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WO1988001266A1 - New piperidines - Google Patents

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Publication number
WO1988001266A1
WO1988001266A1 PCT/EP1987/000437 EP8700437W WO8801266A1 WO 1988001266 A1 WO1988001266 A1 WO 1988001266A1 EP 8700437 W EP8700437 W EP 8700437W WO 8801266 A1 WO8801266 A1 WO 8801266A1
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WIPO (PCT)
Prior art keywords
methyl
formula
compounds
ethyl
salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP1987/000437
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German (de)
French (fr)
Inventor
Dieter Flockerzi
Hermann Amschler
Klaus Eistetter
Manfrid Eltze
Kurt Klemm
Norbert Kolassa
Karl Sanders
Christian Schudt
Wolf-Rüdiger Ulrich
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Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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Publication of WO1988001266A1 publication Critical patent/WO1988001266A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • the invention relates to new piperidines, 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 piperidines of the formula I.
  • A1 means 2-6C-alkylene
  • R1 is 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R2 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R4 and R5 are identical or different and hydrogen, hydroxy, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, in whole or in part Are fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylanuino,
  • A is -CH 2 -C (R8) R9-CH 2 -, R8 is aryl and R9 is aryl, wherein Aryl for a ring of the formula
  • R10 and R11 are the same or different and have the meaning hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and the salts of these compounds.
  • 2-6C-Alkylene is straight-chain or branched and stands for example for ethylene (-CH 2 -CH 2 -), trimethylene (-CH 2 -CH 2 -CH 2 -), tetramethylene (-CH 2 -CH 2 -CH 2 - CH 2 -), pentamethylene (-CH 2 -CH 2 -CH 2 -CH 2 -), hexamethylene (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -), 1, 2-dimethylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene and 2-ethylpropylene, with ethylene and trimethylene being preferred.
  • 1-6C-alkyl is straight-chain or branched and means, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or in particular ethyl or methyl radical.
  • 3-7C-alkoxyalkyl is, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or especially methoxyethyl radical.
  • Halogen in the sense of the invention means bromine, fluorine and especially chlorine.
  • 1-4C-alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec.-butyl, t-8utyl, propyl, isopropyl, ethyl or in particular methyl radical.
  • 1-4C-alkoxy contains one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy and ethoxy radicals are preferred.
  • 1-4C-Alkoxy which is wholly or partly substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.
  • 1-4C-alkoxycarbonyl contains one of the 1-4C-alkoxy radicals mentioned above.
  • the methoxycarbonyl and the ethoxycarbonyl radical are preferred.
  • acetyl radical is preferred.
  • mono- or di-1-4C-alkylamino contains one or two of the 1-4C-alkyl radicals mentioned above. Preference is given to di-1-4C-alkylamino, and in particular dimethyl-, diethyl- or diisopropylamino.
  • Aryl represents phenyl substituted by R10 and R11.
  • the following may be mentioned as exemplary preferred aryl radicals: phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-methylphenyl , 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 3,6-dichlorophenyl, 3,4-dimethylphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
  • 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, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunid, piretanide, Etacrynic acid, tienilic acid or 4-chloro-sulfamoyl-benzoic acid.
  • the compounds of the invention can be characterized by
  • A1 means ethylene (-CH 2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -),
  • R1 is methyl, ethyl or methoxyethyl
  • R2 means methyl
  • R3 denotes methyl, ethyl or methoxyethyl
  • R8 means aryl
  • R9 means aryl
  • R10 and R11 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxyl or trifluoromethyl, and the salts of the compounds.
  • Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl means A1 means ethylene (-CH 2 -CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 - ) means R1 means methyl or ethyl, R2 means methyl, R3 means methyl or ethyl, R8 means phenyl or 4-methoxyphenyl and R9 means phenyl or 4-methoxyphenyl, and their salts.
  • Preferred compounds according to the invention are those of the formula Ia in which Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or benzoxdiazolyl,
  • A1 means ethylene (-CH 2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -) means, R1 means methyl or ethyl, R2 means methyl,
  • R3 is methyl or methoxyethyl
  • R8 is phenyl
  • R9 is phenyl, and their salts.
  • Particularly preferred compounds according to the invention are those of the formula Ia in which
  • Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl
  • A1 means trimethylene (-CH 2 -CH 2 -CH 2 -),
  • R1 means methyl or ethyl
  • R2 means methyl
  • R3 denotes methyl or methoxyethyl
  • R9 means phenyl, and their salts.
  • Examples of compounds according to the invention which may be mentioned are: 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid -3-methyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5- dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyll-2-methyl-4- (3-nitrophenyl) pyridine-3,5- dicarboxylic acid 3-propyl-5-methyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxy
  • the compounds of formula I have a chiral center at the 4-position in 1,4-dihydropyridine.
  • the invention therefore encompasses both the enantiomers and, if a further chirality center is present, the diastereomers, and also 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 the formulas II to VIII have the substituents or symbols Cy, A1, R1, R2, R3, R4, R5, R8 and R9 have the meanings given in the subclaims and the dependent claims.
  • a to f is carried out in suitable, preferably inert, organic solvents.
  • suitable, preferably inert, organic solvents include alcohols, such as ethanol, methanol, isopropanol or, in particular, t-butanol, hydrocarbons, such as toluene or xylene, 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 hexamidophosphoric acid triamide , or chlorinated hydrocarbons such as methylene chloride, chloroform or tetrachlorethylene.
  • alcohols such as ethanol, methanol, isopropanol or, in particular, t-butanol
  • hydrocarbons such as toluene or xylene
  • ethers such as di
  • 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, especially 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 (for example in ammonia in variants b and d) is also used if desired can be.
  • the substances according to the invention are isolated and purified in a manner known per se, for. B. in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier 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
  • Oie salts are obtained by filtering, falling over, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted into the free bases by alkalization, for example with aqueous ammonia solution, 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 compounds IV are prepared, for example, analogously to the method described by Troostwijk and Kellog in J.C.S. Chem. Comm., 1977, page 932, or analogously to the method disclosed in European patent application 0089167.
  • the 4,4-diphenylpiperidylalkanols required for the preparation of compound IV of the starting materials are described in EP-A-0176956.
  • Mp Means melting point, h stands for hours, Kp. Stands for boiling point, dec. means decomposition.
  • the reaction mixture is poured into a mixture of 140 ml of 1N hydrochloric acid and 100 ml of ice and the aqueous phase is extracted 3 times with 200 ml of ethyl acetate each time.
  • the oily residue obtained is chromatographed on a 3 ⁇ 30 cm silica gel column using ethyl acetate as the eluent. After concentration to constant weight, the product fraction gives 12 g of the title compound as a viscous oily residue.
  • Example 2 Analogously to Example 1, the title compound is obtained from 6.0 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) -propoximethyl] -crotonic acid methyl ester (crude product) and 2.42 g of 2-acetyl-3- ( 3-nitrophenyl) acrylic acid methyl ester after 10 h reaction time in 20 ml tert. -Butanol as a fine yellowish powder with a melting point of 113-128 ° C (amorphous, precipitated in petroleum ether / diethyl ether 1: 1); Yield: 3.53 g.
  • the starting compound 3-amino-3- [3 - (4,4-diphenylpiperidinyl-1) -propoximethyl] -crotonic acid methyl ester is obtained analogously to Example 1 from 4- [3- (4,4-diphenylpiperidinyl-1) propoxy ] -3-oxobutane carboxylic acid methyl ester and ammonia.
  • the oily product (crude product) obtained is reacted directly without further purification.
  • the starting compound 4- [3- (4,4-diphenylpiperidinyl-1) propoxy] -3-oxobutanecarboxylic acid methyl ester is obtained analogously to Example 1 from 3- (4,4-diphenylpiperidinyl-1) propanol and 4-chloroacetoacetic acid methyl ester. 3.
  • the title compound is prepared analogously to Example 1 from 5.30 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -crotonic acid ethyl ester and 2.73 g of 2-acetyl-3- (2,3 -dichlorophenyl) -acrylic acid methyl ester in 20 ml tert. Butanol; Reaction time 6 h; M.p .: 116-126 ° C (slow flow, amorphous precipitated); Yield: 3.62 g.
  • the title compound is prepared analogously to Example 1 from 5.30 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -crotonic acid ethyl ester and 2.46 g of 2-acetyl-3- (4-benzo [c] [1,2,5] oxdiazolyl) acrylic acid methyl ester in 20 ml tert-butanol; Reaction time 6 h; M.p .: 116-128 ° C (slow flow, amorphous precipitated). Yield: .4.73 g.
  • the title compound is prepared analogously to Example 1 from 5.30 g of 3-amino - 3- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -crotonic acid ethyl ester and 2.93 g of 2-acetyl-3- (3- 2.-methoxyethyl nitrophenyl) acrylic acid in 20 ml tert. Butanol; Reaction time 5 h; M.p .: 78-108 ° C (slow flow, amorphous precipitated). Yield: 5.61 g.
  • Ananolg Example 1 gives the starting compound 3-amino- [2- (4,4-diphenylpiperidinyl-1) -ethoxymethyl] -crotonic acid methyl ester from 4- [2- (4,4-diphenylpiperidinyl-1) -ethoxy] -3- oxobutane carboxylic acid methyl ester and ammonia.
  • the oily crude product obtained is reacted directly without further purification.
  • the starting compound 4- [2- (4,4-diphenylpiperidinyl-1) -ethoxy] -3-oxobutanecarboxylic acid methyl ester is obtained analogously to Example 1 from 2- (4,4-diphenylpiperidinyl-1) -ethanol and 4-chloroacetoacetic acid methyl ester.
  • the compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are in particular effective vasodilators with coronary therapeutic properties.
  • the pharmacological activity of the compounds according to the invention is particularly evident in a slowly occurring and strong drop in blood pressure.
  • the compounds according to the invention have an inhibitory effect on calcium influx and a promotional effect on potassium outflow from cells, smooth muscle relaxing and peripheral, coronary, cerebral and renal vasodilator and salidiuretic, antithrombotic and favorable hemorheological 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.
  • Examples of advantageous properties of the compounds I are: the extent of the lowering of blood pressure, the good controllability of the lowering of the blood pressure, the excellent bioavailability, the wide therapeutic range, the lack of central side effects, the lack of kinetic interactions with other substances, the lack of a development of tolerance, the balanced physical properties, the great stability and especially the surprisingly small increase in heart rate.
  • the excellent activity of the compounds of the formula I and their salts according to the invention permits their use in human medicine, with primary (essential) and secondary, arterial and pulmonary hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.) being used as indications, peripheral and cerebral circulation disorders (stroke, temporary cerebral circulatory disorders, migraines, dizziness, renal artery narrowing etc.), hypertrophic cardiomyopathy, heart failure, diseases that are based on increased water and sodium retention and diseases that are based on an increased influx of calcium, such as spasms smooth muscle Organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia and arteriosclerosis.
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cerebral circulation disorders stroke, temporary cerebral circulatory disorders, migraines, dizziness, renal artery narrowing etc.
  • 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 ingredients for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example cyclodextrins) can be used.
  • the active substances can be administered orally, rectally, by inhalation 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, alpha-1 receptor blockers, alpha-2 receptor stimulators , beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine stimulators, such as blockers nifedipine, hydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefruside, clopamide, spironolactone
  • other vasodilators such as other vasodilators, antihypertensives
  • 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 male 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.
  • Blood pressure measurement is done in a warming chamber at 36 ° C to achieve better blood flow to 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 is used to measure the systolic arterial pressure.
  • 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 compounds are identified by consecutive numbers that correspond to the numbers of the examples.
  • 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)
  • Hydrogenated Pyridines (AREA)

