CN116751178A - 一种取代2h-苯并吡喃-3-甲酰苯胺类化合物及其制备方法与应用 - Google Patents
一种取代2h-苯并吡喃-3-甲酰苯胺类化合物及其制备方法与应用 Download PDFInfo
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- CN116751178A CN116751178A CN202310734851.8A CN202310734851A CN116751178A CN 116751178 A CN116751178 A CN 116751178A CN 202310734851 A CN202310734851 A CN 202310734851A CN 116751178 A CN116751178 A CN 116751178A
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- Prior art keywords
- benzopyran
- carboxamide
- halogen
- substituted
- compound
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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Abstract
本发明公开了一种取代2H‑苯并吡喃‑3‑甲酰苯胺类化合物及其制备方法与应用,取代2H‑苯并吡喃‑3‑甲酰苯胺类化合物的结构如式I所示,
Description
技术领域
本发明涉及医药技术领域,特别是涉及一种取代2H-苯并吡喃-3-甲酰苯胺类化合物及其制备方法与在防治辐射损伤中的应用。
背景技术
辐射防护药物即辐射损伤预防药物和/或辐射损伤治疗药物,能直接对抗辐射所致的多系统损伤,有效减轻急性放射病的症状,为后续的综合救治赢得了宝贵的时机。
氨巯基类化合物是最早研发的小分子辐射防护剂,代表药物为氨磷汀(amifostine,WR2721),化学名为2-(3-氨基丙胺)-乙基硫代磷酸酯,曾作为抗辐射药物,其在体内经代谢脱去磷酸酯后发挥药效。该药物在动物模型上表现出很强的抗辐射活性,但因其发挥辐射防护作用的剂量接近中毒剂量而被放弃,调整用药剂量用于减轻癌症患者放疗的毒副作用后经美国FDA批准上市。目前美国处于临床研究阶段的小分子抗辐射药物有5-AED(5-雄烯二醇)、BIO 300(染料木素)和Ex-RAD。
发明内容
本发明的目的是针对现有技术中存在的技术缺陷,
第一方面,提供一种取代2H-苯并吡喃-3-甲酰苯胺类化合物,其结构为式I:
其中,R1选自H、卤素、烷氧基;R2、R3、R4、R5独立选自H、卤素、烷基、烷氧基、NO2中任意一个。
所述烷基为甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基;优选甲基、乙基或叔丁基;
所述烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基或叔丁氧基;优选甲氧基、乙氧基或叔丁氧基。
R1选自卤素、烷氧基;R2、R4、R5独立选自H、卤素、烷基中任意一个;R3选自H、卤素、烷基、烷氧基、NO2。
R1选自H;R2选自卤素;R3选自H、卤素、烷基、烷氧基、NO2;R4、R5独立选自H、卤素、烷基中任意一个。
R1、R2选自H;R3选自卤素;R4选自H、烷基;R5选自H、卤素、烷基、烷氧基;
优选的,R1、R2选自H;R3选自卤素;R4选自H;R5选自H、卤素、烷基;或
优选的,R1、R2选自H;R3选自卤素;R4选自烷基;R5选自H、卤素、烷氧基。
R1、R2、R3选自H;R4、R5选自卤素。
包括以下中的任何一种:
N-(4-氟-2-甲氧基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2-氟-4-氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,3,4-三氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4’-氟-2’-甲基苯基-)-2H-苯并吡喃-3-甲酰胺;
N-(2’,4’-二氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4,5-三氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2-甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(3-氟-4-氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-溴苯基)-2H-苯并吡喃-3-甲酰胺;
N-(3,5-二甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二甲氧基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2-氟-4-硝基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(3-氯-2-甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-氯-3-甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,3-二甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-溴苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺;
N-(4-氟苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二氟苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺;
N-(4-溴苯基)-7-溴-2H-苯并吡喃-3-甲酰胺;
N-(4-氟苯基)-7-溴-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二氟苯基)-7-溴-2H-苯并吡喃-3-甲酰胺。
第二方面,本发明提供一种组合物,包括上述取代2H-苯并吡喃-3-甲酰苯胺类化合物、其几何异构体、其药学上可接受的盐、其水合物或其溶剂化合物,以及药用载体或赋形剂。
第三方面,本发明提供一种制备上述取代2H-苯并吡喃-3-甲酰苯胺类化合物的方法,步骤如下:
步骤(1):将式Ⅱ化合物与二氯亚砜加热回流,至式Ⅱ化合物完全转化,反应式见式1,减压蒸干,将残余物溶解于适当溶剂,制成反应液A;
步骤(2):将式Ⅲ的化合物溶解于适当溶剂,并加入有机碱,制成反应液B;
步骤(3):将反应液B置于冰浴下搅拌,滴加反应液A,然后室温反应至完全,得式I所示化合物;
所述溶剂优选二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺和吡啶;所述有机碱优选4-二甲氨基吡啶、三乙胺、吡啶和N-甲基吗啉。
第四方面,本发明提供上述取代2H-苯并吡喃-3-甲酰苯胺类化合物或上述组合物在制备预防和/或治疗辐射损伤(尤其是电离辐射损伤)药物中的应用。
本发明提供的具辐射防治活性的化合物具有高效低毒、防治兼备、质量稳定、服用方便、口服注射均有效等特点,能有效延长辐射小鼠的生存期,为研制高效安全的辐射防护药物提供了新的思路和方向。
附图说明
图1-图3所示为化合物D-18的1H NMR图、13C NMR图和MS图。
图4所示为动物实验中小鼠30天存活率变化曲线。
具体实施方式
术语
除非另外定义,所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明,本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义,否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术,是本领域技术人员已知的。一般而言,前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施,这些文献在本说明书中被引用和讨论。
