EP1181292A1 - Pyrozolo [3,4-d][1,2,3] triazines with an anticonvulsive action and methods for producing the same - Google Patents

Pyrozolo [3,4-d][1,2,3] triazines with an anticonvulsive action and methods for producing the same

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Publication number
EP1181292A1
EP1181292A1 EP00935086A EP00935086A EP1181292A1 EP 1181292 A1 EP1181292 A1 EP 1181292A1 EP 00935086 A EP00935086 A EP 00935086A EP 00935086 A EP00935086 A EP 00935086A EP 1181292 A1 EP1181292 A1 EP 1181292A1
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EP
European Patent Office
Prior art keywords
pyrazolo
dihydro
triazin
formula
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP00935086A
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German (de)
French (fr)
Inventor
Thomas Arnold
Klaus Unverferth
Hans-Joachim Lankau
Angelika Rostock
Reni Bartsch
Thomas Kronbach
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AWD Pharma GmbH and Co KG
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Arzneimittelwerk Dresden GmbH
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Publication of EP1181292A1 publication Critical patent/EP1181292A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the invention relates to pyrazolo [3,4-d] [1, 2,3] triazin-4-ones and their tautomers which contain a benzyl radical in the 6-position, processes for their preparation and their use as medicaments, in particular for Treatment of various forms of epilepsy.
  • Epilepsy is a change in behavior in the form of convulsions. The reason is short-term, extremely strong neuronal discharges of the brain. Overall, approximately 5% of all people experience an epileptic seizure in their life, 1% suffer from epilepsy.
  • the invention is therefore based on the object of providing compounds with favorable pharmacological properties which can be used as medicaments, in particular for the treatment of epilepsy.
  • these new compounds are 6-ar (alkyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-ones of the general formula 1
  • X hydrogen or dC 4 alkyl
  • Y hydrogen, halogen, -C 4 alkyl, -C 4 alkoxy, trifluoromethyl or
  • Trifluoromethoxy and m 1 or 2 mean.
  • Examples of compounds of general formula 1 are:
  • 3-aminopyrazole-4-carboxylic acid nitriles can be alkylated with a suitably substituted benzyl halide under phase transfer conditions.
  • acid saponification of the nitrile, preferably in conc. Sulfuric acid gives compounds of formula 2 [R. K. Robins; J. Am. Chem. Soc 1956, 784].
  • the compounds according to the invention have strong anticonvulsant effects, which are described in more detail below.
  • mice ip application
  • rats po application
  • mice ip application
  • rats po application
  • mice ip application
  • rats po application
  • mice ip application
  • mice ip application
  • rats po application
  • mice ip application
  • mice ip application
  • rats po application
  • Table 1 Antiepileptic Drugs, Third. Ed., Raven Press, New York 1989
  • the compounds of formula 1 according to the invention are suitable for the production of pharmaceutical compositions.
  • This pharmaceutical composition is suitable for the production of pharmaceutical compositions.
  • compositions contain at least one of the invention
  • the pharmaceutical preparations can, for example, be administered parenterally (intravenously, intramuscularly subcutaneously) or orally.
  • the application forms can be prepared by methods which are generally known and customary in pharmaceutical practice.
  • the solvent is removed in vacuo for hours and the crude product is recrystallized from a suitable solvent, preferably alcohol.

Abstract

The invention relates to 3,6-dihydro-pyrazolo[3,4-d][1,2,3]triazine-4-ones and tautomers thereof containing a benzyle radical in position 6, to methods for producing the same and to their use as medicaments, especially for treating different forms of epilepsy.

