CA1166255A - 4,5-dihydro-2-substituted-6-(pyridinyl)-3(2h)- pyridazinones, preparation and cardiotonic use thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
2-R-4,5-dihydro-4-R'-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as cardiotonics, where R is lower-alkyl, R' is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-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 a lower-alkyl 4-oxo-4-PY-2-R'-butanoate or lower-alkyl 4-(sN)-4-cyano-4-PY-2-R'-butanoate with N-R-hydrazine where BW is 4-morpholinyl, 1-piperidinyl or l-pyrrolidinyl. Also shown are: a) cardiotonic compositions and a method for increasing cardiac contractility using said compounds or salts where R is lower-alkyl b) the use of I as intermediates in preparing the corresponding 2-R-4-R'-6-PY-3(2H)-pyridazinones; and, c) the preparation of said lower alkyl 4-(BN)-4-cyano-4-PY-2-R'-butanoates.

Description

s Thi~ invention relates ~o 4,5-dihydro-6-(pyridinyl)-3(2~l-pyridazinones~ which may bear a 2-substituent, useful as cardiotonic agents, to their preparation, and to their use as cardiotonic agents.
Haginiwa et al. [Yakugaku Zasshi 98 (1), 67 - 71 ~1978l; Chem. Abstrs. 88, 170,096v ~1978)] reacted 3(2H)-pyridazinone with pyridine l-oxide and platinized Pd-C
catalyst to produce 6-~2-pyridinyl)-3~2H)-pyridazinone.
Yoshitomi Pharmaceutical Ind., Ltd. Japanese Patent Applicatlon Disclosure No. 19,987/79, published February 15, 1979 and based on Application No. 85,192/77, filed July lS, 1977, discloses, inter alla, the preparatlon of 4,5-dihydro-6-(4-pyridinyl)-3~2H)-pyrldazinone by re-fluxing for two hours an ethanolic solution of 3-(iso-nicotinoyl)propanoic acid [same as r-oxo-y-(4-pyridinyl)-butyric acid] and hydrazine hydrate. 4,5-Dihydro-6-~4-pyridinyll-3~2H~-pyridazinone and closely related 4,5 di-hydro-6-~4- or 3- or 2-pyridinyl)-5-R-3(2H)~pyridaziJIones, . ~

D`~;~ 3 7 0 0A
, 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 ~hey 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. Che~. 38, 4044-48 (1973); J. Med. Chem. 17, 281-286 (1974)] show a me~hod for preparing 3-(substituted-benzoyl)-3-sub~tituted-alkanoic acids and their reaction with hydraæine to prepare 6-(sub-stituted-phenyl)-5-substituted-4,5-dihydro-3(2H) pyrida-zinones, hypotensive agents.
Curran and Ross [J~ Med. Chem. 17, 273-281 (1974)]
show the preparation of 6-phenyl-4,5-dihydro-3(2H)-pyrida-zinones, hypotensive agents, by refluxing the requisite 3-benzoylpropionic acid with hydrazine hydra~e in ethanol.
Albright, McEvoy and Moran [~. Heterocyclic Chem.
15, 881-892 (1978)] show the use of q-(substituted-phenyl)-4-morpholineacetonitriles in 1,4-additions to ethyl acrylate, ethyl crotonate, methyl ~-methylacrylate, acrylonitrile, methylacrylonitrile, crotononitrlle and cinnamonitrile to produce 4-cyano-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(2~)-pyridazinones and, in turn, their dehydro-genation 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.

s McEvoy and Albright [~. Org. Chem. 44, 4597-4603 (1979)] 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 3-pyridinyl)-4-(4-morpholinyl~butanenitrile.
Leete et al. [J. Org. Chem. 37, 4465-6 (1972)] shows the reaction of 2-(3-pyridinyl)-2-(4-morpholinyl)ethanenitrile with acrylonitrile to produce 4-cyano-4-(3-pyridinyl)-4-(4-morpholinyl)butanenitrile and its conversion by heating it withacetic acid, water and tetrahydrofuran to 4-oxo-4-(3-pyridinyl)-butanenitrile.
The present invention provides novel 2-R-4,5-dihydro-4-R'-6-PY-3(2H)-pyridazinones having formula I

