CN115785064A - 三取代吡啶衍生物的制备及作为芳香烃受体调节物的应用 - Google Patents
三取代吡啶衍生物的制备及作为芳香烃受体调节物的应用 Download PDFInfo
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Abstract
本公开涉及一种如式(I)所示的具有AhR激活作用的化合物、其用途及制备方法,该化合物具有明显的AhR激动活性。
Description
技术领域
本公开涉及医药领域,特别涉及一种具有AhR激活作用的三取代吡啶衍生物,其用途及制备方法。
背景技术
芳香烃受体(arylhydrocarbon receptor,AhR)是一种靠配体激活的转录因子,为碱性螺旋-环-螺旋转录因子(basichelix-loop-helix/Per-ARNT-Sim,bHLH-PAS)家族的成员之一。AhR广泛存在于生物体内,哺乳动物、两栖动物、爬行动物和鸟类的体内都含有AhR蛋白。AhR在人体内多种细胞中表达,不仅对机体血管发育、神经功能调节发挥着重要作用,还对自身免疫紊乱、肿瘤等多种疾病发生过程中具有重要的调节作用,已成为药物研发重点关注的靶点。
AhR蛋白的功能结构域由3部分组成:bHLH结构域、PAS结构域和1个富含谷氨酸的结构域。bHLH结构域位于AhR蛋白的N-末端,辅助AhR结合到靶基因的启动子区域和蛋白质二聚化;PAS结构域通过与AhR核转运蛋白(AhR nuclear translocator,ARNT)连接并与配体结合来辅助蛋白二聚化,形成蛋白复合物;C-末端区域是一个富含谷氨酸的结构域,发挥募集和转录激活的作用。在未激活的形式下,AhR通常在细胞质中与热休克蛋白90(Hsp90)、p23、X相关蛋白2(XAP2)和AhR相关蛋白9(ARA9)形成多蛋白复合体。经典信号通路表现为,当AhR与配体结合并被激活,其发生构象的改变,暴露出核定位信号序列,受体-配体复合物易位至细胞核,在核内和ARNT形成异二聚体,AhR/ARNT复合物结合靶基因启动子的异源生物响应元件(其核心序列:5’-TNGCGTG-3’),启动靶基因表达。靶基因包括细胞色素P450酶(CYP1A1、CYP1A2、CYP1B1)、谷胱甘肽巯基转移酶、鸟苷二磷酸葡糖醛酸糖基转移酶、NAD(P)H依赖的醌氧化还原酶-1、醛脱氢酶3A1和抗乳腺癌蛋白基因等。从而参与许多重要的生理过程,如细胞周期和增殖的调控、免疫应答、昼夜节律、肿瘤诱发、脂类代谢有关基因的表达等。
AhR通过与不同结构性质的外源性或内源性配体结合,还表现出不同的生物学效应。其外源性配体主要由多环芳香烃(PAHs)、多氯联苯(PCBs)、天然化合物和小分子类等组成;内源性配体包括色氨酸代谢产物、血红素代谢产物、花生四烯酸代谢产物等。一方面,AhR可被配体激活,导致下游CYP1A1等基因表达水平提高及靶基因表达产物Ⅰ相或II相外源物质代谢酶增多,促进机体对外源性毒物的代谢,从而保护机体不受外源物质影响,例如AhR受体激动剂MCDF(6-甲基1,3,8-三氯二苯呋喃),能诱导靶基因CYP1A1的表达,增强其代谢,从而抑制雌激素受体阴性的乳腺癌肿瘤细胞的增殖。另一方面调节AhR与其他肿瘤相关信号通路,如AhR-ER、AhR-丝裂原活化蛋白激酶(mitogen activated protein kinases,MAPKs),在肿瘤发生中起作用。例如,DIM(3,3'-吲哚甲烷)能通过AhR依赖途径强烈地抑制ER-α的表达及雌激素信号通路,减少人类乳腺癌的发病风险。
近年来,AhR在免疫领域备受关注,特别是在炎症发生的过程中AhR可促进具有抗炎作用的Treg细胞的产生。AhR激动剂可通过激活AhR诱导Th0细胞向Treg细胞分化,减轻实验性自身免疫性脑脊髓炎。AhR激动剂TCDD给药可通过增强Treg细胞的增殖,而抑制了小鼠模型中自身免疫疾病的进展,或提高移植物存活率。AhR激动剂本维莫德已经在动物和临床应用中表现出明确的治疗银屑病和特异性皮炎的作用。在动物实验中,本维莫德和拉喹莫德等AhR激动剂还能够通过增强调节treg细胞的免疫功能,具有治疗关节炎、多发性硬化症、炎症性肠炎的作用。最新研究表明,色氨酸代谢物可以通过激活AhR通路减轻神经炎症对帕金森等神经退行性疾病有治疗作用。AhR激动剂-Z425228478可以通过激活AhR可以细菌性角膜炎的炎症反应。
总之,AhR激动剂对银屑病、关节炎、特应性皮炎、帕金森、多发性硬化症、炎症性肠炎、哮喘、系统性红斑狼疮、移植物抗宿主病、细菌性角膜炎、肿瘤等多种疾病的治疗和预防具有潜在的应用价值。
发明内容
本公开的目的在于提供一种新型的化合物的合成及其在AhR(芳香烷烃受体)激动剂药物中的应用,所述化合物作为AhR激动剂,具有活性高,选择性好且毒副作用低等优点。
本发明的一方面,提供一种式(I)所代表的化合物或其药学上可接受的盐,
其中:
m选自0、1、2或3;n选自0、1、2或3;
A环选自5-7元芳基、5-7元的单环杂芳基、9-12元的双环杂芳基、5-7元的杂环烷基、9-12元的部分不饱和双环杂环基;
m个R2彼此相同或不相同,其中,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、-S(O)2R6、5-7元杂环烷基,所述C1-6酰基、5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代,所述C1-6烷基任选地被一个或多个卤素、-C(=O)NR4R5取代;
R1选自氢、氘、卤素、C1-6烷基、C1-6烯基、C3-6环烷基,所述C1-6烷基、C1-6烯基、C3-6环烷基任选地被一个或多个卤素所取代;
B环选自5-7元芳基、5-7元单环杂芳基、9-12元双环杂芳基、9-12元部分不饱和双环杂环基、8-12元饱和螺环杂环基;
n个R3彼此相同或不相同,其中,R3选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、卤素、氰基、含有1-2个分别独立选自N、O、S原子的5-7元杂环烷基,所述C1-6烷基、C3-6环烷基、C1-3酰基任选地被一个或多个卤素、氰基所取代。
R4、R5、R6各自独立地选自氢、C1-6烷基、C3-6环烷基。
在另一方面,本公开涉及下式(I)所代表的化合物或其药学上可接受的盐:
其中:
m选自0、1、2或3;n选自0、1、2或3;
A环选自5-7元芳基、5-7元的单环杂芳基、9-12元的双环杂芳基、5-7元的杂环烷基、9-12元的部分不饱和双环杂环基;
在一些具体实施方式中,A环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元的单环杂芳基、含有1-2个分别独立选自N、O、S原子的9-12元的双环杂芳基、含有1-2个分别独立选自N、O、S原子的5-7元的杂环烷基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基;
