No abstract

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.

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.

Dibenzo[b,f]-1,4-thiazepin-11(10H)-ones IIa-IIc reacted with phosphorus pentasulfide in pyridine under the formation of the thiones IIIa-IIIc which were transformed by treatment with hydrazine hydrate in 1-butanol to the hydrazine derivatives IVa-IVc. Reactions with triethyl orthoformate in ethanol in the presence of sulfuric acid effected cyclization to dibenzo[b,f]-1,2,4-triazolo[4,3-d]-1,4-thiazepine (Va) and its chloro derivatives Vb, Vc which were treated with bromine in a boiling mixture of chlorofom and pyridine and gave the 3-bromo derivatives VIa-VIc. The title compounds Ia-Ic were obtained by substitution reactions with an excess of boiling 1-methylpiperazine. An attempt at preparing an analogous 14H-dibenzo[b,g]-1,2,4-triazolo[4,3-d]-1,4-thiazocine derivative was discontinued in the stage of reaction of the thione X with hydrazine hydrate which resulted in the azine XI. Compounds Ia-Ic on intravenous administration are highly toxic and inactive in tests for CNS effects; compound Ic showed a clear anticholinergic activity.

The development of dopaminergic supersensitivity was evaluated, after single oral administration of the long-acting neuroleptic drug isofloxythepin, in nigrostriatal and tuberoinfundibular system in the rat. Isofloxythepin (5 mg/kg orally) increased concentration homovanillic acid (HVA) in the striatum for up to 24 h after administration, whereas a significant decrease below control values was found after 4-5 days. A similar biphasic effect appeared in behavior, since there was an enhancement of apomorphine stereotypy 4-5 days after administration of isofloxythepin (5 and 10 mg/kg orally). Both findings agree with the hypothesis of development of nigrostriatal dopaminergic supersensitivity at long intervals after isofloxythepin. On the other hand, the increase in prolactin (PRL) secretion induced by isofloxythepin indicated only the blocking action of this drug on dopamine receptors in the tuberoinfundibular system, and provided no evidence for tuberoinfundibular dopaminergic supersensitivity after neuroleptic treatment. It is concluded that a single dose of isofloxythepin is capable of inducing dopaminergic supersensitivity in the nigrostriatal system, but not in the tuberoinfundibular system.