NL8101269A - NEW PYRAZOLOPYRIDINONES AND PYRIDINYL NICOTINATES AND CARDIOTONIC PREPARATIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

t *

LS 874-209 P & C

Novel pyrazolopyridinones and pyridinyl nicotinates, as well as cardiotonic preparations containing these compounds.

The invention relates to pyrazolopyridinones suitable as cardiotonic agents and pyridinyl nicotinates suitable as chemical intermediates and as cardiotonic agents.

Chemical Abstracts, Vol 87, 29,357t, 1977, reports, inter alia, that Acta Pol.Pharm. 1976, 33 (3), 289-293 mentions the condensation of RCOCf ^ CHO (R = Me, Ph, 3- and 4-pyridyl, and 6-methyl-3-pyridyl) with NCC ^ CONHN ^ in an alkaline medium under obtaining pyrazolopyridines which were also prepared by reacting Me 6- (3- and 4-pyridyl) -2-chloromicotinates or 6- (3- and 4-pyridyl) -2-chloro-3-cyanopyridines with 80% N ^ N ^. ^ O. The original article states on page 291 that these compounds may also exist in the tautomeric 1,2-dihydro-6-R-3H-pyrazolo [3,4-b] pyridin-3-one form.

In a later article by P. Nantka-Namirski and L. Kaczmarek 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)] 15 mentions, inter alia, the reaction of 3-cyano-5- (4-pyridinyl) pyridin-2-one (also called 1,2-dihydro-2-oxo-5- (4 pyridinyl) called 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-carbon-20 acid.

The invention provides 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridin-3-ones according to formula (1) of the formula sheet, wherein R is a lower alkyl group, a lower hydroxyalkyl group, a 2,3-dihydroxypropyl group or a lower alkoxyalkyl group, Q represents a hydrogen atom or a lower alkyl group, and PY represents a 4- or 3-pyridinyl group or a 4- or 3-pyridinyl group with 1 or 2 lower alkyl groups as a substituent (s) and addition salts thereof with acids. These compounds are suitable as cardiotonic agents, as evidenced by standard pharmacological tests. Preferred compounds of formula (1) are those wherein PY is a 4-pyridinyl group or.

30 is a 3-pyridinyl group, R is a methyl group, ethyl group or 2-hydroxyethyl group and Q is a hydrogen atom, methyl group or ethyl group.

The compounds of formula (1) may exist as tautomers, i.e. 1,2-dihydro-1R-5-PY-6-Q-1H-pyrazolo [3,4-b] pyridin-3-ones of formula ( 1) and / or as 1R-5-PY-6-Q-1H-pyrazolo [3,4-b] pyridin-35-3-ols of formula (IA), as illustrated by the equilibrium shown on the formula sheet. Given the preferences for known pyrazolo [3,4-b] pyridin-3-ones, the preferred tautomeric structure is represented by formula (1); therefore, the names are based on the structure of formula (1), although this includes the other tautomeric structure.

The invention also provides low alkyl 2-halo-5-PY-6-Q nicotinates according to formula (2) of the formula sheet, wherein Q represents a hydrogen atom 5 or a lower alkyl group, R 'represents a lower alkyl group, X a chlorine or bromine atom and PY a 4- or 3-pyridinyl group or a 4- or 3-pyridinyl group with 1 or 2 lower alkyl groups as substituent (s), and addition salts thereof with acids. The compounds of formula (2) and their salts are generally suitable as cardiotonic agents, as evidenced by standard pharmacological tests. Preferred compounds of formula (2) are those in which PY is a 4-pyridinyl or 3-pyridinyl group, Q is a methyl or ethyl group, X is a chlorine atom and R 'is a methyl or ethyl group. The compounds of formula (2) are also suitable as intermediates in the preparation of 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] -15-pyridine-3- ones according to formula (1).

