CN103467391A - 一类含饱和氮杂环酰胺的二芳基甲基哌嗪化合物及其应用 - Google Patents
一类含饱和氮杂环酰胺的二芳基甲基哌嗪化合物及其应用 Download PDFInfo
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- CN103467391A CN103467391A CN2013104343006A CN201310434300A CN103467391A CN 103467391 A CN103467391 A CN 103467391A CN 2013104343006 A CN2013104343006 A CN 2013104343006A CN 201310434300 A CN201310434300 A CN 201310434300A CN 103467391 A CN103467391 A CN 103467391A
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- China
- Prior art keywords
- benzoyl
- dimethyl
- piperazinyl
- hydroxybenzyl
- luorobenzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明公开了一类含饱和氮杂环酰胺取代的二芳基甲基哌嗪类化合物,或其药学可接受的酯、或其药学可接受的盐,本发明提供的化合物为δ阿片受体激动剂,可用于帕金森症的治疗,相对于现有的BW373U86和SNC80等二芳基甲基哌嗪类δ受体激动剂,本发明提供的化合物以代谢稳定性较好的饱和氮杂环酰胺结构片段替代了原有的N-二乙基酰胺,预期可提高代谢稳定性,更好地发挥化合物的治疗效果。
Description
技术领域
本发明涉及一类二芳基甲基哌嗪化合物,尤其涉及含饱和氮杂环酰胺取代的二芳基甲基哌嗪化合物,及其在制备治疗帕金森症的药物中的应用。
背景技术
帕金森症(Parkinson’s disease)是一种常见的神经退行性疾病,多发于老年人,病理表现主要是多巴胺能神经元的变性死亡,导致纹状体多巴胺显著减少 [1]。帕金森症的治疗目前主要针对多巴胺不足,采用左旋多巴等药物治疗 [2]。但患者经三到五年治疗后疗效减弱,出现“开关”现象、异常不自主运动等副作用,并逐渐加重,严重影响患者生活质量 [2]。如在用药时辅以多巴胺激动剂,可减缓上述现象的发生,但不能防止。值得注意的是,一旦患者出现左旋多巴引起的异常不自主运动,即使改用其它多巴胺类药物也易于引发。因此,研发基于不同机制的药物成为目前帕金森症临床治疗的迫切需要。
δ受体是阿片受体的一种亚型,属于G蛋白偶联受体,分布于中枢神经***和外周神经***。通常认为,δ阿片受体与其它阿片受体如μ和κ受体等共同参与调节对疼痛的感知,阿片药物靶向于μ、δ和κ受体,产生相应的生理作用 [3,4]。传统的阿片类药物,例如***、芬太尼、***等,主要作用于中枢神经***的μ阿片受体,常作为镇痛药物以治疗严重疼痛。研究发现,选择性δ受体激动剂如BW373U86等无强效镇痛作用 [5-7],与***同时使用,能减弱***引起的依赖性、呼吸抑制,并且提高***的镇痛作用 [8,9]。
近来的研究表明,阿片受体***的信号传导与多巴胺***有密切联系。在左旋多巴引起的异常不自主运动的动物模型研究中,发现基底核中内啡肽的合成量增加,在帕金森症患者尸体的组织检查中也发现同样的现象,表明μ阿片受体活化参与了在长期左旋多巴治疗中异常不自主运动的发生发展,而选择性μ阿片受体拮抗剂可完全抑制异常不自主运动的发生 [10-12]。另一方面,在大鼠模型研究中,δ阿片受体的内源性配体脑啡肽能降低去极化引起的苍白球GABA释放,而此现象与抗帕金森症相关 [13],因而激活δ受体具有潜在的抗帕金森症作用 [14-17]。
上述结果表明,具有δ受体激动活性同时无μ受体激动活性的化合物应可用于帕金森症的治疗。例如,由BW373U86 [5] 衍生得到的SNC80 [18],动物实验表明具有明显的抗帕金森症作用 [16]。专利申请US 2007/0066625公布了一类N-二乙基酰胺二芳基甲基哌嗪类δ激动剂,在利血平或氟哌啶醇诱导的帕金森症大鼠模型实验中能明显减少异常不自主运动。因此,此类化合物具备独特的优点,可明显减轻传统多巴胺药物引起的副作用,是前景良好的抗帕金森症药物。
然而,现有的δ受体激动剂大多含有较易代谢的N-二乙基酰胺或N-二甲基酰胺结构片段,限制了临床应用价值。例如SNC80 [18],动物实验表明其代谢稳定性差,造成生物利用度低,不能口服给药。
基于前期研究,本发明的目的是提供一类含有饱和氮杂环酰胺取代的二芳基甲基哌嗪类δ阿片受体激动剂,以改善化合物的代谢稳定性。
参考文献
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发明内容
本发明的目的在于提供一种二芳基甲基哌嗪化合物,该化合物为通式(I)所示结构式的二芳基甲基哌嗪化合物、或其药学可接受的酯、或其药学可接受的盐,
其中:R1选自氢、氟、氯、溴、碘、羟基或C1-C2烷氧基;R2选自氢、氟、氯、溴或碘,取代位置为A环的2、3或4位;n表示1、2、3、4或5,相应于B环为4-8元环,即通称为吖丁啶、吡咯烷、哌啶、氮杂环庚烷、氮杂环辛烷的饱和氮杂环。
优选的本发明化合物包括:
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-(α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-(3-羟基苄基))-(1-哌啶基)-苯甲酰胺;
4-((α R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷。
本发明中所述化合物药学可接受的酯,选自但不限于:甲酸酯、乙酸酯、丙酸酯、丁酸酯、三氟乙酸酯、油酸酯、硬脂酸酯等。
本发明中所述化合物药学可接受的盐,选自但不限于:硫酸盐、盐酸盐、氢溴酸盐、磷酸盐、三氟乙酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、三氟甲磺酸盐、樟脑磺酸盐、甲酸盐、乙酸盐、丙酸盐、己酸盐、己二酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、富马酸盐、马来酸盐、乳酸盐、琥珀酸盐等。
本发明化合物的合成方法是以一个四组分串联反应为关键步骤,由芳基甲醛、手性二甲基哌嗪和苯并三氮唑首先缩合得到不稳定的加合物,再与芳基格氏试剂发生不对称取代反应,再经后处理得到相应的目标化合物。
