Fluorinated tricyclic neuroleptics with prolonged action: 3-Fluoro-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepins with less common substituents in position 8

1983 ◽  
Vol 48 (1) ◽  
pp. 144-155 ◽  
Author(s):  
Karel Šindelář ◽  
Jiřina Metyšová ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Amino Alcohol ◽  
Diazonium Salt ◽  
Cuprous Chloride ◽  
Hydroxy Ketone ◽  
Phenyl Acetic Acid ◽  
Prolonged Action ◽  
Chloro Derivative ◽  
Sedative Effects ◽  
Cuprous Cyanide ◽  
Central Depressant

Cyclization of [4-fluoro-2-(4-nitrophenylthio)phenyl]acetic acid resulted in 3-fluoro-8-nitrodibenzo[b,f]thiepin-10(11H)-one (IIa) which was transformed via the intermediates IVa and Va to the compound Ia. Its reduction gave the amino alcohol Ib. 8-Amino-3-fluorodibenzo[b,f]thiepin-10(11H)-one (IIb) was diazotized and the diazonium salt was converted by treatment with sulfur dioxide and cuprous chloride, followed by dimethylamine, to the N,N-dimethylsulfonamide IIc. Its processing via the intermediates IVc and Vc afforded Ic. Reduction of the amino ketone IIb gave the amino alcohol IVb which was transformed by the Beech method to the hydroxy ketone IVd. Id was obtained via the chloro derivative Vd. A reaction of 3-fluoro-8-iodo-10,11-dihydrodibenzo[b,f]thiepin-10-ol with cuprous cyanide in dimethylformamide led to the cyano alcohol IVe which was used for concluding the synthesis of Ie. Compounds Ia - Id are neuroleptics with central depressant and cataleptic activity; the sedative effects reveal protraction in all cases. In the test of catalepsy the least active compound Ib shows, however, a clear prolongation of this effect. Compound Ia is the most active one in the test of antiapomorphine activity but its effects are not protracted.

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.

scholarly journals Toxicity and Neuropharmacological Effects of Elenine

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Eduardo Navarro ◽  
S. J. Alonso ◽  
R. Navarro
Keyword(s):  
Open Field ◽  
Field Test ◽  
Chemical Structure ◽  
Open Field Test ◽  
Control Group ◽  
General Behaviour ◽  
Similar Chemical ◽  
Sedative Effects ◽  
Traction Test ◽  
Central Depressant

Elenine is the aglycone of elenoside, a cytotoxic arylnaphthalene lignan (NSC 644013-W/1) derived fromJusticia hyssopifolia. (Family: Acanthaceae). Elenoside is a β-D-glucoside, with a similar chemical structure to etoposide, exhibiting central depressant activity. In the present study, elenine was given to mice and rats at doses of 10, 20, and 40 mg/kg. Acute toxicity (24 h) and general behaviour in mice was studied as well as its effects on muscular relaxant activity, locomotor activity (Varimex test), and the open-field test and were compared with 10 mg/kg of chlorpromazine. Elenine produced a reduction in the permanence time in muscular relaxant activity (traction test). Spontaneous activity was lower in the Varimex test. The ambulation and rearing were lower compared with the control group, and an increase in boluses was observed in the open-field test. Thus, it can be concluded that elenine has central sedative effects at lower doses than those used with elenoside and has a possible application in conditions of anxiety.

Tricyclic psychotropic agents containing two chalcogen atoms in the central ring: 8-Substituted 6-(4-piperidyl)-6H-dibenz[b,e]-1,4-oxathiepins

1982 ◽  
Vol 47 (11) ◽  
pp. 3077-3093 ◽  
Author(s):  
Karel Šindelář ◽  
Jiřina Metyšová ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiří Protiva ◽  
...  
Keyword(s):  
Secondary Amine ◽  
Amino Alcohol ◽  
Sodium Hydride ◽  
Amino Alcohols ◽  
Central Ring ◽  
Psychotropic Agents ◽  
High Degree ◽  
By Products ◽  
Antiapomorphine Effect ◽  
Central Depressant

2-(2-Fluorophenylthio)benzaldehydes IXa-c and 5-chloro-2-(2-fluorophenylthio)acetophenone were treated with 1-methyl-4-piperidylmagnesium chloride and 3-dimethylaminopropylmagnesium chloride, respectively, and the resulting amino alcohols VIa-c, XVII and XVIII were cyclized with sodium hydride in dimethylformamide. In addition to the title compounds Ia-c, XIX and XX, several types of by-products were obtained. Demethylation of compound Ib by the chloroformate method afforded the secondary amine IIb which was transformed to the amino alcohols IIIb and Vb. Compounds Ia-c are very potent neuroleptics with a high degree of central depressant and cataleptic activity. The amino alcohol Vb exhibits a very strong antiapomorphine effect in rats.

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.

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.

Fluorinated tricyclic neuroleptics with prolonged action: 7-Fluoro-11-[4-(2-hydroxyethyl)piperazino]-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin

1986 ◽  
Vol 51 (3) ◽  
pp. 698-722 ◽  
Author(s):  
Miroslav Protiva ◽  
Jiří Jílek ◽  
Miroslav Rajšner ◽  
Josef Pomykáček ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Tartaric Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Active Component ◽  
Phenyl Acetic Acid ◽  
Prolonged Action ◽  
Neuroleptic Agent ◽  
Synthetic Sequence ◽  
Hydroxyethyl Piperazine

Substitution reaction of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f,]thiepin with 1-(2-hydroxyethyl)piperazine gave the title compound I which proved a very potent and longacting oral neuroleptic agent (isofloxythepin). Its resolution by means of dibenzoyl-(+)- and -(-)-tartaric acid led to (-)- and (+)-enantiomer out of which the former represents the neuroleptically active component. In the synthetic sequence leading to I, preparation of two key intermediates was re-elaborated using new partial sequences: 4-fluoro-2-iodobenzoic acid (XIII) from 4-fluoro-2-nitroaniline (V) via the nitrile VI and the acids VIII and XII, and [4-fluoro-2-(4-iso-propylphenylthio)phenyl]acetic acid (XVIII) from XIII via XIV and the compounds XV-XVII. The sulfoxides and N-oxides XIX-XXII were prepared as potential metabolites of isofloxythepin (I).

Noncataleptic potential neuroleptics: 2-Methyl-10-(4-methylpiperazino)- and -10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (9) ◽  
pp. 2677-2688 ◽  
Author(s):  
Vladimír Valenta ◽  
Jiří Jílek ◽  
Josef Pomykáček ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Rat Brain ◽  
The Other ◽  
Phenyl Acetic Acid ◽  
Dopamine Metabolites ◽  
Other Hand ◽  
The One ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant

[5-Methyl-2-(phenylthio)phenyl]acetic acid (XV) was synthesized on the one hand from the acid VIII using the known homologization technique via the alcohol X and nitrile XII, on the other from 5-methyl-2-(phenylthio)acetophenone (XIII) by means of the Willgerodt reaction. Via the intermediates XIX and XX, the synthesis led to 10-chloro-2-methyl-10,11-dihydrodibenzo[b,f]thiepin (XXI), giving by treatment with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine the title compounds III and IV. These compounds have low cataleptic and high central depressant activity; on the other hand, they do not influence the levels of dopamine metabolites in the rat brain which is considered an indication of their lacking the neuroleptic character.

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.

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.

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