CN1073565C - 新的3-(哌啶-4-基)-1,2-苯并异噁唑和3-(哌嗪-4-基)-1,2-苯并异噁唑化合物,制备它们的方法以及含有它们的药物组合物 - Google Patents
新的3-(哌啶-4-基)-1,2-苯并异噁唑和3-(哌嗪-4-基)-1,2-苯并异噁唑化合物,制备它们的方法以及含有它们的药物组合物 Download PDFInfo
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- CN1073565C CN1073565C CN97105471A CN97105471A CN1073565C CN 1073565 C CN1073565 C CN 1073565C CN 97105471 A CN97105471 A CN 97105471A CN 97105471 A CN97105471 A CN 97105471A CN 1073565 C CN1073565 C CN 1073565C
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
新的式Ⅰ化合物,其中的A,m,n,E和Y如说明书定义。这些新化合物与其生理上可接受的盐被用作药物。
Description
本发明涉及新的1,2-苯并异噁唑化合物,制备它们的方法以及含有它们的药物组合物。
在文献中许多3-(哌啶-4-基)-1,2-苯并异噁唑和3-(哌嗪-4-基)-1,2-苯并异噁唑化合物是已知的,专利说明书WO9418197,US4458076A和US4352811A描述了与本申请化合物最接近的化合物,这些化合物具有抗精神病或止痛的功能。
本发明的化合物是3-(哌啶-4-基)-1,2-苯并异噁唑和3-(哌嗪-4-基)-1,2-苯并异噁唑化合物,它们不同于已知的化合物,因为在哌啶或哌嗪环的1-位上其取代基不同,并且具有不同的药理性质。事实上,进行体内和体外的多种药理试验已经证明本发明化合物是5HT2A血清素受体、α1-肾上腺素能受体和多巴胺能受体的拮抗剂。与作为参照物的产品,例如氟哌丁苯和利螺环酮相比,它们具有抗精神病活性,但是,它们不会引起副作用,特别是不会引起椎体外副作用(extrapyrimidaleffects)。已知抗精神病药常常会引起很明显的副作用,因此限制了它们的使用。在临床应用上,显然椎体外副作用涉及抗精神病化合物的D2多巴胺能受体-阻断性质。与已知的产品相比本发明化合物是非常弱的D2多巴胺能阻断剂。另一方面,它们与D4多巴胺能受体的亲和力很高,显然大于对D2受体的亲和力,这种选择性说明了为什么本发明的产品无椎体外副作用。
多巴胺能系统的机能亢进不仅与精神分裂症有关,而且与很多中枢神经系统的疾病例如焦虑-抑郁疾病、冲动性(impulsive)疾病和攻击行为有关。本发明的产品特别是用作抗精神病药、抗焦虑药和抗攻击行为的药物,也可以用作止痛药。
本发明特别涉及式Ⅰ的1,2-苯并异噁唑化合物以及当有光学异构体存在时,还涉及它们的光学异构体,和其药用有机和无机酸盐,A表示具有1-10个碳原子的直链或支链烷基基团,或被一个或多个卤原子或羟基或烷氧基任意取代的苯基,m表示0或1,n表示1或2,E表示N或CH,Y表示氢或卤原子,和具有1-5个碳原子的烷氧基。
本发明还涉及制备式Ⅰ化合物的方法,其特征是:
在碱金属碳酸盐如碳酸钾存在下,在极性溶剂如甲乙酮或甲基异丁基酮之中使其中E和Y如上文定义的式Ⅱ化合物或者与其中n如上文定义的式Ⅲ化合物进行反应得到下式Ⅳ的化合物其中n、E和Y如上文定义,然后,在碱金属氢化物如氢化钠存在下,在极性溶剂如二甲亚砜之中使其与A和m如上文定义,X为卤素的式Ⅴ化合物A-(CH2)m-X (Ⅴ)进行反应而得到式Ⅰ化合物;或者
化合物Ⅲ和Ⅵ是已知产物,或者可由已知原料按照常规的方法合成。
本发明化合物不同于现有技术化合物之处不仅在于它们的化学结构,而且还在于它们的药理和治疗活性,这些活性已经得到证明:体外
用克隆人的D2和D4受体结合、5HT2A受体结合和、α1-受体结合进行研究。体内
-用阿扑吗啡诱导的垂直试验模型
-大鼠的反应回避调节模型,和
-分离喂养的小鼠的攻击行为的模型最后,可能已经证实在大鼠的僵住状模型中没有副作用。
这些活性和没有令人讨厌的副作用使本发明化合物在治疗精神病、焦虑-抑郁症和攻击行为特别有价值。
