[3H-Benzothiazol-(2Z)-ylidene]-(2-chloro-pyrimidin-4-yl)-acetonitrile | 861411-30-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: [3H-Benzothiazol-(2Z)-ylidene]-(2-chloro-pyrimidin-4-yl)-acetonitrile
• 英文别名: (Z)-2-(Benzo[d]thiazol-2(3H)-ylidene)-2-(2-chloropyrimidin-4-yl)acetonitrile；(2Z)-2-(3H-1,3-benzothiazol-2-ylidene)-2-(2-chloropyrimidin-4-yl)acetonitrile
• CAS: 861411-30-5
• 化学式: C₁₃H₇ClN₄S
• 分子量: 286.744
• InChiKey: KNHMVCIERLWSIP-XYOKQWHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  86.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [3H-Benzothiazol-(2Z)-ylidene]-(2-chloro-pyrimidin-4-yl)-acetonitrile 在 三乙胺 、 肼 作用下， 以 乙醇 为溶剂， 反应 72.0h， 生成 (2Z)-2-(3H-1,3-benzothiazol-2-ylidene)-2-(2-hydrazinylpyrimidin-4-yl)acetonitrile
  参考文献：
  名称：

  Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal Kinase

  摘要：

  Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA).

  DOI：

  10.1021/jm0310986
• 作为产物：
  描述：

  2,4-二氯嘧啶 、 苯并噻唑-2-乙腈 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以84%的产率得到[3H-Benzothiazol-(2Z)-ylidene]-(2-chloro-pyrimidin-4-yl)-acetonitrile
  参考文献：
  名称：

  Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal Kinase

  摘要：

  Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA).

  DOI：

  10.1021/jm0310986

文献信息

• Benzothiazole Formulations and Use Thereof
  申请人：Esposito Pierandrea

  公开号：US20080051397A1

  公开（公告）日：2008-02-28

  The present invention is related to macrogol glyceride pharmaceutical formulations containing benzothiazole derivatives. In particular, the invention is related to benzothiazole stearoyl macrogol pharmaceutical formulations, method of preparation and use thereof.

  本发明涉及含有苯并噻唑衍生物的大聚乙二醇甘油酯制剂。具体地，本发明涉及苯并噻唑硬脂酰大聚乙二醇制剂，其制备方法和用途。
• [EN] BENZAZOLE DERIVATIVES FOR THE TREATMENT OF SCLERODERMA<br/>[FR] DERIVES DE BENZAZOLE POUR LE TRAITEMENT DE SCLERODERMIE
  申请人：APPLIED RESEARCH SYSTEMS

  公开号：WO2003047570A1

  公开（公告）日：2003-06-12

  The present invention is related to the use of benzazole derivatives of formula (I) for the treatment and/or prevention of scleroderma and its therapeutic implications selected in the group consisting of systemic sclerosis, scleroderma-like disoders, sine scleroderma, liver cirrhosis, interstitial pulmonary fibrosis, Dupuytren's contracture, keloid and other scarring/wound healing abnormalities, postoperative adhesions and reactive fibrosis, as well as chronic heart failure, in particular after myocardial infarction.

  本发明涉及使用式(I)的苯并咪唑衍生物治疗和/或预防硬皮病及其治疗意义的方法，所述治疗意义包括系统性硬化症、类硬皮病、纯皮硬化症、肝硬化、间质性肺纤维化、杜普伊特伦收缩、瘢痕增生/伤口愈合异常、术后粘连和反应性纤维化，以及慢性心力衰竭，特别是心肌梗死后。
• Process for the Preparation of Piperazine Benzothiazoles
  申请人：Schiavo Cesare

  公开号：US20100121057A1

  公开（公告）日：2010-05-13

  The present invention discloses a process for the preparation of compounds of formula (I) where the groups and symbols are as defined in the description, said process comprising a) reacting a benzothiazol-2-ylacetonitrile bearing group R 1 with an activated pyrimidine, in a reaction medium; then treating the obtained derivative in said reaction medium with a weak base anion exchange resin; then, after removing said resin and isolating the reaction product, reacting it with a substituted piperazine-benzyl-alkyloxy. The final product can optionally be salified. The invention also relates to the preparation of N-acyl-substituted piperazine-benzyl-alkyloxy, comprising treating a bromide-alkyl-phenyl-4-ester wherein the ester group is selected from COOMe or COOEt with DIBAL to obtain (4-bromomethyl-phenyl)-methanol and reacting the latter with 1-piperazin-1-yl-acyl. The processes here disclosed present a number of advantages, for example, higher yield and purity of final product. Moreover, in case of piperazine group bearing hydrogen or an acyl group in position 4, the preparation of the intermediate substituted piperazine-benzyl-alkyloxy (V) need no protection/deprotection steps.
• US7259162B2
  申请人：——

  公开号：US7259162B2

  公开（公告）日：2007-08-21
• US7314878B2
  申请人：——

  公开号：US7314878B2

  公开（公告）日：2008-01-01