CN1291194A - 取代的1,2,4-三唑并[3,4-a]哒嗪 - Google Patents
取代的1,2,4-三唑并[3,4-a]哒嗪 Download PDFInfo
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- CN1291194A CN1291194A CN99803190A CN99803190A CN1291194A CN 1291194 A CN1291194 A CN 1291194A CN 99803190 A CN99803190 A CN 99803190A CN 99803190 A CN99803190 A CN 99803190A CN 1291194 A CN1291194 A CN 1291194A
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- Prior art keywords
- methyl
- triazolo
- compound
- phthalazines
- isoxazole
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
公开了取代的三唑并哒嗪衍生物、其在认知增强治疗中的用途、包含它的组合物及其制备方法。
Description
本发明涉及一种取代的三唑并哒嗪衍生物、其治疗用途、包含它的组合物和其制备方法。
现在我们已经发现,获得具有认知增强作用的药物是可能的,它们由于降低了惊厥药前体(proconvulsant)作用的风险而可以使用,惊厥药前体作用以前描述为苯并二氮杂受体部分或全部反兴奋剂(inverse agonist)。优选的反兴奋剂为α5受体的反兴奋剂,并在α1和α2和α3受体结合位点相对无活性。
欧洲专利申请0085840和0134946描述了1,2,4-三唑并[3,4-a]酞嗪衍生物的相关系列,指出其具有抗焦虑作用。然而,在这两个说明书中对于本发明的化合物既没有公开也没有任何暗示,而且在该申请中公开的化合物也不具有任何认知增强特性。
本发明提供了为3-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-4-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪的化合物。
通过在由McNamara和Skelton,Psychobiology,21:101-108报道的Morris水迷宫(Watermaze)中测试所述化合物,可以证明认知增强作用。使用在WO-A-9625948中公开的方法可以计算在各种受体亚型上的功效。
因此,本发明的化合物例如可以用于各种中枢神经系统疾病。这些疾病包括谵妄、痴呆以及遗忘和其它认知障碍。谵妄的实例是起因于物质中毒或物质脱瘾的谵妄,起因于多重病原学的谵妄和NOS(不另作详细说明的)谵妄。痴呆的实例是早期发作的阿尔茨海默型痴呆,可以是无并发症的,或者可以具有谵妄、妄想或抑郁情绪;晚期发作的阿尔茨海默氏型痴呆,可以是无并发症的,或者可以具有谵妄、妄想或抑郁情绪;血管性痴呆,可以是无并发症的,或者可以具有谵妄、妄想或抑郁情绪;起因于HIV病的痴呆;起因于头部创伤的痴呆;起因于帕金森病的痴呆;起因于亨廷顿舞蹈病的痴呆;起因于Pick’s病的痴呆;起因于克雅氏综合症的痴呆;为物质持续诱导的痴呆或起因于多重病原学的痴呆;以及NOS痴呆。遗忘症的实例是起因于特殊医学状态的遗忘,或为物质持续诱导的遗忘症,或为NOS遗忘症。
本发明也提供包含本发明化合物和药学上可接受的载体的药用组合物。这些组合物最好是以诸如片剂、丸剂、胶囊、粉剂、颗粒剂、无菌的非肠道注射用的溶液或悬浮液、计量的气溶剂或液体喷雾剂、滴剂、安瓿、透皮贴剂、自动注射器或栓剂的单位剂量形式,经口、胃肠外、鼻内、舌下或直肠给予;或者通过吸入或吹入给予。为了制备诸如片剂的固体组合物,将主要的活性成分与药用载体混合,以形成含有本发明化合物或其药学上可接受的盐的均一混合物的固体预制组合物,所述药用载体有例如常规的片剂组分(诸如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙或树胶)或表面活性剂(诸如脱水山梨醇一油酸酯、聚乙二醇)和其它的药用稀释剂(例如水)。