EP0714301A1 - Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments - Google Patents

Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments

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Publication number
EP0714301A1
EP0714301A1 EP94926199A EP94926199A EP0714301A1 EP 0714301 A1 EP0714301 A1 EP 0714301A1 EP 94926199 A EP94926199 A EP 94926199A EP 94926199 A EP94926199 A EP 94926199A EP 0714301 A1 EP0714301 A1 EP 0714301A1
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EP
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Prior art keywords
general formula
carbon atoms
compounds
medicaments
alkylated
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.)
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Application number
EP94926199A
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German (de)
French (fr)
Inventor
Siegfried Zaiss
Dieter Neuser
Johannes-Peter Stasch
Siegfried Goldmann
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Bayer AG
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Bayer AG
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Publication of EP0714301A1 publication Critical patent/EP0714301A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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

Definitions

  • the present invention relates to the use of partially known N-alkylated 1,4-dihydropyridinedicarboxylic acid esters as antiatherosclerotic medicaments, in particular their use for restenosis prophylaxis after angioplasty and vascular surgical measures.
  • N-alkylieite 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I) N-alkylieite 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I)
  • R 1 represents hydrogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen or methyl
  • R 2 represents hydrogen, halogen, nitro, hydroxy, trifluoromethyl or methyl
  • R 3 represents hydrogen or cyano
  • R 2 and R 3 together form a condensed benzo ring
  • R 4 and R 5 are the same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms,
  • R 6 represents straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 7 carbon atoms
  • 1,2-Trimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 4- (4-chloro-3-trifluoromethylphenyl) -1-cyclopropyl-2 are particularly preferred , 6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in the control of atherosclerosis, in particular for restenosis prophylaxis after angioplasty and vascular surgery.
  • the compounds according to the invention thus show an unforeseeable, valuable pharmacological spectrum of action.
  • the compounds according to the invention inhibit smooth muscle cell proliferation.
  • Vascular wall injuries lead to neointimal cell growth and consequently to a narrowing of the free vascular lumen. This process is the main cause of restenosis problems after vascular opening measures, such as percutaneous angioplasties, endarterectomies or bypass operations.
  • the compounds according to the invention can therefore be used in medicines for the treatment and prophylaxis of residual enosis, e.g. after angioplasty and vascular surgery.
  • the compounds according to the invention can also be used for the treatment of atherosclerosis.
  • a balloon catheter is introduced into the carotid artery, this is inflated and the inside of the blood vessel is injured by moving the catheter [Clowes A.W., et al., Lab. Invest. Vol. 49, No. 3, p. 327, 1983].
  • This damage causes neointimal smooth muscle proliferation, which cause stenoses.
  • the extent of the vasoconstriction in the animals is determined after approximately 2 weeks by histological processing of the blood vessels by measuring the area of the proliferation tissue on vascular cross sections.
  • the compounds according to the invention surprisingly significantly inhibit the vascular constrictions, as can be seen from the table below.
  • the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
  • solutions of the active ingredient can be used using suitable liquid carrier materials.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the use of partially known N-alkylated 1,4 dihydropyridine dicarboxylic acid esters of general formula (I), wherein R1-R6 have the meanings indicated in the description, as anti-atherosclerotic drugs, in particular their use to prevent restenosis following angioplasty and surgery on the blood vessels.

