ピペラジン

外観

白色～うすい黄色, 結晶

性質

ピペラジンは無色葉状晶で、水やエチレングリコールに溶けます。ピペラジンの水溶液は強塩基性を示し、pKaは9.8です。10%の水溶液のpHは10.8〜11.8です。空気中の湿気や二酸化炭素を吸収します。ピペラジンはジエチルエーテルに溶けません。

なお、ピペラジンの融点は104°C、沸点は145〜146°Cです。引火点は65°C、発火点は320°Cです。シクロヘキサン (英: Cyclohexane) のメチレン基2つをNHで置換した構造を持っています。また、ピペラジンのような6員環のことを、ピペラジン環と呼びます。

反応

ピペラジンの反応

ピペラジンの持つアミノ基は、容易に二酸化炭素と反応します。ピペラジンと二酸化炭素の比率によって、ピペラジンカルバメート (英: Piperazine carbamate) やピペラジンビカルバメート (英: Piperazine bicarbamate) が生じます。溶媒中に遊離しているピペラジンは限られているため、揮発性は低く、ピペラジン六水和物が沈殿する速度は低いです。

解説

ピペラジン，板状晶．融点104 ℃，沸点145 ℃．Kb1 9×10－15，Kb2 4×10－9．水，エタノールに易溶．強塩基で，空気中の二酸化炭素を吸収する．リン酸，酒石酸，アジピン酸との塩は動物用駆虫剤であり，また，アンチモン，ビスマス，金の検出試薬として使われる．遮光，密栓して保存する．

森北出版「化学辞典（第2版）

用途

アンチモン、ビスマス、金の検出試薬、ウレタン触媒、有機合成原料、医薬中間体原料、駆除薬（ヒト及び動物のぎょう虫やかい虫の駆除）原料、エポキシ樹脂硬化剤）

合成法

ピペラジンは、ピラジン (英: Pyrazine) をとアルコールで還元すると得られます。また、水酸化ナトリウムを用いて、1,2-ジクロロエタン (英: 1,2-Dichloroethane) とアンモニアの反応で生成します。さらに、エチレングリコールと1,2-ジアミノエタン (英: 1,2-Diaminoethane) の脱水縮合でも合成可能です。

効能

駆虫薬

製法

ピラジンをナトリウムとアルコールとで還元すると得られるピペラジン．

使用上の注意

不活性ガス封入

説明

Piperazine is contained in pyrazinobutazone, an equimolecular sah of piperazine and phenylbutazone. Among occupational cases, most were reported in the pharmaceutical industry or laboratory, in nurses and in veterinarians.

化学的特性

Piperazine is white to cream-colored needles or powder. Characteristic ammonia-like odor. Combustible solids that do not easily ignite.

使用

Labelled Piperazine

定義

ChEBI: An azacycloalkane that consists of a six-membered ring containing two nitrogen atoms at opposite positions.

適応症

Piperazine (Vermizine) contains a heterocyclic ring that lacks a carboxyl group. It acts on the musculature of the helminths to cause reversible flaccid paralysis mediated by chloride-dependent hyperpolarization of the muscle membrane. This results in expulsion of the worm. Piperazine acts as an agonist at gated chloride channels on the parasite muscle.
Piperazine has been used with success to treat A. lumbricoides and E. vermicularis infections, although mebendazole is now the agent of choice. Piperazine is administered orally and is readily absorbed from the intestinal tract. Most of the drug is excreted in the urine within 24 hours.
Piperazine is an appropriate alternative to mebendazole for the treatment of ascariasis, especially in the presence of intestinal or biliary obstruction. Cure rates of more than 80% are obtained following a 2-day regimen.
Side effects occasionally include gastrointestinal distress, urticaria, and dizziness. Neurological symptoms of ataxia, hypotonia, visual disturbances, and exacerbations of epilepsy can occur in patients with preexisting renal insufficiency. It should not be used in pregnant women because of the formation of a potentially carcinogenic and teratogenic nitrosamine metabolite. Concomitant use of piperazine and chlorpromazine or pyrantel should be avoided.

世界保健機関（WHO）

Piperazine was first used as a treatment for gout earlier this century and its anthelminthic activity was discovered in 1949. It is also considerably cheaper than other anthelminthic drugs. In some countries where ascariasis is not endemic and where piperazine was used predominantly for the treatment of pinworm it has been withdrawn from use on the grounds that other more effective and less toxic drugs are now available (see full list). In other such countries, however, piperazine remains available in over-the-counter preparations. Clinical dosages occasionally induce transient neurological signs and concern has been expressed that in some circumstances the drug may generate small amounts of nitrosamine in the stomach. However, it is widely considered that these trace doses are unlikely to give rise to a significant carcinogenic potential. (Reference: (WHODIB) WHO Drug Information Bulletin, 1: 5, , 1983)

一般的な説明

Needle-like white or colorless crystals. Shipped as a solid or suspended in a liquid medium. Very corrosive to skin, eyes and mucous membranes. Solid turns dark when exposed to light. Flash point 190°F. Used as a corrosion inhibitor and as an insecticide.

空気と水の反応

Flammable. Absorbs water and carbon dioxide from air. Soluble in water.

反応プロフィール

1,4-Diazacyclohexane neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Absorbs carbon dioxide from the air, which can cause dry crystals to seem to melt. May generate hydrogen, a flammable gas, in combination with strong reducing agents such as hydrides. 1,4-Diazacyclohexane is sensitive to light; 1,4-Diazacyclohexane absorbs water and carbon dioxide from air. 1,4-Diazacyclohexane may be corrosive to aluminum, magnesium and zinc. .

