2-[5-(3-Methoxy-phenoxy)-pentylsulfanyl]-4,5-diphenyl-1H-imidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-[5-(3-Methoxy-phenoxy)-pentylsulfanyl]-4,5-diphenyl-1H-imidazole
• 英文别名: 2-[5-(3-methoxyphenoxy)pentylsulfanyl]-4,5-diphenyl-1H-imidazole
• 化学式: C₂₇H₂₈N₂O₂S
• 分子量: 444.598
• InChiKey: AVKOGGRBMYCVSB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  32
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  72.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  安息香精油 在 2,6-二甲基吡啶 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 2-[5-(3-Methoxy-phenoxy)-pentylsulfanyl]-4,5-diphenyl-1H-imidazole
  参考文献：
  名称：

  Novel aryloxyalkylthioimidazoles as inhibitors of acyl-CoA: cholesterol-O-acyltransferase

  摘要：

  A series of aryloxyalkylthioimidazoles have been synthesized and evaluated for their ability,to interfere with the enzyme acyl-CoA (cholesterol-O-acyltransferase) (ACAT, EC 2.3.1.26). Most of the molecules possessed a good in vitro ACAT inhibitory activity with IC50 values ranging between 0.1 and 2.0 mu M Some of them, eg, 2-{5-[(4-isobutoxycarbonyl)phenoxy]-pentylthio} -4,5-diphenylimidazole 13, 2-{3-[(4-isobutoxycarbonyl)phenoxy]-2-oximinopropylthio}-4,5-diphenylimidazole 21, 2-{3-[(4-isobutoxycarbonyl)phenoxy]-2-hydrazonecarboxamidepropylthio) -4,5-diphenylimidazole 26, 2-[5-(2-pyridoxy)-pentylthio]-4,5-diphenylimidazole 40 and 2-{5-[(3,5-diterbutyl-4-hydroxy)phenylthio]pentylthio}-4,5-diphenylimidazole 42, were more potent (range of activity 10-90 nM). They were also more potent with respect to the reference CI-976. When administered orally in hyperlipemic rats, at 10 and 50 mg/kg doses, some representative compounds, like 2-{3-[(4-isobutoxycarbonyl)phenoxy]-2-hydroxypropylthio}-4,5-diphenylimidazole 1, 13 and 26, reduced VLDL/LDL-associated cholesterol levels by 30-50% and increased HDL cholesterol levels by 15-50%. In addition, liver accumulation of esterified cholesterol was counteracted (50-80% reduction) and liver ACAT ex vivo activity was decreased by 70-85%. Finally, the good efficacy displayed in an endogenous model of hypertriglyceridemia strongly supports the hypothesis of a good systemic availability, which constitutes one of the principal properties of a valuable ACAT inhibitor.

  DOI：

  10.1016/0223-5234(96)88207-9

文献信息

• 4,5-DIPHENYLIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS ACYL COENZYME A: CHOLESTEROL-0-ACYL-TRANSFERASE (ACAT) INHIBITOR
  申请人：PHARMACIA S.p.A.

  公开号：EP0680472A1

  公开（公告）日：1995-11-08
• [EN] 4,5-DIPHENYLIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS ACYL COENZYME A: CHOLESTEROL-0-ACYL-TRANSFERASE (ACAT) INHIBITOR<br/>[FR] DERIVES DE 4,5-DIPHENYLIMIDAZOLE, LEUR PREPARATION ET LEUR UTILISATION EN TANT QU'INHIBITEUR DE L'ACYL-COENZYME-A: CHOLESTEROL-O-ACYL-TRANSFERASE (ACAT)
  申请人：PHARMACIA S.P.A.

