Noncataleptic neuroleptic agents: 2-Halogeno-8-isopropyl-10-piperazino-10,11-dihydrodibenzo[b,f,]thiepins

1984 ◽  
Vol 49 (1) ◽  
pp. 86-109 ◽  
Author(s):  
Zdeněk Polívka ◽  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
...  
Keyword(s):  
Potassium Hydroxide ◽  
Polyphosphoric Acid ◽  
Pharmacological Profile ◽  
Substitution Reactions ◽  
Biochemical Tests ◽  
Neuroleptic Agent ◽  
Fluoro Derivatives ◽  
Iodo Derivative ◽  
Hydroxyethyl Piperazine ◽  
Acetic Acids

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.

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.

Potential psychotropic and antihistamine agents: 1- and 3-alkyl-9-(3-dimethylaminopropylidene)-thioxanthenes and 3-alkyl-11-piperazino-10,11-dihydrodibenzo[b,f]thiepins

1982 ◽  
Vol 47 (11) ◽  
pp. 3134-3147 ◽  
Author(s):  
Miroslav Protiva ◽  
Zdeněk Šedivý ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Potassium Hydroxide ◽  
Polyphosphoric Acid ◽  
Substitution Reactions ◽  
Tertiary Alcohols ◽  
Alkyl Derivatives ◽  
Antitussive Effect ◽  
Antihistamine Activity ◽  
Acid Catalyzed ◽  
High Doses ◽  
The Individual

Reactions of 3-methylthiophenol and 3-ethylthiophenol with 2-iodobenzoic acid and (2-iodophenyl)acetic acid in the presence of potassium hydroxide and copper gave the acids IVab and Xab. The acids IVab afforded by cyclization with sulfuric acid mixtures of 1- and 3-alkylthioxanthones (Va + VIa, Vb + VIb) which were separated by crystallization or chromatography and the individual compounds were identified by spectra. The slightly prevailing 3-alkyl derivatives Vab were reacted with 3-dimethylaminopropylmagnesium chloride to give the tertiary alcohols VIIab which were transformed by the acid catalyzed dehydration to the title compounds Iab. 1-Ethylthioxanthone (VIb) afforded similarly via the tertiary alcohol VIII the title compound IX. The acids Xab were cyclized with polyphosphoric acid unequivocally to the ketones XIab which were converted via the alcohols XIIab to the chloro derivatives XIIIab. Substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine led to the title compounds IIab and IIIb. The compounds prepared (I-III) have antihistamine activity and are more or less central depressant. Compounds Ib, IIb and IIIb revealed a clear cataleptic activity and compound Ib showed also antireserpine activity. Compound IX is centrally depressant only in high doses but it has anticonvulsant effects and a significant antitussive effect.

Fluorinated neuroleptics of the 10-piperazino-10,11-dihydrodibenzo[b,f]thiepin series; 6-Fluoro derivatives of perathiepin, octoclothepin, doclothepin and some related compounds

1979 ◽  
Vol 44 (7) ◽  
pp. 2139-2155 ◽  
Author(s):  
Irena Červená ◽  
Jiřina Metyšová ◽  
Václav Bártl ◽  
Miroslav Protiva
Keyword(s):  
Metabolic Pathway ◽  
Pharmacological Profile ◽  
Fluoro Derivative ◽  
Sedative Effects ◽  
Neuroleptic Agent ◽  
A Minor ◽  
Derivatives Of ◽  
Related Compounds ◽  
Fluoro Derivatives ◽  
Central Depressant

The synthesis of a series of 6-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins Ic-IIIc, Vc and VIc is described; these compounds are derivatives of the neuroleptic agents perathiepin (Ia), octoclothepin (IIIa), doclothepin (Va) and their hydroxyethyl analogues IIa and VIa in which the metabolic hydroxylation to position 6 was made impossible by blockade. The synthesis used common procedures via the intermediates VII-XVIII. Fluorination in position 6 does not influence much the pharmacological profile of the compounds indicating that hydroxylation in position 6 is only a minor metabolic pathway. The most interesting substance is the 6-fluoro derivative of octoclothepin (IIIc) which is a potent central depressant and neuroleptic agent with some protraction of the sedative effects.

