4-Methylpyrazole

Description

Fomepizole is the first drug indicated as an antidote for ethylene glycol poisoning (it has also shown promise as a treatment for methanol poisoning). Fomepizole is 4-methyl-1H-pyrazole active as a synthetic alcohol dehydrogenase inhibitor, blocking the formation of toxic ethylene glycol metabolites which are responsible for a severe metabolic acidosis and renal failure. In limited human studies, it reversed the toxicity of potentially lethal doses of ethylene glycol. The main urinary metabolite has been reported to be 4-carboxypyrazole by oxidation of the methyl group. Compared with the current treatment (ethanol), the duration of action is longer and the safety is improved, with no toxic effects reported.

Description

Fomepizole is a competitive inhibitor of alcohol dehydrogenase, the enzyme that catalyzes metabolism of ethylene glycol and methanol to toxic metabolites. At 10 μM in monkeys, it can prevent the formation of toxic alcohol metabolites that generate metabolic acidosis. This compound is typically used as an antidote for ethylene glycol or methanol poisoning.

Chemical Properties

clear colourless to yellowish liquid after melting

Originator

Orphan Medical (US)

Uses

Useful as an antidote in methanol and ethylene glycol poisoning.

Uses

Antidote in methanol or ethylene glycol poisoning;Alcohol dehydrogenase inhibitor

Uses

antidote to ethylene glycol or methanol poisoning

Uses

Fomepizole (4-Methylpyrazole) can be used as:

• A reactant to prepare 4-methyl-1-phenyl-1H-pyrazole by reacting with bromobenzene via N-arylation using a copper catalyst.
• A starting material for the synthesis of 4-methyl-3(5)-nitropyrazole by nitration.
• A ligand in the preparation of gallium(III) complex of 4-methylpyrazole as potential antitumor and antiviral agent.

Definition

ChEBI: A member of the class of pyrazoles that is 1H-pyrazole substituted by a methyl group at position 4.

Manufacturing Process

Preparation of 4-methylpyrazole
1.0 g (6.67 mmol) of sodium iodide is added to a suspension of 560 g (4.0 mol) of 70% strength sulfuric acid and 62.5 g (1.0 mol) of 80% strength hydrazine hydrate and, at 125°C, 86.4 g (1.2 mol) of isobutyraldehyde are pumped under the surface of the suspension over the course of 2 hours using a metering pump. During and up to 100 min after the addition of isobutyraldehyde, a total of 175 g of water was distilled out, with the temperature of the mixture rising to 135°C. The solution is cooled and adjusted to pH 8.6 with 820 g (5.125 mol) of 25% strength sodium isobutyraldehyde hydroxide solution and is extracted with isobutanol. The combined extracts are concentrated to 82 g in a rotary evaporator and then distilled. The main fraction (boiling point 82°C/7 mbar; 49 g) consists of 82% 4-methylpyrazole. Yield: 49% of theory.

brand name

Antizol (Jazz).

Therapeutic Function

Antidote

General Description

4-Methylpyrazole inhibits CYP2E1 activity. It also acts as alcohol dehydrogenase inhibitor.

Biochem/physiol Actions

Alcohol dehydrogenase inhibitor.

References

[1] Patent: WO2006/115626, 2006, A2. Location in patent: Page/Page column 8-9
[2] Patent: US2007/244330, 2007, A1. Location in patent: Page/Page column 2; 3