术语“烷基”是指脂肪族烃基团,可以是支链或直链的烷基。根据结构,烷基可以是单价基团或双价基团(即亚烷基)。在本发明中,烷基优选是具有1-8个碳原子的烷基,更优选具有1-6个碳原子的“低级烷基”,甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解,本文提到的“烷基”包括可能存在的所有构型和构象的该烷基,例如本文提到的“丙基”包括正丙基和异丙基,“丁基”包括正丁基、异丁基和叔丁基,“戊基”包括正戊基、异戊基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基,其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“环烷基”是指单环或多环基,其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构,环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中,环烷基优选是具有3-8个碳原子的环烷基,更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子,其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构,芳基可以是单价基团或双价基团(即亚芳基)。
术语“芳氧基”是指-O-芳基,其中芳基如本文中定义。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构,杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子,例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷,吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构,杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构,其中至少一个氢被卤原子置换。在某些实施方式中,如果两个或更多氢原子被卤原子置换,所述卤原子彼此相同或不同。
术语“氨基”是指-NH2基团。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“酯基”是指具有式-COOR的化学部分,其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’,其中R和R’各自独立地为氢或烷基。
术语“氨酰基”或“胺酰基”是指-CO-NH2基团。
术语“烷基氨酰基”或“烷基胺酰基”是指-CO-NH-R基团,其中R为本文定义的烷基。
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生,并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代,所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中,氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
本发明提供的化合物,为取代2H-苯并吡喃-3-甲酰苯胺类化合物,其结构为式Ⅰ:
其中,R1选自H、卤素、烷氧基;R2、R3、R4、R5独立选自H、卤素、烷基、烷氧基、NO2中任意一个。
例如:R1选自H、F、Cl、Br、OCH3中任意一个;R2、R3、R4、R5独立选自H、F、Cl、Br、CH3、OCH3、NO2中任意一个。
以上取代2H-苯并吡喃-3-甲酰苯胺类化合物还包括式Ⅰ化合物的几何异构体、其药学上可接受的盐、其水合物或溶剂化合物以及可药用载体或赋形剂的药物组合物。其中:异构体或水合物,如光学异构体或消旋体化合物;药学上可接受的盐,可以是式Ⅰ化合物的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、溴化物、碘化物、乙酸盐、丙酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、庚酸盐、癸酸盐、丙炔酸盐、草酸盐、丙二酸盐、丁二酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、2-丁炔-1,4-二酸盐、3-环己炔-2,5-二酸盐、苯甲酸盐、氯代苯甲酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、马尿酸盐、β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐、谷氨酸盐、精氨酸盐、赖氨酸盐等,优选盐酸盐和磷酸盐。
本发明提供的取代2H-苯并吡喃-3-甲酰苯胺类化合物可为口服或非胃肠道用药。口服用药可以是片剂、丸剂、颗粒剂、胶囊剂、包衣剂、口服液、乳剂、散剂;非肠胃道用药可以是注射剂、栓剂、或其它适宜的形式。制造以上剂型所用的辅料均是常用的助剂,如片剂、胶囊剂、包衣剂等固体剂型所用的助剂包括淀粉、明胶、阿拉伯胶、硅石、聚乙二醇;液体剂型所用的溶剂如水、乙醇、丙二醇、植物油类(如玉米油,花生油,橄榄油等)等。其它助剂,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂,色素等也为常用助剂。
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合,可以合成式(I)的化合物。另外,本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导,也可以利用以下的合成方法。
所述反应可以按顺序使用,以提供本文描述的化合物;或它们可以用于合成片段,所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
可以使用与下述类似的方法,通过使用适当的可选择的起始原料,合成化合物。用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应,并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改,以引入本文提供的分子中的各种部分。
如果需要,反应产物可以使用常规技术分离和纯化,包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征,包括物理常数和图谱数据。
本发明还提供式Ⅰ化合物的制备方法,取代2H-苯并吡喃-3-甲酰苯胺类化合物的合成步骤如下:
步骤(1):将式Ⅱ化合物与二氯亚砜加热回流,至式Ⅱ化合物完全转化后减压蒸干,反应式见式1。将残余物溶解于适当溶剂,制成反应液A;
步骤(2):将式Ⅲ的化合物溶解于适当溶剂,并加入有机碱,制成反应液B;
步骤(3):将反应液B置于冰浴下搅拌,滴加反应液A,然后室温反应至完全,得式I所示化合物。
溶剂优选二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺和吡啶;有机碱优选4-二甲氨基吡啶、三乙胺、吡啶和N-甲基吗啉。
本发明提供的具有式Ⅰ结构的取代2H-苯并吡喃-3-甲酰苯胺类化合物可用于预防和/或治疗辐射损伤,可能适用于预防和/或治疗辐射造成的机体损伤,包括不同辐射剂量对人或动物造成的头晕、乏力、食欲下降等早期症状,DNA损伤,消化道损伤,造血系统损伤和脑损伤等。
以下结合具体实施例,更具体地说明本发明的内容,并对本发明作进一步阐述,但这些实施例绝非对本发明进行限制。
以下具体实施例说明本发明化合物的制备及其性质,实施例并非穷举。实施例中使用的试剂均为市场购买,核磁共振谱用布鲁克600M超导核磁仪测定,ESI质谱用美国安捷伦1260-G6230A型质谱仪测定,高分辨率质谱用美国布鲁克9.4T超高性能混合型串联傅里叶变换离子回旋共振质谱Q-FT-ICR-MS测定。
实施例1:N-(4-氟-2-甲氧基苯基)-2H-苯并吡喃-3-甲酰胺(D-1)的合成
2H-苯并吡喃-3-甲酸的合成,见式2:
2.444g(20.0mmol)水杨醛、1.274g(24.0mmol)丙烯腈以及0.269g(2.4mmol)的三乙烯二胺置于35mL微波反应瓶中。将反应瓶置于CEM Discovery SP微波合成仪中。在微波140℃条件下,反应30min。冷却后取出,加入适量二氯甲烷,将溶液转移至100mL圆底烧瓶中,减压蒸干。烧瓶中加入5M的氢氧化钠溶液40mL,搅拌下回流3h。冷至室温,用5M盐酸调至酸性,乙酸乙酯萃取,无水硫酸镁干燥,蒸干得粗品。柱层析分离,得白色固体2.445g,收率69.4%,m.p.116-117℃。
