LU83221A1 - PYRAZOLOPYRIDINONES AND PYRIDINYLNICOTINATES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Description

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This invention relates to pyrazolopyridinones useful as cardiotonic agents and pyridinylnicotinates useful as intermediates of chemical synthesis and cardiotonic agents.

5 Chemical Abstracts, Vol. 87, item 39, 357t, 1977, indicates, among other things, that Acta Pol. Pharm. 1976, 33 (3), 289-93 (Pol) describes RCOCI ^ CHO (R = Me, Ph, 3- and 4-pyridyle or 6-methyl-3-pyridyle) which is condensed in an alkaline medium with NCCH2 = CONHNH2 to obtain pyrazolopyridines which are also prepared by reaction of methyl 6- (3- and 4-pyridyl) -2-chloronicotinates or 6- (3- and 4-pyridyl) -2-chloro-3 -cyanopyridines with 80% hydrazine hydrate. The original article (p. 291) shows that the compounds can also exist in tautomeric form 1,2-dihydro-6-R-3H-15 pyrazolo [3,4-b] pyridin-3-one.

In a later article entitled "Cancerstatics III. Synthesis and Some Chemical Transformations of 3-Cyano-5- (pyridinyl-4) pyrid-2-one" [Pol. J. Pharmacol. Pharm. , 30, 707-712 (1978)], P. Nantka-Namirski and L. Kaczmarek describe inter alia the reaction of 3-cyano-5- (4-pyridinyl) pyridin-2-one [also called 1,2 -dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile] with phosphorus oxychloride to prepare 2-chloro-3-cyano-5- (4-pyridinyl) pyridine [also called 2-chloro-5 - (4-pyridinyl) nicotinonitrile] and the acid hydrolysis of the 3-cyano compound to the corresponding 3-carboxylic acid.

The present invention relates to 1,2-dihydro-1-R-

5-PY-6-Q-3H-pyrazolo [3,4-b] pyridin-3-ones of formula I

> ’30 'Wn _, = 0

Q I H

R

In which R is a lower alkyl, hydroxy-lower alkyl, 2,3-dihydroxypropyl or lower alkoxyalkyl group, Q is a hydrogen atom or a lower alkyl group and PY is a 4- or 3-pyridinyl or 4- group or 2 3-pyridinyl having one or two lower alkyl substituents, or their acid addition salts. These compounds are useful as cardiotonic agents, as demonstrated by conventional pharmacological test procedures. The preferred embodiments are those of formula I where PY is a 4-pyridinyl or 3-pyridinyl group, R is a methyl, ethyl or 2-hydroxyethyl group and Q is a hydrogen atom or a methyl or ethyl group.

The compounds of formula I can exist in 10 tautomeric forms, that is to say in the form of 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridine-3-one of formula I ^ and / or in the form of lR-5-PY-6-Q-1H-pyrazolo [3,4-b] -pyridine-3-ol of formula IA, represented below: q xh q! k

R

20 1 AI

Structure preferences for known analogous pyrazolo [3,4-b] pyridine-3-ones would indicate that formula I above is the preferred tautomeric structure; it is therefore preferred to use the names given based on formula I, although it is understood that either or both of the structures are contemplated herein.

The present invention also relates to the lower alkyl 2-halo-v 5-PY-6-Q-nicotinates of the formula II COOR '

”YY

Q x II

in which Q is a hydrogen atom or a lower alkyl group, R1 is a lower alkyl group, X is 35 <3 * a chlorine or bromine atom and PY is a 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower alkyl substituents, or their acid addition salts. The compounds of formula II and their salts are generally usable as cardiotonic agents, as shown in standard pharmacological test procedures. The preferred compounds are those of formula II where PY is a 4-pyridinyl or 3-pyridinyl group, Q is a methyl or ethyl group, X is chlorine and R 'is a methyl or ethyl group. The compounds of formula II can also be used as intermediates in the preparation of 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridine-3- "" ones of formula (I).

1,2-dihydro-1R-5-PY-6-Q-3H-15 pyrazolo [3,4-b] pyridine-3-one of formula I can be obtained by a process which consists in reacting a 2- lower alkyl halo-5-PY-6-Q-nicotinate of formula (II) with a 1-R-hydrazine (III) where PY, R and Q have the meanings given above for the compound of formula I and halo denotes chlorine or bromine, preferably chlorine.

