非甾体抗炎药炎清片的应用基础研究
|
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。
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.
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。
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.
引文
1. 王静,张平,王丽红. 非甾体抗炎药不良反应研究与进展[J]. 临床药学, 2001, 8(7): 32-33.
2. 傅得兴,黄公怡. 非甾体抗炎药的不良反应及改进抗炎药物治疗的新发展[J]. 中国新药杂志,2000,9(9):604-608.
3. 仉文升, 李安良. 药物化学[M].北京:高等教育出版社, 1999.349-381.
4. 陈望忠. 两种新的选择性环氧合酶-2 抑制剂[J]. 国外医学·药学分册, 1997,24(3):168.
5. 施桂英. 非甾体抗炎药的合理应用[J]. 专家评说,2000,4(4):12-16.
6. Lipsky PE, Abramson SB, Crofford LJ, et al. The classification of cycloox-ygenase inhibitors[J]. Rheumatol,1998, 25: 2298- 2303.
7. Wright JM. The double- edged sword of COX- 2 selective NSAIDs. CMAJ, 2002, 167: 1131- 1137.
8. Bresalier RS, Sandler RS, Quan Hui, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. New Engl J Med, 2005, 352: 1092- 1102.
9. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associ-ated with celecoxib in a clinical trial for colorectal adenoma prevention. Ne-w Engl J Med, 2005, 352: 1071- 1080.
10. 张凤山,聂英坤. 非甾体抗炎药[J]. 哈尔滨医科大学学报,2002,4:342-344.
11. 赵晓军,韩英. COX- 2抑制剂对预防结肠癌的作用[J]. 中国医刊,2002,37(5) :24.
12. 李晓红,李红良,任先达. 非甾体抗炎药在肿瘤研究中的进展[J]. 国外医学药学分册, 29(3):139.
13. 赵娥. 环氧化酶- 2 抑制剂抗肿瘤作用的研究进展[J]. 中国药房,2002,13(6):374.
14. 董振海,隋明秀,董华军. 非甾体抗炎镇痛药的研究和应用进展[J]. 中国医刊,2004,39(2):50-52.
15. Vane JR ,Booting RM. Mechanism of action of nonsteriodal anti-inflamm-atory drugs[J]. Am J Med, 1998, 104(3A): 2.
16. Fosslien E. Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system[J]. Ann Clin Lab Sci 1998 , 28 :67.
17. Jouzeau J Y,Terlain B ,Abid A,et al. Cyclo-oxygenase isoenzymes. How r-ecent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs[J],1997, 53 :563.
18. Ferraz J G,Wallace JL ,Mcknighe W,et al. Induction of cyclo-oxygenase 1 and 2 in therat stomach during endotoxemia:role in resistance to damage[J]. Gastroenterol,1997, 113:195.
19. Crofford LJ, Tan B ,Mccarthy CJ, et al. Involvement of nuclear factor ka-ppa b in the regulation of cyclo-oxygenase-2-expression by interleukin-1 in rheumatoid synoviocytes[J]. Arthritis Rheum, 1997,40 :2226.
20. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal antiinflammatory drugs [J].Am J Med , 1998 , 104 :413.
21. 刘雁,李志军. 非甾体抗炎药物的药理及临床应用进展[J]. 中国医院药学杂志,2000,20(12):748-750.
22. 沈华,张静丽. 双氯芬酸用于偏头疼初探[J]. 国外医药合成药、生化药、制剂分册,2001,22(4):223-224.
23. 王淑月,贾湘曼,高记华. 非甾体抗炎药的临床应用进展[J]. 疑难病杂志,2002,1(2): 123-124.
24. Sheng H , Shao J , Kirkland SC , et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2 [J ] .J Clin Invest, 1997,99: 2254.
25. Thun MJ. NSAID use and decreased risk of gastrointestinal cancers[J]. Gastroe -nterol Clin North Am, 1996,25: 333.
26 .Steward WF, Kaws C, Corrada M, et al. Risk of Alzheiner’s disease and duration of NASID use[J]. Neurol, 1997, 47: 626.
27. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs[J]. Am J Med, 1998, 104: 413.
28. Van Ryn J , Pairet M. Selective cyclooxygenase-2 inhibitors : pharmacology, clinical effects and therapeutic potential[J]. Exp Opin Invest Drugs, 1997,6: 609.
29. 郭胜才,潘锋君. 非甾体抗炎药的进展[J]. 华西药学杂志,2000,15(6):469.
30. Jouzeau JY,Terlain B. Cyclo-oxygenase isoenzymes: how recent findings affect thinking about nonsteroidal anti-inflammatory drugs [J]. Drugs ,1997 ,53 (4) : 563.
31. American Rheumatism Association (ARA) Glossary Committee [M]. Dictionary of the Rheumatic Diseases, Vol.1: Signs and Symptoms. New York, NY, Contact Associates International, 1998.
32. Cannon G, Caldwell J, Holt P, et al. MK-0966, a specific COX-2 inhibitor, has clinical efficacy comparable to diclofenac in the treatment of knee and hip osteoarthritis(OA) in a 26-week controlled clinical trial [abstract no. 983] [I]. Arthritis Rheum, 1998, 41 Suppl:S196.
