3,5-二甲基金刚胺 | 19982-08-2

• 物质功能分类: 原料药 - 神经系统用药 - 抗震颤麻痹药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 3,5-二甲基金刚胺
• 中文别名: 二甲金刚烷胺；美金刚胺；盐酸美金刚；美金胺；美金刚
• 英文名称: memantine*
• 英文别名: 3,5-dimethyladamantan-1-amine；1-amino-3,5-dimethyladamantane；3,5-dimethyl-1-adamantanamine；Memantine
• CAS: 19982-08-2
• 化学式: C₁₂H₂₁N
• mdl: MFCD00214336
• 分子量: 179.305
• InChiKey: BUGYDGFZZOZRHP-UHFFFAOYSA-N

物化性质

• 熔点：
  258 °C
• 沸点：
  239.8±8.0 °C(Predicted)
• 密度：
  1.046
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Oil
• 蒸汽压力：
  1.9X10-4 mm Hg at 25 °C (est)
• 稳定性/保质期：

  在常温常压下保持稳定，应避免与强氧化剂接触。

• 解离常数：
  pKa = 10.7 (est)
• 保留指数：
  1305

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  26
• 氢给体数：
  1
• 氢受体数：
  1

ADMET

代谢

这种药物在肝脏中部分代谢。肝脏的CYP450酶系统并未主要参与这种药物的代谢。

This drug is partially metabolized in the liver. The hepatic CYP450 enzyme system does not majorly contribute to the metabolism of this drug.

来源:DrugBank

代谢

美金刚经部分肝脏代谢。肝脏微粒体CYP450酶系统在美金刚的代谢中并不起重要作用。

Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏微粒体细胞色素P-450（CYP）同工酶系统在美金刚代谢中不起重要作用。

The hepatic microsomal cytochrome P-450 (CYP) isoenzyme system does not play a substantial role in the metabolism of memantine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大约20%会代谢成1-氨基-3-羟基甲基-5-甲基-金刚烷和3-氨基-1-羟基-5,7-二甲基-金刚烷。 消除途径：美金刚经历部分肝脏代谢。约48%的给药药物以不变形式在尿液中排出；其余部分主要转化为三种极性代谢物，这些代谢物对NMDA受体拮抗活性极小：N-葡萄糖苷酸结合物、6-羟基美金刚和1-亚硝基脱氨美金刚。它主要以不变的形式在尿液中排出。 半衰期：60-100小时

Excreted largely unchanged. About 20% is metabolized to 1-amino-3-hydroxymethyl-5-methyl-adamantane and 3-amino-1-hydroxy-5,7-dimethyl-adamantane. Route of Elimination: Memantine undergoes partial hepatic metabolism. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. It is excreted predominantly in the urine, unchanged. Half Life: 60-100 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别和使用：美金刚是一种油。它被处方用于治疗中到重度的阿尔茨海默病。美金刚的作用机制是通过阻断NMDA受体。人类暴露和毒性：在临床试验和全球市场经验中，单独或与其他药物和/或酒精联合使用时，美金刚过量的迹象和症状最常包括激动、乏力、心动过缓、混乱、昏迷、眩晕、ECG改变、血压升高、乏力、意识丧失、精神疾病、不安、运动迟缓、嗜睡、昏迷、步态不稳、视觉幻觉、眩晕、呕吐和虚弱。一名患者在使用美金刚后可能出现了肾损伤和高钾血症。两名阿尔茨海默病患者在长期使用美金刚后报告了反复意识丧失的情况，停药后情况得以解决。关于美金刚的心血管效果知之甚少，但已有心动过缓和心血管存活率降低的报道与其使用有关。在体外人淋巴细胞染色体畸变试验中，美金刚未产生遗传毒性潜力。动物研究：在新生小鼠中，美金刚治疗暂时改善了依赖于海马的记忆形成。在大鼠中，美金刚给药显著剂量依赖性地减弱了与乙醇相关的行为改变。在体外S. typhimurium或E. coli逆向突变试验，或在大鼠体内染色体损伤的细胞遗传学试验和体内小鼠微核试验中评估时，美金刚未产生遗传毒性潜力。在使用中国仓鼠V79细胞的体外基因突变试验中，结果是不确定的。