2-(tert.amino)-11-(4-methylpiperazino)dibenzo[b,f]thiepins and their 10,11-dihydro derivatives; Synthesis and neuroleptic activity

1987 ◽  
Vol 52 (3) ◽  
pp. 793-803 ◽  
Author(s):  
Vojtěch Kmoníček ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Acetic Acid ◽  
Potassium Hydroxide ◽  
Polyphosphoric Acid ◽  
Titanium Tetrachloride ◽  
Aqueous Potassium Hydroxide ◽  
Neuroleptic Agent ◽  
Arylacetic Acids ◽  
Neuroleptic Activity ◽  
Central Depressant

Reactions of (2-iodophenyl)acetic acid with 4-(dimethylamino)thiophenol, 4-piperidinothiophenol, and 4-morpholinothiophenol in boiling aqueous potassium hydroxide solutions in the presence of copper gave the arylacetic acids IVabc which were cyclized with polyphosphoric acid at 130 °C to 8-(tert.amino)dibenzo[b,f]thiepin-10(11H)-ones Vabc. The following reactions with 1-methylpiperazine in boiling benzene in the presence of titanium tetrachloride afforded the enamines IIabc. Compounds IIa and IIc were reduced with diborane to the 10,11-dihydro compounds Ia and Ic. Compound Ia (the 8-dimethylamino derivative of perathiepin) is a typical incisive neuroleptic agent with very strong cataleptic, antiapomorphine, central depressant, and antiadrenergic activities. The morpholino derivative Ic and the enamines IIb and IIc are less active.

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.

N-substituted aminomethyl 4-cyclopentylphenyl ketones and 2-amino-1-(4-cyclopentylphenyl)ethanol: Synthesis and pharmacological screening

1983 ◽  
Vol 48 (2) ◽  
pp. 642-648 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Miroslav Protiva
Keyword(s):  
Secondary Amines ◽  
Lithium Aluminium Hydride ◽  
Substitution Reactions ◽  
Rotarod Test ◽  
Lithium Aluminium ◽  
Spontaneous Motility ◽  
Pharmacological Screening ◽  
Higher Doses ◽  
Hydroxyethyl Piperazine ◽  
Ethanol Synthesis

The non-characterized bromo derivative Ia, obtained by bromination of 4-cyclopentylacetophenone, afforded by substitution reactions with diethylamine, benzylmethylamine, benzylisopropylamine, piperidine, morpholine, 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine the amino ketones IIa-VIIIa which were reduced with lithium aluminium hydride to the aminoalcohols IIb-VIIIb. Compounds IIIb and IVb were debenzylated by catalytic hydrogenation on palladium to the secondary amines IXb and Xb. The compounds prepared have central stimulant effects in higher doses which appears also in the rotarod test and in the evaluation of spontaneous motility. They have mostly a mild spasmolytic effect of the anticholinergic type, some of them bring about local anesthetic and diuretic effects. The adrenolytic and hypotensive effects were found only with single compounds.

α-(4-Tolyl)dopamine, derivatives and analogues; Synthesis and pharmacological screening

1983 ◽  
Vol 48 (5) ◽  
pp. 1447-1464 ◽  
Author(s):  
Vladimír Valenta ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
Marie Bartošová ◽  
...  
Keyword(s):  
Acetic Anhydride ◽  
Hydrobromic Acid ◽  
Benzoyl Chloride ◽  
Substitution Reactions ◽  
Low Degree ◽  
Anticataleptic Activity ◽  
Pharmacological Screening ◽  
Higher Doses ◽  
Hydroxyethyl Piperazine ◽  
Antiarrhythmic Effects

