CN119431382A 一种四氢蒂巴因衍生物及其制备方法和用途 （中国科学院上海药物研究所）

一种四氢蒂巴因衍生物及其制备方法和用途本申请涉及一种四氢蒂巴因衍生物及其制四氢蒂巴因衍生物或者其药学上可接受的盐类及其制备方法，并且涉及此类衍生物在制备镇活性及κ受体的亚型选择性方面得到了显著提2R2选自HC62_C62_C651C6取代或被选自A组的取代基取代的C1_C6烷氧基酰基，未取代或被选自A组的取代基取代的其中，选自A组的取代基各自独立地选自未取代或被选自B组的取代基取代的C1_C6烷1_C6烷基；R2选自HC42_C42_C453R5选自HC43657636环烷基取代或被选自A组的取代基取代的5_9元杂芳基酰基，未取代或被选自A组的取代基取代的R5选自HC4363114烷基245679.一种组合物，其包含治疗有效量的根据权利要求110.根据权利要求1至8任一项所述的衍生物或其药学上可接受的盐，或者根据权利要根据权利要求1至8任一项所述的衍生物或其药学上可接受的盐，或者根据权利要求98秘等典型阿片类药物的副作用密切相关，目前还没有找到通过μ阿片受体实现镇痛与成瘾现曾在二十世纪八九十年代掀起过一股ĸ激动剂研究的热潮，但随着代表性药物依那朵林(enadoline)及螺朵林(spiradoline)II期临床试验的失败使得ĸ激动剂的研究陷入了低物制备中的应用又重新引起了关注。由于许多吗啡类结构激动剂由于保留有较强的阿片μ(烯)基四氢蒂巴因衍生物或者其药学上可接受的盐类及其制备方法，并且此类衍生物在9C62_C6C6C424243657环烯3C636576或被选自A组的取代基取代的C3_C6环烷基C1_C6烷基，未取代或被选自A组的取代基取代的代或被选自A组的取代基取代的5_9元杂芳C6576组的取代基取代的C3_C6环烷基C1_C4烷酰基，未取代或被选自A组的C4烷基21A组的取代基各自独立地选自C1_C6C6[0018]根据本发明的如通式(I)所示的衍生物或者其药学上可接受的盐的一实施方式，[0019]根据本发明的如通式(I)所示的衍生物或者其药学上可接受的盐的一实施方式，[0020]根据本发明的如通式(I)所示的衍生物或者其药学上可接受的盐的一实施方式，[0028]根据本发明，所述药学上可接受的盐可以是通式(I)所示的衍生物与无机酸或有[0029]根据本发明的另一方面，提供一种如通式(I)所示的衍生物或者其药学上可接受C62_C6=CH_的衍生物在一定还原性条件下转化制备。所述的该还原条件选自Pd/C催化氢化下还12本发明未明确定义的术语具有本领域技术人员所普遍理解的"vv"且转棒疲劳试验显示镇静中枢副作用弱。γ质核比(m/z)表示。高分辨质谱(ESI_HRMS)用ABSCIEXTRIPLETOF5600+质谱仪进行测定。固体的熔点采用毛细管法在熔点仪上测定，测定仪器为WRS_1B数字熔点仪。1HNMR在司GF254型硅胶板(0.5mm)。化合物纯度由Agilent1260HPLC测得，流动相体系为甲醇：加热48h，停止反应，反应液过滤除去钯碳，滤液旋干得到白色泡沫状固体1.0g，收率：中加入3mL四氢铝锂的四氢呋喃溶液(1N)，冰浴下，缓慢滴加前一步的产物的四氢呋喃溶HNMR(400MHz,CDCl3)δCNMR(151MHz,CDCl3)δ153.30,147.22,141.78,139.13,132.94,128.99,126.56,124.01,121.05,118.83,113.62,92.40,30.05,22.64,20.04,13.17,9.40,4.37,3.03.[0094]N环丙甲基7α[2'(N'环丙甲基)氨基]苯基6αCNMR(151MHz,CDCl3)δ1429.07,28.66,22.45,15.15,10.29,2.88,2.82,2.63.[0098]N环丙甲基7α[2'(N'环戊甲基)氨基]苯基6α146.89,130.90,128.83,128.19,126.96,118.99,117.09,113.97,111.33,109.01,97.96,30.88,30.85,29.68,29.27,28.43,25.49,25.36,19.17,15.76,3.43.23.00,15.82,9.45,3.97,3.41.[0110]N环丙甲基7α(2'对三氟甲基苄氨基)苯基6α,14α内亚乙基四氢蒂巴因+HNMR(400MHz,CDCl3)δ7.59CNMR(151MHz,CDCl3)13CNMR(151MHz,CDCl3)δ148.01,147.01,144.29,142.26,129.14,128.93,128.24,127.31,127.04,126.80,125.43,125.41,14.09,3.35,0.99.+:670.4.1HNMR(400MHz,30.29,29.68,29.21,28.47,22.95,15.71,9.48,3.94,3.42.CDCl3)δ168.37,146.73,141.85,137.85,133.70,132.73,128.17,126.70,125.08,124.92,35.13,33.87,28.99,24.35,22.99,15.38,14.16,9.37,3.90,3.52.33.71,29.66,29.08,27.77,27.02,15.35,14.16,3.43.μL三乙胺(0.34mmol,3.0eq)，置于冰浴中，边搅拌边缓慢滴加30μL三甲基乙酰氯经硅胶柱层析分离(PE/EA/Et3N＝100/20/1)得到白色泡沫状固体22.0mg，收率：35.9%35.80,33.71,29.66,29.08,27.77,27.02,15.35,14.16,3.43.[0130]N环丙甲基7α(2'丙戊酰氨基)苯基6α,14α内亚乙基四氢蒂巴因(15)的制65.0mgHATU(0.17mmol,1.5eq)，35μL二异丙基乙胺(0.22mmol,2.0eq)，2029.69,29.07,28.86,28.52,20.59,20.33,19.89,14.94,13.66,13.58,13.32,12.53,3.56,2.80.