3,17beta-Dihydroxyestra-1,3,5(10)-trien-16alpha-carboxylic acid | 345294-76-0

• 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: 3,17beta-Dihydroxyestra-1,3,5(10)-trien-16alpha-carboxylic acid
• 英文别名: (8R,9S,13S,14S,16R,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-16-carboxylic acid
• CAS: 345294-76-0
• 化学式: C₁₉H₂₄O₄
• 分子量: 316.397
• InChiKey: ZJTRULPAEZNZLZ-VMENWCDDSA-N

物化性质

• 沸点：
  546.5±50.0 °C(Predicted)
• 密度：
  1.291±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3,17beta-Dihydroxyestra-1,3,5(10)-trien-16alpha-carboxylic acid 在 lithium aluminium tetrahydride 、 氯化亚砜 作用下， 以 四氢呋喃 为溶剂， 反应 3.25h， 生成 16α-hydroxymethylestra-1,3,5(10)-trien-3,17β-diol
  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 、 盐酸 、 lithium aluminium tetrahydride 、 硫酸 、 氢气 、 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 丙酮 为溶剂， 50.0 ℃ 、101.33 kPa 条件下， 反应 80.75h， 生成 3,17beta-Dihydroxyestra-1,3,5(10)-trien-16alpha-carboxylic 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

文献信息

• Synthesis and Evaluation of B-, C-, and D-Ring-Substituted Estradiol Carboxylic Acid Esters as Locally Active Estrogens
  作者：David C. Labaree、Jing-xin Zhang、Heather A. Harris、Craig O'Connor、Toni Y. Reynolds、Richard B. Hochberg

  DOI：10.1021/jm0204340

  日期：2003.5.1

  great influence on hormonal activity and esterase hydrolysis. Formate esters at 7alpha and 15alpha were good estrogens, but lengthening the chain to acetate dramatically decreased hormonal activity. However, the 7alpha-formate esters were not enzymatically hydrolyzed. At 11beta, the acetate (methyl ester) was an effective estrogen, but increasing the chain length to propionate dramatically reduced hormonal

  我们合成了雌二醇的衍生物，这些衍生物经过结构修饰以用作“软”雌激素，并在人体的地理有限区域内发挥作用。没有全身作用的雌激素。我们以前已经显示了用16alpha取代的雌二醇类似物在类固醇环附近羧基化，既不与雌激素受体结合，也不激活雌激素反应性基因。但是，当羧酸被掩盖为酯时，它们会与受体结合并刺激雌激素反应。通过非特异性酯酶的酶促水解可以使这些雌激素失活，从而限制了它们的作用范围。在这里，我们描述了我们的持续研究，旨在通过在7α-，11β-，在甾体核中的15α-位和雌激素受体容纳大的取代基的位置。测试了这些化合物的雌激素受体结合（雌激素受体α和β），在培养的石川细胞中刺激雌激素敏感基因以及作为酶促水解的底物。在体内试验中测试了可能的候选药物的全身和局部雌激素作用。生物学研究表明，无论连接点如何，所有短链羧酸C-1至C-3均无激素作用，而许多酯则具有雌激素作用。类固醇核上的位点对激素活性和酯酶水
• 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CH2 ；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、 、CH2CH2F、CH2CHF2或CH2 ，m为0。更优选地，R为甲基、乙基、CH2CH2F、CH2CHF2或CH2 ，m为0。
• 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.