Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug.

The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e.

Angiotensin converting enzyme inhibitors as antihypertensive agents: 1-[(2-mercaptocycloalkyl)carbonyl]-L-prolines.

The synthesis of 1-[(2-mercaptocyclopentyl)carbonyl]-L-prolines, 1-[(2-mercaptocyclobutyl)carbonyl]-L-prolines and related benzoyl derivatives as pure isomers is described. The abilities of all the compounds to inhibit angiotensin converting enzyme (ACE) in vitro and in vivo and to lower the systolic blood pressure in renal hypertensive dogs were determined. Three of them, namely 1-[[2-(benzoylthio)cyclopentyl]carbonyl]-L-proline (10f(R,S], 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline (10g(R,S], and 1-[[2-(benzoylthio)cyclobutyl]carbonyl]-L-proline (16f(R,S], were found to be as potent as captopril in reducing blood pressure.

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog.

The metabolic fate of a new anti-hypertensive, 1-pyrrolyl-pyridazinamine, was studied in male Beagle dogs given both p.o. and i.

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine+ ++ hydrochloride. I. Studies in the rat.

The metabolic fate of a new anti-hypertensive, 1-pyrrolyl pyridazinamine, was studied in male Wistar rats after both p.o. and i.

Potential antihypertensives. Synthesis of 6-substituted-N-(4H-1,2,4-triazol-4-yl)-3-pyridazinamines and 3-substituted-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazines.

A series of 6-substituted-N-(4H-1,2,4-triazol-4-yl)-3-pyridazinamines [(II), Scheme 1] and 3-substituted-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl) pyridazines [(XII), Scheme 3-5] were synthesized. The compounds were evaluated for their oral antihypertensive activity in rats (SHR) and only some compounds of structure (XII) induced a moderate decrease in systolic blood pressure.

Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog.

The pharmacokinetics of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new antihypertensive agent, was studied in rats and dogs. The 14C-labelled compound was synthesized by a microscale procedure with 45% chemical yield and 98% radiochemical purity. In both animal species, MDL-899 was rapidly absorbed from the gastro-intestinal tract, achieving peak plasma levels in 0.

Antihypertensives. N-1H-Pyrrol-1-yl-3-pyridazinamines.

The hypothesis that the side effects of hydralazine, such as mutagenicity and lupus erythematosus like syndrome, might be due to the NHNH2 group prompted us to incorporate part of this moiety into a pyrrole ring. Therefore, we prepared a series of N-1H-pyrrol-1-yl-3-pyridazinamines and a limited number of N-1H-pyrrol-1-yl-1-phthalazinamines by reaction of 3-hydrazinopyridazines and 1-hydrazinophthalazines with gamma-diketones. Most of these compounds, especially in the pyridazine series, showed moderate to strong antihypertensive activity in spontaneously hypertensive rats.

Synthesis of potential antihypertensive compounds: N-(4,5-dihydroimidazol-2-yl-amino)pyrroles.

A series of N-(4,5-dihydroimidazol-2-yl-amino)pyrroles (V) were prepared by reaction of the 2-hydrazino-2-imidazolines with 2,5-diketones. Noticeable oral antihypertensive activity in renal hypertensive dogs was shown by N-(4,5-dihydroimidazol-2-yl-amino)-2,5-dimethyl pyrrole.

Synthesis of three metabolites of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine. A new rearrangement of 3-[1-methylethyliden)hydrazino] derivative.

The synthesis of three metabolites (I), (II), (III) , isolated from rat urine, of the hypotensive compound 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride (IV), is described. The first metabolite, 3-[bis-(2-hydroxyethyl)amino]pyridazine (I) (Scheme 1) was obtained either by reaction of 6(3)-chloro-3(6)-[bis-(2-hydroxyethyl)amino]pyridazine-N-oxide (V) with hydrazine hydrate or by catalytic hydrogenation of 3-chloro-6-[bis(2-hydrxyethyl)amino]pyridazine (VI). 3-Methyl-6-[bis-(2-hydroxyethyl)amino]-2-triazolo [4,3-b]pyridazine (II) was prepared (Scheme 2) by reaction of (IV) with acetic anhydride and subsequent hydrolysis of the resutling 6-[bis-(2-acetyloxyethyl)amino]-s-triazolo[4,3-b]pyridazine (VII).

Synthesis of 1-hydroxy and 1-acyloxypyrrolidin-2-ones.

A series of 1-hydroxypyrrolidin-2-ones (v) has been prepared by reduction of gamma-nitrocarboxylic acid esters with Zn dust in the presence of ammonium chloride. Acylation of compounds (v) gave the corresponding 1-acyloxypyrrolidin-2-ones (VI). None of the synthesized compounds showed any significant antiflammatory activity.

The reaction of phthalazino(2,3-b)phthalazine-5,12(7H, 14H)-diones with nitrous acid.

3,4-Dihydrophthalazin-1(2H)-one (I) was oxidized to phthalazin-1(2H)-one (III) with nitrous acid or with ferric chloride . Phthalazino [2,3-b] phthalazine-5,12(7H, 14H)-diones (IV) did not react with ferric chloride but they were oxidized with nitrous acid to 2-[1(2H)-oxo-2-phthalazinyl] methylbenzoic acids (V) and (VI). The formation of (V) or (VI) depends upon the substituents of compounds (IV).