EP0302871A1 - Dérivés de 1,4-Dihydropyridines - Google Patents

Dérivés de 1,4-Dihydropyridines

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Publication number
EP0302871A1
EP0302871A1 EP87902503A EP87902503A EP0302871A1 EP 0302871 A1 EP0302871 A1 EP 0302871A1 EP 87902503 A EP87902503 A EP 87902503A EP 87902503 A EP87902503 A EP 87902503A EP 0302871 A1 EP0302871 A1 EP 0302871A1
Authority
EP
European Patent Office
Prior art keywords
formula
methyl
ethyl
ester
diphenylpiperidyl
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.)
Withdrawn
Application number
EP87902503A
Other languages
German (de)
English (en)
Inventor
Dieter Flockerzi
Hermann Amschler
Klaus Eistetter
Manfrid Eltze
Kurt Klemm
Norbert Kolassa
Karl Sanders
Christian Schudt
Wolf-Rüdiger Ulrich
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 EP0302871A1 publication Critical patent/EP0302871A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/12—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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new amines and ethers, 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 amines and ethers of the formula I.
  • R 1 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R4 and: R5 are the same or different and are hydrogen, hydroxy, halogen, nitno, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl , 2-5C-acyl, amino or mono- or di-1-4C-alkylamino,
  • R10 and R11 are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and in which either
  • R3 is 1-6C-alkyl or 3-7C-alkoxyalkyl, or
  • R2 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl and
  • R3 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, where
  • A2 means 2-4C-alkylene or 2C-alkyleneoxy-2C-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 radical.
  • 3-7C-Alkoxyalkyl stands for example for an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-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-8utyl, 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 the ethoxy radical 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 especially 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 here 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.
  • 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.
  • 2-4C-alkylene stands for ethylene (-CH 2 -CH 2 -), trimethylene (-CH 2 -CH 2 -CH 2 -) and tetramethylene (-CH 2 -CH 2 -CH 2 -CH 2 -), whereby Ethylene is preferred.
  • 2-C-Alkyleneoxy-2C-alkylene stands for ethylene which is substituted by ethyleneoxy (-CH 2 -CH 2 -O-CH 2 -CH 2 -).
  • 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 , 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, etacrylic acid or 4-tienilic acid -Chlor-sulfamoyl-benzoic acid.
  • One embodiment (embodiment a) of the invention is compounds of the formula Ia
  • R1 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R2 means amino (NH 2 )
  • R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl
  • 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 means aryl
  • R9 means aryl
  • 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.
  • E denotes ethylene (-CH 2 CH 2 -), trimethylene (-CH 2 -CH 2 -CH 2 -) or pentamethylene (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -),
  • R1 means methyl
  • R2 means amino (NH 2 )
  • R3 denotes methyl, ethyl or methoxyethyl
  • R8 means aryl and R9 means aryl, where aryl represents a ring of the formula
  • 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.
  • Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl or benzoxdiazolyl means E means ethylene (-CH 2 -CH 2 -), trimethylene (-CH 2 -CH 2 -CH 2 -) or pentamethylene
  • (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -) means, R1 means methyl, R2 means amino (NH 2 ), R3 means methyl or ethyl, R8 means phenyl and R9 means phenyl, and their salts.
  • E means ethylene (-CH 2 -CH 2 -) or trimethylene (-CH 2 -CH 2 -CH 2 -),
  • R1 means methyl
  • R2 means amino (NH 2 )
  • R3 denotes methyl or ethyl
  • R9 means phenyl, and their salts. Examples of compounds of embodiment a according to the invention which may be mentioned are:
  • a further embodiment (embodiment b) of the invention are compounds of the formula Ib
  • A1 means 2-4C-alkylene
  • A2 is 2-4C-alkylene or 2C-alkyleneoxy-2C-alkylene
  • R1 and R2 are the same or different and are hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl mean
