WO2005028451A1 - Tetrahydrochinoxalines et leur utilisation comme agonistes du recepteur a l'acetylcholine m2 - Google Patents

Tetrahydrochinoxalines et leur utilisation comme agonistes du recepteur a l'acetylcholine m2 Download PDF

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Publication number
WO2005028451A1
WO2005028451A1 PCT/EP2004/009934 EP2004009934W WO2005028451A1 WO 2005028451 A1 WO2005028451 A1 WO 2005028451A1 EP 2004009934 W EP2004009934 W EP 2004009934W WO 2005028451 A1 WO2005028451 A1 WO 2005028451A1
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formula
compound
alkyl
compounds
salts
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PCT/EP2004/009934
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German (de)
English (en)
Inventor
Alexander Kuhl
Peter Kolkhof
Leila Telan
Jan-Georg Peters
Klemens Lustig
Raimund Kast
Klaus Münter
Johannes-Peter Stasch
Hanna Tinel
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Bayer Healthcare Ag
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Publication of WO2005028451A1 publication Critical patent/WO2005028451A1/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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to tetrahydroquinoxalines, a process for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases.
  • Acetylcholine is the carrier of the parasympathetic nervous system. This part of the vegetative nervous system has a decisive influence on fundamental processes of various organ functions, e.g. Lungs, bladder, stomach and intestines, glands, brain, eyes, blood vessels and heart.
  • Acetylcholine itself is not therapeutically applicable due to the very rapid activation by acetylcholinesterase, but its effect can be reduced by direct parasympathomimetics, e.g. the carbachol, are imitated.
  • Active ingredients that act agonistically like acetylcholine at the muscarinic (M) acetylcholine receptors can, depending on the organ or tissue system, influence and control numerous functions. For example, activation of muscarinic acetylcholine receptors in the brain can affect the memory and processes of learning processes and pain processing.
  • the muscarinic M2 acetylcholine receptor which is particularly strongly expressed in cardiac muscle cells, is able to reduce the heart rate and contractility after beta-adrenergic stimulation (B. Rauch, F. Niroomand, J. Eur. Heart. 1991, 12, 76-82). Both effects reduce myocardial oxygen consumption.
  • WO 00/39103 describes tetrahydroquinoxalm derivatives for the treatment of diseases which are caused by cell adhesion, such as, for. B. inflammatory diseases or arteriosclerosis.
  • the object of the present invention is to provide medicaments for the treatment of diseases, in particular cardiovascular diseases.
  • the present invention relates to compounds of the formula
  • X represents CH or N
  • R 1 represents phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by 1 to 3 substituents, independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, arnino, trifluoromethyl, trifluoromethoxy, nitro, cyano, alkyl, alkoxy, alkylamino , Alkoxycarbonyl, arninocarbonyl and alkyl arninocarbonyl,
  • R 2 represents cycloalkyl, which is optionally substituted by 1 to 3 substituents, selected independently of one another from the group consisting of halogen, hydroxy, amino, alkyl, alkoxy and alkylamino,
  • R 3 represents alkyl or cycloalkyl, alkyl and cycloalkyl optionally being substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl, and cycloalkyl can also be substituted by alkyl,
  • R 4 represents hydrogen or (-CC 4 ) alkyl
  • R 5 represents hydrogen or (CC 4 ) alkyl
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, compounds mentioned below as exemplary embodiment (s) and their Salts, solvates and solvates of the salts, insofar as the compounds mentioned below of formula (I) are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to the enantiomers or diastereomers and their respective mixtures.
  • the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.
  • the present invention encompasses all tautomeric forms.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • salts are also included which are not themselves suitable for pharmaceutical applications but can be used for example for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, maleic acid.
  • Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
  • Alkyl per se and "alk” and "alkyl” in alkoxy represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents.
  • (-C-C 3 ) alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical each having 1 to 3 carbon atoms per alkyl substituent, examples and preferably being mentioned: methylamino, ethylamino, n-propylamino, isopropylamino , tert-butylamino, n-pentylamino, n-hexylamino, NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt- Butyl-N-mefhylamino, N-ethyl-Nn-p
  • Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents.
