16α-allyl-3-(benzyloxy)estra-1,3,5(10)-trien-17β-ol | 106139-63-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 16α-allyl-3-(benzyloxy)estra-1,3,5(10)-trien-17β-ol
• 英文别名: 3-benzyloxy-16α-allylestra-1,3,5(10)-triene-17β-ol；16α-allyl-3-benzyloxyestra-1,3,5(10)-trien-17β-ol；16alpha-Allyl-3-benzyloxyestra-1,3,5(10)-trien-17beta-ol；(8R,9S,13S,14S,16R,17S)-13-methyl-3-phenylmethoxy-16-prop-2-enyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-ol
• CAS: 106139-63-3
• 化学式: C₂₈H₃₄O₂
• 分子量: 402.577
• InChiKey: MPMKDERJUDLROP-YWJGSQKRSA-N

物化性质

• 沸点：
  547.0±50.0 °C(Predicted)
• 密度：
  1.093±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  16α-allyl-3-(benzyloxy)estra-1,3,5(10)-trien-17β-ol 在 吡啶 、 chromium(VI) oxide 、 氯化亚砜 、 硼烷四氢呋喃络合物 、 硫酸 作用下， 以 四氢呋喃 、 甲醇 、 二乙二醇二甲醚 、 丙酮 为溶剂， 反应 26.75h， 生成 methyl 3-(3-benzyloxy-17β-hydroxyestra-1,3,5(10)-trien-16α-yl)propanoate
  参考文献：
  名称：

  Estradiol-16α-carboxylic Acid Esters as Locally Active Estrogens

  摘要：

  We attempted to design analogues of estradiol to act as locally active estrogens without significant systemic action. We synthesized a series of 16a-carboxylic acid substituted steroids and their esters and tested their action in several assays of estrogenic action, including estrogen receptor (ER) binding, estrogenic potency in Ishikawa cells (human endometrial carcinoma), rat uterine weight (systemic action), and mouse vaginal reductases (local action). All of the estradiol substituted carboxylic acids (formic, acetic and propionic acids) were devoid of estrogenic action. To the contrary, many of the esters had marked estrogenic potency in the receptor and the Ishikawa assays. The esters of the 16 alpha -formic acid series had the highest ER affinity with little difference between the straight-chain alcohol esters (from methyl to n-butyl). However, estrogenic action in the Ishikawa assay decreased precipitously with esters longer than the ethyl ester. This decrease correlated well with the increased rate of esterase hydrolysis of longer esters as determined in incubations with rat hepatic microsomes. The most promising candidates, the methyl, ethyl, and fluoroethyl esters of the formate series, were tested for systemic and local action in the in vivo models. All three, especially the fluoroethyl ester, showed divergence between systemic and local estrogenic action. These metabolically labile estrogens will be extremely useful for the therapeutic treatment of the vaginal dyspareunia of menopause in women for whom systemic estrogens are contraindicated.

  DOI：

  10.1021/jm000523h
• 作为产物：
  描述：

  3-O-苄基雌酮 在 lithium aluminium tetrahydride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 反应 13.5h， 生成 16α-allyl-3-(benzyloxy)estra-1,3,5(10)-trien-17β-ol
  参考文献：
  名称：

  A short, stereoselective route to 16.alpha.-(substituted-alkyl)estradiol derivatives

  摘要：

  DOI：

  10.1021/jo00378a015

文献信息

• Estradiol-16alpha-carboxylic acid esters as locally active estrogens
  申请人：——

  公开号：US20020143002A1

  公开（公告）日：2002-10-03

  The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 16&agr;-carboxylic acid substituted steroids and their esters is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure: 1 Where R is H, a C 1 to C 5 alkyl, vinyl, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 or CH 2 CF 3 ; and m is from 0-2, or a pharmaceutically acceptable salt thereof. Preferably, R is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, neo-pentyl, vinyl, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 or CH 2 CF 3 and m is 0. More preferably, R is methyl, ethyl, CH 2 CH 2 F, CH 2 CHF 2 or CH 2 CF 3 and m is 0.

