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 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 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.

scholarly journals The crystal structure, Hirshfeld surface analysis and energy frameworks of 2-[2-(methoxycarbonyl)-3,6-bis(methoxymethoxy)phenyl]acetic acid

2020 ◽  
Vol 76 (7) ◽  
pp. 1101-1106
Author(s):  
Mustapha Tiouabi ◽  
Raphaël Tabacchi ◽  
Helen Stoeckli-Evans
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bond ◽  
Acetic Acid ◽  
Hydrogen Bonds ◽  
Title Compound ◽  
Hirshfeld Surface ◽  
Supramolecular Framework ◽  
Phenyl Acetic Acid ◽  
Oh Groups ◽  
Compound C

In the title compound, C14H18O8, (I), the methoxycarbonyl [–C(=O)OCH3] and the acetic acid [–CH2C(=O)OH] groups are inclined to the benzene ring by 79.24 (11) and 76.71 (13)°, respectively, and are normal to each other with a dihedral angle of 90.00 (13)°. In the crystal, molecules are linked by a pair of O—H...O hydrogen bonds forming the familiar acetic acid inversion dimer. The dimers are linked by two C—H...O hydrogen bonds and an offset π–π interaction [intercentroid distance = 3.6405 (14) Å], forming layers lying parallel to the (10\overline{1}) plane. The layers are linked by a third C—H...O hydrogen bond and a C—H...π interaction to form a supramolecular framework.

Fluorinated tricyclic neuroleptics with prolonged action: 3-Fluoro-8-trifluoromethyl derivatives of 10-(4-methylpiperazino)- and 10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo-[b,f]thiepin

1981 ◽  
Vol 46 (1) ◽  
pp. 118-140 ◽  
Author(s):  
Karel Šindelář ◽  
Miroslav Ryska ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Prolonged Action ◽  
Substitution Reactions ◽  
Isolation And Characterization ◽  
Chloro Derivative ◽  
Derivatives Of ◽  
Enol Ester ◽  
Preparative Purpose ◽  
Hydroxyethyl Piperazine

A reaction of (4-fluoro-2-iodophenyl)acetic acid with 4-(trifluoromethyl)thiophenol gave the acid VIII which was cyclized with the reagent consisting from methanesulphonic acid and phosphorus pentoxide and afforded the methanesulphonic enol ester XIX. The alkaline hydrolysis resulted in 3-fluoro-8-trifluoromethyldibenzo[b,f]thiepin-10(11H)-one (XVI) which was transformed via the alcohol XXIV to the chloro derivative XXV. Substitution reactions with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine resulted in the title compounds IV and V. These products are very potent cataleptic neuroleptic agents with a prolongation of duration of the effects comparable to that of isofloxythepin and tefluthixol. A series of further synthetic experiments aimed at alternative syntheses of the acid VIII and the ketone XVI; their results were mostly not of use for preparative purpose but they led to isolation and characterization of a series of interesting heterocyclic products (XVII, XVIII, XXII, XXIII, XXIX-XXXI, XXXVI-XXXIX).

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.

Noncataleptic potential neuroleptics: 2-Methyl-10-(4-methylpiperazino)- and -10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (9) ◽  
pp. 2677-2688 ◽  
Author(s):  
Vladimír Valenta ◽  
Jiří Jílek ◽  
Josef Pomykáček ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Rat Brain ◽  
The Other ◽  
Phenyl Acetic Acid ◽  
Dopamine Metabolites ◽  
Other Hand ◽  
The One ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant

[5-Methyl-2-(phenylthio)phenyl]acetic acid (XV) was synthesized on the one hand from the acid VIII using the known homologization technique via the alcohol X and nitrile XII, on the other from 5-methyl-2-(phenylthio)acetophenone (XIII) by means of the Willgerodt reaction. Via the intermediates XIX and XX, the synthesis led to 10-chloro-2-methyl-10,11-dihydrodibenzo[b,f]thiepin (XXI), giving by treatment with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine the title compounds III and IV. These compounds have low cataleptic and high central depressant activity; on the other hand, they do not influence the levels of dopamine metabolites in the rat brain which is considered an indication of their lacking the neuroleptic character.

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).

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.

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