CN103787992B - N,n-双取代苯并氮杂环-2-胺类化合物及其用途 - Google Patents
N,n-双取代苯并氮杂环-2-胺类化合物及其用途 Download PDFInfo
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- CN103787992B CN103787992B CN201410027159.2A CN201410027159A CN103787992B CN 103787992 B CN103787992 B CN 103787992B CN 201410027159 A CN201410027159 A CN 201410027159A CN 103787992 B CN103787992 B CN 103787992B
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- phenyl
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- quinoline
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
本发明主要涉及N,N-双取代苯并氮杂环-2-胺类化合物及其用途。所述N,N-双取代苯并氮杂环-2-胺类化合物为式I所示化合物,或其与可药用酸或碱所成的盐。本发明所提供的化合物对与心脑血管疾病密切相关的RhoA蛋白酶表现出较强的抑制活性。这表明本发明化合物有望开发成RhoA蛋白酶小分子抑制剂类心脑血管疾病治疗药物。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,更具体涉及N,N-双取代苯并氮杂环-2-胺类化合物及其制备方法和用途。
背景技术
心脑血管疾病是一种严重威胁人类,特别是50岁以上中老年人健康的常见病,在我国尤为突出。我国心脑血管疾病的总发病率和死亡率已经接近或超过许多发达国家,而且仍呈上升趋势。统计资料表明,我国城市人口心脑血管疾病病死率为200/10万,农村为142/10万,分别占死亡构成的37%和28%,居死亡原因的首位。因此,心脑血管疾病已经是危害人类特别是老年人生命的第一大杀手。
据目前研究,血管痉挛是心脑血管疾病重要的病理生理机制之一。开发针对新靶标和具有新作用机制的解除血管痉挛的治疗药物具有重要的市场前景和科学意义。血管痉挛的主要途径是通过细胞内钙浓度升高导致细胞收缩,临床上通过抑制该途径可达到降血压、抑制血管痉挛等作用,该类药物即为被广泛应用的钙通道阻滞剂。上世纪九十年代初研究发现细胞内尚存在不依赖于细胞内钙浓度变化的Rho(主要是RhoA)/ROCK介导途径,在细胞收缩中也起着重要作用。钙依赖的细胞收缩是通过钙离子内流后,促使钙调素(CaM)途径激活肌球蛋白轻链激酶(MLCK),导致MLC磷酸化,继而肌球蛋白与肌动蛋白结合,从而调节细胞骨架,引起血管平滑肌细胞收缩。而RhoA/ROCK则一方面通过抑制肌球蛋白轻链磷酸酶(MLCP)活性,降低了对磷酸化的MLC的去磷酸化作用,间接增加磷酸化MLC(MLC-P)的浓度,另一方面利用其自身磷酸激酶活性直接磷酸化MLC,双重上调磷酸化MLC(MLC-P)水平,从而达到调节细胞骨架,引起血管平滑肌细胞收缩的作用。
Rho家族蛋白质是小G蛋白的Ras超家族成员,是一组具有GTP酶活性的鸟苷酸结合蛋白,于1985年作为Ras同源物被首次克隆出来,包含RhoA、RhoB和RhoC三种异构体,其中RhoA被研究的最广泛。RhoA含有所有小GTP结合蛋白中高度保守的GDP/GTP结合区和GTP酶活性区,有两种可相互转换的构像,即与GDP结合的非活化态和与GTP结合的活化态,两种状态之间的转换使其能够发挥一种类似“分子开关”的作用。这种转换主要受到三类细胞内蛋白的调节:(1)鸟核苷酸交换因子(guanosinenucleotideexchangefactors,GEFs),它能促进GDP/GTP交换反应,激活RhoA蛋白,是RhoA蛋白的正调控因子;(2)GTP酶活化蛋白(GTPase–activatingproteins,GAPs),它能通过增加RhoA内在的GTP酶活性而使其失活转为无活性的GDP结合形式,是负调控因子;(3)GDP解离抑制因子(GDPdissociationinhibitors,GDIs),它能阻抑GDP从GTP酶上分离,则可稳定RhoA与GDP的结合,从而使其保持非活性状态,也是负调控因子。在上述三类蛋白的整体作用下,通过调节RhoA与GTP/GDP结合的比率,共同调节RhoA的功能。
RhoA的主要功能是调节肌动蛋白细胞骨架,肌动蛋白细胞骨架在细胞形状改变、迁移、黏附以及胞质分裂中起重要作用。RhoA分子功能的多样性与其下游效应分子的多样性有关,已经发现的RhoA的下游效应分子包括Rho激酶(Rho-associatedcoiled-coilformingproteinserine/threoninekinase,ROCK)、p21活化激酶(p21-activatedkinase,PAK)、PKN、Citron、PI3K等,这些分子介导了RhoA的作用。其中ROCK是目前功能研究最为清楚的RhoA下游靶效应分子,属于丝氨酸/苏氨酸蛋白激酶家族成员,它以两种同源性极高的异构体形式存在(Rokα/ROCKII和Rokβ/ROCKI)。近年来研究表明RhoA/ROCK通路在心脑血管疾病中起重要作用,特别是参与了高血压的发生与发展过程。
进一步的研究表明,钙依赖收缩是血管平滑肌细胞收缩的主要触发因素,而非钙依赖RhoA/ROCK收缩在血管平滑肌细胞收缩的持久阶段更为重要,这直接导致RhoA/ROCK途径在血管舒缩以及调节血压的过程中起着重要的作用。通过调控RhoA/ROCK途径,可改善许多血管疾病的发生及病程,诸如高血压、肺动脉高压、动脉粥样硬化、脑缺血等。
目前有关RhoA/ROCK调控途径的药物开发主要针对的是RhoA下游信号蛋白ROCK(包括ROCKI和ROCKII),相关抑制剂已有许多文献报道,当前已有一个此类抑制剂fasudil在包括中国在内的多个国家批准上市,同时还有5个此类抑制剂(INS-117548、K-1152、SNJ-1656、SAR407899和DE-104)正在进行临床I/II研究,这些临床候选药物的适应症集中在心血管疾病治疗、青光眼治疗和神经保护等。最初在日本上市的fasudil被用于治疗脑血管痉挛,其后的研究表明fasudil对包括心绞痛、高血压、冠状动脉痉挛、冠脉再通手术后再狭窄和动脉粥样硬化在内的心血管疾病均有良好的治疗作用。但由于其脑穿透能力较低,因此最近科学家正在研究将其制成脂质体治疗蛛网膜下腔出血引发的脑血管痉挛,希望通过定向给药增加局部药物浓度,减少不良反应,提高治疗效果。
由于已有的RhoA激酶(ROCK)抑制剂有种种不理想之处,寻找其上游蛋白RhoA抑制剂成为另一种方向,目前仅有的RhoA抑制剂是一类叫做外酶C3转移酶(exoenzymeC3transferase,C3)的大分子或其衍生物,由于它极差的膜通透性和易于体内降解的缺陷,限制了它的治疗用途,Tremblay等人发展的透膜性好的C3融合蛋白BA-210作为神经保护药正在进行II期临床研究,Lee等人发展了透膜性好的重组蛋白TAT-C3,用于神经再生治疗。这些研究从实验上支持了RhoA抑制剂发展成治疗药物的可能。如果我们针对RhoA蛋白的GTP结合域设计一些小分子竞争性抑制剂,可以阻止RhoA活化成RhoA-GTP形式,而只有后者才能与ROCK的RhoA蛋白结合域结合,暴露ROCK的催化活性中心,将ROCK激活,同时发生定向转位与MLC靠近。因此小分子抑制剂可以起到类似于大分子C3相同的RhoA抑制效果,同时小分子抑制剂可以克服大分子成药性差的缺陷。发明人已经发现了一类取代苯并氮杂环类衍生物作为小分子RhoA抑制剂,本发明人已就该类化合物申请专利(专利授权号:ZL201010244757.7),本申请的化合物为苯并氮杂环类化合物的新颖结构衍生物,结构类型突破了苯并氮杂环类化合物,而且RhoA抑制活性也有一定的提高。
综上所述,针对RhoA/ROCK通路设计治疗心血管疾病药物是可行的,考虑到目前国际国内有关直接针对RhoA蛋白GTP结合域的抑制剂研究报道很少的状况。基于RhoA-GTP结合域设计心血管疾病治疗药物具有重要的现实意义。
发明内容
本发明所涉及的化合物具有全新的N,N-双取代苯并氮杂环-2-胺类结构,对RhoA蛋白酶抑制活性的测试结果显示,本发明部分化合物对RhoA有较强的抑制活性,为今后进一步设计开发新型RhoA蛋白酶小分子抑制剂类心脑血管疾病治疗药物奠定了结构基础。
本发明的一个目的是,提供一种N,N-双取代苯并氮杂环-2-胺类化合物。所述的N,N-双取代苯并氮杂环-2-胺类化合物为式I所示化合物,或其在药学上可接受的(与可药用酸或碱所成的)盐。
式I中,R1为氢(H),C1~C4直链或支链的烷基,取代的C1~C4直链或支链的烷基;X为CH或N;A为取代的C6~C10芳环基;
其中,所示取代的C1~C4直链或支链的烷基的取代基选自:苯基,羟基(-OH),羧酸基(-COOH),酰胺基(-CONH2),环丙基,环戊基,环己基,吡啶基,或中一种;
