GB2076807A - 4,5-Dihydro-6(pyridinyl)-3(2H)- pyridazinones - Google Patents

Abstract

2-R-4,5-dihydro-4-R'-6-PY- 3(2H)-pyridazinones (I) or salts thereof, which are useful as cardiotonics, where R is alkyl or hydroxyalkyl, R' is hydrogen or methyl and where R can also be hydrogen when R' is methyl and PY is 4- or 3- pyridinyl or 4- or 3-pyridinyl having one or two alkyl substituents, are prepared by reacting 4-oxo-4-PY-2- R'-butanenitrile with an N-R-hydrazine salt of a strong inorganic acid or organic sulfonic acid or by reacting an alkyl 4-oxo-4-PY-2-R'-butanoate or alkyl 4-(BN)-4-cyano-4-PY-2-R'- butanoate with N-R-hydrazine where BN is 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl. Compounds (I) may be converted to the corresponding 2-R-4- R'-6-PY-3(2H)-pyridazinones and their salts. The preparation of the starting materials and 2-(BN)-2-PY- ethanenitriles is described.

Description

SPECIFICATION 4,5-dihydro-6-(pyridinyl)-3(2H)-pyridazinones useful as cardiotonics and preparation thereof This invention relates to 2-substituted 4,5-dihydro-6-(pyridinyl)-3(2H)-pyridazonones, 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-(2pyridinyl)-3 (2H)-pyridazinone.

Yoshitomi Pharmaceutical Ind., Ltd. Japanese Patent Application Disclosure No. 1 9,987/79, published February 1 5, 1979 and based on Application No. 85,192/77 filed July 1 5, 1977, discloses, inter alia, the preparation 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 hydrazine hydrate. 4,5-Dihydro-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 anti-thrombus 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".

McEvoy and Allen [J. Org. Chem. 38,4044-48 (1973); J. Med. Chem. 17, 281-286 (1974)] show a method for preparing 3-(substituted-benzoyl)-3-substituted-alkanoic acids and their reaction with hydrazine to prepare 6-(substituted-phenyl)-5-substituted-4,5-dihydro-3 (2 H)-pyridazinones, hypotensive agents.

Curran and Ross [J. Med. Chem. 1 7, 273-281(1974)] show the preparation of 6-phenyl-4,5dihydro-3 (2H)-pyridazinones, hypotensive agents, by refluxing the requisite 3-benzoylpropionic acid with hydrazine hydrate in ethanol.

Albright, McEvoy and Moran [J. Heterocyclic Chem. 15, 881-892 (1978)] show the use of a (substituted-phenyl)-4-morpholineacetonitriles in 1,4-additions to ethyl acrylate, ethyl crotonate, methyl a-methylacrylate, acrylonitrile, methylacrylonitrile, crotononitrile and cinnamonitrile to produce 4cyano-4-(4-morpholinyl)-4-(substituted-phenyl)-butanenitriles and butanoic acid esters, and their conversion by reaction with hydrazine to 6-(substituted-phenyl)-4,5-dihydro-3 (2H)-pyridazones and, in turn their dehydrogenation by reaction with bromine to produce 6-(substituted-phenyl)-3-(2H)pyridazinones optionally bearing methyl at the 4-or 5-position of the pyridazinone ring.

McEvoy and Albright IJ. Org. Chem. 44, 4597--4603 (1 979)] show inter alia, the reaction of 2- cyano-2-(4 or 3-pyridinyl)-2-(4-morpholinyl) ethanenitrile with acrylonitrile or ethyl acrylate to produce respectively ethyl 4-cyano-4- (4- or 3-pyridinyl)-4-(4-morpholinyl) butanoate or 4-cyano-4-(4- or 3pyridinyl)-4-(4-morpholinyl)butanenitrile.

Leete et al. [J. Org. Chem. 37,4465-6 (1972)] show the reaction of 2-(3-pyridinyl)-2-(4morpholinyl)ethanenitrile with acrylonitrile to produce 4-cyano-4-(3-pyridinyl)-4-(4morpholinyl)butanenitrile and its conversion by heating it with acetic acid, water and tetrahydrofuran to 4-oxo-4-(3-pyridinyl)butanenitrile.

