CN112239433A - 一种环己烷衍生物、制备方法及其应用 - Google Patents
一种环己烷衍生物、制备方法及其应用 Download PDFInfo
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- CN112239433A CN112239433A CN201910647774.6A CN201910647774A CN112239433A CN 112239433 A CN112239433 A CN 112239433A CN 201910647774 A CN201910647774 A CN 201910647774A CN 112239433 A CN112239433 A CN 112239433A
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- compound
- pharmaceutically acceptable
- reaction
- methanol
- dichloromethane
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Abstract
本发明属于化学药物领域,具体提供了一种环己烷衍生物或其立体异构体、药学上可接受的盐及其制备方法与应用。所述环己烷衍生物可用于治疗或预防需要调节多巴胺D2、D3和/或5HT‑2受体的病症。且本发明制备方法采用低廉易得的化工产品作为起始原料,且每步合成产率均较高,因此,生产成本较低。
Description
技术领域
本发明属于化学药物领域,具体涉及一种环己烷衍生物、制备方法及其 应用。
背景技术
精神分裂症是一种复杂而严重的精神障碍,通常起病于青少年晚期及成 年早期。且精神分裂症的结局尚不理想:一项纳入了50项转归研究的系统 综述显示,达到临床及社会康复的患者中位比例仅为13.5%,且精神分裂症 患者的预期寿命也显著低于一般人群,主要由躯体疾病造成。就全球而言, 精神分裂症患者的数量呈逐年上升趋势,从1990年的1310万(95%UI, 11.6-14.8,单位为百万,下同)增加至2016年的2090万(95%UI,18.5-23.4), 且70.8%的患者集中于25-54岁年龄段,东亚和南亚地区的患者数量最多, 2016年分别达到720万(95%UI,6.4-8.1)及400万(95%UI,3.5-4.5)左 右,而东亚也是患者数量净增最多的地区;大洋洲的患者最少,约28000人。 撒哈拉以南地区患者总数约130万(95%UI,1.1-1.5)。
全球范围内,精神分裂症所导致的伤残相关寿命损失年(YLDs)为1340 万(95%UI,9.9-16.7),占2016年全部YLDs的1.7%。与患病率类似,精 神分裂症相关疾病负担的重灾区为30-40岁,男性与女性无显著差异。中低 收入国家的精神分裂症相关疾病负担约为发达国家的4倍,很大程度上与前 者人口的迅速增加有关。研究估计,全球约有2100万人罹患精神分裂症, 且将随着人口的老龄化增加继续上升;大部分患者生活在中低收入国家,而 正是这些国家的精神分裂症治疗存在明显不足。
目前临床上常用治疗精神障碍药-抗精神病药物为阿立哌唑、利培酮、 帕利哌酮等,但是由于该类疾病发病率高,难于治愈,致死致残率较高等特 点,市场仍缺乏有效的治疗药物,且随着发病率逐年提高,而该类病人又需 长期服药,病人和社会的负担均较为沉重,临床上仍需更为有效的药物开发。
发明内容
为了解决上述问题,本发明提供了一种环己烷衍生物、制备方法及其应 用。
本发明的第一个目的是提供一种环己烷衍生物,所述环己烷衍生物为式 I所示的化合物或其立体异构体,及其药学上可接受的盐:
其中,
R1和R2独立地选自:氢、卤素、C1-C6链状烷基、C3-C6环烷基,烷氧 基、或R1和R2可与相邻的碳原子形成吡咯、噻吩、呋喃、哌啶;
所述烷基、环烷基可进一步被一个或多个的卤素、羟基、氨基、羧基、 氰基取代;
优选的,R1和R2独立地选自:氢、卤素、C1-C4烷基、或R1和R2可与 相邻的碳原子形成吡咯、噻吩;
优选的,R1和R2独立地选自:氢、氟、氯、溴、甲基、乙基、正丙基、 异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、甲氧基、乙 氧基、或R1和R2可与相邻的碳原子形成噻吩;
优选的,R1和R2独立地选自:氢、氟、氯、甲基、乙基、环丙基、甲 氧基、三氟甲基、或R1和R2可与相邻的碳原子形成噻吩;
优选的,R4和R5独立地选自:氢、甲基、乙基;
更优选的,式I所示化合物选自:
在某些实施方案中,所述药学上可接受的盐为无机酸盐或有机酸盐;优 选地,所述无机酸盐为硫酸盐、盐酸盐、硝酸盐、磷酸盐、或氢溴酸盐。所 述有机酸盐为乙酸盐、甲酸盐、甲磺酸盐、三氟乙酸盐、马来酸盐、酒石酸 盐、琥珀酸盐、富马酸盐、柠檬酸盐、苯磺酸盐、苯甲酸盐、乳酸盐、苹果 酸盐、氨基酸盐中的任一种;优选地,所述氨基酸盐为天冬氨酸盐、谷氨酸 盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、 脯氨酸盐、色氨酸盐、丝氨酸盐、酪氨酸盐、半胱氨酸盐、蛋氨酸盐、天冬 酰胺盐、谷氨酰胺盐、或苏氨酸盐。
本发明的第二目的是提供制备式I所示化合物、其立体异构体或其药学 上可接受的盐的方法,具体如下:
步骤1:化合物8与化合物8a在有机碱存在下发生酰基化反应,得到化 合物8P;
步骤2:化合物M与化合物X进行缩合反应,得终产物式I化合物。
其中,
化合物8可以通过本发明实施例中所记载的方法制备,也可通过其他常 规方法制备,或市售产品购买。所述化合物8可以是顺式或者反式,亦可以 最后使用式I化合物通过色谱分离或者结晶以获得其顺反立体异构体。
所述有机碱选自三乙胺、二异丙基乙胺或吡啶中的一种或几种。
本发明的第三个目的是提供式I所示化合物、其立体异构体或其药学上 可接受的盐在制备治疗或预防需要调节多巴胺D2、D3和/或5HT-2受体的病 症的药物中的用途。
其中所述需要调节多巴胺受体的病症为:精神病、药物滥用、伴随有认 知缺损的精神分裂症、轻度到中度认知缺陷、痴呆、伴随有痴呆的精神病状 况、进食障碍、注意力缺陷疾病、儿童多动症、精神病性抑郁症、躁狂症、 妄想狂样和妄想类障碍、运动障碍、焦虑、性功能障碍、睡眠障碍、呕吐、 攻击、孤独症。
具体的,
所述精神病为精神分裂症、情感分裂性精神障碍。
所述药物滥用为酒精、可卡因、尼古丁、类鸦片的滥用。
所述进食障碍为神经性贪食症。
所述运动障碍为帕金森病、精神抑制引起的帕金森综合征、迟发性运动 障碍。
