(2S,3S)-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-3,5-dihydro-2H-1,5-benzothiazepin-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: (2S,3S)-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-3,5-dihydro-2H-1,5-benzothiazepin-4-one
• 化学式: C₁₇H₁₇NO₄S
• 分子量: 331.392
• InChiKey: DDCMSFIMXFOYFK-CVEARBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  93.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3S)-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-3,5-dihydro-2H-1,5-benzothiazepin-4-one 在 吡啶 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 rel-(2R,3R)-3-(乙酰氧基)-5-[2-(二甲基氨基)乙基]-2,3-二氢-8-甲氧基-2-(4-甲氧基苯基)-1,5-苯并噻嗪-4(5H)-酮
  参考文献：
  名称：

  烷基，烷氧基，烷硫基或氨基取代的2,3-二氢-1,5-苯并噻唑啉-4（5H）-one的合成生物学评估。

  摘要：

  合成了被1,5-苯并噻氮平骨架的稠合苯环上的烷基，烷氧基，烷硫基，羟基或氨基取代的2,3-二氢-1,5-苯并噻唑啉-4（5H）-并使其血管舒张，降压和血小板聚集抑制活性进行了研究。（-）-顺-3-乙酰氧基-5- [2-（二甲基氨基）乙基] -2,3-二氢-8-甲基-2-（4-甲基苯基）-1,5-苯并噻嗪-4（5H ）-（（-）-13e）被选作血小板聚集的有效抑制剂进行进一步研究。

  DOI：

  10.1248/cpb.45.1008
• 作为产物：
  描述：

  2-氨基-6-甲氧基苯并噻唑 在 氢氧化钾 、 sodium hydroxide 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 xylene 为溶剂， 反应 13.0h， 生成 (2S,3S)-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-3,5-dihydro-2H-1,5-benzothiazepin-4-one
  参考文献：
  名称：

  烷基，烷氧基，烷硫基或氨基取代的2,3-二氢-1,5-苯并噻唑啉-4（5H）-one的合成生物学评估。

  摘要：

  合成了被1,5-苯并噻氮平骨架的稠合苯环上的烷基，烷氧基，烷硫基，羟基或氨基取代的2,3-二氢-1,5-苯并噻唑啉-4（5H）-并使其血管舒张，降压和血小板聚集抑制活性进行了研究。（-）-顺-3-乙酰氧基-5- [2-（二甲基氨基）乙基] -2,3-二氢-8-甲基-2-（4-甲基苯基）-1,5-苯并噻嗪-4（5H ）-（（-）-13e）被选作血小板聚集的有效抑制剂进行进一步研究。

  DOI：

  10.1248/cpb.45.1008

文献信息

• Synthesis and Antihypertensive Activity of 3-Acetoxy-2,3-dihydro-5-(2-(dimethylamino)ethyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (Diltiazem) Derivatives Having Substituents at the 8 Position.
  作者：Hiroaki YANAGISAWA、Koichi FUJIMOTO、Yasuo SHIMOJI、Takuro KANAZAKI、Kanako MIZUTARI、Hiroshi NISHINO、Hiroshi SHIGA、Hiroyuki KOIKE

  DOI：10.1248/cpb.40.2055

  日期：——

  In order to improve the potency and duration of biological actions of diltiazem, a number of 1, 5-benzothiazepine derivatives having the substituents at the 8 position were prepared and evaluated for their antihypertensive activity in spontaneously hypertensive rats. The introduction of methyl, ethyl, isopropyl, benzyl, methoxy, ethoxy, phenoxy, and methylthio groups increased the antihypertensive activity and prolonged duration of action, whereas cyclohexyl, cyclopentoxy, tolyloxy, p-methoxyphenoxy and phenylthio derivatives were less active than diltiazem. Among them, the 8-benzyl and phenoxy derivatives showed the most potent and long-lasting antihypertensive action.

  为了改善地尔硫卓的药效和生物作用持续时间，我们制备了一些在 8 位上具有取代基的 1，5-苯并硫氮杂卓衍生物，并对其在自发性高血压大鼠体内的抗高血压活性进行了评估。甲基、乙基、异丙基、苄基、甲氧基、乙氧基、苯氧基和甲硫基的引入增加了抗高血压活性并延长了作用时间，而环己基、环戊基、甲苯基、对甲氧基苯氧基和苯硫基衍生物的活性低于地尔硫卓。其中，8-苄基和苯氧基衍生物的降压作用最强且持续时间最长。
• 1,5-benzothiazepine derivatives and their pharmaceutical use
  申请人：Tanabe Seiyaku Co., Ltd.

