CN103130793B - 3-(1-芳基哌啶-4-基)-2-芳基噻唑啉-4-酮类化合物、其制备方法及用途 - Google Patents
3-(1-芳基哌啶-4-基)-2-芳基噻唑啉-4-酮类化合物、其制备方法及用途 Download PDFInfo
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- CN103130793B CN103130793B CN201210499480.1A CN201210499480A CN103130793B CN 103130793 B CN103130793 B CN 103130793B CN 201210499480 A CN201210499480 A CN 201210499480A CN 103130793 B CN103130793 B CN 103130793B
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- thiazolin
- compound
- benzylpiperidin
- pharmaceutically acceptable
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Abstract
本发明属于医药化工领域,涉及3‑(1‑芳基哌啶‑4‑基)‑2‑芳基噻唑啉‑4‑酮类化合物、其可药用盐、其制备方法及用途。具体地,本发明涉及式I所示的化合物或其可药用盐。本发明的化合物或其可药用盐具有明显的N型钙离子通道阻断活性并具有良好的药代动力学性质,能够有效地防治或缓解疼痛,具有作为新的预防和/或治疗与治疗疼痛、中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、或肾机能不全的药物的潜力。
Description
技术领域
本发明属于医药化工领域,涉及3-(1-芳基哌啶-4-基)-2-芳基噻唑啉-4-酮类化合物、其可药用盐、其制备方法及用途。
背景技术
N型钙离子通道属于电压门控钙通道(VDCC)的一个亚型,由α1β亚单位构成,具有高电压激活、较快速失活的特点,主要分布在神经组织中,可被w-conotoxin GVIA(wCgTx)阻滞。N型钙离子通道已被确证为具有临床相关性的新型药物作用靶标,研究表明,N型钙离子通道阻断剂在治疗中风与脑缺血、镇痛尤其是神经源性疼痛,以及在减少酒精嗜求和治疗酒精中毒、肾保护等方面方面具有良好的应用前景(Cox B.,Current Review of Pain,2000,4:488-498.NewtonPM and Messing RO.Channels.2009,3(2):77-81.Aritomi S,,etal.Am J Nephrol.2011,33:168-175.)。目前的研究结果表明,N型钙离子通道是疼痛产生和痛觉传导过程中的一个重要环节(VanegasH,Schaible HG.Pain.2000,85:9-18;SlukaKA.J.Pharmacol.Exp.Ther.1998,287:232-237;Saegusa H,Kurihara T,Zong S,etal.EMBO.J.2001,20(10):2349-2356;Mori Y,Nishida M,Shimizu,S,et al.TrendsCardiovasc Med.2002,12(6):270-275;Ogasawara M,Kurihara T,Hu Q,et al.FEBSLett.2001,508:181-186),由于针对N型钙离子通道的阻断剂直接作用于N型钙离子通道,不涉及第二信使或G蛋白,因此不易产生成瘾性。高选择性的N型钙离子通道阻断剂ω-芋螺毒素(ω-conotoxin)MVIIA 已于2004年12月被美国FDA批准进入市场销售,其临床 实践表明,N型钙离子通道阻断剂已被证实为治疗疼痛的一个新型靶标,具有良好的应用前景。
针对N型钙离子通道已发展出了多个系列的小分子化合物(Yamamoto T andTakahara A.Current Topics in Med Chem.2009,9:377-395.),其中,WO99/43658公开的4-哌啶基苯胺类小分子化合物作为可口服的选择性的N型钙离子通道阻断剂表现出明显的镇痛活性;Teodori等(J Med Chem.2004,47:6070-6081.)、Knutsen等(Bioorg Med ChemLett.2007,17(3):662-667.)、Yamamoto等(Bioorg Med Chem.2006,14:5333-5339.BioorgMed Chem Lett.2008,18(17):4813-4816.)、Tyagarajan等(Bioorg Med Chem Lett.2011,21(17):869-873.)的研究也取得了一定的进展。小分子N型钙离子通道阻断剂NMED-160曾经进入到II期临床研究,其相关化合物的研究也得到了较好的结果(Zamponi GW,et al.,Bioorg Med ChemLett.2009,19:6467-6472.Pajouhesh H,et al.,Bioorg MedChemLett.2010,20:1378-1383.)。但总体而言,目前的研究存在一定缺陷。一方面,这些化合物在生物活性方面及通道的选择性方面仍存在不足;另一方面,这些化合物的药代动力学性质较差,需通过侧脑室给药等在临床上非简单易行的给药途径才能产生足够的药理活性,因而,对开发新型的小分子N型钙离子通道阻断剂仍存在需求。
发明内容
本发明人经过深入的研究和创造性的劳动,得到了一类3-(1-芳基哌啶-4-基)-2-芳基噻唑啉-4-酮类化合物。本发明人还惊奇地发现,该类化合物表现出明显的N型钙离子通道阻断活性并具有良好的药代动力学性质,能够有效地防治或缓解疼痛,具有作为新的预防和/或治疗与治疗疼痛、中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、或肾机能不全的药物的潜力。
本发明的一个方面涉及式I所示的化合物或其可药用盐:
其中:
R1和R2独立地代表氢原子、C1-8烷基、取代的C1-8烷基、C3-8链烯基、C3-8环烷基、取代的C3-8环烷基、C1-8烷氧基、C5-20芳基、取代的C5-20芳基、C5-20芳氧基、C3-20杂芳基、取代的C3-20杂芳基、C5-20杂芳氧基、C3-20 杂环基、取代的C3-20杂环基、或取代的C3-20杂环基氧基;
g代表C0-8亚烷基、取代的C1-8亚烷基或羰基;
所述取代独立地为被一个或多个取代基所取代,所述取代基独立地选自卤素、C1-8烷基、C1-8烷氧基、C3-10环烷基、氰基、硝基、巯基、甲硫基、亚甲二氧基、三氟甲基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、C1-8烷基磺酰基、羟基、苯氧基、C5-20杂芳氧基、C5-20芳基、C3-20杂环基和C3-20杂芳基。
根据本发明,通式I的化合物的可药用盐包括其无机酸盐或有机酸盐,其中包括但不限于:盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、羟乙酸盐、丙酸盐、丁酸盐、草酸盐、己二酸盐、藻酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、苦味酸盐、天冬氨酸盐、葡糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐、丙酮酸盐、乙醇酸盐、丙二酸盐、三氟乙酸盐、苹果酸盐、水杨酸盐、对氨基水杨酸盐、扑酸盐和抗坏血酸盐等;优选通式I的化合物的盐酸盐。
本发明还涉及本发明任一项所述的化合物的溶剂化物(例如水合物、醇合物)以及立体异构体。
本发明通式I的化合物或其可药用盐还可以形成溶剂化物,例如水合物、醇合物等。上述化合物还可以是前药或可在体内代谢变化后 释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
根据本发明,通式I的化合物如以立体异构体形式存在,其中的不对称中心可为R-构型或S-构型。本发明包括所有可能的立体异构体如对映异构体或非对映异构体,以及两种或多种立体异体的混合物,例如对映异构体和/或非对映异构体的任何所需比例的混合物。如果存在顺/反异构体,本发明涉及其顺式形式或反式形式或二者的混合物。如果需要,单一立体异构体的制备可根据常规方法拆分混合物,或通过立体选择性合成制备。如果存在机动的氢原子,本发明也涉及其互变异构形式。
根据本发明任一项所述的化合物或其可药用盐,其中,所述取代基被叔丁基、甲基、三氟甲基、氯、氟、溴、碘、甲氧基、乙氧基、羟基、二甲氨基、二乙氨基、或亚甲二氧基所取代。
根据本发明任一项所述的化合物或其可药用盐,其中,
R1和R2独立地代表苯基、苄基、被一个或多个卤素原子取代的苄基、被一个或多个C1-3烷基取代的苄基、被一个或多个卤素原子和一个或多个卤代C1-3烷基所取代的苄基、被一个或多个卤素原子和一个或多个C1-3烷氧基所取代的苄基、吡啶甲基、噻吩甲基、被一个或多个卤素原子或者一个或多个C1-3烷基或者一个或多个C1-3烷氧基所取代的吡啶甲基、被一个或多个卤素原子或者一个或多个C1-3烷基或者一个或多个C1-3烷氧基所取代的噻吩甲基、苄氧基苄基、芴基、被一个或多个硝基取代的苄基、被一个或多个硝基取代的胡椒基、被一个或多个卤素原子取代的苄氧基苄基、二甲胺基苄基、4-羟基-3,5-二叔丁基苄基、或苯并噁唑啉-2-酮基;
g为C1-3亚烷基亚烷基或
其中当被多个卤素原子取代时,卤素原子相同或不同;所述卤素原子或卤代为选自氟、氯、溴、以及碘原子中的任一种或多种。
根据本发明任一项所述的化合物或其可药用盐,其中,所述C1-3 烷基为甲基,所述C1-3烷氧基为甲氧基;和/或g为亚甲基。
根据本发明任一项所述的化合物或其可药用盐,其选自如下的化合物1-47及其可药用盐:
(1)(±)3-(1-苄基哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,
(2)(±)3-(1-苄基哌啶-4-基)-2-(2-氟苯基)-噻唑啉-4-酮,
(3)(±)3-(1-苄基哌啶-4-基)-2-(2-氯-6-氟苯基)-噻唑啉-4-酮,
(4)(±)3-(1-苄基哌啶-4-基)-2-(2-溴苯基)-噻唑啉-4-酮,
(5)(±)3-(1-苄基哌啶-4-基)-2-(4-溴苯基)-噻唑啉-4-酮,
(6)(±)3-(1-苄基哌啶-4-基)-2-苯基-噻唑啉-4-酮,
(7)(±)3-(1-苄基哌啶-4-基)-2-(3-氟苯基)-噻唑啉-4-酮,
(8)(±)3-(1-苄基哌啶-4-基)-2-(2-甲基苯基)-噻唑啉-4-酮,
(9)(±)3-(1-苄基哌啶-4-基)-2-(3-甲基苯基)-噻唑啉-4-酮,
(10)(±)3-(1-苄基哌啶-4-基)-2-(4-甲基苯基)-噻唑啉-4-酮,
