WO2005087740A1 - Derives de fluorenone 1, 4,-dihydropyridine - Google Patents

Derives de fluorenone 1, 4,-dihydropyridine Download PDF

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Publication number
WO2005087740A1
WO2005087740A1 PCT/EP2005/002129 EP2005002129W WO2005087740A1 WO 2005087740 A1 WO2005087740 A1 WO 2005087740A1 EP 2005002129 W EP2005002129 W EP 2005002129W WO 2005087740 A1 WO2005087740 A1 WO 2005087740A1
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Prior art keywords
alkyl
alkylamino
substituted
group
alkoxy
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PCT/EP2005/002129
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German (de)
English (en)
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Jens-Kerim ERGÜDEN
Peter Kolkhof
Peter Sandner
Alexander Kuhl
Johannes-Peter Stasch
Elisabeth Pook
Karl-Heinz Schlemmer
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Bayer Healthcare Ag
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Publication of WO2005087740A1 publication Critical patent/WO2005087740A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to substituted dihydropyridines and processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases.
  • Fluorenone-substituted dihydropyridines with two carboxylic acid ester substituents are described in R. Budriesi et al., Eur. J. Pharmacol. 1998, 359 (2/3), 161-170 and A. Rampa et al., ⁇ rzneim. Forsch. 1992, 42 (11), 1284-1286 as calcium antagonists.
  • Fluorenone-substituted dihydropyridines with a carboxylic acid ester and a phosphonic acid ester substituent are described in R. Budriesi et al., Arzneistoff. Forsch. 1996, 46 (4), 374-377.
  • Aldosterone plays a key role in maintaining fluid and electrolyte homeostasis by controlling sodium retention and potassium secretion in the epithelium of the distal nephron, which helps to keep the extracellular volume constant and thus regulate blood pressure.
  • aldosterone has direct effects on the structure and function of the cardiovascular system, although the underlying mechanisms have not yet been exhaustively clarified (RE Booth, JP Johnson, JD Stockand, Adv. Phys ' iol. Educ. 2002, 26 ( 1), 8-20).
  • aldosterone antagonists are used as potassium-sparing diuretics and for hereditary type I hyperaldosteronism.
  • aldosterone antagonists have also been used in heart failure patients where there is a significant reduction in all-cause mortality (S. A. Dogrell, L. Brown, Exp. Opin. Luvest. Drugs 2001, 10 (5), 943-954).
  • the invention relates to compounds of the formula (I)
  • R 1 is a group of the formula
  • R represents hydrogen or halogen
  • Heterocyclyl or heteroaryl can be substituted with 1, 2 or 3 substituents, independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, thioxo, hydroxy, amino, hydroxycarbonyl, arinocarbonyl, CC 6 -alkyl, CC 6 -alkoxy, -CC 6 -alkylamino, -CC 6 -alkoxycarbonyl and - Cg-alkylaminocarbonyl,
  • R 7 represents 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl or -NR S R 9 , in which
  • Heterocyclyl or heteroaryl can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen,
  • R 8 represents hydrogen or - -alkyl
  • R 9 represents CC 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heterocyclic or 5- to 10-membered heteroaryl,
  • Cycloalkyl, aryl, heterocyclyl or heteroaryl can be substituted with
  • Alkyl can be substituted by a substituent C 3 -C 7 -cycloalkyl, C 6 -cio-aryl, 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl,
  • Cycloalkyl, aryl, heterocyclyl or heteroaryl can in turn be substituted with 1, 2 or 3 substituents, independently of one another selected from the group consisting of halogen,
  • R 4 denotes amino, trifluoromethyl, methyl, ethyl, C 1 -C 3 -alkyl-O-CH 2 - or CC 3 -alkyl-S-CH 2 - # ,
  • R 5 -C 6 alkyl which can be substituted with 1, 2 or 3 substituents, independently of one another selected from the group consisting of halogen, hydroxy, amino, -C 6 alkoxy,
  • Cycloalkyl, aryl, heterocyclyl or heteroaryl can in turn be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, CC 6 alkyl, C ⁇ -C 6 -alkoxy, CC 6 - alkylamino, CC 6 alkoxycarbonyl xmd -C ⁇ -alkylaminocarbonyl,
  • C 3 -C 7 cycloalkyl which can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 6 alkyl, C 1 -C 6 - alkoxy, C r C 6 -alkylamino, -C-C 6 -alkoxycarbonyl and C ⁇ -C 6 -alkylaminocarbonyl,
  • R 10 represents C] -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl,
  • Alkyl can be substituted with 1, 2 or 3 substituents, independently of one another selected from the group consisting of halogen, hydroxy, amino, CC 6 - alkoxy, C 1 -C 6 alkylamino, arylamino, C 3 -C 7 cycloalkyl, C 6 -C ⁇ 0 aryl, 5- to 7- membered heterocyclyl xmd 5- to 10-membered heteroaryl,
  • Cycloalkyl, aryl, heterocyclyl or heteroaryl can in turn be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 6 - Alkyl, -CC 6 alkoxy, CC 6 -Al ylammo, -C ö alkoxycarbonyl and -
  • Cycloalkyl, heterocyclyl, aryl or heteroaryl can be substituted with 1, 2 or
  • substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, hydroxy, amino,
  • 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. From such mixtures of
  • Enantiomers and / or diastereomers can be used to isolate the stereoisomerically uniform constituents in a known manner.
