[2-(4-Trifluoromethylphenyl)-6-methoxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone | 185416-29-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [2-(4-Trifluoromethylphenyl)-6-methoxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
• 英文别名: [2-(4-Trifluoromethylphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone；[6-methoxy-2-[4-(trifluoromethyl)phenyl]-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
• CAS: 185416-29-9
• 化学式: C₃₀H₂₈F₃NO₃S
• 分子量: 539.618
• InChiKey: UFMPYPBWIMYFGH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  67
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  [2-(4-Trifluoromethylphenyl)-6-methoxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 以24%的产率得到[2-(4-Trifluoromethylphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
  参考文献：
  名称：

  Structure−Activity Relationships of Selective Estrogen Receptor Modulators:  Modifications to the 2-Arylbenzothiophene Core of Raloxifene

  摘要：

  The 8-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in, vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

  DOI：

  10.1021/jm9606352
• 作为产物：
  描述：

  6-甲氧基-N,N-二甲基苯并[b]噻吩-2-胺 以 四氢呋喃 、 氯苯 为溶剂， 反应 10.5h， 生成 [2-(4-Trifluoromethylphenyl)-6-methoxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
  参考文献：
  名称：

  Structure−Activity Relationships of Selective Estrogen Receptor Modulators:  Modifications to the 2-Arylbenzothiophene Core of Raloxifene

  摘要：

  The 8-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in, vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

  DOI：

  10.1021/jm9606352

文献信息

• Benzo [B] thiophene compounds, and compositions for treating bone loss,
  申请人：Eli Lilly and Company

  公开号：US05998442A1

  公开（公告）日：1999-12-07

  The invention provides benzo[b]thiophene compounds, formulations, and methods of inhibiting bone loss or bone resorption, particularly osteoporosis, and cardiovascular-related pathological conditions including hyperlipidemia and related cardiovascular pathologies.

  这项发明提供了苯并[b]噻吩化合物、配方和抑制骨质流失或骨吸收的方法，特别是针对骨质疏松症和与心血管相关的病理条件，包括高脂血症和相关的心血管病理条件。
• Benzo[B]thiophene compounds, intermediates, processes, compositions, and methods
  申请人：ELI LILLY AND COMPANY

  公开号：EP0826683A1

  公开（公告）日：1998-03-04

  The invention provides benzo[b]thiophene compounds, formulations, and methods of inhibiting bone loss or bone resorption, particularly osteoporosis, and cardiovascular-related pathological conditions including hyperlipidemia and related cardiovascular pathologies. The benzo[b]thiophenes have the following formula: wherein: X is -CH2-, -CH(OH)-, or -CO-; R1 is -H, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R2, R3, and R4 are, independently, -R1, -F, -Cl, C1-C4 alkyl, or -CF3, with the proviso that R3 and R4 are not both hydrogen unless R2 is CF3, and with the further proviso that when X is -CH2-, then R3 is -H, -Cl, -F, C1-C4 alkyl, or CF3; n is 2 or 3; and R5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof.

  本发明提供了苯并[b]噻吩化合物、制剂以及抑制骨丢失或骨吸收（尤其是骨质疏松症）和心血管相关病症（包括高脂血症和相关心血管病症）的方法。 苯并[b]噻吩具有下式： 其中 X是-CH2-、-CH(OH)-或-CO-； R1 是-H、-OH、-O（C1-C4 烷基）、-OCOAr（其中 Ar 是苯基或取代苯基）、-OCO（C1-C6 烷基）或 -OSO2（C4-C6 烷基）； R2、R3 和 R4 独立地是-R1、-F、-Cl、C1-C4 烷基或-CF3，但 R3 和 R4 不能都是氢，除非 R2 是 CF3，而且当 X 是-CH2-时，R3 是-H、-Cl、-F、C1-C4 烷基或 CF3； n 是 2 或 3；以及 R5 是 1-哌啶基、1-吡咯烷基、甲基-1-吡咯烷基、二甲基-1-吡咯烷基、4-吗啉基、二甲基氨基、二乙基氨基或 1-六亚甲基亚氨基；或其药学上可接受的盐或溶液。
• Benzo[b]thiophene compounds, intermediates, processes, compositions and methods
  申请人：Eli Lilly & Company

  公开号：EP1493741A2

  公开（公告）日：2005-01-05

  The invention provides benzo[b]thiophene compounds, formulations, and methods of inhibiting bone loss or bone resorption, particularly osteoporosis, and cardiovascular-related pathological conditions including hyperlipidemia and related cardiovascular pathologies.

  本发明提供了苯并[b]噻吩化合物、制剂和抑制骨质流失或骨吸收（尤其是骨质疏松症）以及心血管相关病症（包括高脂血症和相关心血管病症）的方法。
• US5998442A
  申请人：——

  公开号：US5998442A

  公开（公告）日：1999-12-07
• Structure−Activity Relationships of Selective Estrogen Receptor Modulators:  Modifications to the 2-Arylbenzothiophene Core of Raloxifene
  作者：Timothy A. Grese、Stephen Cho、Don R. Finley、Alexander G. Godfrey、Charles D. Jones、Charles W. Lugar、Michael J. Martin、Ken Matsumoto、Lewis D. Pennington、Mark A. Winter、M. Dee Adrian、Harlan W. Cole、David E. Magee、D. Lynn Phillips、Ellen R. Rowley、Lorri L. Short、Andrew L. Glasebrook、Henry U. Bryant

  DOI：10.1021/jm9606352

  日期：1997.1.1

  The 8-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in, vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.