PY -- O
N - N

or pharmaceutically-acceptable acid-addition salts thereof, where PY is 4- or 3-pyridinyl or 4~ or 3-pyridinyl having one or two (Cl-C6)-alkyl substituents, R is hydrosen or (Cl-C6)-alkyl and R' is hydrogen or methyl, provided that where R is hydrogen, R' is methyl and PY is 4-pyridinyl. These compounds where R is hydrogen or (Cl-C6)-alkyl are useful as cardiotonic agents, as determined by standard cardiotonic ,, -~

g~,S

evaluation procedures. All of the compounds of formula I also are use~ul as intermediates in the preparation of 2-R-6-PY-3(2H)-pyridazinones, cardiotonic agents. Pre~erred embodiments are those where PY is 4-pyridinyl or 3-pyridinyl, R is methyl or ethyl, and Rl is hydrogen, or where PY is 4-pyridinyl, R is hydrogen and R' is methyl.
According to the invention there is provided a process for preparing a 2-R-4,5-dihydro-4-R'-6-P~-3(2H)pyridazinone of the formula R' PY ~ / (I) _ I

or an acid-addition salt thereof, where PY is 4- or 3-pyridinyl, or 4- or 3-pyridinyl having one or two (Cl-C6)-alkyl substituents, R is hydrogen or (Cl-C6~-alkyl, and R' is hydrogen or methyl, provided that where R is hydrogen, R' is methyl and PY is 4-pyridinyl, which comprises reacting a butanoic acid derivative selected from 2-R'-4-oxo-4-PY-butanenitrile, (Cl-C6)-alkyl

2-R'-4-oxo-4-PY-butanoate and (Cl-C6)-alkyl 2-R'-4-(BN)-4-cyano-4-PY-butanoate, where (BN) is 4-morpholinyl, l-piperidinyl or l-pyrrolidinyl, with N-R-hydra~ine or a salt thereof with a ~ -5-~ rj strong inorganic acid or an organic sulfonic acid, and where required converting a product so obtained into an acid addition salt thereof.
In preferred embodiments, this process is run using 2-R'-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.
The invention also provides a process for the preparation of 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H~-pyridazinone or a pharmaceutically-acceptable acid-addition salt thereof, which comprises reacting a (Cl-C6)-alkyl 2-methyl-4-(BN)-4-cyano-4-(4-pyridinyl)butanoate with hydrazine, where (sN) is 4-morpholinyl, l-piperidinyl or l-pyrrolidinyl, and where required converting the product into a pharmaceutically-acceptable acid-addition salt thereof.
A composition aspect of the invention resides in the novel cardiotonic compounds o formula (I) may be formulated as compositions for increasing cardiac contractility, such a composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, a cardiotonically~
effective amount of a cardiotonic 2-R-4,5-dihydro-4-R'-6-PY-

3(2H)-pyridazinone (formula I) or pharmaceutically-acceptable acid-addition salt thereof, where R is (Cl-C6)-alkyl, R' is hydrogen or methyl and, P~ is de-Eined as in formula I or where R is hydrogen, R' is methyl and PY is 4-pyridinyl.
The novel cardiotonic compounds may be employed for increasing cardiac contractility in a patient requiring ~ -6-such treatment by administering orally or parenterally in a solid or liquid dosage form to such patient a composition com-prising a pharmaceutically-acceptable inert carrier and, as the active component thereof, a cardiotonically~effective amount of 2-R-4,5-dihydro-4-R'-6-PY-3(2~)-pyridazinone or pharmaceutically-acceptable acid-addition salt thereof, where R is hydrogen or (Cl-C6)-alkyl, and PY and R' are defined as in formula I.
Preferred emboidments are those where PY is 4-pyridinyl or 3-pyridinyl, R is methyl or ethyl, and R' is hydrogen, or where PY is 4-pyridinyl, R is hydrogen and R' is methyl.
The lower-alkyl groups as used herein, e.g., as one of the meanings for R (formula I), or as a substituent for PY (formula I) are 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 is 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-pyridinyll 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-pyridinyll 2,6-di-n-hexyl-4-pyridinyl, and the like.

, . ~i . .

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 cardiotonically-active 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, ~ ; ~8-DN 3700h ;P;~br~l quinic acid, and the like, giving ~he hydrochloride, ;
sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, éthanesulfonate, benzenesul-fonate, 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 con-taining 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 acid-addition salts are within the scope of our inventio~. 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 i5 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 formula I were assigned on the basis of evidence provided by infrar~d, nuclear magentic resonance and mass spec~ra, and by the correspondence of the calculated and found values for the elemental analysis.
~he manner of making and using the instant inven~
tion 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 Z-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-di-hydro-4-R'-6-PY-3(?H)-pyridazinone is carried out by heating the reactants at about 65 - 120C. in a suitable sol~ent, preferably at about 8~ - 100C. in a mixture o~ water and a lower alkanol. The reaction is preferably run by refluxing 2-R'-4-oxo-4-PY-butanenitrile 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, et~anesulfonic acid, benzenesulfonic acid, and the like acids. Other lower-alkanols useful as solvents are methanol, n-propanol, 2-propanol7 n-butanol, 2-butanol and 2-methyl-n-propanol. Thls reaction is illustrated below in Examples A-l thru A-15.

