Potential psychotropic and antihistamine agents: 1- and 3-alkyl-9-(3-dimethylaminopropylidene)-thioxanthenes and 3-alkyl-11-piperazino-10,11-dihydrodibenzo[b,f]thiepins

1982 ◽  
Vol 47 (11) ◽  
pp. 3134-3147 ◽  
Author(s):  
Miroslav Protiva ◽  
Zdeněk Šedivý ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Potassium Hydroxide ◽  
Polyphosphoric Acid ◽  
Substitution Reactions ◽  
Tertiary Alcohols ◽  
Alkyl Derivatives ◽  
Antitussive Effect ◽  
Antihistamine Activity ◽  
Acid Catalyzed ◽  
High Doses ◽  
The Individual

Reactions of 3-methylthiophenol and 3-ethylthiophenol with 2-iodobenzoic acid and (2-iodophenyl)acetic acid in the presence of potassium hydroxide and copper gave the acids IVab and Xab. The acids IVab afforded by cyclization with sulfuric acid mixtures of 1- and 3-alkylthioxanthones (Va + VIa, Vb + VIb) which were separated by crystallization or chromatography and the individual compounds were identified by spectra. The slightly prevailing 3-alkyl derivatives Vab were reacted with 3-dimethylaminopropylmagnesium chloride to give the tertiary alcohols VIIab which were transformed by the acid catalyzed dehydration to the title compounds Iab. 1-Ethylthioxanthone (VIb) afforded similarly via the tertiary alcohol VIII the title compound IX. The acids Xab were cyclized with polyphosphoric acid unequivocally to the ketones XIab which were converted via the alcohols XIIab to the chloro derivatives XIIIab. Substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine led to the title compounds IIab and IIIb. The compounds prepared (I-III) have antihistamine activity and are more or less central depressant. Compounds Ib, IIb and IIIb revealed a clear cataleptic activity and compound Ib showed also antireserpine activity. Compound IX is centrally depressant only in high doses but it has anticonvulsant effects and a significant antitussive effect.

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.

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.

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.

scholarly journals Acid Catalyzed Reactions of alpha-Allenic and alpha-Acetylenic Tertiary Alcohols.

1973 ◽  
Vol 27 ◽  
pp. 1629-1636 ◽  
Author(s):  
Lars-Inge Olsson ◽  
Alf Claesson ◽  
Conny Bogentoft ◽  
Gábor Merényi ◽  
Marcel G. van der Hoeven ◽  
...  
Keyword(s):  
Tertiary Alcohols ◽  
Acid Catalyzed ◽  
Catalyzed Reactions

THE EPIMERIZATION OF DELCOSINE

1961 ◽  
Vol 39 (8) ◽  
pp. 1579-1587 ◽  
Author(s):  
Vinko Skarić ◽  
Léo Marion
Keyword(s):  
Infrared Spectra ◽  
Potassium Hydroxide ◽  
Methoxyl Group ◽  
Hydroxyl Group ◽  
Sodium Amalgam ◽  
Acid Catalyzed ◽  
Nitrogen Ring

Delcosine has been assigned tentatively the same C—N skeleton as lycoctonine. In lycoctonine, ring A carries at C-1 a methoxyl group which is directed away from the nitrogen ring. In delcosine, C-1 carries a hydroxyl group which has the opposite configuration and is directed towards the nitrogen. An attempt to correlate the two structures first involves epimerization at C-1 in delcosine. This has been carried out by oxidation of desethyldelcosine to an azomethine, the ethiodide of which, by the action of methanolic potassium hydroxide, is converted to oxo-1-epidelcosine in two steps. Oxo-1-epidelcosine in an acid-catalyzed rearrangement is transformed to a pinacone which, after methylation, gives O,O-dimethyl-anhydro-oxo-1-epidelcosine. This compound was compared with O-methylanhydro-oxolycoctonine, prepared from oxolycoctonine, but was not identical. Removal of a methoxyl, which in each compound is ortho to a carbonyl, by the action of sodium amalgam, produced O,O-dimethyl-6-desmethoxy-anhydro-oxo-1-epidelcosine and O-methyl-6-desmethoxy-anhydro-oxolycoctonine, which are not identical, but show in their infrared spectra much less dissimilarity than the spectra of the pair of compounds from which they were derived. These results are discussed in terms of the structure of delcosine.

THE ACID HYDROLYSIS OF GLYCOSIDES: I. GENERAL CONDITIONS AND THE EFFECT OF THE NATURE OF THE AGLYCONE

1964 ◽  
Vol 42 (6) ◽  
pp. 1456-1472 ◽  
Author(s):  
T. E. Timell
Keyword(s):  
Acid Hydrolysis ◽  
Equilibrium Concentration ◽  
Rate Coefficients ◽  
Acidity Function ◽  
Tertiary Alcohols ◽  
Conjugate Acid ◽  
Rate Of Hydrolysis ◽  
Acid Catalyzed ◽  
Opposing Effects ◽  
Hydrolysis Of

First-order rate coefficients and energies and entropies of activation have been determined for the acid-catalyzed hydrolysis of a number of methyl D-glycopyranosides and disaccharides. The relation between the logarithm of the rate coefficients and values for Hammett's acidity function was linear, although different for different acids. All compounds had entropies of activation indicating a unimolecular reaction mechanism. Glucosides of tertiary alcohols were hydrolyzed very rapidly, triethylmethyl β-D-glucopyranoside, for example, 30,000 times taster than the corresponding methyl compound.Increase in size of the aglycone caused a slight increase in the rate of hydrolysis of β-D-glucopyranosides, steric hindrance thus being of no significance. Electron-attracting substituents in the aglycone had little or no influence on the rate of hydrolysis, obviously because they would tend to lower the equilibrium concentration of the conjugate acid, while facilitating the subsequent heterolysis, the two opposing effects more or less cancelling out. These results were discussed in connection with recent studies on the acid hydrolysis of various phenyl glycopyranosides and with reference to the postulated occurrence of an activating inductive effect in oligo- and poly-saccharides containing carboxyl or other electronegative groups at C-5. It was concluded that there is little evidence for the existence of any such effect and that, for example, pseudoaldobiouronic acids should be hydrolyzed at the same rate as corresponding neutral disaccharides.

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