The analysis of our previous studies on the search for synthetic analgesics among N-R-amides of bicyclic hetaryl-3-carboxylic acids has been performed; on its basis N-hetaryl(aryl)-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides have been selected as new study objects. The “one pot synthesis” of these compounds, which is simple to perform and at the same time highly effective, has been offered. The method consists in the initial reaction of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and N,N′-carbonyldiimidazole in anhydrous N,N-dimethylformamide with the subsequent amidation of imidazolide formed with hetarylalkyl- or benzylamines in the same solvent. The peculiarities of 1H- and 13C-NMR spectra of the substances obtained, as well as their electrospray ionization liquid chromato-mass spectra are discussed. According to the results of the pharmacological tests carried out on the model of carrageenan inflammation it has been found that all without exception N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides demonstrate the statistically significant analgesic and anti-inflammatory properties. Among the substances presented in this article analgesics and antiphlogistics, which increase the pain threshold and suppress the inflammatory response more effectively than Lornoxicam and Diclofenac in the same doses, have been identified. The molecular and crystal structures of a large group of the substances synthesized have been studied by X-ray diffraction analysis. Comparison of these data with the results of biological tests has revealed the fact of excellent correlation between the molecular conformations of N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides recorded in the crystal and the potency of their analgesic effect. N-Thiophen-2-ylmethyl- and N-4-methoxybenzyl-amides of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid has shown a high analgesic and anti-inflammatory effect, therefore, they deserve more careful research.

In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam.

In order to reveal the regularities of the "structure-biological activity" relationship by interaction of esters of 1-R-4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazin-3-carboxylic acids and trifluoromethyl substituted anilines in boiling xylene with good yields and purity the corresponding N-aryl-4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazin-3-carboxamides have been synthesized. The structure of the compounds obtained has been confirmed by the data of elemental analysis and NMR 1 Н spectroscopy. It has been shown that the presence of trifluoromethyl groups having the powerful electron-withdrawing properties affects the position of signals of the aniline moiety protons: comparing to the spectra of the model methyl derivatives they undergo a significant paramagnetic shift. According to the results of the pharmacological studies conducted it has been found that the replacement of methyl groups in the anilide moiety of 1-R-4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazin-3-carboxamides to trifluoromethyl has a different effect on their analgesic activity, which can remain at the original level, be completely lost or significantly increase. However, N-aryl-4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazin-3-carboxamides definitely lose the ability to influence in any way on the excretory renal function after this chemical modification. СИНТЕЗ ТА БІОЛОГІЧНА АКТИВНІСТЬ ТРИФТОРОМЕТИЛЗАМІЩЕНИХ АНІЛІДІВ 4-ГІДРОКСИ-2,2-ДІ-ОКСО-1Н-2λ 6 ,1-БЕНЗОТІАЗИН-3-КАРБОНОВИХ КИСЛОТ Л.О.Петрушова, І.В.Українець, С.П.Дзюбенко, Л.О.Гріневич Ключові слова: аніліди; 2,1-бензотіазини; синтез; трифторометильна группа; аналгетична активність; діуретичні властивості З метою виявлення закономірностей зв'язку «структура-біологічна активність» взаємодією естерів 1-R-4-гідрокси-2,2-діоксо-1H-2λ 6 ,1-бензотіазин-3-карбонових кислот та трифторометилзаміщених анілінів у киплячому ксилолі з добрими виходами і чистотою синтезовані відповідні N-арил-4-гідрокси-2,2-діоксо-1Н-2λ 6 ,1-бензотіазин-3-карбоксаміди. Будова одержаних сполук доведена даними елементного аналізу та спектроскопії ЯМР 1 Н. Показано, що присутність трифторометильних груп, які виявляють сильні електроноакцепторні властивості, позначається на положенні сигналів протонів анілідних фрагментів-порівняно зі спектрами модельних метильних похідних вони піддаються суттєвому парамагнітному зсуву. За результатам проведених фармакологічних випробовувань знайдено, що заміна метильних груп в анілідному фрагменті 1-R-4-гідрокси-2,2-діоксо-1Н-2λ 6 ,1-бензотіазин-3-карбоксамідів на трифторометильні по-різному впливає на їх аналгетичну активність, яка може залишатися на вихідному рівні, повністю втрачатися або ж значно посилюватися. А ось здатність впливати будь-яким чином на сечовидільну функцію нирок N-арил-4-гідрокси-2,2-діоксо-1Н-2λ 6 ,1-бензотіазин-3-карбоксаміди після зазначеної хімічної модифікації однозначно втрачають.

With the aim of deducing a structure-biological dependence we have carried out the synthesis of quinoline-3-carboxylic acid N-R-amides with a p-methoxyphenyl substituent in the amide part of the molecule. The effects of the compounds prepared on the excretory function of the kidney are discussed. Using a system of simplex descriptors and the method of tree type classification a QSAR model has been constructed which is suitable for prediction of the diuretic activity of novel quinolinecarboxylic acid N-R-amides.The ability of 4-hydroxy-2-quinolones to show clear diuretic activity was first discovered accidentally amongst 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid arylalkylamides about 20 years ago [2]. In later extended screening studies a similar type of biological activity was revealed in the closely structurally related amide derivatives of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-and also 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids ([3-5] and [6-7] respectively). In this way it was possible to show several important structure-biological activity relationships. Firstly, the need was revealed for the presence of an aryl fragment in the amide part of the molecule. Secondly, it was experimentally confirmed that there was a marked increase in diuretic action with approach of the aryl ring to the amide nitrogen atom. Hence in the series 3-arylpropylamide → 2-arylethylamide → benzylamide → anilide with the same substituents in the aromatic ring the most active generally proved to be the anilide. Thirdly, the most powerful positive effect on

Keywords: 2-aminopyrimidine, 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, bromination, antitubercular activity, X-ray structural analysis.Pyrimidine bases occur in a number of the most widespread heterocyclic systems in nature. Occurring in nucleic acids and coenzymes these compounds play a direct role in encoding and transmitting hereditary information, in the metabolism of carbohydrates and lecithin, and also in many biochemical processes important for animals and plants [2]. As a result, natural pyrimidines have an extremely broad spectrum of biological activities: from vitamins and regulators of biosynthesis amongst specific living organism proteins to antibiotics and alkaloids and to tetrodotoxin [3] which is one of the most powerful non-protein neurotoxins. Of course, pharmaceutical chemistry has not stood aside from the facts listed. As a result, to this day around 100 synthetic preparations [4] based on pyrimidine have been created and indeed used in medicinal practice. The majority of them fit into four broad categories of well known substances: barbiturates, sulfanilamides, antimicrobial pyrimidine-2,4-diamines, and antitumor agents [3]. Less impressive but none the less valuable for public health are such pharmacological groups as diuretics, antihypertensive and antihistamine agents, anticonvulsants, vitamins etc. [3,4].