技术领域technical field
本发明涉及一类新化合物的制备与应用，具体是2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备及其在作为流感病毒神经氨酸酶抑制剂的应用。The invention relates to the preparation and application of a class of novel compounds, specifically the preparation of 2-(5-acylthiazole-2-imino)-4-thiazolinone and its application as an influenza virus neuraminidase inhibitor.
背景技术Background technique
Makam等[Eur.J.Med.Chem.,2013.69:564-576，Eur.J.Pharm.Sci.,2014.52:138-145]报道了系列2-(2-亚肼基)噻唑衍生物(A)具有良好的抗结核分枝杆菌作用和抗疟疾作用；Grozav等[Int.J.Mol.Sci.,2014.15(12):22059-22072]合成了系列苄亚肼基噻唑化合物(B)，发现其对两种癌细胞(MDA-MB231和HeLa)具有明显抗增殖活性；Ignat等[Arch.Pharm.Chem.Life Sci.,2012.345(7):574-583]发现含噻吩嗪基的噻唑腙(C)对结肠癌和肝癌细胞具有抗增殖活性。Makam et al. [Eur.J.Med.Chem., 2013.69:564-576, Eur.J.Pharm.Sci., 2014.52:138-145] reported a series of 2-(2-hydrazino)thiazole derivatives (A ) has good anti-tuberculosis mycobacterium effect and anti-malarial effect; Grozav et al. [Int.J.Mol.Sci., 2014.15 (12): 22059-22072] synthesized a series of benzylhydrazonothiazole compounds (B), found It has obvious antiproliferative activity on two cancer cells (MDA-MB231 and HeLa); Ignat et al. C) Antiproliferative activity against colon and liver cancer cells.
发明内容Contents of the invention
本发明解决的技术问题是提供一类2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮、其制备方法、药物组合物和用途。The technical problem solved by the present invention is to provide a class of 2-(5-acylthiazole-2-imino)-4-thiazolinone, its preparation method, pharmaceutical composition and application.
为解决本发明的技术问题，本发明提供如下技术方案：In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:
本发明技术方案的第一方面是提供了一类如结构式Ⅰ所示的2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮：The first aspect of the technical solution of the present invention provides a class of 2-(5-acylthiazole-2-imino)-4-thiazolinones as shown in structural formula I:
其中，R选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R1选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；Y1选自：氢、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；Y2、Y4选自：氢、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、羟基、C1～C2烷氧基、氨基或硝基；Y3选自：氢、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、羧基、C1～C2烷氧羰基、羟基、C1～C2烷氧基、氟、氯、溴、碘、氨基、乙酰氨基、二甲氨基或硝基。Among them, R is selected from: C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl; R1 is selected from: C1 ~C2 alkyl, C3 ~ C4 straight chain alkyl or C3 ~C4 branched chain alkyl; Y1 is selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched alkane group; Y2 , Y4 are selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl, hydroxyl, C1 ~C2 alkoxy , amino or nitro; Y3 is selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl, carboxyl, C1 ~C2 alkoxy Carbonyl, hydroxyl, C1 -C2 alkoxy, fluorine, chlorine, bromine, iodine, amino, acetamido, dimethylamino or nitro.
本发明技术方案的第一方面还提供了结构式Ⅱ所示的2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮及其在药学上可接受的盐：The first aspect of the technical solution of the present invention also provides 2-(5-acylthiazole-2-imino)-4-thiazolinone shown in structural formula II and pharmaceutically acceptable salts thereof:
其中，R选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R1选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R2选自：氢、C1～C2烷基、C3～C4直链或C3～C4支链烷基。Among them, R is selected from: C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl; R1 is selected from: C1 ~C2 alkyl, C3 ~ C4 straight chain alkyl or C3 ~C4 branched chain alkyl; R2 is selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain or C3 ~C4 branched chain alkyl.
