4-(tert-butyldimethylsilyloxymethyl)-1-(triphenylmethyl)imidazole | 127056-57-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 4-(tert-butyldimethylsilyloxymethyl)-1-(triphenylmethyl)imidazole
• 英文别名: 4-<(tert-butyldimethylsilyloxy)methyl>-1-(triphenylmethyl)imidazole；4-[[(tert-butyldimethylsilyl)oxy]methyl]-1-(triphenylmethyl)imidazole；4-(tert-butyldimethylsilanyloxymethyl)-1-trityl-1H-imidazole；4-tert-butyldimethylsilyloxymethyl-1-tritylimidazole；4-(tert-butyldimethylsilyloxymethyl)-1-triphenylmethylimidazole；4-(tert-butyl-dimethyl-silanyloxymethyl)-1-trityl-1H-imidazole；Imidazole, 1-trityl-4-t-butyl-dimethylsiloxy-；tert-butyl-dimethyl-[(1-tritylimidazol-4-yl)methoxy]silane
• CAS: 127056-57-9
• 化学式: C₂₉H₃₄N₂OSi
• 分子量: 454.687
• InChiKey: LJXGESHWGFHORY-UHFFFAOYSA-N

物化性质

• 沸点：
  535.1±45.0 °C(Predicted)
• 密度：
  1.00±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.25
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(tert-butyldimethylsilyloxymethyl)-1-(triphenylmethyl)imidazole 在 二乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 、 乙腈 为溶剂， 反应 18.0h， 生成 2-{1-[5-(tert-butyldimethylsilanyloxymethyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl}benzonitrile
  参考文献：
  名称：

  Structure–Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors

  摘要：

  CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing's disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs.

  DOI：

  10.1021/acs.jmedchem.5b00407
• 作为产物：
  描述：

  叔丁基二甲基氯硅烷 在 咪唑 、 4-二甲氨基吡啶 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 4.0h， 生成 4-(tert-butyldimethylsilyloxymethyl)-1-(triphenylmethyl)imidazole
  参考文献：
  名称：

  Synthesis of 1,5-disubstituted imidazoles including an imidazole analogue of prostaglandin from 4(5)-hydroxymethylimidazole.

  摘要：

  1-(6-羧基己基)-5-[(E)-3-羟基-1-辛烯基]咪唑，一种前列腺素的咪唑类似物，由4(5)-羟甲基咪唑盐酸盐合成。关键步骤包括对4(5)-叔丁基二甲基硅氧甲基咪唑进行位点选择性烷基化，以得到主要1,5-二取代的咪唑。

  DOI：

  10.1248/cpb.37.1481

文献信息

• Inhibitors of prenyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US06441017B1

  公开（公告）日：2002-08-27

  The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemothera-peutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.

  本发明涉及抑制萜基-蛋白转移酶（FTase）和致癌基因蛋白Ras的大环化合物。该发明还涉及含有本发明化合物的化疗组合物以及抑制萜基-蛋白转移酶和致癌基因蛋白Ras的方法。
• Inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05856326A1

  公开（公告）日：1999-01-05

  The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

  本发明涉及抑制法尼基-蛋白转移酶（FTase）和致癌基因蛋白Ras法尼酰化的化合物。该发明还涉及含有本发明化合物的化疗组合物以及抑制法尼基-蛋白转移酶和致癌基因蛋白Ras法尼酰化的方法。
• [EN] ORGANIC COMPOUNDS AS AGENTS FOR THE TREATMENT OF ALDOSTERONE MEDIATED CONDITIONS<br/>[FR] COMPOSES ORGANIQUES SERVANT D'AGENTS POUR LE TRAITEMENT D'ETATS PATHOLOGIQUES INDUITS PAR L'ALDOSTERONE
  申请人：NOVARTIS AG

  公开号：WO2004014914A1

  公开（公告）日：2004-02-19

  Compounds of formula (I), provide pharmacological agents which are inhibitors of the P450 enzyme, aldosterone synthase, and thus may be employed for the treatment of aldosterone mediated conditions. Accordingly, the compounds of formula (I) may be employed for prevention, delay of progression, or treatment of hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis, and remodeling following hypertension and endothelial dysfunction. Preferred are the compounds of formula (I) which are selective inhibitors of aldosterone synthase devoid of undesirable side effects due to general inhibition of cytochrome P450 enzymes.

  公式（I）的化合物提供了抑制P450酶、醛固酮合成酶的药理剂，因此可用于治疗醛固酮介导的疾病。因此，公式（I）的化合物可用于预防、延缓进展或治疗低钾血症、高血压、充血性心力衰竭、肾功能衰竭，特别是慢性肾功能衰竭、再狭窄、动脉粥样硬化、X综合征、肥胖、肾病、心肌梗死后、冠心病、胶原蛋白增生、纤维化以及高血压和内皮功能障碍后的重塑。首选的是选择性抑制醛固酮合成酶的公式（I）化合物，不会因对细胞色素P450酶的普遍抑制而产生不良副作用。
• WO2007/117982
  申请人：——

  公开号：——

  公开（公告）日：——
• 3-Aminopyrrolidinone Farnesyltransferase Inhibitors:  Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency
  作者：Ian M. Bell、Steven N. Gallicchio、Marc Abrams、Lorena S. Beese、Douglas C. Beshore、Hema Bhimnathwala、Michael J. Bogusky、Carolyn A. Buser、J. Christopher Culberson、Joseph Davide、Michelle Ellis-Hutchings、Christine Fernandes、Jackson B. Gibbs、Samuel L. Graham、Kelly A. Hamilton、George D. Hartman、David C. Heimbrook、Carl F. Homnick、Hans E. Huber、Joel R. Huff、Kelem Kassahun、Kenneth S. Koblan、Nancy E. Kohl、Robert B. Lobell、Joseph J. Lynch,、Ronald Robinson、A. David Rodrigues、Jeffrey S. Taylor、Eileen S. Walsh、Theresa M. Williams、C. Blair Zartman

  DOI：10.1021/jm010531d

  日期：2002.6.1

  A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.