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WO1988007531A1 - Nouveaux composes optiquement actifs - Google Patents

Nouveaux composes optiquement actifs Download PDF

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Publication number
WO1988007531A1
WO1988007531A1 PCT/EP1988/000240 EP8800240W WO8807531A1 WO 1988007531 A1 WO1988007531 A1 WO 1988007531A1 EP 8800240 W EP8800240 W EP 8800240W WO 8807531 A1 WO8807531 A1 WO 8807531A1
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Prior art keywords
methyl
dimethyl
dihydro
pyridine
denotes
Prior art date
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PCT/EP1988/000240
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German (de)
English (en)
Inventor
Wolf-Rüdiger Ulrich
Dieter Flockerzi
Karl Sanders
Norbert Kolassa
Kurt Klemm
Hermann Amschler
Manfrid Eltze
Christian Schudt
Klaus Eistetter
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Takeda GmbH
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Byk Gulden Lomberg Chemische Fabrik GmbH
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    • 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
    • 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 optically active compounds, 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.
  • 1,4-dihydropyridine derivatives substituted in the 4-position have pharmacologically useful properties. It is also known that these 1,4-dihydropyridine derivatives - provided they are substituted differently (asymmetrically) in positions 2 and 6 and / or in positions 3 and 5 - have a chiral center in position 4. It is also known that the pharmacological properties of 1,4-dihydropyridines can be influenced by the absolute configuration in the 4-position. Due to these different pharmacological properties, various attempts have been made to produce enantiomerically pure 1,4-dihydropyridines [see e.g. DE-OS 2935451, DE-OS 3320616, EP-A2 0166296, Shibaruma et al. Chem. Pharm. Bull. 28: 2809 (1980)].
  • the invention relates to optically active dihydropyridines of the formula I.
  • R1 and R2 are the same or different and are hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,
  • R3 denotes 1-6C-alkyl or 3-7C-alkoxyalkyl
  • R4 and R5 are the same or different and are hydrogen, hydroxy, halogen,
  • A denotes -CH 2 -C (R6) R7-CH 2 - or -CH 2 -NR8-CH 2 -,
  • R6 is hydrogen (H) or aryl
  • R7 denotes aryl or arylcarbonyl
  • R8 aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4C-alkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1 -4C-alkyl, diheteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenyl carbonyl, where Aryl for a ring of the formula
  • R9 and R10 are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and
  • Heteroaryl is a 5- or 6-membered heterocycle with one or two identical or different heteroatoms from the group consisting of oxygen (O), sulfur (S) or nitrogen (N), which is unsaturated or partially or completely saturated and one or two Can carry substituents from the group 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl or cyan, 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-l-methyl ethyl, 2-ethoxy-1-methyl ethyl 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 ethoxycarbonyl radicals 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 R9 and R10.
  • 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-ethoxyphenyl , 2-methylphenyl, 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 3,6-dichlorophenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,4-methylenedioxyphenyl, 2 -Trifluoromethylphenyl and 3-trifluoromethylphenyl.
  • Aryl-1-4C-alkyl stands for 1-4C-alkyl which is substituted by aryl.
  • aryl The following are mentioned as exemplary preferred aryl-1-4C-alkyl radicals: 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 1-phenethyl, 2-phenylethyl, 3-chlorobenzyl, 2,5-dimethylbenzyl, 4-fluorobenzyl, 3 -Methylbenzyl and especially benzyl.
  • Aryl-2-4C-alkenyl and aryl-2-4C-alkynyl are alkenyl and alkynyl radicals having 2 to 4 carbon atoms which are substituted by aryl. Examples include the 3-phenyl-2-propenyl radical and the 3-phenyl-2-propynyl radical.
  • Arylcarbonyl stands for a carbonyl group which is substituted by aryl.
  • arylcarbonyl groups are 4-chlorophenylcarbonyl, 2-hydroxyphenylcarbonyl (salicyloyl), 4-hydroxyphenyl carbonyl and in particular 4-fluorophenylcarbonyl and benzoyl groups.
  • Examples of preferred (substituted) heteroaryl radicals are the radicals: furyl, in particular 2-furyl, thienyl, in particular 2-thienyl, pyrimidyl, in particular 2-pyrimidyl, 3-cyano-2-pyridyl, thiazolyl, in particular 2-thiazolyl and pyridyl, especially 3-pyridyl and preferably 2-pyridyl.
  • Heteroaryl carbonyl stands for a carbonyl group which is substituted by heteroaryl.
  • the nicotinoyl and 2-furoyl radicals may be mentioned as exemplary preferred heteroarylcarbonyl radicals.
  • Heteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl.