本发明的第四个目的是提供一种药物组合物,所述药物组合物包括:所 述式I化合物、其立体异构体或其药学上可接受的盐作为活性成分及至少一 种药学上可接受的辅料,例如载体或赋形剂。
在某些实施方案中,所述组合物是通过口服、注射、透皮、鼻腔、黏膜 以及吸入方式使用的。
本发明所述的药物组合物可含有一种或多种本发明化合物。在一些实施 方案中,所述药物组合物可含有一种以上的本发明化合物。例如,在一些实 施方案中,所述药物组合物可含有两种或多种本发明化合物。此外,所述药 物组合物可任选地还包含一种或多种其他的药物活性化合物。
根据本发明,所述药物组合物包含本发明式I化合物与常规药用载体或 赋形剂。该药物组合物可通过例如口服或非肠道等途径给药。本发明的药物 组合物可按本领域常规方法制备成各种剂型,包括但不限于片剂、胶囊、溶 液、悬浮液、颗粒剂或注射剂等,例如口服或非肠道等途径给药。
本发明所述药物组合物可以每单位剂量含有预定量的活性成分的单位 剂型存在。这种单位可含有0.001-1000mg,例如,0.05mg、0.1mg、0.5mg、 1mg、10mg、20mg、50mg、80mg、100mg、150mg、200mg、250mg、300mg、 500mg、750mg或1000mg的本发明化合物,其取决于所治疗的疾病、给药 途径和受试者的年龄、体重和症状,或者药物组合物可以每单位剂量含有预 定量的活性成分的单位剂型存在。在另一实施方案中,所述单位剂量组合物 是含有本文所述的每日剂量或亚剂量或其适当分数的活性成分的那些。此 外,这种药物组合物可通过本领域技术人员熟知的任意方法制备。
术语定义
在本文中用于本发明描述中的术语仅是为了描述具体实施方案而不旨 在限制本发明。通常,本文使用的各种术语和短语具有本领域技术人员公知 的一般含义,即便如此,本文仍然希望在此对这些术语和短语作更详尽的说 明和解释,提及的术语和短语如有与公知含义不一致的,以本文所表述的含 义为准。
本文中,术语“链状烷基”是指具有指定碳原子数的一价饱和烃链。例 如,C1-C5链状烷基是指具有1-5个碳原子的烷基。所述链状烷基可为直链 或支链的。在一些实施方案中,支链烷基可能具有一个、两个或三个分支。 示例性链状烷基包括,但不限于,甲基、甲基乙基、乙基、丙基(包括正丙 基和异丙基)、甲基丙基、丁基(包括正丁基、异丁基和叔丁基)、戊基(包括 正戊基、异戊基和新戊基)。
本文中,术语“环烷基”意指具有3-6个碳原子并且具有单环或二环 或多个稠合环(包括稠合和桥连环系)的饱和环状烃基。例如,C3-C6环烷基是 指具有3-6个碳原子的环烷基。“环烷基”的典型实例包括但不限于单环结 构,诸如环丙基,环丁基,环戊基,环己基等。
本文中,单位“M”代表mol/L,“μM”代表μmol/L,“nM”代表 nmol/L。
本文中,“受试者”是指哺乳动物受试者(例如,狗、猫、马、牛、绵 羊、山羊、猴等)和人受试者,包括男性和女性受试者且包括新生儿、婴儿、 少年、青少年、成人和老年受试者且还包括各种种族和族裔,包括,但不限 于,白人、黑人、亚洲人、美洲印第安人和西班牙裔。
本文中,“药学上可接受的盐”是指保留目标化合物的所需生物活性并 表现出最小的不希望的毒理学效应的盐。这些药学上可接受的盐可在该化合 物的最终分离和纯化过程中原位制备或者通过单独地将其游离酸或游离碱 形式的纯化的化合物分别与合适的碱或酸反应进行制备。
本文中,提及本发明化合物或其他药物活性剂的“治疗有效量”是指在 合理的医学判断范围内,足以治疗或预防患者疾病但足够低地避免严重副作 用(在合理的利益/风险比)的量。化合物的治疗有效量将根据所选择的具体化 合物(例如考虑化合物的效力、有效性和半衰期);所选择的给药途径;所治 疗的疾病;所治疗的疾病的严重性;所治疗的患者的年龄、大小、体重和身 体疾病;所治疗的患者的医疗史;治疗持续时间;并行疗法的性质;所需的 治疗效果;和类似因素而变化,但仍可由本领域技术人员进行常规确定。
另外需要指出,本发明化合物使用剂量和使用方法取决于诸多因素,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。优选的使 用剂量介于0.001-1000mg/kg体重/天。该使用量以每天单一剂量进行给药 或以每天若干亚剂量进行给药,例如每天给药2、3、4、5或6个剂量。或 者所述给药可间歇进行,例如每隔一天一次、每周一次或每月一次。盐或溶剂合物等的治疗有效量可确定为通式(I)化合物本身的治疗有效量的比例。
本文中,所用术语“化合物”是指如上所定义的式I所示化合物,其呈 任意形式,包括各种立体异构体、任意盐或非盐形式(例如,作为游离酸或 游离碱的形式,或作为盐,尤其是其药学上可接受的盐)及其任意物理形式 (例如,包括非固体形式(例如,液体或半固体形式)和固体形式(例如, 无定形或结晶形式)),以及各种形式的混合物。
与现有技术相比,本发明具有如下技术效果:
1、本发明提供了一种环己烷衍生物,经研究,其对5HT-2B、D2L、D3A 均具有较高的亲和力,可用于治疗或预防需要调节多巴胺D2、D3和/或5HT-2 受体的病症。
2、本发明环己烷衍生物的制备方法,采用低廉易得的化工产品作为起 始原料,且每步合成产率均较高,因此,生产成本较低。
具体实施方式
下面结合实施例对本发明的环己烷衍生物、制备方法及其应用进行说 明。应理解,这些实施例仅用于解释本发明而不用于限制本发明的范围。对 外应理解,在阅读了本发明的内容之后,本领域技术人员对本发明作各种改 动或修改,这些等同形式同样落于本申请所附权利要求书所限定的范围。
以下实施例中未注明具体条件者,按照常规条件进行。所用试剂或仪器 未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1化合物9的制备
1.工艺路线:
2.操作方法:
(1)
将化合物1(80.0g,329mmol,1.00eq)溶解在四氢呋喃(550毫升),滴加 BH3-Me2S(10M、115ml,3.50eq)在0℃搅拌1小时,然后升温至20℃搅拌 2小时。薄层色谱(石油醚:乙酸乙酯=1:1),检测到一个极性较低的主要新点。 停止反应,降温至0℃,加入NaHCO3水溶液(600毫升),用乙酸乙酯(300 毫升x 2)萃取。合并有机层用盐水洗涤(300毫升),无水Na2SO4干燥,过滤, 滤液减压蒸馏。浓缩物直接用于下一步,无需精制。得到化合物2粗品(78.0 g),为白色固体。
1H NMR:ET7748-129-P1A1 400MHz CDCl3
4.38(s,1H),3.44-3.46(m,2H),3.38(s,1H),2.02-2.05(m,2H),1.80-1.83(m,2H),1.43(s,9H),1.02-1.14(m,4H).
