美雌醇 | 72-33-3

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 雌激素及孕激素类药
• 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
• 中文名称: 美雌醇
• 中文别名: 炔雌醇甲醚；3-甲氧基-17α-乙炔雌二醇
• 英文名称: mestranol
• 英文别名: (8R,9S,13S,14S,17R)-17-ethynyl-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-ol
• CAS: 72-33-3
• 化学式: C₂₁H₂₆O₂
• 分子量: 310.436
• InChiKey: IMSSROKUHAOUJS-MJCUULBUSA-N

物化性质

• 熔点：
  153-155 °C(lit.)
• 比旋光度：
  +2～+8°(D/20℃)(c=1, 1,4-dioxane)
• 沸点：
  390.58°C (rough estimate)
• 密度：
  1.0865 (rough estimate)
• 溶解度：
  乙腈：1mg/mL；乙醇：1mg/mL；甲醇：1mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from methanol or acetone
• 蒸汽压力：
  9.75X10-9 mm Hg at 25 °C (est)
• 稳定性/保质期：
  The shelf life of Norinyl-1 tablets is 5 years.
• 分解：
  When heated to decomposition it emits acrid smoke and irritating fumes.

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

Mestranol是一种合成雌激素，它可以迅速被吸收并广泛代谢为炔雌醇。炔雌醇能够快速且良好地从胃肠道吸收，但在肠壁会发生一定程度的首次通过代谢。与其他许多雌激素相比，炔雌醇在肝脏中的代谢速度较慢。排泄主要通过肾脏进行，部分也会出现在粪便中。

Mestranol is rapidly absorbed and extensively metabolised to ethinylestradiol. Ethinylestradiol is rapidly and well absorbed from the gastro-intestinal tract but is subject to some first-pass metabolism in the gut-wall. Compared to many other estrogens it is only slowly metabolized in the liver. Excretion is via the kidneys with some appearing also in the feces.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在体内，它迅速经历肝脏去甲基化，转化为炔雌醇，这是它的活性形式。/雌激素/

In the body it undergoes rapid hepatic demethylation to ethinyl estradiol, which is its active form. /Estrogens/

来源:Hazardous Substances Data Bank (HSDB)

代谢

美雌酚（Mestranol），是炔雌二醇的3-甲基醚，比炔雌二醇更具亲脂性，并且对脂肪组织的亲和力更大，大鼠实验已经证明了这一点。美雌酚本身在抗生育作用的靶位点上并不显著地与雌激素受体结合；其激素有效性依赖于转化为炔雌二醇。在大鼠中，约35%的美雌酚剂量会转化为炔雌二醇，在 mice 中为61%，在兔中为56%，在人体中为54%。去甲基化部分随后遵循特定物种典型的炔雌二醇途径，例如，在大鼠中为2-羟基化，在兔和豚鼠中为D-同环化。美雌酚在非人灵长类动物中也被去甲基化为炔雌二醇。

Mestranol, the 3-methyl ether of ethinyloestradiol, is more lipophilic than ethinyloestradiol and has a greater affinity for adipose tissues, as shown by experiments in rats. Mestranol itself does not bind significantly to estrogen receptors at the sites of their antifertility action; its hormonal effectiveness relies on transformation to ethinyloestradiol. About 35% of a mestranol dose is transformed into ethinyloestradiol in rats, 61% in mice, 56% in rabbits and 54% in man. The demethylated portion then follows the pathways for ethinyloestradiol that are typical for the particular species, e.g., 2-hydroxylation in rats and D-homoannulation in rabbits and guinea-pigs. Mestranol is also demethylated to ethinylestradiol in non-human primates.

来源:Hazardous Substances Data Bank (HSDB)

代谢

mestranol在人体内的代谢与炔雌醇的代谢密切相关。Mestranol通过脱甲基转化为炔雌醇：给志愿者静脉注射（14）C-美雌醇后，约50%的剂量脱甲基转化为炔雌醇。血浆中的主要化合物是炔雌醇-3-硫酸盐。

The metabolism of mestranol in humans is closely related to that of ethinyloestradiol. Mestranol is transformed to ethinyloestradiol by demethylation: after i.v. administration of (14)C-mestranol to human volunteers, about 50% of the dose is demethylated to ethinylestradiol. The main compound found in plasma is ethinyloestradiol-3-sulfate.

