瘙痒等治疗用药方面具有良好的应用前景。
基于现有技术的基础，本申请的发明人拟提供具有通式(I)的7β-甲基-奈培酮衍生物化合物及其制备方法和在制备阿片受体治疗药物中的用途。
发明内容
本发明的目的是基于现有技术的基础，提供作为阿片受体配基的化合物及其制备方法和药物用途，尤其涉及具有通式(I)的7β-甲基-奈培酮衍生物化合物及其制备方法和在制备阿片受体治疗药物中的用途。
所述的阿片受体治疗药物可用于镇痛、抗抑郁、阿片成瘾性戒断治疗、止痒等治疗。
本发明提供了作为阿片受体配基的化合物，具有以下通式(I)：
其中
R1表示H或CH3；
R2表示-CH＝CH-或-CH2-CH2-；
R3表示H或CH3；
R4表示苯基及取代苯基或萘基及取代萘基，取代基由以下基团中的一个或两个组成：C1-C3烷基,C1-C3烷氧基，-X,-CX3，其中X表示F,Cl,Br。
本发明的具有通式(I)的化合物；以蒂巴因为原料，通过N-脱甲基、N-酰化、Diels-Alder反应、还原、氧化、格氏反应等相关转化方法合成；
式中R1＝H的衍生物可以由(I)式中R1＝CH3的衍生物在一定条件下转化制备；所述的转化制备条件是指BBr3/CH2Cl2，不同浓度的H2SO4、不同浓度的 HBr、甲磺酸或者KOH/一缩二乙二醇(DEG)，丙硫醇钠/HMPA，优选 BBr3/CH2Cl2。
这是本领域所熟知的，(I)式中R2为-CH2CH2-的衍生物可以通过(I)式中R4 为-CH＝CH-的衍生物在一定还原性条件下转化制备，所述的还原条件包括但不限于Pd/C催化氢化下还原。
这也是本领域所熟知的，式中R3＝H的衍生物可以通过(I)式中R3＝CH3的衍生物在一定条件下转化得到，所述的转化条件为不同浓度的H2SO4、不同浓度的HBr、甲磺酸或者KOH/一缩二乙二醇(DEG)。
具有通式(I)的化合物可以通过具有通式(II)的化合物经格氏反应及氧化反应制备，所述的格氏反应条件包括但不限于卤代烃/正丁基锂/惰性溶剂或卤代烃 /Mg/惰性溶剂，所述惰性溶剂选自四氢呋喃、苯、甲苯、二甲苯及其混合物或无溶剂条件。所述的氧化反应条件包括但不限于草酰氯/无水二甲基亚砜或者戴斯- 马丁氧化剂或者2-碘酰基苯甲酸或者琼斯试剂。
本发明提供了通式(I)的7β-甲基-奈培酮衍生物化合物的制备方法，通过下述合成路线：
DIAD：偶氮二甲酸二异丙酯；Py：吡啶；EA：乙酸乙酯；R-Br：溴代烷；
DMP：戴斯-马丁试剂。
本发明涉及的具有通式(I)的化合物属于阿片受体配基，采用放射性受体配体结合实验，测定配基对于阿片受体三种亚型的亲和力以及选择性，采用 [35S]GTPγS结合实验测定配基的激动抑制活性，结果显示，通式(I)的化合物具有镇痛、抗抑郁、阿片成瘾性戒断、止痒等作用。
进一步，本发明的通式(I)的7β-甲基-奈培酮衍生物化合物可用于制备阿片受体治疗药物；所述的阿片受体治疗药物可用于临床镇痛，尤其是治疗或缓解手术期间的疼痛、慢性疼痛、神经性疼痛及癌症疼痛，以及抗抑郁、阿片成瘾性戒断治疗或止痒治疗。
具体实施方式
本发明将通过下面的实施例阐述。
实施例1同法可制备具有通式(I)的化合物，其中，
2的制备
在氩气保护下，向三颈瓶中加入蒂巴因(500mg,1.6mmol,1eq)无水乙腈 5mL、和偶氮二甲酸二异丙酯(0.34mL,1.7mmol,1.1eq)，回流4h，冷却至室温，过夜。反应液旋干，残余物加甲醇5mL溶解，加吡啶盐酸(185mg,1.6mmol, 1eq)搅拌两天。抽滤，用甲醇和乙酸乙酯洗滤饼，得215mg白色固体1，产率 40％，熔点：260.3℃(分解点)；
1H-NMR(400MHz,CDCl3)δ6.68(d,J＝8.2Hz,1H),6.62(d,J＝8.2Hz,1H), 5.50(d,J＝6.4Hz,1H),5.27(s,1H),5.03(d,J＝6.4Hz,1H),3.85(s,3H),3.60(s, 3H),3.17(ddd,Ja＝17.6,Jb＝13.8,Jc＝4.2Hz,3H),2.93(dd,Ja＝13.7Hz,Jb＝4.8 Hz,1H),2.07(td,Ja＝12.5Hz,Jb＝5.1Hz,3H),1.83(d,J＝12.5Hz,1H)ppm； ESIMS：m/z 298(M+H+,100)
3的制备
将2(50mg,0.15mmol,1eq)溶于5ml无水二氯甲烷中,加入Et3N(0.05mL,0.44mmol,2.6eq),0℃下搅拌，逐滴加入环丙酰氯(0.02mL,0.20mmol,1.2eq), 室温下搅拌过夜。用2*1mL 1mol/L盐酸洗，水洗，饱和食盐水洗涤，无水硫酸钠干燥，旋干得56mg微黄色油状物2，产率91％；
