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-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.

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.

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.

Highly polar potential metabolites of the neuroleptic agent oxyprothepin: Synthesis of 2-hydroxy-8-methylsulfonyl and 3-hydroxy-8-methylsulfonyl derivatives of 10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1985 ◽  
Vol 50 (2) ◽  
pp. 519-537 ◽  
Author(s):  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiří Schlanger ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Acetic Acid ◽  
Potassium Carbonate ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Methoxybenzoic Acid

The acid XI, obtained by reaction of (2-iodo-5-methoxyphenyl)acetic acid with 4-(methylsulfonyl)thiophenol (VIII) in dimethylformamide in the presence of potassium carbonate and copper, was transformed via intermediates XIIa-XIVa to compound XVa. Demethylation with boron tribromide afforded compound III, the potential metabolite of oxyprothepin (II). Its oxidation with hydrogen peroxide in acetic acid gave the sulfoxide XVII, which is a further potential metabolite. A reaction of 2-iodo-4-methoxybenzoic acid with VIII and potassium carbonate in dimethylformamide in the presence of copper afforded the acid XIX whose ester XXI was reduced with diborane to the alcohol XXII; hydrogenolysis to compound XXIII was also observed. The alcohol XXII was processed via compounds XXIV and XXV to the acid XXVI which was cyclized in a low yield to the ketone XIIb. A further processing via the intermediates XIIIb and XIVb led to compound XVb. Demethylation gave compound IV, another potential metabolite.

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 metabolites of tricyclic neuroleptics and their fluorinated analogues; 3-Hydroxy-, 3-methoxy- and 3-fluoro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (7) ◽  
pp. 2108-2123 ◽  
Author(s):  
Miroslav Protiva ◽  
Karel Šindelář ◽  
Zdeněk Šedivý ◽  
Jiřina Metyšová
Keyword(s):  
Acetic Acid ◽  
Benzoic Acid ◽  
Oral Administration ◽  
Phenolic Compound ◽  
Methoxy Derivative ◽  
Fluoro Derivative ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Central Depressant

4-Methoxy-2-(phenylthio)benzoic acid (V) was transformed in four steps to the homologous acid IXa which was cyclized to 3-methoxydibenzo[b,f]thiepin-10(11H)-one (Xa). The 3-methoxy derivative III of perathiepin (I) was synthesized via the intermediates XIa and XIIa, and demethylated with boron tribromide to the phenolic compound II. The analogous 3-fluoro derivative IV was synthesized from (4-fluoro-2-iodophenyl)acetic acid (XVII), the preparation of which by several procedures is described. Whereas III has only mild tranquilizing activity, II is more potent than perathiepin (I) in the tests for central depressant and cataleptic effects. The 3-fluoro derivative IV, while lacking the properties of a neuroleptic agent, is highly central depressant and this effect shows some prolongation after oral administration.

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 the neuroleptic agent octoclothepin; Synthesis of 8-chloro-2,6-dihydroxy and 8-chloro-3,6-dihydroxy derivatives of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1981 ◽  
Vol 46 (5) ◽  
pp. 1199-1209 ◽  
Author(s):  
Miroslav Protiva ◽  
Zdeněk Šedivý ◽  
Josef Pomykáček ◽  
Emil Svátek ◽  
Jiří Holubek
Keyword(s):  
Acetic Acid ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of

[2-(4-Chloro-2-methoxyphenylthio)-5-methoxyphenyl]acetic acid (V) and [2-(4-chloro-2-methoxyphenylthio)-4-methoxyphenyl]acetic acid (XVII) were synthesized and cyclized to 8-chloro-2,6-dimethoxy (VII) and 8-chloro-3,6-dimethoxydibenzo[b,f]thiepin-10(11H)-one (XVIII). Two further steps afforded dichlorodimethoxy derivatives XI and XXII which reacted with 1-methylpiperazine and gave the 8-chloro-2,6-dimethoxy (II) and 8-chloro-3,6-dimethoxy derivative of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin (IV). Demethylations with boron tribromide resulted in the title compounds I and III being new potential metabolites of the neuroleptic agent octoclothepin.

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.

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.

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