来源:Hazardous Substances Data Bank (HSDB)

代谢

美雌酚已知的人类代谢物包括炔雌醇。

Mestranol has known human metabolites that include ethinylestradiol.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

美雌酚是乙炔雌二醇的3-甲基醚。乙炔雌二醇是雌二醇的合成衍生物。乙炔雌二醇口服生物活性高，几乎用于所有现代复方口服避孕药中。它能够与（并激活）雌激素受体。美雌酚是乙炔雌二醇的生物惰性前药，在肝脏中脱甲基转化为乙炔雌二醇，转化效率为70%。 雌激素扩散进入靶细胞并与其蛋白受体相互作用。靶细胞包括女性生殖道、乳腺、下丘脑和垂体。雌激素增加肝脏对性激素结合球蛋白（SHBG）、甲状腺结合球蛋白（TBG）和其他血清蛋白的合成，并抑制前垂体分泌的促卵泡激素（FSH）。雌激素与黄体酮的组合抑制了下丘脑-垂体系统，减少了促性腺激素释放激素（GnRH）的分泌。

Mestranol is the 3-methyl ether of ethinylestradiol. Ethinylestradiol, is a synthetic derivative of estradiol. Ethinylestradiol is orally bio-active and the estrogen used in almost all modern formulations of combined oral contraceptive pills. It binds to (and activates) the estrogen receptor. Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver with a conversion efficiency of 70%. Estrogens diffuse into their target cells and interact with a protein receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. The combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌性证据

评估：有足够的人类证据表明绝经后雌激素治疗的致癌性。有足够的实验动物证据表明雌二醇和雌酮的致癌性。对于结合型马雌激素、雌马烯和雌三醇在实验动物中的致癌性，证据有限。对于d-雌马烯宁在实验动物中的致癌性，证据不足。总体评估：绝经后雌激素治疗对人类具有致癌性（第1组）。/绝经后雌激素治疗/

Evaluation: There is sufficient evidence in humans for the carcinogenicity of post-menopausal estrogen therapy. There is sufficient evidence in experimental animals for the carcinogenicity of estradiol and estrone. There is limited evidence in experimental animals for the carcinogenicity of conjugated equine estrogens, equilin and estriol. There is inadequate evidence in experimental animals for the carcinogenicity of d-equilenin. Overall evaluation: Post-menopausal estrogen therapy is carcinogenic to humans (Group 1). /Post-menopausal estrogen therapy/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 相互作用

24只C57L品系处女鼠（MTV-）分成两组，每组分别接受7或70微克的 mestranol:norethynodrel（1:50）混合物油剂灌胃，每周5次，从动物13周大开始。在高剂量组中，有7/7只在存活84-89周后被解剖时发现垂体肿瘤；而在低剂量组中，有6/11只发现垂体肿瘤；相比之下，对照组中有2/15只在存活90周后被发现垂体肿瘤。在这项研究中，以及在一个使用 norethisterone:ethinyloestradiol（50:1）的并行实验中，发现了10/96只处理过的老鼠患有肝癌，但不同处理组内的分布情况并未报告。48只对照老鼠中没有发现肝癌。

Groups of 24 virgin female C57L mice (MTV-) received 7 or 70 ug of a mixture of mestranol:norethynodrel (1:50) in oil by gavage, 5 times per week, commencing when the animals were 13 weeks of age. Pituitary tumors were found at autopsy in 7/7 mice given the higher dose that lived 84-89 weeks and in 6/11 mice given the lower dose, compared with 2/15 controls that lived 90 weeks. In this, and in a concurrent experiment with norethisterone:ethinyloestradiol (50:1), hepatomas were found in 10/96 treated mice, but the distribution within the different treatment groups was not reported. No hepatomas occurred among 48 control mice.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

未阉割的雄性（C3H x RIII）Fl小鼠（MTV+），给予3毫克/千克（ppm）的Ovulen（90%乙炔诺酮二醋酸酯和10%甲雌醇）混合入饲料（摄入量，7.5-10.0微克/鼠/天），其乳腺肿瘤发生率从0/76增加到14/25；在阉割的雄性中，发生率从10/61增加到21/28。未阉割雌性小鼠的高自发发生率（161/167）和肿瘤诱导的短潜伏期（30-33周）没有改变（37/38）。在卵巢切除的雌性中，Ovulen没有改变肿瘤发生率（对照组为28/34，与之相比为20/26），但卵巢切除的雌性（从49周到26周）和阉割的雄性（从82周到43周）的潜伏期都缩短了。