进一步的，优选的化合物选自：2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(4-氯亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(4-羟基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(4-羟基-3-甲氧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(2-羟基-3-甲氧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(3，4-二氧亚甲基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(4-羧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(3-硝基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(3-氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、5-(4-乙酰氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮或5-(4-二甲氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮。Further, preferred compounds are selected from: 2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone, 5-(4-chlorobenzylidene)-2-(4 -Methyl-5-acetylthiazole-2-imino)-4-thiazolinone, 5-(4-hydroxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-ylidene Amino)-4-thiazolinone, 5-(4-hydroxy-3-methoxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazoline Ketone, 5-(2-hydroxy-3-methoxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone, 5-(3, 4-Dioxymethylenebenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone, 5-(4-carboxybenzylidene)-2 -(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone, 5-(3-nitrobenzylidene)-2-(4-methyl-5-acetylthiazole -2-imino)-4-thiazolinone, 5-(3-aminobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone, 5-(4-Acetamidobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone or 5-(4-dimethylaminobenzylidene) -2-(4-Methyl-5-acetylthiazole-2-imino)-4-thiazolinone.
本发明技术方案的第二方面是提供了第一方面所述结构式I所示的2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备方法，其特征在于它的制备反应如下：The second aspect of the technical solution of the present invention is to provide the preparation method of 2-(5-acylthiazole-2-imino)-4-thiazolinone shown in the structural formula I described in the first aspect, which is characterized in that its preparation The response is as follows:
其中，R选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R1选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；Y1选自：氢、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；Y2、Y4选自：氢、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、羟基、C1～C2烷氧基、氨基或硝基；Y3选自：氢、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、羧基、C1～C2烷氧羰基、羟基、C1～C2烷氧基、氟、氯、溴、碘、氨基、乙酰氨基、二甲氨基或硝基；X选自：氯、溴或碘。Among them, R is selected from: C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl; R1 is selected from: C1 ~C2 alkyl, C3 ~ C4 straight chain alkyl or C3 ~C4 branched chain alkyl; Y1 is selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched alkane group; Y2 , Y4 are selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl, hydroxyl, C1 ~C2 alkoxy , amino or nitro; Y3 is selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl, carboxyl, C1 ~C2 alkoxy Carbonyl, hydroxyl, C1 -C2 alkoxy, fluorine, chlorine, bromine, iodine, amino, acetamido, dimethylamino or nitro; X is selected from: chlorine, bromine or iodine.
本发明技术方案的第二方面是提供了第一方面所述结构式Ⅱ所示的2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备方法，其特征在于它的制备反应如下：The second aspect of the technical solution of the present invention is to provide the preparation method of 2-(5-acylthiazole-2-imino)-4-thiazolinone shown in the structural formula II described in the first aspect, which is characterized in that its preparation The response is as follows:
其中，R选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R1选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R2选自：氢、C1～C2烷基、C3～C4直链或C3～C4支链烷基；X、X1和X2选自：氯、溴或碘。Among them, R is selected from: C1 ~C2 alkyl, C3 ~C4 straight chain alkyl or C3 ~C4 branched chain alkyl; R1 is selected from: C1 ~C2 alkyl, C3 ~ C4 straight chain alkyl or C3 ~C4 branched chain alkyl; R2 is selected from: hydrogen, C1 ~C2 alkyl, C3 ~C4 straight chain or C3 ~C4 branched chain alkyl; X, X1 andX2 are selected from: chlorine, bromine or iodine.
本发明技术方案的第三方面是提供含有第一方面所述化合物及其药学上可接受的盐的药物组合物，该药物组合物含有治疗有效量的本发明的2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮及其药学上可接受的盐，以及任选的含有药用载体。其中所述的药用载体指药学领域常用的药用载体；该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物及其药学上可接受的盐与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂组合，制成适于人或动物使用的任何剂型。本发明化合物及其药学上可接受的盐在其药物组合物中的含量通常为0.1％～95％重量百分比。The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition containing the compound described in the first aspect and a pharmaceutically acceptable salt thereof. The pharmaceutical composition contains a therapeutically effective amount of the 2-(5-acylthiazole- 2-imino)-4-thiazolinone and pharmaceutically acceptable salts thereof, and optionally contain a pharmaceutically acceptable carrier. The pharmaceutical carrier mentioned therein refers to the commonly used pharmaceutical carrier in the field of pharmacy; the pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compound of the present invention and a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and its pharmaceutically acceptable salt in its pharmaceutical composition is usually 0.1%-95% by weight.
