5 (BICYCLIC NITROGEN-HETEROARYL)PYRID-2-ONES AND THEIR USE FOR INCREASING CARDIAC CONTRACTILLITY

Abstract: Cardiotonic 5-bicyclic-heteroarly-substituted-2-pyridone compounds, pharmaceutical compositions, and a method for the treatment of congestive heart failure.

Description: 5 (BICYCLIC PYrai 2-ONES AND ' THEIR USE FOR INCREASING CARDIAC CONTRACTTTiT.T'TY Field of the Invention This invention relates to novel 5-bicyσlic- 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 glyσosides 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. OMPI StoS 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, loweral ylamino, or dilowe alkylamino (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(lH)-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. Patent No. 4,107,315. At 10 mg/kg, however, an increase in heart rate is observed. 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. Bormann has reported other 3-amino substituted pyridone cardiotonics having various monoσyσlic heterocyclic substituents in the 5-position (GB 2070606A; PCT published Appl. No. PCT/CH81/00023) . Pyridones wherein the 5-position is substituted by a bicyclic heteroaryl group have not been reported. OMH ?to The present invention relates to a class of novel 5-bicyclic-heteroaryl-substituted-2-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: wherein: Rl is hydrogen, alkyl, hydroxyalkyl, or phenloweralkyl; R3 is hydrogen, halo, alkyl, haloalkyl, cyano, amino, guanidino, thioureido, ureido, carboxyl, alkoxy, hydroxy, hydroxyalkyl, carba oyl, acylamino, alkylamino, dialkylamino or nitro; R4 and Rg are each independently hydrogen or alkyl; R5 is a bicyclic heteroaryl group comprising a heteroaryl ring fused to an ortho-phenylene group, said heteroaryl ring including one or two nitrogen atoms in said ring; OMPI * and wherein: one or more of the heteroaryl group hydrogen atoms may be substituted by halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkylamino, dialkylamino, amino, alkoxy, ar lkoxy, acylamino, cyano or nitro; and, the acid addition salts thereof. This invention also relates to methods of pre¬ paring 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 treat¬ ment 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 parti¬ cular usefulness as cardiotonic agents are described by the Formulae II to XI. OMPI swm (V) (VI) (VII) OMPI ^&/?NATIO ( X) ( XI ) wherein: R* j _, R3, R4 and Rg are as described above, and R and R' are each independently hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, dialkylamino, alk lamino, amino, acylamino, alkoxy, aralkoxy, cyano or nitro. The preferred compounds are those defined by Formulae II to XI wherein the 6-position or the 7-position of the bicyclic heteroaryl group is R* substituted by the aforesaid substituents other than hydrogen. The more preferred compounds are those defined by Formulae II to XI, wherein: Rl is hydrogen, loweralkyl of C1-C3 carbon atoms or hydrox loweralkyl of C2-C3 carbon atoms; R3 is hydrogen, halo or haloloweralkyl of C2-C3 carbon atoms; R4 is hydrogen or loweralkyl of C -C3 carbon atoms; Rg is hydrogen or loweralkyl of C1-C3 carbon atoms; ^NATIO;S R and R' are each independently hydrogen, lower¬ alkyl, amino, mono- or di-lower alkylamino, hydroxy, lower alkoxy, benzyloxy, cyano, halolowe lkyl, halo or nitro. Most preferred are those compounds disclosed by Formulae II to XI, wherein: R^ is methyl, ethyl or hydroxyethyl; R3 is hydrogen, fluoro, chloro, bromo or trifluoromethyl; R4 is hydrogen; Rg is hydrogen, methyl or ethyl; and R and R* are hydrogen, methyl, ethyl, methoxy, benzyloxy, cyano, nitro, amino, alkylamino, or dialkyl- a ino. A special embodiment of the preferred compounds includes those compounds of Formula I, wherein: R is methyl, ethyl or hydroxyethyl; 3 is fluoro, chloro, bromo or trifluoromethyl; R 4 is hydrogen; R5 is 4-guinolinyl, 2-quinolinyl, 1-isoquino- linyl, or 3-isoquinolinyl; and Rg is methyl or ethyl. A second special embodiment of the preferred compounds includes those compounds of Formulae II-XI wherein the R* substituent in the six-position or the seven-position of the heteroaryl group is hydrogen, trifluoromethyl, nitro, halo, or cyano; provided