4,5-Dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridine also can be pre-pared ~y-reacting 4-oxo-2-methyl-4-(4-pyridinyl)-butyronitrile with a hydra-zine salt of a strong inorganic or organic sulfonic acid to produce 4,5-di-hydro-6-(4-pyridinyl)-3(2H)-pyridazinone. This reaction is carried out by heating the reactants at about 65 - 120C. in a suitable solvent, preferably at about 80 - lQ0C. in a mixture of water and a lower alkanol. The reaction is preferably run by refluxing 4-oxo-2-methyl-4-(4-pyridinyl)butyronitrile with hydrazine sulfate in aqueous ethanol. Other hydrazine salts usable are hydrazine dihydrochloride, 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. Other solvents can be used, e.g., dimethylformamide.
The intermediate 2-~BN~-2-(4-pyridinyl)ethane-nitriles are generally known compounds, e.g., Janssen et al., J. Am. Pharm. Assoc., Sci.
Ed., 44 465 - 7 (19551, and are prepared by generally known methods.

The intermed~ate 2~ 4-oxo-4-PY-butanenitriles are generally kn~wn compounds, e.gO, Ste~ter et al. Chem.
Ber. lQ7, 210 ~1~74), Leete et al. J. Org. Chem. 37, 4466 (19721 and Stetter et al. United States Patent 4,014,889 (March 29, 1977), and are prepared by generally known methods. Preparation of these compounds is illustrated below in Examples C-l thru C-6.
The reaction of lower-alkyl 2~R'-4-oxo-4-PY
6utanoate or iower-alkyl 2-R'-4-(BN)-4-cyano-4-PY-butanoate lQ with N-R-hydrazine to produce 2-R-4,5-dihydro-4-R'-6-PY-3(2H)-pyridazinone is earried out by heating the reactants at about 65 - 120C. in a suitable solvent, preferably at - lOa -~W 3700~

about 80-100C. in a lower-alkanol. The reaction i5 pre-ferably 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 illus-trated below in Examples A 16 through A-23.
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-tBN)-4-cyano-4-PY-butanoa~e (II) is carried out under anhydrous conditions by mixing the reactants at about 25C. to 60C., preferably about 30C. to 50C., in a suitable solvent in the presence of a basic condensing agent. ~he reaction is conveniently run by mixing the reactants at about 30C. to 50C. 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 tetra-hydrofuran, benzene and the like. Suitable basic condensing agents include alkali hydroxides, e.g., potassium or sodium hydroxide, alkali lower-alkoxides, e.g., sodium methoxide or potassium ethoxide, sodium hydride, and the like.

1. 4,5-Dihydro-4~methyl-6-~4~pyridinyl)-3~2~
pyri~dazi~none ~ A mi~ture cont~ining 15 g. o~ 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 re~luxed wit~ stirring ~or a~out seventeen hours and the solvent was distilled o~ In vacuo. The remaining crystal-line residue was recrystallized from ethyl acetateJ dried at 90C. and combined with anotKer sample of the same com pound prepared by the same procedure starting with 11 g. of methy-l 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 120C. to yield 10 g. of 4,5-dihydro-4-methyl-6-(4-pyridinyl~-3(2H~-pyridazinone, m.p. 184 - 185qC., tautomeric with 4,5-dihydro-4-methyl-~-(4-pyridinyl~-3-pyridazinol.

- lla -p~?1~

Acid-addition salts o~ 4,5-dihydro-4-methy1-6-(4-pyri~dinyl~-3~2H~pyri~dazinone are conveniently prepared by adding to a mixture of 1 g. o$ 4,5-dihydro-4-methy1-6-~4-pyridinyl~-3(2H~-pyridazinone in ab~ut 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 e~aporation and collecting the preclpitated salt, e.g., dihydrochlorlde, dimethanesw~onate, sulfate, respectively. Also, the mono-lactate or monohydrochloride acid-addition salt is con-veniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each o~ 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3~2H)-pyridazinone and lactic acid or hydrochloric acid, respectlvely.
~ollowing the procedure described in Example A-24 but using in place of methrl 4-cyano-2-methy~l-4-(4-mor-pholinyl~-4-(4-pyridinyllbutanoate a molar equivalent quanti-ty of the appropriate lcwer-alkyl, pre~erably, methyl or ethyl, 4-cyano-2-methyl-4-(BN~-4-(4-pyridinyl)butanoate where 2Q BN is l-piperidinyl or l-pyrrolidinyl, it is contemplated that 4,5-dihydro-4-methyl-6-(4-pyridinvl)-3(2H)-pyridazinone can be obtained.~
The preparation of the intermediate lower-alkyl 4-(BN~-4-cyano-2-methyl-4-(4-pyridinyl)butanoate is illustrated as follows for the compound where BN is 4-morpholinyl and laNer-alkyl is methyl: To a mixture contalning 16 g. of 2-(4-morph~liny~1l-2-(4-pyridinyl)ethanenitrile and 150 ml. of tetrahydrofuran in a ~lask equipped wlth a stlrrer and - llb -2t~

