NO810833L - PROCEDURE FOR PREPARATION OF PYRAZOLPYRIDINONES AND PYRIDINYLNICOTINATES - Google Patents

PROCEDURE FOR PREPARATION OF PYRAZOLPYRIDINONES AND PYRIDINYLNICOTINATES

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Publication number
NO810833L
NO810833L NO810833A NO810833A NO810833L NO 810833 L NO810833 L NO 810833L NO 810833 A NO810833 A NO 810833A NO 810833 A NO810833 A NO 810833A NO 810833 L NO810833 L NO 810833L
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Norway
Prior art keywords
pyridinyl
dihydro
methyl
pyrazolo
lower alkyl
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NO810833A
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Norwegian (no)
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George Yohe Lesher
Monte Deane Gruett
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Sterling Drug Inc
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Priority claimed from US06/130,623 external-priority patent/US4265895A/en
Priority claimed from US06/130,628 external-priority patent/US4264612A/en
Application filed by Sterling Drug Inc filed Critical Sterling Drug Inc
Publication of NO810833L publication Critical patent/NO810833L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Description

Foreliggende oppfinnelse angår pyrazolopyridinoner som kan brukes som kardiotoniske midler samt pyr i-dinylniko-tinater som kan brukes som kjemiske mellomprodukter og som kardiotoniske midler. The present invention relates to pyrazolopyridinones which can be used as cardiotonic agents as well as pyr idinyl nicotinates which can be used as chemical intermediates and as cardiotonic agents.

Chemical Abstracts, bind 87, avsnitt 39,357t, 1977 angir bl.a. at Acta Pol. Pharm. 1976, 33(3), 289-93 (Pol) viser at når RCOCH2CHO (R = Me, Ph, 3- og 4-pyridyl, og 6-metyl-3-pyridyl) kondenseres i et alkalisk medium med NCCH2= CONHNH2, så får man fremstilt pyrazolopyridiner, og at disse også kan fremstilles ved en reaksjon mellom Me 6-(3- og 4-pyridyl)-2-klornikotinater eller 6-(3- eller 4-pyridyl)-2-klor-3-cyanopyridiner og 80% NH2NH2.H20. Den orginale ar-tikkelen (side 291) viser at nevnte forbindelser også kan eksitere i en tautomerisk form, dvs. 1,2-dihydro-6-R-3H-pyrazolo[3,4-b]pyridin-3-on. Chemical Abstracts, volume 87, section 39,357t, 1977 states, inter alia that Acta Pol. Pharm. 1976, 33(3), 289-93 (Pol) shows that when RCOCH2CHO (R = Me, Ph, 3- and 4-pyridyl, and 6-methyl-3-pyridyl) is condensed in an alkaline medium with NCCH2= CONHNH2, then pyrazolopyridines are produced, and that these can also be produced by a reaction between Me 6-(3- and 4-pyridyl)-2-chloronicotinates or 6-(3- or 4-pyridyl)-2-chloro-3-cyanopyridines and 80% NH 2 NH 2 .H 2 O. The original article (page 291) shows that said compounds can also exist in a tautomeric form, i.e. 1,2-dihydro-6-R-3H-pyrazolo[3,4-b]pyridin-3-one.

I en senere artikkel med tittelen "Cancerstatics III. Synthesis and Some Chemical Transformations of 3-Cyano-5-(pyridinyl-4)pyrid-2-one" [Pol. J. Pharmacol. Pharm. 30, 707-712 (1978)], viser P. Nantka-Namirski og L. Kaczmarek bl.a. at man kan reagere 3-cyano-5-(4-pyridinyl)pyridin-2-on [alternativt kalt 1,2-dihydro-2-okso-5-(4-pyridinyl)niko-nitril med fosforoksyklorid og få fremstilt 2-klor-3-cyano-5-(4-pyridinyl)pyridin [alternativt kalt 2-klor-5-(4-pyridinyl ) nikotinonitril] , og at en syrehydrolyse av 3-cyanofor-bindelsen vil gi den tilsvarende 3-karboksylsyren. In a later paper 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 show i.a. that one can react 3-cyano-5-(4-pyridinyl)pyridin-2-one [alternatively called 1,2-dihydro-2-oxo-5-(4-pyridinyl)nico-nitrile with phosphorus oxychloride and obtain 2- chloro-3-cyano-5-(4-pyridinyl)pyridine [alternatively called 2-chloro-5-(4-pyridinyl) nicotinonitrile], and that an acid hydrolysis of the 3-cyano-bond will give the corresponding 3-carboxylic acid.

Foreliggende oppfinnelse angår 1,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-on med formel I The present invention relates to 1,2-dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-one of formula I

hvor R er lavere alkyl, lavere hydroksyalkyl, 2,3-dihydroksypropyl eller lavere alkoksyalkyl, Q er hydrogen eller lavere alkyl, og PY er 4- eller 3-pyridinyl eller 4- eller 3-pyridinyl med én eller to lavere alkylsubstituenter, samt syre- where R is lower alkyl, lower hydroxyalkyl, 2,3-dihydroxypropyl or lower alkoxyalkyl, Q is hydrogen or lower alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two lower alkyl substituents, as well as acid -

addisjonssalter av nevnte forbindelser. Disse forbindelser, kan brukes som kardiotoniske midler slik dette kan bestemmes ved standard farmakologiske prøver. Foretrukne forbindelser er de med formel I hvor PY er 4-pyridinyl eller 3-pyridinyl, R er metyl, etyl eller 2-hydroksyetyl og Q er hydrogen, metyl eller etyl. addition salts of said compounds. These compounds can be used as cardiotonic agents as this can be determined by standard pharmacological tests. Preferred compounds are those of formula I where PY is 4-pyridinyl or 3-pyridinyl, R is methyl, ethyl or 2-hydroxyethyl and Q is hydrogen, methyl or ethyl.

Forbindelser med formel I kan eksistere i tauto-meriske former, dvs. som 1,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-on med formel I og/eller 1-R-5-PY-6-Q-lH-pyrazolo[3,4-b]pyridin-3-ol i formel IA, noe som er vist nedenfor: Compounds of formula I may exist in tautomeric forms, i.e. as 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-1H-pyrazolo[3,4-b]pyridin-3-ol of formula IA, which is shown below:

Strukturelle preferanser for analoge kjente pyrazolo[3,4-b]pyridin-3-oner synes å indikere at den foretrukne tautomeriske struktur har formel I, dvs. at det er foretrukket å bruke navner basert på denne struktur, skjønt det er underforstått at begge strukturer inngår i foreliggende oppfinnelse. Structural preferences for analogous known pyrazolo[3,4-b]pyridin-3-ones seem to indicate that the preferred tautomeric structure has formula I, i.e. it is preferred to use names based on this structure, although it is understood that both structures are included in the present invention.

Foreliggende oppfinnelse angår også lavere alkyl-2-halogen-5-PY-6-Q-nikotinater med formel II The present invention also relates to lower alkyl-2-halo-5-PY-6-Q-nicotinates of formula II

hvor Q er hydrogen eller lavere alkyl, R<1>er lavere alkyl, where Q is hydrogen or lower alkyl, R<1> is lower alkyl,

X er klor eller brom og PY er 4- eller 3-pyridinyl eller 4-eller 3'-pyridinyl med én eller to lavere alkylsubstituenter, eller syreaddisjonssalter av slike forbindelser. Forbindelser med formel II og deres salter kan brukes som kardiotoniske midler slik dette kan bestemmes ved standard farmakologiske prøver. Foretrukne forbindelser er de med formel II hvor PY er 4-pyridinyl eller 3-pyridinyl, Q er metyl eller etyl, X er klor og R' er metyl eller etyl. Forbindelser med formel II kan også brukes som mellomprodukter for fremstilling av l,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-oner med formel (I). X is chlorine or bromine and PY is 4- or 3-pyridinyl or 4- or 3'-pyridinyl with one or two lower alkyl substituents, or acid addition salts of such compounds. Compounds of formula II and their salts can be used as cardiotonic agents as determined by standard pharmacological tests. Preferred compounds are those of formula II where PY is 4-pyridinyl or 3-pyridinyl, Q is methyl or ethyl, X is chlorine and R' is methyl or ethyl. Compounds of formula II can also be used as intermediates for the preparation of 1,2-dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-ones of formula (I).

Man kan fremstille nevnte 1,2-dihdryo-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-on med formel I ved hjelp Said 1,2-dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-one of formula I can be prepared using

av en fremgangsmåte hvor man reagerer et lavere alkyl-2-halogen-5-PY-6-Q-nikotinat (II) med et 1-R-hydrazin (III), hvor PY, R og Q har samme betydning som angitt ovenfor for forbindelser med formel I, og halogen er klor eller brom, fortrinnsvis klor. of a process in which a lower alkyl-2-halo-5-PY-6-Q-nicotinate (II) is reacted with a 1-R-hydrazine (III), where PY, R and Q have the same meaning as stated above for compounds of formula I, and halogen is chlorine or bromine, preferably chlorine.