N-(4-氟-2-甲氧基苯基)-2H-苯并吡喃-3-甲酰胺的合成,见式3:
25mL圆底烧瓶中加入0.529g(3.0mmol)的2H-苯并吡喃-3-甲酸,加入6mL二氯亚砜,加热回流1.5h,减压蒸干。加入10mL干燥四氢呋喃溶解,制成反应液A。将0.353g(2.5mmol)4-氟-2-甲氧基苯胺溶于5mL干燥的四氢呋喃中,加入0.42mL三乙胺(3.0mmol)制成反应液B。在冰浴搅拌下,将反应液A缓慢加入反应液B。室温搅拌反应3h,加入100mL水稀释,析出固体,抽滤并用水洗涤固体,晾干得粗品。柱层析分离,得淡黄色固体0.660g,收率88.2%。m.p.149-151℃.1H NMR(600MHz,DMSO-d6)δ9.30(s,1H),7.56(d,J=8.7Hz,1H),7.48(s,1H),7.26(t,J=7.9Hz,2H),7.04-6.96(m,2H),6.88(d,J=7.9Hz,1H),6.77(td,J=8.6,2.7Hz,1H),4.96(d,J=1.0Hz,2H),3.84(s,3H).13C NMR(151MHz,DMSO-d6)δ163.67(s),160.61(d,J=241.7Hz),154.70(s),153.82(d,J=10.5Hz),131.72(s),129.10(s),128.42(s),126.95(s),126.63(d,J=10.1Hz),123.04(d,J=3.0Hz),122.33(s),121.62(s),116.18(s),106.51(d,J=22.2Hz),100.42(d,J=26.8Hz),64.80(s),56.63(s).MS(ESI-TOF)m/z:300.10(M+H)+,322.08(M+Na)+。
实施例2:N-(2-氟-4-氯苯基)-2H-苯并吡喃-3-甲酰胺(D-2)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2-氟-4-氯苯胺,得白色粉末0.635g,收率83.7%。m.p.127-128℃.1H NMR(600MHz,DMSO-d6)δ9.99(s,1H),7.61(s,1H),7.52(d,J=3.9Hz,2H),7.29(dd,J=7.6,2.6Hz,3H),6.99(d,J=0.9Hz,1H),6.89(d,J=8.0Hz,1H),4.97(d,J=1.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ163.84(s),155.73(d,J=250.66Hz),154.80(s),131.99(s),130.21(d,J=9.6Hz),129.50(s),129.24(s),128.07(s),126.25(s),125.15(d,J=12.08),125.02(d,J=3.02Hz),122.41(s),121.48(s),117.04(s),116.25(s),64.70(s).MS(ESI-TOF)m/z:304.05(M+H)+,326.03(M+Na)+。
实施例3:N-(2,3,4-三氟苯基)-2H-苯并吡喃-3-甲酰胺(D-3)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,3,4-三氟苯胺,得白色固体0.650g,收率85.2%。m.p.128-129℃.1H NMR(600MHz,DMSO-d6)δ10.14(s,1H),7.52(s,1H),7.35(d,J=5.3Hz,2H),7.29(dd,J=6.6,4.9Hz,2H),7.00(d,J=1.0Hz,1H),6.89(d,J=8.0Hz,1H),4.97(d,J=1.2Hz,2H).HRMS(ESI)m/z:Calculated for C16H11F3NO2 +([M+H]+)306.0736,Found 306.0737。
实施例4:N-(4-氟-2-甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-4)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为4-氟-2-甲基苯胺,得白色固体0.612g,收率86.4%。m.p.147-149℃.1H NMR(600MHz,DMSO-d6)δ9.67(s,1H),7.47(s,1H),7.28(dd,J=7.7,3.4Hz,3H),7.13(dd,J=9.7,2.8Hz,1H),6.99(s,2H),6.89(t,J=9.3Hz,1H),4.98(d,J=1.1Hz,2H),2.21(s,3H).13C NMR(151MHz,DMSO-d6)δ163.67(s),160.61(d,J=241.6Hz),154.70(s),153.82(d,J=10.5Hz),131.72(s),129.10(s),128.42(s),126.95(s),126.63(d,J=10.1Hz),123.04(d,J=3.0Hz),122.33(s),121.62(s),116.18(s),106.52(d,J=22.65Hz),100.43(d,J=25.67Hz),100.34(s),64.80(s),56.63(s).MS(ESI-TOF)m/z:284.11(M+H)+,306.09(M+Na)+。
实施例5:N-(2,4-二氟苯基)-2H-苯并吡喃-3-甲酰胺(D-5)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,4-二氟苯胺,得白色粉末0.564g,收率78.6%。m.p.123-125℃.1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),7.54(td,J=8.9,6.2Hz,1H),7.51(s,1H),7.35(ddd,J=10.9,9.2,2.8Hz,1H),7.30-7.26(m,2H),7.11(ddd,J=8.3,2.9,1.4Hz,1H),6.99(d,J=0.9Hz,1H),6.89(d,J=8.0Hz,1H),4.97(d,J=1.2Hz,2H).HRMS(ESI)m/z:Calculated for C16H12F2NO2 +([M+H]+)288.0831,Found288.0830。
实施例6:N-(2,4,5-三氟苯基)-2H-苯并吡喃-3-甲酰胺(D-6)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,4,5-三氟苯胺,得白色固体0.640g,收率83.9%。m.p.149-151℃.1H NMR(600MHz,DMSO-d6)δ10.04(s,1H),7.77-7.63(m,2H),7.53(s,1H),7.32-7.26(m,2H),7.03-6.97(m,1H),6.89(d,J=8.0Hz,1H),4.97(d,J=1.0Hz,2H).HRMS(ESI)m/z:Calculated for C16H11F3NO2 +([M+H]+)306.0736,Found306.0736。
实施例7:N-(2-甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-7)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2-甲基苯胺,得白色粉末0.561g,收率84.6%。m.p.118-120℃.1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),7.48(s,1H),7.33-7.22(m,4H),7.20(s,1H),7.16(d,J=7.3Hz,1H),6.99(t,J=7.4Hz,1H),6.88(d,J=8.0Hz,1H),4.99(s,2H),2.22(s,3H).13C NMR(151MHz,DMSO-d6)δ163.72(s),154.72(s),136.41(s),134.03(s),131.67(s),130.80(s),129.05(s),128.29(s),127.17(s),126.83(s),126.43(d,J=7.8Hz),122.34(s),121.68(s),116.19(s),64.93(s),18.38(s).MS(ESI-TOF)m/z:266.12(M+H)+,288.10(M+Na)+。