Description

Verwendung von N-alkylierten 1,4-Dihydropyridindicarbonsäureestern als Arznei¬ mittelUse of N-alkylated 1,4-dihydropyridinedicarboxylic acid esters as medicaments
Die vorliegende Erfindung betrifft die Verwendung von teilweise bekannten N-alky¬ lierten 1,4-Dihydropyridindicarbonsäureeestern als antiatherosklerotische Arznei¬ mittel, insbesondere ihre Verwendung zur Restenoseprophylaxe nach Angioplastien und gefaßchirurgischen Maßnahmen.The present invention relates to the use of partially known N-alkylated 1,4-dihydropyridinedicarboxylic acid esters as antiatherosclerotic medicaments, in particular their use for restenosis prophylaxis after angioplasty and vascular surgical measures.
Es ist bereits bekannt, daß 4-Nitro-phenylsubstituierte 1,4-Dihydropyridine auch eine Hemmung der Bildung fibromuskulären Plaques bewirken [vgl. DE 32 22367].It is already known that 4-nitro-phenyl-substituted 1,4-dihydropyridines also inhibit the formation of fibromuscular plaques [cf. DE 32 22367].
Es wurde nun gefunden, daß N-alkylieite 1,4-Dihydropyridindicarbonsäureester der allgemeinen Formel (I)It has now been found that N-alkylieite 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I)
in welcher R1 für Wasserstoff, Nitro, Cyano, Trifluormethyl, Trifluormethoxy, Halogen oder Methyl steht,in which R 1 represents hydrogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen or methyl,
R2 für Wasserstoff, Halogen, Nitro, Hydroxy, Trifluormethyl oder Methyl steht,R 2 represents hydrogen, halogen, nitro, hydroxy, trifluoromethyl or methyl,
R3 für Wasserstoff oder Cyano steht,R 3 represents hydrogen or cyano,
oderor
R2 und R3 gemeinsam einen ankondensierten Benzoring bilden,R 2 and R 3 together form a condensed benzo ring,
R4 und R5 gleich oder verschieden sind und für geradkettiges oder verzweigtes Alkyl mit bis zu 8 Kohlenstoffatomen stehen, das gegebenenfalls durch Alkoxy mit bis zu 4 Kohlenstoffatomen substituiert ist,R 4 and R 5 are the same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms,
R6 für geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoffatomen oder für Cycloalkyl mit 3 bis 7 Kohlenstoffatomen steht,R 6 represents straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 7 carbon atoms,
neben ihrer hämorheologischen Wirkung überraschenderweise eine starke inhibi- torische Wirkung der Glattmuskelzellproliferation besitzen und somit geeignet sind zur Verwendung bei der Bekämpfung von Atherosklerose, insbesondere zur Rest¬ enoseprophylaxe nach Angioplastien und gefaßchirurgischen Maßnahmen.In addition to their hemorheological effect, they surprisingly have a strong inhibitory effect on smooth muscle cell proliferation and are therefore suitable for use in combating atherosclerosis, in particular for residual ene prophylaxis after angioplasty and vascular surgical measures.
Besonders bevorzugt sind l,2,6-Trimethyl-4-(4-trifluormethylphenyl)-l,4-dihydro- pyridin-3,5-dicarbonsäuredimethylester und 4-(4-Chlor-3-trifluormethylphenyl)-l- cyclopropyl-2,6-dimethyl- 1 ,4-dihydropyridin-3,5-dicarbonsäuredimethylester bei der Bekämpfung von Atherosklerose, insbesondere zur Restenoseprophylaxe nach Angioplastien und gefäßchirurgischen Maßnahmen.1,2-Trimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 4- (4-chloro-3-trifluoromethylphenyl) -1-cyclopropyl-2 are particularly preferred , 6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in the control of atherosclerosis, in particular for restenosis prophylaxis after angioplasty and vascular surgery.
