16320-04-0

• 常用中文名：孕三烯酮
• 常用英文名：Gestrinone
• CAS号：16320-04-0
• 分子式：C₂₁H₂₄O₂
• 分子量：308.414
• 相关类别： 原料药 激素及调节内分泌功能类药 避孕药
• 发布时间：2018-05-27 08:00:00
• 更新时间：2024-01-14 15:49:59
• Gestrinone (R2323) 是用于治疗子宫内膜异位症的合成类固醇激素。抑制平滑肌瘤的IC50值为43.67 μM。

名称

• 中文名: 孕三烯酮
• 英文名: Gestrinone
• 中文别名: 13-乙基-17Α-乙炔基-17-羟基-4,9,11-雌三烯-3-酮; D-18甲基-17α-乙炔基-17β-羟基-4,9,11-雌甾三烯-3-酮
• 英文别名: D-GESTRINONE; Dimetriose; TridoMose; 13b-Ethyl-17a-ethynyl-D4,9,11-gonatriene-17b-ol-3-one; (17a)-13-Ethyl-17-hydroxy-18,19-dinorpregna-4,9,11-trien-20-yn-3-one; 13b-Ethyl-17a-ethynyl-17b-hydroxy-4,9,11-gonatrien-3-one; Dimetrose; MFCD00865561; gestrigone; (17α)-13-Ethyl-17-hydroxy-18,19-dinorpregna-4,9,11-trien-20-yn-3-one; 18,19-Dinorpregna-4,9,11-trien-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-; Gestrinone; (8S,13S,14S,17R)-13-Ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one; 13-ETHYL-17α-ETHYNYL-17β-HYDROXY-4,9,11-GONATRIENE-3-ONE; NeMestran

物化性质

• 密度: 1.2±0.1 g/cm3
• 沸点: 507.6±50.0 °C at 760 mmHg
• 熔点: 154ºC
• 分子式: C₂₁H₂₄O₂
• 分子量: 308.414
• 闪点: 214.9±22.7 °C
• 精确质量: 308.177643
• PSA: 37.30000
• LogP: 3.27
• 外观性状: 淡黄色固体
• 蒸汽压: 0.0±3.0 mmHg at 25°C
• 折射率: 1.607
• 储存条件: -20°C Freezer

生物活性

• 描述: Gestrinone (R2323) 是用于治疗子宫内膜异位症的合成类固醇激素。抑制平滑肌瘤的IC50值为43.67 μM。
• 相关类别:
  信号通路 >> 其他 >> 雌激素受体/ERR
  研究领域 >> 炎症/免疫
• 靶点:

  IC50: 43.67 μM (leiomyoma cells)[2]

• 体外研究: 尽管存在内源性类固醇,但雌甾酮与雌激素,黄体酮和雄激素的子宫内膜受体结合,占据类固醇靶细胞中类固醇的所有特异性结合位点[1]。雌激素对60小时的平滑肌瘤细胞生长的抑制作用强于20小时和40小时。平滑肌瘤细胞看起来密度较小,细胞质萎缩,细胞间连接减少,超过10μM孕三烯酮治疗时观察到核聚集。在浓度为0.1-3.0μM时,雌甾酮治疗以浓度依赖性方式降低雌激素α的相对mRNA水平[2]。
• 体内研究: 通过用氟他胺和达那唑或孕三烯酮的组合治疗,增强了雌激素敏感终点,阴道角化和子宫孕酮受体浓度。这些数据表明,达那唑和孕三烯酮具有雌激素活性,这些活性被这些药物的雄激素成分所掩盖[3]。用一周治疗后,用孕三烯酮处理的平均激素结合球蛋白从56.4nM下降到28.1nM,在4周后分别下降到7.1nM [4]。
• 细胞实验: 将雌甾酮溶解在DMSO中并在细胞培养基中稀释。培养基中DMSO的最终浓度为0.5％。将细胞在96孔板中培养，并用DMSO或分级浓度的孕三烯酮（0.1,0.5,1.0,5.0,10,50或100μM）处理20,40和60小时。读取450nm处的吸光度（OD）以确定每个孔中的细胞活力[2]。
• 参考文献:

  [1]. Tamaya T, et al. Gestrinone (R2323) binding to steroid receptors in human uterine endometrial cytosol. Acta Obstet Gynecol Scand. 1986;65(5):439-41.

  [2]. Zhu Y, et al. Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK. Biomed Pharmacother. 2012 Dec;66(8):569-77.

  [3]. Snyder BW, et al. Studies on the mechanism of action of danazol and gestrinone (R2323) in the rat: evidence for a masked estrogen component. Fertil Steril. 1989 Apr;51(4):705-10.

  [4]. Dowsett M, et al. A comparison of the effects of danazol and gestrinone on testosterone binding to sex hormone binding globulin in vitro and in vivo. Clin Endocrinol (Oxf). 1986 May;24(5):555-63.

