CN114195798B - 7α-甲基稠环吗啡类衍生物及其制备方法和用途 - Google Patents

7α-甲基稠环吗啡类衍生物及其制备方法和用途 Download PDF

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CN114195798B
CN114195798B CN202111672837.7A CN202111672837A CN114195798B CN 114195798 B CN114195798 B CN 114195798B CN 202111672837 A CN202111672837 A CN 202111672837A CN 114195798 B CN114195798 B CN 114195798B
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邵黎明
刘景根
李炜
王瑜珺
孔令辉
叶荣荣
孙惠姣
柴景蕊
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Abstract

本发明属于制药领域，涉及具有式I和式II的7α‑甲基稠环吗啡类化合物及其制备方法和用途。该类化合物通过蒂巴因与取代苯乙烯类试剂反应并经一系列转化方法制备，具有阿片受体结合活性，包括SLL‑604、SLL‑627和SLL‑631在内的多个化合物是选择性κ受体配基或μ/κ双重配基，可应用于镇痛、抗抑郁、阿片类药物成瘾戒断、止痒等治疗领域的研究和开发。

Description

7α-甲基稠环吗啡类衍生物及其制备方法和用途
技术领域
本发明属于制药领域，具体涉及7α-甲基稠环吗啡类衍生物及其制备方法和用途。
背景技术
阿片受体广泛参与疼痛调制、成瘾等多种生理和病理活动，主要分为μ、δ、κ和ORL1受体。其中，μ受体主要介导镇痛、淡漠、欣快、心率减缓、呼吸抑制、肠蠕动抑制和成瘾性，吗啡是其经典的激动剂。δ受体在脑内的分布与运动整合作用、嗅觉及识别功能有关，并且对μ受体具有调节作用，参与耐受性依赖性的形成。κ受体广泛分布于脑内参与调解奖赏、情绪及认知功能的区域，在外周组织、神经末梢、免疫细胞也有表达，它可以调节镇痛和胃肠道功能，比如进食、肠道蠕动以及其他的一些神经内分泌功能。已有文献报道κ受体配基具有阿片类药物是目前临床上使用最广泛的麻醉性镇痛药物类型，以吗啡及可待因等为代表的阿片μ受体激动剂存在明显的呼吸抑制、成瘾性等不良反应。与之相比，选择性阿片κ受体激动剂同样具有镇痛活性，但不出现μ受体激动剂的耐受性、成瘾性等问题，也不引起呼吸抑制、产生便秘等副作用，然而κ受体激动剂会诱发幻觉、镇静、烦躁不安等中枢副作用，在一定程度上限制了这一类化合物的开发及应用。此外，κ受体激动剂还具有抗吗啡作用以及抗炎、抗关节炎、止痒等药理活性，且对心血管也具有一定的保护作用。
内源性强啡肽可激活κ受体，组成有别于其他阿片系统的κ受体/内源强啡肽系统，在长期应激条件下该系统会导致啮齿类动物出现多种抑郁样表现。κ受体拮抗剂具有抗抑郁活性，Alkermes公司开发的抗抑郁药物ALKS 5461(由兼具κ拮抗活性和μ受体激动活性的丁丙诺啡与选择性μ受体拮抗剂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，选择性κ配基及μ/κ双重配基在镇痛、抗抑郁、阿片成瘾性戒断、止痒等治疗领域具有良好的应用前景。
发明内容
为解决上述问题，本发明的目的在于提供一种具有阿片受体结合活性的7α-稠环吗啡类化合物，该类化合物可以用于镇痛、抗抑郁、阿片成瘾性戒断治疗、止痒等治疗领域。
本发明的另一个目的在于提供选择性κ配基以及μ/κ双重配基，以成为潜在的镇痛、抗抑郁、阿片成瘾性戒断治疗、止痒药物。
本发明的还一目的在于提供具有式(I)和式(II)所表示的稠环吗啡类化合物、立体异构体或其在药学上可接受的盐及其制备方法。
本发明提供了作为阿片受体配基的化合物、立体异构体或其在药学上可接受的盐，如式(I)所示：
其中，式I和式II中：R1表示H或CH3；R2表示-CH2-CH2-；R3表示H或CH3；R4表示H、CH3或C1-C3烷基、卤素、甲氧基、卤代(C1-3)烷基、苯基任意取代或未取代的苯基或萘基；
或，
R1表示H或CH3；R2表示-CH＝CH-；R3表示H或CH3；R4表示H、CH3或C1-C3烷基、卤素、甲氧基、卤代(C1-3)烷基、苯基任意取代或未取代的苯基或萘基；
式I中，R5表示H；
R4中卤素取代基选自氯、氟。
优选地，本发明中式(I)具有如下结构：
其中，R1表示H或CH3；R2表示-CH2-CH2-或-CH＝CH-；R3表示H或CH3；R4表示H、CH3或C1-C3烷基、卤素、甲氧基、卤代(C1-3)烷基、苯基任意取代或未取代的苯基或萘基；R4中卤素取代基选自氯、氟。
或者，R1表示H或CH3；R2表示-CH2-CH2-；R3表示H或CH3；R4表示H、CH3或C1-C3烷基、卤素、甲氧基、卤代(C1-3)烷基、苯基任意取代或未取代的苯基或萘基；R4中卤素取代基选自氯、氟。
优选地，本发明中式(I)具有如下结构：
其中，R1表示H或CH3；R2表示-CH＝CH-或-CH2-CH2-；R3表示H或CH3；R5表示H。
本发明提供了作为阿片受体配基的另一种化合物或其在药学上可接受的盐，如式(II)所示：
其中，R1表示H或CH3；R2表示-CH2-CH2-；R3表示H或CH3；R4表示H、C1-C3烷基、任意取代的苯基或萘基。
或者，R1表示H或CH3；R2表示-CH＝CH-；R3表示H或CH3；R4表示H、CH3或C1-C3烷基、卤素、甲氧基、卤代(C1-3)烷基、苯基任意取代或未取代的苯基或萘基。
本发明中，术语"药学上可接受的盐"是指由药学上可接受的无毒的酸制备而成的盐，包括无机酸和有机酸。合适的无毒酸包括无机和有机酸，但不限于，例如乙酸、海藻酸、邻氨基苯甲酸、苯磺酸、苯甲酸、棒脑磺酸、拘橡酸、乙烯基磺酸、甲酸、延胡索酸、呋喃甲酸、葡糖酸、谷氨酸、葡萄糖醛酸、半乳糖醛酸、环氧丙酸、氢溴酸、盐酸、乳酸、顺丁烯二酸、苹果酸、扁桃酸、甲磺酸、半乳糖二酸、硝酸、帕莫酸(pamoic)、泛酸、苯乙酸、丙酸、磷酸、水杨酸、硬脂酸、琥珀酸、硫酸、酒石酸等。
本发明的有益效果：本发明涉及的式(I)和式(II)所表示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，可测定配基对三种受体的亲和力以及选择性，采用[35S]GTPγS结合实验可测定化合物对三种受体的激动或拮抗功能活性，进而提示其在镇痛、抗抑郁、阿片成瘾性戒断治疗、止痒等治疗领域中的潜在用途。
附图说明
