CN113861203B - 4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物及其制备方法和用途 - Google Patents
4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物及其制备方法和用途 Download PDFInfo
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- CN113861203B CN113861203B CN202111317282.4A CN202111317282A CN113861203B CN 113861203 B CN113861203 B CN 113861203B CN 202111317282 A CN202111317282 A CN 202111317282A CN 113861203 B CN113861203 B CN 113861203B
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- pyrrolo
- pyrimidine
- compound
- methyl
- carboxamide
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 125
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Abstract
本发明涉及药物化学和药物治疗学领域,具体涉及一种4‑芳香炔基取代的7H‑吡咯并[2,3‑d]嘧啶酰胺类化合物、及其作为代谢型谷氨酸受体第五亚型(mGluR5)负性变构调节剂的用途。
Description
技术领域
本发明属于药物化学和药物治疗学领域,具体涉及一种4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物及其作为代谢型谷氨酸受体第五亚型(mGluR5)负性变构调节剂,特别是制备用于治疗中枢神经系统和精神系统类相关疾病,如脆性X染色体综合征、帕金森左旋多巴诱导的多动症(PD-LID)、胃食管返流疾病(GERD)、焦虑、抑郁和药物成瘾等疾病的用途。
背景技术
谷氨酸(Glu)是哺乳动物中枢神经系统中最主要的兴奋性神经递质,对维持神经系统正常功能起着重要作用。谷氨酸在神经系统内的大量释放和堆积是多种神经细胞损伤和神经变性疾患的病理基础。有研究报道,中枢及外周血中Glu含量升高与抑郁症密切相关。慢性应激刺激后谷氨酸大量释放,并选择性作用于海马神经元,细胞外堆积的兴奋性氨基酸(EAA)递质持续而强烈地作用于膜受体,使细胞膜通透性增高,引起Ca2+大量内流,造成细胞内Ca2+超载,产生神经元损害。动物实验研究表明,谷氨酸受体拮抗剂CGP(一种竞争性的NMDAR受体拮抗剂)可以减少大鼠强迫游泳的不动时间,产生抗抑郁效果。
谷氨酸受体(GluR)主要分为离子型谷氨酸受体(iGluRs)和代谢型谷氨酸受体(mGluRs)。离子型谷氨酸受体拮抗剂通过直接阻断谷氨酸的突触后效应,在动物模型中取得了一定的治疗效果,但是其同时也阻断了正常的兴奋性传递,产生严重的副作用,如精神症状、眩晕、疲劳等,因此限制了这类化合物的临床应用;而mGluRs通过突触前机制抑制谷氨酸的释放,减少了iGluRs拮抗剂所产生的毒副作用,从而有望成为某些神经或精神系统疾病治疗的新靶点。
mGluRs属于GPCR超家族中C族的成员之一。依据其蛋白序列同源性、受体偶联的第二信使系统信号转导机制以及对不同激动剂的特异性,可以将其分为三类:第一类mGluR1/mGluR5、第二类mGluR2/mGluR3、以及第三类mGluR4/mGluR6/mGluR7/mGluR8。而mGluR5主要在中枢神经系统(CNS)中高度表达,富集在大脑皮层、海马和基底核神经节等与神经系统和精神疾病相关的区域。在许多研究中,抑郁症患者表现出谷氨酸能神经递质功能亢奋,通过抗抑郁药物治疗可以减少大鼠脑内谷氨酸的释放。mGluR5受体不仅分布于突触前膜,在突触后膜也有部分分布,阻断mGluR5受体的活性不仅可以减少谷氨酸的释放,同时还可以减弱NMDA受体的活性,起到协同抗抑郁的效果。因此,近年来mGluR5已经成为治疗抑郁症的重要靶点之一。
针对mGluR5的药物设计,早期的研究主要集中在设计内源性配体的小分子竞争性拮抗剂,但是由于mGluRs结合位点的高度保守性,因此很难获得对受体亚型有很好选择性的化合物。另外,很多内源性的配体往往是谷氨酸衍生物,缺乏合适的药代动力学性质和CNS的渗透性,使得这些化合物很难用于临床研究。近年来,mGluR5的负变构调节剂(negative allosteric modulators)引起人们的广泛关注。化合物不是结合到内源性配体位点,而是作用于GPCR跨膜区域的变构位点,因此不直接拮抗受体功能,而是间接地减弱谷氨酸诱导的活性,进而克服了mGluRs内源性位点竞争性拮抗剂选择性差和渗透性差的缺陷。因此,mGluR5的负性变构调节位点被认为是一个非常理想的药物靶标,在此基础上设计新颖的mGluR5负性变构调节剂,用于中枢神经系统和精神系统类相关疾病(如脆性X染色体综合征、帕金森左旋多巴诱导的多动症、胃食管返流疾病、自闭症、疼痛、焦虑、抑郁和药物成瘾等)的治疗,具有非常重要的意义和很好的应用前景。
综上所述,本领域迫切需要开发新型的mGluR5负性变构调节剂。
发明内容
本发明的目的是提供4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物及其制备方法和用途。
为达此目的,本发明采用以下技术方案:
一方面,本发明提供了一种4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物,其结构如下式I所示:
其中,选自取代或未取代的苯基、取代或未取代的六元杂芳基、取代或未取代的噻唑基;R选自取代或未取代的苯基、取代或未取代的六元杂芳基;其中取代基为1、2、3或4个选自下组的取代基:卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、C3-C8卤代环烷基、氰基、硝基、氨基;所述杂芳基独立地含有1~4个选自氧、硫、氮中的杂原子;所述卤素为F、Cl、Br或I;所述六元杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、吡喃基或吗啉基中的任意一种。
本发明中,作为优选技术方案,在式I中,选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻唑基;R选自取代或未取代的苯基、取代或未取代的吡啶基;其中取代基为1、2、3或4个选自下组的取代基:卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、C3-C8卤代环烷基、氰基、硝基、氨基;所述卤素为F、Cl、Br或I。
本发明中,作为优选技术方案,在式I中,选自苯基、4-氟苯基、4-甲氧基苯基、4-甲基苯基、吡啶-2-基或2-甲基噻唑-4-基;R选自取代或未取代的苯基、取代或未取代的吡啶基;其中取代基为1、2、3或4个选自下组的取代基:卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氨基;所述卤素为F、Cl、Br或I。
