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.

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.

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.

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.

1-(3-Dimethylamino-1-phenylpropyl)piperazines and related compounds: Synthesis and pharmacological screening

1981 ◽  
Vol 46 (11) ◽  
pp. 2729-2733 ◽  
Author(s):  
Jiří Jílek ◽  
Josef Pomykáček ◽  
Jiří Němec ◽  
Miroslav Protiva
Keyword(s):  
Short Duration ◽  
Secondary Amine ◽  
Thionyl Chloride ◽  
Local Anaesthetic ◽  
Antiarrhythmic Action ◽  
Substitution Reactions ◽  
Pharmacological Screening ◽  
Hydrolysis Of ◽  
Related Compounds ◽  
Antiarrhythmic Effects

Substitution reactions of N,N-dimethyl-3-chloro-3-phenylpropylamine with 1-methylpiperazine and a series of analogues afforded 1-(3-dimethylamino-1-phenylpropyl)piperazines I-V. A similar substitution with piperidine resulted in the diamine VIII. Hydrolysis of the carbamate V gave the secondary amine VI which was transformed by alkylation with cyclopropylmethyl bromide to compound VII. 3-Dimethylamino-3-phenylpropanol was treated with thionyl chloride to give N,N-dimethyl-3-chloro-3-phenylpropylamine (IX) which reacted with 1-methylpiperazine and afforded the triamine X. The maleates of the amines prepared exhibited hypotensive effects of short duration (III, IV, VI, VII, X) and moderate antiarrhythmic effects (V-VIII). The phenylpiperazine derivative III showed a significant antiarrhythmic action and a high local anaesthetic activity.

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.

10-[4-(3-Hydroxypropyl)piperazino]-8-methylsulfonyl-10,11-dihydrodibenzo[b,f]thiepin and some related potential metabolites of the neuroleptic agents oxyprothepin and methiothepin

1980 ◽  
Vol 45 (2) ◽  
pp. 529-538 ◽  
Author(s):  
Vladimír Valenta ◽  
Antonín Dlabač ◽  
Marie Bartošová ◽  
Emil Svátek ◽  
Miroslav Protiva
Keyword(s):  
Selective Oxidation ◽  
Secondary Amine ◽  
Title Compound ◽  
Substitution Reaction ◽  
Oxidation Reactions ◽  
Neuroleptic Agent ◽  
Selective Oxidation Reactions

Substitution reaction of 10-chloro-8-methylsulfonyl-10,11-dihydrodibenzo[b,f]thiepin with 1-(3-hydroxypropyl)piperazine afforded the title compound IV which was transformed by selective oxidation reactions to the sulfoxide X, N-oxide XII and N,S-dioxide XIII. The secondary amine VII was prepared via the carbamate VI and oxidized to the sulfoxide XI. Reaction of 10-chloro-8-methylsulfonyl-10,11-dihydrodibenzo[b,f]thiepin with ethylenediamine gave the diamine XIV which was oxidized to the corresponding sulfoxide XV. Compounds IV, VII and X-XV are potential metabolites of the neuroleptic agent oxyprothepin (II); compounds VII, XI, XIV and XV are potential metabolites of methiothepin (I). Out of the compounds prepared, only the title compound IV preserves the neuroleptic character.

Regio-, Stereo- and Enantioselective α-Addition of Carbonyl Nucleo-philes to Allenamides Catalyzed by a Synergistic Copper/Enamine System

2020 ◽  
Author(s):  
Rémi Blieck ◽  
Sebastien Lemouzy ◽  
Marc Taillefer ◽  
Florian Monnier
Keyword(s):  
Catalytic System ◽  
Secondary Amine ◽  
Primary Amine ◽  
Synergistic Catalysis ◽  
Enantioselective Addition ◽  
Amine Catalysts

A dual copper/enamine catalytic system is found to enable an intermolecular enantioselective α-addition of various carbonyl nucleophiles to allenamides. Secondary amine catalysts allowed the highly enantioselective addition of aldehydes, while using primary amine catalysts led to the enantioselective addition of ketoester nucleophiles. The process was found to be highly regio-, stereo- and enantio-selective and represented the first allene hydrofunctionalization using an synergistic catalysis involving copper

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.

Aminkomplexe des Goldes, Teil 9: Gold(I)-halogenid-Komplexe mit primären und azyklischen sekundären Aminen und ihre Oxidation zu Gold(III)-Derivaten

2018 ◽  
Vol 73 (1) ◽  
pp. 43-74 ◽  
Author(s):  
Cindy Döring ◽  
Peter G. Jones
Keyword(s):  
Hydrogen Bonds ◽  
Structure Analysis ◽  
Secondary Amine ◽  
Primary Amine ◽  
Solvent Free ◽  
Secondary Amines ◽  
Primary Amines ◽  
Direct Reaction ◽  
X Ray

AbstractThe reaction of (tht)AuX (X=Cl or Br; tht=tetrahydrothiophene) with various primary amines L leads to products of the form [L2Au]+X−. Packing diagrams of the corresponding structures are dominated by N–H···X hydrogen bonds and (in some cases) aurophilic contacts. The cyclohexylamine derivative was already known as its dichloromethane ⅔-solvate; we have isolated the solvent-free compound and its pentane ¼-solvate, which all show different packing patterns. With acyclic secondary amines, the products are more varied; LAuX and [L2Au]+[AuX2]− were also found. These gold(I) products were generally formed in satisfactory quantities. The attempted oxidation to Au(III) derivatives with PhICl2 or Br2 proved impossible for the primary amine derivatives [although isopropylamine-trichloridogold(III) was obtained unexpectedly from the corresponding cyanide] and unsatisfactory for the secondary amine derivatives. Products LAuX3 and [L2AuX2]+[AuX4]− were identified but were formed in disappointing yields. In isolated cases protonated products (LH)+[AuCl4]−, (LH+)3[AuCl4]−(Cl−)2 or [(Et2N)2CH]+[AuBr4]− were formed, presumably by involvement of the dichloromethane solvent and/or adventitious water. Here also the yields were poor, and some products arose as mixtures. Direct reaction of amines with AuCl3 or (tht)AuX3 was also unsuccessful. All products were characterized by X-ray structure analysis.

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