顺式-4-苯基硫代-L-脯氨酸 (佐芬普利中间体) | 81653-77-2

• 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
• 中文名称: 顺式-4-苯基硫代-L-脯氨酸 (佐芬普利中间体)
• 中文别名: 顺式-4-苯基硫代-L-脯氨酸(佐芬普利中间体)；L-脯氨酸,4-(苯基硫代)-,(4S)-
• 英文名称: (S)-4-phenylthio-L-proline
• 英文别名: (4S)-4-(phenylthio)-L-proline；(2S,4S)-4-phenylthio-pyrrolidine-2-carboxlic acid；(2S,4S)-4-phenylsulfanylpyrrolidin-1-ium-2-carboxylate
• CAS: 81653-77-2
• 化学式: C₁₁H₁₃NO₂S
• 分子量: 223.296
• InChiKey: PCIUUPKYZVILEM-UWVGGRQHSA-N

物化性质

• 沸点：
  417-417.7℃[at 101 325 Pa]
• LogP：
  1.3

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  顺式-4-苯基硫代-L-脯氨酸 (佐芬普利中间体) 在 三甲基溴硅烷 、 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 48.0h， 生成 (2S,4S)-1-{2-[Hydroxy-(4-phenyl-butyl)-phosphinoyl]-acetyl}-4-phenylsulfanyl-pyrrolidine-2-carboxylic acid
  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

文献信息

• [EN] PROLINE DERIVATIVES HAVING AFFINITY FOR THE CALCIUM CHANNEL ALPHA-2-DELTA SUBUNIT<br/>[FR] DERIVES DE PROLINE PRESENTANT UNE AFFINITE POUR LA SOUS-UNITE ALPHA-2-DELTA DU CANAL DE CALCIUM
  申请人：PFIZER LTD

  公开号：WO2004039367A1

  公开（公告）日：2004-05-13

  The compounds of formula (I) or a pharmaceutically acceptable salt, solvate or pro-drug thereof, are proline derivatives useful in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, fibromyalgia, arthritis, neuropathalogical disorders, sleep disorders, visceral pain disorders and gastrointestinal disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included. Wherein either X is O, S, NH or CH2 and Y is CH2 or a direct bond, or Y is O, S or NH and X is CH2; and R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, heteroaryl or aryl, where any ring may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, Cl-C6 alkyl, Cl-C6 alkenyl, CI-C6 alkynyl, Cl-C6 alkoxy, hydroxyC,-C6 alkyl, Cl-C6 alkoxyC,-C6 alkyl, perfluoro Cl-C6 alkyl, perfluoroC,-C6 alkoxy, Cl-C6 alkylamino, di- C1-C6 alkylamino, aminoC1-C6 alkyl, Cl-C6 alkylaminoC,-C6 alkyl, di-Cl-C6 alkylaminoC,-C6 alkyl, CI-C6acyl, C1-C6acyloxy, Cl-C6acyloxyC,-C6 alkyl, Cl-C6 acylamino, Cl-C6 alkylthio, C1-C6 alkylthiocarbonyl, C1-C6 alkylthioxo, C1-C6 alkoxycarbonyl, Cl-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, aminosulfonyl, Cl-C6 alkylaminosulfonyl, di-Cl-C6 alkylaminosulfonyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, phenyl and monocyclic heteroaryl; or a pharmaceutically acceptable salt, solvate or pro-drug thereof.

  化学式（I）的化合物或其药学上可接受的盐、溶剂化合物或前药是脯氨酸衍生物，在治疗癫痫、晕厥发作、运动减退、颅内疾病、神经退行性疾病、抑郁症、焦虑、恐慌、疼痛、纤维肌痛、关节炎、神经病理性疾病、睡眠障碍、内脏疼痛疾病和胃肠疾病的治疗中有用。包括制备最终产品和在过程中有用的中间体的方法。还包括含有一种或多种该化合物的药物组合物。其中X为O、S、NH或CH2，Y为CH2或直接键，或Y为O、S或NH，X为CH2；R为3-12环状烷基、4-12环状杂环烷基、杂芳基或芳基，其中任何环都可以选择性地用一个或多个取代基独立选择自卤素、羟基、氰基、硝基、氨基、羟基羰基、Cl-C6烷基、Cl-C6烯基、Cl-C6炔基、Cl-C6烷氧基、羟基C1-C6烷基、Cl-C6烷氧基C1-C6烷基、全氟Cl-C6烷基、全氟C1-C6烷氧基、Cl-C6烷基氨基、二-Cl-C6烷基氨基、氨基C1-C6烷基、Cl-C6烷基氨基C1-C6烷基、二-Cl-C6烷基氨基C1-C6烷基、Cl-C6酰基、C1-C6酰氧基、Cl-C6酰氧基C1-C6烷基、Cl-C6酰胺基、Cl-C6烷基硫基、C1-C6烷基硫羰基、C1-C6烷基硫氧基、C1-C6烷氧羰基、Cl-C6烷基磺基、C1-C6烷基磺酰胺基、氨基磺基、Cl-C6烷基氨基磺基、二-Cl-C6烷基氨基磺基、3-8环状烷基、4-8环状杂环烷基、苯基和单环杂芳基；或其药学上可接受的盐、溶剂化合物或前药。
• 11C-Radiosynthesis and preliminary human evaluation of the disposition of the ACE inhibitor [11C]zofenoprilat
  作者：Mario Matarrese、Aldo Salimbeni、Elia Anna Turolla、Damiano Turozzi、Rosa Maria Moresco、Davide Poma、Fulvio Magni、Sergio Todde、Claudio Rossetti、Maria Teresa Sciarrone、Giuseppe Bianchi、Marzia Galli Kienle、Ferruccio Fazio

