WO1988002750A1 - 1,4-dihydropyridine - Google Patents

1,4-dihydropyridine Download PDF

Info

Publication number
WO1988002750A1
WO1988002750A1 PCT/EP1987/000597 EP8700597W WO8802750A1 WO 1988002750 A1 WO1988002750 A1 WO 1988002750A1 EP 8700597 W EP8700597 W EP 8700597W WO 8802750 A1 WO8802750 A1 WO 8802750A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
carboxylic acid
dihydro
ester
nitrophenyl
Prior art date
Application number
PCT/EP1987/000597
Other languages
German (de)
French (fr)
Inventor
Wolf-Rüdiger Ulrich
Hermann Amschler
Klaus Eistetter
Manfrid Eltze
Dieter Flockerzi
Kurt Klemm
Norbert Kolassa
Karl Sanders
Christian Schudt
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 WO1988002750A1 publication Critical patent/WO1988002750A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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

Definitions

  • the invention relates to new 1,4-dihydropyridines, 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 1,4-dihydropyridines of the formula I.
  • R1 and R2 are the same or different and are hydrogen, 1-6C-alkyl or
  • Ar is a cycle of the formula
  • R3 means 1-SC-alkyl
  • 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,
  • A represents CH 2 (methylene), O (oxygen), S (sulfur) or substituted methylene of the formula C (R6) R7, in which
  • R6 is hydrogen or 1-6C-alkyl and R7 denotes 1-6C-alkyl, 1-4C-alkoxy, aryl or heteroaryl,
  • R8 means aryl
  • R9 means aryl
  • R10 1-4C-alkyl, 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, hetsroarylcarbonyl, arylsulfunyl or aryl-1-4 C - a lky lca rbonyl means, wherein
  • R11 and R12 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, x is an integer from 0 to 4 and y is an integer from 0 to 4, where x and / or y are not 0 or 1 when A is 0 (oxygen) or S (sulfur), and the salts of these compounds.
  • 1-6C-alkyl is chain or branched and means, for example, a hexyl, neopentyl, isopentyl, butyl, 1-butyl, sac.-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, tsopropyl, ethyl or in particular methyl radical.
  • 1-4C-Alko ⁇ y 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, 1,1,1,2-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 radicals R7 which may be mentioned are: phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-methylphenyl and 3-trifluoromethylphenyl.
  • heteroaryl radicals R7 which may be mentioned are: furyl, in particular 2-furyl, thienyl, in particular 2-thienyl, and pyridyl, in particular 3-pyridyl.
  • exemplary aryl radicals R8 and R9 are the 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-oimethylphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
  • aryl radicals R10 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- Methylphenyl, 3-chloro-4-methylphenyl, 3, 4-dichlorophenyl, 3, 6-dichlorophenyl, 3, 4-dimethylphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
  • Aryl-1-4C-alkyl stands for 1-4C-alkyl which is substituted by aryl.
  • Ary 1-1-4C-alkyl radicals which may be mentioned are: 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.
  • 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-dichlorobenzhydryl.
  • heteroaryl radicals R10 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, in particular 3- Pyridyl and preferably 2-pyridyl.
  • Heteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl.
  • Hetyroaryl-1-4C-alkyl is, for example, 2- (2-yridyl) ethyl.
  • 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 1-4-C-alkyl which is substituted by two heteroaryl radicals.
  • Di-heteroaryl-1-4C-alkyl is, for example, di-pyrid2-yl-methyl.
  • Arylcarbonyl stands for a carbonyl group which is substituted by aryl.
  • arylcarboriyl groups which may be mentioned are 4-chlorophenylcarbonyl, 2-hydroxyphenylcarbonyl (salicyloyl), 4-hydroxyphenylcarbonyl and in particular 4-fluorophenylcarbonyl and benzoyl groups.
  • Heteroarylcarbonyl stands for a carbonyl group which is substituted by heteroaryl.
  • the nicotinoyl and 2-furoyl radicals may be mentioned as exemplary heteroarylcarbonyl radicals.
  • Arylsulfonyl stands for a sulfonyl group which is substituted by aryl.
  • exemplary arylsulfonyl radicals are the phenylsulfonyl, the
  • the aryl-1-4C-alkylcarbonyl radical may be mentioned, for example, the 2-phenylpropionyl radical.
  • An example of an aryl-2-4C-alkenylcarbonyl radical is the cinnamoyl rest.
  • 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, senzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, metembonac, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrynic acid, tienilic acid or 4-chloro-sulfamoyl-benzoic acid.
  • water-soluble and water-insoluble acid addition salts such
  • R1 means methyl
  • R2 means methyl
  • Ar is a cycle of the formula
  • R3 means methyl
  • Cy means 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl
  • G means C (R9) R9 or N-R10, where R8 means phenyl, R9 means phenyl and
  • R10 means phenyl, 2-methoxyphenyl or benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
  • the invention particularly preferably relates to compounds of the formula I in which R1 is methyl, R2 is methyl, Ar is a cycle of the formula
  • R3 means methyl
  • G is C (R8) R9 or N-R10, where
  • R8 means phenyl
  • R9 means phenyl
  • R10 means phenyl, 2-methoxyphenyl or benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
  • G is C (R8) R9 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
  • a further embodiment of the invention are compounds of the formula I in which Ar is a cycle of the formula 3
  • G denotes N-R10 and R1, R2, R3, R4, R5, R5, R7, R10, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
  • a further embodiment of the invention are compounds of the formula I in which Ar is a cycle of the formula
  • a further embodiment of the invention are compounds of the formula I in which Ar is a cycle of the formula
  • G denotes N-R10 and R1, R2, R4, R5, RS, R7, R10, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above.
  • R1 means methyl or ethyl
  • R2 means methyl or ethyl
  • R3 means methyl or ethyl
  • R8 means aryl
  • R9 means aryl
  • R11 and R12 are the same or different and have the meaning hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
  • Preferred compounds of embodiment a are those of the formula Ia, in which
  • R1 means methyl
  • R2 means methyl
  • R3 means methyl
  • Cy is 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl, R8 is phenyl or 4-methoxyphenyl, R9 is phenyl or 4-methoxyphenyl and the grouping - (CH 2 ) x means -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
  • R1, R2, R3, R4, R5, R6, R7, R10, R11, R12, Cy, A, x and y have the meanings given above.
  • R1 means methyl or ethyl
  • R2 means methyl or ethyl
  • R3 denotes methyl or ethyl
  • A means CH 2 (methylene) and
  • R10 means aryl, 2-pyridyl or 2-pyrimidyl, where
  • R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
  • compounds of embodiment b to be emphasized are those of the formula Ib, in which R1 denotes methyl or ethyl, R2 denotes methyl or ethyl, R3 denotes methyl or ethyl,
  • A means CH 2 (methylene ) means and R10 means diaryl-methyl, wherein aryl represents a ring of the formula
  • R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
  • preferred compounds of embodiment b are those of the formula Ib in which
  • R1 means methyl
  • R2 means methyl
  • R3 means methyl
  • Cy is 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl
  • R10 is phenyl, 2-methoxyphenyl or 2-pyridyl and the grouping is - (CH 2 ) x -A - (CH 2 ) y - means ethylene or propylene, and the salts of these compounds.
  • preferred compounds of embodiment b are those of the formula Ib in which R1 is methyl, R2 is methyl, R3 is methyl,
  • Cy means 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl
  • R10 means benzhydryl and the grouping is - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene means, and the salts of these compounds.
  • R1, R2, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above.
  • R1 means methyl or ethyl
  • R2 means methyl or ethyl
  • R8 means aryl
  • R9 means aryl
  • R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
  • R1 is methyl
  • R2 is methyl
  • Cy 3-nitrophenyl 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethyl phenyl, 2-difluoromethoxyphenyl or Senzoxdiazolyl means
  • R8 is phenyl or 4-methoxyphenyl
  • R9 is phenyl or 4-methoxyphenyl and the grouping is - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene and the salts of these compounds.
  • R1, R2, R4, R5, R6, R7, R10, R11, R12, Cy, A, x and y have the meanings given above.
  • R1 means methyl or ethyl
  • R2 means methyl or ethyl
  • A means CH 2 (methylene) and
  • R10 means aryl, 2-pyridyl or 2-pyrimidyl, where
  • R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
  • Cy phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl , 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethyl methylene or benzox - Diazolyl means A means CH 2 (methylene) and R10 means diaryl-methyl, where aryl represents a ring of the formula
  • R11 and R12 are the same or different and the meaning is hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoro- have methyl, x denotes an integer from 0 to 4 and y denotes the number 0, and the salts of these compounds.
  • preferred compounds of embodiment d are those of the formula Id in which
  • R1 means methyl
  • R2 means methyl
  • Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzodicol,
  • R10 means phenyl, 2-methoxyphenyl or 2-pyridyl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
  • preferred compounds of embodiment d are those of the formula Id in which
  • R1 means methyl
  • R2 means methyl
  • Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl,
  • R10 means benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
  • the compounds of formula I have a chiral center at the 4-position in 1,4-dihydropyridine.
  • the invention therefore encompasses both the enantiomers and, if a further chirality center is present, the diastereomers, and also their mixtures and racemates.
  • Another object of the invention is a process for the preparation of the compounds according to the invention and their salts.
  • the process is characterized in that
  • Embodiments of the method are those in which the formulas II to XII have the substituents or symbols R1, R2, R3, R4, R5, RS, R7, R8, R9, R10, R11, R12, Ar, Cy, A, G , x and y dis in the dependent and subsidiary claims have the meanings indicated, Z together with the carbonyl group, to which it is attached, a carboxyl group or a reactive carboxylic acid derivative and L represents a leaving group.
  • a to f is carried out in suitable, preferably inert, organic solvents.
  • suitable, preferably inert, organic solvents include alcohols, such as ethanol, methanol, isopropanol or in particular t-butanol, hydrocarbons, such as toluene or xylene, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethylsulfo ⁇ id, acetonitrile acid or hexamethylphosphoric acid , or chlorinated hydrocarbons such as methylene chloride, chloroform or tetrachlorethylene.
  • alcohols such as ethanol, methanol, isopropanol or in particular t-butanol
  • hydrocarbons such as toluene or xylene
  • ethers such as dioxane
  • reaction temperatures can vary within a wide range. In general, the implementation
  • the process can be carried out at atmospheric pressure or at elevated pressure, working at atmospheric pressure being the rule and elevated pressure can be 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 is also desired (for example in ammonia in variants b and d) can be used.
  • the reaction is preferably in the presence of a water-releasing or water-binding condensing agent (such as, for example, dicycloo e Chlorine atom! if desired, the reaction is to be carried out in the presence of a sase (for example a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate).
  • a water-releasing or water-binding condensing agent such as, for example, dicycloo e Chlorine atom!
  • a sase for example a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate.
  • 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 carfaonate, such as potassium carbonate) or using an excess of amine XII.
  • the substances according to the invention are isolated and purified in a manner known per se, for. B. in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
  • Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. 8. 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 suitable solvent e.g. 8. 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.
  • the slide salts are obtained by filtering, falling over, precipitating with a non-solvent for the addition salt or by evaporating the solvent.
  • Salts obtained can be converted into dis-free bases by alkalization, for example with aqueous ammonia solution, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
  • Some of the starting compounds are known from the literature or can be prepared analogously to methods known from the literature.
  • the keto compounds VII, in which Ar represents a 2-alkyltetrazol-5-yl radical, are analogous to T. Isida et al., J. Org. Chem. 36, 3807 (1971) can be obtained by rearrangement from XIII.
  • XIII is from appropriately substituted 5-R2-isoxazoles by alkylation z. B. with Di-R3 sulfates and subsequent reaction with alkali azide in analogy to R. B. Woodward et al., Tetrahedron Suppl. 7, 415 (1966) accessible. -
  • the keto compounds VII, in which Ar represents a 1,3,4-oxadiazol-2-yl radical, are described in the monthly magazines Chem. 113, 781 (1982).
  • the Akenone II can, for example, by condensation of VII with
  • ß-Ketocarbonklarivate IV 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 (1973)].
  • the connections 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 (1973)].
  • IX are accessible from corresponding starting compounds analogously to process variants a to f.
  • Compounds X can be obtained by reacting corresponding peridines or piperazines with omega-haloalkanols.
  • the dihydropyridine derivatives XI are obtained by reacting enamines of the formula V with, for example, appropriately substituted omega-halo-2-acyl-acrylic acid esters, which in turn are accessible from aldehydes of the formula VIII and suitable beta-keto-omega-halocarboxylic acid esters.
  • the mixture is stirred for a further 5 hours at room temperature and again left to stand overnight.
  • the mixture is evaporated to dryness in vacuo, the residue. taken up in 1.6 1 of methylene chloride and then so much water added that just two clear phases are formed.
  • the aqueous phase is extracted again with methylene chloride, the combined organic phases are dried over sodium sulfate and then evaporated to dryness in vacuo.
  • the spontaneously crystallizing residue is triturated with ethyl acetate, suction filtered, washed with ethyl acetate and dried. 93 g of mp 74-76 ° C. are obtained.
  • Example D Analogously to Example D, the title compound is obtained starting from 2- (4-benzhydryl-1-piperazinyl) ethanol as an oil, which is reacted further without purification.
  • the compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are in particular effective vasodilators with coronary therapeutic properties.
  • the pharmacological activity of the compounds according to the invention is particularly evident in a slowly occurring and strong drop in blood pressure.
  • the compounds according to the invention have an inhibitory effect on calcium influx and a promotional effect on potassium outflow from cells, smooth muscle relaxing and peripheral, coronary, cerebral and renal vasodilator and salidiuretic, antithrombotic and favorable hemorheological properties.
  • the compounds according to the invention differ surprisingly and advantageously from the compounds of the prior art in their excellent activity, which is paired with low toxicity and the absence of significant side effects.
  • Examples of advantageous properties of the compounds I are: the extent of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly small increase in heart rate 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 circulatory disorders (stroke, tampora cerebral circulatory disorders, migraines, dizziness, renal artery narrowing etc.), hypertrophic cardiomyophthia, heart failure, diseases that are based on an echoed water and sodium retention and diseases based on an increased influx of calcium, such as spasms of smooth muscle organs (respiratory tract, gastrointestinal tract, urogenital tract, etc.), as well as arrhythmia and arteriosclerosis.
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cerebral circulatory disorders stroke, tampora cerebral circulatory disorders, migraines, dizzi
  • 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 medicinal products are produced by processes known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active ingredients for example antioxidants, dispersants, emulsifiers, defoamers, flavor correctants, preservatives, solubilizers, colorants or, in particular, permeation promoters and co-formers (eg cyclodextrins) can be used.
  • the active compounds 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.
  • 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.
  • parenteral treatment similar or (in particular in the case of intravenous administration of the active compounds) generally lower doses 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 contain one or more other pharmacologically active constituents of other pharmaceutical groups, such as other vasodilators, antihypertensives, alpha-1 receptor blockers, alpha-2-lichstimulatoren, beta-1-adrenergic antagonists, beta-2-Rezeptorstimulatoren, ACE inhibitors, nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, analgesics, lipid lowering agents, anticoagulants, Anticholinargika, Mathylxanthine, antiarrhythmic agents, antihistamines, Dopaminstimulatoren, serotonin feltorsnblocker etc., such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate
  • the antihypertensive activity of the compounds according to the invention can be demonstrated on the model of the spontaneously hypertensive rat.
  • the compounds listed below are given in the doses given on four consecutive days on 6 male rats (strain SHR / N / Ibm / 8m, 250-350 g) with genetically determined high pressure (systolic high pressure> 130 mmHg) administered once a day by gavage. Blood pressure is measured 6 and, if necessary, 2 or 24 hours after substance administration.
  • the blood pressure is measured in a warm chamber at 36 ° C in order to achieve better circulation in 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. After the blood flow in the tail artery has been stopped, the cuff pressure is continuously reduced. The return of the. Pulse waves during pressure relief are automatically recognized and printed out as systolic blood pressure (Bühler, R. et al .: Microprocassor-based automation of blood pressure measurement in the conscious rat.
  • the tiara is trained for 14 days before the substance test. In the second week of training, blood pressure pre-values are collected. Animal groups that received substance are checked against a control group.
  • the tested compounds are identified by consecutive numbers that correspond to the numbers in the examples Table I shows for the representatives of the compounds according to the invention the percentage reduction in blood pressure (BP) after oral administration in the rat.
  • BP blood pressure

Abstract

Compounds having formula (I), in which the substituents and symbols have the meanings described in the first claim, constitute compounds with interesting pharmacological properties.

