CN114685361A - 荜茇酰胺类化合物以及包含该化合物的免疫调节剂 - Google Patents
荜茇酰胺类化合物以及包含该化合物的免疫调节剂 Download PDFInfo
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明提供新型荜茇酰胺类化合物以及包含上述化合物、其药学上可接受的盐或溶剂化物作为有效成分的免疫调节剂、用于免疫调节的健康功能食品。
Description
技术领域
本发明涉及新型荜茇酰胺类化合物、包含该化合物的免疫调节剂以及用于免疫调节的健康功能食品。
背景技术
免疫是指通过区分人体内自我(self)与非我(non-self),识别人体内自然发生或来自外界的有害物质后进行清除,从而维持机体稳态的反应。免疫反应对于抵抗从外部侵入人体的病毒、细菌和寄生虫等有害菌以及抵抗或消除内部产生的癌细胞很重要。
然而,当免疫系统的某些构成要素出现缺陷时,不会对有害物质发生免疫反应,这种免疫缺陷分为先天性免疫缺陷和后天继发性免疫缺陷。先天性免疫缺陷为B细胞及T细胞等免疫细胞本来就不存在的疾病,可以通过基因治疗、抗体注入或骨髓移植来治疗。另一方面,后天继发性免疫缺陷是指,虽然免疫构成要素本身存在,但由此产生的免疫反应过程中发生异常,可以通过增进它们的构成要素功能来改善疾病状态。
另一方面,当免疫功能异常增强时,使用免疫抑制剂进行治疗。然而,免疫抑制剂存在因降低身体免疫力而经常导致其他副作用的问题。
最近,这种因免疫功能异常而产生的免疫疾病正在增加,因而正积极开发能够增进或抑制免疫功能的免疫调节物质。这种免疫调节物质通过刺激免疫细胞来增进或抑制体内免疫功能,对此,韩国专利公开第10-2006-0047447号公开了如下内容:以特定化学式表示的单乙酰二酰基甘油化合物可用于治疗各种免疫系统的功能下降引起的疾病或癌症、关节炎、特应症、痴呆症等的各种疾病。
发明内容
本发明要解决的技术问题
另一方面,本发明人合成了具有规定化学结构的新型荜茇酰胺类化合物,并发现该新型化合物以免疫细胞作为对象具有优异的抗氧化活性、细胞因子产生抑制能力和/或细胞质内信号转导抑制能力,从而完成了本发明。
因此,本发明的目的在于,提供新型荜茇酰胺类化合物及其衍生物、其药学上可接受的盐、或溶剂化物。
此外,本发明的另一目的在于,提供包含上述新型荜茇酰胺类化合物作为有效成分的免疫调节剂、以及用于免疫调节的健康功能食品。
本发明的其他目的及优点可以通过以下发明的详细说明及权利要求书来明确说明。
技术方案
为了实现上述目的,本发明提供以下述式1表示的化合物、其药学上可接受的盐、或溶剂化物:
式1
在所述式1中,
R2至R4彼此相同或不同,各自独立地选自由氢、氘、卤素、硝基、羟基、氨基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C20的烷氧基、C1~C20的酮基、C1~C20的酯基、C6~C20的芳基、核原子数5至20个的杂芳基、以及C6~C20的芳氧基组成的组,或它们与相邻的基团键合来形成C6~C20的芳基或核原子数5至20个的杂芳环,但当R2至R4相同时除外,
R1是选自以下述结构式的取代基,
在所述式中,
X是选自由F、Cl、Br以及I组成的组的卤素元素,
Y是C1~C10的烷基,
所述R2~R4的烷基、酮基、酯基、芳基、杂芳基各自独立地能够被选自由氘、卤素、氰基、硝基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C6~C40的芳基、核原子数5至40个的杂芳基、C6~C40的芳氧基、C1~C40的烷氧基、C6~C40的芳胺基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C40的烷基甲硅烷基、C1~C40的烷基硼基、C6~C40的芳基硼基、C6~C40的芳基膦基、C6~C40的芳基氧化膦基以及C6~C40的芳基甲硅烷基组成的组中的一种以上的取代基取代,此时当所述取代基为多个时,它们能够相同或不同。
此外,本发明提供包含所述以式1表示的化合物、其药学上可接受的盐、或溶剂化物作为有效成分的免疫调节剂。
此外,本发明提供包含所述以式1表示的化合物、其药学上可接受的盐、或溶剂化物作为有效成分的用于调节免疫的健康功能食品。
同时,本发明提供以式1表示的化合物、其药学上可接受的盐、或溶剂化物在制备免疫调节用药物中的用途。
有益效果
根据本发明一实施例,上述以式1表示的化合物作为以往未知的新型荜茇酰胺类衍生物,对于免疫细胞表现出优异的抗氧化活性、细胞因子生成抑制能力和/或细胞质内信号转导抑制能力,因此可以有效地用作免疫调节剂。
根据本发明的效果不限于以上示出的内容,本发明包含更多种效果。
附图说明
图1是示出使用本发明的荜茇酰胺类化合物的一氧化氮生成抑制能力的结果的图。
图2是示出使用本发明的荜茇酰胺类化合物的羟基自由基抑制结果的图。
图3至图5分别是示出使用本发明的荜茇酰胺类化合物的炎性细胞因子基因表达抑制结果的图。
图6至图10分别是示出使用本发明的荜茇酰胺类化合物的T细胞依赖性细胞因子基因表达抑制结果的图。
图11至图14分别是示出使用本发明的荜茇酰胺类化合物的报告基因表达抑制结果的图。
具体实施方式
以下,详细说明本发明。
本说明书中使用的术语(包括技术和科学术语)可以以本发明所属领域的普通技术人员能够普遍理解的含义使用。此外,除非特别明确定义,否则不应理想地或过度地解释常用的辞典中定义的术语。
在整个说明书中,当某一部分“包括”某一构成要素时,除非另有说明,否则意味着还可能包括其他结构要素,而不是排除其他构成要素。而且,在本说明书中,“预防”等术语意味着从疾病的病因抑制其发生或延迟其发生,“治疗”等术语意味着即使没有完全治愈但也能通过抑制症状的进展和/或恶化来阻止损伤的进展,或通过改善部分或全部症状来向治愈方向进行诱导。
<荜茇酰胺类化合物>
本发明的一个实例涉及以下述式1表示的化合物,具体地,涉及新型荜茇酰胺类化合物及其衍生物,其药学上可接受的盐、或溶剂化物。
式1
在所述式1中,
R2至R4彼此相同或不同,各自独立地选自由氢、氘、卤素、硝基、羟基、氨基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C20的烷氧基、C1~C20的酮基、C1~C20的酯基、C6~C20的芳基、核原子数5至20个的杂芳基、以及C6~C20的芳氧基组成的组,或它们可通过与相邻的基团(group)键合来形成C6~C20的芳基或核原子数5至20个的杂芳环,但当R2至R4相同时除外,
R1是选自以下述结构式的取代基。
在所述式中,
波浪部是指与所述式1键合的部分,
X是选自由F、Cl、Br以及I组成的组的卤素元素,
Y是C1~C10的烷基,
所述R2~R4的烷基、酮基、酯基、芳基、杂芳基各自独立地能够被选自由氘、卤素、氰基、硝基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C6~C40的芳基、核原子数5至40个的杂芳基、C6~C40的芳氧基、C1~C40的烷氧基、C6~C40的芳胺基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C40的烷基甲硅烷基、C1~C40的烷基硼基、C6~C40的芳基硼基、C6~C40的芳基膦基、C6~C40的芳基氧化膦基以及C6~C40的芳基甲硅烷基组成的组中的一种以上的取代基取代,此时当所述取代基为多个时,它们能够相同或不同。
以往,荜茇酰胺是两个环连接到α,β-不饱和羰基链的查耳酮(chalcone)形式的化合物,上述两个环中的一个苯环连接有3个甲氧基(-OMe),另一个具有2-哌啶酮结构。相比之下,根据本发明的式1的化合物具有如下的结构,即将荜茇酰胺的苯环的3,4-位置变更为硝基或其他取代基,而作为其他环合成具有2-吡咯烷酮和/或各种形式的氮化合物,并将其连接到α,β-不饱和羰基链。
在上述式1的以具体例中,R1可以是选自下述结构式的部分(moiety)。
此外,R2至R4彼此相同或不同,各自独立地选自由氢、硝基、羟基、包含C1-C6的烷基的酯基、以及C1-C6的烷氧基组成的组,或相邻的两个取代基相互键合来形成C6-C10的芳基或包含至少一个氮和氧原子的核原子数5至10个的杂环。
在本发明中,上述R2~R4的烷基、酮基、酯基、芳基、杂芳基各自独立地能够被选自由氘、卤素、氰基、硝基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C6~C40的芳基、核原子数5至40个的杂芳基、C6~C40的芳氧基、C1~C40的烷氧基、C6~C40的芳胺基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C40的烷基甲硅烷基,C1~C40的烷基硼基、C6~C40的芳基硼基、C6~C40的芳基膦基、C6~C40的芳基氧化膦基以及C6~C40的芳基甲硅烷基组成的组中的一种以上的取代基取代,此时当所述取代基为多个时,它们能够相同或不同。
在一个优选具体例中,上述式1的化合物可以根据R2至R4的种类来进一步具体化为下述式2至式5中的任一种。然而,不限于此。
式2
式3
式4
式5
所述式2至5中,
R1如上述式1中所定义。
R5至R7彼此相同或不同,各自独立地选自由氢、羟基、C1~C6的烷基,C1~C6的烷氧基、C1~C6的酮基、以及C1~C6的酯基组成的组。
环A可以是碳原子数20个以下的单环或多环烃环基,具体地,可以选自由环烷环(cycloalkyl ring)、杂环烷环(heterocycloalkyl ring)、芳环以及杂芳环组成的组。这种构成环A的至少一个碳可以被选自由氘、卤素、氰基、硝基、C1~C40的烷基、C6~C40的芳基、以及核原子数5至40个的杂芳基组成的组中的一种以上的取代基取代。
如上所述的本发明的以式1表示的化合物可以进一步具体化为以下例示的化合物。然而,本发明的以式1表示的化合物不限于以下例示。
在本发明中,“烷基”是指衍生自碳原子数1至40个的直链或支链的饱和烃的一价取代基。其例可以包括甲基、乙基、丙基、异丁基、仲丁基、戊基、异戊基、己基等,但不限于此。
在本发明中,“烯基(alkenyl)”是指衍生自具有一个以上碳-碳双键的碳原子数2至40个的直链或支链的不饱和烃的一价取代基。其具体例可以包括乙烯基(vinyl)、烯丙基(allyl)、异丙烯基(isopropenyl)、2-丁烯基(2-butenyl)等,但不限于此。
在本发明中,“炔基(alkynyl)”是指衍生自具有一个以上碳-碳三键的碳原子数2至40个的直链或支链的不饱和烃的一价取代基。其具体例可以包括乙炔基(ethynyl),2-丙炔基(2-propynyl)等,但不限于此。
在本发明中,“芳基”是指衍生自单环或两个以上的环组合的碳原子数6至40个的芳烃的一价取代基。此外,还可以包括两个以上的环相互单纯侧连(pendant)或稠合的形式。这种芳基的具体例可以包括苯基、萘基、菲基、蒽基等,但不限于此。
