DE3116791A1 - "4,5-DIHYDRO-6- (PYRIDINYL) -3 (2H) -PYRIDAZINONE, VALUABLE AS A CARDIOTONIC AGENT, AND THEIR PRODUCTION" - Google Patents

Description

STERLING DRUG INC., New York, N.Y. / UNITED STATES

4,5-Dihydro-6- (pyridinyl) -3 (2H) -pyridazinones, Valuable as Cardiotonic Agents, and Their Preparation

description

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

Haginiwa et al., [Yakugaku Zasshi, 9-8 (1), 67-71 (1978); Chem. Abstr. 88, 17O, O96v (19 78)] have 3 (2H) -pyridazinone with pyridine ~ 1-oxide and platinum-coated Pd-C catalyst to produce 6- (2-pyridinyl) -3 (2H) -pyridazinone.

Yoshitomi Pharmaceutical Ind., Ltd., JA patent application No. 19987/79, published February 15, 1979 and based on Patent Application No. 85192/77 dated July 15, 1977, discloses, inter alia, the preparation of 4,5-dihydro-6- (4-pyridinyl) -3 (2H) -pyridazinone by refluxing an ethanolic solution of 3- (isonicotinoyl ) propionic acid [same as v -'- oxo y ^ - (4-pyridinyl) butyric acid] and hydrazine hydrate. 4,5-dihydro-6- (4-pyridinyl) -3 (2H) -pyridazinone and closely adjacent to this 4,5-dihydro-6- (4- or 3- or 2-pyridinyl) -5-R-3 (2H) -pyridazinones, in which R · Is H or lower alkyl are those (page 2 of the English Translation), which is "valuable not only as medicinal products, such as hypotensive and anti-thrombotic agents because of their pharmacological effects, such as the hypotensivG, which inhibits platelet coagulation and stabilizes the membrane Effect, but also as intermediates for the synthesis of such drugs "are.

Jl I D / a I

McEvoy and Allen [J.Org.Chem. _38: 4044-48 (1973); J.Med.Chem. 17 , 281-286 (1974)] show a method for the preparation of 3- (substituted-benzoyl) -3-substituted-alkanoic acids and their reaction with hydrazine to prepare 6- (substituted-phenyl) -5-substituted-4, 5-dihydro-3 (2H) -pyridazinones, hypotensive agents.

Curran and Ross [J.Med.Chem. 17., 273-281 (1974)] show the Production of 6-phenyl-4,5-dihydro-3 (2H) -pyridazinones, hypotensive agents, by refluxing the required 3-benzoyl propionic acid with hydrazine hydrate in ethanol.

Albright, McEvoy and Moran [J. Heterocyclic Chem. JL5_, 881-892 (1978)] show the use of oc- (substituted-phenyl) -4-morpholine-acetonitriles in 1,4-additions to ethyl acrylate, ethyl crotonate, methyl a-methyl acrylate, acrylonitrile, methacrylonitrile, Croton nitrile and cinnamonitrile for the production of 4-cyano-4- (4 ~ morpholinyl) -4- (substituted-phenyl) -butanenitriles and butyric acid esters and their conversion by reaction with hydrazine to 6- (substituted-phenyl) -4,5-dihydro-3 (2H) -pyridazinones and subsequently their dehydrogenation by reaction with bromine to produce 6- (substituted-phenyl) -3 (2H) -pyridazinones, which optionally carry methyl in the 4- or 5-position of the pyridazinone ring.

McEvoy and Albright [J.Org.Chem 44, 4597-4603 (1979)] show, inter alia, the reaction of 2-cyano-2- (4- or 3-pyridinyl) -2- (4-morpholinyl) -ethane-nitrile with acrylonitrile or ethyl acrylate to produce either ethyl-4-cyano-4- (4- or 3-pyridinyl) -4- (4-morpholinyl) -butanoate or 4-cyano-r4- (4- or 3-pyridinyl) -4- (4 ~ morpholinyl) -butane-nitrile.

Leete et al. [J.Org.Chem. 37_, 4465-6 (19 72)] show the reaction of 2- (3-pyridinyl) -2- (4-morpholinyl) -ethane-nitrile with acrylonitrile for the preparation of 4-cyano-4- (3-pyridinyl) -4- (4-morpholinyl) -butane-nitrile and its conversion to 4-oxo-4- (3-pyridinyl) -butan-nitrile by heating with acetic acid, water and tetrahydrofuran.

