EP0393074A1 - Nouvelles pyrrolidines - Google Patents

Nouvelles pyrrolidines

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Publication number
EP0393074A1
EP0393074A1 EP88909530A EP88909530A EP0393074A1 EP 0393074 A1 EP0393074 A1 EP 0393074A1 EP 88909530 A EP88909530 A EP 88909530A EP 88909530 A EP88909530 A EP 88909530A EP 0393074 A1 EP0393074 A1 EP 0393074A1
Authority
EP
European Patent Office
Prior art keywords
methyl
ethyl
formula
nitrophenyl
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.)
Pending
Application number
EP88909530A
Other languages
German (de)
English (en)
Inventor
Dieter Flockerzi
Wolf-Rüdiger Ulrich
Karl Sanders
Klaus-Dieter Beller
Klaus Eistetter
Manfrid Eltze
Rainer Boer
Bernhard Kohl
Hermann Amschler
Kurt Klemm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0393074A1 publication Critical patent/EP0393074A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to new pyrrolidines, 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 pyrrolidines of the formula I.
  • R1 is 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R2 is 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R3 denotes hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R4 and R5 are the same or different and are hydrogen, hydroxy, halogen,
  • Nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1 -4C-alkylamino mean
  • R6 phenyl or substituted phenyl with one, two or three identical or different substituents from the group halogen, hydroxy, nitro, cyano trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl , Amino and mono- or di -1-4C-alkyl amino means and
  • E means 2-5C-alkylene, and the salts of these compounds.
  • 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 rest.
  • 3-7C-alkoxyalkyl is, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2ethoxy-1-methylethyl or in particular 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-butyl, 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.
  • 2-5C-acyl contains one of the 1-4C-alkyl radicals mentioned above.
  • the acetyl radical is preferred.
  • mono- or di-1-4C-alkylamino contains one or two of the 1-4C-alkyl radicals mentioned above.
  • Di-1-4C-alkylamino is preferred, and in particular dimethyl-, diethyl- or diisopropylamino.
  • 2-5C-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 -), 1,2-dimethylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene and 2 -Ethylpropylen, with ethylene and trimethylene being preferred.
  • 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, besunide, piretanide, etacrynic acid or tetracrynic acid, tetrailic acid, or 4-chloro-sulfamoyl-benzoic acid.
  • R1 is methyl, ethyl or methoxyethyl
  • R2 is methyl, ethyl or methoxyethyl
  • R3 denotes methyl, ethyl or methoxyethyl
  • R6 phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 3 -Methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 3-chloro-4-methylphenyl, 3,4-dimethylphenyl, 4-aminophenyl, 2,4 -Diaminophenyl, 4-nitrophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or 3,4,5-trihydroxyphenyl and
  • Cy means 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2-trifluoromethylphenyl, R1 means methyl or ethyl, R2 means methyl or ethyl, R3 means methyl or ethyl,
  • R6 is 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 4-nitrophenyl and E is ethylene (-CH 2 CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -), and the salts of these compounds .
  • Preferred compounds according to the invention are those of the formula I in which
  • Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl
  • R1 means methyl or ethyl
  • R2 means methyl or ethyl
  • R3 denotes methyl or ethyl
  • E means ethylene (-CH 2 -CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -), and their salts.
  • Particularly preferred compounds according to the invention are those of the formula I in which
  • R1 means methyl
  • R2 means methyl
  • R3 denotes methyl or ethyl
  • E means ethylene (-CH Z -CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -), and their salts.
  • the compounds of the formula I each have a chiral center at the 4-position in the 1,4-dihydropyridine and at the 2-position in the pyrrolidine ring.
  • the invention therefore encompasses both the enantiomers and 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 VII have the substituents or symbols Cy, R1, R2, R3, R4, R5, R6 and E have the meanings given in the subclaims and subclaims and X represents an escape group.
  • reaction II with III takes place in a manner known for the preparation of tertiary amines.
  • leaving group X which is preferably a halogen atom, in particular a chlorine or bromine atom
  • the reaction can, if desired, be carried out in the presence of a base (e.g. an inorganic carbonate such as potassium carbonate) or by using an excess of amine III.
  • reaction of II with III, of IV with V and of VI with VII is carried out in suitable, preferably inert, organic solvents.
  • suitable, preferably inert, organic solvents include hydrocarbons such as toluene or xylene; Ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether; or ketones such as acetone or ethyl methyl ketone; chlorinated hydrocarbons such as methylene chloride, chloroform, tetrachlorethylene or dichloroethane; or other organic solvents such as dimethylformamide.
  • 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.
  • the diastereomerically pure compounds of the formula I and their salts which are a preferred subject of the invention, are obtained, on the one hand, from racemic mixtures of the compounds II by reacting them with an enantiomerically pure amine III and separating the diastereomers obtained in a conventional manner.
  • the diastereomerically pure compounds according to the invention are obtained by starting from racemic amines III and enantiomerically pure 1,4-dihydropyridine derivatives of the formula II and then carrying out diastereomer separation, or by using enantiomerically pure amines III and enantiomerically pure 1,4-dihydropyridine derivatives of Formula II runs out.
  • the diastereomerically pure compounds according to the invention are obtained according to process variants b or c by starting from enantiomerically pure benzylidene carboxylic acid derivatives V or enamine derivatives VI. After reaction of enantiomerically pure V or VI with an enamine IV or cinnamic acid derivative VII, a mixture of diastereomers is obtained which can be separated in a conventional manner.
  • Enantiomerically pure 1,4-dihydropyridine derivatives of the formula II are obtained starting from enantiomerically pure N-protected 1,4-dihydropyridinecarboxylic acids which are known or can be prepared in a known manner in an analogous manner [Chem. Pharm. Bull. 28, 2809 (1980)] by reaction with bifunctional alkylene derivatives X-E-X, in which E has the meanings given above and X represents an escape group, in particular a halogen atom, preferably a bromine atom, and subsequent elimination of the N-protecting group.
  • the reaction of the N-protected dihydropyridinecarboxylic acids is preferably carried out under basic conditions in the presence of a phase transfer catalyst.
  • a phase transfer catalyst In addition to onium salts, such as, for example, tetrabutylammonium bromide or benzyltriethylammonium chloride, the catalysts mentioned are, above all, crown ethers, such as dibenzo- [18] crown-6, dicyclohexyl- [18] crown-6 and in particular [18] crown-6.
