Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1987-07-21
1989-09-19
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
540493, 540495, 540500, 540504, 544 61, 544 62, 544114, 544230, 544284, 544238, 544354, 544231, 548305, 564221, C07D40310, A61K 3150, A61K 31505, A61K 3155
Patent
active
048683000
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention relates to substituted benzodiazinones useful as cardiotonic agents for the treatment of congestive heart failure. This invention also relates to methods for increasing cardiac contractility using said compounds, and pharmaceutical compositions including 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 seen 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-phenylthiazole 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, filed Aug. 23, 1982, now abandoned, and cardiotonic dizaheterocyclic-5-substituted pyridyl compounds are disclosed in U.S. Pat. No. 4,432,979 and U.S. Pat. Nos. 4,514,400 and 4,539,321, all of which are assigned to the same assignee as the present application.
Cardiotonic 4,5-dihydro-5-[4-(H-imidazol-1-yl)phenyl]-3(2)-pyridazinones are disclosed in Bristol et al., J. Med. Chem. 22, 1099 (1984); cardiotonic imidazolyl substituted pyridazinones are disclosed in U.S. Pat. No. 4,521,416, and cardiotonic benzothiazolone substituted pyridazinones are disclosed in published EPO patent application Ser. No. 84108656.4 (Publ. No. 0132817). Cardiotonic compounds including a pyrazole group are disclosed in published EPO patent application Ser. No. 84303456.2 (Publ. No. 0126651) and (U.S. Pat. Nos. 4,526,895 and 4,526,982.
SUMMARY OF THE INVENTION
The present invention relates to a method for increasing cardiac contractility in humans and other mammals comprising the administration of an effective inotropic amount of a heterocyclic substituted benzodiazinone compound.
The preferred method comprises the administration of benzodiazinone compounds substituted by either a pyridazinone or hydroxy pyrazolyl ring.
This invention comprises particularly the administration to a patient of an effective inotropic amount of a benzodiazinone compound within the scope by Formula I: ##STR4## where z is 0 or 1; ##STR5## where a and b are 0, 1 or 2 and a+b=0, 1 or 2; R, R.sup.1, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each independently double bond when a or b=2; bond when R.sub.n is hydrogen and z=1; --(CH.sub.2).sub.d --, where d is 2 to 5; when and a+b=1; and ##STR6## where R.sub.60 is hydrogen, alkyl or may also contain 0-2 additional hetero atoms selected from N, O and S; or a pharmaceutically acceptable salt thereof.
This invention also relates to novel compounds which comprise compounds of Formula I provided that when a+b=0 and z is 1, then at least one of R.sub.n, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is other than hydrogen; and pharmaceutical compositions which comprise compounds of Formula I and which are effective in increasing cardiac contractility in humans.
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
REFERENCES:
patent: 4026891 (1977-05-01), Austel
patent: 4258185 (1981-03-01), Nakao
patent: 4361563 (1982-11-01), Austel
Curran et al., Chem. Abs. 81, 20766 (1974).
Campbell Henry F.
Faith William C.
Kuhla Donald E.
Molino Bruce F.
Studt William L.
Berch Mark L.
Rorer Pharmaceutical Corporation
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