(3-cyclopentyloxy-4-difluoromethoxyphenyl) acetonitrile | 153587-15-6

• 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: (3-cyclopentyloxy-4-difluoromethoxyphenyl) acetonitrile
• 英文别名: (3-Cyclopentyloxy-4-difluoromethoxyphenyl)acetonitrile；2-[3-cyclopentyloxy-4-(difluoromethoxy)phenyl]acetonitrile
• CAS: 153587-15-6
• 化学式: C₁₄H₁₅F₂NO₂
• 分子量: 267.275
• InChiKey: OTQKYEODWPXGPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  42.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3-cyclopentyloxy-4-difluoromethoxyphenyl) acetonitrile 在 镍 sodium hydroxide 、 苄基三乙基氯化铵 、 氨 、 氢气 作用下， 以 甲醇 为溶剂， 生成
  参考文献：
  名称：

  咪唑-2-酮和2-氰基氨基咪唑衍生物的合成和生物学评估：新系列的PDE4抑制剂。

  摘要：

  该交流描述了一系列新的咪唑-2-酮和2-氰基氨基咪唑衍生物的合成和体外PDE4抑制活性。还在体内模型中测试了所描述的化合物，以评估其局部给药后的抗炎活性以及胃肠道副作用。几种化合物被证明是有效的PDE4抑制剂，某些2-氰基氨基咪唑类药物与参考化合物相比，胃肠道副作用较小，但局部给药后仍具有抗炎活性。

  DOI：

  10.1016/s0960-894x(01)00817-4
• 作为产物：
  描述：

  4-difluoromethoxy-3-(cyclopentyloxy)phenylmethanol 在 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 2.0h， 生成 (3-cyclopentyloxy-4-difluoromethoxyphenyl) acetonitrile
  参考文献：
  名称：

  咪唑-2-酮和2-氰基氨基咪唑衍生物的合成和生物学评估：新系列的PDE4抑制剂。

  摘要：

  该交流描述了一系列新的咪唑-2-酮和2-氰基氨基咪唑衍生物的合成和体外PDE4抑制活性。还在体内模型中测试了所描述的化合物，以评估其局部给药后的抗炎活性以及胃肠道副作用。几种化合物被证明是有效的PDE4抑制剂，某些2-氰基氨基咪唑类药物与参考化合物相比，胃肠道副作用较小，但局部给药后仍具有抗炎活性。

  DOI：

  10.1016/s0960-894x(01)00817-4

文献信息

• Compounds useful for treating allergic or inflammatory diseases
  申请人：SmithKline Beecham Corporation

  公开号：US05449686A1

  公开（公告）日：1995-09-12

  Novel cyclohexanes of Formulas (I) and (II) ##STR1## are described herein. They inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production; these compounds are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase V.

  本文描述了化学式（I）和（II）的新型环己烷化合物。它们抑制肿瘤坏死因子的产生，并可用于治疗由TNF产生介导或加重的疾病状态；这些化合物还可用于介导或抑制磷酸二酯酶V的酶活性。
• [EN] CONDENSED HETEROCYCLIC COMPOUNDS AS PDE-IV INHIBITORS FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS<br/>[FR] COMPOSES CONDENSES HETEROCYCLIQUES UTILISES COMME INHIBITEURS DE PDE-IV DANS LE TRAITEMENT DE TROUBLES INFLAMMATOIRES ET ALLERGIQUES
  申请人：GLENMARK PHARMACEUTICALS LTD

  公开号：WO2004016596A1

  公开（公告）日：2004-02-26

  The present invention relates to novel heterocyclic compounds that inhibit phosphodiesterase type 4 (PDE4). The compounds are useful for treating inflammatory conditions, diseases of the central nervous system and insulin resistant diabetes , (formula I) wherein P is selected from the group consisting of bond, oxygen, sulfur and NR1; wherein P1 is selected from the group consisting of hydrogen, halogen atom, -OR1, -S(O)mR1, -C(O)R1, formly amine, nitro and -NRxRy. R2 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, CN, -CH=CR3R3. The ring 'A' is selected from the group consisting of substituted or unsubstituted aryl ring, and optionally substituted saturated or unsaturated five to seven membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S, and NR1; wherein R1, Rx, Ry and R3 are as defined in the description.

  本发明涉及一种新型杂环化合物，其抑制磷酸二酯酶4型（PDE4）。这些化合物可用于治疗炎症性疾病、中枢神经系统疾病和胰岛素抵抗性糖尿病，（式I）其中P选自键，氧，硫和NR1的组；其中P1选自氢，卤素原子，-OR1，-S（O）mR1，-C（O）R1，甲酰胺，硝基和-NRxRy的组。R2选自氢，卤素，取代或未取代的烷基，取代或未取代的环烷基，CN，-CH=CR3R3。环'A'选自取代或未取代的芳基环，以及可选地取代的饱和或不饱和的含有一个或多个来自O、S和NR1的杂原子的五至七元杂环环，其中R1、Rx、Ry和R3如描述中所定义。
• Piperidine derivative compounds and drugs containing the compounds as the active ingredient
  申请人：Ochiai Hiroshi

  公开号：US20050080107A1

  公开（公告）日：2005-04-14

  A piperidine derivative of formula (I) (wherein all symbols are as described in the specification.) and an intermediate for the preparation thereof. The compound of formula (I) has phosphodiesterase 4 inhibitory activity, and it is useful for the prevention and/or treatment of inflammatory diseases, diabetic diseases, allergic diseases, autoimmune diseases, ocular diseases, osteoporosis, bone fracture, osteoarthritis, obesity, bulimia, depression, Parkinson's disease, dementia, ischemia-reperfusion injury, leukemia, acquired immunodeficiency deficiency syndrome (AIDS), shock, systemically inflammatory responsive diseases (SIRS), etc.

  公式（I）的哌啶衍生物（其中所有符号如说明书所述）及其制备的中间体。公式（I）化合物具有磷酸二酯酶4抑制活性，可用于预防和/或治疗炎症性疾病，糖尿病性疾病，过敏性疾病，自身免疫性疾病，眼部疾病，骨质疏松症，骨折，骨关节炎，肥胖症，暴食症，抑郁症，帕金森病，痴呆症，缺血再灌注损伤，白血病，获得性免疫缺陷综合症（AIDS），休克，全身炎症反应性疾病（SIRS）等。
• Highly potent PDE4 inhibitors with therapeutic potential
  作者：Hiroshi Ochiai、Tazumi Ohtani、Akiharu Ishida、Kensuke Kusumi、Masashi Kato、Hiroshi Kohno、Yoshihiko Odagaki、Katuya Kishikawa、Susumu Yamamoto、Hiroshi Takeda、Takaaki Obata、Hisao Nakai、Masaaki Toda

  DOI：10.1016/j.bmc.2004.06.032

  日期：2004.9

  The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo(TM) 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure-activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented. (C) 2004 Elsevier Ltd. All rights reserved.
• Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study
  作者：Chang Huang、Qiu‐Ping Zhong、Lv Tang、Hai‐Tao Wang、Jiang‐Ping Xu、Zhong‐Zhen Zhou

  DOI：10.1111/cbdd.13438

  日期：2019.4

  AbstractPhosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q2), conventional coefficient (r2), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC50 values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.