As part of a general investigation of new antibacterial agents,1 we have prepared a series of 1-alkyl-1,8-naphthyridin-4-one-3-carboxylic acid derivatives. Several members of the series, listed in Table I, were found to be highly effective antibacterial agents both in vitro and in vivo.These 1-alkyl-1,8-naphthyridines are prepared as outlined. The appropriate 6-substituted-2-aminopyridine (I) is condensed with diethyl ethoxymethylenemalonate and the resulting diethyl N-(6substituted-2-pyridyl)-aminomethylenemalonate (II) is cyclized in refluxing Dowtherm A or diethyl phthalate to give the ethyl 4-hydroxy-1,8-naphthyridine-3-carboxylate derivative (III).2 Hydrolysis of the ester (III) to the corresponding acid and alkylation in alcoholwater with potassium hydroxide gives the desired 1-alkyl-1,8-naphthyridin-4-one-3-carboxylic acid (IV). Alternatively, the same

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1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.

SUMMARYThe cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, waa investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-1000 /ig/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 /ig/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na + ,K + -activated ATPase. Ore Res 45: 666-677, 1979 A LARGE number of agents have positive inotropic effects on the heart. However, of these, only two classes of compounds have been found to be useful in the treatment of heart failure in man. The cardiac glycosides have enjoyed a valued position for nearly 200 years in spite of the fact that they have a narrow therapeutic range, and digitalis intoxication is one of the most common drug-induced adverse reactions in this country (Mason et al., 1971;Beller et al., 1971;Doherty and Kane, 1975). The catecholamines have limitations in that they are arrhythmogenic, are chronotropic, have a short duration of action, and cannot be given orally (Goldberg, 1968). Dopamine (Goldberg, 1974;Beregovich et al., 1974) and the synthetic catecholamine, amine dobutamine (Tuttle and Mills, 1975;Goldberg et al, 1977), both of which have been introduced recently for clinical use, suffer from most of the same drawbacks as the older catecholamines. Other inotropic agents, such as glucagon (Farah and Tuttle, 1960;Glick et al., 1968) has proved of value in the management of congestive heart failure (Cohn and Franciosa, 1977;Mehta, 1977).The development of an orally active non-catechol and non-glycoside cardiotonic agent has been the goal of this laboratory for several years (Alousi and Farah, 1975;Alousi et al., 1978;Farah and Alousi, 1978). Amrinone (Win 40680), a 5-amino-3,4'-bipyridine-6(lH)-one, is a novel chemical entity with rather unique cardiac inotropic properties Farah and Alousi, 1978). In this report, the action of amrinone on the heart is studied in several models, and in light of these res...

N -(4-Aminobenzyl )-3-morpholone.-4-(4-Nltrobenzyl)-3morpholone (9.0 g.) in 500 ml. of absolute ethanol was reduced catalytically with palladium-on-charcoal at an initial

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The transformation of 3-bromo-1,6-naphthyridin-2(1H)-ones 8 to thiazolo[4,5-b][1,6]naphthyridin-2(1H)-ones 12 resulted in a 2-9-fold increase in cAMP phosphodiesterase (PDE) III inhibitory potency. Unlike the secondary binding sites on the cAMP PDE III isozyme which interact with the methyl group of milrinone (2) and CI-930 (4), the site which interacts with the 5-substituents of 1,6-naphthyridin-2(1H)-ones and the 8-substituents of thiazolo[4,5-b][1,6]naphthyridin-2(1H)-ones 12 is able to accommodate a diverse group of substituents which have different steric and electronic requirements.

The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridines with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylates has provided access to the corresponding 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The antibacterial activity of these derivatives was studied with the finding that the optimal 1- and 7-position substituents for Gram positive activity are cyclopropyl and 4-(2,6-dimethylpyridinyl), respectively. We find that for the fluorine-substituted derivatives studied, the position of the fluorine on the quinolone nucleus or the number of fluorine atoms does not seem to be important for good Gram positive activity. For 1-cyclopropyl 7-(2,6-dimethyl-4-pyridinyl) derivatives, the 6-fluoro 4a, 8-fluoro 10d, 6,8-difluoro 10b, and 5,6,8-trifluoro 8, all provided equal antibacterial activity against Staphylococcus aureus ATCC 29213. There is also a correlation between the substitution on the 7-(4-pyridinyl) group and the Gram positive activity, particularly for S. aureus, clearly indicating that the 2,6-dimethylpyridinyl group is optimal. The MIC50 value for the most potent agents in this study against S. aureus ATCC 29213 is 0.008 microgram/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 microgram/mL, respectively, against this organism.