The present invention resides in 2-R-4,5-dihydro-4-R'-6-PY-3 (2H)-pyridazinones having formula I

or acid-addition salt, thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two loweralkyl substituents, R is lower-alkyl or lower-hydroxyalkyl and R' is hydrogen or methyl and where R can also be hydrogen when R' is methyl. These compounds where R is lower-alkyl or hydrogen are useful as cardiotonic agents, as determined by standard cardiotonic evaluation procedures. Preferred embodiments are those where PY is 4-pyridinyl or 3-pyridinyl, R is methyl or ethyl, and R' is hydrogen.

The above compounds of Formula I where R' is hydrogen are also described as intermediates in the preparation of 2-R-6-PY-3 (2H)-pyridazinones, cardiotonic agents, in our Application Serial No.

8027262 filed 21 August 1980 (Serial No. 2,057,438). The compounds of Formula I where R' is methyl can also be used to prepare corresponding novel 2-R-4-methyi-6-PY-3 (2H)-pyridazinones.

4,5-Dihydro-4-methyl-6-(4-pyridinyl)-3-(2H)-pyridazinone (I: PY is 4-pyridinyl, R' is methyl, R is hydrogen) may exist in tautomeric forms, that is, as 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3 (2H)pyridazinone having the formula IA and/or as 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3-pyridazinol having Formula IB, illustrated as follows (PY is 4-pyridinyl):

Actually, the two tautomers (IB and IA) are so closely interrelated as to be considered essentially one and the same compound and in any given set of circumstances such compound capable of tautomerism can exist in either or both tautomeric forms. Although we have preferred to use the name based on structure IA, it is understood that either or both structure are comprehended herein.

One can produce a 2-R-4,5-dihydro-4-R'-6-PY-3 (2H)-pyridazinone of Formula I by reacting 2-R'4-oxo-4-PY-butanenitrile, lower-alkyl 2-R'-4-oxo-4-PY-butanoate or lower-alkyl 2-R'-4-(BN)-4-cyano4-PY-butanoate with N-R-hydrazine or its salt of a strong inorganic acid or organic sulfonic acid to produce 2-R-4,5-dihydro-4-R'-6-PY-3 (2H)-pyridazinone, where PY, R' and R are defined as in Formula I. In preferred embodiments, this process is run using 2-R'-4-oxo-4-PY-butanenitrile and N-R-hydrazine salt of a strong inorganic or a organic sulfonic acid, e.g., N-R-hydrazine sulfate or dihydrochloride, or using methyl 2-R'-4-oxo-4-PY-butanoate or methyl 2-R'-4-(4-morpholinyl)-4-cyano-4-(PY)-butanoate with N-R-hydrazine.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceuticallyacceptable inert carrier and, as the active component thereof, a cardiotonically-effective amount of a 2 R-4,5-dihydro-4-R'-6-PY-3 (2H)-pyridazinone (Formula I) or pharmaceutically-acceptable acid-addition salt thereof, where R is lower-alkyl and, PY and R' are defined as in Formula I, or R' is methyl, R is hydrogen and PY is 4-pyridinyl.

For increasing cardiac contractility in a patient requiring such treatment one can administer orally or parenterally in a solid or liquid dosage form to such patient a composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, a cardiotonicallyeffective amount of 2-R-4,5-dihydro-4-R'-6PY-3 (2H)-pyridazinone or pharmaceutically-acceptable acid-addition salt thereof, where R is lower alkyl, and PY and R' are defined as in Formula I, or R' is methyl, R is hydrogen and PY is 4-pyridinyl.

The term "lower-alkyl" as used herein, e.g., as one of the meanings for R (Formula I), or as a substituent for PY (Formula I) 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, n-hexyl and the like.

The symbol PY as used here, e.g., as the 6-substituent in the compounds having Formula I, 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 Formula I, means hydroxyalkyl radicals having from 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 compounds of the invention having formula I, 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 salt 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 cardiotonicallyactive compounds (I) 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, sulfa mate, acetate, citrate, lactate, ta rtrate, 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 formula I were assigned on the basis of evidence provided by infrared, nuclear magnetic resonance and mass spectra, and by the correspondence of the calculated and found values for the elemental analysis.

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 2-R'-4-oxo-4-PY-butanenitrile with an N-R-hydrazine salt of a strong inorganic or organic sulfonic acid to produce 2-R-4,5-dihydro-4-R'-6-PY-3 (2H)-pyridazinone is carried out by heating the reactants at about 65-1 200C. in a suitable solvent, preferably at about 80-1 000C. in a mixture of water and a lower alkanol. The reaction is preferably run by refluxing 2-R'-4-oxo-4PYbutanenitrile with hydrazine sulfate in aqueous ethanol. Other N-R-hydrazine salts usable are N-R- hydrazine dihydrochloride, N-R-hydrazine dimethanesulfonate, and the like salts derived from phosphoric acid, ethanesulfonic acid, benzenesulfonic acid, and the like acids. Other lower-alkanols useful as solvents are methanol, n-propanol, 2-propanol, n-butanol, 2-butanol and 2-methyl-n-propanol.

