氯米芬 | 911-45-5

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 促性激素类药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 中文名称: 氯米芬
• 中文别名: N,N-二乙基-2-[4-(1,2-二苯基-2-氯乙烯基)苯氧基]乙胺
• 英文名称: clomiphene
• 英文别名: 2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-N,N-diethylethanamine；2-{4-[2-chloro-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanamine；zuclomiphene citrate；clomiphene citrate；zuclomiphene；2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine
• CAS: 911-45-5
• 化学式: C₂₆H₂₈ClNO
• 分子量: 405.967
• InChiKey: GKIRPKYJQBWNGO-UHFFFAOYSA-N

物化性质

• 熔点：
  117.25°C
• 沸点：
  509.0±50.0 °C(Predicted)
• 密度：
  1.0166 (rough estimate)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 稳定性/保质期：
  UNSTABLE TO AIR AND LIGHT

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

在大鼠肝微粒体中孵化非甾体抗雌激素氯米芬导致了4-羟基代谢物、N-去乙基代谢物和N-氧化物代谢物的形成，这与之前在兔微粒体中类似实验只检测到前两种代谢物的结果在定性上有所不同。口服氯米芬后，未能在尿液中检测到药物或其代谢物。在粪便提取中，唯一可检测到的消除产物是4-羟基氯米芬。

INCUBATION OF THE NONSTEROIDAL ANTIESTROGEN CLOMIPHENE WITH RAT LIVER MICROSOMES RESULTED IN THE FORMATION OF THE 4-HYDROXY-, N-DESETHYL-, & N-OXIDE METABOLITES, IN QUALITATIVE CONTRAST TO RESULTS PREVIOUSLY OBTAINED ANALOGOUSLY WITH RABBIT MICROSOMES IN WHICH ONLY THE FIRST 2 METABOLITES WERE DETECTED. ORAL ADMIN OF CLOMIPHENE RESULTED IN NO DETECTABLE URINARY ELIMINATION OF THE DRUG OR ITS METABOLITES. 4-HYDROXYCLOMIPHENE WAS THE SOLE DETECTABLE ELIMINATION PRODUCT IN FECAL EXTRACTIONS.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在克罗米芬治疗期间，关于血清转氨酶水平的信息很少，克罗米芬通常以低剂量短期给药。有少数报道称服用克罗米芬的患者出现了轻度的血清酶水平升高，但没有确凿的特异质性、临床明显的肝损伤案例。 用于治疗女性不孕的药物通常通过刺激卵巢卵泡起作用，这可能导致卵巢过度刺激综合征（OHSS），偶尔会伴有血清酶水平升高甚至黄疸。这种综合征通常在卵巢通过促性腺激素或克罗米芬刺激后的4到14天内出现，其特点是腹部疼痛和膨胀，伴有腹水和卵巢增大以及卵巢囊肿。可能会有明显的液体转移，出现血液浓缩和快速发作的严重腹水和胸腔积液。大约25%到40%的OHSS患者肝功能测试升高，通常是ALT和AST值轻到中度升高，但血清胆红素和碱性磷酸酶水平升高不明显。肝功能测试异常随着OHSS的解决而恢复，通常在发病后2到3周内。在严重的情况下，OHSS可能是致命的，但死亡通常是由于脱水、休克和败血症而不是肝衰竭。在典型的肝酶异常病例中，肝脏组织学显示非特异性变化，如窦状扩张、轻度脂肪积聚和以巨噬细胞和淋巴细胞为主的局部炎症浸润。与人类绒毛膜促性腺激素（hCG）诱导排卵相比，克罗米芬引起的OHSS较少见。 可能性评分：C（可能是卵巢过度刺激综合征中临床明显肝损伤的原因）。

