ketoconazole | 65277-42-1

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗真菌类药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: ketoconazole
• 英文别名: ketokonazole；cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine；1-(4-(4-(((2R,4S)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethan-1-one；KTC；KET；1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
• CAS: 65277-42-1
• 化学式: C₂₆H₂₈Cl₂N₄O₄
• 分子量: 531.439
• InChiKey: XMAYWYJOQHXEEK-OZXSUGGESA-N

物化性质

• 熔点：
  148-152 °C
• 沸点：
  753.4±60.0 °C(Predicted)
• 密度：
  1.4046 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  溶于甲醇：50mg/mL
• LogP：
  4.350
• 物理描述：
  COLOURLESS CRYSTALS OR POWDER.
• 颜色/状态：
  Crystals from 4-methylpentanone
• 蒸汽压力：
  6.41X10-14 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic fumes of /hydrogen chloride and nitrogen oxides/.
• 解离常数：
  pKa1 = 3.96 (amine); pKa2 = 6.75 (imine) (est)
• 碰撞截面：
  214.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  69.1
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

酮康唑部分在肝脏中通过氧化和降解咪唑环和哌嗪环、氧化O-脱烷基化以及芳香族羟基化代谢为几种无活性代谢物。

Ketoconazole is partially metabolized, in the liver, to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：酮康唑被用作抗真菌药物。人类暴露和毒性：在酮康唑治疗期间，可能会出现血清天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和碱性磷酸酶浓度的暂时性增加。在接受口服酮康唑的患者中发生了严重的肝毒性，包括一些致命的病例或需要肝移植的病例。肝毒性可能是肝细胞型（大多数情况下）、胆汁淤积型或混合型损伤。尽管酮康唑引起的肝毒性通常在停药后可逆，但恢复可能需要几个月的时间，罕见情况下会导致死亡。症状性肝毒性通常在酮康唑治疗的前几个月内明显，但偶尔也可能在治疗的第一周内出现。一些患有酮康唑诱导的肝毒性的患者没有明显的肝病风险因素。在高剂量短期治疗和低剂量长期治疗的患者中报告了严重的肝毒性。许多肝毒性病例发生在接受药物治疗指甲真菌病（甲癣）或慢性、难治性皮肤真菌病的患者中。在一些儿童中报告了酮康唑诱导的肝炎。通常剂量（即，每天200-400毫克）的酮康唑已被报告暂时（持续2-12小时）抑制睾丸睾酮合成。可能会出现血清促黄体生成激素（LH）浓度的补偿性增加。每天800-1200毫克的剂量已被报告对睾酮合成有更持久的影响；在一项研究中，接受这些高剂量的男性中，大约30%的接受800毫克每天治疗的人和所有接受1200毫克每天治疗的人，血清睾酮浓度整天保持在亚正常水平（即，小于300 ng/dL）。精子减少、性欲减退和阳痿在这些男性中经常发生，而无精子症则很少发生。该药物显然在体外和体内直接抑制肾上腺类固醇和睾酮的合成。酮康唑主要通过阻断几种P-450酶系统（例如，11β-羟化酶、C-17,20-裂解酶、胆固醇侧链裂解酶）来抑制类固醇合成。总的来说，结果表明许多常用的唑类抗真菌剂在体内作为内分泌干扰物发挥作用，尽管在体内的作用模式有所不同。由于酮康唑已知在人类中引起许多内分泌干扰效应。动物研究：经口给药后，在小鼠、大鼠和豚鼠中通过镇静、僵直、共济失调、震颤、惊厥和致死前失去翻正反射（剂量大于320 mg/kg）表现出毒性。在狗中，毒性表现为腹泻和呕吐（剂量大于80 mg/kg）。酮康唑已通过口服（灌胃）和静脉途径给予小鼠、大鼠、豚鼠和狗。静脉给药后的毒性在小鼠、大鼠和豚鼠表现为痉挛、惊厥和呼吸困难；小鼠和豚鼠在致死前失去翻正反射，狗也出现毒性。狗的毒性还表现为舔舐和惊厥。在大鼠中，治疗组和对照组之间的肿瘤发生率和类型没有显著差异，除了高剂量雌性大鼠的总体肿瘤率降低。在发育研究中，大鼠的死胎发生率从对照组的0.5%增加到40 mg/kg剂量的32.7%，并且在两个窝中发生了食仔现象。在小鼠中，尾部附睾的精子活动力和密度显著下降。酮康唑处理的小鼠的生育力显著下降（50%阴性）。睾丸、附睾、精囊和腹侧前列腺的总蛋白质和唾液酸含量显著减少。睾丸的胆固醇含量升高，而精囊的果糖含量显著降低。酮康唑处理改变了生殖道的生化环境。在兔中，酮康唑在40 mg/kg/天的较高剂量下产生了母体毒性、胚胎毒性和致畸性的证据。在使用显性致死突变试验或Ames沙门氏菌微囊体激活试验评估时，酮康唑没有显示出任何突变潜力。生态毒性研究：酮康唑诱导了虹鳟鱼中的CYP1A和CYP3A表达。然而，酮康唑最显著的效果是在虹鳟鱼和孔雀鱼中CYP3A催化活性减少了60至90%。