在本发明中,“杂芳基”是指衍生自核原子数5至40个的单杂环或多杂环芳烃的一价取代基。此时,环中的一个以上的碳,优选1至3个碳被N、O、S或Se等杂原子取代。此外,还可以包括两个以上的环相互单纯侧连(pendant)或稠合的形式,进而还可以包括与芳基稠合的形式。这种杂芳基的例可以包括如吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基等6-元单环;如酚噻吩基(phenoxathienyl)、吲哚嗪基(indolizinyl)、吲哚基(indolyl)、嘌呤基(purinyl)、喹啉基(quinolyl)、苯并噻唑(benzothiazole)、咔唑基(carbazolyl)等的多环以及2-呋喃基、N-咪唑基、2-异恶唑基、2-吡啶基、2-嘧啶基等,但不限于此。
在本发明中,“烷氧基”是以R’O-表示的一价取代基,上述R’指碳原子数1至40个的烷基,可包括直链(linear)、支链(branched)或环状(cyclic)结构。烷基氧基的例子,可举出甲氧基、乙氧基、正丙氧基、1-丙氧基、叔丁氧基、正丁氧基、戊氧基等,但不限于此。
在本发明中,“环烷基”是指衍生自碳原子数3至40个的单环或多环非-芳香族烃的一价取代基。这种环烷基的例可以包括环丙基、环戊基、环己基、降冰片基(norbornyl)、金刚烷(adamantine)等,但不限于此。
在本发明中,“杂环烷基”是指源自碳原子数3至40个的非-芳香族烃的一价取代基,环中一个以上的碳,优选1至3个碳被杂原子如N、O、S或Se取代。作为这种杂环烷基的例可以包括吗啉、哌嗪等,但不限于此。
在本发明中,“稠合环”是指稠合脂肪族环、稠合芳香族环、稠合杂脂肪族环、稠合杂芳香族环或它们组合的形式。
此外,本发明提供以式1表示的化合物的盐,优选提供药学上可接受的盐。
其中,“药学上可接受的盐”是指在纯医学判断范围内,适用于与人体和低等动物组织接触使用而不会引起过度毒性、刺激、过敏反应等的盐。上述药学上可接受的盐是本领域众所周知的,作为一例,详细描述于文献(S.M.Berge et al.,J.ParmaceuticalSciences,66,1,1977)中。盐可以在最终分离和纯化本发明的化合物的过程中在相同反应体系中制备,或通过另外与无机碱或有机碱反应来制备。碱加成盐形式的优选实例可以包括如铵盐、锂、钠、钾、镁、钙等的盐的碱盐以及碱土金属盐,如一级、二级、三级脂肪族和芳香族胺的有机碱的盐,如甲胺、乙胺、丙胺、异丙胺、4种丁胺异构体、二甲胺、二乙胺、二乙醇胺、二丙胺、二异丙胺、二正丁胺、吡咯烷、哌啶、吗啉、三甲胺、三乙胺、三丙胺、奎宁环(quinuclidine)、吡啶、喹啉以及异喹啉、苄星(benzathine)、N-甲基-D-葡糖胺、2-氨基-2-(羟甲基)-1,3-丙二醇、海巴胺(hydrabamine)盐,以及基于如精氨酸、赖氨酸等的氨基酸的盐等。
此外,本发明可以包括上述以式1表示的化合物的水合物或溶剂化物、它们的衍生物化合物。在上述溶剂化物中,对溶剂没有特别限制,可以包括本领域公知的常规溶剂。
<免疫调节剂>
本发明的另一个实例涉及包含以下述式1表示的化合物、其药学上可接受的盐、或溶剂化物作为有效成分的免疫调节剂。具体地,上述免疫调节剂可以是抑制免疫反应的免疫抑制剂。
在本说明书中,“有效成分”是指单独表现出目标活性或与本身没有活性的载体一起表现出活性的成分,对其具体含量值没有特别限制。
相对于组合物总重量,根据本发明的免疫调节剂可以包含0.01至99重量百分比的式1的化合物作为有效成分,具体地,可以包含0.1至95重量百分比。此外,除了上述有效成分以外,本发明的免疫调节剂还可以包含表现出相同或类似功能的一种以上有效成分。
本发明的免疫调节剂可以包括药剂学上合适且生理学上可接受的制剂中通常使用的载体、稀释剂、赋形剂或它们的混合物。药学上可接受的载体只要是能适用于将组合物递送到生物体内,则均可以使用。具体地,载体是记载于现有文件(Merck Index,13th ed.,Merck&Co.Inc.)中的化合物、盐水、无菌水、林格氏溶液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇或它们的混合物。此外,可以根据需要添加抗氧化剂、缓冲剂、抑菌剂等常规添加剂。
在将上述组合物制剂化的情况下,可以添加通常使用的填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等的稀释剂或赋形剂。
本发明的免疫调节剂可以剂型化为口服制剂或非口服制剂。口服制剂可包括固体制剂及液体制剂。上述固体制剂可以是片剂、丸剂、散剂、颗粒剂、胶囊剂或锭剂,这种固体制剂可以通过向上述组合物添加至少一种赋形剂来制备。上述赋形剂可以是淀粉、碳酸钙、蔗糖、乳糖、明胶或它们的混合物。此外,上述固体制剂可包括润滑剂,作为其例,包括硬脂酸镁、滑石等。另外,液体制剂可以是混悬剂、内服液剂、乳剂或糖浆。此时,上述液体制剂可以包括润湿剂、甜味剂、芳香剂、保存剂等赋形剂。
上述非口服制剂可包括注射剂、栓剂、呼吸系统吸入用粉末、喷雾用气雾剂、粉剂和霜剂等。上述注射剂可包括无菌水溶液、非水性溶液、悬浮剂、乳剂等。此时,作为非水性溶剂或悬浮剂,可以使用丙二醇、聚乙二醇、橄榄油等的植物油、或油酸乙酯等可注射的酯。
根据目的,本发明的免疫调节剂可以是口服或非经胃肠道给药。非经胃肠道给药可包括腹膜内、直肠内、皮下、静脉内、肌肉内或胸腔内注射方式。
上述免疫调节剂可以以药学上的有效剂量来进行给药。这可能根据疾病的类型、严重程度、药物活性、患者对药物的敏感性、给药时间、给药途径、治疗周期、同时使用的药物等而不同。然而,为了获得优选效果,根据本发明的药物组合物中所含有效成分可以是0.0001至1000mg/kg,具体以0.001至500mg/kg的剂量给药,所述给药可以是一天一次或数次。
本发明的免疫调节剂可以单独给药或与其他治疗剂联合给药。联合给药时,给药可以是依次给药或同时给药。
<用于调节免疫的健康功能食品>
根据本发明的另一实例涉及包含以下述式1表示的化合物、其药学上可接受的盐、或溶剂化物作为有效成分的用于调节免疫的健康功能食品。
其中,“健康功能食品”是指以辅助健康为目的,将具有对人体有益功能的特定成分作为原料,或通过对视频原料所含的特定成分进行提取、浓缩、纯化、混合等来制造和加工的食品,可具有与疾病的预防和疾病的恢复等相关的功能。
根据本发明的健康功能食品可以直接添加上述化合物或与其他食品或食品组合物一起使用。此时,有效成分的使用量可根据使用目的来适当地确定,对其并没有特别限制。通常,当制备食品或饮料时,与总重量相比,可以添加0.001至99重量百分比的根据本发明的式1的化合物、其异构体、药学上可接受的盐或溶剂化物,具体地,可以添加0.1至95重量百分比。
除了如上所述的式1的化合物、其异构体、药学上可接受的盐或溶剂化物以外,本发明的健康功能食品可以包含本领域食品组合物中常用的成分。例如,可以包含选自由有机酸、磷酸盐、抗氧化剂、乳糖、酪蛋白、糊精、葡萄糖、白砂糖和山梨糖醇组成的组中的一种以上的添加剂。此外,还可以包含各种营养剂、维生素、矿物质(电解质)、如合成调味剂和天然调味剂等的调味剂、着色剂和增稠剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、用于碳酸饮料的碳酸化剂等。
本发明的健康功能食品可以制备成本领域通常制备的任意剂型,作为一例,以片剂、颗粒剂、丸剂、胶囊剂、液体制剂、糖浆剂或饮料剂型形式提供的健康功能食品也属于本发明的范畴。
在本发明的健康功能食品中,对于可添加上述式1的化合物、其异构体、药学上可接受的盐或溶剂化物的食品的种类不进行限定。例如,可以包括各种食品类、粉末、颗粒、片剂、胶囊、糖浆剂、饮料、口香糖、茶、维生素复合物、健康功能食品类等。更具体的例子包括肉类、香肠、面包、巧克力、糖果类、零食类、饼干类、比萨、拉面、其他面类、口香糖类、包括冰淇淋在内的乳制品、各种汤、饮料、茶、能量饮料、酒精饮料和维生素复合物、其他营养剂,但不限于这些种类的食物。
同时,本发明提供以式1表示的化合物、其药学上可接受的盐、或溶剂化物在制备免疫调节用药物中的用途。
本发明的免疫调节用药物的制备中使用的以式1表示的化合物、其药学上可接受的盐、或溶剂化物可以具有如上所述的特征。
以下,通过实施例更详细地说明本发明。对于本领域普通技术人员而言显而易见的是,这些实施例用于更具体说明本发明,本发明的范围可以根据本发明的要旨而定,而不是受这些实施例的限制。
制备例1:化合物1的合成
1-1:(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-3-(苯基硒烷基)哌啶-1-基)丙-1-烯-
1-基)苯甲酸甲酯((E)-methyl-2-methoxy-5-(3-oxo-3-(2-oxo-3-(phenylselanyl)
piperidin-1-yl)prop-1-en-1-yl)benzoate)(化合物1f)的制备
在氩气气氛下,在25mL的圆底烧瓶中加入(E)-2-甲氧基-5-(3-氧代-3-(2-氧代哌啶-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物1e)(0.22g,0.68mmol),加入四氢呋喃(3.70mL)后,使温度降低至-78℃,滴加LDA(二异丙基氨基锂)(0.45mL,0.88mmol,2.0M溶液),搅拌45分钟。将苯基氯化硒(0.14g,0.75mmol)溶解在四氢呋喃(3.75mL)中,在-78℃条件下缓慢加入,搅拌4.5小时。反应结束后,添加水,分解剩余LDA后,在0℃条件下再搅拌15分钟,用二氯甲烷提取2次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸发后,通过硅胶层析(乙酸乙酯/己烷=1/4至1/3)分离,得到作为白色固体的(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-3-(苯基硒烷基)哌啶-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物1f)(100mg,31.2%)。
1H NMR(400MHz,氯仿-d)δ7.95(d,J=2.3Hz,1H),7.72-7.68(m,2H),7.67-7.60(m,2H),7.38-7.31(m,3H),7.05(d,J=15.6Hz,1H),6.98(d,J=8.8Hz,1H),4.11(t,J=5.3Hz,1H),3.95(s,3H),3.92(s,3H),3.71(ddd,J=13.7,9.2,4.6Hz,1H),2.32(tq,J=10.5,5.4Hz,1H),2.19-2.05(m,2H),1.26(d,J=2.7Hz,2H).
