GB2075500A - 6-(Pyridinyl)-4-substituted- 3(2H)-pyridazinones - Google Patents

Abstract

2-R-4-R'-6-PY-3(2H)- pyridazinones (I) or salts thereof, where PY is 4-or 3-pyridinyl or 4- or 3-pyridinyl having one or two alkyl substituents, R is hydrogen, alkyl or hydroxyalkyl, and R' is amino, carbamyl, carboxy, aminocarbamyl or carbalkoxy, which are useful as intermediates and some as cardiotonics, are prepared by reacting dialkylhydroxy[2-oxo-2-PY- ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH2. nHxAn (III) to produce alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4- pyridazine carboxylate (Ia where R' is carbalkoxy) and reacting Ia with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2-R- 3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib where R' is aminocarbamyl). 4-Amino-2-R-6-PY- 3(2H)-pyridazinones (Ie), particularly useful as cardiotonics, are prepared by: a) reaction of 2-R-6-PY-3-(2H)- pyridazinone with hydrazine; b) conversion from 2,3-dihydro-2-R-3- oxo-6-PY-4-pyridazinecarboxamide (Ic); or, c) conversion from 2,3- dihydro-2-R-3-oxo-6-PY-4- pyridazinecarboxylic acid hydrazide (Ib). Also shown are: the preparation of II from PY-COCH3 (IV) and the conversion of Ia to Ic (I, where R' is carbamyl) or Id (I where R' is carboxy).

Description

SPECIFICATION 6-(Pyridinyl)-4-substituted-3(2H)-pyridazinones, Useful as Cardiotonic Agents, and Preparation This invention relates to 6-(pyridinyl)-4-substituted-3(2H)-pyridazinones, useful as cardiotonic agents, to their preparation, and to their use as cardiotonic agents.

Haginiwa et al. [Yakugaku Zasshi 98 (1), 67-71(1978); Chem. Abstrs. 88, 170,096v (1978)] reacted 3(2H)pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)3(2H)-pyridazinone.

Yoshitomi Pharmaceutical Ind., Ltd. Japanese Patent Application Disclosure No. 1 9,987/79, published February 15, 1979 and based on Application No. 85,192/77 filed July 1 5, 1977, discloses, inter alia, the preparation of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone by refluxing for two hours an ethanolic solution of 3-(isonicotinoyl)propanoic acid [same as y-oxo-y-(4-pyridinyl)butyric acid] and hydrazi ne hydrate. 4,5-Di hydro-6-(4-pyridinyl )-3 (2H)-pyridazinone and closely related 4,5-dihydro-6 (4- or 3- or 2-pyridinyl)-5-R-3(2H)pyridazinones, where R is H or lower alkyl, are said (page 2 of English translation) to be "useful not only as medicines such as hypotensive and antithrombus agents because they have pharmacological actions such as hypotensive, blood platelet coagulation-inhibitory and membrane-stabilizing actions, but also as intermediates for the synthesis of such medicines." The present invention resides in the 2-R-4-R'-6-PY-3(2H)-pyridazinones having Formula I

or acid-addition salts thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R' is amino, carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy.The compounds of Formula I where R' is -NH2 (amino) and said salts are useful as cardiotonic agents, as determined by standard cardiotonic evaluation procedures. Preferred embodiments are those where R' is amino, PY is 4-pyridinyl or 3-pyridinyl and R is hydrogen, methyl, ethyl or 2-hydroxyethyl. Also other compounds of Formula I except those where R' is carboxy or those where R' is lower-carbalkoxy when R is hydrogen are similarly useful as cardiotonic agents; the compounds of Formula I where R' is carboxy or where R' is lower-carbalkoxy when R is hydrogen are useful as intermediates, e.g., in preparing the corresponding compounds where R' is carbamyl. Also, the compounds where R' are carbamyl or aminocarbamyl are useful as intermediates in preparing the compounds of Formula I where R' is amino.Preferred embodiments of Formula I where R' is other than amino are those where R is hydrogen, methyl or ethyl, R' is carbamyl or aminocarbamyl and PY is 4-pyridinyl or 3-pyridinyl.

The compounds of Formula I where R is hydrogen may exist in tautomeric forms, that is, as 6-PY-3(2H)-pyridazinones of Formula I and/or as 4-R'-6-PY-3-pyridazinols of Formula IA, illustrated as follows

Structural preferences for known 3(2H)-pyridazinones or 3-pyridazinols would indicate the above Formula I to be the preferred tautomeric structure; thus, we have preferred to use the names based on structure I, although it is understood that either or both structures are comprehended herein.

One can react di(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH2. nHxAn (III) to produce lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4pyridazinecarboxylate (la:l where R' is lower-carbalkoxy). One can react la with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib:'l where R' is aminocarbamyl), where PY and R are defined as above for Formula I, preferably 4 pyridinyl and hydrogen or methyl, respectively, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or an organic sulfonic acid.

One can convert lower-alkyl, 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (la) to 2,3dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide (Ic:l where R' is carbamyl) either directly by reaction with ammonia or via the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid (Id:l where R' is carboxy) by hydrolyzing the ester to acid, reacting the acid with a chlorinating agent to form the acid chloride and reacting the latter with ammonia to form said carboxamide (Ic where R' is carbamyl), where R and PY have the meanings given above for Formula I, preferably hydrogen or methyl and 4-pyridinyl, respectively.

One can prepare the compounds of Formula le (I where R' is amino) by reacting a 2-R-6-PY3(2H)-pyridazinone with hydrazine. One can also react 2,3-dihydro-2-R-3-oxo-6-PY-4pyridazinecarboxamide (Ic) with a reagent capable of converting carbamyl to amino to produce 4 a mino-2-R-6-PY-3(2H)-pyridazinone (le) or react 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib) with a reagent capable of converting carboxylic acid hydrazide to amino, where R and PY have the meanings given above for the compounds of Formula I. The conversion of Ic to le is preferably carried out using aqueous alkali metal hypohalite, preferably hypobromite or hypochlorite.

The conversion of Ib to le is preferably carried out using nitrous acid.

Another aspect of the invention resides in the di(lower-alkyl) hydroxy[2-oxo-2-PYethyl]propanedioates of Formula II

or an acid-addition salt thereof where PY is defined as above for Formula I, preferably 4-pyridinyl, or 3pyridinyl and R1 is lower-alkyl, preferably ethyl or methyl.