所述取代的C6~C10芳环基的取代基选自:羧酸基(-COOH),三唑基,或由羧酸基(-COOH)、磺酸基(-SO3H)、或取代的C1~C3烃基中一种;曲线标记处为取代位(下同)。
本发明另一个目的在于,揭示式I所示化合物,或其在药学上可接受的盐的一种用途,即,式I所示化合物或其在药学上可接受的盐在制备预防或治疗RhoA介导的疾病(主要是心脑血管疾病)的药物中的应用。
具体实施方式
在本发明一个优选的技术方案中,R1为C1~C4直链或支链的烷基,取代的C1~C4直链或支链的烷基;X为CH或N;A为取代的苯基;
其中,所述取代的C1~C4的直链或支链的烷基的取代基选自:苯基,羟基(-OH),羧酸基(-COOH),酰胺基(-CONH2),环丙基,环戊基,环己基,吡啶基,或中一种;
所述取代的苯基的取代基选自:由羧酸基(-COOH)取代的C1~C3烃基中一种。
进一步的优选方案是:R1为C1~C4直链或支链的烷基,取代的C1~C4直链或支链的烷基;X为CH或N;A为取代的苯基;
其中,所述取代的C1~C4直链或支链的烷基的取代基选自:苯基,羟基(-OH),羧酸基(-COOH),酰胺基(-CONH2),环丙基,环戊基,环己基,吡啶基,或中一种;
所述取代的苯基的取代基选自:由羧酸基(-COOH)取代的乙烯基或乙基中一种。
更进一步的优选方案是:R1为甲基,乙基,异丙基,正丁基,苄基,由羧酸基(-COOH)、环丙基、环戊基、环己基、羟基(-OH)、吡啶基或酰胺基(-CONH2)取代的甲基,或由羟基(-OH)、或取代的乙基;X为CH或N;A为或
在本发明另一个优选的技术方案中,R1为氢(H);X为CH或N;A为取代的C6~C10芳环基;
所述取代的C6~C10芳环基的取代基选自:羧酸基(-COOH),三唑基,或由磺酸基(-SO3H)、或取代的C1~C3烃基中一种。
进一步的优选方案是:R1为H;X为CH或N;A为取代的苯基或萘基;
其中,所述的取代的苯基或萘基的取代基选自:羧酸基(-COOH),三唑基,或由磺酸基(-SO3H)、或取代的甲基、乙基或乙烯基中一种。
更进一步的优选方案是:R1为H;X为CH或N;A为 或
本发明还提供通式I结构的取代咪唑-1-乙烯类化合物IA~IH及其中间体II~XX的制备方法,具体合成策略分别如下。
IA和IB的合成:
式中R1和X的含义与前文所述相同。
具体包括如下步骤:
1)将2-羟基喹喔啉或2-羟基喹啉溶于苯膦酰二氯中,氮气保护下,100~120℃回流反应10~20h。冷却至室温,缓缓倒入冰水中。抽滤,水洗,晾干,得2-氯喹喔啉或2-氯喹啉(中间体II)。
2)将间硝基肉桂酸溶于乙醇,滴加少量浓硫酸,氮气保护下,回流反应10~20h。冷却至室温,减压蒸除溶剂,用无机碱将反应体系调至碱性,有机溶液萃取,取有机层,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得间硝基肉桂酸乙酯(中间体III)。
3)将中间体III溶于乙醇,加入二氯亚锡,回流反应10~20h。冷却至室温,减压蒸除溶剂,用无机碱将反应体系调至碱性,有机溶液萃取,取有机层,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得间氨基肉桂酸乙酯(中间体IV)。
4)将间硝基肉桂酸替换成间氨基苯丙酸,其余所需条件和方法类似于中间体III,制得间氨基苯丙酸乙酯(中间体V)。
5)将中间体II和中间体IV溶于无水N,N-二甲基甲酰胺中,在120~140℃,氮气保护的条件下回流10~20h。冷却至室温,向反应体系中加入适量水,用有机溶剂萃取,取有机层,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得(E)-3-{3-[N-(喹喔啉-2-基)氨基]苯基}丙烯酸乙酯或(E)-3-{3-[N-(喹啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VI)。将中间体IV替换成中间体V,其余所需条件和方法类似于中间体VI,制得(E)-3-{3-[N-(喹喔啉-2-基)氨基]苯基}丙酸乙酯或(E)-3-{3-[N-(喹啉-2-基)氨基]苯基}丙酸乙酯(中间体VIII)。
6)将中间体VI溶于无水N,N-二甲基甲酰胺中,在氮气保护和冰浴的条件下,分批加入氢化钠,搅拌10~30分钟。向反应体系中分批缓慢加入R1取代的卤化物,室温搅拌10~20h。向反应体系中加入适量的水,有机溶剂萃取。取有机层,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得(E)-3-{3-[N-R1-N-(喹喔啉-2-基)氨基]苯基}丙烯酸乙酯或(E)-3-{3-[N-R1-N-(喹啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VII)。将中间体VI替换成中间体VIII,其余所需条件和方法类似于中间体VII,制得(E)-3-{3-[N-R1-N-(喹喔啉-2-基)氨基]苯基}丙酸乙酯或(E)-3-{3-[N-R1-N-(喹啉-2-基)氨基]苯基}丙酸乙酯(中间体IX)。
7)将中间体VII溶于甲醇,加入一水合氢氧化锂,30~50℃反应10~20h。减压蒸除溶剂,残余物加适量的水,用稀盐酸将反应体系的pH调至5.5,析出大量固体,抽滤,水洗,晾干,得目标物(E)-3-{3-[N-R1-N-(喹喔啉-2-基)氨基]苯基}丙烯酸或(E)-3-{3-[N-R1-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA)。将中间体VII替换成中间体IX,其余所需条件和方法类似于目标物IA,制得目标物(E)-3-{3-[N-R1-N-(喹喔啉-2-基)氨基]苯基}丙酸或(E)-3-{3-[N-R1-N-(喹啉-2-基)氨基]苯基}丙酸(IB)。
IC的合成:
式中X的含义与前文所述相同。
具体包括如下步骤:
1)将间硝基苯甲醛、盐酸羟胺、碳酸铯溶于二甲基亚砜和水的混合溶液中,在100℃下搅拌7小时后,加入醋酸钯,继续搅拌12小时。将反应液冷却至室温,并加入适量水。有机溶剂萃取,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化,得间硝基苯甲酰胺(中间体X)。
2)将中间体X溶于N,N-二甲基甲酰胺二甲基缩醛中,105℃回流5小时。冷却至室温,减压蒸除溶剂,残余物用戊烷洗涤,即可得(E)-N-[(二甲基氨基)亚甲基]-3-硝基苯甲酰胺(中间体XI)。
3)将中间体XI溶于冰醋酸中,加入水合肼,在氮气保护、90℃的条件下,反应12小时。冷却至室温,减压蒸除大部分溶剂,抽滤,将滤饼用乙酸乙酯溶解,并用饱和碳酸氢钠溶液洗涤两次,将获得的有机相减压蒸除溶剂得到白色晶体,为3-(3-硝基苯基)-4H-1,2,4-三唑(中间体XII)。
4)将中间体III替换成中间体XII,其余所需条件和方法类似于中间体IV,制得3-(4H-1,2,4-三唑-3-基)苯胺(中间体XIII)。
5)将中间体II和中间体XIII溶于无水N,N-二甲基甲酰胺中,在120~140℃,氮气保护的条件下回流10~20h。冷却至室温,向反应体系中加入适量水,用有机溶剂萃取,取有机层,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得终产物N-[3-(4-H-1,2,4-三唑-3-基)苯基]喹喔啉-2-胺或N-[3-(4-H-1,2,4-三唑-3-基)苯基]喹啉-2-胺(IC)。
ID的合成:
式中X的含义与前文所述相同。
具体包括如下步骤:
1)将间硝基肉桂酸替换成6-氨基萘-2-甲酸,其余所需条件和方法类似于中间体III,制得6-氨基-萘-2-甲酸乙酯(中间体XIV)。
2)将中间体IV替换成中间体XIV,其余所需条件和方法类似于中间体VI,制得6-[N-(喹喔啉-2-基)氨基]-萘-2-甲酸乙酯或6-[N-(喹啉-2-基)氨基]-萘-2-甲酸乙酯(中间体XV)。
3)将中间体VII替换成中间体XV,其余所需条件和方法类似于目标物IA,制得目标物6-[N-(喹喔啉-2-基)氨基]-萘-2-甲酸或6-[N-(喹啉-2-基)氨基]-萘-2-甲酸(ID)。
IE和IF的合成:
式中X的含义与前文所述相同。
具体包括如下步骤:
将中间体VI溶于甲醇,在0℃条件下,加入甲醇钠和羟胺水溶液。TLC监测反应。反应结束后,减压蒸除溶剂,加入适量水,用稀盐酸将反应体系的pH调至5.5,有固体析出,抽滤,水洗,晾干即可得目标物(E)-N-羟基-3-{3-[N’-(喹喔啉-2-基)氨基]苯基}丙烯酰胺和(E)-N-羟基-3-{3-[N’-(喹啉-2-基)氨基]苯基}丙烯酰胺(IE)。将中间体VI替换成中间体VIII,其余所需条件和方法类似于目标物IE,制得目标物(E)-N-羟基-3-{3-[N’-(喹喔啉-2-基)氨基]苯基}丙酰胺和(E)-N-羟基-3-{3-[N’-(喹啉-2-基)氨基]苯基}丙酰胺(IF)。
IG的合成:
式中X的含义与前文所述相同。
具体包括如下步骤:
1)将间硝基苯乙酸溶于无水四氢呋喃中,氮气保护下,逐滴加入硼烷的四氢呋喃溶液,室温反应10~20h。逐滴加入少量水淬灭反应。加入无机碱溶液,将反应体系调至碱性。有机溶剂萃取,取有机层,干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得间硝基苯乙醇(中间体XVI)。
2)将中间体III替换成中间体XVI,其余所需条件和方法类似于中间体IV,制得间氨基苯乙醇(中间体XVII)。
3)将中间体IV替换成中间体XVII,其余所需条件和方法类似于中间体VI,制得2-[3-N-(喹喔啉-2-基)氨基苯基]乙醇或2-[3-N-(喹啉-2-基)氨基苯基]乙醇(中间体XVIII)。
4)在0℃,氮气保护的条件下,将中间体XVIII溶于无水二氯甲烷中,加入四溴化碳和三苯基膦,20~30℃搅拌1~5h。有机溶剂萃取,取有机层,干燥,过滤,减压蒸除溶剂,残余物经柱层析分离纯化得N-[3-(2-溴乙基)苯基]喹喔啉-2-胺或N-[3-(2-溴乙基)苯基]喹啉-2-胺(中间体XIX)。
5)将中间体XIX、亚硫酸钠、四丁基溴化铵溶于水,回流2~5h。将反应冷至室温,有机溶剂洗涤两次。取水层,用稀盐酸将水层的pH调至2,减压蒸除水。残余物溶于甲醇,并搅拌0.5小时。抽滤,取滤液,减压蒸除甲醇得目标物2-[3-N-(喹喔啉-2-基)氨基]苯基乙磺酸或2-[3-N-(喹啉-2-基)氨基]苯基乙磺酸(IG)。
IH的合成:
式中X的含义与前文所述相同。
具体包括如下步骤:
1)将中间体IV替换成间氨基苯甲醇,其余所需条件和方法类似于中间体VI,制得[3-N-(喹喔啉-2-基)氨基]苯甲醇或[3-N-(喹啉-2-基)氨基]苯甲醇(中间体XX)。
2)将中间体XX、三乙胺、4-二甲氨基吡啶溶于无水四氢呋喃中。在20~30℃、氮气保护下,逐滴加入氯磷酸二乙酯。加毕继续搅拌10~20h。将反应液倒入饱和硫酸氢钾溶液中。有机溶剂萃取,取有机层。先用饱和碳酸氢钠溶液洗涤两次,再用饱和氯化钠溶液洗涤两次。无水硫酸镁干燥,抽滤,减压蒸除溶剂,残余物经柱层析分离纯化得目标物3-[N-(喹喔啉-2-基)氨基]苯甲氧基磷酸二乙酯或3-[N-(喹啉-2-基)氨基]苯甲氧基磷酸二乙酯(IH)。
根据上述制备方法的教导,本领域普通技术人员无需创造性劳动,即可获得式IA~IH所包含的所有化合物。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明,但不以任何方式限制本发明的保护范围。实施例中的所有参数以及其余的说明,除另有说明外,都是以质量(克)为单位。
实施例1
2-氯喹喔啉(中间体II-1)的制备。
将2.000g2-羟基喹喔啉溶于20mL苯膦酰二氯中,在氮气保护的条件下,110℃回流反应12h。TLC监测反应。反应完全后,将反应液冷却至室温,缓缓倒入冰水中并不断搅拌。产物析出后,抽滤,水洗,晾干,即可得到1.830g2-氯喹喔啉(中间体II-1),产率81%。
1H-NMR(400MHz,CDCl3):δ8.54(s,1H),7.92–7.81(m,1H),7.80–7.72(m,1H),7.63–7.50(m,2H).
实施例2
2-氯喹啉(中间体II-2)的制备。
除了将2-羟基喹喔啉替换成2-羟基喹啉之外,其余所需原料、试剂及制备方法同实施例1,得1.911g中间体2-氯喹啉(中间体II-2),收率是85%。
1H-NMR(400MHz,CDCl3):δ8.14(d,J=8.6Hz,1H),8.08(d,J=8.5Hz,1H),7.83(d,J=8.2Hz,1H),7.80–7.73(m,1H),7.58(m,1H),7.41(d,J=8.6Hz,1H).
实施例3
间硝基肉桂酸乙酯(中间体III)的制备。
将2.000g间硝基肉桂酸溶于40mL乙醇,缓慢滴加1mL浓硫酸,在氮气保护条件下,回流反应12h。TLC监测反应。反应结束后,将反应体系冷却至室温,减压蒸除溶剂,用饱和碳酸氢钠溶液将反应体系调至碱性,用乙酸乙酯萃取,取有机层,干燥,抽滤,减压蒸除溶剂得粗产物。经柱层析分离纯化得2.000g中间体间硝基肉桂酸乙酯(中间体III),产率88%。
1H-NMR(400MHz,CDCl3):δ7.62(d,J=15.8Hz,1H),7.20(t,J=7.6Hz,1H),6.98(d,J=7.8Hz,1H),6.88(s,1H),6.76(d,J=8.1Hz,1H),6.40(d,J=16.2Hz,1H),4.28(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H).
实施例4
间氨基肉桂酸乙酯(中间体IV)的制备。
将2.000g中间体III溶于40mL乙醇,加入10.350g二氯亚锡,回流反应12h。TLC监测反应。反应结束后,将反应体系冷却至室温,减压蒸除溶剂,加入过量饱和碳酸氢钠溶液,将反应体系调为碱性,乙酸乙酯萃取,取有机层,干燥,抽滤,减压蒸除溶剂得粗产物。经柱层析分离纯化得1.698g中间体间氨基肉桂酸乙酯(中间体IV),产率98%。
1H-NMR(400MHz,CDCl3):δ7.62(d,J=16.0Hz,1H),7.20(t,J=7.8Hz,1H),6.98(d,J=7.6Hz,1H),6.88(s,1H),6.76(d,J=7.9Hz,1H),6.40(d,J=16.0Hz,1H),4.28(q,J=7.1Hz,2H),3.76(s,2H),1.36(t,J=7.1Hz,3H).
实施例5
间氨基苯丙酸乙酯(中间体V)的制备。
除了将间硝基肉桂酸替换成间氨基苯丙酸之外,其余所需原料、试剂及制备方法同实施例3,得中间体间氨基苯丙酸乙酯(中间体V),收率是85%。
1H-NMR(400MHz,CDCl3):δ7.18–7.04(m,1H),6.65(d,J=7.7Hz,1H),6.59(d,J=6.3Hz,2H),4.15(q,J=7.1Hz,2H),3.52(s,2H),2.92–2.84(m,2H),2.70–2.52(m,2H),1.26(dd,J=9.6,4.7Hz,3H).
实施例6
(E)-3-{3-[N-(喹喔啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VI-1)的制备。
将200mg中间体II-1和230mg中间体IV溶于无水2mLN,N-二甲基甲酰胺中,在130℃,氮气保护的条件下回流12小时。TLC监测反应。反应结束后,将反应体系冷却至室温,向反应体系中加入适量水,用乙酸乙酯萃取,取有机层,干燥,抽滤,蒸干溶剂得粗产物。经柱层析分离纯化得313mg中间体(E)-3-{3-[N-(喹喔啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VI-1),产率81%。
1H-NMR(400Hz,CDCl3):δ8.45(s,1H),8.02(s,1H),7.94(d,J=8.0Hz,1H),7.80-7.84(m,2H),7.71(d,J=16.0Hz,1H),7.65(t,J=7.6Hz,1H),7.49(t,J=8.0Hz,1H),7.39(t,J=8.0Hz,1H),7.25(d,J=7.6Hz,1H),6.48(d,J=16.0Hz,1H),4.30(q,2H),1.36(t,J=7.2Hz,3H).
实施例7
(E)-3-{3-[N-(喹啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VI-2)的制备。
除了将中间体II-1替换成II-2之外,其余所需原料、试剂及制备方法同实施例6,得254mg中间体(E)-3-{3-[N-(喹啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VI-2),收率是51%。
1H-NMR(400MHz,CDCl3):δ7.95(d,J=8.9Hz,1H),7.88(s,1H),7.84(d,J=8.4Hz,1H),7.76–7.60(m,4H),7.35(m,2H),7.24(d,J=7.7Hz,1H),6.96(d,J=8.9Hz,1H),6.48(d,J=16.0Hz,1H),4.31(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).
实施例8
3-{3-[N-(喹喔啉-2-基)氨基]苯基}丙酸乙酯(中间体VIII-1)的制备。
除了将中间体IV替换成中间体V之外,其余所需原料、试剂及制备方法同实施例6,得313mg中间体3-{3-[N-(喹喔啉-2-基)氨基]苯基}丙酸乙酯(中间体VIII-1),产率62%。
1H-NMR(400MHz,Acetone-d6):δ8.41(s,1H),7.91(dd,J=8.2,0.9Hz,1H),7.83(s,1H),7.79(dd,J=8.2,0.7Hz,1H),7.66(dd,J=8.0,1.6Hz,1H),7.64–7.55(m,2H),7.47–7.38(m,1H),7.26(t,J=8.0Hz,1H),6.92(d,J=7.6Hz,1H),4.19–4.12(m,2H),2.97(t,J=7.7Hz,2H),2.68(t,J=7.7Hz,2H),1.27–1.21(m,3H).
