CN1278823A - 1′－[4－[1－(4－氟苯基)－1h－吲哚－3－基]－1－丁基]－螺[异苯并呋喃－1(3h),4′－哌啶]氢卤化物 - Google Patents
1′－[4－[1－(4－氟苯基)－1h－吲哚－3－基]－1－丁基]－螺[异苯并呋喃－1(3h),4′－哌啶]氢卤化物 Download PDFInfo
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- CN1278823A CN1278823A CN98810910A CN98810910A CN1278823A CN 1278823 A CN1278823 A CN 1278823A CN 98810910 A CN98810910 A CN 98810910A CN 98810910 A CN98810910 A CN 98810910A CN 1278823 A CN1278823 A CN 1278823A
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及1’－[4－[1－(4－氟苯基)－1H－吲哚－3－基]－1－丁基]－螺[异苯并呋喃－1(3H),4’－哌啶]的氢卤化物,含有其酸加成盐的药物组合物以及它们在精神的和神经病学的疾病治疗中的应用。
Description
本发明涉及1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]与氢氯酸、氢溴酸或氢碘酸的氢卤化物，含有这种酸加成盐的药物组合物和它们在精神的和神经病学疾病治疗中的应用。
发明背景
国际专利申请第WO 92／22554公开了认为对精神和神经病领域的治疗有用的系列σ受体配体。这些化合物的结构活性关系由Perregaard J．等人(J．Med．Chem．1995，38，11，P．1998—2008)做了进一步的研究。
作为本发明的目的的这些化合物之一，具有以下的通式：
Perregaard J．等人在J．Med．Chem．1995，38，11，P．1998—2008揭示这种化合物是一种有效的和选择性的σ配体。此外，还对这种化合物的抗焦虑潜力在鼠类黑／白探察实验(black／white explorationtest)中进行了实验，这是一种抗焦虑活性的动物模型前兆性实验，并且发现在大剂量范围内有效力。
从生物学和σ受体功能的研究显示，σ受体配体在精神和神经疾病领域中的治疗是有用的，包括精神和运动疾病，如张力和迟发的运动障碍，以及与杭廷顿氏舞蹈病或图雷特氏病综合征和帕金森氏病相关的运动失调症(Walker，J．M．等人，PharmacologicalReviews，1990，42，355)。这种已知的σ—受体配体林卡唑在治疗精神病方面表现出临床效力(Snyder，S．H．，Largent，B．L．J．Neuropsychiatry 1989，1，7)，还描述了在动物模型实验中表现出抗引起幻觉活性的一组σ—受体配体(国际专利申请第WO 9103243)。
还报道了σ—受体配体涉及在大脑中NMDA受体有间接关系的进程的调节，并且在活体内实验中作为抗局部缺血剂起作用(Rao，T．S．等人，Molecular Phamacology,1990，37，978)。除了局部缺血症之外，它们在其它这种NMDA受体有间接关系的活动(如癫痫和惊厥)的治疗中也是有用的。
还有，已经发现某些σ—受体配体在动物模型实验中显示了抗遗忘的作用(Early等人，Brain Research，1991，546，281—286)。
σ—配体在动物模型实验中显示出影响中枢乙酰胆硷的水平(Matsuno等人，Brain Research，1992，575，315—319；Junien等人，Eur．J．Pharm．1991，200，343—345)并因而可以具有治疗阿耳茨海默型老年痴呆症的潜力。
最后，已经揭示出具有σ—受体活性的某些胍衍生物作为抗焦虑药物是有用的(国际专利申请第WO 9014067)。
因此，有效地作用在中枢神经系统中σ受体上的化合物被认为在治疗焦虑、精神病、癫痫、惊厥、运动机能紊乱、运动障碍、遗忘症、脑血管疾病、阿耳茨海默氏型老年性痴呆症和帕金森氏病的中具有潜在的用途。
带自由基的1'—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]是一种油，因此对于固体药物制剂如片剂或胶囊的制备没有用处。对于一种药物的服用，作为固体物的口服是优选的和最方便的方法，所以特别需要能够与各种辅药或稀释剂混合并形成片剂或装入胶囊中的固体形式的化合物、其适用的药物学可接受的盐的。化合物1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]第一次是在国际专利申请第WO92／22544(第5a号化合物)公开，呈草酸加成盐的形式。
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的另一种酸加成盐，叫作延胡索酸盐，在Perregaard，等人 J．Med．Chem．1995，38，11，p．1998—2008中公开。
这两种游离碱和延胡索酸盐的水溶解度都很低，而水溶解度已知是可能危害药物生物可利用率的一种性质。此外，用大鼠和狗的实验表明1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的延胡索酸盐的生物利用度有限。
令人惊异的是，已经发现1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’哌啶]的氢氯化物的相对生物利用度比延胡索酸盐的大三倍。
本发明的氢氯化物还具有比1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的延胡索酸盐高的水溶解度。
发明内容
依据本发明，提供具有高生物利用度的1，—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的新的氢卤化物。
在一个本发明特别优选的实施例中，本发明的酸加成盐是1，—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢氯化物。
在本发明的另一个实施例中涉及1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢溴化物。
