tert-butyl 4-(2-(benzo[d]oxazol-2-ylthio)ethyl)piperazine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶唑类
• 英文名称: tert-butyl 4-(2-(benzo[d]oxazol-2-ylthio)ethyl)piperazine-1-carboxylate
• 英文别名: Tert-butyl 4-[2-(1,3-benzoxazol-2-ylsulfanyl)ethyl]piperazine-1-carboxylate
• 化学式: C₁₈H₂₅N₃O₃S
• 分子量: 363.481
• InChiKey: FITVTAIRQFXIQU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  84.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-bromo-N-(2-methyl-6-(methylthio)pyridin-3-yl)acetamide 、 tert-butyl 4-(2-(benzo[d]oxazol-2-ylthio)ethyl)piperazine-1-carboxylate 在 三氟乙酸 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 4.0h， 以80%的产率得到2-(4-(2-(benzo[d]oxazol-2-ylthio)ethyl)piperazin-1-yl)-N-(2-methyl-6-(methylthio)pyridin-3-yl)acetamide
  参考文献：
  名称：

  Syntheses and pharmacokinetic evaluations of four metabolites of 2-(4-(2-((1H-benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis-(methylthio)pyridin-3-yl)acetamide hydrochloride [K-604], an acyl-CoA:cholesterol O-acyltransferase-1 inhibitor

  摘要：

  We synthesized and identified four metabolites of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)-1 inhibitor, K-604 (1). Two of the metabolites M1 and M2, were prepared from 1 using a combination reagent of hydrogen peroxide and sodium tungstate with either phosphoric acid or trifluoroethanol as the solvent to control the regioselectivity. Upon exposure of 4b to tert-butyl hypochlorite at -78 degrees C, the monosulfoxidation afforded synthetic intermediate of M3 in excellent yield. The efficient synthesis of M4 was established. The in vitro metabolic study exhibited a high clearance value (720 mu L/min/mg protein) of 1 using human liver microsomes. We orally administered a single dose of 10 mg/kg of 1 to monkeys because the in vitro metabolic patterns are quite similar. Fortunately, the drug concentration of 1 was much higher than those of M1, M2, M3 and M4.

  DOI：

  10.1016/j.bmc.2020.115457
• 作为产物：
  描述：

  2-巯基苯并恶唑 、 叔丁基-4-(2-羟乙基)哌嗪-1-羧酸酯 在 4-二甲氨基吡啶 、 甲基磺酰氯 、 三乙胺 、 18-冠醚-6 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 4-(2-(benzo[d]oxazol-2-ylthio)ethyl)piperazine-1-carboxylate
  参考文献：
  名称：

  Syntheses and pharmacokinetic evaluations of four metabolites of 2-(4-(2-((1H-benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis-(methylthio)pyridin-3-yl)acetamide hydrochloride [K-604], an acyl-CoA:cholesterol O-acyltransferase-1 inhibitor

  摘要：

  We synthesized and identified four metabolites of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)-1 inhibitor, K-604 (1). Two of the metabolites M1 and M2, were prepared from 1 using a combination reagent of hydrogen peroxide and sodium tungstate with either phosphoric acid or trifluoroethanol as the solvent to control the regioselectivity. Upon exposure of 4b to tert-butyl hypochlorite at -78 degrees C, the monosulfoxidation afforded synthetic intermediate of M3 in excellent yield. The efficient synthesis of M4 was established. The in vitro metabolic study exhibited a high clearance value (720 mu L/min/mg protein) of 1 using human liver microsomes. We orally administered a single dose of 10 mg/kg of 1 to monkeys because the in vitro metabolic patterns are quite similar. Fortunately, the drug concentration of 1 was much higher than those of M1, M2, M3 and M4.

  DOI：

  10.1016/j.bmc.2020.115457

文献信息

• Novel cyclic diamine compounds and medicine containing the same
  申请人：Kowa Company, Ltd.

