5-oxo-5-(phenylmethoxy)pentyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-3-<(1,1-dimethylethoxy)carbonyl>-5-oxazolidinecarboxylate | 134848-93-4

• 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: 5-oxo-5-(phenylmethoxy)pentyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-3-<(1,1-dimethylethoxy)carbonyl>-5-oxazolidinecarboxylate
• 英文别名: 3-O-tert-butyl 5-O-(5-oxo-5-phenylmethoxypentyl) (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-1,3-oxazolidine-3,5-dicarboxylate
• CAS: 134848-93-4
• 化学式: C₃₀H₄₅NO₇
• 分子量: 531.69
• InChiKey: XVIHRUNHOQGBCL-AZGAKELHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  38
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  91.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-oxo-5-(phenylmethoxy)pentyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-3-<(1,1-dimethylethoxy)carbonyl>-5-oxazolidinecarboxylate 在 palladium on activated charcoal 叠氮磷酸二苯酯 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 16.0h， 生成 (3R,4S,7S)-4-(cyclohexylmethyl)-7-<<(1,1-dimethylethoxy)carbonyl>amino>-3-hydroxy-2,6,10-trioxo-1-oxa-5,9-diazacyclotetradecane
  参考文献：
  名称：

  Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors

  摘要：

  Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65-mu-M, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

  DOI：

  10.1021/jm00113a005
• 作为产物：
  描述：

  delta-戊内酯 在 4-二甲氨基吡啶 、 sodium hydroxide 、 四丁基溴化铵 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 24.0h， 生成 5-oxo-5-(phenylmethoxy)pentyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-3-<(1,1-dimethylethoxy)carbonyl>-5-oxazolidinecarboxylate
  参考文献：
  名称：

  Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors

  摘要：

  Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65-mu-M, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

  DOI：

  10.1021/jm00113a005

文献信息

• Highly potent, orally active diester macrocyclic human renin inhibitors
  作者：Ann E. Weber、Mark G. Steiner、Philip A. Krieter、Adria E. Colletti、James R. Tata、Thomas A. Halgren、Richard G. Ball、John J. Doyle、Terry W. Schorn

  DOI：10.1021/jm00099a004

  日期：1992.10

  moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.

  用酯键取代通用结构1和2的大环肾素抑制剂中的一个酰胺键，可得到谷氨酸衍生的抑制剂3和丝氨酸衍生的抑制剂4。尽管这种氧-氮交换对谷氨酸系列的效价影响很小，在丝氨酸系列中，效力大大提高。在本系列中，事实证明，14元环化合物比相应的13元环衍生物更有效。在对应于P2'的位置上环的取代通常增加了效力。通过不对称合成和X射线晶体学分析，对于4-吗啉代甲基衍生物（4o），在该中心的绝对构型显示为R。用各种取代基取代抑制剂4o的“ Boc-Phe”部分会导致亚纳摩尔抑制剂，其中一种（“
• Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors
  作者：Ann E. Weber、Thomas A. Halgren、John J. Doyle、Robert J. Lynch、Peter K. S. Siegl、William H. Parsons、William J. Greenlee、Arthur A. Patchett

  DOI：10.1021/jm00113a005

  日期：1991.9

  Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65-mu-M, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.