本发明的另一目的是提供一种含有通式(I)所示结构式的二芳基甲基哌嗪化合物或其药学可接受的酯、或其药学可接受的盐的药物组合物,即以通式(I)所示结构式的二芳基甲基哌嗪化合物或其药学可接受的酯、或其药学可接受的盐作为主要有效活性成分,还可加入一种或多种药物上可接受的辅料,以改善药物吸收效果或便于服用,如制成胶囊或丸剂、粉剂、片剂、粒剂、口服液和注射液等;本发明所述的辅料包括药学领域常规的填充剂、稀释剂、粘合剂、赋形剂、吸收促进剂、表面活性剂和稳定剂等,必要时还可加入香味剂、色素和甜味剂等。
本发明化合物使用方法包括给所述患者施用有效量的药物,可采用任何适当的给药方式施用这些治疗单体化合物或组合物,例如选自下列方式的给药方式:口服、直肠、局部、舌下、粘膜、鼻、眼、皮下、肌内、静脉内、经皮、脊椎、鞘内、关节内、动脉内、蛛网膜下、支气管、淋巴和子宫给药。
本发明化合物为δ阿片受体激动剂,可用于帕金森症的治疗。相对于现有的BW373U86和SNC80等二芳基甲基哌嗪类δ受体激动剂,本发明提供的化合物以代谢稳定性较好的饱和氮杂环酰胺结构片段替代了原有的N-二乙基酰胺,预期可提高代谢稳定性,更好地发挥化合物的治疗效果。
具体实施方式
通过下面给出的本发明的制备实施例和药理实验可以进一步清楚地了解本发明,但并不构成对本发明保护范围的限定,本实施例中方法如无特殊说明的均按常规方法操作,所用试剂如无特殊说明的采用常规试剂或按常规方法配置的试剂。
实施例1:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备
具体合成方法如下:
步骤一、(4-甲酰基)苯甲酰基-1-哌啶的制备:取4-甲酰基苯甲酸(50.0 g,333.3 mmol),溶于二氯甲烷(500 ml)中,冰浴降温至0℃左右,缓慢滴加二氯亚砜(78.6 g,666.6 mmol),搅拌,滴加完毕后撤去冰浴,加热至回流直到反应完为止;降至室温,浓缩反应液得到4-甲酰基苯甲酰氯,然后在冰浴条件下,将溶于二氯甲烷(250 ml)的哌啶(28.26 g,333.3 mmol)溶液转入4-甲酰基苯甲酰氯中,搅拌1 h,加入水(500 ml),分出有机相,用无水硫酸钠干燥有机相,浓缩得油状物50.0 g,产率69%;
1H NMR (400 MHz, CDCl3) δ 10.01(s, 1H), 7.89 (d, J = 11.4 Hz, 2H), 7.51 (d, J = 10.7 Hz 2H), 3.69 (s, 2H), 3.26 (s, 2H), 1.65-1.53 (m, 4H), 1.48-1.45 (m, 2H);
步骤二、(2R,5S)-1-(3-氟苄基)-2,5-二甲基哌嗪的制备:称取反式2,5-二甲基哌嗪碱(114.0 g, 1.0 mol)和其双盐酸盐(187.0 g, 1.0 mol)置于烧瓶中,加入无水乙醇(1000 ml),搅拌下水浴加热至60-70oC使其充分溶解后缓慢滴加新蒸馏过的3-氟苄氯(144.5 g, 1.0 mol),剧烈搅拌,约1-3小时滴完,继续保温反应1小时后冷却至室温,过滤,滤饼用无水乙醇(200 ml)洗涤;合并滤液,蒸除乙醇,加入水(500 ml),搅拌下用10%NaOH溶液调节pH值大于12后,用二氯甲烷萃取。萃取液用无水硫酸镁干燥,过滤,浓缩得1-(3-氟苄基)-2,5-二甲基哌嗪消旋体213.4 g,产率96%;消旋体经手性酒石酸成盐结晶拆分得到异构体(2R,5S)-1-(3-氟苄基)-2,5-二甲基哌嗪72.6 g,产率34%;
1H NMR (400 MHz, CDCl3) δ7.26-7.07 (m, 3H), 6.93-6.89 (m, 1H), 4.06 (d, J = 13.7 Hz, 1H), 3.05 (d, J = 13.7 Hz, 1H), 2.90 (dd, J= 12.1, 3.0 Hz, 1H), 2.80-2.78 (m, 1H), 2.66-2.59 (m, 2H), 2.24-2.23 (m, 1H), 1.76 (br, 1H), 1.64 (t, J = 10.8 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H);
步骤三、3-(溴代苯氧基)叔丁基二甲基硅烷的制备:将3-溴苯酚(30.1 g, 174 mmol)溶于DMF (200 ml)中,室温下加入TBSCl (26.2 g,174 mmol)和咪唑(23.7 g,348 mmol),室温搅拌3 h。反应完毕后,加入饱和碳酸氢钠溶液淬灭。石油醚萃取,水、盐水依次洗涤,无水硫酸镁干燥,浓缩得透明浅黄色液体38.6 g,产率77%;
1H NMR (400 MHz, CDCl3) δ 7.25-7.03 (m, 3H), 6.58-6.43 (m, 1H), 0.98 (s, 9H), 0.20 (s, 6H);
步骤四、(3-叔丁基二甲基硅烷氧基)苯基溴化镁的制备:称取镁条(1.5 g,61.7 mmol)置于圆底烧瓶中,加入无水四氢呋喃(90 ml),将3-(溴代苯氧基)叔丁基二甲基硅烷(14.4 g,50.1 mmol)转入镁条中,升温至45℃反应,镁条完全溶解后即得浅棕色透明的(3-叔丁基二甲基硅烷氧基)苯基溴化镁的无水四氢呋喃溶液,冷却至室温备用;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备:在一个装配冷凝器和Dean-Stark分水器的圆底烧瓶中加入(4-甲酰基)苯甲酰基-1-哌啶(6.70 g,30.85 mmol)、苯并三氮唑(3.67 g,30.85 mmol)、(2R,5S)-1-(3-氟苄基)-2,5-二甲基哌嗪(6.86 g,30.85 mmol)和甲苯(100 ml),在氮气保护下加热回流至除水完全,然后冷却到室温,氮气保护下加入无水四氢呋喃(50 ml),将步骤四中制备的(3-叔丁基二甲基硅烷氧基)苯基溴化镁溶液缓缓加入,再继续室温搅拌至反应完全,加入饱和氯化铵水溶液淬灭,乙酸乙酯萃取,有机层经无水硫酸镁干燥,过滤,蒸除溶剂得棕色粘稠油状物;将该油状物在室温下溶解于甲醇(100 ml)和1 N盐酸(50 ml)混合液中,搅拌1.5小时,反应完毕后,加入水(50 ml)稀释,用10%NaOH调节pH至9后用乙酸乙酯萃取产物,合并萃取液,分别用水和饱和盐水洗涤,无水硫酸镁干燥,减压除去溶剂,粗产物经硅胶柱层析纯化得白色固体4.93 g,产率31%;
1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 20.3 Hz, 3H), 7.26-7.20 (m, 3H), 7.13-7.11 (m, 2H), 7.02-7.05 (m, 2H), 6.93-6.88 (m, 2H), 5.00 (s, 1H), 3.88 (d, J = 10.3 Hz, 2H), 3.69 (s, 2H), 3.37 (s, 2H), 3.19 (d, J = 15.4 Hz, 1H), 2.66-2.56 (m, 4H), 2.01-1.85 (m, 3H), 1.50 (d, J = 20.1 Hz, 6H), 1.07-1.04 (m, 6H)。
实施例1所述的合成方法同样适用于实施例2-8。
