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.

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.

Noncataleptic neuroleptics: Potential metabolites of 2-chloro-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,fthiepin

1979 ◽  
Vol 44 (10) ◽  
pp. 3008-3018 ◽  
Author(s):  
Vladimír Valenta ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
Marie Bartošová ◽  
Miroslav Protiva
Keyword(s):  
Secondary Amine ◽  
Title Compound ◽  
Primary Amine ◽  
Pyridine Derivative ◽  
Oxidation Reactions ◽  
Substitution Reactions ◽  
Piperazine Derivatives ◽  
Antihistamine Activity ◽  
Hydrolysis Of ◽  
Central Depressant

The synthesis of nine potential metabolites of the title compound is being described. Using oxidation reactions, compound I was transformed to the S-oxide VII, A-oxide IX and A,S-dioxide X. Substitution reactions of 2,10-dichloro-10,11-dihydrodibenzo[b,f]thiepin with 1-ethoxycarbonylpiperazine, piperazine and ethylenediamine afforded the amines II, III, IV and XIII. Leuckart reaction of 2-chlorodibenzo[b,f]thiepin-10(11H)-one led in addition to the expected formamido derivative XI to the heptacyclic pyridine derivative XIV. Hydrolysis of compounds II and XI gave the secondary amine III and the primary amine XII. Oxidation of substances III, XII and XIII afforded the sulfoxides VIII, XV and XVI. Most of the prepared piperazine derivatives exhibit some central depressant, adrenolytic and antihistamine activity.

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.

Neuroleptic 2-chloro-11-(2-piperazineethoxy)-10,11-dihydrodibenzo[b,f]thiepins: Synthesis and pharmacology

1984 ◽  
Vol 49 (8) ◽  
pp. 1810-1815 ◽  
Author(s):  
Václav Bártl ◽  
Jiří Jílek ◽  
Jiřina Metyšová ◽  
Martin Valchář ◽  
Antonín Dlabač ◽  
...  
Keyword(s):  
Alkaline Hydrolysis ◽  
Boron Trifluoride ◽  
Boron Trifluoride Etherate ◽  
Dopamine Metabolism ◽  
Substitution Reactions ◽  
Activity Profile ◽  
Hydrolysis Of ◽  
Brain Striatum ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant

A reaction of 8-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-ol with 2-bromoethanol and boron trifluoride etherate produced the 2-bromoethyl ether II which was subjected to substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)piperazine, 1-(3-hydroxypropyl)piperazine and 1-ethoxycarbonylpiperazine to give the title piperazinoethoxy compounds IV-VII. Alkaline hydrolysis of the carbamate VII afforded the monosubstituted piperazine VIII. Compounds IV-VI are neuroleptics with an interesting activity profile: they are little toxic, have strong central depressant and antimorphine activity, mild cataleptic effects, they intensively increase the dopamine metabolism in the rat brain striatum and are almost free of the peripheral adrenolytic efficacy.

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.

Potential hypnotics and anxiolytics: Synthesis of 2-bromo-4-(2-chlorophenyl)-9-[4-(2-methoxyethyl)piperazino]-6H-thieno[3,2,4-triazolo[4,3-a]-1,4-diazepine and of some related compounds

1984 ◽  
Vol 49 (3) ◽  
pp. 621-636 ◽  
Author(s):  
Zdeněk Polívka ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jan Metyš ◽  
Miroslav Protiva
Keyword(s):  
Title Compound ◽  
Point Of View ◽  
Triethyl Orthoformate ◽  
Substitution Reactions ◽  
Bromo Derivative ◽  
Anticonvulsant Activities ◽  
Related Compounds

The synthesis of 2,9-dibromo-4-(2-chlorophenyl)-6H-thieno[3,2-f]-1,2,4-triazolo[4,3-a]-1,4,diazepine (XX) has been carried out. The substitution reactions of XX with 1-(2-methoxyethyl) piperazine, 1-(3-methoxypropyl)piperazine, 1-(2-ethoxyethyl)piperazine and 1-(2-methylthiothyl)-piperazine afforded the title compound XXIV and its analogues XXV-XXVII. N-Alkylations of 2-bromo-4-(2-chlorophenyl)-9-piperazino-6H-thieno[3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine (XXIII) with 2-phenoxyethyl bromide and 2-phenylthioethyl bromide gave compounds XXVIII and XXIX. Cyclization of 5-(2-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine(XVIIIa) by treatment with triethyl orthoformate resulted in 4-(2-chlorophenyl)-6H-thieno[3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine (XIX) which could be brominated only to the 9-bromo derivative XXI; attempts at further bromination to position 2 were unsuccessful. Some contribution to the syntheses of etizolam (I) and its dechloro analogue V in the stage of intermediates are being described. Compounds XXIV-XXIX were pharmacologically tested from the point of view of discoordinating and anticonvulsant activities; they proved less active than the analogous 8-chloro-6-(2-chlorophenyl)-1-piperazino-4H-striazolo[4,3-a]-1,4-benzodiazepines.

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 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.

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

1983 ◽  
Vol 48 (12) ◽  
pp. 3433-3443 ◽  
Author(s):  
Zdeněk Polívka ◽  
Jiří Holubek ◽  
Jan Metyš ◽  
Zdeněk Šedivý ◽  
Miroslav Protiva
Keyword(s):  
Hydrazine Hydrate ◽  
Title Compound ◽  
Acid Hydrazide ◽  
Ethyl Esters ◽  
Ethyl Chloroacetate ◽  
Related Compounds ◽  
Central Depressant

Ethyl esters of 4-substituted piperazinoacetic acids IIIa-f were prepared by alkylation of 1-(ethoxycarbonylmethyl)piperazine with 2-methoxyethyl bromide, 2-ethoxyethyl bromide, 2-methylthioethyl chloride, 2-phenoxyethyl bromide and 2-phenylthioethyl bromide or by reactions of 1-(3-methoxypropyl)piperazine and 1-(2-methylthioethyl)piperazine with ethyl chloroacetate. Reactions of the esters with hydrazine hydrate gave the hydrazides IVa-f. Their treatment with 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-thione resulted in the title compound Ia and analogues Ib-f. 1-(4-Methylpiperazinomethyl) derivatives Ig and IIg were similarly prepared from 4-methylpiperazinoacetic acid hydrazide (IVg). Compound Ig showed significant central depressant and anticonvulsant (electroshock) activity in mice. The enlargement of the substituent in position 4 of the piperazine residue results in an important decrease of these activities.

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