5-((5-cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-carbonyl)amino)isophthalic acid dibenzyl ester | 269070-88-4

• 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-((5-cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-carbonyl)amino)isophthalic acid dibenzyl ester
• 英文别名: 5-[(5-Cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-carbonyl)-amino]-isophthalic Acid Dibenzyl Ester；dibenzyl 5-[[5-(cycloheptylmethyl)-2-naphthalen-2-yl-1H-imidazole-4-carbonyl]amino]benzene-1,3-dicarboxylate
• CAS: 269070-88-4
• 化学式: C₄₄H₄₁N₃O₅
• 分子量: 691.827
• InChiKey: UELGELZJPYDDAH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.4
• 重原子数：
  52
• 可旋转键数：
  13
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-((5-cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-carbonyl)amino)isophthalic acid dibenzyl ester 在 palladium on activated charcoal 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以94%的产率得到5-((5-cycloheptylmethyl-2-(naphthalen-2-yl)-1H-imidazole-4-carbonyl)amino)isophthalic 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
• 作为产物：
  描述：

  环庚醋酸 在 4-二甲氨基吡啶 、 Oxone 、 sodium hydroxide 、 ammonium acetate 、 1-羟基苯并三唑 、 溶剂黄146 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 155.0h， 生成 5-((5-cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-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

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）。
• [EN] COMPOUNDS AND METHODS<br/>[FR] COMPOSES ET PROCEDES
  申请人：SMITHKLINE BEECHAM CORP

  公开号：WO2003031434A1

  公开（公告）日：2003-04-17

  Disclosed are compounds of formula (I) wherein the formula variables are as defined herein. The compounds of this invention are non-peptide, reversible inhibitors of type 2 methionine aminopeptidase. Also disclosed is the use of such compounds in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity.

  本发明揭示了式(I)的化合物，其中式变量如本文所定义。本发明的化合物是非肽类，可逆抑制剂，可抑制2型蛋氨酸氨肽酶。本发明还揭示了这些化合物在治疗由血管生成介导的疾病方面的用途，如癌症、血管瘤、增生性视网膜病变、类风湿性关节炎、动脉粥样硬化性新生血管形成、牛皮癣、眼部新生血管形成和肥胖症。
• [EN] PHARMACEUTICAL COMPOSITIONS COMPRISING PROTON PUMP INHIBITORS AND GASTRIN/CHOLECYSTOKININ RECEPTOR LIGANDS<br/>[FR] COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES INHIBITEURS DE LA POMPE A PROTONS ET DES LIGANDS DU RECEPTEUR DES GASTRINES/CHOLECYSTOKININES
  申请人：BLACK JAMES FOUNDATION

