Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1986-07-28
1989-04-04
Warden, Robert J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514253, 5142285, 5142335, 5142352, 544 60, 544 62, 544128, 544363, 546157, 546158, C07D21522
Patent
active
048187550
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel bicyclic heteroaryl substituted thiazoles useful as cardiotonic agents for the treatment of congestive heart failure. This invention also relates to methods for increasing cardiac contractility using said compounds, pharmaceutical compositions and methods for the preparation of said compounds.
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.
REPORTED DEVELOPMENTS
Drugs which increase the tone of the heart muscle are described as having positive inotropic activity and are characterized as cardiotonic agents. Digitalis glycosides have long been used to increase myocardial contractility and reverse the detrimental changes see in congestive heart failure. More recently, dopamine, dobutamine, and amrinone have been used to provide necessary inotropic support for the failing heart.
Inotropic drugs include the 5-pyridyl substituted pyridones disclosed in U.S. Pat. Nos.: 4,004,012; 4,072,746; 4,107,315; 4,137,233; 4,199,586; 4,271,168; and 4,107,315; in GB 2070606A; and in PCT published Appl. No. PCT/CH81/00023. Other cardiotonic drugs include the diazacyclic substituted carbostyril compounds disclosed in U.S. Pat. Nos. 4,414,390 and 4,415,572 and the 5-phenyl-thiazole compounds disclosed in U.S. Pat. No. 4,418,070.
Cardiotonic bicyclic heteroaryl-5-substituted pyridyl compounds are disclosed in U.S. Ser. No. 410,646, and cardiotonic diazaheterocyclic-5-substituted pyridyl compounds are disclosed in U.S. Pat. No. 4,432,979 and U.S. Ser. Nos. 314,692 and 493,336, all of which are assigned to the same assignee as the present application.
SUMMARY OF THE INVENTION
The present invention relates to a class of bicyclic N-heteroaryl ring substituted thiazoles which exhibit cardiotonic activity in humans and mammals.
The more preferred compounds of the present invention include thiazoles substituted by a bicyclic N-heteroaryl ring and where the total number of carbon atoms in the bicyclic ring is no greater than about ten.
This invention relates particularly to the bicyclic lactam compounds within the scope by Formula I: ##STR1## wherein m=1 or 2; --(CH.sub.2).sub.d --, where d is 2 to 5, where n is 0; double bond in an imidazo[2.1-b]thiazole ring system; alkylmercapto, alkylsulfinyl or alkylsulfonyl; or acetamido; carbon-carbon double bond; with the atoms to which they are attached form an imidazo[2.1-b]thiazole ring system including two additional carbon atoms and either one sulfur atom or one additional nitrogen atom; aralkylamino, guanidino, amidino, hydroxyl, hydroxyalkyl, hydroxyalkylamino, aminoalkylamino, di-alkylaminoalkylamino, aminoalkyl, mono- or di-alkylaminoalkyl, ##STR2## or together with either R.sub.5 or A form a carbon-heteroatom double bond in said imidazo[2.1-b]thiazole ring system; represents the carbon-carbon single bond to the position on the fused bicyclic ring ortho to the Y and Z groups, provided that one of R.sub.7 or R.sub.8 is other than hydrogen or lower alkyl; ##STR3## or a pharmaceutically acceptable salt thereof.
This invention also relates to methods for preparing the compounds of the present invention, to the use of such compounds in pharmaceutical compositions which are effective in increasing cardiac contractility in humans and to the uses of such compositions in the treatment of cardiac failure in humans and other mammals.
DETAILED DESCRIPTION
Certain of the compounds encompassed within the present invention, and particularly, 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 Formula
Campbell Henry F.
Kuhla Donald E.
Molino Bruce F.
Studt William L.
Barron Alexis
Benson Robert
Nicholson James A.
Rorer Pharmaceutical Corporaton
Savitzky Martin F.
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