Abstract:In contrast to stnatal membranes of adult rats, where high- (& = Nezirochem. 60, 469-476 (1993).

ChemInform Abstract A large variety of title compounds such as (VI) and (VIII) are synthesized using reaction sequences generally exemplified in the scheme for (VI). Some of the 2-(methoxy-and hydroxy-phenylthio)benzylamines prepared, especially compounds (VIIIa), indicate properties of potential antidepressants being highly active and selective inhibitors of 5-hydroxytryptamine reuptake in the brain structures and having the typical antireserpine activity. The most interesting compound of the series is (VI) (hydrogen maleate VUFB-15468) which is undergoing preclinical studies. On the basis of its structure, some further compounds are prepared.

Reactions of 5-fluoro, 5-chloro- and 5-bromo-2-iodobenzoic acid with 4-isopropylthiophenol in solutions of potassium hydroxide in the presence of copper gave the acids VIIabc which were transformed via the intermediates VIIIabc-Xabc to 2-[5-halogeno-2-(4-isopropylphenylthio)-phenyl]acetic acids XIabc. Their cyclization with polyphosphoric acid resulted in 2-halogeno-8-isopropyldibenzo[b,f]thiepin-10(11H)-ones XIIabc.The 2-iodo ketone XIId was obtained from 2-(2-chloro-5-nitrophenyl)acetic acid by treatment with 4-isopropylthiophenol, by the following reduction of the resulting nitro acid XIe with hydrazine to the amino acid XIf, by its cyclization to the amino ketone XIIf and finally by its diazotization and reaction with potassium iodide. The ketones XIIa-d were reduced to the alcohols XIIIa-d giving by treatment with hydrogen chloride the chloro compounds XIVa-d. Substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine afforded the title compounds Vabc and VIa-d. Only the fluoro derivatives Va and VIa showed a clear cataleptic activity in rats. The other compounds are very little active in this line and the iodo derivative VId was found to be completely inactive in a high oral dose, but it revealed an intensive antidopaminergic action in biochemical tests. By its pharmacological profile it resembles the known noncataleptic neuroleptic agent clozapine.

Reactions of ethyl(2-(phenylthio)phenyl)acetimidate (X) hydrochloride with ammonia and the corresponding amines resulted in amidines V-X. Heating (2-(phenylthio)phenyl)acetonitrile with 2-aminoethylammonium toluene-4-sulfonate led to the 2-imidazoline XI. Reactions of (2-(phenylthio)phenyl)acetonitrile and the lower homologue with hydroxylamine gave the amidoximes XIII and XV; XIII was oxidized to the sulfoxide XIV. Compounds VII, XI, and XIII showed some antireserpine activity which indicates thymoleptic and antidepressant potentiality. On the other hand, none of the compounds tested did show any noteworthy affinity to the [3H]imipramine and [3H]desipramine binding sites in the rat hypothalamus.