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.

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.

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.

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 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-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.

scholarly journals 2-(5-Fluoro-3-isopropylsulfanyl-7-methyl-1-benzofuran-2-yl)acetic acid

2012 ◽  
Vol 68 (4) ◽  
pp. o946-o946
Author(s):  
Hong Dae Choi ◽  
Pil Ja Seo ◽  
Uk Lee
Keyword(s):  
Acetic Acid ◽  
Hydrogen Bonds ◽  
Alkaline Hydrolysis ◽  
Title Compound ◽  
Compound C ◽  
Hydrolysis Of

The title compound, C14H15FO3S, was prepared by alkaline hydrolysis of ethyl 2-(5-fluoro-3-isopropylsulfanyl-7-methyl-1-benzofuran-2-yl)acetate. In the crystal, molecules are linkedviapairs of O—H...O hydrogen bonds, forming inversion dimers. These dimers are connected by weak C—H...O hydrogen bonds.

Fluorinated tricyclic neuroleptics: Synthesis and pharmacology of 8-fluoro-4-(4-methylpiperazino)-4,5-dihydrothieno[2,3-b]-1-benzothiepin

1979 ◽  
Vol 44 (10) ◽  
pp. 2997-3007 ◽  
Author(s):  
Miroslav Rajšner ◽  
František Mikšík ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Tricyclic Ketone ◽  
Central Depressant

A reaction of (4-fluoro-2-iodophenyl)acetic acid with 2-thiophenethiol gave the acid V which was cyclized to 8-fluorothieno[2,3-b]-1-benzothiepin-4(5H)-one (VII); two further steps led to 4-chloro-8-fluoro-4,5-dihydrothieno[2,3-b]-1-benzothiepin (IX). A substitution reaction with 1-methylpiperazine resulted in the title compound which showed a very strong central depressant and cataleptic activity, being at the same time almost inactive in the test of inhibition of apomorphine stereotypies in rats. Ethyl 2-amino-5-ethylthiopene-3-carboxylate (X) was transformed by multi-step procedures to the acids XV, XIX and XXVI out of which only the first one could be cyclized to a tricyclic ketone, i.e. 2-ethyldithieno[2,3-b; 3',2'-e]thiopyran-4-one (XX).

Reaction of some 3-(phenylthioaryl)propionic acids with polyphosphoric acid; Formation of 2H-cyclopenta[k,l]thioxanthenes

1979 ◽  
Vol 44 (7) ◽  
pp. 2124-2138 ◽  
Author(s):  
Jiří O. Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Miroslav Ryska ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Propionic Acid ◽  
Polyphosphoric Acid ◽  
Main Product ◽  
Product Formation ◽  
Acid Formation ◽  
Phenyl Propionic Acid ◽  
Isomeric Acid ◽  
By Products ◽  
Predominant Product

The cyclization of 3-[2-(phenylthio)phenyl]propionic acid (I) with polyphosphoric acid gave equal amounts of 4-(phenylthio)indanone (III) and 2H-cyclopenta[k,l]thioxanthene (VI), accompanied with a small amount of the macrocyclic diketone V. Compound VI was evidently formed via the cation XII and 7-(phenylthio)indanone (X) which was quantitatively dehydrocyclized. Similar cyclization of the isomeric acid XIIIa yielded 5-(phenylthio)indanone (XVIII) as the main product; formation of VI could be detected only chromatographicaly. Cyclization of 3-[2-(chloro-5-(phenylthio)phenyl]propionic acid (XIIIb) gave 3-chloro-2H-cyclopenta[k,l]thioxanthene (VII) as the predominant product. From the by-products formed, only 4-chloro-7-(phenylthio)indanone (XI) could be identified, being the precursor of compound VII. Treatment of thioxanthene-9-acetic acid (XXII) with polyphosphoric acid resulted in a cleavage with thioxanthone (XXIII) and thioxanthene (XXIV) as the main products.

Systhesis, Characterization and Spectroscopic Properties of (2E,6E)-2,6-Bis(2,3,4-tri-methoxy-benzylidene)cyclohexanone

2011 ◽  
Vol 396-398 ◽  
pp. 2338-2341
Author(s):  
Xing Chuan Wei ◽  
Zhi Li Liu ◽  
Kun Zhang ◽  
Zhi Yun Du ◽  
Xi Zheng
Keyword(s):  
Crystal Structure ◽  
Acetic Acid ◽  
Hydrogen Bonds ◽  
Title Compound ◽  
Spectroscopic Properties ◽  
Spectral Studies ◽  
Double Bonds ◽  
X Ray ◽  
Π Interactions ◽  
X Ray Crystallography

In this paper, (2E,6E)-2,6-Bis(2,3,4-tri-methoxy -benzylidene)cyclohexanone (omitted as tmbcho) (1) was obtained by the reaction of acetic acid, tetrahydrofuran, cyclohexanone and 2,3,4-tri-methoxy-benzaldehyde. Three non-classic hydrogen bonds were observed in the compound. X-ray crystallography shows that the crystal structure is stabilized by intermolecular C-H•••π interactions and it contains plenty of conjugated double bonds. The title compound was characterized by UV-vis and fluorescent spectral studies.

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