Prodrugs of Neuraminidase Inhibitors

Abstract

A new class of neuramidase inhibitor prodrugs is provided characterized by a prodrug moiety of a carboxyl group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide or a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide; a primary alcohol modified to form an esterified single amino acid, dipeptide or tripeptide of zanavimir of the unaltered therapeutic agent. Exemplary therapeutic agents so modified to form prodrugs include zanavimir, oseltamivir and peramivir. The prodrug has increased oral bioavailability relative to the unaltered neuraminidase inhibitor and is effective in the inhibition of viral infections involving neuraminidase in the viral reproductive cycle.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority of U.S. Provisional Patent Application Ser. No. 61 / 045,104 filed Apr. 15, 2008, which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention in general relates to neuraminidase inhibitor prodrugs, and in particular to neuraminidase inhibitor amino acid prodrugs that provide modified bioavailability and active cellular transport relative to the drug itself.BACKGROUND OF THE INVENTION[0003]Numerous potentially effective therapeutic agents often exhibit poor bio-pharmaceutical properties. This problem, which can preclude the effective oral use of a potential therapeutic agent, is generally targeted with analog methodology, screening ligands, for the biopharmaceutical properties of permeability and metabolism. However, this approach can lead to less desirable drug candidates because properties that optimize biopharmaceutical properties of a molecule may not be the properties or s...

AI Technical Summary

Benefits of technology

[0006]A prodrug of a neuraminidase inhibitor is provided having the formula (I):where R1 is an amino acid residue having the formula —C(O)CH(R′)NH2, a dipeptide residue having the formula —C(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, a tripeptide residue having the formula —C(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)N(H)C(O)(CH2)nCH(R′″)NH2, —H, —COC(CH3)2CH2R*, —COCH2CH2R* or —COCH3; n is zero, one or two (corresponding to an α, β or γ amino acid, respectively); R2 is a nullity or —CR*R**, —O or —CR*(OH); R* is −H, —C1-C8 alkyl, or —C1-C6 alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; R** is R* or an electron of covalent bond; R3 is an sp2 hybridized C or CR*; R4 is CR*R** when R3 is CR* and an sp2 hybridized C when R3 is the sp2 hybridized C forming an ethylenic unsaturation therebetween, R4 is —CH; R5 is —CR*R** and R** is the electron of a covalent bond when bonded to R2 or R7 to form a 5- or 6-member cyclic structure; R6 is —NH—C(O)—CH2R*, R7 is a nullity, —CR*R** and R8 is —CR*(OR11)CR*(OR12)CHR*(OR13); R11, R12 and R13 are each independently an amino acid residue having the formula —C(O)(CH2)nCH(R′)NH2, a dipeptide residue having the formula —C(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, a tripeptide residue having the formula —C(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)N(H)C(O)(CH2)nCH(R′″)NH2, —H, —COC(CH3)2CH2R*, —COCH2CH2R*, or —COCH3; R9 and R10 are each independently an amino acid residue having the formula —C(O)(CH2)nCH(R′)NH2, a dipeptide residue having the formula —C(O)(CH2)nH(R′)N(H)C(O)(CH2)nCH(R″)NH2, a tripeptide residue having the formula —C(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)N(H)C(O)CH(R′″)NH2 or —H; L1 is a nullity, —[(CH2)nCH(CH2R*)O]m or —[(CH2)nCH2O]m, with the proviso that L1 is —[(CH2)nCH(CH2R*)O]m or —[(CH2)nCH2O]m when R1 is a single amino acid residue, a dipeptide residue or a tripeptide residue; m is 1; L2 is a nullity, —C(O)(CH2)nCH(CH2R*)O or —C(O)O(CH2)nCH2O with the proviso that L2 is —C(O)[(CH2)nCH(CH2R*)O]m or —C(O)O[(CH2)nCH2O]m when R9 or R10 is a single amino acid residue or a dipeptide residue; R′, R″ and R′″ are in each occurrence independently selected amino acid side chain; with the proviso that at least one of R1, R9, R10, R11, R12 or R13 is a single α, β or γ amino acid residue, a dipeptide residue or a tripeptide residue. In a specific preferred embodiment of the prodrug of formula (I) n is zero in each occurrence and R* is H in each occurrence. The prodrug has increased oral bioavailability relative to the unaltered neuraminidase inhibitor and is effective in the inhibition of viral infections involving neuraminidase in the viral reproductive cycle.

Problems solved by technology

Numerous potentially effective therapeutic agents often exhibit poor bio-pharmaceutical properties.

However, this approach can lead to less desirable drug candidates because properties that optimize biopharmaceutical properties of a molecule may not be the properties or structure that optimize its ligand binding and ultimate efficacy.

A problem associated with rendering a poorly soluble therapeutic agent orally bioavailable is that the transport and release of the active agent from a transport species are unpredictable.

Yet a robust delivery prodrug actively transported into cells bearing PEPT1 and / or PEPT2 transport receptors has remained elusive.

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