恩氯米芬 | 15690-57-0

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 雄激素及同化激素类药
• 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: 恩氯米芬
• 中文别名: 顺氯米芬(氯米芬)
• 英文名称: clomiphene
• 英文别名: Clomiphen；clomifene；Enclomiphene；2-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine
• CAS: 15690-57-0
• 化学式: C₂₆H₂₈ClNO
• 分子量: 405.967
• InChiKey: GKIRPKYJQBWNGO-OCEACIFDSA-N

物化性质

• 熔点：
  149.0-150.5°
• 沸点：
  509.0±50.0 °C(Predicted)
• 密度：
  1.104±0.06 g/cm3(Predicted)
• 溶解度：
  1.5 [ug/mL]
• 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

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仅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)

代谢

肝脏的

Hepatic

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

氯米芬具有既有的雌激素和抗雌激素性质，但其确切的作用机制尚未确定。氯米芬似乎能刺激促性腺激素、卵泡刺激激素（FSH）和黄体生成素（LH）的释放，这导致卵巢卵泡的发育和成熟、排卵以及随后的黄体的发展和功能，从而实现妊娠。促性腺激素的释放可能是由于直接刺激下丘脑-垂体轴，或者是由于与子宫、垂体或下丘脑的内源性雌激素竞争，从而减少雌激素对下丘脑-垂体轴的抑制性影响。氯米芬没有明显的孕酮、雄激素或抗雄激素效应，似乎也不会干扰垂体-肾上腺或垂体-甲状腺功能。

Clomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.

来源:Toxin and Toxin Target Database (T3DB)

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的解决而恢复正常，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。在典型的肝酶异常案例中，肝脏组织学显示非特异性变化，如窦状扩张、轻度脂肪积聚和局部炎症浸润，伴有巨噬细胞和淋巴细胞。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

• 药物性肝损伤

化合物：氯米芬

Compound:clomiphene

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

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/克罗米芬柠檬酸盐/后，粪便中可检测到微量，持续长达六周。

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在粪便中排出，较少部分在尿液中排出。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、肠肝循环和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

促排卵的药物中，恩氯米芬是一种抗性激素药物。它主要用于治疗无排卵的女性不育症、黄体功能不足以及因精子过少导致的男性不育症等。此外，恩氯米芬还可以用于治疗绝经后女性因雌激素水平低下引起的不孕症。

反应信息

• 作为反应物：
  描述：

  恩氯米芬 在 1-氯乙基氯甲酸酯 、 1,8-双二甲氨基萘 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 N-desethyl chlomiphene
  参考文献：
  名称：

  PROCESS FOR THE PREPARATION OF CLOMIPHENE

  摘要：

  公开了一种改进的制备活性药物成分氯米芬特别是反式氯米芬的方法，使用醋酸或三氟乙酸。

  公开号：

  US20160152551A1
• 作为产物：
  描述：

  2-二乙氨基氯乙烷盐酸盐 在 tris-(dibenzylideneacetone)dipalladium(0) 、 copper(l) iodide 、 三苯胂 、 sodium ethanolate 、 lithium chloride 、 copper dichloride 作用下， 以 乙醇 为溶剂， 反应 130.0h， 生成 恩氯米芬
  参考文献：
  名称：

  克罗米芬和他莫昔芬的立体有择合成二苯乙炔的锡铜

  摘要：

  摘要 二苯乙炔的立体有择反式-锡铜反应得到 1,2-二金属芪，通过钯催化与芳基碘偶联可将其加工成克罗米芬或他莫昔芬。

  DOI：

  10.1080/00397919508011484

文献信息

• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• [EN] BRUTON'S TYROSINE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON
  申请人：PFIZER

  公开号：WO2014068527A1

  公开（公告）日：2014-05-08

  Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)

  本文披露了一种与Bruton's酪氨酸激酶（BTK）形成共价键的化合物。公开了制备这些化合物的方法。还披露了包括这些化合物的药物组合物。公开了使用BTK抑制剂的方法，单独或与其他治疗剂联合治疗自身免疫疾病或症状、异源免疫疾病或症状、癌症，包括淋巴瘤，以及炎症性疾病或症状的方法。 (化学式I)
• [EN] PROCESSES FOR MAKING TRIAZOLO[4,5D] PYRAMIDINE DERIVATIVES AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉS DE PREPARATION DE DÉRIVÉS DE TRIAZOLO [4,5 D] PYRIMIDINE ET INTERMÉDIAIRES DE CEUX-CI
  申请人：CORVUS PHARMACEUTICALS INC

  公开号：WO2018183965A1

  公开（公告）日：2018-10-04

  Provided herein are, inter alia, methods for making triazolo[4,5]pyramidine derivatives and intermediates thereof that are useful for treating diseases.

  本文提供了制备三氮杂[4,5]吡啶衍生物及其中间体的方法，这些衍生物对治疗疾病有用。
• [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2009139916A1

  公开（公告）日：2009-11-19

  The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

  本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法，以及预防或治疗高增殖性疾病（如癌症）的方法，其中包括向受体施用本发明的化合物或包含这种化合物的组合物。