美索哒嗪 | 5588-33-0

• 物质功能分类: 医药中间体 - 杂环化合物 - 哒嗪类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 中文名称: 美索哒嗪
• 中文别名: 甲砜哒嗪；10-[2-(1-甲基哌啶-2-基)乙基]-2-甲基亚砜吩噻嗪
• 英文名称: mesoridazine
• 英文别名: thioridazine 2-sulfoxide；thioridazine；10-[2-(1-methyl-2-piperidyl)ethyl]-2-methylsulphinylphenothiazine；10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfinylphenothiazine
• CAS: 5588-33-0
• 化学式: C₂₁H₂₆N₂OS₂
• 分子量: 386.582
• InChiKey: SLVMESMUVMCQIY-UHFFFAOYSA-N

物化性质

• 熔点：
  128-131 °C
• 沸点：
  570.5±50.0 °C(Predicted)
• 密度：
  1.1234 (rough estimate)
• 溶解度：
  乙腈：微溶； DMSO：加热下微溶；甲醇：微溶
• 物理描述：
  Solid
• 颜色/状态：
  Oily product
• 稳定性/保质期：
  STABLE IN SOLN OF PH 4.0-6.5; SOLN ARE LIGHT-SENSITIVE /BESYLATE/
• 分解：
  When heated to decomposition it emits very toxic fumes of sulfoxides and nitroxides.
• 保留指数：
  3326;3319.2;3326

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  68.1
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

噻嗪二胺-2-亚磺酰亚胺在大鼠体内可能生成噻嗪二胺-2,5-二磺酰亚胺：Zehnder, K等，生物化学药理学，11，535（1962年）。/来自表格/

THIORIDAZINE-2-SULFOXIDE PROBABLY YIELDS THIORIDAZINE-2,5-DISULFOXIDE IN RAT: ZEHNDER, K ET AL, BIOCHEM PHARMAC, 11, 535 (1962). /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

硫利哒嗪-2-亚砜是硫利哒嗪的人类已知代谢物。

Thioridazine 2-sulfoxide is a known human metabolite of Thioridazine.

来源:NORMAN Suspect List Exchange

代谢

半衰期：24至48小时

Half Life: 24 to 48 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

基于动物研究，美索利扎丙，与其他吩噻嗪类药物一样，间接作用于网状结构，从而减少传入网状结构的神经元活动，而不影响其激活大脑皮层的固有功能。此外，吩噻嗪类药物至少部分通过抑制下丘脑中枢来发挥其活性。从神经化学的角度来看，吩噻嗪类药物被认为通过中枢肾上腺素阻断作用来产生效果。

Based upon animal studies, mesoridazine, as with other phenothiazines, acts indirectly on reticular formation, whereby neuronal activity into reticular formation is reduced without affecting its intrinsic ability to activate the cerebral cortex. In addition, the phenothiazines exhibit at least part of their activities through depression of hypothalamic centers. Neurochemically, the phenothiazines are thought to exert their effects by a central adrenergic blocking action.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：美索里嗪

Compound:mesoridazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：5

Severity Grade:5

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

从胃肠道吸收良好。

Well absorbed from the gastrointestinal tract.

来源:DrugBank

吸收、分配和排泄

猴子（10天周期）通过尿液和粪便排出的硫利哒嗪总量为64-76%，美索哒嗪为83-92%（粪便排出量是前者的2-4倍）。后者的较大排出量可能是因为整体组织吸附较少或肠肝循环不那么广泛。

TOTAL URINARY & FECAL EXCRETION BY MONKEYS (10 DAY PERIOD) OF THIORIDAZINE WAS 64-76% & 83-92% FOR MESORIDAZINE (FECAL EXCRETION 2-4 TIMES GREATER). GREATER EXCRETION OF LATTER MAY BE DUE TO LESSER OVERALL TISSUE ADSORPTION OR LESS EXTENSIVE ENTERO-HEPATIC CYCLING.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从消化道吸收良好。作用开始与持续时间及代谢命运...尚未...精确确定/人类，口服，肌肉注射/.在动物研究中，大约2/3的剂量...通过胆汁排入粪便，1/3的剂量...通过尿液排出。/盐酸贝瑟酯/

WELL ABSORBED FROM GI TRACT. ONSET & DURATION OF ACTION & METABOLIC FATE... NOT...PRECISELY DETERMINED /HUMAN, ORAL, IM/. IN ANIMAL STUDIES, APPROX 2/3 OF DOSE...EXCRETED IN FECES VIA BILE & 1/3 OF DOSE...EXCRETED IN URINE. /BESYLATE/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