The lower alkyl 2-halo-6-Q-5-PY-nicotinates of formula II can be obtained by a process which comprises the steps of hydrolysis of 1,2-dihydro-6-Q-2-oxo-5 -PY-nicotinonitrile to produce 1,2-dihydro-6-Q-2-oxo-5-25 PY-nicotinic acid, the reaction of said acid with a mineral halogenating agent to obtain the 2-halo halide - 6-Q-5-PY-nicotinoyl and the reaction of the halide with a lower alkanol to obtain the lower alkyl 2-halo-6-Q-5-PY-nicotinate, where halo denotes chlorine or bromine and * 30 PY is as defined for formula II above. The preferred embodiments of the process are those which make it possible to obtain the aforementioned preferred compounds for formula II, halo is a chlorine atom and the lower alkyl part of the resulting ester is a methyl or ethyl group.

A cardiotonic composition intended to increase cardiac contractility comprises a pharmaceutically acceptable carrier and, as active principle, an effective amount of a 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3 , 4-b] - 4 pyridine-3-one cardiotonic of formula I or a lower alkyl 2-halo-5-PY- 6-Q-nicotinate of formula II, or one of their acid addition salts pharmaceutically acceptable.

Cardiac contractility can be increased in a patient in need of such treatment by administering to that patient, orally or parenterally, in a solid or liquid dosage form, an effective amount of a 1,2-dihydro-1 “R- 5-PY-6-Q-3H-pyrazolo [3,4-b] pyridine-3-one cardiotonic of formula I or of a lower alkyl 2-halo-5-PY-6-Q-nicotinate of formula II or a pharmaceutically acceptable acid addition salt thereof.

The term "lower alkyl" as used herein, for example as meaning of R or Q or as a substituent of PY in formulas I and II, or as a lower alkyl group in 2-halo-5-PY-6 -Q- intermediate lower alkyl nicotinate of formula (II), denotes alkyl radicals having from one to six carbon atoms, in straight or branched chain, represented by methyl, ethyl, n-propyl, isopropyl, n- butyl, s-butyl, t-butyl, isobutyl, n-amyl, n-hexyl, etc.

Examples of PY for formulas I and II where 'PY is a 4- or 3-pyridinyl group having one or two lower alkyl substituents are: 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-diiso-propyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, etc.

The expression "lower hydroxyalkyl" as used herein, for example for one of the definitions of R in formula I, denotes hydroxyalkyl radicals having from two to six carbon atoms, in straight or branched chain and where at at least two carbon atoms separate the hydroxy group and the nitrogen atom in position 1 of the pyrazolo- [3,4-b] pyridine ring, represented by the 2-hydroxy-ethyl, 3-hydroxypropyl, 2-hydroxypropyl groups, 4-hydroxybutyl, 5 3- hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, etc.

The expression "lower alkoxyalkyl" as used herein, for example for one of the definitions of R in formula I, denotes alkoxyalkyl radicals having from three to six carbon atoms, in straight or branched chain and where at at least two carbon atoms separate the oxygen atom due to the alkoxyalkyl group and the nitrogen atom in position 1 from the pirazolo [3,4-b] pyridine ring, represented by the 2-methoxyethyl, 2-ethoxy-10 groups ethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxybutyl, 4-ethoxybutyl, 3-ethoxypropyl, 3-n-propoxypropyl, etc.

The compounds of formulas I and II can be used 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. Acid addition salts are simply a more convenient form 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 salts preferably include those which produce, when combined with the free base, pharmaceutically acceptable salts, i.e. salts of which the 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 (I or II) are not vitiated by side effects attributable to the anions . In implementing the invention, it is convenient to use the free base form; however, suitable pharmaceutically acceptable salts within the scope of the invention are those 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, methanesulionic acid, ethane-sulfonic acid, benzenesulfonic acid, toluene-tallow acid onic, cyclohexylsulfamic acid, quinic acid, etc., giving the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tarträte, methanesulfonate, 6 ethanesulfonate, benzenesulfonate, cyclohexylsulfamate and quinate respectively.

The acid addition salts of the basic compounds of formulas (I and II) 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 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 concentration of the solution.

Although the pharmaceutically acceptable salts of the basic compound of formula I or II are preferred, all of the acid addition salts fall within the scope of the present 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 product, for example when the salt is formed simply for the purpose of purification or identification, or when used as an intermediate to prepare a pharmaceutically acceptable salt by ion exchange procedures.

