Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-22
2003-12-30
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254010, C514S254050, C514S227800, C514S235800, C514S252110, C514S254070, C544S058500, C544S121000, C544S357000, C544S369000, C544S370000, C544S366000, C548S267800, C548S313700
Reexamination Certificate
active
06670363
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the derivatives of specially substituted azole compounds which have improved antifungal activity as compared to known compounds such as fluconazole and itraconazole and the processes for the preparation thereof. This invention also relates to pharmaceutical compositions containing the compounds of the present invention and their use in treating and/or preventing 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 “immuno-compromised: as a result of diabetes, cancer, prolonged steroid therapy, organ transplantation antirejection therapy, the acquired immune deficiency syndrome (AIDS) or other physiologically or immunologically compromising syndromes, are especially susceptible to opportunistic fungal infections. Most of these infections are caused by opportunistic pathogens, like species of Candida and Aspergillus and
Cryptococcus neoformans
. During the last 20 years, the incidence of sepsis fungal infection caused by candida species has increased significantly in debilitated and immuno-compromised patients. In addition, the more aggressive and frequently used broad spectrum antibiotic, antineoplastic and immunosuppressive chemotherapies have also augmented fungal infections.
Cryptococcosis 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 to 20% of these patients die and 30 to 60% patients succumb within a year. Amphoteracin B has changed disseminated cryptococcosis from uniformly fatal infection to curable infection but since Amphoteracin B penetrates the central nervous system poorly, interventricular AID injection may have to be administered for successful management of severe cases of patients with cryptococcal meningitis. 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 Amphoteracin 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.
In addition, the emergence of fluconazole-resistant isolates of pathogenic yeasts, particularly in HIV-positive patients, and the general nature of treating fungal infections caused by Aspergillus species, are of growing concerns among infections disease specialists. The precise incidence of infections caused by Aspergillus species is difficult to determine due to lack of accurate, reliable diagnostic methodologies and poor diagnosis. The majority of Aspergillus infections in AIDS patients occur in late stage disease when immune cell functions are minimal. Impaired neutrophil and macrophage function is related to increased infection rates with Aspergillus species. The most common species of Aspergillus causing disease in AIDS patients are
A. fumigatus
(83%),
A. flavus
(9%),
A. niger
(5%) and
A. terreus
(3%).
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 miconazole, clotrimazole and tioconazole, which were potent against a wide range of fungi pathogenic to human. However, their in-vitro activity 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.
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;—demethylase, 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 caused ovarian cancer in animals. This may be due to its high protein binding properties.
Thus, the antifungals available in the market suffer with drawbacks such as, toxicity, narrow spectrum of activity and fungistatic profile rather fungicidal. Some of them also exhibit drug-drug interactions and, as a result, therapy becomes very complex. In view of the high incidence of fungal infections in immunocompromised patients and the recent trends for the steady increase of the populations of such patients, demands for new antifungal agents with broad spectrum of activity and good pharmacokinetic properties has increased. Thus, the continuing demand for safe and effective broad spectrum antifungal agent with favourable pharmacokinetic properties has spurred both the design and development of new systemically active antifungal triazoles. The development of earlier compounds which were referred to as second generation triazoles and which included SCH 39304 (Genaconazole), SCH42427 (Saperaconazole) and BAY R 8783 (Electrazole) had to be discontinued as a result of safety concerns. Another promising second generation triazole, D0870, a derivative of fluconazole, exhibited significant variations in plasma pharmacokinetics besides having weak antiaspergillus 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, while ER 30346's anti-aspergillus activity, both in vitro and in vivo, is at best, only equal to itraconazole's activity. SCH 56592, is a hydroxylated analogue of itraconazole with potent in-vitro and in-vivo activity, but is undetectable even when the serum drug concentration after several days of treatment are 25 to 100 times above the MIC for the most resistant
C. neoformans
. Thus, the potent activity of SCH 56592 for
C.neoformans
is partially negated by its low concentration at the site of infection to the central nervous system. The above azole candidates are discussed in the following publications: SCH 56592
; Antimicrob. Agents Chemother
, 40, 1910 (1996); 36
th
Interscience conference Antimicrob Agents Chemother, September, 1996, New Orleans, Abst. F87-F102; TAK-187; 36
th
Interscience conference
Antimicrob Aqents Chemother
, September, 1996, New Orleans, Abst. F74; EP 567892; ER-30346
: Drugs of the Future
, 21, 20 (1996).
Various compounds having thiol, sulphone, sulphonamides, N-di-substituted sulphonamides, triazoles and tetrazoles of the second asymmetric centre of fluconazole with various side chains have been covered in U.S. Pat. Nos. 5,466,820; 5,371,181 and 5,371,101 assigned to Takeda. But none of them satisfies the above-described medical needs completely, either being weak in spectrum, potency, safety or having undesired pharmacokinetics.
Despite the therapeutic success of fluconazole and itraconazole, there remains a significant need for improved, broad spectrum, better tolerated, less toxic, more potent antifungal compounds with minimal potential for development of resistance among target fungi.
SUMMARY OF THE INVENTION
The p
Arora Jasbir Singh
Arora Sudershan K.
Rattan Ashok
Verma Ashwani Kumar
Deshmukh Jayadeep R.
Hare William
Heibel George E.
Ranbaxy Laboratories Limited
Shah Mukund J.
LandOfFree
Azole compounds as therapeutic agents for fungal infections does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Azole compounds as therapeutic agents for fungal infections, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Azole compounds as therapeutic agents for fungal infections will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3167620