  • the present invention encompasses all tautomeric forms.
  • salts are physiologically acceptable salts of Compounds of the invention preferred.
  • 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 of 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, for example, preferably 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 1 to 16 carbon
  • 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.
  • Alkylaminocarbonyl and alkoxycarbonyl represent a linear or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably
  • Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylamino represents an alkylamino radical having one or two (independently elected th) alkyl substituents, by way of example and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N. N-dimethylamino, N, N-
  • C 1 -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.
  • Alkylaminocarbonyl represents an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, for example and preferably for methylaminocarbonyl,
  • C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylammocarbonyl radical each having 1 to 3 carbon atoms per alkyl substituent.
  • Arylamino stands for an aryl substituent attached via an amino group, where another substituent such as e.g. Aryl or alkyl, is bound, by way of example and preferably for phenylamino, ⁇ aphthylamine, phenylmethylamino or diphenylamino.
  • Alkoxycarbonyl exemplifies and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Cycloalkyl stands for a cycloalkyl group with generally 3 to 8, preferably 5 to 7 carbon atoms, examples and preferably for cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl stands for a mono- to tricyclic aromatic radical with usually 6 to 14 carbon atoms; exemplary and preferably for aryl are phenyl, ⁇ aphthyl and phenanthrenyl.
  • Heteroaryl stands for an aromatic, mono- or bicyclic radical with generally 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and ⁇ , by way of example and preferably for thienyl, furyl , Pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, hnidazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
  • Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series ⁇ , O , S, SO, SO 2 .
  • the Heterocyclyl residues can be saturated or partially unsaturated.
  • Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • a symbol * on a carbon atom means that the compound is present in enantiomerically pure form with regard to the configuration on this carbon atom, which in the context of the present invention means an enantiomeric excess of more than 90% (> 90% ee).
  • 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.
  • R 1 is a group of the formula
  • R represents hydrogen or halogen.
  • Heterocyclyl or heteroaryl can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, thioxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 6 alkyl , -C ⁇ -alkoxy, -C-C 6 alkylamino, CC 6 -alkoxycarbonyl xmd C
  • R 7 represents 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl
  • Heterocyclyl or heteroaryl can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, thioxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 6 alkyl, C 1 -C 6 -alkoxy, -Ce-alkylamino, -C-C 6 -alkoxycarbonyl xmd -CC 6 -alkylaminocarbonyl,
  • R 3 denotes amino, trifluoromethyl or methyl
  • R 4 denotes amino, trifluoromethyl or methyl
  • R s CC 6 alkyl which can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, hydroxy, amino, CC 6 alkoxy, Ci-C ⁇ -alkylamino, 5- to 7-membered Heterocyclyl and 5- to 10-membered heteroaryl,
  • Heterocyclyl or heteroaryl can be substituted on the side with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 6 alkyl, C ⁇ - C 6 alkoxy, C 6 alkyl alkyl, C 6 alkoxycarbonyl and C 6 alkylammocarbonyl,
  • Wonn R 10 stands for d-Cs-alkyl, C 3 -C 7 cycloalkyl, C 6 -C ⁇ 0 aryl, 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl,
  • Alkyl can be substituted with 1, 2 or 3 substituents, independently of one another selected from the group consisting of halogen, hydroxyl, amino, -C ⁇ -
  • Heterocyclyl or heteroaryl can in turn be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 6 alkyl, C ⁇ - C 6 - alkoxy, Ci-C ⁇ -alkylamino, Ci-C ö -alkoxycarbonyl xmd Ci-C ß - alkylaminocarbonyl,