本发明中,作为另一优选技术方案,在式I中,选自苯基、4-氟苯基、4-甲氧基苯基、4-甲基苯基、吡啶-2-基或2-甲基噻唑-4-基;R选自苯基、4-氟苯基、4-氯苯基、4-甲基苯基、4-甲氧基苯基、4-碘苯基、3,4-二氯苯基、4-叔丁基苯基、4-二甲氨基苯基、3-氯苯基、4-三氟甲氧基苯基、吡啶-3-基。
作为本发明进一步优选的技术方案,所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物为具有通式I的结构并采用如下表1所示化合物中的任意一种或至少两种的组合。
表1
表1中代表苯基、代表4-氟苯基、代表4-氯苯基、代表4-溴苯基、代表4-碘苯基、代表4-甲基苯基、代表4-甲氧基苯基、代表4-环丙基苯基、代表4-氰基苯基、代表4-硝基苯基、代表吡啶-2-基、代表吡啶-3-基、代表4-叔丁基苯基、代表4-二甲氨基苯基、代表4-三氟甲氧基苯基、代表3-氯苯基、代表3,4-二氯苯基、代表哒嗪-3-基、代表吡嗪-2-基、代表嘧啶-4-基、代表2-甲基噻唑-4-基。
本发明中作为特别优选的技术方案,所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物为选自如下表2化合物中的任意一种或至少两种的组合:
表2
本发明所述烷基是指直链或支链形式的烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、特丁基、正戊基、异戊基、正己基等基团。卤代烷基是指烷基被一个或多个卤原子取代的基团。烷氧基是指烷基末端连有氧原子的基团,例如甲氧基、乙氧基、正丙氧基、异丙氧基、特丁氧基等。卤代烷氧基是指烷氧基被一个或多个卤原子取代的基团。卤素为F、Cl、Br或I。
本发明所用术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、特丁基、正戊基、异戊基、正己基等。术语“C1-C6卤代烷基”是指具有卤素原子取代的1至6个碳原子的直链或支链烷基,非限制性地包括二氟甲基、三氟甲基等。术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、正丙氧基、异丙氧基和特丁氧基等。术语“C1-C6卤代烷氧基”是指具有卤素原子取代的1至6个碳原子的直链或支链烷氧基,非限制性地包括二氟甲氧基、三氟甲氧基等。术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。术语“C3-C8卤代环烷基”是指在环上具卤素取代的3至8个碳原子的环状烷基,非限制性地包括1-氯代环丙基、1-氯代环丁基等。
在本发明中,所述特定基团之前的C1-C6、C3-C8等表示基团中所含碳原子的个数,例如C1-C6表示碳原子数可以为1、2、3、4、5或6的基团、C3-C8表示碳原子数可以为3、4、5、6、7或8的基团。
本发明另一方面提供了一种通式I表示的化合物的制备方法,除另有注明外,反应式中各基团定义同上文。
制备方法:
本发明通式I化合物的制备路线如下所示:
其中:Hal选自氟、氯、溴或碘;和R取代基的限定与上文相同,在此不再赘述。
制备过程具体包括如下步骤:
步骤1:通式III化合物与通式IV化合物反应得到通式V化合物。
所述通式III化合物与通式IV化合物的摩尔比为1:1.0-2.0,例如1:1.0、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9或1:2.0。
步骤1的反应是在催化剂和碱的作用下进行的,所述催化剂选自铜催化剂、钯催化剂、钯铜合金催化剂、镍催化剂、铂催化剂中的任意一种或至少两种的组合;所述碱为有机碱和/或无机碱,所述有机碱选自三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、甲醇钠、乙醇钠、叔丁醇钠或叔丁醇钾中的任意一种或至少两种的组合,所述无机碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或氢化钠中的任意一种或至少两种的组合。
步骤1中,反应溶剂选自甲苯、乙腈、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮或六甲基磷酰三胺中的任意一种或至少两种的组合。
步骤1的反应温度为大于等于0℃且小于等于反应溶剂的沸点,例如25℃、30℃、35℃、40℃、45℃、50℃、60℃、70℃、75℃、80℃、85℃、90℃等,或者在溶剂沸点即回流状态下进行反应。
步骤1的反应时间为0.5-48小时,例如0.5小时、1小时、3小时、5小时、8小时、10小时、12小时、15小时、18小时、20小时、23小时、25小时、28小时、30小时、33小时、35小时、38小时、40小时、44小时或48小时。
步骤2:通式V化合物水解得到通式II化合物。
步骤2中,所述水解是在水、甲醇、乙醇、四氢呋喃或1,4-二氧六环中任意一种或至少两种的混合溶剂中进行的。
优选地,步骤2所述水解是在碱性物质存在下进行的,所述碱性物质优选氢氧化钠、氢氧化钾或氢氧化锂。
优选地,所述碱性物质的用量为通式V化合物摩尔量的1-5倍,例如,1倍、1.3倍、1.5倍、2倍、2.5倍、3倍、3.5倍、4倍、4.5倍或5倍。
优选地,步骤2的反应温度为大于等于0℃且小于等于反应溶剂的沸点,例如25℃、30℃、35℃、40℃、45℃、50℃、60℃、70℃、75℃、80℃、85℃、90℃等,或者在溶剂沸点即回流状态下进行反应。
步骤3:通式II化合物与通式VI化合物缩合反应得到通式I化合物。
步骤3中,所述缩合反应是在二氯甲烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮或甲苯中任意一种或至少两种的混合溶剂中进行的。
优选地,步骤3所述缩合反应是在碱性物质存在下进行的,所述碱性物质优选三乙胺、N,N-二异丙基乙胺、吡啶、甲醇钠、乙醇钠、叔丁醇钠或叔丁醇钾中的任意一种或至少两种的组合。
优选地,步骤3所述缩合反应是在缩合剂存在下进行的,所述缩合剂优选二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBt)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)或二异丙基碳二亚胺(DIC)、((1H-苯并[d][1,2,3]三唑-1-基)氧基)三(二甲基氨基)鏻六氟磷酸盐(V)(BOP)中的任意一种或至少两种的组合。
步骤3中,所述通式II化合物与通式VI化合物及缩合剂的摩尔比为1:1.0-2.0:1.0-2.0,例如1:1.0:1.0、1:1.1:1.1、1:1.2:1.2、1:1.3:1.3、1:1.4:1.4、1:1.5:1.5、1:1.6:1.6、1:1.7:1.7、1:1.8:1.8、1:1.9:1.9或1:2.0:2.0。
优选地,步骤3的反应温度为大于等于0℃且小于等于反应溶剂的沸点,例如25℃、30℃、35℃、40℃、45℃、50℃、60℃、70℃、75℃、80℃、85℃、90℃等,或者在溶剂沸点即回流状态下进行反应。
优选地,步骤3的反应时间为0.5-48小时,例如0.5小时、1小时、3小时、5小时、8小时、10小时、12小时、15小时、18小时、20小时、23小时、25小时、28小时、30小时、33小时、35小时、38小时、40小时、44小时或48小时。