Description

1.4-Dihydropyridine 1,4-dihydropyridines
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft neue 1, 4-Dihydropyridine, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende Arzneimittel. Die erfindungsgemäßen Verbindungen werden in der pharmazeutischen Industrie zur Herstellung von Arzneimitteln eingesetzt.The invention relates to new 1,4-dihydropyridines, processes for their preparation, their use and medicaments containing them. The compounds according to the invention are used in the pharmaceutical industry for the production of medicaments.
Bekannter technischer HintergrundKnown technical background
Es ist bekannt, daß bestimmte, auf verschiedene Weise substituierte 1, 4-Dihydropyridinderivate pharmakologisch nützliche Eigenschaften aufweisen. Oberraschenderweise wurde nun gefunden, daß die unten näher beschriebenen neuen Verbindungen besonders interessante pharmakologische Eigenschaften aufweisen, durch die sie sich von den Verbindungen des Standes der Technik in vorteilhafter Weise unterscheiden.It is known that certain 1,4-dihydropyridine derivatives substituted in various ways have pharmacologically useful properties. Surprisingly, it has now been found that the new compounds described in more detail below have particularly interesting pharmacological properties, by which they differ from the compounds of the prior art in an advantageous manner.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind neue 1,4-Dihydropyridine der Formel IThe invention relates to new 1,4-dihydropyridines of the formula I.
I)I)
Figure imgf000003_0001
Figure imgf000003_0001
worinwherein
R1 und R2 gleich oder verschieden sind und Wasserstoff, 1-6C-Alkyl oderR1 and R2 are the same or different and are hydrogen, 1-6C-alkyl or
3-7C-Alkoxyalkyl bedeuten, Ar einen Cyclus der Formel
Figure imgf000004_0001
3-7C-Alkoxyalkyl, Ar is a cycle of the formula
Figure imgf000004_0001
darstellt, worinrepresents what
R3 1-SC-Alkyl bedeutet,R3 means 1-SC-alkyl,
Cy einen Cyclus der FormelCy a cycle of the formula
Figure imgf000004_0002
Figure imgf000004_0002
darstellt, in dem Y Sauerstoff (0), Schwefel (S), Vinylen (-CH=CH-), Azomethin (-CH=N-) ader eine Gruppe der Formelrepresents, in which Y represents oxygen (0), sulfur (S), vinylene (-CH = CH-), azomethine (-CH = N-) or a group of the formula
Figure imgf000004_0003
Figure imgf000004_0003
bedeutet, worinmeans what
R4 und R5 gleich oder verschieden sind und Wasserstoff, Hydroxy, Halogen, Nitro, Cyano, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy, 1-4C-Alkoxycarbonyl, 2-5C-Acyl, Amino oder Mono- oder Di-1 -4C-alkylamino bedeuten,R4 and R5 are identical or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, Mean 2-5C-acyl, amino or mono- or di-1-4C-alkylamino,
A CH2 (Methylen), O (Sauerstoff), S (Schwefel) oder substituiertes Methylen der Formel C(R6)R7 bedeutet, worinA represents CH 2 (methylene), O (oxygen), S (sulfur) or substituted methylene of the formula C (R6) R7, in which
R6 Wasserstoff oder 1-6C-Alkyl und R7 1-6C-Alkyl, 1-4C-Alkoxy, Aryl oder Heteroaryl bedeutet,R6 is hydrogen or 1-6C-alkyl and R7 denotes 1-6C-alkyl, 1-4C-alkoxy, aryl or heteroaryl,
G C(R8) R9 oder N-R10 bedeute , wobeiG C (R8) R9 or N-R10 means where
R8 Aryl bedeutet,R8 means aryl,
R9 Aryl bedeutet undR9 means aryl and
R10 1-4C-Alkyl, Aryl, Aryl-1-4C-alkyl, Aryl-2-4C-alkenyl, Aryl-2-4C- alkinyl, Diaryl-1-4C-alkyl, Heteroaryl, Heteroaryl-1-4C-alkyl, Heteroaryl-aryl-1-4C-alkyl, Di-heteroaryl-1-4C-alkyl, Arylcarbonyl, Hetsroarylcarbonyl, Arylsulfunyl oder Aryl-1-4 C - a lky lca rbonyl bedeutet, wobeiR10 1-4C-alkyl, 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, hetsroarylcarbonyl, arylsulfunyl or aryl-1-4 C - a lky lca rbonyl means, wherein
Aryl für einen Ring der FormelAryl for a ring of the formula
Figure imgf000005_0001
Figure imgf000005_0001
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), 1-4C-Alkyl, 1-4C-Alkoxy, Halogen, Hydroxy oder Trifluormethyl haben, undis in which R11 and R12 are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and
Heteroaryl für einen 5- oder 6-gliedrigen Heterocyclus mit einem oder zwei gleichen oder verschiedenen Heteroatomen aus der Gruppe Sauerstoff (O), Schwefel (S) oder Stickstoff (N) steht, der ungesättigt oder teilweise oder g a n z gesättigt ist und der einen oder zwei Substituenten aus der Gruppe 1-4C-Alkyl, 1-4C-Alkoxy, Halogen, Trifluormethyl oder Cyan tragen kann, x eine ganze Zahl von 0 bis 4 bedeutet und y eine ganze Zahl von 0 bis 4 bedeutet, wobei x und/oder y nicht die Bedeutung 0 oder 1 haben, wenn A 0 (Sauerstoff) oder S (Schwefel) bedeutet, und die Salze dieser Verbindungen.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, x is an integer from 0 to 4 and y is an integer from 0 to 4, where x and / or y are not 0 or 1 when A is 0 (oxygen) or S (sulfur), and the salts of these compounds.
1-6C-Alkyl ist gandkettig oder verzweigt und bedeutet beispielsweise einen Hexyl-, Neopentyl-, Isopentyl-, Butyl-, 1-Butyl-, sac.-Butyl-, t-Butyl-, Propyl-, Isopropyl- oder insbesondere Ethyl- oder Methylrest. 3-7C-Alkoxyalkyl steht beispielsweise für einen Ethoxyethyl-, Propoxy- ethyl-, Isopropoxyethyl-, Butoxyethyl-, Methoxypropyl-, 2-Methoxy-1-me- thylethyl-, 2-Ethoxy-1-methylethyl- oder insbesondere Methoxyethylrest.1-6C-alkyl is chain or branched and means, for example, a hexyl, neopentyl, isopentyl, butyl, 1-butyl, sac.-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 im Sinne der Erfindung bedeutet Brom, Fluor und insbesondere Chlor.Halogen in the sense of the invention means bromine, fluorine and especially chlorine.
1-4C-Alkyl ist geradkettig oder verzweigt und bedeutet beispielsweise einen Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Tsopropyl-, Ethyl- oder ins besondere Methylrest.1-4C-alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec-butyl, t-butyl, propyl, tsopropyl, ethyl or in particular methyl radical.
1-4C-Alkoκy enthält neben dem Sauerstoffatom einen der vorstehend genannten 1 -4C-Alkylreste. Bevorzugt sind der Methoxy- und der Ethoxyrest.In addition to the oxygen atom, 1-4C-Alkoκy contains one of the 1 -4C-alkyl radicals mentioned above. The methoxy and ethoxy radicals are preferred.
Ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoxy ist beispielsweise 1,1,1,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder insbesondere Difluormethoxy.1-4C-Alkoxy which is wholly or partly substituted by fluorine is, for example, 1,1,1,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.
1-4C-Alkoxycarbonyl enthält neben der Carbonylgruppe einen der vorstehend genannten 1-4C-Alkoxyreste. Bevorzugt sind der Methoκycarbonyl- und der Ethoxycarbonylrest.In addition to the carbonyl group, 1-4C-alkoxycarbonyl contains one of the 1-4C-alkoxy radicals mentioned above. The methoxycarbonyl and ethoxycarbonyl radicals are preferred.
2-5C-Acyl enthält neben der Carbonylgruppe einen der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist der Acetylrest.In addition to the carbonyl group, 2-5C-acyl contains one of the 1-4C-alkyl radicals mentioned above. The acetyl radical is preferred.
Mono- oder Di-1-4C-alkylamino enthält neben dem Stickstoffatom einen oder zwei der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist Di-1-4C- alkylamino, und hier insbesondere Dimethyl-, Diethyl- oder Diisopropylamino.In addition to the nitrogen atom, 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.
Als beispielhafte Arylreste R7 seien genannt die Reste: Phenyl, 4-Methoxy- phenyl, 4-Chlorphenyl, 4-Methylphenyl, 4-Fluorphenyl, 2-Chlorphenyl, 2-Me- thoxyphenyl, 2-Methylphenyl und 3-Trifluormethylphenyl.Examples of aryl radicals R7 which may be mentioned are: phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-methylphenyl and 3-trifluoromethylphenyl.
Ais beispielhafte Heteroarylreste R7 seien genannt die Reste: Furyl, insbesondere 2-Furyl, Thienyl, insbesondere 2-Thienyl, und Pyridyl, insbesondere 3-Pyridyl. Als beispielhafte Arylreste R8 und R9 seien genannt die Reste: Phenyl, 4-Methoxyphenyl, 4-Chlorphenyl, 4-Methylphenyl, 4-Fluorphenyl, 3-Fluorphenyl, 3-Chlorphenyl, 2-Chlorphenyl, 3-Methoxyphenyl, 2-Methoxyphenyl, 2-Methylphenyl, 3-Chlor-4-methylphenyl, 3, 4-Dichlorphenyl, 3,6-Dichlorphenyl, 3 , 4-Oimethylphenyl, 2-Trifluormethylphenyl und 3-Trifluormethylphenyl.Examples of heteroaryl radicals R7 which may be mentioned are: furyl, in particular 2-furyl, thienyl, in particular 2-thienyl, and pyridyl, in particular 3-pyridyl. Exemplary aryl radicals R8 and R9 are the 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-oimethylphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
Als beispielhafte Arylreste R10 seien genannt die Reste: Phenyl, 4-Methoxyphenyl, 4 -Chlorphenyl, 4-Me thylphenyl, 4 -Fluorphenyl, 3-Fluorphenyl, 3-Chlorphenyl, 2-Chlorphenyl, 3-Methoxyphenyl, 2-Methoxyphenyl, 2-Methylphenyl, 3 -Chlor-4 -methylphenyl, 3 , 4-Dichlorphenyl, 3 ,6-Dichlorphenyl, 3 ,4-Dimethylphenyl, 2-Trifluormethylphenyl und 3-Trifluormethylphenyl.Examples of aryl radicals R10 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- Methylphenyl, 3-chloro-4-methylphenyl, 3, 4-dichlorophenyl, 3, 6-dichlorophenyl, 3, 4-dimethylphenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl.
Aryl-1-4C-alkyl steht für 1-4C-Alkyl, das durch Aryl substituiert ist. Als beispielhafte Ary 1-1-4C-alkylreste seien genannt die Reste: 4-Methylbenzyl, 4-Methoxybenzyl, 4-Chlorbenzyl, 1-Phenethyl, 2-Phenylethyl, 3-Chlorbenzyl, 2,5-Dimethylbenzyl, 4-Fluorbenzyl, 3-Methylbenzyl und insbesondere Benzyl.Aryl-1-4C-alkyl stands for 1-4C-alkyl which is substituted by aryl. Ary 1-1-4C-alkyl radicals which may be mentioned are: 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 und Aryl-2-4C-alkinyl steht für Alkenyl- und Alkinylreste mit 2 bis 4 Kohlenstoffatomen, die durch Aryl substituiert sind. Beispielsweise seien der 3-Phenyl-2-propenylrest und der 3-Phenyl-2- propinylrest genannt.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.
Diaryl-1-4C-alkyl ist 1-4C-Alkyl, das durch zwei Arylreste substituiert ist. Diaryl-1-4C-alkyl ist insbesondere Diphenylmethyl (Benzhydryl), oder substituiertes Benzhydryl, wie z.B. 4,4'-Difluorbenzhydryl, 4,4'-Dimethylbenzhydryl, 4 ,4'-Dimethoxybenzhydryl oder 4,4-Dichlorbenzhydryl.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-dichlorobenzhydryl.
Als beispielhafte Heteroarylreste R10 seien genannt die Reste: Furyl, insbesondere 2-Furyl, Thienyl, insbesondere 2-Thienyl, Pyrimidyl, insbesondere 2-Pyrimidyl, 3-Cyan-2 -pyridyl, Thiazolyl, insbesondere 2-Thiazolyl sowie Pyridyl, insbesondere 3-Pyridyl und vorzugsweise 2-Pyridyl.The following are examples of heteroaryl radicals R10: 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, in particular 3- Pyridyl and preferably 2-pyridyl.
Heteroaryl-1-4C-alkyl ist 1-4C-Alkyl, das durch Heteroaryl substituiert ist. Hetyroaryl-1-4C-alkyl ist beispielsweise 2-(2--yridyl)-ethyl. Heteroaryl-aryl-1-4C-alkyl ist 1-4C-Alkyl, das durch Heteroaryl und Aryl substituiert ist. Heteroaryl-aryl-1-4C-alkyl ist beispielsweise 2-Pyridylphenylmethyl.Heteroaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by heteroaryl. Hetyroaryl-1-4C-alkyl is, for example, 2- (2-yridyl) ethyl. 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 ist 1-4-C-Alkyl, das durch zwei Heteroarylreste substituiert ist. Di-heteroaryl-1-4C-alkyl ist beispielsweise Di-pyrid2-yl-methyl.Di-heteroaryl-1-4C-alkyl is 1-4-C-alkyl which is substituted by two heteroaryl radicals. Di-heteroaryl-1-4C-alkyl is, for example, di-pyrid2-yl-methyl.
Arylcarbonyl steht für eine Carbonylgruppe, die durch Aryl substituiert ist. Als Arylcarboriylgruppen seien beispielsweise-die 4-Chlorphenylcarbonyl, 2-Hydroxyphenylcarbonyl- (Salicyloyl-), die 4-Hydroxyphenylcarbonyl- und insbesondere die 4-Fluorphenylcarbonyl- und die Benzoylgruppe genannt.Arylcarbonyl stands for a carbonyl group which is substituted by aryl. Examples of arylcarboriyl groups which may be mentioned are 4-chlorophenylcarbonyl, 2-hydroxyphenylcarbonyl (salicyloyl), 4-hydroxyphenylcarbonyl and in particular 4-fluorophenylcarbonyl and benzoyl groups.
Heteroarylcarbonyl steht für eine Carbonylgruppe, die durch Heteroaryl substituiert ist. Als beispielhafte Heteroarylcarbonylreste seien der Nicotinoyl- und der 2-Furoylrest genannt.Heteroarylcarbonyl stands for a carbonyl group which is substituted by heteroaryl. The nicotinoyl and 2-furoyl radicals may be mentioned as exemplary heteroarylcarbonyl radicals.
Arylsulfonyl steht für eine Sulfonylgruppe, die durch Aryl substituiert ist. Als beispielhafte Arylsulfonylreste seien der Phenylsulfonyl-, derArylsulfonyl stands for a sulfonyl group which is substituted by aryl. Exemplary arylsulfonyl radicals are the phenylsulfonyl, the
4-Chlorphenylsulfonyl- und der 4-Methoxyphenylsulfonylrest genannt.4-chlorophenylsulfonyl and the 4-methoxyphenylsulfonyl radical called.
Als Aryl-1-4C-alkylcarbonylrest sei beispielsweise der 2-Phenylpropionylrest genannt. Als Aryl-2-4C-alkenylcarbonylrest sei beispielsweise der Cinnamoylrast genannt.The aryl-1-4C-alkylcarbonyl radical may be mentioned, for example, the 2-phenylpropionyl radical. An example of an aryl-2-4C-alkenylcarbonyl radical is the cinnamoyl rest.
Als Salze kommen alle Salze mit Säuren in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der pharmazeutischenIndustrie üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die beispielsweise bei der Herstellung der erfindungsgemäßen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze übergeführt. Als solche eignen sich beispielsweise wasserlösliche und wasserunlösliche Säureadditionssalze, wie das Hydrochlorid, Hydrobromid, Hydroiodid, Phosphat, Nitrat, Sulfat, Acetat, Citrat, Gluconat, Senzoat, Hibenzat, Fendizoat, Butyrat, Sulfosalicylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Metembonac, Stearat, Tosilat, 2-Hydroxy-3-naphthoat, 3-Hydroxy-2-naphthoat oder Mesilat, aber auch Salze mit Bumetanid, Furosemid, Azosemid, Galosemid, Besunid, Piretanid, Etacrynsäure, Tienilinsäure oder 4-Chlor-sulfamoyl-benzoesäure.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 commonly used in the pharmaceutical industry. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, senzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, metembonac, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrynic acid, tienilic acid or 4-chloro-sulfamoyl-benzoic acid.
Bevorzugter Gegenstand der Erfindung sind Verbindungen der Formel I, worinPreferred objects of the invention are compounds of formula I, wherein
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
Ar einen Cyclus der FormelAr is a cycle of the formula
Figure imgf000009_0001
Figure imgf000009_0001
darstellt, worinrepresents what
R3 Methyl bedeutet,R3 means methyl,
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, G C(R9)R9 oder N-R10 bedeutet, wobei R8 Phenyl bedeutet, R9 Phenyl bedeutet undCy means 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl, G means C (R9) R9 or N-R10, where R8 means phenyl, R9 means phenyl and
R10 Phenyl, 2-Methoxyphenyl oder Benzhydryl bedeutet und die Gruppierung -(CH2)x -A-(CH2)y - Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R10 means phenyl, 2-methoxyphenyl or benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
Besonders bevorzugter Gegenstand der Erfindung sind Verbindungen der Formel I, worin R1 Methyl bedeutet, R2 Methyl bedeutet, Ar einen Cyclus der Formel
Figure imgf000010_0001
The invention particularly preferably relates to compounds of the formula I in which R1 is methyl, R2 is methyl, Ar is a cycle of the formula
Figure imgf000010_0001
darstellt, worinrepresents what
R3 Methyl bedeutet,R3 means methyl,
Cy 3-Nitrophenyl bedeutet,Cy 3-nitrophenyl means
G C(R8) R9 oder N-R10 bedeutet, wobeiG is C (R8) R9 or N-R10, where
R8 Phenyl bedeutet,R8 means phenyl,
R9 Phenyl bedeutet undR9 means phenyl and
R10 Phenyl, 2-Methoxyphenyl oder Benzhydryl bedeutet und die Gruppierung -(C H2)x -A-(CH2)y - Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R10 means phenyl, 2-methoxyphenyl or benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
Eine Ausgestaltung der Erfindung (Ausgestaltung a) sind Verbindungen der Formel I, worin Ar ein Cyclus der FormelOne embodiment of the invention (embodiment a) are compounds of the formula I in which Ar is a cycle of the formula
R >
Figure imgf000010_0002
R>
Figure imgf000010_0002
darstellt-, G C(R8) R9 bedeutet und R1, R2, R3 , R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben, und ihre Salze.represents-, G is C (R8) R9 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
Eine weitere Ausgestaltung der Erfindung (Ausgestaltung b) sind Verbindungen der Formel I, worin Ar ein Cyclus der Formel 3
Figure imgf000011_0001
A further embodiment of the invention (embodiment b) are compounds of the formula I in which Ar is a cycle of the formula 3
Figure imgf000011_0001
darstellt, G N-R10 bedeutet und R1, R2, R3 , R4, R5, R5, R7, R10, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben, und ihre Salze.represents, G denotes N-R10 and R1, R2, R3, R4, R5, R5, R7, R10, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