Die erfindungsgemäßen Verbindungen zeigen somit ein nicht vorhersehbares, wertvolles pharmakologisches Wirkspektrum. Die erfindungsgemäßen Verbindungen inhibieren die Glattmuskelzellproliferation. Gefaßwandverletzungen führen zu einem neointimalen Zellwachstum und folglich zu einer Einengung des freien Gefäßlumens. Dieser Vorgang ist die Hauptursache für Restenoseprobleme nach gefäßeröff enden Maßnahmen, wie perkutanen Angio¬ plastien, Endarteriektomien oder Bypass-Operationen.The compounds according to the invention thus show an unforeseeable, valuable pharmacological spectrum of action. The compounds according to the invention inhibit smooth muscle cell proliferation. Vascular wall injuries lead to neointimal cell growth and consequently to a narrowing of the free vascular lumen. This process is the main cause of restenosis problems after vascular opening measures, such as percutaneous angioplasties, endarterectomies or bypass operations.
Sie können deshalb in Arzneimitteln zur Behandlung und Prophylaxe von Rest- enose, z.B. nach Angioplastien und gefäßchirurgischen Maßnahmen eingesetzt werden. Darüberhinaus können die erfindungsgemäßen Verbindungen auch zur Behandlung von Atherosklerose eingesetzt werden.They can therefore be used in medicines for the treatment and prophylaxis of residual enosis, e.g. after angioplasty and vascular surgery. In addition, the compounds according to the invention can also be used for the treatment of atherosclerosis.
Die erfindungsgemäßen Verbindungen sind teilweise bekannt [vgl. DOS 40 11 695].Some of the compounds according to the invention are known [cf. DOS 40 11 695].
Zur Feststellung der antiproliferativen Wirkung der erfindungsgemäßen Verbin¬ dungen wird Ratten ein Ballonkatheter in die Halsschlagader eingeführt, dieser aufgeblasen und die Innenseite des Blutgefäßes durch Bewegen des Katheters verletzt [Clowes A.W., et al., Lab. Invest. Vol. 49, No. 3, p. 327, 1983]. Diese Schädigung bewirkt eine neointimale Glattmuskelproliferation, die Stenosen verursachen. Das Ausmaß der Gefäßeinengung bei den Tieren wird nach ca. 2 Wochen durch histologische Aufarbeitung der Blutgefäße bestimmt, indem an Gefäßquerschnitten die Fläche des Proliferationsgewebes vermessen wird. Die erfindungsgemäßen Verbindungen inhibieren überraschenderweise die Gefä߬ einengungen signifikant, wie aus der nachstehenden Tabelle ersichtlich ist.To determine the antiproliferative effect of the compounds according to the invention, a balloon catheter is introduced into the carotid artery, this is inflated and the inside of the blood vessel is injured by moving the catheter [Clowes A.W., et al., Lab. Invest. Vol. 49, No. 3, p. 327, 1983]. This damage causes neointimal smooth muscle proliferation, which cause stenoses. The extent of the vasoconstriction in the animals is determined after approximately 2 weeks by histological processing of the blood vessels by measuring the area of the proliferation tissue on vascular cross sections. The compounds according to the invention surprisingly significantly inhibit the vascular constrictions, as can be seen from the table below.
