2-（二乙胺基）-N-（2，4,6-三甲氧苯基）乙酰胺的合成

目的：研究2-（二乙胺基）-N-（2,4,6-三甲氧苯基）乙酰胺的简便合成方法。方法：以苯胺为起始原料合成1,3,5-三甲氧基苯,经硝化、还原、酰化、烷基化反应得到目标化合物。结果：目标化合物经。HNMR确认结构。结论：本合成方法具有原料易得、条件温和、操作简便等优点。     

雷西莫特(resiquimod)的合成

目的：研究雷西莫特的合成。方法：以3-氨基4（α-羟基-2-甲基丙氨基）喹啉为原料，经缩合、N-氧化、氨基化等反应合成雷西莫特。结果：合成的雷西莫特的总收率42％，经元素分析、MS、UV、IR、1HNMR、13CNMR．DEPT等测试，确证了结构。结论：本法合成雷西莫特原料易得，便于工业化生产。     

氯沙坦的合成

目的：探索氨沙坦新的合成方法。方法：以戊腈为原料，经3步反应制备中间体4，以2-氰基-4＇-甲基联苯为原料，经3步反应制备中间体8。中间体4与8经N-烷基化反应、还原反应、脱三苯甲基合成了目标化合物氯沙坦。结果：目标物经红外光谱、核磁共振氢谱、质谱和元素分析确证其化学结构，以戊腈计总收率达51.8％。结论：该方法原料易得，操作简便，易于工业化生产。     

新型钛(Ⅳ)配合物的合成

目的：合成两个新的双（β-二酮络）钛（Ⅳ）配合物。方法：以三氟乙酸为起始原料，经酯化、缩合、配合等步骤制备而成。结果：产物经元素分析、红外光谱等确证。结论：此合成线路完全可行。     

格列卫合成工艺研究

目的：探索格列卫合成新路线。方法以2-氨基-4-硝基甲苯为原料,经加成、环化、还原、缩合、成盐等步骤合成格列卫。结果该路线摩尔总收率26.9%,产品相对含量99.8%。结论该方法提高了合成收率,降低了成本,是一条工业化的合成路线。     

吡咯-2-硫代甲酰胺的简易合成方法

目的：改进制备吡咯-2-硫代甲酰胺的方法。方法：以硫氰酸钾、氯甲酸乙酯和吡咯为原料经亲电取代，水解等反应合成制备目标产物。结果：该方法工艺简单，后处理方便，且产率高，反应条件温和。结论：该合成路线易于工业化生产。     

N-羟乙基-2-(3''''-硝基联苯基-4-亚甲磺酰基)乙酰胺的合成

目的：合成磷酸二酯酶3B（PDE3B）选择性抑制剂N-羟乙基-2-（3＇-硝基联苯基-4-亚甲磺酰基）乙酰胺.方法：以对溴苄溴为初始原料经Williamson成醚反应、氧化、酰化和Suzuki偶联4步反应合成了目标化合物.结果：目标产物的结构经核磁共振氢谱、碳谱、质谱及红外光谱等确证,4步反应的总收率为24.8%.结论：该合成路线原料易得,操作简便,可用于放大制备.     

泮库溴铵的合成

目的：合成中长效非去极化型肌松药泮库溴铵。方法：以5α-雄甾-2-烯-17-酮为起始原料经酯化、氧化、开环、还原、乙酰化,最后与溴甲烷成盐等6步反应合成泮库溴铵。结果：泮库溴铵的结构经核磁共振谱确证,总收率为22.1%。结论：本路线可简化实验操作,降低成本,适合工业化生产。     

7-氨基-3-(丙-1-烯基)-4-头孢烷酸的合成

目的：研究头孢丙烯中间体7-氨基-3-(丙-1-烯基)-4-头孢烷酸的合成工艺。方法：以GCLE为起始原料,经Wittig反应、脱4、7位保护基制得产品。控制反应原料的纯度、反应温度。结果：总收率达到60％。结论：该合成工艺原料易得,反应条件较温和,有一定的工业生产价值。     