本发明化合物及其药学上可接受的盐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、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。The compound of the present invention and its pharmaceutically acceptable salt or the pharmaceutical composition containing it can be administered in the form of unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity , oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
本发明化合物及其药学上可接受的盐可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。The compounds of the present invention and their pharmaceutically acceptable salts can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
为了将本发明化合物及其药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。In order to make the compound of the present invention and its pharmaceutically acceptable salt into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, auxiliary agents, etc. Fluid. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecylsulfonate, etc.; lubricant and flow aid The agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.
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。Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。In order to make the administration unit into a capsule, the active ingredient compound of the present invention and its pharmaceutically acceptable salt can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention and its pharmaceutically acceptable salts can also be prepared into granules or pellets with diluents, binders, and disintegrating agents, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the compound of the present invention and pharmaceutically acceptable salt tablets thereof can also be used to prepare the compound of the present invention and pharmaceutically acceptable salt thereof. Salt capsules.
为将本发明化合物及其药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。In order to prepare the compound of the present invention and its pharmaceutically acceptable salts into injections, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as a solvent and an appropriate amount of commonly used solubilizers, co-solvents, pH regulators, Osmotic regulator. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary.
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。In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.
本发明技术方案的第四方面是提供本发明第一方面所述2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮及其药学上可接受的盐以及第三方面所述药物组合物在制备流感病毒神经氨酸酶抑制剂方面的应用。The fourth aspect of the technical solution of the present invention is to provide the 2-(5-acylthiazole-2-imino)-4-thiazolinone and its pharmaceutically acceptable salts described in the first aspect of the present invention and the third aspect. Application of the pharmaceutical composition in the preparation of influenza virus neuraminidase inhibitors.
有益技术效果：Beneficial technical effects:
本发明的2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮是一类新结构类型的具有流感病毒神经氨酸酶抑制活性的化合物。The 2-(5-acylthiazole-2-imino)-4-thiazolinone of the present invention is a new type of compound with influenza virus neuraminidase inhibitory activity.
具体实施方式detailed description
以下实施例旨在说明本发明而不是对本发明的进一步限定。The following examples are intended to illustrate the present invention without further limiting the invention.
实施例1Example 1
2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
200mmol乙酰丙酮和30mL丙酮，冰浴搅拌，分批加入220mmol NBS，反应5h，抽滤，二氯甲烷洗，水洗，二氯甲烷萃取，无水硫酸钠干燥，减压脱溶得浅黄色油状液体3-溴乙酰丙酮，收率84％。200mmol acetylacetone and 30mL acetone, stirred in an ice bath, added 220mmol NBS in batches, reacted for 5h, filtered with suction, washed with dichloromethane, washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and precipitated under reduced pressure to obtain a light yellow oily liquid 3-Bromoacetylacetone, yield 84%.
得到的3-溴乙酰丙酮、110mmol硫脲和60mL乙醇，回流4h，冷却后抽滤，乙醇洗，滤饼溶于100mL水中，氨水调节pH>10，析出大量白色固体，抽滤，乙醇洗，水洗，干燥得白色固体4-甲基-5-乙酰基-2-氨基噻唑，收率78％，m.p.245～249℃。1H NMR(400MHz，DMSO-d6)δ:7.82(s，2H，NH2)，2.40(s，3H，COCH3)，2.32(s，3H，CH3)。The obtained 3-bromoacetylacetone, 110mmol thiourea and 60mL ethanol were refluxed for 4h, filtered with suction after cooling, washed with ethanol, the filter cake was dissolved in 100mL of water, adjusted to pH>10 with ammonia water, a large amount of white solid was precipitated, filtered with suction, washed with ethanol, Washed with water and dried to obtain white solid 4-methyl-5-acetyl-2-aminothiazole, yield 78%, mp 245-249°C.1 H NMR (400 MHz, DMSO-d6 ) δ: 7.82 (s, 2H, NH2 ), 2.40 (s, 3H, COCH3 ), 2.32 (s, 3H, CH3 ).