图1是式(I)和式(II)所表示化合物的合成路线；反应条件：(a)DIAD/乙腈，回流，4h；吡啶盐酸盐，甲醇，室温，2天；(b)环丙甲酰氯，三乙胺，二氯甲烷，室温，12h；(c)甲基丙烯醛，四氟硼酸锂，室温，28h；(d)氢气，钯碳，乙醇，室温，8h；(e)氢化铝锂，四氢呋喃，室温，2h；(f)草酰氯，二甲亚砜，二氯甲烷，三乙胺，-78℃到室温，2h；(g)卤代物，正丁基锂，四氢呋喃，-78℃，0.25h；(h)戴斯马丁氧化剂，二氯甲烷，2h；(i)苯甲酰氯，二氯甲烷，三乙胺，室温，2h；(j)氢化钠，N,N-二甲基甲酰胺，溴苄，室温，3h。
具体实施方式
实验及样品分析所用仪器：1HNMR在Varian Mercury plus 400核磁共振仪上测定，13CNMR在Bruker 600MHz核磁共振仪上测定。LS-MS由Agilent 1100Series LC/MSD1946D型质谱仪测定。特殊化学试剂购自探索、毕得、安耐吉、sigma、Alfa、Acros和Adamas等试剂公司。一般化学试剂购自国药集团上海化学试剂公司。主要溶剂包括石油醚，乙酸乙酯，二氯甲烷，甲醇等，购自国药集团，均为合成级。柱层析硅胶采用黄海化工厂化学纯硅胶，一般为200-300目。试剂处理方法参照Purification ofLaboratory Chemicals(1988年版)处理。
实施例1
N-环丙甲基-7α-甲基-7β-羟甲基-6α,14α-endo-亚乙基-四氢去甲蒂巴因
反应路线：
反应条件：(a)DIAD/乙腈，回流，4h；吡啶盐酸盐，甲醇，室温，2天；(b)环丙甲酰氯，三乙胺，二氯甲烷，室温，12h；(c)甲基丙烯醛，四氟硼酸锂，室温，28h；(d)氢气，钯碳，乙醇，室温，8h；(e)氢化铝锂，四氢呋喃，室温，2h。
反应步骤：
a)将蒂巴因(1g,3.2mmol,1eq)加入50mL规格的三颈瓶中，再加入无水乙腈(10mL)使之溶解，氩气置换三次，使用滴液漏斗向上述溶液中缓慢滴加偶氮二甲酸二异丙酯(0.68mL,3.5mmol,1.1eq)，滴加完毕后回流反应4h，冷却至室温。减压蒸馏除去反应液的溶剂，加入甲醇(10mL)溶解残留物，再向其中加入吡啶盐酸(370mg,3.2mmol,1eq)，搅拌，室温下反应48h后，抽滤，滤饼用甲醇和乙酸乙酯洗涤三次，烘干得450mg白色固体2，收率47％。mp:260.3℃，1HNMR(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＝3.2Hz,3H),2.93(dd,Ja＝13.7Hz,Jb＝3.8Hz,1H),2.07(td,Ja＝12.5Hz,Jb＝5.1Hz,3H),1.83(d,J＝12.5Hz,1H).ESIMS：m/z 298.1([M+H+],100)。
b)将化合物2(800mg，2.7mmol，1eq)加入50mL规格的三颈瓶中，加入无水二氯甲烷(20mL)使之溶解，再加入三乙胺(1ml，7.0mmol，2.6eq)，冰水浴下向上述溶液中缓慢滴加环丙甲酰氯(335mg，3.24mmol，1.2eq)，滴加完毕后室温搅拌过夜。反应液依次用1N盐酸(10mLx 2)和水(10mL)洗，合并有机相，饱和食盐水(15mL)洗涤，用无水硫酸钠干燥，过滤，滤液浓缩得1.1g淡黄色油状物3，收率：89％。1HNMR(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),3.98(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).ESIMS：m/z 366.2([M+H+],100)。
c)将甲基丙烯醛(2g，28.2mmol，6eq)加入25mL规格的茄形瓶中，再加入化合物3(1.7g，4.7mmol，1eq)和LiBF4(442mg，4.7mmol，1eq)，上述混合物搅拌均匀，室温下反应过夜。向混合物加入二氯甲烷(50mL x 3)和水(30mL)萃取，合并有机相，饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤，滤液浓缩后使用硅胶柱层析进行分离(石油醚：乙酸乙酯＝2:1)，先出组分为650mg白色固体4b，收率：27％。mp:166.3-170.3℃,1H NMR(400MHz,CDCl3)δ9.85(s,1H),6.67(d,1H,J＝8.0Hz),6.57(d,1H,J＝8.0Hz),6.14-6.07(2d,1H),5.57(d,1H,J＝12.0Hz),5.33(d,1H,J＝8.0Hz),4.76(d,1H,0.4H),4.57-4.53(m,1.6H),4.15-4.10(m,1H),3.85(s,3H),3.72(s,3H),3.42(dt,1H,Ja＝12.0Hz,Jb＝4.0Hz),3.11-3.05(dd,1H,Ja＝8.0Hz,Jb＝4.0Hz),2.88-2.83(m,1H),2.43-2.35(dt,1H,Ja＝12.0Hz,Jb＝8.0Hz),1.85-1.76(m,1H),1.69-1.65(m,1H),1.09-1.03(m,5H),0.91-0.76(m,2H).ESIMS:m/z 436.2(M+H+,100).
d)将化合物4b(700mg，1.6mmol，1eq)加入100mL规格的烧瓶中，再加入乙醇(20mL)，氩气保护下，加入10％Pd/C(105mg，15wt％)，氢气置换三次，使茄形瓶充满氢气，室温下搅拌8h。过滤，滤液旋干得到600mg白色固体5，收率：85％。1HNMR(400MHz,CDCl3)δ9.82(s,1H),6.75(d,J＝8.1Hz,1H),6.61(d,J＝7.9Hz,1H),4.87(d,J＝7.0Hz,1H),4.40(s,1H),4.04(dd,J＝13.8,5.4Hz,1H),3.86(s,3H),3.49(s,3H),3.28(t,J＝12.0Hz,1H),3.04–2.92(m,1H),2.83(dd,J＝21.2,10.8Hz,1H),2.75(s,0.6H),2.70(s,0.4H),2.40(td,J＝13.1,5.7Hz,1H),1.82–1.68(m,2H),1.65(s,1H),1.57(d,J＝12.0Hz,1H),1.50(d,J＝13.4Hz,1H),1.31(s,1H),1.26(d,J＝9.8Hz,3H),1.03(dd,J＝20.1,13.1Hz,3H),0.85(d,J＝8.6Hz,1H),0.76(s,1H).13C NMR(151MHz,CDCl3)δ206.93,171.89,146.47,142.12,132.16,126.77,119.80,114.97,94.45,78.76,56.99,53.35,51.48,50.28,46.13,37.64,36.28,33.68,32.24,31.94,27.96,20.08,16.62,11.47,7.55,6.95.HMRS:calc.forC26H31NO5([M+H]+)438.23.
