Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-05-29
2003-12-16
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007100
Reexamination Certificate
active
06664241
ABSTRACT:
2. BACKGROUND OF THE INVENTION
2.1 Field of the Invention
The present invention relates generally to derivatives of polyene macrolides. In particular, the present invention relates to water-soluble amide derivatives of polyene macrolides useful for treating or preventing topical and/or systemic fungal infections in plants, humans and animals.
2.2 Description of Related Art
Many polyene macrolides are known that have antifungal properties useful for treating topical and/or systemic fungal infections. Examples of these polyene macrolides include amphotericin B, aureofacin, candicidin, candidin, levorin, mycoheptin, nystatin, partricin A, partricin B, perimycin, pimaricin, polyfungin, rimocidin and trichomycin. However, due to their amphoteric character, these compounds generally have limited solubility in aqueous solutions, which in turn limits their usefulness in the treatment of systemic fungal infections. In prior attempts to modify these compounds, some of the derivatives exhibited undesirable toxic properties when used systemically. For example, while amphotericin B methyl ester (AME) exhibited lower acute, nephro- and hepato-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 the product was never brought to market.
Many derivatives of polyene macrolides have been developed, in part to address these limitations. One class of derivatives include certain polyene macrolides substituted at the amino group of the amino sugar residue. 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. 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 have lower toxicity than other N-alkyl polyene macrolide derivatives.
Other derivatives reported in the literature include amides of certain polyene macrolides derivatives. For example, U.S. Pat. No. 4,783,527 to Falkowski et al. teaches alkyl, isoalkyl and heterocyclic amide derivatives of polyene macrolides. Jarzbeslo et al., 1982, J. Antibiot. 35(2):220-229 teach aliphatic amides of amphotericin B. Czerwinski et al., 1990, J. Antibiot. 43(6):980-683 teach amphotericin B 2-morpholinoethylamide. Grzybowska & Borowski, 1990, J. Antibiot. 43(7):907-908 teach hydrazides of amphotericin B, candidin, aureofacin and nystatin. Graybill et al., 1998, Antimicrobial Agents and Chemother. 42(1)147-150 and Yamashita et al., 1995, J. Am. Chem. Soc. 117(23):6249-6253 teach oligo(ethlene glycol) amides of ampotericin B. Chéron et al., 1988, Biochem. Pharmacol. 37(5):827-836 teach certain alkyl amides of amphotericin B that are further amidated at the polyene amino sugar residue. Lastly, Bruzzese et al., 1996, Eur. J. Med. Chem. 31:965-972, U.S. Pat. No. 5,296,597 to Bruzzese et al. and U.S. Pat. No. 5,298,495 to Bruzzese et al. teach certain amide derivatives of partricins A and B.
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 macrolide derivatives that exhibit antifungal activity and that have improved water solubility and/or toxicity properties.
3. SUMMARY OF THE INVENTION
In one aspect, the present invention provides new polyene macrolide amide derivatives that have antifungal activity and that have increased water solubility as compared with amphotericin B (AmB) and amphotericin B methyl ester (AME). The polyene macrolide amide derivatives generally comprise a “core” polyene macrolide backbone derived from any of a variety of parent polyene macrolides having two features: an exocyclic carboxyl group and an amino sugar residue. The exocyclic carboxyl group of the parent polyene macrolide is amidated with substituents that increase the water-solubility of the resultant polyene as compared with AmB and AME. In one class of polyene macrolide amide derivatives of the invention, the nitrogen atom of the primary amino group of the amino sugar residue (“amino nitrogen”) is substituted with a carbohydrate residue, which may be a mono-, di-, oligo- or polysaccharide. In all of the compounds of the invention, the amino nitrogen may be optionally alkylated. In embodiments in which the amino nitrogen is dialkylated, the alkyl groups may be the same or different.
While not intending to be bound by any particular theory of operation, the increased water-solubility of the amide derivatives of the invention is believed to be due to the presence of one or more of the same or different water solubility-increasing substituents attached to and/or including the nitrogen atom of the amide group (“amide nitrogen”). The water-solubility increasing substituents are generally polar in character, typically by virtue of including one or more of the same or different substituted or unsubstituted heteroatoms (e.g., S, O, N, NH, etc.).
In one embodiment, the water-solubility increasing substituents are hydrocarbons such as, by way of example and not limitation, linear and branched alkyls, cycloalkyls, aryls and arylalkyls that are substituted with one or more of the same or different polar substituents. Typical polar substituents include, but are not limited to, —OH, —SH, ═O (oxo), ═S (thioxo), —NH
2
, ═NH (imino), —C(═NH)—NH
2
(amidino), —NH—C(═NH)—NH
2
(guanidino), —C(O)H, —C(O)OH, —C(O)O
−
M
+
, —C(O)NH
2
, —N
3
, —CN, —X, —CX
3
, etc., where each X is independently a halogen, preferably F, Cl or Br and M
+
represents a monovalent counter ion such as Na
+
, K
+
, etc. The polar-substituted alkyls, cycloalkyls, aryls and arylalkyls may also be optionally substituted with one or more of the same or different non-polar substituents, e.g., alkyls, cycloalkyls, aryls and arylalkyls, etc.
In another embodiment, the water-solubility increasing substituents are hydrocarbons in which one or more of the carbon atoms are replaced with the same or different heteroatoms to form, by way of example and not limitation, linear and branched heteroalkyls, cycloheteroalkyls, heteroaryls and heteroarylalkyls. One or more of the carbon atoms and/or heteroatoms (e.g., N) of these heteroalkyl, cycloheteroalkyl, heteroaryl and heteroarylalkyl groups may be further substituted with one or more of the same or different polar or non-polar substituents, as described above.
In still another embodiment, the water solubility-increasing substituents, taken together with the amide nitrogen to which they are bonded, form a saturated or unsaturated nitrogen-containing ring. The ring ma
Baldwin Christopher J.
Chang Conway C.
Dang Binh T.
Loury David J.
Simon Reyna J.
Micrologix Biotech Inc.
Peselev Elli
Seed IP Law Group PLLC
LandOfFree
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