LU83320A1 - 4,5-DIHYDRO-6- (PYRIDINYL) -3 (2H) -PYRIDAZINONES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Description

* 1 i%%

This invention relates to 4,5-dihydro-6- (pyridinyl) -3 (2H) -pyridazinones 2-substituted useful as cardiotonic agents, their preparation and their use as cardiotonic agents.

5 Haginiwa et al. [Yakugaku Zasshi £ 8 ^ (1), 67-71 (1978)

Chem. Abstrs. 8_8, 170.096v (1978)] describe the reaction of 3 (2H) -pyridazinone with pyridpne-1-oxide and a Pd-C catalyst treated with platinum to obtain 6- (2-pyridinyl) -3 (2H ) -pyridazinone.

10 Japanese patent publication No. 19,987/79 published on February 15, 1979 and based on application No. 85 192/77 filed July 15, 1977, describes, among other things, the preparation of 4,5-dihydro-6 - (4-pyridinyl) -3 (2H) -pyridazinone by reflux heating for two hours of an ethanolic solution of 3- (iso-nicotinoyl) propanoic acid [i.e. γ- acid οχο-γ- (4-pyridinyl) butyric] and hydrated hydrazine. It is indicated (page 2 of the English translation) that 4,5-dihydro-6- (4-pyridinyl) -3- (2H) -pyridazinone and 4,5-dihydro-6- (4- or 3- or 2-pyridinyl) -5-R-3- (2H) -20 nearby pyridazinones, where R is a hydrogen atom or a lower alkyl group, are "usable not only as drugs as hypotensive agents and antithrombosis because they have pharmacological actions such as hypotension, inhibition of the coagulation of blood platelets * and stabilization of the membranes, but also as intermediates for the synthesis of such drugs ".

McEvoy and Allen [J. Org. Chem. 38: 4044-48 (1973); J. Med. Chem. 1-7, 281-286 (1974)] describe a process for the preparation of 3- (3- substituted benzoyl) -alkanoic acids and their reaction with hydrazine to prepare the 6- (substituted phenyl) -4,5-dihydro -3 (2H) pyridazinones 5-substituted, useful as hypotensive agents.

Curran and Ross [J. Med. Chem. Γ7, 273-281 (1974)] 35 describe the preparation of 6-phenyl-4,5-dihydro-3 (2H) - pyridazinones, as hypotensive agents, by refluxing the necessary 3-benzoylpropionic acid with hydrazine hydrated in ethanol.

L

/ 2

Albright, McEvoy and Moran tJ. Heterocyclic Chem. 15, 881-892 (1978)] describe the use of a- (substituted phenyl) -4-morpholine-acetonitriles in 1,4 additions to ethyl acrylate, ethyl crotonate, l 'a-5 methyl methylacrylate, acrylonitrile, methyl-acrylonitrile, crotonitrile and cinnamonitrile to obtain 4-cyano-4- (4-morpholinyl) -4- (substituted phenyl) -butanenitriles and butanoic esters , and their transformation by reaction with hydrazine to 6-10 (substituted phenyl) -4,5-dihydro-3 (2H) -pyridazinones and, then, their dehydrogenation by reaction with bromine to obtain 6- (substituted phenyl ) -3- (2H) -pyridazinones optionally carrying a methyl group in position 4 or 5 of the pyridazinone ring.

15 McEvoy and Albright [J. Org. Chem. 44_, 4597-4603 (1979)] describe inter alia the reaction of 2-cyano-2- (4- or 3-pyridinyl) -2- (4-morpholinyl) ethanenitrile with acrylonitrile or ethyl acrylate to obtain respectively 4-cyano-4- (4- or 3-pyridinyl) -4- (4-morpholinyl) butanoate or ethyl 4-cyano-4- (4- or 3-pyridinyl) -4- ( 4-morpholinyl) butanenitrile.

Leete et al. [J. Org. Chem. 3] 7, 4465-6 (1972)] describe the reaction of 2- (3-pyridinyl) -2- (4-morpholinyl) -ethanenitrile with acrylonitrile to obtain 4-cyano-4- (3-pyridinyl ) '- 4- (4-morpholinyl) butanenitrile and its transformation by heating with acetic acid, water and tetrahydrofuran into 4-oxo-4- (3-pyridinyl) butanenitrile.

