Launched – 1983, Bristol-Myers Squibb
Tioconazole is an antifungal medication of the imidazole class used to treat infections caused by a fungus or yeast. It is marketed under the brand names Trosyd and Gyno-Trosyd (Pfizer). Tioconazole ointments serve to treat women’s vaginal yeast infections.They are available in one day doses, as opposed to the 7-day treatments more common in use in the past.
Side effects (for the women’s formulas) may include temporary burning/irritation of the vaginal area, moderate drowsiness, headachesimilar to a sinus headache, hives, and upper respiratory infection. These side effects may be only temporary, and do not normally interfere with the patient’s comfort enough to outweigh the end result.
|Systematic (IUPAC) name|
|ATC code||D01 G01|
|Mol. mass||387.711 g/mol|
Imidazole derivatives, in particular, l-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole, commonly referred to as tioconazole, are known for their antifungal therapeutic properties. US 4,062,966 discloses a process for the preparation of l-aryl-2-(l -imidazolyl) alkyl ethers and thioethers which employs arylation of an appropriate 1 -aryl-2-(l -imidazolyl)alkanol or alkane thiol having the formula
wherein Rl to R4 are each H or C,^ alkyl, Ar is phenyl, or substituted phenyl wherein said substitutents are halogen, C,^ alkyl, C,_6 alkoxy, thienyl, or halothienyl, and, Z is oxygen or sulfur. In accordance with US’966, the reaction comprises converting the alcohol or thiol in a suitable solvent to its alkali metal derivative by treatment with a strong base, such as an alkali metal amide or hydride, and reacting with the appropriate aralkyl halide ofthe formula
where n is 1 or 2, Y is an aromatic heterocyclic group or substituted heterocyclic group, wherein substitutents are halogen, C,.6 alkyl, or C,.6 alkoxy atoms, thienyl or halothienyl group, and X is a halogen, preferably chlorine. Tetrahydrofuran (THF) is the preferred solvent taught in US ‘966. Reaction temperatures may range from about 0 °C to reflux temperature ofthe solvent and reaction times range from about 1 hour to about 24 hours. The product is isolated with water, extracted with ether, and may be purified as the free base or converted to a salt, e.g. the hydrochloride, and purified by recrystallization. A disadvantage ofthe process disclosed in US ‘966 is that THF is a peroxide generator which presents the potential for an explosion. From a commercial viewpoint, peroxide generators are not preferred due to the dangers associated therewith.
GB 1 522 848 discloses a process for the preparation of imidazoles useful as antifungal agents involving a labor intensive, multi-sequence reaction of an imidazole ether with a reactive ester. Like US ‘966, THF is employed presenting similar concerns in the synthesis ofthe desired imidazole product.
According to the Pharmaceutical Manufacturing Encyclopedia, tioconazole is prepared by dissolving l-(2,4-dichlorophenyl)-2-(l- imidazolyl)ethanol in THF and sodium hydride and heating to about 70 βC. The resulting mixture is then contacted with 2-chloro-3- chloromethylthiophene and heated to reflux (about 67 CC). The resulting product is filtered, saturated with hydrogen chloride, triturated and recrystallized to obtain the purified tioconazole hydrochloride product having a melting point of about 170 βC. This salt must then be freebased to form the product used in pharmaceutical formulations. This route, like those discussed above, also presents the dangers of a potential explosion. There is thus a continuing need for a commercially viable, synthetic route for the production of imidazoles, in particular tioconazole.
see US 4062966
- Tioconazole, Mayo Clinic
Gymer, G.E.; DE 2619381 .References2:
Hillier, K.; Blancafort, P.; Castaner, J.; Serradell, M.N.; Tioconazole. Drugs Fut 1980, 5, 10, 509.
- Growth quantification and rapid drug susceptibility testing of uropathogenic Candida albicans by isothermal microcalorimetry
28th Congr Eur Assoc Urol (March 15-19, Milan) 2013, Abst 618
- Difference in percutaneous absorption and intracutaneous distribution in guinea pigs among topical antifungal drugs (tioconazole solution, tioconazole cream, miconazole nitrate solution and bifonazole solution)
Biol Pharm Bull 2004, 27(9): 1428
- A randomized comparison of the nail surface remainder of three nail lacquers containing amorolfine 5%, ciclopirox 8%, or tioconazole 28% in healthy volunteers
63rd Annu Meet Am Acad Dermatol (AAD) (February 18-22, New Orleans) 2005, Abst P1805
Antimycotic imidazole derivative. Prepn: G. E. Gymer, BE 841309; idem, (1976, 1977 both to Pfizer).
Antifungal spectrum: S. Jevons, Antimicrob. Agents Chemother. 15, 597 (1979); F. C. Odds, J. Antimicrob. Chemother. 6,749 (1980).
Pharmacology: M. S. Marriott et al., Dermatologica 166, Suppl. 1, 1 (l983).
Clinical trial in dermatomycosis: Y. M. Clayton et al., Clin. Exp. Dermatol. 7, 543 (1982). Series of articles on pharmacology and clinical efficacy in gynecological use:Gynak. Rundsch. 23, Suppl. 1, 1-60 (l983).