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.

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 analogues of the tricyclic neuroleptics; 7-Fluoro and 7-trifluoromethyl derivative of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1980 ◽  
Vol 45 (4) ◽  
pp. 1086-1098 ◽  
Author(s):  
Karel Šindelář ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Alkaline Hydrolysis ◽  
Title Compound ◽  
Polyphosphoric Acid ◽  
Titanium Tetrachloride ◽  
Keto Acid ◽  
Methanesulfonyl Chloride ◽  
Trifluoromethyl Derivative ◽  
By Products ◽  
Central Depressant

Reaction of 3-fluorothiophenol with (2-iodophenyl)acetic acid gave the acid VIII which was cyclized with polyphosphoric acid to the ketone XII. The first title compound VI was prepared via the intermediates XV and XVIII. Treatment of the ketone XII with 1-methylpiperazine in the presence of titanium tetrachloride resulted in the enamine XXIII. The similarly prepared acid IX was cyclized to the ketone XIII. By-products were the di-acid X and the enol-lactone XXIV, affording by alkaline hydrolysis the keto acid XXV. The synthesis of the second title compound VII was carried out from the ketone XIII via the intermediates XVI and XIX. 10,11-Dihydrodibenzo[b,f]thiepin-3,11-diol (XVII) gave by treatment with methanesulfonyl chloride and by the following reaction with 1-methylpiperazine the salt of 1-methylpiperazine with dibenzo[b,f]thiepin-3-ol (XXII) and 1-methyl-4-(methylsulfonyl)piperazine (XXVI)). Whereas the compound VI has low central depressant and cataleptic activity, the corresponding enamine XXIII is very potent in both lines. The trifluoromethyl derivative VII has the character of a neuroleptic but its depressant and cataleptic activity are ten times lower than those of the 8-trifluoromethyl isomer.

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.

Oxidation of Ethanol on Sn-Mo Oxide Catalysts

1992 ◽  
Vol 57 (3) ◽  
pp. 439-445
Author(s):  
Magdy A. Wassel ◽  
Nalla K. Allahaverdova ◽  
Tofki G. Alkhazov
Keyword(s):  
Acetic Acid ◽  
Potassium Hydroxide ◽  
Pulse Method ◽  
Conversion Ratio ◽  
Mo Catalyst ◽  
Acid Ratio ◽  
Aqueous Potassium Hydroxide ◽  
The Stability ◽  
Primary Oxidation ◽  
Oxidation Of Ethanol

To determine the acidic and basic properties of the title catalysts, the adsorption of NH3 and SO2 was compared using pulse method. It was found that this characteristics undergoes changes when the Sn-Mo catalyst is treated with aqueous potassium hydroxide solutions of different concentrations. The catalyst treated with the more concentrated KOH solution possesses mainly properties of a base. When studying the oxidation of ethanol it has been found that the αCO2/αaldehyde conversion ratio increases with the time of contact of the mixture with the catalyst while the αCO2/α acid ratio is not affected. The study of two alcohols deuterated either in OH group (C2H5OD) or in the alkyl group ((C2D5OH) has shown that the substitution of C-H for C-D bond enhances the stability of the primary oxidation product, deuterated ethanal, so that it is not transformed further to acetic acid.

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.

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.

Noncataleptic neuroleptic agents: 2-Halogeno-8-isopropyl-10-piperazino-10,11-dihydrodibenzo[b,f,]thiepins

1984 ◽  
Vol 49 (1) ◽  
pp. 86-109 ◽  
Author(s):  
Zdeněk Polívka ◽  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
...  
Keyword(s):  
Potassium Hydroxide ◽  
Polyphosphoric Acid ◽  
Pharmacological Profile ◽  
Substitution Reactions ◽  
Biochemical Tests ◽  
Neuroleptic Agent ◽  
Fluoro Derivatives ◽  
Iodo Derivative ◽  
Hydroxyethyl Piperazine ◽  
Acetic Acids

