[Phthalazines. XI. Reaction of 1-substituted and 1,4-disubstituted phthalazine N-oxides with acetic anhydride and acid chloride (author's transl)].
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Acetates↗
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3-Hydroxymethyl-s-triazolo[3,4-a]phthalazine, a novel urinary hydralazine metabolite in man.
The elucidation of the structure of a new major metabolic product of hydralazine, 3-hydroxymethyl-s-triazolo[3,4-a]-phthalazine, is described. The structures of several other previously described metabolites of the drug, phthalazone, s-triazolo[3,4-a]phthalazine, and 3-methyl-s-triazolo[3,4-a]phthalazine, are confirmed. A metabolic pathway of hydralazine is also proposed.
Humans↗
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). Strucutres (V) and (VI) were established by pKa measurements in methylcellosolve and by mass and N.M.R. spectra.
Indicators and Reagents↗
[Synthesis and pharmacologic testing of 1-oxo-pyridazine and 1-oxo-phthalazine-2-acetic acid derivatives].
The title compounds, starting from variously substituted beta-benzoylpropionic or beta-benzoylbenzoic acids, were prepared by cyclocondensation with alpha-ethylhydrazinoacetate monohydrochloride and subsequent alcaline hydrolysis or aminolysis of the 2-carbethoxymethyl-1,2,5,6-tetrahydro-1-oxo-pyridazines or 1,2-dihydro-1-oxo-phthalazines respectively. The 1-oxo-phthalazines 42 and 34 have a weak anticonvulsive effect. Like a large number of the other synthezized compounds, they show a central sedative component and are relatively nontoxic.
Acetates↗
Synthesis of some phthalazine derivatives chemically related to hydralazine.
The potent antihypertensive properties of hydralazine and dihydralazine prompted the synthesis of sixteen new phthalazine derivatives with thiosemicarbazide or beta-propionamide residues to investigate their possible antihypertensive activity.
Hydralazine↗
A new ionizable chromophore of 1,4-bis(alkylamino)benzo[g]phthalazine which interacts with DNA by intercalation.
The tricyclic heteroaromatic nucleus of 1,4-bis(alkylamino)benzo[g]phthalazine can be protonated at physiological pH, depending on the nature of the side chains. The interaction of the 3-methoxypropyl derivative with calf thymus and closed, circular DNA has been studied with UV-vis spectroscopy and NMR. The effect of drug binding on the topology of closed, circular DNA was determined by topoisomerase-I catalyzed relaxation of the complex followed by gel electrophoresis. The results strongly support intercalative binding and suggest that this series of compounds are promising targets for anticancer activity evaluation.
DNA↗
[Phthalazinilides. The action of ethyl bromopyruvate on phthalazine].
Our investigation for obtaining carbon-nitrogen stable ilides continued by the synthesis of new phthalazinic derivatives by the action of ethyl brompyruvate. The structure of the obtained products was confirmed by chemical and spectral analyses. The results regarding their antimicrobial action are also presented.
Anti-Bacterial Agents↗
Toxicological studies of 1-[2-(1,3-dimethyl-2-butenylidene)-hydrazino]-phthalazine, a new antihypertensive drug, in mice and rats.
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Anemia↗
Anti-convulsant effect of phthalazino-2,3b-phthalazine-5(14H),12(7h)-dione (L-5418). I. Behavioral effect.
Since it had been demonstrated that L5418 has an anti-convulsant effect with no relation to its anti-inflammatory properties, comparative studies were carried out with the use of currently available anti-convulsant agents as controls. L-5418 inhibited tonic convulsions induced by maximal electroshock and strychinine in mice and prevented animals from the death sequence. L-5418 had an inhibitory effect on tonic convulsions induced by pentetrazol and N-sulfamoyl-hexahydroazepine (SaH 41-178), but not on clonic convulsions by those compounds at even a high dosage or on clonic convulsions induced by picrotoxin and bemegride. Trimethadione produced an inhibitory effect on both tonic and clonic convulsions. The hypnotic agents, phenobarbital and glutethimide inhibited both convulsions, but a higher dose was required in the case of clonic convulsions. Anti-convulsant agents are classified into three different groups according to their mode of action. L-5418 had the same mode of action as seen with diphenylhydantoin and carbamazepine. As L-5418 did not inhibit tremor induced by tremorine, an anti-Parkinson effect was ruled out. When L-5418 was administered alone, the animals did not lose the righting reflex nor show muscle relaxation observed in inclined screen and rotarod tests. Moreover, the compound had no influence on the aggressive behavior induced by electrical stimulation or olfactory bulb ablation. L-5418 possesses a selective anti-convulsant effect, yet has no sedative, tranquilizing or disturbing effects on movement such as equilibrium disturbance or muscle relaxation. L-5418 may prove useful for grand mal epilepsy as it is less toxic than diphenylhydantoin and carbamazepine.
Aggression↗
Anti-convulsant effect of phthalazino-[2,3b]-phthalazine-5(14H), 12(7H)-dione (L-5418). II. Electroencephalographic study.
