Synthesis and anxiolytic activity of 1-phenyl-2-(4-aryl-1,3,4,5-tetrahydropyrido[2,3-b][1 ,4]diazepin-2-ylidene)-ethanone.

A two-step, general synthesis of 1-phenyl-2-(4-aryl-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepin-2-ylidene)-ethanones 3-9 is presented. This synthesis employs a condensation of 2,3-diaminopyridine with benzoylacetone followed by a basic-activated cyclization reaction with substituted benzaldehydes for final closure of the seven-membered ring. Molecular diversity is fixed by appropriate aldehydes: 2-chloro-, 4-chloro-, 2-bromo-, 4-bromo-, 4-fluoro-, 4-trifluoro- and 3-bromo-4,5-dimethoxybenzaldehyde. Compounds 4, 6, 8, 9 and 10 were examined for their anxiolytic activity. The most active was the compound with the chlorophenyl substituent i.e. 1-phenyl-2-{4-(4-chlorophenyl)-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepin-2-ylidene}-ethanone (4).

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.

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.

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).

Aminoacetyl derivatives of 1,5-benzodiazepin-2-one.

A series of six compounds, 5-chloroacetyl-4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one and 5-dialkilaminoacetyl derivatives of 4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one, have been synthesized. 5-Diizobutylaminoacetyl-4-methyl-1H-tetrahydro-1,5-benzodiazepi n-2-one showed weak analgesic and antiinflammatory activity.

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.

5-Carboxylic derivatives of some 1,5-benzodiazepines.

5-Methoxy-, ethoxy- and phenoxycarbonyl derivatives of 2-methyl-4-phenyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic ethyl ester (1) and 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-one (2) were obtained. 5-Methoxycarbonyl- (3) and 5-phenoxycarbonyl- (5) derivatives of 1 exerted analgesic action in doses of 0.1 LD50. Compounds 3, 5 and 7 a (5-ethoxycarbonyl-) in a dose as low as 0.063 LD50, and compound 8 (5-phenoxycarbonyl-1H-tetrahydro-1,5-benzodiazepin-2-one)--in a dose of 0.004 LD50 prolonged hexobarbital sleeping time. The toxicity of all the compounds was low.

Acylated derivatives of 1,5-benzodiazepines.

N-Acylated derivatives of 2-methyl-2-ethoxycarbonyl-4-phenyl-1H-tetrahydro-1,5-benzodiazepine (1) and 2-cyano-4-methyl-1H-tetrahydro-1,5-benzodiazepine (3-12) were obtained. From among compounds 3-12, compound 3 have shown a strong synergism with hexobarbital and antiserotonin and anticonvulsant activity, and compounds 5 and 7 have displayed antiserotonin properties. A strong antireserpine action, comparable with imipramine, has been found for compound 12, which also have antagonized electrogenic seizures.

Synthesis and pharmacological investigations of derivatives 6-azabenzodiazepines.

Acylated derivatives 4-6 of 2-aminomethylene-4-phenyl-1H-tetrahydro-6-azabenzo-1,5-diazepine 3, and carbonyl derivatives 7-10 of 6-azabenzo-1,5-diazepines were obtained. They did not display any particular pharmacological activity in screening tests: 2 exerted a weak hypotensive action and 8 possessed negligible anticonvulsant properties.

Derivatives of 1H-tetrahydrobenzodiazepine-1,5.

Synthesis of acyl derivatives of 2-aminomethylene-4-phenyl-1H-tetrahydrobenzodiazepine-1,5: compounds 5, 7 and 8, of a Schiff base 6 acids 9 and 10, and esters of aryl- or alkyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acids 11-14 is described. Compounds 9-13 showed potent antagonism towards pentetrazol, and compound 13 also potentiated the action of DOPA and had antiserotonin properties.

7,7'-Bi-(2-cyano-4-aryl) alkyl (-1H-tetrahydrobenzodiazepines-1,5).

Bi-benzodiazepine nitriles 1-8 were obtained in a modified manner as potential psychotropic agents. In screening experiments 3 acted as a potent antagonist of pentetrazol, compounds 1-4 and 7 had antiserotonin action, and 5 potentiated the effects of DOPA [5].