Ein e weitere Ausgestaltung der Erfindung (Ausgestaltung c) sind Verbindungen der Formel I, worin Ar ein Cyclus der FormelA further embodiment of the invention (embodiment c) are compounds of the formula I in which Ar is a cycle of the formula
Figure imgf000011_0002
Figure imgf000011_0002
darstellt, G C(R8)R9 bedeutet und R1, R2, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben, und ihre Salze.represents G C (R8) R9 and R1, R2, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
Eine weitere Ausgestaltung der Erfindung (Ausgestaltung d) sind Verbindungen der Formel I, worin Ar ein Cyclus der Formel A further embodiment of the invention (embodiment d) are compounds of the formula I in which Ar is a cycle of the formula
Figure imgf000012_0001
Figure imgf000012_0001
darstellt, G N-R10 bedeutet und R1, R2 , R4, R5, RS, R7, R10, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben, und ihre Salze.represents, G denotes N-R10 and R1, R2, R4, R5, RS, R7, R10, R11, R12, Cy, A, x and y have the meanings given above, and their salts.
Verbindungen der Ausgestaltung a können charakterisiert werden durch die allgemeine Formel IaCompounds of embodiment a can be characterized by the general formula Ia
(Ia)(Ia)
Figure imgf000012_0002
Figure imgf000012_0002
worin R1, R2, R3 , R4, R5, R6, R7, R8, R9, R11 , R12, Cy , A, x und y die oben angegebenen Bedeutungen haben.wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above.
Hervorzuhebende Verbindungen der Ausgestaltung a sind solche der Formel Ia, worinCompounds of embodiment a to be emphasized are those of the formula Ia in which
R1 Methyl oder Ethyl bedeutet, R2 Methyl oder Ethyl bedeutet, R3 Methyl oder Ethyl bedeutet,R1 means methyl or ethyl, R2 means methyl or ethyl, R3 means methyl or ethyl,
Cy Phenyl, 2-Nitrophenyl, 3-Nitrophenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluorme thoxyphenyl, 3-Dirluormethoxyphenyl, 2-Chlor- phenyl, 3-Chlorphenyl, 2 ,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluor- phenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl oder Benzox- diazolyl bedeutet,Cy phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) - phenyl, 2-difluoromethoxyphenyl, 3-Dirluormethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2, 3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzoxediazolyl,
A CH2 (Methylen) bedeutet,A means CH 2 (methylene),
R8 Aryl bedeutet undR8 means aryl and
R9 Aryl bedeutet, wobeiR9 means aryl, where
Aryl für einen Ring der FormelAryl for a ring of the formula
Figure imgf000013_0001
Figure imgf000013_0001
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasseritoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluormethyl haben, x eine ganze Zahl von 0 bis 4 bedeutet und y die Zahl 0 bedeutet, und die Salze dieser Verbindungen.in which R11 and R12 are the same or different and have the meaning hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
Bevorzugte Verbindungen der Ausgestaltung a sind solche der Formel Ia, worinPreferred compounds of embodiment a are those of the formula Ia, in which
R1 Methyl bedeutet, R2 Methyl bedeutet, R3 Methyl bedeutet,R1 means methyl, R2 means methyl, R3 means methyl,
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2 ,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, R8 Phenyl oder 4-Me thoxyphenyl bedeutet, R9 Phenyl oder 4-Methoxyphenyl bedeutet und die Gruppierung -(CH2)x -A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.Cy is 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl, R8 is phenyl or 4-methoxyphenyl, R9 is phenyl or 4-methoxyphenyl and the grouping - (CH 2 ) x means -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
Verbindungen der Ausgestaltung b können charakterisiert werden durch die allgemeine Formel Ib,
Figure imgf000014_0001
Compounds of embodiment b can be characterized by the general formula Ib,
Figure imgf000014_0001
worin R1, R2, R3 , R4, R5, R6, R7, R10, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben.wherein R1, R2, R3, R4, R5, R6, R7, R10, R11, R12, Cy, A, x and y have the meanings given above.
Hervorzuhebende Vebindungen der Ausgestaltung b sind in einem erstenConnections of design b to be emphasized are in a first
Aspekt solche der Formel Ib, worinAspect of those of the formula Ib, in which
R1 Methyl oder Ethyl bedeutet,R1 means methyl or ethyl,
R2 Methyl oder Ethyl bedeutet,R2 means methyl or ethyl,
R3 Methyl oder Ethyl bedeutet,R3 denotes methyl or ethyl,
Cy Phenyl, 2-Nitrophenyl, 3-Nitrophenyl, 2-Cyanoph-enyl, 3-Cyanophenyl, 2-11,1,2, 2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoxyphenyl, 2-Chlorphenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluorphenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl oder Benzoκ- diazolyl bedeutet,Cy phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-11,1,2, 2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) - phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzo-diazolyl,
A CH2 (Methylen) bedeutet undA means CH 2 (methylene) and
R10 Aryl, 2-Pyridyl oder 2-Pyrimidyl bedeutet, wobeiR10 means aryl, 2-pyridyl or 2-pyrimidyl, where
Aryl für einen Ring der FormelAryl for a ring of the formula
Figure imgf000014_0002
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluormethyl haben, x eine ganze Zahl von 0 bis 4 bedeutet und y die Zahl 0 bedeutet, und die Salze dieser Verbindungen.
Figure imgf000014_0002
is in which R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
Hervorzuhebende Vebindungen der Ausgestaltung b sind in einem weiteren Aspekt solche der Formel Ib, worin R1 Methyl oder Ethyl bedeutet, R2 Methyl oder Ethyl bedeutet, R3 Methyl oder Ethyl bedeutet,In a further aspect, compounds of embodiment b to be emphasized are those of the formula Ib, in which R1 denotes methyl or ethyl, R2 denotes methyl or ethyl, R3 denotes methyl or ethyl,
Cy Phenyl, 2 -Nitrophenyl, 3 -Nitropheny 1, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoxyphenyl, 2-Chlorphenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluorphenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl oder Benzox- diazolyl bedeutet, A CH2 (Methylen) bedeutet und R10 Diaryl-methyl bedeutet, wobei Aryl für einen Ring der FormelCy phenyl, 2 -nitrophenyl, 3 -nitropheny 1, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) - phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzoxydiazolyl, A means CH 2 (methylene ) means and R10 means diaryl-methyl, wherein aryl represents a ring of the formula
Figure imgf000015_0001
Figure imgf000015_0001
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluormethyl haben, x eine ganze Zahl von 0 bis 4 bedeutet und y die Zahl 0 bedeutet, und die Salze dieser Verbindungen. Bevorzugte Verbindungen der Ausgestaltung b sind in einem ersten Aspekt solche, der Formel Ib, worinis in which R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections. In a first aspect, preferred compounds of embodiment b are those of the formula Ib in which
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
R3 Methyl bedeutet,R3 means methyl,
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2 ,3-Dichlorphenyl, 2-Trifluormethyl- phenyl, 2- Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, R10 Phenyl, 2-Methoxyphenyl oder 2-Pyridyl bedeutet und die Gruppierung -(CH2)x -A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.Cy is 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl, R10 is phenyl, 2-methoxyphenyl or 2-pyridyl and the grouping is - (CH 2 ) x -A - (CH 2 ) y - means ethylene or propylene, and the salts of these compounds.
Bevorzugte Verbindungen der Ausgestaltung b sind in einem weiteren Aspekt solche der Formel Ib, worin R1 Methyl bedeutet, R2 Methyl bedeutet, R3 Methyl bedeutet,In a further aspect, preferred compounds of embodiment b are those of the formula Ib in which R1 is methyl, R2 is methyl, R3 is methyl,
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2 ,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, R10 Benzhydryl bedeutet und die Gruppierung - (CH2)x -A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.Cy means 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl, R10 means benzhydryl and the grouping is - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene means, and the salts of these compounds.
Die Verbindungen der Ausgestaltung c können charakterisiert werden durch die allgemeine Formel Ic,The compounds of embodiment c can be characterized by the general formula Ic,
Figure imgf000016_0001
worin R1, R2, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben.
Figure imgf000016_0001
wherein R1, R2, R4, R5, R6, R7, R8, R9, R11, R12, Cy, A, x and y have the meanings given above.
Hervorzuhebende Verbindungen der Ausgestaltung c sind solche der FormelCompounds of embodiment c to be emphasized are those of the formula
Ic, worinIc, where
R1 Methyl oder Ethyl bedeutet,R1 means methyl or ethyl,
R2 Methyl oder Ethyl bedeutet,R2 means methyl or ethyl,
Cy Phenyl, 2 -Nitrophenyl, 3-Nitrophenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoxyphenyl, 2-Chlorphenyl, 3-Chlorphenyl, 2 ,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluorphenyl, 2-Trifluormethylphenyl, 3 -Trifluormethylphenyl oder Benzoxdiazolyl bedeutet,Cy Phenyl, 2 -nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl , 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2, 3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzoxdiazolyl,
A CH2 (Methylen) bedeutet,A means CH 2 (methylene),
R8 Aryl bedeutet undR8 means aryl and
R9 Aryl bedeutet, wobeiR9 means aryl, where
Aryl für einen Ring der Formel lAryl for a ring of formula I
Figure imgf000017_0001
Figure imgf000017_0001
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluormethyl haben, x eine ganze Zahl von 0 bis 4 bedeutet und y die Zahl 0 bedeutet, und die Salze dieser Verbindungen.is in which R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
Bevorzugte Verbindungen der Ausgestaltung c sind solche der Formel Ic, worinPreferred compounds of embodiment c are those of the formula Ic in which
R1 Methyl bedeutet, R2 Methyl bedeutet, Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethyl- phenyl, 2-Difluormethoxyphenyl oder Senzoxdiazolyl bedeutet,R1 is methyl, R2 is methyl, Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethyl phenyl, 2-difluoromethoxyphenyl or Senzoxdiazolyl means
R8 Phenyl oder 4-Methoxyphenyl bedeutat,R8 is phenyl or 4-methoxyphenyl,
R9 Phenyl oder 4-Methoxyphenyl bedeutet und die Gruppierung -(CH2)x-A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R9 is phenyl or 4-methoxyphenyl and the grouping is - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene and the salts of these compounds.
Verbindungen der Ausgestaltung d können charakterisiert werden durch die allgemeine Formel Id,Compounds of embodiment d can be characterized by the general formula Id,
Figure imgf000018_0001
Figure imgf000018_0001
worin R1, R2, R4, R5, R6, R7, R10, R11, R12, Cy, A, x und y die oben angegebenen Bedeutungen haben.wherein R1, R2, R4, R5, R6, R7, R10, R11, R12, Cy, A, x and y have the meanings given above.
Hervorzuhebende Vebindungen der Ausgestaltung d sind in einem ersten Aspekt solche der Formel Id, worinIn a first aspect, compounds of design d which are to be emphasized are those of the formula Id in which
R1 Methyl oder Ethyl bedeutet,R1 means methyl or ethyl,
R2 Methyl oder Ethyl bedeutet,R2 means methyl or ethyl,
Cy Phenyl, 2-Nitrophenyl, 3-Nitrophenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluormethoxyphenyl, 3-Difluormethoxyphenyl, 2-Chlor- phenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluor- phenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl oder Benzox- diazolyl bedeutet,Cy phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl , 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or benzoxediazolyl,
A CH2 (Methylen) bedeutet undA means CH 2 (methylene) and
R10 Aryl, 2-Pyridyl oder 2-Pyrimidyl bedeutet, wobeiR10 means aryl, 2-pyridyl or 2-pyrimidyl, where
Aryl für einen Ring der Formel
Figure imgf000019_0001
Aryl for a ring of the formula
Figure imgf000019_0001
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluormethyl haben, x eine ganze Zahl von 0 bis 4 bedeutet und y die Zahl 0 bedeutet, und die Salze dieser Verbindungen.is in which R11 and R12 are the same or different and are hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoromethyl, x is an integer from 0 to 4 and y is 0 and the salts of these connections.
Hervorzuhebende Veb ind u n gen der Ausgestaltung d sind in einem weiteren Aspekt solche der Formel Id, worin R1 Methyl oder Ethyl bedeutet, R2 Methyl oder Ethyl bedeutet,In a further aspect, conditions to be emphasized are those of the formula Id in which R1 denotes methyl or ethyl, R2 denotes methyl or ethyl,
Cy Phenyl, 2-Nitrophenyl, 3-Nitrophenyl, 2-Cyanophenyl, 3-Cyanophenyl, 2-(1,1,2,2-Tetrafluorethoxy)-phenyl, 3-(1,1,2,2-Tetrafluorethoxy)- phenyl, 2-Difluormethoκyphenyl, 3-Difluormethoxyphenyl, 2-Chlor- phenyl, 3-Chlorphenyl, 2,3-Dichlorphenyl, 2-Fluorphenyl, 3-Fluor- phenyl, 2-Trifluormethylphenyl, 3-Tri f luo rme th y lphenyl oder Benzox- diazolyl bedeutet, A CH2 (Methylen) bedeutet und R10 Diaryl-methyl bedeutet, wobei Aryl für einen Ring der FormelCy phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl , 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethyl methylene or benzox - Diazolyl means A means CH 2 (methylene) and R10 means diaryl-methyl, where aryl represents a ring of the formula
Figure imgf000019_0002
Figure imgf000019_0002
steht, worin R11 und R12 gleich oder verschieden sind und die Bedeutung Wasserstoff (H), Methyl, Methoxy, Chlor, Fluor, Hydroxy oder Trifluor- methyl haben, x eine ganze Zahl von 0 bis 4 bedeutet und y die Zahl 0 bedeutet, und die Salze dieser Verbindungen.where R11 and R12 are the same or different and the meaning is hydrogen (H), methyl, methoxy, chlorine, fluorine, hydroxy or trifluoro- have methyl, x denotes an integer from 0 to 4 and y denotes the number 0, and the salts of these compounds.
Bevorzugte Verbindungen der Ausgestaltung d sind in einem ersten Aspekt solche der Formel Id, worinIn a first aspect, preferred compounds of embodiment d are those of the formula Id in which
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoκdiazolyl bedeutet,Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzodicol,
R10 Phenyl, 2-Methoxyphenyl oder 2-Pyridyl bedeutet und die Gruppierung -(CH2)x -A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R10 means phenyl, 2-methoxyphenyl or 2-pyridyl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
Bevorzugte Verbindungen der Ausgestaltung d sind in einem weiteren Aspekt solche der Formel Id, worinIn a further aspect, preferred compounds of embodiment d are those of the formula Id in which
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2 ,3-Dichlorphenyl, 2-Trifluormethyl- phenyl, 2-Difluormethoκyphenyl oder Benzoxdiazolyl bedeutet,Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2, 3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl,
R10 Benzhydryl bedeutet und die Gruppierung -(CH2)x -A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R10 means benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
Als erfindungsgemäße Verbindungen seien beispielsweise genannt:The following compounds may be mentioned as examples:
1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(2,3-Dichlorpheny])-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(2-Cyanphenyl)-1,4-dihydro-2,5-dimethyl-5-(2-methyltetrazol-5-yl)pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyllester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-trifluormethylphe¬nyl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyllester4-(2-ChIarphsnyl)-1,4-dihydro-2,6-dimethyl-5-(2-methylterazol -5-yl)pyri din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]estar 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-nitrophenyl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]e s t e r 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)- pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-trifluormethylphenyl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2-Chlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-nitrophenyl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 1,4-Dihydro-2,6-dimethyl-5-(2-ethyltetrazol-5-yl)-4-(3-nitrophenyl)-pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 1,4-Dihydro-2,6-dimethyl-5-(2-ethyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyri¬din-3-carbonsäure-{2-[2-(4,4-diphenyl-1-piperidinyl)ethoκy]ethyl}ester4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-{2-[2-(4,4-diphenyl-1-piperidinyl)ethoxy]ethyl}ester1,4-Dihydro-2,6-dimethyl-5-(2-ethyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-{3-[4,4-di-(4-methoxyphenyl)-1-piperidinyl]-propyl}ester1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyri¬din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)pyri din-3-carbonsäure-{3-[4-{2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)-ethyl]-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-[3-(4-phenyl-1-piperazinyl)-propyl]-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-{2-[4-[2-pyridyl)-1-piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl!-4-(3-nitrophenyl)pyrl-din-3-carbonsaure-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)pyri¬din-3-carbonsäure-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-ester,4-(2,3-Dichiorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)-ethyl]-ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-[3-(4-phenyl-1-piperazinyl)-propyl]-ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl}ester,4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazo1-5-yl)-pyridin-3-carbonsäure-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl}ester,4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-[2-{4-benzhydryl-1-piperazinyl)-ethyl]ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-pyridin-3-carbonsäure-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyri¬din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyri¬din-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyri¬din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyri¬din-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl)-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-trifluormethylphenyl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}- ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-trifluormethylphenyl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}- ester, 4-(2-Chlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-y)!pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Chlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)pyridin-3-carbönsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(2-methyItetrazol- 5-yl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}- ester, 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-nitrophenyl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(2-nitrophenyl)pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}- ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol- 5-yl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-ethyltetrazol-5-yl)-4-(3-nitrophenyl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-ethyltetrazol-5-yl)-4-(3-nitrophenyl)pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyridin-3-carbonsäure-[2-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethoxy}ethyl]- ester 4-{2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)- pyridin-3-carbonsänre-[2-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethoxy}- ethyl]ester 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyriJ V
Figure imgf000023_0001
4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[3-(4,4-diphenyI-1-piperidinyl)propyl]ester 4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 1,4-Dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-4-(2-trifluormethylphe¬nyl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester4-(2-Chlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester 4-(2-Difiuormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2,3-Dichlorphenyl}-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)py¬ridin-3-carbonsäure-[2-(4,4-diehenyl-1-piperidinyl)ethyl]ester 4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 1,4-Dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-4-(2-trifluormethylphe¬nyl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester4-(2-Chiorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[2-(4,4-diphenyl-1-piperidinyl)ethyl]ester1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{2-[2-(4,4-diphenyl-1-piperidinyl)ethoxy]ethyl}ester4-(2,3-Dichlorphenyl)-1,4-dihydro-2,3-dimethyl-5-{1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{2-[2-(4,4-diphenyl-1-piporidinyl)-ethoxy]ethyl}ester 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-estar, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)-ethyl]-ester, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[3-(4-phenyl-1-piperazinyl)-propyl]-ester, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl!-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[2-(4-benzhydryl-1-piperazinyl)-ethyl]-ester, 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[3-(4-benzhydryl-1-piperazinyl)-propyl]-ester 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)- pyridin-3-carbonsäure-{2-[4-(2-methoκyphenyl)-1-piperazinyl]ethyl}-ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)- pyridin-3-carbonsäure-{3-[4-(2-methoκyphenyl)-1-piperazinyl]-propyl}- ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-U,3,4-oxadiazol-2-yl)- pyridin-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)-ethyl]-ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)- pyridin-3-carbonsäure-[3-(4-phenyl-1-piperazinyl)-propyl]-ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl]estar, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{3-[4-(2-pyridyl)-1-piperazinyl]-propyl}ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[2-(4-benzhydryl-1-piperazinyl)-ethyl]ester, 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridιn-3-carbonsäure-[3-(4-benzhydryl-1-piperazinyl!-propyl]-ester 4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperιzinyl]-ethyl}-ester,4-(2-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazyol-2-yl)-pyri din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,4-(3-Cyanphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,1,4-Dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-4-(2-trifluormethylphe¬nyl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 1,4-Dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl]-4-(2-trifluormethylphe¬nyl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 4-(2-Chlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,4-(2-Chlorphenyl]-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)pyri¬din-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4-(2,-1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2,1,3-Benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-pro¬pyl}-ester,. 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester,1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester,4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl!-pyridin-3-carbonsäure-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-ester, 4-(2-Difluormethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-ester, 1,4-Dihydro-2-6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-[2-{2-[4-(2-methoκypheriyi)-1-piperazinyl]ethoxy}ethyl]-ester 4-(2,3-Dichlorphenyl)-1,4-dihydro-2,6-dimethyl-5-(1,3,4-oxadiazol-2-yl)-pyridin-3-carbonsäure-[2-{2-[4-(2-methoxyphenyl)-1-piperazinyllethoxy}-ethyllester und die Salze dieser Verbindungen. Die Verbindungen der Formel I besitzen an der 4-Position im 1,4-Dihydropyridin ein Chiralitätszentrum. Die Erfindung umfaßt daher sowohl die Enantiomeren und bei Vorliegen eines weiteren Chiralitätszentrums die Diastereomeren, als auch deren Gemische und Racemate.1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [3- (4,4-diphenyl- 1-piperidinyl) propyl] ester 4- (2,3-dichloropheny]) - 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid [3 - (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (2-cyanophenyl) -1,4-dihydro-2,5-dimethyl-5- (2-methyltetrazol-5-yl) pyridine- 3-carboxylic acid- [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (3-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazole-5- yl) pyridine-3-carboxylic acid- [3- (4,4-diphenyl-1-piperidinyl) propyl ester 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4 - (2-Trifluoromethylphenyl) pyridine-3-carboxylic acid- [3- (4,4-diphenyl-1-piperidinyl) propyl ester 4- (2-chlorophyll) -1,4-dihydro-2,6-dimethyl-5 - (2-methylterazol -5-yl) pyri din-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-2,6-dimethyl -5- (2-methyltetrazole-5-yl) pyridine-3-carboxylic acid- [3- (4,4-diphenyl-1-piperidinyl) propyl] estar 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (2-nitrophenyl) pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (2-difluoromethoxyphenyl) -1 , 4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 1,4- Dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- [2- (4,4-diphenyl -1-piperidinyl) ethyl] ester 4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- [2- (4th , 4-diphenyl-1-piperidinyl) ethyl] ester 4- (3-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- [ 2- (4,4-di phenyl-1-piperidinyl) ethyl] ester 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (2-trifluoromethylphenyl) pyridine-3-carboxylic acid- [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid - [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-2,6-dimethyl-5- (2nd -methyltetrazole-5-yl) -pyridine-3-carboxylic acid- [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazole- 5-yl) -4- (2-nitrophenyl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 4- (2-difluoromethoxyphenyl) -1,4-dihydro- 2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 1,4-dihydro-2,6 -dimethyl-5- (2-ethyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 1, 4-Dihydro-2,6-dimethyl-5- (2-ethyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [2- (4,4-diphenyl-1-piperidinyl ) eth yl] ester 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid {2- [2- ( 4,4-diphenyl-1-piperidinyl) ethoκy] ethyl} ester 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine- 3-carboxylic acid {2- [2- (4,4-diphenyl-1-piperidinyl) ethoxy] ethyl} ester 1,4-dihydro-2,6-dimethyl-5- (2-ethyltetrazol-5-yl) -4 - (3-nitrophenyl) pyridine-3-carboxylic acid {3- [4,4-di- (4-methoxyphenyl) -1-piperidinyl] propyl} ester 1,4-dihydro-2,6-dimethyl-5 - (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 1 , 4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyri din-3-carboxylic acid {3- [4- {2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl ) -4- (3-nitrophenyl) pyridine-3-carboxylic acid [2- (4-phenyl-1-piperazinyl) ethyl] ester, 1,4-dihydro-2,6-dimethyl-5- ( 2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid [3- (4-phenyl-1-piperazinyl) propyl] ester, 1,4-dihydro-2, 6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid {2- [4- [2-pyridyl) -1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl! -4- (3-nitrophenyl) pyrl-din-3-carboxylic acid- {3- [4- (2nd -pyridyl) -1-piperazinyl] -propyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridin-3 -carboxylic acid- [2- (4-benzhydryl-1-piperazinyl) ethyl] ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3- nitrophenyl) pyridine-3-carboxylic acid [3- (4-benzhydryl-1-piperazinyl) propyl] ester 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5 - (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2,3-dichiorphenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl ) -pyridine-3-carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6- dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid [2- (4-phenyl-1-piperazinyl) ethyl] ester, 4- (2,3-dichlorophenyl) -1, 4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid [3- (4-phenyl-1-piperazinyl) propyl] ester, 4- (2nd , 3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- {2- [4- (2-pyridyl) -1- piperazinyl] ethyl} ester, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazo1-5-yl) pyridine-3-carboxylic acid {3- [4- (2-pyridyl) -1-piperazinyl] propyl} ester, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl ) -pyridine-3-carboxylic acid [2- {4-benzhydryl-1-piperazinyl) ethyl] ester, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- ( 2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- [3- (4th -benzhydryl-1-piperazinyl) -propyl] -ester4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid - {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazole-5 -yl) pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (3-cyanophenyl) -1,4-dihydro-2,6 -dimethyl-5- (2-methyltetrazol-5-yl) pyridin-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (3-cyanophenyl ) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridin-3-carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] - propyl) ester, 1,4-Dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (2-trifluoromethylphenyl) pyridine-3-carboxylic acid- {2- [4- (2-methoxyphenyl) - 1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (2-trifluoromethylphenyl) pyridine-3-carboxylic acid- {3rd - [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-y )! pyridine-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl- 5- (2-methyltetrazol-5-yl) pyridine-3-carbonic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2,1,3-benzoxdiazole- 4-yl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- {2- [4- (2-methoxyphenyl) -1-piperazinyl ] -ethyl} - ester, 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridin-3 -carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4 - (2-nitrophenyl) pyridine-3-carbon Acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (2-nitrophenyl) pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6 -dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-ethyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- {2- [4- (2- methoxyphenyl) -1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-ethyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid - {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3rd -nitrophenyl) pyridine-3-carboxylic acid- [2- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethoxy} ethyl] ester 4- {2,3-dichlorophenyl) -1,4-dihydro -2,6-dim ethyl 5- (2-methyltetrazol-5-yl) pyridine-3-carboxylic acid - [2- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethoxy} ethyl] ester 1,4-dihydro -2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) -pyriJ V
Figure imgf000023_0001
4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- [3- (4, 4-diphenyl-1-piperidinyl) propyl] ester 4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine- 3-carboxylic acid- [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (3-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4- oxadiazol-2-yl) pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 1,4-dihydro-2,6-dimethyl-5- (1,3, 4-oxadiazol-2-yl) -4- (2-trifluoromethylphenyl) pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (2-chlorophenyl) -1 , 4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid - [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (1,3,4-oxadiazole-2- yl) -pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 4- (2-difluoromethoxyphenyl) -1, 4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester 1, 4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid- [2- (4,4- diphenyl-1-piperidinyl) ethyl] ester 4- (2,3-dichlorophenyl} -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridin 3-carboxylic acid [2- (4,4-diehenyl-1-piperidinyl) ethyl] ester 4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4- oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 4- (3-cyanophenyl) -1,4-dihydro-2,6-dimethyl -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 1,4-dihydro-2,6 -dimethyl-5- (1,3,4-oxadiazol-2-yl) -4- (2-trifluoromethylphenyl) pyridine-3-carboxylic acid- [2- (4,4-diphenyl-1-piperidinyl) ethyl ] ester4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4, 4-diphenyl-1-piperidinyl) ethyl] ester 4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-ox adiazol-2-yl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5 - (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 4- (2-difluoromethoxyphenyl) -1, 4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4,4-diphenyl-1-piperidinyl) ethyl] ester 1, 4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid {2- [2- (4th , 4-diphenyl-1-piperidinyl) ethoxy] ethyl} ester 4- (2,3-dichlorophenyl) -1,4-dihydro-2,3-dimethyl-5- {1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid {2- [2- (4,4-diphenyl-1-piporidinyl) ethoxy] ethyl} ester 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- {2- [4- (2nd -methoxyphenyl) -1-piperazinyl] -ethyl} -estar, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) - pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4-phenyl-1-piperazinyl) ethyl] ester, 1,4-dihydro-2,6-dimethyl 4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [3- (4-phenyl-1-piperazinyl) propyl] ester, 1, 4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl! -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- {2- [4- (2-pyridyl ) -1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine- 3-carboxylic acid {3- [4- (2-pyridyl) -1-piperazinyl] propyl} ester, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1st , 3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4-benzhydryl-1-piperazinyl) ethyl] ester, 1,4-dihydro-2,6-dimethyl-4- (3- nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [3- (4-benzhydryl-1-piperazinyl) propyl] ester 4- (2,3-dichlorophenyl) ) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- {2- [4- (2-methoxyphenyl) -1- piperazinyl] ethyl} ester, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid - {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5-U, 3rd , 4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4-phenyl-1-piperazinyl) ethyl] ester, 4- (2,3-dichlorophenyl) -1,4-dihydro- 2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [3- (4-phenyl-1-piperazinyl) propyl] ester, 4- (2nd , 3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- {2- [4- (2-pyridyl ) -1-piperazinyl] ethyl] estar, 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine -3-carboxylic acid {3- [4- (2-pyridyl) -1-piperazinyl] propyl} ester, 4- (2,3-dichlorophenyl) -1,4-dihydro -2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid [2- (4-benzhydryl-1-piperazinyl) ethyl] ester, 4- (2nd , 3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid- [3- (4-benzhydryl-1- piperazinyl! -propyl] ester 4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid - {2- [4- (2-methoxyphenyl) -1-piperιzinyl] ethyl} ester, 4- (2-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3, 4-oxadiazol-2-yl) pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (3-cyanophenyl) -1.4 dihydro-2,6-dimethyl-5- (1,3,4-oxadiazyol-2-yl) pyri din-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (3-cyanophenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 1,4-dihydro- 2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) -4- (2-trifluoromethylphenyl) pyridine-3-carboxylic acid {2- [4- (2-methoxyphenyl) - 1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl] -4- (2-trifluoromethylphenyl) pyridine- 3-carboxylic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-5- (1st , 3,4-oxadiazol-2-yl) pyridin-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2-chlorophenyl] -1 , 4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridin-3-carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} ester, 4- (2, -1,3-benzoxdiazol-4-yl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2,1,3-benzoxdiazol-4-yl) -1 , 4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] - pro¬pyl} ester ,. 