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WO1986003748A1 - New piperazine derivatives - Google Patents

New piperazine derivatives Download PDF

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Publication number
WO1986003748A1
WO1986003748A1 PCT/EP1985/000708 EP8500708W WO8603748A1 WO 1986003748 A1 WO1986003748 A1 WO 1986003748A1 EP 8500708 W EP8500708 W EP 8500708W WO 8603748 A1 WO8603748 A1 WO 8603748A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
ester
formula
methyl
piperazinyl
Prior art date
Application number
PCT/EP1985/000708
Other languages
German (de)
French (fr)
Inventor
Wolf-Rüdiger Ulrich
Herman Amschler
Klaus Eistetter
Manfrid Eltze
Dieter Flockerzi
Kurt Klemm
Norbert Kolassa
Karl Sanders
Christian Schudt
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gesellschaft M
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gesellschaft M filed Critical Byk Gulden Lomberg Chemische Fabrik Gesellschaft M
Priority to JP61500269A priority Critical patent/JPS62501972A/en
Publication of WO1986003748A1 publication Critical patent/WO1986003748A1/en
Priority to DK397786A priority patent/DK397786D0/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new piperazine derivatives, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry for the production of medicaments.
  • the invention relates to new piperazine derivatives of the formula I.
  • R1, R2 and R3 are the same or different and are hydrogen, C 1 -C 6 - are alkyl, C 3 -C 7 -alkoxyalkyl, aryl, aryl-C 1 -C 6 -alkyl or aryloxy-C 1 -C 6 -alkyl, R4 is C 1 -C 4 -alkoxy wholly or predominantly substituted by fluorine, R5 Aryl, heteroaryl, aryl-C 1 -C 4 alkyl, heteroaryl-C 1 -C 4 alkyl,
  • Di-heteroaryl-C 1 -C 4 alkyl means and A means straight-chain or branched C 2 -C 5 alkylene, which by
  • C 1 -C 4 alkoxy or aryl may be substituted and their salts.
  • C 1 -C 6 -alkyl is straight-chain or branched and means, for example, hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or in particular Ethyl or methyl radical.
  • C 3 -C 7 alkoxyalkyl is, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or especially methoxyethyl radical.
  • Aryl generally stands for phenyl or substituted phenyl with one or two identical or different substituents from the group halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -alkoxycarbonyl, C 2 -C 5 -acyl, amino and mono- or di-C 1 -C 4 -alkylamino.
  • Aryl-C 1 -C 6 -alkyl is C 1 -C 6 -alkyl which is substituted by aryl.
  • Aryl-C 1 -C 6 -alkyl is, for example, phenethyl, 3- (4-chlorophenyl) propyl or in particular benzyl.
  • Aryloxy-C 1 -C 6 -alkyl is C 1 -C 6 -alkyl which is substituted by aryloxy.
  • Aryloxy-C 1 -C 6 alkyl is, for example, phenoxyethyl.
  • Halogen means bromine, fluorine and especially chlorine.
  • C 1 -C 4 alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl or in particular methyl radical.
  • C 1 -C 4 alkoxy contains, in addition to the oxygen atom, one of the above-mentioned C 4 alkyl radicals. The methoxy and ethoxy radicals are preferred.
  • C 1 -C 4 alkoxycarbonyl contains one of the C 1 -C 4 alkoxy radicals mentioned above.
  • the methoxycarbonyl and the ethoxycarbonyl radical are preferred.
  • C 2 -C 5 acyl contains one of the C 1 -C 4 alkyl radicals mentioned above.
  • the acetyl radical is preferred.
  • mono- or di-C 1 -C 4 -alkylamino contains one or two of the above-mentioned C 1 -C 4 -alkyl radicals.
  • Di-C 1 -C 4 -alkylamino is preferred, and here in particular oimethyl-, diethyl- or diisopropylamino.
  • C 1 -C 4 alkoxy which is wholly or predominantly substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.
  • Heteroaryl for the purposes of the present invention represents the radicals pyridyl-, in particular 2-pyridyl-, and pyrimidyl-, in particular 2-pyrimidyl-, which are substituted by one or two identical or different substituents from the group halogen, trifluoromethyl, C 1 -C 4 -alkyl and
  • C 1 -C 4 alkoxy may be substituted.
  • ArylC 1 -C 4 alkyl is C 1 -C 4 alkyl which is substituted by aryl.
  • ArylC 1 -C 4 alkyl is, for example, 2-phenylethyl, 2- (2,4-dimethoxyphenyl) ethyl, benzyl or 4-chlorobenzyl.
  • Heteroaryl C 1 -C 4 alkyl is C 1 -C 4 alkyl which is substituted by heteroaryl.
  • Heteroaryl C 1 -C 4 alkyl is, for example, 2- (2-pyridyl) ethyl.
  • Diaryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by two aryl radicals.
  • Diaryl-C 1 -C 4 -alkyl is especially oiphenylmethyl (benzhydryl), or substituted benzhydryl, such as 4,4'-difluorobenz hydryl, 4, 4 '-dimethylbenzhydryl, 4, 4' -dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl.
  • Heteroaryl-aryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by heteroaryl and aryl.
  • Heteroaryl-aryl-C 1 -C 4 -alkyl is, for example, 2-pyridyl-phenylmethyl.
  • Di-heteroaryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by two heteroaryl radicals.
  • Di-heteroaryl-C 1 -C 4 -alkyl is, for example, di-pyrid-2-yl-methyl.
  • Straight-chain or branched C 2 -C 5 -alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and in particular ethylene or propylene.
  • C 2 -C 5 alkylene substituted by C 1 -C 4 alkoxy is, for example, 1-methoxypropylene, 2-ethoxypropylene or 1, 2-dimethoxyethylene.
  • Aryl-substituted C 2 -C 5 -alkylene is, for example, 1-phenylethylene or 2- (4-chlorophenyl) propylene.
  • Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrylic acid Tienilic acid or 4-chloro-sulfamoyl-benzoic acid.
  • R1, R2 and R3 are the same or different and are C 1 - C 6 - alkyl or C 3 -C 7 - mean alkoxyalkyl,
  • R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine
  • R5 is phenyl, 2-pyridyl or 2-pyrimidyl which is substituted by one or two identical or different substituents from the group hydrogen, halogen, trifluoromethyl, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy and
  • A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy
  • A means ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy
  • A means ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • A means ethylene or propylene, and their salts.
  • a further embodiment (embodiment b) of the invention are compounds of the formula I in which
  • R1, R2 and R3 are the same or different and are C 1 -C 6 alkyl or C 3 -C 7 alkoxyalkyl,
  • R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine
  • A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy, R5 benzhydryl, 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl,
  • 4,4'-dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl and A is ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 is 1, 1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy
  • R5 is benzhydryl and A is ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • A means ethylene or propylene, and their salts.
  • the compounds of the formula I have chirality centers at the 4-position in 1,4-dihydropyridine and optionally in part A.
  • the invention therefore includes both the enantiomers and diastereomers as well as their mixtures and racemates.
  • Another object of the invention is a process for the preparation of the compounds according to the invention and their salts.
  • the process is characterized in that
  • Embodiments of the process are those in which in the formulas II to X the substituents or symbols R1, R2, R3, R4, R5 and A have the meanings given in the subclaims and dependent claims and Z together with the carbonyl group to which it is bound is a carboxyl group or a reactive carboxylic acid derivative.
  • the method according to variants a to f is preferred as inert organic solvents.
  • examples include alcohols, such as ethanol, methanol, isopropanol or, in particular, t-butanol, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or hexamethylphosphoric triamide, or chlorinated hydrocarbons such as methylene chloride Chloroform or tetrachlorethylene.
  • alcohols such as ethanol, methanol, isopropanol or, in particular, t-butanol
  • ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such
  • reaction temperatures can vary within a wide range. In general, the reaction is carried out at temperatures between 20 ° C. and 150 ° C., preferably between 20 ° C. and 100 ° C., in particular at the boiling point of the solvent used.
  • the process can be carried out at atmospheric pressure or at elevated pressure, working at atmospheric pressure being the rule and elevated pressure being used in particular in the case of reactions with ammonia.
  • the substances involved in the reaction are generally used in molar amounts, but - depending on the reaction condition - an excess (if desired, for example in ammonia in variants b and d) is also used can be.
  • variants a to f When carrying out the process according to variant g, similar reaction conditions are used as for variants a to f, but - depending on the nature of the substituent Z - additional measures may be necessary.
  • Z represents a hydroxyl group
  • the reaction should preferably be carried out in the presence of a water-releasing or water-binding condensing agent (such as dicyclohexylcarbodiimide).
  • Z represents a halogen atom (e.g. a chlorine atom)
  • the reaction can, if desired, be carried out in the presence of a base (e.g. a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate).
  • a base e.g. a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate.
  • the substances according to the invention are isolated and purified in a manner known per se, for. B. such that the solvent in Vacuum was distilled off and the residue obtained was recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
  • Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
  • Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
  • the starting compounds are known from the literature or can be prepared analogously to methods known from the literature.
  • the cinnamic acid derivatives II and the benzylidenecarboxylic acid derivatives VI can be prepared, for example, in analogy to G. Jones ["The Knoevenagel Condensation” in Org. Reactions, Vol. XV, 204f (1967)].
  • the enamine derivatives III and the enamines V are, for example, analogous to A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)].
  • ⁇ -ketocarboxylic acid derivatives IV and keto compounds VII can, according to D.
  • Mp. Means melting point
  • decomp. means decomposition
  • Example 2 Analogously to Example 1, 5.6 g of the free base are made from 5 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] propan-1-ol, 2 ml of a 50% strength diketene solution in acetone, 3.2 g Obtain 3-aminocrotonic acid (2-methoxyethyl) ester and 3.44 g of 2-difluoromethoxybenzaldehyde as a solid foam, which is converted into the crystalline fumarate with 1.03 g of fumaric acid. Yield: 5.8 g of mp 149-151 ° C (dec.). 3.
  • the compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are particularly effective vasodilators with coronary therapeutic properties.
  • the pharmacological activity of the compounds according to the invention which is paired with a low toxicity, is particularly evident in a slowly occurring, strong and long-lasting drop in blood pressure.
  • the compounds according to the invention have peripheral, coronary, cerebral and renal vasodilator and salidiuretic properties.
  • the compounds according to the invention differ surprisingly and advantageously from the compounds of the prior art in their excellent activity, which is paired with low toxicity and the absence of significant side effects.
  • advantageous properties are: the extent of the reduction in blood pressure, the prolonged persistence of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly small and disappearing heart rate increase after repeated administration, the excellent bioavailability, the great therapeutic breadth, the lack of central side effects, that Lack of kinetic interactions with other substances, the lack of tolerance development, the balanced physical properties and the great stability.
  • the excellent activity of the compounds of formula I and their salts according to the invention permits their use in human medicine, with primary (essential) and secondary hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.), peripheral and cere as indications bral circulation disorders (stroke, temporary cerebral circulatory disorders, renal artery narrowing etc.), cardiac insufficiency and diseases that are based on increased water and sodium retention.
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cere as indications bral circulation disorders (stroke, temporary cerebral circulatory disorders, renal artery narrowing etc.)
  • cardiac insufficiency and diseases that are based on increased water and sodium retention.
  • Another object of the invention is therefore a method for the treatment of mammals, especially humans, who are suffering from one of the above-mentioned diseases.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I.
  • the invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
  • the invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example Cyclodex trine) can be used.
  • the active substances can be administered orally or parenterally (in particular perlingually, intravenously or percutaneously).
  • the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • similar or generally lower doses in particular when the active compounds are administered intravenously
  • the dose is slowly switched to a higher dose. After the desired therapeutic success has been reached, the dose is reduced again.
  • the pharmaceutical preparations can also include one or more other pharmacologically active constituents of other groups of medicaments, such as other vasodilators, antihypertensives, ⁇ -receptor blockers, B-receptor blockers, ACE inhibitors , Nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, etc., such as nifedipine, dihydralazine, prazosin, propranolol, labetalol, captopril, isosorbide dinitrate, digoxin, mefruside, clopamide, spironolactone, chlorthalidone, furosididridiniazine, furosididrochloride, furosididrochloride, furosidide hydrochloride, polyhydric chloride, furosidol chloride, furosidol chloride, furosidol chloride, furosidol chloride, furos
  • the antihypertensive activity of the compounds according to the invention can be demonstrated on the model of the spontaneously hypertensive rat.
