Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part III.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-13 were synthesized and evaluated for their pharmacological activity. Compounds 5, 7, 9, 10 and 12 showed antiaggressive effect, compounds 6 and 10 showed synergism with hexobarbital while compound 6 exerted analgesic activity.

Carboxylic esters derivatives of 2-thioxo-1H-2,3,4,5-tetrahydropyrido-[2,3-e]-1,3,4-triazepin-5-ones and 2-thioxo-1H-2,3,4,5-tetrahydro-1,3,4-benzotriazepin-5-ones.

2-Thioxo-1H-2,3,4,5-tetrahydropyrido[2,3-e]-1,3,4-triazep in -5-ones [I] and 2-thioxo-1H-2,3,4,-5-tetrahydro-1,3,4-benzotriazepin-5-ones [V] furnish with methyl, ethyl and phenyl chloroformates two series of the corresponding 3-methoxy-, ethoxy- and phenoxycarbonyl triazepines. In the pharmacological screening, compounds [I], [V] and [II] showed an antianxiety activity in the four plate test, compounds [II] and [III] inhibited the 5-HTP- induced head twitches, and compound [VI] showed an analgesic activity in the "writing" test. The replacement of the benzene ring by the pyridine one in triazepines is accompanied by the enhancement of anxiolytic activity as well as toxicity.

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part II.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-20 were synthesized and evaluated for their pharmacological activity. Compounds 11-14, 17-19 showed antiaggressive effect, compounds 5, 8, 9, 11, 12 and 19 displayed antiserotonin activity while compound 14 exerted antireserpine action.

Acylated derivatives of 1,5-benzodiazepines. Part II.

Acylated derivatives of 4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one (1) and of 2-methyl-4-phenyl-1H-tetrahydro-1,5-benzodiazepino-2-carboxylic acid ethyl ester (10) were synthesized and preliminarily tested on their central activity. Acylation was carried out with alpha, beta-unsaturated acid chlorides, dicarboxylic acid monoester monochlorides, and dicarboxylic acid dichlorides. Compounds 2, 3, 11 and 12 had analgesic, compounds 4, 11 and 12--anticonvulsant, and compounds 3 and 11--antiaggressive properties.

Synthesis and properties of 4-substituted-1-piperazinyl-propyl derivatives of 1-phenyl-7-methylpyrimido-[4,5-d]pyrimidin-4-one.

In reactions of 1-phenyl-7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimido[ 4,5-d]pyrimidin e (1) with 1-(3-chloropropyl)-4-methyl(phenyl, 3-chlorophenyl, 2-pyrimidynyl, 2-thiazolyl)piperazines (5), mixtures of isomeric N- and S-substituted derivatives of compound 1 (3 and 4) were obtained. Isomers were separated by fractional crystallization. The structure of novel compounds 3 and 4 was confirmed by elemental and spectral analyses.

Synthesis and pharmacological properties of derivatives of alpha-amino-beta-(p-chlorobenzoyl)-propionic acid and alpha-amino-gamma-(p-chlorophenyl)-tetrahydrofuran-2-one.

Several new alpha-aminoderivatives of gamma-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. alpha-Aminoderivatives of beta-(p-chlorobenzoyl)-propionic acid 2-13 were used as the substrates. After the reduction with NaBH4 at 10-12 degrees C and cyclization the compounds were converted into the appropriate derivatives of tetrahydrofuran-2-one 16-26.

Synthesis and anticonvulsant properties of some arylsuccinate methylpyridylimides.

In reaction of alpha-phenyl, alpha-p-chlorophenyl and alpha-m-chlorophenylsuccinic acid with various aminopyridines, N-pyridyl-substituted succinimides (compounds 1-14) were obtained. These compounds were investigated for their CNS activity. Compounds 1, 2, 5, 6 and 7 displayed anticonvulsant properties in the maximum electroshock test.

Synthesis and preliminary pharmacological investigation of the central action of derivatives of 3-aminomethyl-5-(p-chlorophenyl)-tetrahydrofuran-2-one and 2-aminomethyl-4-(p-chlorophenyl)-4-hydroxybutyric acid.

Using 3-cyano-5-(p-chlorophenyl)-tetrahydrofuran-2-one 4, 3-aminomethyl derivatives of 5-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. The starting material under alkaline hydrolysis yielded 5-(p-chlorophenyl)-tetrahydrofuran-2-one-3-carboxylic acid 5, which was transformed, via an acid chloride, into amide 6. From acid 5 by aminomethylation compounds 7-12 were obtained.