The 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridin-3-ones of formula (1) can be prepared by reacting a lower alkyl 2-halogen- 5-PY-6-Q nicotinate of formula (2) with 1-R-hydrazine (3), wherein PY, R and Q have the meanings given above for the compounds of formula (1) and "halogen" chlorine or bromine and preferably is chlorine.

The lower alkyl 2-halo-6-Q-5-PY-nicotinates of formula (2) can be prepared by hydrolysis of 1,2-dihydro-6-2 "2-oxo-5-PY-nicotinonitrile to give 1 2-dihydro-6-Q-2-oxo-5-PY-nicotinic acid, reaction of the acid with an inorganic halogenating agent to give 2-halogen-6-Q-5-PY-nicotonoyl halide and reaction of the halide with a lower alkanol to give lower alkyl 2-halogen-6-Q-5-PY-nicotinate, wherein "halogen" is chlorine or bromine and PY has the meanings given above for formula (2). Preferred embodiments of this method are those which provide the above preferred compounds of formula (2), wherein "halogen" is chlorine and the lower alkyl group of the resulting ester is a methyl or ethyl group.

The present cardiotonic preparations for increasing cardiac contractility contain a pharmaceutically acceptable carrier and as active ingredient an effective amount of a cardio-tonic 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridin-3-one of formula (1) or a lower alkyl 2-halogen-5-PY-6-Q nicotinate of formula (2) or a pharmaceutically acceptable addition salt thereof with an acid.

Cardiac contraction can be increased in a patient in need of such treatment by providing this patient with an effective amount of a cardiotonic 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [ 3,4-b] pyridin-3-one of formula (1) or a pharmaceutically acceptable addition salt thereof with an acid or a lower alkyl 2-halogen-5-PY-6-Q-nicotinate according to formula (2) or administering a pharmaceutically acceptable addition salt thereof with an acid orally or parenterally in a solid or liquid dosage form.

The term "lower alkyl group" as used herein which term is used herein as one of the meanings for R and Q and as a substituent of PY in formulas (1) and (2) and as the alkyl portion of the lower alkyl 2-halogen- 5-PY-6-Q nicotinate of formula (2) 'means an alkyl group of 1 to 6 carbon atoms and a straight or branched chain chain, for example methyl, ethyl, n.propyl, isopropyl, b.butyl, sec.butyl, tert -butyl, isobutyl, n-pentyl, n-hexyl, and the like.

Examples of the groups represented by the symbol PY in formulas (1) and (2), wherein PY is a 4-, 3- or 2-pyridinyl group with 1 or 2 lower alkyl groups as substituent (s) 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 mentioned), 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 name "low hydroxyalkyl group" used herein as one of the meanings for R in formula (1) means a straight or branched chain hydroxyalkyl group of 2-6 carbon atoms, of which at least 2 carbon atoms represent the hydroxy group and the nitrogen atom in position 1 of separating the pyrazolo [3,4-b] pyridine ring, for example 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl, 6-hydroxy-30 hexyl and the like.

The name "lower alkoxyalkyl group" used herein as one of the meanings for R in formula (1) means a straight or branched chain alkoxyalkyl group having 3-6 carbon atoms, of which at least 2 carbon atoms are the oxygen atom of the alkoxyalkyl group and the nitrogen at the position 35 Separate 1 from the pyrazolo [3,4-b] pyridine ring, for example 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxybutyl, 4-ethoxy-butyl, 3-ethoxypropyl, 3-n-propoxypropyl and such.

The compounds of formulas (1) and (2) are valuable both in the form of the free base and in the form of an addition salt with an acid.

8101269 9 * - 4 -

The addition salts with an acid are simply a more suitable form to be used, and in practice the use of the salt form boils down to the use of the base form. The acids which can be used to prepare the addition salts are preferably those which, when combined with the free base, give pharmaceutically acceptable salts, ie salts whose anions are relatively harmless to the animal organism when administered pharmaceutical doses of the salts so that the beneficial cardiotonic properties of the free base ((1) or (2)) are not compromised by side effects attributable to the anions. According to the invention, it has been found suitable to use the free base form; however, it is also possible to use suitably pharmaceutically acceptable salts obtained from mineral acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfaminic acid, 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid (quinic acid) and the like; the salts of these acids are hydrochlorides, sulfates, phosphates, sulfamates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, cyclohexylsulfamates and 1,3,4,5-tetra-20-hydroxycyclohexane-carnoxylates.