  • R3 denotes hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl
  • 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 means aryl
  • R9 means aryl
  • 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.
  • A1 means ethylene (-CH 2 CH 2 -),
  • A2 denotes ethylene (-CH 2 CH 2 -) or ethyleneoxyethylene (-CH 2 -CH 2 -O-CH 2 -CH 2 -),
  • R1 means methyl
  • R2 means methyl
  • R3 denotes methyl, ethyl or methoxyethyl
  • R8 means aryl
  • R9 means aryl
  • Aryl for a ring of the formula 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.
  • Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl or benzoxdiazolyl means A1 means ethylene (-CH 2 CH 2 -), A2 means ethylene (-CH 2 CH 2 -) or ethyleneoxyethylene (-CH 2 -CH 2 -O-CH 2 -CH 2 -) means, R1 means methyl, R2 means methyl, R3 means methyl or ethyl, R8 means phenyl and R9 means phenyl, and their salts.
  • A1 means ethylene (-CH 2 CH 2 -),
  • A2 means ethylene (-CH 2 CH 2 -),
  • R1 means methyl
  • R2 means methyl
  • R3 means methyl
  • R9 means phenyl, and their salts. Examples of compounds of embodiment b according to the invention which may be mentioned are:
  • the compounds of the formula I have a chiral center at the 4-position in the 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 method are those in which, in the formulas IIa, IIb, IIIa, IIIb and IV to XII, the substituents or symbols Cy, E, A1, A2, R1, R2, R3, R4, R5, R8 and R9, the have meanings given in the subclaims and subsidiary claims, Z together with the carbonyl group, to which it is bound, represents a carboxyl group or a reactive carboxylic acid derivative and Y represents a leaving group.
  • the process according to 1. and 2. 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.
  • 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, acet
  • reaction temperatures can vary within a wide range. In general, the reaction is carried out at temperatures between 20 ° C. and 150 ° C., preferably between 20 ° C. and 100 ° C., in particular at the boiling point of the solvent used.
  • the process according to the invention according to 1 is carried out in the presence of a basic condensing agent, for example in the presence of an alkali alcoholate, such as sodium methylate or sodium ethylate.
  • a basic condensing agent for example in the presence of an alkali alcoholate, such as sodium methylate or sodium ethylate.
  • the method according to 2. can be carried out at normal pressure or at elevated pressure, working at atmospheric pressure being the rule and increased pressure being used in particular in the case of reactions with ammonia.
  • the substances involved in the reaction are generally used in molar amounts, but - depending on the reaction condition - an excess (if desired, for example in ammonia in variants b and d) is also used can be.
  • reaction conditions are used as for variants a to f.
  • the reaction takes place in a manner known for the production of secondary or tertiary amines.
  • 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 XII.
  • a base e.g. an inorganic carbonate such as potassium carbonate
  • the enantiomerically pure compounds and their salts which are also the subject of the invention, are obtained, for example, by reacting the racemates obtained by the process described above with an enantiomerically pure optically active acid, separating the diastereomeric salts obtained, from the desired diastereomeric salts Enantiomers are released by adding base and, if desired, subsequently converted into their salts.
  • optically active acids examples include di-0, 0'-p-toluoyl tartaric acid or in particular di-0.0'-benzoyl tartaric acid. Recrystallization is preferably suitable as the separation process.
  • 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.
  • This process for the production of enantiomerically pure compounds is preferably used for the production of the enantiomerically pure dihydropyridines of embodiment a.
  • the enantiomerically pure compounds according to the invention are obtained by starting from enantiomerically pure intermediates.
  • the enantiomerically pure 1,4-dihydropyridines of the formula IX are particularly suitable here name, from which the desired enantiomerically pure end products according to the invention are obtained by reaction with the amine derivatives X - as described in process variant g. This route is preferably followed for the production of the enantiomerically pure dihydropyridines of embodiment b.
