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.

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 0.0025--0.01 of their LD50 synergistically with chloral hydrate and strongly with hexobarbital, delayed convulsions induced with pentetrazole and potentiated the central action of DOPA in mice pargyline-inhibited MAO activity. They did not antagonize electrogenic convulsions, amphetamine potentiated motility and the action of reserpine, and had no analgetic action. Their LD50s were 670-- 1660 mg/kg.

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.

Synthesis and pharmacological properties of new derivatives of 4-methyl-5-oxalo-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one and beta-oxo-5-(4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2 -one)propionic acid.

5-Ethoxalyl 4-methyl-1H-2,3,4,5-tetrahydro 1,5-benzodiazepin-2 -one [I] and 5-ethoxymalonyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepi n-2-one [IV] were subjected to transesterification using alcohols (propanol, butanol, pentanol) giving derivatives II-IV, VII, VIII. The derivatives I and VI were caused to undergo ammonolysis giving 4-methyl-5-oxamoyl-1H-2,3,4,5 tetrahydro 1,5-benzodiazepin-2-one [V] and 5-malonamoyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin++ +-2-one [IX]. The compounds I-IX were tested towards their psychotropic activity. The preparates I, III and V had an anxiolytic action in the four-plate test. The anxiolytic properties of the compound V were confirmed in the test of the black-white box. The antagonism of all investigated compounds for toward reserpine, first of all of the preparations III, IV, V and IX, indicates an antidepressive activity dependent on a stimulation of the adrenergic system.

Synthesis of new derivatives of 4-methyl-5-ethoxalyl-1H-2,3,4,5- tetrahydro-1,5-benzodiazepin-2-one and their psychotropic and anti-proliferative activities.

5-Ethoxalyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin -2-one [I] was treated with some selected secondary amines (dimethyl-, diethyl-, dipropyl-, disobutylamine or with morpholine) and methyl-hydrazine. Amides II-IV and hydrazide VII were obtained. Compounds II, IV and VI were tested for their psychotropic activity; they showed a weak toxicity. Compounds II and VI showed an anxiolytic activity. Compounds I, II, IV, VI and VII were screened for their cytotoxic (anti-proliferative) activity in vitro by using different human cancer cell lines. None of them revealed any inhibiting effect against the tumor lines used.

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.

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.

N,N-Dicyclohexylhexahydrodiazepines and N,N-dicyclohexylperhydrodiazocines as possible antiinflammatory agents.

Four 6,6-disubstituted 1,4-dicyclohexyl-5,7-diketohexahydro-7H-dro-7H-diazepines [1,4] (I a-d) and three 3,3-disubstituted 1,5-dicyclohexyl-2,4-diketoperhydrodiazocines [1,5] (II a-c) were prepared and their structure and pharmacological activity were investigated.

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 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. Some of them (7, 8, 12) in reactions of ammono-, amino-, and hydrazinolysis yielded corresponding derivatives of 2-aminomethyl-4-(p-chlorophenyl)-4-hydroxybutyric acid 13-20. In pharmacological tests compounds 10 displayed analgesic activity while compounds 2 and 3 revealed anxiolytic properties.

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.

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 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. In pharmacological tests compounds 9 and 26 abolished the aggressiveness in isolated mice while compound 8 showed antiinflammatory activity.