本发明还涉及含有本发明的氢卤化物盐的药物组合物以及这些盐在制备药物组合物中的应用以及它们用于治疗焦虑、精神病、癫痫、惊厥、运动机能紊乱、运动障碍、遗忘症、脑血管疾病、阿耳茨海默氏型老年性痴呆症和帕金森氏病。
本文中，1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢卤化物是指1'—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢氯化物、氢溴化物或氢碘化物，并且包括它们的酸酐、半—、一—和二水合物以及它们的溶剂合物。
本发明的氢卤化物可以通过以下方法来获得：将1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]与盐酸、氢溴酸或氢碘酸在惰性溶剂中沉淀处理、分离并可选择性地用已知方法重结晶，如果需要，用湿或干磨法或其它适宜的方法将结晶产物微粉化，或用溶剂—乳化方法制备颗粒。
氢卤化物加成盐的沉淀优选在惰性溶剂，如醇(如乙醇、2—丙醇和正丙醇)之类的惰性极性溶剂中进行。
根据本发明，1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢卤化物可以用任何合适的方式，如口服或胃肠外的方式用药，并且这种盐可以呈任何适于这种用药的形式，如呈片剂、胶囊、粉剂、糖浆或用于注射的溶液或分散剂的形式。优选地，并且根据本发明的目的，本发明的盐以固体药物的形式，适用的如片剂或胶囊用药。
固体药物制剂的制备方法在本领域中是众所周知的。如片剂可以通过将活性成分与常规的辅药和／或稀释剂混合并随后将混合物用常规的压片机压制来制备。辅药和／或稀释剂的例子包括：玉米淀粉、乳糖、滑石粉、硬脂酸镁、明胶、树胶等。任何其它的辅药或添加剂如矫色剂、香气剂、防腐剂等都可以使用，条件是它们与活性成分相容。
本发明的盐最合宜以单位剂型如片剂或胶囊口服，片剂或胶囊的活性成分含量从约10微克／天／千克体重～25毫克／天／千克体重，或在25微克／天／千克体重～10毫克／天／千克体重之间。合适的日剂量是在1．0和160毫克／天之间。
本发明将用以下的实施例具体说明。这些实施例不可以作为限定解释。
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的延胡索酸盐可以按照Perregaard，J．等人J．Med．Chem．1995，38，11，p．1998—2008(化合物14f)描述的方法来制备。实施例1
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]
将1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]延胡索酸盐(69克)悬浮于水(350毫升)和乙基乙酸酯(350毫升)中。通过加入浓氢氧化钠水溶液将混合物制成碱性(pH10—12)，并搅拌到溶解为止。含水层用乙酸乙酯(2×100毫升)萃取而混合的有机萃取物经硫酸钠干燥并真空蒸发。实施例2
1，—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]，氢氯化物
将1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶](10．3克)和2—丙醇(100毫升)加热回流。将溶液冷却到45℃。滴加盐酸水溶液(2．2毫升，36％)而形成标题化合物沉淀。将悬浮液加热回流并冷却至周围的温度。将悬浮液用冰冷却，过滤出来并干燥。产率：1．01克(90％)。这种盐是单盐并且根据我们的调查研究是一种无水盐(anhydrate)。KF：0．51％；HPLC 100．8％；DSC[开始／峰值最大(onset／peakmax)]222．5℃／223．8℃。CHN(计算／测量)：C：73．38／73．13；H：6．57／6．56；N：5．70／5．80。实施例3
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶氢溴化物
将1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶](1．05克，油)和2—丙醇(10毫升)搅拌并加热直到油溶解为止。滴加氢溴酸水溶液(2．5毫升，47％HBr)而形成标题化合物沉淀。往悬浮液中再加入2—丙醇(5毫升)和氢溴酸水溶液(2．5毫升，47％HBr)。将悬浮液在冰上冷却并将沉淀过滤出来和干燥。实施例4
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶氢碘化物
将1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶](1．0克，油)和2—丙醇(15毫升)搅拌并加热直到油溶解为止。滴加氢碘酸水溶液(1毫升，57％HI)而形成标题化合物结晶。往悬浮液中再加入2—丙醇(10毫升)和氢碘酸水溶液(4毫升57％HI)。将悬浮液在冰上冷却并将沉淀过滤出来和干燥。生物利用度研究
在小猎犬(Beagle dogs)多次用药之后，如以下的研究所描述的那样探讨1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶的盐的生物利用度。
在这个研究中使用二组小猎犬，每组4条，(2条雄性，2条雌性)。
各组的小狗每天为一次用药剂量10毫克／千克体重／天(按游离碱计算)1，—[4—[1—(4—氟苯基)—1H吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶的延胡索酸盐和氢氯化物，用药7天。
在每天用药之前和之后的规定时间从实验动物抽取用于制备血清的血样并使用HPLC分析。实验动物
将四条雄性和雌性专门饲养的小猎犬(都是由Interfauna，Ltd．，Huntingdon，UK提供)随机地成对分配到二个研究组的一组中。
在实验开始时，这些狗大约是12—38个月大，重量9．8—13．0千克。剂量和配方
将相应于每千克体重10．0毫克(～21997微摩尔)的1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶的各种盐的一次用药量，精确称量制成胶囊。每条狗的实验化合物的计算剂量以是研究开始时每条狗的体重为基础计算的。用药
实验动物每天一次在08∶00和09∶00之间用药，用药7天。血样采样和血清制备