Abstract

The new piperidines having formula (I), in which the substituents and symbols have the meaning given in the description of the invention, are new compounds with surprising pharmacological properties.

Description

Neue Pioeridine New pioeridines

Anwendungsqebiet der ErfindungField of application of the invention

Die Erfindung betrifft neue Piperidine, 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 piperidines, 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. Aus der europäischen Patentanmeldung 176956 sind beispielsweise antihypertensiv wirksame 1,4-Dihydropyridine mit 4,4-Diphenylpiperidinyl-1-alkylesterrest in 5-Stellung bekannt. Aus der europaischen Patentanmeldung 60674 sind anti-ischämisch und antihypertensiv wirksame 1,4-Dihydropyridine mit substituiertem Aminoalkoxymethylrest. in 2-Stellung bekannt, 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 application 176956, for example, discloses 1,4-dihydropyridines with 4,4-diphenylpiperidinyl-1-alkyl ester residue in the 5-position which have antihypertensive activity. European patent application 60674 describes 1,4-dihydropyridines with a substituted aminoalkoxymethyl radical which are anti-ischemic and antihypertensive. known in the 2-position, 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 Piperidine der Formel IThe invention relates to new piperidines of the formula I.

Figure imgf000003_0001
worin Cy einen Cyclus der Formel
Figure imgf000003_0001
wherein Cy is a cycle of the formula

Figure imgf000004_0001
Figure imgf000004_0001

darstellt, in dem Y Sauerstoff (O), Schwefel (S), Vinylen (-CH=CH-), Azomethin (-CH=N-) oder eine Gruppe der Formelrepresents in which Y represents oxygen (O), sulfur (S), vinylene (-CH = CH-), azomethine (-CH = N-) or a group of the formula

oder

Figure imgf000004_0003
Figure imgf000004_0002
bedeutet,or
Figure imgf000004_0003
Figure imgf000004_0002
means

A1 2-6C-Alkylen bedeutet,A1 means 2-6C-alkylene,

R1 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet,R1 is 1-6C-alkyl or 3-7C-alkoxyalkyl,

R2 Wasserstoff, 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet,R2 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,

R3 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet, R4 und R5 gleich oder verschieden sind und Wasserstoff, Hydroxy, Halogen, Nitro, Cyano, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkpxy, ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy, 1-4C-Alkoxycarbonyl, 2-5C-Acyl, Amino oder Mono- oder Di-1-4C-alkylanuino bedeuten,R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl, R4 and R5 are identical or different and hydrogen, hydroxy, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, in whole or in part Are fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylanuino,

R6 und R7 gemeinsam und unter Einschluß des Stickstoffatoms, an das beide gebunden sind, einen Rest der FormelR6 and R7 together and including the nitrogen atom to which both are attached form a radical of the formula

Figure imgf000004_0004
darstellen, worin A -CH2-C(R8)R9-CH2- bedeutet, R8 Aryl bedeutet und R9 Aryl bedeutet, wobei Aryl für einen Ring der Formel
Figure imgf000004_0004
in which A is -CH 2 -C (R8) R9-CH 2 -, R8 is aryl and R9 is aryl, wherein Aryl for a ring of the formula

Figure imgf000005_0001
steht, worin R10 und R11 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), 1-4C-Alkyl, 1-4C-Alkoxy, Halogen, Hydroxy oder Trifluormethyl haben, und die Salze dieser Verbindungen.
Figure imgf000005_0001
is in which R10 and R11 are the same or different and have the meaning hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and the salts of these compounds.

2-6C-Alkylen ist geradkettig oder verzweigt und steht beispielsweise für Ethylen (-CH2-CH2-), Trimethylen (-CH2-CH2-CH2-), Tetramethylen (-CH2-CH2-CH2-CH2-), Pentamethylen ( -CH2-CH2-CH2-CH2-CH2-), Hexamethylen (-CH2-CH2-CH2-CH2-CH2-CH2-), 1,2-Dimethylethylen, 1,1-Dimethylethylen, 2,2-Dimethylethylen, Isopropyliden, 1-Methylethylen und 2-Ethylpropylen, wobei Ethylen und Trimethylen bevorzugt sind.2-6C-Alkylene is straight-chain or branched and stands for example for ethylene (-CH 2 -CH 2 -), trimethylene (-CH 2 -CH 2 -CH 2 -), tetramethylene (-CH 2 -CH 2 -CH 2 - CH 2 -), pentamethylene (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -), hexamethylene (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -), 1, 2-dimethylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene and 2-ethylpropylene, with ethylene and trimethylene being preferred.

1-6C-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.1-6C-alkyl is straight-chain or branched and means, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or in particular ethyl or methyl radical.

3-7C-Alkoxyalkyl steht beispielsweise für einen Ethoxyethyl-, Propoxyethyl-, Isopropoxyethyl-, Butoxyethyl-, Methoxypropyl-, 2-Methoxy-1-me- thylethyl-, 2-Ethoxy-1-methylethyl- oder insbesondere Mcthoxyethylrest.3-7C-alkoxyalkyl is, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or especially methoxyethyl radical.

Halogen im Sinne der Erfindung bedeutet Brom, Fluor und insbesondere Chlor.Halogen in the sense of the invention means bromine, fluorine and especially chlorine.

1-4C-Alkyl ist geradkettig oder verzweigt und bedeutet beispielsweise einen Butyl-, i-Butyl-, sec.-Butyl-, t-8utyl-, Propyl-, Isopropyl-, Ethyl- oder insbesondere Methylrest.1-4C-alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec.-butyl, t-8utyl, propyl, isopropyl, ethyl or in particular methyl radical.

1-4C-Alkoxy enthält neben dem Sauerstoffatom einen der vorstehend genannten 1-4C-Alkylreste. Bevorzugt sind der Methoxy- und der Ethoxyrest. Ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy ist beispielsweise 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder insbesondere Difluormethoxy-In addition to the oxygen atom, 1-4C-alkoxy contains one of the 1-4C-alkyl radicals mentioned above. The methoxy and ethoxy radicals are preferred. 1-4C-Alkoxy which is wholly or partly substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.

1-4C-Alkoxycarbonyl enthält neben der Carbonylgruppe einen der vorstehend genannten 1-4C-Alkoxyreste. Bevorzugt sind der Methoxycarbonyl- und der Ethoxycarbonylrest.In addition to the carbonyl group, 1-4C-alkoxycarbonyl contains one of the 1-4C-alkoxy radicals mentioned above. The methoxycarbonyl and the ethoxycarbonyl radical are preferred.

2-5C-Acyl enthält neben der Carbonylgruppe einen der vorstehend genannten2-5C-acyl contains one of the above in addition to the carbonyl group

1-4C-Alkylreste. Bevorzugt ist der Acetylrest.1-4C alkyl groups. The acetyl radical is preferred.

Mono- oder Di-1-4C-alkylamino enthält neben dem Stickstoffatom einen oder zwei der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist Di-1-4C- alkylamino, und hier insbesondere Dimethyl-, Oiethyl- oder Diisopropyl- amino.In addition to the nitrogen atom, mono- or di-1-4C-alkylamino contains one or two of the 1-4C-alkyl radicals mentioned above. Preference is given to di-1-4C-alkylamino, and in particular dimethyl-, diethyl- or diisopropylamino.

