Synthesis and hypotensive activity of some heterocyclic analogues of GYKI-12 743.

[1,4]Benzodioxanylmethyl-, [1,4]benzodioxanylmethylaminopropyl- and phenoxyethylaminoethyl-substituted lactams were synthesised and their hypotensive activity was investigated. Some of these compounds show moderate to high hypotensive effect, but they had more toxic and/or side effects than GYKI-12 743.

Synthesis of pyridylthiazoles as antisecretory agents.

4-(3-Pyridyl)thiazole and 2-methylimidazo[1,2-a]pyridine derivatives with anticholinergic antisecretory activity were synthesized. Most of the compounds (3-16) were formed from carbohydrazide 2 and carbonitrile 9. Some thiazole derivatives, most of them containing nitrogen attached to the thiazole C-2 (19-20), were prepared from 17 and 18 by known method. Compounds 12 and 19b exerted a significant antisecretory whereas 5b, 12 and 19b an antiulcer activity.

The CNS effects of 5-aminobenzoic acids inhibiting the biosynthesis of prostaglandins.

It was found that the 2,5-diaminobenzoic acid derivatives 1 activating the biosynthesis of prostaglandins have CNS side effects. The replacement of the 2-NH group in 1 by O or S resulted an inhibition of prostaglandin biosynthesis and increased CNS activity.

Synthesis of thiazole derivatives with positive inotropic effect.

Thiazole derivatives with potential positive inotropic effect were synthesized. The highest activity (medium positive inotropic effect) was exhibited by ethyl 2-(2-hydroxyethylamino)-4-phenylthiazole-5-carboxylate (3b) of which several derivatives have been prepared. Among these derivatives only those which could presumably easily removed in the living organism to give 3b exhibited a medium positive inotropic effect (6, 8b). It was assumed that the effect of 3b had a beta-agonist character.

Studies in the field of pyridazine compounds. Part 21. Structural studies on 6-H-pyrimido[1,2-b]-1,2,4-triazolopyridazines.

The structure of 7,8-dihydro-6H-pyrimido [1,2-b]-1,2,4-triazolo [3,4-f] pyridazine (2a) was confirmed by 1H and 13C NMR spectroscopy and by preparation of the isomeric [5,1-f] pyridazine 3. Some derivatives of 6H-pyrimido [1,2-b]-1,2,4,-triazolo [3,4-f]pyridazine were prepared. Compounds 2a, 2b and 9a showed a positive inotropic effect.

Preparation of new [1,2,4]triazolo[4,3-b]pyridazines. Part 12: Studies in the field of pyridazine compounds.

6-Substituted-[1,2,4]triazolo[4,3-b]pyridazine-3-methanol, -aldehyde, -nitrile, -chloromethyl and -aminomethyl derivatives of potential antihypertensive activity were synthesized. The reduction of methyl[1,2,4]triazolo[4,3-b] pyridazine-3-carboxylate by lithium aluminium hydride and potassium borohydride was examined. The new compounds failed to exhibit hypotensive or antihypertensive effect. Compound 2a was a minor metabolite of GYKI-11679 [7].

Influence on turnover and level of hypothalamic noradrenaline by a new antihypertensive agent (GYKI 11679).

In an attempt to delineate the possible importance of the concentration of noradrenaline at hypothalamic noradrenergic receptor sites in a hypotensive response to a drug, the action of a new antihypertensive agent, 1-(6-morpholino-3-pyridazynyl)-2-(1-[tert-butoxycarbonyl]-2-propylidene)-diazane (GYKI 11679), on the turnover rate and the endogenous level of noradrenaline (NA) in rat hypothalamus was examined. An effective, antihypertensive i.p. dose of the compound (10 mg/kg) produced a significant but relatively short-lasting reduction in the hypothalamic noradrenaline content, whereas no change was observed in the cardiac catecholamine level. The NA turnover determinations, carried out in GYKI 11679-pretreated rats by measuring the disappearance of labeled NA at 1, 2, 3, and 5 h after the injection of the radioactive amine, showed that a 10 mg/kg i.p. dose of the compound, given 1 h prior to the i.c.v. administration of the labeled NA, increased the turnover rate of noradrenaline to a great extent. The estimated half-lives of NA in the hypothalamus of the treated and of the non-treated animals were calculated as 1.72 and 3.62 h, respectively. In vitro studies showed that the spontaneous outflow of noradrenaline from hypothalamic slices was accelerated by GYKI 11679 in a dose-dependent manner in a concentration range of 10(-5) to 10(-7) M. In a 10-fold higher range, GYKI 11679 produced inhibition of both the hypothalamic and the adrenal tyrosine hydroxylase activity but did not alter DOPA-decarboxylase, dopamine-beta-hydroxylase, or monoamine oxidase activities. Direct in vivo measurements of catecholamine synthesis by determining the 3H-catecholamines (CA) formed from [3H]tyrosine in the hypothalamus after an i.c.v. administration of the labeled precursor showed a moderate increase in [3H]CA formation following a 10 mg/kg dose of the compound. When GYKI 11679 was administered in a 75 mg/kg i.p. dose to rats, the transformation was reduced by approximately 50%. Adenylate cyclase activity measurements did not show stimulatory or inhibitory actions of the drug on the NA-stimulated adenylate cyclase of the rat hypothalamus, in accordance with previous results. This suggests that the increased NA turnover (utilization) caused by an effective, antihypertensive dose of GYKI 11679 is the direct consequence of an increased outflow, which occurs primarily in the hypothalamus. The increased activity of the noradrenergic neurons in this brain region might lead to a reduced sympathetic activity in the periphery and thus to a significant decrease in blood pressure.