The addition salts of the basic compounds of formula (1) or (2) with an acid are prepared by dissolving the free base in an aqueous solution or an aqueous alcohol solution or other suitable solvent containing the respective acid, and the salt isolation by evaporating the solution, or by converting the free base and the acid together in an organic solvent, in which case the salt can be separated directly or obtained by concentrating the solution.

Although pharmaceutically acceptable salts of the basic compounds of formulas (1) and (2) are preferred, all addition salts with an acid are within the scope of the invention. All addition salts with an acid are suitable as a source of the free base form, even if the salt in question is only desirable as an intermediate product, for example when the salt is only formed for purification or identification purposes or when the salt is used as an intermediate for the preparing a pharmaceutically acceptable salt by ion exchange.

The molecular structure of the compounds of formulas (1) and (2) was determined based on the infrared spectrum, the nuclear magnetic resonance spectrum and the mass spectrum, and by the correspondence between the calculated and found values in the elemental analysis.

8101269 '% - 5 -

The preparation and use of the present compounds is described in more detail below.

The preparation of 1,2-dihydro-1R-5-PY-6-Q-3H-pyrazolo [3,4-b] pyridin-3-ones of formula (1) by reaction of lower alkyl 3-halogen-5- PY-5 6-Q nicotinate (2) with 1-R-hydrazine (3) is performed by heating the reactants in a suitable solvent at about 50 ° - 100 ° C and preferably about 65 ° - 85 ° C. The conversion is conveniently carried out by refluxing the reactants in a low alkanol, preferably methanol or ethanol.

The lower alkyl 2-halogen-5-PY-6-Q nicotinate is easily prepared by reacting a 1,2-dihydro-2-oxo-5-PY-6-Q nicotinic acid with excess phosphorus oxychloride, preferably with a catalytic amount of dimethylformamide, to give 2-chloro-5-PY-6-Q'-nicotinoyl chloride, and reaction of the latter with low alkanol. The conversion is conveniently carried out by heating the reactants on a steam bath. Other suitable solvents include acetonitrile, dioxane and the like. Other suitable inorganic halogenating agents include PCl 4, PBr 4 and PCl 4.

The preparation of the 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 U.S. Pat. No. 4,004,012 .

The 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 acid is suitably carried out by heating the nitrile on a steam bath 25 with an aqueous mineral acid, for example 50% sulfuric acid, the method of which is further explained in the Dutch patent application mentioned below.

The 1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) -nicotinonitriles are prepared according to the method described in the three paragraphs below, which is described in Dutch patent application 8006399.

The preparation of 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketone by reacting PY-methyl-lower alkyl ketone with dimethylformamide di (lower alkyl) acetal is performed by mixing the reactants in the presence or absence of a suitable solvent. The reaction is suitably carried out at room temperature, ie about 20 ° - 25 ° C, or by heating the reactants to a temperature up to about 100 ° C, preferably in an aprotic solvent, which can suitably hexamethylphosphoramide because of the method used to prepare the PY-methyl-lower alkyl ketone, as described in Example Cl. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane and the like. The reaction can also be carried out without a solvent, preferably using an excess of dimethylformamide di (lower alkyl) acetal.

The PY-methyl-lower alkyl ketones are generally known compounds which are prepared according to known methods [eg as described in Ree. trav. chim. 72, 522 (1953); United States Patent 3,133,077; Bull. Soc. Chim. France 1968, 4132; Chem. Abstrs. 79, 8539h, (1973); Chem. Abstrs. 81, 120,401a (1974); J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87, 6594q (1977); J. Org. Chem. 43, 2286 (1978)].