  • (-C-C 3 ) -Alkylaminocarbonyl stands for example for a monoalkylaminocarbonyl radical with 1 to 3 carbon atoms or for a dialkylamino-carbonyl radical with 1 to 3 carbon atoms per alkyl substituent.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkanediyl stands for a straight-chain or branched saturated alkanediyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkanediyl radical having 1 to 4 carbon atoms is preferred. Examples include and are preferably methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1 , 4-diyl, butane-l, 3-diyl, butane-2,4-diyl, pentane-l, 5-diyl, pentane-2,4-diyl, 2-methylpentane-2,4-diyl.
  • Cycloalkyl stands for a cycloalkyl group with generally 3 to 8, preferably 3 to 6 carbon atoms, by way of example and preferably for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl stands for a mono- or tricyclic aromatic, carbocyclic radical with generally 6 to 14 carbon atoms, for example and preferably for phenyl, naphthyl and phenanthrenyl.
  • Halogen stands for fluorine, chlorine, bromine and iodine.
  • radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
  • A represents (CC 6 ) alkanediyl
  • X represents CH or N
  • R 1 represents phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by a substituent, independently selected from the group consisting of halogen, hydroxy, amino, alkyl, alkoxy, alkylamino, alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl,
  • R 2 represents (C 3 -C 6 ) cycloalkyl
  • R 3 represents (CC 6 ) alkyl or (C 3 -C 6 ) cycloalkyl, alkyl and cycloalkyl optionally being substituted by 1 to 3 substituents selected independently of one another from the group consisting of hydroxy, trifluoromethyl and (C 1 -C 4 ) alkoxy,
  • R 4 represents hydrogen or methyl
  • R 5 represents hydrogen or methyl
  • A represents ethane-l, l-diyl or pentane-l, l-diyl
  • X represents CH or N
  • R 1 represents phenyl or pyridyl, where phenyl and pyridyl are substituted by a methoxy group
  • R 2 represents cyclopropyl
  • R 3 represents (C 3 -C 6 ) alkyl
  • R 4 represents hydrogen
  • R 5 represents hydrogen or methyl
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of another combination, regardless of the respectively specified combinations of the radicals. - ⁇
  • the present invention also relates to a process for the preparation of the compounds of the formula (I), which is characterized in that
  • a and R 1 have the meaning given above, in the presence of conventional condensing agents, if appropriate in the presence of a base or
  • R, R, R and R have the meaning given above, and
  • Y 1 represents halogen, preferably bromine or chlorine, with compounds of the formula
  • R 3 has the meaning given above, in the presence of a base.
  • Y, R, R and R have the meaning given above, first with compounds of formula (V) and then with trifluoroacetic acid or hydrogen chloride in dioxane to cleave the tert-butyl ester.
  • R 2 has the meaning given above
  • R 2 and R 5 have the meaning given above
  • R 2 and R 5 have the meaning given above
  • R 4 and R 5 have the meaning given above
  • R 2 and R 4 have the meaning given above
  • R 2 and R 4 have the meaning given above
  • R 2 has the meaning given above
  • R 2 has the meaning given above
  • the amide coupling in process step (II) + (TU) -> (I) is generally carried out in inert solvents, preferably in a temperature range from room temperature to 50 ° C. at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol ether such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacet
  • Typical condensing agents are, for example, carbodiimides such as e.g. N, N'-Diefhyl-, N, N, '- Dipropyl-, N, N'-Diisopropyl-, N, N'-Dicyclohexylcarbodiimid, N- (3-Dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene
  • carbodiimides such as e.g. N, N'-Diefhyl-, N, N, '- Dipropyl-, N, N'-Diisopropyl-, N, N'-Dicyclohexylcarbodiimid, N- (3-Dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (ED
  • PS-carbodiimide or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium- perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium phosphonium , or 0- (benzotriazol-l-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2-
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate or organic bases
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and diisopropylethylamine in methylene chloride or dimethylformamide is preferred.
  • Process steps (IV) + (V) -> (I); (LX) + (XVUJ) -> (XLX) and (XXII) + (XXm) -> (XXI) as well as the first substep of (V) + (VT) -> (IT) are generally carried out in inert solvents , optionally in the presence of a base, preferably in a temperature range from 0 ° C to 50 ° C at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or Trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetonitrile, dimethyl acetate amide, ethyl acetate form , Dimethylacetamide, 1, 2-dimethoxyethane, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, or mixtures of the solvents
  • Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine.