  • Suitable bases which are used at least in a molar ratio, preferably in excess, are inorganic bases, such as alkali metal hydroxides (for example sodium or potassium hydroxide), or in particular alkali metal carbonates (for example sodium or preferably potassium carbonate).
  • alkali metal hydroxides for example sodium or potassium hydroxide
  • alkali metal carbonates for example sodium or preferably potassium carbonate
  • the hydroxides or carbonates used are preferably used in finely powdered form.
  • the reaction takes place (depending on the type of phase transfer catalyst and the base used) in water-containing or anhydrous organic solvents, or in a mixture of water and an organic solvent which is immiscible or hardly miscible with water.
  • water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or benzene.
  • water-containing or water-free solvents are dichloromethane, acetonitrile or acetone.
  • reaction temperature depends on the other reaction conditions, temperatures between 20 ° C. and the boiling point of the solvent used being generally preferred.
  • Enantiomerically pure amines III are obtained from their racemates by reaction with enantiomerically pure optically active acids, such as, for example, di-0,0'-p-toluoyltartaric acid or di-0,0'-benzoyltartaric acid, and subsequent separation of the diastereomeric salts in a conventional manner Way, e.g. B. by recrystallization.
  • optically active acids such as, for example, di-0,0'-p-toluoyltartaric acid or di-0,0'-benzoyltartaric acid
  • the configuratively uniform diastereomeric salts separated by means of these methods are obtained by adding preferably inorganic bases, such as e.g. Ammonia, or with the aid of basic ion exchangers in the optically active, enantiomerically pure compounds of the invention.
  • inorganic bases such as e.g. Ammonia
  • basic ion exchangers in the optically active, enantiomerically pure compounds of the invention.
  • the isolation and purification of the substances according to the invention obtained is carried out 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, for example 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 then added.
  • a suitable solvent for example 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 then added.
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
  • Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
  • the starting compounds II, III, IV, V, VI and VII are known from the literature or they can be prepared analogously to methods known from the literature.
  • the starting compounds II used as a racemate can be used in a manner known per se e.g. according to the following reaction scheme:
  • the amines of formula III are e.g. B. from US Patent 4,279,918.
  • the Benzy! Idencarboxylic acid derivatives V and the cinnamic acid derivatives VII can be prepared, for example, in analogy to G. Jones ["The Knoevenagel Condensation” in Org. Reactions, Vol. XV, 204f (1967)].
  • the enamines IV and the enamine derivatives VI are, for example, analogous to A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)].
  • Mp Means melting point, h stands for hours, Kp. Stands for boiling point, dec. means decomposition.
  • Example 2 Analogously to Example 2, the title compound is obtained from 1.81 g ( ⁇ ) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid-3-methyl -5 - (3-bromopropyl) ester and 1.00 g of (+) - 2- (4-chlorobenzyl) pyrrolidine hydrochloride as a fine yellowish powder with a melting range of 125-140 ° C (slow flow). Yield: 1.81 g.
  • Example 4 Analogously to Example 4, the title compound is obtained when ( ⁇ ) -2- (4-methoxibenzyl) pyrrolidine is used as a fine yellowish powder with a melting range of 138-148 ° C (decomposition). Yield: 69% of theory.
  • Example 4 Analogously to Example 4, the title compound is obtained when ( ⁇ ) -2- (3,4-dimethoxibenzyl) pyrrolidine is used as a fine yellowish powder with a melting range of 115-126 ° C (slow flow). Yield: 56% of theory.
  • Ammonia gas is introduced into a solution of acetoacetic acid ⁇ 3- [2 - (-) - (4-chlorobenzyl) pyrrolidinyl-1] propyl ⁇ ester in 2-propanol with ice cooling and stirring until saturated. After standing overnight at 0 ° C., the mixture is concentrated in a water jet vacuum at a bath temperature of 70 ° C. to a constant weight. The yellowish oil obtained is without further
  • the compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. In particular, they represent effective vasodilators with coronary therapeutic properties.
  • the pharmacological activity of the compounds according to the invention which is paired with a low toxicity, is particularly evident in a rapidly occurring, strong and optimally sustained reduction in blood pressure after oral administration.
  • 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, antiarteriosclerotic 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 reduction in blood pressure, the optimal stopping of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly low increase in heart rate, the excellent bioavailability, the wide therapeutic range, the lack of central side effects, the lack of kinetic effects Interactions with other substances, the lack of tolerance, the balanced physical properties and great stability.
  • 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 circulatory disorders (stroke, temporary cerebral circulatory disorders, migraines, dizziness, renal artery narrowing etc.), hypertrophic cardiomyopathy, heart failure, diseases due to increased water and sodium retention and diseases that are based on an increased influx of calcium, such as spasms of smooth muscle organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia, arteriosclerosis and cell damage of various origins (e.g. hypoxia) can be considered.
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cerebral circulatory disorders stroke, temporary cerebral circulatory disorders, migraines
  • Another object of the invention is therefore a method for the treatment of mammals, especially humans, who are suffering from one of the above-mentioned diseases.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I.
  • the invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
  • the invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulators, defoamers, taste correctors, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (eg 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 contain 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, antihistamininulants, dopantinistiniminators, dopersin blockers such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone,
  • 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 to prevent circulation and an annular piezocrystal transducer to record the pulse waves are pushed onto the tail.
  • the cuff pressure is continuously reduced. The return of the pulse waves during pressure relief is automatically recognized and printed out as systolic blood pressure (Bühler, R. et al.: Microproces sor-based automation of blood pressure measurement in the conscious rat.
  • the animals are trained for 14 days before the substance test.
  • blood pressure pre-values are collected.
  • Groups of animals receiving substance are tested against a control group.
  • 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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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