33. Truitt K, Ettinger W, Schnitzer T, et al. Rofecoxib, a COX-2 inhibitor, has clinical efficacy and overall safety in treating osteoarthritis patients 80 years and older [abstract no. 895]. In: XIV European League AgainstRheumatism Congress, 1999, 6-11: Glasgow.
34. 祝丹. 非甾体抗炎药物的进展,中国医院药学杂志,2002,22(6):369- 370.
35. 彭涛,王林编译. 第二代环氧合酶-2抑制剂,国外医学药学分册,2003,30(5):291-294.
36. 陈宜鸿,刘屏 奥湿克的药理特性及临床应用[J]. 中国医院药学杂志, 1999,19(2) :93.
37. 张伦. 双氯芬酸市场浅析[J]. 中国药房,2004,15(7):394-396.
38. 卓海通,卡德尔,凌树森等. 口服双氯芬酸钾胶囊剂药代动力学及生物利用率研究[J].中国临床药理学杂志, 1998, 14(1):44.
39. 王彤,励建安,顾晓圆等. 消炎镇痛新药—双氯芬酸钾片临床疗效[J]. 中国康复医学杂, 1998,13(2).
40 张先洲,蔡鸿生,姜俊勇等. 双氯灭痛滴眼液的研制[J]. 中国药学杂志,1995,30(4):212.
41 周晕,张胜,徐丹. 双氯灭痛肠溶片释放度试验[J]. 西北药学杂志,1996,11(3):122
42. 吴晴斋,屈步华,李德平等. 双氯灭痛缓释片的初步研制[J]. 新兴医药研究,1993,3(2):8.
43. 姚振均,沈秀文,陈文俊等. 双氯芬酸缓释片临床观察[J]. 中国临床药学杂志,1996,5(3):110.
44. 邢文荣,邢启德,夏晴等. 双氯芬酸钠控释骨架片的研制[J]. 新兴医药研究 1996,6(2):60.
45. 汤真,张振家,李丽等. 双氯灭痛缓释微丸的制备及体外溶出度测定[J]. 药学实践杂志,1997,15(1):15.
46. 于西全,左晖,唐鲁平等. 复方双氯灭痛微胶囊的制备及溶出度研究[J]. 中国医院药学杂志 1998,18(2):65.
47. 刘尚礼. 灭氯灭痛注射液(Olfen)的临床应用[J]. 广州医药. 1993,24(2):50.
48. 劳志英. 酮洛芬和双氯芬酸肌肉注射止痛作用的比较[J]. 新药与临床,1995,14(5):264.
49. 李治淮,傅凤华,李晓红等. 双氯芬酸搽剂的抗炎镇痛作用[J]. 中国药学杂志,1996,31(9):525.
50. 郭随章,屠锡德,王俊红灯,双氯芬酸凝胶剂的研制[J]. 中国药科大学学报,1997,28(2):73.
51. 丁长海,陈学广,徐建华等. 外用双氯芬酸钠凝胶治疗类风湿性关节炎的临床研究[J]. 中国临床药理学杂志,1995,11(1):11.
52. 刘树琴,徐建华,孙龙云等. 双氯芬酸钠凝胶治疗骨关节炎的疗效与安全性[J]. 药学实践杂志, 1997,15(1):3.
53. 王晓燕,郭代红,黄次波. 双氯灭痛霜剂的制备及临床应用[J]. 人民军医药学专刊, 1994,(2):48.
54. 李平,翟所迪,徐耀庭等. 双氯灭痛胶浆剂的制备及应用[J]. 中国医院药学杂志, 1992,12(7):329.
55 徐耀庭,陈修城,李文广等. 双氯灭痛对膀胱逼尿肌收缩的影响及临床应用[J]. 中华泌尿外科杂志, 1996,17(9):557.
56. 王章元,李高,杨光. 双氯灭痛栓的研制[J]. 中国医院药学杂志, 1992,12(4):163.
57. 裘元松,潘毓鸣. 双氯灭痛治疗肾绞痛疗效观察[J]. 现代应用药学, 1996,13(2): 46.
58. 莫克俭,邹龙云,王仁顺等. 双氯芬酸栓治疗肾绞痛40例[J]. 人民军医,1997,40(4):197.
59. 侯金成,王海峰. 双氯芬酸的制剂开发与临床应用[J]. 中国药业,1998,7(12):35-36.
60. 于莎莎, 杨振芸. .妇产科中小手术后双氯芬酸钾镇痛效果观察[J]. 首都医科大学学报, 2000, 21(2):164-165.
61. Vane J R. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-likedrugs. Nature(New Biol), 1971, 231:233-235.
62. 施桂英.认识双氯芬酸钾[J].中华全科医师杂志, 2006, 5(3):166-167.
63. 刘春红. 双氯芬酸胆碱分析方法研究[J]. 郑州大学2004级硕士研究生毕业论文.
64. 朱世琴, 朱为宏, 田忆凯. 2,6-二氯二苯胺的合成工艺评述[J]. 江苏化工,2000, 28(11):19-21.
65. 陈芬儿, 邓燕, 户业丽等.双氯芬酸钠合成工艺研究Ⅱ-取代乙酰苯胺重排法[J].中国医药杂志, 1995,29(8):339.