that if both positions are substituted by R', then at least one of the R' substituents is other than hydrogen. A third special embodiment of the preferred com¬ pounds includes those compounds of Formulae II-XI wherein R' in the six-position or the seven-position of the hetero¬ aryl group is hydrogen, hydroxy, mono- or di-lower alkyl- OMPI amino, amino, benzyloxy, lower alkoxy, acetyl amino, hydroxy lower alkyl or lower alkyl; provided that if both positions are R 1 substituted, then at least one of the R* substituents is other than hydrogen. Other embodiments include those compounds wherein: R_, R3 and R4 are all hydrogen; R_ , R4 and Rg are all hydrogen; R3, R4 and Rg are all hydrogen; R ] _ and R4 are both hydrogen; R3 and R4 are both hydrogen; R4 and Rg are both lower alkyl; and R4 and Rg are both hydrogen. As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Alkyl" means a saturated aliphatic hydrocarbon which may be either straight- or branched-chained containing from about one to about 5 carbon atoms. "Lower alkyl" means an alkyl group as above, having 1 to about 3 carbon atoms. The term "halo" includes all four halogens; namely, fluorine, chlorine, bromine and iodine. "Haloalkyl" refers to a loweralkyl hydrocarbon group which may be substituted by one or more halo groups, such as trifluoromethyl, trifluorethyl, chloromethyl, etc. "Phenloweralkyl" means a lower alkyl group in which one or more hydrogens is substituted by a phenyl group. Preferred groups are benzyl and phenethyl, etc. "Acylamino" means an amino group substituted by an acyl radical of a lower alkanoic acid such as acetyl, propioπyl, butyryl, valeryl or stearoyl. OMPI $V~. wσo "Hydroxy alkyl" means an alkyl group substituted by a hydroxy group. Preferred hydroxy loweralkyl groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxyproρyl, or 3-hydroxypropyl. The compounds of this invention may be useful both in the free base form and in the form of salts, and both forms are within the scope of the invention. Acid addition salts can be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitiated by side effects ascribable to the anions. In practicing the invention it is convenient to form the free base form; however, appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfoniσ acid, cyclohexylsulfamic acid, quinic acid, and the like, giving the hydrochloride, sulfate, phosphate, sulfa ate, acetate, citrate, lactate, tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively. OMPI $ 1PO The acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution. When a base is used for salt formation, it is preferred to form the same from a sodium or potassium base such as sodium hydroxide or potassium hydroxide. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. The compounds of this invention may be prepared by one of the following synthetic routes. The pyridone ring may be formed in essentially two steps by first reacting a bicyclic heteroarylmethyl compound with an appropriate activated methylidene reagent such as a Vilsmeier reagent and thereby result in the formation of the iminium salt of the <*-bicyclic- heteroaryl, -enamino ketone or aldehyde. If desired, the iminium salt may be hydrolyzed to the 3-enamino ketone or aldehyde for use in subsequent steps. An exemplary reaction is detailed in Scheme I. OMPI Scheme I The substitution pattern in the final product is prede¬ termined in this reaction sequence by the choice of activated methylidene reagent which ensures symmetry in the R4 and Rg position of the final product. The acti¬ vated methylidene reagent provides the carbon units which, in this reaction sequence, form the C-R4 and C-Rg groups of the pyridone ring. By choosing dimethyl- acetamide (R'=Me), for example, both R4 and Rg are methyl in the final product. Treatment of the <*, - enamino carbonyl compound or the iminum salt thereof with c^-cyano acetamide in the presence of base results in the 3-cyano pyridone X, which may be hydrolyzed to the 3-carbamoyl compound XI or the 3-carboxylic acid XII. (Scheme II) XI XII Scheme II Assymetry in the R4 and Rg positions of the final product may be introduced by using a bicyclic heteroarylketone as the starting material. The