Aryl steht für durch R10 und R11 substituiertes Phenyl. Als beispielhafte bevorzugte Arylreste seien genannt die Reste: Phenyl, 4-Methoxyphenyl, 4-Chlorphenyl, 4-Methylphenyl, 4-Fluorphenyl, 3-Fluorphenyl, 3-Chlorphenyl, 2-Chlorphenyl, 3-Methoxyphenyl, 2-Methoxyphenyl, 2-Methylphenyl, 3-Chlor-4-methylphenyl, 3,4-Dichlorphenyl, 3,6-Dichlorphenyl, 3,4-Dimethylphenyl, 2-Trifluormethylphenyl und 3-Trifluormethylphenyl.Aryl represents phenyl substituted by R10 and R11. The following may be mentioned as exemplary preferred aryl radicals: phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-methylphenyl , 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 3,6-dichlorophenyl, 3,4-dimethylphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.

Als Salze kommen alle Salze mit Säuren in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der pharmazeutischen Indus trie üblicherweise verwendeten, anorganischen und organischen Säuren. Pharmakαlogisch 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, Fendi- zoat, Butyrat, Sulfosalicylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Metembonat, Stearat, Tosilat, 2-Hydroxy-3-naph- thoat, 3-Hydroxy-2-naphthoat oder Mesilat, aber auch Salze mit Bumetanid, Furosemid, Azosemid, Galosemid, Besunid, Piretanid, Etacrynsäure, Tienilinsaure oder 4-Chlor-sulfamoyl-benzoesäure. Die erfindungsgemäßen Verbindungen können charakterisiert werden durch die folgende Formel laAll 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, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunid, piretanide, Etacrynic acid, tienilic acid or 4-chloro-sulfamoyl-benzoic acid. The compounds of the invention can be characterized by the following formula la

Figure imgf000007_0002
worin die Substituenten und Symbole die oben genannten Bedeutungen haben.
Figure imgf000007_0002
wherein the substituents and symbols have the meanings given above.

Hervorzuhebende erfindungsgemäße Verbindungen sind solche der Formel la, worinCompounds according to the invention which are to be emphasized are those of the formula Ia in which

Cy Phenyl, 2-Nitrophenyl, 3-Nitrophenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoxyphenyl, 2-Chlorphenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluorphenyl, 2-Trifluormethylphenyl, 3-Trifluαrmethylphenyl oder Benzoxdiazolyl bedeutet,Cy phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl , 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzoxdiazolyl,

A1 Ethylen (-CH2CH2-) oder Trimethylen (-CH2-CH2-CH2- ) bedeutet,A1 means ethylene (-CH 2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -),

R1 Methyl, Ethyl oder Methoxyethyl bedeutet,R1 is methyl, ethyl or methoxyethyl,

R2 Methyl bedeutet,R2 means methyl

R3 Methyl, Ethyl oder Methoxyethyl bedeutet,R3 denotes methyl, ethyl or methoxyethyl,

R8 Aryl bedeutet undR8 means aryl and

R9 Aryl bedeutet, wobeiR9 means aryl, where

Aryl für einen Ring der FormelAryl for a ring of the formula

Figure imgf000007_0001
steht, worin R10 und R11 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluor- methyl haben, und die Salze der Verbindungen.
Figure imgf000007_0001
is in which R10 and R11 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxyl or trifluoromethyl, and the salts of the compounds.

Besonders hervorzuhebende erfindungsgemäße Verbindungen sind solche derParticularly noteworthy compounds according to the invention are those of

Formel la, worinFormula la, in which

Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, A1 Ethylen (-CH2-CH2-) oder Trimethylen (-CH2-CH2-CH2-) bedeutet, R1 Methyl oder Ethyl bedeutet, R2 Methyl bedeutet, R3 Methyl oder Ethyl bedeutet, R8 Phenyl oder 4-Methoxyphenyl bedeutet und R9 Phenyl oder 4-Methoxyphenyl bedeutet, und ihre Salze.Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl means A1 means ethylene (-CH 2 -CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 - ) means R1 means methyl or ethyl, R2 means methyl, R3 means methyl or ethyl, R8 means phenyl or 4-methoxyphenyl and R9 means phenyl or 4-methoxyphenyl, and their salts.

Bevorzugte erfindungsgemäße Verbindungen sind solche der Formel la, worin Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl oder Benzoxdiazolyl bedeutet,Preferred compounds according to the invention are those of the formula Ia in which Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or benzoxdiazolyl,

A1 Ethylen (-CH2CH2-) oder Trimethylen (-CH2-CH2-CH2-) bedeutet, R1 Methyl oder Ethyl bedeutet, R2 Methyl bedeutet,A1 means ethylene (-CH 2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -) means, R1 means methyl or ethyl, R2 means methyl,

R3 Methyl oder Methoxyethyl bedeutet, R8 Phenyl bedeutet und R9 Phenyl bedeutet, und ihre Salze.R3 is methyl or methoxyethyl, R8 is phenyl and R9 is phenyl, and their salts.

Besonders bevorzugte erfindungsgemäße Verbindungen sind solche der Formel la, worinParticularly preferred compounds according to the invention are those of the formula Ia in which

Cy 3-Nitrophenyl oder 2,3-Dichlorphenyl bedeutet,Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl,

A1 Trimethylen (-CH2-CH2-CH2-) bedeutet,A1 means trimethylene (-CH 2 -CH 2 -CH 2 -),