66. 傅建龙,杨清国,梁洁红. 双氯芬酸钠合成工艺改进[J]. 中国医药工业杂志,2000,31(7):296-297.
67. 唐熏,李筱芳,王家坡等. 制备双氯灭痛的新工艺研究[J]. 湖南大学学报(自然科学版), 2000,27(3):29-33.
68. 郭涛,牟平,丁立新等. 双氯芬酸赖氨酸盐的研制[J]. 中国药学杂志, 1996,31(7):421-423.
69.李汉洙,崔文花,尹寿玉等. 双氯灭痛赖氨酸盐的制备及其含量测定[J]. 延边医学院学报, 1994,17(2):126-128.
70. 刘利娥 阎素清,刘洁等 双氯芬酸胆碱的研制 河南医科大学学报 2000,35(5):443-444.
71. Hahn, D.A.; Gilman,E. Isomerization in the Hydantoin series induced by the action of Hydrogen Chloride.J.Amer.Chem.Soc. 47,2953(1925).
72. Elinor Ware. The Chemistry of the Hydantoins. Chemical Reviews. 403-455(1950).
73.《化学化工辞典》编委会;化学工业出版社辞典编辑部北学化工辞典(下册).化学工业出版社.2668(2003).
74. Iva,B.B; Ivan,G.P; Valentin,S.D. Alkaline Hydrolysis of Hydantoin, 3- Methylhydantoin, and 1-acetyl-3-methylurea. Effect of ring Size on the Cleavage of Acylureas.J.Chem.Soc.PerkinⅡ,887-892(1978).
75. Inokuma,S; Yamahara,T. Production Of Alpha-Amino Acids. DE 2614411 (1976).
76. Zundel,J. Preparation Of Alpha-Aminoacids From Hydantoins. DE 2028220 (1970).
77. Mitsugi,K; Sano,K . Method For Producing L-Amino Acid. US4016037 (1977).
78. Degen,L; Perricone,E. Method Of Converting Racemic Hydantoins Into Optically Active Aminoacids DE2631048(1977).
79. Orfeo,O.O; Renee,A.C; Herman,S.Substitution in the Hydantoin Ring. J.Chem. Soc.Perkin Trans.,1(2),219(1974).
80.Tyler,W. Acid Catalyzed Alkylation Of Hydantoin. US3847933(1974).
81. Marquwz,VE.In tramolecularC ydizationsL eading to N–Bridge head Bicyclics 5,5 -di phenydantoinD erivatives.J.Org.Chem.37,2558(1972)
82. Marshall, F.J. Lithium Aluminum Hydride reduction of Some Hydantoins, Barbit –urats and Thiouracils.J.Amer.Chem.Soc. 78,3696(1956).
83. 张天宝,岳木生,黄小波,等.二氯二甲基乙内酰脲复方消毒剂性能的实验室观察[J].中国消毒学杂志,1997,14(4):204～207.
84. 刘继敏,赵 勇.溴氯海因杀灭微生物效果与稳定性的试验观察[J].中国消毒学杂志,2001,18(4):218～222.
85. 陈 强,李清禄.复方溴氯海因消毒剂的性能[J].福建农林大学学报(自然科学版),2003,32(2):227～229.
86. 陈荣凤,薛广波,顾春英,等.二溴二甲基乙内酰脲的消毒杀菌作用[J].疾病控制杂志,2001,5(1):15～17.
87. 李清禄,林新华.复方二氯海因消毒剂的制备与性能[J]福建医科大学学报,2001, 35(2):176～179.
88. 张胜利,许祖勋,黄锦霞,等.N,N-二卤代二甲基乙内酰脲的合成及杀菌性能研究.湖北大学学报(自然科学版),2002,75(1):63～65.
89. 陈荣凤,薛广波,顾春英.卤化二甲基乙内酰脲消毒杀菌剂研究进展[J].上海预防医学杂志,1999,11(11):503～505.
90. 刑 华.溴氯海因、二溴海因对嗜水气单胞菌、柱状曲桡杆菌抑菌试验[J].中国水产,2001(8):81.
91. 赵春兰,石 磊,宋 晖,等.溴氯二甲基乙内酰脲复方消毒剂杀灭微生物效果与腐蚀性实验观察[J].中国消毒学杂志,1999,16(4):205～208.
92. 陈荣凤,薛广波.二溴二甲基乙内酰脲消毒剂机理的实验室研究[J].南方护理学报,2002,9(5):69～71.
93. 李明威,王占杰. 1,3-二氯-5,5-二甲基海因的合成与应用[J].化学世界,1991,32(12):533～535。
94. 林立辉,朱少凡.二氯二甲基海因及其复方消毒剂性能的实验观察[J].中国消毒学杂志,1996,13(4):193～196.
95. Endou Hitoshi,Ienaga K. Pharmaceutical composition containing a hydantoin derivative and use of said derivative[P].JP: EP0780125, 1997-06-25.
96. Launay Michele,Potin Dominique,Maillet MJ,et al. Hydantoin compounds useful as anti-inflammatory agents[P].FR: US2002143035,2002-10-03.
