(S)-5-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine | 183550-59-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (S)-5-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine
• 英文别名: (3S)-5-[[3,5-bis(trifluoromethyl)phenyl]methyl]-3-methyl-7-phenyl-3,4-dihydro-2H-pyrido[2,3-b][1,5]oxazocin-6-one
• CAS: 183550-59-6
• 化学式: C₂₅H₂₀F₆N₂O₂
• 分子量: 494.436
• InChiKey: NLHDZIOBAMLXHA-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3,5-双三氟甲基苄醇 在 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 (S)-5-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine
  参考文献：
  名称：

  Amide-based atropisomers in tachykinin NK1-receptor antagonists: synthesis and antagonistic activity of axially chiral N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one

  摘要：

  A series of novel N-benzylcarboxamide derivatives of bicyclic compounds, 3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one and 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one, were synthesized by cyclization of N-benzyl-2-chloro-N-(2-hydroxyethyl)-and -(3-hydroxypropyl)-nicotinamides, respectively. Atropisomerism was observed in 5-[3,5-bis(trifluoromethyl)benzyl]-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-ones due to steric hindrance of the carboxamide moiety and restriction of its rotation. Cyclization of N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-[(2S)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenylnicotinamide gave (3S)5-[3,5-bis(trifluoromethyl)benzyl]-3,8-dimethyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3b][1,5]oxazocin-6-one, which exists predominantly in the thermodynamically stable aR-conformer in CDCl3. This compound showed excellent NK1-antagonistic activity with IC50 value (in vitro inhibition of [I-125]-Bolton-Hunter-substance P binding in human IM-9 cells) of 0.47 nM, which is ca. 200-fold more potent than that of its enantiomer, indicating that the atropisomer chirality affects NK1-receptor recognition. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.01.097

文献信息

• Heterocyclic compounds, their production and use
  申请人：——

  公开号：US20020132817A1

  公开（公告）日：2002-09-19

  A compound represented by the formula: 1 wherein ring M is a heterocyclic ring wherein —X═Y< is one of —N═C<, —CO—N< or —CS—N<; R a and R b are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, with the proviso that at least one of them is an optionally substituted heterocyclic ring; Ring C is an optionally substituted homocyclic or heterocyclic ring; Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and n is an integer from 1 to 6, or a salt thereof has a tachykinin receptor antagonistic activity in vitro, and is useful for preventing or treating depression, anxiety, manic-depressive illness or psychopathy.

  一种由以下通式表示的化合物：1，其中环M为杂环环，其中—X═Y<为—N═C<、—CO—N<或—CS—N<之一；Ra和Rb彼此连接形成环A，或者它们相同或不同，独立地表示氢原子或环M上的取代基；环A和环B独立地表示可任选取代的碳环或杂环环，条件是至少一个为可任选取代的杂环环；环C为可任选取代的碳环或杂环环；环Z为可任选取代的含氮杂环环；n为1至6的整数，或其盐在体外具有速激肽受体拮抗活性，并可用于预防或治疗抑郁症、焦虑症、双相情感障碍或精神病。
• Heterocyclic compounds, their production and use as tachykinin receptor antagonists
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1184036A2

  公开（公告）日：2002-03-06

  A compound represented by the formula: wherein ring M is a heterocyclic ring wherein is one of -N=C<, -CO-N< or -CS-N<; Ra and Rb are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, with the proviso that at least one of them is an optionally substituted heterocyclic ring; Ring C is an optionally substituted homocyclic or heterocyclic ring; Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and n is an integer from 1 to 6, or a salt thereof has a tachykinin receptor antagonistic activity in vitro, and is useful for preventing or treating depression, anxiety, manic-depressive illness or psychopathy.

  式所代表的化合物： 其中环 M 是杂环，其中 是-N=C<、-CO-N<或-CS-N<中的一种； Ra 和 Rb 相互结合形成环 A，或者它们相同或不同，并独立地代表氢原子或环 M 上的取代基； 环 A 和环 B 独立地代表任选取代的同环或杂环，但其中至少有一个是任选取代的杂环； 环 C 是任选取代的均环或杂环； 环 Z 是任选取代的含氮杂环；以及 n 是 1 至 6 的整数，或其盐在体外具有速激肽受体拮抗活性，可用于预防或治疗抑郁症、焦虑症、躁狂抑郁症或精神病。
• PREVENTIVES/REMEDIES FOR EMOTIONAL DISORDERS
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1323429A1

  公开（公告）日：2003-07-02

  An agent for the prophylaxis or treatment of an emotional disorder, which contains the NK-1 receptor antagonist having particular properties of (1) having no serotonin uptake inhibitory effect, (2) being capable of migrating into the hypothalamus, or (3) having an inhibitory effect on micturition reflex, an agent for the prophylaxis or treatment of depression accompanied by urinary frequency, urinary incontinence and/or irritable bowel syndrome, which contains an NK-1 receptor antagonist, an agent for the prophylaxis or treatment of a mood disorder of patients with urinary frequency and urinary incontinence, and a circadian rhythm controller for the hypothalamic endocrine system are provided.