e)将化合物5(250mg，0.58mmol，1eq)加入25mL规格的茄形瓶中，再加入无水四氢呋喃(6mL)使之溶解，冰水浴下向上述溶液中缓慢加入氢化铝锂(1M in THF，2.3mL，2.3mmoL，4eq)，室温下搅拌2h。冰水浴下向反应液中加入含水的四氢呋喃淬灭，再加入1M氢氧化钠水溶液沉降，抽滤，热的四氢呋喃洗涤滤饼三次，滤液干燥浓缩后使用硅胶柱层析分离(石油醚：乙酸乙酯＝4:1)，得到200mg无色油状物6，收率82％。1H NMR(400MHz,CDCl3)δ6.73(s,1H),6.58(s,1H),4.87(d,J＝71.5Hz,1H),4.05(s,1H),3.89(s,3H),3.49(s,3H),3.28(d,J＝29.2Hz,2H),2.97(d,J＝16.5Hz,2H),2.59(s,1H),2.23(s,4H),1.67(s,1H),1.65–1.41(m,3H),1.28(t,J＝15.8Hz,6H),1.08(d,J＝11.0Hz,1H),0.86(d,J＝7.9Hz,3H),0.49(s,1H),0.06(s,1H).13C NMR(151MHz,CDCl3)δ146.65,141.95,133.46,128.53,119.21,114.52,95.01,81.24,71.00,59.92,58.58,57.10,53.12,45.95,43.77,40.28,36.05,33.39,29.71,28.37,23.22,22.70,17.27,9.37,4.31,3.26.HMRS:calc.forC26H35NO4([M+H]+)426.26。
实施例2
N-环丙甲基-7α-甲基-7β-醛基-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线：
反应条件：(f)草酰氯，二甲亚砜，二氯甲烷，三乙胺，-78℃到室温，2h。
反应步骤：
f)向茄形瓶中加入草酰氯(0.06mL，0.74mmol，1.25eq)、无水二氯甲烷(3mL)，冷却至-78℃，逐滴加入无水二甲亚砜(0.11mL，1.53mmol，2.6eq)溶于无水二氯甲烷(2mL)配成的溶液，搅拌5min；向上述混合物加入化合物6(250mg，0.59mmol，1eq)溶于无水二氯甲烷(1mL)的溶液，搅拌20min；再加入三乙胺(0.41mL，2.94mmol，5eq)，移出-78℃干冰-丙酮浴，室温下反应2h。反应液依次用饱和氯化铵溶液(5mL x 3)和饱和碳酸氢钠溶液(5mL x 3)洗涤，合并有机相，用饱和食盐水(5mL)洗涤，加入无水硫酸钠干燥后过滤，滤液浓缩得210mg黄色油状物7，收率：84％。1HNMR(400MHz,CDCl3)δ9.84(s,1H),6.72(d,J＝7.7Hz,1H),6.58(d,J＝7.5Hz,1H),4.52(s,1H),3.88(t,J＝2.9Hz,3H),3.48(d,J＝1.7Hz,3H),3.30(s,1H),3.00(d,J＝18.0Hz,1H),2.72(s,1H),2.42(s,4H),2.00(s,1H),1.67(dd,J＝18.7,11.6Hz,1H),1.58–1.45(m,2H),1.33(s,3H),1.24(s,2H),1.04(s,2H),0.86(d,J＝10.6Hz,2H),0.56(s,2H),0.20(s,1H).13C NMR(151MHz,CDCl3)δ206.48,146.51,142.03,132.84,128.04,119.35,114.86,94.12,78.72,59.75,58.46,57.03,53.36,51.50,45.53,44.05,36.44,35.53,29.70,28.77,23.17,20.24,16.89,8.76,4.72,3.42.HMRS:calc.forC26H33NO4([M+H]+)424.25.
实施例3
(20R)-N-环丙甲基-7α-甲基-7β-(1-苯基-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线：
反应条件：(g)卤代物，正丁基锂，四氢呋喃，-78℃，0.25h。
反应步骤：
g)将溴苯(188mg，1.2mmol，10eq)、无水四氢呋喃(2.5mL)加入Schlenk管中，冷却至-78℃，置换氩气三次，在氩气保护下，向上述反应液中逐滴加入正丁基锂(2.4M in n-hexane，0.5mL，1.2mmol，10eq)，搅拌10min，再缓慢向其中注入化合物7(50mg，0.12mmol，1eq)的无水四氢呋喃溶液(1mL)，保持-78℃反应0.25h。移出干冰-丙酮浴，加饱和氯化铵溶液淬灭，加入乙酸乙酯(10mL x 3)和水(10mL)萃取，合并有机相，用饱和食盐水(15mL)洗涤后，加入无水硫酸钠干燥，过滤，滤液浓缩后使用硅胶柱层析分离(二氯甲烷：甲醇＝20:1)，得到37mg黄色油状物8a，收率：62％。1H NMR(400MHz,CDCl3)δ7.83(s,2H),7.38(t,J＝7.3Hz,2H),7.25(d,J＝7.1Hz,1H),6.78(d,J＝7.9Hz,1H),6.62(d,J＝8.1Hz,1H),5.76(s,1H),5.16(s,1H),3.93(s,3H),3.74(s,1H),3.58(s,3H),3.32(s,1H),3.06(d,J＝18.9Hz,1H),2.75(s,4H),1.66(dd,J＝20.8,11.3Hz,2H),1.46(t,J＝12.0Hz,1H),1.36–1.24(m,3H),1.12(s,1H),0.91(d,J＝11.5Hz,2H),0.79(s,3H),0.75–0.62(m,3H),0.42(s,1H),0.08(s,1H).13C NMR(151MHz,CDCl3)δ147.16,143.40,142.67,132.80,128.70,128.33,127.50,123.37,119.07,115.80,93.31,77.97,75.93,58.90,58.47,57.22,53.47,46.31,45.76,44.01,36.93,35.27,29.69,28.76,25.03,24.57,18.66,6.05,3.13.HMRS:calc.forC32H39NO4([M+H]+)502.2952,found 502.2962.Single-Crystal X-ray StructureAnalysis C32H39NO4,Orthorhombic,Space group P 212121, β＝90°,/>Z＝4,Dc＝1.265Mg/m3,F(000)＝1080,μ＝0.651mm-1,Final R1＝0.0520,wR2＝0.1407for 339parameters with[I>2σ(I)]andR1＝0.0564,wR2＝0.1472。
实施例4
N-环丙甲基-7α-甲基-7β-(1-对甲苯基-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用对甲基溴苯替换溴苯，得到黄色油状物8b，收率：56％。1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.27(d,J＝1.8Hz,1H),7.21(d,J＝5.6Hz,2H),6.77(s,1H),6.63(s,1H),5.78(s,1H),5.11(s,1H),3.93(s,3H),3.84(s,1H),3.58(d,J＝1.5Hz,3H),3.37(s,1H),3.06(d,J＝19.2Hz,1H),2.91(s,1H),2.77(s,2H),2.62(s,1H),2.33(s,3H),2.00(s,2H),1.72–1.59(m,2H),1.46(s,1H),1.33–1.23(m,3H),1.16(s,1H),0.91(d,J＝18.5Hz,2H),0.80(s,3H),0.76–0.69(m,1H),0.45(s,1H),0.07(d,J＝1.6Hz,1H).13CNMR(151MHz,CDCl3)δ147.23,142.73,140.27,137.18,132.81,129.07,128.58,123.33,119.03,115.82,93.27,77.99,75.81,58.92,58.42,57.22,53.48,46.31,45.85,43.98,36.95,35.24,29.70,28.79,24.58,22.69,21.08,18.73,6.07,3.12,1.02.HMRS:calc.for C33H41NO4([M+H]+)516.31。