本发明所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物的制备过程中,涉及到中间体化合物II,其结构如下式II所示:
其中,选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻唑基,其中取代基为1、2、3或4个选自下组的取代基:卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、C3-C8卤代环烷基、氰基、硝基;所述卤素为F、Cl、Br或I。
在本发明中式II所述中间体的制备方法在上文描述式I制备方法时已有涉及,在此不再赘述。
在本发明中,表3中展示了本发明化合物式II所述中间体化合物的代表性化合物,但本发明并不限定于此。
表3
另一方面,本发明提供了如上所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐。
在本发明中,所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐同样能够发挥与所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物同样的作用效果。
另一方面,本发明所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物、其互变异构体、对映体、非对映体或其药学上可接受的盐可用于治疗与代谢型谷氨酸受体第五亚型(mGluR5)靶点相关的疾病,优选用于治疗选自下组的疾病:脆性X染色体综合征、帕金森左旋多巴诱导的多动症(PD-LID)、胃食管返流疾病(GERD)、焦虑、抑郁、药物成瘾等疾病的用途。
其中,药学上可接受的盐如下:
本发明提供了通式I化合物的可药用的盐,具体地为通式I化合物与无机酸或有机酸反应形成常规的可药用盐。例如,常规的可药用盐可通过通式I化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者通式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
mGluR5负性变构调节剂相关疾病:
脆性X染色体综合征(fragile X syndrome,FXS),又称马丁-贝尔综合征,是一种由单基因Fmr1突变引起的智力障碍疾病。男性发病率约为1/1500,女性发病率约为1/2500。临床症状表现为不同程度的智力低下、注意力缺陷、活动过度、焦虑伴情绪波动、强迫症、自闭症,还可以出现运动协调不良和癫痫患病率增高,以及其它非神经系统症状如特殊面容、大耳、关节过度伸展和青春期后巨睾症等。
对于脆性X染色体综合征,目前暂无批准的用于治疗脆性X染色体综合征的药物,现有的治疗手段如特殊教育、行为疗法、社会技能训练和药物治疗等可改善部分患病个体的预后,对继发症状有帮助,但是不能有效地解决脆性X染色体综合征的核心缺损。目前常用药物主要有大剂量叶酸(可改善患者行为和运动能力、语言质量等,但对智力的改善不明显,对成年患者无效),抗抑郁药,中枢神经系统兴奋剂(哌甲酯、右苯丙胺等,对于改善注意力缺乏、活动过度有较好的效果,但副作用大)以及抗躁狂药物(硫利达嗪,用以治疗行为和情绪障碍)。
脆性X综合征是由单个基因FMR1的突变引起的,当FMR1基因发生突变时会阻碍其编码蛋白FMRP表达,导致大脑中FMRP缺失。在正常情况下FMRP蛋白可以控制或阻断大脑细胞中mGluR5激活的信号途径。FMRP缺失时,mGluR5信号过度激活从而导致大脑神经元联系异常以及与脆性X综合征相关的行为及认知障碍。研究表明,通过特异性地抑制mGluR5,可明显改善FXS患者症状,安全性好且副作用小。因此,mGluR5的负性变构调节位点被认为是一个非常理想的脆性X染色体综合征的药物靶标,在此基础上设计新颖的mGluR5负性变构调节剂,用于此类疾病的治疗,具有非常重要的意义和很好的应用前景。
帕金森病(Parkinson's disease,PD)又称震颤麻痹,是仅次于阿尔兹海默症的第二大中枢神经系统退行性疾病,主要临床症状为运动迟缓、静止性震颤、肌肉僵直、步态和姿势异常。目前左旋多巴的广泛应用使帕金森患者的症状得到较为满意的控制,但长期应用(超过五年)后大部分患者会出现左旋多巴诱发的异动症(LID)。
在PD中,由于D2受体介导的对纹状体-苍白球神经元抑制作用减弱,间接通路的谷氨酸传导活性明显增强,因此降低间接通路的活性是治疗PD的主要目标,可通过抑制谷氨酸能神经传导来实现。通过药物阻滞谷氨酸受体活性可以减少谷氨酸能神经元的传入,阻断左旋多巴引起的纹状体内基因异常表达,并削弱LID。mGluR5高度表达于纹状体的投射神经元上,而不存在于自主神经系统的靶器官,克服了传统药物直接作用于多巴胺系统带来的不良反应。研究也表明,mGluR5负性变构调节剂可降低PD大鼠发生LID的机率;而已有临床药物也显示,mGluR5负性变构调节剂具有良好的安全性、耐受性及抗运动障碍的有效性。
胃食管反流病(gastroesophageal reflux disease,GERD)是指胃内容物反流引起不适症状和/或并发症的一种疾病,除引起糜烂性食管炎、Barrett’s食管和食管腺癌外,还可引起慢性咳嗽、慢性喉炎、支气管哮喘、牙侵蚀症等食管外表现。
目前临床上治疗GERD的主要药物是质子泵抑制剂(PPI),但因存在PPI抵抗性患者,其症状不一定与酸相关,且停药后常导致患者病情复发,长期服用也给患者带来一定不良反应。而其他药物如H2受体抑制剂,促动力药,内脏痛觉调节剂,抗酸剂等,多数只对轻度患者有效,这些均限制了其在临床上的应用;且传统治疗药物均只能在一定程度上缓解症状,不能针对发病机制达到治疗效果。一过性食管下段括约肌松弛(TLESR)异常是GERD的主要发病机制之一。研究证实,选择性mGluR5负性变构调节剂能有效抑制TLESR,降低患者返流次数,延长返流间隔时间。这提示mGluR5负性变构调节剂作为抗反流药物治疗GERD很有前景。
本发明采用HDB Fluo-6钙荧光检测法测试mGluR5体外活性,选用工具分子MPEP作为阳性对照药,其IC50值为20.8nM。从下表6的数据可以看出,本发明新合成的部分化合物活性值与阳性对照药相当,对mGluR5靶点有较好的抑制活性,具有潜在治疗该靶点相关疾病的功效。小鼠悬尾实验和小鼠自主活动实验结果表明,化合物7和化合物39具有一定的抗抑郁效果。
附图说明
图1是实施例3中小鼠悬尾实验结果。
具体实施方式
下面结合具体实施例,进一步阐述本发明。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
(一)合成实施例
合成实施例1:
N-苯基-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号1)的制备:
(1)7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯的制备,具体制备方法如下:
