6-甲氧基-2-(4-甲氧苯基)苯并[b]噻吩及其异构体的合成研究

目的 合成盐酸雷洛昔芬关键中间体6-甲氧基-2-(4-甲氧苯基)苯并Lb]噻吩。方法 以4-甲氧基苯乙酮为原料，经溴代、硫醚化先制得α-(3—甲氧苯硫基)-4-甲氧基苯乙酮，再在多聚磷酸(PPA)的催化下，经环合及重排制得目标产物。结果 与结论从目标产物母液中分离得到3个异构体，它们的化学结构根据高分辨质谱、核磁共振氢谱与红外光谱测试数据确认。改用甲硝酸为催化剂，可提高目标产物的收率。     

COX—2抑制剂Rofecoxib合成路线图解

Rofecoxib(1)，商品名Vioxx，化学名4-(4-甲磺酰)苯基-3-苯基-2(5H)-呋喃酮，由美国Merck Sharp & Dohme公司开发，1999年6月首次在墨西哥上市，同年7月在美国和英国上市。本品为一特异性II型环氧合酶抑制剂[1]，主要用于缓解股关节炎，耐受性较好，对胃粘膜或十二脂肠粘膜的损伤远比布洛芬或阿司匹林轻[2]。其合成路线国外报道较多[3]，现归纳如下： 　　1. 有机金属试剂2(M=Li,Mg)同3在铜盐(X=Cl,Br,I)存在下进行1，4-加成反应，并用三烷基甲硅烷基氯TMSCl生成烯醇醚4，然后用Ito的方法反应得5，引入碘得6，同苯硼酸偶合得7，最后用过乙酸或MMPP，MPPM或H2O2氧化得1[4，5]。     

α-溴-(2-羟基-4-甲磺酰胺基-5-苯氧基)苯乙酮的合成

以3-甲磺酰胺基-4-苯氧基苯甲醚为原料，在AlCl3作用下，经付-克乙酰化同时脱甲基化反应得到（2-羟基-4-甲磺酰胺基-5-苯氧基）苯乙酮，再经溴化得到标题化合物，总收率70%。     

1-[2-(2,4-二氟苯基)-2,3-环氧丙基]-1H-1,2,4-三唑甲烷磺酸盐的合成

1- [2 - ( 2 ,4-二氟苯基 ) - 2 ,3-环氧丙基 ]- 1 H- 1 ,2 ,4-三唑甲烷磺酸盐 ( 1 )是合成氟康唑等抗真菌药物的关键中间体。文献 [1]以间二氟苯 ( 2 )为原料 ,与氯乙酰氯反应生成 α-氯 - 2 ,4-二氟苯乙酮 ( 3) ,3在甲苯中与三唑反应生成 2 ,4-二氟 - α- ( 1 H- 1 ,2 ,4-三唑 - 1 -基 )苯乙酮 ( 4 ) ,4与 ylid试剂碘化三甲基硫盐反应形成环氧化物 ,再与甲磺酸成盐得到 1。此法第 2步和第 3步收率均很低 ,分别为 8.7%和2 1 .84% ,成品生产成本较高。本文参照文献 [2 ]的相转移催化三唑烷基化方法 ,以 TEBA为相转移催化剂 ,K2 CO3 为…     

乙氧苯柳胺在家兔体内的主要代谢产物

采用高效液相色谱法对家兔口服乙氧苯柳胺（Ｎ－（４－乙氧苯基）－２－羟基苯甲酰胺）后在尿中的代谢物进行了分离与检测．用β－Ｄ－葡糖苷酸酶和该酶加专属性抑制剂葡糖二酸－１，４－内酯分别对尿样进行水解处理，发现该药的主要代谢物为β－Ｄ－葡糖醛酸结合物，其含量超过尿中代谢物总量的８０％．利用色谱保留值和紫外双波长吸收比对酶解后的主要生成物进行定性分析，证明该代谢物为乙氧苯柳胺葡糖醛酸结合物（Ｎ－（４－乙氧苯基）－苯甲酰胺－２－Ｏ－葡糖苷酸）．此外，在家兔给药后０～１２ｈ尿样中未检测出乙氧苯柳胺原形药物及其可能的代谢产物水杨酸．     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-(N-甲基-N-取代苄基氨基)-2-丙醇的合成及抗真菌活性研究