  一种用于预防或治疗情感障碍的制剂，其中含有 NK-1 受体拮抗剂，其特殊性质为：(1) 无血清素摄取抑制作用；(2) 能迁移到下丘脑；或 (3) 对排尿反射有抑制作用、提供了一种预防或治疗伴有尿频、尿失禁和/或肠易激综合征的抑郁症的药物，其中含有一种 NK-1 受体拮抗剂；一种预防或治疗伴有尿频和尿失禁的患者的情绪障碍的药物；以及一种下丘脑内分泌系统昼夜节律控制器。
• COMBINATION DRUGS
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1352659A1

  公开（公告）日：2003-10-15

  A pharmaceutical agent containing an NK-1 receptor antagonist, an NK-2 receptor antagonist and/or an anti-cholinergic drug in combination is provided, which is useful as a prophylactic or therapeutic agent of urinary frequency, urinary incontinence, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel syndrome, emesis, depression, anxiety, manic depressive psychosis or schizophrenia. More particularly, a pharmaceutical agent is provided, which contains a compound represented by the formula (I), wherein M ring is a heterocyclic ring having -N=C<, -CO-N< or -CS-N< as a partial structure ― X ------¯ Y < ; Ra and Rb are bonded to each other to form ring A, or the same or different and each is a hydrogen atom or a substituent for ring M; ring A and ring B are each a homocyclic or heterocyclic ring optionally having substituents and at least one of them is a heterocyclic ring optionally having substituents; ring C is a homocyclic or heterocyclic ring optionally having substituents; ring Z is an optionally substituted heterocyclic ring containing nitrogen; and n is an integer of 1 to 6, or a salt thereof or a prodrug thereof, and an NK-2 receptor antagonist and/or an anti-cholinergic drug in combination.

  本发明提供了一种含有 NK-1 受体拮抗剂、NK-2 受体拮抗剂和/或抗胆碱能药物组合的药剂，可作为尿频、尿失禁、哮喘、慢性阻塞性肺病、类风湿性关节炎、骨关节炎、疼痛、咳嗽、肠易激综合征、呃逆、抑郁、焦虑、躁狂抑郁性精神病或精神分裂症的预防或治疗药物。更具体地说，提供了一种药剂，它含有由式（I）代表的化合物，其中 M 环是具有 -N=C<、-CO-N< 或 -CS-N< 作为部分结构的杂环 - X ------¯ Y < ；Ra 和 Rb 相互键合形成环 A，或相同或不同，并且各自是氢原子或环 M 的取代基；环 A 和环 B 各自为可选具有取代基的均环或杂环，且其中至少一个为可选具有取代基的杂环；环 C 为可选具有取代基的均环或杂环；环 Z 为可选取代的含氮杂环；以及 n 为 1 至 6 的整数，或其盐或其原药，以及 NK-2 受体拮抗剂和/或抗胆碱能药物的组合。
• Combination drugs
  申请人：——

  公开号：US20040058914A1

  公开（公告）日：2004-03-25

  A pharmaceutical agent containing an NK-1 receptor antagonist, an NK-2 receptor antagonist and/or an anti-cholinergic drug in combination is provided, which is useful as a prophylactic or therapeutic agent of urinary frequency, urinary incontinence, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel syndrome, emesis, depression, anxiety, manic depressive psychosis or schizophrenia. More particularly, a pharmaceutical agent is provided, which contains a compound represented by the formula (I), wherein M ring is a heterocyclic ring having —N═C<, —CO—N< or —CS—N< as a partial structure —X Y<; R a and R b are bonded to each other to form ring A, or the same or different and each is a hydrogen atom or a substituent for ring M; ring A and ring B are each a homocyclic or heterocyclic ring optionally having substituents and at least one of them is a heterocyclic ring optionally having substituents; ring C is a homocyclic or heterocyclic ring optionally having substituents; ring Z is an optionally substituted heterocyclic ring containing nitrogen; and n is an integer of 1 to 6, or a salt thereof or a prodrug thereof, and an NK-2 receptor antagonist and/or an anti-cholinergic drug in combination. 1

  本发明提供了一种含有 NK-1 受体拮抗剂、NK-2 受体拮抗剂和/或抗胆碱能药物组合的药剂，可作为尿频、尿失禁、哮喘、慢性阻塞性肺病、类风湿性关节炎、骨关节炎、疼痛、咳嗽、肠易激综合征、呃逆、抑郁、焦虑、躁狂抑郁性精神病或精神分裂症的预防或治疗药物。更具体地说，提供了一种药物制剂，它含有由式（I）代表的化合物，其中 M 环是部分结构为-N═C<、-CO-N<或-CS-N<的杂环-X Y<; R a 和 R b 相互键合形成环 A，或相同或不同，且各自为氢原子或 M 环的取代基；环 A 和环 B 各自为可选具有取代基的同环或杂环，且其中至少一个为可选具有取代基的杂环；环C是任选具有取代基的均环或杂环； 环Z是任选取代的含氮杂环； n是1至6的整数，或其盐或其原药，以及NK-2受体拮抗剂和/或抗胆碱能药物的组合。 1