There is little information on serum aminotransferase levels during clomiphene therapy which is typically given in low doses for a short time only. There have been a few reports of mild serum enzyme elevations in patients taking clomiphene, but no convincing instances of idiosyncratic, clinically apparent liver injury with its use. Drugs used to treat infertility in women typically act by stimulation of the ovarian follicles which can lead to the ovarian hyperstimulation syndrome (OHSS), which can occasionally be accompanied by serum enzyme elevations and even jaundice. This syndrome typically arises within 4 to 14 days of ovarian stimulation with gonadotropins or clomiphene and is characterized by the onset of abdominal pain and distension with ascites and enlarged ovaries and ovarian cysts. There can be marked fluid shifts with hemoconcentration and rapid onset of severe ascites and pleural effusions. Liver tests are elevated in 25% to 40% of patients with OHSS, typically with mild-to-moderate increases in ALT and AST values, but minimal or no elevations in serum bilirubin and alkaline phosphatase levels. The liver test abnormalities resolve with resolution of the OHSS, usually within 2 to 3 weeks of onset. In severe instances, OHSS can be fatal, but death is usually due to dehydration, shock and septicemia rather than hepatic failure. In typical cases with abnormal liver enzymes, liver histology reveals nonspecific changes of sinusoidal dilatation, mild fat accumulation and focal inflammatory infiltrates with macrophages and lymphocytes. OHSS is less common with clomiphene than with human chorionic gonadotropin (hCG) induction of ovulation. Likelihood score: C (probable cause of clinically apparent liver injury as a part of the ovarian hyperstimulation syndrome).

来源:LiverTox

毒理性

• 致癌性证据

致癌性分类：1）人类证据：不足；2）动物证据：不足。对人类致癌风险的总体评估为第3组：该物质对人类致癌性不可分类。

Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) evidence in animals: inadequate. Overall summary evaluation of carcinogenic risk to humans is Group 3: The agent is not classifiable as to its carcinogenicity to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：在一项研究中，克米芬在一位妇女的乳汁中发现了低量存在。几项研究发现，克米芬能够抑制那些不希望母乳喂养的女性的泌乳。它似乎通过降低血清催乳素，尤其是催乳素在刺激后的激增来发挥作用。克米芬很可能会干扰哺乳母亲的泌乳。 ◉ 对母乳喂养婴儿的影响：一位每天以2.04毫克/公斤的剂量服用克米芬的妇女部分母乳喂养了她的婴儿。她没有观察到她的婴儿出现任何不良反应。 ◉ 对泌乳和母乳的影响：一项双盲研究比较了克米芬50毫克/天，持续10天（n=110），100毫克/天，持续5天（n=26）和安慰剂（n=41）在抑制非哺乳产后母亲泌乳和缓解疼痛及乳房充血方面的效果。根据妇女的报告，两种剂量的克米芬都比安慰剂有效，但100毫克/天的剂量比50毫克/天的剂量略胜一筹。 一项研究比较了克米芬100毫克/天，持续5天（n=60）与安慰剂（n=30）在抑制泌乳和乳房充血症状方面的效果。在分娩后12小时内开始服用克米芬比在分娩后12小时或更长时间开始服用，在所有测量指标上效果都更佳，这是由医生观察员判断的；两种治疗方法都比单纯使用机械措施，如乳房束缚更有效。 一项随机试验比较了克米芬50毫克，每天两次，持续14天（n=15），溴隐亭2.5毫克，每天两次，持续14天（n=15），己烯雌酚5毫克，每天三次，持续14天（n=15），丙酸睾酮75毫克，肌内注射一次（n=15）和安慰剂，每天三次口服（n=15）在降低血清催乳素和产后泌乳方面的效果。治疗三天后，克米芬将血清催乳素降至基线的65%，而接受溴隐亭治疗的患者血清催乳素降至基线的35%。克米芬在抑制泌乳和乳房充血症状方面也比溴隐亭效果差。 一项研究比较了克米芬100毫克/天，持续7天（n=10）与安慰剂（n=12），在产后第一天开始服用。克米芬在抑制泌乳或降低血清催乳素浓度方面并不比安慰剂更有效。 在产后第一周不希望母乳喂养的妇女中，一组接受了克米芬50毫克，每天两次（n=10），另一组接受了安慰剂（n=10）。接受克米芬的妇女在使用乳房泵时，血清催乳素没有从基线值上升；而接受安慰剂的妇女在刺激后出现了正常的血清催乳素上升。 研究了80名产后妇女。40人在产后第一天开始服用克米芬50毫克，每天两次，持续5天；20人在产后第四天开始服用克米芬50毫克，每天两次，持续5天；另外20人服用安慰剂。所有服用克米芬的妇女都经历了泌乳抑制，以及乳房充血、不适和血清催乳素的减少。对于产后第一天的妇女，血清催乳素浓度在第3天统计学上低于基线，对于产后第四天开始的妇女，在第5天低于基线。安慰剂既没有抑制泌乳，也没有抑制血清催乳素。

