WO2001083490A1 - Substituted pyrazole derivative - Google Patents

Substituted pyrazole derivative Download PDF

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Publication number
WO2001083490A1
WO2001083490A1 PCT/EP2001/004418 EP0104418W WO0183490A1 WO 2001083490 A1 WO2001083490 A1 WO 2001083490A1 EP 0104418 W EP0104418 W EP 0104418W WO 0183490 A1 WO0183490 A1 WO 0183490A1
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Prior art keywords
compound
formula
combination
medicaments
reaction
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PCT/EP2001/004418
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German (de)
French (fr)
Inventor
Alexander Straub
Cristina Alonso-Alija
Armin Kern
Johannes-Peter Stasch
Klaus Dembowsky
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Bayer Aktiengesellschaft
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Priority to AU2001256305A priority Critical patent/AU2001256305A1/en
Publication of WO2001083490A1 publication Critical patent/WO2001083490A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a substituted pyrazole derivative, a process for its preparation and its use as a medicament, in particular as a medicament for the treatment of cardiovascular diseases.
  • WO 98/16223 discloses the use of l-benzyl-3- (substituted-hetaryl) -condensed pyrazole derivatives for the treatment of special diseases of the cardiovascular system and the central nervous system.
  • WO 98/16507 discloses heterocyclylmethyl-substituted pyrazole derivatives and their
  • WO 98/23619 also discloses substituted pyrazole derivatives for the treatment of cardiovascular diseases.
  • the present invention relates to a substituted pyrazole derivative of the formula (I)
  • the compound of the formula (I) according to the invention can also be present in the form of hydrate or in the form of its salts.
  • salts with organic or inorganic bases or acids may be mentioned here.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the compound according to the invention can be salts of the substance according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • mineral acids for example, particular preference is given to Salts with hydrochloric acid,
  • Hydrobromic acid sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compound according to the invention.
  • metal or ammonium salts of the compound according to the invention.
  • Sodium, potassium, magnesium or calcium salts and also ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol,
  • the compound according to the invention can exist in stereoisomeric forms (enantiomers).
  • the invention relates to both the enantiomers and their mixture.
  • the racemic forms can be uniformly stereoisomerically known
  • the compound of formula (I) according to the invention shows an unforeseeable, valuable pharmacological spectrum of action. In particular, it leads to vascular relaxation, inhibition of platelet aggregation and a reduction in blood pressure, as well as an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.
  • the compound of the formula (I) according to the invention enhances the action of substances which inhibit the cGMP
  • cardiovascular diseases such as for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks , peripheral circulatory disorders, prevention of restenosis such as after thrombolysis therapies, percutaneous transluminal angioplasty (PTA), percutaneous transluminal
  • Coronary angioplasties bypass and for the treatment of arteriosclerosis, asthmatic diseases and diseases of the genitourinary system such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence.
  • the compound of formula (I) described in the present invention also represents an active ingredient for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
  • diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances.
  • the active ingredient is also suitable for regulating cerebral blood flow and is therefore an effective means of combating migraines.
  • the compound of formula (I) according to the invention can be used to combat painful conditions.
  • the invention comprises the combination of the compound of the formula (I) according to the invention with organic nitrates and NO donors.
  • Organic nitrates and NO donors in the context of the invention are generally substances which develop their therapeutic effect through the release of NO or NO species.
  • Sodium nitroprusside, nitroglycerin, isosorbide di-nitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
  • the invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP).
  • cGMP cyclic guanosine monophosphate
  • These are in particular inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reif-Snyder (1990) TiPS 11 pp. 150 to 155. These inhibitors potentiate the action of the compound according to the invention and increase the desired pharmacological effect.
  • the compound of the formula (II) is obtainable in a multistage synthesis from the sodium salt of the cyanobenzofruvic acid ethyl ester (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934, 512, 97) known from the literature.
  • This ethyl pyridine derivative l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxylate is subjected to a multistage sequence consisting of converting the ester with ammonia into the corresponding amide, dehydration with a dehydrating agents such as trifluoroacetic anhydride to give the corresponding nitrile derivative, reaction of the nitrile derivative with sodium methylate and final reaction with ammonium chloride are converted into the compound of the formula (II).
  • inorganic or organic bases can be used as bases.
  • bases preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali or alkaline earth metal alcohol such as
  • Inert organic solvents are suitable as solvents. These include ethers such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or
  • Trichlorethylene hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane is particularly preferred.
  • the reaction is carried out with heating to temperatures between 60 ° C and 110 ° C and normal pressure.
  • the reaction mixture is allowed to react for about 5-24 hours, preferably 12 to 24 hours.
  • the compound of the formula (III) is then obtained by cleaving the azo group.
  • metals in particular zinc, can be used as reducing agents in the presence of mineral acids such as hydrochloric acid, Na 2 SO 4 , boranes or hydrogen in the presence of a catalyst.
  • the use of hydrogen in the presence of Raney-Ni is preferred.
  • the solvents mentioned above can be used as solvents.
  • Dimethylformamide (DMF) is particularly preferred.
  • the reaction is preferably carried out with heating, for example at 50-80 ° C., and a hydrogen pressure of 30 to 80 bar, preferably 50 to 70 bar. The reactants are allowed to react for about 24 hours.
  • the compound of formula (III) is reacted with a hydroxyl-protected 2-hydroxyacetaldehyde and the imino group formed is then reduced.
  • the conventional, the skilled person come as protective groups for the hydroxy function known hydroxyl protecting groups in question.
  • the solvents mentioned above can be used as solvents. Methanol is particularly preferred.
  • the reaction is preferably carried out at room temperature and normal pressure.
  • the imino group obtained by this reaction is preferably reduced in situ to the corresponding secondary amino group.
  • the reducing agents known to the person skilled in the art for this reaction such as alkali metal hydrides, for example
  • Lithium aluminum hydride or sodium borohydride or sodium cyanoborohydride, alkali metals such as sodium in ethanol or hydrogen can be used in the presence of a catalyst. Reduction with sodium cyanoborohydride in the presence of a dehydrating agent such as molecular sieve is preferred according to the invention. The reduction is preferably carried out at room temperature and is complete after about 2 to 8 hours, preferably after about 3 to 5 hours.
  • the compound of formula (I) according to the invention is obtained from the hydroxyl-protected ethanolamine derivative thus obtained by deprotection of the hydroxyl group and subsequent reaction with glyoxal.
  • deprotectant depends on the selected protective group.
  • fluoride compounds such as tetrabutylammonium fluoride can preferably be used under conditions which are conventional for these reactions and known to the person skilled in the art.
  • the reaction with glyoxal preferably in the form of its hydrate, is carried out under a protective gas atmosphere, for example under nitrogen or a noble gas such as argon.
  • the reaction is carried out at room temperature for about 12 to 24 hours.
  • the solvents mentioned above can also be used as solvents for these last steps, tetrahydrofuran (THF) being particularly preferred.
  • THF tetrahydrofuran
  • acetal compounds thereof can also be used, if appropriate in the presence of acids.
  • BABA n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6
  • the solution obtained from 1. is mixed with 61.25 ml (60.77 g, 0.613 mol) of dimethylammoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under argon for 3 days.
  • the solvent is then evaporated in vacuo, the residue is poured into 2 liters of water and extracted three times with 1 liter of ethyl acetate.
  • the free base is obtained by shaking out with dilute NaHCO 3 solution and extracting with ethyl acetate.
  • the solid which is insoluble in both phases is filtered off with suction.
  • the ethyl acetate phase also contains small amounts of the free base.
  • Rabbits are anesthetized and bled by the blow of the neck.
  • the aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths with carbohydrate gas at 37 ° C
  • Phenylephrine added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is examined in increasing doses in each further run and the level of the contraction is compared with the level of the contraction achieved in the last previous run. From this, the concentration is calculated which is required to reduce the level of the control value by 50% (ICso).