One can react acetylpyridine of the formula PY-COCH3 (IV) with di(lower-alkyl)oxomalonate to produce di(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) where PY is defined as in Formula I above, preferably 4-pyridinyl.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceuticallyacceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic 2-R 4-R'-6-PY-3(2H)-pyridazinone of Formula I, that is, where R' is amino, carbamyl, aminocarbamyl or lower-carbalkoxy, R is hydrogen, lower-alkyl or lower-hydroxyalkyl but is only lower-alkyl or lowerhydroxyalkyl when R' is lower-carbalkoxy, and PY is defined as in Formula I or a pharmaceuticallyacceptable acid-addition salt thereof. Preferred such cardiotonic compounds are those where PY is 4pyridinyl or 3-pyridinyl.

For increasing cardiac contractility in a patient requiring such treatment one administers orally or parenterally in a solid or liquid dosage form to such patient an effective amount of a cardiotonic 2-R-4 R"-6-PY-3(2H)-pyridazinone or pharmaceutically-acceptable acid-addition salt thereof as defined The term "lower-alkyl" as used herein, e.g., as one of the meanings for R (Formulas I, la, Ib, Ic, Id, le or lil), the meaning for R1 (Formula II) or as a substituent for PY (Formula I, la, Ib, Ic, Id, le or II) means alkyl radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl.

The symbol PY as used here, e.g., as the 6-substituent in the compounds having Formulas I, la, lb, Ic, Id, le or II, means 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two "lower-alkyl" substituents, illustrated by 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3- pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl, 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl 4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl- 4-pyridinyl, and the like.

The term "lower-hydroxyalkyl", as used herein, e.g., as one of the meanings for R in formulas I, la, Ib, Ic, Id, le or Ill, means hydroxyalkyl radicals having form two to six carbon atoms and having its hydroxy group and its free valence bond (or connecting linkage) on different carbon atoms which can be arranged as straight or branched chains, illustrated by 2-hydroxyethyl, 2-hydroxypropyl, 3- hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy- 1,1 -dimethylethyl, 4-hydroxybutyl, 5- hydroxyamyl, 6-hydroxyhexyl, and the like.

The term "lower-carbalkoxy", as used herein, as one of the meanings for R' in formulas I and Ia, means carbalkoxy radicals where the alkoxy portion can be straight or branch-chained and has from one to six carbon atoms, as illustrated by carbomethoxy, carbethoxy, carbo-n-propoxy, carbisopropoxy, carbo-n-butoxy, carbo-tert.-butoxy and carbo-n-hexoxy.

The compounds of the invention having formulas I, la, Ib, Ic, le and II are useful both in the free base form and in the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts 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 relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base of the cardiotonically-active compounds of the invention are not vitiated by side effects ascribable to the anions.In practicing the invention, it is convenient to use 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 acid such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like, giving the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compound 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.

Although pharmaceutically-acceptable salts of said basic compound are preferred, all acidaddition salts are within the scope of our invention. 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 or identification, or when it is used as an intermediate in preparing a pharmaceutically-acceptable salt by ion exchange procedures.

The molecular structures of the compounds of the invention were assigned on the basis of evidence provided by infrared, nuclear magnetic resonance and mass spectra, and by the correspondence of calculated and found values for the elemental analyses.

The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of pharmaceutical chemistry to make and use the same, as follows.

The reaction of acetylpyridine of the formula PY-COCH3 (IV) with di(lower-alkyl) oxomalonate to produce di(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II), where PY is defined as in formula I above, is carried out by heating the reactants at about 800C to 1 200C, preferably about 909C to 1 1 OOC. The reaction is conveniently run on a steam bath. The reaction is preferably run using diethyl or dimethyl oxomalonate. This preparation is illustrated hereinbelow in Examples A-l through A-9.

The preparation of lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylates by reacting di(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH2. nHxAn (III), where PY and R are defined as in formula I above and n, x and An are defined as in formula Ill above, is carried out by heating the reactants at about 600C to 1000C, preferably about 750C to 850C, and preferably in the presence of a suitable solvent, e.g., a lower-alkanol such as methanol, ethanol or isopropyl alcohol. Other suitable solvents would be dioxane, tetrahydrofuran, pyridine, ethylene glycol, and the like. Preferred R-hydrazine salts are the dihydrochlorides or sulfates.

This preparation is illustrated below in Examples C-2 through C-17. Also note Example B-l where diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate was refluxed with hydrazine monohydrochloride in methanol for a relatively short period (less than 2 hours) to produce ethyl 2,3,4,5-tetrahydro-4-hyd roxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate which, as shown in Example C-l,was readily dehydrated by treating a solution of it in a suitable solvent, e.g., acetonitrile, ethanol, tetrahydrofuran or dioxane with hydrogen chloride to produce ethyl 2,3-dihydro-3-oxo-6-(4pyridinyl)-4-pyridazinecarboxylate.

The conversion of the lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (la) to the corresponding 4-pyridazinecarboxamide (Ic) was conveniently carried out by bubbling ammonia into a solution of la in an inert appropriate solvent, e.g., a lower-alkanol, preferably ethanol or methanol. Other suitable solvents include isopropyl alcohol, acetonitrile, tetrahydrofuran, dioxane and the like. The reaction is readily run at room temperature. This preparation is illustrated below in Examples D-1 through D-16.

The conversion of lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylate (la) to the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylic acid hydrazide (Ib) by reaction with hydrazine hydrate or anhydrous hydrazine is carried out by heating the reactants at about 600C to about 1000C, preferably about 750C to 850C in a suitable solvent, e.g., a lower-alkanol, preferably methanol, ethanol or isopropyl alcohol. Other suitable solvents include pyridine, tetrahydrofuran, dioxane and the like. This preparation is illustrated below in Examples E-l through E-16.

The hydrolysis of lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylate (la) to the corresponding carboxylic acid (Id) is carried out by heating the ester (la) with aqueous alkali metal hydroxide solution, e.g., preferably aqueous sodium hydroxide solution, conveniently done by heating the reactants on a steam bath. Alternatively, the hydrolysis of said 4-pyridazinecarboxylate (la) to 4pyridazinecarboxylic acid (Id) can be carried out by heating the ester (la) with an aqueous solution of a strong inorganic acid, e.g., hydrochloric acid, sulfuric acid, and the like. This hydrolysis is illustrated below in Examples F-l through F-1 6.