健康ハザード

Piperazine is a corrosive substance. The solidand its concentrated aqueous solutions areirritants to the skin and eyes. The irritanteffect in rabbits’ eyes was severe.
The toxic symptoms from ingestion ofpiperazine include nausea, vomiting, excitement,change in motor activity, somnolence,and muscle contraction. The toxicity of thiscompound is low, however. The oral LD50value in rats is 1900 mg/kg. The inhalationtoxicity is very low. The inhalation LC50value in mice is 5400 mg/m³/2 h.

火災危険

Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors and sewers explosion hazards. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form.

使用用途

ピペラジンのクエン酸塩、リン酸塩、アジピン酸塩は、蟯虫や回虫などに対する動物用寄生虫駆除剤として使用されています。寄生虫駆除剤として効果を発揮する作用機序は、次のメカニズムです。

まず、γ-アミノ酪酸 (GABA) 様物質として、GABA受容体に作用します。寄生虫の体性筋細胞に存在するGABA受容体に作用して、神経筋伝達の障害を起こします。蟯虫や回虫を可逆的に麻痺させ、寄生虫を排便とともに体外へ排出可能です。

応用例（製薬）

A synthetic chemical, most commonly formulated as the citrate, but also available as the adipate, edetate calcium and tartrate salts.

接触アレルゲン

Piperazine is contained in pyrazinobutazone, an equimolar salt of piperazine and phenylbutazone. Among occupational cases, most were reported in the pharmaceutical industry or laboratory workers, in nurses, and in veterinarians.

薬物動態学

Activity against intestinal worms requires that a substantial amount remains in the gut. However, after oral administration a variable amount is rapidly absorbed from the small intestine and subsequently excreted in the urine. Its half-life is extremely variable.

臨床応用

Hexahydropyrazine or diethylenediamine (Arthriticine,Dispermin) occurs as colorless, volatile crystals of the hexahydratethat are freely soluble in water. After the discoveryof the anthelmintic properties of a derivative diethylcarbamazine,the activity of piperazine itself was established.Piperazine is still used as an anthelmintic for the treatmentof pinworm (Enterobius [Oxyuris] vermicularis) and roundworm(Ascaris lumbricoides) infestations. It is available invarious salt forms, including the citrate (official in the USP)in syrup and tablet forms. Piperazine blocks the response of the ascaris muscleto acetylcholine, causing flaccid paralysis in the worm,which is dislodged from the intestinal wall and expelled inthe feces.

副作用

Some people develop hypersensitivity, requiring cessation of treatment. Transient, mild gastrointestinal or neurological symptoms may occur.

安全性プロファイル

Moderately toxic by ingestion, skin contact, intravenous, and subcutaneous routes. Mildly toxic by inhalation. A skin and severe eye irritant. Excessive absorption can cause urticaria, vomiting, diarrhea, blurred vision, and weakness. Combustible when exposed to heat or flame; can react vigorously with oxidizing materials. Explodes on contact with dicyanofurazan. To fight fire, use alcohol foam, mist, dry chemical, water spray. When heated to decomposition it emits highly toxic fumes of NOx.

職業ばく露

(Piperazine): Primary irritant (w/o allergic reaction),

発がん性

No increase in lung adenomas was produced in mice administered 0.69–18.75mg of piperazine/ kg in drinking water for 20–25 weeks and sacrificed 10–13 weeks later. Mice fed the equivalent of 938 mg/kg in the diet for 28 weeks and sacrificed at 40 weeks failed to show any significant increase in the incidence of lung adenomas. An increase in lung adenomas was produced in this bioassay by administration of piperazine together with sodium nitrate, suggesting the formation of the active nitroso derivative. Sodium ascorbate inhibited tumor formation, in theory, by preventing piperazine nitrosation (304). Coadministration of 250 ppm piperazine and 500 ppm sodium nitrate in drinking water did not produce tumors in rats. None of these studies were conducted using currently accepted methods for evaluating carcinogenic potential but piperazine alone, in these assays, was noncarcinogenic.

環境運命予測

This molecule has a simple chemical structure and molecular weight of 86.14. It has a strong alkaline base soluble in water (1:18), glycerol, and glycols, but is only sparingly soluble in alcohol and insoluble in ether. Piperazine is not expected to hydrolyze in water. The photodegradation half-life is approximately 0.8 h. The piperazine molecule is easily denaturalized by diverse environmental factors and has a low potential for bioaccumulation or biomagnification. To improve its stability, it is usually formulated as different salts such as adipate, citrate, phosphate, hexahydrate, and sulfate. Most piperazine salts are white crystalline powders that are readily soluble in water.Exceptions are adipates, which dissolve to only a maximum concentration of 5% in water, and phosphate, which is insoluble.

輸送方法

UN2579 Piperazine, Hazard class: 8; Labels: 8-Corrosive material.

純化方法

Piperazine crystallises from EtOH or anhydrous *benzene and is dried at 0.01mm. It can be sublimed under vacuum and purified by zone melting. The hydrochloride has m 172-174o (from EtOH), and the dihydrochloride crystallises from aqueous EtOH and has m 318-320o (dec, sublimes at 295-315o). The picrate has m ~200o, and the picrolonate crystallises from dimethylformamide ( m 259-261o). [Beilstein 23 H 4, 23 I 4, 23 II 3, 23 III/IV 15, 23/1 V 30.]

不和合性

Aqueous solution is a strong base. Violent reaction with strong oxidizers and dicyanofurazan. 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, nitrogen compounds, carbon tetrachloride. Attacks aluminum, copper, nickel, magnesium and zinc.