睾内酯 | 968-93-4

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并吡喃类
• 中文名称: 睾内酯
• 中文别名: 睾内酯usp限制；睾内酯酮；睾内酪；睾内酯 usp限制
• 英文名称: testolactone
• 英文别名: 17α-oxa-D-homo-androst-1,4-diene-3,17-dione；17a-oxa-D-homo-1,4-androstadien-3,17-dione；testololactone；teslac；17a-oxa-D-homo-androsta-1,4-diene-3,17-dione；(4aS,4bR,10aR,10bS,12aS)-10a,12a-dimethyl-4,4a,4b,5,6,10b,11,12-octahydro-3H-naphtho[2,1-f]chromene-2,8-dione
• CAS: 968-93-4
• 化学式: C₁₉H₂₄O₃
• 分子量: 300.398
• InChiKey: BPEWUONYVDABNZ-DZBHQSCQSA-N

物化性质

• 熔点：
  218-219°
• 比旋光度：
  D23 -45.6° (c = 1.24 in chloroform)
• 沸点：
  482.0±45.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、甲醇（微溶）
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from acetone
• 气味：
  PRACTICALLY ODORLESS
• 蒸汽压力：
  1.7X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable in light, air, and normal temp.
• 旋光度：
  Specific optical rotation: -45.6 deg (c= 1.24 in chloroform) at 23 °C/D

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.684
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

肝脏的。在肝脏中代谢成几个衍生物，所有这些衍生物都保留了内酯D环。

Hepatic. Metabolized to several derivatives in the liver, all of which preserve the lactone D-ring.

来源:DrugBank

代谢

Testolactone 主要在肝脏代谢并在尿液中排出。在给予Testolactone后，尿液中回收的化合物包括3a, 13alpha-二羟基-13,17-塞科-5beta-雄甾-1-烯-17-酸内酯及其葡萄糖苷酸，以及未改变的Testolactone。

Testolactone is metabolized primarily in the liver and excreted in urine. Compounds recovered in urine after testolactone administration have included 3a, 13alpha-dihydroxy-13,17-seco-5beta-androsta-1-ene-17-oic acid lactone and its glucuronide, and unchanged testolactone.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当同时给药时，睾内酯可能增加口服抗凝剂的效果。应监测血浆抗凝剂水平，并相应调整抗凝剂剂量。

When administered concurrently, testolactone may increase the effects of oral anticoagulants. Plasma anticoagulant levels should be monitored and the anticoagulant dosage adjusted accordingly.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道。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……。预见并处理癫痫发作……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，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……。/毒药A和B/

Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于昏迷、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽插管以控制气道。使用带有气囊面罩的装置进行正压通气技术可能有益。监测心率和必要时治疗心律失常。 ... 开始静脉输液，使用5%葡萄糖盐水/生理盐水： "保持开放"，最低流速/。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿。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。 ... 使用地西泮（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。 /毒药A和B/

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

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：亚慢性或预慢性暴露/ Delta 1-Testolactone，一种没有内在激素作用的雄激素衍生物，已知可以阻断雄激素向雌激素的芳香化。这项研究旨在评估其对成年雄性大鼠血清睾酮和雌二醇的影响。单独使用时，testolactone在所使用的剂量下并未影响T/E2水平。连续15天注射人绒毛膜促性腺激素导致血清睾酮水平增加了十倍，尽管血清雌二醇没有增加。当与人绒毛膜促性腺激素一起给药时，testolactone并未改变莱迪希细胞（Leydig cell）的反应。然而，先用testolactone处理的动物增加了对注射人绒毛膜促性腺激素的睾丸反应，超过了盐水处理的动物。还进行了研究以阐明成年雄性大鼠雌激素的来源。这些实验表明（1）大部分雌二醇并非来自睾丸，而是来自肾上腺；（2）在大鼠中，testolactone不影响雄激素前体转化为雌二醇；（3）尽管没有明显抑制雌二醇的产生，testolactone导致了莱迪希细胞对人绒毛膜促性腺激素反应性的增加。

