[(S)-1-((4aS,5R)-2-Benzyl-1,3-dioxo-octahydro-pyrido[1,2-c]pyrimidin-5-ylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester | 193203-27-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: [(S)-1-((4aS,5R)-2-Benzyl-1,3-dioxo-octahydro-pyrido[1,2-c]pyrimidin-5-ylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(2S)-1-[[(4aS,5R)-2-benzyl-1,3-dioxo-4,4a,5,6,7,8-hexahydropyrido[1,2-c]pyrimidin-5-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamate
• CAS: 193203-27-9
• 化学式: C₃₁H₃₇N₅O₅
• 分子量: 559.665
• InChiKey: JRSRZYFBWXHHNX-ZNZIZOMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  41
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [(S)-1-((4aS,5R)-2-Benzyl-1,3-dioxo-octahydro-pyrido[1,2-c]pyrimidin-5-ylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester 、 叔丁基异氰酸酯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 生成 (4aS,5R)-2-benzyl-5-(tert-butyl-aminocarbonyl-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine
  参考文献：
  名称：

  5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-Based Potent and Selective CCK₁ Receptor Antagonists:  Structural Modifications at the Tryptophan Domain

  摘要：

  Analogues of the previously reported potent and highly selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhyropyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK1 receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3,3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK1 receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.

  DOI：

  10.1021/jm991078x
• 作为产物：
  描述：

  异氰酸苄酯 在 sodium hydride 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 [(S)-1-((4aS,5R)-2-Benzyl-1,3-dioxo-octahydro-pyrido[1,2-c]pyrimidin-5-ylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester
  参考文献：
  名称：

  1,3-二氧杂氢吡啶并[1,2-c]嘧啶衍生物的合成及其立体化学构效关系：有效的和选择性的胆囊收缩素-A受体拮抗剂。

  摘要：

  描述了基于1,3-二氧杂氢吡啶并[1,2-c]嘧啶骨架的新型强效和选择性非肽胆囊收缩素-A（CCK-A）受体拮抗剂的合成与立体化学结构-活性的关系。这是八个非对映异构体系列中最有效的成员，（4aS，5R）-2-苄基-5- [N-[（叔丁氧羰基）-L-色氨酸]-氨基]-1,3-二氧杂氢吡啶并[1,2] -c]嘧啶显示出纳摩尔浓度的CCK-A受体亲和力，并且在CCK-A处的效力高于在CCK-B受体处的8000倍。作为CCK-A拮抗剂，该化合物以低浓度抑制胰腺腺泡细胞中CCK-8诱发的淀粉酶的释放，与典型的拮抗剂Devazepide相似。已经发现对CCK-A受体结合和选择性的高度严格的立体化学要求。L-Trp和4a

  DOI：

  10.1021/jm9703247

文献信息

• Synthesis and Stereochemical Structure−Activity Relationships of 1,3-Dioxoperhydropyrido[1,2-<i>c</i>]pyrimidine Derivatives:  Potent and Selective Cholecystokinin-A Receptor Antagonists
  作者：Mercedes Martín-Martínez、José M. Bartolomé-Nebreda、Isabel Gómez-Monterrey、Rosario González-Muñiz、M. Teresa García-López、Santiago Ballaz、Ana Barber、Ana Fortuño、Joaquín Del Río、Rosario Herranz

  DOI：10.1021/jm9703247

  日期：1997.10.1

  non-peptide cholecystokinin-A (CCK-A) receptor antagonists based on the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine skeleton are described. The most potent member of this series of eight diastereoisomers, (4aS,5R)-2-benzyl-5-[N-[(tert-butoxycarbonyl)-L-tryptophyl]-amino] - 1,3-dioxoperhydropyrido[1,2-c]pyrimidine, displays nanomolar CCK-A receptor affinity and higher than 8000-fold potency at the CCK-A than

  描述了基于1,3-二氧杂氢吡啶并[1,2-c]嘧啶骨架的新型强效和选择性非肽胆囊收缩素-A（CCK-A）受体拮抗剂的合成与立体化学结构-活性的关系。这是八个非对映异构体系列中最有效的成员，（4aS，5R）-2-苄基-5- [N-[（叔丁氧羰基）-L-色氨酸]-氨基]-1,3-二氧杂氢吡啶并[1,2] -c]嘧啶显示出纳摩尔浓度的CCK-A受体亲和力，并且在CCK-A处的效力高于在CCK-B受体处的8000倍。作为CCK-A拮抗剂，该化合物以低浓度抑制胰腺腺泡细胞中CCK-8诱发的淀粉酶的释放，与典型的拮抗剂Devazepide相似。已经发现对CCK-A受体结合和选择性的高度严格的立体化学要求。L-Trp和4a
• 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-<i>c</i>]pyrimidine-Based Potent and Selective CCK₁ Receptor Antagonists:  Structural Modifications at the Tryptophan Domain
  作者：José M. Bartolomé-Nebreda、Isabel Gómez-Monterrey、M. Teresa García-López、Rosario González-Muñiz、Mercedes Martín-Martínez、Santiago Ballaz、Edurne Cenarruzabeitia、Miriam LaTorre、Joaquín Del Río、Rosario Herranz

  DOI：10.1021/jm991078x

  日期：1999.11.1

  Analogues of the previously reported potent and highly selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhyropyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK1 receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3,3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK1 receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.