Substituted piperidines having GPR119 agonistic activity
Inventors
Yang, Jae Sung • Baek, Gye Rim • Kim, Yoon Jung • Ahn, Chi Young • Lee, Jae Young • Jung, Il Hoon • Kim, Mi Kyung • Kang, So Mi • Lee, Hyo Ju • Chae, Yu Na • Cheong, Ye Hwang • Kim, Tae Hyoung • Yang, Eun Kyoung • Son, Moon Ho • Shin, Chang Yell
Assignees
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Publication Number
US-10428055-B2
Publication Date
2019-10-01
Expiration Date
Abstract
The present invention relates to a substituted piperidines represented by following Chemical Formula 1, which have a GPR119 agonistic activity, a method for preparing the same, and a pharmaceutical composition including the same: wherein A, B, and X are defined therein.
Core Innovation
The invention relates to compounds represented by Chemical Formula 1, or pharmaceutically acceptable salts or stereoisomers thereof. The compounds include moiety A selected from oxadiazolyl, dihydrooxazolyl, thiazolyl or thiadiazolyl, and moiety B selected from pyridinyl, pyrimidinyl, pyrazinyl or oxadiazolyl, with each moiety optionally and independently substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkyl-OH as stated in the inputs. Each X is independently F, Cl, Br or I, and the disclosed examples include substituted heterocycles within the Chemical Formula 1 framework, including stereoisomers and enumerated compounds.
The invention further includes a method that activates G protein-coupled receptor 119 in a subject by administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer. The invention thus centers on Chemical Formula 1 compounds and their use for GPR119 activation and glucose tolerance improvement, in the context of subjects having selected metabolic diseases or disorders.
The invention also includes a process for preparing a compound represented by Chemical Formula 1. The process includes reacting a compound represented by Chemical Formula 4 with methanesulfonyl chloride to provide a compound represented by Chemical Formula 5, reacting the compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 12a in the presence of bases and solvents to provide a compound represented by Chemical Formula 8, and then transforming the intermediate via further reacting steps to reach Chemical Formula 1.
Claims Coverage
The consolidated claim coverage includes three inventive features: a Chemical Formula 1 compound class, a method of activating G protein-coupled receptor 119 by administration of the compound, and a process for preparing Chemical Formula 1 compounds. The independent claim scope is built around the A/B heteroaryl framework and the halogen variable X, with dependent coverage narrowing the compound scope and extending to use and process claims.
Chemical formula 1 heteroaryl compounds with defined A, B, and X substituents
A compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or stereoisomer, wherein A is oxadiazolyl, dihydrooxazolyl, thiazolyl or thiadiazolyl, B is pyridinyl, pyrimidinyl, pyrazinyl or oxadiazolyl, and each X is independently F, Cl, Br or I, with optional and independent substitution as stated in the inputs.
Activating G protein-coupled receptor 119 by administration of the chemical formula 1 compound
A method that activates G protein-coupled receptor 119 in a subject by administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer, including subjects having selected metabolic diseases or disorders.
Process for preparing chemical formula 1 via defined intermediates
A process for preparing a compound represented by Chemical Formula 1 comprising reacting Chemical Formula 4 with methanesulfonyl chloride to provide Chemical Formula 5, reacting Chemical Formula 5 with Chemical Formula 12a in the presence of bases and solvents to provide Chemical Formula 8, and further transforming the intermediate through successive reacting steps to reach Chemical Formula 1.
The consolidated claims are anchored on the Chemical Formula 1 heteroaryl compound class with defined A, B, and X variables, together with a GPR119 activation use claim and a process claim for preparing Chemical Formula 1 through defined intermediates.
Stated Advantages
The compounds act as GPR119 agonists.
The compounds are associated with incretin secretion, pancreatic beta cells, and GLP-1.
Treatment or prevention of metabolic diseases.
Improvement of glucose tolerance in vivo.
Activation of G protein-coupled receptor 119.
Documented Applications
Treatment or prevention of metabolic diseases, including type 2 diabetes, obesity, dyslipidemia, hypertension, hemostatic disorder, and cardiovascular disease.
Incretin secretion related to GLP-1 from pancreatic beta cells.
Human GPR119 activation assay measuring cAMP in hGPR119-expressing HEK293 cells with relative activation versus OEA.
In vivo glucose tolerance improvement test in fasted C57BL/6 mice with oral administration and glucose challenge.
Activating G protein-coupled receptor 119 in a subject by administering a therapeutically effective amount of the compound of claim 1.
Use in subjects having at least one selected metabolic disease or disorder including cardiovascular disease, a hemostatic disorder, diabetes, obesity, hypertension, or dyslipidemia.
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