1H-NMR(400MHz,CDCl3)δ6.70(d,J＝8.3Hz,1H),6.62(d,J＝8.1Hz,1H), 5.64(d,J＝6.7Hz,1H),5.33(s,1H),5.05(d,J＝6.3Hz,1H),4.98(s,1H),3.86(s,3H), 3.61(s,3H),3.47-2.91(m,4H),1.79(d,J＝7.39Hz,2H),1.51-1.28(m,1H),0.83(m, 4H)ppm；ESIMS：m/z 366(M+H+,100)
4的制备
向2-甲基丙烯醛(1.3mL,4.4mmol,1.8eq)中加入3(890mg,2.4mmol,1 eq)、LiBF4(228mg,2.4mmol,1eq)，室温下搅拌20h。加水萃取两次，饱和食盐水洗，无水硫酸钠干燥，旋干。柱层析分离，石油醚：乙酸乙酯＝2:1洗脱，后出组分为265mg白色固体4，收率25％，熔点：166.3-170.3℃；
1H-NMR(400MHz,CDCl3)δ9.45(s,0.5H),9.36(s,0.5H),6.61(d,J＝8.1Hz, 1H),6.50(d,J＝7.9Hz,1H),6.06(t,J＝8.2Hz,1H),5.49(dd,Ja＝18.1Hz,Jb＝8.9 Hz,1H),5.25(d,J＝7.1Hz,0.5H),4.86(s,1H),4.75(d,J＝6.8Hz,0.5H),4.54(dd, Ja＝14.0Hz,Jb＝5.1Hz,0.5H),4.13(dd,Ja＝14.0Hz,Jb＝5.0Hz,0.5H),3.77(s, 3H),3.62(2s,3H),3.40(t,J＝11.8Hz,1H),3.17-2.95(m,2H),2.30-2.20(td,Ja＝ 13.0Hz,Jb＝7.9Hz,0.5H),2.17-2.09(td,Ja＝13.2Hz,Jb＝5.8Hz,0.5H),1.97-1.73 (m,4H),1.25(s,3H),1.00(m,2H),0.75(m,2H)ppm；ESIMS：m/z 436(M+H+, 100)
5的制备
将4(800mg,0.52mmol)溶于30mL乙酸乙酯中，氩气保护下加入64mg 10％Pd/C,氢气置换三次，室温搅拌24h。过滤得723mg白色泡沫5，产率90％，熔点：176.1-178.4℃；
1H NMR(400MHz,CDCl3)δ9.71(s,0.6H),9.70(s,0.4H),6.77(d,J＝7.7Hz, 1H),6.63(d,J＝8.0Hz,1H),4.92(d,J＝6.9Hz,1H),4.84(s,1H),4.54(dd,Ja＝14 Hz,Jb＝5.6Hz,0.6H),4.36(d,J＝6.9Hz,1H),4.06(dd,Ja＝15Hz,Jb＝6Hz, 0.6H),3.90(s,3H),3.50(s,2H),3.47(s,1H),3.35(td,Ja＝13.4,Jb＝3.2Hz,0.4H), 3.06(dd,Ja＝18.5Hz,Jb＝6.9Hz,0.6H),2.97(dd,Ja＝18.7Hz,Jb＝7.2Hz,0.4H), 2.89(d,J＝18.6Hz,1H),2.82(td,Ja＝13.7Hz,Jb＝4.0Hz,1H),2.72(d,J＝18.4 Hz,1H),2.46-2.38(m,1H),2.28(td,Ja＝13.1Hz,Jb＝5.7Hz,1H),2.17(td,Ja＝13.4Hz,Jb＝5.8Hz,1H),1.78-1.64(m,3.6H),1.51(d,J＝14.9Hz,0.4H),1.34-1.18 (m,5H),1.17-1.06(m,1H),1.04-0.95(m,2H),0.85-0.77(m,2H)ppm；ESIMS：m/z 438(M+H+,100)
6的制备
向装有5(500mg,1.1mmol,1eq)的茄型瓶中加入10mL无水四氢呋喃,冰水浴下搅拌，缓慢注入1M LiAlH4的四氢呋喃溶液(4.6mL,4.6mmol,4eq)，室温下搅拌2h；
冰水浴搅拌下，缓慢滴加H2O的THF溶液至不再有气泡产生，滴加1M NaOH水溶液至有大颗粒沉降，停止搅拌，上层为澄清溶液。抽滤，硅藻土助滤，热THF多次洗涤，滤液旋干。柱层析分离，石油醚：乙酸乙酯＝4:1洗脱，得410 mg无色油状物6，收率85％；