The present invention relates to 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinones of formula I

P Y A Κ = Ω I

\ /

N-N

R

Or their acid addition salts, where PY is a 4- or 3-pyridinyl or 4- or 3-pyridinyl group having one or two lower alkyl substituents, R is a lower alkyl r 3 or lower hydroxyalkyl group and R 'is a hydrogen atom or a methyl group and where R can also be a hydrogen atom when R' is a methyl group. The compounds where R is a lower alkyl group or a hydrogen atom can be used as cardiotonic agents, as shown in standard cardiotonic test procedures. Preferred compounds are those in which PY is a 4-pyridinyl or 3-pyridinyl group, R is a methyl or ethyl group, and R 'is a hydrogen atom. The foregoing compounds of

Formula I where R 'is a hydrogen atom are described as intermediates in the preparation of 2-R-6-PY-3 (2H) -pyridazinones, which can be used as cardiotonic agents, in patent application No. $ i? Tï filed August 15, 1980. The compounds of Formula I where R 'is a methyl group can also be used to prepare the new 2-R-4-methyl-6-PY-3 (2H) -pyridazinones.

4,5-dihydro-4-methyl-6- (4-pyridinyl) -3- (2H) -20 pyridazinone (I: PY is a 4-pyridinyl group, R 'is a methyl group and R is an atom of hydrogen) can exist in tautomeric form, i.e. in the form of 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone of Formula IA and / or in form of 4,5-dihydro-4-methyl-6- (4-25 pyridinyl) -3-pyridazinol of Formula IB, shown below (PY is a 4-pyridinyl group).

Ή_ίΤ "· ^" vJr

IB IA

In fact, the two tautomers (IB and IA) are so close to each other that they can be considered essentially as one and the same compound and, under any given conditions, such a tautomeric compound can exist in either or both of the tautomeric forms. Although it is preferred to use the name based on Formula IA, it is understood that either or both of the structures are c 4 contemplated here.

A 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinone of Formula I can be obtained 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-cyano-4-PY-butanoate with NR -hydrazine or its salt formed with a strong mineral acid or an organic sulfonic acid, to obtain 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinone, where PY, R 'and R are as defined in Formula I. In the preferred embodiments, this process is carried out using 2-R'-4-oxo-4-PY-butanenitrile and a salt of NR-hydrazine and d 'a strong mineral acid or an organic sulfonic acid, for example NR-hydrazine sulfate or dihydrochloride, or using methyl 2-R'-4-oxo-4-PY-15 butanoate or 2- Methyl R'-4- (4-morpholinyl) -4-cyano-4- (PY) -butanoate with NR-hydrazine.

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

To increase cardiac contractility in a patient in need of such treatment, the patient may be administered, orally or parenterally and in solid or liquid dosage form, a composition comprising a pharmaceutically acceptable inert carrier and, as a component active, a cardiotonically effective amount of a 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinone or one of its acid addition salts pharma-35 ceutically acceptable, where R is a lower alkyl group and PY and R 'are as defined in Formula I, or R' is a methyl group, R is a hydrogen atom and PY is a group 4- pyridinyl.

J "5 The expression" lower alkyl "as used herein, for example as one of the meanings of R (Formula I), or as a substituent of PY (Formula I) denotes alkyl radicals having from one to six atoms of carbon which may be in a straight or branched chain, represented by the methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, n-hexyl, etc. groups.

The symbol PY as it is used here, for example as the substituent in position 6 of the compounds of Formula I, 10 denotes the groups 4- or 3-pyridinyl or 4- or 3- pyridinyl having one or two lower alkyl substituents, represented by the 2-methyl-4-pyridinyl, 2.6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (also called 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, etc.

The term "lower hydroxyalkyl" as used herein, for example, as one of the meanings of R in Formula I, denotes hydroxyalkyl radicals having two to six carbon atoms and of which the hydroxy group and the free valence bonds (or rac-25 bond) are found on different carbon atoms which may be in a straight or branched chain, represented by the groups 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxv- 2-methylpropyl, 2-hydroxy-l, 1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl, 6-hydroxy-30 hexyl, etc.

