tert-butyl N-[(2S)-1-[[(4aR,5S)-2-[4-(dimethylamino)phenyl]-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 | 352274-94-3

• 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: tert-butyl N-[(2S)-1-[[(4aR,5S)-2-[4-(dimethylamino)phenyl]-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: 352274-94-3
• 化学式: C₃₂H₄₀N₆O₅
• 分子量: 588.707
• InChiKey: JJJPQHYVLGYMSL-GMQQYTKMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(2S)-1-[[(4aR,5S)-2-[4-(dimethylamino)phenyl]-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 在 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 18.75h， 生成 2-adamantyl N-[(2S)-1-[[(4aR,5S)-2-[4-(dimethylamino)phenyl]-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
  参考文献：
  名称：

  5-(Tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-Based Cholecystokinin Receptor Antagonists:  Reversal of CCK₁ Receptor Subtype Selectivity toward CCK₂ Receptors

  摘要：

  With the aim of reversing selectivity or antagonist/agonist functionality in the 5-(tryptophylamino)- 1,3-dioxoperhydropyrido [1,2-c] pyrimidine-derived potent and highly selective CCK1 antagonists, a series of 4-benzyl and 4-methyl derivatives have been synthesized. Whereas the introduction of the benzyl group led, in all cases, to complete loss of the binding affinity, the incorporation of the methyl group gave a different result depending on the stereochemistry of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold. Thus, the introduction of the methyl group into the (4aS,5R)-diastereoisomers, giving a (4S)-configuration, produced a Mold increase in the CCK1, binding potency and selectivity. However, the same structural manipulation in the opposite (4aR,5S)-stereochemistry, leading to a (4R,4aR,5S)-configuration, produced reversal of the selectivity for CCK1 to the CCK2 receptors. The replacement of the Boc group at the tryptophan moiety by a 2-adamantyloxycarbonyl group also contributed to that reversal. The resulting compounds displayed moderate CCK2 antagonist activity in rat and human receptors, and a very small partial agonist effect on the production of inositol phosphate in COS-7 cells transfected with the wild-type human CCK2 receptor.

  DOI：

  10.1021/jm0498755
• 作为产物：
  描述：

  [2-(4-Dimethylamino-phenyl)-1,3-dioxo-octahydro-pyrido[1,2-c]pyrimidin-5-yl]-carbamic acid tert-butyl ester 在 TEA 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 18.75h， 生成 tert-butyl N-[(2S)-1-[[(4aR,5S)-2-[4-(dimethylamino)phenyl]-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
  参考文献：
  名称：

  5-(Tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-Based Cholecystokinin Receptor Antagonists:  Reversal of CCK₁ Receptor Subtype Selectivity toward CCK₂ Receptors

  摘要：

  With the aim of reversing selectivity or antagonist/agonist functionality in the 5-(tryptophylamino)- 1,3-dioxoperhydropyrido [1,2-c] pyrimidine-derived potent and highly selective CCK1 antagonists, a series of 4-benzyl and 4-methyl derivatives have been synthesized. Whereas the introduction of the benzyl group led, in all cases, to complete loss of the binding affinity, the incorporation of the methyl group gave a different result depending on the stereochemistry of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold. Thus, the introduction of the methyl group into the (4aS,5R)-diastereoisomers, giving a (4S)-configuration, produced a Mold increase in the CCK1, binding potency and selectivity. However, the same structural manipulation in the opposite (4aR,5S)-stereochemistry, leading to a (4R,4aR,5S)-configuration, produced reversal of the selectivity for CCK1 to the CCK2 receptors. The replacement of the Boc group at the tryptophan moiety by a 2-adamantyloxycarbonyl group also contributed to that reversal. The resulting compounds displayed moderate CCK2 antagonist activity in rat and human receptors, and a very small partial agonist effect on the production of inositol phosphate in COS-7 cells transfected with the wild-type human CCK2 receptor.

  DOI：

  10.1021/jm0498755

文献信息

• 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-<i>c</i>]pyrimidine-Based Potent and Selective CCK₁ Receptor Antagonists:  Structure−Activity Relationship Studies on the Substituent at N2-Position
  作者：José M. Bartolomé-Nebreda、Rosario Patiño-Molina、Mercedes Martín-Martínez、Isabel Gómez-Monterrey、M. Teresa García-López、Rosario González-Muñiz、Edurne Cenarruzabeitia、Miriam Latorre、Joaquín Del Río、Rosario Herranz

  DOI：10.1021/jm010813d

  日期：2001.6.1

  To establish structure-activity relationships a new series of analogues of the highly potent and selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) modified at N2-position of the central scaffold has been prepared and evaluated as CCK receptor ligands. With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitro functional activity evaluation suggest the importance of the lipophilic character and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for potent and selective binding and antagonist activity at CCK1 receptor subtype. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have emerged as more potent and selective CCK1 receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)stereochemistry at the central bicyclic skeleton as an essential structural requirement for potent binding to this receptor subtype.
• 5-(Tryptophylamino)-1,3-dioxoperhydropyrido[1,2-<i>c</i>]pyrimidine-Based Cholecystokinin Receptor Antagonists:  Reversal of CCK₁ Receptor Subtype Selectivity toward CCK₂ Receptors
  作者：Pilar Muñoz-Ruiz、M. Teresa García-López、Edurne Cenarruzabeitia、Joaquín Del Río、Marlene Dufresne、Magali Foucaud、Daniel Fourmy、Rosario Herranz

  DOI：10.1021/jm0498755

  日期：2004.10.1

  With the aim of reversing selectivity or antagonist/agonist functionality in the 5-(tryptophylamino)- 1,3-dioxoperhydropyrido [1,2-c] pyrimidine-derived potent and highly selective CCK1 antagonists, a series of 4-benzyl and 4-methyl derivatives have been synthesized. Whereas the introduction of the benzyl group led, in all cases, to complete loss of the binding affinity, the incorporation of the methyl group gave a different result depending on the stereochemistry of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold. Thus, the introduction of the methyl group into the (4aS,5R)-diastereoisomers, giving a (4S)-configuration, produced a Mold increase in the CCK1, binding potency and selectivity. However, the same structural manipulation in the opposite (4aR,5S)-stereochemistry, leading to a (4R,4aR,5S)-configuration, produced reversal of the selectivity for CCK1 to the CCK2 receptors. The replacement of the Boc group at the tryptophan moiety by a 2-adamantyloxycarbonyl group also contributed to that reversal. The resulting compounds displayed moderate CCK2 antagonist activity in rat and human receptors, and a very small partial agonist effect on the production of inositol phosphate in COS-7 cells transfected with the wild-type human CCK2 receptor.