实施例5
N-环丙甲基-7α-甲基-7β-(1-对甲氧基苯基-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用对甲氧基溴苯替换溴苯，得到黄色油状物8c，收率：52％。1H NMR(400MHz,CDCl3)δ7.41(s,2H),6.89(d,J＝8.0Hz,2H),6.71(d,J＝7.8Hz,1H),6.54(d,J＝7.3Hz,1H),5.67(s,1H),5.05(s,1H),3.91(s,3H),3.82(s,3H),3.74–3.62(m,1H),3.57(s,3H),3.30(d,J＝11.0Hz,1H),2.98(d,J＝18.7Hz,1H),2.63(s,1H),2.38(s,1H),2.26(s,3H),2.16(s,1H),1.64(dd,J＝20.5,11.9Hz,1H),1.39(d,J＝14.2Hz,2H),1.29(s,1H),1.26(s,3H),0.86(s,3H),0.83–0.80(m,2H),0.49(s,2H),0.13(s,1H).13C NMR(151MHz,CDCl3)δ158.94,146.85,141.69,136.62,135.04,129.49,128.62,118.62,114.43,113.32,94.61,79.29,76.32,59.83,59.47,57.17,55.26,53.39,45.98,45.22,43.76,36.73,35.50,29.70,28.53,24.87,22.69,19.10,14.12,9.55,4.16,3.28.HMRS:calc.for C33H41NO5([M+H]+)532.31.
实施例6
N-环丙甲基-7α-甲基-7β-(1-对三氟甲基苯基-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用对三氟甲基溴苯替换溴苯，得到黄色油状物8d，收率：47％。1H NMR(400MHz,CDCl3)δ8.02(s,2H),7.68(d,J＝8.2Hz,2H),6.80(d,J＝8.2Hz,1H),6.64(d,J＝8.4Hz,1H),5.76(s,1H),5.25(s,1H),3.93(s,3H),3.61(s,1H),3.57(s,3H),3.37(s,1H),3.06(d,J＝19.6Hz,1H),2.91(s,1H),2.79(s,2H),2.22(s,0.4H),2.01(s,0.6H),1.66(s,3H),1.48(s,1H),1.30(d,J＝10.0Hz,3H),1.14(d,J＝13.4Hz,1H),0.96(s,1H),0.88(s,2H),0.79(s,3H),0.75–0.70(m,1H),0.45(s,1H),0.07(s,1H).13C NMR(151MHz,CDCl3)δ147.19,146.98,142.89,132.57,129.87,129.63,129.17,125.36,123.15,119.17,115.87,93.28,77.79,75.42,58.89,58.30,57.19,53.48,46.31,45.93,44.00,36.97,35.19,29.71,29.37,28.79,25.07,18.44,6.18,6.00,3.12.HMRS:calc.forC33H38F3NO4([M+H]+)570.28.
实施例7
N-环丙甲基-7α-甲基-7β-(1-(3,5-二甲基苯基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用3,5-二甲基溴苯替换溴苯，得到黄色油状物8e，收率：40％。1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.27(s,1H),6.90(s,1H),6.77(s,1H),6.62(s,1H),5.76(s,1H),5.07(s,1H),3.92(s,3H),3.57(d,J＝2.3Hz,3H),3.39(s,1H),3.04(d,J＝18.7Hz,1H),2.91(s,1H),2.75(s,2H),2.38(s,6H),2.26(d,J＝37.8Hz,1H),2.01(s,1H),1.74(s,3H),1.65(d,J＝9.7Hz,2H),1.43(d,J＝17.6Hz,1H),1.32(dd,J＝22.3,12.6Hz,3H),1.25(s,2H),1.21–1.09(m,1H),0.87(s,2H),0.82(s,2H),0.44(s,1H).13C NMR(151MHz,CDCl3)δ147.30(s),143.19(s),142.78(s),138.10(s),132.71(s),129.35(s),126.22(s),123.37(s),118.97(s),115.91(s),93.23(s),77.88(s),75.93(s),59.04(s),58.32(s),57.24(s),53.48(s),46.27(s),45.72(s),43.92(s),37.01(s),35.38(s),29.71(s),28.77(s),25.18(s),24.59(s),21.30(s),18.69(s),14.12(s),9.45(s),6.06(s),3.20(s).HMRS:calc.for C34H43NO4([M+H]+)530.33。
实施例8
N-环丙甲基-7α-甲基-7β-(1-(3-甲氧基苯基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用3,5-二甲基溴苯替换溴苯，得到黄色油状物8f，收率：42％。1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.32(t,J＝7.6Hz,1H),7.15(s,1H),6.81(d,J＝8.2Hz,1H),6.77(d,J＝8.1Hz,1H),6.61(d,J＝8.3Hz,1H),5.69(s,1H),5.15(s,1H),3.92(s,3H),3.89(s,3H),3.66(s,1H),3.56(s,3H),3.35(s,1H),3.04(d,J＝18.7Hz,1H),2.76(s,3H),1.86(s,2H),1.66(dd,J＝20.7,11.3Hz,3H),1.45(t,J＝11.7Hz,1H),1.27(d,J＝19.7Hz,3H),1.17(s,1H),0.90(d,J＝25.1Hz,2H),0.78(s,4H),0.70(s,1H),0.43(s,1H).13C NMR(151MHz,CDCl3)δ158.64,146.12,145.49,140.93,134.43,128.22,128.00,120.30,117.95,113.64,113.33,112.25,94.09,78.67,59.33,59.10,56.51,54.60,52.78,45.23,44.66,43.03,36.08,34.92,31.76,29.08,27.81,24.25,22.26,18.42,9.00,3.35,2.77.HMRS:calc.for C33H41NO5([M+H]+)532.31。
实施例9
N-环丙甲基-7α-甲基-7β-(1-(4-异丙基苯基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用4-异丙基溴苯替换溴苯，得到黄色油状物8g，收率：45％。1H NMR(400MHz,CDCl3)δ8.03(s,2H),7.67(d,J＝8.0Hz,2H),6.80(d,J＝7.6Hz,1H),6.64(d,J＝8.4Hz,1H),5.75(s,1H),5.24(s,1H),3.93(s,3H),3.91–3.87(m,1H),3.56(s,3H),3.36(s,1H),3.06(d,J＝19.6Hz,1H),2.91(s,1H),2.78(s,2H),2.22(s,1H),2.01(s,1H),1.65(s,2H),1.62(s,3H),1.47(s,1H),1.32(d,J＝8.2Hz,2H),1.25(s,6H),1.13(d,J＝13.4Hz,1H),0.95(s,1H),0.88(s,2H),0.78(s,3H),0.76–0.65(m,1H),0.44(s,1H).13C NMR(151MHz,CDCl3)δ147.33,146.45,141.96,139.87,131.99,127.80,125.68,122.55,118.23,115.11,92.47,77.17,75.03,58.13,57.58,56.46,52.71,45.58,45.09,43.17,36.18,34.45,33.03,31.16,28.92,28.59,28.01,24.32,23.83,23.22,21.92,17.96,13.35,5.31,2.35.HMRS:calc.for C35H45NO4([M+H]+)544.34。