实施例8:N-(2,4-二甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-8)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,4-二甲基苯胺,得白色固体0.609g,收率87.2%。m.p.112-114℃.1H NMR(600MHz,DMSO-d6)δ9.58(s,1H),7.45(s,1H),7.28-7.24(m,2H),7.14(d,J=7.9Hz,1H),7.06(s,1H),7.01-6.96(m,2H),6.88(d,J=8.0Hz,1H),4.97(s,2H),2.27(s,3H),2.17(s,3H).13C NMR(151MHz,DMSO-d6)δ163.72(s),154.69(s),135.51(s),133.82(d,J=13.1Hz),131.62(s),131.33(s),129.01(s),128.10(s),127.24(s),126.98(s),126.79(s),122.33(s),121.71(s),116.18(s),64.94(s),21.00(s),18.30(s).MS(ESI-TOF)m/z:280.13(M+H)+,302.11(M+Na)+。
实施例9:N-(4-氯苯基)-2H-苯并吡喃-3-甲酰胺(D-9)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为4-氯苯胺,得黄色固体0.616,收率86.3%。m.p.161-163℃.1H NMR(600MHz,DMSO-d6)δ10.18(s,1H),7.78-7.72(m,2H),7.48(s,1H),7.40(d,J=8.8Hz,2H),7.32-7.25(m,2H),6.99(t,J=7.4Hz,1H),6.88(d,J=8.0Hz,1H),4.98(d,J=1.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ163.91(s),154.74(s),138.31(s),131.86(s),129.14(s),129.04(s),128.68(s),127.64(s),127.14(s),122.40(s),122.04(s),121.52(s),116.24(s),64.78(s).MS(ESI-TOF)m/z:286.06(M+H)+,308.04(M+Na)+。
实施例10:N-(3-氟-4-氯苯基)-2H-苯并吡喃-3-甲酰胺(D-11)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为3-氟-4-氯苯胺,得黄色固体0.670g,收率88.2%。m.p.131-133℃.1H NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.07-7.97(m,1H),7.71-7.63(m,1H),7.48(s,1H),7.41(dd,J=11.4,6.7Hz,1H),7.28(dd,J=15.2,7.6Hz,2H),7.00(t,J=7.4Hz,1H),6.89(d,J=8.0Hz,1H),4.98(s,2H).13C NMR(151MHz,DMSO-d6)δ163.91(s),154.76(s),153.76(d,J=243.11Hz),136.60(s),131.93(s),129.16(s),128.89(s),126.89(s),122.40(s),121.90(s),121.43(s),120.75(s),119.49(d,J=18.2Hz),117.32(d,J=19.63Hz)116.25(s),64.71(s).MS(ESI-TOF)m/z:304.05(M+H)+,326.04(M+Na)+。
实施例11:N-(4-溴苯基)-2H-苯并吡喃-3-甲酰胺(D-12)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为4-溴苯胺,得白色固体0.687g,收率83.2%。m.p.173-175℃.1H NMR(600MHz,DMSO-d6)δ10.18(s,1H),7.72-7.67(m,2H),7.52(dd,J=6.8,2.1Hz,2H),7.48(s,1H),7.29(dd,J=9.3,7.9Hz,2H),6.99(s,1H),6.88(d,J=8.1Hz,1H),4.98(s,2H).13C NMR(151MHz,DMSO-d6)δ161.63(s),152.48(s),136.48(s),129.61(d,J=12.6Hz),126.86(s),126.44(s),124.86(s),120.12(d,J=6.0Hz),119.24(s),113.97(s),62.52(s).MS(ESI-TOF)m/z:330.01(M+H)+,353.99(81M+Na)+。
实施例12:N-(3,5-二甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-13)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为3,5-二甲基苯胺,得白色粉末0.591g,收率84.6%。m.p.143-144℃.1H NMR(600MHz,DMSO-d6)δ9.88(s,1H),7.46(s,1H),7.33(s,2H),7.26(dd,J=12.5,4.7Hz,2H),7.01-6.97(m,1H),6.88(d,J=7.8Hz,1H),6.73(s,1H),4.97(d,J=1.3Hz,2H),2.25(s,6H).13C NMR(151MHz,DMSO-d6)δ163.65(s),154.68(s),139.13(s),138.01(s),131.71(s),129.04(s),128.19(s),127.43(s),125.60(s),122.36(s),121.63(s),118.35(s),116.20(s),64.85(s),21.59(s).MS(ESI-TOF)m/z:280.13(M+H)+,302.12(M+Na)+。
实施例13:N-(2,4-二甲氧基苯基)-2H-苯并吡喃-3-甲酰胺(D-14)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,4-二甲氧基苯胺,得白色固体0.676g,收率86.9%。m.p.147-149℃.1H NMR(600MHz,DMSO-d6)δ9.16(s,1H),7.49(s,1H),7.45(d,J=3.1Hz,1H),7.31-7.24(m,2H),6.99(ddd,J=8.4,6.3,2.6Hz,2H),6.88(d,J=8.1Hz,1H),6.71(dd,J=8.9,3.1Hz,1H),4.98(d,J=1.2Hz,2H),3.80(s,3H),3.70(s,3H).13C NMR(151MHz,DMSO-d6)δ163.46(s),154.72(s),153.30(s),145.41(s),131.77(s),129.20(s),128.43(s),127.75(s),127.05(s),122.30(s),121.59(s),116.17(s),112.44(s),110.35(s),109.82(s),64.77(s),56.66(s),55.82(s).MS(ESI-TOF)m/z:312.12(M+H)+,334.10(M+Na)+。
实施例14:N-(2-氟-4-硝基苯基)-2H-苯并吡喃-3-甲酰胺(D-16)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2-氟-4-硝基苯胺,得黄色粉末0.563g,收率71.6%。m.p.136-138℃.1H NMR(600MHz,DMSO-d6)δ10.12(s,1H),7.96(dd,J=7.7,1.7Hz,1H),7.85(s,1H),7.82-7.78(m,1H),7.54(t,J=7.5Hz,1H),7.46-7.42(m,2H),7.37-7.33(m,1H),7.02(t,J=7.4Hz,1H),6.93(d,J=8.2Hz,1H),5.09(s,2H).13C NMR(151MHz,DMSO-d6)δ190.42(s),162.86(s),155.25(s),151.29(s),136.19(s),135.86(s),133.22(s),131.46(s),130.18(s),128.43(s),127.30(s),124.32(s),122.53(s),121.31(d,J=72.7Hz),116.39(s),64.29(s)。