  • the isolation and purification of the substances according to the invention obtained after 1 or 2 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, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent.
  • Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
  • the starting compounds are known from the literature or can be prepared analogously to methods known from the literature.
  • the benzylidene carboxylic acid derivatives IIIa can be prepared, for example, in analogy to G. Jones ["The Knoevenagel Condensation” in Org. Reactions, Vol. XV, 204f (1967)].
  • the amidines IIa can be prepared according to H. Yamanaka et al., Heterocycles (1976), 1854.
  • the cinnamic acid derivatives Ilb and the benzylidenecarboxylic acid derivatives VI can be prepared, for example, in analogy to G. Jones ["The Knoevenagel Condensation” in Org. Reactions, Vol. XV, 204f (1967)].
  • the enamine derivatives IIIb and the enamines V are in for example analogous to AC Cope [J. Amer. Chem. Soc. 67, 1017 (1945)].
  • ß-Ketocarb ⁇ nklanderivate IV and keto compounds VII can according to D. Borrmann ["reaction of diketene with alcohols, phenols and mercaptans" in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 4, 230ff (1968)] or Y. Oikawa et al. [J. Org. Chem. 43, 2087 (1978)].
  • the compounds IX are accessible from corresponding starting compounds analogously to process variants a to f.
  • the enantiomerically pure 1,4-dihydropyridines IX required for the production of enantiomerically pure compounds are known from Chem. Pharm. Bull. 28, 2309 (1980) or can be obtained analogously thereto.
  • Compounds X can be obtained by reacting corresponding piperidines with omega-haloalkanols.
  • the dihydropyridine derivatives XI are obtained by reacting enamines of the formula V with, for example, appropriately substituted omega-halogen-2-acyl-acrylic acid esters, which in turn are accessible from aldehydes of the formula VIII and suitable beta-keto-omega-halo-gencarboxylic acid esters.
  • Mp Means melting point, h stands for hours, Kp. Stands for boiling point, dec. means decomposition.
  • the product fraction is concentrated, the residue is taken up in dichloromethane and mixed with ethereal hydrochloric acid. After the product solution has been concentrated again, the residue is dissolved in about 10 ml of dichloromethane and the title compound is amorphously precipitated by slowly dropping it into 500 ml of a well-stirred mixture of equal parts of diethyl ether and petroleum ether. Mp: 124-138 ° C, yield: 4.9 g.
  • Example 1 described the title compound as an amorphous powder, mp: 106-115 ° C (slow flow); Yield: 2.5 g.
  • Example 4 Analogously to Example 4, the title compound is obtained from 3.60 g of acetyl-3- (3-nitrophenyl) acrylic acid [5- (4,4-diphenylpiperidyl-1) pentyl] ester, 1.11 g of ethyl amidinoacetate hydrochloride and 0.153 g sodium in
  • Example 4 Analogously to Example 4, the title compound is obtained from 5.00 g of 2-acetyl-3- (2,3-dichlorophenyl) acrylic acid [3- (4,4-diphenylpiperidyl-1) propyl] ester, 1.55 g Amidinoacetic acid ethyl ester hydrochloride and 210 mg sodium in 25 ml abs. After transfer into the semifumarate, ethanol as hard, cubic crystals of mp: 191-93 ° C (from methanol / diethyl ether); Yield: 5.05 g.
  • Example 4 Analogously to Example 4, the title compound is obtained from 6.11 g of 2-acetyl-3- (4-benzo [c] [1.2.5] oxdiazolyl) acrylic acid- [3- (4,4-diphenylpiperidyl-1) -pro- pyl] ester, 2.01 g Amidinoessigêt Acideethylester hydrochloride and 276 mg sodium in 35 ml abs. Ethanol as fine yellowish crystal flakes, mp: 127-131 ° C (slow flow, from methanol / diethyl ether); Yield: 2.7 g.
  • Example 4 Analogously to Example 4, the title compound is obtained from 4.02 g of 2-acetyl-3- (2-chlorophenyl) acrylic acid- [3- (4,4-diphenylpiperidyl-1) -propyl] ester, 1.33 g of amidinoacetic acid ethyl ester. hydrochloride and 184 mg sodium in 50 ml abs. Ethanol as fine yellowish crystal platelets with a melting point of: 125-128 ° C. (from methanol / diethyl ether); Yield: 2.71 g.
  • Example 4 Analogously to Example 4, the title compound is obtained from 4.28 g of 2-acetyl-3- (2-trifluoromethylphenyl) acrylic acid [3- (4,4-diphenylpiperidyl-1) propyl] ester, 1.33 g of amidinoacetic acid ethyl ester. hydrochloride and 184 mg sodium in 40 ml abs. Ethanol as fine yellowish crystal platelets with a melting point of 115-117 ° C. (from methanol / diethyl ether), yield: 3.32 g. 11.
