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氯丙嗪 | 34468-21-8

中文名称
氯丙嗪
中文别名
3-(2-氯-10H-吩噻嗪-10-基)-N,N-二甲基丙-1-胺
英文名称
2-chloro-N,N-dimethyl-10H-phenothiazine-10-propanamine
英文别名
chlorpromazin;chlorpromazine;CPZ;chloropromazine;CHL;3-(2-chlorophenothiazin-10-yl)-N,N-dimethylpropan-1-amine
氯丙嗪化学式
CAS
34468-21-8;50-53-3
化学式
C17H19ClN2S
mdl
MFCD00133295
分子量
318.87
InChiKey
ZPEIMTDSQAKGNT-UHFFFAOYSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

物化性质

  • 熔点:
    56.5°C
  • 沸点:
    bp0.8 200-205°
  • 密度:
    1.1644 (rough estimate)
  • 溶解度:
    可溶于氯仿(少许)、甲醇(少许)
  • 物理描述:
    Solid
  • 颜色/状态:
    Oily liquid
  • 气味:
    Amine odor
  • 蒸汽压力:
    5.17X10-6 mm Hg at 25 °C (est)
  • 水溶性:
    -5.01
  • 稳定性/保质期:

    Chlorpromazine and its hydrochloride salt darken on prolonged exposure to light. Commercially available preparations of chlorpromazine and its hydrochloride salt should be protected from light.

  • 分解:
    When heated to decomposition it emits very toxic fumes of /hydrogen chloride/, nitroxides, and sulfoxides.
  • Caco2细胞的药物渗透性:
    -4.7
  • 解离常数:
    pKa = 9.3
  • 碰撞截面:
    170.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
  • 保留指数:
    2525;2443;2480;2474;2481;2474;2452;2490;2479;2526;2499;2540;2525;2486;2487;2480.1;2484;2490.2;2504;2480;2486;2440;2452;2474;2480;2481;2500;2480;2490;2486;2514.4;2440;2515;2538;2490;2490;2449.5

计算性质

  • 辛醇/水分配系数(LogP):
    5.2
  • 重原子数:
    21
  • 可旋转键数:
    4
  • 环数:
    3.0
  • sp3杂化的碳原子比例:
    0.29
  • 拓扑面积:
    31.8
  • 氢给体数:
    0
  • 氢受体数:
    3