实施例9
3-{3-[N-(喹啉-2-基)氨基]苯基}丙酸乙酯(中间体VIII-2)的制备。
除了将中间体IV替换成中间体V之外,其余所需原料、试剂及制备方法同实施例7,得294mg中间体3-{3-[N-(喹啉-2-基)氨基]苯基}丙酸乙酯(VIII-2),收率是58%。
1H-NMR(400MHz,CDCl3):δ7.92(d,J=8.9Hz,1H),7.78(d,J=8.4Hz,1H),7.64(d,J=8.0Hz,1H),7.59(dd,J=11.2,4.1Hz,1H),7.44(d,J=8.0Hz,1H),7.40(s,1H),7.33–7.27(m,2H),6.98(d,J=8.9Hz,1H),6.93(d,J=7.5Hz,1H),4.14(q,J=7.1Hz,2H),2.97(t,J=7.8Hz,2H),2.66(t,J=7.8Hz,2H),1.24(t,J=7.1Hz,3H).
实施例10
(E)-3-{3-[N-乙基-N-(喹喔啉-2-基)氨基]苯基}丙烯酸(IA-1)的制备。
将238mg中间体VI-1溶于4mL无水DMF中,在氮气保护和冰浴的条件下,分批加入36mg氢化钠,搅拌15分钟。15分钟后,向反应体系中分批缓慢加入600μL碘乙烷,室温搅拌12小时。TLC监测反应。反应结束后,向反应体系中加入适量的水,用乙酸乙酯萃取。取有机层,干燥,抽滤,减压蒸除溶剂得粗产物。经柱层析分离纯化得178mg中间体(E)-3-{3-[N-乙基-N-(喹喔啉-2-基)氨基]苯基}丙烯酸乙酯(中间体VII-1)。将178mg中间体VII-1溶于4mL甲醇,加入43mg一水合氢氧化锂,40℃反应过夜。TLC监测反应。反应结束后,减压蒸除溶剂,加入1N稀盐酸,将反应体系的PH调至5.5,析出大量固体,抽滤,水洗,晾干,得140mg终产物(E)-3-{3-[N-乙基-N-(喹喔啉-2-基)氨基]苯基}丙烯酸(IA-1),两步产率59%。
1H-NMR(400MHz,DMSO-d6):δ8.15(s,1H),7.82(d,J=8.1Hz,2H),7.70(t,J=7.5Hz,2H),7.67–7.54(m,3H),7.46(d,J=8.2Hz,2H),6.64(d,J=16.0Hz,1H),4.10(dd,J=14.2,7.1Hz,2H),1.22(t,J=7.0Hz,3H);MS(ESI)m/z320.1[M+1]+.
实施例11
(E)-3-{3-[N-乙基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-2)的制备。
除了将中间体VI-1替换成中间体VI-2之外,其余所需原料、试剂及制备方法同实施例10,得113mg终产物(E)-3-{3-[N-乙基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-2),两步收率是57%。
1H-NMR(400MHz,DMSO-d6):δ7.91(s,1H),7.75–7.60(m,5H),7.56–7.53(m,2H),7.39–7.36(m,1H),7.28–7.25(m,1H),6.61(d,J=16.0Hz,2H),4.14(dd,J=14.1,7.1Hz,2H),1.21(t,J=6.9Hz,3H);MS(ESI)m/z319.1[M+1]+.
实施例12
(E)-3-{3-[N-羧甲基-N-(喹喔啉-2-基)氨基]苯基}丙烯酸(IA-3)的制备。
除了将原料碘乙烷替换成溴乙酸甲酯之外,其余所需原料、试剂及制备方法同实施例10,得90mg终产物(E)-3-{3-[N-羧甲基-N-(喹喔啉-2-基)氨基]苯基}丙烯酸(IA-3),两步收率是27%。
1H-NMR(400MHz,Acetone-d6):δ8.37(s,1H),7.95(s,1H),7.87(d,J=8.2Hz,1H),7.75(t,J=10.9Hz,3H),7.66(dd,J=14.1,7.0Hz,3H),7.49(t,J=7.5Hz,1H),6.64(d,J=16.1Hz,1H),4.86(s,2H);MS(ESI)m/z372.1[M+23]+.
实施例13
(E)-3-{3-[N-羧甲基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-4)的制备。
除了将中间体碘乙烷替换成溴乙酸甲酯之外,其余所需原料、试剂及制备方法同实施例11,得31mg终产物(E)-3-{3-[N-羧甲基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-4),两步收率是10%。
1H-NMR(400MHz,Acetone-d6):δ7.99(d,J=9.1Hz,1H),7.85(s,1H),7.82–7.75(m,2H),7.73–7.66(m,2H),7.65–7.54(m,3H),7.32(t,J=7.4Hz,1H),6.87(d,J=9.1Hz,1H),6.61(d,J=16.0Hz,1H),4.92(s,2H);MS(ESI)m/z349.1[M+1]+.
实施例14
(E)-3-{3-[N-甲基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-5)的制备。
除了将原料碘乙烷替换成三氟甲磺酸甲酯之外,其余所需原料、试剂及制备方法同实施例11,得60mg终产物(E)-3-{3-[N-甲基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-5),两步收率是14%。
1H-NMR(400MHz,Acetone-d6):δ7.94(d,J=9.2Hz,1H),7.75(dd,J=17.3,8.0Hz,4H),7.66(d,J=7.6Hz,1H),7.60(dd,J=16.5,8.2Hz,2H),7.48(d,J=7.6Hz,1H),7.31(t,J=7.4Hz,1H),6.85(d,J=9.3Hz,1H),6.64(d,J=16.0Hz,1H),3.68(s,3H);MS(ESI)m/z305.1[M+1]+.
实施例15
(E)-3-{3-[N-异丙基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-6)的制备。
除了将原料碘乙烷替换成2-碘丙烷之外,其余所需原料、试剂及制备方法同实施例11,得159mg终产物(E)-3-{3-[N-异丙基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-6),两步收率是37%。
1H-NMR(400MHz,DMSO-d6):δ7.81(t,J=8.2Hz,2H),7.63(dd,J=20.5,11.3Hz,5H),7.57–7.51(m,1H),7.28(d,J=7.7Hz,1H),7.21(t,J=7.6Hz,1H),6.61(d,J=15.9Hz,1H),6.20(d,J=9.1Hz,1H),5.61–5.34(m,1H),1.15(d,J=6.8Hz,6H);MS(EI)m/z332.2(M+),317.1(100%).
实施例16
(E)-3-{3-[N-苄基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-7)的制备。
除了将原料碘乙烷替换成苄基溴之外,其余所需原料、试剂及制备方法同实施例11,得352mg终产物(E)-3-{3-[N-苄基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-7),两步收率是45%。
1H-NMR(400MHz,DMSO-d6):δ7.93(d,J=9.0Hz,1H),7.72–7.63(m,2H),7.59(d,J=8.6Hz,1H),7.51(dd,J=15.8,8.0Hz,3H),7.39(t,J=7.9Hz,1H),7.31(t,J=6.8Hz,3H),7.27–7.19(m,3H),7.14(t,J=7.4Hz,1H),6.77(d,J=9.1Hz,1H),6.48(d,J=16.0Hz,1H),5.39(s,2H);MS(EI)m/z380.2(M+),380.2(100%).
实施例17
(E)-3-{3-[N-氨甲酰甲基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-8)的制备。
除了将原料碘乙烷替换成碘乙酰胺之外,其余所需原料、试剂及制备方法同实施例11,得136mg终产物(E)-3-{3-[N-氨甲酰甲基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-8),两步收率是26%。
1H-NMR(400MHz,DMSO-d6):δ7.95(d,J=9.0Hz,1H),7.76(s,1H),7.72(d,J=7.8Hz,1H),7.60(dd,J=15.2,7.4Hz,3H),7.53(t,J=6.9Hz,1H),7.52–7.44(m,3H),7.27(t,J=7.3Hz,1H),7.07(s,1H),6.77(d,J=9.2Hz,1H),6.54(d,J=16.0Hz,1H),4.63(s,2H);MS(ESI)m/z348.1[M+1]+.
实施例18
(E)-3-{3-[N-(2-叔丁基二甲基硅氧基乙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-9)的制备。
除了将原料碘乙烷替换成硅醚保护的2-碘乙醇之外,其余所需原料、试剂及制备方法同实施例11,得102mg终产物(E)-3-{3-[N-(2-叔丁基二甲基硅氧基乙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-9),两步收率是10%。
1H-NMR(400MHz,DMSO-d6):δ7.92(d,J=9.2Hz,1H),7.73(s,1H),7.70(d,J=7.4Hz,1H),7.67–7.54(m,4H),7.50(t,J=7.7Hz,1H),7.42(d,J=8.1Hz,1H),7.30–7.23(m,1H),6.70(d,J=9.1Hz,1H),6.57(d,J=16.0Hz,1H),4.17(t,J=6.3Hz,2H),3.93(t,J=6.3Hz,2H),0.82(s,9H),0.00(s,6H);MS(ESI)m/z449.2[M+1]+.
实施例19
(E)-3-{3-[N-(2-羟乙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-10)的制备。
在氮气保护的条件下,将193mg终产物IA-9溶于2mL无水四氢呋喃中,加入1mL四丁基氟化铵的四氢呋喃溶液(1M),室温搅拌过夜。TLC监测反应。反应结束后,减压蒸除溶剂,经柱层析分离纯化得69mg终产物(E)-3-{3-[N-(2-羟乙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-10),产率48%。
1H-NMR(400MHz,DMSO-d6):δ7.91(d,J=9.1Hz,1H),7.74(s,1H),7.70(d,J=7.9Hz,1H),7.61(dd,J=13.0,7.9Hz,3H),7.56(d,J=7.0Hz,1H),7.51(t,J=7.7Hz,1H),7.42(d,J=8.1Hz,1H),7.26(t,J=7.2Hz,1H),6.67(d,J=9.1Hz,1H),6.57(d,J=16.0Hz,1H),4.13(t,J=6.2Hz,2H),3.71(t,J=6.2Hz,2H);MS(ESI)m/z335.1[M+1]+.