(2)
将化合物2(76.0g,331mmol,1.00eq)加入至四氢呋喃(530ml),降温至 0℃,在此温度下,滴加完三乙醇胺(50.3g,497mmol,50.3ml,1.50eq)和对甲基 苯磺酰氯(45.6g,397mmol,30.8ml,1.20eq)。然后升温至20℃,反应液搅拌3 小时。TLC(石油醚:乙酸乙酯=1:1,产物:Rf=0.6)监测反应。反应完全后, 将反应液倒入水中(1000mL),用乙酸乙酯(500mL)萃取。水相再用乙酸乙 酯(500ml x 2)萃取,合并有机相用盐水洗涤,无水Na2SO4干燥,过滤,滤 液减压蒸馏,得到化合物3粗品(80.0g,收率78.5%)为白色固体。
1H NMR:ET20729-23-P1A1 400MHz CDCl3
4.38(s,1H),4.02-4.04(m,2H),3.40(s,1H),3.00(s,3H),2.06-2.07(m,2H),1.85-1.87(m,2H),1.70-1.72(m,1H),1.45(s,9H),1.06-1.17(m,4H).
(3)
将化合物3(80.0g,260mmol,1.00eq)加入至DMSO(800ml),在20℃,加 完氰化钠(31.9g,650mmol,2.50eq)。然后升温至90℃,反应液搅拌4小时。 TLC(石油醚:乙酸乙酯=2:1,产物:Rf=0.6)监测反应。反应完全后,将反应 液倒入水中(1500mL),用乙酸乙酯(800ml x 3)萃取,合并有机相用盐水洗 涤,无水Na2SO4干燥,过滤,滤液减压蒸馏,得到化合物4粗品(53.0g,收 率85.4%)为淡黄色固体。
1H NMR:ET20729-24-P1A1 400MHz CDCl3
4.37-4.39(m,1H),3.39(s,1H),2.24-2.26(m,2H),2.04-2.08(m,2H),1.89-1.92(m,2H),1.64-1.65(m,1H),1.44(s,9H),1.15-1.21(m,4H).
(4)
将化合物4(53.0g,222mmol,1.00eq)加入至乙醇(260ml),在20℃,加完 氢氧化钾水溶液(49.9g,889mmol,4.00eq),水(260ml)。然后升温至85℃, 反应液搅拌12小时。TLC(石油醚:乙酸乙酯=3:1,产物:Rf=0.3)监测反应。 反应完全后,将反应液降至室温,减压蒸馏,浓缩物溶于水(500ml),用 1M的盐酸溶液调PH=3-4之间,过滤,得到化合物5粗品(35.0g,收率61.2%) 为白色固体。
1H NMR:ET20729-27-P1A1 400MHz CDCl3
11.98(s,1H),6.63-6.65(m,1H),3.14(s,1H),2.06-2.08(m,2H),1.69-1.75(m,4H),1.52-1.66(m,1H),1.36(s,9H),1.10-1.14(m,2H),0.94-1.00(m,2H).
(5)
将化合物5(35.0g,136mmol,1.00eq),N,O-二甲基羟胺盐酸盐 (21.2g,217mmol,1.60eq)和三乙醇胺(27.5g,272mmol,37.9ml,2.00eq)加入 至二氯甲烷(240ml),降温至0℃,滴加EDCI(57.4g,299mmol,2.20 0eq)和 HOBt(18.4g,136mmol,1.00eq)。然后升温至20℃,反应液搅拌3小时。TLC(石 油醚:乙酸乙酯=1:1,产物:Rf=0.4)监测反应。反应完全后,将反应液倒入 水中(500mL),用二氯甲烷(200ml x 2)萃取,合并有机相用盐水洗涤,无水 Na2SO4干燥,过滤,滤液减压蒸馏,浓缩物过硅胶柱(洗脱剂石油醚:乙酸 乙酯=100:1~0:1),得到化合物6粗品(38.0g,收率84.0%,纯度90.3%) 为淡黄色固体。
1H NMR:ET20729-31-P1A1 400MHz CDCl3
4.40-4.42(m,1H),3.66(s,3H),3.36-3.37(m,1H),3.17(s,3H),2.29-2.31(m,2H),1.97-2.00(m,2H),1.79-1.85(m,3H),1.43(s,9H),1.05-1.18(m,4H).
(6)
将化合物6(38.0g,126mmol,1.00eq)溶于四氢呋喃(650ml),降温至0℃, 滴加MeMgBr(3M,105ml,2.50eq),然后升温至20℃,反应液搅拌4小时。 TLC(石油醚:乙酸乙酯=1:1,产物:Rf=0.6)监测反应。反应完全后,在反应 液中加入10%硫酸氢钠(35mL),用乙酸乙酯(30ml x 3)萃取,合并有机相 用盐水洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏,得到化合物7粗品 (35.0g)为白色固体。
1H NMR:ET20729-33-P1A1 400MHz CDCl3
4.37-4.38(m,1H),3.36-3.38(m,1H),2.31-2.33(m,2H),2.12(s,3H),1.96-1.99(m,2H),1.74-1.77(m,3H),1.44(s,9H),1.01-1.14(m,4H).
(7)
将化合物7(35.0g,137mmol,1.00eq)溶于乙酸乙酯(240ml),降温至0℃, 滴加HCl/EtOAc(4M,343ml,10.0eq),然后升温至40℃,反应液搅拌3小时。 TLC(石油醚:乙酸乙酯=1:1)监测反应。反应完全后,过滤,滤饼减压干燥, 得到化合物8粗品(20.0g,收率76.1%)为白色固体。
1H NMR:ET20729-36-P1A1 400MHz MeOD
3.02-3.06(m,1H),2.41-2.43(m,2H),2.13(s,3H),1.81-1.86(m,3H),1.39-1.43(m,2H),1.07-1.11(m,2H).