实施例2:4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤二、五:
步骤二、(2R,5S)-1-苄基-2,5-二甲基哌嗪的制备:以苄氯为原料,采用实施例1步骤二所述方法制得1-苄基-2,5-二甲基哌嗪消旋体,产率93%;再经手性酒石酸成盐结晶拆分得到(2R,5S)-1-苄基-2,5-二甲基哌嗪,产率37%;
1H NMR (400 MHz, CDCl3) δ 7.22-7.32 (m, 5H), 4.10 (d, J = 13.5 Hz, 1H), 3.09 (d, J = 13.5 Hz, 1H), 2.91 (dd, J= 12.1, 3.1 Hz, 1H), 2.83-2.74 (m, 1H), 2.70-2.60 (m, 2H), 2.28-2.17 (m, 1H), 1.63 (dd, J= 11.0, 10.3 Hz, 1H), 1.49 (br, 1H), 1.14 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H);
步骤五、4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备:以(2R,5S)-1-苄基-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率31%;
1H NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 3H), 7.40-7.32 (m, 3H), 7.29-7.20 (m, 1H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.72 (d, J = 21.3 Hz, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.60 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.25-1.17 (m, 3H), 1.15-1.10 (m, 3H)。
实施例3:4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤二、五:
步骤二、(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪的制备:以3-氯苄氯为原料,采用实施例1步骤二所述方法制得1-(3-氯苄基)-2,5-二甲基哌嗪消旋体,产率92%;再经手性酒石酸成盐结晶拆分得到(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪,产率35%;
1H NMR (400 MHz, CDCl3) δ 7.26-7.22 (m,2H), 7.06-7.04 (m, 2H), 4.07 (d, J = 13.7 Hz, 1H), 3.06 (d, J = 13.7 Hz, 1H), 2.91 (dd, J= 12.1, 3.0 Hz, 1H), 2.80-2.78 (m, 1H), 2.65-2.59 (m, 2H), 2.24-2.23 (m, 1H), 1.76 (br, 1H), 1.65 (t, J = 10.7 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H).
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备:以(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率38%;
1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 4H), 4.95 (s, 1H), 3.70-3.62 (m, 4H), 3.42 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.65 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.25-1.17 (m, 3H), 1.15-1.10 (m, 3H)。
实施例4:4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤二、五:
步骤二、(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪的制备:以3-溴苄氯为原料,采用实施例1步骤二所述方法制得1-(3-溴苄基)-2,5-二甲基哌嗪消旋体,产率95%;再经手性酒石酸成盐结晶拆分得到(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪,产率33%;
1H NMR (400 MHz, CDCl3) δ 7.36-7.05 (m, 4H), 4.27 (d, J = 10.7 Hz, 1H), 3.26 (d, J = 23.7 Hz, 1H), 2.91-2.82 (m, 1H), 2.80-2.78 (m, 1H), 2.65-2.59 (m, 2H), 2.24-2.23 (m, 1H), 1.86 (br, 1H), 1.65 (t, J = 10.7 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.94-0.85 (m, 3H)。
步骤五、4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备:以(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率32%;
1H NMR (400 MHz, CDCl3) δ 7.53-7.52 (m, 2H), 7.27-7.30 (m, 2H), 7.14-7.16 (m, 1H), 7.13-7.10 (m, 2H), 7.07-7.05 (m, 1H), 6.95 (t, 2H), 6.73-6.69 (m, 2H), 5.04 (s, 1H), 4.67(br, 1H), 3.90-3.88 (m, 2H), 3.62-3.53 (m, 2H), 3.30 (s, 2H), 2.69-2.59 (m, 4H), 2.07-1.99 (m, 2H), 1.24-1.23 (m, 6H), 1.11 (d, J = 5.8 Hz, 6H)。
实施例5:4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤二、五:
步骤二、(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪的制备:以3-溴苄氯为原料,采用实施例1步骤二所述方法制得1-(3-碘苄基)-2,5-二甲基哌嗪消旋体,产率96%;再经手性酒石酸成盐结晶拆分得到(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪,产率38%;
