Classifications

• • 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
• • 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
• • 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
  • 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 enantiomers, 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 pharmaceuticals.
• 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 differently (asymmetrically) substituted 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.
• the invention thus relates in a first aspect to enantiomerically pure dihydropyridines of the formula I.
• R1 and R2 are identical 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,
• E denotes straight-chain or branched 2-5C-alkylene, which can be substituted by 1-4C-alkoxy or aryl;
• A denotes -CH 2 -C (R6) R7-CH 2 - or -CH 2 -NR8-CH 2 -, R6 is hydrogen (H) or aryl and
• 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, di-heteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, where
• R9 and R10 are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and heteroaryl for a 5- or 6-membered heterocycle one or two identical or different heteroatoms from the group oxygen (O), sulfur (S) or nitrogen (N), which is unsaturated or partially or completely saturated and which has one or two substituents from the group 1-4C-alkyl, 1 -4C-alkoxy, halogen, trifluoromethyl or cyan, and the salts of these compounds, excluding the (S) -enantiomer of the compound, in which Cy is 3-nitrophenyl, R1, R2 and R3 is methyl, E Propylene means A is CH 2 -C (R6) R7-CH 2 and R6 and R7 are phenyl.
• 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-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.
• Straight-chain or branched 2-5C-alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 2,2-dimethylihylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and in particular ethylene or propylene.
• Aryl represents phenyl substituted by R9 and R10.
• preferred aryl radicals which may be mentioned are: 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.
• the following are mentioned as exemplary preferred aryl-1-4C-alkyl residues: 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-hydroxyphenylcarbonyl 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.
• Heteroarylcarbonyl stands for a carbonyl group which is substituted by heteroaryl.
• Examples of preferred heteroarylcarbonyl radicals are the nicotinoyl and the 2-furoyl radical.
• 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-alkyl carbonyl radical may be mentioned, for example, the 2-phenylpropionyl radical.
• the aryl-2-4C-alkenyl carbonyl radical may be mentioned, for example, the cinnamoyl radical.
• 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.
• the invention thus relates to new, for the first time isolated or isolatable enantiomerically pure 1,4-dihydropyridines of the formula I.
• Preferred objects of the invention are enantiomerically pure compounds of
• Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl
• R1 and R2 are identical or different and denote 1-4C-alkyl
• R3 means 1-4C-alkyl
• E means ethylene or propylene
• A denotes -CH 2 -C (R6) R7-CH 2 - or -CH 2 -NR8-CH 2 -,
• R6 represents hydrogen (H) or phenyl
• R7 means phenyl
• R8 means aryl or benzhydryl
• Aryl for a ring of the formula stands in which R9 and R10 are the same or different and the meaning
• An embodiment (embodiment a) of the invention are enantiomerically pure compounds of the formula I, in which Cy, R1, R2, R3, R4, R5 and E have the meanings mentioned at the outset, A -CH 2 -C (R6) R7-CH 2 - means R6 means hydrogen (H) and
• R7 means aryl or arylcarbonyl, where aryl has the meaning given at the outset, and the salts of these compounds.
• Cy means 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
• R1 means methyl or ethyl
• R2 means methyl or ethyl
• R3 denotes methyl or ethyl
• E means ethylene or propylene
• R6 means hydrogen
• R7 means phenyl, benzoyl, 4-chlorobenzoyl or 4-fluorobenzoyl, and their salts.
• Particularly preferred compounds of embodiment a are those of the formula Ia, in which
• Cy 3-nitrophenyl means, Rl means methyl, R2 means methyl, R3 means methyl, E means ethylene or propylene, R6 means hydrogen and R7 means phenyl, and their salts.
• a further embodiment (embodiment b) of the invention are enantiomerically pure compounds of the formula I in which Cy, R1, R2, R3, R4, R5 and E have the meanings mentioned above, A denotes -CH 2 -NR8-CH 2 -,
• 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, di heteroaryl-1-4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, Aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl means, where aryl and heteroaryl have the meanings given above, and the salts of these compounds.
• Cy means 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl,
• R1 means methyl or ethyl
• R2 means methyl or ethyl
• R3 denotes methyl or ethyl
• E means ethylene or propylene
• R1 means methyl
• R2 means methyl
• R3 means methyl
• E means ethylene or propylene
• R8 phenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-ethoxy-4-fluorophenyl or
• a further embodiment (embodiment c) of the invention are enantiomerically pure compounds of the formula I in which
• Cy, R1, R2, R3, R4, R5 and E have the meanings mentioned at the outset
• A denotes -CH 2 -C (R6) R7-CH 2 -
• R6 denotes aryl and R7 means aryl, where aryl has the meaning given above, and the salts of these compounds, excluding the (S) -enantiomer of the compound, in which Cy has the meaning 3-nitrophenyl, R1, R2 and R3 means methyl, E propylene means and R6 and R7 are phenyl.
