氨鲁米特 | 125-84-8

• 物质功能分类: 原料药 - 抗肿瘤药 - 激素类抗肿瘤药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 氨鲁米特
• 中文别名: 头孢哌酮；3-乙基-3-(4-氨基苯基)-2,6-哌啶二酮；氨格鲁米特；氨苯哌酮；氨苯哌啶酮；氨苯乙哌啶酮
• 英文名称: aminoglutethimide
• 英文别名: aminogluthetimide；3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione；AMG
• CAS: 125-84-8
• 化学式: C₁₃H₁₆N₂O₂
• mdl: MFCD00010122
• 分子量: 232.282
• InChiKey: ROBVIMPUHSLWNV-UHFFFAOYSA-N

物化性质

• 熔点：
  152-154 °C(lit.)
• 沸点：
  374.44°C (rough estimate)
• 密度：
  1.1099 (rough estimate)
• 溶解度：
  H2O：0.2 mg/mL，微溶
• 物理描述：
  Solid
• 颜色/状态：
  Cyrstals from methanol or ethyl acetate
• 蒸汽压力：
  4.96X10-10 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 碰撞截面：
  164.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 保留指数：
  2227
• 稳定性/保质期：
  在常温常压下，该物质是稳定的。

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.384
• 拓扑面积：
  72.2
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

肝脏。在最初48小时内，34-54%的给药剂量以未改变的药物形式通过尿液排出，另外一部分以N-乙酰衍生物的形式排出。

Hepatic. 34-54% of the administered dose is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as an N-acetyl derivative.

来源:DrugBank

代谢

肝脏；主要代谢物是N-乙酰氨基米妥；个体之间在乙酰化速率上可能存在遗传变异。

Hepatic; the major metabolite is N-acetylaminoglutethimide; there may be genetic variation among individuals in the rate of acetylation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

已经在长期使用氨鲁米特治疗的患者尿液中鉴定出了四种氨鲁米特的代谢物。这些是3-乙基哌啶-2,6-二酮残基羟基化的产物，即3-(4-氨基苯基)-3-乙基-5-羟基哌啶-2,6-二酮及其乙酰氨基类似物，3-(4-氨基苯基)-3-(1-羟基乙基)哌啶-2,6-二酮，以及3-(4-氨基苯基)-3-(2-羧酰胺乙基)四氢呋喃-2-酮，后者是由3-(4-氨基苯基)-3-(2-羟基乙基)哌啶-2,6-二酮重排形成的内酯。...这些新的代谢物与氨鲁米特以及之前鉴定出的主要代谢物3-(4-乙酰氨基苯基)-3-乙基哌啶-2,6-二酮和3-(4-羟基氨基苯基)-3-乙基哌啶-2,6-二酮相比，是较小的组成部分。在大鼠和人类之间存在着明显的物种差异，因为大鼠尿液中几乎所有的代谢物都是N-乙酰化的，而大多数人类的代谢物则不是。然而，哌啶二酮残基的5-羟基化在两个物种中都是立体选择性的，仅形成顺式异构体。合成的顺式-3-(4-氨基苯基)-3-乙基-5-羟基哌啶-2,6-二酮在体外并不抑制目标酶系统——脱酶和芳香化酶的活性，因此，与其他至今描述的代谢物一样，是药物的失活产物。

Four ... metabolites of aminoglutethimide have been identified in the urine of patients being treated chronically with the drug. These were products of hydroxylation of the 3-ethylpiperidine-2,6-dione residue, namely 3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione and its acetylamino analog, 3-(4-aminophenyl)-3-(1-hydroxyethyl)piperidine-2,6-dione, and 3-(4-aminophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, the lactone formed by rearrangement of 3-(4-aminophenyl)-3-(2-hydroxyethyl)piperidine-2,6-dione. ... These new metabolites were minor constituents compared with aminoglutethimide and with the previously identified major metabolites 3-(4-acetylaminophenyl)-3-ethylpiperidine-2,6-dione and 3-(4-hydroxylaminophenyl)-3-ethylpiperidine-2,6-dione. There were marked species differences between rat and human inasmuch as almost all the metabolites in the urine of the rat were N-acetylated whereas most of the human metabolites were not. However, 5-hydroxylation of the piperidinedione residue was stereoselective in the same sense in both species, the cis isomer being formed exclusively. Synthetic cis-3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione did not inhibit the activity of the target enzyme systems desmolase and aromatase in vitro, and therefore, like other metabolites so far described, is an inactivation product of the drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