(11)(±)3-(1-苄基哌啶-4-基)-2-(3-氟-4-氯苯基)-噻唑啉-4-酮,
(12)(±)3-(1-苄基哌啶-4-基)-2-(3-吡啶基)-噻唑啉-4-酮,
(13)(±)3-(1-苄基哌啶-4-基)-2-(4-吡啶基)-噻唑啉-4-酮,
(14)(±)3-(1-苄基哌啶-4-基)-2-(2-氯苯基)-噻唑啉-4-酮,
(15)(±)3-(1-苄基哌啶-4-基)-2-[3,5-二(三氟甲基)苯基]-噻唑啉-4-酮,
(16)(±)3-(1-苄基哌啶-4-基)-2-(3-氯-4-氟苯基)-噻唑啉-4-酮,
(17)(±)3-(1-苄基哌啶-4-基)-2-(2-氟-4-三氟甲基苯基)-噻唑啉-4-酮,
(18)(±)3-(1-苄基哌啶-4-基)-2-(3-溴-4-氟苯基)-噻唑林-4-酮,
(19)(±)3-(1-苄基哌啶-4-基)-2-(4-氟苄氧基-苯基)-噻唑啉-4-酮,
(20)(±)3-(1-苄基哌啶-4-基)-2-(3-氟-4-甲氧基苯基)-噻唑啉-4-酮,
(21)(±)3-(1-苄基哌啶-4-基)-2-(4-正丁氧基苯基)-噻唑啉-4-酮,
(22)(±)3-(1-苄基哌啶-4-基)-2-(2-噻吩基)-噻唑啉-4-酮,
(23)(±)3-(1-苄基哌啶-4-基)-2-(2-呋喃基)-噻唑啉-4-酮,
(24)(±)3-(1-苄基哌啶-4-基)-2-(5-甲基呋喃-2-基)-噻唑啉-4-酮,
(25)(±)3-(1-苄基哌啶-4-基)-2-(5-甲基噻吩-2-基)-噻唑啉-4-酮,
(26)(±)3-(1-苄基哌啶-4-基)-2-(5-溴呋喃-2-基)-噻唑啉-4-酮,
(27)(±)3-(1-苄基哌啶-4-基)-2-(2,3-二甲氧基苯基)-噻唑啉-4-酮,
(28)(±)3-(1-苄基哌啶-4-基)-2-(4-苄氧基苯基)-噻唑啉-4-酮,
(29)(±)3-(1-苄基哌啶-4-基)-2-(2-芴基)-噻唑啉-4-酮,
(30)(±)3-(1-苄基哌啶-4-基)-2-(4-溴苯基-3-吡啶基)-噻唑啉-4-酮,
(31)(±)3-(1-苄基哌啶-4-基)-2-胡椒基-噻唑啉-4-酮,
(32)(±)3-(1-苄基哌啶-4-基)-2-(4-硝基苯基)-噻唑啉-4-酮,
(33)(±)3-[1-(3-氟苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(34)(±)3-[1-(4-氟苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(35)(±)3-[1-(2-氟苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(36)(±)3-[1-(2-溴苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(37)(±)3-[1-(4-溴苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(38)(±)3-[1-(3-吡啶甲基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(39)(±)3-[1-(2-噻吩甲基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(40)(±)3-[1-(4-苄氧基苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮,
(41)(±)3-[1-(4-二甲胺基苄基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮,
(42)(±)3-[1-(3-吡啶甲基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮,
(43)(±)3-[1-(2-噻吩甲基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮,
(44)(±)3-[1-(4-二甲胺基苄基)哌啶-4-基]-2-(2-溴苯基)-噻唑啉-4-酮,
(45)(±)3-[1-(4-羟基-3,5-二叔丁基苄基)哌啶-4-基]-2-(2-溴苯基)-噻唑啉-4-酮,
(46)(±)3-(1-苄基哌啶-4-基)-2-(6-硝基-胡椒基)-噻唑啉-4-酮,
(47)(±)6-(3-(4-(2-(2-氯-6-氟苯基)-4-噻唑啉酮-3-基)哌啶-1-基)丙酰基)苯并噁唑啉-2-酮。
上述化合物1-47的式I取代基团如下面的表1所示。
表1:化合物1-47的取代基团
本发明的另一方面涉及本发明中任一项所述的化合物或其可药用盐的制备方法。
可以采用如下所示的合成路线合成本发明的通式I的化合物,另外,也可参见本发明实施例中的详细描述。根据需要,还可以与酸反应转化为其可药用盐。
首先以4-氨基-1-苄基哌啶为起始原料,在苯中和商品化的醛回流反应2-2.5小时生成烯胺(II),而后烯胺和巯基乙酸在苯中回流反应2-2.5小时,脱水生成化合物III,化合物III和氯甲酸乙酯在甲苯中回流反应5.5小时后蒸干溶剂得化合物IV,将化合物IV溶于50ml乙醇和4ml 40%氢氧化钠溶液,回流反应6小时后停止反应,即脱去取保护基,得到各种R2取代的化合物V。最后,将化合物V在干燥的二氯甲烷中与商品化的醛搅拌反应0.5-2小时,然后加入三乙酰氧基硼氢化钠,在室温或加热条件下反应8-72小时,或使化合物V在干燥的丙酮或干燥的乙腈中,在N2保护下,与商品化的卤代物在无水碳酸钾等碱性条件下,加热回流2-24小时进行卤代反应,得到式(Ⅰ)目标化合物。
根据需要,通式I的化合物还可以与适宜的酸反应转化为其可药用盐。
在本发明的一个实施方案中,本发明中任一项所述的化合物或其可药用盐的制备方法,包括下述步骤:
(1)4-氨基-1-苄基哌啶与醛反应生成如式II所示的烯胺,
(2)式II所示的化合物和巯基乙酸反应生成如式III所示的化合物,
(3)式III所示化合物与氯甲酸乙酯反应,生成如式IV所示的化合物,
(4)式IV所示化合物碱性条件下脱保护后生成如式V所示的化合物,
(5)式V所示化合物与卤代物或醛反应生成如式I所示的化合物,
上述式Ⅰ、Ⅱ、Ⅲ、Ⅳ中的R1、R2或g的定义如上面的任一项所述。
本发明的再一方面涉及一种药物组合物,其包含至少一种本发明中任一项所述的化合物或其可药用盐;可选地,所述药物组合物还包含药学上可接受的载体或辅料。
本发明的活性化合物可以本身形式给药的,或者以药物组合物形式给药,其中活性化合物是与一种或多种药学上可接受的载体、赋形剂或稀释剂混合的。本发明的药物组合物通常是按常规方式配制的,使用一种或多种生理学上可接受的载体或赋形剂,它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂取决于所选择的 给药途径,可以按照本领域熟知的常识进行制备。
可用于本发明药物组合物的药用载体或赋形剂包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,聚乙烯-聚氧丙烯嵌段聚合物和羊毛脂。
本发明的通式I的化合物或含有它的药物组合物的给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。给药剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。还可以制备成缓释制剂、控释制剂及各种微粒给药系统。
本发明的再一方面涉及本发明中任一项所述的化合物或其可药用盐或者本发明的药物组合物作为N型钙离子通道阻断剂或抑制剂的用途。
本发明的再一方面涉及一种在体内或体外阻断或抑制N型钙离子通道的方法,包括使用有效量的本发明中任一项所述的化合物或其可药用盐或者本发明的药物组合物的步骤。
本发明的再一方面涉及本发明中任一项所述的化合物或其可药用盐或者本发明的药物组合物在制备治疗和/或预防和/或辅助治疗疼痛、中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、或肾机能不全的药物中的用途;具体地,所述疼痛为手术后疼痛、偏头痛、内脏痛或神经性疼痛。
本发明的再一方面涉及一种治疗和/或预防和/或辅助治疗疼痛、 中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、或肾机能不全的药物中的方法,包括给予受试者有效量的本发明中任一项所述的化合物或其可药用盐或者本发明的药物组合物的步骤;具体地,所述疼痛为手术后疼痛、偏头痛、内脏痛或神经性疼痛。
N型钙离子通道已被确证为具有临床相关性的新型药物作用靶标,研究表明,N型钙离子通道阻断剂在治疗中风与脑缺血、镇痛尤其是神经源性疼痛,以及在减少酒精嗜求和治疗酒精中毒、肾保护等方面方面具有良好的应用前景(Cox B.,Current Review ofPain,2000,4:488-498.Newton PM and Messing RO.Channels.2009,3(2):77-81.AritomiS,,et al.Am J Nephrol.2011,33:168-175.)。
实验结果表明,本发明化合物对N型钙离子通道有明显的阻断作用并表现出较好的选择性。此外,在小鼠醋酸扭体模型中,本发明化合物在灌胃给药条件下即能够表现出明显的镇痛活性,表明其药代动力学性质和镇痛活性较好,可以通过口服给药途径用来预防和/或治疗手术后疼痛、偏头痛、内脏痛、神经性疼痛等各种疼痛、中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、肾机能不全等病症;另一方面,N型钙离子通道阻断剂的镇痛作用与和μ阿片受体的作用没有相关性,因此其在产生镇痛作用的同时不会导致成瘾性的发生。因此,本发明化合物可以用于预防和/或治疗手术后疼痛、偏头痛、内脏痛、神经性疼痛等各种疼痛、中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、肾机能不全等病症。
本发明的化合物或其药学上可接受的衍生物可以单独给药或与其它本发明化合物联合给药,和/或与其它已知治疗剂联合给药。
本发明的化合物针对不同患者的特定使用剂量和使用方法决定于诸多因素,包括患者的年龄,体重,性别,自然健康状况,营养状况,化合物的活性强度,服用时间,代谢速率,病症的严重程度以及诊治医师的主观判断。通常,本发明化合物的给药量将在0.01mg/kg体重至100mg/kg体重的范围内,更优选为0.1mg/kg体重至10mg/kg体重,特别是1mg/kg体重至5mg/kg体重。
本发明化合物的单位剂型通常将含有0.1至99重量%活性物质,更通常为5至75重量%活性物质。举例来说,单位剂型可以含有1mg至1g化合物,更通常为10mg至500mg化合物,例如在50mg与400mg化合物之间,剂量通常为100mg至200mg化合物。
在本发明中:
术语“卤素”为氟、氯、溴或碘。
