Methyl 3-(3,17beta-dihydroxyestra-1,3,5(10)-trien-16alpha-yl)-propanoate | 345295-00-3

• 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: Methyl 3-(3,17beta-dihydroxyestra-1,3,5(10)-trien-16alpha-yl)-propanoate
• 英文别名: methyl 3-[(8R,9S,13S,14S,16R,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-16-yl]propanoate
• CAS: 345295-00-3
• 化学式: C₂₂H₃₀O₄
• 分子量: 358.478
• InChiKey: HSWFNBDKEAQDFS-BGJLUCPFSA-N

物化性质

• 沸点：
  512.9±50.0 °C(Predicted)
• 密度：
  1.168±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Methyl 3-(3,17beta-dihydroxyestra-1,3,5(10)-trien-16alpha-yl)-propanoate 在 5percent aq. KOH 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以59%的产率得到3-(3,17beta-Dihydroxyestra-1,3,5(10)-trien-16alpha-yl)propanoic acid
  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 5percent Pd/C 吡啶 、 chromium(VI) oxide 、 氯化亚砜 、 硼烷四氢呋喃络合物 、 硫酸 、 氢气 、 二异丁基氢化铝 、 lithium tri-t-butoxyaluminum hydride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正庚烷 、 二乙二醇二甲醚 、 乙基苯 、 丙酮 、 甲苯 为溶剂， -78.0~150.0 ℃ 、101.33 kPa 条件下， 反应 65.75h， 生成 Methyl 3-(3,17beta-dihydroxyestra-1,3,5(10)-trien-16alpha-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

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。
• ESTROGEN RECEPTOR BETA SELECTIVE LIGANDS
  申请人：OR-GENIX THERAPEUTICS, INC.

  公开号：US20200377546A1

  公开（公告）日：2020-12-03

  An estrogen receptor β selective ligand can be a compound according to Structure 1: wherein m is 0, 1, or 2 and R is H, a C 1 to C 5 alkyl group, vinyl, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , or CH 2 CF 3 . A composition (e.g., pharmaceutical or cosmetic composition) can include an effective amount of a compound according to Structure 1 and a physiologically acceptable carrier, diluent, or excipient, formulated for topical administration. A method (e.g., therapeutic or cosmetic method) can include administering to a subject in need thereof an effective amount of a compound according to Structure 1 or a composition including Structure 1. Administration can be topical (e.g., to skin, scalp or mucosa).
• US6476012B2
  申请人：——

  公开号：US6476012B2

  公开（公告）日：2002-11-05
• [EN] ESTRADIOL-16 alpha -CARBOXYLIC ACID ESTERS AS LOCALLY ACTIVE ESTROGENS<br/>[FR] ESTERS D'ACIDE CARBOXYLIQUES OESTRADIOL-16 DOLLAR G(A) UTILES EN TANT QU'OESTROGENES ACTIFS AU NIVEAU LOCAL
  申请人：UNIV YALE

  公开号：WO2002058634A2

  公开（公告）日：2002-08-01

  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 16α-carboxylic acid substituted steroids sand 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: I 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 CH2CF ?3? and m is 0. More preferbly, R is methyl, ethyl, CH2CH2F, CH2CHF2 or CH2CF2 and m is 0.
• [EN] ESTROGEN RECEPTOR BETA SELECTIVE LIGANDS<br/>[FR] LIGANDS SÉLECTIFS DU RÉCEPTEUR BÊTA DES ŒSTROGÈNES
  申请人：OR GENIX THERAPEUTICS INC

  公开号：WO2018039110A1

  公开（公告）日：2018-03-01

  An estrogen receptor β selective ligand can be a compound according to Structure 1: wherein m is 0, 1, or 2 and R is H, a C1 to C5 alkyl group, vinyl, CF3, CH2CH2F, CH2CHF2, or CH2CF3. A composition (e.g., pharmaceutical or cosmetic composition) can include an effective amount of a compound according to Structure 1 and a physiologically acceptable carrier, diluent, or excipient, formulated for topical administration. A method (e.g., therapeutic or cosmetic method) can include administering to a subject in need thereof an effective amount of a compound according to Structure 1 or a composition including Structure 1. Administration can be topical (e.g., to skin, scalp or mucosa).