drying tube was added wlth stirring G ml. of 30% potassium hydroxide in methanol, followed by 8.5 g. of methyl meth-acrylate. Wlthin thlrty minutes an exothermlc reaction en-sued and a white solid began to separate. The reaction mix-ture was stirred ~or one hour and then allowed to stand at room temperature overnight. The reaction mixture was concen-trated by heating in vacuo to remove the solvent and the re-maining residue was triturated with absolute ether (about 60~ ml.) and flltered. The filtrate was concentrated to a volume o~ about 50 ml., cooled, treated with 50 ml. o~ n-hexane and chilled. The product that separated was collected and dr~ed at 70C. to yield 11 g. of methyl 4-cyano-2-methyl-4-~4-morpholinyl)-4-(4-pyrldinyl)butanoate, m.p. 93 - 94C.
~ollcwing the above procedure described abov0 for pr~parlng methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-~4-pyrldinyl)butanoate but using in place of 2-(4-morpholinyl)-2-(4-pyrldinyl)ethanenitrile and methyl me~hacrylate molar equivalent quantities respectively o~ the appropriate 2-(BN~-2-(4-pyridlnyl)ethanenitrile and lower-alkyl meth-2Q acrylate, it is contemplated that there can be obtained the following corresponding lower-alkyl 4-cyano-2-methyl-4-(BN~-2-(4-pyridinyl)butanoates: methyl 4-cyano-2-methyl-4-(l~piperidinyl)-4-(4-pyridinyl)butanoate; methyl 4-cyano 2-meth~l-4-~4-pyridiny~1~-4-Cl-pyrrolidinyl)butanoate;
ethy~l 4-cyano-2-methyl~4-~4-mQrphQl~nyl~4-(4~pyridinyl)-butanoate; and, n-propyl 4-cyano-4-(4-pyridinyl)-2-methyl-4-~4-morpholinyl~utanoate.

- llc -The int~rmediate 2-~BN~-2~PY-ethanenitriles (III3 are generally known compounds, e.g., Janssen et al., J. Am.
Pharm. Assoc., Sci. Ed., 44, 465-7 ~19~5), and are prepared by genexally known methods. Preparation of these compounds is illustrated below in Examples E-l through E-5~
The conversion of the intermediate 4,5-dihydxo-2-R-4-R'-6-PY-3(2H)-pyridazinones by reaction with bromine to the corresponding 2-R-4-R'-6-P~-3(2H)-pyridazinones, ~he 2-R-4-R'-6-PY-3(2H~-pyridazinones produce~ by the conversion and the use of the latter where R' iQ hydrogen as cardio-tonics are disclosed and claimed in said copending Appli-cation Serial No. 144,576. This conversion and products produced thereby are illustrated below in Examples B-l ~hrough B-15 for compounds where R' is hydrogen and in Examples B-16 through ~-2~ for compounds where R' is methyl The following examples will further illustrate the invention without, however, limiting it thereto.
A. 4,5-Dihydr~-2-R-4--'-6-PY-3(2H)-pyr~dazinones A-l. 4 ! 5-Dihydro-2-methyl-6-(4-pyrldi~y~
3(2H)-~yridazinone - To a stirred hot solu~ion 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 15 hours). The solvent was distilled off in vacuo and the resulting solid was recrystallized from ethanol and dried in a vacu~um oven at 65C. overnight to yield 10.5 g. o~ 4,5-dihydro-2-methyl~
6-(4-pyridinyl)-3~2H)pyridazinone a~ its monohydrochloride, m.p. 219-225C. with decomposition.

Acid-addition salts o 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone are eonveniently prepared by add-ing 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 aeid, to a pH of about 2 to 3, ehilling the mixture after partia-l evaporation and colleeting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively.
Also, the laetate or hydrochloride acid-addition salt of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone is eon-viently 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 proeedure deseribed in Example A-l but using in place of N-methylhydrazine dihydrochloride a molar equivalent quantity of the appropriate N-R-hydrazine dihydro-chloride or other salt of a strong inorganie acid or organic sulfonic acid, it is contemplated that there ean be obtained the corresponding 4,5-dihydro-2-R-6-(4-pyridinyl)-3(2H)-pyridazinones (or salts thereof) of Examples A-2 thru A-6.
~-2. 2-Ethyl-4,5-dihydro-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.

