2-<4-(3,5-dimethylpyrazol-1-yl)but-1-yl>-2-methylpropane-1,3-diol | 145283-01-8

• 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-<4-(3,5-dimethylpyrazol-1-yl)but-1-yl>-2-methylpropane-1,3-diol
• 英文别名: 2-[4-(3,5-dimethyl-1-pyrazolyl)butyl]-2-methyl-1,3-propanediol；2-[4-(3,5-Dimethylpyrazol-1-yl)butyl]-2-methylpropane-1,3-diol
• CAS: 145283-01-8
• 化学式: C₁₃H₂₄N₂O₂
• 分子量: 240.346
• InChiKey: JBFHICJHCRDSGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  58.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-<4-(3,5-dimethylpyrazol-1-yl)but-1-yl>-2-methylpropane-1,3-diol 在 氨 、 sodium 、 4-甲基苯磺酸吡啶 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 18.67h， 生成 1-{4-[2-(4,5-Diphenyl-1H-imidazol-2-yl)-5-methyl-[1,3]dioxan-5-yl]-butyl}-3,5-dimethyl-1H-pyrazole
  参考文献：
  名称：

  Acyl-CoA:Cholesterol O-Acyltransferase (ACAT) Inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as Potent Inhibitors of ACAT

  摘要：

  The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.

  DOI：

  10.1021/jm9505876
• 作为产物：
  描述：

  diethyl (4-bromobutyl)methylmalonate 在 lithium aluminium tetrahydride 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 26.25h， 生成 2-<4-(3,5-dimethylpyrazol-1-yl)but-1-yl>-2-methylpropane-1,3-diol
  参考文献：
  名称：

  Acyl-CoA:Cholesterol O-Acyltransferase (ACAT) Inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as Potent Inhibitors of ACAT

  摘要：

  The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.

  DOI：

  10.1021/jm9505876

文献信息

• Imidazoles
  申请人：RHONE POULENC RORER LIMITED

  公开号：EP0506437A1

  公开（公告）日：1992-09-30

  Imidazole derivatives of the formula: wherein R¹ represents optionally substituted phenyl, R² represents alkyl optionally substituted by hydroxy, X¹ represents a bond, oxygen, -S(0)n-, -CH₂0- or - CH₂N(R⁶)-, wherein n is 0, 1 or 2 and R⁶ represents hydrogen, alkyl, acyl alkylsulphonyl or, -C(X³)NR⁷R⁸, wherein X³ represents oxygen or sulphur and R⁷ and R⁸ represent hydrogen, alkyl, or optionally substituted phenyl, m is zero or 1 to 8, X² represents a bond, oxygen, -S(0)p- wherein p is 0, 1 or 2, or a group -C(0)NR⁴-, -C(S)NR⁴-, -OC(0)NR⁴-, -OC(S)NR⁴-, -NR⁴C(0)- or -NR⁴C(S)-, wherein R⁴ represents hydrogen or alkyl and R³ represents optionally substituted heterocyclyl, or cycloalkyl or, except when X¹ and X² are direct bonds, R³ represents optionally substituted phenyl, or R³ represents amino, alkylamino, benzylamino, benzyl(alkyl)amino, dialkylamino, aminoalkyl, alkylaminoalkyl, benzylaminoalkyl, benzyl(alkyl)aminoalkyl or dialkylaminoalkyl, or a cyclic imino group, and salts thereof possess useful pharmacological properties.