羟基胺谷司亭（3-乙基-3-(4-羟基氨基苯基)-2,6-哌啶二酮）已被识别为长期使用该药物的患者尿液中胺谷司亭（3-(4-氨基苯基)-3-乙基-2,6-哌啶二酮）的一种新型代谢物。这种代谢物是通过反相薄层色谱分离出来的，并且通过与合成化合物的质谱和色谱性质进行比较而得到鉴定。羟基胺谷司亭不稳定；它容易被氧化成硝基谷司亭，并且在质谱仪中不均匀地分解成这个化合物和胺谷司亭。在研究的四个患者中，没有一个在第一次服用药物后的尿液中检测到这种代谢物。在一个患者中，它在第二次服用后出现，在另外两个患者中，在七到八天内出现，这表明它的形成是由药物诱导的，并且它可能是慢性治疗期间胺谷司亭半衰期减小的代谢物。一位患者在使用第一次剂量后和六周治疗后的高效液相色谱法检查的代谢物轮廓提供了证据，表明羟基胺谷司亭的形成是以主要代谢物N-乙酰胺谷司亭为代价的。

Hydroxylaminoglutethimide (3-ethyl-3-(4-hydroxylaminophenyl)-2,6-piperidinedione) has been identified as a novel metabolite of aminoglutethimide (3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione) in the urine of patients treated chronically with this drug. The metabolite was isolated by reverse-phase thin-layer chromatography, and characterized by comparison of its mass spectrum and chromatographic properties with those of the synthetic compound. Hydroxylaminoglutethimide is unstable; it is readily oxidized to nitrosoglutethimide and disproportionates in the mass spectrometer into this compound and aminoglutethimide. In none of four patients studied was the metabolite detected in the urine after the first dose of the drug. In one patient it appeared after the second dose and in two more within seven to eight days suggesting that its formation is drug-induced, and that it may be the metabolite responsible for the diminished half-life of aminoglutethimide during chronic therapy. The profile of metabolites from one patient, examined by high-performance liquid chromatography after the first dose and again after six weeks of therapy afforded evidence that the formation of hydroxylaminoglutethimide was at the expense of a major metabolite N-acetylaminoglutethimide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

羟基胺谷司亭[3-乙基-3-(4-羟基胺苯基)哌啶-2,6-二酮](HxAG)，胺谷司亭[3-(4-氨基苯基)-3-乙基哌啶-2,6-二酮](AG)和N-乙酰胺谷司亭(N-AcAG)已经通过高效液相色谱法进行了量化，使用m-胺谷司亭(间位AG)作为内标，在连续24小时的尿液中收集，该尿液来自一个接受长期AG治疗且未补充类固醇的患者。HxAG是AG诱导的主要代谢途径的产物，因为[HxAG]/[AG]的比值随时间上升。相比之下，[N-AcAG]/[AG]的比值随时间下降。一种快速、简单的比色分析法已经被用来量化接受不同剂量AG的男女患者尿液中的HxAG，并显示即使在低剂量(每天两次125毫克)下，诱导代谢也是一种普遍现象。

Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 hr urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

氨鲁米特减少D5-孕烯醇酮的生成，并阻断类固醇合成中的几个其他步骤，包括C-11、C-18和C-21羟基化以及将雄激素转化为雌激素所需的芳香化羟基化，这是通过氨鲁米特与细胞色素P-450复合物的结合介导的。具体来说，该药物与芳构酶结合并抑制其活性，这对于从雄烯二酮和睾酮生成雌激素至关重要。肾上腺皮质醇分泌减少后，垂体促肾上腺皮质激素（ACTH）的分泌增加，这将克服氨鲁米特对肾上腺皮质类固醇合成的阻断。可以通过同时给予氢化可的松来抑制ACTH分泌的补偿性增加。由于氨鲁米特增加了地塞米松的代谢速率，而不是氢化可的松的代谢速率，因此后者作为肾上腺糖皮质激素替代品更受青睐。尽管氨鲁米特抑制了甲状腺产生甲状腺素的过程，但甲状腺刺激激素（TSH）的补偿性增加常常足够大，以至于可以克服氨鲁米特对甲状腺合成的抑制作用。尽管TSH增加，但氨鲁米特并未与催乳素分泌增加有关联。