实施例15:N-(3-氯-2-甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-17)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为3-氯-2-甲基苯胺,得白色固体0.619g,收率82.6%。m.p.162-164℃.1H NMR(600MHz,DMSO-d6)δ9.92(s,1H),7.50(s,1H),7.35(d,J=7.7Hz,1H),7.30-7.22(m,4H),6.99(t,J=7.4Hz,1H),6.89(d,J=8.0Hz,1H),4.99(d,J=2.5Hz,2H),2.23(s,3H).13C NMR(151MHz,DMSO-d6)δ163.94(s),154.76(s),138.09(s),134.27(s),132.54(s),131.80(s),129.12(s),128.75(s),127.34(s),127.18(s),126.79(s),126.12(s),122.37(s),121.59(s),116.22(s),64.85(s),15.84(s).MS(ESI-TOF)m/z:300.09(M+H)+,322.07(M+Na)+。
实施例16:N-(4-氯-3-甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-18)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为4-氯-3-甲基苯胺,得白色固体0.648g,收率86.5%。m.p.161-163℃.1H NMR(600MHz,DMSO-d6)δ10.09(s,1H),7.70(d,J=2.4Hz,1H),7.57(d,J=8.7Hz,1H),7.47(s,1H),7.36(d,J=8.6Hz,1H),7.27(dd,J=13.4,7.6Hz,2H),6.99(t,J=7.4Hz,1H),6.88(d,J=8.0Hz,1H),4.98(s,2H),2.31(s,3H).13CNMR(151MHz,DMSO-d6)δ163.82(s),154.73(s),138.23(s),135.94(s),131.84(s),129.40(s),129.12(s),128.61(s),127.97(s),127.15(s),122.94(s),122.39(s),121.53(s),119.69(s),116.24(s),64.78(s),20.35(s).MS(ESI-TOF)m/z:300.09(M+H)+,322.07(M+Na)+。
实施例17:N-(4-氟苯基)-2H-苯并吡喃-3-甲酰胺(D-19)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为4-氟苯胺,得白色固体0.561g,收率83.4%。m.p.132-134℃.1H NMR(600MHz,DMSO-d6)δ10.11(s,1H),7.72(dd,J=8.5,5.1Hz,2H),7.46(s,1H),7.28(dd,J=16.1,7.6Hz,2H),7.18(t,J=8.9Hz,2H),6.99(t,J=7.8Hz,1H),6.88(d,J=8.1Hz,1H),4.98(d,J=1.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ163.74(s),158.69(d,J=239.9Hz),154.71(s),135.67(d,J=2.2Hz),131.78(s),129.08(s),128.40(s),127.27(s),122.39(d,J=2.6Hz),122.35(s),121.56(s),116.23(s),115.70(d,J=22.2Hz),64.82(s).MS(ESI-TOF)m/z:270.10(M+H)+,292.08(M+Na)+。
实施例18:N-(2,3-二甲基苯基)-2H-苯并吡喃-3-甲酰胺(D-20)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,3-二甲基苯胺,得白色固体0.566g,收率81.1%。m.p.186-188℃.1H NMR(600MHz,DMSO-d6)δ9.71(s,1H),7.47(s,1H),7.27(dd,J=13.5,7.5Hz,2H),7.07(d,J=3.0Hz,3H),6.98(t,J=7.4Hz,1H),6.88(d,J=8.0Hz,1H),4.98(d,J=1.2Hz,2H),2.27(s,3H),2.08(s,3H).13C NMR(151MHz,DMSO-d6)δ163.84(s),154.70(s),137.48(s),136.23(s),133.08(s),131.63(s),129.02(s),128.15(s),127.98(s),127.24(s),125.71(s),124.96(s),122.33(s),121.71(s),116.18(s),64.95(s),20.60(s),14.73(s).MS(ESI-TOF)m/z:280.13(M+H)+,302.12(M+Na)+。
实施例19:N-(2,4-二氯苯基)-2H-苯并吡喃-3-甲酰胺(D-21)的合成
按实施例1的方法,仅将4-氟-2-甲氧基苯胺替换为2,4-二氯苯胺,得黄色固体0.656g,收率81.9%。m.p.140-142℃.13C NMR(151MHz,DMSO-d6)δ163.86(s),154.81(s),137.21(s),132.43(s),132.02(s),129.39(s),129.27(s),128.48(s),128.39(s),128.27(s),127.26(s),126.31(s),122.43(s),121.46(s),116.27(s),64.70(s).MS(ESI-TOF)m/z:320.03(M+H)+,342.01(M+Na)+。
实施例20:N-(4-溴苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺(D-22)的合成
7-甲氧基-2H-苯并吡喃-3-甲酸的合成,见式4:
3.043g(20.0mmol)4-甲氧基水杨醛、1.274g(24.0mmol)丙烯腈以及0.269g(2.4mmol)的三乙烯二胺置于35mL微波反应瓶中。将反应瓶置于CEM Discovery SP微波合成仪中。在微波140℃条件下,反应30min。冷却后取出,加入适量二氯甲烷,将溶液转移至100mL圆底烧瓶中,减压蒸干。烧瓶中加入5M的氢氧化钠溶液40mL,搅拌下回流3h。冷至室温,用5M盐酸调至酸性,乙酸乙酯萃取,无水硫酸镁干燥,蒸干得粗品。柱层析分离,得白色固体3.011g,收率73.0%,m.p.127-129℃。
N-(4-溴苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺的合成,见式5:
25mL圆底烧瓶中加入0.619g(3.0mmol)的7-甲氧基-2H-苯并吡喃-3-甲酸,加入6mL二氯亚砜,加热回流1.5h,减压蒸干。加入10mL干燥四氢呋喃溶解,制成反应液A。将0.430g(2.5mmol)4-溴苯胺溶于5mL干燥的四氢呋喃中,加入0.42mL三乙胺(3.0mmol)制成反应液B。在冰浴搅拌下,将反应液A缓慢加入反应液B。室温搅拌反应3h,加入100mL水稀释,析出固体,抽滤并用水洗涤固体,晾干得粗品。柱层析分离,得白色固体0.739,收率82.1%。m.p.175-177℃.1H NMR(600MHz,DMSO-d6)δ10.08(s,1H),7.68(d,J=8.8Hz,2H),7.51(d,J=8.7Hz,2H),7.46(s,1H),7.22(d,J=8.3Hz,1H),6.58(d,J=8.4Hz,1H),6.49(d,J=2.3Hz,1H),4.95(d,J=0.9Hz,2H),3.77(s,3H).13C NMR(151MHz,DMSO-d6)δ161.85(s),160.37(s),154.13(s),136.68(s),129.69(s),128.00(s),126.78(s),121.46(s),120.12(s),113.30(s),112.32(s),106.45(s),99.67(s),62.68(s),53.70(s).MS(ESI-TOF)m/z:360.03(M+H)+,382.01(M+Na)+。
