rel-(3aS,6S,6aR)-6-methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester

• 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: rel-(3aS,6S,6aR)-6-methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester
• 英文别名: benzyl (3aS,6S,6aR)-6-methyl-5-oxo-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylate
• 化学式: C₁₅H₁₈N₂O₃
• 分子量: 274.32
• InChiKey: CIORCZZUODKGFY-WCFLWFBJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  rel-(3aS,6S,6aR)-6-methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester 在 palladium on activated charcoal 氢气 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 水 、 异丙醇 为溶剂， 反应 4.08h， 生成 (3S,3aR,6aS)-1-(cyclopropylcarbonyl)-3-methylhexahydropyrrolo[3,2-b]pyrrol-2(1H)-one
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5‘-trans-Lactams (5-Oxo-hexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability

  摘要：

  A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K-i) against the viral enzyme. The. SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.

  DOI：

  10.1021/jm030810w
• 作为产物：
  描述：

  (2R,3S)-3-amino-2-ethoxycarbonylmethylpyrrolidine-1-carboxylic acid benzyl ester 在 叔丁基氯化镁 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 5.51h， 生成 rel-(3aS,6S,6aR)-6-methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxohexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 2. Potency and Chirality

  摘要：

  The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.

  DOI：

  10.1021/jm0102203

文献信息

• [EN] PYROLOPYRROLONE DERIVATIVES<br/>[FR] DERIVES DE PYROLOPYRROLONE
  申请人：GLAXO GROUP LIMITED

  公开号：WO1998043975A1

  公开（公告）日：1998-10-08

  (EN) The present invention relates to therapeutically active bicyclic compounds, processes for the manufacture of said compounds, pharmaceutical formulations containing said compounds and the use of said compounds in treatment and prophylaxis, particularly of viral infections, more particularly of infections caused by viruses which encode for a serine protease enzyme, especially viruses of the herpes family. Thus, according to one aspect of this invention, we provide a compound of general formula (I) wherein R represents H, substituted or unsubstituted C1-3 alkyl; R1 represents optionally substituted heteroaryl or fused heteroaryl with one to four heteroatoms, R5CO, R5NHCO, R5CS or R5NHCS wherein R5 may be substituted or unsubstituted and represents H, C1-6 alkyl, C1-6 alkenyl, C3-7 cylcoalkyl or fused cycloalkyl, heteroaryl or fused heteroaryl containing one to four heteroatoms, aryl or fused aryl, or arylC1-3alkyl; R2 represents R6-X- or R3CO, wherein R3 may be substituted or unsubstituted and represents (A), (B), (C), (D), (E), (F), (G), or (H), optionally including one or more further heteroatoms; R4 represents R6-X-; R6 is optionally substituted heterocyclic or fused heterocyclic with 1-4 heteroatoms, heteroaryl or fused heteroaryl with 1-4 heteroatoms, C3-10cycloalkyl or fused cycloalkyl, aryl or fused aryl; and X represents a linker group chosen from C=O, NHC=O, C(=O)C=O, CH=CHCO, CH2CO, CH2 or SO2; and salts and solvates thereof.(FR) La présente invention concerne des composés bicycliques thérapeutiquement actifs, des procédés de fabrication desdits composés, des compositions pharmaceutiques contenant lesdits composés et l'utilisation desdits composés dans le traitement et la prophylaxie d'infections virales en particulier et, notamment, d'infections causées par des virus qui codent une enzyme sérine protéase, en particulier les virus de la famille de l'herpès. Ainsi, selon un mode de réalisation de l'invention, cette dernière concerne un composé de la formule générale (I) dans laquelle, R représente H, un alkyle C1-3 substitué ou non; R1 représente un hétéroaryle éventuellement substitué ou un hétéroaryle condensé contenant de un à quatre hétéroatomes, R5CO, R5NHCO, R5CS ou R5NHCS où R5 peut être substitué ou non et représente H, alkyle C1-6, alcényle C1-6, cycloalkyle C3-7 ou un cycloalkyle condensé, hétéroaryle ou un hétéroaryle condensé contenant de un à quatre hétéroatomes, un aryle ou un aryle condensé, ou un arylC1-3alkyle; R2 représente R6-X- ou R3CO, où R3 peut être substitué ou non et représente (A), (B), (C), (D), (E), (F), (G), ou (H) qui contiennent éventuellement au minimum un hétéroatome supplémentaire; R4 représente R6-X-; R6 représente un hétérocyclique éventuellement substitué ou un hétérocyclique condensé contenant de un à quatre hétéroatomes, un hétéroaryle ou un hétéroaryle condensé contenant de un à quatre hétéroatomes, un cycloalkyle C3-10 ou un cycloalkyle condensé, un aryle ou un aryle condensé; et X représente un groupe de liaison choisi parmi C=O, NHC=O, C(=O)C=O, CH=CHCO, CH2CO, CH2 ou SO2. L'invention concerne en outre des sels et solvates de ces composés.

