氯普噻吨 | 113-59-7

• 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: 氯普噻吨
• 中文别名: 反式-2-氯-9-(3-二甲胺基亚丙基)硫杂蒽；泰尔登；氯丙硫蒽；(Z)N,N-二甲基-3-(2-氯9H-亚噻吨基)-1-丙胺；氯丙硫新；(Z)-N,N-二甲基-3-(2-氯-9H-亚噻吨基)-1-丙胺
• 英文名称: chlorprothixene
• 英文别名: (Z)-2-chloro-9-(3-dimethylaminopropylidene)-thioxanthene；chloroprothixene；taractan；zCPTX；2-chloro-10-(3-dimethylaminopropylidene)thioxanthene；(3Z)-3-(2-chlorothioxanthen-9-ylidene)-N,N-dimethylpropan-1-amine
• CAS: 113-59-7
• 化学式: C₁₈H₁₈ClNS
• 分子量: 315.867
• InChiKey: WSPOMRSOLSGNFJ-AUWJEWJLSA-N

物化性质

• 熔点：
  97-98°
• 沸点：
  160 °C(Press: 0.04 Torr)
• 密度：
  1.1048 (rough estimate)
• 溶解度：
  DMSO：33.33 mg/mL（105.52 mM；需要超声波）H2O：< 0.1 mg/mL（不溶）
• 颜色/状态：
  Pale yellow crystals.
• 气味：
  SLIGHT AMINE-LIKE ODOR
• 稳定性/保质期：
  SENSITIVE TO LIGHT & AIR
• 分解：
  When heated to decomposition it emits toxic fumes of /hydrogen chloride, sulfur oxide, and nitrogen oxide/.
• 碰撞截面：
  169.8 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  28.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

未改变的氯丙嗪、磺酰氧化物衍生物和N-去甲基磺酰氧化物已在接受治疗的狗和老鼠尿液中被发现。羟基化和葡萄糖苷酸化在狗体内也会发生，但尚未完成这些生物转化产物的鉴定。

UNCHANGED CHLORPROTHIXENE, THE SULFOXIDE DERIVATIVE & N-DEMETHYL SULFOXIDE HAVE BEEN IDENTIFIED IN THE URINE OF TREATED DOGS & RATS. HYDROXYLATION & GLUCURONIDATION ALSO OCCUR IN DOGS, BUT IDENTIFICATION OF THOSE BIOTRANSFORMATION PRODUCTS HAS NOT BEEN ACCOMPLISHED.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠中产生去甲基氯普噻嗪。/来自表格/

YIELDS DEMETHYLCHLORPROTHIXENE IN RAT. /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在狗和精神性患者口服给药后，在尿液和粪便中发现了多种3-、7-、4-、6-和8-羟基化代谢物。羟基化之后，这些代谢物与葡萄糖醛酸和/或硫酸结合，以便于排出体外。

FOLLOWING ORAL ADMIN TO DOG & PSYCHIATRIC PT SEVERAL 3-, 7-, 4-, 6-, & 8-HYDROXYLATED METABOLITES FOUND IN URINE & FECES. HYDROXYLATION WAS FOLLOWED BY CONJUGATION WITH GLUCURONIC &/OR SULFURIC ACID FOR EXCRETION.

来源:Hazardous Substances Data Bank (HSDB)

代谢

药物以100毫克/公斤的剂量通过灌胃给予大鼠，随着年龄从3周到24周的增加，药物的代谢速度更快。

DRUG ADMIN TO RATS BY GAVAGE AT 100 MG/KG WAS METABOLIZED MORE RAPIDLY WITH INCR AGE FROM 3-24 WK.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与酒精或产生中枢神经系统抑制的药物、麻醉药、巴比妥类药物和阿片类（麻醉性）止痛药同时使用，可能会增强并延长这些药物或硫杂蒽类药物的中枢神经系统抑制作用；可能需要调整剂量。/硫杂蒽类药物/

Concurrent use with alcohol or CNS depression-producing medications, anesthetics, barbiturates, and opioid (narcotic) analgesics may potentiate and prolong the CNS depressant effects of either these medications or the thioxanthenes; dosage adjustments may be necessary. /Thioxanthenes/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与噻吨类药物同时使用可能会抑制amphetamine的中枢神经系统刺激作用，因为噻吨类药物通过α-肾上腺素能阻滞作用；此外，当噻吨类药物与amphetamine同时使用时，其抗精神病效果可能会降低。/噻吨类药物/

