Studies on Azole Compounds. III. Reactions of Oxazole N-Oxides with Phosphoryl Chloride and Acetic Anhydride

Goto, Yoshinobu; Yamazaki, Motoyoshi; Hamana, Masatomo

doi:10.1248/cpb.19.2050

Cited by 29 publications

(21 citation statements)

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“…Z-selective acid catalyzed water elimination and subsequent deprotection yielded phenol 32 in an overall yield of 72 %. Following the method of Goto et al, [27] butane-2,3-dione mono-oxime 34 was reacted with 2-fluorobenzaldehyde 33 furnishing oxazole N-oxide 35 that was subsequently treated with POCl 3 to give chloromethyl oxazole 36. Coupling of phenol 32 and oxazole 36 was most conveniently accomplished with Cs 2 CO 3 and KI.…”

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confidence: 99%

Design and Biological Evaluation of Novel, Balanced Dual PPARα/γ Agonists

Grether¹,

Bénardeau²,

Benz³

et al. 2009

ChemMedChem

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An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.

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confidence: 99%

Design and Biological Evaluation of Novel, Balanced Dual PPARα/γ Agonists

Grether¹,

Bénardeau²,

Benz³

et al. 2009

ChemMedChem

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“…15 Scheme showed a simple synthetic route to the oxazoles. Butane-2,3-dione mono-oxime 13 was reacted with benzaldehyde 12 and hydrochloric acid in dioxane to afford oxazole N-oxide 14.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Oxime Ethers of β-Oxo-γ-phenylbutanoic Acids as PPAR α and -γ Dual Agonists

Han¹,

Koh²,

Kim³

et al. 2012

Bulletin of the Korean Chemical Society

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“…Chloromethyloxazole 17 15) was reacted with methyl 4-hydroxybenzoate under basic conditions to yield 18. Hydrolysis of 18 gave 5 in good yield.…”

Section: Chemistrymentioning

confidence: 99%

Studies on Non-Thiazolidinedione Antidiabetic Agents. 3. Preparation and Biological Activity of the Metabolites of TAK-559

Matsumoto

Odaka

et al. 2004

Chem. Pharm. Bull.

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Peroxisome proliferator-activated receptor gamma (PPARg) is one of a subfamily of PPARs encoded by independent genes. Three human PPARs, designated PPARa, PPARg, and PPARd, have been identified. [3][4][5] Recent studies suggest that PPARg ligands have the ability to lower plasma glucose and triglyceride levels in insulin-resistant animal models.6) Some glucose and lipid lowering agents, which have transcriptional activity at PPARg, are currently used for clinical treatment of type 2 diabetes. 7-9)In a previous paper, we showed (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (TAK-559) (1), a novel oxyiminoalkanoic acid derivative, had strong functional activity at PPARg (Chart 1).2) TAK-559 also exhibits marked glucose and lipid lowering activities in insulin-resistant animal models, KKA y mice and Wistar fatty rats, 2,[10][11][12][13] and is under clinical trials. Metabolites M-I, M-II, M-III and M-IV were found during preclinical and clinical studies on TAK-559 (1), and their proposed structures are shown in Chart 1. To confirm the structures and to study the biological properties of the metabolites, compounds 2-5 (Charts 2-4) were synthesized and their biological activities were evaluated by both in vitro and in vivo experiments. Analytical high-performance liquid chromatography (HPLC) and mass spectroscopy (MS) of isolated metabolites (M-I, M-II, M-III, M-IV) and synthesized compounds (2-5) were shown to be identical respectively (data not shown). Transactivation activities of compounds 1-5 for human PPAR subtypes were examined using in vitro experiments, and the glucose and lipid lowering effects of the compounds were evaluated in Wistar fatty rats using in vivo experiments. The results are described below. ChemistryCompounds 2 and 3 were synthesized from commercially available 6a and 6b, respectively (Chart 2). Friedel-Crafts acylation of 6a-b gave aryl ketones 7a-b, of which the methoxy groups were converted into hydroxy groups using boron tribromide to yield 8a-b. Reactions of 8a-b with 9 2) gave aldoximes, which were hydrolyzed to afford 2 and 3.Compound 4 was prepared following the procedure described in Chart 3. The hydroxy group of compound 10 14)was protected using chloromethyl methyl ether to give 11. Lithiation at the 5-position of the oxazole 11 with n-butyllithium, followed by treatment with N,N-dimethylformamide, yielded aldehyde 12. Reduction of 12 gave the corresponding alcohol, which was protected using tert-butylchlorodiphenylsilane to yield 13. Selective removal of the methoxymethyl group of 13 was achieved using bromotrimethylsilane to give alcohol 14. Compound 14 was reacted with methanesulfonyl chloride, then coupled with 15 2) to provide 16. Removal of the tert-butyldiphenylsilyl group of 16 and subsequent hydrolysis of the ester group gave the desired compound 4.Chart 4 shows the synthesis of 5. Chloromethyloxazole 17 15) was reacted with methyl 4-hydroxybenzoate under basic conditions to yield 18. Hydrolysis of 18 gave 5 in good yield. Results...

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Studies on Azole Compounds. III. Reactions of Oxazole N-Oxides with Phosphoryl Chloride and Acetic Anhydride

Cited by 29 publications

References 0 publications

Design and Biological Evaluation of Novel, Balanced Dual PPARα/γ Agonists

Design and Biological Evaluation of Novel, Balanced Dual PPARα/γ Agonists

Design and Synthesis of Oxime Ethers of β-Oxo-γ-phenylbutanoic Acids as PPAR α and -γ Dual Agonists

Studies on Non-Thiazolidinedione Antidiabetic Agents. 3. Preparation and Biological Activity of the Metabolites of TAK-559

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