将4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(3.00g,12.52mmol,1.0eq)用N,N-二甲基甲酰胺溶解(50mL),室温下依次加入双三苯基膦二氯化钯(1.75g,2.50mmol,0.2eq)、碘化亚铜(953.61mg,5.01mmol,0.4eq)和三乙胺(6.33g,62.59mmol,5.0eq),氮气保护下缓慢滴入苯乙炔(1.53g,15.02mmol,1.2eq),加完原料,体系升温至70℃下反应2h,TLC监测至反应不再进行时,结束反应。将反应液冷却至室温,向反应液中加入水(50mL),用乙酸乙酯萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到黄色固体产物7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(1.68g,收率:43.97%)。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.82–7.74(m,2H),7.56–7.50(m,3H),7.41(s,1H),4.37(q,J=7.1Hz,2H),4.01(s,3H),1.36(t,J=7.1Hz,3H).HRMS(ESI)calcd for C18H15N3O2[M+H+]:306.1237,found:306.1590.
(2)7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备,具体制备方法如下:
将7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(1.68g,5.50mmol,1.0eq)用50mL甲醇溶解,室温下加入10%的氢氧化钠水溶液(1.10g,27.51mmol,5.0eq),体系50℃下反应2.5h,用3M盐酸调节体系PH=1-2,浅褐色固体析出,过滤,固体烘干,得到产物即为7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(1.38g,收率:90.19%)。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.78(d,J=6.7Hz,2H),7.55–7.48(m,3H),7.42(s,1H),4.03(s,3H).HRMS(ESI)calcd for C16H11N3O2[M+H+]:278.0924,found:278.1326.
(3)N-苯基-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(200.00mg,721.30μmol,1.0eq)用30mL二氯甲烷溶解,室温下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(152.10mg,793.43μmol,1.1eq)和1-羟基苯并三唑(HOBt)(107.21mg,793.43μmol,1.1eq),室温反应30min后,加入苯胺(73.89mg,793.43μmol,1.1eq)和三乙胺(145.98mg,1.44mmol,2.0eq),然后体系室温下继续搅拌12h,待反应结束后,向反应液中加入水(50mL),用二氯甲烷萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到淡黄色固体产物N-苯基-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(134.66mg,收率:52.98%)。
化合物1的1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.95(s,1H),7.81–7.77(m,4H),7.64(s,1H),7.57–7.52(m,3H),7.41–7.36(m,2H),7.15(t,J=7.4Hz,1H),4.06(s,3H).HRMS(ESI)calcd for C22H16N4O[M+H+]:353.1397,found:353.1706.
合成实施例2:
N-(吡啶-3-基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的(化合物编号11)的制备:
将7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(150.00mg,540.97μmol,1.0eq)用30mL N,N-二甲基甲酰胺溶解,室温下依次加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)(226.26mg,595.07μmol,1.1eq)、N,N-二异丙基乙胺(139.83mg,1.08mmol,2.0eq)和3-氨基吡啶(56.00mg,595.07μmol,1.1eq),加完原料体系室温下继续搅拌2-3h,待反应结束后,向反应液中加入水(50mL),用乙酸乙酯萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=1:1),得到淡黄色固体产物N-(吡啶-3-基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(82.99mg,收率:43.41%)。
化合物11的1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.96–8.93(m,2H),8.35(dd,J=4.7,1.5Hz,1H),8.22–8.18(m,1H),7.78(dd,J=7.6,1.9Hz,2H),7.68(s,1H),7.57–7.53(m,3H),7.42(dd,J=8.3,4.7Hz,1H),4.05(s,3H).HRMS(ESI)calcd for C21H15N5O[M+H+]:354.1349,found:354.3260.
合成实施例3:
N-(4-三氟甲氧基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的(化合物编号14)的制备:
(1)N-(4-三氟甲氧基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(200.00mg,721.30μmol,1.0eq)用30mL N,N-二甲基甲酰胺溶解,室温下依次加入((1H-苯并[d][1,2,3]三唑-1-基)氧基)三(二甲基氨基)鏻六氟磷酸盐(V)(BOP)(382.82mg,865.56μmol,1.2eq)、N,N-二异丙基乙胺(139.83mg,1.08mmol,1.5eq)和4-三氟甲氧基苯胺(140.54mg,793.43μmol,1.1eq),然后体系室温下继续搅拌2.5h,待反应结束后,用1M氢氧化钠水溶液淬灭反应(30mL),乙酸乙酯萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到淡黄色固体产物N-(4-三氟甲氧基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(128.64mg,收率:40.87%)。
化合物14的1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.94(s,1H),7.91(d,J=9.1Hz,2H),7.77(dd,J=7.6,1.9Hz,2H),7.64(s,1H),7.56–7.52(m,3H),7.39(d,J=8.6Hz,2H),4.05(s,3H).HRMS(ESI)calcd for C23H15F3N4O2[M+H+]:437.1220,found:437.1513.
