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Tioconazole UK-20349 an antifungal agent

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Tioconazole;UK-20349;Trosyd;Trosyl;Vagistat-1

l-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole,

1-[2-(2-Chloro-3-thienylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

65899-73-2

Launched – 1983, Bristol-Myers Squibb

Trademarks: Fungibacid (Asche); Gyno-Trosyd (Pfizer); Trosyd (Pfizer); Trosyl (Pfizer); Vagistat (BMS); Zoniden (Irbi)
Molecular Formula: C16H13Cl3N2OS
Molecular Weight: 387.71
Percent Composition: C 49.57%, H 3.38%, Cl 27.43%, N 7.23%, O 4.13%, S 8.27%
Derivative Type: Hydrochloride
Molecular Formula: C16H13Cl3N2OS.HCl
Molecular Weight: 424.17
Percent Composition: C 45.31%, H 3.33%, Cl 33.43%, N 6.60%, O 3.77%, S 7.56%
Properties: Crystals, mp 168-170°.
Melting point: mp 168-170°
Therap-Cat: Antifungal (topical).

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.[1]They are available in one day doses, as opposed to the 7-day treatments more common in use in the past.

Tioconazole topical (skin) preparations are also available for ringworm, jock itch, athlete’s foot, and tinea versicolor or “sun fungus”.

 

 

Side effects

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.

Tioconazole
Tioconazole.svg
Systematic (IUPAC) name
(RS)-1-[2-[(2-Chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
Clinical data
Trade names Vagistat-1
AHFS/Drugs.com monograph
Legal status
Routes Topical
Identifiers
CAS number 65899-73-2 Yes
ATC code D01AC07 G01AF08
PubChem CID 5482
DrugBank DB01007
KEGG D00890 Yes
Synonyms Thioconazole
Chemical data
Formula C16H13Cl3N2OS 
Mol. mass 387.711 g/mol

 

 

http://www.google.com/patents/EP0934279A1?cl=en

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

Figure imgf000003_0001

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

X-(CH2)η-Y

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

http://www.google.com/patents/US4062966

………………………….

References

  1.  Tioconazole, Mayo Clinic
  2. References1:

    Gymer, G.E.; DE 2619381 .

    References2:

    Hillier, K.; Blancafort, P.; Castaner, J.; Serradell, M.N.; Tioconazole. Drugs Fut 1980, 5, 10, 509.

  3. 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
  4. 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
  5. 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

 

Literature References:

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).

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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