(8)
将化合物8(20.0g,104mmol,1.00eq),二甲氨基甲酰氯 8a(23.2g,229mmol,31.9ml,2.20eq),溶于二氯甲烷(140ml),降温至0℃, 滴加三乙醇胺(23.2g,229mmol,31.9ml,2.20eq),然后升温至20℃,反应液搅 拌12小时。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.4)监测反应。反应完全 后,在反应液中加入水(200mL),用二氯甲烷(100ml x 3)萃取,合并有机相 用盐水洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏,浓缩物过硅胶柱(洗脱剂石油醚:乙酸乙酯=100:1~0:1),得到化合物9(13.0g,收率53.8%,纯 度97.8%)为白色固体。
1H NMR:ET20729-37-P1B2 400MHz MeOD
5.88-5.90(m,1H),3.46-3.49(m,1H),2.87(s,6H),2.37-2.39(m,2H),2.12(s,3H),1.86-1.89(m,2H),1.73-1.77(m,3H),1.21-1.37(m,2H),1.04-1.07(m, 2H).
实施例2化合物10的制备
1.工艺路线:
2.操作方法:
前七步反应与化合物9的制备工艺一致,最后一步反应如下:
将化合物8(20.0g,104mmol,1.00eq),异氰酸钾(11.1g,130mmol,1.25 eq),加入二氯甲烷(500ml)中,加入三乙胺(26.3g,260mmol,2.5eq), 室温下反应12小时。TLC(二氯甲烷:甲醇=5:1,产物:Rf=0.9)监测反应。 反应完全后,减压蒸馏,浓缩物过硅胶柱(洗脱剂石油醚:乙酸乙酯= 100:1~0:1),得到化合物10(11.4g,收率53.6%,纯度97.3%)为白色固体。 1H NMR:ET20729-74-P1A1 400MHz CDCl3
4.80-4.82(m,1H),4.55(s,2H),3.43-3.47(m,1H),2.33-2.34(m,2H),2.13(s,3H),1.96-2.05(m,2H),1.73-1.79(m,3H),1.03-1.17(m,4H).
实施例3 M1的制备:
(1)将化合物9(141.95mg,627.20*10-3mmol,1.00eq),1-(2,3-二氯苯基)哌嗪(167.83mg,627.20*10-3mmol,1.00eq),氰基硼氢化钠(39.41mg,1254.40*10-3 mmol,2.00eq),无水氯化锌(85.49mg,627.20*10-3mmol,1.00eq)溶于甲醇 (20ml),升温至75℃,反应液搅拌30小时。TLC(乙酸乙酯:甲醇=10:1, 产物:Rf=0.3)监测反应。化合物9基本反应完全,加水(50ml),用二氯甲 烷(50ml x 2)萃取,合并有机相用水(50ml)洗涤,无水Na2SO4干燥,过滤, 滤液减压蒸馏(T=55℃),浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1), 得到M1(40m g,TLC单点)为类白色固体。
(2)将化合物9(142.00mg,627.20*10-3mmol,1.00eq),1-(2,3-二氯苯基)哌嗪(167.83mg,627.20*10-3mmol,1.00eq),氰基硼氢化钠(39.41mg,1254.40*10-3 mmol,2.00eq),醋酸(37.63mg,627.20*10-3mmol,1.00eq)溶于甲醇(20ml), 升温至50℃,反应液搅拌10d。TLC(乙酸乙酯:甲醇=10:1,产物:Rf=0.3) 监测反应。化合物9基本反应完全,加水(50ml),用二氯甲烷(50ml x 2) 萃取,合并有机相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸 馏(T=55℃),浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到M1(159m g,纯度98.65%)为类白色固体。
1H NMR:400MHz DMSO
7.50-7.30(m,2H),7.15-7.17(m,1H),5.83-5.85(d,1H),3.54-3.55(m, 1H),3.36-3.31(m,3H),2.75(s,6H),2.65-2.55(m,3H),1.77-1.71(m,4H),1.42(m, 2H),1.29-1.18(m,5H),1.03-1.02(d,1H),0.90-0.93(m,3H).
质谱:+ESI 441.22m/z:440.21
实施例4 M2的制备:
将化合物9(230.55mg,1.02mmol,1.02eq),1-(4氟苯基)哌嗪 (180.40mg,1.00mmol,1.00eq),氰基硼氢化钠(126.53mg,2.01mmol,2.00 eq),无水氯化锌(137.61mg,1.01mmol,1.00eq)溶于甲醇(20ml),升温至75℃, 反应液搅拌27小时。TLC(二氯甲烷:甲醇=20:1,产物:Rf=0.6)监测反应。 化合物9基本反应完全,加水(50ml),用二氯甲烷(50mlx 2)萃取,合并 有机相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃),得粗品360mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到 M2(205m g,98.99%)为土黄色固体。
1H NMR:400MHz DMSO
7.06-7.04(m,2H),6.94(m,2H),5.84-5.82(d,1H),3.30(m,1H),3.04(m, 4H),2.75(s,6H),2.65-2.52(d,4H),1.77-1.71(m,4H),1.43(m,1H),1.29-1.09(m, 5H),0.96-0.93(m,5H).
质谱:+ESI 391.30m/z:390.28
实施例5 M3的制备:
(1)将化合物9(231.54mg,1.02mmol,1.02eq),1-(3氯-4氟苯基)哌嗪二盐酸 盐(287.77mg,1.00mmol,1.00eq),氰基硼氢化钠(173.15mg,2.76mmol,2.76 eq),无水氯化锌(137.45mg,1.01mmol,1.00eq)溶于甲醇(20ml),升温至75℃, 反应液搅拌6d。TLC(二氯甲烷:甲醇=20:1,产物:Rf=0.7)监测反应。化合 物9基本反应完全,加水(50ml),用二氯甲烷(50ml x 2)萃取,合并有机 相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃),得 粗品413mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到M3(115m g,TLC单点)为土黄色固体。
(2)将1-(3氯-4氟苯基)哌嗪二盐酸盐(350mg,1.00mmol,1.00eq)加入1.5ml 水,加入2ml乙酸乙酯,用饱和氢氧化钠水溶液调PH=12左右,萃取,水 相再用乙酸乙酯(2ml x3)萃取,合并有机相用水(5ml)洗涤,有机相减压蒸馏 (T=55℃),得1-(3氯-4氟苯基)哌嗪样品(244mg,收率93.4%),化合物 9(282.98mg,1.25mmol,1.1eq),氰基硼氢化钠(173.15mg,2.76mmol,2.76eq), 无水氯化锌(137.45mg,1.01mmol,1.00eq)溶于甲醇(20ml),升温至75℃,反 应液搅拌30小时。TLC(二氯甲烷:甲醇=20:1,产物:Rf=0.7)监测反应。化 合物9基本反应完全,加水(50ml),用二氯甲烷(50ml x 2)萃取,合并有 机相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃), 得粗品413mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到 M3(115m g,TLC单点)为土黄色固体。
1H NMR:400MHz DMSO
7.25-7.23(m,1H),7.05-7.04(d,1H),6.92-6.90(d,1H),5.83-5.81(d,1H), 3.33(m,1H),3.07(m,4H),2.75(s,6H),2.60-2.51(d,4H),1.77-1.74(m,4H), 1.42-1.39(m,1H),1.29-1.07(m,5H),0.92-0.90(m,5H).
