(2-{N-(4-cyanophenyl)-N-[(3-methyl-3H-imidazol-4-yl)methyl]amino}ethyl)carbamic acid tert-butyl ester | 865788-39-2

• 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: (2-{N-(4-cyanophenyl)-N-[(3-methyl-3H-imidazol-4-yl)methyl]amino}ethyl)carbamic acid tert-butyl ester
• 英文别名: 4-[(2-{N-tert-butoxycarbonyl}-aminoethyl)-(3-methyl-3H-imidazol-4-ylmethyl)-amino]-benzonitrile；{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}carbamic acid tert-butyl ester；{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)-amino]-ethyl}-carbamic acid tert-butyl ester；tert-butyl N-[2-[4-cyano-N-[(3-methylimidazol-4-yl)methyl]anilino]ethyl]carbamate
• CAS: 865788-39-2
• 化学式: C₁₉H₂₅N₅O₂
• 分子量: 355.44
• InChiKey: LTIQZFXRRWRNDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  83.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2-{N-(4-cyanophenyl)-N-[(3-methyl-3H-imidazol-4-yl)methyl]amino}ethyl)carbamic acid tert-butyl ester 在 三氟乙酸 作用下， 生成 4-[(2-aminoethyl)-(3-methyl-3H-imidazol-4-ylmethyl)-amino]-benzonitrile
  参考文献：
  名称：

  结构简单，有效的疟原虫选择性法呢基转移酶抑制剂可阻止疟原虫的生长。

  摘要：

  第三世界国家要求立即获得廉价的治疗剂，以应对疟疾造成的高死亡率。在这里，我们报告了一类新的抗疟疾蛋白法呢基转移酶（PFT）抑制剂，该抑制剂的设计重点是简单的分子结构，以便于根据最近经过验证的抗疟疾目标轻松进行治疗。这一系列新颖的化合物代表了第一个报道的恶性疟原虫选择性PFT抑制剂（选择性高达145倍），其中铅抑制剂表现出出色的体外活性（IC（50）<1 nM）和对低浓度培养的寄生虫的毒性（ED （50）<100 nM）。报告了吸收，代谢和口服生物利用度的初步研究。

  DOI：

  10.1021/jm060081v
• 作为产物：
  描述：

  [2-(4-cyanophenylamino)ethyl]carbamic acid tert-butyl ester 、 1-甲基-1氢-5-醛基-咪唑 在 sodium cyanoborohydride 作用下， 以 甲醇 为溶剂， 反应 0.33h， 以85%的产率得到(2-{N-(4-cyanophenyl)-N-[(3-methyl-3H-imidazol-4-yl)methyl]amino}ethyl)carbamic acid tert-butyl ester
  参考文献：
  名称：

  结构简单，有效的疟原虫选择性法呢基转移酶抑制剂可阻止疟原虫的生长。

  摘要：

  第三世界国家要求立即获得廉价的治疗剂，以应对疟疾造成的高死亡率。在这里，我们报告了一类新的抗疟疾蛋白法呢基转移酶（PFT）抑制剂，该抑制剂的设计重点是简单的分子结构，以便于根据最近经过验证的抗疟疾目标轻松进行治疗。这一系列新颖的化合物代表了第一个报道的恶性疟原虫选择性PFT抑制剂（选择性高达145倍），其中铅抑制剂表现出出色的体外活性（IC（50）<1 nM）和对低浓度培养的寄生虫的毒性（ED （50）<100 nM）。报告了吸收，代谢和口服生物利用度的初步研究。

  DOI：

  10.1021/jm060081v

文献信息

• Compound and Methods For the Treatment of Cancer and Malaria
  申请人：Hamilton Andrew

  公开号：US20080312287A1

  公开（公告）日：2008-12-18

  Formula (I): Where R 1 is an optionally substituted C 3 -C 12 hydrocarbyl group (preferably a cyclic alkyl group), an optionally substituted heterocyclic group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group; R is a C(O) y R′ group (preferably forming an optionally substituted C 2 -C 5 acyl group), or a S(O) x R′ group, where y is 0 or 1 and x is 0, 1 or 2 and R′ is H or an optionally substituted C 1 -C 12 alkyl group, or R′ is an optionally substituted C 5 -C 12 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from H, an optionally substituted C 1 -C 12 hydrocarbyl group, including a C 5 -C 12 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group, or R 5 and R 6 , R 7 and R 8 or R 9 and R 10 together form a keto (C═O) group; R N is H, an optionally substituted C 1 -C 12 hydrocarbyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic group, or an optionally substituted heteroaromatic group; A is Formula (II): a Formula (III): group, or a Formula (IV) or Formula (V) group, where Z is N, O or S; R a is H, a C 1 -C 12 optionally substituted hydrocarbyl group or an optionally substituted aromatic group; n is from 0 to 3; and pharmaceutically acceptable salts thereof. Compounds according to the invention are useful in one or more aspects to inhibit farnesyl transferase, or to treat malaria, neoplasia, a hyperproliferative disease state or arthritis, including rheumaroid arthritis or osteoarthritis.

