Modification of the reaction of 4-(4-fluorophenyllbutyrc1actone with fiucrobenzene and aluminium chloride led to a reliable synthesis of 4,4-bis(4-fiucrophenyl)butyric acid (II). Its reduction with sodium dihydridobis(2-methoxyethoxy)aluminate afforded the alcohcl III giving by treatment with hydrobromic acid the bromide IV. The alkylation of 4-(4-chloro-3-trifiuoromethylphenyl)-4-piperidinol with bromide IV represents the last step of an efficient synthesis of the neuroleptic agent penfiuridol (I). Alkylation of 1-(2-hydroxyethyl)piperazine with bromide IVis a new method of synthesis of the amino alcohol VIII which was transformed to esters IX-XI. Cyclization of the acid II yielded 7-fiuoro-4-(4-fiuorophenyl)-1-tetralone (XV) giving by reduction and by the following reaction with thionyl chloride the chI oro derivatIve XVIII. Substitution reactions with secondary amines afforded the cyclic analogue of penfiuridol XIX and piperazine derivatives XX-XXII in the form of stereoisomeric mixtures, the separation of which was only partly successful. These cyclic analogues are typical by a complete loss of the neuroleptic character of their effects. Reaction of the tetralone XV with sodium azide resulted in a mixture of isomeric lactams which was separated and the products identified by spectra as benzazepinones XXIV and XXVI. The former was also obtained by the Beckmann rearrangement of the oxime XVI and was reduced to 8-fiuoro-4-(4-fiuorophenyl)-2,3,4,5-tetrahydro-lH-1-benzazepine (XXV) . This compound revealed in higher doses stimulant and anorectic activity.

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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 vicinal aromatic dibromo derivatives Ia-d with the system copper(I) cyanide-tetramethylurea gave the vicinal dicyano derivatives IIa-d; products of partial substitution, Va-d, demethylation and deacetylation, IIIa-c, were also formed. The compounds IIIa-c were also prepared by direct demethylation of compounds IIa-c with the system anhydrous aluminium chloride-dichloroethane. The structures of selected compounds were determined by spectral methods. Compounds IIa-d have proved to have a moderate antineoplastic effect in animals with some transplantable experimental tumours.

A series of substituted cyclohexylacetic acids I has been obtained by hydrogenation of the unsaturated analogues II and III. Esters of these analogues were prepared by the Horner-Wittig reaction of the corresponding cyclohexanones IV and/or 2-cyclohexenones V with triethyl phosphonoacetate. These esters were obtained in two isomeric forms (Z and E), differing in the double bond in the exo-position. The derivatives with a substituent in the 2-position exhibited a partial shift of the double bond to the cyclohexane ring; this shift was especially marked in the 2-phenyl derivative. With the acids I-III, activation of fibrinolysis was assessed by the hanging clot method; the anti-inflammatory effect was assessed by inhibition of two experimental model inflammations. The regression equation relating fibrinolytic capacity to lipophilicity was a quadratic one, the logarithm of optimum lipophilicity being log Popt = 5.55. A qualitative assessment of the anti-inflammatory effect in relation to lipophilicity suggests that log Popt is probably higher than with arylaliphatic acids. These acids seem to have an active site different from that of the acids I-III.