  • reaction with an acid in the second process step from (V) + (VI) -> (JJ) generally takes place in inert solvents, preferably in a temperature range from 0 ° C. to 50 ° C. at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, or other solvents such as dimethylformamide, dioxane or tetrahydrofuran, methylene chloride or dioxane is preferred.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • other solvents such as dimethylformamide, dioxane or tetrahydrofuran, methylene chloride or dioxane is preferred.
  • Process step (VH) + (Vffl) -> (VI) is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from 0 ° C. to the reflux of the solvent at atmospheric pressure.
  • Bases are, for example, amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, or mixtures of these bases, preference is given to triethylamine or a mixture of triethylamine and DBU.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, or other solvents dimethylformamide or tetrahydrofuran, methylene chloride is preferred.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, or other solvents dimethylformamide or tetrahydrofuran, methylene chloride is preferred.
  • Process step (VIU) + (LX) -> (X) takes place in two stages.
  • the first stage is carried out in inert solvents with 2 equivalents of the compounds of the formula (VIU), based on the compounds of the formula (LX), in the presence of 2 equivalents of a base, preferably in a temperature range from 0 ° C. to 50 ° C. normal pressure.
  • the second stage closes without Working up the reaction mixture and is carried out by adding a further base and heating the reaction mixture to reflux of the solvent.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol such as xylene glycol, such as xylene glycol, such as xylene glycol, and diethylene glycol xylene glycol , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethyl sulfoxide, ace
  • Bases are, for example, alkali hydroxides such as sodium or potassium hydroxide, or alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferred for the first stage is diisopropylethylamine or triethylamine, preferably for the second stage is DBU.
  • alkali hydroxides such as sodium or potassium hydroxide
  • alkali carbonates such as cesium carbonate, sodium or potassium carbonate
  • amides such as lithium diisopropylamide
  • other bases such as DBU, triethylamine or diisopropylethylamine, preferred for the first stage is diisopropylethylamine or triethylamine, preferably for the second stage is DBU.
  • Deacylation in process step (X) -> (XI) is generally carried out in a solvent, in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. at atmospheric pressure.
  • Solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane or tetrahydrofuran, or mixtures of the solvents with water, a mixture of dioxane and water being preferred.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane or tetrahydrofuran
  • solvents with water, a mixture of dioxane and water being preferred.
  • Bases are, for example, alkali hydroxides such as lithium, sodium or potassium hydroxide, sodium hydroxide is preferred.
  • reaction with borane in process steps (XI) -> (VUa); (XIV) -> (Vllb); (XVII) -> (VIIc) and (XX) -> (VUd) are generally carried out in inert solvents, preferably in a temperature range from 40 ° C. to the reflux of the solvent at normal pressure.
  • Inert solvents are, for example, ethers such as dioxane or tetrahydrofuran, tetrahydrofuran is preferred.
  • the reaction with ⁇ -keto esters or diketones in the process steps (LX) + (XH) -> (XJ ⁇ T) and (LX) + (XV) -> (XVI) is generally carried out in inert solvents, in the presence of acetic acid, preferably in a temperature range from room temperature to 40 ° C at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane or tetrahydrofuran; methylene chloride is preferred.
  • the reduction with sodium cyanoborohydride in process steps (Xm) -> (XIV) and (XVI) -> (XVII) is generally carried out in inert solvents, in the presence of acetic acid, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, alcohols such as methanol or ethanol; methanol is preferred.
  • the cyclization in process step (XLX) -> (XX) is generally carried out in inert solvents, preferably with reflux of the solvent at normal pressure.
  • Inert solvents are, for example, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone, dimethylformamide is preferred.
  • the reduction in process step (XXI) -> (LX) takes place in inert solvents, preferably in a temperature range from room temperature to 50 ° C. at normal pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, propanol, isopropanol or butanol or ethyl acetate or diethyl ether, methanol or ethanol being preferred.
  • Reducing agent is, for example, hydrogen;
  • catalysts are tin dichloride, titanium trichloride or palladium on activated carbon. The combination of palladium on activated carbon and hydrogen is preferred.
  • the compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action.