当称这些预制组合物为均一时,意思是指所述活性成分均匀地分散到整个组合物中,使得该组合物可以容易地再分到诸如片剂、丸剂和胶囊的等效单位剂型中。然后将这种固体预制组合物再分到含有0.1至约500mg的本发明活性成分的上述类型的单位剂型中。典型的单位剂型含有由1至100mg(例如1、2、5、10、25、50或100mg)的活性成分。新组合物的片剂或丸剂可以包衣,或者可以复合,以提供一种具有延长作用优点的剂型。例如,所述片剂或丸剂可以包含一种内部剂量组分和一种外部剂量组分,后者为覆盖前者的包膜的形式。两种组分可以由肠衣层分开,该肠衣层用来在胃中抵抗分解,并使内部组分完整地通过十二指肠,或延迟释放。许多物质可以用作这种肠衣层或包膜,这些物质包括许多聚合酸(polymeric acids)以及聚合酸与诸如紫胶、鲸腊醇和乙酸纤维素的物质的混合物。
可以掺入本发明所述新组合物的、经口或通过注射给予的液体形式包括水溶液、合适的调味糖浆、水性或油性悬浮液和用食用油(诸如棉子油、芝麻油、椰子油或花生油)调味的乳液以及酏剂和类似的药用溶媒。用作水性悬浮液的合适的分散剂或悬浮剂包括合成的和天然的树胶,诸如黄蓍胶、阿拉伯树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。
本发明还提供了本发明的化合物在用于增强认知(最好是在患诸如阿尔茨海默氏病的痴呆病人中增强认知)作用的药物生产中的用途。
为了增强认知作用,合适的剂量水平是每天每公斤体重约0.01至250mg,优选是每天每公斤体重约0.01至100mg,而特别优选是每天每公斤体重约0.01至5mg。所述化合物可以以每天1至4次的方式给予。然而在某些情况下,可以使用这些限制之外的剂量。
最好是例如使用杵和臼或此外的工业等效物,将本发明的化合物在配制前研磨成粒度在1和10微米之间的颗粒,优选小于5微米。所述化合物可以通过本领域已知的方法微粉化或声波(sonicised)降解,或者可以例如通过在US-A-5145684中公开的方法纤化(nanonised)。
本发明也提供一个生产本发明化合物的方法,它包括使3-(5-甲基异噁唑-3-基)-6-(1H-1,2,3-三唑-5-基)甲基氧基-1,2,4-三唑并[3,4-a]酞嗪与甲基化剂,如六甲基二硅叠氮化锂(hexamethyldisilazide)反应。
该反应一般在诸如DMF的溶剂中,一般于0℃以下的温度和热至约室温的温度,以及一般在诸如氮气的惰性气体下进行。反应混合物一般允许静止4-12小时。需要的产物一般通过诸如制备HPLC的常规分离技术由其它反应产物中纯化。
在上述任一合成阶段中,可能必须和/或希望保护任一相关分子上的敏感基或反应基。这可以利用常规的保护基团实现,诸如在Protective Groups in Organic Chemistry,J.F.W.McOmie编辑,PlenumPress,1973;和T.W.Greene & P.G.M.Wuts,Protective Groups inOrganic Synthesis,John Wiley & Sons,1991中描述的那些保护基团。所述保护基团可以使用本领域已知的方法在随后的适宜阶段除去。
按照本发明的化合物有效地抑制[3H]-除草定(flumazenil)与稳定地在Ltk-细胞中表达的含有α5亚单位的人GABAA受体的苯并二氮杂结合位点的结合。试剂
·磷酸缓冲盐溶液(PBS)。
·检定缓中液:于室温下的10mM KH2PO4,100mM KCl,pH7.4。
·在检定缓冲液中的[3H]-除草定(18nM的α1β3γ2细胞;18nM的α2β3γ2细胞;10nM的α3β3γ2细胞;10nM的α5β3γ2细胞)。
·在检定缓冲液中的100μM氟硝安定。
·在检定缓冲液中重悬浮的细胞(1盘10ml)。收获细胞
由细胞中除去上清液。加入PBS(大约20ml)。刮出细胞并置入一50ml离心管中。再用10ml PBS重复此步骤,以确保取出大部分细胞。通过在台式离心机中于3000rpm离心20分钟,将细胞沉淀,然后冷冻(如果需要)。以每盘(25厘米×25厘米)细胞10ml缓冲液重悬浮所述沉淀。检定
可以在深96孔板中或在试管中进行。每个试管含有:
·300μl检定缓冲液。
·50μl[3H]-除草定(终浓度为α1β3γ2:1.8nM;α2β3γ2:1.8nM;α3β3γ2:1.0nM;α5β3γ2:1.0nM)。
