Derivatives of polyene macrolides and preparation and use...

Details Derivatives of polyene macrolides and preparation and use... Derivatives of polyene macrolides and preparation and use...

2001-12-20

2003-05-13

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S006500, C536S018500

Reexamination Certificate

active

06562796

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to derivatives of polyene macrolides. In particular, the present invention relates to water soluble glycosyl derivatives of polyene macrolides useful for treating or preventing topical and/or systemic fungal infections in humans and animals.
2. Description of Related Art
Many polyene macrolides are known that have antifungal properties useful in treating topical and/or systemic fungal infections. Examples of these polyene macrolides include amphotericin B, aureofacin, candicidin, candidin, levorin, mycoheptin, nystatin, perimycin, pimaricin, polyfungin, rimocidin and trichomycin. However, due to their macrocyclic nature and amphoteric character, these compounds generally have poor solubility in aqueous solutions, which limits their usefulness in the treatment of systemic fungal infections. In addition, these polyene macrolides exhibit undesirable toxic properties when used systemically. For example, while amphotericin B methyl ester (AME) exhibited lower acute, nephro and hepto toxicity than amphotericin B in rats and dogs, in the only clinical trial conducted with AME in patents with systemic fungal infections, many patients developed progressive neurological dysfunction associated with white matter degeneration, see Ellis et al., 1988, Tox. Path. 16(1):1; Parmegiani et al., 1987, Antimicrob. Agents Chemo. 31(11):1756-1760; Hoeprich et al., 1985, Diag. Microbiol. Infect. Dis. 3:47-58; Massa et al., 1985, Fund. App. Tox. 5:737-753; Keim Jr., et al., 1976, Antimicrob. Agents Chemo. 10(4):687-690; and Keim Jr., et al., 1973, Science 179:584-586. The incidence and severity of these complications increased with the amount of AME administered (Id.). In fact, the toxicity of AME was so severe that the clinical trial was canceled and product was never brought to market.
Many derivatives of polyene macrolides have been developed, in part to address these limitations. For example, U.S. Pat. No. 4,093,796 to Falkowski et al. teaches polyene macrolides substituted at the sugar amino group with a saccharide. U.S. Pat. No. 4,195,172 to Falkowski et al. teaches N-methylglucamine salts of N-glycosyl derivatives of polyene macrolides in which the amino group of the polyene macrolide is substituted with an aldose or ketose mono- or oligosaccharide. U.S. Pat. No. 4,294,958 to Falkowski et al. teaches trimethylammonium salts of polyene macrolides, including the methyl esters. U.S. Pat. No. 4,365,058 to Falkowski et al. teaches esters of polyene macrolides that are substituted at the sugar amino group with non-sugar substituents. U.S. Pat. No. 4,783,527 to Falkowski et al. teaches amides of polyene macrolides substituted at the amide nitrogen with an alkyl, isoalkyl or heterocyclic group. U.S. Pat. No. 5,314,999 to Seman et al. teaches polyene macrolides substituted at the N position with a 1-amino-1-deoxyketose group, which itself may be further substituted. U.S. Pat. No. 5,942,495 to Borowski et al. teaches N-alkyl-N-glycosyl derivatives of polyene macrolides that are reported to have antifungal activity, form water soluble salts with acids and lower toxicity than other N-alkyl polyene macrolide derivatives.
None of the foregoing derivatives provide an optimum combination of water solubility, low toxicity, and potency as an antifungal agent. Since AmB is still the drug of choice for many indications, there is a need for polyene macrolides that exhibit antifungal activity and that have improved water solubility and/or toxicity properties.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a new class of polyene macrolide derivatives that exhibit surprisingly superior antifungal activity, increased water solubility and lower toxicity than amphotericin B (AmB) and amphotericin B methyl ester (AME). The polyene macrolide derivatives of the invention comprise a “core” polyene macrolide backbone derived from any of a variety of polyene macrolides having two features: a carboxyl substituent and an amino sugar substituent. In the polyene macrolide derivatives of the invention, the carboxyl substituent of the “core” is converted to an alkyl or arylalkyl ester, thioester or amide, and the amino group of the amino sugar is substituted with a carbohydrate residue, which may be a mono, oligo or polysaccharide.
Specifically, the present invention provides polyene macrolide derivatives according to structural formula (I):
including the pharmaceutically acceptable salts thereof, wherein:
R
1
is a polyene macrolide backbone;
CH
2
—R
2
is a carbohydrate residue, where the illustrated CH
2
includes the anomeric carbon of a terminal carbohydrate saccharide;
R
3
is alkyl or arylalkyl; and
X is O, S or NH.
In one important embodiment, the polyene macrolide derivatives are compounds according to structural formula (I), with the proviso that when R
1
is a polyene macrolide backbone derived from amphotericin B, X is O, and R
3
is methyl, lower alkanyl or lower alkyl, then R
2
is other than fructosyl.
In another aspect, the present invention provides methods for making these new polyene macrolide derivatives. According to the method, a parent polyene macrolide is reacted according to known methods to yield the corresponding alkyl or arylalkyl ester, thioester or amide. The ester, thioester or amide is then reacted with an appropriate reducing sugar under Amadori rearrangement conditions to yield a new polyene macrolide derivative according to the invention.
In another aspect, the present invention provides pharmaceutical compositions including the new polyene macrolide derivatives, or pharmaceutically acceptable salts thereof, as well as methods for treating and/or preventing fungal infections in plants or animals, including humans. The pharmaceutical compositions generally comprise one or more polyene macrolide derivatives of the invention and a pharmaceutically acceptable carrier, excipient or diluent. The choice of carrier, excipient or diluent will depend upon the mode of administration.
The method generally involves administering to a plant or animal, including a human, one or more of the polyene macrolide derivatives or pharmaceutical compositions of the invention in an amount effective to treat or prevent a fungal infection in the plant, animal or human. The polyene macrolide derivatives or pharmaceutical compositions may be administered systemically or applied topically, depending on the nature of the fungal infection.


