CN114075102B - 2,3-二芳基茚衍生物、其制法及药物组合物与用途 - Google Patents
2,3-二芳基茚衍生物、其制法及药物组合物与用途 Download PDFInfo
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- CN114075102B CN114075102B CN202010839497.1A CN202010839497A CN114075102B CN 114075102 B CN114075102 B CN 114075102B CN 202010839497 A CN202010839497 A CN 202010839497A CN 114075102 B CN114075102 B CN 114075102B
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Abstract
本发明属于生物医药领域,涉及2,3‑二芳基茚衍生物、其制法及药物组合物与用途,具体涉及到一类如通式(I)和(II)所示的2,3‑二芳基茚型衍生物及其药学上可接受的盐,并公开了该类化合物单体或药用组合物在制备炎症免疫相关疾病治疗药物中的应用。
Description
技术领域
本发明涉及生物医药领域,具体涉及到一类2,3-二芳基茚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。天然产物具有来源广泛、毒性低、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。
低聚茋类化合物是由二苯乙烯单体以多种方式进行偶联聚合形成的聚合度和聚合方式不同的多酚类化合物。从生源上分析,这类天然产物均由二苯乙烯单体(白藜芦醇,异丹叶大黄素,氧化白藜芦醇等)聚合形成。该类化合物表现出多种多样的的生物活性,例如抗炎活性,抗肿瘤活性,抗菌活性,抗真菌活性,抗氧化活性等。Gnetulin是1993年从植物Gnetum.ula中发现的一个具有2,3-二芳基二氢茚型结构的异丹叶大黄素二聚体类化合物,随后,在多种买麻藤属的植物中相继发现了该化合物(如Gnetum macrostachyum、Gnetumhainanense、Gnetum parvifolium等)。目前文献报道的与Gnetulin具有相似骨架的天然产物共有6个(gnetulin,gnemontanin C,gnetuhainin J,quadrangularin A,ampelopsin D,gnemontanin D和Parthenocissin A)。该类化合物在天然界含量较低,样品缺乏,目前,对该类化合物的合成及活性研究报道不多。
本发明的发明人在研究中发现Gnetulin是一个肝保护及NO抑制活性显著的天然活性先导化合物,据此对该化合物的全合成进行了深入的研究,完成了该化合物两个光学异构体及其消旋体的对映选择性全合成。在此基础上,对该化合物进行了系统的结构衍生化和构效关系研究,发现了一类与2,3-二芳基二氢茚结构不同的新型天然产物类似物——2,3-二芳基茚衍生物具有显著的NO抑制活性。与2,3-二芳基二氢茚结构类化合物相比,2,3-二芳基茚衍生物结构中减少了两个不对称碳原子,比gnetulin及其类似物减少了一个苯环及一个环外双键,结构更加简化。文献检索显示,该类化合物的结构及抗炎活性均未见文献报道,是一类新型结构的NO抑制活性衍生物,具有作为抗炎药物候选物开发的潜在应用价值。
发明内容
本发明要解决的技术问题是,提供一类新结构的2,3-二芳基茚衍生物,其制法、药物组合物与用途。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供了如通式(I)和(II)所示的2,3-二芳基茚衍生物,及其药学上可接受的盐:
其中,X选自O、S、NH、CH2;
R2、R3、R4、R5、R6、R9、R10、R11、R12、R13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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R1、R8各自独立地选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的苄基、取代或未取代的苄氧基、取代或未取代的C3-6环烷基、取代或未取代的C3-6环烷氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的C1-6的烷硫基、甲氧甲氧基、β-D吡喃葡萄糖基氧基、磺酰氧基、磷酰氧基、F、Cl、Br、I;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R7选自氢、羟基、硝基、氰基、羧基、苯基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的C1-6的氨基、取代或未取代的C1-6的烷硫基、取代或未取代的C1-6的烷基亚砜基、取代或未取代的C1-6的烷基砜基、取代或未取代的C3-6的环烷基、取代或未取代的C3-6的环烷氧基、β-D吡喃葡萄糖基氧基、磺酰氧基、磷酰氧基、F、Cl、Br、I;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(I)所示的2,3-二芳基茚衍生物包括,但不限定于通式(IA)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(IA)所示:
其中,Y选自O、NH、S、/>CH2;
R2、R3、R4、R5、R6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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R1选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的苄基、取代或未取代的苄氧基、取代或未取代的C3-6环烷基、取代或未取代的C3-6环烷氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的C1-6的烷硫基、甲氧甲氧基、β-D吡喃葡萄糖基氧基、磺酰氧基、磷酰氧基、F、Cl、Br、I;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R14选自氢、苯基、取代或未取代的C1-6的烷基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C3-6的环烷基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(IA)所示的2,3-二芳基茚衍生物包括,但不限定于通式(IAa)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(IAa)所示:
其中,Y选自O、NH、S、/>CH2;
R2、R3、R4、R5、R6、R15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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R14选自氢、苯基、取代或未取代的C1-6的烷基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C3-6的环烷基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(IAa)的2,3-二芳基茚衍生物包括,但不限定于通式(IAb)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(IAb)所示:
其中,Y选自O、NH、S、/>CH2;
R2、R3、R4、R5、R6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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R14选自氢、苯基、取代或未取代的C1-6的烷基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C3-6的环烷基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(I)所示的2,3-二芳基茚衍生物包括但不限定于通式(IB)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(IB)所示:
其中,R2、R3、R4、R5、R6、R15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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R7选自氢、羟基、硝基、氰基、羧基、苯基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的C1-6的氨基、取代或未取代的C1-6的烷硫基、取代或未取代的C1-6的烷基亚砜基、取代或未取代的C1-6的烷基砜基、取代或未取代的C3-6的环烷基、取代或未取代的C3-6的环烷氧基、β-D吡喃葡萄糖基氧基、磺酰氧基、磷酰氧基、F、Cl、Br、I;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(IB)所示的2,3-二芳基茚衍生物包括,但不限定于通式(IBa)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(IBa)所示:
其中,R2、R3、R4、R5、R6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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R7选自氢、羟基、硝基、氰基、羧基、苯基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的C1-6的氨基、取代或未取代的C1-6的烷硫基、取代或未取代的C1-6的烷基亚砜基、取代或未取代的C1-6的烷基砜基、取代或未取代的C3-6的环烷基、取代或未取代的C3-6的环烷氧基、β-D吡喃葡萄糖基氧基、磺酰氧基、磷酰氧基、F、Cl、Br、I;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(II)所示的2,3-二芳基茚衍生物包括,但不限定于通式(IIA)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)所示:
其中,R9、R10、R11、R12、R13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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I;
R8选自氢、羟基、硝基、氰基、氨基、羧基、苯基、甲氨基、二甲氨基、取代或未取代的C1-6的烷基、取代或未取代的C1-6的烷氧基、取代或未取代的C1-6的酰基、取代或未取代的C1-6的酰氧基、取代或未取代的苄基、取代或未取代的苄氧基、取代或未取代的C3-6环烷基、取代或未取代的C3-6环烷氧基、取代或未取代的C1-6的烷氧酰基、取代或未取代的C2-6的不饱和烷基、取代或未取代的C2-6的不饱和烷氧基、取代或未取代的C1-6的烷硫基、甲氧甲氧基、β-D吡喃葡萄糖基氧基、磺酰氧基、磷酰氧基、F、Cl、Br、I;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(IIA)所示的2,3-二芳基茚衍生物包括但不限定于通式(IIAa)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(IIAa)所示:
其中,R9、R10、R11、R12、R13、R16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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
根据本发明,优选的通式(IIAa)所示的2,3-二芳基茚衍生物包括,但不现定于通式(IIAb)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(IIAb)所示:
其中,R9、R10、R11、R12、R13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、甲氧基甲基、β-D吡喃葡萄糖基、磺酰基、磷酰基;所述取代为单取代、二取代、三取代、四取代,取代基各自独立地选自羟基、硝基、氰基、氨基、羧基、C1-6的烷基、C1-6的烷氧基、F、Cl、Br、I。
具体来说,通式(I)、(IA)、(IAa)、(IAb)、(IB)、(IBa)及(II)、(IIA)、(II Aa)、(IIAb)所示的2,3-二芳基茚衍生物及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(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)、(IA)、(IAa)、(IAb)、(IB)、(IBa)及(II)、(IIA)、(IIAa)、(IIAb)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,本发明中要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2,3-二芳基茚衍生物或其医学上可接受的盐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2,3-二芳基茚衍生物具有抑制巨噬细胞炎症因子NO过量生成的活性。
本发明技术方案的第四方面是提供第一方面所述2,3-二芳基茚衍生物的制备方法。
用于制备本发明化合物的原料,如3,5-二羟基苯乙酮和香草醛可通过商业购买获得,关键中间体1a可参考文献[Adv.Synth.Catal.2019,361,3768-3776]的方法制备获得。关键中间体化合物1a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(1b)。
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进行反应,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1b。
步骤二、化合物1b与NBS进行溴代反应制备其溴代产物(1c)。
步骤一所得产物1b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。
步骤三、香草醛与氯甲基甲醚反应制备MOM保护酚羟基的香草醛中间体化合物(1d)。
香草醛在二氯甲烷中,以DIPEA为催化剂,与氯甲基甲醚在室温条件下进行反应,反应产物经分离制备得到MOM保护羟基的香草醛衍生物1d。
步骤四、溴代产物1c与香草醛衍生物1d通过羟醛缩合反应制备中间体产物1e。
溴代产物1c与香草醛衍生物1d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,反应产物经分离制备得到2′-溴代查尔酮衍生物1e。
步骤五、2′-溴代查尔酮1e通过Heck反应进行分子内关环反应合成得到3-芳基茚酮1f。
步骤四所得产物1e在氯化钯和碳酸钾催化下在DMF中进行环合反应,反应产物经分离制备得到2-芳基茚酮1f。
步骤六、2-芳基茚酮产物1f在Pd/C催化下与氢气反应制备关键中间体产物1a。
步骤五所得2-芳基茚酮1f在甲醇和乙酸乙酯的混合溶液中,以Pd/C为催化剂,在0.2~0.4MPa氢气压力下与氢气进行还原反应,产物经分离制备得到关键中间体产物1a。
本发明所述化合物的基本合成方法包括如下步骤:
