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At least 19 recordsLinked to original sources
PubMed1979

[Unexpected anti-inflammatory activity of rigid structures derived from 6-arylpyridazinone antihypertensive agents. II. Synthesis and activity of 5H-indeno(1,2-c)pyridazine and 5H-indeno(1,2-c)pyridazin-3-one].

The synthesis of 5H-indeno[1,2-c]pyridazine (V) and of some derivatives were reported. The compounds synthesised generally retained the antiinflammatory activity exhibited by the 4,4a-dihydro derivatives of this class, previously tested. Moreover (V) showed analgesic and antipyretic properties higher than those of acetylsalicylic acid.

Animals↗
PubMed1979

Metabolites of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride in rat urine.

In 24 hr urine of rats orally given 150 mg/kg of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride (DL 150), no unchanged compound was detected. Three metabolites, less polar than DL 150, were isolated, their structures assigned by UV, MS, IR and 1H NMR spectroscopies, and confirmed by synthesis. They are: 3-[bis-(2-hydroxyethyl)amino]-6-isopropoxypyridazine (1); 3-[bis-(2-hydroxyethyl)amino]pyridazine (2); 3-methyl-6-[bis-(2-hydroxyethyl)amino]-s-triazolo[4,3-b]pyridazine (3). The metabolism of DL 150 in the rat follows some of the metabolic pathways reported for hydralazine.

Animals↗
PubMed1979

[3-Hydrazinepyridazine derivatives. III. Synthesis and anti-hypertensive activity of new 3-(2-acylhydrazine)-pyridazine-6-alkylamino substitutes].

The synthesis of 2-(6-dialkylamino-3-pyridazinyl)hydrazinecarboxylates (II) and hydrazides (V) from the corresponding 3-chloro-6-dialkylaminopyridazines (I) is described. The 6-substituted derivatives of 2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazine-3-ones (III) and 1,2,4-triazolo[4,3-b)pyridazines (VI) were obtained by thermal cyclization of (II) and (V), respectively. The new acyl derivatives were evaluated together with todralazine and budralazine as antihypertensive agents in comparison with propildazine and hydralazine. The ethoxycarbonyl compound [(II g), ISF 2469] exhibits good antihypertensive activity particularly via oral administration. Its interesting pharmacodynamic properties, including slow onset and long-lasting action, qualify it for further pharmacological and clinical studies.

Animals↗
PubMed1979

The cardioactive properties of SC4453, a digoxin analogue with a C17 beta-pyridazine ring.

SC4453 is a digoxin analogue with a pyridazine instead of a lactone ring in C17 beta. SC4453 was compared with digoxin with respect to effect on contractility and on activity of the sodium pump in guinea-pig isolated left atria stimulated at 3.3 Hz. The two glycosides stimulated the sodium pump at low concentrations and inhibited at high concentrations. At the time to peak inotropic effect, for a similar inhibition of the Na pump, the increase in systolic tension was higher with SC4453 than with digoxin, whereas the increase in diastolic tension was similar for both. These observations confirm that the inhibition of the Na pump is not the only mechanism responsible for the positive inotropic effect of cardiac glycosides.

Animals↗
PubMed1978

Effect of the diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d]-pyridazine (DS-511) and its derivatives on ADH-cyclic AMP system in rat renal medullary slices.

The effect of the diuretics, 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) and its 4'-hydroxy derivative [DS-511(4'-OH)] on the ADH-cyclic AMP system was studied in slices of rat renal medulla. These compounds alone did not affect the basal level of cyclic AMP in the slices. Preincubation with 10(-6) mol DS-511 or 10(-7) to 10(-5) mol DS-511-(4'-OH) in the presence of theophylline, inhibited arginine vasopressin stimulated formation of cyclic AMP, but after washing the slices the formation was restored. Etacrynic acid required higher concentrations such as 10(-5) and 10(4-) mol to cause inhibition. No effect was observed with furosemide and hydrochlorothiazide in concentrations up to 10(-4) mol. DS-511(4'-OH) at concentrations higher than 10(-6) mol inhibited the activity of cyclic AMP-phosphodiesterase in the medullary homogenate. These results suggest the water diuretic action of DS-511 is partly mediated by its inhibition of the ADH-cyclic AMP system.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Effect of 1,4-dimorpholino-7-(4-hydroxyphenyl)pyrido[3,4-d]) pyridazine [DS-511(4'-OH)] on the transepithelial transport of sodium and water and the permeability to urea in the toad urinary bladder.