  • the compounds listed below are given in the doses given on four consecutive days on 6 rats (strain SHR / N / Ibm / Bm ⁇ , 250-350 g) with genetically determined high pressure (systolic blood pressure> 180 mmHg) administered once a day by gavage. Blood pressure is measured 6 and, if necessary, 2 or 24 hours after substance administration.
  • the blood pressure measurement is carried out in a heat chamber at 36 ° C in order to achieve better circulation in the tail artery.
  • the animals are placed in perforated perforated metal cages and measured 20-40 minutes after warming up.
  • an annular cuff with an inflatable rubber membrane to prevent blood flow and an annular piezo crystal sensor to record the pulse waves are pushed onto the tail.
  • the cuff pressure is continuously reduced.
  • the return of the pulse waves during pressure relief is automatically recognized and printed out as systolic blood pressure (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat.
  • the animals are trained for 14 days before the substance test.
  • blood pressure pre-values are collected.
  • Groups of animals receiving substance are tested against a control group.
  • the examined connections are identified by consecutive numbers, which are assigned as follows:
  • Table I shows for the representatives of the compounds according to the invention the percentage reduction in blood pressure (BP) after oral administration in the rat.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Piperazine derivatives have the general formula (I) wherein R1, R2 and R3 are the same or different and represent hydrogen, C1-C6-alkyl, C3-C7 alkoxy alkyl, aryl, aryl-C1-C6-alkyl or aryloxy-C1-C6-alkyl, R4 represents C1-C4-alkoxy substituted completely or for its major part with fluorine, R5 represents aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, diaryl-C1-C4-alkyl, heteroaryl-aryl-C1-C4-alkyl or di-heteroaryl-C1-C4-alkyl. Said derivatives and salts thereof are new compositions for the treatment and prophylaxy of diseases due to circulation troubles.

Description

Neue PiperazinderivateNew piperazine derivatives
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft neue Piperazinderivate, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende Arzneimittel. Die erfindungsgemäßen Verbindungen werden in der pharmazeutischen Industrie zur Herstellung von Arzneimitteln eingesetzt.The invention relates to new piperazine derivatives, processes for their preparation, their use and medicaments containing them. The compounds according to the invention are used in the pharmaceutical industry for the production of medicaments.
Bekannter technischer HintergrundKnown technical background
Es ist bekannt, daß bestimmte, auf verschiedene Weise substituierte 1,4-Dihydropyridinderivate pharmakologisch nützliche Eigenschaften aufweisen. Insbesondere seien die europäischen Patentanmeldungen 0094159 und 0097821 und die französische Patentanmeldung 2414501 genannt. Überraschenderweise wurde nun gefunden, daß die unten näher beschriebenen neuen Verbindungen besonders interessante pharmakologische Eigenschaften aufweisen, durch die sie sich von den Verbindungen des Standes der Technik in vorteilhafter Weise unterscheiden.It is known that certain 1,4-dihydropyridine derivatives substituted in various ways have pharmacologically useful properties. European patent applications 0094159 and 0097821 and French patent application 2414501 may be mentioned in particular. Surprisingly, it has now been found that the new compounds described in more detail below have particularly interesting pharmacological properties, by which they differ from the compounds of the prior art in an advantageous manner.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind neue Piperazinderivate der Formel IThe invention relates to new piperazine derivatives of the formula I.
Figure imgf000003_0003
Figure imgf000003_0002
Figure imgf000003_0001
worin
Figure imgf000003_0003
Figure imgf000003_0002
Figure imgf000003_0001
wherein
R1, R2 und R3 gleich oder verschieden sind und Wasserstoff, C1-C6- alkyl, C3-C7-alkoxyalkyl, Aryl, Aryl-C1-C6-alkyl oder Aryloxy- C1-C6-alkyl bedeuten, R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy bedeutet, R5 Aryl, Heteroaryl, Aryl-C1-C4-alkyl, Heteroaryl-C1-C4-alkyl,R1, R2 and R3 are the same or different and are hydrogen, C 1 -C 6 - are alkyl, C 3 -C 7 -alkoxyalkyl, aryl, aryl-C 1 -C 6 -alkyl or aryloxy-C 1 -C 6 -alkyl, R4 is C 1 -C 4 -alkoxy wholly or predominantly substituted by fluorine, R5 Aryl, heteroaryl, aryl-C 1 -C 4 alkyl, heteroaryl-C 1 -C 4 alkyl,
Oiaryl-C1-C4-alkyl, Heteroaryl-aryl-C1-C4-alkyl oderOiaryl-C 1 -C 4 alkyl, heteroaryl-aryl-C 1 -C 4 alkyl or
Di-heteroaryl-C1-C4-alkyl bedeutet und A geradkettiges oder verzweigtes C2-C5-alkylen bedeutet, das durchDi-heteroaryl-C 1 -C 4 alkyl means and A means straight-chain or branched C 2 -C 5 alkylene, which by
C1-C4-alkoxy oder Aryl substituiert sein kann und ihre Salze.C 1 -C 4 alkoxy or aryl may be substituted and their salts.
C1-C6-alkyl ist geradkettig oder verzweigt und bedeutet beispielsweise einen Hexyl-, Neopentyl-, Isopentyl-, Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Isopropyl- oder insbesondere Ethyl- oder Methylrest.C 1 -C 6 -alkyl is straight-chain or branched and means, for example, hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or in particular Ethyl or methyl radical.
C3-C7-alkoxyalkyl steht beispielsweise für einen Ethoxyethyl-, Propoxy- ethyl-, Isopropoxyethyl-, Butoxyethyl-, Methoxypropyl-, 2-Methoxy-1-methylethyl-, 2-Ethoxy-1-methylethyl- oder insbesondere Methoxyethylrest.C 3 -C 7 alkoxyalkyl is, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or especially methoxyethyl radical.
Aryl steht allgemein für Phenyl oder substituiertes Phenyl mit einem oder zwei gleichen oder verschiedenen Substituenten aus der Gruppe Halogen, Hydroxy, Nitro, Cyano, Trifluormethyl, C1-C4-alkyl, C1-C4- alkoxy, C1-C4-alkoxycarbonyl, C2-C5-acyl, Amino und Mono- oder Di-C1-C4-alkylamino.Aryl generally stands for phenyl or substituted phenyl with one or two identical or different substituents from the group halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -alkoxycarbonyl, C 2 -C 5 -acyl, amino and mono- or di-C 1 -C 4 -alkylamino.
Aryl-C1-C6-alkyl ist C1-C6-alkyl, das durch Aryl substituiert ist. Aryl-C1-C6-alkyl ist beispielsweise Phenethyl, 3- (4-Chlorphenyl)-propyl oder insbesondere Benzyl.Aryl-C 1 -C 6 -alkyl is C 1 -C 6 -alkyl which is substituted by aryl. Aryl-C 1 -C 6 -alkyl is, for example, phenethyl, 3- (4-chlorophenyl) propyl or in particular benzyl.
Aryloxy-C1-C6-alkyl ist C1-C6-alkyl, das durch Aryloxy substituiert ist. Aryloxy-C1-C6-alkyl ist beispielsweise Phenoxyethyl.Aryloxy-C 1 -C 6 -alkyl is C 1 -C 6 -alkyl which is substituted by aryloxy. Aryloxy-C 1 -C 6 alkyl is, for example, phenoxyethyl.
Halogen bedeutet Brom, Fluor und insbesondere Chlor.Halogen means bromine, fluorine and especially chlorine.
C1-C4-alkyl ist geradkettig oder verzweigt und bedeutet beispielsweise einen Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Isopropyl-, Ethyl- oder insbesondere Methylrest. Cι-C4-alkoxy enthält neben dem Sauerstoffatom einen der vorstehend genannten C.-C4-alkylreste. Bevorzugt sind der Methoxy- und der Ethoxy- rest.C 1 -C 4 alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl or in particular methyl radical. C 1 -C 4 alkoxy contains, in addition to the oxygen atom, one of the above-mentioned C 4 alkyl radicals. The methoxy and ethoxy radicals are preferred.
C1-C4-alkoxycarbonyl enthalt neben der Carbonylgruppe einen der vorstehend genannten C1-C4-alkoxyreste. Bevorzugt sind der Methoxycarbonyl- und der Ethoxycarbonylrest.In addition to the carbonyl group, C 1 -C 4 alkoxycarbonyl contains one of the C 1 -C 4 alkoxy radicals mentioned above. The methoxycarbonyl and the ethoxycarbonyl radical are preferred.
C2-C5-acyl enthält neben der Carbonylgruppe einen der vorstehend genannten C1-C4-alkylreste. Bevorzugt ist der Acetylrest.In addition to the carbonyl group, C 2 -C 5 acyl contains one of the C 1 -C 4 alkyl radicals mentioned above. The acetyl radical is preferred.
Mono- oder Di- C1-C4-alkylamino enthält neben dem Stickstoffatom einen oder zwei der vorstehend genannten C1-C4-alkylreste. Bevorzugt ist Di- C1-C4-alkylamino, und hier insbesondere Oimethyl-, Oiethyl- oder Diisopropylamino.In addition to the nitrogen atom, mono- or di-C 1 -C 4 -alkylamino contains one or two of the above-mentioned C 1 -C 4 -alkyl radicals. Di-C 1 -C 4 -alkylamino is preferred, and here in particular oimethyl-, diethyl- or diisopropylamino.
Ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy ist beispielsweise 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder insbesondere Difluormethoxy.C 1 -C 4 alkoxy which is wholly or predominantly substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.
Heteroaryl im Sinne der vorliegenden Erfindung steht für die Reste Pyridyl-, insbesondere 2-Pyridyl-, und Pyrimidyl-, insbesondere 2-Pyrimidyl-, die durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe Halogen, Trifluormethyl, C1-C4-alkyl undHeteroaryl for the purposes of the present invention represents the radicals pyridyl-, in particular 2-pyridyl-, and pyrimidyl-, in particular 2-pyrimidyl-, which are substituted by one or two identical or different substituents from the group halogen, trifluoromethyl, C 1 -C 4 -alkyl and
C1-C4-alkoxy substituiert sein können.C 1 -C 4 alkoxy may be substituted.
Aryl- C1-C4-alkyl ist C1-C4-alkyl, das durch Aryl substituiert ist. Aryl- C1-C4-alkyl ist beispielsweise 2-Phenylethyl, 2-(2,4-Dimethoxyphenyl)-ethyl, Benzyl oder 4-Chlorbenzyl.ArylC 1 -C 4 alkyl is C 1 -C 4 alkyl which is substituted by aryl. ArylC 1 -C 4 alkyl is, for example, 2-phenylethyl, 2- (2,4-dimethoxyphenyl) ethyl, benzyl or 4-chlorobenzyl.
Heteroaryl- C1-C4-alkyl ist C1-C4-alkyl, das durch Heteroaryl substituiert ist. Heteroaryl- C1-C4-alkyl ist beispielsweise 2-(2-Pyridyl)-ethyl.Heteroaryl C 1 -C 4 alkyl is C 1 -C 4 alkyl which is substituted by heteroaryl. Heteroaryl C 1 -C 4 alkyl is, for example, 2- (2-pyridyl) ethyl.
Diaryl- C1-C4-alkyl ist C1-C4-alkyl, das durch zwei Arylreste substituiert ist. Diaryl- C1-C4-alkyl ist insbesondere Oiphenylmethyl (Benzhydryl), oder substituiertes Benzhydryl, wie z.B. 4,4'-Difluorbenz hydryl, 4 , 4 ' -Dimethylbenzhydryl, 4, 4' -Dimethoxybenzhydryl oder 4,4'-Di- chlorbenzhydryl .Diaryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by two aryl radicals. Diaryl-C 1 -C 4 -alkyl is especially oiphenylmethyl (benzhydryl), or substituted benzhydryl, such as 4,4'-difluorobenz hydryl, 4, 4 '-dimethylbenzhydryl, 4, 4' -dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl.
Heteroaryl-aryl-C1-C4-alkyl ist C1-C4-alkyl, das durch Heteroaryl und Aryl substituiert ist. Heteroaryl-aryl-C1-C4-alkyl ist beispielsweise 2-Pyridyl-phenylmethyl.Heteroaryl-aryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by heteroaryl and aryl. Heteroaryl-aryl-C 1 -C 4 -alkyl is, for example, 2-pyridyl-phenylmethyl.
