CN117105763A - 卤代查尔酮杂环衍生物、其制法及药物组合物与用途 - Google Patents
卤代查尔酮杂环衍生物、其制法及药物组合物与用途 Download PDFInfo
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Abstract
本发明属于医药领域,公开了卤代查尔酮衍生物、其制法及药物组合物与用途。具体涉及一类如通式(I)所示的卤代查尔酮衍生物及其医学上可接受的盐,及该类化合物单体或药用组合物在制备炎症和/或炎症免疫相关疾病治疗药物中的应用。
Description
技术领域
本发明属于医药领域,具体涉及到一类卤代查尔酮衍生物或其医学上可接受的盐、含有这些衍生物的药用组合物及其在炎症和/或炎症免疫相关疾病的临床治疗中的应用。
背景技术
炎症是人类疾病的病症基础,与疾病的众多病变互为因果,为疾病病理过程的关键环节。然而,当前抗炎药物,如皮质激素类和非甾体类抗炎药,临床应用中仍存在较多的问题,如易引起消化道不适、出血,增加心脏病或全身凝血障碍性疾病发生等不良反应风险。因此,寻找更为安全有效的抗炎药物仍是当前抗炎药物研究与开发的重要任务。
以活性天然产物为基础研发新药,是现代药物研发的重要途径之一。天然产物及其类似物具有来源广泛、毒性低和副作用小等特点。从传统中草药中发现具有显著活性的天然先导化合物,通过结构修饰,结合系统的体内外活性测试以及成药性综合评价,从中寻找安全高效的候选化合物作为临床上有用的原型药物,是药物研究开发的重要方向。
查耳酮是一类具有多种生物活性的重要天然产物。从生源上看,该类化合物由芳香醛酮发生交叉羟醛缩合产生。查尔酮类化合物显示有多种多样的药理活性。文献报道其具有抗肿瘤、抗寄生虫、抗HIV、抗菌、抗炎、抗氧化、清除自由基、抗胃溃疡、抑制磷酸二酯酶以及抗脱发、促进毛发再生等多种生物活性。文献报道,富含查尔酮的植物长期用于多种疾病的治疗中。从不同植物中分离发现的不同结构的查尔酮类化合物已被用于癌症、病毒和心血管相关疾病的治疗中。例如,甘草在中国被用于治疗胃和十二指肠溃疡、支气管哮喘、食物中毒和药物中毒,以及湿疹和荨麻疹等皮肤病。生长于南太平洋地区且富含查尔酮的植物卡瓦胡椒(Piper Thystium),具有显著的抗炎、抗氧化和肝保护作用,可用于多种疾病的治疗。东南亚地区常用的食品香料圆形肉豆蔻(Boesenbergia Rotunda)是一种多用途的民间药物。Lophira alata是一种生长在非洲热带雨林中的富含查尔酮二聚体的药用植物,用于治疗牙痛、肝脏感染、女性不育、发烧和其他疾病。从有机合成的角度分析,查尔酮的α,β烯酮结构是软亲电试剂,更倾向于和巯基化合物这类软亲核试剂发生相互作用,而不是和核酸中的硬亲核试剂如氨基、羟基反应而导致突变或癌症,因而具有较高的安全性。因此,对活性查尔酮类化合物进行深入的活性和构效关系研究,对开发和利用该类化合物具有重要意义。
卤代查尔酮衍生物是我们在长期对多酚类化合物进行合成及构效关系研究中发现的一类新结构类型的活性化合物,为天然产物查尔酮的类似物。本专利对该类化合物进行了系统的结构改造和炎症因子NO抑制活性筛选实验,结果显示,以多环芳烃或芳杂环环取代2′-卤代查尔酮的B环,显著地提高了该类化合物的活性,所得化合物在动物模型上显示显著的体内抗炎活性,具有显著的开发研究潜力,本发明对深入开发利用该类化合物有重要意义。
发明内容
本发明要解决的技术问题是,提供一类新结构的卤代查尔酮衍生物及其制法、药物组合物与用途。
本发明技术方案的第一方面是提供一种如通式(I)、(II)、(IIA)、(IIB)、(III)、(IIIA)、(IIIB)、(IV)、(IVA)、(IVB)、(V)、(VI)、(VII)和(VIII)所示的新结构2′-卤代查尔酮衍生物。
本发明技术方案的第二方面是提供一种药物组合物,其中包括至少一个如通式(I)、(II)、(IIA)、(IIB)、(III)、(IIIA)、(IIIB)、(IV)、(IVA)、(IVB)、(V)、(VI)、(VII)和(VIII)所示的卤代查尔酮衍生物、或其药学上可接受的盐和制药领域中常用的载体。
本发明技术方案的第三方面是提供如通式(I)、(II)、(IIA)、(IIB)、(III)、(IIIA)、(IIIB)、(IV)、(IVA)、(IVB)、(V)、(VI)、(VII)和(VIII)所示的卤代查尔酮衍生物或其药学上可接受的盐,在制备用于预防、治疗和辅助治疗各种炎症免疫相关疾病的药物中的应用。
本发明技术方案的第四方面是提供第一方面所述衍生物的制备方法。
所述的各种炎症免疫疾病包括:类风湿性关节炎、骨关节炎、风湿性关节炎、痛风性关节炎、红斑狼疮综合症、支气管炎、滑囊炎、腱鞘炎、牛皮癣、湿疹、烧伤、皮炎、炎性肠病、克劳恩病、胃炎、过敏性肠综合症、溃疡性结肠炎、多发性硬化症、自身免疫性脑脊髓炎、结肠直肠癌、结节性动脉炎、甲状腺炎、风热湿、牙龈炎、牙周炎、口腔溃疡、肾炎、损坏后发生的肿胀、心肌缺血、各种感染性肺炎、理化性肺炎以及变态反应性肺炎、痉挛性肛部痛和直肠裂、肝胆囊炎、胆管炎、硬化性胆管炎或原发性胆汁性肝硬变和胆囊炎。本发明所述的化合物包括其衍生物和药效学上可接受的盐。
具体而言,本发明涉及如通式(I)所示的卤代查尔酮衍生物,或其药学上可接受的盐:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R选自取代或未取代的萘基、取代或未取代的喹啉基、取代或未取代的吡啶基、取代或未取代的吲哚基、取代或未取代的呋喃基、取代或未取代的苯并呋喃基、取代或未取代的吡咯基、取代或未取代的咔唑基;其中所述萘基、喹啉基、吡啶基、吲哚基、呋喃基、苯并呋喃基、吡咯基、咔唑基的取代基选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、亚甲二氧基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;取代类型包括单取代,二取代,三取代或四取代;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(I)所示的卤代查尔酮衍生物,包括但不限定于通式(II)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(II)所示:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R3选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(II)所示的卤代查尔酮衍生物,包括但不限定于通式(IIA)和(IIB)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(IIA)和(IIB)所示:
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R3选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(I)所示的卤代查尔酮衍生物,包括但不限定于通式(III)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(III)所示:
其中,X选自F、Cl、Br、I;
R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R4选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(III)所示的卤代查尔酮衍生物,包括但不限定于通式(IIIA)和(IIIB)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(IIIA)和(IIIB)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R4选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(I)所示的卤代查尔酮衍生物,包括但不限定于通式(IV)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(IV)所示:
其中,X选自F、Cl、Br、I;
R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(IV)所示的卤代查尔酮衍生物,包括但不限定于通式(IVA)和(IVB)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(IVA)和(IVB)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(I)所示的卤代查尔酮衍生物,包括但不限定于通式(V)、(VI)和(VII)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(V)、(VI)和(VII)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R5和R6各自独立地选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
根据本发明,优选的通式(I)所示的卤代查尔酮衍生物,包括但不限定于通式(VIII)所示的化合物,及其药学上可接受的盐,其特征在于,所述化合物如通式(VIII)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R7选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
具体来说,通式((I)、(II)、(IIA)、(IIB)、(III)、(IIIA)、(IIIB)、(IV)、(IVA)、(IVB)、(V)、(VI)、(VII)和(VIII)所示的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物选自如下群组(化合物代号对应于实施例中的化合物代号):
本发明技术方案的第二方面是提供了一种含有药物有效剂量的如通式(I)、(II)、(IIA)、(IIB)、(III)、(IIIA)、(IIIB)、(IV)、(IVA)、(IVB)、(V)、(VI)、(VII)和(VIII)各情况所述的化合物和药学上可接受的载体的药物组合物。