Aminoglutethimide reduces the production of D5-pregnenolone and blocks several other steps in steroid synthesis, including the C-11, C-18, and C-21 hydroxylations and the hydroxylations required for the aromatization of androgens to estrogens, mediated through the binding of aminoglutethimide to cytochrome P-450 complexes. Specifically, the drug binds to and inhibits aromatase which is essential for the generation of estrogens from androstenedione and testosterone. A decrease in adrenal secretion of cortisol is followed by an increased secretion of pituitary adrenocorticotropic hormone (ACTH), which will overcome the blockade of adrenocortical steroid synthesis by aminoglutethimide. The compensatory increase in ACTH secretion can be suppressed by the simultaneous administration of hydrocortisone. Since aminoglutethimide increases the rate of metabolism of dexamethasone but not that of hydrocortisone, the latter is preferred as the adrenal glucocorticoid replacement. Although aminoglutethimide inhibits the synthesis of thyroxine by the thyroid gland, the compensatory increase in thyroid-stimulating hormone (TSH) is frequently of sufficient magnitude to overcome the inhibition of thyroid synthesis due to aminoglutethimide. In spite of an increase in TSH, aminoglutethimide has not been associated with increased prolactin secretion.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

从胃肠道快速且完全吸收。片剂的生物利用度等同于同剂量溶液给药。

Rapidly and completely absorbed from gastrointestinal tract. The bioavailability of tablets is equivalent to equal doses given as a solution.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

过量症状包括呼吸抑制、低通气、低血压、脱水导致的低血容量性休克、嗜睡、乏力、昏迷、共济失调、眩晕、疲劳、恶心和呕吐。

Symptoms of overdose include respiratory depression, hypoventilation, hypotension, hypovolemic shock due to dehydration, somnolence, lethargy, coma, ataxia, dizziness, fatigue, nausea, and vomiting.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性数据

大鼠口服LD50（毫克/千克）：1800；狗，>100。大鼠静脉注射LD50（毫克/千克）：156；狗，>100。

Oral LD50s (mg/kg): rats, 1800; dogs, >100. Intravenous LD50s (mg/kg): rats, 156; dogs, >100.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

从胃肠道快速且完全吸收。片剂的生物利用度等同于同剂量溶液给药。

Rapidly and completely absorbed from gastrointestinal tract. The bioavailability of tablets is equivalent to equal doses given as a solution.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在摄入单次口服剂量后，头48小时内，34%-54%的药物以原形从尿液中排出，另外一部分以N-乙酰衍生物的形式排出。

After ingestion of a single oral dose, 34%-54% is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as the N-acetyl derivative.

来源:DrugBank

吸收、分配和排泄

Cytadren口服给药后能迅速且完全吸收。在6名健康男性志愿者中，服用250毫克片剂后平均最高血药浓度为5.9微克/毫升，平均时间为1.5小时。片剂的生物利用度等同于等剂量溶液给药。

Cytadren is rapidly and completely absorbed after oral administration. In 6 healthy male volunteers, maximum plasma levels of Cytadren averaged 5.9 ug/mL at a medium of 1.5 hours after ingestion of 250 mg tablets. The bioavailability of tablets is equivalent to equal doses given as a solution.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氨鲁米特穿过胎盘...