根据三唑类抗真菌药物作用靶酶－羊毛甾醇14α－去甲基化酶的三维晶体结构和药物与酶活性的位点的对接结果，设计合成了11个1－（1H－1，2，4－三唑－1－基）－2（2，4－二氟苯基）－3－（N－甲基－N－取代苄基氨基）－2－丙醇化合物，11个目标化合物均系首次报道，体外抗真菌活性试验结果表明，所有目标化合物对七种致病真菌都有不同程度的抗真菌活性，而且都比氟康唑的体外抗真菌活性好，化合物11的抗菌谱最广，抗真菌活性最高，对新型隐球菌，白色念珠菌，羊毛状小孢子菌和红色毛癣菌的抗菌活性比酮康唑高，有进一步开发的价值。化合物3，4，10也表现出较高的抗真菌活性。     

2—苄氧基—及2—（2—苯基乙氧基）—5—氟—4（3H）—嘧啶酮的合成

自安本三治等报道,2-苄氧基-5-氟-4(3H)-嘧啶酮(1)具有抗肿瘤活性后,Baba等即以1为中间体,又合成了一系列糖苷类化合物,它们均具有抗肿瘤活性。因此我们进行了1及其同系物的合成研究。文献报道,1可由3在封管中与NaH和Ph CH_2OH反应而得,收率78.2％。     

1—（4—甲氧基）苯基—2—丙胺的合成

以对羟基苯乙酸为原料,采用了一条新路线合成了平喘药福莫特罗重要中间体1-（4-甲氧基）苯基-2-丙胺,反应总收率38%。方法操作简单、可行,适于实验室合成。     

药物对映体含量测定的核磁共振法研究──Ⅱ．3，4－环氧－3，4－二氢－2，2－二甲基－6－乙酰胺基－7－硝基－二氢－1－苯骈吡喃

报道了位移试剂Ｅｕ（ＦＯＤ）３、Ｅｕ（ＨＦＣ）３，存在下３，４－环氧－３，４－二氢－２，２－二甲基－６－乙酰胺基－７－硝基－二氢－１－苯骈吡喃（Ⅰ）的镧诱导位移（ＬＩＳ）值；在手性位移试剂Ｅｕ（ＨＦＣ）３存在下，观察到５－Ｈ和８－Ｈ明显的对映体位移差值（△△δ），据此，可对化合物Ⅰ直接进行对映体的定量分析。当Ｅｕ（ＨＦＣ）３：Ⅰ为０．９５５（０．７０５）（摩尔比）时，８－Ｈ（５－Ｈ）的（＋）和（－）对映体两峰峰谷高度为峰高的３．５％（７．１％），即当对映体之一的含量不低于３．５％（７．１％）时，可对化合物Ⅰ的对映体含量进行精确的直接测定。     

2-(2,6-二氯苯胺基)苯乙酸4-(4-苯基-1,2,5-噁二唑-2-氧化物-3-)甲氧基苯甲酯的合成工艺改进

目的 改进2-(2，6-二氯苯胺基)苯乙酸4-(4-苯基-1，2，5-噁二唑-2．氧化物-3-)甲氧基苯甲酯的合成工艺。方法 以桂醇为原料，经环合、氯化、醚化及酯化4步反应合成2-(2，6-二氯苯胺基)苯乙酸4-(4-苯基-1，2，5-噁二唑-2-氧化物-3-)甲氧基苯甲酯。环合反应中，改用乙酸为溶剂；醚化反应中以乙腈代替N，N-二甲基甲酰胺作溶剂；酯化反应中，二环己基碳化二亚胺改以滴加的方式投料。结果与结论 总收率提高到48％。本法具有反应条件温和、后处理简单、收率高等优点。     

Third-generation antiepileptic drugs: mechanisms of action,pharmacokinetics and interactions

This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.     

Biomedical applications of selective metal complexes of indole,benzimidazole, benzothiazole and benzoxazole: A review (From 2015 to 2022)

Indole, benzoxazole benzothiazole and benzimidazole are excellent classes of organic heterocyclic compounds. These compounds show significant application in pharmacy, industries, dyes, medicine, polymers and food packages. These compounds also form metal complexes with copper, zinc, cadmium, nickel, cobalt, platinum, gold, palladium chromium, silver, iron, and other metals that have shown to be significant applications. Recently, researchers have attracted enormous attention toward heterocyclic compounds such as indole, benzimidazole, benzothiazole, benzoxazole, and their complexes due to their excellent medicinal applications such as anti-ulcerogenic, anti-cancer, antihypertensive, antifungal, anti-inflammatory, antitubercular, antiparasitic, anti-obesity, antimalarial, antiglycation, antiviral potency, antineuropathic, analgesic antioxidant, antihistaminic, and antibacterial potentials. In this article, we summarize the medicinal applications of these compounds as well as their metal complexes. We hope this article will help researchers in designing and synthesizing novel and potent compounds with significant applications in various fields.     