The reaction of 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketone with cc-cyanoacetamide to prepare 1,2-dihydro-2-oxo-5-PY-6-R-nicotino-nitrile is preferably carried out by heating the reactants in a suitable solvent in the presence of a basic condensation agent. The reaction is conveniently conducted using an alkali metal low alkoxide, preferably sodium methoxide or ethoxide, in dimethylformamide. The reaction can be carried out in refluxing dimethyl formamide using sodium methoxide. Instead, methanol and sodium methoxide or ethanol and sodium ethoxide as resp. solvent and basic condensing agent are used; however, a longer heating period is then required. Examples of other basic condensing agents and solvents are sodium hydride, lithium diethylamide, lithium diisopropylamide and the like, in an aprotic solvent such as tetrahydrofuran, acetonitrile, ether, benzene, dioxane and the like.

The following non-limiting examples further illustrate the invention.

A. Low alkyl 2-halo-5-PY-6-Q-decotinates A-1. Methyl 2-chloro-5- (4-pyridinyl) nicotinate

A suspension of 54 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid, 500 ml of phosphorus oxychloride and 10 drops of dimethylformamide was heated on a steam bath for 4½ hours, during which hydrogen chloride was developed and the largest part of the solid dissolved. The reaction mixture was allowed to stand at room temperature overnight, then filtered through diatomaceous earth to remove a small amount of yellow solid. The excess phosphorus oxychloride in the filtrate was distilled off under reduced pressure and the syrupy residue cooled. 500 ml of absolute methanol were added to this material; the mixture was shaken well with periodic cooling in an ice bath, the syrup slowly dissolving to form an almost white solid. The 8101269 * - 7 mixture was well cooled in an ice bath and the solid collected and air dried. The solid obtained (44.7 g, melting point 295 ° -300 ° C with decomposition) was taken up in about 500 ml of water and the solution was filtered. The filtrate was made basic to a pH of 8.0 with 3N ammonium hydroxide (about 70 ml needed). The large amount of light yellow solid was collected, washed with water and air dried. The solid was then taken up in 400 ml of dichloromethane and a small water layer separated. The dichloromethane layer was separated, washed with water, dried over anhydrous magnesium sulfate, and then evaporated to dryness on a rotary evaporator to obtain 35.6 g of a cream colored solid, mp 110 ° - 112 ° C.

Part of this product, methyl 2-chloro-5- (4-pyridinyl) nicotinate, was recrystallized from 50 ml of acetonitrile, air dried and then dried in a vacuum oven at 60 ° C for 6 hours to obtain 6, 7 g of product, melting point 112.5 ° - 113 ° C.

According to the method described in Example A1, however, instead of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid and methanol, use molar equivalent amounts of the respective 1,2-dihydro-2-oxo-5 -PY-nicotinic acid and lower alkanol, the corresponding lower alkyl 2-chloro-5-PY-nicotinates of Examples A-2 to A-7 are obtained.

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

A-3. n.Propyl 2-chloro-5- (2-methyl-3-pyridinyl) nicotinate.

A-4. Isopropyl 2-chloro-5- (5-methyl-3-pyridinyl) nicotinate.

A-5. n.Butyl 2-chloro-5- (3-ethyl-4-pyridinyl) nicotinate.

25 A-6. n.Hexyl 2-chloro-5- (2-methyl-4-pyridinyl) nicotinate.

A-7. Methyl 2-chloro-5- (2,6-dimethyl-4-pyridinyl) nicotinate.

According to the method described in Example A1, wherein instead of phosphorus oxychloride a molar equivalent amount of another halogenating agent and in Example A-9 a molar equivalent amount of another low alkanol were used, the low alkyl 2-halogen- 5- (4-pyridinyl) nicotinates of Examples A-8 and A-9.