1-2:(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-5,6-二氢吡啶-1(2H)-基)丙-1-烯-1-
基)苯甲酸甲酯((E)-methyl-2-methoxy-5-(3-oxo-3-(2-oxo-5,6-dihydropyridin-1
(2H)-yl)prop-1-en-1-yl)benzoate)(化合物1)
在氩气气氛下,在25mL的圆底烧瓶中加入上述1-1中制备的(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-3-(苯基硒烷基)哌啶-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物1f)(0.10g,0.21mmol),四氢呋喃(2.00mL)后,使温度降低至0℃,滴加过氧化氢(0.05mL,0.59mmol,30%溶液),搅拌15分钟后,升温至室温,再搅拌30分钟。反应结束后,添加饱和碳酸氢钠溶液,用二氯甲烷提取2次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸发后,通过硅胶层析(乙酸乙酯/己烷=1/1.5)分离,得到作为白色固体的(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-5,6-二氢吡啶-1(2H)-基)丙-1-烯-1-基)苯甲酸甲酯(化合物1)(40mg,60.6%)。
1H NMR(400MHz,氯仿-d)δ8.01(d,J=2.4Hz,1H),7.74-7.66(m,2H),7.43(d,J=15.7Hz,1H),7.00-6.92(m,2H),6.05(dt,J=9.6,1.8Hz,1H),4.04(t,J=6.5Hz,2H),3.94(s,3H),3.90(s,3H),2.48(tdd,J=6.3,4.2,1.9Hz,2H).
13C NMR(101MHz,氯仿-d)δ168.92,166.08,165.86,160.38,145.51,142.33,133.42,131.75,127.39,125.87,120.69,120.48,112.24,56.22,52.20,41.65,24.81.
制备例2:(E)-2-甲氧基-5-(3-(4-甲基哌嗪-1-基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯((E)-methyl-2-methoxy-5-(3-(4-methylpiperazin-1-yl)-3-oxoprop-1-en-1-yl)benzoate)(化合物2)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入(E)-3-(4-甲氧基-3-(甲氧基羰基)苯基)丙烯酸(化合物2b)(0.20g,0.85mmol),加入二氯甲烷(12.0mL),使温度降低至0℃,缓慢加入三乙胺(0.18mL,1.28mmol)和特戊酰氯(0.12mL,0.94mmol),在相同温度下搅拌45分钟。之后,将甲基哌嗪(2d)(0.15mL,1.28mmol)缓慢加入到反应混合物,室温搅拌2小时。反应结束后,将饱和碳酸氢钠溶液加入到混合物,终止反应,添加水以稀释混合物。水溶液层用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤2次,用无水硫酸钠干燥,减压蒸馏除去混合物的溶剂后,通过硅胶层析(甲醇/二氯甲烷=1/25)分离,得到作为淡黄色油状的(E)-2-甲氧基-5-(3-(4-甲基哌嗪-1-基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(化合物2)(250mg,61.4%)。
1H NMR(400MHz,氯仿-d)δ8.00(d,J=2.3Hz,1H),7.66-7.56(m,2H),6.98(d,J=8.7Hz,1H),6.80(d,J=15.4Hz,1H),3.94(s,3H),3.92(s,3H),3.73-3.62(m,4H),2.45(t,J=5.1Hz,4H),2.33(s,3H).
制备例3:化合物3的合成
3-1:3,3-二氯哌啶-2-酮(3,3-dichloropiperidin-2-one)(化合物3f)的制备
在氩气气氛下,在100mL的圆底烧瓶中加入哌啶-2-酮(化合物3e)(2.00g,20.18mmol),加入氯仿(20.00mL)后,使温度降低至0℃,以10分钟缓慢加入五氯化磷(12.80g,61.33mmol),并在60℃回流搅拌。反应结束后,使温度降低至室温后,将混合物放入冰水中。水溶液层用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸镁干燥,减压蒸发后,无需额外的纯化过程,得到作为白色固体的3,3-二氯哌啶-2-酮(化合物3f)(4.00g)。
1H NMR(400MHz,氯仿-d)δ6.18(s,1H),3.44(td,J=6.2,2.4Hz,2H),2.82-2.74(m,2H),2.15-2.05(m,2H).
3-2:3-氯-5,6-二氢吡啶-2(1H)-酮(3-chloro-5,6-dihydropyridin-2(1H)-one)
(化合物3d)的制备
在氩气气氛下,在50mL的圆底烧瓶中加入上述3-1中制备的3,3-二氯哌啶-2-酮(化合物3f)(4.00g,24.04mmol),加入二甲基甲酰胺(12.00mL)后,添加碳酸锂(3.70g,49.30mmol),在120℃加热搅拌7小时。反应结束后,使温度降低至室温后,将混合物放入冰水中。水溶液层用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸镁干燥后,通过硅胶层析(乙酸乙酯/己烷=1/1.5至1/1)分离,得到作为棕色固体的3-氯-5,6-二氢吡啶-2(1H)-酮(化合物3d)(0.55g,17.6%)。
1H NMR(400MHz,氯仿-d)δ6.78(t,J=4.6Hz,1H),6.70(s,1H),3.53-3.43(m,2H),2.48(td,J=7.1,4.5Hz,2H).
3-3:(E)-5-(3-(3-氯-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-
2-甲氧基苯甲酸甲酯((E)-methyl-5-(3-(3-chloro-2-oxo-5,6-dihydropyridin-1(2H)-
yl)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate)(化合物3)的制备
在氩气气氛下,在25mL的圆底烧瓶中加入上述3-2中制备的3-氯-5,6-二氢吡啶-2(1H)-酮(化合物3d)(0.10g,0.77mmol),加入四氢呋喃(1.50mL)后,使温度降低至-78℃,滴加LDA(0.40mL,0.77mmol,2.0M溶液),搅拌45分钟。将(E)-5-(3-氯-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物3c)(0.16g,0.64mmol)溶解于四氢呋喃(1.50mL)中,在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次,乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为白色固体的(E)-5-(3-(3-氯-2-氧代-5,6-二羟基吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物3)(98mg,43.8%)。
1H NMR(400MHz,氯仿-d)δ8.02(d,J=2.3Hz,1H),7.74(d,J=15.3Hz,1H),7.71-7.69(m,1H),7.43(d,J=15.6Hz,1H),7.09(t,J=4.6Hz,1H),6.98(d,J=8.7Hz,1H),4.09(t,J=6.5Hz,2H),3.95(s,3H),3.91(s,3H),2.57(td,J=6.5,4.6Hz,2H).
13C NMR(101MHz,氯仿-d)δ168.52,166.01,161.46,160.58,143.43,141.09,133.53,131.84,128.29,127.13,120.59,119.91,112.27,56.24,52.23,41.76,25.32.
制备例4:化合物5的合成
4-1:(E)-3-(4-甲氧基-3-(甲氧基羰基)苯基)丙烯酸((E)-3-(4-methoxy-3-
((ethoxycarbonyl)phenyl)acrylic acid)(化合物5b)的制备
将搅拌好的碳酸钾水溶液(1.06g/2.50mL蒸馏水,7.64mmol)、乙二醇(2.50mL)、丙烯酸(0.48mL,6.76mmol)、乙醇(0.25mL),甲酸钠(14.0mg,0.20mmol)、和PdCl2(DMAP)4(13.0mg,0.02mmol)的混合物加入到5-碘-2-甲氧基苯甲酸甲酯(化合物5a)(1.50g,5.14mmol)。将混合物小心搅拌5分钟后,回流直至形成黑色钯沉淀。将反应混合物冷却至室温后,用1N盐酸溶液调节至pH 1。过滤生成的固体后,用水洗涤3次,干燥,得到白色固体化合物(E)-3-(4-甲氧基-3-(甲氧基羰基)苯基)丙烯酸(化合物5b)(1.02g,83.4%)。
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),7.94-7.87(m,2H),7.56(d,J=16.0Hz,1H),7.20(d,J=8.7Hz,1H),6.45(d,J=15.9Hz,1H),3.86(s,3H),3.80(s,3H),2.09(s,1H).
13C NMR(101MHz,DMSO-d6)δ167.60,165.81,159.23,142.53,133.05,130.48,126.40,120.66,117.98,112.96,60.19,56.08,52.02.
4-2:1H-吡咯-2(5H)-酮(1H-pyrrol-2(5H)-one)(化合物5d)的制备
在氩气气氛在,在圆底烧瓶中加入吡咯(5.0mL,72.0mmol)和碳酸钡(1.50g,7.60mmol)后,加入蒸馏水(0.30L),并滴加30%过氧化氢(9.0mL)。安装冷凝器,回流5小时后,使温度降低至室温,使用10%亚硝酸钠溶液去除剩余过氧化氢。搅拌直至没有泡沫,用滤纸过滤,减压蒸馏溶剂。用1,4-二恶烷(50.0mL)溶解暗红色固体后,再用滤纸过滤,用1,4-二恶烷(50.0mL)洗涤后,用无水硫酸钠干燥,减压蒸馏,得到作为暗红色液体的1H-吡咯-2(5H)-酮(化合物5d)(1.42g,23.9%)。
1H NMR(400MHz,CDCl3):δ9.27(1H,br s),7.16-7.19(1H,dt,J=6.0,1.8Hz),6.17-6.19(1H,d,J=6.0Hz).4.50(2H,d,J=1.8Hz).
13C NMR(101MHz,CDCl3):δ175.5,146.2,127.8,49.2.
4-3:(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-1-
基)苯甲酸甲酯((E)-methyl-2-methoxy-5-(3-oxo-3-(2-oxo-2,5-dihydro-1H-pyrrol-1-
yl)prop-1-en-1-yl)benzoate)(化合物5)的制备
在氩气气氛下,在50mL的圆底烧瓶中加入上述制备例4-2中制备的1H-吡咯-2(5H)-酮(化合物5d)(0.21g,2.55mmol),加入四氢呋喃(3.30mL)后,使温度降低至-78℃,滴加LDA(1.30mL,2.55mmol,2.0M溶液),搅拌45分钟。将(E)-5-(3-氯-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物5c)(0.54g,2.12mmol)溶解于四氢呋喃(2.70mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取,用饱和氯化钠溶液洗涤乙酸乙酯层,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为黄色固体的(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物5)(75mg,30.0%)。
1H NMR(400MHz,CDCl3)δ8.06(d,J=2.3Hz,1H),7.96(d,J=15.7Hz,1H),7.86(d,J=15.7Hz,1H),7.78(dd,J=8.7,2.3Hz,1H),7.35(dt,J=6.0,2.1Hz,1H),7.01(d,J=8.8Hz,1H),6.22(dt,J=6.0,1.9Hz,1H),4.54(t,J=2.0Hz,2H),3.96(s,3H),3.92(s,3H).