1H-NMR(400MHz,CDCl3)δ6.72(d,J＝8.1Hz,1H),6.57(d,J＝8.0Hz,1H), 4.87(s,1H),4.01(dd,Ja＝27.5Hz,Jb＝10.2Hz,2H),3.89(s,3H),3.53(s,3H), 3.20-2.92(m,3H),2.67-2.16(m,8H),1.79-1.51(m,4H),1.38(s,3H),1.29-1.01(m, 2H),0.90-0.74(m,3H),0.53-0.44(m,2H),0.11-0.07(m,2H)ppm；ESIMS：m/z 426 (M+H+,100)
7的制备
向干燥茄型瓶中加入草酰氯(0.1mL,1.2mmol,1.3eq)、3.5mL无水二氯甲烷，
-78℃搅拌；缓慢加入无水二甲亚砜(0.2mL,2.5mmol,2.6eq)溶于7mL 无水二氯甲烷配成的溶液，搅拌10min；将6(400mg,1.0mmol,1eq)溶于2mL 无水二氯甲烷，加入上述溶液中，搅拌40min；再加入三乙胺(0.6mL,4.7mmol, 5eq)，缓慢升至室温，搅拌2h。反应液用饱和氯化铵洗涤两次，饱和碳酸氢钠溶液洗涤一次，饱和食盐水洗涤一次，有机相用无水硫酸钠干燥，旋干得380 mg黄色油状物7，产率95％；
1H NMR(400MHz,CDCl3)δ9.77(s,1H),6.71(d,J＝7.5Hz,1H),6.57(d,J＝ 7.7Hz,1H),4.84(s,1H),3.89(s,3H),3.49(s,3H),3.21-2.89(m,3H),2.55-2.12(m, 11H),1.80-1.56(m,5H),1.35(s,4H),1.17-1.09(m,2H),0.86-0.71(m,2H), 0.56-0.06(m,4H)ppm；ESIMS：m/z 424(M+H+,100)
8的制备
向干燥、氩气保护的Schlenk管中加入溴苯或间甲氧基溴苯或4-溴联苯(0.1mmol,10eq)溶于0.5mL无水四氢呋喃配成的溶液，冷却至-78℃，缓慢滴加 n-BuLi的正己烷溶液(1mmol,10eq)，搅拌1h，缓慢注入7(0.09mmol,1eq) 溶于0.5mL无水四氢呋喃配成的溶液，-78℃搅拌2h。反应液用饱和氯化铵溶液淬灭，加水和乙酸乙酯萃取，饱和氯化钠溶液洗，有机层用无水无水硫酸钠干燥，旋干，制备分离，得8a-c；
8a，R＝Ph，13mg白色固体，产率21％
1H NMR(400MHz,CDCl3)δ7.44-7.37(m,2H),7.33-7.28(m,2H),7.27-7.22 (m,1H),6.71(d,J＝8.0Hz,1H),6.55(d,J＝8.1Hz,1H),5.02(s,1H),4.89(s,1H), 3.89(s,3H),3.45(s,3H),3.20-2.94(m,2H),2.60(s,1H),2.35-2.21(m,5H),2.11(s, 1H),1.87(m,1H),1.72-1.53(m,3H),1.45-1.25(m,2H),0.96(s,3H),0.90-0.72(m, 2H),0.61-0.45(m,2H),0.18-0.07(m,2H)ppm；ESIMS：m/z 502(M+H+,100),熔点：220.2-222.5℃
8b，R＝m-OCH3Ph，18mg无色油状物，产率33％
1H NMR(400MHz,CDCl3)δ7.23(d,J＝7.8Hz,1H),6.99-6.92(m,2H),6.79 (d,J＝8.0Hz,1H),6.73(d,1H),6.59(d,1H),5.00(s,1H),4.92(s,1H),3.90(s,3H), 3.82(s,3H),3.48(s,3H),3.00(m,1H),2.70-2.54(m,1H),2.50-2.39(m,1H), 2.36-1.98(m,5H),1.94-1.85(m,1H),1.68-1.58(m,3H),1.29-1.25(m,2H),0.96(s, 3H),0.90-0.83(m,1H),0.80-0.70(m,2H),0.67-0.46(m,2H),0.30-0.03(m,2H)ppm； 13C NMR(600MHz,CDCl3)δ159.3,147.1,142.3,129.0,120.5,119.1,114.8, 113.6,112.8,94.2,76.5,59.3,58.7,57.0,55.3,53.0,45.3,45.0,36.3,35.0,32.0,29.7, 29.3,22.6,18.3,14.1,5.2,3.1ppm；HMRS:calc.for C33H41NO5([M+H]+) 532.3058,found 532.3056；purity:88％,tR＝3.3min