  • Compound (I): IC 50 1200 nM
  • mice Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery and a catheter for substance administration into the femoral vein. The substance to be tested is administered intravenously in Transcutol / Cremophor / EL / H 2 O (10% / 10% / 80%) in a volume of 1 ml / kg. Compound (I) induces a dose-dependent and long-lasting lowering of blood pressure in rats. After intravenous administration of 0.1 mg / kg and 0.3 mg / kg, a maximum drop in blood pressure of -17 mm and - 41 mm Hg was observed.

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Abstract

The invention relates to a substituted pyrazole derivative of formula (I), to a method for the production thereof, and to its use as a medicament, in particular, as a medicament for treating cardiovascular diseases.

Description

Substituiertes PyrazolderivatSubstituted pyrazole derivative
Die vorliegende Erfindung betrifft ein substituiertes Pyrazolderivat, ein Verfahren zu seiner Herstellung und seine Verwendung als Arzneimittel, insbesondere als Arzneimittel zur Behandlung von Herz-Kreislauf-Erkrankungen.The present invention relates to a substituted pyrazole derivative, a process for its preparation and its use as a medicament, in particular as a medicament for the treatment of cardiovascular diseases.
Es ist bereits bekannt, dass l-Benzyl-3-(substituierte heteroaryl)-kondensierte Pyrazol- Derivate die Thrombozytenaggregation inhibieren (vgl. EP 667 345 AI).It is already known that 1-benzyl-3- (substituted heteroaryl) -condensed pyrazole derivatives inhibit platelet aggregation (cf. EP 667 345 AI).
WO 98/16223 offenbart die Verwendung von l-Benzyl-3-(substituiertes-Hetaryl)-kon- densierten Pyrazolderivaten zur Behandlung von speziellen Erkrankungen des Herz-Kreislaufsystems und des Zentralnervensystems.WO 98/16223 discloses the use of l-benzyl-3- (substituted-hetaryl) -condensed pyrazole derivatives for the treatment of special diseases of the cardiovascular system and the central nervous system.
WO 98/16507 offenbart Heterocyclylmethyl-substituierte Pyrazolderivate und ihreWO 98/16507 discloses heterocyclylmethyl-substituted pyrazole derivatives and their
Verwendung bei der Behandlung von Herz-Kreislauf-Erkrankungen.Use in the treatment of cardiovascular diseases.
WO 98/23619 offenbart ebenfalls substituierte Pyrazolderivate zur Behandlung von Herz-Krei slauf-Erkrankungen.WO 98/23619 also discloses substituted pyrazole derivatives for the treatment of cardiovascular diseases.
Die vorliegende Erfindung betrifft ein substituiertes Pyrazol-Derivat der Formel (I)The present invention relates to a substituted pyrazole derivative of the formula (I)
Figure imgf000002_0001
sowie dessen Isomere, Hydrate und Salze.
Figure imgf000002_0001
and its isomers, hydrates and salts.
Die erfindungsgemäße Verbindung der Formel (I) kann auch in Hydratform oder in Form ihrer Salze vorliegen. Im allgemeinen seien hier Salze mit organischen oder anorganischen Basen oder Säuren genannt.The compound of the formula (I) according to the invention can also be present in the form of hydrate or in the form of its salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
Im Rahmen der vorliegenden Erfindung werden physiologisch unbedenkliche Salze bevorzugt. Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindung können Salze des erfindungsgemäßen Stoffes mit Mineralsäuren, Carbonsäuren oder Sulfonsäuren sein. Besonders bevorzugt sind z.B. Salze mit Chlorwasserstoffsäure,Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the compound according to the invention can be salts of the substance according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid,
Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethan- sulfonsäure, p-Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Propionsäure, Milchsäure, Weinsäure, Zitronensäure, Fumarsäure, Maleinsäure oder Benzoesäure.Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologisch unbedenkliche Salze können ebenso Metall- oder Ammoniumsalze der erfindungsgemäßen Verbindung sein. Besonders bevorzugt sind z.B. Natrium-, Kalium-, Magnesium- oder Calciumsalze, sowie Ammoniumsalze, die abgeleitet sind von Ammoniak, oder organischen Aminen wie beispielsweise Ethylamin, Di- bzw. Triethylamin, Di- bzw. Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol,Physiologically acceptable salts can also be metal or ammonium salts of the compound according to the invention. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, and also ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol,
Arginin, Lysin oder Ethylendiamin.Arginine, lysine or ethylenediamine.
Die erfindungsgemäßen Verbindung kann in stereoisomeren Formen (Enantiomere) existieren. Die Erfindung betrifft sowohl die Enantiomeren als auch deren Gemisch. Die Racemformen lassen sich in bekannter Weise in die stereoisomer einheitlichenThe compound according to the invention can exist in stereoisomeric forms (enantiomers). The invention relates to both the enantiomers and their mixture. The racemic forms can be uniformly stereoisomerically known
Bestandteile trennen.Separate components.
Die erfindungsgemäße Verbindung der Formel (I) zeigt ein nicht vorhersehbares, wertvolles pharmakologisches Wirkspektrum. Insbesondere fuhrt sie zu einer Gefäßrelaxation, Thrombozytenaggregationshemmung und zu einer Blutdrucksenkung sowie zu einer Steigerung des koronaren Blutflusses. Diese Wirkungen sind über eine direkte Stimulation der löslichen Guanylatzyklase und einem intrazellulären cGMP-Anstieg vermittelt. Außerdem verstärkt die erfindungs- gemäße Verbindung der Formel (I) die Wirkung von Substanzen, die den cGMP-The compound of formula (I) according to the invention shows an unforeseeable, valuable pharmacological spectrum of action. In particular, it leads to vascular relaxation, inhibition of platelet aggregation and a reduction in blood pressure, as well as an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. In addition, the compound of the formula (I) according to the invention enhances the action of substances which inhibit the cGMP
Spiegel steigern, wie beispielsweise EDRF (Endothelium derived relaxing factor), NO- Donatoren, Protoporphyrin IX, Arachidonsäure oder Phenylhydrazinderivate.Increase levels, such as EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
Sie kann daher in Arzneimitteln zur Behandlung von kardiovaskulären Erkrankungen wie beispielsweise zur Behandlung des Bluthochdrucks und der Herzinsuffizienz, stabiler und instabiler Angina pectoris, peripheren und kardialen Gefäßerkrankungen, von Arrhythmien, zur Behandlung von thromboembolischen Erkrankungen und Ischämien wie Myokardinfarkt, Hirnschlag, transistorisch und ischämische Attacken, periphere Durchblutungsstörungen, Verhinderung von Restenosen wie nach Thrombo- lysetherapien, percutan transluminalen Angioplastien (PTA), percutan transluminalenIt can therefore be used in medicinal products for the treatment of cardiovascular diseases such as for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks , peripheral circulatory disorders, prevention of restenosis such as after thrombolysis therapies, percutaneous transluminal angioplasty (PTA), percutaneous transluminal
Koronarangioplastien (PTCA), Bypass sowie zur Behandlung von Arteriosklerose, asthmatischen Erkrankungen und Krankheiten des Urogenitalsystems wie beispielsweise Prostatahypertrophie, erektile Dysfunktion, weibliche sexuelle Dysfunktion und Inkontinenz eingesetzt werden.Coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis, asthmatic diseases and diseases of the genitourinary system such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence.
Die in der vorliegenden Erfindung beschriebene Verbindung der Formel (I) stellt auch einen Wirkstoff zur Bekämpfung von Krankheiten im Zentralnervensystem dar, die durch Störungen des NO/cGMP-Systems gekennzeichnet sind. Insbesondere ist sie geeignet zur Beseitigung kognitiver Defizite, zur Verbesserung von Lern- und Gedächt- nisleistungen und zur Behandlung der Alzheimer'schen Krankheit. Sie eignet sich auch zur Behandlung von Erkrankungen des Zentralnervensystems wie Angst-, Spannungsund Depressionszuständen, zentralnervös bedingten Sexualdysfunktionen und Schlafstörungen, sowie zur Regulierung krankhafter Störungen der Nahrungs-, Genuss- und Suchtmittelaufhahme. Weiterhin eignet sich der Wirkstoff auch zur Regulation der cerebralen Durchblutung und stellt somit wirkungsvolle Mittel zur Bekämpfung von Migräne dar.The compound of formula (I) described in the present invention also represents an active ingredient for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. In particular, it is suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease. It is also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances. The active ingredient is also suitable for regulating cerebral blood flow and is therefore an effective means of combating migraines.