13C NMR(101MHz,氯仿-d)δ170.21,166.02,165.20,160.68,146.84,144.71,133.49,132.25,127.87,127.16,120.56,117.39,112.32,56.25,52.25,51.11.
制备例5:化合物4的合成
5-1:(E)-2-羟基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-1-
基)苯甲酸甲酯((E)-methyl-2-hydroxy-5-(3-oxo-3-(2-oxo-2,5-dihydro-1H-pyrrol-1-
yl)prop-1-en-1-yl)benzoate)(化合物4a)的制备
在氩气气氛的圆底烧瓶中加入上述制备例4中制备的(E)-2-甲氧基-5-(3-氧代-3-(2-氧代-2,5-二氢-1-吡咯-1-烯-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物5)(70mg,0.23mmol)和四氢呋喃(4.0mL),使温度降低至0℃,10分钟后缓慢添加三溴化硼溶液(1.0M的二氯甲烷溶液,0.70mL,0.69mmol),搅拌4小时,并使反应温度逐渐升至室温。通过TLC确认是否反应,若反应完成,将反应温度再降至0℃,用0.50mL的1N盐酸溶液终止反应。在相同温度下,再搅拌10分钟后,用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸发后,通过硅胶层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为棕色固体的(E)-2-羟基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物4a)(10mg,15.2%)。
1H NMR(400MHz,氯仿-d)δ11.05(s,1H),8.11(d,J=2.3Hz,1H),7.95(d,J=15.8Hz,1H),7.85(d,J=15.8Hz,1H),7.80(dd,J=8.7,2.3Hz,1H),7.35(dt,J=6.0,2.1Hz,1H),7.03(d,J=8.7Hz,1H),6.22(dt,J=6.0,1.9Hz,1H),4.54(t,J=1.9Hz,2H),3.99(s,3H).
5-2:(E)-2-乙酰氧基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-
1-基)苯甲酸甲酯((E)-methyl-2-acetoxy-5-(3-oxo-3-(2-oxo-2,5-dihydro-1H-pyrrol-
1-yl)prop-1-en-1-yl)benzoate)(化合物4)的制备
在氩气气氛下,在圆底烧瓶中加入制备例5-1中制备的(E)-2-羟基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物4a)(10mg,0.04mmol)和二氯甲烷(1.0mL),使温度降低至0℃。10分钟后,加入三乙胺(11.2μL,0.08mmol)搅拌5分钟。在相同温度,缓慢添加乙酸钠(5.70μL,0.08mmol),温度保持0℃,搅拌1小时。通过TLC确认是否反应,反应完成后,用1.0mL的蒸馏水终止反应,用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸发后,通过硅胶层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为黄色固体的(E)-2-乙酰氧基-5-(3-氧代-3-(2-氧代-2,5-二氢-1H-吡咯-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物4)(5.0mg,43.5%)。
1H NMR(400MHz,氯仿-d)δ8.24(d,J=2.2Hz,1H),8.05(d,J=15.8Hz,1H),7.89(d,J=15.8Hz,1H),7.85(dd,J=8.4,2.3Hz,1H),7.37(dt,J=6.2,2.1Hz,1H),7.16(d,J=8.4Hz,1H),6.23(dt,J=6.1,1.9Hz,1H),4.55(t,J=2.0Hz,2H),3.91(s,3H),2.37(s,3H).
制备例6:(E)-5-(3-乙酰氨基-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯((E)-methyl-5-(3-acetamido-3-oxoprop-1-en-1-yl)-2-methoxybenzoate)(化合物6)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入(E)-5-(3-氯-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物6c)(0.22g,0.85mmol),加入二甲基甲酰胺(12.00mL)后,添加乙酰胺(0.06mL,1.23mmol),回流搅拌16小时。反应结束后,使温度降低至室温后,减压蒸馏去除混合物的溶剂后,通过硅胶层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为白色固体的(E)-5-(3-乙酰氨基-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物6)(30mg,12.7%)。
1H NMR(400MHz,氯仿-d)δ8.11(s,1H),8.03(d,J=2.4Hz,1H),7.77(d,J=15.6Hz,1H),7.68(dd,J=8.8,2.5Hz,1H),7.01(d,J=8.7Hz,1H),6.79(d,J=15.7Hz,1H),3.96(s,3H),3.92(s,3H),2.45(s,3H).
制备例7:(E)-5-(3-(烯丙胺)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯((E)-methyl-5-(3-(allylamino)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate)(化合物7)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入(E)-5-(3-氯-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物7c)(0.22g,0.85mmol),加入乙醚(2.50mL)后,使温度降低至0℃,缓慢加入烯丙胺(7d)(0.64mL,8.50mmol),在相同温度搅拌10分钟。反应结束后,减压蒸馏去除混合物的溶剂后,通过硅胶层析(乙酸乙酯/己烷=1/3至1/2)分离,得到作为白色固体的(E)-5-(3-(烯丙胺)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物7)(172mg,73.5%)。
1H NMR(400MHz,氯仿-d)δ7.99(d,J=2.4Hz,1H),7.63-7.56(m,2H),6.98(d,J=8.7Hz,1H),6.34(d,J=15.6Hz,1H),5.90(ddt,J=17.1,10.2,5.6Hz,1H),5.63(s,1H),5.29-5.13(m,2H),4.03(tt,J=5.8,1.5Hz,2H),3.94(s,3H),3.91(s,3H).
制备例8:(E)-2-甲氧基-5-(3-氧代-3-(2-氧代哌啶-1-基)丙-1-烯-1-基)苯甲酸甲酯((E)-methyl-2-methoxy-5-(3-oxo-3-(2-oxopiperidin-1-yl)prop-1-en-1-yl)benzoate)(化合物8)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入2-哌啶酮(化合物8d)(0.15g,1.53mmol),加入四氢呋喃(2.00mL)后,使温度降低至-78℃,滴加LDA(0.80mL,1.53mmol,2.0M溶液),搅拌45分钟。将(E)-5-(3-氯-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物8c)(0.32g,1.27mmol)溶解在四氢呋喃(1.60mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次,乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,进行减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2.5至1/2)分离,得到作为白色固体的(E)-2-甲氧基-5-(3-氧代-3-(2-氧代哌啶-1-基)丙-1-烯-1-基)苯甲酸甲酯(化合物8)(215mg,53.5%)。
1H NMR(400MHz,氯仿-d)δ8.00(d,J=2.3Hz,1H),7.69-7.64(m,2H),7.36(d,J=15.6Hz,1H),6.98(d,J=8.7Hz,1H),3.94(s,3H),3.90(s,3H),3.80(td,J=5.2,4.2,2.2Hz,2H),2.65-2.57(m,2H),1.95-1.84(m,4H).
制备例9:化合物9的合成
9-1:3,3-二溴哌啶-2-酮(3,3-dibromopiperidin-2-one)(化合物9f)的制备
在氩气气氛下,在100mL的圆底烧瓶中加入哌啶-2-酮(化合物9e)(2.00g,20.18mmol),加入二氯甲烷(40.00mL)后,使温度降低至0℃,以5分钟缓慢添加五氯化磷(8.40g,40.36mmol)后,搅拌5分钟。在相同温度,加入碘化锌(0.20g,0.61mmol)后,将温度上升至室温,搅拌1小时。1小时后,缓慢加入溶解在二氯甲烷(20.00mL)的双原子溴(2.20mL,40.36mmol),在相同温度搅拌12小时。反应结束后,使温度降低至室温后,将混合物放入冰水中。水溶液层用二氯甲烷提取5次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸镁干燥,减压蒸馏去除混合物的溶剂,通过硅胶层析(乙酸乙酯/己烷=1/2.5至1/1)分离,得到作为白色固体的3,3-二溴哌啶-2-酮(化合物9f)(1.32g,25.5%)。
1H NMR(400MHz,氯仿-d)δ6.17(s,1H),3.47(td,J=6.2,2.4Hz,2H),3.02-2.95(m,2H),2.08-2.01(m,2H).
9-2:3-溴-5,6-二氢吡啶-2(1H)-酮(3-bromo-5,6-dihydropyridin-2(1H)-one)
(化合物9d)的制备
在氩气气氛下,在50mL的圆底烧瓶中加入上述制备例9-1中制备的3,3-二溴哌啶-2-酮(化合物9f)(1.32g,5.14mmol),加入二甲基甲酰胺(10.00mL)后,添加碳酸锂(0.72g,9.80mmol)和氯化锂(0.22g,5.24mmol),在120℃加热搅拌13小时。反应结束后,使温度降低至室温后,将混合物放入冰水中。水溶液层用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸镁干燥后,通过硅胶层析(乙酸乙酯/己烷=1/1.5至1/1)分离,得到作为亮棕色固体的3-溴-5,6-二氢吡啶-2(1H)-酮(化合物9d)(0.36g,39.9%)。
1H NMR(400MHz,氯仿-d)δ7.05(t,J=4.6Hz,1H),6.96(s,1H),3.49(td,J=7.1,2.8Hz,2H),2.43(td,J=7.1,4.5Hz,2H)
9-3:(E)-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-
2-甲氧基苯甲酸甲酯((E)-methyl-5-(3-(3-bromo-2-oxo-5,6-dihydropyridin-1(2H)-
yl)-3-oxoprop-1-en-1-yl)-2-methoxybenzoate)(化合物9)的制备
在氩气气氛下,在25mL的圆底烧瓶中加入上述制备例9-2中制备的3-溴-5,6-二氢吡啶-2(1H)-酮(化合物9d)(0.14g,0.77mmol),加入四氢呋喃(1.50mL)后,使温度降低至-78℃,滴加LDA(0.40mL,0.77mmol,2.0M溶液),搅拌45分钟。将(E)-5-(3-氯-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物9c)(0.16g,0.64mmol)溶解于四氢呋喃(1.50mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次,乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为白色固体的(E)-5-(3-(3-溴-2-氧代-5,6-二羟基吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物9)(91mg,36.1%)。
1H NMR(400MHz,氯仿-d)δ8.01(d,J=2.3Hz,1H),7.77-7.68(m,2H),7.42(d,J=15.6Hz,1H),7.36(t,J=4.6Hz,1H),6.98(d,J=8.7Hz,1H),4.10(t,J=6.5Hz,2H),3.95(s,3H),3.91(s,3H),2.53(td,J=6.5,4.5Hz,2H).