术语“烷基”表示饱和的直链或支链的烃链。所述烷基优选包含1-8个碳原子,更优选1-6个碳原子,最优选1-4个碳原子。所述烷基的例子包括例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-乙基-丁基、己基、庚基、辛基等。
术语“亚烷基(C0-8亚烷基)”表示无基团或形式上消除了两个氢原子的烷基,所述亚烷基的例子包括例如亚甲基、1,2-亚乙基、亚乙基、亚异丙基、1,3-亚丙基等。
术语“烷氧基”表示“烷基-O-”,其中烷基如上所定义。
术语“链烯基”表示包含一个或多个双键的碳链。所述链烯基优选包含2-8个碳原子,更优选3-8个碳原子,更优选3-6个碳原子,最优选2-4个碳原子。所述链烯基的例子包括乙烯基、1-或2-丙烯基、烯丙基、1-,2-或3-丁烯基、3-甲基-丁-2-烯基、4-甲基-3-烯-1-戊基等。
术语“环烷基”表示环状烷基。所述环烷基优选包含3-10个碳原子,更优选3-8个碳原子,最优选3-6个碳原子。所述环烷基的例子包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基等。
术语“芳基”优选包含5-20个碳原子,更优选6-18个碳原子,最优选6-12个碳原子。所述芳基的例子包括苯基、苄基、萘基、蒽基等。
术语“芳氧基”表示“芳基-O-”,其中芳基如上所定义。
术语“杂环基”优选包含3-20个碳原子、更优选4-18个碳原子、更优选5-16个碳原子,以及1-3个选自氧、氮和硫的杂原子。所述杂 环基的例子包括四氢呋喃基、吡咯烷基、哌啶基、吗啉基等、噻唑烷基等。
术语“杂环基氧基”表示“杂环基-O-”,其中杂环基如上所定义。
术语“杂芳基”优选包含3-20个碳原子、更优选4-18个碳原子、更优选5-16个碳原子,最优选6-12个碳原子,以及1-3个选自氧、氮和硫的杂原子。所述杂芳基的例子包括吡咯基、吡啶基、咪唑基、呋喃基、吡喃基、噻吩基、嘧啶基、吡嗪基、哒嗪基、吲哚基、喹啉基、吡啶并吡啶基等。
术语“杂芳氧基”表示“杂芳基-O-”,其中杂芳基如上所定义。
术语“取代的”表示所述基团上含有一个或多个取代基,所述取代基的例子包括但不局限于卤素、C1-8烷基、C1-8烷氧基、C3-10环烷基、氰基、硝基、巯基、甲硫基、三氟甲基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、C1-8烷基磺酰基、羟基、苯氧基、C5-20杂芳氧基、C5-20芳基、C3-20杂环基和C3-20杂芳基。这些取代基本身还可以任选地被一个或多个另外的取代基取代,所述另外的取代基选自叔丁基、甲基、三氟甲基、氯、氟、溴、甲氧基、乙氧基、羟基、二甲氨基、二乙氨基和亚甲二氧基。
术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。
术语“给药”包括所有直接与间接释放化合物到其预期作用部位的手段。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领 域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:(±)3-(1-苄基哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮
氮气保护下,将3.72g(0.03mol)4-氟苯甲醛、5.71g(0.03mol)4-氨基-1-苄基哌啶溶于50ml苯中,反应瓶装有分水器,回流反应2小时,无水分出,降至室温,加入5.53g(0.06mol)巯基乙酸,而后升温回流反应2小时后,无水生成。停止反应,将反应液降至室温后倒入30ml饱和碳酸钠水溶液,二氯甲烷萃取,有机层饱和氯化钠水溶液洗、水洗,无水硫酸钠干燥,滤出硫酸钠,回收二氯甲烷,得淡黄色油状物,无水乙醇重结晶,得白色固体10.37g,m.p.153-155℃,产率93.3%。 1H-NMR(DMSO-d6,ppm)δ:7.44-7.48(m,2H),7.17-7.30(m,7H),5.95-5.96(d,1H,J=1.40Hz),3.93-3.97(dd,1H,J1=1.68Hz,J2=15.68Hz),3.60-3.68(m,1H),3.54-3.58(d,1H,J=15.68Hz),3.35(s,2H),2.64-2.80(m,2H),1.79-1.97(m,3H),1.23-1.50(m,3H)。MS[M+H]+:371.5。
实施例2:(±)3-(1-苄基哌啶-4-基)-2-(2-氟苯基)-噻唑啉-4-酮
称取2.48g(0.02mol)2-氟苯甲醛和3.81g(0.02mol)4-氨基-1-苄基哌啶,以及3.68g(0.04mol)巯基乙酸,按实施例1的合成方法合成,得白色固体5.52g,m.p.159-161℃,产率74.5%。1H-NMR(DMSO-d6,ppm)δ:7.05-7.33(m,9H),5.92(s,1H),3.97-4.03(m,1H),3.87-3.91(dd,1H,J1=1.40Hz,J2=15.40Hz),3.54-3.58(d,1H,J=15.40Hz),3.43(s,2H),2.72-2.95(m,2H),1.91-2.05(m,3H),1.45-1.74(m,3H)。MS[M+H]+:371.2。
实施例3:(±)3-(1-苄基哌啶-4-基)-2-(2-氯-6-氟苯基)-噻唑啉-4-酮
称取4.77g(0.03mol)2-氯-6-氟苯甲醛和5.71g(0.03mol)4-氨基-1-苄基哌啶,以及5.53g(0.06mol)巯基乙酸,按实施例1的合成方法合成,得白色固体9.12g,m.p.148-150℃,产率75%。1H-NMR(DMSO-d6,ppm)δ:7.22-7.27(m,8H),6.30(s,1H),3.93-4.02(m,2H),3.58-3.63(dd,1H,J1=3.92Hz,J2=15.40Hz),3.44(s,2H),2.70-2.95(m,2H),1.87-2.09(m,3H),1.12-1.73(m,3H)。MS[M+H]+:405.2。
实施例4:(±)3-(1-苄基哌啶-4-基)-2-(2-溴苯基)-噻唑啉-4-酮
称取5.55g(0.03mol)2-溴苯甲醛和5.71g(0.03mol)4-氨基-1-苄基哌啶,以及5.53g(0.06mol)巯基乙酸,按实施例1的合成方法合成,得白色固体11.13g,m.p.147-149℃,产率86%。1H-NMR(DMSO-d6,ppm)δ:7.65-7.67(d,2H,J=7.84Hz),7.37-7.44(m,2H),7.27-7.30(m,3H),7.20-7.23(m,3H),6.01(s,1H),3.81-3.85(dd,2H,J1=1.40Hz,J2=15.40Hz),3.75(m,1H),7.65-7.67(d,1H,J=15.40Hz),3.37(s,2H),2.68-2.81(m,2H),1.82-1.95(m,3H),1.18-1.68(m,3H)。MS[M+H]+:433.2。
实施例5:(±)3-(1-苄基哌啶-4-基)-2-(4-溴苯基)-噻唑啉-4-酮
称取5.55g(0.03mol)4-溴苯甲醛和5.71g(0.03mol)4-氨基-1-苄基哌啶,以及5.53g(0.06mol)巯基乙酸,按实施例1的合成方法合成,得白色固体11.15g,m.p.146-149℃,产率73.4%。1H-NMR(DMSO-d6,ppm)δ:7.55-7.57(m,2H),7.36-7.38(m,2H),7.20-7.30(m,5H),5.95(d,1H,J=1.12Hz),3.91-3.95(dd,2H,J1=1.12Hz,J2=15.68Hz),3.62-3.69(m,1H),3.54-3.58(d,1H,J=15.68Hz),3.36(s,2H), 2.65-2.80(m,2H),1.81-1.95(m,3H),1.21-1.52(m,3H)。MS[M+H]+:433.1。
实施例6:(±)3-(1-苄基哌啶-4-基)-2-苯基-噻唑啉-4-酮
称取0.32g(0.003mol)苯甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.86g,m.p.153-155℃,产率87.2%。1H-NMR(CDCl3,ppm)δ:7.18-7.41(m,10H),5.92(d,1H,J=1.40Hz),3.91-3.96(dd,1H,J1=1.40Hz,J2=15.68Hz),3.54-3.67(m,2H),3.35(s,2H),2.62-2.79(m,2H),1.77-1.98(m,3H),1.23-1.52(m,3H)。MS[M+H]+:353.3。
实施例7:(±)3-(1-苄基哌啶-4-基)-2-(3-氟苯基)-噻唑啉-4-酮
称取0.37g(0.003mol)2-氟苯甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.05g,m.p.160-161℃,产率95%。1H-NMR(DMSO-d6,ppm)δ:7.12-7.44(m,9H),5.96(s,1H),3.96-4.01(dd,1H,J1=1.68Hz,J2=15.68Hz),3.53-3.70(m,2H),3.36(s,2H),2.65-2.81(m,2H),1.81-1.95(m,3H),1.21-1.53(m,3H)。MS[M+H]+:370.7。
实施例8:(±)3-(1-苄基哌啶-4-基)-2-(2-甲基苯基)-噻唑啉-4-酮
称取0.48g(0.004mol)2-甲基苯甲醛和0.76g(0.004mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.15g,m.p.119-121℃,产率78.4%。 1H-NMR(DMSO-d6,ppm)δ:7.20-7.30(m,9H),6.03(d,1H,J=1.12Hz),3.74-3.78(d,1H,J=15.40Hz),3.53-3.67(m,2H),3.36(s,2H),2.66-2.80(m,2H),2.34(s,3H),1.80-1.95(m,3H),1.32-1.64(m, 3H)。MS[M+H]+:366.9。
实施例9:(±)3-(1-苄基哌啶-4-基)-2-(3-甲基苯基)-噻唑啉-4-酮
称取0.48g(0.004mol)3-甲基苯甲醛和0.76g(0.004mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.60g,m.p.145-146℃,产率80.5%。 1H-NMR(DMSO-d6,ppm)δ:7.11-7.30(m,9H),5.87(s,1H),3.91-3.95(dd,1H,J1=1.40Hz,J2=15.40Hz),3.53-3.66(m,2H),3.35(s,2H),2.63-2.80(m,2H),2.31(s,3H),1.78-1.98(m,3H),1.26-1.52(m,3H)。MS[M+H]+:367.2。
