Fluorinated tricyclic neuroleptics with prolonged action: 8-Methoxy, 8-ethoxy, 8-ethylthio and 8-hydroxy derivatives of 3-fluoro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1982 ◽  
Vol 47 (5) ◽  
pp. 1382-1391 ◽  
Author(s):  
Jiří Jílek ◽  
Josef Pomykáček ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Acetic Acid ◽  
Polyphosphoric Acid ◽  
Prolonged Action ◽  
Substitution Reactions ◽  
Methoxy Derivative ◽  
Chloro Derivatives ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Central Depressant ◽  
Boiling Toluene

Acids IIa-c were prepared by reactions of (4-fluoro-2-iodophenyl)acetic acid with 4-methoxythiophenol, 4-ethoxythiophenol and 4-(ethylthio)thiophenol and cyclized with polyphosphoric acid in boiling toluene to dibenzo[b,f]thiepin-10(11H)-ones IIIa-c. Reduction with sodium borohydride afforded the alcohols IVa-c which were treated with hydrogen chloride and gave the chloro derivatives Va-c. Substitution reactions with 1-methylpiperazine resulted in the title compounds Ia-c out of which the methoxy derivative Ia was transformed by demethylation with boron tribromide to the phenol Id. Compounds Ia-d are very potent neuroleptics exhibiting a clear prolongation of the central depressant and some prolongation of the cataleptic activity.

Potential metabolites of tricyclic neuroleptics: 2,8-Dihydroxy and 3,8-dihydroxy derivatives of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (10) ◽  
pp. 2987-2996 ◽  
Author(s):  
Miroslav Protiva ◽  
Karel Šindelář ◽  
Zdeněk Šedivý ◽  
Josef Pomykáček
Keyword(s):  
Acetic Acid ◽  
Polyphosphoric Acid ◽  
Substitution Reactions ◽  
Piperazine Derivatives ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Isomeric Acid ◽  
Central Depressant ◽  
Methoxybenzoic Acid

A synthesis of the title compounds II and III, potential metabolites of the neuroleptic agent perathiepin I, was carried out. A reaction of (2-iodo-5-methoxyphenyl)acetic acid with 4-methoxythiophenol afforded the acid VI. The isomeric acid XI was obtained from 2-iodo-4-methoxybenzoic acid by reaction with 4-methoxythiophenol and via intermediates VIII-X. Both acids (VI,XI) were cyclized with polyphosphoric acid to dimethoxydibenzo[b,f]thiepin-10(11H)-onesXIIab which were transformed via the alcohols XIIIab to the chloro compounds XIVab. Substitution reactions with 1-methylpiperazine gave the piperazine derivatives IV and V and dimethoxydibenzo[b,f]thiepins XVab. The dimethoxy compounds IV and V were demethylated with boron tribromide to the diaminodiphenols II and III. The central depressant and cataleptic activity of compounds II-V is lower than that of the unsubstituted substance I.

Fluorinated tricyclic neuroleptics with prolonged action: 8-Alkyl derivatives of 3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

1984 ◽  
Vol 49 (11) ◽  
pp. 2638-2648 ◽  
Author(s):  
Jiří Jílek ◽  
Miroslav Rajšner ◽  
Jiřina Metyšová ◽  
Josef Pomykáček ◽  
Miroslav Protiva
Keyword(s):  
Polyphosphoric Acid ◽  
Titanium Tetrachloride ◽  
Prolonged Action ◽  
Substitution Reactions ◽  
Piperazine Derivatives ◽  
Alkyl Derivatives ◽  
Chloro Derivatives ◽  
Derivatives Of ◽  
By Products ◽  
Hydroxyethyl Piperazine

Reactions of (4-fluoro-2-iodophenyl)acetic or (2-bromo-4-fluorophenyl)acetic acid with 4-methylthiophenol, 4-ethylthiophenol and 4-isopropylthiophenol under various conditions afforded the acids IIIa-c which were cyclized with polyphosphoric acid to 8-alkyl-3-fluorodibenzo-[b,f]thiepin-10(11H)-ones IVa-c. The alcohols Va-c, which were obtained by reduction of the ketones with sodium borohydride, were transformed by treatment with hydrogen chloride to the chloro derivatives Via-c. Their substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine afforded the title compounds Ib, Ic and IIa. The corresponding 2-alkyl-7-fluorodibenzo[b,f]thiepins VIIa-c were obtained as by-products. Reaction of the ketone IVc with 1-methylpiperazine in the presence of titanium tetrachloride gave the enamine VIII. The piperazine derivatives prepared are very potent neuroleptic agents with regard to their acute activities. Important prolongation of the effects was found mainly with the isopropyl compounds Ic and VIII.