The molecular structure of the compound of formula I or II was assigned on the basis of the data provided by the infrared, nuclear magnetic resonance and mass spectra, and by the correspondence between the calculated and found values for the elemental analysis.

Preparation of 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridine-3-one (I) is carried out by reaction of 2-halo-5-PY -6-lower alkyl-nicotinate (II) with 1-R-hydrazine (III), by heating the reagents in an appropriate solvent to about 50 ° C-100 ° C, preferably about 65 ° C to 85 ° C. The reaction is conveniently carried out by heating the reagents to reflux in a lower alkanol, preferably methanol or ethanol.

Lower alkyl 2-halo-5-PY-6-Q-nicotinate is readily prepared by reacting 1,2-dihydro-2-oxo-5-PY-6-Q-nicotinic acid with excess phosphorus oxychloride, preferably with a catalytic amount of dimethylformamide, to obtain 2-chloro-5-PY- * '6-Q'-nicotinoyl chloride and reacting the latter with a lower alkanol. The reaction is conveniently carried out by heating the reactants on a steam bath. Other suitable solvents include acetonitrile, dioxane, 5 etc. Other suitable mineral halogenating agents include PCl ^, PBr ^ and PCl ^.

The preparation of known 1,2-dihydro-2-oxo-5-PY-nicotinic acids by hydrolysis of the corresponding 1,2-dihydro-2-oxo-5-PY-nicotinonitrile is described in the U.S. Patent 10. N ° 4.004.012.

Hydrolysis of 1,2-dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinonitrile to obtain 1,2-dihydro-6- • · (lower alkyl) -2-oxo- 5-PY-nicotinic is conveniently carried out by heating the nitrile on a steam bath with an aqueous mineral acid, for example 50% sulfuric acid, as illustrated in more detail in the patent application mentioned below. .

The 1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) -nicotinonitriles are prepared by the procedure described in the following three paragraphs and are described in patent application No. 82.957 filed on 26 November 198 (

The preparation of 1-PY-2- (dimethyl-amino) ethenyl (lower alkyl) ketone is carried out by reacting PY-25 methyl (lower alkyl) ketone with a di (lower alkyl) acetal of dimethylformamide, by mixing reagents in the presence or absence of an appropriate solvent. The reaction is conveniently carried out at room temperature, i.e., about 20-25 ° C, or by heating the reagents to about 100 ° C, preferably in an aprotic solvent, conveniently hexamethylphosphoramide due to the process used to prepare PY-methyl (lower alkyl) ketone.

Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, etc. The reaction can also be carried out using no solvent, preferably using an excess of the di-alkyl acetal of dimethylformamide.

8

The intermediate PY-methyl (lower alkyl) ketones are generally known compounds which are prepared by known methods [for example, described in Rec. trav. chem 72, 522 (1953); U.S. Patent 3,133,077 (5-12-64); Bull.

5 Soc. Chim. France 1968, 4132; Chem. Abstrs. 79> 8539h (1973); Chem. Abstrs. 81, 120, 401a (1974); J. Org. Chem. 39.3834 (1974); Chem. Abstrs. £ 7, 6594q (1977); , J. Org. Chem. £ 3,228 (1978)].

The reaction of l-PY-2- (dimethylaroino) ethenyl 10 (lower alkyl) ketone with α-cyanoacetamide to obtain 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile is preferably performed by heating the reagents in a suitable solvent in the presence of a basic condensing agent. The reaction is generally carried out using an alkaline lower alcoholate, preferably sodium methylate or ethylate, in dimethylformamide. In carrying out the invention, the reaction is carried out by heating the dimethylformamide at reflux and using sodium methylate. Methanol and sodium methylate or ethanol and sodium ethylate can also be used as the solvent and basic condensing agent respectively; however, a longer heating period is required. Other basic condensing agents and other solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, etc., in an aprotic solvent, for example tetrahydrofuran, acetonitrile, ether , benzene, dioxane, etc.

The following examples will better illustrate the invention without however limiting it.

