Nicorandil derivatives

Inventors

Gupta, Shalabh • Dugar, Sundeep

Assignees

Unicycive Therapeutics Inc

Abstract

Disclosed herein are pyridyl compounds. Also described are specific conjugated nicorandil compounds. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the pyridyl compounds are disclosed for the treatment of diseases or conditions related to kidney or kidney functions.

Core Innovation

The disclosed subject matter relates to nicorandil-derived pyridyl/conjugated nicorandil compounds and to nitrate/nitrooxy pyridinium compounds comprising compounds of Formula (I) and related subformulas (IIa)-(Vb), together with a counter-ion X−. The definitions of substituents include R1, R2, R3, and a Y substituent, where Y is a linking/conjugating group that connects to the pyridyl/conjugated nicorandil scaffold, and the compounds are also defined using pharmacologically acceptable anions such as halides and sulfonates.

The compounds are further defined using substituent groups R1, R2 and R3 to form structural variants corresponding to formulas (IIIa)/(IIIb), (IVa)/(IVb) and (Va)/(Vb). Representative compounds are exemplified as Compounds 1–6, including iodide salt forms (I−), and the disclosure provides preparation and characterization information such as LC/TLC monitoring, melting points and MS m/z values.

The disclosure states that the conjugated nicorandil compounds can form nicorandil in vivo, including a note that Compound A converts completely to nicorandil in rat plasma over time with no trace detected. Pharmaceutical compositions containing the compounds are also disclosed, and the described approach uses administering an effective treating amount of a compound according to the specified formulas, or a pharmaceutical composition thereof, for kidney-related therapeutic use.

The problem addressed is treatment and/or prevention/amelioration of kidney diseases and conditions, including chronic kidney disease (CKD) and acute kidney injury (AKI), including contrast induced nephropathy and other AKI settings described in the disclosure. The stated conditions include diabetic nephropathy, IgA nephropathy, acute kidney failure/acute kidney disease, and AKI scenarios such as drug-induced AKI (cisplatin-, aminoglycoside-, and tenofovir-induced AKI), transplant-related ischemia, and perioperative/ICU/dialysis-related AKI.

Claims Coverage

The consolidated content includes an independent claim directed to treating acute kidney injury or contrast induced nephropathy by administering a compound of formula (Va) or formula (Vb), or a pharmaceutical composition, where X− is a counter ion. Additional dependent claims refine the independent claim by specifying particular choices of formula and counter ion, as well as pharmaceutical composition, administration route, and compound quality features.

Across the independent claim and its dependents, the core coverage is a treating method for acute kidney injury or contrast induced nephropathy using compounds of formula (Va) or formula (Vb) with a counter ion X−, further refined by specific counter-ion choice, non-aqueous formulation components, oral administration, and purity/chemical stability constraints.

Stated Advantages

Documented Applications