  • Cycloalkyl, heterocyclyl, aryl or heteroaryl can be substituted with 1, 2 or 3 substituents, independently of one another - selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, oxo, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, CC 6 alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, CC 6 -alkoxycarbonyl and C 1 -C 6 -alkylaminocarbonyl,
  • R 1 is a group of the formula
  • R 6 represents hydrogen
  • R 2 cyano, oxadiazolyl, thiadiazolyl, triazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl,
  • Oxadiazolyl, thiadiazolyl, triazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furyl, pyrrolyl, benzothiazolyl or benzooxazolyl can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of oxo, thioxo,
  • R 7 represents oxadiazolyl, thiadiazolyl, triazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furyl, pynolyl, benzothiazolyl or benzooxazolyl,
  • Oxadiazolyl, thiadiazolyl, triazolyl can be substituted with 1, 2 or 3 substituents, independently selected from the group consisting of oxo, thioxo, C 1 -C 6 alkyl, -C ⁇ -alkoxy and C ⁇ -C 6 - alkylamino,
  • R 3 represents trifluoromethyl or methyl
  • R 4 represents trifluoromethyl or methyl
  • R 5 denotes Ci-C ff -alkyl or -OR 10 ,
  • R 10 represents Ci-C ⁇ -alkyl or C 3 -C 7 cycloalkyl
  • Alkyl can be substituted with a substituent -C ö alkoxy, -C -C 6 alkylamino, pyrrolidinyl, piperidinyl, piperazinyl, Mo holinyl, thiomorpholinyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furyl, pynolyl, indolinyl or isoindolinyl .
  • Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furyl, pynolyl, indolinyl or isoindolinyl can in turn be substituted with 1 or 2 substituents, independently selected from the group consisting of oxo, d-j-alkyl , CC 6 alkoxy and CC 6 alkylamino,
  • the invention further relates to a process for the preparation of the compounds of the formula (I), wherein
  • R 1 has the meaning given above, in a one-step process (one-pot process) initially with compounds of the formula (HI)
  • R 2 and R 3 have the meaning given above
  • R 4 xmd R 5 have the meaning given above,
  • R 4 xmd R 5 have the meaning given above,
  • reaction according to process [A], the second step of process [B] and the second step of process [C] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 10 ° C. to the reflux Solvent at normal pressure.
  • Bases are, for example, alcoholates such as sodium or potassium methoxide or sodium or potassium ethanolate or potassium tert-butoxide, or alkali and alkaline earth metal carbonates such as cesium carbonate, sodium or potassium carbonate, potassium tert-butoxide being preferred.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as acetonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or glacial acetic acid; iso is preferred propanol.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol
  • other solvents such as acetonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or glacial acetic acid
  • iso is preferred propanol.
  • Implementation of the first stage of the process [B] and the first stage of the process. [C] is generally carried out in inert solvents, if appropriate in the presence of piperidine and / or an acid, preferably in a temperature range from 50 ° C. to the reflux of the solvents at atmospheric pressure.
  • Acids are, for example, glacial acetic acid, sulfuric acid, formic acid, camphorsulphonic acid or p-toluenesulphonic acid, glacial acetic acid is preferred.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride,
  • Trichloromethane carbon tetrachloride, trichloroethane or 1,2-dichloroethane, or other solution medium, such as acetonitrile, pridine, toluene, benzene, chlorobenzene or hexane, methylene chloride is preferred.
  • the reaction can also be carried out with piperidinium acetate in methylene chloride.
  • the compounds of the formulas (II) are known or can be synthesized from the corresponding starting compounds by known processes, for. B. by reaction of substituted methoxycarbonyl-phenyl-boronic acids and phenyl-bromides in a Suzuki reaction with an associated Friedel-Crafts acylation analogous to Dewar and Grisdale, J. Org. Chem. 1963, 28n, 1759.