用于血清制备的血样(约3ml)在以下规定的时间在每天用药之前和之后从颈部特罗拉尔氏静脉抽取：
第1天：在用药之前和在用药1、2、3、4、6、8和12小时之后。
第2～6天：在用药之前和用药3小时之后。
第7天：在用药之前和在用药1、2、3、4、6、8、12、24、48、72和96小时之后。上述采血时间相当于：在第1天第一次用药之前和第一次用药1、2、3、4、6、8、1 2、24、27、48、51、72、75、96、99、120、123、144、145、146、147、148、150、152、156、168、192、216和240小时之后。
记录下每一条狗相对第一次用药的准确采血时间。
采血后将血样在室温凝结30～90分钟。将凝结的血样在1000g离心分离15分钟并将分离的血清转移到清洁的试管中。血清试样在约—20℃贮存直到分析时为止。药物鉴定
得到的血清试样在液—液萃取后通过假常态(pseudo—nornal)相HPLC—方法分析1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶的含量。1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[5—氟—异苯并呋喃—1(3H)，4’—哌啶作为内标使用。血清试样使用以下的参照物质、萃取流程和高效液相色谱法(HPLC)分析1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶的含量。参考物质
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]，延胡索酸盐，
1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[5—氟—异苯并—呋喃—1(3H)，4’—哌啶](ISTD)，
1’—[5—苯基—1—苯基]—螺[异苯并呋喃—1(3H)，4’—哌啶](稳定剂)。萃取方法
将乙醇(50微升)、100微升2 NNaOH和4．0毫升含有1％异丁醇的正庚烷加入到500微升血清试样中。将试样震摇15分钟，以约2000g离心分离5分钟然后在乙醇／干冰浴槽中冷冻。将有机相转移到清洁的试管中并在40℃氮气(N2)下蒸发。将残留物溶于150微升用于HPLC的流动相(见下文)中并用HPLC分析75微升。HPLC方法柱： HP Hypersil(100×4．6毫米I．D．，5微米颗粒)柱温度： 35℃流动相组成：乙腈：0．25 M乙酸铵(98：2 v／v)流动相流速：1．0毫升／分检测： 荧光(激发：257纳米，发射：380纳米)注射体积： 75微升运行时间： 14分钟保留时间： 1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]：～9．7分钟，1’[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[5—氟异苯并呋喃—1(3H)，4’—哌啶](ISTD)：～6．5分钟。所有的血清试样都作为一次测定进行分析。
对于每个1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]试样，定量的界限是2ng，使用500微升分析血清，相当于8．80 nmol／l血清。
用每个试样每种化合物在0～500ng范围内的1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的已知量掺加的对照狗的血清制备用于1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶](ISTD)的血清浓度计算的校准试样，并且在每个分析日对该校准试样进行分析，
用1，—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]已知量掺加的对照狗的血清(每个试样1、50或400ng)制备质量控制(QC)试样，并且在每个分析日对质量控制试样进行分析。计算
1，—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的血清浓度(ng／ml和nmol／l)从通过分析得到的准确量(ng)和用于分析的血清的体积来计算。
用药第7日后(AUC0-24，7)，从时间为0到24时，采用线性梯形法计算在血清浓度对时间的曲线下面的面积。
与延胡索酸盐的生物利用度对比，1’—[4—[1—(4—氟苯基)—1H—吲哚—3基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]氢氯化物的相对口服生物利用度，是以接受氢氯化物的狗实验组得到的平均AUC0—24，7值与接受延胡索酸盐的狗对比组得到的平均AUC0—24,7值之间的比来计算的。
结果列于表1中：
| 酸加成盐 | AUC0-24.7 | Frel(与延胡索酸盐对比) | |
| 平均 | SD | ||
| 延胡索酸盐 | 4017 | 2403 | - |
| 氢氯化物 | 12023 | 3699 | 2.99 |
表1：口服后1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]氢氯化物的相对生物利用度Frel。
Claims (10)
1、1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢卤化物和其水合物和／或溶剂合物。
2、权利要求1的氢卤化物，它是1’—[4—[1—(4—氟苯基)—1H—吲哚—3—基]—1—丁基]—螺[异苯并呋喃—1(3H)，4’—哌啶]的氢氯化物，其水合物和／或溶剂合物。
3、一种药物组合物，含有权利要求1的氢氯化物并且带有至少一种药物学可接受的载体或稀释剂。
4、权利要求3的药物组合物，其中的氢卤化物是氢氯化物。
5、用于焦虑、精神病、癫痫、惊厥、运动机能紊乱、运动障碍、遗忘症、脑血管疾病、阿耳茨海默氏型老年性痴呆症和帕金森氏病的治疗方法，包括给患有这类疾病的客体施用治疗有效剂量的权利要求1的氢卤化物。
6、权利要求5的方法，其中所治疗的是焦虑症。
7、权利要求5或6的方法，其中所使用的氢卤化物是氢氯化物。
8、权利要求1的氢卤化物在制备治疗焦虑、精神病、癫痫、惊厥、运动机能紊乱、运动障碍、遗忘症、脑血管疾病、阿耳茨海默氏型老年性痴呆症和帕金森氏病的药物组合物中的应用。
9、权利要求8的应用，其中的疾病是焦虑症。