Description

Antikonvulsiv wirkende Pyrazolo[3,4-d][1,2,3]triazine und Verfahren zu ihrer HerstellungAnticonvulsant pyrazolo [3,4-d] [1,2,3] triazines and process for their preparation
Die Erfindung betrifft Pyrazolo[3,4-d][1 ,2,3]triazin-4-one und deren Tautomere, die in 6-Stellung einen Benzyl-Rest enthalten, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel, insbesondere zur Behandlung von Epilepsien verschiedener Formen.The invention relates to pyrazolo [3,4-d] [1, 2,3] triazin-4-ones and their tautomers which contain a benzyl radical in the 6-position, processes for their preparation and their use as medicaments, in particular for Treatment of various forms of epilepsy.
Unsubstituiertes Pyrazolo[3,4-d][1 ,2,3]triazin-4-on wurde 1968 beschrieben [Cheng et al., J. Pharm. Sei. 1968, 57, 1044). Durch Diazotierung von substituierten Aminopyrazolcarboxamiden wurden bislang nur 7-substituierte Triazinderivate erhalten [Gatta, Franco, Luciani, Maria, Palazzo, J. Heterocycl. Chem. 1989, 26, 613].Unsubstituted pyrazolo [3,4-d] [1, 2,3] triazin-4-one was described in 1968 [Cheng et al., J. Pharm. 1968, 57, 1044). To date, only 7-substituted triazine derivatives have been obtained by diazotization of substituted aminopyrazole carboxamides [Gatta, Franco, Luciani, Maria, Palazzo, J. Heterocycl. Chem. 1989, 26, 613].
Isomere Verbindungen wie 7-(2-Fluorbenzyl)-3,6-dihydro-pyrazolo- [3,4-d][1 ,2,3]triazin-4-on und 7-(2-Fluorbenzyl)-7H-imidazo[4,5-d][1 ,2,3]triazin- 4-on wurden 1995 beschrieben [J. L. Kelley, D. C. Wilson, V. L. Styles, F. E. Soroko, B. R. Cooper, J. Heterocyclic Chem. 1995, 32, 1417]. 3,6-Dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-one und Tautomere, die einen (substituierten) Benzylrest in 6-Position besitzen, sind bisher nicht in der Literatur beschrieben wurden.Isomeric compounds such as 7- (2-fluorobenzyl) -3,6-dihydro-pyrazolo- [3,4-d] [1, 2,3] triazin-4-one and 7- (2-fluorobenzyl) -7H-imidazo [4,5-d] [1, 2,3] triazin- 4-one were described in 1995 [J. L. Kelley, D.C. Wilson, V.L. Styles, F.E. Soroko, B.R. Cooper, J. Heterocyclic Chem. 1995, 32, 1417]. 3,6-Dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-ones and tautomers which have a (substituted) benzyl radical in the 6-position have not hitherto been described in the literature.
Epilepsien sind Verhalteπsänderungen in Form von Krämpfen. Der Grund sind kurzeitige, extrem starke neuronale Entladungen des Gehirns. Insgesamt erleiden ca. 5 % aller Menschen in ihrem Leben einen epileptischen Anfall, 1 % erkranken an einer Epilepsie.Epilepsy is a change in behavior in the form of convulsions. The reason is short-term, extremely strong neuronal discharges of the brain. Overall, approximately 5% of all people experience an epileptic seizure in their life, 1% suffer from epilepsy.
Grundsätzlich sind für die Entstehung von Krampfanfällen zwei Faktoren zu berück-sichtigen, die krankhaften Entladungen in Gruppen von Nervenzellen und/oder die fehlende Erregungsbegrenzung, die eine Ausbreitung der krankhaften Erregung ermöglicht, das heißt, es besteht eine gesteigerte Instabilität des Zellmembranpotentials mit einer Tendenz zu elektrischen Spontanentladungen.Basically, two factors have to be taken into account for the development of seizures, the pathological discharges in groups of nerve cells and / or the lack of excitation limitation, which enables the spread of pathological excitation, that is, there is an increased Instability of the cell membrane potential with a tendency to spontaneous electrical discharges.