97. Ienaga, Kazuharu; Nakamura K. Hydantoin derivatives [J]. Chem Abstr,104:109642c 1985.
98. Sun Qun, Kyle DJ. Aryl substituted hydantoin compounds and their use as sodium channel blockers[P].US: WO2004010950, 2004-02-05.
99. 江明性主编. 药理学. 北京,人民卫生出版社,第四版,1997,99～103.
100.张会常,赵亚清主编. 120 种老药临床新用. 北京,人民军医出版社,1995,57.
101. Wong P T H, Tan S F. Jpn.J.Pharmacol., 1989, 49(3), 309～315.
102. Wong P T H, Tan S F. Teo W L. Asia Pac.J.Pharmacol, 1989, 4(2), 107～112.
103. Lumiere A, Perrin F. Bull.Soc.Chim, 1924, 35(4), 1022～1026.
104.江明性主编. 药理学. 北京,人民卫生出版社,第四版,1997,309.
105. Eilis and co-workers. Arch. Pharmacol., 1972, 83, 275.
106. Janos M, Janos E, Sandor H. J. Agri. Food Chem, 1993, 41(1), 148～152.
107. Itoi A, Omura M, Ogata H. Jpn, Kokai, Tokyo, Koho Jp 04, 360, 873, 1992.
108. Seki T. Jpn, Kokai, Tokyo, Koho Jp 09, 278, 645, 1996.
109. Okazaki T, Umishio K, Kato M. Jpn, Kokai, Tokyo, Koho Jp 05, 186, 429, 1993.
110. Peter H P. PCT Int. Appl. WO 88, 05, 653, 1988.
111. Edward H P. PCT Int. Appl. WO 89, 10, 696, 1989.
112. Thomas W T. U.S, US 4, 698, 165., 1987.
113. Vinod Chintamani M, Kamal Kishore N, Roshan Pirosha. G. Indian IN 171, 574, 1992.
114. Philip G S. PCT Int. Appl. WO 96, 11, 882, 1996.
115. Wada M, Mochizuki M. Jpn, Kokai, Tokyo, Koho Jp 03, 252, 452. 1991.
116. Klaus Wilhelm L. Arno S, Peter Eduart K. Ger. Offen. DE 3,739, 612, 1987.
117. Grigore N. Rom. RO 105,421. 1994.
118.Udo R, Josef O H, Horst R. Ger. Offen. DE 3, 517, 753, 1986.
119.Yarita T. Jpn, Kokai, Tokkyo, Koho Jp 09, 256, 186, 1997.
120. Yarita T. Asakawa T. Jpn, Kokai, Tokkyo, Koho Jp 09, 256, 185, 1997.
121. Yarita T. Asakawa T. Jpn, Kokai, Tokyo, Koho Jp 09, 256, 187, 1997.
122. Kuzushima T, Sekine I, Yuasa M. Jpn, Kokai, Tokyo, Koho Jp 09, 256, 190, 1997.
123. Steven H C, Dane C, Davaid A W. Eur. Pat. Appl. EP 471, 591, 1992.
124. U.S. US 5, 342, 593., 1994.
125. Yasuda H. Jpn, Kokai, Tokyo, Koho Jp 08, 269, 012, 1996.
126.Yasuda H. Jpn, Kokai, Tokyo, Koho Jp 08, 269, 018, 1996.
127.Akimoto T, Watanabe M, Nagasaki S. Jpn, Kokai, Tokyo, Koho Jp 62, 03, 792, 1987.
128. Ishikawa T, Kimura H. Jpn, Kokai, Tokyo, Koho Jp 63, 56, 278. 1988.
129.Oliviveri R, Fascetti E, Angelini L. Biotech. & Bioeng. 1981,23(10), 2173～2183.
130. European Patent Number US2003225286
131. European Patent Number EP1243261
132 . European Patent Number EP0780125
133. Janpanese Patent Publication Number 2003-171367
134. 余凌翀.有机化学中的人名反应.科学出版社.42 (1984)
135. Li, P.J. Synthesis of 1-Substituted and 1,3-Disubstituted 5-Hydantoin -carboxylates. J.Org.Chem.40,3414(1975).
136. Iwata,K; Hara,S,Process For The Preparation Of Hydantoin Derivatives. US 3946033 (1976).
137. Bayerlein,F;Kolbeck,W. Process For The Production Of 5, 5- Diphenyl- hydantoin. US3646056(1972).
138.Merten,R; Rottmaier,L. Preparation Of Hydantoins By Reacting Esters Of Ethylene-1,2-Dicarboxylic Acids And Ureas AndThioureas. DE2539730(1977)
139. Hermann,B. Verfahren zur Darstellung von Hydantoinen. DE566094 (1932).
140. Henze,H.R; Speer,J.R. Identification of Carbonyl Compounds through Conversion into Hydantoins.J.Amer. Chem.Soc.64,522(1964).
141. A.I.迈耶斯.有机合成中的杂环化合物.化学工业出版社.164( 1985).
142. 余凌翀. 有机化学中的人名反应,科学出版社.68 (1984).
143. Inagaki,H. Production Of Hydantoin.JP61072761 (1986).
144. Takeuchi,K. Preparation Of Hydrantoin.JP61083164(1986).
145. Halbert, C. W; Don, V. W. Production of Hydantoin and Glycine. US2663713 (1953).
146.William, F.G; Carl,E.S. Preparation of Hydantoin. US2402134(1946).