根据本发明,本发明化合物可以以异构体的形式存在,而且通常所述的“本发明化合物”包括该化合物的异构体。
根据本发明的实施方案,所述的本发明化合物还包括其药学上可接受的盐、盐的水合物或前体药物。
本发明还涉及含有作为活性成分的本发明化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1~95%重量的本发明化合物。在单元剂型中本发明化合物一般含量为0.1~100mg,优选的单元剂型含有4~50mg。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时,如果需要,可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔黏膜、皮肤、腹膜或直肠等。本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其它剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂,也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
例如为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子,如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、单硬脂酸甘油酯、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将本发明化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇酯、脂肪酸等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明中药学成份的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围:本发明的化合物的用量为0.001~100mg/kg体重,优选为0.1~60mg/kg体重,更优选为1~30mg/kg体重,最优选为2~15mg/kg体重。成人患者服用的本发明化合物每日为10~500mg,优选为10~100mg,可一次服用或分2~3次服用;儿童服用的剂量按照每kg体重5~30mg,优选为10~20mg/kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药,这受限于给药医生的临床经验以及治疗手段的给药方案。本发明的化合物或组合物可单独服用,或与其它治疗药物或对症药物合并使用。
本发明技术方案的第三方面是提供一类卤代查尔酮衍生物及其药学上可接受的盐、盐的水合物或前体药物在制备炎症免疫相关疾病药物中的应用。
所述的炎症免疫疾病包括、风湿性关节炎、痛风性关节炎红斑狼疮综合症、支气管炎、滑囊炎、腱鞘炎、牛皮癣、湿疹、烧伤、皮炎、炎性肠病、克劳恩病、胃炎、过敏性肠综合症、溃疡性结肠炎、多发性硬化症、自身免疫性脑脊髓炎、结肠直肠癌、结节性动脉炎、甲状腺炎、风湿热、牙龈炎、牙周炎、口腔溃疡、肾炎、损坏后发生的肿胀、心肌缺血、各种感染性肺炎、理化性肺炎以及变态反应性肺炎、痉挛性肛部痛和直肠裂、肝胆囊炎、胆管炎、硬化性胆管炎、原发性胆汁性肝硬变和胆囊炎等。
炎症免疫性疾病在细胞水平上的普遍特征表现为:巨噬细胞过度活化,产生过量NO。因此,本发明进行了化合物对LPS诱导的原代小鼠腹腔巨噬细胞NO生成的抑制实验,从细胞水平上说明2′-卤代查尔酮衍生物具有抑制巨噬细胞NO生成的活性。
本发明技术方案的第四方面是提供第一方面所述衍生物的制备方法。
用于制备本发明化合物的原料,如3,5-二羟基苯乙酮等可通过商业购买获得,关键中间体1a和1c可参考文献[Adv.Synth.Catal.2019,361,3768-3776]的方法制备获得,关键中间体1b可参考文献[Chem.Eur.J.2015,21,11976-11979]的方法制备获得。关键中间体化合物1a~1c的基本合成方法包括如下步骤:
步骤一、3,5-二羟基苯乙酮与氯甲基甲醚反应制备MOM保护二个羟基的3,5-二羟基苯乙酮中间体(1a)。
3,5-二羟基苯乙酮在二氯甲烷溶液中,以DIPEA为催化剂,与氯甲基甲醚在室温条件下反应,反应产物经分离制备得到MOM保护二个羟基的3,5-二羟基苯乙酮化合物1a。
步骤二、化合物1a与NCS进行氯代反应制备其氯代产物(1b)。
步骤一所得产物1a在DMF中与NCS在室温下进行氯代反应,反应混合物经分离制备得到其氯代产物1b。
步骤三、化合物1a与NBS进行溴代反应制备其溴代产物(1c)。
步骤一所得产物1a在DMF中与NBS在室温下进行溴代反应,反应混合物经分离制备得到其溴代产物1c。
本发明所述化合物的基本合成方法包括如下步骤:
步骤一、氯代产物1b或溴代产物1c与取代或未取代的苯甲醛衍生物通过羟醛缩合反应制备相应结构的卤代查尔酮衍生物。
氯代产物1b或溴代产物1c与取代或未取代的苯甲醛衍生物在甲醇水混合溶液中,以NaOH为催化剂,在室温下进行羟醛缩合反应合成相应的MOM保护羟基的卤代查尔酮衍生物。
步骤二、MOM保护羟基的卤代查尔酮衍生物在酸性条件下全部或部分脱除MOM保护基制备相应的羟基衍生物。
MOM保护羟基的卤代查尔酮衍生物在甲醇溶液中与氢溴酸在50℃下进行反应,所得产物经分离制备得到全部或部分羟基脱除MOM保护基的卤代查尔酮衍生物。
有益技术效果
本发明的发明人在天然产物全合成和活性研究的过程中,发现天然产物衍生物2′-溴代查尔酮具有较强的抗炎活性。在此基础上,以芳杂环或多环芳烃取代查尔酮的B环,进一步对卤代查尔酮进行了合成和结构衍生化修饰,合成了一系列B环不同结构的查尔酮衍生物,并对所得到的衍生物进行了炎症抑制活性评价,获得了对炎症具有显著体内抑制活性的新结构化合物。研究所得查尔酮衍生物为一类新型结构的活性化合物,具有进一步开发成为治疗炎症相关疾病新药的潜在应用价值。迄今为止,该类化合物的结构及活性研究未见有文献报道过。现有文献和技术中未见关于查尔酮衍生物或其医学上可接受的盐,及该类化合物用于治疗炎症性疾病的报道。因此,本发明的内容具有显著的创新性。
发明详述:
本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。
以下提供本发明化合物各种基团的定义,除另行定义外,它们在说明书和权利要求书中统一使用。
本发明所提及的术语“烷基”是指具有指定数目碳原子数的烷基,其可以为直链或支链的烷基,例如提及的“C3-6的环烷基”是指碳原子数为3、4、5、6的取代或未取代的环烷基,可以包括C3-5环烷基、C3-4环烷基、C4-6环烷基、C4-5环烷基、C5-6环烷基等表示的子范围的基团,以及优选的具体基团,例如环丙烷基、环戊烷基以及环己烷基。
本发明所提及的术语“C1-6的烷基”是指碳原子数为1、2、3、4、5、6的直链或支链烷基,可以包括C1-5烷基、C1-4烷基、C2-5烷基、C2-4烷基、C2-3烷基、C3-5烷基等表示的子范围的基团,以及优选的具体基团,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基等。
本发明所提及的术语“C1-6烷氧基”是指碳原子数为1、2、3、4、5、6的烷氧基,包括C1-5烷氧基、C1-2烷氧基、C2-4烷氧基、C2-3烷氧基、C3-4烷氧基等表示的子范围的基团,以及优选的具体基团例如甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、仲丁基氧基、叔丁基氧基等。
本发明所提及的术语“C1-6不饱和烷基”是指碳原子数为1、2、3、4、5、6的不饱和烷基,可以包括C1-5的不饱和烷基、C1-4的不饱和烷基、C2-5的不饱和烷基、C2-4的不饱和烷基等表示的子范围的基团,以及优选的具体基团,例如乙烯基、乙炔基、异丙烯基、异丙炔基、异丁烯基、异戊烯基、1,4-二丁烯基。
本发明所提及的术语“C1-6的酰基”是指碳原子数为1、2、3、4、5、6的酰基,可以包括C1-5酰基、C1-3酰基、C2-5酰基、C2-3酰基、C3-4酰基等表示的子范围的基团,以及优选的具体基团,例如甲酰基、乙酰基、丙酰基等。
本发明所提及的“C1-6的酰氧基”是指碳原子数为1、2、3、4、5、6的直链或支链酰氧基,可以包括C1-5酰氧基、C1-3酰氧基、C2-5酰氧基、C2-3酰氧基、C3-4酰氧基等表示的子范围的基团,以及优选的具体基团,例如甲酰氧基、乙酰氧基、丙酰氧基等。
本发明所提及的“C1-6的烷氧酰基”是指碳原子数为1、2、3、4、5、6的烷氧酰基,可以包括C1-5烷氧酰基、C1-3烷氧酰基、C2-5烷氧酰基、C2-3烷氧酰基、C3-4烷氧酰基等表示的子范围的基团,以及优选的具体基团,例如甲氧酰基、乙氧酰基等;
本发明所提及的术语“C1-6的烷硫基”是指碳原子数为1、2、3、4、5、6的直链或支链烷硫基,可以包括C1-5烷硫基、C1-3烷硫基、C2-5烷硫基、C2-3烷硫基、C3-4烷硫基等表示的子范围的基团,以及优选的具体基团,例如甲硫基、乙硫基等。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
化合物1a,1b和1c的制备方法:
步骤一、3,5-二羟基苯乙酮10g(65.79mmol)溶解于300ml二氯甲烷中,室温搅拌下加入DIPEA(43.42ml,263mmol),缓慢滴加氯甲基甲醚液体(21.2g,263mmol),保持室温搅拌10h,TLC检测反应完全,停止反应。向反应液中加入300ml水,以二氯甲烷萃取,有机相依次以5%氢氧化钠溶液洗涤,饱和氯化钠溶液洗涤,无水硫酸镁干燥,减压抽虑,滤液减压浓缩。所得无色油状液体以200-300目硅胶进行柱层析分离,石油醚:丙酮(10:1)洗脱,得无色油状液体化合物1a(15.78g,产率80%)。化合物1a的理化常数如下:
化合物1a:无色油状液体,1H NMR(500MHz,acetone-d6):δ:7.26(d,J=2.29Hz,2H),6.93(t,J=2.27Hz,1H),5.19(s,4H),3.48(s,3H),2.56(s,3H);(+)-ESI-MS:m/z263.0[M+Na]+.