60mmol 4-甲基-5-乙酰基-2-氨基噻唑、120mmol三乙胺和100mL二氯甲烷，冰浴搅拌30min，滴加120mmol氯乙酰氯，反应4.0h。反应液倒入冰水，二氯甲烷萃取，依次饱和碳酸钠溶液洗、水洗，无水硫酸钠干燥，脱溶，乙醇/水重结晶得白色晶体4-甲基-5-乙酰基-2-(氯乙酰氨基)噻唑，收率61％，m.p.175～176℃。1H NMR(400MHz，CDCl3)δ:4.32(s，2H，CH2)，2.66(s，3H，COCH3)，2.54(s，3H，CH3)。60mmol of 4-methyl-5-acetyl-2-aminothiazole, 120mmol of triethylamine and 100mL of dichloromethane were stirred in an ice bath for 30min, and 120mmol of chloroacetyl chloride was added dropwise to react for 4.0h. The reaction solution was poured into ice water, extracted with dichloromethane, washed successively with saturated sodium carbonate solution, washed with water, dried over anhydrous sodium sulfate, precipitated, recrystallized from ethanol/water to obtain white crystal 4-methyl-5-acetyl-2- (Chloroacetamido)thiazole, yield 61%, mp 175-176°C.1 H NMR (400 MHz, CDCl3 ) δ: 4.32 (s, 2H, CH2 ), 2.66 (s, 3H, COCH3 ), 2.54 (s, 3H, CH3 ).
16mmol 4-甲基-5-乙酰基-2-(氯乙酰氨基)噻唑、20mL乙醇和24mmol硫氰酸钾，回流6.0h；冷却，析出固体，抽滤，依次乙醇洗、饱和食盐水洗、水洗，干燥得棕色固体2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，收率94％，m.p.197～199℃。1H NMR(400MHz，DMSO-d6)δ:12.29(s，1H，CONH)，4.03(s，2H，CH2)，2.60(s，3H，COCH3)，2.48(s，3H，CH3)。16mmol 4-methyl-5-acetyl-2-(chloroacetylamino)thiazole, 20mL ethanol and 24mmol potassium thiocyanate, reflux for 6.0h; cool, precipitate solid, filter with suction, wash with ethanol, saturated brine, and water in sequence , and dried to obtain brown solid 2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone, yield 94%, mp 197～199°C.1 H NMR (400MHz, DMSO-d6 ) δ: 12.29 (s, 1H, CONH), 4.03 (s, 2H, CH2 ), 2.60 (s, 3H, COCH3 ), 2.48 (s, 3H, CH3 ).
实施例2Example 2
2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
用1,3-二溴-5,5,-二甲基海因(DBDMH)替代实施例1中的NBS，按实施例1制备方法制备得到2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮。With 1,3-dibromo-5,5,-dimethylhydantoin (DBDMH) instead of NBS in Example 1, 2-(4-methyl-5-acetylthiazole was prepared according to the preparation method of Example 1 -2-imino)-4-thiazolinone.
实施例3Example 3
2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
用1,3-二氯-5,5,-二甲基海因(DCDMH)替代实施例1中的NBS，按实施例1制备方法制备得到2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮。With 1,3-dichloro-5,5,-dimethylhydantoin (DCDMH) instead of NBS in Example 1, 2-(4-methyl-5-acetylthiazole was prepared according to the preparation method of Example 1 -2-imino)-4-thiazolinone.
实施例4Example 4
5-(4-氯亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(4-chlorobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol 4-氯苯甲醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流10h；冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥得黄色固体5-(4-氯亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.285～288℃，收率44％；1H NMR(400MHz，DMSO-d6)δ：12.95(s，1H，CONH)，7.74(s，1H，＝CH)，7.70–7.60(m，4H，C6H4)，2.67(s，3H，COCH3)，2.50(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol 4-chlorobenzaldehyde and 6.0mmol anhydrous sodium acetate, add 15mL acetic acid and stir to dissolve, reflux for 10h ; cooling, suction filtration, washing with ethanol, saturated brine, water, and drying to give yellow solid 5-(4-chlorobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino) -4-Thiazolinone, mp285～288°C, yield 44%;1 H NMR (400MHz, DMSO-d6 )δ: 12.95 (s, 1H, CONH), 7.74 (s, 1H, =CH), 7.70 - 7.60 (m,4H ,C6H4 ), 2.67 (s, 3H, COCH3), 2.50 (s, 3H,CH3) .
