S-[(2R)-3-氯-2-甲基-3-氧代丙基]苯硫代甲酸酯 | 74654-91-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: S-[(2R)-3-氯-2-甲基-3-氧代丙基]苯硫代甲酸酯
• 中文别名: S-[(2R)-3-氯-2-甲基-3-羰基丙基]苯甲硫酸酯
• 英文名称: (S)-3-(benzoylthio)-2-methylpropanoylchloride
• 英文别名: 3-(benzoylthio)-2(S)-methylpropionyl chloride；3-benzoylthio-2(R)-methylpropionyl chloride；R-3-Benzoylthio-2-methylpropanoyl chloride；S-Benzoyl-3-mercapto-2-methylpropanoyl chloride；S-[(2R)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate
• CAS: 74654-91-4
• 化学式: C₁₁H₁₁ClO₂S
• 分子量: 242.726
• InChiKey: MJZHAVYNYFDSMZ-MRVPVSSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  59.4
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 海关编码：
  2930909090

反应信息

• 作为反应物：
  描述：

  S-[(2R)-3-氯-2-甲基-3-氧代丙基]苯硫代甲酸酯 在 三丁基膦 、 sodium carbonate 、 对甲苯磺酸 作用下， 以 水 、 甲苯 、 苯 为溶剂， 反应 41.5h， 生成
  参考文献：
  名称：

  Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines

  摘要：

  Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.

  DOI：

  10.1021/jm00401a014
• 作为产物：
  描述：

  (S)-(-)-3-苯甲酰巯基-2-甲基丙酸 在 吡啶 、 氯化亚砜 作用下， 反应 7.0h， 生成 S-[(2R)-3-氯-2-甲基-3-氧代丙基]苯硫代甲酸酯
  参考文献：
  名称：

  （巯基丙酰基）二氢吲哚-2-羧酸和相关化合物作为有效的血管紧张素转化酶抑制剂和降压药。

  摘要：

  合成了1-（3-巯基-2-甲基-1-氧丙基）二氢吲哚-2-羧酸（7b）及其相关化合物，以检测其抑制血管紧张素转化酶（ACE）和降低收缩压的能力自发性高血压大鼠（SHR）。前体1- [3-（苯甲硫基）-2-甲基-1-氧丙基]二氢吲哚-2-羧酸（6b）的所有四种可能的立体异构体均具有绝对立体化学特征。通过用2-甲氧基乙胺处理方便地除去前体的苯甲酰基以得到7b。苯甲酰基衍生物6的四个立体异构体中的三个以下列顺序显示了体外ACE抑制活性：6b（S，S）大于6b（S，R）大于6b（R，S）。具有R，R构型的立体异构体基本上是无活性的。用Et或OMe组取代吲哚核的C5处，仅引起抑制活性的微小变化。硫醇7b（S，S）是这项研究中合成的最具活性的ACE抑制剂，其体外效能是卡托普利的3倍。与卡托普利相比，效力的增强可能是由于7b（S，S）的疏水性增加，并表明在ACE的活性位点存在疏水口袋。在自发性高血压大鼠

  DOI：

  10.1021/jm00357a014

文献信息

• Angiotensin converting enzyme inhibitors: N-Substituted monocyclic and bicyclic amino acid derivatives
  作者：James L. Stanton、Norbert Gruenfeld、Joseph E. Babiarz、Michael H. Ackerman、Robert C. Friedmann、Andrew M. Yuan、William Macchia

  DOI：10.1021/jm00363a011

  日期：1983.9

  (14a-x),- N-arylalanines (15a,b),-N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure--activity relationship for each series is discussed. The

  N-（3-巯基丙酰基）-N-芳基甘氨酸（14a-x），-N-芳基丙氨酸（15a，b），-N-环烷基甘氨酸（16a-k）和-1,2,3,4-的合成描述了四氢异喹啉-3-羧酸（17a-d），-1,2,3,4-四氢喹啉-2-羧酸（18a-f）和-二氢吲哚-2-羧酸（19a-k）。报道了每种化合物对血管紧张素转化酶（ACE）的体外抑制作用，并讨论了每个系列的结构-活性关系。讨论了ACE的体内抑制作用和各系列代表性化合物的降压作用。最有效的化合物19d的体外ACE IC50为2.6 X 10（-9）M，并且以10 mg / kg po的剂量在85 mm的自发性高血压大鼠中降低了血压。
• Studies on angiotensin-converting enzyme inhibitors. I. Syntheses and angiotensinconverting enzyme inhibitory activity of 2-(3-mercaptopropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives.
  作者：KIMIAKI HAYASHI、YASUHIKO OZAKI、KENICHI NUNAMI、TOMOFUMI UCHIDA、JYOJI KATO、KEIZO KINASHI、NAOTO YONEDA

