Kubo, Osamu; Takami, Kazuaki; Kamaura, Masahiro; Watanabe, Koji; Miyashita, Hirohisa; Abe, Shinichi; Matsuda, Kae; Tsujihata, Yoshiyuki; Odani, Tomoyuki; Iwasaki, Shinji; Kitazaki, Tomoyuki; Murata, Toshiki; Sato, Kenjiro published an article in 2021. The article was titled 《Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives》, and you may find the article in Bioorganic & Medicinal Chemistry.HPLC of Formula: 18621-18-6 The information in the text is summarized as follows:
The designs, syntheses, and biol. activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives I [R = Cl, 5-methylsulfonylindolin-1-yl, 4-methylsulfonylcyclohexoxy, etc.; R1 = cyano, tert-butoxycarbonyl, 3-(1-fluoro-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl, etc.] and II [R2 = Cl, (1-tert-butoxycarbonyl-4-piperidyl)amino, (1-tert-butoxycarbonyl-4-piperidyl)-ethyl-amino, etc.] as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, and also discussed the conformational preference of representative compounds To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, were replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group I [R = 5-methylsulfonylindolin-1-yl, R1 = tert-butoxycarbonyl] not only enhanced GPR119 agonist activity but also considerably improved the human ether-a-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as Et analog II [R2 = (1-tert-butoxycarbonyl-4-piperidyl)-ethyl-amino]. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, I [R = 5-methylsulfonylindolin-1-yl, R1 = 3-(1-fluoro-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl] was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration.Azetidin-3-ol hydrochloride(cas: 18621-18-6HPLC of Formula: 18621-18-6) was used in this study.
Azetidin-3-ol hydrochloride(cas:18621-18-6) is one of azetidine.Azetidines (azacyclobutanes) constitute a well-known class of heterocyclic compounds. Azetidine scaffold has been discovered in several natural products.HPLC of Formula: 18621-18-6 Several pharmacologically important synthetic compounds also contain azetidine ring. Because of inherent ring strain, the synthesis of azetidines is a challenging endeavor.
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