  • Heteroaryl-1-4C-alkyl is, for example, 2- (2-pyridyl) ethyl.
  • Diaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two aryl radicals. Diaryl-1-4C-alkyl is especially diphenylmethyl (benzhydryl), or substituted benzhydryl, e.g. 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl, 4,4'-dimethoxybenzhydryl or 4,4'Dichlorbenzhydryl.
  • Heteroaryl-aryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl and aryl.
  • Heteroaryl-aryl-1-4C-alkyl is, for example, 2-pyridylphenylmethyl.
  • Di-heteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two heteroaryl radicals.
  • Di-heteroaryl-1-4C-alkyl is, for example, di-pyrid-2-yl-methyl.
  • Arylsulfonyl stands for a sulfonyl group which is substituted by aryl.
  • the phenylsulfonyl, the 4-chlorophenylsulfonyl and the 4-methoxyphenylsulfonyl radical may be mentioned as exemplary preferred arylsulfonyl radicals.
  • the aryl-1-4C-alkylcarbonyl radical may be mentioned, for example, the 2-phenylpropionyl radical.
  • the cinnamoyl radical may be mentioned as an aryl-2-4C-alkenylcarbonyl radical.
  • All 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 arise 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.
  • Preferred objects of the invention are optically active compounds of formula I, wherein
  • R1 and R2 are identical or different and mean 1-4C-alkyl, R3 means 1-4C-alkyl, E means vinylene or ethynylene, m means the number 1, n means the number 1,
  • A means -CH 2 -C (R6) R7-CH 2 - or -CH 2 -NR8-CH 2 -, R6 means phenyl, R7 means phenyl, R8 means aryl or benzhydryl, where aryl represents a ring of the formula
  • R9 and R10 are the same or different and are hydrogen (H), 1-4C-alkoxy or halogen, and the salts of these compounds.
  • One embodiment (embodiment a) of the invention are optically active compounds of the formula I, in which Cy, R1, R2, R3, R4, R5, E, m and n have the meanings mentioned above, A -CH 2 -C (R6) R7 -CH 2 - means R6 means hydrogen (H) and
  • R7 means aryl or aryl carbonyl, where aryl has the meaning given above, and the salts of these compounds.
  • R1 means methyl
  • R2 means methyl
  • R3 means methyl
  • E denotes vinylene or ethynylene
  • m denotes the number 1
  • n denotes the number 1
  • R6 means hydrogen
  • R7 means phenyl, and their salts. The following may be mentioned as exemplary, particularly noteworthy connections of embodiment a:
  • a further embodiment (embodiment b) of the invention are optically active compounds of the formula I, in which Cy, R1, R2, R3, R4, R5, E, m and n have the meanings mentioned above,
  • a -CH 2 -NR8-CH 2 - means
  • R8 aryl, aryl-1-4C-alkyl, aryl-2-4C-alkenyl, aryl-2-4C-alkynyl, diaryl-1-4Calkyl, heteroaryl, heteroaryl-1-4C-alkyl, heteroaryl-aryl-1-4C -alkyl, di heteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, where aryl and heteroaryl have the meanings given above, and the salts of these compounds .
  • R1 means methyl
  • R2 means methyl
  • R3 denotes methyl or ethyl
  • E denotes vinylene or ethynylene and m denotes the number 1, n denotes the number 1,
  • R8 phenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, benzhydryl or 2-pyridyl, and their salts.
  • Cy 3-nitrophenyl means, R1 means methyl, R2 means methyl, R3 means methyl or ethyl, E means vinylene or ethynylene, m means the number 1, n means the number 1 and
  • R8 represents phenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl or benzhydryl, and their salts.
  • a further embodiment (embodiment c) of the invention are optically active compounds of the formula I, in which Cy, R1, R2, R3, R4, R5, E, m and n have the meanings mentioned above, A -CH 2 -C (R6) R7-CH 2 - means, R6 means aryl and
  • R7 means aryl, where aryl has the meaning given at the outset, and the salts of these compounds.
  • Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
  • R1 means methyl
  • R2 means methyl
  • R3 denotes methyl or ethyl
  • E denotes vinylene or ethynylene
  • m denotes the number 1
  • n denotes the number 1
  • R6 represents phenyl or 4-methoxyphenyl
  • R7 means phenyl or 4-methoxyphenyl, and their salts.
  • R1 means methyl
  • R2 means methyl
  • R3 denotes methyl or ethyl
  • E denotes vinylene or ethynylene
  • m denotes the number 1
  • n denotes the number 1
  • R6 is phenyl and R7 is phenyl, and their salts.
  • the invention relates both to the enantiomerically pure compounds of the formula I and to their mixtures and racemates.
  • the invention further relates to a process for the preparation of the compounds according to the invention and their salts.
  • the process is characterized in that optically active N-protected dihydropyridinecarboxylic acids of the formula II
  • R1, R2, R3 and Cy have the meanings given above and SG represents a protective group, with an omega-dihaloalkene or -alkyne Hal- (CH 2 ) m -E- (CH 2 ) n -Hal, in which shark means halogen and E, m and n have the meanings given at the outset and, after the protective group SG has been split off, the halogen ester III obtained
