二氯尼特 | 579-38-4

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗阿米巴病及抗滴虫病药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 二氯尼特
• 中文别名: 地洛奈特
• 英文名称: diloxanide
• 英文别名: ZINC00001299；2,2-dichloro-N-(4-hydroxyphenyl)-N-methylacetamide
• CAS: 579-38-4
• 化学式: C₉H₉Cl₂NO₂
• 分子量: 234.082
• InChiKey: GZZZSOOGQLOEOB-UHFFFAOYSA-N

物化性质

• 熔点：
  175°
• 沸点：
  356.2±42.0 °C(Predicted)
• 密度：
  1.439±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：33.33（最大浓度 mg/mL）；142.39（最大浓度 mM）
• 保留指数：
  2420

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

水解成呋喃酸和二氯杀螨，后者发生广泛的葡萄糖醛酸化（99%的二氯杀螨以葡萄糖醛酸苷形式存在，1%以游离二氯杀螨在系统循环中）。

Hydrolyzed to furoic acid and diloxanide, which undergoes extensive glucuronidation (99% of diloxanide occurs as glucuronide and 1% as free diloxanide in the systemic circulation).

来源:DrugBank

吸收、分配和排泄

• 吸收

生物利用度为90%（以二氯散剂型计算），然而二氯散糠酸酯从胃肠道吸收较慢。

Bioavailability is 90% (in diloxanide parental form), however diloxanide furoate is slowly absorbed from the gastrointestinal tract.

来源:DrugBank

吸收、分配和排泄

• 消除途径

肾脏（90%，快速以葡萄糖苷酸代谢物形式排泄）。10% 以地洛硝酯形式随粪便排出。

Renal (90%, rapidly excreted as glucuronide metabolite). 10% is excreted in the feces as diloxanide.

来源:DrugBank

制备方法与用途

生物活性

Diloxanide 是一种抗原虫制剂，可用于研究无症状肠道阿米巴病或其他由组织内阿米巴原虫及其他原虫引起的感染。Diloxanide 是一种活性的鲁米那抗阿米巴试剂，在胃肠道中由其前药二氯尼特糠酸酯（HY-B1147）水解产生。

体内研究

Diloxanide 通过口服给药（剂量为 75-200 mg/kg，持续三天，每天一次）从其前药 Diloxyanide furoate 在胃肠道中水解而来。在断乳大鼠实验中，不同剂量的 Diloxyanide furoate 均显示出显著疗效：

• 当剂量为 200 mg/kg 时，所有治疗组的大鼠均被治愈且结肠内未见阿米巴病变。
• 在其他剂量下：
  • 150 mg/kg 的治疗使 85% 的大鼠痊愈；
  • 100 mg/kg 的治疗使 77% 的大鼠痊愈；
  • 75 mg/kg 的治疗使 44.4% 的大鼠痊愈。

该药物在大鼠体内的半数有效剂量（ED50）为 77.9 mg/kg。

反应信息

• 作为反应物：
  描述：

  二氯尼特 、 4-(methylsulfonyl)benzyl bromide 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 α,α-Dichlor-N-methyl-p-(4-methylsulfonyl-benzyloxy)-acetanilid
  参考文献：
  名称：

  269.氨苄青霉素的化学疗法。一些N-取代的二氯乙酰胺

  摘要：

  DOI：

  10.1039/jr9620001420
• 作为产物：
  描述：

  甲醇 、 糠酸二氯尼特 在 phosphate buffer 作用下， 以 乙腈 为溶剂， 生成 糠酸（呋喃甲酸） 、 2-糠酸甲酯 、 二氯尼特
  参考文献：
  名称：

  Stability studies on diloxanide furoate: effect of pH, temperature, gastric and intestinal fluids

  摘要：

  The degradation of the amoebicide diloxanide furoate in alkaline medium at different temperatures was investigated using both a spectrophotometric and a developed HPLC method. In solutions, the drug was found to undergo decomposition, i.e., temperature and pH dependent. The pH-rate profile at pH between 7.6 and 9.6 indicated a first-order dependence of Kobs on [-OH]. Arrhenius plot obtained at pH 8 was linear between 40 and 63 degrees C. The estimated activation energy of hydrolysis was found to be 18.25 kcal degree.mol(-1). The effect of simulated gastric and intestinal fluids on the drug was also investigated. A new thin-layer chromatographic (TLC) procedure for the fractionation of the drug and its alkaline hydrolysis products has been developed and was found to compare favorably with that of the British Pharmacopoeia. Three hydrolysis products of a basic methanolic solution of the drug, namely furoic acid, diloxanide and methylfuroate could be identified by the use of TLC, HPLC, infrared and mass spectrometry.

  DOI：

  10.1016/j.farmac.2003.11.015

文献信息

• [EN] PROGRAMMABLE POLYMERIC DRUGS<br/>[FR] MÉDICAMENTS POLYMÈRES PROGRAMMABLES
  申请人：SONY CORP

  公开号：WO2020210689A1

  公开（公告）日：2020-10-15

  Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, R4, R5, L, L1, L2, M and n are as defined herein. Methods associated with preparation and use of such compounds are also provided.

  披露了作为生物活性化合物有用的化合物。这些化合物具有以下结构（I）：或其立体异构体、互变异构体或盐，其中R1、R2、R3、R4、R5、L、L1、L2、M和n如本文所定义。还提供了与这些化合物的制备和使用相关的方法。
• [EN] TREATMENT OF INFECTIONS<br/>[FR] TRAITEMENT D'INFECTIONS
  申请人：ASCENDIS PHARMA AS

  公开号：WO2020064844A1

  公开（公告）日：2020-04-02

  The present invention relates among other aspects to a conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use in a method of preventing or treating an infection, wherein said conjugate is water-insoluble and comprises a polymeric moiety -Z to which a plurality of moieties -L2-X0D-L1-D are covalently conjugated, wherein each -D is independently an antibiotic moiety; each -L1- is independently a linker moiety to which -D is covalently and reversibly conjugated; each -X0D- is independently absent or a linkage and each -L2- is independently either a chemical bond or a spacer moiety.

