5,5-ジフェニルヒダントイン 化学特性,用途語,生産方法
外観
白色の粉末
溶解性
水 ＜0.01 g/100 mL at 19℃。エタノール,水酸化ナトリウム溶液に可溶、クロロホルムに微溶、水に不溶。
解説
5,5-ジフェニルヒダントイン，分解点295～298 ℃．エタノール，アルカリ水溶液に可溶，クロロホルムに微溶．大脳皮質に作用して，抗けいれん，抗てんかん，抗不整脈作用などを示す．注射用にはナトリウム塩が用いられる．
森北出版「化学辞典（第2版）
用途
薬理研究用。
用途
水酸化ナトリウム溶液
［用途（作用）］ナトリウム透過性抑制作用を
示します。
用途
ナトリウム透過性抑制作用を 示します。
効能
抗てんかん薬
製造
5,5-ジフェニルヒダントイン，フェニトインともいう．ベンゾフェノンのエタノール溶液に炭酸アンモニウムとシアン化ナトリウムの水溶液を加えて加熱すると，ヒダントイン塩が生成するので，それを中和すると得られる．
毒性
LD50 2500 mg/kg(ラット，経口)．
商品名
アレビアチン (大日本住友製薬); アレビアチン (大日本住友製薬); ヒダントール (藤永製薬); ヒダントール (藤永製薬)
説明
The drug was first approved for the treatment of epilepsy by the
Food and Drug Administration in 1953 and marketed by
Parke-Davis as Dilantin. Its primary mechanism of action
appears to block voltage-sensitive sodium channels in the brain
(especially in the motor cortex), producing a delay in electrical
recovery in neurons and stabilizing the threshold against
hyperexcitability.
化学的特性
white crystals or powder
使用
5,5-Diphenylhydantoin has been used for phenytoin treatment. It has also been used to slow down or prevent mesoendoderm cell migration.
定義
ChEBI: A imidazolidine-2,4-dione that consists of hydantoin bearing two phenyl substituents at position 5.
一般的な説明
Fine white or almost white crystalline powder. Odorless or almost odorless. Tasteless.
空気と水の反応
Insoluble in water.
反応プロフィール
5,5-Diphenylhydantoin is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). 5,5-Diphenylhydantoin is incompatible with strong oxidizers and strong bases.
火災危険
Flash point data for 5,5-Diphenylhydantoin are not available; however, 5,5-Diphenylhydantoin is probably combustible.
作用機序
Phenytoin is indicated for initial monotherapy or adjunct treatment of complex partial or tonic-clonic seizures, convulsive status
epilepticus, and prophylaxis. It often is selected for initial monotherapy because of its high efficacy and relatively low incidence
of side effects. Phenytoin is not used in the treatment of absence seizures, because it may increase their frequency of
occurrence. Phenytoin binds to and stabilizes the inactivated state of sodium channels, thus producing a
use-dependent blockade of repetitive firing and inhibition of the spread of seizure activity to adjacent cortical areas.
薬理学
In terms of its effect on the CNS, phenytoin is considered an excellent antiepileptic drug
with insignificant sedative effects. Even in large doses it does not cause hypnosis. It is presumed that phenytoin facilitates secretion of sodium ions from nerve cells, which reduces
the stimulation of neurons. This in turn prevents the activation of neurons upon receiving
impulses from the epileptogenic center. In addition, phenytoin reduces the incoming flow
of potassium ions during repolarization. It is possible that phenytoin significantly slows the
distribution of excitation in the brain as a direct result of the redistribution of the ion flow.
臨床応用
Phenytoin (Dilantin) was originally introduced for the
control of convulsive disorders but has
now also been shown to be effective in the treatment of
cardiac arrhythmias. Phenytoin appears to be particularly
effective in treating ventricular arrhythmias in children.
Phenytoin, like lidocaine, is more effective in the treatment
of ventricular than supraventricular arrhythmias.
It is particularly effective in treating ventricular arrhythmias
associated with digitalis toxicity, acute myocardial
infarction, open-heart surgery, anesthesia, cardiac
catheterization, cardioversion, and angiographic
studies.
Phenytoin finds its most effective use in the treatment
of supraventricular and ventricular arrhythmias
associated with digitalis intoxication. The ability of
phenytoin to improve digitalis-induced depression of
A-V conduction is a special feature that contrasts with
the actions of other antiarrhythmic agents.
副作用
The most common side effect in children receiving
long-term therapy is gingival hyperplasia, or overgrowth
of the gums (occurs in up to 50% of patients).
Although the condition is not serious, it is a cosmetic
problem and can be very embarrassing to the patient.
Hirsutism also is an annoying side effect of phenytoin,
particularly in young females. Thickening of subcutaneous
tissue, coarsening of facial features, and enlargement
of lips and nose (hydantoin facies) are often seen
in patients receiving long-term phenytoin therapy.