  • the compounds of the formulas (IH) xmd (VI) are known or can be synthesized from the corresponding starting compounds by known processes, for. B. analogous to C. Kashima et al., Bull. Chem. Soc. Jpn. 1973, 46, 310-313; C. Kashima, Y. Yamamoto, Bull. Chem. Soc. Jpn. 1979, 52 (6), 1735-1737; EP 716081 and A. W. Lutz, S.H. Trotto, J. Heterocycl. Chem. 1972, 9.
  • the compounds of the formulas (IV) are known or can be synthesized from the corresponding starting compounds by processes known to those skilled in the art for the preparation of ⁇ -keto esters.
  • the compounds of the formulas (V) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the compounds according to the invention act as antagonists of the mineral corticoid receptor and show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of various diseases, in particular cardiovascular diseases.
  • Examples include: atrial and ventricular arrhythmias, myocardial infarction, arterioslderosis, heart failure, hypertension, pulmonary hypertension, stable and unstable angina pectoris, myocardial ischemia, transient and ischemic attacks, stroke, inflammatory cardiovascular diseases, coronary artery disease, peritoneal heart disease, coronary artery disease, peritoneal heart disease, coronary artery disease, peritoneal heart disease, coronary heart disease, peripheral circulation disorders, restenoses such as after thrombolysis treatments, percutaneous transluminal angioplasties (PTA) xmd transluminal coronary angioplasties (PTCA), coronary artery spasm, thrombosis, thromboembolic ill gen, bypass surgery, heart transplants, edema formation such as for example pulmonary edema, renal edema or herzinsuffiziens memoriens memoriens memoriens memoriens memoriens memoriens memoriens memoriens memoriens memoriens
  • the compounds according to the invention are suitable for the prophylaxis xmd / or treatment of acute kidney failure, inflammatory diseases, asthmatic diseases, chronic obstructive airways disease (COPD), pain conditions, prostate hypertrophies, incontinence, cystitis, hyperactive bladder, renal insufficiency, diseases of the adrenal gland, such as
  • Example pheochromocytoma xmd adrenal apoplexy diseases of the intestine such as Crohn's disease or diarrhea, hyperaldosteronism, anti-acne treatment, menstrual disorders, contraception, cancer or electrolyte disorders such as hypercalcemia.
  • the compounds of the invention are also suitable for use as a diuretic.
  • 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 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.
  • suitable Combination active ingredients may be mentioned by way of example and preferably: ACE inhibitors, angiotensin II receptor inhibitors, beta-blockers, aspirin, loop diuretics, potassium supplements, calcium antagonists, statins and / or digitalis derivatives.
  • the compounds according to the invention can act systemically and / or locally.
  • they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • state-of-the-art, fast and / or modified application forms which release the compounds according to the invention and contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as e.g. 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
  • rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity Coated
  • Parenteral administration can be done by bypassing a resorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on one
  • 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 forms including powder inhalers, nebulizers
  • nasal drops, solutions, sprays 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, milk, pastes, foams , 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 auxiliaries.
  • auxiliaries include, among other things, carrier substances (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
  • carrier substances for example, microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl sulfate, polyoxysorbit
  • the present invention further relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and to their use for the aforementioned purposes.
  • Method 4 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; 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; Fl ⁇ ss: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.
  • Method 5 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 ⁇ rxm; 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.
  • Method 6 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; 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.
  • Method 7 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 mx 250 ⁇ m x 0.25 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (hold for 0.30 min), 50 ° C / min ⁇ 120 ° C, 16 ° C / min ⁇ 250 ° C, 30 ° C / min ⁇ 300 ° C (hold 1.7 min).
  • Method 8 Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml HClO ⁇ l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B, 6.7 min 2% B, 7.5 min 2% B; Flow: 0.75 ml min; Oven: 30 ° C; UV detection: 210 nm.
  • alkenes used as starting compounds are in the form of E / Z mixtures.
  • Example A2 The compound from Example A2 (5.21 g, 25.0 mmol) is placed in 180 ml of dichloromethane and the compound from Example AI (2.89 g, 27.5 mmol), acetic acid (1.72 ml, 30.0 mmol) and piperidine (0.25 ml, 2.50 mmol) added. The mixture is stirred at the boiling point on a water separator for 4 h. After cooling to RT, the mixture is diluted with 30 ml of dichloromethane and washed with water (twice 50 ml), the organic phase is dried over sodium sulfate and the
  • the compound is obtained as fraction 1 by chromatographic diastereomer separation (Method 1) of 9.00 g of the compound from Example A8. 3.50 g (39% of theory) of product are obtained.