ADMET

代谢
在肝脏和肾脏中广泛代谢。它主要通过细胞色素P450同工酶CYP2D6(主要途径)、CYP1A2和CYP3A4进行广泛代谢。已经识别出大约10到12种主要代谢物。吩噻嗪核和N-二甲氨基丙基侧链在3位和7位发生羟基化,并发生去甲基化,也代谢成N-氧化物。在尿液中,20%的氯丙嗪及其代谢物以未结合的形式作为未改变的药物、脱甲基氯丙嗪、脱二甲氨基氯丙嗪、它们的亚砜代谢物和氯丙嗪-N-氧化物排出。其余80%由结合代谢物组成,主要是O-葡萄糖苷酸和少量醚硫酸盐的单羟基和二羟基衍生物氯丙嗪及其亚砜代谢物。主要代谢物是N-脱二甲氨基氯丙嗪的单葡萄糖苷酸和7-羟基氯丙嗪。大约37%的氯丙嗪给药量通过尿液排出。
Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine.
来源:DrugBank
代谢
尽管氯丙嗪的确切代谢命运尚未明确建立,但该药物在肝脏和肾脏中广泛代谢。已经鉴定出在人体内以可观数量出现的约10-12种代谢物。除了在吩噻嗪核的3号和7号位置发生羟基化外,氯丙嗪的N-二甲基基丙基侧链还发生去甲基化,并且也被代谢成N-氧化物。尿液中发现了两种主要的代谢物群。未结合部分,占尿液中排出的氯丙嗪及其代谢物的大约20%,包括未改变的药物、去甲氯丙嗪、去二甲氯丙嗪、它们的亚砜代谢物和氯丙嗪-N-氧化物。结合部分,占尿液中排出的氯丙嗪及其代谢物的大约80%,主要是由O-葡萄糖苷酸组成,其中含有少量氯丙嗪及其亚砜代谢物的单羟基和双羟基衍生物的醚硫酸盐。尿液中发现的主要代谢物是N-去二甲氯丙嗪的单葡萄糖苷酸和7-羟基氯丙嗪
Although the exact metabolic fate of chlorpromazine is not clearly established, the drug is extensively metabolized, principally in the liver and kidneys. About 10-12 metabolites which occur in humans in appreciable quantities have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is also metabolized to an N-oxide. Two principal groups of metabolites have been found in urine. The unconjugated fraction, which represents approximately 20% of chlorpromazine and its metabolites excreted in urine, consists of unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The conjugated fraction, which represents approximately 80% of chlorpromazine and its metabolites excreted in urine, consists principally of O-glucuronides, with small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites found in urine are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine.
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
在人中产生2-氯吩噻嗪;可能在狗和人体中产生丙嗪……。在人、大鼠、家兔、小鼠、狗、绵羊、豚鼠中产生去甲基氯丙嗪……。在人、大鼠、家兔、狗中产生氯丙嗪亚砜……。在人、大鼠、家兔、狗、猪、绵羊、豚鼠、小鼠中产生氯丙嗪-N-氧化物……。在人、大鼠、狗中产生3-羟基氯丙嗪……。在人、大鼠、绵羊、狗、家兔、豚鼠中产生7-羟基氯丙嗪……。/来自表格/
Yields 2-chlorophenothiazine in man; promazine probably in dog and in man ... . Yields demethylchlorpromazine in man, rat, rabbit, mouse, dog, sheep, guinea pig ... . Yields chlorpromazine sulfoxide in man, rat, rabbit, dog ... . Yields chlorpromazine-n-oxide in man, rat, rabbit, dog, pig, sheep, guinea pig, mouse ... . Yields 3-hydroxychlorpromazine in man, rat, dog ... . Yields 7-hydroxychlorpromazine in man, rat, sheep, dog, rabbit, guinea pig ... . /From table/
来源:Hazardous Substances Data Bank (HSDB)
代谢
至少有10到12种氯丙嗪的代谢物在人体中以可观的量存在。从数量上来说,这些代谢物中最重要的包括去甲氯丙嗪(双甲基化)、吩噻嗪(整个侧链被移除)、甲氧基和羟基产物,以及羟基化合物的葡萄糖苷酸结合物。在尿液中,以7-羟基化和脱烷基化(去甲)代谢物及其结合物为主。
As least 10 or 12 metabolites of chlorpromazine occur in human beings in appreciable quantities. Quantitatively, the most important of these are nor2-chlorpromazine (doubly methylated), chlorphenothiazine (removal of the entire side chain), methoxy and hydroxy products, and glucuronide conjugates of the hydroxylated compounds. In urine, 7-hydroxylated and dealkylated (nor2) metabolites and their conjugates predominate.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
鉴定:氯丙嗪是一种抗精神病药物。它是一种合成二甲胺生物吩噻嗪氯丙嗪为白色至奶油白色(碱和盐酸)。粉末或蜡状固体(碱);结晶性粉末(盐酸)。氯丙嗪实际上不溶于。在稀释的矿物酸中自由溶解;在稀释的碱氢氧化物中实际上不溶。人类暴露:主要风险和靶器官:主要的药理作用是精神药理。它还具有镇静和止吐作用。氯丙嗪在中央神经系统的所有层面上都有作用,主要在皮质下平,以及多个器官系统。氯丙嗪具有强烈的肾上腺素能拮抗作用和微弱的周围抗胆碱能活性;神经节阻断作用相对较小。它还具有一定的抗组胺和抗血清素活性。临床效果摘要:中枢神经系统抑制可能从嗜睡进展到昏迷,最终出现无反射。在早期或轻度中毒中,一些患者会出现不安、混乱和兴奋。可能出现震颤或肌肉抽搐、痉挛、僵直、惊厥、肌肉张力减退、吞咽困难。过量的外周症状包括肌张力障碍、斜颈、眼球震颤危象和角弓反张。可能会遇到低体温或高体温。可能出现呼吸困难和发绀、呼吸和/或血管运动崩溃、呼吸抑制和窘迫、突然的呼吸暂停甚至发绀。可能出现低血压、心动过速、心律失常、传导缺陷、心室纤颤或心脏骤停。禁忌症:在昏迷状态或存在大量中枢神经系统抑制剂酒精巴比妥酸盐、麻醉剂、麻醉药等)的情况下不要使用,因为氯丙嗪会延长并增强这些中枢抑制剂的作用。应谨慎给心血管或肝脏疾病的人使用氯丙嗪。有证据表明,由于肝硬化导致的肝性脑病患者对氯丙嗪的中枢作用更为敏感(例如,大脑功能障碍和脑电图异常减慢)。由于这种中枢抑制效果,应谨慎用于患有严重哮喘、肺气肿和急性呼吸道感染的慢性呼吸系统疾病患者,特别是在儿童中。因为它可以抑制咳嗽反射,呕吐物吸入是可能的。皮下注射是禁忌的。暴露途径:口服:氯丙嗪以片剂或糖浆形式口服给药。注射:它以可注射形式存在,通过肌肉或静脉途径使用。其他:使用栓剂通过肛门途径。暴露途径的吸收:口服给药的氯丙嗪的吸收取决于剂型,液剂给出最高的血浆药物浓度。血浆峰浓度在2至3小时达到。在达到的血浆浓度方面,受试者之间存在广泛的变化(十倍或更多)。食物在胃中可能会显著降低血浆浓度,以及与抗胆碱能抗帕森病药物的联合使用。由于首过效应,口服给药后的血浆浓度远低于肌肉注射后的血浆浓度。暴露途径的分布:氯丙嗪在体内广泛分布,并穿过血脑屏障,在大脑中达到比血浆更高的浓度。氯丙嗪及其代谢物也穿过胎盘屏障,并分泌在乳汁中。氯丙嗪高度与血浆蛋白结合,在临床血液浓度范围内(0.01至1 mcg/mL)从91.8%变化到97%。结合很容易逆转。暴露途径的生物半衰期:尽管氯丙嗪本身的血浆半衰期据报道只有几个小时,但代谢物的消除可能非常延长。血液研究显示范围为2至3天,尿液研究最多约18天。氯丙嗪引起的改变可能在停药后持续的时间比这些时间更长。持续的治疗效果与给药氯丙嗪的确切关系尚不确定。有可能微量的氯丙嗪和/或代谢物以缓慢可逆或相对不可逆的方式在活性部位持续存在。看起来一些氯丙嗪在脂肪组织中储存,并在停止氯丙嗪给药后缓慢动员。代谢:氯丙嗪的代谢途径包括羟基化,与葡萄糖醛酸的结合,N-氧化,氧化原子,和脱烷基。在人中,经过长期使用后,未结合的氯丙嗪代谢物在肺和肝脏中的浓度最高。在体内组织中发现的对羟基氯丙嗪似乎是一种活性代谢物。由于有证据表明氯丙嗪可以引起肝微粒体酶诱导,它可能加速其自身的代谢;这可能是维持固定剂量方案期间自由药物血浆浓度逐渐降低的原因。已经推测出168种可能的氯丙嗪代谢物,并且实际上从人类尿液中分离出许多。在人中,氯丙嗪及其亚磺酸酯的尿液排泄量从每日剂量的1%到20%不等。尿液中的自由氯丙嗪与亚磺酸酯的平均比例约为1:16。有大量证据表明亚磺酸酯经历了额外的代谢,可能转化为磺酮。各种吩噻嗪生物氯丙嗪
