[2-(4-Methoxyphenyl)methyl-6-methoxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone | 185416-72-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [2-(4-Methoxyphenyl)methyl-6-methoxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
• 英文别名: [2-(4-Methoxyphenyl)methyl-6-methoxybenzothien-3-yl] [4-[2-(1-piperdinyl)ethoxy]phenyl]methanone；[2-(4-Methoxyphenyl)methyl-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone；[2-(4-Methoxyphenyl)methyl-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone；[6-methoxy-2-[(4-methoxyphenyl)methyl]-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
• CAS: 185416-72-2
• 化学式: C₃₁H₃₃NO₄S
• 分子量: 515.673
• InChiKey: OQULHFNJQQGNLA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  76.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  [2-(4-Methoxyphenyl)methyl-6-methoxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone 在 三氯化硼 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 20.0h， 以86%的产率得到[2-(4-Hydroxyphenyl)methyl-6-hydroxybenzothien-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-Methoxyphenyl)methyl-6-methoxybenzothien-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

• Benzothiophene compounds
  申请人：Eli Lilly and Company

  公开号：US05728724A1

  公开（公告）日：1998-03-17

  The present invention relates to compounds of formula I ##STR1## wherein R.sup.1 is --H, --OH, --O(C.sub.1 -C.sub.4 alkyl), --OCOC.sub.6 H.sub.5, --OCO(C.sub.1 -C.sub.6 alkyl), or --OSO.sub.2 (C.sub.4 -C.sub.6 alkyl); R.sup.2 is 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, benzothienyl, or --CH.sub.2 C.sub.6 H.sub.5 ; any of which may be optionally substituted with 1-3 substituents independently selected from the group halo, --OH, --O(C.sub.1 -C.sub.4 alkyl), --OCOC.sub.6 H.sub.5, --OCO(C.sub.1 -C.sub.6 alkyl), or --OSO.sub.2 (C.sub.4 -C.sub.6 alkyl); X is --CH.sub.2 --, --CO--, or --CH(OH)--; n is 2 or 3; and R.sup.3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; or a pharmaceutically acceptable salt thereof. The present invention further relates to pharmaceutical compositions containing compounds of formula I, and the use of such compounds, for alleviating the symptoms of post-menopausal syndrome, particularly osteoporosis, cardiovascular related pathological conditions, and estrogen-dependent cancer. The compounds of the present invention also are useful for inhibiting uterine fibroid disease and endometriosis in women and aortal smooth muscle cell proliferation, particularly restenosis, in humans.

  本发明涉及式I的化合物，其中R.sup.1是--H，--OH，--O（C.sub.1-C.sub.4烷基），--OCOC.sub.6H.sub.5，--OCO（C.sub.1-C.sub.6烷基）或--OSO.sub.2（C.sub.4-C.sub.6烷基）; R.sup.2是1-萘基，2-萘基，2-噻吩基，3-噻吩基，苯并噻吩基或--CH.sub.2C.sub.6H.sub.5；其中任何一个可以选择性地被1-3个取代基独立地选自卤素，--OH，--O（C.sub.1-C.sub.4烷基），--OCOC.sub.6H.sub.5，--OCO（C.sub.1-C.sub.6烷基）或--OSO.sub.2（C.sub.4-C.sub.6烷基）; X是--CH.sub.2--，--CO--或--CH（OH）--; n为2或3; R.sup.3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，二甲胺，二乙胺或1-己亚胺；或其药学上可接受的盐。本发明还涉及含有式I化合物的制药组合物，以及使用这种化合物缓解绝经后综合症状，特别是骨质疏松症，心血管相关病理状况和雌激素依赖性癌症的症状。本发明的化合物还可用于抑制女性子宫肌瘤和子宫内膜异位症以及抑制主动脉平滑肌细胞增殖，特别是再狭窄。
• Benzothiophene and naphthalene derived constrained SERMs
  作者：Owen B. Wallace、Henry U. Bryant、Pamela K. Shetler、Mary D. Adrian、Andrew G. Geiser

  DOI：10.1016/j.bmcl.2004.07.072

  日期：2004.10

  For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line. (C) 2004 Elsevier Ltd. All rights reserved.
• US5728724A
  申请人：——

  公开号：US5728724A

  公开（公告）日：1998-03-17
• 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.