实施例5Example 5
5-(4-羟基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(4-hydroxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol 4-羟基苯甲醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流18h。冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥得棕黄色固体5-(4-羟基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.302～305℃，收率60％；1H NMR(400MHz，DMSO-d6)δ：12.77(s，1H，CONH)，10.38(s，1H，OH)，7.67(s，1H，＝CH)，7.53(d，J＝8.0Hz，2H，C6H42，6-H)，6.95(d，J＝8.0Hz，2H，C6H43，5-H)，2.68(s，3H，COCH3)，2.50(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol 4-hydroxybenzaldehyde and 6.0mmol anhydrous sodium acetate, add 15mL acetic acid and stir to dissolve, reflux for 18h . Cool, filter with suction, wash with ethanol in turn, wash with saturated brine, wash with water, and dry to obtain 5-(4-hydroxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino) as a brown solid -4-thiazolinone, mp302～305°C, yield 60%;1 H NMR (400MHz, DMSO-d6 )δ: 12.77(s, 1H, CONH), 10.38(s, 1H, OH), 7.67( s, 1H, =CH), 7.53 (d, J = 8.0Hz, 2H, C6 H4 2, 6-H), 6.95 (d, J = 8.0Hz, 2H, C6 H4 3, 5-H ), 2.68 (s, 3H, COCH3 ), 2.50 (s, 3H, CH3 ).
实施例6Example 6
5-(4-羟基-3-甲氧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(4-hydroxy-3-methoxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol香草醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流12h。冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥得棕黄固体5-(4-羟基-3-甲氧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.255～260℃，收率31％；1H NMR(400MHz，DMSO-d6)δ：12.80(s，1H，CONH)，10.17(s，1H，OH)，7.63(s，1H，＝CH)，7.21(s，1H，C6H32-H)，7.12(d，J＝8.0Hz，1H，C6H36-H)，7.01(d，J＝8.0Hz，1H，C6H35-H)，3.86(s，3H，OCH3)，2.61(s，3H，COCH3)，2.47(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol vanillin and 6.0mmol anhydrous sodium acetate were added to 15mL acetic acid and stirred to dissolve, and refluxed for 12h. Cool, filter with suction, wash with ethanol in turn, wash with saturated brine, wash with water, and dry to obtain 5-(4-hydroxy-3-methoxybenzylidene)-2-(4-methyl-5-acetylthiazole) as a brown solid -2-imino)-4-thiazolinone, mp255～260°C, yield 31%;1 H NMR (400MHz, DMSO-d6 )δ: 12.80(s, 1H, CONH), 10.17(s, 1H , OH), 7.63 (s, 1H, =CH), 7.21 (s, 1H, C6 H3 2-H), 7.12 (d, J=8.0Hz, 1H, C6 H3 6-H), 7.01 (d, J=8.0 Hz, 1H, C6H35- H), 3.86 (s, 3H,OCH3) , 2.61 (s, 3H, COCH3), 2.47 (s, 3H,CH3) .
实施例7Example 7
5-(2-羟基-3-甲氧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(2-hydroxy-3-methoxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol异香草醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流15h。趁热倒入饱和食盐水中，抽滤，水洗，干燥得黄褐色固体5-(2-羟基-3-甲氧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.259～263℃，收率51％；1H NMR(400MHz，DMSO-d6)δ：12.80(s，1H，CONH)，9.58(s，1H，OH)，7.62(s，1H，＝CH)，7.16–7.13(m，2H，C6H45，6-H)，7.10(s，1H，C6H42-H)，3.85(s，3H，OCH3)，2.70(s，3H，COCH3)，2.51(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol isovanillin and 6.0mmol anhydrous sodium acetate were added to 15mL acetic acid and stirred to dissolve, and refluxed for 15h. Pour into saturated brine while hot, filter with suction, wash with water, and dry to obtain 5-(2-hydroxy-3-methoxybenzylidene)-2-(4-methyl-5-acetylthiazole-2) as a yellowish-brown solid -imino)-4-thiazolinone, mp259～263°C, yield 51%;1 H NMR (400MHz, DMSO-d6 )δ: 12.80(s, 1H, CONH), 9.58(s, 1H, OH ), 7.62 (s, 1H, =CH), 7.16–7.13 (m, 2H, C6 H4 5, 6-H), 7.10 (s, 1H, C6 H4 2-H), 3.85 (s, 3H,OCH3 ), 2.70 (s, 3H, COCH3), 2.51 (s, 3H,CH3) .