  • the compounds according to the invention can be used alone or in combination with other active substances for the treatment and / or prophylaxis of cardiovascular diseases, in particular coronary heart disease, angina pectoris, myocardial infarction, stroke, atherosclerosis, essential, pulmonary and malignant hypertension, heart failure, heart failure, cardiac arrhythmias or thromboembolic disorders.
  • cardiovascular diseases in particular coronary heart disease, angina pectoris, myocardial infarction, stroke, atherosclerosis, essential, pulmonary and malignant hypertension, heart failure, heart failure, cardiac arrhythmias or thromboembolic disorders.
  • the present invention furthermore relates to the use of the compounds according to the invention for the treatment and or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention furthermore relates to the use of the compounds according to the invention for the production of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an atherosclerotically effective amount of the compounds according to the invention.
  • the present invention furthermore relates to medicaments containing at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • the compounds according to the invention can act systemically and / or locally.
  • they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the state-of-the-art is suitable for rapid and or modified application forms which release the compounds according to the invention and which contain the compounds according to the invention in crystalline and or amorphized and / or dissolved form, such as Tablets (non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Tablets non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention
  • Coated tablets granul
  • Parenteral administration can be done by bypassing an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbal
  • absorption e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medication forms including powder inhalers, nebulizers
  • nasal drops, solutions, sprays including tablets, films / wafers or capsules to be applied lingually, sublingually or buccally, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as plasters), Milk, pastes, foams, scattering powder, implants or stents.
  • the compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • auxiliaries include Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (for example antioxidants such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides) and taste and / or odor corrections.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl sulfate
  • the present invention furthermore relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non- contain toxic, pharmaceutically suitable auxiliaries, and their use for the aforementioned purposes.
  • the amount is approximately 0.1 to 10 mg / kg, preferably approximately 0.5 to 5 mg / kg body weight.
  • Method 1 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 ⁇ m; Eluent A: 5 ml of HCl water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
  • Method 2 Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A - 0.2 min 100% A -> 2.9 min 30% A - 3.1 min 10% A - »4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.
  • Method 3 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6mm; Eluent A: water + 500 ⁇ l 50% formic acid / 1; Eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0 min 10% B ⁇ 3.0 min 95% B-> 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min- 3.0 min 3.0 ml / min- 4.0 min 3.0 ml / min; UV detection: 210 nm.
  • LCMS Method 4
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm
  • Eluent A 1 1 water + 0.5 ml 50% formic acid
  • eluent B 1 1 acetonitrile + 0.5 ml 50% formic acid
  • Flow 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min
  • Oven 50 ° C
  • UV detection 210 nm.
  • Method 5 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A - 0.2 min 100% A ⁇ 2.9 min 30% A - 3.1 min 10% A - »4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.
  • LCMS Method 6
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 ⁇ m
  • Eluent A water + 500 ⁇ l 50% formic acid / 1
  • eluent B acetonitrile + 500 ⁇ l 50% formic acid / 1
  • Oven 50 ° C
  • Flow 0.8 ml / min
  • UV detection 210 nm.
  • Method 7 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A ⁇ »2.5 min 30% A -» 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
  • the compounds listed in Table 1 are prepared analogously to the compound from Example 7A from the corresponding starting materials and purified on silica gel (mobile phase cyclohexane / ethyl acetate).
  • reaction mixture is concentrated in vacuo and by means of preparative HPLC (column: Phenomenex Luna C18 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 54.8% water, 45% acetonitrile, 0.2% trifluoroacetic acid; oven: RT; flow: 25 ml / min; UV detection: 210 nm) separately. 14.3 mg (13% of theory) of the product are obtained.
  • the preparation is carried out using the compound from Example 15A and [1- (6-methoxypyridin-3-yl) ethyl] amine by the method described for Example 1.
  • the cleaning takes place by means of preparative HPLC (method 8).
  • the preparation is carried out using the compound from Example 16A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1.
  • the cleaning takes place by means of preparative HPLC (method 8).
  • the preparation is carried out using the compound from Example 15A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1.
  • the cleaning takes place by means of preparative HPLC (method 8).
  • the preparation is carried out using the compound from Example 17A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1.
  • the cleaning takes place by means of preparative HPLC (method 8).
  • the preparation is carried out using the compound from Example 18A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1.
  • the cleaning takes place by means of preparative HPLC (method 8).
