tert-butyl (R)-3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate | 95779-67-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tert-butyl (R)-3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate
• 英文别名: tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate；tert-butyl 2-[(3R)-3-amino-4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl]acetate
• CAS: 95779-67-2
• 化学式: C₁₅H₂₀N₂O₃S
• 分子量: 308.401
• InChiKey: HBBIPUCUTBNKJJ-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  97.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (R)-3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate 在 盐酸 、 4 A molecular sieve 、 sodium cyanoborohydride 作用下， 以 乙醇 、 溶剂黄146 、 乙酸乙酯 为溶剂， 生成 3(R)-amino>-5-(carboxymethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride
  参考文献：
  名称：

  Synthesis and angiotensin converting enzyme inhibitory activity of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. I.

  摘要：

  新型血管紧张素转化酶（ACE）抑制剂的设计与合成，包括(R)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯硫氮杂环-5-乙酸（7, 26, 33 和 37）以及(S)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯氧氮杂环-5-乙酸（8 和 27），本文进行了描述。这些系列中的一些化合物在体外和体内显示出强烈的ACE抑制活性。同时讨论了结构-活性关系。

  DOI：

  10.1248/cpb.34.1128
• 作为产物：
  描述：

  氯乙酸叔丁酯 在 sodium hydride 、 一水合肼 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.33h， 生成 tert-butyl (R)-3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate
  参考文献：
  名称：

  Synthesis and angiotensin converting enzyme inhibitory activity of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. I.

  摘要：

  新型血管紧张素转化酶（ACE）抑制剂的设计与合成，包括(R)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯硫氮杂环-5-乙酸（7, 26, 33 和 37）以及(S)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯氧氮杂环-5-乙酸（8 和 27），本文进行了描述。这些系列中的一些化合物在体外和体内显示出强烈的ACE抑制活性。同时讨论了结构-活性关系。

  DOI：

  10.1248/cpb.34.1128

文献信息

• Synthesis and angiotensin converting enzyme inhibitory activity of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. II.
  作者：KATSUMI ITOH、MASAKUNI KORI、YOHIYUKI INADA、KOHEI NISHIKAWA、YUTAKA KAWAMATSU、HIROSADA SUGIHARA

  DOI：10.1248/cpb.34.2078

  日期：——

  A series of (R)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acids (4 and 13)and (S)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzoxazepine-5-acetic acids (5 and 14) having an(S)-ω-amino-1-carboxyalkylamino group at the 3-position was prepared as part of our search for long-acting angiotensin converting enzyme (ACE) inhibitors. A number of derivatives had potent in vitro and in vivo ACE inhibitory activities. The structure-activity relationship of the series indicated that the duration of in vivo ACE inhibitory activity depends on the length of the carbon chain in the ω-aminoalkylamino substituent at the 3-position. The most prolonged activity was observed with (S)-8-amino-1-carboxyoctylamino derivatives (4d and 5d).

  一系列具有(S)-ω-氨基-1-羧基烷胺基的(R)-3-氨基-4-氧代-2,3,4,5-四氢-1,5-苯并噻二嗪-5-乙酸(4和13)以及(S)-3-氨基-4-氧代-2,3,4,5-四氢-1,5-苯并噁二嗪-5-乙酸(5和14)作为我们寻找长效血管紧张素转换酶(ACE)抑制剂的一部分被合成。多个衍生物显示出强大的体外和体内ACE抑制活性。该系列化合物的结构-活性关系表明，体内ACE抑制活性的持续时间取决于3-位上ω-氨基烷胺取代基的碳链长度。具有最长活性的是(S)-8-氨基-1-羧基辛胺基衍生物(4d和5d)。
• Piperidine compounds and pharmaceutical uses thereof
  申请人：Yoshitomi Pharmaceutical Industries, Ltd.

  公开号：US04882326A1

  公开（公告）日：1989-11-21

  Piperidine compounds of the formula: ##STR1## or isomers thereof as well as pharmaceutically acceptable salts and/or hydrate forms thereof, and piperidine compounds of the formula: ##STR2## or isomers thereof as well as salt and/or hydrate forms thereof. In the above formulae, A represents a methylene group, an oxygen atom or a sulfur atom; B represents an oxygen atom or a sulfur atom; R.sup.1 and R.sup.2 independently represent a hydrogen atom, a lower alkyl group or an aralkyl group; R.sup.3 represents a hydrogen atom or an amino protecting group; Z represents an amino group or a protected amino group, a hydroxy group, or a reactive atom or group; m represents 1 or 2; and n represents the integer of 0 to 3. Piperidine compounds (I) possess an inhibitory activity against angiotensin-converting enzyme, and exhibit a long lasting hypotensive activity and are useful as antihypertensive agents. Piperidine compounds (II) are useful as intermediates for said piperidine compounds (I).

