Prodrugs of L-BHDU and methods of treating viral infections

Inventors

Singh, Uma Sharan • Chu, Chung

Assignees

Anterogen Co Ltd • University of Georgia Research Foundation Inc

Abstract

In an embodiment, the invention is directed to prodrug compounds of L-BHDU according to the chemical structure I:Where R1 is a —(CH2)n—O—R1a group or a —(CH2)j—O—C(O)Ok—R2a group;R2 is H, a —(CH2)n—O—R1a group or a —(CH2)j—O—C(O)Ok—R2a group;R1a is independently a C6-C30 alkyl group, often a C12-C22 alkyl group, often a C14-C20 alkyl group or a C16-C18 alkyl group, often a C16 or C18 alkyl group;R2a is independently a C1-C12 alkyl group, often a C2-C6 alkyl group, a C3-C4 alkyl group, an isopropyl, t-butyl or sec-butyl group, or an isopropyl or t-butyl group;Each j is independently 1-6, 1-3, often 1 or 2;Each k is 0 or 1;Each n is independently 1-6, 1-4, 2-4 or 2 or 3; orA pharmaceutically acceptable salt, solute or polymorph thereof. Additional embodiments are directed to pharmaceutical compositions based upon the disclosed chemical compounds and methods of treating or reducing the likelihood of VZV, HSV-1 or HSV-2 infections. Methods of synthesizing compounds according to the present invention represent further embodiments of the invention.

Core Innovation

The invention relates to prodrug compound variants of β-L-BHDU, defined by chemical structure I in which substituents R1 and R2 are selected according to structural moieties including —(CH2)n—O—R1a or —(CH2)j—O—C(O)Ok—R2a, with defined integer parameters n, j, and k. The substituent choices specify R1a as a C6–C30 alkyl group and R2a as a C1–C12 alkyl group, with option ranges that include specific smaller sets such as C2–C6, C3–C4, isopropyl, t-butyl, sec-butyl, or isopropyl or t-butyl. The scope further includes pharmaceutically acceptable salt, solute or polymorph forms of the prodrug compounds.

The invention also includes narrower embodiments of β-L-BHDU prodrug compounds by fixing key parameters, such as defining a compound structure where R1 is —(CH2)n—O—R1a with n set to 2 or 3 and R1a limited to C16 or C18 alkyl groups. Additional specific structural embodiments define R1 and R2 as each being —(CH2)j—O—C(O)O—R2a with restricted values of j and k, and where R2a is independently an isopropyl or a t-butyl group, again including pharmaceutically acceptable salt, solute or polymorph forms.

From a therapeutic standpoint, the disclosed invention is directed to pharmaceutical compositions and methods for inhibiting or resolving viral infections and related complications caused by VZV, including complications such as postherpetic neuralgia, zoster multiplex, myelitis, herpes ophthalmicus, and zoster sine herpete. The disclosed use includes treatment of VZV infection in a patient or subject, including cases involving wild type VZV or mutant VZV categories (TK-, TS-, or TK-TS-). The disclosure further supports combination therapy in which the pharmaceutical composition includes additional named antiviral bioactive agents.

Claims Coverage

The document includes three independent claims covering three inventive features: a broad class of β-L-BHDU prodrug compounds, a more specific compound with restricted R1 chain length and R1a alkyl options, and another specific compound with restricted j/k values and R2a choice. Dependent claims further refine structural parameters and extend to pharmaceutical compositions and treatment indications for VZV/HSV-1/HSV-2 complications with specified antiviral bioactive agents.

Overall, the claim coverage centers on parameterized β-L-BHDU prodrugs defined by chemical structure I, with dependent refinements that lock specific integer values and specific alkyl selections. The broader framework is consistently extended to pharmaceutically acceptable salt/solvate/polymorph forms and is supported by dependent claim refinements for pharmaceutical compositions and VZV/HSV-1/HSV-2 treatment and complication indications with named antiviral bioactive agents.

Stated Advantages

Documented Applications