替沃噻吨 | 3313-26-6

• 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 - 苯并噻喃类
• 中文名称: 替沃噻吨
• 中文别名: N,N-二甲基-9-[3-(4-甲基-1-哌)亚丙基]噻吨-2-磺酰胺；N，N-二甲基-9-[3-(4-甲基-1-哌)亚丙基]噻吨-2-磺酰胺
• 英文名称: Thiothixene
• 英文别名: (9Z)-N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]thioxanthene-2-sulfonamide
• CAS: 3313-26-6
• 化学式: C₂₃H₂₉N₃O₂S₂
• 分子量: 443.6
• InChiKey: GFBKORZTTCHDGY-UWVJOHFNSA-N

物化性质

• 熔点：
  147～152℃
• 沸点：
  599.0±60.0 °C(Predicted)
• 密度：
  1.269±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  White to tan crystals cis-, trans- mixture)
• 气味：
  Practically odorless
• 味道：
  Has very bitter taste
• 蒸汽压力：
  2.56X10-12 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 3.70X10-16 atm-cu m/mol at 25 °C (est)
• 分解：
  When heated to decomposition it emits very toxic fumes of /sulfur oxides and nitrogen oxides/.
• 碰撞截面：
  201.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 稳定性/保质期：
  在常温常压下，该物质保持稳定。

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  77.5
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

硫替噻嗪在肝脏中代谢，并主要通过胆汁消除，以未改变的药物形式和作为去甲基、亚砜、去甲基亚砜以及羟基化的硫替噻嗪衍生物的形式主要在粪便中排出。

Thiothixene is metabolized in the liver and is excreted mainly in feces via biliary elimination as unchanged drug and as the demethyl, sulfoxide, demethylated sulfoxide, and hydroxylated thiothixene derivatives.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：硫替噻嗪是一种固体。它是一种抗精神病药和 dopamine 拮抗剂。硫替噻嗪胶囊在治疗精神分裂症方面是有效的。人体研究：迟发性运动障碍，一种可能不可逆转的、非自愿的、运动障碍的综合症，可能在服用抗精神病药物（包括硫替噻嗪）的患者中发展。有时被称为神经阻滞剂恶性综合症（NMS）的一种可能致命的症状综合体与抗精神病药物（包括硫替噻嗪）有关。NMS的临床表现包括高热、肌肉僵硬、精神状态改变和自主神经系统不稳定的证据（不规则脉搏或血压、心动过速、出汗过多和心脏节律失常）。过量的表现包括肌肉抽搐、嗜睡和眩晕。大量过量的症状可能包括中枢神经系统抑制、僵硬、虚弱、斜颈、震颤、流涎、吞咽困难、低血压、步态障碍或昏迷。患有与痴呆相关的精神病的老年患者使用抗精神病药物时，死亡风险增加。硫替噻嗪可能会增加或增强其他中枢神经系统抑制剂（包括酒精）、抗胆碱能药物或降压药物的作用。动物研究：在硫替噻嗪的动物生殖研究中，大鼠和家兔的受孕率和产仔数有所下降，吸收率有所上升。在给大鼠（5至15 mg/kg/天）、家兔（3至50 mg/kg/天）和猴子（1至3 mg/kg/天）在妊娠前和妊娠期间反复口服硫替噻嗪后，未观察到致畸作用。

IDENTIFICATION AND USE: Thiothixene is a solid. It is antipsychotic agent and dopamine antagonist. Thiothixene capsules are effective in the management of schizophrenia. HUMAN STUDIES: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Manifestations of overdose include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Thiothixene may be additive with or may potentiate the action of other CNS depressants (including alcohol), anticholinergics, or hypotensive agents. ANIMAL STUDIES: In animal reproduction studies with thiothixene, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. After repeated oral administration of thiothixene to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物的名称：硫替噻嗪

Compound:thiothixene

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：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

在42名患者中测量了59次血浆硫噻嗪浓度，作为常规治疗药物监测的一部分。数据收集包括合并用药、吸烟史和人口统计学变量。进行回顾性分析，以评估这些参数对口服硫噻嗪清除率的影响。当患者按合并用药分类（即无相互作用药物、酶/清除诱导剂和酶/清除抑制剂）时，发现硫噻嗪的清除率会被酶诱导药物（例如，抗惊厥药）显著增加，而被清除抑制剂（例如，西咪替丁）降低。在无相互作用和抑制剂组中，吸烟显著增加了硫噻嗪的肝脏清除率，但在诱导剂组中则不然。诱导剂组中显著更多的患者血浆硫噻嗪浓度无法检测到，与其他组相比。当整个患者群体按年龄二等分时，50岁以下的患者的平均清除率（48.2 +/- 37.8升/分钟）显著高于等于或大于50岁者（20.0 +/- 12.6升/分钟）。在这个队列中，男性的清除率（49.2 +/- 38.7升/分钟）显著高于女性（22.0 +/- 13.5升/分钟）。在监测血浆硫噻嗪浓度时考虑这些药代动力学变异性的潜在来源，可以实现更适当的硫噻嗪剂量调整。需要受控的前瞻性研究来验证这些发现。

Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫替噻嗪在体内分布广泛，给药后可能在体内停留数周。

Thiothixene is widely distributed into body tissues and may remain in the body for several weeks following administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Thiothixene is well absorbed from the GI tract. Therapeutic response may occur within a few days to several weeks following oral administration of the drug. Plasma concentrations required for therapeutic effects are not known. 硫噻嗪从胃肠道吸收良好。口服给药后，治疗反应可能在几天到几周内出现。治疗所需血浆浓度尚不清楚。

Thiothixene is well absorbed from the GI tract. Therapeutic response may occur within a few days to several weeks following oral administration of the drug. Plasma concentrations required for therapeutic effects are not known.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两项实验报告了急性单次测试剂量的硫噻嗪（Navane）与年龄的相关性。在第一项研究中，28名男性受试者服用了20毫克口服剂量，并在2小时后抽取了血清。平均年龄为30岁，血清水平与年龄的相关性为0.43，P小于0.02。在第二项年龄较大的组别中，平均年龄为41岁，25名受试者服用了10毫克口服剂量。与年龄的相关性为0.41，P小于0.05。在之前的研究中，这样的急性水平被发现与稳态血清水平和药物的临床反应相关。...

Two experiments are reported in which acute single test dose levels of thiothixene (Navane) were correlated with age. In the first study 20 mg oral doses were given to 28 male subjects and serum levels were drawn 2 hr later. Mean age was 30 and correlation of serum level with age was 0.43, P less than 0.02. In a second older group with a mean age of 41, 10 mg oral doses were given to 25 subjects. A correlation with age of 0.41, P less than 0.05 was obtained with age. In prior work such acute levels have been found to correlate with steady-state serum levels and with clinical response to the medication. ...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• 海关编码：
  2935904000
• RTECS号：
  XO1400000
• WGK Germany：
  2

制备方法与用途

替沃噻吨(Tiotixene)概述

替沃噻吨(Tiotixene)是一种具有硫杂蒽结构的抗精神痛药物，在国外已较为广泛应用于慢性精神分裂症患者的治疗。国内由上海第一制药厂试制成功，尚未用于临床。该药囊剂在家兔进行的动力学研究已经报道。

用途

替沃噻吨具有较强的抗精神病作用，适用于急慢性精神病中的淡漠、孤独及主动性减退等症状；也可用于焦虑症的治疗。替沃噻吨抗幻觉和妄想的作用较弱，无镇静催眠效果。对于慢性精神分裂症的行为退缩、主动性的降低以及情感淡漠有振奋效果。此外，它对情感性精神病的躁动或抑郁状态、急性精神分裂症中的幻觉与妄想也有疗效，并且比氯普噻吨更为有效。

药理作用

替沃噻吨是一种具有哌嗪侧链的噻吨类药物，其作用类似于氯丙嗪。虽然它的镇静效果较弱，但抗精神病作用更强，并具备抗焦虑和抗抑郁的效果。替沃噻吨的疗效优于氯普噻吨。

药代动力学

口服吸收良好，1～3小时可达血药峰值。半衰期(t1/2)为34小时。单剂量服用后24小时内仍保持较高血药浓度。8周用药后血药浓度下降较快，但仍然保持良好的量效关系，因此建议每天一次给药。

生物活性

(Z)-替沃噻吨是5-羟色胺受体的拮抗剂，来源于专利 US 20150141345 A1。

靶点

serotonin

体外研究

(Z)-替沃噻吨能够促进细胞存活和/或塑形，并在有毒物质作用下抑制细胞死亡，特别是在神经元细胞中表现出明显效果。它是一种(Z)-（顺式）异构体的替沃噻吨，同时也是合成前体和降解产物。

反应信息

• 作为反应物：
  描述：

  2-碘酰苯甲酸 、 替沃噻吨 生成 (9E)-N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]-10,10-dioxothioxanthene-2-sulfonamide
  参考文献：
  名称：

  EL-BRASHY, A. M., TALANTA, 37,(1990) N1, C. 1087-1090

  摘要：

  DOI：

文献信息

• [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] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：UNIV EMORY

  公开号：WO2013181135A1

  公开（公告）日：2013-12-05

  The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

  该披露涉及喹唑啉衍生物、组合物以及相关方法。在某些实施例中，该披露涉及NADPH-氧化酶（Nox酶）和/或髓过氧化物酶的抑制剂。
• [EN] COMT INHIBITING METHODS AND COMPOSITIONS<br/>[FR] PROCÉDÉS D'INHIBITION DE LA COMT ET COMPOSITIONS ASSOCIÉES
  申请人：LIEBER INST FOR BRAIN DEV

  公开号：WO2016123576A1

  公开（公告）日：2016-08-04

  The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.

  这些发明包括一种抑制受试者中COMT酶的方法，以及式I的化合物或其药用可接受盐，这些化合物在治疗由COMT介导的各种疾病中有用，包括帕金森病和/或精神分裂症。

表征谱图