IDENTIFICATION AND USE: Ketokonazole is used as antifungal medication. HUMAN EXPOSURE AND TOXICITY: Transient increases in serum AST, ALT, and alkaline phosphatase concentrations may occur during ketoconazole therapy. Serious hepatotoxicity has occurred in patients receiving oral ketoconazole, including cases that were fatal or required liver transplantation. Hepatotoxicity may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury. Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug, recovery may take several months and rarely death has occurred. Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy, but occasionally may be apparent within the first week of therapy. Some patients with ketoconazole-induced hepatotoxicity had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving high oral ketoconazole dosage for short treatment durations and in patients receiving low oral dosage of the drug for long durations. Many of the reported cases of hepatotoxicity occurred in patients who received the drug for the treatment of tinea unguium (onychomycosi or the treatment of chronic, refractory dermatophytoses. Ketoconazole-induced hepatitis has been reported in some children. Usual dosages (ie, 200-400 mg daily) of ketoconazole have been reported to transiently (for 2-12 hours) inhibit testicular testosterone synthesis. A compensatory increase in serum luteinizing hormone (LH) concentrations may occur. Dosages of 800-1200 mg daily have been reported to have a more prolonged effect on testosterone synthesis; in one study in males receiving these high dosages, serum testosterone concentrations remained at a subnormal level (ie, less than 300 ng/dL) throughout the day in about 30% of those receiving 800 mg daily and in all of those receiving 1200 mg daily. Oligospermia, decreased libido, and impotence often occurred in these males and azoospermia occurred rarely. The drug apparently directly inhibits synthesis of adrenal steroids and testosterone in vitro and in vivo. Ketoconazole appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (eg, 11beta-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme). Overall the results show that many of the commonly used azole fungicides act as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole is known to implicate numerous endocrine-disrupting effects in humans. ANIMAL STUDIES: After oral administration toxicity was manifested in mice, rats and guinea pigs by sedation, catalepsy, ataxia, tremors, convulsions and pre-lethal loss of the righting reflex at doses >320 mg/kg. In dogs, toxicity was manifested by diarrhea and vomiting at doses >80 mg/kg. Ketoconazole has been administered by the oral (gavage) and intravenous routes to mice, rats, guinea pigs and dogs. Toxicity after intravenous administration was manifested by spasms, convulsions and dyspnea in rats, mice and guinea pigs; pre-lethal loss of the righting reflex occurred in mice and guinea pigs, and dogs. Toxicity in dogs was also manifested by licking and convulsions. In rats the overall incidence of and type of tumors was not significantly different between treated and control groups, except for high-dosed female rats who had a decrease of the overall tumor rate. In developmental studies in rats the incidence of stillborn fetuses increased from a control value of 0.5% to 32.7% in rats dosed with 40 mg/kg and cannibalization of young occurred in two litters. In mice a significant decline in sperm motility and density in cauda epididymis was noted. A sharp decline in fertility (50% negative) in ketoconazole treated mice was observed. A significant reduction in the total protein and sialic acid contents of testes, epididymis, seminal vesicle and ventral prostate were noticed. The cholesterol contents of testes were raised while fructose contents of seminal vesicle were reduced significantly. The ketoconazole treatment altered the biochemical milieu of the reproductive tract. In the rabbit, ketoconazole produces evidence of maternal toxicity, embryotoxicity and teratogenicity at a high dose of 40 mg/kg/day. Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. ECOTOXICITY STUDIES: Ketoconazole induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