步骤一、MOM保护羟基的2,3-二芳基茚型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2,3-二芳基茚型衍生物在甲醇溶液中与盐酸在室温下进行反应,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2,3-二芳基茚型衍生物。
步骤二、带有游离羟基的2,3-二芳基茚型衍生物通过羟基全乙酰化的方法制备相应的乙酰化衍生物。
带有游离羟基的2,3-二芳基茚型衍生物在吡啶溶液中,与适量的醋酸酐试剂进行乙酰化反应,反应产物经分离制备得到羟基全乙酰化的茚型衍生物。
步骤三、带有游离羟基的2,3-二芳基茚型衍生物与溴苄反应,使羟基与溴苄生成苄醚合成羟基苄醚化的2,3-二芳基茚型衍生物。
带有游离羟基的茚型衍生物在无水丙酮溶液中,在K2CO3存在下,与适量的溴苄进行苄醚化反应,反应产物经分离制备得到羟基全苄醚化的2,3-二芳基茚型衍生物。
步骤四、2,3-二芳基茚酮衍生物与NaBH4反应合成2,3-二芳基茚醇衍生物。
羟基保护的2,3-二芳基茚酮衍生物在THF中与NaBH4进行还原反应,产物经分离制备合成相应的2,3-二芳基茚醇衍生物。
步骤五、2,3-二芳基茚醇衍生物与碘甲烷发生甲醚化反应生成2,3-二芳基茚醇醚衍生物。
酚羟基保护的2,3-二芳基茚醇衍生物在丙酮溶液中,在K2CO3催化下与碘甲烷进行甲醚化反应,反应产物经分离得到2,3-二芳基茚醇醚衍生物。
步骤六、3-芳基茚酮与芳基溴通过α芳基化反应合成2,3-二芳基茚酮衍生物。
以醋酸钯和叔丁醇钾为催化剂,3-芳基茚酮与芳基溴在甲苯中发生α芳基化反应,产物经分离制备合成2,3-二芳基茚酮衍生物。
有益技术效果
本发明的发明人在对闭苞买麻藤中分离得到的2,3-二芳基二氢茚型天然产物Gnetulin的合成及活性研究过程中,发现合成该化合物的中间体2,3-二芳基茚对LPS诱导原代小鼠腹腔巨噬细胞NO的生成具有显著的抑制活性。在此基础上对该类化合物进行了进一步的合成和结构衍生化研究以及NO抑制活性评价,确证了该类化合物的抗炎活性,该类化合物是一类新结构的对NO具有显著抑制活性的天然产物衍生物,具有进一步开发的潜在价值。
本专利涉及的2,3-二芳基茚型化合物均为新结构化合物。目前,对2,3-二芳基茚型结构类型化合物的NO抑制活性和构效关系研究尚未见文献报道。现有文献和技术中未见关于2,3-二芳基茚型结构类型的化合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。
如本发明所提及的术语“C1-16烷基”是指碳原子数为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16的烷基,可以包括C2-16烷基、C2-10烷基、C3-8烷基、C2-6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乙基、正丙基、异丙基、正丁基、正戊基、正己基、仲丁基、叔丁基,进一步优选正丁基;本发明所提及的“C1-6烷基”是指碳原子数为1、2、3、4、5、6的烷基,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。
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。
实施例中中间体化合物1a的合成路线:
实施例1:
2-(3,5-二甲氧甲氧基苯基)-3-(3-甲氧基-4-甲氧甲氧基苯基)-4,6-二甲氧甲氧基-1H-茚-1-酮(1)
化合物1的合成路线:
化合物1a(5g,9.0 12.0mmol)溶解于10ml甲苯中,依次加入化合物1g(8.8g,24.0mmol)、醋酸钯(112.5mg,0.4 0.5mmol)、xphos(333.2mg,0.7mmol)和叔丁醇钠(1.73g,18mmol)。在密封瓶中120℃反应3h,TLC检测显示反应结束,停止反应。反应液冷却至室温,加入50ml水稀释,硅藻土过滤后,用乙酸乙酯萃取,有机相合并,饱和氯化钠溶液洗涤三次,无水硫酸镁干燥,抽虑,滤液减压浓缩,以200-300目硅胶柱层析,石油醚:二氯甲烷:丙酮(40:10:1)洗脱得化合物1(2.0g,27%)。
化合物1:红色油状液体(yield=27%);1H NMR(500MHz,MeOH)δ:7.10(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),6.98(d,J=2.0Hz,1H),6.93(dd,J=8.0Hz,2.0Hz,1H),6.85(d,J=2.0Hz,1H),6.56(t,J=3.2Hz,1H),6.53(d,J=2.0Hz,2H),5.25(s,2H),5.22(s,2H),5.00(s,4H),4.94(s,2H),3.74(s,3H),3.50(s,6H),3.38(s,6H),3.23(s,3H);13CNMR(125MHz,MeOH)δC:196.7,161.6,160.2,159.1,153.9,151.0,148.2,135.4,134.4,132.2,130.4,124.8,122.8,117.5,114.7,112.7,111.8,110.1,107.5,105.4,96.7,96.0,95.7,95.6(2×C),56.7,56.6,56.5(2×C),56.1,56.1;HRESIMS:m/z 613.2269,calcd forC32H37O12[M+H]+,613.2280.