  • the compound is obtained as fraction 2 by chromatographic diastereomer separation (Method 1) of 9.00 g of the compound from Example A8. 4.00 g (44% of theory) of product are obtained.
  • Example A8 The compound from Example A8 (1.00 g, 1.84 mmol) is placed in 150 ml of ethyl acetate, DBU (0.96 ml, 6.44 mmol) is added at RT and the mixture is stirred for 1 h.
  • the reaction mixture is mixed with 100 ml of ethyl acetate and 100 ml of 1N hydrochloric acid and stirred at RT for 5 min.
  • the organic phase is separated off, washed with 50 ml of water and 50 ml of saturated sodium chloride solution and dried over magnesium sulfate.
  • Example AI 1 The preparation is as described for Example AI 1 from the compound from Example A9 (3.30 g, 6.07 mmol). 2.02 g (93% of theory) of product are obtained.
  • Example A1 The compound from Example A1 (400 mg, 1.12 mmol) in 16 ml of anhydrous THF (suspension) is introduced under argon, N, N'-carbonyldiimidazole (228 mg, 1.40 mmol) is added at RT and the mixture is left overnight at RT stirred (clear solution). The mixture is concentrated and the residue is dried in an oil pump vacuum (foam). A portion of the product is crystallized with diethyl ether (overnight in the refrigerator), suction filtered and dried at 40 ° C in a vacuum drying cabinet. 185 mg (41% of theory) of a crystalline solid are obtained.
  • Example A14 The preparation is as described for Example A14 from the compound from Example AI 3 (2.10 g, 5.89 mmol). The residue obtained is mixed with 50 ml of ethyl acetate-diethyl ether mixture 1: 1 and left overnight in the refrigerator. The precipitated solid is filtered off with suction, washed with diethyl ether (twice 20 ml) and dried at 40 ° C. in a vacuum drying cabinet. 2.12 g (89% of theory) of product are obtained.
  • the combined product fractions are finely cleaned by preparative HPLC (YMC GEL ODS-AQ S-5/15 ⁇ m; eluent gradient: acetonitrile-water 10:90 - »95: 5).
  • the product obtained is washed with a little diethyl ether, suction filtered and dried in an oil pump vacuum. 64 mg (21% of theory) of a solid are obtained.
  • the compound is obtained as a (-) enantiomer by chromatographic separation of enantiomers (Method 3) of 60 mg of the compound from Example 2. 20 mg of product are obtained.
  • the organic phase is dried over sodium sulfate, concentrated and purified chromatographically on silica gel 60 (mobile phase gradient: cyclohexane - cyclohexane / ethyl acetate 1.5: 1). After removal of the solvent, 70 mg (10% of theory) of a solid are obtained.
  • connection is prepared as described in Example 1 from the corresponding starting compounds. Batch size: 1.00 mmol. 247 mg (50% of theory) of product (mixture of diastereomers) are obtained.
  • Example AI 5 The compound from Example AI 5 (100 mg, 0.25 mmol) is placed in 2 ml of (R) - (-) - 2-butanol, DMAP (3 mg, 0.02 mmol) is added at RT and the mixture is 2 h at 100 ° C stirred. The reaction mixture is concentrated, the residue is purified on a Biotage cartridge 12M (KP-Sil TM silica gel, mobile phase: isohexane / ethyl acetate 60:40) and the combined product fractions are concentrated on a rotary evaporator.
  • Biotage cartridge 12M KP-Sil TM silica gel, mobile phase: isohexane / ethyl acetate 60:40
  • the compound is obtained as a (-) enantiomer by chromatographic separation of enantiomers (Method 2) of 50 mg of the compound from Example 14. 23 mg of product are obtained.
  • the identification of antagonists of the human mineral corticoid receptor (MR) and the quantification of the effectiveness of the substances described here is carried out using a recombinant cell line.
  • the cell is originally derived from an ovary epithelial cell of the hamster
  • the GAL4-D ⁇ A binding domain (amino acids 1-147) from the vector pFC2-dbd (company Stratagene) with the PCR-amplified ligand binding domains of the mineral corticoid receptor (MR, amino acids 734-985), the glucocorticoid receptor (GR, amino acids 443-777), the progesterone receptor (PR, amino acids 680-933) and the androgen receptor (AR, amino acids 667-919) are cloned into the vector pIRES2 (Clontech).
