奋乃静 | 58-38-8

• 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: 奋乃静
• 中文别名: 过二苯嗪；2-氯-10-[3-(4-甲基哌嗪-1-基)丙基]吩噻嗪；过非那嗪；丙氯拉嗪；4-[3-(2氯吩噻嗪-10-基)丙基]-1-呱嗪乙醇；氯吩嗪；羟哌氯丙嗪；6-氨基-2-(氟甲基)-3-(2-甲基苯基)-4-(3H)-1,3-二氮杂萘酮；普鲁氯嗪；甲哌氯丙嗪
• 英文名称: prochlorperazine
• 英文别名: 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]phenothiazine；2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine；prochloroperazine；prochlorpromazine；Prochlorperazin；2-chloro-10-[3-(4-methylpiperazin-1-yl)propyl]phenothiazine
• CAS: 58-38-8
• 化学式: C₂₀H₂₄ClN₃S
• 分子量: 373.95
• InChiKey: WIKYUJGCLQQFNW-UHFFFAOYSA-N

物化性质

• 熔点：
  228 °C
• 沸点：
  260-275 °C(Press: 2 Torr)
• 密度：
  1.1679 (rough estimate)
• 溶解度：
  可溶于氯仿（少许）、乙酸乙酯（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Viscous liquid
• 蒸汽压力：
  1.18X10-9 mm Hg at 25 °C (est)
• 水溶性：
  -4.4
• 稳定性/保质期：
  SENSITIVE TO LIGHT.
• 分解：
  When heated to decomposition it emits very toxic fumes of sulfoxides, nitroxides, and /hydrogen chloride/.
• 解离常数：
  pKa = 8.1
• 碰撞截面：
  183.7 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2937;2965;2970;2954;2970;2945.2;2980.7;2943;2997;2983;2921;2985;2954;2947.2

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

氯丙嗪经过肝脏代谢，涉及氧化、羟基化、脱甲基、亚砜形成以及与葡萄糖醛酸的结合。氧化反应由CYP2D6介导。口服和颊部给药后在血浆中检测到了N-去甲基氯丙嗪，以及氯丙嗪亚砜、氯丙嗪7-羟基和氯丙嗪亚砜4'-N-氧化物，氯丙嗪可能进入肠肝循环。

Prochlorperazine undergoes hepatic metabolism involving oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The oxidation reaction is mediated by CYP2D6. N-desmethyl prochlorperazine was detected in the plasma, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, following oral and buccal administration. Prochlorperazine may enter the enterohepatic circulation.

来源:DrugBank

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

主要在肝脏通过氧化、羟基化、脱甲基、亚砜形成和与葡萄糖醛酸结合进行代谢；侧链的代谢改变也可能发生。

Metabolized primarily in liver /by/ oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid; metabolic alterations in side chain may also occur.

来源:Hazardous Substances Data Bank (HSDB)

代谢

经过对大鼠长期给予哌嗪取代的吩噻嗪类药物后，组织中含有了药物代谢物，其中哌嗪环通过多次氧化N-脱烷基化反应断裂，生成了取代的乙二胺。因此，从氯丙嗪中得到了N-[γ-(2-氯吩噻嗪基-10)-丙基]乙二胺...

After chronic administration of piperazine-substituted phenothiazine drugs ... to rats, tissues contained drug metabolites, in which piperazine ring fission by multiple oxidative n-dealkylation had occurred to give substituted ethylenediamine. Thus, n-[gamma-(2-chlorphenothiazinyl-10)-propyl]ethylenediamine ... from prochlorperazine ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

产生产氧-2-氯-10-(3-(4-甲基哌嗪-1-基)丙基)吩噻嗪和2-氯-10-(3-(4-甲基哌嗪-1-基)丙基)吩噻嗪亚砜的大鼠

Yields 2-chloro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine-n-oxide and 2-chloro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine sulfoxide in rats

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

氯丙嗪的作用机制尚未完全确定，但可能主要与其抗多巴胺能效应有关。氯丙嗪阻断了D2体的树突自身受体，导致中脑边缘系统突触后多巴胺受体的阻断和多巴胺周转率的增加。氯丙嗪还具有抗吐效果，这可以归因于在化学感受器触发区的多巴胺阻断。氯丙嗪还阻断了抗胆碱能和α-肾上腺素能受体，其中α(1)-肾上腺素能受体的阻断导致镇静、肌肉松弛和低血压。