Man kan fremstille nevnte lavere alkyl-2-halogen-6-Q-5-PY-nikotinat med formel II ved hjelp av en fremgangsmåte hvor man hydrolyserer et 1,2-dihydro-6-Q-2-okso-5-PY-nikotinonitril slik at man får fremstilt en 1,2-dihydro-6-Q-2-okso-5-PY-nikotinsyre, hvoretter denne reagerer med et uorganisk halogeneringsmiddel til et 2-halogen-6-Q-5-PY-nikotinoylhalogenid som deretter reageres med en lavere alkanol til et lavere alkyl-2-halogen-6-Q-5-PY-nikotinat hvor halogen er klor eller brom og PY er som definert i formel II ovenfor. Foretrukne utførelser av denne fremgangsmåte er de som gir de ovenfor nevnte foretrukne forbindelser med formel II, og hvor halogen er klor og den nevnte lavere al-kyldelen av den resulterende ester er metyl eller etyl. Said lower alkyl-2-halo-6-Q-5-PY-nicotinate of formula II can be prepared by means of a method in which a 1,2-dihydro-6-Q-2-oxo-5-PY- nicotinonitrile so that a 1,2-dihydro-6-Q-2-oxo-5-PY-nicotinic acid is produced, after which this reacts with an inorganic halogenating agent to a 2-halo-6-Q-5-PY-nicotinoyl halide which then react with a lower alkanol to a lower alkyl-2-halo-6-Q-5-PY-nicotinate where halogen is chlorine or bromine and PY is as defined in formula II above. Preferred embodiments of this method are those which give the above-mentioned preferred compounds of formula II, and where halogen is chlorine and the mentioned lower alkyl portion of the resulting ester is methyl or ethyl.

En kardiotonisk sammensetning for å øke hjertets kontraktilitet består av et farmasøytisk akseptabelt bære-, stoff og som en aktiv komponent en effektiv mengde av et kardiotonisk 1,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]-pyridin-3-on med formel I eller et lavere alkyl-2-halogen-5-PY-6-Q-nikotinat med formel II eller et farmasøytisk akseptabelt syreaddisjonssalt av slike forbindelser. A cardiotonic composition for increasing cardiac contractility comprises a pharmaceutically acceptable carrier and as an active component an effective amount of a cardiotonic 1,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3, 4-b]-pyridin-3-one of formula I or a lower alkyl-2-halo-5-PY-6-Q-nicotinate of formula II or a pharmaceutically acceptable acid addition salt of such compounds.

Man kan øke hjertets kontraktilitet i en pasient hvor en slik behandling er ønskelig eller nødvendig, ved at nevnte pasient oralt eller parenteralt i en fast eller flytende doseringsform tilføres en effektiv mengde av et kardiotonisk 1,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-on med formel I eller et lavere alkyl-2-halogen-5-PY-6-Q-nikotinat med formel II eller et farmasøytisk.akseptabelt syreaddisjonssalt av en slik forbindelse. One can increase the contractility of the heart in a patient where such treatment is desirable or necessary, by said patient being administered orally or parenterally in a solid or liquid dosage form an effective amount of a cardiotonic 1,2-dihydro-l-R-5-PY-6 -Q-3H-pyrazolo[3,4-b]pyridin-3-one of formula I or a lower alkyl-2-halo-5-PY-6-Q-nicotinate of formula II or a pharmaceutically acceptable acid addition salt of a such connection.

Med begrepet "lavere alkyl" slik det brukes her, f.eks. i forbindelse med betydningen av symbolene R eller Q eller som substituent i PY i formel I eller II eller som nevnte lavere alkylgruppe i det intermediære lavere alkyl-2-. halogen-5-PY-6-Q-nikotinat (II) , forstås alkylradikaler med fra 1-6 karbonatomer som kan være i rette eller grenede kjeder, f.eks. metyl, etyl, n-propyl, isopropyl, n-butyl, sek.-butyl, tert.-butyl, isobutyl, n-amyl, n-heksyl o-l. With the term "lower alkyl" as used herein, e.g. in connection with the meaning of the symbols R or Q or as a substituent in PY in formula I or II or as said lower alkyl group in the intermediate lower alkyl-2-. halogen-5-PY-6-Q-nicotinate (II) , is understood as alkyl radicals with from 1-6 carbon atoms which can be in straight or branched chains, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-amyl, n-hexyl o-l.

Illustrerende eksempler på PY i formel I eller II hvor PY er 4-, 3- eller 2-pyridinyl med 1 eller 2 lavere alkylsubstituenter, er følgende_ 2-metyl-4-pyridinyl, 2,6-dimetyl-4-pyridinyl, 3-metyl-4-pyridinyl, 2-metyl-3-pyridinyl, 6-metyl-3-pyridinyl (alternativt kalt 2-metyl-5-pyridinyl), 2,3-dimetyl-4-pyridinyl, 2,6-dimetyl-4-pyridinyl, 2-etyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-heksyl-4-pyridinyl, 2,6-dietyl-4-pyridinyl, 2,6-dietyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-di-n-heksyl-4-pyridinyl o.l. Illustrative examples of PY in formula I or II where PY is 4-, 3- or 2-pyridinyl with 1 or 2 lower alkyl substituents are the following_ 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3- methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively called 2-methyl-5-pyridinyl), 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4 -pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2 ,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, etc.

Med begrepet "lavere hydroksyalkyl" slik det brukes her, f.eks. i forbindelse med symbolet R i formel I, forstås hydroksyalkylradikaler med fra 2-6 karbonatomer i rette eller grenede kjeder, og hvor det er minst 2 karbonatomer som skiller hydroksygruppen og 1-ringnitrogenatomet i pyrazolo[3,4-b]pyridinringen, og som eksempler kan nevnes 2-hydroksyetyl, 3-hydroksypropyl, 2-hydroksypropyl, 4-hydroksybutyl, 3-hydroksybutyl, 5-hydroksyamyl, 6-hydroksyheksyl o.l. With the term "lower hydroxyalkyl" as used herein, e.g. in connection with the symbol R in formula I, hydroxyalkyl radicals with from 2-6 carbon atoms in straight or branched chains are understood, and where there are at least 2 carbon atoms separating the hydroxy group and the 1-ring nitrogen atom in the pyrazolo[3,4-b]pyridine ring, and which examples can be mentioned 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl and the like.

Med begrepet "lavere alkoksyalkyl" slik det brukes her, f.eks. i forbindelse med betydningen av symbolet R i formel I, forstås alkoksyalkylradikaler med fra 3-6 karbonatomer som kan være i rette eller grenede kjeder og hvor det er minst to karbonatomer som skiller oksygenatomet i alkok-syalkylgruppen og 1-ringnitrogenatomet i pyrazolo[3,4-b]-pyridinringen og som eksempler kan man nevne 2-metoksyetyl, 2-etoksyetyl, 3-metoksypropyl, 2-metoksypropyl, 2-metoksy-butyl, 4-etoksybutyl, 3-etoksypropyl, 3-n-propoksypropyl o.l. With the term "lower alkoxyalkyl" as used herein, e.g. in connection with the meaning of the symbol R in formula I, alkoxyalkyl radicals are understood with from 3-6 carbon atoms which can be in straight or branched chains and where there are at least two carbon atoms separating the oxygen atom in the alkoxyalkyl group and the 1-ring nitrogen atom in pyrazolo[3, the 4-b]-pyridine ring and as examples one can mention 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxy-butyl, 4-ethoxybutyl, 3-ethoxypropyl, 3-n-propoxypropyl etc.