◉ Summary of Use during Lactation:Clomiphene appeared in low amounts in milk in one woman. Several studies found that clomiphene suppresses lactation in women who did not want to breastfeed. It appears to act by lowering serum prolactin, especially the post-stimulation surge in serum prolactin. It is likely that clomiphene would interfere with lactation in a nursing mother. ◉ Effects in Breastfed Infants:A woman who was taking clomiphene in a dose of 2.04 mg/kg daily partially breastfed her infant. She did not observe any adverse effects in her infant. ◉ Effects on Lactation and Breastmilk:A double-blind study compared clomiphene in dosages of 50 mg daily for 10 days (n = 110), 100 mg daily for 5 days (n = 26) and placebo (n = 41) in their ability to suppress lactation and relieve pain and engorgement in nonnursing postpartum mothers. Both dosages of clomiphene were superior to placebo as reported by the women, but the 100 mg daily dosage was somewhat superior to the 50 mg daily dosage. A study compared clomiphene 100 mg daily for 5 days (n = 60) to placebo (n = 30) in suppressing lactation and symptoms of engorgement. Starting clomiphene within 12 hours of delivery was more effective in all measures than starting it 12 hours or more after delivery as judged by a physician observer; both treatments were more effective than mechanical measures alone such as breast binding. A randomized trial compared clomiphene 50 mg twice daily for 14 days (n = 15) to bromocriptine 2.5 mg twice daily for 14 days (n = 15), diethylstilbestrol 5 mg 3 times daily for 14 days (n = 15), testosterone propionate 75 mg intramuscularly once (n = 15), and placebo 3 times daily by mouth (n = 15) in their ability to reduce serum prolactin and lactation postpartum. After three days of treatment, serum prolactin was reduced to 65% of baseline by clomiphene compared to a drop to 35% in patients who received bromocriptine. Clomiphene was also less effective than bromocriptine in suppressing lactation and symptoms of engorgement. A study compared clomiphene 100 mg daily for 7 days (n = 10) to placebo (n = 12) started on the first day postpartum. Clomiphene was no more effective than placebo in suppressing lactation or reducing serum prolactin concentrations. Women in the first week postpartum who did not wish to breastfeed received either clomiphene 50 mg twice daily (n = 10) or placebo (n = 10). Women who received clomiphene did not experience a rise in serum prolactin from baseline values during use of a breast pump; those given placebo had the normal post-stimulation rise in serum prolactin. Eighty postpartum women were studied. Forty received clomiphene 50 mg twice daily for 5 days beginning the first day postpartum; 20 received clomiphene 50 mg twice daily for 5 days beginning the fourth day postpartum; and, 20 received placebo. All women receiving clomiphene experienced inhibition of lactation, and reductions in breast engorgement, discomfort and serum prolactin. Prolactin serum concentrations became statistically lower than baseline on day 3 for the women who were 1 day postpartum and on day 5 for those who were 4 days postpartum at the outset. Placebo did not suppress lactation nor suppress serum prolactin.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 人类毒性摘录

报告了一名28岁女性在接受氯米芬疗法两个周期（每天100毫克，连续五天的两个疗程）后发生卵巢颗粒细胞瘤的病例。两名28岁和29岁的女性在接受这种疗法后被诊断出双侧乳腺癌。氯米芬诱导排卵后观察到葡萄胎...并且也报告了子宫肌瘤的快速增大。/氯米芬/