制备例10:(E)-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-羟基苯甲酸甲酯((E)-methyl-5-(3-(3-bromo-2-oxo-5,6-dihydropyridin-1(2H)-yl)-3-oxoprop-1-en-1-yl)-2-hydroxybenzoate)(化合物10)的合成
在氩气气氛的圆底烧瓶中加入上述制备例9中制备的(E)-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物9)(220mg,0.56mmol)和四氢呋喃(10.0mL),使温度降低至-10℃,10分钟后,缓慢添加三溴化硼溶液(1.0M二氯甲烷溶液,1.60mL,1.67mmol),搅拌1小时,并使反应温度逐渐升至常温。通过TLC确认是否反应,若反应完成,将反应温度再降至0℃,用1.50mL的1N盐酸溶液终止反应。在相同温度再搅拌10分钟后,用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过硅胶层析(乙酸乙酯/己烷=1/3至1/2)分离,得到作为白色固体的(E)-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-羟基苯甲酸甲酯(化合物10)(76.5mg,35.9%)。
1H NMR(400MHz,氯仿-d)δ11.03(s,1H),8.07(d,J=2.3Hz,1H),7.76–7.68(m,2H),7.41(d,J=15.6Hz,1H),7.36(t,J=4.6Hz,1H),7.00(d,J=8.6Hz,1H),4.10(t,J=6.5Hz,2H),3.99(s,3H),2.53(td,J=6.5,4.6Hz,2H).
制备例11:(E)-2-乙酰氧基-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯((E)-methyl-2-acetoxy-5-(3-(3-bromo-2-oxo-5,6-dihydropyridin-1(2H)-yl)-3-oxoprop-1-en-1-yl)benzoate)(化合物11)的合成
在氩气气氛下,在圆底烧瓶中加入上述制备例10中制备的(E)-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-羟基苯甲酸甲酯(化合物10)(30mg,0.08mmol)和二氯甲烷(2.0mL),温度降至0℃。10分钟后,加入三乙胺(20.3μL,0.16mmol),搅拌5分钟。在相同温度缓慢加入乙酰氯(11.4μL,0.16mmol)后,温度继续维持0℃,并搅拌1小时。通过TLC确认是否反应,反应结束后,用2.0mL的蒸馏水终止反应。之后,用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过硅胶层析(乙酸乙酯/己烷=1/3至1/2)分离,得到作为黄色固体的(E)-2-乙酰氧基-5-(3-(3-溴-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(化合物11)(34.0mg,87.4%)。
1H NMR(400MHz,氯仿-d)δ8.20(d,J=2.2Hz,1H),7.78(dd,J=8.5,2.4Hz,1H),7.74(d,J=15.7Hz,1H),7.49(d,J=15.6Hz,1H),7.37(t,J=4.6Hz,1H),7.13(d,J=8.4Hz,1H),4.11(t,J=6.5Hz,2H),3.90(s,3H),2.54(td,J=6.4,4.5Hz,2H),2.36(s,3H).
制备例12:(E)-5-(3-(3-氯-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-羟基苯甲酸甲酯((E)-methyl-5-(3-(3-chloro-2-oxo-5,6-dihydropyridin-1(2H)-yl)-3-oxoprop-1-en-1-yl)-2-hydroxybenzoate)(化合物12)的合成
在氩气气氛的圆底烧瓶中加入上述制备例3中制备的(E)-5-(3-(3-氯-2-氧代-5,6-二羟基吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯甲酸甲酯(化合物3)(240mg,0.69mmol)和四氢呋喃(13.0mL),温度降至-10℃。10分钟后,缓慢添加三溴化硼溶液(1.0M的二氯甲烷溶液,2.06mL,2.06mmol),搅拌1小时,并使反应温度逐渐升至常温。通过TLC确认是否反应,若反应完成,将反应温度再降至0℃,用1.50mL的1N盐酸溶液终止反应。在相同温度再搅拌10分钟后,用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过硅胶层析(乙酸乙酯/己烷=1/3至1/2)分离,得到作为白色固体的(E)-5-(3-(3-氯-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-羟基苯甲酸甲酯(化合物12)(55.7mg,24.1%)。
1H NMR(400MHz,氯仿-d)δ11.03(s,1H),8.08(d,J=2.5Hz,1H),7.76–7.69(m,2H),7.42(d,J=15.6Hz,1H),7.10(t,J=4.6Hz,1H),7.00(d,J=8.6Hz,1H),4.09(t,J=6.5Hz,2H),3.99(s,3H),2.57(td,J=6.5,4.6Hz,2H).
制备例13:(E)-2-乙酰氧基-5-(3-(3-氯-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯((E)-methyl-2-acetoxy-5-(3-(3-chloro-2-oxo-5,6-dihydropyridin-1(2H)-yl)-3-oxoprop-1-en-1-yl)benzoate)(化合物13)的合成
在氩气气氛下,在圆底烧瓶中加入上述制备例12中制备的(E)-5-(3-(3-氯-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)-2-羟基苯甲酸甲酯(化合物12)(41mg,0.12mmol)和二氯甲烷(2.0mL),温度降至0℃。10分钟后,加入三乙胺(33.5μL,0.24mmol),搅拌5分钟。在相同温度缓慢添加乙酸钠(17.1μL,0.24mmol)后,温度继续维持0℃,搅拌1小时。通过TLC确认是否反应,反应结束后,用2.0mL的蒸馏水终止反应。用二氯甲烷提取3次,有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过硅胶层析(乙酸乙酯/己烷=1/3至1/2)分离,得到作为黄色固体的(E)-2-乙酰氧基-5-(3-(3-氯-2-氧代-5,6-二氢吡啶-1(2H)-基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(化合物13)(30.0mg,66.2%)。
1H NMR(400MHz,氯仿-d)δ8.20(d,J=2.2Hz,1H),7.81–7.71(m,2H),7.50(d,J=15.6Hz,1H),7.15–7.09(m,2H),4.10(t,J=6.5Hz,2H),3.90(s,3H),2.59(td,J=6.4,4.6Hz,2H),2.36(s,3H).
制备例14:化合物14的合成
14-1:(E)-3-(3-硝基苯基)丙烯酸((E)-3-(3-nitrophenyl)acrylic acid)(化合
物14b)的制备
在氩气气氛下,在0℃,在装有碳酸钾(3.32g,24.0mmol)的圆底烧瓶中缓慢加入无水乙酸(8.0mL,84.6mmol),温度逐渐上升至常温,搅拌5分钟后,缓慢添加3-硝基苯甲醛(3-nitrobenzaldehyde)(化合物14a)(3.02g,20.0mmol)。在165℃回流反应混合物,搅拌15小时。反应结束后,温度降至常温,添加冰水后,用过滤装置过滤固体,用水洗涤数次后干燥。将得到的固体混合物溶解在乙酸乙酯(30.0mL)溶剂,用饱和碳酸氢钠水溶液(20.0mL)洗涤2次后,弃去乙酸乙酯层。用3N氯化氢水溶液酸化碳酸氢钠水溶液层后,用乙酸乙酯溶剂提取2次。有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,充分干燥,得到作为米黄色(beige)固体的(E)-3-(3-硝基苯基)丙烯酸(化合物14b)(2.20g,56.8%)。
1H NMR(400MHz,CDCl3+CD3OD):δ8.28(1H,t,J=1.6Hz),8.14(1H,ddd,J=8.4,2.4,1.2Hz),7.76(1H,dt,J=8.0,1.6Hz),7.62(1H,d,J=16.0Hz),7.50(1H,t,J=8.0Hz),6.46(1H,d,J=16.0Hz).
14-2:(E)-1-(3-(3-硝基苯基)丙烯酰)-1H-吡咯-2(5H)-酮((E)-1-(3-(3-
nitrophenyl)acryloyl)-1H-pyrrol-2(5H)-one)(化合物14)的制备
在氩气气氛下,在50mL的圆底烧瓶中加入1H-吡咯-2(5H)-酮(化合物14d)(0.11g,1.25mmol),加入四氢呋喃(1.50mL)后,使温度降低至-78℃,滴加LDA(0.63mL,1.25mmol,2.0M溶液),搅拌45分钟。将(E)-3-(3-硝基苯基)丙烯酰氯(化合物14c)(0.22g,1.04mmol)溶解在四氢呋喃(2.0mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取,乙酸乙酯层用饱和氯化钠溶液洗涤,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/3至1/2)分离,得到作为淡棕色固体的(E)-1-(3-(3-硝基苯基)丙烯酰)-1H-吡咯-2(5H)-酮(化合物14)(81mg,30.2%)。
1H NMR(400MHz,氯仿-d)δ8.39(t,J=2.0Hz,1H),8.23(ddd,J=8.2,2.3,1.1Hz,1H),7.83(dt,J=7.8,1.4Hz,1H),7.71(d,J=16.0Hz,1H),7.59(t,J=7.9Hz,1H),6.57(d,J=16.0Hz,1H),4.24(t,J=6.7Hz,2H).
13C NMR(100MHz,CDCl3):δ170.3,164.6,148.9,147.4,143.0,136.8,133.9,130.1,127.9,124.8,123.4,121.9,51.2.
制备例15:化合物15的合成
15-1:(E)-1-(3-(3-硝基苯基)丙烯酰)哌啶-2-酮((E)-1-(3-(3-nitrophenyl)
acryloyl)piperidin-2-one)(化合物15e)
在氩气气氛下,在25mL的圆底烧瓶中加入2-哌啶酮(化合物15d)(0.14g,1.40mmol),加入四氢呋喃(1.50mL)后,使温度降低至-78℃,滴加LDA(0.70mL,1.40mmol,2.0M溶液),搅拌45分钟。将(E)-3-(3-硝基苯基)丙烯酰氯(化合物15c)(0.25g,1.16mmol)溶解在四氢呋喃(1.80mL),在-78℃缓慢添加,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次,乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为白色固体的(E)-1-(3-(3-硝基苯基)丙烯酰)哌啶-2-酮(化合物15e)(165mg,52.1%)。
1H NMR(400MHz,氯仿-d)δ8.39(t,J=2.0Hz,1H),8.20(ddd,J=8.1,2.2,1.0Hz,1H),7.86(dt,J=7.8,1.4Hz,1H),7.67(d,J=15.7Hz,1H),7.56(t,J=8.0Hz,1H),7.50(d,J=15.6Hz,1H),3.82(ddd,J=6.4,4.2,1.5Hz,2H),2.67–2.59(m,2H),1.95–1.86(m,4H).