  本发明涉及雌二醇的类似物，其在最优选实施方式中作为局部活性雌激素而没有显著的全身作用。本发明提供了一系列16α-羧酸取代类固醇及其酯，其在治疗与更年期症状相关的药物组合物中表现出优异的生物活性。因此，本发明涉及以下结构的化合物：1其中R为H、C1到C5的烷基、乙烯基、CF3、CH2CH2F、CH2CHF2或CH2CF3；m为0-2，或其药学上可接受的盐。优选地，R为甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、新戊基、乙烯基、CF3、CH2CH2F、CH2CHF2或CH2CF3，m为0。更优选地，R为甲基、乙基、CH2CH2F、CH2CHF2或CH2CF3，m为0。
• Estradiol-16&agr;-carboxylic acid esters as locally active estrogens
  申请人：Yale University

  公开号：US06476012B2

  公开（公告）日：2002-11-05

  The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 16&agr;-carboxylic acid substituted steroids and their esters is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure: Where R is H, a C1 to C5 alkyl, vinyl, CF3, CH2CH2F, CH2CHF2 or CH2CF3; and m is from 0-2, or a pharmaceutically acceptable salt thereof. Preferably, R is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, neo-pentyl, vinyl, CF3, CH2CH2F, CH2CHF2 or CH2CF3 and m is 0. More preferably, R is methyl, ethyl, CH2CH2F, CH2CHF2 or CH2CF3 and m is 0.

  本发明涉及雌二醇的类似物，其在最优选的实施方式中作为局部活性雌激素而不具有显著的全身作用。提供了一系列16α-羧酸取代类固醇及其酯，其表现出优异的生物活性，可用于制备用于治疗与更年期症状相关的药物组合物。因此，本发明涉及符合以下结构的化合物：其中R为H、C1至C5烷基、乙烯基、CF3、CH2CH2F、CH2CHF2或CH2CF3；m为0-2，或其药学上可接受的盐。优选地，R为甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、新戊基、乙烯基、CF3、CH2CH2F、CH2CHF2或CH2CF3，m为0。更优选地，R为甲基、乙基、CH2CH2F、CH2CHF2或CH2CF3，m为0。
• A short, stereoselective route to 16.alpha.-(substituted-alkyl)estradiol derivatives
  作者：Thomas L. Fevig、John A. Katzenellenbogen

  DOI：10.1021/jo00378a015

  日期：1987.1
• Estrogen receptor binding tolerance of 16α-substituted estradiol derivatives
  作者：Thomas L. Fevig、Michael K. Mao、John A. Katzenellenbogen

  DOI：10.1016/0039-128x(88)90046-3

  日期：1988.5

  In order to examine the tolerance of the estrogen receptor for 16 alpha-substituents in estradiol, we have synthesized various 16 alpha-substituted estrogens and determined their binding affinity for receptor by a competitive radiometric binding assay. The substituents ranged from small, single-atom substituents (halogens), two-atom substituents (halomethyl groups), to larger alkyl groups and ultimately alkyl groups bearing various functionality, including fluorescent (nitrobenzoxadiazole, NBD) and photoreactive (nitroazidophenyl, NAP) groups. The estrogen receptor seems to have a moderate tolerance for bulky substituents: All of the halogen and halomethyl substituents bind with an affinity at least 50% that of estradiol; in the three atom alkyl series, the affinity declined markedly from propargyl (44%) and allyl (38%) to propyl (5%), suggestive of detailed steric constraints or a preference for unsaturation. The larger, more highly functionalized derivatives ranged in affinity from 0.1-7%, with the highest affinity binders being benzyl (5%) and 4-phenoxy-2(E)-butenyl (7%); most of the lowest affinity ones were the bulky fluorescent and photoreactive derivatives. Thus, the estrogen receptor has good tolerance for estradiol derivatives substituted at the 16 alpha-position with nonpolar groups of moderate bulk; however, with groups of larger bulk, affinity is much lower and becomes highly dependent upon the polarity and detailed structure of the substituents.
• US6476012B2
  申请人：——

  公开号：US6476012B2

  公开（公告）日：2002-11-05