-~ 3~5 A-5. 4,5-Dihydro-2-isobutyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-6. 2-n-Hexyl-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.
Following the procedure described in Example A-l but using in place 4-oxo-4-(4-pyridinyl~bwtanenitrile a molar equivalent quantity of the appropriate 4-oxo-4-PY-butanenitrile, it is contemplated that the 4,5-dihydro-6-P~-2-methyl-3(2H)-pyridazinones of Examples A-ll through A-15 can be obtained.
A-ll. 4,5-Dihydro-2-methyl-6-(3-pyridinyl)-3(2H)-pyridazinone.
A-12. 4,5-Dihydro-2-methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.
A-13. 4,5-Dihydro-2-methyl-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone.
A-14. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4,5-dihydro-2-methyl-3(2H)-pyridazinone.
A-15. 4,5-Dihydro-2-methyl-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

~ -14-,. ~ ,~.

2$.5 A-16. ~ 2,4 imet ~1 ~ r i ~
3(2H)-pyridazlnone- ~ A ~ixtuxe containing 16 g. o~ methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, 30 ml. of N-methylhydrazine and 220 ml. of absolute ethanol was refluxed with stirring for about seventeen hours. The ethanol was distilled off in vacuo and the remaini~g oily material was placed on a column of silica gel (7 cm. high and 15 cm. in diameter) in a large scintered glass funnel and eluted with a 50-50 mixture ~by volume) of ether and n-hexane. Evaporation of the eluants containing the bulk of the product, as indicated by tlc analysis (CHC13: CH30H: i-C3H7NH2/90%: 5%: 5% by volume), yielded solid product, which was recrystallized from ether-n-hexane and dried in vacuo at 50C. to yield 3.0 g. of 4,5 dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p~ 71-81C.
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-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml. of aqueous methanol the appropriate acid, e.gO, 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-16 but using in place of methyl 4-cyano-4-~4-morpholinyl)-4-(4-1~ ~L 6 ~ 5 n5 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 N-R~hydrazine, it is contemplated that the corresponding 4,5-dihydro-4-methyl-6-PY-2-R-3(2H)-pyridazinones of Examples A-17 through A-22 can be obtained.
A-17. 4,5-Dihydro-2,4-dimethyl-6-(3-pyridinyl)-3(2H)-pyridazinone.
A-18. 2-Ethyl-4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-l9. 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-21. 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-3t2H)-pyridazinone.
Following the procedure described in Example A-16 but using in place of methyl 4-cyano-4-(4-morpholinyl)-4-(4-pyridinyl)-2-methylbutanoate a molar equi~alent quantity of methyl 2-methyl-4~oxo-4-t4-pyridinyl)butanoate, it is contem-plated 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-l but using in place of 4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of 2-methyl-4-oxo-4-(4-pyridinyl)butane-- nitrile.

,~ .

~N 3700 ~" 3~ S

B . 2-R- ~ dazinones ~These compounds where R' is hydrogen and their prepaxati~n are di~closed and claimed in said copending Application Serial No. 144,576, filed April 28, 19~0.]
B-l. 2-Methyl-6-(4-pyridlnyl)-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 wi~h stirxing 100 ml. of bromine, and the resulting reaction mix~ure was refluxed overnight and then allowed to cool to room ~emperature. The solid that had separated was collected, stirred with 150 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 mix~uxe was extracted with chloroform. The chloroform extract was heated ln vacuo to remove the solvent and the resulting solid was recrys-~allized from methanol-ether and dried in a vacuum o~en at 60C. overnight to yield 15 g. of 2-methyl-6~(4-pyridinyl)-3(2H)-pyridazinone, m.p. 175-185C.
Acid-addition salts o~ 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)-pyri-dazinone 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 collectin~g the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, respectively.
Also, the lactate or hydrochloride acid-addition salt of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone i~ conveniently s prepared in a~ueous solution by addiny to water with stirring molar equivalent ~uantities each o~ 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid, respectively.
Following the procedure described in Example B-l but using in place of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone or monohydrochloride thereof a corresponding molar equivalent quantity of the appropriate 4,5-dihydro-2-R-4-R'-6-PY-pyridazinone or monohydrochloride salt thereof, it is contemplated that the corresponding 2-R-4-R'-6-PY-3(2H)-pyridazinones of Examples B-2 thru ~-6 and B-ll thru B-22 can be obtained.
B-2. 2-Ethyl-6-~4-pyridinyl)-3(2H)-pyridazinone.
B-3. 2-Isopropyl-6-(4-pyridinyl) 3(2H)-pyridazinone.
B-4. 2-n-Propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-5. 2-Isobutyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-6. 2-n-Hexyl-6-(4-pyridinyl)-3(2H3-pyridazinone.
B-ll. 2-Methyl-6-(3-pyridinyl)-3(2H) pyrldazinone.
B-12. 2-Methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.
B-13. 2-Methyl-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone.
B-14. 6-(3-Ethyl-4-pyridinyl)-2-methyl-3(2H)-pyridazinone.