  公开号：US04590188A1

  公开（公告）日：1986-05-20

  Novel 1,5-benzothiazepine derivatives of the formula: ##STR1## wherein R.sup.1 is lower alkyl or lower alkoxy, R.sup.2 is hydrogen atom or lower alkanoyl, each one of R.sup.3 and R.sup.4 is lower alkyl, Ring A is a substituted benzene ring of the formula: ##STR2## R.sup.a is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy, each one of R.sup.b and R.sup.c is lower alkyl, lower alkoxy or halogen atom, and either one of R.sup.d and R.sup.e is fluorine atom and the other one is hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof are disclosed. Said derivative (I) and its salt are useful as a hypotensive agent and/or a cerebral or coronary vasodilator.

  公开了式子为：##STR1##的新型1,5-苯并噻唑衍生物，其中R.sup.1是较低的烷基或较低的烷氧基，R.sup.2是氢原子或较低的烷酰基，R.sup.3和R.sup.4中的每一个是较低的烷基，环A是式子为：##STR2##的取代苯环，R.sup.a是较低的烷基，较低的烷氧基，较低的烷硫基或苄氧基，R.sup.b和R.sup.c中的每一个是较低的烷基，较低的烷氧基或卤素原子，R.sup.d和R.sup.e中的任意一个是氟原子，另一个是氢原子，或其药学上可接受的酸加盐。所述衍生物(I)及其盐可用作降压剂和/或脑血管或冠状血管扩张剂。
• Novel 1,5-benzothiazepine derivatives, processes for preparing the same and pharmaceutical compositions
  申请人：Tanabe Seiyaku Co., Ltd.

  公开号：EP0154838A1

  公开（公告）日：1985-09-18

  Novel 1,5-benzothiazepine derivatives of the formula: wherein R1 is lower alkyl or lower alkoxy, R2 is hydrogen atom or lower alkanoyl, each one of R3 and R4 is lower alkyl, Ring A is a substituted benzene ring of the formula: Ra is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy, each one of Rb and R° is lower alkyl, lower alkoxy or halogen atom, and either one of Rd and Re is fluorine atom and the other one is hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof and processes for their production. In form of pharmaceutical compositions said derivative (I) and its salt are useful as a hypotensive agent and/or a cerebral or coronary vasodilator.

  式中的新型 1，5-苯并硫氮杂卓衍生物： 其中R1为低级烷基或低级烷氧基，R2为氢原子或低级烷酰基，R3和R4各自为低级烷基，环A为式中的取代苯环： Ra为低级烷基、低级烷氧基、低级烷硫基或苄氧基，Rb和R°各自为低级烷基、低级烷氧基或卤原子，Rd和Re中的一个为氟原子，另一个为氢原子，或其药学上可接受的酸加成盐及其生产工艺。在药物组合物中，所述衍生物 (I) 及其盐可用作降血压剂和/或脑或冠状动脉血管扩张剂。
• Process for resolving chiral intermediates used in making calcium channel blockers
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0430544A1

  公开（公告）日：1991-06-05

  This process enables preparation of the preferred (+)-threo enantiomer by resolution of its racemic mixture of a compound of the formula wherein Y1 and Y2 are each independently lower alkyl and R1 is hydrogen or lower alkyl. The compound is treated with a chiral acid (tartaric acid preferred) in an organic solvent (ethanol preferred) to yield the (+)-threo enantiomer, which is then recovered from the reaction mixture. This enantiomer may then be used to produce the preferred (+)-cis enantiomer of certain benzothiazepine cardiovascular agents.

  该工艺可通过解析式中化合物的外消旋混合物，制备优选的(+)-三对映体。 其中 Y1 和 Y2 各自独立地为低级烷基，R1 为氢或低级烷基。在有机溶剂（乙醇为佳）中用手性酸（酒石酸为佳）处理该化合物，生成(+)-三对映体，然后从反应混合物中回收该对映体。这种对映体可用于生产某些苯并硫氮杂卓类心血管药物的(+)-顺式对映体。
• Benzazepinone calcium channel blockers. 5. Effects on antihypertensive activity associated with N1 and aromatic substituents
  作者：Jagabandhu Das、David M. Floyd、S. David Kimball、Keith J. Duff、Michael W. Lago、John Krapcho、Ronald E. White、Richard E. Ridgewell、Mary T. Obermeier

  DOI：10.1021/jm00092a011

  日期：1992.7

  We have shown that the pyrrolidinylmethyl substituent on the lactam nitrogen (Nl) of benzazepinone and benzothiazepinone calcium channel blocking agents is resistant to metabolic deamination and generally increases the duration and potency of antihypertensive activity in spontaneously hypertensive rats (SHR) relative to (N,N-dimethylamino) ethyl analogs. Additionally, compounds possessing a substituent on the fused aromatic ring are more resistant to metabolic deacylation of the C3 hydroxy function, which may explain why aromatic substituents also frequently increase the potency and/or duration of antihypertensive activity. Our data also indicate the in antihypertensive activity associated with these structural modifications is independent of any effects of potency in vitro. Overall, we interpret these results to indicate that these structural modifications improve antihypertensive activity as a result of increased metabolic stability and, consequently, oral bioavailability.