优选地,A环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元的单环杂芳基、含有1-2个分别独立选自N或O的9-12元的双环杂芳基、含有1-2个N原子的5-7元的杂环烷基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基;
优选地,A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、异吲哚啉基、吡啶酮基、异吲哚啉酮基;
优选地,A环选自苯基、嘧啶基、吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、异吲哚啉基、吡啶酮基、异吲哚啉酮基;
优选地,A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、吡啶酮基、异吲哚啉酮基;
在一些具体实施方式中,m个R2彼此相同或不相同,其中,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、5-7元杂环烷基,所述C1-6酰基、5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代;
优选地,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基,所述C1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代;
优选地,R2选自C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、含有1-2个N原子的5-7元杂环烷基,所述C1-3酰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代;
优选地,R2选自C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、含有1-2个N原子的5-7元杂环烷基,所述C1-3羰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个甲基、-N(CH3)2所取代;
优选地,R2选自甲基、乙基、丙基、异丙基、环丙烷基、甲氧基、甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基,所述甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基任选地被一个或多个甲基、-N(CH3)2所取代;
在一些具体实施方式中,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、-S(O)2R6、含有1-2个分别独立选自N、O原子的5-7元杂环烷基,所述C1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代,所述C1-6烷基任选地被一个或多个卤素、-C(=O)NR4R5取代;所述C1-6烷基任选地被一个或多个卤素、-C(=O)NR4R5取代;
优选地,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、-S(O)2R6、含有1-2个分别独立选自N、O原子的5-7元杂环烷基,所述C1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代;所述C1-6烷基任选地被一个或多个氟、氯、溴、碘、-C(=O)NH4R5取代;
优选地,R2选自C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、-S(O)2R6、含有1-2个N原子的5-7元杂环烷基,所述C1-3酰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代,所述C1-6烷基任选地被一个或多个氟、-C(=O)NH4R5取代;
优选地,R2选自C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、-S(O)2R6、含有1-2个N原子的5-7元杂环烷基,所述C1-3羰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个甲基、-N(CH3)2所取代,所述C1-6烷基任选地被一个或多个氟、-C(=O)NH2取代;在一些具体实施方式中,R4、R5各自独立地选自氢、C1-6烷基,更优选氢和甲基。
在一些具体实施方式中,R6各自独立地选自C1-6烷基和C3-6环烷基,更优选甲基、丙基和环丙基。
在一些具体实施方式中,R2选自甲基、乙基、二氟甲基、异丙基、环丁烷基、环丙烷基、甲氧基、甲酰基、-CH2C(=O)NH2、-S(O)2CH3、-S(O)2(CH2)2CH3、-C(=O)CH2N(CH3)2、
在一些具体实施方式中,R1选自氢、氘、卤素、C1-6烷基、C1-6烯基、C3-6环烷基,所述C1-6烷基、C1-6烯基、C3-6环烷基任选地被一个或多个卤素所取代;
优选地,R1选自氢、氘、卤素、C1-3烷基、C1-3烯基、C3-6环烷基,所述C1-3烷基、C1-3烯基、C3-6环烷基任选地被一个至三个卤素所取代;
优选地,R1选自氢、氘、氟、C1-3烷基、C1-3烯基,所述C1-3烷基、C1-3烯基、C3-6环烷基任选地被一个至三个氟所取代;
优选地,R1选自氟、甲基、乙基、氟甲基、二氟甲基、三氟甲基、异丙基、异丙烯基、环丙烷基;
优选地,R1选自氟、甲基、异丙基、异丙烯基、环丙烷基;
优选地,R1为甲基;
在一些具体实施方式中,B环选自5-7元芳基、5-7元单环杂芳基、9-12元双环杂芳基、9-12元部分不饱和双环杂环基、8-12元饱和螺环杂环基;
优选地,B环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元单环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元双环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N、O、S原子8-12元饱和螺环杂环基;
优选地,B环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元单环杂芳基、含有1-3个分别独立选自N或O原子的9-12元双环杂芳基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N或O原子8-12元饱和螺环杂环基;
优选地,B环选自苯基、吡啶基、吡唑基、苯并二氧戊环基、氮杂螺辛烷基、四氢异喹啉基;
在一些具体实施方式中,n个R3彼此相同或不相同,其中,R3选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、卤素、氰基、含有1-2个分别独立选自N、O、S原子的5-7元杂环烷基,所述C1-6烷基、C3-6环烷基、C1-3酰基任选地被一个或多个卤素、氰基所取代;
优选地,R3不同时选自烷氧基和杂环烷基;
