GB2073179A

GB2073179A - Pyrazolopyridinones and Pyridinylnicotinates

Info

Publication number: GB2073179A
Application number: GB8107632A
Authority: GB
Original assignee: Sterling Drug Inc
Current assignee: STWB Inc
Priority date: 1980-03-17
Filing date: 1981-03-11
Publication date: 1981-10-14
Also published as: IL62306A0; ES8205410A1; DE3110313A1; DK117081A; NL8101269A; NO810833L; PH15978A; FI810779L; NZ196453A; PT72674B; ES500395A0; SE8101592L; PT72674A; AU6813881A; IT1141999B; FR2478098A1; LU83221A1; IT8120272A0

Abstract

1,2-Dihydro-1-R-5-PY-6-Q-3H- pyrazoloÄ3,4-bÜpyridin-3-ones of the general formula I: <IMAGE> (R=alkyl, hydroxyalkyl, 2,3- dihodroxypropyl, alkoxyalkyl; Q=H, alkyl; PY=3- or 4-pyridyl optionally bearing one or two alkyl substituents) and acid-addition salts thereof, which are cardiotonic agents, are prepared by reacting an alkyl 2-halo-5-PY-6-Q- nicotinate with 1-R-hydrazine. The alkyl 2-halo-5-PY-6-Q-nicotinates and acid addition salts thereof are intermediates or cardiotonics.

Description

SPECIFICATION Pyrazolopyridinones and Pyridinylnicotinates useful as Cardiotonics This invention relates to pyrazolopyridinones; useful as cardiotonics and pyridinylnicotinates useful as chemical intermediates and cardiotonics.

Chemical Abstracts, Vol. 87, item 39,357t, 1977, reports, int al., that Acta Pol. Pharm. 1976, 33(3), 289-93 (Pol) shows RCOCH2CHO (R=Me, Ph, 3- and 4-pyridyl, and 6-methyl-3-pyridyl) condensed in an alk. medium with NCCH2=CONHNH2 to give pyrazolopyridines, which were also prepared by the reaction of Me 6-(3- and 4-pyridyl)-2-chloronicotinates or 6-(3- and 4-pyridyl)2chloro-3-cyanopyridines with 80% NH2NH2.H2O. The original article (p. 291) shows that said compounds can also exist in tautomeric 1 ,2-dihydro-6-R-3H-pyrazolo[3,4-b]pyridin-3-one form.

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

The present invention resides in 1 ,2-dihydro- 1 -R-5-PY-6-Q-3 H-pyrazolo[3,4-bjpyridin-3-one, having Formula I

where R is lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxy-propyl or lower-alkoxyalkyl, Q is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or acid-addition salts thereof. These compounds are useful as cardiotonic agents, as determined by standard pharmacological evaluation procedures. Preferred embodiments are those of Formula I where pv is 4-pyridinyl or 3-pyridinyl, R is methyl, ethyl or 2-hydroxyethyl and Q is hydrogen, methyl cr ethyl.

The compound of Formula I may exist in tautomeric forms, that is, as the 1 ,2-dihydro-1 -R-5-PY 6-Q-3H-pyrazolo[3,4-b]pyridin-3-one of Formula I and/or -1-R-5-PY-6-Q-1 H-pyrazolo[3,4-b]pyridin-3-ol of Formula IA, illustrated as follows:

Structural preferences for analogous known pyrazolo[3,4-bjpyridin-3-ones would indicate the above Formula I to be the preferred tautomeric structure; thus, it is preferred to use the names based on structure I, although it is understood that either or both structures are comprehended herein.

The present invention also resides in lower-alkyl 2-halo-5-PY-6-O-nicotinates having Formula II

where 0 is hydrogen or lower-alkyl, R' is lower-alkyl, X is chloro or bromo, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or acid-addition salts thereof. The compounds of Formula II and said salts are generally useful as cardiotonic agents, as determined by standard pharmacological evaluation procedures. Preferred embodiments are those of formula II where PY is 4-pyridinyl or 3-pyridinyl, O is methyl or ethyl, X is chloro and R' is methyl or ethyl. The compounds of Formula II also are useful as intermediates in the preparation of 1 ,2-dihydro-1 -R-5-PY- 6-Q3H-pyrazolo[3,4-b]pyridine-3-ones, (I).