REFERENCES:
patent: 3244590 (1966-04-01), Schaffner et al.
patent: 3780173 (1973-12-01), Bruzzese et al.
patent: 3961047 (1976-06-01), Bruzzese et al.
patent: 4035567 (1977-07-01), Sipos
patent: 4035568 (1977-07-01), Schaffner et al.
patent: 4038382 (1977-07-01), Bruzzese et al.
patent: 4093796 (1978-06-01), Falkowski et al.
patent: 4195172 (1980-03-01), Falkowski et al.
patent: 4235993 (1980-11-01), Sipos et al.
patent: 4272525 (1981-06-01), Wright
patent: 4294958 (1981-10-01), Falkowski et al.
patent: 4342750 (1982-08-01), Gordon
patent: 4351937 (1982-09-01), Stefanska et al.
patent: 4365058 (1982-12-01), Falkowski et al.
patent: 4783527 (1988-11-01), Falkowski et al.
patent: 4824944 (1989-04-01), Stefanska et al.
patent: 4883785 (1989-11-01), Chow et al.
patent: 5066646 (1991-11-01), Driver et al.
patent: 5100876 (1992-03-01), Driver et al.
patent: 5116960 (1992-05-01), Driver et al.
patent: 5204330 (1993-04-01), Driver et al.
patent: 5296597 (1994-03-01), Bruzzese et al.
patent: 5298495 (1994-03-01), Bruzzese et al.
patent: 5314999 (1994-05-01), Seman et al.
patent: 5567685 (1996-10-01), Linden et al.
patent: 5939399 (1999-08-01), Vertesy et al.
patent: 5942495 (1999-08-01), Borowski et al.
patent: 5965156 (1999-10-01), Proffitt et al.
patent: 5981721 (1999-11-01), Mohan
patent: WO 96/35701 (1996-11-01), None
patent: WO 01/91758 (2001-12-01), None
Beau, “Polyene Macrolides: Stereostructural Elucidation and Synthetic Studies of a Few Members,”Recent Progress in the Chemical Synthesis of Antibiotics(1990) 135-182.
Bennett, “Antifungal Agents,”Goodman and Gilman's: The

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