RESUMEN
The amin- and phenyl substituted 6,8-dioxabicyclooctanes 10 and 11 show distinct CNS-activities. Intensity and profile depend on the type of amine and the stereochemistry of the products. Therefore, we have synthesized 6,8-dioxabicyclooctanes with different amine-phenyl distances and examined their CNS-activities on mice as well as by receptor binding studies with the PCP-binding site which is part of the NMDA-receptor-complex.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Fármacos del Sistema Nervioso Central/síntesis química , Animales , Compuestos Bicíclicos con Puentes/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Ratones , Ensayo de Unión Radioligante , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de Fenciclidina/efectos de los fármacosRESUMEN
The butadiene derivatives 10a-c react with the oxa-bicyclooctanone 9 to give the cyclohexene annulated oxatropanes 11a-c. The acetoxyderivatives 11b and 11c can be transformed into the cyclohexadiene or benzene derivatives 13 and 12, respectively. 11a reacts with HN3 to afford the tricyclic oxazepanone 14 which can be reduced to give 15a; the oxime-tosylate 16b reacts with Al(CH3)3/DIBALH to yield the oxazepane 15c. Treatment of the oxabicyclooctanes 9 and 19 with benzonitrile oxide or diazomethane affords the isoxazoline or pyrazoline annulated oxatropanes 21, 22, and 20, respectively. 21 was reduced to the amino alcohol 23. 15c and 23 show CNS-activity in the mouse.
Asunto(s)
Fármacos del Sistema Nervioso Central/síntesis química , Ciclohexanos/síntesis química , Piranos/síntesis química , Tropanos/síntesis química , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Fármacos del Sistema Nervioso Central/farmacología , Ciclohexanos/farmacología , Ratones , Piranos/farmacología , Tropanos/farmacologíaRESUMEN
Reaction of the 8-oxabicyclooctenone and -octanone derivatives 3 and 4 with aniline and metal hydrides yields the 3 alpha-isomers of the aniline derivatives 7 and 8, preferably. The configuration can be determined by NMR-spectroscopy and by cyclization to the scopoline analogue 9b. Depending on the N-substitution the pyran rings of the alpha-isomers are flattened (7,8) or deformed to give a boat conformation (10,11,13). The conformationally restricted aniline derivative 18 can be obtained from 4 with 2-aminobenzaldehyde and diborane, trans-configuration is preferred in 18. Some substrates reveal CNS-effects in mice.
Asunto(s)
Compuestos de Anilina/síntesis química , Fármacos del Sistema Nervioso Central/síntesis química , Piranos/síntesis química , Tropanos/síntesis química , Analgésicos/síntesis química , Analgésicos/farmacología , Compuestos de Anilina/farmacología , Animales , Fármacos del Sistema Nervioso Central/farmacología , Ratones , Piranos/farmacología , Tropanos/farmacologíaRESUMEN
The amino nitriles 4a,b and 5a,b, prepared from (1S,5R)-6,8-dioxabicyclo[3,2,1]octan-4-one (2), react with phenylmagnesium bromide to afford the diastereomeric 4-amino-4-phenyl derivatives 7a,b and 8a,b, respectively. The diastereomeric piperidine derivatives 7b and 8b show different CNS-activity.
Asunto(s)
Compuestos Bicíclicos con Puentes , Sistema Nervioso Central/efectos de los fármacos , Piperidinas , Agresión/efectos de los fármacos , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Ratones , EstereoisomerismoRESUMEN
The alcohols 2, the amines 5, 7 and 10, the indole- and quinoline-derivatives 13 and 14, the enamines 3 and 4 and the silylenolethers 17 and 18 were prepared starting with the title compound 1. The 1-(7-phenyl-7-pyranodioxinyl)-piperidines 10-cis and 10-trans show striking CNS-activity. The transisomer is about twice as active as the cis-isomer.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Dioxanos/síntesis química , Piranos/síntesis química , Animales , Conducta Animal/efectos de los fármacos , Dioxanos/química , Dioxanos/farmacología , Hexobarbital/farmacología , Ratones , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Piranos/química , Piranos/farmacología , Sueño/efectos de los fármacosRESUMEN
The phenyl-pyranyl-piperidin derivative 5, prepared from the title compound 2, shows a strong stimulating effect in animals. Reactions of 2 with 2-amino-phenylcarbonyl derivatives or phenylhydrazine can lead to [3,2-b] as well as [3,4-b] annulated pyranes. Regioselective reactions in 2- or 4-position of 2 are successful after conversion to the enamine 14a, the silylenolether 24 and the lithioenamine 29. Cycloadditions, cyclocondensations or electrophilic aldoleractions yield the pyrano-pyranes 16 and 19a, resp., or the hydroxybenzyl- and hydroxybenzylidenpyranes 25 and 30, resp.
Asunto(s)
Estimulantes del Sistema Nervioso Central/síntesis química , Pironas/síntesis química , Animales , Fenómenos Químicos , Química , Ratones , Pironas/farmacologíaRESUMEN
The dihydro-dimethoxyfuran carboxylic ester 3 reacts with different mercaptoalkyl carboxylates to give the carbomethoxyalkylthio-tetrahydrofuran carboxylic esters 4. Methanol elimination of 4 yields the dihydrofuran derivatives 5. 4 and 5 can be oxidized to afford the sulfoxides 6 and the sulfones 7, respectively. 4 reacts with primary amines to give the title compounds 8. Derivatives of 8 can be cyclized to afford the thienopyrroles 11 and 12 as well as the thienopyranopyrrole 14. The mercaptopyrrole carboxylic ester 10 is obtained from 8f by elimination of propenic acid. 8e shows bronchodilatoric activity in low concentration.