合成实施例4:
N-(4-甲氧基苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号23)的制备:
(1)7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯的制备,具体制备方法如下:
将4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.30g,9.60mmol,1.0eq)用N,N-二甲基甲酰胺溶解(50mL),室温下依次加入双三苯基膦二氯化钯(1.35g,1.92mmol,0.2eq)、碘化亚铜(731.10mg,3.84mmol,0.4eq)和三乙胺(4.86g,47.98mmol,5.0eq),氮气保护下缓慢滴入2-乙炔基吡啶(1.19g,11.52mmol,1.2eq),加完原料,体系升温至70℃下反应7h,TLC监测至反应不再进行时,结束反应。将反应液冷却至室温,向反应液中加入水(50mL),用乙酸乙酯萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=2:1),得到淡黄色固体产物7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.14g,收率:72.79%)。1HNMR(400MHz,Chloroform-d)δ8.97(s,1H),8.73–8.65(m,1H),7.77–7.69(m,2H),7.53(s,1H),7.36–7.31(m,1H),4.40(q,J=7.1Hz,2H),4.13(s,3H),1.41(t,J=7.1Hz,3H).HRMS(ESI)calcd for C17H14N4O2Na[M+Na+]:329.1009,found:329.1771.
(2)7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备,具体制备方法如下:
将7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(1.17g,3.82mmol,1.0eq)用50mL甲醇溶解,室温下加入10%的氢氧化钠水溶液(763.86mg,19.10mmol,5.0eq),体系50℃下反应2h,用3M盐酸调节体系PH=1-2,淡黄色固体析出,过滤,固体烘干,得到产物即为7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(965.77mg,收率:91.11%)。1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.72–8.70(m,1H),7.96–7.93(m,2H),7.56–7.52(m,1H),7.39(s,1H),4.04(s,3H).HRMS(ESI)calcd forC15H10N4O2[M+H+]:279.0877,found:279.1512.
(3)N-(4-甲氧基苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(500.00mg,1.80mmol,1.0eq)用30mL二氯甲烷溶解,室温下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(379.57mg,1.98mmol,1.1eq)和1-羟基苯并三唑(HOBt)(267.08mg,1.98mmol,1.1eq),室温反应30min后,加入4-甲氧基苯胺(243.41mg,1.98mmol,1.1eq)和三乙胺(363.65mg,3.59mmol,2.0eq),然后体系室温下继续搅拌12h,待反应结束后,向反应液中加入水(50mL),用二氯甲烷萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=2:1),得到淡黄色固体产物N-(4-甲氧基苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(472.87mg,收率:68.64%)。
化合物23的1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.97(s,1H),8.74–8.70(m,1H),7.96(td,J=7.7,1.8Hz,1H),7.88(d,J=7.8Hz,1H),7.70(d,J=9.1Hz,2H),7.61(s,1H),7.57–7.52(m,1H),6.95(d,J=9.1Hz,2H),4.06(s,3H),3.75(s,3H).HRMS(ESI)calcdfor C22H17N5O2Na[M+Na+]:406.1280,found:406.1841.
合成实施例5:
N-苯基-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号33)的制备:
(1)4-((4-氟苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯的制备,具体制备方法如下:
将4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.10g,8.76mmol,1.0eq)用N,N-二甲基甲酰胺溶解(50mL),室温下依次加入双三苯基膦二氯化钯(1.23g,1.75mmol,0.2eq)、碘化亚铜(667.53mg,3.50mmol,0.4eq)和三乙胺(4.43g,43.81mmol,5.0eq),氮气保护下缓慢滴入4-氟苯乙炔(1.26g,10.51mmol,1.2eq),加完原料,体系升温至70℃下反应5h,TLC监测至反应不再进行时,结束反应。将反应液冷却至室温,向反应液中加入水(50mL),用乙酸乙酯萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到黄色固体产物4-((4-氟苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(1.48g,收率:52.30%)。1HNMR(400MHz,DMSO-d6)δ8.93(s,1H),7.90–7.84(m,2H),7.46(s,1H),7.36(t,J=8.8Hz,2H),4.38(q,J=7.1Hz,2H),4.02(s,3H),1.37(t,J=7.1Hz,3H).HRMS(ESI)calcd forC18H14FN3O2[M+H+]:324.1143,found:324.1660.
(2)4-((4-氟苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备,具体制备方法如下:
将4-((4-氟苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(1.48g,4.58mmol,1.0eq)用50mL甲醇溶解,室温下加入10%的氢氧化钠水溶液(915.43mg,22.89mmol,5.0eq),体系50℃下反应3h,用3M盐酸调节体系PH=1-2,浅褐色固体析出,过滤,固体烘干,得到产物即4-((4-氟苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸(1.26g,收率:93.33%)。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.90–7.84(m,2H),7.46(s,1H),7.35(t,J=8.9Hz,2H),4.03(s,3H).HRMS(ESI)calcd for C16H10FN3O2[M+H+]:296.0830,found:296.1104.
(3)N-苯基-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将4-((4-氟苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸(210.00mg,711.22μmol,1.0eq)用30mL二氯甲烷溶解,室温下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(149.97mg,782.34μmol,1.1eq)和1-羟基苯并三唑(HOBt)(105.71mg,782.34μmol,1.1eq),室温反应30min后,加入苯胺(72.86mg,782.34μmol,1.1eq)和三乙胺(143.94mg,1.42mmol,2.0eq),然后体系室温下继续搅拌12h,待反应结束后,向反应液中加入水(50mL),用二氯甲烷萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到淡黄色固体产物N-苯基-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(131.53mg,收率:49.93%)。
化合物33的1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.94(s,1H),7.88–7.83(m,2H),7.80(d,J=8.0Hz,2H),7.63(s,1H),7.42–7.36(m,4H),7.14(t,J=7.4Hz,1H),4.05(s,3H).HRMS(ESI)calcd for C22H15FN4O[M+H+]:371.1703,found:371.1647.