15-2:(E)-1-(3-(3-硝基苯基)丙烯酰)-3-(苯基硒烷基)哌啶-2-酮((E)-1-(3-
(3-nitrophenyl)acryloyl)-3-(phenylselanyl)piperidin-2-one)(化合物15f)的制备
在氩气气氛下,在25mL的圆底烧瓶中加入上述制备例15-1中制备的(E)-1-(3-(3-硝基苯基)丙烯酰)哌啶-2-酮(化合物15e)(0.16g,0.60mmol),加入四氢呋喃(3.50mL)后,使温度降低至-78℃,滴加LDA(0.40mL,0.78mmol,2.0M溶液),搅拌45分钟。将苯基氯化硒(0.13g,0.66mmol)溶解在四氢呋喃(3.50mL),在-78℃条件下缓慢加入,搅拌4小时。反应结束后,添加水分解剩余LDA后,在0℃条件下再搅拌15分钟,用二氯甲烷提取2次。有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过硅胶层析(乙酸乙酯/己烷=1/4至1/3)分离,得到作为白色固体的(E)-1-(3-(3-硝基苯基)丙烯酰)-3-(苯基硒烷基)哌啶-2-酮(化合物15f)(30mg,11.7%)。
1H NMR(400MHz,氯仿-d)δ8.33(t,J=2.0Hz,1H),8.21(ddd,J=8.2,2.3,1.0Hz,1H),7.78(dt,J=7.8,1.4Hz,1H),7.72–7.69(m,2H),7.65(d,J=15.6Hz,1H),7.56(t,J=8.0Hz,1H),7.43–7.34(m,3H),7.10(d,J=15.6Hz,1H),4.13(ddd,J=5.2,4.2,1.0Hz,1H),4.08–3.95(m,1H),3.70(ddd,J=14.0,9.7,4.6Hz,1H),2.46–2.28(m,1H),2.25–2.05(m,2H),1.90(dt,J=14.3,5.1Hz,1H).
15-3:(E)-1-(3-(3-硝基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮((E)-1-(3-(3-
nitrophenyl)acryloyl)-5,6-dihydropyridin-2(1H)-one)(化合物15)的制备
在氩气气氛下,在25mL的圆底烧瓶中加入上述制备例15-2中制备的(E)-1-(3-(3-硝基苯基)丙烯酰)-3-(苯基硒烷基)哌啶-2-酮(化合物15f)(28mg,0.07mmol),加入四氢呋喃(1.00mL)后,使温度降低至0℃,滴加过氧化氢(20μL,0.18mmol,30%溶液),搅拌15分钟后,温度上升至常温,再搅拌30分钟。反应结束后,添加饱和碳酸氢钠溶液,用二氯甲烷提取2次。有机层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过硅胶层析(乙酸乙酯/己烷=1/2)分离,得到作为白色固体的(E)-1-(3-(3-硝基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮(化合物15)(7.10mg,37.4%)。
1H NMR(400MHz,氯仿-d)δ8.41(t,J=2.0Hz,1H),8.21(ddd,J=8.1,2.2,1.0Hz,1H),7.88(d,J=7.7Hz,1H),7.73(d,J=15.7Hz,1H),7.60–7.54(m,2H),7.03–6.94(m,1H),6.07(dt,J=9.7,1.9Hz,1H),4.06(t,J=6.5Hz,2H),2.51(tdd,J=6.4,4.2,1.9Hz,2H).
制备例16:(E)-3-氯-1-(3-(3-硝基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮((E)-3-chloro-1-(3-(3-nitrophenyl)acryloyl)-5,6-dihydropyridin-2(1H)-one)(化合物16)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入3-氯-5,6-二氢吡啶-2(1H)-酮(化合物16d)(0.17g,1.31mmol),加入四氢呋喃(2.0mL)后,使温度降低至-78℃,滴加LDA(0.70mL,1.31mmol,2.0M溶液),搅拌45分钟。将(E)-3-(3-硝基苯基)丙烯酰氯(化合物16c)(0.23g,1.09mmol)溶解在四氢呋喃(1.50mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次。乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为淡黄色固体的(E)-3-氯-1-(3-(3-硝基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮(化合物16)(135mg,40.7%)。
1H NMR(400MHz,氯仿-d)δ8.40(t,J=2.0Hz,1H),8.23(ddd,J=8.2,2.3,1.0Hz,1H),7.90(d,J=7.7Hz,1H),7.75(d,J=15.7Hz,1H),7.61–7.53(m,2H),7.13(t,J=4.6Hz,1H),4.11(t,J=6.5Hz,2H),2.60(td,J=6.5,4.6Hz,2H).
制备例17:(E)-3-溴-1-(3-(3-硝基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮((E)-3-bromo-1-(3-(3-nitrophenyl)acryloyl)-5,6-dihydropyridin-2(1H)-one)(化合物17)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入3-溴-5,6-二氢吡啶-2(1H)-酮(化合物17d)(0.22g,1.25mmol),加入四氢呋喃(2.0mL)后,使温度降低至-78℃,滴加LDA(0.63mL,1.25mmol,2.0M溶液),搅拌45分钟。将(E)-3-(3-硝基苯基)丙烯酰氯(化合物17c)(0.22g,1.04mmol)溶解在四氢呋喃(1.50mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次,乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2.5至1/2)分离,得到作为淡黄色固体的(E)-3-溴-1-(3-(3-硝基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮(化合物17)(110mg,30.1%)。
1H NMR(400MHz,氯仿-d)δ8.40(t,J=2.0Hz,1H),8.22(ddd,J=8.1,2.3,1.0Hz,1H),7.90(d,J=7.6Hz,1H),7.75(d,J=15.6Hz,1H),7.62–7.53(m,2H),7.39(t,J=4.6Hz,1H),4.12(t,J=6.5Hz,2H),2.56(td,J=6.4,4.6Hz,2H).
制备例18:化合物18的合成
18-1:(E)-3-(2,3-二氢苯并[b][1,4]二恶烷-6-基)丙烯酸((E)-3-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)acrylicacid)(化合物18b)的制备
在氩气气氛下,在0℃条件将无水乙酸(4.0mL,42.2mmol)缓慢加入到装有碳酸钾(1.04g,7.54mmol)的圆底烧瓶,使温度逐渐上升至常温,搅拌5分钟后,缓慢加入2,3-二氢苯并[b][1,4]二恶烷-6-甲醛(化合物18a)(0.99g,6.03mmol)。在165℃回流反应混合物,搅拌15小时。反应结束后,将温度降至常温(1小时内生成固体),添加冰水后,用过滤装置过滤固体,用水洗涤数次后干燥。将得到的固体混合物溶解在乙酸乙酯(30.0mL)溶剂,用饱和碳酸氢钠水溶液(20.0mL)洗涤2次后,弃去乙酸乙酯层。用3N氯化氢水溶液酸化碳酸氢钠水溶液层后,用乙酸乙酯溶剂提取2次。有机层用饱和氯化钠溶液洗涤1次,用无水硫酸镁干燥,减压蒸馏后,充分干燥,得到作为白色固体的(E)-3-(2,3-二氢苯并[b][1,4]二恶烷-6-基)丙烯酸(化合物18b)(0.48g,38.9%)。
1H NMR(400MHz,CDCl3):δ7.67(1H,d,J=16.0Hz),7.08(1H,d,J=2.0Hz),7.06(1H,dd,J=8.4,2.0Hz),6.88(1H,d,J=8.4Hz),6.29(1H,d,J=15.6Hz),4.31–4.26(4H,m).
18-2:(E)-1-(3-(2,3-二氢苯并[b][1,4]二恶烷-6-基)丙烯酰)-1H-吡咯-2(5H)-
酮((E)-1-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acryloyl)-1H-pyrrol-2(5H)-
one)(化合物18)的制备
在氩气气氛下,在50mL的圆底烧瓶中加入1H-吡咯-2(5H)-酮(化合物18d)(58mg,0.69mmol),加入四氢呋喃(1.0mL)后,使温度降低至-78℃,滴加LDA(0.35mL,0.69mmol,2.0M溶液),搅拌45分钟。将(E)-3-(2,3-二氢苯并[b][1,4]二恶烷-6-基)丙烯酰氯(化合物18c)(120mg,0.58mmol)溶解在四氢呋喃(1.2mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取,乙酸乙酯层用饱和氯化钠溶液洗涤,用无水硫酸镁干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/2至1/1)分离,得到作为白色固体的(E)-1-(3-(2,3-二氢苯并[b][1,4]二恶烷-6-基)丙烯酰)-1H-吡咯-2(5H)-酮(化合物18)(10mg,10.1%)。
1H NMR(400MHz,氯仿-d)δ7.90(d,J=15.7Hz,1H),7.80(d,J=15.7Hz,1H),7.33(dt,J=6.1,2.0Hz,1H),7.21–7.13(m,2H),6.87(d,J=8.3Hz,1H),6.21(dt,J=6.1,1.9Hz,1H),4.52(t,J=2.0Hz,2H),4.31–4.26(m,4H).
13C NMR(101MHz,氯仿-d)δ170.21,165.50,146.74,145.99,145.90,143.75,128.68,128.01,122.72,117.74,117.44,116.84,64.68,64.28,51.18.
制备例19:化合物19的合成
19-1:3,5-二氯苯甲酸乙酯(ethyl-3,5-dichlorobenzoate)(化合物19b)的制备
在氩气气氛下,在0℃条件将浓缩硫酸(0.29mL)缓慢添加到溶解在无水乙醇(11.0mL)溶剂的3,5-二氯苯甲酸(化合物19a)(1.05g,5.50mmol)。在80℃回流反应混合物,搅拌15小时。反应结束后,将温度降常温,通过减压蒸发去除全部溶剂后,将混合物溶解在乙酸乙酯(80.0mL)溶剂,用饱和碳酸氢钠水溶液(15.0mL)洗涤2次,用水(20.0mL)洗涤2次,用饱和氯化钠溶液(20.0mL)洗涤1次,用无水硫酸镁干燥,减压蒸馏后,充分干燥,得到固体状态的3,5-二氯苯甲酸乙酯(化合物19b)(1.15g,95.2%)。
Rf=0.75(乙酸乙酯/己烷=1/5)
19-2:3,5-二氯苯甲酰肼(3,5-Dichlorobenzohydrazide)(化合物19c)的制备
在氩气气氛下,在常温将水合肼(0.38mL,7.85mmol)添加到溶解在无水乙醇(12.0mL)溶剂的3,5-二氯苯甲酸乙酯(化合物19b)(1.15g,5.24mmol)。在80℃回流反应混合物,搅拌15小时。反应结束后,温度降至常温,减压蒸发去除全部溶剂。向混合物添加冰水后,使用过滤装置过滤固体,用水和己烷洗涤数次后,充分干燥,得到作为白色固体的3,5-二氯苯甲酰肼(化合物19c)(0.98g,90.4%)。不需要其他纯化过程,用于下一步反应。
Rf=0.21(乙酸乙酯/己烷=1/1)
1H NMR(400MHz,DMSO-d6):δ10.00(1H,br s),7.83(2H,d,J=1.6Hz),7.79(1H,t,J=1.6Hz),4.59(2H,br s).