  本发明涉及治疗活性双环化合物、制备该化合物的方法、含有该化合物的制药组合物以及该化合物在治疗和预防中的应用，特别是病毒感染，尤其是由编码丝氨酸蛋白酶酶的病毒引起的感染，特别是疱疹病毒家族的病毒。因此，根据本发明的一个方面，我们提供了一个通式（I）的化合物，其中R代表H、取代或未取代的C1-3烷基；R1代表可选取代的杂环芳基或含有1-4个杂原子的融合杂环芳基，R5CO、R5NHCO、R5CS或R5NHCS，其中R5可以取代或未取代，代表H、C1-6烷基、C1-6烯基、C3-7环烷基或融合的环烷基、杂环芳基或含有1-4个杂原子的融合杂环芳基、芳基或融合芳基，或芳基C1-3烷基；R2代表R6-X-或R3CO，其中R3可以取代或未取代，代表（A）、（B）、（C）、（D）、（E）、（F）、（G）或（H），可包括一个或多个进一步的杂原子；R4代表R6-X-；R6是可选取代的杂环或含有1-4个杂原子的融合杂环、杂环芳基或含有1-4个杂原子的融合杂环芳基、C3-10环烷基或融合的环烷基、芳基或融合芳基；X代表从C=O、NHC=O、C（=O）C=O、CH=CHCO、CH2CO、CH2或SO2中选择的连接基团；以及其盐和溶剂化物。
• Design and Synthesis of Pyrrolidine-5,5-<i>trans-</i>lactams (5-Oxo-hexahydro-pyrrolo[3,2-<i>b</i>]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 1. The α-Methyl-<i>trans</i>-lactam Template
  作者：Alan D. Borthwick、S. Jane Angier、Andrew J. Crame、Anne M. Exall、Terry M. Haley、Graham J. Hart、Andrew M. Mason、Andrew M. K. Pennell、Gordon G. Weingarten

  DOI：10.1021/jm000078q

  日期：2000.11.1

  Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta -methyl-, desmethyl-, and alpha -methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown that these inhibitors can bind covalently and reversibly to the viral enzyme in a time-dependent manner by a mechanism which is consistent; with acylation of HCMV delta Ala protease at the active site nucleophile Ser 132. SAR in this series of pyrrolidine-5,5-trans-lactams has defined the relative stereochemisty of the methyl substituent adjacent to the lactam carbonyl, the functionality on the lactam nitrogen, and the mechanism of action of this novel series of serine protease inhibitors against the HCMV dAla protease. Activity decreases on moving from the alpha -methyl to the desmethyl to the beta -methyl series. This selectivity is the opposite of that observed for these templates against the elastase and thrombin enzymes. The activity against HCMV delta Ala protease is the greatest with inhibitors based on the Cbz-protected alpha -methyl-5,5-trans-lactam template which have low micromolar activity against the viral enzyme.
• Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3: potency and plasma stability
  作者：Alan D Borthwick、Anne M Exall、Terry M Haley、Deborah L Jackson、Andrew M Mason、Gordon G Weingarten

  DOI：10.1016/s0960-894x(02)00294-9

  日期：2002.7

  Mechanism-based inhibitors of HCMV protease, which Lire stable to human plasma (greater than or equal to20h) and have single-figure potency in the muM range against HCMV protease, have been developed based on the dansylprohne alpha-methyl pyrrolidine-5,5-translactam nucleus. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Borthwick, Alan D.; Crame, Andrew J.; Davies, David E., Synlett, 2000, # 4, p. 504 - 508
  作者：Borthwick, Alan D.、Crame, Andrew J.、Davies, David E.、Exall, Anne M.、Jackson, Deborah L.、Mason, Andrew M.、Pennell, Andrew M. K.、Weingarten, Gordon G.

  DOI：——

  日期：——
• PYROLOPYRROLONE DERIVATIVES
  申请人：GLAXO GROUP LIMITED

  公开号：EP0973775A1

  公开（公告）日：2000-01-26