Peripheral neuropathy and chronic cerebellar degeneration
have been reported, but they are rare.
There is evidence that phenytoin is teratogenic in
humans, but the mechanism is not clear. However, it is
known that phenytoin can produce a folate deficiency,
and folate deficiency is associated with teratogenesis.
Only a few well-documented drug combinations
with phenytoin may necessitate dosage adjustment.
Coadministration of the following drugs can result in
elevations of plasma phenytoin levels in most patients:
cimetidine, chloramphenicol, disulfiram, sulthiame, and
isoniazid (in slow acetylators). Phenytoin often causes a
decline in plasma carbamazepine levels if these two
drugs are given concomitantly.
Ethotoin and mephenytoin are congeners of phenytoin
that are marketed as AEDs in the United States.
They are not widely used.
安全性プロファイル
Confirmed carcinogen
producing lymphoma, Hodgkin's disease,
tumors of the skin and appendages.
Experimental carcinogenic and tumorigenic
data. A human poison by ingestion. Poison
experimentally by ingestion, subcutaneous,
intravenous, and intraperitoneal routes.
Moderately toxic by an unspecified route.
Experimental teratogenic and reproductive
effects. Human systemic effects by
ingestion: dermatitis, change in motor
activity (specific assay), ataxia (loss of
muscle coordmation), degenerative brain
changes, encephalitis, hallucinations,
dtstorted perceptions, irritabihty, and jaundice. Human teratogenic effects by
ingestion: developmental abnormalities of
the central nervous system, carlovascular
(circulatory) system, musculoskeletal system,
craniofacial area, skin and skin appendages,
eye, ear, other developmental abnormalities.
Effects on newborn include abnormal
growth statistics (e.g., reduced weight gain),
physical abnormakties, other postnatal
measures or effects, and delayed effects.
Human mutation data reported. A drug for
the treatment of grand mal and
psychomotor seizures. When heated to
decomposition it emits toxic fumes of NOx
職業ばく露
Phenytoin is an amide pharmaceutical used in the treatment of grand mal epilepsy, Parkinson’s syndrome; and in veterinary medicine. Human exposure to phenytoin occurs principally during its use as a drug. Figures on the number of patients using phenytoin are not available, but phenytoin is given to a major segment of those individuals with epilepsy. The oral dose rate is initially 100 mg given 3 times per day and can gradually increase by 100 mg every 24 weeks until the desired therapeutic response is obtained. The intravenous dose is 200350 mg/day.
薬物相互作用
Plasma phenytoin concentrations are increased in the
presence of chloramphenicol, disulfiram, and isoniazid,
since the latter drugs inhibit the hepatic metabolism of
phenytoin. A reduction in phenytoin dose can alleviate
the consequences of these drug–drug interactions.
発がん性
Phenytoin and its sodium salt are reasonably anticipated to be human carcinogens based on sufficient evidence from studies in experimental animals.
環境運命予測
Routes and Pathways
Exposure is usually oral, but the intravenous route may be used
to treat status epilepticus.
Relevant Physicochemical Properties
Appearance: clear, colorless, or slightly yellow in solution
Solubility: ethyl alcohol
Solubility in water
practically insoluble in water. 1 g dissolves in about 75 ml of ethanol or 30 ml of acetone.
輸送方法
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.
純化方法
Crystallise the hydantoin from EtOH. [Beilstein 24 III/IV 1748.]
不和合性
Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Similar organic amides react with azo and diazo compounds, releasing toxic gases. Contact with reducing agents can release flammable gases. Amides are very weak bases but they can react as acids, forming salts. Mixing amides with dehydrating agents such as phosphorus pentoxide or thionyl chloride generates the corresponding nitrile.
予防処置
Phenytoin either should not be used or should be used
cautiously in patients with hypotension, severe bradycardia,
high-grade A-V block, severe heart failure, or
hypersensitivity to the drug.
Because of the increase in A-V transmission observed
with phenytoin administration, it should not be
given to patients with atrial flutter or atrial fibrillation.
Phenytoin will probably not restore normal sinus
rhythm and may dangerously accelerate the ventricular
rate.
5,5-ジフェニルヒダントイン 上流と下流の製品情報
原材料
準備製品
2,4,6-トリフルオロフェノール
4,5-dihydroxy-4,5-diphenylimidazolidin-2-one
1-Imidazolidineacetic acid, 2,5-dioxo-4,4-diphenyl-, ethyl ester
3a,6a-ジフェニル-3a,4,6,6a-テトラヒドロイミダゾ[4,5-d]イミダゾール-2,5(1H,3H)-ジオン
クレアチニン
1,3-ジブロモ-5,5-ジフェニルヒダントイン