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

or their acid addition salts, wherein

PY 4- or 3-pyridinyl or 4- or 3-pyridinyl with a or two lower alkyl substituents,

R is lower alkyl or lower hydroxyalkyl and R ^{1 is} hydrogen or methyl,

and wherein R can also be hydrogen when R ^{1 is} methyl. These compounds, where R is lower alkyl or hydrogen, are of value as cardiotonic agents as determined by standard cardiotonic scoring methods. Preferred embodiments are those in which PY is 4-pyridinyl or 3-pyridinyl, R is methyl or ethyl and R ^{1 is} hydrogen. The above compounds of formula 1, in which R ^{1 is} hydrogen, are also described in DE-OS 3,032,137 as intermediates in the preparation of 2-R-6-PY-3 (2H) -pyridazinones, cardiotonic agents. The compounds of the formula I in which R ^{1 is} methyl can also be used to prepare the corresponding new 2-R-4-methyl-6-PY-3 (2H) -pyridazinones.

4,5-Dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone (I: PY is 4-pyridinyl, R ^f is methyl, R is hydrogen) can exist in tautomeric forms, ie as 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) -pyridasinone of the formula IA and / or as 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3 -pyridazole of formula IB, represented by the following scheme (PY is 4-pyridinyl):

31

IB

In fact, the two tautomers (IB and IA) are so close to each other connected so that they can be viewed essentially as one and the same connection and given any given Such a compound, which is capable of tautomerism, may be in one or both tautomeric forms exist. Although it has been preferred to use the name in relation to the structure IA, it goes without saying that either or both structures are included herein.

Can be a 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinone of the formula I may be prepared by reacting 2-R ¹ -4-oxo-4-PY-butane nitrile, lower-alkyl-2-R ¹ -4-OXO-4-PY-butanoate or lower-alkyl-2-R'-4- (BN) -4-cyano-4-PY-butanoate with NR-hydrazine or His Sau ζ with a strong inorganic acid or an organic sulfonic acid for the preparation of 2-R-4,5-dihydro- 4_R «_6-PY-3 (2H) -pyridazinone, in which PY, R ¹ and R are defined as in formula I. are. In preferred embodiments, this process is carried out using 2-R'-4 ~ 0xo-4-PY-butar-nitrile and an NR-hydrazine salt ζ a strong inorganic acid or an organic sulfonic acid, such as NR-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 NR-hydrazine.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceutically acceptable inert carrier and, as the active component, a cardiotonically 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, wherein R is lower-alkyl and PY and R ^{1 are} as defined in formula I or R ^{1 is} methyl, R is water

- 7 -
Is substance and PY is 4-pyridinyl.

To increase cardiac contractility in a patient in need of such treatment, a composition may be administered orally or parenterally in a solid or liquid dosage form to such patient which comprises a pharmaceutically acceptable inert carrier and, as the active component, a cardiotonically effective amount of 2- R-4,5-Dihydro-4-R'-6-PY-3 (2H) -pyridazinone or a pharmaceutically acceptable acid addition salt thereof, wherein R is lower alkyl and PY and R ^{1 are} as defined in Formula I or R ^{1 is} methyl, R is hydrogen and PY is 4-pyridinyl.

As used herein the term "lower alkyl" e.g. as one of the meanings for R (formula I) or as a substituent for PY (formula I), denotes alkyl radicals with 1 to 6 carbon atoms, which can be arranged straight-chain or branched, for example. Methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, n-hexyl, and the like.

The symbol PY as used here, e.g. as a 6-substituent in the compounds of formula I, means 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two "lower alkyl" substituents, e.g. 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively referred to as 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 here, for example as one of the meanings for R '.n of the formula I, means Ilyilroxyalkylrer.to with 2 bin d Koh enstoffntoman and dlo Jl ti c »IJytl noJcyciJUH ¹ ' - uiul llii.f .. · Irch · Vd 1 c. ■ -.) · i ndvitin (luk-r linking bond) have on different carbon atoms and which can be straight-chain or branched,

ι ι b / a ι

e.g. 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-l, 1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, and the like.

The compounds according to the invention, which have the formula I, are valuable both in the free base form and in the form of the acid addition salts, and both forms are present within the scope of the invention. The acid addition salts are simply a more convenient form to use, and in in practice, the use of the salt form inherently boils down to the use of the base form. The acids used to manufacture of the acid addition salts which can be used preferably include those when combined with the free base result in pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the organism in pharmaceutical doses of the salts are, so that the favorable cardiotonic properties that of the free base of the cardiotonically active compounds (I) according to the invention inherent, are not adversely affected by side effects attributable to the anions. During execution of the invention it is beneficial to use the free base form; however, suitable pharmaceutically acceptable salts are within the scope of the invention those derived from mineral acids, such as hydrochloric acid, sulfuric acid ,. Phosphoric acid and sulfamic acid, and organic acids, such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p -tpluenesulphonic acid, Cyclohexylsulfamic acid, quinic acid and the like, which are the hydrochloride, sulfate, phosphate, sulfamate, acetate, Citrate, lactate, tar stepped, methanesulfonate, ethanesulfonate, benzenesulfonate, p-Toluenesulfonate, cyclohexylsulfamate or »the Chinese salt result.