Aminoglutethimide crosses the placenta ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

aminoglutethimide 是否会分布到乳汁中尚不清楚。

It is not known weather aminoglutethimide is distributed into breast milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 海关编码：
  2925190090
• 危险品运输编号：
  3249
• 危险类别：
  6.1(b)
• RTECS号：
  MA4026950
• 包装等级：
  III
• 危险标志：
  GHS07
• 危险性描述：
  H315,H319,H335
• 危险性防范说明：
  P261,P305 + P351 + P338
• 储存条件：
  存储条件：2-8°C，密闭保存。

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : DL-Aminoglutethimide
CAS-No. : 125-84-8
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008 [EU-GHS/CLP]
Skin irritation (Category 2)
Eye irritation (Category 2)
Specific target organ toxicity - single exposure (Category 3)
Classification according to EU Directives 67/548/EEC or 1999/45/EC
Irritating to eyes, respiratory system and skin.
Label elements
Labelling according Regulation (EC) No 1272/2008 [CLP]
Pictogram
Signal word Warning
Hazard statement(s)
H315 Causes skin irritation.
H319 Causes serious eye irritation.
H335 May cause respiratory irritation.
Precautionary statement(s)
P261 Avoid breathing dust/ fume/ gas/ mist/ vapours/ spray.
P305 + P351 + P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove
contact lenses, if present and easy to do. Continue rinsing.
Supplemental Hazard none
Statements
According to European Directive 67/548/EEC as amended.
Hazard symbol(s)
R-phrase(s)
R36/37/38 Irritating to eyes, respiratory system and skin.
S-phrase(s)
S26 In case of contact with eyes, rinse immediately with plenty of water and
seek medical advice.
S36 Wear suitable protective clothing.
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
Synonyms : 3-(p-Aminophenyl)-3-ethylpiperidine-2,6-dione
3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedione
Formula : C13H16N2O2
Molecular Weight : 232,28 g/mol
Component Concentration
Aminoglutethimide
CAS-No. 125-84-8 -
EC-No. 204-756-4

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Section 4. FIRST AID MEASURES
Description of first aid measures
General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician.
In case of skin contact
Wash off with soap and plenty of water. Consult a physician.
In case of eye contact
Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.
If swallowed
Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician.
Most important symptoms and effects, both acute and delayed
Indication of any immediate medical attention and special treatment needed
no data available

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Section 5. FIREFIGHTING MEASURES
Extinguishing media
Suitable extinguishing media
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx)
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

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Section 6. ACCIDENTAL RELEASE MEASURES
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure
adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.
Environmental precautions
Do not let product enter drains.
Methods and materials for containment and cleaning up
Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed
containers for disposal.
Reference to other sections
For disposal see section 13.

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Section 7. HANDLING AND STORAGE
Precautions for safe handling
Avoid contact with skin and eyes. Avoid formation of dust and aerosols.
Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire
protection.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Specific end uses
no data available

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Section 8. EXPOSURE CONTROLS/PERSONAL PROTECTION
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and
at the end of workday.
Personal protective equipment
Eye/face protection
Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested
and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Immersion protection
Material: Nitrile rubber
Minimum layer thickness: 0,11 mm
Break through time: > 480 min
Material tested:Dermatril® ( Z677272, Size M)
Splash protection
Material: Nitrile rubber
Minimum layer thickness: 0,11 mm
Break through time: > 30 min
Material tested:Dermatril® ( Z677272, Size M)
data source: KCL GmbH, D-36124 Eichenzell, phone [phone], test method: EN374
If used in solution, or mixed with other substances, and under conditions which differ from EN 374,
contact the supplier of the CE approved gloves. This recommendation is advisory only and must
be evaluated by an Industrial Hygienist familiar with the specific situation of anticipated use by our
customers. It should not be construed as offering an approval for any specific use scenario.
Body Protection
impervious clothing, The type of protective equipment must be selected according to the
concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher
level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges.
Use respirators and components tested and approved under appropriate government standards
such as NIOSH (US) or CEN (EU).

