Neuroleptic 2-chloro-11-(2-piperazineethoxy)-10,11-dihydrodibenzo[b,f]thiepins: Synthesis and pharmacology

1984 ◽  
Vol 49 (8) ◽  
pp. 1810-1815 ◽  
Author(s):  
Václav Bártl ◽  
Jiří Jílek ◽  
Jiřina Metyšová ◽  
Martin Valchář ◽  
Antonín Dlabač ◽  
...  
Keyword(s):  
Alkaline Hydrolysis ◽  
Boron Trifluoride ◽  
Boron Trifluoride Etherate ◽  
Dopamine Metabolism ◽  
Substitution Reactions ◽  
Activity Profile ◽  
Hydrolysis Of ◽  
Brain Striatum ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant

A reaction of 8-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-ol with 2-bromoethanol and boron trifluoride etherate produced the 2-bromoethyl ether II which was subjected to substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)piperazine, 1-(3-hydroxypropyl)piperazine and 1-ethoxycarbonylpiperazine to give the title piperazinoethoxy compounds IV-VII. Alkaline hydrolysis of the carbamate VII afforded the monosubstituted piperazine VIII. Compounds IV-VI are neuroleptics with an interesting activity profile: they are little toxic, have strong central depressant and antimorphine activity, mild cataleptic effects, they intensively increase the dopamine metabolism in the rat brain striatum and are almost free of the peripheral adrenolytic efficacy.

Potential antipsychotic agents: 2-Chloro- and 2-methyl-11-(2-piperazinoethoxy)-6,11-dihydrodibenzo[b,e]thiepins and some related compounds; Synthesis and pharmacology

1984 ◽  
Vol 49 (11) ◽  
pp. 2520-2530 ◽  
Author(s):  
Václav Bártl ◽  
Karel Šindelář ◽  
Vladimír Valenta ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
...  
Keyword(s):  
Sulfuric Acid ◽  
Alkaline Hydrolysis ◽  
Antipsychotic Agents ◽  
Similar Reaction ◽  
Substitution Reactions ◽  
Single Product ◽  
Hydrolysis Of ◽  
Related Compounds ◽  
Hydroxyethyl Piperazine ◽  
Neuroleptic Activity

Reactions of 2-chloro- and 2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ol with 2-bromoethanol in the presence of sulfuric acid in boiling benzene afforded the 2-bromoethyl ethers VIa and VIb which were transformed by substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)-piperazine and 1-(ethoxycarbonyl)piperazine to the title compounds. Alkaline hydrolysis of the carbamate IVa gave the secondary amine IIIa. Treatment of the bromo ether VIa with 4-(4-chloro-3-trifluoromethylphenyl)piperidin-4-ol resulted in the piperidine derivative VIIa. Substitution reaction of 11-chloro-6,11-dihydrodibenzo[b,e]thiepin with 1-(2-methoxyethyl)piperazine and 1-(2-ethoxyethyl)piperazine led to the amino ethers VIII and IX. Reaction of 11-chloro-11-phenyl-6,11-dihydrodibenzo[b,e]thiepin with 2-dimethylaminoethanethiol in dimethylformamide at 90°C gave a mixture of two isomeric bases which was separated to the expected sulfide X and the base XII, resulting evidently after the rearrangement of the primary carbocation. A similar reaction of 3-dimethylaminopropanethiol afforded a single product of structure XI. Out of the compounds prepared, the ether VIII was found most interesting: it is little toxic and has significant antireserpine activity in two tests (is considered a potential antidepressant). The ethers Iab, Iab, IIIa and VIIa did not reveal the expected neuroleptic activity.

Enolic Ortho Esters. I. Preparation and Birch Reduction of Some Coumarinoid Ortho Esters

1989 ◽  
Vol 42 (8) ◽  
pp. 1235 ◽  
Author(s):  
DJ Collins ◽  
LM Downes ◽  
AG Jhingran ◽  
SB Rutschmann ◽  
GJ Sharp
Keyword(s):  
Carbon Tetrachloride ◽  
Acid Hydrolysis ◽  
Boron Trifluoride ◽  
Boron Trifluoride Etherate ◽  
High Yield ◽  
Ortho Ester ◽  
Birch Reduction ◽  
High Yields ◽  
Ortho Esters ◽  
Hydrolysis Of

Phenolic ortho esters such as 4′,4′-dimethylspiro[2H-1-benzopyran-2,2′-[1,3]dioxolan] (7b) and 4′,4′-dimethyl-3,4-dihydrospiro[2H-1-benzopyran-2,2′-[1,3]dioxolan] (9c) were prepared in low yields by reaction of 2H-1-benzopyran-2-one (5) or 3,4-dihydro-2H-1-benzopyran-2-one (8a) with 2,2-dimethyloxiran in carbon tetrachloride in the presence of boron trifluoride etherate. 3,4-Dihydrospiro[2H-1-benzopyran-2,2′-[1,3] dioxoan ] (9a) and the corresponding 7-methoxy compound (9e) were obtained in high yield by reaction of (8a) or its 7-methoxy analogue (8b) with 1,2-bis(trimethylsily1oxy)ethane (10) in the presence of trimethylsilyl trifluoromethane-sulfonate . Birch reduction of phenolic ortho esters such as (9c) and (9e) afforded the enolic ortho esters 4′,4′-dimethyl-3,4,5,8-tetrahydrospiro[2H-1-benzopyran-2,2′-[1,3] dioxola n] (11a) and 7-methoxy-3,4,5,8-tetrahydrospiro[2H-1-benzopyran-2,2′-[1,3]dioxolan] (llc) in high yields. Birch reduction of 4′,4′,5′,5′-tetramethylspiro[2H-1-benzopyran-2,2′-[1,3]dioxolan] (7c) gave a 1 : 3 mixture of 4′,4′,5′,5′-tetramethyl-3,4-dihydrospiro[2H-1-benzopyran-2,2′-[l,3] dioxolan ] (9d) and the corresponding 3,4,5,8-tetrahydro compound (11b). Acid hydrolysis of the enolic ortho ester (11a) gave 67% of 2-hydroxy-2-methylpropyl 3-(2-oxocyclohex-3-enyl) propanoate (20).

