US2004029817A1PendingUtilityA1
Derivatives of polyene macrolides and preparation and use thereof
Est. expiryJan 14, 2020(expired)· nominal 20-yr term from priority
C07H 17/08A61P 31/10
46
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Claims
Abstract
The present invention provides a new class of polyene macrolide derivatives useful for treating or preventing fungal infections. The new polyene macrolide derivatives exhibit surprisingly superior antifungal activity and water solubility compared to amphotericin B methyl ester (AME). In addition, the new polyene macrolide derivatives have improved water solubility and lower toxicity than both amphotericin B (AmB) and AME.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . An polyene macrolide of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a polyene backbone;
CH 2 —R 2 is a carbohydrate residue, where the illustrated CH 2 comprises the anomeric carbon of a terminal carbohydrate saccharide;
R 3 is alkyl or arylalkyl; and
X is O, S or NH,
with the proviso that when R 1 is a polyene backbone derived from amphotericin B, X is O, and R 3 is methyl, then R 2 is other than fructosyl.
2 . The polyene macrolide of claim 1 , wherein R 1 is a polyene backbone derived from amphotericin B aureofacin, candicidin, candidin, levorin, mycoheptin, nystatin, partricin, perimycin, pimaricin, polyfungin, rimocidin or trichomycin.
3 . The polyene macrolide of claim 2 , wherein R 1 is a polyene backbone derived from amphotericin B or nystatin.
4 . The polyene macrolide of claim 1 , wherein X is O.
5 . The polyene macrolide of claim 1 , wherein X is NH.
6 . The polyene macrolide of claim 1 , wherein CH 2 —R 2 is an Amadori rearrangement product of a reducing carbohydrate selected from Table 1.
7 . The polyene macrolide of claim 1 , wherein CH 2 —R 2 is a monosaccharide.
8 . The polyene macrolide of claim 7 , wherein CH 2 —R 2 is selected from the group consisting of glucopyranose, mannopyranose, galactopyranose, fructopyranose and tagatopyranose.
9 . The polyene macrolide of claim 1 , wherein CH 2 —R 2 is an oligosaccharide or a polysaccharide.
10 . The polyene macrolide of claim 9 , wherein CH 2 —R 2 is selected from the group consisting of 4-O-(β-D-galactopyranosyl)-D-fructopyranose, 4-O-(β-D-glucopyranosyl)-D-fructopyranose, 4-O-(β-D-galactopyranosyl)-D-fructopyranose, 1-O-(α-D-glucopyranosyl)-D-fructopyranose, sucrose, maltose, lactose, cellobiose, L-rhinnose and D-ribose.
11 . The polyene macrolide of claim 1 , wherein R 3 is lower alkyl, methyl, allyl or benzyl.
12 . The polyene macrolide of claim 11 , wherein R 1 is a polyene backbone derived from amphotericin B.
13 . The polyene macrolide of claim 11 , wherein CH 2 —R 2 is selected from the group consisting of 4-O-(β-D-galactopyranosyl)-D-fructopyranose, 4-O-(β-D-glucopyranosyl)-D-fructopyranose, 4-O-(β-D-galactopyranosyl)-D-fructopyranose and 4-O-(α-D-glucopyranosyl)-D-fructopyranose.
14 . The polyene macrolide of claim 1 , which has the formula:
15 . The polyene macrolide of claim 1 , which has the formula:
16 . The polyene macrolide of claim 1 , which has the formula:
17 . The polyene macrolide of claim 1 , which has the formula:
18 . A method of making a polyene macrolide derivative according to claim 1 , comprising reacting an ester, thioester or amide polyene macrolide derivative according to structural formula (II):
wherein R 1 , X and R 3 are as previously defined in claim 1 , with a reducing carbohydrate under Amadori rearrangement conditions.
19 . The method of claim 16 , in which the molar ratio of reducing carbohydrate to ester, thioester or amide polyene macrolide derivative is about 2:1.
20 . The method of claim 16 in which the reaction is carried out under non-anhydrous conditions.
21 . The compound produced by the method of claim 16 , wherein when R 1 is derived from amphotericin B, X is O and R 3 is methyl, lower alkanyl or lower alkyl, then the reducing carbohydrate is not D-mannose or α-D-glucose.
22 . A pharmaceutical composition comprising a polyene macrolide derivative according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
23 . A method for treating a fungal infection, comprising the step of administering to a host having a fungal infection a therapeutically effective amount of a polyene macrolide of formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
Y is O, S or NH;
R 4 is a polyene backbone;
CH 2 —R 5 is a carbohydrate residue, where the illustrated CH 2 comprises the anomeric carbon of a terminal carbohydrate saccharide; and
R 6 is alkyl or arylalkyl.
24 . The method of claim 23 wherein said polyene macrolide is administered by topical application.
25 . The method of claim 23 wherein said polyene macrolide is the polyene macrolide according to claim 1 .
26 . The method of claim 23 wherein said polyene macrolide is the polyene macrolide according to claim 13 .
27 . The method of claim 23 wherein said polyene macrolide is the polyene macrolide according to claim 14 .
28 . The method of claim 23 wherein said polyene macrolide is the polyene macrolide according to claim 15 .
29 . The method of claim 23 wherein said polyene macrolide is the polyene macrolide according to claim 16 .
30 . The method of claim 23 wherein said polyene macrolide is the polyene macrolide according to claim 17 .
31 . A method of preventing a fungal infection, comprising the step of administrating to a subject an amount of a polyene macrolide derivative effective to prevent the fungal infection, wherein the polyene macrolide derivative has the formula (III).
or a pharmaceutically acceptable salt thereof, wherein:
Y is O, S or NH;
R 4 is a polyene backbone;
CH 2 —R 5 is a carbohydrate residue, where the illustrated CH 2 comprises the anomeric carbon of a terminal carbohydrate saccharide; and
R 6 is alkyl or arylalkyl.Join the waitlist — get patent alerts
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