  • Example 4 Analogously to Example 4, the title compound is obtained from 4.98 g of 2-acetyl-3- (3-nitrophenyl) acrylic acid [2r (4,4-diphenylpiperidyl-1) ethyl] ester, 1.52 g of methyl amidinoacetate hydrochloride and 230 mg sodium in 40 ml abs. Methanol as a fine yellowish powder, mp: 110-116 ° C, slow flow (precipitated in petroleum ether / diethyl ether (2 + 1); yield: 3.12 g.
  • acetoacetic acid ⁇ 2- [2- (2- (4,4-diphenylpiperidyl-1) ethoxy) ethoxy] ethyl ⁇ ester is prepared in an analogous manner - starting from triethylene glycol monochlorohydrin and by prior reaction as described for C.
  • 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, strong and optimally sustained 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, 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 good controllability of the reduction in blood pressure, which - especially in the case of the compounds of embodiment a - surprisingly low heart rate increase compared to the compounds of the prior art, the excellent bioavailability, the large therapeutic breadth, the lack of central side effects, the lack of kinetic interactions with other substances, the lack of tolerance development, the balanced physical properties and the great stability.
  • the excellent activity of the compounds of 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 (brain stroke, temporary cerebral circulatory disorders, migraines, dizziness, renal Narrowing of the arteries etc.), hypertrophic cardiomyopathy, heart failure, diseases based on increased water and sodium retention and diseases based on increased calcium influx such as spasms of smooth muscle organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia, arteriosclerosis and Cell damage of different origins (e.g. hypoxia) can be considered.
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cerebral circulation disorders (brain stroke, temporary cerebral circulatory disorders,
  • 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 ingredient carriers for example antio-kidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives
  • 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, cardiotics, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dopamine stimulants, such as dopamine stimulants, such as nifedipine, hydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefruside, clo
  • 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 administered in the specified doses on four consecutive days on 6 male rats (strain SHR / N / Ibm / 8m, 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 blood flow and an annular piezo crystal sensor to record the pulse waves are pushed onto the tail.
  • the cuff pressure is continuously reduced. The return of the pulse waves during pressure relief is automatically recognized and printed out as systolic blood pressure (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat.
  • the animals are trained for 14 days before the substance test.
  • blood pressure pre-values are collected.
  • Groups of animals receiving substance are tested against a control group.
  • the connections examined are identified by consecutive numbers that correspond to the respective example numbers.
  • 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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Dihydropyridine de formule (I) dans laquelle R6 et R7 représentent conjointement, et y compris l'atome d'azote auquel ils sont tous deux liés, un résidu de formule (II), dans laquelle A est -CH2-C(R8)R9-CH2-; R8 est aryle et R9 est aryle, aryle représentant un composé cyclique de formule (III) dans laquelle R10 et R11 sont identiques ou différents et sont hydrogène, alkyle, alkoxy, halogène, hydroxy ou trifluorométhyle, et où soit E est alkylène, R2 amino et R3 alkyle ou alkoxyalkyle, soit E est A1-0-A2, R2 est hydrogène, alkyle ou alkoxyalkyle et R3 est hydrogène, alkyle ou alkoxyalkyle, A1 étant alkylène et A2 étant alkylène ou alkylèneoxy-alkylène. Sont également décrits les sels de ces composés, ainsi qu'un procédé pour leur production et leur utilisation comme médicaments.
EP87902503A 1986-04-22 1987-04-17 Dérivés de 1,4-Dihydropyridines Withdrawn EP0302871A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH163386 1986-04-22
CH1623/86 1986-04-22
CH1633/86 1986-04-22
CH162386 1986-04-22

