硫利达嗪 | 50-52-2

• 物质功能分类: 原料药 - 神经系统用药 - 抗精神病药
• 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: 硫利达嗪
• 中文别名: 10-[2-(1-甲基-2-哌啶基)乙基]-2-甲硫基-10H-吩噻嗪；硫醚嗪；甲硫达嗪
• 英文名称: thioridazine
• 英文别名: Thioridazin；10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfanylphenothiazine
• CAS: 50-52-2
• 化学式: C₂₁H₂₆N₂S₂
• 分子量: 370.583
• InChiKey: KLBQZWRITKRQQV-UHFFFAOYSA-N

物化性质

• 熔点：
  72-74°
• 沸点：
  bp0.02 230°
• 密度：
  1.1693 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  几乎不溶于水，极易溶于二氯甲烷，易溶于甲醇，溶于乙醇（96%）。
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from acetone
• 气味：
  Faint
• 味道：
  Very bitter
• 蒸汽压力：
  3.69X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：
  STABLE IN MODERATE HEAT ... , DARKENS ON EXPOSURE TO LIGHT /THIORIDAZINE HYDROCHLORIDE/
• 解离常数：
  pKa = 9.5
• 碰撞截面：
  184.9 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  3114;3094;3105;3117;3117;3080;3100;3116;3120;3114;3125;3125.4;3128.8;3092.9;3105;3125;3080;3100;3135;3114;3104.5;3070;3104;3089

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  25
• 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：
  57.1
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

主要代谢物包括环上第5位的磺酰氧基产物（不活跃）或第2位取代基上的产物（包括活性代谢物美索利扎品）。哌啶环的脱甲基反应非常迅速...。

Major metabolites include sulfoxy products at ring position 5 (inactive) or at substituent at position 2 (including active metabolite mesoridazine). Demethylation of piperidine ring is very rapid ... .

来源:Hazardous Substances Data Bank (HSDB)

代谢

尽管吩噻嗪类药物的确切代谢途径尚未明确建立，但这类药物会被广泛代谢，主要在肝脏通过羟基化、氧化、脱甲基、亚砜形成以及与葡萄糖醛酸结合；侧链的代谢改变也可能发生。/吩噻嗪一般声明/

Although the exact metabolic fate of phenothiazines has not been clearly established, the drugs are extensively metabolized, principally in the liver via hydroxylation, oxidation, demethylation, sulfoxide formation, and conjugation with glucuronic acid; metabolic alterations in the side chain also may occur. /Phenothiazine General Statement/

来源:Hazardous Substances Data Bank (HSDB)

代谢

大多数吩噻嗪类药物的代谢物在药理上是无效的；然而，某些代谢物（例如，7-羟基氯丙嗪，美索利嗪）显示出适度的药理活性，并可能对药物的作用有所贡献。有限的证据表明，一些吩噻嗪类药物（例如，氯丙嗪）可能会诱导其自身的代谢。/吩噻嗪类药物一般声明/

Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (eg, 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs. There is limited evidence to indicate that some phenothiazines (eg, chlorpromazine) may induce their own metabolism. /Phenothiazine General Statement/

来源:Hazardous Substances Data Bank (HSDB)

代谢

硫利哒嗪及其代谢物通过一种选择性的高效液相色谱法在五例尸检血液样本中进行了测定；其中两例死亡归因于药物过量，另外三例死亡由于自然原因或创伤。此外，通过一种非特异性的荧光法在这些血液样本和肝脏标本中测定了总硫利哒嗪类似物的含量。血液中硫利哒嗪的浓度为0.78-8.85 mg/L；美索哒嗪的浓度为0.52-26.8 mg/L；硫非哒嗪的浓度为0.00-0.87 mg/L。硫利哒嗪-5-亚磺酸立体异构体DL,LD和DD,LL对的浓度范围分别为0.02-0.56 mg/L和0.03-0.83 mg/L。硫利哒嗪代谢物谱对于区分治疗性给药和严重过量没有帮助。肝脏似乎是评估硫利哒嗪过量的首选标本。

Thioridazine and metabolites were determined by a selective HPLC technique in blood from five post-mortem cases; two deaths attributed to drug overdose and three deaths due to natural causes or trauma. Additionally, total thioridazine-like compounds were determined in these blood samples and liver specimens by a nonspecific fluorometric technique. Blood concentrations were: thioridazine, 0.78-8.85 mg/L; mesoridazine, 0.52-26.8 mg/L; and sulforidazine, 0.00-0.87 mg/L. Thioridazine-5-sulfoxide stereoisomeric DL,LD, and DD,LL pair concentrations ranged from 0.02-0.56 and 0.03-0.83 mg/L, respectively. Thioridazine metabolite profiles were not helpful in differentiating therapeutic administration from severe overdose. Liver appears to be the specimen of choice in the assessment of thioridazine overdose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

