RESUMEN
The synthesis and pharmacological activity of new (E),(Z)-[6-(alkylamino)-11H-dibenz[b,e]azepin-11- ylidene]acetonitriles 12-45 and (E),(Z)-[6-(aminoalkoxy)-11H-dibenz[b,e]azepin-11-ylidene] acetonitriles 46-51 are described. The introduction of the cyanomethylene group into the 11-position of the 11H-dibenz[b,e]azepine framework has been carried out by a Wittig-Horner reaction under mild conditions. The (E),(Z) isomers were separated by fractional crystallization, assignment being achieved by X-ray analysis. A number of (E),(Z)-[6-(alkylamino)-11H-dibenz-[b,e]azepin-11-ylidene] acetonitriles (12, 14, 16, 20) show potent neuroleptic activity (2-7 times that of clozapine) in animal tests. The screening included tests for sedative and anticholinergic activity in mice, apomorphine and tryptamine antagonism in rats, and muscle-relaxing activity in rabbits. The divergence in the activity profile in the case of the separated (E),(Z) isomers has been observed as an interesting new aspect: the (Z) isomers show a significantly higher sedative and muscle-relaxant activity, whereas the (E) isomers possess a higher anticholinergic efficacy and somewhat greater apomorphine antagonism. Broad changes in the basic side chain were made in order to investigate structure-activity relationships. The important geometrical parameters for the molecules, obtained by X-ray analysis, were compared with the corresponding features in dopamine agonists and antagonists.
Asunto(s)
Antipsicóticos/síntesis química , Dibenzazepinas/síntesis química , Animales , Antipsicóticos/farmacología , Dibenzazepinas/farmacología , Femenino , Técnicas In Vitro , Ratones , Conformación Molecular , Actividad Motora/efectos de los fármacos , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Investigations were conducted with the combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) in a dose ratio of 5:1, with respect to pharmacological activity and possible side effects. The effects obtained with the combination CN 3123 were compared with those of the single substances. In a dose range comparable to that as used in clinical treatment, there were no effects on cardiovascular or respiratory functions, on functions of autonomic and central nervous system, on contractility of smooth muscles and on data of clinical chemistry such as urine and electrolyte excretion, blood sugar, blood coagulation and liver function tests. Doses which are 5 to 10 times higher than the initial dose or 10 to 20 times higher than the maintenance dose used in man caused an increase of urine and sodium excretion without influencing potassium and chloride output. There were no signs of sedation as alteration of motility or EEG patterns, but in mice and rats there was an increase in both duration and depth of anaesthesia caused by barbiturates or ether. Only in a dose range 30 to 40 times higher than the initial dose for man there were some slight alterations with respect to cardiovascular system and liver function tests. In vitro, with high concentrations of CN 3123 there was a weak, unspecific spasmolytic effect on the isolated ureter and an increase in the refractory period of the guinea pig atrium. There were no hints that the side effects seen with separate administration of high or very high doses of sulfamoxole or trimethoprim were increased or poteniated by their simultaneous administration. Slight side effects in animals were only observed with doses exceeding the tenfold of the doses for therapeutic use in men. Therefore, the therapeutic range of CN 3123 seems to be more than adequate.
Asunto(s)
Sulfamoxol/farmacología , Trimetoprim/farmacología , Animales , Conducta Animal/efectos de los fármacos , Coagulación Sanguínea/efectos de los fármacos , Glucemia/metabolismo , Gatos , Sistema Nervioso Central/efectos de los fármacos , Diuresis/efectos de los fármacos , Perros , Combinación de Medicamentos , Femenino , Cobayas , Hemodinámica/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Conejos , Ratas , Sulfamoxol/administración & dosificación , Sulfamoxol/efectos adversos , Trimetoprim/administración & dosificación , Trimetoprim/efectos adversos , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
The butyrophenone melperone (Eunerpan) in mice and rats caused a prominetn inhibition of spontaneous activity, whereas cataleptogenic and apomorphine-antagonistic properties were less pronounced. In rats the sleep-cycle was altered: decrease of wakefulness, increase of slow-wave sleep and a moderate reduction of rapid eye movement-(REM) sleep. In contrast to thioridazine and chlorpromazine the effect lasted only for 4 h, followed by a slight REM rebound. In rabbits melperone caused a decrease of muscle tone and with somewhat higher doses an inhibition of the arousal-reaction. As seen by the computerized spontaneous cortical EEG, dosages below 1 mg/kg caused a shift of the dominant frequency from theta- to delta-rhythm and an increase of power. Therefore the neuropharmacological pattern of the butyrophenone melperone is closely related to those of thioridazine or chlorpromazine, without, however, having their long action.