实施例8Example 8
5-(3，4-二氧亚甲基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(3,4-dioxymethylenebenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol胡椒醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流8h。冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥后得黄褐色固体5-(3，4-二氧亚甲基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.283～285℃，收率51％；1H NMR(400MHz，DMSO-d6)δ：12.83(s，1H，CONH)，7.68(s，1H，＝CH)，7.22(d，J＝7.2Hz，1H，C6H46-H)，7.17(s，1H，C6H42-H)，7.13(d，J＝7.2Hz，1H，C6H45-H)，6.14(s，2H，CH2)，2.66(s，3H，COCH3)，2.50(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol piperonal and 6.0mmol anhydrous sodium acetate were added to 15mL acetic acid, stirred and dissolved, and refluxed for 8h. Cool, filter with suction, wash with ethanol, saturated brine, water, and dry to obtain 5-(3,4-dioxymethylenebenzylidene)-2-(4-methyl-5-acetyl) as a yellowish-brown solid Thiazole-2-imino)-4-thiazolinone, mp283～285°C, yield 51%;1 H NMR (400MHz, DMSO-d6 )δ: 12.83(s, 1H, CONH), 7.68(s, 1H, = CH), 7.22 (d, J = 7.2Hz, 1H, C6 H4 6-H), 7.17 (s, 1H, C6 H4 2-H), 7.13 (d, J = 7.2Hz, 1H,C6H45- H), 6.14 (s, 2H,CH2 ), 2.66 (s, 3H, COCH3), 2.50 (s, 3H,CH3) .
实施例9Example 9
5-(4-羧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(4-carboxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol 4-甲酰基苯甲酸和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流10h。冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥后得黄色固体5-(4-羧基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.313～315℃，收率92％；1H NMR(400MHz，DMSO-d6)δ：13.25(s，1H，CO2H)，12.99(s，1H，CONH)，8.07(d，J＝5.2Hz，2H，C6H43，5-H)，7.77–7.71(m，3H，＝CH，C6H42，6-H)，2.67(s，3H，COCH3)，2.50(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol 4-formylbenzoic acid and 6.0mmol anhydrous sodium acetate, add 15mL acetic acid and stir to dissolve, reflux 10h. Cool, filter with suction, wash with ethanol in turn, wash with saturated brine, wash with water, and dry to obtain a yellow solid 5-(4-carboxybenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino) -4-Thiazolinone, mp313～315°C, yield 92%;1 H NMR (400MHz, DMSO-d6 )δ: 13.25(s, 1H, CO2 H), 12.99(s, 1H, CONH), 8.07 (d, J = 5.2 Hz, 2H, C6 H4 3, 5-H), 7.77–7.71 (m, 3H, = CH, C6 H4 2, 6-H), 2.67 (s, 3H, COCH3), 2.50 (s, 3H,CH3) .
实施例10Example 10
5-(3-硝基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(3-nitrobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol 3-硝基苯甲醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流11h。冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥后得土黄色固体5-(3-硝基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.303～306℃，收率75％；1H NMR(400MHz，DMSO-d6)δ：13.04(s，1H，CONH)，8.50(s，1H，C6H42-H)，8.29(d，J＝6.4Hz，1H，C6H46-H)，8.08(d，J＝6.4Hz，1H，C6H44-H)，7.88(s，1H，＝CH)，7.84(s，1H，C6H45-H)，2.67(s，3H，COCH3)，2.51(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol 3-nitrobenzaldehyde and 6.0mmol anhydrous sodium acetate, add 15mL acetic acid and stir to dissolve, reflux 11h. Cool, filter with suction, wash with ethanol successively, wash with saturated saline, wash with water, and dry to obtain khaki solid 5-(3-nitrobenzylidene)-2-(4-methyl-5-acetylthiazol-2-ylidene) Amino)-4-thiazolinone, mp303～306°C, yield 75%;1 H NMR (400MHz, DMSO-d6 )δ: 13.04(s, 1H, CONH), 8.50(s, 1H, C6 H4 2-H), 8.29(d, J=6.4Hz, 1H, C6 H4 6-H), 8.08(d, J=6.4Hz, 1H, C6 H4 4-H), 7.88(s, 1H, =CH), 7.84 (s, 1H,C6H45- H), 2.67 (s, 3H, COCH3), 2.51 (s, 3H,CH3) .