One can produce the 1 ,2-dihydro-1 -R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-one of Formula I by a process which comprises reacting lower-alkyl 2-halo-5-PY-6-Q-nicotinate (II) with 1 -R-hydrazine (III), where PY, R and Q have the meanings given above for the compound of Formula I and halo is chloro or bromo, preferably chloro.

One can produce the lower-alkyl 2-halo-6-Q-5-PY-nicotinate of Formula II by a process which comprises the steps of hydrolyzing 1,2-dihydro-6-Q-2-oxo-5-PY-nicotinonitrile to produce 1,2 dihydro-6-Q-2-oxo-5-PY-nicotinic acid, reacting said acid with an inorganic halogenating agent to produce 2-halo-6-Q-5-PY-nicotinoyl halide and reacting the halide with a lower alkanol to produce lower-alkyl 2-halo-6-Q-5-PY-nicotinate, where halo is chloro or bromo and PY is defined as in Formula II above. Preferred embodiments of this process are those which produce the above-said preferred embodiments for Formula II, halo is chloro and the lower-alkyl portion of the resulting ester is methyl or ethyl.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceuticallyacceptable carrier and, as the active component thereof, an effective amount of a cardiotonic 1,2 dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-one of Formula I, or lower-alkyl 2-halo-5-PY-6-Qnicotinate of Formula II, or pharmaceutically-acceptable acid-addition salt thereof.

One can increase cardiac contractility in a patient requiring such treatment by administering orally or parenterally in a solid or liquid dosage form to such patient an effective amount of a cardiotonic 1 ,2-dihydro-1 -R-5-PY-6-Q-3H-pyrazolo[3,4-bjpyridin-3-one of Formula I or lower-alkyl 2halo-5-PY-6-Q-nicotinate of Formula II or pharmaceutically-acceptable acid-addition salt thereof.

The term "lower-alkyl" as used herein, e.g., as the meaning for R or O or as a substituent for PY in Formula I or II or as the lower-alkyl moiety of the intermediate lower-aikyl 2-halo-5-PY-6-Q-nicotinate (II), means alkyl radicals having from 1 to 6 carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and the like.

Illustrative of PY in Formula I or II where PY is 4-, 3- or 2-pyridinyl having 1 or 2 lower-alkyl substituents are the following: 2-methyl-4pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2- methyl-3-pyridinyl, 6-methyl-3-pyridinyl, (alternatively named 2-methyl-5-pyridinyl), 2,3-dimethyl-4 pyridi nyl, 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 herein, e.g., for one of the meanings for R in Formula I, means hydroxy-aikyl radicals having from two to six carbon atoms which can be arranged as straight or branched chains and at least two carbon atoms of which separate hydroxy and the 1-ring nitrogen atom of the pyrazolo[3,4-b]pyridine ring,illustrated by 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy- propyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, and the like.

The term "lower-alkoxyalkyl" as used herein, e.g., for one of the meanings for R in Formula I, means alkoxy-alkyl radicals having from three to six carbon atoms which can be arranged as straight or branched chains and at least two carbon atoms of which separate the oxygen atom of alkoxyalkyl and the 1-ring nitrogen atom of the pyrazolo[3,4-b]pyridine ring, illustrated by2-methoxyethyl,2-ethoxy- ethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxybutyl, 4-ethoxybutyl, 3-ethoxypropyl, 3-n- propoxypropyl, and the like.

The compounds of Formulas I and II are useful both in the free base form and in the form of acidaddition salts, and, both forms are within the purview of the invention. The acid-addition salts are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base (I or II) are not vitiated by side effects ascribable to the anions.In practicing the invention, it is convenient to use the free base form; however, appropriate pharmaceutically-acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid: and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like, giving the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, ta rtrate, methanesulfonate, ethanesulfonate, benzenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compound (I or II) are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Although pharmaceutically-acceptable salts of said basic compound (I or II) are preferred, all acid-addition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmaceutically-acceptable salt by ion exchange procedures.