步骤二、化合物1a(0.7g,2.917mmol)溶解于20ml干燥的CH2Cl2中,搅拌下加入2,4,6-三甲基苯胺(40mg,0.29mmol),NCS(0.467g,3.5mmol),避光室温反应12h,停止反应。反应液中加入15ml水,二氯甲烷萃取,有机相以饱和氯化钠溶液洗涤,无水硫酸镁干燥,减压浓缩,所得固体以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(40:1:3)洗脱,得油状液体1b(0.712g,产率89%)。化合物1b的理化常数如下:
化合物1b:油状液体,1H NMR(400MHz,Acetone-d6)δH:7.02(d,J=2.7Hz,1H),6.85(d,J=2.7Hz,1H),5.32(s,2H),5.23(s,2H),3.49(s,3H),3.44(s,3H),2.55(s,3H).13C NMR(400MHz,Acetone-d6)δC:199.68,156.84,154.03,142.11,112.05,108.33,106.64,95.30,94.62,55.80,55.51,29.98.(+)-ESI-MS:m/z 297.0[M+Na]+.
步骤三、化合物1a(0.7g,2.917mmol)溶解于40ml干燥的DMF中,搅拌下加入NBS(0.519g,2.916mmol),避光室温搅拌反应8h,停止反应。反应液中加入50ml水,乙酸乙酯萃取,有机相以饱和氯化钠溶液洗涤,无水硫酸镁干燥,减压浓缩,所得固体以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(40:1:3)洗脱,得油状液体1c(0.6g,产率64.5%)。化合物1c的理化常数如下:
化合物1c:无色油状液体,1H NMR(500MHz,DMSO-d6)δH:7.46(s,1H),7.28(s,1H),5.80(s,2H),5.71(s,2H),3.98(s,3H),3.93(s,3H),3.02(s,3H).13C NMR(500MHz,DMSO-d6)δC:201.17,158.18,155.31,145.25,108.59,106.36,100.36,95.69,95.03,56.28,55.97,30.23.(+)-ESI-MS:m/z 341.0[M+Na]+.
实施例1:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(5-氯呋喃-2-基)-(2E)-2-丙烯-1-酮(1)
化合物1的合成路线:
化合物1b 860mg(3.13mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体125mg(1.2eq)。室温搅拌10分钟,加入化合物5-氯-2-糠醛408mg(3.13mmol),搅拌下继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:3)洗脱,得黄色油状液体1(1.08g,89%)。化合物1的理化参数如下:
化合物1:黄色油状液体(yield=89%);1H NMR(400MHz,Acetone-d6)δ7.20(d,J=16.0Hz,1H),7.03(d,J=2.7Hz,1H),7.02(d,J=3.6Hz,1H),6.83(dd,J=15.9,0.6Hz,1H),6.78(d,J=2.7Hz,1H),6.56(d,J=3.6Hz,1H),5.32(s,2H),5.23(s,2H),3.49(s,3H),3.44(s,3H).13C NMR(400MHz,Acetone-d6)δ191.94,156.83,153.96,150.83,140.92,139.51,130.76,123.56,119.16,112.50,110.18,108.68,106.40,95.23,94.60,55.78,55.48.(+)-HR ESIMS:m/z=387.0391,calcd for C17H17O6Cl2[M+H]+:387.0396.
实施例2:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(5-甲基呋喃-2-基)-(2E)-2-丙烯-1-酮(2)
化合物2的合成路线:
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入5-甲基-2-糠醛220mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:3)洗脱,得无色油状液体2(638mg,87%)。
化合物2:无色油状液体(yield=87%);1H NMR(500MHz,Acetone-d6)δ7.16(d,J=15.8Hz,1H),7.02(d,J=2.7Hz,1H),6.84(d,J=3.4Hz,1H),6.77–6.69(m,2H),6.26(d,J=3.3Hz,1H),5.32(s,2H),5.22(s,2H),3.49(s,3H),3.44(s,3H),2.36(s,3H).13C NMR(400MHz,Acetone-d6)δ192.18,156.81(C×2),153.91,149.59,141.36,132.20,121.74,119.15,112.40,109.67,108.57,106.11,95.23,94.60,55.76,55.46,12.93.(+)-HRESIMS:m/z=367.0941,calcd for C18H20O6Cl[M+H]+:367.0942.
实施例3:
1-(2-氯-3,5-二羟基苯基)-3-(5-甲基呋喃-2-基)-(2E)-2-丙烯-1-酮(3)
化合物2 366mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应10小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得无色油状液体化合物3(251mg,90%)。
化合物3:无色油状液体(yield=90%);1H NMR(400MHz,Acetone-d6)δH:8.75(s,1H),8.63(s,1H),7.07(d,J=15.8Hz,1H),6.76(d,J=3.3Hz,1H),6.64(d,J=15.9Hz,1H),6.55(d,J=2.7Hz,1H),6.35(d,J=2.9Hz,1H),6.18(d,J=2.8Hz,1H),2.28(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.57,156.94,156.63,154.20,149.63,141.21,132.05,121.95,118.89,109.60,107.53,106.90,104.78,12.92.(+)-HR ESIMS:m/z=279.0417,calcd forC14H12O4Cl[M+H]+:279.0418.
实施例4:
1-(2-溴-3,5-二甲氧甲基苯基)-3-(5-氯呋喃-2-基)-(2E)-2-丙烯-1-酮(4)
化合物1c 638mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入5-氯-2-糠醛272mg(2mmol),继续反应10h。反应液以30ml水稀释,过滤,甲醇洗涤,所得固体经干燥得白色固体化合物4(766mg,89%)。
化合物4:白色固体(yield=89%);1H NMR(400MHz,Acetone-d6)δH:7.14(d,J=15.9Hz,1H),7.00(d,J=3.5Hz,1H),6.97(d,J=2.6Hz,1H),6.77(d,J=15.9Hz,1H),6.73(d,J=2.6Hz,1H),6.55(d,J=3.5Hz,1H),5.30(s,2H),5.21(s,2H),3.47(s,3H),3.42(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.88,157.67,154.83,150.83,143.18,139.52,130.91,123.46,119.12,110.18,108.82,105.86,100.99,95.19,94.57,55.80,55.48.(+)-HR ESIMS:m/z=430.9888,calcd for C17H17O6BrCl[M+H]+:430.9891.
化合物5~7的合成方法
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化合物4 431mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得无色油状液体化合物5(116mg,30%),6(97mg,25%)和7(120mg,35%)。
合成终产物5~7(化合物代号对应于实施例中的化合物代号)
实施例5:
1-(2-溴-3-羟基-5-甲氧甲基苯基)-3-(5-氯呋喃-2-基)-(2E)-2-丙烯-1-酮(5)
化合物5:无色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:9.15(s,1H),7.19(d,J=15.9Hz,1H),7.05(d,J=3.5Hz,1H),6.84(d,J=2.0Hz,1H),6.82(d,J=15.7Hz,1H),6.64(d,J=2.7Hz,1H),6.60(d,J=3.5Hz,1H),5.22(s,2H),3.46(s,3H).13CNMR(400MHz,Acetone-d6)δC:193.03,157.63,155.18,150.87,143.05,139.45,130.86,123.54,119.01,110.14,107.69,105.41,98.49,94.44,55.37.(+)-HR ESIMS:m/z=386.9624,calcd for C15H13O5BrCl[M+H]+:386.9629.
实施例6:
1-(2-溴-3-甲氧甲基-5-羟基苯基)-3-(5-氯呋喃-2-基)-(2E)-2-丙烯-1-酮(6)
化合物6:无色油状液体(yield=25%);1H NMR(400MHz,Acetone-d6)δH:8.94(s,1H),7.17(d,J=15.9Hz,1H),7.05(d,J=3.5Hz,1H),6.86(d,J=2.7Hz,1H),6.80(d,J=15.5Hz,1H),6.60(d,J=3.5Hz,1H),6.57(d,J=2.7Hz,1H),5.31(s,2H),3.52(s,3H).13CNMR(400MHz,Acetone-d6)δC:193.09,157.79,154.94,150.84,143.16,139.45,130.82,123.62,119.00,110.14,108.49,104.78,98.32,95.06,55.67.(+)-HR ESIMS:m/z=386.9626,calcd for C15H13O5BrCl[M+H]+:386.9629.