温和且短暂的肝酶升高发生在4%到20%的口服酮康唑的患者中。这些异常通常是暂时的和无症状的，很少需要调整剂量或停药。酮康唑引起的临床明显肝毒性在文献中有很好的描述，估计发生在1/2,000到1/15,000的用户中。肝损伤通常表现为急性肝炎样的图片，在开始治疗后的1到6个月内。虽然大多数病例表现为肝细胞损伤的模式，但也描述了胆汁淤积型。皮疹、发热和嗜酸性粒细胞增多是罕见的，自身抗体的形成也是如此。停止治疗后的恢复可能会延迟，通常需要1到3个月。已经描述了严重病例，包括急性肝衰竭、死亡或需要紧急肝移植。

Mild and transient elevations in liver enzymes occur in 4% to 20% of patients on oral ketaconazole. These abnormalities are usually transient and asymptomatic and uncommonly require dose adjustment or discontinuation. Clinically apparent hepatotoxicity from ketaconazole is well described in the literature and is estimated to occur in 1:2,000 to 1:15,000 users. The liver injury typically presents with an acute hepatitis-like picture 1 to 6 months after starting therapy. While most cases present with a hepatocellular pattern of injury, cholestatic forms have been described. Rash, fever and eosinophilia are rare as is autoantibody formation. Recovery upon stopping therapy may be delayed and generally takes 1 to 3 months. Severe cases with acute liver failure and death or need for emergency liver transplantation have been described.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：由于缺乏关于哺乳期间使用酮康唑或左酮康唑的已发表经验，以及其潜在的肝酶抑制和肝毒性，建议使用其他药物。生产商建议服用酮康唑或左酮康唑的母亲在治疗期间以及最后一次剂量的1天后避免哺乳。 母亲使用酮康唑洗发水或在皮肤上局部使用对哺乳婴儿几乎无风险。然而，由于婴儿可能通过口腔摄入，以及有更安全的替代品可用，哺乳母亲应避免在乳房或乳头上局部使用。只有水溶性的乳膏或凝胶产品应涂抹在乳房上，因为软膏可能会使婴儿通过舔食接触到高水平的矿物石蜡。 哺乳婴儿的影响：一名母亲口服酮康唑200毫克，持续10天，未在她的1个月大的哺乳婴儿中注意到不良反应。 对泌乳和母乳的影响：截至修订日期，未找到相关的已发表信息。

◉ Summary of Use during Lactation:Because there is little published experience with ketoconazole or levoketoconazole during breastfeeding and its potential liver enzyme inhibition and liver toxicity, other agents are preferred. The manufacturers recommend that mothers taking ketoconazole or levoketoconazole avoid breastfeeding during treatment and for 1 day after the last dose. Use of ketoconazole shampoo or topical use on the skin by the mother poses little to no risk to the breastfed infant. However, topical use on the breast or nipples should be avoided in nursing mothers because of possible oral ingestion by the infant and the availability of safer alternatives. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking. ◉ Effects in Breastfed Infants:A mother taking ketoconazole 200 mg orally for 10 days noticed no adverse effects in her breastfed 1-month-old infant. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 暴露途径

该物质可以通过摄入被身体吸收。

The substance can be absorbed into the body by ingestion.

来源:ILO-WHO International Chemical Safety Cards (ICSCs)

毒理性

• 吸入症状

咳嗽。

Cough.

