1-[3-(hydroxymethyl)phenyl]-3-[(3R)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]urea | 153825-72-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 1-[3-(hydroxymethyl)phenyl]-3-[(3R)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]urea
• CAS: 153825-72-0
• 化学式: C₂₄H₂₂N₄O₃
• 分子量: 414.464
• InChiKey: XVZNUHHOCFWGHT-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  94
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-[3-(hydroxymethyl)phenyl]-3-[(3R)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]urea 在 sodium hydroxide 、 四丁基氟化铵 、 对甲苯磺酸 、 三丁基氧化锡 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 4-{3-[3-((R)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-ureido]-benzyloxycarbonylamino}-3-(tetrahydro-pyran-2-yloxy)-butyric acid
  参考文献：
  名称：

  Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with decreased hydrophobicity

  摘要：

  In order to study structure-activity relationships of the previously reported dual histamine H-2 and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H(2)A, or a phenyl ring at the C-5 of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H(2)A. The latter (type II) involved hybrid compounds with the C-5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, ({2-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl]ethylcarbamoyl}methyl)carbamic acid 3-{3-[5-(3-hydroxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]ureido}benzyl ester (18), showed potent dual histamine H-2 and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H-2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00074-6
• 作为产物：
  描述：

  1,3-dihydro-1-methyl-5-phenyl-3(R)-<<(4-nitrophenoxy)carbonyl>amino>-2H-1,4-benzodiazepin-2-one 以50%的产率得到
  参考文献：
  名称：

  Bock Mark G., DiPardo Robert M., Evans Ben E., Rittle Kenneth E., Whitter+, J. Med. Chem, 36 (1993) N 26, S 4276- 4292

  摘要：

  DOI：

文献信息

• Development of 1,4-benzodiazepine cholecystokinin type B antagonists
  作者：Mark G. Bock、Robert M. DiPardo、Ben E. Evans、Kenneth E. Rittle、Willie L. Whitter、Victor M. Garsky、Kevin F. Gilbert、James L. Leighton、Kenneth L. Carson

  DOI：10.1021/jm00078a018

  日期：1993.12

  4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is

  描述了一系列3-（芳基脲基）-5-苯基-1,4-苯并二氮杂卓，肽激素胆囊收缩素（CCK）的非肽拮抗剂。通过对CCK-A选择性3-甲酰胺基-1,4-苯并二氮杂卓MK-329的合理修饰而衍生，本文记载了有效的，口服有效的化合物的开发，其中对CCK-B受体亚型具有选择性。从这些研究中得出的主要铅结构是L-365,260，该化合物已提交临床评估。讨论了通过适当的结构修饰来调节这些苯并二氮杂the的受体相互作用的能力的细节，这暗示了进一步完善这类化合物的CCK-B受体亲和力和选择性的可能性。
• Synthesis and Biological Evaluation of a New Reversely Linked Type of Dual Histamine H2 and Gastrin Receptor Antagonist.
  作者：Yasuyuki KAWANISHI、Shoichi ISHIHARA、Kimio TAKAHASHI、Tadahiko TSUSHIMA、Sanji HAGISHITA、Michio ISHIKAWA、Yasunobu ISHIHARA

  DOI：10.1248/cpb.45.116

  日期：——

  In an attempt to improve the low oral absorbability of previously reported dual histamine H2 and gastrin receptor antagonists, compounds of a different type were synthesized and evaluated for biological activity. These new compounds bear a histamine H2 receptor antagonist (H2A) pharmacophore moiety attached to a gastrin receptor antagonist (GA) pharmacophore moiety in a reversed manner, namely the head-to-head manner, different from the previously reported head-to-tail manner. These new hybrid compounds were classified into three types : type I, the regular amide type bearing a roxatidine moiety; type II, the reversed amide type bearing a roxatidine moiety; and type III, hybrid compounds bearing a famotidine moiety directly connected to a GA moiety without a spacer. Among them, only (R)-1-[3-(N'-4-[2-(N-aminosulfonylamidino)ethylthiomethyl]thiazol-2-yl}guanidinomethyl)phenyl]-3-(1-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-3-yl)urea (42), belonging to type III, showed a weak but distinct histamine H2 receptor-antagonistic activity as well as a modest gastrin receptor-antagonistic activity. Of most importance was the finding that this compound showed a weak but clearly improved in vivo oral antigastric acid secretory activity as a result of the structural changes, including the decreased molecular weight.

  为了提高先前报道的双重组胺H2和胃泌素受体拮抗剂的低口服吸收性，合成并评估了一类不同类型的化合物的生物活性。这些新的化合物以一种反转的方式，即头对头的方式，连接一个组胺H2受体拮抗剂（H2A）药效团部分和一个胃泌素受体拮抗剂（GA）药效团部分，这与先前报道的头对尾方式不同。这些新的杂化化合物分为三种类型：I型，常规酰胺型具有roxatidine部分；II型，反转酰胺型具有roxatidine部分；III型，直接连接famotidine部分和GA部分，不含间隔基的杂化化合物。其中，只有(R)-1-[3-(N'-4-[2-(N-氨基磺酰基氨基)乙硫甲基]噻唑-2-基}胍甲基)苯基]-3-(1-甲基-2-氧-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂卓-3-基)脲（42），属于III型，显示出微弱的但明显的组胺H2受体拮抗活性以及适度的胃泌素受体拮抗活性。最重要的是，发现这种化合物由于结构变化，包括分子量的降低，显示出了微弱但明显改善的体内口服抗胃酸分泌活性。
• Synthesis and pharmacological evaluation of highly potent dual histamine H2 and gastrin receptor antagonists
  作者：Yasuyuki Kawanishi、Shoichi Ishihara、Tadahiko Tsushima、Kaoru Seno、Masanori Miyagoshi、Sanji Hagishita、Michio Ishikawa、Noriko Shima、Mayumi Shimamura、Yasunobu Ishihara

  DOI：10.1016/s0960-894x(96)00249-1

  日期：1996.7

  The chemical modification of the dual histamine H-2 and gastrin receptor antagonists described in our preceding paper, particularly the modification of spacers as well as the alteration of their connecting bonds at the gastrin receptor antagonist site (GA) from the amide bond to the carbamate bond, significantly improved not only their dual activity but also the GA versus CCK-A receptor selectivity. Copyright (C) 1996 Elsevier Science Ltd
• Bock Mark G., DiPardo Robert M., Evans Ben E., Rittle Kenneth E., Whitter+, J. Med. Chem, 36 (1993) N 26, S 4276- 4292
  作者：Bock Mark G., DiPardo Robert M., Evans Ben E., Rittle Kenneth E., Whitter+

  DOI：——

  日期：——
• Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with decreased hydrophobicity
  作者：Yasuyuki Kawanishi、Shoichi Ishihara、Tadahiko Tsushima、Sanji Hagishita、Michio Ishikawa、Yasunobu Ishihara

  DOI：10.1016/s0968-0896(97)00074-6

  日期：1997.7

  In order to study structure-activity relationships of the previously reported dual histamine H-2 and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H(2)A, or a phenyl ring at the C-5 of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H(2)A. The latter (type II) involved hybrid compounds with the C-5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, (2-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl]ethylcarbamoyl}methyl)carbamic acid 3-3-[5-(3-hydroxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]ureido}benzyl ester (18), showed potent dual histamine H-2 and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H-2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability. (C) 1997 Elsevier Science Ltd.