The molecular structure of the compound of Formula I or II was assigned on the basis of evidence provided by infrared, nuciear magnetic resonance and mass spectra, and by the correspondence of calculated and found values for the elementary analysis.

The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of pharmaceutical chemistry to make and use the same, as follows.

The preparation 1 ,2-dihydro-1 -R-5PY-6-Q-3H-pyrazolo-[3,4-bJpyridin-3-one (I) by reacting lower-alkyl 2-halo-5-PY-6-Q-nicotinate (II) with 1-R-hydrazine (III) is carried out by heating the reactants in a suitable solvent at about 500C. to 1000C., preferably about 650C. to 850C. The reaction is conveniently run by refluxing the reactants in a lower-alkanol, preferably methanol or ethanol.

The 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 produce 2-chloro-5-PY-6-Q'-nicotinoyl chloride and reacting the latter with a lower-alkanol. The reaction is conveniently run by heating the reactants on a steam bath. Other suitable solvents include acetonitrile, dioxane, and the like. Other suitable inorganic halogenating agents include PAL3, PBr3 and PAL5.

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 shown in U.S. Patent 4,004,012.

The hydrolysis of 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-PY-nicotinonitrile to produce 1,2-dihydro 6-(lower-alkyl)-2-oxo-5-PY-nicotinic acid is conveniently run by heating the nitrile on a steam bath with an aqueous mineral acid, e.g., 50% sulfuric acid, as further illustrated in our below-mentioned application.

The intermediate 1 ,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)-nicotinonitriles are prepared by the procedure described in the following three paragraphs and is disclosed in our Application Serial No.

8037856 filed 26 November, 1 980.

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 carried out by mixing the reactants in the presence or absence of a suitable solvent. The reaction is conveniently run at room temperature, i.e., about 20--2 5 OC, or by warming the reactants up to about 1000C., preferably in an aprotic solvent, conveniently hexamethylphosphoramide because of the method used to prepare the PY-methyl lower-alkyl ketone, as noted below in Example C-i. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, and the like. Also, the reaction can be run using no solvent, preferably using an excess of dimethylformamide di-(loweralkyl)acetal.

The intermediate PY-methyl lower-alkyl ketones are generally known compounds which are prepared by known methods [e.g., as given in Rec. trav. chim 72,522(1953); U.S. Pat. 3,133,077 (512-64); Bull. Soc. Chim. France 1968, 4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs. 81, 120,401 a (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 a-cyanoacetamide to produce 1 ,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile is carried out preferably by heating the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently run using an alkali lower-alkoxide, preferably sodium methoxide or ethoxide, in dimethylformamide. In practicing the invention, the reaction was carried out in refluxing dimethylformamide using sodium methoxide.

Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide can be used as solvent and basic condensing agent, respectively; however, a longer basic period is required. Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, and the like, in an aprotic solvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the like.

The following examples will further illustrate the invention without, however, limiting it thereto.

A. Lower-alkyl 2-Halo-5-PY-6-0-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 phosphorous oxychloride and 10 drops of dimethylformamide was heated on a steam bath for 4 1/2 hours during which time hydrogen chloride was evolved and most of the solid dissolved. The reaction mixture was allowed to stand overnight at room temperature and was then filtered through diatomaceous earth to remove a small quantity of yellow solid. The excess phosphorus oxychloride in the filtrate was distilled off in vacuo and the syrupy residue was cooled. To this material was added 500 ml. of absolute methanol and the mixture was shaken well with periodic cooling in an ice bath, whereupon the syrup slowly dissolved and a nearly white solid formed.The mixture was cooled well in an ice bath and the solid was collected and air dried. The resulting solid (44.7 g., m.p. 295-3000C.

with decomposition) was taken up in about 500 ml. of water and the solution filtered. The filtrate was basified to pH 8.0 with 3N ammonium hydroxide solution (about 70 ml. required). The copious pale yellow solid was collected, washed with water and air-dried. The solid was then taken up in 400 ml. of methylene dichloride whereupon a small water layer separated. The methylene dichloride layer was separated, washed with water, dried over an anhydrous magnesium sulfate and then evaporated to dryness on a rotary vaporizer to yield 35.6 g. of a cream-colored solid, m.p. 1 10--1 120C. A portion 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 600C. for 6 hours to yield 6.7 g. of the product, m.p.