来源:ILO-WHO International Chemical Safety Cards (ICSCs)

吸收、分配和排泄

酮康唑可迅速从胃肠道吸收。口服给药后，酮康唑在胃液中溶解并转化为盐酸形式，然后从胃部吸收。

Ketoconazole is rapidly absorbed from the GI tract. Following oral administration, ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

食物对酮康唑在胃肠道吸收的速度和程度的影响尚未明确确定。一些临床医生报告称，与食物同服相比，空腹服用酮康唑会导致更高的血药浓度。然而，制造商表示，与食物同服酮康唑可以增加吸收的程度，并使血药浓度更加一致。制造商建议，食物通过增加酮康唑的溶解速度和/或程度（例如，通过增加胆汁分泌）或延迟胃排空来增加酮康唑的吸收。

The effect of food on the rate and extent of GI absorption of ketoconazole has not been clearly determined. Some clinicians have reported that administration of ketoconazole to fasting individuals results in higher plasma concentrations of the drug than does administration with food. However, the manufacturer states that administration of ketoconazole with food increases the extent of absorption and results in more consistent plasma concentrations of the drug. The manufacturer suggests that food increases absorption of ketoconazole by increasing the rate and/or extent of dissolution of ketoconazole (e.g., by increasing bile secretions) or by delaying stomach emptying.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

酮康唑是一种弱的双性剂，因此需要酸性环境才能溶解和吸收。

Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服酮康唑的生物利用度取决于胃内胃内容的pH值；pH值增加会导致药物吸收减少。在获得性免疫缺陷综合症（AIDS）患者中报告了酮康唑的生物利用度降低，这可能是由于该病状相关的胃低氯血症；在这些患者中，同时给予稀释的盐酸溶液可以正常化药物的吸收。198 同时给予酸性饮料可能会增加某些无胃酸个体的口服酮康唑的生物利用度。

The bioavailability of oral ketoconazole depends on the pH of the gastric contents in the stomach; an increase in the pH results in decreased absorption of the drug. Decreased bioavailability of ketoconazole has been reported in patients with acquired immunodeficiency syndrome (AIDS), probably because of gastric hypochlorhydria associated with this condition; concomitant administration of dilute hydrochloric acid solution normalized absorption of the drug in these patients.198 Concomitant administration of an acidic beverage may increase bioavailability of oral ketoconazole in some individuals with achlorhydria.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  T
• 安全说明：
  S36,S45
• 危险类别码：
  R25
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险品运输编号：
  UN 2811 6.1/PG 3
• 危险类别：
  6.1(b)
• RTECS号：
  TK7912300
• 包装等级：
  III
• 危险标志：
  GHS06,GHS08,GHS09
• 危险性描述：
  H301,H360F,H373,H410
• 危险性防范说明：
  P201,P273,P301 + P310,P308 + P313,P501

制备方法与用途

酮康唑是一种广谱抗真菌药，具有以下特点和用途：

1. 作用机制：酮康唑通过抑制真菌细胞膜上的麦角固醇生物合成所需的酶而发挥其抗菌作用。这种抑制作用导致真菌细胞膜的通透性增加，并使细胞内的游离氨基酸水平降低。

2. 适应症：

   • 脚气（足癣）
   • 头皮屑过多
   • 慢性黏膜皮肤念珠菌病
   • 口腔念珠菌感染（口腔真菌感染）
   • 念珠菌尿路感染
   • 白假丝酵母菌引起的深部真菌感染，如念珠菌病、隐球菌病等

3. 应用范围：

   • 皮肤：用于治疗各种由念珠菌和/或糠秕孢子菌引起的皮肤病。
   • 头皮：用于治疗头皮屑过多（脂溢性皮炎）。
   • 阴道：可用于阴道念珠菌感染。

4. 化学性质：白色结晶性粉末，熔点146℃，不溶于水。在生产中可通过特定的有机合成反应获得。

5. 注意事项和警告：

   • 对肝功能有潜在影响，治疗期间需定期监测肝功能。
   • 可引起光敏反应，应避免长时间暴露于阳光下。
   • 孕妇及哺乳期妇女使用时需谨慎，因为存在致畸风险和可能的乳汁分泌减少。
   • 与其他药物（如西咪替丁）合用时需间隔至少2小时。