本发明还涉及药物组合物,该组合物含有式Ⅰ化合物或其生理上可接受的盐作为活性成分,并结合有一种或多种适合于药用的赋形剂。
通常如此得到的药物组合物的单位剂量形式含有0.5-25mg的活性成分。它们可以是,例如是片剂、糖衣丸、明胶胶囊、栓剂或注射用或可以饮用的溶液,它们可通过口服、直肠或非肠道途径给药。
施用剂量可以根据患者的年龄和体重、给药的途径、疾病的性质和有关的治疗而变化,剂量范围是0.5-25mg活性成分,每天1-3次。
下面给出的非限制性实施例说明了本发明。熔点是在显微镜下用Kofler加热板测定的。
实施例11-{2-[4-(6-氟-1,2-苯并异噫唑-3-基)哌啶-1-基]乙基}-3-异丙基咪
唑烷-2-酮步骤1 1-{2-[4-(6-氟-1,2-苯并异噫唑-3-基)哌啶-1-基]乙基}咪唑烷-2-酮
在三颈瓶中加入21.4g(0.144mo1)1-(2-氯乙基)咪唑烷-2-酮、23.6g(0.107mol)4-(6-氟-1,2-苯并异噁唑-3-基)哌啶、92.9g(0.67mol)碳酸钾、2.6g碘化钾和524ml甲基异丁基酮,使其回流一夜,然后浓缩反应混合物并将其溶于水/乙酸乙酯的混合物。滗析,有机相用水洗涤多次,用常规盐酸溶液萃取,用氢氧化钠溶液使酸性相呈碱性,用二氯甲烷萃取,用硫酸镁干燥。蒸发后残余物用80ml乙腈重结晶,得到与预期产物一致的22g固体,m.p.=137-141℃(产率=46%)。步骤2标题化合物
把5g(0.015mol)上述步骤得到的产物溶于16ml二甲亚砜,分批加入1.2g(0.03mol)氢化钠,使反应物接触半小时,然后倾入4.22g(0.045mol)2-溴丙烷,混合物于室温搅拌过夜。将混合物溶于水,再溶于二氯甲烷,滗析,有机相用盐水洗涤,用硫酸镁干燥和真空浓缩,得到的油在硅胶上色谱纯化(洗脱液:二氯甲烷/甲醇95∶5)得到预期的产物,m.p.=121-123℃(产率=39%)。
实施例21-{2-[4-(6-氟-1,2-苯并异噫唑-3-基)哌嗪-1-基]乙基}-3-异丙基咪
唑烷-2-酮
此产物用与实施例1相同的方法制备,只是用4-(6-氟-1,2-苯并异噁唑-3-基)哌嗪代替步骤1中4-(6-氟-1,2-苯并异噁唑-3-基)哌啶,如此得到标题化合物,其熔点为125-127℃。
实施例31-{2-[4-(6-氟-1,2-苯并异噫唑-3-基)哌嗪-1-基]乙基}-3-乙基咪唑
烷-2-酮
此产物用与实施例1相同的方法制备,只是用4-(6-氟-1,2-苯并异噁唑-3-基)哌嗪代替步骤1中4-(6-氟-1,2-苯并异噁唑-3-基)哌啶,和用溴乙烷代替步骤2中2-溴丙烷,如此得到标题化合物的盐酸化物,其熔点为201-204℃。
实施例41-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-异丁基咪
唑烷-2-酮
此产物用与实施例1相同的方法制备,只是用1-溴-2-甲基丙烷代替步骤2中2-溴丙烷。
实施例51-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-苯基咪唑
烷-2-酮步骤11,1-[双-(2-羟基乙基)]-3-苯基脲
于10℃,在三颈瓶中装入溶于37ml二氯甲烷的18.25g(0.168mol)异氰酸苯基酯,向其中倾入15.62g(0.136mol)二乙醇胺和163ml二氯甲烷的混合物,使此混合物在此温度下放置1小时,然后在室温过夜,真空浓缩后得到36.5g预期的产物(产率=100%)。步骤21,1-[双-(2-氯乙基)]-3-苯基脲
把39g(0.137mol)上述步骤得到的产物溶于100ml二氯甲烷,保持温度为0℃,倾入26.64ml(0.365mol)亚硫酰二氯将化合物回流4小时,于室温放置过夜,真空浓缩后得到43.7g预期的产物(产率=96%)。步骤3 1-(2-氯乙基)]-3-苯基咪唑烷-2-酮
把43.7g(0.167mol)步骤2得到的产物先在120℃加热3小时,再在140℃加热6小时,气体停止逸出并冷却后,得到的油在硅胶上色谱纯化(洗脱液:二氯甲烷100%)得到与预期产物一致的23.2g白色固体,m.p.=92℃(产和61.7%)。步骤4标题化合物