30 A. 2-Halo-5-PY-6 ~ Lower alkyl Q-nicotinates A-1. Methyl 2-Chloro-5- (4-pyridinyl) nicotinate

A suspension containing 54 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid, 500 ml of phosphorus oxychloride and 10 drops of is heated in a steam bath for 4 and a half hours. dimethylformamide, and during this period hydrochloric acid is released and most of the solid dissolves. The reaction mixture is allowed to stand overnight at room temperature and then filtered through diatomaceous earth to remove a small amount of yellow solid. The excess phosphorus oxychloride contained in the filtrate is distilled under vacuum and the syrupy residue is cooled. To this material is added 500 ml of absolute methanol and the mixture is carefully stirred by periodically cooling it in an ice bath, which causes the syrup to slowly dissolve and form an almost white solid. The mixture is carefully cooled in an ice bath, the solid is collected and air dried. The resulting solid is taken up (44.7 g, m.p. 295-300 ° C with decomposition) in about 500 ml of water and the # solution is filtered. The filtrate is made alkaline at pH 8.0 with a 3N ammonium hydroxide solution (approximately 70 ml is required). The abundant pale yellow solid is collected, washed with water, and air dried. The solid is then taken up in 400 ml of methylene dichloride and a small aqueous layer is separated. The methylene dichloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness in a rotary evaporator to give 35.6 g of a creamy solid , pf 110-112 ° C. Part of this product, methyl 2-chloro-5- (4-pyridinyl) nicotinate, is recrystallized from 50 ml of acetonitrile, air dried and then dried in a vacuum oven at 60 ° C. 6 hours, which gives 6.7 g of product, mp 112.5-25 113 ° C.

Following the procedure described in Example A1 but using instead 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid and methanol equimolar amounts of acid 1 , 2-dihydro-2-oxo-5-PY-nicotinic and the appropriate lower alkanol respectively, it can be seen that the corresponding lower alkyl 2-chloro-5-PY-nicotinates of Examples A can be obtained -2 to A-7.

A-2. Ethyl 2-Chloro-5- (3-pyridinyl) nicotinate.

A-3. 2-Chloro-5- (2-methyl-3-pyridinyl) n-propyl nicotinate A-4. Isopropyl 2-Chloro-5- (5-methyl-3-pyridinyl) nicotinate.

AT 5. 2-Chloro-5- (3-ethyl-4-pyridinyl) 10 n-butyl nicotinate.

A-6. 2-chloro-5- (2-methyl-4-pyridinyl) - n-hexyl nicotinate A-7. 2-Chloro-5- (2,6-dimethyl-4-pyridinyl) -5 methyl nicotinate

Following the procedure described in Example A1 but using instead of phosphorus oxychloride or lower alkanol, equimolar amounts of the appropriate halogenating agent and lower alkanol respectively, it can be seen that the lower alkyl 2-halo-5- (4-pyridinyl) nicotinates of Examples A-8 and A-9 can be obtained.

AT 8. Methyl 2-Bromo-5- (4-pyridinyl) nicotinate, using phosphorus tribromide or phosphorus oxybromide and absolute methanol.

A-9. Ethyl 2-Chloro-5- (4-pyridinyl) nicotinate using phosphorus trichloride, phosphorus pentachloride or sulfuryl chloride and absolute ethanol.

Following the procedure described in Example 20 A1 but using, in place of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid, an equimolar amount of acid 1, 2-dihydro-2-oxo-5-PY-6- (lower alkyl) suitable nicotinic and methanol or an equimolar amount of the appropriate lower alkanol, it is seen that the 2-chloro-5- can be obtained PY-6- (lower alkyl) corresponding lower alkyl nicotinates of Examples A-10 to A-20.

Ά-10. Methyl 2-Chloro-6-methyl-5- (4-pyridinyl) nicotinate A-11. Ethyl 2-Chloro-6-ethyl-5- (4-pyridinyl) nicotinate A-12. Methyl 2-Chloro-6-methyl-5- (3-pyridinyl) nicotinate A-13 Methyl 2-Chloro-6-n-propyl-5- (4-pyridinyl) nicotinate 35 A-14. Ethyl 2-Chloro-6-isopropyl-5- (4-pyridinyl) nicotinate A-15. Methyl 6-n-butyl-2-chloro-5- (4-pyridinyl) nicotinate I 1 A-16. Methyl 2-Chloro-6-isobutyl-5- (4-pyridinyl) nicotinate A-17. Ethyl 2-Chloro-5- (4-pyridinyl) -6-t-butyl-nicotinate 5 A-18. Methyl 2-Chloro-6-n-pentyl-5- (4-pyridinyl) nicotinate A-19. 2-Ghloro-6-ethyl-5- (2-methyl) -4-pyridinyl) n-butyl nicotinate A-20. 2-Chloro-6-ethyl-5- (3-pyridinyl) isopropyl nicotinate A-21. Ethyl 2-Chloro-6-methyl-5- (4-pyridinyl) nicotinate, m.p. 105-106.5 ° C. (cardio-tonic inactive).