The compounds of the invention of Formula I can be used both in the form of the free base and in the form of the acid addition salts, and these two types of forms form part of the field of the invention. The acid addition salts are simply a more convenient farm for use; and in practice, the use of the salt form inherently corresponds to the use of the base form. The acids which can be used to prepare the acid addition salt preferably include those which, when combined with the free base, give pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal body at pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base of the cardiotonically active compounds of Formula (I) the invention is not tainted by side effects attributable to anions. In practicing the invention, it is convenient to use the free base form; however, suitable pharmaceutically acceptable salts falling within the scope of the invention are those obtained from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p ~ toluenesulfonic acid, l cyclohexylsulfamic acid, quinic acid, etc., giving respectively the hydrochlor-20 te, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methariesulfonate, ethanesulfonate, benzenesulfona-te, p-toluenesulfonate, cyclohexylsulfamate and quinate.

The acid addition salts of the basic compound are prepared by dissolving the free base in an aqueous or aqueous-alcoholic solution or in other suitable solvents containing the appropriate acid and isolating the salt by evaporation of the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution. ·

Although the pharmaceutically acceptable salts of the basic compound are preferred, all of the acid addition salts are within the scope of the invention. The acid addition salts can all be used as sources of the free base form even if the particular salt is in itself only sought as an intermediate, for example when the salt is formed only for the purpose of purification or identification, or when used as an intermediate for the preparation of a pharmaceutically acceptable salt 7 in the ion exchange procedures.

The molecular structures of the compounds of Formula I were assigned on the basis of data provided by the infrared, nuclear magnetic resonance and mass spectra, and by the correspondences between the calculated and found values for the elemental analysis.

The reaction of a 2-R'-4-oxo-4-PY-butane-nitrile with a salt of NR-hydrazine and a strong mineral acid or an organic sulfonic acid is carried out to obtain the 10 2 -R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinone, by heating the reagents to around 65 ~ 120 ° C in an appropriate solvent, preferably to around 80-100 ° C in a mixture of water and a lower alkanol. The reaction is preferably carried out by refluxing the 2-R'-4 ~ oxo-4-PY-butane ~ 15 nitrile with hydrazine sulfate in aqueous ethanol. Other NR-hydrazine salts which can be used are NR-hydrazine dihydrochloride, NR-hydrazine dimethane sulfonate, and similar salts obtained from phosphoric acid, ethanesulfonic acid. 20, benzenesulfonic acid, and the like. Other lower alkanols which can be used 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-1 to 25 A-15.

The intermediate 2-R, -4-oxo-4-PY-butanenitriles are generally known compounds, for example Stetter et al. Chem. Ber. 107, 210 (1974), Leete et al. J. Org. Chem. 37, 4466 (1972) and the U.S. Patent. Nos. 4,014,889, and are prepared by generally known methods. The preparation of these compounds is illustrated below in Examples C-1 to C-6.

The reaction of a lower alkyl 2-R'-4-oxo-4-PY-butanoate or of a 2-R'-4- (BN) -4-cyano-4-PY-butanoate lower alkyl with NR-hydrazine to obtain 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinone is carried out by heating the reagents to around 65-120 ° C in a suitable solvent, preferably at about 80-100 ° C in a lower alkanol. The reaction is preferably carried out by heating the reagents to reflux 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-16 through A-24.

The intermediate lower alkyl 2-R'-4-oxo-4-PY-butanoates and / or the corresponding acids are generally known compounds [Wada et al. J. Am. Chem. Soc. 76, 155 (1954) 3, which is easily obtained by hydrolysis of the known 2-R'-4-oxo-4-PY-butanenitriles and esterification of the 2-R'-4-oxo-4-PY- acids resulting butanoic.

Reaction of 2- (BN) -2-PY-ethanenitrile (III) with a lower alkyl (IV) 2-R'-2-propenoate to obtain 2-R'-4- (BN) -4- lower alkyl cyano-4-PY-butanoate of formula (II) is carried out under anhydrous conditions by mixing the reactants at about 25 ° C - 60 ° C, preferably at about 30 ° C - 50 ° C, in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently carried out by mixing the reactants at about 30 ° -50 ° C in dry tetrahydrofuran in the presence of an alkali hydroxide in methanol. Other suitable solvents are the other lower alkanols, for example ethanol and isopropyl alcohol, dimethylformamide, acetonitrile, tetrohydrofuran, benzene, etc.

