咪达那新合成工艺的改进

目的：对咪达那新的合成工艺进行改进。方法：以二苯乙腈为起始原料,经缩合1、缩合2及水解得到目标产物。结果：经三步合成了目标产物,总收率为68%,目标化合物结构经1HNMR和MS确证。结论：本合成方法原料易得,反应条件温和,适合工业化生产。     

JNJ-40411813合成工艺研究

目的研究抗精神分裂症药物JNJ-40411813合成新方法。方法以4-溴吡啶-2(1H)-酮为起始原料,经烷烃化、偶合及卤代3步反应得到目标产物JNJ-40411813。结果与结论目标化合物的结构经1H-NMR、13C-NMR、LRMS和HRMS等确证。该合成路线反应步骤简短,操作简便,反应条件温和,适合工业化生产。     

3,5-二甲基-2-(3'''',5''''-二氟苯基)-2-吗啉醇盐酸盐的合成

目的：合成抗抑郁药安非他酮类似物3，5-二甲基-2-（3’，5’-二氟苯基）-2-吗啉醇盐酸盐。方法：以3，5-二氟苯丙酮为原料，经溴代、胺化、环合、酸化合成了目标产物。结果：合成目标产物的总收率为77．3％，中间体和产物经红外光谱和核磁共振谱确证。结论：以溴化铜为α-溴代反应溴化剂进行澳代反应，选择性高，产物易于分离。在非质子极性溶剂中进行胺化反应，反应时间短，溶剂无毒性，具有较高的应用价值。     

C0X—2抑制剂celecoxib的合成工艺改进

研究选择性COX-2抑制剂celecoxib的合成工艺。以对苯乙酮为原料，经缩合、环合反应得到目标化合物，并将二步反应合并为一步进行。产物结构经^1H—NMR、元素分析确证，收率为48．5％。该法成本低，反应条件温和，收率高，易于生产。     

米格列奈中间体顺式全氢异吲哚的合成工艺改进

目的：改进米格列奈的重要中间体顺式全氢异吲哚的合成工艺。方法：将顺式六氢邻苯二甲酸酐和尿素反应，得顺式六氢邻苯二甲酰亚胺，再经氢化铝锂还原两个羰基，合成顺式全氢异吲哚。结果：合成得到目标产物，纯度大于98％，两步反应的总收率达56．3％，其结构经^1HNMR和ESI-MS确证。结论：该合成工艺所用原料易得，反应条件温和，产物纯度和收率高，适合于工业化生产。     

亚甲基二膦酸的合成

目的：改进工艺，合成药用原料亚甲基二膦酸。方法：以亚膦酸三异丙酯为原料，经取代、缩合、水解等反应而合成目标产物。结果：产物结构经红外光谱、核磁共振等分析确证；制成药盒符合中国药典2000年版标准。结论：此合成工艺实用可行。     

COX-2抑制剂celecoxib的合成工艺改进

研究选择性COX 2抑制剂celecoxib的合成工艺。以对苯乙酮为原料 ,经缩合、环合反应得到目标化合物 ,并将二步反应合并为一步进行。产物结构经1H NMR、元素分析确证 ,收率为48 5 %。该法成本低 ,反应条件温和 ,收率高 ,易于生产。     

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。     

抗痛风药物febuxostat的合成

目的合成新型抗痛风药物febuxostat（1）。方法以羟基苯腈为原料，经硫代甲酰化得到对羟基硫代苯甲酰胺（3），3经环合得到2－（4－羟基苯基）－4－甲基－噻唑－5－羧酸乙酯（4），4与乌洛托品反应，得到中间体2－（3－甲酰基－4－羟基苯基）－4－甲基－噻唑－5－羧酸乙酯（5），之后再经醚化、氰化、水解得到目标产物（1）。结果与结论中间体及目标化合物的结构经^1H—NMR和FAB-MS确证。该合成路线中使用的原料和试剂价廉易得，反应条件温和易控，操作简便。     

阿法骨化醇合成的新方法

目的：合成阿法骨化醇。方法：以维生素D3为原料，经酯化、关环、氧化、开环、水解5步反应合成目标化合物。结果：本方法避开了光照反应，产物总收率为17．2％。结论：本方法提高了收率，操作安全，适合于工业化生产。     

P-glycoprotein limits the brain penetration of olopatadine hydrochloride, H1-receptor antagonist

Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-glycoprotein (P-gp) on brain penetration and plasma concentration of olopatadine. The uptake amount of olopatadine in human P-gp transfected LLC-PK1 cells (LLC-GA5-COL150) was lower than that in LLC-PK1. The uptake of olopatadine in LLC-GA5-COL150 was increased in the same level as that in LLC-PK1 in the presence of cyclosporine A, a P-gp inhibitor. After intravenous or oral administration of olopatadine to wild type (WT) and mdr1a/1b knockout (KO) mice at a dose of 1 mg/kg, the brain concentration in KO mice was higher than that in WT mice. On the other hand, the plasma concentration of olopatadine after either route of administration was not different between WT and KO mice. These results suggest that olopatadine is a substrate of P-gp, and that P-gp limits the brain penetration but dose not affect the plasma concentration of olopatadine.     