De nouvelles pyrrolidines ayant la formule (I), dans laquelle les substituants et les symboles ont la signification donnée dans la description, représentent des composés nouveaux ayant des propriétés pharmacologiques surprenantes.
EP88909530A 1987-10-27 1988-10-24 Nouvelles pyrrolidines Pending EP0393074A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH422387 1987-10-27
CH4223/87 1987-10-27

Publications (1)

Publication Number Publication Date
EP0393074A1 true EP0393074A1 (fr) 1990-10-24

Family

ID=4272097

Family Applications (2)

Application Number Title Priority Date Filing Date
EP88117660A Withdrawn EP0314038A1 (fr) 1987-10-27 1988-10-24 Pyrrolidines
EP88909530A Pending EP0393074A1 (fr) 1987-10-27 1988-10-24 Nouvelles pyrrolidines

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP88117660A Withdrawn EP0314038A1 (fr) 1987-10-27 1988-10-24 Pyrrolidines

Country Status (8)

Country Link
EP (2) EP0314038A1 (fr)
JP (1) JPH03500647A (fr)
AU (1) AU2614288A (fr)
IL (1) IL88161A0 (fr)
NZ (1) NZ226717A (fr)
PT (1) PT88869B (fr)
WO (1) WO1989003824A1 (fr)
ZA (1) ZA888010B (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0506801A1 (fr) * 1989-12-22 1992-10-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles dihydropyridines
GB9405833D0 (en) * 1994-03-24 1994-05-11 Pfizer Ltd Separation of the enantiomers of amlodipine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1983003249A1 (fr) * 1982-03-17 1983-09-29 Yoshitomi Pharmaceutical Derives de 1,4-dihydropyridine-3,5-dicarboxylate
WO1984002702A1 (fr) * 1983-01-11 1984-07-19 Takeda Chemical Industries Ltd Derives de dihydropyridine
CH663616A5 (de) * 1983-06-21 1987-12-31 Sandoz Ag 1,4-dihydropyridin-derivate und sie enthaltende pharmazeutische zubereitungen.
DE3587851D1 (de) * 1984-09-28 1994-07-21 Byk Gulden Lomberg Chem Fab Neue Diarylverbindungen.
AU5312086A (en) * 1984-12-21 1986-07-22 Byk Gulden Lomberg Chemische Fabrik Gmbh New piperazine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8903824A1 *

Also Published As

Publication number Publication date
WO1989003824A1 (fr) 1989-05-05
AU2614288A (en) 1989-05-23
NZ226717A (en) 1990-04-26
JPH03500647A (ja) 1991-02-14
PT88869B (pt) 1993-01-29
EP0314038A1 (fr) 1989-05-03
IL88161A0 (en) 1989-06-30
ZA888010B (en) 1989-06-28

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