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"Process For The Synthesis Of New Triazole Compounds As Therapeutic Agents For Fungal Infections"

Abstract: A process for the synthesis of new triazole compounds as therapeutic agents for fungal infections having improved antifungal activity as compared with bluconazole and itraconazole.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
05 May 2003
Publication Number
15/2010
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

RANBAXY LABORATORIES LIMITED
19, NEHRU PLACE, NEW DELHI-110019, INDIA.

Inventors

1. ASHWANI KUMAR VERMA
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122002, HARYANA, INDIA.
2. SUDERSHAN KUMAR ARORA
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122002, HARYANA, INDIA.
3. JASBIR SINGH ARORA
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122002, HARYANA, INDIA.
4. ASHOK RATTAN
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122002, HARYANA, INDIA.

Specification

The present invention relates to a process for the synthesis of new triazole compounds of Formula lA, as shown in the accompanied drawings, as therapeutic agents for fungal infection having improved antifungal activity as compared with bluconazole and itraconazole. 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. 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 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 i^g/ml], since the drug has low potency (IC50 = 4.8 i^M) against lanosterol 14a - 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 pharmacol

Documents

Application Documents

# Name Date
1 671-del-2003-abstract.pdf 2011-08-21
1 671-del-2003-form-3.pdf 2011-08-21
2 671-del-2003-claims.pdf 2011-08-21
2 671-del-2003-form-2.pdf 2011-08-21
3 671-del-2003-correspondence-others.pdf 2011-08-21
3 671-del-2003-form-19.pdf 2011-08-21
4 671-del-2003-correspondence-po.pdf 2011-08-21
4 671-del-2003-form-1.pdf 2011-08-21
5 671-del-2003-drawings.pdf 2011-08-21
5 671-del-2003-description (complete).pdf 2011-08-21
6 671-del-2003-description (complete).pdf 2011-08-21
6 671-del-2003-drawings.pdf 2011-08-21
7 671-del-2003-correspondence-po.pdf 2011-08-21
7 671-del-2003-form-1.pdf 2011-08-21
8 671-del-2003-correspondence-others.pdf 2011-08-21
8 671-del-2003-form-19.pdf 2011-08-21
9 671-del-2003-claims.pdf 2011-08-21
9 671-del-2003-form-2.pdf 2011-08-21
10 671-del-2003-form-3.pdf 2011-08-21
10 671-del-2003-abstract.pdf 2011-08-21