抗过敏药盐酸奥洛他定的合成工艺研究

目的合成新型抗过敏药盐酸奥洛他定.方法以对羟基苯乙酸和苯酞为原料,经亲核取代、脱水环合、Wittig反应、成盐制备盐酸奥洛他定.结果目标化合物的结构经氢谱、质谱确证,总收率约5.9%.结论改进了合成路线,为进一步工业生产和临床应用打下基础.     

The noncompetitive antagonism of histamine H1 receptors expressed in Chinese hamster ovary cells by olopatadine hydrochloride: its potency and molecular mechanism

Calcium responses to various concentrations of histamine were monitored in Chinese hamster ovary cells stably expressing the human histamine H(1) receptor. The effects of various histamine H(1) receptor antagonists on the dose-response curve for histamine were evaluated. Olopatadine hydrochloride (olopatadine) inhibited the histamine-induced maximum response (pD(2)': 7.5) but had insignificant effects on histamine EC(50) values. This noncompetitive property exhibited by olopatadine, which was also observed in human umbilical vein endothelial cells, was the most striking among the antihistamines tested in this study. The geometrical isomer of olopatadine (E-isomer), which had a similar binding affinity to the histamine H(1) receptor as olopatadine, showed a mixed antagonistic profile (competitive and noncompetitive). These results indicate that the geometry around the double bond in the dimethylaminopropylidene group is critical for the potent noncompetitive property of olopatadine. Furthermore, binding mode analyses suggest that the protonated amine group in the dimethylaminopropylidene moiety of olopatadine forms an ionic bond with Glu 181 that is present in the second extracellular loop of the histamine H(1) receptor, whereas the amine group of the E-isomer does not. The second extracellular loop in aminergic G-protein-coupled receptors contributes to ligand binding and therefore the noncompetitive property of olopatadine may be explained by the interaction with Glu 181.     

Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities.

Olopatadine, a new histamine H(1) receptor-selective antagonist, is a tricyclic drug containing an alkylamino moiety. Some compounds containing a similar alkylamino group form a cytochrome p450 (p450) -iron (II)-nitrosoalkane metabolite complex [metabolic intermediate complex (MIC)], thereby causing quasi-irreversible inhibition of the p450. There was concern that olopatadine might also form MICs, therefore, the present investigation was undertaken to explore this possibility. We identified the enzymes catalyzing olopatadine metabolism and investigated the effect of olopatadine on human p450 activities. During incubation with human liver microsomes in the presence of a NADPH-generating system, olopatadine was metabolized to two metabolites, M1 (N-monodemethylolopatadine) and M3 (olopatadine N-oxide) at rates of 0.330 and 2.50 pmol/min/mg protein, respectively. Troleandomycin and ketoconazole, which are both selective inhibitors of CYP3A, significantly reduced M1 formation but specific inhibitors of other p450 isozymes did not decrease M1 formation. Incubation of olopatadine with cDNA-expressed human p450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4. The formation of M3 was enhanced by N-octylamine and was inhibited by thiourea. High specific activity of M3 formation was exhibited by cDNA-expressed flavin-containing monooxygenase (FMO)1 and FMO3. Olopatadine did not inhibit p450 activities when it was simultaneously incubated with substrates for different p450 isozymes. Also, p450 activities in human liver microsomes were unaffected by pretreatment with olopatadine or M1. Furthermore, spectral analysis revealed that neither olopatadine nor M1 formed an MIC. Therefore, it is unlikely that olopatadine will cause drug-drug interactions involving p450 isozymes.     

Brain histamine H receptor occupancy of orally administered antihistamines measured by positron emission tomography with (11)C-doxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen

AIMS: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. METHODS: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with (11)C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H(1)R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H(1)R occupancy was examined. RESULTS: H(1)R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H(1)R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H(1)R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H(1)R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). CONCLUSION: It is suggested that 5 mg oral olopatadine, with its low H(1)R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H(1) receptor (H(1)R), histamine H(1) receptor occupancy (H(1)RO), dopamine D(2) receptor (D(2)R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV).     

Properties of olopatadine hydrochloride, a new antiallergic/antihistaminic drug

Olopatadine hydrochloride (CAS 140462-76-6, KW-4679, AL-4943A; hereinafter referred to as olopatadine) is a novel antiallergic drug that is a selective histamine H1 receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibits the tachykininergic contractions in guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Oral administration of olopatadine at doses of 0.03 mg/kg or higher reduces the symptoms of experimental allergic cutaneous responses and rhinoconjunctivitis in sensitized animals. Preclinical and clinical evaluations have demonstrated that olopatadine is a safe drug. After oral administration to healthy volunteers, olopatadine was rapidly and extensively absorbed. Unlike most other antiallergic drugs which are eliminated via hepatic metabolism, olopatadine is mainly excreted into urine. Olopatadine did not affect cytochrome P450 activities in human liver microsomes and consequently drug-drug metabolic interactions are unlikely. In double-masked clinical trials, olopatadine was shown to be effective at alleviating symptoms of allergic diseases. The drug (Allelock) was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, cutaneous pruritis, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. An ophthalmic solution of olopatadine is also useful for the treatment of allergic conjunctivitis: this formulation (Patanol) was approved in the USA and the European Union for the treatment of seasonal and perennial allergic conjunctivitis in 1996 and 2002, respectively.     