The ketone XIII, obtained by Friedel-Crafts reaction of toluene with homoveratroyl chloride, was converted by the Leuckart reaction to the formamido derivative IXb which was used as the starting product for the synthesis of amines IIIb-Vb. Reduction of the ketone XIII gave the alcohol XVI which was treated with hydrogen chloride and afforded the chloro compound XVII. Its substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)piperazine and 1-phenylpiperazine resulted in the piperazines VIb-VIIIb. Acylations of the amine IIIb with acetic anhydride and homoveratroyl chloride gave the amides Xb and XIb which, together with the formamide IXb, were subjected to the Bischler-Napieralski reaction. 3,4-Dihydroisoquinolines XXII-XXIV were obtained and reduced to the 1,2,3,4-tetrahydroisoquinolines XXVb-XXVIIb. Treatment of XXVIIb with formaldehyde afforded the berbine derivative XXVIII. Demethylation of the amine IIIb with hydrobromic acid resulted in the title compound IIIa. Similar demethylations of the dimethoxyamines IVb-VIIIb, XXVb and XXVIb led to the dihydroxyamines IVa-VIIIa, XXVa and XXVIa which are dopamine derivatives. Reaction of Va with benzoyl chloride gave the dibenzoate XXX. The CNS activities of the compounds prepared are of a low degree. Several of them (IIIa-VIa, IIIb-Vb, XXVb) show in higher doses signs of central stimulant action but only for compound IVa an antireserpine effect was proven. The expected anticataleptic activity was found only in a low degree with compound VIIIa; on the contrary, compounds IIIa and XXVa are procataleptogenic. Some compounds (IIIa, IXb, XXVIa, XXVIII) potentiated thiopental. In single cases local anaesthetic, spasmolytic, hypotensive, hypertensive, hypoglycaemic, diuretic and antiarrhythmic effects were observed.

Potential noncataleptic neuroleptic agents: 2,3-Dichloro-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrobenzo[b,f]thiepin

1984 ◽  
Vol 49 (4) ◽  
pp. 992-1001 ◽  
Author(s):  
Jiří Urban ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
Miroslav Protiva
Keyword(s):  
Benzoic Acid ◽  
Potassium Carbonate ◽  
Title Compound ◽  
Substitution Reaction ◽  
Polyphosphoric Acid ◽  
Dopamine Metabolism ◽  
Nitro Derivative ◽  
High Dose ◽  
Chloro Derivative ◽  
Hydroxyethyl Piperazine

The 6-nitro derivative V, obtained by nitration of 3,4-dichlorobrombenzene, was transformed via the amine VI and nitrileVII to 2-bromo-4,5-dichlorobenzoic acid (IX). Its reaction with thiophenol in 3-methyl-1-butanol in the presence of potassium carbonate and catalytic amounts of copper and cuprous iodide afforded 4,5-dichloro-2-(phenylthio)benzoic acid (Xa) which was reduced to the alcohol XIa. The transformation to the homologous acid XIVa proceeded via noncharacterized intermediates XIIa and XIIIa. The cyclization with polyphosphoric acid at 150 °C resulted in 2,3-dichlorodibenzo[b,f]thiepin-10(11H)-one (XV) which was reduced to the alcohol XVI. Treatment with hydrogen chloride gave the unstable chloro derivative XVII whose substitution reaction with 1-(2-hydroxyethyl)piperazine led to the title compound II. Its dimethanesulfonate showed properties of a little toxic and noncataleptic tranquillizer. Because it does not influence the dopamine metabolism in rat brain in a rather high dose, it cannot be considered a neuroleptic.

Potential noncataleptic neuroleptic agents: Synthesis and pharmacology of 7-chloro-4-[4-(2-hydroxyethyl)piperazino]-4,5-dihydrothieno[2,3-b]-1-benzothiepin

1983 ◽  
Vol 48 (10) ◽  
pp. 2970-2976 ◽  
Author(s):  
Zdeněk Polívka ◽  
Martin Valchář ◽  
Miroslav Protiva
Keyword(s):  
Sodium Borohydride ◽  
Potassium Carbonate ◽  
Title Compound ◽  
Potassium Hydroxide ◽  
Dopamine Metabolism ◽  
High Dose ◽  
Chloro Derivative ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant ◽  
Boiling Toluene

Heating of 2,5-dichloroacetophenone with 2-thiophenethiol, potassium carbonate and copper gave 5-chloro-2-(2-thienylthio)acetophenone (V) which was subjected to the Willgerodt reaction with sulphur and morpholine. The product was a mixture of the thiomorpholide VI and oxothiomorpholide VII. After a partial separation the predominanting product VI was hydrolyzed without characterization with ethanolic potassium hydroxide to give the acid VIII. Cyclization by treatment with phosphorus pentoxide in boiling toluene gave 7-chlorothieno[2,3-b]-1-benzothiepin-4(5H)-one (X) which was reduced with sodium borohydride to the alcohol XII. A reaction with hydrogen chloride in benzene led to the chloro derivative XIII whose substitution reaction with 1-(2-hydroxyethyl)piperazine afforded the title compound IV. The product has strong central depressant and discoordinating activity, a low cataleptic efficity but in a relatively high dose it does not influence the dopamine metabolism in the rat brain.

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