Ketocanazole | 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: Ketocanazole
• 英文别名: 1-[4-[4-[[(2R)-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: 531.4
• InChiKey: XMAYWYJOQHXEEK-NASUQTAISA-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)

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：酮康唑用作抗真菌药物。人类暴露和毒性：在酮康唑治疗期间，血清AST、ALT和碱性磷酸酶浓度可能会暂时增加。接受口服酮康唑的患者中发生了严重的肝毒性，包括一些致命的或需要肝移植的病例。肝毒性可能是肝细胞型的（在大多数情况下）、胆汁淤积型的或损伤的混合模式。尽管酮康唑诱导的肝毒性通常在停药后是可逆的，但恢复可能需要几个月的时间，偶尔也会有死亡的情况。酮康唑治疗的前几个月内通常会出现症状性肝毒性，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。在接受高剂量口服酮康唑短期治疗的患者和接受低剂量长期治疗的患者中报告了严重的肝毒性。许多报告的肝毒性病例发生在接受药物治疗的甲真菌病（onychomycosis）患者或慢性难治性皮肤真菌病患者中。酮康唑诱导的肝炎在一些儿童中有所报道。通常剂量（即，每天200-400毫克）的酮康唑据报道会暂时（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。据报道，每天800-1200毫克的剂量对睾酮合成的抑制作用更为持久；在一项研究中，接受这些高剂量的男性中，大约30%接受800毫克每天治疗的人以及所有接受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）。这些男性中经常出现少精子症、性欲减退和阳痿，而无精子症则很少发生。该药物显然直接抑制了肾上腺类固醇和睾酮的合成，无论是在体外还是体内。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。已知酮康唑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、抽搐和致死前失去翻正反射（剂量>320 mg/kg）表现出毒性。在狗中，通过腹泻和呕吐（剂量>80 mg/kg）表现出毒性。酮康唑通过口服（灌胃）和静脉给药途径给予小鼠、大鼠、豚鼠和狗。静脉给药后的毒性在小鼠、大鼠和豚鼠中表现为痉挛、抽搐和呼吸困难；在狗中，小鼠和豚鼠出现致死前失去翻正反射，狗也会出现舔舐和抽搐。在大鼠中，治疗组和对照组之间肿瘤的总发生率和类型没有显著差异，除了高剂量的雌性大鼠肿瘤总发生率降低。在大鼠的发育研究中，死胎的发生率从对照组的0.5%增加到接受40 mg/kg剂量的32.7%，并且在两个窝中发生了幼仔的同类相食。在小鼠中，观察到附睾尾部的精子活动力和密度显著下降。在接受酮康唑治疗的小鼠中观察到生育力（50%阴性）的急剧下降。在睾丸、附睾、精囊和腹侧前列腺中，总蛋白和唾液酸含量显著降低。睾丸中的胆固醇含量升高，而精囊中的果糖含量显著降低。酮康唑治疗改变了生殖道的生化环境。在兔中，酮康唑在高剂量40 mg/kg/天时产生了母体毒性、胚胎毒性和致畸性的证据。在使用显性致死突变试验或 Ames Salmonella 微粒体激活试验评估时，酮康唑没有显示出任何致突变潜力。生态毒性研究：酮康唑诱导了虹鳟鱼中CYP1A和CYP3A的表达。然而，酮康唑最显著的效果是在虹鳟鱼和孔雀鱼中CYP3A催化活性降低了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

口服酮康唑的患者中，有4%至20%的人会出现轻度和短暂的肝酶升高。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。文献中对酮康唑引起的明显肝毒性有详细描述，估计发生率在1:2,000到1:15,000使用者之间。肝损伤通常表现为急性肝炎样的症状，在开始治疗后的1到6个月内出现。虽然大多数病例表现为肝细胞损伤模式，但也描述了胆汁淤积性形式。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的情况。