Other basic condensing agents include alkali hydroxides, for example potassium or sodium hydroxide, lower alkali alcoholates, for example sodium methylate or potassium ethlate, sodium hydride, etc. ..

30 The 2- (BN) -2-PY-ëthanenitriles intermediates of

Formula (III) are generally known compounds, for example Janssen et al., J. Am. Pharm. Assoc., Sci. Ed., 44, 465-7 (1955), and are prepared by generally known methods. The preparation of these compounds is illustrated below in Examples E-1 to E-5.

Transformation of 4,5-dihydro-2-R-4-R'-6-PY-3 (2H) -pyridazinones by reaction with bromine into 2-R-4-R'-6-PY-3 (2H ) -pyridazinones, the 2-R-4-R'-6-PY-3 (2H) -pyridazinones obtained by transformation and the use of the latter when R “is a hydrogen atom as Cardiotonic agents are described and claimed in the patent application mentioned on page 3, line 14. This transformation and the products thus obtained are illustrated below in Example B1 for a compound where R 'is a hydrogen atom and in Examples B-2 to B-9 for the compounds where R' is a group methyl.

The following Examples illustrate the invention without, however, limiting it.

A. 4,5-dihydro-2-R-4-R'-6-PY-3 (2H) -pvridazinones A-1. 4,5-dihydro-2-methvl-6- (4-pyridinvl) -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, 32 g of 4-oxo-4- (4-pyridinyl) -butanenitrile are added and the resulting reaction mixture is heated at reflux overnight (about 15 hours). The solvent is distilled in vacuo and the resulting solid is recrystallized from ethanol and dried in a vacuum oven at 65 ° C overnight to give 10.5 g of 4,5-dihydro-2- methyl-6- (4-pyridinyl) -3 (2H) -pyridazinones as monohydrochloride, mp 219-225 ° C with decomposition.

The acid addition salts of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone are conveniently prepared by adding 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, acid sulfuri-30 que) to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated (respectively the hydrochloride, methanesulfonate or sulfate for example). The lactate or hydrochloride of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone is also conveniently prepared in aqueous solution by adding to water, with stirring, equimolar amounts of 4,5-dihydro-2-methyl) -6- (4-pyridinyl) -3 (2H) -pyridazinone and lactic acid or hydrochloric acid respectively.

10

Following the procedure described in Example A1 but using instead of N-methvlhydrazine dihydrochloride an equimolar amount of the appropriate NR-hydrazine dihydrochloride or other salt obtained from NR-hydrazine and d a strong mineral acid or an organic sulfonic acid, it can be seen that the corresponding 4,5-dihydro-2-R-6- (4-pyridinyl) -3 (2H) -pyridazinones (or their salts) of Examples A-2 to A-10.

10 A-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.

AT 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. - 20 A-7. 2- (2-hydroxyethyl) -4,5-dihydro-6- (4-pyridinyl) - 3 (2H) -pyridazinone, m.p. 142-144 ° C.

AT 8. 2- (2-hydroxypropyl) -4,5-dihydro-6- (4-pyridinyl) - 3 (2H) -pyridazinone.

A-9. 2- (3-hydroxypropyl) -4,5-dihydro-6- (4-pyridinyl) - 25 3 (2E) -pyridazihone.

A-10. 2- (4-hydroxybutyl) -4,5-dihydro-6- (4-pyridinyl) -3 (2H) -pyridazinone.

Following the procedure described in Example A1 but using instead of 4-oxo-4- (4-pyridinÿl) -30 butanenitrile an equimolar amount of the appropriate 4-oxo-4-PY-butanenitrile, it is seen that 4,5-dihydro-6-PY-2-methyl-3 (2H) -pyridazinones from Examples A-11 to A-15 can be obtained.

A-ll. 4,5-dihydro-2-methyl-6- (3-pyridinyl) -3 (2H) -35 pyridazinone.

A-l2. 4,5-dihydro ~ 2-methyl-6- (2-methyl-3-pyridinyl) -3 (2H) -pyridazinone.

A-l3. 4,5-dihydro-2-methyl-6- (5-methyl-3-pyridinyl) -3 (2H) -pyridazinone.

* · 'Η 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.

