Compositions and methods of treatment with prodrugs of tizoxanide, an analogue or salt thereof

Inventors

Rossignol, Jean-Francois • Stachulski, Andrew

Assignees

Romark Laboratories LC

Abstract

Prodrugs of tizoxanide, an analog or salt thereof are disclosed. The prodrugs have an ester moiety comprising an amino acid moiety, and increase the bioavailability of the tizoxanide, an analog or salt thereof. Compositions and methods of treating an intracellular protozoan infection, a viral infection or a cancer are also disclosed.

Core Innovation

The invention relates to prodrugs of tizoxanide and analogues and pharmaceutically acceptable salts in which an ester moiety containing an amino acid moiety is used to increase bioavailability. The prodrug structure is defined by a phenyl-containing formula (I) with substituent groups R1 through R5 selected from broad classes of optionally substituted groups, with each of R1 through R5 comprising 1 to 60 atoms.

At least one of R1 through R5 is required to be either an amino acid moiety bound to the phenyl in formula (I) through an ester moiety, where the amino acid moiety is selected from a defined set of amino acid moieties, or a moiety represented by Formula A. Formula A imposes defined selections for R′ and R′′ as well as constraints on R6 and R9, including selection rules for which substituents may be present and which must be hydrogen.

The disclosed subject matter further includes pharmaceutically acceptable salts and pharmaceutical compositions formulated as solid oral dosage forms comprising controlled-release and immediate-release portions. Therapeutic methods are also described for intracellular protozoan infections, viral infections, and cancers, including combination components such as vaccines, immunostimulants, neuraminidase inhibitors, recombinant sialidase fusion proteins, and anticancer drugs.

Claims Coverage

The independent claim covers a specific compound, or a pharmaceutically acceptable salt, defined by substituent groups R1–R5 on a phenyl-containing formula, with a required prodrug functionality implemented either as an amino acid ester moiety or via a defined Formula A moiety. The coverage is driven by one principal inventive feature: at least one substituent position implements an amino acid ester prodrug design, with additional structural constraints when Formula A is used.

The claim coverage centers on a prodrug-bearing phenyl-containing compound where at least one substituent position implements an ester-linked amino acid moiety from a specified amino acid set or an alternative Formula A moiety with specified R′/R′′ selections and R6/R9 constraints, with the remainder of R1–R5 allowed to vary within the enumerated optionally substituted group classes.

Stated Advantages

Documented Applications