IDENTIFICATION AND USE: Memantine is an oil. It is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor. HUMAN EXPOSURE AND TOXICITY: Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. Renal impairment and hyperkalaemia possibly associated with memantine administration was described in one patient. Two cases of repeated loss of consciousness were reported after long-term memantine treatment in patients with Alzheimer disease, which resolved after its discontinuation. Little is known about the cardiovascular effects of memantine but there have been reports of bradycardia and reduced cardiovascular survival associated with its use. Memantine produced no evidence of genotoxic potential in vitro in chromosomal aberration test in human lymphocytes. ANIMAL STUDIES: In newborn mice treatment with memantine temporally improves hippocampus-dependent memory formation. In rats memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, or in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

美金刚通过非竞争性NMDA受体拮抗作用发挥其效果，优先结合于NMDA受体激活的阳离子通道。痴呆患者大脑中持续性增加的谷氨酸水平足以对抗由Mg²⁺离子引起的NMDA受体的电压依赖性阻断，并允许Ca²⁺离子持续进入细胞，最终导致神经元退化。研究表明，美金刚比Mg²⁺离子更有效地与NMDA受体结合，从而有效阻止通过NMDA通道的Ca²⁺离子的持续流入，同时保留由高浓度突触释放的谷氨酸引起的通道的瞬时生理激活。因此，美金刚能够保护免受谷氨酸慢性升高浓度的伤害。美金刚也对类型3血清素（5-HT₃）受体具有拮抗活性，其效力与对NMDA受体的效力相似，并且对尼古丁乙酰胆碱受体的拮抗活性较低。这种药物对γ-氨基丁酸（GABA）、苯二氮卓、多巴胺、肾上腺素、组胺或甘氨酸受体没有亲和力，也不对电压依赖性钙、钠或钾通道有作用。

Memantine exerts its action through uncompetitive NMDA receptor antagonism, binding preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the voltage-dependent block of NMDA receptors by Mg²⁺ ions and allow continuous influx of Ca²⁺ ions into cells, ultimately resulting in neuronal degeneration. Studies suggest that memantine binds more effectively than Mg²⁺ ions at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca²⁺ ions through the NMDA channel whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus memantine protects against chronically elevated concentrations of glutamate. Memantine also has antagonistic activity at the type 3 serotonergic (5-HT₃) receptor with a potency that is similar to that at the NMDA receptor, and lower antagonistic activity at the nicotinic acetylcholine receptor. This drug has no affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在大型的安慰剂对照试验中，美金刚治疗期间血清酶升高的发生率与安慰剂组相似，并且没有报告出现临床上明显的肝损伤。然而，自从美金刚进入临床使用以来，至少有一份报告将其与临床上明显的肝毒性联系起来。发病时间为3周，临床综合征表现为急性胆汁淤积性肝炎，病情严重程度为轻至中度，停药后迅速可逆（案例1）。免疫过敏和自身免疫特征未出现。

In large placebo controlled trials, the rate of serum enzyme elevations during memantine therapy was similar to that in patients on placebo and no instances of clinically apparent liver injury were reported. Nevertheless, since its introduction into clinical use, memantine has been implicated in at least one report of clinically apparent hepatotoxicity. The time to onset was 3 weeks and the clinical syndrome was that of an acute cholestatic hepatitis which was mild-to-moderate in severity and rapidly reversible upon drug discontinuation (Case 1). Immunoallergic and autoimmune features were not present.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：美金刚

Compound:memantine

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

吸收、分配和排泄

• 吸收

口服给药后，美金刚吸收良好。大约在3-7小时内达到峰值血药浓度。在正常治疗剂量下，美金刚表现出线性药代动力学。食物对美金刚吸收没有影响，因此可以在不考虑食物的情况下服用此药。

After an oral dose, memantine is well absorbed. Its peak drug concentrations are attained in about 3-7 hours. Memantine shows linear pharmacokinetics when given at normal therapeutic doses. This drug can be taken without regard to food, as there is no effect of food on memantine absorption.