Beispiel Proliferationsgewebe in μm2 x 1000 (%)Example proliferation tissue in μm 2 x 1000 (%)
Nr. Kontrolle 10 mg/kg p.o.Control 10 mg / kg p.o.
1 129 (100%) 76 (59 %)1 129 (100%) 76 (59%)
2 125 (100%) 56 (45 %) Die neuen Wirkstoffe können in bekannter Weise in die üblichen Formulierungen überführt werden, wie Tabletten, Dragees, Pillen, Granulate, Aerosole, Sirupe, Emulsionen, Suspensionen und Lösungen, unter Verwendung inerter, nicht¬ toxischer, pharmazeutisch geeigneter Trägerstoffe oder Lösemittel. Hierbei soll die therapeutisch wirksame Verbindung jeweils in einer Konzentration von etwa 0,5 bis 90-Gew.-% der Gesamtmischung vorhanden sein, d.h. in Mengen, die ausreichend sind, um den angegebenen Dosierungsspielraum zu erreichen.2 125 (100%) 56 (45%) The new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
Die Formulierungen werden beispielsweise hergestellt durch Verstrecken der Wirkstoffe mit Lösemitteln und/oder Trägerstoffen, gegebenenfalls unter Verwendung von Emulgiermitteln und/oder Dispergiermitteln, wobei z.B. im Fall der Benutzung von Wasser als Verdünnungsmittel gegebenenfalls organische Lösemittel als Hilfslösemittel verwendet werden können.The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
Die Applikation erfolgt in üblicher Weise, vorzugsweise oral oder parenteral, insbesondere perlingual oder intravenös.The application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
Für den Fall der parenteralen Anwendung können Lösungen des Wirkstoffs unter Verwendung geeigneter flüssiger Trägermaterialien eingesetzt werden.In the case of parenteral use, solutions of the active ingredient can be used using suitable liquid carrier materials.
Im allgemeinen hat es sich als vorteilhaft erwiesen, bei intravenöser Applikation Mengen von etwa 0,001 bis 1 mg/kg, vorzugsweise etwa 0,01 bis 0,5 mg kg Körper¬ gewicht zur Erzielung wirksamer Ergebnisse zu verabreichen, und bei oraler Applikation beträgt die Dosierung etwa 0,01 bis 20 mg/kg, vorzugsweise 0,1 bis 10 mg/kg Körpergewicht.In general, it has proven to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg kg, of body weight for intravenous administration in order to achieve effective results, and the dosage is for oral administration about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit vom Körpergewicht bzw. der Art des Applikationsweges, vom individuellen Verhalten gegenüber dem Medikament, der Art von dessen Formulierung und dem Zeitpunkt bzw. Intervall, zu welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muß. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.
Beispiel 1example 1
l,2,6-Trimethyl-4-(4-trifluormethylphenyl)-l,4-dihydropyridin-3,5-dicarbon- säuredimethylesterl, 2,6-trimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid, dimethyl ester