实施例10
N-环丙甲基-7α-甲基-7β-(1-(3,4-二氯苯基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用3,4-二氯溴苯替换溴苯，得到黄色油状物8h，收率：50％。1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.58(s,1H),7.51(s,1H),6.77(d,J＝7.9Hz,1H),6.61(d,J＝7.9Hz,1H),5.67(s,1H),5.12(s,1H),3.92(s,3H),3.58(s,1H),3.53(s,3H),3.04(d,J＝18.9Hz,2H),2.73(s,2H),2.25–2.18(m,0.4H),2.03(d,J＝19.9Hz,0.6H),1.86(s,2H),1.67(dd,J＝20.7,11.7Hz,2H),1.42(d,J＝11.6Hz,1H),1.27(d,J＝12.7Hz,4H),1.08(s,1H),0.96–0.86(m,2H),0.81(s,3H),0.73–0.64(m,1H),0.39(s,1H),0.07(s,1H).13CNMR(151MHz,CDCl3)δ146.38,143.04,142.08,130.95,130.74,129.92,129.39,129.12,127.63,118.46,114.97,92.73,74.26,58.30,57.97,56.51,52.78,45.58,45.12,43.39,36.23,34.67,29.07,28.01,26.59,23.73,22.06,17.83,13.49,5.38,2.59.HMRS:calc.for C32H37Cl2NO4([M+H]+)570.22。
实施例11
N-环丙甲基-7α-甲基-7β-(1-(4-联苯基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用4-溴联苯替换溴苯，得到黄色油状物8i，收率：39％。1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.65(dd,J＝15.9,7.4Hz,4H),7.56(d,J＝8.1Hz,1H),7.42(t,J＝7.5Hz,2H),7.32(t,J＝7.1Hz,1H),6.80(d,J＝7.9Hz,1H),6.65–6.58(m,1H),5.80(s,1H),5.21(s,1H),3.93(s,3H),3.67(d,J＝12.9Hz,1H),3.59(s,3H),3.38(s,1H),3.06(d,J＝19.2Hz,1H),2.90(d,J＝12.4Hz,1H),2.77(s,2H),2.55(s,1H),1.70(s,2H),1.53–1.44(m,1H),1.35(d,J＝16.2Hz,2H),1.27(d,J＝12.8Hz,2H),1.19(d,J＝12.6Hz,1H),0.94(d,J＝12.0Hz,1H),0.85(s,3H),0.76(d,J＝27.1Hz,3H),0.45(s,1H),0.07(s,1H).13C NMR(151MHz,CDCl3)δ146.79,143.52,141.59,140.86,140.21,135.05,130.03,129.75,128.87,128.77,128.64,127.24,127.04,126.57,124.38,123.48,118.61,114.37,94.74,79.36,76.64,59.91,59.57,57.17,53.39,45.95,45.34,43.72,36.72,29.71,28.48,24.90,22.70,19.08,14.12,9.63,4.11,3.32.HMRS:calc.for C38H43NO4([M+H]+)578.33.
实施例12
N-环丙甲基-7α-甲基-7β-(1-(2-萘基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例3中的反应步骤(g)，用2-萘基替换溴苯，得到黄色油状物8j，收率：40％。1H NMR(400MHz,CDCl3)δ8.56(s,1H),8.22(s,1H),7.82(d,J＝25.0Hz,3H),7.45(d,J＝5.9Hz,2H),6.79(d,J＝6.9Hz,1H),6.63(s,1H),5.83(s,1H),5.33(s,1H),3.94(d,J＝5.3Hz,3H),3.70(s,1H),3.61(d,J＝5.1Hz,3H),3.38(s,1H),3.05(d,J＝18.5Hz,1H),2.88(d,J＝19.5Hz,1H),2.72(d,J＝33.0Hz,3H),1.86(s,1H),1.65(d,J＝13.2Hz,2H),1.48(s,1H),1.27–1.13(m,3H),0.98–0.85(m,2H),0.82(s,3H),0.70(s,2H),0.44(s,2H),0.08(s,1H).13CNMR(151MHz,CDCl3)δ147.26,142.80,140.72,133.70,133.01,132.68,128.93,127.68,127.35,127.24,127.09,125.81,125.74,123.29,119.07,115.81,93.26,77.94,75.92,58.89,58.28,57.21,53.55,46.57,45.86,43.96,37.01,35.18,29.33,28.78,25.11,24.59,18.64,6.01,3.11,1.02.HMRS:calc.for C36H41NO4([M+H]+)552.31.
实施例13
N-环丙甲基-7α-甲基-7β-(3-羟丙基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线：
反应步骤：
将化合物7(50mg，0.118mmol，1eq)溶于1.5mL无水四氢呋喃中，置于封管，冰水浴下向其中缓慢滴加格式试剂乙基氯化镁(2M in THF，0.35mL，0.708mmol，6eq)，保持冰浴反应1h。向反应液中滴加饱和氯化铵溶液至沉淀消失，加入乙酸乙酯(10mL)和水(5mL)萃取，有机相依次用饱和碳酸氢钠溶液(5mL x 3)和饱和食盐水(10mL)洗涤，加入无水硫酸钠干燥，过滤，滤液浓缩后使用硅胶柱层析分离(二氯甲烷：甲醇＝20:1)，得到13mg黄色油状物8，收率：24％。1HNMR(400MHz,CDCl3)δ6.75(d,J＝8.1Hz,1H),6.59(d,J＝8.2Hz,1H),5.55(s,1H),3.90(s,3H),3.79(d,J＝9.2Hz,1H),3.49(s,3H),3.31(s,1H),3.01(d,J＝18.7Hz,2H),2.74(s,3H),2.22(d,J＝7.3Hz,1H),1.85(dd,J＝13.2,6.7Hz,1H),1.64(dd,J＝20.2,11.6Hz,3H),1.52–1.40(m,2H),1.26(d,J＝15.6Hz,4H),1.08(s,3H),1.04(t,J＝7.3Hz,3H),0.86(t,J＝10.3Hz,2H),0.67(s,2H),0.36(s,1H),0.06(s,1H).13CNMR(151MHz,CDCl3)δ147.06,142.60,133.12,123.69,119.06,115.48,93.38,78.79,76.48,58.89,57.16,53.20,45.94,44.16,37.45,36.58,31.92,29.70,28.98,25.43,22.69,21.65,18.49,14.13,11.41,5.98,3.24.HMRS:calc.for C28H39NO4([M+H]+)454.30.