来源:DrugBank

吸收、分配和排泄

• 消除途径

这种药物主要在尿液中排泄。大约48%的服用美金刚胺以原形在尿液中排泄。剩余的药物代谢为三种主要代谢物。这些代谢物是N-葡萄糖苷酸结合物、6-羟基美金刚胺和1-亚硝基脱氨美金刚胺，它们表现出最小的NMDA受体拮抗活性。

This drug is mainly excreted in the urine. Approximately 48% of administered memantine is excreted unchanged in urine. The remainder of the drug is metabolized to three main metabolites. These metabolites are the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine, which show minimal NMDA receptor antagonist activity.

来源:DrugBank

吸收、分配和排泄

• 分布容积

_memantine的平均分布体积为9-11 L/kg._

The mean volume of distribution of memantine is 9-11 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

这种药物通过肾脏的活跃管分泌被清除。这种药物的管重吸收取决于pH值。

This drug is cleared by active tubular secretion in the kidneys. Tubular reabsorption of this drug is pH dependent.

来源:DrugBank

吸收、分配和排泄

美金刚主要通过尿液以原型（大约48%）排泄，其终末消除半衰期大约为60-80小时。剩余部分主要转化为三种极性代谢物，这些代谢物对NMDA受体拮抗活性最小：N-葡萄糖苷酸结合物、6-羟基美金刚和1-亚硝基去氨美金刚。总共有74%的给药剂量以母药和N-葡萄糖苷酸结合物的总和形式被排泄。肾清除涉及由pH依赖性肾小管重吸收调节的活跃肾小管分泌。

Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours. The remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S24/25
• 海关编码：
  2921300090
• 储存条件：
  在密封的贮藏器中存放，并置于阴凉、干燥处保存。

SDS

Name:	1 3-Dimethyl-5-aminoadamantane hydrochloride Material Safety Data Sheet
Synonym:	1-Amino-3,5-dimethyladamantane hydrochloride; Memantine hydrochloride; 3,5-Dimethyl-1-adamantanamine hydrochloride; DMAA hydrochloride; Tricyclo(3.3.1.1(sup 3,7))decan-1-amine hydrochloride
CAS:	19982-08-2

Section 1 - Chemical Product MSDS Name:1 3-Dimethyl-5-aminoadamantane hydrochloride Material Safety Data Sheet
Synonym:1-Amino-3,5-dimethyladamantane hydrochloride; Memantine hydrochloride; 3,5-Dimethyl-1-adamantanamine hydrochloride; DMAA hydrochloride; Tricyclo(3.3.1.1(sup 3,7))decan-1-amine hydrochloride

---

Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
19982-08-2	1,3-Dimethyl-5-aminoadamantane hydroch	99	255-219-6

Hazard Symbols: None Listed.
Risk Phrases: None Listed.

---

Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Not available.
Potential Health Effects
Eye:
Dust may cause mechanical irritation.
Skin:
May cause skin irritation.
Ingestion:
May cause irritation of the digestive tract. May cause central nervous system effects and/or neurological effects.
Inhalation:
May cause respiratory tract irritation.
Chronic:
No information found.

---

Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid immediately.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Wash clothing before reuse.
Ingestion:
If victim is conscious and alert, give 2-4 cupfuls of milk or water.
Never give anything by mouth to an unconscious person. Get medical aid.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

---

Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion. This material in sufficient quantity and reduced particle size is capable of creating a dust explosion.
Extinguishing Media:
Use water spray, dry chemical, carbon dioxide, or appropriate foam.

---

Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container. Avoid generating dusty conditions. Provide ventilation.