1H NMR (400 MHz, CDCl3) δ 7.26-7.22 (m, 3H), 7.06-7.04 (m,1H), 4.27 (d, J = 13.7 Hz, 1H), 3.26 (d, J = 10.1Hz, 1H), 2.88-2.82 (m, 1H), 2.79-2.68 (m, 1H), 2.64 (d, J = 21.3 Hz, 2H), 2.24-2.20 (m, 1H), 1.86 (br, 1H), 1.65 (t, J = 10.7 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.94-0.85 (m, 3H)。
步骤五、4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶的制备:以(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率30%;
1H NMR (400 MHz, CDCl3) δ 7.43-7.25 (m, 4H), 7.20-7.06 (m, 3H), 7.07-6.95 (m, 2H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 6H), 1.10 (d, J = 5.8 Hz, 3H), 1.00-0.87 (m, 3H)。
实施例6:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤三、四、五,无步骤三:
步骤四、苯基溴化镁的制备:以溴苯为原料,采用实施例1步骤四所述方法制得苯基溴化镁的无水四氢呋喃溶液,冷却备用;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-哌啶的制备:以苯基溴化镁为原料,采用实施例1步骤五所述方法制得,为白色固体,产率18%;
1H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 2H), 7.28 (m, 5H), 7.21 (m, 3H), 7.04 (m, 2H), 6.90 (br t, J = 8.2 Hz, 1H), 3.87 (d, J = 13.5 Hz, 2H), 3.53 (br, m, 2H), 3.28 (m, 2H), 3.18 (d, J = 13.8 Hz, 1H), 2.67 (m, 2H), 2.57 (m, 2H), 2.02 (dd, J = 8.2 Hz, 3H), 1.94 (dd, J = 10.8, 8.1 Hz, 3H), 1.22 (m, 2H), 1.15 (d, J = 6.1 Hz, 3H), 1.06 (d, J = 6.1 Hz, 3H)。
实施例7:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤三、四、五,无步骤三:
步骤四3-氟苯基溴化镁的制备:以3-氟溴苯为原料,采用实施例1步骤四所述方法制得3-氟苯基溴化镁的无水四氢呋喃溶液,冷却备用;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-哌啶的制备:以3-氟苯基溴化镁为原料,采用实施例1步骤五所述方法制得,为白色固体,产率21%;
1H NMR (400 MHz, CDCl3) δ 7.44 (m, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.22 (m, 1H), 7.14 (t, J = 7.8 Hz, 2H), 7.00 (m, 5H), 3.89 (d, J = 13.9 Hz, 2H), 3.54 (br, m, 2H), 3.28 (m, 2H), 3.19 (d, J = 13.6 Hz, 1H), 2.68 (m, 2H), 2.47 (m, 2H), 2.00 (dd, J = 8.2 Hz, 3H), 1.90 (m, 3H), 1.32 (m, 2H), 1.20 (d, J = 10.1 Hz, 3H), 1.10 (d, J = 6.1 Hz, 3H)。
实施例8:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-哌啶的制备
合成方法同实施例1,不同在于步骤三、四、五:
步骤三、3-溴苯甲醚的制备:称取3-溴苯酚(0.10 g, 1.0 mmol),碘甲烷(0.28 g, 2.0 mmol),氢氧化钠(0.16 g, 4.0 mmol)溶入DMF (10 ml)中,室温搅拌。反应完毕后加入水(200 ml),石油醚-乙酸乙酯混合液萃取,有机相经干燥过滤,浓缩得3-溴苯甲醚0.17 g,产率91%;
1H NMR (400 MHz, CDCl3) δ 7.26 (m, 3H), 7.10 (m, 1H), 3.57 (s, 3H)。
步骤四、(3-甲氧基)苯基溴化镁的制备:以3-溴苯甲醚为原料,采用实施例1步骤四所述方法制得(3-甲氧基)苯基溴化镁的无水四氢呋喃溶液,冷却备用;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-哌啶的制备:以(3-甲氧基)苯基溴化镁为原料,采用实施例1步骤五所述方法制得,为白色固体,产率19%;
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 2H), 7.38 (m, 2H), 7.28 (m, 5H), 7.00 (m, 3H), 5.16 (s, 1H), 4.01 (s, 3H), 3.28 (m, 3H), 3.16 (dd, J = 14.0, 5.2 Hz, 1H), 2.84 (dd, J = 14.0, 7.0 Hz, 2H), 2.72 (dd, J = 11.0, 2.8 Hz, 2H), 2.50 (m, 1H), 2.09 (m, 1H), 1.55 (m, 4H), 1.40 (m, 4H), 1.09 (m, 6H)。
实施例1-8的合成方法同样适用于实施例9-32。
实施例9:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备:
合成方法同实施例1,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吖丁啶的制备:以吖丁啶为原料,采用实施例1步骤一所述方法制得,浅黄色油状物,产率78%;
1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 7.48 (d, J = 9.7 Hz, 2H), 7.30 (d, J = 15.6 Hz, 2H), 3.52-3.87 (m, 4H), 2.57-2.46 (m, 2H).
