guanabenz acetate | 60329-04-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: guanabenz acetate
• 英文别名: (E)-2-(2,6-dichlorobenzylidene)hydrazinecarboximidamide acetate；(E)-guanabenz acetate；E-GA；E-guanabenz；2-(2,6-dichlorophenylmethylene)hydrazinecarboximidamide monoacetate；(E)-(diaminomethylideneamino)-[(2,6-dichlorophenyl)methylidene]azanium;acetate
• CAS: 60329-04-6
• 化学式: C₂H₄O₂*C₈H₈Cl₂N₄
• 分子量: 291.137
• InChiKey: MCSPBPXATWBACD-GAYQJXMFSA-N

物化性质

• 熔点：
  191-194 °C (decomp)
• 颜色/状态：
  White solid from acetonitrile
• 气味：
  Slight odor
• 溶解度：
  Solubility of 50 mg/ml in alcohol at 25 °C
• 解离常数：
  pKa = 8.1

计算性质

• 辛醇/水分配系数(LogP)：
  1.69
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

代谢

关那苯是广泛代谢的。关那苯代谢的部位尚未确定，但该药物可能经历广泛的首过代谢。关那苯主要通过羟基化形成(E)-对-羟基关那苯(4-羟基关那苯)，这大部分与葡萄糖醛酸结合。关那苯的一小部分在苯甲基碳处裂解，形成2,6-二氯苯甲醇，这似乎完全结合了。关那苯的一小部分也显然经历了N-葡萄糖醛酸化。其他次要代谢物包括(Z)-关那苯和可能的(Z)-对-羟基关那苯((Z)-4-羟基关那苯异构体)；这些代谢物几乎完全结合了。还形成了许多其他未识别的代谢物。关那苯的(Z)-异构体口服给药后大约具有未改变药物25%的降压活性。动物研究表明，口服给药后(E)-对-羟基关那苯无效，但在大剂量腹腔给药后产生轻微的降压效果。关那苯的其他代谢物无效。

Guanabenz is extensively metabolized. The site(s) of guanabenz metabolism has not been determined, but the drug probably undergoes extensive firstpass metabolism. Guanabenz is metabolized principally by hydroxylation to form (E)-p-hydroxyguanabenz (4-hydroxyguanabenz), which is largely conjugated with glucuronic acid. A small fraction of guanabenz is cleaved at the benzal carbon to form 2,6-dichlorobenzyl alcohol, which is apparently completely conjugated. A small fraction of guanabenz also apparently undergoes N-glucuronidation. Other minor metabolites include (Z)-guanabenz and possibly (Z)-p-hydroxyguanabenz (Z-isomer of 4-hydroxyguanabenz); these metabolites are apparently almost completely conjugated. Numerous other, unidentified metabolites are also formed. The (Z)-isomer of guanabenz appears to have about 25% of the hypotensive activity of the unchanged drug following oral administration. Animal studies indicate that (E)-p-hydroxyguanabenz is inactive following oral administration but produces a slight hypotensive effect following intraperitoneal administration of large doses. Other metabolites of guanabenz are inactive.

来源:Hazardous Substances Data Bank (HSDB)

代谢

口服剂量的甘氨苯扎大约有10%以(E)-对羟基甘氨苯扎的形式通过尿液排出，25%以(E)-对羟基甘氨苯扎的葡萄糖苷酸结合物形式排出，1%以未改变的甘氨苯扎形式排出，5%以甘氨苯扎的结合物形式排出，1%以(Z)-甘氨苯扎形式排出，1%以(Z)-甘氨苯扎的结合物形式排出，不到1%可能以(Z)-对羟基甘氨苯扎形式排出，2%以(Z)-对羟基甘氨苯扎的结合物形式排出，2%以2,6-二氯苄醇的结合物形式排出，其余以未识别的代谢物及其结合物形式排出。

About 10% of an oral dose of guanabenz is excreted in urine as (E)-p-hydroxyguanabenz, 25% as the glucuronide conjugate of (E)-p-hydroxyguanabenz, 1% as unchanged guanabenz, 5% as guanabenz conjugates, 1% as (Z)-guanabenz, 1% as (Z)guanabenz conjugates, less than 1% possibly as (Z)-p-hydroxyguanabenz, 2% as (Z)-p-hydroxyguanabenz conjugates, 2% as 2,6-dichlorobenzyl alcohol conjugates, and the remainder as unidentified metabolites and their conjugates.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当关那苯与包括酒精、吩噻嗪类、巴比妥类或苯二氮卓类在内的其他中枢神经系统抑制剂同时使用时，可能会出现中枢神经系统抑制作用增强。

Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当关那苯与其他降压药（包括利尿剂）联合使用时，关那苯的降压效果可能会增加。

When guanabenz is administered with other hypotensive agents, including diuretics, the hypotensive effect of guanabenz may be increased.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

关阿苯，与降糖药（例如，胰岛素，氯丙嗪）同时使用，似乎不会干扰血糖浓度的控制。

Guanabenz, administered concurrently with antidiabetic agents (eg, insulin, chlorpropramide), does not appear to interfere with the control of blood glucose concentration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

在治疗急性关那比唑过量后，几个1-3岁的儿童在12小时内完全且平稳地恢复；治疗方法包括洗胃和给予活性炭悬浮液、血管加压药和液体。

... A complete and uneventful recovery occurred within 12 hrs after treatment of acute guanabenz overdosage in several children 1-3 yr of age; treatment included gastric lavage and administration of an activated charcoal slurry, vasopressor, and fluids.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

鉴于托拉唑啉治疗的成功率不一，且大多数医生对此药物不熟悉，因此不能将其推荐为首选管理策略。只有在触觉刺激、纳洛酮、阿托品、静脉输液和多巴胺治疗失败后，才应考虑使用它。

Given that tolazoline treatment is variably successful and that most physicians are unfamiliar with this agent, it cannot be recommended in the primary management strategy... . It should be considered only after tactile stimulation, naloxone, atropine, iv fluids, and dopamine have failed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

关阿苯经历了广泛的首过肝代谢。其消除半衰期为7-14小时，肾清除率为0.09-0.131升/分钟。少于2%以原形从尿液中排出。大约80%的剂量在头24小时内通过尿液排出。

Guanabenz undergoes extensive first-pass hepatic metabolism. Its elimination half-life is 7-14 hr, and its renal clearance is 0.09-0.131 l/min. Less than 2% is excreted unchanged in the urine. About 80% of a dose is excreted in urine in the first 24 hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在禁食状态下给药后，通常在2-5小时内达到血浆冠那苯的最高浓度。在禁食的健康受试者中，单次口服16毫克剂量后，血浆冠那苯的平均峰值浓度为2.4-2.7纳克/毫升（范围：1.2-5.2纳克/毫升），而在肝功能受损的禁食受试者（慢性酒精性肝病）中为7.8纳克/毫升（范围：3-16纳克/毫升）。...这些患者中的这些改变可能是由增强的口服生物利用度（继发于门脉系统短路和/或固有清除率降低）和冠那苯的肝清除率降低所引起的。

Following oral administration, at least 70-80% of a dose of guanabenz acetate is absorbed. The effect of food on the absorption of guanabenz acetate has not been determined. Following oral administration of the drug in fasting individuals, peak plasma guanabenz concentrations usually occur within 2-5 hr. Following a single 16 mg oral dose, peak plasma guanabenz concentrations average 2.4-2.7 ng/ml (range: 1.2-5.2 ng/ml) in fasting healthy individuals and 7.8 ng/ml (range: 3-16 ng/ml) in fasting individuals with hepatic impairment (chronic alcohol-induced liver disease). ... Such alterations in these patients may result from enhanced oral bioavailability (secondary to portosystemic shunting and/or decreased intrinsic clearance) and decreased hepatic clearance of guanabenz.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

醋酸胍那苄的降压作用在口服给药后1小时内开始，并在2-7小时内达到峰值。降压作用的时间长短不一；制造商表示，降压作用在6-8小时内显著减弱，血压在12小时内恢复到基线值；然而，单剂量的降压作用可能持续12小时或更长时间。

The hypotensive effect of guanabenz acetate begins within 1 hr after oral administration and peaks within 2-7 hr. The duration of hypotensive effect is variable; the manufacturer states that the hypotensive effect is substantially diminished within 6-8 hr and that blood pressure returns to baseline values within 12 hr; however, the hypotensive effect of a single dose can persist for 12 or more hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

关于胍那苄的分布信息有限。在大鼠静脉注射后，胍那苄迅速且广泛地分布到中枢神经系统；药物在大脑中的浓度比同时期的血浆浓度高3-70倍。在人类中，胍那苄似乎也广泛分布。在服用16毫克和32毫克口服剂量后，胍那苄的表观稳态分布体积分别平均约为93升/千克和147升/千克。胍那苄的表观分布体积在肝功能损害的患者中似乎明显减少。