147. Janpanese Patent Publication number 2002-338536.
2. 傅得兴,黄公怡. 非甾体抗炎药的不良反应及改进抗炎药物治疗的新发展[J]. 中国新药杂志,2000,9(9):604-608.
3. 仉文升, 李安良. 药物化学[M].北京:高等教育出版社, 1999.349-381.
4. 陈望忠. 两种新的选择性环氧合酶-2 抑制剂[J]. 国外医学·药学分册, 1997,24(3):168.
5. 施桂英. 非甾体抗炎药的合理应用[J]. 专家评说,2000,4(4):12-16.
6. Lipsky PE, Abramson SB, Crofford LJ, et al. The classification of cycloox-ygenase inhibitors[J]. Rheumatol,1998, 25: 2298- 2303.
7. Wright JM. The double- edged sword of COX- 2 selective NSAIDs. CMAJ, 2002, 167: 1131- 1137.
8. Bresalier RS, Sandler RS, Quan Hui, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. New Engl J Med, 2005, 352: 1092- 1102.
9. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associ-ated with celecoxib in a clinical trial for colorectal adenoma prevention. Ne-w Engl J Med, 2005, 352: 1071- 1080.
10. 张凤山,聂英坤. 非甾体抗炎药[J]. 哈尔滨医科大学学报,2002,4:342-344.
11. 赵晓军,韩英. COX- 2抑制剂对预防结肠癌的作用[J]. 中国医刊,2002,37(5) :24.
12. 李晓红,李红良,任先达. 非甾体抗炎药在肿瘤研究中的进展[J]. 国外医学药学分册, 29(3):139.
13. 赵娥. 环氧化酶- 2 抑制剂抗肿瘤作用的研究进展[J]. 中国药房,2002,13(6):374.
14. 董振海,隋明秀,董华军. 非甾体抗炎镇痛药的研究和应用进展[J]. 中国医刊,2004,39(2):50-52.
15. Vane JR ,Booting RM. Mechanism of action of nonsteriodal anti-inflamm-atory drugs[J]. Am J Med, 1998, 104(3A): 2.
16. Fosslien E. Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system[J]. Ann Clin Lab Sci 1998 , 28 :67.
17. Jouzeau J Y,Terlain B ,Abid A,et al. Cyclo-oxygenase isoenzymes. How r-ecent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs[J],1997, 53 :563.
18. Ferraz J G,Wallace JL ,Mcknighe W,et al. Induction of cyclo-oxygenase 1 and 2 in therat stomach during endotoxemia:role in resistance to damage[J]. Gastroenterol,1997, 113:195.
19. Crofford LJ, Tan B ,Mccarthy CJ, et al. Involvement of nuclear factor ka-ppa b in the regulation of cyclo-oxygenase-2-expression by interleukin-1 in rheumatoid synoviocytes[J]. Arthritis Rheum, 1997,40 :2226.
20. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal antiinflammatory drugs [J].Am J Med , 1998 , 104 :413.
21. 刘雁,李志军. 非甾体抗炎药物的药理及临床应用进展[J]. 中国医院药学杂志,2000,20(12):748-750.
22. 沈华,张静丽. 双氯芬酸用于偏头疼初探[J]. 国外医药合成药、生化药、制剂分册,2001,22(4):223-224.
23. 王淑月,贾湘曼,高记华. 非甾体抗炎药的临床应用进展[J]. 疑难病杂志,2002,1(2): 123-124.
24. Sheng H , Shao J , Kirkland SC , et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2 [J ] .J Clin Invest, 1997,99: 2254.
25. Thun MJ. NSAID use and decreased risk of gastrointestinal cancers[J]. Gastroe -nterol Clin North Am, 1996,25: 333.
26 .Steward WF, Kaws C, Corrada M, et al. Risk of Alzheiner’s disease and duration of NASID use[J]. Neurol, 1997, 47: 626.
27. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs[J]. Am J Med, 1998, 104: 413.
28. Van Ryn J , Pairet M. Selective cyclooxygenase-2 inhibitors : pharmacology, clinical effects and therapeutic potential[J]. Exp Opin Invest Drugs, 1997,6: 609.
29. 郭胜才,潘锋君. 非甾体抗炎药的进展[J]. 华西药学杂志,2000,15(6):469.
30. Jouzeau JY,Terlain B. Cyclo-oxygenase isoenzymes: how recent findings affect thinking about nonsteroidal anti-inflammatory drugs [J]. Drugs ,1997 ,53 (4) : 563.
31. American Rheumatism Association (ARA) Glossary Committee [M]. Dictionary of the Rheumatic Diseases, Vol.1: Signs and Symptoms. New York, NY, Contact Associates International, 1998.
32. Cannon G, Caldwell J, Holt P, et al. MK-0966, a specific COX-2 inhibitor, has clinical efficacy comparable to diclofenac in the treatment of knee and hip osteoarthritis(OA) in a 26-week controlled clinical trial [abstract no. 983] [I]. Arthritis Rheum, 1998, 41 Suppl:S196.
