((S)-2-cyano-2-hydroxy-1-isopropylethyl)carbamic acid benzyl ester | 437755-80-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ((S)-2-cyano-2-hydroxy-1-isopropylethyl)carbamic acid benzyl ester
• 英文别名: (3S)-3-benzyloxycarbonylamino-2-hydroxy-4-methylpentanenitrile；((S)-2-Cyano-2-hydroxy-1-isopropyl-ethyl)-carbamic acid benzyl ester；benzyl N-[(2S)-1-cyano-1-hydroxy-3-methylbutan-2-yl]carbamate
• CAS: 437755-80-1
• 化学式: C₁₄H₁₈N₂O₃
• 分子量: 262.309
• InChiKey: GXIXPIHWXFEJFR-ABLWVSNPSA-N

物化性质

• 沸点：
  471.4±45.0 °C(predicted)
• 密度：
  1.162±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  82.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ((S)-2-cyano-2-hydroxy-1-isopropylethyl)carbamic acid benzyl ester 在 palladium on activated charcoal N-甲基吗啉 、 二氯乙酸 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 乙酰氯 、 氯甲酸异丁酯 作用下， 以 乙醇 、 氯仿 、 二甲基亚砜 、 甲苯 为溶剂， -20.0~25.0 ℃ 、344.73 kPa 条件下， 反应 128.5h， 生成 (R)-<(benzyloxycarbonyl)-L-valyl>-N-<1-<(5-cyanobenzoxazol-2-yl)carbonyl>-2-methylpropyl>-L-prolinamide
  参考文献：
  名称：

  Peptidyl .alpha.-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl .alpha.-ketobenzoxazoles

  摘要：

  A series of peptidyl alpha-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase (HNE). These compounds inhibit HNE by forming both a covalent bond between the ketone carbonyl carbon atom and the hydroxyl group of Ser-195 and a hydrogen bond between the benzoxazole nitrogen atom and His-57. Appending to the parent benzoxazole ring a variety of substituents which spanned a range of physicochemical properties had only a modest effect on in, vitro potency (K-i = 3-0.4 nM). This apparent lack of a significant effect is believed to result from the fact that any increased ketone carbonyl activation by the ring substituent is counter balanced by a corresponding decrease in the hydrogen-bonding ability of the benzoxazole nitrogen atom. In contrast to the results in vitro, maximizing in vive activity was critically dependent upon the choice of the benzoxazole ring substituent. Several substituted peptidyl alpha-ketobenzoxazoles effectively inhibited HNE-induced lung injury when administered intratracheally 24 h prior to the enzyme.

  DOI：

  10.1021/jm00020a011
• 作为产物：
  描述：

  CBZ-L-valine methoxymethylamide 在 lithium aluminium tetrahydride 、 sodium hydrogensulfite 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 26.25h， 生成 ((S)-2-cyano-2-hydroxy-1-isopropylethyl)carbamic acid benzyl ester
  参考文献：
  名称：

  The Discovery of Potent, Selective, and Reversible Inhibitors of the House Dust Mite Peptidase Allergen Der p 1: An Innovative Approach to the Treatment of Allergic Asthma

  摘要：

  Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.

  DOI：

  10.1021/jm501102h

文献信息

• Pyruvamide Compounds as Inhibitors of Dust Mite Group 1 Peptidase Allergen and Their Use
  申请人：Robinson Clive

  公开号：US20120322722A1

  公开（公告）日：2012-12-20

  The present invention pertains generally to the field of therapeutic compounds and more specifically to certain pyruvamide compounds of the formula (X) (for convenience, collectively referred to herein as “PVA compounds”), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.

  本发明一般涉及治疗化合物领域，更具体地涉及某些丙酮酰胺化合物的公式（X）（为方便起见，以下统称为“PVA化合物”），该化合物在某些情况下抑制尘螨1组蛋白酶过敏原（例如Der p 1、Der f 1、Eur m 1）。本发明还涉及包含这种化合物的药物组合物，以及在体外和体内使用这种化合物和组合物来抑制尘螨1组蛋白酶过敏原，并用于治疗由尘螨1组蛋白酶过敏原介导的疾病和疾病，通过抑制尘螨1组蛋白酶过敏原而得到缓解的疾病和疾病；哮喘；鼻炎；过敏性结膜炎；特应性皮炎；由尘螨引发的过敏症状；由尘螨1组蛋白酶过敏原引发的过敏症状；以及犬类特应性。
• Substituted heterocyclic compounds useful as inhibitors of (serine
  申请人：Cortech, Inc.