R1 Methyl oder Ethyl bedeutet,R1 means methyl or ethyl,

R2 Methyl bedeutet,R2 means methyl

R3 Methyl oder Methoxyethyl bedeutet,R3 denotes methyl or methoxyethyl,

R8 Phenyl undR8 phenyl and

R9 Phenyl bedeutet, und ihre Salze. Als erfindungsgemäße Verbindungen seien beispielsweise genannt: 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyll-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsaure-3-propyl-5-methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methoxiethyl-5-methylester 1,4-Dihydro-8-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-isopropyl-5-methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-propyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methoxiethyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-isopropyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-propylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-propylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methoxiethyl-5-propylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-isopropyl-5-propylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-methoxiethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyll-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methoxiethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-propyl-5-methoxiethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-isopropyl-5-methoxiethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-isopropylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-isopropylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-32-methyl-4-(3- nitrophenyl)-pyridin-3,5-dicarbonsäure-3-propyl-5-isopropylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propαximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methoxiethyl-5-isopropylester1,4-0ihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäurediethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäuredipropylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäuredimethoxiethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäurediisopropylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-nitrophenyl)-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[3-(4,-4-dlphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-nitrophenyl)-pyridin-3,5-dicarbonsäuredieethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-trifluormethylphenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-trifluormethylphenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyll-2-methyl-4-(2-trifluormethylphenyl)-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-(2-trifluormethylphenyl)-pyridin-3,5-dicarbonsäurediethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-[3- (1,1,2,2-tetrafluorethoxil-phenyl]-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-[3- (1,1,2,2-tetrafluorethoxi)-phenyl]-pyridin-3,5-dicarbonsäure-3-ethyl-5- -methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-[3- (1,1,2,2-tetrafluorethoxil-phenyl]-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-4-[3- (1,1,2,2-tetrafluorethoxi)-phenyl]-pyridin-3,5-dicarbonsäurediethylester 4-(2-Difluormethoxiphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 4-(2-Difluormethoxiphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)propoximethyl]-2-methyl-pyridin-3,5-dicarbonsaure-3-ethyl-5-methylester 4-(2-Difluormethoxiphenyl)-1,4-dihydro-6-[3-(4,4-dip6enylpiperidyl-1)propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 4-(2-Difluormethoxiphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäurediethylester 4-(2,3-Dichlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 4-(2,3-Dichlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 4-(2,3-Dichlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 4-(2,3-0ichlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäurediethylester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)- propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäurediethylester 4-(3-Cyanphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarboπsäure-3-methyl-5-ethylester 4-(3-Cyanphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime-thyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 4-(3-Cyanphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 4-(3-Cyanphenyl)-1,4-dihydro-8-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäurediethylester 4-(3-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 4-{3-Chlorphenyl)-l,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 4-(3-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime- thyl]-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 4-(3-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäurediethylester 4-(2-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 4-(2-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbαnsäure-3-ethyl-5-methylester 4-(2-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 4-(2-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoxime¬thyl]-2-methryi-pyridin-3,5-dicarbonsäurediethylester 1,4-Dihydxo-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-4-(3-fluorphe¬nyl)-2-methyl-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-4-(3-fluorphe¬nyl)-2-methyl-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-4-(3-fluorphe¬nyl)-2-methyl-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[3-(4,4-diphenylpiperidyl-1)-propoximethyl]-4-(3-fluorphe¬nyl)-2-methyl-pyridin-3,5-dicarbonsäurediethylester 1,4-Dihydro-6-[2-(4,4-dirphenylpiperidyl-1)-ethoximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[2-(4,4-diphenylpiperidyl-1)-ethoximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 1,4-Dihydro-6-[2-(4,4-diphenylpiperidyl-1)-ethoximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[2-(4,4-diphenylpiperidyl-1)-ethoximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäurediethylester 1,4-Dihydro-6-[4-(4,4-diphenylpiperidyl-1)-butyloximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[4-(4,4-diphenylpiperidyl-1)-butyloximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester 1,4-Dihydro-6-[4-(4,4-diphenylpiperidyl-1)-butyloximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäuredimethylester 1,4-Dihydro-6-[4-(4,4-diphenylpiperidyl-1)-butyloximethyl]-2-methyl-4-(3¬nitrophenyl)-pyridin-3,5-dicarbonsäurediethylester 1,4-Dihydro-6-[5-(4,4-diphenylpiperidyl-1)-pentyloximethyl]-2-methyl-4-[3¬nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester 1,4-Dihydro-6-[5-(4,4-diphenylpiperidyl-1)-pentyloximethyl]-2-methyl-4-(3 nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylesterR9 means phenyl, and their salts. Examples of compounds according to the invention which may be mentioned are: 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid -3-methyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5- dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyll-2-methyl-4- (3-nitrophenyl) pyridine-3,5- dicarboxylic acid 3-propyl-5-methyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5 -dicarboxylic acid-3-methoxyethyl-5-methyl ester 1,4-dihydro-8- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-isopropyl-5-methyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3 , 5-dicarboxylic acid-3-propyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine- 3,5-dicarboxylic acid 3-methoxyethyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid -3-isopropyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5- 3-methyl-5-propyl dicarboxylate, 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5 3-ethyl-5-propyl dicarboxylic acid 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- (3-nitrophenyl) -pyridine-3, 5-dicarboxylic acid-3-methoxyethyl-5-propyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3 , 5-dicarboxylic acid-3-isopropyl-5-propyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine- 3,5-dicarboxylic acid 3-methyl-5-methoxyethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyll-2-methyl-4- (3-nitrophenyl) pyridine- 3,5-dicarboxylic acid 3-ethyl-5-methoxyethyl ester 1,4 Dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3-propyl-5-methoxyethyl ester 1, 4-Dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-isopropyl-5-methoxyethyl ester 1 , 4-Dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-isopropyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid-3-ethyl-5- isopropyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -32-methyl-4- (3- nitrophenyl) pyridine-3,5-dicarboxylic acid 3-propyl-5-isopropyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propαximethyl] -2-methyl-4- (3rd -nitrophenyl) -pyridine-3,5-dicarboxylic acid-3-methoxyethyl-5-isopropyl ester 1,4-0ihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- (3rd -nitrophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3 , 5-dicarboxylic acid diethyl 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid dipropyl ester 1,4 -Dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid dimethoxyethyl ester 1,4-dihydro-6- [3 - (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid diisopropyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl -1) -propoxymethyl] -2-methyl-4- (2-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4- d iphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (2-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [3- (4,4 -diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid dimethyl ester 1,4-dihydro-6- [3- (4, -4-dlphenylpiperidyl-1) - propoximethyl] -2-methyl-4- (2-nitrophenyl) pyridine-3,5-dicarboxylic acid, diethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl- 4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl -4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyll-2-methyl -4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid, dimethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- (2-trifluoromethylphenyl) ) -pyridine-3,5-dicarboxylic acid diethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- [3- (1,1,2,2 -tet rafluoroethoxil-phenyl] pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-4- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [3- (4,4- diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- [3- (1,1,2,2-tetrafluoroethoxil-phenyl] pyridine-3,5-dicarboxylic acid dimethyl ester 1,4-dihydro-6- [3- ( 4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-4- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] pyridine-3,5-dicarboxylic acid diethyl 4- (2-difluoromethoxiphenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 4- (2-difluoromethoxiphenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid-3-ethyl-5-methyl ester 4- (2-difluoromethoxiphenyl) -1,4-dihydro-6- [3- (4,4-dip6enylpiperidyl-1) propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid dimethyl ester 4- (2-difluoromethoxiphenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyl] -2-methyl-pyridine -3,5-dicarboxylic acid diethyl 4- (2,3-dichlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-pyridine-3,5- 3-methyl-5-ethyl dicarboxylate 4- (2,3-dichlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-pyridine-3 , 5-dicarboxylic acid 3-ethyl-5-methyl ester 4- (2,3-dichlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl- pyridine-3,5-d dimethyl icarboxylate 4- (2,3-0ichlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -2-methyl-pyridine-3,5-dicarboxylic acid diethyl 4- (2 , 1,3-Benzoxdiazol-4-yl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid-3-methyl -5-ethyl ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoximethyl] -2-methyl-pyridine- 3,5-dicarboxylic acid 3-ethyl-5-methyl ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) - propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid dimethyl ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid diethyl 4- (3-cyanophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2 -methyl-pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 4- (3-cyanophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime-thyl ] -2-methyl-pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester 4- (3-cyanophenyl) -1 , 4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2-methyl-pyridine-3,5-dicarboxylic acid dimethyl ester 4- (3-cyanophenyl) -1,4-dihydro- 8- [3- (4,4-diphenylpiperidyl-1) -propoxime-ethyl] -2-methyl-pyridine-3,5-dicarboxylic acid, diethyl 4- (3-chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2-methyl-pyridine-3,5-dicarboxylic acid-3-methyl-5-ethyl ester 4- {3-chlorophenyl) -l, 4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2-methyl-pyridine-3,5-dicarboxylic acid-3-ethyl-5-methyl ester 4- (3-chlorophenyl) -1,4-dihydro -6- [3- (4,4-diphenylpiperidyl-1) -propoxime- thyl] -2-methyl-pyridine-3,5-dicarboxylic acid dimethyl ester 4- (3-chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2- methyl pyridine-3,5-dicarboxylic acid diethyl 4- (2-chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2-methyl-pyridine-3 , 5-dicarboxylic acid-3-methyl-5-ethyl ester 4- (2-chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2-methyl- 3-ethyl-5-methyl-pyridine-3,5-dicarboxylate 4- (2-chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime-ethyl] -2 -methyl-pyridine-3,5-dicarboxylic acid dimethyl ester 4- (2-chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) -propoxime¬thyl] -2-methryipyridine- Diethyl 3,5-dicarboxylate 1,4-dihydxo-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -4- (3-fluorophenyl) -2-methyl-pyridine-3,5-dicarboxylic acid -3-methyl-5-ethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1) propoxymethyl] -4- (3-fluorophenyl) -2-methyl-pyridine-3, 5-dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [3- (4, 4-diphenylpiperidyl-1) -propoximethyl] -4- (3-fluorophenyl) -2-methyl-pyridine-3,5-dicarboxylic acid dimethyl ester 1,4-dihydro-6- [3- (4,4-diphenylpiperidyl-1 ) -propoximethyl] -4- (3-fluorophenyl) -2-methyl-pyridine-3,5-dicarboxylic acid, diethyl 1,4-dihydro-6- [2- (4,4-dirphenylpiperidyl-1) -ethoxymethyl] - 2-methyl-4- (3¬nitrophenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 1,4-dihydro-6- [2- (4,4-diphenylpiperidyl-1) ethoxymethyl] -2-methyl-4- (3¬nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester 1,4-dihydro-6- [2- (4,4-diphenylpiperidyl-1) -ethoxymethyl ] -2-methyl-4- (3¬nitrophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester 1,4-dihydro-6- [2- (4,4-diphenylpiperidyl-1) -ethoximethyl] -2-methyl-4 - (3¬nitrophenyl) pyridine-3,5-dicarboxylic acid diethyl ester 1,4-dihydro-6- [4- (4,4-diphenylpiperidyl-1) butyloximethyl] -2-methyl-4- (3¬nitrophenyl) - 3-methyl-5-ethyl-pyridine-3,5-dicarboxylate 1,4-dihydro-6- [4- (4,4-diphenylpiperidyl-1) -butyloximethyl] -2-methyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid -3-ethyl-5-methyl ester 1,4-dihydro-6- [4- (4,4-diphenylpiperidyl-1) butyloximethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5- dimethyl dicarboxylate 1,4-dihydro-6- [4- (4,4-diphenylpiperidyl-1) butyloximethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid diethyl 1,4-dihydro- 6- [5- (4,4-diphenylpiperidyl-1) pentyloximethyl] -2-methyl-4- [3¬nitrophenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester 1,4-dihydro -6- [5- (4,4-diphenylpiperidyl-1) pentyloximethyl] -2-methyl-4- (3rd nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester

1,4-Dihydro-6-[5-(4,4-diphenylpiperidyl-1)-pentyloximethyl]-2-methyl-4-(3nitrophenyl)-pyridin-3,5-dicarbonsäuredimethylester1,4-Dihydro-6- [5- (4,4-diphenylpiperidyl-1) pentyloximethyl] -2-methyl-4- (3nitrophenyl) pyridine-3,5-dicarboxylic acid, dimethyl ester

1,4-Dihydro-6-[5-(4,4-diphenylpiperidyl-1)-pentyloximethyl]-2-methyl-4-(3nitrophenyl)-pyridin-3,5-dicarbonsäurediethylester1,4-Dihydro-6- [5- (4,4-diphenylpiperidyl-1) pentyloximethyl] -2-methyl-4- (3nitrophenyl) pyridine-3,5-dicarboxylic acid, diethyl ester

1,4-Dihydro-6-[6-(4,4-diphenylpiperidyl-1)-hexyloximethyl]-2-methyl-4-(3nitrophenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester1,4-Dihydro-6- [6- (4,4-diphenylpiperidyl-1) hexyloximethyl] -2-methyl-4- (3nitrophenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5-ethyl ester

1,4-Dihydro-6-[6-{4,4-diphenylpiperidyl-1)-hexyloximethyl]-2-methyl-4-(3nitrophenyl)-pyridin-3,5-dicarbonsäure-3-ethyl-5-methylester1,4-Dihydro-6- [6- {4,4-diphenylpiperidyl-1) hexyloximethyl] -2-methyl-4- (3nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester

1,4-Dihydro-6-[6-(4,4-diphenylpiperidyl-1)-hexyloximethyl]-2-methyl-4-(3nitrophenyl)-pyridin-3,5-dicarbonsäuredimethylester1,4-Dihydro-6- [6- (4,4-diphenylpiperidyl-1) hexyloximethyl] -2-methyl-4- (3nitrophenyl) pyridine-3,5-dicarboxylic acid, dimethyl ester

1,4-Dihydro-6-[6-(4,4-diphenylpiperidyl-1)-hexyloximethyl]-2-methyl-4-(3nitrophenyl)-pyridin-3,5-dicarbonsäurediethylester und ihre Salze.1,4-Dihydro-6- [6- (4,4-diphenylpiperidyl-1) hexyloximethyl] -2-methyl-4- (3nitrophenyl) pyridine-3,5-dicarboxylic acid, diethyl ester and its salts.