The conversion of 2,3-dihydro-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib) to 4-amino2-R-6-PY-3(2H)-pyridazinone (le) is carried out by reacting Ib with a reagent capable of converting carboxylic acid hydrazide to amino. This reaction is run by first reacting Ib with nitrous acid in aqueous medium at a low temperature, preferably below 50C, to form the corresponding 4-pyridazinecarboxylic acid azide in situ and then heating the reaction mixture, preferably about 45 to 650C, until evolution of nitrogen ceases. This conversion is illustrated below in Example G-1 and G-23 thru G-41.

The conversion of 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide (Ic) to 4-amino-2-R-6 PY-3(2H)-pyridazinone (le) is carried out by reacting Ic with a reagent capable of converting carbamyl to amino. The reaction is conveniently run by heating an aqueous mixture containing Ic and an alkali metal hypohalite, preferably hypobromite or hypochlorite, and then acidifying the reaction mixture, preferably with an aqueous mineral acid, e.g., hydrochloric acid. The reaction can be run from about 500C to 1200 C, preferably about 700C to 1 000C. This conversion is illustrated below in Examples G42 thru G-6 1.

The conversion of 2-R-6-PY-3-(2H)-pyridazinone to 4-amino-2-R-6-PY-3(2H)-pyridazinone (le) by reaction with hydrazine hydrate or anhydrous hydrazine is carried out by heating the reactants in the absence or presence of a suitable inert solvent at about 800C to about 1300 C, preferably about 900C to 1 1 OOC. Although the reaction is preferably run using excess hydrazine or hydrazine hydrate as the solvent, it can be run using a suitable inert solvent, e.g., dioxane, ethanol, ethylene glycol dimethyl ether, and the like. Alternatively, the reaction can be run in an autoclave with or without a solvent. This conversion is illustrated below in Examples G-2 through G-22.

The preparation of the intermediate (4,5-dihydro-2-(lower-alkyl)-6-PY-3 (2H)-pyridazinones by reacting a 4-oxo-4-PY-butanenitrile with N-R hydrazine salt of a strong inorganic acid or organic sulfonic acid, the resulting 4,5-dihydro-2-(lower-alkyl or lower-hydroxyalkyl)-6-PY-3(2H)pyridazinones and their use as cardiotonic agents are the subject of our Application No. 8112639 filed 23 April, 1981.

The preparation of the intermediate 4,5-dihydro-6-PY-3 (2H)-pyridazinones or tautomeric 4,5dihydro-6-PY-3-pyridazinols by reacting 4-oxo-4-PY-butanenitrile is illustrated below in Examples H-l through H-6.

The intermedaite 4-oxo-4-PY-butanenitriles are generally known compounds, e.g., Stetter et al., Chem. Ber. 107, 210 (1974), and are prepared by generally known methods.

The conversion of the intermediate 4,5-dihydro-2-R-6-PY-3(2H)-pyridazinones or where R is H the tautomeric 4,5-dihydro-6-PY-3-pyridazinols by reaction with bromine to the corresponding intermediate 2-R-6-PY-3 (2H)-pyridazinones, the latter 2-R-6-PY-3(2 H)-pyridazinones and their use as cardiotonics are the subject of our copending Application Serial No. 8027262 filed 21 August, 1980 (Serial No. 2,057,438).

The following examples will further illustrate the invention without, however, limiting it thereto.

A. Di-(lower-alkyl) Hydroxy[2-oxo-2-(pyridinyl)ethyljpropanedioates A-i. Diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioateA mixture containing 8.71 g of diethyl oxomalonate and 6.06 g of 4-acetylpyridine was heated on a steam bath for 3 hours and then cooled. A small sample of the reaction mixture in a small test tube was partially solidified by rubbing the sample with a glass rod against the inside of the test tube. The remainder of the cooled reaction mixture was dissolved in 13 ml of methanol, the solution chilled and seeded with crystals formed in the small test tube and the resulting mixture was allowed to solidify.The solid was collected and washed with small quantity of methanol and air dried to yield 4.7 g of diethyl hydroxy[2-oxo-2-(4 pyridinyl)ethyl]propanedioate, m.p. 130-i 31.5 0C. More product was obtained from the mother liquor as follows: the above filtrate was evaporated to dryness on a rotary evaporator while heating on a steam bath and the residue was heated for an additional hour on said bath. Since the residue had not solidified, a small sample in a test tube when covered with ethanol and seeded with the above product gave a solid. The solid was dissolved in a minimum amount warm ethanol, the resulting solution concentrated briefly on a steam bath and then chilled.The resulting solid was collected, washed with a small quantity of ethanol and air-dried to yield another 4.4 g of diethyl hydroxy[2-oxo-2-(4 pyridinyl)ethyl]propanedioate, m.p. 127-1 300C. The combined two crops (4.7 +4.4=9.1 g of 61.7% yield) was dissolved in about 23 ml of hot methanol and the solution then chilled thoroughly. The separated white solid was rinsed with a little methanol, air-dried briefly and then dried at 250C over P205 at 10 mm over the weekend, thereby yielding 7.4 g of diethyl hydroxy[2-oxo-2-(4 pyridinyl)ethyl]propanedioate, m.p. 131--132 C.

Following the procedure described in Example A-l but using in place of 4-acetylpyridine a corresponding molar equivalent quantity of the appropriate 3- or 4-acetylpyridine, it is contemplated that there can be obtained the corresponding diethyl hydroxy[2-oxo-2-(pyridinyl)ethyl]propanedioates of Examples A-2 thru A-6.

A-2. Diethyl hydroxy[2-oxo-2-(3-pyridinyl)ethyl]propanedioate using 3-acetylpyridine.

A-3. Diethyl hydroxy[2-oxo-2-(2-methyl-3-pyridinyl)ethyl] propanedioate using 3-acetyl-2methylpyridine.

A-4. Diethyl hydroxy[2-oxo-2-(5-methyl-3-pyridinyl)ethyl] propanedioate using 3-acetyl-5methylpyridine.

A-5. Diethyl hydroxy[2-oxo-2-(3-ethyl-4-pyridinyl)ethyl]propanedioate using 4-acetyl-3ethylpyridine.

