CN102267971B - 脂环并[c]苯并吡喃酮衍生物及其应用 - Google Patents
脂环并[c]苯并吡喃酮衍生物及其应用 Download PDFInfo
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- CN102267971B CN102267971B CN2011102209624A CN201110220962A CN102267971B CN 102267971 B CN102267971 B CN 102267971B CN 2011102209624 A CN2011102209624 A CN 2011102209624A CN 201110220962 A CN201110220962 A CN 201110220962A CN 102267971 B CN102267971 B CN 102267971B
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- benzopyran
- cyclopenta
- dihydro
- butoxy
- piperazine
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Abstract
本发明公开了一种脂环并[c]苯并吡喃酮衍生物及其应用,脂环并[c]苯并吡喃酮衍生物,为式I所示的化合物或其盐。本发明的化合物,既能明显改善MK-801诱导的高活动性,又能有效改善阿扑吗啡诱导的攀爬症状,并且在有效剂量下不引起EPS。由于这些体外作用靶点和体内药理模型与多巴胺功能紊乱导致的神经系统疾病,特别是精神分裂症密切相关,因此本发明涉及的化合物具有治疗神经精神类疾病的作用,尤其对精神分裂症有治疗作用。在MK-801诱导高活动性和阿朴吗啡诱导的攀爬的两个动物模型中ED50更小,作用更强,而且在动物僵住症的模型中ED50更大,治疗指数更大。
Description
技术领域
本发明属于药物化学领域,具体涉及一种脂环并[c]苯并吡喃酮衍生物及其在治疗精神神经疾病中的应用。
背景技术
传统上习惯把通过阻断多巴胺D2受体发挥药理作用的抗精神病药物称为第一代抗精神病药物,即“典型”抗精神病药物(如氟哌啶醇),它们治疗精神分裂症阳性症状有突破性,但未能治疗阴性症状和认知障碍。典型抗精神病药物一般有严重的EPS副作用,并且对三分之一的精神分裂症病人无效。
20世纪60年代以后,又陆续开发了一系列新一代抗精神病药,包括齐拉西酮(Ziprasidone,)、利培酮(Risperidone)等,被称为第二代抗精神病药物,即新型抗精神病药,虽然它们各自的药理作用不完全一致,但却具有共同的药理特征,即对5-羟色胺(5-HT)受体(5-HT1A、5-HT2A、5-HT2C)和去甲肾上腺素(NA)受体(α1、α2)的亲和力远比对D2受体的要高,导致D2/5-HT2A的比值较低。其临床效果与第一代抗精神病药物相比有更多优势,不但对阳性症状与传统抗精神病药同样有效,而且对阴性症状、认知缺陷症状有效,作用谱更广,但是这些药物有QT间隙延长,高泌乳素血症和体重增加等不良反应。因此寻找能对精神分裂症阳性、阴性症状和认知障碍有效,而且副作用小的药物是现在研究的热点。
5-羟色胺系统在调节的前额叶皮层(PFC)的功能中起着重要作用,包括情绪控制,认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度羟色胺受体亚型5-HT1A和5-HT2A。最近得到证明PFC和NMDA受体通道是5-HT1AR的目标,这两个受体调节大脑皮层兴奋性神经元,从而影响认知功能。实际上,各种临床前数据表明5-HT1AR可能是抗精神病药发展药物的新目标。非典型抗精神药物(如olanzapine,aripiprazole等)对5-HT1AR的高亲和力及其低的EPS副作用均说明5-羟色胺系统在调节的前额叶皮层(PFC)的功能中起着重要作用,包括情绪控制、认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度5-羟色胺受体亚型5-HT1A和5-HT2A。最近研究表明5-HT1A激动剂与非典型抗精神病药物治疗相关,能改善阴性症状和认知障碍。在应用非典型抗精神病药物氯氮平治疗精神分裂症中,人们发现5-HT2A在其中起着很重要的作用,涉及到感知、情绪调节以及运动控制的各个方面。阻断5-HT2A受体可使多巴胺的释放正常化,而起到抗精神病作用。另外,5-HT2C受体与体重增加密切相关。
D3受体在脑内的分布情况主要选择性分布于边缘系统,脑内有两条主要DA神经通路,一条是黑质纹状体通路,调控运动功能,另一条是中脑腹侧被盖区伏隔核前额叶皮层DA通路,与学习认知和情感活动密切相关,其功能异常将导致精神分裂症,该DA通路也是脑内奖赏效应(reward efects)的主要通路,D3R在两条DA神经通路中都有分布,并和其他DA受体亚型间存在着复杂相互作用,可能作为抗精神病药物治疗的一个目标,选择性D3受体的拮抗作用能减少精神分裂症的消极和认知症状,此外能阻止锥体外系副作用,包括迟发性运动障碍,帕金森病。因此,寻找一个多受体结合副作用小的抗精神分裂症药物对临床治疗具有重要意义。
发明内容
本发明的目的之一是公开一种脂环并[c]苯并吡喃酮衍生物,提供一种新的具有更好药学活性的脂环并[c]苯并吡喃酮衍生物,以满足临床应用的需要。
本发明的另一目的是提供一种上述脂环并[c]苯并吡喃酮衍生物在制备治疗神经精神类疾病药物方面的应用。
本发明所述的脂环并[c]苯并吡喃酮衍生物,为式I所示的化合物或其盐:
其中:
n1为1,2或3;
n2为3,4或5;
X为CH或N;
Ar为式II或式III;
其中:
Q为O或S;
R1,R2,R3,R4或R5分别独立地代表氢、卤素、C1-C5的烷基、取代的C1-C5的烷基或C1-C5的烷氧基,取代的C1-C5的烷基的取代基为卤素,优选的取代基为氟;
优选的,所述C1-C5的烷基为甲基;
优选的,所述的取代的C1-C5的烷基为三氟甲基;
优选的,所述C1-C5的烷氧基为甲氧基;
优选的,R1,R2,R3,R4或R5所代表的卤素为氯或氟;