The effects of olopatadine hydrochloride on the number of scratching induced by repeated application of oxazolone in mice

It is suggested that atopic dermatitis is a skin disease associated with itching as subjective symptoms, and histamine H(1) receptor antagonists are used in order to prevent the itching, and the deterioration for scratch by itching. Histamine H(1) receptor selective anti-histamine olopatadine hydrochloride (olopatadine; Allelock shows consistent efficacy and safety in the treatment of allergic disorders. We investigated the possible efficacy of olopatadine on the number of scratching induced by repeated application of oxazolone in BALB/c mice. The repeated treatment of olopatadine significantly inhibited the ear swelling and the increased number of scratching. It significantly inhibited the increased production of interleukin (IL)-4, IL-1beta and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lesioned ear. Moreover, it significantly inhibited the increased production of nerve growth factor (NGF) and substance P. On the other hand, loratadine, bepotastine and chlorpheniramine did not inhibit the ear swelling and the increased number of scratching. These results indicate that olopatadine inhibited not only the increased production of cytokines but also NGF and substance P unlike other histamine H(1) receptor antagonists. It was suggested that olopatadine suppressed the increased number of scratching by the anti-inflammatory effects. Therefore, olopatadine appears to exert additional biological effects besides its blockade of a histamine H(1) receptor.     

盐酸奥洛他定在中国变应性鼻炎人群的非劣效临床研究设计及其定量分析*

目的:通过非劣性设计,评价盐酸奥洛他定片剂治疗变应性鼻炎的安全性和有效性。方法:以盐酸氯雷他定片为对照,采用随机、双盲双模拟、多中心、平行对照、非劣效临床研究。两组各120例。试验组早晚各1次口服盐酸奥洛他定,每次5 mg;对照组早晨服用氯雷他定片10 mg。按双模拟方法编盲,以症状体征总积分下降值为主要疗效指标,非劣效标准(δ)设为1分,疗程2周。结果:用药后2周,两组各项症状明显改善,症状体征总积分和生活质量评估等级较用药前显著下降(P<0.01);作为主要疗效指标的症状总积分差值(FAS集),组间差值95%可信区间为[-0.260,0.880],即试验组不劣于对照组(P<0.05)。对照组有效率为61.5%,不良反应发生率为9.2%;试验组有效率62.4%,不良反应发生率为5.8%,组间差异无统计学意义(P>0.05)。结论:盐酸奥洛他定治疗变应性鼻炎疗效确切,不劣于对照药氯雷他定,患者耐受性好,未发现严重不良反应。     

Effect of olopatadine hydrochloride, a novel antiallergic agent, on the QT interval in dogs]

Olopatadine hydrochloride (olopatadine), a novel antiallergic agent, is effective in the treatment of allergic rhinitis, chronic urticaria, eczema and dermatitis. It has been reported that terfenadine and astemizole cause side effects on the circulatory system such as QT prolongation followed by serious ventricular arrhythmias (torsades de pointes). To investigate the possibility of QT prolongation, we used both conscious normal dogs and hypokalemia-anesthetized dogs under two conditions: 1) olopatadine used alone and 2) olopatadine used in combination with itraconazole, the CYP3A4-inhibiting antifungal agent, in the present investigation. The group treated with terfenadine alone (30 mg/kg, p.o.) and the group treated with a combination of terfenadine (10 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) had a significantly prolonged QT interval. On the other hand, the group treated with olopatadine alone (30 mg/kg, p.o.) and the group treated with a combination of olopatadine (30 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) did not show any significant changes in QT interval. Moreover, olopatadine (1 and 5 mg/kg, i.v.) did not influence the QT interval in hypokalemia-anesthetized dogs. These results suggest that there is very little possibility of QT prolongation as a result of clinically used olopatadine.     

液相色谱-串联质谱法测定人血浆中奥洛他定的浓度

目的建立人血浆中奥洛他定浓度测定的液相色谱-串联质谱（LC—MS／MS）定量方法。方法以地氯雷他定为内标,血浆样品经蛋白沉淀处理后,在0．2mL·min^-1的流速下以乙腈-甲醇-0．1％甲酸水溶液（25：5：70,V／V／V）为流动相进行等度洗脱,采用CAPCELLPAKC18柱（50mm×2．1mm,3．5μm）分离。样品经电喷雾离子源（ESI）正离子化后,通过三重四极杆串联质谱仪,采用多反应离子检测方式测定奥洛他定（m／z338．2／165．2）和内标地氯雷他定（m／z311．1／259．1）的浓度。结果奥洛他定质量浓度在1～200μg·L^-1内线性良好,定量下限为1μg·L^-1,方法回收率为85％-115％,批内、批间RSD均〈10％。结论本方法专属性强、灵敏度高,操作简便、快速,符合生物样品分析要求,适用于临床药动学研究。