[(1S)-1-(4-tert-butoxybenzyl)-2-oxo-2-[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]carbamic acid tert-butyl ester | 422572-65-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [(1S)-1-(4-tert-butoxybenzyl)-2-oxo-2-[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(2S)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]-1-oxo-1-[(3S)-3-(5-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]propan-2-yl]carbamate
• CAS: 422572-65-4
• 化学式: C₃₆H₄₂N₄O₄
• 分子量: 594.754
• InChiKey: ITRYUUTYDCMURO-SMCANUKXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  44
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  96.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [(1S)-1-(4-tert-butoxybenzyl)-2-oxo-2-[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]carbamic acid tert-butyl ester 在 溴 作用下， 以 氯仿 为溶剂， 反应 1.0h， 生成 [2-[(3S)-3-(4-bromo-5-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-(1S)-1-(4-tert-butoxybenzyl)-2-oxo-ethyl]carbamic acid tert-butyl ester
  参考文献：
  名称：

  Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders

  摘要：

  A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K-i delta = 0.9 nM; K-i mu = 55 nM; K-i kappa = 124 nM; EC50 delta = 13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 mug (40% inhibition) and 100 mug (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.

  DOI：

  10.1021/jm030548r
• 作为产物：
  描述：

  N-叔丁氧羰基-(S)-1,2,3,4-四氢异喹啉-3-羧酸 在 N-甲基吗啉 、 ammonium acetate 、 1-羟基苯并三唑 、 溶剂黄146 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 、 氯甲酸异丁酯 作用下， 以 二氯甲烷 为溶剂， 反应 90.0h， 生成 [(1S)-1-(4-tert-butoxybenzyl)-2-oxo-2-[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]carbamic acid tert-butyl ester
  参考文献：
  名称：

  Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders

  摘要：

  A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K-i delta = 0.9 nM; K-i mu = 55 nM; K-i kappa = 124 nM; EC50 delta = 13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 mug (40% inhibition) and 100 mug (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.

  DOI：

  10.1021/jm030548r

文献信息

• TRIPEPTIDYL PEPTIDASE INHIBITORS
  申请人：Breslin Joseph Henry

  公开号：US20080108653A1

  公开（公告）日：2008-05-08

  The present invention is concerned with novel compounds of formula (I) which are inhibitors of a membrane tripeptidyl peptidase responsible for the inactivation of endogenous neuropeptides such as cholecystokinis (CCKs). The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds. wherein n is an integer 0 or 1; X represents O; S; or —(CR 4 R 5 ) m — wherein m is an integer 1 or 2; R 4 and R 5 are each independently from each other hydrogen or C 1-4 alkyl; R 1 is C 1-6 alkylcarbonyl optionally substituted with hydroxy; C 1-6 alkyloxycarbonyl; aminoC 1-6 alkylcarbonyl wherein the C 1-6 alkyl group is optionally substituted with C 3-6 cycloalkyl; mono- and di(C 1-4 alkyl)aminoC 1-6 alkylcarbonyl; aminocarbonyl substituted with aryl; C 1-6 alkylcarbonyloxyC 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonylaminoC 1-6 alkylcarbonyl wherein the amino group is optionally substituted with C 1-4 alkyl; an amino acid; C 1-6 alkyl substituted with amino; or arylcarbonyl; R 2 is an optionally substituted 5-membered heterocycle, or R 2 is optionally substituted benzimidazole; R 3 is a bivalent radical —CH 2 CH 2 — optionally substituted with halo or phenylmethyl; or R 3 is a bivalent radical of formula

  本发明涉及公式（I）的新化合物，该化合物是膜三肽基肽酶的抑制剂，该酶负责失活内源性神经肽，如胆囊收缩素（CCK）。本发明还涉及制备此类化合物的方法，包括含有该化合物的制药组合物以及该化合物作为药物的用途。 其中，n是整数0或1；X代表O、S或-（CR4R5）m-，其中m是整数1或2；R4和R5各自独立于氢或C1-4烷基；R1是C1-6烷基羰基，可选地取代羟基；C1-6烷氧羰基；氨基C1-6烷基羰基，其中C1-6烷基基团可选地取代C3-6环烷基；单和双（C1-4烷基）氨基C1-6烷基羰基；取代芳基的氨基羰基；C1-6烷基羰氧基C1-6烷基羰基；C1-6烷氧羰基氨基C1-6烷基羰基，其中氨基可选地取代C1-4烷基；氨基酸；取代氨基的C1-6烷基；或芳基羰基；R2是可选取代的5-成员杂环，或R2是可选取代的苯并咪唑；R3是二价基团-CH2CH2-，可选地取代卤素或苯甲基；或R3是公式的二价基团
• US7947713B2
  申请人：——

  公开号：US7947713B2

  公开（公告）日：2011-05-24
• US8247432B2
  申请人：——

  公开号：US8247432B2

  公开（公告）日：2012-08-21
• Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders
  作者：Henry J. Breslin、Tamara A. Miskowski、Bryan M. Rafferty、Santosh V. Coutinho、Jeffrey M. Palmer、Nathaniel H. Wallace、Craig R. Schneider、Edward S. Kimball、Sui-Po Zhang、Jian Li、Raymond W. Colburn、Dennis J. Stone、Rebecca P. Martinez、Wei He

  DOI：10.1021/jm030548r

  日期：2004.10.1

  A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K-i delta = 0.9 nM; K-i mu = 55 nM; K-i kappa = 124 nM; EC50 delta = 13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 mug (40% inhibition) and 100 mug (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.