实施例7:
1-(2-溴-3,5-二羟基苯基)-3-(5-氯呋喃-2-基)-(2E)-2-丙烯-1-酮(7)
化合物7:无色油状液体(yield=35%);1H NMR(400MHz,Acetone-d6)δH:8.95(s,1H),8.76(s,1H),7.15(d,J=15.9Hz,1H),7.03(d,J=3.5Hz,1H),6.78(d,J=15.9Hz,1H),6.65(d,J=2.7Hz,1H),6.57(d,J=3.5Hz,1H),6.43(d,J=2.7Hz,1H).13C NMR(400MHz,Acetone-d6)δC:193.25,157.76,155.22,150.88,143.04,139.38,130.78,123.69,118.90,110.11,107.20,104.54,96.05.(+)-HR ESIMS:m/z=342.9368,calcd for C13H9O4BrCl[M+H]+:342.9367.
实施例8:
1-(2-溴-3,5-二甲氧甲基苯基)-3-(5-甲基呋喃-2-基)-(2E)-2-丙烯-1-酮(8)
化合物1c 638mg(2mmol)以30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)溶解,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入5-甲基-2-糠醛220mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:3)洗脱得无色油状液体8(765mg,93%)。
化合物8:无色油状液体(yield=93%);1H NMR(500MHz,Acetone-d6)δH:7.17(d,J=15.9Hz,1H),7.03(d,J=2.7Hz,1H),6.88(d,J=3.3Hz,1H),6.77(d,J=2.7Hz,1H),6.74(d,J=15.8Hz,1H),6.31(d,J=3.3Hz,1H),5.37(s,2H),5.28(s,2H),3.54(s,3H),3.48(s,3H),2.41(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.11,157.63,156.80,154.78,149.59,143.61,132.36,121.63,119.09,109.66,108.71,105.60,100.99,95.18,94.57,55.79,55.47,12.92.(+)-HR ESI MS:m/z=411.0434,calcd for C18H20O6Br[M+H]+:411.0437.
化合物9~11的合成方法
化合物8 411mg(1mmol)溶解于20ml干燥甲醇中,50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得无色油状液体化合物9(110mg,30%),10(92mg,25%)和11(97mg,30%)。
合成终产物9~11(化合物代号对应于实施例中的化合物代号)
实施例9:
1-(2-溴-3-羟基-5-甲氧甲基苯基)-3-(5-甲基呋喃-2-基)-(2E)-2-丙烯-1-酮(9)
化合物9:无色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:9.07(s,1H),7.13(d,J=15.8Hz,1H),6.85(d,J=3.2Hz,1H),6.81(d,J=2.7Hz,1H),6.70(d,J=15.9Hz,1H),6.59(d,J=2.7Hz,1H),6.29–6.24(m,1H),5.20(s,2H),3.44(s,3H),2.37(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.27,157.60,156.72,155.10,149.62,143.49,132.31,121.70,118.97,109.63,107.59,105.13,98.50,94.44,55.35,12.92.(+)-HR ESIMS:m/z=367.0173,calcd for C16H16O5Br[M+H]+:367.0175.
实施例10:
1-(2-溴-3-甲氧甲基-5-羟基苯基)-3-(5-甲基呋喃-2-基)-(2E)-2-丙烯-1-酮(10)
化合物10:无色油状液体(yield=25%);1H NMR(400MHz,Acetone-d6)δH:8.88(s,1H),7.12(d,J=15.8Hz,1H),6.85(d,J=3.3Hz,1H),6.82(d,J=2.7Hz,1H),6.68(d,J=15.8Hz,1H),6.52(d,J=2.7Hz,1H),6.27(dd,J=3.3,0.9Hz,1H),5.29(s,2H),3.50(s,3H),2.37(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.34,157.74,156.72,154.90,149.59,143.59,132.28,121.79,118.96,109.63,108.38,104.52,98.33,95.05,55.66,12.92.(+)-HR ESIMS:m/z=367.0171,calcd for C16H16O5Br[M+H]+:367.0175.
实施例11:
1-(2-溴-3,5-二羟基苯基)-3-(5-甲基呋喃-2-基)-(2E)-2-丙烯-1-酮(11)
化合物11:无色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:8.90(s,1H),8.73(s,1H),7.12(d,J=15.8Hz,1H),6.84(d,J=3.3Hz,1H),6.68(d,J=15.8Hz,1H),6.63(d,J=2.7Hz,1H),6.40(d,J=2.7Hz,1H),6.26(dd,J=3.3,0.9Hz,1H),2.37(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.52,157.71,156.63,155.15,149.62,143.47,132.23,121.86,118.84,109.59,107.07,104.26,96.07,12.92.(+)-HR ESIMS:m/z=322.9911,calcd for C14H12O4Br[M+H]+:322.9913.
实施例12:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(呋喃-2-基)-(2E)-2-丙烯-1-酮(12)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入糠醛192mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得产物混合物以硅胶柱层析分离得无色油状液体12(656mg,93%)。
化合物12:无色油状液体(yield=93%);1H NMR(400MHz,Acetone-d6)δH:7.80(d,J=1.8Hz,1H),7.28(d,J=15.9Hz,1H),7.05(d,J=2.7Hz,1H),6.99(d,J=3.5Hz,1H),6.86(d,J=15.9Hz,1H),6.80(d,J=2.7Hz,1H),6.65(dd,J=3.4,1.8Hz,1H),5.35(s,2H),5.25(s,2H),3.52(s,3H),3.46(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.20,156.82,153.94,150.96,146.21,141.10,132.10,123.33,117.20,112.97,112.47,108.65,106.29,95.23,94.60,55.76,55.46.(+)-HR ESIMS:m/z=353.0782,calcd for C17H18O6Cl[M+H]+:353.0786.
实施例13:
1-(2-氯-3,5-二羟基苯基)-3-(呋喃-2-基)-(2E)-2-丙烯-1-酮(13)
化合物12 353mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应10小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:2)洗脱得无色油状液体化合物13(238mg,90%)。
化合物13:无色油状液体(yield=90%);1H NMR(400MHz,Acetone-d6)δH:8.82(s,1H),8.69(s,1H),7.74(s,1H),7.21(d,J=15.9Hz,1H),6.93(d,J=3.4Hz,1H),6.79(d,J=15.9Hz,1H),6.61(d,J=2.8Hz,1H),6.60–6.58(m,1H),6.41(d,J=2.7Hz,1H).13C NMR(400MHz,Acetone-d6)δC:192.60,156.97,154.24,151.00,146.08,140.96,131.93,123.54,116.97,112.91,107.57,106.98,104.94.(+)-HR ESIMS:m/z=265.0262,calcd forC13H10O4Cl[M+H]+:265.0262.
实施例14:
1-(2-溴-3,5-二甲氧甲基苯基)-3-(呋喃-2-基)-(2E)-2-丙烯-1-酮(14)
化合物1c 638mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入糠醛192mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:2)洗脱得无色油状液体14(739mg,93%)。
化合物14:无色油状液体(yield=93%);1H NMR(400MHz,Acetone-d6)δH:7.75(d,J=1.6Hz,1H),7.20(d,J=15.9Hz,1H),6.97(d,J=2.7Hz,1H),6.93(d,J=3.5Hz,1H),6.78(d,J=15.9Hz,1H),6.73(d,J=2.7Hz,1H),6.60(dd,J=3.6Hz,1.6Hz,1H),5.30(s,2H),5.21(s,2H),3.48(s,3H),3.42(s,3H).13C NMR(101MHz,Acetone-d6)δC:193.17,157.64,154.81,150.95,146.23,143.34,132.28,123.22,117.18,112.98,108.80,105.76,101.01,95.19,94.57,55.81,55.49.(+)-HR ESIMS:m/z=397.0279,calcd for C17H18O6Br[M+H]+:397.0281.
化合物15~17的合成方法
化合物14 397mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得无色油状液体化合物15(123.6mg,35%),16(106mg,30%)和17(93mg,30%)。
合成终产物15~17(化合物代号对应于实施例中的化合物代号)
实施例15:
1-(2-溴-3-羟基-5-甲氧甲基苯基)-3-(呋喃-2-基)-(2E)-2-丙烯-1-酮(15)
化合物15:无色油状液体(yield=35%);1H NMR(500MHz,Acetone-d6)δH:9.09(s,1H),7.78(s,1H),7.23(d,J=16.0Hz,1H),6.97(d,J=3.4Hz,1H),6.82(d,J=2.5Hz,1H),6.81(d,J=16.0Hz,1H),6.65–6.63(m,1H),6.61(d,J=2.5Hz,1H),5.20(s,2H),3.44(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.30,157.62,155.15,150.99,146.16,143.23,132.20,123.29,117.05,112.94,107.66,105.29,98.50,94.44,55.35.(+)-HR ESIMS:m/z=353.0017,calcd for C15H14O5Br[M+H]+:353.0019.