B. 1,2-Dihydro-5- (pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-15 ones B-1. 1,2-Dihydro-1-methyl-5- (4-pyridinyl) -3H- pyrazolo [3,4-b3pyridine-3-one

A solution containing 4.2 g of methyl 2-chloro-5- (4-pyridinyl) -nicotinate, 5 ml of 1,1-dimethylhydrazine and 50 ml of methanol is heated to reflux while stirring for 20 hours. the reaction mixture is cooled, the solid is collected, washed with ethanol and dried at 90 ° C., which gives 1.7 g of 1,2-dihydro-1-methyl-5- (4- pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one. This 1.7 g of 1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo- [3,4-b] pyridine-3-one is combined with 4.3 g and 1 , 4 g of corresponding product obtained in two other tests and the combined product is recrystallized from 30 ml of dimethylformamide and dried in an oven under vacuum at 90 ° C., which gives 4.7 g of 1,2-dihydro -1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] -pyridine-3-one, pf 265-267 ° C.

The preceding preparation is preferably carried out using 1-methylethylrazine in place of 1,1-dimethylhydrazine, as follows: to a hot stirred solution of 5.0 g of 2-chloro-5- (4-pyridinyl ) methyl nicotinate in 40 ml of methanol, 5 ml of 1-methylhydrazine are added and the resulting reaction mixture is heated with stirring for 18 hours. The reaction mixture containing a small amount of solid is cooled. Since only a little more solid separates out, the solvent is removed using a rotary evaporator. The resulting yellow solid is collected, washed with water and dried in a vacuum oven at 90 ° C., and 4.3 g of 1,2-dihydro-1-methyl-5 are obtained. - (4-pyridinyl-3H-pyrazolo [3,4-b] pyridine-3-one, mp 263-265 ° C.

For comparison, the following compound is prepared, which differs from Example B1 in that it has no substituent in position 1 (other than the hydrogen atom) when the compound of Example B1 comprises a methyl group, by the following procedure: a solution containing 16.6 g of methyl 2-chloro-5- (4-pyridinyl) nicotinate, 19 ml of is heated under reflux in a steam bath for 19 hours hydrazine hydrate and 150 ml of methanol and the mixture containing a yellow solid is carefully cooled in ice and the solid is collected. The solid is air dried, 11.2 g, and it is combined with 1.6 g of the corresponding product obtained in another test following the same procedure, and the combined product is recrystallized from 440 ml of dimethyl- 20 formaraide, washed with ether and dried in a vacuum oven at 95 ° C, which gives 9.5 g of 1,2-dihydro-5- (4-pyridinyl) -3H-pyrazolo [3, 4-b] pyridine-3-one, pf > 300 ° C. In contrast to Example B-1, the compound of which is active on the cardiotonic level, it is found that this unsubstituted compound in position 1 is inactive in the tests on cat atria in vitro, cardiotonic selection tests described below.

By following the procedure described in Example B1 but using instead of 1,1-dimethylhydrazine or 1-methylhydrazine an equimolar amount of the appropriate 1-R-hydrazine, it can be seen that one can obtain the corresponding 1,2-dihydro-1R-5- (4-pyridinyl) 3H-pyrazolol3,4-b] pyridine-3-ones from Examples B-2 to B-13.

B-2. 1,2-Dihydro-1- (2-methoxypropyl) -5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one.

B-3. 1,2-Dihydro-1-ethyl-5- (4-pyridinyl) -3H-pyrazolol3,4-b] pyridine-3-one using 1-ethylhydrazine.

B-4. 1,2-Dihydro-1-n-propyl-5- (4-pyridinyl) -3H-13 pyrazolo [3,4-b] pyridine-3-one using 1-n-propyl-hydrazine.

B-5. 1,2-Dihydro-1-isopropyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1-isopropyl-5 hydrazine.

B-6. 1,2-Dihydro-1-n-butyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1-n-butyl-hydrazine.

