11-(3-[4-(2-Hydroxyethyl)piperazino]propylidene)-6,11-dihydrodibenzo[b,e]thiepin, its 2-chloro derivative and some related compounds as potential antipsychotic agents; Synthesis and pharmacology

1984 ◽  
Vol 49 (8) ◽  
pp. 1816-1826 ◽  
Author(s):  
Václav Bártl ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
Stanislav Wildt ◽  
Miroslav Protiva
Keyword(s):  
Acetic Anhydride ◽  
Amino Alcohol ◽  
Substitution Reaction ◽  
Antipsychotic Agents ◽  
Substitution Reactions ◽  
Chloro Derivative ◽  
Cns Effects ◽  
Related Compounds ◽  
Depot Antipsychotics ◽  
Hydroxyethyl Piperazine

Substitution reactions of (E)-11-(3-bromopropylidene)-6,11-dihydrodibenzo[b,e]thiepin (VIIIa) and its 2-chloro derivative VIIIb with 1-(2-hydroxyethyl)piperazine gave the title compounds IIIa and IIIb which afforded by treatment with acetic anhydride, decanoyl chloride and 3,4,5-trimethoxybenzoyl chloride the esters IVab-VIab. Reduction of the olefinic compounds IIIa and IIIb with hydrolytic acid resulted in the saturated amines IXa and IXb. The piperazine derivativeX was obtained by a substitution reaction of 2,11-dichloro-6,11-dihydrobenzo[b,e]thiepin with 1-(2-hydroxyethyl)piperazine. The amino alcohols IIIa and IIIb, as well as their acetates and 3,4,5-trimethoxybenzoates, are almost devoid of the CNS effects. The decanates Va and Vb have not the properties of the depot antipsychotics (neither antidepressants, nor neuroleptics). The saturated amino alcohol IXa showed some antihistamine, spasmolytic and adrenolytic effects.

Potential antipsychotic agents: 2-Chloro- and 2-methyl-11-(2-piperazinoethoxy)-6,11-dihydrodibenzo[b,e]thiepins and some related compounds; Synthesis and pharmacology

1984 ◽  
Vol 49 (11) ◽  
pp. 2520-2530 ◽  
Author(s):  
Václav Bártl ◽  
Karel Šindelář ◽  
Vladimír Valenta ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
...  
Keyword(s):  
Sulfuric Acid ◽  
Alkaline Hydrolysis ◽  
Antipsychotic Agents ◽  
Similar Reaction ◽  
Substitution Reactions ◽  
Single Product ◽  
Hydrolysis Of ◽  
Related Compounds ◽  
Hydroxyethyl Piperazine ◽  
Neuroleptic Activity

Reactions of 2-chloro- and 2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ol with 2-bromoethanol in the presence of sulfuric acid in boiling benzene afforded the 2-bromoethyl ethers VIa and VIb which were transformed by substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)-piperazine and 1-(ethoxycarbonyl)piperazine to the title compounds. Alkaline hydrolysis of the carbamate IVa gave the secondary amine IIIa. Treatment of the bromo ether VIa with 4-(4-chloro-3-trifluoromethylphenyl)piperidin-4-ol resulted in the piperidine derivative VIIa. Substitution reaction of 11-chloro-6,11-dihydrodibenzo[b,e]thiepin with 1-(2-methoxyethyl)piperazine and 1-(2-ethoxyethyl)piperazine led to the amino ethers VIII and IX. Reaction of 11-chloro-11-phenyl-6,11-dihydrodibenzo[b,e]thiepin with 2-dimethylaminoethanethiol in dimethylformamide at 90°C gave a mixture of two isomeric bases which was separated to the expected sulfide X and the base XII, resulting evidently after the rearrangement of the primary carbocation. A similar reaction of 3-dimethylaminopropanethiol afforded a single product of structure XI. Out of the compounds prepared, the ether VIII was found most interesting: it is little toxic and has significant antireserpine activity in two tests (is considered a potential antidepressant). The ethers Iab, Iab, IIIa and VIIa did not reveal the expected neuroleptic activity.

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 hypnotics and anxiolytics in the 4H-s-triazolo[4,3-a]-1,4-benzodiazepine series: 8-Chloro-6-(2-chlorophenyl)-1-[4-(2-methoxyethyl)piperazino]-4H-s-triazolo[4,3-a]-1,4-benzodiazepine and some related compounds

1983 ◽  
Vol 48 (8) ◽  
pp. 2395-2410 ◽  
Author(s):  
Zdeněk Polívka ◽  
Miroslav Ryska ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jan Metyš ◽  
...  
Keyword(s):  
Title Compound ◽  
Substitution Reaction ◽  
Gradual Decrease ◽  
Substitution Reactions ◽  
Bromo Derivative ◽  
Related Compounds ◽  
Very High

1-Bromo derivatives XIIa and XIIb were prepared by bromination of 8-chloro-6-phenyl-4H-s-triazolo[4,3-a]-1,4-benzodiazepine (XIa) and its 6-(2-chlorophenyl) analogue XIb with bromine in chloroform in the presence of pyridine. Substitution reactions with 1-(2-methoxyethyl)piperazine (XIVb), 1-(3-methoxypropyl)piperazine (XVb), 1-(2-ethoxyethyl)piperazine (XVIb) and 1-(2-methylthioethyl)piperazine (XVIIb) afforded the title compound IIb and analogues IIa and IIIb-Vb. A substitution reaction of the bromo derivative XIIb with piperazine gave the 1-piperazino derivative VIIIb which was alkylated with 2-phenoxyethyl bromide and 2-phenylthioethyl bromide to give compounds VIb and VIIb. The title compound IIb has very high anticonvulsant and discoordinating activities in mice. The enlargement of the substituent R1 (compounds IIIb-VIIb) results in a gradual decrease of the effects mentioned.