A pilot study of heavy metal concentration in various environments and fishes in the Upper Sakarya River Basin,Turkey

In this study, concentration of lead, cadmium, copper, cobalt, nickel, and manganese were measured in water, sediment, and fish (Cyprinus carpio and Barbus plebejus) samples at the upper Sakarya river basin in Sept. 1995–1996 period. Also, physical parameters of selected stations in the Sakarya river were measured. Mean concentrations of lead, cadmium, copper, nickel, and manganese differed between water, sediment, and fish samples by seasons. Mean concentrations of lead, cadmium, and cobalt increased in sediment samples in October and August. In water samples only cadmium and cobalt increased in October whereas lead and copper increased in August. Also, high levels of manganese concentrations were detected in water and sediment samples and fish tissue during the study. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 367–373, 1999     

Relative in vitro affinity of hepatic metallothionein for metals

The ability of selected metals (Ag, Al, As, Ca, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Mo, Ni, Pb, Tl and V) to displace Zn from Zn-metallothionein (Zn-MT) was quantitated. Of the metals tested Cd had the highest affinity for MT, with 1.33 microM displacing 50% of the 65Zn bound to MT (EC50), followed by Pb (1.46 microM), Cu (1.93 microM), Hg (3.93 microM), Zn (8.06 microM), Ag (10.4 microM), Ni (474 microM) and Co (880 microM). As, Ca and Mo had a limited ability to displace Zn from MT while Al, Cr, Fe, Mg, Mn, Tl and V had no effect on Zn binding even at 1.0 mM.     

苦参碱类生物碱免疫促进作用的研究进展

苦参碱类生物碱具有广泛的生物活性,如保护心、肝、肺、肾、脑、血管作用,对心脏有正性肌力、负性频率、抗心律失常作用,还有升高白细胞,平喘,抗溃疡,抗肝纤维化以及镇静、催眠、镇痛等中枢神经药理作用,也具有抗肿瘤、免疫调节、抗菌、抗病毒、抗炎等药理作用。苦参碱类生物碱对机体免疫功能具有双向调节作用,在高剂量时表现为免疫抑制作用,在低剂量时表现为免疫促进作用。综述氧化苦参碱、苦参碱、槐定碱和槐果碱的免疫促进作用,为进一步开发研究和临床应用提供参考。     

Novel modes of antifungal drug administration

Administration of antifungals by routes other than that for which the agent was designed or approved have been utilised in attempts to provide directed therapy, reduce adverse effects and improve drug penetration into selected infection sites, such as the central nervous system, lungs and peritoneum. The most widely investigated agent utilising a novel method of drug delivery is amphotericin B. Dose forms for this agent include topicals (aerosol, nasal spray, irrigations, pastes, absorbable sponges, impregnated bone cement and gelatin), oral dosage forms (solutions, suspensions, tablets and so on) and ophthalmic preparations (drops, ointments and injections). Amphotericin B has been administered by routes such as oral, endobronchial, intrathecal, intracisternal, intra-articular, intraperitoneal, ophthalmic and as an antibiotic ‘line lock’. Nystatin has been administered as an aerosol, percutaneous paste and bladder washes. Azoles, such as miconazole, fluconazole, ketoconazole and posaconazole, have been administered by novel methods but to a lesser degree. Most of these reports involve miconazole. The dose forms and routes of administration for azoles have included irrigants (bladder, joint), ophthalmic preparations (eye drops, intraocular injections, ointments), impregnated bone cement, endobronchial and intrathecal administration. Finally, both methylene blue (bladder washes) and flucytosine (peritoneal lavage, ophthalmic eye drops) have also been employed. Adequate evaluations of both the safety and efficacy of these therapies are most often hindered by prior or concomitant antifungal therapies, comorbidities and the lack of controlled clinical trials. In addition, the availability of newer treatment options, which demonstrate significant improvement in drug distribution and treatment-related adverse effects make many such novel modes of administration less practical or necessary. In contrast, the inhalation of antifungal aerosols, such as amphotericin B, is rapidly becoming a viable prophylactic option.     