  • M2AChR human M2 acetylcholine receptor
  • test cell line constitutively expresses a modified form of the calcium-sensitive photoprotein aequorin, which after reconstitution with the co-factor coelenterazine emits light when the free calcium concentration in the inner mitochondrial compartment increases (Rizzuto R, Simpson AW, Brini M, Pozzan T .; Nature 358 (1992) 325-327).
  • the cell is stably transfected with the human M2AChR (Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon, DJ, EMBO Journal 6 (1987) 3923-3929) and the gene that is responsible for the promiscuous G ⁇ 6 coded protein (Amatruda TT, Steele DA, Slepak VZ, Simon MI, Proceedings in the National Academy of Science USA 88 (1991), 5587-5591).
  • M2AChR Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon, DJ, EMBO Journal 6 (1987) 3923-3929
  • the gene that is responsible for the promiscuous G ⁇ 6 coded protein Amatruda TT, Steele DA, Slepak VZ, Simon MI, Proceedings in the National Academy of Science USA 88 (1991), 5587-5591.
  • the resulting M2AChR test cell responds to stimulation of the recombinant M2ACh receptor with an intracellular release of calcium ions, which can be quantified by the resulting aequorin luminescence with a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17 (1996) 235-237).
  • corresponding CHO Kl cells are used, which likewise have the gene of the calcium-sensitive photoprotein aequorin and the gene of the Ml, M3 or M5 receptor subtype or in the case of M4 receptor subtypes are additionally stably transfected with the gene of the promiscuous G ⁇ ⁇ 6 protein.
  • Test procedure The cells are placed in culture medium (DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES; Gibco Cat. # 21331-020; belongs to: Invitrogen GmbH, 76131 the day before the test Düsseldorf) plated in 384 (or 1536) well microtiter plates and kept in a cell incubator (96% humidity, 5% v / v C0 2 , 37 ° C).
  • culture medium DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES; Gibco Cat. # 21331-020; belongs to: Invitrogen GmbH, 76131 the day before the test Düsseldorf
  • 384 or 1536
  • the culture medium is replaced by a Tyrode solution (in mM: 140 NaCl, 5 KC1, 1 MgCl 2 , 2 CaCl 2 , 20 glucose, 20 HEPES), which also contains the co-factor coelenterazine (50 ⁇ M), and the microtiter plate then incubated for another 3-4 hours.
  • a Tyrode solution in mM: 140 NaCl, 5 KC1, 1 MgCl 2 , 2 CaCl 2 , 20 glucose, 20 HEPES
  • the resulting light signal is measured in the luminometer. The results are shown in Table A:
  • Stably transfected CHO Kl cells which express the human muscarinic M2 receptor are, after reaching 80% confluency, in 10 ml binding buffer (20 mM 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid, 5 mM magnesium chloride, pH 7.4) per 175 cm 2 cell culture bottle suspended and homogenized using an Ultra-Turrax device. The homogenates are centrifuged at 1000 g and 4 ° C for 10 minutes. The supernatant is removed and centrifuged at 20,000 g and 4 ° C. for 30 minutes. The membrane sediment with the M2 receptors is taken up in 10 ml of binding buffer and stored at -70 ° C.
  • 2 nM 3 H-oxotremorin M (200 GBq / mmol, PerkinElmer) are incubated for 60 minutes with 100-1000 ⁇ g / ml M2 membranes per batch (0.2 ml) in the presence of the test substances at room temperature. The incubation is stopped by centrifugation at 10 000 g for 10 minutes and then washing with 0.1% bovine serum albumin in binding buffer at 4 ° C. It is centrifuged for another 10 minutes at 10000 xg and 4 ° C. The sediment is resuspended in 0.1 ml of 1N sodium hydroxide solution and transferred to scintillation tubes.
  • the radioactivity bound to the membranes is quantified using an LS6000 IC scintillation counter from BeckmanCoulter. ed.
  • the non-specific binding is defined as radioactivity in the presence of 10 ⁇ M oxotremorine M and is usually less than 5% of the total radioactivity bound.
  • the binding data (IC 50 and dissociation constant Ki) are determined using the GraphPad Prism Version 3.02 program.
  • anesthetized guinea pigs are removed from the heart and inserted into a conventional Langendorff apparatus.
  • the coronary arteries are perfused at a constant volume (10 ml / min) and the resulting perfusion pressure is registered by a corresponding pressure transducer.