19-3:2-(3,5-二氯苯甲酰基)肼基羰酰氯(2-(3,5-dichlorobenzoyl)
hydrazinecarbonyl chloride)(化合物19d)的制备
在氩气气氛下,在0℃条件将氯乙酰氯(0.45mL,5.68mmol)添加到溶解在无水乙腈(18.0mL)溶剂的3,5-二氯苯甲酰肼(化合物19c)(0.97g,4.73mmol)后,立即缓慢加入40%氢氧化钠水溶液(1.5eq),再搅拌2小时。反应结束后,加入冰水(20.0mL),用过滤装置过滤固体,用水洗涤数次后,充分干燥。为了完全干燥固体化合物,将其溶解在乙酸乙酯(200.0mL)溶剂,用无水硫酸镁干燥,减压蒸馏后,得到2-(3,5-二氯苯甲酰基)肼基羰酰氯(化合物19d)(0.93g,70.0%)。不需要其他纯化过程,用于下一步反应。
Rf=0.54(乙酸乙酯/己烷=1/1)
19-4:2-(氯甲基)-5-(3,5-二氯苯基)-1,3,4,-恶二唑(2-(chloromethyl)-5-(3,
5-dichlorophenyl)-1,3,4-oxadiazole)(化合物19e)的制备
在氩气气氛下,在常温将三氯氧磷(0.62mL,6.63mmol)添加到溶解在无水乙腈(18.0mL)溶剂的2-(3,5-二氯苯甲酰基)肼基羰酰氯(化合物19d)(0.93g,3.31mmol)后,在90℃回流,搅拌4小时。反应结束后,温度降至常温,减压蒸馏去除溶剂。向混合物加入饱和碳酸氢钠水溶液(15.0mL)后,用乙酸乙酯溶剂(50.0mL)提取3次,用水(30.0mL)洗涤3次,用饱和氯化钠溶液(30mL)洗涤1次,用无水硫酸镁干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/10)分离,得到作为白色固体的2-(氯甲基)-5-(3,5-二氯苯基)-1,3,4,-恶二唑(化合物19e)(0.68g,77.7%)。
Rf=0.48(乙酸乙酯/己烷=1/5)
1H NMR(400MHz,CDCl3):δ7.98(2H,d,J=2.0Hz),7.56(1H,t,J=2.0Hz),4.79(2H,s)
13C NMR(100MHz,CDCl3):δ164.1,163.0,136.4,132.3,126.1,125.6,33.0.
19-5:(E)-3-(4-羟基-3,5-二甲氧基苯基)丙烯酸乙酯((E)-ethyl-3-(4-
hydroxy-3,5-dimethoxyphenyl)acrylate)(化合物19g)的制备
在氩气气氛下,在0℃条件将5滴浓缩硫酸缓慢添加到溶解在无水乙醇(10.0mL)溶剂的(E)-3-(4-羟基-3,5-二甲氧基苯基)丙烯酸(化合物19f)(0.45g,2.0mmol)。在80℃回流反应混合物,搅拌15小时。反应结束后,温度降至常温,减压蒸馏去除全部溶剂后,向混合物加入水(20.0mL),用乙酸乙酯(35.0mL)溶剂提取3次。有机层用饱和碳酸氢钠水溶液(25.0mL)洗涤1次,用水(30.0mL)洗涤3次,用饱和氯化钠溶液(30.0mL)洗涤1次,用无水硫酸镁干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/10)分离,得到(E)-3-(4-羟基-3,5-二甲氧基苯基)丙烯酸乙酯(化合物19g)(0.47g,92.9%)。
Rf=0.52(乙酸乙酯/己烷=2/3)
19-6:(E)-3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧
基苯基)丙烯酸乙酯((E)-ethyl-3-(4-((5-(3,5-dichlorophenyl)-1,3,4-oxadiazol-2-
yl)methoxy)-3,5-dimethoxyphenyl)acrylate)(化合物19h)的制备
在氩气气氛下,在常温将碳酸钾添加到溶解在无水二甲基甲酰胺(3.0mL)溶剂的(E)-3-(4-羟基-3,5-二甲氧基苯基)丙烯酸乙酯(化合物19g)(0.23g,0.91mmol),搅拌5分钟。将溶解在无水二甲基甲酰胺(3.0mL)溶剂的2-(氯甲基)-5-(3,5-二氯苯基)-1,3,4,-恶二唑(化合物19e)(0.24g,0.91mmol)、碘化钾(0.02g,0.09mmol)缓慢添加到上述混合物(化合物19g)。在65℃条件下将反应混合物搅拌6小时。反应结束后,温度降至常温,用过滤装置过滤固体,用乙酸乙酯(25.0mL)、水(20.0mL)洗涤。向过滤的液体添加水(20.0mL),并用乙酸乙酯(50.0mL)溶剂提取2次。有机层用水(25.0mL)洗涤3次,用饱和氯化钠溶液(25.0mL)洗涤1次,用无水硫酸镁干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/4-1/3)分离,得到作为白色绒毛状固体的(E)-3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧基苯基)丙烯酸乙酯(化合物19h)(0.40g,91.8%)。
Rf=0.45(乙酸乙酯/己烷=1/2)
1H NMR(400MHz,CDCl3):δ8.00(2H,d,J=2.0Hz),7.58(1H,d,J=16.0Hz),7.55(1H,t,J=2.0Hz),6.73(2H,s),6.35(1H,d,J=16.0Hz),5.29(2H,s),4.27(2H,q,J=7.2Hz),1.34(3H,t,J=7.2Hz)
13C NMR(100MHz,CDCl3):δ166.9,163.7,163.6,153.6,144.3,137.0,136.3,132.0,131.7,126.4,125.5,118.5,105.0,63.7,60.8,56.3,14.5.
19-7:(E)-3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧
基苯基)丙烯酸((E)-3-(4-((5-(3,5-dichlorophenyl)-1,3,4-oxadiazol-2-yl)
methoxy)-3,5-dimethoxyphenyl)acrylic acid)(化合物19i)的制备
在氩气气氛下,在常温将氢氧化钾(0.12g,2.09mmol)添加到溶解在无水乙醇(7.0mL)溶剂的(E)-3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧基苯基)丙烯酸乙酯(化合物19h)(0.40g,0.83mmol),在80℃回流并搅拌3小时。反应结束后,温度降至常温,减压蒸馏去除全部溶剂后,向混合物加入冰水(10.0mL),用1N盐酸酸化,用过滤装置过滤固体。固体化合物用水洗涤数次,充分干燥,得到作为黄色固体的(E)-3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧基苯基)丙烯酸(化合物19i)(0.29g,77.5%)。
1H NMR(400MHz,DMSO-d6):δ10.10(1H,br s),7.90(2H,d,J=2.0Hz),7.88(1H,t,J=2.0Hz),7.53(1H,d,J=16.0Hz),7.09(2H,s),6.58(1H,d,J=16.0Hz),4.51(2H,s),3.86(6H,s)
13C NMR(100MHz,DMSO-d6):δ167.9,167.0,162.5,152.4,143.4,137.3,135.6,134.4,131.3,130.6,126.4,6.9,163.7,163.6,153.6,144.3,137.0,136.3,132.0,131.7,126.3,119.6,105.7,70.8,56.2.
19-8:(E)-3-氯-1-(3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,
5-二甲氧基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮((E)-3-chloro-1-(3-(4-((5-(3,5-
dichlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-3,5-dimethoxyphenyl)acryloyl)-
5,6-dihydropyridin-2(1H)-one)(化合物19)的合成
在氩气气氛下,在25mL的圆底烧瓶中加入3-氯-5,6-二氢吡啶-2(1H)-酮(化合物19k)(25mg,0.19mmol),加入四氢呋喃(1.0mL)后,使温度降低至-78℃,滴加LDA(0.10mL,0.19mmol,2.0M溶液),搅拌45分钟。将(E)-3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧基苯基)丙烯酰氯(化合物19j)(76mg,0.16mmol)溶解在四氢呋喃(1.0mL),在-78℃条件下缓慢加入,搅拌1小时。反应结束后,用1N盐酸分解剩余LDA后,用乙酸乙酯提取2次,乙酸乙酯层用饱和氯化钠溶液洗涤1次,用无水硫酸钠干燥,减压蒸馏后,通过柱层析(乙酸乙酯/己烷=1/4至1/3)分离,得到作为淡棕色固体的(E)-3-氯-1-(3-(4-((5-(3,5-二氯苯基)-1,3,4-恶二唑-2-基)甲氧基)-3,5-二甲氧基苯基)丙烯酰)-5,6-二氢吡啶-2(1H)-酮(化合物19)(8.90mg,9.90%)。
1H NMR(400MHz,氯仿-d)δ8.00(d,J=1.9Hz,2H),7.69(d,J=15.6Hz,1H),7.55(t,J=1.9Hz,1H),7.44(d,J=15.5Hz,1H),7.10(t,J=4.6Hz,1H),6.68(s,2H),5.28(s,2H),4.10(t,J=6.5Hz,2H),3.81(s,6H),2.58(td,J=6.4,4.5Hz,2H).
