(E)-N,N-二甲基-9-[3-(4-甲基-1-哌嗪基)亚丙基]-9H-硫蒽-2-磺酰胺 | 3313-27-7

• 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: (E)-N,N-二甲基-9-[3-(4-甲基-1-哌嗪基)亚丙基]-9H-硫蒽-2-磺酰胺
• 中文别名: E-替沃噻吨；反式-氨砜噻吨
• 英文名称: thiothixene
• 英文别名: (E)-Thiothixene；(9E)-N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]thioxanthene-2-sulfonamide
• CAS: 3313-27-7
• 化学式: C₂₃H₂₉N₃O₂S₂
• 分子量: 443.634
• InChiKey: GFBKORZTTCHDGY-UFWORHAWSA-N

物化性质

• 熔点：
  138-142°C
• 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（轻微）、DMSO（轻微、加热）、乙酸乙酯（轻微）
• 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)
• 分解：
  When heated to decomposition it emits very toxic fumes of /sulfur oxides and nitrogen oxides/.

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

塞克斯丁在肝脏中代谢，并主要通过胆汁消除以原药形式和作为去甲基、亚砜、去甲基亚砜以及羟基化的塞克斯丁衍生物在粪便中排出。

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

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：由于没有关于在母乳喂养期间使用硫替噻嗪的已发表经验，因此首选其他抗精神病药物。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：硫替噻嗪已引起乳汁分泌过多。高催乳素血症似乎是乳汁分泌过多的原因。这种高催乳素血症是由药物在结节-漏斗通路中的多巴胺阻断作用引起的。已建立泌乳的母亲体内的催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Because there is no published experience with thiothixene during breastfeeding, other antipsychotic agents are preferred. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Thiothixene has caused galactorrhea. Hyperprolactinemia appears to be the cause of the galactorrhea. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

肝微粒体酶诱导剂，如卡马西平，被发现能显著增加硫替派的清除率。接受这些药物的病人应观察硫替派疗效降低的迹象。

Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在这项研究中，健康的志愿者接受了噻替辛的给药，并且在给予噻替辛之前三天进行了帕罗西汀的预处理，以确定帕罗西汀是否降低了噻替辛的清除率。十名健康的、未使用药物的志愿者（4名女性和6名男性，平均年龄38±12岁）被随机分配在两个不同的场合接受单次20毫克口服噻替辛。在其中一次给药时，噻替辛在帕罗西汀（每天20毫克）预处理三天后同时给予。在另一次给药时，噻替辛在没有帕罗西汀预处理的情况下给予。两次研究日之间至少间隔2周。在两个研究日，噻替辛给药后，在接下来的72小时内收集10毫升血液样本。噻替辛的任何药代动力学参数都没有因为帕罗西汀三天的治疗而显著改变。可能是CYP2D6同工酶对噻替辛清除率的高比例不负责，但不能排除较长时间的帕罗西汀预处理可能会引起一些对噻替辛清除的抑制作用。

In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 +/- 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre-treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 mL blood samples were collected over the next 72 hr. None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thiothixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

硫替噻嗪可能会增加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的作用，或者与之有加和作用。

Thiothixene may be additive with or may potentiate the action of other CNS depressants (including alcohol), anticholinergics, or hypotensive agents.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在42名患者中测量了59个血浆硫喷妥钠浓度，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喷妥钠清除率的影响。当根据合并用药将患者分组（即，无相互作用药物、酶/清除诱导剂和酶/清除抑制剂）时，发现诱导剂（如抗惊厥药）显著增加了硫喷妥钠的清除率，而清除抑制剂（如西咪替丁）则降低了清除率。在无相互作用和抑制剂组中，吸烟显著增加了硫喷妥钠的肝脏清除率，但在诱导剂组中则不然。诱导剂组中有显著更多的患者血浆中硫喷妥钠浓度不可检测，与其他组相比。当整个患者群体按年龄二分时，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50岁的患者（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）。在监测血浆硫喷妥钠浓度时考虑这些药代动力学变异性的潜在来源，可能实现更适当的硫喷妥钠剂量。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