8c，R＝Biphenyl，16mg微黄色油状物，产率30％
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.8Hz,2H),7.53(d,J＝6.3Hz,2H), 7.44(dd,J＝13.4,7.2Hz,4H),7.34(d,J＝6.7Hz,1H),6.71(d,J＝7.9Hz,1H),6.55 (d,J＝7.6Hz,1H),5.06(s,1H),4.89(s,1H),3.89(s,3H),3.46(s,3H),3.15(s,1H), 2.97(d,J＝17.8Hz,1H),2.64-2.53(m,1H),2.47-2.36(m,1H),2.35-2.22(m,5H), 2.21-2.17(m,1H),1.93-1.82(m,1H),1.68-1.52(m,2H),1.47-1.23(m,2H),1.01(s, 3H),0.89-0.68(m,2H),0.60-0.42(m,2H),0.19-0.03(m,2H)ppm.13C NMR(600 MHz,CDCl3)δ150.0,143.8,141.7,140.8,140.0,133.9,130.4,129.0,128.7,128.5, 127.2,127.1,127.0,126.5,126.1,118.8,114.3,94.7,77.9,60.0,58.9,57.1,52.9,45.5, 43.9,36.2,35.6,33.3,29.2,22.6,18.6,9.4,4.4,3.2ppm；HMRS:calc.for C38H43NO4([M+H]+)578.3265,found578.3243；purity:93％,tR＝4.6min
8d，R＝p-CF3Ph，26mg无色油状物,产率50％
1H NMR(400MHz,CDCl3)δ7.53(dd,J＝19.4,8.0Hz,4H),6.71(d,J＝7.9 Hz,1H),6.56(d,J＝7.9Hz,1H),5.07(s,1H),4.86(s,1H),3.89(s,3H),3.41(s,3H), 3.16(s,1H),2.98(d,J＝18.3Hz,1H),2.63(s,1H),2.44-2.23(m,7H),1.84-1.75(m, 1H),1.72-1.62(m,1H),1.61-1.54(m,1H),1.43-1.32(m,1H),1.32-1.22(m,1H), 0.99(s,3H),0.93-0.71(m,2H),0.62-0.47(m,2H),0.24-0.10(m,2H)ppm.13C NMR(600MHz,CDCl3)δ148.7,146.9,129.2,128.4,125.1,124.6,118.9,114.4, 94.5,77.8,76.7,60.0,58.9,57.1,52.8,45.6,45.5,43.9,36.2,35.8,33.3,29.7,29.3, 22.8,22.2,18.5,9.4,4.4,3.3ppm.HMRS:calc.for C33H38F3NO4([M+H]+) 570.2826,found 570.2832；purity:98％,tR＝3.6min
9的制备
取8a-c(0.02mmol,1eq)溶于3mL无水二氯甲烷，冰水浴下搅拌，缓慢加入戴斯马丁试剂(8mg,0.02mmol,2eq)，室温搅拌4h。冰水浴下，加饱和硫代硫酸钠溶液和碳酸氢钠溶液淬灭，萃取，有机相旋干，制备分离得9a-c；
9a(SLL-603)，R＝Ph，3mg微黄色油状物,产率33％