112.5--113"C.

Following the procedure described in Example A-l but using in place of 1 ,2-dihydro-2-oxo-5-(4pyridinyl) nicotinic acid and methanol molar equivalent quantities of the appropriate 1 ,2-dihydro-2- oxo-5-PY-nicotinic acid and lower-alkanol, respectively, it is contemplated that the corresponding lower-alkyl 2-chloro-5-PY-nicotinoates of Examples A-2 through A-7 can be 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.

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

A-7. Methyl 2-chloro-5-(2,6-di methyl-4-pyridi nyl)nicotinate.

Following the procedure described in Example A-l but using in place of phosphorus oxychloride or lower-alkanol molar equivalent quantities of the appropriate halogenating agent and lower-alkanol, respectively, it is contemplated that the designated lower-alkyl 2-halo-5-(4-pyridinyl)nicotinate of Examples A-8 or A-9 can be obtained.

A-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 A-l but using in place of 1 ,2-dihydro-2-oxo-5-(4pyridinyl)nicotinic acid a molar equivalent quantity of the appropriate 1 ,2-dihydro-2-oxo-5-PY-6- (lower-alkyl)nicotinic acid and either methanol or a molar equivalent quantity of the appropriate loweralkanol, it is contemplated that the corresponding lower-alkyl 2-chloro-5-PY-6-(lower-alkyl)nicotinates of Examples A-10 through A-20 can be obtained.

A-10. Methyl 2-chloro-6-methyl-5-(4-pyridinyl)-nicotinate.

A-li. 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.

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

A-16. Methyl 2-chloro-6-isobutyl-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)nicotinate.

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

A-21. Ethyl 2-chloro-6-methyl-5-(4-pyridinyl)-nicotinate, m.p. 105-i 06.50C. (found to be inactive as cardiotonic).

B. I ,2-Dihydrn-5-(pyridinyl)-3H-pyrazolo[3,4bjpyridin-3-ones B- 1 ,2-Dihydro- 1 -methyl-5-(4-pyridinyl)-3 H-pyrazolo[3,4-b] pyridin-3-one A solution containing 4.2 g. of methyl 2-chloro-5-(4-pyridinyl)nicotinate, 5 ml of 1,1dimethylhydrazine and 50 ml. of methanol was refluxed with stirring for 20 hours the reaction mixture was then cooled, the solid collected, washed with ethanol and dried at 900 C. to produce 1.7 g of 1,2 dihyd ro-l -methyi-5-(4-pyridinyl)-3 H-pyrazolo[3,4b]pyridine-3-one. This 1.7 g. of 1,2-dihydro-1- methyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridine-3-one was combined with 4.3 g. and 1.4 g. portions of corresponding product obtained from two other runs and the combined product was recrystallized from 30 ml. of dimethylformamide and dried in a vacuum oven at 90"C. to yield 4.7 g of 1,2-dihydro 1 -methyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-bjpyridine-3-one, m.p. 265-267 0C.

The above preparation was preferably run using 1-methylhydrazine instead of 1,1dimethylhydrazine, as follows: To a stirred warm solution of 5.0 g. of methyl 2-chloro-5-(4pyridinyl)nicotinate in 40 ml. of methanol was added 5 ml. of 1-methylhydrazine and the resulting reaction mixture was refluxed with stirring for eighteen hours. The reaction mixture containing a small amount of solid was cooled. Since only little additional solid separated, the solvent was removed using a rotary evaporator. The remaining yellow solid was collected, washed with water and dried in a vacuum oven at 90 C. to yield 4.3 g. of 1,2-dihydro-l -methyl-5-(4-pyridinyl-3H-pyrazolo[3,4- b]pyridin-3-one, m.p. 263-2650C.

