Combination therapy to treat mycobacterium diseases

Inventors

Locher, Christopher Phillip • Bennani, Youssef Laafiret • Grillot, Anne-Laure • O'Dowd, Hardwin • Perola, Emanuele • Le Tiran, Arnaud • Charifson, Paul S.

Assignees

Spero Therapeutics Inc

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein X and R are as defined herein. The compounds of formula (I) are useful as gyrase and/or topoisomerase IV inhibitors for treating bacterial infections. The compounds of formula (I) either possess a broad range of anti-bacterial activity and advantageous toxicological properties or are prodrugs of compounds having said activity.

Core Innovation

The invention relates to controlling, treating, or reducing the advancement, severity or effects of a mycobacterium disease by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), wherein R is hydrogen or fluorine and X is hydrogen or a phosphate-related group, or a pharmaceutically acceptable salt thereof. The compound is administered in combination with one or more antibiotic compounds selected from a specified list of antibiotics.

The invention also relates to inhibiting the growth of drug sensitive and drug resistant mycobacteria cells by contacting the cells with a compound of formula (I) having R as hydrogen or fluorine and X selected from hydrogen and specified phosphate-related forms, or a pharmaceutically acceptable salt thereof. The contacting is performed in combination with one or more antibiotic compounds comprising multiple named antibiotic agents selected from classes and specific drugs listed in the claim, with a proviso that when certain antibiotic compounds are used, an additional antibiotic is also present.

The partial content further describes preparation and characterization of benzimidazole/pyrimidine derivatives including phosphorylation-derived phosphate prodrugs/salts and phosphate intermediate salts, as well as conversion to a methanesulfonate salt. The preparation includes chiral resolution to obtain an (R)-enantiomer and absolute stereochemistry confirmation by single-crystal X-ray diffraction, together with formation of dibenzyl phosphate and disodium phosphate salts and Boc-protected intermediates.

Claims Coverage

Two independent claims are provided: one directed to a method of controlling, treating or reducing a mycobacterium disease in a patient, and one directed to inhibiting growth of drug sensitive and drug resistant mycobacteria cells by contacting the cells. Across these claims, the coverage centers on a phosphate-containing compound of formula (I) (or a pharmaceutically acceptable salt) combined with one or more antibiotic compounds selected from explicitly listed antibiotics; the independent claims also include enumerated structural definitions for R and X, and in one direction M+ and D2+.

The claim set is directed to a phosphate-containing compound defined by formula (I) (or a pharmaceutically acceptable salt) combined with explicitly enumerated antibiotic compounds. One independent claim covers patient administration for controlling, treating, or reducing mycobacterium disease effects, and the other covers contacting drug sensitive and drug resistant mycobacteria cells to inhibit growth, including an explicit proviso about adding an additional antibiotic in a particular multi-antibiotic combination.

Stated Advantages

Documented Applications