IDENTIFICATION: Chlorpromazine is an antipsychotic medication. It is a synthetic dimethylamine derivative of phenothiazine. Chlorpromazine is a white to creamy-white (Base and hydrochloride). Powder or waxy solid (Base); crystallline powder (Hydrochloride). Chlorpromzaine is practically insoluble in water. Freely soluble in dilute mineral acids; practically insoluble in dilute alkali hydroxides. HUMAN EXPOSURE: Main risks and target organs: The principal pharmacological actions are psychotropic. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system, primarily at subcortical levels, as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weak peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. Summary of clinical effects: Central nervous depression may progress from drowsiness to coma, ultimately with areflexia. In early or mild intoxications, some patients suffer from restlessness, confusion and excitement. Tremor or muscular twitching, spasm, rigidity, convulsions, muscular hypotonia, difficulty in swallowing may be present. Extrapyramidal signs of overdose include dystonia, torticollis, oculogyric crises and opisthotonos. Either hypothermia or hyperthermia may be encountered. Difficulty in breathing, cyanosis, respiratory and/or vasomotor collapse, respiratory depression and distress, sudden apnea and even cyanosis may occur. Hypotension, tachycardia, cardiac arrhythmias, conduction defects, ventricular fibrillation or cardiac arrest may occur. Contraindications: Do not use in comatose states or in the presence of large amounts of central nervous system depressants (alcohol, barbiturates, anesthetics, narcotics, etc.) because chlorpromazine prolongs and intensifies the action of such CNS depressants. Chlorpromazine should be administered cautiously to persons with cardiovascular or liver disease. There is evidence that patients with a history of hepatic encephalopathy due to cirrhosis have increased sensitivity to the CNS effect of chlorpromazine (e.g. impaired cerebration and abnormal slowing of the EEG). Because of this CNS depressant effect, it should be used with caution in patients with chronic respiratory disorders such as severe asthma, emphysema and acute respiratory infections, particularly in children. Because it can suppress the cough reflex, aspiration of vomitus is possible. Subcutaneous injection is contraindicated. Routes of entry: Oral: Chlorpromazine is available in tablet or syrup forms for oral ingestion. Parenteral: It is present in injectable forms for use through the intramuscular or intravenous routes. Other: Rectal route with suppositories. Absorption by route of exposure: The absorption of orally administered chlorpromazine is dependent on the dosage form, the elixir giving the highest plasma concentration of drug. Peak plasma levels are reached at 2 to 3 hours. There is a wide inter-subject variability (ten times or more) in the plasma concentrations achieved. Plasma concentrations may be decreased significantly by food in the stomach and by the concomitant administration of anticholinergic antiparkinsonism drugs. Owing to the first-pass effect, plasma concentrations following oral administrations are much lower than those following intramuscular administrations. Distribution by route of exposure: Chlorpromazine is widely distributed in the body and crosses the blood-brain barrier to achieve higher concentrations in the brain than in the plasma. Chlorpromazine and its metabolites also cross the placental barrier and are excreted in milk. Chlorpromazine is highly bound to plasma proteins, varying from 91.8% to 97% over the range of clinical blood concentrations (0.01 to 1 mcg/mL). Binding is easily reversed. Biological half-life by route of exposure: Although the plasma half-life of chlorpromazine itself has been reported to be only a few hours, elimination of the metabolites may be very prolonged. Blood studies show a range of 2 to 3 days and for the