For purpose of comparison, the following compound, which differs structurally from Example B-l in having no 1 -substituent (other than hydrogen) where Example B-1 has methyl, was prepared by the following procedure: a solution containing 16.6 g. of methyl 2-chloro-5-(4-pyridinyl)nicotinoate 19ml.

of hydrazine hydrate and 1 50 ml. of methanol was refluxed on a steam bath for 19 hours and the mixture containing a yellow solid was cooled well in ice and the solid collected. The solid was air-dried, 11.2 g., and combined with a 1.6 g. portion of corresponding product obtained in another run following the same procedure and the combined product was recrystallized from 440 ml. of dimethyl-formamide, washed with ether and dried in a vacuum oven at 950C. to yield 9.5 g. of 1 ,2-dihydro-5-(4-pyridinyl) 3H-pyrazolo[3,4-bjpyridin-3-one, m.p. > 3000C. In contrast to the cardiotonically-active Example B-l , this 1-substituted compound was found to be inactive when tested in the in vitro cardiotonic cat atria screen as shown hereinbelow.

Following the procedure described in Example B-l but using in place of 1,1-dimethylhydrazine or 1methylhydrazine a molar equivalent quantity the appropriate 1-R-hydrazine. it is contemplated that the corresponding 1,2-dihydro-1-R-5-(4-pyridinyl)3H-pyrazolo[3,4-b] pyridin3-ones of Examples B-2 through B-13 can be obtained.

B-2. 1 ,2-Dihydro-i -(2-methoxypropyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-bjpyridin-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[3,4-b]pyridin-3-one using l-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 l-n- butylhydrazine.

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

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

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

B-10.1,2-Dihydro-1-(n-hexyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one using 1 -(n hexyl)hydrazine.

B- 11. 1 ,2-Dihydro- 1 -(2-ethoxyethyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-bjpyridin-3-one using 1 -(2ethoxy-ethyl)hydrazine.

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

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

Following the procedure in Example B-l but using in place of methyl 2-chloro-5-(4 pyridinyl)nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine respectively, corresponding molar equivalent quantities of the respective appropriate methyl or other lower-alkyl 2-chloro-5-PY nicotinate and 1-R-hydrazine, it is contemplated that there can be obtained the corresponding 1,2dihydro-1 -R-5-PY-3H-pyrazolo[3,4-b]pyridin-3-ones of Examples B-14 through B-19.

B- 14. 1 ,2-Dihydro- 1-methyl-S (3-pyridinyl)-3 H-pyrazolo[3,4-bjpyridin-3-one.

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

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- 8. 1 ,2-Dihydro- 1 -(2-methoxyethyl)-S-(2-methyl-4-pyridinyl)-3 H-pyrazolo[3,4-b]pyridin-3- one.

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

Following the procedure described in Example B-l but using in place of methyl 2-chloro-5-(4 pyridinyl)nicotinate and 1 , 1 -dimethylhydrazine or 1 -methylhydrazine corresponding molar equivalent quantities of the appropriate methyl or other lower-aikyl 2-chloro-5-PY-nicotinate and l-(lower- hydroxyalkyl )-hydrazine, it is contemplated that the 1,2-dihydro-3-oxo-5-PY-3H-pyrazolo[3,4- b]pyridine-1-(lower-alkanols) of Example B-20 through B-27 can be obtained.

B-20. 1 ,2-Dihydro-3-oxo-S-(3-pyridinyl)-3 H-pyrazolo[3 4-bipyridine- methanol.

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

B-22.1,2-Dihydro-3-oxo-5-(5-methyl-3-pyridinyl)-3 -(n-propanol).

B-23.1,2-Dihydro-3-oxo-5-(4-pyridinyl)-3 H-pyrazolo[3,4-b] pyridine- 1 -(2-propanol).

B-24. 1 ,2-Dihydro-3-oxo-S-(3-ethyl-4-pyridinyl)-3 H-pyrazolo[3,4-b]pyridine- 1 -(2-buta nol).

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- methanol.