5 A-16. 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) - pyridazinone.

The mixture is refluxed with stirring for approximately 17 hours a mixture containing 16 g of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate, 30 ml of 10 N-methylhydrazine and 220 ml of absolute ethanol. The ethanol is distilled under vacuum and the oily residue is placed on a column of silica gel (7 cm in height and 15 cm in diameter) in a large sintered glass funnel and eluted with a 50-50 mixture by volume d ether and n-hexane. The evaporation of the eluents containing the major part of the product, as shown by a TLC analysis (mixture 90%, 5% and 5% by volume of chloroform, methanol and isopropylene), provides the solid product which recrystallized from a mixture of ether and n-hexane and dried under vacuum at 50 ° C to obtain 3.0 g of 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, pf 71-81 ° C.

The 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-25 2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone in approximately 20 ml of aqueous methanol, the appropriate acid (for example hydrochloric acid, methanesulfonic acid, sulfuric acid), to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated (eg hydrochloride, methanesulfonate or sulfate respectively). The lactate or hydrochloride of 4,5-dihvdro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone is also conveniently prepared, in aqueous solution, by adding to water and Stirring equimolar amounts of 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone and lactic acid or hydrochloric acid respectively.

According to the procedure described in Example A-16 but using instead 4-cyano-4- (4-morpholinyl) - 12 4- (4-pyridinyl) -2-methyl-methylbutanoate and N- methylhydrazine, corresponding equimolar amounts of lower alkyl 4-cyano-4- (BN) -4-PY-2-methylbutanoate and NR-hydrazine, it can be seen that the 4,5- dihydro-4-methyl-6-PY-2-R-3 (2H) -pyridazino-nes corresponding to Examples A-17 to A-23.

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) -10 3 (2H) -pyridazinone.

A-19. 4,5-dihydro-4-methyl-2-n-propyl-6- (4-pyridinyl) - 3 (2H) -pyridazinone.

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

15 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-3 (2H) -pyridazinone.

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

Following the procedure described in Example A-16 but using instead of methyl 4-cyano-4- (4-morpholinyl) -4- (4-pyridinyl) -2-methylbutanoate an equimolar amount of 2 -methyl-4-oxo-4- (4-pyridinyl) -25 methyl butanoate, it can be seen that 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 can be obtained (2H) -pyridazinone. This same compound can also be obtained by following the procedure described in Example A1 but using instead of 4-oxo-4- (4-pyridinyl) butanenitrile an equimolar quantity of 2-methyl-4- oxo-4- (4-pyridinyl) butanenitrile.

A-24. 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) - pyridazinone

The mixture is refluxed with stirring for approximately 17 hours a mixture containing 15 g of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate, 26 ml of hydrated hydrazine at 85% and 220 ml of absolute ethanol, then the solvent is distilled under vacuum. The crystalline residue is recrystallized from ethyl acetate, dried at 1390 ° C. and combined with another sample of the same compound prepared by the same procedure, starting with 11 g of 4-cyano- Methyl 2-methyl - 4- (4-morpholinyl) -4- (4-pyridinyl) -butanoate and recrystallizing the product from acetonitrile. The combined samples are recrystallized from isopropyl alcohol using bleaching charcoal and dried at 120 ° C., which gives 10 g of 4,5-dihydro-4-methyl-6- (4-pyridinvl) -3 (2H ) -pyridazinone, mp 184-185 ° C, tautomer of 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3-10 pyridazinol.

The acid addition salts of 4,5-dihydro-4-methvl-6- (4-pyridinyl) -3 (2H) -pyridazinone are prepared by following the same procedure as that described in Example A1. .

Following the procedure described in Example A-24 but using instead of methyl 4-cvano-2 ~ methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate an equimolar amount suitable lower alkyl 4-cyano-2-methyl-4- (BN) -4- (4-pyridinyl) butanoate, preferably the methyl or ethyl ester where BN is a 1-piperidinyl group or 1 -pyrrolidinyl, it can be seen that 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone can be obtained.