实施例10:(±)3-(1-苄基哌啶-4-基)-2-(4-甲基苯基)-噻唑啉-4-酮
称取0.48g(0.004mol)4-甲基苯甲醛和0.76g(0.004mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.27g,m.p.164-165℃,产率86.6%。 1H-NMR(DMSO-d6,ppm)δ:7.16-7.30(m,9H),5.87(d,1H,1.40Hz),3.89-3.93(dd,1H,J1=1.40Hz,J2=1.68Hz),3.53-3.64(m,2H),3.36(s,2H),2.50-2.80(m,2H),2.30(s,3H),1.81-1.98(m,3H),1.26-1.51(m,3H)。MS[M+H]+:367.8。
实施例11:(±)3-(1-苄基哌啶-4-基)-2-(3-氟-4-氯苯基)-噻唑啉-4-酮
称取0.48g(0.003mol)3-氟-4-氯苯甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.09g,m.p.131-133℃,产率89.7%。 1H-NMR(DMSO-d6,ppm)δ:1H-NMR(DMSO-d6,ppm)δ:7.49-7.61(m,2H),7.20-7.31(m,6H),5.98(s,1H),3.99-4.03(d,1H,J=15.40Hz),
3.37(s,2H),2.67-2.81(m,2H),1.80-1.97(m,3H),1.22-1.53(m,3H)。MS[M+H]+:405.3。
实施例12:(±)3-(1-苄基哌啶-4-基)-2-(3-吡啶基)-噻唑啉-4-酮
称取0.43g(0.004mol)3-吡啶甲醛和0.76g(0.004mol)4-氨基-1-苄基哌啶,以及0.76g(0.008mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.05g,m.p.158-160℃,产率73.4%。1H-NMR(DMSO-d6,ppm)δ:8.64(d,1H,J=1.96Hz),8.52-8.53(d,1H,J=4.76Hz),7.84-7.86(d,1H,J=7.84Hz),7.19-7.42(m,6H),6.01(s,1H),4.00-4.04(d,1H,J=15.40Hz),3.57-3.71(m,2H),3.36(s,2H),2.50-2.81(m,2H),1.82-1.96(m,3H),1.17-1.52(m,3H)。MS[M+H]+:354.0。
实施例13:(±)3-(1-苄基哌啶-4-基)-2-(4-吡啶基)-噻唑啉-4-酮
称取0.43g(0.004mol)4-吡啶甲醛和0.76g(0.004mol)4-氨基-1-苄基哌啶,以及0.76g(0.008mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.10g,m.p.169-171℃,产率77.8%。1H-NMR(DMSO-d6,ppm)δ:8.55-8.57(dd,2H,J1=1.40Hz,J2=8.40Hz),7.39-7.41(dd,2H,J1=1.68Hz,J2=8.40Hz),7.20-7.30(m,5H),5.98(s,1H),3.94-3.98(dd,1H,J1=1.40Hz,J2=15.68Hz),3.72-3.76(m,1H),3.55-3.58(d,1H,J=15.68Hz),3.27(s,2H),2.65-2.80(m,2H),1.81-1.92(m,3H),1.18-1.55(m,3H)。MS[M+H]+:354.3。
实施例14:(±)3-(1-苄基哌啶-4-基)-2-(2-氯苯基)-噻唑啉-4-酮
称取0.28g(0.002mol)2-氯苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法 合成,得白色固体0.66g,m.p.136-138℃,产率85.3%。1H-NMR(DMSO-d6,ppm)δ:7.20-7.51(m,9H),6.09(d,1H,J=1.12Hz),3.82-3.86(dd,1H,J1=1.12Hz,J2=15.96Hz),3.74-3.77(m,1H),3.57-3.61(d,1H,J=15.96Hz),3.36(s,2H),2.65-2.82(m,2H),1.81-1.93(m,3H),1.17-1.65(m,3H)。MS[M+H]+:387.2。
实施例15:(±)3-(1-苄基哌啶-4-基)-2-(3,5-二三氟甲基苯基)-噻唑啉-4-酮
称取0.48g(0.002mol)3,5-二三氟甲基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.83g,m.p.150-152℃,产率84.9%。1H-NMR(DMSO-d6,ppm)δ:7.19-7.28(d,3H,J=15.96Hz),7.19-7.28(m,5H),6.23(d,1H,J=1.12Hz),4.08-4.12(dd,1H,J1=1.40Hz,J2=15.68Hz),3.73-3.77(m,1H),3.57-3.61(d,1H,J=15.68Hz),3.37(s,2H),2.65-2.81(m,2H),1.84-1.95(m,3H),1.09-1.52(m,3H)。MS[M+H]+:489.3。
实施例16:(±)3-(1-苄基哌啶-4-基)-2-(3-氯-4-氟苯基)-噻唑啉-4-酮
称取0.32g(0.002mol)3-氯-4-氟苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.62g,m.p.131-133℃,产率76.5%。 1H-NMR(DMSO-d6,ppm)δ:7.67-7.69(dd,1H,J1=1.68Hz,J2=1.96Hz),7.40-7.47(m,2H),7.20-7.31(m,5H),5.98(d,1H,J=1.12Hz),4.00-4.04(dd,1H,J1=1.40Hz,J2=15.68Hz),3.66-3.72(m,1H),3.54-3.58(d,1H,J=15.68Hz),3.36(s,2H),2.66-2.81(m,2H),1.79-1.94(m,3H),1.20-1.51(m,3H)。MS[M+H]+:405.3。
实施例17:(±)3-(1-苄基哌啶-4-基)-2-(2-氟-4-三氟甲基苯基)-噻唑啉-4-酮
称取0.38g(0.002mol)2-氟-4-三氟甲基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.45g,m.p.115-117℃,产率51.3%。1H-NMR(DMSO-d6,ppm)δ:7.62-7.78(m,3H),7.20-7.30(m,5H),6.17(s,1H),3.84-3.88(d,1H,J=15.40Hz),3.71-3.77(m,1H),3.61-3.65(d,1H,J=15.68Hz),3.35(s,2H),2.66-2.82(m,2H),1.83-1.93(m,3H),1.17-1.58(m,3H)。MS[M+H]+:439.3。
实施例18:(±)3-(1-苄基哌啶-4-基)-2-(3-溴-4-氟苯基)-噻唑林-4-酮
称取0.41g(0.002mol)3-溴-4-氟苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.61g,m.p.99-101℃,产率67.9%。 1H-NMR(DMSO-d6,ppm)δ:7.78-7.79(dd,1H,J1=1.96Hz,J2=2.24Hz),7.20-7.49(m,7H),5.98(s,1H),3.99-4.03(d,1H,J=15.68Hz),3.65-3.71(m,1H),3.53-3.57(d,1H,J=15.68Hz),3.35(s,2H),2.66-2.81(m,2H),1.79-1.94(m,3H),1.20-1.50(m,3H)。MS[M+H]+:449.2。
实施例19:(±)3-(1-苄基哌啶-4-基)-2-(4-氟苄氧基-苯基)-噻唑啉-4-酮
称取0.46g(0.002mol)4-氟苄氧基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.72g,m.p.114-116℃,产率75.5%。 1H-NMR(DMSO-d6,ppm)δ:7.49-7.52(m,2H),7.19-7.35(m,9H),6.69-7.01(d,2H,J=8.68Hz),5.87(s,1H),5.08(s,2H),3.91-3.94(dd,1H,J1=1.40Hz,J2=15.40Hz),3.53-3.62(m,2H),3.35(s,2H),2.63-2.79(m,2H),1.76-1.98(m,3H),1.25-1.49(m, 3H)。MS[M+H]+:477.3。
实施例20:(±)3-(1-苄基哌啶-4-基)-2-(3-氟-4-甲氧基苯基)-噻唑啉-4-酮
称取0.31g(0.002mol)3-氟-4-甲氧基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.66g,m.p.126-128℃,产率82.5%。1H-NMR(DMSO-d6,ppm)δ:7.36-7.41(t,1H,J=8.68Hz),7.19-7.30(m,5H),6.78-6.88(m,2H),5.99(s,1H),3.82-3.86(d,1H,J=15.68Hz),3.78(s,1H),3.65-3.68(m,1H),3.57-3.61(d,1H,J=15.68Hz),3.35(s,2H),2.64-2.81(m,2H),1.80-1.92(m,3H),1.15-1.55(m,3H)。MS[M+H]+:401.1。
实施例21:(±)3-(1-苄基哌啶-4-基)-2-(4-正丁氧基苯基)-噻唑啉-4-酮
称取0.36g(0.002mol)4-正丁氧基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.49g,m.p.114-116℃,产率58.3%。 1H-NMR(DMSO-d6,ppm)δ:7.19-7.32(m,7H),6.89-6.92(d,2H,J=8.68Hz),5.86(d,1H,J=1.12Hz),3.89-3.98(m,3H),3.53-3.59(m,2H),3.35(s,2H),2.63-2.78(m,2H),1.67-1.98(m,5H),1.26-1.46(m,5H),0.91-0.95(t,3H,7.28Hz)。MS[M+H]+:425.3。
实施例22:(±)3-(1-苄基哌啶-4-基)-2-(2-噻吩基)-噻唑啉-4-酮