• Cy means 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 2,3-methylenedioxyphenyl or benzoxdiazolyl, R1 means methyl or ethyl, R2 means methyl or ethyl, R3 means methyl or ethyl E is ethylene or propylene, R6 is phenyl or 4-methoxyphenyl and R7 is phenyl or 4-methoxyphenyl, and their salts, excluding the (S) -enantiomer of the compound in which Cy is 3-nitrophenyl, R1, R2 and R3 are methyl, E is propylene and R6 and R7 are phenyl.
• Cy means 3-nitrophenyl or 2,3-dichlorophenyl
• R1 means methyl
• R2 means methyl
• R3 means methyl or ethyl
• E is ethylene or propylene
• R6 is phenyl and R7 is phenyl
• their salts excluding the (S) -enantiomer of the compound in which Cy is 3-nitrophenyl, R1, R2 and R3 is methyl, E is propylene and R6 and R7 are phenyl.
• the invention further relates to a process for the preparation of the compounds of the formula I.
• R1 and R2 are the same or different and are hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl,
• R3 is 1-6C-alkyl or 3-7C-alkoxyalkyl.
• R4 and R5 are the same or different and are hydrogen, hydroxy, halogen,
• E denotes straight-chain or branched 2-5C-alkylene, which can be substituted by 1-4C-alkoxy or aryl,
• A is -CH 2 -C (R6)
• R7-CH 2 - or -CH 2 -NR8-CH 2 - means R6 is hydrogen (H) or aryl and R7 is aryl or arylcarbonyl
• R8 is 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, di-heteroaryl-1 -4C-alkyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, aryl-1-4C-alkylcarbonyl or aryl-2-4C-alkenylcarbonyl, where
• R9 and R10 are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and heteroaryl for a 5- or 6-membered heterocycle with one or two identical or different heteroatoms from the group oxygen (O), Sulfur (S) or nitrogen (N), which is unsaturated or partially or fully saturated and which can carry one or two substituents from the group 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl or cyano, and their Salts.
• O oxygen
• S sulfur
• N nitrogen
• the reaction of II with omega-dihaloalkanes is preferably carried out under basic conditions in the presence of a phase transfer catalyst.
• omega-dihaloalkanes preference is given to mentioning 1,2-dihaloethanes and 1,3-dihalopropanes, in particular 1,2-dibromoethane and 1,3-dibromopropane.
• crown ethers such as dibenzo [18] crown-6, dicyclohexyl [18] crown-6 and in particular [18] crown-6 mentioned.
• Suitable bases which are used at least in a molar ratio, preferably in excess, are inorganic bases, such as alkali metal hydroxides (e.g. sodium or potassium hydroxide), or in particular alkali metal carbonates (e.g. sodium or preferably potassium carbonate).
• alkali metal hydroxides e.g. sodium or potassium hydroxide
• alkali metal carbonates e.g. 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.
• 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 dihaloalkanes and which can be smoothly cleaved off at the end.
• 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. According to the invention, the protective group can also be split off after the reaction with the amine IV.
• 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 using an excess of amine IV.
• a base e.g. an inorganic carbonate such as potassium carbonate
• amine IV an excess of amine IV.
• the isolation and purification of the compounds I according to the invention obtained is carried out in a manner known per se, for. B. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or one of the usual cleaning methods, such as for example, subject to column chromatography on a suitable support 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), or an open-chain or cyclic ether, such as dioxane or tetrahydrofuran, which the 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.
• Refinements of the method are those in which the substituents and symbols have the meanings mentioned for the compounds of refinements a, b and c. Processes to be emphasized, preferred and particularly preferred are those in which the substituents and symbols have the meanings given for the preferred and particularly preferred compounds to be emphasized.
• 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.
• organometallic compounds such as butyllithium
• metal hydrides in particular sodium hydride
• 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.
• 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 described, for example, in DE-OS 2847237.
• the compound II which is initially obtained as a racemate, can be separated with the aid of enantiomerically pure, optically active bases in a conventional manner via the diastereomeric salts into the enantiomers (+) - II and (-) - II [see, for example, Chem. Pharm. Bull. 23, 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 in 20 ml of dichormethane dissolved and the solution washed with sodium bicarbonate solution and water, dried over sodium sulfate and concentrated. The residue is dried under high vacuum.
• the solid foam (1.2 g) is treated with 0.68 g of 4,4-diphenylpiperidine hydrochloride and 1 g of potassium carbonate in one Mixture of 15 ml of toluene and 5 ml of water heated to boiling for 21 h. After cooling, the phases are separated. The organic phase is washed twice with water and concentrated.
• the residue is chromatographed on a silica gel column using chloroform / ethanol 95: 5 as the eluent.
• the product When standing at room temperature, the product crystallizes spontaneously or after seeding or rubbing; it is suction filtered after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80-100 ° C.
• the crude product is dissolved in dichloromethane for cleaning. After adding 800 ml of dioxane, the dichloromethane is distilled off again. After inoculating and standing for 16 hours
• 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