treatment of the o£,£-enamino ketone with an appropriate nucleophile, such in the presence of base, provides that R* will occupy the R4 position of the pyridone. (Scheme III) ) NCCH 2 COMK 2 base Scheme III The 3-halo compound may be prepared by way of the 3-amido or the 3-H compound, the former compound being prepared by hydrolyzing the cyano compound and the latter compound being prepared by deσarboxylation of the carboxylic acid (Scheme IV) . Scheme IV The 3-trifluororaethyl compound XIV may be prepared by treating the 3-carboxy compound XIII with diethylamino sulfur trifluoride ( Scheme V) . ' jTEX^ OMPI ^5i?NATlθ XIII XIV Scheme V The following are illustrative examples of the preparation of the compounds of this invention and should not be construed as limitations thereof. OMPI EXAMPLE I THE PREPARATION OF 3-CARBAMOYL-5- (4-QϋINOLINYL)-2(lH) PYRIDONE Step 1 N-[3-dimethylamino-2-(4-quinolinyl)-propenylidenel N-methylmethaneiminium chloride hydrochloride A solution of 326 g of phosgene in 700 ml CH 2 C1 2 is cooled in an ice bath and added dropwise to DMF (767.6 g) while stirring at a temperature below 0 β C. A solution of 4-methylquinoline (100.2 g) in CH 2 C1 2 (100 ml) is added dropwise to the DMF-phosgene solution while maintaining the temperature below 0 β C. The reaction mixture is heated to reflux and about 350 ml of CH C1 2 is distilled off while maintaining the reaction mixture temperature at about 60°C for a period of 2-1/2 hours. The reaction mixture is cooled, stirred overnight, filtered and the solid washed with DMF. The solid is taken up in a mixture of diethyl ether, CH 2 C1 2 and DMF, stirred and filtered. The solid is again taken up in ethyl acetate and acetonitrile, stirred, filtered and air dried to give the desired iminium hydrochloride as a yellow solid, M.P. 169-170°C dec. Step 2 3-carbamoyl-5-(4-quinolinyl)-2(lH) pyridone A 50% mineral oil dispersion of sodium hydride (12.0 g) is added to a solution of finely ground malonamide (11.2 g) in DMF (200 ml) and the mixture stirred at RT for 20 minutes. The methyl methaneiniminium chloride hydrochloride from the preceding step (32.6 g) is added as a solid to the reaction mixture. After the addition of the hydrochloride, the reaction mixture is heated and OMPI • ATI stirred for 3 hours at a temperature of about 100°C. The reaction mixture is cooled, filtered and the resulting solid washed with DMF and ether. The filtrate is concentrated under vacuum and the residual solid and the filtered solid are combined, dissolved in water and stirred overnight. The aqueous mixture is filtered through a pad of celite and the filtrate extracted with ether. The aqueous layer is made acidic by the dropwise addition of glacial acetic acid. The resulting precipitate is filtered, washed with H 2 0 and air dried. The solid is crystallized from DMF to give after filtering and vacuum drying at 90°C overnight the desired pyridone as a tan solid, M.P. > 250°C. EXAMPLE II THE PREPARATION OF 3-BROMO- 5-(4-QϋINOLINYL)-2(lK) PYRIDONE Step 1 3-Carboxy-5-(4-quinolinyl)-2(lH) pyridone 38.1 g of 3-carbamyl-5-(4-quinolinyl)-2(lH) pyridone are suspended in 150 ml of H 2 0. 150 ml of concentrated sulfuric acid are added to the stirred suspension. The mixture is refluxed for 4 hours, cooled and stirred overnight. The reaction mixture is diluted with H 2 0 to about 1.5 1, and while stirring the pH adjusted to about 5 by the addition of solid a 2 Cθ3« The resulting solid is filtered, washed with H 2 0 and air dried. The solid is taken up in boiling DMF, treated with charcoal and hot filtered. The filtrate is concentrated to about 1 1 and 800 ml of hot H 2 0 added. The resulting precipitate is filtered from the cooled mixture and the solid washed with H 2 0 and vacuum dried overnight to give the desired carboxylic acid as a yellow solid, M.P. > 250°C. OMPI W1PO Step 2 5-(4-Quinolinyl)-2(lH) pyridone A mixture of 3-carboxy-5-(4-quinolinyl)-2(lH) pyridone (39.4 g) and quinoline (250 ml) is refluxed under nitrogen for 24 hours, allowed to cool and stirred for a week. The reaction mixture is poured into about 1.5 1 of ether and the resulting precipitate filtered, washed well with ether and air dried. The solid is