Urea, N-cycloheptyl-N-((4-(4-fluorophenoxy)phenyl)methyl)-N'-(6-methyl-2,4-bis(methylsulfonyl)-3-pyridinyl)- | 215589-63-2

• 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: Urea, N-cycloheptyl-N-((4-(4-fluorophenoxy)phenyl)methyl)-N'-(6-methyl-2,4-bis(methylsulfonyl)-3-pyridinyl)-
• 英文别名: 1-cycloheptyl-1-[[4-(4-fluorophenoxy)phenyl]methyl]-3-[6-methyl-2,4-bis(methylsulfonyl)pyridin-3-yl]urea
• CAS: 215589-63-2
• 化学式: C₂₉H₃₄FN₃O₆S₂
• 分子量: 603.736
• InChiKey: UFRBZRWETFGORO-UHFFFAOYSA-N

物化性质

• 熔点：
  129-130 °C
• 沸点：
  842.3±65.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  140
• 氢给体数：
  1
• 氢受体数：
  8

安全信息

• 储存条件：
  存储条件：2-8℃，请密封并保持干燥。

制备方法与用途

生物活性

FR-190809 是一种有效、可口服且无肾上腺毒性的酰基辅酶 A-胆固醇酰基转移酶 (ACAT) 抑制剂，其 IC50 值为 45 nM。

靶点

IC50: ACAT

体外研究

FR-190809 能抑制泡沫细胞的形成，其 IC50 值为 215 nM。

反应信息

• 作为反应物：
  描述：

  Urea, N-cycloheptyl-N-((4-(4-fluorophenoxy)phenyl)methyl)-N'-(6-methyl-2,4-bis(methylsulfonyl)-3-pyridinyl)- 在 镍 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 1.25h， 生成 N-cycloheptyl-N-<4-(4-fluorophenoxy)benzyl>-N'-<6-methyl-2-(methylsulfonyl)pyridin-3-yl>urea
  参考文献：
  名称：

  Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase. 3. Discovery of a Novel Series of N-Alkyl-N-[(fluorophenoxy)benzyl]-N‘-arylureas with Weak Toxicological Effects on Adrenal Glands

  摘要：

  A series of N-alkyl-N-[(fluorophenoxy)benzyl] -N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.

  DOI：

  10.1021/jm980399q
• 作为产物：
  描述：

  Urea, N-cycloheptyl-N-((4-(4-fluorophenoxy)phenyl)methyl)-N'-(6-methyl-2,4-bis(methylthio)-3-pyridinyl)- 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 以71%的产率得到Urea, N-cycloheptyl-N-((4-(4-fluorophenoxy)phenyl)methyl)-N'-(6-methyl-2,4-bis(methylsulfonyl)-3-pyridinyl)-
  参考文献：
  名称：

  Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase. 3. Discovery of a Novel Series of N-Alkyl-N-[(fluorophenoxy)benzyl]-N‘-arylureas with Weak Toxicological Effects on Adrenal Glands

  摘要：

  A series of N-alkyl-N-[(fluorophenoxy)benzyl] -N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.

  DOI：

  10.1021/jm980399q

文献信息

• UREA DERIVATIVES AND THEIR USE AS ACAT-INHIBITORS
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0784612A1

  公开（公告）日：1997-07-23
• [EN] UREA DERIVATIVES AND THEIR USE AS ACAT-INHIBITORS<br/>[FR] DERIVES D'UREE ET LEUR UTILISATION COMME INHIBITEURS DE L'ACAT
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：WO1996010559A1

  公开（公告）日：1996-04-11

  (EN) Urea derivatives of formula (I), wherein R1 is a group of formula (1) (in which R4 is aryl which may have suitable substituent(s), or heterocyclic group which may have suitable substituent(s), and Y is bond, lower alkylene, -S-, -O-, (a), =CH-, -CONH-, (b), (in which R7 is lower alkyl), -NHSO2-, -SO2NH-, -SO2NHCO- or -CONHSO2-); or thiazolyl, imidazolyl, pyrazolyl, pyridyl, thienyl, furyl, isoxazolyl or chromanyl, each of which may have suitable substituent(s); R2 is lower alkyl, lower alkoxy(lower)alkyl, cycloalkyl, ar(lower)alkyl which may have suitable substituent(s), heterocyclic group or heterocyclic(lower)alkyl, R3 is aryl which may have suitable substituent(s) or heterocyclic group which may have suitable substituent(s), and n is 0 or 1, and a pharmaceutically acceptable salt thereof which are useful as a medicament in the treatment of hypercholesterolemia, hyperlipidemia and atherosclerosis.(FR) Cette invention se rapporte à des dérivés d'urée, représentés parr la formule (I), où R1 représente un groupe de la formule (1) (dans laquelle R4 représente aryle qui peut comporter un ou des substitutants appropriés, ou un groupe hétérocyclique qui peut comporter un ou des substituants appropriés; et Y représente une liaison, alkylène inférieur, -S-, -O-, (a), =CH-, -CONH-, (b) (où R7 représente alkyle inférieur), -NHSO2-, -SO2NH-, -SO2NHCO- ou -CONHSO2-); ou alors R1 représente thiazolyle, imidazolyle, pyrazolyle, pyridyle, thiényle, furyle, isoxazolyle ou chromanyle, chacun de ces éléments pouvant comporter un ou des substituants appropriés; R2 représente alkyle inférieur, alcoxy inférieur alkyle(inférieur), cycloalkyle, aralkyle(inférieur) pouvant comporter un ou des substituants appropriés, un groupe hétérocyclique ou alkyle(inférieur) hétérocyclique; R3 représente aryle pouvant comporter un ou des substituants appropriés ou un groupe hétérocyclique pouvant comporter un ou des substituants appropriés; et n est égal à 0 ou à 1; ainsi qu'à un sel pharmaceutiquement acceptacle de ces composés, qui peuvent être utilisés comme médicament dans le traitement de l'hypercholestérolémie, de l'hyperlipidémie et de l'athérosclérose.
• Inhibitors of Acyl-CoA:Cholesterol <i>O</i>-Acyltransferase. 3. Discovery of a Novel Series of <i>N</i>-Alkyl-<i>N</i>-[(fluorophenoxy)benzyl]-<i>N</i>‘-arylureas with Weak Toxicological Effects on Adrenal Glands
  作者：Akira Tanaka、Takeshi Terasawa、Hiroyuki Hagihara、Noriko Ishibe、Masae Sawada、Yuri Sakuma、Masaharu Hashimoto、Hisashi Takasugi、Hirokazu Tanaka

  DOI：10.1021/jm980399q

  日期：1998.10.1

  A series of N-alkyl-N-[(fluorophenoxy)benzyl] -N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.