塞曲司特(Seratrodast)的合成

目的：合成塞曲司特并对其合成工艺进行改进。方法：以庚二酸单乙酯为起始原料，经氯化，付-克反应、还原、水解、缩合等步骤合成了塞曲司特，结果：五步反应的总收率为64%。所得产物经熔点，红外光谱和核磁共振确证。结论：此合成工艺可行，具有工业化生产价值。     

顶空气相色谱法测定咪喹莫特中残留溶剂二甲基甲酰胺

目的：建立咪喹莫特中残留溶剂二甲基甲酰胺（DMF）检测的新方法。方法：采用顶空气相色谱法,Agilent HPPLOT/Q毛细管柱（30 m×0.530 mm,40.0μm）,氢火焰离子化检测器（FID）,载气为氮气,进样口温度为250℃,检测器温度为270℃,程序升温进行测定。结果：残留溶剂二甲基甲酰胺与其它残留溶剂的分离度符合要求,在所考察的浓度范围内线性关系良好,平均回收率分别为94.6%,RSD为4.0%（n=9）。定量限和检测限分别为4.809,0.963μg·ml-1。结论：该顶空气相色谱法简便﹑准确﹑灵敏度高﹑可以用于咪喹莫特中二甲基甲酰胺残留量的测定。     

咪喹莫特乳膏的制备与治疗尖锐湿疣的临床应用

目的：研制治疗尖锐湿疣的新型外用免疫调节药咪喹莫特乳膏，并观察其临床疗效。方法：苯甲醇、异硬脂酸、十八醇等加热融化为油相，甘油、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等加热融化为水相，将油相加入水相制成乳膏基质，把咪喹莫特细粉加入乳膏基质制备咪喹莫特乳膏。采用紫外分光光度法测定其含量，并观察咪喹莫特乳膏治疗125例尖锐湿疣患者的疗效。结果：该制剂制备简单，质量可控，临床治疗尖锐湿疣患者，治疗8周总有效率97.6%。 结论：咪喹莫特乳膏是治疗尖锐湿疣的有效药物，可作为第一线药物应用于临床。     

Effect of food on the pharmacokinetics and bioavailability of oral imiquimod relative to a subcutaneous dose

OBJECTIVES: The present study, the first clinical pharmacokinetic report of the immune response modifier imiquimod, was conducted to assess the effect of food on the oral absorption of imiquimod, to characterize its pharmacokinetics, and to estimate its oral bioavailability. SUBJECTS AND METHODS: Sixteen healthy male volunteers completed this open-label, randomized, three-period crossover study. Subjects received a 100 mg oral dose of imiquimod after fasting in one period, after a standarized, high fat meal in another, and a 30 mg subcutaneous dose in the third period. RESULTS: The oral bioavailability of imiquimod was on average 47%, and independent of whether imiquimod was administered with or without food. Oral imiquimod was absorbed in both fasted and non-fasted states with an absorption half-life of approximately 1 hour. However, there seemed to be a delay in the initiation of the absorption process when food was administered, which translated in to a Tmax of approximately 2.6 hours while fasting and one hour later in the non-fasted state. Imiquimod was rapidly eliminated with a half-life of approximately 2.5 hours and a total body clearance of approximately 970 ml/hxkg. Although equivalence could not be established due to the large intersubject variability, no significant differences in rate (Cmax) and extent (AUC) of oral absorption were observed between the fasted and non-fasted states. In addition, the Cmax, AUC and bioavailability values for individual subjects were consistent between both oral treatments. CONCLUSION: This study suggests that food does not have a major effect on the rate, extent of absorption or bioavailability of oral imiquimod, and thus, it is suitable to administer imiquimod orally in either the fasted or non-fasted states.     