B-7. 1,2-Dihydro-1-isobutyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1-isobutyl-hydrazine.

v B-8. 1,2-Dihydro-1- (2-butyl) -5- (4-pyridinyl) -3H- v * # pyrazolo [3,4-b] pyridine-3-one using 1- (2-butyl) -hydrazine.

15 B-9. 1,2-Dihydro-1- (n-amyl) -5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1- (n-amyl) -hydrazine.

B-10. 1,2-Dihydro-1- (n-hexyl) -5- (4-pyridinyl) -3H- pyrazolo [3,4-b] pyridine-3-one using 1- (n-hexyl) -20 hydrazine .

B — 11. 1,2-Dihydro-1- (2-ethoxyethyl) -5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1- (2-ethoxyethyl) hydrazine.

B-12. 1,2-Dihydro-1- (2-methoxyethyl) -5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1- (2-methoxyethyl) hydrazine.

B-13. 1,2-Dihydro-1- (3-methoxypropyl) -5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one using 1- (3-methoxypropyl) hydrazine.

Following the procedure of Example B1 but using instead of methyl 2-chloro-5- (4-pyridinyl) nicotinate and 1,1-dimethylhydrazine or 1-methyl-hydrazine respectively, corresponding equimolar amounts of methyl 2-chloro-5-PY-nicotinate or other lower alkyl group and 1-R-hydrazine i, it can be seen that 1,2-dihydro can be obtained -lR- 5-PY-3H-pyrazolo [3,4-bJpyridine-3-ones corresponding to Examples B-14 to B-19.

kr 14 B-14. 1,2-Dihydro-1-methyl-5- (3-pyridinyl) -3H- i pyrazolo [3,4-b] pyridine-3-one.

! B-15. 1,2-Dihydro-5- (2-methyl-3-pyridinyl) -3H-! pyrazolo [3,4-b] pyridine-3-one.

5 B-16. 1,2-Dihydro-1-ethyl-5- (5-methyl-3-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-3-one.

B-17. 1,2-Dihydro-1-methyl-5- (3-ethyl-4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one.

B-18. 1,2-Dihydro-1- (2-niethoxyethyl) -5- (2-methyl-4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one.

B-19. 1,2-Dihydro-1-methyl-5- (2,6-dimethyl-4- - pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one.

»» ·

Following the procedure described in Example B1 but using instead methyl 2-chloro-5- (4-pyridinyl) -15 nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine, corresponding equimolar amounts of methyl or lower alkyl 2-chloro-5-PY-nicotinate and suitable 1- (hydroxyalkyl lower) hydrazine, it can be seen that 1,2-dihydro-3-oxo can be obtained -5-PY-3H-20 pytazolo [3,4-b] pyridine-1- (lower alkanols) from Examples B-20 to B-27.

B-20. 1,2-Dihydro-3-oxo-5- (3-pyridinyl) -3H- pyrazolo [3,4-b] pyridine-1-ethanol.

B-21. 1,2-Dihydro-3-oxo-5- (2-methyl-3-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-1-ethanol.

B-22. 1,2-Dihydro-3-oxo-5- (5-methyl-3-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-1- (n-propanol).

B-23. 1,2-Dihydro-3-oxo-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-1- (2-propanol).

30 B-24. 1,2-Dihydro-3-oxo-5- (3-ethyl-4-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-1- (2-butanol).

B-25. 1,2-Dihydro-3-oxo-5- (2-raethyl-4-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-1-ethanol.

B-26. 1,2-Dihydro-3-oxo-5- (2,6-dimethyl-4-pyridinyl) - 35 3H-pyrazolo [3,4-b] pyridine-l ~ ethanol.

B-27. 1,2-Dihydro-3-oxo-5- (4-pyridinyl) -3H-pyrazolo- [3,4-b] pyridine-1-ethanol.

Following the procedure described in Example 15 B1 but using instead methyl 2-chloro-5- (4-pyridinyl) -nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine / equimolar amounts of suitable methyl or lower alkyl 2-chloro-5-PY-6- (lower alkyl) nicotinate and / or appropriate 1-R-hydrazine respectively, it can be seen that the 1 , 2-dihydro-1R-5-PY-6-Q-1H-pyrazolo [3,4-b] pyridine-3-ones corresponding to Examples B-28 to B-41.

B-28. 1,2-Dihydro-1,6-dimethyl-5- (4-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-3-one.