6. 化学生产：酮康唑可由1-乙酰基-4-(4-羟基苯)哌嗪、氢氧化钠以及苯中的硫酸二甲酯经过一系列反应合成得到。

7. 毒性和储存要求：

   • 酮康唑属于高毒性化学品，需小心处理。
   • 存储时应保持低温干燥环境，并与食品原料分开存放以确保安全。

总之，酮康唑是一种重要的抗真菌药物，在临床治疗上具有广泛的应用价值。然而其使用过程中需要注意相关禁忌症以及不良反应的发生。

反应信息

• 作为反应物：
  描述：

  ketoconazole 生成 米诺地尔
  参考文献：
  名称：

  Nanoparticles comprising half esters of poly (methyl vinyl ether-co-maleic anhydride) and uses thereof

  摘要：

  本发明涉及一种基于半(C1-C4)烷基酯的聚(甲基乙烯醚-co-马来酸酐) (PVM/MA) 共聚物的纳米颗粒，其制备和用途，该纳米颗粒可以封装或包含所需的产品。适用于农业、化妆品、食品或制药领域。

  公开号：

  EP2510930A1
• 作为产物：
  描述：

  1-乙酰基-4-(4-羟基苯基)哌嗪 在 四丁基溴化铵 、 三氟乙酸 、 sodium hydroxide 作用下， 以 水 、 二甲基亚砜 、 甲苯 为溶剂， 反应 32.0h， 生成 ketoconazole
  参考文献：
  名称：

  一种酮康唑的制备方法

  摘要：

  本发明属于医药合成的技术领域，尤其涉及一种酮康唑的制备方法。本发明提供的酮康唑的制备方法，包括：S101：将式I所示的化合物和式Ⅱ所示的化合物在酸性介质中混合反应，得到酮康唑。本发明使用的式I所示的化合物和式Ⅱ所示的化合物的空间位阻大，因此，式I所示的化合物和式Ⅱ所示的化合物混合反应形成的1，3‑二氧戊环的顺反选择性显著提高，从而省略脱苯甲酰基的步骤，最终，使得酮康唑的生产周期缩短和成本降低，同时减少了液溴等危险物质的使用，解决现有技术中合成酮康唑时步骤繁多，且收率和纯度低的技术缺陷。

  公开号：

  CN107739373B
• 作为试剂：
  描述：

  睾酮 在 human liver microsome 、 还原型辅酶II(NADPH)四钠盐 、 还原型辅酶Ⅰ 、 ketoconazole 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.17h， 生成 6,17-二羟基-6b,17b-雄甾-4-烯-3-酮
  参考文献：
  名称：

  In vitro evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole

  摘要：

  DOI：

  10.1080/00498254.2021.1897898

文献信息

• [EN] BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS<br/>[FR] COMPOSÉS BENZAMIDE OU BENZAMINE À UTILISER EN TANT QU'ANTICANCÉREUX POUR LE TRAITEMENT DE CANCERS HUMAINS
  申请人：UNIV TEXAS

  公开号：WO2017007634A1

  公开（公告）日：2017-01-12

  The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.

  所描述的发明提供了用于治疗对胆固醇生物合成抑制作出反应的肿瘤的小分子抗癌化合物。这些化合物选择性地抑制肿瘤来源的癌细胞中的胆固醇生物合成途径，但不影响正常分裂的细胞。
• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
  申请人：——

  公开号：US20020143182A1

  公开（公告）日：2002-10-03

  The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): 1 wherein: (a) m is an integer 0 or 1; (b) R 12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar 3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar 4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R 5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.

  该发明涉及某些对治疗癌症和其他疾病有用的杂环化合物，其具有以下式（I）： 1 其中： (a) m是整数0或1； (b) R12是烷基，取代烷基，环烷基，取代环烷基，杂环基，取代杂环基，杂芳基，取代杂芳基，芳基或取代芳基残基； (c) Ar3是芳基，取代芳基，杂芳基或取代杂芳基残基； (d) Ar4是芳基，取代芳基，杂芳基或取代杂芳基残基； (e) R5是氢，羟基，烷基或取代烷基； (f) - - - - - 代表存在或不存在的键；以及 (g) W、X、Y和Z独立或一起是C(O)、C(S)、S、O或NH；或其药学上可接受的盐。
• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
  申请人：Rewcastle Gordon William

  公开号：US20110009405A1

  公开（公告）日：2011-01-13

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了式I的嘧啶基和1,3,5-三嗪基苯并咪唑化合物，以及它们的药物组合物、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。