  DOI：10.1248/cpb.31.570

  日期：——

  (3S)-2-[(2S)-3-Mercapto-2-methylpropionyl]-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid [(3S), (2S)-6a] was prepared by the reaction of (3S)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester [(3S)-2a] or benzyl ester [(3S)-2b] with 3-benzoylthio-2-methylpropionyl chloride (3a), followed by fractional crystallization and removal of the protective group. The absolute configuration of (3S), (2S)-6a was confirmed by X-ray diffraction analysis of the thiazepino [4, 3-b] isoquinoline compound (7) derived from 6a. Resolution of 3-benzoylthio-2-methylpropionic acid (8) was completed by using optically active phenylalanine amide as a resolving agent. The other optical isomers of (3S), (2S)-6a were prepared by the reaction of (3S)- or (3R)-2b with optically active 3a. The in vitro ACE inhibitory activity of each isomer of 6a was evaluated. Among them, (3S), (2S)-6a was found to be the most potent inhibitor with an IC50 value of 8.6×10-9M. Compound (3S), (2S)-6a induced a dose-dependent inhibition of the pressor response to angiotensin I after oral administration to normotensive anesthetized rats. Moreover, (3S), (2S)-6a markedly reduced the systolic blood pressure in renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR). The in vivo ACE inhibitory activity and the hypotensive effects of (3S), (2S)-6a were comparable to those of captopril.

  (3S)-2-[(2S)-3-巯基-2-甲基丙酰基]-1, 2, 3, 4-四氢异喹啉-3-羧酸[(3S), (2S)-6a]是通过(3S)-1, 2, 3, 4-四氢异喹啉-3-羧酸叔丁基酯[(3S)-2a]或苄基酯[(3S)-2b]与3-苯甲酰硫-2-甲基丙酰氯(3a)反应制备而成，随后通过分馏结晶去除保护基团。通过对由6a衍生的噻唑烯[4, 3-b]异喹啉化合物(7)进行X射线衍射分析，确认了(3S), (2S)-6a的绝对构型。使用光学活性的苯丙氨酸酰胺作为分解剂完成了3-苯甲酰硫-2-甲基丙酸(8)的分解。通过(3S)-或(3R)-2b与光学活性3a反应制备了(3S), (2S)-6a的其他光学异构体。评估了每种6a异构体的体外ACE抑制活性。其中，(3S), (2S)-6a被发现是最有效的抑制剂，IC50值为8.6×10^-9M。化合物(3S), (2S)-6a在该显混合型麻醉大鼠口服给药后，诱导了对血管紧张素I的加压反应的剂量依赖性抑制。此外，(3S), (2S)-6a显著降低了肾性高血压大鼠(RHR)和自发性高血压大鼠(SHR)的收缩压。(3S), (2S)-6a的体内ACE抑制活性和降压效果与卡托普利相当。
• Chromanyl glycines
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04521607A1

  公开（公告）日：1985-06-04

  New bicyclic compounds, inclusive of salts thereof, of the formula: ##STR1## wherein R.sup.1 and R.sup.2, which may be the same or different, each represent hydrogen, halogen, lower alkyl, hydroxyl, lower alkyloxy or aralkyloxy, or R.sup.1 and R.sup.2 jointly represent lower alkylenedioxy; R.sup.3 and R.sup.4 each represent hydrogen or lower alkyl; R.sup.5 represents hydrogen, lower alkyl or --CH.sub.2 SR.sup.7 (R.sup.7 represents hydrogen or acyl); R.sup.6 represents hydrogen or acyl, or R.sup.6 and R.sup.7 jointly represent a single bond; X represents --CH.sub.2 --, --O-- or >N--R.sup.8 (R.sup.8 represents hydrogen, acyl or lower alkyl); and n represents 2, 3 or 4, have inhibitory activities of angiotensin converting enzyme and bradykinin decomposing enzyme, and are useful as antihypertensive agents.

  新的双环化合物，包括其盐，其化学式如下：##STR1## 其中R.sup.1和R.sup.2，可以相同也可以不同，分别代表氢、卤素、低烷基、羟基、低烷氧基或芳基氧基，或者R.sup.1和R.sup.2共同代表低烷二氧基；R.sup.3和R.sup.4分别代表氢或低烷基；R.sup.5代表氢、低烷基或--CH.sub.2SR.sup.7（R.sup.7代表氢或酰基）；R.sup.6代表氢或酰基，或者R.sup.6和R.sup.7共同代表一个单键；X代表--CH.sub.2--、--O--或>N--R.sup.8（R.sup.8代表氢、酰基或低烷基）；n代表2、3或4，具有抑制肾素-血管紧缩素转化酶和激肽降解酶的活性，并可用作降压药物。
• 1,1'-[Dithiobis(2-alkyl-1-oxo-3,1-propanediyl)]-bis[2,3-dihydro-1H-indole
  申请人：American Home Products Corporation