...REPORTED A CASE OF GRANULOSA-CELL TUMOR OF THE OVARY IN A 28-YR OLD FEMALE WHO HAD RECEIVED CLOMIPHENE CITRATE THERAPY FOR TWO CYCLES (2 FIVE-DAY COURSES OF 100 MG PER DAY). TWO CASES OF BILATERAL BREAST CANCER WERE REPORTED IN WOMEN AGED 28 AND 29 WHO HAD RECEIVED SUCH THERAPY. MOLAR PREGNANCIES HAVE BEEN OBSERVED FOLLOWING INDUCTION OF OVULATION BY CLOMIPHENE CITRATE...AND RAPID ENLARGEMENT OF UTERINE FIBROIDS HAS ALSO BEEN REPORTED. /CLOMIPHENE CITRATE/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

一名28岁的男性，每天服用1毫克“环氯米芬柠檬酸盐”（安氯米芬，反式异构体）共10周，发展成了含有精原细胞瘤和成熟成人畸胎瘤成分的生殖细胞肿瘤。/氯米芬柠檬酸盐的反式异构体/

A 28-YEAR OLD MALE WHO HAD RECEIVED 1 MG 'CISCLOMIPHENE CITRATE' (ENCLOMIPHENE, THE TRANS ISOMER) DAILY FOR 10 WK DEVELOPED A GERM-CELL TUMOR WITH ELEMENTS OF SEMINOMA AND MATURE ADULT TERATOMA. /TRANS- ISOMER OF CLOMIPHENE CITRATE/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

基于早期使用14C标记的克罗米芬进行研究，该药物在人体内口服吸收良好。

Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.

来源:DrugBank

吸收、分配和排泄

• 消除途径

基于早期使用14C标记的氯米芬柠檬酸盐的研究，该药物在人体内口服吸收良好，主要在粪便中排泄。平均尿排泄率大约为8%，粪便排泄率约为42%。

Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.

来源:DrugBank

吸收、分配和排泄

SC剂量的(14)C氯米芬酸......在雌性豚鼠新生儿的组织中分布......雌激素反应性组织对(14)C表现出高亲和力。(14)C的水平在子宫中保持恒定......卵巢和血浆中的水平下降......在肾上腺中增加。/氯米芬酸/

SC DOSE OF (14)C CLOMIPHENE CITRATE...WAS DISTRIBUTED IN TISSUES OF FEMALE GUINEA PIG NEONATES... ESTROGENIC-RESPONSIVE TISSUES SHOWED HIGH AFFINITY FOR (14)C. LEVELS OF (14)C...CONSTANT IN UTERUS...THOSE IN OVARIES & PLASMA DECLINED...IN ADRENALS INCR. /CLOMIPHENE CITRATE/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大约一半的摄入剂量在五天内被排出；在服用后六周内的粪便中仍可检测到微量./克罗米芬citrate/

ABOUT ONE-HALF OF THE INGESTED DOSE IS EXCRETED IN FIVE DAYS; TRACES APPEAR IN THE FECES UP TO SIX WEEKS AFTER ADMIN. /CLOMIPHENE CITRATE/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

克罗米芬口服后吸收良好。药物及其代谢物主要随粪便排出，较少部分通过尿液排出。较长的血浆半衰期（大约5到7天）主要是由于血浆蛋白结合、肠肝循环以及在脂肪组织中的积累。也可能产生具有长半衰期的活性代谢物。

Clomiphene is well absorbed following oral administration. The drug and its metabolites are eliminated primarily in the feces and to a lesser extent in the urine. The rather long plasma half-life (approximately 5 to 7 days) is due largely to plasma protein binding, enterophepatic circulation, and accumulation in fatty tissues. Active metabolites with long half-lives also may be produced.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