Reactions of 5-fluoro, 5-chloro- and 5-bromo-2-iodobenzoic acid with 4-isopropylthiophenol in solutions of potassium hydroxide in the presence of copper gave the acids VIIabc which were transformed via the intermediates VIIIabc-Xabc to 2-[5-halogeno-2-(4-isopropylphenylthio)-phenyl]acetic acids XIabc. Their cyclization with polyphosphoric acid resulted in 2-halogeno-8-isopropyldibenzo[b,f]thiepin-10(11H)-ones XIIabc.The 2-iodo ketone XIId was obtained from 2-(2-chloro-5-nitrophenyl)acetic acid by treatment with 4-isopropylthiophenol, by the following reduction of the resulting nitro acid XIe with hydrazine to the amino acid XIf, by its cyclization to the amino ketone XIIf and finally by its diazotization and reaction with potassium iodide. The ketones XIIa-d were reduced to the alcohols XIIIa-d giving by treatment with hydrogen chloride the chloro compounds XIVa-d. Substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine afforded the title compounds Vabc and VIa-d. Only the fluoro derivatives Va and VIa showed a clear cataleptic activity in rats. The other compounds are very little active in this line and the iodo derivative VId was found to be completely inactive in a high oral dose, but it revealed an intensive antidopaminergic action in biochemical tests. By its pharmacological profile it resembles the known noncataleptic neuroleptic agent clozapine.

Synthesis of potential neuroleptics and tranquillizers: 2-(tert.Amino)-9-(3-dimethylaminopropylidene)thioxanthenes

1986 ◽  
Vol 51 (4) ◽  
pp. 937-947 ◽  
Author(s):  
Vojtěch Kmoníček ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Protiva
Keyword(s):  
Sulfuric Acid ◽  
Potassium Hydroxide ◽  
Polyphosphoric Acid ◽  
Benzoic Acids ◽  
Geometrical Isomers ◽  
Dilute Sulfuric Acid ◽  
Aqueous Potassium Hydroxide ◽  
Iodobenzoic Acid

4-Dimethylamino-, 4-pyrrolidino-, 4-piperidino-, 4-morpholino- and 4-(4-methylpiperazino)-thiophenol (IIIa-IIIe), which were prepared by two methods and characterized as the 2,4-dinitrodiphenyl sulfides IVb-IVe, were transformed by treatment with 2-iodobenzoic acid and copper in aqueous potassium hydroxide to 2-(4-tert.aminophenylthio)benzoic acids (Va-Ve). Cyclization with polyphosphoric acid gave thioxanthones VIa-VIe which were treated with 3-dimethylaminopropylmagnesium chloride to give the diamino alcohols VIIa-VIId. VIIa, VIIc and VIId were dehydrated by heating with dilute sulfuric acid which resulted in mixtures of geometrical isomers of the olefinic bases Ia, Ic and Id. Crystallization of bases or salts led to homogeneous or almost homogeneous (Z)-isomers belonging to the active chlorprothixene series. The products are devoid of cataleptic and antiapomorphine activities and show only some properties of mild tranquillizers

Tricyclic compounds containing two chalcogen atoms in the central seven-membered rings as potential drugs: Synthesis of 3-chloro-6-(1-methyl-4-piperidyl)-6H-dibenz[b,e]-1,4-oxathiepin and 6-oxodibenz[b,e]-1,4-oxathiepin-2-acetic acid

1984 ◽  
Vol 49 (11) ◽  
pp. 2531-2540 ◽  
Author(s):  
Karel Šindelář ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Potassium Hydroxide ◽  
Hydrogen Bromide ◽  
Secondary Alcohol ◽  
Sodium Hydride ◽  
Dopamine Turnover ◽  
Tricyclic Compounds ◽  
Aqueous Potassium Hydroxide ◽  
By Products ◽  
Brain Striatum

2-(4-hloro-2-fluorophenylthio)benzaldehyde (IIa) was subjected to treatment with 1-methyl-4-piperidylmagnesium chloride and the resulting secondary alcohol IIIa was cyclized with sodium hydride to the title compound Ia. In this synthesis, two by-products were isolated and identified as compounds IV and VIa. Repeating the synthesis of compound Ib by a similar way led to isolation of Vb and VII. Reaction of thiosalicylic acid with (3-iodo-4-methoxyphenyl)acetic acid in boiling aqueous potassium hydroxide in the presence of copper gave the methoxy diacid IX which was demethylated with hydrogen bromide in acetic acid to the hydroxy diacid X. Heating with acetic anhydride afforded the title lactone acid VIII. Compound Ia is an almost noncataleptic neuroleptic with a rather low antidopaminergic activity in the test of influencing the dopamine turnover and metabolism in the rat brain striatum. The acid VIII showed some antiinflammatory activity in the test of carrageenan-induced edema of rat's paw.

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