Prodrug derivatives of (E)-N-methyl-N-((3-M ethylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide
In part, the present disclosure is directed to prodrug derivatives of (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide compounds with significant solubility and bioavailability profiles.
1. A compound represented by:
2. A pharmaceutically acceptable composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
3. The pharmaceutically acceptable composition of claim 2 , wherein the composition is a powder, tablet, pill, or capsule.
4. The pharmaceutically acceptable composition of claim 2 , wherein the composition is a sterile aqueous composition.
5. The compound of claim 1 , wherein the compound has at least 2-fold greater oral bioavailability on a molar basis as compared to (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide or salts thereof.
6. A pharmaceutically acceptable composition suitable for oral administration, comprising a compound represented by:
and
a pharmaceutically acceptable excipient suitable for the oral administration.
7. A pharmaceutically acceptable composition for intravenous administration, comprising:
a compound represented by:
and
a pharmaceutically acceptable excipient suitable for the intravenous administration.
8. A compound prepared by a process comprising:
contacting a compound of formula III:
with a compound of formula IV:
to form a compound of formula II:
contacting a Brønsted acid and the compound of formula II to form a mixture; and
contacting ethanolamine and the mixture to form the compound represented by:
9. A method of preparing the compound of claim 1 , comprising:
contacting a compound of formula III:
with a compound of formula IV:
to form a compound of formula II:
contacting a Brønsted acid and the compound of formula II to form a mixture; and
contacting ethanolamine and the mixture.
10. The method of claim 9 , wherein the Brønsted acid is trifluoroacetic acid.
11. The method of claim 9 , wherein the method further comprises contacting formula IV with a base.
12. The method of claim 9 , wherein contacting a compound of formula III with a compound of formula IV occurs in a solvent.
13. A method of treating a Staphylococcus aureus bacterial infection in a patient in need thereof comprising administering a pharmaceutically effective amount of the compound of claim 1 .
14. A method of treating a Staphylococcus aureus bacterial infection, comprising administering to a patient in need thereof the pharmaceutical composition of claim 2 , wherein when the composition is administered to said patient, the method provides a mean plasma level at least 2 times higher than that obtained by administering the same amount, on a molar basis, of (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin- 3 -yl)acrylamide or salts thereof, at about 4 hours after administration.
15. The method of claim 14 , wherein the patient is a human.
16. The method of claim 15 , wherein administering is selected from the group consisting of orally administering, intravenously administering, subcutaneously administering, topically administering, and administration by inhalation.
17. The method of claim 16 , wherein administering is orally administering.
18. The method of claim 16 , wherein administering is intravenously administering or subcutaneously administering.
19. The method of claim 16 , further comprising administering to said patient a compound selected from the group consisting of an oxazolidinone, a lipoglycopeptide, vancomycin, teicoplanin, a glycopeptide, a penicillin, a cephalosporin, a puromutalin, a fusidane, a lincosamide, rifamycin and/or arbekacin.
20. The method of claim 16 , further comprising administering to said patient a compound selected from the group consisting of linezolid, daptomycin, teicoplanin, and telavancin.
21. The method of claim 16 , further comprising administering to said patient a compound selected from the group consisting of quinolones, fluoroquinolones, carbapenems, aminoglycosides, aminocyclitols, diaminopyrimidines, tetracyclines, glycyclines, streptogramins, macrolides, and sulfamides.
22. The method of claim 13 , wherein the Staphylococcus aureus is methicillin-resistant.