101530-10-3

• 常用中文名：拉诺康唑
• 常用英文名：Astat
• CAS号：101530-10-3
• 分子式：C₁₄H₁₀ClN₃S₂
• 分子量：319.832
• 相关类别： 原料药 人工合成抗感染类药 抗真菌类药
• 发布时间：2018-04-03 08:00:00
• 更新时间：2024-01-10 16:22:41
• Lanoconazole 是一种强效口服咪唑类抗真菌 (antifungal) 试剂,具有广谱的体内外抗真菌活性。Lanoconazole 通过抑制 sterol 14-alpha 去甲基酶,阻断真菌膜上的 ergosterol 生物合成,从而干扰 ergosterol 的生物合成。Lanoconazole 可用于皮肤真菌病和甲真菌病的研究。

名称

• 中文名: 拉诺康唑
• 英文名: Lanoconazole
• 中文别名: 兰诺康唑; (±)-(E)-Α-[4-(2-氯苯基)-1,3-二硫戊烷-2-亚基]-1H-咪唑-1-乙腈; [4-(2-氯苯基)-1,3-亚二硫戊环-2-基]-2-咪唑-1-基-乙腈
• 英文别名: (2Z)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1-yl)ethanenitrile; [4-(2-Chloro-phenyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-yl-acetonitrile; (E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazol-1-yl acetonitrile; (E)-(±)-a-[4-(2-Chlorophenyl)-1,3-dithiolan-2-ylidene]-1H-imidazole-1-acetonitrile; latoconazole; nnd-318; (+-)-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile; MFCD00865590; (2Z)-[4-(2-Chlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1-yl)acetonitrile; 2-(1-imidazolyl)-2-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]acetonitrile; [4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1-yl)acetonitrile; 2-[4-(2-Chlorophenyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-yl-acetonitrile; tjn-318; 1H-Imidazole-1-acetonitrile, α-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-, (αZ)-; (4-(2-Chlorophenyl)-1,3-dithiolan-2-ylidene)-1-imidazolylacetonitrile; Astat; itrile

物化性质

• 密度: 1.4±0.1 g/cm3
• 沸点: 477.6±55.0 °C at 760 mmHg
• 熔点: 141.50C
• 分子式: C₁₄H₁₀ClN₃S₂
• 分子量: 319.832
• 闪点: 242.6±31.5 °C
• 精确质量: 319.000458
• PSA: 92.21000
• LogP: 3.38
• 外观性状: 淡黄色晶体
• 蒸汽压: 0.0±1.2 mmHg at 25°C
• 折射率: 1.725
• 储存条件: 2-8°C
• 分子结构:

  1、 摩尔折射率：88.56

  2、 摩尔体积（cm³/mol）：223.0

  3、 等张比容（90.2K）：619.3

  4、 表面张力（dyne/cm）：59.4

  5、 极化率（10-24cm3）：35.11

• 计算化学:

  1.疏水参数计算参考值（XlogP）:3.3

  2.氢键供体数量:0

  3.氢键受体数量:4

  4.可旋转化学键数量:2

  5.互变异构体数量:无

  6.拓扑分子极性表面积92.2

  7.重原子数量:20

  8.表面电荷:0

  9.复杂度:445

  10.同位素原子数量:0

  11.确定原子立构中心数量:0

  12.不确定原子立构中心数量:1

  13.确定化学键立构中心数量:1

  14.不确定化学键立构中心数量:0

  15.共价键单元数量:1

• 更多:

  1.性状：淡黄色结晶。

  2.熔点141.5℃。

生物活性

• 描述: Lanoconazole 是一种强效口服咪唑类抗真菌 (antifungal) 试剂,具有广谱的体内外抗真菌活性。Lanoconazole 通过抑制 sterol 14-alpha 去甲基酶,阻断真菌膜上的 ergosterol 生物合成,从而干扰 ergosterol 的生物合成。Lanoconazole 可用于皮肤真菌病和甲真菌病的研究。
• 相关类别:
  研究领域 >> 感染
  信号通路 >> 抗感染 >> 真菌
  研究领域 >> 炎症/免疫
• 靶点:

  IC50: antifungal[1]

• 体内研究: Lanoconazole(耳用治疗；0.3%-3%；6天)剂量依赖性抑制estpa诱导的刺激性皮炎,抑制中性粒细胞趋化因子(如角质形成细胞衍生的趋化因子和巨噬细胞炎症蛋白)的产生,并抑制中性粒细胞向炎症部位的浸润[2]。与生理盐水对照组相比,兰诺唑(口服；3、10或30 mg/kg；每天一次；3周)显著抑制新生隐球菌。此外,它还显著降低了新生梭菌在雌性小鼠肺和脑中的生长[3]。动物模型：BALB/c小鼠[2]剂量：0.3%-3%剂量给药：耳部治疗结果：LCZ对TPA所致小鼠耳部肿胀有抑制作用。动物模型：4周龄C57BL/6小鼠腹腔感染LP-BM5小鼠白血病病毒[3]剂量：3、10或30mg/kg给药：口服给药结果：抑制正常和新生鼠脑炎模型小鼠的新生鼠生长。
• 参考文献:

  [1]. Shokoohi GR, et al. In Vitro Activities of Luliconazole, Lanoconazole, and Efinaconazole Compared with Those of Five Antifungal Drugs against Melanized Fungi and Relatives.Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e00635-17.