Forbindelser med formel I og II kan.brukes både i form av den frie basen eller i form av syreaddisjonssalter, og begge former ligger innenfor oppfinnelsen. Syreaddi-sjonssaltene er ofte mer hensiktsmessige i form i praksis, Compounds of formula I and II can be used both in the form of the free base or in the form of acid addition salts, and both forms are within the scope of the invention. The acid addition salts are often more appropriate in form in practice,

og bruken av saltet vil i praksis gi samme effekt som den frie basen. Syrer som kan brukes for fremstilling av syre-addis jonssalter innbefatter fortrinnsvis de som kombinert med den frie basen gir farmasøytisk akseptable salter, dvs. salter som er relativt ufarlige og uskadelige i dyreorga-nismen i farmasøytiske doser av saltet, slik at de fordel-aktige kardiotoniske egenskaper som forefinnes i den frie basen (I eller II) ikke svekkes av sideeffekter som kan til-skrives anionene. I gjennomføring av oppfinnelsen kan det imidlertid ofte være hensiktsmessig å bruke den frie base-formen, men man kan også bruke farmasøytisk akseptable salter, f.eks. fremstilt ved hjelp av mineralsyrer såsom salt-syre, svovelsyre og sulfaminsyre, eller organiske syrer såsom eddiksyre, sitronsyre, melkesyre, tartarsyre, metansul-fonsyre, etansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, cykloheksylsulfaminsyre, kininsyre o.l., hvorved man får fremstilt hydrokloridet, sulfatet, fosfatet, sulfamatet, acetatet, citratet, laktatet, tartratet, metansulfonatet, etansulfo-natet, benzensulfonatet, cykloheksylsulfamatet og kinatet, henholdsvis. and the use of the salt will in practice give the same effect as the free base. Acids which can be used for the production of acid addition salts preferably include those which, combined with the free base, give pharmaceutically acceptable salts, i.e. salts which are relatively harmless and innocuous in the animal organism in pharmaceutical doses of the salt, so that the beneficial cardiotonic properties found in the free base (I or II) are not impaired by side effects attributable to the anions. In implementing the invention, however, it can often be appropriate to use the free base form, but you can also use pharmaceutically acceptable salts, e.g. produced using mineral acids such as hydrochloric acid, sulfuric acid and sulfamic acid, or 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 etc., whereby the hydrochloride, sulfate is produced , the phosphate, the sulfamate, the acetate, the citrate, the lactate, the tartrate, the methanesulfonate, the ethanesulfonate, the benzenesulfonate, the cyclohexylsulfamate and the quinate, respectively.

Syreaddisjonssalter av den basiske forbindelsen Acid addition salts of the basic compound

(i og II) kan fremstilles enten ved at man oppløser den frie basen i en vandig eller vandig-alkolisk oppløsning eller et annet egnet oppløsningsmiddel som inneholder nevnte passende syre, hvoretter man isolerer saltet ved å fordampe oppløs-ningen, eller ved at man reagerer den frie basen og syren i et organisk oppløsningsmiddel, og i et slikt .tilfelle kan saltet skilles direkte ut eller kan oppnås ved at man konsen- (i and II) can be prepared either by dissolving the free base in an aqueous or aqueous-alcoholic solution or another suitable solvent containing said suitable acid, after which the salt is isolated by evaporating the solution, or by reacting the free base and the acid in an organic solvent, and in such a case the salt can be separated directly or can be obtained by concentrating

trerer oppløsningen. changes the solution.

Skjønt farmasøytisk akseptable salter av nevnte basiske forbindelse er foretrukket, så ligger alle syreaddisjonssalter innenfor oppfinnelsen. Alle typer syreaddisjonssalter kan brukes som utgangspunkt for fremstilling av den frie basen, enten det spesielle saltet som sådant bare er ønskelig som et intermediært produkt, f.eks. når man ønsker å fremstille saltet for å rense eller identifisere forbindelsen, eller når nevnte salt brukes som et mellomprodukt for fremstilling av et farmasøytisk akseptabelt salt ved en ione-utbytning. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are within the scope of the invention. All types of acid addition salts can be used as a starting point for the preparation of the free base, whether the particular salt as such is only desirable as an intermediate product, e.g. when one wishes to prepare the salt to purify or identify the compound, or when said salt is used as an intermediate for the preparation of a pharmaceutically acceptable salt by ion exchange.

Molekylstrukturen på forbindelser med formel I eller TI ble fastslått på basis av infrarødt spektrum, kjerne-magnetrisk resonansspektra og massespektra, og ved en over-ensstemmelse mellom beregnede og fundne verdier i elemen-tæranalyser. The molecular structure of compounds of formula I or TI was established on the basis of infrared spectrum, nuclear magnetic resonance spectra and mass spectra, and by an agreement between calculated and found values in elemental analyses.

Fremgangsmåten for fremstilling av de foreliggende forbindelser vil nå bli mer detaljert beskrevet. The process for producing the present compounds will now be described in more detail.

Fremstillingen av 1,2-dihydro-l-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-on.(I) ved at man reagerer et lavere alkyl-2-halogen-5-PY-6-Q-nikotinat (II) med et 1-R-hydrazin (III) utføres ved at man oppvarmer reaktantene i et egnet oppløsningsmiddel ved fra 50 - 100°C, fortrinnsvis mellom 65 og 85°C. Reaksjonen utføres hensiktsmessig ved at man koker reaktantene under tilbakeløp i en lavere alkanol, fortrinnsvis metanol eller etanol. The preparation of 1,2-dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-one.(I) by reacting a lower alkyl-2-halo-5 -PY-6-Q-nicotinate (II) with a 1-R-hydrazine (III) is carried out by heating the reactants in a suitable solvent at from 50 - 100°C, preferably between 65 and 85°C. The reaction is suitably carried out by boiling the reactants under reflux in a lower alkanol, preferably methanol or ethanol.

Nevnte lavere alkyl-2-halogen-5-PY-6-Q-nikotinat kan lett fremstilles ved at man reagerer 1,2-dihydro-2-okso-5-PY-6-Q-nikotinsyre med et overskudd av fosforoksyklorid, fortrinnsvis med en katalytisk mengde dimetylformamid, hvorved man får fremstilt 2-klor-5-PY-6-Q<1->nikotinoylklorid som deretter reageres med lavere alkanol. Reaksjonen utføres hensiktsmessig ved at man oppvarmer reaktantene på et dampbad. Andre egnede oppløsningsmidler innbefatter acetonitril, dioksan og lignende. Andre egnede uorganiske halogenerings-midler innbefatter PCl^/PBr3 °<3 PC^-^ • Said lower alkyl 2-halo-5-PY-6-Q-nicotinate can be easily prepared by reacting 1,2-dihydro-2-oxo-5-PY-6-Q-nicotinic acid with an excess of phosphorus oxychloride, preferably with a catalytic amount of dimethylformamide, whereby 2-chloro-5-PY-6-Q<1->nicotinoyl chloride is produced, which is then reacted with lower alkanol. The reaction is conveniently carried out by heating the reactants in a steam bath. Other suitable solvents include acetonitrile, dioxane and the like. Other suitable inorganic halogenating agents include PCl^/PBr3 °<3 PC^-^ •

Fremstillingen av de kjente 1,2-dihydro-2-okso-5- The preparation of the known 1,2-dihydro-2-oxo-5-

PY-nikotinsyrer ved hydrolyse av de tilsvarende 1,2-dihydro-2-okso-5-PY-nikotinonitriler er vist i US-PS 4.004.012. PY-nicotinic acids by hydrolysis of the corresponding 1,2-dihydro-2-oxo-5-PY-nicotinonitriles are shown in US-PS 4,004,012.

Hydrolysen av 1,2-dihydro-6-(lavere alkyl)-2-okso-5-PY-niktinonitril for å fremstille 1,2-dihydro-6-(lavere alkyl)-2-okso-5-PY-nikotinsyre, kan hensiktsmessig utføres ved at man oppvarmer nitrilet på et dampbad mqd en vandig mineralsyre, f.eks. 50% svovelsyre, noe som er illustrert i den nedenfor nevnte patentsøknad. The hydrolysis of 1,2-dihydro-6-(lower alkyl)-2-oxo-5-PY-nictinonitrile to produce 1,2-dihydro-6-(lower alkyl)-2-oxo-5-PY-nicotinic acid, can conveniently be carried out by heating the nitrile on a steam bath mqd an aqueous mineral acid, e.g. 50% sulfuric acid, which is illustrated in the patent application mentioned below.

De intermediære 1,2-dihydro-2-okso-5-PY-6-(lavere alkyl)-nikotinonitriler fremstilles ved en fremgangsmåte som er beskrevet i de etterfølgende tre avsnitt og beskrevet i den verserende patentsøknad nr. 803550 innsendt 25.11.1980. The intermediate 1,2-dihydro-2-oxo-5-PY-6-(lower alkyl)-nicotinonitriles are prepared by a method which is described in the following three paragraphs and described in the pending patent application No. 803550 submitted on 25/11/1980.