Concurrent use with thioxanthenes may inhibit the CNS-stimulating effects of amphetamines due to alpha-adrenergic blockage by the thioxanthenes; also, the antipsychotic effects of thioxanthenes may be reduced when they are used concurrently with amphetamines. /Thioxanthenes/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用抗酸药或吸附性止泻药可能会抑制口服吩噻嗪类药物的吸收。/吩噻嗪类/

Concurrent use of antacids or adsorbent antidiarrheals may inhibit the absorption of an orally administered thioxanthene. /Thioxanthenes/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

抗胆碱能效应，尤其是混淆、幻觉、噩梦和眼内压升高，当抗胆碱药或其他具有抗胆碱作用的药物、抗运动障碍药或抗组胺药与硫杂蒽类药物同时使用时，可能会因硫杂蒽类药物的次级抗胆碱作用而增强。/硫杂蒽类药物/

Anticholinergic effects, especially confusion, hallucinations, nightmares, and increased intraocular pressure, may be potentiated when anticholinergics or other medications with anticholinergic action, antidyskinetic agents, or antihistamines are used concurrently with thioxanthenes, because of secondary anticholinergic action of thioxanthenes. /Thioxanthenes/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

治疗基本上是对症和支持性的，可能包括以下措施：为了减少吸收 - 早期洗胃通常很有帮助。不要试图诱导呕吐，因为这可能会导致头部和颈部的肌张力障碍反应，可能会导致呕吐物吸入。给予活性炭悬浮液。给予盐水泻药。/硫杂蒽类/

Treatment is essentially symptomatic and supportive and may consist of the following: to decrease absorption - early gastric lavage is often helpful. Not attempting to induce emesis because a dystonic reaction of the head and neck may develop that could result in aspiration of vomitus. Administering activated charcoal slurry. Administering saline cathartic. /Thioxanthenes/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

不完全的生物利用度。

Incomplete bioavailability.

来源:DrugBank

吸收、分配和排泄

药物部分从胃肠道吸收。在静脉注射后，药物在10-30分钟内发挥作用。它被代谢，可能是在肝脏中...游离氯普噻吨及其亚砜代谢物通过尿液和粪便排出。

.../IT/ IS PARTIALLY ABSORBED FROM THE GI TRACT. FOLLOWING IM ADMIN, THE DRUG EXERTS ITS EFFECTS WITHIN 10-30 MINUTES. IT IS METABOLIZED, PRESUMABLY IN THE LIVER...FREE CHLORPROTHIXENE & ITS SULFOXIDE METABOLITE ARE EXCRETED IN THE URINE & FECES.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

三环类药物，氯丙嗪，在体内广泛分布，并且在大约1000升的总体分布容积中趋于达到均衡...

TRICYCLIC AGENT, CHLORPROTHIXENE, IS...EXTENSIVELY DISTRIBUTED IN BODY & HAS OVERALL DISTRIBUTION VOL IN MAN APPROACHING 1000 L...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射后药物动力学遵循两室模型。...总体分布容积非常大。口服给药（15毫克）的生物利用度较差，尽管从肠道吸收化合物似乎很好。

AFTER IV ADMIN PHARMACOKINETICS FOLLOWED 2 COMPARTMENT MODEL. ...TOTAL VOL OF DISTRIBUTION WAS VERY LARGE. AFTER ORAL ADMIN (15 MG) BIOAVAILABILITY WAS POOR, ALTHOUGH ABSORPTION OF CMPD FROM THE GUT APPEARED TO BE GOOD.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

随着大鼠年龄从3周到24周的增长，代谢发生得更快。3周大的大鼠大脑、肝脏、肾脏和肺中的氯丙嗪、N-去甲基氯丙嗪和总胺的水平大约是6周大鼠的两倍。器官中的含量在雌性大鼠中高于雄性大鼠。

METABOLISM OCCURRED MORE RAPIDLY WITH INCR AGE FROM 3-24 WK IN RATS. LEVELS OF CHLORPROTHIXENE, N-DEMETHYLCHLORPROTHIXENE & TOTAL AMINES IN BRAIN, LIVER, KIDNEYS & LUNG OF 3-WK OLD RATS WERE ABOUT TWICE THOSE IN 6-WK OLD RATS. AMT IN ORGANS WERE HIGHER IN FEMALES THAN IN MALES.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2932999099
• WGK Germany：
  1
• 储存条件：
  -20°C

制备方法与用途

作用

本品为硫杂蒽类（噻唑类）抗精神病药，其作用与氯丙嗪相似但较弱。具有安定、镇静、抗抑郁及抗焦虑的作用，且抗胆碱能与抗肾上腺素能作用相对较低。临床上常用于伴有抑郁和焦虑症状的精神分裂症、更年期精神病、情感性精神病、抑郁症以及分裂情感性精神病和焦虑性神经症。对改善焦虑、紧张、抑郁、消极情绪及睡眠障碍效果明显，但对木僵和淡漠等症状疗效不佳。此外，对精神分裂症单纯型和紧张型的效果较差，对抗幻觉和妄想的作用也不如吩噻嗪类药物。另有报道指出，本品还可用于治疗焦虑性神经官能症。

生物活性

Chlorprothixene与多巴胺受体（D1、D2、D3、D5）及组胺受体（H1、5-HT2、5-HT6、5-HT7）具有较强的结合力，Ki值分别为18 nM、2.96 nM、4.56 nM、9 nM、3.75 nM、9.4 nM和3 nM。然而，它对H3受体的亲和力不强，Ki值大于1000 nM。此外，Chlorprothixene还与稳定转染HEK-293细胞的小鼠5-HT6受体以及短暂表达COS-7细胞的小鼠5-HT7受体具有高亲和力，Ki值分别为3 nM和5.6 nM。研究表明，用Chlorprothixene处理Vero 76细胞可抑制SARS-CoV的复制。

体内研究

Clorprothixene作用于大脑，通过抑制突触后中脑缘多巴胺能受体D1和D2以及下丘脑和垂体激素释放来发挥其药理作用。过量使用时，Clorprothixene还会影响肾上腺髓质和大脑的活性，减少iproniazid对Reserpine诱导的儿茶酚胺释放提供的保护，并降低小鼠脑部5-HT、NE（去甲肾上腺素）和DA（多巴胺）。此外，用Clorprothixene处理小鼠支气管上皮细胞时，通过抑制酸性鞘磷脂酶而不是中性鞘磷脂酶，可修复正常神经鞘氨醇浓度，从而降低囊肿性纤维化的小鼠炎症发生，并阻止绿脓杆菌感染。

化学性质

淡黄色结晶性粉末。熔点为97-98℃。不溶于乙醇、乙醚和氯仿。其盐酸盐([6469-93-8])，熔点221℃，可溶于水。

用途

本品是一种硫杂蒽类抗精神病药，虽然其抗精神病作用较氯丙嗪弱，但镇静作用更强。此外，该药物还具有抗抑郁和抗焦虑的作用。适用于治疗抑郁或焦虑型精神分裂症、更年期抑郁症及焦虑性神经官能症等。

生产方法

邻氨基苯甲酸经重氮化、缩合、环合制得母核2-氯硫杂蒽酮，然后与1-氯-3-二甲氨基丙烷加成得到2-氯-9-(3-二甲氨基丙基)-9-羟基硫杂蒽。通过消除反应获得α,β-泰尔登，分离出α-泰尔登后，将回收的β-泰尔登转化成α-泰尔登，合并精制得成品。

反应信息

• 作为反应物：
  描述：

  氯普噻吨 在 水 作用下， 以 乙腈 为溶剂， 生成 氯普噻吨杂质
  参考文献：
  名称：

  Photophysics and Photochemistry ofz-Chlorprothixene in Acetonitrile

  摘要：

  AbstractChlorprothixene (CPTX, Taractan®) is a low potency antipsychotic mainly used for the treatment of psychotic disorders (e.g. schizophrenia) and acute mania occurring as part of bipolar disorders. As in the case of other numerous drugs used in the treatment of psychiatric disorders, CPTX presents geometric isomerism. Therefore, in vitro irradiation induces a rapid Z/E isomerization, which can affect its pharmacokinetic properties. This photoisomerization is not dependent on the oxygen concentration. The Z/E quantum yields determined for zCPTX in acetonitrile are 0.22 and 0.21 in anaerobic and aerobic environments, respectively. In the presence of water, both isomers decompose to produce 2‐chlorothioxanthone (CTX) after prolonged irradiation. This process strongly depends on the water concentration and the irradiation time, i.e. it is autocatalyzed by the CTX through a triplet‐energy transfer mechanism. The protonation state of the terminal amino group, on the other hand, has no effect on the isomerization process, but inhibits the formation of CTX. These results indicate that the phototoxicity of zCPTX is somehow affected by the formation of CTX.

