Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1984-04-19
1986-06-03
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514252, 514341, 544238, 544239, 544240, 544241, 544317, 544320, 544333, A61K 31505, A61K 31495, C07D23902, C07D40100
Patent
active
045930287
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel 5-heteroaryl-substituted-2-pyridones, useful as cardiotonic agents for the treatment of congestive heart failure, to their preparation and to pharmaceutical compositions comprised thereof.
REPORTED DEVELOPMENTS
Congestive heart failure is a life-threatening condition in which myocardial contractility is depressed so that the heart is unable to adequately pump the blood returning to it. Normal pathologic sequelae include decreased cardiac output, venous pooling, increased venous pressure, edema, increased heart size, increased myocardial wall tension, and eventually cessation of contractility. Digitalis glycosides have long been used to increase myocardial contractility and reverse the detrimental changes seen in congestive heart failure. More recently, dopamine, dobutamine, and amrinone have been used to provide necessary inotropic support for the failing heart.
Other reported inotropic drugs include the 5-pyridyl substituted pyridones, reported by Lesher and Opalka, where cardiotonic activity is exhibited when the substituents in the 3-position of the pyridones are hydrogen, cyano, amino, acetylamino, loweralkylamino, or diloweralkylamino (see U.S. Pat. Nos. 4,004,012, 4,072,746, 4,107,315, 4,137,233); when the 3-position of the pyridone is substituted by diloweralkyl amino methylene malonate (see U.S. Pat. No. 4,199,586); and when the 3-position is acylamino (see U.S. Pat. No. 4,271,168). The most preferred 5-pyridyl-pyridone, "Amrinone", 3-amino-5-(4-pyridyl)-2(1H)-pyridone, is reported to cause a 39 to 98% increase in cardiac contractile force with a duration of action of more than three hours at doses of 1.9 to 10 mg/kg, as reported in U.S. Pat. No. 4,107,315. At 10 mg/kg, however, an increase in heart rate is observed.
Bormann has reported other 3-amino substituted pyridone cardiotonics having various heterocyclic substituents in the 5-position (GB 2070606A; PCT published Appl. No. PCT/CH81/00023).
Lesher and Opalka have reported that 5-(4-pyridyl)-pyridones where the 3-position is halo substituted are useful intermediates for the preparation of compounds having cardiotonic properties. Pyridones wherein the 5-position is substituted by a heteroaryl group other than pyridyl and the 3-position is other than amino have not been reported to have positive inotropic activity or cardiotonic activity.
The present invention relates to a class of novel 5-heteroaryl-3-substituted pyridones which exhibit cardiotonic activity in humans and mammals and which have the advantage of producing relatively small increases in heart rate at doses producing a positive inotropic effect.
SUMMARY OF THE INVENTION
This invention relates to the novel compounds described by the structural Formula I: ##STR1## wherein: R.sub.1 is hydrogen, alkyl, hydroxyalkyl, or phenloweralkyl; in the ring, wherein one or more of the hetero ring hydrogen atoms may be substituted by halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkylamino, dialkylamino, amino, acylamino, cyano or nitro; and, salts thereof.
This invention also relates to methods of preparing the compounds of Formula I, to pharmaceutical compositions for use in increasing cardiac contractility in humans and to the uses of these compunds in the treatment of cardiac failure in humans and other mammals.
DETAILED DESCRIPTION
Certain of the compounds of Formula I may exist in enolic or tautomeric forms, and all of these forms are considered to be included within the scope of this invention.
The compounds of this invention which have particular usefulness as cardiotonic agents are described by the Formulae II to VII. ##STR2## wherein: R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are as described above, and R.sub..alpha., R.sub..beta., R.sub..gamma., R.sub..delta. and R.sub..epsilon. are each independently hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, dialkylamino, alkylamino, amino, acylamino, cyano or nitro.
The more preferred compounds are those disclosed by Formulae II to VII, wherein: hydroxyloweralkyl of C.sub.2 -C
REFERENCES:
patent: 4107315 (1978-08-01), Lesher
patent: 4432979 (1984-02-01), Campbell
Barron Alexis
Daus Donald G.
Nicholson James A.
Savitzky Martin F.
Shen Cecilia
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