实施例14
N-环丙甲基-7α-甲基-7β-苯甲酰基-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成步骤：
反应条件：(h)戴斯马丁氧化剂，二氯甲烷，2h。
反应步骤：
h)将化合物8a(50mg，0.1mmol，1eq)加入25mL茄形瓶中，加入无水二氯甲烷(3mL)使之溶解，冰水浴下缓慢加入戴斯马丁试剂(84mg，0.2mmol，2eq)，室温下搅拌2h。向反应液中滴加饱和硫代硫酸钠溶液淬灭，再加入二氯甲烷(10mL x 3)和水(5mL)萃取，合并有机相，用饱和食盐水洗涤，加入无水硫酸钠干燥，过滤，滤液浓缩后使用薄层制备分离，用二氯甲烷：甲醇＝20:1展开，得18mg黄色油状物9a，收率：43％。1HNMR(400MHz,CDCl3)δ7.68(d,J＝6.6Hz,2H),7.42–7.35(m,3H),6.73(s,1H),6.58(s,1H),5.25(s,1H),3.91(s,3H),3.54(s,3H),3.00(s,2H),2.69(s,1H),2.27(s,4H),1.72(d,J＝9.0Hz,3H),1.50(s,3H),1.25(s,5H),0.88(s,3H),0.44(d,J＝42.3Hz,1H),0.09(d,J＝15.2Hz,1H).13CNMR(151MHz,CDCl3)δ211.79,146.85,141.36,130.06,129.75,128.69,128.43,127.92,127.62,119.19,115.22,93.04,79.07,59.62,58.54,57.11,54.23,53.26,45.18,42.93,37.14,29.70,28.58,25.68,22.70,19.74,17.45,14.13,6.09,3.42.HMRS:calc.for C32H37NO4([M+H]+)500.28.
实施例15
N-环丙甲基-7α-甲基-7β-对甲苯基甲酰基-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8b替换8a，得到黄色油状物9b，收率：48％。1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.9Hz,2H),7.17(d,J＝7.7Hz,2H),6.75(d,J＝6.5Hz,1H),6.61(s,1H),5.27(s,1H),3.90(s,3H),3.53(s,3H),3.35(s,1H),3.04(d,J＝17.4Hz,2H),2.66(s,1H),2.37(s,3H),2.27(d,J＝39.6Hz,2H),2.02(s,1H),1.71(dd,J＝19.9,11.9Hz,2H),1.52(s,5H),1.39–1.19(m,4H),1.00–0.83(m,2H),0.55(s,2H),0.07(s,1H).13CNMR(151MHz,CDCl3)δ210.66,146.63,141.94,140.39,138.12,134.18,128.29,128.15,124.33,118.93,114.53,93.03,79.15,59.64,58.56,56.96,54.08,53.11,45.29,43.80,42.98,36.90,29.56,28.43,25.62,22.55,21.26,17.54,9.18,4.39,3.23.HMRS:calc.for C33H39NO4([M+H]+)514.30
实施例16
N-环丙甲基-7α-甲基-7β-((4-甲氧基苯基)-甲酰基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8c替换8a，得到黄色油状物9c，收率：47％。1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.5Hz,2H),6.86(d,J＝8.1Hz,2H),6.73(d,J＝8.2Hz,1H),6.58(d,J＝8.1Hz,1H),5.25(s,1H),3.90(t,J＝2.8Hz,3H),3.84(t,J＝2.8Hz,3H),3.53(t,J＝2.8Hz,3H),3.30(s,1H),3.03(d,J＝19.1Hz,2H),2.87(s,1H),2.41(s,3H),2.22(s,0.4H),2.00(s,0.6H),1.71(d,J＝7.8Hz,1H),1.55(s,3H),1.38–1.26(m,5H),0.90(dd,J＝17.4,8.5Hz,3H),0.54(s,2H),0.19(s,1H).13C NMR(151MHz,CDCl3)δ208.74,161.44,146.81,142.12,139.96,133.06,131.03,127.62,119.02,114.88,112.86,92.96,79.18,59.80,58.78,57.14,55.32,54.27,53.27,45.32,44.08,43.24,36.98,29.70,28.60,25.87,17.84,14.12,8.50,4.65,3.43.HMRS:calc.for C33H39NO5([M+H]+)530.29。.
实施例17
N-环丙甲基-7α-甲基-7β-((4-三氟甲基苯基)-甲酰基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8d替换8a，得到黄色油状物9d，收率：40％。1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.2Hz,2H),7.63(d,J＝8.3Hz,2H),6.74(s,1H),6.61(s,1H),5.14(s,1H),3.91(t,J＝3.4Hz,3H),3.54(d,J＝2.2Hz,3H),3.36(s,1H),3.04(d,J＝18.4Hz,2H),2.74(s,1H),2.32(s,3H),1.79–1.68(m,2H),1.47(d,J＝23.4Hz,5H),1.40–1.20(m,4H),0.91(d,J＝26.1Hz,2H),0.48(d,J＝57.5Hz,1H),0.16(s,1H),0.10–0.01(m,1H).13C NMR(151MHz,CDCl3)δ211.63,146.66,145.10,131.61,131.39,127.89,124.82,124.67,123.01,119.20,114.77,93.51,79.44,59.85,58.68,57.13,54.48,53.23,45.47,44.17,42.82,37.10,29.71,29.37,28.51,25.60,17.21,14.12,9.12,4.70,3.38.HMRS:calc.for C33H36F3NO4([M+H]+)568.27。
实施例18
N-环丙甲基-7α-甲基-7β-((3,5-二甲基苯基)-甲酰基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8e替换8a，得到黄色油状物9e，收率：38％。1H NMR(400MHz,CDCl3)δ7.27(d,J＝3.3Hz,2H),7.04(s,1H),6.75(d,J＝8.2Hz,1H),6.60(d,J＝7.7Hz,1H),5.29(s,1H),3.90(s,3H),3.53(s,3H),3.03(d,J＝18.6Hz,1H),2.38(s,1H),2.33(s,6H),2.32–2.26(m,2H),2.20(dd,J＝17.4,9.4Hz,1H),1.81(s,1H),1.74–1.52(m,3H),1.49(s,4H),1.37(s,1H),1.33(s,1H),1.26(d,J＝12.9Hz,3H),0.97–0.80(m,3H),0.56(s,1H),0.06(s,1H).13C NMR(151MHz,CDCl3)δ212.14,146.81,142.26,141.51,137.10,131.60,129.33,126.21,125.53,119.05,114.77,92.99,79.31,59.77,57.14,54.22,53.21,45.23,44.01,43.13,37.14,31.93,29.70,28.59,25.68,22.70,21.37,17.71,14.12,9.05,4.57,3.40.HMRS:calc.for C34H41NO4([M+H]+)528.31.