Auch eignet er sich zur Prophylaxe und Bekämpfung der Folgen cerebraler Infarkt- geschehen (Apoplexia cerebri) wie Schlaganfall, cerebraler Ischämien und des Schädel-It is also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and the skull
Hirn-Traumas. Ebenso kann die erfindungsgemäße Verbindung der Formel (I) zur Bekämpfung von Schmerzzuständen eingesetzt werden.Brain trauma. Likewise, the compound of formula (I) according to the invention can be used to combat painful conditions.
Darüber hinaus umfasst die Erfindung die Kombination der erfindungsgemäßen Verbindung der Formel (I) mit organischen Nitraten und NO-Donatoren.In addition, the invention comprises the combination of the compound of the formula (I) according to the invention with organic nitrates and NO donors.
Organische Nitrate und NO-Donatoren im Rahmen der Erfindung sind im allgemeinen Substanzen, die über die Freisetzung von NO bzw. NO-Species ihre therapeutische Wirkung entfalten. Bevorzugt sind Natriumnitroprussid, Nitroglycerin, Isosorbiddi- nitrat, Isosorbidmononitrat, Molsidomin und SIN-1.Organic nitrates and NO donors in the context of the invention are generally substances which develop their therapeutic effect through the release of NO or NO species. Sodium nitroprusside, nitroglycerin, isosorbide di-nitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
Außerdem umfasst die Erfindung die Kombination mit Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) inhibieren. Dies sind insbesondere Inhibitoren der Phosphodiesterasen 1, 2 und 5; Nomenklatur nach Beavo und Reif- snyder (1990) TiPS 11 S. 150 bis 155. Durch diese Inhibitoren wird die Wirkung der erfindungsgemäßen Verbindung potenziert und der gewünschte pharmakologische Effekt gesteigert.The invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are in particular inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reif-Snyder (1990) TiPS 11 pp. 150 to 155. These inhibitors potentiate the action of the compound according to the invention and increase the desired pharmacological effect.
Die erfindungsgemäße Verbindung der Formel (I) lässt sich gemäß folgendem Reaktionsschema herstellen:
Figure imgf000006_0001
The compound of the formula (I) according to the invention can be prepared according to the following reaction scheme:
Figure imgf000006_0001
ridinridin
Figure imgf000006_0002
Figure imgf000006_0002
Raney-Ni / H2 Raney-Ni / H 2
Figure imgf000006_0003
Figure imgf000006_0003
Figure imgf000006_0004
Figure imgf000006_0004
Figure imgf000006_0005
Das erfindungsgemäße Herstellungsverfahren für die Verbindung der Formel (I) ist dadurch gekennzeichnet, dass
Figure imgf000006_0005
The production process according to the invention for the compound of formula (I) is characterized in that
die Verbindung der Formel (II)the compound of formula (II)
Figure imgf000007_0001
Figure imgf000007_0001
mit Phenylazomalondinitril in Gegenwart einer Base und anschließende Umsetzung mit Wasserstoff in Gegenwart eines Katalysators zu der Verbindung der Formel (III)with phenylazomalononitrile in the presence of a base and subsequent reaction with hydrogen in the presence of a catalyst to give the compound of the formula (III)
Figure imgf000007_0002
Figure imgf000007_0002
umgesetzt wird, und diese anschließend durch Reaktion mit einem hydroxyl- geschützten 2-Hydroxyacetaldehyd, Reduktion der erhaltenen Iminogruppe, Abspaltung der Hydroxy-Schutzgruppe und Umsetzung mit Glyoxal in die Verbindung der Formel (I) überführt wird. Die Verbindung der Formel (II) ist in einer mehrstufigen Synthese aus dem literaturbekannten Natriumsalz des Cyanobrenztraubensäureethylesters (Borsche und Man- teuffel, Liebigs. Ann. Chem. 1934, 512, 97) erhältlich. Durch dessen Umsetzung mit 2-Fluorbenzylhydrazin unter Erhitzen und Schutzgasatmosphäre in einem inerten Lösungsmittel wie Dioxan erhält man den 5-Amino-l-(2-fluorbenzyl)-pyrazol-3- carbonsäureethylester, der durch Umsetzung mit Dimethylammoacrolein im sauren Medium unter Schutzgasatmosphäre und Erhitzen zum entsprechenden Pyridin- derivat cyclisiert. Dieses Pyridinderivat l-(2-Fluorbenzyl)-lH-pyrazolo[3,4-b]pyri- din-3-carbonsäureethylester wird durch eine mehrstufige Sequenz, bestehend aus Überführung des Esters mit Ammoniak in das entsprechende Amid, Dehydrati- sierung mit einem wasserentziehenden Mittel wie Trifluoressigsäureanhydrid zum entsprechenden Nitrilderivat, Umsetzung des Nitrilderivats mit Natriummethylat und abschließende Reaktion mit Ammoniumchlorid in die Verbindung der Formel (II) überführt.is reacted, and this is subsequently converted into the compound of the formula (I) by reaction with a hydroxyl-protected 2-hydroxyacetaldehyde, reduction of the imino group obtained, elimination of the hydroxy protective group and reaction with glyoxal. The compound of the formula (II) is obtainable in a multistage synthesis from the sodium salt of the cyanobenzofruvic acid ethyl ester (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934, 512, 97) known from the literature. By reacting it with 2-fluorobenzylhydrazine under heating and in a protective gas atmosphere in an inert solvent such as dioxane, 5-amino-l- (2-fluorobenzyl) -pyrazole-3-carboxylic acid ethyl ester is obtained, which is obtained by reaction with dimethylammoacrolein in an acidic medium under a protective gas atmosphere and heating cyclized to the corresponding pyridine derivative. This ethyl pyridine derivative l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxylate is subjected to a multistage sequence consisting of converting the ester with ammonia into the corresponding amide, dehydration with a dehydrating agents such as trifluoroacetic anhydride to give the corresponding nitrile derivative, reaction of the nitrile derivative with sodium methylate and final reaction with ammonium chloride are converted into the compound of the formula (II).
Die Synthese von Phenylazomalondinitril aus Anilin und Malondinitril durch Diazotierung ist literaturbekannt ((L.F.Cavalieri, J.F.Tanker, A.Bendich J.Am.Chem.Soc. 1949, 71,533).The synthesis of phenylazomalondinitrile from aniline and malondinitrile by diazotization is known from the literature ((L.F. Cavalieri, J.F. Tanker, A.Bendich J.Am.Chem.Soc. 1949, 71,533).
Die Umsetzung der Verbindung der Formel (II) mit Phenylazomalondinitril erfolgt inThe reaction of the compound of formula (II) with phenylazomalondinitrile is carried out in
Gegenwart einer Base. Als Basen können hierbei im allgemeinen anorganische oder organische Basen eingesetzt werden. Hierzu gehören vorzugsweise Alkalihydroxide wie zum Beispiel Natriumhydroxid oder Kaliumhydroxid, Erdalkalihydroxide wie zum Beispiel Bariumhydroxid, Alkalicarbonate wie Natriumcarbonat oder Kaliumcarbonat, Erdalkalicarbonate wie Calciumcarbonat, oder Alkali- oder Erdalkalialkohol ate wiePresence of a base. In general, inorganic or organic bases can be used as bases. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali or alkaline earth metal alcohol such as
Natrium- oder Kaliummethanolat, Natrium- oder Kaliumethanolat oder Kalium- tert.butylat, oder organische Amine (Trialkyl(CrC6)-amine) wie Triethylamin, oder Heterocyclen wie l,4-Diazabicyclo[2.2.2]octan (DABCO), 1 ,8-Diazabicyclo- [5.4.0]undec-7-en (DBU), Pyridin, Diaminopyridin, Methylpiperidin oder Morpholin. Es ist auch möglich, als Basen Alkalimetalle wie Natrium und deren Hydride wieSodium or potassium methoxide, sodium or potassium ethanol or potassium tert-butoxide, or organic amines (trialkyl (CrC 6 ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1 , 8-diazabicyclo- [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium and their hydrides as bases
Natriumhydrid einzusetzen. Bevorzugt ist Natriummethanolat. Als Lösemittel eignen sich hierbei inerte organische Lösemittel. Hierzu gehören Ether, wie Diethylether oder Tetrahydrofuran, DME, Dioxan, Alkohole wie Methanol und Ethanol, Halogenkohlenwasserstoffe wie Dichlormethan, Trichlormethan, Tetrachlor- methan, 1,2-Dichlorethan, Trichlorethan, Tetrachlorethan, 1,2-Dichlorethan oderUse sodium hydride. Sodium methoxide is preferred. Inert organic solvents are suitable as solvents. These include ethers such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or
Trichlorethylen, Kohlenwasserstoffe wie Benzol, Xylol,Toluol, Hexan, Cyclohexan, oder Erdölfraktionen, Nitromethan, Dimethylformamid, Aceton, Acetonitril oder Hexa- methylphosphorsäuretriamid. Ebenso ist es möglich, Gemische der Lösemittel einzusetzen. Besonders bevorzugt ist Tetrahydrofuran, Dimethylformamid, Toluol, Dioxan oder Dimethoxyethan.Trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane is particularly preferred.