10、权利要求8～9的应用，其特征在于，所使用的氢卤化物是氢氯化物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1267/1997 | 1997-11-07 | ||
| DK126797 | 1997-11-07 |
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| Publication Number | Publication Date |
|---|---|
| CN1278823A true CN1278823A (zh) | 2001-01-03 |
| CN1105115C CN1105115C (zh) | 2003-04-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN98810910A Expired - Fee Related CN1105115C (zh) | 1997-11-07 | 1998-11-06 | 1′－[4－[1－(4－氟苯基)－1h－吲哚－3－基]－1－丁基]－螺[异苯并呋喃－1(3h),4′－哌啶]氢卤化物 |
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| JP (1) | JP3605358B2 (zh) |
| KR (1) | KR100399274B1 (zh) |
| CN (1) | CN1105115C (zh) |
| AR (1) | AR023010A1 (zh) |
| AT (1) | ATE288918T1 (zh) |
| AU (1) | AU749094B2 (zh) |
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| TR (1) | TR200001267T2 (zh) |
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| UA (1) | UA64769C2 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2001279607A1 (en) * | 2000-08-15 | 2002-02-25 | H. Lundbeck, A/S | Pharmaceutical composition containing 1'-(4-(1-(4-fluorophenyl)-1h-indole-3-yl) -1-butyl)-spiro(isobenzofuran-1(3h),4'-piperidine) |
| WO2004026855A1 (en) * | 2002-09-20 | 2004-04-01 | H. Lundbeck A/S | Method for manufacture of dihydroisobenzofuran derivatives |
| US20050020483A1 (en) | 2003-06-12 | 2005-01-27 | Donna Oksenberg | Sigma ligands for neuronal regeneration and functional recovery |
| WO2007012319A1 (de) * | 2005-07-29 | 2007-02-01 | Sigma-Aldrich Production Gmbh | Ionisierungsadditive enthaltende lc/ms-blends |
| EP2377530A3 (en) | 2005-10-21 | 2012-06-20 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
| WO2007053596A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) * | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| AU2007223036A1 (en) * | 2006-03-08 | 2007-09-13 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| EP2026813A2 (en) * | 2006-05-09 | 2009-02-25 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
| JP2009536669A (ja) | 2006-05-09 | 2009-10-15 | ブレインセルス，インコーポレイティド | アンジオテンシン調節による神経新生 |
| US20100009983A1 (en) * | 2006-05-09 | 2010-01-14 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
| KR20090064418A (ko) * | 2006-09-08 | 2009-06-18 | 브레인셀즈 인코퍼레이션 | 4-아실아미노피리딘 유도체 포함 조합물 |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| CA2663347A1 (en) * | 2006-09-19 | 2008-03-27 | Braincells, Inc. | Ppar mediated modulation of neurogenesis |
| US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5109002A (en) * | 1989-09-08 | 1992-04-28 | Du Pont Merck Pharmaceutical Company | Antipsychotic 1-cycloalkylpiperidines |
| NZ243065A (en) * | 1991-06-13 | 1995-07-26 | Lundbeck & Co As H | Piperidine derivatives and pharmaceutical compositions |
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