A-8. Methyl 2-bromo-5- (4-pyridinyl) nicotinate using phosphorus tribromide or posforoxy bromide and absolute methanol.

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

According to the method described in Example A1, wherein instead of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid, a molar equivalent amount of the 1,2-dihydro-2-oxo-5- PY-6- (low 8101269 ψ w-8-alkyl) nicotinic acid and methanol or using a molar equivalent amount of the respective low alkanol, the corresponding low alkyl 2-chloro-5-PY-6- (low alkyl) nicotinates of Examples A-10 through A-20.

5 A-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.

A-14. Ethyl 2-chloro-6-isopropyl-5- (4-pyridinyl) nicotinate.

10 A-15. Methyl 6-n-butyl-2-chloro-5- (4-pyridinyl) nicotinate.

A-16. Methyl 2-chloro-6-isonuty1-5- (4-pyridinyl) nicotinate.

A-17. Ethyl 2-chloro-5- (4-pyridinyl) -6-tert-butyl nicotinate.

A-18. Methyl 2-chloro-6-n-pentyl-5- (4-pyridinyl) nicotinate.

A-19. n.Butyl 2-chloro-6-ethyl-5- (2-methyl-4-pyridinyl) .hicotinate.

15 A-20. Isopropyl 2-chloro-6-ethyl-5- (3-pyridinyl) nicotinate.

A-21. Ethyl 2-chloro-6-methyl-5- (4-pyridinyl) nicotinate, mp 105 ° - 106.5 ° C (this compound was found to be ineffective as a cardiotonic agent).

B. 1,2-Dihydro-5- (pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-ones 20 B-1. 1,2-Dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one - A solution of 4.2 g of methyl 2-chloro-5- (4 pyridinyl nicotinate, 5 ml of 1,1-dimethylhydrazine and 50 ml of methanol were refluxed with stirring for 20 hours; then the reaction mixture was cooled and the solid collected, washed with ethanol and dried at 90 ° C to obtain 1.7 g of 1,2-dihydro-1-methyl 1-5- (4-pyridinyl) - 3H-pyrazolo [3,4-b] pyridin-3-one. This amount of 1.7 g of 1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one was combined with the amounts obtained in two other experiments 4.3 g and 1.4 g corresponding product; the combined products were recrystallized from 30 ml of dimethyl-30 formamide and dried in a vacuum oven at 90 ° C to obtain 4.7 g of 1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one, mp 265 ° - 267 ° C.

The above preparation was carried out with 1-methylhydrazine instead of 1,1-dimethylhydrazine as follows (this preparation with 1-methylhydra-35zine is preferred): To a warm solution of 5.0 g of methyl 2-chloro- 5- (4-pyridinyl) nicotinate in 40 ml of methanol, 5 ml of 1-methylhydrazine were added with stirring; the resulting reaction mixture was refluxed with stirring for 18 hours. The reaction mixture, which contained a small amount of solid, was cooled. Since only a small amount of further solids separated out, the solvent was removed using a rotary evaporator. The residual yellow solid was collected, washed with water and dried in a vacuum oven at 90 ° C to give 4.3 µl of 2-dihydro-1-methyl-5- (4-pyridinyl) -5 3H-pyrazolo [ 3,4-b] pyridin-3-one, mp 263 ° - 265 ° C.

For comparison, the compound mentioned below, which differs structurally therein from the compound of Example B1, was prepared in the manner described below in that it has no substituent in position 1 (ie, a group other than hydrogen), while the compound of Example 1 B1 in this place contains a methyl group as a substituent: A solution of 3.6 g of methyl 2-chloro-5- (4-pyridinyl) nicotinate, 19 ml of hydrazine hydrate and 150 ml of methanol was placed on a steam bath for 19 hours. refluxed; the mixture containing a yellow solid was cooled well in ice and the solid was collected. The solid was air dried to give 11.2 gm. this amount was combined with an amount of 1.6 g of corresponding product obtained in another test carried out by the same method; the combined products were recrystallized from 440 ml of dimethylformamide, washed with ether and dried in a vacuum oven at 95 ° C to obtain 9.5 µl of 2-dihydro-5- (4-pyridinyl) -3H- pyrazolo [3,4-b] pyridin-3-one, melting point Λ 300 ° C. In contrast to the cardiotonically active compound of Example B-1, this 1-unsubstituted compound was found to be ineffective in the in vitro cardiac cardiac experiment of cat's atria.