Information on the distribution of guanabenz is limited. Following iv administration in rats, guanabenz is rapidly and extensively distributed into the CNS; brain concentrations of the drug are 3-70 times higher than concurrent plasma concentrations. In humans, guanabenz appears to be extensively distributed. The apparent steady state volume of distribution of guanabenz averages approximately 93 and 147 l/kg after 16 and 32 mg oral doses, respectively. The apparent volume of distribution of guanabenz appears to be substantially decreased in patients with hepatic impairment.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  guanabenz acetate 以83%的产率得到
  参考文献：
  名称：

  TSUJIKAWA TERUAKI; MIZUTA EIJI; HAYASHI MASANORI, YAKUGAKU DZASSI, YAKUGAKU ZASSNI, J. PHARM. SOS. JAR. , 1976, 96+

  摘要：

  DOI：
• 作为产物：
  描述：

  氨基胍碳酸氢盐 、 2,6-二氯苯甲醛 、 溶剂黄146 以 乙醇 为溶剂， 反应 12.0h， 生成 guanabenz acetate
  参考文献：
  名称：

  THERAPEUTIC COMPOUNDS

  摘要：

  该发明提供了式Ia′、Ib′、Ic′和Id′的化合物及其药学上可接受的盐，其中变量A、R6、R7、R8、R9、Rx、L、X、Y和Z的含义如本文所述。这些化合物对于减少内质网应激并在动物体内产生镇痛作用是有用的。

  公开号：

  US20180230105A1

文献信息

• BICYCLIC COMPOUNDS AND USE AS ANTIDIABETICS
  申请人：Fang Jing

  公开号：US20100029650A1

  公开（公告）日：2010-02-04

  The present invention relates to novel compounds that are useful in the treatment of metabolic disorders, particularly type II diabetes mellitus and related disorders, and also to the methods for the making and use of such compounds.

  本发明涉及一种新型化合物，该化合物在治疗代谢性疾病，特别是Ⅱ型糖尿病及相关疾病方面具有用途，并且还涉及制备和使用这种化合物的方法。
• [EN] FUMAGILLOL COMPOUNDS AND METHODS OF MAKING AND USING SAME<br/>[FR] COMPOSÉS DE FUMAGILLOL, ET LEURS PROCÉDÉS DE FABRICATION ET D'UTILISATION
  申请人：ZAFGEN INC

  公开号：WO2018031877A1

  公开（公告）日：2018-02-15

  Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

  本文披露了富马醇类化合物及其在治疗医学疾病（如肥胖症）中的用途方法。提供了富马醇类化合物的药物组合物和制备方法。这些化合物被认为对蛋氨酸氨肽酶2具有活性。
• Heterocyclic compounds
  申请人：Yamamoto Hiroshi

  公开号：US20070072908A1

  公开（公告）日：2007-03-29

  The present invention provides a compound represented by the following formula [1′] or a salt thereof: wherein ring A, R 2 , R 3 , R 4 and X are as defined in the description, and an agent for the treatment or prophylaxis of a pathology involving glucocorticoid, or a 11βHSD1 inhibitor, containing the compound or a salt thereof.

  本发明提供了由以下式[1']表示的化合物或其盐： 其中环A，R2，R3，R4和X如描述中所定义，并且包含该化合物或其盐的用于治疗或预防涉及糖皮质激素的病理或11βHSD1抑制剂的药剂。
• FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
  申请人：Corkey Britton Kenneth

  公开号：US20120289493A1

  公开（公告）日：2012-11-15

  The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: wherein Q, R 1 , X 1 , X 2 , Y and R 2 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

  本公开涉及一类为钠通道抑制剂的化合物，以及它们在治疗各种疾病状态中的应用，包括心血管疾病和糖尿病。在特定实施例中，该化合物的结构由式I给出： 其中Q、R1、X1、X2、Y和R2如本文所述，以及制备和使用该化合物的方法，以及含有该化合物的药物组合物。
• [EN] BENZYLBENZENE DERIVATIVES AND METHODS OF USE<br/>[FR] DÉRIVÉS DE BENZYLBENZÈNE ET PROCÉDÉS D'UTILISATION
  申请人：THERACOS INC

  公开号：WO2009026537A1

  公开（公告）日：2009-02-26

  Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT inhibition.

  提供了对钠依赖性葡萄糖共转运蛋白SGLT具有抑制作用的化合物。该发明还提供了制药组合物、制备这些化合物的方法、合成中间体以及使用这些化合物的方法，独立地或与其他治疗剂联合使用，用于治疗受SGLT抑制影响的疾病和症状。