urinary studies up to about 18 days. Chlorpromazine brings about changes that can persist much longer than these times after discontinuation of the drug. The exact relationship of persisting therapeutic effects to administered chlorpromazine is uncertain. There is the possibility that minute amounts of chlorpromazine and/or metabolites persist at active sites in slowly reversible or relatively irreversible ways. It also seems that some chlorpromazine is stored in adipose tissue and slowly mobilized after stopping chlorpromazine administration. Metabolism: Paths of metabolism of chlorpromazine include hydroxylation, and conjugation with glucuronic acid, N-oxidation, oxidation of a sulfur atom, and dealkylation. In man, after chronic use, the highest concentration of unconjugated chlorpromazine metabolites is found in the lung and liver. The 7-hydroxy chlorpromazine that is found in body tissues appears to be an active metabolite. Since there is some evidence that chlorpromazine can cause hepatic microsomal enzyme induction, it may accelerate its own metabolism; this may account for progressively decreasing plasma concentrations of free drug during maintenance of a fixed dosage schedule. One hundred and sixty-eight possible metabolites of chlorpromazine have been postulated and many of them actually isolated from human urine. In man, urinary excretion of chlorpromazine plus its sulfoxides varies from 1 to 20% of the daily dose administered. The average ratio of free chlorpromazine to the sulfoxide in the urine is about 1:16. There is much evidence that the sulfoxide undergoes additional metabolism, probably to sulfones. The various phenothiazine congeners of chlorpromazine undergo similar metabolic degradation. Demethylation is another method of detoxication by the liver. Elimination by route of exposure: Chlorpromazine is excreted in both urine and feces. Mode of action: Chlorpromazine has a wide range of activity arising from its depressant actions on the central nervous system and its alpha-adrenergic blocking and weak antimuscarinic activities. Chlorpromazine possesses sedative properties but patients usually develop tolerance rapidly to the sedation. Its action on the autonomic system produces vasodilation, hypotension, and tachycardia. Salivary and gastric secretions are reduced. The sulfoxides of the phenothiazines have been intensively studied and found to be significantly less potent than the parent compound. Teratogenicity: If given in high doses over a long period during pregnancy, chlorpromazine may cause damage to the retina of the fetus. Interactions: Chlorpromazine may block the antihypertensive effects of guanethidine. Patients being treated with phenothiazines should be advised that their susceptibility to alcohol may be increased. Chlorpromazine has been shown to increase the miotic and sedative effects of morphine. Chlorpromazine may enhance the respiratory depression produced particularly by CNS depressants. Mutual inhibition of liver enzymes concerned with the metabolism of both chlorpromazine and the other drug (e.g. a tricyclic antidepressant) might result in increased plasma-concentrations of either drug. Chlorpromazine is reported to interfere with a number of laboratory tests, such as pregnancy tests, thyroid function tests, the Coombs' test where a false positive result can be achieved, and adrenal medullary tests. It is also reported to interfere with estimations for serum 5-hydroxyindole-acetic acid, blood urea, urinary ketones and steroids, urinary porphobilinogen, and vitamin B12. Main adverse effects: Therapeutic doses of chlorpromazine, may cause palpitation, nasal stuffiness, dry mouth, and slight constipation. The patient may complain of being cold, drowsy, or weak. Orthostatic hypotension, which may result in syncope. A mild elevation of temperature may be seen during the first few days, particularly if the drug is given parenterally. On the other hand, hypothermia can occur and may be due both to the action on the heat regulating center and to direct peripheral vasodilation. Sensitivity and adaptation to environmental temperature change are impaired so that fatal hyperthermia and heat stroke are possible complications. Chlorpromazine has produced hematological disorders, including agranulocytosis, eosinophilia, leucopenia, hemolytic anemia, aplastic anemia, thrombocytopenic purpura and pancytopenia. Hyperglycemia, hypoglycemia and glycosuria have also been reported.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