优选地,R3选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、卤素、氰基、含有1-2个分别独立选自N或O原子的5-7元杂环烷基、所述C1-6烷基、C1-3酰基任选地被一个至三个氟所取代,所述C3-6环烷基任选地被一个或多个氰基所取代;
优选地,R3选自溴、氟、氯、氰基、三氟甲基、甲基。
本公开涉及上述化合物或其药学上可接受的盐,其中,包括式(II)所代表的化合物或其药学上可接受的盐:
其中,n、m、A、L、R1、R2、R3的定义如上述所定义。
本公开涉及上述化合物或其药学上可接受的盐,其中,所述化合物具有以下式(IIa)、(IIb)、(IIc)、(IId)、(IIe)或(IIf)所示的结构:
其中,X4、X5、X6选自N、NH或CH,n、m、R1、R2、R3的定义如上述所定义。本公开提供了下列化合物或其药学上可接受的盐:
本公开涉及上述化合物的制备方法,所述方法包括以下一种:
合成路线1:
步骤一:化合物1A与化合物1A-1Suzuki偶联反应得到化合物1B;
步骤二:化合物1B经过萃取纯化后得到化合物1C;
步骤三:化合物1C与化合物1C-1缩合反应得到化合物A1。
在一些具体实施方式中,合成路线1中,步骤一:向化合物1A中加入化合物1A-1,加入1,4-二氧六环、水、碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应,纯化后得到化合物1B;
步骤二:用醇溶剂溶解所述化合物1B,滴加碱性溶液,反应,调节PH至酸性,经过萃取纯化后得到1C;
步骤三:将所述化合物1C用N,N-二甲基甲酰胺溶解,加入化合物1C-1、HATU、胺,滴加DIPEA,反应结束后,纯化得到化合物A1。
合成路线2:
步骤一:化合物2A与化合物2A-1缩合反应得到化合物2B;
步骤二:化合物2B与化合物2B-1Suzuki偶联反应得到化合物A2。
在一些具体实施方式中,合成路线2中,步骤一:将化合物2A用N,N-二甲基甲酰胺溶解,加入HATU、胺、化合物2A-1,滴加DIPEA,反应结束后,纯化得到化合物2B;
步骤二:向所述化合物2B中加入2B-1,加入1,4-二氧六环、水、碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应,纯化后得到化合物A2。
合成路线3:
步骤一:化合物3A与化合物缩合反应得到化合物3B;
步骤二:化合物3B与R1-B(OH)2Suzuki偶联反应得到化合物3C;
步骤三:化合物3C与化合物3C-1Suzuki偶联反应得到化合物A3。
在一些具体实施方式中,反应路线3中,步骤一:将化合物3A用N,N-二甲基甲酰胺溶解,加入HATU、胺、化合物3A-1,滴加DIPEA,反应结束后,纯化得到化合物3B;
步骤二:向所述化合物3B中加入R1-B(OH)2、1,4-二氧六环、水、碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应,纯化后得到化合物3C;
步骤三:向所述化合物3C中加入化合物3C-1,加入1,4-二氧六环、水,室温搅拌下加入碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应,纯化得到化合物A3。
合成路线4:
步骤一:化合物2A与化合物2A-1缩合反应得到化合物4B;
步骤二:化合物4B与对甲苯磺酰氯反应得到化合物4C;
步骤三:化合物4C与N,N-二异丙基乙胺(DIPEA)反应得到化合物4D;
步骤四:化合物4D脱氢反应得到化合物4E;
步骤五:化合物4E与化合物4E-1Suzuki偶联反应得到化合物A4。
在一些具体实施方式中,合成路线4中,步骤一:将化合物2A用N,N-二甲基甲酰胺溶解,加入HATU、化合物2A-2,室温条件下滴加DIPEA,反应结束后,纯化得到化合物4B;
步骤二:将所述化合物4B和三乙胺溶于四氢呋喃中,反应5分钟,将对甲苯磺酰氯加到反应体系中,反应结束后萃取、干燥,去除溶剂,得到化合物4C,并且将其直接用于下一步;
步骤三:将所述化合物4C溶于四氢呋喃溶液中,加入DIPEA,反应10小时,萃取,干燥,纯化后得到化合物4D;
步骤四:将所述化合物4D溶于无水二氯甲烷中,加入2,3-二氯-5,6-二氰基苯醌和4A分子筛,反应结束后,过滤并洗涤,去除溶剂,得到化合物4D;
步骤五:将所述化合物4D按照合成路线1的方法和步骤进行反应后,得到化合物A4。
本公开提供了一种药物组合物,所述药物组合物包含上述的化合物或其药学上可接受的盐和药学上可接受的辅料。
本公开提供了上述的化合物或其药学上可接受的盐、上述药物组合物在制备治疗患者的AhR介导的病症的药物中的应用。
本公开提供了上述的化合物或其药学上可接受的盐、上述药物组合物在制备AHR激动剂中的应用。
本公开涉及一种激活有需要的患者中的AhR的方法,其包含向所述患者施用上述化合物或其药学上可接受的盐、上述药物组合物。
本公开涉及一种用于治疗有需要的患者的AhR介导的病症的方法,其包含向所述患者施用上述化合物或其药学上可接受的盐、上述的药物组合物。
优选地,所述AhR介导的病症包括但不限于银屑病、关节炎、特应性皮炎、帕金森、多发性硬化症、炎症性肠炎、哮喘、系统性红斑狼疮、移植物抗宿主病、细菌性角膜炎、肿瘤。
本公开的化合物具有AhR抑制作用。
具体实施方式
根据本公开的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本公开上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
I.定义
除非另有其它明确表示,否则在整个说明书和权利要求书中,术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分,而并未排除其它元件或其它组成部分。
本发明化合物可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。外消旋体、非对映异构体、对映异构体都包括在本发明的范围之内。
在本公开中,数字范围是指给定范围中的各个整数。例如,“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子;“C1-3”是指该基团可具有1个碳原子、2个碳原子或3个碳原子。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“被取代的”或“取代”是指特定原子或基团上的任意一个或多个氢原子被取代基取代,只要特定原子或基团的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即=O)时,意味着两个氢原子被取代。除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如Rn)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被一个至三个R所取代,则所述基团可以任选地至多被三个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