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Delta 1- Testolactone, an androgen derivative without intrinsic hormonal action, is known to block the aromatization of androgens to estrogens. This study was designed to assess its effect upon serum testosterone and estradiol in the adult male rat. By itself, testolactone did not affect T/E2 levels in the dosages utilized. Daily injections of human chorionic gonadotropin for 15 days caused a tenfold rise in serum testosterone, although there was no increase in serum estradiol. When given along with human chorionic gonadotropin, testolactone did not alter the Leydig cell response. However, pretreatment of animals with testolactone increased the testicular response to human chorionic gonadotropin over that of saline treated animals. Studies were also carried out to delineate the sources of estrogen in the adult male rat. These experiments demonstrate that (1) the majority of estradiol is not testicular in origin but is derived from the adrenal; (2) the conversion of androgen precursors to estradiol in the rat is not affected by testolactone; and (3) in spite of no demonstrable inhibition of estradiol production, testolactone causes an increased Leydig cell responsiveness to human chorionic gonadotropin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验动物：发育或生殖毒性/ 己烯雌酚已被证明在给予大鼠5-15倍于常规人类剂量的情况下，会导致胎儿死亡率增加、胎儿发育异常以及生长中的幼崽死亡；然而，在兔子上以2.5-7.5倍于常规人类剂量的给药研究中，并未显示出致畸作用。

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Testolactone has been shown to produce increased fetal mortality, abnormal fetal development, and mortality in growing pups when administered to rats at 5-15 times the usual human dosage; however, studies in rabbits at dosages of 2.5-7.5 times the usual human dosage demonstrated no teratogenic effects.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

Testolactone is well absorbed from the gastrointestinal tract. 睾内酯从胃肠道吸收良好。

Testolactone is well absorbed from the gastrointestinal tract.

来源:DrugBank

吸收、分配和排泄

• 消除途径

尚未有关于睾内酯对人类肾上腺功能影响的临床报告；然而，一项研究指出，大多数接受每天150毫克口服治疗的患者的尿液中17-酮类固醇的排泄量有所增加。它在肝脏中被代谢为多种衍生物，所有这些衍生物都保留了内酯D环。这些代谢物以及一些未代谢的药物都会通过尿液排出体外。

No clinical effects in humans of testolactone on adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/day orally. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine.

来源:DrugBank

吸收、分配和排泄

消除：肾脏。

Elimination: Renal.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚睾内酯是否分布到乳汁中。

It is not known whether testolactone is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从胃肠道吸收良好。

Well absorbed from the gastrointestinal tract.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  睾内酯 在 哌啶 、 吡啶 、 硫化氢 作用下， 生成 1α,5-disulfanediyl-17a-oxa-D-homo-5α-androstane-3,17-dione
  参考文献：
  名称：

  Thiosteroids. III.¹ The Transannular Addition of Hydrogen Disulfide to the Steroid A Ring

  摘要：

  DOI：

  10.1021/ja01525a075
• 作为产物：
  描述：

  睾酮 在 Fusarium oxysporum SC₁₃₀₁ 作用下， 以 二甲基亚砜 为溶剂， 反应 15.0h， 以98%的产率得到睾内酯
  参考文献：
  名称：

  新分离出的尖孢镰刀菌SC1301对类固醇的有效多步功能性生物转化

  摘要：

  从土壤样品中分离出一种真菌尖孢镰刀菌SC1301，该菌可以转化雄甾4烯-3,17-二酮，雄甾1,4-二烯3,17-二酮，脱氢表雄酮，孕酮，睾丸激素和孕烯醇酮。睾丸内酯的产率为76–98％。特别是对于孕酮和孕烯醇酮，需要进行多步功能转换，包括20-酮类固醇的氧化酯化，酯的水解，C-17 OH基团的氧化，17-酮类固醇的氧化内酯化，1-脱氢，C-3 OH的氧化基团和Δ5 →4 C C键迁移，可以有效地进行以产生睾丸内酯的单一产物。这是F. oxysporum的第一个例子物种显示出环D内酯化的催化能力。该结果与以前报道的紧密相关的真菌F. oxysporum var明显不同。立方体，主要在类固醇的不同位置上介导羟基化作用。另外，尖孢镰刀菌SC1301可以用作生产睾丸内酯的有价值的生物催化剂。

  DOI：

  10.1016/j.tet.2012.10.047

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。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [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。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。