毒性和生态

CHEMICAL IDENTIFICATION RTECS NUMBER : JF7964000 CHEMICAL NAME : 18,19-Dinor-17-alpha-pregna-4,9,11-trien-20-yn-3-one, 13-ethyl-17-hydroxy- CAS REGISTRY NUMBER : 16320-04-0 LAST UPDATED : 199612 DATA ITEMS CITED : 13 MOLECULAR FORMULA : C21-H24-O2 MOLECULAR WEIGHT : 308.45 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 1 gm/kg TOXIC EFFECTS : Behavioral - altered sleep time (including change in righting reflex) Skin and Appendages - dermatitis, other (after systemic exposure) Nutritional and Gross Metabolic - other changes REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,701,1988 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 1 gm/kg TOXIC EFFECTS : Sense Organs and Special Senses (Eye) - visual field changes Behavioral - altered sleep time (including change in righting reflex) Nutritional and Gross Metabolic - other changes REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,701,1988 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 1 gm/kg TOXIC EFFECTS : Behavioral - altered sleep time (including change in righting reflex) Behavioral - convulsions or effect on seizure threshold Gastrointestinal - other changes REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,701,1988 ** REPRODUCTIVE DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 400 ug/kg SEX/DURATION : female 8 day(s) pre-mating TOXIC EFFECTS : Reproductive - Maternal Effects - menstrual cycle changes or disorders Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated) REFERENCE : CCPTAY Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- Volume(issue)/page/year: 14,275,1976 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 1200 ug/kg SEX/DURATION : female 12 week(s) pre-mating TOXIC EFFECTS : Reproductive - Maternal Effects - menstrual cycle changes or disorders REFERENCE : FESTAS Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- Volume(issue)/page/year: 31,278,1979 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Implant DOSE : 1800 ug/kg SEX/DURATION : female 48 week(s) pre-mating TOXIC EFFECTS : Reproductive - Maternal Effects - menstrual cycle changes or disorders Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated) REFERENCE : CCPTAY Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- Volume(issue)/page/year: 11,625,1975 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intravaginal DOSE : 185 ug/kg SEX/DURATION : female 28 day(s) pre-mating TOXIC EFFECTS : Reproductive - Fertility - other measures of fertility REFERENCE : CCPTAY Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- Volume(issue)/page/year: 14,671,1976 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intravaginal DOSE : 2600 ug/kg SEX/DURATION : female 26 week(s) pre-mating TOXIC EFFECTS : Reproductive - Maternal Effects - menstrual cycle changes or disorders REFERENCE : FESTAS Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- Volume(issue)/page/year: 49,418,1988 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 50 mg/kg SEX/DURATION : female 6-15 day(s) after conception TOXIC EFFECTS : Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Effects on Embryo or Fetus - fetal death REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,713,1988 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 500 ug/kg SEX/DURATION : female 6-15 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,713,1988 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 20 mg/kg SEX/DURATION : female 15-18 day(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - parturition REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,737,1988 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 1200 mg/kg SEX/DURATION : female 15-18 day(s) after conception lactating female 20 day(s) post-birth TOXIC EFFECTS : Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 16,737,1988 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Implant DOSE : 2486 ug/kg SEX/DURATION : female 1 year(s) pre-mating TOXIC EFFECTS : Reproductive - Fertility - other measures of fertility REFERENCE : CCPTAY Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- Volume(issue)/page/year: 15,335,1977

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制备

【方法一】
方法1：化合物(Ⅰ)和化合物(Ⅱ)经Robinson环合，得双环化物(Ⅲ)。还原后再苯甲酰化，得到(Ⅳ)。部分水解后，用醋酐处理，得烯醇内酯(V)。和化合物(Ⅵ)的格氏试剂反应后，再水解得到三环化物(Ⅶ)。在四氢吡咯作用下，环合得(Ⅷ)。水解得(Ⅸ)，用二氯二氢醌(DDQ)脱氢，引入最后一个双键得(X)。水解脱去苯甲酰基成醇，再氧化得3，17-二酮(Ⅺ)。在酸存在下和乙二醇反应得3-缩酮(Ⅻ)。和乙炔溴化镁反应，引入乙炔基，再脱去保护基得到孕三烯酮。
方法2：把化合物(ⅩⅣ)加入2.5ml乙酸、2.5ml水和0.25ml丙酮酸的溶液中，在氮气气氛中加热回流lh。冷却，倾入冰水中。加入过量的碳酸氢钠，用乙醚提取。提取液水洗至中性，真空蒸馏至于，得65mg粗品。该粗品溶入二氯甲烷，用硅酸镁层析，洗脱液为二氯甲烷，得51mg产品。先用乙酸乙酯，再用苯一环己烷(1：1)混合液重结晶，得36mg的孕三烯酮，熔点154℃。