实施例20
(E)-3-{3-[N-(3-羟丙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-11)的制备。
除了将原料碘乙烷替换成3-碘-1-丙醇之外,其余所需原料、试剂及制备方法同实施例11,得216mg终产物(E)-3-{3-[N-(3-羟丙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-11),两步收率是49%。
1H-NMR(400MHz,Methanol-d4):δ7.81(d,J=9.1Hz,1H),7.63(d,J=7.9Hz,1H),7.59(d,J=7.8Hz,2H),7.54(d,J=8.3Hz,3H),7.48(t,J=7.7Hz,1H),7.33(d,J=7.5Hz,1H),7.23(t,J=7.4Hz,1H),6.63(d,J=9.2Hz,1H),6.48(d,J=16.0Hz,1H),4.25(t,J=6.3Hz,2H),3.63(t,J=5.8Hz,2H),1.83–1.75(m,2H);MS(ESI)m/z347.1[M-1]-.
实施例21
(E)-3-{3-[N-(2-(哌啶-1-基)乙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-12)的制备。
除了将原料碘乙烷替换成2-哌啶乙基氯盐酸盐之外,其余所需原料、试剂及制备方法同实施例11,得239mg终产物(E)-3-{3-[N-(2-(哌啶-1-基)乙基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-12),两步收率是63%。
1H-NMR(400MHz,Methanol-d4):δ7.83(d,J=9.1Hz,1H),7.68(d,J=8.4Hz,1H),7.61(d,J=7.7Hz,1H),7.57–7.50(m,2H),7.45(dt,J=15.4,7.8Hz,2H),7.36(d,J=16.0Hz,1H),7.30–7.21(m,2H),6.58(d,J=9.1Hz,1H),6.44(d,J=16.0Hz,1H),4.42(t,J=5.8Hz,2H),3.35(t,J=5.8Hz,2H),1.83(dd,J=12.4,7.1Hz,4H),0.79(d,J=9.5Hz,5H);MS(ESI)m/z400.2[M-1]-.
实施例22
(E)-3-{3-[N-正丙基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-13)的制备。
除了将原料碘乙烷替换成1-碘丙烷之外,其余所需原料、试剂及制备方法同实施例11,得398mg终产物(E)-3-{3-[N-正丙基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-13),两步收率是95%。
1H-NMR(400MHz,Acetone-d6):δ7.85(d,J=9.1Hz,1H),7.75–7.62(m,5H),7.56(t,J=7.7Hz,2H),7.41(d,J=7.7Hz,1H),7.24(t,J=7.0Hz,1H),6.69(d,J=9.1Hz,1H),6.61(d,J=16.1Hz,1H),4.16–4.11(m,2H),1.84–1.69(m,2H),0.97(t,J=7.4Hz,3H);MS(ESI)m/z331.2[M-1]-.
实施例23
(E)-3-{3-[N-正丁基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-14)的制备。
除了将原料碘乙烷替换成1-碘丁烷之外,其余所需原料、试剂及制备方法同实施例11,得390mg终产物(E)-3-{3-[N-正丁基-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-14),两步收率是90%。
1H-NMR(400MHz,Acetone-d6):δ7.89(d,J=8.7Hz,1H),7.70(dd,J=20.7,10.4Hz,5H),7.59(t,J=7.7Hz,2H),7.45(d,J=7.7Hz,1H),7.27(t,J=7.3Hz,1H),6.70(d,J=9.2Hz,1H),6.63(d,J=16.0Hz,1H),4.24(s,2H),1.78–1.69(m,2H),1.51–1.38(m,2H),0.95(t,J=7.4Hz,3H);MS(ESI)m/z345.2[M-1]-.
实施例24
(E)-3-{3-[N-(环丙基甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-15)的制备。
除了将原料碘乙烷替换成溴甲基环丙烷之外,其余所需原料、试剂及制备方法同实施例11,得188mg终产物(E)-3-{3-[N-(环丙基甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-15),两步收率是43%。
1H-NMR(400MHz,DMSO-d6):δ7.91(d,J=8.1Hz,1H),7.78–7.60(m,5H),7.55(dt,J=15.4,7.5Hz,2H),7.40(d,J=7.7Hz,1H),7.27(d,J=6.5Hz,1H),6.61(t,J=12.0Hz,2H),3.98(d,J=6.8Hz,2H),1.27–1.15(m,1H),0.40(d,J=6.7Hz,2H),0.17(q,J=5.1Hz,2H);MS(ESI)m/z343.2[M-1]-.
实施例25
(E)-3-{3-[N-(环戊基甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-16)的制备。
除了将原料碘乙烷替换成碘甲基环戊烷之外,其余所需原料、试剂及制备方法同实施例11,得100mg终产物(E)-3-{3-[N-(环戊基甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-16),两步收率是21%。
1H-NMR(400MHz,Methanol-d4):δ7.92(d,J=9.3Hz,1H),7.72(dd,J=22.9,7.1Hz,3H),7.60(dt,J=15.3,8.1Hz,4H),7.42(d,J=7.8Hz,1H),7.31(t,J=7.3Hz,1H),6.74(d,J=9.3Hz,1H),6.55(d,J=16.0Hz,1H),4.17(d,J=7.6Hz,2H),2.35(dt,J=15.0,7.6Hz,1H),1.74(td,J=12.4,8.5Hz,4H),1.64–1.50(m,2H),0.91(d,J=9.8Hz,2H);MS(ESI)m/z371.2[M-1]-.
实施例26
(E)-3-{3-[N-(环己基甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-17)的制备。
除了将原料碘乙烷替换成溴甲基环己烷之外,其余所需原料、试剂及制备方法同实施例11,得111mg终产物(E)-3-{3-[N-(环己基甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-17),两步收率是23%。
1H-NMR(400MHz,DMSO-d6):δ7.87(d,J=9.2Hz,1H),7.66(d,J=7.6Hz,1H),7.60(d,J=8.2Hz,1H),7.50(dt,J=15.2,9.3Hz,4H),7.31(t,J=13.3Hz,2H),7.23(t,J=6.9Hz,1H),6.64(d,J=9.1Hz,1H),6.52(d,J=15.9Hz,1H),4.02(d,J=6.6Hz,2H),1.67(dd,J=49.2,25.9Hz,7H),1.25(d,J=10.2Hz,1H),1.13(t,J=9.4Hz,3H);MS(ESI)m/z385.2[M-1]-.
实施例27
(E)-3-{3-[N-((吡啶-2-基)甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-18)的制备。
除了将原料碘乙烷替换成2-溴甲基吡啶盐酸盐之外,其余所需原料、试剂及制备方法同实施例11,得184mg终产物(E)-3-{3-[N-((吡啶-2-基)甲基)-N-(喹啉-2-基)氨基]苯基}丙烯酸(IA-18),两步收率是38%。
1H-NMR(400MHz,DMSO-d6):δ8.52(d,J=4.4Hz,1H),8.01(d,J=9.2Hz,1H),7.84(s,1H),7.75(dd,J=11.1,8.0Hz,2H),7.64–7.52(m,6H),7.49(d,J=6.3Hz,2H),7.28(d,J=6.3Hz,1H),6.88(d,J=9.1Hz,1H),6.56(d,J=16.0Hz,1H),5.49(s,2H);MS(ESI)m/z380.1[M-1]-.
实施例28
3-{3-[N-乙基-N-(喹喔啉-2-基)氨基]苯基}丙酸(IB-1)的制备。
除了将中间体VI-1替换成中间体VIII-1之外,其余所需原料、试剂及制备方法同实施例10,得142mg终产物3-{3-[N-乙基-N-(喹喔啉-2-基)氨基]苯基}丙酸(IB-1),两步收率是71%。
1H-NMR(400MHz,DMSO-d6):δ8.07(s,1H),7.81(d,J=7.0Hz,1H),7.74–7.67(m,1H),7.67–7.56(m,1H),7.50–7.38(m,2H),7.26(dd,J=17.2,9.5Hz,3H),4.06(q,J=7.0Hz,2H),2.88(t,J=7.5Hz,2H),2.58(t,J=7.6Hz,2H),1.20(t,J=7.0Hz,3H);MS(ESI)m/z322.2[M+1]+.
实施例29
3-{3-[N-乙基-N-(喹啉-2-基)氨基]苯基}丙酸(IB-2)的制备。
除了将中间体VI-2替换成中间体VIII-2之外,其余所需原料、试剂及制备方法同实施例11,得204mg终产物3-{3-[N-乙基-N-(喹啉-2-基)氨基]苯基}丙酸(IB-2),两步收率是49%。
1H-NMR(400MHz,Methanol-d4):δ7.80(d,J=9.2Hz,1H),7.73(d,J=8.5Hz,1H),7.63(d,J=8.0Hz,1H),7.60–7.52(m,1H),7.43(t,J=7.7Hz,1H),7.29–7.19(m,3H),7.15(d,J=6.8Hz,1H),6.62(d,J=9.2Hz,1H),4.16(q,J=7.0Hz,2H),2.98(t,J=7.5Hz,2H),2.64(t,J=7.5Hz,2H),1.28(t,J=7.1Hz,3H);MS(ESI)m/z321.2[M+1]+.
