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.

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 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.

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-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 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.

Potential metabolites of the noncataleptic neuroleptics: Synthesis of 2-chloro-6-hydroxy(and methoxy)-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1981 ◽  
Vol 46 (9) ◽  
pp. 2245-2253 ◽  
Author(s):  
Miroslav Protiva ◽  
Zdeněk Šedivý ◽  
Josef Pomykáček ◽  
Václav Bártl ◽  
Jiří Holubek ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Phenyl Acetic Acid ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Hydroxyethyl Piperazine

[5-Chloro-2-(2-methoxyphenylthio)phenyl]acetic acid (VI), obtained via the acetophenone derivative IV, was cyclized to 2-chloro-6-methoxydibenzo[b,f]thiepin-10(11H)-one (VIIIa). 2,10-Dichloro-6-methoxy-10,11-dihydrodibenzo[b,f]thiepin (Xa) was prepared via the alcohol IXa and its substitution reaction with 1-(2-hydroxyethyl)piperazine gave the compound III. Demethylation with boron tribromide in chlorobenzene resulted in the title compound II which is a potential metabolite of the noncataleptic neuroleptic agent docloxythepin.

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.

ChemInform Abstract: DIHALO DERIVATIVES OF NAPHTHOSTYRIL-N-ACETIC ACID

1978 ◽  
Vol 9 (34) ◽  
Author(s):  
A. P. KARISHIN ◽  
A. A. PECHKA ◽  
N. F. GRINEVA
Keyword(s):  
Acetic Acid ◽  
Derivatives Of
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