The acid addition salts of these basic compounds are prepared either by dissolving the free base in aqueous solution or aqueous-alcoholic solution or another suitable solvent containing the appropriate acid, and then Isolation of the salt by evaporation of the solution or by

Reaction of the free base and the acid in an organic solvent, in which case the salt .sich separates off directly or can be obtained by concentrating the solution.

Although pharmaceutically acceptable salts of the basic compound are preferred, all acid addition salts are within the scope of the invention. All acid addition salts are valuable as sources for the free base forir, even if that single salt per se only desired as an intermediate product is used, e.g. if the salt is only used for the purpose of torment or identification is formed or when it is used as an intermediate for the preparation of a pharmaceutically acceptable salt Ion exchange process is used.

The molecular structures of Formula I were based on of the result obtained by IR, NMR and mass spectra and by the agreement of calculated and found values for elemental analysis.

How To Make And Use The Present Invention will now be described in detail so as to enable a person skilled in the art of pharmaceutical chemistry to to carry them out and to use them.

The reaction of 2 - R '- ^ oxo- ^ PY- butane nitr.il with an NR hydrazine salt of a strong inorganic acid or organic sulfonic acid to produce 2-R-4,5-dihydro-4-R'-6 -Py-3 -pyridazinone (2H) is carried out by heating the reactants at about 65 to 120 ⁰ C in a suitable solvent, preferably to about 80 to 100 C in a mixture of water and a lower alkanol. The reaction is preferably carried out by refluxing 2-R'-4-oxo-4-PY-butanonitrile with hydrazine sulfate in aqueous ethanol. Other useful NR hydrazine salts are NR hydrazine dihydrochloride, NR hydrazine dimethanesulfonate and similar salts derived from phosphoric acid, xthanesulfonic acid, benzenesulfonic acid and like acids. Other alkanols that can be used as solvents are methanol, n-propanol, 2-propanol, n- ^ butanol,

ό Ί I b 7

2-butanol and 2-methyl-n-propanol. This reaction is in the described below in Examples A-I to A-15.

The 2-R'-4-oxo-4-PY-butane-nitrile intermediates are generally known compounds, see, for example, Stetter et al », Chem.Ber. 107 , -210 (1974), Leete et al., J.Org.Chem. 37_, 4466 (1972) and Stetter et al., U.S. Patent 4,014,889 (March 29, 1977) and are prepared by well known methods. The preparation of these compounds is described below in Examples CI to CG.

The reaction of lower alkyl 2-R'-4-oxo-4-PY-butanoate or low ~ Al] cyl-IR ^t -4- (BN) -4-cyano-4-PY-butanoate with NR hydrazine for the preparation of 2-R-4,5-dihydro-4-R ^f -6-PY-3 (2H) -pyridazinon is by heating the reactants to about 65 to 120 ⁰ C in a suitable solvent, preferably to about 80 to 100 C in a lower alkanol. The reaction is preferably carried out 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 described below in Examples A-16 through A-24.

The lower-alkyl-2-R'-4-oxo-4-PY-butanoate intermediates and / or the corresponding acids are well known compounds _; en [Wada et al., J. Am. Chem. Soc. 7j5> 155 (1954)], which can easily be obtained by hydrolysis of the generally known 2-R'-4-0xo-4-PY-butar-nitriles and esterification of the 2-R * -4-0xo-4-PY- }> utanoic acids can be produced.

The reaction of 2- (BN) -2-PY-ethane-nitrile (III) with lower-alkyl-2-R'-2-propenoate (IV) to produce lower-alkyl-2-R'-4- ( BIJ) -4-cyano-4-PY-butanoate (II) is MGEN-cond under anhydrous carried out by mixing the reactants at about 25 b .s 60 C, preferably about 30 to 50 ⁰ C, in a solvent in geeignete.ι Presence of a basic condensation agent. The reaction is conveniently carried out by mixing the reactants at about 30 to 50 ° C

in dry tetrahydrofuran in the presence of an alkali hydroxide in methanol. Other suitable solvents are other low ones 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 methoxide or potassium ethoxide, sodium hydride and the like.