B. 2-R-4-R'-6 (PY) -3 (2h) -pyrydazinones 25 B-1. 2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone To a hot solution containing 28 g of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) monohydrochloride -pyridazinone and 140 ml of acetic acid, 100 ml of bromine are added with stirring and the resulting reaction mixture is heated at reflux overnight, then allowed to cool to room temperature. The solid which has separated is collected, stirred with 150 ml of water and, to the aqueous mixture, sodium bisulfite is added until bubbling stops. To the resulting pale yellow solution, sufficient solid sodium bicarbonate is added to make it moderately basic to sunflower and the resulting mixture is extracted with chloroform. The chloroform extract is heated in vacuo to remove the solvent and the resulting solid is recrystallized from a mixture of 14 methanol and ether and dried in a vacuum oven at 60 ° C overnight, giving 15 g of 2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, pf 175-185 ° C.

The 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-1-6- (4- pyridinyl) -3 (2H) -pyridazinone in about 20 ml of aqueous methanol, the appropriate acid (e.g. hydrochloric acid, methanesulfonic acid, sulfuric acid) up to a pH 10 of about 2 to 3, by cooling the mixture after partial evaporation and collecting the salt which has precipitated (for example the hydrochloride, the methanesulfonate, the sulfate respectively). The lactate or hydrochloride of 2-methyl-6- (4-pyridinyl) -15 3 (2H) -pyridazinone is also conveniently prepared in aqueous solution, by adding equimolar amounts of 2-methyl to water with stirring. - 6- (4-pyridinyl) -3 (2H) -pyridazinone and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example 20 B1 but using 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone or its mono-hydrochloride instead an equimolar amount of the appropriate 4,5-dihydro-2-R-4-R'-6-PY-pyridazinone or of its monohydrochloride, it can be seen that the 2-R-4-R * -6 can be obtained -PY-25 3 (2h) -pyridazinones corresponding to Examples B-2 to B-9.

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

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

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

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

B-6. 2-isopropyl-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-PY-butanenitriles C-1. 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 10 minutes, a dropwise addition is made over three hours solution containing 64.2 g of 4-pyridine-carboxaldehyde in 500 ml of acetonitrile and the resulting mixture is stirred at room temperature for one hour. To the stirred solution is slowly added over a 10 hour period a solution of 24.5 g of acrylonitrile in 200 ml of acetonitrile, and the resulting reaction mixture is stirred overnight at room temperature. The reaction mixture is freed from the solvent in vacuo at a temperature not exceeding 54 ° C. The semi-solid residue is cooled, carefully mixed with 400 ml of chloroform and the mixture is filtered. The chloroform is distilled under vacuum at a temperature not exceeding 50 ° C. and the oily residue is extracted with three 200 ml portions of toluene. The toluene solution is filtered on diatomaceous earth and the filtrate is distilled in vacuo below 50 ° C to remove the toluene. The residue crystallizes on cooling. We save a small sample and dissolve the rest in 50 ml of hot isopropyl alcohol. The solution is cooled and then diluted slowly with 125 ml of ether, cooled and inoculated with a crystal obtained from the small sample. The separating crystalline product is collected, washed with 25 ml of a 1: 3 by volume mixture of isopropyl alcohol and ether, and air-dried to give 52.1 g of 4-oxo-4- (4-pyridinyl) butanenitrile, mp

53.5-55 ° C.

By following the procedure described in Example C1, but using instead of 4-pyridinecarboxal-dehyde an equimolar amount of the appropriate 4- or 3-PY-carboxal-dehyde, it can be seen that the Corresponding 4-oxo-4-PY-butanenitriles of Examples C-2 to C-6.

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.

16 C-5. 4- (3-ethyl-4-pyridinyl) -4-oxobutanenitrile.

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

Following the procedure described in Example C-1 but using an equimolar amount of methacrylonitrile in place of acrylonitrile, it is seen that the corresponding compound of Example C-1 can be obtained.

C-l. 2-methyl-4-oxo-4- (4-pyridinvl) butanenitrile.

D. 4- (BN) -4-cyano-4-PY-2-R'-lower alkyl butanoates 10 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 150 ml of tetrahydrofuran in a flask equipped with a stirrer and a drying tube, stirring 6 ml of 30% potassium hydroxide in methanol, then 8.5 g of methyl methacrylate. An exothermic reaction takes place within thirty minutes and a white solid begins to separate. The reaction mixture is stirred for one hour and then allowed to stand at room temperature overnight. The reaction mixture is concentrated by heating under vacuum to remove the solvent and the remaining residue is triturated with absolute ether (about 600 ml) and filtered. The filtrate is concentrated to a volume of about 50 ml, cooled, treated with 50 ml of n-hexane and cooled. The product which separates is collected and dried at 70 ° C., which gives 11 g of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate, m.p. 93-94 ° C.