合成实施例6:
N-(4-甲氧基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号55)的制备:
(1)4-((4-甲氧基苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯的制备,具体制备方法如下:
将4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.20g,9.18mmol,1.0eq)用N,N-二甲基甲酰胺溶解(50mL),室温下依次加入双三苯基膦二氯化钯(1.29g,1.84mmol,0.2eq)、碘化亚铜(699.31mg,3.67mmol,0.4eq)和三乙胺(4.64g,45.90mmol,5.0eq),氮气保护下缓慢滴入4-甲氧基苯乙炔(1.46g,11.02mmol,1.2eq),加完原料,体系升温至70℃下反应5h,TLC监测至反应不再进行时,结束反应。将反应液冷却至室温,向反应液中加入水(50mL),用乙酸乙酯萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到淡黄色固体产物4-((4-甲氧基苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.30g,收率:74.68%)。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.73(d,J=8.3Hz,2H),7.42(s,1H),7.06(d,J=8.3Hz,2H),4.37(q,J=7.1Hz,2H),4.01(s,3H),3.84(s,3H),1.37(t,J=7.1Hz,3H).HRMS(ESI)calcd for C19H17N3O3[M+H+]:336.1343,found:336.1986.
(2)4-((4-甲氧基苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备,具体制备方法如下:
将4-((4-甲氧基苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.30g,6.86mmol,1.0eq)用50mL甲醇溶解,室温下加入10%的氢氧化钠水溶液(1.37g,34.29mmol,5.0eq),体系50℃下反应2.5h,用3M盐酸调节体系PH=1-2,淡黄色固体析出,过滤,固体烘干,得到产物即4-((4-甲氧基苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸(2.00g,收率:94.79%)。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.73(d,J=8.5Hz,2H),7.43(s,1H),7.04(d,J=8.6Hz,2H),4.01(s,3H),3.82(s,3H).HRMS(ESI)calcd forC17H13N3O3[M+H+]:308.1030,found:308.1544.
(3)N-(4-甲氧基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将4-((4-甲氧基苯基)乙炔基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸(170.00mg,553.20μmol,1.0eq)用30mL二氯甲烷溶解,室温下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(116.65mg,608.52μmol,1.1eq)和1-羟基苯并三唑(HOBt)(82.23mg,608.52μmol,1.1eq),室温反应30min后,加入4-甲氧基苯胺(74.94mg,608.52μmol,1.1eq)和三乙胺(111.96mg,1.11mmol,2.0eq),然后体系室温下继续搅拌12h,待反应结束后,向反应液中加入水(50mL),用二氯甲烷萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=2:1),得到淡黄色固体产物N-(4-甲氧基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(99.52mg,收率:43.62%)。
化合物55的1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.90(s,1H),7.74–7.68(m,4H),7.58(s,1H),7.08(d,J=8.8Hz,2H),6.95(d,J=9.1Hz,2H),4.04(s,3H),3.84(s,3H),3.76(s,3H).HRMS(ESI)calcd for C24H20N4O3[M+H+]:413.1608,found:413.1926.
合成实施例7:
N-苯基-7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号83)的制备:
(1)7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯的制备,具体制备方法如下:
将4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(5.00g,20.86mmol,1.0eq)用N,N-二甲基甲酰胺溶解(100mL),室温下依次加入双三苯基膦二氯化钯(2.93g,4.17mmol,0.2eq)、碘化亚铜(1.59g,8.35mmol,0.4eq)和三乙胺(10.56g,104.32mmol,5.0eq),氮气保护下缓慢滴入4-乙炔基-2-甲基噻唑(3.08g,25.04mmol,1.2eq),加完原料,体系升温至100℃下反应4h,TLC监测至反应不再进行时,结束反应。将反应液冷却至室温,向反应液中加入水(100mL),用乙酸乙酯萃取(50mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到淡黄色固体产物7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(1.02g,收率:15.00%)。1H NMR(400MHz,Chloroform-d)δ9.13(s,1H),7.69(s,1H),7.40–7.34(m,1H),4.45(q,J=7.1Hz,2H),4.20(s,3H),2.89(s,3H),1.46(t,J=7.1Hz,3H).HRMS(ESI)calcd for C16H14N4O2S[M+H+]:327.0910,found:327.3804.
(2)7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备,具体制备方法如下:
将7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙(1.01g,3.09mmol,1.0eq)用50mL甲醇溶解,室温下加入10%的氢氧化钠水溶液(618.88mg,15.47mmol,5.0eq),体系66℃下反应2.5h,用3M盐酸调节体系PH=1-2,淡黄色固体析出,过滤,固体烘干,得到粗产物即为7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(692.39mg,收率:约75.00%),粗产物未经纯化直接投下一步。HRMS(ESI)calcd for C14H10N4O2S[M+H+]:299.0597,found:299.3272.
(3)N-苯基-7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(200.00mg,670.42μmol,1.0eq)用30mL二氯甲烷溶解,室温下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(141.37mg,737.46μmol,1.1eq)和1-羟基苯并三唑(HOBt)(99.65mg,737.46μmol,1.1eq),室温反应30min后,加入苯胺(68.68mg,737.46μmol,1.1eq)和三乙胺(135.68mg,1.34mmol,2.0eq),然后体系室温下继续搅拌12h,待反应结束后,向反应液中加入水(50mL),用二氯甲烷萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=2:1),得到淡黄色固体产物N-苯基-7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(61.99mg,收率:24.76%)。
化合物83的1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.11(s,1H),8.49(d,J=7.6Hz,1H),8.14(d,J=8.0Hz,1H),8.01(s,1H),7.79(d,J=7.9Hz,2H),7.40(s,1H),7.16(t,J=7.4Hz,1H),4.11(s,3H),2.82(s,3H).HRMS(ESI)calcd for C20H15N5OS[M+H+]:374.1070,found:374.4384.