实施例21:N-(4-氟苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺(D-23)的合成
按实施例20的方法,仅将4-溴苯胺替换为4-氟苯胺,得白色粉末0.578g,收率77%。m.p.140-142℃.1H NMR(600MHz,DMSO-d6)δ10.01(s,1H),7.74-7.68(m,2H),7.45(s,1H),7.22(d,J=8.4Hz,1H),7.17(t,J=8.9Hz,2H),6.59(s,1H),6.49(d,J=2.4Hz,1H),4.95(d,J=1.0Hz,2H),3.77(s,3H).13C NMR(151MHz,DMSO-d6)δ162.45(s),157.64(d,J=240.4Hz),154.37(s),134.48(d,J=2.2Hz),129.35(s),126.60(s),126.37(s),124.23(s),122.68(s),121.30(d,J=7.6Hz),119.75(s),118.07(s),114.63(d,J=22.3Hz),64.14(s).MS(ESI-TOF)m/z:300.11(M+H)+,322.09(M+Na)+。
实施例22:N-(2,4-二氟苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺(D-24)的合成
按实施例20的方法,仅将4-溴苯胺替换为2,4-二氟苯胺,得黄色粉末0.589g,收率74.2%。m.p.138-139℃.1H NMR(600MHz,CDCl3)δ8.28(d,J=8.8Hz,1H),7.61(s,1H),7.12-7.06(m,2H),6.90(t,J=5.0Hz,2H),6.52(dd,J=8.4,2.4Hz,1H),6.45(d,J=2.4Hz,1H),5.06(d,J=1.1Hz,2H),3.81(s,3H).HRMS(ESI)m/z:Calculated for C17H14F2NO3 +([M+H]+)318.0936,Found 318.0935。
实施例23:N-(4-溴苯基)-7-溴-2H-苯并吡喃-3-甲酰胺(D-25)的合成
7-溴-2H-苯并吡喃-3-甲酸的合成,见式6:
4.020g(20.0mmol)4-溴水杨醛、1.274g(24.0mmol)丙烯腈以及0.269g(2.4mmol)的三乙烯二胺置于35mL微波反应瓶中。将反应瓶置于CEM Discovery SP微波合成仪中。在微波140℃条件下,反应30min。冷却后取出,加入适量二氯甲烷,将溶液转移至100mL圆底烧瓶中,减压蒸干。烧瓶中加入5M的氢氧化钠溶液40mL,搅拌下回流3h。冷至室温,用5M盐酸调至酸性,乙酸乙酯萃取,无水硫酸镁干燥,蒸干得粗品。柱层析分离,得类白色固体3.933g,收率77.1%,m.p.118-120℃。
N-(4-溴苯基)-7-溴-2H-苯并吡喃-3-甲酰胺的合成,见式7:
25mL圆底烧瓶中加入0.765g(3.0mmol)的7-溴-2H-苯并吡喃-3-甲酸,加入6mL二氯亚砜,加热回流1.5h,减压蒸干。加入10mL干燥四氢呋喃溶解,制成反应液A。将0.430g(2.5mmol)4-溴苯胺溶于5mL干燥的四氢呋喃中,加入0.42mL三乙胺(3.0mmol)制成反应液B。在冰浴搅拌下,将反应液A缓慢加入反应液B。室温搅拌反应3h,加入100mL水稀释,析出固体,抽滤并用水洗涤固体,晾干得粗品。柱层析分离,得黄色固体0.851g,收率83.2%。m.p.197-199℃.1H NMR(600MHz,DMSO-d6)δ10.20(s,1H),7.70-7.66(m,2H),7.52(d,J=8.8Hz,2H),7.45(s,1H),7.25(d,J=8.1Hz,1H),7.19(d,J=1.8Hz,1H),7.13(d,J=1.3Hz,1H),5.01(d,J=1.3Hz,2H).13C NMR(151MHz,DMSO-d6)δ163.72(s),155.48(s),138.64(s),131.96(s),130.50(s),127.77(s),127.56(s),125.35(s),123.88(s),122.42(s),120.79(s),119.19(s),115.81(s),65.19(s).MS(ESI-TOF)m/z:409.92[M(79Br81Br)+H]+。
实施例24:N-(4-氟苯基)-7-溴-2H-苯并吡喃-3-甲酰胺(D-26)的合成
按实施例23的方法,仅将4-溴苯胺替换为4-氟苯胺,得白色固体0.707g,收率81.2%。m.p.183-185℃.1H NMR(600MHz,DMSO-d6)δ10.14(s,1H),7.71(dd,J=9.2,5.0Hz,2H),7.45-7.42(m,1H),7.25(d,J=8.1Hz,1H),7.21-7.16(m,3H),7.13(d,J=1.8Hz,1H),5.01(d,J=1.4Hz,2H).13C NMR(151MHz,DMSO-d6)δ162.45(s),157.64(d,J=240.4Hz),154.37(s),134.48(d,J=2.2Hz),129.35(s),126.60(s),126.37(s),124.23(s),122.68(s),121.30(d,J=7.6Hz),119.75(s),118.07(s),114.63(d,J=22.3Hz),64.14(s).MS(ESI-TOF)m/z:348.00(M+H)+,369.99(M+Na)+。
实施例25:N-(2,4-二氟苯基)-7-溴-2H-苯并吡喃-3-甲酰胺(D-27)的合成
按实施例23的方法,仅将4-溴苯胺替换为2,4-二氟苯胺,得黄色粉末0.652g,收率71.2%。m.p.144-145℃.1H NMR(600MHz,DMSO-d6)δ9.96(s,1H),7.54(d,J=6.2Hz,1H),7.49(s,1H),7.35(s,1H),7.25(d,J=8.1Hz,1H),7.19(dd,J=8.0,1.4Hz,1H),7.16-7.06(m,2H),5.00(d,J=1.3Hz,2H).HRMS(ESI)m/z:Calculated for C16H12BrF2NO2 +([M+H]+)365.9936,Found 364.9936。
以上实施例的化合物均有1H NMR图、13C NMR图和MS图以确证化合物的结构。由于篇幅限制,以化合物D-18为例,其1H NMR图、13C NMR图和MS图见图1-图3。
实施例1-25的目标化合物结构式见表1。
表1实施例1-25的目标化合物结构
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实验一:体外抗辐射活性评价实验
对表1中的目标化合物进行了抗辐射活性评价。在体外培养的细胞给予辐射照射前进行化合物处理,辐射照射后通过检测细胞增殖的方式评价化合物对照射细胞的保护作用。使用RS2000生物学辐照仪(Rad Source Technologies Inc.)对细胞进行X射线照射。
表1所列化合物分别用DMSO配制成浓度为1.0mM和2.0mM的储备液,使用时用培养基稀释。
取对数生长的AHH-1细胞(人外周血B淋巴细胞,商购),轻轻吹打使细胞均匀悬浮,使用细胞计数仪计数,用含10%胎牛血清的RPMI-1640培养基(gibco)调整细胞密度为1.5×105个/mL。将细胞接种到96孔板中,每孔100μL,即每孔15000个细胞,96孔板最外圈的孔分别用200μL纯净水填充。设置辐射对照组(细胞照射但不给予化合物处理),待测化合物组(细胞照射且给予表1所列化合物处理),阴性照射组(细胞正常培养,不照射)和空白组(无细胞无化合物,每孔100μL培养基),每组设置3个复孔。96孔板在5%二氧化碳恒温培养箱孵育4-6h后,待测化合物组加入50μL经培养基稀释的相应化合物的储备液(使化合物浓度达到设定的终浓度),阴性照射组和空白组加入50μL经培养基稀释的DMSO(与待测化合物组含相同浓度DMSO)。于5%二氧化碳恒温培养箱中放置24小时后,取出置于RS2000生物学辐照仪中给予9.0Gy剂量的照射。继续于5%二氧化碳恒温培养箱中孵育24小时。配制一定量的培养基稀释的CCK-8溶液(培养基与CCK-8原液(试剂盒中自带)体积比为38:12),每孔加入50μL CCK-8溶液,于5%二氧化碳恒温培养箱中孵育2小时,用酶标仪检测450nm下的吸光度(OD)值,计算存活率。