Intact male (C3H x RIII)Fl mice (MTV+) given 3 mg/kg (ppm) Ovulen (90% ethynodiol diacetate and 10% mestranol) mixed into the diet (intake, 7.5-10.0 ug/mouse per day) showed an increased incidence of mammary tumors, from 0/76 to 14/25; in castrated males, the incidence was increased from 10/61 to 21/28. The high spontaneous incidence (161/167) and short latent period of tumor induction (30-33 weeks) in intact females were not altered (37/38). In ovariectomized females the tumor incidence was not altered by Ovulen (28/34 in controls as compared with 20/26), but the latent period was reduced in both ovariectomized females (from 49 to 26 weeks) and castrated males (from 82 to 43 weeks).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Mestranol与雌激素受体的结合不良，其雌激素作用是由于它在肝脏中迅速脱甲基转化为炔雌醇；然而，脱甲基过程并不完全，因此为了达到相似的效果，必须比炔雌醇施用更多的Mestranol。

Mestranol binds poorly to the estrogen receptor and its estrogenic effect is due to its rapid demethylation in the liver to form ethinylestradiol; however, demethylation is not complete and more mestranol must be administered than ethinylestradiol to achieve similar effects.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

代谢物在尿液中的排泄率从10-27%不等；乙炔雌二醇代谢物的排泄率从36-54%不等。当美雌醇分子中的第2或第4位被氚标记或用(14)C标记时，14-45%的放射性物质会释放到体水中。

The excretion of metabolites in urine ranged from 10-27%; that of ethinyloestradiol metabolites ranges from 36-54%. When position 2 or 4 of the mestranol molecule is tritiated or marked with (14)C, between 14-45% of the radioactivity is released into the body water.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S26,S36/37,S36/37/39,S45
• 危险类别码：
  R40,R36/37/38,R48
• WGK Germany：
  3
• 海关编码：
  29372900
• RTECS号：
  RC8960000
• 危险标志：
  GHS07,GHS08
• 危险性描述：
  H315,H319,H351
• 危险性防范说明：
  P281,P305 + P351 + P338

制备方法与用途

用途

美雌醇是一种雌激素类药物，在临床上用于治疗卵巢功能不全、闭经、功能性子宫出血及更年期综合征等症状。

生物活性

Mestranol 是炔雌醇的3-甲基醚，是一种高效的雌激素受体激动剂，并且是第一个用于口服避孕的药物。

靶点

Target	Value
Estrogen receptor

体外研究

美雌醇广泛代谢为羟基化产物，其生物活性尚未得到充分表征。

体内研究

在大鼠体内实验中，给予Mestranol (0.2 mg/kg) 后观察到表达谷胱甘肽-S-转移酶(PGST) 的AHF在肝脏中的百分比增加。与对照组相比，低剂量Mestranol给药有增加病灶肝细胞标记指数的趋势，而高剂量则显示出显著差异。同时，在饮食中分别给予Mestranol (0.02 mg/kg 和 0.2 mg/kg) 后，非病灶标记指数减少，与仅摄入基础饮食的大鼠相比，未起始给药的实验组表现出更多的非病灶肝的标记增加。此外，Mestranol (50 mg/100 mg b.wt.) 显著减少了大鼠额皮质和孤束核(NTS) 中α-2-肾上腺素受体的数量，并且在蓝斑核中也观察到α-1 和 α-2-肾上腺素受体数量的减少。

反应信息

• 作为反应物：
  描述：

  美雌醇 在 盐酸 、 sodium tetrahydroborate 、 5%-palladium/activated carbon 、 氨 、 sodium methylate 、 sodium 、 对甲苯磺酸 、 三乙胺 、 三氯氧磷 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 叔丁醇 为溶剂， 反应 55.08h， 生成 诺美孕酮醋酸酯
  参考文献：
  名称：

  醋酸去甲孕甾醇的改进合成方法

  摘要：

  口服避孕药（OCs）是合成类固醇或孕激素，在结构上与睾丸激素或孕激素有关。已经合成了许多孕激素并批准用于OC，激素替代疗法（HRT）或某些妇科疾病的治疗。醋酸诺美孕酮（NOMAc）是新批准的OC，并已在许多国家迅速接受OC或HRT。NOMAc的合成仍然具有挑战性且成本很高。我们开发了一种新颖且经过改进的合成NOMAc的方法，共11个步骤，并且在不使用危险试剂的情况下总体收率良好。