氯丙嗪在不同类型的突触后受体上起到拮抗剂(阻断剂)的作用 - 在多巴胺能受体(亚型D1、D2、D3和D4上,对生产性和非生产性症状具有不同的抗精神病特性),在5-HT1和5-HT2型血清素能受体上(具有抗焦虑、抗抑郁和抗攻击性质,以及减轻锥体外系副作用的作用,但也可能导致体重增加、血压下降、镇静和射精困难),在组胺能受体(H1受体上,引起镇静、止吐、眩晕、血压下降和体重增加),α1/α2受体(具有抗副交感神经作用,降低血压、反射性心动过速、眩晕、镇静、过度流涎和失禁以及性功能障碍,但也可能减轻假性帕森病 - 有争议)以及在毒蕈碱(胆碱能)M1/M2受体上(引起抗胆碱能症状,如口干、视力模糊、便秘、排尿困难/不能排尿、窦性心动过速、心电图变化和记忆丧失,但抗胆碱能作用可能减轻锥体外系副作用)。 此外,氯丙嗪是突触前多巴胺再摄取的弱抑制剂,可能导致(轻度)抗抑郁和抗帕森病效果。这种作用也可能解释精神运动性激动和精神病症状的加剧(在临床使用中非常罕见)。
Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
  • 肝毒性
氯丙嗪长期治疗的患者中,据报道多达40%的人会出现肝功能测试异常,但升高很少会超过正常上限的3倍。基转移酶异常通常是自限性的,不伴随症状,即使不停药也会逆转。 氯丙嗪也是众所周知的急性胆汁淤积性肝损伤的原因。文献中报道了许多因氯丙嗪引起的临床上明显的急性肝损伤的实例,估计在每500名接触者中会发生1例。氯丙嗪曾经是美国药物诱导肝损伤最常见的原因,但随着其使用量的减少,现在很少报道与氯丙嗪相关的黄疸。临床表现和病程都很明确。黄疸的发作通常在1到5周内,血清酶升高的模式通常是胆汁淤积性或混合性(案例1)。免疫过敏表现(发热、皮疹和嗜酸性粒细胞增多)在某些但不是所有病例中出现,这些表现通常是轻微和自限性的。自身抗体的形成是罕见的。最重要的是,氯丙嗪黄疸可能会持续很长时间,并可能与消失胆管综合征相关(案例2)。 可能性评分:A(临床上明显的肝损伤的众所周知的原因)。
Liver test abnormalities have been reported to occur in up to 40% of patients on long term therapy with chlorpromazine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually self-limited and unaccompanied by symptoms, reversing even without discontinuation. Chlorpromazine is also a well known cause of acute cholestatic liver injury. Numerous instances of clinically apparent acute liver injury due to chlorpromazine have been reported in the literature, which is estimated to occur in 1:500 persons exposed. Chlorpromazine was formerly the most common cause of drug induced liver injury in the United States, but with the decrease in its use, chlorpromazine associated jaundice is now rarely reported. The clinical presentation and course are well defined. The onset of jaundice is usually within 1 to 5 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed (Case 1). Immunoallergic manifestations (fever, rash and eosinophilia) occur in some but not all cases, and these manifestations are usually mild and self-limited. Autoantibody formation is rare. Most importantly, chlorpromazine jaundice can be prolonged and associated with vanishing bile duct syndrome (Case 2). Likelihood score: A (well known cause of clinically apparent liver injury).
来源:LiverTox
毒理性
  • 药物性肝损伤
化合物:氯丙嗪
Compound:chlorpromazine
来源:Drug Induced Liver Injury Rank (DILIrank) Dataset
毒理性
  • 药物性肝损伤
DILI 注解:较少的药物性肝损伤关注
DILI Annotation:Less-DILI-Concern
来源:Drug Induced Liver Injury Rank (DILIrank) Dataset
吸收、分配和排泄
  • 吸收
容易从胃肠道吸收。由于肝脏的首过代谢,生物利用度会有所变化。
Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver.
来源:DrugBank
吸收、分配和排泄
  • 消除途径
肾脏,大约37%通过尿液排出
Kidneys, ~ 37% excreted in urine
来源:DrugBank
吸收、分配和排泄
  • 分布容积
20 升/千克
20 L/kg
来源:DrugBank
吸收、分配和排泄
氯丙嗪从胃肠道和注射部位迅速吸收;然而,口服给药后,药物在吸收过程中(在胃肠道粘膜中)和首次通过肝脏时发生大量代谢。虽然在人类中尚未明确建立,但在动物中,氯丙嗪及其代谢物会经历肠肝循环。
Chlorpromazine hydrochloride is rapidly absorbed from the GI tract and from parenteral sites of injection; however, following oral administration, the drug undergoes considerable metabolism during absorption (in the GI mucosa) and first pass through the liver. Although not clearly established in humans, chlorpromazine and its metabolites undergo enterohepatic circulation in animals.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
相同口服剂量的氯丙嗪,其峰值血浆浓度在个体间存在显著差异。这种变异性被认为是由生物利用度的广泛个体间差异所致,显然是因为首次通过代谢率的遗传差异。由于首次通过代谢,较少的氯丙嗪以未改变药物的形式到达系统循环,因此口服给药后峰值血浆氯丙嗪浓度远低于肌内给药后。
Considerable interindividual variations in peak plasma concentrations have been reported with the same oral dose of chlorpromazine. The variability is thought to result from wide interindividual variation in bioavailability, apparently because of genetic differences in the rate of first-pass metabolism. As a result of first-pass metabolism, less chlorpromazine reaches systemic circulation as unchanged drug, and peak plasma chlorpromazine concentrations are much lower following oral administration than following im administration.
来源:Hazardous Substances Data Bank (HSDB)