存活率(%)=(待测化合物组OD值-空白组OD值)/(阴性对照组OD值-空白组OD值)×100%
存活率采用平均值±标准差表示,存活率数据的组间比较采用SPSS 13.0软件进行单因素方差分析,P<0.05表示差异有显著统计学意义。以表2-表4所列化合物为例,实验结果见表2-4。
表2化合物对9.0Gy受照AHH-1细胞的辐射保护作用(一)
表2的实验结果表明,在20μM下与辐射对照组相比,D-4、D-5、D-6、D-11、D-12、D-18和D-19可以显著提高受照细胞的存活率,表现出了明显的抗辐射活性。发明人分析:取代2H-苯并吡喃-3-甲酰苯胺类化合物胺基苯环上的取代基对活性有重要的影响,且胺基苯环对位(R3)有氟取代、溴取代等的卤素取代对抗辐射活性有利;胺基苯环对位(R3)有卤素取代的同时胺基苯环间位(R4)有烷基或卤素取代对抗辐射活性有利;胺基苯环的邻位(R5)或间位(R2或R4)分别为卤素取代对抗辐射活性有利;苯并吡喃上有卤素或烷氧基取代也表现出较好的抗辐射活性。
选择表2实验中可以显著提高细胞存活的化合物D-4、D-5、D-6、D-11、D-12、D-18和D-19以及后续合成的化合物D-22、D-23、D-24、D-25、D-26和D-27评价其在不同浓度下对细胞存活的影响,其终浓度设置为20μM、40μM和60μM,照射剂量为9.0Gy,实验步骤同前,实验结果见表3和表4(表2-表4显示三批实验结果)。
表3化合物对9.0Gy受照AHH-1细胞的辐射保护作用(二)
表4化合物对9.0Gy受照AHH-1细胞的辐射保护作用(三)
表3和表4实验结果表明,在20-60μM范围内与辐射对照组相比,化合物可以显著提高受照细胞的存活,大部分化合物随着药物浓度增加对受照AHH-1细胞的保护作用增强,化合物D-19和化合物D-23在三个浓度下细胞存活率数值基本都是最高的。
实验二:细胞毒性评价实验
选择表1所列化合物评价其在20-80μM范围内对AHH-1细胞的毒性。
取对数生长的AHH-1细胞,轻轻吹打使细胞均匀悬浮,使用细胞计数仪计数,用培养基调整细胞密度为1.5×105个/mL。将细胞接种到96孔板中,每孔100μL,即每孔15000个细胞,96孔板最外圈的孔用200μL纯净水填充。设置阴性对照组,待测化合物组。细胞培养3h后,阴性对照组加入含DMSO的培养液50μL(按6μL DMSO分散于194μL培养基的比例配置),待测化合物组分别加入配好的60μM、120μM、180μM和240μM待测化合物溶液50μL(配制过程同实验一),化合物终浓度分别为20μM、40μM、60μM和80μM。每组设置3个复孔。另取96孔板设置空白组,每孔加入含DMSO的培养液150μL(比例同前)。
将接种有细胞的96孔板和空白组96孔板置于37℃,5%二氧化碳(CO2)的恒温培养箱中培养24h。按照CCK-8试剂盒(商购)的说明配制一定量的培养基稀释的CCK-8溶液(培养基与CCK-8原液(试剂盒自带)体积比为38:12),每孔加入50μL CCK-8溶液。于5%二氧化碳恒温培养箱中孵育3小时,用酶标仪检测450nm下的吸光度(OD)值。
细胞存活率通过以下公式计算:存活率(%)=(待测化合物OD值-空白组OD值)/(阴性对照组OD值-空白组OD值)×100%,细胞存活率采用平均值±标准差表示,存活率数据的组间比较采用SPSS 13.0软件进行单因素方差分析,P<0.05表示差异有显著统计学意义。以D-5、D-18、D-19、D-22、D-23、D-24、D-25、D-26和D-27为例,实验结果见表5。
表5化合物对AHH-1细胞增殖的影响
实验结果表明,在20-80μM范围内,随着化合物浓度的增加AHH-1细胞的增殖受到抑制。化合物浓度为20-60μM时,表5中化合物对AHH-1细胞的增殖影响不大。
实验三:辐照小鼠30天存活实验
选择表1所列化合物开展辐照小鼠30天存活实验,阳性药物选择Ex-RAD和尼尔雌醇。成年雄性C57/BL小鼠由北京斯贝福生物科技有限公司繁殖,小鼠体重为20~22g,实验动物许可证号:SCXK(京)2019-0010。小鼠在SPF级实验室饲养,每只笼子5只小鼠,饲以专门为小鼠配制的饲料,自由饮水,动物实验室温度保持在25℃,相对湿度在40%-70%,每天日照12小时。溶媒为含20wt%羟丙基-β-环糊精(HPCD)的生理盐水,Ex-RAD用溶媒配制成浓度为30mg/mL的溶液;尼尔雌醇用溶媒配制成浓度为0.5mg/mL的溶液;化合物用溶媒配制成浓度为20mg/mL的悬浊液。
以化合物D-19和D-23为例,实验设置辐射对照组(给予含20%HPCD的生理盐水),尼尔雌醇组5mg/kg和Ex-RAD组300mg/kg(阳性对照组),200mg/kg D-19组以及200mg/kg D-23组。辐射对照组、D-19组、D-23组以及Ex-RAD组采用腹腔注射给药,于照射前24小时和15min各给药一次,每次0.2mL/只,尼尔雌醇组采用灌胃给药方式,于照射前24小时给药一次,每次0.2mL/只。辐照射线为60Goγ射线,辐照剂量为8.6Gy,照射剂量率55.69cGy/min,照射方式为全身照射。观察小鼠30天存活情况,以辐照当天为0天,观察小鼠从0天到30天的存活情况,从照射当天为0天,于照射后的1,4、7、10、14、18、22、30天,称量小鼠的体重,记录小鼠30天体重变化。
小鼠体重和存活率数据采用GraphPad Prism 5软件进行统计分析,实验结果均采用表示,组间差异采用单因素方差分析,P<0.05表示差异具有显著统计学意义,结果见表6和表7。
表6小鼠30天存活实验
组别 | 照前小鼠只数 | 30天小鼠只数 | 小鼠存活率 |
辐射对照组 | 10 | 0 | 0% |
尼尔雌醇组 | 10 | 5 | 50% |
Ex-RAD组 | 10 | 2 | 20% |
D-19组 | 10 | 7 | 70% |
D-23组 | 10 | 2 | 20% |
由图1、表6可以看出,在给予全身8.6Gy的照射后,辐射对照组小鼠在10天内迅速死亡(结合表7);阳性药Ex-RAD组小鼠辐照后30天存活率为20%,尼尔雌醇组小鼠辐照后30天存活率为50%,D-23组存活率为20%,D-19组存活率为70%。与辐射对照组相比,化合物D-19对小鼠生存曲线进行统计学分析,采用graphpad进行计算,差异具有统计学意义(p=0.0027),说明化合物D-19能显著提高辐照后小鼠的存活率,具有一定的抗辐射效果。
表7受辐照小鼠30天体重变化表
由表7受辐照小鼠30天体重变化表可知,在照射后0-10天,各组小鼠体重持续降低,其中Ex-RAD组体重降低持续至第18天,化合物D-19组和D-23组体重降低分别持续至第7天和第10天。之后各给药组小鼠体重开始恢复,至22天基本恢复至照射前水平。其中D-19组的小鼠体重在照射后第10天至第30天,体重增长幅度显著大于Ex-RAD组。该结果表明D-19在200mg/Kg剂量下具有较好的辐射保护作用,可以有效提高受到致死剂量辐射照射小鼠的存活率和恢复速度。
实验四:化合物对辐照小鼠血象影响实验
选择D-19开展辐照小鼠30天血象变化实验,阳性药物选择Ex-RAD和尼尔雌醇。成年雄性C57/BL小鼠由北京斯贝福生物科技有限公司繁殖,小鼠体重为18~20g,实验动物许可证号:SCXK(京)2019-0010。小鼠在SPF级实验室饲养,每只笼子5只小鼠,饲以专门为小鼠配制的饲料,自由饮水,动物实验室温度保持在25℃,相对湿度在40%-70%,每天日照12小时。溶媒为含20wt%羟丙基-β-环糊精(HPCD)的生理盐水,Ex-RAD用溶媒配制成浓度为30mg/mL的溶液;尼尔雌醇用溶媒配制成浓度为0.5mg/mL的溶液;D-19用溶媒配制成浓度为30mg/mL的悬浊液。