用与实施例1步骤1所述相同的方法,只是用1-(2-氯乙基)]-3-苯基咪唑烷-2-酮代替1-(2-氯乙基)]咪唑烷-2-酮,在硅胶上色谱纯化(洗脱液:二氯甲烷/环己烷80∶20)得到预期的3.8g产物,m.p.=158-160℃(产率=56%)。
实施例61-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-叔丁基咪
唑烷-2-酮
此产物用与实施例5相同的方法制备,只是在合成的步骤1中用异氰酸叔丁基酯代替异氰酸苯基酯,如此得到化合物的盐酸化物,其熔点为205-208℃。
实施例73-苄基-1-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}咪唑
烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸苄基酯代替异氰酸苯基酯,预期化合物的熔点为126-130℃。
实施例81-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-(2-乙氧
基苯基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸2-乙氧基苯基酯代替异氰酸苯基酯,如此得到化合物的盐酸化物,其熔点为217-218℃。
实施例91-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-(2-氯苯
基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸2-氯苯基酯代替异氰酸苯基酯,如此得到的化合物的盐酸化物其熔点为223-227℃。
实施例101-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-(3-氯苯
基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸3-氯苯基酯代替异氰酸苯基酯,如此得到化合物的盐酸化物,其熔点为223-227℃。
实施例111-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-(2,6-
二氯苯基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸2,6-二氯苯基酯代替异氰酸苯基酯,如此得到化合物的盐酸化物,其熔点为237-241℃。
实施例121-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-(4-甲氧
基苯基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸4-甲氧基苯基酯代替异氰酸苯基酯,预期的化合物的熔点为154-157℃。
实施例131-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-(2,3-
二氯苯基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸2,3-二氯苯基酯代替异氰酸苯基酯,如此得到化合物的盐酸化物,其熔点为218-222℃。
实施例141-{2-[4-(6-氟-1,2-苯并异噫唑-3-基)哌啶-1-基]乙基}-3-(4-羟基
苯基)咪唑烷-2-酮
此产物用与实施例5相同的方法得到,只是在合成的步骤1中用异氰酸4-羟基苯基酯代替异氰酸苯基酯,预期的化合物的熔点为190-194℃。
实施例1 51-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-苯基-3,
4,5,6-四氢-(2H)-嘧啶-2-酮步骤1 1-苯基-3,4,5,6-四氢-(2H)-嘧啶-2-酮
将2.5g(16.5mM)N'-苯基丙烷-1,3-二胺溶于56.5ml无水四氢呋喃,在溶液中倾入3.8g(23.3mM)羰基二咪唑在115ml无水四氢呋喃中的混合物,混合物在室温放置过夜。将混合物浓缩,溶于乙酸乙酯,用常规盐酸洗涤和用硫酸镁干燥,得到2g与预期产物一致的白色固体,其熔点为210-211℃。步骤2 1-(2-氯乙基)-3-苯基-3,4,5,6-四氢-(2H)-嘧啶-2-酮
