[(3E)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate | 35189-28-7

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 避孕药
• 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
• 英文名称: [(3E)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate
• CAS: 35189-28-7
• 化学式: C₂₃H₃₁NO₃
• 分子量: 369.5
• InChiKey: KIQQMECNKUGGKA-JJIBRWJFSA-N

物化性质

• 熔点：
  216°C
• 比旋光度：
  D25 +110°
• 沸点：
  497.9±45.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶，5mg/mL（澄清溶液）
• 颜色/状态：
  Crystals from methylene chloride
• 蒸汽压力：
  2.62X10-11 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: +110 deg at 25 °C/D

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  58.9
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

Norgestimate 通过首次通过（肠道和/或肝脏）机制迅速且完全代谢为norelgestromin (NGMN) 和 norgestrel (NG)，它们是norgestimate的主要活性代谢物。

Norgestimate is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Norgestimate 在胃肠道和/或肝脏中通过首过效应被广泛代谢。Norgestimate 的主要活性代谢物是 norelgestromin。随后，norelgestromin 在肝脏中进一步代谢，代谢物包括同样具有活性的 norgestrel，以及各种羟基化和结合的代谢物。

Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate's primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active, and various hydroxylated and conjugated metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

除了17-去乙酰诺孕酯外，已经识别出诺孕酯的多种代谢物在给予放射性标记的诺孕酯后出现在人类尿液中。这些包括18,19-二去甲-17-孕-4-烯-20-炔-3-酮,17-羟基-13-乙基,(17alpha)-(-); 18,19-二去甲-5beta-17-孕烷-20-炔,3alpha,17beta-二羟基-13-乙基,(17alpha)，以及这些代谢物的各种羟基化代谢物和共轭物。

In addition to 17-deacetyl norgestimate, a number of metabolites of norgestimate have been identified in human urine following administration of radiolabeled norgestimate. These include 18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17alpha)-(-); 18,19-Dinor-5beta-17-pregnan-20-yn,3alpha,17beta-dihydroxy-13-ethyl,(17alpha), various hydroxylated metabolites and conjugates of these metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

关于左炔诺孕酮、炔诺酮以及结构相关的避孕类固醇的代谢信息有限。左炔诺孕酮和炔诺酮都会在A环的α,β-不饱和酮上进行广泛的还原。左炔诺孕酮还会在碳2和碳16位置上进行羟基化。这两种化合物的代谢物主要以硫酸盐形式在体内循环。在尿液中，左炔诺孕酮的代谢物主要以葡萄糖醛酸苷形式存在，而炔诺酮的代谢物则大约等量以硫酸盐和葡萄糖醛酸苷形式存在。在与炔诺酮结构相关的孕激素中，醋酸炔诺酮、乙炔雌二醇二醋酸酯、炔诺酮庚酸酯，以及可能的林司特诺尔，都会迅速发生水解，并转化为母体化合物及其代谢物。没有确凿的证据表明去炔雌醇会转化为炔诺酮。在与左炔诺孕酮结构相关的孕激素中，似乎去氧孕烯和孕二烯都不会转化为母体化合物。然而，有证据表明，诺孕酯至少部分可以转化为左炔诺孕酮。...

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

含有圣约翰草（金丝桃属贯叶连翘）的草药产品可能会诱导肝酶（细胞色素P450）和P-糖蛋白转运体，并可能降低避孕类固醇的有效性。这也可能导致突破性出血。

Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

联合激素避孕药在共同给药时已被证明可以显著降低拉莫三嗪的血浆浓度，这是由于诱导了拉莫三嗪葡萄糖醛酸化。这可能会减少对癫痫的控制；因此，可能需要调整拉莫三嗪的剂量。

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β受体激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流速/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

诺孕酯（NGM）和炔雌醇（EE）在口服给药后迅速吸收。

Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

norelgestromin（NGMN）和炔雌醇（EE）的峰值血清浓度通常在服用MonoNessa后2小时达到。与单次给药相比，多次给药250微克诺孕酯（NGM）/ 35微克剂量的累积量大约为NGMN和EE的2倍。NGMN的药代动力学在NGM剂量为180微克至250微克时呈剂量比例。... NGMN和NG的稳态浓度在第21天达到。由于与性激素结合球蛋白（SHBG）的高亲和力结合，观察到诺孕烯的非线性累积（大约8倍），这限制了其生物活性。

Peak serum concentrations of norelgestromin (NGMN) and ethinyl estradiol (EE) are generally reached by 2 hours after administration of MonoNessa. Accumulation following multiple dosing of the 250 ug Norgestimate (NGM)/ 35 ug dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose proportional following NGM doses of 180 ug to 250 ug. ... Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of norgestrel is observed as a result of high affinity binding to SHBG (sex hormone-binding globulin), which limits its biological activity.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

norelgestromin 和 norgestrel 高度结合（>97%）血清蛋白。Norelgestromin 与白蛋白结合，不与 SHBG 结合，而 norgestrel 主要与 SHBG 结合。

Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

norelgestromin 和 ethinyl estradiol 的代谢物通过肾脏和粪便途径排出。在给予 14C-norgestimate 后，分别有 47%（45-49%）和 37%（16-49%）的给药放射性在尿液和粪便中排出。尿液中未检测到未改变的 norgestimate。

The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged norgestimate was not detected in the urine.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S26,S36/37
• 危险类别码：
  R63,R22,R36/38,R62
• WGK Germany：
  3
• 海关编码：
  2937230000
• 危险品运输编号：
  NONH for all modes of transport

制备方法与用途

生物活性

Norgestimate 是一种合成的孕激素类似物，是一种具有口服活性、高度选择性的孕激素（progestin），且雄激素作用最小。它常用于口服避孕药。

体外研究

Norgestimate 能转化为至少两种活性代谢物：levonorgestrel 3-oxime（去乙酰基 norgestimate；norelgestromin）和 levonorgestrel。

化学性质

白色或类白色的结晶粉末

文献信息

• Method for site-specific polyvalent display on polymers
  申请人：Kirshenbaum Kent

  公开号：US20120122779A1

  公开（公告）日：2012-05-17

  The present invention relates to novel complex peptidomimetic products comprising multiple homogeneous or heterogeneous pendant groups that are site-specifically positioned along a linear oligomer or polymer scaffold and methods of making thereof. More specifically, the invention relates to N-substituted glycine peptoid oligomers or peptoids and their use as substrates for azide-alkyne [3+2]-cycloaddition conjugation reactions and subsequent additional rounds of oligomerization and cycloaddition. The methods of the invention may also be used to generate peptoid-peptide hybrid or peptide products comprising multiple homogeneous or heterogeneous pendant groups, which are positioned precisely along the linear oligomer or polymer scaffold.
• US8524663B2
  申请人：——

  公开号：US8524663B2

  公开（公告）日：2013-09-03
• US9107959B2
  申请人：——

  公开号：US9107959B2

  公开（公告）日：2015-08-18