实验设置辐射对照组(给予含20%HPCD的生理盐水),尼尔雌醇组5mg/kg和Ex-Rad组300mg/kg(阳性药组),D-19组300mg/kg。辐射对照组、D-19组以及Ex-Rad组采用腹腔注射给药,于照射前24小时和15min各给药一次,每次0.2mL/只,尼尔雌醇组采用灌胃给药方式,于照射前24小时给药一次,每次0.2mL/只。辐照射线为60Goγ射线,辐照剂量为6.0Gy,照射剂量率72.81cGy/min(选定适宜的辐照条件以确保辐照对照组小鼠在实验期间能存活),照射方式为全身照射。以辐照当天为0天计算,分别于照射前、照射后第1、4、7、10、14、18、22、30天对小鼠进行尾静脉采血,检测外周血白细胞计数,红细胞计数,血红蛋白含量和血小板计数。实验结果表8-表11。
表8辐照后30天小鼠白细胞计数
表8数据表明,辐照后第1、4天,各组小鼠白细胞数大幅降低。在辐照后第7、10、14和18天,辐射对照组、Ex-RAD组以及尼尔雌醇组的小鼠白细胞数变化不明显,而D-19组白细胞数一直在升高,且从辐照后第7天至第22天该组白细胞数升高幅度都显著高于辐射对照组和Ex-RAD组。在辐照后30天,各组小鼠白细胞明显升高,但数据差异无统计学意义。
表9辐照后30天小鼠红细胞含量
表9数据表明,辐照后各组小鼠的红细胞数大幅降低,辐照后第18、22和30天各组红细胞数开始回升。其中给药组D-19表现突出,在第1、4、7、10、14、18和22天,红细胞数显著高于辐射照射组和Ex-RAD组,且D-19组红细胞数回升速率明显高于其它各组。
表10辐照后30天小鼠血红蛋白含量
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表10数据表明,辐照后第1、4、7、10和14天,辐射对照组和Ex-RAD组小鼠血红蛋白含量快速降低,第18天开始回升。D-19以及尼尔雌醇组小鼠血红蛋白含量在第10天开始回升,且在第10、14和18天的血红蛋白含量显著高于辐射对照组。
表11辐照后30天小鼠血小板计数
表11数据表明,辐照后第1、4和7天,各组小鼠血小板数大幅降低。辐射对照组和Ex-RAD组小鼠血小板数在辐照后10天内持续降低。尼尔雌醇组小鼠血小板数在第10、14和18天显著高于辐射对照组。D-19组小鼠血小板数在第10、14天显著高于辐射对照组和Ex-RAD组。
对辐照小鼠30天血象的白细胞计数、红细胞计数、血红蛋白含量和血小板计数结果进行分析,发现辐照后各指标均经历下降期和恢复期,在第30天各指标恢复至照前水平,说明6.0Gy的全身照射在照射后30天内对小鼠的造血系统造成了损伤,但并不致命。与辐射对照组相比,尼尔雌醇组、D-19组可以显著改善这4项指标,其中化合物D-19组表现较为突出,说明其对辐照后小鼠的造血系统的恢复具有促进作用,具有开发为抗辐射药物的潜力。
以上所述仅是本发明的优选实施方式,应当指出的是,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,其结构为式Ⅰ:
其中,R1选自H、卤素、烷氧基;R2、R3、R4、R5独立选自H、卤素、烷基、烷氧基、NO2中任意一个。
2.根据权利要求1所述取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,所述烷基为甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基;优选甲基、乙基或叔丁基;
所述烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基或叔丁氧基;优选甲氧基、乙氧基或叔丁氧基。
3.根据权利要求1或2所述取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,R1选自卤素、烷氧基;R2、R4、R5独立选自H、卤素、烷基中任意一个;R3选自H、卤素、烷基、烷氧基、NO2。
4.根据权利要求1或2所述取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,R1选自H;R2选自卤素;R3选自H、卤素、烷基、烷氧基、NO2;R4、R5独立选自H、卤素、烷基中任意一个。
5.根据权利要求1或2所述取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,R1、R2选自H;R3选自卤素;R4选自H、烷基;R5选自H、卤素、烷基、烷氧基;
优选的,R1、R2选自H;R3选自卤素;R4选自H;R5选自H、卤素、烷基;或
优选的,R1、R2选自H;R3选自卤素;R4选自烷基;R5选自H、卤素、烷氧基。
6.根据权利要求1或2所述取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,R1、R2、R3选自H;R4、R5选自卤素。
7.根据权利要求1-6任一所述取代2H-苯并吡喃-3-甲酰苯胺类化合物,其特征在于,包括以下中的任何一种:
N-(4-氟-2-甲氧基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2-氟-4-氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,3,4-三氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4’-氟-2’-甲基苯基-)-2H-苯并吡喃-3-甲酰胺;
N-(2’,4’-二氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4,5-三氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2-甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(3-氟-4-氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-溴苯基)-2H-苯并吡喃-3-甲酰胺;
N-(3,5-二甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二甲氧基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2-氟-4-硝基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(3-氯-2-甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-氯-3-甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-氟苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,3-二甲基苯基)-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二氯苯基)-2H-苯并吡喃-3-甲酰胺;
N-(4-溴苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺;
N-(4-氟苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二氟苯基)-7-甲氧基-2H-苯并吡喃-3-甲酰胺;
N-(4-溴苯基)-7-溴-2H-苯并吡喃-3-甲酰胺;
N-(4-氟苯基)-7-溴-2H-苯并吡喃-3-甲酰胺;
N-(2,4-二氟苯基)-7-溴-2H-苯并吡喃-3-甲酰胺。
8.一种组合物,包括权利要求1-7任一所述取代2H-苯并吡喃-3-甲酰苯胺类化合物、其几何异构体、其药学上可接受的盐、其水合物或其溶剂化合物,以及药用载体或赋形剂。
9.一种制备权利要求1-7任一所述取代2H-苯并吡喃-3-甲酰苯胺类化合物的方法,其特征在于,步骤如下:
步骤(1):将式Ⅱ化合物与二氯亚砜加热回流,至式Ⅱ化合物完全转化,反应式见式1,减压蒸干,将残余物溶解于适当溶剂,制成反应液A;
步骤(2):将式Ⅲ的化合物溶解于适当溶剂,并加入有机碱,制成反应液B;
步骤(3):将反应液B置于冰浴下搅拌,滴加反应液A,然后室温反应至完全,得式I所示化合物;
所述溶剂优选二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺和吡啶;所述有机碱优选4-二甲氨基吡啶、三乙胺、吡啶和N-甲基吗啉。
10.权利要求1-7任一所述取代2H-苯并吡喃-3-甲酰苯胺类化合物或权利要求8所述组合物在制备预防和/或治疗辐射损伤药物中的应用。
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