把1.76g(10mM)上述步骤得到的产物溶于15ml无水二甲亚砜。分批加入0.81g(20mM)60%的氢化钠。使反应物接触3小时,然后把1.7ml(20mM)1-溴-2-氯乙烷倾入其中,混合物于室温放置过周末。加入350ml蒸馏水,用二氯甲烷萃取,滗析,有机相经洗涤和用硫酸镁干燥。蒸发后得到1.8g油状预期的产物(产率=76%)。步骤3标题化合物
用与实施例1步骤1所述相同的方法,只是用上述得到的1-(2-氯乙基)]-3-苯基-3,4,5,6-四氢-(2H)-嘧啶-2-酮代替1-(2-氯乙基)]咪唑烷-2-酮,用硅胶色谱纯化(洗脱液:二氯甲烷/环己烷80∶20)得到预期的产物。
实施例16:药理研究体外
化合物与5HT2A血清素受体、α1-肾上腺素能受体和D2和D4多巴胺能受体的相互作用是按照Millan等人(J.Pharm.Exp.Ther.,275,885-898.,1995)所述,用常规的结合研究方法测定。试验条件详细列于下表:
受体 | 样品,组织 | [3H]-配体(nM) | NSB(10μM) | 孵化时间,T℃ |
5HT2A | 大鼠,额皮质 | 酮色林(1.0) | 螺环哌丁苯 | 90分钟,25℃ |
α1 | 大鼠,额皮质 | 哌唑嗪(0.2) | 酚胺唑啉 | 90分钟,25℃ |
D2 | 大鼠,纹状体 | 螺环哌丁苯(0.2) | 利螺环酮 | 90分钟,25℃ |
D4 | 人,CHO细胞 | 螺环哌丁苯(0.2) | 氟哌丁苯 | 90分钟,25℃ |
将结合于受体的放射配体与游离的放射配体分离是通过GF/B过滤器过滤来进行的,用Brandle Cell收获型的过滤装置以0.3%聚乙烯亚胺对该过滤器进行预处理。在过滤器中加入闪烁的液体,用β-计数器对放射活性计数。用非线形回归法测定IC50(抑制放射性配体50%的结合时的化合物浓度)。然后用Cheng-Prussof公式计算K1:
Ki=IC50/(1+L°/Kd)其中L°是放射配体的浓度,Kd是在饱和试验中测定的放射配体的离解常数。
本发明化合物对5HT2A和α1受体的K1值小于10-8M。关于相对于D4而言D2选择性对于D4受体的亲合力比对D2受体大10倍(对D4的≤5nM,对D2的≥50hM)。体内1.用阿扑吗啡(0.75mg/kg,s.c.)诱导的小鼠的垂直试验
此试验在Protais等人Psychopharmacology,50,1-6(1976)中描述,该试验用于评价可能具有抗精神病产物的多巴胺能拮抗活性。把已经给药阿扑吗啡的小鼠放在一个装有垂直棒的笼子里,此小鼠在大部分时间里回呆在笼子的顶部不动,用它的四个爪子抓住垂直棒。如果在给药阿扑吗啡之前先给药多巴胺能拮抗剂产物则会中断垂直行为。
试验:在皮下(s.c.)给药本发明的产物或溶剂(对照组)之后立刻把小鼠放在装有垂直棒的圆桶状的笼子(直径14cm,高14cm)里,30分钟后给动物一定剂量(0.75mg/kg,s.c.)的阿扑吗啡,在注射阿扑吗啡后10和20分钟时观察动物,,每次测定以下述记分(score)方法之一记分:0(四爪着地),1(小鼠直立,二爪抓棒),或2(小鼠的四爪都抓着棒)。用于记录结果的垂直记分是0-4(两次记分的和),每个试验组至少有5只动物。
统计分析:本发明产物在垂直试验中的作用是通过把给药化合物的每组与对照组(溶剂)的记分进行比较来评价的,采用Mann和Whitney的U试验方法,得到概率为p<0.05。
ID50抑制剂量是与对照组相比,使其平均垂直记分减少一半时的化合物剂量。
结果:作为实例,在此试验中实施例5化合物的ID50是0.22mg/kg。2.大鼠的反应回避调节此试验通常用于鉴别抗精神病产物,参见P.A.Janssen,C.J.E.Niemegeers,Arzneim-Forsch,1037-1043(1961)。
试验在有两个隔间的笼子中进行,该笼子装有能通电的板,用下述方式调节的大鼠进行试验:在给光信号时,为了避免受到电击,动物必须由它所处的隔间转移到另一隔间。动物对光信号的反应是调节回避反应(Avoidance response)。如果动物不能作出反应,在光信号结束时它将受到电击直到它进入另一隔间。对电击的反应是不可调节逃避反应(Escape responce)。
通常,与抑制不可调节的回避反应时的计量相比,抗精神病药物在较低计量时就可抑制可调节的回避反应。这使得它们不同于其他类型的药物(具体的,巴比妥酸盐和苯并二氮杂),这些药物可类似的抑制两种反应。
