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 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.

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.

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.

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.

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.

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 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.

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.

Tricyclic potential neuroleptics: 2-chloro-11-[4-(4-fluoroaralkyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepins and related compounds

1980 ◽  
Vol 45 (11) ◽  
pp. 3182-3189 ◽  
Author(s):  
Václav Bártl ◽  
Antonín Dlabač ◽  
Miroslav Protiva
Keyword(s):  
Ethyl Bromide ◽  
Substitution Reactions ◽  
Butyl Bromide ◽  
Piperazine Derivatives ◽  
Hydrolysis Of ◽  
Related Compounds ◽  
Central Depressant

Alkylation of 1-ethoxycarbonylpiperazine with 4-fluorobenzyl bromide, 2-(4-fluorophenyl)ethyl bromide and 4,4-bis(4-fluorophenyl)butyl bromide gave the carbamates IIa, IIb and IIf. Two further similar compounds (IIc, IId) were obtained by reactions of 1-(2-chloroethyl)-4-ethoxycarbonylpiperazine with 4-fluorophenol, and with 4-fluorothiophenol, respectively. Hydrolysis of carbamates IIa-f resulted in piperazine derivatives IIIa-f affording the title compounds by substitution reactions with 2,11-dichloro-10,11-dihydrodibenzo[b,f]thiepin. Out of the compounds prepared only the fluorophenethyl derivative Ib and the fluorobenzoylpropyl derivative Ie maintain the neuroleptic character, i.e. clear central depressant and 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.

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