33. Truitt K, Ettinger W, Schnitzer T, et al. Rofecoxib, a COX-2 inhibitor, has clinical efficacy and overall safety in treating osteoarthritis patients 80 years and older [abstract no. 895]. In: XIV European League AgainstRheumatism Congress, 1999, 6-11: Glasgow.
34. 祝丹. 非甾体抗炎药物的进展,中国医院药学杂志,2002,22(6):369- 370.
35. 彭涛,王林编译. 第二代环氧合酶-2抑制剂,国外医学药学分册,2003,30(5):291-294.
36. 陈宜鸿,刘屏 奥湿克的药理特性及临床应用[J]. 中国医院药学杂志, 1999,19(2) :93.
37. 张伦. 双氯芬酸市场浅析[J]. 中国药房,2004,15(7):394-396.
38. 卓海通,卡德尔,凌树森等. 口服双氯芬酸钾胶囊剂药代动力学及生物利用率研究[J].中国临床药理学杂志, 1998, 14(1):44.
39. 王彤,励建安,顾晓圆等. 消炎镇痛新药—双氯芬酸钾片临床疗效[J]. 中国康复医学杂, 1998,13(2).
40 张先洲,蔡鸿生,姜俊勇等. 双氯灭痛滴眼液的研制[J]. 中国药学杂志,1995,30(4):212.
41 周晕,张胜,徐丹. 双氯灭痛肠溶片释放度试验[J]. 西北药学杂志,1996,11(3):122
42. 吴晴斋,屈步华,李德平等. 双氯灭痛缓释片的初步研制[J]. 新兴医药研究,1993,3(2):8.
43. 姚振均,沈秀文,陈文俊等. 双氯芬酸缓释片临床观察[J]. 中国临床药学杂志,1996,5(3):110.
44. 邢文荣,邢启德,夏晴等. 双氯芬酸钠控释骨架片的研制[J]. 新兴医药研究 1996,6(2):60.
45. 汤真,张振家,李丽等. 双氯灭痛缓释微丸的制备及体外溶出度测定[J]. 药学实践杂志,1997,15(1):15.
46. 于西全,左晖,唐鲁平等. 复方双氯灭痛微胶囊的制备及溶出度研究[J]. 中国医院药学杂志 1998,18(2):65.
47. 刘尚礼. 灭氯灭痛注射液(Olfen)的临床应用[J]. 广州医药. 1993,24(2):50.
48. 劳志英. 酮洛芬和双氯芬酸肌肉注射止痛作用的比较[J]. 新药与临床,1995,14(5):264.
49. 李治淮,傅凤华,李晓红等. 双氯芬酸搽剂的抗炎镇痛作用[J]. 中国药学杂志,1996,31(9):525.
50. 郭随章,屠锡德,王俊红灯,双氯芬酸凝胶剂的研制[J]. 中国药科大学学报,1997,28(2):73.
51. 丁长海,陈学广,徐建华等. 外用双氯芬酸钠凝胶治疗类风湿性关节炎的临床研究[J]. 中国临床药理学杂志,1995,11(1):11.
52. 刘树琴,徐建华,孙龙云等. 双氯芬酸钠凝胶治疗骨关节炎的疗效与安全性[J]. 药学实践杂志, 1997,15(1):3.
53. 王晓燕,郭代红,黄次波. 双氯灭痛霜剂的制备及临床应用[J]. 人民军医药学专刊, 1994,(2):48.
54. 李平,翟所迪,徐耀庭等. 双氯灭痛胶浆剂的制备及应用[J]. 中国医院药学杂志, 1992,12(7):329.
55 徐耀庭,陈修城,李文广等. 双氯灭痛对膀胱逼尿肌收缩的影响及临床应用[J]. 中华泌尿外科杂志, 1996,17(9):557.
56. 王章元,李高,杨光. 双氯灭痛栓的研制[J]. 中国医院药学杂志, 1992,12(4):163.
57. 裘元松,潘毓鸣. 双氯灭痛治疗肾绞痛疗效观察[J]. 现代应用药学, 1996,13(2): 46.
58. 莫克俭,邹龙云,王仁顺等. 双氯芬酸栓治疗肾绞痛40例[J]. 人民军医,1997,40(4):197.
59. 侯金成,王海峰. 双氯芬酸的制剂开发与临床应用[J]. 中国药业,1998,7(12):35-36.
60. 于莎莎, 杨振芸. .妇产科中小手术后双氯芬酸钾镇痛效果观察[J]. 首都医科大学学报, 2000, 21(2):164-165.
61. Vane J R. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-likedrugs. Nature(New Biol), 1971, 231:233-235.
62. 施桂英.认识双氯芬酸钾[J].中华全科医师杂志, 2006, 5(3):166-167.
63. 刘春红. 双氯芬酸胆碱分析方法研究[J]. 郑州大学2004级硕士研究生毕业论文.
64. 朱世琴, 朱为宏, 田忆凯. 2,6-二氯二苯胺的合成工艺评述[J]. 江苏化工,2000, 28(11):19-21.
65. 陈芬儿, 邓燕, 户业丽等.双氯芬酸钠合成工艺研究Ⅱ-取代乙酰苯胺重排法[J].中国医药杂志, 1995,29(8):339.
66. 傅建龙,杨清国,梁洁红. 双氯芬酸钠合成工艺改进[J]. 中国医药工业杂志,2000,31(7):296-297.
