【作者】 李桂英；

【导师】 王恩思；

【作者基本信息】 吉林大学 ， 生物化学与分子生物学， 2007， 博士

【摘要】 炎清片(双氯芬酸钾-1-甲基海因片)是新的化药复方制剂,是复方非甾体抗炎药。非甾体抗炎药(Nonsteroidal anti-inflammatory drugs,NSAIDs)是临床上应用最广泛的一类具有抗炎、镇痛和解热作用而非类固醇结构的药物。但是,在临床使用过程中发现,大部分的NSAIDs都存在着不同程度的毒副作用,所以限制了这类药物的长期使用。因此,开发新型安全可靠的NSAIDs,将成为NSAIDs新的研究热点之一,而开发复方制剂是新药开发的一个途径。复方制剂炎清片,既保留了单药的抗炎作用,同时又降低了单药的毒副作用,因此安全性高,患者更易接受。本项研究的复方非甾体抗炎药物-炎清片,主要成份为双氯芬酸钾和1-甲基海因,是治疗类风湿和骨关节炎的一类新药。由于单药双氯芬酸钾的不良反应很多,主要为腹部疼痛以及恶心、呕吐、腹泻、腹部痉孪、过敏反应(如哮喘)、水肿等。为了降低其毒副作用,与1-甲基海因组成复方制剂。1-甲基海因是从动物药蛤蟆油中提取分离出来的一个单体,抗炎作用是1-甲基海因的主要药效之一。药效学实验还验证,1-甲基海因也有很好的止咳化痰作用,且毒副性极低。药理实验研究表明,由于在复方炎清片中加入了1-甲基海因,其抗炎活性与双氯芬酸钾相当,但其毒副作用明显低于双氯芬酸钾片。在工艺研究方面,结合工业生产的需要,建立了这两种单药的化学合成工艺。其中我们建立的1-甲基海因的合成路线与国内外报道相比较,具有成本低,收率高,合成步骤简单,更适合工业化生产,实现了绿色化学。关键中间体及最终化合物的结构经紫外光谱、红外光谱、核磁共振氢谱及碳谱得到确证。采用高效液相法测定了原料药及制剂中双氯芬酸钾和1-甲基海因的含量,较好地控制了该药的质量。在药物配伍研究方面,设立多个给药剂量,筛选出双氯芬酸钾和1-甲基海因这两种化合物的最佳配伍比例,在该配伍下的复方制剂-炎清片,抗炎活性与单药双氯芬酸钾对照组相当,同时又降低了毒副作用。总之,本研究的结果为研制和开发新药炎清片奠定了基础。更多还原