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备:以(4-甲酰基)苯甲酰基-1-吖丁啶为原料,采用实施例1步骤五所述方法制得,为白色固体,产率18%;
1H NMR (400 MHz, CDCl3) δ 7.54-7.30 (m, 6H), 7.26-7.11 (m, 2H), 7.08-7.05 (m, 2H), 6.93-6.80 (m, 2H), 5.30 (s, 1H), 3.95 (d, J = 15.3 Hz, 1H), 3.55 (s, 2H), 3.47 (s, 2H), 3.22 (d, J = 20.4 Hz, 1H), 3.05-2.87 (m, 3H), 2.27-2.20 (m, 2H), 1.99 (d, J = 20.1 Hz, 6H), 1.50-1.44 (m, 3H)。
实施例10:4-((αR)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基苯甲酰基-1-吖丁啶的制备
合成方法同实施例6,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吖丁啶的制备:同实施例9步骤一;
步骤五、4-((αR)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基苯甲酰基-1-吖丁啶的制备:以(4-甲酰基)苯甲酰基-1-吖丁啶和苯基溴化镁为原料,采用实施例1步骤五所述方法制得,为白色固体,产率25%;
1H NMR (400 MHz, CDCl3) δ 7.55-7.40 (m, 5H), 7.35-7.20 (m, 4H), 7.15-7.00 (m, 4H), 4.84 (s, 1H), 4.00-3.55 (m, 6H), 2.52-2.40 (m, 2H), 2.30-2.10 (m, 6H), 1.61-1.40 (m, 6H)。
实施例11:4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备
合成方法同实施例2,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吖丁啶的制备:同实施例9步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备:以(4-甲酰基)苯甲酰基-1-吖丁啶和(2R,5S)-1-苄基-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率21%;
1H NMR (400 MHz, CDCl3) δ 7.43-7.32 (m, 6H), 7.29-7.20 (m, 1H), 7.15-6.99 (m, 6H), 4.82 (s, 1H), 3.75-3.70 (m, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 2H), 2.73-2.60 (m, 2H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 5H), 1.25-1.17 (m, 3H)。
实施例12:4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备
合成方法同实施例3,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吖丁啶的制备:同实施例9步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备:以(4-甲酰基)苯甲酰基-1-吖丁啶和(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率28%;
1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 4H), 4.95 (s, 1H), 3.70-3.62 (m, 4H), 3.42 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.65 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 5H), 1.15-1.10 (m, 2H)。
实施例13:4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备
合成方法同实施例4,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吖丁啶的制备:同实施例9步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备:以(4-甲酰基)苯甲酰基-1-吖丁啶和(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率19%;
1H NMR (400 MHz, CDCl3) δ 7.53-7.52 (m, 2H), 7.27-7.30 (m, 2H), 7.14-7.16 (m, 1H), 7.13-7.10 (m, 2H), 7.07-7.05 (m, 1H), 6.95 (t, 2H), 6.73-6.69 (m, 2H), 5.30 (s, 1H), 3.95 (d, J = 15.3 Hz, 1H), 3.55 (s, 2H), 3.47 (s, 2H), 3.23 (d, J = 20.4 Hz, 1H), 3.05-2.87 (m, 4H), 2.27-2.20 (m, 2H), 1.98 (d, J = 20.1 Hz, 5H), 1.50-1.44 (m, 3H)。
实施例14:4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备
合成方法同实施例5,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吖丁啶的制备:同实施例9步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶的制备:以(4-甲酰基)苯甲酰基-1-吖丁啶和(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,为白色固体,产率17%;
1H NMR (400 MHz, CDCl3) δ 7.43-7.25 (m, 4H), 7.20-7.06 (m, 3H), 7.07-6.95 (m, 3H), 6.73-6.69 (m, 2H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 4H), 1.11 (d, J = 5.8 Hz, 3H)。
实施例15:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例1,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:以吡咯烷为原料,采用实施例1步骤一所述方法制得,无色油状物,产率82%;
1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.43 (d, J = 19.7 Hz, 2H), 7.32 (d, J = 30.6 Hz, 2H), 3.62-3.81 (m, 4H), 2.43-2.30 (m, 2H), 2.26-2.15 (m, 2H);
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷为原料,采用实施例1步骤五所述方法制得,白色固体,产率24%;
1H NMR (400 MHz, CDCl3) δ 7.30-7.13 (m, 12H), 4.81 (s, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.39 (s, 3H), 3.11-2.87 (m, 4H), 2.57 (dd, J = 11.1, 2.6 Hz, 4H), 2.41 (s, 1H), 2.34 (m, 1H), 1.90-1.77 (m, 3H), 1.00 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H)。
实施例16:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例6,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:同实施例15步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷和苯基溴化镁为原料,采用实施例1步骤五所述方法制得,白色固体,产率36%;
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.24 (m, 5H), 7.13 (m, 1H), 7.10 (t, J = 7.7 Hz, 2H), 6.64 (m, 3H), 5.13 (s, 1H), 3.95 (d, J = 13 Hz, 2H), 3.55 (m, 2H), 3.29 (m, 2H), 2.65 (dd, J = 9.0, 2.0 Hz, 2H), 1.99 (m, 2H), 1.24 (m, 4H), 1.12 (m, 3H), 1.09 (d, J = 6.1 Hz, 3H), 1.03 (m, 3H)。
实施例17:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例7,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:同实施例15步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷和3-氟苯基溴化镁为原料,采用实施例1步骤五所述方法制得,白色固体,产率30%;
1H NMR (400 MHz, CDCl3) δ 7.50 (m, 3H), 7.41 (m, 5H), 7.23 (m, 1H), 7.11 (d, J = 10.0 Hz, 2H), 7.00 (m, 3H), 5.02 (s, 1H), 3.95 (m, 2H), 3.50 (m, 2H), 3.29 (m, 2H), 2.60 (dd, J = 10.0, 5.0 Hz, 2H), 2.02 (m, 2H), 1.20 (m, 4H), 1.15 (m, 3H), 1.09 (d, J = 8.3 Hz, 3H), 0.87 (m, 3H)。
