Synthesis of ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate, a hypolipidemic agent, and related compounds

Abstract

A series of 2-aryl and 2-alkyl derivatives of 5-furyl-4-oxazoleacetic acid and their homologues having alkyl groups at the alpha-position of the acids were synthesized and evaluated for their hypolipidemic activities in Sprague-Dawley rats. On the basis of the structure-activity relationships and subacute toxicities, ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate (35) was selected as a candidate compound for development. Compound 35 reduced serum cholesterol and triglyceride levels by 23% and 35%, respectively, at a dose of 0.05% in a diet in normal rats, and it was about 10 times more active in hereditary hyperlipidemic rats (THLR/1) than in normal rats. Compound 35 inhibited platelet aggregation in vitro and also normalized hyperaggregability of hyperlipidemic plasma platelet ex vivo.

Identification of Human UDP-Glucuronosyltransferase Isoform(s) Responsible for the Glucuronidation of 2-(4-Chlorophenyl)-5-(2-Furyl)-4-Oxazoleacetic Acid (TA-1801A)

“…When TA-1801, 1) an ester prodrug of TA-1801A [2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetic acid, Fig. 1], was administered orally to humans, the glucuronide of TA-1801A was the most abundant metabolite in human urine.…”

The Use of 5-Hydroxymethylfurfural towards Fine Chemicals: Synthesis and Direct Arylation of 5-HMF-Based Oxazoles

“…Amid heterocycles, the oxazole ring is present in different molecules of interest ( Figure 1, 1-3). [16][17][18][19][20][21] The furyl-oxazole scaffold also has presence in chemical or medical literature and its main applications were in the development of molecules with hypoglycemic, [22][23][24] antilipidemic, 23,25,26 antiinflammatory, 27,28 antinoceptive 29 and cardioprotective 30 activities. The usual synthetic routes for oxazole-containing compounds are the oxidative cyclization of amides, α,γ-unsaturated amides, propargylic amides or iminoketones, the annulation of alkynes and nitriles, the ring expansion of ketoaziridines, the Van Leusen reaction between an aldehyde and the commercial reagent tosylmethyl isocyanide (TosMIC), among others.…”

“…69 We obtained compounds containing substituents in the para (5-12, 14-19), meta (20)(21)(22)(23)(24), and ortho (27-31) positions of the aryl ring. Additionally, compounds containing a C2-heteroayl bond (13,(25)(26) and di-or tri-substituted aryl rings (32-35, 37) were also obtained. Noticeably, lower yields (38-41%) were obtained with -N and -S containing heterocycles, such as 3iodopyridine (13), 4-iodopyridine (25) and 3-iodothiophene (26).…”

“…Additionally, compounds containing a C2-heteroayl bond (13,(25)(26) and di-or tri-substituted aryl rings (32-35, 37) were also obtained. Noticeably, lower yields (38-41%) were obtained with -N and -S containing heterocycles, such as 3iodopyridine (13), 4-iodopyridine (25) and 3-iodothiophene (26). The aryl substituents were chosen to cover a range of functional groups with different electronic (electron-donating and electron-withdrawing groups), steric and physicochemical properties.…”

Synthesis of 5-alkyl-4-oxazoleacetic acid derivatives with hypolipidemic activities.

“…Chemistry Ethyl 4-oxazoleacetates(17-25)and the acids(26-31)were synthesized(as outlined in Chart 1)according to our previously reported method. 2,3)The key intermediates,ethyl 3-(Nacylamino)-4-oxobutyrates (8)(9)(10)(11)(12)(13)(14)(15)(16),were prepared in two ways: by introduction of an acetic (6H,d,J=6Hz). MS m/z:340(M+).…”