·50μl缓冲液或溶剂溶媒(例如10%DMSO)(如果化合物溶解在10%DMSO(总)中);测试化合物或氟硝安定(测定非特异性结合),10μM终浓度。
·100μl细胞。
试样于40℃温育1小时,然后用或Tomtec或Brandel细胞收集器将其过滤到GF/B滤器上,接着用3×3ml冰冷的检定缓冲液清洗。干燥滤器并通过液体闪烁计数来计数。如果使用液体闪烁计数,那么总结合的预期值为3000-4000dpm(总计数)和少于200dpm(非特异性结合),或者如果使用meltilex固体闪烁计数,那么总结合的预期值为1500-2000dpm(总计数)和少于200dpm(非特异性结合)。通过非线性最小平方回归分析测定结合参数,由此可以计算出测试化合物的抑制常数Ki。
按照本发明的化合物有效地抑制[3H]-除草定与稳定地在Ltk-细胞中表达的含有α5亚单位的人GABAA受体的苯并二氮杂结合位点的结合。
在上述检定中测试所附实施例的化合物,发现其具有[3H]Ro 15-1788置换的100nM或更少的人GABAA受体的α5亚单位的Ki值。
已经表明,本发明的化合物在大鼠水迷宫测试(Morris,Learning和Motivation,1981,12,239 ff)中有增强认知作用。可以在WO-A-9625948中找到证明本化合物增强认知作用的方法学的更多细节。这已经在0.3mg/kg的最小有效剂量得到证明,在此剂量本发明的化合物占有40%的受体。在3mg/kg的剂量下也已得到证明。
本发明的化合物可以按以下实施例所述制备。反应条件的精确细节和反应步骤的明显修改,完全在技术人员的能力范围内。
中间体16-氯-3-(5-甲基异噁唑-3-基)-1,2,4-三唑并[3,4-a]酞嗪a)1-氯-4-肼基酞嗪
向沸腾的一水合肼(37.3ml,0.765mmol)的乙醇(500ml)溶液中加入1,4-二氯酞嗪(20.0g,0.100mol),并将混合物回流加热半小时。将该混合物冷却至室温,通过过滤收集固体并用乙醚清洗。用正丁醇和氨水溶液(比重0.91)处理该物质,加热直至所述固体溶解。分离出有机层,真空蒸发,残余物同二甲苯共沸(2次)并真空干燥,得到标题-肼(11.5g,59%),1H NMR(250MHz,d6DMSO)δ7.84-8.04(3H,m,Ar-H);8.20(1H,m,Ar-H);MS(ES+)m/e 194[MH]+。b)5-甲基异噁唑-3-羧酸
在氮气流下小心地使丙酮基丙酮(10g,88mmol)和硝酸(比重1.42)/水(2∶3)(50ml)的混合物回流,并沸腾1小时。将该溶液冷却至室温并过夜老化。通过过滤收集产生的固体,用冷却水(2×7ml)和己烷清洗并真空干燥,得到标题-酸(4.4g,40%),1H NMR(CDCl3)δ2.50(3H,d,J=0.8Hz,Me),6.41(1H,d,J=0.8Hz,Ar-H)。c)6-氯-3-(5-甲基异噁唑-3-基)-1,2,4-三唑并[3,4-a]酞嗪
于0℃在氮气下,向搅拌的1-氯-4-肼基酞嗪(8.00g,41.2mmol)的二氯甲烷(1升)悬浮液中连续加入5-甲基异噁唑-3-羧酸(5.24g,41.3mmol)、二(2-氧代-3-噁唑烷基)次膦酸氯(phosphinic chloride)(10.5g,41.2mmol)和三乙胺(11.5ml,82.5mmol)。混合物于0℃搅拌2小时并于室温过夜。真空蒸发溶剂,用水研磨残余物并过滤出固体,用己烷清洗并真空干燥,得到酮肼(11g),MS(ES+)m/e 304[MH]+。将酮肼(11g)和盐酸三乙胺(2.2g,20%重量)的二甲苯(500ml)溶液回流加热3小时。将该混合物冷却至室温并真空蒸发溶剂。残余物在二氯甲烷中溶解,用水清洗(2次),干燥(MgSO4)并真空蒸发,固体重结晶(二氯甲烷/己烷)得到标题-化合物(6.8g,58%),1H NMR(360MHz,CDCl3)δ2.59(3H,s,Me),6.90(1H,s,Ar-H),7.95(1H,m,Ar-H),8.07(1H,m,Ar-H),8.34(1H,m,Ar-H),8.78(1H,s,Ar-H);MS(ES+)m/e 286[MH]+。
相关实施例13-(5-甲基异噁唑-3-基)-6-(2-吡啶基)甲氧基-1,2,4三唑并[3,4-a]酞嗪
于室温在氮气下,向搅拌的2-吡啶甲醇(470mg,4.27mmol)的DMF(60ml)溶液中加入氢化钠(244mg,60%分散到油中,6.10mmol),搅拌混合物0.25小时。在此后加入中间体1(1160mg,4.07mmol),搅拌混合物2小时。真空除去溶剂,残余物溶于二氯甲烷中,用水清洗(2次),干燥(MgSO4)并真空蒸发。在硅胶上快速层析,用3%甲醇/二氯甲烷洗脱,接着重结晶(二氯甲烷/己烷),得到标题-产物(640mg,44%),mp 234-236℃;1H NMR(360MHz,CDCl3)δ2.59(3H,d,J=0.8Hz,Me),5.77(2H,s,CH2),6.82(1H,d,J=0.8Hz,Ar-H),7.30(1H,m,Ar-H),7.74-7.85(3H,m,Ar-H),7.95(1H,m,Ar-H),8.33(1H,d,J=7.8Hz,Ar-H),8.64-8.72(2H,m,Ar-H);MS(ES+)m/e359[MH]+;实测值C,62.93;H,3.56;N,22.94。C19H14N6O20.05(CH2Cl2)理论值C,63.10;H,3.92;N,23.17%。
相关实施例26-(6-溴吡啶-2-基)甲氧基-3-(5-甲基异噁唑-3-基)-1,2,4-三唑并[3,4-a]酞嗪
由中间体1和2-溴吡啶-6-甲醇(Tetrahedron Lett1996,50,2537)按照相关实施例1给出的步骤制备标题化合物。通过向反应混合物中加入水分离该产物,滤去产生的沉淀。在硅胶上快速层析,用乙酸乙酯洗脱,重结晶(乙酸乙酯-甲醇),得到标题-酞嗪,mp 247.5-249℃;1H NMR(360MHz,CDCl3)δ2.61(3H,d,J=0.7Hz,Me),5.73(2H,s,CH2),6.82(1H,d,J=0.7Hz,Ar-H),7.48(1H,d,J=7.8Hz,Ar-H),7.63(1H,t,J=7.7Hz,Ar-H),7.76(1H,d,J=7.4Hz,Ar-H),7.84(1H,t,J=8.4Hz,Ar-H),7.98(1H,t,J=8.4Hz,Ar-H),8.31(1H,d,J=8.5Hz,Ar-H),8.70(1H,d,Ar-H);MS(ES+)m/e 437[MH]+;实测值C,52.27;H,2.85;N,19.14。C19H13N6O2Br.0.1(H2O)理论值C,51.98;H,3.03;N,18.60%。
中间体26-羟基-3-(5-甲基异噁唑-3-基)-1,2,4-三唑并[3,4-a]酞嗪
向搅拌的中间体1(1.0g,3.5mmol)的二噁烷(37.5ml)溶液中加入氢氧化钠(0.67g,17mmol)的水(7.5ml)溶液,混合物回流加热4小时。真空蒸发溶剂,在水和二乙醚之间分配残余物。分出水层,用乙醚清洗(1次),然后用2N盐酸酸化,直至pH值达到2。滤去由溶液中沉淀出的固体,用二氯甲烷提取水性滤液(3次)。干燥(MgSO4)合并的提取物并真空蒸发,合并沉淀得到标题产物(0.45g,48%),1HNMR(250MHz,d6-DMSO)δ2.58(3H,d,J=0.7Hz,Me),7.07(1H,d,J=0.9Hz,Ar-H),7.94(1H,m,Ar-H),8.08(1H,m,Ar-H),8.24(1H,d,J=7.4Hz,Ar-H),8.54(1H,d,J=7.4Hz,Ar-H),13.32(1H,brs,NH);MS(ES+)m/e 268[MH]+。
相关实施例33-(5-甲基异噁唑-3-基)-6-(1H-1,2,3-三唑-5-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪a)5-甲酰基-1-[2-(三甲基甲硅烷基)乙氧基]甲基-1,2,3-三唑