The 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 4- methyl cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate in about 20 ml of aqueous methanol, the appropriate acid (for example hydrochloric acid, methanesulfonic acid, sulfuric acid) to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated (for example the hydrochloride, methanesulfonate or sulfate * '17 respectively). The methyl lactate or hydrochloride of 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate is also conveniently prepared in aqueous solution, adding to water with stirring. 5 equimolar amounts of 4-cvano-2-methyl-4- (4-morpholinyl) - 4- (methyl 4-pyridinyl-butanoate and lactic acid or hydrochloric acid respectively.

Following the procedure described in Example Dl but using 2- (4-morpholinyl) -2- (4-> pyridinyl) ethanenitrile and methyl methacrylate instead of equimolar amounts of 2- (BN) -2-PY-ethanenitrile and suitable lower alkyl methacrylate, it can be seen that the corresponding lower alkyl 4-cyano-2-methyl-4- (BN) -4-PY-butanoates can be obtained from Examples D -2 to D-6.

15 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- (3-20 pyridinyl) butanoate.

D-5. 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridiny1) ethyl butanote.

D-6. N-propyl 4-cyano-4- (3-ethyl-4-pyridinyl) -2-methyl-4- (4-morpholinyl) butanoate.

25 E. 2- (BN) -2-PY-ethanenitriles

These generally known intermediates can be prepared by reaction of a cyclic amine of formula BN-H and of an alkaline cyanide such as a PY-aldehyde / bisulfite complex according to Janssen et al [J. Am. Pharm. Assoc., Sci. Ed. 44, 30 465-7 (1955)] or according to the following procedure described in Example E-1.

E-l. 2- (4-morpholinyl) -2- (4-pyridinyl) ethanenitrile

A mixture containing 72 g of 4-pyridinecarboxaldehyde, 140 g of morpholine, 152 g of p-toluenesulfonic acid and 800 ml of tetrahydrofuran is heated to reflux with stirring for two hours, then it is allowed to cool to ambient temperature. . To the stirred reaction mixture, 64 g of potassium cyanide in 20 ml of water are added and the resulting reaction mixture is heated at reflux for 2 hours and allowed to stand overnight at room temperature . The reaction mixture is filtered and the filtrate is heated in vacuo to remove the solvent. To the gummy residue obtained is added about 800 ml of chloroform and about 300 ml of a saturated solution of sodium chloride. The mixture is stirred for two hours and filtered. The heterogeneous filtrate is transferred to a separatory funnel, stirred carefully, the layer of chloroform is removed and heated in vacuo to remove the chloroform. The residue is boiled with about 300 ml of water, cooled and sown, causing the separation of pale yellow crystals. The filtrate is concentrated in vacuo to a volume of about 60 ml and a second crop of pale yellow crystals is obtained. The combined crops are first dried - from yellow crystals in a vacuum oven at 133 millibars and 25 ° C, then for 100 hours on? 2 ° 5 To obtain 40 g of 2 - (4 - morpholinyl) -2 - ( 4-pyridinyl) ethanenitrile, mp 64-65 ° C.

Following the procedure described in Example 20E1 and using equimolar amounts of the appropriate pyridine-carboxaldehyde and the appropriate amine of formula (BN-H) in place of 4-pyridinecarboxaldehyde and morpholine, it is seen that the corresponding 2- (BN) -2-PY-ethanenitriles from Examples E-2 to E-5 can be obtained.

25 E-2. 2- (4-pyridinyl) -2- (1-pyrrolidinyl) ethanenitrile.

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

E-4. 2- (3-ethyl-4-pyridinyl) -2- (4-morpholinyl) ethane nitrile.

E-5. 2- (5-methyl-3-pyridinyl) -2- (4-morpholinyl) ethane-nitrile.

The usefulness of the compounds of Formula I or their salts as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological test procedures, for example, in that they cause a significant increase in the force of contraction. isolated cat atria and papillary muscles and in that they cause a significant increase in the force of cardiac contraction in the anesthetized dog, with small or minimal changes in heart speed and blood pressure. Detailed descriptions of these procedures can be found in the U.S. Patent.