Die Verbindungen der Formel I besitzen an der 4-Position im 1,4-Dihydropyridin ein Chiralitätszentrum. Die Erfindung umfaßt daher sowohl die Enantiomeren und bei Vorliegen eines weiteren Chiralitatszentrums die Diastereomeren, als auch deren Gemische und Racemate.The compounds of formula I have a chiral center at the 4-position in 1,4-dihydropyridine. The invention therefore encompasses both the enantiomers and, if a further chirality center is present, the diastereomers, and also 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 imgf000013_0001
mit Enaminderivaten der Formel III
Figure imgf000014_0004
oder
Figure imgf000013_0001
with enamine derivatives of the formula III
Figure imgf000014_0004
or

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 imgf000014_0003
oder
Figure imgf000014_0003
or

c) Enamine der Formel Vc) Enamines of formula V

Figure imgf000014_0002
mit Benzylidencarbonsaurederivaten der Formel VI
Figure imgf000014_0002
with benzylidenecarboxylic acid derivatives of the formula VI

Figure imgf000014_0001
oder d ) Ketoverbindungen der Formel VI I
Figure imgf000014_0001
or d) keto compounds of the formula VI I

( VI I )

Figure imgf000015_0001
mit Ammoniak und Benzylidencarbonsaurederivaten der Formel VI, oder(VI I)
Figure imgf000015_0001
with ammonia and benzylidenecarboxylic acid derivatives of the formula VI, or

e) Aldehyde der Formel VIII

Figure imgf000015_0003
e) aldehydes of the formula VIII
Figure imgf000015_0003

(VIII)

Figure imgf000015_0002
mit Enaminen der Formel V und ß-Ketocarbonsäurederivaten der Formel IV, oder(VIII)
Figure imgf000015_0002
with 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 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 Cy, A1, R1, R2, R3, R4, R5, R8 und R9 die oben angegebenen Bedeutungen haben.f) reacting aldehydes of the formula VIII with enamine derivatives of the formula III and keto compounds of the formula VII as such (s) or in the form of their salts and, if desired, subsequently converting the salts obtained into the free bases or the bases obtained into the salts, where Cy, A1, R1 , R2, R3, R4, R5, R8 and R9 have the meanings given above.

Ausgestaltungen des Verfahrens sind solche, bei denen in den Formeln II bis VIII die Substituenten bzw. Symbole Cy, A1, R1, R2, R3, R4, R5, R8 und R9 die in den Unter- und Nebenansprüchen angegebenen Bedeutungen haben.Embodiments of the process are those in which the formulas II to VIII have the substituents or symbols Cy, A1, R1, R2, R3, R4, R5, R8 and R9 have the meanings given in the subclaims and the dependent claims.

Das Verfahren gemäß den Varianten a bis f wird in geeigneten, vorzugsweise inerten organischen Lösungsmitteln durchgeführt. Beispielsweise seien genannt Alkohole, wie Ethanol, Methanol, Isopropanol oder insbesondere t-Butanol, Kohlenwasserstoffe, wie Toluol oder Xylol, 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 process according to variants a to f is carried out in suitable, preferably inert, organic solvents. Examples include alcohols, such as ethanol, methanol, isopropanol or, in particular, t-butanol, hydrocarbons, such as toluene or xylene, 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 hexamidophosphoric acid 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 20ºC und 150ºC, vorzugsweise zwischen 20ºC und 100ºC, 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, especially 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 Überschuß (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 (for example in ammonia in variants b and d) is also used if desired can be.

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. in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier 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.

Oie Salze werden durch Filtrieren, Umfallen, Ausfällen mit einem Nichtlösungsmittel für das Anlagerungssalz oder durch Verdampfen des Lösungsmittels gewonnen. 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.Oie salts are obtained by filtering, falling over, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted into the free bases by alkalization, for example with aqueous ammonia solution, 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 Verbindungen IV werden beispielsweise analog zu der von Troostwijk und Kellog im J. C. S. Chem. Comm., 1977, Seite 932, beschriebenen Methode bzw. analog zu dem in der europäischen Patentanmeldung 0089167 offenbarten Verfahren hergestellt. Die für die Herstellung der Verbindung IV der Ausgangsstoffe benötigten 4,4-Diphenylpiperidylalkanole sind in der EP-A-0176956 beschrieben.The starting compounds are known from the literature or can be prepared analogously to methods known from the literature. The compounds IV are prepared, for example, analogously to the method described by Troostwijk and Kellog in J.C.S. Chem. Comm., 1977, page 932, or analogously to the method disclosed in European patent application 0089167. The 4,4-diphenylpiperidylalkanols required for the preparation of compound IV of the starting materials are described in EP-A-0176956.

Das vorstehende Herstellungsverfahren ist lediglich zur Verdeutlichung angegeben, und die Herstellung der erfindungsgemäßen Verbindungen der Formel I ist nicht auf dieses Verfahren beschränkt. Vielmehr ist auch jede Modifikation dieses Verfahrens in gleicher Weise für die Herstellung der erfindungsgemäßen Verbindungen anwendbar.The above preparation process is given for illustration only, and the preparation of the compounds of formula I according to the invention is not limited to this process. Rather, any modification of this process can also 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, h steht für Stunden, 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, h stands for hours, Kp. Stands for boiling point, dec. means decomposition.

B e i s p i e l eB e i s p i e l e

1. 1,4-Dihvdro-6-[3-(4,4-diohenylpiperidinyl-1)-propoximethyl]-2-methyl4-(3-nitroohenyl)-pyridin-3,5-dicarbonsäure-3-methyl-5-ethylester-hydrochlorid1. 1,4-Dihvdro-6- [3- (4,4-diohenylpiperidinyl-1) propoxymethyl] -2-methyl4- (3-nitroohenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5- ethyl hydrochloride

4,23 g 3-Amino-3-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-erotonsäureethylester und 2,49 g 2-Acetyl-3-(3-nitrophenyl)-acrylsäuremethylester werden in einer Stickstoffatmosphäre in 80 ml tert.-Butanol 8 h unter Rückfluß zum Sieden erhitzt. Die abgekühlte Lösung wird weitgehend eingeengt und der Rückstand über eine 3 x 25 cm Kieselgelsäule mit Dichlormethan/Methanαl (98:2) als Eluens chromatographiert. Nach dem Einengen der Prbduktfraktion nimmt man den Rückstand in wenig Dichlormethan auf und versetzt die Lösung mit etherischer Salzsäure. Nach erneutem Einengen bis zur Trockne wird der erhaltene fest aufgeschäumte Rückstand in 10 ml Dichlormethan gelöst und das Produkt durch Eintropfen der Lösung in 2 1 Petrolether/Diethylether (4:1) amorph ausgefällt. Ausbeute: 4,57 g; Schmelzbereich: 103 - 110ºC.4.23 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) -propoximethyl] -erotonic acid and 2.49 g of 2-acetyl-3- (3-nitrophenyl) -acrylic acid methyl ester are in a nitrogen atmosphere in 80 ml of tert-butanol heated to boiling under reflux for 8 h. The cooled solution is largely concentrated and the residue is chromatographed on a 3 × 25 cm silica gel column using dichloromethane / methane αl (98: 2) as the eluent. After concentrating the product fraction, the residue is taken up in a little dichloromethane and the solution is treated with ethereal hydrochloric acid. After again concentrating to dryness, the solidly foamed residue obtained is dissolved in 10 ml of dichloromethane and the product is precipitated amorphously by dropping the solution in 2 l of petroleum ether / diethyl ether (4: 1). Yield: 4.57 g; Melting range: 103-110 ° C.

Die Ausgangsverbindung 3-Amino-3-[3-(4,4-diphenylpiperidinyl-1)-proooximethyl]-crotonsäureethylester wird wie folgt erhalten:The starting compound 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) -proooximethyl] -crotonic acid ethyl ester is obtained as follows:

4,27 g 4-[3-(4,4-Diphenylpiperidinyl-1)-propoxi]-3-oxobutancarbonsäureethylester werden in 60 ml mit Ammoniak gesättigtem 2-Propanol gelöst. Bei Raumtemperatur wird für 8 h ein feiner Ammoniak-Strom in die klare Lösung eingeleitet und anschließend die Lösung noch 12 h bei Raumtemperatur stehen gelassen. Nach dem Einengen des Ansatzes nimmt man den erhaltenen öligen Rückstand in 100 ml Diethylether/Petrolether (4:1) auf und filtriert nach 3 h Stehenlassen den ausgeflockten Niederschlag ab. Das klare Filtrat wird im Vakuum bis zur Gewichtskonstanz eingeengt. Der erhaltene gelbliche ölige Rückstand besteht aus der DC-reinen Titelverbindung, die sofort weiter umgesetzt wird. Ausbeute: 3,66 g. 4-[3-(4,4-Diphenylpiperidinyl-1)-oropoxi]-3-oxobutancarbonsäureethylester4.27 g of ethyl 4- [3- (4,4-diphenylpiperidinyl-1) propoxy] -3-oxobutanecarboxylate are dissolved in 60 ml of 2-propanol saturated with ammonia. At room temperature, a fine stream of ammonia is passed into the clear solution for 8 h and then the solution is left to stand at room temperature for 12 h. After concentrating the mixture, the oily residue obtained is taken up in 100 ml of diethyl ether / petroleum ether (4: 1) and the flocculated precipitate is filtered off after standing for 3 h. The clear filtrate is concentrated in vacuo to constant weight. The yellowish oily residue obtained consists of the DC-pure title compound, which is immediately reacted further. Yield: 3.66 g. 4- [3- (4,4-Diphenylpiperidinyl-1) oropoxy] -3-oxobutanecarboxylic acid ethyl ester