A-6. Diethyl hydroxy[2-oxo-2-(2 ,6-dimethyl-4-pyridinyl)ethyl]propanedioate using 4-acetyl-2,6dimethyl-pyridine.

Following the procedure described in Example A-l but using in place of diethyl oxomalonate a molar equivalent quantity of the appropriate di-(lower-alkyl) oxomalonate, it is contemplated that there can be obtained the corresponding di(lower-alkyl) esters of Examples A-7 through A-9.

A-7. Dimethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate.

A-8. Di-n-propyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl] propanedioate.

A-9. Diisobutyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl] propanedioate.

B. Lower-alkyl 2,3,4, 5-Tetra hydro-2-R-4-hydrnxy-3-oxo-6-PY-4-pyridazinecarboxylatos B-i. Ethyl 2,3,4,5-Tetra hydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate-A 5.9 g portion of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate was added to a warm solution containing 1.4 g of hydrazine monohydrochloride in 1 50 ml of methanol, the resulting reaction mixture was refluxed gently for 1 hour and 45 minutes, cooled briefly and then stripped to dryness on a roto vaporizer. The resulting gummy residue was warmed with a small quantity of acetonitrile to produce a crystalline material; the mixture was then chilled.The crystals were collected, washed with a small quantity of acetonitrile and air-dried to yield 2.25 g ethyl 2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4pyridinyl)-4-pyridazinecarboxylate hydrochloride, m.p. 160-1 630C with decomposition. A 1.65 g portion of this monohydrochloride was dissolved in about 10 ml of water, the solution filtered and solid sodium bicarbonate was added in small portions until the evolution of carbon dioxide ceased. The precipitated white solid was collected, rinsed with water and dried over P206 at 10 mm and 250C for six hours to yield 1.2 g of ethyl 2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4- pyridazinecarboxylate, m.p. 193-i 950C with decomposition.

As shown in Example C-l,the 4-hydroxy-tetrahydro product of the immediately preceding paragraph is readily dehydrated by treating it with a strong inorganic acid or an organic sulfonic acid, preferably hydrogen chloride, to produce ethyl 2 ,3-dihydro-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxylate. Thus, it appears that the conversions shown in Examples C-2 through C-17 go through the corresponding lower-alkyl 2,3 ,4,5-tetrahydro-4-hydroxy-3-oxo-6-PY-4- pyridazinecarboxylates, none of which was actually isolated other than the product of Example B-1.

C. Lower-alkyl 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylates C-i. Ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylates-This preparation shows the conversion of Example B-l to the entitled compound. Into a one liter portion of acetonitrile was bubbled gaseous hydrogen chloride with stirring for about 5 minutes. To this mixture was added 9.5 g of ethyl 2,3,4,5-tetrahyd ro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and hydrogen chloride was bubbled into the mixture for an additional 1 5 minutes. The reaction mixture was stirred for 1 hour whereupon the solid separated.The reaction mixture was stirred for an additional 2 hours and then allowed to stand at room temperature overnight (about 1 5 hours). The white solid was collected, dried in a vacuum oven for 2 hours at 400C over P205 to yield 8.0 g of ethyl 2,3-dihydro-3oxo-6-(4-pyridinyl)-4-pyridazincarboxylate dihydrochloride, m.p. 212--2200C with decomposition.

The hydrochloride salt was dissolved in a minimum quantity of water and solution basified with solid sodium bicarbonate. The resulting precipitate was collected, washed with water and dried in a vacuum oven over P205 at 25 or overnight to yield 5.5 g of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxylate, m.p. 196-1970C.

C-2. Ethyl 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate-The following synthesis of the entitled compound was carried out directly using Example A-i. To a warm solution containing 1 6.0 g of hydrazine dihydrochloride in 11 of absolute ethanol was added with stirring 44.25 g of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate rinsed in with 250 ml of absolute ethanol and the resulting reaction mixture was refluxed for 1 9 hours. About 300 ml of the ethanol was distilled off under reduced pressure and the remaining reaction mixture was evaporated on a roto vaporizer to obtain a tan solid. The solid was slurried with 100 ml of water and the mixture transferred to a 500 ml flask, rinsing the material with an additional 25 ml of water.To the aqueous mixture was cautiously added solid sodium bicarbonate until evolution of carbon dioxide ceased. The solid was collected, rinsed with water, air-dried and then dried in a vacuum oven over P205 at 10 mm in 250C to yield ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-3. Ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate-A mixture containing 26 g of 1 -methyihydrazine dihydrochloride, 148 g of diethyl hydroxy[2-oxo-2-(4pyridinyl)ethyl]propanedioate in 1 500 ml of absolute ethanol was refluxed with stirring overnight (about 1 5 hours), the reaction mixture was heated in vacuo to remove the solvent and the residual gummy material was taken up in about 600 ml of water and the aqueous solution basified with solid potassium carbonate until basic to litmus. The precipitated solid was collected and later combined with additional product obtained from the filtrate which had been found to still be acidic.The filtrate was basified with 10% aqueous potassium carbonate and the alkaline mixture was extracted with chloroform and the chloroform extract heated in vacuo to remove the solvent. The resulting solid product was combined with the above-said product and the combined material was recrystallized from ethyl acetate and n-hexane and dried first at 40 C for 17 hours and then at 600C for 17 hours to produce 34 g of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, m.p.

128-1 290C.

Acid-addition salts of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate are conveniently prepared by adding to a mixture of 1 g of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4pyridinyl)-4-pyridazinecarboxylate in about 20 ml of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively.Alternatively, the lactate or hydrochloride acid-addition salt of ethyl 2,3-dihydro-2methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of ethyl 2,3-dihydro-2-methyl-3-oxo-6 (4-pyridinyl)-4-pyridazinecarboxylate and lactic acid or hydrochloric acid, respectively.

Following the procedure described above in Example C-2 but using in place of diethyl hydroxy[2oxo-2-(4-pyridinyl)ethyl]propanedioate a molar equivalent quantity of the appropriate diethyl hydroxy[2-oxo-2-(pyridinyl)ethyl]propanedioate, it is contemplated that there can be obtained the corresponding ethyl 2,3-dihydro-3-oxo-6-(pyridinyl)-4-pyridazinecarboxylates of Examples C-4 thru C8.