N ° 4.072.746.

When tested by the procedure on cat ear-5 and papillary muscles isolated, it is found that the compounds of Formula I or their pharmaceutically acceptable acid addition salts cause, at doses of 10, 30, 100 and / or 300 µg / ml, significant increases (i.e. greater than 25%) in papillary muscle strength and significant increases (i.e. greater than 25%) the strength of the right atrium, while causing a lower percentage increase (about a third or less compared to the percentage increase in the strength of the right atrium of the strength of the papillary muscle) in the speed of the right atrium. For example, when tested at doses of 10, 30 and 100 µg / ml according to this procedure, it is found that the compound of Example A1, i.e. 4,5-dihydro- 2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone as its monohydrochloride, causes increases of 35 to 77% in the strength of the papillary muscle and / or the strength of the right atrium ; when tested at a dose of 100 µg / ml according to a comparable procedure using the isolated papillary muscles and guinea pig auricles, the compound of Example A-16 was found, i.e. 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, causes respective increases of 75% and 63% in the strength of the papillary muscle and the strength of the right atrium. It is found that 4,5-dihydro-4-methyl-6- (4-30 pyridinyl) -3 (2H) -pyridazinone (Example A-24) causes respective increases of 139% and 86% in muscle strength papillary and right atrium strength at 100 ug / ml and an increase in papillary muscle strength of 45% at a dose of 30 ug / ml.

35 In clinical practice, the compound or its salt of Formula I

where R is a lower alkyl group will normally be administered orally or parenterally in various dosage forms. Solid compositions for oral administration include tablets, pills,

\ U

* 20 A.

powders and granules. In such solid compositions, at least one of the active compounds is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions can also contain complementary substances other than inert diluents, for example lubricants, such as magnesium stearate, talc, etc.

The preparations according to the invention intended for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspension media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersing agents.

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

The percentage of active ingredient in the compositions can be varied to obtain the appropriate dosage. The dose administered to a particular patient will vary according to the judgment of the clinician using the following criteria: route of administration, duration of treatment, size and condition of the patient, potency of the active compound and the patient's reaction thereto. An effective dose of active compound can therefore only be determined by the physician by considering all of these criteria and using his best judgment on the behavior of the patient.

Claims (7)

2. Compound according to Claim 1, where R is a methyl or ethyl group. 3. Compound according to either of Claims 1 and 2, where PY is a 4- or 3-pyridinyl group. 4. 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyri dazinone or a pharmaceutically acceptable acid addition salt thereof. 5. 4,5-Dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone or a pharmaceutically acceptable acid addition salt thereof. 6. Process for the preparation of a compound according to any one of Claims 1, 2 and 3, characterized in that it consists in reacting a 2-R'-4-oxo-4-PY-butane-nitrile, a lower alkyl 2-R'-4-oxo-4-PY-butanoate or a lower alkyl 2-R'-4- (Bn) -4-cyano-4-PY-butanoate with NR- hydrazine or one of its salts formed with a strong mineral acid or an organic sulfonic acid and, if desired, converting the free base obtained into one of its acid addition salts. 7. Method according to Claim 6, characterized in that a 2-R-4-oxo-2-R'-4-PY-butanenitrile and a salt of NR-hydrazine and of strong mineral acid or d are reacted organic sulfonic acid. * 22 ", * w η 8. Method according to Claim 6, characterized in that methyl 2-R'-4- (1-morpholinyl) -4-cyano-4-PY-butanoate or 2-R'-4- is reacted methyl oxo-4-PY-butanoate and NR-hydrazine. 9. Cardiotonic composition intended to increase the cardiac contractility, characterized in that it comprises an inert carrier acceptable on the pharmaceutical level and, as active component, an effective amount on the cardiotonic level of a compound according to any one. as in claims 1 to 4, wherein R is a lower alkyl group, or a compound according to Claim 5, or a pharmaceutically acceptable salt thereof. 10. Compound intended to increase the cardiac contractility in a patient in need of such treatment, characterized in that it is a compound according to any one of Claims 1 to 4, in which R is a lower alkyl group, or a compound according to Claim 5, or a pharmaceutically acceptable acid addition salt thereof.