  公开号：WO1995014673A1

  公开（公告）日：1995-06-01

  (EN) The invention provides new diphenylimidazoles of formula (I) wherein: Ph is phenyl; and wherein A) when Z is 4,5-diphenylimidazol-2-ylthio, then p is zero and Y is a --(Ch2)m--X--(CH2)n-- group in which a) m and n being the same are 1 or 2 and X is (1), (2) or (3), wherein R is hydrogen or an optionally omega-hydroxy substituted C1-C10 alkyl chain, or b) m and n are 2 and X is (4), (5), (6) or (7), in which q is 1 or 2; or B) when Z is an aryloxy group unsubstituted or substituted by a substituent chosen from C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alcoxy, halogen, amino or an aryloxy group substituted by two substituents chosen from C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halogen, amino, nitro, C1-C6 alkoxy-carbonyl, di(C1-C6 alkyl) amino and --NHCONH-C1-C6 alkyl, or an aryloxy or arylthio group substituted by three sustituents chosen independently from hydroxy and C1-C6 alkyl, or a group chosen from 2-pyridyloxy, an optionally substituted imidazo[1,2-b]pyrazol-1-yl group, 2,3--dihydro-1H-imidazo[1,2--b]pyrazol-1-yl and (8) in which R1 is (9), (10) or (11), in which each of R2, R3 and R4 independently is hydrogen, C1-C4 alkyl or C1-C4 alkoxy; then p is zero or 1 and Y is a --(CH2)m--X--(CH2)n-- group wherein m and n are 1, X is a --(CH A)t-- group wherein A is hydrogen or hydroxy and t is zero or an integer of 1 to 10, or a group chosen from (12), (13), (14), (15) in which R is as defined above; or C) when Z is thiazolidin--2,4--dione--5--yl, then p is zero and Y is a bond or a --(CH2)m--X--(CH2)n-- group in which m and n are 1, X is a --(CH2)t-- group in which t is as defined above, and the pharmaceutically acceptable forming salts thereof, which have an ACAT inhibiting activity and are thus useful in the treatment of dyslipidemia, atherosclerosis and coronary diseases.(FR) L'invention se rapporte à des nouvelles diphénylimidazoles de la formule générale (I), dans laquelle Ph est phényle et dans laquelle: A) lorsque Z est 4,5-diphénylimidazol-2-ylthio, alors p vaut zéro et Y est un groupe --(Ch2)m--X--(CH2)n--, dans lequel: a) m et n étant égaux valent 1 ou 2 et X est (1), (2) ou (3), formules dans lesquelles R est hydrogène ou une chaîne alkyle C1-C10 facultativement substituée par oméga-hydroxy, ou b) m et n valent 2 et X est (4), (5), (6) ou (7), formules dans lesquelles Q vaut 1 ou 2; ou B) lorsque Z est un groupe aryloxy non substitué ou substitué par un substituant choisi parmi alkyle C1-C6, halo-alkyle C1-C6, alcoxy C1-C6, halogène, amino ou un groupe aryloxy substitué par deux substituants choisis parmi alkyle C1-C6, halo-alkyle C1-C6, alcoxy C1-C6, halogène, amino, nitro, alcoxy C1-C6-carbonyle, di(alkyle C1-C6)amino et --NHCONH-alkyle C1-C6, ou un groupe aryloxy ou arylthio substitué par trois substituants choisis indépendamment parmi hydroxy et alkyle C1-C6, ou un groupe choisi parmi 2--pyridyloxy, ou un groupe imidazo[1,2-b]pyrazol-1-yle facultativement substitué, 2,3--dihydro-1H-imidazo[1,2--b]pyrazol-1-yle et (8), où R1 est (9), (10) ou (11), formules dans lesquelles chacun des R2, R3 et R4 représente indépendamment hydrogène, alkyle C1-C4 ou alcoxy C1-4; alors p vaut zéro ou 1 et Y est un groupe --(CH2)m--X--(CH2)n--, dans lequel m et n valent 1, X est un groupe --(CH A)t--, dans lequel A est hydrogène ou hydroxy et t vaut zéro ou est un nombre entier compris entre 1 et 10, ou un groupe choisi parmi (12), (13), (14), (15), où R est tel que défini ci-dessus; ou C) lorsque Z est thiazolidine--2,4--dione--5--yle, alors p vaut zéro et Y est une liaison ou un groupe --(CH2)m--X--(CH2)n, dans lequel m et n valent 1, X est un groupe --(CH2)t--, dans lequel t est tel que défini ci-dessus. L'invention se rapporte également aux sels pharmacologiquement acceptables de ces composés, lesquels ont une activité inhibitrice de l'ACAT et sont par conséquent utiles dans le traitement d'une lipidémie anormale, de l'athérosclérose et des coronaropathies.
• Novel aryloxyalkylthioimidazoles as inhibitors of acyl-CoA: cholesterol-O-acyltransferase
  作者：M Bani、R Bormetti、W Ceccarelli、R Fiocchi、M Gobetti、M Lombroso、S Magnetti、V Olgiati、M Palladino、M Villa、E Vanotti

  DOI：10.1016/0223-5234(96)88207-9

  日期：1995.1

  A series of aryloxyalkylthioimidazoles have been synthesized and evaluated for their ability,to interfere with the enzyme acyl-CoA (cholesterol-O-acyltransferase) (ACAT, EC 2.3.1.26). Most of the molecules possessed a good in vitro ACAT inhibitory activity with IC50 values ranging between 0.1 and 2.0 mu M Some of them, eg, 2-5-[(4-isobutoxycarbonyl)phenoxy]-pentylthio} -4,5-diphenylimidazole 13, 2-3-[(4-isobutoxycarbonyl)phenoxy]-2-oximinopropylthio}-4,5-diphenylimidazole 21, 2-3-[(4-isobutoxycarbonyl)phenoxy]-2-hydrazonecarboxamidepropylthio) -4,5-diphenylimidazole 26, 2-[5-(2-pyridoxy)-pentylthio]-4,5-diphenylimidazole 40 and 2-5-[(3,5-diterbutyl-4-hydroxy)phenylthio]pentylthio}-4,5-diphenylimidazole 42, were more potent (range of activity 10-90 nM). They were also more potent with respect to the reference CI-976. When administered orally in hyperlipemic rats, at 10 and 50 mg/kg doses, some representative compounds, like 2-3-[(4-isobutoxycarbonyl)phenoxy]-2-hydroxypropylthio}-4,5-diphenylimidazole 1, 13 and 26, reduced VLDL/LDL-associated cholesterol levels by 30-50% and increased HDL cholesterol levels by 15-50%. In addition, liver accumulation of esterified cholesterol was counteracted (50-80% reduction) and liver ACAT ex vivo activity was decreased by 70-85%. Finally, the good efficacy displayed in an endogenous model of hypertriglyceridemia strongly supports the hypothesis of a good systemic availability, which constitutes one of the principal properties of a valuable ACAT inhibitor.