Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-21
2004-03-23
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S384000, C544S366000, C548S263400, C548S263800, C548S264600
Reexamination Certificate
active
06710049
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the derivatives of specially substituted azole compounds which have improved antifungal activity as compared with presently available agents in this class and the processes for the preparation thereof. This invention also relates to pharmaceutical preparations containing the compounds of the present invention and their use in treating and/or preventing the fungal infections in mammals, preferably humans.
BACKGROUND OF THE INVENTION
Life threatening, systemic fungal infections continue to be a significant problem in health care today. In particular, patients who become “immunocompromised” as a result of diabetes, cancer, prolonged steroid therapy, organ transplantation anti-rejection therapy, the acquired immune deficiency syndrome (AIDS) or other physiologically or immunologically comprising syndromes, are especially susceptible to opportunistic fungal infections.
Since the 1950s and 1960s and until recently, the key opportunistic fungal pathogens with which clinicians had to contend were
Candida albicans, Asperigillus fumigatus
, and the zygomiycetes, which cause mucormycosis, a rapidly fatal infection especially in diabetic patients. Today, non-albicans Candida have become more frequent, as have other Aspergillus species. Candida species are now the fourth most common cause of nosocomial blood stream infection and they are associated with an extremely high mortality rate of 40%. From 1980 to 1990, the incidence of fungal infections in the US hospitals nearly doubled, from 2.0 to 3.8% of patients discharged. The most marked increase in fungal infection rates occurred not only in transplant units or oncology centers, but also in surgical services. These changing patterns demonstrate that fungal infections are no longer limited to the most severly immunosuppressed patients.
During the past two decades, a substantial shift in the epidemiology of candidemia due to different Candida species has occurred. In the 1960s and 1970s,
Candida albicans
accounted for 85-90% of cases of candidemia. In 1999, however, only 42% of candidemia cases were caused by
C. alibicans
, while non-albicans candida accounted for the remainder.
Cryptococosis is a leading cause of morbidity among AIDS patients. The incidence of life threatening cryptococcal infection among these patients have been estimated to vary from 10 to 30%. During initial therapy, 10-20% of these patients die and 30 to 60% patients succumb within a year.
Penicillinium marneffei
has been frequently isolated from HIV+ patients, especially in Southeast Asia.
The most common causative agent of mucormycosis is rhizopus, a common bread mould that lives on any organic material. Other pathogens include Mucor, Rhizomucor and Absidia. Zygomycetes include twenty different fungi, all appearing the same histologically. The severely immunocompromised patient may become infected with zygomycetes via respiratory inhalation.
Fusarium is the most prevalent plant fungus worldwide, and it is now recognized as human pathogen as well. Fusarium infections can occur in immunocompetent or immuno suppressed individuals. Fusarium infection is life-threatening and associated with a poor prognosis.
Penicillium marneffei
is an environmental fungi that can cause serious, life-threatening infections in immunosuppressed patients.
Penicillium marneffei
has gained particular attention during the AIDS pandemic, as it may produce disease that is clinically indistinugishable from disseminated histoplasmosis.
Invasive aspergillosis has also become a leading cause of death, mainly among patients suffering from acute leukaemia or after allogenic bone marrow transfusion and after cytotoxic treatment of these conditions. It also occurs in patients with condition such as AIDS and chronic granulomatous disease. At present, only Amphotericin B and itraconazole are available for treatment of aspergillosis. Inspite of their activity in-vitro, the effect of these drugs in-vivo against
Aspergillus fumigatus
remains low and as a consequence mortality from invasive aspergillosis remains high.
Over the last three decades important progress has been made in the therapy of systematic fungal infections. Although chemotherapeutic agents such as flucytosine and potassium iodide are effective against selected fungal diseases, the primary drugs used to treat systemic mycoses are amphotericin B and the azole compounds. Despite the general effectiveness of amphotericin B, it is associated with a number of complications and unique toxicities that limit its use. Furthermore, the drug is poorly absorbed from the gastrointestinal tract necessitating intravenous administration. In addition, amphotericin B penetrates poorly into cerebrospinal fluid (CSF) of both normal and inflamed meninges.
The problems associated with amphotericin B have stimulated search for new agents. Within the available drugs to treat fungal infections, the azole class appears to be most promising. This class of compounds inhibits the biosynthesis of ergosterol in fungi, which is the main constituent of fungal cell membrane. Of the various representative antifungals, early azoles used were clotrimazole, miconazole, and tioconazole, which were potent against a wide range of fungi pathogenic to human. Clortrimazole was the first oral azole proven to be effective in experimental and human mycosis. However, brief courses of treatment with clotrimazole lead to the induction of liver microsomal enzymes which in turn increase the metabolism of the drug, thereby diminishing its antifungal activity. In contrast, miconazole, which became available around the same time as clotrimazole, is not rapidly metabolized and is an effective intravenous therapy for many systemic fungal diseases. Unfortunately, the use of miconazole is limited by its multiple toxic effects.
The in-vitro activity of clotrimazole, miconazole and tioconazole was not well exhibited in in-vivo models due to poor oral bioavailability and metabolic vulnerability. Ketoconazole was the first drug that could be used against systemic fungal infection and successfully delivered through oral route. However, it was still quite susceptible to metabolic inactivation and also caused impotence and gynacomastia probably due to its activity against human cytochrome P450 enzymes.
Even with the advent of ketoconazole, the search for improved antifungal azole agents has continued due in part to concerns over the potential for toxicity and poor penetration into cerebrospinal fluid (CSF) associated with ketoconazole. Several azoles have been developed as topical agents primarily directed at superficial candidal and dermatophytic infections.
Fluconazole is the current drug of choice for treatment of severe infections caused by Candida species and
C.neoformans
. However, fluconazole has only weak activity against isolates of Aspergillus species [minimum inhibitory concentration (MIC) values of 400 &mgr;g/ml], since the drug has low potency (IC
50
=4.8 &mgr;M) against lanosterol 14&agr;-de-methylase, the target enzyme in the fungus. Itraconazole, another triazole antifungal compound, generally is more active than fluconazole in the treatment of aspergillosis, but its activity in the clinic remains mixed as it showed variable oral availability, low solubility and very high protein binding besides causing ovarian cancer in animals.
The development of the earlier compounds which included SCH 39304 (Genoconazole), SCH 42427 (Saperaconazole) and BAY R 8783 (Electrazole) had to be discontinued as a result of safety concerns. Another promising triazole, D0870, a derivative of fluconazole, exhibited significant variations in plasma pharmacokinetics besides having weak anti-Aspergillus activity. Other fluconazole derivatives in different stages of development include Voriconazole and ER 30346 (BMS 207147). Voriconazole also shows non-linear pharmacokinetics besides some concern regarding its ocular toxicity. ER 30346's anti-aspergillus activity, both in-vitro and in-vivo, is at best, only equal to itraconaz
Katoch Rita
Rattan Ashok
Salman Mohammed
Sattigeri Jitendra
Verma Ashwani Kumar
Bernhardt Emily
Deshmukh Esq. Jayadeep R.
Heibel Esq. George E.
Ranbaxy Laboratories Limited
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