实施例30
3-{3-[N-羧甲基-N-(喹喔啉-2-基)氨基]苯基}丙酸(IB-3)的制备。
除了将中间体VI-1替换成中间体VIII-1之外,其余所需原料、试剂及制备方法同实施例12,得28mg终产物3-{3-[N-羧甲基-N-(喹喔啉-2-基)氨基]苯基}丙酸(IB-3),两步收率是9%。
1H-NMR(400MHz,Acetone-d6):δ8.29(s,1H),7.86(d,J=8.1Hz,1H),7.71(d,J=8.3Hz,1H),7.65(t,J=7.6Hz,1H),7.53–7.48(m,2H),7.48–7.45(m,1H),7.42(d,J=7.8Hz,1H),7.35(d,J=7.4Hz,1H),4.79(s,2H),3.01(t,J=7.6Hz,2H),2.71(t,J=7.6Hz,2H);MS(ESI)m/z374.1[M+23]+.
实施例31
3-{3-[N-羧甲基-N-(喹啉-2-基)氨基]苯基}丙酸(IB-4)的制备。
除了将中间体VI-2替换成中间体VIII-2之外,其余所需原料、试剂及制备方法同实施例13,得12mg终产物3-{3-[N-羧甲基-N-(喹啉-2-基)氨基]苯基}丙酸(IB-4),两步收率是4%。
1H-NMR(400MHz,Acetone-d6):δ7.93(d,J=9.1Hz,1H),7.78–7.65(m,2H),7.59(t,J=7.6Hz,1H),7.49–7.39(m,2H),7.34(d,J=7.5Hz,1H),7.29(t,J=7.3Hz,2H),6.81(d,J=9.1Hz,1H),4.80(s,2H),2.99(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H);MS(ESI)m/z351.1[M+1]+.
实施例32
间硝基苯甲酰胺(中间体X)的制备。
将100mg间硝基苯甲醛、56mg盐酸羟胺、259mg碳酸铯溶于1.5mL二甲基亚砜和0.5mL水的混合溶液中,在100℃下搅拌7小时后,加入8mg醋酸钯,继续搅拌12小时。TLC监测反应。反应结束后,将反应液冷却至室温,并加入适量水。用乙酸乙酯萃取,取有机层,干燥,抽滤,减压蒸除溶剂,得粗产物。经柱层析分离纯化,得到63mg中间体间硝基苯甲酰胺(中间体X),产率57%。
1H-NMR(400MHz,Methanol-d4):δ8.78–8.72(m,1H),8.41(m,J=8.2,2.2,1.0Hz,1H),8.30–8.25(m,1H),7.74(t,J=8.0Hz,1H).
实施例33
(E)-N-[(N’,N’-二甲基氨基)亚甲基]-3-硝基苯甲酰胺(中间体XI)的制备。
将370mg中间体X溶于2mLN,N-二甲基甲酰胺二甲基缩醛中,105℃回流5小时。TLC监测反应。反应结束后,将反应体系冷却至室温,蒸干溶剂。残余物用戊烷洗涤,即可得391mg中间体(E)-N-[(N’,N’-二甲基氨基)亚甲基]-3-硝基苯甲酰胺(中间体XI),产率79%。
1H-NMR(400MHz,CDCl3):δ9.17–9.09(m,1H),8.72(s,1H),8.61(d,J=7.7Hz,1H),8.37(m,1H),7.63(t,J=7.9Hz,1H),3.32(s,3H),3.28(s,3H).
实施例34
3-(3-硝基苯基)-4-H-1,2,4-三唑(中间体XII)的制备。
将294mg中间体XI溶于4mL冰醋酸中,向反应体系中加入150mg水合肼,在氮气保护、90℃的条件下,反应12小时。TLC监测反应。反应结束后,将反应体系冷却至室温,减压蒸除溶剂至溶剂不再减少,抽滤,将滤饼用乙酸乙酯溶解,并用饱和碳酸氢钠溶液洗涤两次,最终得到91mg白色晶体,中间体3-(3-硝基苯基)-4-H-1,2,4-三唑(中间体XII),产率36%。
1H-NMR(400MHz,CDCl3):δ9.02(s,1H),8.49(d,J=7.8Hz,1H),8.40(s,1H),8.31(d,J=8.0Hz,1H),7.68(t,J=8.0Hz,1H).
实施例35
3-(4-H-1,2,4-三唑-3-基)苯胺(中间体XIII)的制备。
除了将中间体III替换成中间体XII之外,其余所需原料、试剂及制备方法同实施例4,得310mg中间体3-(4-H-1,2,4-三唑-3-基)苯胺(中间体XIII),产率95.6%。
1H-NMR(400MHz,CDCl3):δ9.34(s,1H),8.63(d,J=7.7Hz,1H),8.51(s,1H),8.47(d,J=8.0Hz,1H),7.71(t,J=8.1Hz,1H).
实施例36
N-[3-(4-H-1,2,4-三唑-3-基)苯基]喹喔啉-2-胺(IC-1)的制备。
除了将中间体IV替换成中间体XIII之外,其余所需原料、试剂及制备方法同实施例6,得88mg终产物N-[3-(4-H-1,2,4-三唑-3-基)苯基]喹喔啉-2-胺(IC-1),产率49%。
1H-NMR(400MHz,Acetone-d6):δ9.28(s,1H),8.76(s,1H),8.61(s,1H),8.28(d,J=7.9Hz,1H),7.91(d,J=8.2Hz,1H),7.83(d,J=8.2Hz,2H),7.72–7.66(m,1H),7.54–7.47(m,2H);MS(ESI)m/z289.1[M+1]+.
实施例37
N-[3-(4-H-1,2,4-三唑-3-基)苯基]喹啉-2-胺(IC-2)的制备。
除了将中间体IV替换成中间体XIII之外,其余所需原料、试剂及制备方法同实施例7,得185mg终产物N-[3-(4-H-1,2,4-三唑-3-基)苯基]喹啉-2-胺(IC-2),收率是59%。
1H-NMR(400MHz,Acetone-d6):δ8.76(s,1H),8.38(s,1H),8.29(d,J=8.0Hz,1H),8.07(d,J=8.9Hz,1H),7.83(d,J=8.3Hz,1H),7.76(t,J=8.0Hz,2H),7.64–7.59(m,1H),7.46(t,J=7.8Hz,1H),7.38–7.28(m,1H),7.20–7.06(m,1H);MS(ESI)m/z288.1[M+1]+.
实施例38
6-氨基萘-2-甲酸乙酯(中间体XIV)的制备。
除了将间硝基肉桂酸替换成6-氨基-2-萘甲酸之外,其余所需原料、试剂及制备方法同实施例3,得1.042g中间体6-氨基萘-2-甲酸乙酯(中间体XIV),产率88%。
1H-NMR(400MHz,CDCl3):δ8.45(s,1H),7.95(dd,J=8.6,1.7Hz,1H),7.78–7.74(m,1H),7.59(d,J=8.7Hz,1H),7.03–6.93(m,2H),4.41(q,J=7.1Hz,2H),4.03(s,2H),1.43(t,J=7.1Hz,3H).
实施例39
6-[N-(喹喔啉-2-基)氨基]萘-2-甲酸乙酯(中间体XV-1)的制备。
除了将中间体IV替换成中间体XIV之外,其余所需原料、试剂及制备方法同实施例6,得120mg中间体6-[N-(喹喔啉-2-基)氨基]萘-2-甲酸乙酯(中间体XV-1),产率58%。
1H-NMR(400MHz,CDCl3):δ8.61(s,1H),8.56(d,J=8.8Hz,2H),8.09(dd,J=8.5,1.6Hz,1H),7.98(dd,J=8.5,3.6Hz,2H),7.92(d,J=8.3Hz,1H),7.88(d,J=8.7Hz,1H),7.75–7.64(m,2H),7.59–7.51(m,1H),4.45(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H).
实施例40
6-[N-(喹啉-2-基)氨基]萘-2-甲酸乙酯(中间体XV-2)的制备。
除了将中间体IV替换成中间体XIV之外,其余所需原料、试剂及制备方法同实施例7,得155mg中间体6-[N-(喹啉-2-基)氨基]萘-2-甲酸乙酯(中间体XV-2),收率是74%。
1H-NMR(400MHz,CDCl3):δ8.55(s,1H),8.38(d,J=1.9Hz,1H),8.05(dd,J=8.6,1.6Hz,1H),8.02–7.98(m,1H),7.91(t,J=8.7Hz,2H),7.82(d,J=8.6Hz,1H),7.69(d,J=8.0Hz,1H),7.68–7.58(m,2H),7.39–7.34(m,1H),7.07(d,J=8.9Hz,1H),4.44(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H).
实施例41
6-[N-(喹喔啉-2-基)氨基]萘-2-甲酸(ID-1)的制备。
将120mg中间体XV-1溶于5mL甲醇,加入30mg一水合氢氧化锂,40℃反应12h。TLC监测反应。反应结束后,减压蒸除溶剂,加入1N稀盐酸,将反应体系的PH调至5.5,析出大量固体,抽滤,水洗,晾干,得81mg终产物6-[N-(喹喔啉-2-基)氨基]萘-2-甲酸(ID-1),产率74%。
1H-NMR(400MHz,DMSO-d6):δ10.46(s,1H),9.10(s,1H),8.75(s,1H),8.60(s,1H),8.17(d,J=8.9Hz,1H),8.09–7.90(m,4H),7.84–7.77(m,1H),7.61(t,J=7.6Hz,1H);MS(ESI)m/z316.1[M+1]+.