Nur etwa 60 - 80 % der Patienten werden derzeit unter einer medikamentösen Behandlung anfallsfrei. Bestimmte Formen der Epilepsie können jedoch noch nicht ausreichend behandelt werden.Only about 60-80% of patients are currently seizure-free under drug treatment. However, certain forms of epilepsy cannot be adequately treated.
Hinzu kommt, daß durch die Applikation von auf dem Markt befindlichen Antikonvulsiva unerwünschte Nebenwirkungen, wie Neurotoxizität und Idiosynkrasien auftreten können.In addition, the application of anticonvulsants on the market can cause undesirable side effects, such as neurotoxicity and idiosyncrasies.
Der Erfindung liegt deshalb die Aufgabe zugrunde, Verbindungen mit günstigen pharmakologischen Eigenschaften zur Verfügung zu stellen, die als Arzneimittel, insbesondere zur Behandlung von Epilepsien, eingesetzt werden können.The invention is therefore based on the object of providing compounds with favorable pharmacological properties which can be used as medicaments, in particular for the treatment of epilepsy.
Entsprechend der vorliegenden Erfindung sind diese neuen Verbindungen 6-Ar(alkyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-one der allgemeinen Formel 1According to the present invention, these new compounds are 6-ar (alkyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-ones of the general formula 1
Formel 1 oder deren Tautomeren, wobeiFormula 1 or its tautomers, wherein
X = Wasserstoff oder d-C4-Alkyl;X = hydrogen or dC 4 alkyl;
Y = Wasserstoff, Halogen, Cι-C4-Alkyl, Cι-C4-Alkoxy, Trifluormethyl oderY = hydrogen, halogen, -C 4 alkyl, -C 4 alkoxy, trifluoromethyl or
Trifluormethoxy und m = 1 oder 2 bedeuten. Als Beispiele für Verbindungen der allgemeinen Formel 1 seien genannt:Trifluoromethoxy and m = 1 or 2 mean. Examples of compounds of general formula 1 are:
6-(2-Fluorbenzyl)-3,6-dihydro-ρyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(2-Chlorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(2-Trifluormethylbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1,2,3]triazin-4-on 6-(2-Methylbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(3-Chlorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1,2,3]triazin-4-on 6-(3-Trifluormethylbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(4-Fluorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(4-Chlorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-fluorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one 6- (2-chlorobenzyl) -3,6-dihydro-pyrazolo [ 3,4-d] [1, 2,3] triazin-4-one 6- (2-trifluoromethylbenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4 -one 6- (2-methylbenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one 6- (3-chlorobenzyl) -3,6-dihydro- pyrazolo [3,4-d] [1,2,3] triazin-4-one 6- (3-trifluoromethylbenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazine -4-one 6- (4-fluorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazin-4-one 6- (4-chlorobenzyl) -3,6- dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(2-Chlor-6-fluorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(2-Chlorbenzyl)-5-methyl-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-(2-Chior-4-fluorbenzyl)-5-methyl-3,6-dihydro-ρyrazolo[3,4-d][1 ,2,3]triazin-4- on 6-Benzyl-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-chloro-6-fluorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one 6- (2-chlorobenzyl) -5-methyl- 3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one 6- (2-chloro-4-fluorobenzyl) -5-methyl-3,6-dihydro-pyrazolo [ 3,4-d] [1, 2,3] triazin-4-one 6-benzyl-3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazin-4-one
Das Verfahren zur Herstellung von Verbindungen der Formel 1 und deren Tautomere beruht auf der Cyclisierung von 3-Aminopyrazol-4-carbonsäure- amiden der allgemeinen Formel 2The process for the preparation of compounds of the formula 1 and their tautomers is based on the cyclization of 3-aminopyrazole-4-carboxylic acid amides of the general formula 2
