Terbinafine

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

Terbinafine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Originator

  Lamisil,Novartis,UK

• Verwenden

  Terbinafine (Lamisil) is a second-generation allylamine that is related to naftifine; however, it is 10 to 100 times more potent in vitro. It is fungicidal, whereas griseofulvin, ketoconazole, itraconazole, and other azole derivatives are all fungistatic. Because it is fungicidal, duration of therapy is shorter, and relapse rates are less than with other oral or topical therapies. Terbinafine acts by inhibiting squalene epoxidase and thereby decreasing synthesis of ergosterol, an essential component of fungal cell membranes. It is highly lipophilic and concentrates in the stratum corneum, sebum, and hair follicles. Slightly better cure rates are attained with b.i.d. than with daily dosing.
  

• Definition

  ChEBI: A tertiary amine that is N-methyl-1-naphthalenemethylamine in which the amino hydrogen is replaced by a 3-(tertbutylethynyl)allyl group. An antifungal agent administered orally (generally as the hydrochloride salt) for the t eatment of skin and nail infections.

• Indications

  Terbinafine (Lamisil) is a second-generation allylamine that is related to naftifine; however, it is 10 to 100 times more potent in vitro. It is fungicidal, whereas griseofulvin, ketoconazole, itraconazole, and other azole derivatives are all fungistatic. Because it is fungicidal, duration of therapy is shorter, and relapse rates are less than with other oral or topical therapies.
  Terbinafine acts by inhibiting squalene epoxidase and thereby decreasing synthesis of ergosterol, an essential component of fungal cell membranes. It is highly lipophilic and concentrates in the stratum corneum, sebum, and hair follicles. Slightly better cure rates are attained with b.i.d. than with daily dosing.

• Manufacturing Process

  To an ice-cooled solution of N-methyl-1-naphthalenemethylamine hydrochloride (2.1 g) in methanol (40 ml) and water (10 ml) was added sodium hydroxide powder (2 g) followed by dropwise addition of epichlorohydrin (8 ml). The mixture was heated at 60°C for 3 h, then cooled to room temperature. Volatile materials were removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic phase was collected, dried over sodium sulfate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 A) using a solvent gradient of a mixture of hexane and ethyl acetate (95:5, 90:10 and 85:15) as eluent, affording the N-methyl-N-naphthylmethyl-2,3-epoxypropane (1.85 g, 81.5%) as an oil.
  To a solution of 3,3-dimethylbutyne (2.95 ml) in dry THF (50 ml) at -78°C was added a 2.5 M solution of n-BuLi in hexane (10 ml) dropwise. The mixture was allowed to warm to room temperature over 15 min and stirred at that temparature for a further 15 min, then was cooled back to -78°C and BF3OEt2 (3 ml) was added dropwise. The mixture was stirred for 15 min and 1.8 g of N-methyl-N-naphthylmethyl-2,3-epoxypropane, dissolved in THF (10 ml), was added dropwise. After stirring at -78°C for 2 h, saturated sodium bicarbonate solution (15 ml) was added, and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2 times 25 ml), and the combined organic fractions was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 a) using a mixture of hexane and ethyl acetate (85:15) as eluent, thereby affording the N-methyl-N-(1-naphthylmethyl)-2-hydroxy-heptan-4-ynyl-1-amine as an oil (1.95 g, 79%).
  To an ice-cooled solution of N-methyl-N-(1-naphthylmethyl)-2-hydroxyheptan- 4-ynyl-1-amine (155 mg) in THF (10 ml) was added Et3N (0.35 ml) followed by methanesulfonyl chloride (0.075 ml). The resulting mixture was stirred at 0°C for 3 h, then filtered. The filtrate was concentrated in vacuo, dissolved in toluene (10 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.37 ml) was added. The resulting mixture was heated at 80°C for 4 h, cooled to room temperature then poured onto a silica gel column and eluted with hexane (100%) followed by a mixture of hexane and ethyl acetate (95:5). Thus, a mixture of E- and Z-isomers of N-methyl-N-(1- naphthylmethyl)-6,6-dimethylhept-2-en-4-ynyl)-1-amine were obtained in a ratio of 2:5 (95 mg, 66%).

• Therapeutic Function

  Antifungal

• Synthesis Reference(s)

  Tetrahedron Letters, 29, p. 1509, 1988 DOI: 10.1016/S0040-4039(00)80338-X

• Antimicrobial activity

  Terbinafine is active against a wide range of pathogenic fungi, including dermatophytes (Epidermophyton, Microsporum and Trichophyton spp.), various Candida spp., Aspergillus spp., some dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum and Sporothrix schenckii) and many dematiaceous fungi.

• Acquired resistance

  Resistance has not been reported.

• Pharmazeutische Anwendungen

  A synthetic allylamine available as the hydrochloride for oral and topical administration.

• Pharmakokinetik

  Oral absorption: 70–80%
  C_max 250 mg oral: c. 1 mg/L after 2 h
  Plasma half-life: c. 17 h
  Volume of distribution: 1000 L
  Plasma protein binding: >99%
  Blood concentrations increase in proportion to dosage. It is lipophilic and is rapidly and extensively distributed to body tissues. It reaches the stratum corneum by diffusion through the dermis and epidermis, and secretion in sebum. Diffusion from the nail bed is the major factor in its rapid penetration of nails. It is metabolized by the liver and the inactive metabolites are mostly excreted in the urine. The elimination half-life is prolonged in patients with hepatic or renal impairment.

• Clinical Use

  Terbinafine hydrochloride can be used in Tinea pedis, tinea corporis, tinea cruris, tinea capitis, Onychomycosis caused by dermatophytes.

• Nebenwirkungen

  These include abdominal discomfort, loss of appetite, nausea, diarrhea, headache, impairment of taste, rash and urticaria. Serious skin reactions, including Stevens– Johnson syndrome, and rare hepatotoxic reactions, including jaundice, cholestasis and hepatitis, are occasionally encountered.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antibacterials: concentration reduced by rifampicin.

• Stoffwechsel

  Terbinafine undergoes extensive first pass loss. It is hepatically metabolised to two major inactive metabolites, 80% of which are renally excreted.

Terbinafine Upstream-Materialien And Downstream Produkte

Terbinafine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(323)Suppliers

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