2-Cycloheptylmethyl-5-naphthalen-2-yl-1H-pyrrole-3-carboxylic acid | 869996-79-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-Cycloheptylmethyl-5-naphthalen-2-yl-1H-pyrrole-3-carboxylic acid
• 英文别名: 2-(cycloheptylmethyl)-5-naphthalen-2-yl-1H-pyrrole-3-carboxylic acid
• CAS: 869996-79-2
• 化学式: C₂₃H₂₅NO₂
• 分子量: 347.457
• InChiKey: YAXCSRIWYPQGEX-UHFFFAOYSA-N

物化性质

• 沸点：
  564.3±38.0 °C(Predicted)
• 密度：
  1.186±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  53.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-Cycloheptylmethyl-5-naphthalen-2-yl-1H-pyrrole-3-carboxylic acid 在 吡啶 、 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 生成 5-[(2-Cycloheptylmethyl-5-naphthalen-2-yl-1H-pyrrole-3-carbonyl)-amino]-isophthalic acid dibenzyl ester
  参考文献：
  名称：

  Scaffold Hopping with Molecular Field Points:  Identification of a Cholecystokinin-2 (CCK₂) Receptor Pharmacophore and Its Use in the Design of a Prototypical Series of Pyrrole- and Imidazole-Based CCK₂ Antagonists

  摘要：

  A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK2) receptor antagonist 5 (JB93182), based on features shared with two related series. The technique uses "field points" as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK1. In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.

  DOI：

  10.1021/jm049069y
• 作为产物：
  描述：

  2-溴代-2-乙酰基萘 在 sodium hydroxide 、 ammonium acetate 、 potassium carbonate 、 溶剂黄146 、 sodium iodide 作用下， 以 乙醇 、 丙酮 为溶剂， 生成 2-Cycloheptylmethyl-5-naphthalen-2-yl-1H-pyrrole-3-carboxylic acid
  参考文献：
  名称：

  Scaffold Hopping with Molecular Field Points:  Identification of a Cholecystokinin-2 (CCK₂) Receptor Pharmacophore and Its Use in the Design of a Prototypical Series of Pyrrole- and Imidazole-Based CCK₂ Antagonists

  摘要：

  A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK2) receptor antagonist 5 (JB93182), based on features shared with two related series. The technique uses "field points" as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK1. In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.

  DOI：

  10.1021/jm049069y

文献信息

• Gastrin and cholecystokinin receptor ligands
  申请人：James Black Foundation Limited

  公开号：US06479531B1

  公开（公告）日：2002-11-12

  Compounds of formula (I) and their pharmaceutically acceptable salts are ligands at gastrin and/or cholecystokinin receptors. X and Y are independently ═N—, —N(R5)—═CH—, —S— or —O—. n is from 1 to 4; R1 is H or C1 to C15 hydrocarbyl R2 is selected from H, Me, Et, Pr and OH, R3 is selected from H, Me, Et and Pr; or (when n is greater than 1) each R3 is independently selected from H, Me, Et and Pr, or two R3 groups on neighbouring carbon atoms are linked to form a C3 to C6 carbocylic ring, or R2 and R3 on the same carbon atom together represent an ═O group; R4 is C1 to C15 hydrocarbyl Z is —(NR7)a—CO—(NR8)b— (wherein a is 0 or 1, b is 0 or 1, —CO—NR7—CH2—CO—NR8—, —CO—O—, —CH2—CH2—, —CH═CH—, —CH2—NR8— or a bond; Q is —R9V, or (II), (wherein R9 is —CH2—; —CH2—CH2—; or (III), R9 and R8, together with the nitrogen atom to which R8 is attached, form a piperidine or pyrrolidine ring which is substituted by V; V is —CO—NH—SO2—Ph, —SO2—NH—CO—Ph, —CH2OH, or a group of the formula —R10U, (wherein U is —COOH, tetrazolyl, —CONHOH— or —SO3H; and R10 is a bond; C1 to C6 hydrocarbylene, —O—(C1 to C3 alkylene)—; —SO2NR11—CHR12—; —CO—NR11—CHR12—, or —NH—(CO)c—CH2—, c being 0 or 1).

  化合物的结构式（I）及其药学上可接受的盐是胃泌素和/或胆囊收缩素受体的配体。X和Y独立地为═N—，—N(R5)—═CH—，—S—或—O—。n为1至4；R1为H或C1至C15烃基；R2从H，Me，Et，Pr和OH中选择；R3从H，Me，Et和Pr中选择；或（当n大于1时）每个R3独立地从H，Me，Et和Pr中选择，或相邻碳原子上的两个R3基团连接形成C3至C6碳环，或R2和R3在同一碳原子上共同表示一个═O基团；R4为C1至C15烃基；Z为—(NR7)a—CO—(NR8)b—（其中a为0或1，b为0或1，—CO—NR7—CH2—CO—NR8—，—CO—O—，—CH2—CH2—，—CH═CH—，—CH2—NR8—或键；Q为—R9V，或（II），（其中R9为—CH2—；—CH2—CH2—；或（III），R9和R8，与R8连接的氮原子一起形成被V取代的哌啶或吡咯烷环；V为—CO—NH—SO2—Ph，—SO2—NH—CO—Ph，—CH2OH，或具有式—R10U的基团，（其中U为—COOH，四唑基，—CONHOH—或—SO3H；R10为键；C1至C6烃基亚烷，—O—（C1至C3亚烷基）—；—SO2NR11—CHR12—；—CO—NR11—CHR12—，或—NH—（CO）c—CH2—，其中c为0或1）。
• GASTRIN AND CHOLECYSTOKININ RECEPTOR LIGANDS
  申请人：JAMES BLACK FOUNDATION LIMITED

  公开号：EP1178969B1

  公开（公告）日：2005-07-13
• US6479531B1
  申请人：——

  公开号：US6479531B1

  公开（公告）日：2002-11-12
• Scaffold Hopping with Molecular Field Points:  Identification of a Cholecystokinin-2 (CCK₂) Receptor Pharmacophore and Its Use in the Design of a Prototypical Series of Pyrrole- and Imidazole-Based CCK₂ Antagonists
  作者：Caroline M. R. Low、Ildiko M. Buck、Tracey Cooke、Julia R. Cushnir、S. Barret Kalindjian、Atul Kotecha、Michael J. Pether、Nigel P. Shankley、J. G. Vinter、Laurence Wright

  DOI：10.1021/jm049069y

  日期：2005.11.1

  A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK2) receptor antagonist 5 (JB93182), based on features shared with two related series. The technique uses "field points" as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK1. In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.