(3'R,4'R)-tert-butyl 4'-{{6''-[benzyl(tert-butoxycarbonyl)-amino]-4''-methylpyridin-2''-yl}methyl}-3'-[2''-[tert-butoxycarbonyl(3'''-fluorophenethyl)amino]ethoxy]pyrrolidine-1'-carboxylate | 1018910-16-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (3'R,4'R)-tert-butyl 4'-{{6''-[benzyl(tert-butoxycarbonyl)-amino]-4''-methylpyridin-2''-yl}methyl}-3'-[2''-[tert-butoxycarbonyl(3'''-fluorophenethyl)amino]ethoxy]pyrrolidine-1'-carboxylate
• 英文别名: (3R,4R)-tert-butyl 3-{{6'-[benzyl(tert-butoxycarbonyl)amino]-4'-methylpyridin-2'-yl}methyl}-4-{2'-[(tert-butoxycarbonyl)(3-fluorophenethyl)amino]ethoxy}pyrrolidine-1-carboxylate；tert-butyl (3R,4R)-3-[6-(benzyl-tert-butoxycarbonyl-amino)-4-methyl-pyridin-2-ylmethyl]-4-(2-{tert-butoxycarbonyl-[2-(3-fluoro-phenyl)-ethyl]-amino}-ethoxy)-pyrrolidine-1-carboxylate；tert-butyl (3R,4R)-3-[[6-[benzyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-4-methylpyridin-2-yl]methyl]-4-[2-[2-(3-fluorophenyl)ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]pyrrolidine-1-carboxylate
• CAS: 1018910-16-1
• 化学式: C₄₃H₅₉FN₄O₇
• 分子量: 762.962
• InChiKey: DATMYFZTWJOTCO-ILFWFZRHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  55
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  111
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (3'R,4'R)-tert-butyl 4'-{{6''-[benzyl(tert-butoxycarbonyl)-amino]-4''-methylpyridin-2''-yl}methyl}-3'-[2''-[tert-butoxycarbonyl(3'''-fluorophenethyl)amino]ethoxy]pyrrolidine-1'-carboxylate 在 20 % Pd(OH)2/C 、 氢气 作用下， 以 乙醇 为溶剂， 反应 36.0h， 以80%的产率得到(3'R,4'R)-tert-butyl 3'-{2''-[tert-butoxycarbonyl(3'''-fluorophenethyl)amino]ethoxy}-4'-{[6''-(tert-butoxycarbonylamino)-4''-methylpyridin-2''-yl]methyl}pyrrolidine-1'-carboxylate
  参考文献：
  名称：

  Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives

  摘要：

  Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2 ''-(3 ''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2 ''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437-5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.

  DOI：

  10.1021/jm100947x
• 作为产物：
  描述：

  trans-[6-(1-benzyl-4-hydroxy-pyrrolidin-3-ylmethyl)-4-methyl-pyridin-2-yl]-carbamic acid tert-butyl ester 在 甲醇 、 sodium hydroxide 、 偶氮二甲酸二异丙酯 、 水 、 sodium hydride 、 臭氧 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.83h， 生成 (3'R,4'R)-tert-butyl 4'-{{6''-[benzyl(tert-butoxycarbonyl)-amino]-4''-methylpyridin-2''-yl}methyl}-3'-[2''-[tert-butoxycarbonyl(3'''-fluorophenethyl)amino]ethoxy]pyrrolidine-1'-carboxylate
  参考文献：
  名称：

  WO2008/42353

  摘要：

  公开号：

文献信息

• Chiral Synthesis of Pyrrolidine Core Compounds en route to Neuronal Nitric Oxide Synthase Inhibitors
  申请人：Silverman Richard B.

  公开号：US20120004415A1

  公开（公告）日：2012-01-05

  A chiral synthesis of pyrrolidine compounds en route to selective neuronal nitric oxide synthase inhibitors, and representative inhibitor compounds heretofore unattainable.

  一种手性合成吡咯烷化合物的方法，可制备选择性神经型一氧化氮合酶抑制剂和以前无法获得的代表性抑制剂化合物。
• Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
  申请人：Silverman B. Richard

  公开号：US20080108814A1

  公开（公告）日：2008-05-08

  Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.

  肽类类似物化合物可抑制神经元一氧化氮合酶(nNOS)，用于潜在的治疗神经退行性疾病，如中风、阿尔茨海默病、帕金森病、亨廷顿病等。
• Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability
  作者：Graham R. Lawton、Hantamalala Ralay Ranaivo、Laura K. Chico、Haitao Ji、Fengtian Xue、Pavel Martásek、Linda J. Roman、D. Martin Watterson、Richard B. Silverman

  DOI：10.1016/j.bmc.2009.02.017

  日期：2009.3

  Overproduction of nitric oxide by neuronal nitric oxide synthase ( nNOS) has been linked to several neurodegenerative diseases. We have recently designed potent and isoform selective inhibitors of nNOS, but the lead compound contains several basic functional groups. A large number of charges and hydrogen bond donors can impede the ability of molecules to cross the blood brain barrier and thereby limit the effectiveness of potential neurological therapeutics. Replacement of secondary amines in our lead compound with neutral ether and amide groups was made to increase bioavailability and to determine if the potency and selectivity of the inhibitor would be impacted. An ether analogue has been identified that retains a similar potency and selectivity to that of the lead compound, and shows increased ability to penetrate the blood brain barrier. (C) 2009 Elsevier Ltd. All rights reserved.
• Acid-facilitated debenzylation of N-Boc, N-benzyl double protected 2-aminopyridinomethyl pyrrolidine derivatives
  作者：Haitao Ji、Qing Jing、Jinwen Huang、Richard B. Silverman

  DOI：10.1016/j.tet.2011.12.013

  日期：2012.2

  2-Aminopyridinomethyl pyrrolidines represent a class of highly potent and selective neuronal nitric oxide synthase inhibitors. Conditions for a Mitsunobu reaction of a naphthol and a hindered secondary alcohol were optimized to give good to excellent yields. A key step in the synthesis of these inhibitors is the deprotection of the benzyl group from the N-Boc and N-Bn double protected 2-aminopyridine ring at a late stage of the synthesis, which has been proven difficult in our previous syntheses. Acetic acid was found to facilitate the N-Bn deprotection. (C) 2011 Elsevier Ltd. All rights reserved.
• Selective Neuronal Nitric Oxide Synthase Inhibitors
  申请人：Silverman Richard B.

  公开号：US20120258513A1

  公开（公告）日：2012-10-11

  Compounds and related methods for selective inhibition of neuronal nitric oxide synthase over inducible and endothelial isoforms, such compounds as can provide reduced cationic character and enhanced bioavailability.