硫利达嗪阻断了大脑中的突触后边缘多巴胺能D1和D2受体；阻断了α-肾上腺素能效应，抑制了下丘脑和垂体激素的释放，并且据信它抑制了网状激活系统，从而影响基础代谢率、体温、觉醒状态、血管运动张力和呕吐。

Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

长期使用吩噻嗪类药物的患者中，肝功能测试异常的比例较高，但升高的程度很少超过正常上限的3倍。转氨酶异常通常是轻微的、无症状的，并且是暂时的，即使在继续用药的情况下也会逆转。极少数情况下，由于硫利达嗪导致的临床上明显的急性肝损伤已有报道，有些病例与氯丙嗪黄疸病例相似。黄疸的出现发生在治疗后的几周到几个月内，血清酶升高的模式通常是胆汁淤积型的，尽管也报道了肝细胞型的病例。免疫过敏表现（发热、皮疹和嗜酸性粒细胞增多）并不突出，未检测到自身抗体。一些病例与粒细胞缺乏症有关，这是吩噻嗪类药物罕见但已知的并发症。

Liver test abnormalities have been reported to occur in a high proportion of patients on long term phenothiazine therapy, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to thioridazine, with some resemblance to cases of chlorpromazine jaundice. The onset of jaundice occurred within a few weeks to several months of therapy and the pattern of serum enzyme elevations was typically cholestatic, although hepatocellular patterns have also been reported. Immunoallergic manifestations (fever, rash and eosinophilia) were not prominent and autoantibodies were not detected. Some cases were associated with agranulocytosis which is a rare but known complication of the phenothiazines.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物的名称：硫利达嗪

Compound:thioridazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-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

吸收、分配和排泄

• 吸收

百分之六十

60%

来源:DrugBank

吸收、分配和排泄

动物实验和体外研究表明，硫利达嗪对黑色素颗粒有亲和力，并倾向于在接近葡萄膜色素的地方积累。

Experimental studies in animals and in vitro have demonstrated that thioridazine has affinity for melanin granules and tends to accumulate in close association with uveal pigment ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 药代动力学和代谢 ... 类似于氯丙嗪，但硫利哒嗪对肠道的强烈抗胆碱能作用可能会改变其自身的吸收 ... 。血桨中的硫利哒嗪浓度相对较高（每毫升数百纳克），这可能归因于其相对的水溶性 ... 。

... Pharmacokinetics and metabolism ... similar ... to chlorpromazine, but strong anticholinergic action of thioridazine on the gut may modify its own absorption ... . Concentrations of thioridazine in plasma are relatively high (hundreds of nanograms per milliliter), possibly owing to its relative hydrophilicity ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在48名服用硫氮杂蒽的患者中，平均不与血清蛋白结合的量为0.15%，侧链亚砜的量为1.66%，侧链砜的量为1.17%，环状亚砜的量为1.7%。

In 48 patients taking thiordazine the mean amount not bound to serum proteins was 0.15%, that of the side-chain sulfoxide 1.66%, side-chain sulfone 1.17%, and ring sulfoxide 1.7%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫利哒嗪及其代谢物在通过气液相色谱法测量的大脑、肝脏和肾脏标本中进行了检测，这些标本是从两名因急性硫利哒嗪中毒而死亡的对象的尸检中获得的。尽管在两个案例中测得的硫利哒嗪及其代谢物的绝对浓度不同，但每种组织的代谢模式，以每种组织中总药物百分比的术语表示，却是非常相似的。然而，大脑、肝脏和肾脏的代谢模式与接受硫利哒嗪治疗方案的受试者的血浆代谢物模式形成了鲜明对比。正如这个例子所展示的，尸检标本是人类药理学数据的一个宝贵（但很少使用）来源。

Thioridazine and metabolites were measured in brain, liver, and kidney specimens, obtained postmortem from two subjects whose deaths were related to acute intoxication with thioridazine, by gas-liquid chromatography. Although the absolute concentration measured for thioridazine and metabolites differed in the two cases, the metabolic pattern for each tissue, expressed in terms of the percentage of total drug in each tissue, was quite similar. The brain, liver, and kidney metabolic patterns, however, are in sharp contrast to the plasma metabolite patterns observed for subjects on a therapeutic regimen of thioridazine. As this example demonstrates, postmortem specimens are a valuable (but seldom used) source of human pharmacological data.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  F,T
• 安全说明：
  S16,S36/37,S45,S61
• 危险类别码：
  R11,R23/24/25,R39/23/24/25,R52/53
• WGK Germany：
  1,3
• 海关编码：
  2934302300
• 储存条件：
  本品应密封、避光且在干燥条件下保存。

制备方法与用途

用途

甲硫哒嗪属于酚噻嗪类哌啶族抗精神病药。1958年由德国汉诺威Sandoz药厂合成，并同年用于临床；1988年实现国产化后逐步推广使用。该药物能有效改善精神分裂症患者的幻觉、妄想、思维形式障碍和怪异行为，同时还能改善情感淡漠、焦虑抑郁等阴性症状。研究表明，甲硫哒嗪的抗精神病作用与氯丙嗪相当，同样选择性地作用于中脑边缘多巴胺系统，因此锥体外系副作用较少，病人容易耐受，是临床上常用的药物之一。