设备:设备包括用中心隔板分成两个隔间的笼子;在隔板上开的门,它使动物能由一个隔间到另一隔间(LE916型,LETIVCA)。每个隔间的平板是可通电的格板。笼子的操作(光信号,控制通过格板的电流)并记录动物由一个隔间到另一隔间的运动是由计算机(CPMPAQ386S)完成的,使用SHUTTLE8(LETICA)的软件。
试验:动物以它们自己作为对照。每个日试验期包括10次试验,间隔是30秒。一个试验包括给光信号(10秒),接着,根据动物对光信号的反应给或不给电击(0.460mA,最长时间5秒)。本发明产物对回避反应的作用以动物接受溶剂的对照期(Control Session)之后一天中出现的试验期(Test Session)来评价。产物或溶剂在开始试验之前30秒时给药,使用的参数是回避反应的次数,
统计分析:对每种药物计量,把试验期中回避反应的次数与同一动物在对照期得到的次数相比较,用Wilcoxon Test试验方法,得到概率为p<0.05。
结果:作为实例,在此试验中,皮下给药实施例5化合物的ID50是0.88mg/kg。3.分离喂养的小鼠的攻击行为的试验
此试验通常用于评价药物对小鼠的抗攻击活性,其中的小鼠已经分离喂养数月。
动物:试验用小鼠是CD小鼠(Charles River),在到达动物房时的体重22-25g。到达后立即把动物分别喂养在用不透明的黑色的聚酯制成的笼子(23×14×13cm)中,笼子有网格的盖,在实验室放较长时间(大约6个月)。
小鼠对的选择:在此试验中长期使用的有攻击行为的小鼠对的选择在动物分离喂养一个月后开始。每周一次或两次把从另一格笼子中拿出来的小鼠(入侵者)放在(居住者)小鼠的笼子里,观察二只动物,看它们在试验期间是不是互相攻击(嗅,追逐,掐,咬),试验结束时(最长时间10分钟),把每只小鼠再放到各自的笼子中。如果出现攻击,在下一次试验中还用同一对进行试验;如果没有发生攻击,在下一次试验中这一对的每一只小鼠就要与另外的小鼠放在—起。这样,在每周1或2次试验的连续试验期间,就选出了试验中使用的确定的小鼠对。配对选择是以动物在一次又一次的试验中其好斗的稳定性、开始第一次攻击前的潜伏期的长短和攻击的频率与时间为基础的。对于用此方式选出的小鼠对,每周用快速试验检查其参数,在试验日的二天前不处理。
试验:每周进行一次试验。在把每对的两只小鼠放在—起前30分钟时,给每只小鼠进行同样的处理(本发明产物或溶剂),仍然把它们放在各自的笼子里。在T0分钟时把入侵者小鼠放入居住者小鼠的笼子里3分钟。记录第一次攻击前的潜伏期(以秒计)以及攻击的次数和总时间(以秒计)。占优势的一只小鼠与另一只小鼠(通常居住者小鼠是占优势的小鼠)有关的逆转也要记录下来。
试验结束时,把入侵者小鼠放回到自己的笼子里;动物仍放在分离的笼子里直到下一次快速试验和下周的试验。
统计分析:药物对攻击行为的作用是以下述方法评价的:把接受产物(处理组)的小鼠对的攻击次数和时间与接受溶剂(对照组)的小鼠对进行比较,用方差分析(ANOVA),接着再用Dunnett试验方法,得到概率为p<0.05。
攻击次数和时间的ID50抑制剂量是指与对照组得到的平均次数和时间相比能把每个数值的平均值减少一半的药物剂量。
结果:作为实例,在此试验中,皮下给药实施例5化合物的ID50是0.18mg/kg。4.大鼠僵住状的诱导
给精神分裂症患者长期施用“典型的”精神抑制药或抗精神病药(氟哌丁苯,氯丙嗪)时常常引起不希望有的帕金森症类型的椎体外综合症(EPS),特别是固定的现象,参见Divis等人,Neuroleptics:Neurochemical,Behavioral,and Clinical Perspectives,Coyle,J.T.和Enna,S.J.Raven Press,纽约,1983。但是,“典型的”抗精神病药(氯氮平)几乎不引起椎体外综合症。试验:动物放在各自的笼子里,试验前一天禁食,但是可随意饮水。僵住状试验包括把动物的每个后爪放在其同一侧的前爪上,测量动物保持这种“爪子交叉”位置的时间(秒)(最长30秒)。每只动物进行三次连续试验(每次2分钟),把动物从笼子里拿出来,放在工作台表面。在皮下注射或口服本发明产物或溶剂之后1小时进行此试验。三次试验的平均值表示每只动物的僵住状的时间(以秒计)。每试验组有5只动物。