质谱:+ESI 425.25m/z:424.24
实施例6 M4的制备:
将1-(3,4-二氟苯基)哌嗪盐酸盐(260.00mg,1.11mmol,1.00eq)加入1.5ml 水,加入2ml乙酸乙酯,用饱和氢氧化钠水溶液调PH=12左右,萃取,水 相再用乙酸乙酯(2ml x3)萃取,合并有机相用水(5ml)洗涤,有机相减压蒸馏 (T=55℃),得1-(3氯-4氟苯基)哌嗪样品(219.0mg,收率100%),化合物 9(337.21mg,1.33mmol,1.2eq),氰基硼氢化钠(167.27mg,2.65mmol,2.40eq), 无水氯化锌(150.49mg,1.10mmol,1.00eq)溶于甲醇(20ml),升温至75℃,反 应液搅拌27小时。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.8)监测反应。化 合物9基本反应完全,加水(50ml),用二氯甲烷(50ml x 2)萃取,合并有 机相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃), 得粗品507mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到 M4(235m g,纯度98.51%)为类白色固体。
1H NMR:400MHz DMSO
7.25-7.22(m,1H),6.95(d,1H),6.72(d,1H),5.83-5.81(d,1H),3.33(m, 1H),3.07(m,4H),2.75(s,6H),2.60-2.50(d,4H),1.76-1.74(m,4H),1.39(m,1H), 1.27-1.11(m,5H),0.92-0.90(m,5H).
质谱:+ESI 409.29m/z:408.27
实施例7 M7的制备:
(1)将化合物10(198.78mg,1.00mmol,1.00eq),1-(2,3-二氯苯基)哌嗪(268.40mg,1.00mmol,1.00eq),氰基硼氢化钠(126.99mg,2.00mmol,2.00 eq),无水氯化锌(137.30mg,1.01mmol,1.00eq)溶于甲醇(20ml),升温至75℃, 反应液搅拌3d。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.5)监测反应。化合 物10基本反应完全,加水(50ml),用二氯甲烷(50ml x 3)萃取,合并有机 相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃),得 粗品300mg.
(2)将化合物10(247.85mg,1.255mmol,1.00eq),1-(2,3-二氯苯基)哌嗪(292.0mg,1.255mmol,1.00eq),氰基硼氢化钠(157.80mg,2.51mmol,2.00 eq),醋酸(75.4mg,1.255mmol,1.00eq)溶于甲醇(20ml),升温至50℃,反应 液搅拌3d。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.5)监测反应。化合物10 基本反应完全,加水(50ml),用二氯甲烷(50ml x 3)萃取,合并有机相用 水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃),得粗品 500mg,与反应1的粗品合批过硅胶柱(洗脱剂二氯甲烷:甲醇=15:1),得到M7(210m g,纯度98.26%)(交叉段400m g,纯度大于85%)为浅灰色固体。 1H NMR:400MHz DMSO
7.38(m,2H),7.23(d,1H),5.81-5.79(d,1H),5.31(s,2H),3.50(m,3H),3.24(m,2H),3.10-3.06(m,2H),1.81-1.69(m,4H),1.61(m,1H),1.46(m,1H), 1.29-1.19(m,4H),1.17(m,1H),1.07-0.91(m,6H).
质谱:+ESI 413.19m/z:412.18
实施例8 M8的制备:
将化合物10(263.41mg,1.33mmol,1.20eq),1-(4氟苯基)哌嗪 (199.98mg,1.11mmol,1.00eq),氰基硼氢化钠(167.45mg,2.66mmol,2.00 eq),无水氯化锌(151.55mg,1.11mmol,1.00eq)溶于甲醇(20ml),升温至75℃, 反应液搅拌4d。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.4)监测反应。化合 物10基本反应完全,加水(50ml),用二氯甲烷(50ml x3)萃取,合并有机 相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃),得粗品371mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=20:1-15:1),得到 M8(268m g,98.01%)为土黄色固体。
1H NMR:400MHz DMSO
7.06-7.02(m,2H),6.95-6.93(m,2H),5.75-5.73(d,1H),5.28(s,2H),3.22(m,1H),3.04(m,4H),2.69(m,1H),2.50(d,2H),1.81-1.78(d,2H),1.73-1.70 (d,2H),1.43-1.41(m,1H),1.29-1.24(m,1H),1.08-0.91(m,8H).
质谱:+ESI 363.25m/z:362.25
实施例9 M9的制备:
将1-(3氯-4氟苯基)哌嗪二盐酸盐(310.05mg,1.10mmol,1.00eq)加入 1.5ml水,加入2ml乙酸乙酯,用饱和氢氧化钠水溶液调PH=12左右,萃取, 水相再用乙酸乙酯(2ml x3)萃取,合并有机相用水(5ml)洗涤,有机相减压蒸 馏(T=55℃),得1-(3氯-4氟苯基)哌嗪样品(236.0mg,收率100%),化合 物10(262.39mg,1.32mmol,1.20eq),氰基硼氢化钠(138.56mg,2.2mmol,2.00 eq),无水氯化锌(149.93mg,1.10mmol,1.00eq)溶于甲醇(20ml),升温至75℃, 反应液搅拌3d。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.5)监测反应。化合 物10基本反应完全,加水(50ml),用二氯甲烷(50ml x 3)萃取,合并有机 相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸馏(T=55℃),得 粗品416mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=20:1-15:1),得到 M9(193m g,纯度98.83%)为土黄色固体。
1H NMR:400MHz DMSO
7.25-7.20(m,1H),7.05(m,1H),6.93-6.90(m,1H),5.76-5.74(d,1H),5.29(s,2H),3.22(m,1H),3.08(m,4H),2.71(m,1H),2.60(m,2H),2.51(d,2H),1.81-1.79 (d,2H),1.73-1.70(d,2H),1.42-1.38(m,1H),1.28-1.24(m,1H),1.09-0.90(m, 8H).