Di-heteroaryl-C1-C4-alkyl ist C1-C4-alkyl, das durch zwei Heteroarylreste substituiert ist. Di-heteroaryl-C1-C4-alkyl ist beispielsweise Di-pyrid-2-yl-methyl.Di-heteroaryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by two heteroaryl radicals. Di-heteroaryl-C 1 -C 4 -alkyl is, for example, di-pyrid-2-yl-methyl.
Geradkettiges oder verzweigtes C2-C5-alkylen ist beispielsweise Tetramethylen, 1,2-Dimethylethylen, 2,2-Dimethylethylen, Isopropyliden, 1-Methylethylen, 2-Ethylpropylen und insbesondere Ethylen oder Propylen.Straight-chain or branched C 2 -C 5 -alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and in particular ethylene or propylene.
Durch C1-C4-alkoxy substituiertes C2-C5-alkylen ist beispielsweise 1-Methoxy-propylen, 2-Ethoxy-propylen oder 1 , 2-Dimethoxyethylen.C 2 -C 5 alkylene substituted by C 1 -C 4 alkoxy is, for example, 1-methoxypropylene, 2-ethoxypropylene or 1, 2-dimethoxyethylene.
Durch Aryl substituiertes C2-C5-alkylen ist beispielsweise 1-Phenylethylen oder 2-(4-Chlorphenyl)-propylen.Aryl-substituted C 2 -C 5 -alkylene is, for example, 1-phenylethylene or 2- (4-chlorophenyl) propylene.
Als Salze kommen alle Salze mit Säuren in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der pharmazeutischen Industrie üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die beispielsweise bei der Herstellung der erfindungsgemäßen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze übergeführt. Als solche eignen sich beispielsweise wasserlösliche und wasserunlösliche Säureadditionssalze, wie das Hydrochlorid, Hydrobromid, Hydroiodid, Phosphat, Nitrat, Sulfat, Acetat, Citrat, Gluconat, Benzoat, Hibenzat, Fendizoat, Butyrat, Sulfosalicylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Embonat, Metembonat, Stearat, Tosilat, 2-Hydroxy-3-naphthoat, 3-Hydroxy-2-naphthoat oder Mesilat, aber auch Salze mit Bumetanid, Furosemid, Azosemid, Galosemid, Besunid, Piretanid, Etacrynsäure, Tienilinsäure oder 4-Chlor-sulfamoyl-benzoesäure. Eine Ausgestaltung (Ausgestaltung a) der Erfindung sind Verbindungen der Formel I , worinAll salts with acids can be considered as salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in the pharmaceutical industry. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrylic acid Tienilic acid or 4-chloro-sulfamoyl-benzoic acid. One embodiment (embodiment a) of the invention are compounds of the formula I in which
R1, R2 und R3 gleich oder verschieden sind und C 1 - C6 - alkyl oder C3-C7- alkoxyalkyl bedeuten,R1, R2 and R3 are the same or different and are C 1 - C 6 - alkyl or C 3 -C 7 - mean alkoxyalkyl,
R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy bedeutet,R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine,
R5 durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe Wasserstoff, Halogen, Trifluormethyl, C1-C4-alkyl und C1-C4-alkoxy substituiertes Phenyl, 2-Pyridyl oder 2-Pyrimidyl bedeutet undR5 is phenyl, 2-pyridyl or 2-pyrimidyl which is substituted by one or two identical or different substituents from the group hydrogen, halogen, trifluoromethyl, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy and
A geradkettiges oder verzweigtes C2-C5-alkylen bedeutet, und ihre Salze.A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
Hervorzuhebende Verbindungen der Ausgestaltung a sind solche, in denenCompounds of configuration a to be emphasized are those in which
R1 Methyl oder Ethyl,R1 methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy,R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy,
R5 Phenyl, 2-Chlorphenyl, 3-Chlorphenyl, 4-Chlorphenyl, 2,3-Dichlorphenyl, 3,4-Dichlorphenyl, 4-Fluorphenyl, 3-Trifluormethylphenyl, 2-Methoxyphenyl, 4-Methoxyphenyl, 2-Ethoxyphenyl, 2-Methylphenyl, 3-Chlor-4-methylphenyl, 3,4-Dimethylphenyl oder 2-Pyridyl undR5 phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl , 3-chloro-4-methylphenyl, 3,4-dimethylphenyl or 2-pyridyl and
A Ethylen oder Propylen bedeutet, und ihre Salze.A means ethylene or propylene, and their salts.
Bevorzugte Verbindungen der Ausgestaltung a sind solche, in denenPreferred connections of embodiment a are those in which
R1 Methyl oder Ethyl,R1 methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy,R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy,
R5 Phenyl oder 2-Methoxyphenyl undR5 phenyl or 2-methoxyphenyl and
A Ethylen oder Propylen bedeutet, und ihre Salze.A means ethylene or propylene, and their salts.
Besonders bevorzugte Verbindungen der Ausgestaltung a sind solche, in denenParticularly preferred connections of embodiment a are those in which
R1 Methyl,R1 methyl,
R2 Methyl,R2 methyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 Difluormethoxy,R4 difluoromethoxy,
R5 Phenyl oder 2-Methoxyphenyl undR5 phenyl or 2-methoxyphenyl and
A Ethylen oder Propylen bedeutet, und ihre Salze.A means ethylene or propylene, and their salts.
Eine weitere Ausgestaltung (Ausgestaltung b) der Erfindung sind Verbindungen der Formel I, worinA further embodiment (embodiment b) of the invention are compounds of the formula I in which
R1, R2 und R3 gleich oder verschieden sind und C1-C6-alkyl oder C3-C7- alkoxyalkyl bedeuten,R1, R2 and R3 are the same or different and are C 1 -C 6 alkyl or C 3 -C 7 alkoxyalkyl,
R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy bedeutet,R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine,
R5 Diphenylmethyl (Benzhydryl) bedeutet, wobei die beiden Phenylreste jeweils durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe Wasserstoff, Halogen, Trifluormethyl, C1-C4- alkyl und C1-C4-alkoxy substituiert sind undR5 diphenylmethyl (benzhydryl), wherein each of the two phenyl groups by one or two identical or different substituents from the group of hydrogen, halogen, trifluoromethyl, C 1 -C 4 - alkoxy alkyl and C 1 -C 4 substituted and
A geradkettiges oder verzweigtes C2-C5-alkylen bedeutet, und ihre Salze.A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
Hervorzuhebende Verbindungen der Ausgestaltung b sind solche, in denenCompounds of configuration b to be emphasized are those in which
R1 Methyl oder Ethyl,R1 methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy, R5 Benzhydryl, 4,4'-Difluorbenzhydryl, 4,4'-Dimethylbenzhydryl,R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy, R5 benzhydryl, 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl,
4,4'-Dimethoxybenzhydryl oder 4,4'-Dichlorbenzhydryl bedeutet und A Ethylen oder Propylen bedeutet, und ihre Salze.4,4'-dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl and A is ethylene or propylene, and their salts.
Bevorzugte Verbindungen der Ausgestaltung b sind solche, in denenPreferred connections of embodiment b are those in which
R1 Methyl oder Ethyl,R1 methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1 ,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy, R5 Benzhydryl und A Ethylen oder Propylen bedeutet, und ihre Salze.R4 is 1, 1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy, R5 is benzhydryl and A is ethylene or propylene, and their salts.
Besonders bevorzugte Verbindungen der Ausgestaltung b sind solche, in denenParticularly preferred connections of embodiment b are those in which
R1 Methyl,R1 methyl,
R2 Methyl,R2 methyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 Difluormethoxy,R4 difluoromethoxy,
R5 Benzhydryl undR5 benzhydryl and
A Ethylen oder Propylen bedeutet, und ihre Salze.A means ethylene or propylene, and their salts.
Als erfindungsgemäße Verbindungen seien beispielsweise genannt:The following compounds may be mentioned as examples:
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-chlorphenyl)-1-piperazinyl]- propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2-chlorophenyl) -1-piperazinyl] - propyl} ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2-ethoxyphenyl) -1-piperazinyl] -propyl} -ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-dicarbonsäure-3-ethylester-5-[3-(4-phenyl-1-piperazinyl)-propyl]-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [3- (4-phenyl-1-piperazinyl) propyl] - ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di carbonsäure-3-ethylester-5-{3-[4-{3-chlorphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di carboxylic acid 3-ethyl ester 5- {3- [4- {3-chlorophenyl) -1-piperazinyl] propyl} ester,
4- ( 2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(4-chlorphenyl)-1-piperazinyl]- propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (4-chlorophenyl) -1-piperazinyl] - propyl} ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(2,3-dichlorphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {3- [4- (2,3-dichlorophenyl) - 1-piperazinyl] -propyl} ester,
4-( 2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(3,4-dichlorphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl}-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(4-fluorphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(3-trifluormethylphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(4-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-C4-(2-methylphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-C4-(3-chlor-4-methylphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(3,4-dimethylphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-{2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(2-chlorphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(3-chlorphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5- {2-[4-(4-chlorphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Diflυormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5- {2-[4-(2,3-dichlorphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(3,4-dichlorphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4-fluorphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-{3-trifluormethylphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5- 2-[4-(2-methylphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(3-chlor-4-methylphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(3,4-dimethylphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl}-ester, 2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-methylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}- ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {3- [4- (3,4-dichlorophenyl) - 1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl} -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {3- [ 4- (4-fluorophenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3- ethyl ester 5- {3- [4- (3-trifluoromethylphenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5- {3- [4- (4-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2, 6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester 5- {3-C4- (2-methylphenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1 , 4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {3-C4- (3-chloro-4-methylphenyl) -1-piperazinyl] -propyl} - ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-eth ylester-5- {3- [4- (3,4-dimethylphenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine- 3,5-di-carboxylic acid 3-ethyl ester-5- {3- [4- (2-pyridyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro- 2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester 5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- {2-difluoromethoxyphenyl ) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (2-chlorophenyl) -1-piperazinyl] ethyl} - ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (3-chlorophenyl) -1- piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester- 5- {2- [4- (2,3-dichlorophenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3, 5-di-carboxylic acid 3-ethyl ester 5- {2- [4- (3,4-dichlorophenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro- 2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (4-fluorophenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl ) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- {3-trifluoromethylphenyl) -1-piperazinyl] -ethyl} - ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid-3-ethyl ester-5- {2 - [4- (4-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid - 3-ethyl ester-5- 2- [4- (2-methylphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3 , 5-di-carboxylic acid 3-ethyl ester 5- {2- [4- (3-chloro-4-methylphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1.4 -dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (3,4-dimethylphenyl) -1-piperazinyl] ethyl} ester, 4 - (2-Difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (2-pyridyl) -1-piperazinyl ] ethyl} ester, 2,6-diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2- methoxyphenyl) -1-piperazinyl] propyl} ester, 2,6-diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} - ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-(2-methoxyethyl)-ester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,2,6-Diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- {3- [4- (2-methoxyphenyl ) -1-piperazinyl] propyl} esters,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-methylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-methyl ester-5- {3- [4- (2-methoxyphenyl) -1- piperazinyl] propyl} esters,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-(2-methoxyethyl)-ester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3- (2-methoxyethyl) ester-5- {3- [4- (2nd -methoxyphenyl) -1-piperazinyl] -propyl} ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-ethylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,2,6-Diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-methylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,2,6-Diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-(2-methoxyethyl)-ester-5-{2-[4-(2-methoxyphenyl)-1-pipera¬zinyl]-ethyl}-ester,2,6-Diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- {2- [4- (2-methoxyphenyl ) -1-piperazinyl] ethyl} esters,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-methylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-(2-methoxyethyl)-ester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-(2-methoxyethyl)-ester-5-{2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-(2-methoxyethyl)-ester-5-[2-(4-phenyl-1-piperazinyl)-ethyl]-ester, 1,4-Dihydro-2,6-dimethyl-4-[2-(1,1,2,2-tetrafluorethoxy)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-[2-(2,2,2-trifluorethoxy)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-(2-trifluormethoxyphenyl)-pyridin-3,5-di carbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-[2-(1,1,2,2-tetrafluorethoxy)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethylester-5-{2-[4-(2-methoxyphenyl)-1piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-[2-(2,2,2-trifluorethoxy)-phenyl]-pyridin- 3,5-dicarbonsäure-3-ethyles er-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-(2-trifluormethoxyphenyl)-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(4,4'-difluorbenzhydryl)-1-pipera¬zinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(4,4'-dichlorbenzhydryl)1-pipera¬zinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{3-[4-(4,4'-dimethoxybenzhydryl)-1-pipera¬zinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4,4'-difluorbenzhydryl)1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4,4'-dichlorbenzhydryl)1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4,4'-dimethylbenzhydryl)1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4,4'-dimethoxybenzhydryl)-1-piperazinyl]-ethyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-methyl ester-5- {2- [4- (2-methoxyphenyl) -1- piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di¬ carboxylic acid 3- (2-methoxyethyl) ester -5 {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di¬ carboxylic acid 3- (2-methoxyethyl) ester-5- {2- [4- (2-ethoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro- 2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3- (2-methoxyethyl) -ester-5- [2- (4-phenyl-1-piperazinyl) -ethyl] ester, 1,4- Dihydro-2,6-dimethyl-4- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2nd -methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-4- [2- (2,2,2-trifluoroethoxy) phenyl] pyridine-3,5- 3-ethyl dicarboxylate 5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethoxyphenyl) - pyridine 3,5-di carboxylic acid 3-ethyl ester 5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-4- [2- (1, 1,2,2-tetrafluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester 5- {2- [4- (2-methoxyphenyl) -1piperazinyl] ethyl} ester, 1,4- Dihydro-2,6-dimethyl-4- [2- (2,2,2-trifluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl er-5- {2- [4- (2- methoxyphenyl) -1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethoxyphenyl) pyridine-3,5-dicarboxylic acid-3-ethyl ester-5- { 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid -3-ethyl ester-5- [3- (4-benzhydryl-1-piperazinyl) propyl] ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5 -di¬carboxylic acid-3-ethyl ester-5- {3- [4- (4,4'-difluorobenzhydryl) -1-piperazylzopropyl} ester, 4- (2-difluoromethoxyphenyl) -1,4- dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {3- [4- (4,4'-dichlorobenzhydryl) 1-piperazyl] propyl} -ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {3- [4- (4,4 ' -dimethylbenzhydryl) -1-piperazinyl] -propyl} -ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid-3-ethyl ester-5- {3- [4- (4,4'-dimethoxybenzhydryl) -1-piperazyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3 , 5-di-carboxylic acid 3-ethyl ester 5- [2- (4-benzhydryl-1-piperazinyl) ethyl] ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl -pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (4,4'-difluorobenzhydryl) 1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1 , 4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester 5- {2- [4- (4,4'-dichlorobenzhydryl) 1-piperazinyl] ethyl} ester , 4- (2-Difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (4,4'-dimethylbenzhydryl ) 1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (4,4'-dimethoxybenzhydryl) -1-piperazinyl] ethyl} ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-ethylester-5-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester, 2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-methylester-5-{3-[4-(4,4'-difluorbenzhydryl)-1-piperazinyl]-propyl}-ester,2,6-Diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [3- (4-benzhydryl-1-piperazinyl) propyl] - ester, 2,6-diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5- {3- [4- (4,4'-difluorobenzhydryl) -1-piperazinyl] propyl} esters,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-(2-methoxyethyl)-ester-5-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-methylester-5-{3-[4-(4,4'-dichlorbenzhydryl)-1-pipera¬zinyl]-propyl}-ester,2,6-diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- [3- (4-benzhydryl-1- piperazinyl) propyl] ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-methyl ester-5- {3- [4- (4,4'-dichlorobenzhydryl) -1-piperazylzopropyl} ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-(2-methoxyethyl)-ester-5-[3-(4-benzhydry1-1-piperazinyl)-propyl]-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid-3- (2-methoxyethyl) -ester-5- [3- (4-benzhydry1- 1-piperazinyl) propyl] ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-ethylester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester, 2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-methylester-5-{2-[4-(4,4'-difluorbenzhydryl)-1-piperazinyl]-ethyl}-ester,2,6-Diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [2- (4-benzhydryl-1-piperazinyl) ethyl] - ester, 2,6-diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5- {2- [4- (4,4'-difluorobenzhydryl) -1-piperazinyl] ethyl} ester,
2,6-Diethyl-4-(2-difluormethoxyphenyl)-1,4-dihydropyridin-3,5-dicarbon¬säure-3-(2-methoxyethyl)-ester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester,2,6-diethyl-4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- [2- (4-benzhydryl-1- piperazinyl) ethyl] esters,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-methylester-5-{2-[4-(4,4'-dichlorbenzhydryl)-1-pipera¬zinyl]-ethyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid 3-methyl ester-5- {2- [4- (4,4'-dichlorobenzhydryl) -1-piperazinyl] ethyl} ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-pyridin-3,5-di¬carbonsäure-3-(2-methoxyethyl)-ester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-di-carboxylic acid-3- (2-methoxyethyl) ester-5- [2- (4-benzhydryl- 1-piperazinyl) ethyl] ester,
1,4-Dihydro-2,6-dimethyl-4-[2-(1,1,2,2-tetrafluorethoxy)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethylester-5-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester,1,4-Dihydro-2,6-dimethyl-4- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [3- ( 4-benzhydryl-1-piperazinyl) propyl] esters,
1,4-Dihydro-2,6-dimethyl-4-[2-(2,2,2-trifluorethoxy)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[[-(4,4'-difluorbenzhydryl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-(2-trifluormethoxyphenyl)-pyridin-3,5-di carbonsäure-3-ethylester-5-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester,1,4-Dihydro-2,6-dimethyl-4- [2- (2,2,2-trifluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3 - [[- (4,4'-difluorobenzhydryl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethoxyphenyl) pyridine-3,5-di carboxylic acid 3-ethyl ester 5- [3- (4-benzhydryl-1-piperazinyl) propyl] ester,
1,4-Dihydro-2,6-dimethyl-4-[2-(1,1,2,2-tetrafluorethoxy)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethylester-5-{2-[4-(4,4'-dimethylbenz¬hydryl)-1-piperazinyl]-ethyl}-ester,1,4-Dihydro-2,6-dimethyl-4- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {2- [ 4- (4,4'-dimethylbenzhydryl) -1-piperazinyl] ethyl} esters,
1,4-Dihydro-2,6-dimethyl-4-[2-(2,2,2-trifluorethoxy)-phenyl]-pyridin- 3,5-dicarbonsäure-3-ethylester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester,1,4-Dihydro-2,6-dimethyl-4- [2- (2,2,2-trifluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [2- (4- benzhydryl-1-piperazinyl) ethyl] ester,
1,4-Dihydro-2,6-dimethyl-4-(2-trifluormethoxyphenyl)-pyridin-3,5-di¬carbonsäure-3-ethylester-5-{2-[4-(4,4'-dimethoxybenzhydryl)-1-piperazinyl]-ethyl}-ester, und ihre Salze.1,4-Dihydro-2,6-dimethyl-4- (2-trifluoromethoxyphenyl) pyridine-3,5-di-carboxylic acid 3-ethyl ester-5- {2- [4- (4,4'-dimethoxybenzhydryl) -1-piperazinyl] ethyl} esters, and their salts.
Die Verbindungen der Formel I besitzen an der 4-Position im 1,4- Dihydropyridin und gegebenenfalls im Teil A Chiralitatszentren. Die Erfindung umfaßt daher sowohl die Enantiomeren und Diastereomeren als auch deren Gemische und Racemate.The compounds of the formula I have chirality centers at the 4-position in 1,4-dihydropyridine and optionally in part A. The invention therefore includes both the enantiomers and diastereomers as well as their mixtures and racemates.
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen und ihrer Salze. Das Verfahren ist dadurch gekennzeichnet, daß manAnother object of the invention is a process for the preparation of the compounds according to the invention and their salts. The process is characterized in that
a) Zimtsäurederivate der Formel IIa) Cinnamic acid derivatives of the formula II
Figure imgf000015_0002
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0001
mit Enaminderivaten der Formel III with enamine derivatives of the formula III
Figure imgf000016_0001
Figure imgf000016_0001
oderor
b) Zimtsäurederivate der Formel II mit Ammoniak und ß-Ketocarbonsäurederivaten der Formel IVb) cinnamic acid derivatives of the formula II with ammonia and β-ketocarboxylic acid derivatives of the formula IV
Figure imgf000016_0002
oder
Figure imgf000016_0002
or
c) Enamine der Formel Vc) Enamines of formula V
Figure imgf000016_0004
Figure imgf000016_0003
Figure imgf000016_0004
Figure imgf000016_0003
mit Benzylidencarbonsaurederivaten der Formel VI with benzylidenecarboxylic acid derivatives of the formula VI
Figure imgf000017_0001
oder
Figure imgf000017_0001
or
d) Ketoverbindungen der Formel VIId) keto compounds of the formula VII
Figure imgf000017_0002
mit Ammoniak und Benzylidencarbonsaurederivaten der Formel VI, oder
Figure imgf000017_0002
with ammonia and benzylidenecarboxylic acid derivatives of the formula VI, or
e) Aldehyde der Formel VIIIe) aldehydes of the formula VIII
Figure imgf000017_0003
Figure imgf000017_0003
mit Enaminen der Formel V und ß-Ketocarbonsäurederivaten der Formel IV, oder f) Aldehyde der Formel VIII mit Enaminderivaten der Formel III und Ketoverbindungen der Formel VII, oderwith enamines of the formula V and β-ketocarboxylic acid derivatives of the formula IV, or f) aldehydes of the formula VIII with enamine derivatives of the formula III and keto compounds of the formula VII, or
g) 1 ,4-Dihydropyridine der Formel IXg) 1, 4-dihydropyridines of the formula IX
Figure imgf000018_0001
mit Piperazinderivaten der Formel X
Figure imgf000018_0003
Figure imgf000018_0002
als solche(n) oder in Form ihrer Salze umsetzt und gewünschtenfalls anschließend erhaltene Salze in die freien Basen oder erhaltene Basen in die Salze überführt, wobei R1, R2, R3, R4, R5 und A die oben angegebenen Bedeutungen haben und Z gemeinsam mit der Carbonylgruppe, woran es gebunden ist, eine Carboxylgruppe oder ein reaktives Carbonsäurederivat (z. B. ein Carbonsäurehalogenid) darstellt.
Figure imgf000018_0001
with piperazine derivatives of the formula X
Figure imgf000018_0003
Figure imgf000018_0002
as such (s) or in the form of their salts and, if desired, subsequently obtained salts are converted into the free bases or bases obtained into the salts, where R1, R2, R3, R4, R5 and A have the meanings given above and Z together with the Carbonyl group to which it is attached represents a carboxyl group or a reactive carboxylic acid derivative (e.g. a carboxylic acid halide).
Ausgestaltungen des Verfahrens sind solche, bei denen in den Formeln II bis X die Substituenten bzw. Symbole R1, R2, R3, R4, R5 und A die in den Unter- und Nebenansprüchen angegebenen Bedeutungen haben und Z gemeinsam mit der Carbonylgruppe, woran es gebunden ist, eine Carboxylgruppe oder ein reaktives Carbonsäurederivat darstellt.Embodiments of the process are those in which in the formulas II to X the substituents or symbols R1, R2, R3, R4, R5 and A have the meanings given in the subclaims and dependent claims and Z together with the carbonyl group to which it is bound is a carboxyl group or a reactive carboxylic acid derivative.
Das Verfahren gemäß den Varianten a bis f wird in geeigneten, Vorzugs weise inerten organischen Lösungsmitteln durchgeführt. Beispielsweise seien genannt Alkohole, wie Ethanol, Methanol, Isopropanol oder insbesondere t-Butanol, Ether, wie Dioxan, Diethylether, Tetrahydrofuran, Glykolmonoethylether, Glykoldimethylether oder sonstige, beispielsweise polare Lösungsmittel wie Dimethylformamid, Dimethylsulfoxid, Acetonitril oder Hexamethylphosphorsäuretriamid, oder chlorierte Kohlenwasserstoffe wie Methylenchlorid, Chloroform oder Tetrachlorethylen.The method according to variants a to f is preferred as inert organic solvents. Examples include alcohols, such as ethanol, methanol, isopropanol or, in particular, t-butanol, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or hexamethylphosphoric triamide, or chlorinated hydrocarbons such as methylene chloride Chloroform or tetrachlorethylene.
