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
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12454540-B2
Publication Date
2025-10-28
Expiration Date
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-C30alkyl 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 is directed to L-BHDU prodrug compounds defined by a chemical structure I in which R1 and R2 follow specified patterns and linkages to alkyl groups R1a and R2a, together with the defined ranges for j, k, and n and inclusion of pharmaceutically acceptable salts. The disclosed prodrug candidates include ODE-L-BHDU, HDP-L-BHDU, POM-L-BHDU, and POC-L-BHDU.
The document presents L-BHDU prodrug compounds as antiviral prodrugs intended for use against VZV and HSV-1/HSV-2 in view of limitations in treating these viral infections, including concerns relating to bioavailability, resistance, and side effects. It also notes that 5-FU is incompatible with brivudine.
The document further describes pharmaceutical compositions and methods for treating or preventing viral infections using the claimed L-BHDU prodrug compounds, including treatment of VZV, HSV-1, and HSV-2. Embodiments also include additional bioactive agents and co-administration approaches with other antiviral agents, and VZV complication management including postherpetic neuralgia, zoster multiplex, myelitis, herpes ophthalmicus, and zoster sine herpete.
Claims Coverage
The independent claims cover four inventive features: L-BHDU prodrug compounds of chemical structure I, narrower specific structural compounds within that class, pharmaceutical compositions, and methods for treating viral infections.
L-BHDU prodrug compounds with chemical structure I substituent constraints
A prodrug compound of L-BHDU according to chemical structure I, where R1 and R2 are selected from specified -(CH2)n-O-R1a or -(CH2)j-O-C(O)k-R2a patterns (or R2 being H), with R1a independently C12-C22 alkyl, R2a independently C1-C12 alkyl, each j independently 1-6, each k 0 or 1, each n independently 2-4, and inclusion of a pharmaceutically acceptable salt thereof.
Specific L-BHDU prodrug with R1 as -(CH2)n-O-R1a and n=2 or 3
A compound according to chemical structure with R1 being a -(CH2)n-O-R1a group where n is 2 or 3, R1a is a C16 or C18 alkyl group, and R2 is H, or a pharmaceutically acceptable salt thereof.
L-BHDU prodrug with (CH2)j-O-C(O)k-R2a groups and restricted R2a
A compound according to the chemical structure where R1 and R2 are each a -(CH2)j-O-C(O)O^k-R2a group, with R2a independently an isopropyl or a t-butyl group, each j is 1, each k is 0 or 1, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with effective amount of the claimed compound and a pharmaceutically acceptable carrier
A pharmaceutical composition comprising an effective amount of a compound according to the chemical structure, including a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, additive or excipient.
Method of treating a viral infection by administering an effective amount to a patient
A method of treating a viral infection in a patient in need comprising administering an effective amount of a compound according to the chemical structure, or a pharmaceutically acceptable salt thereof, wherein the viral infection is a VZV infection, HSV-1 infection, or HSV-2 infection.
The claim set centers on defined L-BHDU prodrug structures based on chemical structure I with specific constraints on R1/R2 linkages and alkyl substituents, including particular embodiments with n=2 or 3 and R1a as C16/C18, or with j=1 and R2a as isopropyl or t-butyl. The claims also cover pharmaceutical compositions and methods for treating VZV, HSV-1, or HSV-2 infections in a patient.
Stated Advantages
Superior antiviral activity for selected L-BHDU prodrugs in the NuSkin SCID-Hu skin xenograft model, including enhanced activity for POM-L-BHDU and ODE-L-BHDU.
Reduced effectiveness reported for POC-L-BHDU in the described comparative results.
Tolerability indicated by tolerability/weight change results in the described in vivo evaluation.
Antiviral activity against HSV-2 reported for POM-L-BHDU.
Documented Applications
Treatment of VZV (varicella-zoster virus) infections in a patient using an effective amount of the claimed compound or composition.
Treatment of HSV-1 (herpes simplex virus I) infections in a patient using an effective amount of the claimed compound or composition.
Treatment of HSV-2 (herpes simplex virus II) infections in a patient using an effective amount of the claimed compound or composition.
Inhibiting or resolving VZV complications in a patient, including postherpetic neuralgia, zoster multiplex, myelitis, herpes ophthalmicus, and zoster sine herpete.
Therapeutic or prophylactic use against VZV and HSV-1/HSV-2 as described in the document.
Interested in licensing this patent?