Fluorinated tricyclic neuroleptics with prolonged action: 3-Fluoro-8-trifluoromethyl derivatives of 10-(4-methylpiperazino)- and 10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo-[b,f]thiepin

1981 ◽  
Vol 46 (1) ◽  
pp. 118-140 ◽  
Author(s):  
Karel Šindelář ◽  
Miroslav Ryska ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Prolonged Action ◽  
Substitution Reactions ◽  
Isolation And Characterization ◽  
Chloro Derivative ◽  
Derivatives Of ◽  
Enol Ester ◽  
Preparative Purpose ◽  
Hydroxyethyl Piperazine

A reaction of (4-fluoro-2-iodophenyl)acetic acid with 4-(trifluoromethyl)thiophenol gave the acid VIII which was cyclized with the reagent consisting from methanesulphonic acid and phosphorus pentoxide and afforded the methanesulphonic enol ester XIX. The alkaline hydrolysis resulted in 3-fluoro-8-trifluoromethyldibenzo[b,f]thiepin-10(11H)-one (XVI) which was transformed via the alcohol XXIV to the chloro derivative XXV. Substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine resulted in the title compounds IV and V. These products are very potent cataleptic neuroleptic agents with a prolongation of duration of the effects comparable to that of isofloxythepin and tefluthixol. A series of further synthetic experiments aimed at alternative syntheses of the acid VIII and the ketone XVI; their results were mostly not of use for preparative purpose but they led to isolation and characterization of a series of interesting heterocyclic products (XVII, XVIII, XXII, XXIII, XXIX-XXXI, XXXVI-XXXIX).

Fluorinated tricyclic neuroleptics with prolonged action: 3-Fluoro-8-halogeno derivatives of 10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

1981 ◽  
Vol 46 (8) ◽  
pp. 1788-1799 ◽  
Author(s):  
Miroslav Protiva ◽  
Karel Šindelář ◽  
Jiřina Metyšová ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Amino Acid ◽  
Amino Ketone ◽  
Prolonged Action ◽  
Derivatives Of ◽  
Central Depressant

Reactions of (4-fluoro-2-iodophenyl)acetic acid with 4-fluoro and 4-bromothiophenol gave the acids IIIa and IIIc which were cyclized to 3-fluoro-8-halogenodibenzo[b,f]thiepin-10(11H)-ones IVa and IVc. The title compounds Ia and IIc were obtained via the intermediates VIac and VIIac. Reactions of (4-fluoro-2-mercaptophenyl)acetic acid or 6-fluorobenzo[b]thiophen-2(3H)-one with 4-chloronitrobenzene afforded the nitro acid IIIe which was reduced to the amino acid IIIf. Cyclization gave the amino ketone IVf which was transformed to the iodo ketone IVd. Proceeding via the intermediates VId and VIId led to the final product IId. Compounds Ia and IIcd have strong central depressant and cataleptic activity; prolongation of the effect is connected merely with the central depressant component of the action.

Potential metabolites of the neuroleptic agents belonging to the 8-methylthio-10-piperazino-10,11-dihydrodibenzo[b,f]thiepin series; Synthesis of 2-hydroxy and 3-hydroxy derivatives

1985 ◽  
Vol 50 (10) ◽  
pp. 2179-2190 ◽  
Author(s):  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Alkaline Hydrolysis ◽  
Potassium Salts ◽  
Substitution Reactions ◽  
Piperazine Derivatives ◽  
Prolonged Duration ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Neuroleptic Activity