Formel 2 worin X = Wasserstoff oder Cι-C4-Alkyl;Formula 2 wherein X = hydrogen or -CC 4 alkyl;
Y = Halogen, Cι-C4-Alkyl, Cι-C4-Alkoxy, Trifluormethyl oder Trifluormethoxy und m = 1 oder 2 bedeuten, mit Natriumnitrit in wässriger Salzsäure oder mit Alkylnitriten in salzsaurem Ethanol.Y = halogen, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, trifluoromethyl or trifluoromethoxy and m = 1 or 2, with sodium nitrite in aqueous hydrochloric acid or with alkyl nitrites in hydrochloric ethanol.
Das Verfahren zur Herstellung von Verbindungen der Formel 2 geht vonThe process for the preparation of compounds of formula 2 starts from
3-Aminopyrazol-4-carbonsäurederivaten aus [R. K. Robins; J. Am. Chem. Soc 1956, 784; P.Schmidt, J. Druey Helv. Chim. Acta 1956, 39, 986]. Durch Alkylierung unter Phasen-Transfer-Bedingungen mit einem geeignet substituierten Benzylhalogenid erhält man die Verbindungen der Formel 2 [S. Senda, K. Hirota, G.-N. Yang, Chem. Pharm. Bull 1972, 20(2), 391].3-aminopyrazole-4-carboxylic acid derivatives from [R. K. Robins; J. Am. Chem. Soc 1956, 784; P. Schmidt, J. Druey Helv. Chim. Acta 1956, 39, 986]. Alkylation under phase transfer conditions with a suitably substituted benzyl halide gives the compounds of the formula 2 [S. Senda, K. Hirota, G.-N. Yang, Chem. Pharm. Bull 1972, 20 (2), 391].
Alternativ können 3-Aminopyrazol-4-carbonsäurenitrile unter Phasen-Transfer- Bedingungen mit einem geeignet substituierten Benzylhalogenid alkyliert werden. Durch saure Verseifung des Nitrils vorzugsweise in konz. Schwefelsäure erhält man Verbindungen der Formel 2 [R. K. Robins; J. Am. Chem. Soc 1956, 784].Alternatively, 3-aminopyrazole-4-carboxylic acid nitriles can be alkylated with a suitably substituted benzyl halide under phase transfer conditions. By acid saponification of the nitrile, preferably in conc. Sulfuric acid gives compounds of formula 2 [R. K. Robins; J. Am. Chem. Soc 1956, 784].
Die erfindungsgemäßen Verbindungen weisen starke antikonvulsive Wirkungen auf, die nachfolgend näher beschrieben werden.The compounds according to the invention have strong anticonvulsant effects, which are described in more detail below.
Antikonvulsive WirksamkeitAnticonvulsant effectiveness
Die erfindungsgemäßen Verbindungen wurden in vivo an Mäusen (i.p.- Applikation) oder Ratten (p.o.-Applikation) nach dem international üblichen Standard (Pharmac.Weekblad, Sc.Ed. 14, 132 (1992) und Antiepileptic Drugs, Third. Ed., Raven Press, New York 1989) auf ihre antikonvulsive Wirkung getestet (Tabelle 1 ).The compounds according to the invention were in vivo in mice (ip application) or rats (po application) according to the international standard (Pharmac.Weekblad, Sc.Ed. 14, 132 (1992) and Antiepileptic Drugs, Third. Ed., Raven Press, New York 1989) tested for their anticonvulsant activity (Table 1).
Für die orale Wirkung wurden analoge Ergebnisse erhalten. Beispielsweise wurde für die Verbindung 2 (6-(2-Chlorbenzyl)-3,6-dihydro- pyrazolo[3,4-d][1 ,2,3]triazin-4-on) bei der Ratte im Maximalen Elektroschock die ED50 (p.o.) zu 3 mg/kg und für die Neurotoxizität die NT50 > 250 mg/kg bestimmt. Tabelle 1: Antikonvulsive Wirkung von ausgewählten Pyrazolo[3,4-d]triazinen der Formel 1Analogous results were obtained for the oral effect. For example, for compound 2 (6- (2-chlorobenzyl) -3,6-dihydropyrazolo [3,4-d] [1,2,3] triazin-4-one) in rats, the ED50 was in maximum electroshock (po) at 3 mg / kg and the NT 50 > 250 mg / kg for neurotoxicity. Table 1: Anticonvulsant activity of selected pyrazolo [3,4-d] triazines of the formula 1