The 2- (BN) -2-PY-ethane-nitrile intermediates (III) are general known compounds, see e.g. Janssen et al, J. Am. Pharm. Assoc, Sci., Ed. 44, 465-7 (1955), and are produced by well known methods. The preparation of these compounds is described below in Examples E-I to E-5.

The conversion of the 4,5-dihydro-2 ~ R-4-R'-6-PY-3 (2H) -pyridazinone intermediates by reaction with bromine to the corresponding 2-R-4-R'-6-PY- 3 (2H) -pyridazinones, the 2-R-4-R'-6-PY-pyridazinones prepared by the conversion and use of the latter, wherein R ^{1 is} hydrogen, as cardiotonic agents are disclosed and claimed in the above mentioned DE -OS 30 32 137. This conversion and the products made thereby are described below in Example BI for a compound in which R 'is hydrogen, and in Examples B-2 to B-9 for compounds in which R' is methyl.

The following examples explain the invention in detail.

A. 4,5-Dihydro-2-R-4-R'-6-PY-3 (2H) ~ pyridazinone

A-1 x 4, S-Dihydro ^ -methyl-e- (4-pyridinyl) -? (2H) -pyrida: ^ in on

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 ~ 0xo-4 - (4-pyridinyl) -tutan-nitrile were added, and the resulting reaction mixture was refluxed overnight (about 15 hours). The solvent

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was distilled off in vacuo and the resulting solid was recrystallized from ethanol and placed in a vacuum oven dried at 65 ° C. overnight to give 10.5 g of 4j5-dihydro-2-methy1-6- (4-pyridinyl) -3 (2H) -pyridazinone as its monohydrochloride, F 219 to 225 ° C (dec.).

The acid addition salts of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone are usually prepared by adding 1 g of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone to a mixture in about 20 ml of aqueous methanol the appropriate acid, e.g. hydrochloric acid, methanesulfonic acid, sulfuric acid, up to a pH of about 2 to 3 is added, the mixture cools after partial evaporation and the precipitated Salt, e.g. the hydrochloride, methanesulphonate or sulphate, collects. Likewise, the lactate or hydrochloride acid addition salt is used of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone Conveniently prepared in aqueous solution by adding molar amounts equivalent to water with stirring each of 4,5-dihydro-2-methy1-6- (4-pyridinyl) -3 (2H) -pyridazinone and adding lactic acid and hydrochloric acid, respectively.

Following the procedure described in Example A-I, but under Use of a molar equivalent amount of the suitable N-R-hydra:; in-dihydrochloride or another salt of a strong one inorganic acid or an organic sulfonic acid instead of N-methylhydrazine dihydrochloride, one can use the corresponding 4,5-DIhydro-2-R-6- (4-pyridinyl) -3 (2H) -pyridazinone (or Salts thereof) of Examples A-2 to A-IO.

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

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

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

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

A-6. 2-n -.-Iexyl-4,5-dihydro-6 ~ (4-pyridinyl) -3 (2H) -pyridasinone.

A-7. 2- (2-hydroxyethyl) -4,5-dihydro-6- (4-pyridinyl) -3 (2H) -pyridazinone, F 142 to 144 ° C.

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

A-9. 2- (3-hydroxypropyl) -4,5-dihydro-6- (4-pyridinyl) -3 (2H) -pyridazinone.

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

Following the procedure described in Example A-I, however using the appropriate 4-0xo-4-PY-butane-nitrile instead of 4-0x0-4- (4-pyridinyl) -butane-nitrile, one can use the 4,5-Dihydro ~ 6-PY-2-methyl-3 (2H) -pyridazinone of the examples A-II to A-15 obtained.

A-Il. 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.

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

A mixture containing 16 g of methyl 4-cyano ~ 2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate, 30 ml of N-methylhycrazine and 220 ml of absolute ethanol was about Treated at reflux for 17 hours. The ethanol was distilled off in vacuo and the remaining oily material was placed in a silica gel column (7 cm high and 15 cm in diameter) in a large sintered glass funnel and eluted with a 50/50 volume mixture of ether and η-hexane. Evaporation of the eluent containing the mass of the product, as shown by Dünnschichchromatographie analysis (CHCl ₃ ZCH Ohi ₃ iC ₃ H ₇ NH ₂ / 9O: 5: 5 by volume - / -) resulted in a solid

Product that recrystallizes from ether / η-hexane and in vacuo was dried at 50 ° C to give 3.0 g of 4, 5 ~ dih-ydro-2, 4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, F 71 to 81 ° C.