  • Preferred omega-dihaloalkenes or alkynes are 1,4-dihalo-2-butenes and 1,4-dihalo-2-butynes, in particular 1,4-dichloro-2-butene and 1,4-dichloro-2-butyne .
  • phase ethers such as dibenzo [18] crown-6, dicyclohexyl- [18] crown-6 and in particular [18] crown-6 may be mentioned as phase transfer catalysts.
  • 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 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 in the reaction of II with dihaloalkenes or alkynes depends on the other reaction conditions, temperatures between 20 ° C. and the boiling point of the solvent used being generally preferred.
  • Protective groups SG are, in particular, those groups which can be introduced easily and in high yields into the precursor on which compound II is based, which do not undergo any side reactions when reacting II with dihaloalkenes or -alkynes and which in the end split off smoothly again can be.
  • Preferred protective groups SG are, for example, alkoxymethyl groups or benzyloxymethyl groups, in particular the ethoxymethyl group.
  • the protective group is split off in an acidic medium, for example in 1N hydrochloric acid or preferably in anhydrous formic acid, under reaction conditions as are known to the person skilled in the art.
  • the halogen esters III are reacted with amines IV in a manner familiar to the person skilled in the art for the reaction of alkyl halides with secondary amines.
  • the reaction is carried out in suitable, preferably inert, organic solvents in the presence of water or without water.
  • suitable, preferably inert, organic solvents include ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether; Ketones such as acetone or ethyl methyl ketone; aromatic hydrocarbons such as xylene or toluene; or chlorinated hydrocarbons such as methylene chloride, chloroform, tetrachlorethylene or dichloroethane; or polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide.
  • 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 normal pressure or at elevated pressure, with working at normal pressure being the rule.
  • the reaction is carried out in the presence of a base (e.g. an inorganic carbonate such as potassium carbonate or an organic amine such as diisopropylethylamine) or using an excess of amine IV.
  • a base e.g. an inorganic carbonate such as potassium carbonate or an organic amine such as diisopropylethylamine
  • the isolation and purification of the compounds I 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, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), or an open-chain or cyclic ether, such as dioxane or tetrahydrofuran, which contains the desired acid, or to which the desired acid is then added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • an open-chain or cyclic ether such as dioxane or tetrahydrofuran
  • Salts 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.
  • pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
  • the new compounds III are also the subject of the invention.
  • the optically active compounds of the formula II are known in some cases [Chem. Pharm. Bull. 28 (9) 2809-2812 (1980)], partly new. You can in a known manner [Chem. Pharm. Bull. 28 (9) 2809-2812 (1980)] or by a new process.
  • the procedure is expediently such that the haloethyl ester V is deprotonated in the 1 position and then reacted with a compound SG-X, where X stands for a suitable escape group.
  • the deprotonating agents that can be used are those agents for which the acidity of the proton on the nitrogen is high enough to achieve anion formation.
  • metal hydrides in particular sodium hydride, should preferably be mentioned.
  • the escape group X of the compound SG-X is a group which is easily split off when SG-X is reacted with the deprotonated V.
  • X is preferably a halogen atom, in particular a chlorine atom.
  • the deprotonation and subsequent introduction of the protective group is carried out in inert, anhydrous solvents, as are suitable for working with strong deprotonating agents.
  • inert, anhydrous solvents include open-chain or cyclic ethers such as diethyl ether, dioxane or tetrahydrofuran.
  • the reaction is preferably carried out under mild reaction conditions at temperatures around or below 0 ° C.
  • Residues that can have a mesomeric electron-attracting effect are particularly suitable as acceptor residues in the further implementation.
  • examples include the nitro group or the azido group, preferably the nitrile group or a substituted sulfonyl group.
  • the halogen exchange in the N-protected haloethyl ester of the formula VI is preferably carried out by reaction with salts whose anions are suitable for functioning as covalently bound acceptor substituents.
  • reaction with inorganic cyanides in particular with potassium cyanide or sodium cyanide, or the reaction with alkali metal sulfinates, in particular with sodium 4-toluenesulfinate, if desired with the addition of catalytic amounts of a quaternary ammonium salt, such as, for example, teträbutylammonium cyanide or benzyltriethyl ammonium chloride, is preferred in inert, preferably aprotic , polar solvents such as