The acid VI, prepared by reaction of potassium salts of (2-iodo-5-methoxyphenyl)acetic acid and 4-(methylthio)thiophenol in the presence of copper, was transformed via intermediates VII-IX to 2-methoxy-8-methylthio-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins X and XI. Their demethylation with boron tribromide afforded 2-hydroxy derivatives of the neuroleptic agents methiothepin and oxyprothepin I and II. 11-Chloro-7-methoxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin was subjected to substitution reactions with 1-methylpiperazine and 1-(ethoxycarbonyl)piperazine and gave piperazine derivatives XIII and XIV, out of which the latter gave the secondary amine XV by alkaline hydrolysis. The ethers XIII and XV were also cleaved with boron tribromide and gave 3-hydroxy derivatives of methiothepin (III) and its demethyl derivative IV. The phenols I, II, and IV are potential metabolites of the mentioned neuroleptic agents; compound III, which already was identified as a metabolite, disclosed properties of a strong and cataleptic neuroleptic agent with prolonged duration of the effects. The methoxy compounds X, XI, and XIII are practically devoid of the neuroleptic activity.

Potential metabolites of the neuroleptic agent chlorprothixene; synthesis and pharmacology of the 3-, 4-, 6- and 7-hydroxy and methoxy derivatives of 2-chloro-9-(3-dimethylaminopropylidene)-thioxanthenes

1980 ◽  
Vol 45 (11) ◽  
pp. 3166-3181 ◽  
Author(s):  
Karel Šindelář ◽  
Jiří Jílek ◽  
Jiří Körbl ◽  
Fedir Jančik ◽  
Emil Svátek ◽  
...  
Keyword(s):  
Ir Spectra ◽  
Polyphosphoric Acid ◽  
Amino Alcohols ◽  
Geometric Isomers ◽  
Pyridine Hydrochloride ◽  
Neuroleptic Agent ◽  
Acid Catalyzed ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Central Depressant

Cyclization of the acids IV-VII with sulfuric or polyphosphoric acid resulted in the thioxanthones VIIIa-d which were treated with 3-dimethylaminopropylmagnesium chloride and gave the amino alcohols Xa-d. Their acid catalyzed dehydrations afforded the methoxy derivatives of chlorprothixene IIIa-d, mostly in form of mixtures of geometric isomers. Whereas the results of attempts to demethylate these products with boron tribromide gave mostly unsatisfactory results, the demethylation with pyridine hydrochloride at 190-200 °C was successful; alcohols X were the most suitable starting materials. In this manner, the hydroxy derivatives of chloroprothixene IIa-d were obtained, mostly as pure geometric isomers. The configuration was assigned on the basis of their IR spectra. Z-Isomers are potential metabolites of the neuroleptic agent chlorprothixene (I). Compounds II and III are little toxic, have low central depressant activity and are inactive cataleptically.

Potential metabolites of tricyclic neuroleptics and their fluorinated analogues; 3-Hydroxy-, 3-methoxy- and 3-fluoro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (7) ◽  
pp. 2108-2123 ◽  
Author(s):  
Miroslav Protiva ◽  
Karel Šindelář ◽  
Zdeněk Šedivý ◽  
Jiřina Metyšová
Keyword(s):  
Acetic Acid ◽  
Benzoic Acid ◽  
Oral Administration ◽  
Phenolic Compound ◽  
Methoxy Derivative ◽  
Fluoro Derivative ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Central Depressant

4-Methoxy-2-(phenylthio)benzoic acid (V) was transformed in four steps to the homologous acid IXa which was cyclized to 3-methoxydibenzo[b,f]thiepin-10(11H)-one (Xa). The 3-methoxy derivative III of perathiepin (I) was synthesized via the intermediates XIa and XIIa, and demethylated with boron tribromide to the phenolic compound II. The analogous 3-fluoro derivative IV was synthesized from (4-fluoro-2-iodophenyl)acetic acid (XVII), the preparation of which by several procedures is described. Whereas III has only mild tranquilizing activity, II is more potent than perathiepin (I) in the tests for central depressant and cataleptic effects. The 3-fluoro derivative IV, while lacking the properties of a neuroleptic agent, is highly central depressant and this effect shows some prolongation after oral administration.