Die Reaktionstemperaturen können - je nach Reaktivität der Edukte - in einem weiten Bereich variieren. Im allgemeinen wird die Umsetzung bei Temperaturen zwischen 20°C und 150°C, vorzugsweise zwischen 20°C und 100°C, insbesondere bei der Siedetemperatur des verwendeten Lösungsmittels durchgeführt.Depending on the reactivity of the starting materials, the reaction temperatures can vary within a wide range. In general, the reaction is carried out at temperatures between 20 ° C. and 150 ° C., preferably between 20 ° C. and 100 ° C., in particular at the boiling point of the solvent used.
Das Verfahren kann bei Normaldruck oder bei erhöhtem Druck durchgeführt werden, wobei das Arbeiten bei Normaldruck die Regel ist und erhöhter Druck insbesondere bei Umsetzungen mit Ammoniak zur Anwendung kommen kann.The process can be carried out at atmospheric pressure or at elevated pressure, working at atmospheric pressure being the rule and elevated pressure being used in particular in the case of reactions with ammonia.
Bei der Durchführung des erfindungsgemäßen Verfahrens gemäß Varianten a bis f werden die an der Reaktion beteiligten Stoffe in der Regel jeweils in molaren Mengen eingesetzt, wobei jedoch - je nach Reaktionsbedingung - gewunschtenfalls auch ein Oberschuß (beispielsweise an Ammoniak bei den Varianten b und d) eingesetzt werden kann.When carrying out the process according to the invention according to variants a to f, the substances involved in the reaction are generally used in molar amounts, but - depending on the reaction condition - an excess (if desired, for example in ammonia in variants b and d) is also used can be.
Bei der Durchführung des Verfahrens gemäß Variante g kommen ähnliche Reaktionsbedingungen wie bei den Varianten a bis f zur Anwendung, jedoch sind - je nach Art des Substituenten Z - gegebenenfalls zusätzliche Maßnahmen erforderlich. Stellt Z beispielsweise eine Hydroxylgruppe dar, so ist die Reaktion bevorzugt in Gegenwart eines wasserabspaltenden oder wasserbindenden Kondensationsmittels (wie z.B. Dicyclohexylcarbodiimid) durchzuführen. Stellt Z ein Halogenatom (z.B. ein Chloratom) dar, so ist die Reaktion gewunschtenfalls in Gegenwart einer Base (z. B. eines tertiären organischen Amins, wie Triethylamin, oder eines anorganischen Carbonates, wie Natriumcarbonat) durchzuführen.When carrying out the process according to variant g, similar reaction conditions are used as for variants a to f, but - depending on the nature of the substituent Z - additional measures may be necessary. If Z represents a hydroxyl group, for example, the reaction should preferably be carried out in the presence of a water-releasing or water-binding condensing agent (such as dicyclohexylcarbodiimide). If Z represents a halogen atom (e.g. a chlorine atom), the reaction can, if desired, be carried out in the presence of a base (e.g. a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate).
Die Isolierung und Reinigung der erfindungsgemäßen Substanzen erfolgt in an sich bekannter Weise z. B. derart, daß man das Lösungsmittel im Vakuum abdestilliert und den erhaltenen Rückstand aus einem geeigneten Lösungsmittel umkristallisiert oder einer der üblichen Reinigungsmethoden, wie beispielsweise der Säulenchromatographie an geeignetem Trägermaterial, unterwirft.The substances according to the invention are isolated and purified in a manner known per se, for. B. such that the solvent in Vacuum was distilled off and the residue obtained was recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
Säureadditionssalze erhält man durch Auflösen der freien Base in einem geeigneten Lösungsmittel, z.B. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, oder einem niedermolekularen aliphatischen Alkohol (Ethanol, Isopropanol), das die gewünschte Säure enthält, oder dem die gewünschte Säure anschließend zugegeben wird.Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added.
Die Salze werden durch Filtrieren, Umfallen, Ausfällen mit einem Nichtlösungsmittel für das Anlagerungssalz oder durch Verdampfen des Lösungsmittels gewonnen.The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
Erhaltene Salze können durch Alkalisierung, z.B. mit wäßriger Ammoniaklösung, in die freien Basen umgewandelt werden, welche wiederum in Säureadditionssalze übergeführt werden können. Auf diese Weise lassen sich pharmakologisch nicht verträgliche Säureadditionssalze in pharmakologisch verträgliche Säureadditionssalze umwandeln.Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
Die Ausgangsverbindungen sind literaturbekannt oder können in Analogie zu literaturbekannten Methoden hergestellt werden. Die Zimtsäurederivate II und die Benzylidencarbonsaurederivate VI können beispielsweise in Analogie zu G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)] hergestellt werden. Die Enaminderivate III bzw. die Enamine V sind beispielsweise analog A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)] erhältlich. ß-Ketocarbonsäurederivate IV und Ketoverbindungen VII können gemäß D. Borrmann ["Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" in Houben-Weyl, Methoden der Organischen Chemie, Vol. VII/4, 230ff (1968)] oder Y. Oikawa et al. [J. Org. Chem. 43, 2087 (1978)] hergestellt werden. Die Verbindungen IX sind aus entsprechenden Ausgangsverbindungen analog Verfahrensvariante a bis f zugänglich. Verbindungen X sind durch Umsetzung entsprechender Piperazine mit ω-Halogenalkanolen erhältlich.The starting compounds are known from the literature or can be prepared analogously to methods known from the literature. The cinnamic acid derivatives II and the benzylidenecarboxylic acid derivatives VI can be prepared, for example, in analogy to G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)]. The enamine derivatives III and the enamines V are, for example, analogous to A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)]. β-ketocarboxylic acid derivatives IV and keto compounds VII can, according to D. Borrmann ["Reaction of diketene with alcohols, phenols and mercaptans" in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 4, 230ff (1968)] or Y. Oikawa et al. [J. Org. Chem. 43, 2087 (1978)]. The compounds IX are accessible from corresponding starting compounds analogously to process variants a to f. Compounds X can be obtained by reacting corresponding piperazines with ω-haloalkanols.
Die vorstehenden Herstellungsverfahren sind lediglich zur Verdeutlichung angegeben, und die Herstellung der erfindungsgemäßen Verbindungen der Formel I ist nicht auf diese Verfahren beschränkt. Vielmehr ist auch jede Modifikation dieser Verfahren in gleicher Weise für die Herstellung der erfindungsgemäßen Verbindungen anwendbar.The above preparation processes are given for illustration only, and the preparation of the compounds of the invention Formula I is not limited to these processes. Rather, any modification of these processes can be used in the same way for the preparation of the compounds according to the invention.
Die folgenden Herstellungsbeispiele sollen die Erfindung näher erläutern, ohne sie einzuschränken. Schmp. bedeutet Schmelzpunkt, Kp. steht für Siedepunkt, Zers. bedeutet Zersetzung. The following production examples are intended to explain the invention in more detail without restricting it. Mp. Means melting point, Kp. Stands for boiling point, decomp. means decomposition.
BeispieleExamples
1. 4-(2-Difluormethoxyphenyl)-1,4-dihvdro-2,6-dimethylpyridin-3,5- dicarbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester-fumarat1. 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -ester-fumarate
5 g 3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propan-1-ol in 25 ml Toluol werden mit 2 ml einer 50%igen Diketenlösung in Aceton versetzt und das Gemisch 3 Tage bei Raumtemperatur stehengelassen. Dann wird das Lösungsmittel im Vakuum abdestilliert und der Rückstand zusammen mit 2,6 g 3-Aminocrotonsäureethylester und 3,44 g 2-Difluormethoxybenzaldehyd in 70 ml tert.Butanol gelöst. Die erhaltene Lösung wird ca. 20 Stunden unter Stickstoff zum Sieden erhitzt. Nach Abkühlen wird das Lösungsmittel im Vakuum abdestilliert und der Rückstand über eine Kieselgelsäule mit Essigsäureethylester als Laufmittel chromatographiert. Die chromatographisch reinen Fraktionen werden im Vakuum eingedampft und schließlich im Hochvakuum getrocknet. Man erhält 4,62 g erstarrten Schaum, der in 30 ml Methanol gelöst und dann mit 0,895 g Fumarsäure versetzt wird. Nach Filtrieren wird zur Trockene eingedampft und der Rückstand mit Tetrahydrofuraπ/Diethylether angerieben. Der Niederschlag wird abgesaugt, mit Oiethylether gewaschen und getrocknet. Man erhält 4,5 g der Titelverbindung vom Schmp. 123-126°C (Zers.).5 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] propan-1-ol in 25 ml of toluene are mixed with 2 ml of a 50% strength diketene solution in acetone and the mixture is left to stand for 3 days at room temperature. The solvent is then distilled off in vacuo and the residue is dissolved in 70 ml of tert-butanol together with 2.6 g of 3-aminocrotonic acid ethyl ester and 3.44 g of 2-difluoromethoxybenzaldehyde. The solution obtained is heated to boiling under nitrogen for about 20 hours. After cooling, the solvent is distilled off in vacuo and the residue is chromatographed on a silica gel column using ethyl acetate as the eluent. The chromatographically pure fractions are evaporated in a vacuum and finally dried in a high vacuum. 4.62 g of solidified foam are obtained, which is dissolved in 30 ml of methanol and then mixed with 0.895 g of fumaric acid. After filtration, the mixture is evaporated to dryness and the residue is triturated with tetrahydrofuraπ / diethyl ether. The precipitate is filtered off, washed with ethyl ether and dried. 4.5 g of the title compound of mp 123-126 ° C. (dec.) Are obtained.
2. 4-(2-Difluormethoχyphenyl)-1,4-dihvdro-2,6-dimethylpyridin-3,5- dicarbonsäure-3-(2-methoxyethyl)-ester-5-{3-[4-(2-methoxyphenyl)- 1-Piperazinyl]-propyl}-ester-fumarat2. 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- {3- [4- (2-methoxyphenyl ) - 1-piperazinyl] propyl} ester fumarate
Analog Beispiel 1 werden 5,6 g der freien Base aus 5 g 3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propan-1-ol, 2 ml einer 50%igen Diketenlösung in Aceton, 3,2 g 3-Aminocrotonsäure-(2-methoxyethyl)-ester und 3,44 g 2-Difluormethoxybenzaldehyd als fester Schaum erhalten, der mit 1,03 g Fumarsäure in das kristalline Fumarat übergeführt wird. Ausbeute: 5,8 g vom Schmp. 149-151°C (Zers.). 3. 4-(2-Difluormethoxyphenvl)-1,4-dihvdro-2,6-dimethvlPvridin-3,5-dicarbonsäure-3-methylester-5-{3-[4-(2-methoχyphenyl)-1-piperazinyl]-propyl]}-ester-fumaratAnalogously to Example 1, 5.6 g of the free base are made from 5 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] propan-1-ol, 2 ml of a 50% strength diketene solution in acetone, 3.2 g Obtain 3-aminocrotonic acid (2-methoxyethyl) ester and 3.44 g of 2-difluoromethoxybenzaldehyde as a solid foam, which is converted into the crystalline fumarate with 1.03 g of fumaric acid. Yield: 5.8 g of mp 149-151 ° C (dec.). 3. 4- (2-Difluoromethoxyphenvl) -1,4-dihydro-2,6-dimethvlPvridin-3,5-dicarboxylic acid 3-methyl ester-5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl]} - ester fumarate
Analog Beispiel 1 werden aus 5 g 3 - [ 4 - ( 2-Methoxyphenyl)-1-piperazinyl]-propan-1-ol, 2 ml einer 50%igen Diketenlösung in Aceton, 2,3 g 3-Aminocrotonsäuremethylester und 3,44 g 2- Difluormethoxybenzaldehyd 4,5 g der freien Base als fester Schaum erhalten, der mit 0,89 g Fumarsäure in das kristalline Fumarat übergeführt wird. Ausbeute: 4,37 g vom Schmp. 127-129°C (Zers.).Analogously to Example 1, 5 g of 3 - [4 - (2-methoxyphenyl) -1-piperazinyl] propan-1-ol, 2 ml of a 50% diketene solution in acetone, 2.3 g of 3-aminocrotonic acid methyl ester and 3.44 g 2-difluoromethoxybenzaldehyde 4.5 g of the free base are obtained as a solid foam which is converted into the crystalline fumarate with 0.89 g of fumaric acid. Yield: 4.37 g of mp. 127-129 ° C (dec.).