  • the cleavage of the acceptor ethyl residue under basic conditions following the halogen exchange is a reaction familiar to the person skilled in the art, as is e.g. is described in DE-OS 2847237.
  • the compound II which is initially obtained as a racemate, can be separated in a conventional manner via the diastereomeric salts into the enantiomers (+) - II and (-) - II using enantiomerically pure, optically active bases [see e.g. Chem. Pharm. Bull. 28, 2809 (1980)] [1]. Cinchonidine and cinchonine are particularly enantiomerically pure optically active bases.
  • haloethyl esters V used as starting compounds are e.g. known from DE-OS 2847237.
  • Mp Means melting point, h stands for hours, Kp. Stands for boiling point, dec. means decomposition.
  • Ether is understood to mean diethyl ether.
  • the formic acid is distilled off in vacuo, the residue is dissolved in 30 ml of dichloromethane, the solution is extracted with sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to about half. After adding about 60 to 70 ml of diisopropyl ether, the dichloromethane is further distilled off in vacuo, a solid precipitating out, which is filtered off with suction, washed with diisopropyl ether, dried and reacted further without further purification.
  • Fumaric acid is transferred to the fumarate. After crystallization from 2-propanol, 2.6 g of the title compound of mp 172-174 ° C (dec.) And
  • the mother liquor is evaporated to dryness in vacuo, the residue is dissolved in 2 l of chloroform and, after the addition of 1 l of water, vigorous stirring is carried out by adding 2N hydrochloric acid and adding a stable pH of 2 to 3.
  • the phases are separated, the organic phase is shaken with 0.01N hydrochloric acid until cinchonidine is no longer detectable (thin layer chromatography), washed with water and dried.
  • the residue is dried under high vacuum and 85.6 g of it, together with 54.5 g of cinchonine, are dissolved in about 2.4 l of boiling ethanol.
  • the product which crystallized out after standing at room temperature for 3 days is filtered off with suction, washed with ethanol and recrystallized again from ethanol. You get
  • 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 coronartherapeuti properties.
  • the pharmacological activity of the compounds according to the invention which is paired with a low toxicity, is particularly evident in a slowly occurring, strong and long-lasting reduction 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.
  • the advantageous properties of the compounds I include, for example, the extent of the reduction in blood pressure, the prolonged persistence of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly low and disappearing heart rate increase after repeated administration, the excellent bioavailability, the large therapeutic range, the lack of a central one 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 (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 of smooth muscular organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia, arteriosclerosis and cell damage of various origins (eg hypoxia).
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cerebral circulation disorders stroke, temporary cerebral circulatory disorders, migraines, dizziness,
  • Another object of the invention is therefore a method for the treatment of mammals, especially humans, who are suffering from one of the above-mentioned diseases.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I.
  • the invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
  • the invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, 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 individuals administered to achieve the desired result.
  • 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.
  • 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, antihistimulants, seropotinininators, dopaminotiners etc., such as nifedipine, dihydrazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefrus
  • 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 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 blood flow and an annular Piezokriri sensor is pushed onto the tail to detect the pulse waves.
  • 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 checked against a control group.
  • the examined compounds are identified by lapping numbers that match 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des dihydropyridines optiquement actives de formule (I) dans laquelle les substituants et les symboles ont les notations indiquées dans la description, sont de nouveaux composés présentant des propriétés pharmacologiques étonnantes.
PCT/EP1988/000240 1987-03-27 1988-03-24 Nouveaux composes optiquement actifs Ceased WO1988007531A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1185/87-9 1987-03-27
CH118587 1987-03-27