Publications (1)

Publication Number Publication Date
EP0302871A1 true EP0302871A1 (fr) 1989-02-15

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ID=25688198

Family Applications (2)

Application Number Title Priority Date Filing Date
EP87105748A Pending EP0242829A1 (fr) 1986-04-22 1987-04-17 Dihydropyridines, leur procédé de préparation et leur application comme médicaments
EP87902503A Withdrawn EP0302871A1 (fr) 1986-04-22 1987-04-17 Dérivés de 1,4-Dihydropyridines

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Application Number Title Priority Date Filing Date
EP87105748A Pending EP0242829A1 (fr) 1986-04-22 1987-04-17 Dihydropyridines, leur procédé de préparation et leur application comme médicaments

Country Status (8)

Country Link
US (1) US5064839A (fr)
EP (2) EP0242829A1 (fr)
JP (1) JPH01500118A (fr)
AU (1) AU7390187A (fr)
IL (1) IL82294A (fr)
NZ (1) NZ220022A (fr)
PT (1) PT84732B (fr)
WO (1) WO1987006579A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1541188A (en) * 1987-03-27 1988-11-02 Byk Gulden Lomberg Chemische Fabrik Gmbh New optically active compounds
WO1988007525A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Enantiomeres de 1,4-dihydropyridine
EP0401256B1 (fr) * 1988-02-19 1993-05-26 Byk Gulden Lomberg Chemische Fabrik GmbH Dexniguldipine optiquement pure et ses derives pour traiter des affections tumorales
EP0506801A1 (fr) * 1989-12-22 1992-10-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles dihydropyridines
EP0616531A1 (fr) * 1991-12-13 1994-09-28 Byk Gulden Lomberg Chemische Fabrik GmbH Utilisation de la 1,4-dihydropyridine pour le traitement de dermatoses
GB9405833D0 (en) * 1994-03-24 1994-05-11 Pfizer Ltd Separation of the enantiomers of amlodipine
PL448416A1 (pl) 2024-04-25 2025-03-03 Uniwersytet Przyrodniczy W Lublinie Biostymulator roślinny
PL247048B1 (pl) 2024-04-25 2025-05-05 Univ Of South Bohemia In Ceske Budejovice Biostymulator roślinny i sposób jego wytwarzania

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849576A (en) * 1964-01-29 1974-11-19 Oreal Process and cosmetic compositions for the treatment of skin and scalp
US3849396A (en) * 1973-01-08 1974-11-19 Upjohn Co Lincomycin and clindamycin 1-o-ethers
US3852279A (en) * 1973-03-12 1974-12-03 Squibb & Sons Inc 7-substituted -3,3a,4,5,6,7-hexahydro-3-substituted-2h- pyrazolo (4,3-c)pyridines
GB1521471A (en) * 1974-06-05 1978-08-16 Randall & Son Ltd J Token-deposit locks
SE429652B (sv) * 1978-06-30 1983-09-19 Haessle Ab 2.6-dimetyl-4-(2.3-diklorfenyl)-1.4-dihydropyridin-3.5-dikarboxylsyra-3-metylester-5-etylester
EP0024638A1 (fr) * 1979-08-30 1981-03-11 Byk Gulden Lomberg Chemische Fabrik GmbH Acides quinoléinone alkylcarboxyliques substitués, leur préparation et médicaments les contenant
US4387219A (en) * 1979-11-13 1983-06-07 Sterling Drug Inc. 2-Hydroxy gentamicin compounds
US4603135A (en) * 1983-10-17 1986-07-29 Takeda Chemical Industries, Ltd. Substituted piperazinyl alkyl esters of 2-amino-4-aryl-1,4-dihydro-6-alkyl-3,5-pyridinedicarboxylates
US4755512A (en) * 1984-04-11 1988-07-05 Bristol-Myers Company Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moities
IL75400A (en) * 1984-06-16 1988-10-31 Byk Gulden Lomberg Chem Fab Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same
ATE107284T1 (de) * 1984-09-28 1994-07-15 Byk Gulden Lomberg Chem Fab Neue diarylverbindungen.
IL76839A (en) * 1984-10-31 1988-08-31 Byk Gulden Lomberg Chem Fab Picoline derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same
US4886819A (en) * 1986-08-27 1989-12-12 The Green Cross Corporation Dihydropyridine derivatives and pharmaceutical composition thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8706579A1 *

Also Published As

Publication number Publication date
PT84732A (de) 1987-05-01
AU7390187A (en) 1987-11-24
EP0242829A1 (fr) 1987-10-28
JPH01500118A (ja) 1989-01-19
US5064839A (en) 1991-11-12
WO1987006579A1 (fr) 1987-11-05
PT84732B (pt) 1989-12-29
IL82294A0 (en) 1987-10-30
NZ220022A (en) 1990-04-26
IL82294A (en) 1991-11-21

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