The acid addition salts of 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinones 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.g. hydrochloric acid, Methanesulfonic acid, sulfuric acid, up to a pH value of about 2 to ■ 3 is added, the mixture after partial evaporation cools and the precipitated salt, e.g. the hydrochloride, methanesulfonate or sulfate, collects. Likewise, the lactate or hydrochloride acid addition salt of 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone Conveniently prepared in ■ aqueous solution by adding to water with stirring molar equivalent amounts each of 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone and adding lactic acid and hydrochloric acid, respectively.

Following the procedure described in Example A-16, however using appropriate molar equivalent amounts of the appropriate lower alkyl 4-cyano-4- (BN) -4-PY-2-methylbutanoate and N-R hydrazine in place of methyl 4-cyano-4- (4-morpholinyl) -4- (4-pyridinyl) -2-methylbutanoate and N-methylhydrazine can be the corresponding 4,5-dihydro-4-methyl-6-PY-2-R-3 (2H) -pyridazinones of Examples A-17 to A-23 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-19. 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-3 (2H) -pyridazinone.

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

Following the procedure described in Example A-16, however using a molar equivalent amount of methyl 2-methyl-4-oxo-4- (4-pyridinyl) butanoate in place of Methyl 4-cyano-4- (4-morpholinyl) -4- (4-pyrid 1.nylj ^ -methylbutanoat, one can use 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) - 3 (2H) -pyridazinone obtained. Likewise, the same compound can be obtained according to the method of Example A-I, but using a molar equivalent amount of 2-methyl-4-oxo-4- (4-pyridinyl) -butane-nitrile instead of 4-0XO-4- (4-pyridinyl) -butane-nitrile.

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

A mixture containing 15 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 added with stirring refluxed for about 17 hours and the solvent was distilled off in vacuo. The remaining crystalline residue was umkristallisier- from ethyl acetate, combined and dried at 90 ⁰ C of another sample of the same compound, which, starting from 11 g according to the same manner methyl 4-cyano-2-methyl-4- (4-morpholinyl ) -4- (4-pyridinyl) butanoate and by recrystallizing the product from acetonitrile. The combined samples were recrystallized from isopropyl alcohol using decolorizing charcoal and dried at 120 ° C. to give 10 g of 4,5-dihydro-4-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, melting point 184 to 185 ° C, tautomeric with 4,5-dihydro-4-methyl-6- (4-pyridinyl ') -3-pyridazinol.

J I I D / a I

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

Following the procedure described in Example A-24, however using a molar equivalent amount of the appropriate. lower alkyl, preferably methyl or ethyl, -4-cyano-2-methyl-4- (BN) -4- (4-pyridinyl) butanoate, wherein BN1 is piperidinyl or 1-pyrrolidinyl, instead of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate, can be 4,5-dihydro-4-methyl-6 ~ (4-pyridinyl) -3 (2H) -pyridazinone can be obtained.

BI. 2-Methy1-6- (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, 100 ml of bromine were added with stirring, and the resulting reaction mixture was refluxed overnight and then allowed to cool to room temperature. The solid that separated was collected with 150 ml of water was stirred, and sodium bisulfite was added to the aqueous mixture until bubbling ceased Sufficient solid sodium bicarbonate was added to the resulting pale yellow solution to make it mildly varnish. base, and the resulting mixture was extracted with chloroform. The chloroform extract was in vacuo heated to remove the solvent, and the resulting solid was recrystallized from methane oil / ether and converted into dried in a vacuum oven at 60 ° C overnight to give 15 g of 2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, melting point 175 to 185 ° C, to surrender.

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-Methy1-6- (4-pyridinyl) -3 (2H) -pyridazinone in about 20 ml of aqueous methanol the appropriate acid, e.g. hydrochloric acid, methanesulfonic acid, sulfuric acid,

the mixture is added to a pH of about 2 to 3 cools after partial evaporation and the precipitated salt, e.g. the hydrochloride, methanesulfonate or sulfate, collects. Likewise, the lactate or hydrochloride acid addition salt of 2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone is beneficial prepared in aqueous solution by adding molar equivalent amounts of 2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone to water with stirring and adding lactic acid and hydrochloric acid, respectively.

Following the procedure described in Example B-I, however using a corresponding molar equivalent amount of the appropriate 4,5-dihydro-2-R-4-R'-6-PY-pyridazinone or the Monohydrochloride salt thereof in place of 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone or its monohydrochloride, one can use the corresponding 2-R-4-R'-6-PY-3 (2H) -pyridazinones of 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. 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- (η-Butyl) -4-methy1-6- (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-methy1-6- (4-pyridinyl) -3 (2H) -pyridazinone.