在式I中,当n1为1或2,n2为3或4时,R1或R2选自氢、卤素或C1-C5的烷基,优选氢、氯或甲基;
在式I中,当Ar为式II时,X为N,R3或R4选自氢、卤素、取代的C1-C5的烷基、C1-C5的烷基或C1-C5的烷氧基,取代的C1-C5的烷基的取代基为卤素,优选的R3或R4选自氢、氯、氟、甲基、三氟甲基或甲氧基;
在式I中,当Ar为式III时,Q优选O或S,X选自N或CH,R5选自氢或卤素,优选氢或氟;
上述脂环并[c]苯并吡喃酮衍生物,优选如下化合物或其盐:
(1)7-{3-[4-(2,3-二甲基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(2)7-{3-[4-(2,3-二氯苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(3)7-{3-[4-(3-三氟甲基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(4)7-{3-[4-(2-甲氧基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(5)7-{3-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基]}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(6)7-{3-[4-(2-甲氧基苯基)哌嗪-1-基]-丙氧基}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(7)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(8)7-{4-[4-(4-甲氧基苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(9)7-{4-[4-(4-氟苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮;
(10)10、7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(11)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(12)7-{4-[4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-丁氧基]}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(13)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(14)7-{4-[4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基]}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(15)7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(16)7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-8-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(17)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基-丁氧基]}-8-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(18)3-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮、
(19)3-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮;
(20)3-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-4-甲基-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮或
(21)3-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-4-甲基-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮。
所述的盐为含有药物上可接受的阴离子盐:如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐或硫酸氢盐、磷酸盐或酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐等。
所述脂环并[c]苯并吡喃酮衍生物的制备方法,包括如下步骤:
先合成脂环并[c]苯并吡喃酮的母体,然后通过一个碳链与哌嗪基或哌啶基取代的1,2-苯并异噁唑或1,2-苯并异噻唑连接而成,反应通式如下:
试剂和反应条件:
(i)无水甲醇,浓硫酸,回流;
(ii)无水三氯化铝,三乙胺,二氯甲烷,室温;
(iii)五水硝酸铋,80℃;
(iv)1,3二溴丙烷或1,4二溴丁烷,无水碳酸钾,丙酮,回流;
(v)乙腈,无水碳酸钾,碘化钾,回流。
其中:起始原料
购自阿拉丁试剂;
反应通式中,
n1、n2、X、Ar、Q、R1,R2和R3的定义如前所述;
本发明还涉及一种药物组合物,其包含治疗有效量的式I化合物或其盐和药学上可接受的载体,所述载体,如香料、甜味剂、液体或固体填料或稀释剂等常用载体物质,并可采用本领域公知的方法,制成常见的药用制剂,如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂或针剂,制剂通常含有重量百分比为1-99%的有效成分;