1H NMR(400MHz,CDCl3)δ7.70(d,J＝6.4Hz,2H),7.43-7.32(m,3H),6.72 (d,J＝8.1Hz,1H),6.58(d,J＝7.9Hz,1H),4.91(s,1H),3.90(s,3H),3.47(s,3H), 3.18(s,1H),2.99(d,J＝18.3Hz,1H),2.61(s,1H),2.44-2.36(m,2H),2.35-2.28(m, 3H),2.26-2.15(m,1H),1.74-1.64(m,3H),1.58(s,3H),1.48-1.23(m,2H),0.91-0.74 (m,2H),0.56-0.44(m,2H),0.14-0.05(m,2H)ppm.13C NMR(CDCl3)δ211.6, 146.6,141.9,141.7,133.7,130.0,128.9,128.2,127.6,119.1,114.3,94.0,78.5,59.9, 58.6,57.0,54.9,52.6,46.0,43.9,41.7,36.3,33.6,28.7,24.2,22.8,17.9,9.4,4.4,3.2 ppm；HMRS:calc.for C32H37NO4([M+H]+)500.2795,found 500.2800；purity＝93％,tR＝3.7min
9b(SLL-614)，R＝m-OCH3Ph，2mg微黄色油状物,产率17％
1H NMR(400MHz,CDCl3)δ7.28(d,J＝4.6Hz,3H),6.96(d,1H),6.72(d,J ＝7.5Hz,1H),6.58(d,J＝7.7Hz,1H),4.91(s,1H),3.90(s,3H),3.83(s,3H),3.49(s, 3H),3.17(s,1H),2.98(d,J＝17.8Hz,1H),2.62(s,1H),2.45-2.38(m,2H), 2.37-2.28(m,3H),2.24-2.16(m,1H),1.87-1.72(m,1H),1.63(s,3H),1.47-1.21(m, 4H),0.90-0.75(m,2H),0.55-0.43(m,2H),0.12-0.07(m,2H)ppm；13C NMR(600 MHz,CDCl3)δ211.5,158.8,146.6,142.9,141.9,133.6,128.8,128.7,120.6,119.1, 116.0,114.1,113.2,94.0,78.5,59.8,58.5,57.0,55.3,52.8,46.1,43.9,41.8,36.3, 33.6,29.7,28.8,24.1,22.8,17.9,9.4,4.5,3.1ppm；HMRS:calc.for C33H39NO5 ([M+H]+)530.2901,found 530.2904；purity＝100％,tR＝4.0min
9c(SLL-621)，R＝Biphenyl，8mg无色油状物,产率66％
1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.2Hz,2H),7.61(t,J＝9.0Hz,4H), 7.46(t,J＝7.5Hz,2H),7.38(t,J＝7.3Hz,1H),6.73(d,J＝8.1Hz,1H),6.59(d,J＝ 8.1Hz,1H),4.93(s,1H),3.90(s,3H),3.50(s,3H),3.19(d,J＝6.2Hz,1H),2.99(d, J＝18.2Hz,1H),2.65-2.56(m,1H),2.46-2.29(m,6H),2.25-2.18(m,1H),1.74-1.66 (m,2H),1.65(s,3H),1.47-1.24(m,2H),0.89-0.74(m,2H),0.56-0.45(m,2H), 0.14-0.07(m,2H)ppm.13C NMR(600MHz,CDCl3)δ210.8,146.6,142.8,141.9, 140.4,140.1,133.6,129.0,128.9,128.8,127.7,127.2,126.3,119.1,114.3,94.1,78.5, 59.9,58.6,57.0,55.0,52.7,46.0,43.9,41.7,36.3,33.7,29.7,28.7,24.2,22.8,17.9, 9.4,4.5,3.1ppm；HMRS:calc.forC38H41NO4([M+H]+)576.3108,found 576.3113；purity＝100％,tR＝4.9min
9d(SLL-622)，R＝p-CF3Ph，9mg无色油状物,产率80％