  [2]. Nakamura A, et al. Anti-inflammatory effect of lanoconazole on 12-O-tetradecanoylphorbol-13-acetate- and 2,4,6-trinitrophenyl chloride-induced skin inflammation in mice.Mycoses. 2020 Feb;63(2):189-196.

  [3]. Furukawa K, et al. Lanoconazole, a new imidazole antimycotic compound, protects MAIDS mice against encephalitis caused by Cryptococcus neoformans.J Antimicrob Chemother. 2000 Sep;46(3):443-50.

毒性和生态

毒理学数据: 急性毒性LD50雄、雌小鼠，雄、雌大鼠(mg/kg)：3224，2715，993，652口服；2158，1743，1655，2596腹腔注射；全部＞5000皮下注射。急性毒性LD50大鼠致死量：＞5000mg/kg。 LD50(mg/kg)：雄小鼠,经口3224,腹腔注射2158,皮下注射>5000;雌小鼠,经口2715,腹腔注射1743,皮下 注射>5000;雄大鼠,经口993,腹腔注射1655,皮下注射>5000;雌大鼠,经口652,腹腔注射2596,皮下注射>5000. CHEMICAL IDENTIFICATION RTECS NUMBER : NI3393500 CHEMICAL NAME : 1H-Imidazole-1-acetonitrile, alpha-(4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene)-, (E)-(+-)- CAS REGISTRY NUMBER : 101530-10-3 LAST UPDATED : 199612 DATA ITEMS CITED : 17 MOLECULAR FORMULA : C14-H10-Cl-N3-S2 MOLECULAR WEIGHT : 319.84 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 652 mg/kg TOXIC EFFECTS : Autonomic Nervous System - other (direct) parasympathomimetic Lungs, Thorax, or Respiration - respiratory depression Skin and Appendages - hair REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LD - Lethal dose ROUTE OF EXPOSURE : Administration onto the skin SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >5 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 1655 mg/kg TOXIC EFFECTS : Autonomic Nervous System - other (direct) parasympathomimetic Behavioral - rigidity (including catalepsy) Behavioral - muscle contraction or spasticity REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LD - Lethal dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >5 gm/kg TOXIC EFFECTS : Behavioral - changes in motor activity (specific assay) Skin and Appendages - hair Nutritional and Gross Metabolic - weight loss or decreased weight gain REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 2715 mg/kg TOXIC EFFECTS : Autonomic Nervous System - other (direct) parasympathomimetic Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 1743 mg/kg TOXIC EFFECTS : Behavioral - somnolence (general depressed activity) Skin and Appendages - hair Nutritional and Gross Metabolic - body temperature decrease REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LD - Lethal dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >5 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,195,1992 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Mammal - dog DOSE/DURATION : 2 gm/kg TOXIC EFFECTS : Behavioral - somnolence (general depressed activity) Liver - other changes Blood - normocytic anemia REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,137,1992 ** OTHER MULTIPLE DOSE TOXICITY DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 5040 mg/kg/4W-C TOXIC EFFECTS : Liver - other changes Endocrine - changes in spleen weight Skin and Appendages - dermatitis, other (after systemic exposure) REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,273,1992 TYPE OF TEST : TCLo - Lowest published toxic concentration ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 4550 mg/kg/26W-I TOXIC EFFECTS : Liver - changes in liver weight Kidney, Ureter, Bladder - changes in bladder weight Nutritional and Gross Metabolic - weight loss or decreased weight gain REFERENCE : KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 26,2439,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Administration onto the skin SPECIES OBSERVED : Mammal - dog DOSE/DURATION : 9100 mg/kg/26W-I TOXIC EFFECTS : Liver - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases REFERENCE : KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 26,2417,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Mammal - dog DOSE/DURATION : 700 mg/kg/4W-C TOXIC EFFECTS : Liver - changes in liver weight Blood - normocytic anemia Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,137,1992 ** REPRODUCTIVE DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 7875 mg/kg SEX/DURATION : male 63 day(s) pre-mating TOXIC EFFECTS : Reproductive - Fertility - male fertility index (e.g. # males impregnating females per # males exposed to fertile nonpregnant females) REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,353,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 550 mg/kg SEX/DURATION : female 7-17 day(s) after conception TOXIC EFFECTS : Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Effects on Newborn - stillbirth REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,369,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 550 mg/kg SEX/DURATION : female 7-17 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Newborn - live birth index (measured after birth) Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive) Reproductive - Effects on Newborn - behavioral REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,369,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 2600 mg/kg SEX/DURATION : female 7-21 day(s) after conception lactating female 21 day(s) post-birth TOXIC EFFECTS : Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,383,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 1300 mg/kg SEX/DURATION : female 6-13 day(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - other effects REFERENCE : OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 43,395,1992