  公开号：US05618792A1

  公开（公告）日：1997-04-08

  The present invention relates to certain substituted oxadiazole, thiadiazole and triazole peptoids which are useful as inhibitors of serine proteases including human neutrophil elastase, equivalently known as human leukocyte elastase.

  本发明涉及某些取代的噁唑啉、噻唑啉和三唑啉肽类化合物，它们可用作丝氨酸蛋白酶的抑制剂，包括人类嗜中性粒细胞弹性蛋白酶，等效地称为人类白细胞弹性蛋白酶。
• Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
  申请人：Robinson Clive

  公开号：US08541363B2

  公开（公告）日：2013-09-24

  The present invention pertains generally to the field of therapeutic compounds and more specifically to certain pyruvamide compounds of the formula (X) (for convenience, collectively referred to herein as “PVA compounds”), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.

  本发明涉及治疗化合物领域，更具体地涉及某些式为（X）的丙酮酰胺化合物（为方便起见，在此统称为“PVA化合物”），它们可以抑制尘螨群1肽酶过敏原（例如Der p 1、Der f 1、Eur m 1）。本发明还涉及包含这些化合物的制药组合物，以及使用这些化合物和组合物在体内和体外抑制尘螨群1肽酶过敏原，并用于治疗由尘螨群1肽酶过敏原介导的疾病和障碍，这些疾病和障碍可以通过抑制尘螨群1肽酶过敏原得到改善，如哮喘、鼻炎、过敏性结膜炎、特应性皮炎、由尘螨引起的过敏症状、由尘螨群1肽酶过敏原引起的过敏症状和犬过敏症。
• Peptidic human leukocyte elastase (HLE) inhibitors
  申请人：ZENECA INC.

  公开号：EP0291234A2

  公开（公告）日：1988-11-17

  The invention provides a series of novel heterocyclic ketones of formula I (set out hereinafter) and pharmaceutically acceptable base-addition salts thereof, in which the values of R4, L, A, X and Q have the meanings defined in the following specification. The compounds of formula I are inhibitors of human leukocytic elastase. The invention also provides pharmaceutical compositions containing a compound of formula I, or a pharmaceutically acceptable base-addition salt thereof, and processes and intermediates for the manufacture of compounds of formula I.

  本发明提供了一系列新颖的式 I 杂环酮类化合物（如下所述）及其药学上可接受的碱加成盐，其中 R4、L、A、X 和 Q 的值具有以下说明书中定义的含义。式 I 的化合物是人白细胞弹性蛋白酶的抑制剂。本发明还提供了含有式 I 化合物或其药学上可接受的碱加成盐的药物组合物，以及制造式 I 化合物的工艺和中间体。
• Development of a highly water-soluble peptide-based human neutrophil elastase inhibitor; AE-3763 for treatment of acute organ injury
  作者：Yasunao Inoue、Tomoki Omodani、Ryotaro Shiratake、Hiroshi Okazaki、Akemi Kuromiya、Taeko Kubo、Fuminori Sato

  DOI：10.1016/j.bmc.2009.09.020

  日期：2009.11

  A series of peptide-based transition-state human neutrophil elastase (HNE) inhibitors with N-terminal acidic moieties were synthesized and their inhibitory activity against HNE was evaluated both in vitro and in vivo. Our results show that compounds containing cyclic amide bridged acidic moieties at the N-terminal have not only improved water solubility but also high in vivo potency. Among these compounds, AE-3763 showed remarkable efficacy in hamster models of elastase-induced lung hemorrhage and lipopolysaccharide (LPS)-induced lung injury as well as in a mouse model of LPS/galactosamine-induced acute multiple organ dysfunctions. The water solubility of AE-3763 (>1000 mg/ml in H(2)O) was also far superior to that of any of the other compounds synthesized. Thus, it is believed that AE-3763 would be useful for treatment of HNE-associated respiratory disorders, such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and acute exacerbation of chronic obstructive pulmonary disease (COPD). (C) 2009 Elsevier Ltd. All rights reserved.