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).

Neuroleptic agents derived from perathiepin: 6,7-Dichloro derivative of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin and related compounds

1981 ◽  
Vol 46 (7) ◽  
pp. 1607-1613 ◽  
Author(s):  
Jiří Jílek ◽  
Josef Pomykáček ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Benzoic Acid ◽  
Title Compound ◽  
Titanium Tetrachloride ◽  
Substitution Reactions ◽  
Related Compounds ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant ◽  
Dichloro Derivative ◽  
Iodobenzoic Acid

The reaction of 2,3-dichlorothiophenol with 2-iodobenzoic acid gave 2-(2,3-dichlorophenylthio)benzoic acid (V) which was transformed in four steps to the homological acid IX. Cyclization resulted in 6,7-dichlorodibenzo[b,f]thiepin-10(11H)-one (X) which was converted via the alcohol XI to the trichloro compound XII. Substitution reactions of XII with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine afforded the title compound I and its hydroxyethyl analogue II. Reaction of the ketone X with 1-methylpiperazine and titanium tetrachloride gave the enamine III. Compounds I-III exhibit mild central depressant and relatively strong cataleptic activity.

Basic amides of 2,4,5-trichlorophenoxyacetic, 2,4,6-trimethylphenoxyacetic and 4-bromo-3,5-dimethylphenoxyacetic acid and some related compounds; Synthesis and pharmacological screening

1983 ◽  
Vol 48 (4) ◽  
pp. 1089-1096 ◽  
Author(s):  
Vladimír Valenta ◽  
Jiří Němec ◽  
Miroslav Protiva
Keyword(s):  
Local Anaesthetic ◽  
Methyl Esters ◽  
Acid Chlorides ◽  
Basic Amides ◽  
Pharmacological Screening ◽  
Cns Effects ◽  
Related Compounds ◽  
Hydroxyethyl Piperazine

Reactions of methyl esters II of 2,4,5-trichlorophenoxyacetic (Ia), 2,4,6-trimethylphenoxyacetic (Ib) and 4-bromo-3,5-dimethylphenoxyacetic acid (Ic) with 2-diethylaminoethylamine, 2-morpholinoethylamine, 3-morpholinopropylamine, 1-methylpiperazine, 3-(4-methylpiperazino)propylamine, 3-[4-(2-tolyl)piperazino]propylamine and 1,4-bis(3-aminopropyl)piperazine in boiling ethanol gave the basic amides Va-XIc which were isolated as hydrochlorides. Reactions of the acid chlorides IVa and IVb with 1,4-bis(2-hydroxyethyl)piperazine and 1,4-bis(3-hydroxypropyl)piperazine in dimethylformamide resulted directly in dihydrochlorides of diesters XIIab and XIIIab. The compounds prepared have only weak CNS effects (mostly of the depressant type); they have local anaesthetic, mild hypotensive (some of them adrenolytic), antiarrhythmic and peripheral vasodilating activities.

Fluorinated analogues of tricyclic neuroleptics: 6,9-difluoro derivative of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1980 ◽  
Vol 45 (10) ◽  
pp. 2688-2694 ◽  
Author(s):  
Irena Červená ◽  
Marta Hrubantová ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Polyphosphoric Acid ◽  
Satisfactory Yield ◽  
Chloro Derivative ◽  
Cns Activity

The acid VI, obtained from 2,5-difluorothiophenol (IV) and (2-iodophenyl)acetic acid, afforded by cyclization with polyphosphoric acid 6,9-difluorodibenzo[b,f]thiepin-10(11H)-one (VII) in a satisfactory yield. Two further steps led to the chloro derivative X giving by a substitution reaction with 1-methylpiperazine the title compound III. This substance exhibits some 10% incoordinating activity of the unsubstituted compound I and an indication of cataleptic activity, in contrast to the inactive analogous dichloro compound II. The bulky atom of chlorine in the vicinity of the methylpiperazine residue interferes evidently with the CNS activity; the influence of the atom of fluorine is much less pronounced in this line.

Noncataleptic neuroleptic agents: 2-(4-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethyl)piperazine-1-yl)ethanol and some related compounds

1988 ◽  
Vol 53 (11) ◽  
pp. 2731-2741 ◽  
Author(s):  
Jiří Jílek ◽  
Martin Valchář ◽  
Jiří Holubek ◽  
Nataša Dlohožková ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Preclinical Studies ◽  
Acid Chlorides ◽  
Substitution Reactions ◽  
Related Compounds

10-(2-Bromoethoxy)-2-chloro-10,11-dihydrodibenzo[b,f]thiepin (X), prepared by two methods, was subjected to substitution reactions with 2-(1-piperazinyl)ethanol, 3-(1-piperazinyl)propanol, 1-methylpiperazine, 3-(1-piperazinyl)propionamide, piperazine, and 1-(ethoxycarbonyl)piperazine and gave the title compounds II-VII. The alcohol II was esterified by treatment with acid chlorides to compounds VIII and IX. Compounds II, V, and VIII proved to be noncataleptic neuroleptic agents and II (clopithepin, VÚFB-17 076) was selected for preclinical studies.

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