[0134]N环丙甲基7α(2'苯甲酰氨基)苯基6α,14α内亚乙基四氢蒂巴因(16)的制+:576.9.1HNMR(400MHz,CDCl3)δ818.75,14.10,9.46,4.09,3.36.13CNMR(151MHz,CDCl3)δ168.24,162.39,146.4136.98,134.40,128.50,126.87,125.51,125.30,125.15,119.31,119.12,118.91,114.65,33.76,29.68,28.97,22.93,19.17,15.43,14.10,13.71,9.45,3.93,3.48.CNMR(151MHz,CDCl3)δ169.60,167.69,164.25,148.92,146.60,141.85,137.80,134.39,131.92,130.88,128.81,128.31,128.09,126.85,126.27,125.26,125.06,123.68,119.16,114.04,97.76,29.06,19.15,15.47,14.16,13.70,3.42.燥，减压浓缩后经硅胶柱层析分离(DCM/MeOH＝30/1)得到淡黄色固体46.0mg，收率：165.00,146.57,141.87,140.82,138.32,137.20,132.34,129.97,128.81,128.29,126.79,124.79,124.66,124.02,119.24,113.69,98.18,79.16,59.78,58.76,56.62,53.12,46.50,19.85,15.45,14.10,3.45.减压浓缩后经硅胶柱层析分离(DCM/MeOH＝30/1)得到白色泡沫状固体52.0mg，收率：CNMR(151MHz,CDCl3)δ162.60,146.58,137.69,136.09,134.74,133.43,130.79,129.90,128.35,127.02,125.55,125.21,124.67,119.42,113.99,97.99,79.33,59.66,58.64,56.70,53.40,53.20,39.41,38.59,35.70,33.84,29.68,29.02,22.67,15.47,14.10,3.45,1.00.[0154]N环丙甲基7α[2'(吲哚5甲酰氨基)]苯基6α,14α内亚乙基四氢蒂巴因138.60,137.72,128.24,127.81,126.79,126.51,125.67,125.01,124.54,120.90,120.77,119.23,113.55,111.22,103.91,98.13,79.12,59.76,58.74,56.57,53.12,46.43,43.66,39.41,38.60,35.70,33.97,29.68,29.05,23.00,15.47,4.07,3.46.干燥，减压浓缩后经硅胶柱层析分离(PE/EA＝5/1)得到白色泡沫状固体24.0mg，收率：151.76,146.59,142.40,141.90,138.15,137.86,135.02,131.77,129.56,128.33,126.83,124.68,120.87,119.69,119.28,114.07,98.21,79.35,59.79,58.78,56.81,53.08,46.42,43.61,39.74,39.45,35.66,35.06,33.94,29.00,22.97,15.44,9.35,3.99,3.46.[0162]N环丙甲基7α(2'苯乙酰氨基)苯基6α,14α内亚乙基四氢蒂巴因(23)的制65.0mgHATU(0.17mmol,1.5eq)，35μL二异丙基乙胺(0.22mmol,2.0eq)，18mg苯乙酸146.98,143.59,141.79,137.81,135.13,132.85,131.77,128.77,128.121.20,118.98,118.07,113.68,93.33,59.85,58.54,56.63,51.16,46.08,43.97,43.86,36.39,36.11,35.68,29.67,29.64,22.77,18.75,14.10,9.46,4.09,3.36.C22.67,15.18,14.19,14.07,4.01,3.59,1.00.减压浓缩后经硅胶柱层析分离(DCM/MeOH＝50/1)得到白色泡沫状固体45.0mg，收率：相，无水硫酸钠干燥，减压浓缩后经硅胶柱层析分离(DCM/MeOH＝50/1)得到淡黄色固体146.77,137.74,133.96,130.90,129.39,129.25,128.82,128.00,126.55,126.39,126.17,124.86,124.62,119.27,119.00,105.84,96.87,65.55,59.55,58.37,57.11,55.30,52.60,47.77,38.46,35.36,33.56,29.68,28.89,22.67,19.17,18.33,15.14,14.10,13.71,4.06,3.30.[0181]向10mL单口反应瓶中加入2mLDCM，加入上一步反应浓缩物，边搅拌边缓慢滴加(s,2H).13CNMR(151MHz,CDCl3)13CNMR(151MHz,CDCl3)δ146.64,146.42,141.42,127.78,126.20,118.50,118.46,116.54,113.99,96.43,77.71,58.96,58.06,56.37,52.80,51.90,45.41,43.62,37.65,35.33,33.78,31.31,29.08,28.74,22.73,22.07,15.37,13.50,3.83,2.76,0.40.35.0mg无水碳酸钠(0.34mmol,3.0eq)，冰浴下边搅拌边缓慢滴加34μL氯甲酸苄酯经硅胶柱层析分离(PE/EA＝5/1)得到白色固体17.0mg，收率：25.5％.ESI一MS(M+H)+:22.65,15.45,14.09,4.70,3.43.CNMR(151MHz,CDCl3)δ163.88,151.45,146.89,144.12,141.99,138.07,133.56,128.36,128.18,126.78,124.86,124.36,119.49,119.30,114.74,31.50,30.16,29.68,29.15,22.67,14.07,3.49.[0195]药理结合力筛选使用的化合物均为游离碱形式。实验积100uL。在37℃温育30min，然后置冰浴中终止反应。在