(1S)-[2-(5-bromopyridin-3-yloxy)-1-hydroxymethyl-ethyl]carbamic acid tert-butyl ester | 552332-01-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1S)-[2-(5-bromopyridin-3-yloxy)-1-hydroxymethyl-ethyl]carbamic acid tert-butyl ester
• 英文别名: (1S)-[2-(5-bromo-pyridin-3-yloxy)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester；tert-butyl N-[(2S)-1-(5-bromopyridin-3-yl)oxy-3-hydroxypropan-2-yl]carbamate
• CAS: 552332-01-1
• 化学式: C₁₃H₁₉BrN₂O₄
• 分子量: 347.209
• InChiKey: QYDFRXBGGRDJQS-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  80.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1S)-[2-(5-bromopyridin-3-yloxy)-1-hydroxymethyl-ethyl]carbamic acid tert-butyl ester 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 以92%的产率得到(2S)-2-(5-bromopyridin-3-yloxymethyl)aziridine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019
• 作为产物：
  描述：

  (R)-(+)-N-(叔丁氧基羰基)-O-(叔丁基二甲基甲硅烷基)丝氨酸醇 在 四丁基氟化铵 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 (1S)-[2-(5-bromopyridin-3-yloxy)-1-hydroxymethyl-ethyl]carbamic acid tert-butyl ester
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019

文献信息

• Kinase inhibitors
  申请人：——

  公开号：US20030199511A1

  公开（公告）日：2003-10-23

  Compounds having the formula 1 are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.

  具有以下化学式的化合物对抑制蛋白激酶很有用。还公开了抑制蛋白激酶的组合物以及在患者中抑制蛋白激酶的方法。
• Cyclopentane heptan(ene) acyl sulfonamide, 2-alkyl or 2-arylalkyl, or 2-heteroarylalkenyl derivatives as therapeutic agents
  申请人：Allergan Sales, Inc.

  公开号：US20030027846A1

  公开（公告）日：2003-02-06

  The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula I; 1 wherein a hatched line represents the &agr; configuration, a triangle represents the &bgr; configuration, a straight line, e.g. at the 9, 11 or 15 position represents either the &agr; or &bgr; configuration, a dotted line represents the presence or absence of a double bond; a wavy line represents a cis or trans bond; X is 0, S, NH or (CH 2 ) n ; n is 0 or an integer of from 1 to 4; Y is C 1 -C 5 n-alkyl, C 3 -C 7 cycloalkyl, phenyl, furanyl, thienyl, pyridinyl, thiazolyl, benzothienyl, benzofuranyl, naphthyl, or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C 1 -C 5 alkyl, halogen, CF 3 , CN, NO 2 , N(R 2 ) 2 , CO 2 R 2 and OR 2 ; Z is (CH 2 ) n or a covalent bond; R is C 1 -C 6 lower alkyl or Z-CF 3 or mesylate or triflate; R 1 is H, R 2 or COR 2 ;and R 2 is H or C 1 -C 5 lower alkyl or 9, 11 or 15 esters thereof.

  本发明提供了一种治疗眼压增高或青光眼的方法，包括向患有眼压增高或青光眼的动物施用一种由通式I表示的化合物的治疗有效量；其中，虚线表示α构型，三角形表示β构型，直线，例如在9、11或15位置表示α或β构型，点线表示双键的存在或缺失；波浪线表示顺式或反式键；X为0、S、NH或（CH2）n；n为0或1至4的整数；Y为C1-C5烷基、C3-C7环烷基、苯基、呋喃基、噻吩基、吡啶基、噻唑基、苯并噻吩基、苯并呋喃基、萘基或其取代衍生物，其中取代基可以选择自C1-C5烷基、卤素、CF3、CN、NO2、N（R2）2、CO2R2和OR2的群；Z为（ ）n或共价键；R为C1-C6低烷基或Z- 或甲烷磺酸盐或三氟甲磺酸盐；R1为H、R2或COR2；R2为H或C1-C5低烷基或其9、11或15酯。
• US6706755B2
  申请人：——

  公开号：US6706755B2

  公开（公告）日：2004-03-16
• US6831175B2
  申请人：——

  公开号：US6831175B2

  公开（公告）日：2004-12-14