  • the reporter construct which contains five copies of the GAL4 binding site upstream of a thymidine kinase promoter, leads to the expression of the Firefly
  • Luciferase (Photinus pyralis) after activation and binding of the GAL4 steroid hormone receptor Chimeras by the respective specific agonists aldosterone (MR), dexamethasone (GR), progesterone (PR) xmd dihydrotestosterone (AR).
  • MR aldosterone
  • GR dexamethasone
  • PR progesterone
  • Test procedure The MR, GR, PR and AR cells are placed in medium (Optimem, 2.5% FCS, 2 mM Glutamine, 10 mM HEPES in 96- (or 384- or 1536-) holes the day before the test - Microtiter plates are plated out and kept in a cell incubator (96% humidity, 5% v / v CO 2 , 37 ° C.) On the day of the test, the substances to be tested are taken up in the medium mentioned above and added to the cells for about 10 to 30 minutes After adding the test substances, the specific agonists of the steroid hormone receptors are added. After a further incubation time of 5 to 6 hours, the luciferase activity is measured with the aid of a video camera. The measured relative light units, depending on the substance concentration, result in a sigmoid stimulation curve. The calculation of the IC 5 o values are carried out using the computer program GraphPad PRISM (version 3.02).
  • Table A shows selected compounds with IC 50 values.
  • the animals were given the following accesses with polyethylene tubes (PE-50; fritrame-die ® ) as catheter material on a temperature-controlled surface under isoflurane anesthesia as described above: a venous catheter in the jugular vein, an additional venous catheter in the femoral vein and a bladder catheter, which is opened after the opening of the abdominal cavity and presentation of the bladder via a small incision. After these interventions, all openings are closed again, a bolus dose (1.5 ml) of isotonic sodium chloride solution (Fresenius) is administered via the jugular vein and then a continuous injection of isotonic sodium chloride solution (4 ml / h) is started. After a recovery period of one
  • the urine is collected for one hour xmd used as a starting value. Then a permanent infusion of aldosterone (1 ⁇ g / h; company SIGMA) is administered via the femoral vein and the test substance (treatment group) or the solution vehicle without test substance (control group) is administered as an intraperitoneal bolus, both in the treatment group and in the control group the hourly urine collected over a period of five hours.
  • the volume and the concentration of sodium (Na *) and potassium (K + ) are determined using standard flame-photometric methods and the Na + / K "i" quotient is calculated from this.
  • the rats are killed with a throat cut after the experiment. After the abdominal cavity has been opened, the complete removal of both adrenal glands is checked, the kidneys are removed and the expression of the genes induced by aldosterone, serum and
  • Glucocorticoid kinase sgk-1
  • ⁇ EnaC epithelial sodium channel
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrrolidone (PVP 25) (from BASF, Germany) and 2 mg magnesium stearate.
  • lactose monohydrate
  • corn starch 50 mg
  • PVP 25 polyvinylpyrrolidone
  • MVP 25 polyvinylpyrrolidone
  • 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 compound of Example 1 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.
  • Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
  • the solution is sterile filtered (pore diameter 0.22 ⁇ m) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

Abstract

La présente invention concerne des dihydropyridines substituées de la formule (I) et leur procédé de production, leur utilisation destinée au traitement et/ou à la prévention de maladies ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou à la prévention de maladies, notamment de maladies cardiovasculaires.