"吩噻嗪类药物可穿过胎盘屏障，并可能出现在哺乳期母亲的乳汁中...吩噻嗪类药物及其代谢物通过尿液、胆汁和粪便排出。某些代谢物和游离药物在治疗结束后最多6个月内可在尿液中检测到...已停止使用/人类，口服，肌注/"

PHENOTHIAZINES CROSS PLACENTAL BARRIER & MAY APPEAR IN MILK OF NURSING MOTHERS...PHENOTHIAZINES &...METABOLITES...EXCRETED IN URINE, BILE, & FECES. CERTAIN METABOLITES &...FREE DRUGS...DETECTED IN URINE UP TO 6 MO AFTER THERAPY...DISCONTINUED /HUMAN, ORAL, IM/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吩噻嗪类药物...从胃肠道和注射部位吸收良好。通常...在大约3小时内从血浆中清除...分布到大多数身体组织...未改变的药物在脑中浓度高...代谢物在肺、肝、肾脏中占主导地位...脾脏/人类，口服，肌注/

PHENOTHIAZINES...ABSORBED WELL FROM GI TRACT & FROM PARENTERAL SITES. GENERALLY...CLEARED FROM PLASMA WITHIN APPROX 3 HR...DISTRIBUTED TO MOST BODY TISSUES...HIGH CONCN OF UNCHANGED DRUG...IN BRAIN...METABOLITES PREDOMINATE IN LUNG, LIVER, KIDNEYS...SPLEEN /HUMAN, ORAL, IM/

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

TPS-23（HY-B0965A）是噻嗪的代谢物，是一种口服活性的吩噻嗪类抗精神病药物。中瑞他嗪能够有效且迅速地阻断人类乙醚-a-go-go相关基因(hERG)通道，在人类胚胎肾293细胞中以550 nM（0 mV）的IC50值阻断hERG电流。美索里达嗪则可用于研究精神分裂症及其他某些精神疾病。

反应信息

• 作为反应物：
  描述：

  美索哒嗪 在 potassium permanganate 作用下， 以 丙酮 为溶剂， 以52%的产率得到磺达嗪
  参考文献：
  名称：

  硫代哒嗪三种主要代谢物的简便合成

  摘要：

  三大代谢产物的高效，温和的合成2 - 4重要的抗精神病药甲硫哒嗪（共1）已经制定出来。通过在酸性条件下用NaIO 4氧化1制备具有环亚砜部分的心脏毒性代谢物2，产率为96％。四个不同的程序在阐明的选择性侧链硫化物氧化1至美索达嗪（3），产生高达91％的产率。最后，sulforidazine（4）合成通过亚砜的氧化3中任一的KMnO存在4或在基本条件下t -BuOOH。除了用t- BuOOH氧化外，所有反应均在几分钟内在温和条件下进行，可很好地重现，并提供中至高收率的所需产物，可通过柱色谱法轻松纯化。

  DOI：

  10.1002/hlca.200590089
• 作为产物：
  描述：

  硫利达嗪 在 三氯化铝 、 titanium(III) chloride 、 双氧水 作用下， 以 甲醇 为溶剂， 反应 0.08h， 以91%的产率得到美索哒嗪
  参考文献：
  名称：

  硫代哒嗪三种主要代谢物的简便合成

  摘要：

  三大代谢产物的高效，温和的合成2 - 4重要的抗精神病药甲硫哒嗪（共1）已经制定出来。通过在酸性条件下用NaIO 4氧化1制备具有环亚砜部分的心脏毒性代谢物2，产率为96％。四个不同的程序在阐明的选择性侧链硫化物氧化1至美索达嗪（3），产生高达91％的产率。最后，sulforidazine（4）合成通过亚砜的氧化3中任一的KMnO存在4或在基本条件下t -BuOOH。除了用t- BuOOH氧化外，所有反应均在几分钟内在温和条件下进行，可很好地重现，并提供中至高收率的所需产物，可通过柱色谱法轻松纯化。

  DOI：

  10.1002/hlca.200590089

文献信息

• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• [EN] ERK INHIBITORS<br/>[FR] INHIBITEURS D'ERK
  申请人：MERCK SHARP & DOHME

  公开号：WO2016100050A1

  公开（公告）日：2016-06-23

  The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

  本发明提供了一种化合物(I)或其药学上可接受的盐、酯和前药，这些化合物是ERK2抑制剂。该发明还提供了一种包括至少一种化合物(I)和药学上可接受的载体的有效量的药物组合物。该发明还提供了一种包括至少一种化合物(I)的有效量和至少一种其他药学活性成分的有效量（例如，化疗药物等）以及药学上可接受的载体的药物组合物。

表征谱图