[1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-7-yl)indazole-3-carboxamide] | 109889-09-0

• 物质功能分类: 原料药 - 消化系统用药 - 止吐催吐药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: [1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-7-yl)indazole-3-carboxamide]
• 英文别名: granisetron；brl43694；1-methyl-N-[(1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]indazole-3-carboxamide
• CAS: 109889-09-0
• 化学式: C₁₈H₂₄N₄O
• 分子量: 312.415
• InChiKey: MFWNKCLOYSRHCJ-AGUYFDCRSA-N

物化性质

• 沸点：
  532.0±40.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)
• 溶解度：
  25℃：二甲基亚砜
• 熔点：
  219 °C (HCl salt)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

主要在肝脏进行；经历N-去甲基化和芳香环氧化，然后进行结合。动物研究表明，一些代谢物可能具有5-HT3受体拮抗剂活性。

Primarily hepatic; undergoes N -demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may have 5-HT 3 receptor antagonist activity.

来源:DrugBank

代谢

格雷司琼已知的人类代谢物包括7-羟基格雷司琼和9'-去甲基格雷司琼。

Granisetron has known human metabolites that include 7-Hydroxygranisetron and 9'-Desmethylgranisetron.

来源:NORMAN Suspect List Exchange

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：目前没有关于在哺乳期间使用格雷司琼的信息。在获得更多数据之前，哺乳期间应谨慎使用格雷司琼。可以选择使用其他药物。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：一位正在给一个8个月大婴儿哺乳的母亲，每天6到8次，因阑尾炎入院接受手术。在手术过程中，她接受了格雷司琼、头孢唑啉、酮咯酸、罗库溴铵、琥珀胆碱和舒芬太尼。患者还接受了两次静脉注射丙泊酚150毫克，随后不久又注射了50毫克。术后，她接受了对乙酰氨基酚、头孢唑啉、布洛芬和泮托拉唑，以及按需使用的氧可酮和晕海宁。手术后22小时，母亲第一次挤出乳汁，发现乳汁呈浅绿色。使用未经验证的分析方法对绿色乳汁进行分析，未检测到丙泊酚。绿色在术后第4天消失，当她恢复哺乳时。作者判断，绿色可能是由于丙泊酚或其代谢物引起的。

◉ Summary of Use during Lactation:No information is available on the use of granisetron during breastfeeding. Until more data become available, granisetron should be used with caution during breastfeeding. An alternate drug may be preferred. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:A woman nursing an 8-month-old infant 6 to 8 times daily was admitted to the hospital for an appendectomy. During the procedure she received granisetron, cefazolin, ketorolac, rocuronium, succinylcholine, and sufentanil. The patient also received 2 boluses of intravenous propofol of 150 mg followed shortly thereafter by a 50 mg dose. Postoperatively, she was receiving acetaminophen, cefazolin, ibuprofen, and pantoprazole, as well as oxycodone and dimenhydrinate as needed. Twenty-two hours after the procedure, the mother extracted milk for the first time and noted it to be light green in color. Analysis of the green milk using a nonvalidated assay detected no propofol. The green color faded and was absent by postoperative day 4 when she resumed breastfeeding. The authors judged that the green color was possibly caused by propofol or one of its metabolites.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

百分之六十五

65%

来源:DrugBank

吸收、分配和排泄

• 吸收

吸收迅速且完全，但由于首次通过代谢，口服生物利用度降低到大约60%。

Absorption of is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism.

来源:DrugBank

吸收、分配和排泄

• 消除途径

剂量的剩余部分以代谢物的形式排出，48%通过尿液，38%通过粪便。

The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces.

来源:DrugBank

吸收、分配和排泄

• 清除

0.52 升/小时/千克 [癌症患者，每日两次，每次1毫克，连续服用7天]

0.52 L/h/kg [Cancer Patients with 1 mg bid for 7 days]

来源:DrugBank

安全信息

• 海关编码：
  2934999090
• 储存条件：
  -20℃

制备方法与用途

格拉司琼的作用机制与临床应用

作用机制：

格拉司琼是一种高选择性的5-HT3受体拮抗剂。它通过竞争性地结合中枢和外周神经末梢的5-HT3受体来发挥作用，从而减少呕吐反射的发生，有效预防多种原因引起的恶心、呕吐。

