Keywords: amides, 2-hydroxy-4-oxo-4H-pyrido-[1,2-a]pyrimidine-3-carboxylic acids, tricarbonylmethane heterocyclic derivatives, diuretic activity, X-ray structural analysis.The problem of discovering novel classes of chemical substances capable of diuretic action, and particularly important, those which are highly efficient and safe diuretic medicines has not lost its urgency even over recent decades. Interesting substances investigated within this scheme are amidated 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids derivatives [2,3]. Although for a long time high diuretic activity has not been considered a characteristic of quinolone compounds, several of these materials proved extremely promising and have been subjected to broad pharmacological investigation to this time. With this in mind we have carried out the synthesis and biological screening to reveal the ability of the series of structurally related 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid N-R-amides 1-3 to increase the diuretic kidney function.It was found that the alkylamides 1a-u (Table 1) can be prepared by the reaction of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (4) with a two, or better three, fold excess of the corresponding alkylamine in refluxing ethanol. It was initially proposed that it was necessary to use quite a large excess of the _______ * For Communication 143 see [1].

the synthesized compounds exist in DMSO solution in the 2-hydroxy-4-oxo form while in the crystal (at least for the case of the unsubstituted derivative) X-ray analysis shows that it occurs in the bipolar 2,4-dioxo form.Interest in 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives is principally due to their broad spectrum of biological activity. Based on this molecular system there have been synthesized bicyclic diaza sugars which inhibit β-glucosidase with high specificity [2]. 2-(Benzothiazol-2-yl) derivatives are novel, oral inhibitors of human leukocyte elastase suitable for treating chronic obstructive illnesses of the lungs, asthma, emphysema, cystic fibrosis, and various inflammatory reactions [3]. Substituted ethylenediamines containing the pyrido-[1,2-a]pyrimidine fragment are effective in the fight against microbacterial infection, not just tubercular [4]. 4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides find use as agents for the prophylaxis of gastric problems arising from the use of nonsteroidal anti-inflammatory agents [5]. 2-Amino-4H-pyrido[1,2-a]pyrimidin-4-ones actively inhibit the aggregation of human thrombocytes [6] and their analogs with a tetrazole fragment in position 3 the synthesis of leukotrienes [7].We have continued our work on preparative methods of synthesis and a study of the structure, chemical reactivity, and biological properties of 4-hydroxy-2-quinolinones and heterocycles related to them. This report concerns ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate.

Continuing the search for new potential analgesics among the derivatives of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, the possibility of obtaining its esters by the alkylation of the corresponding sodium salt with iodoethane in dimethyl sulfoxide (DMSO) at room temperature was studied. It was found that under such conditions, together with the oxygen atom of the carboxyl group, a heteroatom of nitrogen is also alkylated. Therefore, the product of the reaction studied is a mixture of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate (major) and its 1-ethyl-substituted analog (minor). A simple but very effective method of preparative separation of these compounds was proposed. Moreover, the heterogeneous crystallization from ethanol was revealed to result in a monoclinic polymorphic form of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate, while the homogeneous crystallization results in its orthorhombic form. The molecular and crystal structures of both forms were confirmed by X-ray diffraction analysis, and the phase purity by powder diffraction study. The pharmacological tests carried out on the model of a carrageenan edema showed that the screening dose of 20 mg/kg of 1-ethyl-substituted ester and the orthorhombic form of its analog unsubstituted in position 1 exhibited weak anti-inflammatory and moderate analgesic effects. At the same time, the monoclinic form of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate appeared to be both a powerful analgesic and an anti-inflammatory agent that exceeded Piroxicam and Meloxicam in the same doses by these indicators. A detailed comparative analysis of the molecular and crystal structures of two polymorphic forms of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate was carried out using quantum chemical calculations of the energies of pairwise interactions between molecules. An explanation of the essential differences of their biological properties based on this was offered.

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Fused pyrimidine derivatives R 0515 4-Hydroxy-2-quinolones. Part 120. Synthesis and Structure of Ethyl 2-Hydroxy--4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate. -(UKRAINETS, I. V.; BEREZNYAKOVA, N. L.; PETYUNIN, G. P.; TUGAIBEI, I. A.; RYBAKOV, V. B.; CHERNYSHEV, V. V.; TUROV, A. V.; Chem. Heterocycl.