methyl 8-chloro-3,4,5,6-tetrahydro-2,6-methano-2H-1-benzoxocin-10-carboxylate | 142034-46-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: methyl 8-chloro-3,4,5,6-tetrahydro-2,6-methano-2H-1-benzoxocin-10-carboxylate
• 英文别名: methyl 8-chloro-2,6-methano-2H-3,4,5,6-tetrahydro-1-benzoxocin-10-carboxylate；Methyl 4-chloro-8-oxatricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-6-carboxylate
• CAS: 142034-46-6
• 化学式: C₁₄H₁₅ClO₃
• 分子量: 266.724
• InChiKey: MZTSPMMALAMSFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 8-chloro-3,4,5,6-tetrahydro-2,6-methano-2H-1-benzoxocin-10-carboxylate 在 lithium hydroxide 、 氯化亚砜 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 2.25h， 生成 N-<1-azabicyclo<2.2.2>octan-3(R)-yl>-8-chloro-2(R),6(S)-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin-10-carboxamide
  参考文献：
  名称：

  Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides

  摘要：

  Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (K(i) = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1-mu-g/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4-mu-g/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.

  DOI：

  10.1021/jm00083a015
• 作为产物：
  描述：

  methyl 5-chloro-3-(3'-cyclohexenyloxy)salicylate 在 硫酸 、 caesium carbonate 作用下， 反应 5.0h， 生成 methyl 8-chloro-3,4,5,6-tetrahydro-2,6-methano-2H-1-benzoxocin-10-carboxylate
  参考文献：
  名称：

  Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides

  摘要：

  Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (K(i) = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1-mu-g/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4-mu-g/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.

  DOI：

  10.1021/jm00083a015

文献信息

• 2,6-methano-2H-1-benzoxocincarboxylic acids, esters and amides
  申请人：Rhone-Poulenc Rorer Pharmaceuticals Inc.

  公开号：US05288731A1

  公开（公告）日：1994-02-22

  Novel compounds which are 2,6-methano-2H-1-benzoxocincarboxamides having 5-HT.sub.3 -antagonist properties including unique CNS, antiemetic and gastric prokinetic activities and which are void of any significant D.sub.2 receptor binding affinity, therapeutic compositions and methods of treatment of disorders which result from 5-HT.sub.3 activity using said compounds. Processes for their preparation and the preparation of their intermediates are also disclosed.

  具有5-HT.sub.3-拮抗作用的独特中枢神经系统、抗恶心和胃动力促进活性的2,6-甲基-2H-1-苯并氧吲哚羧酰胺类新化合物，不具有任何显著的D.sub.2受体结合亲和力，使用这些化合物治疗由5-HT.sub.3活性引起的疾病的治疗组合物和方法。还披露了它们的制备过程及其中间体的制备方法。
• PROCESS FOR PREPARING MULTICYCLIC OXY-CONTAINING RING COMPONENTS
  申请人：RHONE-POULENC RORER INTERNATIONAL (HOLDINGS) INC.

  公开号：EP0559656A1

  公开（公告）日：1993-09-15
• US5288731A
  申请人：——

  公开号：US5288731A

  公开（公告）日：1994-02-22
• [EN] 2,6-METHANO-2H-1-BENZOXOCINCARBOXAMIDES AS 5-HT3-ANTAGONISTS
  申请人：——

  公开号：WO1992009284A1

  公开（公告）日：1992-06-11

  [EN] Novel compounds which are 2,6-methano-2H-1-benzoxocincarboxamides having 5-HT3-antagonist properties including unique CNS, anti-emetic and gastric prokinetic activities and which are void of any significant D2 receptor binding affinity, processes for their preparation, therapeutic compositions and methods of treatment of disorders which result from 5-HT3 activity using said compounds are disclosed.
  [FR] Des nouveaux composés qui sont des 2,6-méthano-2H-1-benzoxocincarboxamides ayant des propriétés inhibitrices de 5-HT3, y compris une action unique sur le système nerveux central, anti-émétique et gastrique procinétique, et qui sont exempts de toute affinité de liaison importante au récepteur D2, des procédés de préparation desdits composés,des compositions thérapeutiques et des méthodes de traitement des troubles qui résultent de l'activité de 5-HT3 faisant appel auxdits composés sont décrits.
• [EN] PROCESS FOR PREPARING MULTICYCLIC OXY-CONTAINING RING COMPONENTS
  申请人：——

  公开号：WO1992009592A1

  公开（公告）日：1992-06-11

  [EN] This invention relates to stereospecific processes for the preparation, separation and purification of multicyclic oxy-containing ring system compounds such as dibenzofuran and benzoxocine-type compounds which exhibit 5HT3-antagonist properties including unique CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D2 receptor binding affinity.
  [FR] Procédés stéréospécifiques pour la préparation, la séparation et la purification de composés système multicycliques à teneur en oxy, tels que des composés du type dibenzofuranne et benzoxocine qui présentent des propriétés anti-5HT3, notamment une activité sur le système nerveux central, une activité procinétique gastrique et une activité antiémétique uniques en leur genre. En outre, lesdits composés n'ont aucune capacité de liaison significative de récepteur D2.