L-5418 has an anti-convulsant effect which is similar to that of diphenylhydantoin. The effects of L-5418 on EEG activity in rabbits with acute and chronic implantation of electrodes were studied in comparison with those of currently available anti-convulsants. Intravenous administration of L-5418 increased a slow-wave sleep pattern in the spontaneous EEG, which was also induced by diphenylhydantoin. With respect to the focal seizure in the cerebral cortex induced by local application of penicillin, L-5418 showed suppressive effects on the frequency and duration of seizure discharge, and on the spread of seizure discharge to other parts of the brain. The efficacy was about twice that of diphenylhydantoin. L-5418 and dephenylhydantoin did not increase the threshold of seizures induced by bemegride while trimethadione raised the threshold. L-5418 also showed suppressive effects twice as active as diphenylhydantoin on after-discharge induced by electrical stimulation of the hippocampus and amygdala. This suppressive effect on after-discharge of the limbic system may be parallel with the suppressive effect on psychomotor seizure. From these results of L-5418 on an experimental model of epilepsy, it is suggested that L-5418 has suppressive effects similar to that of diphenylhydantoin on convulsion and the efficacy proved to be twice that of diphenylhydantoin in the EEG study.
Animals↗
Reactions of 4-aryl-1-hydrazinophthalazines with carbonyl compounds.
Reaction of 1-hydrazino-4-phenylphthalazine and 4-benzyl-1-hydrazinophthalazine with different carbonyl compounds are described. With oxalic acid, the two cyclic amidrazones reacted to give 6-aryl-1,2,4-triazolo[3,4-a]phthalazines. Reaction with diethyl oxalate, however, afforded the corresponding 7-aryl-3,4-dioxo-1,2,4-triazino[3,4-a]phthalazines. With pyruvic acid, ethyl pyruvate, or methyl phenyl glyoxylate the corresponding hydrazones were obtained which were cyclized to 7-aryl-3-methyl or 7-aryl-3-phenyl-1,2,4-triazino[3,4-a]phthalazines, respectively. Whereas the reaction of the two cyclic amidrazones with acetylacetone or ethyl phenyl propiolate gave pyrazole derivatives, their reaction with ethyl acetoacetate gave 6-aryl-3-methyl-1,2,4-triazolo[3,4-a]phthalazines. The results of biological testing of representative examples of the prepared compounds as insecticides and nematicides are reported.
Acetoacetates↗
[Cyclic hydrazides. II. (1) Synthesis of 3-aminopyrazolo[1,2-b]hthalazine-1(1H),5(10 H)-diones].
The synthesis is described of a number of 3-aminopyrazolo[1,2-b]phthalazine-1(1H),5(10H)-diones (I) differently substituted on the amino group and in position 2, through condensation of alpha-chloro-beta-chlorocarbonylenamines (IV) with the 3,4-dihydrophthalazin-1(2H)-one (III). Alternatively cyanoacetylchlorides are condensed with (III) giving directly the 3-aminopyrazolo[1,2-b]phthalazine-1(1H),5(10H)-diones with the primary amino function (VII).
Anti-Inflammatory Agents↗
Metabolism of hydralazine by activated leukocytes: implications for hydralazine induced lupus.
Hydralazine is associated with a lupus-like syndrome. There is evidence that many drug hypersensitivity reactions are due to reactive metabolites. Incubation of hydralazine with activated neutrophils or monocytes led to the production of phthalazinone, phthalazine and 3 unidentified metabolites. Formation of the metabolites, with the exception of phthalazine, required activation of the leukocytes. Using radiolabelled hydralazine, covalent binding to activated neutrophils was observed. Oxidation of hydralazine catalyzed by myeloperoxidase (MPO) produced the same metabolites and covalent binding to protein. We conclude that hydralazine is metabolized by activated leukocytes to a reactive metabolite which may be associated with hydralazine induced lupus.
Chromatography, High Pressure Liquid↗
High-performance liquid chromatographic studies of reaction of hydralazine with biogenic aldehydes and ketones.
To understand hydrazone formation in hydralazine metabolism, the reaction of hydralazine with various biogenic aldehydes and ketones (acetone, pyruvic acid, acetoacetic acid, formaldehyde, and acetaldehyde) in pH 7.4 buffer was studied for potential alterations in hydralazine pharmacokinetics secondary to alcoholism and diabetes. The corresponding hydrazones were isolated, and their structures were characterized. High-performance liquid chromatography was used to monitor the reactions. An aqueous solvent reversed-phase liquid chromatographic system was used to separate hydralazine and its derivatives. Reaction of hydralazine with formaldehyde or acetaldehyde produced the corresponding hydrazones. Formation of an s-triazolo ring system yielded the known s-triazolo[3,4-alpha]phthalazine and 3-methyl-s-triazolo[3,4-alpha]phthalazine metabolites, which also were isolated and characterized and suggested nonenzymatic metabolism.