Eine Mischung aus 5,22 g (0,03 mol) 4-Trifluormethylbenzaldehyd, 7,04 g (0,06 mol) Acetessigsäuremethylester und 2,07 g (0,03 mol) Methylamin-Hydrochlorid in 20 ml Pyridin wird 5 Stunden unter Rückfluß gerührt Nach dem Abdestillieren des Pyridins wird zwischen Wasser und Methylenchlorid verteilt, die organische Phase gewaschen mit Wasser, getrocknet über Natriumsulfat und eingedampft. Der Rückstand wird aus Methanol umkristallisiert. Schmp.: 154-155°C Ausbeute: 7,88 g (68,5% d.Th.)A mixture of 5.22 g (0.03 mol) of 4-trifluoromethylbenzaldehyde, 7.04 g (0.06 mol) of methyl acetoacetate and 2.07 g (0.03 mol) of methylamine hydrochloride in 20 ml of pyridine is added for 5 hours Reflux stirred After the pyridine had been distilled off, the mixture was partitioned between water and methylene chloride, the organic phase was washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol. Mp: 154-155 ° C yield: 7.88 g (68.5% of theory)
Beispiel 2Example 2
4-(4-Chlor-3-trifluormethylphenyl)- 1 -cyclopropyl-2,6-dimethyl- 1 ,4-dihydro- pyridin-3,5-dicarbonsäuredimethylester 4- (4-Chloro-3-trifluoromethylphenyl) -1-cyclopropyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester
Verfahren AProcedure A
Eine Lösung von 23,3 g (0,15 mol) 3-Cyclopropylamino-crotonsäuremethylester, 46,0 g (0,15 mol) (4-Chlor-3-trifluormethylbenzyliden)-acetessigsäuremethylester und 17,7 g (0,15 mol) Pyridin-hydrochlorid in 100 ml Pyridin wird 7,5 h unter Rückfluß gerührt. Nach dem Abdampfen im Vakuum wird der Rückstand zwischen 120 ml Methylenchlorid und 150 ml Wasser verteilt. Die organische Phase gibt nach dem Eindampfen ein harziges Rohprodukt, das aus 100 ml Cyclohexan umkristallisiert wird. Schmp.: 131-135°C Ausbeute: 35,0 g (52,6% d.Th.)A solution of 23.3 g (0.15 mol) of 3-cyclopropylamino-crotonic acid methyl ester, 46.0 g (0.15 mol) of (4-chloro-3-trifluoromethylbenzylidene) -acetoacetic acid methyl ester and 17.7 g (0.15 mol ) Pyridine hydrochloride in 100 ml of pyridine is stirred under reflux for 7.5 h. After evaporation in vacuo, the residue is partitioned between 120 ml of methylene chloride and 150 ml of water. After evaporation, the organic phase gives a resinous crude product which is recrystallized from 100 ml of cyclohexane. Mp: 131-135 ° C yield: 35.0 g (52.6% of theory)
Verfahren BProcedure B
Eine Lösung von 4,17 g (0,02 mol) 4-Chlor-3-trifluormethylbenzaldehyd, 4,65 g (0,04 mol) Acetessigsäuremethylester, 1,96 g (0,021 mol) Cyclopropylamin- Hydrochlorid in 20 ml Pyridin wird 4 h unter Rückfluß gerührt. Nach dem Eindampfen wird der Rückstand zwischen 40 ml Methylenchlorid und 50 ml Wasser verteilt. Aus der organischen Phase erhält man durch Eindampfen ein öliges Rohprodukt, das mit Cyclohexan und n-Pentan zur Kristallisation gebracht wird. Schmp.: 131-134°CA solution of 4.17 g (0.02 mol) of 4-chloro-3-trifluoromethylbenzaldehyde, 4.65 g (0.04 mol) of methyl acetoacetate, 1.96 g (0.021 mol) of cyclopropylamine hydrochloride in 20 ml of pyridine becomes 4 h stirred under reflux. After evaporation, the residue is partitioned between 40 ml of methylene chloride and 50 ml of water. Evaporation gives an oily crude product from the organic phase, which is crystallized with cyclohexane and n-pentane. Mp: 131-134 ° C
Ausbeute: 3,33 g (37,5% d.Th.) Yield: 3.33 g (37.5% of theory)