C. 4 ~ 0xo-4-PY-butane-nitrile

CI. 4-0x0-4- (4-pyridinyl) -butane-nitrile

After stirring for 10 minutes, this was added to a stirred mixture containing 29.4 g of sodium cyanide and 500 ml of acetonitrile Mixture dropwise over 3 hours a solution containing 64.2 g of 4-pyridinecarboxaldehyde in 500 ml of acetonitrile, added, and the resulting mixture was 1 hour at

Jl Ib / a I

Room temperature stirred. A solution of 24.5 g of acrylonitrile was slowly added to the stirred mixture over the course of one hour in 200 ml of acetonitrile was added, and the resulting reaction mixture was stirred at room temperature overnight. the Reaction mixture was stripped of solvent in vacuo at a temperature not exceeding 54 ° C. The semi-solid residue was cooled, mixed well with 400 ml of chloroform and the mixture filtered. The chloroform was added in vacuo a temperature not above 50 ° C, and the remaining oily residue was with three 200 ml portions of toluene extracted. The toluene solution was replaced by diatomaceous earth filtered, and the. Piltrat was distilled in vacuo below 50 C to remove the toluene. The residue crystallized while cooling. A small sample was saved and the remainder was dissolved in 50 ml of warm isopropyl alcohol. The solution was cooled and then slowly diluted with 125 ml of ether, cooled and with a crystal obtained from the small sample, vaccinated. The crystalline product that separated was collected with 25 ml of a 1: 3 (v / v) mixture of isopropyl alcohol: ether washed and air-dried to give 52.1 g of 4-0xo-4- (4-pyridinyl) -butane-nitrile, P 53.5 bis 55 ° C.

Following the procedure described in Example C-I, however using a molar equivalent amount of the appropriate 4- or 3-PY-carboxaldehyde instead of 4-pyridinecarboxaldehyde, the corresponding 4-0xo-4-PY-butanenitriles of Examples C-2 to C-6 can be obtained.

C-2. 4-oxo-4- (3-pyridinyl) butane nitrile.

C-3. 4- (2-methyl-3-pyridinyl) -4-oxo-butan-nitrile.

C-4. 4- (5-methyl-3-pyridinyl) -4-oxo ~ butan-nitrile.

C-5. 4- (3-ethyl-4-pyridinyl) -4-oxo-butan-nitrile.

C-6. 4- (2,6-dimethyl-4-pyridinyl) -4-oxo-butan-nitrile.

Following the procedure described in Example C-I, however using a molar equivalent amount of methacrylonitrile instead of acrylonitrile, one can use the corresponding Obtained compound of Example C-7.

C-7. 2-methyl-4-oxo-4- (4-pyridinyl) butane nitrile.

D. Low-alkyl-4- (BN) -4-cyano-4 ~ PY-2-R'-butanoate

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-pyridinyD-ethane-nitrile and 150 ml of tetrahydrofuran, in a vessel equipped with a stirrer and a drying tube with stirring, 6 ml of 30% potassium hydroxide in methanol, followed of 8.5 g of methyl methacrylate was added. An exothermic reaction occurred within 30 minutes and a white solid began to separate. The reaction mixture was left for 1 hour stirred and then left to stand at room temperature overnight. The reaction mixture was heated in vacuo for removal of the solvent was concentrated 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, treated with 50 ml of η-hexane and cooled chilled. The product that separated was collected and dried at 70 ° C to give 11 <j methyl-4-cyanc-2-methyl ~ 4 ~ (4 ~ morpholinyl) -4- (4-pyridinyl) butanoate, m.p. 3 to 94 ° C. ■

The acid addition salts of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyl) butanoate are favored. prepared by adding the appropriate acid, for example hydrochloric acid, to a mixture of 1 g of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyricinyl) butanoate in about 20 ml of aqueous methanol Adds methanesulfonic acid, sulfuric acid, up to a pH value of about 2 to 3, the mixture cools after partial evaporation and the alXene salt, -uB the hydrochloride, kethanesulfonate or sulfate, is collected. as well

becomes the lactate or hydrochloride acid addition salt of Methyl 4-cyano-2- methyl-4- (4-morpholinyl) ~ 4- (4-pyridinyl) butanoate favorably prepared in aqueous solution by adding molar equivalent amounts of each to water with stirring. • Because of methyl 4-cyano-2-methyl-4- (4-morpholinyl) -4- (4-pyridinyD-butanoate and adding lactic acid and hydrochloric acid, respectively.