According to the method described in Example B1, wherein instead of 1,1-dimethylhydrazine or 1-methylhydrazine a molar equivalent amount of the corresponding 1-R-hydrazine is used, the corresponding 1,2-dihydro-1R is obtained -5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-ones from Examples B-2 to B-13.

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

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

B-4. 1,2-Dihydro-1-n-propyl-5- (4-pyridinyl) -3H-pyrazolo [, 34-b] pyridin-3-one using 1-n-propylhydrazine.

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

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

8101269 y ** - 10 - B-7. 1,2-Dihydro-1-isobutyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one using 1-isobutylhydrazine.

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

5 B-9. 1,2-Dihydri-1- (n-pentyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one using 1- (n-pentyl) hydrazine.

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

B1 1,2-Dihydro-1- (2-ethoxyethyla-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] -10 pyridin-3-one using 1- (2-ethoxyethyl) hydrazine.

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

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

According to the procedure of Example B1, however, instead of methyl 2-chloro-5- (4-pyridinyl) nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine, molar equivalent amounts of the respective lower alkyl 3-chloro-5- Using PY-nicotinate and the appropriate 1-R-hydrazine, the corresponding 1,2-dihydro-1R-5-PY-3H-pyrazolo [3,4-b] -20-pyridin-3-ones of Examples B- is obtained. 14 through B-19.

B-14. 1,2-Dihydri-1-methyl-5- (3-pyridinyl) -3H-pyrazolo [3,4b] pyridin-3-one.

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

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

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

B-18. 1,2-Dihydro-1- (2-methoxyethyl) -5- (2-methyl-4-pyridinyl) -3H-30 pyrazolo [3,4-b] pyridin-3-one.

B-19. 1,2-Dihydro-1-methyl-5- (276-dimethyl-4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one.

According to the method described in Example B1, however, instead of methyl 2-chloro-5- (4-pyridinyl) nicotinate and 1,1-dimethyl-35 hydrazine or 1-methylhydrazine, molar equivalent amounts of the respective methyl or other lower alkyl 2-chloro-5-PY-nicotinate and the corresponding 1- (low hydroxyalkyl) hydrazine, 1,2-dihydro-3-oxo-5-PY-3H-pyrazolo [3,4-b] pyridine is obtained 1- (lower alkanols) of Examples B-20 to B-27.

8101269 - 11 - B-r20. 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.

5 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).

B-24. 1,2-Dihydri-3-oxo-5- (3-ethyl-4-pyridinyl) -3H-pyrazolo [3,4-b] -10 pyridine-1- (2-butanol).

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

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

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

According to the process described in Example B1, however, instead of methyl 2-chloro 5- (4-pyridinyl) nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine, molar equivalent amounts of the respective methyl or other layer alkyl 2-chloro-5-PY-6- (lower alkyl) nicotinate and / or 1-R-hydrazine, the corresponding 1,2-dihydro-1R-5-PY-6-Q-1H-pyrazolo is obtained [ 3,4-b] pyridin-3-ones of Examples B-28 to B-41.

B-28. 1,2-Dihydro-1,6-dimethyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] -25 pyridin-3-one.

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

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

30 B-31. 1-Ethyl-1,2-dihydro-6-methyl-5- (3-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-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] -35-pyridine-1-ethanol.

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

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

8101269 r f * - 12 - B-36. 6-n-Butyl-1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one.