To elucidate the mechanism of the inhibitory action of 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) on water and sodium reabsorption at the renal tubules, the effect of DS-511 (4'-OH), which is similar in diuretic effect to but more water-soluble than DS-511, on the transepithelial transport of sodium and water and permeability to urea was studied in isolated toad urinary bladder. Application of DS-511(4'-OH) at concentrations above 2 x 10(-4) mol/l to the serosal side of the bladder depressed the transepithelial potential difference, short circuit current (SCC), and membrane conductance as well as the increased response of the SCC to arginine vasopressin (AVP) and cyclic AMP. The effect of DS-511 (4'-OH) applied to the mucosal side was delayed in onset and less pronounced. Neither serosal nor mucosal 10(-3) mol/l DS-511(4'-OH) depressed the increased response of the SCC to amphotericin B. 2 x 10(-4) mol/l DS-511 (4'-OH) applied to the serosal side did not affect osmotic water flow, but potentiated the increase in water flow caused by AVP. Basal urea permeability as well as the increase in urea permeability caused by AVP were depressed by serosal 10(-3) mol/l DS-511 (4'-OH). The results show that DS-511(4'-OH) has two actions, the depression of the transepithelial transport of sodium and urea, and the potentiation of the increased water permeability caused by AVP.

Amphotericin B↗
PubMed1979

Possible psychopharmacological agents. Part 9: Synthesis and CNS activity of some new fluorine-containing 1,2,4-triazolo[4,3-b]pyridazines.

A number of new fluorine-containing 1,2,4-triazolo[4,3-b]pyridazines have been synthesized by the condensation of 4-amino-(4H)-1,2,4-triazole with appropriate fluorinated beta-diketones in glacial acetic acid. All synthesized compounds were characterized by their m.p.'s, nitrogen analysis, IR, 1H NMR and 19F NMR. A representative number of compounds was screened for their CNS activity and found to be mild stimulants.

Analgesics↗
PubMed1977

Comparison of the hypotensive and diuretic effects of 1,4-dimorpholino-7-phenylpyrido[3,4]pyridazine (DS-511) and hydrochlorothiazide in Doca, renal and spontaneously hypertensive rats.

The hypotensive and diuretic activities of a new diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d] pyridazine (DS-511), were compared with those of hydrochlorothiazide (HC) in DOCA, renal and spontaneously hypertensive rats. The results obtained were: 1. During the developing stage of DOCA-hypertension the daily treatment of rats with DS-511 and HC showed significant hypotensive action. During this period the diuretic activity of both agents was clear. 2. During the equilibrium stage of DOCA-hypertension the hypotensive action of DS-511 was indistinct despite its diuretic activity. The hypotensive and diuretic action of HC was not clear. 3. In renal-hypertensive rats the daily treatment of DS-511 and HC caused significant, but weaker hypotension than that in the developing stage of DOCA-hypertension. In these animals the diuretic activity of both agents was clear. 4. In spontaneously hypertensive rats the daily treatment with DS-511 and HC exhibited a similar hypotensive and diuretic action. 5. In all three kinds of hypertensive rats the diuretic activity of DS-511 was similar to that of HC in the excretion of urine and sodium, but the former was less kaliuretic than the latter.

Animals↗
PubMed1978

Inhibitory effect of 1,4-dimorpholino-7-phenylpyrido[3,4-d]-pyridazine (DS-511) and its 4'-hydroxy derivative on antidiuretic action of vasopressin in rats.

The water-diuretic features of 1,4-dimorpholino-7-phenylpyridol[3,4-d]-pyridazine (DS-511) and its water-soluble 4'-OH derivative [DS-511(4'-OH)] were investigated. In saline-infused rats the minimum i.v. diuretic dose of DS-511(4'-OH) was 1.0 micrograms/kg/min, while in water-diuretic rats the minimum dose was 50 micrograms/kg/min. Intravenous infusion of DS-511 or DS-511(4'-OH) at rates of 1 to 10 micrograms/kg/min caused a dose-dependent inhibition of the ADH-induced antidiuresis in water-diuretic rats, and a decrease in urinary osmolality. However, hydrochlorothiazide even at 500 micrograms/kg/min did not alter the antidiuresis, but increased the osmolality. Furosemide at a rate of 10 micrograms/kg/min increased urinary excretion of water and sodium in both saline-infused and water-diuretic rats, but the same dose did not inhibit the ADH-induced antidiuresis. These findings indicate that the specific anti-ADH action at relatively low doses of DS-511 and DS-511(4'-OH) is partly involved in the diuretic mechanism of these agents.

Animals↗
PubMed1978

1,4-Dimorpholino-7-phenylpyrido[3,4-d]pyridazine (SD-511) as a new type of diuretic agent.

Diuretic features of 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) were studied in rats and mice. DS-511 was similar in diuretic effect to that of hydrochlorothiazide (HC) in both species, but was more water diuretic and less potassium-releasing than HC. After oral administration of DS-511 to rats the diuretic effect promptly appeared and lasted for 4 to 5 h. These patterns on onset and duration were similar to those of furosemide and acetazolamide (AZ). DS-511 was effective in experimentally induced acidotic and alkalotic rats. When DS-511 was used in combinations with other diuretics such as HC, AZ and triamterene at their maximum effective doses, urine volume and sodium excretion further increased, but potassium did not. Diuretic activity of DS-511 was not reduced by daily oral administration for 10 days to rats. In rats DS-511 reversed antidiuretic hormone (ADH)-induced antidiuresis. These findings suggest that DS-511 differs in mode and/or site of action from the known diuretics.

Acidosis↗