Highly polar potential metabolites of the neuroleptic agent oxyprothepin: Synthesis of 2-hydroxy-8-methylsulfonyl and 3-hydroxy-8-methylsulfonyl derivatives of 10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1985 ◽  
Vol 50 (2) ◽  
pp. 519-537 ◽  
Author(s):  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiří Schlanger ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Acetic Acid ◽  
Potassium Carbonate ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Methoxybenzoic Acid

The acid XI, obtained by reaction of (2-iodo-5-methoxyphenyl)acetic acid with 4-(methylsulfonyl)thiophenol (VIII) in dimethylformamide in the presence of potassium carbonate and copper, was transformed via intermediates XIIa-XIVa to compound XVa. Demethylation with boron tribromide afforded compound III, the potential metabolite of oxyprothepin (II). Its oxidation with hydrogen peroxide in acetic acid gave the sulfoxide XVII, which is a further potential metabolite. A reaction of 2-iodo-4-methoxybenzoic acid with VIII and potassium carbonate in dimethylformamide in the presence of copper afforded the acid XIX whose ester XXI was reduced with diborane to the alcohol XXII; hydrogenolysis to compound XXIII was also observed. The alcohol XXII was processed via compounds XXIV and XXV to the acid XXVI which was cyclized in a low yield to the ketone XIIb. A further processing via the intermediates XIIIb and XIVb led to compound XVb. Demethylation gave compound IV, another potential metabolite.

Potential metabolites of the neuroleptic agents noroxyclothepin and oxyclothepin; Synthesis of 8-chloro-3-hydroxy-10-[4-(2-hydroxyethyl)piperazino]- and -10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (12) ◽  
pp. 3617-3626 ◽  
Author(s):  
Karel Šindelář ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Miroslav Ryska ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
Amino Alcohols ◽  
Substitution Reactions ◽  
Pyridine Hydrochloride ◽  
Methanesulfonyl Chloride ◽  
Piperazine Derivatives ◽  
Boron Tribromide ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant

Substitution reactions of 8,10-dichloro-3-methoxy-10,11-dihydrodibenzo[b,f]thiepin with 1-(2-hydroxyethyl)piperazine and 1-(3-hydroxypropyl)piperazine gave the piperazine derivatives IX andX; their demethylation with boron tribromide led to unfavourable results. New procedure for the synthesis of phenolic amines was elaborated starting with demethylation of 8-chloro-3-methoxydibenzo[b,f]thiepin-10(11H)-one with pyridine hydrochloride, followed by reduction of the hydroxyketone XIII to the diol XIV. Reaction with methanesulfonyl chloride in the presence of triethylamine resulted in the dimethanesulfonic ester XV which was treated with 1-(2-hydroxyethyl)piperazine and 1-(3-hydroxypropyl)piperazine. The aliphatic sulfoester group underwent substitution, confirmed by isolation of compound XII. The aminolysis afforded phenolic compounds VII and VIII being potential metabolites of the neuroleptic agents noroxyclothepin (III) and oxyclothepin (IV). Both phenolic amino alcohols have only very low central depressant and cataleptic activity.

Potential noncataleptic neuroleptic agents; 2,6-Dichloro-, 2,7-dichloro- and 2,8-dichloro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

1986 ◽  
Vol 51 (1) ◽  
pp. 156-166 ◽  
Author(s):  
Miroslav Protiva ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
Stanislav Wildt ◽  
Irena Červená ◽  
...  
Keyword(s):  
Rat Brain ◽  
Acid Level ◽  
Homovanillic Acid ◽  
Dopaminergic Receptors ◽  
Substitution Reactions ◽  
Neuroleptic Agent ◽  
Chloro Derivatives ◽  
Derivatives Of ◽  
Brain Striatum

Substitution reactions of 2,6,10-trichloro-, 2,7,10-trichloro- and 2,8,10-trichloro-10,11-dihydrodibenzo[b,f]thiepin (Vabc) with 1-(2-hydroxyethyl)piperazine, 1-methylpiperazine and 1-benzylpiperazine gave the title compounds IIabc, IIIab and IVab. The new chloro compounds Va and Vb were obtained in 6 steps starting from reactions of 2,5-dichloroacetophenone with 2-chlorothiophenol or 3-chlorothiophenol. Compounds IIabc are 6-chloro, 7-chloro and 8-chloro derivatives of the noncataleptic neuroleptic agent docloxythepin (I). They are almost devoid of cataleptic activity and do not inhibit the apomorphine stereotypies in rats. Compounds IIab have a clozapine-like affinity to dopaminergic receptors in the rat brain striatum; the affinity of IIc is much higher. On the other hand only compounds IIb and IIIa prove a significant antidopaminergic activity in vivo (increase significantly the homovanillic acid level in the rat brain striatum).

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