称取0.34g(0.003mol)2-噻吩甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.02g,m.p.134-136℃,产率94.8%。1H-NMR(DMSO-d6,ppm)δ:7.54-7.55(m,1H),7.21-7.31(m,6H),6.96-6.97(dd,1H, J1=3.92Hz,J2=7.56Hz),6.30(s,1H),3.83-3.87(dd,1H,J1=1.12Hz,J2=15.40Hz),3.58-3.62(m,2H),3.37(s,2H),2.68-2.81(m,2H),1.81-2.08(m,3H),1.43-1.47(m,3H)。MS[M+H]+:359.2。
实施例23:(±)3-(1-苄基哌啶-4-基)-2-(2-呋喃基)-噻唑啉-4-酮
称取0.29g(0.003mol)2-呋喃甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.85g,m.p.116-118℃,产率82.5%。1H-NMR(DMSO-d6,ppm)δ:7.65(d,1H,J=0.84Hz),7.21-7.31(m,5H),6.43-6.49(m,2H),6.04(d,1H,J=1.40Hz),3.81-3.85(dd,1H,J1=1.40Hz,J2=15.40Hz),3.65-3.71(m,1H),3.53-3.56(d,1H,J=15.40Hz),3.38(s,2H),2.66-2.83(m,2H),1.82-1.97(m,3H),1.08-1.49(m,3H)。MS[M+H]+:343。
实施例24:(±)3-(1-苄基哌啶-4-基)-2-(5-甲基呋喃-2-基)-噻唑啉-4-酮
称取0.33g(0.003mol)5-甲基呋喃-2-甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.05g,m.p.160-161℃,产率95%。 1H-NMR(DMSO-d6,ppm)δ:7.21-7.32(m,5H),6.33-6.34(d,1H,J=3.08Hz),6.03(dd,1H,J1=1.84Hz,J2=7.84Hz),5.95(d,1H,J=1.40Hz),3.79-3.83(dd,1H,J1=1.40Hz,J2=15.40Hz),3.64-3.70(m,1H),3.50-3.54(d,1H,J=15.40Hz),3.38(s,2H),2.68-2.83(m,2H),2.24(s,3H),1.82-1.98(m,3H),1.16-1.48(m,3H)。MS[M+H]+:357.3。
实施例25:(±)3-(1-苄基哌啶-4-基)-2-(5-甲基噻吩-2-基)-噻唑啉-4-酮
称取0.25g(0.002mol)5-甲基噻吩-2-甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.60g,m.p.151-153℃,产率80.5%。 1H-NMR(DMSO-d6,ppm)δ:7.22-7.37(m,5H),6.98-6.99(m,1H),6.62-6.63(m,1H),6.18(s,1H),3.79-3.82(d,1H,J=15.69Hz),3.55-3.59(m,2H),3.38(s,2H),2.70-2.81(m,2H),2.41(s,3H),1.81-2.08(m,3H),1.46-1.55(m,3H)。MS[M+H]+:373.2。
实施例26:(±)3-(1-苄基哌啶-4-基)-2-(5-溴呋喃-2-基)-噻唑啉-4-酮
称取0.35g(0.002mol)5-溴呋喃-2-甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.71g,m.p.158-160℃,产率84.5%。 1H-NMR(DMSO-d6,ppm)δ:7.24-7.37(m,5H),6.24-6.27(dd,2H,J1=3.36Hz,J2=7.28Hz),5.61(s,1H),3.93-4.00(m,2H),3.47-3.73(m,3H),2.79-2.97(m,2H),1.23-2.07(m,6H)。MS[M+H]+:423.0。
实施例27:(±)3-(1-苄基哌啶-4-基)-2-(2,3-二甲氧基苯基)-噻唑啉-4-酮
称取0.33g(0.002mol)2,3-二甲氧基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.65g,m.p.122-123℃,产率78.8%。 1H-NMR(DMSO-d6,ppm)δ:7.19-7.30(m,5H),7.00-7.08(m,2H),6.84-6.85(d,1H,J=7.56Hz),6.02(s,1H),3.80-3.85(m,7H),3.53-3.67(m,2H),3.36(s,2H),2.64-2.80(m,2H),1.79-1.91(m,3H),1.23-1.58(m,3H)。MS[M+H]+:413.1。
实施例28:(±)3-(1-苄基哌啶-4-基)-2-(4-苄氧基苯基)-噻唑啉-4-酮
称取0.42g(0.002mol)4-苄氧基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.70g,m.p.104-106℃,产率76.1%。 1H-NMR(DMSO-d6,ppm)δ:7.19-7.46(m,12H),6.99-7.01(d,2H,J=8.68Hz),5.86(s,1H),5.10(s,2H),3.89-3.93(d,1H,J=15.40Hz),3.53-3.61(m,2H),3.35(s,2H),2.64-2.79(m,2H),1.77-1.99(m,3H),1.25-1.49(m,3H)。MS[M+H]+:459.6。
实施例29:(±)3-(1-苄基哌啶-4-基)-2-(2-芴基)-噻唑啉-4-酮
称取0.58g(0.003mol)2-芴甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.03g,m.p.155-157℃,产率77.9%。1H-NMR(DMSO-d6,ppm)δ:7.88-7.91(t,2H,J=7.56Hz),7.58-7.61(t,2H,J=7.28Hz),7.16-7.43(m,8H),6.01(s,1H),3.98-4.02(d,1H,J=15.41Hz),3.94(s,2H),3.58-3.71(m,2H),3.35(s,2H),2.60-2.79(m,2H),1.76-2.01(m,3H),1.27-1.55(m,3H)。MS[M+H]+:441.4。
实施例30:(±)3-(1-苄基哌啶-4-基)-2-(4-溴苯基-3-吡啶基)-噻唑啉-4-酮
称取0.53g(0.002mol)4-溴苯基-3-吡啶甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得白色固体0.78g,m.p.203-205℃,产率76.5%。 1H-NMR(DMSO-d6,ppm)δ:8.74(s,1H),8.58-8.59(d,1H,J=4.76Hz),7.78-7.80(d,1H,J=8.40Hz),7.19-7.33(m,8H),5.62(s,1H),4.05(br s,1H),3.53-3.63(m,2H),3.35(s,2H),2.62-2.67(t,2H,J=11.82Hz),1.76-1.82(t,2H,J=10.64Hz),1.30-1.38(m,3H),1.05-1.08(m,1H)。MS[M+H]+:508.3。
实施例31:(±)3-(1-苄基哌啶-4-基)-2-胡椒基-噻唑啉-4-酮
称取0.45g(0.003mol)胡椒基-2-甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.00g,m.p.146-148℃,产率86.6%。 1H-NMR(DMSO-d6,ppm)δ:7.20-7.37(m,5H),6.85-6.98(m,3H),6.03-6.04(d,2H,J=5.04Hz),5.85(d,1H,J=1.40Hz),3.95-3.99(dd,1H,J1=1.40Hz,J2=15.40Hz),3.51-3.62(m,2H),3.34(s,2H),2.66-2.80(m,2H),1.78-1.99(m,3H),1.30-1.49(m,3H)。MS[M+H]+:397.0。
实施例32:(±)3-(1-苄基哌啶-4-基)-2-(4-硝基苯基)-噻唑啉-4-酮
称取0.30g(0.002mol)4-硝基苯甲醛和0.38g(0.002mol)4-氨基-1-苄基哌啶,以及0.37g(0.004mol)巯基乙酸,按实施例1的合成方法合成,得黄色固体0.65g,m.p.119-121℃,产率81.2%。 1H-NMR(DMSO-d6,ppm)δ:8.21-8.23(d,2H,J=8.68Hz),7.67-7.69(d,2H,J=8.68Hz),7.19-7.29(m,2H),6.15(s,1H),3.95-3.99(dd,1H,J1=1.40Hz,J2=15.40Hz),3.75-3.78(m,1H),3.58-3.61(d,1H,J=15.40Hz),3.36(s,2H),2.63-2.81(m,2H),1.79-1.94(m,3H),1.16-1.56(m,3H)。MS[M+H]+:398.4。
实施例33:(±)3-[1-(3-氟苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.74g(0.002mol)3-(1-苄基哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮溶于50ml甲苯中,室温搅拌下加入0.33g(0.003mol)氯甲酸乙酯,回流反应5.5小时后蒸干溶剂,将残余物溶于50ml乙醇和4ml 40%氢氧化钠溶液,回流反应6小时后停止反应,蒸干溶剂,加入100ml蒸馏水,二氯甲烷萃取,有机层饱和氯化钠溶液洗、水洗,无水硫酸钠干燥过夜,滤出硫酸钠,回收二氯甲烷,得黄色油状物0.42g, 产率75%。
称取0.13g(0.001mol)3-氟苯甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,溶于25ml干燥的二氯甲烷,室温搅拌反应1小时,冰浴下加入0.32g(0.0015mol)三乙酰氧基硼氢化钠,于冰浴中继续搅拌半小时后升至室温,搅拌反应8小时后停止反应。向反应液中加入20ml二氯甲烷,而后用饱和碳酸氢钠溶液洗、饱和氯化钠溶液洗、水洗。二氯甲烷层加入适量无水硫酸钠干燥过夜。过滤,回收二氯甲烷后得淡黄色油状物,无水乙醇重结晶,得白色固体0.32g,m.p.130-132℃,产率82.1%。1H-NMR(DMSO-d6,ppm)δ:7.45-7.49(m,2H),7.30-7.35(m,1H),7.18-7.23(m,2H),7.01-7.06(m,3H),5.96(d,1H,J=1.68Hz),3.93-3.97(dd,1H,J1=1.68Hz,J2=15.68Hz),3.55-3.65(m,2H),3.38(s,2H),2.64-2.80(m,2H),1.80-1.99(m,3H),1.24-1.51(m,3H)。MS[M+H]+:389.0。