在-78℃及氮气下于0.08小时内,将正丁基锂(6.8ml的1.6M其己烷溶液,10.9mmol)滴加到搅拌的1-[2-(三甲基-甲硅烷基)乙氧基]甲基-1,2,3-三唑(J.Heterocycl.Chem1992,29,1203)(2.077g,10.42mmol)的THF(30ml)溶液中。在0.67小时内让该溶液升温至-60℃,然后重新冷却至-78℃,加入DMF(0.9ml,11.6mmol)。使该混合物升温至室温,搅拌16.5小时。加入饱和的氯化铵溶液(50ml),用二乙醚提取反应混合物(3×80ml)。干燥(MgSO4)合并的乙醚提取物,真空蒸发,残余物上硅胶层析,用30%乙酸乙酯/已烷洗脱,得到标题-三唑(1.713g,72%),1H NMR(360MHz,CDCl3)δ0.01(9H,s,Me3Si),0.92-0.99(2H,m,CH2),3.64-3.69(2H,m,CH2),6.05(2H,s,CH2),8.31(1H,s,Ar-H),10.12(1H,s,CHO)。b)5-羟甲基-1-[2-(三甲基甲硅烷基)乙氧基]甲基-1,2,3-三唑
于0℃、氮气下,向搅拌的前述三唑(1.704g,7.495mmol)的甲醇(8ml)溶液中加入氢硼化钠(0.284g,7.51mmol)。混合物于0℃搅拌半小时,室温下搅拌半小时。加入水,在二氯甲烷和饱和的盐水之间分配该混合物。分出水层,再用二氯甲烷提取(2次)。干燥(MgSO4)合并的有机层并真空蒸发,残余物上硅胶层析,用70%乙酸乙酯/己烷洗脱,得到标题-产物(1.34g,78%),1H NMR(360MHz,CDCl3)δ0.00(9H,s,Me3Si),0.90-0.95(2H,m,CH2),3.58-3.63(2H,m,CH2),4.84(2H,s,CH2),5.80(2H,s,CH2),7.68(1H,s,Ar-H)。c)3-(5-甲基异噁唑-3-基)-6{1-[2-(三甲基甲硅烷基)乙氧基]甲基-1,2,3-三唑-5-基}甲氧基-1,2,4-三唑并[3,4-a]酞嗪
由中间体1和前述的乙醇按照实施例10所述步骤制备标题化合物,360MHz(360MHz,CDCl3)δ0.00(9H,s,Me3Si),0.88-0.93(2H,m,CH2),2.63(3H,s,Me),3.61-3.66(2H,m,CH2),5.92(2H,s,CH2),5.97(2H,s,CH2),6.89(1H,s,Ar-H),7.86(1H,m,Ar-H),8.02(1H,t,J=7.7Hz,Ar-H),8.18(1H,s,Ar-H),8.23(1H,d,J=8.0Hz,Ar-H),8.76(1H,d,J=8.0Hz,Ar-H);MS(ES+)m/e 479[MH]+。d)3-(5-甲基异噁唑-3-基)-6-(1H-1,2,3-三唑-5-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪
将前述产物、乙醇(10ml)和2N HCl(20ml)的混合物于50℃加热15.25小时。用饱和的碳酸钠溶液碱化该溶液至pH为12,真空蒸发溶剂。残余物同乙醇共沸(2次),上硅胶层析,用0-4%甲醇/二氯甲烷(梯度洗脱液)洗脱,得到标题产物,1H NMR(400MHz,CDCl3)δ2.65(3H,s,Me),5.73(2H,s,CH2),7.02(1H,s,Ar-H),7.87(1H,t,J=7.8Hz,Ar-H),7.99-8.03(2H,m,2个Ar-H),8.24(1H,d,J=8.2Hz,Ar-H),8.72(1H,d,J=7.9Hz,Ar-H);MS(ES+)m/e 349[MH]+。
实施例13-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-5-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪、3-(5-甲基异噁唑-3-基)-6-(2-甲基-1,2,3-三唑-4-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪和3-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-4-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪
于-31℃在氮气下,将六甲基二硅叠氮化锂(1.63ml的1M THF溶液,1.63mmol)滴加到搅拌的按相关实施例3制备的3-(5-甲基异噁唑-3-基)-6-(1H-1,2,3-三唑-5-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪(241mg,0.626mmol)的DMF(50ml)溶液中。使该混合物1.5小时内升温至-23℃,滴加甲基碘(0.10ml,1.6mmol),让反应物升温至室温过夜。加入水并真空蒸发溶剂。残余物在二氯甲烷和水之间分配,分出水相,用二氯甲烷再提取(1次)。合并的有机相用盐水清洗(1次),干燥(MgSO4)并真空蒸发。残余物上硅胶层析,用0-5%甲醇/二氯甲烷(梯度洗脱液)洗脱,接着通过制备HPLC(YMC硅胶柱,250×20毫米),用5%甲醇/1-氯丁烷洗脱,分离三唑异构体:
