5-<2-(methylsulfonyl)pyrimidin-4-yl>-1-methyl-4-<3-(trifluoromethyl)phenyl>-2-<4-(N-(benzyloxycarbonyl)piperidinyl)>imidazole | 200801-95-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-<2-(methylsulfonyl)pyrimidin-4-yl>-1-methyl-4-<3-(trifluoromethyl)phenyl>-2-<4-(N-(benzyloxycarbonyl)piperidinyl)>imidazole
• 英文别名: 4-[5-(2-methylsulfonylpyrimidin-4-yl)-1-methyl-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester；Benzyl 4-[1-methyl-5-(2-methylsulfonylpyrimidin-4-yl)-4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine-1-carboxylate
• CAS: 200801-95-2
• 化学式: C₂₉H₂₈F₃N₅O₄S
• 分子量: 599.634
• InChiKey: RUHVWPYNNKIIIG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  116
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  5-<2-(methylsulfonyl)pyrimidin-4-yl>-1-methyl-4-<3-(trifluoromethyl)phenyl>-2-<4-(N-(benzyloxycarbonyl)piperidinyl)>imidazole 在 palladium on activated charcoal 氢气 作用下， 以 异丙醇 为溶剂， 140.0 ℃ 、101.33 kPa 条件下， 反应 24.17h， 生成 (S)-{4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethylphenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(1-phenylethyl)amine
  参考文献：
  名称：

  Design and Synthesis of Potent, Selective, and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38 Mitogen-Activated Protein Kinase

  摘要：

  Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis; The SAR leading to the development of selectivity against c-Raf and JNK2 alpha 1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a a-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

  DOI：

  10.1021/jm9805236
• 作为产物：
  描述：

  3-(三氟甲基)苯甲酰氯 在 乙酸铵 、 盐酸 、 Oxone 、 titanium(III) chloride 、 溶剂黄146 、 三乙胺 、 lithium diisopropyl amide 、 sodium nitrite 作用下， 以 甲醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 58.83h， 生成 5-<2-(methylsulfonyl)pyrimidin-4-yl>-1-methyl-4-<3-(trifluoromethyl)phenyl>-2-<4-(N-(benzyloxycarbonyl)piperidinyl)>imidazole
  参考文献：
  名称：

  Design and Synthesis of Potent, Selective, and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38 Mitogen-Activated Protein Kinase

  摘要：

  Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis; The SAR leading to the development of selectivity against c-Raf and JNK2 alpha 1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a a-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

  DOI：

  10.1021/jm9805236

文献信息

• Substituted imidazoles having cytokine inhibitory activity
  申请人：Merck & Co., Inc.

  公开号：US05859041A1

  公开（公告）日：1999-01-12

  Compounds represented by formula I: ##STR1## are disclosed. .sup.AR represents an aromatic group containing 6-10 atoms; and ##STR2## represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 O or S atom. A pharmaceutical composition is also included. Methods of treating cancer and cytokine mediated diseases are also included.

  公式I代表的化合物被披露。.sup.AR代表含有6-10个原子的芳香族基团；而##STR2##代表含有至少一个N原子的4至10个成员非芳香族杂环，并且可选地含有1-2个额外的N原子和0-1个O或S原子。还包括一种药物组合物。还包括治疗癌症和细胞因子介导疾病的方法。
• SUBSTITUTED IMIDAZOLES HAVING CYTOKINE INHIBITORY ACTIVITY
  申请人：MERCK & CO., INC.

  公开号：EP0906307B1

  公开（公告）日：2005-04-27
• EP0906307A4
  申请人：——

  公开号：EP0906307A4

  公开（公告）日：2002-05-29
• [EN] SUBSTITUTED IMIDAZOLES HAVING CYTOKINE INHIBITORY ACTIVITY<br/>[FR] IMIDAZOLES SUBSTITUES INHIBANT LA CYTOKINE
  申请人：MERCK & CO., INC.

  公开号：WO1997047618A1

  公开（公告）日：1997-12-18

  (EN) Compounds represented by formula (I) are disclosed. AR represents an aromatic group containing 6-10 atoms; and (a) represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 O or S atom. A pharmaceutical composition is also included. Methods of treating cancer and cytokine mediated diseases are also included.(FR) L'invention concerne des composés représentés par la formule (I). Dans la formule, AR représente un groupe aromatique de 6 à 10 atomes; (a) représente un hétérocycle non aromatique à 4 ou 10 éléments comprenant au moins un atome de N et, facultativement, un ou deux atomes supplémentaires de N et 0 ou 1 atome de O ou S. On décrit par ailleurs une composition pharmaceutique et des procédés pour le traitement du cancer et des maladies à médiation cytokinique.
• Design and Synthesis of Potent, Selective, and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38 Mitogen-Activated Protein Kinase
  作者：Nigel J. Liverton、John W. Butcher、Christopher F. Claiborne、David A. Claremon、Brian E. Libby、Kevin T. Nguyen、Steven M. Pitzenberger、Harold G. Selnick、Garry R. Smith、Andrew Tebben、Joseph P. Vacca、Sandor L. Varga、Lily Agarwal、Kim Dancheck、Amy J. Forsyth、Daniel S. Fletcher、Betsy Frantz、William A. Hanlon、Coral F. Harper、Scott J. Hofsess、Matthew Kostura、Jiunn Lin、Sylvie Luell、Edward A. O'Neill、Chad J. Orevillo、Margaret Pang、Janey Parsons、Anna Rolando、Yousif Sahly、Denise M. Visco、Stephen J. O'Keefe

  DOI：10.1021/jm9805236

  日期：1999.6.1

  Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis; The SAR leading to the development of selectivity against c-Raf and JNK2 alpha 1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a a-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.