Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-07-10
2004-02-17
Weddington, Kevin E. (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C514S183000, C514S291000
Reexamination Certificate
active
06693189
ABSTRACT:
BACKGROUND OF THE INVENTION
Rapamycin is a macrolide antibiotic produced by
Streptomyces hygroscopicus
. It was first identified by its antifungal activity but has been more often studied as an immunosuppressive agent.
A large number of structural variants of rapamycin have been reported, typically arising as alternative fermentation products or from synthetic efforts to improve the compound's therapeutic index as an immunosuppressive agent. For example, the extensive literature on analogs, homologs, derivatives and other compounds related structurally to rapamycin (“rapalogs”) include among others variants of rapamycin having one or more of the following modifications relative to rapamycin: demethylation, elimination or replacement of the methoxy at C7, C42 and/or C29; elimination, derivatization or replacement of the hydroxy at C13, C43 and/or C28; reduction, elimination or derivatization of the ketone at C14, C24 and/or C30; replacement of the 6-membered pipecolate ring with a 5-membered prolyl ring; and alternative substitution on the cyclohexyl ring or replacement of the cyclohexyl ring with a substituted cyclopentyl ring. In nearly all cases, potent immunosuppressive activity is reported to accompany antifungal activity of the rapalogs. Additional historical information is presented in the background sections of U.S. Pat. Nos. 5,525,610; 5,310,903 and 5,362,718.
U.S. Pat. No. 5,527,907 is illustrative of the patent literature. That document discloses a series of compounds which were synthesized in an effort to make immunosuppressant rapalogs with reduced side effects. The compounds are disclosed via seven Markush structures, each followed by two to five or more columns of text listing possible substituents at various positions on the rapamycin ring. The document includes over 180 synthetic examples. The many variants of that invention were reported to be potent immunosuppressive agents.
While rapamycin is known to adversely affect the growth of fungi such as
Candida albicans
and
Microsporum gypseum
, its potent immunosuppressive activity renders it an unlikely candidate for use as an antifungal agent. Even some of the more recent patent documents such as WO 94102136 (SmithKline Beecham), WO 95116691 (Sandoz), U.S. Pat. No. 5,583,139 (Abbott) and U.S. Pat. No. 5,527,907 (Abbott), despite their extensive sets of structural modifications to rapamycin, fail to suggest even the possibility of reducing rapamycin's immunosuppressive activity without sacrificing its antifungal activity—let alone any structural approach for doing so—as would be desired or required in an antifungal agent. Indeed, the expectation that optimal response to any antifungal agent would require an active immune system in the treated patient appears to rule out the use of a rapalog. Thus it is not surprising that there are no known reports of the clinical development of rapamycin or a rapalog for treating or preventing infection by a pathogenic fungus in humans or other animals.
Meanwhile, although pathogenic fungi represent an increasing clinical challenge, existing antifungal agents are hampered by issues of efficacy, toxicity and the development and/or discovery of strains of pathogenic fungi that are resistant to drugs currently available or under development. By way of example, fungi that are pathogenic in humans include among others Candida spp. including
C. albicans, C. tropicalis, C. kefyr, C. krusei and C. galbrata
; Aspergillus spp. including
A. fumigatus
and
A. flavus; Cryptococcus neoformans
; Blastomyces spp. including
Blastomyces dermatitidis; Pneumocystis carinii; Coccidioides immitis; Basidiobolus ranarum
; Conidiobolus spp.;
Histoplasma capsulatum
; Rhizopus spp. including
R. oryzae
and
R. microsporus
; Cunninghamella spp.; Rhizomucor spp.;
Paracoccidioides brasiliensis; Pseudallescheria boydii; Rhinosporidium seeberi
; and
Sporothrix schenckii
[Kwon-Chung, K. J. and Bennett, J. E. (1992): Medical Mycology (Lea and Febiger, Malvern, Pa.)].
As described by Turner and Rodriguez, 1996
, Current Pharmaceutical Design,
2, 209-224:
The need for new antifungal agents has never been greater. Over the past ten years the incidence of life-threatening fungal infections has increased dramatically as the population of immunocompromised individuals including cancer, organ transplant, and AIDS patients has increased.
Also contributing to this risk is the increased use of broad-spectrum antibiotics, increased use of invasive medical techniques, and an aging patient population.
While there is little in the literature to suggest the feasibility of any pharmaceutical approach for harnessing the antifungal activity of rapamycin or the rapalogs, non-immunosuppressive derivatives of rapamycin that retain anti-fungal activity would be of great interest for the treatment or prevention of pathogenic fungal infection.
SUMMARY OF THE INVENTION
In a distinct departure from the extensive literature of rapalog investigations, including results from some of the world's leading pharmaceutical research organizations, this invention provides, inter alia, a method and materials for treating or preventing infection by a pathogenic fungus in a mammalian subject, particularly a human patient, by administering to the subject a rapalog—but without causing untoward immunosuppression. The method comprises administering to the subject a composition comprising an effective antifungal amount of a non-immunosuppressive antifungal rapalog.
From a pharmaceutical perspective, this invention provides a method for preventing or treating a pathogenic fungus in a subject which involves administering to the subject a composition comprising a sub-immunosuppressive amount of a rapalog, e.g., administering the rapalog in an amount and manner which provides the intended antifungal effect but fails to impart an untoward immunosuppressive effect. Preferably the rapalog is a non-immunosuppressive antifungal rapalog.
Important applications of this invention include, among others, the treatment or prevention of infection in a patient by a pathogenic fungus such as those listed above or referred to below.
One aspect of this invention is the treatment or prevention of infection in a patient by a pathogenic fungus which is resistant to one or more other antifungal agents, especially an agent other than rapamycin or a rapalog, including e.g. amphotericin B or analogs or derivatives thereof (including 14(s)-hydroxyamphotericin B methyl ester, the hydrazide of amphotericin B with 1-amino-4-methylpiperazine, and other derivatives) or other polyene macrolide antibiotics, including, e.g., nystatin, candicidin, pimaricin and natamycin; flucytosine; griseofulvin; echinocandins or aureobasidins, incluing naturally occurring and semi-synthetic analogs; dihydrobenzo[a]napthacenequinones; nucleoside peptide antifungals including the polyoxins and nikkomycins; allylamines such as naftifine and other squalene epoxidease inhibitors; and azoles, imidazoles and triazoles such as, e.g., clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, terconazole, itraconazole or fluconazole and the like. For additional conventional antifungal agents and new agents under deveopment, see e.g. Turner and Rodriguez, 1996, Recent Advances in the Medicinal Chemistry of Antifungal Agents,
Current Pharmaceutical Design,
2, 209-224.
Another aspect of the invention is the treatment or prevention of infection in a patient by a pathogenic fungus in cases in which the patient is allergic to, otherwise intolerant of, or non-responsive to one or more other antifungal agents or in whom the use of other antifungal agents is otherwise contra-indicated. Those other antifungal agents include, among others, those antifungal agents disclosed above and elsewhere herein.
In the foregoing methods for treatment or prevention, a rapalog, preferably a non-immunosuppressive antifungal rapalog, is administered to the subject in an effective antifungal amount.
Another aspect of this invention is the treatment or prevention of infecti
Clackson Timothy P.
Gilman Michael Z.
Holt Dennis A.
Keenan Terence P.
Rozamus Leonard
Ariad Gene Therapeutics, Inc.
Berstein David L.
Weddington Kevin E.
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