最小极性的异构体(HPLC溶剂系统):3-(5-甲基异噁唑-3-基)-6-(2-甲基-1,2,3-三唑-4-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪1H NMR(400MHz,CDCl3)δ2.59(3H,s,Me),4.21(3H,s,Me),5.73(2H,s,CH2),6.89(1H,s,Ar-H),7.79(1H,m,Ar-H),7.94(1H,m,Ar-H),8.10(1H,s,Ar-H),8.22(1H,d,J=8.0Hz,Ar-H),8.67(1H,d,J=8.0Hz,Ar-H);MS(ES+)m/e 363[MH]+。
中等极性的异构体:3-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-4-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪1H NMR(400MHz,CDCl3)δ2.60(3H,s,Me),4.09(3H,s,Me),5.78(2H,s,CH2),6.90(1H,d,J=0.8Hz,Ar-H),7.80(1H,m,Ar-H),7.94(1H,m,Ar-H),8.25(1H,d,J=8.0Hz,Ar-H),8.65(1H,d,J=8.0Hz,Ar-H),8.73(1H,s,Ar-H);MS(ES+)m/e 363[MH]+。
最大极性的异构体(HPLC溶剂系统):3-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-5-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪1H NMR(400MHz,CDCl3)δ2.56(3H,s,Me),4.19(3H,s,Me),5.76(2H,s,CH2),6.82(1H,s,Ar-H),7.80(1H,m,Ar-H),7.96(1H,m,Ar-H),8.04(1H,s,Ar-H),8.12(1H,d,J=8.8Hz,Ar-H),8.67(1H,d,J=8.0Hz,Ar-H);MS(ES+)m/e 363[MH]+。
Claims (5)
1.3-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-4-基)甲氧基-1,2,4-三唑并[3,4-a]酞嗪。
2.含有权利要求1所述化合物和药学上可接受的载体的药用组合物。
3.3-(5-甲基异噁唑-3-基)-6-(1-甲基-1,2,3-三唑-4-基)甲基氧基-1,2,4-三唑并[3,4-a]酞嗪在治疗人或动物机体的方法中的用途。
4.权利要求1的化合物在用于增强认知作用的药物生产中的用途。
5.在患有认知功能降低的患者中增强认知功能的方法,它包括给予该患者认知功能增强量的权利要求1的化合物。
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PCT/GB1998/001307 WO1998050385A1 (en) | 1997-05-08 | 1998-05-06 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
GBPCT/GB98/01307 | 1998-05-06 | ||
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JP2002504554A (ja) | 2002-02-12 |
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NZ505695A (en) | 2002-03-01 |
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