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 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.

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

1981 ◽  
Vol 46 (9) ◽  
pp. 2222-2233 ◽  
Author(s):  
Zdeněk Polívka ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Phosphorus Pentoxide ◽  
Lithium Aluminium Hydride ◽  
Lithium Aluminium ◽  
Chloro Derivative ◽  
Neuroleptic Agent ◽  
Long Acting ◽  
Animal Tests

Diazotization of 4-fluoroanthranilic acid (V) and the following reaction with sodium disulfide gave the dithio diacid VII which was reduced with lithium aluminium hydride to 4-fluoro-2-mercaprobenzyl alcohol (XI). Its reaction with 2-chloro-5-iodothiophene afforded the alcohol XIII which was transformed via the chloride XIV and the nitrile XV to [2-(5-chloro-2-thienylthio)-4-fluorophenyl]acetic acid (XVI). Cyclization with phosphorus pentoxide in toluene resulted in 2-chloro-8-fluorothieno[2,3-b]-1-benzothiepin-4(5H)-one (XVIII) which was converted via the alcohol XIX to the chloro derivative XX. The substitution reaction with 1-methylpiperazine led to the title compound IV which is a long-acting and very potent tranquillizer but did not reveal, in the animal tests performed, the properties of a neuroleptic agent.

Fluorinated tricyclic neuroleptics with prolonged action: 7-Fluoro-11-[4-(2-hydroxyethyl)piperazino]-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin

1986 ◽  
Vol 51 (3) ◽  
pp. 698-722 ◽  
Author(s):  
Miroslav Protiva ◽  
Jiří Jílek ◽  
Miroslav Rajšner ◽  
Josef Pomykáček ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Tartaric Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Active Component ◽  
Phenyl Acetic Acid ◽  
Prolonged Action ◽  
Neuroleptic Agent ◽  
Synthetic Sequence ◽  
Hydroxyethyl Piperazine

Substitution reaction of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f,]thiepin with 1-(2-hydroxyethyl)piperazine gave the title compound I which proved a very potent and longacting oral neuroleptic agent (isofloxythepin). Its resolution by means of dibenzoyl-(+)- and -(-)-tartaric acid led to (-)- and (+)-enantiomer out of which the former represents the neuroleptically active component. In the synthetic sequence leading to I, preparation of two key intermediates was re-elaborated using new partial sequences: 4-fluoro-2-iodobenzoic acid (XIII) from 4-fluoro-2-nitroaniline (V) via the nitrile VI and the acids VIII and XII, and [4-fluoro-2-(4-iso-propylphenylthio)phenyl]acetic acid (XVIII) from XIII via XIV and the compounds XV-XVII. The sulfoxides and N-oxides XIX-XXII were prepared as potential metabolites of isofloxythepin (I).

Potential metabolites of the noncataleptic neuroleptics: Synthesis of 2-chloro-6-hydroxy(and methoxy)-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1981 ◽  
Vol 46 (9) ◽  
pp. 2245-2253 ◽  
Author(s):  
Miroslav Protiva ◽  
Zdeněk Šedivý ◽  
Josef Pomykáček ◽  
Václav Bártl ◽  
Jiří Holubek ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Phenyl Acetic Acid ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Hydroxyethyl Piperazine

[5-Chloro-2-(2-methoxyphenylthio)phenyl]acetic acid (VI), obtained via the acetophenone derivative IV, was cyclized to 2-chloro-6-methoxydibenzo[b,f]thiepin-10(11H)-one (VIIIa). 2,10-Dichloro-6-methoxy-10,11-dihydrodibenzo[b,f]thiepin (Xa) was prepared via the alcohol IXa and its substitution reaction with 1-(2-hydroxyethyl)piperazine gave the compound III. Demethylation with boron tribromide in chlorobenzene resulted in the title compound II which is a potential metabolite of the noncataleptic neuroleptic agent docloxythepin.

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).

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.

Synthesis of 7-chloro-5-(6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-2-methylamino-3H-1,4-benzodiazepine 4-oxide and of some related compounds

1979 ◽  
Vol 44 (12) ◽  
pp. 3604-3616 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Miroslav Rajšner ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Protiva
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Similar Reaction ◽  
Chloroacetyl Chloride ◽  
New Approaches ◽  
Related Compounds

The base catalyzed condensation of 4-chloronitrobenzene with 2-(cyanomethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene afforded the 2,1-benzisoxazole derivative VIa which was reduced with iron in acetic acid to the 2-aminophenone VIIa. Its oxime IXa was treated with chloroacetyl chloride in acetic acid and gave the 4-substituted 6-chloro-2-chloromethylquinazoline 3-oxide (Xa). The treatment with methylamine in methanol led to the substitution reaction with a simultaneous ring elargement and the title compound IVa was formed. A similar reaction with 1-methylpiperazine proceeded without rearrangement resulting in the quinazoline XIa. The object of further experiments was the preparation of the lactam Va, the norpethidine derivative XV and some new approaches to intermediates useful in the synthesis of 5-(2-chlorophenyl)-7ethyl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-ones.

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 Crystal structure of 2,4-dinitrophenyl 4-methylbenzenesulfonate: a new polymorph

2015 ◽  
Vol 71 (9) ◽  
pp. 1085-1088 ◽  
Author(s):  
Tyler A. Cooley ◽  
Sean Riley ◽  
Shannon M. Biros ◽  
Richard J. Staples ◽  
Felix N. Ngassa
Keyword(s):  
Crystal Structure ◽  
Nucleophilic Substitution ◽  
Torsion Angle ◽  
Title Compound ◽  
Substitution Reaction ◽  
Sulfonate Group ◽  
Acta Cryst ◽  
Crystal Stability ◽  
Compound C ◽  
Centroid Distance

The title compound, C13H10N2O7S, was synthesizedviaa nucleophilic substitution reaction between 2,4-dinitrophenol andp-toluenesulfonyl chloride. This crystal structure is a polymorph of CSD entry WUVYUH [Vembuet al.(2003).Acta Cryst, E59, o378–380]. The aromatic substituents on the sulfonate group are orientedgaucheto one another with a C—O—S—C torsion angle of −62.0 (3)°. The supramolecular features that contribute to the crystal stability are offset π–π [centroid–centroid distance = 3.729 (2) Å] and multiple C—H...O interactions.

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