合成实施例8:
N-苯基-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号90)的制备:
(1)7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯的制备,具体制备方法如下:
将4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(4.00g,16.69mmol,1.0eq)用N,N-二甲基甲酰胺溶解(100mL),室温下依次加入双三苯基膦二氯化钯(2.34g,3.34mmol,0.2eq)、碘化亚铜(1.27g,6.68mmol,0.4eq)和三乙胺(8.44g,83.45mmol,5.0eq),氮气保护下缓慢滴入4-甲基苯乙炔(2.33g,20.03mmol,1.2eq),加完原料,体系升温至70℃下反应2h,TLC监测至反应不再进行时,结束反应。将反应液冷却至室温,向反应液中加入水(100mL),用乙酸乙酯萃取(50mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=4:1),得到黄色固体产物7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(4.06g,收率:76.17%)。1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),7.69(d,J=8.1Hz,2H),7.47(s,1H),7.33(d,J=7.7Hz,2H),4.39(q,J=7.1Hz,2H),4.04(s,3H),2.39(s,3H),1.37(t,J=7.1Hz,3H).HRMS(ESI)calcd for C19H17N3O2[M+H+]:320.1394,found:320.1745.
(2)7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备,具体制备方法如下:
将7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(2.60g,8.14mmol,1.0eq)用50mL甲醇溶解,室温下加入10%的氢氧化钠水溶液(1.63g,40.71mmol,5.0eq),体系50℃下反应2h,用3M盐酸调节体系PH=1-2,浅褐色固体析出,过滤,固体烘干,得到产物即7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(2.19g,收率:92.40%)。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.69(d,J=8.1Hz,2H),7.48(s,1H),7.32(d,J=8.0Hz,2H),4.04(s,3H),2.38(s,3H).HRMS(ESI)calcd forC17H13N3O2[M+H+]:292.1081,found:292.1456.
(3)N-苯基-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备,具体制备方法如下:
将7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(200.00mg,686.57μmol,1.0eq)用30mL二氯甲烷溶解,室温下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(144.78mg,755.22μmol,1.1eq)和1-羟基苯并三唑(HOBt)(102.05mg,755.22μmol,1.1eq),室温反应30min后,加入苯胺(70.33mg,755.22μmol,1.1eq)和三乙胺(138.95mg,1.37mmol,2.0eq),然后体系室温下继续搅拌12h,待反应结束后,向反应液中加入水(50mL),用二氯甲烷萃取(30mL*3),有机层经饱和食盐水洗涤、无水硫酸钠干燥后,减压浓缩,残余物经柱色谱提纯(淋洗液为石油醚:乙酸乙酯=3:1),得到淡黄色固体产物N-苯基-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(99.32mg,收率:39.48%)。
化合物90的1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.93(s,1H),7.80(d,J=7.8Hz,2H),7.71–7.60(m,3H),7.44–7.31(m,4H),7.18–7.12(m,1H),4.05(s,3H),2.39(s,3H).HRMS(ESI)calcd for C23H18N4O[M+H+]:367.1553,found:367.1989.
除上面描述的化合物外,表1中化合物可参照合成实施例1-8中相似的方法制备或可制备,下文表4中给出了参照合成实施例1-8合成的部分化合物核磁和高分辨质谱数据。
表4
本发明的其他通式I化合物可参照上述方法合成。
(二)药理活性试验实施例
实施例1:化合物物理化学参数如下表5
表5化合物物理化学性质相关参数
注:化合物的物理化学属性(LogP、CLogP和tPSA值)为ChemOffice软件包中的Chemdraw软件预测数值。
结果显示,该类化合物的物理化学属性(LogP、CLogP和tPSA等)与阳性药(MPEP)相当,具有良好的成药性。
实施例2:mGluR5体外活性测试
实验材料:HEK293/mGluR5细胞系,Fluo-6钙离子荧光染料,阳性对照MPEP
实验仪器:FLIPR Tetra实时荧光成像分析系统
实验方法:HDB Fluo-6钙荧光检测法
实验原理:HDB Fluo-6钙离子荧光检测法是一种快速、简便、可靠的检测细胞内钙离子浓度变化的荧光检测方法。Fluo 6-AM荧光染料是Fluo 6的一种乙酰甲酯衍生物,通过培养,能够轻易穿透细胞膜,进入到细胞中。该荧光染料进入细胞后会被细胞内酯酶所水解,产生的Fluo 6由于是极性分子,不易透过脂质双分子膜,会被滞留在细胞内,随后会和钙离子(Ca2+)结合并发出荧光。
表达目的GPCR受体蛋白(mGluR5)的细胞首先用钙离子敏感的荧光探针标定,然后用化合物刺激。刺激之后,受体激活引发钙离子动员,荧光探针捕获到钙离子后可引发荧光信号,信号可用荧光读板仪读出。如果筛选的化合物能够激活mGluR5,则可以使钙流反应大大升高;反之,如果筛选的化合物能够拮抗mGluR5,则可以使钙流反应大大降低。实验结果如下表6:
表6化合物对mGluR5的抑制作用
阳性化合物结构如下:
实验结论:在生物活性评价中,我们选用工具分子MPEP作为阳性对照药,其IC50值为20.8nM。从上表已经获得的数据可以看出,新合成的部分化合物活性值与阳性对照药相当,对mGluR5靶点有较好的抑制活性,具有潜在治疗该靶点相关疾病的功效。
实施例3:动物体内药效学研究——小鼠悬尾实验
实验原理:悬尾实验(Tail Suspension Test,TST)是一种经典而又能快速评价抗抑郁药物、兴奋药物、镇静药物药效的方法。其原理是利用小鼠悬尾后企图逃脱但又无法逃脱,从而放弃挣扎,进入特有的抑郁不动状态,实验过程中记录动物不动时间来反映抑郁状态,抗抑郁药物、兴奋药物能明显地缩短改变其状态。
实验方法:取体重为18-22g小鼠,雌雄各半,适应饲养后,随机分成空白组、氟西汀组(20mg/kg)、化合物7组(5mg/kg)、化合物39组(5mg/kg),各组按剂量灌胃给药,连续15天,空白组给予等容量1%CMC-Na。末次给药后30分钟,分别将各组小鼠悬挂在SuperTst自主活动分析系统中,适应2分钟,观察记录4分钟内小鼠悬尾不动时间(实验结果见图1)。
实验结论:阳性对照氟西汀能够改善小鼠悬尾实验过程中的“不动时间”,受试化合物7在5mg/kg给药剂量下能明显降低小鼠悬尾实验过程的“不动时间”,受试化合物39在5mg/kg给药剂量下能够降低小鼠悬尾实验过程的“不动时间”。
实施例4:动物体内药效学研究——小鼠自主活动实验
实验仪器:ZZ-6型小鼠自主活动仪,成都泰盟实验仪器公司生产。
试验方法:取体重为18-22g小鼠,雌雄各半,适应饲养后,随机分成空白组、氟西汀组(20mg/kg)、化合物7高剂量组(20mg/kg)、化合物7低剂量组(5mg/kg)、化合物39高剂量组(20mg/kg)、化合物39低剂量组(5mg/kg),各组按剂量灌胃给药,连续15天,空白组给予等容量1%CMC-Na。末次给药后30分钟,将小鼠放入ZZ-6自主活动仪中适应2分钟,观察记录5分钟内各组小鼠的活动次数及站立次数(实验结果见下表7)。
表7化合物对小鼠自主活动影响
与空白组比,*p<0.05
实验结论:给药各组小鼠的活动次数无明显改变,差异无统计学意义;氟西汀组小鼠的站立次数明显增加,与空白组比差异有统计学意义(p<0.05);化合物7和化合物39各组有增加小鼠站立次数的趋势。
本发明通过上述讲授内容来说明本发明的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物及其制备方法和用途,但本发明并不局限于上述所述内容。所属技术领域的技术人员应该明了,对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (8)