C-4. Ethyl 2,3-dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylate.

C-5. Ethyl 2,3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylate.

C-6. Ethyl 2,3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylate.

C-7. Ethyl 6-(3-ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylate.

C-8. Ethyl 2,3-dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylate.

Following the procedure described in Example C-3 but using in place of 1-methylhydrazine dihydrochloride a molar equivalent quantity of the corresponding 1-R-hydrazine dihydrochloride or other salt of a strong inorganic acid or an organic sulfonic acid, it is contemplated that there can be obtained the corresponding ethyl 2,3-dihydro-2-R-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylates of ExamplesC-9thruC-17.

C-9. Ethyl 2-ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-i O. Ethyl 2-isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-i 1. Ethyl 2,3-dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-12. Ethyl 2,3-dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C- 13. Ethyl 2-n-hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C- 14. Ethyl 2,3-dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-15. Ethyl 2,3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-16. Ethyl 2,3-dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C- 17. Ethyl 2,3-dihydro-2-(4-hydroxbutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

D. Lower-alkyl 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamides D-i. 2,3-Dihydrn-2-methyl-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxamide-Ammonia was bubbled into 800 ml of absolute ethanol with stirring over a period of 20 minutes. To the mixture was then added 50 g of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate; the reaction mixture was stirred for 40 minutes and then allowed to stand at room temperature overnight.

The precipitate was collected, washed with absolute ethanol, recrystallized from absolute ethanol and dried in a vacuum oven overnight to yield 15 g of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxamide, m.p. 234-2350C. Another 17.5 g of product was obtained by distilling off the solvent from the mother liquor.

Acid-addition salts of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide are conveniently prepared by adding to a mixture of 1 g of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxamide in about 20 ml of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively. Alternatively, the lactate or hydrochloride acid-addition salt of 2,3-dihydro-2-methyl-3oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxamide and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example D-l but using in place of ethyl 2,3-dihydro-2methyl-3-oxo-6-(4-pyridinyi)-4-pyridazinecarboxylate a molar equivalent quantity of the appropriate ethyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate, it is contemplated that there can be obtained the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamides of Examples D-2 thru D-16.

D-2. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxa mide.

D'-4. 2,3-Dihydrn-6-(2-methyl-3-py?idinyl)-3-oxo-pyridazinecarboxamide.

D-S. 2,3-Dihydro-6-( S-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxamide.

D-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxamide.

D-7. 2,3-Dihydro-6-(2 ,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxamide.

D-8. 2-Ethyl-2 ,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxam ide.

D-9. 2-lsopropyl-2,3-dihyd ro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxam ide.

D- 10. 2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)- 4-pyridazinecarboxam ide.

Dli. 2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4- pyridazinecarboxamide.

D- 12. 2-n-Hexyl-2,3-dihydrn-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D- 13. 2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D- 14. 2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxa mide.

Dl S. 2 ,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-16.2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

E. 2,3-Dihydro-2-R-3-oxo-6-PY-4pyridazinecarboxylic Acid Hydrazides E-1.2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazides-A mixture containing 10 g of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and 300 ml of absolute ethanol was heated on a steam bath with stirring for about 10 minutes. To the resulting stirred solution was added 4 g of anhydrous hydrazine whereupon a solid began precipitating out within 5 minutes. The reaction mixture was heated for about 1 hour with stirring. The separated solid was collected, dried in a vacuum oven at 650C over P205 overnight to yield 9.4 g of 2,3-dihydro-3-oxo6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide, m.p. > 300 0C.

E-2. 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide-This preparation was carried out following the procedure described in Example E-l using 8.5 g of ethyl 2,3 dihyd ro-2-methyl-3-oxo-6(4-pyridinyl)-4-pyridazinecarboxylate, 10.8 g of anhydrous hydrazine and 1 50 ml of ethanol. The reaction was run a second time using the same quantities of reactants. The products were combined and recrystallized from absolute ethanol to produce 10 g of 2,3-dihydro-2methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide, m.p. 209-21 00C. A second crop of 3 g, m.p. 212-21 30C was obtained from the mother liquor.

Acid-addition salts of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide are conveniently prepared by adding to a mixture of 1 g of 2,3-dihydro-2-methyl-3-oxo-6-(4- pyridinyl)-4-pyridazinecarboxylic acid hydrazide in about 20 ml of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively.Alternatively, the lactate or hydrochloride acid-addition salt of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4- pyridazinecarboxylic acid hydrazide is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 2,3 dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example El but using in place of ethyl 2,3-dihydro-3-oxo-6 (4-pyridinyl)-4-pyridazinecarboxylate a molar equivalent quantity of the appropriate ethyl 2,3-dihydro2-R-3-oxo-6-PY-4-pyridazinecarboxylate, it is contemplated that there can be obtained the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazides of Examples E-3 thru E-16.

E-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide.

E-5.2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide.

E-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylic acid hydrazide.

E-7. 2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide.

E-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E-9. 2-lsopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E- 10. 2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E- 11. 2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E- 12. 2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E- 13. 2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E- 14. 2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

El S. 2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

E-16.2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide.

F. 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic Acids F-i. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid-A mixture containing 10 g of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and 100 ml of 5% aqueous sodium hydroxide solution was heated on a steam bath for 6 hours, allowed to cool to room temperature and then treated slowly with acetic acid until solid began to separate. The mixture was allowed to stand until no more solid separated and the solid was then collected, dried in a vacuum oven over P205 at 450C to yield 7.7 g of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid, m.p. > 31 00C.

F-2. 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic Acid-To a mixture containing diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate and 40 ml of absolute ethanol was added 4.6 g of 1-methylhydrazine which had previously been treated with 6 ml of 6N hydrochloric acid. The reaction mixture was refluxed overnight and then the solvent distilled off in vacuo. The remaining yellow residue was treated with 300 ml of 20% aqueous sodium hydroxide solution and the mixture heated on a steam bath overnight. The reaction mixture was allowed to cool to room temperature and the separated solid was collected.The solid was recrystallized from 120 ml of acetic acid using decolorizing charcoal and the hot filtrate after removal of the decolorizing charcoal was treated with 1 20 ml of hot water. The resulting solution was allowed to cool and the resulting mixture containing crystalline product was allowed to stand over the weekend. The solid was collected and dried in a vacuum oven at 800C over P206 overnight to yield 9.4 g of 2,3-dihydro-2-methyl-3-oxo-6 (4-pyridinyl)-4-pyridazineca rboxylic acid, m.p. 267--268 OC.