The mechanism of action of prochlorperazine has not been fully determined, but may be primarily related to its antidopaminergic effects. Prochlorperazine blocks the D2 somatodendritic autoreceptor, resulting in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Prochlorperazine also has anti-emetic effects, which can be attributed to dopamine blockade in the chemoreceptor trigger zone. Prochlorperazine also blocks anticholinergic and alpha-adrenergic receptors, the blockade of alpha(1)-adrenergic receptors resulting in sedation, muscle relaxation, and hypotension.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在氯丙嗪治疗期间，肝脏测试异常并不常见，这可能是因为它很少长期给予或慢性高剂量使用。在治疗期间可能会出现氨基转移酶升高，但它们通常是轻微的、无症状的、短暂的，并且在继续用药的情况下也是可逆的。已经报道过由于氯丙嗪引起的临床上明显的急性肝损伤的罕见病例，这些病例类似于与氯丙嗪相关的胆汁淤积性肝损伤。黄疸的出现通常在1到4周内，血清酶升高的模式通常是胆汁淤积性或混合型。在某些病例中会出现免疫过敏特征（发热和嗜酸性粒细胞增多），但它们通常是轻微的和自限性的；自身抗体罕见。肝脏活检通常显示胆汁淤积性肝炎。重要的是，氯丙嗪引起的黄疸可能会延长，并且已经与罕见的消失胆管综合征（案例1）相关联，这可能是致命的，或者最终需要肝移植。

Liver test abnormalities are uncommon during prochlorperazine therapy, perhaps because it is rarely given long term or in high doses chronically. Aminotransferase elevations can occur during therapy, but they are usually mild, asymptomatic and transient and reversible even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to prochlorperazine which resemble the cholestatic liver injury associated with chlorpromazine. The onset of jaundice is usually within 1 to 4 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Immunoallergic features (fever and eosinophilia) occur in some cases, but they are usually mild and self-limited; autoantibodies are rare. Liver biopsy typically shows a cholestatic hepatitis. Importantly, prochlorperazine jaundice can be prolonged and has been associated with rare cases of vanishing bile duct syndrome (Case 1) that can be fatal or ultimately require liver transplantation.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：氯丙嗪

Compound:prochlorperazine

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

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，据报道，氯丙嗪能很好地从胃肠道吸收。药理作用的出现大约在口服给药后30至40分钟，肌肉注射后10至20分钟。所有给药途径的作用持续时间大约为3至4小时。在健康志愿者中口服给药后，平均口服生物利用度约为12.5%。在这些患者中，达到最高血浆浓度的时间约为5小时。重复口服给药导致氯丙嗪及其代谢物的积累。在多次每日两次给药后，氯丙嗪的稳态在7天内达到。

Following oral administration, prochlorperazine is reported to be well absorbed from the gastrointestinal tract. The onset of pharmacological action is about 30 to 40 minutes following oral administration and 10 to 20 minutes following intramuscular administration. The duration of action for all routes is about 3 to 4 hours. Following oral administration in healthy volunteers, the mean oral bioavailability was about 12.5%. In these patients, the time to reach the peak plasma concentrations was about 5 hours. Repeated oral dosing resulted in an accumulation of prochlorperazine and its metabolite. Following multiple twice daily dosing, the steady state of prochlorperazine was reached by 7 days.

来源:DrugBank

吸收、分配和排泄

• 消除途径

氯丙嗪主要经粪便和胆汁排泄。尿液中可以检测到少量的未改变的氯丙嗪及其代谢物。

Prochlorperazine is reported to be mainly excreted via the feces and bile. Low quantities of unchanged prochlorperazine and its metabolite were detectable in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在一项初步的药代动力学研究中，涉及健康志愿者，静脉注射6.25毫克和12.5毫克氯丙嗪后，平均表观分布容积分别约为1401升和1548升。据报道，氯丙嗪主要分布到大多数身体组织中，高浓度分布在肝脏和脾脏中。有证据表明，吩噻嗪类药物会排入哺乳期母亲的乳汁中。

In a preliminary pharmacokinetic study involving healthy volunteers, the mean apparent volume of distribution following intravenous administration of 6.25 mg and 12.5 mg prochlorperazine were approximately 1401 L and 1548 L, respectively. Prochlorperazine is reported to be distributed to most body tissues with high concentrations being distributed into liver and spleen. There is evidence that phenothiazines are excreted in the breast milk of nursing mothers.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康志愿者中，注射给予丙氯拉嗪的平均血浆清除率（CL）约为0.98升/小时 x 千克。平均肾清除率大约为23.6毫升/小时。

The mean plasma clearance (CL) of prochlorperazine following intravenous administration in healthy volunteers was approximately 0.98L/h x kg. The mean renal clearance was about 23.6 mL/h.

