[2-(1-Naphthyl)-6-hydroxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [2-(1-Naphthyl)-6-hydroxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
• 英文别名: [2-(1-Naphthyl)-6-hydroxybenzothien-3-yl] [4-[2-(1-piperdinyl)ethoxy]phenyl]methanone；[2-(1-Naphthyl)-6-hydroxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone；[2-(1-Naphthyl)-6-hydroxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone；(6-hydroxy-2-naphthalen-1-yl-1-benzothiophen-3-yl)-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
• 化学式: C₃₂H₂₉NO₃S
• 分子量: 507.653
• InChiKey: UPNAHMSJUMHPOR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  78
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  [2-(1-Naphthyl)-6-methoxybenzothien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone 在 三氯化铝 、 丙烷-1-硫醇 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 5.0h， 以53%的产率得到[2-(1-Naphthyl)-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

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。
• US5728724A
  申请人：——

  公开号：US5728724A

  公开（公告）日：1998-03-17
• [EN] BENZOTHIOPHENE COMPOUNDS<br/>[FR] COMPOSES DE BENZOTHIOPHENE
  申请人：ELI LILLY AND COMPANY

  公开号：WO1997006796A1

  公开（公告）日：1997-02-27

  (EN) The present invention relates to compounds of formula (I) wherein R1 is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); R2 is 1-naphthyl, 2-naphthyl, 1-thienyl, 2-thienyl, benzothienyl, or -CH2C6H5; any of which may be optionally substituted with 1-3 substituents independently selected from the group halo, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6 alkyl), or -OSO2(C4-C6 alkyl); X is -CH2-, -CO-, or -CH(OH)-; n is 2 or 3; and R3 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), optionally containing estrogen or progestin, and the use of such compounds, alone, or in combination with estrogen or progestin, 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.(FR) L'invention concerne des composés représentés par la formule (I) dans laquelle R1 représente -H, -OH, -O(alkyleC1-C4), -OCOC6H5, -OCO(alkyleC1-C6) ou -OSO2(alkyleC4-C6); R2 représente 1-naphtyle, 2-naphtyle, 1-thiényle, 2-thiényle, benzothiényle ou -CH2C6H5, tous ces constituants pouvant être éventuellement substitués par 1-3 substituants sélectionnés indépendamment dans le groupe halo, -OH, -O(alkyleC1-C4), -OCOC6H5, -OCO(alkyleC1-C6) ou -OSO2(alkyleC4-C6); X représente -CH2-, -CO- ou -CH(OH)-; n est 2 ou 3; R3 représente 1-pipéridinyle, 1-pyrrolidinyle, méthyle-1-pyrrolidinyle, diméthyle-1-pyrrolidinyle, 4-morpholino, diméthylamino, diéthylamino ou 1-hexaméthylèneimino; ou un de leurs sels pharmaceutiquement acceptable. L'invention concerne, de plus, des compositions pharmaceutiques contenant des composés représentés par la formule (I), contenant éventuellement un oestrogène ou une progestine, ainsi que l'utilisation de ces composés, seuls ou combinés à un oestrogène ou une progestine, afin de soulager les symptômes du syndrome de post-ménopause, en particulier, l'ostéoporose, les états pathologiques d'origine cardio-vasculaire et le cancer dépendant des oestrogènes. Ces composés sont également utiles pour inhiber la fibrose utérine et l'endométriose chez la femme, ainsi que la prolifération cellulaire des muscles lisses de l'aorte, en particulier, la resténose, chez l'homme.
• 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.