实施例34:(±)3-[1-(4-氟苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.19g(0.0015mol)4-氟苯甲醛和0.42g(0.0015mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.43g(0.002mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.32g,m.p.163-165℃,产率55%。1H-NMR(DMSO-d6,ppm)δ:7.45-7.48(m,2H),7.07-7.25(m,6H),5.95(s,1H),3.93-3.97(dd,1H,J1=1.40Hz,J 2=15.40Hz),3.54-3.64(m,2H),3.34(s,2H),2.63-2.78(m,2H),1.77-1.96(m,3H),1.22-1.50(m,3H)。MS[M+H]+:388.9。
实施例35:(±)3-[1-(2-氟苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.13g(0.001mol)2-氟苯甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰 氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.30g,m.p.150-152℃,产率76.9%。1H-NMR(DMSO-d6,ppm)δ:7.44-7.48(m,2H),7.10-7.32(m,6H),5.95(d,1H,J=1.68Hz),3.92-3.97(dd,1H,J1=1.68Hz,J2=15.68Hz),3.54-3.62(m,2H),3.42(s,2H),2.66-2.81(m,2H),1.82-1.97(m,3H),1.23-1.50(m,3H)。MS[M+H]+:389.2。
实施例36:(±)3-[1-(2-溴苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.19g(0.001mol)2-溴苯甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.40g,m.p.153-155℃,产率88.9%。1H-NMR(DMSO-d6,ppm)δ:7.55-7.57(m,1H),7.45-7.49(m,2H),7.31-7.37(m,2H),7.15-7.22(m,3H),5.96-5.97(d,1H,J=1.40Hz),3.92-3.97(dd,1H,J1=1.40Hz,J2=15.40Hz),3.54-3.64(m,2H),3.44(s,2H),2.68-2.82(m,2H),1.91-1.99(m,3H),1.27-1.50(m,3H)。MS[M+H]+:451.2。
实施例37:(±)3-[1-(4-溴苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.19g(0.001mol)4-溴苯甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.37g,m.p.135-137℃,产率82.2%。1H-NMR(DMSO-d6,ppm)δ:7.44-7.48(m,4H),7.16-7.22(m,4H),5.95-5.96(d,1H,J=1.40Hz),3.93-3.97(dd,1H,J1=1.40Hz,J2=1.40Hz),3.55-3.65(m,2H),3.33(s,2H),2.62-2.78(m,2H),1.78-1.98(m,3H),1.24-1.50(m,3H)。MS[M+H]+:451.3。
实施例38:(±)3-[1-(3-吡啶甲基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.16g(0.001mol)3-吡啶甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.34g,m.p.146-148℃,产率91.4%。1H-NMR(DMSO-d6,ppm)δ:8.40-8.44(m,2H),7.17-7.62(m,6H),5.92-5.95(d,1H,J=1.40Hz),3.93-3.97(dd,1H,J1=1.40Hz,J2=15.40Hz),3.55-3.65(m,2H),3.39(s,2H),2.64-2.79(m,2H),1.81-1.99(m,3H),1.22-1.51(m,3H)。MS[M+H]+:372.2。
实施例39:(±)3-[1-(2-噻吩甲基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.17g(0.001mol)2-噻吩甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.31g,m.p.117-119℃,产率82.1%。1H-NMR(DMSO-d6,ppm)δ:6.88-7.49(m,7H),5.96(s,1H),5.06(s,2H),3.93-3.97(d,1H,J=15.68Hz),3.55-3.64(m,4H),2.69-2.85(m,2H),1.79-1.97(m,3H),1.21-1.51(m,3H)。MS[M+H]+:377.3。
实施例40:(±)3-[1-(4-苄氧基苄基)哌啶-4-基]-2-(4-氟苯基)-噻唑啉-4-酮
称取0.22g(0.001mol)4-苄氧基苯甲醛和0.28g(0.001mol)3-(哌啶-4-基)-2-(4-氟苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.40g,m.p.142-144℃,产率83.8%。1H-NMR(DMSO-d6,ppm)δ:7.10-7.48(m,11H),6.91-6.93(d,2H,J=8.68Hz),5.95(s,1H),5.06(s,2H),3.93-3.97(dd,1H,J1=1.40Hz,J2=15.40Hz),3.54-3.65(m,2H), 3.28(s,2H),2.62-2.78(m,2H),1.74-1.94(m,3H),1.19-1.49(m,3H)。MS[M+H]+:477.3。
实施例41:(±)3-[1-(4-二甲胺基苄基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮
称取0.22g(0.0015mol)4-二甲胺基苯甲醛和0.42g(0.0015mol)3-(哌啶-4-基)-2-(2-氟苯基)-噻唑啉-4-酮,以及0.45g(0.002mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.51g,m.p.134-136℃,产率82%。1H-NMR(DMSO-d6,ppm)δ:7.37-7.48(m,2H),7.20-7.25(m,2H),6.98-6.70(d,2H,J=8.68Hz),6.61-6.64(d,2H,J=8.68Hz),6.04(s,1H),3.84-3.87(d,1H,J=15.12Hz),3.58-3.70(m,2H),3.22(s,2H),2.61-2.84(m,8H),1.75-1.88(m,3H),1.12-1.57(m,3H)。MS[M+H]+:414.4。
实施例42:(±)3-[1-(3-吡啶甲基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮
称取0.16g(0.0015mol)3-吡啶甲醛和0.42g(0.0015mol)3-(哌啶-4-基)-2-(2-氟苯基)-噻唑啉-4-酮,以及0.45g(0.002mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.49g,m.p.156-158℃,产率87.7%。1H-NMR(DMSO-d6,ppm)δ:8.39-8.44(m,2H),7.59-7.61(m,1H),7.37-7.49(m,2H),7.30-7.33(m,1H),7.19-7.25(m,2H),6.05(d,1H,J=1.40Hz),3.84-3.88(dd,1H,J1=1.12Hz,J2=8.12Hz),3.66-3.72(m,1H),3.58-3.62(dd,1H,J1=1.68Hz,J2=7.68Hz),3.40(s,2H),2.63-2.80(m,2H),1.83-1.92(m,3H),1.17-1.58(m,3H)。MS[M+H]+:372.5。
实施例43:(±)3-[1-(2-噻吩甲基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮
称取0.17g(0.0015mol)2-噻吩甲醛和0.42g(0.0015mol)3-(哌啶 -4-基)-2-(2-氟苯基)-噻唑啉-4-酮,以及0.45g(0.002mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.47g,m.p.139-141℃,产率84.5%。1H-NMR(DMSO-d6,ppm)δ:7.38-7.50(m,3H),7.20-7.26(m,2H),6.06-6.93(m,2H),6.06(d,1H,J=1.12Hz),3.84-3.88(dd,1H,J1=1.12Hz,J2=8.12Hz),3.57-3.71(m,4H),2.67-2.86(m,2H),1.83-1.92(m,3H),1.14-1.58(m,3H)。MS[M+H]+:377.3。
实施例44:(±)3-[1-(4-二甲胺基苄基)哌啶-4-基]-2-(2-溴苯基)-噻唑啉-4-酮
称取0.15g(0.001mol)4-二甲胺基苯甲醛和0.35g(0.001mol)3-(哌啶-4-基)-2-(2-溴苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.40g,m.p.158-160℃,产率84.3%。1H-NMR(DMSO-d6,ppm)δ:7.65-7.67(d,1H,J=7.84Hz),7.25-7.44(m,3H),6.99-7.00(d,2H,J=8.40Hz),6.62-6.64(d,2H,J=8.68Hz),6.00(s,1H),3.82-3.86(dd,1H,J1=1.12Hz,J2=8.12Hz),3.55-3.77(m,2H),3.23(s,2H),2.63-2.84(m,8H),1.66-1.87(m,4H),1.12-1.43(m,2H)。MS[M+H]+:474.3。