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Section 9. PHYSICAL AND CHEMICAL PROPERTIES
Information on basic physical and chemical properties
a) Appearance Form: powder
Colour: off-white
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing Melting point/range: 152 - 154 °C - lit.
point
f) Initial boiling point and no data available
boiling range
g) Flash point no data available
h) Evaporation rate no data available
i) Flammability (solid, gas) no data available
j) Upper/lower no data available
flammability or
explosive limits
k) Vapour pressure no data available
l) Vapour density no data available
m) Relative density no data available
n) Water solubility no data available
o) Partition coefficient: n- no data available
octanol/water
p) Autoignition no data available
temperature
q) Decomposition no data available
temperature
r) Viscosity no data available
s) Explosive properties no data available
t) Oxidizing properties no data available
Other safety information
no data available

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Section 10. STABILITY AND REACTIVITY
Reactivity
no data available
Chemical stability
no data available
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available

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Section 11. TOXICOLOGICAL INFORMATION
Information on toxicological effects
Acute toxicity
LD50 Intraperitoneal - mouse - 625 mg/kg
Remarks: Behavioral:Somnolence (general depressed activity). Behavioral:Antipsychotic.
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitization
no data available
Germ cell mutagenicity
no data available
Carcinogenicity
IARC: No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
Damage to fetus possible
Developmental Toxicity - Human - female - Oral
Specific Developmental Abnormalities: Urogenital system.
Specific target organ toxicity - single exposure
Inhalation - May cause respiratory irritation.
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Potential health effects
Inhalation May be harmful if inhaled. Causes respiratory tract irritation.
Ingestion
May be harmful if swallowed.
Skin May be harmful if absorbed through skin. Causes skin irritation.
Eyes
Causes serious eye irritation.
Additional Information
RTECS: MA4026950

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Section 12. ECOLOGICAL INFORMATION
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
no data available
Other adverse effects
no data available

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Section 13. DISPOSAL CONSIDERATIONS
Waste treatment methods
Product
Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed
professional waste disposal service to dispose of this material. Dissolve or mix the material with a
combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.
Contaminated packaging
Dispose of as unused product.

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Section 14. TRANSPORT INFORMATION
UN number
ADR/RID: - IMDG: - IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA: Not dangerous goods
Transport hazard class(es)
ADR/RID: - IMDG: - IATA: -
Packaging group
ADR/RID: - IMDG: - IATA: -
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

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SECTION 15 - REGULATORY INFORMATION
N/A

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

药理作用

氨鲁米特又名氨基导眠能，为芳香化酶抑制剂，是格鲁米特（导眠能）的衍生物。它通过阻断芳香化酶而抑制雌激素生成，减少雌激素对乳腺癌的促进作用，从而起到抑制肿瘤生长的效果。

此外，氨鲁米特可在肾上腺皮质和腺体外组织两个不同部位阻断雄激素的生物合成，产生药物性肾上腺切除作用。在腺体内，它主要阻止胆固醇转变为孕烯醇酮，从而抑制肾上腺皮质中自体激素的生物合成；在周围组织中则具有强力的芳香化酶抑制作用，阻止雄激素转变为雌激素。绝经后妇女的雌激素主要来源是雄烯二酮在脂肪、肌肉和肝脏中的芳香化转变，而氨鲁米特对这一过程的抑制效果比对肾上腺皮质激素合成的抑制强10倍。垂体后叶分泌的ACTH能对抗氨鲁米特抑制肾上腺皮质激素合成的作用，因此使用本品时可合用氢化可的松以阻滞这种作用。

该药物主要治疗晚期乳腺癌（绝经后及雌激素受体阳性者疗效较好）、卵巢癌、前列腺癌和肾上腺皮质癌。此外，它也用于皮质醇增多症（库欣综合征）及因肾上腺肿瘤引起类似症状的情况。

药动学

氨鲁米特口服后胃肠道吸收迅速而完全，生物利用度约为75%，1.5小时血药浓度达峰值。长期高剂量（每日500mg）口服时，血药峰浓度（Cmax）平均为9μg/ml；长期低剂量（每日125～250mg）口服时，Cmax为0.5～1.5μg/ml。单次用药半衰期约为12.5小时，连续给药2周后，半衰期缩短至6～7小时。血浆蛋白结合率为20%～25%，主要在肝脏代谢，代谢产物主要为N-乙酰氨鲁米特。药物以原形和代谢产物形式主要通过尿液排出，少量从胆汁中排出。

不良反应

1. 神经系统：嗜睡、眩晕、共济失调、眼球震颤。
2. 消化系统：食欲不振、恶心、呕吐、便秘、腹泻以及肝炎。
3. 皮肤：皮疹、瘙痒，极罕见剥脱性皮炎、Stevens-Johnson综合征、Lyell综合征。
4. 呼吸系统：过敏性肺炎。
5. 血液系统：中性粒细胞减少、血小板减少，甚至全血细胞减少，偶有粒细胞缺乏。
6. 内分泌系统：个别出现肾上腺或甲状腺功能减退、女性男性化等。