Die Reaktion wird unter Erhitzen auf Temperaturen zwischen 60°C und 110°C und Normaldruck durchgeführt. Man lässt das Reaktionsgemisch etwa 5-24 Stunden, vorzugsweise 12 bis 24 Stunden reagieren.The reaction is carried out with heating to temperatures between 60 ° C and 110 ° C and normal pressure. The reaction mixture is allowed to react for about 5-24 hours, preferably 12 to 24 hours.
Anschließend wird durch Spaltung der Azogruppe die Verbindung der Formel (III) erhalten. Als Reduktionsmittel können hierfür Metalle, insbesondere Zink, in Gegenwart von Mineralsäuren wie Salzsäure, Na2SO4, Borane oder Wasserstoff in Gegenwart eines Katalysators verwendet werden. Erfindungsgemäß bevorzugt ist die Verwendung von Wasserstoff in Gegenwart von Raney-Ni ekel.The compound of the formula (III) is then obtained by cleaving the azo group. For this purpose, metals, in particular zinc, can be used as reducing agents in the presence of mineral acids such as hydrochloric acid, Na 2 SO 4 , boranes or hydrogen in the presence of a catalyst. According to the invention, the use of hydrogen in the presence of Raney-Ni is preferred.
Als Lösemittel können die vorstehend genannten Lösemittel eingesetzt werden. Besonders bevorzugt ist hierbei Dimethylformamid (DMF) Die Reaktion wird vorzugsweise unter Erwärmen, beispielsweise bei 50-80°C, und einem Wasserstoffdruck von 30 bis 80 bar, vorzugsweise 50 bis 70 bar durchgeführt. Man lässt die Reaktionspartner etwa 24 Stunden reagieren.The solvents mentioned above can be used as solvents. Dimethylformamide (DMF) is particularly preferred. The reaction is preferably carried out with heating, for example at 50-80 ° C., and a hydrogen pressure of 30 to 80 bar, preferably 50 to 70 bar. The reactants are allowed to react for about 24 hours.
Die Verbindung der Formel (III) wird mit einem hydroxylgeschützten 2-Hydroxy- acetaldehyd umgesetzt und anschließend die entstandene Iminogruppe reduziert. Als Schutzgruppen für die Hydroxyfünktion kommen die herkömmlichen, dem Fachmann bekannten Hydroxylschutzgruppen in Frage. Bevorzugt ist die Verwendung einer Silylschutzgruppe, insbesondere der t-Butyldimethylsilylschutzgruppe.The compound of formula (III) is reacted with a hydroxyl-protected 2-hydroxyacetaldehyde and the imino group formed is then reduced. The conventional, the skilled person come as protective groups for the hydroxy function known hydroxyl protecting groups in question. The use of a silyl protective group, in particular the t-butyldimethylsilyl protective group, is preferred.
Als Lösemittel können die vorstehend genannten Lösemittel eingesetzt werden. Besonders bevorzugt ist hierbei Methanol. Die Reaktion wird vorzugsweise bei Raumtemperatur und Normaldruck durchgeführt.The solvents mentioned above can be used as solvents. Methanol is particularly preferred. The reaction is preferably carried out at room temperature and normal pressure.
Die durch diese Umsetzung erhaltene Iminogruppe wird vorzugsweise in situ zur entsprechenden sekundären Aminogruppe reduziert.. Hierfür können die dem Fachmann für diese Reaktion bekannten Reduktionsmittel wie Alkalimetallhydride, beispielsweiseThe imino group obtained by this reaction is preferably reduced in situ to the corresponding secondary amino group. For this purpose, the reducing agents known to the person skilled in the art for this reaction, such as alkali metal hydrides, for example
Lithiumaluminiumhydrid oder Natriumborhydrid oder Natriumcyanoborhydrid, Alkalimetalle wie Natrium in Ethanol oder Wasserstoff in Gegenwart eines Katalysators verwendet werden. Erfindungsgemäß bevorzugt ist die Reduktion mit Natriumcyanoborhydrid in Gegenwart eines wasserentziehenden Mittels wie Molekularsieb. Die Reduktion wird vorzugsweise bei Raumtemperatur durchgeführt und ist nach etwa 2 bis 8 Stunden, vorzugsweise nach etwa 3 bis 5 Stunden abgeschlossen.Lithium aluminum hydride or sodium borohydride or sodium cyanoborohydride, alkali metals such as sodium in ethanol or hydrogen can be used in the presence of a catalyst. Reduction with sodium cyanoborohydride in the presence of a dehydrating agent such as molecular sieve is preferred according to the invention. The reduction is preferably carried out at room temperature and is complete after about 2 to 8 hours, preferably after about 3 to 5 hours.
Aus dem so erhaltenen hydroxylgeschützten Ethanolaminderivat wird die erfindungsgemäße Verbindung der Formel (I) durch Entschützung der Hydroxylgruppe und an- schließende Umsetzung mit Glyoxal erhalten. Die Wahl des Entschützungsmittels ist abhängig von der gewählten Schutzgruppe. Im Fall der erfindungsgemäß bevorzugten Silylschutzgruppen können vorzugsweise Fluoridverbindungen wie Tetrabutylammo- niumfluorid unter für diese Reaktionen herkömmlichen und dem Fachmann bekannten Bedingungen verwendet werden.The compound of formula (I) according to the invention is obtained from the hydroxyl-protected ethanolamine derivative thus obtained by deprotection of the hydroxyl group and subsequent reaction with glyoxal. The choice of deprotectant depends on the selected protective group. In the case of the silyl protecting groups preferred according to the invention, fluoride compounds such as tetrabutylammonium fluoride can preferably be used under conditions which are conventional for these reactions and known to the person skilled in the art.
Die Reaktion mit Glyoxal, vorzugsweise in Form dessen Hydrats, wird unter Schutzgasatmosphäre, beispielsweise unter Stickstoff oder einem Edelgas wie Argon durchgeführt. Die Reaktion wird bei Raumtemperatur für etwa 12 bis 24 Stunden durchgeführt. Als Lösemittel kommen für diese letzten Schritte ebenfalls die vorstehend ge- nannten Lösemittel in Frage, wobei Tetrahydrofuran (THF) besonders bevorzugt ist. Anstelle von Glyoxal können auch Acetalverbindungen davon - gegebenenfalls in Gegenwart von Säuren - eingesetzt werden.The reaction with glyoxal, preferably in the form of its hydrate, is carried out under a protective gas atmosphere, for example under nitrogen or a noble gas such as argon. The reaction is carried out at room temperature for about 12 to 24 hours. The solvents mentioned above can also be used as solvents for these last steps, tetrahydrofuran (THF) being particularly preferred. Instead of glyoxal, acetal compounds thereof can also be used, if appropriate in the presence of acids.