实施例18:4-((α-R)-α-(2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例2,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:同实施例15步骤一;
步骤五、4-((α-R)-α-(2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷和(2R,5S)-1-苄基-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率26%;
1H NMR (400 MHz, CDCl3) δ 7.40-7.20 (m,7H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.72 (d, J = 21.3 Hz, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.60 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.20-1.11 (m, 4H)。
实施例19:4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例3,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:同实施例15步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷和(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率32%;
1H NMR (400 MHz, CDCl3) δ 7.55-7.46 (m, 3H), 7.40-7.30 (m, 3H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 3H), 4.95 (s, 1H), 3.70-3.62 (m, 4H), 3.42 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.65 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 4H), 1.15-1.10 (m, 4H), 0.90-0.78 (m, 2H)。
实施例20:4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例4,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:同实施例15步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷和(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率27%;
1H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 4H), 7.23-7.10 (m, 3H), 7.07-6.95 (t, 2H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 3.90-3.88 (m, 2H), 3.62-3.53 (m, 2H), 3.30 (s, 2H), 2.69-2.59 (m, 4H), 2.07-1.99 (m, 2H), 1.24-1.23 (m, 4H), 1.10 (d, J = 5.8 Hz, 6H)。
实施例21:4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备
合成方法同实施例5,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-吡咯烷的制备:同实施例15步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷的制备:以(4-甲酰基)苯甲酰基-1-吡咯烷和(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率22%;
1H NMR (400 MHz, CDCl3) δ 7.55-7.25 (m, 4H), 7.20-7.11 (m, 2H), 7.07-6.95 (m, 3H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 4H), 1.11 (d, J = 5.8 Hz, 3H), 1.00-0.87 (m, 3H)。
实施例22:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备
合成方法同实施例1,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环庚烷的制备:以氮杂环庚烷为原料,采用实施例1步骤一所述方法制得,无色油状物,产率76%;
1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 7.56-7.50 (m, 2H), 7.45-7.32 (m, 2H), 3.52-3.40 (m, 4H), 2.43-2.28 (m, 6H), 2.23-2.15 (m, 2H);
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环庚烷为原料,采用实施例1步骤五所述方法制得,白色固体,产率21%;
1H NMR (400 MHz, CDCl3) δ 7.26 (ddd, J = 13.9, 5.2, 2.9 Hz, 8H), 7.14-7.02 (m, 4H), 5.10 (s, 1H), 4.05 (d, J = 13.0 Hz, 3H), 3.58 (s, 1H), 3.09 (d, J = 13.0 Hz, 2H), 2.72 (dd, J = 11.5, 2.6 Hz, 1H), 2.64 (dd, J = 11.2, 2.9 Hz, 2H), 2.51-2.36 (m, 2H), 2.03-1.90 (m, 4H), 1.13 (d, J = 6.2 Hz, 6H), 1.06 (d, J = 6.0 Hz, 6H)。
实施例23:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-氮杂环庚烷的制备
合成方法同实施例6,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环庚烷的制备:同实施例22步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-氮杂环庚烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环庚烷和苯基溴化镁为原料,采用实施例1步骤五所述方法制得,白色固体,产率35%;
1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.1 Hz, 2H), 7.33 (m, 2H), 7.29 (d, J = 9.4 Hz, 2H), 7.24 (m, 2H), 7.20 (d, J = 7.3 Hz, 3H), 6.90 (t, J = 8.2 Hz, 2H), 5.15 (s, 1H), 3.81 (d, J = 13.1 Hz, 1H), 3.54 (m, 2H), 3.28 (m, 2H), 3.14 (d, J = 13.1 Hz, 1H), 2.65 (m, 2H), 1.98 (m, 2H), 1.93 (m, 4H), 1.23 (m, 4H), 1.10 (d, J = 6.3 Hz, 3H)。
实施例24:4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备
合成方法同实施例2,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环庚烷的制备:同实施例22步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环庚烷和(2R,5S)-1-苄基-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率32%;
1H NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 3H), 7.40-7.32 (m, 3H), 7.29-7.20 (m, 1H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.73 (d, J = 21.3 Hz, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.60 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.34-1.28 (m, 2H), 1.25-1.17 (m, 3H), 1.15-1.10 (m, 3H)。
实施例25:4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备
合成方法同实施例3,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环庚烷的制备:同实施例22步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环庚烷和(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率29%;
1H NMR (400 MHz, CDCl3) δ 7.44-7.35 (m, 3H), 7.34-7.20 (m, 3H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.75-3.70 (d, J = 21.3 Hz, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.60 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.35-1.11 (m, 6H), 1.05-0.88 (m, 2H)。
实施例26:4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备