crystallized from isopropyl alcohol after treatment with charcoal to give after filtering and vacuum drying overnight the desired product as a tan solid, M.P. 217-218°C. Step 3 3-Bromo-5-(4-quinolinyl)-2(lH) pyridone A solution of bromine (9.5 g) in glacial acetic acid (20 ml) is added dropwise to a stirred solution of 5-(4-quinolinyl)-2(lH) pyridone (11.1 g) in glacial acetic acid (300' ml) at RT. The reaction mixture is stirred at 40-45°C for about 1 hour, poured into ice-H 2 0 and the pH adjusted to about 6 by the addition of 50% aqueous sodium hydroxide. The mixture is allowed to stand overnight. Sodium bisulfite (about 5 g) is added to the mixture which is stirred a few minutes. The resultant solid is filtered and washed well with H 2 0. The solid is crystallized from isopropyl alcohol and after filtering and vacuum drying overnight gives the bromo pyridine compound as a pinkish purple solid, M.P. 227.5-229 β C. OMPI sA.,. WIPO , EXAMPLE III THE PREPARATION OF 3-BROMO-1- METHYL-5-(4-QUINOLINYL)-2-PYRIDONE A 50% mineral oil suspension of NaH (1.7 g) is added to a solution of 3-bromo-5-(4-quinolinyl)-2(lH) pyridone (7.0 g) in dry DMF (100 ml) and the mixture is stirred for 1 hour. Methyl iodide (4.9 g) is added to the stirred mixture via pipette. The reaction mixture is stirred for 1 hour, filtered and the filtrate concentrated under vacuum. The solid and the concentrated filtrate are suspended in H 0 and ethyl acetate, filtered, washed with ethyl acetate and H 2 0, and air dried. The solids are combined and crystallized from DMF to give the desired methyl pyridone as a tan solid, M.P. > 250°C. EXAMPLE IV THE PREPARATION OF 3-BROMO-l- ETHYL-5-(4-QϋINOLINYL)-2-PYRIDONE A 50% mineral oil suspension of NaH (1.7 g) is added to a solution of 3-bromo-5-(4-quinolinyl)-2(1H) pyridone in dry DMF (100 ml) and the mixture stirred for 1 hour. Ethyl bromide (3.8 g) is added to the reaction mixture which is stirred at RT overnight. The reaction is concentrated under vacuum and the residue partitioned between H 2 0 and ether. The insoluble solid is filtered and washed with ether and H 2 0. The solid is crystallized from ethyl acetate to give after filtering and vacuum drying the desired ethyl pyridone, M.P. > 250°C. The following list of compounds may be prepared accordin to the above-described reaction sequences and using analogous reaction conditions and starting materials, which are either commercially available or prepared by methods known to those skilled in the art. TABLE A 6-methyl-5-(2-quinolinyl)-2(1H)-pyridone 6-methyl-5-[6-methyl-(2-quinolinyl) ]-2(1H)-pyridone 6-methyl-5-[6-methoxy-(2-quinolinyl) 3-2(1H)-pyridone 6-ethyl-5-(4-quinolinyl)-2(1H)-pyridone 6-ethyl-5-[6-methyl-(4-quinolinyl) ]-2(1H)-pyridone 6-ethyl-5-[6-methoxy-(4-quinolinyl) ]-2(1H)-pyridone 3-bromo-6-methyl-5-(2-quinolinyl)-2(1H)-pyridone 3-bromo-[6-methyl-(2-quinolinyl) ]-2(1H)-pyridone 3-chloro-[6-methoxy-(2-quinolinyl) ]-2(1H)-pyridone 3-chloro-6-ethyl-5-(4-quinolinyl)-2(lH)-pyridone 3-bromo-[6-methyl-(4-quinolinyl) ]-2(1H)-pyridone 3-chloro-6-ethyl-5-(2-quinolinyl) -2(1H)-pyridone 6-methyl-3-trifluoromethyl-5-(2-quinoliπyl)-2(lH)- pyridone 6-methyl-3-trifluoromethyl-5-[6-methyl-(2-quinolinyl) ]- 2(1H) -pyridone 6-ethyl-3-trifluoromethyl-5-[6-methoxy-(2-quinolinyl) ]- 2(1H)-pyridone 6-ethyl-3-trifluoromethyl-5-(4-quinolinyl)-2(lH)- pyridone 6-ethyl-3-trifluoromethyl-5-[6-methyl-(4-quinolinyl) ]- 2(1H)-pyridone 6-ethyl-3-trifluoromethyl-5-[6-methoxy-(4-quinolinyl) J- 2(1H)-pyridone l,6-dimethyl-5-(2-quinolinyl ) -2-pyridone OMPI ^-rιθ TABLE A l-ethyl-6-methyl-5-[6-methyl-(2-quinolinyl) J-2-pyridone 1,6-dimethyl-5-[δ-methoxy-1-methyl-(2-quinoliny ) ]-2- pyridone l,6-diethyl-5-(4-quinolinyl)-2-pyridone 6-ethyl-l-methyl-5-[6-methyl-(4-quinolinyl) ]-2-pyridone 1,6-diethyl-5-(6-methoxy-(4-quinolinyl) ]-2-pyridone 3-bromo-l,6-dimethyl-5-(2-quinolinyl)-2-pyridone 3-bromo-l-ethyl-6-methyl-5-[6-methyl-(2-quinolinyl) 3-2- pyridone 3-chloro-l,6-dimethyl-5-[6-methoxy-(2-quinolinyl) ]-2- pyridone 3-chloro-l,6-diethyl-5-(4-quinolinyl)-2-pyridone 3-bromo-6-ethyl-l-methyl-5-[6-methyl-(4-quinolinyl) 3-2- pyridone 3-chloro-l,6-diethyl-5-[6-methoxy-(4-quinolinyl) ]-2- pyridone 