WO1988002750A1 - 1,4-dihydropyridine - Google Patents

1,4-dihydropyridine Download PDF

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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
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Prior art keywords
formula
carboxylic acid
dihydro
ester
nitrophenyl
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PCT/EP1987/000597
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German (de)
English (en)
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
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Publication of WO1988002750A1 publication Critical patent/WO1988002750A1/fr

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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des composés ayant la formule (I), dans laquelle les substituants et les symboles ont les notations décrites dans la première revendication, constituent de nouveaux composés à propriétés pharmacologiques intéressantes.
PCT/EP1987/000597 1986-10-15 1987-10-13 1,4-dihydropyridine WO1988002750A1 (fr)

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
CH4111/86-0 1986-10-15
CH411186 1986-10-15
CH4129/86-7 1986-10-15

Publications (1)

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

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Family Applications (1)

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

Country Status (2)

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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001769A1 (fr) * 1977-10-22 1979-05-16 Bayer Ag Esters contenant du soufre d'acides dihydro-1,4-pyridine carboxyliques, leur préparation et leur application comme médicaments
EP0128010A2 (fr) * 1983-06-02 1984-12-12 Teijin Limited Dérivés de 1,4-dihydropyridines, leur procédé de préparation et utilisation en pharmacie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001769A1 (fr) * 1977-10-22 1979-05-16 Bayer Ag Esters contenant du soufre d'acides dihydro-1,4-pyridine carboxyliques, leur préparation et leur application comme médicaments
EP0128010A2 (fr) * 1983-06-02 1984-12-12 Teijin Limited Dérivés de 1,4-dihydropyridines, leur procédé de préparation et utilisation en pharmacie

Also Published As

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

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