消风止痒颗粒中毛蕊花糖苷、焦地黄苯乙醇苷B1、升麻素苷、升麻素、5-O-甲基维斯阿米醇苷、亥茅酚苷、苍术素醇、白术内酯Ⅱ和苍术素的HPLC法测定及其化学计量学综合评价

目的建立HPLC法同时测定消风止痒颗粒中毛蕊花糖苷、焦地黄苯乙醇苷B1、升麻素苷、升麻素、5-O-甲基维斯阿米醇苷、亥茅酚苷、苍术素醇、白术内酯Ⅱ和苍术素,并采用化学计量学方法对检测结果进行综合评价。方法采用Agilent Zorbax SB-C18色谱柱(250 mm×4.6 mm,5μm);以乙腈-0.2%磷酸溶液为流动相,梯度洗脱;检测波长:330 nm(0~14 min检测毛蕊花糖苷和焦地黄苯乙醇苷B1)、254 nm(14~31 min检测升麻素苷、升麻素、5-O-甲基维斯阿米醇苷和亥茅酚苷)、270 nm(31~55 min检测苍术素醇、白术内酯Ⅱ和苍术素);体积流量0.9 mL/min;柱温25℃;进样量10μL。采用SPSS26.0统计软件对消风止痒颗粒中9种成分进行聚类分析和主成分分析。结果毛蕊花糖苷、焦地黄苯乙醇苷B1、升麻素苷、升麻素、5-O-甲基维斯阿米醇苷、亥茅酚苷、苍术素醇、白术内酯Ⅱ和苍术素分别在2.53~63.25、1.09~27.25、8.17~204.25、2.38~59.50、4.07~101.75、1.74~43.50、0.66~16.50、1.47~36.75、2.86~71.50μg/m L线性关系良好;平均回收率分别为99.01%、98.17%、100.13%、97.63%、98.72%、97.22%、96.93%、99.24%、100.01%,RSD值分别为1.42%、1.26%、0.72%、1.55%、0.84%、1.06%、1.18%、0.67%、0.95%;11批样品聚类分析为3类,主成分1~3是影响消风止痒颗粒质量评价的主要因子。结论该方法操作简便、重复性好,可作为消风止痒颗粒中多指标成分质量评价模式。     

A comparison of the efficacy of cilazapril versus cilazapril plus hydrochlorothiazide in patients with mild to moderate essential hypertension

Summary The efficacy of cilazapril monotherapy and in combination with hydrochlorothiazide 12.5 mg was compared in a multicentre, double blind, randomised parallel group study in 87 patients with mild to moderate essential hypertension over 8 weeks. After a 2 week single blind placebo run-in period, patients received either 2.5 mg cilazapril or 2.5 mg cilazapril plus 12.5 mg hydrochlorothiazide once daily. At Week 4 the cilazapril dose was increased from 2.5 mg to 5.0 mg if the mean sitting diastolic blood pressure was greater than 90 mmHg or had not decreased by more than 10 mmHg.After 8 weeks treatment 72% of patients responded to 2.5 mg cilazapril increasing to 88% with cilazapril 5.0 mg. For cilazapril plus hydrochlorothiazide, 83% responded to 2.5 mg cilazapril increasing to 96% on 5.0 mg cilazapril.The high response rate to low dose cilazapril monotherapy and hydrochlorothiazide combination therapy has important implications for minimising the cost of therapy with ACE inhibitors.Inhibace General Practice Study Group: Drs. Atkinson, Bevin, Choy, DeLacey, Dine, Doerr, Dykes, Eames, Edwards, Ford, Gare, Haycock, Haywood, Hendy, Hunter, Loan, Lowe, Mules, Nealie, Parker, Pollock, Rasalingham, Reekie, Richmond, Sandin, Staub, Suckling, Surynt, Vickers, Wellington, Wells, Wong and Young     

Hemodialyzer clearances of gentamicin,kanamycin, tobramydn,amikacin, ethambutol. procainamide,and flucytosine,with a technique for planning therapy