Following the procedure described in Example D-I, however using molar equivalent amounts of the appropriate 2- (BN) -2 ~ PY-ethane nitrile and lower alkyl methacrylate instead of 2- (4-morpholinyl) -2- (4-pyridinyl) ethane nitrile and methyl methacrylate, one can use the corresponding lower-alkyl-4-cyano-2-methyl-4- (BN) -4-PY-butanoate of Examples D-2 to 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-ethane-nitrile

These well-known intermediates can be prepared by adding a cyclic amine of the formula BN-H and an alkali metal cyanide with a PY-aldehyde-bisulfite complex accordingly Janssen et al. [J.Am.Pharm.Assoc., Sci. Ed. _44, 465-7 (1955)] or according to the alternative procedure according to Example E-I implements.

EGG. 2- (4-Morpholinyl) -2- (4-pyridinyl) -etha: i-nitrile

A mixture containing 72 g of 4-pyridinecarboxaldehyde, 140 g of morpholine, 152 g of p-toluenesulfonic acid and 80O ml of tetrahydrofuran was refluxed with stirring for 2 hours and then allowed to cool to room temperature. 64 g of potassium cyanide in 20 ml of water were added to the stirred reaction mixture, and the resulting reaction mixture was refluxed for 2 hours and left to stand at room temperature overnight. The reaction mixture was filtered and the piltrate was heated in vacuo to remove the solvent. To the resulting gummy residue were added about 800 ml of chloroform and about 300 ml of saturated sodium chloride solution. The mixture was stirred for 2 hours and filtered. The heterogeneous filtrate was transferred to a separatory funnel, shaken well, and the chloroform layer was stripped and heated in vacuo to remove the chloroform. The residue was with about. Boiled 300 ml of water, cooled and inoculated, whereupon pale yellow crystals separated. The filtrate was concentrated in vacuo to a volume of about 60 ml and a second portion of pale yellow crystals were obtained. The combined portions of the yellow crystals were first dried in a vacuum oven at 100 mm and 25 ° C and then 100 hours over PpO ₅ to give 40 g of 2- (4-morpholinyl) -2- (4-pyridinyl) ethane nitrile, F 64 to 65 ° C.

According to the procedure described in Example E-I under Use of molar equivalent amount of the corresponding suitable pyridinecarboxaldehyde and amine (BN-H) instead of 4-pyridinecarboxaldehyde and morpholine can be the corresponding 2- (BN) -2-PY-ethane-nitriles of Examples E-2 to E-5 were obtained.

E-2. 2- (4-pyridinyl) -2- (1-pyrrolidinyl) ethane nitrile.

E-3. 2- (1-piperidinyl) -2- (4-pyridinyl) -ätlun-nitrile.

E-4. 2- (3-Ethyl-4-pyridinyl) -2- (4-morpholir <yl) -ethane-nitrile.

J Ί ί b 7 y I

"" Ν. W «^ W.

- 22 -

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

The advantages of the compounds of formula I or their salts as cardiotonic agents are demonstrated by their effectiveness in pharmacological Standard test procedures demonstrated, e.g. by showing a significant increase in the contractile strength of the isolated cat atria and papillary muscle and by having a significant increase in cardiac contractility strength causes little or minimal changes in heart rate and blood pressure in the anesthetized dog. Detailed descriptions of these test procedures can be found in U.S. Patent 4,072,746.

When examined using isolated cat atria and the papillary muscle method, the compounds of formula I or their pharmaceutically acceptable acid addition salts in doses of 10, 30, 100 and / or 300 μg / ml were found to be suitable for inducing significant increases, ie Increases greater than 25 % in papillary muscle strength, and significant increases, that is, greater than 25%, in right atrial strength, while a smaller percentage increase (about one third or less of the percent increase in right atrial strength or papillary muscle strength) in the right atrial velocity · is brought about. When, for example, tests were carried out using this procedure at doses of 10, 30 and 100 ug / ml, it was found that the compound of Example AI, ie 4,5-dihydro-2-methyl-6- (4-pyridinyl) -3 ( 2H) -pyridazinone, as monohydrochloride, induces increases of 35 % to 77 % in papillary muscle strength and / or right atrial strength; when tested at 100 jag / ml by the comparable test procedure using isolated guinea pig atria and papillary muscles, the compound of Example A-16, ie 4,5-dihydro-2,4-dimethyl-6- (4-pyridinyl) -3 (2H) -pyridazinone, induced increases of 75 % and 63% in papillary muscle strength and right atrial strength, respectively. 4,5 ~ Dihydro ~ 4-methyl-6- (4-pyridinyl) -3 (2H) -pyridazinone (Example A-24) was found to be suitable, increases of 139 % and 86 % in the papillary muscle

strength and the right atrial strength at "OO iug / ml and one Increase in papillary muscle strength of 45% in papillary muscle strength at 30 µg / ml.