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.8Hz,2H),7.62(d,J＝7.9Hz,2H), 6.73(d,J＝7.8Hz,1H),6.59(d,J＝7.5Hz,1H),4.90(s,1H),3.90(s,3H),3.48(s, 3H),3.18(s,1H),2.99(d,J＝18.2Hz,1H),2.66-2.57(m,1H),2.43-2.36(m,2H), 2.35-2.38(m,3H),2.26-2.18(m,1H),1.75-1.61(m,3H),1.54(s,3H),1.39-1.24(m, 2H),0.90-0.75(m,2H),0.57-0.44(m,2H),0.13-0.07(m,2H)ppm.13C NMR(600 MHz,CDCl3)δ211.2,141.9,133.4,131.5,131.3,128.8,128.2,124.8,124.6,123.0, 119.2,114.3,93.7,78.6,59.9,58.6,56.97,55.0,52.6,46.2,43.8,41.4,36.3,33.7, 28.7,23.9,22.9,18.0,9.4,4.4,3.2ppm；HMRS:calc.for C33H36F3NO4([M+H]+) 568.2669,found 568.2673；purity＝100％,tR＝4.6min。
实施例2放射性配体结合实验
药理结合力筛选使用的化合物均为游离碱形式。实验分总结合管和非特异结合管，另设几组样品管加入待筛选的化合物。总结合管中加表达阿片κ、μ和δ受体的细胞悬液80uL，三个管中分别加入[3H]U69593、[3H]DAMGO、 [3H]DPDPE，(终浓度为0.35nM)10uL；相对应的非特异管分别加入U50488、 DAMGO、DPDPE使其终浓度为1uM；样品管加相同浓度的药物10ul(终浓度为1uM)，用50mM Tris.HCl(pH 7.4)调节至终体积100uL。在37℃温育30min，然后置冰浴中终止反应。在Millipore样品收集器上经GF/C(Whatman)玻璃纤维滤纸负压抽滤。用冰冷的50mM Tris.HCl(pH 7.4)冲洗三次，每次3mL，滤纸烘干后，置于0.5mLEppendorf管，加0.5mL亲脂闪烁液，Beckman LS-6500多功能液体闪烁计数仪测定放射性强度。每一浓度为二复管。抑制率＝(总结合率dpm －样品管dpm)/(总结合管dpm－非特异性结合管dpm)×100％。用Prism 5.0软件计算IC50。按下式计算Ki值，Ki＝IC50/(1+[L]/Kd)，[L]为所加标记配体的浓度， Kd为标记配体的平衡解离参数，实验结果如表1所示。
表1
实施例3[35S]GTPγS结合实验
Bradford蛋白浓度测定试剂盒测蛋白浓度：将标准蛋白BSA按浓度分别为0、50、100、200、250μg/ml以及待测样品分别加到96孔板中，每孔加20μl；各孔加 G250染色液200μl，室温放置3-5min，用酶标仪测定A595波长的吸光度。根 据标准曲线计算出蛋白浓度。
表2
制备的膜受体用反应缓冲液(R.B)稀释到所需浓度，如表2所示加样(单位： μl)。将反应管于27℃水浴中孵育1小时，以玻璃纤维膜进行减压过滤并液闪计 数。按下列公式进行计算：
[35S]GTPγS结合率＝100×(cpmsample-cpmnon-specific)/(cpmbasal-cpmnon-specific) 实验结果如表3所示
表3

Claims (8)

1.通式(I)的化合物，
其中
R1表示H或CH3；
R2表示-CH＝CH-或-CH2-CH2-；
R3表示H或CH3；
R4表示苯基及取代苯基、萘基及取代萘基、联苯基及取代联苯基，取代基由以下基团中的一个或两个组成：C1-C3烷基,C1-C3烷氧基，-X,-CX3，其中X表示F,Cl,Br。
2.如权利要求1所述的化合物，其中R1＝H。
3.如权利要求1所述的化合物，其中R2＝-CH2-CH2-。
4.如权利要求1所述的化合物，其中R3＝H。
5.如权利要求1所述的化合物，其中R4＝苯基，间甲氧基苯基，联苯基，对三氟甲基苯基。
6.权利要求1所述的通式(I)的化合物的制备方法，其特征在于，以蒂巴因为原料，通过N-脱甲基、N-酰化、Diels-Alder反应、还原、氧化、格氏反应等相关转化方法合成；按下述合成路线：
DIAD：偶氮二甲酸二异丙酯；Py：吡啶；EA：乙酸乙酯；R-Br：溴代烷；DMP：戴斯-马丁试剂。
7.如权利要求1-5项任意之一项所述的化合物在制备镇痛、抗抑郁、阿片成瘾性戒断治疗、止痒药物中的用途。
8.如权利要求7所述的用途，其特征在于，所述的镇痛为治疗或缓解手术期间的疼痛、慢性疼痛、神经性疼痛及癌症疼痛。
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