Mesoionic Xanthine Research Articles

A preliminary investigation of Mesoionic Xanthine analogues as inhibitors of platelet aggregation

A series of mesoionic xanthines (e.g. mesoionic thiazolopyrimidines, 3, and thiadiazolopyrimidines, 5) and related analogues were examined as inhibitors of human platelet aggregation. Appropriately substituted compounds were found to fully inhibit platelet aggregation, and anhydro-(6-ethyl-8-isopentyl-7-oxo-5-hydroxy-1,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide) (5b) was 40 times more potent than the structurally related xanthine theophylline (1). Gel filtration studies suggest that compound 5b irreversibly inhibits aggregation and this might be due to its ability to act as a latent acylation agent.

ChemInform Abstract: A Facile Preparation of Some Novel Class II Mesoionic Xanthine Acyclonucleosides.

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A facile preparation of some novel class II mesoionic xanthine acyclonucleosides

AbstractThe synthesis of the first examples of Class II mesoionic xanthine acyclonucleosides is described. A series of mesoionic anhydro‐(8‐methoxyalkyl‐5‐hydroxy‐7‐oxothiazolo[3,2‐a]pyrimidinium hydroxides), Class II mesoionic analogs isoconjugate with xanthine, were prepared by the thermal condensation of methoxyalkyl‐2‐aminothiazoles with substituted bis(2,4,6‐trichlorophenyl)malonic esters. The memoxyalkyl‐2‐aminothiazoles were prepared via an aromatic nucleophilic substitution reaction between 2‐bromothiazole and the appropriate methoxyalkylamine in excess. The resulting 8‐methoxyalkyl‐substituted mesoionic xanthines were demethylated using iodotrimethylsilane in acetonitrile at room temperature to afford the corresponding mesoionic anhydro‐(8‐hydroxyalkyl‐5‐hydroxy‐7‐oxothiazolo[3,2‐a]pyrimidinium hydroxides) as the Class II mesoionic xanthine acyclonucleosides.

Non-xanthine heterocycles: Activity as antagonists of A 1 and A 2-adenosine receptors

A variety of non-xanthine heterocycles were found to be antagonists of binding of [ 3H]phenylisopropyladenosine to rat brain A 1-adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxamidoadenosine with A 2-adenosine receptors in human platelet and rat pheochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A 1 and A 2-adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N 6-substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A 1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A 1 and A 2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A 1- and A 2-adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and β-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak non-competitive adenosine antagonist.

Studies of amine‐induced ring opening of some mesoionic xanthines

AbstractThe ring‐opening reactions of seven mesoionic thiazolo[3,2‐a]pyrimidine‐5,7‐diones by a series of primary and secondary amines have been investigated. The rates of the ring fission of five N(8)‐substituted mesoionic xanthines with benzylamine were measured and found to follow second order kinetics. The Hammett relationship is followed with ϱ value of + 0.48 in p‐dioxane as solvent. The dependence of rates on temperatures has been studied for the N(8)‐ethyl derivative; the energy of activation (ΔE*) is 25.3 kcals mol−1, the enthalpy of activation (ΔH*) is 24.7 kcals mol−1 and the entropy of activation (ΔS*) is — 4.9 e.u. A slight increase in rate of reaction was observed when the solvent was changed from p‐dioxane to dimethyl sulfoxide. In p‐dioxane at constant mesoionic xanthine concentration, the rate constant for ring opening decreased with increasing benzylamine concentration. These results are consistent with a bimolecular nucleophilic mechanism proceeding by the rate‐determining formation of a charged tetrahedral transition state.

Correlation of biological activities of mesoionic and benz-fused mesoionic xanthine analogs with van der Waals volume and molecular connectivity.

The adenosine cyclic 3',5'-monophosphate (c-AMP) phosphodiesterase (PDE) inhibitory activity of a series of mesoionic 1,3,4-thiadiazolopyrimidines and of a group of benz-fused mesoionic xanthine analogs are found to be significantly correlated with the van der Waals volume (VW) of the substituents or the first order valence connectivity index (1 chi V) of the molecule. From the correlating equations it is observed that the size of the substituents at certain positions, of pyrimidine ring particularly, in the molecule are determinative to the activity. Further based on these equations it may be suggested that PDE inhibition by this class of drugs involves either hydrophobic interaction or van der Waals type of interaction. In certain cases steric and electronic factors are also indicated to affect the inhibition.

Carbon‐13 nuclear magnetic resonance spectra of some mesoionic xanthine analogs

AbstractNatural abundance 13C NMR chemical shifts have been experimentally determined for a series of mesoionic thiazolo[3,2‐a]pyrimidine‐5,7‐diones. The spectral data are compared with those of related mesoionic dihydrothiazolo[3,2‐a]pyrimidine‐5,7‐diones and mesoionic 1,3,4‐thiadiazolo[3,2‐a]pyrimidine‐5,7‐diones. Resonable correlation between the observed 13C NMR chemical shifts and CNDO/2 total charge densities have been obtained for the different carbon atoms of 8‐methylthiazolo[3,2‐a]pyrimidine‐5,7‐dione.

Synthesis of mesoionic xanthine nucleosides

The synthesis of the first examples of Class II mesoionic xanthine nucleosides is described. Tri-O-acetylribofuranosylaminothiazole is cyclized by condensation with bis (2,4,6-tri-chlorophenyl) malonate and the resultant product is de-protected to yield anhydro (8-β- D -ribofuranosyl-5-hydroxy-7-oxothiazolo [3,2-a] pyrimidinium hydroxide); the glucosyl derivative is prepared in a similar manner.

Imidazo[1,2‐α]pyrimidines and 1,2,4‐triazolo[1,5‐α]pyrimidines: Two new examples of mesoionic xanthine analogs

AbstractSeveral derivatives of mesoionic imidazo[1,2‐α]pyrimidine‐5,7‐dione and 1,2,4‐triazolo[1,5‐α]pyrimidine‐5,7‐dione, two new examples of mesoionic xanthine ring systems, were prepared and characterized. These compounds were conveniently prepared by the condensation of bis‐(2,4,6‐trichlorophenyl) malonates with the appropriately substituted alkylaminoimiazole or 1,2,4‐triazole.

ChemInform Abstract: MESOIONIC XANTHINE ANALOGS AS INHIBITORS OF CYCLIC AMP PHOSPHODIESTERASE

AbstractDie Umsetzung von 2‐Aminothiazol (I) mit Acylchloriden oder Anhydriden ergibt die Amide (II), die mit LiAlH4 zu den Aminen (III) reduziert werden.

Mesoionic Xanthine Analogs as Inhibitors of Cyclic AMP Phosphodiesterase

Several derivatives of two mesoionic xanthine analogs, mesoionic thiazolo[3,2-a]pyrimidine-5,7-diones and mesoionic 1,3,4-thiadiazolo[3,2-a]pyrimidine-5,7-diones, were synthesized and evaluated as inhibitors of cyclic AMP phosphodiesterase. A significant number of these compounds demonstrated theophylline-like activity.