Following the procedure described in Example F-l but using in place of ethyl 2,3-dihydro-3-oxo6-(4-pyridinyl)-4-pyridazinecarboxylate a molar equivalent quantity of the appropriate ethyl 2,3dihydro-2-R-3-oxo-6-PY-4-pyridazine carboxylate, it is contemplated that there can be obtained the corresponding 2,3-dihydro-2-R-2,3-dihydro-3-oxo-6-PY-4-pyridazinecarboxylic acids of Example F-3 thru F-16.

F-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylic acid.

F-4. 2 ,3-Dihydrn-6-(2-methyl3-pyridinyl)-3-oxo-4pyridazinecarboxylic acid.

F-5.2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid.

F-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylic acid.

F-7. 2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid.

F-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F-9. 2-lsopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F-i 0. 2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F-11.2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F-i 2. 2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F-i 3. 2,3-Dihydrn-2-(2-hydrnxyethyl)-3-oxo-6-(4pyridinyl)-4-pyridazinecarboxylic acid.

F- 14. 2,3-Dihydrn-2-(2-hydrnxyprnpyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F-15.2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

F- 16. 2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

G. 4-Amino-6-PY-2-R-3(2H)-pyridazinones G- 1. 4-Amino-6-(4-pyridinyl)-3 (2H)-pyridazinone-The following procedure describes the preparation of the entitled compound from the corresponding 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxylic acid hydrazide (Example E-1). To a mixture containing 28 g of 2,3-dihydro-3-oxo6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and 700 ml of concentrated hydrochloric acid and 400 ml of water, said mixture cooled in an ice-sodium chloride bath was added a solution containing 20 g of sodium nitrite in 75 ml of water with vigorous stirring over a 30 minute period keeping the internal temperature below 50C. The cold reaction mixture was stirred in the ice-salt bath for an additional 45 minutes and then at room temperature for 30 minutes and then heated gently on a steam bath.When the internal temperature reached 55--600C evolution of nitrogen became rapid. The source of steam was removed until the reaction moderated. The reaction mixture was then heated on a steam bath for 2 hours and chilled in an ice bath. The separated solid was filtered off and washed with water (See below for identification of this solid). The combined aqueous acidic filtrate and washings were concentrated to dryness in vacuo and to the residue was added aqueous ammonium hydroxide solution until the mixture was slightly basic. The mixture was reacidified with acetic acid and cooled in an ice bath. The resulting yellow solid was collected, washed with water and dried.This solid (14. 2 g) was suspended in 50 ml of 10% potassium bicarbonate solution, treated with 100 ml of water and the resulting mixture stirred for 1 hour at room temperature. The yellow solid was collected, washed with water and dried in an oven at 900C. The solid was dissolved in 300 ml of 6N hydrochloric acid by heating on a steam bath. The hot solution was filtered and the filtrate was allowed to stand at room temperature overnight. The bright yellow crystalline product was collected, washed with a small amount of distilled water and dried in an oven at 85 OC to yield 6.8 g of 4-amino-6-(4-pyridinyl)-3(2H)pyridazinone monohydrochloride monohydrate, m.p. > 3400C. The above tan solid, which had been filtered off from the acetic reaction mixture and washed with water, was dissolved in aqueous ammonium hydroxide solution and the solution filtered. The filtrate was acidified with acetic acid whereupon solid crystallized. The mixture was cooled in an ice bath. The crystalline material was collected, washed with water and dried in an oven at 800C to yield 13.5 g of material, m.p. > 3200C., which was identified by its NMR spectrum to be the same as Example F-l,that is, 2,3-dihydro-3-oxo6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

The above procedures of Example G-1 first procedes through the acid azide as seen by the following isolation of the acid azide as its monohydrochloride: To a solution chilled in an ice bath and containing 3.0 g of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and 60 ml of 6N hydrochloric acid was added dropwise with stirring a solution containing 3.0 g of sodium nitrite in 10 ml of water over a 30 minute period. The reaction mixture was then stirred for an additional 1 hour, allowing the reaction mixture to warm up to room temperature. The separated solid was collected, washed with water and dried in a vacuum oven over P205 at 250C for 48 hours to yield 3.0 g of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazine-carboxylic acid azide monohydrochloride, m.p.

> 3000 C.

G-2. 4-Amino-6-(4-pyridinyl)-3(2H)-pyridazinone-The following procedure describes the preparation of the entitled compound by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-pyridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixture containing 10 g of 6-(4-pyridinyl)3(2H)-pyridazinone and 70 ml of hydrazine hydrate was heated on a steam bath for 3 days and the excess hydrazine distilled off in vacuo. The remaining residue was heated with about 300 ml of methanol and the solid was collected by filtration. The solid was combined with the corresponding solid obtained from another run starting wtih 1 5.7 g of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21 ml of hydrazine hydrate and the combined solids were dissolved in aqueous potassium carbonate solution and reprecipitated by addition of acetic acid.The precipitate was dried for 9 hours at 400C over P205 and then overnight at 800 C. After its NMR spectrum had shown the solid still to contain acetic acid, it was next dried in a vacuum oven at 800C for 2 days to yield 18.2 g (69% yield) of 4-amino-6-(4pyridinyl)-3(2H)-pyridazinone, m.p. > 3000 C.

Acid-addition salts of 4-am i no-6-(4-pyridinyl)-3(2 H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively. Also, the lactate or hydrochloride acid-addition sa It of 4-amino-6-(4-pyridinyl)-3 (2 H)-pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4-amino-6-(4-pyridinyl)-3(2H)pyridazinone and lactic acid or hydrochloric acid, respectively.

G-3. 4-Amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. 229--2350C., 6.4 g, was prepared following the procedure described in Example G-2 using 12 g of 2-methyl-6-(4-pyridinyl)3(2H)-pyridazinone and 100 ml of hydrazine hydrate, followed by recrystallization from acetonitrile using decolorizing charcoal.