In eine auf -10ºC gekühlte und mit Stickstoff begaste Suspension von 4,95 g Natriumhydrid. (80 % in Paraffinöl) in 100 ml absolutem Tetrahydrofuran werden innerhalb von 10 Minuten 22,16 g 3-(4,4-Diphenylpiperidyl-1)propanol eingetragen. Nach 30 Minuten Rühren der bei -10ºC gehaltenen Suspension werden 12,35 g 4-Chloracetessigsäureethylester so zugetropft, daß die Temperatur des Gemisches nicht über -8ºC ansteigt (Zutropfzeit ca. 1,5 h). Nach vollständigem Zutropfen wird der Ansatz 30 Minuten bei -10ºC und anschließend noch 6 h unter Erwärmenlassen auf Raumtemperatur gerührt. Das Reaktionsgemisch wird in eine Mischung von 140 ml IN Salzsäure und 100 ml Eis gegossen und die wäßrige Phase 3 mal mit je 200 ml Essigsaureethylester extrahiert. Nach dem Trocknen der organischen Phase und Einengen chromatographiert man den erhaltenen öligen Rückstand über eine 3 x 30 cm Kieselgelsäule mit Essigsaureethylester als Eluens. Die Produktfraktion ergibt nach dem Einengen bis zur Gewichtskonstanz 12 g der Titelverbindung als zähen öligen Rückstand.In a suspension of 4.95 g sodium hydride cooled to -10 ° C and nitrogen-gassed. (80% in paraffin oil) in 100 ml of absolute tetrahydrofuran 22.16 g of 3- (4,4-diphenylpiperidyl-1) propanol are introduced within 10 minutes. After stirring the suspension kept at -10 ° C for 30 minutes, 12.35 g of ethyl 4-chloroacetoacetate are added dropwise so that the temperature of the mixture does not rise above -8 ° C (dropping time approx. 1.5 hours). After the dropwise addition is complete, the mixture is stirred at -10 ° C. for 30 minutes and then for a further 6 hours while being warmed to room temperature. The reaction mixture is poured into a mixture of 140 ml of 1N hydrochloric acid and 100 ml of ice and the aqueous phase is extracted 3 times with 200 ml of ethyl acetate each time. After the organic phase has been dried and concentrated, the oily residue obtained is chromatographed on a 3 × 30 cm silica gel column using ethyl acetate as the eluent. After concentration to constant weight, the product fraction gives 12 g of the title compound as a viscous oily residue.

2. 1,4-Dihydro-6-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-2-methyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-dimethylester-hvdrochlorid2. 1,4-Dihydro-6- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -2-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester hydrochloride

Analog Beispiel 1 erhält man die Titelverbindung aus 6,0 g 3-Amino-3-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-crotonsäuremethylester (Rohprodukt) und 2,42 g 2-Acetyl-3-(3-nitrophenyl)-acrylsäuremethylester nach 10 h Reaktionszeit in 20 ml tert. -Butanol als feines gelbliches Pulver vom Schmp. 113-128ºC (amorph, ausgefällt in Petrolether/Diethylether 1:1); Ausbeute: 3,53 g.Analogously to Example 1, the title compound is obtained from 6.0 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) -propoximethyl] -crotonic acid methyl ester (crude product) and 2.42 g of 2-acetyl-3- ( 3-nitrophenyl) acrylic acid methyl ester after 10 h reaction time in 20 ml tert. -Butanol as a fine yellowish powder with a melting point of 113-128 ° C (amorphous, precipitated in petroleum ether / diethyl ether 1: 1); Yield: 3.53 g.

Die Ausgangsverbindung 3-Amino-3- [ 3 - ( 4 , 4 -diphenylpiperidinyl- 1 ) - propoximethyl ] -croton s ä uremethylester erhält man analog Beispiel 1 aus 4-[3-(4,4-Diphenylpiperidinyl-1)-propoxi]-3-oxobutancarbonsäuremethylester und Ammoniak. Das erhaltene ölige Produkt (Rohprodukt) wird ohne weitere Reinigung direkt weiter umgesetzt.The starting compound 3-amino-3- [3 - (4,4-diphenylpiperidinyl-1) -propoximethyl] -crotonic acid methyl ester is obtained analogously to Example 1 from 4- [3- (4,4-diphenylpiperidinyl-1) propoxy ] -3-oxobutane carboxylic acid methyl ester and ammonia. The oily product (crude product) obtained is reacted directly without further purification.

Die Ausgangsverbindung 4-[3-(4,4-Diphenylpiperidinyl-1)-propoxi]-3-oxobutancarbonsäuremethylester erhält man analog Beispiel 1 aus 3-(4,4-Diphenylpiperidinyl-1)-propanol und 4-Chloracetessigsäuremethylester. 3. 4-(2,3-Dichlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidinyl-1)propoximethyl]-2-methyl-pyridin-3.5-dicarbonsIure-5-ethyl-3-methylester-hvdrochloridThe starting compound 4- [3- (4,4-diphenylpiperidinyl-1) propoxy] -3-oxobutanecarboxylic acid methyl ester is obtained analogously to Example 1 from 3- (4,4-diphenylpiperidinyl-1) propanol and 4-chloroacetoacetic acid methyl ester. 3. 4- (2,3-dichlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidinyl-1) propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid 5-ethyl-3 methyl ester hydrochloride

Die Titelverbindung wird analog Beispiel 1 hergestellt aus 5,30 g 3-Amino-3-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-crotonsäureethylester und 2,73 g 2-Acetyl-3-(2,3-dichlorphenyl)-acrylsäuremethylester in 20 ml tert. -Butanol; Reaktionszeit 6 h; Schmp.: 116-126ºC (langsames Zerfließen, amorph ausgefällt); Ausbeute: 3,62 g.The title compound is prepared analogously to Example 1 from 5.30 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -crotonic acid ethyl ester and 2.73 g of 2-acetyl-3- (2,3 -dichlorophenyl) -acrylic acid methyl ester in 20 ml tert. Butanol; Reaction time 6 h; M.p .: 116-126 ° C (slow flow, amorphous precipitated); Yield: 3.62 g.

4. 4-(4-Benzo[e][1,2,5]oxdiazolyl)-1,4-dihydro-6-[3-(4,4-diphenyl-piperidinyl-1)-propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-5-ethyl-3-methylester-hvdrochlorid4. 4- (4-Benzo [e] [1,2,5] oxdiazolyl) -1,4-dihydro-6- [3- (4,4-diphenyl-piperidinyl-1) propoxymethyl] -2-methyl -pyridine-3,5-dicarboxylic acid 5-ethyl-3-methyl ester hydrochloride

Die Titelverbindung wird analog Beispiel 1 hergestellt aus 5,30 g 3-Amino-3-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-crotonsäureethylester und 2,46 g 2-Acetyl-3-(4-benzo[c][1,2,5]oxdiazolyl)-acrylsauremethylester in 20 ml tert.-Butanol; Reaktionszeit 6 h; Schmp.: 116-128ºC (langsames Zerfließen, amorph ausgefällt). Ausbeute: .4,73 g.The title compound is prepared analogously to Example 1 from 5.30 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -crotonic acid ethyl ester and 2.46 g of 2-acetyl-3- (4-benzo [c] [1,2,5] oxdiazolyl) acrylic acid methyl ester in 20 ml tert-butanol; Reaction time 6 h; M.p .: 116-128 ° C (slow flow, amorphous precipitated). Yield: .4.73 g.

5. 4-(2-Chlorphenyl)-1,4-dihydro-6-[3-(4,4-diphenylpiperidinyl-1)propoximethyl]-2-methyl-pyridin-3,5-dicarbonsäure-dimethylesterhydrochlorid5. 4- (2-Chlorophenyl) -1,4-dihydro-6- [3- (4,4-diphenylpiperidinyl-1) propoximethyl] -2-methyl-pyridine-3,5-dicarboxylic acid dimethyl ester hydrochloride

Die Titelverbindung wird analog Beispiel 1 hergestellt aus 6 g 3-Amino-3-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-crotonsäuremethylesterThe title compound is prepared analogously to Example 1 from 6 g of 3-amino-3- [3- (4,4-diphenylpiperidinyl-1) -propoximethyl] -crotonic acid methyl ester

(Rohprodukt) und 2,32 g 2-Acetyl-3-(2-chlorphenyl)-acrylsäuremethylester in 20 ml tert. -Butanol; Reaktionszeit 12 h; Schmp.: 119-131ºC (langsames Zerfließen, amorph ausgefällt). Ausbeute: 2,43 g.(Crude product) and 2.32 g of 2-acetyl-3- (2-chlorophenyl) acrylic acid methyl ester in 20 ml of tert. Butanol; Response time 12 h; M.p .: 119-131 ° C (slow flow, amorphous precipitated). Yield: 2.43 g.

6. 1,4-Dihvdro-6-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-2-methyl- 4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-5-ethyl-3-(2-methoxiethyl)-ester-hydrochlorid6. 1,4-Dihvdro-6- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -2-methyl- 4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 5-ethyl 3- (2-methoxyethyl) ester hydrochloride

Die Titelverbindung wird analog Beispiel 1 hergestellt aus 5,30 g 3-Amino--3-[3-(4,4-diphenylpiperidinyl-1)-propoximethyl]-crotonsäureethylester und 2,93 g 2-Acetyl-3-(3-nitrophenyl)-acrylsäure-2.-methoxiethylester in 20 ml tert. -Butanol; Reaktionszeit 5 h; Schmp.: 78-108ºC (langsames Zerfließen, amorph ausgefällt). Ausbeute: 5,61 g.The title compound is prepared analogously to Example 1 from 5.30 g of 3-amino - 3- [3- (4,4-diphenylpiperidinyl-1) propoxymethyl] -crotonic acid ethyl ester and 2.93 g of 2-acetyl-3- (3- 2.-methoxyethyl nitrophenyl) acrylic acid in 20 ml tert. Butanol; Reaction time 5 h; M.p .: 78-108 ° C (slow flow, amorphous precipitated). Yield: 5.61 g.