术语“烷基”指饱和的脂族烃基团,包括直链的或支链的饱和烃基,所述烃基具有所示出的碳原子数。如术语“C1-6烷基”包括C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基,实例包括,但不限于,甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、正己基、2-己基、3-己基等。其可以是二价的,例如亚甲基、亚乙基。
术语“烷氧基”可以为直链、支化或环状的。烷氧基的碳原子数没有特别限制,但优选为1至20。其具体实例包括甲氧基、乙氧基、正丙氧基、异丙氧基(isopropoxy)、异丙基氧基(i-propyloxy)、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、新戊氧基、异戊氧基、正己氧基、3,3-二甲基丁氧基、2-乙基丁氧基、正辛氧基、正壬氧基、正癸氧基等,但不限于此。
术语“羰基”或“羧基”包括化合物和片段的碳通过双键与氧原子连接的结构。含有羰基的部分的实例包括醛、酮、羧酸、酰胺、酯、酸酐等。
术语“酰基”是羰基的碳原子连接到氢(即甲酰基),脂族基团(C1-C6烷基,C1-C6烯基,C1-C6炔基,例如乙酰基),环烷基(C3-C8环烷基),杂环基(C3-C8杂环烷基和C5-C6杂芳基),芳基(C6芳基,例如苯甲酰基)相连的羰基结构。酰基可以是未取代的或取代的酰基(例如水杨酰基)。
在本公开中,卤素基团的实例可以包括氟、氯、溴或碘。
在本公开中,术语“环烷基”是指单环饱和烃体系,无杂原子和双键。例如,术语“C3-6环烷基”的实例包括环丙基、环丁基、环戊基、环己基。
在本公开中,术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团,其通过从母体芳香环体系的单一碳原子上除去一个氢原子而得到。其包括饱和、部分不饱和的环,或芳香碳环稠合的芳环的双环基团。其具体实例包括苯基或萘基,但不限于此。
在本公开中,术语“杂环烷基”是指具有环碳原子和1至2个环杂原子的5-12元饱和非芳香体系。杂环基的具体实例包括哌啶基或四氢吡咯基,但不限于此。
在本公开中,术语“杂芳基”指包含至少一个独立地选自氮、氧和硫杂原子的一价芳基,杂芳基可为单环,也可以为多环体系,例如二环,其中两个或两个以上的环以并环、桥环或螺环形式存在,其中至少一个环含有一个或多个杂原子。杂芳基的具体实例包括吡啶基、噻吩基、咪唑基、嘧啶基、吡啶基、呋喃基、吡嗪基、噻唑基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、咪唑并吡啶基、苯并呋喃基、哒嗪基、异吲哚基、吡啶酮基,但不限于此。
术语“杂环”是指具有环碳原子和1至2个环杂原子的5-12元饱和非芳香体系,其中杂原子独立地选自氮、硫或氧原子。在含有一或多个氮原子的杂环基团中,连接点可为碳或氮原子,只要原子价容许。杂环可为单环或多环体系,例如二环,其中两个或两个以上的环以并环、桥环或螺环形式存在,其中至少一个环含有一个或多个杂原子。在螺环杂环基中,两个不同的环共有一个原子,螺环杂环基的一个实例是氮杂螺戊烷基,但不限于此。
术语“部分不饱和双环杂环”表示包含C原子和N、O、S等杂原子中的至少一种共同作为环成员的双环基团,该双环基团为部分不饱和的,其包含至少一个C-C双键,最大不饱和杂环包含环大小允许的最多的C-C双键以及C原子和杂原子的双键,部分不饱和双环杂环包含低于环大小允许的双键数量,部分不饱和双环杂环的具体实例包括但不限于苯并呋喃基、苯并噻吩基、喹喔啉基、喹唑啉基、异吲哚啉酮基、蝶啶基等。
缩写:
Ts:对甲苯璜酰基;
DIPEA:N,N-二异丙基乙胺;
药物或药物组合物
术语“药学上可接受的”是指在合理的医学判断的范围内适合用于与人类和动物的组织接触而没有,与合理利益/风险比相称的,过度毒性、刺激、过敏反应或其它问题或并发症的那些化合物、材料、组合物和/或剂型。
术语“药学上可接受的盐”是指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例如酸(包括有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本公开的药物或药物组合物可以经口地、局部地、肠胃外地或粘膜地(例如,含服地、通过吸入或直肠地)以包含常规的非-毒性药学可接受的载体的剂量单位配制剂施用。
对于以片剂或胶囊形式的口服给药,活性药物组分可以与非-毒性的、药学可接受的辅料如粘结剂(例如,预胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填料(例如,乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇和其它还原性和非-还原性糖类、微晶纤维素、硫酸钙或磷酸氢钙);润滑剂(例如,硬脂酸镁、滑石粉或硅土、硬脂酸、硬脂基富马酸酯钠、甘油二十二烷酸酯、硬脂酸钙等);崩解剂(例如,马铃薯淀粉或羟乙酸淀粉钠);或润湿剂(例如,月桂基硫酸钠)、着色剂和调味剂、明胶、甜味剂、天然和合成的胶(如阿拉伯胶、黄蓍胶或藻朊酸盐)、缓冲盐、羧甲纤维素、聚乙二醇、蜡、等。对于以液体形式的口服给药,所述药物组分可以与非-毒性、药学可接受的惰性载体(例如,乙醇、甘油、水)、防沉降剂(例如,山梨糖醇糖浆、纤维素衍生物或氢化的可食用脂肪)、乳化剂(例如,卵磷脂或阿拉伯胶)、非-水性载体(例如,扁桃油、油酯类、乙醇或经分馏的植物油)、保藏剂(例如,p-羟基苯甲酸甲酯或p-羟基苯甲酸丙酯或山梨酸)等组合。还可以加入稳定剂如抗氧化剂(BHA、BHT、桔酸丙酯、抗坏血酸钠、柠檬酸)以稳定所述剂型。
包含作为活性化合物的片剂可以通过本领域熟知的方法包衣。包含作为活性化合物的式I化合物的本公开的所述组合物还可以引入小珠、微球或微胶囊,例如由聚乙醇酸/乳酸(PGLA)构建的。用于口服给药的液体的制剂可以采取例如溶液,糖浆剂,乳液或混悬液的形式或者它们可以呈现为在使用前用水或其它适宜的辅料重构的干产品。用于口服给药的制剂可以适宜地配制以使活性化合物受控或延迟地释放。
本公开的药物或药物组合物可以经肠胃外递送,即,通过静脉内(i.v.)、脑室内(i.c.v.)、皮下(s.c.)、腹膜内(i.p.)、肌内(i.m.)、皮下(s.d.)或皮内(i.d.)施用,通过直接注射,经例如快速浓注或连续输液。用于注射的配制剂可以单位剂型呈现,例如在具有添加的保藏剂的安瓿瓶或多-剂量容器中。所述组合物可以采用赋形剂(excipient)的形状,在油或水性载体中的混悬液、溶液或乳液的形式,并可以包含配制试剂如防沉降剂、稳定剂和/或分散剂。备选地,所述活性成分可以以粉末形式在使用前用适宜的载体(例如无菌无热原水)重构。
本公开的药物或药物组合物还可以配制用于直肠给药,例如呈栓剂或保留灌肠(例如,包含常规栓剂基质如可可油或其它甘油酯)。
