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.

Potential noncataleptic neuroleptic agents: 2,3-Dichloro-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrobenzo[b,f]thiepin

1984 ◽  
Vol 49 (4) ◽  
pp. 992-1001 ◽  
Author(s):  
Jiří Urban ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
Miroslav Protiva
Keyword(s):  
Benzoic Acid ◽  
Potassium Carbonate ◽  
Title Compound ◽  
Substitution Reaction ◽  
Polyphosphoric Acid ◽  
Dopamine Metabolism ◽  
Nitro Derivative ◽  
High Dose ◽  
Chloro Derivative ◽  
Hydroxyethyl Piperazine

The 6-nitro derivative V, obtained by nitration of 3,4-dichlorobrombenzene, was transformed via the amine VI and nitrileVII to 2-bromo-4,5-dichlorobenzoic acid (IX). Its reaction with thiophenol in 3-methyl-1-butanol in the presence of potassium carbonate and catalytic amounts of copper and cuprous iodide afforded 4,5-dichloro-2-(phenylthio)benzoic acid (Xa) which was reduced to the alcohol XIa. The transformation to the homologous acid XIVa proceeded via noncharacterized intermediates XIIa and XIIIa. The cyclization with polyphosphoric acid at 150 °C resulted in 2,3-dichlorodibenzo[b,f]thiepin-10(11H)-one (XV) which was reduced to the alcohol XVI. Treatment with hydrogen chloride gave the unstable chloro derivative XVII whose substitution reaction with 1-(2-hydroxyethyl)piperazine led to the title compound II. Its dimethanesulfonate showed properties of a little toxic and noncataleptic tranquillizer. Because it does not influence the dopamine metabolism in rat brain in a rather high dose, it cannot be considered a neuroleptic.

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.

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.

Fluorinated analogues of tricyclic neuroleptics: 6,9-difluoro derivative of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1980 ◽  
Vol 45 (10) ◽  
pp. 2688-2694 ◽  
Author(s):  
Irena Červená ◽  
Marta Hrubantová ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Polyphosphoric Acid ◽  
Satisfactory Yield ◽  
Chloro Derivative ◽  
Cns Activity

The acid VI, obtained from 2,5-difluorothiophenol (IV) and (2-iodophenyl)acetic acid, afforded by cyclization with polyphosphoric acid 6,9-difluorodibenzo[b,f]thiepin-10(11H)-one (VII) in a satisfactory yield. Two further steps led to the chloro derivative X giving by a substitution reaction with 1-methylpiperazine the title compound III. This substance exhibits some 10% incoordinating activity of the unsubstituted compound I and an indication of cataleptic activity, in contrast to the inactive analogous dichloro compound II. The bulky atom of chlorine in the vicinity of the methylpiperazine residue interferes evidently with the CNS activity; the influence of the atom of fluorine is much less pronounced in this line.

The synthesis of D-angolosamine

1977 ◽  
Vol 55 (6) ◽  
pp. 1100-1103 ◽  
Author(s):  
Hans H. Baer ◽  
Fawzy F. Z. Georges
Keyword(s):  
Sodium Borohydride ◽  
Catalytic Hydrogenation ◽  
Title Compound ◽  
Amino Glycoside ◽  
Starting Point ◽  
Simplified Procedure

The synthesis of 2,3,6-trideoxy-3-dimethylamino-D-arabino-hexose hydrochloride (10) (D-angolosamine, a constituent of the antibiotic, angolamycin) is described. First, a simplified procedure for the preparation of methyl 6-deoxy-α-D-glucopyranoside from methyl α-D-glucopyranoside is recorded. The deoxy derivative served as the starting point for sequential preparation of methyl 3,6-dideoxy-3-nitro-α-D-glucopyranoside (1), its 2,4-diacetate (2), its 4-monoacetate (3), its 2-O-mesyl-4-acetate (4), its 2-mesylate (5), and methyl 2,3,6-trideoxy-3-nitro-α-D-erythro-hex-2-enopyranoside (6) essentially according to procedures previously established (in part, in the L-series). Treatment of 5 or 6 with sodium borohydride produced methyl 2,3,6-trideoxy-3-nitro-α-D-arabino-hexopyranoside (7). Catalytic hydrogenation of 7 gave the corresponding 3-amino glycoside hydrochloride (8) which was hydrolyzed to furnish 3-amino-2,3,6-trideoxy-D-arabino-hexose hydrochloride (9) (D-acosamine, the enantiomer of a component of the antibiotic, actinoidin). N,N-Dimethylation of 8 followed by hydrolysis afforded the crystalline title compound (10).

THE SYSTEM KOH–K2CO3–H2O AT LOW TEMPERATURES: I. PHASE EQUILIBRIA

1958 ◽  
Vol 36 (7) ◽  
pp. 1064-1069 ◽  
Author(s):  
A. A. Lang ◽  
A. J. Sukava
Keyword(s):  
Phase Equilibria ◽  
Phase Diagrams ◽  
Potassium Carbonate ◽  
Low Temperatures ◽  
Potassium Hydroxide ◽  
Compound Formation

Phase diagrams for the system KOH–K2CO3–H2O were determined for 25°, 10°, 0°, −10°, −20°, −40°, and −60°. The stable hydrates of potassium hydroxide were the di- and tetra-hydrates; those of potassium carbonate were the sesqui- and hexa-hydrates. No compound formation between KOH and K2CO3 was detected.

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.

Synthesis of 3-chloro-5-(4-methylpiperazino)-6,7-dihydro-5H-dibenzo[b,g]thiocin, an eight-membered ring homologue of the neuroleptic agent octoclothepin

1980 ◽  
Vol 45 (2) ◽  
pp. 491-503 ◽  
Author(s):  
Karel Šindelář ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Miroslav Protiva
Keyword(s):  
Propionic Acid ◽  
Title Compound ◽  
Benzyl Chloride ◽  
Sodium Hydride ◽  
Diethyl Malonate ◽  
Membered Ring ◽  
Aluminium Chloride ◽  
Phenyl Propionic Acid ◽  
Neuroleptic Agent ◽  
Central Depressant

Alkylation of diethyl malonate with 2-(4-chlorophenylthio)benzyl chloride, the following hydrolysis and decarboxylation gave 3-[2-(4-chlorophenylthio)phenyl]propionic acid (IV); its chloride was cyclized in low yield by treatment with aluminium chloride to 4-(4-chlorophenylthio)indanone (V). The corresponding methylpiperazine derivative VIII was prepared viaintermediates VI and VII. A reaction of 3-(2-mercaptophenyl)propionic acid with 5-chloro-2-iodobenzoic acid and the following esterification resulted in the diester XVI which was cyclized by a Dieckmann reaction using sodium hydride in toluene to give ethyl 3-chloro-5-hydroxy-7H-dibenzo[b,g]thiocin-6-carboxylate (XVII). The acid hydrolysis afforded the ketone XVIII which was transformed via the intermediates XX and XXI to the title compound II. The product has a mild central depressant activity but it lacks the character of a neuroleptic agent.

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.

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