This reaction is illustrated below in Examples A-i thru A--l 5.

The intermediate 2-R'-4-oxo-4-PY-butanenitriles are generally known compounds, e.g., Stetter et ai. Chem. Ber. 107, 210 (1974), Leete et al. J. Org. Chem. 37,4466(1972) and and Stetted yet al. U.S.

Patent 4,014,889 (Mar. 29, 1977), and are prepared by generally known methods. Preparation of these compounds is illustrated below in Examples C-i thru C-6.

The reaction of lower-alkyl 2-R'-4-oxo-4-PY-buta noate or lower-alkyl 2-R'-4-(BN)-4-cya no-4-PY- butanoate with N-R-hydrazine to produce 2-R-4,5-dihydro-4-R'6-PY-3 (2H)-pyridazinone is carried out by heating the reactants at about 65-i 200 C. in a suitable solvent, preferably at about 80-1 000C. in a lower-alkanol. The reaction is preferably run by refluxing the reactants in ethanol. Other lower-alkanols suitable as solvents are methanol, n-butanol, 2-butanol and 2-methyl-n-propanol. This reaction is illustrated below in Examples A-i 6 through A-24.

The intermediate lower-alkyl 2-R'-4-oxo-4-PY-butanoates and/or corresponding acids are generally known compounds [Wada et al. J. Am. Chem. Soc. 76, 155 (1954)], which are readily obtained by hydrolysis of said generally known 2-R'-4-oxo-4-PY-butanenitriles and esterification of the resulting 2-R'-4-oxo-4-PY-butanoic acids.

The reaction of 2-(BN)-2-PY-ethanenitrile (III) with lower-alkyl 2-R'-2-propenoate (IV) to produce lower-alkyl 2-R'-4-(BN)-4-cyano-4-PY-butanoate (II) is carried out under anhydrous conditions by mixing the reactants at about 250C. to 600 C., preferably about 300 C. to 500 C., in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently run by mixing the reactants at about 300C. to 500C. in dry tetrahydrofuran in the presence of an alkali hydroxide in methanol. Other suitable solvents are other lower-alkanols, e.g., ethanol or isopropyl alcohol, dimethylformamide, acetonitrile tetrahydrofuran, benzene and the like.Suitable basic condensing agents include alkali hydroxides, e.g., potassium or sodium hydroxide, alkali lower-alkoxides, e.g., sodium methoxoide or potassium ethoxide, sodium hydride, and the like.

The intermediate 2-(BN)-2-PY-ethanenitriles (III) are generally known compounds, e.g., Janssen et al., J. Am. Pharm. Assoc., Sci. Ed., 44, 465--7 (1955), and are prepared by generally known methods.

Preparation of these compounds is illustrated below in Examples E-i through E-5.

The conversion of the intermediate 4,5-dihydro-2-R-4-R'-6-PY-3 (2H)-pyridazinones by reaction with bromine to the corresponding 2-R-4-R'-6-PY-3 (2H)-pyridazinones, the 2-R-4-R'-6-PY-3 (2H)pyridazinones produced by the conversion and the use of the latter where R' is hydrogen as cardiotonics are disclosed and claimed in our above co-pending Application. This conversion and products produced thereby is illustrated below in Example B-l for a compounds where R' is hydrogen and in Examples B-2 through B-9 for compounds where R' is methyl.

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

A. 4, 5-Dihydro-2-R-4-R '-6-P Y-3 (2H)-pyridazinones A--l. 4,5-Dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone -- To a stirred hot solution containing 25.6 g of N-methylhydrazine dihydrochloride, 400 ml. of absolute ethanol and 70 ml. of water was added 32 g. of 4-oxo-4-(4-pyridinyl)butanenitrile and the resulting reaction mixture was refluxed overnight (about 1 5 hours). The solvent was distilled off in vacuo and the resulting solid was recrystallized from ethanol and dried in a vacuum oven at 65 OC. overnight to yield 10.5 g. of 4,5dihydro-2-methyl-6-(4-pyridinyl)3 (2H) pyridazinone as its monohydrochloride, m.p. 21 9--225 OC, with decomposition.