实施例42
6-[N-(喹啉-2-基)氨基]萘-2-甲酸(ID-2)的制备。
除了将中间体XV-1替换成中间体XV-2之外,其余所需原料、试剂及制备方法同实施例41,得120mg终产物6-[N-(喹啉-2-基)氨基]萘-2-甲酸(ID-2),收率是84%。
1H-NMR(400MHz,DMSO-d6):δ9.90(s,1H),9.09(s,1H),8.52(s,1H),8.17(d,J=8.8Hz,1H),8.07(d,J=8.9Hz,1H),7.95(s,2H),7.88(t,J=9.0Hz,2H),7.81(d,J=8.1Hz,1H),7.67(t,J=7.7Hz,1H),7.38(t,J=7.4Hz,1H),7.20(d,J=8.9Hz,1H);MS(ESI)m/z315.1[M+1]+.
实施例43
(E)-N-羟基-3-{3-[N’-(喹喔啉-2-基)氨基]苯基}丙烯酰胺(IE-1)的制备。
将200mg中间体VI-1溶于5mL甲醇,在0℃条件下,加入甲醇钠(100mg钠,8mL甲醇)和2mL羟胺水溶液。TLC监测反应。反应结束后,减压蒸除溶剂,加入少量水,用1N稀盐酸将反应体系的PH调至5.5,有固体析出,抽滤,水洗,晾干即可得65mg终产物(E)-N-羟基-3-{3-[N’-(喹喔啉-2-基)氨基]苯基}丙烯酰胺(IE-1),产率34%。
1H-NMR(400MHz,DMSO-d6):δ10.94(s,1H),10.11(s,1H),9.11(s,1H),8.60(s,1H),8.44(s,1H),7.88(t,J=6.7Hz,3H),7.69(t,J=7.7Hz,1H),7.50(dd,J=12.0,3.7Hz,2H),7.43(t,J=7.9Hz,1H),7.23(d,J=7.8Hz,1H),6.52(d,J=15.6Hz,1H);MS(ESI)m/z329.1[M+23]+.
实施例44
(E)-N-羟基-3-{3-[N’-(喹啉-2-基)氨基]苯基}丙烯酰胺(IE-2)的制备。
除了将中间体VI-1替换成中间体VI-2之外,其余所需原料、试剂及制备方法同实施例43,得107mg终产物(E)-N-羟基-3-{3-[N’-(喹啉-2-基)氨基]苯基}丙烯酰胺(IE-2),收率是56%。
1H-NMR(400MHz,Acetone-d6):δ8.82(s,1H),8.56(s,1H),8.07(d,J=8.9Hz,1H),7.95(d,J=7.7Hz,1H),7.84(d,J=8.3Hz,1H),7.75(d,J=7.9Hz,1H),7.63(dd,J=15.9,8.1Hz,2H),7.35(dt,J=17.5,7.4Hz,3H),7.22(d,J=7.5Hz,1H),7.10(d,J=8.9Hz,1H),6.65(d,J=15.6Hz,1H);MS(ESI)m/z306.1[M+1]+.
实施例45
N-羟基-3-{3-[N’-(喹喔啉-2-基)氨基]苯基}丙酰胺(IF-1)的制备。
除了将中间体VI-1替换成中间体VIII-1之外,其余所需原料、试剂及制备方法同实施例43,得188mg终产物N-羟基-3-{3-[N’-(喹喔啉-2-基)氨基]苯基}丙酰胺(IF-1),产率98%。
1H-NMR(400MHz,DMSO-d6):δ10.43(s,1H),9.91(s,1H),8.74(s,1H),8.56(s,1H),7.88(dd,J=16.7,8.0Hz,2H),7.76(d,J=7.0Hz,2H),7.66(t,J=7.6Hz,1H),7.48(t,J=7.5Hz,1H),7.29(t,J=7.8Hz,1H),6.89(d,J=7.2Hz,1H),2.85(t,J=7.8Hz,2H),2.35–2.29(m,2H);MS(ESI)m/z331.1[M+23]+.
实施例46
N-羟基-3-{3-[N’-(喹啉-2-基)氨基]苯基}丙酰胺(IF-2)的制备。
除了将中间体VI-1替换成中间体VIII-2之外,其余所需原料、试剂及制备方法同实施例43,得172mg终产物N-羟基-3-{3-[N’-(喹啉-2-基)氨基]苯基}丙酰胺(IF-2),收率是90%。
1H-NMR(400MHz,DMSO-d6):δ10.44(s,1H),9.38(s,1H),8.73(s,1H),8.05(d,J=8.9Hz,1H),7.89(d,J=8.0Hz,1H),7.80–7.67(m,3H),7.58(t,J=7.6Hz,1H),7.29(t,J=7.4Hz,1H),7.24(t,J=7.8Hz,1H),7.06(d,J=8.9Hz,1H),6.81(d,J=7.4Hz,1H),2.83(t,J=7.8Hz,2H),2.31(t,J=7.8Hz,2H);MS(ESI)m/z308.1[M+1]+.
实施例47
间硝基苯乙醇(中间体XVI)的制备。
在氮气保护的条件下,将200mg间硝基苯乙酸溶于2mL无水四氢呋喃中,并逐滴加入1mL硼烷的四氢呋喃溶液(1M),室温反应12h。TLC监测反应。反应结束后,逐滴加入少量水,淬灭反应。加入过量饱和碳酸氢钠溶液,将反应体系调至碱性。用乙酸乙酯萃取,取有机层,干燥,抽滤,减压蒸除溶剂得粗产物。经柱层析分离纯化得125mg中间体间硝基苯乙醇(中间体XVI),产率68%。
1H-NMR(400MHz,Acetone-d6):δ8.16(s,1H),8.08(d,J=8.2Hz,1H),7.73(d,J=7.6Hz,1H),7.58(t,J=7.9Hz,1H),3.85(t,J=5.0Hz,2H),2.97(t,J=5.8Hz,2H).
实施例48
间氨基苯乙醇(中间体XVII)的制备。
除了将中间体III替换成中间体XVI之外,其余所需原料、试剂及制备方法同实施例4,得1.181g中间体间氨基苯乙醇(中间体XVII),产率92%。
1H-NMR(400MHz,Acetone-d6):δ8.22(s,1H),8.16(d,J=8.2Hz,1H),7.79(d,J=7.6Hz,1H),7.65(t,J=7.9Hz,1H),3.81(t,J=7.0Hz,2H),3.38(t,J=7.0Hz,2H).
实施例49
2-[3-N-(喹喔啉-2-基)氨基]苯乙醇(中间体XVIII-1)的制备。
除了将中间体IV替换成中间体XVII之外,其余所需原料、试剂及制备方法同实施例6,得186mg中间体2-[3-N-(喹喔啉-2-基)氨基]苯乙醇(XVIII-1),产率48%。
1H-NMR(400MHz,DMSO-d6):δ9.89(s,1H),8.55(s,1H),7.92(d,J=8.0Hz,1H),7.85(d,J=8.1Hz,1H),7.72(d,J=12.1Hz,2H),7.64(t,J=7.6Hz,1H),7.46(t,J=7.5Hz,1H),7.28(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),4.69(t,J=5.2Hz,1H),3.66(dd,J=12.7,6.6Hz,2H),2.76(t,J=7.1Hz,2H).
实施例50
2-[3-N-(喹啉-2-基)氨基]苯乙醇(中间体XVIII-2)的制备。
除了将中间体IV替换成中间体XVII之外,其余所需原料、试剂及制备方法同实施例7,得197mg中间体2-[3-N-(喹啉-2-基)氨基]苯乙醇(XVIII-2),收率是51%。
1H-NMR(400MHz,DMSO-d6):δ9.86(s,1H),8.51(s,1H),7.90(d,J=8.1Hz,1H),7.83(d,J=7.9Hz,2H),7.71(d,J=11.8Hz,2H),7.62(t,J=7.7Hz,1H),7.43(t,J=7.3Hz,1H),7.26(t,J=8.0Hz,1H),6.87(d,J=7.7Hz,1H),4.68(t,J=5.0Hz,1H),3.62(dd,J=12.8,6.4Hz,2H),2.74(t,J=7.3Hz,2H).
实施例51
N-[3-(2-溴乙基)苯基]喹喔啉-2-胺(中间体XIX-1)的制备
在0℃,氮气保护的条件下,将174mg中间体XVIII-1溶于2mL无水二氯甲烷中,加入261mg四溴化碳和207mg三苯基膦,室温搅拌1小时。用乙酸乙酯萃取,取有机层,干燥,过滤,减压蒸除溶剂得粗产物。经柱层析分离纯化158mg得中间体N-[3-(2-溴乙基)苯基]喹喔啉-2-胺(中间体XIX-1),产率74%。
1H-NMR(400MHz,Acetone-d6):δ9.13(s,1H),8.55(s,1H),7.97(d,J=11.7Hz,2H),7.87(d,J=8.1Hz,1H),7.80(d,J=8.3Hz,1H),7.66(t,J=7.6Hz,1H),7.48(t,J=7.6Hz,1H),7.33(t,J=7.8Hz,1H),7.00(d,J=7.5Hz,1H),3.74(t,J=7.4Hz,2H),3.22(t,J=7.4Hz,2H).
实施例52
N-[3-(2-溴乙基)苯基]喹啉-2-胺(中间体XIX-2)的制备。
除了将中间体XVIII-1替换成中间体XVIII-2之外,其余所需原料、试剂及制备方法同实施例51,得131mg中间体N-[3-(2-溴乙基)苯基]喹啉-2-胺(中间体XIX-2),收率是79%。
1H-NMR(400MHz,Acetone-d6):δ8.67(s,1H),8.10–7.98(m,2H),7.94(d,J=8.0Hz,1H),7.78(d,J=8.4Hz,1H),7.72(d,J=8.0Hz,1H),7.59(t,J=7.6Hz,1H),7.29(dd,J=13.9,7.1Hz,2H),7.07(d,J=8.9Hz,1H),6.92(d,J=7.6Hz,1H),3.74(t,J=7.5Hz,2H),3.20(t,J=7.4Hz,2H).