7. 1,4-Dihydro-6- [2-(4.4-diphenylpiperidinyl-1)-ethoximethyl]-2-methyl4-(3-nitrophenyl)-pyridin-3,5-dicarbonsäure-dimethylester-hydrochlorid7. 1,4-Dihydro-6- [2- (4,4-diphenylpiperidinyl-1) ethoxymethyl] -2-methyl4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester hydrochloride

Die Titelverbindung wird analog Beispiel 1 hergestellt aus 5,0 g 3-Amino- -[2-(4,4-diphenylpiperidinyl-1)-ethoximethyl]-crotonsäuremethylesterThe title compound is prepared analogously to Example 1 from 5.0 g of 3-amino- - [2- (4,4-diphenylpiperidinyl-1) -ethoximethyl] -crotonic acid methyl ester

(Rohprodukt) und 2,37 g 2-Acetyl-3-(3-nitrophenyl)-acrylsauremethylester in 20 ml tert. Butanol; Reaktionszeit 7 h; Schmp.: 124-139ºC (langsames Zerfließen, amorph ausgefällt). Ausbeute: 3,25g.(Crude product) and 2.37 g of 2-acetyl-3- (3-nitrophenyl) acrylic acid methyl ester in 20 ml of tert. Butanol; Response time 7 h; M.p .: 124-139 ° C (slow flow, amorphous precipitated). Yield: 3.25 g.

Die Ausgangsverbindung 3-Amino-[2-(4,4-diphenylpiperidinyl-1)-ethoximethyl]-crotonsäuremethylester erhält man ananolg Beipiel 1 aus 4-[2-(4,4.-Diphenylpiperidinyl-1)-ethoxi]-3-oxobutancarbonsäuremethylester und Ammoniak. Das erhaltene ölige Rohprodukt wird ohne weitere Reinigung direkt weiter umgesetzt.Ananolg Example 1 gives the starting compound 3-amino- [2- (4,4-diphenylpiperidinyl-1) -ethoxymethyl] -crotonic acid methyl ester from 4- [2- (4,4-diphenylpiperidinyl-1) -ethoxy] -3- oxobutane carboxylic acid methyl ester and ammonia. The oily crude product obtained is reacted directly without further purification.

Die Au s gangsverbindung 4-[2-(4,4-Diphenylpiperidinyl-1)-ethoxi]-3-oxobutancarbonsäuremethylester erhält man analog Beispiel 1 aus 2-(4,4-Diphenylpiperidinyl-1)-ethanol und 4-Chloracetessigsäuremethylester. The starting compound 4- [2- (4,4-diphenylpiperidinyl-1) -ethoxy] -3-oxobutanecarboxylic acid methyl ester is obtained analogously to Example 1 from 2- (4,4-diphenylpiperidinyl-1) -ethanol and 4-chloroacetoacetic acid methyl ester.

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 zeigt sich insbesondere in einer langsam eintretenden und starken Blutdrucksenkung. Darüberhinaus besitzen die erfindungsgemäßen Verbindungen hemmende Wirkung auf den Calciumeinstrom sowie fördernde Wirkung auf den Kaliumausstrom von Zellen, glattmuskulär relaxierende und peripher, coronar, cerebral und renal gefäßerweiternde sowie salidiuretische, antithrombotische und günstige hämorheologische Eigenschaften.The compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are in particular effective vasodilators with coronary therapeutic properties. The pharmacological activity of the compounds according to the invention is particularly evident in a slowly occurring and strong drop in blood pressure. In addition, the compounds according to the invention have an inhibitory effect on calcium influx and a promotional effect on potassium outflow from cells, smooth muscle relaxing and peripheral, coronary, cerebral and renal vasodilator and salidiuretic, antithrombotic and favorable hemorheological 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.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.

Als vorteilhafte Eigenschaften der Verbindungen I sind beispielsweise zu nennen: das Ausmaß der Blutdrucksenkung, die gute Steuerbarkeit der Blutdrucksenkung, 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, die große Stabilität und insbesondere der überraschend geringe Anstieg der Herzfrequenz.Examples of advantageous properties of the compounds I are: the extent of the lowering of blood pressure, the good controllability of the lowering of the blood pressure, the excellent bioavailability, the wide therapeutic range, the lack of central side effects, the lack of kinetic interactions with other substances, the lack of a development of tolerance, the balanced physical properties, the great stability and especially the surprisingly small increase in heart rate.

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, arterielle und pulmonale Hypertonien aller Schweregrade, koronare Herzkrankheiten (Koronarinsuffizienz, Angina Pectoris, Myocardinfarkt etc.), periphere und cerebrale Zirkulationsstörungen (Gehirnschlag, temporäre cerebrale Durchblutungsstörungen, Migräne, Schwindel, renale Arterienverengung etc.), hypertrophe Kardiomyopathie, Herzinsuffizienz, Krankheiten, die auf einer erhöhten Wasser- und Natriumretention beruhen und Krankheiten, die auf einem erhöhten Calciumeinstrom beruhen, wie z.B. Spasmen glattmuskulärer Organe (Atemwege, Gastrointestinaltrakt, Urogenitaltrakt etc.) sowie Arrhythmie und Arteriosklerose, in Betracht kommen.The excellent activity of the compounds of the formula I and their salts according to the invention permits their use in human medicine, with primary (essential) and secondary, arterial and pulmonary hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.) being used as indications, peripheral and cerebral circulation disorders (stroke, temporary cerebral circulatory disorders, migraines, dizziness, renal artery narrowing etc.), hypertrophic cardiomyopathy, heart failure, diseases that are based on increased water and sodium retention and diseases that are based on an increased influx of calcium, such as spasms smooth muscle Organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia and arteriosclerosis.

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 erfindungsgemäβen 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, Aerosolen, Sprays, Salben, Cremes, Gelen 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 ingredients) according to the invention are used as pharmaceuticals either as such or, preferably, in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, plasters (eg as TTS), emulsions, suspensions, aerosols, sprays, Ointments, creams, gels or solutions are used, the active substance content advantageously being between 0.1 and 95%.

Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Tabletten, Hilfsstoffen und anderen Wirkstoffträgem können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z.B. Cyclodextrine) verwendet werden. Die Wirkstoffe können oral, rektal, per inhalationem oder parenteral (insbesondere perlingual, intravenös oder percutan) appliziert 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, gel formers, suppository bases, tablets, auxiliaries and other active ingredients, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example cyclodextrins) can be used. The active substances can be administered orally, rectally, by inhalation 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 Fächmann 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 Fächmann 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, alpha-1-Rezeptorenblocker, alpha-2-Rezeptorstimulatoren, beta-1-Rezeptorenblocker, beta-2-Rezeptorstimulatoren, ACE-Hemmstoffe, Nitroverbindungen, Cardiotonika, Diuretika, Saluretika, Alkaloide, Analgetika, Lipidsenker, Antikoagulantien, Anticholinergika, Methylxanthine, Antiarrhythmika, Antihistaminika, Dopaminstimulatoren, Serotonin-Rezeptorenblocker etc., wie Nifedipin, Dihydralazin, Prazosin, Clonidin, Atenolol, Labetalol, Fenoterol, Captopril, Isosorbiddinitrat, Digoxin, Milrinon, Mefrusid, Clopamid, Spironolacton, Chlorthalidon, Furosemid, Polythiazid, Hydrochlorothiazid, Reserpin, Dihydroergocristin, Rescinnamin, RauwolfiaGesamtalkaloide, Acetylsalicylsäure, Bezafibrat, Warfarin, Atropin, Theophyllin, Lidocain, Astemizol, Bromocryptin, Ketanserin 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, alpha-1 receptor blockers, alpha-2 receptor stimulators , beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine stimulators, such as blockers nifedipine, hydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, RauwolfiaGesamtalkaloide, acetylsalicylic acid, bezafibrate, War Farin, atropine, theophylline, lidocaine, astemizole, bromocryptine, ketanserin 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 männlichen 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 male 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 36ºC vorgenommen, um eine bessere Durchblutung der Schwanzarterie zu erreichen. Hierzu werden die Tiere in perforierte Lochblechkafige verbracht und 20 - 40 Min. nach Beginn der Aufwärmung gemessen. Zur Messung des systolischen arteriellen Drucks wird eine ringförmige Manschette mit aufblasbarer Gummimembran zur.Blood pressure measurement is done in a warming chamber at 36 ° C to achieve better blood flow to the tail artery. For this purpose, 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 is used to measure the systolic arterial pressure.

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.Blood circulation is stopped and a ring-shaped piezocrystal transducer for detecting the pulse waves is 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 den Nummern der Beispiele entsprechen.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 compounds are identified by consecutive numbers that correspond to the numbers of the examples.

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

%-Änderungen (BP) an genetisch hypertonen Ratten nach täglich einmaliger p.o. -Applikation an vier aufeinanderfolgenden Tagen (N=6/Dosis); die Dosis in mg/kg ist auf die freie Base berechnet.% Changes (BP) in genetically hypertensive rats after daily p.o. -Application on four consecutive days (N = 6 / dose); the dose in mg / kg is calculated on the free base.