Fremstillingen av l-PY-2-(dimetylamino)etenyl-lavere alkylketon ved at man reagerer PY-metyl-lavere alkylketon med dimetylformamid-di- (lavere alkyl) acetal* utføres ved at man blander reaktantene i nærvær eller fravær av et egnet oppløsningsmiddel. Reaksjonen utføres hensiktsmessig ved romtemperatur, dvs. fra 2 0 - 25°C, eller ved at man oppvarmer reaktantene til ca. 100°C, fortrinnsvis i et aprotisk opp-løsningsmiddel, hensiktsmessig heksametylfosforamid på grunn av den fremgangsmåte som brukes for å fremstille PY-metyl-lavere alkylketon slik dette er angitt i eksempel C-l. Andre egnede oppløsningsmidler innbefatter tetrahydrofuran, dimetylformamid, acetonitril, eter, benzen, dioksan o.l. Videre kan reaksjonen utføres uten noe oppløsningsmiddel, da fortrinnsvis ved at man bruker et overskudd av dimetylformamid-di-(lavere alkyl)acetal. ;De nevnte intermediære PY-metyl-lavere alkylketoner er generelt kjente forbindelser og kan fremstilles ved hjelp av kjente fremgnagsmåter [f.eks. slik det er angitt i Ree. trav. chim. 72, 522 (1953), US-PS 3.133.077 (5-12-64), Bull. Soc- Chim. France 1968, 4132, Chem. Abstrs. 79, 8539h (1973), Chem. Abstrs. 81, 12,401a (1974), J. Org. Chem. 39, 3834 ;(1974), Chem. Abstrs. 87, 6594q (1977), J. Org. Chem. 43 2286 ;(1978)]. ;Reaksjonen mellom et l-PY-2-(dimetylamino)etenyl-lavere alkylketon og et a-cyanoacetamid for fremstilling av 1,2-dihydro-2-okso-5-PY-6-R-nikotinonitril, utføres hensiktsmessig ved at man oppvarmer reaktantene i et egnet oppløs-ningsmiddel i nærvær av et basisk kondensasjonsmiddel. Reaksjonen kan hensiktsmessig utføres i et alkali-lavere alk-oksyd, fortrinnsvis natriummetoksyd eller -etoksyd, i di-metylf ormamid. Ved gjénnomf øring av oppfinnelsen ble "-reaksjonen utført i kokende dimetylformamid idet man brukte natriummetoksyd. Alternativt kan man bruke metanol og natriummetoksyd eller etanol og natriumetoksyd som oppløsnings-midlet og det basiske kondensasjonsmiddel, henholdsvis, men ;i dette tilfelle vil man imidlertid trenge en lengre reak-sjonsperiode. Andre basiske kondensasjonsmidler og oppløs-ningsmidler innbefatter natriumhydrid, litiumdietylamid, li-tiumdiisopropylamid o.l., i et aprotisk oppløsningsmiddel såsom tetrahydrofuran, acetonitril, eter, benzen, dioksan og lignende. ;De følgende eksempler illustrerer oppfinnelsen. ;A. Lavere alkyl- 2- halogen- 5- PY- 6- Q- nikotinater ;A-I. Metyl- 2- klor- 5-( 4- pyridinyl) nikotinat ;En suspensjon inneholdende 54 g 1,2-dihydro-2-okso-5-(4-pyridinyl)nikotinsyre, 500 ml fosforoksyklorid og 10 dråper dimetylformamid ble holdt på et dampbad i 4,5 timer og hydrogenklorid utviklet seg. og mesteparten av de faste stoffer løste seg. Reaksjonsblandingen ble hensatt over natten ved romtemperatur, og ble så filtrert gjennom dia-tomerjord for å fjerne en mindre mengde av et gult fast stoff. Overskuddet av fosforoksyklorid i filtratet ble av-destillert i vakuum, og det sirupaktige residuum ble avkjølt. Det ble så tilsatt 500 ml absolutt metanol og blandingen ble ristet under periodevis avkjøling med isbad, og nevnte sirup løste seg langsomt og man fikk dannet et hvitt fast stoff. Blandingen ble så avkjølt på et isbad og det faste stoff ble frafiltrert og lufttørket. Det veide 44,7 g og et smeltepunkt med dekomponering på 2 95 - 300°C, og det ble oppløst i 500 ml vann og oppløsningen ble så filtrert. Filtratet ble gjort basisk til pH 8,0 med 3N ammoniumhydroksydoppløsning (ca. 7 0 ml var nødvendig). Man fikk et iøynefallende blek- gult faststoff som ble frafiltrert, vasket med vann og luft-tørket. Det ble så oppløst i 400 ml metylendiklorid og man fikk utskilt et lite vannlag. Metylendikloridlaget ble utskilt, vasket med vann og tørket over vannfritt magnesium-sulfat og så fordampet til tørrhet i et roterende fordampningsapparat, hvorved man fikk 35,6 g av et lyst gult fast stoff, smeltepunkt 110 - 112°C. En del av dette produkt, dvs. metyl-2-klor-5-(4-pyridinyl)nikotinat ble omkrystallisert fra 50 ml acetonitril, lufttørket og så tørket i en vakuumovn ved 6 0°C i 6 timer, hvorved man fikk 6,7 g produkt med et smeltepunkt på 112,5 - 113°C. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel A-I, men istedenfor 1,2-dihydro-2-okso-5-(4-pyridinyl ) nikotinsyre og metanol, bruke molare ekvivalente mengder av en passende 1,2-dihydro-2-okso-5-PY-nikotinsyre og en lavere alkanol, henholdsvis, kan man fremstille de tilsvarende lavere alkyl-2-klor-5-PY-nikotinater som er angitt i eksemplene A-2 til A-7 nedenfor. ;A-2. Etyl-2-klor-5-(3-pyridinyl)nikotinat. ;A-3. n-propyl-2-klor-5-(2-metyl-3-pyridinyl)-nikotinat. ;A-4. Isopropyl-2-klor-5-(5-metyl-3-pyridinyl)-nikotinat. ;A-5. n-butyl-2-klor-5-(3-etyl-4-pyridinyl)nikotinat. ;A-6. n-heksyl-2-klor-5-(2-metyl-4-pyridinyl)nikotinat. ;A-7. Metyl-2-klor-5-(2,6-dimetyl-4-pyridinyl)-nikotinat. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel A-I, men istedenfor fosforoksyklorid eller nevnte lavere alkanol, bruke molare ekvivalente mengder av et passende halogeneringsmiddel og en lavere alkanol, henholdsvis, kan man fremstille de angitte lavere alkyl-2-halogen-5-(4-pyridinyl)nikotinater som er nevnt i eksemplene A-8 eller A-9 nedenfor. ;A-8. Metyl-2-brom-5-(4-pyridinyl)nikotinat ved at man brukte fosfortribromid eller fosforoksybromid og absolutt metanol. ;A-9. Etyl-2-klor-5-(4-pyridinyl)nikotinat ved ;å bruke fosfortriklorid, fosforpentaklorid eller sulfuryl-klorid og absolutt etanol. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel A-I, men istedenfor 1,2-dihydro-2-okso-5-(4-pyridinyl ) nikotinsyre , bruke en molar ekvivalent mengde av en passende 1,2-dihydro-2-okso-5-PY-6-(lavere alkyl)nikotin-syre og enten metanol eller en molar ekvivalent mengde av en passende lavere alkanol, kan man fremstille de tilsvarende lavere alkyl-2-klor-5-PY-6-(lavere alkyl)nikotinater som er nevnt i eksemplene A-10 til A-20 nedenfor. ;A-10. Metyl-2-klor-6-metyl-5-(4-pyridinyl)nikotinat . ;A-ll. Etyl-2-klor-6-etyl-5-(3-pyridinyl)nikotinat. ;A-12. Metyl-2-klor-6-metyl-5-(3-pyridinyl)nikotinat. ;A—13. Metyl-2-klor-6-n-propyl-5-(4-pyridinyl)-nikotinat. ;A-i-14 .. Etyl-2-klor-6-isopropyl-5- (4-pyridinyl)nikotinat. ;A-15. Metyl-6-n-butyl-2-klor-5-(4-pyridinyl)nikotinat . ;A-16. Metyl-2-klor-6-isobutyl-5-(4-pyridinyl)nikotinat. ;A-17. Etyl-2-klor-5-(4-pyridinyl)-6.tert.butyl-nikotinat. ;A-I8. Metyl-2-klor-6-n-pentyl-5-(4-pyridinyl)nikotinat. ;A-19. n-butyl-2-klor-6-etyl-5-(2-metyl)-4-pyridinyl )nikotinat. ;A-20. Isopropyl-2-klor-6-etyl-5-(3-pyridinyl)nikotinat. ;A-21. Etyl-2-klor-6-metyl-5-(4-pyridinyl)nikotinat , smeltepunkt 105 - 106,5°C. (Viste seg å være inaktiv som kardiotonisk middel). ;B. 1, 2- dihydro- 5-( pyridinyl)- 3H- pyrazolo[ 3, 4- b] pyridin- 3- oner B-l. 1, 2- dihydro- l- metyl- 5-( 4- pyridinyl)- 3H- pyrazolo[ 3, 4- b] pyridin- 3- on ;En oppløsning inneholdende 4,2 g metyl-2-klor-5-(4-pyridinyl)nikotinat, 5 ml 1,1-dimetylhydrazin og 50 ml metanol ble kokt under tilbakeløp og røring i 20 timer, hvoretter blandingen ble avkjølt, og det faste stoff frafiltrert, vasket med etanol og tørket ved 90°C. Man fikk derved fremstilt 1,7 g 1,2-dihydro-l-metyl-5-(4-pyridinyl)-3H-pyrazolo-[3,4-b]pyridin-3-on. Nevnte 1,7 g ble slått sammen med 4,3 gram og 1,4 g av tidligere fremstilte produkter, og det samlede produkt ble omkrystallisert fra 3 0 ml dimetylformamid og tørket i-en vakuumovn ved 90°C, hvorved man fikk 4,7 g 1,2-dihydro-l-metyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on, smeltepunkt 2 65 - 267°C. ;Ovennevnte syntese ble fortrinnsvis utført ved å bruke 1-metylhydrazin istedenfor 1,1-dimetylhydrazin på følgende måte: En rørt varm oppløsning av 5,0 g metyl-2-klor-5-(4-pyridinyl)nikotinat i 40 ml metanol ble tilsatt 5 ml 1-metylhydrazin og reaksjonsblandingen ble kokt ved tilbakeløp i 18 timer. Den inneholdt da en mindre mengde fast stoff og ble avkjølt. Ettersom man da bare fikk utskilt små mengder fast stoff, ble oppløsningsmidlet fjernet i et roterende fordampningsapparat. Det gjenværende faste gule stoff ble frafiltrert, vasket med vann og tørket i en vakuumovn ved 90°C til 4,3 g 1,2-dihydro-l-metyl-5-(4-pyridinyl ) -3H-pyrazolo [ 3 , 4 -b] pyridin-3-on, smeltepunkt 263 - 265°C. ;Som en sammenligning fremstilte man den følgende forbindelsen som skiller seg strukturet fra forbindelsen fra eksempel B-l ved at der var ingen 1-substituent (forskjellig fra hydrogen), mens man i eksempel B-l hadde en metylgruppe. Denne forbindelsen ble fremstilt på følgende måte: En opp-løsning inneholdende 16,6 g metyl-2-klor-5-(4-pyridinyl)-nikotinat, 19 ml hydrazinhydrat og 150 ml metanol ble kokt under tilbakeløp på et dampbad i 19 timer, hvoretter blandingen inneholdende et gult fast stoff ble avkjølt i is og det faste stoffet frafiltrert. Det ble lufttørket, og 11,2 g produkt ble slått sammen med 1,6 g fra et tidligere forsøk, og det samlede produkt ble omkrystallisert fra 440 ml dimetylformamid, vasket med eter og tørket i en vakuumovn ved 95°C, noe som ga 9,5 g 1,2-dihydro-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on, smeltepunkt over 300?C. I motsetning til den kardiotonisk aktive forbindelsen fra eksempel B-l, så det viste det seg at denne 1-usubstituerte forbindelsen var inaktiv når den ble undersøkt i en in vitro-kardiotonisk prøve på et katteatrium. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel B-l, men istedenfor 1,1-dimetylhydrazin eller 1-metylhydrazin, bruke en molar ekvivalent mengde av et passende 1-R-hydrazin, kan man få fremstilt de tilsvarende 1,2-dihydro-l-R-5-(4-pyridinyl)3H-pyrazolo[3,4-b]pyridin-3-oner som er nevnt i eksempel B-2 til B-13 nedenfor. ;B-2. 1,2-dihydro-l-(2-metoksypropyl)-5-(4-pyridinyl )-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-3. 1,2-dihydro-l-etyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved jå bruke 1-etylhydrazin. ;B-4. 1,2-dihydro-l-n-propyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-n-propylhydrazin. ;B-5. 1,2-dihydro-l-isopropyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-isopropylhydrazin. ;B-6. 1,2-dihydro-l-n-butyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-n-butylhydrazin. ;B-7. 1,2-dihydro-l-isobutyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-isobutylhydrazin. ;B-8. 1,2-dihydro-l-(2-butyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-(2-butyl)hydrazin. ;B-9. 1,2-dihydro-l-(n-amyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-(n-amyl)hydrazin. ;B-10. 1,2-dihydro-l-(n-heksyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-(n-heksyl)hydrazin. ;B-ll. 1,2-dihydro-l-(2-etoksyetyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved å bruke 1-(2-etoksyetyl)-hydrazin. ;B-12. 1,2-dihydro-l-(2-metoksyetyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ved bruke 1-(2-metoksyetyl)-hydrazin. ;B-13. 1,2-dihydro-l-(3-metoksypropyl)-5-(4-pyridinyl ) -3H-pyrazolo [ 3 , 4-b] pyridin-3-on ved å bruke l-(3-met-oksypropy1)hydrazin. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel B-l, men istedenfor metyl-2-klor-5-(4-pyridinyl)-nikotinat og 1,1-dimetylhydrazin eller 1-metylhydrazin henholdsvis, bruke en molar ekvivalent mengde av et passende metyl-eller annet lavere alkyl-2-klor-5-PY-nikotinat og 1-R-hydrazin, kan man fremstille de tilsvarende 1,2-dihydro-l-R-5-PY-3H-pyrazolo[3,4-b]pyridin-3-oner som er nevnt i eksemplene B-lr til B-19. ;B-14. 1,2-dihydro-l-metyl-5-(3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-15. 