Anmerkungen zur Tabelle 1 : Notes on Table 1:
1 ) Numerierung der Verbindungen entsprechend der Beispiele in Tabelle 21) Numbering of the compounds according to the examples in Table 2
2) Verteilungskoeffizient Octanol/Wasser, n = nicht gemessen 3) Maus p.: MES = maximaler Elektroschock, PTZ = s.c. Pentetrazol2) Octanol / water partition coefficient, n = not measured 3) Mouse p .: MES = maximum electric shock, PTZ = s.c. Pentetrazole
4) in mg/kg4) in mg / kg
5) in % der geschützten Tiere5)% of protected animals
Aus Tabelle 1 ist ersichtlich, daß die erfindungsgemäßen Verbindungen stark antikonvulsiv wirksam sind und keine oder nur eine geringe Neurotoxizität aufweisen.It can be seen from Table 1 that the compounds according to the invention are highly anticonvulsant and have no or only a low neurotoxicity.
Die erfindungsgemäßen Verbindungen der Formel 1 sind zur Herstellung pharmazeutischer Zusammensetzungen geeignet. Diese pharmazeutischenThe compounds of formula 1 according to the invention are suitable for the production of pharmaceutical compositions. This pharmaceutical
Zusammensetzungen enthalten mindestens eine der erfindungsgemäßenCompositions contain at least one of the invention
Verbindungen der allgemeinen Formel 1 sowie gegebenenfalls übliche pharmazeutische Träger- und/oder Hilfsstoffe.Compounds of general formula 1 and, if appropriate, customary pharmaceutical carriers and / or auxiliaries.
Die pharmazeutischen Zubereitungen können beispielsweise parenteral (intravenös, intramuskulär subkutan) oder oral verabreicht werden.The pharmaceutical preparations can, for example, be administered parenterally (intravenously, intramuscularly subcutaneously) or orally.
Die Applikationsformen können nach in der pharmazeutischen Praxis allgemein bekannten und üblichen Verfahren hergestellt werden.The application forms can be prepared by methods which are generally known and customary in pharmaceutical practice.
Die folgenden Beispiele dienen der weiteren Erläuterung der Erfindung ohne diese zu beschränken. Allgemeine Vorschrift zur Herstellung der Verbindungen der Formel 1 und deren Tautomere gemäß Tabelle 2, Beispiele 1 - 12The following examples serve to further illustrate the invention without restricting it. General instructions for the preparation of the compounds of formula 1 and their tautomers according to Table 2, Examples 1-12
30 mmol Verbindung der Formel 2 wird in 100 ml Wasser und 10 ml konzentrierter Salzsäure suspendiert und mit einer Lösung von 50 mmol Natriumnitrit in 20 ml Wasser versetzt. Nach Beendigung der Zugabe wird 4 Stunden gerührt und das Produkt abfiltriert.30 mmol of compound of formula 2 is suspended in 100 ml of water and 10 ml of concentrated hydrochloric acid and a solution of 50 mmol of sodium nitrite in 20 ml of water is added. After the addition has ended, the mixture is stirred for 4 hours and the product is filtered off.
Alternativ werden 30 mmol Verbindung der Formel 2 in 100ml Ethanol gelöst und 50 mmol Alkylnitrit vorzugsweise Pentylnitrit zugetropft. Nach 4-10Alternatively, 30 mmol of compound of formula 2 are dissolved in 100 ml of ethanol and 50 mmol of alkyl nitrite, preferably pentyl nitrite, are added dropwise. After 4-10
Stunden wird das Lösungsmittel im Vakuum entfernt und das Rohprodukt aus einem geeigneten Lösungsmittel vorzugsweise Alkohol umkristallisiert.The solvent is removed in vacuo for hours and the crude product is recrystallized from a suitable solvent, preferably alcohol.
Tabelle 2: 3,6-Dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-one, Beispiele 1 - 12Table 2: 3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazin-4-one, Examples 1-12