实施例16:
1-(2-溴-3-甲氧甲基-5-羟基苯基)-3-(呋喃-2-基)-(2E)-2-丙烯-1-酮(16)
化合物16:无色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:8.90(s,1H),7.78(d,J=1.7Hz,1H),7.21(d,J=15.9Hz,1H),6.97(d,J=3.5Hz,1H),6.83(d,J=2.7Hz,1H),6.79(d,J=15.9Hz,1H),6.64(dd,J=3.5,1.8Hz,1H),6.54(d,J=2.7Hz,1H),5.29(s,2H),3.50(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.39,157.77,154.92,150.96,146.16,143.34,132.18,123.38,117.04,112.94,108.46,104.66,98.33,95.06,55.67.(+)-HR ESIMS:m/z=353.0016,calcd for C15H14O5Br[M+H]+:353.0019.
实施例17:
1-(2-溴-3,5-二羟基苯基)-3-(呋喃-2-基)-(2E)-2-丙烯-1-酮(17)
化合物17:无色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:8.94(s,1H),8.76(s,1H),7.78(d,J=1.8Hz,1H),7.21(d,J=15.9Hz,1H),6.97(d,J=3.4Hz,1H),6.80(d,J=15.9Hz,1H),6.64(d,J=2.8Hz,1H),6.63(dd,J=3.5,1.8Hz,1H),6.43(d,J=2.7Hz,1H).13C NMR(400MHz,Acetone-d6)δC:193.59,157.75,155.20,150.99,146.09,143.21,132.13,123.45,116.94,112.92,107.14,104.42,96.04.(+)-HR ESIMS:m/z=308.9755,calcd for C13H10O4Br[M+H]+:308.9757.
实施例18:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(1-甲基-1H-吡咯-2-基)-(2E)-2-丙烯-1-酮(18)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入N-甲基吡咯-2-甲醛218mg(2mmol),继续反应10h。停止反应,反应液以30ml水稀释,过滤。所得固体以甲醇洗涤,干燥得黄色固体化合物18(622mg,85%)。
化合物18:黄色固体(yield=85%);1H NMR(500MHz,Acetone-d6)δH:7.47(d,J=15.7Hz,1H),7.04(d,J=2.6Hz,2H),6.89(d,J=3.1Hz,1H),6.82(d,J=2.3Hz,1H),6.80(d,J=10.6Hz,1H),6.22–6.18(m,1H),5.35(s,2H),5.26(s,2H),3.77(s,3H),3.53(s,3H),3.47(s,3H).13C NMR(400MHz,Acetone-d6)δC:191.66,156.67,153.89,142.00,133.53,129.44,128.95,120.29,113.68,112.63,109.63,108.69,106.11,95.23,94.56,55.75,55.44,33.63.(+)-HR ESIMS:m/z=366.1099,calcd for C18H21O5NCl[M+H]+:366.1102.
实施例19:
1-(2-溴-3,5-二甲氧甲基苯基)-3-(1-甲基-1H-吡咯-2-基)-(2E)-2-丙烯-1-酮(19)
化合物1c 638mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入N-甲基吡咯-2-甲醛218mg(2mmol),继续反应10h。反应液以30ml水稀释,过滤,所得固体以甲醇洗涤、干燥,得黄色固体化合物19(697mg,85%)。
化合物19:黄色固体(yield=85%);1H NMR(400MHz,Acetone-d6)δH:7.38(d,J=15.7Hz,1H),6.99–6.97(m,1H),6.94(d,J=2.7Hz,1H),6.83(dd,J=4.0,1.1Hz,1H),6.74–6.68(m,2H),6.16–6.11(m,1H),5.29(s,2H),5.21(s,2H),3.71(s,3H),3.47(s,3H),3.41(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.61,157.50,154.75,144.25,133.65,129.44,128.94,120.16,113.67,109.63,108.83,105.61,101.26,95.18,94.53,55.77,55.45,33.63.(+)-HR ESI MS:m/z=410.0596,calcd for C18H21O5NBr[M+H]+:410.0597.
实施例20:
3-(苯并呋喃-2-基)-1-(2-氯-3,5-二甲氧甲基苯基)-(2E)-2-丙烯-1-酮(20)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入苯并呋喃-2-甲醛292mg(2mmol),继续反应10h。TLC检测反应完全,反应液以30ml水稀释,过滤,所得固体以甲醇洗涤、干燥,得白色固体化合物20(723mg,90%)。
化合物20:白色固体(yield=90%);1H NMR(400MHz,Acetone-d6)δH:7.67(ddd,J=7.8,1.2,0.8Hz,1H),7.55(dq,J=8.4,0.8Hz,1H),7.43–7.39(m,1H),7.42(d,J=15.9Hz,1H),7.33(s,1H),7.27(ddd,J=8.0,7.3,0.9Hz,1H),7.09(dd,J=15.9,0.6Hz,1H),7.04(d,J=2.7Hz,1H),6.82(d,J=2.7Hz,1H),5.32(s,2H),5.22(s,2H),3.49(s,3H),3.43(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.04,156.88,155.75,154.01,152.51,140.90,132.06,128.58,127.12,126.00,123.62,122.18,113.35,112.54,111.32,108.77,106.52,95.26,94.62,55.80,55.50.(+)-HR ESIMS:m/z=403.0938,calcd for C21H20O6Cl[M+H]+:403.0942.
实施例21:
3-(苯并呋喃-2-基)-1-(2-溴-3,5-二甲氧甲基苯基)-(2E)-2-丙烯-1-酮(21)
化合物1c 638mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入苯并呋喃-2-甲醛292mg(2mmol),继续反应10h。反应液以30ml水稀释、过滤,所得固体以甲醇洗涤、干燥,得白色固体化合物21(803mg,90%)。
化合物21:白色固体(yield=90%);1H NMR(400MHz,Acetone-d6)δH:7.67(d,J=7.8Hz,1H),7.56(dd,J=8.4,0.9Hz,1H),7.44–7.40(m,1H),7.39(d,J=15.9,1H),7.33(s,1H),7.30–7.21(m,1H),7.04(dd,J=15.9,0.3Hz,1H),7.00(d,J=2.7Hz,1H),6.78(d,J=2.7Hz,1H),5.32(s,2H),5.23(s,2H),3.49(s,3H),3.42(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.03,157.71,155.76,154.87,152.50,143.14,132.25,128.58,127.13,125.89,123.63,122.18,113.34,111.32,108.91,105.97,101.02,95.21,94.59,55.83,55.51.(+)-HR ESIMS:m/z=447.0435,calcd for C21H20O6Br[M+H]+:447.0437.
化合物22~24的合成方法
化合物21 447mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得无色油状液体化合物22(109mg,27%),23(121mg,30%)和24(107mg,30%)。
合成终产物22~24(化合物代号对应于实施例中的化合物代号)
实施例22:
3-(苯并呋喃-2-基)-1-(2-溴-3-羟基-5-甲氧甲基苯基)-(2E)-2-丙烯-1-酮(22)
化合物22:无色油状液体(yield=27%);1H NMR(400MHz,Acetone-d6)δH:9.16(s,1H),7.71(dt,J=7.8,1.0Hz,1H),7.59(dd,J=8.4,0.8Hz,1H),7.48–7.42(m,1H),7.39(d,J=15.9,1H),7.37(s,1H),7.30(td,J=7.6,0.9Hz,1H),7.08(d,J=16.1Hz,1H),6.85(d,J=2.7Hz,1H),6.68(d,J=2.7Hz,1H),5.22(s,2H),3.45(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.13,157.68,155.75,155.23,152.55,143.04,132.16,128.60,127.07,125.98,123.60,122.16,113.20,111.31,107.79,105.52,98.51,94.46,55.38.(+)-HR ESIMS:m/z=403.0174,calcd for C19H16O5Br[M+H]+:403.0175.
实施例23:
3-(苯并呋喃-2-基)-1-(2-溴-3-甲氧甲基-5-羟基苯基)-(2E)-2-丙烯-1-酮(23)
化合物23:无色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:8.94(s,1H),7.71(ddd,J=7.8,1.2,0.7Hz,1H),7.59(dd,J=8.4,0.8Hz,1H),7.45(ddd,J=8.4,7.2,1.3Hz,1H),7.40(d,J=15.9Hz,1H),7.37(s,1H),7.30(ddd,J=8.0,7.3,0.9Hz,1H),7.06(d,J=15.9Hz,1H),6.87(d,J=2.7Hz,1H),6.60(d,J=2.7Hz,1H),5.31(s,2H),3.51(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.19,157.84,155.75,154.99,152.53,143.14,132.11,128.60,127.07,126.06,123.60,122.16,113.19,111.31,108.56,104.89,98.35,95.08,55.69.(+)-HR ESIMS:m/z=403.0173,calcd for C19H16O5Br[M+H]+:403.0175.