Die Erfindung wird nachstehend durch ein bevorzugtes Ausführungsbeispiel näher erläutert, auf welches sie jedoch nicht eingeschränkt ist. Soweit nicht anders angegeben, beziehen sich nachstehend alle Mengenangaben auf Gewichtsprozente. The invention is explained in more detail below by a preferred exemplary embodiment, to which, however, it is not restricted. Unless otherwise stated, all quantities given below refer to percentages by weight.
BeispieleExamples
Abkürzunger L:Abbreviation L:
RT: RaumtemperaturRT: room temperature
EE: EssigsäureethylesterEE: ethyl acetate
MCPBA: m-ChlorperoxybenzoesäureMCPBA: m-chloroperoxybenzoic acid
BABA: n-Butylacetat/n-Butanol/Eisessig/Phosphatpuffer pH 6BABA: n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6
(50:9:25.15; org. Phase)(50: 9: 25.15; original phase)
Laufmittel für die Dünnschichtchromatographie:Eluents for thin layer chromatography:
TI El: Toluol - Essigsäureethylester (1:1)TI El: toluene - ethyl acetate (1: 1)
TI EtOHl : Toluol - Methanol (1:1)TI EtOHl: toluene - methanol (1: 1)
C1 E1: Cyclohexan - Essigsäureethylester (1:1)C1 E1: cyclohexane - ethyl acetate (1: 1)
C1 E2: Cyclohexan - Essigsäureethylester (1 :2)C1 E2: cyclohexane - ethyl acetate (1: 2)
1. Herstellung von 5-Amino- 1 -(2-fluorbenzyl)-pyrazol-3-carbonsäureethylester1. Preparation of 5-amino-1 - (2-fluorobenzyl) -pyrazole-3-carboxylic acid ethyl ester
Figure imgf000012_0001
Figure imgf000012_0001
100 g (0.613 mol) Natriumsalz des Cyanobrenztraubensäureethylester (Darstellung analog Borsche und Manteuffel, Liebigs Ann. 1934, 512, 97) werden unter gutem Rühren unter Argon in 2.5 1 Dioxan bei Raumtemperatur mit 111.75 g (75 ml, 0.98 mol) Trifluoressigsäure versetzt und 10 min gerührt, wobei ein großer Teil des Eduktes in Lösung geht. Dann gibt man 85.93 g (0.613 mol) 2-Fluorbenzylhydrazin hinzu und kocht über Nacht. Nach Abkühlen werden die ausgefallenen Kristalle des Natriumtrifluoracetats abgesaugt, mit Dioxan gewaschen und die Lösung roh weiter umgesetzt.100 g (0.613 mol) sodium salt of ethyl cyanobrenzenate (representation analogous to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) are mixed with 111.75 g (75 ml, 0.98 mol) trifluoroacetic acid while stirring well under argon in 2.5 1 dioxane at room temperature Stirred for 10 min, a large part of the starting material going into solution. Then 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine are added and cook over night. After cooling, the precipitated crystals of sodium trifluoroacetate are filtered off with suction, washed with dioxane and the solution is further reacted raw.
Herstellung von 1 -(2-Fluorbenzyl)-lH-pyrazolo[3,4-blpyridin-3-carbonsäure- ethylesterPreparation of 1 - (2-fluorobenzyl) -lH-pyrazolo [3,4-blpyridine-3-carboxylic acid, ethyl ester
Figure imgf000013_0001
Figure imgf000013_0001
Die aus 1. erhaltene Lösung wird mit 61.25 ml (60.77 g, 0.613 mol) Dimethylammoacrolein und 56.28 ml (83.88 g, 0.736 mol) TrifTuoressigsäure versetzt und unter Argon 3 Tage lang gekocht. Anschließend wird das Lösungsmittel im Vakuum verdampft, der Rückstand in 2 1 Wasser gegeben und dreimal mit je 1 1 Essigester extrahiert. Die vereinigten organischen Phasen werden mit Magnesiumsulfat getrocknet und einrotiert. Man chromatographiert auf 2.5 kg Kieselgel und eluiert mit einem Toluol / Toluol-Essigester=4:l -Gradienten. Ausbeute: 91.6 g (49.9 % d.Th. über zwei Stufen). Smp. 85°C Rf (SiO2, TlEl): 0.83 Herstellung von l-(2-Fluorbenzyl)-lH-pyrazolo[3,4-b]pyridin-3-carboxamidThe solution obtained from 1. is mixed with 61.25 ml (60.77 g, 0.613 mol) of dimethylammoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under argon for 3 days. The solvent is then evaporated in vacuo, the residue is poured into 2 liters of water and extracted three times with 1 liter of ethyl acetate. The combined organic phases are dried with magnesium sulfate and evaporated. It is chromatographed on 2.5 kg of silica gel and eluted with a toluene / toluene ethyl acetate = 4: 1 gradient. Yield: 91.6 g (49.9% of theory over two stages). Mp 85 ° CR f (SiO 2 , TlEl): 0.83 Preparation of l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxamide
Figure imgf000014_0001
Figure imgf000014_0001
10.18 g (34 mmol) des in Beispiel 2 erhaltenen Esters werden in 150 ml mit Ammoniak bei 0 - 10°C gesättigtem Methanol vorgelegt. Man rührt zwei Tage bei Raumtemperatur und engt anschließend im Vakuum ein. Rf (SiO2, TlEl): 0.3310.18 g (34 mmol) of the ester obtained in Example 2 are placed in 150 ml of methanol saturated with ammonia at 0-10 ° C. The mixture is stirred at room temperature for two days and then concentrated in vacuo. R f (SiO 2 , TlEl): 0.33
4. Herstellung von 3-Cyano-l-(2-fluorbenzyl)-lH-pyrazolo[3,4-blpyridin4. Preparation of 3-cyano-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-blpyridine
Figure imgf000014_0002
Figure imgf000014_0002
36.1 g (133 mmol) l-(2-Fluorbenzyl)-lH-pyrazolo[3,4-b]pyridin-3-carboxamid aus Beispiel 3 werden in 330 ml THF gelöst und mit 27 g (341 mmol) Pyridin versetzt.36.1 g (133 mmol) of l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxamide from Example 3 are dissolved in 330 ml of THF and 27 g (341 mmol) of pyridine are added.
Anschließend gibt man innerhalb von 10 min 47.76 ml (71.66 g, 341 mmol) Tri- fluoressigsäureanhydrid hinzu, wobei die Temperatur bis auf 40°C ansteigt. Man rührt über Nacht bei Raumtemperatur. Anschließend wird der Ansatz in 11 Wasser gegeben und dreimal mit je 0.5 1 Essigester extrahiert. Die organische Phase wird mit gesättigter Natriumhydrogencarbonatlösung und mit 1 N HCl gewaschen, mit MgS04 getrocknet und einrotiert. Ausbeute: 33.7 g (100% d.Th.) Smp: 81°C Rf (SiO2, TlEl): 0.74Then 47.76 ml (71.66 g, 341 mmol) of trifluoroacetic anhydride are added over the course of 10 min, the temperature rising to 40.degree. The mixture is stirred overnight at room temperature. The mixture is then poured into 11 water and extracted three times with 0.5 l of ethyl acetate each time. The organic phase is with saturated sodium bicarbonate solution and washed with 1N HCl, dried with MgS0 4 and evaporated. Yield: 33.7 g (100% of theory) mp: 81 ° CR f (SiO 2 , TlEl): 0.74
5. Herstellung von (2-Fluorbenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -carboximid- säuremethylester5. Preparation of (2-fluorobenzyl) - 1 H-pyrazolo [3, 4-b] pyridine-3-carboximidic acid methyl ester
Figure imgf000015_0001
Figure imgf000015_0001
Man löst 30.37 g (562 mmol) Natriummethylat in 1.5 1 Methanol und gibt 36.45 g (144.5 mmol) 3-Cyano-l-(2-fluorbenzyl)-lH-pyrazolo[3,4-b]pyridin (aus Beispiel 4) hinzu. Man rührt 2 Stunden bei Raumtemperatur und setzt die erhaltene Lösung direkt für die nächste Stufe ein. 30.37 g (562 mmol) of sodium methylate are dissolved in 1.5 l of methanol and 36.45 g (144.5 mmol) of 3-cyano-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine (from Example 4) are added , The mixture is stirred for 2 hours at room temperature and the solution obtained is used directly for the next step.