  DOI：10.1016/j.bmc.2003.10.054

  日期：2004.2

  (4S)-1-[(S)-3-Mercapto-2-methylpropanoyl]-4-phenylthio-L-proline (Zofenoprilat, 2), the active metabolite of the potent ACE inhibitor Zofenopril Calcium (1), was labelled with carbon-11 (t(1/2)=20.4 min) to evaluate its pharmacokinetics behaviour in human body using Positron Emission Tomography (PET). [C-11]2 labelling procedures were based on the use of immobilized Grignard reagent and the acylation of (S)-4-phenylthio-L-proline methyl ester (5) with C-11-labelled methacryloyl chloride, followed by a Michael addition with thiobenzoic acid. The radiochemical yield was 5-10% (EOB, decay corrected) and specific radioactivity ranged from 0.5 to 1.5 Ci/mumol (18.5-55.5 GBq/mumol). Preliminary in vivo human evaluation of [C-11]2 showed that the drug accumulates in organs which express high levels of ACE, like lungs and kidneys, and in organs involved in drug metabolism such as the liver and gall bladder. Results of the distribution of [C-11]2 showed a measurable concentration of the drug in the target tissues such as the kidney and to a minor extent, the heart, where it can afford organ protection. (C) 2003 Elsevier Ltd. All rights reserved.

  (4S)-1-[(S)-3-巯基-2-甲基丙酰基]-4-苯基硫代-L-脯氨酸（佐芬普利拉，2），是强效ACE抑制剂佐芬普利钙（1）的活性代谢物，经碳-11标记（t(1/2)=20.4分钟），用于通过正电子发射断层扫描（PET）评估其在人体中的药代动力学行为。[C-11]2的标记程序基于固定化Grignard试剂的使用，以及(S)-4-苯基硫代-L-脯氨酸甲酯（5）与C-11标记的甲基丙烯酰氯的酰化反应，随后与硫代苯甲酸发生迈克尔加成反应。放射化学产率为5-10%（EOB，经衰变校正），比活度范围为0.5至1.5 Ci/μmol（18.5-55.5 GBq/μmol）。对[C-11]2的初步人体体内评估显示，该药物在表达高水平ACE的器官（如肺和肾）中积累，并在参与药物代谢的器官（如肝和胆囊）中也可见。[C-11]2的分布结果显示，在靶组织（如肾）中可测量到药物的浓度，且在某种程度上的心脏组织中也能观察到，这表明其可能提供器官保护作用。© 2003 Elsevier Ltd. 保留所有权利。
• Substituted peptide compounds
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04470973A1

  公开（公告）日：1984-09-11

  Substituted peptide compounds of the formula ##STR1## are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.

  揭示了公式##STR1##的替代肽化合物。由于其抑制血管紧张素转换酶的活性，这些化合物可用作降压剂，并根据X的定义，也可能由于其脑啡肽酶抑制活性而用作镇痛剂。
• Hydroxy substituted peptide compounds
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04514391A1

  公开（公告）日：1985-04-30

  Hydroxy substituted peptide compounds of the formula ##STR1## are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.

  公开了化学式为##STR1##的羟基取代肽化合物。由于其抑制血管紧张素转化酶的活性，这些化合物可用作降压剂，并且根据X的定义，它们也可能由于其脑啡肽酶抑制活性而用作镇痛剂。
• ZOFENOPRIL CALCIUM
  申请人：Gore Vinayak G.

  公开号：US20090176860A1

  公开（公告）日：2009-07-09

  The present invention relates to zofenopril calcium form A substantially free of other forms of zofenopril calcium and to zofenopril calcium having a chemical purity of more than 98.5%. The present invention also relates to methods of preparing such zofenopril calcium. It further relates to compositions comprising such zofenopril calcium. Zofenopril calcium, (4S)-1-[(2S)-3-benzoylthio-2-methylpropionyl]-4-(phenylthio)-L-proline calcium salt, has the following structure:

  本发明涉及基本上不含其他形式的左非诺普利钙的左非诺普利钙A型，以及化学纯度超过98.5%的左非诺普利钙，还涉及制备此类左非诺普利钙的方法。此外，还涉及包含此类左非诺普利钙的组合物。左非诺普利钙，即(4S)-1-[(2S)-3-苯甲酰硫基-2-甲基丙酰]-4-(苯硫基)-L-脯氨酸钙盐，具有以下结构：