Noncataleptic neuroleptics: Potential metabolites of 2-chloro-10-[4-(2-hydroxyethyl)piperazino]-10,11-dihydrodibenzo[b,fthiepin

1979 ◽  
Vol 44 (10) ◽  
pp. 3008-3018 ◽  
Author(s):  
Vladimír Valenta ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
Marie Bartošová ◽  
Miroslav Protiva
Keyword(s):  
Secondary Amine ◽  
Title Compound ◽  
Primary Amine ◽  
Pyridine Derivative ◽  
Oxidation Reactions ◽  
Substitution Reactions ◽  
Piperazine Derivatives ◽  
Antihistamine Activity ◽  
Hydrolysis Of ◽  
Central Depressant

The synthesis of nine potential metabolites of the title compound is being described. Using oxidation reactions, compound I was transformed to the S-oxide VII, A-oxide IX and A,S-dioxide X. Substitution reactions of 2,10-dichloro-10,11-dihydrodibenzo[b,f]thiepin with 1-ethoxycarbonylpiperazine, piperazine and ethylenediamine afforded the amines II, III, IV and XIII. Leuckart reaction of 2-chlorodibenzo[b,f]thiepin-10(11H)-one led in addition to the expected formamido derivative XI to the heptacyclic pyridine derivative XIV. Hydrolysis of compounds II and XI gave the secondary amine III and the primary amine XII. Oxidation of substances III, XII and XIII afforded the sulfoxides VIII, XV and XVI. Most of the prepared piperazine derivatives exhibit some central depressant, adrenolytic and antihistamine activity.

Potential noncataleptic neuroleptic agents: Synthesis and pharmacology of 7-chloro-4-[4-(2-hydroxyethyl)piperazino]-4,5-dihydrothieno[2,3-b]-1-benzothiepin

1983 ◽  
Vol 48 (10) ◽  
pp. 2970-2976 ◽  
Author(s):  
Zdeněk Polívka ◽  
Martin Valchář ◽  
Miroslav Protiva
Keyword(s):  
Sodium Borohydride ◽  
Potassium Carbonate ◽  
Title Compound ◽  
Potassium Hydroxide ◽  
Dopamine Metabolism ◽  
High Dose ◽  
Chloro Derivative ◽  
Hydroxyethyl Piperazine ◽  
Central Depressant ◽  
Boiling Toluene

Heating of 2,5-dichloroacetophenone with 2-thiophenethiol, potassium carbonate and copper gave 5-chloro-2-(2-thienylthio)acetophenone (V) which was subjected to the Willgerodt reaction with sulphur and morpholine. The product was a mixture of the thiomorpholide VI and oxothiomorpholide VII. After a partial separation the predominanting product VI was hydrolyzed without characterization with ethanolic potassium hydroxide to give the acid VIII. Cyclization by treatment with phosphorus pentoxide in boiling toluene gave 7-chlorothieno[2,3-b]-1-benzothiepin-4(5H)-one (X) which was reduced with sodium borohydride to the alcohol XII. A reaction with hydrogen chloride in benzene led to the chloro derivative XIII whose substitution reaction with 1-(2-hydroxyethyl)piperazine afforded the title compound IV. The product has strong central depressant and discoordinating activity, a low cataleptic efficity but in a relatively high dose it does not influence the dopamine metabolism in the rat brain.

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.

Aminocyclitols. III. Synthesis of diaminocyclohexanediols

1979 ◽  
Vol 57 (14) ◽  
pp. 1870-1876 ◽  
Author(s):  
Gerry Kavadias ◽  
Robert Droghini
Keyword(s):  
Thionyl Chloride ◽  
Sodium Azide ◽  
Ring Opening ◽  
Boron Trifluoride ◽  
Boron Trifluoride Etherate ◽  
Reaction Sequence ◽  
Acidic Hydrolysis ◽  
Ring Opening Reactions ◽  
Cis And Trans ◽  
Hydrolysis Of

Reaction of N,N′-diethoxycarbonyl-2,5-dideoxystreptamine (1b) with thionyl chloride produced the iminoether dihydrochloride 8 which, upon simple treatment with water gave the di-N,O-carbonyl compound 9. Acidic hydrolysis of 9 yielded the aminocyclitol 2a. Alternatively, 2a was prepared from N,N′-dibenzoyl-2,5-dideoxystreptamine (1c) via the oxazoline 10 followed by acidic hydrolysis. Treatment of 1c with triethyl orthoacetate in the presence of boron trifluoride etherate produced the oxazoline 11 and the latter product was hydrolyzed to give 3a. By the same reaction sequence, 1e and 1h were converted to the oxazolines 12 and 13 which upon acidic hydrolysis provided the enantiomeric aminocyclitols 4 and 5. Ring-opening reactions of cis- and trans-1,4-diepoxycyclohexanes (14 and 16) with sodium azide to the diazido compounds 15 and 17, followed by reduction, afforded the aminocyclitols 6 and 7.

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