6. Herstellung von l-(2-Fluorbenzyl)lH-pyrazolor3,4-blpyridin-3-carboxamidin (Verbindung II)6. Preparation of l- (2-fluorobenzyl) lH-pyrazolor3,4-blpyridine-3-carboxamidine (Compound II)
Figure imgf000016_0001
Figure imgf000016_0001
Die aus Beispiel 5 erhaltene Lösung von (2-Fluorbenzyl)-lH-pyrazolo[3,4-b]pyridin- 3-carboximidsäuremethylester in Methanol wird mit 33.76 g (32.19 ml, 562 mmol) Eisessig und 9.28 g (173 mmol) Ammoniumchlorid versetzt und über Nacht unter Rückfluss gerührt. Man verdampft das Lösungsmittel im Vakuum, verreibt den Rückstand gut mit Aceton und saugt den ausgefallenen Feststoff ab. Man gibt in 2 1The solution of (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester in methanol obtained from Example 5 is combined with 33.76 g (32.19 ml, 562 mmol) glacial acetic acid and 9.28 g (173 mmol) ammonium chloride added and stirred under reflux overnight. The solvent is evaporated off in vacuo, the residue is triturated well with acetone and the precipitated solid is filtered off with suction. You give 1 in 2
Wasser, versetzt unter Rühren mit 31.8 g Natriumcarbonat und extrahiert dreimal mit insgesamt 1 1 Essigester, trocknet die organische Phase mit Magnesiumsulfat und dampft im Vakuum ein. Ausbeute 27.5 g (76.4 % d.Th. über zwei Stufen) Smp.: 86°CWater, 31.8 g of sodium carbonate are added with stirring and extracted three times with a total of 1 l of ethyl acetate, the organic phase dries with magnesium sulfate and evaporates in vacuo. Yield 27.5 g (76.4% of theory over two stages) mp: 86 ° C
Rf (SiO2, TlEtOHl): 0.08 R f (SiO 2 , TlEtOHl): 0.08
7. Herstellung von von 2-|"l-(2-Fluorobenzyl)-lH-pyrazolo[3,4-blpyridin-3-yll- 5-[(E)-phenyldiazenyll-4,6-pyrimidindiamin7. Manufacture of 2- | " 1- (2-Fluorobenzyl) -IH-pyrazolo [3,4-blpyridin-3-yll-5 - [(E) -phenyldiazenyll-4,6-pyrimidine diamine
Figure imgf000017_0001
Figure imgf000017_0001
Man gibt zu einer gerührten Lösung von 21.92 g (71.7 mmol) l-(2-Fluorbenzyl)lH- pyrazolo[3,4-b]pyridin-3-carboxamidin in Toluol aus Beispiel 6 3.87 g Natrium- methanolat und anschließend 12.2 g (71.7 mmol) Phenylazomalononitril (L.F.Cavalieri, J.F.Tanker, A.Bendich J.Am.Chem.Soc, 1949, 71, 533). Man rührt über Nacht bei 110°C und lässt abkühlen. Der hierbei ausgefallene Feststoff wird abgesaugt und mit Ethanol gewaschen. Nach Trocknung erhält man 23 g (73 % d.Th.) der Zielverbindung. 3.87 g of sodium methoxide are added to a stirred solution of 21.92 g (71.7 mmol) of l- (2-fluorobenzyl) lH-pyrazolo [3,4-b] pyridine-3-carboxamidine in toluene from Example 6 and then 12.2 g ( 71.7 mmol) phenylazomalononitrile (LFCavalieri, JFTanker, A.Bendich J.Am.Chem.Soc, 1949, 71, 533). The mixture is stirred at 110 ° C. overnight and allowed to cool. The solid which has precipitated out is filtered off with suction and washed with ethanol. After drying, 23 g (73% of theory) of the target compound are obtained.
Darstellung von 2-|T -(2-Fluorobenzyl)-lH-pyrazolo[3,4-b1pyridin-3-yll- 4,5,6-pyrimidintriamin Trihydrochlorid (Verbindung (III)Preparation of 2- | T - (2-fluorobenzyl) -lH-pyrazolo [3,4-b1pyridin-3-yll-4,5,6-pyrimidinetriamine trihydrochloride (compound (III)
Figure imgf000018_0001
Figure imgf000018_0001
5 g (11.38 mmol) 2-[l-(2-Fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)- phenyldiazenyl]-4,6-pyrimidindiamin aus Beispiel 7 werden mit 800 mg 50 proz. Raney-Nickel in Wasser in 60 ml DMF 22 Stunden lang bei 65 bar Wasserstoffdruck und 62°C hydriert. Man saugt vom Katalysator über Kieselguhr ab, dampft die Lösung im Vakuum ein und rührt mit 5 N HCl. Der ausgefallene gelbbraune Niederschlag wird abgesaugt und getrocknet. Man erhält 3.1 g (59.3 % d. Th.) der Zielverbindung. Die freie Base erhält man durch Ausschütteln mit verdünnter NaHCO3- Lösung und extrahieren mit Essigester. Der in beiden Phasen unlösliche Feststoff wird abgesaugt. Auch die Essigesterphase enthält geringe Mengen der freien Base. 5 g (11.38 mmol) of 2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5 - [(E) - phenyldiazenyl] -4,6-pyrimidinediamine Example 7 are with 800 mg 50 percent. Raney nickel in water in 60 ml DMF hydrogenated for 22 hours at 65 bar hydrogen pressure and 62 ° C. It is suctioned off from the catalyst over Kieselguhr, the solution is evaporated in vacuo and stirred with 5 N HCl. The precipitated yellow-brown precipitate is filtered off and dried. 3.1 g (59.3% of theory) of the target compound are obtained. The free base is obtained by shaking out with dilute NaHCO 3 solution and extracting with ethyl acetate. The solid which is insoluble in both phases is filtered off with suction. The ethyl acetate phase also contains small amounts of the free base.