质谱:+ESI 397.22m/z:396.21
实施例10 M10的制备:
将1-(3,4-二氟苯基)哌嗪盐酸盐(252.00mg,1.05mmol,1.00eq)加入1.5ml 水,加入2ml乙酸乙酯,用饱和氢氧化钠水溶液调PH=12左右,萃取,水 相再用乙酸乙酯(2ml x3)萃取,合并有机相用水(5ml)洗涤,有机相减压蒸馏 (T=55℃),得1-(3氯-4氟苯基)哌嗪样品(209.0mg,收率98.2%),化合物 10(251.73mg,1.27mmol,1.2eq),氰基硼氢化钠(159.44mg,2.53 mmol,2.00eq),无水氯化锌(143.58mg,1.05mmol,1.00eq)溶于甲醇(20ml), 升温至75℃,反应液搅拌4d。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.8)监 测反应。化合物10基本反应完全,加水(50ml),用二氯甲烷(50ml x 3) 萃取,合并有机相用水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压蒸 馏(T=55℃),得粗品382.0mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇= 30:1),得到M10(199m g,纯度98.24%)为类白色固体。
1H NMR:400MHz DMSO
7.26-7.21(m,1H),6.97(m,1H),6.71-6.69(m,1H),5.76-5.74(d,1H),5.29(s,2H),3.24-3.22(m,1H),3.08(m,4H),2.71(m,1H),2.60(m,2H),2.52-2.51(d,2H), 1.81-1.78(d,2H),1.73-1.70(d,2H),1.42-1.38(m,1H),1.30-1.24(m,1H), 1.10-0.92(m,8H).
质谱:+ESI 381.25m/z:380.24
实施例11 M5的制备
将化合物11(300.72mg,1.32mmol,1.00eq),1-(3-三氟甲基苯基)哌嗪(306.28mg,1.32mmol,1.00eq),氰基硼氢化钠(166.25mg,2.64mmol,2.00 eq),无水氯化锌(179.04mg,1.32mmol,1.00eq)溶于甲醇(30ml),升温至75℃, 反应液搅拌28-30小时。TLC(二氯甲烷:甲醇=20:1,产物:Rf=0.7)监测反应。 化合物10基本反应完全,加水(50ml),用二氯甲烷(50ml x 3)萃取,合并 有机相用水(50ml)洗涤,无水Na2SO4干燥30分钟,过滤,滤液减压蒸馏 (T=55℃),得粗品523mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到M5(324.55m g,99.88%)为土黄色固体。
1H NMR:400MHz DMSO
7.43-7.39(m,1H),7.22-7.20(m,1H),7.14(m,1H),7.07-7.05(d,1H),5.85-5.83(d, 1H),3.34(s,1H),3.18(m,1H),3.08(m,4H),2.75(s,6H),2.62(m,2H),2.51(s, 2H),1.74(s,4H),1.43-1.40(m,1H),1.28-1.24(m,1H),1.21-1.10(m,5H), 0.92-0.91(m,5H).
质谱:+ESI 441.29m/z:440.28
实施例12 M6的制备
将化合物9(304.27mg,1.34mmol,1.00eq),1-(苯并[B]噻吩-4基)哌嗪(293.87mg,1.34mmol,1.00eq),氰基硼氢化钠(127.47mg,2.01mmol,1.5eq), 无水氯化锌(183.00mg,1.34mmol,1.00eq)溶于甲醇(30ml),升温至75℃,反 应液搅拌23-25小时。TLC(二氯甲烷:甲醇=20:1,产物:Rf=0.6)监测反应。 化合物9基本反应完全,加水(50ml),用二氯甲烷(50ml x 3)萃取,合并 有机相用水(50ml)洗涤,无水Na2SO4干燥30分钟,过滤,滤液减压蒸馏 (T=55℃),得粗品520mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇=30:1),得到M6(200m g,98.20%)为土黄色固体。
1H NMR:400MHz DMSO
7.71-7.69(m,1H),7.63-7.61(m,1H),7.42(m,1H),7.30-7.26(m,1H), 6.91-6.89(d,1H),5.87-5.85(d,1H),,3.35(m,2H),3.06(m,4H),2.76-2.64(m, 7H),2.58-2.51(m,2H),1.76(s,4H),1.47(s,1H),1.32-1.15(m,(m,5H), 0.98-0.92(m,5H).
质谱:+ESI 429.27m/z:428.26
实施例13 M11的制备
将化合物10(300.00mg,1.51mmol,1.00eq),1-(3-三氟甲基苯基)哌嗪(348.49mg,1.51mmol,1.00eq),氰基硼氢化钠(190.60mg,3.02mmol,2.00 eq),无水氯化锌(208.59mg,1.51mmol,1.00eq)溶于甲醇(30ml),升温至75℃, 反应液搅拌47小时。TLC(二氯甲烷:甲醇=10:1,产物:Rf=0.5)监测反应。 化合物10基本反应完全,加水(50ml),用二氯甲烷(50ml x 4)萃取,合并 有机相用水(50ml)洗涤,无水Na2SO4干燥30分钟,过滤,滤液减压蒸馏 (T=55℃),得粗品535mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇= 30:1-15:1),得到M11(177.25m g,99.23%)为土黄色固体。
1H NMR:400MHz DMSO
7.43-7.39(m,1H),7.22-7.20(m,1H),7.14(m,1H),7.06-7.05(m, 1H),5.77-5.75(d,1H),5.30(s,2H),3.18(m,5H),2.72(m,1H),2.61(m,2H),2.51 (d,3H),1.81-1.78(d,2H),1.73-1.70(d,2H),1.42-1.27(m,2H),1.09-0.90(m, 8H).
质谱:+ESI 413.26m/z:412.25
实施例14 M12的制备
将化合物10(301.15mg,1.52mmol,1.00eq),1-(苯并[B]噻吩-4基)哌嗪(331.50mg,1.52mmol,1.00eq),氰基硼氢化钠(144.53mg,2.28mmol,1.5eq), 无水氯化锌(208.19mg,1.52mmol,1.00eq)溶于甲醇(30ml),升温至75℃,反 应液搅拌23-25小时。TLC(二氯甲烷:甲醇=20:1,产物:Rf=0.6)监测反应。 化合物10基本反应完全,加水(50ml),用二氯甲烷(50ml x 4)萃取,合并 有机相用水(50ml)洗涤,无水Na2SO4干燥30分钟,过滤,滤液减压蒸馏(T=55℃),得粗品540mg,浓缩物过硅胶柱(洗脱剂二氯甲烷:甲醇= 20:1-10:1),得到M12(81m g,98.21%)为土黄色固体。
1H NMR:400MHz DMSO
7.70-7.68(m,1H),7.62-7.60(m,1H),7.42-7.41(m,1H),7.29-7.25(m,1H),6.90-6.88(d,1H),5.79-5.77(d,1H),5.31(s,2H),3.26-3.22(m,1H),3.05(s,4H), 2.74-2.51(m,5H),1.82-1.80(d,2H),1.75-1.72(d,2H),1.47-1.44(m,12H), 1.33-1.30(m,1H),1.10-0.97(m,8H).