实施例11Example 11
5-(3-氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(3-aminobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-5-(3-硝基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮、10mL乙酸、10mL二氯甲烷、1mL水和适量铁粉，常温过夜反应。抽滤，滤饼，二氯甲烷洗、萃取，饱和碳酸钠溶液洗，水洗，无水硫酸钠干燥，脱溶得浅黄色固体5-(3-氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.225～227℃，收率24％；1H NMR(400MHz，DMSO-d6)δ：10.18(s，1H，CONH)，7.55(s，1H，＝CH)，7.19(t，1H，C6H45-H)，6.77–6.79(m，2H，C6H42,4-H)，6.69(d，J＝7.7Hz，1H，C6H46-H)，2.66(s，3H，COCH3)，2.50(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino)-5-(3-nitrobenzylidene)-2-(4-methyl-5-acetylthiazole-2- Imino)-4-thiazolinone, 10mL acetic acid, 10mL dichloromethane, 1mL water and appropriate amount of iron powder were reacted at room temperature overnight. Suction filtration, filter cake, washing with dichloromethane, extraction, washing with saturated sodium carbonate solution, washing with water, drying over anhydrous sodium sulfate, precipitation to obtain light yellow solid 5-(3-aminobenzylidene)-2-(4-methyl1 H NMR (400MHz, DMSO-d6 )δ: 10.18(s, 1H, CONH ), 7.55 (s, 1H, =CH), 7.19 (t, 1H, C6 H4 5-H), 6.77–6.79 (m, 2H, C6 H4 2,4-H), 6.69 (d, J = 7.7 Hz, 1H, C6 H4 6-H), 2.66 (s, 3H, COCH3 ), 2.50 (s, 3H, CH3 ).
实施例12Example 12
5-(4-乙酰氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(4-acetylaminobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol 4-氨基苯甲醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流10h。冷却，抽滤，依次乙醇洗，饱和食盐水洗，水洗，干燥后得棕褐色固体5-(4-乙酰氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.275～277℃，收率75％；1H NMR(400MHz，DMSO-d6)δ：12.86(s，1H，CONH)，10.29(s，1H，CONH)，7.76(d，J＝8.0Hz，2H，C6H42，6-H)，7.66(s，1H，＝CH)，7.59(d，J＝8.0Hz，2H，C6H43，5-H)，2.67(s，3H，噻唑-COCH3)，2.51(s，3H，噻唑-CH3)，2.09(s，3H，NCOCH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol 4-aminobenzaldehyde and 6.0mmol anhydrous sodium acetate, add 15mL acetic acid and stir to dissolve, reflux for 10h . Cool, filter with suction, wash with ethanol successively, wash with saturated saline, wash with water, and dry to obtain tan solid 5-(4-acetylaminobenzylidene)-2-(4-methyl-5-acetylthiazole-2-ylidene) Amino)-4-thiazolinone, mp275～277°C, yield 75%;1 H NMR (400MHz, DMSO-d6 )δ: 12.86(s, 1H, CONH), 10.29(s, 1H, CONH), 7.76 (d, J = 8.0Hz, 2H,C6H42 ,6 -H), 7.66 (s, 1H, =CH), 7.59 (d, J = 8.0Hz, 2H,C6H43 ,5 -H), 2.67 (s, 3H, thiazole-COCH3 ), 2.51 (s, 3H, thiazole-CH3 ), 2.09 (s, 3H, NCOCH3 ).
