Description
Terbinafine hydrochloride(78628-80-5) is the first orally active allylamine antifungal with 30-fold
greater antifungal activity than naftifine. The compound is indicated for the treatment
of ringworm and fungal nail infections. Terbinatine hydrochloride acts on a single
fungal enzyme, squalene epoxidase, interfering with the biosynthesis of ergosterols in
cell membranes. Unlike other antifungal agents, it does not inhibit cytochrome P450
enzymes.
Chemical Properties
Terbinafine hydrochloride is an off-white crystalline material that is soluble in polar organic solventssuch as methanol, ethanol, and methylene chloride but isonly slightly soluble in water. The highly lipophilic freebase is insoluble in water.
Originator
Sandoz (Switzerland)
Uses
Terbinafine hydrochloride(78628-80-5) is a synthetic allylamine antifungal. It is used to treat dermatophyte infections of the toenail/fingernail, ringworm and jock itch. It is used in adsorption, partition and stability studies.
Definition
ChEBI: A hydrochloride obtained by reaction of terbinafine with one molar equivalent of hydrogen chloride.
Indications
Terbinafine Hydrochloride is a synthetic allylamine antifungal
agent, structurally related to naftifine. It inhibits fungal sterol biosynthesis
by inhibiting the enzyme squalene 2,3-epoxidase. The deficiency of
ergosterol and concomitant accumulation of squalene within the fungal
cell results in cell death. It can be fungicidal or fungistatic, depending on
the concentration used, and is effective against dermatophytes, Aspergillus,
blastomycosis, and histoplasmosis. It is only minimally effective against
Candida.
Manufacturing Process
To prepare terbinafine hydrochloride, N-methyl-1-naphthalene methylamine hydrochloride (29 kg) was added to a reactor containing dimethylformamide (70.4 liters) and water (11 liters). The mixture was stirred for 15 minutes until fully dissolved. Sodium carbonate (11 kg) was added and the reaction mixture was cooled to 13 °C. Then, 1-chloro-6,6-dimethyl-2-heptene-4-yne (22 kg) was slowly added at a temperature range of 11 to 14 °C. The mixture was stirred for 60 minutes at 12-14 °C, then heated to 55 °C and maintained at 60 °C for 5 hours. Thin layer chromatography was used to confirm completion of the reaction. The mixture was cooled to room temperature and water (99 liters) was added. The mixture was extracted three times with dichloromethane (75 liters in total). The organic layer was washed twice with water (88 liters in total) and additional water (18 liters) was added to the organic layer, which was then cooled to 13 °C. The pH of the reaction mass was adjusted to 0.2 by adding 36% aqueous hydrochloric acid (15 liters) and stirring for 30 minutes. The organic layer was separated and washed three times with water (267 liters in total). The final organic layer was transferred to a reactor and the solvent was distilled below 45 °C. Petroleum ether (11.8 liters) was added and the solvent was completely distilled below 50 °C. An additional amount of petroleum ether (68 liters) was added and the mixture was heated to reflux. After 30 minutes of stirring at reflux, the mixture was cooled to 50 °C. The solid formed was allowed to settle for 60 minutes and the top petroleum ether layer was decanted. This decantation process was repeated twice more. Finally, 44 liters of petroleum ether was added, heated to reflux for 30 minutes, and then cooled to 25 °C. The mixture was stirred for 60 minutes at 20-25 °C, centrifuged to collect the solid, and washed twice with petroleum ether (2x16 liters). The solid was then spin-dried for about 60 minutes to obtain 29.3 kg of crude terbinafine hydrochloride as a semi-dry solid.
WO2007096904A2 Improved process for the preparation of terbinafine hydrochloride and novel crystalline form of terbinafine
Therapeutic Function
Antifungal
General Description
Terbinafine Hydrochloride(78628-80-5) is a synthetic allylamine derivative structurally related to naftifine, antifungal Terbinafine Hydrochloride blocks ergosterol biosynthesis by inhibition of squalene epoxidase, part of the sterol synthesis pathway for the fungal cell membrane.
Biological Activity
Terbinafine is a broad-spectrum antifungal agent that has activity against T. rubrum, T. metagrophytes, T. verrucosum, E. floccosum, M. canis, A. fumigatus, and S. schenckii (MIC50s = 0.003-0.8 μg/ml). It selectively inhibits C. albicans squalene epoxidase over rat liver epoxidase (IC50s = 0.03 and 77 μM, respectively). Terbinafine (90-120 μM) induces cell cycle arrest at the G0/G1 phase in COLO 205 tumor cells and human umbilical vein endothelial cells (HUVECs). Formulations containing terbinafine have been used in the treatment of nail and skin fungal infections.
Biochem/physiol Actions
Mode of Action: Inhibits squalene epoxidase, preventing biosynthesis of ergosterol.Antimicrobial spectrum: Antifungal and antimycotic. Fungicidal against dermatopytes and some yeasts; fungistatic against Candida albicans.
Clinical Use
Terbinafine hydrochloride (Lamisil) is available for
topical and systemic use (oral tablet) in the treatment of
dermatophyte skin and nail infections. Terbinafine also
exhibits in vitro activity against filamentous and dimorphic
fungi, but its clinical utility in treating infections
with these organisms has not yet been established. It is
used most commonly in the treatment of onychomycosis;
in this setting, terbinafine is superior to griseofulvin
and at least equivalent to itraconazole.When given systemically,
terbinafine is 99% protein bound and accumulates
in fat, skin, and nails, persisting for weeks.
Cerebrospinal fluid penetration is less than 10%.
Dosage reductions are required with renal or hepatic
insufficiency. Although terbinafine has little effect on
hepatic cytochrome P450 enzyme systems, it does minimally
enhance cyclosporine clearance. Oral terbinafine
is generally well tolerated but occasionally causes gastric
distress and liver enzyme elevation.
Side effects
Adverse reactions include lens and retinal disturbances (red/green visual
perception), metallic taste disturbance that may last up to 4 weeks after
medication discontinuation, hepatoxicity, and pancytopenia. Five percent of
patients will experience delayed gastric emptying with symptoms of nausea,
fullness, and/or dyspepsia. Terbinafine does not appear to have any effect on
the cytochrome P-450 systems (Check baseline CBC and LFTs; repeat if taken
for >6 weeks).
Synthesis
Terbinafine is produced from olefin metathesis of 1,3-dichloropropene and neohexene followed by reaction with N-methyl-1-naphthalenemethanamine.
Veterinary Drugs and Treatments
Terbinafine may be useful for treating dermatophytic and other
fungal infections in dogs and cats.
Terbinafine may also be useful for treating birds for systemic
mycotic (e.g., aspergillosis) infections.