  公式（I）：其中R1是可选取的取代C3-C12烃基（优选为环烷基）、可选取的取代杂环基、可选取的取代芳香基或可选取的取代杂芳基；R是C（O）yR′基团（优选为形成可选取的取代C2-C5酰基的基团），或S（O）xR′基团，其中y为0或1，x为0、1或2且R′为H或可选取的取代C1-C12烷基，或R′为可选取的取代C5-C12环烷基、可选取的取代杂环基、可选取的取代芳香基或可选取的取代杂芳基；R5、R6、R7、R8、R9和R10各自独立地选自H、可选取的取代C1-C12烃基（包括C5-C12环烷基）、可选取的取代杂环基、可选取的取代芳香基或可选取的取代杂芳基，或R5和R6、R7和R8或R9和R10一起形成酮（C═O）基团；RN为H、可选取的取代C1-C12烃基、可选取的取代杂环基、可选取的取代芳香基或可选取的取代杂芳基；A为公式（II）：公式（III）：基团，或公式（IV）或公式（V）基团，其中Z为N、O或S；Ra为H、C1-C12可选取的取代烃基或可选取的取代芳香基；n为0至3；以及其药学上可接受的盐。根据本发明的化合物在一个或多个方面中有用，以抑制法尼酰基转移酶，或治疗疟疾、新生物、高增殖病态或关节炎，包括类风湿性关节炎或骨关节炎。
• DUAL INHIBITORS OF FARNESYLTRANSFERASE AND GERANYLGERANYLTRANSFERASE I
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc.

  公开号：US20130190355A1

  公开（公告）日：2013-07-25

  Many GTPases such as Ras, Ral and Rho require post-translational farnestylation or geranylgeranylation for mediating malignant transformation. Dual farnesyltransferase (FT) (FTI) and geranylgeranyltransferase-I (GGT-1) inhibitors (GGTI) were developed as anticancer agents from based on an ethylenediamine scaffold. On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating extensive structure-activity relationship studies. The most potent inhibitor is compound exhibited an in vitro hFTase IC 50 value of 25 nM and a whole cell H-Ras processing IC 50 value of 90 nM. Several of the inhibitors proved highly selective for hFTase over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of an inhibitor cocrystallized with farnesyl pyrophosphate in the active site of rat FTase illustrates that the para-benzonitrile moiety is stabilized by a π-π stacking interaction with the Y361β residue, suggesting an importance of this component of the inhibitors.

  许多GTP酶如Ras、Ral和Rho需要经过翻酰基化或戊二烯基化的后翻译修饰，以介导恶性转化。双重翻酰基转移酶(FT)(FTI)和戊二烯基转移酶-I(GGT-1)抑制剂(GGTI)是基于乙二胺支架开发的抗癌剂。基于四倍取代乙二胺支架，这些抑制剂结构简单，易于衍生，便于进行广泛的构效关系研究。其中最有效的抑制剂表现出25 nM的体外hFTase IC50值和90 nM的整个细胞H-Ras处理IC50值。其中几种抑制剂对相关的戊二烯基转移酶酶(GGTase-I)高度选择性。一种抑制剂与磷酸戊二烯基共结晶于大鼠FTase的活性位点中的晶体结构表明，对苯二腈基团通过与Y361β残基的π-π堆积相互作用稳定，表明这些抑制剂的这个组分的重要性。
• Structurally Simple Farnesyltransferase Inhibitors Arrest the Growth of Malaria Parasites
  作者：Matthew P. Glenn、Sung-Youn Chang、Oliver Hucke、Christophe L. M. J. Verlinde、Kasey Rivas、Carrie Hornéy、Kohei Yokoyama、Frederick S. Buckner、Prakash R. Pendyala、Debopam Chakrabarti、Michael Gelb、Wesley C. Van Voorhis、Saïd M. Sebti、Andrew D. Hamilton

  DOI：10.1002/anie.200500674

  日期：2005.8.5
• Structure-Based Design and Synthesis of Potent, Ethylenediamine-Based, Mammalian Farnesyltransferase Inhibitors as Anticancer Agents
  作者：Steven Fletcher、Erin Pusateri Keaney、Christopher G. Cummings、Michelle A. Blaskovich、Michael A. Hast、Matthew P. Glenn、Sung-Youn Chang、Cynthia J. Bucher、Ryan J. Floyd、William P. Katt、Michael H. Gelb、Wesley C. Van Voorhis、Lorena S. Beese、Said M. Sebti、Andrew D. Hamilton

  DOI：10.1021/jm1001748

  日期：2010.10.14

  A potent class of anticancer. human farnesyltransferase (111:Tase) inhibitors has been identified by "piggy-backing" on potent, antimalarial inhibitors of Plosmodium falciparum farnesyltransferase (P/FTase). On the basis of a 4-Fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure activity relationship (SA R) study reported herein. Our most potent inhibitor is compound If, which exhibited an in vitro hFTase IC50 value of 25 nm and a whole cell H-Ras processing IC50 value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective For hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-l). A crystal structure of inhibitor la co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of la is stabilized by pi-pi stacking interaction with the Y361 beta residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.
• US9040563B2
  申请人：——

  公开号：US9040563B2

  公开（公告）日：2015-05-26