  公开号：WO2001085167A1

  公开（公告）日：2001-11-15

  Pharmaceutical compositions comprising a proton pump inhibitor and a compound of the formula (I) or its pharmaceutically acceptable salts, are useful in treating gastrointestinal disorders. X and Y are independently =N-,-N(R5)- (R5 being selected from H, Me, Et, Pr, Bn, -OH and -CH¿2COOR?6, wherein R6 represents H, Me, Et, Pr or Bn), =CH-, -S- or -O-; n is from 1 to 4; R1 is H or C¿1? to C15 hydrocarbyl wherein up to three C atoms may optionally be replaced by N, O and/or S atoms and up to three H atoms may optionally be replaced by halogen atoms; R?2¿ is selected from H, Me, Et, Pr and OH, each R2 being independently selected from H, Me, Et, Pr and OH when n is greater than 1; R3 (when n is 1) 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 which are linked by a double bond; or R?2 and R3¿ on the same carbon atom are linked to form a C¿3? to C6 carbocylic ring, or two R3 groups are absent from neighbouring carbon atoms which are linked by a double bond; or R?2 and R3¿ on the same carbon atom together represent an =O group; R4 is C1 to C15 hydrocarbyl wherein up to two C atoms may optionally be replaced by N, O and/or S atoms and up to two H atoms may optionally be replaced by halogen atoms; Z is -(NR7)a-CO-(NR8)b- (wherein a is 0 or 1, b is 0 or 1, and R?7 and R8¿ are independently selected from the groups recited above for R6), -CO-NR7-CH2-CO-NR8-, -CO-O-, -CH¿2?-CH2-, -CH=CH-, -CH2-NR?8¿- or a bond; Q is -R9V, or (II) (wherein R9 is -CH¿2?-; -CH2-CH2-; or (III) R?9 and R8¿, together with the nitrogen atom to which R8 is attached, form a piperidine or pyrrolidine ring which is substitued by V; V is -CO-NH-SO¿2?-Ph, SO2-NH-CO-Ph, -CH2OH, or a group of the formula -R?10¿U, (wherein U is -COOH, tetrazolyl, -CONHOH- or -SO¿3?H; and R?10¿ is a bond; C¿1? to C6 hydrocarbylene, optionally substituted by hydroxy, amino or acetamido; -O-(C1 to C3 alkylene)-; -SO2NR?11-CHR12¿-;-CO-NR?11 -CHR12-, R11 and R12¿ being independently selected from H and methyl; or -NH-(CO)¿c?-CH2-, c being 0 or 1); T is C1 to C6 hydrocarbyl, -NR?6R7¿ (wherein R?6 and R7¿ are as defined above), -OMe, -OH, -CH¿2?OH, halogen or trihalomethyl; m is 1 or 2; p is from 0 to 3; and q is from 0 to 2, with the proviso that q is 1 or 2 when Z is a bond).

  含有质子泵抑制剂和公式(I)化合物或其药学上可接受的盐的制剂，可用于治疗胃肠道疾病。其中，X和Y独立地等于=N-，-N（R5）-（其中R5选择自H，Me，Et，Pr，Bn，-OH和-CH2COOR6，其中R6表示H，Me，Et，Pr或Bn），=CH-，-S-或-O-；n为1至4；R1为H或C1至C15烃基，其中最多可以用N，O和/或S原子替换最多三个C原子，并且最多可以用卤素原子替换最多三个H原子；当n大于1时，R2从H，Me，Et，Pr和OH中选择，每个R2独立地从H，Me，Et，Pr和OH中选择；当n为1时，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，或者相邻碳原子上的两个R3基团通过双键连接；或R2和R3在同一碳原子上连接形成C3至C6的环状碳基环，或相邻碳原子上缺少两个R3基团，这些碳原子由双键连接；或R2和R3在同一碳原子上一起表示=O基团；R4为C1至C15烃基，其中最多可以用N，O和/或S原子替换最多两个C原子，并且最多可以用卤素原子替换最多两个H原子；Z为-(NR7)a-CO-(NR8)b-（其中a为0或1，b为0或1，且R7和R8独立地从上述R6群中选择），-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，连同R8所连接的氮原子，形成一个被V取代的哌啶或吡咯烷环；V为-CO-NH-SO2-Ph，SO2-NH-CO-Ph，-CH2OH或式-R10U的基团（其中U为-COOH，四唑基，-CONHOH-或-SO3H；R10为键；C1至C6烃基亚烷基，可选择性地被羟基，氨基或乙酰氨基取代；-O-（C1至C3烷基）-；-SO2NR11-CHR12-，-CO-NR11-CHR12-，其中R11和R12独立地选择自H和甲基；或-NH-（CO）c-CH2-，其中c为0或1）；T为C1至C6烃基，-NR6R7（其中R6和R7如上所定义），-OMe，-OH，-CH2OH，卤素或三卤甲基；m为1或2；p为0至3；q为0至2，但前提是当Z为键时，q为1或2。
• COMPOUNDS AND METHODS
  申请人：SmithKline Beecham Corporation

  公开号：EP1434772A1

  公开（公告）日：2004-07-07
• EP1434772A4
  申请人：——

  公开号：EP1434772A4

  公开（公告）日：2005-05-04