实施例24:
3-(苯并呋喃-2-基)-1-(2-溴-3,5-二羟基苯基)-(2E)-2-丙烯-1-酮(24)
化合物24:无色油状液体(yield=30%);1H NMR(500MHz,Acetone-d6)δH:8.99(s,1H),8.79(s,1H),7.71(d,J=7.8Hz,1H),7.59(d,J=8.3Hz,1H),7.48–7.35(m,3H),7.30(t,J=7.5Hz,1H),7.06(d,J=15.9Hz,1H),6.67(d,J=2.5Hz,1H),6.48(d,J=2.5Hz,1H).13C NMR(400MHz,Acetone-d6)δC:193.35,157.82,155.74,155.28,152.58,143.02,132.05,128.61,127.02,126.13,123.58,122.14,113.08,111.30,107.27,104.66,96.06.(+)-HR ESIMS:m/z=358.9910,calcd for C17H12O4Br[M+H]+:358.9913.
实施例25:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(萘-2-基)-(2E)-2-丙烯-1-酮(25)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入化合物2-萘甲醛312mg(2mmol),继续反应10h。反应液以30ml水稀释,过滤,所得固体以甲醇洗涤、干燥,得白色固体化合物25(669mg,81%)。
化合物25:白色固体(yield=81%);1H NMR(400MHz,Acetone-d6)δH:8.16(d,J=1.7Hz,1H),7.94(d,J=8.6Hz,2H),7.92–7.88(m,2H),7.61(d,J=16.2Hz,1H),7.58–7.50(m,2H),7.23(d,J=16.2Hz,1H),7.04(d,J=2.7Hz,1H),6.81(d,J=2.7Hz,1H),5.32(s,2H),5.23(s,2H),3.49(s,3H),3.43(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.80,156.84,153.97,146.16,141.32,134.60,133.47,132.18,130.93,128.79,128.71,127.78,127.60,126.83,126.58,123.78,112.55,108.74,106.31,95.26,94.63,55.79,55.49.(+)-HR ESIMS:m/z=413.1145,calcd for C23H22O5Cl[M+H]+:413.1150.
化合物26-28的合成路线:
化合物25 413mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得无色油状液体化合物26(92mg,25%),27(92mg,25%)和28(120mg,37%)。
合成终产物26~28(化合物代号对应于实施例中的化合物代号)
实施例26:
1-(2-氯-3-羟基-5-甲氧甲基苯基)-3-(萘-2-基)-(2E)-2-丙烯-1-酮(26)
化合物26:无色油状液体(yield=25%);1H NMR(400MHz,Acetone-d6)δH:9.07(s,1H),8.20(s,1H),7.99–7.96(m,2H),7.96–7.92(m,2H),7.65(d,J=16.1Hz,1H),7.62–7.54(m,2H),7.27(d,J=16.1Hz,1H),6.87(d,J=2.8Hz,1H),6.71(d,J=2.8Hz,1H),5.23(s,2H),3.45(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.88,156.87,154.20,146.04,141.92,141.18,134.58,133.48,132.23,130.87,128.77,128.70,127.77,127.56,126.81,126.61,123.80,107.71,105.91,94.50,55.37.(+)-HR ESIMS:m/z=369.0885,calcd forC21H18O4Cl[M+H]+:369.0888.
实施例27:
1-(2-氯-3-甲氧甲基-5-羟基苯基)-3-(萘-2-基)-(2E)-2-丙烯-1-酮(27)
化合物27:无色油状液体(yield=25%);1H NMR(400MHz,Acetone-d6)δH:8.89(s,1H),8.20(s,1H),8.00–7.91(m,4H),7.63(d,J=16.1Hz,1H),7.60–7.54(m,2H),7.24(d,J=16.1Hz,1H),6.90(d,J=2.7Hz,1H),6.63(d,J=2.7Hz,1H),5.32(s,2H),3.52(s,3H).13CNMR(400MHz,Acetone-d6)δC:193.02,156.97,154.09,145.99,141.37,134.58,133.48,132.21,130.85,128.77,128.70,127.77,127.57,126.81,126.71,123.78,110.08,108.30,105.14,95.13,55.66.(+)-HR ESIMS:m/z=369.0884,calcd for C21H18O4Cl[M+H]+:369.0888.
实施例28:
1-(2-氯-3,5-二羟基苯基)-3-(萘-2-基)-(2E)-2-丙烯-1-酮(28)
化合物28:无色油状液体(yield=37%);1H NMR(500MHz,Acetone-d6)δH:8.93(s,1H),8.80(s,1H),8.24(s,1H),8.03–7.96(m,4H),7.67(d,J=16.2Hz,1H),7.61(dq,J=12.4,6.9,6.3Hz,2H),7.28(d,J=16.1Hz,1H),6.72(d,J=2.5Hz,1H),6.55(d,J=2.4Hz,1H).13C NMR(400MHz,Acetone-d6)δC:192.88,156.87,154.20,146.04,141.92,141.18,134.58,133.48,132.23,130.87,128.77,128.70,127.77,127.56,126.81,126.61,123.80,107.71,105.91.(+)-HR ESIMS:m/z=325.0623,calcd for C19H14O3Cl[M+H]+:325.0626.
实施例29:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(6-甲氧基萘-2-基)-(2E)-2-丙烯-1-酮(29)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入化合物6-甲氧基-2-萘甲醛372mg(2mmol),继续反应10h。反应液以30ml水稀释,过滤,滤饼以甲醇洗涤、干燥,得白色固体化合物29(753mg,85%)。
化合物29:白色固体(yield=85%);1H NMR(400MHz,Acetone-d6)δH:8.13(s,1H),7.92(s,1H),7.90(s,2H),7.63(d,J=16.1Hz,1H),7.39(d,J=2.1Hz,1H),7.25–7.19(m,2H),7.10(d,J=2.7Hz,1H),6.86(d,J=2.5Hz,1H),5.39(s,2H),5.29(s,2H),3.98(s,3H),3.56(s,3H),3.49(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.78,159.33,156.82,153.95,146.59,141.47,136.31,130.82,130.29,129.91,128.78,127.68,125.46,124.39,119.47,112.53,108.70,106.20,106.10,95.26,94.63,55.78,55.48,54.91.(+)-HRESIMS:m/z=443.1252,calcd for C24H24O6Cl[M+H]+:443.1255.
化合物30-32的合成路线:
化合物29 443mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,经硅胶柱层析分离得无色油状液体化合物30(116mg,29%),31(100mg,25%)和32(131mg,37%)。
合成终产物30~32(化合物代号对应于实施例中的化合物代号)
实施例30:
1-(2-氯-3-羟基-5-甲氧甲基苯基)-3-(6-甲氧基萘-2-基)-(2E)-2-丙烯-1-酮(30)
化合物30:无色油状液体(yield=29%);1H NMR(400MHz,Acetone-d6)δH:9.06(s,1H),8.11(s,1H),7.88(d,J=8.8Hz,1H),7.87(s,2H),7.61(d,J=16.1Hz,1H),7.36(d,J=2.5Hz,1H),7.23–7.17(m,2H),6.86(d,J=2.7Hz,1H),6.69(d,J=2.8Hz,1H),5.22(s,2H),3.95(s,3H),3.45(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.88,159.30,156.84,154.18,146.47,141.33,136.28,130.76,130.28,129.95,128.79,127.66,125.49,124.40,119.45,109.92,107.64,106.10,105.79,94.49,55.36,54.91.(+)-HR ESIMS:m/z=399.0990,calcd for C22H20O5Cl[M+H]+:399.0993.
实施例31:
1-(2-氯-3-甲氧甲基-5-羟基苯基)-3-(6-甲氧基萘-2-基)-(2E)-2-丙烯-1-酮(31)
化合物31:无色油状液体(yield=25%);1H NMR(400MHz,Acetone-d6)δH:8.89(s,1H),8.11(s,1H),7.90–7.86(m,3H),7.58(d,J=16.1Hz,1H),7.36(d,J=2.6Hz,1H),7.22–7.14(m,2H),6.89(d,J=2.7Hz,1H),6.61(d,J=2.7Hz,1H),5.31(s,2H),3.95(s,3H),3.51(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.02,159.30,156.95,154.06,146.43,141.52,136.28,130.74,130.28,129.93,128.80,127.67,125.59,124.38,119.45,108.26,106.09,105.04,95.12,55.66,54.91.(+)-HR ESIMS:m/z=399.0992,calcd for C22H20O5Cl[M+H]+:399.0993.