In clinical practice, the compound or salt thereof of formula I wherein R is lower-alkyl .int, normally administered orally or parenterally in numerous dosage forms. Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, "is at least one of the effective compounds with at least one inert diluent such as starch, calcium carbonate, sugar or lactose, mixed. These compositions can also contain additional substances other than the inert diluents. hold, e.g. lubricants 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 suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectables organic esters such as ethyl oleate. These compositions can also contain adjuvants, such as stabilizing, preserving, contain wetting, emulsifying and dispersing agents.

This can be done e.g. by filtration through a bacteria-retentive Filters, by incorporating sterilizing agents into the compositions, by irradiation or by heating sterilized. They can also be prepared in the form of solid sterile compositions, which in sterile Water or other sterile injectable medium can be released immediately before use.

The percentage of active ingredient in this composition and the procedure for increasing cardiac contractility can

I 1 \ JI \ J

art can be varied so that a suitable dosage is achieved
will. The dose administered to a particular patient will vary depending on the judgment of the clinician using the following criteria: route of administration, duration of treatment, patient size and condition, drug efficacy, and patient response. An effective dosage amount of the active ingredient can therefore only be determined by the clinician
who takes all criteria into account and makes the best possible assessment for the patient.

Claims (10)

Dr. F. Zumstein Sr. - Dr. E. Assmann Dr.R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Being a ringer? Or. F.:Zurnstein jun. PATENTANWÄLTE βΟΟΟ Munich 2 · Br «uhausstrasse 4 -Telephone Sommel-Nr. 22 5341 ■ Telegremme Zumpat -Telex 529979 20 / IO / N Case 3700-3660 Patent claims 1. A 4,5-dihydro-2-R-4-R'-6 ~ PY-3 (2H) -pyridazinone der Formula I. or an acid addition salt thereof, wherein PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two lower alkyl substituents, R is lower alkyl or lower hydroxyalkyl and R 'V is hydrogen or methyl and wherein R can also be hydrogen when R 'is methyl. 2. A compound according to claim 1, wherein R is methyl or ethyl. 3. Compound according to claim '1 or 2, worir PY 4- or Is 3-pyridinyl. 4. 4,5-Dihydro-2-methyl-6- (4-pyridinyl) -3 (2H) -pyriclaiT.inone or a pharmaceutically acceptable acid addition salt from it. 5. 4, 5 ~ dihydro-4-methyl-6 ~ (4-pyridinyl) -3 ( 'H) -pyridazinone or a pharmaceutically vortrcjolicl.oc ί' · '<urenriditon:. "R, ■ ol thereof.. ■ ": -;> YV :. · :: · 5116791 ■ 6. A method for preparing a compound according to any one of claims 1 to 3, characterized in that one • 2-R «-4-0xo-4-PY-butan-nitrile, lower-alkyl-2-R'-4-oxo-4-PY-butanoate or lower-alkyl-2-R'-4- (BN ) 4-cyano-4-PY butanoate, where BN is 4-morpholinyl, 1- piperidinyl or 1-pyrrolidinyl with NR-hydrazine or its salt with a strong inorganic acid or organic sulfonic acid and optionally a free base obtained in a Acid addition salt converts from it .. 7. The method according to claim 6, characterized in that 2-R-4-oxo-2-R'-4-PY-butane-nitrile and an N-R-hydrazine salt brings an organic sulfonic acid or an organic sulfonic acid to the reaction. 8. The method according to claim 6, characterized in that methyl-2-R · -4- (1-morpholinyl) -4-cyano-4-PY-butanoate or Brings methyl 2-R'-4-oxo-4-PY-butanoate and N-R-hydrazine to the reaction. 9 .. A cardiotonic composition for increasing cardiac contractility, characterized in that the The composition comprises a pharmaceutically acceptable inert carrier and cardiotonic as the active component effective amount of a compound according to any one of claims ■ to 4, wherein R is lower-alkyl, or a compound according to claim 5 or a pharmaceutically acceptable acid addition salt thereof. 10. A link to increasing cardiac contractility in a patient in need of such treatment, characterized in that it contains a compound according to any one of claims 1 to 4, wherein R is lower-alkyl or a compound according to claim 5 or a pharmaceutically acceptable acid addition salt thereof.