实施例19
N-环丙甲基-7α-甲基-7β-((3-甲氧基苯基)-甲酰基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8f替换8a，得到黄色油状物9f，收率：45％。1H NMR(400MHz,CDCl3)δ7.28–7.25(m,3H),6.96(s,1H),6.75(s,1H),6.60(s,1H),5.25(s,1H),3.93–3.90(m,3H),3.84(dd,J＝5.1,1.4Hz,3H),3.56–3.53(m,3H),3.37(s,1H),3.02(s,2H),2.68(s,1H),2.29(s,3H),1.91(s,1H),1.79–1.64(m,2H),1.50(s,4H),1.29(d,J＝30.7Hz,3H),0.99–0.70(m,3H),0.51(s,2H),0.08(dd,J＝5.1,3.0Hz,1H).13CNMR(151MHz,CDCl3)δ211.72,158.87,146.74,142.68,141.89,128.70,120.47,119.10,116.28,114.52,112.81,93.44,79.38,59.81,58.80,57.10,55.33,54.31,53.26,45.57,43.92,43.14,37.09,29.70,28.54,25.63,22.69,17.46,9.41,3.36.HMRS:calc.forC33H39NO5([M+H]+)530.29。
实施例20
N-环丙甲基-7α-甲基-7β-((4-异丙基苯基)-甲酰基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8g替换8a，得到黄色油状物9g，收率：40％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),6.73(d,J＝8.1Hz,1H),6.58(d,J＝8.1Hz,1H),5.27(s,1H),3.90(s,3H),3.53(s,3H),3.48(d,J＝13.1Hz,1H),3.27(s,1H),3.03(d,J＝18.8Hz,1H),2.95–2.87(m,1H),2.60(s,1H),2.39(s,3H),1.74–1.64(m,1H),1.59(d,J＝12.1Hz,1H),1.53(s,3H),1.49(d,J＝12.3Hz,1H),1.36(s,1H),1.33–1.29(m,1H),1.26(s,3H),1.25(s,3H),1.20(d,J＝7.0Hz,1H),0.96–0.82(m,3H),0.52(s,2H),0.18(s,2H).13C NMR(151MHz,CDCl3)δ210.70,151.35,146.76,142.04,138.59,133.89,128.57,127.63,125.69,118.98,114.77,93.12,79.31,59.86,58.83,57.14,54.27,53.24,45.40,43.99,43.16,37.03,34.02,29.70,28.59,25.80,23.78,23.76,17.80,14.12,8.71,4.57,3.41.HMRS:calc.for C35H43NO4([M+H]+)542.33.
实施例21
N-环丙甲基-7α-甲基-7β-(1-(4-联苯基)-羟甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8i替换8a，得到黄色油状物9i，收率：35％。1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.0Hz,2H),7.61(t,J＝8.6Hz,4H),7.45(t,J＝7.4Hz,2H),7.37(t,J＝7.2Hz,1H),6.75(d,J＝8.0Hz,1H),6.60(d,J＝8.1Hz,1H),5.28(d,J＝12.1Hz,1H),3.91(s,3H),3.56(s,3H),3.29(d,J＝72.9Hz,1H),3.05(d,J＝18.6Hz,2H),2.45(s,3H),1.79–1.68(m,2H),1.62(s,1H),1.58–1.48(m,4H),1.44–1.21(m,5H),1.00–0.79(m,2H),0.57(s,2H),0.22(s,1H).13C NMR(151MHz,CDCl3)δ210.90,146.73,142.83,142.16,140.30,139.87,133.42,129.93,129.39,128.77,127.68,127.13,126.25,119.04,114.93,93.02,79.19,59.71,58.65,57.08,54.31,53.21,45.21,44.15,43.01,37.02,29.64,28.53,25.69,17.54,14.05,8.38,4.72,3.36.HMRS:calc.for C38H41NO4([M+H]+)576.32。
实施例22
N-环丙甲基-7α-甲基-7β-((2-萘基)-甲酰基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8j替换8a，得到黄色油状物9j，收率：40％。1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.90(d,J＝7.2Hz,1H),7.87–7.78(m,3H),7.52(d,J＝5.4Hz,2H),6.74(d,J＝7.1Hz,1H),6.59(d,J＝7.4Hz,1H),5.29(s,1H),3.91(s,3H),3.60(s,3H),3.47(s,1H),3.03(d,J＝18.2Hz,2H),2.68(s,1H),2.28(s,4H),1.75(dd,J＝20.4,11.7Hz,1H),1.56(s,5H),1.28(d,J＝20.0Hz,4H),0.91(d,J＝12.8Hz,1H),0.80(s,1H),0.50(s,2H),0.11(s,1H).13C NMR(151MHz,CDCl3)δ211.64,146.64,141.83,138.74,134.35,133.91,132.34,129.16,128.41,127.56,127.26,127.15,126.30,125.12,118.96,114.47,93.49,79.62,59.98,58.93,57.12,54.58,53.28,45.72,43.79,43.34,37.06,29.70,28.55,25.87,22.70,17.73,9.49,4.32,3.33.HMRS:calc.for C36H39NO4([M+H]+)550.30。
实施例23
N-环丙甲基-7α-甲基-7β-乙酰基-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线及反应步骤：
参考实施例14中的反应步骤(h)，用化合物8k替换8a，得到黄色油状物9k，收率：65％。1H NMR(400MHz,CDCl3)δ6.71(s,1H),6.56(s,1H),4.63(s,1H),3.88(s,3H),3.43(s,3H),2.99(d,J＝17.1Hz,2H),2.71(d,J＝32.9Hz,2H),2.60–2.48(m,1H),2.24(s,3H),1.61(dd,J＝20.2,12.3Hz,3H),1.47(s,3H),1.30(s,1H),1.25(s,2H),1.18–1.10(m,1H),1.03(t,J＝7.1Hz,3H),0.87(d,J＝7.0Hz,3H),0.46(s,2H),0.07(d,J＝3.5Hz,2H).13C NMR(151MHz,CDCl3)δ214.56,146.51,141.73,128.51,119.12,115.56,114.55,93.95,78.58,59.92,58.99,57.13,53.18,45.22,43.62,39.86,36.59,34.39,29.70,28.67,22.70,18.50,17.17,14.13,9.49,8.37,4.06,3.46.HMRS:calc.for C28H37NO4([M+H]+)452.28。
实施例24
N-环丙甲基-7α-甲基-7β-甲酰基-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线：
反应步骤：
参考实施例13的反应步骤，用甲基氯化镁替换乙基氯化镁，得到黄色油状化合物8l，收率：29％，ESIMS：m/z 440.3([M+H+],100)；再参考实施例14的步骤(h)，用化合物8l替换8a，得到黄色油状物9l，收率：70％。1HNMR(400MHz,CDCl3)δ6.71(d,J＝7.5Hz,1H),6.56(d,J＝7.0Hz,1H),4.63(s,1H),3.87(s,3H),3.46(s,3H),2.98(d,J＝18.1Hz,2H),2.66(s,1H),2.34(s,1H),2.28(s,3H),2.25–2.06(m,1H),1.91(d,J＝75.7Hz,3H),1.61(dd,J＝15.2,4.7Hz,2H),1.46(s,3H),1.24(s,5H),0.87(s,3H),0.51(s,1H),0.10(d,J＝28.5Hz,1H).HMRS:calc.for C27H35NO4([M+H]+)438.26.