• 主要应用于：
  • 化疗引起的恶心和呕吐
  • 放射治疗导致的恶心和呕吐

临床应用：

格拉司琼通过提供对5-HT3受体的高度选择性结合来防止化疗药物及其他致吐因素引发的呕吐反应。它具有快速起效、作用持久的特点，被广泛用于预防及控制这些不良反应。

药代动力学与药理特性

药代动力学：

• 分布广泛
• 血清蛋白结合率约为65%
• 主要通过N去烷基化及芳香环氧化后再共轭化代谢
• 主要经尿液和粪便排泄

不良反应：

• 头痛、便秘为主要常见轻至中度不良反应
• 过敏反应（如皮疹）少见，严重过敏休克罕见
• 肝功能指标一过性升高但通常在正常范围内

注意事项与禁忌

• 禁忌症：

  • 对本品或其成分过敏者禁用
  • 胃肠道梗阻患者禁用

• 注意事项：

  • 高血压未控制者使用时单日剂量不宜超过10mg，以免引起血压进一步升高
  • 注射制剂需现配现用且应在避光、室温条件下存放不超过24小时

药物相互作用

• 地塞米松可增强格拉司琼的药效
• 酮康唑可能通过CYP3A同工酶系抑制本品代谢，但临床意义不明

生产方法

1. 由1-甲基-1H-吲唑-3-甲酰氯和3-氨基-9-甲基-9-氮杂二环[3．3．1]壬烷反合成得到格拉司琼；
2. 通过氯化氢-乙醇酸化过程获得盐酸格拉司琼。

这些信息涵盖了关于格拉司琼的基本理化性质、药代动力学特征以及其临床应用和潜在副作用。此外，还提供了生产方法及药物相互作用等相关内容，为使用者提供全面的信息支持。

反应信息

• 作为反应物：
  描述：

  盐酸 、 cobalt(II) chloride hexahydrate 、 水 、 [1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-7-yl)indazole-3-carboxamide] 以 盐酸 、 甲醇 为溶剂， 生成 diaqua[1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-7-yl)indazole-3-carboxamide]cobalt(II) tetrachloride dodecahydrate
  参考文献：
  名称：

  Granisetron, an antiemetic drug, and its cobalt complex

  摘要：

  The crystal structures of granisetron [systematic name: 1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]nonan-7-yl)indazole-3- carboxamide], C(18)H(24)N(4)O, (I), an antinauseant and antiemetic agent, and its Co(II) complex, diaqua[1-methyl-N-(9-methyl-9-azoniabicyclo[3.3.1]nonan-7-yl) indazole-3-carboxamide] cobalt(II) tetrachloride dodecahydrate, [Co(C(18)H(25)-N(4)O)(2)(H(2)O)(2)]Cl(4)center dot 12H(2)O, (II), have been determined by X-ray diffraction. The granisetron molecule is in an extended conformation in both structures. Twisting of the central carboxamide group facilitates the Co(II) coordination in (II). The Co(II) atom is located on an inversion centre. The azabicyclononane ring adopts a chair-boat conformation in both structures. The molecules in (I) are linked into centrosymmetric dimers and form tetracyclic rings through C-H center dot center dot center dot O hydrogen-bonding interactions. The simultaneous presence of free chloride ions in conjunction with a number of hydration water molecules in (II) provides interesting hydrogen-bond patterns. This study can aid in the investigation of the properties of metal complexes with active pharmaceuticals in which the drug molecules play the role of a ligand.

  DOI：

  10.1107/s0108270109055449

文献信息

• [EN] BRUTON'S TYROSINE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON
  申请人：PFIZER

  公开号：WO2014068527A1

  公开（公告）日：2014-05-08

  Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)

  本文披露了一种与Bruton's酪氨酸激酶（BTK）形成共价键的化合物。公开了制备这些化合物的方法。还披露了包括这些化合物的药物组合物。公开了使用BTK抑制剂的方法，单独或与其他治疗剂联合治疗自身免疫疾病或症状、异源免疫疾病或症状、癌症，包括淋巴瘤，以及炎症性疾病或症状的方法。 (化学式I)
• [EN] BICYCLIC COMPOUNDS AS KINASES INHIBITORS<br/>[FR] COMPOSÉS BICYCLIQUES UTILISÉS EN TANT QU'INHIBITEURS DES KINASES
  申请人：ZHANG DAWEI

  公开号：WO2013173254A1

  公开（公告）日：2013-11-21

  The present invention is directed to novel bicyclic compounds, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are useful for the treatment of protein kinases mediated diseases and conditions. Novel bicyclic compounds disclosed herein include quinazolines and quinolines.

  本发明涉及新颖的双环化合物，它们的衍生物，药用可接受的盐，溶剂和水合物。本发明的化合物和组合物具有蛋白激酶抑制活性，并可用于治疗蛋白激酶介导的疾病和症状。本文披露的新颖双环化合物包括喹唑啉和喹啉。
• 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。