安全

• 符号: GHS07
• 信号词: Warning
• 危害声明: H302
• 个人防护装备: dust mask type N95 (US);Eyeshields;Gloves
• 危害码 (欧洲): Xn: Harmful;
• 风险声明 (欧洲): R22
• 危险品运输编码: NONH for all modes of transport
• RTECS号: NI3393500

制备

1. 2-(1-咪唑基)乙腈与二硫化碳和氢氧化钾在二甲基甲酰胺中反应得连二硫酸酯的二钾盐，然后和1-(2-氯苯基)-1，2-二(甲磺酰氧基)乙烷环合。经硅胶柱层析分离(E)和(Z)异构体，而得拉诺康唑。

2. 推荐参考文献[4-6]并根据文献[10]进行了改进的方法和路线进行制备和合成.

(1).1-(2-氯苯基)-1,2-乙二醇的制备

在反应瓶中加入2-氯扁桃酸5.0g（0.027mol）、甲醇15ml、浓H2SO4 0.2g,搅拌回流反应3h.反应液冷至室温,用2mol/L NaOH水溶液调至PH中性,在冰浴冷却下,向反应混合物中分次加入硼氢化钠1.1g(0.029mol),加毕,冰浴冷却下继续搅拌反应30min, 移去冰浴升至室温,搅拌反应2h.用稀盐酸PH至中性,减压蒸除部分溶剂,剩余物加水15ml稀释,用氯仿(25ml*3)提取,合并有机相,无水MgSO4干燥,过滤,滤液减压回收溶剂,得白色固体1-(2-氯苯基)-1,2-乙二醇 3.64g.收率80.1%,mp99~100 ºC

(2).1-(2-氯苯基)-1,2-乙二醇二甲磺酸酯的制备

在反应瓶中加入1-(2-氯苯基)-1,2-乙二醇二甲磺酸酯13.5g(0.078mol)、无水二氯甲烷150ml、三乙胺18.9g(0.187mol),搅拌下于0~5 ºC 滴加甲磺酰氯19.7g(0.172mol),滴毕,于0~5 ºC

搅拌反应1h.升至室温,继续搅拌反应1h.在冰水浴冷却下,用1mol/L盐酸溶液处理,分出有机层,用饱和NaHCO3水溶液洗,水洗,无水MgSO4干燥,过滤.滤液减压蒸除溶剂,得黏稠油状物,将其溶于乙醚50ml,冰浴冷却下放置3h.析出结晶,抽滤,淡黄色固体1-(2-氯苯基)-1,2-乙二醇二甲磺酸酯 20.9g(经干燥)收率83.7%,mp90~92 ºC

(3) E-(+_)a-[4-(2-氯苯基)]-1,3-二硫戊环-2-亚基]-1H-咪唑基乙腈(兰诺康唑)的合成

在反应瓶中加入粉状KOH(纯度82%)9.0g(0.137mol)和DMSO70ml,搅拌悬浮,冰浴冷却(0 ºC)滴加1-咪唑基乙腈6.1g(0.057mol)、二硫化碳4.4g(0.057mol)和DMSO 30ml混合液,

30min滴完,室温搅拌反应1h.同温下,于30min内向反应液内滴入E-(+_)a-[4-(2-氯苯基)]-1,3-二硫戊环-2-亚基]-1H-咪唑基乙腈 18.8g(0.057mol)与DMSO170ml的混合液,滴毕,续室温搅拌2h.将反应液倒入冰水500ml中,乙酸乙酯(200ml*3)提取,合并有机相,水洗,无水MgSO4干燥,过滤,滤液减压蒸除溶剂,得黏稠油状物,经硅胶柱色谱分离,得黄色固体E-(+_)a-[4-(2-氯苯基)]-1,3-二硫戊环-2-亚基]-1H-咪唑基乙腈 6.36g.收率30.2%,mp142 ºC .

(4).酸催化异构化

上步在色谱分离后同时分离得到(Z)-异构体 5.45g,收率20.5%,mp129~130 ºC .

将(Z)-异构体 0.20g、二氧六环2ml加到盛有8.84mol/L氢溴酸溶液2ml的反应瓶中(25ml容积),于80 ºC 搅拌反应1h.冷至室温,用稀K2CO3水溶液调至PH中性,用乙酸乙酯(10ml*3)提取,有机层用无水MgSO4干燥,过滤,滤液减压蒸除溶剂,得黏稠状油状剩余物,1经硅胶柱色谱分离纯化得1-(2-氯苯基)-1,2-乙二醇二甲磺酸酯 0.08g,收率40%.回收(Z)-异构体 0.07g,回收率35%.