4. 4-(2-Difluormethoxyphenyl)-1,4-dihvdro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-ethylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]- ethyl}-ester-fumarat4. 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] - ethyl} ester fumarate
Analog Beispiel 1 werden aus 4,7 g 2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethanol, 2 ml einer 50%igen Diketenlösung in Aceton, 2,6 g 3-Aminocrotonsäureethylester und 3,44 g 2-Difluormethoxybenzaldehyd 3,8 g der freien Base erhalten, die mit 0,75 g Fumarsäure in das kristalline Fumarat übergeführt werden. Ausbeute 3,73 g vom Schmp. 108-111°C (Zers.).Analogously to Example 1, 4.7 g of 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethanol, 2 ml of a 50% strength diketene solution in acetone, 2.6 g of 3-aminocrotonic acid ethyl ester and 3.44 g of 2nd -Difluoromethoxybenzaldehyde 3.8 g of the free base obtained, which are converted into the crystalline fumarate with 0.75 g of fumaric acid. Yield 3.73 g of mp. 108-111 ° C (dec.).
5. 4-(2-Difluormethoχyphenyl)-1,4-dihvdro-2,6-dimethylpyridin-3,5- dicarbonsäure-3-ethylester-5-[2-(4-ohenyl-1-piperazinyl)-ethyllester-fumarat5. 4- (2-Difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [2- (4-ohenyl-1-piperazinyl) ethyl ester fumarate
Analog Beispiel 1 werden aus 4,1 g 2-(4-Phenyl-1-piperazinyl)-ethanol, 2 ml 50%iger Diketenlösung in Aceton, 2,6 g 3-Aminocrotonsäureethylester und 3,44 g 2-Difluormethoxybenzaldehyd 3,6 g freie Base erhalten und mit 0,74 g Fumarsäure in das kristalline Fumarat übergeführt. Ausbeute: 3,8 g vom Schmp. 126-128°C (Zers.).Analogously to Example 1, 4.1 g of 2- (4-phenyl-1-piperazinyl) ethanol, 2 ml of 50% diketene solution in acetone, 2.6 g of 3-aminocrotonic acid ethyl ester and 3.44 g of 2-difluoromethoxybenzaldehyde 3.6 g of free base obtained and converted into the crystalline fumarate with 0.74 g of fumaric acid. Yield: 3.8 g of mp. 126-128 ° C (dec.).
6. Bis-4-(2-difluormethoχyphenyl)-1,4-dihvdro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-(2-methoxyethyl)-ester-5-[2-(4-benzhydryl-1- piperazinyl)-ethyl]-ester-tris-fumarat6. bis-4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- [2- (4-benzhydryl- 1-piperazinyl) ethyl] ester tris fumarate
4,14 g 2-(2-Difluormethoxybenzyliden)-acetessigsäure-2-methoxyethylester und 5 g 3-Aminocrotonsäure-2-(4-benzhydryl-1-piperazinyl)-ethylester werden in 30 ml tert. Butanol 16 Stunden unter Stickstoff zum Sieden erhitzt. Dann wird das Lösungsmittel im Vakuum abdestilliert und der Rückstand über eine Kieselgelsäule mit Chloroform/Ethanol 95:5 als Laufmittel chromatografiert. Die chromatografisch einheitlichen Fraktionen werden im Vakuum eingedampft und im Hochvakuum getrocknet. Man erhält 6,46 g erstarrten Schaum, der in 50 ml Methanol gelöst und dann mit 1,1 g Fumarsäure versetzt wird. Nach Filtrieren wird zur Trockne eingedampft und der Rückstand mit Ether zur Kristallisation gebracht. Der Niederschlag wird abgesaugt und aus Acetonitril umkristallisiert. Man erhält 4,6 g der Titelverbindung mit Schmp. 119-123°C (Zers.).4.14 g of 2- (2-difluoromethoxybenzylidene) -acetoacetic acid-2-methoxyethyl ester and 5 g of 3-aminocrotonic acid 2- (4-benzhydryl-1-piperazinyl) ethyl ester are tert in 30 ml. Butanol under nitrogen for 16 hours Boiling heated. Then the solvent is distilled off in vacuo and the residue is chromatographed on a silica gel column using chloroform / ethanol 95: 5 as the eluent. The chromatographically uniform fractions are evaporated in a vacuum and dried in a high vacuum. 6.46 g of solidified foam are obtained, which is dissolved in 50 ml of methanol and then mixed with 1.1 g of fumaric acid. After filtering, the mixture is evaporated to dryness and the residue is crystallized with ether. The precipitate is filtered off and recrystallized from acetonitrile. 4.6 g of the title compound with mp 119-123 ° C. (dec.) Are obtained.
7. 4-(2-Difluormethoχyphenyl)-1.4-dihvdro-2.6-dimethylpyridin-3.5- dicarbonsäure-3-methylester-5-[2-(4-benzhvdryl-1-piperazinyl)- ethyl]-ester-fumarat7. 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- [2- (4-benzhvdryl-1-piperazinyl) ethyl] ester fumarate
Analog Beispiel 6 werden aus 3,35 g 2-(2-Difluormethoxybenzyliden)-acetessigsäuremethylester und 4,7 g 3-Aminocrotoπsäure-2-(4-benzhydryl-1-piperazinyl)-ethylester 5,57 g der freien Base erhalten, die mit 1 g Fumarsäure aus Acetonitril 3,9 g der Titelverbindung mit Schmp. 122-125°C liefern.Analogously to Example 6, from 3.35 g of 2- (2-difluoromethoxybenzylidene) -acetoacetic acid methyl ester and 4.7 g of 3-aminocrotonic acid 2- (4-benzhydryl-1-piperazinyl) ethyl ester, 5.57 g of the free base are obtained with 1 g of fumaric acid from acetonitrile 3.9 g of the title compound with mp 122-125 ° C.
8. 4-(2-Difluormethoχyphenyl)-1,4-dihvdro-2,6-dimethylpyridin-3,5- dicarbonsäure-3-ethylester-5-[3-(4-benzhvdryl-1-piperazinyl)-propyl]-ester-fumarat8. 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- [3- (4-benzhvdryl-1-piperazinyl) propyl] - ester fumarate
Analog Beispiel 1 werden aus 7,89 g Acetessigsäure-3-(4-benzhydryl-1-piperazinyl)-propylester, 2,58 g 3-Aminocrotonsäureethylester und 3,44 g 2-Difluormethoxybenzaldehyd nach Chromatografie über eine Kieselgelsäule mit Chloroform/Methanol 9:1 als Laufmittel 6,9 g der freien Base erhalten, die zusammen mit 1,2 g Fumarsäure in 50 ml Methanol gelöst werden. Es wird zur Trockne eingeengt und dann der Rückstand mit Ether angerieben. Der Niederschlag wird abgesaugt, mit Ether gewaschen und getrocknet. Man erhält 5,7 g der Titelverbindung vom Schmp. 131-135°C (Zers.). 9. 4-(2-Difluormethoxyphenyl)-1,4-dihvdro-2,6-diemthylpyridin-3,5- dicarbonsäure-3-(2-methoxyethyl)-ester-5-[3-(4-benzhvdryl-1-piperazinyl)-propyl]-ester-fumaratAnalogously to Example 1, 7.89 g of 3- (4-benzhydryl-1-piperazinyl) propyl acetoacetate, 2.58 g of 3-aminocrotonic acid ethyl ester and 3.44 g of 2-difluoromethoxybenzaldehyde after chromatography on a silica gel column with chloroform / methanol 9 : 1 6.9 g of the free base are obtained as eluent, which are dissolved together with 1.2 g of fumaric acid in 50 ml of methanol. It is evaporated to dryness and then the residue is triturated with ether. The precipitate is filtered off, washed with ether and dried. 5.7 g of the title compound of mp 131-135 ° C. (dec.) Are obtained. 9. 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- [3- (4-benzhvdryl-1- piperazinyl) propyl] ester fumarate
Analog Beispiel 8 werden aus 7,89 g Acetessigsäure-3-(4-benzhydryl-1-piperazinyl)-propylester, 3,18 g 3-Aminocrotonsäure-2-methoxyethylester und 3,44 g 2-Difluormethoxybenzaldehyd 5,2 g der freien Base erhalten, die mit 0,875 g Fumarsäure 4,7 g der Titelverbindung mit Schmp. 127-130°C (Zers.) liefert. Analogously to Example 8, 7.89 g of 3- (4-benzhydryl-1-piperazinyl) propyl acetoacetate, 3.18 g of 2-methoxyethyl 3-aminocrotonic acid and 3.44 g of 2-difluoromethoxybenzaldehyde become 5.2 g of the free Base obtained which, with 0.875 g of fumaric acid, gives 4.7 g of the title compound with mp. 127-130 ° C. (dec.).
Gewerbliche AnwendbarkeitIndustrial applicability
Die erfindungsgemäßen Verbindungen der Formel I und ihre Salze besitzen wertvolle Eigenschaften, die sie gewerblich verwertbar machen. Sie stellen insbesondere wirksame Vasodilatoren mit coronartherapeutischen Eigenschaften dar. Die pharmakologische Wirksamkeit der erfindungsgemäßen Verbindungen, die gepaart ist mit einer geringen Toxizität, zeigt sich insbesondere in einer langsam eintretenden, starken und langanhaltenden Blutdrucksenkung. Darüberhinaus besitzen die erfindungsgemäßen Verbindungen peripher, coronar, cerebral und renal gefäßerweiternde sowie salidiuretische Eigenschaften.The compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are particularly effective vasodilators with coronary therapeutic properties. The pharmacological activity of the compounds according to the invention, which is paired with a low toxicity, is particularly evident in a slowly occurring, strong and long-lasting drop in blood pressure. In addition, the compounds according to the invention have peripheral, coronary, cerebral and renal vasodilator and salidiuretic properties.
In ihrer ausgezeichneten Wirksamkeit, die gepaart ist mit einer geringen Toxizität und dem Fehlen wesentlicher Nebenwirkungen, unterscheiden sich die erfindungsgemäßen Verbindungen in überraschender und vorteilhafter Weise von den Verbindungen des Standes der Technik. Als vorteilhafte Eigenschaften sind beispielsweise zu nennen: das Ausmaß der Blutdrucksenkung, das lange Anhalten der Blutdrucksenkung, die gute Steuerbarkeit der Blutdrucksenkung, die überraschend geringe und bei wiederholter Gabe verschwindende Herzfrequenzsteigerung, die ausgezeichnete Bioverfügbarkeit, die große therapeutische Breite, das Fehlen zentraler Nebenwirkungen, das Fehlen kinetischer Interaktionen mit anderen Substanzen, das Ausbleiben einer Toleranzentwicklung, die ausgewogenen physikalischen Eigenschaften und die große Stabilität.The compounds according to the invention differ surprisingly and advantageously from the compounds of the prior art in their excellent activity, which is paired with low toxicity and the absence of significant side effects. Examples of advantageous properties are: the extent of the reduction in blood pressure, the prolonged persistence of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly small and disappearing heart rate increase after repeated administration, the excellent bioavailability, the great therapeutic breadth, the lack of central side effects, that Lack of kinetic interactions with other substances, the lack of tolerance development, the balanced physical properties and the great stability.
Die ausgezeichnete Wirksamkeit der erfindungsgemäßen Verbindungen der Formel I und ihrer Salze gestattet ihren Einsatz in der Humanmedizin, wobei als Indikation insbesondere primäre (essentielle) und sekundäre Hypertonien aller Schweregrade, koronare Herzkrankheiten (Koronarinsuffizienz, Angina Pectoris, Myocardinfarkt etc.), periphere und cere brale Zirkulationsstörungen (Gehirnschlag, temporäre cerebrale Durchblutungsstörungen, renale Arterienverengung etc.), Herzinsuffiziens und Krankheiten, die auf einer erhöhten Wasser- und Natriumretention beruhen, in Betracht kommen.The excellent activity of the compounds of formula I and their salts according to the invention permits their use in human medicine, with primary (essential) and secondary hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.), peripheral and cere as indications bral circulation disorders (stroke, temporary cerebral circulatory disorders, renal artery narrowing etc.), cardiac insufficiency and diseases that are based on increased water and sodium retention.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behandlung von Säugetieren, insbesondere Menschen, die an einer der obengenannten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Individuum eine therapeutisch wirksame und pharmakologisch verträgliche Menge einer oder mehrerer Verbindungen der Formel I verabreicht.Another object of the invention is therefore a method for the treatment of mammals, especially humans, who are suffering from one of the above-mentioned diseases. The method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I.