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

Following the procedure described in Example B-1 but using in place of methyl 2-chloro-5-(4pyridinyl)nicotinate and 1, l-dimethylhydrazine or 1-methylhydrazine molar equivalent quantities of the appropriate methyl or other lower-alkyl 2-chloro-5-PY-6(lower-alkyl)nicotinate and/or 1-R-hydrazine, respectively, it is contemplated that the corresponding 1,2-dihydro-1-R-5-PY-6-Q-1 H-pyrazolo[3,4b]pyridin-3-ones of Examples B-28 through B-41 can be obtained.

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

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

B-30.1,2-Dihydro-6-methyl-5-(4-pyndinyl)-3H-pyrazolo[3,4-b]pyridin-3-one.

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

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

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

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

B-35.1,2-Dihydro-6-isopropyl-5-(4-pyridinyl)-3 H-pyrazolo[3,4-b] pyridin-3-one.

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

B-3 7. 1 ,2-Dihydro-6-isobutyl-3-oxo-S-(4-pyridinyl)-3 H-pyrazolo[3,4-bjpyridine- 1 -ethanol.

B-38.1,2-Dihydro-5-(4-pyridinyl)-6-tert.-butyl-3 H-pyrazolo[3,4-b]pyridin-3-one.

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

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

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

Following the procedure described in Example B-20 but using in place of 1 -(2hydroxyethyl)hydrazine a corresponding molar equivalent quantity of 1-(2,3-dihydroxypropyl)hydrazine and either methyl 2-chloro-5-(4-pyridinyl)nicotinate or a corresponding molar equivalent quantity of the appropriate methyl or lower-alkyl 2-chloro-5-PY-6-Q-nicotinate, it is contemplated that there can be obtained the 1 2-dihydro- 1 -(2,3-dihydroxypropyl)-S-PY-6-Q-3 H-pyrazolo (3,4b]pyridin-3-ones of Examples B-42 through B-44.

B-42. 1 ,2-Dihydro- 1 -(2,3-dihydroxypropyl)-S-(4-pyridinyl)- 1 H-pyrazolo(3,4-b]pyridin-3-one.

B-43. 1,2-Dihydro-l -(2,3-dihydroxypropyl)-6-methyl-S-(4-pyridinyl)- 1 H-pyrazolo[3,4-b]pyridin3-one.

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

The usefulness of the compounds of Formulas I or il or salts thereof as a cardiotonic agent is demonstrated by their effectiveness in standard pharmacological test procedures, for example, in causing a significant increase in the contractile force of the isolated cat atria and papillary muscle. A detailed description of this test procedure appears in U.S. Patent 4,072,746.

When tested by said isolated cat atria and papillary muscle procedure, the 1,2-dihydro-5 (pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-ones of Formula I when tested at a dose of 100 yg./ml., were found to cause significant increase, that is, about 25% or greater in papillary muscle force and a significant increase, that is, about 25% or greater, in right atrial force, while causing a lower percentage increase (about one-half or less than the percentage increase in right atrial force or papillary muscle force) in right atrial rate.For example, when tested at 100 Slg./ml. by this procedure, the 1,2-dihydro-l methyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one was found to cause respective percentages increases of 23%, 42% and 12% in papillary muscle force, right atrial force and right atrial rate. In contrast 1 ,2-dihydro-S-(4-pyridinyl)-3H-pyrazolo[3,4-bjpyridin-3-one when tested at 100 g./ml. by this procedure was found to be essentially inactive that is, to cause respective percentage increases of only 6%, 14% and 10% in papillary muscle force, right atrial force and right atrial rate.