术语“治疗”包括抑制、缓解、预防或消除与所治疗的疾病、病症或失调相关的一种或多种症状或副作用。术语“有效量”或“治疗有效量”是指足以治疗、抑制或减轻被治疗的疾病状态的一种或多种症状或以其它方式提供期望的药理学和/或生理学作用的剂量。精确的剂量将根据多种因素而变化,如受试者依赖的变量(例如,年龄、免疫系统健康等)、疾病或病,以及所施用的治疗。有效量的效果可以相对于对照。这些对照在本领域中是已知的并且在本文中讨论,并且可以是例如在药物或药物组合施用之前或没有施用时的受试者的状况,或在药物组合的情况下,可以将组合效果与仅施用一种药物的效果进行比较。
术语“药物组合物”意指包含本公开所述化合物或其药学上可接受的盐,以及依施用方式和剂型的性质而定的至少一种选自以下药学上可接受的成分的组合物,包括但不限于:载体、稀释剂、佐剂、赋形剂、防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂、香味剂、抗菌剂、抗真菌剂、润滑剂、分散剂、温敏材料、温度调节剂、黏附剂、稳定剂、助悬剂等。
II.实施例
下面参照实施例进一步阐释本公开。对本公开的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本公开限定为所公开的精确形式,并且很显然,根据本公开说明书的教导,可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本公开的特定原理及其实际应用,从而使得本领域的技术人员能够实现并利用本公开的各种不同的示例性实施方案以及各种不同的选择和改变。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
由化学式(I)表示的化合物可以如下述合成路线1、2、3或4制备。取代基可以通过该技术领域中已知的方法来结合,取代基的种类、位置或个数可以根据该技术领域中已知的技术而变更。可以如下述合成路线1、2、3或4那样结合取代基,但并不限定于此。
本公开化合物采用以下合成路线制备:
合成路线1:
步骤一:向单口瓶中加入6-氯-3-R1基吡啶甲酸甲酯,加入1A-1,1,4-二氧六环和水,加入碳酸钾,加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,用硅胶纯化,得到化合物1B;
步骤二:向单口瓶中加入1B,用甲醇溶解,滴加2N NaOH水溶液,室温反应4小时,用2N盐酸调节PH至3-4,用乙酸乙酯和水萃取,合并有机相,旋除溶剂得到化合物1C;
步骤三:将1C用N,N-二甲基甲酰胺溶解,加入HATU,胺,滴加DIPEA,室温反应。反应结束后,旋除溶剂,用硅胶纯化,得到化合物A1。
合成路线2:
步骤一:将6-氯-3-R1基吡啶甲酸用N,N-二甲基甲酰胺溶解,加入HATU,胺,滴加DIPEA,室温反应一小时。反应结束后,旋除溶剂,用硅胶纯化,得到化合物2B;
步骤二:向单口瓶中加入2B,加入2B-1,1,4-二氧六环和水,加入碳酸钾,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,用硅胶纯化,得到化合物A2。
合成路线3:
步骤一:将3-溴-6-氯-2-吡啶甲酸用N,N-二甲基甲酰胺溶解,加入HATU,胺,滴加DIPEA,室温反应。反应结束后,旋除溶剂,用硅胶纯化,得到化合物3B;
步骤二:向单口瓶中加入3B,加入R1-B(OH)2,1,4-二氧六环和水,碳酸钾,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,用硅胶纯化得到化合物3C;
步骤三:向单口瓶中加入3C,加入硼酸,1,4-二氧六环和水,室温搅拌下加入碳酸钾,[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物,氩气置换3次,升温至100摄氏度反应6小时,自然冷却至室温,用硅胶纯化,得到化合物A3。
合成路线4:
步骤一:将6-氯-3-R1基吡啶甲酸用N,N-二甲基甲酰胺溶解,加入HATU,D L-苯甘胺醇,室温条件下滴加DIPEA,滴加结束后,室温反应2小时。反应结束后,旋除溶剂,用硅胶纯化,得到化合物4B;
步骤二:将4B和三乙胺溶于四氢呋喃中,0摄氏度下搅拌5分钟,然后将对甲苯磺酰氯缓慢滴加到反应体系中,滴加完毕后升至室温反应6小时。旋除溶剂,通过乙酸乙酯和水萃取三次,合并有机相,用无水硫酸钠干燥,旋除溶剂,得到粗品(4C)直接用于下一步;
步骤三:将4C溶于四氢呋喃溶液中,加入DIPEA,升温至75摄氏度,保温反应10小时。将反应液旋除溶溶剂,加入乙酸乙酯和水萃取三次,合并有机相,用无水硫酸钠干燥,旋干溶剂,用硅胶纯化得到4D;
步骤四:将4D溶于无水二氯甲烷中,加入2,3-二氯-5,6-二氰基苯醌和4A分子筛,室温反应4小时。反应结束后,抽滤,滤饼用无水二氯甲烷洗涤2次,旋除溶剂得到4E;
步骤五:将4E按照合成路线1的方法进行操作后,得到最后的终产物。
实施例1:化合物1的制备
以合成路线1的方式制备化合物1,具体反应如下:
步骤一:向单口瓶中加入6-氯-3-甲基吡啶甲酸甲酯(185.6mg,1mmol),加入5-嘧啶硼酸(185.9mg,1.5mmol),1,4-二氧六环(10mL)和水(2mL),室温搅拌下加入碳酸钾(414mg,3mmol),加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40.8mg,0.05mmol),氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,残留物加入乙酸乙酯和水萃取,分液,有机相水洗至中性,加入无水硫酸钠干燥,过滤,滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚=1/5),得到化合物1A(3-甲基-6-(嘧啶-5-基)吡啶甲酸甲酯)184.1mg,收率:80%,Ms+1:230.1;
步骤二:向单口瓶中加入3-甲基-6-(嘧啶-5-基)吡啶甲酸甲酯(92mg,0.5mmol),加入甲醇(5mL)溶解,于0℃下滴加2N NaOH水溶液(1mL),滴加结束后,室温反应4小时,TLC点板,原料反应完全,用2N盐酸调节PH至3-4,用乙酸乙酯和水萃取三次,合并有机相,旋除溶剂得到化合物1B(3-甲基-6-(嘧啶-5-基)吡啶甲酸)的粗品80mg,直接用于下一步。Ms+1:216.1;
步骤三:将上一步得到的粗品用N,N-二甲基甲酰胺溶解至于50mL单口瓶中,加入HATU(212.8mg,0.56mmol),4-溴苯胺(78mg,0.45mmol),室温条件下滴加DIPEA(144mg,1.12mmol),滴加结束后,室温反应一小时。反应结束后,旋除溶剂,用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物1(N-(4-溴苯基)-3-甲基-6-(嘧啶-5-基)吡啶酰胺)45mg,收率:32.7%,Ms+1:370.2。
表1按照实施例1的方法合成的化合物和数据表征
实施例2:化合物14的制备
以合成路线2的方式制备化合物14,具体反应如下:
