tert-butyl N-(3-((1R)-2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)-1-triethylsilyloxyethyl)phenyl)-N-methylsulfonylcarbamate | 1221179-01-6

• 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: tert-butyl N-(3-((1R)-2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)-1-triethylsilyloxyethyl)phenyl)-N-methylsulfonylcarbamate
• 英文别名: (R)-((3-(2-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino)-1-triethylsilyloxy)ethyl)phenyl)-N-tert-butoxycarbonylmethanesulfonamide；tert-butyl N-(2-hydroxyethyl)-N-[(2R)-2-[3-[(2-methylpropan-2-yl)oxycarbonyl-methylsulfonylamino]phenyl]-2-triethylsilyloxyethyl]carbamate
• CAS: 1221179-01-6
• 化学式: C₂₇H₄₈N₂O₈SSi
• 分子量: 588.838
• InChiKey: SCXVYTBYVABHIX-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.68
• 重原子数：
  39
• 可旋转键数：
  16
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  131
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl N-(3-((1R)-2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)-1-triethylsilyloxyethyl)phenyl)-N-methylsulfonylcarbamate 在 盐酸 、 硼烷四氢呋喃络合物 、 三苯基膦 、 sodium hydroxide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 甲苯 为溶剂， 反应 29.0h， 生成 N-(3-((1R)-1-hydroxy-2-(2-((3-(hydroxymethyl)-1H-indazol-6-yl)oxy)ethylamino)ethyl)phenyl)methanesulfonamide dihydrochloride
  参考文献：
  名称：

  Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β₃-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects

  摘要：

  Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human A-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant beta(3)-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the alpha(1A)-AR (EC50 = 219 nM, selectivity: alpha(1A)/beta(3) = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for beta(3)-AR agonistic activity versus au-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent beta(3)-AR agonistic activity (EC50 = 13 nM) and high selectivity (alpha(1A)/beta(3) = >769-fold). Compound 11 was also inactive toward beta(1) and beta(2)-ARs and showed dose dependent beta(3)-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.

  DOI：

  10.1021/acs.jmedchem.5b00638
• 作为产物：
  描述：

  N-benzyl-N-(3-((1R)-2-iodo-1-triethylsilyloxy-ethyl)phenyl)methanesulfonamide 在 4-二甲氨基吡啶 、 20% palladium hydroxide-activated charcoal 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 tert-butyl N-(3-((1R)-2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)-1-triethylsilyloxyethyl)phenyl)-N-methylsulfonylcarbamate
  参考文献：
  名称：

  Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β₃-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects

  摘要：

  Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human A-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant beta(3)-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the alpha(1A)-AR (EC50 = 219 nM, selectivity: alpha(1A)/beta(3) = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for beta(3)-AR agonistic activity versus au-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent beta(3)-AR agonistic activity (EC50 = 13 nM) and high selectivity (alpha(1A)/beta(3) = >769-fold). Compound 11 was also inactive toward beta(1) and beta(2)-ARs and showed dose dependent beta(3)-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.

  DOI：

  10.1021/acs.jmedchem.5b00638

文献信息

• INDAZOLE COMPOUNDS
  申请人：Nakano Seiji

  公开号：US20100160256A1

  公开（公告）日：2010-06-24

  Provided are compounds represented by the following formula (A-1) and formula (1), or salts thereof. The compounds of formula (A-1) and formula (1) or salts thereof have 133 adrenergic receptor agonist activity, and thus are useful as therapeutic and prophylactic agent for diabetes mellitus, obesity, hyperlipidemia, depression, diseases caused by gallstones or hypermotility of the biliary tract, diseases caused by hyperactivity of the digestive tract, interstitial cystitis, overactive bladder or urinary incontinence, or as therapeutic and prophylactic agents for diseases concomitant with decreased tears.

  提供的是以下公式（A-1）和公式（1）所代表的化合物，或其盐。公式（A-1）和公式（1）的化合物或其盐具有133肾上腺素受体激动剂活性，因此可作为治疗和预防糖尿病、肥胖、高脂血症、抑郁症、胆石症或胆道高动力性疾病、消化系统过度活动引起的疾病、间质性膀胱炎、膀胱过度活动或尿失禁的药物，或作为治疗和预防伴随眼泪减少的疾病的药物。
• INDAZOLE DERIVATIVES
  申请人：NAKANO Seiji

  公开号：US20100152265A1

  公开（公告）日：2010-06-17

  Compounds represented by the Formula (A-1) and the Formula (1) or salt thereof are provided. The compounds represented by the Formula (A-1) and the Formula (1) or salt thereof have a β3 adrenergic receptor agonist activity, and therefore are useful as an agent for the prevention and treatment of diabetes, obesity, hyperlipidemia, depression, biliary stone, a disorder derived from hyperactivity of biliary tract, a disorder derived from hyperactivity of digestive tract, interstitial cystitis, overactive bladder, urinary incontinence or a disorder derived from decreased tear secretion, etc.

  提供由化学式（A-1）和化学式（1）或其盐表示的化合物。由化学式（A-1）和化学式（1）或其盐表示的化合物具有β3肾上腺素能受体激动剂活性，因此可用作预防和治疗糖尿病、肥胖症、高脂血症、抑郁症、胆结石、胆道过度活动引起的疾病、消化道过度活动引起的疾病、间质性膀胱炎、膀胱过度活动、尿失禁或泪液分泌减少引起的疾病等。
• Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β₃-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects
  作者：Yasuhiro Wada、Hiromitsu Shirahashi、Taisuke Iwanami、Masami Ogawa、Seiji Nakano、Akifumi Morimoto、Ken-ichi Kasahara、Eiichi Tanaka、Yoshio Takada、Shigeki Ohashi、Mutsuhiro Mori、Satoshi Shuto

  DOI：10.1021/acs.jmedchem.5b00638

  日期：2015.8.13

  Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human A-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant beta(3)-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the alpha(1A)-AR (EC50 = 219 nM, selectivity: alpha(1A)/beta(3) = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for beta(3)-AR agonistic activity versus au-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent beta(3)-AR agonistic activity (EC50 = 13 nM) and high selectivity (alpha(1A)/beta(3) = >769-fold). Compound 11 was also inactive toward beta(1) and beta(2)-ARs and showed dose dependent beta(3)-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.