  • a decrease in perfusion pressure in this arrangement corresponds to a relaxation of the coronary arteries.
  • the pressure that is developed by the heart during each contraction is measured via a balloon inserted into the left ventricle and another pressure sensor.
  • the frequency of the isolated beating heart is calculated from the number of contractions per unit of time.
  • mice Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery. The substances to be tested are administered orally in Transcutol, Cremophor EL, H 2 0 (10% / 20% / 70%) in a volume of 1 ml / kg.
  • Continuous blood pressure measurements over 24 hours are carried out on spontaneously hypertensive 200-250g free-moving female rats (MOL: SPRD).
  • MOL free-moving female rats
  • the animals are chronically implanted with pressure transducers (Data Sciences Inc., St. Paul, MN, USA) in the descending abdominal aorta below the renal artery and the associated transmitter is fixed in the abdominal cavity.
  • the animals are kept individually in type m cages, which are positioned on the individual receiving stations, and are adapted to a 12-hour light / dark rhythm. Water and feed are freely available.
  • the blood pressure of each rat is recorded every 5 minutes for 10 seconds.
  • the measuring points are combined for a period of 15 minutes and the average value is calculated from these values.
  • test compounds are dissolved in a mixture of Transcutol (10%), Cremophor (20%), H 2 0 (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight.
  • the test doses are between 0.3-30 mg / kg body weight. d) Blood pressure and heart rate measurements on anesthetized dogs
  • the experiments are carried out in dogs (Mongrel) of both sexes with a body weight between 20 and 30 kg. Anesthesia is slow i.v. Injection of 25 mg / kg thiopental (Trapanal®) was initiated and continued during the experiment with a continuous infusion of 0.08 mg / kg / h fentanyl (Fentanyl®) and 0.25 mg / kg / h droperidol (Dehydrobenzperidol®). Alloferin (0.02 mg / kg / h) is added as a muscle relaxant. The dogs are artificially ventilated with 1 part laughing gas and 3 parts oxygen. The test substances are administered intravenously via the femoral vein.
  • a MillarTip catheter for recording left ventricular pressure or calculating contractility is inserted into the left ventricle via the carotid artery.
  • a hollow catheter is inserted into the aorta through the femoral artery and connected to a pressure transducer to measure peripheral blood pressure.
  • the circumflex ramus (LCX) or the interventricular ramus (LAD) of the left coronary artery is dissected and an electromagnetic flow head is applied to measure the coronary flow.
  • the EKG is recorded via an extremity lead and an EKG amplifier, the heart rate and EKG parameters are determined via the measured ECG.
  • Oxygen saturation at the coronary sinus is determined using a Swan-Gantz oximetry TD catheter.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are dried with the magnesium stearate for 5 min. mixed.
  • This mixture is compressed with a conventional tablet press (tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the pressing.
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol, the active ingredient is added to the suspension.
  • the water is added with stirring.
  • the mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete.

Abstract

L'invention concerne des tétrahydrochinoxalines de la formule I où A, X, R1, R2, R3, R4 et R ont la définition donnée dans la revendication 1, leur procédé de production et leur utilisation pour produire des médicaments destinés au traitement et/ou à la prévention de maladies, notamment de maladies cardiovasculaires.
PCT/EP2004/009934 2003-09-18 2004-09-07 Tetrahydrochinoxalines et leur utilisation comme agonistes du recepteur a l'acetylcholine m2 WO2005028451A1 (fr)

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Publication number Priority date Publication date Assignee Title
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US7601716B2 (en) 2006-05-01 2009-10-13 Cephalon, Inc. Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors
EP2433937A1 (fr) 2007-08-31 2012-03-28 Purdue Pharma LP Composés de pipéridine de type quinoxaline substituée et leurs utilisations
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WO2014102589A1 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine du type quinazolin-4(3h)-one et utilisations de ceux-ci
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066057A1 (fr) * 2002-02-08 2003-08-14 Bayer Healthcare Ag Quinoxalinones et leur utilisation notamment pour traiter des affections cardiovasculaires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066057A1 (fr) * 2002-02-08 2003-08-14 Bayer Healthcare Ag Quinoxalinones et leur utilisation notamment pour traiter des affections cardiovasculaires

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