步骤一:将6-氯-3-甲基吡啶甲酸用(79.8mg,0.47mmol)N,N-二甲基甲酰胺溶解至于50mL单口瓶中,加入HATU(212.8mg,0.56mmol),间甲基苯胺(48mg,0.45mmol),室温条件下滴加DIPEA(144mg,1.12mmol),滴加结束后,室温反应一小时。反应结束后,旋除溶剂,用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物14A(6-氯-3-甲基-N-(间甲苯基)吡啶酰胺)56.5mg,收率:46.6%,Ms+1:260.1;
步骤二:向单口瓶中加入6-氯-3-甲基-N-(间甲苯基)吡啶酰胺(56.5mg,0.22mmol),加入吲唑-6-硼酸(53mg,0.33mmol),1,4-二氧六环(5mL)和水(1mL),室温搅拌下加入碳酸钾(91mg,0.66mmol),加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8mg,0.01mmol),氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,残留物加入乙酸乙酯和水萃取,分液,有机相水洗至中性,加入无水硫酸钠干燥,过滤,滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物14(6-(1H-吲唑-6-基)-3-甲基-N-(间甲苯基)吡啶酰胺)52mg,收率:69.5%,Ms+1:343.2。
表2按照实施例14的方法合成的化合物和数据表征
实施例3:化合物38的制备
以合成路线3的方式制备化合物38,具体反应如下:
步骤一:将3-溴-6-氯-2-吡啶甲酸用(237mg,1mmol)N,N-二甲基甲酰胺溶解至于50mL单口瓶中,加入HATU(456mg,1.2mmol),对三氟甲基苯胺(177.2mg,1.1mmol),室温条件下滴加DIPEA(387mg,3mmol),滴加结束后,室温反应一小时。反应结束后,旋除溶剂,用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物38A(3-溴-6-氯-N-(4-(三氟甲基)苯基)吡啶酰胺)265mg,收率:69.8%,Ms+1:379.1;
步骤二:向单口瓶中加入3-溴-6-氯-N-(4-(三氟甲基)苯基)吡啶酰胺(75.8mg,0.2mmol),加入环丙基硼酸(25.8mg,0.3mmol),1,4-二氧六环(5mL)和水(1mL),室温搅拌下加入碳酸钾(82.8mg,0.6mmol),加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(16mg,0.02mmol),氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,残留物加入乙酸乙酯和水萃取,分液,有机相水洗至中性,加入无水硫酸钠干燥,过滤,滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物38B(5-氯-3-环丙基-N-(4-(三氟甲基)苯基)吡啶酰胺)37mg,收率:54.2%,Ms+1:341.1;
步骤三:向单口瓶中加入5-氯-3-环丙基-N-(4-(三氟甲基)苯基)吡啶酰胺(18mg,0.053mmol),加入1-甲基-1H-吡唑-4-硼酸(10mg,0.08mmol),1,4-二氧六环(5mL)和水(1mL),室温搅拌下加入碳酸钾(18mg,0.13mmol),加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(3mg,0.004mmol),氩气置换3次,升温至100摄氏度反应6小时,自然冷却至室温,减压蒸除溶剂,残留物加入乙酸乙酯和水萃取,分液,有机相水洗至中性,加入无水硫酸钠干燥,过滤,滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚=1/4),得到化合物38(3-环丙基-6-(1-甲基-1H-吡唑-4-基)-N-(4(三氟甲基)苯基)吡啶酰胺)6mg,收率:29.3%,Ms+1:387.1。
表3按照实施例38的方法合成的化合物和数据表征
实施例4:化合物42的合成
具体反应如下:
步骤一:将6-氯-3-甲基吡啶甲酸用(171.6mg,1mmol)N,N-二甲基甲酰胺溶解至于50mL单口瓶中,加入HATU(456mg,1.2mmol),D L-苯甘胺醇(165.4mg,1.2mmol),室温条件下滴加DIPEA(322.5mg,2.5mmol),滴加结束后,室温反应2小时。反应结束后,旋除溶剂,用硅胶纯化(乙酸乙酯/石油醚=1/4),得到化合物42A(6-氯-N-(2-羟基-1-苯乙基)-3-甲基吡啶酰胺)220mg,收率:75.8%,Ms+1:291.1;
步骤二:将6-氯-N-(2-羟基-1-苯乙基)-3-甲基吡啶酰胺(220mg,0.76mmol)和三乙胺(191.9mg,1.9mmol)溶于四氢呋喃中,至于50mL单口瓶中,0摄氏度下搅拌5分钟,然后将对甲苯磺酰氯(289.8mg,1.52mmol)缓慢滴加到反应体系中,滴加完毕后升至室温反应6小时。通过LC-Ms检测,原料反应完全。旋除溶剂,通过乙酸乙酯和水萃取三次,合并有机相,用无水硫酸钠干燥,旋除溶剂,得淡黄色粗品(化合物42B)直接用于下一步;
步骤三:将上一步得到的粗品溶于20mL四氢呋喃溶液置于50mL单口瓶中,加入DIPEA(588.24mg,4.56mmol),升温至75摄氏度,保温反应10小时。用LC-Ms监测原料反应完全。将反应液旋除溶溶剂,加入乙酸乙酯和水萃取三次,合并有机相,用无水硫酸钠干燥,旋干溶剂,用硅胶纯化(乙酸乙酯/石油醚=1/3)得到类白色固体(化合物42C,3-(6-氯-3-甲基吡啶-2-基)-4-苯基-4,5-二氢恶唑)180mg,收率:87%,Ms+1:273.1;
步骤四:将3-(6-氯-3-甲基吡啶-2-基)-4-苯基-4,5-二氢恶唑(180mg,0.66mmol)溶于无水二氯甲烷中,加入2,3-二氯-5,6-二氰基苯醌(300mg,1.32mmol)和4A分子筛(100mg),室温反应4小时。用LC-Ms监测原料反应完全。反应结束后,抽滤,滤饼用无水二氯甲烷洗涤2次,旋除溶剂得到淡黄色油状物化合物42D(2-(6-氯-3-甲基吡啶-2-基)-4-苯恶唑)112mg,收率:99%,Ms+1:271.1;
步骤五:将2-(6-氯-3-甲基吡啶-2-基)-4-苯恶唑56mg按照实施例1的方法进行操作后,得到2-(3-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-4-苯恶唑30mg,收率:45.8%,Ms+1:317.1。
表4按照实施例42的方法合成的化合物和数据表征
实施例5:化合物92的制备
以合成路线2的方式制备化合物92,具体反应如下:
步骤一:将6-氯-3-甲基吡啶甲酸(798mg,4.7mmol)用N,N-二甲基甲酰胺溶解至于50mL单口瓶中,加入HATU(2128mg,5.6mmol),间三氟甲基苯胺(720mg,4.5mmol),室温条件下滴加DIPEA(1440mg,11.2mmol),滴加结束后,室温反应一小时。反应结束后,旋除溶剂,用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物92A(6-氯-3-甲基-N-(间三氟甲苯基)吡啶酰胺)960mg,收率:65%,Ms+1:315.1;
步骤二:向单口瓶中加入6-氯-3-三氟甲基-N-(间三氟甲苯基)吡啶酰胺(31.5mg,0.1mmol),加入4-吡唑硼酸频哪醇酯(19.4mg,0.1mmol),1,4-二氧六环(5mL)和水(1mL),室温搅拌下加入碳酸钾(27.6mg,0.2mmol),加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8mg,0.01mmol),氩气置换3次,升温至95摄氏度反应4小时,自然冷却至室温,减压蒸除溶剂,残留物加入乙酸乙酯和水萃取,分液,有机相水洗至中性,加入无水硫酸钠干燥,过滤,滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物92B(3-甲基-6-吡唑-4-基-N-三氟甲基吡啶甲酰胺)32mg,收率:92.2%,Ms+1:347.2。
步骤三:向单口瓶中加入3-甲基-6-吡唑-4-基-N-三氟甲基吡啶甲酰胺(32mg,0.09mmol),加入二氯甲烷(5mL),室温搅拌下加入三乙胺(19mg,0.19mmol),将体系降温至0摄氏度,滴加甲基磺酰氯(11mg,0.1mmol),升温至25摄氏度反应2小时,减压蒸除溶剂,残留物加入乙酸乙酯和水萃取,分液,有机相水洗至中性,加入无水硫酸钠干燥,过滤,滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚=1/3),得到化合物92(3-甲基-6-甲磺酰基-4-吡唑-N-三氟甲基苯吡啶甲酰胺)32mg,收率:83.7%,Ms+1:425.1。
表5按照实施例92的方法合成的化合物和数据表征
实施例6:化合物46的制备
将6-氯-3-甲基-N-(4-(三氟甲基)苯基)吡啶酰胺(31.4mg,0.1mmol)溶于无水的N-甲基吡咯烷酮(5mL)中,加入碳酸钾(41.4mg,0.3mmol),升温至165摄氏度反应6小时,自然冷却至室温,用硅胶纯化(乙酸乙酯/石油醚=1/3)得到3-甲基-6-吗啉-N-(4-(三氟甲基)苯基)吡啶酰胺20mg,收率:54.8%,Ms+1:366.1。1H NMR(400MHz,CDCl3)δ9.13(s,1H),7.84-7.78(m,2H),7.72-7.66(m,2H),7.42(m,1H),7.13(d,J=8.6Hz,1H),3.86-3.82(m,4H),3.79-3.75(m,4H),2.62(d,J=1.0Hz,3H)。
实施例7:本公开化合物体外激动AhR靶点的效果实验
以上化合物的体外活性在以下测定中证明:
使用HepG2-LuciaTMAhR细胞来对小分子化合物激动芳烃受体(aryl hydrocarbonreceptor,AhR)进行筛选。HepG2-LuciaTMAhR细胞是由人类HepG2肝癌细胞系改造而来,用于通过监测荧光素酶报告蛋白的活性来研究AhR基因组信号传导诱导。
(1)实验材料
DMEM培养基购自Gibco公司,青、链霉素购自Hyclone公司,Tapinarof购自MedChemExpress(MCE)公司,Dual Luciferase Reporter Assay Kit购自诺唯赞生物科技有限公司。
(2)实验方法
HepG2-LuciaTMAhR细胞采用DMEM+10% FBS+1%青/链霉素培养基,置于37℃、5%CO2的培养箱中培养。实验时,消化收集处于对数生长期的HepG2-LuciaTMAhR细胞,以8×103cells/well接种于96孔板中,置于37℃、5%CO2的细胞培养箱中培养过夜。次日,用培养基稀释待测化合物到相应浓度(0.001-10μM)并加入到96孔板相应孔中,每个样品浓度3个复孔,每块板同时设置3个溶剂对照孔和3个阳性药(Tapinarof 10μM)对照孔,每次测试同时也将阳性药Tapinarof稀释后加入测试,加药后将96孔板置于37℃、5% CO2的细胞培养箱中培养24h。培养结束前10min,将Dual Luciferase Reporter Assay Kit中的5×CellLysis Buffer和ddH2O按照1:4的比例混合制备成1×Cell Lysis Buffer备用,培养结束后,去掉培养基,每孔加入20μL 1×Cell Lysis Buffer,置于水平振荡仪上振荡15min,使细胞充分裂解。期间,以50:1的比例将适量的反应终止缓冲液(Stop&Reaction Buffer)和荧光素酶底物(Renilla Substrate)混匀备用(避光),同时准备好不透光的96孔白板。细胞裂解完成后将细胞裂解液(取13μL)转移至96孔白板的对应孔中,使用微孔板发光检测仪测定结果。并按照以下公式计算DRE荧光素酶活性倍数(DRE Luciferase activity(fold)):
DRE荧光素酶活性倍数=样品复孔平均值/溶剂对照复孔平均值
通过样品和阳性药Tapinarof(10μM)的荧光素酶活性倍数可评估样品对AhR的激动效果。最后,使用Graphpad Prism 5.0软件拟合曲线并计算出待测化合物激动AhR靶点的EC50值,如下表所示,其中,“AAAAA”表示EC50<20nM;“AAAA”表示EC50大于等于20nM且小于200nM;“AAA”表示EC50大于等于200nM且小于等于500nM;“AA”表示EC50大于等于500nM且小于等于1000nM;“A”表示EC50>1000nM;对于激动倍数值,其中“BBB”表示高于10倍;“BB”表示倍数大于等于5且小于等于10;“B”表示倍数小于5。
表6体外测定各实施例化合物的EC50值和激动效果
Claims (10)
1.式(I)所代表的化合物或其药学上可接受的盐,
其中:
m选自0、1、2或3;n选自0、1、2或3;
A环选自5-7元芳基、5-7元的单环杂芳基、9-12元的双环杂芳基、5-7元的杂环烷基、9-12元的部分不饱和双环杂环基;
m个R2彼此相同或不相同,其中,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、-S(O)2R6、5-7元杂环烷基,所述C1-6酰基、5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代,所述C1-6烷基任选地被一个或多个卤素、-C(=O)NR4R5取代;
R1选自氢、氘、卤素、C1-6烷基、C1-6烯基、C3-6环烷基,所述C1-6烷基、C1-6烯基、C3-6环烷基任选地被一个或多个卤素所取代;
B环选自5-7元芳基、5-7元单环杂芳基、9-12元双环杂芳基、9-12元部分不饱和双环杂环基、8-12元饱和螺环杂环基;
R4、R5、R6各自独立地选自氢、C1-6烷基、C3-6环烷基。