实施例25
N-环丙甲基-7α-甲基-7β-(苯酯基-甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线：
反应条件：(i)苯甲酰氯，二氯甲烷，三乙胺，室温，2h。
反应步骤：
氩气保护下，将化合物6(100mg，0.235mmol，1eq)加入25mL规格的茄形瓶中，加入5mL无水二氯甲烷使之溶解，加入三乙胺(0.1mL,0.7mmol,3eq)，冰水浴搅拌下，向上述溶液中逐滴加入苯甲酰氯(0.05mL，0.423mmol，1.8eq)，滴加完毕后室温下反应2h。冰水浴下加水淬灭，加入二氯甲烷(5mL x 3)和水(5mL)萃取，合并有机相，用饱和食盐水洗涤，加入无水硫酸钠干燥，过滤，滤液浓缩后使用硅胶柱层析分离得到25mg淡黄色油状物10，收率：20％。1HNMR(400MHz,CDCl3)δ8.12(s,2H),7.54(d,J＝18.9Hz,1H),7.50–7.44(m,2H),6.73(s,1H),6.58(s,1H),4.96(s,1H),4.46(s,2H),3.92–3.89(m,3H),3.45(s,3H),3.11–2.91(m,2H),2.85(s,1H),2.58(s,1H),2.32(s,4H),1.71–1.59(m,2H),1.49(s,1H),1.30(d,J＝4.7Hz,3H),1.25(d,J＝5.5Hz,2H),1.07(d,J＝16.7Hz,1H),0.87(s,1H),0.75(s,1H),0.46(s,2H),0.07(s,2H).13C NMR(151MHz,CDCl3)δ167.09,146.71,141.73,133.61,132.79,131.61,130.67,129.69,128.33,118.99,114.50,94.28,77.92,69.95,59.75,58.75,57.09,53.10,45.73,43.65,41.31,39.35,35.86,33.63,28.56,22.69,22.59,17.66,9.38,4.20,3.25.HMRS:calc.for C33H39NO5([M+H]+)552.2720,found 552.2709.
实施例26
N-环丙甲基-7α-甲基-7β-(苄氧基-甲基)-6α,14α-endo-亚乙基-四氢去甲蒂巴因
合成路线：
反应条件：(j)氢化钠，N,N-二甲基甲酰胺，溴苄，室温，3h。
反应步骤：
将化合物6(50mg，0.117mmol，1eq)溶于无水二甲基甲酰胺(2mL)中，加入干燥、氩气保护的茄形瓶中，冰浴下，向其中缓慢加入氢化钠(28mg，0.7mmol，6eq)，0℃反应30min后逐滴加入溴化苄(0.02mL，0.18mmol，1.5eq)，室温下搅拌反应3h。冰浴下，向上述反应液中缓慢滴加10％醋酸淬灭，加入二氯甲烷(5mL x 3)和水(5mL)萃取，合并有机相，用饱和食盐水洗涤，再加入无水硫酸钠干燥，过滤，滤液浓缩后使用薄层制备分离，用二氯甲烷：甲醇＝20:1展开，得24mg黄色油状物11。收率：40％。1H NMR(400MHz,CDCl3)δ7.53(s,2H),7.33(d,J＝6.8Hz,2H),7.25(d,J＝6.9Hz,1H),6.75(d,J＝7.5Hz,1H),6.60(d,J＝7.6Hz,1H),5.58(s,1H),4.78(s,1H),4.54(d,J＝11.2Hz,1H),3.89(s,3H),3.77(s,1H),3.49(s,3H),3.20(d,J＝7.6Hz,2H),3.01(d,J＝18.7Hz,1H),2.91–2.52(m,3H),2.12(s,2H),1.56(d,J＝7.8Hz,1H),1.40(d,J＝11.9Hz,2H),1.32(d,J＝13.0Hz,2H),1.26(s,2H),1.04(s,3H),0.88(s,2H),0.73(s,3H),0.41(s,1H).13C NMR(151MHz,CDCl3)δ147.09,142.62,138.39,132.21,128.54,128.19,127.35,123.22,119.04,115.26,91.91,77.64,76.09,73.94,58.93,58.32,56.97,53.22,45.60,44.00,41.90,38.89,36.57,29.69,28.93,24.88,22.77,18.85,6.01,3.29.HMRS:calc.for C33H41NO4([M+H]+)538.29.
实施例27
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。竞争结合实验包括总结合管、非特异性结合管以及测试样品管，各管加入50μL适当浓度的细胞悬液和10μL[3H]标记的配体(μ受体使用[3H]DAMGO 51.5Ci/mmol，δ受体使用[3H]DPDPE 57.4Ci/mmol，κ受体使用[3H]U6959343.6Ci/mmol)，使相当于20-30μg的表达膜受体蛋白和1-2nmoL的[3H]标记配体，非特异性结合管另加10μL相应配体(相当于1μmoL)，测试样品管另加10μL不同浓度的测试化合物，各管加入相应体积的50mM Tris-HCl缓冲液调节终体积为100μL。混合均匀后置于30℃恒温水浴孵育30min，转移至冰水中终止孵育。在Millipore样品收集器上经GF/C(whatman)玻璃纤维滤纸负压抽滤，用冰的Tris-HCl缓冲液冲洗试管三次，过滤结束后将滤纸烘干，置于0.5mL的EP管中，加入0.5mL亲脂性闪烁液，PERKIN ELMER PRI-CARB 2910液体闪烁计数仪测定放射性强度，按照公式(抑制率＝(总结合管dpm-样品管dpm)/(总结合管dpm-非特异性结合管dpm)×100％)计算各化合物的抑制率，用Prism 5.0软件计算IC50及相应的Ki值。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.化合物对阿片受体亚型的亲和力及选择性数据
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实施例28：[35S]GTPγS结合实验
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。制备的膜受体用反应缓冲液(R.B)稀释到所需浓度，各反应管按照表2所示体积加样后，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，按公式：[35S]GTPγS结合率＝100×(cpm样品管-cpm非特异管)/(cpm总结合管-cpm非特异管)进行计算。
表2.[35S]GTPγS实验中各反应管中的试剂组成及相应体积
实验结果如表3所示。
表3.化合物对阿片受体亚型的功能活性
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Claims (2)

1.稠环吗啡类化合物或其药学可接受的盐，
其特征在于，所述化合物具体为如下结构：
2.一种如权利要求1所述的化合物在制备镇痛、抗抑郁、阿片成瘾性戒断治疗、止痒药物中的应用。
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