Figure imgf000026_0001
Figure imgf000026_0001

Claims

Patentansprüche Claims 1. Verbindungen der Formel la1. Compounds of formula la
Figure imgf000027_0001
Figure imgf000027_0001
 worin Cy einen Cyclus der Formelwherein Cy is a cycle of the formula
Figure imgf000027_0002
Figure imgf000027_0002
 darstellt, in dem Y Sauerstoff (O), Schwefel (S), Vinylen (-CH=CH-), Azomethin (-CH=N-) oder eine Gruppe der Formelrepresents in which Y represents oxygen (O), sulfur (S), vinylene (-CH = CH-), azomethine (-CH = N-) or a group of the formula oder
Figure imgf000027_0003
Figure imgf000027_0004
bedeutet,or
Figure imgf000027_0003
Figure imgf000027_0004
means A1 2-6C-Alkylen bedeutet,A1 means 2-6C-alkylene, R1 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet,R1 is 1-6C-alkyl or 3-7C-alkoxyalkyl, R2 Wasserstoff, 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet, R3 1-6C-Alkyl oder 3-7C-Alkoxyalkyl bedeutet,R2 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl, R4 und R5 gleich oder verschieden sind und Wasserstoff, Hydroxy, Halogen, Nitro, Cyano, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy, 1-4C-Alkoxycarbonyl, 2-5C-Acyl, Amino oder Mono- oder Di-1-4C-alkylamino bedeuten,R4 and R5 are identical or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, Mean 2-5C-acyl, amino or mono- or di-1-4C-alkylamino, R8 Aryl bedeutet undR8 means aryl and R9 Aryl bedeutet, wobeiR9 means aryl, where Aryl für einen Ring der FormelAryl for a ring of the formula
Figure imgf000028_0001
steht, worin R10 und R11 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), 1-4C-Alkyl, 1-4C-Alkoxy, Halogen, Hydroxy oder Trifluormethyl haben, und die Salze dieser Verbindungen.
Figure imgf000028_0001
is in which R10 and R11 are the same or different and have the meaning hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and the salts of these compounds. 2. Verbindungen der Formel la nach Anspruch 1, worin2. Compounds of formula la according to claim 1, wherein Cy Phenyl, 2-Nitrophenyl, 3-Nitrαphenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoκyphenyl, 2-Chlorphenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluorphenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl oder Benzoxdiazolyl bedeutet,Cy phenyl, 2-nitrophenyl, 3-nitrαphenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzoxdiazolyl, A1 Ethylen (-CH2CH2-) oder Trimethylen (-CH2-CH2-CH2-) bedeutet,A1 means ethylene (-C H2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -), R1 Methyl, Ethyl oder Methoxyethyl bedeutet,R1 is methyl, ethyl or methoxyethyl, R2 Methyl bedeutet,R2 means methyl R3 Methyl, Ethyl oder Methoxyethyl bedeutet,R3 denotes methyl, ethyl or methoxyethyl, R8 Aryl bedeutet undR8 means aryl and R9 Aryl bedeutet, wobeiR9 means aryl, where Aryl für einen Ring der Formel
Figure imgf000029_0001
steht, worin R10 und R11 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluormethyl haben, und die Salze der Verbindungen.Aryl for a ring of the formula
Figure imgf000029_0001
is where R10 and R11 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, and the salts of the compounds. 3. Verbindungen der Formel la nach Anspruch 1, worin3. Compounds of formula la according to claim 1, wherein Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, A1 Ethylen (-CH2-CH2-) oder Trimethylen (-CH2-CH2-CH2- ) bedeutet, R1 Methyl oder Ethyl bedeutet, R2 Methyl bedeutet, R3 Methyl oder Ethyl bedeutet, R8 Phenyl oder 4-Methoxyphenyl bedeutet und R9 Phenyl oder 4-Methoxyphenyl bedeutet, und ihre Salze.Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl means A1 means ethylene (-CH 2 -CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 - ) means R1 means methyl or ethyl, R2 means methyl, R3 means methyl or ethyl, R8 means phenyl or 4-methoxyphenyl and R9 means phenyl or 4-methoxyphenyl, and their salts. 4. Verbindungen der Formel la nach Anspruch 1, worin4. Compounds of formula la according to claim 1, wherein Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Oichlorphenyl oder Benzoxdiazolyl bedeutet, A1 Ethylen (-CH2CH2-) oder Trimethylen (-CH2-CH2-CH2-) bedeutet, R1 Methyl oder Ethyl bedeutet, R2 Methyl bedeutet,Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-oichlorophenyl or benzoxdiazolyl means A1 means ethylene (-CH 2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -), R1 means methyl or ethyl, R2 means methyl R3 Methyl oder Methoxyethyl bedeutet, R8 Phenyl bedeutet und R9 Phenyl bedeutet, und ihre Salze.R3 is methyl or methoxyethyl, R8 is phenyl and R9 is phenyl, and their salts. 5. Verbindungen der Formel la nach Anspruch 1, worin5. Compounds of formula la according to claim 1, wherein Cy 3-Nitrophenyl oder 2,3-Dichlorphenyl bedeutet,Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl, A1 Trimethylen (-CH2-CH2-CH2-) bedeutet,A1 means trimethylene (-CH 2 -CH 2 -CH 2 -), R1 Methyl oder Ethyl bedeutet,R1 means methyl or ethyl, R2 Methyl bedeutet, R3 Methyl oder Methoxyethyl bedeutet,R2 means methyl R3 denotes methyl or methoxyethyl, R8 Phenyl undR8 phenyl and R9 Phenyl bedeutet, und ihre Salze.R9 means phenyl, and their salts. 6. Verfahren zur Herstellung der Verbindungen der Formel la nach Anspruch 1, dadurch gekennzeichnet, daß man6. A process for the preparation of the compounds of formula la according to claim 1, characterized in that a) Zimtsäurederivate der Formel IIa) Cinnamic acid derivatives of the formula II
Figure imgf000030_0001
mit Enaminderivaten der Formel III
Figure imgf000030_0001
with enamine derivatives of the formula III
Figure imgf000030_0002
oder
Figure imgf000030_0002
or 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 imgf000030_0003
oder c) Enamine der Formel V
Figure imgf000030_0003
or c) enamines of formula V
Figure imgf000031_0001
mit Benzylidencarbonsaurederivaten der Formel VI
Figure imgf000031_0001
with benzylidenecarboxylic acid derivatives of the formula VI
Figure imgf000031_0002
oder d) Ketoverbindungen der Formel VII
Figure imgf000031_0002
or d) keto compounds of the formula VII
Figure imgf000031_0003
mit Ammoniak und Benzylidencarbonsaurederivaten der Formel VI, oder e) Aldehyde der Formel VIII
Figure imgf000031_0003
with ammonia and benzylidenecarboxylic acid derivatives of the formula VI, or e) aldehydes of the formula VIII
Figure imgf000031_0004
mit Enaminen der Formel V und ß-Ketocarbonsäurederivaten der Formel IV, oder
Figure imgf000031_0004
with 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 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 Cy, A1, R1, R2, R3, R4, R5, R8 und R9 die in Anspruch 1 angegebenen Bedeutungen haben.f) reacting aldehydes of the formula VIII with enamine derivatives of the formula III and keto compounds of the formula VII as such (s) or in the form of their salts and, if desired, subsequently converting the salts obtained into the free bases or the bases obtained into the salts, where Cy, A1, R1 , R2, R3, R4, R5, R8 and R9 have the meanings given in claim 1. 7. Arzneimittel enthaltend eine oder mehrere Verbindungen nach einem oder mehreren der Ansprüche 1 bis 5 und/oder ihre pharmakologisch verträglichen Salze.7. Medicament containing one or more compounds according to one or more of claims 1 to 5 and / or their pharmacologically acceptable salts. 8. Verbindungen nach einem oder mehreren der Andptüche 1 bis 5 und ihre pharmakologisch verträglichen Salze zur Anwendung bei der Behandlung und/oder Prophylaxe von Hypertonie, kofonaren Herzkrankheiten, peripheren und cerebralen Zirkulationsstörungen und/oder Krankheiten, die auf einer erhöhten Wasser- oder Natriumretention beruhen.8. Compounds according to one or more of Andptuche 1 to 5 and their pharmacologically acceptable salts for use in the treatment and / or prophylaxis of hypertension, cofonar heart diseases, peripheral and cerebral circulatory disorders and / or diseases which are based on increased water or sodium retention . 9. Verwendung von Verbindungen. nach einem oder mehreren der Ansprüche 1 bis 5 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 beruhen. 9. Use of connections. according to one or more of claims 1 to 5 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 which are based on increased water or sodium retention.
PCT/EP1987/000437 1986-08-14 1987-08-10 New piperidines Ceased WO1988001266A1 (en)

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EP0060674A1 (en) * 1981-03-14 1982-09-22 Pfizer Limited Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them
EP0176956A2 (en) * 1984-09-28 1986-04-09 Byk Gulden Lomberg Chemische Fabrik GmbH Diaryl derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024714A1 (en) * 1998-10-26 2000-05-04 Esteve Quimica S.A. Intermediate for the synthesis of amlodipine, preparation process and corresponding utilization
ES2151850A1 (en) * 1998-10-26 2001-01-01 Esteve Quimica Sa Intermediate for the synthesis of amlodipine, preparation process and corresponding utilization
AU752042B2 (en) * 1998-10-26 2002-09-05 Esteve Quimica, S.A. Intermediate for the synthesis of amlodipine, preparation process and corresponding utilization
US6603006B2 (en) 1998-10-26 2003-08-05 Esteve Química, S.A. Intermediate for the synthesis of amlodipine, a process for the preparation thereof and corresponding use

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