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

5 B-38. 1,2-Dihydro-5- (4-pyridinyl) -6-tert-butyl-3H-pyrazolo [3,4-b] pyridin-3-one.

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

B-40. 1,6-Diethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -3H-pyrazolo-10 [3,4-b] pyridin-3-one.

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

According to the procedure of Example B-20, wherein instead of 1- (2-hydroxyethyl) hydrazine, a molar equivalent amount of 1- (2,3-15 dihydroxypropyl) hydrazine and methyl 2-chloro-5- (4-pyridinyl) is used. nicotinate or a molar equivalent of the corresponding methyl or lower alkyl 2-chloro-5-PY-6-Q nicotinate, 1,2-dihydro-1- (2,3-dihydroxypropyl) -5-PY- is obtained 6-Q-3H-pyrazolo [3,4-b] pyridin-3r-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] pyridin-3-one.

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

B-44. 1,2-Dihydro-1- (2,3-dihydroxypropyl) -5- (3-pyridinyl) -1H-pyrazolo-25 [3,4-b] pyridin-3-one.

The suitability of the compounds of formulas (1) and (2) and their salts as cardiotonic agents is evidenced by their activity in standard pharmacological tests; for example, these compounds cause a significant increase in the contractile force of the isolated atrial and papillary muscle of cats. A detailed description of this test method is given in U.S. Pat. No. 4,072,746.

When tested according to the above test with isolated atria and papillary muscle of cats, the 1,2-dihydro-5- (pyridinyl) -3h-pyrazolo [3,4-b] pyridin-3-ones of formula (1) doses of 100 μς / ml cause a significant increase, i.e., about 25% or more, in the papillary muscle strength and a significant increase, that is, about 25% or more, in the contraction force of the right atrium, while a lesser increase (about half or less of the percentage 810126 9 - 13 - increase in the contraction force of the right atrium and papillary muscle) in the rate of contraction of the right atrium.

For example, 1,2-dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo- [3,4-b] pyridin-3-one was found in the above test in a dose of 100 yug / ml an increase in resp. the papillary muscle strength, the right atrial strength and the contraction speed of the right atrium of resp.

23%, 42% and 12%. In contrast, 1,2-dihydro-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one was found to be practically ineffective when tested by this method at a dose of 100 µg / ml. ie, this compound caused an increase in the papillary muscle strength, the right heart atrial force, and the contraction rate of the right atrium, respectively. only 6%, 14% and 10%.

In studies of the isolated cat's atrial and papillary muscle test, the low alkyl 2-halogen-5-PY-6-Q'-nicotinates at 15 doses of 10, 30 and 100 µg / ml were found to increase significantly, i.e. greater than 25%, in the papillary muscle strength, and causing a significant increase, that is, about 20% or more, in the contraction force of the right atrium, while a lesser increase (about 1/3 or less in the percentage increase in the contraction force of the right heart and papillary muscle) in the rate of contraction of the right heart. For example, methyl 2-chloro-5- (4-pyridinyl) nicotinate was found in studies of the above experiment in doses of 10, 30 and 100 µg / ml to show an increase in papillary muscle strength, right ventricle strength and right heart contraction rate, respectively.

25 35%, 17% and 5%; 43%, 29% and 10%? and 76%, 112% and 25%.

The invention also provides a cardiotonic composition for increasing the contractile capacity of the heart, which composition is a pharmaceutically acceptable carrier and as active ingredient a cardiotonic 30 1,2-dihydro-5-PY-6-Q-3H-pyrazolo [3, 4-b] pyridin-3-one of formula (1) or a cardiotonic low alkyl 2-halogen-5-PY-6-Q nicotinate of formula (2) or a pharmaceutically acceptable addition salt thereof with an acid. To increase cardiac contraction in a patient, these compounds or salts thereof are normally administered orally or parenterally in a wide variety of dosage forms.

