Synthesis and antiprotozoal activity of pyridine thioaryl ethers

By reaction of pyridine nitro derivatives containing a mobile halogen atom with thiols of the benzene series, twelve thioaryl ethers of nitropyridine were obtained. However, 2-chloro-3-nitropyridine and 2-chloro-5-nitropyridine were used as reactive pyridine compounds. The reaction was carried out in dimethylformamide (DMFA) or dimethyl sulfoxide (DMSO) in the presence of bases: sodium ethylate, potash, sodium hydride. Generally, the yields exceeded 90%. The sulfur containing derivatives of aromatic series were 2-mercaptobenzoic acid (compound 1 of Table 1), methyl ester of 2-mercaptobenzoic acid (compounds 2 and 3 of Table 1), compound 3 being obtained by reduction of nitro group of compound 2. Also the amides of 2-mercaptobenzoic acid were used: 3-dimethylaminopropylamide of 2-mercaptobenzoic acid (compound 4 of Table 1), and also the reduction product of compound 4 to 3-aminopyridine derivative (compound 5 of Table 1) and morfolide of 2-mercaptobenzoic acid (compound 6 of Table 1). To make the water-soluble a sodium salt of 2-mercaptobenzoic acid was obtained (compound 7 of Table 1). A number of compounds with the pyridine ring nitrogroup reduced to amine (compounds 8, 10 of Table 1), as well as a number of derivatives containing both free (compounds 9, 10 of Table 1) and acylated amino group (compound 11 of Table 1) were also obtained. We also prepared compound 12 representing a product of interaction of 2-chloro-3-nitropyridine with 2-mercapto-3-acetylpyridine. We should note that the best nitrogroup reductant for the synthesis of compounds 3, 5, 7, and 10 is powdered iron in alcohol medium containing both inorganic and organic acids (hydrochloric or acetic acid). The application of other reducing agents (sodium sulfide and ammonium sulfide) led to strong resinification of the reaction mixture. The compounds were recrystallized from organic solvents (ethyl acetate, benzene, ethanol) for purification. Significant antiprotozoic activity was found in 7 of 12 compounds (58%), with 3-nitro-2-chloropyridine being the most active (7.8 and 3.9 ?g/ml). To enhance the activity, the synthesis of compounds with an amino group in the benzene ring as well as the introduction of both donor and acceptor substituents into the benzene ring is recommended.

A DEVELOPMENT OF AN EFFECTIVE METHOD FOR THE SYNTHESIS OF 2-(5-OXO-4,5-DIHYDRO-1,2,4-OXADIAZOL-3-YL)BENZOIC ACID

2-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid was synthesized using a new effective method – thermal heterocyclization of 3-(hydroxyimino)isoindolin-1-one, which occurs as a result of its interaction with 1,1'-carbonyldiimidazole (CDI) and subsequent base-promoted cycleopening of the obtained intermediate 3H,5H-[1,2,4]oxadiazolo[3,4-a]isoindole-3,5-dione. Direct cyclization of 3-(hydroxyimino)isoindolin-1-one by the reaction with diethyl carbonate in the presence of sodium ethylate in ethanol at room temperature and under heating was unsuccessful. The same result was observed when using triphosgene in the presence of triethylamine in dichloromethane. Treating 3-(hydroxyimino)isoindolin-1-one with methyl chloroformate gave 3-(((methoxycarbonyl)oxy)-imino)isoindolin-1-one which was thermally stable and was not cyclized into the desired acid by boiling in toluene and o-xylene for 24 hours. The reflux of the excess of CDI with 3-(hydroxyimino)isoindolin-1-one in anhydrous ethyl acetate and subsequent alkaline hydrolysis gave the desired 2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid in a total yield of 90%. An attempt to stop the process at the stage of formation of the intermediate 3H,5H-[1,2,4]oxadiazolo[3,4-a]isoindole-3,5-dione by carrying out the reaction in the absence of a base failed. Its partial hydrolysis took place during the reaction, and especially at the stage of isolation, and as a result a mixture of 3H,5H-[1,2,4]oxadiazolo[3,4-a]isoindole-3,5-dione and 2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid was formed in a ratio of about 2:3. The obtained substance after mixing with aqueousmethanolic NaOH solution and subsequent acidification with 1M HCl was quantitatively converted into the pure desired acid. The developed method allows the use of 3-(hydroxyimino)isoindolin-1-ones as convenient starting materials for the preparation of vic-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)aromatic acids and subsequently related compounds, in particular isomeric vic-carbamimidoyl(hetero)aromatic carboxylic acids, which cannot be obtained by other currently known methods. All the compounds obtained during the development of the method were studied by means of NMR spectroscopy.

Some derivatives of 5-(2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl)pentanoic acid

Using the chloride method esters II - X, amides XI - XIV, and condensates with amino acid esters XV - XVII were prepared from 5-(2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl)pentanoic acid (I); the amides XIII and XIV were also prepared by aminolysis of ester II. The derivative of glycine, XVIII, was obtained on saponification of ester XV, also obtained by condensation of triethyl ester of N-(6,6-dicarboxyhexanol)glycine (XXIII) with guanidine hydrochloride in a medium containing sodium ethylate. Hydrazinolysis of ethyl ester XXIV gave hydrazine XIX. Disubstituted ureas XX - XXI were obtained on reaction of esters VI and XXIV with 2-chloroethyl isocyanate; saponification of the ester function in the urea derivative XX led to the free acid XXII. Reaction of acid I with an excess of diazomethane gave a mixture of compounds in which compound XXV (a product of esterification and O-methylation) and XXVI( a product of esterification, O-methylation, and N-methylation) predominated. None of the substances prepared displayed a clear ant-tumour activity. Some of the substances tested affected the weight of experimental tumours (XV, XVI, XX, XXV) or protracted the survival time of experimental animals (XXVI, XX). Substance XX had the broadest spectrum of activity.