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl ) -pyridin-3-carboxylic acid- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester, 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6- dimethyl-5- (1,3,4-oxadiazol-2-yl! pyridine-3-carboxylic acid {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} ester, 4- (2nd -Difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- {3- [4- (2-methoxyphenyl) - 1-piperazinyl] -propyl} ester, 1,4-dihydro-2-6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) -pyri¬din- 3-carboxylic acid- [2- {2- [4- (2-methokypheriyi) -1-piperazinyl] ethoxy} ethyl] ester 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- [2- {2- [4- (2-methoxyphenyl) -1-piperazinyllethoxy} ethyl ester and the salts of these compounds. The compounds of formula I have a chiral center at the 4-position in 1,4-dihydropyridine. The invention therefore encompasses both the enantiomers and, if a further chirality center is present, the diastereomers, and also their mixtures and racemates.
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen und ihrer Salze. Das Verfahren ist dadurch gekennzeichnet, daß manAnother object of the invention is a process for the preparation of the compounds according to the invention and their salts. The process is characterized in that
a) Alkenone der Formel IIa) Alkenones of the formula II
(II)
Figure imgf000027_0002
(II)
Figure imgf000027_0002
mit Enaminderivaten der Formel IIIwith enamine derivatives of the formula III
(III(III
Figure imgf000027_0001
oder
Figure imgf000027_0001
or
b) Alkenone der Formel II mit Ammoniak und ß -Ketocarbonsäure- derivaten der Formel IV ( IV !
Figure imgf000028_0003
oder c) Enamine der Formel Vb) Alkenones of the formula II with ammonia and β-ketocarboxylic acid derivatives of the formula IV (IV!
Figure imgf000028_0003
or c) enamines of formula V
(V)
Figure imgf000028_0002
mit Benzylidencarbonsäurederivaten der Formel VI(V)
Figure imgf000028_0002
with benzylidenecarboxylic acid derivatives of the formula VI
(VI),
Figure imgf000028_0001
oder d) Ketoverbindungen der Formel VII (VI),
Figure imgf000028_0001
or d) keto compounds of the formula VII
Figure imgf000029_0001
Figure imgf000029_0001
mit Ammoniak und Benzylidencarbonsaurederivaten der Formel VI, oderwith ammonia and benzylidenecarboxylic acid derivatives of the formula VI, or
e) Aldehyde der Formel VIIIe) aldehydes of the formula VIII
Figure imgf000029_0002
Figure imgf000029_0002
mit Enaminen der Formel V und ß-Ketocarbonsäurederivaten der Formel IV, oderwith enamines of the formula V and β-ketocarboxylic acid derivatives of the formula IV, or
f) Aldehyde der Formel VIII mit Enaminderivaten der Formel III und Ketoverbindungen der Formel VII, oderf) aldehydes of the formula VIII with enamine derivatives of the formula III and keto compounds of the formula VII, or
g) 1 , 4-Dihydropyridine der Formel IXg) 1, 4-dihydropyridines of the formula IX
Figure imgf000029_0003
mit Aminderivaten der Formel X
Figure imgf000029_0003
with amine derivatives of the formula X
( X ) ,
Figure imgf000030_0003
od er h ) 1 , 4 - Dihyd ropyridinderiva te der Formel XI(X),
Figure imgf000030_0003
or he h) 1, 4-Dihyd ropyridinderiva te of formula XI
Figure imgf000030_0002
mit Aminen der Formel XI I
Figure imgf000030_0002
with amines of the formula XI I
( xi ^ .
Figure imgf000030_0001
als solche(n) oder in Form ihrer Salze umsetzt und gewünschtenfalls anschließend erhaltene Salze in die freien Basen oder erhaltene Basen in die Salze überführt, wobei R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, Ar, Cy, A, G, x und y die oben angegebenen Bedeutungen haben, Z gemeinsam mit der Carbonylgruppe, woran es gebunden ist, eine Carboxylgruppe oder ein reaktives Carbonsäurederivat (z. 8. ein Carbonsäurehalogenid) und L eine Fluchtgruppe darstellt. ( xi ^.
Figure imgf000030_0001
as such (s) or in the form of their salts and, if desired, subsequently obtained salts are converted into the free bases or bases obtained into the salts, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, Ar, Cy, A, G, x and y have the meanings given above, Z together with the carbonyl group to which it is attached is a carboxyl group or a reactive carboxylic acid derivative (z. 8. a carboxylic acid halide) and L represents a leaving group .
Ausgestaltungen des Verfahrens sind solche, bei denen in den Formeln II bis XII die Substituenten bzw. Symbole R1 , R2, R3, R4, R5, RS, R7, R8, R9, R10, R11, R12, Ar, Cy, A, G, x und y dis in den Unter- und Nebenansprüchen angegebenen Bedeutungen haben, Z gemeinsam mit der Carbonylgruppe, woran es gebunden ist, eine Carboxylgruppe oder ein reaktives Carbonsäurederivat und L eine Fluchtgruppe darstallt.Embodiments of the method are those in which the formulas II to XII have the substituents or symbols R1, R2, R3, R4, R5, RS, R7, R8, R9, R10, R11, R12, Ar, Cy, A, G , x and y dis in the dependent and subsidiary claims have the meanings indicated, Z together with the carbonyl group, to which it is attached, a carboxyl group or a reactive carboxylic acid derivative and L represents a leaving group.
Das Verfahren gemäß den Varianten a bis f wird in geeigneten, vorzugsweise inerten organischen Lösungsmitteln durchgeführt. Beispielsweise seien genannt Alkohole, wie Ethanol, Methanol, Isopropanol oder insbesondere t-Butanol, Kohlenwasserstoffe, wie Toluol oder Xylol, Ether, wie Dioxan, Diethylather, Tetrahydrofuran, Glykolmonoethylether, Glykoldimethylether oder sonstige, beispielsweise polare Lösungsmittel wie Dimethylformamid, Dimethylsulfoκid, Acetonitril oder Hexamethylphosphorsäuretriamid, oder chlorierte Kohlenwasserstoffe wie Methylenchlorid, Chloroform oder Tetra- chlorethylen.The process according to variants a to f is carried out in suitable, preferably inert, organic solvents. Examples include alcohols, such as ethanol, methanol, isopropanol or in particular t-butanol, hydrocarbons, such as toluene or xylene, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethylsulfoκid, acetonitrile acid or hexamethylphosphoric acid , or chlorinated hydrocarbons such as methylene chloride, chloroform or tetrachlorethylene.
Die Reaktionstemperaturen können - je nach Reaktivität der Edukte - in einem weiten Bereich variieren. Im allgemeinen wird die Umsetzung beiDepending on the reactivity of the starting materials, the reaction temperatures can vary within a wide range. In general, the implementation
Temperaturen zwischen 20°C und 150°C, vorzugsweise zwischen 20°C undTemperatures between 20 ° C and 150 ° C, preferably between 20 ° C and
100°C, insbesondere bei der Siedetemperatur des verwendeten Lösungsmittels durchgeführt.100 ° C, especially at the boiling point of the solvent used.
Das Verfahren kann bei Normaldruck oder bei erhöhtem Druck durchgeführt werden, wobei das Arbeiten bei Normaldruck die Regel ist und erhöhter Druck insbesondere bei Umsetzungen mit Ammoniak, zur Anwendung kommen kann.The process can be carried out at atmospheric pressure or at elevated pressure, working at atmospheric pressure being the rule and elevated pressure can be used in particular in the case of reactions with ammonia.
Bei der Durchführung des erfindungsgemäßen Verfahrens gemäß Varianten a bis f werden die an der Reaktion beteiligten Stoffe in der Regel jeweils in molaren Mengen eingesetzt, wobei jedoch - je nach Reaktionsbedingung - gewünsch tenfalls auch ein Überschuß ( beispielsweise an Ammoniak bei den Varianten b und d) eingesetzt werden kann.When carrying out the process according to the invention according to variants a to f, the substances involved in the reaction are generally used in molar amounts, but - depending on the reaction condition - an excess is also desired (for example in ammonia in variants b and d) can be used.
Bei der Durchführung des Verfahrens gemäß Variante g kommen ähnliche Reaktionsbedingungen wie bei den Varianten a bis f zur Anwendung, jedoch sind - je nach Art des Substituenten Z - gegebenenfalls zusätzliche Maßnahmen erforderlich. Stellt Z beispielsweise eine Hydroxylgruppe dar, so ist die Reaktion bevorzugt in Gegenwart eines wasserabspaltenden oder wasserbindendnn Kondensationsmittels (wie z.B. Dicycloo e
Figure imgf000031_0001
Chloratom! dar, so ist dis Reaktion gewünschtenfalls in Gegenwart einer Sase (z. B. eine-s tertiären organischen Amins, wie Triethylamin , oder eines anorganischen Carbonates, wie Natriumcarbonat) durchzuführen.When carrying out the process according to variant g, similar reaction conditions are used as for variants a to f, but - depending on the nature of the substituent Z - additional measures may be necessary. If Z represents a hydroxyl group, for example, the reaction is preferably in the presence of a water-releasing or water-binding condensing agent (such as, for example, dicycloo e
Figure imgf000031_0001
Chlorine atom! if desired, the reaction is to be carried out in the presence of a sase (for example a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate).
Bei der Durchführung des Verfahrens gemäß Variante h kommen ähnliche Reaktionsbedingungen wie bei den Varianten a bis f zur Anwendung. Die Umsetzung erfolgt in einer Weise, wie sie für die Herstellung von sekundären bzw. tertiären Aminen bekannt ist. Je nach Art der Fluchtgruppe L, die vorzugsweise ein Halogenatom, insbesondere ein Chlor- oder δromatom ist, kann die Reaktion gewünschtenfalls in Gegenwart einer Base (z.B. eines anorganischen Carfaonates, wie Kaliumcarbonat) oder unter Einsetzung eines Überschusses von Amin XII durchgeführt werden.When carrying out the process according to variant h, similar 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. Depending on the nature of the leaving group L, which is preferably a halogen atom, in particular a chlorine or δromatom, the reaction can, if desired, be carried out in the presence of a base (e.g. an inorganic carfaonate, such as potassium carbonate) or using an excess of amine XII.
Die Isolierung und Reinigung der erfindungsgemäßen Substanzen erfolgt in an sich bekannter Weise z. B. derart, daß man das Lösungsmittel im Vakuum abdestilliert und den erhaltenen Rückstand aus ainem geeigneten Lösungsmittel umkristallisiert oder einer der üblichen Reinigungsmethoden , wie beispielsweise der Säulenchromatographie an geeignetem Trägermaterial, unterwirft.The substances according to the invention are isolated and purified in a manner known per se, for. B. in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
Säureadditionssalze erhält man durch Auflösen der freien Base in einem geeigneten Lösungsmittal, z.8. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, oder einem niedermolekularen ali- phatischan Alkohol (Ethanol, Isopropanol), das die gewünschte Säure enthält, oder dem die gewünschte Säure anschließend zugegeben wird .Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. 8. 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.
Dia Salze werden durch Filtrieren, Umfallen, Ausfällen mit einem Nichtlösungsmittel für das Anlagerungssalz oder durch Verdampfen des Lösungsmittels gewonnen.The slide salts are obtained by filtering, falling over, precipitating with a non-solvent for the addition salt or by evaporating the solvent.
Erhaltene Salze können durch Alkalisierung, z.B. mit wäßriger Ammoniaklösung, in dis freien Basen umgewandelt werden, welche wiederum in Säuraadditionssalze übergeführt werden können. Auf diese Weise lassen sich pharmakologisch nicht verträgliche Säureadditionssalze in pharmakologisch verträgliche Säureadditionssalze umwandeln. Die Ausgangsverbindungen sind teilweise literaturbekannt oder können in Analogie zu litera turbekannten Methoden hergestellt werden. Die Ketoverbindungen VII, in denen Ar einen 2-Alkyltetrazol-5-ylrest darstellt, sind in Analogie zu T. Isida et al., J. Org . Chem. 36, 3807 (1971) durch Umla- gerung aus XIII erhältlich.Salts obtained can be converted into dis-free bases by alkalization, for example with aqueous ammonia solution, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts. Some of the starting compounds are known from the literature or can be prepared analogously to methods known from the literature. The keto compounds VII, in which Ar represents a 2-alkyltetrazol-5-yl radical, are analogous to T. Isida et al., J. Org. Chem. 36, 3807 (1971) can be obtained by rearrangement from XIII.
(XIII.(XIII.
Figure imgf000033_0001
Figure imgf000033_0001
XIII ist aus entsprechend substituierten 5-R2-Isoxazolen durch Alkylierung z. B. mit Di-R3-sulfaten und anschließende Umsetzung mit Alkaliazid in Analogie zu R. B. Woodward et al., Tetrahedron Suppl. 7, 415 (1966) zugänglich. - Die Ketoverbindungen VII, in denen Ar einen 1,3,4-Oxadiazol-2- ylrest darstellt, sind in den Monatsheften Chem. 113. 781 (1982) beschrieben. - Die Akenone II können beispielsweise durch Kondensation von VII mitXIII is from appropriately substituted 5-R2-isoxazoles by alkylation z. B. with Di-R3 sulfates and subsequent reaction with alkali azide in analogy to R. B. Woodward et al., Tetrahedron Suppl. 7, 415 (1966) accessible. - The keto compounds VII, in which Ar represents a 1,3,4-oxadiazol-2-yl radical, are described in the monthly magazines Chem. 113, 781 (1982). - The Akenone II can, for example, by condensation of VII with
VIII in Analogie zu G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)] oder - sofern Ar einen 2-Alkyltetrazol-5- ylrest darstellt - von XIII mit VIII und anschließende Umlagerung gemäß T. Isida et al. J. Org. Chem. 36, 3807 (1971) hergestellt werden. Die Enaminderivate III und die Benzylidencarbonsäurederiva te VI sind teilweise aus der EP-A-0 175 956 bekannt oder analog erhältlich. Die Enamine V sind beispielsweise analog A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)] erhältlich. ß-Ketocarbonsäurederivate IV können gemäß D. Borrmann ["Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" in Houben-Weyl, Methoden der Organischen Chemie, Vol. VII/4, 230ff (1968)] oder Y. Oikawa et al. [J. Org. Chem. 43, 2087 (1973)] hergestellt werden. Die VerbindungenVIII in analogy to G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)] or - if Ar represents a 2-alkyltetrazol-5-yl radical - of XIII with VIII and subsequent rearrangement according to T Isida et al. J. Org. Chem. 36, 3807 (1971). The enamine derivatives III and the benzylidenecarboxylic acid derivatives VI are known in part from EP-A-0 175 956 or can be obtained analogously. The enamines V are, for example, analogous to A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)]. ß-Ketocarbonsäurederivate IV 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 (1973)]. The connections
IX sind aus entsprechenden Ausgangsverbindungen analog Verfahrensvariante a bis f zugänglich. Verbindungen X sind durch Umsetzung entsprechender Pi- peridine bzw. Piperazine mit omega-Halogenalkanolen erhältlich. Die Dihydropyridinderivate XI erhält man durch Umsetzung von Enaminen der Formel V mit z.B. entsprechend substituierten omega-Halogen-2-acyl-acrylsäureestern, die ihrerseits wiederum aus Aldehyden der Formel VIII und geeigneten beta-Keto-omega-halogencarbonsäureestern zugänglich sind.IX are accessible from corresponding starting compounds analogously to process variants a to f. Compounds X can be obtained by reacting corresponding peridines or piperazines with omega-haloalkanols. The dihydropyridine derivatives XI are obtained by reacting enamines of the formula V with, for example, appropriately substituted omega-halo-2-acyl-acrylic acid esters, which in turn are accessible from aldehydes of the formula VIII and suitable beta-keto-omega-halocarboxylic acid esters.