合成方法同实施例4,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环庚烷的制备:同实施例22步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环庚烷和(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率23%;
1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 6H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 3H), 4.95 (s, 1H), 3.70-3.62 (m, 4H), 3.42 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.65 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.25-1.17 (m, 3H), 1.16-1.11 (m, 2H), 0.98-0.70 (m, 3H)。
实施例27:4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备
合成方法同实施例5,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环庚烷的制备:同实施例22步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环庚烷和(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率17%;
1H NMR (400 MHz, CDCl3) δ 7.45-7.43 (d, J = 20.3 Hz, 2H), 7.26-7.20 (m, 3H), 7.13-7.11 (m, 3H), 7.02-7.05 (m, 2H), 6.93-6.88 (m, 2H), 5.00 (s, 1H), 3.91-3.87 (d, J = 10.3 Hz, 1H), 3.69 (s, 2H), 3.37 (s, 2H), 3.20-3.17 (d, J = 15.4 Hz, 1H), 2.66-2.56 (m, 4H), 2.01-1.85 (m, 2H), 1.52-1.47 (d, J = 20.1 Hz, 6H), 1.07-1.04 (m, 6H), 0.97-0.83 (m,3H)。
实施例28:4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备
合成方法同实施例1,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环辛烷的制备:以氮杂环辛烷为原料,采用实施例1步骤一所述方法制得,无色油状物,产率67%;
1H NMR (400 MHz, CDCl3) δ 10.01 (s,1H), 7.76-7.63 (m, 3H), 7.60 (m, 1H), 3.61-3.56 (m, 4H), 2.54-2.30 (m 5H), 2.28-2.15 (m, 3H), 2.05-1.90 (m, 2H);
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环辛烷为原料,采用实施例1步骤五所述方法制得,白色固体,产率18%;
1H NMR (400 MHz, CDCl3) δ 7.27-7.22 (m, 4H), 7.07 (m, 3H), 6.95 (m, 5H), 5.90 (m, 1H), 5.36 (s, 1H), 3.48 (dd, J = 13.5, 5.2 Hz, 4H), 2.85 (m, 3H), 2.68 (dd, J = 11.5, 2.5 Hz, 4H), 2.58-2.37 (m, 4H), 2.31 (m, 3H), 2.14-1.94 (m, 4H), 1.21 (d, J = 6.0 Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H)。
实施例29:4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备
合成方法同实施例2,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环辛烷的制备:同实施例28步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环辛烷和(2R,5S)-1-苄基-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率20%;
1H NMR (400 MHz, CDCl3) δ 7.43-32 (m, 6H), 7.29-7.20 (m, 1H), 7.15-6.99 (m, 6H), 4.82 (s, 1H), 3.75-3.70 (m, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 2H), 2.73-2.60 (m, 2H), 2.53-2.40 (m, 3H), 2.38-2.20 (m, 4H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 5H), 1.25-1.17 (m, 4H)。
实施例30:4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备
合成方法同实施例3,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环辛烷的制备:同实施例28步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环辛烷和(2R,5S)-1-(3-氯苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率17%;
1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 6H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 3H), 4.95 (s, 1H), 3.70-3.62 (m, 4H), 3.42 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.65 (m, 4H), 2.55-2.34 (m, 3H), 2.33-2.21 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.15-1.10 (m, 3H)。
实施例31:4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备
合成方法同实施例4,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环辛烷的制备:同实施例28步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环辛烷和(2R,5S)-1-(3-溴苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率13%;
1H NMR (400 MHz, CDCl3) δ 7.50-7.30 (m, 4H), 7.14-7.16 (m, 1H), 7.13-7.10 (m, 2H), 7.07-7.05 (m, 1H), 6.95 (t, 2H), 6.73-6.69 (m, 2H), 5.30 (s, 1H), 4.02-3.87 (d, J = 15.3 Hz, 1H), 3.55 (s, 2H), 3.47 (s, 2H), 3.22 (d, J = 20.4 Hz, 1H), 3.05-2.87 (m, 4H), 2.60-2.56 (m, 3H), 2.27-2.20 (m, 2H), 2.00 (d, J = 20.1 Hz, 6H), 1.73-1.60 (m, 5H), 1.50-1.44 (m, 2H)。
实施例32:4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备
合成方法同实施例5,不同在于步骤一、五:
步骤一、(4-甲酰基)苯甲酰基-1-氮杂环辛烷的制备:同实施例28步骤一;
步骤五、4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷的制备:以(4-甲酰基)苯甲酰基-1-氮杂环辛烷和(2R,5S)-1-(3-碘苄基)-2,5-二甲基哌嗪为原料,采用实施例1步骤五所述方法制得,白色固体,产率21%;
1H NMR (400 MHz, CDCl3) δ 7.33-7.25 (m, 4H), 7.20-7.06 (m, 3H), 7.07-6.95 (m, 2H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.30-2.21 (m, 3H), 2.15-2.00 (m, 3H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 6H), 1.11-1.04 (m, 4H)。
实施例33:阿片受体结合实验
本发明化合物的阿片受体亲和性通过阿片受体结合实验进行测定(参照Payza, K., Binding and activity of opioid ligands at the cloned human delta, mu and kappa receptors. in The Delta Receptor, Chang, Porreca & Wood eds. 2004, Marcel Dekker, Inc. New York, Basel中所述方法),具体步骤如下:
鼠脑细胞膜制备:鼠脑组织(雄性白化Sprague-Dawley 大鼠的大脑或雄性白化豚鼠的小脑)采用冰冷的Tris-HCl 缓冲液清洗(pH 7.4、50 mM、25℃),Tris-HCl 缓冲液包含以下蛋白酶抑制剂:50μg/ml亮氨酸酶抑制剂,200μg/ml杆菌肽和0.5μg/ml蛋白酶抑制剂(Aprotinin);每1 g湿重脑组织加入10倍体积上述冰冷的Tris-HCl缓冲液,并采用含有四氟乙烯玻璃珠(0.13-0.18 mm)的机械匀浆机使脑组织匀浆化;匀浆液在4℃、6000 g离心15 min,收集上清液并在41000 g下离心30 min;每1 g湿重脑组织膜沉淀用10倍体积的10 mM Tris-蔗糖缓冲液(0.32 M)重新悬浮并采用组织研磨机处理(10s,低速),超声处理后的匀浆液在4℃、41000 g离心30 min;膜沉淀物用含有蛋白酶抑制剂的50 mM Tris缓冲液重新悬浮,蛋白质终浓度为40~50 μg/ml;悬浮后的膜颗粒用液氮或-80℃冻存,使用前用Bandford法测定蛋白浓度。