质谱:+ESI 401.24m/z:400.23
为了评价本发明化合物的药效活性,进行如下试验例。
试验例1 5HT-2B受体拮抗活性测试
1目的
本研究的目的是通过FLIPR Ca法检测化合物对5HT2B的拮抗活性。
2材料和仪器
2.1材料和试剂
2.2仪器
仪器 | 供应商 | 型号 |
FLIPR TETRA仪器 | Molecular Devices | 0296 |
3实验程序
3.1细胞培养和试剂准备
1)细胞株:Flp-In-CHO-5HT2B stable pool
2)完全培养基:Ham's F-12K+10%FBS+1x青霉素链霉素(PS)+ 600μg/ml潮霉素B.
3)接种培养基:Ham's F-12K+10%透析的FBS.
4)分析缓冲液:1X HBSS+20MM HEPES。
3.2化合物信息
稀释系数:3倍,最终DMSO浓度:0.1%。
3.3IC50测定
1)用完整的培养基培养Flp-In-CHO-5HT2B稳定细胞系,使细胞密度维持 在亚融合状态。
2)将7.5K细胞/孔的25μL细胞接种于384孔细胞培养板(康宁,3764) 中的细胞培养基中,37℃5%二氧化碳浓度下培养。
3)用5mM丙苯酸配制2X A组分,放于室温。
4)使细胞培养板在室温下平衡10分钟,最后一次洗涤步骤后,将培养基换 成测定缓冲液,每孔保留20μl测定缓冲液,然后在每孔中加入20μl 2×A 组分含有5mM的丙苯酸,200g,3-5s,37℃孵育2h。
5)配制参比品和测试品工作液(6x)。
6)将384孔细胞培养板从培养箱中取出,置于室温下10分钟,将10μl6x 测试品工作液加入所示的分析孔中,室温下培养30分钟。
7)制备24nm 5HT工作液(6x)。
8)将10μlof 5HT加入384孔细胞培养板中,立即用FLIPR Tetra采集数 据。
3.4数据分析
1)Z’factor=1-3*(SDMax+SDMin)/(MeanMax-MeanMin);
2)CVMax=(SDMax/MeanMax)*100%;
3)CVMin=(SDMin/MeanMin)*100%;
4)S/B=信号/背景;
5)空白对照(Min):0.1%DMSO
6)阳性对照(Max):100nM的RS-127445
7)IC50值计算方程:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度的对数;Y:比率。
4结果与结论
1)测试质量控制参数通过,结果可靠;
2)试验化合物对于5HT-2B受体均具有拮抗活性,且化合物M1、M9、M11、 M12表现出较为显著的拮抗活性,具体结果列表如下:
化合物编号 | IC50值(nM) |
M1 | 2.44 |
M3 | 4.77 |
M5 | 5.96 |
M6 | 6.02 |
M7 | 9.10 |
M9 | 3.32 |
M11 | 2.62 |
M12 | 3.10 |
试验例2化合物D2L受体活性cAMP分析
1研究摘要
D2L受体的cAMP测定用于确定被测化合物是否对D2L受体具有激动剂活 性,以评价化合物的靶选择性和安全性。
2试剂和消耗品
2.1材料和试剂
2.2仪器
仪器 | 供应商 | 型号 |
EnVision | Perkin Elmer | 2203-1060 |
3实验程序
3.1细胞培养和配方
1)细胞株:Flp-In-CHO-D2L
2)生长培养基:Ham'sF12K+10%FBS+1*Ps+800μg/mlHB
3)分析缓冲液:1X HBSS+20mM HEPES+0.1%BSA+500μM IBMX
3.2化合物信息
化合物编号 | 分子量 | DMSO储存液(mM) |
M1 | 440.21 | 10 |
M3 | 424.24 | 10 |
M5 | 440.28 | 10 |
M6 | 428.26 | 10 |
M7 | 412.18 | 10 |
M9 | 396.21 | 10 |
M11 | 412.24 | 10 |
M12 | 400.23 | 10 |
3.3实验程序
3.3.1细胞培养和播种
1)将Flp-In-CHO-D2L培养于37℃,5%CO2的生长培养基中;
2)按8000个细胞/孔将Flpin-CHO-D2L接种到384孔检测板(6007680-50, PE)中,使用生长培养基
3)将细胞在37C、5%二氧化碳环境下培养过夜。
3.3.2检测
1)制备缓冲液:1*HBSS,0.1%BSA,20mM HEPES和500μM IBMX。
2)在分析缓冲液中制备8*化合物。
3)取出细胞板培养基(第3.3.3步制备),每孔加入15μl分析缓冲液。
4)加入2.5μl化合物(步骤3准备)。37℃孵育5分钟。
5)用分析缓冲液制备8*forskolin。
6)在细胞板中加入2.5μl 8*forskolin。在37℃下培养10分钟。
7)用裂解液配制20*cAMP-d2和20*Anti-cAMP-Eu3+。
8)向细胞板中加入10μl cAMP-d2。然后在细胞板中加入10μl抗 Anti-cAMP-Eu3+。
9)在室温下培养1h。
10)在Envision 2104读板器上,在665nm和615nm的波长读板。
3.4数据分析
1)Z’factor=1-3*(SDMax+SDMin)/(MeanMax-MeanMin);
2)CVMax=(SDMax/MeanMax)*100%;
3)CVMin=(SDMin/MeanMin)*100%;
4)S/B=信号/背景;
5)用GraphPad’s的非线性化公式计算化合物EC50:
Y=Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))
X:化合物浓度的对数;Y:%活性。
4结果与结论
1)测试质量控制参数通过,结果可靠;
2)试验化合物对于多巴胺D2L受体均具有亲和力,且化合物M6、M7、M12表现出较为显著的亲和活性,具体结果列表如下:
化合物编号 | EC50值(nM) |
M1 | 4.70 |
M3 | 2.61 |
M5 | 3.45 |
M6 | 1.26 |
M7 | 1.98 |
M9 | 3.02 |
M11 | 2.10 |
M12 | 0.99 |
试验例3多巴胺D3A均相时间分辨荧光(HTRF)结合分析
1目的
本研究的目的是通过HTRF结合试验测定复方多巴胺D3A的结合能力。
2材料和仪器
2.1材料和试剂
2.2仪器
仪器 | 供应商 | 型号 |
EnVision | Perkin Elmer | 2203-1060 |
3实验程序
3.1化合物信息
稀释系数:3倍,最终DMSO浓度:0.1%。
3.2IC50测定
1)用ddH2O将5x TLB缓冲液稀释至1x。
2)从储存液浓度开始,制备5倍系列稀释的参比化合物和3倍系列稀释的 供试化合物,将160nl稀释的化合物转移到384孔板上,在200g,RT下离 心1分钟,在384孔板上加入40μl 1X TLB,形成4X化合物板。在室温下 搅拌15分钟。
3)用1X TLB将TAG-Lite多巴胺D2红色拮抗剂稀释至12nM(4X)。