Die vorstehenden Herstellungsverfahren sing lediglich zur Verdeutlichung angegeben, und die Herstellung der erfindungsgemäßen Verbindungen der Formel I ist nicht auf diese Verfahren beschränkt. Vielmehr ist auch jede Modifikation dieser Verfahren in gleicher Weise für die Herstellung der erfindungsgemäßen Verbindungen anwendbar.The above preparation processes are given for illustration only, and the preparation of the compounds of formula I according to the invention is not restricted to these processes. Rather, any modification of these processes can be used in the same way for the preparation of the compounds according to the invention.
Die folgenden Herstellungsbeispiele sollen die Erfindung näher erläutern, ohne sie einzuschränken. Fp. bedeutet Schmelzpunkt, h steht für Stunden, Kp. steht für Siedepunkt, Zers. bedeutet Zersetzung. The following production examples are intended to explain the invention in more detail without restricting it. Fp. Means melting point, h stands for hours, Kp. Stands for boiling point, dec. means decomposition.
Bei s pieleAt games
EndprodukteEnd products
1. 1,4-Dihydro-2,6-dimethyl-5-(2-methyl-tetrazol-5-yl)-4-(3-nitrophe- nyl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]- ester-hemifumarat1. 1,4-dihydro-2,6-dimethyl-5- (2-methyl-tetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [3- (4, 4-diphenyl-1-piperidinyl) propyl] ester hemifumarate
2.7 g 2-(2-Methyltetrazol-5-yl)-1-(3-nitrophenyl)-1-buten-3-on und2.7 g of 2- (2-methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one and
3.8 g 3-Aminocrotonsäure-[3-(4,4-diphenyl-1-piperidinyl)propyl]ester werden in 50 ml tert. Butanol gelöst. Das Gemisch wird 26 Stunden unter einer Stickstoffathmosphare zum Sieden erhitzt. Danach wird im Vakuum zur Trockne eingedampft und der Rückstand über eine Kieselgelsäule mit Chloroform/Ethanol 95:5 als Laufmittel chromatographiert. Die reinen Produktfraktionen werden vereinigt und im Vakuum eingeengt. Der nach Trocknen in Hochvakuum zurückbleibende erstarrte Schaum (4,4 g) wird in 20 ml Methanol gelöst, 0,4g Fumarsäure zugegeben und das Gemisch solange erwärmt, bis eine klare Lösung enstan- den ist. Es wird filtriert, wieder eingeengt und der Rückstand mit3.8 g of 3-aminocrotonic acid [3- (4,4-diphenyl-1-piperidinyl) propyl] ester are tert in 50 ml. Butanol dissolved. The mixture is heated to boiling under a nitrogen atmosphere for 26 hours. The mixture is then evaporated to dryness in vacuo and the residue is chromatographed on a silica gel column using chloroform / ethanol 95: 5 as the eluent. The pure product fractions are combined and concentrated in vacuo. The solidified foam (4.4 g) which remains after drying under high vacuum is dissolved in 20 ml of methanol, 0.4 g of fumaric acid is added and the mixture is warmed until a clear solution is obtained. It is filtered, concentrated again and the residue with
Ether/Ethanol angerieben, abgesaugt, mit Ether gewaschen und getrock- net. Man erhält 3,9 g der Titelverbindung vom Fp. 180-82°C (Zers.)Grated ether / ethanol, suction filtered, washed with ether and dried. 3.9 g of the title compound of mp 180 ° -82 ° C. (dec.) Are obtained.
2. 1,4-Dihydro-2,6-dimethyl-5-(2-methyl-tetrazol-5-yl)-4-(3-nitrophe- nyl)oyridin-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)ethyl)lester-he- mifumarat2. 1,4-Dihydro-2,6-dimethyl-5- (2-methyl-tetrazol-5-yl) -4- (3-nitrophenyl) oyridine-3-carboxylic acid- [2- (4-phenyl -1-piperazinyl) ethyl) lester hemifumarate
1,6 g 2-(2-Methyltetrazol-5-yl-1-(3-nitrophenyl)-1-buten-3-on und 1,9 g 3-Aminocrotonsäure-[2-(4-phenyl-1-piperazinyl) ethyllester in 30 ml 2-Propanol werden unter einer Stickstoffathmosphare 20 Stunden zum Sieden erhitzt. Das nach Einengen des Reaktionsgemisches verbleibende öl wird über eine Kieselgelsäule mit Chloroform/Methanol 9:1 als Laufmittel chromatograflert. Die reinen. Produktfraktionen werden zur Trockene eingedampft, das zurückbleibende öl (3,2 g) in 20 ml Methanol gelöst und 0,34 g Fumarsäure unter Erwärmen zugegeben. Noch in der Wärme beginnt die Titelverbindung auszukristallisieren. Nach Stehen über Nacht wird abesaugt, mit Methanol gewaschen und nochmals aus ca. 35 ml Ethanol umkristallisiert. Nach Absaugen, Waschen mit Ethanol und Trocknen im Vakuum erhält man 2,5 g der Titelverbindung vom Fp. 162-164°C.1.6 g of 2- (2-methyltetrazol-5-yl-1- (3-nitrophenyl) -1-buten-3-one and 1.9 g of 3-aminocrotonic acid- [2- (4-phenyl-1-piperazinyl ) ethyl esters in 30 ml of 2-propanol are heated to boiling under a nitrogen atmosphere for 20 hours, the oil remaining after concentration of the reaction mixture is chromatographed on a silica gel column using chloroform / methanol 9: 1 as the eluent, and the pure product fractions are evaporated to dryness residual oil (3.2 g) dissolved in 20 ml of methanol and 0.34 g of fumaric acid was added with heating the heat starts to crystallize the title compound. After standing overnight, the product is filtered off with suction, washed with methanol and recrystallized again from about 35 ml of ethanol. After suction, washing with ethanol and drying in vacuo, 2.5 g of the title compound of mp 162-164 ° C are obtained.
3. 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)- pyridin-3-carbonsäure-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}- ester-hemifurarat3. 1,4-Dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [3- [4- (2-methoxyphenyl ) -1-piperazinyl] propyl} - ester hemifuran
Analog Beispiel 2 werden aus 2,7 g 2-(2-Methyltetrazol-5-yl)-1-(3-ni- trophenyl) -1 -buten-3-on und 3,3 g 3-Aminocrotonsäure-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}ester 3,5 g der freien Base erhalten und in 30 ml Methanol mit 0,35 g Fumarsäure in das Hemifumarat überführt. Nach zweimaligem Umkristallisieren aus Ethanol/2-Propanol erhält man 2,7 g der Titelverbindung vom Fp. 168,5-170,5°C (Zers.).Analogously to Example 2, 2.7 g of 2- (2-methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one and 3.3 g of 3-aminocrotonic acid- {3- Obtained [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester 3.5 g of the free base and converted into the hemifumarate in 30 ml of methanol with 0.35 g of fumaric acid. After recrystallization twice from ethanol / 2-propanol, 2.7 g of the title compound of mp 168.5-170.5 ° C. (decomp.) Are obtained.
4. 1,4-Dihydro-2.6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)- pyridin-3-carbonsäure-[3-[4-benzhydryl-1-piperazinyl)propyl]ester-fu- marat4. 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [3- [4-benzhydryl-1-piperazinyl) propyl] ester fumarate
Analog Beispiel 2 werden aus 2,43 g 2-(2-Methyltetrazol-5-yl)-1- (3-nitrophenyl)-1-buten-3-on und 3,5 g 3-Aminocrotonsäure-[3-(4-benzhydryl-1-piperazinyl)propyl]ester 3,2 g der freien Base erhalten und mit 0,8 g Fumarsäure in das Fumarat überführt. Die methanolische Lösung wird zur Trockene eingedampft und der Rückstand aus Ether/Ethyl- acetat kristallisiert. Man erhält 2,4 g der Titelverbindung vom Fp. 135-140°C.Analogously to Example 2, 2.43 g of 2- (2-methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one and 3.5 g of 3-aminocrotonic acid- [3- (4th -benzhydryl-1-piperazinyl) propyl] ester 3.2 g of the free base obtained and converted into the fumarate with 0.8 g of fumaric acid. The methanolic solution is evaporated to dryness and the residue is crystallized from ether / ethyl acetate. 2.4 g of the title compound of mp 135-140 ° C. are obtained.
5. 1,4-Dihydro-2,6-dimethyl-5-(2-methyItetrazol-5-yl)-4-(3-nitrophenyl)- pyridin-3-carbonsäure-[2-(4-benzhydryl-1-piperazinyl)ethyllester-fumarat5. 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [2- (4-benzhydryl-1- piperazinyl) ethyl ester fumarate
Analog Beispiel 2 werden aus 4,1 g 2-(2-Methyltetrazol-5-yl)-1-(3-ni- trophenyl)-1-buten-3-on und 5,7 g 3-Aminocrotonsäure-[2-(4-benzhy- dryl-1-piperazinyl) ethyllester 3,85 g der freien Base erhalten und mit 0,7 g Fumarsäure in das Fumarat überführt. Die methanolische Lösung wird zur Trockene eingedampft und der Rückstand aus Ethylacetat kristallisiert. Man erhält 2,9 g der Titelverbindung vom Fp. 143-146°C.Analogously to Example 2, 4.1 g of 2- (2-methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one and 5.7 g of 3-aminocrotonic acid [2- (4-benzohydryl-1-piperazinyl) ethyl ester 3.85 g of the free base obtained and converted into the fumarate with 0.7 g of fumaric acid. The methanolic solution is evaporated to dryness and the residue from ethyl acetate crystallized. 2.9 g of the title compound of mp 143-146 ° C. are obtained.
6. 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)- pyridin-3-carbonsäυre-{3-[4-(2-methoxyphenyl-1-piperazinyl)propyl}- ester6. 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl-1-piperazinyl) propyl} ester
1,4 g 2-Acetonyl-1,3,4-oxadiazol, 1,7 g 3-Nitrobenzaldehyd und 3,7 g 3-Aminocrotonsäure-{3-[4-[2-methoxyphenyl)-1-piperazinyl]propyl}ester werden in 60 ml tert. Butanol gelöst und das Gemisch 22 Stunden unter einer Stickstoffathmosphare zum Sieden erhitzt. Nach Abkühlen wird mit Ether versetzt und angerieben. Das auskristallisierte Produkt wird abgesaugt und noch zweimal aus Ethylacetat bzw. Ethylacetat/ Ethanol umkristallisiert. Man erhält 2,5 g der Titelverbindung vom Fp. 187-189°C.1.4 g of 2-acetonyl-1,3,4-oxadiazole, 1.7 g of 3-nitrobenzaldehyde and 3.7 g of 3-aminocrotonic acid- {3- [4- [2-methoxyphenyl) -1-piperazinyl] propyl} esters are tert in 60 ml. Butanol dissolved and the mixture heated to boiling under a nitrogen atmosphere for 22 hours. After cooling, ether is added and the mixture is rubbed in. The product which has crystallized out is filtered off with suction and recrystallized twice more from ethyl acetate or ethyl acetate / ethanol. 2.5 g of the title compound of mp. 187-189 ° C. are obtained.
7. 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1.3,4-oxadiazol-2-yl)- pyridin-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)ethyl]ester7. 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid- [2- (4-phenyl- 1-piperazinyl) ethyl] ester
1,9 g 2-Acetonyl-1,3,4-oxadiazol, 2,3 g 3-Nitrobenzaldehyd und 4,35 g 3-Aminocrotonsäure-[2-(4-phenyl-1-piperazinyl)ethyl]ester werden in 100 ml 2-Propanol gelöst und das Gemisch 22 Stunden unter einer Stickstoffathmosphare zum Sieden erhitzt. Nach Abkühlen wird die Lösung im Vakuum etwa zur Hälfte eingeengt und dann 2 Tage bei Raumtemperatur stehengelassen. Das auskristallisierte Produkt wird abgesaugt und noch einmal aus 2-Propanol umkristallisiert. Man erhält 4,5 g der Titelverbindung vom Fp. 158-150°C. 1.9 g of 2-acetonyl-1,3,4-oxadiazole, 2.3 g of 3-nitrobenzaldehyde and 4.35 g of 3-aminocrotonic acid [2- (4-phenyl-1-piperazinyl) ethyl] ester are converted into 100 ml of 2-propanol dissolved and the mixture heated to boiling under a nitrogen atmosphere for 22 hours. After cooling, the solution is concentrated in vacuo by about half and then left to stand at room temperature for 2 days. The product which has crystallized out is filtered off with suction and recrystallized again from 2-propanol. 4.5 g of the title compound of mp 158-150 ° C. are obtained.
AusgangsverbindungenOutput connections
A. 2- (2-Methyltetrazol-5-yl)-1-(3-nitrophenyl)-1-buten-3-onA. 2- (2-Methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one
8 g 2-(1-Methyltetrazol-5-yl)-1-(3-nitrophenyl)-1-buten-3-on werden in einem Glasautoklaven in 120 ml Methylnodid 96 Stunden auf 150°C erhitzt. Nach Abkühlen wird das überschüssige Methyljodid abdestilliert und der Rückstand mit Ethylacetat versetzt; dabei kristallisiert die Titelverbindung aus. Es wird abgesaugt, mit Ethylacetat gewaschen und getrocknet. Man erhält 4,6 g vom Fp. 166-72°C.8 g of 2- (1-methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one are heated in a glass autoclave in 120 ml of methylnodide at 150 ° C. for 96 hours. After cooling, the excess methyl iodide is distilled off and the residue is mixed with ethyl acetate; the title compound crystallizes out. It is filtered off, washed with ethyl acetate and dried. 4.6 g of mp 166-72 ° C. are obtained.
B. 2-(1-Methyltetrazol-5-yl)-1-(3-nitrophenyl)-1-buten-3-onB. 2- (1-Methyltetrazol-5-yl) -1- (3-nitrophenyl) -1-buten-3-one
27 g 3-Nitrobenzaldehyd und 25 g 5-Acetonyl-1-methyltetrazol werden in 250 ml Dichlorethan gelöst. In die Lösung wird bei 0°C trockener Chlorwasserstoff bis zur Sättigung eingeleitet. Das Reaktionsgefäß wird fest verschlossen und dann 4 Tage bei Raumtemperatur stehengelassen. Das Reaktionswasser wird im Scheidetrichter abgetrennt und zur Trockne eingeengt, der Rückstand wird in 500 ml Methylenchlorid gelöst, die Lösung mit 250 ml 0,1 N Natronlauge und mit Wasser gewaschen, über Natriumsulfat getrocknet und wieder eingeengt. Der halbkristalline Rückstand wird mit 80 ml Ethylacetat versetzt und die Mischung zum Sieden erhitzt. Nach langsamem Abkühlen und 12-stündigem Stehen bei 5°C wird das kristalline Produkt abgesaugt, mit kaltem27 g of 3-nitrobenzaldehyde and 25 g of 5-acetonyl-1-methyltetrazole are dissolved in 250 ml of dichloroethane. Dry hydrogen chloride is introduced into the solution at 0 ° C until saturation. The reaction vessel is tightly closed and then left to stand for 4 days at room temperature. The water of reaction is separated off in a separating funnel and evaporated to dryness, the residue is dissolved in 500 ml of methylene chloride, the solution is washed with 250 ml of 0.1N sodium hydroxide solution and with water, dried over sodium sulfate and concentrated again. The semi-crystalline residue is mixed with 80 ml of ethyl acetate and the mixture is heated to boiling. After slow cooling and standing at 5 ° C for 12 hours, the crystalline product is filtered off with cold
Ethylacetat gewaschen und getrocknet. Man erhält 23,1 g der Titelver- bmdung vom Fp. 144-146°C.Washed and dried ethyl acetate. 23.1 g of the title compound of mp 144-146 ° C. are obtained.
C. 5-Acetonyl-1-methyltetrazolC. 5-Acetonyl-1-methyltetrazole
78 g 5-Methyl-isoxazol werden in 180 ml absolutem Toluol gelöst und dann 103 ml Dimethylsulfat unter kräftigem Rühren bei 70-80°C zugetropft. Danach wird 1 Stunde unter Rückfluß zum Sieden erhitzt und über Nacht stehengelassen. Das überstehende Toluol wird vom entstandenen öl abdekantiert, das Öl noch zweimal mit Ether verrührt und je- weils abdekantiert und dann im Vakumm getrocknet. Das ölige Produkt wird in 300 ml Ethanol ge löst. 60,9 g Natriumazid werden portionsweise unter kräftigem Rühren zugegeben, wobei durch externe Kühlung, die Innentemperatur bei 30-40°C gehalten wird. Nach beendeter Zugabe wird noch 5 Stunden bei Raumtemperatur gerührt und wiederum über Nacht stehengelassen. Das Gemisch wird im Vakuum zur Trockne eingeengt, der Rückstand. in 1,6 1 Methylenchlorid aufgenommen und dann soviel Wasser zugesetzt, daß gerade zwei klare Phasen entstehen. Nach Trennung der Phasen wird die wässerige Phase nochmals mit Methylenchlorid extrahiert, die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und dann in Vakuum zur Trockne eingedampft. Der spontan kristallisierende Rückstand wird mit Ethylacetat verrieben, abgesaugt, mit Ethylacetat gewaschen und getrocknet. Man erhält 93 g vom Fp. 74-76°C.78 g of 5-methyl-isoxazole are dissolved in 180 ml of absolute toluene and 103 ml of dimethyl sulfate are then added dropwise at 70-80 ° C. with vigorous stirring. The mixture is then heated to boiling under reflux for 1 hour and left to stand overnight. The supernatant toluene is decanted off from the resulting oil, the oil is stirred twice more with ether and decanted and then dried in a vacuum. The oily product is dissolved in 300 ml of ethanol. 60.9 g of sodium azide are added in portions with vigorous stirring, the internal temperature being kept at 30-40 ° C. by external cooling. After the addition has ended, the mixture is stirred for a further 5 hours at room temperature and again left to stand overnight. The mixture is evaporated to dryness in vacuo, the residue. taken up in 1.6 1 of methylene chloride and then so much water added that just two clear phases are formed. After separation of the phases, the aqueous phase is extracted again with methylene chloride, the combined organic phases are dried over sodium sulfate and then evaporated to dryness in vacuo. The spontaneously crystallizing residue is triturated with ethyl acetate, suction filtered, washed with ethyl acetate and dried. 93 g of mp 74-76 ° C. are obtained.
D . 3-Aminocrotonsäure-{3-[4-(2-rnethoxyphenyl)-1-piperazinyl]-propyl}- esterD. 3-aminocrotonic acid {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester
25 g 3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propanol werden in 100 ml Methylenchlorid gelöst und mit einer Spatels-pitze 4-Dimethylaminopy- ridin versetzt. Dann werden unter kräftigem Rühren 20 ml einer 50%igan Diketenlösung in Aceton zugetropft. Das Gemisch wird über Nacht bei Raumtemperatur stehengelassen. Nach Einengen im Vakuum wird der verbliebene Rückstand unter Kühlung mit ca. 200 ml einer gesättigten Lösung von Ammoniak in Isopropanol versetzt und das Gemisch drei Tage im gut verschlossenen Gefäß bei Raumtemperatur stehengelassen. Nach Animpfen mit der Titelverbindung beginnt das Produkt zu kristallisieren. Es wird gut gekühlt, abgesaugt und über Calcium° chlorid getrocknet. Man erhält 28,5 g vom Fp. 114-115°C.25 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] propanol are dissolved in 100 ml of methylene chloride and a spatula tip of 4-dimethylaminopyridine is added. Then 20 ml of a 50% diketene solution in acetone are added dropwise with vigorous stirring. The mixture is left overnight at room temperature. After concentration in vacuo, about 200 ml of a saturated solution of ammonia in isopropanol are added to the remaining residue while cooling, and the mixture is left to stand in a well-sealed vessel at room temperature for three days. After inoculation with the title compound, the product begins to crystallize. It is cooled well, suctioned off and dried over calcium chloride. 28.5 g of mp 114-115 ° C. are obtained.
E. 3 -Aminocrotonsäure-[2-(4-phenyl-1-pierazinyl)ethyl]esterE. 3 aminocrotonic acid [2- (4-phenyl-1-pierazinyl) ethyl] ester
Analog Bei spiel D erhält man die Titelverbindung ausgehend von 2-(4-Phenyl-1-piperazinyl)elthanol. Fp. 58-60°C (aus Methanol). F. 3-Aminocrotonsäure-[3-(4-benzhvdryl-1-piperazinyl)propyllesterAnalogously to game D, the title compound is obtained starting from 2- (4-phenyl-1-piperazinyl) ethanol. Mp 58-60 ° C (from methanol). F. 3-aminocrotonic acid [3- (4-benzhvdryl-1-piperazinyl) propyl ester
Analog Beispiel D erhält man die Titelverbindung ausgehend vonAnalogously to example D, the title compound is obtained from
3- (4-Benzhydryl-1-piperzinyl)propanol als Öl, das ohne weitere Rei nigung weiter umgesetzt wird.3- (4-Benzhydryl-1-piperzinyl) propanol as an oil, which is further reacted without further purification.
G. 3-Aminoerotonsäure-[2-(4-benzhydryl-1-piperazinyl)ethyllesterG. 3-Aminoerotonic acid [2- (4-benzhydryl-1-piperazinyl) ethyl ester
Analog Seispiel D erhält man die Titelverbindung ausgehend von 2-(4-Benzhydryl-1-piperazinyl)ethanol als öl, das ohne Reinigung weiter umgesetzt wird. Analogously to Example D, the title compound is obtained starting from 2- (4-benzhydryl-1-piperazinyl) ethanol as an oil, which is reacted further without purification.
Gewerbliche AnwendbarkeitIndustrial applicability
Die erfindungsgemäßen Verbindungen der Formel I und ihre Salze besitzen wertvolle Eigenschaften, die sie gewerblich verwertbar machen. Sie stellen insbesondere wirksame Vasodilatoren mit coronartherapeutischen Eigenschaften dar. Die pharmakologische Wirksamkeit der erfindungsgemäßen Verbindungen zeigt sich insbesondere in einer langsam eintretenden und starken Blutdrucksenkung. Darüberhinaus besitzen die erfindungsgemäßen Verbindungen hemmende Wirkung auf den Calciumeinstrom sowie fördernde Wirkung auf den Kaliumausstrom von Zellen, glattmuskulär relaxierende und peripher, coronar, cerebral und renal gefäßerweiternde sowie salidiuretische, antithrombotische und günstige hämorheologische Eigenschaften.The compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are in particular effective vasodilators with coronary therapeutic properties. The pharmacological activity of the compounds according to the invention is particularly evident in a slowly occurring and strong drop in blood pressure. In addition, the compounds according to the invention have an inhibitory effect on calcium influx and a promotional effect on potassium outflow from cells, smooth muscle relaxing and peripheral, coronary, cerebral and renal vasodilator and salidiuretic, antithrombotic and favorable hemorheological properties.
In ihrer ausgezeichneten Wirksamkeit, die gepaart ist mit einer geringen Toxizität und dem Fehlen wesentlicher Nebenwirkungen, unterscheiden sich die erfindungsgemäßen Verbindungen in überraschender und vorteilhafter Weise von den Verbindungen des Standes der Technik.The compounds according to the invention differ surprisingly and advantageously from the compounds of the prior art in their excellent activity, which is paired with low toxicity and the absence of significant side effects.
Als vorteilhafte Eigenschaften der Verbindungen I sind beispielsweise zu nennen: das Ausmaß der Blutdrucksenkung, die gute Steuerbarkeit der Blut- drucksenkung, die im Vergleich zu den Verbindungen des Standes der Technik überraschend geringe Herzfrequenzsteigerung, die ausgezeichnete BioverfGg- barkeit, die große therapeutische Breite, das Fehlen zentraler Nebenwirkungen, das Fehlen kinetischer Interaktionen mit anderen Substanzen, das Ausbleiben einer Toleranzentwicklung, die ausgewogenen physikalischen Eigenschaften und die große Stabilität.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, the surprisingly small increase in heart rate 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.
Die ausgezeichnete Wirksamkeit der erfindungsgemäßsn Verbindungen der Formel I und ihrer Salze gestattet ihren Einsatz in der Humanmedizin, wobei als Indikation insbesondere primäre (essentielle) und sekundäre, arterielle und pulmonale Hypertonien aller Schweregrade, koronare Herzkrankheiten (Koronarinsuffizienz, Angina Pectoris, Myocardinfarkt etc.), periphere und cerebrale Zirkulationsstörungen (Gehirnschlag, tamporära cerebrale Durchblutungsstörungen, Migräne, Schwindel, renale Arterienverengung etc.), hypertrophe Kardiomyophthie, Herzinsuffizienz, Krankheiten, die auf einer echöhtan Wasser- und Natriumretention beruhen und Krankheiten, die auf einem erhöhten Calciumeinstrom beruhen, wie z.B. Spasmen glattmuskulärer Organe (Atemwege, Gastrointestinaltrakt, Urogenitaltrakt etc.) sowie Arrhythmie und Arteriosklerose, in Betracht kommen.The excellent activity of the compounds of the formula I and their salts according to the invention permits their use in human medicine, with primary (essential) and secondary, arterial and pulmonary hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.) being used as indications, peripheral and cerebral circulatory disorders (stroke, tampora cerebral circulatory disorders, migraines, dizziness, renal artery narrowing etc.), hypertrophic cardiomyophthia, heart failure, diseases that are based on an echoed water and sodium retention and diseases based on an increased influx of calcium, such as spasms of smooth muscle organs (respiratory tract, gastrointestinal tract, urogenital tract, etc.), as well as arrhythmia and arteriosclerosis.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behandlung von Säugetieren, insbesondere Menschen, die an einer der obengenannten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Individuum eine therapeutisch wirksame und pharmakologisch verträgliche Menge einer oder mehrerer Verbindungen der Formel I verabreicht. Gegenstand der Erfindung sind außerdem die Verbindungen der Formel I zur Anwendung bei der Behandlung der genannten Krankheiten.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.
Ebenso umfaßt die Erfindung die Verwendung von Verbindungen der Formel I bei der Herstellung von Arzneimitteln, die zur Bekämpfung der genannten Krankheiten eingesetzt werden.The invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die eine oder mehrere Verbindungen der allgemeinen Formel I enthalten.The invention further relates to medicaments which contain one or more compounds of the general formula I.
Die Arznaimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die erfindungsgemäßen pharmakologisch wirksamen Verbindungen (=Wirkstoffe) entweder als solche, oder vorzugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emulsionen, Suspensionen, Aerosolen, Sprays, Salben, Cremes, Gelen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95% beträgt.The medicinal products are produced by processes known per se and familiar to the person skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as medicinal products either as such, or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions, aerosols, sprays, Ointments, creams, gels or solutions are used, the active substance content advantageously being between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Tabletten, Hilfsstoffen und anderen Wirkstoffträgem können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentian, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromo- toren und Komplaxbildner (z.B. Cyclodextrine) verwendet werden. Die Wirkstoffe können oral, rektal, per inhalationem oder parenteral (insbesondere perlingual, intravenös oder percutan) appli∑iert werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablets, auxiliaries and other active ingredients, for example antioxidants, dispersants, emulsifiers, defoamers, flavor correctants, preservatives, solubilizers, colorants or, in particular, permeation promoters and co-formers (eg cyclodextrins) can be used. The active compounds can be administered orally, rectally, by inhalation or parenterally (in particular perlingually, intravenously or percutaneously).
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,01 bis etwa 10, vorzugsweise 0,05 bis 5 mg/kg Körpergewicht, gewünschtenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Regel niedrigera Dosierungen zur Anwendung kommen. Bei einschleichender Dosierung wird zu Beginn der Behandlung eine geringere Oosis verabreicht, dann langsam auf eine höhere Dosis übergegangen. Nach Erreichen des gewünschten Therapieerfolges wird wieder auf eine niedrigere Dosis zurückgegangen.In general, it has proven to be advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or (in particular in the case of intravenous administration of the active compounds) generally lower doses can be used. If the dose creeps in, a lower dose is administered at the beginning of the treatment, then the dose is slowly switched to a higher dose. After the desired therapeutic success has been reached, the dose is reduced again.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.The determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.
Sollen die erfindungsgemäßen Verbindungen und/oder ihre Salze zur Behandlung der genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere andere pharmakologisch aktive Bestandteile anderer Arzneimittelgruppen, wie andere Vasodilatoren, Antihypertensiva, alpha-1-Rezeptoren blocker, alpha-2-Rezeptorstimulatoren, beta-1-Rezeptorenblocker, beta-2-Rezeptorstimulatoren, ACE-Hemmstoffe, Nitroverbindungen, Cardiotonika, Diuretika, Saluretika, Alkaloide, Analgetika, Lipidsenker, Antikoagulantien, Anticholinargika, Mathylxanthine, Antiarrhythmika, Antihistaminika, Dopaminstimulatoren, Serotonin-Rezeptorsnblocker etc., wie Nifedipin, Dihydralazin, Prazosin, Clonidin, Atenolol, Labetalol, Fenoterol, Captopril, Isosorbiddinitrat, Digoxin, Milrinon, Mefrusid, Clopamid, Spironolacton, Chlorthalidon, Furosemid, Polythiazid, Hydrochlorothiazid, Reserpin, Dihydroergocristin, Rescinnamin, Rauwolfia-Gesamtalkaloide, Acetylsalicylsäure, Bezafibrat, Warfarin, Atropin, Theophyllin, Lidocain, Astemizol, Bromocryptin, Ketanserin etc. enthalten. PharmakologieIf the compounds according to the invention and / or their salts are to be used for the treatment of the diseases mentioned, the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other pharmaceutical groups, such as other vasodilators, antihypertensives, alpha-1 receptor blockers, alpha-2- Rezeptorstimulatoren, beta-1-adrenergic antagonists, beta-2-Rezeptorstimulatoren, ACE inhibitors, nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, analgesics, lipid lowering agents, anticoagulants, Anticholinargika, Mathylxanthine, antiarrhythmic agents, antihistamines, Dopaminstimulatoren, serotonin Rezeptorsnblocker etc., such as nifedipine, dihydralazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefrusid, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, resergocalinium hydride, reserginicinalinolidium, reserginicinhydrochloride, resergin aminolidium, resergin aminolinethalidium, resergin aminoletin, resergin aminolinethalidium, resergin aminoletin, resergin aminoletin, resergin aminoletin, resergin aminoletin, resergin aminoletin, resergin aminoletin, acetaminophen, resergin aminoletin, resergin aminoletin, resergin aminolidium, resergin aminoletin, resergin aminoletin, acetaminophenin , W arfarin, atropine, theophylline, lidocaine, astemizole, bromocryptin, ketanserin etc. pharmacology
Die antihypertensive Wirksamkeit der erfindungsgemäßen Verbindungen kann am Modell der spontan hypertonen Ratte nachgewiesen werden.The antihypertensive activity of the compounds according to the invention can be demonstrated on the model of the spontaneously hypertensive rat.
Zur Bestimmung dar antihypertensiven Wirkung werden die unten aufgeführten Verbindungen in den angegebenen Dosen an vier aufeinander folgenden Tagen an je 6 männlichen Ratten (Stamm SHR/N/ Ibm/8m, 250-350 g) mit genetisch bedingtem Hochdruck (systolischer 31utdruck > 130 mmHg) täglich einmal mittels Schlundsonde verabfolgt. Die Messung des Blutdrucks erfolgt jeweils 6 und gegebenenfalls 2 oder 24 Stunden nach Substanzgabe.To determine the antihypertensive effect, the compounds listed below are given in the doses given on four consecutive days on 6 male rats (strain SHR / N / Ibm / 8m, 250-350 g) with genetically determined high pressure (systolic high pressure> 130 mmHg) administered once a day by gavage. Blood pressure is measured 6 and, if necessary, 2 or 24 hours after substance administration.
Dia Blutdruckmessung wird in einer Warmekammer bei 36°C vorgenommen, um eine bessere Durchblutung der Schwanzarterie zu erreichen. Hierzu werden die Tiere in perforierte Lochblechkäfige verbracht und 20 - 40 Min. nach Beginn der Aufwärmung gemessen. Zur Messung des systolischen arteriellen Drucks wird eine ringförmige Manschette mit aufblasbarer Gummimembran zur Unterbindung der Durchblutung und ein ringförmiger Piezokristallaufnehmer zur Erfassung der Pulswellen auf den Schwanz aufgeschoben. Nach erfolgter Unterbindung des Blutstroms in der Schwanzarterie wird der Manschettendruck kontinuierlich reduziert. Die Wiederkehr der. Pulswellen bei Druckablassen wird automatisch als systolischer Blutdruck erkannt und ausgedruckt (Bühler, R. et al.: Microprocassor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international Symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 4982, S. 410-413). Pulssignale und Druckverlauf werden zur Auswertung graphisch aufgezeichnet.The blood pressure is measured in a warm chamber at 36 ° C in order to achieve better circulation in the tail artery. For this purpose, the animals are placed in perforated perforated metal cages and measured 20-40 minutes after warming up. To measure the systolic arterial pressure, 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. After the blood flow in the tail artery has been stopped, the cuff pressure is continuously reduced. The return of the. Pulse waves during pressure relief are automatically recognized and printed out as systolic blood pressure (Bühler, R. et al .: Microprocassor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international Symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 4982, pp. 410-413). Pulse signals and pressure curve are recorded graphically for evaluation.
Zur Gewöhnung an den MeRvorgang werden dia Tiara vor Substanzprüfung 14 Tage trainiert. In der zweiten Trainingswoche werden Blutdruck-Vorwerte erhoben. Tiergruppen, die Substanz erhalten, werden- gegen eine Kontroll- gruppe geprüft.To get used to the measuring process, the tiara is trained for 14 days before the substance test. In the second week of training, blood pressure pre-values are collected. Animal groups that received substance are checked against a control group.
In der anschließenden Tabelle werden die untersuchten Verbindungen durch laufende Nummern gekennzeichnet, die den Nummern dar Beispiele entsprachen r Tabelle I gibt für die Vertreter der erfindungsgemäßen Verbindungen die prozentuale Senkung des Blutdrucks (BP) nach oraler Verabreichung bei der Ratte wieder.In the table below, the tested compounds are identified by consecutive numbers that correspond to the numbers in the examples Table I shows for the representatives of the compounds according to the invention the percentage reduction in blood pressure (BP) after oral administration in the rat.
Tabelle ITable I
%-Änderungen (BP) an genetisch hypertonen Ratten nach täglich einmaliger p. o. -Applikation an vier aufeinanderfolgenden Jagen (N=6/Dosis).% Changes (BP) in genetically hypertensive rats after daily p. o. application on four successive hunts (N = 6 / dose).
Figure imgf000045_0001
Figure imgf000045_0001