Darstellung von N5-(2- { Ftert-Butyl(dimethyl)silyl"loxy} ethyl)-2- 1 -(2-fluoro- benzyl)- 1 H-pyrazolo [3 ,4-b1pyridin-3-yl1 -4,5 ,6-pyrimidintriaminPreparation of N5- (2- {Ftert-Butyl (dimethyl) silyl " loxy} ethyl) -2- 1 - (2-fluorobenzyl) - 1 H-pyrazolo [3, 4-b1pyridin-3-yl1 -4, 5, 6-pyrimidine triamine
Figure imgf000019_0001
Figure imgf000019_0001
Man löst 6 g (17.13 mmol) 2-[l-(2-Fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]- 4,5,6-pyrirnidintriamin aus Beispiel 8 in 200 ml Methanol und gibt 3.28 g (18.84 mmol) t-Butyldimethylsilyloxyacetaldehyd hinzu. Anschließend werden 30g Molsieb, und nach 10 Minuten 1.35 g (22.26 mmol) Natriumcyanoborhydrid sowie 4 ml Eisessig hinzugegeben und 5 Stunden bei Raumtemperatur gerührt. Man dekantiert vom Molsieb ab, gibt 35 g Kieselgel hinzu und dampft im Vakuum ein. Der Rückstand wird auf einer SiO2-Säule mit Toluol/Essigester = 5:1 -> Essigester Gradienten chromatographiert. Man erhält nach einer Vorfraktion (Rf[SiO2, Toluol/Essigester=l :l]=0.67; Bis(TBDMS-Oxyethyl)- Verbindung) als Hauptfraktion 3.3 g (37.9 % d.Th.) eines gelben Feststoffes6 g (17.13 mmol) of 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] - 4,5,6-pyrimidine triamine from Example 8 are dissolved in 200 ml of methanol and adds 3.28 g (18.84 mmol) of t-butyldimethylsilyloxyacetaldehyde. Then 30 g molecular sieve, and after 10 minutes 1.35 g (22.26 mmol) sodium cyanoborohydride and 4 ml glacial acetic acid are added and the mixture is stirred for 5 hours at room temperature. Decant from the molecular sieve, add 35 g of silica gel and evaporate in vacuo. The residue is chromatographed on a SiO2 column using toluene / ethyl acetate = 5: 1 → ethyl acetate gradient. After a pre-fraction (R f [SiO 2 , toluene / ethyl acetate = 1: 1] = 0.67; bis (TBDMS-oxyethyl) compound), the main fraction obtained is 3.3 g (37.9% of theory) of a yellow solid
Rf (SiO2, Toluol/Essigester = 1:1): 0.27 und 0.22 (Doppelfleck, im UV stark leuchtend). 10. Darstellung von 3-Amino-5-[ 1 -(2-fluorobenzyl)-lH-pyrazolo[3,4-blpyridin- 3-yll-10-oxa-l,4,6,8-tetraazatricyclor7.3.1.02,71trideca-2,4,6-trien-13-ol (Verbindung I)R f (SiO 2 , toluene / ethyl acetate = 1: 1): 0.27 and 0.22 (double stain, very bright in the UV). 10. Preparation of 3-amino-5- [1 - (2-fluorobenzyl) -IH-pyrazolo [3,4-blpyridin-3-yll-10-oxa-l, 4,6,8-tetraazatricyclor 7.3.1.02 , 71trideca-2,4,6-trien-13-ol (Compound I)
Figure imgf000020_0001
Figure imgf000020_0001
Man löst 1.5 g (2.95 mmol) N5-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidintriamin aus Beispiel 9 in 20 ml Tetrahydrofuran (THF), gibt 2.68 ml (2.95 mmol) einer 1.1 M Lösung von Tetrabutylammoniumfluorid in THF hinzu und rührt 2 Stunden lang bei Raumtemperatur. Das Dünnschichtchromatogramm zeigt vollständigen Umsatz zu einem neuen Hauptprodukt, 2-( {4,6-Diamino-2-[ 1 -(2-fluorbenzyl)- 1 H-pyrazolo[3,4-b]pyri- din-3-yl]-5-pyrimidinyl}amino)ethanol (Rf[SiO2,Essigester]=0.12; Edukt:0.7). Η-NMR (300 MHz, DMSO): δ = 2.85 (m, 2H, CH2), 3.15 (m, 1H), 3.45 (m, 2H), 4.8 (t, 1H), 5.8 (s, 2H, CH2Ph), 6.15 (s, 4H, 2 NH2), 7.1 (m, 2H), 7.2 (m, 1H), 7.311.5 g (2.95 mmol) of N5- (2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) -2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine are dissolved -3-yl] -4,5,6-pyrimidine triamine from Example 9 in 20 ml of tetrahydrofuran (THF), adds 2.68 ml (2.95 mmol) of a 1.1 M solution of tetrabutylammonium fluoride in THF and stirred for 2 hours at room temperature. The thin layer chromatogram shows complete conversion to a new main product, 2- ({4,6-diamino-2- [1 - (2-fluorobenzyl) -1 H-pyrazolo [3,4-b] pyridine-3-yl] -5-pyrimidinyl} amino) ethanol (Rf [SiO 2 , ethyl acetate] = 0.12; educt: 0.7). Η NMR (300 MHz, DMSO): δ = 2.85 (m, 2H, CH 2 ), 3.15 (m, 1H), 3.45 (m, 2H), 4.8 (t, 1H), 5.8 (s, 2H, CH 2 Ph), 6.15 (s, 4H, 2 NH 2 ), 7.1 (m, 2H), 7.2 (m, 1H), 7.31
(m, 2H), 8.6 (dd, 1H, pyrazolopyridin H6), 9.05 (dd, 1H, pyrazolopyridin H4).(m, 2H), 8.6 (dd, 1H, pyrazolopyridine H6), 9.05 (dd, 1H, pyrazolopyridine H4).
Anschließend gibt man unter Rühren unter Argon 693 mg (0.69 ml, 2.95 mmol) einer 40 proz. wässrigen Glyoxalhydratlösung hinzu und rührt über Nacht. Im HPLC ist vollständiger Umsatz zu zwei neuen Hauptprodukten zu erkennen. Die Lösung wird im Vakuum eingedampft und auf einer RP-8 Säule mit einem Gradienten von Acetonitril/Wasser= 10/90 -> 90/10 eluiert. Die zweite Fraktion enthält die gewünschte Verbindung. Sie wird im Vakuum vom Acetonitril-Anteil befreit und das ausgefallene Produkt aus der wässrigen Lösung abgesaugt und mit Ether gewaschen. Man erhält 150 mg eines schwachgelben Pulvers.Then, while stirring under argon, 693 mg (0.69 ml, 2.95 mmol) of a 40 percent. aqueous glyoxal hydrate solution and stir overnight. Complete sales of two new main products can be seen in the HPLC. The solution is evaporated in vacuo and eluted on an RP-8 column with a gradient of acetonitrile / water = 10/90 -> 90/10. The second fraction contains the desired compound. It is freed from the acetonitrile portion in vacuo and that filtered off the precipitated product from the aqueous solution and washed with ether. 150 mg of a pale yellow powder are obtained.
Η-NMR (400 MHz, CD3CN, Austausch mit MeOH): δ= 3.0 (m,lH), 3.18(m, 1H), 3.22-3.34(m, 2H), 4.5(s, 1H), 4.8 (d, 1H), 5.8 (s,2H,CH2), 5.95 (d, 1H, Austausch., OH), 6.2(breites s, 2H, Austausch, NH2), 7.11 (m, 2H, 2-fluorbenzyl), 7.22 (m, 2H, fluorbenzyl), 7.34 (dd, 1H, pyrazolopyridin H5), 8.05 ppm(lH, d, Austausch, OH), 8.6 (dd, 1H, pyrazolopyridin H6), 9.05 (dd, 1H, pyrazolopyridin H4).Η NMR (400 MHz, CD 3 CN, exchange with MeOH): δ = 3.0 (m, 1H), 3.18 (m, 1H), 3.22-3.34 (m, 2H), 4.5 (s, 1H), 4.8 ( d, 1H), 5.8 (s, 2H, CH 2 ), 5.95 (d, 1H, exchange., OH), 6.2 (broad s, 2H, exchange, NH 2 ), 7.11 (m, 2H, 2-fluorobenzyl) , 7.22 (m, 2H, fluorobenzyl), 7.34 (dd, 1H, pyrazolopyridine H5), 8.05 ppm (lH, d, exchange, OH), 8.6 (dd, 1H, pyrazolopyridine H6), 9.05 (dd, 1H, pyrazolopyridine H4) ).
Biologische UntersuchungenBiological studies
1. Stimulation der rekombinanten löslichen Guanylatcyclase (sGC) in vitro1. Stimulation of the recombinant soluble guanylate cyclase (sGC) in vitro
Die Untersuchungen zur Stimulation der rekombinanten löslichen Guanylatcyclase (sGC) durch die erfindungsgemäße Verbindung wurde nach der in folgender Literaturstelle im Detail beschriebenen Methode durchgeführt: M. Hoenicka, E.M.The investigations into the stimulation of the recombinant soluble guanylate cyclase (sGC) by the compound according to the invention were carried out according to the method described in detail in the following literature reference: M. Hoenicka, E.M.
Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer und J.-P. Stasch: Purified soluble guanylyl cyclase expressed in a baculovirus/Sf9 system: Stimulation by YC- 1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999) 14.Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer and J.-P. Stasch: Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: Stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999) 14.
Die Aktivierung der sGC durch eine Prüfsubstanz wird als n-fache Stimulation derThe activation of the sGC by a test substance is called n-fold stimulation of the
Basalaktivität angegeben.Basal activity specified.
