Synthesis, structure–property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor

5-Alkyl-1,3-Oxazole Derivatives of 6-Amino-Nicotinic Acids as Alkyl Ester Bioisosteres are Antagonists of the P2Y 12 Receptor

“…Preparative HPLC was performed on a Waters YMC-ODS AQS-3 120 Angstrom 3 × 500 mm or on a Waters Delta Prep System using Kromasil C8, 10 µm columns. Gradient: 95% 0.1 M ammonium acetate buffer: 5% CH 3 CN → 100% CH 3 CN [19]. 1 H NMR measurements were performed on a Varian Mercury VX 400 spectrometer, operating at a 1 H frequency of 400 MHz or on Varian UNITY plus 400, 500 and 600 spectrometers, operating at 1 H frequencies of 400, 500 and 600 MHz, respectively.…”

“…These include the thienopyridine prodrugs ticlopidine and clopidogrel, whose active metabolites bind irreversibly to the receptor [7], and ticagrelor [8,9], the first reversibly binding, direct-acting P2Y 12 antagonist. Other examples of P2Y 12 antagonists include piperazinylglutamate-pyridines and -pyrimidines [10-13], thienopyrimidines [14], anthraquinones [15], adenosine analogs [16], and dinucleoside polyphosphates and nucleotides [17].Series of urea [18], sulfonylurea [19] and acyl sulfonamide [20] derivatives of ethyl nicotinates, exemplified by compounds 1-3 (FiguRe 1), are antagonists of the P2Y 12 receptor. A common structural motif of these compounds is the ethyl ester functionality that may be prone to metabolism.…”

“…Series of urea [18], sulfonylurea [19] and acyl sulfonamide [20] derivatives of ethyl nicotinates, exemplified by compounds 1-3 (FiguRe 1), are antagonists of the P2Y 12 receptor. A common structural motif of these compounds is the ethyl ester functionality that may be prone to metabolism.…”

“…The 5-ethyl-oxazole 31 ( FiguRe 5) was prepared from 28 by an eight-step procedure [19]. The use of a Swern oxidation of the secondary alcohol early in the sequence increased the overall yield compared with the synthesis of oxazoles 12-14 ( FiguRe 3) where aromatization was made by a lower-yielding procedure with DDQ.…”

“…This was cyclized with POCl 3 to give 5-ethyl-oxazole 32. The ethyl ester 33 [19] was hydrolyzed and then treated in a similar fashion to provide 34. The ester hydrolysis product of 33 was difficult to handle due to low solubility in organic solvents and the sequence leading to 34 was difficult to reproduce. These issues were circumpassed by protection of 35 (the sodium salt of 33, FiguRe 7) with a 2-(trimethylsilyl)ethoxymethyl (SEM) group to give the regioisomers 36 and 37 (94:6 ratio).…”