实施例2:
2-(3,5-二羟基苯基)-3-(3-甲氧基-4-羟基苯基)-4,6-二羟基-1H-茚-1-酮(2)
化合物2和3的合成路线:
化合物1(100mg,0.163mmol)溶解于10ml甲醇中,加入25当量浓盐酸,室温反应10h,TLC检测显示反应结束。以饱和的碳酸氢钠溶液调节反应液PH至中性,加入20ml水稀释,乙酸乙酯萃取,有机相合并,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。所得固体以200-300目硅胶柱层析,二氯甲烷:甲醇(10:1)洗脱得无色油状液体2(19mg,30%)和3(9mg,12%)。
化合物2:黑色固体:1H NMR(400MHz,Acetone-d6)δ:8.90-7.87(5H),7.06(d,J=1.6Hz,1H),6.93(dd,J=8.0Hz,2.0Hz,1H),6.77(d,J=8.4Hz,1H),6.64(d,J=2.4Hz,1H),6.39(d,J=2.4Hz,1H),6.19(t,J=2.0Hz,1H),6.16(d,J=2.4Hz,1H),3.73(s,3H);13C NMR(125MHz,Acetone-d6)δC:196.0,161.0,159.9,158.7(2×C),153.6,148.2,147.4,136.2,134.9,130.6,126.6,123.4,119.0,115.1,114.0,109.4(2×C),108.8,105.4,102.2,56.2;HRESIMS:m/z 393.0960,calcd for C22H17O7,[M+H]+,393.0969.
实施例3:
2-(3,5-二羟基苯基)-3-(3-甲氧基-4-羟基苯基)-4-甲氧甲氧基-6-羟基-1H-茚-1-酮(3)
制备方法见实施例2。
化合物3:黑色固体:1H NMR(400MHz,Acetone-d6)δ:8.06-7.84(3H),7.00(d,J=2.0Hz,1H)6.90(d,J=2.4Hz,1H),6.86(dd,J=8.0Hz,2.0Hz,1H),6.81(d,J=2.0Hz,1H),6.76(d,J=8.0Hz,1H),6.18(t,J=2.0Hz,1H),6.15(d,J=2.4Hz,1H),5.24(s,2H),4.94(s,2H),3.72(s,3H),3.44(s,3H),3.20(s,3H);13C NMR(125MHz,MeOH)δC:197.2,177.8,161.4,160.3,159.1(2×C),153.8,148.8,148.1,135.8,134.7,132.7,126.8,124.0,115.4,114.5,110.4,109.7(2×C),107.4,102.7,96.2,95.7,56.6,56.5,56.4;HRESIMS:m/z 481.1486,calcd for C26H25O9,[M+H]+,481.1493.
实施例4:
2-(3,5-二乙酰氧基苯基)-3-(3-甲氧-4-乙酰氧基苯基)-4,6-二乙酰氧基-1H-茚-1-酮(4)
化合物4的合成路线:
化合物2(50mg,0.127mmol)溶解于5ml干燥吡啶中,加入乙酸酐(323mg,3.166mmol),搅拌10h,TLC检测反应结束,停止反应。反应液以水稀释,乙酸乙酯萃取,有机相合并,依次以饱和硫酸铜,饱和氯化钠溶液洗涤,无水硫酸镁干燥,过滤,滤液浓缩,所得固体以石油醚:乙酸乙酯:二氯甲烷(8:1:3,v/v/v)为展开剂,硅胶制备板制备分离得化合物4(24.6mg,31%).
化合物4:灰色固体,1H NMR(500MHz,CD3OD):δ:7.29(1H,d,J=1.94Hz),7.12(1H,d,J=8.02Hz),7.01(1H,d,J=1.78Hz),6.95(1H,d,J=1.95Hz),6.92(1H,dd,J=8.08Hz,1.91Hz),6.85(2H,d,J=2.04Hz),6.84(1H,d,J=1.89Hz),3.74(3H,s),2.29(3H,s),2.28(3H,s),2.21(6H,s),1.68(3H,s);13C NMR(125MHz,CD3OD)δ:194.54,170.62,170.52,170.35,170.33,157.01,154.18,153.00,152.15,146.22,141.90,134.22,133.57,133.35,133.19,133.10,124.51,123.66,121.59,121.45,116.67,116.58,113.54,56.52,20.81,20.78,20.41,20.13.(+)-ESI-MS m/z:625.3[M+Na]+.