体外证明,本发明所涉及的化合物物对多巴胺D2,D3,5HT1A和5HT2A受体具有较高的亲和力,而与5HT2C的亲和力低,本发明的脂环并[c]苯并吡喃酮衍生物,既能明显改善MK-801诱导的高活动性,又能有效改善阿扑吗啡诱导的攀爬症状,并且在有效剂量下不引起EPS。由于这些体外作用靶点和体内药理模型与多巴胺功能紊乱导致的神经系统疾病,特别是精神分裂症密切相关,因此本发明涉及的化合物具有治疗神经精神类疾病的作用,尤其对精神分裂症有治疗作用。可应用于制备治疗或预防神经精神类疾病药物,所述神经精神类疾病包括精神障碍、焦虑症、人格障碍、抑郁症、狂躁症、偏头痛、癫痫或痉挛性障碍、儿童期障碍、帕金森病、认知障碍、神经变性、神经毒性和局部缺血,优选精神分裂症。
本发明涉及所述的衍生物还可能用于制备其他中枢神经系统疾病药物,例如用于治抑郁症、记忆障碍以及与智力、学习相关的功能障碍性疾病的药物。
本发明的环并[c]苯并吡喃酮衍生物或其盐,可经口服或静脉注射,施加于需要治疗的患者,剂量一般为0.001~30mg/kg体重天,具体可根据患者的年龄、病情等,具体由医师决定。
本发明中式I表示的化合物,既能明显改善MK-801诱导的高活动性,又能有效改善阿扑吗啡诱导的攀爬症状,并且在有效剂量下不引起EPS。由于这些体外作用靶点和体内药理模型与多巴胺功能紊乱导致的神经系统疾病,特别是精神分裂症密切相关,因此本发明涉及的化合物具有治疗神经精神类疾病的作用,尤其对精神分裂症有治疗作用。
式I的化合物是对申请号为201110080555.1的已申请专利所涉及的苯并吡喃酮类衍生物的发展和改进。本发明的优选化合物与D2,D3,5HT1A和5HT2A受体亲和力更高,与5HT2C受体亲和力低,在MK-801诱导高活动性和阿朴吗啡诱导的攀爬的两个动物模型中ED50更小,作用更强,而且在动物僵住症的模型中ED50更大,治疗指数更大。动物模型比较和体外受体结果比较分别列于表5和表6。
具体实施方式
下面的实施例只是以说明为目的而不作为本发明的限制。
实施例1
7-{3-[4-(2,3-二甲基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
1)7.3g己二酸(50mmol)和40ml无水甲醇加入到烧瓶中,在搅拌下缓慢滴加2ml浓硫酸,加热,回流反应5小时,冷却至室温,减压蒸去溶剂,用30ml二氯甲烷和25ml水稀释,水层用二氯甲烷(30mlX2)萃取,合并有机层,有机层用饱和的碳酸氢钠溶液洗至中性,然后用饱和NaCl洗涤,用无水硫酸镁干燥,过滤,减压蒸去溶剂,得己二酸二甲酯8g,收率91.9%。
2)取己二酸二甲酯8.7g(50mmol),无水三氯化铝(20g),100ml干燥的二氯甲烷,在冰浴下冷却至0℃.在0℃条件下缓慢滴加三乙胺(氢氧化钠干燥,45ml),滴加完毕,撤去冰浴,在室温下反应4小时,TLC监测反应完毕,将反应液缓慢倾入冰水混合物中,搅拌30分钟,分出有机层,水层用二氯甲烷(50mlX2)萃取,合并有机层,有机层用水洗,然后用饱和NaCl洗涤,用无水硫酸镁干燥,过滤,减压蒸去溶剂,得2-氧代环戊羧酸甲酯5.1g,收率71.8%。
3)取2-氧代环戊羧酸甲酯7.1g(50mmol),间苯二酚5.5g(50mmol),五水硝酸铋,加热至80℃,反应4小时,停止反应,冷至室温,将反应液倾入水中,有浅黄色固体析出,搅拌30分钟,过滤,得固体,用95%的乙醇重结晶的白色固体5.8g,收率57.4%。
4)取第三步产物5g,无水碳酸钾6g,丙酮50ml,1,3-二溴丙烷8g,加热回流反应6小时,冷至室温,过滤,蒸干溶剂,得浅黄色油状物,过柱得白色固体5g。
5)取第二步产物0.51g,加入2,3-二甲基苯基哌嗪盐酸盐0.61g,无水碳酸钾2g,碘化钾0.2g和乙腈25ml,加热回流反应12小时,冷至室温,蒸干溶剂,加入适量二氯甲烷,水洗,分去水层,有机层加无水硫酸镁干燥,蒸干溶剂,得浅黄色油状物,柱层析得白色固体0.48g。
1H NMR(CDCl3)δ2.03-2.26(m,10H),2.59-2.66(m,6H),2.89-3.04(m,8H),4.11(t,2H,J=12.8Hz),6.84-6.94(m,4H),7.06-7.08(m,1H),7.33(d,1H,J=8.4Hz)MS(ESI)m/z 433.3([M+H]+).
实施例2
7-{3-[4-(2,3-二氯苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2,3-二甲基苯基哌嗪盐酸盐换成2,3-二氯苯基哌嗪盐酸盐,按实施例1的方法制备目标化合物。
1H NMR(CDCl3)δ2.03-2.23(m,4H),2.60-2.68(m,6H),2.89(t,2H,J=15.2Hz),3.02-3.08(m,6H),4.11(t,2H,J=12.4Hz),6.84-6.98(m,3H),7.14-7.16(m,2H),7.33(d,1H,J=8.4Hz)MS(ESI)m/z 473.2([M+H]+).
实施例3
7-{3-[4-(3-三氟甲基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2,3-二甲基苯基哌嗪盐酸盐换成3-三氟甲基苯基哌嗪盐酸盐,按实施例1的方法制备目标化合物。
1H NMR(CDCl3)δ2.03-2.23(m,4H),2.59-2.66(m,6H),2.89(t,2H,J=14.8Hz),3.04(t,2H,J=15.8Hz),3.26(t,4H,J=10Hz),4.11(t,2H,J=12.4Hz),6.84-6.87(m,2H),7.06-7.11(m,3H),7.32-7.34(m,2H)
MS(ESI)m/z 473.3([M+H]+).
实施例4
7-{3-[4-(2-甲氧基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2,3-二甲基苯基哌嗪盐酸盐换成2-甲氧基苯基哌嗪盐酸盐,按实施例1的方法制备目标化合物。
1H NMR(CDCl3)δ2.05-2.21(m,4H),2.62(t,2H,J=14.4Hz),2.70(s,br,4H),2.87-2.89(m,2H),3.02-3.12(m,6H),3.87(s,3H),4.10(t,2H,J=12.4Hz),6.84-7.00(m,6H),7.32-7.34(m,1H)
MS(ESI)m/z 435.3([M+H]+).