4)准备一根含有5毫升1X TLB的15毫升样品管。在37摄氏度水浴中解 冻标记的冷冻细胞,直到冰融化(1-2分钟)。快速将细胞移入15毫升样品 管中,倒转3-5次混合,与1200g,室温,离心5分钟。
5)轻轻吸取上清液(不要倒出上清液)。将细胞再悬浮于1X TLB的1ml 中,用移液枪轻轻混匀10-15次,再加1X TLB的1.7ml,倒转数次搅拌均 匀。
6)每孔加入10μl标记细胞,于200g,室温离心3-5s。
7)将5μl 4x化合物添加到指定的分析孔中;将5μl 4x Tag Lite多巴胺D2 红色拮抗剂添加到每个分析孔中。测定板于200g,室温离心1分钟,室温孵 育7h。
8)用Envision仪通过HTRF模块(激光器)读取和收集数据。
3.3数据分析
1)Ratio=A665nm/B615nm
2)Z’factor=1-3*(SDMax+SDMin)/(MeanMax-MeanMin);
3)CVMax=(SDMax/MeanMax)*100%;
4)CVMin=(SDMin/MeanMin)*100%;
5)阴性对照(高):DMSO(0.1%终浓度)
6)阳性对照(低):1,000nM的PD128907
7)IC50值计算方程:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度的对数;Y:A665nm/B615nm的HTRF比率。
4结果与结论
1)测试质量控制参数通过,结果可靠;
2)试验化合物对于多巴胺D3A受体均具有亲和力,且化合物M1、M5、 M6、M7、M11、M12表现出较为显著的亲和活性,具体结果列表如下:
化合物编号 | IC50值(nM) |
M1 | 0.36 |
M3 | 1.66 |
M5 | 0.98 |
M6 | 0.68 |
M7 | 0.53 |
M9 | 1.29 |
M11 | 0.43 |
M12 | 0.46 |
最后应当说明的是:以上实施例仅用以说明本发明的技术方案而非对其 限制;尽管参照较佳实施例对本发明进行了详细的说明,所属领域的普通技 术人员应当理解:依然可以对本发明的具体实施方式进行修改或者对部分技 术特征进行等同替换;而不脱离本发明技术方案的精神,其均应涵盖在本发 明请求保护的技术方案范围当中。
Claims (10)
2.权利要求1所述的环己烷衍生物或其立体异构体,及其药学上可接受的盐,其特征在于,所述R1和R2独立地选自:氢、卤素、C1-C4烷基、或R1和R2可与相邻的碳原子形成吡咯、噻吩。
优选的,R1和R2独立地选自:氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、甲氧基、乙氧基、或R1和R2可与相邻的碳原子形成噻吩;
更优选的,R1和R2独立地选自:氢、氟、氯、甲基、乙基、环丙基、甲氧基、三氟甲基、或R1和R2可与相邻的碳原子形成噻吩;
R4和R5独立地选自:氢、甲基、乙基。
4.权利要求1所述的环己烷衍生物或其立体异构体,及其药学上可接受的盐,其特征在于,所述药学上可接受的盐为无机酸盐或有机酸盐;
优选地,所述无机酸盐为硫酸盐、盐酸盐、硝酸盐、磷酸盐、或氢溴酸盐;所述有机酸盐为乙酸盐、甲酸盐、甲磺酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、富马酸盐、柠檬酸盐、苯磺酸盐、苯甲酸盐、乳酸盐、苹果酸盐、氨基酸盐中的任一种;
更优选地,所述氨基酸盐为天冬氨酸盐、谷氨酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、脯氨酸盐、色氨酸盐、丝氨酸盐、酪氨酸盐、半胱氨酸盐、蛋氨酸盐、天冬酰胺盐、谷氨酰胺盐、或苏氨酸盐。
6.权利要求1所述化合物或其立体异构体,及其药学上可接受的盐在制备治疗或预防需要调节多巴胺D2、D3和/或5HT-2受体的病症的药物中的应用。
7.权利要求6所述应用,其特征在于,所述需要调节多巴胺受体的病症为:精神病、药物滥用、伴随有认知缺损的精神分裂症、轻度到中度认知缺陷、痴呆、伴随有痴呆的精神病状况、进食障碍、注意力缺陷疾病、儿童多动症、精神病性抑郁症、躁狂症、妄想狂样和妄想类障碍、运动障碍、焦虑、性功能障碍、睡眠障碍、呕吐、攻击、孤独症。
8.权利要求6所述应用,其特征在于,所述精神病为精神分裂症、情感分裂性精神障碍;所述药物滥用为酒精、可卡因、尼古丁、类鸦片的滥用;所述进食障碍为神经性贪食症;所述运动障碍为帕金森病、精神抑制引起的帕金森综合征、迟发性运动障碍。
9.一种药物组合物,其特征在于,含有式I化合物或其立体异构体,或其药学上可接受的盐,以及一种或多种药学上可接受的辅料。
10.权利要求9所述药物组合物,其特征在于,所述组合物是片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂。
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CN101679330A (zh) * | 2007-05-18 | 2010-03-24 | 吉瑞工厂 | (硫代)氨基甲酰基-环己烷衍生物的代谢产物 |
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CN103380122A (zh) * | 2011-02-17 | 2013-10-30 | 霍夫曼-拉罗奇有限公司 | 新苯并间二氧杂环戊烯哌嗪化合物 |
CN105339357A (zh) * | 2013-03-15 | 2016-02-17 | 艾伯维德国有限责任两合公司 | 适用于治疗对多巴胺d3受体的调节有反应的病症的酰基氨基环烷基化合物 |
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CN1829703A (zh) * | 2003-08-04 | 2006-09-06 | 匈牙利吉瑞大药厂 | 作为d3/d2受体拮抗剂的(硫代)氨基甲酰基-环己烷衍生物 |
CN101679330A (zh) * | 2007-05-18 | 2010-03-24 | 吉瑞工厂 | (硫代)氨基甲酰基-环己烷衍生物的代谢产物 |
US20120129870A1 (en) * | 2007-12-17 | 2012-05-24 | Wenying Chai | Piperazinyl derivatives useful as modulators of the neuropeptide y2 receptor |
CN103380122A (zh) * | 2011-02-17 | 2013-10-30 | 霍夫曼-拉罗奇有限公司 | 新苯并间二氧杂环戊烯哌嗪化合物 |
CN105339357A (zh) * | 2013-03-15 | 2016-02-17 | 艾伯维德国有限责任两合公司 | 适用于治疗对多巴胺d3受体的调节有反应的病症的酰基氨基环烷基化合物 |
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