(S)-5-((S)-2-hydroxyl(cyclohexylethyl))-5H-imidazo[5,1-a]isoindole | 1402837-23-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (S)-5-((S)-2-hydroxyl(cyclohexylethyl))-5H-imidazo[5,1-a]isoindole
• 英文别名: NLG919；(S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol；(S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-α]isoindol-5-yl)ethanol；(1S)-1-cyclohexyl-2-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]ethanol
• CAS: 1402837-23-3
• 化学式: C₁₈H₂₂N₂O
• 分子量: 282.385
• InChiKey: YTRRAUACYORZLX-WMZOPIPTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  38
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  2'-碘苯乙酮 在 4-二甲氨基吡啶 盐酸 、 正丁基锂 、 dimethyl sulfide borane 、 dicyclohexylmethylamine 、 sodium hydride 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 、 (S)-2-甲基-CBS-恶唑硼烷 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 75.5h， 生成 (S)-5-((S)-2-hydroxyl(cyclohexylethyl))-5H-imidazo[5,1-a]isoindole
  参考文献：
  名称：

  [EN] FUSED IMIDAZOLE DERIVATIVES USEFUL AS IDO INHIBITORS
  [FR] DÉRIVÉS D'IMIDAZOLE FUSIONNÉS POUVANT ÊTRE EMPLOYÉS EN TANT QU'INHIBITEURS D'IDO

  摘要：

  公开号：

  WO2012142237A8

文献信息

• Chiral resolution, absolute configuration determination, and stereo-activity relationship study of IDO1 inhibitor NLG919
  作者：Wen-Qiang Liu、Fang-Fang Lai、Jie Zhang、Li Sheng、Yan Li、Li Li、Xiao-Guang Chen

  DOI：10.1016/j.tet.2018.05.005

  日期：2018.6

  acid as resolution reagent, optical pure (R)-2 (e.e. > 99%, yield = 70%) was obtained. The mechanism of chiral resolution was clarified through single-crystal X-ray diffraction of the diastereomeric salt. The absolute configurations of four stereoisomers of 1 were established through electronic circular dichroism spectra, quantum chemical calculation and transition metal method. Their IDO1 inhibitory

  NLG919（1）在化学结构上具有两个手性碳原子，是一种有效的吲哚胺2，3-二加氧酶1（IDO1）抑制剂。我们开发了一种制备1的所有立体异构体的有效方法，关键步骤是外消旋中间体2的手性拆分。最佳分离度的溶剂体系为二氯甲烷和正戊烷或石油醚。使用（ - ） -二- p -toluoyl- ð -酒石酸作为拆分试剂，光学纯的（- [R ）- 2获得（ee＞ 99％，产率＝ 70％）。通过非对映异构体盐的单晶X射线衍射阐明了手性拆分的机理。通过电子圆二色性光谱，量子化学计算和过渡金属方法建立了四个1的立体异构体的绝对构型。通过体外和小鼠药理试验评估了它们对IDO1的抑制活性，表明C5的S构型对抑制IDO1起重要作用，而对C2'的立体化学对小鼠的IDO1抑制活性影响很小。
• Fused Imidazole Derivatives Useful as IDO Inhibitors
  申请人：NewLink Genetics Corporation

  公开号：US20140066625A1

  公开（公告）日：2014-03-06

  Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleanine 2,3-dioxygenase (IDO) mediated immunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease.

  目前提供IDO抑制剂及其制药组合物，用于调节吲哚胺2,3-双加氧酶的活性；治疗吲哚胺2,3-双加氧酶（IDO）介导的免疫抑制；治疗受益于抑制吲哚胺-2,3-双加氧酶酶活性的医疗状况；增强包括给予抗癌药物在内的抗癌治疗的有效性；治疗与癌症相关的肿瘤特异性免疫抑制；以及治疗与传染病相关的免疫抑制。
• COMPOSITIONS COMPRISING FUSED IMIDAZOLE DERIVATIVES USEFUL AS IDO INHIBITORS
  申请人：Newlink Genetics Corporation

  公开号：EP3348558A1

  公开（公告）日：2018-07-18

  Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleamine 2,3-dioxygenase (IDO) mediated inimunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosuppression associated with an infectious disease.

  目前提供的IDO抑制剂及其药物组合物可用于调节吲哚胺-2,3-二氧化酶的活性；治疗吲哚胺-2,3-二氧化酶（IDO）介导的免疫抑制；治疗从抑制吲哚胺-2,3-二氧化酶酶活性中获益的病症；提高抗癌治疗的有效性，包括施用抗癌剂；治疗与癌症相关的肿瘤特异性免疫抑制；以及治疗与传染性疾病相关的免疫抑制。
• IDO inhibitors
  申请人：NewLink Genetics Corporation

  公开号：US10233190B2

  公开（公告）日：2019-03-19

  Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease.

  目前提供的 IDO 抑制剂及其药物组合物可用于调节吲哚胺-2,3-二氧 化酶的活性；治疗吲哚胺-2,3-二氧 化酶（IDO）介导的免疫抑制；治疗从抑制吲哚胺-2,3-二氧 化酶酶活性中获益的病症；提高抗癌治疗的有效性，包括施用抗癌剂；治疗与癌症相关的肿瘤特异性免疫抑制；以及治疗与传染病相关的免疫抑制。
• Discovery of Clinical Candidate (1<i>R</i>,4<i>r</i>)-4-((<i>R</i>)-2-((<i>S</i>)-6-Fluoro-5<i>H</i>-imidazo[5,1-<i>a</i>]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1
  作者：Sanjeev Kumar、Jesse P. Waldo、Firoz A. Jaipuri、Agnieszka Marcinowicz、Clarissa Van Allen、James Adams、Tanay Kesharwani、Xiaoxia Zhang、Richard Metz、Angela J. Oh、Seth F. Harris、Mario R. Mautino

  DOI：10.1021/acs.jmedchem.9b00662

  日期：2019.7.25

  A novel class of 5-substituted 5H-imidazo[5,1-a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5H-imidazo[5,1-a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.