~ -18-., - -.~

a5~

B-15. 2-Methyl-6-(2,6-dimethyl-4-pyridinyl)-pyridazinone.
B-16. 2,4~Dimethyl-6-(4-pyridinyl)-3(2H)-pyrida~inone.
B-17. 2,4-Dimethyl-6-(3-pyridinyl)-3(2H)-pyridazinone.
~ -18. 2-Ethyl-4-methyl-6-(4-pyridinyl)-3~ 2H) -pyridazinone.
B-l9. 4-Methyl-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyrida~inone.
B-20. 2-Isopropyl-4-methyl-6-(4-pyridinyl)-3~2H)-pyridazinone~
B-21. 2-(n-Butyl)-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-22. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4-methyl-3(2H)-pyridazinone.
C. 4-Oxo-4-PY-butanenitriles C-l. 4-Oxo-4-(4-pyridinyl)butanenitrile - 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 ln vacuo of solvent at a temperature not exceeding 54C. The ~19-$~i semi-solid residue was cooled, mixed well with 400 ml. of chloroform, and the mixtuxe filtered. The chloroform was distilled off 1n vacuo at a temperature not exceeding 50C.
and the residual oily residue was extracted with ~hree 200 ml. portions of toluene. The toluene solution was filtered through dia~omaceous earth and the filtrate was distilled in vacuo below 50C. 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 ethex, chilled and seaded with a crys~al obtained from said tiny sample. The crystalline product that separated was collected, washed with 25 ml. of 1:3 (v:v) mixture of isopropyl alochol:ether, and air dried to yisld 52.1 g. of 4-oxo-4-~4-pyridinyl)butanenitrile, m.p. 53.5-55C.
Following the procedure described in Example C-l but using in place of 4-pyridinecarboxaldehyde a molar equivalent quanti~y of the appropriate 4- or 3 PY-carboxal-dehyde, it is contemplated that there can be obtained the corresponding 4 oxo-4-PY-butanenitriles of Fxamples 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-~yridinyl)-4-oxobutanenitrile.
C-5. 4-(3-Ethyl-4-pyridinyl)-4-oxobutanenitrile~
C-6. 4-~2,6-Dimethyl-4-pyridinyl)-4-oxobutane-nitrile.
Following the procedure de8cribed in Example C-l but using in place of acrylonitrile a molar equivalent '~ Z~

quantit~ of methacrylonitrile, it is contemplated tha~ 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-tBN)-4-CY_NO-4-PY-~-R'-BUTANOATES
D-l. Meth~l 4-C~ano-2~methyl-4-(4_morpholi~
4-(4-pyridinyl)butanoa~e - To a mixture containing 16 g. of 2-(4-morpholinyl)-2-~4-pyridinyl)ethanenitrile and 150 ml.
of tetrahydrofuran in a flask equipped with a stirrer and drying tube was added with stirring 6 ml. of 30% po~assium hydroxide in methanol, followed by 8.5 g. of methyl me~h-acrylate. Within thirty minu~es 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 n-hexane and chilled. The product that separated was collected and dried at 70C. to yield 11 g. of methyl 4-cyano-2-methyl-4-t4-moxpholinyl)-4-~4-pyridinyl)butanoate, m.p. 93-94~C.
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-t4-morpholinyl)-4-(4-pyridinyl)butanoate in about 20 ml. of aqueous me~hanol the appropriate acid, e.g., hydrochloric acid, methanesulonic acid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., 37~0A

hydrochloride, methanesulfonate, sulfate, respectively.
Also, the lactate or hydrochloride acid addition salt of methyl 4-cyano-2-methyl 4-(4-morpholinyl)-4-(4-pyridinyl)-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-l but using in place of 2-(4-morpholinyl)-2-~4-pyridinyl)-ethanenitrile and methyl methacrylate molar equivalent quantities respectively of the appropriate 2-(BN)-2-PY-ethanenitrile and lower-alkyl methacrylate, i~ is contem-plated that thexe 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-pyridinyl)butanoate.
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-ETHANENITRILES - These generally known ., . . .. _ _ _ . ~, _ intermediates can be prepared by reacting a cyclic amine of the formula BN-H and an alkali cyanide with a PY-aldehyde-bisulfite 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-l.