  DOI：

  10.1021/op4003533
• 作为产物：
  描述：

  雌酚酮 在 potassium tert-butylate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 丙酮 为溶剂， 反应 2.0h， 生成 美雌醇
  参考文献：
  名称：

  醋酸去甲孕甾醇的改进合成方法

  摘要：

  口服避孕药（OCs）是合成类固醇或孕激素，在结构上与睾丸激素或孕激素有关。已经合成了许多孕激素并批准用于OC，激素替代疗法（HRT）或某些妇科疾病的治疗。醋酸诺美孕酮（NOMAc）是新批准的OC，并已在许多国家迅速接受OC或HRT。NOMAc的合成仍然具有挑战性且成本很高。我们开发了一种新颖且经过改进的合成NOMAc的方法，共11个步骤，并且在不使用危险试剂的情况下总体收率良好。

  DOI：

  10.1021/op4003533

文献信息

• [EN] TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS<br/>[FR] ADMINISTRATION CIBLÉE D'UN MÉDICAMENT FAISANT APPEL À DES COUPLEURS FONDÉS SUR L'AFFINITÉ
  申请人：INVICTUS ONCOLOGY PVT LTD

  公开号：WO2015148126A1

  公开（公告）日：2015-10-01

  The current invention discloses targeted drug delivery conjugates comprising a targeting moiety linked to a drug via a molecule having an affinity for the targeting moiety. Typically, the conjugate comprises a targeting ligand and a molecule of interest, e.g., a therapeutic agent. The targeting ligand and the molecule of interest are linked to each other via an affinity ligand. The affinity ligand is further covalently or non-covalently linked to a drug or therapeutic agent. The drug can be modified to make it more soluble and so that it cleaves from the linking molecule at the target site.

  当前的发明揭示了包括通过具有与靶向基团亲和力的分子连接到药物的靶向药物传递共轭物。通常，该共轭物包括一个靶向配体和一个感兴趣的分子，例如，一个治疗剂。靶向配体和感兴趣的分子通过一个亲和配体相互连接。该亲和配体进一步以共价或非共价方式连接到药物或治疗剂。药物可以被修改以使其更溶解，并使其在靶点处从连接分子中解离。
• Oligonucleotides comprising a non-phosphate backbone linkage
  申请人：Manoharan Muthiah

  公开号：US20060287260A1

  公开（公告）日：2006-12-21

  One aspect of the present invention relates to a ribonucleoside substituted with a phosphonamidite group at the 3′-position. In certain embodiments, the phosphonamidite is an alkyl phosphonamidite. Another aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-phosphate linkage. Representative non-phosphate linkages include phosphonate, hydroxylamine, hydroxylhydrazinyl, amide, and carbamate linkages. In certain embodiments, the non-phosphate linkage is a phosphonate linkage. In certain embodiments, a non-phosphate linkage occurs in only one strand. In certain embodiments, a non-phosphate linkage occurs in both strands. In certain embodiments, a ligand is bound to one of the oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, a ligand is bound to both of the oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-phosphate linkage. Representative non-phosphate linkages include phosphonate, hydroxylamine, hydroxylhydrazinyl, amide, and carbamate linkages. In certain embodiments, the non-phosphate linkage is a phosphonate linkage. In certain embodiments, a ligand is bound to the oligonucleotide strand. In certain embodiments, the oligonucleotide comprises at least one modified sugar moiety.

  本发明的一个方面涉及在3'-位置用磷酰胺基团取代的核糖核苷。在某些实施例中，磷酰胺基团是烷基磷酰胺基团。本发明的另一个方面涉及包含至少一个非磷酸酯连接的双链寡核苷酸。代表性的非磷酸酯连接包括磷酸酯、羟胺、羟基肼基、酰胺和碳酸酯连接。在某些实施例中，非磷酸酯连接是磷酸酯连接。在某些实施例中，非磷酸酯连接仅出现在一条链中。在某些实施例中，非磷酸酯连接出现在两条链中。在某些实施例中，配体结合到包含双链寡核苷酸的寡核苷酸链中的一条链上。在某些实施例中，配体结合到包含双链寡核苷酸的寡核苷酸链中的两条链上。在某些实施例中，寡核苷酸链包含至少一个修饰的糖基团。本发明的另一个方面涉及包含至少一个非磷酸酯连接的单链寡核苷酸。代表性的非磷酸酯连接包括磷酸酯、羟胺、羟基肼基、酰胺和碳酸酯连接。在某些实施例中，非磷酸酯连接是磷酸酯连接。在某些实施例中，配体结合到寡核苷酸链上。在某些实施例中，寡核苷酸包含至少一个修饰的糖基团。
• Oligonucleotides comprising a C5-modified pyrimidine
  申请人：Manoharan Muthiah

