3,4-Dihydro-2,4-dimethyl-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine | 105773-01-1

• 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: 3,4-Dihydro-2,4-dimethyl-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine
• 英文别名: 2-(2-Hydroxy-5-methoxyphenyl)-2,4-dimethyl-1,4-benzothiazin-3-one
• CAS: 105773-01-1
• 化学式: C₁₇H₁₇NO₃S
• 分子量: 315.393
• InChiKey: FZPPBNSKTADLPV-UHFFFAOYSA-N

物化性质

• 熔点：
  176-177 °C(Solv: ethyl ether (60-29-7); hexane (110-54-3))
• 沸点：
  557.8±50.0 °C(Predicted)
• 密度：
  1.270±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  75.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3,4-Dihydro-2,4-dimethyl-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine 在 sodium hydride 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 2-[2-[3-[2-(1,3-Benzodioxol-5-yloxy)ethyl-methylamino]propoxy]-5-methoxyphenyl]-2,4-dimethyl-1,4-benzothiazin-3-one
  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
• 作为产物：
  描述：

  2,4-二甲基-1,4-苯并噻嗪-3-酮 在 三氯化铝 、 磺酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 3,4-Dihydro-2,4-dimethyl-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine
  参考文献：
  名称：

  A Novel, Convenient Synthesis of 2-Aryl-3-oxo-3,4-dihydro-2H-1,4-benzothiazines

  摘要：

  一种合成2-芳基-3-氧代-3,4-二氢-2H-1,4-苯并噻嗪的新方法是将取代苯与2-氯-3-氧代-3,4-二氢-2H-1,4-苯并噻嗪进行Friedel-Crafts类型的反应。该方法因其简单性和良好的产率而便捷。

  DOI：

  10.1055/s-1988-27648

文献信息

• 2-ARYLBENZOTHIAZINE DERIVATIVES
  申请人：SANTEN PHARMACEUTICAL CO., LTD.

  公开号：EP0233291A1

  公开（公告）日：1987-08-26

  2-Arytbenzothiazine derivatives represented by general formula (I) and salts thereof, a process for their preparation, and drugs containing them for treating circulatory organ diseases, wherein R' and R2 may be the same or different and each represents H, lower alkyl, OH, (non)substituted lower alkoxy, acyloxy, -0-THP, halogen, N02, NH2, lower alkylamino or (II): R3 represents H or lower alkyl; R4 represents H, lower alkyl, cycloalkyl, OH, lower alkoxy, SH, lower alkylthio, arylthio, halogen, CN, formyl lower alkyl, lower alkoxy, lower alkyl or (III); R5, R6. R7, and R8 may be the same or different and each represents H, (non)substituted lower alkyl, cycloalkyl, acyl, (non)substituted phenyl or (non)substituted pyridyl, or R5 and R6, or R7 and R8, may be bound to each other to form a (non)substrtuted piperidine ring, a (non)substituted piperazine ring or a morpholine ring; Z represents H, lower alkyl, lower alkoxy. OH. halogen, CN, N02, halogenated lower alkyl or lower alkanoyloxy; A represents straight-chain or branched lower alkylene; B represents straight-chain or branched lower alkylene optionally substituted by OH, and n represents O or 1, provided that R4 and Z do not represent a hvdroaen atom at the same time when n is 0.

  通式(I)代表的2-芳基苯并噻嗪衍生物及其盐、其制备方法以及含有它们的治疗循环器官疾病的药物，其中R'和R2可以相同或不同，各自代表H、低级烷基、OH、（非）取代的低级烷氧基、酰氧基、-0-THP、卤素、N02、NH2、低级烷基氨基或(II)：R3 代表 H 或低级烷基；R4 代表 H、低级烷基、环烷基、OH、低级烷氧基、SH、低级烷硫基、芳基硫基、卤素、CN、低级烷基甲酰基、低级烷氧基、低级烷基或 (III)；R5、R6.R5、R6、R7 和 R8 可以相同或不同，各自代表 H、（非）取代的低级烷基、环烷基、酰基、（非）取代的苯基或（非）取代的吡啶基，或 R5 和 R6 或 R7 和 R8 可以相互结合形成一个（非）取代的哌啶环、一个（非）取代的哌嗪环或一个吗啉环；Z 代表 H、低级烷基、低级烷氧基、低级烷基硫代、低级烷基硫代、低级烷基硫代、低级烷氧基、低级烷基或(III)。OH、卤素、CN、N02、卤代低级烷基或低级烷酰氧基；A 代表直链或支链低级亚烷基；B 代表任选被 OH 取代的直链或支链低级亚烷基，n 代表 O 或 1，但当 n 为 0 时，R4 和 Z 不能同时代表一个氢原子。
• FUJITA, MASANOBU;OTA, ATSUTOSHI;ITO, SUSUMU;YAMAMOTO, KOJI;KAWASHIMA, YOI+, SYNTHESIS,(1988) N, C. 599-604
  作者：FUJITA, MASANOBU、OTA, ATSUTOSHI、ITO, SUSUMU、YAMAMOTO, KOJI、KAWASHIMA, YOI+

  DOI：——

  日期：——
• FUJITA, MASANOBU;ITO, SUSUMU;OTA, ATSUTOSHI;KATO, NOBUHARU;YAMAMOTO, KOJI+, J. MED. CHEM., 33,(1990) N, C. 1898-1905
  作者：FUJITA, MASANOBU、ITO, SUSUMU、OTA, ATSUTOSHI、KATO, NOBUHARU、YAMAMOTO, KOJI+

  DOI：——

  日期：——
• US4739050A
  申请人：——

  公开号：US4739050A

  公开（公告）日：1988-04-19
• Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines
  作者：Masanobu Fujita、Susumu Ito、Atsutoshi Ota、Nobuharu Kato、Koji Yamamoto、Yoichi Kawashima、Hideyasu Yamauchi、Junichi Iwao

  DOI：10.1021/jm00169a011

  日期：1990.7

  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.