实施例45:(±)3-[1-(4-羟基-3,5-二叔丁基苄基)哌啶-4-基]-2-(2-溴苯基)-噻
唑啉-4-酮
称取0.24g(0.001mol)4-羟基-3,5-二叔丁基苯甲醛和0.35g(0.001mol)3-(哌啶-4-基)-2-(2-溴苯基)-噻唑啉-4-酮,以及0.32g(0.0015mol)三乙酰氧基硼氢化钠,按实施例33的合成方法合成,得白色固体0.38g,m.p.180-182℃,产率67.9%。1H-NMR(DMSO-d6,ppm)δ:7.54-7.56(d,2H,J=8.68Hz),7.37-7.39(d,2H,J=8.40Hz),6.89(s,2H),6.75(s,1H),5.95(d,1H,J=1.12Hz),3.93-3.97(dd,1H,J1=1.40Hz,J2=15.40Hz),3.64-3.70(m,1H),3.55-3.59(d,1H, J=15.40Hz),3.25(s,2H),2.62-2.82(m,2H),1.71-1.95(m,3H),1.28-1.55(m,21H)。MS[M+H]+:559.1。
实施例46:(±)3-(1-苄基哌啶-4-基)-2-(6-硝基-胡椒基)-噻唑啉-4-酮
称取0.45g(0.003mol)5-硝基-胡椒-2-甲醛和0.57g(0.003mol)4-氨基-1-苄基哌啶,以及0.55g(0.006mol)巯基乙酸,按实施例1的合成方法合成,得白色固体1.00g,m.p.146-148℃,产率86.6%。 1H-NMR(DMSO-d6,ppm)δ:7.69(s,1H),7.21-7.37(m,5H),7.04(s,1H),6.25-6.27(d,1H,J=5.32Hz),6.14(s,2H),3.86-3.90(d,1H,J=15.40Hz),3.65-3.67(m,1H),3.46-3.50(d,1H,J=15.68Hz),3.35(s,2H),2.69-2.81(m,2H),1.80-1.96(m,3H),1.40-1.56(m,3H)。MS[M+H]+:442.5。
实施例47:(±)6-(3-(4-(2-(2-氯-6-氟苯基)-4-噻唑啉酮-3-基)哌啶-1-基)丙
酰基)苯并噁唑啉-2-酮
称取0.45g(0.002mol)6-(3-氯丙酰基)苯并噁唑啉-2-酮和0.70g(0.002mol)3-(哌啶-4-基)-2-(2-氯-6-氟苯基)-噻唑啉-4-酮,溶于30ml丙酮,加入0.22g(0.002mol)三乙胺,塞好,室温放置24小时,滤出析出的固体,乙醚洗、水洗,得淡黄色固体0.66g,m.p.116-118℃,产率74.7%。1H-NMR(DMSO-d6,ppm)δ:7.78-7.80(dd,2H,J1=1.68Hz,J2=7.68Hz),7.27-7.48(m,2H),7.12-7.14(dd,2H,J1=2.24Hz,J2=7.24Hz),6.26(s,1H),3.68-3.86(m,3H),3.06-3.10(t,2H,J=7.28Hz),2.74-2.95(m,2H),2.55-2.61(m,2H),0.95-1.99(m,6H)。MS[M+H]+:504.3。
下面的生物试验用来进一步说明本发明。
实施例48:实施例化合物的镇痛作用
实验目的:测定化合物在小鼠醋酸扭体模型上的镇痛活性
实验材料:昆明种小鼠(18-22g),雌雄各半,由军事医学科学院实验动物中心提供。
实验方法:
将小鼠称重,标记,分组,每组10只,灌胃给药(30mg/kg)。40分钟后,腹腔注射0.6%醋酸0.4ml,5分钟后记录在随后15分钟内小鼠扭体的次数,按下式计算药物对小鼠醋酸扭体的抑制率,从而评价药物的镇痛效果,结果见表2。
表2:化合物镇痛作用评价结果
以上实施例化合物镇痛作用评价结果表明,本发明化合物在小鼠 醋酸扭体模型上表现出明显的镇痛作用。
以下实施例中用到的cDNAs质粒α1B(GeneBank accession no.AF055477)/α2δ(AF286488)/β1b(L06110),兔α1C(X15539),人α1A (NM000068),大鼠α1E(NM009782)和大鼠HERG(U04270)(本领域技术人员可以参照GeneBank中的序列自行构建,也可以参照例如Zhang S,Su R,Zhang C et al.,C101,a novel 4-amino-piperidinederivativeselectively blocks N-type calcium channels.European JournalofPharmacology,2008,587(1-3):42-47中的方法构建。)。
实施例49:实施例化合物的N-型钙通道电流抑制活性
实验目的:测定化合物对爪蟾卵母细胞瞬时表达的N型钙通道(α1B/β1b/α2δ)的电流抑制作用。
实验材料:爪蟾卵母细胞。
实验方法:
(1)细菌培养
100LB溶液,100μL氨苄青霉素,1ml分别表达α1B,α2δ,β1b质粒的大肠杆菌于37℃下,以200转/分的转速振摇12-17小时,备用。
(2)提取质粒
取4ml细菌培养物用台式离心机(13000g)离心5分钟,弃取上轻液,并将试管倒置于纸巾上吸去剩余的培养液。
加入250μL细胞悬浮液,旋涡震荡或吹打以充分悬浮细胞(细胞充分悬浮十分关键),将悬浮的细胞转移至5ml的消毒离心管中(注意:以后不要再旋涡震荡以免切断染色体DNA)。加入250μL细胞裂解液并颠倒4次,以充分混合。孵育时间大约1-5分钟,不要超过5分钟,否则质粒DNA会出现缺口(注意:加入碱性蛋白酶溶液前观察裂解液部分澄清非常必要,但是孵育时间不要超过5分钟)。
加入10μL碱性蛋白酶溶液并颠倒离心管4次以充分混合,于室温孵育5分钟。碱性蛋白酶能够灭活核酸酶以及其他细菌裂解过程中释放出的能够影响分离质粒质量的蛋白。
加入350μL中和液并迅速颠倒4次以充分混合,于室温将细胞裂解液以最大速度(14000g)离心10分钟。
将澄清的裂解液大约850μL转移到准备好的离心柱中,不要搅动或将任何白色沉淀与上清液一同转移。
用离心机以最大速度于室温离心1分钟,从收集管上取下离心管并弃去收集管中的液体,将离心柱重新插入到收集管上。
加入750μL先前用95%的乙醇稀释过的柱清洗液。
用离心机以最大速度于室温离心1分钟,从收集管上取下离心管并弃去收集管中的液体,将离心柱重新插入到收集管上。
加入250μL柱清洗,重复清洗一次。
用离心机以最大速度于室温离心2分钟。
将离心柱转移至一个新的1.5ml消毒的离心管中,操作时需小心,不要将清洗液与离心柱一同转移。
将离心柱再转移至一个新的1.5ml消毒的离心管中,加入100μL去核算酶的水,以洗脱质粒DNA(可等2分钟,便于完全溶解),于室温用离心机以最大速度离心1分钟。
洗脱后将离心柱取出,并弃之。合并离心液于-20℃条件下保存备用。
(3)爪蟾卵母细胞的分离和培养
将手术器械在75%的乙醇中浸泡30分钟,取出凉干。5号丝线在沸水中消毒10分钟。
将爪蟾掩埋于碎冰中约40分钟,使其麻醉。取出已麻醉的爪蟾,腹部向上置于平铺的碎冰上,并用碎冰掩埋其头部和四肢。用酒精棉球消毒下腹部皮肤,然后用针头挑起(正中偏左或右),用眼科剪刀剪开1cm左右的小口。用同样的方法剪开肌肉层(注意不要损伤任何内脏器官,剪开肌肉层后即可看到卵母细胞)。用镊子和剪刀取出1cm3 大小的小叶,放入预先准备好的含有OR-2(含青霉素)的培养液皿中,分别缝合肌肉层和皮肤层。
将卵母细胞转移到无菌的玻璃管中重复用OR-2溶液清洗,至洗 净残留的血液为止。加入胶原酶溶液振摇消化约1小时,更换新胶原酶溶液继续振摇约1小时(此时可看到大多数已分离或单个细胞)。
除去消化液,用OR-2溶液清洗5-6次,转入盛有ND-96溶液的培养皿中挑选V期成熟的细胞置于ND-96溶液中,于1℃条件下用生化培养箱保存备用,每天换液一次。
(4)注入质粒
将质粒α1B,α2δ,β1b按照浓度1:1:1的比例注入爪蟾卵母细胞,每个细胞约注入50nM。注入后的细胞置于ND-96培养液中,温度18℃放置培养48小时后记录电流。
(5)电流记录
灌流方法给药,流速为3ml/min,药物浓度为10μmol/L。采用双电极电压钳技术,将细胞钳制在-100mV,以10mV为步阶,去极化至+60mV,记录电流。
N-型钙通道电流抑制实验结果见表3。
表3:N-型钙通道电流抑制实验结果
化合物 | 电流抑制率% | 细胞个数 |
4 | 73.6 | 3 |
5 | 66.5 | 3 |
13 | 23.6 | 3 |
14 | 78.4 | 3 |
25 | 41.2 | 3 |
41 | 83.9 | 3 |
44 | 30.2 | 3 |
以上结果表明,本发明的化合物对N-型钙通道具有较强的抑制作用。
实施例50:实施例化合物对P/Q-型钙通道、Herg通道、钠通道、钾通道电流抑制活
性
(一)P/Q型及Herg通道DNA的酶切线性化
1.钙通道各亚基(α2δ、β1b、α1B、α1E、α1A、α1C)和Herg通道DNA各按下列体系进行酶切:
质粒DNA按上述反应体系进行酶切,37℃下温育反应1h。
2.DNA的纯化和去RNA酶
a.在已酶切的质粒DNA样品中加入0.1体积的10×蛋白酶K缓冲液、0.1体积的5%SDS溶液、20mg/ml的蛋白酶K(终浓度为100μg/ml),37℃下温育反应1h;
b.将上述反应物转移至干净的1.5ml eppendorf管中,加入等体积的Tris平衡酚:氯仿:异戊醇(25:24:1),振荡1min,室温下(20-25℃)以12000rpm的速度离心2min(若有机相和无机相不能充分分开,延长时间重新离心);
c.小心将上层水相转移至另一干净的1.5ml eppendorf管中,弃去两相间的界面层和有机相;
d.加入等体积的氯仿:异戊醇(24:1),室温下(20-25℃)以12000rpm的速度离心2min;
e.小心将上层水相转移至另一干净的1.5ml eppendorf管中,加入0.1体积的3M醋酸钠(pH5.2)和2.5体积的95%乙醇,振荡
混匀,放置于-20℃中过夜(12-16h);
f.低温(<4℃)下以12000rpm的速度离心40min;
g.小心移出上清液,注意不要搅动沉淀,用吸头吸尽附于管壁的所有液滴;
h.在上步所得沉淀中加入半管70%乙醇,振荡混匀,低温(<4℃)下以12000rpm的速度离心2min;
i.小心移出上清液,重复上一步;
j.室温下(20-25℃)下将1.5ml eppendorf管敞口放置,直至残留液体挥干;
k.加入适当体积的去核酶水(Nuclease-free water),充分漂洗管壁,混匀,使模板DNA完全溶解,测其浓度值后,保存于-20℃备用。
3.钙离子通道各亚基及HERG通道cDNA体外转录成cRNA。(候云德.分子克隆实验指南.第二版.科学出版社.2002.来茂德主编.医学分子生物学.人民卫生出版社.1999.)
