2H-1,4-Benzothiazin-3(4H)-one, 2-[2-[3-[[2-(1,3-benzodioxol-5-yloxy)ethyl]methylamino]propoxy]-5-methoxyphenyl]-4-methyl-, (2R)-, (2E)-2-butenedioate (1:1) (9CI) | 116476-13-2

• 物质功能分类: 原料药 - 循环系统用药 - 防治心绞痛药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 2H-1,4-Benzothiazin-3(4H)-one, 2-[2-[3-[[2-(1,3-benzodioxol-5-yloxy)ethyl]methylamino]propoxy]-5-methoxyphenyl]-4-methyl-, (2R)-, (2E)-2-butenedioate (1:1) (9CI)
• 英文别名: 2-[2-[3-[2-(1,3-benzodioxol-5-yloxy)ethyl-methylamino]propoxy]-5-methoxyphenyl]-4-methyl-1,4-benzothiazin-3-one
• CAS: 116476-13-2；116476-16-5；123388-07-8；127732-49-4
• 化学式: C₂₉H₃₂N₂O₆S
• 分子量: 536.649
• InChiKey: RKXVEXUAWGRFNP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  95
• 氢给体数：
  0
• 氢受体数：
  8

制备方法与用途

这段文本描述了合成富马酸司莫地尔的方法。它分步骤介绍了两种主要方法：一种是通过环己基碳化二亚胺(DCC)的参与，另一种是通过偶氮二羧酸二乙酯作为试剂。

第一种方法包括以下步骤：

1. 在冰浴下，将DCC、4-(二甲氨基)吡啶和目标化合物加入到二甲基甲酰胺中反应。
2. 反应后处理得到产物(V)和(Ⅵ)。
3. 使用硼氢化钙对化合物(V)进行还原得到(+)-(I)，通过重结晶进一步纯化。
4. 进一步合成得到富马酸司莫地尔。

第二种方法包括以下步骤：

1. 将目标化合物(I)与偶氮二羧酸二乙酯和三苯膦反应，然后用盐酸处理并进行硅胶柱层析得到产物(Ⅶ)。
2. 再次进行一系列反应（加入碘化钠、回流等）后，最终通过富马酸的乙醇溶液结晶得到目标产物(+)-(Ⅶ)。

这两种方法都可以进一步用于合成(-)-富马酸司莫地尔。整个过程涉及到多种有机化学技术，如滴加、硅胶柱层析、重结晶和反应条件控制等。

反应信息

• 作为产物：
  描述：

  2-<2-(3-chloropropoxy)-5-methoxyphenyl>-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine 在 碳酸氢钠 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 2H-1,4-Benzothiazin-3(4H)-one, 2-[2-[3-[[2-(1,3-benzodioxol-5-yloxy)ethyl]methylamino]propoxy]-5-methoxyphenyl]-4-methyl-, (2R)-, (2E)-2-butenedioate (1:1) (9CI)
  参考文献：
  名称：

  Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines

  摘要：

  As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.

  DOI：

  10.1021/jm00169a011

文献信息

• NEUROGENESIS BY MUSCARINIC RECEPTOR MODULATION
  申请人：Barlow Carrolee

  公开号：US20070049576A1

  公开（公告）日：2007-03-01

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  该即时披露描述了通过刺激或增加神经发生来治疗中枢神经系统和外周神经系统的疾病和病症的方法。该披露包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经生成剂结合以刺激或激活新神经细胞的形成。
• NOVEL BENZOTHIAZINE DERIVATIVES
  申请人：SANTEN PHARMACEUTICAL CO., LTD.

  公开号：EP0237573A1

  公开（公告）日：1987-09-23

  Novel benzothiazine derivatives represented by the following general formula (I), process for their preparation, and agents for treating diseases of circulatory organs containing these compounds as effective ingredients: wherein R' represents one or more groups selected from among a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group and a lower alkoxycarbonyloxy group, R2 represents a hydrogen atom, a lower alkyl group or a (C3 - C6) cycloalkyl group, R3 represents one or more of a hydrogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyloxy group, a lower alkanoyl group, an amino group, a lower alkylamino group, a lower alkanoylamino group and a lower alkoxycarbonyloxy group, or (CH2)n, R4 represents a hydrogen atom or a lower alkyl group, A and B which may be the same or different and each represents a lower alkylene group containing 1 to 6 carbon atoms, and n represents 3 or4.

  由以下通式(I)表示的新型苯并噻嗪衍生物、其制备方法以及含有这些化合物作为有效成分的治疗循环器官疾病的制剂：其中 R'代表一个或多个选自氢原子、低级烷基、卤素原子、硝基、羟基、低级烷氧基、低级烷酰氧基、氨基、低级烷基氨基和低级烷氧基羰基的基团；R2 代表氢原子、低级烷基或 (C3 - C6) 环烷基；R3 代表氢原子、低级烷基、羟基R4 代表氢原子或低级烷基，A 和 B 可以相同或不同，各自代表含有 1 至 6 个碳原子的低级亚烷基，n 代表 3 或 4。
• DRUG FOR IMPROVING BRAIN FUNCTION
  申请人：SANTEN PHARMACEUTICAL CO., LTD

  公开号：EP0429676A1

  公开（公告）日：1991-06-05

  A drug for improving brain functions, comprising a specified 2-phenyl-3-oxo-2H-1,4-benzothiazine derivative. It is effective in treating various diseases accompanied by lowering in brain functions, such as those caused by cerebral ischemia, e.g. cerebral infarction or transient cerebral ischemia, those caused as the sequela of brain edema, cerebral hemorrhage, etc., those caused by injuries, e.g. contusion, or central nervous system degeneration and regressive diseases, e.g. dementia, psychosis. neurosis, or Alzheimer disease.

  一种改善脑功能的药物，由特定的 2-苯基-3-氧代-2H-1,4-苯并噻嗪衍生物组成。它能有效治疗伴有脑功能降低的各种疾病，如脑缺血引起的疾病，如脑梗塞或短暂性脑缺血，脑水肿、脑出血等后遗症引起的疾病，外伤引起的疾病，如挫伤，或中枢神经系统退化和退行性疾病，如痴呆、精神病、神经衰弱或阿尔茨海默病。
• Neurogenesis by muscarinic receptor modulation with sabcomelin
  申请人：Braincells, Inc.

  公开号：EP2258359A2

  公开（公告）日：2010-12-08

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  本公开描述了通过刺激或增加神经发生来治疗中枢和周围神经系统疾病和病症的方法。本公开包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经发生剂联合使用，以刺激或激活新神经细胞的形成。
• Neurogenesis by muscarinic receptor modulation
  申请人：Braincells, Inc.

  公开号：EP2275095A2

  公开（公告）日：2011-01-19

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  本公开描述了通过刺激或增加神经发生来治疗中枢和周围神经系统疾病和病症的方法。本公开包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经发生剂联合使用，以刺激或激活新神经细胞的形成。