  公开号：US20040038987A1

  公开（公告）日：2004-02-26

  The present invention offers novel cyclic diamine compounds and a pharmaceutical composition containing the same. The present invention relates to a compound represented by the formula (I) or salt(s) or solvate(s) thereof. 1 (In the formula, 2 is an optionally substituted divalent residue of benzene, pyridine, cyclohexane or naphthalene or is a vinylene group where Ar is an optionally substituted aryl group; X is —NH—, oxygen atom or sulfur atom; Y is —NR 1 —, oxygen atom, sulfur atom, sulfoxide or sulfone; Z is a single bond or —NR 2 —; R 1 is hydrogen atom, optionally substituted lower alkyl group, optionally substituted aryl group or optionally substituted silyl lower alkyl group; R 2 is hydrogen atom, optionally substituted lower alkyl group, optionally substituted aryl group or optionally substituted silyl lower alkyl group; l is an integer of from 0 to 15; m is an integer of 2 or 3; and n is an integer of from 0 to 3). The compound of the present invention is useful as a pharmaceutical composition, particuarly as an inhibitor of acyl coenzyme A cholesterol acyltransferase (ACAT).

  本发明提供了新颖的环状二胺化合物以及含有该化合物的药物组合物。本发明涉及由式(I)表示的化合物或其盐或溶剂化合物。(在该式中，2是苯、吡啶、环己烷或萘的可选择取代的二价残基，或者是Ar为可选择取代芳基的乙烯基；X为—NH—、氧原子或硫原子；Y为—NR1—、氧原子、硫原子、亚砜或砜；Z为单键或—NR2—；R1为氢原子、可选择取代的较低烷基、可选择取代的芳基或可选择取代的硅烷较低烷基；R2为氢原子、可选择取代的较低烷基、可选择取代的芳基或可选择取代的硅烷较低烷基；l为0到15的整数；m为2或3的整数；n为0到3的整数)。本发明的化合物可用作药物组合物，特别是作为酰辅酶A胆固醇酰基转移酶(ACAT)的抑制剂。
• HYDROXYALKYL CYCLIC DIAMINE COMPOUNDS
  申请人：Shibuya Kimiyuki

  公开号：US20070088159A1

  公开（公告）日：2007-04-19

  The present invention is directed to a process for producing a compound ( 5 ) from the compound ( 1 ). By use of the compound ( 1 ), a variety of cyclic diamine derivatives ( 5 ) or salts thereof, useful as drugs, can be produced in an industrially advantageous manner with a constant yield.

  本发明涉及从化合物（1）制备化合物（5）的方法。通过使用化合物（1），可以以工业上优势的方式生产出各种环状二胺衍生物（5）或其盐，这些衍生物可用作药物，并且产量稳定。
• Method for Producing Cyclic Diamine Derivative
  申请人：Shibuya Kimiyuki

  公开号：US20080045714A1

  公开（公告）日：2008-02-21

  The present invention provides an industrially useful method for synthesizing a cyclic diamine derivative (4) or a salt thereof which serves as an ACAT inhibitor. A 2-hydroxyacetylaminopyridine compound represented by formula (1), and a method for producing a cyclic diamine derivative represented by formula (4) or a salt thereof from compound (1) through 1) Step A-1, 2) Steps B-1 and B-2, or 3) Steps B-1, B-3, and B-4.

  本发明提供了一种工业上有用的方法，用于合成作为ACAT抑制剂的环状二胺衍生物(4)或其盐。一种由式(1)表示的2-羟基乙酰氨基吡啶化合物，以及从化合物(1)通过1)步骤A-1、2)步骤B-1和B-2，或3)步骤B-1、B-3和B-4制备由式(4)表示的环状二胺衍生物或其盐的方法。
• NOVEL CYCLIC DIAMINE COMPOUNDS AND MEDICINE CONTAINING THE SAME
  申请人：Kowa Co., Ltd.

  公开号：EP0987254B1

  公开（公告）日：2004-12-22
• US6969711B2
  申请人：——

  公开号：US6969711B2

  公开（公告）日：2005-11-29