1.一种4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物,其特征在于其结构通式如下式I所示:
其中,选自取代或未取代的苯基、取代或未取代的六元杂芳基、取代或未取代的噻唑基;R选自取代或未取代的苯基、取代或未取代的六元杂芳基;其中取代基为1、2、3或4个选自下组的取代基:卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、C3-C8卤代环烷基、氰基、硝基、氨基;所述卤素为F、Cl、Br或I;所述六元杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基中的任意一种。
2.根据权利要求1所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物,其特征在于:
选自苯基、4-氟苯基、4-甲氧基苯基、4-甲基苯基、吡啶-2-基或2-甲基噻唑-4-基;R选自取代或未取代的苯基、取代或未取代的吡啶基;其中取代基为1、2、3或4个选自下组的取代基:卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氨基;所述卤素为F、Cl、Br或I。
3.根据权利要求1所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物,其特征在于所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物选自如下化合物中的任意一种或至少两种的组合:
N-苯基-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号1);
N-(4-氟苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号2);
N-(4-氯苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号3);
N-(4-碘苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号5);
N-(4-甲基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号6);N-(4-甲氧基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号7);
N-(吡啶-3-基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号11);N-(4-叔丁基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号12);
N-(4-二甲基氨基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号13);
N-(4-三氟甲氧基苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号14);
N-(3-氯苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号15);N-(3,4-二氯苯基)-7-甲基-4-(苯基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号16);
N-(4-氟苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号18);
N-(4-甲氧基苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号23);
N-(4-叔丁基苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号28);
N-(4-二甲胺基苯基)-7-甲基-4-(吡啶-2-基乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号29);
N-苯基-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号33);N-(4-氟苯基)-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号34);
N-(4-氯苯基)-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号35);
N-(4-甲基苯基)-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号38);
N-(4-甲氧基苯基)-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号39);
N-(4-叔丁基苯基)-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号44);
N-(4-二甲胺基苯基)-7-甲基-4-((4-氟苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号45);
N-苯基-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号49);
N-(4-氟苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号50);
N-(4-甲基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号54);
N-(4-甲氧基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号55);
N-(4-叔丁基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号60);
N-(4-二甲胺基苯基)-7-甲基-4-((4-甲氧基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号61);
N-苯基-7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号83);
N-(4-甲基苯基)-7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号87);
N-(4-甲氧基苯基)-7-甲基-4-((2-甲基噻唑-4-基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号88);
N-苯基-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号90);N-(4-氟苯基)-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号91);
N-(4-氯苯基)-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号92);
N-(4-甲基苯基)-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号95);
N-(4-甲氧基苯基)-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号96);
N-(4-叔丁基苯基)-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号97);
N-(4-二甲胺基苯基)-7-甲基-4-((4-甲基苯基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物编号98)。
4.一种权利要求1所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物的制备方法,其特征在于制备路线如下所示:
其中:Hal选自氟、氯、溴或碘。
5.根据权利要求4所述的制备方法,其特征在于包括如下步骤:
步骤1:在催化剂和碱的作用下,通式III化合物与通式IV化合物反应得到通式V化合物;
步骤2:在碱性物质存在下,通式V化合物水解得到通式II化合物;
步骤3:在碱性物质和缩合剂的存在下,通式II化合物与通式VI化合物缩合反应得到通式I化合物。
6.一种权利要求1所述的4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物的用途,其特征在于:所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物在制备mGluR5负性变构调节剂中的应用。
7.根据权利要求6所述的用途,其特征在于:
所述4-芳香炔基取代的7H-吡咯并[2,3-d]嘧啶酰胺类化合物用于制备与代谢型谷氨酸受体第五亚型mGluR5相关疾病的治疗药物中的应用。
8.根据权利要求7所述的用途,其特征在于:
所述与代谢型谷氨酸受体第五亚型mGluR5相关疾病为脆性X染色体综合征、帕金森左旋多巴诱导的多动症PD-LID、胃食管返流疾病GERD、焦虑、抑郁或药物成瘾疾病。
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