  本发明涉及一种共轭物或其药用可接受的盐，或包含所述共轭物或其药用可接受的盐的药物组合物，用于预防或治疗感染的方法，其中所述共轭物不溶于水，包括一个聚合物基团-Z，其中多个基团-L2-X0D-L1-D以共价结合方式共轭，其中每个-D独立地是抗生素基团；每个-L1-独立地是连接基团，与-D以共价和可逆方式结合；每个-X0D-独立地不存在或是一个连接，每个-L2-独立地是化学键或间隔基团。
• [EN] PYRAZOLO [4, 3-D] PYRIMIDINES USEFUL AS KINASE INHIBITORS<br/>[FR] PYRAZOLO[4,3-D]PYRIMIDINES UTILES EN TANT QU'INHIBITEURS DE KINASES
  申请人：ORIGENIS GMBH

  公开号：WO2012143144A1

  公开（公告）日：2012-10-26

  The present invention relates to novel compounds of formula (I) that are capable of inhibiting one or more kinases, especially SYK (Spleen Tyrosine Kinase), LRRK2 (Leucine-rich repeat kinase 2) and/or MYLK (Myosin light chain kinase) or mutants thereof. The compounds find applications in the treatment of a variety of diseases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, alzheimer's disease, parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases.

  本发明涉及一种能够抑制一个或多个激酶，特别是SYK（脾酪氨酸激酶）、LRRK2（富含亮氨酸重复的激酶2）和/或MYLK（肌球蛋白轻链激酶）或其突变体的化合物的新颖化合物（I）的公式。这些化合物在治疗各种疾病中发挥作用。这些疾病包括自身免疫疾病、炎症性疾病、骨疾病、代谢性疾病、神经和神经退行性疾病、癌症、心血管疾病、过敏、哮喘、阿尔茨海默病、帕金森病、皮肤疾病、眼部疾病、传染病和与激素相关的疾病。
• [EN] HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE KINASES
  申请人：ORIGENIS GMBH

  公开号：WO2012143143A1

  公开（公告）日：2012-10-26

  The present invention relates to novel compounds of formula (I) that are capable of inhibiting one or more kinases, especially SYK (Spleen Tyrosine Kinase), LRRK2 (Leucine-rich repeat kinase 2) and/or MYLK (Myosin light chain kinase) or mutants thereof. The compounds find applications in the treatment of a variety of diseases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, alzheimer's disease, parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases.

  本发明涉及一种能够抑制一个或多个激酶，特别是SYK（脾酪氨酸激酶）、LRRK2（富含亮氨酸重复激酶2）和/或MYLK（肌球蛋白轻链激酶）或其突变体的化合物的新颖化合物（I）的公式。这些化合物在治疗各种疾病中发挥作用。这些疾病包括自身免疫疾病、炎症性疾病、骨疾病、代谢性疾病、神经和神经退行性疾病、癌症、心血管疾病、过敏、哮喘、阿尔茨海默病、帕金森病、皮肤疾病、眼部疾病、传染病和与激素相关的疾病。
• Hydroxylated nebivolol metabolites
  申请人：O'Donnell P. John

  公开号：US20070014733A1

  公开（公告）日：2007-01-18

  Hydroxylated nebivolol metabolites increase NO release from human endothelial cell preparations in a concentration dependent fashion following acute administration. In addition, hydroxylated nebivolol metabolites, including but not limited to 4-hydroxy-6,6′difluoro-, 4-hydroxy-5-phenol-6,6′difluoro-, and 4-hydroxy-8-pheno-6,6′difluoro-, have the ability to increase the capacity for NO release in human endothelial cells following chronic administration. This invention provides hydroxylated nebivolol metabolites and compositions comprising nebivolol and/or at least one hydroxylated metabolite of nebivolol and/or at least one additional compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof. In addition, this invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol that is capable of releasing a therapeutically effective amount of nitric oxide to a targeted site affected by the vascular disease. Also, this invention is directed to the treatment and/or prevention of migraine headaches administering at least one hydroxylated metabolite of nebivolol. This invention may also be used in conjunction with or as a single treatment of metabolic syndrome disorders.

  羟基化奈必洛尔代谢物在急性给药后以浓度依赖性方式增加人内皮细胞制剂的一氧化氮释放。此外，羟基化奈必洛尔代谢物，包括但不限于4-羟基-6,6'-二氟代-、4-羟基-5-苯酚-6,6'-二氟代-和4-羟基-8-苯并-6,6'-二氟代-，在慢性给药后能够增加人内皮细胞的一氧化氮释放能力。本发明提供了羟基化奈必洛尔代谢物和包含奈必洛尔和/或至少一种羟基化奈必洛尔代谢物和/或至少一种用于治疗心血管疾病的附加化合物的组合物，以及可药用的盐。此外，本发明还提供了通过给药至少一种能够释放治疗有效量的一氧化氮到受血管疾病影响的靶向部位的羟基化奈必洛尔代谢物来治疗和/或预防血管疾病的方法。本发明还涉及通过给药至少一种羟基化奈必洛尔代谢物来治疗和/或预防偏头痛。本发明还可以与治疗代谢综合征障碍的其他治疗联合使用，或作为单一治疗。

表征谱图