  DOI：

  10.1111/j.1751-1097.2009.00584.x
• 作为产物：
  描述：

  盐酸氯普噻吨 在 sodium hydroxide 作用下， 以 水 为溶剂， 生成 氯普噻吨
  参考文献：
  名称：

  Photophysics and Photochemistry ofz-Chlorprothixene in Acetonitrile

  摘要：

  AbstractChlorprothixene (CPTX, Taractan®) is a low potency antipsychotic mainly used for the treatment of psychotic disorders (e.g. schizophrenia) and acute mania occurring as part of bipolar disorders. As in the case of other numerous drugs used in the treatment of psychiatric disorders, CPTX presents geometric isomerism. Therefore, in vitro irradiation induces a rapid Z/E isomerization, which can affect its pharmacokinetic properties. This photoisomerization is not dependent on the oxygen concentration. The Z/E quantum yields determined for zCPTX in acetonitrile are 0.22 and 0.21 in anaerobic and aerobic environments, respectively. In the presence of water, both isomers decompose to produce 2‐chlorothioxanthone (CTX) after prolonged irradiation. This process strongly depends on the water concentration and the irradiation time, i.e. it is autocatalyzed by the CTX through a triplet‐energy transfer mechanism. The protonation state of the terminal amino group, on the other hand, has no effect on the isomerization process, but inhibits the formation of CTX. These results indicate that the phototoxicity of zCPTX is somehow affected by the formation of CTX.

  DOI：

  10.1111/j.1751-1097.2009.00584.x

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] ISOTOPE ENHANCED AMBROXOL FOR LONG LASTING AUTOPHAGY INDUCTION<br/>[FR] AMBROXOL À ISOTOPE AMÉLIORÉ POUR INDUCTION D'AUTOPHAGIE DURABLE
  申请人：STC UNM

  公开号：WO2018148113A1

  公开（公告）日：2018-08-16

  The present invention is directed to 13C and/or 2H isotope enhanced ambroxol ("isotope enhanced ambroxol") and its use in the treatment of autophagy infections, especially mycobacterial and other infections, disease states and/or conditions of the lung, such as tuberculosis, especially including drug resistant and multiple drag resistant tuberculosis. Pharmaceutical compositions comprising isotope enhanced amhroxol, alone or in combination with an additional bioactive agent, especially rifamycin antibiotics, including an additional autophagy modulator (an agent which is active to promote or inhibit autophagy), thus being useful against, an autophagy mediated disease state and/or condition), especially an antophagy mediated disease state and/or condition which occurs in the lungs, for example, a Mycobacterium infection. Chronic Obstructive Pulmonary Disease (COPD), asthma, pulmonary fibrosis, cystic fibrosis, Sjogren's disease and lung cancer (small cell and non-small cell lung cancer, among other disease states and/or conditions, especially of the lung. Methods of treating autophagy disease states and/or conditions, especially including autophagy disease states or conditions which occur principally in the lungs of a patient represent a further embodiment of the present invention. An additional embodiment includes methods of synthesizing compounds according to the present invention as otherwise disclosed herein.

  本发明涉及13C和/或2H同位素增强的氨溴索（“同位素增强的氨溴索”）及其在治疗自噬感染，特别是结核分枝杆菌和其他感染、疾病状态和/或肺部疾病条件中的用途，如肺结核，特别是包括耐药和多重耐药结核病。包括同位素增强的氨溴索的药物组合物，单独或与额外的生物活性剂（特别是利福霉素类抗生素，包括额外的自噬调节剂（一种能够促进或抑制自噬的剂），因此对抗自噬介导的疾病状态和/或条件有用），特别是在肺部发生的自噬介导的疾病状态和/或条件，例如分枝杆菌感染。慢性阻塞性肺病（COPD）、哮喘、肺纤维化、囊性纤维化、干燥综合征和肺癌（小细胞和非小细胞肺癌等其他肺部疾病状态和/或条件，特别是肺部疾病状态和/或条件。治疗自噬疾病状态和/或条件的方法，特别包括治疗主要发生在患者肺部的自噬疾病状态或条件的方法，代表本发明的另一实施例。另一实施例包括根据本发明在此披露的其他方法合成化合物的方法。
• [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。