1,6-dimethyl-3-trifluoromethyl-5-(2-quinolinyl)-2- pyridone l-ethyl-6-methyl-3-trifluormethyl-5-[6-methyl-(2- quinolinyl) 3-2-pyridone 1,6-dimethyl-3-trifluoromethyl-5-[6-methoxy-(2-quino- linyl) J-2-pyridone l,6-diethyl-3-trifluoromethyl-5-(4-quinolinyl)-2- pyridone 6-ethyl-l-methyl-3-trifluoromethyl-5-[6-methyl-(4-quino- linyl ) ] -2-pyridone l , 6-diethyl-3-trif luoromethyl-5- [ 6-methoxy- ( 4-quino- linyl) J -2-pyridone 4 , 6-dimethyl-5-( 2-quinolinyl) -2 ( lH) -pyridone 4-ethyl-6-methyl-5- [ 6 -methyl- ( 2-quinolinyl) 3 -2 ( lH) - pyridone , 6-dimethyl-5-[ 6-methoxy- ( 2-quinolinyl) 1 -2 ( lH) -pyridone , 6-diethyl-5- ( 4-quinolinyl ) -2 ( lH) -pyridone OMPI TABLE A 6-ethyl-4-methyl-5-[6-methyl-(4-quinolinyl) -2(lH)- pyridone 4,6-diethγl-5-[6-methoxγ-(4-quinolinyl) -2(lH)-pyridone 3-bromo-4,6-dimethyl-5-(2-quinolinyl)-2(1H)-pyridone 3-bromo-4-ethyl-6-methyl-5-C6-methyl-(2-quinolinyl) 3- 2(1H)-pyridone 3-chloro-4,6-dimethyl-5-[6-methoxy-(2-quinolinyl) 3- 2(lH)-pyridone 3-chloro-4,6-diethyl-5-(4-quinoliny )-2(lH)-pyridone 3-bromo-6-ethyl-4-methyl-5-C6-methyl-(4-quinolinyl) 1-2(1H) pyridone 3-chloro-4,6-diethyl-5-C6-methoxy-(4-quinolinyl) Ϊ-2(1H)- pyridone 4,6-dimethyl-3-trifluoromethyl-5-(2-quinolinyl)-2(lH)- pyridone 4-ethγl-6-methyl-3-trifluoromethyl-5-[6-methyl-(2-quino- linyl) 3-2(lH)-pyridone 4,6-dimethyl-3-tri luoromethyl-5-[6-methoxy-(2-quino- linyl) 3-2(lH)-pyridone 4,6-diethyl-3-trifluoromethyl-5-(4-quinolinyl)-2(lH)- pyridone 6-ethyl-4-methyl-3-trifluoromethyl-5-[6-methyl-C4-quino- linyl) 3-2(1H)-pyridone 4,6-diethyl-3-trifluoromethyl-5-[6-methoxy-(4-quino- linyl) 1-2(lH)-pyridone 1,4,6-trimethyl-5-(2-quinolinyl)-2-pyridone l,4-diethyl-6-methyl-5-[6-methyl-(2-quinolinyl) 3-2- pyridone 1,4,6-trimethyl-5-16-methoxy-(2-quinolinyl) J-2-pyridone 1,4,6-triethyl-5-(4-quinolinyl)-2-pyridone l,4-dimethyl-6-ethyl-5-[6-methyl-(4-quinolinyl)3-2- pyridone OMPI TABLE A 1,4,6-triethy1-5-[6-methoxy-(4-quinolinyl) 1-2-py idone 3-bromo-l,4,6-trimethyl-5-(2-quinolinyl)-2-pyridone 3-bromo-l,4-diethyl-6-methyl-5-[6-methyl-(2-quinolinyl) 1 ■ 2-pyridone 3-chloro-l,4,6-trimethyl-5-[6-methoxy-(2-quinolinyl) 1- 2-pyridone 3-σhloro-l,4,6-triethyl-5-(4-quinolinyl)-2-py idone 3-bromo-l,4-dimethyl-6-ethyl-5-[6-methyl-(4-quinolinyl) ] ■ 2-pyridone 3-chloro-l,4,6-triethyl-5-[6-methoxy-(4-quinolinyl) 3-2- pyridone 3-trifluoromethyl-1,4,6-trimethyl-5-(2-quinolinyl)-2- pyridone l,4-diethyl-6-methyl-3-trifluoromethyl-5-[6-methyl-(2- quinolinyl) ]-2-pyridone 3-trifluoromethyl-1,4,6-trimethyl-5-[6-methoxy-(2-quino- linyl) 3-2-pyridone 1,4,6-triethyl-3-trifluoromethyl-5-(4-quinolinγl)-2- pyridone l,4-diethyl-6-ethyl-3-trifluorometh l-5-[6-methyl-(4- quinolinyl) 3-2-pyridone 1,4,6-triethy1-3-trifluoromethyl-5-16-methoxy-(4-quino- linyl) 3-2-pyridone TABLE B -(2-quinolinyl)-2(lH)-pyridone -(4-quinolinyl)-2(IH)-pyridone -(1-isoquinolinyl)-2(lH)-pyridone -(3-isoquinolinyl)-2(IH)-pyridone -(1-phthalazinyl)-2(lH)-pyridone -(2-quinoxalinyl)-2(IH)-pyridone -(2-quinazolinyl)-2(IH)-pyridone -(4-quinazolinyl)-2(lH)-pyridone -(3-cinnolinyl)-2(lH)-pyridone -(4-cinnolinyl)-2(lH)-pyridone -bromo-l-methyl-5-(2-quinolinyl)-2-py idone -bromo-l-ethyl-5-( -quinolinyl)-2-pyridone -bromo-l-methyl-5-(1-isoquinolinyl)-2-pyridone -bromo-l-ethyl-5-{3-isoquinolinyl)-2-pyr done -bromo-l-methyl-5-(l-phthalazinyl)-2-pyridone -bromo-l-ethyl-5-(2-quinoxalinyl)-2-pyridone -bromo-l-methyl-5-(2-quinazolinyl)-2-pyridone -bromo-l-ethyl-5-(4-quinazolinyl)-2-py idone -bromo-l-methyl-5-(3-cinnolinyl)-2-pyridone -bromo-l-ethyl-5-(4-cinnolinyl)-2-pyridone -bromo-5-(2-quinolinyl)-2(lH)-pyridone -bromo-5-(4-quinolinyl)-2(lH)-pyridone -bromo-5-(l-isoquinolinyl)-2(IH)-pyridone -bromo-5-(3-isoquinolinyl)-2(lH)-pyridone -bromo-5-(1-phthalazinyl)-2(lH)-pyridone -bromo-5-(2-quinoxalinyl)-2(lH)-pyridone -bromo-5-(2-quinazolinyl)-2(lH)-pyridone -bromo-5-(4-quinazolinyl)-2(lH)-pyridone -bromo-5-(3-cinnolinyl)-2(IH)-pyridone -bromo-5-(4-cinnolinyl)-2(lH)-pyridone -trifluoromethyl-5-<2-quinolinyl)-2(lH)-pyridone -trifluoromethyl-5-(4-quinolinyl)-2(IH)-pyridone -trifluoromethyl-5- ( l-isoquinolinyl ) -2(lH)-pyridone TABLE B 3-trifluoromethyl-5-(3-isoquinolinyl)-2(lH)-pyridone 3-trifluoromethyl-5-(1-phthalazinyl)-2(IH)-pyridone 