Claims

Patentansprüche Claims
1. 1,4-Dihydropyridine der Formel I1. 1,4-dihydropyridines of the formula I
(i;(i;
Figure imgf000046_0003
Figure imgf000046_0003
worinwherein
R1 und R2 gleich oder verschieden sind und Wasserstoff, 1-6C-Alkyl oderR1 and R2 are the same or different and are hydrogen, 1-6C-alkyl or
3-7C-Alkoxyalkyl bedeuten, Ar einen Gyclus der Formel3-7C-Alkoxyalkyl, Ar is a cycle of the formula
Figure imgf000046_0001
Figure imgf000046_0001
darstellt, worinrepresents what
R3 1-6C-Alkyl bedeutet,R3 denotes 1-6C-alkyl,
Cy einen Cyclus der FormelCy a cycle of the formula
Figure imgf000046_0002
darstellt, in dem Y Sauerstoff (O), Schwefel (S), Vinylen -CH=CH-) , Azomethin (-CH=N-) oder eine Gruppe der Formel
Figure imgf000046_0002
represents in which Y represents oxygen (O), sulfur (S), vinylene -CH = CH-), azomethine (-CH = N-) or a group of the formula
Figure imgf000047_0002
bedeutet, worin
Figure imgf000047_0002
means what
R4 und R5 gleich oder verschieden sind und Wasserstoff, Hydroxy, Halogen, Nitro, Cyano, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder teilweise durch Fluor substituiertes 1-4C-Alkoκy, 1 -4C-Alkoxycar- bonyl, 2-5C-Acyl, Amino oder Mono- oder Di-1-4C-alkylamino bedeuten,R4 and R5 are the same or different and are hydrogen, hydroxy, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycar- bonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylamino,
A CH2 (Methylen), 0 (Sauerstoff), S (Schwefel) oder substituiertes Methylen der Formel C(R6)R7 bedeutet, worinA represents CH 2 (methylene), 0 (oxygen), S (sulfur) or substituted methylene of the formula C (R6) R7, in which
R6 Wasserstoff oder 1-6C-Alkyl undR6 is hydrogen or 1-6C-alkyl and
R7 1-6C-Alkyl, 1-4C-Alkoxy, Aryl oder Heteroaryl bedeutet,R7 denotes 1-6C-alkyl, 1-4C-alkoxy, aryl or heteroaryl,
G C(R8)R9 oder N-R10 bedeutet, wobeiG is C (R8) R9 or N-R10, where
R8 Aryl bedeutet,R8 means aryl,
R9 Aryl bedeutet undR9 means aryl and
R10 1-4C-Alkyl, Aryl, Aryl- 1 -4C-alkyl, Aryl-2-4C-alkenyl, Aryl-2-4C- alkinyl, Diaryl-1-4C-alkyl, Heteroaryl, Heteroaryl-1-4C-alkyl, Heteroaryl-aryl-1-4C-alkyl, Di-heteroaryl-1-4C-alkyl, Arylcarbonyl, Heteroarylcarbonyl, Arylsulfonyl oder Aryl-1-4C-alkylcarbonyl bedeutet, wobeiR10 1-4C-alkyl, 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 or aryl-1-4C-alkylcarbonyl, where
Aryl für einen Ring der FormelAryl for a ring of the formula
Figure imgf000047_0001
steht, worin R11 und R12 gleich oder verschiaden sind und die Bedeutung Wasserstoff (H), 1-4C-Alkyl, 1-4C-Alkoxy, Halogen, Hydroxy oder Trifluormethyl haben, und
Figure imgf000047_0001
is in which R11 and R12 are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy or trifluoromethyl, and
Heteroaryl für einen 5- oder 6-gliedrigen Heterocyclus mit einem oder zwei gleichen oder verschiedenen Heteroatomen aus der Gruppe Sauerstoff (0), Schwefel (S) oder Stickstoff (N) steht, der ungesättigt oder teilweise oder ganz gesättigt ist und der einen oder zwei Substituenten aus der Gruppe 1-4C-Alkyl, 1-4C-Alkoxy, Halogen, Trifluormethyl oder Cyan tragen kann, x eine ganze Zahl von 0 bis 4 bedeutet und y eine ganze Zahl von 0 bis 4 bedeutet, wobei x und/oder y nicht die Bedeutung 0 oder 1 haben, wenn A 0 (Sauerstoff) oder S (Schwefel) bedeutet, und die Salze dieser Verbindungen.Heteroaryl is a 5- or 6-membered heterocycle with one or two identical or different heteroatoms from the group consisting of oxygen (0), 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, x is an integer from 0 to 4 and y is an integer from 0 to 4, where x and / or y are not 0 or 1 when A is 0 (oxygen) or S (sulfur), and the salts of these compounds.
2. Verbindungen der Formel I, nach Anspruch 1, worin2. Compounds of formula I, according to claim 1, wherein
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
Ar einen Cyclus der FormelAr is a cycle of the formula
Figure imgf000048_0001
darstellt, worin
Figure imgf000048_0001
represents what
R3 Methyl bedeutet,R3 means methyl,
Cy 3-Nitrophenyl bedeutet,Cy 3-nitrophenyl means
G C(R8)R9 oder N-R10 bedeutet, wobeiG is C (R8) R9 or N-R10, where
R8 Phenyl bedeutet,R8 means phenyl,
R9 Phenyl bedeutet undR9 means phenyl and
R10 Phenyl, 2-Methoxyphenyl oder Benzhydryl bedeutet und die Gruppierung -(CH2)x-A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze diaser Verbindungen. R10 means phenyl, 2-methoxyphenyl or benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
3. Verbindungen nach Anspruch 1, charakterisiert durch die Formel Ia,3. Compounds according to claim 1, characterized by the formula Ia,
Figure imgf000049_0002
worin R1 Methyl bedeutet, R2 Methyl bedeutet, R3 Methyl bedeutet, cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet,
Figure imgf000049_0002
where R1 is methyl, R2 is methyl, R3 is methyl, cy is 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl,
R8 Phenyl oder 4-Methuxyphenyl bedeutet, R9 Phenyl oder 4-Methoxyphenyl bedeutet und die Gruppierung -(CH2)x-A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R8 is phenyl or 4-methoxyphenyl, R9 is phenyl or 4-methoxyphenyl and the grouping is - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene and the salts of these compounds.
4. Verbindungen nach Anspruch 1, charakterisiert durch die Formel Ib,4. Compounds according to claim 1, characterized by the formula Ib,
Figure imgf000049_0001
Figure imgf000049_0001
worinwherein
R1 Methyl bedeutet, R2 Methyl bedeutet, R3 Methyl bedeutet, Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet, R10 - Phenyl, 2-Methoxyphenyl, 2-Pyridyl oder Benzhydryl bedeutet und die Gruppierung -(CH2)x-A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R1 means methyl, R2 means methyl, R3 means methyl, Means Cy 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl, R10 means phenyl, 2-methoxyphenyl, 2-pyridyl or benzhydryl and the grouping - (CH 2 ) x - A- (CH 2 ) y - means ethylene or propylene, and the salts of these compounds.
5. Die Verbindungen nach Anspruch 1, charakterisiert durch die Formel Ic,5. The compounds according to claim 1, characterized by the formula Ic,
Figure imgf000050_0002
Figure imgf000050_0002
worinwherein
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethylphenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet,Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl,
R8 Phenyl oder 4-Methoxyphenyl bedeutet,R8 represents phenyl or 4-methoxyphenyl,
R9 Phenyl oder 4-Methoxyphenyl bedeutet und die Gruppiarung -(CH2)x-A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R9 is phenyl or 4-methoxyphenyl and the grouping is - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene and the salts of these compounds.
6. Verbindungen nach Anspruch 1, charakterisiert durch die Formel Id,6. Compounds according to claim 1, characterized by the formula Id,
Figure imgf000050_0001
worin
Figure imgf000050_0001
wherein
R1 Methyl bedeutet,R1 means methyl
R2 Methyl bedeutet,R2 means methyl
Cy 3-Nitrophenyl, 2-Chlorphenyl, 2,3-Dichlorphenyl, 2-Trifluormethyl- phenyl, 2-Difluormethoxyphenyl oder Benzoxdiazolyl bedeutet,Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl or benzoxdiazolyl,
R10 Phenyl, 2-Methoxyphenyl, 2-Pyridyl oder Benzhydryl bedeutet und die Gruppierung -(CH2)x-A-(CH2)y- Ethylen oder Propylen bedeutet, und die Salze dieser Verbindungen.R10 means phenyl, 2-methoxyphenyl, 2-pyridyl or benzhydryl and the grouping means - (CH 2 ) x -A- (CH 2 ) y - ethylene or propylene, and the salts of these compounds.
7. Verbindung nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus7. A compound according to claim 1 selected from the group consisting of
1,4-Dihydro-2,6-dimethyl-5-(2-methyl-tetrazol-5-yl)-4-(3-nitrophenyl)-pyridin-3-carbonsäure-[3-(4,4-diphenyl-1-piperidinyl!propyllester 1,4-Dihydro-2,6-dimethyl-5-(2-methyl-tetrazol-5-yl)-4-(3-nitrophenyl)-pyridin-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)ethyl)]ester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyridin-3-carbonsäure-{3-[4-(2-methoκyphenyl)-1-piperazinyl]propyl}ester 1,4-Dihydro-2,6-dimeth.yl-5-(2-methyltetrazol-5-yl)-4-(3-nitrophenyl)-pyri¬din-3-carbonsäura-[3-(4-benzhydryl-1-piperazinylIpropyllester 1,4-Dihydro-2,6-dimethyl-5-(2-methyltetrazol-5-yl]-4-(3-nitrophenyl)-pyri¬din-3-carbonsäure-[2-(4-benzhydryl-1-piperazinyl)ethyllester 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-{3-[4-(2-methoκyphenyl-1-piperazinyl)propyl}ester 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1,3.,4-oxadiazol-2-yl)-pyri¬din-3-carbonsäure-[2-(4-phenyl-1-piperazinyl)ethyl]ester und den Salzen dieser Verbindungen.1,4-Dihydro-2,6-dimethyl-5- (2-methyl-tetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [3- (4,4-diphenyl- 1-piperidinyl! Propyl ester 1,4-dihydro-2,6-dimethyl-5- (2-methyl-tetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- [2- (4th -phenyl-1-piperazinyl) ethyl)] ester 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl) pyridine-3-carboxylic acid- { 3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} ester 1,4-dihydro-2,6-dimeth.yl-5- (2-methyltetrazol-5-yl) -4- (3-nitrophenyl ) -pyridine-3-carboxylic acid- [3- (4-benzhydryl-1-piperazinylpropyl ester 1,4-dihydro-2,6-dimethyl-5- (2-methyltetrazol-5-yl] -4- (3- nitrophenyl) pyridin-3-carboxylic acid [2- (4-benzhydryl-1-piperazinyl) ethyl ester 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1.3 , 4-oxadiazol-2-yl) pyridine-3-carboxylic acid {3- [4- (2-methoxyphenyl-1-piperazinyl) propyl} ester 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3., 4-oxadiazol-2-yl) pyridin-3-carboxylic acid [2- (4-phenyl-1-piperazinyl) ethyl] ester and the salts thereof Connections n.
8. Verfahren zur Herstellung der Verbindungen der Formel I nach Anspruch 1 und ihren Salzen, dadurch gekennzeichnet, daß man8. A process for the preparation of the compounds of formula I according to claim 1 and their salts, characterized in that
a) Alkenone der Formel IIa) Alkenones of the formula II
Figure imgf000051_0001
mit Enaminderivaten der Formel III
Figure imgf000051_0001
with enamine derivatives of the formula III
(II] (II ]
oder
Figure imgf000052_0004
or
Figure imgf000052_0004
b) Alkenone der Formel II mit Ammoniak und ß-Ketocarbonsäure- derivaten der Formel IVb) Alkenones of the formula II with ammonia and β-ketocarboxylic acid derivatives of the formula IV
(IV)(IV)
Figure imgf000052_0003
oder
Figure imgf000052_0003
or
c) Enamine der Formel Vc) Enamines of formula V
CV),
Figure imgf000052_0002
mit Benzylidencarbonsäurederivaten der Formel VICV),
Figure imgf000052_0002
with benzylidenecarboxylic acid derivatives of the formula VI
(VI),(VI),
Figure imgf000052_0001
oder
Figure imgf000052_0001
or
d ) Ketoverbindungen der Formel VI Id) keto compounds of the formula VI I
(VII),
Figure imgf000053_0004
mit Ammoniak und Benzylidencarbonsäurederivaten der Formel VI, oder(VII),
Figure imgf000053_0004
with ammonia and benzylidenecarboxylic acid derivatives of the formula VI, or
e) Aldehyde der Formel VIIIe) aldehydes of the formula VIII
(VIII)
Figure imgf000053_0003
mit Enaminen der Formel V und ß-Ketocarbonsäurederivaten der Formel IV, oder(VIII)
Figure imgf000053_0003
with enamines of the formula V and β-ketocarboxylic acid derivatives of the formula IV, or
f) Aldehyde der Formel VIII mit Enaminderivaten der Formel III und Ketoverbindungen der Formel VII, oderf) aldehydes of the formula VIII with enamine derivatives of the formula III and keto compounds of the formula VII, or
g) 1,4-Dihydropyridine der Formel IXg) 1,4-dihydropyridines of the formula IX
(IX),(IX),
Figure imgf000053_0002
mit Aminderivaten der Formel X
Figure imgf000053_0002
with amine derivatives of the formula X
(X),
Figure imgf000053_0001
oder(X),
Figure imgf000053_0001
or
h ) 1 , 4-Dihydropyridinderivate der Formel XIh) 1, 4-dihydropyridine derivatives of the formula XI
Figure imgf000054_0002
mit Aminen der Formel XII
Figure imgf000054_0002
with amines of formula XII
(XII!
Figure imgf000054_0001
(XII!
Figure imgf000054_0001
als solche(n) oder in Form ihrer Salze umsetzt und gewünschtenfalls anschließend erhaltene Salze in die freien 8asen oder erhaltene Basen in die Salze überführt, wobei R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, Ar, Cy, A, G, x und y die in Anspruch 1 angegebenen Bedeutungen haben, Z gemeinsam mit der Carbonylgruppe, woran es gebunden ist, eine Carboxylgruppe oder ein reaktives Carbonsäurederivat (z. B. ein Carbonsäurehalo- genid) und L eine Fluchtgruppe darstellt.as such (s) or in the form of their salts and, if desired, subsequently obtained salts are converted into the free 8ases or bases obtained, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, Ar, Cy, A, G, x and y have the meanings given in claim 1, Z together with the carbonyl group to which it is attached, a carboxyl group or a reactive carboxylic acid derivative (for example a carboxylic acid halide) and L represents an escape group.
9. Arzneimittel enthaltend eine oder mehrere Verbindungen nach einem oder mehreren der Ansprüche 1 bis 7 und/oder ihre pharmakologisch verträglichen Salze.9. Medicament containing one or more compounds according to one or more of claims 1 to 7 and / or their pharmacologically acceptable salts.
10. Verbindungen nach einem oder mehreren der Ansprüche 1 bis 7 und/oder ihre pharmakologisch verträglichen Salze zur Anwendung bei der Behandlung und/oder Prophylaxe yon Hypertonie, koronaren Herzkrankheiten, peripheran und cerebralen Zirkulationsstörungen und/oder Krankheiten, die auf einer erhöhten Wasser- oder Natriumretention beruhen. 10. Compounds according to one or more of claims 1 to 7 and / or their pharmacologically acceptable salts for use in the treatment and / or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulatory disorders and / or diseases based on an increased water or Sodium retention based.
11. Verwendung von Verbindungen nach einem oder mehreren der Ansprüche 1 bis 7 und/oder ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Behandlung und/oder Prophylaxe von Hypertonie, koronaren Herzkrankheiten, peripheren und cerebralen Zirkulationsstörunge und/oder Krankheiten, die auf einer erhöhten Wasser- oder Natriumretention beruhen. 11. Use of compounds according to one or more of claims 1 to 7 and / or their pharmacologically acceptable salts for the manufacture of medicaments for the treatment and / or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulatory disorders and / or diseases based on increased water or sodium retention.
PCT/EP1987/000597 1986-10-15 1987-10-13 1,4-dihydropyridine WO1988002750A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CH4112/86-1 1986-10-15
CH411286 1986-10-15
CH412986 1986-10-15
CH411186 1986-10-15
CH4111/86-0 1986-10-15
CH4129/86-7 1986-10-15

Publications (1)

Publication Number Publication Date
WO1988002750A1 true WO1988002750A1 (en) 1988-04-21

Family

ID=27174719

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1987/000597 WO1988002750A1 (en) 1986-10-15 1987-10-13 1,4-dihydropyridine

Country Status (2)

Country Link
AU (1) AU8154087A (en)
WO (1) WO1988002750A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001769A1 (en) * 1977-10-22 1979-05-16 Bayer Ag Sulfur-containing esters of 1,4-dihydropyridine carboxylic acids, their preparation and pharmaceutical use
EP0128010A2 (en) * 1983-06-02 1984-12-12 Teijin Limited 1,4-Dihydropyridine derivative, process for production thereof and pharmaceutical use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001769A1 (en) * 1977-10-22 1979-05-16 Bayer Ag Sulfur-containing esters of 1,4-dihydropyridine carboxylic acids, their preparation and pharmaceutical use
EP0128010A2 (en) * 1983-06-02 1984-12-12 Teijin Limited 1,4-Dihydropyridine derivative, process for production thereof and pharmaceutical use thereof

Also Published As

Publication number Publication date
AU8154087A (en) 1988-05-06

Similar Documents

Publication Publication Date Title
EP0176956B1 (en) Diaryl derivatives
JPH0542431B2 (en)
US4994461A (en) 1,4-dihydropyridine enantiomers
DE3208628A1 (en) NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS
DE3234684A1 (en) NEW DIHYDROPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS
DE3512995A1 (en) DIHYDROPYRIDINYLDICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
JPH0676380B2 (en) Novel 1,4-dihydropyridines
DE3711991A1 (en) DIHYDROPYRIDINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS
DE3601397A1 (en) SUBSTITUTED 1,4-DIHYDROPYRIDIN-3-CARBONIC ACID PIPERAZIDES, METHOD FOR THE PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS
DE3244178A1 (en) 1,4-DIHYDROPYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS
EP0244595A2 (en) Dihydropyridine derivatives, process for their preparation and their use as pharmaceutical compounds
WO1987006579A1 (en) New amines and ethers
US5015650A (en) Circulation-active basic 4-aryl-DHP amides
EP0236838A2 (en) Aminoester-dihydropyridines, process for their preparation and their use
DE3816361A1 (en) (-)-Menthyl 1,4-dihydropyridinedicarboxylates
DE3709796C2 (en) Process for the preparation of diarylpiperidyl-1,4-dihydropyridine dicarboxylic acid derivatives
WO1988007531A1 (en) New optically active compounds
WO1986003748A1 (en) New piperazine derivatives
WO1988002750A1 (en) 1,4-dihydropyridine
DE3712371A1 (en) SUBSTITUTED 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
DE2616991A1 (en) Thio-substd. dihydro-pyridine derivs. - coronary vasodilators and antihypertensives prepd. e.g. by reacting dicarbonyl cpds. with amines and thio-substd. ketones
WO1989003824A1 (en) New pyrrolidines
HU196791B (en) Process for producing new, optically active dihydropyridines and pharmaceutical compositions containing them
DE3627742A1 (en) Substituted 1,4-dihydropyridine-3-carboxylic acid derivatives
DE3816360A1 (en) (-)-Menthyl 2-amino-1,4-dihydropyridinedicarboxylates

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU DK FI HU JP KR NO US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE