CN101291939B - 作为mGluR5受体拮抗剂的噻唑并[4,5-C]吡啶衍生物 - Google Patents
作为mGluR5受体拮抗剂的噻唑并[4,5-C]吡啶衍生物 Download PDFInfo
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- CN101291939B CN101291939B CN2006800386693A CN200680038669A CN101291939B CN 101291939 B CN101291939 B CN 101291939B CN 2006800386693 A CN2006800386693 A CN 2006800386693A CN 200680038669 A CN200680038669 A CN 200680038669A CN 101291939 B CN101291939 B CN 101291939B
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- pyridin
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- thiazolo
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Abstract
本发明涉及通式(I)化合物，在式(I)中，R1、R2和R3如说明书中所定义，该化合物作为代谢性谷氨酸受体拮抗剂，可用于治疗或预防mGluR5受体介导的疾病。
Description
本发明涉及下列通式I的杂环衍生物及其药学上可接受的盐：
其中：
R1为氢、卤素、氰基、低级烷氧基、低级烷基或被卤素取代的低级烷基，或者为环烷基、-(CH2)n-O-低级烷基、-C(O)R’，其中R’为低级烷基、低级烷氧基或NR2；
R2为芳基或5-或6-元杂芳基；
R3为氢、OR、NR2、低级烷基、环烷基、芳基、杂环烷基、5-或6-元杂芳基、C(O)NR2、被卤素取代的低级烷基或-C(O)R’，其中R’为低级烷基、低级烷氧基或NR2；
其中所述R2和R3的芳基、环烷基、杂环烷基或5-或6-元杂芳基可以是未取代的或者被下列基团取代：卤素、氰基、低级烷基、低级烷氧基、S(O)2-烷基、S(O)-烷基、-C(O)R’，其中R’为低级烷基、低级烷氧基或NR2；
R为氢或低级烷基；
n为0、1或2。
现令人惊奇地发现，通式I的化合物是代谢型(metabotropic)谷氨酸受体的拮抗剂。式I化合物以其有价值的治疗性能而闻名。它们可以用于治疗或预防mGluR5受体介导的疾病。
此类疾病为急性和/或慢性神经疾病，特别是急性或慢性的疼痛；尿失禁；胃肠道返流病；药物或疾病导致的肝损伤或肝功能衰竭；肥胖或脆性-X综合征或自闭症；神经系统的急性、外伤性和慢性退行性病变，例如阿尔茨海默氏病、老年性痴呆、帕金森氏病、亨廷顿舞蹈病、肌萎缩侧索硬 化症和多重硬化症；精神疾病，例如精神分裂症、焦虑症、抑郁症和药物依赖。
在中枢神经系统(CNS)中，刺激的传导是通过神经元释放的神经递质与神经受体之间的相互作用进行的。
谷氨酸是脑中主要的兴奋性神经递质并在各种中枢神经系统(CNS)功能中起着独特的作用。可以将谷氨酸依赖性刺激受体分为两个大组。第一个大组称为离子型(ionotropic)受体，它可以形成配体控制的离子通道。代谢型谷氨酸受体(mGluR)属于第二大组，并属于G-蛋白偶联受体家族。
目前，人们已知mGluR有8个不同成员，其中某些甚至具有亚型。根据它们的序列同源性、信号转导机制和激动剂选择性，这8种受体可以再分为三个亚组：mGluR1和mGluR5属于第I组，mGluR2和mGluR3属于第II组，而mGluR4、mGluR6、mGluR7和mGluR8属于第III组。
属于第一组的代谢型谷氨酸受体的配体可以用于治疗或预防急性和/或慢性神经性疾病，如精神病、癫痫、精神分裂症、阿尔茨海默氏病、认知障碍和记忆缺陷以及慢性和急性疼痛。
在此方面，可以治疗的其他适应症为由旁路手术或移植引起的脑功能受限、脑供血不足、脊髓损伤、头损伤、怀孕引起的组织缺氧、心脏停搏和低血糖。其他可治疗的适应症为局部缺血、亨廷顿舞蹈病、肌萎缩性侧索硬化症(ALS)、AIDS引起的痴呆、眼损伤、视网膜病、特发性帕金森病或药物引起的帕金森病以及导致谷氨酸功能缺陷的疾病例如肌痉挛、惊厥、偏头痛、尿失禁、尼古丁成瘾、鸦片成瘾、焦虑、呕吐、运动障碍、胃肠道返流病和抑郁。
完全或部分由mGluR5介导的疾病为例如急性、创伤性和慢性神经系统退行性病变，例如阿尔茨海默氏病、老年痴呆、帕金森氏病、亨廷顿舞蹈病、肌萎缩性侧索硬化症和多发性硬化、精神病(如精神分裂症和焦虑症)、抑郁症、疼痛和药物依赖(Expert Opin.Ther.Patents(2002)，12，(12))。
本发明涉及式I化合物、式I化合物及其药学上可接受的盐在制备用于治疗mGluR5受体介导的疾病的药物中的用途，所述疾病为急性和/或慢性神经病，特别是急性或慢性的疼痛；尿失禁；胃肠道返流病；疾病或药 物导致的肝损伤或肝功能衰竭；肥胖或脆性-X综合征或自闭症；神经系统的急性、外伤性和慢性退行性病变，例如阿尔茨海默氏病、老年性痴呆、帕金森氏病、亨廷顿舞蹈病、肌萎缩侧索硬化症和多重硬化症；精神疾病，例如精神分裂症和焦虑症；抑郁症和药物依赖。另外，本发明涉及含有一或多个式I化合物的药物以及此类化合物的制备方法。
不论所述术语单独出现还是组合出现，本说明书中所使用的下列通用术语的定义都适用。
本说明书中所使用的术语“低级烷基”是指具有1-6个碳原子(优选具有1-4个碳原子)的直链或支链饱和烃基，如甲基、乙基、正-丙基、异-丙基、正-丁基、叔丁基等。
术语“低级烷氧基”是指通过氧连接的具有上述定义的低级烷基。“低级烷氧基”的实例包括甲氧基、乙氧基、异丙氧基等。
术语“卤素”是指氟、氯、溴和碘。
术语“被卤素取代的低级烷基”是指被一或多个卤素原子取代的如上文所定义的低级烷基。此类基团的实例包括但不限于被一或多个Cl、F、Br或I原子取代的甲基、乙基、丙基、异丙基、异丁基、仲-丁基、叔-丁基、戊基或正-己基以及那些在本文下面实施例中所特别说明的基团。优选的基团为二氟-或三氟-甲基或乙基。
“芳基”代表由一个单独的环或由一个或多个并且其中至少一个环为芳香环的稠合环组成的芳香碳环基团。优选的芳基为苯基。
术语“5-或6-元杂芳基”是指含有一或多个选自氮、氧或硫的杂原子的芳环。优选的杂芳基中的杂原子选自氮。此类杂芳基的实例为吡啶基、吡嗪基、吡唑基、嘧啶基、哒嗪基、异噁唑基或噻唑基。
术语“杂环烷基”是指含有一或多个选自氮、氧或硫的杂原子并且剩余的为碳原子的饱和的非芳族环。优选的杂环烷基为具有5或6个环成员的杂环烷基。优选的杂环烷基中的杂原子选自氮。此类基团的实例为吗啉基、四氢吡喃基、硫代吗啉基、哌嗪基、吡咯烷基或哌啶基。
术语“环烷基”是指含有3-12个碳原子(优选3-6个碳原子)的饱和的碳环基团。
术语“药学上可接受的盐”是指任何衍生自无机或有机酸或碱的盐。此类盐包括：由无机酸形成的酸加成盐，所述无机酸例如为盐酸、氢溴酸、硫酸、硝酸、磷酸；或由有机酸形成的盐，所述有机酸例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、羟基乙酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对甲苯磺酸或三甲基乙酸。
优选如下定义的式I化合物及其药学上可接受的盐：
其中：
R1为低级烷基；
R2为苯基、噻唑基、吡啶基、嘧啶基或吡唑基，其中环为未取代的或者被卤素或低级烷基所取代；
R3为氢、苯基、吡啶基、嘧啶基或异噁唑基，它可以是未取代的或者被卤素或-SO2-低级烷基所取代。
优选如下定义的式I化合物及其药学上可接受的盐：
其中：
R1为低级烷基；
R2为苯基、噻唑基、吡啶基或吡唑基，其中环为未取代的或者被卤素或低级烷基所取代；
R3为氢、吡啶基。
最优选其中R1为甲基的式I化合物。
另外优选那些其中R3为氢且R2为被卤素取代的苯基的式I化合物， 例如下列化合物：(3-氯代-苯基)-(2-甲基-噻唑并[4，5-c]吡啶-4-基)-胺。
另外优选那些其中R3为吡啶-3-基且R2为甲基-取代的噻唑基的式I化合物，例如下列化合物：
(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺或
(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(4-甲基-噻唑-2-基)-胺。
另外优选那些其中R3为吡啶-3-基且R2为卤素-取代的吡啶基的式I化合物，例如下列化合物：(5-氟-吡啶-2-基)-(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-胺。
另外优选那些其中R3为吡啶-3-基且R2为甲基取代的吡唑-3-基的式I化合物，例如下列化合物：(1-甲基-1H-吡唑-3-基)-(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-胺。
另外优选那些其中R3为被卤素或-S(O)2-低级烷基取代的苯基且R2为甲基-取代的噻唑基或为甲基-取代的嘧啶基的式I化合物，例如下列化合物：
[7-(3，5-二氟-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺；
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-嘧啶-4-基)-胺；
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；和
[7-(3，5-二氟-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺。
另外优选那些其中R3为被卤素或低级烷基取代的吡啶-3-基且R2为甲基-取代的噻唑基、甲基-取代的吡啶基或甲基-取代的嘧啶基的式I化合物，例如下列化合物：
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺；
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-嘧啶-4-基)-胺；
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(5-甲基-吡啶-2-基)-胺；和
[2-甲基-7-(5-甲基-吡啶-3-基)-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺。
另外优选那些其中R3为嘧啶基且R2为甲基-取代的噻唑基、甲基-取代的吡啶基或甲基-取代的嘧啶基的式I化合物，例如下列化合物：
(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-(4-甲基-噻唑-2-基)-胺；
(2-甲基-嘧啶-4-基)-(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-胺；
(2-甲基-吡啶-4-基)-(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-胺；和
(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺。
另外优选那些其中R3为被卤素或低级烷基取代的吡啶-4-基且R2为甲基-取代的噻唑基或甲基-取代的吡啶基的式I化合物，例如下列化合物：
[7-(2-氯代-吡啶-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-吡啶-4-基)-胺；
[7-(2-氯代-吡啶-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；和
[2-甲基-7-(2-甲基-吡啶-4-基)-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺。
另外优选那些其中R3为被低级烷基取代的噁唑基且R2为甲基-取代的噻唑基的式I化合物，例如下列化合物：
[7-(3，5-二甲基-异噁唑-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺。
本发明的式I化合物可以根据多种方法制备。
在一个实施方案中，本发明的方法包括下列变通方法：
a)使式II化合物：
与下式化合物反应：
R2X
获得式I化合物：
其中X为氯、溴或碘，优选溴，R1、R2和R3如上文所定义，并且如果需要的话，将得到的化合物转化为药学上可接受的酸加成盐，或者
b)使式III化合物：
与下式化合物反应：
NH2R2
获得式I化合物：
其中R1、R2和R3如上文所定义，X为氯、溴或碘，优选氯，如果需要的话，将得到的化合物转化为药学上可接受的酸加成盐。
根据步骤a)，需要的式I化合物可以如下制备：将式II化合物与式R2Br化合物溶于无水二氧六环中。加入4，5-二(二苯基膦基)-9，9-二甲基呫 吨、碳酸铯和三(二亚苄基丙酮)二钯氯仿复合物，将反应混合物于130℃加热20小时，获得式I化合物。
本发明的各种方法更详细地描述于下列流程1和2以及实施例1-23中。所有原料(例如化合物IV)为已知的化合物，它们可以根据已知的方法采用得自商业的产品制备，或者直接购自商业。
流程1
其中取代基R1、R2和R3如上所述，其中R3不为氢。
流程2
III-A(R3＝H且X为Cl) I-A(R3＝H)
其中取代基R1和R2如上所述。
式III-A化合物(其中R3为H且X为Cl的式III化合物)可以根据流程1所述制备或者根据WO2002/044189的方法采用得自商业的原料制备。将式III-A化合物和式NH2R2化合物溶于无水二氧六环。加入4，5-二(二苯基膦基)-9，9-二甲基呫吨、碳酸铯和三(二亚苄基丙酮)二钯氯仿复合物，将反应混合物在微波照射中于约150℃搅拌50分钟。然后将反应混合物蒸发并采用常规方法纯化。
式I化合物的药学上可接受的盐可以根据众所周知的方法容易地制备，根据化合物的性质可以将其转化为盐。适用于与碱性式I化合物形成药学上可接受的盐的无机或有机酸为例如盐酸、氢溴酸、硫酸、硝酸、磷酸或柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲烷磺酸、对甲苯磺酸等。含有碱金属或碱土金属(例如钠、钾、钙、镁等)的化合物、碱性胺或碱性氨基酸适合于与酸性化合物形成药学上可接受的盐。
如上所述的式I化合物及其药学上可接受的盐为代谢性谷氨酸受体拮抗剂，可以用于治疗或预防mGluR5受体介导的疾病，例如急性或慢性疼痛；尿失禁；药物或疾病导致的肝损伤或肝功能衰竭；肥胖或脆性-X综合征或自闭症；神经系统的急性、外伤性和慢性退行性病变，例如阿尔茨海默氏病、老年性痴呆、帕金森氏病、亨廷顿舞蹈病、肌萎缩侧索硬化症和多重硬化症；精神疾病，例如精神分裂症和焦虑症；抑郁症和药物依赖，如参考文献中所示：例如“European Journal of Pharmacology(2004)，497(1)，25-27.”；“Journal of Hepatology(2003)，38(2)，179-187”；和“Hepatology(Philadelphia)(2000)，31(3)，649-655”。
式I化合物及其药学上可接受的盐特别用作镇痛药。可治疗的疼痛包括炎性疼痛，如关节炎和类风湿性疾病、脉管炎、神经性痛(如三叉神经痛或疱疹样神经痛)、糖尿病性神经痛、灼痛、痛觉过敏、严重慢性疼痛、手术后疼痛以及与各种病症(如癌症、心绞痛、肾或胆绞痛、月经、偏头痛和痛风)有关的疼痛。
采用下列方法试验所述化合物的药理活性：
为了进行结合实验，采用Schlaeger和Christensen[Cytotechnology15：1-13(1998)]所述方法将编码人mGlu5a受体的cDNA瞬时转染到EBNA细胞中。匀化的细胞膜于-80℃储存直至试验的当天，此时，将其解冻并在15mM Tris-HCl、120mM NaCl、100mM KCl、25mM CaCl2、25mM MgCl2 结合缓冲液(pH 7.4)中重新悬浮并polytronised，使最终测定浓度为20μg蛋白质/孔。
于4℃通过将十二个浓度的[3H]MPEP(0.04-100nM)加入到所述膜(总体积为200μl)中并保持1小时来测定饱和等温线。采用固定浓度的[3H]MPEP(2nM)进行竞争实验并采用11个浓度(0.3-10,000nM)评价试验化合物的IC50值。于4℃培育1小时。
培育结束时，将膜在配有Filtermate 96收集器(Packard BioScience)的Unifilter(96-孔白色微孔板，配有结合的GF/C滤膜，预先用0.1％PEI的洗涤缓冲液溶液培育1小时，Packard Bio-Science，Meiden，CT)上过滤，并用冷的50mM Tris-HCl(pH 7.4)的缓冲液洗涤3次。在10μM MPEP存在下测定非特异性结合。加入45μl Microscint 40(Canberra Packard S.A.，苏黎市，瑞士)并振摇20分钟后，在猝灭校正的Packard Top-count微孔板闪烁计数器上记数滤膜上的放射活性(3分钟)。
为了进行功能性测定，根据Porter等[Br.J.Pharmacol.128：13-20(1999)]描述的方法测定HEK-293细胞中重组人mGlu 5a受体上的[Ca2+]i。采用Fluo 4-AM(由FLUKA获得，最终浓度为0.2μM)将细胞染色。采用荧光成像板读数器(FLIPR，Molecular Devices Corporation，La Jolla，CA，USA)测定[Ca2+]i。与试验化合物一起预培育5分钟，然后加入亚最大量的激动剂来评价拮抗作用。
采用迭代非线性曲线拟合软件(Xcel拟合)，对抑制(拮抗剂)曲线进行四参数对数方程拟合得到IC50值和Hill系数。
对于结合实验，得到试验化合物的Ki值。Ki值的定义如下：
Ki＝IC50/[1+L/Kd]
其中IC50值是使得竞争配体([3H]MPEP)抑制达50％的试验化合物的浓度。L是结合实验中使用的放射配体的浓度，放射配体的Kd值是对制备的每批膜进行经验确定的。
本发明化合物是mGluR 5a受体拮抗剂。在上述测定方法中测定并列于下表中的式I、Ia和Ib化合物的活性范围为Ki＜400nM。
| 实施例 | Ki(nM) | 实施例 | Ki(nM) |
| 1 | 26 | 9 | 61 |
| 2 | 37 | 14 | 45 |
| 3 | 42 | 17 | 128 |
| 4 | 40 | 19 | 29 |
| 5 | 167 | 20 | 87 |
式I化合物及其药学上可接受的盐可以例如药物制剂的形式用作药物。药物制剂可以是口服给药的，例如片剂、包衣片、糖衣丸、硬和软明胶胶囊、溶液剂、乳剂或混悬剂的形式。然而，也可以是直肠给药的形式，例如栓剂形式或非胃肠道给药的形式，例如注射液形式。
式I化合物及其药学上可接受的盐可以与药用惰性的无机或有机载体一起用于制备药物制剂。乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等可以用作例如片剂、包衣片、糖衣丸、硬明胶胶囊的载体。适用于软明胶胶囊的载体为例如，植物油、蜡、脂肪、半固体和液体多元醇等；然而，根据活性物质的性质，在软明胶胶囊中通常并不需要载体。制备溶液剂和糖浆的适当的载体为例如，水、多元醇、蔗糖、转化糖、葡萄糖等。就式I化合物的水溶性盐的注射水溶液而言，可以采用辅料如醇、多元醇、甘油、植物油等，但是通常不是必需的。栓剂的适当的载体为例如天然油或硬化油、蜡、脂肪、半固体或液体多元醇等。
另外，药物制剂可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、 甜味剂、着色剂、矫味剂、改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其他有治疗价值的物质。
如上所述，含有式I化合物或其药学上可接受的盐和治疗惰性的赋形剂的药物以及此类药物的制备方法也是本发明的目的，所述方法包括将一种或多种式I化合物或其药学上可接受的盐和一种或多种其他有治疗价值的物质(如果需要的话)以及一种或多种治疗惰性载体一起制成盖仑剂型。
剂量可以在较宽的范围内变化，它当然要符合每个具体病例的个体要求。一般来说，对于所述的所有适应症而言，口服或非胃肠道给药的有效剂量为0.01-20mg/kg/天，优选剂量为0.1-10mg/kg/天。因此，体重为70kg的成人的每日剂量为0.7-1400mg/天，优选为7-700mg/天。
下列实施例进一步描述本发明：
实施例1
(3-氯代-苯基)-(2-甲基-噻唑并[4，5-c]吡啶-4-基)-胺
将4-氯代-2-甲基-噻唑并[4，5-c]吡啶(100mg，0.54mmol)(实施例A)和3-氯代苯胺(90mg，0.70mmol)溶于3ml无水二氧六环中。加入4，5-二(二苯基膦基)-9，9-二甲基呫吨(63mg，0.1mmol)、碳酸铯(350mg，1.08mmol)和三(二亚苄基丙酮)二钯氯仿复合物(56mg，0.05mmol)，将反应混合物于120℃搅拌16小时。然后将反应混合物蒸发，经硅胶快速色谱纯化(庚烷/乙酸乙酯90∶10-＞30∶70梯度洗脱)。获得为黄色固体的目标产物(20mg，13％)，MS：m/e＝276.3(M+H+)。
实施例2
(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺
步骤1：4-氯代-2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶
将四(三苯膦)钯(0)(52mg，0.05mmol)溶于8ml甲苯中。加入4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(280mg，0.90mmol)(实施例B)、3-吡啶硼酸(133mg，1.08mmol)、2M碳酸钠(2.70ml，5.4mmol)和2ml乙醇，将混合物于80℃搅拌6小时。将反应混合物用水萃取，用乙酸乙酯二次。有机萃取物用水和盐水洗涤，经硫酸钠干燥，过滤并蒸发。粗品产物经硅胶快速色谱纯化(庚烷/乙酸乙酯9∶1-＞0∶100梯度洗脱)。获得为黄色固体的目 标化合物(100mg，42％)，MS：m/e＝263.1(M+H+)。
步骤2：(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺
将4-氯代-2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶(100mg，0.38mmol)和4-氨基-2-甲基噻唑(44mg，0.38mmol)(实施例C)溶于3ml无水二氧六环中。加入4，5-二(二苯基膦基)-9，9-二甲基呫吨(44mg，0.08mmol)和碳酸铯(200mg，0.61mmol)，将该混合物抽干，用氩气充入数次以自溶液中除去氧。加入三(二亚苄基丙酮)二钯氯仿复合物(38mg，0.035mmol)，将反应混合物于100℃搅拌1小时。然后将反应混合物蒸发，经硅胶快速色谱纯化(庚烷/乙酸乙酯90∶10-＞0∶100梯度洗脱)，在二异丙基醚中重结晶。获得为黄色固体的目标产物(20mg，15％)，MS：m/e＝354.1(M+H+)。
实施例3
(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(4-甲基-噻唑-2-基)-胺
根据实施例2步骤2的通用方法，采用4-氯代-2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶和2-氨基-4-甲基噻唑，制备该目标化合物，MS：m/e＝340.1(M+H+)。
实施例4
(5-氟-吡啶-2-基)-(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-胺
根据实施例2步骤2的通用方法，采用4-氯代-2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶和2-氨基-5-氟吡啶，制备该目标化合物，MS：m/e＝338.1(M+H+)。
实施例5
(1-甲基-1H-吡唑-3-基)-(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-胺
根据实施例2步骤2的通用方法，采用4-氯代-2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶和3-氨基-1-甲基吡唑，制备该目标化合物，MS：m/e＝323.3(M+H+)。
实施例6
[7-(3，5-二氟-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)- 胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3，5-二氟苯基硼酸和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝375.1(M+H+)。
实施例7
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3-氟-5-吡啶硼酸和2-氨基-4-甲基噻唑，制备该目标化合物，MS：m/e＝358.2(M+H+)。
实施例8
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-嘧啶-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3-氟-5-吡啶硼酸和4-氨基-2-甲基嘧啶，制备该目标化合物，MS：m/e＝353.2(M+H+)。
实施例9
(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-(4-甲基-噻唑-2-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、5-嘧啶硼酸和2-氨基-4-甲基噻唑，制备该目标化合物，MS：m/e＝341.1(M+H+)。
实施例10
(2-甲基-嘧啶-4-基)-(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、5-嘧啶硼酸和4-氨基-2-甲基嘧啶，制备该目标化合物，MS：m/e＝336.2(M+H+)。
实施例11
(2-甲基-吡啶-4-基)-(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基- 噻唑并[4，5-c]吡啶(实施例B)、5-嘧啶硼酸和2-甲基-4-氨基吡啶，制备该目标化合物，MS：m/e＝335.2(M+H+)。
实施例12
(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)，5-嘧啶硼酸和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝341.0(M+H+)。
实施例13
[7-(2-氯代-吡啶-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-吡啶-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、2-氯代吡啶-4-硼酸和2-甲基-4-氨基吡啶，制备该目标化合物，MS：m/e＝368.1(M+H+)。
实施例14
[7-(2-氯代-吡啶-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、2-氯代吡啶-4-硼酸和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝374.0(M+H+)。
实施例15
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3-氟-5-吡啶硼酸和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝358.2(M+H+)。
实施例16
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基- 噻唑并[4，5-c]吡啶(实施例B)、(3-甲基磺酰基苯基)硼酸和2-氨基-4-甲基噻唑，制备该目标化合物，MS：m/e＝417.2(M+H+)。
实施例17
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-嘧啶-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、(3-甲基磺酰基苯基)硼酸和4-氨基-2-甲基嘧啶，制备该目标化合物，MS：m/e＝412.3(M+H+)。
实施例18
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、(3-甲基磺酰基苯基)硼酸和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝417.2(M+H+)。
实施例19
[7-(3，5-二氟-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3，5-二氟苯基硼酸和2-氨基-4-甲基噻唑，制备该目标化合物，MS：m/e＝375.1(M+H+)。
实施例20
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(5-甲基-吡啶-2-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3-氟-5-吡啶硼酸和2-氨基-5-甲基吡啶，制备该目标化合物，MS：m/e＝352.2(M+H+)。
实施例21
[2-甲基-7-(5-甲基-吡啶-3-基)-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-2-甲基-噻唑并[4，5-c]吡啶-7-硼酸(实施例D)、3-溴-5-甲基吡啶和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝354.3(M+H+)。
实施例22
[2-甲基-7-(2-甲基-吡啶-4-基)-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-2-甲基-噻唑并[4，5-c]吡啶-7-硼酸(实施例D)、4-溴-2-甲基吡啶和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝354.1(M+H+)。
实施例23
[7-(3，5-二甲基-异噁唑-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺
根据实施例2步骤1和步骤2的通用方法，采用4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)、3，5-二甲基异噁唑-4-硼酸和4-氨基-2-甲基噻唑(实施例C)，制备该目标化合物，MS：m/e＝358.1(M+H+)。
中间体的合成
实施例A
4-氯代-2-甲基-噻唑并[4，5-c]吡啶
步骤1：3-硝基-吡啶-4-醇
将4-甲氧基-3-硝基吡啶(25.0g，162mmol)的220ml浓氢溴酸(48％)溶液于100℃回流16小时。将反应混合物冷却，倒入冰水中，用155ml浓NaOH(32％)中和。将悬浮液于5℃搅拌10分钟，过滤。将固体用水洗涤，于50℃且＜30mbar干燥1小时。获得为浅黄色固体的目标产物(20.2g，89％)。
步骤2：3-氨基-吡啶-4-醇
将3-硝基-吡啶-4-醇(20.0g，143mmol)悬浮于1000ml甲醇和20ml DMF中。加入披钯炭(2.0g，10％Pd)，将混合物于室温下氢化4小时。过滤悬浮液，蒸发溶剂。获得为粉色油状物的目标产物(26g，定量)。
步骤3：N-(4-羟基-吡啶-3-基)-乙酰胺
将3-氨基-吡啶-4-醇(15.0，136mmol)悬浮于200ml二氯甲烷中，加入N-乙基二异丙基胺(82ml，477mmol)。于室温下滴加乙酰氯(10.6ml，150mmol)的150ml二氯甲烷溶液。将反应混合物于回流下搅拌3小时并蒸发至干。将残留物在甲醇中搅拌并过滤。蒸发溶剂，获得为白色固体的目标产物(7.2g，35％)，MS：m/e＝151.1(M+H+)。
步骤4：2-甲基-噻唑并[4，5-c]吡啶
将N-(4-羟基-吡啶-3-基)-乙酰胺(3.0g，19.7mmol)溶于150ml吡啶中，加入五硫化磷(4.4g，19.7mmol)。将反应混合物于回流下搅拌2小时并蒸发至干。将残留物溶于水中，用饱和的碳酸氢钠溶液将pH调节至8。水层用乙酸乙酯萃取二次。有机萃取物经硫酸钠干燥，过滤并蒸发。粗品产物(2.3g，78％)无需另外纯化可以直接用于下一步骤。
步骤5：2-甲基-噻唑并[4，5-c]吡啶5-氧化物
将2-甲基-噻唑并[4，5-c]吡啶(2.3g，15.3mmol)溶于150ml氯仿，加入3-氯代过苯甲酸(4.15g，16.8mmol)。将反应混合物于室温下搅拌1小时，然后蒸发。残留物经硅胶快速色谱纯化(二氯甲烷/甲醇100∶0-＞90∶10梯度洗脱)。获得为白色固体的目标产物(2.1g，83％)，MS：m/e＝167.2(M+H+)。
步骤6：4-氯代-2-甲基-噻唑并[4，5-c]吡啶
将2-甲基-噻唑并[4，5-c]吡啶5-氧化物(230mg，1.38mmol)在4ml磷酰氯中回流2小时。将反应混合物蒸发，用乙酸乙酯和饱和的碳酸氢钠溶液萃取。有机萃取物经硫酸钠干燥，过滤并蒸发。残留物经硅胶快速色谱纯化(庚烷/乙酸乙酯90∶10-＞0∶100梯度洗脱)。获得为浅黄色固体的目标产物(180mg，70％)，MS：m/e＝185.1(M+H+)。
实施例B
4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶
步骤1：2-甲基-噻唑-4-甲酸
将2-甲基噻唑-4-甲酸乙酯(17.0g，99.3mmol)溶于150m甲醇中，加入2N NaOH(150ml，300mmol)。将反应混合物于室温下搅拌2小时。蒸发甲醇，残留物用2N HCl酸化至pH 2。水层用乙酸乙酯萃取二次。有机萃取物经硫酸钠干燥，过滤并蒸发。粗品产物(13.0g，91％)无需另外纯化可以 直接用于下一步骤。
步骤2：5-溴-2-甲基-噻唑-4-甲酸
将2-甲基-噻唑-4-甲酸(13.0g，90.8mmol)溶于750ml THF中，将其冷却至-75℃。在30分钟内滴加入正-BuLi(1.6M的THF液；120ml，190.7mmol)。于-75℃将红色悬浮液搅拌15分钟，于0℃搅拌30分钟。于-75℃滴加入溴(5.1ml，100mmol)的20ml环己烷溶液，继续于室温下搅拌2小时。将反应混合物用20ml水淬灭，蒸发，用2N HCl酸化至pH 2。水层用乙酸乙酯萃取二次。合并的有机萃取物经硫酸钠干燥，过滤并蒸发。粗品产物(16.4g，81％)[MS：m/e＝223.0(M+H+)]无需另外纯化可以直接用于下一步骤。
步骤3：5-溴-2-甲基-噻唑-4-甲酸酰胺
将5-溴-2-甲基-噻唑-4-甲酸(14.4g，64.8mmol)溶于100ml DMF中，加入CDI(11.6g，71.3mmol)。将该溶液于60℃搅拌2小时，冷却，加入NH4OH(150ml，973mmol)。将反应混合物于室温下搅拌过夜，用乙酸乙酯和水萃取二次。有机萃取物用水洗涤4次，经硫酸钠干燥，过滤并蒸发。粗品产物(11.3g，79％)[MS：m/e＝222.8(M+H+)]无需另外纯化可以直接用于下一步骤。
步骤4：5-溴-2-甲基-噻唑-4-甲腈
将5-溴-2-甲基-噻唑-4-甲酸酰胺(11.3g，51.1mmol)溶于150ml二氯甲烷中，加入三乙胺(14.2ml，102.2mmol)。于0℃滴加三氟乙酸酐(14.3ml，102.2mmol)，将混合物在无冷却条件下搅拌2小时。反应混合物用饱和的NaHCO3溶液淬灭，用乙酸乙酯萃取。有机萃取物用盐水洗涤，经硫酸钠干燥，过滤并蒸发。粗品产物经硅胶快速色谱纯化(庚烷/乙酸乙酯90∶10-＞20∶80梯度洗脱)。获得为淡黄色固体的目标化合物(6.4g，62％)，MS：m/e＝204.0(M+H+)。
步骤5：2-甲基-5-三甲基硅烷基乙炔基-噻唑-4-甲腈
将5-溴-2-甲基-噻唑-4-甲腈(4.8g，23.6mmol)悬浮于50ml三乙胺中。加入三甲基甲硅烷基乙炔(4.64g，47.3mmol)、三苯膦(186mg，0.7mmol)和二(三苯膦)氯化钯(II)(0.83g，1.18mmol)，将该混合物抽空，充入数次氩 气以自溶液中除去氧。加入碘化铜(I)(45mg，0.24mmol)，将反应混合物于70℃搅拌5小时。残留物溶于水，用乙酸乙酯萃取3次，用水萃取数次。合并的有机萃取物经硫酸钠干燥，过滤并蒸发。粗品产物经硅胶色谱纯化(庚烷/乙酸乙酯90∶10-＞1∶1梯度洗脱)。获得为黑色固体的目标产物(4.1g，79％)。
步骤6：5-(2，2-二甲氧基-乙基)-2-甲基-噻唑-4-甲腈
将2-甲基-5-三甲基硅烷基乙炔基-噻唑-4-甲腈(4.56g，20.7mmol)溶于45ml甲醇中，加入甲醇钠(5.4N的甲醇溶液，11.5ml，62mmol)。将反应混合物于回流下搅拌2小时，用乙酸乙酯和饱和的NaHCO3溶液萃取二次。有机萃取物经硫酸钠干燥，过滤并蒸发。粗品产物(4.5g，＞100％)无需另外纯化可以直接用于下一步骤。
步骤7：5-(2，2-二甲氧基-乙基)-2-甲基-噻唑-4-甲酸酰胺
将2M Na2CO3溶液(64ml，127mmol)、H2O2(30％，43.3ml，424mmol)和45ml水混合，于室温下滴加5-(2，2-二甲氧基-乙基)-2-甲基-噻唑-4-甲腈(4.5g，21mmol)的45ml丙酮溶液。将白色的悬浮液搅拌2小时。蒸发丙酮，含水残留物用乙酸乙酯萃取3次。有机萃取物经硫酸钠干燥，过滤并蒸发。粗品产物(4.8g，98％)无需另外纯化可以直接用于下一步骤。
步骤8：2-甲基-5H-噻唑并[4，5-c]吡啶-4-酮
将5-(2，2-二甲氧基-乙基)-2-甲基-噻唑-4-甲酸酰胺(1.0g，4.3mmol)溶于35ml二氧六环中，加入0.3ml浓硫酸。将反应混合物于室温下搅拌2小时。将白色的悬浮液冷却至0℃，搅拌10分钟。过滤悬浮液，用冷的二氧六环洗涤。将固体于50℃和＜30mbar干燥1小时。获得为白色固体的目标产物(0.7g，97％)，MS：m/e＝167.1(M+H+)。
步骤9：7-碘-2-甲基-5H-噻唑并[4，5-c]吡啶-4-酮
将2-甲基-5H-噻唑并[4，5-c]吡啶-4-酮(770mg，4.6mmol)悬浮于25ml乙腈，加入N-碘琥珀酰亚胺(1.04g，4.6mmol)。将反应混合物回流3小时。将褐色悬浮液冷却至5℃，搅拌15分钟。过滤固体，用冷的乙腈洗涤，于50℃和＜30mbar干燥1小时。粗品产物(830mg，61％)[MS：m/e＝292.9(M+H+)]无需另外纯化可以直接用于下一步骤。
步骤10：4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶
将7-碘-2-甲基-5H-噻唑并[4，5-c]吡啶-4-酮(880mg，3.01mmol)悬浮于POCl3(8.25ml，90.4mmol)，回流4小时。将黑色的反应混合物蒸发，倒入二氯甲烷的冰水溶液。水层用固体NaHCO3中和至pH 7，用二氯甲烷萃取3次。合并的有机萃取物经硫酸镁干燥，过滤并蒸发。粗品产物经硅胶色谱纯化(二氯甲烷/甲醇100∶0-＞95∶5梯度洗脱)。获得为浅黄色固体的目标产物(280mg，30％)，MS：m/e＝311.0(M+H+)。
实施例C
4-氨基-2-甲基噻唑
根据专利EP 321115中所述的制备方法可以制备该目标化合物。
实施例D
4-氯代-2-甲基-噻唑并[4，5-c]吡啶-7-硼酸
将4-氯代-7-碘-2-甲基-噻唑并[4，5-c]吡啶(实施例B)(2.35g，7.56mmol)和硼酸三异丙基酯(1.8ml，7.94mmol)溶于70ml THF中，冷却至-75℃。于-70℃滴加正-丁基锂(1.6M的己烷溶液)(5.0ml，7.94mmol)。将反应混合物于-75℃搅拌1小时，在没有冰浴的情况下搅拌1小时。加入10ml 2N HCl溶液，用乙酸乙酯萃取3次。有机层用水洗涤，经硫酸钠干燥，真空浓缩。残留物在乙腈中结晶，得到为红色固体的目标化合物(520mg，30％)，MS：m/e＝229.2(M+H+)。
药用组合物的制备：
实施例I
下列组成的片剂根据常规方法制备：
mg/片剂
活性成分 100
粉末乳糖 95
白色玉米淀粉 35
聚乙烯吡咯烷酮 8
羧甲基淀粉钠 10
硬脂酸镁 2
片剂重量 250
实施例II
下列组成的片剂根据常规方法制备：
mg/片剂
活性成分 200
粉末乳糖 100
白色玉米淀粉 64
聚乙烯吡咯烷酮 12
羧甲基淀粉钠 20
硬脂酸镁 4
片剂重量 400
实施例III
制备下列组成的胶囊：
mg/胶囊
活性成分 50
结晶乳糖 60
微晶纤维素 34
滑石粉 5
硬脂酸镁 1
胶囊填充重量 150
将具有适当粒度的活性组分、结晶乳糖和微晶纤维素彼此均匀混合、过筛，然后与滑石粉和硬脂酸镁混合。将得到的混合物填充到适当大小的硬明胶胶囊中。
Claims (31)
1.通式I化合物及其药学上可接受的盐：
其中：
R1为C1-6烷基；
R2为苯基、噻唑基、吡啶基、嘧啶基或吡唑基，其中所述环为未取代的或者被卤素或C1-6烷基取代；
R3为氢、苯基、吡啶基、嘧啶基或异
唑基，它可以是未取代的或者被卤素、C1-6烷基或-SO2-C1-6烷基取代。
2.权利要求1的式I化合物及其药学上可接受的盐：
其中：
R1为C1-6烷基；
R2为苯基、噻唑基、吡啶基或吡唑基，其中所述环为未取代的或者被卤素或C1-6烷基取代；
R3为氢或吡啶基。
3.权利要求1或2的式I化合物及其药学上可接受的盐，其中R1为甲基。
4.权利要求3的式I化合物及其药学上可接受的盐，其中R3为氢，R2为被卤素取代的苯基。
5.权利要求4的式I化合物及其药学上可接受的盐，所述化合物为(3-氯代-苯基)-(2-甲基-噻唑并[4，5-c]吡啶-4-基)-胺。
6.权利要求3的式I化合物及其药学上可接受的盐，其中R3为吡啶-3-基，R2为甲基-取代的噻唑基。
7.权利要求6的式I化合物及其药学上可接受的盐，所述化合物为：
(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺或
(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-(4-甲基-噻唑-2-基)-胺。
8.权利要求3的式I化合物及其药学上可接受的盐，其中R3为吡啶-3-基，R2为卤素-取代的吡啶基。
9.权利要求8的式I化合物及其药学上可接受的盐，所述化合物为(5-氟-吡啶-2-基)-(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-胺。
10.权利要求3的式I化合物及其药学上可接受的盐，其中R3为吡啶-3-基，R2为甲基取代的吡唑-3-基。
11.权利要求10的式I化合物及其药学上可接受的盐，所述化合物为(1-甲基-1H-吡唑-3-基)-(2-甲基-7-吡啶-3-基-噻唑并[4，5-c]吡啶-4-基)-胺。
12.权利要求1的式I化合物及其药学上可接受的盐，其中R3为被卤素或-S(O)2-C1-6烷基取代的苯基，R2为甲基-取代的噻唑基或甲基-取代的嘧啶基。
13.权利要求12的式I化合物及其药学上可接受的盐，所述化合物为：
[7-(3，5-二氟-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺；
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-嘧啶-4-基)-胺；
[7-(3-甲磺酰基-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；和
[7-(3，5-二氟-苯基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺。
14.权利要求1的式I化合物及其药学上可接受的盐，其中R3为被卤素或C1-6烷基取代的吡啶-3-基，R2为甲基-取代的噻唑基、甲基-取代的吡啶基或甲基-取代的嘧啶基。
15.权利要求14的式I化合物及其药学上可接受的盐，所述化合物为：
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(4-甲基-噻唑-2-基)-胺；
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-嘧啶-4-基)-胺；
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；
[7-(5-氟-吡啶-3-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(5-甲基-吡啶-2-基)-胺；和
[2-甲基-7-(5-甲基-吡啶-3-基)-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺。
16.权利要求1的式I化合物及其药学上可接受的盐，其中R3为嘧啶基，R2为甲基-取代的噻唑基、甲基-取代的吡啶基或甲基-取代的嘧啶基。
17.权利要求16的式I化合物及其药学上可接受的盐，所述化合物为：
(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-(4-甲基-噻唑-2-基)-胺；
(2-甲基-嘧啶-4-基)-(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-胺；
(2-甲基-吡啶-4-基)-(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-胺；和
(2-甲基-7-嘧啶-5-基-噻唑并[4，5-c]吡啶-4-基)-(2-甲基-噻唑-4-基)-胺。
18.权利要求1的式I化合物及其药学上可接受的盐，其中R3为被卤素或C1-6烷基取代的吡啶-4-基，R2为甲基-取代的噻唑基或甲基-取代的吡啶基。
19.权利要求18的式I化合物及其药学上可接受的盐，所述化合物为：
[7-(2-氯代-吡啶-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-吡啶-4-基)-胺；
[7-(2-氯代-吡啶-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺；和
[2-甲基-7-(2-甲基-吡啶-4-基)-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺。
20.权利要求1的式I化合物及其药学上可接受的盐，所述化合物为：
[7-(3，5-二甲基-异
唑-4-基)-2-甲基-噻唑并[4，5-c]吡啶-4-基]-(2-甲基-噻唑-4-基)-胺。
21.制备权利要求1的式I化合物及其药学上可接受的盐的方法，所述方法包括：
a)使下式化合物：
与下式化合物反应：
R2X，
获得式I化合物：
其中X为氯、溴或碘，R1、R2和R3如权利要求1所定义，如果需要的话，将得到的化合物转化为药学上可接受的酸加成盐，或者
b)使式III化合物：
与下式化合物反应：
NH2R2
获得式I化合物：
其中R1、R2和R3如权利要求1所定义，X为氯、溴或碘，如果需要的话，将得到的化合物转化为药学上可接受的酸加成盐。
22.药物，该药物含有一或多种权利要求1-20中任一项的化合物以及可药用赋形剂，用于治疗或预防mGluR5受体介导的疾病。
23.权利要求22的药物，用于治疗或预防急性和/或慢性神经疾病；尿失禁；胃肠道返流病；药物或疾病导致的肝损伤或肝功能衰竭；肥胖或脆性-X综合征或自闭症；神经系统的急性、外伤性和慢性退行性病变；精神疾病和药物依赖。
24.权利要求23的药物，其中所述退行性病变为阿尔茨海默氏病、老年性痴呆、帕金森氏病、亨廷顿舞蹈病、肌萎缩侧索硬化症或多重硬化症。
25.权利要求23的药物，其中所述急性或慢性神经疾病为急性或慢性疼痛。
26.权利要求23的药物，其中所述精神疾病为精神分裂症、焦虑症和抑郁症。
27.权利要求1-20中任一项的化合物及其药学上可接受的盐在生产用于治疗或预防mGluR5受体介导的疾病的药物中的用途。
28.权利要求27的用途，用于生产治疗或预防下列疾病的药物：急性和/或慢性神经疾病；尿失禁；胃肠道返流病；药物或疾病导致的肝损伤或肝功能衰竭；肥胖或脆性-X综合征或自闭症；神经系统的急性、外伤性和慢性退行性病变；精神疾病和药物依赖。
29.权利要求28的用途，其中所述退行性病变为阿尔茨海默氏病、老年性痴呆、帕金森氏病、亨廷顿舞蹈病、肌萎缩侧索硬化症或多重硬化症。
30.权利要求28的用途，其中所述急性和/或慢性神经疾病为急性或慢性疼痛。
31.权利要求28的用途，其中所述精神疾病为精神分裂症、焦虑症和抑郁症。
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| EP05110461 | 2005-11-08 | ||
| EP05110461.0 | 2005-11-08 | ||
| PCT/EP2006/067794 WO2007054436A2 (en) | 2005-11-08 | 2006-10-26 | Thiazolo [4 , 5-c] pyridine derivatives as mglu5 receptor antagonists |
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| CN101291939A CN101291939A (zh) | 2008-10-22 |
| CN101291939B true CN101291939B (zh) | 2013-02-13 |
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| EP (1) | EP1948667B1 (zh) |
| JP (1) | JP5015166B2 (zh) |
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| CN (1) | CN101291939B (zh) |
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| TW (1) | TWI323261B (zh) |
| WO (1) | WO2007054436A2 (zh) |
| ZA (1) | ZA200803821B (zh) |
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| EA201070143A1 (ru) * | 2007-07-13 | 2010-08-30 | Аддекс Фарма С.А. | Новые гетероароматические производные и их использование в качестве положительных аллостерических модуляторов метаботропных глутаматных рецепторов |
| GB0800411D0 (en) * | 2008-01-10 | 2008-02-20 | Glaxo Group Ltd | Novel compounds |
| SG181715A1 (en) * | 2009-12-18 | 2012-07-30 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mglur5 receptors |
| NZ600605A (en) * | 2009-12-18 | 2013-08-30 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mglur5 receptors |
| JP2019509272A (ja) | 2016-02-23 | 2019-04-04 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ | 脊髄性筋萎縮症の治療のための併用療法 |
| KR102224677B1 (ko) | 2018-08-23 | 2021-03-08 | 가천대학교 산학협력단 | 티아졸로 피페라진 유도체 및 이를 유효성분으로 함유하는 자가면역질환 예방 또는 치료용 조성물 |
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| EP0321115B1 (en) | 1987-12-14 | 1991-08-14 | Sawai Pharmaceutical Co., Ltd. | Carboxamide derivatives having tetrazole and thiazole rings and their use |
| JP2695037B2 (ja) * | 1990-11-07 | 1997-12-24 | 富士通株式会社 | エラーパルス延伸回路 |
| US6107300A (en) * | 1996-03-27 | 2000-08-22 | Dupont Pharmaceuticals | Arylamino fused pyrimidines |
| WO1998005651A1 (en) | 1996-08-01 | 1998-02-12 | Warner-Lambert Company | Novel glutamate receptor antagonists: fused cycloalkyl quinoxalinediones |
| US6658606B1 (en) * | 1997-10-29 | 2003-12-02 | Continental Teves Ag & Co. Ohg | Method and device for checking an error control procedure of a circuit |
| US6110929A (en) * | 1998-07-28 | 2000-08-29 | 3M Innovative Properties Company | Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof |
| AU780191B2 (en) | 1999-08-19 | 2005-03-03 | Astrazeneca Ab | Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists |
| US6660753B2 (en) | 1999-08-19 | 2003-12-09 | Nps Pharmaceuticals, Inc. | Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists |
| WO2002044189A1 (en) | 2000-11-30 | 2002-06-06 | Canon Kabushiki Kaisha | Luminescent element and display |
| WO2002066035A2 (en) * | 2001-02-20 | 2002-08-29 | Chugai Seiyaku Kabushiki Kaisha | Azoles as malonyl-coa decarboxylase inhibitors useful as metabolic modulators |
| UA74419C2 (uk) | 2001-02-21 | 2005-12-15 | Ен Пі Ес Фармасьютікалс, Інк. | Заміщені піридини та їх застосування як антагоністів рецептору метаботропного глутамату |
| CA2442478C (en) | 2001-04-02 | 2010-02-02 | Mark F. Bear | Use of group i mglur antagonists in the treatment of fragile x syndrome, autism, mental retardation |
| US6529046B1 (en) * | 2001-12-12 | 2003-03-04 | Etron Technology, Inc. | Minimum pulse width detection and regeneration circuit |
| EP1556053A4 (en) * | 2002-10-31 | 2006-04-19 | Amgen Inc | ANTI-INFLAMMATORY AGENTS |
| ITMI20030151A1 (it) * | 2003-01-30 | 2004-07-31 | Recordati Ind Chimica E Farma Ceutica S P A | Uso di antagonisti selettivi del recettore mglu5 per il trattamento di disfunzioni neuromuscolari del tratto urinario inferiore. |
| WO2006008545A2 (en) | 2004-07-22 | 2006-01-26 | Astex Therapeutics Limited | Thiazole and isothiazole derivatives as protein kinase inhibitors |
| EP1869052A1 (en) * | 2005-04-06 | 2007-12-26 | AstraZeneca AB | Substituted heterocycles and their use as chk1, pdk1 and pak inhibitors |
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2006
- 2006-10-26 BR BRPI0618636-0A patent/BRPI0618636A2/pt not_active IP Right Cessation
- 2006-10-26 ES ES06807563T patent/ES2382162T3/es active Active
- 2006-10-26 WO PCT/EP2006/067794 patent/WO2007054436A2/en active Application Filing
- 2006-10-26 AT AT06807563T patent/ATE553108T1/de active
- 2006-10-26 AU AU2006311084A patent/AU2006311084A1/en not_active Abandoned
- 2006-10-26 KR KR1020087013474A patent/KR101020431B1/ko not_active Expired - Fee Related
- 2006-10-26 CN CN2006800386693A patent/CN101291939B/zh not_active Expired - Fee Related
- 2006-10-26 JP JP2008539390A patent/JP5015166B2/ja not_active Expired - Fee Related
- 2006-10-26 EP EP06807563A patent/EP1948667B1/en not_active Not-in-force
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- 2006-10-26 RU RU2008115034/04A patent/RU2425834C2/ru not_active IP Right Cessation
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- 2006-11-06 TW TW095140997A patent/TWI323261B/zh not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| KR20080069229A (ko) | 2008-07-25 |
| BRPI0618636A2 (pt) | 2011-09-06 |
| TW200736264A (en) | 2007-10-01 |
| ATE553108T1 (de) | 2012-04-15 |
| AR058179A1 (es) | 2008-01-23 |
| JP5015166B2 (ja) | 2012-08-29 |
| TWI323261B (en) | 2010-04-11 |
| JP2009514923A (ja) | 2009-04-09 |
| KR101020431B1 (ko) | 2011-03-08 |
| WO2007054436A2 (en) | 2007-05-18 |
| IL190989A0 (en) | 2008-12-29 |
| CA2628936A1 (en) | 2007-05-18 |
| RU2008115034A (ru) | 2009-12-20 |
| RU2425834C2 (ru) | 2011-08-10 |
| ES2382162T3 (es) | 2012-06-05 |
| EP1948667A2 (en) | 2008-07-30 |
| US7659401B2 (en) | 2010-02-09 |
| EP1948667B1 (en) | 2012-04-11 |
| US20070105891A1 (en) | 2007-05-10 |
| CN101291939A (zh) | 2008-10-22 |
| AU2006311084A1 (en) | 2007-05-18 |
| WO2007054436A3 (en) | 2007-06-28 |
| ZA200803821B (en) | 2009-03-25 |
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