Acid-addition salts of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone are conveniently prepared by added to a mixture of 1 g. of 4,5-dihydro-2-methyl-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 salt of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example A-i but using in place of N-methylhydrazine dihydrochloride a molar equivalent quantity of the appropriate N-R-hydrazine dihydrochloride or other salt of a strong inorganic acid or organic sulfonic acid, it is contemplated that there can be obtained the corresponding 4,5-dihydro-2-R-6-(4-pyridinyl)-3 (2H)-pyridazinones (or salts thereof) of Examples A-2 thru Am10.

A2. 2-Ethyl-4,5-dihydr6-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A-3. 4,5-Dihydro-2-isopropyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A--4. 4,5-Dihydro-2-n-propyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A--5. 4,5-Dihydro-2-isobutyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A--B 2-n-Hexyl-4,5-dihydro-6-(4-pyridlnyl)-3 (2H)-pyridazinone.

A-7. 2-(;2-Hydroxyethyl)-4,5-dihydro-6-(4-pyridinyl)-3 (2H)-pyridazinone, m.p. 142--1440C.

A-8. 2-(2Hydroxypropyl)-4,5-dihydro-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A9.2-(3-Hydroxypropyl)-4,5-dihydro-6-(4-pyridinyl)-3 (2 H)-pyridazinone.

A-1 0. 2-(4Hydroxybutyl)-4,5-dihydro-6-(4-pyridinyl)-3 (2H)-pyridazinone.

Following the procedure described in Example A-1 but using in place 4-oxo-4-(4pyridinyl)butanenitrile a molar equivalent quantity of the appropriate 4-oxo-4-PY-butanenitrile, it is contemplated that the 4,5-dihydro-6-PY-2-methyl-3 (2H)-pyridazinones of Examples A-i 1 through A-1 5 can be obtained.

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

A-I 2. 4,5-Dihydro-2-methyl-6-(2-methyl-3-pyridinyl)-3 (2H)-pyridazinone.

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

A-1 4. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4,5-dihydro-2-methyl-3 (2H)-pyridazinone.

A-1 5. 4,5-Dihydro-2-methyl-6-(2,6-dimethyl-4-pyridinyl)-3 (2 H)-pyridazinone A-1 6. 4,5-Dihydro-2,4-dimethyl-6-(4-pyridinyl)-3 (2H)-pyridazinone - A mixture containing 16 g.

of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate,30 ml. of Nmethylhydrazine and 220 ml. of absolute ethanol was refluxed with stirring for about seventeen hours.

The ethanol was distilled off in vacuo and the remaining oily material was placed on a column of silica gel (7 cm. high and 1 5 cm. in diameter) in a large scintered glass funnel and eluted with a 5050 mixture (by volume) of ether and n-hexane. Evaporation of the eluants containing the bulk of the product, as indicated by tic analysis (CHCL3: CH3OH: i-C3H7NH2/90%: 5%: 5% by volume), yielded solid product, which was recrystallized from ether-n-hexane and dried in vacuo at 500 C, to yield 3.0 g. of 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3 (2H)-pyridazinone, m.p. 71-81 0C.

Acid-addition salts of 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3 (2H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g. of 4,5-dihydro-2,4-dimethyl6-(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 salt of 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3 (2H)pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3 (2H)-pyridazinone and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example A-1 6 but using in place of methyl 4-cyano-4-(4morpholinyl)-4-(4-pyridinyl)-2-methylbutanoate and N-methylhydrazine corresponding molar equivalent quantities of the appropriate respective lower-alkyl 4-cyano-4-(BN)-4-PY-2-methylbutanoate and NR- hydrazine, it is contemplated that the corresponding 4,5-dihydro-4-methyl -6-PY-2-R-3 (2H)pyridazinones of Examples A-1 7 through A-23 can be obtained.

A-1 7. 4,5-Dihydro-2,4-dimethyl-6-(3-pyridinyl)-3 (2H)-pyridazinone.

A-1 8. 2-Ethyl-4,S-dihydro-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A-1 9. 4,5-Dihydro-4-methyl-2-n-propyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A-20. 4,5-Dihydro-2-isopropyl-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

A-2 1. 2-(n-Butyl)-4,5-dihydro-4-methyl -6-(4-pyridinyl)-3 (2H)-pyridazinone.

A-22. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4,5-dihydro-4-methyl-3 (2 H)-pyridazinone.