来源:DrugBank

吸收、分配和排泄

吩噻嗪类药物通常能很好地从胃肠道和注射部位吸收；然而，吸收可能不稳定，特别是在口服给药后。据报道，不同个体之间的峰值血浆浓度有显著差异。这种变异性可能是由于药物代谢速率的遗传差异、药物在胃肠道腔内的生物降解和/或在吸收过程中（在胃肠道粘膜）和首次通过肝脏时的药物代谢所致。

Phenothiazines are generally well absorbed from the GI tract and from parenteral sites; however, absorption may be erratic, particularly following oral administration. Considerable interindividual variations in peak plasma concentrations have been reported. The variability may result from genetic differences in the rate of metabolism, biodegradation of the drug in the GI lumen, and/or metabolism of the drug during absorption (in the GI mucosa) and first pass through the liver.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S16,S26,S28A,S36,S36/37/39,S38,S45
• WGK Germany：
  3
• 海关编码：
  29159020
• 包装等级：
  II
• 危险类别：
  8
• 危险品运输编号：
  UN 3261 8/PG 2
• 储存条件：
  -20°C，密闭保存，置于干燥处。

制备方法与用途

丙氯拉嗪简介

丙氯拉嗪是一种吩噻嗪类衍生物，属于常用的典型抗精神病药物。它主要用于治疗精神分裂症和其他精神病性障碍，对幻觉妄想、思维障碍、淡漠木僵及焦虑激动等症状有显著疗效。此外，该药物对肝脏和心血管系统的副作用较小，在临床上常用于老年患者或合并有肝脏、心血管系统疾病的精神病人，以及因其他抗精神病药出现心血管不良反应的病人。

丙氯拉嗪还因其镇静作用较弱而较少影响血压，适用于器质性精神病、老年性精神障碍及儿童攻击性行为障碍。

药理作用

丙氯拉嗪的作用与氯丙嗪相似，但其抗精神病作用更强，大约是氯丙嗪的6～10倍。此外，它在安定和止吐方面的效果也较氯丙嗪更显著，然而镇静作用则较弱。其毒性仅为氯丙嗪的三分之一，并且较少引起锥体外系反应。

口服后，丙氯拉嗪被肠道吸收并广泛分布至全身组织，其中脑、肺、肝、脾和肾中的含量最高。一次给药可维持6小时以上的效果。

应用

丙氯拉嗪主要适用于具有焦虑紧张、幻觉妄想、情绪不稳及思维障碍等症状的精神病患者。它主要用于治疗偏执性精神病、反应性精神病以及精神分裂症的偏执型、单纯型和慢性类型。

在严重兴奋躁狂的病人中，因其镇静作用较弱，故氯丙嗪通常是首选药物。此外，丙氯拉嗪也常用于缓解恶心、呕吐及呃逆等症状。

反应信息

• 作为反应物：
  描述：

  奋乃静 在 间氯过氧苯甲酸 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 prochlorperazine N^4'-oxide
  参考文献：
  名称：

  吩噻嗪抗精神病药N氧化物的合成。

  摘要：

  通过用相应母体药物的N-10侧链上的指定氮原子进行氧化合成氯丙嗪N-氧化物，氟奋乃静N4'-氧化物，丙氯嗪N4'-氧化物，磺胺嘧啶N-氧化物和三氟哌嗪N4'-氧化物。 3-氯过氧苯甲酸。在三氟哌嗪的情况下，氧化剂量的逐步增加产生了N1'，N4'-二氧化物和N1'，N4'，S-三氧化物。氯丙嗪和磺胺哒嗪的N'，S-二氧化物通过适当母体药物的过氧化氢氧化获得。

  DOI：

  10.1002/jps.2600820323
• 作为产物：
  描述：

  alkaline earth salt of/the/ methylsulfuric acid 在 铜 、 potassium carbonate 、 N,N-二甲基甲酰胺 作用下， 生成 奋乃静
  参考文献：
  名称：

  GB780193

  摘要：

  公开号：

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。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。
• [EN] ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE<br/>[FR] MODULATEURS DE PROTÉOLYSE À BASE D'ALANINE ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：ARVINAS INC

  公开号：WO2017011590A1

  公开（公告）日：2017-01-19

  The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

  描述涉及抑制凋亡蛋白（TAPs）结合化合物，包括包含相同的A功能化合物，这些化合物作为靶向泛素化的调节剂发挥作用，特别是根据本发明的双功能化合物抑制各种多肽和其他蛋白质的化合物。具体而言，描述提供了一端含有结合到IAP E3泛素连接酶的配体，另一端含有结合到靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。可以合成化合物，表现出与几乎任何类型的靶向多肽的降解/抑制一致的广泛药理活性。
• [EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION CIBLÉE DE PROTÉINES CONTENANT UN BROMODOMAINE
  申请人：ARVINAS INC

  公开号：WO2017030814A1

  公开（公告）日：2017-02-23

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是根据本发明抑制各种多肽和其他蛋白质的化合物。具体而言，本发明涉及一端含有结合泛素连接酶的VHL配体，另一端含有结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。根据本发明的化合物表现出与靶向多肽的降解/抑制一致的广泛的药理活性。
• Benzene Sulfonamide Thiazole and Oxazole Compounds
  申请人：Adams Jerry Leroy

  公开号：US20090298815A1

  公开（公告）日：2009-12-03

  The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.

  本发明提供了噻唑磺胺和噁唑磺胺化合物，含有这些化合物的组合物，以及用作药物制剂的制备方法和使用方法。

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