CN101346377A - 芳基-异噁唑-4-基-咪唑并[1,5-a]吡啶衍生物 - Google Patents
芳基-异噁唑-4-基-咪唑并[1,5-a]吡啶衍生物 Download PDFInfo
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- CN101346377A CN101346377A CNA2006800491806A CN200680049180A CN101346377A CN 101346377 A CN101346377 A CN 101346377A CN A2006800491806 A CNA2006800491806 A CN A2006800491806A CN 200680049180 A CN200680049180 A CN 200680049180A CN 101346377 A CN101346377 A CN 101346377A
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Abstract
本发明涉及式I的芳基－异噁唑－4－基－咪唑并[1，5－a]吡啶衍生物及其可药用的酸加成盐，其中：R1为氢、卤素、羟基、低级烷基、苄氧基或－O－(CH2)－(CO)－五或六元杂芳基，所述杂芳基任选地被芳基和低级烷基取代；R2为氢、低级烷基或－(CO)－Ra；R3为氢、卤素、氰基、低级烷基或－(CO)－Ra；Ra为羟基、低级烷氧基、NR’R”，其中R’和R”各自独立地为氢、环烷基、五或六元杂环烷基、或者任选地被环烷基、氰基、五或六元杂环烷基或五或六元杂芳基取代的低级烷基。现已发现，这类化合物对GABAAα5受体结合位点表现出高亲和性和选择性，并且可用作认知增强剂或用于治疗认知障碍如阿尔茨海默病。
Description
本发明涉及式I的芳基-异噁唑-4-基-咪唑并[1，5-a]吡啶衍生物及其可药用的酸加成盐：
其中：
R1为氢、卤素、羟基、低级烷基、苄氧基或-O-(CH2)-(CO)-五或六元杂芳基，所述杂芳基任选地被芳基和低级烷基取代；
R2为氢、低级烷基或-(CO)-Ra；
R3为氢、卤素、氰基、低级烷基或-(CO)-Ra；
Ra为羟基、低级烷氧基、NR’R”，其中R’和R”各自独立地为氢、环烷基、五或六元杂环烷基、或者任选地被环烷基、氰基、五或六元杂环烷基或五或六元杂芳基取代的低级烷基。
现已发现，该类化合物对GABA Aα5受体的结合位点表现出高亲和性和选择性，并且可用作认知增强剂或用于治疗认知障碍如阿尔茨海默病。
主要的抑制性神经递质γ-氨基丁酸(GABA)被分为两大类：(1)GABA A受体，该受体是配体门控离子通道超家族的成员；和(2)GABA B受体，该受体是G蛋白偶联受体家族的成员。GABA A受体复合物是膜结合的异五聚体的蛋白聚合物，其主要由α、β和γ亚基组成。
目前已经克隆并测序了GABA A受体的总共21个亚基。需要三种类型的亚基(α、β和γ)来构建重组的GABA A受体，该受体与来自哺乳动物脑细胞的天然GABA A受体在生物化学、电生理学和药理学功能上极为接近。有强有力的证据表明，苯二氮的结合位点位于α和γ亚基之间。在重组GABA A受体中，α1β2γ2模拟了典型的I型BzR亚型的许多效应，而α2β2γ2、α3β2γ2和α5β2γ2离子通道被称为II型BzR。
McNamara和Skelton在Psychobiology，21：101-108中指出苯二氮
受体的反相激动剂β-CCM可以增强在Morris水迷宫中的空间学习能力。但是，β-CCM和其他常规的苯二氮受体反相激动剂是促惊厥剂或惊厥剂，从而妨碍了它们在人中用作认知增强剂。此外，这些化合物对GABA A受体亚基之间没有选择性，但是对于GABA A α1和/或α2和/或α3受体结合位点相对而言没有活性的GABA A α5受体部分或完全反相激动剂，则可以用于提供用来增强认知而减少或没有促惊厥活性的药物。也可使用对GABA A α1和/或α2和/或α3受体结合位点没有活性、但对包含α5亚基具有功能选择性的GABA A α5反相激动剂。然而，优选对GABA A α5亚基有选择性并且在GABA A α1、α2和α3受体结合位点相对没有活性的GABA A α5反相激动剂。
本发明的目标是式I的化合物及其可药用的盐、上述化合物的制备、含有它们的药物及其制备方法，以及上述化合物在控制或预防疾病、特别是上文所涉及的疾病或病症或在制备相应药物中的应用。
按照本发明最优选的适应症是阿尔茨海默病。
无论是单独出现还是组合出现，本说明书中所用的一般术语采用以下定义。
本文所用的术语“低级烷基”表示含有1-7个、优选1-4个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基等。
术语“低级烷氧基”表示通过氧原子连接的如上所定义的低级烷基基团。低级烷氧基的实例为甲氧基和乙氧基。