3-trifluoromethyl-5-(2-quinoxalinyl)-2(lH)-pyridone 3-trifluoromethyl-5-(2-quinazolinyl)-2(IH)-pyridone 3-trifluoromethyl-5-(4-quinazolinyl)-2(IH)-pyridone 3-trifluoromethyl-5-(3-cinnolinyl)-2(IH)-pyridone 3-tri luoromethyl-5-(4-cinnolinyl)-2(IH)-pyridone -amino-5-(2-quinolinyl)-2(IH)-pyridone -amino-5-(4-quinolinyl)-2(IH)-pyridone -amino-5-(1-isoquinolinyl)-2(IH)-pyridone -amino-5-(3-isoquinolinyl)-2(lH)-pyridone -aminό-5-(l-phthalazinyl)-2(IH)-pyridone -amino-5-(2-quinoxalinyl)-2(IH)-pyridone -amino-5-(2-quinazolinyl)-2(IH)-pyridone -amino-5-(4-quinazolinyl)-2(IH)-pyridone -amino-5-(3-cinnolinyl)-2(lH)-pyridone -amino-5-( -cinnolinyl)-2(lH)-pyridone -amino-l-methyl-5-(2-quinolinyl)-2-pyridone -amino-l-ethyl-5-(4-quinolinyl)-2-pyridone -amino-l-methyl-5-(1-isoquinolinyl)-2-pyridone -amino-l-ethyl-5-(3-isoquinolinyl)-2-pyridone -amino-l-methyl-5-(l-phthalazinyl)-2-pyridone -amino-l-ethyl-5-(2-quinoxalinyl)-2-pyridone -amino-l-methyl-5-(2-quinazolinyl)-2-pyridone -amino-l-ethyl-5-(4-quinazolinyl)-2-pyridone -amino-l-methyl-5-(3-cinnolinyl)-2-pyridone -amino-l-ethyl-5-(4-cinnolinyl)-2-pyridone -carbamoyl-5-(2-quinolinyl)-2(IH)-pyridone -carbamoyl-5-(4-quinolinyl)-2(IH)-pyridone -carbamoyl-5-(l-isoquinolinyl)-2(IH)-pyridone -carbamoyl-5-(3-isoquinolinyl)-2(lH)-pyridone -carbamoyl-5-(1-phthalazinyl)-2(lH)-pyridone -carbamoy1-5-(2-quinoxalinyl)-2(lH)-pyridone TABLE B -carbamoyl-5-(2-quinazolinyl)-2(lH)-pyridone -carbamoyl-5-(4-quinazolinyl)-2{IH)-pyridone -carbamoyl-5-(3-cinnolinyl)-2(lH)-pyridone -carbamoyl-5-(4-σinnolinyl)-2(IH)-pyridone -carboxyl-5-(2-quinolinyl)-2(IH)-pyridone -carboxyl-5-(4-quinolinyl)-2(IH)-pyridone -carboxyl-5-(1-isoquinolinyl)-2CIH)-pyridone -carboxyl-5-(3-isoquinolinyl)-2(lH)-pyridone -carboxyl-5-(1-phthalazinyl)-2(IH)-pyridone -carboxyl-5-(2-quinoxalinyl)-2(lH)-pyridone -carboxyl-5-(2-quinazolinyl)-2(IH)-pyridone -carboxyl-5-(4-quinazolinyl)-2(lH)-pyridone -carboxyl-5-(3-cinnolinyl)-2(IH)-pyridone -carboxyl-5-(4-cinnolinyl)-2(lH)-pyridone -cyano-5-(2-quinolinyl)-2(IH)-pyridone -cyano-5-(4-quinolinyl)-2(IH)-pyridone -cyano-5-(l-isoquinolinyl)-2(lH)-pyridone -cyano-5-(3-isoquinolinyl)-2(lH)-pyridone -cyano-5-(1-phthalazinyl)-2(lH)-pyridone -σyano-5-(2-quinoxalinyl)-2(lH)-pyridone -cyano-5-(2-quinazolinyl)-2(IH)-pyridone -cyano-5-(4-quinazolinyl)-2(IH)-pyridone -cyano-5-(3-cinnolinyl)-2(lH)-pyridone -cyano-5-(4-cinnolinyl)-2(lH)-pyridone -cyano-l-methyl-5-(2-quinolinyl)-2-pyridone -cyano-l-ethyl-5-(4-quinolinyl)-2-pyridone -cyano-l-methyl-5-(l-isoquinolinyl)-2-pyridone -cyano-l-ethyl-5-(3-isoquinolinyl)-2-pyridone -cyano-l-raethyl-5-(l-phthalazinyl)-2-pyridone -cyano-l-ethyl-5-(2-quinoxalinyl)-2-pyridone -cyano-l-methyl-5-(2-quinazolinyl)-2-pyridone -cyano-l-ethyl-5-(4-quinazolinyl)-2-pyridone -cyano-l-methyl-5-(3-cinnolinyl)-2-pyridone -cyano-l-ethyl-5- ( 4-cinnolinyl)-2-pyridone The compounds of Formula I possess positive inotropic activity and are useful as cardiotonic agents in the treatment of humans and other mammal for cardiac disorders including congestive heart failure. The effectiveness of the compounds of this invention as inotropic agents may be determined by the following pharmacologic tests which evaluate the change in cardiac contractile force upon exposure to a dose of said compounds. The anesthetized dog procedure is a standard test procedure; the inotropic results of this procedure generally correlate with the inotropic activity found in human patient ' s. Anesthetized Dog Procedure Male mongrel dogs are anesthetized with pentobarbital (35 mg/kg i.v.) and intubated. Femoral artery and veins are cannulated for measurement of blood pressure and injection of compounds, respectively. A catheter connected to a Statham transducer is inserted into the left ventricle via the right carotid artery for measurement of left ventricular pressure, left ventricular end diastatic pressure and dP/dt. Lead II ECG and heart rate are also monitored. All parameters are measured on a Beckman Dynagraph. The results of the anesthetized dog test show that the compounds of this invention exhibit positive inotropic activity and show dose related increases in contractile force with relatively small increases in heart rate. A second test