  Piperidine化合物的公式为：##STR1##或其异构体，以及其药学上可接受的盐和/或水合物形式，以及Piperidine化合物的公式为：##STR2##或其异构体，以及其盐和/或水合物形式。在上述公式中，A代表一个亚甲基团、一个氧原子或一个硫原子；B代表一个氧原子或一个硫原子；R.sup.1和R.sup.2独立地代表一个氢原子、一个较低的烷基团或一个芳基烷基团；R.sup.3代表一个氢原子或一个氨基保护基团；Z代表一个氨基或一个受保护的氨基、一个羟基，或一个反应性原子或基团；m代表1或2；n代表0到3的整数。Piperidine化合物(I)具有抑制肾素转化酶的活性，并表现出长效降压活性，可用作降压药物。Piperidine化合物(II)可用作上述Piperidine化合物(I)的中间体。
• Condensed, seven-membered ring compounds and their use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04564612A1

  公开（公告）日：1986-01-14

  Novel condensed, seven-membered ring compounds of the formula: ##STR1## [wherein R.sup.1 and R.sup.2 each represent hydrogen, halogen, trifluoromethyl, lower alkyl or alkoxy, or both jointly form tri- or tetramethylene; R.sup.3 is hydrogen, lower alkyl or aralkyl; R.sup.4 is hydrogen or alkyl, aralkyl or cycloalkylalkyl which may be substituted; X is a group represented by the formula S(O).sub.n (where n is an integer of 0 to 2); Y is a carboxyl group which may be esterified or amidated; m is 1 or 2] and salts thereof. These compounds exhibit inhibitory activity on angiotensin converting enzyme and so forth, and are of value as an agent for diagnosis, prevention and treatment of hypertension.

  这些小说中的新型缩合七元环化合物的化学式为：[其中R.sup.1和R.sup.2分别表示氢、卤素、三氟甲基、低碳基或烷氧基，或者共同形成三元或四元亚甲基；R.sup.3为氢、低碳基或芳基烷基；R.sup.4为氢或烷基、芳基烷基或环烷基烷基，可被取代；X为由S(O).sub.n（其中n为0至2的整数）表示的基团；Y为可酯化或酰胺化的羧基；m为1或2]及其盐。这些化合物表现出对血管紧张素转换酶等的抑制活性，并且在高血压的诊断、预防和治疗方面具有价值。
• Synthesis and angiotensin converting enzyme-inhibitory activity of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. III.
  作者：KATSUMI ITOH、MASAKUNI KORI、YOSHIYUKI INADA、KOHEI NISHIKAWA、YUTAKA KAWAMATSU、HIROSADA SUGIHARA

  DOI：10.1248/cpb.34.3747

  日期：——

  A seires of (R)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acids (8) and (S)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzoxazepine-5-acetic acids (9) having an (S)-1-carboxy-ω-(4-piperidyl)alkyl group on the amino group at the 3-position was prepared as part of a search for long-acting inhibitors of the angiotensin converting enzyme (ACE). The length (n) of the carbon chain in the piperidylalkyl moiety was varied from two six in order to determine the optimal structure. The most prolonged activity in vivo was observed with (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid (8c : CV-5975) on i.v. and p.o. administrations.

  一系列具有(S)-1-羧基-ω-(4-哌啶基)烷基基团的(R)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯噻氮卓-5-乙酸（8）和(S)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯并噻氮卓-5-乙酸（9）被制备，作为寻找具有长效作用的血管紧张素转化酶（ACE）抑制剂的一部分。在哌啶基烷基部分中，碳链的长度(n)从二到六进行了变化，以确定最佳结构。在静脉注射和口服给药中，观察到(R)-3-[(S)-1-羧基-5-(4-哌啶基)戊基]氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯噻氮卓-5-乙酸（8c：CV-5975）具有最持久的体内活性。
• An improved synthesis of the new angiotensin converting enzyme inhibitor CV-5975 via a chemoenzymatic process.
  作者：MASAKUNI KORI、KATSUMI ITOH、HIROSADA SUGIHARA

  DOI：10.1248/cpb.35.2319

  日期：——

  A chemoenzymatic synthesis of the new angiotensin converting enzyme inhibitor CV-5975 (1) is described. The optically active key intermediate for the synthesis of 1, ethyl (R) -6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate ((R) -4), was prepared by kinetic resolution of the racemic α-hydroxyester ((RS) -4) with a lipase and also by asymmetric reduction of the α-oxoester (3) with baker's yeast. The enantiomeric excess (ee) of the α-hydroxyester ((R) -4) produced by these enzymatic procedures exceeded 60%. This optically active alcohol ((R) -4) was converted to its mesylate ((R) -5), which was then subjected to SN2 reaction with the aminobenzothiazepine derivative (2) followed by deprotection to yield 1.

  本文描述了一种新型血管紧张素转换酶抑制剂 CV-5975 (1) 的化学合成方法。合成 1 的光学活性关键中间体(R) -6-(1-苄氧羰基-4-哌啶基) -2-羟基己酸乙酯（(R) -4）是通过外消旋α-羟酯（(RS) -4）与脂肪酶的动力学解析以及α-氧酯（3）与面包酵母的不对称还原制备的。通过这些酶解方法制得的α-羟酯（(R) -4）的对映体过量（ee）超过了 60%。这种具有光学活性的醇（(R) -4）被转化为其甲磺酸酯（(R) -5），然后与氨基苯并硫氮杂卓衍生物（2）发生 SN2 反应，再进行脱保护，得到 1。