统计分析:本发明产物对僵住状时间的作用是用ANOVA,接着再用Dunnett的试验方法进行分析,得到概率为p<0.05。
对僵住状诱导的平均ED50有效剂量是指与最大值30秒相比能产生50%僵住状时间的本发明产物的剂量(用溶剂对照组的值校对)。
结果:作为实例,在此试验中,实施例5化合物的ED50是34mg/kg。与参照化合物例如氟哌丁苯或利螺环酮相比是很优异的,它们在试验中经皮下给药得到的ED50分别是0.15mg/kg和1.2mg/kg。
Claims (6)
2.权利要求1的化合物,该化合物是1-{2-[4-(6-氟1,2-苯并异噁唑-3-基)哌嗪-1-基]乙基}-3-异丙基咪唑烷-2-酮。
3.权利要求1的化合物,该化合物是1-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌嗪-1-基]乙基}-3-乙基咪唑烷-2-酮和其盐酸盐。
4.权利要求1的化合物,该化合物是1-{2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-1-基]乙基}-3-苯基咪唑烷-2-酮。
6.用于治疗精神病、焦虑-抑郁症和攻击行为的药物组合物,其中含有按照权利要求1-4中任意一项的化合物,和一种或多种药学上适当的赋形剂。
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FR9606866A FR2749304B1 (fr) | 1996-06-04 | 1996-06-04 | Nouveaux derives du 3-(piperid-4-yl)1,2-benzisoxazole et du 3-(piperazin-4-yl)1,2-benzisoxazole, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent |
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ATE192745T1 (de) | 2000-05-15 |
FR2749304A1 (fr) | 1997-12-05 |
EP0811622A1 (fr) | 1997-12-10 |
CA2207835C (fr) | 2001-10-02 |
DE69701923T2 (de) | 2000-12-14 |
NZ314992A (en) | 1999-05-28 |
BR9703447A (pt) | 1998-11-10 |
DK0811622T3 (da) | 2000-09-11 |
HUP9700992A3 (en) | 1999-03-29 |
ES2148916T3 (es) | 2000-10-16 |
EP0811622B1 (fr) | 2000-05-10 |
PT811622E (pt) | 2000-08-31 |
PL320325A1 (en) | 1997-12-08 |
ZA974919B (en) | 1997-12-30 |
FR2749304B1 (fr) | 1998-06-26 |
NO308360B1 (no) | 2000-09-04 |
NO972510D0 (no) | 1997-06-02 |
GR3033996T3 (en) | 2000-11-30 |
HU9700992D0 (en) | 1997-07-28 |
CA2207835A1 (fr) | 1997-12-04 |
PL187005B1 (pl) | 2004-04-30 |
CN1171401A (zh) | 1998-01-28 |
DE69701923D1 (de) | 2000-06-15 |
AU715266B2 (en) | 2000-01-20 |
US5780474A (en) | 1998-07-14 |
NO972510L (no) | 1997-12-05 |
AU2464997A (en) | 1997-12-11 |
JPH1059967A (ja) | 1998-03-03 |
HUP9700992A2 (hu) | 1998-12-28 |
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