Evaluation of imiquimod for topical treatment of vaccinia virus cutaneous infections in immunosuppressed hairless mice

Imiquimod is an immune response modifier prescribed as a topical medication for a number of viral and neoplastic conditions. We evaluated the antiviral activity of imiquimod against vaccinia virus (WR strain) cutaneous infections in immunosuppressed (with cyclophosphamide) hairless mice when administered after virus exposure. Primary lesions progressed in severity, satellite lesions developed, and infection eventually killed the mice. Once daily topical treatment with 1% imiquimod cream for 3, 4, or 5 days were compared to twice daily topical treatment with 1% cidofovir cream for 7 days. Survival time of mice in all treated groups was significantly prolonged compared to placebo controls. The mean day of death for the placebo group, 3-day imiquimod, 4-day imiquimod, 5-day imiquimod, and cidofovir groups were 15.5, 20.0, 20.5, 19.5, and 20.5 days post-infection, respectively. All treatment groups showed significant reductions in primary lesion size and in the number of satellite lesions. The cidofovir and 4-day imiquimod treatments delayed the appearance of lung virus titers by 3 and 6 days, respectively, although cutaneous lesion and snout virus titers were not as affected by treatment. Benefits in survival and lesion reduction were observed when imiquimod treatment was delayed from 24, 48, and 72 h post-infection. However, increasing the treatment dose of imiquimod from 1% to 5% led to a significant decrease in antiviral efficacy. These results demonstrate the protective effects of topically administered imiquimod against a disseminated vaccinia virus infection in this mouse model.     

Development of a topically active imiquimod formulation

The purpose of this work was to develop a topical formulation of imiquimod, a novel immune response modifier, to induce local cytokine production for the treatment of external genital and perianal warts. A pH-solubility profile and titration data were used to calculate a pKa of 7.3, indicative of a weak base. Solubility experiments were conducted to identify a solvent that dissolves imiquimod to achieve a 5% formulation concentration. Studies to select surfactants, preservatives, and viscosity-enhancing excipients to formulate an oil-in-water cream indicated that fatty acids were the preferred solvent for topical imiquimod formulations, and isostearic acid (ISA) was selected. A relationship existed between the fatty acid composition of four commercially available ISA sources and the solubility of imiquimod. A combination of polysorbate 60, sorbitan monostearate, and xanthan gum was used to produce a physically stable cream. The preservative system included parabens and benzyl alcohol to meet the USP criteria for preservative activity. An in vitro method was developed to demonstrate that imiquimod was released from the formulation. Topical application of the formulation induced local cytokine activity in mice.     

咪喹莫特微乳的制备及体外透皮评价

制备咪喹莫特微乳并考察其理化性质。载药微乳平均粒径为37.8nm,多分散指数为0.440。体外透皮试验表明,微乳8h累积渗透量明显高于咪喹莫特乳膏。     

咪喹莫特乳膏和鬼臼毒素酊治疗尖锐湿疣疗效对照观察

目的对比观察咪喹莫特乳膏和鬼臼毒素酊治疗尖锐湿疣的疗效。方法将98例患者分为咪喹莫特乳膏组与鬼臼毒素酊组,咪喹莫特乳膏组肌注重组人干扰素a-2b,口服盐酸伐昔洛韦片,病灶局部涂抹咪喹莫特乳膏;鬼臼毒素酊组：肌注重组人干扰素a－2b,口服盐酸伐昔洛韦片,病灶局部涂抹鬼臼毒素酊。结果咪喹莫特乳膏组痊愈53例,复发5例,有效率为91．2％,鬼臼毒素酊组痊愈30例,复发10例,有效率为75．0％,两组比较差异有显著性（P〈0．05）。结论咪喹莫特乳膏较鬼臼毒素酊治疗尖锐湿疣疗效更理想,复发率低。     

