Tricyclic spiro compound
Inventors
Asada, Masaki • Tani, Kousuke • HIROBE, Masaya • HIGUCHI, Satonori • Fuchibe, Kazuhiro • Oikawa, Ryo • KOTANI, Tohru • TAKANO, Hirotsugu
Assignees
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Publication Number
US-12497377-B2
Publication Date
2025-12-16
Expiration Date
Abstract
A medicinal agent for the prevention and/or treatment of diseases caused by EP4 receptor activation is disclosed. A compound having antagonistic activity against the EP4 receptor is contained as an active ingredient in the medicinal agent. The compound represented by the following general formula (I) as defined in the specification, a salt, an N-oxide, or a solvate thereof, or a prodrug of these is useful as a medicinal component having antagonistic activity against the EP4 receptor for the prevention and/or treatment of diseases caused by EP4 receptor activation.
Core Innovation
The invention relates to treating a disease caused by EP4 receptor activation in a subject in need thereof by administering an effective amount of 4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, a solvate thereof, or a prodrug of these. The document further describes the specified compound scaffold and related EP4-relevant small-molecule variants, including a core 4-cyano-2-amino substituted phenyl linked to a spiro[chromene-4,1′-cyclopropane] carbonyl and a butanoic acid group with (2′R,4S) stereochemistry.
The document describes structural exemplars with variations in the carbamoyl substituent and related substituent patterns, including substituted carbamoyl groups, heteroaryl moieties, and changes to a spirochromene/spirobenzofuran core and substituents. It also provides chemical characterization data and structural exemplars for multiple reference-example compounds and conversions.
The document further provides pharmacological evaluation showing EP4 receptor antagonism and associated biochemical measurements, including cAMP inhibition in EP4-expressing CHO cells, as well as hepatic microsome stability data. In addition, it includes an anti-tumor in vivo allograft study using CT26 colorectal cancer in mice, with tumor growth inhibition and oral dosing reported for variant compounds.
Claims Coverage
The claim set centers on one independent method claim directed to treating a disease caused by EP4 receptor activation by administering an effective amount of the specified compound, salt, solvate, or prodrug. The dependent claims further limit the method by selecting EP4-activation disease categories and specific cancer types.
Treating an EP4-activation disease by administering a specified compound
Administering an effective amount of 4-[4-cyano-2-({[(2′R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1′-cyclopropan]-2′-yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, or a solvate thereof, or a prodrug of these, to a subject in need thereof.
Selecting the EP4-activation disease from listed disease conditions
The EP4-activation disease is selected from a listed set of conditions including bone disease, cancer, immune disease, and other enumerated disorders.
Selecting cancer from a listed set of cancer types
The disease is cancer selected from a listed set of specific cancer types.
The inventive coverage is the administration of the specified EP4-targeted compound, or its salt, solvate, or prodrug, to treat diseases caused by EP4 receptor activation, with dependent claims narrowing the treatment to enumerated disease categories and cancer types.
Stated Advantages
Low toxicity.
Prevention/therapy of EP4-activation-caused diseases via EP4 receptor antagonism.
EP4 receptor antagonism and associated biochemical activity are shown in the document.
Hepatic microsome stability data are provided for variant compounds.
Documented Applications
Prevention/therapy of diseases caused by EP4 receptor activation, including bone disease, cancers, immune/allergic disease, neurologic pain/headache, and vasculitis and related conditions.
Treatment of cancer selected from listed cancer types.
Anti-tumor activity in an in vivo allograft model using CT26 colorectal cancer in mice, with reported tumor growth inhibition for oral dosing of variant compounds.
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