67. 唐熏,李筱芳,王家坡等. 制备双氯灭痛的新工艺研究[J]. 湖南大学学报(自然科学版), 2000,27(3):29-33.
68. 郭涛,牟平,丁立新等. 双氯芬酸赖氨酸盐的研制[J]. 中国药学杂志, 1996,31(7):421-423.
69.李汉洙,崔文花,尹寿玉等. 双氯灭痛赖氨酸盐的制备及其含量测定[J]. 延边医学院学报, 1994,17(2):126-128.
70. 刘利娥 阎素清,刘洁等 双氯芬酸胆碱的研制 河南医科大学学报 2000,35(5):443-444.
71. Hahn, D.A.; Gilman,E. Isomerization in the Hydantoin series induced by the action of Hydrogen Chloride.J.Amer.Chem.Soc. 47,2953(1925).
72. Elinor Ware. The Chemistry of the Hydantoins. Chemical Reviews. 403-455(1950).
73.《化学化工辞典》编委会;化学工业出版社辞典编辑部北学化工辞典(下册).化学工业出版社.2668(2003).
74. Iva,B.B; Ivan,G.P; Valentin,S.D. Alkaline Hydrolysis of Hydantoin, 3- Methylhydantoin, and 1-acetyl-3-methylurea. Effect of ring Size on the Cleavage of Acylureas.J.Chem.Soc.PerkinⅡ,887-892(1978).
75. Inokuma,S; Yamahara,T. Production Of Alpha-Amino Acids. DE 2614411 (1976).
76. Zundel,J. Preparation Of Alpha-Aminoacids From Hydantoins. DE 2028220 (1970).
77. Mitsugi,K; Sano,K . Method For Producing L-Amino Acid. US4016037 (1977).
78. Degen,L; Perricone,E. Method Of Converting Racemic Hydantoins Into Optically Active Aminoacids DE2631048(1977).
79. Orfeo,O.O; Renee,A.C; Herman,S.Substitution in the Hydantoin Ring. J.Chem. Soc.Perkin Trans.,1(2),219(1974).
80.Tyler,W. Acid Catalyzed Alkylation Of Hydantoin. US3847933(1974).
81. Marquwz,VE.In tramolecularC ydizationsL eading to N–Bridge head Bicyclics 5,5 -di phenydantoinD erivatives.J.Org.Chem.37,2558(1972)
82. Marshall, F.J. Lithium Aluminum Hydride reduction of Some Hydantoins, Barbit –urats and Thiouracils.J.Amer.Chem.Soc. 78,3696(1956).
83. 张天宝,岳木生,黄小波,等.二氯二甲基乙内酰脲复方消毒剂性能的实验室观察[J].中国消毒学杂志,1997,14(4):204～207.
84. 刘继敏,赵 勇.溴氯海因杀灭微生物效果与稳定性的试验观察[J].中国消毒学杂志,2001,18(4):218～222.
85. 陈 强,李清禄.复方溴氯海因消毒剂的性能[J].福建农林大学学报(自然科学版),2003,32(2):227～229.
86. 陈荣凤,薛广波,顾春英,等.二溴二甲基乙内酰脲的消毒杀菌作用[J].疾病控制杂志,2001,5(1):15～17.
87. 李清禄,林新华.复方二氯海因消毒剂的制备与性能[J]福建医科大学学报,2001, 35(2):176～179.
88. 张胜利,许祖勋,黄锦霞,等.N,N-二卤代二甲基乙内酰脲的合成及杀菌性能研究.湖北大学学报(自然科学版),2002,75(1):63～65.
89. 陈荣凤,薛广波,顾春英.卤化二甲基乙内酰脲消毒杀菌剂研究进展[J].上海预防医学杂志,1999,11(11):503～505.
90. 刑 华.溴氯海因、二溴海因对嗜水气单胞菌、柱状曲桡杆菌抑菌试验[J].中国水产,2001(8):81.
91. 赵春兰,石 磊,宋 晖,等.溴氯二甲基乙内酰脲复方消毒剂杀灭微生物效果与腐蚀性实验观察[J].中国消毒学杂志,1999,16(4):205～208.
92. 陈荣凤,薛广波.二溴二甲基乙内酰脲消毒剂机理的实验室研究[J].南方护理学报,2002,9(5):69～71.
93. 李明威,王占杰. 1,3-二氯-5,5-二甲基海因的合成与应用[J].化学世界,1991,32(12):533～535。
94. 林立辉,朱少凡.二氯二甲基海因及其复方消毒剂性能的实验观察[J].中国消毒学杂志,1996,13(4):193～196.
95. Endou Hitoshi,Ienaga K. Pharmaceutical composition containing a hydantoin derivative and use of said derivative[P].JP: EP0780125, 1997-06-25.
96. Launay Michele,Potin Dominique,Maillet MJ,et al. Hydantoin compounds useful as anti-inflammatory agents[P].FR: US2002143035,2002-10-03.
97. Ienaga, Kazuharu; Nakamura K. Hydantoin derivatives [J]. Chem Abstr,104:109642c 1985.
98. Sun Qun, Kyle DJ. Aryl substituted hydantoin compounds and their use as sodium channel blockers[P].US: WO2004010950, 2004-02-05.