B-29. 6-Ethyl-1,2-dihydro-1-methyl-5- (4-pyridinyl) - * 3H-pyrazolo [3,4-b] pyridine-3-one.

B-30. 1,2-Dihydro-6-methyl-5- (4-pyridinyl) -3H- -pyrazolo [3,4-b] pyridine-3-one.

15 B-31. 1-Ethyl-1,2-dihydro-6-methyl-5- (3-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-3-one.

B-32. 1,2-Dihydro-6-methyl-3-oxo-5- (4-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-1-ethanol.

B-33. 1,2-Dihydro-6-methyl-3-oxo-5- (4-pyridinyl) - 3H-pyrazolo [3, 4-b] pyridine-1-ethanol.

B-34. 1,2-Dihydro-1-methyl-6-n-propyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one.

B-35. 1,2-Dihydro-6-isopropyl-5- ^ (4-pyridinyl) -3H- pyrazolo [3,4-b] pyridine-3-one.

25 B-36. 6-n-Butyl-1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] epididine-3-one.

B-37. 1,2-Dihydro-6-isobutyl-3-oxo-5- (4-pyridinyl) - 3H-pyrazolo [3,4-b] pyridine-1-ethanol.

B-38. 1,2-Dihydro-5- (4-pyridinyl) -6-t-butyl-3H- i; Pyrazolo [3,4-b] pyridine-3-one.

B-39. 1,2-Dihydro-1-methyl-6-n-pentyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3 ~ one.

B-40. 1,6-Diethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-3-one.

35 B-41. 6-Ethyl-1,2-dihydro-3-oxo-5- (3-pyridinyl) - 3H-pyrazolo [3,4-bjpyridine-1-ethanol.

Following the procedure described in Example B-20 but using instead of 1- (2-hydroxyethyl) - * 16 hydrazine a corresponding equimolar amount of 1- (2,3-dihydroxypropyl) hydrazine and 2 methyl chloro-5- (4-pyridinyl) nicotinate or a corresponding equimolar amount of suitable methyl or lower alkyl 2-chloro-5-PY-6-Q-nicotinate, it can be seen that obtain the 1,2-dihydro-1- (2,3-dihydroxypropyl) -5-PY-6-Q-3H-pyrazolo [3,4-b] -pyridine-3-ones from -Examples B-42 to B -44.

B-42. 1,2-Dihydro-1- (2,3-dihydroxypropyl) -5- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-3-one.

20 B-43. 1,2-Dihydro-1- (2,3-dihydroxypropyl) -6-methyl- 5- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-3-one.

B-44. 1,2-Dihydro-1- (2,3-dihydroxypropyl) -5- (3- »'· pyridinyl) -1H-pyrazolo [3,4-b] pyridine-3-one.

The usefulness of the compounds of formulas I and II and their salts as cardiotonic agents is demonstrated by their effectiveness in the procedures of conventional pharmacological tests, for example in that they cause a significant increase in the force of contraction of the cat papillary muscles and atria. A detailed description of this test procedure can be found in the U.S. Patent. No. 4,072,746.

When tested by the above procedure on isolated cat atria and papillary muscles, it is found that 1,2-dihydro-5- (pyridinyl) -3H-25 pyrazolot3,4-b] pyridine-3-ones of formula I, at a dose of. 100 yg / ml, cause a significant increase, i.e., about 25% or more, in papillary muscle strength and a significant increase, i.e., about 25% or more, in the strength of the right atrium, while * 30 causing a lower percentage increase (about half or less the percentage increase in the strength of the right atrium or the strength of the papillary muscle) in the speed of the right atrium. For example, when tested at 100 µg / ml according to this procedure, it is found that 1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b ] py.ridine-3-one causes respective percentages of 23%, 42% and 12% increase in papillary muscle strength, right atrium strength and * 17 right atrium speed . On the contrary, it is found that 1,2-dihydro-5- (4-pyridiny.l) -3II-pyrazolol 3,4-b1pyridine-3-one, at a dose of 100 μg / ml, according to this procedure, is essentially inactive in that it causes only 5 percent increases of 6%, 14% and 10% in papillary muscle strength, right atrium strength and atrium speed right respectively.