Gegenstand der Erfindung sind außerdem die Verbindungen der Formel I zur Anwendung bei der Behandlung der genannten Krankheiten.The invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
Ebenso umfaßt die Erfindung die Verwendung von Verbindungen der Formel I bei der Herstellung von Arzneimitteln, die zur Bekämpfung der genannten Krankheiten eingesetzt werden.The invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die eine oder mehrere Verbindungen der allgemeinen Formel I enthalten.The invention further relates to medicaments which contain one or more compounds of the general formula I.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die erfindungsgemäßen pharmakologisch wirksamen Verbindungen (=Wirkstoffe) entweder als solche, oder vorzugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emulsionen, Suspensionen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95% beträgt.The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds (= active substances) according to the invention are used as medicaments either as such or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, where the active ingredient content is advantageously between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, TablettenHilfsstoffen und anderen Wirkstoffträgern können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z.B. Cyclodex trine) verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gelling agents, suppository bases, tablet auxiliaries and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example Cyclodex trine) can be used.
Die Wirkstoffe können oral oder parenteral (insbesondere perlingual, intravenös oder percutan) appliziert werden.The active substances can be administered orally or parenterally (in particular perlingually, intravenously or percutaneously).
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,01 bis etwa 10, vorzugsweise 0,05 bis 5 mg/kg Körpergewicht, gewunschtenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Regel niedrigere Dosierungen zur Anwendung kommen. Bei einschleichender Dosierung wird zu Beginn der Behandlung eine geringere Dosis verabreicht, dann langsam auf eine höhere Dosis übergegangen. Nach Erreichen des gewünschten Therapieerfolges wird wieder auf eine niedrigere Dosis zurückgegangen.In general, it has proven to be advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or generally lower doses (in particular when the active compounds are administered intravenously) can be used. If the dose creeps in, a lower dose is administered at the beginning of the treatment, then the dose is slowly switched to a higher dose. After the desired therapeutic success has been reached, the dose is reduced again.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.The determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.
Sollen die erfindungsgemäßen Verbindungen und/oder ihre Salze zur Behandlung der genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere andere pharmakologisch aktive Bestandteile anderer Arzneimittelgruppen, wie andere Vasodilatoren, Antihypertensiva, α-Rezeptorenblocker, B-Rezeptorenblocker, ACE-Hemmstoffe, Nitroverbindungen, Cardiotonika, Diuretika, Saluretika, Alkaloide, etc., wie Nifedipin, Dihydralazin, Prazosin, Propranolol, Labetalol, Captopril, Isosorbiddinitrat, Digoxin, Mefrusid, Clopamid, Spironolacton, Chlorthalidon, Furosemid, Polythiazid, Hydrochlorothiazid, Reserpin, Dihydroergocristin, Rescinnamin, Rauwolfia-Gesamtalkaloide etc. enthalten. PharmakologieIf the compounds according to the invention and / or their salts are to be used for the treatment of the diseases mentioned, the pharmaceutical preparations can also include one or more other pharmacologically active constituents of other groups of medicaments, such as other vasodilators, antihypertensives, α-receptor blockers, B-receptor blockers, ACE inhibitors , Nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, etc., such as nifedipine, dihydralazine, prazosin, propranolol, labetalol, captopril, isosorbide dinitrate, digoxin, mefruside, clopamide, spironolactone, chlorthalidone, furosididridiniazine, furosididrochloride, furosididrochloride, furosidide hydrochloride, polyhydric chloride, furosidol chloride, furosidol chloride, polyhydric chloride, furosidol chloride, polyhydric acid , Rauwolfia total alkaloids etc. included. pharmacology
Die antihypertensive Wirksamkeit der erfindungsgemäßen Verbindungen kann am Modell der spontan hypertonen Ratte nachgewiesen werden.The antihypertensive activity of the compounds according to the invention can be demonstrated on the model of the spontaneously hypertensive rat.
Zur Bestimmung der antihypertensiven Wirkung werden die unten aufgeführten Verbindungen in den angegebenen Dosen an vier aufeinander folgenden Tagen an je 6 Ratten (Stamm SHR/N/Ibm/Bm ♂, 250-350 g) mit genetisch bedingtem Hochdruck (systolischer Blutdruck > 180 mmHg) täglich einmal mittels Schlundsonde verabfolgt. Die Messung des Blutdrucks erfolgt jeweils 6 und gegebenenfalls 2 oder 24 Stunden nach Substanzgabe.To determine the antihypertensive effect, the compounds listed below are given in the doses given on four consecutive days on 6 rats (strain SHR / N / Ibm / Bm ♂, 250-350 g) with genetically determined high pressure (systolic blood pressure> 180 mmHg) administered once a day by gavage. Blood pressure is measured 6 and, if necessary, 2 or 24 hours after substance administration.
Die Blutdruckmessung wird in einer Wärmekammer bei 36°C vorgenommen, um eine bessere Durchblutung der Schwanzarterie zu erreichen. Hierzu werden die Tiere in perforierte Lochblechkäfige verbracht und 20 - 40 Min nach Beginn der Aufwärmung gemessen. Zur Messung des systolischen arteriellen Drucks wird eine ringförmige Manschette mit aufblasbarer Gummimembran zur Unterbindung der Durchblutung und ein ringförmiger Piezokristallaufnehmer zur Erfassung der Pulswellen auf den Schwanz aufgeschoben. Nach erfolgter Unterbindung des Blutstroms in der Schwanzarterie wird der Manschettendruck kontinuierlich reduziert. Die Wiederkehr der Pulswellen bei Druckablassen wird automatisch als systolischer Blutdruck erkannt und ausgedruckt (Bühler, R. et al.: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international Symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 1982, S. 410-413). Pulssignale und Druckverlauf werden zur Auswertung graphisch aufgezeichnet.The blood pressure measurement is carried out in a heat chamber at 36 ° C in order to achieve better circulation in the tail artery. For this purpose, the animals are placed in perforated perforated metal cages and measured 20-40 minutes after warming up. To measure the systolic arterial pressure, an annular cuff with an inflatable rubber membrane to prevent blood flow and an annular piezo crystal sensor to record the pulse waves are pushed onto the tail. After the blood flow in the tail artery has been stopped, the cuff pressure is continuously reduced. The return of the pulse waves during pressure relief is automatically recognized and printed out as systolic blood pressure (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international Symposium on rats with spontaneous hypertension and related studies , Rascher, R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 1982, pp. 410-413). Pulse signals and pressure curve are recorded graphically for evaluation.
Zur Gewöhnung an den Meßvorgang werden die Tiere vor Substanzprüfung 14 Tage trainiert. In der zweiten Trainingswoche werden Blutdruck-Vorwerte erhoben. Tiergruppen, die Substanz erhalten, werden gegen eine Kontrollgruppe geprüft. In der anschließenden Tabelle werden die untersuchten Verbindungen durch laufende Nummern gekennzeichnet, die wie folgt zugeordnet sind:To get used to the measuring process, the animals are trained for 14 days before the substance test. In the second week of training, blood pressure pre-values are collected. Groups of animals receiving substance are tested against a control group. In the table below, the examined connections are identified by consecutive numbers, which are assigned as follows:
1fd. Nr. Name der Verbindung1fd. No. Name of the connection
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1- piperazinyl]-propyl}-ester-fumarat4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl } -ester-fumarate
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-(2-methoxyethyl)-ester-5-{3-[4-(2- methoxyphenyl)-1-piperazinyl]-propyl}-ester-fumarat 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-methylester-5-{3-[4-(2-methoxyphenyl)- 1-piperazinyl]-propyl]}-ester-fumarat4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- {3- [4- (2-methoxyphenyl) - 1-piperazinyl] propyl} ester fumarate 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- {3- [4- ( 2-methoxyphenyl) -1-piperazinyl] -propyl]} - ester fumarate
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-ethylester-5-{2-[4-(2-methoxyphenyl)- 1-piperazinyl]-ethyl}-ester-fumarat4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl } -ester-fumarate
Bis-4-(2-difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-(2-methoxyethyl)-ester-5-[2-(4- benzhydryl-1-piperazinyl)-ethyl]-ester-tris-fumarat 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-methylester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester-fumarrt Bis-4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- [2- (4-benzhydryl-1- piperazinyl) ethyl] ester tris fumarate 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- [2- (4-benzhydryl -1-piperazinyl) ethyl] ester fumarrt
Tabelle I gibt für die Vertreter der erfindungsgemäßen Verbindungen die prozentuale Senkung des Blutdrucks (BP) nach oraler Verabreichung bei der Ratte wieder.Table I shows for the representatives of the compounds according to the invention the percentage reduction in blood pressure (BP) after oral administration in the rat.
Tabelle ITable I
X-Änderungen (BP) an genetisch hypertonen Ratten nach täglich einmaliger p.o. -Applikation an vier aufeinanderfolgenden Tagen (N=6/Dosis).X changes (BP) in genetically hypertensive rats after daily po.o. -Application on four consecutive days (N = 6 / dose).
Figure imgf000031_0001
Figure imgf000031_0001

Claims

Patentansorüche 1. Piperazinderivate der Formel IPatent claims 1. Piperazine derivatives of the formula I
Figure imgf000032_0002
Figure imgf000032_0001
worin
Figure imgf000032_0002
Figure imgf000032_0001
wherein
R1, R2 und R3 gleich oder verschieden sind und Wasserstoff, C1-C6- alkyl, C3-C7-alkoxyalkyl, Aryl, Aryl- C1-C6-alkyl oder Aryloxy- C1-C6-alkyl bedeuten, R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy bedeutet, R5 Aryl, Heteroaryl, Aryl-C1-C4-alkyl, Heteroaryl-C1-C4-alkyl,R1, R2 and R3 are the same or different and are hydrogen, C 1 -C 6 alkyl, C 3 -C 7 alkoxyalkyl, aryl, arylC 1 -C 6 alkyl or aryloxyC 1 -C 6 alkyl R4 is completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, R5 is aryl, heteroaryl, aryl-C 1 -C 4 -alkyl, heteroaryl-C 1 -C 4 -alkyl,
Diaryl-C1-C4-alkyl, Heteroaryl-aryl- C1-C4-alkyl oderDiaryl-C 1 -C 4 alkyl, heteroaryl-aryl-C 1 -C 4 alkyl or
Di-heteroaryl-C1-C4-alkyl bedeutet und A geradkettiges oder verzweigtes C2-C5-alkylen bedeutet, das durchDi-heteroaryl-C 1 -C 4 alkyl means and A means straight-chain or branched C 2 -C 5 alkylene, which by
C1-C4-alkoxy oder Aryl substituiert sein kann und ihre Salze.C 1 -C 4 alkoxy or aryl may be substituted and their salts.
2. Verbindungen der Formel I nach Anspruch 1, worin2. Compounds of formula I according to claim 1, wherein
R1, R2 und R3 gleich oder verschieden sind und C1-C6-alkyl oder C3-C7- alkoxyalkyl bedeuten,R1, R2 and R3 are the same or different and are C 1 -C 6 alkyl or C 3 -C 7 alkoxyalkyl,
R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy bedeutet,R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine,
R5 durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe Wasserstoff, Halogen, Trifluormethyl, C1-C4-alkyl und C1-C4-alkoxy substituiertes Phenyl, 2-Pyridyl oder 2-Pyrimidyl bedeutet undR5 by one or two identical or different substituents the group is hydrogen, halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy substituted phenyl, 2-pyridyl or 2-pyrimidyl and
A geradkettiges oder verzweigtes C2-C5-alkylen bedeutet, und ihre Salze.A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
3. Verbindungen der Formel I nach Anspruch 1, worin R1 Methyl oder Ethyl,3. Compounds of formula I according to claim 1, wherein R1 is methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy,R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy,
R5 Phenyl, 2-Chlorphenyl, 3-Chlorphenyl, 4-Chlorphenyl, 2,3-Dichlorphenyl, 3,4-Dichlorphenyl, 4-Fluorphenyl, 3-Trifluormethylphenyl, 2-Methoxyphenyl, 4-Methoxyphenyl, 2-Ethoxyphenyl, 2-Methylphenyl, 3-Chlor-4-methylphenyl, 3,4-Dimethylphenyl oder 2-Pyridyl undR5 phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl , 3-chloro-4-methylphenyl, 3,4-dimethylphenyl or 2-pyridyl and
A Ethylen oder Propylen bedeutet, und ihre Salze.A means ethylene or propylene, and their salts.