Solid preparations for oral administration include pressed tablets, pills, powders and granules. In these solid preparations, at least one of the active compounds is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. In addition to inert diluents, these prepa 8101269 9 v * - 14 - combs may also contain other materials, such as lubricants such as magnesium stearate, talc and the like.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing conventional inert diluents such as water or liquid paraffin. In addition to inert diluents, these preparations may also contain auxiliary agents such as wetting and suspending agents, sweetening agents, flavor and / or fragrance imparting agents and preservatives. According to the invention, the orally to be administered preparations also comprise capsules of absorbable material, such as gelatin, which contain the active component, whether or not in combination with a diluent.

Compositions of the invention to be administered parenterally 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 preparations may also contain auxiliary agents such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents.

The present compositions can be sterilized, for example, by filtering through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiation or by heating.

The formulations can also be prepared in the form of sterile solid materials which can be dissolved in sterile water or other sterile injectable material immediately before use.

The percentage of active ingredient in the composition and the method of increasing cardiac contraction can be varied to obtain an appropriate dose. The dose administered to a particular patient varies depending on the mode of administration, the duration of the treatment, the size, build and condition of the patient, the efficacy of the active component concerned and the response of the patient. Thus, an effective dose of the active ingredient can be determined by the treating physician based on the above factors.

8101269

Claims (9)

1. Compounds of formula (1) of the formula sheet and addition salts thereof with acids, in which formula R represents a lower alkyl group, lower hydroxyalkyl group, 2,3-dihydroxypropyl group or lower alkoxyalkyl group, Q represents a hydrogen atom or a lower alkyl group , and PY a 4- or 3-pyridinyl group or a 4- or 3-pyridinyl group with 1 or 2 lower alkyl groups as substituent (s). Compounds according to claim 1, wherein R is a methyl, ethyl or 2-hydroxyethyl group and Q is a hydrogen atom, methyl group or ethyl group. 103. 1,2-Dihydro-1-methyl-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridin-3-one or a pharmaceutically acceptable addition salt thereof with an acid. 4. 1,2-Dihydro-3-oxo-5- (4-pyridinyl) -3H-pyrazolo [3,4-b] pyridine-1-ethanol or a pharmaceutically acceptable addition salt thereof with an acid. 5. Process for preparing a compound according to claims 1-4, characterized in that a low alkyl 3-halogen-5-PY-6-Q nicotinate is reacted with a 1-R-hydrazine, and if desired a obtained free base into an addition salt thereof with an acid. 6. Compounds of formula (2) and addition salts thereof with acids, in which formula Q is a hydrogen atom or a lower alkyl group, R 'is a lower alkyl group, X is chlorine or bromine and PY is a 4- or 3-pyridinyl group or a 4- or 3-pyridinyl group with 1 or 2 lower alkyl groups as substituent (s). 7. Process for preparing a compound according to claim 6, characterized in that a 2-halo-6-Q-5-PY-nicotinoyl halide is converted with a low alkanol, and if desired, a obtained free base is converted into an addition salt thereof with an acid. 8. Process according to claim 7, characterized in that the 2-halogen- 6-Q-5-PY-nicotinoyl halide prepared by hydrolysis of a 1,2-dihydro- 6-Q-2-oxo-5-PY-nicotinonitrile to obtain a 1,2-dihydro-6-Q-2-oxo-5-PY-nicotinic acid and reaction of this acid with an inorganic halogenating agent. 9. Cardiotonic preparation for increasing the contractile capacity of the heart, containing a pharmaceutically acceptable inert carrier and an active ingredient, characterized in that the active ingredient is an effective amount of a cardiotonic compound of formula (1) or a pharmaceutically acceptable addition salt thereof with an acid or a compound of formula (2) or a pharmaceutically acceptable addition salt thereof with an acid. 8101269 é v LS 874-209 Ned. - Appendix 4 - Sterling Drug Ine. in New York, New York, United States of America PY - | = o (1) L lL j? Q I H - R Ttr0 ^ ΊΟττ0 '! R R (1) "(IA) COOR '(2) Η Q / V" N x 81012 6 9