Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-06-20
1998-01-13
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
5142362, 514252, 544121, 544357, 544337, 544364, 544366, 544370, A61K 31495, A61K 31675, C07D40514, C07F 96558
Patent
active
057079773
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with novel water-soluble broad-spectrum azole antifungals as well as the antifungally active precursors thereof.
Systemic fungal infections in man are relatively rare in temperate countries and many of the fungi that can become pathogenic normally live commensally in the body or are common in the environment. However, the past few decades have witnessed an increasing incidence of numerous life-threatening systemic fungal infections world-wide and these now represent a major threat to many susceptible patients, particularly those already hospitalized. Most of the increase can be attributed to improved survival of immunocompromised patients and the chronic use of antimicrobial agents. Moreover, the flora typical of many common fungal infections is also changing and this is presenting an epidemiological challenge of increasing importance. Patients at greatest risk include those with impaired immune functioning, either directly as a result of immunosuppression from cytotoxic drugs or HIV infection, or secondary to other debilitating diseases such as cancer, acute leukaemia, invasive surgical techniques or prolonged exposure to anti-microbial agents. The most common systemic fungal infections in man are candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis.
Antifungals such as ketoconazole, itraconazole and fluconazole are being increasingly employed for the treatment and prophylaxis of systemic fungal infections in immunocompromised patients. However, concern about fungal resistance to some of these agents, especially the more narrow spectrum ones, e.g. fluconazole, is growing. Worse still, it is recognized in the medical world that about 40% of the people suffering from severe systemic fungal infections are hardly able, or not at all to receive medication via oral administration. This inability is due to the fact that such patients are in coma or suffer from severe gastroparesis. Hence the use of insoluble or sparingly soluble antifungals such as itraconazole or saperconazole, that are difficult to administer intravenously, is heavily impeded.
Consequently, there is a need for new antifungals, preferably broad-spectrum antifungals, against which there is no existing resistance and which can be administered intravenously. Preferably the antifungal should also be available in a pharmaceutical composition suitable for oral administration. This enables the physician to continue treatment with the same drug after the patient has recovered from his condition which required intravenous administration of said drug. (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazo les and 1H-1,2,4-triazoles useful as antifungal and antibacterial agents. Said patent encompasses itraconazole, which is now available as a broadspectrum antifungal on a world-wide basis. hoxy!phenyl!-1-piperazinyl!phenyl!triazolones having improved antimicrobial properties. Said patent encompasses saperconazole. -imidazoles and 1H-1,2,4-triazoles, structurally related to some of the compounds of the present invention, which are taught to have favourable anti-microbial properties. tetrahydrofurans, structurally related to some of the compounds of the present invention, which are taught to have antifungal activity and EP-0,539,938 teaches analogous trisubstituted tetrahydrofuran antifungals.
The present invention concerns novel compounds of formula ##STR4## the pharmaceutically acceptable acid or base addition salts thereof and the stereochemically isomeric forms thereof, wherein a C.sub.1-6 -alkyl-radical and up to two hydrogen atoms in radical (c), (d), (e) or (f) may be replaced by a C.sub.1-6 -alkyl-radical; ##STR5## L is a radical of formula ##STR6## Alk is a C.sub.1-4 alkanediyl radical; R.sup.1 is halo; attached form a pyrrolidine, piperidine, morpholine, piperazine or substituted piperazine ring, said substituted piperazine being a piperazine ring substituted on the 4-position of the piperazine ring with C.sub.1-6 alkyl, hydro
REFERENCES:
patent: 4267179 (1981-05-01), Heeres et al.
patent: 4791111 (1988-12-01), Heeres et al.
patent: 5039676 (1991-08-01), Saksena et al.
Backx Leo Jacobus Jozef
Heeres Jan
Mesens Jean Louis
Odds Frank Christopher
Van der Eycken Luc Alfons Leo
Bernhardt Emily
Janssen Pharmaceutica N.V.
Metz Charles J.
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