Claims

Patentansprüche claims
Verwendung von N-alkylierten 1,4-Dihydropyridindicarbonsäureester der allgemeinen Formel (I)Use of N-alkylated 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I)
in welcherin which
R1 für Wasserstoff, Nitro, Cyano, Trifluormethyl, Trifluormethoxy, Halogen oder Methyl steht,R 1 represents hydrogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen or methyl,
R2 für Wasserstoff, Halogen, Nitro, Hydroxy, Trifluormethyl oder Methyl steht,R 2 represents hydrogen, halogen, nitro, hydroxy, trifluoromethyl or methyl,
R3 für Wasserstoff oder Cyano steht,R 3 represents hydrogen or cyano,
oderor
R2 und R3 gemeinsam einen ankondensierten Benzoring bilden, R4 und R5 gleich oder verschieden sind und für geradkettiges oder verzweigtes Alkyl mit bis zu 8 Kohlenstoffatomen stehen, das gegebenenfalls durch Alkoxy mit bis zu 4 Kohlenstoffatomen substituiert ist,R 2 and R 3 together form a condensed benzo ring, R 4 and R 5 are the same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms,
R6 für geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoff¬ atomen oder für Cycloalkyl mit 3 bis 7 Kohlenstoffatomen steht,R 6 represents straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 7 carbon atoms,
bei der Bekämpfung von atherosklerotischen Erkrankungen.in the fight against atherosclerotic diseases.
2. Verwendung von Verbindungen der allgemeinen Formel (I) gemäß An¬ spruch 1 zur Behandlung und Prophylaxe von Restenosen.2. Use of compounds of general formula (I) according to claim 1 for the treatment and prophylaxis of restenoses.
3. Verwendung von Verbindungen der allgemeinen Formel (I) gemäß An¬ spruch 1 zur Hemmung der Intimaproliferation in Glattmuskelzellen nach Gefäßwandverletzungen.3. Use of compounds of general formula (I) according to claim 1 for inhibiting intimal proliferation in smooth muscle cells after vascular wall injuries.
4. Verwendung von Verbindungen der allgemeinen Formel (I) gemäß An¬ spruch 1 zur Herstellung von Arzneimitteln zur Bekämpfung von athero¬ sklerotischen Erkrankungen.4. Use of compounds of general formula (I) according to claim 1 for the manufacture of medicaments for combating atherosclerotic diseases.
5. Verwendung von Verbindungen der allgemeinen Formel (I) gemäß An¬ spruch 1 zur Herstellung von -A-rzneimitteln zur Prophylaxe und Bekämpfung von Restenosen nach Gefäßverletzungen.5. Use of compounds of general formula (I) according to claim 1 for the preparation of pharmaceuticals for the prophylaxis and control of restenosis after vascular injuries.
6. Antiatherosklerotisches Arzneimittel enthaltend mindestens eine Verbindung der allgemeinen Formel (I) gemäß Anspruch 1. Verfahren zur Herstellung von antiatherosklerotischen Arzneimitteln, dadurch gekennzeichnet, daß man mindestens eine Verbindung der all¬ gemeinen Formel (I) gemäß Anspruch 1 gegebenenfalls unter Verwendung von üblichen Hilfs- und Trägerstoffen in eine geeignete Applikationsform überführt. 6. Antiatherosclerotic medicament containing at least one compound of general formula (I) according to claim 1. Process for the preparation of antiatherosclerotic medicaments, characterized in that at least one compound of the general formula (I) according to Claim 1 is converted, if appropriate using customary auxiliaries and excipients, into a suitable application form.
EP94926199A 1993-08-27 1994-08-16 Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments Withdrawn EP0714301A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4328884 1993-08-27
DE4328884A DE4328884A1 (en) 1993-08-27 1993-08-27 Use of N-alkylated 1,4-dihydropyridinecarboxylic acid esters as medicaments
PCT/EP1994/002723 WO1995005823A1 (en) 1993-08-27 1994-08-16 Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments

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EP0714301A1 true EP0714301A1 (en) 1996-06-05

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EP (1) EP0714301A1 (en)
JP (1) JPH09501923A (en)
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DE19741694C2 (en) * 1997-09-18 2002-10-31 Schering Ag Use of complexes whose ligand is a bis-amine oxime derivative or an N¶2¶S¶2¶ derivative and whose central atom is a radionuclide
ES2271365T3 (en) 2001-12-20 2007-04-16 Bayer Healthcare Ag DERIVATIVES OF 1,4-DIHIDRO-1,4-DIFENYLPIRIDINE.
US10258498B2 (en) * 2011-11-24 2019-04-16 Richter Gedeon Nyrt. 1,4-dihydropyridine derivatives with Hsp modulating activity

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DE3222367A1 (en) * 1982-06-15 1983-12-15 Bayer Ag, 5090 Leverkusen Use of 1,4-dihydropyridines in antiarteriosclerotics and preparation thereof
EP0169009A3 (en) * 1984-07-17 1988-08-31 FISONS plc Novel dihydropyridine derivatives and their production, formulation and use as pharmaceuticals
DE4011695A1 (en) * 1990-04-11 1991-10-17 Bayer Ag USE OF N-ALKYLATED 1,4-DIHYDROPYRIDE INDICARBOXIC ACID ESTERS AS DRUGS, NEW COMPOUNDS AND METHOD FOR THEIR PREPARATION

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HU9600472D0 (en) 1996-04-29
CA2170285A1 (en) 1995-03-02
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CZ43896A3 (en) 1996-05-15
DE4328884A1 (en) 1995-03-02
BG100367A (en) 1996-07-31
CN1129906A (en) 1996-08-28
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KR960703594A (en) 1996-08-31
NO960777L (en) 1996-04-10

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