塞替派辛从胃肠道吸收良好。在口服给药后，治疗反应可能在几天到几周内出现。用于治疗效果所需的血浆浓度尚不清楚。

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

• WGK Germany：
  3

反应信息

• 作为产物：
  描述：

  sodium hydroxide 、 替沃噻吨 、 二氯甲烷 在 二氯甲烷 、 Sodium sulfate-III 、 乙腈 作用下， 以 水 为溶剂， 生成 (E)-N,N-二甲基-9-[3-(4-甲基-1-哌嗪基)亚丙基]-9H-硫蒽-2-磺酰胺
  参考文献：
  名称：

  Conversion of trans- to

  摘要：

  Trans-N,N-二甲基-9-[3-(4-甲基-1-哌嗪基)丙烯基]-噻吩-2-磺酰胺通过在极性有机溶剂中与强碱接触，使其异构化为顺式异构体。通过使用一个溶解度明显小于顺式异构体的有机溶剂，可以从该溶剂中选择性地沉淀出顺式异构体，从而有利于在上清液中进一步异构化为顺式异构体，并分离出来。

  公开号：

  US04107430A1

文献信息

• Methods of using and compositions comprising sibutramine metabolites optionally in combination with other pharmacologically active compounds
  申请人：——

  公开号：US20020010198A1

  公开（公告）日：2002-01-24

  Methods are disclosed for the treatment and prevention of disorders and conditions such as, but are not limited to: eating disorders; weight gain; obesity; irritable bowel syndrome; obsessive-compulsive disorders; platelet adhesion; apnea; affective disorders such as attention deficit disorders, depression, and anxiety; male and female sexual function disorders; restless leg syndrome; osteoarthritis; substance abuse including nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic neuropathy, and chronic pain; migraines; cerebral function disorders; chronic disorders such as premenstrual syndrome; and incontinence. Pharmaceutical compositions and dosage forms are also disclosed which comprise a racemic or optically pure sibutramine metabolite and an optional additional pharmacologically active compound.

  本发明揭示了治疗和预防多种疾病和症状的方法，包括但不限于：进食障碍；体重增加；肥胖症；肠易激综合征；强迫症；血小板粘附；呼吸暂停；情感障碍，如注意力缺陷障碍、抑郁症和焦虑症；男性和女性性功能障碍；不宁腿综合征；骨关节炎；物质滥用，包括尼古丁和可卡因成瘾；嗜睡症；疼痛，如神经病性疼痛、糖尿病神经病变和慢性疼痛；偏头痛；脑功能障碍；经前综合症和失禁。此外，还揭示了包含外消旋或光学纯度西布曲明代谢物和可选的其他药理活性化合物的制药组合物和剂型。
• [EN] METHODS OF USING AND COMPOSITIONS COMPRISING DOPAMINE REUPTAKE INHIBITORS<br/>[FR] PROCEDES D'UTILISATION D'INHIBITEURS DE RECAPTAGE DE LA DOPAMINE ET COMPOSITIONS CONTENANT CES DERNIERS
  申请人：SEPRACOR INC

  公开号：WO2000010551A2

  公开（公告）日：2000-03-02

  Methods are disclosed for the treatment and prevention of disorders and conditions including, but are not limited to, erectile dysfunction, affective disorders, weight gain, cerebral functional disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence. The methods comprise the administration of a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Pharmaceutical compositions and dosage forms are also disclosed that comprise a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Preferred dopamine reuptake inhibitors are racemic or optically pure sibutramine metabolites like desmethylsibutramine and didesmethylsibutramine and pharmaceutically acceptable salts, solvates, and clathrates thereof. Preferred additional pharmacologically active compounds include drugs that affect the central nervous system, such as 5-HT3, antagonists.

  本发明涉及治疗和预防多种疾病和症状的方法，包括但不限于勃起功能障碍、情感障碍、体重增加、脑功能障碍、疼痛、强迫症、物质滥用、慢性疾病、焦虑、进食障碍、偏头痛和失禁。该方法包括给予多巴胺再摄取抑制剂和可选的其他药理活性化合物。还公开了包含多巴胺再摄取抑制剂和可选的其他药理活性化合物的制药组合物和剂型。优选的多巴胺再摄取抑制剂是外消旋或光学纯的西布曲明代谢物，如去甲基西布曲明和二去甲基西布曲明及其药学上可接受的盐、溶剂和包合物。优选的其他药理活性化合物包括影响中枢神经系统的药物，如5-HT3拮抗剂。
• Compositions comprising dopamine reuptake inhibitors and methods of making and using the same
  申请人：Sepracor Inc.

  公开号：US20020183281A1

  公开（公告）日：2002-12-05

  Methods of making and using racemic and optically pure metabolites of sibutramine, and pharmaceutically acceptable salts, solvates, and clathrates thereof, are disclosed. Pharmaceutical compositions and dosage forms are also disclosed which comprise a dopamine reuptake inhibitor, such as a racemic or optically pure sibutramine metabolite, and optionally an additional pharmacologically active compound.

  本发明揭示了制备和使用西布曲明的外消旋体和光学纯异构体代谢物以及其药学上可接受的盐、溶剂合物和包合物的方法。同时还揭示了制备药物组合物和剂型的方法，其中包括多巴胺再摄取抑制剂，例如外消旋体或光学纯的西布曲明代谢物，以及可选的另一种药理活性化合物。
• Methods of treating or preventing restless leg syndrome using sibutramine metabolites
  申请人：——

  公开号：US20040067957A1

  公开（公告）日：2004-04-08

  Methods are disclosed for the treatment and prevention of disorders and conditions such as, but are not limited to: eating disorders; weight gain; obesity; irritable bowel syndrome; obsessive-compulsive disorders; platelet adhesion; apnea; affective disorders such as attention deficit disorders, depression, and anxiety; male and female sexual function disorders; restless leg syndrome; osteoarthritis; substance abuse including nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic neuropathy, and chronic pain; migraines; cerebral function disorders; chronic disorders such as premenstrual syndrome; and incontinence. Pharmaceutical compositions and dosage forms are also disclosed which comprise a racemic or optically pure sibutramine metabolite and an optional additional pharmacologically active compound.

  本发明公开了一种治疗和预防多种疾病和症状的方法，包括但不限于：进食障碍、体重增加、肥胖、肠易激综合征、强迫症、血小板粘附、呼吸暂停、注意力缺陷障碍、抑郁症和焦虑症、男女性功能障碍、不宁腿综合征、骨关节炎、物质滥用，包括尼古丁和可卡因成瘾、嗜睡症、神经性疼痛、糖尿病性神经病和慢性疼痛、偏头痛、脑功能障碍、经前综合症和失禁。本发明还公开了含有外消旋或光学纯度西布曲明代谢物和可选的其他药理活性化合物的制药组合物和剂型。
• Methods of treating or preventing weight gain, obesity, and related disorders
  申请人：Sepracor Inc.

  公开号：US20020188029A1

  公开（公告）日：2002-12-12

  Methods are disclosed for the treatment and prevention of disorders and conditions including, but are not limited to, erectile dysfunction, affective disorders, weight gain, cerebral functional disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence. The methods comprise the administration of a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Pharmaceutical compositions and dosage forms are also disclosed that comprise a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Preferred dopamine reuptake inhibitors are racemic or optically pure sibutramine metabolites and pharmaceutically acceptable salts, solvates, and clathrates thereof. Preferred additional pharmacologically active compounds include drugs that affect the central nervous system, such as 5-HT 3 antagonists.

  本发明揭示了用于治疗和预防多种疾病和症状的方法，包括但不限于勃起功能障碍、情感障碍、体重增加、脑功能障碍、疼痛、强迫症障碍、物质滥用、慢性疾病、焦虑、进食障碍、偏头痛和失禁。该方法包括给予多巴胺再摄取抑制剂和可选的其他药理活性化合物。本发明还揭示了包含多巴胺再摄取抑制剂和可选的其他药理活性化合物的制药组合物和剂型。优选的多巴胺再摄取抑制剂是外消旋或光学纯的西布曲明代谢物及其药学上可接受的盐、溶剂和包合物。优选的其他药理活性化合物包括影响中枢神经系统的药物，如5-HT3拮抗剂。