Hemodialyzer clearance studies have been undertaken on the following drugs: gentamicin, kanamycin, tobramycin, amikacin, ethambutol, procainamide, and flucytosine. The following hemodialyzers were tested: Dow model 4, Kiil, Travenol UF II, and the Extracorporeal EX-03. The studies were predominantly undertaken in vitro,permitting direct comparison between drug clearances on the same dialyzer. Protein binding studies for gentamicin, kanamycin, procainamide, and ethambutol are also reported. Nomograms to facilitate the prediction of drug dosage regimens in dialysis patients are included.This work was supported in part by a grant from the General Clinical Research Centers Program (RR-133) of the Division of Research Resources, National Institutes of Health, and by a research contract (2-2219) from the Artificial Kidney-Chronic Uremia Program of the National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health.This paper was presented in part at the American Society of Nephrology meeting, 1974.     

Patient compliance and therapeutic coverage: comparison of amlodipine and slow release nifedipine in the treatment of hypertension

To study patient compliance in hypertensive outpatients amlodipine (5 mg once daily) and slow release nifedipine (20 mg twice daily) were compared in an open, crossover study in general practices.Four methods of assessment for patient compliance (pill count, taking compliance, days with correct dosing, timing compliance) were used in both study arms. For the latter three assessment a special device, the medication event monitoring system, was used to record the time and date of each opening and closure of the container.The compliance of the 320 hypertensive patients with once-daily amlodipine was markedly superior to twice-daily slow release nifedipine. Therapeutic coverage was also significantly better for amlodipine in the hypertensive patients. Amlodipine was better tolerated than nifedipine slow release.Patient compliance and therapeutic coverage with the calcium antagonist amlodipine given once daily was superior to slow release nifedipine b. d. in hypertensive outpatients recruited in general practice. Statistical Unit: Léon Kaufmann, Marie-Paule Derde, Data Investigation Company Europe, Brussels Participating Investigators: D. Abbate, G. Armand, C.I. Authelet, J.L. Badot, J. Baeck, P. Baeck, P. Bastin, C.I. Bernard, P. Bernard, B. Beyssens, J. Bosly, P. Boudart, J. Bourdeaudhuy, W. Callens, L. Carolides, Y. Catry, E. Cerstelotte, F. Charlier, H. Charloteaux, J.M. Chaudron, L. Christiaen, G. Cornette, P. Cranskens, R. Creteur, N. De Cock, M. De Corte, A. De Vos, P. Defrance, P. Delhaye, G. Deneckere, M. Dobbeleir, A. Dufour, P. Dumont, L. D'Haen, H. D'Haenens, P. Eloy, P. Evrard, C. Fellemans, G. Geeraerts, L. Gielen, D. Grand, J. Grosjean, J. Guffens, R. Guillaume, R. Hacquaert, V. Hamoir, W. Hens, M. Hondeghem, M.C. Humblet-Koch, L. Leven, W. Janssens, L. Jeanfils, J. Jodogne, B. Jortay, W. Ketels, J.M. Krzesinski, E. Langendries, J. Lannoy, M. Leeman, J. Leire, P. Lempereur, L. Lenaerts, F. Lustman, R. Martens, Y. Maus, M. Meroueh, J.P. Meurant, P. Meurant, A. Michiels, E. Mievis, H. Moors, K. Naesens, P. Neels, J. Neven, W. Odeurs, W. Pardon, M. Peduzzi, J. Piette, D. Plessers, P. Putzeys, A. Quoidbach, A. Renaerts, G. Rits, M. Ruhwiedel, M. Salavracos, M. Seret, P. Sibille, M. Taziaux, J. Teucq, H. Therasse, F. Tihon, F. Vandenput, J. Van Elsen, J.P. Van Liefferinge, J. Van Neck, M. Van Pelt, T. Van Vlaenderen, G. Vandenbeylaardt, M. Vandewoude, F. Veldeman, D. Ven, F. Verbruggen, A. Vlaeminck, P. Werion, J. Westerlinck. Advisory Board: Pierre Block, Division of Cardiology, Universiteit Brussels, A.Z.-V.U.B. University Hospital Brussels, Belgium; Guy De Backer, Universiteit Gent, Gent; Jean-Paul Degaute, Hypertension Clinic, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Jean-Marie R. Detry, Division of Cardiology, University of Louvain, St. Luc University Hospital, Brussels, Belgium; Roland Six, Department of Internal Medicine, Vrije Universiteit Brussel, A.Z.-V.U.B., Brussels, Belgium.