实施例5:
1-甲氧基-2-(3,5-二苄氧基苯基)-3-(3-甲氧基-4-苄氧基苯基)-4,6-二苄氧基-1H-茚(5)
化合物5的合成路线:
化合物5a(100mg,0.245mmol)溶解于10ml丙酮中,加入碳酸钾(339mg,2.45mmol),搅拌10分钟后加入苄溴(420mg,2.45mmol),室温反应8h,TLC检测显示反应结束,停止反应。加入20ml水稀释,反应液过滤,乙酸乙酯萃取,有机相合并,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,产物以石油醚:乙酸乙酯:二氯甲烷(13:1:3,v/v/v)为展开剂,硅胶制备板制备分离得化合物5(172mg,82%)。
化合物5:棕色固体,1H NMR(500MHz,acetone-d6),7.02d(1H,J=2.4Hz),7.26d(1H,J=2.4Hz),6.76d(1H,J=8.3Hz),6.20d(1H,J=8.3,2.1Hz),6.28d(1H,J=2.1Hz),6.56t(1H,J=2.2Hz),6.59d(2H,J=2.2Hz),4.62s(1H),3.42s(3H),3.42s(3H),5.23s(2H,PhCH2 ),4.94~5.16m(8H,4×PhCH2 ),7.13~7.54m(25H,5×PhCH2).13C NMR(125MHz,acetone-d6),164.43,160.84(2×C),159.77,157.41,149.97,148.35,140.50,128.0~138.5(30×C,5×PhCH2),124.88,121.62,115.54,114.14,108.77,107.32,107.25,105.50,103.27,71.36,71.00,70.83,70.71(2×C),56.06,51.50,49.42.
实施例6:
2-(3,5-二甲氧甲氧基苯基)-3-(3-甲氧基-4-甲氧甲氧基苯基)-4,6-二甲氧甲氧基-1H-茚-1-醇(6)
化合物6的合成路线:
化合物1(1.00g,1.18 1.64mmol)溶解于15ml THF中,加入甲醇15ml,硼氢化钠(92mg,2.46mmol),室温搅拌0.5h,TLC检测反应结束。加入50ml水稀释反应液,以乙酸乙酯萃取三次,有机相合并,饱和氯化钠溶液洗涤,无水硫酸镁干燥,抽虑,滤液减压浓缩。所得固体以200-300目硅胶柱层析,石油醚:丙酮(10:1)洗脱得化合物6(0.90g,90%)。
化合物6:红色油状液体;1H NMR(500MHz,CDCl3)δ:6.97(d,J=2.0Hz,1H),6.86(d,J=8.0Hz,1H),6.74(d,J=2.0Hz,1H),6.50(m,2H),6.45(d,J=2.0Hz,2H),6.27(d,J=2.0Hz,1H),5.25(m,2H),5.14(s,1H),5.10(s,2H),4.92(m,6H),4.49(s,2H),3.53(s,6H),3.45(s,3H),3.35(s,6H),3.15(s,3H);HRESIMS:m/z 615.2424,calcd for C32H39O12[M+H]+,615.2436.
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):
实验例1:2,3-二芳基茚型衍生物对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NO的含量(NO抑制率同时,用MTT法测定细胞增殖抑制率;并测定对NO生成具有显著抑制活性化合物的IC50值(用Probit加权回归分析法计算)。
实验结果:
结果如表1所示,茚型衍生物6,在保持活性的同时,毒性显著降低。其中,化合物6具有显著的NO生成抑制活性,且细胞毒性低于阳性对照药。
表1.茚型衍生物对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。
Claims (5)
1.如下所示的2,3-二芳基茚衍生物及其药学上可接受的盐:
2.一种药物组合物,由有效剂量的权利要求1所述的2,3-二芳基茚衍生物及其药学上可接受的盐和药学上可接受的载体或辅料组成。
3.根据权利要求2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、注射剂。
4.根据权利要求2的药物组合物,其特征在于,所述药物组合物选自缓释制剂、控释制剂及各种微粒给药系统。
5.权利要求1所述的茚型衍生物及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;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、慢性阻塞性肺疾病、哮喘、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。
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