SDS

SDS:1468e0750d7c0332b7e14e2e28bba8f0
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制备方法与用途

以下是关于盐酸氯丙嗪的关键信息总结:

作用与适应症:
  1. 精神疾病:用于治疗精神分裂症、躁狂症及其他精神病的阳性症状,如兴奋、幻觉、妄想等。
  2. 麻醉前给药及人工冬眠:作为麻醉术前用药或辅助人工冬眠疗法。
  3. 恶心与呕吐: 可用于原因不明的顽固性恶心和呕吐(注意排除器质性疾病)。
  4. 疼痛管理: 与镇痛药物合用治疗癌症患者的剧烈疼痛。
不良反应:
  1. 神经系统:包括锥体外系反应如震颤、运动障碍等;长期使用可能引起迟发性运动障碍,可使用苯海索缓解。
  2. 心血管系统:可能出现低血压及心律失常等问题。
  3. 内分泌与代谢:可能导致催乳素平升高、泌乳现象等。
  4. 消化系统:胃肠道不适如恶心、呕吐可能引起。
  5. 皮肤反应:药物性皮炎、剥脱性皮炎等。
注意事项:
  1. 需注意体位性低血压的风险,建议用药后静卧观察。
  2. 老年患者需谨慎使用,并调整剂量以避免并发症。
  3. 特定情况如严重心血管疾病、青光眼患者应慎用或禁用。
  4. 与某些药物合用时可能会影响其生物利用度。
生产方法:
  1. 缩合反应:在反应锅中加入2-氯吩噻嗪甲苯,加热回流脱后滴加1-二甲胺丙烷甲苯溶液,减压回收溶剂得到目标产物。
  2. 成盐过程:将上述所得化合物与异丙醇搅拌至一定温度,并通入干燥氯化氢形成盐酸盐。