Tabelle 1Table 1
Figure imgf000021_0001
2. Gefäßrelaxierende Wirkung in vitro
Figure imgf000021_0001
2. Vascular relaxant effect in vitro
Kaninchen werden durch Nackenschlag betäubt und entblutet. Die Aorta wird entnommen, von anhaftendem Gewebe befreit, in 1,5 mm breite Ringe geteilt und einzeln unter Vorspannung in 5 ml - Organbäder mit 37°C warmer, carbogenbegasterRabbits are anesthetized and bled by the blow of the neck. The aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths with carbohydrate gas at 37 ° C
Krebs-Henseleit-Lösung folgender Zusammensetzung (mM) verbracht: NaCl: 119; KCl: 4,8; CaCl2 x 2 H20: 1; MgS04 x 7 H20: 1,4; KH2P04: 1,2; NaHC03: 25; Glucose: 10. Die Kontraktionskraft wird mit Statham UC2-Zellen erfasst, verstärkt und über A D-Wandler (DAS-1802 HC, Keithley Instruments München) digitalisiert, sowie parallel auf Linienschreibern registriert. Zur Erzeugung einer Kontraktion wirdKrebs-Henseleit solution with the following composition (mM): NaCl: 119; KCl: 4.8; CaCl 2 x 2 H 2 0: 1; MgSO 4 x 7 H 2 0: 1.4; KH 2 PO 4 : 1.2; NaHC0 3: 25; Glucose: 10. The contraction force is recorded with Statham UC2 cells, amplified and digitized via AD converter (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on line recorders. To create a contraction
Phenylephrin dem Bad kumulativ in ansteigender Konzentration zugesetzt. Nach mehreren Kontrollzyklen wird die zu untersuchende Substanz in jedem weiteren Durchgang in jeweils steigender Dosierung untersucht und die Höhe der Kontraktion mit der Höhe der im letzten Vordurchgang erreichten Kontraktion verglichen. Daraus wird die Konzentration errechnet, die erforderlich ist, um die Höhe des Kontrollwertes um 50 % zu reduzieren (ICso). Verbindung (I): IC50 = 1200 nMPhenylephrine added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is examined in increasing doses in each further run and the level of the contraction is compared with the level of the contraction achieved in the last previous run. From this, the concentration is calculated which is required to reduce the level of the control value by 50% (ICso). Compound (I): IC 50 = 1200 nM
3. Blutdruckmessungen an narkotisierten Ratten3. Blood pressure measurements on anesthetized rats
Männliche Wistar-Ratten mit einem Körpergewicht von 300 - 350 g werden mit Thiopental (100 mg/kg i.p.) anästhesiert. Nach Tracheotomie wird in die Femoral- arterie ein Katheter zur Blutdruckmessung eingeführt und in die Femoral vene ein Katheter zur Substanzgabe. Die zu prüfende Substanz wird in Transcutol/Cremo- phor/EL/H2O (10%/10%/80%) in einem Volumen von 1 ml/kg intravenös verabreicht. Verbindung (I) induziert eine dosisabhängige und langanhaltende Blutdrucksenkung an Ratten. Nach intravenöser Gabe von 0.1 mg/kg und 0.3 mg/kg wurde eine maximale Blutdrucksenkung von -17 mm bzw. - 41 mm Hg beobachtet. Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery and a catheter for substance administration into the femoral vein. The substance to be tested is administered intravenously in Transcutol / Cremophor / EL / H 2 O (10% / 10% / 80%) in a volume of 1 ml / kg. Compound (I) induces a dose-dependent and long-lasting lowering of blood pressure in rats. After intravenous administration of 0.1 mg / kg and 0.3 mg / kg, a maximum drop in blood pressure of -17 mm and - 41 mm Hg was observed.

Claims

Patentansprüche claims
1. Verbindung der Formel (I)1. Compound of formula (I)
Figure imgf000023_0001
Figure imgf000023_0001
sowie deren Isomere, Hydrate und Salze.and their isomers, hydrates and salts.
Verfahren zur Herstellung der Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass die Verbindung der Formel (II)A process for the preparation of the compound according to claim 1, characterized in that the compound of formula (II)
Figure imgf000023_0002
Figure imgf000023_0002
mit Phenylazomalondinitril in Gegenwart einer Base und anschließende Umsetzung mit Wasserstoff in Gegenwart eines Katalysators zu der Verbindung der Formel (III)
Figure imgf000024_0001
with phenylazomalononitrile in the presence of a base and subsequent reaction with hydrogen in the presence of a catalyst to give the compound of the formula (III)
Figure imgf000024_0001
umgesetzt wird, und diese anschließend durch Reaktion mit einem hydroxyl- geschützten 2-Hydroxyacetaldehyd, Reduktion der erhaltenen Iminogruppe, Abspaltung der Hydroxy-Schutzgruppe und Umsetzung mit Glyoxal in die Verbindung der Formel (I) überführt wird.is reacted, and this is subsequently converted into the compound of the formula (I) by reaction with a hydroxyl-protected 2-hydroxyacetaldehyde, reduction of the imino group obtained, elimination of the hydroxy protective group and reaction with glyoxal.
Arzneimittel enthaltend die Verbindung der Formel (I) gemäß Anspruch 1.Medicament containing the compound of formula (I) according to claim 1.
Verfahren zur Herstellung von Arzneimitteln, dadurch gekennzeichnet, dass man die Verbindung der Formel (I) gemäß Anspruch 1, gegebenenfalls mit üblichen Hilfs- und Zusatzstoffen in eine geeignete Applikationsform überführt.Process for the preparation of medicaments, characterized in that the compound of the formula (I) according to Claim 1, optionally with conventional auxiliaries and additives, is converted into a suitable form of administration.
Arzneimittel enthaltend die Verbindung der Formel (I) gemäß Anspruch 1 in Kombination mit organischen Nitraten oder NO-Donatoren.Medicaments containing the compound of formula (I) according to claim 1 in combination with organic nitrates or NO donors.
Arzneimittel enthaltend die Verbindung der Formel (I) gemäß Anspruch 1 in Kombination mit Verbindungen, die den Abbau von cyclischen Guanosin- monophosphat (cGMP) inhibieren.Medicaments containing the compound of formula (I) according to claim 1 in combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP).
Verwendung der Verbindung der Formel (I) gemäß Anspruch 1 zur Herstellung von Arzneimitteln. Use of the compound of formula (I) according to claim 1 for the manufacture of medicaments.
8. Verwendung der Verbindung der Formel (I) gemäß Anspruch 1 bei der Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.8. Use of the compound of formula (I) according to claim 1 in the manufacture of medicaments for the treatment of cardiovascular diseases.
9. Verwendung nach Anspruch 8, wobei die Verbindung der Formel (I) in Kom- bination mit organischen Nitraten oder NO-Donatoren oder in Kombination mit9. Use according to claim 8, wherein the compound of formula (I) in combination with organic nitrates or NO donors or in combination with
Verbindungen, die den Abbau von cyclischen Guanosinmonophosphat (cGMP) inhibieren, eingesetzt wird.Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) is used.
10. Verwendung der Verbindung der Formel (I) gemäß Anspruch 1 bei der Her- Stellung von Arzneimitteln zur Behandlung von thromboembolischen Erkrankungen und Ischämien.10. Use of the compound of formula (I) according to claim 1 in the manufacture of medicaments for the treatment of thromboembolic disorders and ischemia.
11. Verwendung nach Anspruch 10, wobei die Verbindung der Formel (I) in Kombination mit organischen Nitraten oder NO-Donatoren oder in Kombination mit Verbindungen, die den Abbau von cyclischen Guanosinmonophosphat (cGMP) inhibieren, eingesetzt wird.11. Use according to claim 10, wherein the compound of formula (I) is used in combination with organic nitrates or NO donors or in combination with compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP).
12. Verwendung der Verbindung der Formel (I) gemäß Anspruch 1 bei der Herstellung von Arzneimitteln zur Behandlung von sexueller Dysfunktion.12. Use of the compound of formula (I) according to claim 1 in the manufacture of medicaments for the treatment of sexual dysfunction.
13. Verwendung nach Anspruch 12, wobei die Verbindung der Formel (I) in Kombination mit organischen Nitraten oder NO-Donatoren oder in Kombination mit Verbindungen, die den Abbau von cyclischen Guanosinmonophosphat (cGMP) inhibieren, eingesetzt wird. 13. Use according to claim 12, wherein the compound of formula (I) is used in combination with organic nitrates or NO donors or in combination with compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP).
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