When tested by said isolated cat atria and papillary muscle procedure, the loweralkyl 2-halo-5- PY-6-Q'-nicotinates when tested at doses of 10, 30 and 100 ,etg./ml., were found to cause significant increase, that is, greater than 25% in papillary muscle force and a significant increase, that is, about 20% or greater, in right atrial force, while causing a lower percentage increase (about one-third or less than the percentage increase in right atrial force or papillary muscle force) in right atrial rate.For example, when tested at 10, 30 and 100 iig./ml. by this procedure, methyl 2-chloro-5-(4pyridinyl)nicotinate was found to cause respective percentages increases in papillary muscle force, right atrial force and right atrial rate of: 35%, 17% and 5%; 43%, 29% and 10%; and, 76%, 11 2% and 25%, respectively.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceuticallyacceptable carrier and, as the active component thereof, the cardiotonic 1,2-dihydro-5-PY-6-Q-3H- pyrazolo[3,4-b] pyridin-3-one of Formula I or cardiotonic lower-alkyl 2-halo-5-PY-6-Q-nicotinate of Formula II or pharmaceutically-acceptable acid-addition salt thereof. For increasing cardiac contractility in a patient in clinical practice said compound or salt thereof will normally be administered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is admixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions may also contain additional substances other than inert diluents, e.g., lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents.

According to the invention, the compounds for oral administration also include capsuies of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients.

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, vegetabie oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilizing, preserving, wetting, emulsifying 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 manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

The percentages of active component in the said composition and method for increasing cardiac contractility can be varied so that a suitable dosage is obtained. The dosage administered to a particular patient is variable, depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto. An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing the best judgement on the patient's behalf.

Claims

1. A compound having the Formula I (herein) where R is lower-alkyl, lowerhydroxyalkyl, 2,3dihydroxypropyl or lower-alkoxyalkyl, Q is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or an acid-addition salt thereof.

2. A compound according to claim 1, where R is methyl, ethyl, or 2-hydroxyethyl.

3. A compound according to claim 1 or 2, where 0 is hydrogen, methyl or ethyl

4.1,2-Dihydro-1-methyl-5-(4-pyridinyl)-3H-pyrazolo-[3,4-b]pyridin-3-one or a pharmaceuticallyacceptable acid-addition salt thereof.

5. 1 ,2-Dihydro-3-oxo-5-(4-pyridinyl)-3 H-pyrazolo[3,4-b] pyridine- 1 ethanol or a pharmaceutically-acceptable acid-addition salt thereof.

6. A process for preparing a compound according to claim 1, which comprises reacting loweralkyl 2-halo-5-PY-6-Q-nicotinate with a 1-R-hydrazine, and, if desired, converting a free base obtained into an acid-addition salt thereof.

7. A process for preparing a compound according to claim 1, substantially as herein described with reference to Examples Bi-B44.

8. A compound according to claim 1, when prepared by the process according to claim 6 or 7.

9. A compound according to claim 1, substantially as herein described with reference to Examples B1-B44.

10. A compound of Formula

II (herein), wherein Q is hydrogen or lower-alkyl, R' is lower-alkyl, X is chloro or bromo, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or an acid-addition salt thereof.

ii. A compound according to claim 10, where 0 is hydrogen, methyl or ethyl and X is chloro.

1 2. A process for producing a compound according to claim 10 or 11 which comprises reacting a 2-halo-6-Q-5-PY-nicotinoyl halide with a lower-alkanol and, if desired, converting a free base obtained into an acid-addition salt thereof.

1 3. A process according to claim 12, in which the 2-halo-6-Q-5-PY-nicotinoyl halide is produced by hydrolyzing a 1,2-dihydro-6-Q-2-oxo-5-PY-nicotinonitrile to produce a 1,2-dihydro-6-Q-2-oxo-5- PY-nicotinic acid and reacting said acid with an inorganic halogenating agent.

14. A process for preparing a compound according to claim 10, substantially as herein described with reference to Examples A-l to A-20.

1 5. A compound according to claim 10, when prepared by the process according to any one of claims 12 to 14.

1 6. A compound according to claim 10, substantially as herein described with reference to Examples A-l to A-20.

1 7. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic compound according to any one of claims 1--5, 8--1 1, 15 and 16 or a pharmaceutically-acceptable acid-addition salt thereof.

1 8. A compound for use in increasing cardiac contractility in a patient requiring such treatment which comprises a cardiotonic compound according to any one of claims 1--5, 8--1 1, 1 5 and 16 or a pharmaceutically-acceptable acid-addition salt thereof.