A-23. 4,5-Dihydro-2-(2-hydroxyethyl) -4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

Following the procedure described in Example A-1 6 but using in place of methyl 4-cyano-4-(4morpholinyl)-4-(4-pyridinyl)-2-methylbutanoate a molar equivalent quantity of methyl 2-methyl-4-oxo4-(4-pyridinyl)butanoate, it is contemplated that there can be obtained 4,5-dihydro-2,4-dimethyl-6-(4- pyridinyl)-3 (2H)-pyridazinone. Also, this same compound can be obtained following the procedure described in Example A-1 but using place of 4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of 2-methyl-4-oxo-4-(pyridinyl)butanenitrile.

A--24. 4,S-Dihydrn-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone -- A mixture containing 1 5 g.

of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, 26 ml. of 85% hydrazine hydrate and 220 ml. of absolute ethanol was refluxed with stirring for about seventeen hours and the solvent was distilled off in vacuo. The remaining crystalline residue was recrystallized from ethyl acetate, dried at 900 C. and combined with another sample of the same compound prepared by the same procedure starting with ii g. of methyl 4-cyano-2-methyl-4(4-morpholinyl)-4-(4-pyridinyl)butanoate and recrystallizing the product from acetonitrile.The combined samples were recrystallized from isopropyl alcohol using decolorizing charcoal and dried at 1 200C, to yield 1 0 g. of 4,5-dihydro-4methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone, m.p. 184-i 850C., tautomeric with 4,5-dihydro-4-methyl6-(4-pyridinyl)-3-pyriduzinol.

Acid-addition salts of 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone are conveniently prepared by following the same procedure as described in Example A-i.

Following the procedure described in Example A--24 but using in place of methyl 4-cyano-2methyl-4(4-morpholinyl)-4-(4-pyridinyl)butanoate a molar equivalent quantity of the appropriate loweralkyl, preferably, methyl or ethyl, 4-cyano-2-methyl-4-(BN)-4-(4-pyridinyl)butanoate where BN is 1piperidinyl or 1-pyrrolidinyl, it is contemplated that 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3 (2H)pyridazinone can be obtained.

B-i 2-Methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone-To a warm solution containing 28 g. of 4,5 dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone monohydrochloride and 140 ml. of acetic acid was added with stirring 100 ml. of bromine, and the resulting reaction mixture was refluxed overnight and then allowed to cool to room temperature. The solid that had separated was collected, stirred with 1 50 ml. of water and to the aqueous mixture was added sodium bisulfite until bubbling ceased. To the resulting pale yellow solution was added sufficient solid sodium bicarbonate to make it mildly basic to litmus and the resulting mixture was extracted with chloroform.The chloroform extract was heated in vacuo to remove the solvent and the resulting solid was recrystallized from methanol-ether and dried in a vacuum oven at 600 C. overnight to yield 1 5 g. of 2-methyl-6-(4-pyridinyi)-3 (2H)-pyridazinone, m.p.

175-1 850C.

Acid-addition salts of 2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g. of 2-methyl-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, methansulfonate, sulfate, respectively. Also,. the lactate or hydrochloride acid-addition salt of 2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 2-methyl-6-(4-pyridinyl)-3 (2H)pyridazinone and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example B-1 but using in place of 4,5-dihydro-2-methyl-6 (4-pyridinyl)-3 (2H)-pyridazinone or monohydrochoride thereof a corresponding molar equivalent quantity of the appropriate 4,5-dihydro-2-R-4-R'-6-PY-pyridazinone or monohydrochloride salts thereof, it is contemplated that the corresponding 2-R-4-R'-6-PY-3 (2H)-pyridazinones of Examples B-2 thru B-9 can be obtained.

B--2. 2,4-Dimethyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

B-3. 2,4-Dimethyl-6-(3-pyddinyl)-3 (2H)-pyridazinone.

B--4. 2-Ethyl-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

B--5. 4-Methyl-2-n-propyl-6-(4-pyridinyl) 3 (2H)-pyridazinone.

B--6. 2-lsopropyl-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

B-7. 2-(n-Butyl)-4-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.

B-8. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4-methyl-3 (2H)-pyridazinone.

B-9. 2-(2-Hydroxyethyl)-4-methyl-6-(4-pyridinyl) 3 (2H)-pyridazinone.