总之,虽然盐酸氯丙嗪在精神科临床治疗中具有重要作用,但其潜在副作用不容忽视,在使用时需严格遵循医嘱。

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
  • 下游产品
    中文名称 英文名称 CAS号 化学式 分子量
    • 1
    • 2
    • 3

反应信息

  • 作为反应物:
    描述:
    氯丙嗪双氧水 作用下, 以 乙醇 为溶剂, 反应 144.0h, 生成 chlorpromazine N',S-dioxide
    参考文献:
    名称:
    吩噻嗪的代谢:通过气相色谱法和质谱法鉴定N-氧化产物。
    摘要:
    测定了在不同温度下丙嗪,氯丙嗪和甲基三甲嗪的N-氧化物和N-氧化物亚砜代谢产物的固体入口质谱,并将其与获得的N-氧化物和N-氧化物亚砜的主要热解产物的质谱进行了比较。气相色谱-质谱联用 通过将环境温度下的化合物直接插入质谱仪中来产生诊断离子。这些离子将芳基烷基叔胺的N-氧化物与伯和仲芳基烷基胺的N-氧化衍生物区分开来。
    DOI:
    10.1111/j.2042-7158.1975.tb09451.x
  • 作为产物:
    描述:
    盐酸氯丙嗪 在 sodium hydroxide 作用下, 生成 氯丙嗪
    参考文献:
    名称:
    的化学改性
    摘要:
    研究了将氯引入丙嗪及其氧化物类似物的影响。与未取代的丙嗪衍生物相比,Cl-取代的丙嗪衍生物(氯丙嗪 ( ClProm ) 和氯丙嗪-S-氧化物 ( ClProm-O ))的循环伏安法 (CV)显示出负的氧化和还原电位,而它们的光学性质不受影响由 Cl。Ni 促进的ClProm和ClProm-O的偶联反应提供吩噻嗪二聚体。观察到光学和电化学性质受二聚化的影响。
    DOI:
    10.3987/com-21-14589
  • 作为试剂:
    描述:
    二甲基硫air氯仿氯丙嗪叔丁醇 作用下, 以 为溶剂, 以50%的产率得到bis(dimethyl sulfide)radical cation
    参考文献:
    名称:
    Schöneich, Christian; Aced, Ahmed; Asmus, Klaus-Dieter, Journal of the American Chemical Society, 1991, vol. 113, # 1, p. 375 - 376
    摘要:
    DOI:
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文献信息

  • [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
    申请人:BIAL BIOTECH INVEST INC
    公开号:WO2021055627A1
    公开(公告)日:2021-03-25
    The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
    这项发明提供了替代的N-杂环羧酰胺和相关化合物,含有这些化合物的组合物,医疗工具包,以及使用这些化合物和组合物治疗患者的医疗疾病(例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病)的方法。
  • [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。
  • 4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
    申请人:Dunn Robert
    公开号:US20080318941A1
    公开(公告)日:2008-12-25
    The present disclosure provides compounds having affinity for the 5-HT 6 receptor which are of the formula (I): wherein R 1 , R 2 , R 5 , R 6 , B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
    本公开提供了具有亲和力的化合物,其对5-HT 6 受体具有亲和力,其化学式为(I): 其中R1、R2、R5、R6、B、D、E、G、Q、x和n如本文所定义。本公开还涉及制备这种化合物的方法、含有这种化合物的组合物以及使用这些化合物的方法。
  • 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。
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表征谱图

  • 氢谱
    1HNMR
  • 质谱
    MS
  • 碳谱
    13CNMR
  • 红外
    IR
  • 拉曼
    Raman
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mass
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ir
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  • 峰位数据
  • 峰位匹配
  • 表征信息
Shift(ppm)
Intensity
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Assign
Shift(ppm)
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测试频率
样品用量
溶剂
溶剂用量
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