Aldehydes↗
The oxidation of azaheterocycles with mammalian liver aldehyde oxidase.
1. Isoquinoline, cinnoline, quinoxaline, quinazoline and phthalazine were incubated with preparations of rabbit liver aldehyde oxidase. 2. The oxidation products, 1-hydroxyisoquinoline, 4-hydroxycinnoline, 2-hydroxy- and 2,3-dihydroxy-quinoxaline, 4-hydroxy- and 2,4-dihydroxy-quinazoline, and 1-hydroxyphthalazine were identified by comparison of their spectral and chromatographic characteristics with those of authentic compounds. 3. Michaelis-Menten constants are reported for the action of the parent heterocycles with aldehyde oxidase. The compounds reported in this study are among the most efficient substrates yet described for rabbit liver aldehyde oxidase. 4. The compounds in 1 above were incubated with bovine milk xanthine oxidase: only quinazoline and phthalazine yielded significant amounts of metabolites. Km values were calculated for these compounds. 5. Incubation of the heterocycles with rat liver preparations gave qualitatively the same results as those obtained using rabbit liver, but smaller amounts of the oxidation products were detected from rat liver incubations.
Aldehyde Oxidoreductases↗
Some laboratory aspects of hepatic tolerability of diftalone.
The hepatic tolerability of phthalazine-(2,2-b)-phthalazin-5,12-(7H,14H)-dione (diftalone--administered at the dosage of 750 mg/day p.o. for a mean period of 23 days--has been studied in 40 patients by means of: total plasma protein, albumin, fibrinogen, serum glutamin-oxalacetic transaminase, serum glutamic-pyruvic transaminase, lactic dehydrogenase, creatine phosphokinase, alkaline phosphatase, glycemic curve after glucagon and plasmatic elimination of bromosulphalein. A statistically but not clinically significant increase of the SGPT level is the only change observed.
Adult↗
Kinetics of hydralazine elimination.
Hydralazine was given orally in single doses of 10, 25, and 50 mg to 2 slow-acetylating subjects, while 2 rapid-acetylating subjects also received 100- and 150-mg doses on different occasions. Administration of the 50-mg dose to the subjects who were slow acetylators and the 150-mg dose to those who were rapid acetylators caused a disproportionately large increase in the amount of unchanged drug appearing in the systemic circulation as judged from the increases in the ratios of areas under concentration-time curves (AUC) to dose. A modification of the gas-liquid chromatographic hydralazine assay allowed the simultaneous determination of hydralazine and its acetylated metabolite, 3-methyl-s-triazolo-3,4,a-phthalazine (MTP), in serum. It was found that the disproportionately large increases in the AUC/dose ratio of hydralazine upon intake of 50 or 150-mg doses by the slow and rapid-acetylating subjects, respectively, were paralleled by a decrease in the ratio AUCMTP/AUChydralazine during a 6-hr observation period. It is concluded that the acetylation of hydralazine in man is a capacity-limited process.
Acetylation↗
Inhibition of aldehyde reductase by aldose reductase inhibitors.
A broad group of structurally diverse aldose reductase inhibitors including flavonoids, carboxylic acids and hydantoins, have been examined for their ability to inhibit rat kidney aldehyde reductase (EC 1.1.1.19, EC 1.1.1.20) versus rat lens aldose reductase (EC 1.1.1.21). All aldose reductase inhibitors examined inhibited aldehyde reductase to some extent both in the reductive reaction as determined with glyceraldehyde as substrate and NADPH as coenzyme, and in the oxidative reaction where L-gulonic acid was oxidized to D-glucuronic acid in the presence of NADP+. Of the inhibitors examined, 2,7-difluorospirofluorene-9,5'-imidazolidine-2',4'-dion e (Al1576) was the most potent inhibitor requiring only concentrations in the 10(-8) M range to inhibit 50% of the in vitro activity of rat kidney aldehyde reductase (IC50 value), whereas 3-dioxo-1-H-benz[de]isoquinoline-2(3H)-acetic acid (alrestatin) was the least potent inhibitor requiring concentrations in the 10(-5) M range. Both the reductive and oxidative steps appeared equally inhibited by these aldose reductases inhibitors. Moreover, all compounds appeared to inhibit either crude or highly purified rat kidney aldehyde reductase to essentially the same extent. Marked differences in the selectivity of these inhibitors, expressed as the ratio of IC50 values for rat kidney aldehyde reductase versus rat lens aldose reductase with glyceraldehyde as substrate, were observed with selectivity for aldose reductase ranging from ca. 2-fold for Al1576 to 119-fold for 3-(4-bromo-2-fluorobenzyl-4-oxo-3-phthalazine-1-ylacetic acid (Ponalrestat). Kinetic and competition studies suggest that these inhibitors interact with aldehyde reductase at a common site that is not identical to either the substrate or nucleotide binding site. These results suggest that the inhibitor binding sites of rat kidney aldehyde reductase and aldose reductase contain several common characteristics.
Alcohol Dehydrogenase↗