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发表经验，以及其潜在的肝脏酶抑制和肝脏毒性，建议使用其他药物。生产企业建议在治疗期间及最后一剂服用后1天，母亲应避免哺乳。 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，因为药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：一位母亲口服酮康唑200毫克，持续10天，未在她的1个月大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，未找到相关的已发布信息。

◉ 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

这种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

酮康唑从胃肠道迅速吸收。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，在空腹个体中给药酮康唑比随食物给药会产生更高的血浆药物浓度。然而，制造商表示，随食物给药酮康唑能增加吸收的程度，并导致更一致的血浆药物浓度。制造商建议，食物通过增加酮康唑的溶解速率和/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被吸收。

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。

文献信息

• Active agent delivery systems and methods for protecting and administering active agents
  申请人：Mickle Travis

  公开号：US20070232529A1

  公开（公告）日：2007-10-04

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性物质输送系统，更具体地涉及包含氨基酸（作为单个氨基酸或肽）与活性物质共价连接的组合物以及用于给予共轭活性物质组合物的方法。
• ACTIVE AGENT DELIVERY SYSTEMS AND METHODS FOR PROTECTING AND ADMINISTERING ACTIVE AGENTS
  申请人：Mickle Travis

  公开号：US20090253792A1

  公开（公告）日：2009-10-08

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性剂递送系统，更具体地涉及包含氨基酸（作为单个氨基酸或肽）与活性剂共价连接的组合物以及给予共轭活性剂组合物的方法。
• ACTIVE AGENT DELIVERY SYSTEMS AND METHODS FOR PROTECTING AND ADMINISTERING ACTIVE AGENTS
  申请人：Mickle Travis

  公开号：US20090306228A1

  公开（公告）日：2009-12-10

  The present invention relates to active agent delivery systems and more specifically to compositions that comprise amino acids, as single amino acids or peptides, covalently attached to active agents and methods for administering conjugated active agent compositions.

  本发明涉及活性剂递送系统，更具体地涉及包含氨基酸，作为单个氨基酸或肽，与活性剂共价结合的组合物以及用于给予共轭活性剂组合物的方法。
• INHIBITORS OF ALPHA-CRYSTALLIN AGGREGATION FOR THE TREATMENT FOR CATARACT
  申请人：The Regents of The University of Michigan

  公开号：EP3482797A1

  公开（公告）日：2019-05-15

  The invention provides inhibitors of cc-crystallin aggregation and methods of using cc-crystallin aggregation inhibitors to, e.g., treat or prevent cataracts in a subject having or at risk of developing cataracts. The invention further provides high throughput methods of screening compounds for modulation of protein thermal stability, the method comprising contacting a protein with each of a plurality of test compounds; and (b) measuring the melting transition (Tm) of the protein in the presence of each of the plurality of test compounds, wherein a compound that decreases or increases the apparent Tm by at least 2 standard deviations is identified as a pharmacological protein chaperone.

  本发明提供了cc-结晶素聚集抑制剂和使用cc-结晶素聚集抑制剂治疗或预防白内障的方法，例如治疗或预防患有白内障或有患白内障风险的受试者的白内障。本发明进一步提供了筛选调节蛋白质热稳定性的化合物的高通量方法，该方法包括将蛋白质与多种测试化合物中的每一种接触；以及(b)测量蛋白质在多种测试化合物中的每一种存在下的熔化转变（Tm），其中将表观Tm降低或升高至少2个标准差的化合物鉴定为药理学蛋白质伴侣素。
• METHODS AND COMPOSITIONS FOR TREATING DIABETES, METABOLIC SYNDROME AND OTHER CONDITIONS
  申请人：Marin Per

  公开号：US20090233843A1

  公开（公告）日：2009-09-17

  Pharmaceuticals compositions comprising the 2S, 4R, ketoconazole enantiomer or its pharmaceutically acceptable salts, hydrates, and solvates, that are substantially free of the 2R, 4S ketoconazole enantiomer are useful to reduce cortisol synthese and for the treatment of type 2 diabetes, hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other diseases and conditions, including but not limited to Cushing's Syndrome, depression, and glaucoma.