按照下列反应体系顺序加入各反应物:
α1A、β1b、α2δ、α1E、α1A、α1C亚基及Herg通道亚基的线性化模板,
T7Transcription 5×Buffer 20μl;
rNTPs(25mM ATP,CTP,UT各7.5μl+3mM GTP 0.6μl+去核酶水6.9μl)
线性DNA模板(共5-10μg)+去核酶水32.5μl;
Ribom7帽子类似物,40mM 7.5μl;
MixE,10μl。
a.从恒温箱中取出反应物,加入RQ1Rnase-Free Dnase(按每μg模板DNA加1u酶的比例),37℃下温育反应15min;
b.加入等体积的水平衡酚:氯仿:异戊醇(25:24:1),振荡1min,室温下(20-25℃)以12000rpm的速度离心2min(若有机相和无机相不能充分分开,延长时间重新离心);
c.小心将上层水相转移至另一干净的1.5ml eppendorf管中并加入等体积的氯仿:异戊醇(24:1),室温下(20-25℃)以12000rpm的速度离心2min;
d.小心将上清液转移至另一干净的1.5ml eppendorf管中,加入0.1体积的3M醋酸钠(pH5.2)和2.5体积的95%乙醇,振荡混匀,放置于-20℃中过夜(12-16h);
e.低温(<4℃)下以12000rpm的速度离心40min;
f.小心移出上清液,注意不要搅动沉淀,用吸头吸尽附于管壁的所有液滴;
g.在上一步所得沉淀中加入半管70%乙醇;
h.小心移出上清液,重复上一步;
i.室温下(20-25℃)下将1.5ml eppendorf管敞口放置,直至残留液体挥干,加入适当体积的去核酶水(nuclease-free water),充分漂洗管壁,混匀,使mRNA完全溶解,保存于-70℃备用。
4.爪蟾卵母细胞的注射
将专用注射针用两步法电极拉制仪拉制好后,在干净的薄面巾纸上刺一下,使针尖的口径变粗,并在抛光仪上抛光,使得针尖光滑平整。针尖的直径在6-10μm较为合适。安装注射用针之前,先在针内注射矿物油(Light mineral oil)以润滑管壁。根据原始各亚基cRNA的浓度,调整注射浓度大约为2ng/nl分别混合(1:1:1)。取1μl混合好的cRNA小心滴在干净的parafilm上,用微量注射仪将cRNA吸入到注射用针中。(注意:防止RNA酶的污染;防止空气被吸入到注射用针中,这两点均会影响cRNA在卵母细胞中的表达)。将挑选好的健康的Ⅴ、Ⅵ期成熟卵母细胞置入底部粘有网格(防止细胞在平皿中滑动)的培养皿中。仔细调节三维微操纵仪,使针尖接触细胞表面。若细胞状态良好,针尖接触细胞时会感到一定的阻力,同时可看到细胞膜上因张力形成的皱褶。穿刺细胞不易过深,以针尖刚刚穿过细胞膜为宜,将46.5nl cRNA注射入卵母细胞,注射后细胞会轻微鼓胀。等待30s之后,将注射针拔出,观察细胞是否有内容物溢出,如果有应放弃之。另外,若针尖极易刺入细胞时无突破感,表明细胞无张力,细胞状态不佳,意味着此细胞可能无法钳制到所需电位,也应放弃此细胞。将注射好的卵母细胞置于ND-96溶液中,在生化培养箱(18℃)培养48h后(需每天更换ND-96液体),即可分别记录表达的P/Q型通道钙通道电流及Herg通道电流。
5.爪蟾表达的钙通道部分
细胞外液(mM):BaCl25,N-methyl-D-glucamine 50,KCl 5, HEPES 5,用methanesulfonic acid调pH至7.4。
细胞内液为3mM的KCl。BAPTA的配制10mM Hepes溶解BAPTA,用CsOH调节pH至7.2。
(二)原代培养的海马神经元
海马神经元培养
取当天新生Wistar大鼠,用75%乙醇消毒。在无菌条件下取脑,剥离出海马置于冰浴的解剖液中。将海马剪成1-2mm3的组织块,用含0.25%胰蛋白酶的解剖液在37℃下消化30min,然后将消化好的组织块移入种植液中终止消化,在种植液中用适当口径(尖端直径2mm)的滴管吹打细胞,使之均匀分散,制成细胞悬液,取少量悬液以台盼蓝染液记数细胞。加入适量种植液,将细胞按1×105/ml的密度接种在事先涂有多聚赖氨酸的35mm培养皿中,置于36℃10%的二氧化碳培养箱中过夜,24h后更换培养基,将种植液换为2ml饲养液。以后每3天半量换液一次,培养细胞在12-15天期间用于膜片钳实验。为抑制非神经元过度增殖,在培养的第3天向培养基中加入适量阿糖胞苷(每皿中加阿糖胞苷储备液6μl,终浓度为3μg/ml)。
海马神经元记录溶液部分
全细胞记录所用的记录液主要是电极内液和细胞外液。
记录电极内液成份(mM):KCl 140,HEPES 10,EGTA 10,调pH为7.2-7.4。
细胞外液的成分(mM):NaCl 140,KCl 5,MgCl21,HEPES10,Glucose 10,CaCl23,用NaOH调pH值为7.2-7.4。如果实验需要阻断钠电流,可在细胞外液中加入河豚毒素(TTX)1μM。如果实验需要阻断钾电流,而只用CsCl又不能完全阻断钾电流时,可在电极内液和细胞外液中加入四乙基铵(TEA)或4-氨基吡啶(4-AP)。
测定结果如表4所示。
表4:P/Q-型钙通道、Herg通道、
钠通道和钾通道电流测定实验结果
“-”表示化合物对此通道电流无作用。
实验结果表明,本发明化合物对P/Q型钙通道、Herg通道、TTX敏感钠通道和电压门控钾通道无阻断作用。
综上,本发明的化合物能够特异性地阻断或抑制N-型钙通道。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (12)
1.式I所示的化合物或其可药用盐:
其中:
R1代表被一个取代基所取代的C6-12芳基,其中,所述取代基选自单C1-8烷基氨基和二C1-8烷基氨基;
R2代表被一个取代基取代的C6-12芳基,其中,取代基选自卤素、硝基和氰基;
g代表C0-8亚烷基;
或者,
R1代表C6-12芳基;
R2代表C5-16杂芳基,其含1-3个氮原子;或者R2代表被一个取代基取代的C5-16杂芳基,其含1-3个选自氧和硫的原子,其中,取代基为C1-8烷基;或者R2代表被一个取代基取代的C6-12芳基,其中,取代基选自硝基和氰基;
g代表C0-8亚烷基。
2.根据权利要求1所述的化合物或其可药用盐,其中,
R1代表被一个取代基所取代的C6-12芳基,其中的取代基选自二甲氨基和二乙氨基;
R2代表的被一个取代基所取代的C6-12芳基的取代基选自氯、氟、溴和碘;
或者,
R1代表C6-12芳基;
R2代表的被一个取代基取代的C5-16杂芳基的取代基选自叔丁基和甲基。
3.根据权利要求1所述的化合物或其可药用盐,其中,
R1代表二甲胺基苄基;
R2代表被一个卤素原子取代的苄基或被一个硝基取代的苄基;
g为C1-3亚烷基;
或者,
R1代表苯基或苄基;
R2代表被一个硝基取代的苄基;
g为C1-3亚烷基;
所述卤素原子选自氟、氯、溴、以及碘原子中的任一种。
4.根据权利要求3所述的化合物或其可药用盐,其中,g为亚甲基。
5.选自如下的化合物或其可药用盐:
(±)3-(1-苄基哌啶-4-基)-2-(2-氟苯基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(2-溴苯基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(3-吡啶基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(4-吡啶基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(2-氯苯基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(2-噻吩基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(2-呋喃基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(5-甲基呋喃-2-基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(5-甲基噻吩-2-基)-噻唑啉-4-酮,
(±)3-(1-苄基哌啶-4-基)-2-(4-硝基苯基)-噻唑啉-4-酮,
(±)3-[1-(4-二甲胺基苄基)哌啶-4-基]-2-(2-氟苯基)-噻唑啉-4-酮,
(±)3-[1-(4-二甲胺基苄基)哌啶-4-基]-2-(2-溴苯基)-噻唑啉-4-酮;或者上述化合物的可药用盐。
6.权利要求1至4中任一项所述的化合物或其可药用盐的制备方法,包括下述步骤:
(1)4-氨基-1-苄基哌啶与醛反应生成如式II所示的烯胺,
(2)式II所示的化合物和巯基乙酸反应生成如式III所示的化合物,
(3)式III所示化合物与氯甲酸乙酯反应,生成如式IV所示的化合物,
(4)式IV所示化合物碱性条件下脱保护后生成如式V所示的化合物,
(5)式V所示化合物与卤代物或醛反应生成如式I所示的化合物,
上述式Ⅰ、Ⅱ、Ⅲ、Ⅳ、V中的R1、R2或g的定义如权利要求1至4中任一项所述。
7.一种药物组合物,其包含至少一种如权利要求1至5中任一项所述的化合物或其可药用盐。
8.根据权利要求7所述的药物组合物,其中,所述药物组合物还包含药学上可接受的载体或辅料。
9.权利要求1至5中任一项所述的化合物或其可药用盐或者权利要求7或8所述的药物组合物在制备N型钙离子通道阻断剂或抑制剂中的用途。
10.一种非诊断目的的在体外阻断或抑制N型钙离子通道的方法,包括使用有效量的权利要求1至5中任一项所述的化合物或其可药用盐或者权利要求7或8所述的药物组合物的步骤。
11.权利要求1至5中任一项所述的化合物或其可药用盐或者权利要求7或8所述的药物组合物在制备治疗和/或预防和/或辅助治疗疼痛、中风与脑缺血、酒精成瘾与中毒、急性和慢性肾衰竭、或肾机能不全的药物中的用途。
12.根据权利要求11所述的用途,其中,所述疼痛为手术后疼痛、偏头痛、内脏痛或神经性疼痛。
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