Neurotrope und psychotrope Substanzen XIX. 8-Halogenderivate von 10-(4-Methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepin und verwandte Substanzen

Jílek, J. O.; Metyšová, J.; Pomykacek, J.; Protiva, M.

doi:10.1135/cccc19681831

Cited by 14 publications

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“…The mixed anhydride apparently was not formed at all while a base-catalyzed re-esterification took place, giving rise to hydrogen chloride (bound by triethylamine) and carbon dioxide as by-products; I-methylpiperazine did not react with ester X VIa under the conditions used. Reduction of methylpiperazide 24 XVIIa by lithium aluminium hydride in ether yielded the required amine XIX a which was isolated as di(hydrogen maleate).…”

Section: Xtlimentioning

confidence: 99%

Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Rajšner¹,

Svátek²,

Metyšová³

et al. 1977

Collect. Czech. Chem. Commun.

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Six new 8-chloro-3-fluoro-10-piperazino-lO,1l-dihydrodibenzo[b,f]thiepins II-VII were synthesized, amino alcohol II being a highly effective neuroleptic and tranquilizer in acute tests, dioxolane IV prolonging these effects upon oral administration. A new synthesis of acid VIII was developed, proceeding via (2-bromo-4-fluorophenyl)acetic acid (XI). A second geometric isomer of the 3--fluoro derivative of chloroprothixene (XIII) was prepared which, according to the IR spectrum, is of cis-configuration; it is inactive cataleptically and only a weak depressant. Acids XIVab were synthesized using selective bromination of phenylacetamide in the ortho-position. Starting from acid XIVa and via the intermediate XVIIa, 1-[2-(2-p-chlorophenylthiophenyl)-ethyl]-4-methylpiperazine (XIXa) was prepared, a new open model of octoclothepin which acted as an anticonvulsant and showed signs of antihistamine effects.In a previous communication! we described the synthesis of the 3-fluoro derivative of octoclothepin (I) which displayed a high degree of neuroleptic and depressant activity on oral application in acute tests and clear signs of prolongation of these effects. This was explained by a block of metabolic hydroxylation of the octoclothepin molecule by fluorination 1 ,2. The work has now been extended to include several analogues of I with modified N-substituents. Firstly, amino alcohol II was synthesized, this being a 3-fluoro derivative of the highly active noroxyclothepin 3 -5. It was prepared by a substitution reaction of 8, 1O-dichloro-3-fluoro-l 0, l1-dihydrodibenzo[b,f]-thiepinl with 1-(2-hydroxyethyl)piperazine. Its esterification with decanoyl chloride 6 (for method see 4 ) yielded the ester III which is a 3-fluoro derivative of the depot neuroleptic noroxyclothepin decanoate 4 ,7 ,8. Further prepared were IV and V with a 1,3-dioxolane or 4-methyl-l,3-dioxolane residue in the side chain; these are 3-fluoro derivatives of previously prepared octoclothepin analogues 9 which displayed, in comparison with octoclothepin, a much lower toxicity on oral administration. The purpose of synthesis of IV and V was to prepare oral neuroleptics with prolonged effect that would be less toxic than the 3-fluoro derivative of octoclothepin (I). ForPart CXIII in the series Neurotropic and Psychotropic Agents; Part CXI1: This Journal 42,2240 (1977).

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Section: Xtlimentioning

confidence: 99%

Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Rajšner¹,

Svátek²,

Metyšová³

et al. 1977

Collect. Czech. Chem. Commun.

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“…The synthesis of the target compounds 7a − d and 8a − d was achieved by the general method shown in Schemes and . , First, the reaction of the corresponding tricyclic ketones 2a − d , with sodium hydride, followed by addition of allyl bromide afforded the α-allylated ketones 3a − d in good to moderate yields (40−90%, Scheme ). The reduction of ketones 3a − d with L-selectride at −30 °C in THF gave the expected cis alcohols 4a − d with complete diastereoselectivity and excellent yields (90−97%), as it is shown in Scheme .…”

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confidence: 99%

Discovery of New Tetracyclic Tetrahydrofuran Derivatives as Potential Broad-Spectrum Psychotropic Agents

Fernández¹,

Alonso²,

Andrés³

et al. 2004

J. Med. Chem.

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A series of novel tetracyclic tetrahydrofuran derivatives was prepared and evaluated for its potential psychotropic properties. In vitro affinities for multiple dopaminergic, serotonergic, alpha-adrenergic, and histamine receptors and for the norepinephrine transporter as well as the ED(50) values obtained in some in vivo assays for antipsychotic, anxiolytic, and antidepressant potential are reported. Compounds (-)-1, (-)-8d, and (+)-8d have been identified as potential broad-spectrum psychotropic agents.

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“…The crude product was purified by flash chromatography (20% MeOH in EtOAc) to yield 3.65 g (80%) of 8 as a white solid: mp 99−100 °C (lit. 99−101 °C). LC−MS: ELSD, 99.2%; UV, 99.0%, M + , 345.1; R f = 0.30 (solvent C).…”

Section: Methodsmentioning

confidence: 99%

“…The crude product was filtered through silica gel (300 g) (20% MeOH in EtOAc) and recrystallized from EtOH/water to yield 76.2 g (92%) of 10 as white crystals: mp 116−117 °C (lit. 118−119 °C). LC−MS: ELSD, 99.2%; UV, 95.7%; M + , 389.2; R f = 0.16 (solvent B).…”

Section: Methodsmentioning

confidence: 99%

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Exploring the Neuroleptic Substituent in Octoclothepin: Potential Ligands for Positron Emission Tomography with Subnanomolar Affinity for α₁-Adrenoceptors

et al. 2010

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A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors-Bøgesø pharmacophore model for dopamine D(2) and α(1)-adrenoceptor antagonists, with the aim of obtaining selective α(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central α(1)-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl)methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α(1a), α(1b), and α(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D(2), 5-HT(2C), and H(1) receptors, respectively.

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Neurotrope und psychotrope Substanzen XIX. 8-Halogenderivate von 10-(4-Methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepin und verwandte Substanzen

Cited by 14 publications

References 0 publications

Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Discovery of New Tetracyclic Tetrahydrofuran Derivatives as Potential Broad-Spectrum Psychotropic Agents

Exploring the Neuroleptic Substituent in Octoclothepin: Potential Ligands for Positron Emission Tomography with Subnanomolar Affinity for α₁-Adrenoceptors

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Neurotrope und psychotrope Substanzen XIX. 8-Halogenderivate von 10-(4-Methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepin und verwandte Substanzen

Cited by 14 publications

References 0 publications

Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Discovery of New Tetracyclic Tetrahydrofuran Derivatives as Potential Broad-Spectrum Psychotropic Agents

Exploring the Neuroleptic Substituent in Octoclothepin: Potential Ligands for Positron Emission Tomography with Subnanomolar Affinity for α1-Adrenoceptors

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Exploring the Neuroleptic Substituent in Octoclothepin: Potential Ligands for Positron Emission Tomography with Subnanomolar Affinity for α₁-Adrenoceptors