C. 4-Oxo-4-PYbutanenitriles C-i. 4-Oxo-4-(4-pyridinyl)butanenftrlle -To a stirred mixture containing 29.4 g. of sodium cyanide and 500 ml. of acetonitrile, after stirring said mixture for ten minutes, was added dropwise over a period of three hours a solution containing 64.2 g of 4-pyridinecarboxaldehyde in 500 ml. of acetonitrile and the resulting mixture was stirred at room temperature for one hour. To the stirred mixture was added slowly over a period of one hour a solution of 24.5 g. of acrylonitrile in 200 ml. of acetonitrile and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was stripped in vacuo of solvent at a temperature not exceeding 540 C. The semi-solid residue was cooled, mixed well with 400 ml. of chloroform, and the mixture filtered.The chloroform was distilled off in vacuo at a temperature not exceeding 500 C. and the residual oily residue was extracted with three 200 ml. portions of toluene. The toluene solution was filtered through diatomaceous earth and the filtrate was distilled in vacuo below 500 C. to remove the toluene. The residue on chilling crystallized. A tiny sample was saved and the remainder was dissolved in 50 ml. of warm isopropyl alcohol. The solution was cooled and then diluted slowly with 125 ml. of ether, chilled and seeded with a crystal obtained from said tiny sample. The crystalline product that separated was collected, washed with 25 ml. of 1:3 (v:v) mixture of isopropyl alcohol:ether, and air dried to yield 52.1 g. of 4-oxo-4-(4pyridinyl)butanenitrile, m.p. 53.5-55 0C.

Following the procedure described in Example C-i but using in place of 4 pyridinecarboxaldehyde a molar equivalent quantity of the appropriate 4- or 3-PY-carboxaldehyde, it is contemplated that there can be obtained the corresponding 4-oxo-4-PY-butanenitriles of Examples C-2 thru C-6, respectively.

C-2. 4-Oxo-4-(3-pyridinyl)butanenitrile.

C-3. 4-(2-Methyl-3-pyridinyl)-4-oxobutanenitrile.

C-4. 4-(5-Methyl-3-pyridinyl)-4-oxobutanenitrile.

C-S. 4-(3-Ethyl-4-pyridinyl)-4-oxobutanenitrile.

C-6. 4-(2,6-Dimethyl-4-pyridinyl)-4-pyridinyl)-4-oxobutanenitrile.

Following the procedure described in Example C-i but using in place of acrylonitrile a molar equivalent quantity of methacryonitrile, it is contemplated that their can be obtained the corresponding compound of Example C-7.

C-7. 2-Methyl-4-oxo-4-(4-pyridinyl)butanenitrile.

D. LOWER-ALKYL 4-(BN)-4-C YANO-4-PY-2-R'-BUTANOA TES D-1. Methyl 4-Cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate - To a mixture containing 16 g. of 2-(4-morpholinyl)-2-(4-pyridinyl)ethanenitrile and 1 50 ml. of tetrahydrofuran in a flask equipped with a stirrer and drying tube was added with stirring 6 ml. of 30% potassium hydroxide in methanol, followed by 8.5 g. of methyl methacrylate. Within thirty minutes an exothermic reaction ensued and a white solid began to separate. The reaction mixture was stirred for one hour and then allowed to stand at room temperature overnight. The reaction mixture was concentrated by heating in vacuo to remove solvent and the remaining residue was triturated with absolute ether (about 600 ml.) and filtered.The filtrate was concentrated to a volume of about 50 ml., cooled, treated with 50 ml. of nhexane and chilled. The product that separated was collected and dried at 700 C. to yield 11 g. of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, m.p. 93--940C.

Acid-addition salts of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate are conveniently prepared by adding to a mixture of 1 g. of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4 (4-pyridinyl)butanoate 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 salt of methyl 4-cyano-2-methyl 4-(4-morpholinyl)-4-(4pyridinyl)-butanoate is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4(4-pyridinyl)butanoate and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example D-1 but using in place of 2-(4-morpholinyl)-2-(4pyridinyl)-ethanenitrile and methyl methacrylate molar equivalent quantities respectively of the appropriate 2-(BN)-2-PY-ethanenitrile and lower-alkyl methacrylate, it is contemplated that there can be obtained the corresponding lower-alkyl 4-cyano-2-methyl-4-(BN)-4-PY-butanoates of Examples D-2 through D-6.

D-2. Methyl 4-cyano-2-methyl-4-( 1 -piperidinyl)-4-(4-pyridinyljbutanoate.

D-3. Methyl 4-cyano-2-methyl-4-(4-pyridinyl)-4-( 1 -pyrrolidinyl)butanoate.