When tested by the procedure on atria and papillary muscles isolated from cats, we find that the lower alkyl 2-halo-5-PY-6-Q'-nicotinates, in doses of 10, 30 and 100 yg / ml, cause a significant increase, that is to say greater than 25%, in the strength of the papillary muscle and a significant increase, that is to say approximately 20% or more, of the strength of the right atrium, while causing a lower percentage increase (about a third or less of the percentage increase of the strength of the right atrium or the strength of the papillary muscle) in the speed of the right atrium. For example, when tested at 10, 30 and 100 yg / ml according to this procedure, it is found that methyl 2-chloro-5- (4-pyridinyl) nicotinate gives respective percentages of increase in strength of the papillary muscle, the strength of the right atrium and the speed of the right atrium of 35%, 17% and 5%; 43%, 29% and 25 10%; and 76%, 112% and 25%, respectively.

A cardiotonic composition for increasing cardiac contractility includes a pharmaceutically acceptable carrier and, as the active component, 1,2-dihydro-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridine— 3-one cardiotonic of formula I or the lower alkyl 2-halo-5-PY-6-Q-nicotinate of formula II or one of their pharmaceutically acceptable acid addition salts. To increase cardiac contractility in a patient in clinical practice, the compound or its salt will normally be administered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include tablets, pills, c 18 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 may also contain additional substances other than inert diluents, for example lubricants, such as magnesium stearate, talc, etc.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs: containing inert diluents commonly used in the field, such as water and liquid paraffin. Besides inert diluents, such compositions may also contain adjuvants, such as wetting agents and suspending agents, and sweetening, flavoring, flavoring and preserving agents. According to the invention, the compositions for oral administration also include capsules of absorbable material, such as gelatin, containing the active compound with or without the addition of diluents or excipients.

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 suspending 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, emulsifying agents and dispersing agents.

They can be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in 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 in any other sterile injectable medium, immediately before their use.

c 19

The percentages of active compound in said composition intended to increase cardiac contractility can vary so as to allow an appropriate dose to be obtained. The dose administered to a particular patient will vary according to the judgment of the physician using as criteria the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active compound and the reaction of the patient. 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.

• · Λ

Claims (8)

1. Compound of formula I PY rrr QR 10 where R is a lower alkyl, lower hydroxyalkyl, 2,3-dihydroxypropyl or lower alkoxyalkyl group, Q is a hydrogen atom or a lower alkyl group ♦ · and PY is a group 4 - or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower alkyl substituents, or one of its acid addition salts. 2. Compound according to claim 1, characterized in that.R is a methyl, ethyl or 2-hydroxyethyl group and Q is a hydrogen atom or a methyl or ethyl group. 3. 1,2-Dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo- [3,4-b] pyridine-3-one or a pharmaceutically acceptable acid addition salt thereof . 4. 1,2-Dihydro-3-oxo-5- (4-pyridinyl) -3H-pyrazolo- [3,4-b] pyridine-1-ethanol or a pharmaceutically acceptable acid addition salt thereof . - 5. Process for the preparation of a compound according to claim 1, characterized in that a 2-halo is reacted Lower alkyl 5-PY-6-Q-nicotinate with a 1-R-hydrazine and, if desired, the free base obtained is converted to one of its acid addition salts. 6. Compound of formula II COO R1 PY / Y il ΑΛ in which Q is a hydrogen atom or a * 21 * * lower alkyl group, R 'is a lower alkyl group, X is a chlorine or bromine atom and PY is a 4- or 3-pyridinyl or 4- or 3-pyridinyl group having one or two lower alkyl substituents, or one of its acid addition salts. 7. A method of producing a compound according to claim 6, characterized in that a 2-halO “6-Q-5-PY-nicotinoyl halide is reacted with a lower alkanol and, if desired, transforms the free base 10 obtained into one of its acid addition salts. 8. Method according to claim 7, characterized * in that ^ the 2-halo-6-Q-5-PY-nicotinoyl halide is obtained by hydrolysis of a 1,2-dihydro-6-Q-2- oxo ~ 5-PY-nicotinonitrile to obtain a 1,2-dihydro-6-Q-2-oxo-15 5-PY-nicotinic acid and reaction of this acid with a mineral halogenating agent. 9. Cardiotonic composition intended to increase cardiac contractility, characterized in that it comprises an inert carrier which is acceptable from a pharmaceutical point of view and, as active ingredient, an effective amount of a cardiotonic compound according to any one of claims 1 to 4 and 6 or a pharmaceutically acceptable acid addition salt thereof. 10. Compound used to increase 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 and 6 or one of its pharmaceutically acceptable acid addition salts. '