  公开号：US04396773A1

  公开（公告）日：1983-08-02

  Disclosed herein are N-(3-mercapto-2-alkyl-1-oxopropyl)-2,3-dihydro-1H-indole-2-carboxylic acids and derivatives thereof which act as inhibitors of angiotensin converting enzyme and as anti-hypertensive agents. Derivatives include those in which the 3-mercapto group is substituted with phosphate derivatives or is replaced by a variously substituted amino group. The compounds of the invention (excluding disclosed intermediates) have the general formula: ##STR1## wherein: n is 1 or 0; R.sub.1 is hydrogen, lower alkyl, aryl or aralkyl; R.sub.2 is hydrogen or lower alkyl; R.sub.3 is hydrogen, lower alkyl or aroyl; R.sub.5 is hydroxy, amino, or lower alkoxy; X is hydrogen, hydroxy, lower alkyl, lower alkoxy, or halogen; Y is hydrogen, lower alkyl, or aryl; R.sub.4 is -SH, ##STR2## wherein L is O, NR.sub.7 or S (where R.sub.7 is hydrogen or lower alkyl); M is R.sub.8, OR.sub.8, SR.sub.8, or NR.sub.9 R.sub.10 (where R.sub.8 is hydrogen, lower alkyl, aryl, or aralkyl; and R.sub.9 and R.sub.10 are, independently, hydrogen, lower alkyl, or aryl); A is O, NR.sub.13 or S; R.sub.11 and R.sub.12 are, independently, hydrogen, alkyl, aralkyl or aryl; R.sub.13 is hydrogen or lower alkyl; m is 0, 1, 2, or 3; R.sub.20 is hydrogen or aryl; and R.sub.21 is hydroxy or lower alkoxy; or pharmaceutically acceptable salts thereof.

  本文揭示了N-(3-巯基-2-烷基-1-氧代丙基)-2,3-二氢-1H-吲哚-2-羧酸及其衍生物，其作为抑制血管紧张素转化酶和降压药物的作用。衍生物包括那些其中3-巯基团被磷酸衍生物取代或被各种取代的氨基团替换的化合物。发明的化合物（不包括已披露的中间体）具有以下通式： 其中：n为1或0；R.sub.1为氢、低烷基、芳基或芳基烷基；R.sub.2为氢或低烷基；R.sub.3为氢、低烷基或芳酰基；R.sub.5为羟基、氨基或低烷氧基；X为氢、羟基、低烷基、低烷氧基或卤素；Y为氢、低烷基或芳基；R.sub.4为-SH、 其中L为O、NR.sub.7或S（其中R.sub.7为氢或低烷基）；M为R.sub.8、OR.sub.8、SR.sub.8或NR.sub.9R.sub.10（其中R.sub.8为氢、低烷基、芳基或芳基烷基；R.sub.9和R.sub.10分别为氢、低烷基或芳基）；A为O、NR.sub.13或S；R.sub.11和R.sub.12分别为氢、烷基、芳基烷基或芳基；R.sub.13为氢或低烷基；m为0、1、2或3；R.sub.20为氢或芳基；R.sub.21为羟基或低烷氧基；或其药用盐。
• Bicyclic compounds, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0035868A1

  公开（公告）日：1981-09-16

  New bicyclic compounds, inclusive of salts thereof, of the formula: wherein R1 and R2, which may be the same or different, each represent hydrogen, halogen, lower alkyl, hydroxyl, lower alkyloxy or aralkyloxy, or R' and R2 jointly represent lower alkylenedioxy: R3 and R4 each represent hydrogen or lower alkyl; R3 represents hydrogen,lower alkyl or -CH2SR7(R7 represents hydrogen or acyl): R6 represents hydrogen or acyl, or R6 and R7 jointly represent a single bond; X represents -CH2-, -O- orN-R5 (R8 represents hydrogen, acyl or lower alkyl); I and n represents 2, 3 or 4, have inhibitory activities of angiotensin converting enzyme and bradykinin decomposing enzyme, and are useful as antihypertensive agents.

  式中的新双环化合物，包括其盐类： 其中 R1 和 R2（可以相同或不同）各自代表氢、卤素、低级烷基、羟基、低级烷氧基或芳氧基，或 R' 和 R2 共同代表低级亚烷基二氧基：R3 和 R4 各自代表氢或低级烷基；R3 代表氢、低级烷基或- SR7（R7 代表氢或酰基）：R6代表氢或酰基，或R6和R7共同代表单键；X代表-CH2-、-O-或N-R5（R8代表氢、酰基或低级烷基）；I和n代表2、3或4，具有抑制血管紧张素转换酶和缓激肽分解酶的活性，可用作降压药。