procedure which has been found to be an efficient means for ascertaining the inotropic activity of the compounds of this invention is described below. OMPI Guinea Pig Atria Inotropic Screening at Low Calcium Concentrations Guinea pigs are stunned by a sudden blow to the head; their chests are opened and hearts excised and placed in Kreb's medium (concentrations, mM: NaCl, 118.39; KC1, 4.70; MgS0 4 , 1.18; KH 2 P0 4 , 1.18; NaHC0 3 , 25.00; glucose, 11.66; and CaCl 2 , 1.25) gassed with a mixture of 95% 0 2 - 5% C0 2 . Left atria are removed and inserted into warmed (33°C) double jacketed tissue chambers containing oxygenated Kreb's medium (as above). The upper end of each tissue is attached to a Statham Universal Transducing Cell via a Statham Microscale Accessory. Resting tension on each tissue is set at 1 g and adjusted periodically. Massive field stimulation is acheived via a pair of platinum or silver electrodes placed on opposite sides of the tissue. Electrodes are made from 20-gauge silver wire wound into a tight coil approximately 12-14 mm in diameter. Electrodes are connected to a Grass stimulator via a Grass constant current unit. Tissues are driven at 90 pulses per minute with a 5 msec duration at current levels 20% greater than threshold for continuous beat. Cumulative concentrations of test drugs are added to the tissue bath at intervals sufficient to allow developed tension to peak at a new level. The increase in developed tension in each tissue for each compound concentration is measured, and the results are averaged and used to construct cumulative concentration-response curves. Slopes for these regressions are calculated via the method of Finney (1971) and compared using Student's t-test. The compounds of this invention can be normally administered orally or parenterally, in the treatment of cardiac disorders such as heart failure in humans or other mammals. The compounds of this invention, preferably in the form of a salt, may be formulated for administra¬ tion in any convenient way, and the invention includes within its scope pharmaceutical compositions containing at least one compound according to the invention adap¬ ted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents. The compositions may be. formulated in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions, or solu¬ tions, injectable solutions, elixirs, syrups and the like and may contain one or more agents selected from the group including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a pharmaceutically acceptable preparation. The particular carrier and the ratio of inotropic active compound to carrier are determined by the solubility and chemical properties of the compounds, the particular mode of administration and standard pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used in producing tablets. For a capsule form, lactose and high molecular weight polyethylene glycols are among the preferred pharmaceutically acceptable carriers. ΓRI^ OMPI Where aqueous suspensions for oral use are formulated, the carrier can be emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerin and chloroform and their combinations can be employed as well as other materials. For parenteral administration, solutions or sus¬ pensions of these compounds in sesame or peanut oil or aqueous propylene glycol solutions, as well as sterile aqueous solutions of the soluble pharmaceutically accep¬ table salts described herein can be employed. Solutions of the salts of these compounds are especially suited for intramuscular and subcutaneous injection purposes. The aqueous solutions, including those of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes, provided that their pH is properly adjusted, suitably buffered, made isotonic with sufficient saline or glucose and sterilized by heating or by microfiltration. The dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief. Thus, in general, the dosages are those that are therapeutically effective in increasing the contractile force of the heart or in the treatment of cardiac failure. In general, the oral dose may be between about 0.01 mg/kg and about 50 mg/kg (preferably in the range of 0.1 to 10 mg/kg), and the i.v. dose about 0.005 to about 30 mg/kg (preferably in the range of 0.01 to 3 mg/kg) , bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, age, and other factors which may influence response to the drug. The drug may be administered orally 1 to 4 times per day, preferably twice daily. OMPI " ^?NATlθ