• Methyl 3-aminocrotonic esters are dissolved in 1750 ml of isopropanol at 75-80 ° C with stirring and under a nitrogen atmosphere. The mixture is then cooled very slowly in the heating bath. After inoculating with the title link
• the oily residue is dissolved in 600 ml of tetrahydrofuran and the solution is mixed with 33 g of methyl 3-aminocrotonate.
• the mixture is heated to boiling under nitrogen for 24 hours, after cooling the solvent is distilled off in vacuo, the residue is dissolved in dichloromethane and the solution is washed with 0.01N hydrochloric acid and water. After drying over sodium sulfate, the mixture is concentrated again.
• the semi-crystalline residue is 150 ml
• Chloroform ⁇ (prepared from ( ⁇ ) 1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid and cinchonine analogous to Example 1 B) dissolved in 1.5 l of dichloromethane and then mixed with cooling and vigorous stirring with 1.2 l of 0.2 N hydrochloric acid solution. A stable pH of 2 is set in the aqueous phase by adding 2N hydrochloric acid solution. After phase separation, the organic phase is washed four more times with hydrochloric acid solution of pH 2 and then with water, dried over sodium sulfate and concentrated.
• the enantiomerically pure compounds of the formula I and their salts produced by the process according to the invention have valuable properties which make them commercially usable. They are, for example, effective vasodilators with coronary therapeutic properties.
• the pharmacological activity of the compounds according to the invention which is paired with a low toxicity, is evident, for example, in a slowly occurring, strong and long-lasting 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, corona r, cerebral and renal vasodilator and salidiuretic, antithrombotic, antiarteriosclerotic and favorable hemorheological properties.
• the enantiomers of the invention differ surprisingly and advantageously from their racemates in their excellent activity, which is paired with a low toxicity and the absence of significant side effects.
• the fact that the enantiomers according to the invention which have the same configuration in the 4-position of the dihydropyridine as the (-) - 1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl- usable as a preliminary product is particularly surprising.
• the enantiomers which are particularly effective in the main action on the one hand the load due to their less effective stereoisomers, which in some cases can even have opposite effects or increased side effects, is significantly reduced.
• the enantiomers which are weaker in the main activity mentioned above can be used for other therapeutic purposes which were not previously accessible to this class of substances, owing to the main activity predominating in the racemates.
• the advantageous properties of the compounds I include, for example: the extent of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly small heart, which disappears after repeated administration frequency increase, the excellent bioavailability, the great 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, the indication being, for example, primary (essential) and secondary, arterial and pulmonary hypertension of all degrees of severity, coronary heart disease (coronary insufficiency, angina pectoris, myocardial infarction, etc.), 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 calcium influx, 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 (e.g. hypoxia) can be considered.
• coronary heart disease coronary insufficiency, angina pectoris, myocardial infarction, etc.
• peripheral and cerebral circulation disorders stroke, temporary cerebral circulatory disorders, migraine
• 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.
• solvents gel formers, suppository bases, tablet excipients and other active ingredients, antioxidants, dispersants, emulators, defoamers, taste correctors, preservatives, solubilizers, dyes or, in particular, permeation promoters and complexing agents (e.g. 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, antihistamines, dop amine stimulators, serotonin receptor blockers etc., such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefrusid, clo
• other vasodilators such as other vasodilators, antihypertensives
• the antihypertensive activity of the compounds according to the invention can be demonstrated on the model of the spontaneously hypertensive rat.
• the compounds listed below are used 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 .: 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.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Cardiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Heart & Thoracic Surgery (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Hydrogenated Pyridines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (4)

Publications (1)

Family

ID=25686924

Family Applications (2)

Family Applications After (1)

Country Status (8)

Families Citing this family (19)

Family Cites Families (18)

• 1988
  • 1988-03-24 EP EP88903212A patent/EP0343193A1/de active Pending
  • 1988-03-24 AU AU16264/88A patent/AU1626488A/en not_active Abandoned
  • 1988-03-24 DE DE88104691T patent/DE3883627D1/de not_active Expired - Fee Related
  • 1988-03-24 US US07/401,453 patent/US4994461A/en not_active Expired - Fee Related
  • 1988-03-24 WO PCT/EP1988/000239 patent/WO1988007525A1/de not_active Application Discontinuation
  • 1988-03-24 JP JP63503484A patent/JP2625190B2/ja not_active Expired - Lifetime
  • 1988-03-24 ES ES88104691T patent/ES2059416T3/es not_active Expired - Lifetime
  • 1988-03-24 EP EP88104691A patent/EP0296316B1/de not_active Expired - Lifetime
• 1991
  • 1991-12-20 CZ CS913965A patent/CZ281597B6/cs unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events