实施例5
7-{3-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基]}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2,3-二甲基苯基哌嗪盐酸盐换成6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐,按实施例1的方法制备目标化合物。
1H NMR(CDCl3)δ1.90-2.20(m,10H),2.61(t,2H,J=14.8Hz),2.88-2.91(m,2H),3.03-3.11(m,5H),4.11(t,2H,J=12.4Hz),6.85-6.87(m,2H),7.06-7.07(m,1H),7.23-7.35(m,2H),7.70-7.73(m,1H)
MS(ESI)m/z 463.3([M+H]+).
实施例6
7-{3-[4-(2-甲氧基苯基)哌嗪-1-基]-丙氧基}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
用2-甲基间苯二酚为原料,按实施例4的方法制备目标化合物。
1H NMR(CDCl3)δ2.06-2.21(m,4H),2.33(s,3H),2.65-3.12(m,14H),3.87(s,3H),4.13(t,2H,J=12.8Hz),6.83-7.01(m,5H),7.22-7.27(m,1H)
MS(ESI)m/z 449.3([M+H]+)
实施例7
7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例4的方法制备目标化合物。
1H NMR(CDCl3)δ1.74-1.89(m,4H),2.19-2.21(m,3H),2.52(t,2H,J=14.4Hz),2.71(s,br,4H),2.87-2.90(m,2H),3.02-3.13(m,5H),3.86(s,3H),4.05(t,2H,J=12.4Hz),6.83-7.00(m,6H),7.32-7.34(m,4H)
MS(ESI)m/z 449.3([M+H]+)
实施例8
7-{4-[4-(4-甲氧基苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2-甲氧基苯基哌嗪盐酸盐换成4-甲氧基苯基哌嗪盐酸盐,按实施例7的方法制备目标化合物。
1H NMR(CDCl3)δ1.71-1.87(m,4H),2.19(t,2H,J=14.8Hz),2.47(t,2H,J=14.8Hz),2.62-2.64(m,4H),(t,4H,J=10Hz),2.89(t,2H,J=15.2Hz),3.04(t,2H,J=15.2Hz),3.09-3.11(m,4H),3.77(s,3H),4.05(t,2H,J=12.4Hz),6.82-6.92(m,6H),
7.32(d,1H,J=8.4Hz)
MS(ESI)m/z 449.3([M+H]+)
实施例9
7-{4-[4-(4-氟苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮将2-甲氧基苯基哌嗪盐酸盐换成4-氟苯基哌嗪盐酸盐,按实施例7的方法制备目标化合物。
1H NMR(CDCl3)δ1.71-1.89(m,4H),2.19(t,2H,J=15.2Hz),2.47(t,2H,J=14.8Hz),2.62(t,4H,J=10Hz),2.88(t,2H,J=14.8Hz),3.03(t,2H,J=15.2Hz),
3.12(t,2H,J=9.6Hz),4.05(t,2H,J=12.4Hz),6.82-6.97(m,6H),7.32(d,1H,J=9.2Hz)
MS(ESI)m/z 437.2([M+H]+)
实施例10
7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2-甲氧基苯基哌嗪盐酸盐换成6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐,按实施例7的方法制备目标化合物。
1H NMR(CDCl3)δ1.74-1.88(m,4H),2.06-2.21(m,8H),2.48(t,2H,J=14.8Hz),2.87-2.89(m,2H),3.02-3.10(m,5H),4.06(t,2H,J=12.4Hz),6.83-6.86(m,2H),7.04-7.05(m,1H),7.22-7.27(m,1H),7.33(d,1H,J=9.2Hz),7.68-7.71(m,1H)
MS(ESI)m/z 477.3([M+H]+)
实施例11
7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
用1,4-二溴丁烷代替1,3-二溴丙烷,按实施例6的方法制备目标化合物。
1H NMR(CDCl3)δ1.76-1.90(m,4H),2.16-2.20(m,2H),2.33(s,3H)2.51(t,2H,J=14.8Hz),2.67(s,br,4H),2.87-2.90(m,2H),3.00-3.10(m,5H),3.86(s,3H),4.08(t,2H,J=12Hz),6.80-6.99(m,5H),7.21-7.23(m,1H)
MS(ESI)m/z 463.3([M+H]+)
实施例12
7-{4-[4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-丁氧基]}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2-甲氧基苯基哌嗪盐酸盐换成3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐,按实施例11的方法制备目标化合物。
1H NMR(CDCl3)δ1.78-1.92(m,4H),2.17-2.21(m,2H),2.34(s,3H),2.54(t,2H,J=14.4Hz),2.69-2.72(m,4H),2.89-3.03(m,4H),3.57-3.59(m,4H),4.10(t,2H,J=12.4Hz),6.81-6.83(m,1H),7.22-7.27(m,1H),7.34-7.37(m,1H),
7.45-7.49(m,1H),7.80-7.82(m,1H),7.90-7.92(m,1H)
MS(ESI)m/z 490.3([M+H]+)
实施例13
7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
用2-氯间苯二酚代替2-甲基间苯二酚为原料,按实施例11的方法制备目标化合物
1H NMR(CDCl3)δ1.78-1.96(m,4H),2.18-2.22(m,2H),2.51(t,2H,J=14.8Hz),2.67(s,br,4H),2.87-2.90(m,2H),3.01-3.10(m,5H),3.86(s,3H),4.16(t,2H,J=12.4Hz),6.87-6.93(m,5H),7.26-7.28(m,1H)MS(ESI)m/z 483.3([M+H]+)
实施例14
7-{4-[4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基]}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2-甲氧基苯基哌嗪盐酸盐换成3-(1-哌嗪基)-1,2-苯并异噻唑盐酸盐,按实施例13的方法制备目标化合物。