Claims

Patentansprüche claims
1. Neue Verbindungen der allgemeinen Formel 11. New compounds of the general formula 1
Formel 1formula 1
oder deren Tautomeren, worinor their tautomers, wherein
X = Wasserstoff oder C1-C4-Alkyl;X = hydrogen or C 1 -C 4 alkyl;
Y = Wasserstoff, Halogen, Cι-C4-Alkyl, C-ι-C4-Alkoxy, Trifluormethyl oderY = hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl or
Trifluormethoxy und m = 1 oder 2 bedeuten.Trifluoromethoxy and m = 1 or 2 mean.
2. Verbindungen der allgemeinen Formel 1 :2. Compounds of the general formula 1:
6-(2-Fluorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-fluorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(2-Chlorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-chlorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(2-Trifluormethylbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-trifluoromethylbenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazin-4-one
6-(2-Methylbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-methylbenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(3-Chlorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (3-chlorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(3-Trifluormethylbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (3-trifluoromethylbenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(4-Fluorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (4-fluorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(4-Chlorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (4-chlorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(2-Chlor-6-fluorbenzyl)-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4- on6- (2-chloro-6-fluorobenzyl) -3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(2-Chlorbenzyl)-5-methyl-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on6- (2-chlorobenzyl) -5-methyl-3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
6-(2-Chlor-4-fluorbenzyl)-5-methyl-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]tria- zin-4-on6- (2-Chloro-4-fluorobenzyl) -5-methyl-3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazine-4-one
6-Benzyl-3,6-dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-on 6-benzyl-3,6-dihydro-pyrazolo [3,4-d] [1,2,3] triazin-4-one
3. Verfahren zur Herstellung von 3,6-Dihydro-pyrazolo[3,4-d][1 ,2,3]triazin- 4-onen der allgemeinen Formel 1 dadurch gekennzeichnet, daß man eine Verbindung der Formel 23. Process for the preparation of 3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazin-4-ones of the general formula 1, characterized in that a compound of the formula 2
Formel 2Formula 2
worinwherein
X = Wasserstoff oder Cι-C4-Alkyl;X = hydrogen or -CC 4 alkyl;
Y = Wasserstoff, Halogen, Cι-C4-Alkyl, Trifluormethyl oderY = hydrogen, halogen, -CC 4 alkyl, Trifluoromethyl or
Trifluormethoxy und m = 1 oder 2 bedeuten,Trifluoromethoxy and m = 1 or 2,
mit Natriumnitrit im sauren Medium cyclisiert.cyclized with sodium nitrite in acidic medium.
4. Verfahren nach Anspruch 3 dadurch gekennzeichnet, daß zur Cyclisierung von 3-Amino-pyrazol-4-carbonsäureamiden der Formel 2 Alkylnitrite in salzsaurem Ethanol verwendet werden.4. The method according to claim 3, characterized in that for the cyclization of 3-amino-pyrazole-4-carboxamides of the formula 2 alkyl nitrites are used in hydrochloric acid ethanol.
5. Pharmazeutische Zusammensetzungen dadurch gekennzeichnet, daß sie als aktive Substanz mindestens eine Verbindung der allgemeinen Formel 1 und gegebenenfalls physiologisch verträglichen Hilfs-und/oder Trägerstoffe enthalten. 5. Pharmaceutical compositions characterized in that they contain at least one compound of general formula 1 and optionally physiologically compatible auxiliaries and / or carriers as active substance.
6. Pharmazeutische Zusammensetzungen dadurch gekennzeichnet, daß sie als aktive Substanz mindestens eine der Verbindungen gemäß Anspruch 2 und gegebenenfalls physiologisch verträglichen Hilfs-und/oder Trägerstoffe enthalten.6. Pharmaceutical compositions, characterized in that they contain at least one of the compounds according to claim 2 and optionally physiologically compatible auxiliaries and / or carriers as active substance.
7. Verwendung von 3,6-Dihydro-pyrazolo[3,4-d][1 ,2,3]triazin-4-onen der Formel 1 zur Herstellung von Arzneimitteln zur Behandlung von Epilepsien verschiedener Formen.7. Use of 3,6-dihydro-pyrazolo [3,4-d] [1, 2,3] triazin-4-ones of formula 1 for the manufacture of medicaments for the treatment of epilepsy of various forms.
8. Verwendung der Verbindungen gemäß Anspruch 2 zur Herstellung von Arzneimitteln zur Behandlung von epileptischen Erkrankungen. 8. Use of the compounds according to claim 2 for the manufacture of medicaments for the treatment of epileptic diseases.
EP00935086A 1999-05-29 2000-05-20 Pyrozolo [3,4-d][1,2,3] triazines with an anticonvulsive action and methods for producing the same Ceased EP1181292A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19924872 1999-05-29
DE19924872A DE19924872A1 (en) 1999-05-29 1999-05-29 Anticonvulsant pyrazolo [3,4-d] [1,2,3] triazines and process for their preparation
PCT/EP2000/004602 WO2000073309A1 (en) 1999-05-29 2000-05-20 Pyrozolo [3,4-d][1,2,3] triazines with an anticonvulsive action and methods for producing the same

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US (1) US6316448B1 (en)
EP (1) EP1181292A1 (en)
JP (1) JP2003501357A (en)
AR (1) AR024131A1 (en)
AU (1) AU5069600A (en)
CA (1) CA2310174A1 (en)
CO (1) CO5170519A1 (en)
DE (1) DE19924872A1 (en)
HK (1) HK1040512A1 (en)
WO (1) WO2000073309A1 (en)

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US20080274883A1 (en) * 2004-12-23 2008-11-06 Basf Aktiengesellschaft Fungicidal Mixtures
JP6132853B2 (en) * 2011-12-27 2017-05-24 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ Compounds acting at multiple prostaglandin receptors that provide a systemic anti-inflammatory response

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US2925418A (en) * 1960-02-16 Certificate of correction
ZW21687A1 (en) * 1986-12-12 1988-07-20 Hoffmann La Roche Triazine derivatives

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AR024131A1 (en) 2002-09-04
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CA2310174A1 (en) 2000-11-29
CO5170519A1 (en) 2002-06-27
DE19924872A1 (en) 2000-11-30
JP2003501357A (en) 2003-01-14
US6316448B1 (en) 2001-11-13

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