4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide | 907205-86-1

• 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: 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide
• 英文别名: 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide；N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide
• CAS: 907205-86-1
• 化学式: C₂₅H₃₃BrN₄O₂Si
• 分子量: 529.552
• InChiKey: RRBIIRATEAFMIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.68
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  79.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide 在 异丙基氯化镁 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 0.75h， 生成 4-cyano-1H-imidazole-2-carboxylic acid(2-(4,4-dimethyl-cyclohex-1-enyl)-4-{1-[4-(2-methoxy-ethyl)-piperazin-1-yl]-1-methyl-ethyl}-phenyl)-amide
  参考文献：
  名称：

  Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

  摘要：

  Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.09.061
• 作为产物：
  描述：

  4 -溴- 2 - 碘苯甲胺 在 四(三苯基膦)钯 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 sodium carbonate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 5.0h， 生成 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide
  参考文献：
  名称：

  Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

  摘要：

  Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.09.061

文献信息

• INHIBITORS OF C-FMS KINASE
  申请人：Illig Carl R.

  公开号：US20090105296A1

  公开（公告）日：2009-04-23

  The invention is directed to compounds of Formula I: wherein Z, X, J, R 2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

  该发明涉及以下式I的化合物： 其中Z、X、J、R2和W如规范中所述，以及其溶剂化合物、水合物、互变异构体和药学上可接受的盐，能够抑制蛋白酪氨酸激酶，特别是c-fms激酶。本发明还提供了治疗自身免疫疾病；以及伴有炎症成分的疾病；治疗卵巢癌、子宫癌、乳腺癌、前列腺癌、肺癌、结肠癌、胃癌、毛细胞白血病的转移；以及治疗疼痛，包括肿瘤转移或骨关节炎引起的骨骼疼痛，或内脏、炎症和神经源性疼痛；以及骨质疏松症、帕盖特病和其他骨吸收介导发病率的疾病，包括类风湿性关节炎和其他形式的炎症性关节炎、骨关节炎、假体失败、溶骨性肉瘤、骨髓瘤和肿瘤转移至骨骼的方法，其中使用了式I的化合物。
• Inhibitors of c-fms kinase
  申请人：Illig R. Carl

  公开号：US20060189623A1

  公开（公告）日：2006-08-24

  The invention is directed to compounds of Formula I: wherein A, X, R 2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

  本发明涉及式I的化合物：其中A，X，R2和W在规范中列出，以及其溶剂化物，水合物，互变异构体和药学上可接受的盐，该化合物抑制蛋白酪氨酸激酶，特别是c-fms激酶。本发明还提供了使用式I的化合物治疗自身免疫性疾病和具有炎症成分的疾病的方法；治疗卵巢癌，子宫癌，乳腺癌，结肠癌，胃癌，毛细胞白血病和非小细胞肺癌的转移；以及治疗疼痛，包括由肿瘤转移或骨关节炎引起的骨骼疼痛，或内脏，炎症和神经源性疼痛；以及骨质疏松症，帕吉特病和其他骨吸收介导的疾病，包括关节炎，假体失效，溶骨性肉瘤，骨髓瘤和向骨骼的肿瘤转移。
• c-fms kinase inhibitors
  申请人：Player R. Mark

  公开号：US20060258666A1

  公开（公告）日：2006-11-16

  The invention is directed to compounds of Formula II: wherein A, R 1 , R 2 , R 3 , R 4 , X, Y and W are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase.

  本发明涉及公式II的化合物： 其中A、R1、R2、R3、R4、X、Y和W在说明书中有所阐述，以及其溶剂化物、水合物、互变异构体或药学上可接受的盐，其可抑制蛋白酪氨酸激酶，特别是c-fms激酶。
• Inhibitors of C-FMS kinase
  申请人：Illig Carl R.

  公开号：US08674100B2

  公开（公告）日：2014-03-18

  The invention is directed to compounds of Formula I: wherein Z, X, J, R2 and W are as set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. The compounds of formula I are useful for treating a variety of disorders including autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and psoriasis.

  本发明涉及I式化合物：其中Z，X，J，R2和W如规范所述，以及其溶剂化物，水合物，互变异构体和药学上可接受的盐，该化合物抑制蛋白酪氨酸激酶，特别是c-fms激酶。I式化合物对于治疗多种疾病包括自身免疫性疾病如类风湿性关节炎，多发性硬化症和牛皮癣等非常有用。
• Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors
  作者：Kenneth J. Wilson、Carl R. Illig、Jinsheng Chen、Mark J. Wall、Shelley K. Ballentine、Renee L. DesJarlais、Yanmin Chen、Carsten Schubert、Robert Donatelli、Ioanna Petrounia、Carl S. Crysler、Christopher J. Molloy、Margery A. Chaikin、Carl L. Manthey、Mark R. Player、Bruce E. Tomczuk、Sanath K. Meegalla

  DOI：10.1016/j.bmcl.2010.05.013

  日期：2010.7

  During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity. (c) 2010 Elsevier Ltd. All rights reserved.