25 r~

E~ 2- ~ 4~
ni rlle - A mixture containing 72 g. of 4-pyridinecarboxal-dehyde, 140 g. of morpholine, 152 g. of ~-toluenesulfonic acid and 800 ml. of tetrahydrofuran was refluxed with stirring for two hours and then allowed ~o 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. Th~ reaction mixture was filtered and the filtrate was heated in vacuo to remove the solvent. To the resulting gummy residue wa~ added about 800 ml. of chloroform and about 300 ml. of saturated sodium chloride solution. ~he mixture was stirred for two hours and filtered. The heterogeneous filtrate was transferred to a separatory funnel, shaken well, and the chloroform layer drained off and heated ln vacuc 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 ln vacuo to a volume of about 60 ml. and a second crop of pale yellow crystals was obtained.
The combined crops of yellow crystal~ were dried first in a vacuum oven at 100 mm. and 25C., and then for 100 hours over P2O5 to yield 40 g. of 2-(4-morpholinyl~-2-(4-pyri-dinyl)ethanenitrile, m.p. 64-65~C.
Following the procedure described in Example E-l using a molar equivalent quantities of the respectlve appropriate pyridinecarboxaldehyde and amine (BN-H)in place of 4-pyridinecarboxyaldehyde and morpholine, it is con~emplated that there can be obtained the corresponding 2-~N)-2~PY-ethanenitriles of Examples E-2 through E-5.
/

- 23 ~

E-2. 2-(4-Pyridinyl)-2-(1-pyrrolidinyl)ethane nitrile.
E-3. 2-(1-Piperidinyl)-2-(4-pyridinyl)ethane-nitrile.
E-4. 2-(3-Ethyl-4 pyridinyl)-2-(4-morpholinyl)-ethanenitrile.
E-5. 2 (5~Methyl-3-pyridinyl)-2-(4-morpholinyl)-ethanenitrile.
The usefulneQs 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 significant increase in contrac tile orce of the isolated cat atria and papillary muscle and in causing a significant increase in the cardiac con-tractile 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, l9B0.
When tested by said isolated cat atria and pap-illary muscle procedure, the compounds of formula I or pharmaceutically-acceptable acid-addition salts thereof at " doses of 10, 30, 100 and/or 300 yg/ml. were found to cause significant increases, that is, greater than 25% in pap- .
illary muscle force and significant increases, that is, greater than 25%, in right atrial force, while causing a lower percentage increase ~abou~.one-third or less than the percentage increase in right atrial force or papillary muscle force) in ri~ht atrial rate. For example, when tested at dose levels of 10, 30 and 100 ~g/ml. by this procedure, the compound of Example A-l, i.e., 4,5-dihydro-2-2~

methyl-6-~4-pyridiny~ 3(2H)-pyrida~inone 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 ~g/ml. by the comparable test procedure ` using isolated guinea pig atria and papillary muscle, the compound of Example A-16, i.e., 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3~2H~^pyridazinone, was found to cause respective increases of 75% and 63% in papillary muscle force and right atr~al force. Similarly, 4,5-dihydro-4-methyl-6-~4-pyridinyl~-3(2H)-pyridazinone ~A-24) was found to cause respective increases of 139%
and 86% in papillary muscle force and right atrial force at 100 ~g./ml.
and a papillary muscle force increase of 45% in a papillary muscle force at 30 ~g./ml.
The present invention includes within its scope a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable carrier and, as the active component thereof, the cardiotonic compound of formula I or pharmaceutically-acceptable acid-addition salt thereof. The invention also includes within its scope the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering to such patient a cardiotonically-effective amount of a compound of formula I or pharmaceutically-acceptable 2a acid-addition salt thereof. In clinical practice said compound or salt thereof will normally be administered orally or parenterally in a wide variety of dosage forms.
Solid compositions for oral admlnistration 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 addi~tional substances other than inert diluents, e.g., lubricat-ing agents, such as magnesium stearate, talc and the like.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutiorls, suspensions and emulsions.
Examples of organic solvents or suspending media are pro-pylene glycol, polyethylene glycol, vegetable oils s~ch as olive oil and injectable organic esters such a~ ethyl oleate. These compositions can also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dis-persing agents.
They can be sterilized, for example, by filtration through a bacteria~retaining filter, by incorporation of sterilising agen~s 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 ~he 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 con~idering all criteria and utilizing the best judgement on the patient's behalf.