术语“芳基”表示不饱和碳环，例如苯基、苄基或萘基。优选的芳基是苯基。
术语“卤素”表示氯、碘、氟和溴。
术语“环烷基”表示具有3-7个碳环原子的环状烷基环，例如环丙基、环戊基或环己基。
术语“杂环烷基”表示含有1-3个杂原子如N、O或S原子的饱和五或六元环。杂环烷基的实例为吗啉基或四氢吡喃基，以及在那些下文的实施例中具体举例说明的基团。
术语“杂芳基”表示含有1-3个杂原子如N、O或S原子的芳香族五或六元环。所述芳香族的杂芳基的实例为吡啶基、三唑基、异噁唑基、呋喃基、噻吩基、咪唑基、噁唑基或吡嗪基。
术语“可药用的酸加成盐”包括与无机和有机酸如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等形成的盐。
优选的化合物具有低于100nM的结合活性(hKi)，并且对于GABA Aα5亚基有选择性，对GABA A α1、α2和α3受体结合位点相对没有活性。
如上文所述，本发明化合物是式I的化合物及其可药用的酸加成盐，其中：
R1为氢、卤素(优选Cl和Br)、羟基、低级烷基(优选甲基)、苄氧基或-O-(CH2)-(CO)-五或六元杂芳基(优选异噁唑基)，所述杂芳基任选地被芳基(优选苯基)和低级烷基(优选甲基)取代；
R2为氢、低级烷基(优选甲基或乙基)或-(CO)-Ra；
R3为氢、卤素(优选Cl或Br)、氰基、低级烷基(优选甲基或乙基)或-(CO)-Ra；
Ra为羟基、低级烷氧基(优选甲氧基或乙氧基)、NR’R”其中R’和R”各自独立地为氢、环烷基(优选环丙基)、五或六元杂环烷基(优选吗啉基或四氢吡喃基)、或者任选地被环烷基(优选环丙基)、氰基、五或六元杂环烷基(优选吗啉基或四氢吡喃基)或五或六元杂芳基(优选吡啶基或呋喃基)所取代的低级烷基。
在某个本发明的式I化合物的实施方案中，R3为氢，例如以下化合物：
3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶。
在某个本发明的式I化合物的实施方案中，R3为-(CO)-Ra，其中的Ra为低级烷氧基或NR’R”，其中R’和R”各自独立地为氢、环烷基、五或六元杂环烷基、或者任选地被环烷基、氰基、五或六元杂环烷基或者五或六元杂芳基所取代的低级烷基，例如以下的化合物：3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲腈和3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸甲酯。
式I的化合物及其可药用的盐可以通过本领域已知的方法，例如下述方法制备，该方法包括：
将式II的化合物
与亚硫酰氯反应得到式III的化合物，
然后将其与式IV的化合物反应，
得到式V的化合物，
然后，将式V化合物在合适的溶剂如二氯乙烷中、与脱水剂如三氯氧化磷反应，得到式I的化合物
其中R1、R2和R3如上所述，并且如果需要，将式I的化合物转化为可药用的盐。
以下的反应流程更详细地描述了制备式I化合物的方法。
流程图1
在0℃条件下，将5-甲基-3-苯基-异噁唑-4-甲酰氯III与6-氨基甲基-烟腈盐酸盐IV(流程图1中未显示)在乙酸乙酯和水的混合物中反应，得到中间体酰胺V-a，然后可以将其与三氯氧化磷在二氯乙烷中加热回流，得到式I-a的化合物。
流程图2
或者，在0℃条件下，可以将5-甲基-3-苯基-异噁唑-4-甲酰氯III与6-氨基甲基-烟酸甲酯IV(流程图2中未显示)在乙酸乙酯和水的混合物中反应，得到中间体酰胺V-b，然后可以将其与三氯氧化磷在二氯乙烷中加热回流，得到式I-b的化合物。随后，在甲醇、THF、水的混合物中用氢氧化锂使该酯发生皂化反应，得到式I-c的酸，其可以用1-乙基-3-(3’-二甲氨基丙基)碳二亚胺、1-羟基苯并三唑、三乙胺通过标准方法活化，接着与所选择的胺(RNH2)反应，得到式I-d的化合物。
如前所述，式I化合物及其可药用的盐具有有价值的药理学特性。已发现本发明化合物是含有α5亚基的GABA A受体的配体，并因此用于需要增强认知的治疗。
按照下文给出的试验对这些化合物进行研究。
膜的制备和结合试验
通过与[3H]氟马西尼(85Ci/mmol；罗氏公司(Roche))竞争性结合表达大鼠(稳定转染)或人(瞬时转染)的受体(包括成分α1β3γ2、α2β3γ2、α3β3γ2和α5β3γ2)的HEK293细胞来测定化合物对GABA A受体亚型的亲和性。
将细胞碎片悬浮在Krebs-tris缓冲液(4.8mM KCl，1.2mM CaCl2，1.2mM MgCl2，120mM NaCl，15mM Tris；pH 7.5；结合试验缓冲液)中，在冰上用polytron匀浆约20秒，然后在4℃下离心60分钟(50000g；Sorvall，转子：SM24＝20000rpm)。将细胞碎片重悬在Krebs-tris缓冲液中并在冰上通过polytron匀浆约15秒。测定蛋白质(Bradford法，伯乐公司(Bio-Rad))，将其制成1mL的小份并保存在-80℃下。
在200mL体积(96孔板)中进行放射性配体结合试验，所述体积中含有100mL细胞膜、浓度为1nM(对于α1、α2、α3亚基)和0.5nM(对于α5亚基)的[3H]氟马西尼、以及10-10-3×10-6M范围内的待测化合物。非特异性的结合通过10-5M的地西泮来定义，其通常占总结合量的5％以下。试验在4℃下孵育1小时以达到平衡，然后用Packard收集器通过过滤收集到GF/C Uni-filter滤器(Packard)上，并用冰冷的洗涤缓冲液(50mM Tris；pH7.5洗涤。干燥后，通过液体闪烁计数检测滤器上保留的放射性。利用Excel-Fit(微软公司)来计算Ki值，该值是两次测定的平均值。
将所附的实施例的化合物在上述试验中进行测试，发现优选的化合物具有100nM或更低的从大鼠GABA A受体α5亚基置换[3H]氟马西尼的Ki值。在优选的实施方案中，相对于α1、α2和α3亚基，本发明的化合物对α亚具有结合选择性。实施例1的化合物，即3-(5-甲基-3-苯基-异噁唑-4-基-咪唑并[1，5-a]吡啶的Ki[nM]hα5值为77.9nM。
式I化合物及其可药用的酸加成盐可以例如以药物制剂的形式用作药物。所述药物制剂可以例如以片剂、包衣片、糖锭剂、硬和软明胶胶囊、溶液剂、乳剂或混悬剂的形式进行口服给药。然而，也可以例如以栓剂形式经直肠给药，或者例如以注射液的形式进行胃肠外给药。
式I化合物及其可药用的酸加成盐可以与用于生产片剂、包衣片、糖锭剂和硬明胶胶囊的药用惰性的无机或有机赋形剂一起加工。可以使用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等作为例如片剂、糖锭剂和硬明胶胶囊的赋形剂。适合用于软明胶胶囊的赋形剂例如植物油、蜡类、脂肪、半固体和液体的多元醇等。
用于制备溶液剂和糖浆剂的适宜的赋形剂例如水、多元醇、蔗糖、转化糖、葡萄糖等。
用于注射溶液的适宜的赋形剂例如水、醇、多元醇、甘油、植物油等。
用于栓剂的适宜的赋形剂例如天然的或硬化的油、蜡类、脂肪、半液体或液体多元醇等。
此外，所述药物制剂还可以包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲液、掩蔽剂或抗氧化剂。它们还可以包含其他在治疗上有价值的物质。
剂量可在较宽的范围内变化，当然，在每个具体病例中会根据个体需求进行调整。通常，在口服给药的情况下，每人约10-1000mg通式I的化合物的日剂量应当是适宜的，但在需要时也可超过所述上限。
以下实施例是对本发明进行举例说明，而不是限制本发明。所有温度以摄氏度给出。
实施例A
按照常规方式制备具有以下成分的片剂：
mg/片
活性物质 5
乳糖 45
玉米淀粉 15
微晶纤维素 34
硬脂酸镁 1
片重 100
实施例B
制备具有以下成分的胶囊：
mg/胶囊
活性物质 10
乳糖 155
玉米淀粉 30
滑石粉 5
胶囊填充重量 200
将活性物质、乳糖和玉米淀粉首先在混合器中、然后在粉碎机中进行混合。将混合物重新回到混合器中，向其中加入滑石粉并充分混合。通过机器将该混合物填入硬明胶胶囊中。
实施例C
制备具有以下成分的栓剂：
mg/栓剂
活性物质 15
栓剂基质 1285
总重 1300
将栓剂基质在玻璃或钢容器中熔化，充分混合并冷却至45℃。随后将活性物质的细粉加入其中，并搅拌到其完全分散。将混合物倾入适当大小的栓剂模型中，放置冷却，然后将栓剂从模型中取出并单个包装在蜡纸或金属箔中。
以下实施例1-5用来举例说明本发明。不应该将它们视为对本发明的范围的限制，其仅仅是本发明的代表。
实施例1
3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶
a)5-甲基-3-苯基-异噁唑-4-甲酸(吡啶-2-基甲基)-酰胺
将5-甲基-3-苯基-异噁唑-4-甲酸(4.06g，20mmol，可从商业上购买)和亚硫酰氯(5mL)的混合物回流加热3h。蒸发掉全部挥发物，得到黄色油状的5-甲基-3-苯基-异噁唑-4-甲酰氯(4.4g，93％)，其不经进一步纯化即用于下一步反应。向2-吡啶甲基胺(0.182g，1.68mmol)在水(2mL)和乙酸乙酯(4mL)的水溶液混合物中一次性地加入碳酸氢钠(362mg，4.2mmol)。然后，在冰浴中保持0℃并同时剧烈搅拌的条件下，滴加5-甲基-3-苯基-异噁唑-4-甲酰氯(0.31g，1.4mmol)在乙酸乙酯(2mL)中的溶液。滴加完毕后，将反应混合物在室温下搅拌18h。然后将所得的溶液用乙酸乙酯稀释。分离有机层，并用乙酸乙酯萃取水层。然后将合并的萃取物用盐水洗涤，用硫酸钠干燥并浓缩，得到白色固体状的标题化合物(0.38g，93％)。MS：m/e：294.1[M+H]+。
b)3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶
用注射器将三氯氧化磷(0.47mL，5mmol)加入到5-甲基-3-苯基-异噁唑-4-甲酸(吡啶-2-基甲基)-酰胺(0.293g，1mmol)在二氯乙烷(5mL)的溶液中，并将所得混合物加热回流过夜。冷却至室温后，用二氯甲烷稀释该混合物。然后将冷的饱和碳酸氢钠(15mL)缓慢加入，并将混合物用力搅拌15min。分离有机层，并用二氯甲烷萃取水层。将合并的萃取物用水洗涤，用硫酸钠干燥并蒸发。用反相[0.1％氨水(25％)]制备型HPLC进行纯化，得到橙色固体状的标题化合物(0.13g，47％)。MS：m/e：276.1[M+H]+。
实施例2
3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲腈
a)5-甲基-3-苯基-异噁唑-4-甲酸(5-氰基-吡啶-2-基甲基)-酰胺
按照实施例1a所述的方法，用6-氨基甲基-烟腈盐酸盐(0.17g，1mmol)代替2-吡啶甲基胺，将5-甲基-3-苯基-异噁唑-4-甲酰氯(0.266g，1.2mmol)转化为白色固体状的标题化合物(296mg，93％)。MS：m/e：319.0[M+H]+。
b)3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲腈
按照实施例1b所述的方法，将5-甲基-3-苯基-异噁唑-4-甲酸(5-氰基-吡啶-2-基甲基)-酰胺(0.12g，0.377mmol)转化为浅黄色固体状的标题化合物(60mg，44％)。MS：m/e：301.3[M+H]+。
实施例3
3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸甲酯
a)6-{[(5-甲基-3-苯基-异噁唑-4-羰基)-氨基]-甲基}-烟酸甲酯
按照实施例1a所述的方法，用6-氨基甲基-烟酸甲酯(313mg，1.88mmol)（J.Med.Chem.2002，45，5005-5022)代替2-吡啶甲基胺，将5-甲基-3-苯基-异噁唑-4-甲酰氯(0.5g，2.26mmol)转化为白色固体状的标题化合物(0.56g，85％)。MS：m/e：352.0[M+H]+。
b)3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸甲酯
按照实施例1b所述的方法，将6-{[(5-甲基-3-苯基-异噁唑-4-羰基)-氨基]-甲基)-烟酸甲酯(0.56g，1.6mmol)转化为黄色固体状的标题化合物(0.266g，50％)。MS：m/e：334.3[M+H]+。
实施例4
3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸环丙基甲基-酰胺
a)3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸
向3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸甲酯(0.25g，0.75mmol)在水(6mL)和甲醇(3mL)中的混悬液中一次性加入一水合氢氧化锂(0.21g，5mmol)。将反应混合物在室温下搅拌4.5h。蒸发(除去甲醇)后，用乙醚萃取剩余的混合物。然后用HCl水溶液(2N)将水层酸化至约pH5。过滤收集浅黄色的沉淀物，并用水洗涤，得到浅黄色固体的标题化合物(0.2g，83％)。MS：m/e：320.1[M+H]+。
b)3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸环丙基甲
基-酰胺
在室温下将含有3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸(58mg，0.18mmol)、1-乙基-3-(3’-二甲氨基丙基)碳二亚胺(52mg，0.27mmol)、1-羟基苯并三唑(24mg，0.18mmol)、三乙胺(60μL，0.45mmol)和环丙基甲胺(20mg，0.27mmol)的DMF(1mL)溶液搅拌过夜。用反相(0.1％氨水(25％))制备型HPLC进行纯化，得到浅黄色固体状的标题化合物(34mg，50％)。MS：m/e：373.3[M+H]+。
实施例5
3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸(四氢-吡喃-4-基)-酰胺
按照实施例4b所述的方法，用四氢吡喃-4-基胺(28mg，0.27mmol)代替环丙基甲胺，将3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸(58mg，0.18mmol)转化为浅黄色固体状的标题化合物(40mg，55％)。MS：m/e(ESI)：403.3[M+H]+。
Claims (14)
1.式I的芳基-异噁唑-4-基-咪唑并[1，5-a]吡啶衍生物及其可药用的酸加成盐：
其中：
R1为氢、卤素、羟基、低级烷基、苄氧基或-O-(CH2)-(CO)-五或六元杂芳基，所述杂芳基任选地被芳基和低级烷基取代；
R2为氢、低级烷基或-(CO)-Ra；
R3为氢、卤素、氰基、低级烷基或-(CO)-Ra；
Ra为羟基、低级烷氧基、NR’R”，其中R’和R”各自独立地为氢、环烷基、五或六元杂环烷基、或者任选地被环烷基、氰基、五或六元杂环烷基或五或六元杂芳基取代的低级烷基。
2.如权利要求1所述的式I的芳基-异噁唑-4-基-咪唑并[1，2-a]吡啶衍生物，其中R3为氢。
3.如权利要求2所述的式I的芳基-异噁唑-4-基-咪唑并[1，2-a]吡啶衍生物，其中所述化合物为3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶。
4.如权利要求1所述的式I的芳基-异噁唑-4-基-咪唑并[1，2-a]吡啶衍生物，其中R3为-(CO)-Ra，其中的Ra为低级烷氧基或NR’R”，其中R’和R”各自独立地为氢、环烷基、五或六元杂环烷基、或者任选地被环烷基、氰基、五或六元杂环烷基或五或六元杂芳基取代的低级烷基。
5.如权利要求4所述的式I的芳基-异噁唑-4-基-咪唑并[1，2-a]吡啶衍生物，其中所述化合物为3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲腈和3-(5-甲基-3-苯基-异噁唑-4-基)-咪唑并[1，5-a]吡啶-6-甲酸甲酯。
6.制备如权利要求1中所定义的式I化合物的方法，该方法包括将式II的化合物
与亚硫酰氯反应得到式III的化合物，
然后将式III的化合物与式IV的化合物反应
得到式V的化合物，
然后在合适的溶剂中将式V的化合物与脱水剂反应，得到式I的化合物，
其中R1、R2和R3如上所述，并且如果需要，将式I的化合物转化为可药用的盐。
7.如权利要求6所述的方法，其中所述脱水剂为三氯氧化磷，所述溶剂为二氯乙烷。
8.任何通过如权利要求6或7中任意一项所述的方法或等价方法制备的如权利要求1-5中任意一项所述的式I化合物。
9.包含如权利要求1-5中任意一项所述的一种或多种式I化合物和可药用赋形剂的药物。
10.治疗与GABA A α5亚基有关疾病的如权利要求9所述的药物，所述疾病选自认知增强剂或认知障碍。
11.用于治疗阿尔茨海默病的如权利要求10所述的药物。
12.如权利要求1-5中任意一项所述的式I化合物在制备治疗认知增强剂或认知障碍的药物中的用途。
13.如权利要求1-5中任意一项所述的式I化合物在制备治疗阿尔茨海默病的药物中的用途。
14.如上所述的本发明。
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| EA201691594A1 (ru) | 2014-02-13 | 2017-02-28 | Инсайт Корпорейшн | Циклопропиламины в качестве ингибиторов lsd1 |
| WO2016007722A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Triazolopyridines and triazolopyrazines as lsd1 inhibitors |
| US9695180B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors |
| WO2016007731A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Imidazopyridines and imidazopyrazines as lsd1 inhibitors |
| EP3626720A1 (en) | 2015-04-03 | 2020-03-25 | Incyte Corporation | Heterocyclic compounds as lsd1 inhibitors |
| DK3334709T3 (da) | 2015-08-12 | 2025-02-03 | Incyte Holdings Corp | Salte af en lsd1-hæmmer |
| BR102019014802A2 (pt) | 2018-07-20 | 2020-02-04 | Boehringer Ingelheim Int | difluorometil-fenil triazóis |
| WO2020047198A1 (en) | 2018-08-31 | 2020-03-05 | Incyte Corporation | Salts of an lsd1 inhibitor and processes for preparing the same |
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| US6511987B1 (en) * | 1999-11-12 | 2003-01-28 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
| JP2005518357A (ja) * | 2001-11-20 | 2005-06-23 | イーライ・リリー・アンド・カンパニー | ベータ３アドレナリンアゴニスト |
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- 2006-12-18 BR BRPI0620760-0A patent/BRPI0620760A2/pt not_active IP Right Cessation
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- 2006-12-18 RU RU2008125040/04A patent/RU2420527C2/ru not_active IP Right Cessation
- 2006-12-18 AT AT06841391T patent/ATE537171T1/de active
- 2006-12-18 EP EP06841391A patent/EP1968977B1/en not_active Not-in-force
- 2006-12-18 KR KR1020087015509A patent/KR101033719B1/ko not_active IP Right Cessation
- 2006-12-18 US US11/640,768 patent/US7399769B2/en not_active Expired - Fee Related
- 2006-12-18 WO PCT/EP2006/069792 patent/WO2007074089A1/en active Application Filing
- 2006-12-18 CA CA002633536A patent/CA2633536A1/en not_active Abandoned
- 2006-12-18 CN CN2006800491806A patent/CN101346377B/zh not_active Expired - Fee Related
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| TW200734328A (en) | 2007-09-16 |
| KR20080072072A (ko) | 2008-08-05 |
| US20070191421A1 (en) | 2007-08-16 |
| TWI324156B (en) | 2010-05-01 |
| AR058728A1 (es) | 2008-02-20 |
| ATE537171T1 (de) | 2011-12-15 |
| AU2006331363B2 (en) | 2012-07-05 |
| KR101033719B1 (ko) | 2011-05-09 |
| NO20082748L (no) | 2008-09-24 |
| ES2376357T3 (es) | 2012-03-13 |
| RU2008125040A (ru) | 2010-02-10 |
| CN101346377B (zh) | 2011-05-11 |
| WO2007074089A1 (en) | 2007-07-05 |
| RU2420527C2 (ru) | 2011-06-10 |
| JP4864982B2 (ja) | 2012-02-01 |
| IL192236A0 (en) | 2008-12-29 |
| CA2633536A1 (en) | 2007-07-05 |
| US7399769B2 (en) | 2008-07-15 |
| AU2006331363A1 (en) | 2007-07-05 |
| ZA200805354B (en) | 2009-10-28 |
| JP2009521517A (ja) | 2009-06-04 |
| EP1968977B1 (en) | 2011-12-14 |
| BRPI0620760A2 (pt) | 2011-11-22 |
| EP1968977A1 (en) | 2008-09-17 |
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