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 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).

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.

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.

Potential metabolites of the neuroleptic agents belonging to the 8-methylthio-10-piperazino-10,11-dihydrodibenzo[b,f]thiepin series; Synthesis of 2-hydroxy and 3-hydroxy derivatives

1985 ◽  
Vol 50 (10) ◽  
pp. 2179-2190 ◽  
Author(s):  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Alkaline Hydrolysis ◽  
Potassium Salts ◽  
Substitution Reactions ◽  
Piperazine Derivatives ◽  
Prolonged Duration ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Neuroleptic Activity

The acid VI, prepared by reaction of potassium salts of (2-iodo-5-methoxyphenyl)acetic acid and 4-(methylthio)thiophenol in the presence of copper, was transformed via intermediates VII-IX to 2-methoxy-8-methylthio-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins X and XI. Their demethylation with boron tribromide afforded 2-hydroxy derivatives of the neuroleptic agents methiothepin and oxyprothepin I and II. 11-Chloro-7-methoxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin was subjected to substitution reactions with 1-methylpiperazine and 1-(ethoxycarbonyl)piperazine and gave piperazine derivatives XIII and XIV, out of which the latter gave the secondary amine XV by alkaline hydrolysis. The ethers XIII and XV were also cleaved with boron tribromide and gave 3-hydroxy derivatives of methiothepin (III) and its demethyl derivative IV. The phenols I, II, and IV are potential metabolites of the mentioned neuroleptic agents; compound III, which already was identified as a metabolite, disclosed properties of a strong and cataleptic neuroleptic agent with prolonged duration of the effects. The methoxy compounds X, XI, and XIII are practically devoid of the neuroleptic activity.

Highly polar potential metabolites of the neuroleptic agent oxyprothepin: Synthesis of 2-hydroxy-8-methylsulfonyl and 3-hydroxy-8-methylsulfonyl derivatives of 10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin

1985 ◽  
Vol 50 (2) ◽  
pp. 519-537 ◽  
Author(s):  
Jiří Jílek ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiří Schlanger ◽  
Josef Pomykáček ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Acetic Acid ◽  
Potassium Carbonate ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Derivatives Of ◽  
Methoxybenzoic Acid

The acid XI, obtained by reaction of (2-iodo-5-methoxyphenyl)acetic acid with 4-(methylsulfonyl)thiophenol (VIII) in dimethylformamide in the presence of potassium carbonate and copper, was transformed via intermediates XIIa-XIVa to compound XVa. Demethylation with boron tribromide afforded compound III, the potential metabolite of oxyprothepin (II). Its oxidation with hydrogen peroxide in acetic acid gave the sulfoxide XVII, which is a further potential metabolite. A reaction of 2-iodo-4-methoxybenzoic acid with VIII and potassium carbonate in dimethylformamide in the presence of copper afforded the acid XIX whose ester XXI was reduced with diborane to the alcohol XXII; hydrogenolysis to compound XXIII was also observed. The alcohol XXII was processed via compounds XXIV and XXV to the acid XXVI which was cyclized in a low yield to the ketone XIIb. A further processing via the intermediates XIIIb and XIVb led to compound XVb. Demethylation gave compound IV, another potential metabolite.

Potential metabolites of tricyclic neuroleptics and their fluorinated analogues; 3-Hydroxy-, 3-methoxy- and 3-fluoro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

1979 ◽  
Vol 44 (7) ◽  
pp. 2108-2123 ◽  
Author(s):  
Miroslav Protiva ◽  
Karel Šindelář ◽  
Zdeněk Šedivý ◽  
Jiřina Metyšová
Keyword(s):  
Acetic Acid ◽  
Benzoic Acid ◽  
Oral Administration ◽  
Phenolic Compound ◽  
Methoxy Derivative ◽  
Fluoro Derivative ◽  
Neuroleptic Agent ◽  
Boron Tribromide ◽  
Central Depressant

4-Methoxy-2-(phenylthio)benzoic acid (V) was transformed in four steps to the homologous acid IXa which was cyclized to 3-methoxydibenzo[b,f]thiepin-10(11H)-one (Xa). The 3-methoxy derivative III of perathiepin (I) was synthesized via the intermediates XIa and XIIa, and demethylated with boron tribromide to the phenolic compound II. The analogous 3-fluoro derivative IV was synthesized from (4-fluoro-2-iodophenyl)acetic acid (XVII), the preparation of which by several procedures is described. Whereas III has only mild tranquilizing activity, II is more potent than perathiepin (I) in the tests for central depressant and cataleptic effects. The 3-fluoro derivative IV, while lacking the properties of a neuroleptic agent, is highly central depressant and this effect shows some prolongation after oral administration.

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.

Sign in / Sign up

Export Citation Format

Share Document