tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3'-(isopropylamino)-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate | 855481-32-2

• 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: tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3'-(isopropylamino)-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate
• 英文别名: tert-butyl N-[(2R)-2-hydroxy-2-pyridin-3-ylethyl]-N-[2-[4-[4-(methylsulfonylcarbamoyl)-3-(propan-2-ylamino)phenyl]phenyl]ethyl]carbamate
• CAS: 855481-32-2
• 化学式: C₃₁H₄₀N₄O₆S
• 分子量: 596.748
• InChiKey: WSQWDAPZMYWNCG-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  146
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3'-(isopropylamino)-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate 在 盐酸 、 水 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 4'-(2-{[(2R)-2-hydroxy-2-pyridin-3-ylethyl]amino}ethyl)-3-(isopropylamino)-N-(methylsulfonyl)biphenyl-4-carboxamide trihydrochloride
  参考文献：
  名称：

  Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β₃-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies: Part 5

  摘要：

  As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC50 values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.

  DOI：

  10.1021/jm9000709
• 作为产物：
  描述：

  tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-[3'-(isopropylamino)-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate 、 甲酸铵 在 钯 氯仿 、 甲醇 、 水 、 Brine 、 magnesium sulfate 作用下， 以 甲醇 、 水 、 氯仿 为溶剂， 反应 1.0h， 以to give tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3′-(isopropylamino)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (123 mg)的产率得到tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3'-(isopropylamino)-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate
  参考文献：
  名称：

  Aminoalcohol derivatives

  摘要：

  本发明涉及一种化合物公式[I]，其中X是键，—CH2—，—O—或—NH—，R1和R12各自独立地是氢，卤素，较低的烷基等，R2是氢或可选的取代较低烷基，R3是氢或氨基保护基，R4、R5和R6各自独立地是氢或可选的取代较低烷基，R7是—Z-R13，其中Z是键等，R13是羧基，较低的烷氧羰基，（较低的烷基磺酰）氨基甲酰基或较低的烷酰磺酰氨基基，R8是—Y—R9，其中Y是键，—CH2—，—O—，—S—等，R9是氢，较低的烷基，环（较低）烷基等，R11是氢，较低的烷基，较低的烷氧基等，或其盐。本发明的化合物[I]及其药学上可接受的盐对预防和/或治疗排尿频繁或尿失禁非常有用。

  公开号：

  US20050137236A1

文献信息

• Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β₃-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies: Part 5
  作者：Kouji Hattori、Susumu Toda、Masashi Imanishi、Shinji Itou、Yutaka Nakajima、Kenichi Washizuka、Takanobu Araki、Hitoshi Hamashima、Yasuyo Tomishima、Minoru Sakurai、Shigeo Matsui、Emiko Imamura、Koji Ueshima、Takao Yamamoto、Nobuhiro Yamamoto、Hirofumi Ishikawa、Keiko Nakano、Naoko Unami、Kaori Hamada、Yasuhiro Matsumura、Fujiko Takamura

  DOI：10.1021/jm9000709

  日期：2009.5.14

  As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC50 values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.
• Aminoalcohol derivatives
  申请人：Hattori Kouji

  公开号：US20050137236A1

  公开（公告）日：2005-06-23

  The present invention relates to a compound formula[I]: wherein X is bond, —CH 2 —, —O— or —NH—, R 1 and R 12 are each independently hydrogen, halogen, lower alkyl, etc., R 2 is hydrogen or optionally substituted lower alkyl, R 3 is hydrogen or an amino protective group, R 4 , R 5 and R 6 are each independently hydrogen or optionally substituted lower alkyl, R 7 is -Z-R 13 , in which Z is bond, etc., and R 13 is carboxy, lower alkoxycarbonyl, (lower alkylsulfonyl)carbamoyl or lower alkanoylsulfamoyl, R 8 is —Y—R 9 , in which Y is bond, —CH 2 —, —O—, —S—, etc., and R 9 is hydrogen, lower alkyl, cyclo(lower)alkyl, etc., and R 11 is hydrogen, lower alkyl, lower alkoxy, etc., or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiurea or urinary incontinence.

  本发明涉及一种化合物公式[I]，其中X是键，—CH2—，—O—或—NH—，R1和R12各自独立地是氢，卤素，较低的烷基等，R2是氢或可选的取代较低烷基，R3是氢或氨基保护基，R4、R5和R6各自独立地是氢或可选的取代较低烷基，R7是—Z-R13，其中Z是键等，R13是羧基，较低的烷氧羰基，（较低的烷基磺酰）氨基甲酰基或较低的烷酰磺酰氨基基，R8是—Y—R9，其中Y是键，—CH2—，—O—，—S—等，R9是氢，较低的烷基，环（较低）烷基等，R11是氢，较低的烷基，较低的烷氧基等，或其盐。本发明的化合物[I]及其药学上可接受的盐对预防和/或治疗排尿频繁或尿失禁非常有用。