1H NMR(CDCl3)δ1.76-2.20(m,6H),2.54(t,2H,J=14.4Hz),2.68-2.70(m,4H),2.85-2.99(m,2H),3.01-3.03(m,2H),3.55(s,br,4H),4.17(t,2H,J=12Hz),6.85-6.88(m,1H),7.24-7.36(m,2H),7.43-7.47(m,1H),7.77-7.80(m,1H),7.88-7.91(m,1H)
MS(ESI)m/z 510.2([M+H]+)
实施例15
7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
将2-甲氧基苯基哌嗪盐酸盐换成6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐,按实施例13的方法制备目标化合物。
1H NMR(CDCl3)δ1.76-2.23(m,12H),2.51(t,2H,J=14.8Hz),2.87-2.90(m,2H),3.02-3.11(m,5H),4.17(t,2H,J=12.4Hz),6.88-6.91(m,1H),7.04-7.05(m,1H),7.22-7.30(m,2H),7.68-7.72(m,1H)
MS(ESI)m/z 511.3([M+H]+)
实施例16
7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-8-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮
用4-氯间苯二酚代替2-氯间苯二酚为原料,按实施例15的方法制备目标化合物。
1H NMR(CDCl3)δ1.79-2.23(m,12H),2.51(t,2H,J=14.4Hz),2.88-2.92(m,2H),3.00-3.09(m,5H),4.12(t,2H,J=12.4Hz),6.88-6.89(m,1H),7.03-7.05(m,1H),7.23-7.27(m,1H),7.42(s,1H),7.68-7.72(m,1H)
MS(ESI)m/z 511.3([M+H]+)
实施例17
7-{4-[4-(2-甲氧基苯基)哌嗪-1-基-丁氧基]}-8-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮将6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐换成2-甲氧基苯基哌嗪盐酸盐,按实施例16的方法制备目标化合物。
1H NMR(CDCl3)δ1.69-1.95(m,6H),2.19-2.23(m,2H)2.51(t,2H,J=14.8Hz),2.68(s,br,3H),2.88-2.91(m,2H),3.00-3.10(m,5H),3.86(s,3H)4.12(t,2H,J=12.4Hz),6.85-7.00(m,5H),7.41(s,1H)
MS(ESI)m/z 483.3([M+H]+)
实施例18
、3-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮将己二酸换成庚二酸,按实施例10的方法制备目标化合物。
1H NMR(CDCl3)δ1.67-1.87(m,10H),2.06-2.13(m,4H),2.47(t,2H,J=14.8Hz),2.56(t,2H,J=8.8Hz),2.75(t,2H,J=8.8Hz),3.07-3.10(m,3H),4.05(t,2H,J=12.8Hz),6.80-6.85(m,2H),7.04-7.05(m,1H),7.22-7.25(m,1H),7.45(d,1H,J=8.4Hz),
7.68-7.71(m,1H)
MS(ESI)m/z 491.3([M+H]+)
实施例19
3-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮将6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐换成2-甲氧基苯基哌嗪盐酸盐,按实施例18的方法制备目标化合物。
1H NMR(CDCl3)δ1.73-1.87(m,8H),2.47-2.74(m,10H),3.11(s,br,4H),3.86(s,3H)4.04(t,2H,J=12.4Hz),6.78-6.99(m,6H),7.43-7.45(m,1H)
MS(ESI)m/z 463.3([M+H]+)
实施例20
3-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-4-甲基-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮用2-甲基间苯二酚代替间苯二酚为原料,按实施例19的方法制备目标化合物。
1H NMR(CDCl3)δ1.76-1.88(m,8H),2.32(s,3H),2.48-2.75(m,10H),3.11(s,br,4H),3.87(s,3H),4.08(t,2H,J=12.4Hz),6.80-7.00(m,5H),7.35(d,1H,J=8.8Hz)MS(ESI)m/z 477.3([M+H]+)
实施例21
3-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-4-甲基-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮
用2-甲基间苯二酚代替间苯二酚为原料,按实施例18的方法制备目标化合物。
1H NMR(CDCl3)δ1.78-1.88(m,8H),2.07-2.08(m,6H),2.32(s,3H)
2.48(t,2H,J=7.6Hz),2.57-2.75(m,4H),3.08-3.10(m,3H),4.08(t,2H,J=12Hz),
6.81-6.83(m,1H),7.05-7.06(m,1H),7.23-7.26(m,1H),7.35-7.37(m,1H),
7.68-7.71(m,1H)
MS(ESI)m/z 505.3([M+H]+)
表1.实施例制备的优选化合物编号、结构式和相应的基团
实施例22
5HT1A膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含0.1%的抗坏血酸、10um优降宁和4mM CaCl2)于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液(0.05M的Tris-HCl缓冲液,含0.1%的抗坏血酸、10um优降宁和4mM CaCl2),于37℃孵化10min,孵化完后试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3ml B液,用旋涡混合器混匀,再加入5ml C液,离心,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃储存备用。
受体结合实验材料:
同位素配基3H-8-OH-DPAT(67.0Ci/mmol),购自PerkinElmer公司;5-HT,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,匀浆液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入5-HT 100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体3H-8-OH-DPAT 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵10min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2。
实施例23
5HT2A膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液:取6.05gTris溶于1000ml双蒸水中,用浓HCl调PH为7.5)于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液,于37℃孵化10min,孵化完后试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3mlA液,用旋涡混合器混匀,再加入5ml缓冲液,离心,(重复三次离心),离心完毕,弃上清液,将沉淀于-80℃储存备用。
受体结合实验材料:
同位素配基[3H]-Ketanserin(67.0Ci/mmol),购自PerkinElmer公司;Methysergide,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,缓冲液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入Methysergide100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体3H-Ketanserin 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵15min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2。
实施例24
D2膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含NaCl 120mM、KCl 5mM、MgCl21mM、CaCl21mM),于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液,将匀浆完的试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3mlB液,用旋涡混合器混匀,再加入5mlB液,离心,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃储存备用。受体结合实验材料:
同位素配基3H-Spiperone(67.0Ci/mmol),购自PerkinElmer公司;Butaclamol,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,缓冲液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入100μL Butaclamol(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体3H-Spiperone 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵20min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2。
实施例25、D3受体实验
细胞
HEK-293细胞,经48-72小时后受体蛋白在膜上大量表达,将细胞1000rpm离心5min后弃上清,收胞体,存放于-200C冰箱保存。实验时用Tris-Cl(pH 7.4)重悬。
实验材料:
D3受体同位素配基[3H]-Spiperone,购自Amersham公司;(+)Butaclamol,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;脂溶性闪烁液。Tris由吉泰科技有限公司分装。
实验方法:
受体竞争结合实验:将待测化合物与放射性配基各20ul及160ul受体蛋白加入反应试管中,使受试化合物及阳性药物终浓度均为10μmol/L,30℃水浴孵育50min后,即刻移至冰浴终止其反应;在Millipore细胞样品收集器上,经过GF/C玻璃纤维滤纸快速抽滤,并用洗脱液(50mM Tris-HCl,PH 7.4)3ml X3次,用微波炉4~5min烘干,将滤纸移入0.5ml离心管中,加入500ul脂溶性闪烁液。避光静置30min以上,计数测定放射性强度。按以下公式计算各化合物对同位素配基结合的抑制率百分率:
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
实验结果见表2。
实施例26、5HT2C膜的制备
大鼠断头,冰上操作,迅速取脑纹状体,将2个纹状体合到一根离心试管中,加入3ml缓冲液(0.05M的Tris-HCl缓冲液:取6.05gTris溶于1000ml双蒸水中,用浓HCl调PH为7.5)于4档3-4s匀浆,匀浆4次,然后加入5ml缓冲液,于37℃孵化10min,孵化完后试管用天平调整重量,在12000r,4℃离心20min,弃上清液,加入3mlA液,用旋涡混合器混匀,再加入5ml缓冲液,离心,(重复三次离心),离心完毕,弃上清液,将沉淀于-80℃储存备用。
受体结合实验材料:
同位素配基[3H]-mesulergine(67.0Ci/mmol),购自PerkinElmer公司;mianserin,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)先将制备好的膜用适量的匀浆液,用匀浆机分散均匀,将15只试管混入到100ml的容器中,加入适量的匀浆液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL,缓冲液100μL。
(3)总结合管(TB)加入100μL匀浆液,非特异性结合管(NB)加入mianserin 100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M);
(4)各反应管分别加入放射性配体[3H]-mesulergine 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管37℃温孵15min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀;
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。
实验结果见表2。
体外实验结果表明化合物7对四种受体(D2,D3,5HT1A和5HT2A)较强的亲和力,而对5HT2C的亲和力低。
实施例27、MK-801诱导的高活动性化合物体内抗精神分裂活性
实验动物及试剂
健康昆明种小鼠,雌雄各半,体重(20±2)g,由南京青龙山动物养殖中心提供。
抗坏血酸,国药集团化学试剂有限公司;
MK-801,由美国Sigma公司生产,配制方法:用0.1%的维生素C配成1mg/ml的溶液;
受试阳性药物:氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平;
吐温80,浓度10%。
实验方法
选择体重合格的小鼠,随机分为空白组、模型组、阳性对照组(利培酮组)、药物组。空白组、模型组灌胃10%吐温0.1ml/10g,阳性对照组灌胃给利培酮0.1mg/kg,药物组分别灌胃给与相应剂量药物。给药后1h空白组腹腔注射0.1%抗坏血酸0.1ml/10g,模型组、阳性对照组(30min)、药物组腹腔注射MK-801溶液0.1mg/kg。其后测定各组小鼠90分钟内自发活动。
实验结果见表3。
本实验结果表明:与模型组相比,利培酮,化合物7既能明显改善MK-801诱导的高活动性,又能有效的改善阿扑吗啡诱导的攀爬症状,并且在有效剂量下不引起EPS,表明其有明显的抗精神分裂作用。
实施例28、阿扑吗啡诱导小鼠攀爬实验
实验动物
健康KM小鼠,雄性,体重18~22g,由南京青龙山动物养殖中心提供。
主要试剂
受试阳性药物:氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平;
阿扑吗啡,Sigma公司提供,临用前0.9%NaCl(含0.1%维生素C)溶解,现配现用;
维生素C,F20061113,国药集团化学试剂有限公司;
氯化钠注射液,H32026305,徐州市第五制药厂有限公司。
仪器:自制攀爬笼,秒表。
实验方法:阿扑吗啡诱导小鼠攀爬实验
KM小鼠,雄性,体重18~22g,随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组(具体给药剂量见表4),每组10只。阴性对照组和模型组灌胃给予相应溶剂双蒸水,阳性药物组灌胃给予相应阳性药物(溶解时先加微量乙酸,再加双蒸水),化合物各剂量组灌胃给予相应剂量化合物,灌胃体积为0.1ml/10g。灌胃给药1小时后皮下注射阿扑吗啡(1mg/kg),体积为0.1ml/10g。注射阿扑吗啡后,立即放入攀爬笼中,适应5分钟,观察注射阿扑吗啡后第10-11,20-21,30-31分钟的行为并进行评分,评分标准:四足在地板上得分为0;两前足在网笼上得分为1;四只足在网笼上得分为2。
实施例29、僵住症实验方法
实验动物
健康昆明种小鼠,雌雄各半,(22±2)g,由南京青龙山动物养殖中心提供。
主要试剂:
受试药、氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮
仪器:
自制抓棒器材:小鼠盒内放置直径0.3cm,高于工作台5cm的不锈钢棒。
实验方法:
KM小鼠,雌雄各半,体重20~24g,随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组,每组10只。阴性对照组和模型组灌胃给予相应溶剂双蒸水,阳性药物组灌胃给予相应阳性药物(溶解时先加微量乙酸,再加双蒸水),化合物各剂量组灌胃给予相应剂量化合物,灌胃体积为0.1ml/10g。灌胃给药30min、60min、90min时,将小鼠两只前爪轻柔地放在长20cm,直径0.3cm,高于工作台5.5cm的小棒上,再将动物后肢轻放于盒底面,记录小鼠两只前爪在棒上保持姿势的持续时间,以30s僵直不动为阳性反应。如果小鼠前爪一直没有放下,60s时终止观察。统计每个化合物剂量组阳性反应动物数。
实施例30、急性毒性研究
序贯法之限度实验取KM小鼠,雌雄各半,随机分为若干组,每组2-5只,分别为各化合物2000mg/kg组和溶剂组,按0.2ml/10g灌胃给药。观察动物3日内的死亡情况。(如果动物在三日内有3只或3只以上存活,生命状态无明显异常时,继续观察,直至7日后实验结束。如果动物在三日内死亡3只或3只以上时,采用半数致死量法测定其LD50。)
半数致死量法预试验取KM小鼠,雌雄各半,随机分若干组,每组4只,分别为各化合物1500mg/kg、1000mg/kg、500mg/kg组和溶剂组,按0.2ml/10g灌胃给药,观察动物1-3日内的死亡情况。
结果:化合物7的小鼠单次灌服的LD50大于2000mg/kg,与齐拉西酮(>2000mg/kg)相当,远远高于利培酮(82.1mg/kg)和阿立哌唑(93mg/kg),具有较小的急性毒性。
表2化合物对各受体的抑制率或IC50
(注:a表示单元格中数据为IC50值)
表3.优选化合物体内动物模型试验结果
表5.动物模型比较
表6.体外受体结果比较
实施例31、片剂
原辅料过80目筛备用,称取处方量活性成分、微晶纤维素、乳糖、聚维酮K30,加入到高速混合制剂机中,低速搅拌混合均匀,加入适量纯化水,低速搅拌,高速切割制粒,湿颗粒60℃干燥3h,24目筛整粒,加入处方量羧甲淀粉钠、二氧化硅和硬脂酸镁,总混,旋转压片机压片。
实施例32、胶囊剂
原辅料过80目筛备用,称取处方量活性成分、乳糖、淀粉、聚维酮K30,加入到高速混合制剂机中,低速搅拌混合均匀,加入适量纯化水,低速搅拌,高速切割制粒,湿颗粒60℃干燥3h,24目筛整粒,加入处方量二氧化硅和硬脂酸镁,总混,胶囊灌装机填充胶囊。
Claims (19)
2.根据权利要求1所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,取代的C1-C5的烷基的取代基为氟。
3.根据权利要求2所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,所述的取代的C1-C5的烷基为三氟甲基。
4.根据权利要求1所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,所述C1-C5的烷基为甲基。
5.根据权利要求3所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,所述C1-C5的烷基为甲基。
6.根据权利要求1所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,所述C1-C5的烷氧基为甲氧基。
7.根据权利要求5所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,所述C1-C5的烷氧基为甲氧基。
8.根据权利要求1~7任一项所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,R1,R2,R3,R4或R5所代表的卤素为氯或氟。
9.根据权利要求8所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,在式I中,当n1为1或2,n2为3或4时,R1或R2选自氢、卤素或C1-C5的烷基。
10.根据权利要求9所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,R1或R2选自氢、氯或甲基。
11.根据权利要求8所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,在式I中,当Ar为式II时,X为N,R3或R4选自氢、卤素、取代的C1-C5的烷基、C1-C5的烷基或C1-C5的烷氧基,取代的C1-C5的烷基的取代基为卤素。
12.根据权利要求11所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,R3或R4选自氯、氟、甲基、三氟甲基或甲氧基。
13.根据权利要求8所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,在式I中,当Ar为式III时,Q为O或S,X选自N或CH,R5代表氢或卤素。
14.根据权利要求8所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,R5代表氟。
15.脂环并[c]苯并吡喃酮衍生物,其特征在于,为如下化合物或其盐:
(1)7-{3-[4-(2,3-二甲基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(2)7-{3-[4-(2,3-二氯苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(3)7-{3-[4-(3-三氟甲基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(4)7-{3-[4-(2-甲氧基苯基)哌嗪-1-基]-丙氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(5)7-{3-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-正丙氧基]}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(6)7-{3-[4-(2-甲氧基苯基)哌嗪-1-基]-丙氧基}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(7)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(8)7-{4-[4-(4-甲氧基苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(9)7-{4-[4-(4-氟苯基)哌嗪-1-基]-丁氧基}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮;
(10)7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(11)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(12)7-{4-[4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-丁氧基]}-6-甲基-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(13)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(14)7-{4-[4-(3-(1,2-苯并异噻唑)-1-哌嗪基)-正丁氧基]}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(15)7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-6-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(16)7-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-8-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(17)7-{4-[4-(2-甲氧基苯基)哌嗪-1-基-丁氧基]}-8-氯-2,3-二氢-1H-环戊烯并[c]苯并吡喃-4-酮、
(18)3-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮、
(19)3-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮;
(20)3-{4-[4-(2-甲氧基苯基)哌嗪-1-基]-丁氧基}-4-甲基-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮或
(21)3-{4-[4-(3-(6-氟-苯并异恶唑)-1-哌啶基)-丁氧基]}-4-甲基-7,8,9,10-四氢苯并[c]苯并吡喃-6-酮。
16.根据权利要求1~8或15所述的脂环并[c]苯并吡喃酮衍生物,其特征在于,所述的盐为含有药物上可接受的阴离子盐。
17.一种药物组合物,其特征在于,包含治疗有效量的权利要求1~16任一项所述的脂环并[c]苯并吡喃酮衍生物和药学上可接受的载体。
18.权利要求1~16任一项所述的脂环并[c]苯并吡喃酮衍生物在制备治疗神经精神类疾病药物中的应用。
19.根据权利要求18所述的应用,其特征在于:所述神经精神类疾病为精神分裂症。
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CN102267971B (zh) * | 2011-08-03 | 2013-03-27 | 华中科技大学 | 脂环并[c]苯并吡喃酮衍生物及其应用 |
WO2014129989A1 (en) * | 2013-02-21 | 2014-08-28 | Fargem Farmasöti̇k Araştirma Geli̇şti̇rme Merkezi̇ Sanayi̇ Ve Ti̇caret A.Ş. | 3-substituted-6h-benzo[c]chromen-6-ones and 3-substituted-7,8,9,10-tetrahydro-6h-benzo[c]chromen-6-ones against senile dementia |
CN104059046B (zh) * | 2013-03-18 | 2017-02-08 | 江苏恩华药业股份有限公司 | 黄酮类衍生物及其应用 |
CN103694233B (zh) * | 2013-12-10 | 2016-08-17 | 沈阳药科大学 | 苯并异噁唑类化合物及其应用 |
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US4025630A (en) | 1973-09-19 | 1977-05-24 | Abbott Laboratories | Anesthesia methods using benzopyrans and esters thereof as pre-anesthesia medication |
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US4569994A (en) * | 1983-09-19 | 1986-02-11 | Pennwalt Corporation | Dibenzo[b,d]pyranyloxyaminopropanols |
US4701456A (en) * | 1984-09-19 | 1987-10-20 | Warner-Lambert Company | Aminoalkoxybenzopyranones as antipsychotic and anxiolytic agents |
US4678787A (en) * | 1985-01-30 | 1987-07-07 | Warner-Lambert Company | 4H-1-benzopyran-4-ones and their sulfur containing analogs |
US5278174A (en) * | 1990-06-04 | 1994-01-11 | Scios Nova, Inc. | Sigma binding site agents |
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CN102206214B (zh) | 2011-04-07 | 2014-03-12 | 华中科技大学 | 苯并吡喃酮类衍生物及其应用 |
CN102267971B (zh) * | 2011-08-03 | 2013-03-27 | 华中科技大学 | 脂环并[c]苯并吡喃酮衍生物及其应用 |
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