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WO1988007531A1 true WO1988007531A1 (fr) 1988-10-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990009376A1 (fr) * 1989-02-17 1990-08-23 Boehringer Mannheim Italia S.P.A. Procede servant a la preparation de 1,4-dihydorpyridines polysubstituees enantiomeriquement pures
EP0403957A3 (fr) * 1989-06-17 1992-01-22 Fujirebio Inc. Dérivés optiquement actifs de la 1,4-dihydropyridine
DE4041814A1 (de) * 1990-12-24 1992-07-02 Byk Gulden Lomberg Chem Fab Verfahren zur herstellung von dihydrophyridincarbonsaeuren
US5286869A (en) * 1988-12-15 1994-02-15 Fujirebio Kabushiki Kaisha 1,4-dihydropyridine derivatives

Citations (8)

* 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
GB2142021A (en) * 1983-06-21 1985-01-09 Sandoz Ltd 1 4-dihydropyridine derivatives their preparation and pharmaceutical compositions containing them
EP0166296A2 (fr) * 1984-06-22 1986-01-02 Bayer Ag Procédé de préparation de 1,4-dihydropyridines optiquement actives
EP0174654A2 (fr) * 1984-09-14 1986-03-19 Ciba-Geigy Ag Dérivés carbonyles
EP0176956A2 (fr) * 1984-09-28 1986-04-09 Byk Gulden Lomberg Chemische Fabrik GmbH Composés diaryliques
WO1986003748A1 (fr) * 1984-12-21 1986-07-03 Byk Gulden Lomberg Chemische Fabrik Gesellschaft M Nouveaux derives de piperazine
EP0242829A1 (fr) * 1986-04-22 1987-10-28 Byk Gulden Lomberg Chemische Fabrik GmbH Dihydropyridines, leur procédé de préparation et leur application comme médicaments

Patent Citations (8)

* 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
GB2142021A (en) * 1983-06-21 1985-01-09 Sandoz Ltd 1 4-dihydropyridine derivatives their preparation and pharmaceutical compositions containing them
EP0166296A2 (fr) * 1984-06-22 1986-01-02 Bayer Ag Procédé de préparation de 1,4-dihydropyridines optiquement actives
EP0174654A2 (fr) * 1984-09-14 1986-03-19 Ciba-Geigy Ag Dérivés carbonyles
EP0176956A2 (fr) * 1984-09-28 1986-04-09 Byk Gulden Lomberg Chemische Fabrik GmbH Composés diaryliques
WO1986003748A1 (fr) * 1984-12-21 1986-07-03 Byk Gulden Lomberg Chemische Fabrik Gesellschaft M Nouveaux derives de piperazine
EP0242829A1 (fr) * 1986-04-22 1987-10-28 Byk Gulden Lomberg Chemische Fabrik GmbH Dihydropyridines, leur procédé de préparation et leur application comme médicaments

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5286869A (en) * 1988-12-15 1994-02-15 Fujirebio Kabushiki Kaisha 1,4-dihydropyridine derivatives
WO1990009376A1 (fr) * 1989-02-17 1990-08-23 Boehringer Mannheim Italia S.P.A. Procede servant a la preparation de 1,4-dihydorpyridines polysubstituees enantiomeriquement pures
EP0403957A3 (fr) * 1989-06-17 1992-01-22 Fujirebio Inc. Dérivés optiquement actifs de la 1,4-dihydropyridine
DE4041814A1 (de) * 1990-12-24 1992-07-02 Byk Gulden Lomberg Chem Fab Verfahren zur herstellung von dihydrophyridincarbonsaeuren
US5475111A (en) * 1990-12-24 1995-12-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Process for the preparation of dihydropyridinecarboxylic acids

Also Published As

Publication number Publication date
AU1541188A (en) 1988-11-02

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