---

Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use with adequate ventilation. Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Avoid breathing dust.
Storage:
Keep container closed when not in use. Store in a cool, dry, well-ventilated area away from incompatible substances.

---

Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 19982-08-2: CAS# 41100-52-1: Personal Protective Equipment Eyes: Wear appropriate protective eyeglasses or chemical safety goggles as described by OSHA's eye and face protection regulations in 29 CFR 1910.133 or European Standard EN166.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to minimize contact with skin.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

---

Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Powder
Color: white
Odor: None reported.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 258 deg C
Autoignition Temperature: Not applicable.
Flash Point: Not applicable.
Explosion Limits, lower: N/A
Explosion Limits, upper: N/A
Decomposition Temperature:
Solubility in water:
Specific Gravity/Density:
Molecular Formula: C12H21NHCl
Molecular Weight: 215.77

---

Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Dust generation.
Incompatibilities with Other Materials:
Strong oxidizing agents.
Hazardous Decomposition Products:
Hydrogen chloride, nitrogen oxides, carbon monoxide, carbon dioxide.
Hazardous Polymerization: Has not been reported.

---

Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 19982-08-2: YD1958750 CAS# 41100-52-1 unlisted.
LD50/LC50:
Not available.
Not available.
For CAS 19982-08-2, the free base: TDLo Intramuscular (rat): 14.2 mg/kg anticonvulsant. (RTECS) Carcinogenicity:
1,3-Dimethyl-5-aminoadamantane (the free base) - Not listed by ACGIH, IARC, or NTP.
1,3-Dimethyl-5-aminoadamantane hydrochloride - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

---

Section 12 - ECOLOGICAL INFORMATION

---

Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

---

Section 14 - TRANSPORT INFORMATION

IATA
Not regulated as a hazardous material.
IMO
Not regulated as a hazardous material.
RID/ADR
Not regulated as a hazardous material.

---

Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: Not available.
Risk Phrases:
Safety Phrases:
S 24/25 Avoid contact with skin and eyes.
WGK (Water Danger/Protection)
CAS# 19982-08-2: No information available.
CAS# 41100-52-1: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 19982-08-2 is not listed on Canada's Ingredient Disclosure List.
CAS# 41100-52-1 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 19982-08-2 is not listed on the TSCA inventory.
It is for research and development use only.
CAS# 41100-52-1 is not listed on the TSCA inventory.
It is for research and development use only.

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

用途

3,5-二甲基金刚胺具有活泼的反应性和特殊的溶解能力，可用作有机合成原料、纸张处理剂、纤维工业的柔软剂、动物胶的软化剂，还用作测定大米中残留物含量的分析试剂。在有机合成中，3,5-二甲基金刚胺主要用于医药领域，在农药、染料、颜料、香料和助剂方面也有广泛的应用。

适应症

临床用于治疗中度到重度老年性痴呆及震颤麻痹综合征。

合成

1-甲酰胺基-3,5-二甲基金刚烷-1-甲酰胺（工业级，纯度70%，2mmol，按100%纯度计算）的水解分别用选定的碱（6mmol）在选定的溶剂（10ml）或溶剂系统（10ml）中进行。通过在实施例中所示的时间后取等分试样来监测反应。所述等分试样在甲苯和水中分配，分离有机相并用无水Na2SO4干燥，并通过气相色谱法分析确证所得化合物为3,5-二甲基金刚胺。

此外，实验人员采用“一锅法”合成3,5-二甲基金刚胺，在三乙胺存在下以甲苯作溶剂、邻碘苯酚与丙炔酸乙酯反应。这种方法有效避免了在反应过程中使用毒性较大的重氮类化合物的问题，反应步骤少，时间短，操作简便，收率较高，并能更便捷地对目标化合物进行分子结构改造和修饰，具有指导类似化合物合成的作用。

图 3,5-二甲基金刚胺的合成路线

---

请注意，上述文本中包含了一张图片的内容描述“图 3,5-二甲基金刚胺的合成路线”，但实际图片并未显示。