99. 江明性主编. 药理学. 北京,人民卫生出版社,第四版,1997,99～103.
100.张会常,赵亚清主编. 120 种老药临床新用. 北京,人民军医出版社,1995,57.
101. Wong P T H, Tan S F. Jpn.J.Pharmacol., 1989, 49(3), 309～315.
102. Wong P T H, Tan S F. Teo W L. Asia Pac.J.Pharmacol, 1989, 4(2), 107～112.
103. Lumiere A, Perrin F. Bull.Soc.Chim, 1924, 35(4), 1022～1026.
104.江明性主编. 药理学. 北京,人民卫生出版社,第四版,1997,309.
105. Eilis and co-workers. Arch. Pharmacol., 1972, 83, 275.
106. Janos M, Janos E, Sandor H. J. Agri. Food Chem, 1993, 41(1), 148～152.
107. Itoi A, Omura M, Ogata H. Jpn, Kokai, Tokyo, Koho Jp 04, 360, 873, 1992.
108. Seki T. Jpn, Kokai, Tokyo, Koho Jp 09, 278, 645, 1996.
109. Okazaki T, Umishio K, Kato M. Jpn, Kokai, Tokyo, Koho Jp 05, 186, 429, 1993.
110. Peter H P. PCT Int. Appl. WO 88, 05, 653, 1988.
111. Edward H P. PCT Int. Appl. WO 89, 10, 696, 1989.
112. Thomas W T. U.S, US 4, 698, 165., 1987.
113. Vinod Chintamani M, Kamal Kishore N, Roshan Pirosha. G. Indian IN 171, 574, 1992.
114. Philip G S. PCT Int. Appl. WO 96, 11, 882, 1996.
115. Wada M, Mochizuki M. Jpn, Kokai, Tokyo, Koho Jp 03, 252, 452. 1991.
116. Klaus Wilhelm L. Arno S, Peter Eduart K. Ger. Offen. DE 3,739, 612, 1987.
117. Grigore N. Rom. RO 105,421. 1994.
118.Udo R, Josef O H, Horst R. Ger. Offen. DE 3, 517, 753, 1986.
119.Yarita T. Jpn, Kokai, Tokkyo, Koho Jp 09, 256, 186, 1997.
120. Yarita T. Asakawa T. Jpn, Kokai, Tokkyo, Koho Jp 09, 256, 185, 1997.
121. Yarita T. Asakawa T. Jpn, Kokai, Tokyo, Koho Jp 09, 256, 187, 1997.
122. Kuzushima T, Sekine I, Yuasa M. Jpn, Kokai, Tokyo, Koho Jp 09, 256, 190, 1997.
123. Steven H C, Dane C, Davaid A W. Eur. Pat. Appl. EP 471, 591, 1992.
124. U.S. US 5, 342, 593., 1994.
125. Yasuda H. Jpn, Kokai, Tokyo, Koho Jp 08, 269, 012, 1996.
126.Yasuda H. Jpn, Kokai, Tokyo, Koho Jp 08, 269, 018, 1996.
127.Akimoto T, Watanabe M, Nagasaki S. Jpn, Kokai, Tokyo, Koho Jp 62, 03, 792, 1987.
128. Ishikawa T, Kimura H. Jpn, Kokai, Tokyo, Koho Jp 63, 56, 278. 1988.
129.Oliviveri R, Fascetti E, Angelini L. Biotech. & Bioeng. 1981,23(10), 2173～2183.
130. European Patent Number US2003225286
131. European Patent Number EP1243261
132 . European Patent Number EP0780125
133. Janpanese Patent Publication Number 2003-171367
134. 余凌翀.有机化学中的人名反应.科学出版社.42 (1984)
135. Li, P.J. Synthesis of 1-Substituted and 1,3-Disubstituted 5-Hydantoin -carboxylates. J.Org.Chem.40,3414(1975).
136. Iwata,K; Hara,S,Process For The Preparation Of Hydantoin Derivatives. US 3946033 (1976).
137. Bayerlein,F;Kolbeck,W. Process For The Production Of 5, 5- Diphenyl- hydantoin. US3646056(1972).
138.Merten,R; Rottmaier,L. Preparation Of Hydantoins By Reacting Esters Of Ethylene-1,2-Dicarboxylic Acids And Ureas AndThioureas. DE2539730(1977)
139. Hermann,B. Verfahren zur Darstellung von Hydantoinen. DE566094 (1932).
140. Henze,H.R; Speer,J.R. Identification of Carbonyl Compounds through Conversion into Hydantoins.J.Amer. Chem.Soc.64,522(1964).
141. A.I.迈耶斯.有机合成中的杂环化合物.化学工业出版社.164( 1985).
142. 余凌翀. 有机化学中的人名反应,科学出版社.68 (1984).
143. Inagaki,H. Production Of Hydantoin.JP61072761 (1986).
144. Takeuchi,K. Preparation Of Hydrantoin.JP61083164(1986).
145. Halbert, C. W; Don, V. W. Production of Hydantoin and Glycine. US2663713 (1953).
146.William, F.G; Carl,E.S. Preparation of Hydantoin. US2402134(1946).
147. Janpanese Patent Publication number 2002-338536.