氯米芬是一种非甾体化合物，在实验动物中具有微弱的雌激素活性，但在人体内则表现出抗雌激素作用，能够刺激排卵。它具有较强的抗雌激素作用和较弱的雌激素活性。低剂量时，它可以促进垂体前叶分泌促性腺激素，从而诱发排卵；高剂量时，则会明显抑制垂体促性腺激素的释放。对于男性来说，氯米芬还能促进精子生成，对少精症有一定疗效。

反应信息

• 作为反应物：
  描述：

  氯米芬 在 氨 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 3.0h， 生成 反式-氯米芬柠檬酸盐
  参考文献：
  名称：

  CLOMIPHENE SYNTHESIS USING A SINGLE SOLVENT

  摘要：

  本发明提供了一种使用单一溶剂合成氯米芬（cis-氯米芬和trans-氯米芬的混合物）的一锅法。在一个优选的实施例中，单一溶剂是二氯甲烷（DCM，也称为甲基氯）。本发明提供了一种改进的合成氯米芬和纯化氯米芬异构体的方法。

  公开号：

  US20170073302A1
• 作为产物：
  描述：

  苯甲基膦酸二甲酯 在 叔丁基锂 作用下， 反应 0.5h， 生成 氯米芬
  参考文献：
  名称：

  Synthesis with .alpha.-heterosubstituted phosphonates. Part 13. Synthesis of trisubstituted vinyl chlorides

  摘要：

  DOI：

  10.1021/jo00164a036

文献信息

• 一种恩氯米芬的制备方法
  申请人：上海度德医药科技有限公司

  公开号：CN107033013A

  公开（公告）日：2017-08-11

  本发明涉及一种恩氯米芬的制备方法，包括：(1)克罗米芬或其盐、消旋联萘酚磷酸酯于含有醚类溶剂的醇类溶剂中反应，得到固体形式的恩氯米芬与联萘酚磷酸酯复合物；(2)将固体形式的恩氯米芬与联萘酚磷酸酯复合物经游离反应制得恩氯米芬。通过使用含有醚类溶剂的醇类溶剂作为拆分溶剂，恩氯米芬与拆分剂可形成固体复合物直接从拆分溶剂中析出，改善了反应体系的流动性，提供了一种拆分收率高、拆分产品纯度高，成本低、环境污染小，具有较好的工业应用前景的恩氯米芬的制备方法。
• Use of clomiphene to increase bone mass in premenopausal women
  申请人：Yale University

  公开号：US04970237A1

  公开（公告）日：1990-11-13

  This invention relates to the use of clomiphene in preventing osteoporosis in humans and treating human patients experiencing osteoporosis.

  本发明涉及在人体中使用克罗米芬预防骨质疏松症和治疗患有骨质疏松症的患者。
• Al-Hassan, Mohammed I., Synthetic Communications, 1987, vol. 17, # 15, p. 1787 - 1796
  作者：Al-Hassan, Mohammed I.

  DOI：——

  日期：——
• CLOMIPHENE SYNTHESIS USING A SINGLE SOLVENT
  申请人：REPROS THERAPEUTICS INC.

  公开号：US20170073302A1

  公开（公告）日：2017-03-16

  The present invention provides a one-pot method for synthesizing clomiphene (a mixture of the isomers cis-clomiphene and trans-clomiphene) utilizing a single solvent. In a preferred embodiment, the single solvent is dichloromethane (DCM, also known as methylene chloride). The present invention provides an improved method for synthesizing clomiphene and purifying clomiphene isomers.

  本发明提供了一种使用单一溶剂合成氯米芬（cis-氯米芬和trans-氯米芬的混合物）的一锅法。在一个优选的实施例中，单一溶剂是二氯甲烷（DCM，也称为甲基氯）。本发明提供了一种改进的合成氯米芬和纯化氯米芬异构体的方法。
• Synthesis with .alpha.-heterosubstituted phosphonates. Part 13. Synthesis of trisubstituted vinyl chlorides
  作者：Michael D. Crenshaw、Hans Zimmer

  DOI：10.1021/jo00164a036

  日期：1983.8