1,2-dihydro-5-(2-metyl-3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-16. 1,2-dihydro-l-etyl-5-(5-metyl-3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-17. 1,2-dihydro-l-metyl-5-(3-etyl-4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-18. 1,2-dihydro-l-(2-metoksyetyl)-5-(2-metyl-4-pyridiny1)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-19. 1,2-dihydro-l-metyl-5-(2,6-dimetyl-4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel B-l, men istedenfor metyl-2-klor-5-(4-pyridinyl)-nikotinat og 1,1-dimetylhydrazin eller 1-metylhydrazin, bruke molare ekvivalente mengder av et passende metyl- eller annet lavere alkyl-2-klor-5-PY-nikotinat og 1-(lavere hydroksyalkyl)-hydrazin, kan man få fremstilt de tilsvarende 1,2-dihydrq-3-okso-5-PY-3H-pyrazolo[3,4-b]pyridin-1-(lavere alkanoler) som er nevnt i eksemplene B-20 til B-27. ;B-20 1,2-dihydro-3-okso-5-(3-pyridinyl)-3H)-pyrazolo[3,4-b]pyridin-l-etanol. ;B-21. 1,2-dihydro-3-okso-5-(2-metyl-3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;B-22. 1,2-dihydro-3-okso-5-(5-mety1-3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-1-(n-propanol). ;B-23 . 1, 2-dihydro-3-okso-5- (4-pyridinyl) -3H-pyrazolo[3,4-b]pyridin-1-(2-propanol). ;B-24. 1,2-dihydro-3-okso-5-(3-etyl-4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-1-(2-butanol). ;B-25. 1, 2-dihydro-3-okso-5-(2-metyl-4-pyridinyl) - 3H-pyrazolo[3,4-b]pyridin-l-etanol. ;B-26. l,2-dihydro-3-okso-5-(2,6-dimetyl-4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;B-27. 1,2-dihydro-3-okso-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel B-l, men istedenfor metyl-2-klor-5-(4-pyridinyl)-nikotinat og 1,1-dimetylhydrazin eller 1-metylhydrazin, bruke molare ekvivalente mengder av et passende metyl- eller annet lavere alkyl-2-klor-5-PY-6-(lavere alkyl)nikotinat og/eller 1-R-hydrazin, henholdsvis, kan man få fremstilt de tilsvarende 1,2-dihydro-l-R-5-PY-6-Q-lH-pyrazolo[3,4-b]-pyridin-3-oner som er nevnt i eksemplene B-28 til B-41. ;B-28. 1,2-dihydro-l,6-dimetyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B.29. 6-etyl-l,2-dihydro-l-metyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B.30. 1,2-dihydro-6-metyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B.31. 1-etyl-l,2-dihydro-6-metyl-5-(3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B.32. 1,2-dihydro-6-metyl-3-okso-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;B.33. 1,2-dihydro-6-metyl-3-okso-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;B.34. 1,2-dihydro-l-metyl-6-n-propyl-5-(4-pyridinyl )-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-35. 1,2-dihydro-6-isopropyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-36. 6-n-butyl-l,2-dihydro-l-metyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-37. l,2-dihydro-6-isobutyl-3-okso-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;B-38. l,2-dihydro-5-(4-pyridinyl)-6-tert.butyl-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-39. 1,2-dihydro-l-metyl-6-n-pentyl-5-(4-pyridinyl )-3H-pyrazolo[3,4-b]pyridin-3-on. ;B-4 0. 1,6-dietyl-l,2-dihydro-5-(2-mety1-4-pyridinyl) -3H-pyrazolo[3,4-b]pyridin-3-on. ;B-41. 6-etyl-l,2-dihydro-3-okso-5-(3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-l-etanol. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel B-20, men istedenfor 1-(2-hydroksyetyl)hydrazin, bruke en tilsvarende ekvivalent mengde av 1-(2,3-dihydroksypropyl)hydrazin og enten metyl-2-klor-5-(4-pyridinyl)nikotinat eller en tilsvarende molar ekvivalent mengde av en passende metyl- eller lavere alkyl-2-klor-5-PY-6-Q-nikotinat, kan man få fremstilt de tilsvarende 1,2-dihydro-l-(2,3-dihydroksypropyl)-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-oner som er nevnt i eksemplene B-42 til B-44. ;B-42. 1,2-dihydro-l-(2,3-dihydroksypropyl)-5-(4-pyridinyl)-lH-pyrazolo[3,4-b]pyridin-3-on. ;B-4 3. 1,2-dihydro-l-(2,3-dihydroksypropyl)-6-metyl-5-(4-pyridinyl)-lH-pyrazolo[3,4-b]pyridin-3-on. ;B-44. 1,2-dihydro-l-(2,3-dihydroksypropyl)-5-(3-pyridinyl)-lH-pyrazolo[3,4-b]pyridin-3-on. ;Anvendbarheten av forbindelser med formel I eller II eller deres salter som kardiotoniske midler ble vist ved deres effektivitet i standard farmakologiske prøver, f.eks. ved at de ga en betydelig økning i den kontraktile slagkraft i isolerte katteatria og i den papillære muskel. En detaljert beskrivelse av denne prøve er beskrevet i US-PS nr. 4.072.746. ;Når de ble prøvet i nevnte isolerte katteatria eller papillære muskelprøve, så ga 1,2-dihydro-5-(pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-oner med formel I i en dose på ;100 yg/ml, en betydeligøkning, dvs. 25% eller mer i den papillære muskelkraften.:. og en betydelig økning, dvs. ca. ;25% eller mer, i den høyre hjerteforkammerslagkraften, samtidig som man fikk en lavere prosentvis økning (ca. en halv-part eller mindre av den prosentvise økningen i nevnte høyre forkammerslagkraft eller i den papillære muskelkraften) i pulsfrekvensen i høyre forkammer. Når f.eks. 1,2-dihydro-l-metyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on ble prøvet i en dose på 100 yg/ml, så ga denne en henholdsvis prosentvis økning på 23%,'42% og 12% i den papillære muskel-kraf ten, i den høyre forkammerslagkraften og i pulsfrekvensen i høyre forkammer. I motsetning til dette var 1,2-dihydro-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-on i en dose på 100 yg/ml i alt vesentlig inaktiv, dvs. at den ga tilsvarende prosentviseøkninger på bare 6%, 14% og 10%, ;dvs. i den papillære muskelkraften, i høyre forkammerslag-kraf t og i pulsøkning i høyre forkammer. ;Når de ble prøvet i nevnte isolerte katteatria og papillære muskelprøve, så ga nevnte lavere alkyl-2-halogen-5-PY-6-Q'-nikotinater i doser på 10, 30 og 100 yg/ml, en betydelig økning, dvs. mer enn 25% i den papillære muskelkraften og en betydeligøkning, dvs. 20% eller mer, i den høyre forkammerslagkraften, samtidig som man fikk en lavere prosentvisøkning (ca. 1/3 eller mindre av den prosentvise økning i høyre forkammers slagkraft eller i den papillære muskelkraften) i høyre forkammers pulsfrekvens. Når f.eks. metyl-2-klor-5-(4-pyridinyl)nikotinat ble prøvet i en dose på 10, 30 og 100 yg/ml i denne prøve, så fikk man en henholdsvis prosentvis økning i den papillære muskelkraften, i høyre forkammerslagkraften og av pulsfrekvensen i høyre forkammer på '35%, 17% og 5%; 43%, 29% og 10%; og 76%, 112% og 25%, henholdsvis. ;En kardiotonisk sammensetning for å øke hjertets kontraktilitet ifølge, foreliggende oppfinnelse innbefatter et farmasøytisk akseptabelt bærestoff og som den aktive komponent, et kardiotonisk 1,2-dihydro-5-PY-6-Q-3H-pyrazolo-[3,4-b]pyridin-3-on med formel I eller et kardiotonisk lavere alkyl-2-halogen-5-PY-6-Q-nikotinat med formel II eller et farmasøytisk akseptabelt syreaddisjonssalt av en slik forbindelse. For å øke hjertets kontraktilitet i en pasient i klinisk praksis vil nevnte.forbindelse eller et salt av denne normalt bli tilført oralt eller parenteralt i en rekke forskjellige doseringsformer. ;Faste sammensetninger for oral tilførsel innbefatter tabletter, piller, pulvere og granulater. I slike faste sammensetninger eller preparater vil minst én aktiv forbindelse være blandet med minst ett inert fortynningsmid-del som stivelse, kalsiumkarbonat, sukrose eller laktose. Nevnte sammensetninger eller preparater kan også inneholde andre stoffer enn nevnte inerte f or tynnings*midler, f.eks. smøremidler såsom magnesiumstearat,.talkum o.l. The preparation of l-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 suitably carried out at room temperature, i.e. from 20 - 25°C, or by heating the reactants to approx. 100°C, preferably in an aprotic solvent, conveniently hexamethylphosphoramide due to the procedure used to prepare the PY-methyl lower alkyl ketone as set forth in Example C-1. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane and the like. Furthermore, the reaction can be carried out without any solvent, preferably by using an excess of dimethylformamide di-(lower alkyl) acetal. The mentioned intermediate PY-methyl-lower alkyl ketones are generally known compounds and can be prepared by means of known methods [e.g. as stated in Ree. trot chim. 72, 522 (1953), US-PS 3,133,077 (5-12-64), Bull. Soc- Chim. France 1968, 4132, Chem. Abstr. 79, 8539h (1973), Chem. Abstr. 81, 12,401a (1974), J. Org. Chem. 39, 3834; (1974), Chem. Abstr. 87, 6594q (1977), J. Org. Chem. 43 2286; (1978)]. ;The reaction between a 1-PY-2-(dimethylamino)ethenyl lower alkyl ketone and an α-cyanoacetamide for the production of 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile is conveniently carried out by heats the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction can conveniently be carried out in an alkali-lower alkoxide, preferably sodium methoxide or -ethoxide, in dimethylformamide. In carrying out the invention, the reaction was carried out in boiling dimethylformamide using sodium methoxide. Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide can be used as the solvent and the basic condensing agent, respectively, but in this case, however, you will need a longer reaction period. Other basic condensing agents and solvents include 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 examples illustrate the invention. ;A. Lower alkyl- 2- halo- 5- PY- 6- Q- nicotinates ; A- I. 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 dimethylformamide were kept on a steam bath for 4.5 hours and hydrogen chloride evolved and most of the solids dissolved. The mixture was left overnight at room temperature and then filtered through diatomaceous earth to remove a small amount of a yellow solid. The excess of phosphorus oxychloride in the filtrate was distilled off in vacuo, and the syrupy residue was cooled. 500 ml of absolute methanol was then added and the mixture was shaken while periodically cooling with an ice bath, and said syrup slowly dissolved and a white solid was formed. The mixture was then cooled in an ice bath and the solid was filtered off and air dried. It weighed 44.7 g and a melting point with decomposition of 295 - 300°C and was dissolved in 500 ml of water and the solution was then filtered. The filtrate was basified to pH 8.0 with 3N ammonium hydroxide solution (about 70 ml was required). An eye-catching pale yellow solid was obtained which was filtered off, washed with water and air-dried. It was then dissolved in 400 ml of methylene dichloride and a small water layer was separated. The methylene dichloride layer was separated, washed with water and dried over anhydrous magnesium sulfate and then evaporated to dryness in a rotary evaporator to give 35.6 g of a light yellow solid, mp 110-112°C. A portion of this product, i.e. 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 give 6, 7 g of product with a melting point of 112.5 - 113°C. ;Using the procedure described in Examples A-I, but instead of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid and methanol, using molar equivalent amounts of an appropriate 1,2-dihydro-2 -oxo-5-PY-nicotinic acid and a lower alkanol, respectively, one can prepare the corresponding lower alkyl-2-chloro-5-PY-nicotinates indicated in Examples A-2 to A-7 below. 