禁忌

1. 对本药过敏者禁用。
2. 卟啉病患者禁用。
3. 儿童禁用。
4. 带状疱疹或其他感染性疾病患者禁用。
5. 肾上腺皮质功能减退症患者禁用。
6. 肝、肾功能不全者禁用。

用法与用量

口服：每次250mg，每日2次，两周后改为每日3～4次，每日量不超过1g。用药同时应服用氢化可的松40mg（早晨及下午5点各10mg，临睡前20mg），以防止因肾上腺皮质产生氢化可的松减少而引起脑垂体对肾上腺皮质激素的反馈性增加。

生产方法

由2-对氯苯基丁酰胺为原料制得。

类别

有毒物品

毒性分级

中毒

急性毒性

腹腔-小鼠LD50: 625毫克/公斤

可燃性危险特性

可燃；燃烧产生有毒氮氧化物烟雾

储运特性

库房通风低温干燥

灭火剂

干粉、泡沫、砂土、二氧化碳, 雾状水

反应信息

• 作为反应物：
  描述：

  氨鲁米特 在 ethyl 2-((adamantan-1-yl)amino)-2-oxoacetate 、 氧气 、 silver(I) acetate 、 palladium diacetate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 N-(4-(3-ethyl-2,6-dioxopiperidin-3-yl)-2-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodec-1-en-1-yl)phenyl)pivalamide
  参考文献：
  名称：

  配体促进的通过苯甲酰胺间接引入氟化官能团的苯甲酸酯的烯烃化

  摘要：

  我们报告了以4-溴-3,3,4,4-四氟丁烯为氟化试剂的钯催化的，配体促进的，苯甲酰化的C–H含氟烯烃的氟化反应，由于其- CF 2 CF 2 Br官能团。- CF 2 CF 2 H为通过使用温和的还原剂硼氢化钠获得。生物活性化合物，例如氨基戊二酰亚胺衍生物和丙胺在该反应中具有良好的耐受性，这两者都突出了该方法的合成重要性。

  DOI：

  10.1021/acs.joc.0c02701
• 作为产物：
  描述：

  3-乙基-3-(4-硝基苯基)-2,6-哌啶二酮 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 反应 15.0h， 生成 氨鲁米特
  参考文献：
  名称：

  钴催化醚的直接氨基羰基化：高效获得 α-酰胺取代的醚衍生物

  摘要：

  已经实现了醚与胺的新型钴催化羰基化偶联以构建α-羰基化醚。阿夫唑嗪是一种治疗良性前列腺增生（BPH）的药物，可以通过这个过程直接合成。

  DOI：

  10.1002/anie.202203797
• 作为试剂：
  描述：

  1-氧代-5-氮杂螺[2.3]-5-羧酸叔丁酯叔丁基 、 吗啉 在 乙酸乙酯 、 水 、 Brine 、 Sodium sulfate-III 、 silica gel 、 三氟乙酸 、 氨鲁米特 、 hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 1.08h， 以afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil的产率得到3-(Morpholin-4-ylmethyl)azetidin-3-ol
  参考文献：
  名称：

  Azetidines as MEK Inhibitors for the Treatment of Proliferative Diseases

  摘要：

  本发明公开了式(I)的化合物及其药学上可接受的盐和溶剂化物。这些化合物是MEK抑制剂，可用于治疗增生性疾病，如癌症。本发明还公开了含有这些化合物的制药组合物，以及使用本发明的化合物和组合物治疗癌症的方法。

  公开号：

  US20100249096A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20150231142A1

  公开（公告）日：2015-08-20

  The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

  本发明涉及含有上皮钠通道活性抑制剂与至少一种ABC转运蛋白调节剂化合物（A式、B式、C式或D式）的药物组合物。该发明还涉及这些药物配方，以及使用这些组合物治疗CFTR介导的疾病，特别是囊性纤维化的方法。
• [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。

表征谱图