Inhibitors of sodium glucose transporter 1 for constipation

Inventors

Carson, Kenneth Gordon • Goodwin, Nicole Cathleen • Harrison, Bryce Alden • Rawlins, David Brent • Strobel, Eric • Zambrowicz, Brian

Assignees

Lexicon Pharmaceuticals Inc

Abstract

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: the various substituents of which are defined herein.

Core Innovation

The invention provides a method of treating or managing chronic constipation by administering to a patient in need thereof a therapeutically effective amount of N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide, or a pharmaceutically acceptable salt thereof. The compound is described as a chiral sugar-like tetrahydro-2H-pyran moiety with methylthio and trihydroxy substituents connected to a substituted benzyl and phenyl butanamide scaffold.

The disclosure also includes synthesis and characterization of related tetrahydro-2H-pyran derivatives and oxidized analogs, including sulfoxide, sulfone, N-oxide, amide, urea, guanidine, and tetrazole derivatives. It further describes bisformate and formate salts, conversion to tetrazole derivatives with regioisomer separation, and diversification of terminal nitrogen functionalities on a chiral tetrahydropyran core bearing methylthio and trihydroxy substituents.

Pharmaceutical formulation options are described, including oral dosage forms and controlled delivery approaches for enteric delivery using polymer/beads. The document also provides extensive examples of compound-related chemical series content, including advanced intermediates and final analogs that share the same chemical series theme referenced by the named scaffold and linkage motifs.

Claims Coverage

The relevant material includes one independent claim. The claim coverage is limited to a single inventive feature directed to a therapeutic-use method for chronic constipation using a specific N-substituted butanamide or a pharmaceutically acceptable salt as the active agent.

Claim coverage is directed to a single inventive feature: administering a therapeutically effective amount of the specifically defined tetrahydro-2H-pyran butanamide or a pharmaceutically acceptable salt for treating or managing chronic constipation.

Stated Advantages

Documented Applications