- ~6 -

Claims (27)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a 2-R-4,5-dihydro-4-R'-6-PY-3(2H)-pyridazinone of the formula (I) or an acid-addition salt thereof, where PY is 4- or 3-pyridinyl, or 4- or 3-pyridinyl having one or two (C1-C6)-alkyl substituents, R is hydrogen or (C1-C6)-alkyl, and R' is hydrogen or methyl, provided that where R is hydrogen, R' is methyl and PY is 4-pyridinyl, which comprises reacting a butanoic acid derivative selected from 2-R'-4-oxo-4-PY-butanenitrile, (C1-C6)-alkyl 2-R'-4-oxo-4-PY-butanoate and (C1-C6)-alkyl 2-R'-4-(BN)-4-cyano-4-PY-butanoate, where (BN) is 4-morpholinyl, l-piperidinyl or l-pyrrolidinyl, with N-R-hydrazine or a salt thereof with a strong inorganic acid or an organic sulfonic acid, and where required converting a product so obtained into an acid addition salt thereof.

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

3. A process according to claim 1 or 2 wherein R is methyl or ethyl and the acid-addition salt is pharmaceutically acceptable.

4. A process according to claim 1 where R is methyl.

5. A process according to claim 1 wherein R is ethyl.

6. A process according to claim 1, 4 or 5 where PY is 4-pyridinyl and the product is isolated as the base or a pharmaceutically-acceptable acid-addition salt thereof.

7. A process according to claim 1 where R' is hydrogen.

8. A process according to claim 1 wherein R' is methyl.

9. A process according to claim 2 wherein R is methyl or ethyl, R' is hydrogen or methyl, and the salt is pharmaceutically-acceptable.

10. A process according to claim 1 wherein PY is 4-pyridinyl, R is methyl and R' is hydrogen and the product formed is the base.

11. A process according to claim 10 wherein the product is converted to a pharmaceutically-acceptable acid-addition salt thereof.

12. A process for the preparation of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone monohydrochloride which comprises reacting 4-oxo-4-(4-pyridinyl)butanenitrile with N-methylhydrazine dihydrochloride.

13. A process according to claim 12 wherein the reaction is carried out in aqueous ethanol under reflux conditions.

14. A process according to claim 1 wherein PY is 4-pyridinyl, R is hydrogen and R' is mekhyl.

15. A process according to claim 14 wherein the product is converted to a pharmaceutically-acceptable acid-addition salt thereof.

16. A process for the preparation of 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone or a pharmaceutically-acceptable acid-addition salt thereof, which comprises reacting a (C1-C6)-alkyl 2-methyl-4-(BN)-4-cyano-4-(4-pyridinyl)butanoate with hydrazine, where (BN) is 4-morpholinyl, l-piperidinyl or l-pyrrolidinyl, and where required converting the product into a pharmaceutically-acceptable acid-addition salt thereof.

17. A process for preparing 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone which comprises reacting methyl 4-cyano-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate with hydrazine hydrate.

18. A process according to claim 17 wherein the reaction is carried out in ethanol under reflux conditions.

19. A compound of formula (I) defined in claim 1 or an acid-addition salt thereof, when prepared by the process of claim l or by an obvious chemical equivalent thereof.

20. A compound of formula (I) defined in claim l wherein PY is 4-or 3-pyridinyl, R is methyl or ethyl, R' is hydrogen or methyl, and the salt is pharmaceutically-acceptable, when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

21. 4,5-Dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone mono-hydrochloride, when prepared ky the process of claim 12 or by an obvious chemical equivalent thereof.

22. 4,5-Dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone, when prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

23. A process according to claim 1 wherein the butanoic acid deri-vative is 2-R-4-oxo-2-R'-4-PY-butanenitrile and is reacted with an N-R-hydrazine salt of a strong inorganic acid or an organic sulfonic acid.

24. A process according to claim 1 wherein the butanoic acid deri-vative is methyl 2-R'-4-(l-morpholinyl)-4-cyano-4-PY-butanoate or methyl 2-R'-4-oxo-4-PY-butanoate and is reacted with an N-R-hydrazine.

25. A process according to claim 23 or 24 wherein PY is 4- or 3-pyridinyl.

26. A process according to claim 23 or 24 wherein PY is 4- or 3-pyridinyl and R is methyl or ethyl.

27. A process according to claim 23 or 24 wherein PY is 4- or 3-pyridinyl, R is methyl or ethyl and R' is hydrogen or methyl.