【Abstract】 Yanqing Tablets (Diclofenac-1-methylhydantoin Tab) is a compound preparation of new pharmaceutical chemicals ,which is also a compound preparation of NSAIDs. Nonsteroidal anti-inflammatory drugs(NSAIDs) is one of the most applied drugs on clinical application . It is drugs of non-steroidal structure which make functions on anti-inflammatory, analgesia, relieving fever .It is mainly applied in the treatment of the inflammation immunologic diseases such as rheumatic arthritis, arthritis deformans, ostarthritis etc.At present, NSAIDs has been developed into an excellent drugs which make functions on anti-inflammatory and anti-rheumatism and it has various kinds. Its outputs is among the top in the world. However, we discovered that most of NSAIDs had toxicity and side-effects more or less, which affected the long term apply of it . The discovery of its side-effects stimulates the pharmaceutical chemists to do deep researches on the inflammatory reaction mechanism and the mechanism of actions of anti-inflammatory drugs continuously to find a new anti-inflammatory drug with better performance and less poisonous effects. As a new medicine, it should have higer biological activity,meanwhile secure to human body. Therefore, It will be study focus on NSAIDs to develop a new kind of secure and reliable NSAIDs. And the compound preparation is a way of the new drug development ,which has anti-inflammation effct with less side effect and higher security,and easier to be accepted by patients.The essential components of NSAIDs-Yanqing Tablets are diclofenac potassium and 1-mehylhydantoin, which is new pharmaceutical chemicals of first classification, to cure arthritis deformans and ostarthritis. In this medicine, diclofenac potassium is the derivate of Phenylacetic acid, which belongs to the NSAIDs with functions of anti-flammatory, analgesia and pyretolysis. The chemical name of Diclofenac potassiumpotassium is 2-(2-(2,6-dichlorophenyl amino) phenyl) acetate, which is the promotion substitution product of diclofenac sodium, It has stronger effect among the NSAIDs. Its depressant effect to ptostate glanding is stronger than Asp, IMT, etc, and it also has vivid pharmacology characteristic. It can be absorbed quickly, and the absorption rate is also higher. The pharmacokinetics character demonstrated that it can be absorbed quickly and completely for oral use, and the peak time is about one hour, which is two hours faster than sodium salt . Therefore it has better effect on relieving pain than diclofenac sodium. However, diclofenac potassium also has many adverse effects, for example abdomen ache, disgusting, disgorging, diarrhea, abdomen spasm, dyspepsia, gaseous distention, anorexy, gastrointestinal bleeding, haematenesis, dark stools, gastrointestinal tract ulcer, perforation, hemorrhagic, diarrhea, headache, dizziness, efflorescence, cnidosis, SGOT advanced, hepatitis, allergic response, dropsy and so on. To reduce toxicity and side-effects, compoud preparation was made with diclofenac and 1-mehylhydantoin,wich is a monomer separated from Oviductus Ranae,The anti-inflammatory action is one of 1-mehylhydantoin’s pharmacodynamics. Pharmacodynamics experiment confirmed that it also has well functions of relieving cough and reducing sputum. We have already applied for the patent about its application in the preparation of phlegm retention medicine. These all provide safeguard to research and develop this compound. Furthermore, its toxicity is also extremely low, and nearly doesn’t have side effect. The study of pharmacology experiment indicated that because of 1-mehylhydantoin, Yanqing tablets is similar with diclofenac potassium, but its poisonous is lower than diclofenac potassium obviously. At present through our study, we have established the technology suited for the large-scale industry production and the corresponding quality specification, which can control its quality easily.In the technology research aspect, we can determine that its active components are diclofenac potassium and 1-mehylhydantoin on the foundation of pharmacology research. And we also established the chemical synthesis technologies of these two active compounds which are combined with the need of large-scale industry production. The raw materials of this technology are amino benzene and dichloro-phenol, through chlorine acylation reaction, etherification reaction and rearrangement reaction, we synthesized the key intermediate—2,6-dichloro diphenylamino, later this key intermediate, through acylation reaction, cyclization reaction, lytic reaction and so on, synthesized diclofenac potassium. The yield of each reaction is about 85% averagely. At present, the synthesis technology of diclofenac sodium has been reported, however there isn’t literature report about the synthesis technology of diclofenac potassium, which can be looked up in the item investigation information. This technology possess many characteristics: ordinary raw materials, convenient operation, bland reaction conditions, lower cost, shorter route, fine security, and the yield and purity are also high. Therefore, this technology suits to industrialization production. Besides, we synthesized a derivate of diclofenac, methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate. The pharmacodynamics experiments indicate that this compound possess better anti-inflammatory activity than diclofenac potassium.The synthesis of 1-mehylhydantoin can be divided into two steps: the synthesis of N-methylamino acetic acid and the synthesis of 1-mehylhydantoin. The title compound was prepared by“One-pot”method. We used the methylamine and sodium chloroacetate as the main raw materials to synthesis 1-mehylhydantoin. The second step is to to synthesis 1-mehylhydantoin.The N-methylamino acetic acid was synthesized by methylamine and sodium chloroacetate. Next 1-mehylhydantoin was synthesized by cyclization reaction. In this research, the synthesis technology of 1-mehylhydantoin has not been reported. This technology has several characteristics: Firstly, lower cost, higher yield and simple synthesis steps, which all suit to industrialization production. Secondly we avoided to use rank poison drug-hydroxyl acetonitrile, so we have realized the green chemistry. At present, we have applied for a patent of 1-mehylhydantoin, which can establish the foundation to exploit and utilize this compound further. And we synthesized a derivate of 1-mehylhydantoin, hydantoin. The pharmacodynamics experiments indicate that this compound possess excellent anti-inflammatory activity. The structures of the key intermediates and the final compound are ensured by the ultraviolet spectrum, the infrared spectrum, the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum. We determined the contents of diclofenac potassium and 1-mehylhydantoin in the crude drugs and preparation by the method of HPLC, the purities of diclofenac potassium and 1-mehylhydantoin are about 99%. And we has controlled tablets’quality well.We have inspected the stabilities of the crude drugs and the preparation. The result indicated that ,under the condition of ordinary temperature, the character, the identification, the load difference, the water content, the disintegration time, the content and the hygiene index of this drug are not obviously change all, which consist with each stipulation of quality specification protocol. There also proved that the stabilities of this crude drug and its preparation consistent with the new drug requirement.The pharmacodynamics experiments indicate that in the aspect of anti-inflammatory, 1-mehylhydantoin, through the way of intragastric administration, can remarkably suppress the mouse’s swelling of ear as a result of dimethyl benzene. There is significant difference: when compares with dimethyl benzene model control group. All these can explain that 1-mehylhydantoin can obviously suppress the inflammatory reaction which is because of dimethyl benzene. In the aspect of analgesia, the high dosage team of 1-mehylhydantoin has the tendency to reduce the number of times of acetic acid writhing, the medium dosage team can remarkably suppress acetic acid writhing response, and there is not significant difference when the low dosage team compares with the model control group. These can explain that this compound of high or medium dosage has displayed excellent analgesia effect. LD50 is(160.04±43.49)mg/kg after little white mouse drank diclofenac potassium, while LD50 is 22.8 g/kg.Under the condition of 32mg/kg body weight dosage, in the diclofenac potassium masculine medicine control group, the mouse revealed evident toxication phenomenon slightly. However, although the anti-inflammatory active of 1-mehylhydantoin is slightly weaker than diclofenac potassium, there is not toxication phenomenon. This also can demonstrate that the toxicity and side-effects of 1-mehylhydantoin is extremely low.On the aspect of medicine compatibility research, we established the pharmacology model which can reflect the clinical curative effect. We finally screened the best effective dose and the best compatibility propotion by setting up multitude administration dosages, The compound preparation- Yanqing Tablets, employed this compatibility.Its anti- inflammatory activity matches that of the control group of diclofenac potassium, meanwhile the toxicity and side-effects were reduced.In a word, the results of our research established the foundation of the study and development of the new drug- Yanqing Tablets.更多还原