Povilas Vainilavicius

Synthesis and anti-inflammatory activity of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives

The synthesis of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives and the results of anti-inflammatory activity in vivo are described. Most of the tested compounds exhibited anti-inflammatory activity and some of them were more active than acetylsalicylic acid.

Synthesis of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione and its Reactions with Polyfunctional Electrophiles

Summary. In the reaction of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with hydrazine hydrate, 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione was formed. The reactions of the latter with ethyl bromoacetate and chloroacetonitrile in the presence of triethylamine proceeded under formation of the corresponding S-alkylated derivatives, whereas from its reaction with ω-bromoacetophenone and ethyl 4-chloroacetoacetate triazolothiadiazines were obtained. Treatment of the title compound with ethyl 2-chloroacetoacetate led to the formation of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-N-acetylamino-(3-ethoxy-carbonylmethylthio)-1,2,4-triazole. Performing of the latter reaction without basic catalyst gave a triazolothiadiazine. Treatment of the S-alkylated derivatives with sodium methoxide resulted in triazolothiadiazines via a cyclocondensation reaction.

Synthesis of 1-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)acetyl-4-alkyl(aryl)thios emicarbazides and their heterocyclisation to 1,2,4-triazoles and 1,3,4-thiadiazoles

5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)methyl-1,3,4-oxadiazole-2-thione reacts with amines to give 1-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)acetyl-4-alkyl(aryl)thiosemicarbazides, which on treatment with base or acid undergo cyclisation to 4-alkyl-1,2,4-triazole-2-thiones or 4-amino-1,3,4-thiadiazoles, respectively.

Reactions of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with Electrophiles

Summary. Treatment of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with haloalkanes yielded oxadiazole S-alkyl derivatives, whereas its reaction with formaldehyde and amines resulted in formation of oxadiazole N(3)-aminomethyl derivatives. The alkylation of 2-alkylsulfanyl-5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazoles with methyl bromoacetate proceeded at the N(1)-position of pyrimidine to give 2-alkylsulfanyl-5-(1-methoxycarbonylmethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazoles, whereas aminomethylation, bromination, or nitration took place at position 5 of pyrimidine ring and afforded the corresponding 5-pyrimidine substituted derivatives.

Synthesis of novel derivatives of 5-(4,6-dimethyl-2-pyrimidinylsulfanyl)methyl-1,2,4-triazole-3-thione

Alkylation of 5-(4,6-dimethyl-2-pyrimidinylsulfanyl)methyl-1,2,4-triazole-3-thione (2) with various alkyl halides, 4-chlorophenacyl bromide, chloroacetic acid, and α-chloroacetanilide afforded S-substituted 1,2,4-triazoles (3–11). 3-Carboxymethylsulfanyl-5-(4,6-dimethyl-2-pyrimidinylsulfanyl)methyl-1,2,4-triazole (9), in the presence of acetic anhydride, was cyclized to 6-(4,6-dimethyl-2-pyrimidinylsulfanyl)methylthiazolo[3,2-b][1,2,4]triazol-3(2H)-one (12). The later condensed with aromatic aldehydes to give 6-(4,6-dimethyl-2-pyrimidinylsulfanyl)methyl-6-[(1-aryl)methylidene]thiazolo[3,2-b][1,2,4]triazol-3(2H)-ones (13, 14) and under treatment with aniline underwent ring-disclosure reaction to yield 3-(phenylcarbamoyl)methylsulfanyl-5-(4,6-dimethyl-2-pyrimidinylsulfanyl)methyl-1,2,4-triazole (11).

5-(4,6-Diphenyl-2-pyrimidinyl)-1,3,4-oxa(thia)diazoles and 1,2,4-triazoles

Synthesis of 5-(4,6-diphenyl-2-pyrimidinyl)-1,3,4-oxa(thia)diazoles and corresponding 1,2,4-triazoles from 4,6-diphenyl-2-pyrimidinecarboxylic acid hydrazide and 1-(4,6-diphenyl-2-pyrimidinylcarbonyl)-4-phenylthiosemi-carbazide is described.

Synthesis of 4-amino-5-(4,6-Diphenyl-2 -Pyrimidinyl ) -3,4 -dihydro -2h-1,2,4 -triazole -3 -thione and its reactions with C-electrophiles

Abstract4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N(2) atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole.

Synthesis of new pyrimidinylthio-substituted 1,3,4-oxa(thia)diazoles and 1,2,4-triazoles

Novel 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones bearing the pyrimidinylthio- moiety were synthesized by cyclization of a substituted-thiosemicarbazide precursor under different conditions. The thiosemicarbazide intermediates were easily accessed from reaction of biologically active 2-(4,6-dimethylpyrimidin-2-ylthio)acetohydrazide and 2-(2-dimethylamino-6-methyl pyrimidin-4-ylthio)acetohydrazide with cyclohexyl or phenyl isothiocyanate. The compounds are characterized by 1H, 13C NMR, IR spectroscopy and analytical data.

Transformations of methyl 6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinylacetate under oxidative conditions

The oxidation of methyl 6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinylacetate by reagents which oxidized the SMe group to SO2Me gave the products of the further transformation of the corresponding 2-methylsulfonyl-substituted ester obtained: methyl 5,5-dichloro-6-methoxy-6-methyl-2,4-dioxohexahydro-3-pyrimidinylacetate (using Cl2 in 70 or 50% MeOH), its mixture (about 1:10) with methyl 6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinylacetate (Cl2 in 30% MeOH) or only to the latter compound (Cl2 in H2O, m-ClC6H4CO3H in CHCl3, H2O2 in MeOH). The reaction did not take place with NaOCl in DMF.

Synthesis of 6-[4-(allyl/phenyl)-5-thioxo-1,2,4-triazol-3-yl]pyrimidine-2,4-diones and their reaction with electrophiles

Cyclization of 1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonyl-4-R-thiosemicarbazides in basic medium gave 6-(4-R-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-diones (R = Allyl, Ph). Alkylation of the latter with iodomethane occurred at the sulphur atom to give the corresponding methylsulfanyl derivatives. Acetylation using acetyl chloride occurred at the N(1) atom of the triazole ring to the corresponding acetyl derivative when R = Ph but for R = Allyl the acetylation did not occur under the same conditions. In the presence of bromine in refluxing methanol the indicated allyl-substituted compound cyclizes to 6-bromomethyl-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole. Under Mannich and bromination conditions the methylsulfanyl derivatives prepared form derivatives at the 5 position of the uracil ring: 5-methylmorpholino-(piperidino)-and 5-bromo-(4-R-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-diones respectively.