实施例13Example 13
5-(4-二甲氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮的制备Preparation of 5-(4-dimethylaminobenzylidene)-2-(4-methyl-5-acetylthiazole-2-imino)-4-thiazolinone
1.0mmol 2-(4-甲基-5-乙酰基噻唑-2-亚氨基)4-噻唑啉酮、2.0mmol 4-二甲氨基苯甲醛和6.0mmol无水乙酸钠，加入15mL乙酸搅拌溶解，回流10h。冷却，抽滤，乙醇洗，饱和食盐水洗，水洗，干燥后得暗红色固体5-(4-二甲氨基亚苄基)-2-(4-甲基-5-乙酰基噻唑-2-亚氨基)-4-噻唑啉酮，m.p.275～278℃，收率62％；1H NMR(400MHz，DMSO-d6)δ：12.67(s，1H，CONH)，7.64(s，1H，＝CH)，7.51(d，J＝8.0Hz，2H，C6H42,6-H)，6.87(d，J＝8.0Hz，2H，C6H43,5-H)，3.04(s，6H，N(CH3)2)，2.70(s，3H，COCH3)，2.50(s，3H，CH3)。1.0mmol 2-(4-methyl-5-acetylthiazole-2-imino) 4-thiazolinone, 2.0mmol 4-dimethylaminobenzaldehyde and 6.0mmol anhydrous sodium acetate were added to 15mL of acetic acid and stirred to dissolve, Reflux 10h. Cool, filter with suction, wash with ethanol, wash with saturated brine, wash with water, and dry to give dark red solid 5-(4-dimethylaminobenzylidene)-2-(4-methyl-5-acetylthiazole-2-ylidene) Amino)-4-thiazolinone, mp275～278°C, yield 62%;1 H NMR (400MHz, DMSO-d6 )δ: 12.67(s, 1H, CONH), 7.64(s, 1H, =CH) , 7.51 (d, J=8.0Hz, 2H, C6 H4 2,6-H), 6.87 (d, J=8.0Hz, 2H, C6 H4 3,5-H), 3.04 (s, 6H , N(CH3 )2 ), 2.70 (s, 3H, COCH3 ), 2.50 (s, 3H, CH3 ).
实施例14Example 14
2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮抗流感病毒神经氨酸酶活性Anti-influenza virus neuraminidase activity of 2-(5-acylthiazole-2-imino)-4-thiazolinone
1.实验原理1. Experimental principle
化合物MUNANA是神经氨酸酶的特异性底物，在神经氨酸酶作用下产生的代谢产物在360nm照射激发下，可产生450nm荧光，荧光强度的变化可以灵敏地反映神经氨酸酶活性。酶均来自A/PR/8/34(H1N1)病毒毒株。The compound MUNANA is a specific substrate of neuraminidase. The metabolites produced under the action of neuraminidase can produce 450nm fluorescence under the excitation of 360nm irradiation, and the change of fluorescence intensity can sensitively reflect the activity of neuraminidase. The enzymes are all from A/PR/8/34 (H1 N1 ) virus strain.
2.实验方法2. Experimental method
在酶反应体系中，一定浓度样品与流感病毒神经氨酸酶NA悬浮于反应缓冲液中(pH6.5)，加入荧光底物MUNANA启动反应体系，37℃孵育40分钟后，加反应终止液终止反应。在激发波长360nm和发射波长为450nm的参数条件下，测定荧光强度值。根据荧光强度的减少量可以计算化合物对NA活性的抑制率。In the enzyme reaction system, a certain concentration of samples and influenza virus neuraminidase NA are suspended in the reaction buffer (pH 6.5), the fluorescent substrate MUNANA is added to start the reaction system, and after incubation at 37°C for 40 minutes, the reaction termination solution is added to terminate the reaction. reaction. Under the parameter conditions of excitation wavelength 360nm and emission wavelength 450nm, the fluorescence intensity value was measured. The inhibition rate of the compound on NA activity can be calculated according to the decrease of the fluorescence intensity.
3.检测样品：实施例化合物3. Detection sample: embodiment compound
4.活性结果4. Activity Results
优选化合物在反应系统中检测浓度40.0μg/mL时对神经氨酸酶的抑制率及其IC50值列入下表1：The inhibitory rate andIC50 value of the preferred compound to neuraminidase when the detected concentration in the reaction system is 40.0 μg/mL are listed in the following table 1:
表1 2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮对神经氨酸酶的抑制活性Table 1 Inhibitory activity of 2-(5-acylthiazole-2-imino)-4-thiazolinone on neuraminidase
2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮具有良好的抗流感病毒神经氨酸酶活性，可用于制备流感病毒神经氨酸酶抑制剂。The 2-(5-acylthiazole-2-imino)-4-thiazolinone has good anti-influenza virus neuraminidase activity and can be used to prepare influenza virus neuraminidase inhibitors.
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