Synthesis and Anti-Aggregation Activity of 2-[3-Methyl-1-Ethylxanth-8-Ylthio]Acetate Salts Containing Thietanyl and Diox
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Pharmaceutical Chemistry Journal, Vol. 54, No. 5, August, 2020 (Russian Original Vol. 54, No. 5, May, 2020)
SEARCH FOR NEW DRUGS SYNTHESIS AND ANTI-AGGREGATION ACTIVITY OF 2-[3-METHYL-1-ETHYLXANTH-8-YLTHIO]ACETATE SALTS CONTAINING THIETANYL AND DIOXOTHIETANYL RINGS K. G. Gurevich,1 A. L. Urakov,2,* F. A. Khaliullin,3 A. V. Samorodov,3 Yu. V. Shabalina,3 F. Kh. Kamilov,3 D. Z. Murataev,3 and L. I. Bashirova4
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 5, pp. 16 – 20, May, 2020.
Original article submitted April 7, 2020. Reactions of 2-[1-ethyl-3-methyl-7-(thietan-3-yl)- and 2-[1-ethyl-3-methyl-7-(1,1-dioxothietan-3-yl)xanth8-ylthio]acetic acids with amines (diethylamine, monoethanolamine, diethanolamine, triethanolamine, piperidine, cyclohexylamine, and benzylamine) gave 42 – 89% yields of 2-[1-ethyl-3-methyl-xanth-8-ylthio]acetate salts containing thietanyl and dioxothietanyl rings. The structures of the synthesized compounds were confirmed using IR and PMR spectroscopy. The synthesized compounds exhibited anti-aggregation activity. Keywords: xanthines, thietanes, anti-aggregation activity.
The xanthine derivative pentoxifylline is used to correct disturbances of blood rheological properties, suppress erythrocyte and platelet aggregation, lower blood viscosity, and increase erythrocyte elasticity [1]. The salt cyclohexylammonium 2-[3-methyl-1-propyl-7-(1-oxothietan-3-yl)xanth-8-ylthio]acetate exhibited anti-aggregation properties of platelets and was reported by us [2]. Research on the anti-aggregation activities of a series of thietane-containing salts of 2-(3-methyl-1-ethylxanth-8-ylthio)acetic acids has begun [3]. In continuation of the search for xanthine derivatives with anti-aggregation activity, we synthesized new salts of 2-(3-methyl1-ethylxanth-8-ylthio)acetic acids containing thietanyl and dioxothietanyl rings. The starting compounds were 2-[3-methyl-7-(thietan-3yl)- and 2-[3-methyl-7-(1,1-dioxothietan-3-yl)-1-ethylxanth1
2 3 4 *
8-ylthio]acetic acids (1a and 1b), which were synthesized by the literature methods [3]. Salts were produced using the amines diethylamine, monoethanolamine, diethanolamine, triethanolamine, piperidine, cyclohexylamine, and benzylamine. Reactions of 1a with the amines in Me2CO gave 54 – 89% yields of the salts of 2-[3-methyl-7-(thietan-3-yl)1-ethylxanth-8-ylthio]acetic acid (IIa-g). By analogy, 1b gave 42 – 89% yields of salts of 2-[3-methyl-7-(1,1-dioxothietan-3-yl)-1-ethylxanth-8-ylthio]acetic acid (IIh-n). IR spectra of IIa-n exhibited absorption bands for N+–H stretching vibrations at 2200 – 3580 cm–1. Furthermore, spectra of IIh-n contained strong absorption bands for symmetric and asymmetric stretching vibrations of SO2 groups at 1134 – 1147 and 1307 – 1324 cm–1. PMR spectra confirmed formation of the salts and contained characteristic resonances of the thietanyl or dioxothietanyl rings and alkyl substituents. The SCH2 singlets of the thioglycolic acid appeared at ~4 ppm. Resonances of the amine protons were also observed. For example, triplets and
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