PCT/EP2005/002129 2004-03-13 2005-03-01 Derives de fluorenone 1, 4,-dihydropyridine WO2005087740A1 (fr)

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WO2007009607A1 (fr) * 2005-07-18 2007-01-25 Bayer Healthcare Ag Nouvelle utilisation d'activateurs et de stimulateurs de la guanylate cyclase soluble permettant de prevenir ou de traiter des troubles renaux
WO2007140934A1 (fr) * 2006-06-07 2007-12-13 Bayer Healthcare Ag 4-aryl-1,4-dihydro-1,6-naphtyridine substituée et son utilisation
WO2007140894A1 (fr) * 2006-06-07 2007-12-13 Bayer Healthcare Ag Dihydropyridopyrimidines et dihydropyridazines à substitution 5-aryle et leur utilisation comme antagonistes des corticoïdes minéraux
DE102007009494A1 (de) 2007-02-27 2008-08-28 Bayer Healthcare Ag Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung
JP2011506440A (ja) * 2007-12-14 2011-03-03 メルク・シャープ・エンド・ドーム・コーポレイション 鉱質コルチコイド受容体調節剤
US8404723B2 (en) 2006-09-22 2013-03-26 Bayer Intellectual Property Gmbh 3-cyano 5-thiazaheteroaryl-dihydropyridine and the use thereof for the treatment of cardiovascular diseases
RU2470932C9 (ru) * 2007-02-27 2013-06-27 Байер Шеринг Фарма Акциенгезельшафт Замещенные 4-арил-1,4-дигидро-1,6-нафтиридинамиды и их применение
CN109721596A (zh) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 苯基取代的二氢吡啶类化合物及其用途

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CACCAMESE, SALVATORE ET AL: "Fluorenone 1,4-dihydropyridine derivatives with cardiac depression activity: Enantiomeric separation by chiral HPLC and conformational aspects", CHIRALITY, vol. 8, no. 3, 1996, pages 281 - 290, XP002329980 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007009607A1 (fr) * 2005-07-18 2007-01-25 Bayer Healthcare Ag Nouvelle utilisation d'activateurs et de stimulateurs de la guanylate cyclase soluble permettant de prevenir ou de traiter des troubles renaux
US8399471B2 (en) 2006-06-07 2013-03-19 Bayer Intellectual Property Gmbh Aryl-or heteroaryl-substituted pyrido[2,3-d] pyrimidines and pharmaceutical compositions of the same
WO2007140934A1 (fr) * 2006-06-07 2007-12-13 Bayer Healthcare Ag 4-aryl-1,4-dihydro-1,6-naphtyridine substituée et son utilisation
WO2007140894A1 (fr) * 2006-06-07 2007-12-13 Bayer Healthcare Ag Dihydropyridopyrimidines et dihydropyridazines à substitution 5-aryle et leur utilisation comme antagonistes des corticoïdes minéraux
US8404709B2 (en) 2006-06-07 2013-03-26 Bayer Intellectual Property Gmbh Substituted 4-aryl-1,4-dihydro-1,6-naphthyridines and use thereof
JP2009539784A (ja) * 2006-06-07 2009-11-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト ５−アリール置換ジヒドロピリドピリミジン類およびジヒドロピリダジン類および鉱質コルチコイドアンタゴニストとしてのそれらの使用
JP2009539787A (ja) * 2006-06-07 2009-11-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト 置換４−アリール−１，４−ジヒドロ−１，６−ナフチリジン類およびそれらの使用
US8404723B2 (en) 2006-09-22 2013-03-26 Bayer Intellectual Property Gmbh 3-cyano 5-thiazaheteroaryl-dihydropyridine and the use thereof for the treatment of cardiovascular diseases
WO2008104306A2 (fr) * 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
RU2470932C2 (ru) * 2007-02-27 2012-12-27 Байер Шеринг Фарма Акциенгезельшафт Замещенные 4-арил-1,4-дигидро-1,6-нафтиридинамиды и их применение
JP2010519232A (ja) * 2007-02-27 2010-06-03 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト 置換４−アリール−１，４−ジヒドロ−１，６−ナフチリジンアミドおよびそれらの使用
WO2008104306A3 (fr) * 2007-02-27 2009-03-19 Bayer Healthcare Ag Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
DE102007009494A1 (de) 2007-02-27 2008-08-28 Bayer Healthcare Ag Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung
RU2470932C9 (ru) * 2007-02-27 2013-06-27 Байер Шеринг Фарма Акциенгезельшафт Замещенные 4-арил-1,4-дигидро-1,6-нафтиридинамиды и их применение
JP2014012678A (ja) * 2007-02-27 2014-01-23 Bayer Intellectual Property Gmbh 置換４−アリール−１，４−ジヒドロ−１，６−ナフチリジンアミドおよびそれらの使用
JP2011506440A (ja) * 2007-12-14 2011-03-03 メルク・シャープ・エンド・ドーム・コーポレイション 鉱質コルチコイド受容体調節剤
CN109721596A (zh) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 苯基取代的二氢吡啶类化合物及其用途
CN109721596B (zh) * 2017-10-27 2020-12-18 广东东阳光药业有限公司 苯基取代的二氢吡啶类化合物及其用途

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