实施例32:
1-(2-氯-3,5-二羟基苯基)-3-(6-甲氧基萘-2-基)-(2E)-2-丙烯-1-酮(32)
化合物32:无色油状液体(yield=37%);1H NMR(400MHz,Acetone-d6)δH:8.92(s,1H),8.79(s,1H),8.10(s,1H),7.90–7.85(m,3H),7.60(d,J=16.1Hz,1H),7.35(d,J=2.4Hz,1H),7.22–7.13(m,2H),6.69(d,J=2.7Hz,1H),6.50(d,J=2.7Hz,1H),3.94(s,3H).13C NMR(400MHz,Acetone-d6)δC:193.20,159.27,156.99,154.25,146.34,141.35,136.25,130.70,130.28,129.97,128.80,127.66,125.63,124.39,119.43,107.62,107.02,106.09,104.87,54.91.(+)-HR ESIMS:m/z=355.0727,calcd for C20H16O4Cl[M+H]+:355.0731.
实施例33:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(喹啉3-基)-(2E)-2-丙烯-1-酮(33)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入3-喹啉甲醛314mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(8:1:3)洗脱得无色油状液体化合物33(695mg,84%)。
化合物33:无色油状液体(yield=84%);1H NMR(500MHz,Acetone-d6)δH:9.27(s,1H),8.65(s,1H),8.07(d,J=8.4Hz,1H),8.01(d,J=8.2Hz,1H),7.82(t,J=7.6Hz,1H),7.71(d,J=16.3Hz,1H),7.65(t,J=7.5Hz,1H),7.45(d,J=16.3Hz,1H),7.09(d,J=2.4Hz,1H),6.88(d,J=2.5Hz,1H),5.36(s,2H),5.26(s,2H),3.53(s,3H),3.47(s,3H).13CNMR(400MHz,Acetone-d6)δC:192.48,156.86,154.02,149.76,148.88,142.67,141.00,136.12,130.71,129.30,128.75,127.81,127.76,127.72,127.35,112.65,108.85,106.50,95.28,94.63,55.82,55.51.(+)-HR ESIMS:m/z=414.1100,calcd for C22H21O5NCl[M+H]+:414.1102.
实施例34:
1-(2-氯-3,5-二羟基苯基)-3-(喹啉-3-基)-(2E)-2-丙烯-1-酮(34)
化合物33 414mg(1mmol)溶解于20ml干燥甲醇中,在50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应10小时后,反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,经硅胶柱层析分离得无色油状液体化合物34(293mg,90%)。
化合物34:无色油状液体(yield=90%);1H NMR(400MHz,Acetone-d6)δH:9.26(d,J=2.2Hz,1H),8.91(s,1H),8.76(s,1H),8.65(d,J=2.2Hz,1H),8.05(d,J=8.5Hz,1H),7.99(dd,J=8.0,1.4Hz,1H),7.79(ddd,J=8.4,6.9,1.5Hz,1H),7.67(d,J=16.3Hz,1H),7.62(ddd,J=8.2,6.9,1.2Hz,1H),7.39(d,J=16.3Hz,1H),6.66(d,J=2.8Hz,1H),6.51(d,J=2.8Hz,1H).13C NMR(400MHz,Acetone-d6)δC:192.82,157.03,154.32,149.79,148.79,142.35,140.89,136.08,130.66,129.28,128.73,128.00,127.85,127.78,127.34,107.72,107.17,105.17.(+)-HR ESIMS:m/z=326.0577,calcd for C18H13O3NCl[M+H]+:326.0578.
实施例35:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(2-氯喹啉-3-基)-(2E)-2-丙烯-1-酮(35)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入2-氯3-喹啉甲醛383mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:3)洗脱得无色油状液体35(715mg,80%)。
化合物35:无色油状液体(yield=80%);1H NMR(500MHz,Acetone-d6)δH:9.02(s,1H),8.12(d,J=8.1Hz,1H),8.00(d,J=8.5Hz,1H),7.94(d,J=16.1Hz,1H),7.90(d,J=7.6Hz,1H),7.73(t,J=7.6Hz,1H),7.41(d,J=16.1Hz,1H),7.13(d,J=2.7Hz,1H),6.93(d,J=2.7Hz,1H),5.39(s,2H),5.30(s,2H),3.55(s,3H),3.49(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.10,156.88,154.04,149.71,148.00,140.69,139.91,137.31,131.96,130.08,128.71,128.09,127.87,127.30,127.19,112.72,108.87,106.75,95.26,94.62,55.79,55.50.(+)-HR ESIMS:m/z=448.0712,calcd for C22H20O5NCl2[M+H]+:448.0713.
化合物36~38的合成方法
化合物35 448mg(1mmol)溶解于20ml干燥甲醇中,50℃条件下缓慢加入49%的HBr水溶液,保持50℃搅拌反应6小时。反应液降温至-10℃,以饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯萃取,有机相合并,饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩。所得产物混合物以二氯甲烷:甲醇=10:1为洗脱剂,硅胶柱层析分离得淡黄色油状液体化合物36(121mg,30%),37(121mg,30%)和38(126mg,35%)。
合成终产物36~38(化合物代号对应于实施例中的化合物代号)
实施例36:
1-(2-氯-3-羟基-5-甲氧甲基苯基)-3-(2-氯喹啉-3-基)-(2E)-2-丙烯-1-酮(36)
化合物36:淡黄色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:9.15(s,1H),9.01(s,1H),8.11(d,J=8.0Hz,1H),7.98(d,J=8.4Hz,1H),7.93(d,J=16.4Hz,1H),7.89(ddd,J=8.4,6.9,1.2Hz,1H),7.71(ddd,J=8.1,6.9,1.2Hz,1H),7.39(d,J=16.4Hz,1H),6.90(d,J=2.8Hz,1H),6.78(d,J=2.8Hz,1H),5.24(s,2H),3.45(s,3H).13CNMR(400MHz,Acetone-d6)δC:193.02,157.79,155.25,150.64,148.90,141.46,140.62,138.19,132.84,131.02,129.61,128.99,128.76,128.23,128.16,111.00,108.81,107.28,95.39,56.28.
实施例37:
1-(2-氯-3-甲氧甲基-5-羟基苯基)-3-(2-氯喹啉-3-基)-(2E)-2-丙烯-1-酮(37)
化合物37:淡黄色油状液体(yield=30%);1H NMR(400MHz,Acetone-d6)δH:9.03(s,1H),8.96(s,1H),8.11(d,J=8.0Hz,1H),7.99(d,J=8.4Hz,1H),7.92(d,J=16.4Hz,1H),7.89(ddd,J=8.4,6.9,1.2Hz,1H),7.71(ddd,J=8.1,6.9,1.2Hz,1H),7.39(d,J=16.4Hz,1H),6.95(d,J=2.7Hz,1H),6.70(d,J=2.7Hz,1H),5.34(s,2H),3.53(s,3H).13CNMR(101MHz,Acetone-d6)δC:193.17,170.90,157.97,155.05,150.62,148.89,141.72,140.51,138.18,132.84,131.07,129.61,128.99,128.77,128.23,128.13,111.18,110.24,106.49,96.03.
实施例38:
1-(2-氯-3,5-二羟基苯基)-3-(2-氯喹啉-3-基)-(2E)-2-丙烯-1-酮(38)
化合物38:淡黄色油状液体(yield=35%);1H NMR(400MHz,Acetone-d6)δH:9.02(s,2H),8.85(s,1H),8.11(d,J=8.0Hz,1H),7.98(d,J=8.4Hz,1H),7.93(d,J=16.0Hz,1H),7.89(ddd,J=8.4,6.9,1.2Hz,1H),7.71(ddd,J=8.1,6.9,1.2Hz,1H),7.38(d,J=16.0Hz,1H),6.72(d,J=2.8Hz,1H),6.58(d,J=2.8Hz,1H).13C NMR(101MHz,Acetone-d6)δC:193.22,158.00,155.31,150.64,148.88,141.56,140.31,138.14,132.80,131.12,129.61,128.99,128.75,128.25,128.20,108.69,108.17,106.35.
实施例39:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(1-H-吲哚-5-基)-(2E)-2-丙烯-1-酮(39)
化合物1b 549mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入5-吲哚甲醛290mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(10:1:3)洗脱得无色油状液体39(667mg,83%)。
化合物39:无色油状液体(yield=83%);1H NMR(400MHz,Acetone-d6)δH:10.56(s,1H),7.94(s,1H),7.64–7.51(m,3H),7.44(dd,J=3.2,2.4Hz,1H),7.09(d,J=8.0Hz,1H),7.06(d,J=5.3Hz,1H),6.84(d,J=2.7Hz,1H),6.59(ddd,J=2.8,1.9,0.7Hz,1H),5.38(s,2H),5.28(s,2H),3.55(s,3H),3.49(s,3H).13C NMR(400MHz,Acetone-d6)δC:192.70,156.76,153.90,148.87(C×2),141.87,138.04,128.59,126.35,125.93,123.20,123.15,121.33,112.09,108.67,106.01,102.64,95.24,94.62,55.76,55.45.(+)-HRESIMS:m/z=402.1098,calcd for C21H21O5NCl[M+H]+:402.1102.