Acid-addition salts of 4-amino-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g of 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesufonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively. Also, the lactate or hydrochloride acid-addition salt of 4-a mino-2-methyl-6-(4-pyridinyl)-3 (2 H)-pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example G-2 but using in place of 6-(4-pyridinyl)-3(2H)pyridazinone a molar equivalent quantity of the appropriate 2-R-6-PY-3(2H)-pyridazinone, it is contemplated that there can be obtained the 4-amino-2-R-6-PY-3(2H)-pyridazinones of Examples G-4 thru G-22.

G-4. 4-Amino-6-(3-pyridinyl)-3 (2 H)-pyridazinone.

G-5. 4-Amino-6-(2-methyl-3-pyridinyl)-3 (2 H)-pyridazinone.

G-6.4-Amino-6-(5-methyl-3-pyridinyl)-3 (2H)-pyridazinone.

G-7. 4-Amirao-6-(3-ethyl-4-pyridinyl)-3(2H)-p G-8.4-Amino-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

G-9. 4-Amino-2-ethyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-l 0. 4-Amino-2-isopropyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G- 11. 4-Am ino-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G- 12. 4-Amino-2-isobutyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G- 13. 4-Am ino-2-n-hexyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G- 14. 4-Amino-2-(2-hydroxyethyl)-6-(4-pyridinyl)-3(2 H)-pyridazinone.

G- 1 S. 4-Am ino-2-(2-hydroxypropyl)-6-(4-pyridinyl)-3 (2H)-pyridazinone.

G- 1 6. 4-Amino-2-(3-hydroxypropyl)-6-(4-pyridinyl)-3(2H)- pyridazinone.

G- 1 7. 4-Amino-2-(4-hydroxybutyl)-6-(4-pyridinyl)-3 (2H)-pyridazinone.

G- 18. 4-Amino-2-methyl-6-(3-pyridinyl)-3(2H)-pyridazinone.

G-19.4-Amino-2-methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.

G-20. 4-Amino-2-methyl-6-( 5-methyl-3-pyridinyl)-3(2H)-pyridazinone G-21.4-Amino-6-(3-ethyl-4-pyridinyl)-2-methyl-3(2H)-pyridazinone.

G-22. 4-Amino-2-methyl-6-(2,6-di methyl-4-pyridinyl)-3(2 H)-pyridazinone.

Following the procedure described in Example G-1 but using in place of 2,3-dihydro-3-oxo-6-(4pyridinyl)-4-pyridazinecarboxylic acid hydrazide a corresponding molar equivalent quantity of the appropriate 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide, it is contemplated that there can be obtained as Examples G-23 thru G-41 the corresponding 4-amino-6-PY-2-R-3(2H)pyridazinones obtained in Examples G-4 thru G-22, respectively.

G-42. 4-Amino-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone-To a solution containing 9.0 g of sodium hydroxide in 130 ml of water kept at OOC is added dropwise with stirring 2.3 ml of bromine. To the aqueous mixture is added with stirring 8.0 g of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4pyridazinecarboxamide and the resulting reaction mixture is heated on a steam bath for four hours. The reaction mixture is cooled to room temperature, acidified slowly with 6N hydrochloric acid and the resulting acidic mixture is stirred for an additional twenty-five minutes. The acidic mixture is neutralized with 10% aqueous potassium bicarbonate solution and the mixture cooled.The precipitate is collected, washed, dried, recrystallized from acetonitrile, collected, washed with water and dried about 15 hours in a vacuum oven at 65 OC over P205 to yield 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

Following the procedure described in Example G-42 but using in place of 2,3-dihydro-2-meths71- 3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide a molar equivalent quantity of the appropriate 2,3dihydro-3-oxo-6-PY-2-R-4-pyridazinecarboxamide, it is contemplated that there can be obtained as Examples G-43 thru G-61 the corresponding 4-amino-6-PY-2-R-3(2H)-pyridazinones obtained in Examples G-4 thru G-22, respectively.

H. 4,5-Dihydro-2-R-6-PY-3(2H)-pyridazinones H-1. 4,S-Dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone-A mixture containing 2.4 g of 4-oxo-4-(4pyridinyl)butanenitrile (same as y-oxo-y-(4-pyridinyl)butyronitrile), 1.96 g of hydrazine sulfate, 100 ml of absolute ethanol and 100 ml of water was refluxed with stirring overnight (about 15 hours). The reaction mixture was heated in vacuo to remove the solvent mixture. The remaining residue was taken up in water and filtered. The filtrate was neutralized with 10% aqueous sodium bicarbonate solution and a yellow solid separated. The solid was collected, washed with water, dried In vacuo over P205 for four hours. Its nuclear magnetic resonance (nmr) and mass spectra were found to be consistent with that of the desired product but showed traces of impurities.The solid was then recrystallized from absolute ethanol, dried in vacuo over P205 overnight to yield, as golden crystals, 0.9 g of 4,5-dihydro6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. 185-187 OC which is tautomeric with 4,5-dihydro-6-(4pyridinyl)-3-pyridazinol.

The above reaction also can be run by using a molar equivalent quantity of hydrazine dihydrochloride or hydrazine di(methanesulfonate) in place of hydrazine sulfate.

Acid-addition salts of 4,5-dihydro-6-(4-pyridinyl)(2H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesufonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salts, e.g., hydrochloride, methanesulfonate, sulfate, respectively. Also, the lactate or hydrochloride acid-addition salt is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example H-l but using in place of 4-oxo-4-(4pyridinyl)butanenitrile a molar equivalent quantity of the corresponding 4-oxo-4-PY-butanenitrile, it is contemplated that there can be obtained the corresponding 4,5-dihydro-6-PY-3(2H)-pyridazinones of Examples H-2 thru H-6.

H-2.4,5-Dihydro-6-(3-pyridinyl)-3-(2 H)-pyridazinone.

H-3.4,5-Dihydro-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.

H-4. 4,S-Dihydro-6-(S-methyl-3-pyridinyl)-3 (2H)-pyridazinone.

H-S. 6-(3-Ethyl-4-pyridinyl)-4,5-dihydro-3(2H)-pyridazinone.

H-6. 4,5-Dihydro-6-(2,6-dimethyl-4-pyridinyl )-3(1 H)-pyridazinone.

The usefulness of the compound of Formula I where R' is R" and R is lower-alkyl or lowerhydroxyalkyl, i.e., 2-R-4-R"-6-PY-3(2H)-pyridazinones, or salts thereof as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological test procedures, for example, in causing a significant increase in contractile force of the isolated cat atria and papillary muscle. Detailed descriptions of these test procedures appear in U.S. Patent 4,072,746.

