99465-08-4Relevant academic research and scientific papers
2(1H)-Quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives
Alabaster,Bell,Campbell,Ellis,Henderson,Roberts,Ruddock,Samuels,Stefaniak
, p. 2048 - 2056 (2007/10/02)
A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolyisis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 μg/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers, and potency was maintained with either mono- or di- alkylpyridinyl substituents. Introduction of a 4- or 7- methyl group into 3 reduced inotropic activity, whereas the 8-isomer proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27 were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 x 10-7 to 5 x 10-4 M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.
Quinolone inotropic agents
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, (2008/06/13)
A series of novel phenyl-substituted 2-(1H)-quinolone compounds have been prepared, including the 3,4-dihydro derivatives thereof, wherein the phenyl ring moiety is a mono-or di-substituted phenyl group attached to the 5-, 6-, 7- or 8-positions of the qui
6-heteroaryl quinolone inotropic agents
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, (2008/06/13)
A series of novel heterocyclic-substituted 2-(1H)-quinolone compounds have been prepared, including the 3,4-dihydro derivatives thereof, wherein the heterocyclic ring moiety is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl group attached by a nitrogen atom of said group to the 5-, 6-, 7- or 8-positions of the quinolone ring. These particular compounds are useful in therapy as highly potent inotropic agents and therefore, are of value in the treatment of various cardiac conditions. Preferred member compounds include 6-(2,4-dimethylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, 6-(2,4-dimethyl-5-nitroimadazol-1-yl)-8-methyl-2-(1H)-quinolone, 8-methyl-6-(tetrazol-1-yl)-2-(1H)-quinolone, 8-methyl-6-(1,2,4-triazol-4-yl)-2-(1H)-quinolone, and 6-(4-cyano-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, respectively. Methods for preparing these compounds from known starting materials are provided.
Quinolone inotropic agents
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, (2008/06/13)
A heterocyclic-substituted 2-quinolone compound of the formula: STR1 or a pharmaceutically-acceptable salt thereof, wherein "Het" is an optionally substituted 5-or 6-membered monocyclid aromatic heterocyclic group attached by a carbon atom to the 5-, 6-, 7- or 8- position of the quinolone nucleus; R, which is attached to the 5-, 6-, 7- or 8- position, is hydrogen, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylthio, C1 -C4 alkylsulphinyl, C1 -C4 alkylsulphonyl, halo, CF3, hydroxy, hydroxymethyl, or cyano; R1 is hydrogen, cyano (C1 -C4 alkoxy)carbonyl, C1 -C4 alkyl, nitro, halo, --NR3 R4 or --CONR3 R4 where each of R3 and R4 is hydrogen or C1 -C4 alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic group optionally containing a further heteroatom or group selected from O, S and N--R5 where R5 is hydrogen or C 1 -C4 alkyl; R2 is hydrogen, C1 -C4 alkyl, or 2-hydroxyethyl; Y is hydrogen or C1 -C4 alkyl; and the dotted line between the 3- and 4- positions represents an optional bond. The compounds are inotropic agents useful as cardiac stimulants in the treatment of congestive heart failure.