  公开号：US20050288244A1

  公开（公告）日：2005-12-29

  One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one ligand. In certain embodiments, a ligand is bound to only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, both of the oligonucleotide strands of the double-stranded oligonucleotide independently comprise a bound ligand. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. In certain embodiments, a phosphate linkage in one or both of the strands of the oligonucleotide has been replaced with a phosphorothioate or phosphorodithioate linkage. In a preferred embodiment, the ligand is cholesterol or 5β-cholanic acid. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one ligand. In certain embodiments, the oligonucleotide comprises at least one modified sugar moiety. In certain embodiments, a phosphate linkage of the oligonucleotide has been replaced with a phosphorothioate or phosphorodithioate linkage. In a preferred embodiment, the ligand is cholesterol or 5β-cholanic acid. The ligand improves the pharmacokinetic properties of the oligonucleotide.

  本发明的一个方面涉及包含至少一个配体的双链寡核苷酸。在某些实施例中，配体仅结合到构成双链寡核苷酸的两个核苷酸链中的一个。在某些实施例中，双链寡核苷酸的两个核苷酸链都独立地包含一个结合的配体。在某些实施例中，核苷酸链包含至少一个修饰的糖基。在某些实施例中，核苷酸链的一个或两个链中的磷酸酯键已被磷硫酸酯或磷二硫酸酯键替代。在一个首选实施例中，配体是胆固醇或5β-胆烷酸。本发明的另一个方面涉及包含至少一个配体的单链寡核苷酸。在某些实施例中，核苷酸包含至少一个修饰的糖基。在某些实施例中，核苷酸的磷酸酯键已被磷硫酸酯或磷二硫酸酯键替代。在一个首选实施例中，配体是胆固醇或5β-胆烷酸。配体改善了寡核苷酸的药代动力学性能。
• Novel rhenium(i) catalysts for the isomerization of propargylic alcohols into α,β-unsaturated carbonyl compounds: an unprecedented recyclable catalytic system in ionic liquids
  作者：Joaquín García-Álvarez、Josefina Díez、José Gimeno、Christine M. Seifried

  DOI：10.1039/c1cc10768b

  日期：——

  Carbonyl rhenium(I) complexes are efficient catalysts for the regioselective isomerization of terminal propargylic alcohols into α,β-unsaturated aldehydes or ketones which can be used as an unprecedented recyclable catalytic system (up to 10 consecutive runs) in the ionic liquid [BMIM][PF6].

  羰基铼(I)配合物作为催化剂，能够高效地选择性异构化末端炔丙醇为α,β-不饱和醛或酮，这种催化体系前所未有地可在离子液体[BMIM][PF6]中循环使用（多达10次连续运行）。
• A mild two-step propargylation of aromatic bioactive small molecules
  作者：Naoki Kanoh、Toshitaka Okamura、Takahiro Suzuki、Yoshiharu Iwabuchi

  DOI：10.1039/c7ob01587a

  日期：——

  introducing a propargyl group in aromatic bioactive small molecules has been developed. This method features propargylation of aromatic groups using a cationic propargyl hexacarbonyl complex in the presence of cesium carbonate, and decomplexation of the resultant cobalt complexes using 2,2,6,6-tetramethylpiperidine 1-oxonium tetrafluoroborate. These reactions proceed under mild conditions, and thus are

  已经开发了在芳族生物活性小分子中引入炔丙基的两步法。该方法的特征在于在碳酸铯的存在下使用阳离子炔丙基六羰基配合物对芳族基团进行炔丙基化，并使用2,2,6,6-四甲基哌啶1-四氟硼酸氧鎓对所得钴配合物进行解配合。这些反应在温和的条件下进行，因此适用于酸和/或氧化剂敏感的芳族生物活性小分子。

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