实验例1:一氧化氮(NO)生成抑制
对本发明的荜茇酰胺类化合物的一氧化氮(NO)生成抑制能力进行了评价。
在本实验例中,使用测定作为一氧化氮(NO)的代谢物的亚硝酸盐(nitrit e)的量的格里斯试剂(Sigma-Aldrich),评价了NO生成抑制能力。具体地,在96孔板接种Raw264.7细胞,将化合物1~19的各化合物(1μg/mL)预处理2小时后,用脂多糖(LPS,1μg/mL)进行处理,培养24小时。混合反应终止的培养液和相同量的格里斯试剂,反应10分钟后,30分钟内用分光光度计测定在540nm处的吸光度。为求出标准曲线,将硝酸钠(Promega)从100μM浓度按梯度稀释来使用。
如下图1所示,根据本发明的荜茇酰胺类化合物中,在作为一氧化氮生成细胞株的Raw264.7中化合物1、3-6、8-19表现出明显的(p<0.01-0.001)一氧化氮生成抑制活性,尤其化合物3、9-15、18-19表现出显著优异的NO生成抑制活性。
实验例2:抗氧化效果_羟基自由基的清除
为了确认本发明的荜茇酰胺类化合物的抗氧化效果,以如下方式评价了羟基自由基清除能力。
在本实验例中,使用牛血清白蛋白(BSA,Sigma-Aldrich)分解法确认了使蛋白质或酶免受活性氧(reactive oxygen species,ROS)的损伤的抗氧化物质的效果,其中牛血清白蛋白分解法是通过金属离子催化反应来确认。具体地,使作为目标蛋白的BSA的浓度成为8μg/mL,作为一次反应,添加Cu2+(100μM)和H2O2(2.5mM)生成羟基自由基,将BSA和化合物1~19的各化合物(1μg/mL)混合在一起后,进行二次反应。在10%十二烷基硫酸钠(SDS)-聚丙烯酰胺凝胶电泳中对终止反应的各组进行电泳,确认各化合物对BSA蛋白分解的抑制程度后,将其结果示于图2。此时,作为阳性对照组,使用了抗氧化效果优异的抗坏血酸(150μM)。
一次反应后,观察基于生成的活性氧(羟基自由基)的蛋白质分解水平的结果,在只存在活性氧的组、溶剂处理组和荜茇酰胺类化合物1、3-4、6-9、11处理组中蛋白质被完全破坏,未确认基于活性氧的蛋白质的保护能力。相比之下,在根据本发明的荜茇酰胺类化合物2、5、10、12-19的情况下,观察到与作为抗氧化剂的抗坏血酸等同或更高的羟基自由基的清除能力,以及由此产生的蛋白质保护能力(参照以下图2)。
实验例3:炎性细胞因子抑制效果评价
以如下方法确认了炎性细胞因子的表达抑制。
3-1:炎性细胞因子的表达抑制确认
已知基于细胞因子的过度信的号会导致各种疾病。因此,以如下方式确认了根据本发明的化合物的炎性细胞因子表达抑制。
首先,使用分别包含10%胎牛血清的达尔伯克(氏)改良伊格尔(氏)培养基(Dulbecco's Modified Eagle Medium,DMEM)或RPMI1640培养基,在调整为37℃,5%的CO2的CO2培养器中培养了用于实验的小鼠巨噬细胞株Raw264.7。当细胞增殖到90%时,用于后述的实验,以使细胞株不超过20代(passage)的方式进行调节。以上述方法培养的细胞用0.25%胰蛋白酶(trypsin)-EDTA悬浮后,用血细胞计数器对细胞数进行计数。为基因表达试验,以1.5×106细胞/孔的方式接种到6-孔板,预培养2小时后,将化合物1~19与LPS一起处理,反应20小时。反应后,用三唑试剂(Invitrogen)从培养的Raw264.7细胞提取总RNA。具体地,添加1mL的三唑试剂溶解细胞,在室温放置5分钟后,添加200μL的氯仿,以13500rpm离心15分钟。取500μL的透明上清液,转移至新管中,添加相同量的异丙醇后,以13500rpm离心10分钟,沉淀RNA。使用0.75mL的利用焦碳酸二乙酯(DEPC Sigma-Aldrich)处理的蒸馏水稀释的70%乙醇洗涤上述RNA沉淀物,之后在空气中干燥,以用作逆转录样品。第一链cDNA合成是用提取的1μg的总RNA来进行,使用Improm-II逆转录系统(reve rse transcriptionsystem)(Promega)和oligo dT引物,进行了逆转录反应。此外,qPCR分析使用了Rotor-Gene6000(Qiagen,CA,美国),且使用表1的引物定量测定基因表达,并比较分析了β-actin归一化的相对值。
表1
如下图3至5所示,根据本发明的荜茇酰胺类化合物1、3-6、9-15、17-19表现出细胞因子IL-1β基因表达抑制活性,化合物1、3-6、9-19表现出IL-6基因表达抑制活性。此外,化合物1、3、5-6、9-16、19抑制TNF-α基因表达,从而证明了其有效的抗炎活性。
3-2:T细胞依赖性细胞因子基因表达抑制的确认
在本实验例中,分离Balb/c小鼠脾细胞,在体外(Ex-vivo)条件下,通过对如Th1细胞因子(IL-2,IFNγ)、Th2细胞因子(IL-4,IL-10)以及Th17细胞因子(IL-17a)等的T细胞依赖性细胞因子的基因的表达分析确认了荜茇酰胺类化合物1~19的免疫细胞活性抑制能力。为了诱导T细胞依赖性刺激,用CD3单克隆抗体处理Balb/c小鼠脾细胞,刺激T细胞受体复合物,使T细胞活化,在相同条件下,以与实施例3-1相同的方法分析了荜茇酰胺类化合物1~19的T细胞活性抑制能力,并将其结果分别示于图6至10。
图6至7是T细胞依赖性细胞因子中Th1细胞因子衍生的IL-2及IFNγ基因的表达抑制图。如图6所示,本发明的荜茇酰胺类化合物1-11、13-16表现出IL-2基因表达抑制活性,尤其观察到化合物1、3和9的情况下,IL-2基因表达抑制活性等于或大于作为对照物质的环孢霉素(CsA,免疫抑制剂)。
此外,如图7所示,本发明的荜茇酰胺类化合物1-6、8-19表现出对于Th1衍生的IFNγ的表达抑制能力,尤其化合物1、3-5、9、12及14表现出非常高的抑制能力。
图8至9是T细胞依赖性细胞因子中作为Th2衍生的细胞因子的IL-4和IL-10基因的表达抑制图。如图8所示,本发明的荜茇酰胺类化合物1-6、8-18表现出IL-4基因表达抑制活性,尤其证实了化合物1、3、9及11的IL-4基因表达抑制活性等于或大于作为对照物质的环孢霉素(CsA,免疫抑制剂)。
此外,如图9所示,本发明的荜茇酰胺类化合物1-6、8-19明显抑制IL-10的表达。
同时,图10是T细胞依赖性细胞因子中作为Th17衍生的细胞因子的IL-17a基因的表达抑制图。如图10所示,观察到本发明的荜茇酰胺类化合物1-10、12-19表现出IL-17a基因表达抑制活性,尤其,在化合物1、3-5、9及14-15中表现出了优异活性。尤其,本发明的荜茇酰胺类化合物1不仅表现出优于作为对照组的环孢霉素(CSA,免疫抑制剂)的IL-17a表达抑制活性,且与IL-2及IL-4不同地,表现出分别高于化合物3及9至少6倍及3倍以上的基因表达抑制活性。
通过上述结果,可以判断本发明的荜茇酰胺类化合物,尤其化合物1、3和9是有效抑制IL-2、IL-4及IFNγ的新型化合物。尤其,除了化合物7以外的本发明的所有荜茇酰胺类化合物具有对由Th2(辅助T-2细胞)过度表达的IL-10的控制活性,此外,可以通过有效抑制IL-17a(有助于细胞因子IL-23轴),充分证实其作为免疫调节剂的可行性。
实验例4:免疫细胞信号转导抑制活性评价
为了确认与免疫调节有关的基因的细胞内信号转导及过度活性抑制能力,以如下的方式使用报告基因表达分析系统进行了分析。
在本实验例中,从InVivoGen公司购买THP1-Lucia NF-κB、HEK-Lucia RIG-1、HEK-Blue-IL-4/IL-13及HEK-Blue IL-10细胞株来评价了对免疫细胞信号转导的抑制活性,并根据制造商的分析法进行了分析。具体地,利用作为各试验物质的荜茇酰胺类化合物1至19对上述4种细胞株进行处理后,分别用启动子的刺激物质(LPS、3p-hpRNA、白细胞介素-4及白细胞介素-10)进行处理,根据指南诱导反应后,分析了活性抑制能力。将其结果分别示于下图11至14。
图11是利用荜茇酰胺类化合物对为了NF-κB活性而用脂多糖(LPS)刺激的细胞进行处理后,分析了各化合物是否调节NF-κB信号转导路径的图。如下图11所示,观察到本发明的荜茇酰胺类化合物1、3-6、9-17及19具有NF-κB活性抑制效果,尤其,证实了化合物1、3及9具有非常高的NF-κB活性抑制能力。
此外,图12是通过HEK RIG1系统分析了荜茇酰胺类化合物是否抑制RIG1活性的图。
如下图12所示,本发明的荜茇酰胺类化合物1-5、8-15及19表现出RIG1活性抑制效果,尤其,证实了化合物1、3、9及10具有非常高的RIG1活性抑制能力。
此外,图13是通过HEK Blue IL-10系统分析了荜茇酰胺类化合物是否调节STAT3信号路径的图。
STAT3是在细胞质中细胞因子刺激后,向核内部转导信号的重要转录因子。如图13所示,本发明的荜茇酰胺类化合物1、3-6、8-16及19表现出STAT3活性抑制效果,尤其,证实了化合物1、3、9-10、12-13及16具有非常高的STAT3活性抑制能力。
此外,图14是通过HEK Blue IL4/IL-13系统分析了荜茇酰胺类化合物是否调节STAT6信号路径的图。STAT6是通过来自外部的信号来起到各种细胞因子、激素及生长因子表达调节作用的转录因子。此外,IL-4/IL-13及STAT6是Th2的重要调控因子。如下图14所示,本发明的荜茇酰胺类化合物1、3-5、9-10、12-13及16表现出STAT6活性抑制效果,尤其,证实了化合物1、3、12-13及16具有非常高的STAT6活性抑制能力。
通过上述结果可知,本发明的新型荜茇酰胺类化合物具有对NF-κB、RIG1、STAT3、STAT6等免疫细胞信号转导的优异的抑制活性,由此可以证实上述荜茇酰胺类化合物可以有效用作免疫调节剂。
<110> 人类科学有限公司
<120> 荜茇酰胺类化合物以及包含该化合物的免疫调节剂
<130> FP210131PCT
<150> KR 10-2020-0185404
<151> 2020-12-29
<150> KR 10-2021-0128774
<151> 2021-09-29
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Claims (8)
1.一种以下述式1表示的化合物、其药学上可接受的盐、或溶剂化物,其中,
式1
在所述式1中,
R2至R4彼此相同或不同,各自独立地选自由氢、氘、卤素、硝基、羟基、氨基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C20的烷氧基、C1~C20的酮基、C1~C20的酯基、C6~C20的芳基、核原子数5至20个的杂芳基、以及C6~C20的芳氧基组成的组,或它们与相邻的基团键合来形成C6~C20的芳基或核原子数5至20个的杂芳环,但当R2至R4相同时除外,
R1是选自以下述结构式的取代基,
在所述式中,
X是选自由F、Cl、Br以及I组成的组的卤素元素,
Y是C1~C10的烷基,
所述R2~R4的烷基、酮基、酯基、芳基、杂芳基各自独立地能够被选自由氘、卤素、氰基、硝基、C1~C40的烷基、C2~C40的烯基、C2~C40的炔基、C6~C40的芳基、核原子数5至40个的杂芳基、C6~C40的芳氧基、C1~C40的烷氧基、C6~C40的芳胺基、C3~C40的环烷基、核原子数3至40个的杂环烷基、C1~C40的烷基甲硅烷基、C1~C40的烷基硼基、C6~C40的芳基硼基、C6~C40的芳基膦基、C6~C40的芳基氧化膦基以及C6~C40的芳基甲硅烷基组成的组中的一种以上的取代基取代,此时当所述取代基为多个时,它们能够相同或不同。
5.一种免疫调节剂,其中,
包含权利要求1至权利要求4中任一项所述的化合物、其药学上可接受的盐、或溶剂化物作为有效成分。
6.根据权利要求5所述的免疫调节剂,其中,
所述免疫调节剂用于抑制免疫反应。
7.一种用于免疫调节的保健功能食品,其中,
包含权利要求1至权利要求4中任一项所述的化合物、其药学上可接受的盐、或溶剂化物作为有效成分。
8.一种权利要求1至权利要求4中任一项所述的化合物、其药学上可接受的盐、或溶剂化物在制备免疫调节用药物中的用途。
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CN116969927B (zh) * | 2023-06-07 | 2024-03-19 | 中南民族大学 | 一种从荜茇中提取分离的化合物及该化合物在制备抗炎药物中的应用 |
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