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-dimethyl-4-pyridinyl)-nicotinate. By using the method described in Example A-I, but instead of phosphorus oxychloride or said lower alkanol, using molar equivalent amounts of a suitable halogenating agent and a lower alkanol, respectively, one can prepare the indicated lower alkyl-2-halo-5- (4-pyridinyl)nicotinates mentioned in Examples A-8 or A-9 below. A-8. Methyl 2-bromo-5-(4-pyridinyl)nicotinate by using phosphorus tribromide or phosphorus oxybromide and absolute methanol. A-9. Ethyl 2-chloro-5-(4-pyridinyl)nicotinate by using phosphorus trichloride, phosphorus pentachloride or sulfuryl chloride and absolute ethanol. Using the procedure described in Example A-I, but instead of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid, use a molar equivalent amount of an appropriate 1,2-dihydro-2- oxo-5-PY-6-(lower alkyl)nicotinic acid and either methanol or a molar equivalent amount of a suitable lower alkanol, one can prepare the corresponding lower alkyl-2-chloro-5-PY-6-(lower alkyl )nicotinates mentioned in Examples A-10 to A-20 below. ;A-10. Methyl 2-chloro-6-methyl-5-(4-pyridinyl)nicotinate. ;A-ll. Ethyl 2-chloro-6-ethyl-5-(3-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-i-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-I8. 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, melting point 105 - 106.5°C. (Proved to be inactive as a cardiotonic agent). B. 1, 2-dihydro-5-(pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-ones B-1. 1, 2- dihydro-l- methyl- 5-( 4- pyridinyl)- 3H- pyrazolo[ 3, 4-b] pyridin- 3-one; A solution containing 4.2 g of methyl-2-chloro-5-( 4-pyridinyl)nicotinate, 5 ml of 1,1-dimethylhydrazine and 50 ml of methanol were refluxed and stirred for 20 hours, after which the mixture was cooled, and the solid was filtered off, washed with ethanol and dried at 90°C. 1.7 g of 1,2-dihydro-1-methyl-5-(4-pyridinyl)-3H-pyrazolo-[3,4-b]pyridin-3-one was thereby produced. Said 1.7 g was combined with 4.3 grams and 1.4 g of previously prepared products, and the combined product was recrystallized from 30 ml of dimethylformamide and dried in a vacuum oven at 90°C, thereby obtaining 4, 7 g of 1,2-dihydro-1-methyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one, melting point 2 65 - 267°C. ;The above synthesis was preferably carried out using 1-methylhydrazine instead of 1,1-dimethylhydrazine in the following manner: A stirred hot solution of 5.0 g of methyl 2-chloro-5-(4-pyridinyl)nicotinate in 40 ml of methanol was added 5 ml of 1-methylhydrazine and the reaction mixture was refluxed for 18 hours. It then contained a smaller amount of solids and was cooled. As only small amounts of solid material were separated, the solvent was removed in a rotary evaporator. The remaining solid yellow substance was filtered off, washed with water and dried in a vacuum oven at 90°C to 4.3 g of 1,2-dihydro-1-methyl-5-(4-pyridinyl)-3H-pyrazolo [ 3 , 4 -b] pyridin-3-one, melting point 263 - 265°C. As a comparison, the following compound was prepared, which differs structurally from the compound from example B-1 in that there was no 1-substituent (different from hydrogen), whereas in example B-1 there was a methyl group. This compound was prepared as follows: A solution containing 16.6 g of methyl 2-chloro-5-(4-pyridinyl)-nicotinate, 19 ml of hydrazine hydrate and 150 ml of methanol was refluxed on a steam bath for 19 hours. , after which the mixture containing a yellow solid was cooled in ice and the solid filtered off. It was air dried, and 11.2 g of product was combined with 1.6 g from a previous experiment, and the combined product was recrystallized from 440 mL of dimethylformamide, washed with ether, and dried in a vacuum oven at 95°C to give 9.5 g of 1,2-dihydro-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one, melting point above 300? C. In contrast to the cardiotonically active compound of Example B-1, this 1-unsubstituted compound was found to be inactive when tested in an in vitro cardiotonic assay on a feline atrium. By using the procedure described in example B-1, but instead of 1,1-dimethylhydrazine or 1-methylhydrazine, using a molar equivalent amount of a suitable 1-R-hydrazine, the corresponding 1,2-dihydro -1-R-5-(4-pyridinyl)3H-pyrazolo[3,4-b]pyridin-3-ones mentioned in Examples B-2 to B-13 below. 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[3,4-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-l-n-butyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one using 1-n-butylhydrazine. 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. B-9. 1,2-dihydro-1-(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-ll. 1,2-dihydro-1-(2-ethoxyethyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one using 1-(2-ethoxyethyl)-hydrazine. ;B-12. 1,2-dihydro-1-(2-methoxyethyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one using 1-(2-methoxyethyl)hydrazine. ;B-13. 1,2-dihydro-l-(3-methoxypropyl)-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one using l-(3-methoxypropyl)hydrazine . Using the procedure described in Example B-1, but instead of methyl 2-chloro-5-(4-pyridinyl)-nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine respectively, use a molar equivalent amount of an appropriate methyl or other lower alkyl-2-chloro-5-PY-nicotinate and 1-R-hydrazine, one can prepare the corresponding 1,2-dihydro-1-R-5-PY-3H-pyrazolo[3,4-b] pyridin-3-ones mentioned in Examples B-1r to B-19. ;B-14. 1,2-dihydro-1-methyl-5-(3-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one. ;B-15. 1,2-dihydro-5-(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-18. 1,2-dihydro-1-(2-methoxyethyl)-5-(2-methyl-4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one. ;B-19. 1,2-dihydro-1-methyl-5-(2,6-dimethyl-4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one. ;Using the procedure described in Example B-1, but instead of methyl 2-chloro-5-(4-pyridinyl)-nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine, using molar equivalent amounts of an appropriate methyl- or other lower alkyl-2-chloro-5-PY-nicotinate and 1-(lower hydroxyalkyl)-hydrazine, the corresponding 1,2-dihydrq-3-oxo-5-PY-3H-pyrazolo[3, 4-b]pyridine-1-(lower alkanols) mentioned in 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). ;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-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. ;B-27. 1,2-dihydro-3-oxo-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridine-1-ethanol. ;Using the procedure described in Example B-1, but instead of methyl 2-chloro-5-(4-pyridinyl)-nicotinate and 1,1-dimethylhydrazine or 1-methylhydrazine, using molar equivalent amounts of an appropriate methyl- or other lower alkyl-2-chloro-5-PY-6-(lower alkyl)nicotinate and/or 1-R-hydrazine, respectively, the corresponding 1,2-dihydro-1-R-5-PY-6 -Q-1H-pyrazolo[3,4-b]-pyridin-3-ones mentioned in Examples B-28 to B-41. B-28. 1,2-dihydro-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)-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. 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]pyridine-1-ethanol. B.34. 1,2-dihydro-1-methyl-6-n-propyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one. ;B-35. 1,2-dihydro-6-isopropyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one. 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. ;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-4 0. 1,6-diethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-3H-pyrazolo[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. ;Using the procedure described in Example B-20, but instead of 1-(2-hydroxyethyl)hydrazine, using a corresponding equivalent amount of 1-(2,3-dihydroxypropyl)hydrazine and either methyl-2-chloro- 5-(4-pyridinyl)nicotinate or a corresponding molar equivalent amount of a suitable methyl- or lower alkyl-2-chloro-5-PY-6-Q-nicotinate, the corresponding 1,2-dihydro-l -(2,3-Dihydroxypropyl)-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-ones mentioned in 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[3,4-b]pyridin-3-one. The utility of compounds of formula I or II or their salts as cardiotonic agents was demonstrated by their effectiveness in standard pharmacological tests, e.g. in that they produced a significant increase in the contractile force in isolated cat atria and in the papillary muscle. A detailed description of this sample is described in US-PS No. 4,072,746. ;When tested in said isolated cat atria or papillary muscle sample, 1,2-dihydro-5-(pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-ones of formula I at a dose of ; 100 yg/ml, a significant increase ie 25% or more in the papillary muscle force.:. and a significant increase, i.e. approx. ;25% or more, in the right atrial ventricular stroke force, while at the same time a lower percentage increase (about one-half or less of the percentage increase in said right atrial ventricular stroke force or in the papillary muscle force) was obtained in the pulse rate in the right atrium. When e.g. 1,2-dihydro-1-methyl-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one was tested at a dose of 100 µg/ml, then this gave a respectively percentage increases of 23%, 42% and 12% in the papillary muscle force, in the right atrial stroke force and in the pulse frequency in the right atrium. In contrast, 1,2-dihydro-5-(4-pyridinyl)-3H-pyrazolo[3,4-b]pyridin-3-one at a dose of 100 µg/ml was essentially inactive, i.e. that it gave corresponding percentage increases of only 6%, 14% and 10%, i.e. in the papillary muscle force, in the right atrial beat force and in the pulse increase in the right atrium. ;When tested in said isolated cat atria and papillary muscle sample, said lower alkyl-2-halo-5-PY-6-Q'-nicotinates at doses of 10, 30 and 100 µg/ml produced a significant increase, ie .more than 25% in the papillary muscle force and a significant increase, i.e. 20% or more, in the right atrial stroke force, while having a lower percentage increase (about 1/3 or less of the percentage increase in the right atrial stroke force or in the papillary muscle force) in the right atrial heart rate. When e.g. methyl-2-chloro-5-(4-pyridinyl)nicotinate was tested in a dose of 10, 30 and 100 yg/ml in this sample, and a percentage increase was obtained in the papillary muscle force, in the right atrial pulsation force and in the pulse frequency respectively in the right atrium of '35%, 17% and 5%; 43%, 29% and 10%; and 76%, 112% and 25%, respectively. A cardiotonic composition for increasing the contractility of the heart according to the present invention comprises a pharmaceutically acceptable carrier and as the active component, a cardiotonic 1,2-dihydro-5-PY-6-Q-3H-pyrazolo-[3,4-b ]pyridin-3-one of formula I or a cardiotonic lower alkyl-2-halo-5-PY-6-Q-nicotinate of formula II or a pharmaceutically acceptable acid addition salt of such a compound. In order to increase the contractility of the heart in a patient in clinical practice, said compound or a salt thereof will normally be administered orally or parenterally in a number of different dosage forms. Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions or preparations, at least one active compound will be mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. Said compositions or preparations may also contain substances other than said inert diluents, e.g. . lubricants such as magnesium stearate, talc etc.