D-4. Methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(3-pyridinyl)butanoate.

D-5. Ethyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate.

D-6. n-Propyl 4-cyano-4-(3-ethyl-4-pyridinyl)-2-methyl-4-(4-morpholinyl)butanoate.

E. 2-(BN)-2-PY-ETHANENITRlLES -These generally known intermediates can be prepared by reacting a cyclic amine of the formula BN-H and an alkali cyanide with a PY-aldehydebisulfite complex according to Janssen et al [J. Am. Pharm. Assoc., Sci. Ed. 44,465-7 (1955)] or by the following alternative procedure described in Example E-1.

E-1. 2-(4-Morpholinyl)-2-(4-pyridinyl)ethanenitrile - A mixture containing 72 g. of 4pyridinecarboxaldehyde, 140 g. of morpholine, 152 g. of p-toluenesulfonic acid and 800 ml. of tetrahydrofuran was refluxed with stirring for two hours and then allowed to cool to room temperature. To the stirred reaction mixture was added 64 g. of potassium cyanide in 20 ml. of water and the resulting reaction mixture was refluxed for two hours and allowed to stand overnight at room temperature. The reaction mixture was filtered and the filtrate was heated in vacuo to remove the solvent. To the resulting gummy residue was added about 800 ml. of chloroform and about 300 ml. of saturated sodium chloride solution. The mixture was stirred for two hours and filtered.The heterogenous filtrate was transferred to a separatory funnel, shaken well, and the chloroform layer drained off and heated in vacuo to remove the chloroform. The residue was boiled with about 300 ml. of water, chilled and seeded whereupon pale yellow crystals separated. The filtrate was concentrated in vacuo to a volume of about 60 ml. and a second crop of pale yellow crystals was obtained. The combined crops of yellow crystals were dried first in a vacuum oven at 100 mm. and 250C., and then for 100 hours over P2Os to yield 40 g. of 2-(4morpholinyl)-2-(4-pyridinyl)ethanenitrile, m.p. 64-650C.

Following the procedure described in Example E-1 using a molar equivalent quantities of the respective appropriate pyridinecarboxaldehyde and amine (BN-H) in place of 4pyridinecarboxyaldehyde and morpholine, it is contemplated that there can be obtained the corresponding 2-(BN)-2PY-ethanenitriles of Examples E-2 through E-5.

E-2. 2-(4-Pyridinyl)-2-( 1 -pyrrolidinyl)ethanenitrile.

E-3. 2-( 1 Piperidinyl)-2-(4-pyridinyl)ethanenitrile.

E-4. 2-(3-Ethyl-4-pyridinyl)-2-(4-moropholinyl)-ethanenitrile.

E-5. 2-(5-Methyl-3-pyridinyl)-2-(4-morpholinyl)-ethanenitrile.

The usefulness of the compounds of formula I or salts thereof as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological test procedures, for example, in causing a siginificant increase in contractile force of the isolated cat atria and papillary muscle and in causing a significant increase in the cardiac contractile force in the anesthetized dog with low or minimal changes in heart rate and blood pressure. Detailed descriptions of these test procedures appear in U.S. Patent 4,072,746, issued February 7, 1980.

When tested by said isolated cat atria and papillary muscle procedure, the compounds of formula I or pharmaceutically-acceptable acid-addition salts thereof at doses of 10, 30, 100 and/or 300,ug/ml.

were found to cause significant increases, that is, greater than 25% in papillary muscle force and significant increases, that is, greater than 25%, in right atrial force, while causing a lower percentage increase (about one-third or less than the percentage increase in right atrial force or papillary muscle force) in right atrial rate.For example, when tested at dose levels of 10, 30 and 100 Mg/ml. by this procedure, the compound of Example A-i, i.e., 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)pyridazinone as its monohydrochloride, was found to cause increases of 35% to 77% in papillary muscle force and/or right atrial force; when tested at 100 ,ug/ml. by the comparable test procedure using isolated guinea pig atria and papillary muscle, the compound of Example A-i 6, i.e. 4,5-dihydro-2,4dimethyl-6-(4-pyridinyl)-3 (2H)-pyridazinone, was found to cause respective increases of 75% and 63% in papillary muscle force and right atrial force. 4,5-Dihydro-4-methyl-6-(4-pyridinyl)-3 (2H)pyridazinone (Example A-24) was found to cause respective increases of 139% and 86% in papillary muscle force and right atrial force at 100 Mg./ml. and a papillary muscle force increase of 45% in a papillary muscle force at 30 ygiml.