Acyl derivatives of 1,5-benzodiazepines. III. Acyl derivatives of ethyl ester of 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acid.

Two series of derivatives of ethyl ester of 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acid (1) have been synthesized. The acetyl derivative (2) of ester 1 in preliminary pharmacological screening showed analgesic activity in the "writhing" test and the benzoyl derivative (5) exhibited antianxiety properties in the four plate test, while N,N-disubstituted aminoacetyl derivatives of 1 showed analgesic and anticonvulsant activity (10).

Cimetidine-diazepam interaction in the four-plate test.

The study on the synergism of cimetidine with the central anti-anxiety action of diazepam in the four-plate test revealed that cimetidine evidently potentiates the anti-anxiety action of diazepam.

Synthesis and preliminary pharmacological studies on dihydropyrido-1,3,4-triazepinone derivatives.

New 4,5-dihydropyrido-[2,3-e]-1,3,4-triazepin-5-one derivatives (2-9) were synthesized. The preliminary pharmacological tests revealed antinociceptive action of compounds 4-7 and 9 and antianxiety action of compound 4.

Pharmacological properties of new heterocyclic derivatives of 1,5-benzodiazepine.

Sixteen new heterocyclic 1,5-benzodiazepine derivatives (compounds AN8-AN24) were screened for their central action. Compounds AN8-AN10 and AN17 strongly antagonized the action of pentetrazol, compounds AN10, AN14-AN17 and AN22 had potent antiserotonin properties, and compounds AN10, AN19, AN20 and AN23 markedly potentiated the action of DOPA.

1,5-benzodiazepine derivatives with expected psychotropic activity.

By sulfuration of 4-methyl-1H-tetrahydro-1,5-benzodiazepinone-2 (1) its 2-thione 2 was synthesized. From this compound 2-hydrazone 3 and s-triazole derivatives 4 and 5 were obtained. Screening revealed that only compound 2 showed strong inhibitory activity in the spontaneous motility test, weak synergism with hexobarbital, weak antinflammatory activity in the carrageenin test and strong analgesic activity in the hot plate test.

Central action of new derivatives of tetrahydropirimidinedione-4,6.

The central action and LD50 of 11 new 2,5-substituted derivates of tetrahydropirimidinedione-4,6 with an aryl group at C2 were investigated. The most favorable action was exerted by 2-furfurylamine derivatives with an alkil or benzyl group at C5. These compounds acted in doses of 0.

Central action of new imido derivatives of succinic acid.

New imido derivatives of succinic acid were screened pharmacologically with regard to their influence on the central nervous system. No relation was found between the character and position of substituents and depressant action on the CNS. However, it was remarked that potentiation of the central influence of DOPA probably depends on the position of the p-chlorophenyl group.

Studies on the synergism of some hypotensive drugs with ethanol.

Synergism of some hypotensive drugs with ethanol was studied for its influence on the central nervous system. A very strong central action of the drugs and ethanol administered simultaneously in subthreshold doses was observed. Intensity of synergism was calculated by comparing the results with the effective doses of each drug administered seperately.

Synthesis and pharmacological properties of new pyridine derivatives.2,6-bis-[diphenyl-(and dibenzyl)-hydroxymethyl]-piperidines.

Syntheses of 2,6-bis-(diphenylhydroxymethyl)-, 2,6-bis-(dibenzylhydroxymethyl)- and 2,6-bis-(phenylbenzylhydroxymethyl)-pyridines were carried out. These compound were hydrogenated to the corresponding piperidine carbinols. The compounds are of low toxicity and were tested on mice for their CNS activity, using climbing test.

Central action of 2-amino- and 2-amino-5-aryltetrahydropyrimidinediones-4,6.

The influence on the central nervous system of five 2-amino- and 2 amino-5-aryltetrahydropyrimidinedione-4,6 derivatives was studied. The most favorable action was exerted by benzylamine-tetrahydropyrimidinedione, which inhibited spontaneous and amphetamine-induced motility most strongly, acted synergistically with hexobarbital, was the only one of the studied group of compound which delayed convulsions induced with pentamethylenetetrazole and amphetamine, and potentiated most strongly the central action of DOPA in mice with inhibited MAO activity. The weakest effects were produced by methylpiperazinephenyl-tetrahydropyrimidinedione.