4. Verbindungen der Formel I nach Anspruch 1, worin R1 Methyl oder Ethyl,4. Compounds of formula I according to claim 1, wherein R1 is methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy, R5 Phenyl oder 2-Methoxyphenyl und A Ethylen oder Propylen bedeutet, und ihre Salze.R4 is 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy, R5 is phenyl or 2-methoxyphenyl and A is ethylene or propylene, and their salts.
5. Verbindungen der Formel I nach Anspruch 1, worin R1 Methyl,5. Compounds of formula I according to claim 1, wherein R1 is methyl,
R2 Methyl,R2 methyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 Difluormethoxy,R4 difluoromethoxy,
R5 Phenyl oder 2-Methoxyphenyl undR5 phenyl or 2-methoxyphenyl and
A Ethylen oder Propylen bedeutet, und ihre Salze. A means ethylene or propylene, and their salts.
6. Verbindungen der Formel I nach Anspruch 1, worin6. Compounds of formula I according to claim 1, wherein
R1, R2 und R3 gleich oder verschieden sind und C1-C6-alkyl oder C3-C7- alkoxyalkyl bedeuten,R1, R2 and R3 are the same or different and are C 1 -C 6 alkyl or C 3 -C 7 alkoxyalkyl,
R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-alkoxy bedeutet,R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine,
R5 Diphenylmethyl (Benzhydryl) bedeutet, wobei die beiden Phenylreste jeweils durch einen oder zwei gleiche oder verschiedene Substituenten aus der Gruppe Wasserstoff, Halogen, Trifluormethyl, C1-C4- alkyl und C1-C4-alkoxy substituiert sind undR5 diphenylmethyl (benzhydryl), wherein each of the two phenyl groups by one or two identical or different substituents from the group of hydrogen, halogen, trifluoromethyl, C 1 -C 4 - alkoxy alkyl and C 1 -C 4 substituted and
A geradkettiges oder verzweigtes C2-C5-alkylen bedeutet, und ihre Salze.A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
7. Verbindungen der Formel I nach Anspruch 1, worin R1 Methyl oder Ethyl,7. Compounds of formula I according to claim 1, wherein R1 is methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy, R5 Benzhydryl, 4,4'-Difluorbenzhydryl, 4,4'-Dimethylbenzhydryl,R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy, R5 benzhydryl, 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl,
4,4'-Dimethoxybenzhydryl oder 4,4'-Dichlorbenzhydryl bedeutet und A Ethylen oder Propylen bedeutet, und ihre Salze.4,4'-dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl means and A means ethylene or propylene, and their salts.
8. Verbindungen der Formel I nach Anspruch 1, worin R1 Methyl oder Ethyl,8. Compounds of formula I according to claim 1, wherein R1 is methyl or ethyl,
R2 Methyl oder Ethyl,R2 methyl or ethyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Difluormethoxy,R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy,
R5 Benzhydryl undR5 benzhydryl and
A Ethylen oder Propylen bedeutet, und ihre Salze.A means ethylene or propylene, and their salts.
9. Verbindungen der Formel I nach Anspruch 1, worin R1 Methyl,9. Compounds of formula I according to claim 1, wherein R1 is methyl,
R2 Methyl,R2 methyl,
R3 Methyl, Ethyl oder Methoxyethyl,R3 is methyl, ethyl or methoxyethyl,
R4 Difluormethoxy,R4 difluoromethoxy,
R5 Benzhydryl und A Ethylen oder Propylen bedeutet, und ihre Salze.R5 benzhydryl and A means ethylene or propylene, and their salts.
10. Verbindung ausgewählt aus der Gruppe bestehend aus10. Connection selected from the group consisting of
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-ethylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl } -ester,
4-{2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-(2-methoxyethyl)-ester-5-{3-[4-(2-methoxyphenyl)-1- piperazinyl]-propyl}-ester,4- {2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- {3- [4- (2-methoxyphenyl) - 1-piperazinyl] -propyl} ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-methylester-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl]}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl ]} - ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-ethylester-5-{2-[4-(2-methoxyphenyl)-1-piperazinyl]- ethyl}-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl } -ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-ethylester-5-[2-(4-phenyl-1-piperazinyl)-ethyl]- ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester 5- [2- (4-phenyl-1-piperazinyl) ethyl] ester,
Bis-4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin- 3,5-dicarbonsäure-3-(2-methoxyethyl)ester-5-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester,Bis-4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5- [2- (4-benzhydryl-1-piperazinyl ) ethyl] esters,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-methylester-5-[2-(4-benzhydryl-1-piperazinyl)- ethyl]-ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester 5- [2- (4-benzhydryl-1-piperazinyl) ethyl] ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarbonsäure-3-ethylester-5-[3-(4-benzhydryl-1-piperazinyl)-propyl]ester,4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester 5- [3- (4-benzhydryl-1-piperazinyl) propyl] ester,
4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-diemthylpyridin-3,5-dicarbonsäure-3-(2-methoxyethyl)-ester-5-[3-(4-benzhydry1-1-piperazinyl)-propyl]-ester und ihren Salzen.4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid-3- (2-methoxyethyl) ester-5- [3- (4-benzhydry1-1-piperazinyl) -propyl] esters and their salts.
11. Verfahren zur Herstellung von Verbindungen der Formel I nach Anpruch 1, dadurch gekennzeichnet, daß man a) Zimtsäurederivate der Formel II11. A process for the preparation of compounds of formula I according to claim 1, characterized in that a) Cinnamic acid derivatives of the formula II
Figure imgf000036_0001
mit Enaminderivaten der Formel III
Figure imgf000036_0001
with enamine derivatives of the formula III
Figure imgf000036_0002
Figure imgf000036_0002
oderor
b) Zimtsäurederivate der Formel II mit Ammoniak und 8-Ketocarbonsäurederivaten der Formel IVb) cinnamic acid derivatives of the formula II with ammonia and 8-ketocarboxylic acid derivatives of the formula IV
Figure imgf000036_0003
oder c) Enamine der Formel V
Figure imgf000037_0001
mit Benzylidencarbonsäurederivaten der Formel VI
Figure imgf000036_0003
or c) enamines of formula V
Figure imgf000037_0001
with benzylidenecarboxylic acid derivatives of the formula VI
Figure imgf000037_0002
oder
Figure imgf000037_0002
or
d) Ketoverbindungen der Formel VII
Figure imgf000037_0004
d) keto compounds of the formula VII
Figure imgf000037_0004
Figure imgf000037_0003
mit Ammoniak und Benzylidencarbonsäurederivaten der Formel VI, oder
Figure imgf000037_0003
with ammonia and benzylidenecarboxylic acid derivatives of the formula VI, or
e) Aldehyde der Formel VIII e) aldehydes of the formula VIII
Figure imgf000038_0003
Figure imgf000038_0003
mit Enaminen der Formel V und ß-Ketocarbonsäurederivaten der Formel IV, oderwith enamines of the formula V and β-ketocarboxylic acid derivatives of the formula IV, or
f) Aldehyde der Formel VIII mit Enaminderivaten der Formel III und Ketoverbindungen der Formel VII, oderf) aldehydes of the formula VIII with enamine derivatives of the formula III and keto compounds of the formula VII, or
g) 1 ,4-Dihydropyridine der Formel IXg) 1, 4-dihydropyridines of the formula IX
Figure imgf000038_0001
mit Piperazinderivaten der Formel X
Figure imgf000038_0002
als solche(n) oder in Form ihrer Salze umsetzt und gewunschtenfalls anschließend erhaltene Salze in die freien Basen oder erhaltene Basen in die Salze überführt, wobei R1, R2, R3, R4, R5 und A die in Anspruch 1 angegebenen Bedeutungen haben und Z gemeinsam mit der Carbonylgruppe, woran es gebunden ist, eine Carboxylgruppe oder ein reaktives Carbonsäurederivat darstellt.
Figure imgf000038_0001
with piperazine derivatives of the formula X
Figure imgf000038_0002
implemented as such (s) or in the form of their salts and, if desired, salts subsequently obtained are converted into the free bases or bases obtained into the salts, where R1, R2, R3, R4, R5 and A have the meanings given in claim 1 and Z together with the carbonyl group to which it is attached represents a carboxyl group or a reactive carboxylic acid derivative.
12. Arzneimittel enthaltend eine oder mehrere Verbindungen nach einem oder mehreren der Ansprüche 1 bis 10 und/oder ihre pharmakologisch verträglichen Salze.12. Medicament containing one or more compounds according to one or more of claims 1 to 10 and / or their pharmacologically acceptable salts.
13. Verbindungen nach einem oder mehreren der Ansprüche 1 bis 10 und ihre pharmakologisch verträglichen Salze zur Anwendung bei der Behandlung und/oder Prophylaxe von Hypertonie, koronaren Herzkrankheiten, peripheren und cerebralen Zirkulationsstörungen und/oder Krankheiten, die auf einer erhöhten Wasser- oder Natriumretention beruhen.13. Compounds according to one or more of claims 1 to 10 and their pharmacologically acceptable salts for use in the treatment and / or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulatory disorders and / or diseases which are based on increased water or sodium retention .
14. Verwendung von Verbindungen nach einem oder mehreren der Ansprüche 1 bis 10 und ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Behandlung und/oder Prophylaxe von Hypertonie, koronaren Herzkrankheiten, peripheren und cerebralen Zirkulationsstörungen und/oder Krankheiten, die auf einer erhöhten Wasser- oder Natriumretention berohen. 14. Use of compounds according to one or more of claims 1 to 10 and their pharmacologically acceptable salts for the manufacture of medicaments for the treatment and / or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulatory disorders and / or diseases based on an increased water - or deprived of sodium retention.
PCT/EP1985/000708 1984-12-21 1985-12-16 New piperazine derivatives WO1986003748A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988007531A1 (en) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh New optically active compounds
WO1988007525A1 (en) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh 1,4-dihydropyridine enantiomers
EP0255710A3 (en) * 1986-08-04 1989-01-04 The Du Pont Merck Pharmaceutical Company 1,4-dihydropyridine derivatives with calcium agonist and alpha-1-antagonist activity
EP0314038A1 (en) * 1987-10-27 1989-05-03 Byk Gulden Lomberg Chemische Fabrik GmbH Pyrrolidines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2414501A1 (en) * 1978-01-11 1979-08-10 Inst Organicheskogo Sinteza Ak 2,6-DIMETHYL-3,5-DIMETHOXYCARBONYL-4- (O-DIFLUOROMETHOXYPHENYL) -1,4-DIHYDROPYRIDINE
EP0094159A1 (en) * 1982-05-10 1983-11-16 Takeda Chemical Industries, Ltd. Dihydropyridine derivatives, their production and use
EP0097821A2 (en) * 1982-06-03 1984-01-11 Pierrel S.p.A. Dihydropyridines with an antagonistic activity to calcium, process for their preparation, and pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2414501A1 (en) * 1978-01-11 1979-08-10 Inst Organicheskogo Sinteza Ak 2,6-DIMETHYL-3,5-DIMETHOXYCARBONYL-4- (O-DIFLUOROMETHOXYPHENYL) -1,4-DIHYDROPYRIDINE
EP0094159A1 (en) * 1982-05-10 1983-11-16 Takeda Chemical Industries, Ltd. Dihydropyridine derivatives, their production and use
EP0097821A2 (en) * 1982-06-03 1984-01-11 Pierrel S.p.A. Dihydropyridines with an antagonistic activity to calcium, process for their preparation, and pharmaceutical compositions containing them

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0255710A3 (en) * 1986-08-04 1989-01-04 The Du Pont Merck Pharmaceutical Company 1,4-dihydropyridine derivatives with calcium agonist and alpha-1-antagonist activity
WO1988007531A1 (en) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh New optically active compounds
WO1988007525A1 (en) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh 1,4-dihydropyridine enantiomers
EP0296316A1 (en) * 1987-03-27 1988-12-28 Byk Gulden Lomberg Chemische Fabrik GmbH 1,4-Dihydropyridine enantiomers
EP0314038A1 (en) * 1987-10-27 1989-05-03 Byk Gulden Lomberg Chemische Fabrik GmbH Pyrrolidines
WO1989003824A1 (en) * 1987-10-27 1989-05-05 Byk Gulden Lomberg Chemische Fabrik Gmbh New pyrrolidines

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