Claims: WE CLAIM: 1. A compound according to the formula R5 wherein: l is hydrogen, alkyl, hydroxyalkyl or phen- loweralkyl; R3 is hydrogen, halo, alkyl, haloalkyl, cyano, amino, guanidino, thioureido, ureido, carboxyl, alkoxy, hydroxy, hydroxyalkyl, carbamoyl, acylamino, alkylamino, dialkylamino or nitro; R4 and Rg are each independently hydrogen or alkyl; R5 is a bicyclic heteroaryl group comprising a heteroaryl ring fused to an ortho-phenylene group, said heteroaryl ring including one or two nitrogen atoms in said ring; and wherein: one or more of said heteroaryl group hydrogen atoms may be substituted by halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkylamino, dialkylamino, amino, alkoxy, aralkoxy, acylamino, cyano or nitro; or an acid addition salt thereof. 2. A compound according to Claim 1, wherein: R5 is 2-quinolinyl, 4-quinolinyl, 1-isoquino- linyl, 3-isoquinolinyl, 1-phthalazinyl, 2-quinoxalinyl, 2-quinazolinyl, 4-quinazolinyl, 3-σinnolinyl or 4-cinnolinyl; '%7JZE OMPI WIPO ^/?NATIO;$ and wherein: one or more of the hydrogen atoms on the R5 substituent may be replaced by a halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkylamino, dialkylamino, amino, alkoxy, aralkoxy, acylamino, cyano or nitro group. 3. A compound according to Claim 2, wherein: R5 is roTόi R* and wherein R and R* are each independently hydrogen, halo, alkyl, haloalkyl, hydroxylalkyl, hydroxy, alkylamino, dialkylamino, amino, acylamino, alkoxy, aralkoxy, cyano, or nitro. 4. A compound according to Claim 2, wherein: Ri is meth-yl, ethyl or 2-hydroxyethyl; 3 is hydrogen, amino, acylamino, halo, cyano, haloalkyl, mono-or di-alkylamino, alkyl, guanidino, thioureido, ureido, carboxyl, alkoxy, hydroxy, nitro, or carbamoyl; R4 and Rg are hydrogen, methyl or ethyl; R5 is R is hydrogen, hydroxy, lower alkoxy, benzyloxy, amino, alkylamino, lower alkyl, cyano, halo lower alkyl, halo, nitro, or dialkylamino. 5. A compound according to Claim 3 or 4, wherein: R4 is hydrogen; and Rg is methyl or ethyl; 6. A compound according to Claim 3 or 4, wherein R4 and Rg are methyl or ethyl. 7. A compound according to the formula wherein: Ri is lower alkyl; R3 is halo or haloloweralkyl; R4 and Rg are hydrogen or loweralkyl; R5 is 2-quinolinyl, 4-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, or 2-quinolinyl, 4-quinolinyl, 1-isoquinolinyl, or 3-isoquinolinyl substituted in the 6-position by lower alkyl, halo, halo loweralkyl, lower alkoxy, hydroxy, benzyloxy, cyano, nitro, amino, alkylamino, or dialkylamino; or an acid addition salt thereof. 8. A compound according to Claim 7 wherein R4 and Rg are lower alkyl. 9. A compound according to Claim 7 or 8, wherein R5 is 2-quinolinyl or 4-quinolinyl, or 2-guinolinyl or 4-quinolinyl substituted in the 6-position by lower alkyl. 10. 3-Carboxy-5-(4-quinolinyl)-2(lH)-pyridone or a non-toxic salt thereof. OMPI 11. 3-Bromo-5-(4-quinolinyl)-2(IH)-pyridone or a non-toxic salt thereof. 12. 5-(4-quinolinyl)-2(lH)-pyridone or a non-toxic salt thereof. 13. 3-Bromo-l-methyl-5-(4-quinolinyl)-2-pyridone or a non-toxic salt thereof. 14. 3-Bromo-l-ethyl-5-(4-quinolinyl)-2-pyridone or a non-toxic salt thereof. 15. 3-Carbamoyl-5-(4-quinolinyl)-2(IH)-pyridone or a non-toxic salt thereof. 16. A method for increasing cardiac contractility in a human or other mammal which comprises administering thereto an effective cardiotonic amount of a compound according to Claim 1. 17. A cardiotonic composition comprising an effective cardiotonic amount of a compound according to Claim 1 and a pharmaceutically acceptable carrier. OMPI

Inventors: CAMPBELL HENRY FLUD, DODSON STUART ALAN, KUHLA DONALD ERNEST, STUDT WILLIAM LYON, CAMPBELL, HENRY, FLUD, DODSON, STUART, ALAN, KUHLA, DONALD, ERNEST, STUDT, WILLIAM, LYON
Applicants: RORER INT OVERSEAS, RORER INTERNATIONAL (OVERSEAS) INC.
Application year: 1983
Main classification: C07D401
IPC codes: C07D213, C07D215, C07D401