应用

作为抗精神病药物，甲硫哒嗪在临床应用过程中的一些副作用应引起注意。安慰剂试验显示，甲硫哒嗪与氯丙嗪、三氟拉嗪的效果一致。它能有效改善精神分裂症患者的幻觉、妄想、思维形式障碍和怪异行为，并能改善情感淡漠、焦虑抑郁等阴性症状。

在儿童的各种精神障碍中，安定是最常用的精神药物之一，其次是甲硫哒嗪；对于老年病人，甲硫哒嗪能有效控制攻击行为，缓解紧张情绪，消除疑虑。此外，它还能有效缓解焦虑症和抑郁症患者的症状。

药理作用

甲硫哒嗪（Thioridazine）是一种酚噻嗪类哌啶族抗精神病药，化学名称为N-(2．(1-甲基.2-.哌啶)乙基)-3-甲硫一酚噻嗪。该药物具有明显的镇静作用，虽然抗幻觉妄想效果不如氯丙嗪，但锥体外系副作用较小，老年人容易耐受，其优点在于作用缓和。

甲硫哒嗪等酚噻嗪类抗精神病药物主要通过阻滞中脑一边缘系统和中脑一皮层系统的多巴胺受体（主要作用于D2样受体）来发挥疗效。长期使用甲硫哒嗪可能会引起锥体外系的副作用，但通常较轻微。此外，该药物还可能产生其他副反应，如口干、鼻塞、嗜睡、便秘、心动过速、视力模糊等常见症状，以及高血脂、高血糖乃至糖尿病等疾病。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  2-溴-10-[2-(1-甲基-2-哌啶基)乙基]-10H-吩噻嗪	NCI186058	60634-41-5	C20H23BrN2S	403.386

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	(R)-thioridazine	——	C21H26N2S2	370.583
  ——	(+)-thioridazine	114488-10-7	C21H26N2S2	370.583
  去甲硫代利达嗪	2-(methylthio)-10-(2-(piperidin-2-yl)ethyl)-10H-phenothiazine	10538-32-6	C20H24N2S2	356.556
  硫利达嗪N-氧化物	N-Oxide thioridazine	103827-30-1	C21H26N2OS2	386.582
  美索哒嗪	mesoridazine	5588-33-0	C21H26N2OS2	386.582
  磺达嗪	sulforidazine	14759-06-9	C21H26N2O2S2	402.582
  硫利达嗪-5-亚砜	Thioridazine 5-sulfoxide	7776-05-8	C21H26N2OS2	386.582
  ——	Thioridazin-disulfoxid	53926-89-9	C21H26N2O2S2	402.582
  ——	10-(2-(1-methylpiperidin-2-yl)ethyl)-10H-phenothiazine-2-carbonitrile	——	C21H23N3S	349.5

反应信息

• 作为反应物：
  描述：

  硫利达嗪 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 以100%的产率得到盐酸硫利达嗪
  参考文献：
  名称：

  [EN] THE (S)-ENANTIOMER OF MEPAZINE
  [FR] (S)-ÉNANTIOMÈRE DE MÉPAZINE

  摘要：

  本发明涉及(S)-美帕嗪，其在治疗中的适用性，包括(S)-美帕嗪的药物组合物，以及(S)-美帕嗪及其一个中间体的制备方法。

  公开号：

  WO2014207067A1
• 作为产物：
  描述：

  2-(2-fluorophenylthio)-5-(methylthio)aniline 在 sodium hydride 作用下， 以 二甲基亚砜 、 xylene 为溶剂， 反应 9.5h， 生成 硫利达嗪
  参考文献：
  名称：

  Sindelar, Karel; Holubek, Jiri; Koruna, Ivan, Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 6, p. 1586 - 1601

  摘要：

  DOI：

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。
• [EN] OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF AS ANTIBACTERIAL AGENTS<br/>[FR] COMPOSÉS OXAZOLIDINONE ET PROCÉDÉS D'UTILISATION DE CES DERNIERS EN TANT QU'AGENTS ANTIBACTÉRIENS
  申请人：MERCK SHARP & DOHME

  公开号：WO2017066964A1

  公开（公告）日：2017-04-27

  The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosiscomprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or apharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.

  本发明涉及式(I)的噁唑烷酮化合物及其药学上可接受的盐，其中A、E和R1如本文所定义。本发明还涉及包含本发明至少一种噁唑烷酮化合物的组合物。该发明还提供了抑制分枝杆菌细胞生长的方法，以及通过给予治疗有效量的本发明的噁唑烷酮和/或其药学上可接受的盐，或包含该化合物和/或盐的组合物来治疗结核分枝杆菌感染的方法。
• 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。

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