Imiquimod 3.75% cream (Zyclara) for the treatment of actinic keratoses

INTRODUCTION: actinic keratosis is a premalignant disease with a high incidence and is a strong predictor for the development of squamous cell carcinoma. Various treatment options have been established over recent years, including topical treatment with imiquimod, 5-fluorouracil, diclofenac or photodynamic therapy, cryotherapy and surgical procedures. AREAS COVERED: this review covers basic and clinical experiences with imiquimod 3.75% for topical treatment of actinic keratosis of the face and balding scalp and its comparators with special focus on imiquimod 5%. It also covers pharmacology of imiquimod 3.5% and its contribution to the current treatment options of actinic keratoses. EXPERT OPINION: imiquimod 3.75% is an interesting, safe and well-tolerated treatment option for actinic keratoses of the face or balding scalp especially in respect of compliance, as it is indicated for daily use for a shorter time period (2 times, 2-week cycles) and approved for use on larger areas compared with imiquimod 5%. Data from current trials indicate lower efficacy compared with imiquimod 5% cream when applied three times a week for 16 weeks or for two 4-week cycles with a 4-week no-treatment interval, but indicate similar efficacy when compared with a twice-weekly schedule for 16 weeks. An additive effect was observed when combining cryosurgery followed by imiquimod 3.75%.     

Topical imiquimod: a review of its use in genital warts.

Imiquimod is a topically active immunomodulatory agent that is formulated as a 5% cream for application by the patient. It is the first agent of its class, the immune response modifiers, to be used in the treatment of genital warts. In immunocompetent patients with genital warts, imiquimod stimulates the production of interferon-alpha and various other cytokines, and has indirect antiviral activity. In randomised, double-blind, vehicle-controlled clinical trials, complete clearance of warts occurred in 37 to 50% of immunocompetent patients with genital warts treated with imiquimod 5% cream 3 times a week for up to 16 weeks; partial clearance of warts (defined as a reduction in wart area of > or = 50%) was observed in 76% of recipients of imiquimod 5% cream. Rates of complete or partial clearance of warts were significantly higher in patients who applied imiquimod 5% cream 3 times a week than in recipients of imiquimod 1% or vehicle cream, each applied 3 times a week. A between-gender difference in clinical response to imiquimod 5% cream has been reported, with female patients experiencing higher rates of complete clearance of warts than males. Recurrence(s) of > or = 1 wart occurred in 13 to 19% of immunocompetent patients in whom complete clearance of warts had been achieved with imiquimod 5% cream. Imiquimod 5% cream also shows some clearance of warts in immunosuppressed HIV-infected patients with genital warts. Preliminary results of a vehicle-controlled study showed that the rate of partial clearance of warts (defined as a reduction in baseline wart area of >50%) [38%] was significantly higher with imiquimod 5% cream than with vehicle cream; however, the rate of complete clearance was not significantly higher than with vehicle cream. Imiquimod 5% cream is generally well tolerated by immunocompetent and HIV-infected patients. Local skin reactions (mainly mild or moderate), including erythema, itching and burning, are the most commonly reported adverse events, occurring in < or = 67% of patients applying imiquimod 5% cream 3 times a week. The incidence of adverse events is lower in patients applying the cream 3 times a week than with daily application. The incidence of systemic adverse events with imiquimod 5% cream (applied daily or 3 times a week) is similar to that of vehicle cream. The tolerability profile of imiquimod cream appears favourable compared with that of podophyllotoxin. CONCLUSION: Imiquimod 5% cream is a new therapeutic option for patients with genital warts. It produces clearance rates broadly similar to those of other treatment approaches and rates of wart recurrence compare favourably with those reported for established treatments. In contrast to most alternative treatment strategies. which are administered in the physician's office, imiquimod cream is a self-administered therapy for outpatient use.     

Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp

It is timely to compare the efficacy and tolerability of 2 actinic keratosis (AK) therapies--5% 5-fluorouracil (5-FU) cream and imiquimod cream. Thirty-six patients with 4 or more AKs were randomly assigned to receive 5% 5-FU cream twice daily for 2 to 4 weeks or 5% imiquimod cream twice weekly for 16 weeks. Five percent 5-FU was more effective than imiquimod in exposing what were presumed to be subclinical AKs, reducing the final AK count (total AK count declined during the 24-week study by 94% vs. 66%, P < .05), achieving complete clearance (incidence of 84% vs. 24% by week 24, P < .01), and achieving clearance rapidly. Tolerability was similar except for erythema, which was initially significantly higher with 5-FU than imiquimod but resolved rapidly and was significantly lower than imiquimod by week 16. Five percent 5-FU remains the gold standard field therapy for AKs.