In clinical practice said compound or salt thereof of Formula I where R is lower-alkyl will normally be administered orally or parenterally in a wide variety of dosage forms. Solid compositions for oral administration 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.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspensing media are propylene glycol, polyethylene glycol, vegetable oils such as oliver 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 (8)

1. A 4,5-dihydro-2-R-4-R'-6-PY-3 (2H)-pyridazinone having the Formula I (herein) or an acidaddition salt thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is lower-alkyi or lower-hydroxyalkyl and R' is hydrogen or methyl and where R can also be hydrogen when R' is methyl.

2. A compound according to claim 1, where R is methyl or ethyl.

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

4. A compound according to claim 1 or 2, where R' is methyl and R is not hydrogen.

5. 4,5-Dihydro-2-methyl-6-(4-pyridinyl)-3 (2H)-pyridazinone or a pharmaceutically-acceptable acid-addition salt thereof.

6. 4,5-Dihydro-4-methyl -6-(4-pyridinyl)-3 (2H)-pyridazinone or a pharmaceutically-acceptable acid-addition salt thereof.

7. A process for preparing a compound according to any one of claims 1-4, which comprises reacting a 2-R'-4-oxo-4-PY-butanenitrile, lower-alkyl 2-R'-4-oxo-4-PY-butanoate or lower- alkyl 2-R'-4 (BN) 4-cyano-4-PY-butanoate with N-R-hydrazine or its salt of a strong inorganic acid or organic sulfonic acid, and, if desired, converting a free base obtained to an acid-addition salt thereof R', PY, and R being as defined in claim 1 and BN being 4-morpholinyl,1-piperidinyl or 1-pyrrolidinyl.

7. A process for preparing a compound according to any one of claims 1-4, which comprises reacting a 2-R'-4-oxo-4-PY-butanenitrile, lower-alkyl 2-R'-4-oxo-4-PY-butanoate or lower-alkyl 2-R'-4 (BN) 4-cyano-4-PY-butanoate with N-R-hydrazine or its salt of a strong inorganic acid or organic sulfonic acid, and, if desired, converting a free base obtained to an acid-addition salt thereof.

8. A process according to claim 7, in which ?-R-4-oxo-2-R'-4-PY-butanenitrile and an N-R- hydrazine salt of an organic sulfonic acid or an organic sulfonic acid are reacted.

9. A process according to claim 7, in which methyl 2-R'-4-(1 -morpholinyl)-4-cyano-4-PYbutanoate or methyl 2-R'-4-oxo-4-PY-butanoate and N-R-hydrazine are reacted.

10. A process according to claim 7, in which a lower-alkyl 2-methyl-4-(BN)-4-cyano-4-(4pyridinyl)butanoate is reacted with hydrazine or 4-oxo-2-methyl-4-(4-pyridinyl)butyronitrile is reacted with a hydrazine salt of a strong inorganic or sulfonic acid to produce 4,5-dihydro-4-methyl-6-(4pyridinyl)-3 (2H)-pyridazinone or a pharmaceutically acceptable acid-addition salt thereof.

11. A process for preparing a compound according to claim 1, substantially as herein described with reference to Examples A-1 to A-1 6.

12. A process for preparing a compound according to claim 1, substantially as herein described with reference to Examples A-i 7 to A-23.

1 3. A process for preparing a compound according to claim 6, substantially as herein described with reference to Example A-24.

14. A compound when prepared by the process according to any one of claims 7-13.

1 5. A compound according to claim 1, substantially as herein described with reference to Examples A-1 to A1 6.

1 6. A compound according to claim 1, substantially as herein described with reference to Examples A-1 7 to A-23.

1 7. A compound according to claim 6, substantially as herein described with reference to Example A-24.

1

8. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, a cardiotonicallyeffective amount of a compound according to any one of claims 1-5, where R is lower-alkyl or a compound according to claim 6, or a pharmaceutically-acceptable acid-addition salt thereof.

19. A cardiotonic composition according to claim 18, substantially as herein described with reference to the Examples.

20. A compound for increasing cardiac contractility in a patient requiring such treatment which is a compound according to any one of claims 1-5, where R is lower-alkyl or a compound according to claim 6, or a pharmaceutically-acceptable acid-addition salt thereof.

New claims or amendments to claims filed on 14-8-81 New or amended claim