When tested by said isolated cat atria and papillary muscle procedure, said 2-R-4-R"-6-PY3(2H)-pyridazinones or pharmaceutically-acceptable acid-addition salts thereof at doses of 30, 100 and/or 300 g/ml., were found to cause significant increases, that is, greater than 25% in papillary muscle force and/or significant increases, that is, greater than 25%, in right atrial force, while causing a lower percentage increase in right atrial rate. For example, when tested at said dose levels by this procedure, the following preferred compounds of Formula le were found to cause increases of from about 30% to over 200% in papillary muscle force and/or right atrial force: the compounds of Examples G-2 and G-3.When tested at said dose levels by this procedure, the following preferred compounds of Formula la, Ic, and Ib were found to cause increases of 28 to 72% in papillary muscle force and/or right atrial force: the compounds of Examples C-3, D-1 and E-2.

When tested by said anesthetized dog procedure, the compounds of Formula le or pharmaceutically-acceptable acid-addition salts thereof at doses of 1.0, 3.0 and/or 10 mg/kg administered intravenously were found to cause significant increases, that is, 25% or greater, in cardiac contractile force or cardiac contractility with lower changes in heart rate and blood pressure. For example, when tested at said dose levels by this procedure, a preferred compound, Example G-2, was found to cause increases of 46% and greater in contractile force and lower changes in heart rate and blood pressure.

In clinical practice a cardiotonically active compound or salt thereof of the present invention will normally be administered orally or parenterally in a wide variety of dosage form.

Solid composition for oral administration of the cardiotonically active compounds of the invention include compressed tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is admixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions can also contain additional substances other than inert diluents, e.g.

lubricating agents, such as magnesium stearate, talc and the like.

Liquid composition for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions can also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents.

According to the invention, the compounds for oral administration also includes capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents.

They can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, by irradiation or by heating. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

The percentages of active component in the said composition and method for increasing cardiac contractility can be varied so that a suitable dosage is obtained, The dosage administered to a particular patient is variable, depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto. An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing the best judgement on the patient's behalf.

Claims (23)

Claims

1. A 2-R4-R'-6-PY-3(2H)-pyridazinone having the Formula I (herein) or an acid-addition salt thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, loweralkyl or lower-hydroxyalkyl, and R' is amino, carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy.

2. A compound according to claim 1, where PY is 4-pyridinyl or 3-pyridinyl.

3. A compound according to claim 1 or 2, where R' is amino.

4. A compound according to claim 3, where R is hydrogen, methyl, ethyl or 2-hydroxyethyl.

S. 4-Amino-6-(4-pyridinyl)-3(2H)-pyridazinone or a pharmaceutically-accetable acid-addition salt thereof.

6. 4-Amino-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone or a pharmaceutically-acceptable acidaddition salt thereof.

7. A compound according to claim 1 or 2, where R' is carbamyl, aminocarbamyl, lowercarbalkoxy or carboxy.

8. A compound according to claim 7, where R is hydrogen, methyl or ethyl.

9. A process for preparing a compound according to claim 3 or 4, which comprises reacting a 2 R-6-PY-3(2H)-pyridazinone with hydrazine and, if desired, converting a free base obtained into an acidaddition salt thereof.

10. A process for preparing a compound according to claim 3 or 4, which comprises reacting a 2,3-d ihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide with a reagent capable of converting carbamyl to amino and, if desired, converting a free base obtained into an acid-addition salt thereof.

ii. A process for preparing a compound according to claim 3 or 4, which comprises reacting a 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide with a reagent capable of converting carboxylic acid hydrazide to amino and, if desired, converting a free base obtained into an acid-addition salt thereof.

12. A process for preparing a compound according to claim 7 or 8, which comprises reacting a di (lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate with a hydrazine salt of the formula R NHNH2. nHxAn to produce a compound where R' is lower-carbalkoxy, wherein n is 1 or 2, x is 1,2 or 3 and An is an anion of a strong inorganic acid or an organic sulphonic acid, if desired, reacting said compound obtained where R' is lower-carbalkoxy with hydrazine hydrate or anhydrous hydrazine to produce a compound where R' is aminocarbamyl, if desired, reacting a compound obtained where R' is lower-carbalkoxy with ammonia to obtain the compound where R' is carbamyl or hydrolyzing a compound obtained where R' is lower-carbalkoxy to obtain the compound where R' is carboxy, and, if desired, reacting a compound obtained where R' is carboxy with a chlorinating agent to form an acid chloride and reacting said acid chloride with ammonia to form a compound where R' is carbamyl, and, if desired, converting a free base obtained into an acid-addition salt thereof.

1 3. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic compound or pharmaceutically-acceptable acid-addition salt thereof according to any one of claims 1-8, where R' does not include carboxy, and R does not include hydrogen when R' is lower-carbalkoxy.

14. A process for preparing a compound according to claim 1, substantially as herein described with reference to any of the Examples.

15. A compound when prepared by a process according to any one of claims 11, 12 and 14.

16. A compound according to claim 1, or a cardiotonic composition comprising same substantially as herein described with reference to the Examples.

1 7. A compound for increasing cardiac contractility in a patient requiring such treatment which comprises a cardiotonic 4-amino-2-R-6-PY-3(2H)-pyridazinone or pharmaceutically-acceptable acidaddition salt thereof according to any one of claims 1-8, where R' does not include carboxy, and R does not include hydrogen when R' is lower-carbalkoxy.

18. Di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate of the Formula II (herein) or an acid-addition salt thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two loweralkyl substituents, and R1 is lower-alkyl.

19. A compound according to claim 18, where PY is 4-pyridinyl or 3-pyridinyl and R, is methyl or ethyl.

20. A process for preparing a compound according to claim 18, which comprises reacting an acetylpyridine of the formula PY-COCH3 with a di-(lower-alkyl)oxomalonate and, if desired converting a free base obtained into an acid-addition salt thereof.

21. A process for preparing a compound according to claim 18, substantially as herein described with reference to the Examples.

22. A compound when prepared by the process according to claim 20 or 21.

23. A compound according to claim 18, substantially as herein described with reference to the Examples.