  Imidazole衍生物的化学式如下： 其中R¹代表可选择取代的苯基，R²代表可选择取代的烷基，其上带有羟基，X¹代表键，氧，-S(0)n-，-CH₂0-或- CH₂N(R⁶)-，其中n为0，1或2，R⁶代表氢，烷基，酰基烷基磺酰基或，-C(X³)NR⁷R⁸，其中X³代表氧或硫，R⁷和R⁸代表氢，烷基，或可选择取代的苯基，m为零或1至8，X²代表键，氧，-S(0)p-，其中p为0，1或2，或一个基团-C(0)NR⁴-，-C(S)NR⁴-，-OC(0)NR⁴-，-OC(S)NR⁴-，-NR⁴C(0)-或-NR⁴C(S)-，其中R⁴代表氢或烷基，R³代表可选择取代的杂环烷基，或环烷基或，除非X¹和X²是直接键，R³代表可选择取代的苯基，或R³代表氨基，烷基氨基，苄基氨基，苄(烷基)氨基，二烷基氨基，氨基烷基，烷基氨基烷基，苄基氨基烷基，苄(烷基)氨基烷基或二烷基氨基烷基，或一个环状亚胺基团，及其盐具有有用的药理学性质。
• [EN] IMIDAZOLES
  申请人：RHONE-POULENC RORER LIMITED

  公开号：WO1992017470A1

  公开（公告）日：1992-10-15

  (EN) Imidazole derivatives of formula (I), wherein R1 represents optionally substituted phenyl, R2 represents alkyl optionally substituted by hydroxy, X1 represents a bond, oxygen, -S(O)n-, -CH2O- or - CH2N(R6)-, wherein n is 0, 1 or 2 and R6 represents hydrogen, alkyl, acyl alkylsulphonyl or, -C(X3)NR7R8, wherein X3 represents oxygen or sulphur and R7 and R8 represent hydrogen, alkyl, or optionally substituted phenyl, m is zero or 1 to 8, X2 represents a bond, oxygen, -S(O)p-wherein p is 0, 1 or 2, or a group -C(O)NR4-, -C(S)NR4-, -OC(O)NR4-, -OC(S)NR4-, -NR4C(O)- or -NR4C(S)-, wherein R4 represents hydrogen or alkyl and R3 represents optionally substituted heterocyclyl, or cycloalkyl or, except when X1 and X2 are direct bonds, R3 represents optionally substituted phenyl, or R3 represents amino, alkylamino, benzylamino, benzyl(alkyl)amino, dialkylamino, aminoalkyl, alkylaminoalkyl, benzylaminoalkyl, benzyl(alkyl)aminoalkyl or dialkylaminoalkyl, or a cyclic imino group, and salts thereof possess useful pharmacological properties.(FR) On décrit des dérivés de formule (I), dans laquelle R1 représente phényle éventuellement substitué, R2 représente alkyle éventuellement substitué par hydroxy, X1 représente une liaison, oxygène, -S(O)n-, -CH2O- ou -CH2N(R6)-, où n est 0, 1 ou 2 et R6 représente hydrogène, alkyle, acyle, alkylsulphonyle ou -C(X3)NR7R8, où X3 représente oxygène ou soufre et R7 et R8 représentent hydrogène, alkyle ou phényle éventuellement substitué, m est zéro ou 1 à 8, X2 représente une liaison, oxygène, -S(O)p-, où p est 0, 1 ou 2, ou un groupe -C(O)NR4-, -C(S)NR4-, -OC(O)NR4-, -OC(S)NR4-, -NR4C(O)-, ou -NR4C(S)-, où R4 représente hydrogène ou alkyle et R3 représente hétérocyclyle éventuellement substitué, ou cylcloalkyle ou, sauf lorsque X1 et X2 sont des liaisons directes, R3 représente phényle éventuellement substitué, ou R3 représente amino, alkylamino, benzylamino, benzyl(alkyl)amino, dialkylamino, aminoalkyle, alkylaminoalkyle, benzylaminoalkyle, benzyl(alkyl)aminoalkyle ou dialkylaminoalkyle, ou un groupe imino cyclique, et leurs sels. Lesdits composés présentent des propriétés pharmacologiques utiles.
• Acyl-CoA:Cholesterol <i>O</i>-Acyltransferase (ACAT) Inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1<i>H</i>-imidazoles as Potent Inhibitors of ACAT
  作者：Peter C. Astles、Michael J. Ashton、Andrew W. Bridge、Neil V. Harris、Terrance W. Hart、David P. Parrott、Barry Porter、David Riddell、Christopher Smith、Robert J. Williams

  DOI：10.1021/jm9505876

  日期：1996.1.1

  The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.