实施例40:
1-(2-氯-3,5-二甲氧甲基苯基)-3-(9-乙基-9H-卡巴唑-2-基)-(2E)-2-丙烯-1-酮(40)
化合物1c 638mg(2mmol)溶解于30ml甲醇水的混合溶剂(甲醇:水=2:1,v/v)中,加入NaOH固体96mg(1.2eq)。室温搅拌10分钟,加入9-乙基-9H-卡巴唑-2-羧醛446mg(2mmol),继续反应10h。反应液以30ml水稀释,乙酸乙酯萃取,有机相以饱和食盐水洗涤,无水硫酸镁干燥,减压浓缩,所得混合物以200-300目硅胶柱层析分离,石油醚:乙酸乙酯:二氯甲烷(8:1:3)洗脱,得黄色油状液体40(849mg,81%)。
化合物40:黄色油状液体(yield=81%);1H NMR(500MHz,Acetone-d6)δH:8.53(s,1H),8.24(d,J=7.8Hz,1H),7.85(d,J=8.6Hz,1H),7.65(s,1H),7.62(d,J=7.3Hz,2H),7.51(t,J=7.6Hz,1H),7.26(t,J=7.6Hz,1H),7.13(d,J=16.6Hz,1H),7.03(s,1H),6.81(s,1H),5.36(s,2H),5.27(s,2H),4.52(q,J=7.4Hz,2H),3.53(s,3H),3.47(s,3H),1.42(t,J=7.0Hz,3H).13C NMR(400MHz,Acetone-d6)δC:193.63,157.62,154.80,148.21,144.70,141.70,140.61,126.40(C×2),125.51,123.45,123.22,122.83,122.03,120.67,119.69,109.44,109.32,108.85,105.52,101.19,95.22,94.60,55.83,55.50,37.40,13.20.(+)-HR ESI MS:m/z=524.1065,calcd for C27H27O5NBr[M+H]+:524.1067.
药理实验
本发明化合物的抗炎活性的药理试验方法与结果如下(药理实验部分的化合物代号对应于实施例中的化合物代号):
实施例1:查尔酮生物对LPS诱导原代小鼠腹腔巨噬细胞NO生成的抑制活性。
巨噬细胞,执行机体非特异性免疫功能,在细菌脂多糖LPS诱导下可产生NO等炎性因子,参与并介导炎症反应,在多种炎症免疫过程初期与病理发展过程中均有较高的水平。通过检测原代培养的小鼠巨噬细胞NO生成量,可作为体外初步观察和筛选有一定抗炎活性的组分或化合物的指标。
实验方法:
取原代小鼠腹腔巨噬细胞接种于96孔板中,加入不同待测化合物(10-5M)和阳性对照药地塞米松(Dex)预保护1h;然后,加入1μg/ml LPS于37℃、5%CO2培养箱中培养24h后,收集上清液,采用Griess法测定 同时,用MTT法测定细胞增殖抑制率。
实验结果:
结果如表1所示,合成所得卤代查尔酮衍生物NO生成抑制活性显著。其中,化合物35,36和38不仅具有显著的NO生成抑制活性,且细胞毒性显著低于阳性对照药地塞米松。
表1.卤代查尔酮衍生物对LPS诱导原代小鼠腹腔巨噬细胞NO生成的影响.
*浓度:10-5M;治疗方向:抗炎。*化合物代号对应于实施例中的化合物代号。
实验例2:查尔酮衍生物对巴豆油诱导小鼠耳炎的影响
实验方法:
取18-20g的雄性昆明种小鼠,随机分组,各组动物分别于左耳两面涂巴豆油0.02ml;30分钟后,给药组动物皮下注射给予100mg/kg体重受试化合物,模型对照组给予等体积溶媒;给药4h后,脱颈处死小鼠,沿耳廓基线剪下双耳,直径6mm打孔器分别取下左右耳相同位置的耳片,分析天平称重,计算耳肿胀度(耳肿胀度=左耳片重量-右耳片重量)和耳肿胀抑制率[耳肿胀抑制率(%)=(模型组平均耳肿胀度-给药组耳肿胀度)/模型组平均耳肿胀组×100%]。
实验结果:
实验结果如表2所示,化合物35对巴豆油诱导小鼠耳炎的耳肿胀具有明显的抑制作用,显示显著的体内抗炎活性。
表2查尔酮衍生物对巴豆油诱导小鼠耳炎的影响
*给药剂量:50mg/Kg×1次;给药途径:皮下注射;治疗方向:抗炎。
Claims (15)
1.如通式(I)所示的卤代查尔酮衍生物或其药学上可接受的盐:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R选自取代或未取代的萘基、取代或未取代的喹啉基、取代或未取代的吡啶基、取代或未取代的吲哚基、取代或未取代的呋喃基、取代或未取代的苯并呋喃基、取代或未取代的吡咯基、取代或未取代的咔唑基;其中所述萘基、喹啉基、吡啶基、吲哚基、呋喃基、苯并呋喃基、吡咯基、咔唑基的取代基选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、亚甲二氧基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;取代类型包括单取代,二取代,三取代或四取代;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
2.根据权利要求1的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(II)所示:
其中,X选自F、Cl、Br、I;
R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R3选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
3.根据权利要求2的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(IIA)和(IIB)所示:
其中,R1、R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R3选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
4.根据权利要求1的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(III)所示:
其中,X选自F、Cl、Br、I;
R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R4选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
5.根据权利要求4的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(IIIA)和(IIIB)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R4选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
6.根据权利要求1的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(IV)所示:
其中,X选自F、Cl、Br、I;
R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
7.根据权利要求6的-卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(IVA)和(IVB)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
8.根据权利要求1的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(V)、(VI)和(VII)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R5和R6各自独立地选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
9.根据权利要求1的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述化合物如通式(VIII)所示:
其中,R1和R2各自独立地选自氢、取代或未取代的C1-6的烷基、取代或未取代的C1-6的酰基、取代或未取代的苄基、取代或未取代的C3-6的环烷基、环丙甲基、MOM、Glu、SO3H、PO3H2;所述取代为单取代、二取代、三取代、四取代,取代基选自羟基、硝基、氰基、氨基、羧基、C1-6的烷氧基、C3-6的环烷基、F、Cl、Br、I;
R7选自氢、羟基、硝基、氰基、氨基、甲氨基、二甲氨基、C1-6的烷基、C1-6的烷氧基、C1-6的酰基、C1-6的酰氧基、C1-6的烷硫基、羧基、F、Cl、Br、I、Glu、SO3H、PO3H2;
MOM表示甲氧基甲基;Glu表示β-D吡喃葡萄糖基;SO3H表示磺酰基;PO3H2表示磷酰基。
10.根据权利要求1-9中任一项的卤代查尔酮衍生物或其药学上可接受的盐,其特征在于,所述的化合物选自如下群组:
11.一种药物组合物,其特征在于,所述的药物组合物由有效剂量的权利要求1-10任一项所述的卤代查尔酮衍生物或其药学上可接受的盐和药学上可接受的载体或辅料组成。
12.根据权利要求11的药物组合物,其特征在于,所述的药物组合物选自片剂、胶囊、丸剂或注射剂。
13.根据权利要求11的药物组合物,其特征在于,所述药物组合物选自缓释制剂、控释制剂或各种微粒给药系统。
14.权利要求1-10任一项所述的卤代查尔酮衍生物或其药学上可接受的盐在制备治疗和/或预防炎症和/或炎症免疫相关疾病药物中的应用。
15.根据权利要求14的应用,其中炎症和炎症免疫相关疾病包括:类风湿性关节炎、骨关节炎、风湿性关节炎、痛风性关节炎、红斑狼疮综合症、支气管炎、滑囊炎、腱鞘炎、牛皮癣、湿疹、烧伤、皮炎、炎性肠病、克劳恩病、胃炎、过敏性肠综合症、溃疡性结肠炎、多发性硬化症、自身免疫性脑脊髓炎、结肠直肠癌、结节性动脉炎、甲状腺炎、风热湿、牙龈炎、牙周炎、口腔溃疡、肾炎、损坏后发生的肿胀、心肌缺血、各种感染性肺炎、理化性肺炎以及变态反应性肺炎、痉挛性肛部痛和直肠裂、肝胆囊炎、胆管炎、硬化性胆管炎或原发性胆汁性肝硬变和胆囊炎。
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