11-(4-Piperidylidene)-6,11-dihydrodibenzo[b,e]thiepins as potential antipsychotic agents; Synthesis and pharmacology

1984 ◽  
Vol 49 (8) ◽  
pp. 1800-1809 ◽  
Author(s):  
Václav Bártl ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
Miroslav Protiva

The secondary amine VIIIb, prepared by demethylation of 2-chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydrodibenzo[b,e]thiepin (IVb), afforded by alkylation with 2-bromoethanol the amino alcohol Vb which was esterified to the decanoate VIb. A reaction of 5-fluorophthalide with the sodium salt of 4-chlorothiophenol in boiling 1-butanol gave the acid X which afforded by cyclization 2-chloro-8-fluorodibenzo[b,e]thiepin-11(6H)-one (XII). Treatment with 1-methyl-4-piperidylmagnesium chloride resulted in the tertiary alcohol IXc which was transformed by an acid catalyzed dehydration to the desired unsaturated amine IVc. While compounds Vb and IVc showed properties of mild tranquillizers, the ester VIb, surprisingly, brought about a mild dopaminomimetic activity (it potentiates the action of apomorphine, has anticataleptic activity and lowers the homovanillic acid level in the striatum of rat brain.

1983 ◽  
Vol 48 (2) ◽  
pp. 623-641 ◽  
Author(s):  
Zdeněk Polívka ◽  
Miroslav Rajšner ◽  
Jan Metyš ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
...  

In the reaction of thieno[2,3c]-2-benzothiepin-4(9H)-one (VI) with 1-methyl-4-piperidylmagnesium chloride 7-(1-methyl-4-piperidyl)thieno[2,3-c]-2-benzothiepin-4(9H)-one (VIII) is formed in addition to the expected amino alcohol VII. The title compound I was obtained by the acid catalyzed dehydration of the pure alcohol VII. Compound I (pipethiadene) has outstanding antihistamine, antiserotonin, antireserpine and anticataleptic activity and was recommended to clinical trials as a potential antimigraine agent. For pharmacokinetic and metabolic studies there were prepared the NC2H3 analogue of pipethiadene IV and further, as potential metabolites, the demethyl analogue III, S-oxide X, demethyl S-oxide XI, N-oxide XIII and N,S-dioxide XIV. The Witting reaction of the ketone VI with 3-dimethylaminopropylidenetriphenylphosphorane resulted in a mixture of geometric isomers of 4-(3-dimethylamino-propylidene)-4,9-dihydrothieno[2,3-c]-2-benzothiepin with the strongly predominating Z-isomer XVI which was isolated from the mixture by crystallization of the hydrogen maleate. The mixture with the predominating Z-isomer XVI was converted by the treatment with 80% sulfuric acid and dilution with water to a mixture with the predominating E-isomer XV (dithiadene) which was isolated by crystallization of the hydrogen sulfate. Some further new thieno[2,3-c]-2-benzothiepin derivatives were synthesized as potential intermediates.


1986 ◽  
Vol 51 (1) ◽  
pp. 156-166 ◽  
Author(s):  
Miroslav Protiva ◽  
Antonín Dlabač ◽  
Martin Valchář ◽  
Stanislav Wildt ◽  
Irena Červená ◽  
...  

Substitution reactions of 2,6,10-trichloro-, 2,7,10-trichloro- and 2,8,10-trichloro-10,11-dihydrodibenzo[b,f]thiepin (Vabc) with 1-(2-hydroxyethyl)piperazine, 1-methylpiperazine and 1-benzylpiperazine gave the title compounds IIabc, IIIab and IVab. The new chloro compounds Va and Vb were obtained in 6 steps starting from reactions of 2,5-dichloroacetophenone with 2-chlorothiophenol or 3-chlorothiophenol. Compounds IIabc are 6-chloro, 7-chloro and 8-chloro derivatives of the noncataleptic neuroleptic agent docloxythepin (I). They are almost devoid of cataleptic activity and do not inhibit the apomorphine stereotypies in rats. Compounds IIab have a clozapine-like affinity to dopaminergic receptors in the rat brain striatum; the affinity of IIc is much higher. On the other hand only compounds IIb and IIIa prove a significant antidopaminergic activity in vivo (increase significantly the homovanillic acid level in the rat brain striatum).


2005 ◽  
Vol 83 (6-7) ◽  
pp. 793-800 ◽  
Author(s):  
James E Dettwiler ◽  
Laurent Bélec ◽  
William D Lubell

Enantiopure (>99% ee) L-N-tert-butyloxycarbonyl-N-methyl-β-hydroxyvaline (2) was synthesized in six steps and 43% overall yield from D-serine methyl ester (5). Methyl (4S)-N-(9-phenylfluoren-9-yl)-oxazolidine-4-carboxylate (7) was prepared in two steps and 73% yield by N-phenylfluorenation of 5 followed by cyclization of N-(PhF)amino alcohol 6 with formaldehyde and catalytic p-toluenesulfonic acid (PhF = 9-phenylfluoren-9-yl). The addition of MeLi to oxazolidine carboxylate 7 produced the tertiary alcohol 8 in 91% yield. Oxazolidines 8 equilibrated with oxazolidine 9 under acidic conditions. Reduction of pure 8 or the mixture of oxazolidines 8 and 9 with NaCNBH3 and hydrochloric acid in anhydrous dioxane afforded N-methyl amino diol 11 in 86%–92% yields. Attempts to selectively oxidize N-(PhF)amino diol 11 were unsuccessful; however, hydrogenation of 11 in the presence of di-tert-butyl dicarbonate gave the corresponding N-(Boc)amino diol 12 in 82% yield. Selective oxidation of diol 12 was performed using a cocktail containing TEMPO free radical, NaClO2, and NaOCl to give L-N-Boc-N-methyl-β-hydroxyvaline (2) in 87% yield. Coupling of β-hydroxyvaline 2 and (S)-2-hydroxy-3-methylbutanoate (15) was accomplished by using the methodology of Mitsunobu to provide depsipeptide Boc-(S)-HOMeVal-(R)-Hmb (4) for use as a building block in the synthesis of the cyclic antifungal depsipeptide aureobasidin B.Key words: N-methylated amino acid, serine, depsipeptide, aureobasidin.


1992 ◽  
Vol 16 (6) ◽  
pp. 1047-1051 ◽  
Author(s):  
Hidenori Sano ◽  
Yasuo Suzuki ◽  
Koichi Ohara ◽  
Rie Yazaki ◽  
Tatsuya Ishigaki ◽  
...  

1992 ◽  
Vol 57 (9) ◽  
pp. 1937-1946 ◽  
Author(s):  
Pavel Lhoták ◽  
Antonín Kurfürst

The reaction of acetylacetone or sodium salt of oxymethyleneacetone with corresponding aldehydes has been used to prepare 3,5-diacetyl-1,4-dihydropyridines III which have been oxidized to diacetylpyridines VII. These compounds have been transformed by an acid-catalyzed reaction with benzaldehyde into the chalcones VIII which have been utilized for the Kröhnke synthesis of luminophoric terpyridines I and II.


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