Flytende sammensetninger for oral tilførsel innbefatter farmasøytisk akseptable emulsjoner, oppløsninger, suspensjoner, siruper etc. som inneholder inerte fortynnings-midler av den type som vanligvis brukes i den farmasøytiske industri, f.eks. vann og flytende paraffin. Foruten inerte fortynnihgsmidler kan slike sammensetninger også inneholde andre tilsetningsstoffer såsom fukte- og suspenderingsmidler, samt smaksstoffer, søtningsmidler, parfymer og konserveringsmidler. Ifølge foreliggende oppfinnelse kan sammensetninger for oral tilførsel også innbefatte kapsler av et ab-sorberbart materiale, såsom gelatin, og denne kan inneholde aktive komponenter med eller uten tilsetning av fortynnings-midler eller bærestoffer. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups etc. containing inert diluents of the type commonly used in the pharmaceutical industry, e.g. water and liquid paraffin. Besides inert diluents, such compositions may also contain other additives such as wetting and suspending agents, as well as flavourings, sweeteners, perfumes and preservatives. According to the present invention, compositions for oral administration can also include capsules of an absorbable material, such as gelatin, and this can contain active components with or without the addition of diluents or carriers.

Preparater ifølge foreliggende oppfinnelse for par-enteral tilførsel innbefatter sterile vandige, vandig-organiske og organiske oppløsninger, suspensjoner og emulsjoner. Eksempler på organiske oppløsningsmidler eller suspenderende media er propylenglykol, polyetylenglykol, vegetabilske oljer som olivenolje eller injiserbare organiske estere såsom etyl-oleat. Nevnte sammensetninger kan også inneholde tilsetningsstoffer såsom stabilisatorer, konserveringsmidler, fukte- Preparations according to the present invention for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil or injectable organic esters such as ethyl oleate. Said compositions may also contain additives such as stabilizers, preservatives, wetting agents

