【作者】 周小平；

【导师】 杨晓虹；

【作者基本信息】 吉林大学 ， 生物化学与分子生物学， 2005， 博士

【摘要】 本文以4,5-二芳基噁唑类非甾体抗炎药(NSAIDs)奥沙普秦(Oxaprozin)为先导化合物,利用生物电子等排原理及4,5-二芳基噁唑类NSAIDs 的构效关系及NSAIDs 的作用机制,采用与环氧化酶分子对接的方法,辅助设计了3 类新化合物,从中筛选出新化合物3-〔4-(4-氟苯基)-5-(4-氨基磺酰基-3-氟苯基)噁唑-2-基〕丙酸(NC-2142)进行合成,并合成得到七个新的重要中间体,同时也对NC-2142 的合成工艺进行了考察。经药理实验证明NC-2142 对二甲苯、蛋清、角叉菜胶等所致急性炎症均有明显的抑制作用,对小鼠扭体法及热板法致痛也具有明显的抑制作用。由此表明,NC-2142 是一个具有较强的抗炎和镇痛作用且极具开发价值的新化合物。这为进一步研究高效、低毒的新型NSAIDs 提供了一个新的研究方法。更多还原

【Abstract】 Nonsteroidal anti-inflammation drugs(NSAIDs) are among themost widely used therapeutics, primarily for the treatment of pain,inflammation and pyretics. However they may cause seriousgastrointestinal side effect after a along term use, even ulcers, bleedsand perforation, not only for their blocking the PGs production ininflammation cells but also for interfering with the homeostaticproduction of PGs in the gastrointestinal track, which has greatly limitedthe development of this agents. Therefore agents that selectively inhibitthe pathological PGs production while sparing physiological PGsrepresent a major target of drug research.With the discovery of COX-2 in recent years, a lot of selectiveCOX-2 inhibitors have been developed for their good effect, reduced GItoxicity, and improved safety profiles. Unfortunately, the COX-2 inhibitorsstill remain some of the side effects seen with traditional dual COXinhibitors (nonsteroidal anti-inflammatory drugs),especially increae riskof myocardial infarction and strokes after a long term use.It is necessaryto develop a novel class of potent NSAIDs without of serious side effect . A major mechanism of action of NSAIDs is lowering prostaglandinproduction through inhibition of cyclooxygenase ,a key enzyme inprostaglandin biosynthesis.It has been pointed out that inhibiting onlythe cox pathway could shunt the metabolism of arachidonic acid(AA)towards the 5-lipoxygenase(5-LO) pathway which generatesleukotrienes(LTs).Leukotrienes are particularly important mediator ininflammation process and leucocyte activator,which can increasemicrovascular permeability. LTB4 is directly associated with acute gastricand intestinal damage induced by classic NSAIDs. The dual inhibition of COX-2 and 5-LO not only can block theproduction of PGs and LTs,but also reduce the GI-damaging.Obviously,dual acting anti-inflammatory drugs will be an important part ofNSAIDs study. Oxaprozin which was developed by Wyeth USA is a NSAID withlong-term effect NSAIDs. Its mechanism of action is blocking thebiosynthesis of PGs by dual inhibition of COX/5-Lo and haveanalgesic,antipyretic and anti-inflammatory activity. Oxaprozin showed alonger term effect and little GI toxicity than other NSAIDs, but the poorselectivity, high dose and long half life have limited the wide use ofOxaprozin, and the structure modification and optimization of Oxaprozinwould be very promising and valuable.1.Design of target compound Oxaprozin is belong to 4,5-diaryloxazole derivatives. In conclusion,the variants of functionalities at the 2-position of oxazole ring are directlyassociated with the bioactivity. The more side chains the substituentshave, the poorer activity and selectivity are; While the analogues bearinga fluoro moiety in para-position of 4-aryl show strong COX-2 activity invitro and in vivo. Introduction of a para methyl sulfone or sulfonamidesubstituent to 5-aryl can enhance the oral activity and pharmacokineticcharacter. In general, the sulfonamide derivatives were superior tomethyl sulfone derivatives; A halo could be introduced to meta-positionof 5-aryl, among which the fluoro is the best. We have to design our target compound using as the lead,incorporating the SAR and the mechanism of action of 4,5-diaryloxazole.In the process of structure modification of Oxaprozin, we have found thatintroduction of a fluoro and groups with larger polarity such asaminosulfonamide and methylsulfonamide can decurtate the t1/2 andimprove the in vivo absorptiothiand pharmacokinetic character and hasdecreased the dose and reduced side effects in gastric andcardiovascular system by improving selectivity. Therefore it would be anovel class of NSAIDs with better effect and lower toxicity. So wedesigned three types new compounds using InsightⅡand selected anewcompound-3-[4-(4-fluorophenyl)-5-(3-fluorophenyl)-oxazole-2-yl]propanoic acid, which had stronger inhibition activity against COX-2. To study the new compound that we had designed in advance, weinvestigated synthesis and bioactivity evaluation of NC-2142 so that wecould find new type NSAIDs with lower toxicity.2.Sythesis of NC-2142 We designed and improved the synthesis of NC-2142 and selectedan optimized one from several routines. The target compound wassynthesized from intermediate, α-(3-fluophenyl)-4-fluoroaceto-phenone by chlorination and ammonolysis, which was obtained from3-[4-(4-fluorophenyl)-5-(3-fluorophenyl)oxazole-2-yl]propanoic acid bybromination, hydrolysis, esterification and cyclization. In bromination, we have compared several brominating agents,solvents and temperature and found that the best result was NBS,chloroform and 50-60℃. However, the reaction time is long and thenbenzoyl peroxide was used as a catalyst to decrease reaction time. Wealso compared several alkaline reagents, solvents and temperature inhydrolysis and found that the best result was bicarbonate, acetone and50℃. The product of hydrolysis, α-(3-fluophenyl)-α-hydroxy -4-fluoroacetophenone, esterfied with succinic anhydride in pyridine undernitrogen circumstance with temperature at 90-95℃. Then it was cyclizedwith acetic acid ammonium salt and acetic acid at above temperature.Then 3-[4-(4-fluorophenyl)-5-(3-fluorophenyl) oxazole-2-yl] propanoicacid was obtained with 80% yield. In chlorination, we found that theoptimized routine adopted chlorosulfonic acid with 96h at 25℃. Afterpurification of 3-[4-(4-fluorophenyl)-5-(4-amino sul-fonic-3-fluoro-phynyl)-oxazole-2-yl]propanoic acid, the yield of reaction was 20%more than that without purification. We compared many syntheses of α-(3-fluophenyl)-4-fluo roac-更多还原