实施例53
2-[3-N-(喹喔啉-2-基)氨基]苯基乙磺酸(IG-1)的制备。
将68mg中间体XIX-1、40mg亚硫酸钠、2mg四丁基溴化铵溶于2mL水,回流3h。TLC监测反应。反应结束后,将反应冷至室温,用乙酸乙酯洗涤两次。取水层,用1N稀盐酸将水层的PH调至2,减压蒸除水。将得到的胶质残余溶于甲醇,并搅拌0.5h。抽滤,取滤液,减压蒸除溶剂,即可得49mg终产物2-[3-N-(喹喔啉-2-基)氨基]苯基乙磺酸(IG-1),产率72%。
1H-NMR(400MHz,DMSO-d6):δ8.66(s,1H),7.89(dd,J=24.5,5.9Hz,2H),7.74(d,J=15.1Hz,2H),7.66(s,1H),7.47(s,1H),7.30(s,1H),6.91(s,1H),2.92(s,2H),2.78(s,2H);MS(ESI)m/z330.1[M+1]+.
实施例54
2-[3-N-(喹啉-2-基)氨基]苯基乙磺酸(IG-2)的制备。
除了将中间体XIX-1替换成中间体XIX-2之外,其余所需原料、试剂及制备方法同实施例53,得86mg终产物2-[3-N-(喹啉-2-基)氨基]苯基乙磺酸(IG-2),收率是78%。
1H-NMR(400MHz,DMSO-d6):δ8.44(d,J=9.3Hz,1H),7.99(d,J=8.9Hz,1H),7.94(d,J=8.2Hz,1H),7.80(t,J=7.5Hz,1H),7.58(d,J=7.3Hz,1H),7.54(d,J=7.5Hz,2H),7.40(d,J=7.7Hz,1H),7.32(d,J=8.3Hz,1H),7.26(d,J=9.4Hz,1H),3.26(d,J=8.8Hz,2H),3.17(d,J=4.4Hz,2H);MS(ESI)m/z329.1[M+1]+.
实施例55
3-[N-(喹喔啉-2-基)氨基]苯甲醇(中间体XX-1)的制备。
除了将中间体IV替换成间氨基苯甲醇之外,其余所需原料、试剂及制备方法同实施例6,得444mg中间体3-[N-(喹喔啉-2-基)氨基]苯甲醇(XX-1),产率58%。
1H-NMR(400MHz,Acetone-d6):δ8.66(s,1H),8.07(d,J=8.6Hz,1H),7.99(s,1H),7.78(d,J=8.5Hz,1H),7.73(d,J=7.7Hz,1H),7.61(dd,J=11.4,4.3Hz,1H),7.32(t,J=7.6Hz,2H),7.10(d,J=8.8Hz,1H),7.03(d,J=7.6Hz,1H),4.68(s,2H).
实施例56
3-[N-(喹啉-2-基)氨基]苯甲醇(中间体XX-2)的制备。
除了将中间体IV替换成间氨基苯甲醇之外,其余所需原料、试剂及制备方法同实施例7,得646mg中间体3-[N-(喹啉-2-基)氨基]苯甲醇(XX-2),收率是64%。
1H-NMR(400MHz,Acetone-d6):δ8.60(s,1H),8.01(d,J=8.9Hz,2H),7.97(s,1H),7.76(d,J=8.3Hz,1H),7.71(d,J=7.8Hz,1H),7.59(dd,J=11.2,4.1Hz,1H),7.29(t,J=7.8Hz,2H),7.07(d,J=8.9Hz,1H),6.99(d,J=7.5Hz,1H),4.66(s,2H).
实施例57
3-[N-(喹喔啉-2-基)氨基]苯甲氧基磷酸二乙酯(IH-1)的制备。
将409mg中间体XX-1、332μL三乙胺、20mg4-二甲氨基吡啶溶于4mL无水四氢呋喃中。在室温、氮气保护的条件下,逐滴加入232μL氯磷酸二乙酯。室温搅拌16h。TLC监测反应。反应结束后,将反应液倒入饱和硫酸氢钾溶液中。用乙酸乙酯萃取,取有机层。先用饱和碳酸氢钠溶液洗涤两次,再用饱和氯化钠溶液洗涤两次。无水硫酸镁干燥,抽滤,减压蒸除溶剂得粗产物。经柱层析分离纯化得205mg终产物3-[N-(喹喔啉-2-基)氨基]苯甲氧基磷酸二乙酯(IH-1),产率33%。
1H-NMR(400MHz,Acetone-d6):δ9.28(s,1H),8.56(s,1H),8.20(s,1H),8.07(d,J=8.1Hz,1H),7.88(d,J=8.2Hz,1H),7.83(d,J=8.3Hz,1H),7.67(t,J=7.6Hz,1H),7.49(t,J=7.5Hz,1H),7.40(t,J=7.8Hz,1H),7.12(d,J=7.5Hz,1H),5.11(d,J=8.1Hz,2H),4.11(p,J=7.3Hz,4H),1.29(t,J=7.0Hz,6H);MS(ESI)m/z388.1[M+1]+.
实施例58
3-[N-(喹啉-2-基)氨基]苯甲氧基磷酸二乙酯(IH-2)的制备。
除了将中间体XX-1替换成中间体XX-2之外,其余所需原料、试剂及制备方法同实施例57,得261mg终产物3-[N-(喹啉-2-基)氨基]苯甲氧基磷酸二乙酯(IH-2),收率是34%。
1H-NMR(400MHz,Acetone-d6):δ8.31(d,J=9.0Hz,1H),7.89(d,J=8.0Hz,2H),7.86–7.74(m,2H),7.70(s,1H),7.48(dd,J=17.0,8.3Hz,2H),7.30(d,J=9.0Hz,2H),5.12(d,J=8.2Hz,2H),4.15–4.05(m,4H),1.28(t,J=6.8Hz,6H);MS(ESI)m/z387.1[M+1]+.
实施例59本发明化合物对RhoA-GTP结合域抑制活性的测定
采用人脑微血管平滑肌细胞,以含10%胎牛血清的DMEM为培养基,37°C,5%CO2的条件下进行传代培养。试验取3-5代的血管平滑肌细胞,待其生长至70%融合时,换用无血清DMEM培养24小时,然后加入2.5μM化合物进行干预,1小时后,用5μg/mLRhoA激动剂溶血磷脂酸(LPA)刺激细胞3分钟,最后按照Cytoskeleton公司的试剂盒(G-LISARhoAActivationAssayBiochemKit)操作方法,提取细胞中的总蛋白,随之把其加入到预先包被好RBD(RhoBindingDomain)的96孔板中,根据活化状态下的RhoA能与RBD结合,而非活化状态下的RhoA无法与之结合的原理,测定其中活化状态RhoA的含量(以OD490表示),从而得出不同化合物对RhoA的抑制活性。整个试验分为三组:1空白组,即细胞换用无血清DMEM培养24小时后,不用药物干预和溶血磷脂酸的刺激;2对照组,即细胞换用无血清DMEM培养24小时后,不加药物干预,但给予溶血磷脂酸的刺激;3加药组,即细胞换用无血清DMEM培养24小时后,加入药物干预,同时给予溶血磷脂酸的刺激。以下列公式得出待测化合物在2.5μM下百分抑制率,计算公式为:(加药组OD490值-空白组OD490值)/(对照组OD490值-空白组OD490值)×100%,化合物活性测试结果如表1。
表1NN-双取代苯并氮杂环-2-胺类化合物对RhoA抑制率数据
由表1可以看出,本发明的具有结构通式(I)的N,N-双取代苯并氮杂环-2-胺类化合物大部分具有较强的RhoA-GTP抑制活性,说明本发明的化合物为RhoA抑制剂。
实施例60本发明部分化合物对RhoA-GTP结合域半数有效抑制浓度(IC50)的测定
选取2.5μM抑制率在80%以上的化合物测IC50。结果见表2。
表2N,N-双取代苯并氮杂环-2-胺类衍生物类化合物对RhoA抑制IC50
由表2可以看出,本发明的具有结构通式(I)的部分N,N-双取代苯并氮杂环-2-胺类化合物具有微摩级(μM)的RhoA-GTP抑制活性,说明本发明的化合物为RhoA抑制剂。
上述实例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人是能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围之内。
Claims (3)
1.一种N,N-双取代苯并氮杂环-2-胺类化合物,其特征在于,所述的N,N-双取代苯并氮杂环-2-胺类化合物为式I所示化合物,或其在药学上可接受的盐;
式I中,R1为C1~C4直链或支链的烷基,X为CH,A为
2.如权利要求1所述N,N-双取代苯并氮杂环-2-胺类化合物,其特征在于,所述的N,N-双取代苯并氮杂环-2-胺类化合物是:(E)-3-{3-[N-乙基-N-(喹啉-2-基)氨基]苯基}丙烯酸或(E)-3-{3-[N-正丁基-N-(喹啉-2-基)氨基]苯基}丙烯酸。
3.如权利要求1或2所述的N,N-双取代苯并氮杂环-2-胺类化合物或其药学上可接受的盐在制备预防或治疗RhoA介导的疾病的药物中的应用。
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