Terconazol

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

  H413：Kann für Wasserorganismen schädlich sein, mit langfristiger Wirkung.

• 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.

Terconazole Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Terconazole is an antifungal agent somewhat more potent than clotrimazole and useful in the topical treatment of vaginal dermatophytosis and candidiasis.

• Beschreibung

  Terconazole is an orally bioavailable broad-spectrum triazole antifungal agent that completely inhibits growth of T. rubrum, M. audouini, M. canis, and T. verrucosum, as well as some C. albicans and A. fumigatus strains and other fungi when used at a concentration of 100 μg/ml. It also has bacteriostatic activity against E. coli, P. aeruginosa, S. aureus, and S. pyogenes when used at a concentration of 100 μg/ml. Terconazole eliminates vaginal C. albicans candidiasis infection in 97% of rats when administered as a 1% topical ointment and in 50% of rats when orally administered at a dose of 10 mg/kg. It inhibits cytochrome P450 (CYP) isoforms involved in ergosterol biosynthesis, interfering with fungal cell membranes. It decreases synthesis of 14α-desmethyl sterols and increases synthesis of methylated sterols in C. albicans (IC₅₀ = 3 nM). Formulations containing terconazole have been used in the treatment of candidiasis of the vulva and vagina.

• Chemische Eigenschaften

  White or almost white powder.

• Originator

  Janssen (Belgium)

• Verwenden

  Terazol (Ortho-McNeil).

• Verwenden

  Terconazole belongs to a new chemical class of antifungal agents, the triazoles. Terconazole has a far greater selectively for yeast cytochrome P-450 than for mammalian microsomal cytochrome P-450 and is used as topical treatment of mycotic vaginitis. Terconazole may also be used in vitro as a potent antifungal agent to prevent the morphogenetic transformation of yeast into (pseudo-)mycelium form of Candida albicans.

• Indications

  Terconazole (Terazol) is a fungicidal triazole topical preparation effective against many Candida strains. It is used as either a 3-day or a 7-day course (Terazol 7—0.4% cream for 7 days or Terazol 3—0.8% cream for 3 days).

• Definition

  ChEBI: (2R,4S)-terconazole is a 1-(4-{[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-4-isopropylpiperazine in which positions 2 and 4 of the 1,3-dioxolane moiety have R and S configuration, respectively. It is an enantiomer of a (2S,4R)-terconazole.

• Manufacturing Process

  A mixture of 1.6 parts of 1H-1,2,4-triazole, 54 parts of N.Ndimethylformamide and 45 parts of benzene is stirred and refluxed for 2 h. After cooling, 0.78 parts of sodium hydride dispersion 78% are added and the whole is stirred for 30 min at room temperature. Then there are added 8.9 parts of cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethyl benzoate and stirring is continued overnight at 150°C. The reaction mixture is cooled and poured onto water. The product is extracted three times with benzene. The combined extracts are washed twice with water, dried, filtered and evaporated, yielding 8.5 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4- triazol- 1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate as a residue.
  A mixture of 289 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate, 200 parts of sodium hydroxide solution 50%, 1500 parts of 1,4-dioxane and 300 parts of water is stirred and refiuxed for 2 h. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The first fraction is collected and the eluent is evaporated, yielding 89 parts cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4- triazol-1-ylmethyl)-1,3-dioxolane-4-methanol; melting point 138.2°C.
  A mixture of 30.6 parts of cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-l,3-dioxolane-4-methanol and 75 parts of pyridine is stirred at room temperature and there are added dropwise 17.2 parts of methanesulfonyl chloride. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto ice-water and the product is extracted twice with dichloromethane. The combined extracts are washed twice with a diluted hydrochloric acid solution and twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The first fraction is collected and the eluent is evaporated, yielding 21 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate; melting point 98°C.
  A mixture of 1-(4-hydroxyphenyl)-4-(1-methylethyl)piperazine, cis-[2-(2,4- dichloro-phenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4- ylmethyl]methanesulfonate, potassium carbonate and N,N-dimethylformamide is stirred and heated overnight at 120°C. The reaction mixture is cooled and poured onto water. The product is extracted twice with dichloromethane. The combined extracts are washed twice with a potassium carbonate solution, dried, filtered and evaporated. The residue is taken up in methanol and a sodium methanolate solution 30% are added. The whole is stirred and refluxed for 1 h. The mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The cis-1-(4- ((2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4- yl)methoxy)phenyl)-4-(1-methylethyl)piperazine was obtained, melting point 116.3°C.

• Trademarks

  Gyno-terazol;Terazol 3;Tercospor;FUNGISTAT.

• Therapeutic Function

  Antifungal

• Weltgesundheitsorganisation (WHO)

  Terconazole, an antifungal agent, was introduced into medicine in 1980. It is indicated for the treatment of vaginal candidiasis. It is not yet clear whether the adverse effects associated with high dose formulations are due to terconazole itself, to an excipient in the preparation or to fungal constituent.

• Mechanism of action

  Terconazole is effective for fungistatic action for many strains of Candida and dermatophytes. The exact mechanism of its action is unknown, although it inhibits the action of the enzyme lanosterol 1-demethylase of cytochrome P-450 of sensitive fungi (similar to other azols described above), causing a reduction in the amount of ergosterin, which is necessary for the organisms to construct membranes and to retain the appropriate permeability. It is only used externally for treating vulvovaginal candidoses. Synonyms of this drug are terazol, tercospor, and others.

• Clinical Use

  cis-1-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy]phenyl]-4-(1methylethyl)piperazine (Terazol), or terconazole, is a triazolederivative that is used exclusively for the control ofvulvovaginal moniliasis caused by C. albicans and otherCandida species. It is available in creams containing 0.4%and 0.8% of the free base intended for 7-day and 3-day treatmentperiods, respectively. Suppositories containing 80 mgof the free base are also available.

• Synthese

  Terconazole, 1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)- 1,3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)-piperazine (35.2.19), is chemically very similar to ketoconazole, the only difference being that instead of an imidazole ring it contains a triazole ring and the piperazine ring, instead of an acetyl group is substituted by an isopropyl group. It is synthesized from 2,4-dichloroacetophenone, which is reacted with glycerol in the presence of p-toluenesulfonic acid to make a ketal, 2-(2,4-dichlorophenyl)- 2-methyl-4-hydroxymethyl-1,3-dioxolane (35.2.13). Brominating this with molecular bromine at the methyl group and then acylating the free hydroxyl group with benzoyl chloride gives 2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (35.2.14). Reacting this with 1,2,4-triazole in the presence of sodium, followed by the hydrolysis of the protecting benzoyl group with sodium hydroxide gives 2-(2,4- dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (35.2.15). Treating this with methanesulfonyl chloride gives the corresponding mesylate 35.2.16.
  
  The way of making the second necessary fragment, 1-isopropyl-4-(4-hydroxyphenyl)- piperazine (35.2.18) is started from 4-(4-methoxyphenylpiperazine). Reducing this with hydrogen in the presence of acetone and using a palladium on carbon catalyst gives 1- isopropyl-4-(4-methoxyphenyl)piperazine (35.2.17). Treating of the resulting product with concentrated hydrobromic acid removes the protection from the phenol hydroxyl, making 1-isopropyl-4-(4-hydroxyphenyl)piperazine (35.2.18).
  
  Finally, reacting the mesylate (35.2.16) with the resulting 1-isopropyl-4-(4-hydroxyphenyl)piperazine (35.2.18) gives the desired terconazole.
  

Terconazole Upstream-Materialien And Downstream Produkte

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