phenyl (1-phenyl-1H-pyrazol-5-yl)carbamate | 1211399-92-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: phenyl (1-phenyl-1H-pyrazol-5-yl)carbamate
• 英文别名: phenyl N-(2-phenylpyrazol-3-yl)carbamate
• CAS: 1211399-92-6
• 化学式: C₁₆H₁₃N₃O₂
• 分子量: 279.298
• InChiKey: JMGTUUZYIWWOQU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  56.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  phenyl (1-phenyl-1H-pyrazol-5-yl)carbamate 、 (8aS)-8a-methyl-2-[(1S,2R)-2-phenylcyclopropyl]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以90%的产率得到MK-5710
  参考文献：
  名称：

  Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclo- propyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2

  摘要：

  The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.023
• 作为产物：
  描述：

  5-氨基-1-苯基吡唑 、 氯甲酸苯酯 在 水 、 Brine 作用下， 以 1,2-二氯乙烷 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 phenyl (1-phenyl-1H-pyrazol-5-yl)carbamate
  参考文献：
  名称：

  SATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS

  摘要：

  本发明涉及公式I的化合物及其药学上可接受的盐或互变异构体，它们是Sonic Hedgehog途径的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物对于治疗与异常刺猬途径激活相关的疾病是有用的，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌以及上消化道癌症。

  公开号：

  US20110183989A1

文献信息

• [EN] SATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES BICYCLIQUES SATURÉS EN TANT QU'ANTAGONISTES DE SMO
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2010023480A1

  公开（公告）日：2010-03-04

  The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smoantagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.

  本发明涉及公式I的化合物及其药用可接受的盐或互变异构体，这些化合物是Sonic Hedgehog通路的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物可用于治疗与异常刺刺通路激活相关的疾病，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌，以及上消化道癌症。
• Pyridinone Pyrazole Urea and Pyrimidinone Pyrazole Urea Derivatives
  申请人：Devadas Balekudru

  公开号：US20090270350A1

  公开（公告）日：2009-10-29

  This invention is directed generally to substituted pyridinone and pyrimidinone compounds that generally inhibit p38 kinase, TNF, and/or cyclooxygeπase activity. Such substituted pyridinone and pyrimidinone compounds include compounds generally corresponding in structure to the following formula: wherein Z, n, R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c , R 3d , R 4 , R 5 , R 6 , R 7a , R 7b , R 7c , R 7d and R 7e are as defined in this specification. This invention also is directed to compositions of such substituted pyridinones and pyrimidinones (particularly pharmaceutical compositions), and methods for treating disorders (typically pathological disorders) associated with p38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity.

  本发明通常涉及取代的吡啶酮和嘧啶酮化合物，它们通常抑制p38激酶、TNF和/或环氧合酶活性。这些取代的吡啶酮和嘧啶酮化合物包括通常对应于以下结构公式的化合物：其中Z、n、R1、R2a、R2b、R2c、R2d、R2e、R3a、R3b、R3c、R3d、R4、R5、R6、R7a、R7b、R7c、R7d和R7e如本说明书所定义。本发明还涉及这些取代的吡啶酮和嘧啶酮（特别是药物组成物）的组成物，以及用于治疗与p38激酶活性、TNF活性和/或环氧合酶-2活性相关的疾病（通常是病理性疾病）的方法。
• SATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS
  申请人：Branca Danila

  公开号：US20110183989A1

  公开（公告）日：2011-07-28

  The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smoantagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.

  本发明涉及公式I的化合物及其药学上可接受的盐或互变异构体，它们是Sonic Hedgehog途径的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物对于治疗与异常刺猬途径激活相关的疾病是有用的，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌以及上消化道癌症。
• Saturated bicyclic heterocyclic derivatives as SMO antagonists
  申请人：Branca Danila

  公开号：US08470823B2

  公开（公告）日：2013-06-25

  The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smoantagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.

  本发明涉及I式化合物及其药学上可接受的盐或互变异构体，它们是Sonic Hedgehog途径的抑制剂，特别是Smo拮抗剂。因此，本发明的化合物可用于治疗与异常刺猬途径激活有关的疾病，包括癌症，例如基底细胞癌、髓母细胞瘤、前列腺、胰腺、乳腺、结肠、骨骼和小细胞肺癌以及上消化道癌症。
• Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimid azo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 1
  作者：Savina Malancona、Sergio Altamura、Gessica Filocamo、Olaf Kinzel、Jose Ignacio Martin Hernando、Michael Rowley、Rita Scarpelli、Christian Steinkühler、Philip Jones

  DOI：10.1016/j.bmcl.2011.06.024

  日期：2011.8

  The Hedgehog (Hh-) signaling pathway is a key developmental pathway which controls patterning, growth and cell migration in most tissues, but evidence has accumulated showing that many human tumors aberrantly reactivate this pathway. Smoothened antagonists offer opportunities for the treatment of malignancies dependent on the Hh pathway, and the most advanced clinical candidates are demonstrating encourage initial results. A novel series of [6,5]-bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione smoothened antagonists has been identified, and the series has been extensively explored to ascertain the key detriments for activity, demonstrating that the trans-2-phenylcyclopropyl and hydantoin ring systems are critical for potency, while a variety of urea substituents can be tolerated. The combination of these optimal groups gives smoothened antagonists with activity in the low nanomolar range. (C) 2011 Elsevier Ltd. All rights reserved.