midler, emulgeringsmidler og dispergeringsmidler. agents, emulsifiers and dispersants.

Nevnte sammensetninger kan f.eks. steriliseres ved filtrering gjennom et bakteriefilter, ved at man tilsetter steriliserende midler i sammensetningen eller ved at disse bestråles eller oppvarmes. De kan også fremstilles i form av sterile faste sammensetninger som kan oppløses i sterilt vann eller et annet sterilt injiserbart medium umiddelbart før bruk. Said compositions can e.g. sterilized by filtering through a bacterial filter, by adding sterilizing agents to the composition or by irradiating or heating them. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or another sterile injectable medium immediately before use.

Prosenten av den aktive komponent i nevnte sammensetninger samt fremgangsmåten for å øke hjertets kontraktilitet kan varieres slik at man finner en egnet dose. Den dose som tilføres en spesiell pasient vil være variabel og avhengig av legens bedømmelse idet han bruker følgende kriterier: tilførselsvei, varighet av behandling, størrelse og tilstand på pasienten, den aktive komponents styrke og pasi-entens reaksjon overfor nevnte aktive komponent. En effektiv dose av den aktive komponent kan således bare bedømmes av legen idet han tar hensyn til alle kriterier og bruker sitt beste skjønn på vegne av pasienten. The percentage of the active component in said compositions as well as the method for increasing the contractility of the heart can be varied so that a suitable dose is found. The dose given to a particular patient will be variable and dependent on the doctor's judgment as he uses the following criteria: route of administration, duration of treatment, size and condition of the patient, the strength of the active component and the patient's reaction to said active component. An effective dose of the active component can thus only be judged by the doctor taking into account all criteria and using his best judgment on behalf of the patient.

Claims (6)

1. Fremgangsmåte for fremstilling av pyrazolopyridinoner med formel I hvor R er lavere alkyl, lavere hydroksyalkyl, 2,3-dihydroksypropyl eller lavere alkoksyalkyl, Q er hydrogen eller lavere alkyl og PY er 4- eller 3-pyridinyl eller 4- eller 3-pyridinyl med én eller to lavere alkylsubstituenter, eller et syreaddisjonssalt av en slik forbindelse,karakterisertvedat man reagerer et lavere alkyl-2-halogen-5-PY-6-Q-nikotinat med et 1-R-hydrazin, og hvis det er ønskelig, omdanner den fremstilte frie base til et syreaddisjonssalt.1. Process for the preparation of pyrazolopyridinones of formula I where R is lower alkyl, lower hydroxyalkyl, 2,3-dihydroxypropyl or lower alkoxyalkyl, Q is hydrogen or lower alkyl and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two lower alkyl substituents, or an acid addition salt of such a compound, characterized by reacting a lower alkyl-2-halo-5-PY-6-Q-nicotinate with a 1-R-hydrazine, and if desired, converting the produced free base to an acid addition salt. 2. Fremgangsmåte ifølge krav 1,karakterisert vedat R er metyl, etyl eller 2-hydroksyetyl.2. Process according to claim 1, characterized in that R is methyl, ethyl or 2-hydroxyethyl. 3. Fremgangsmåte ifølge krav 1 eller* 2,karakterisert vedat Q er hydrogen, metyl eller etyl.3. Process according to claim 1 or* 2, characterized in that Q is hydrogen, methyl or ethyl. 4. Fremgangsmåte for fremstilling av et pyridinyl-nikotinat med formel II, hvor Q er hydrogen eller lavere alkyl, R<1>er lavere alkyl, X er klor eller brom, og PY er 4- eller 3-pyridinyl eller 4- eller 3-pyridinyl med én eller to lavere alkylsubstituenter eller et syreaddisjonssalt av en slik forbindelse,karakterisert vedat man reagerer et 2-halogen-6-Q-5-PY-nikotinoylhalogenid med en lavere alkanol, og hvis det er ønskelig, omdanner den fremstilte frie basen til et syreaddisjonssalt.4. Method for preparing a pyridinyl nicotinate of formula II, where Q is hydrogen or lower alkyl, R<1> is lower alkyl, X is chlorine or bromine, and PY is 4- or 3-pyridinyl or 4- or 3 -pyridinyl with one or two lower alkyl substituents or an acid addition salt of such a compound, characterized by reacting a 2-halo-6-Q-5-PY-nicotinoyl halide with a lower alkanol and, if desired, converting the free base produced to an acid addition salt. 5. Fremgangsmåte ifølge krav 4,karakterisert vedat nevnte 2-halogen-6-Q-5-PY-nikotinoyl-halogenid fremstilles ved at man hydrolyserer et 1,2-dihydro-6-Q-2-okso-5-PY-nikotinonitr il, hvorved man får fremstilt en 1,2-dihydro-6-Q-2-okso-5-PY-nikotinsyre som deretter reageres med et uorganisk halogeneringsmiddel.5. Process according to claim 4, characterized in that said 2-halo-6-Q-5-PY-nicotinoyl halide is prepared by hydrolyzing a 1,2-dihydro-6-Q-2-oxo-5-PY-nicotinonitre il, whereby a 1,2-dihydro-6-Q-2-oxo-5-PY-nicotinic acid is produced which is then reacted with an inorganic halogenating agent. 6. Fremgangsmåte ifølge krav 4 eller 5,karakterisert vedat Q er hydrogen, metyl eller etyl, og X er klor.6. Method according to claim 4 or 5, characterized in that Q is hydrogen, methyl or ethyl, and X is chlorine.
NO810833A 1980-03-17 1981-03-11 PROCEDURE FOR PREPARATION OF PYRAZOLPYRIDINONES AND PYRIDINYLNICOTINATES NO810833L (en)

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US06/130,628 US4264612A (en) 1980-03-17 1980-03-17 Lower-alkyl 2-halo-5-(pyridinyl)nicotinates, their preparation and use as cardiotonics

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