2.根据权利要求1所述的化合物,其中,A环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元的单环杂芳基、含有1-2个分别独立选自N、O、S原子的9-12元的双环杂芳基、含有1-2个分别独立选自N、O、S原子的5-7元的杂环烷基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基;
优选地,A环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元的单环杂芳基、含有1-2个分别独立选自N或O的9-12元的双环杂芳基、含有1-2个N原子的5-7元的杂环烷基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基;
优选地,A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、异吲哚啉基、吡啶酮基、异吲哚啉酮基;
优选地,A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、吡啶酮基、异吲哚啉酮基;
3.根据权利要求1或2所述的化合物,其中,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、-S(O)2R6、含有1-2个分别独立选自N、O原子的5-7元杂环烷基,所述C1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代,所述C1-6烷基任选地被一个或多个卤素、-C(=O)NR4R5取代;
优选地,R2选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-6酰基、5-7元杂环烷基,所述C1-6酰基、5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代;
优选地,R2选自C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、含有1-2个N原子的5-7元杂环烷基,所述C1-3酰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个C1-3烷基、-NR4R5所取代;
优选地,R2选自C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、含有1-2个N原子的5-7元杂环烷基,所述C1-3羰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个甲基、-N(CH3)2所取代;
优选地,R2选自甲基、乙基、丙基、异丙基、环丙烷基、甲氧基、甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基,所述甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基任选地被一个或多个甲基、-N(CH3)2所取代;
优选地,R4、R5各自独立地选自氢、C1-6烷基,更优选氢和甲基;
优选地,R6各自独立地选自C1-6烷基和C3-6环烷基,更优选甲基、丙基和环丙基;
4.根据权利要求1-3任一项所述的化合物,其中,R1选自氢、氘、卤素、C1-3烷基、C1-3烯基、C3-6环烷基,所述C1-3烷基、C1-3烯基、C3-6环烷基任选地被一个至三个卤素所取代;
优选地,R1选自氢、氘、氟、C1-3烷基、C1-3烯基,所述C1-3烷基、C1-3烯基、C3-6环烷基任选地被一个至三个氟所取代;
优选地,R1选自氟、甲基、乙基、氟甲基、二氟甲基、三氟甲基、异丙基、异丙烯基、环丙烷基;
优选地,R1选自氟、甲基、异丙基、异丙烯基、环丙烷基;
优选地,R1为甲基;
优选地,B环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元单环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元双环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N、O、S原子8-12元饱和螺环杂环基;
优选地,B环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元单环杂芳基、含有1-3个分别独立选自N或O原子的9-12元双环杂芳基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N或O原子8-12元饱和螺环杂环基;
优选地,B环选自苯基、吡啶基、吡唑基、苯并二氧戊环基、氮杂螺辛烷基、四氢异喹啉基;
n个R3彼此相同或不相同,其中,R3选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、卤素、氰基、含有1-2个分别独立选自N、O、S原子的5-7元杂环烷基,所述C1-6烷基、C3-6环烷基、C1-3酰基任选地被一个或多个卤素、氰基所取代;
优选地,R3选自C1-6烷基、C3-6环烷基、C1-3烷氧基、C1-3酰基、卤素、氰基、含有1-2个分别独立选自N或O原子的5-7元杂环烷基、所述C1-6烷基、C1-3酰基任选地被一个至三个氟所取代,所述C3-6环烷基任选地被一个或多个氰基所取代;
优选地,R3选自溴、氟、氯、氰基、三氟甲基、甲基。
7.权利要求1-6任一项的化合物的制备方法,所述方法选自以下合成路线:合成路线1:
步骤一:化合物1A与化合物1A-1Suzuki偶联反应得到化合物1B;
步骤二:化合物1B经过萃取纯化后得到化合物1C;
步骤三:化合物1C与化合物1C-1缩合反应得到化合物A1;
合成路线2:
步骤一:化合物2A与化合物2A-1缩合反应得到化合物2B;
步骤二:化合物2B与化合物2B-1Suzuki偶联反应得到化合物A2;
合成路线3:
步骤一:化合物3A与化合物缩合反应得到化合物3B;
步骤二:化合物3B与R1-B(OH)2Suzuki偶联反应得到化合物3C;
步骤三:化合物3C与化合物3C-1Suzuki偶联反应得到化合物A3;
合成路线4:
步骤一:化合物2A与化合物2A-1缩合反应得到化合物4B;
步骤二:化合物4B与对甲苯磺酰氯反应得到化合物4C;
步骤三:化合物4C与N,N-二异丙基乙胺反应得到化合物4D;
步骤四:化合物4D脱氢反应得到化合物4E;
步骤五:化合物4E与化合物4E-1Suzuki偶联反应得到化合物A4。
8.一种药物组合物,其特征在于,所述组合物包含根据权利要求1-6任一项所述的化合物或其药学上可接受的盐和药学上可接受的辅料。
9.权利要求1-6任一项的化合物或其药学上可接受的盐、权利要求8的药物组合物在制备治疗患者的AhR介导的病症的药物中的应用。
10.权利要求1-6任一项的化合物或其药学上可接受的盐、权利要求8的药物组合物在制备AHR激动剂中的应用。
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