受体结合实验:重悬浮后的鼠脑细胞膜与0.1 nM [3H]δ啡肽II-δ-受体(比活力38.5-40.6 Ci/mmol)、0.1 nM [3H] DAMGO-μ-受体(比活力50 Ci/mmol)或0.1 nM [3H]U69593-κ-受体在2 ml含有4 mM MgCl2、蛋白酶抑制剂和待测化合物(在1.0 nM至100 μM之间设置梯度浓度)的10 mM Tris-HCl缓冲液中25℃温浴90 min,使放射性配体和受体完全平衡。采用细胞收集器(model M-48R, Brandel Instruments, Gaithersberg, MD)用5 ml冰冷的50 mM Tris缓冲液快速过滤通过玻璃纤维滤膜两次以终止配体和受体反应,结合率采用1×10-6 M纳洛酮取代放射性配体来定义,特异性结合率用液闪光谱计数确定,测定的外部标准为40-45%。以结合率数据为纵坐标、浓度为横坐标作图,计算得到受体结合常数(Ki值)。
本发明部分化合物,即化合物1-10、15、16、22、23和28(化合物编号对应与实施例编号),经上述步骤检测其受体亲和性,发现其δ受体Ki值均在1-2000 nM之间,而μ和κ受体Ki值在100-5000 nM之间,均明显大于δ受体Ki值,显示为δ受体选择性配体。
实施例34:人阿片受体内在活性试验
本发明涉及的δ激动剂的阿片受体内在活性通过GTP γ[S35]/GDT交换结合实验进行测定(按照Payza, K., Binding and activity of opioid ligands at the cloned human delta, mu and kappa receptors. in The Delta Receptor, Chang, Porreca & Wood eds. 2004, Marcel Dekker, Inc. New York, Basel中所述方法)。
阿片受体细胞膜制备:使用克隆的能表达人μ、δ或κ受体的HEK-293或CHO细胞的细胞膜,细胞膜的制备方法与上述鼠脑细胞膜制备方法相同。
GTP γ[S35]/GDT交换结合实验:100微克的细胞膜悬浮于50 mM Tris-HCl,pH 7.4的缓冲液中(内含100 mM NaCl, 5 nM MgCl2, 1 mM EDTA, 100 μM [or 15 μM] GTP γ S [比活力1250 Ci/mmol]),加入待测化合物(在1.0 nM至100 μM之间设置梯度浓度),28℃温浴60 min,使放射性[35S]GTPγS和GDP交换结合完全平衡;采用细胞收集器用5 ml冰冷的50 mM Tris-HCl,pH 7.4缓冲液快速过滤通过玻璃纤维滤膜两次以终止[35S]GTPγS和GDP交换结合反应;特异性结合率采用40×10-6 M GTPγS取代放射性[35S]GTPγS来定义;阳性对照药物为BW373U86(δ受体)、DAMGO(μ受体)和U50488(κ受体),设其在10-6 M时激动活性为100%。
本发明部分化合物,即化合物1-10、15、16、22、23和28(编号对应于实施例编号),经上述步骤检测其受体受体内在活性,发现其δ受体内在活性与μ受体内在活性的比值均在2-100倍之间,具有δ受体选择性激动活性。其中,化合物1的内在活性实验结果如下表所示。化合物1对δ受体作用浓度最低,活性最高,作用强度(Emax值)超过δ受体阳性对照药物BW373U86,而κ受体活性最低,为部分激动剂。从表中也可看出化合物1的δ受体激动活性(EC50值31.1 nM,Emax 值156.5%)约为其μ受体激动活性(EC50值1000 nM,Emax值100%)的33倍。
表1:本发明部分化合物对μ和δ受体的内在活性检测结果
实施例35:帕金森症恒河猴模型药效实验
本发明化合物的药效通过MPTP诱导帕金森症猴模型实验进行检测。该实验利用MPTP诱导恒河猴脑损伤,建立帕金森症猴模型,随后静脉注射给予待测药物,定时观察动物的行为变化。
帕金森症恒河猴模型制备:MPTP每日剂量0.2 mg/kg,药物溶液置入缓释泵内,埋置于实验动物皮下,每日进行行为学观察。以Bennazzouz帕金森病临床行为量表评价动物模型,当积分到达8或8以上时建模成功,并给予药物治疗,美多巴作为阳性对照。
实验方案:静脉注射给药2.0 mg/kg治疗症状较重的帕金森症模型猴,症状较轻的帕金森症模型猴作为空白对照(不给予任何药物),观察动物日常行为和进食情况。三天为限,如无效,依次增加剂量;如有效,依次降低剂量。必要时与美多巴治疗情况相比较。
本发明的化合物中,化合物1剂量为2.0 mg/kg时动物行为有明显改善,Bennazzouz行为量表积分从8以上降到6-7,日常行为及饮食均有改善。增加剂量至4.0 mg/kg和6.0 mg/kg,积分降至6以下,两剂量的动物行为无明显差异。减少剂量至1.0 mg/kg和0.5 mg/kg,动物行为稍有改善,但不明显,积分在8上下浮动。
阳性药物美多巴(62.5 mg口服)的治疗效果与化合物1剂量4.0 mg/kg相当。
Bennazzouz临床行为量表:1995年由法国神经科学家Bennazzouz博士提出,目前广泛应用于帕金森病恒河猴模型的行为评价中。该量表是在总结了5年的帕金森病猴模型行为表现的基础上,结合中脑黑质区多巴胺神经元退变的免疫组织化学染色分析结果以及多种人帕金森病临床分级评价量表制定而成,其评价指标包括如下7个帕金森病体征:
震颤(0-3),运动减慢(0-3),姿势变化(0-3),发声变化(0-2),呆滞(0-2),强直(每个上肢0-3),上肢运动(摄食水果的能力,每个上肢0-3),总分0-25。
表2:Bennazzouz量表各项目的分值在成模状态下的统计
说明:4只造模动物运动减慢至少达到中度(≥2),姿势变化至少达到躯干重度弯曲(≥2),两侧上肢的运动能力至少达到采食严重困难的程度(≥2),震颤、僵直、强直等帕金森症症状均有体现。
表3:治疗前后动物帕金森病行为评价结果
说明:4只造模动物Bennazzouz量表积分均大于8,其中2只临床症状明显,达到临床五级标准(即动物为双侧性帕金森病模型,必需依赖辅助才能获取足够的营养,但还能保持坐姿)。动物的临床症状、饮食和日常活动状况在给药后都有不同程度的改善。
以上所述仅是本发明的优选实施方式。应当指出,对于本技术领域的普通技术人员,在不脱离本发明方法的前提下,还可进行若干改进和补充,这些可能的改进和补充也应视为本发明的保护范围。
Claims (6)
2.根据权利要求1所述的化合物,其特征在于:化合物选自
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-(α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吖丁啶;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-吡咯烷;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-哌啶;
4-((α-R)-α-(2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环庚烷;
4-((α-R)-α-((2S,5R)-4-苄基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(2-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-氟苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(4-氟苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-氯苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-溴苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷;
4-((α-R)-α-((2S,5R)-4-(3-碘苄基)-2,5-二甲基-1-哌嗪基)-3-羟基苄基)苯甲酰基-1-氮杂环辛烷。
3.根据权利要求1或2所述化合物,当R1为羟基时,其特征在于:化合物药学可接受的酯选自甲酸酯、乙酸酯、丙酸酯、丁酸酯、三氟乙酸酯、油酸酯、硬脂酸酯。
4.根据权利要求1或2所述化合物,其特征在于:化合物药学可接受的盐选自硫酸盐、盐酸盐、氢溴酸盐、磷酸盐、三氟乙酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、三氟甲磺酸盐、樟脑磺酸盐、甲酸盐、乙酸盐、丙酸盐、己酸盐、己二酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、富马酸盐、马来酸盐、乳酸盐、琥珀酸盐。
5.一种药物组合物,其特征在于:含有权利要求1-4中任一项所述的化合物,以及药学上可接受的稀释剂或载体。
6.权利要求1-4中任一项所述的化合物在制备治疗帕金森症的药物中的应用。
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WO2007027987A2 (en) * | 2005-09-02 | 2007-03-08 | Mount Cook Biosciences, Inc. | Method of treating parkinson's disease with diarylmethylpiperazine compounds exhibiting delta receptor agonist activity |
CN101198330A (zh) * | 2005-04-14 | 2008-06-11 | 蒙特库克生物科学公司 | 新阿片类化合物的组合物及其使用方法 |
CN101318952A (zh) * | 2008-06-04 | 2008-12-10 | 昆明贝尔吉科技有限公司 | δ受体激动剂化合物及其应用 |
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WO2007027987A2 (en) * | 2005-09-02 | 2007-03-08 | Mount Cook Biosciences, Inc. | Method of treating parkinson's disease with diarylmethylpiperazine compounds exhibiting delta receptor agonist activity |
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