EP1507763A1 - Derives de tetrahydroisoquinoline - Google Patents

Derives de tetrahydroisoquinoline

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Publication number
EP1507763A1
EP1507763A1 EP03725144A EP03725144A EP1507763A1 EP 1507763 A1 EP1507763 A1 EP 1507763A1 EP 03725144 A EP03725144 A EP 03725144A EP 03725144 A EP03725144 A EP 03725144A EP 1507763 A1 EP1507763 A1 EP 1507763A1
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EP
European Patent Office
Prior art keywords
mmol
methyl
general formula
dihydro
sulfonyl
Prior art date
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Application number
EP03725144A
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German (de)
English (en)
Inventor
Hilmar Bischoff
Elke Dittrich-Wengenroth
Verena Vöhringer
Heike Heckroth
Andrea Vaupel
Michael Woltering
Michael Otteneder
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Bayer AG
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Bayer Healthcare AG
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Publication of EP1507763A1 publication Critical patent/EP1507763A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom

Definitions

  • the present application relates to new substituted tetrahydroisoquinoline derivatives, processes for their preparation and their use in medicaments, in particular as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of cardiovascular diseases, in particular dyslipidemias, coronary heart diseases and arteriosclerosis.
  • CAD coronary artery disease
  • Fibrates are the only form of therapy for patients in these risk groups today. They act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -alpha (Nature 1990, 347, 645-50). A disadvantage of previously approved fibrates is their weak interaction with the receptor, which leads to high daily doses and significant side effects.
  • PPAR peroxisome proliferator-activated receptor
  • PPAR-delta agonists For the peroxisome proliferator-activated receptor (PPAR) delta (Mol. Endocrinol. 1992, 6, 1634-41), the first pharmacological findings in animal models indicate that potent PPAR-delta agonists also improve HDL / LDL Cholesterol ratio and hypertriglyceridemia.
  • the object of the present invention was to provide new compounds which can be used as PPAR delta modulators.
  • X represents O, S or CH 2 ,
  • R 1 represents halogen, (C ⁇ -C6) alkoxy, (C 2 -C 6) alkenyloxy, (C 3 -C 7) cycloalkoxy, optionally substituted by halogen, (C ⁇ -C 4) -alkyl, trifluoromethyl or ( C ⁇ -C 4 ) -
  • R 2 and R 3 are the same or different and independently of one another are hydrogen or (-CC 6 ) alkyl, which is optionally substituted by phenyl or together with the carbon atom to which they are attached form a 3- to 7-membered, spiro-linked cycloalkyl ring,
  • R 4 and R 5 are the same or different and independently of one another represent hydrogen or (-CC 6 ) -alkyl
  • R 6 represents hydrogen or (C i -C 6 ) alkyl
  • R 7 represents hydrogen or (-CC 6 ) alkyl
  • R 8 represents hydrogen, (C, -C 6 ) alkyl, (-C-C 6 ) alkoxy or halogen,
  • R 9 and R 10 are the same or different and independently of one another represent hydrogen or (-CC) alkyl
  • R 1 ' represents hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid
  • Group is a group that transforms the body in particular
  • Such groups are exemplary and preferably: benzyl, (-CC 6 ) -alkyl or (C-C 8 ) -cycloalkyl, each optionally one or more times, identically or differently, by halogen, hydroxy, amino, (-C-C 6 ) -alkoxy, carboxyl, (-C-C 6 ) - Alkoxycarbonyl, (-CC 6 ) -alkoxycarbonylamino or (-C-C 6 ) alkanoyloxy are substituted, or in particular (-C-C 4 ) -alkyl, which may be one or more, the same or different, by halogen, hydroxy, amino , (-C-C 4 ) alkoxy, carboxyl, (-C-C 4 ) -alkoxycarbonyl, (C ⁇ -C 4 ) -alkoxycarbonylamino or (C ⁇ -C 4 ) - alkanoyloxy is substituted.
  • (C 1 -C 6 ) -alkyl and (CrC 4 ) -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl,
  • (C -C 6 ) alkenyl and (C -C 4 ) alkenyl stand for a straight-chain or branched alkenyl radical having 2 to 6 or 2 to 4 carbon atoms.
  • a straight-chain or branched alkenyl radical with 2 to 4 is preferred
  • Carbon atoms The following may be mentioned as examples and preferably: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.
  • Cycloalkyl stands for a monocyclic cycloalkyl group with 3 to 8 carbon atoms in the context of the invention. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • (C 6 -C ⁇ o) aryl represents an aromatic radical with preferably 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (-C-C 6 ) alkoxy and (-C-C 4 ) alkoxy are within the scope of the invention for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
  • a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy,
  • (C2-C 6) -alkenyloxy and (C 2 -C) alkenyloxy are in the context of the invention a straight-chain or branched alkenyloxy group having 2 to 6 or 2 to 4 carbon atoms.
  • a straight-chain or branched alkenyloxy radical having 2 to 4 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: vinyloxy, allyloxy, isopropenyloxy and n-but-2-en-1-yloxy.
  • (C -C 7 ) cycloalkoxy and (C 5 -C 6 ) cycloalkoxy represent a monocyclic cycloalkoxy radical having 3 to 7 or 5 to 6 carbon atoms.
  • a cycloalkoxy radical having 5 to 6 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: cyclopropoxy, cyclobutoxy, cyclopentoxy and cyclohexoxy.
  • (C l -C 6) - alkoxycarbonyl is in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which is linked via a carbonyl group.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
  • C Q-alkoxycarbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxy radical and is linked via the carbonyl group.
  • An alkoxycarbonylamino radical with 1 to 4 carbon atoms is preferred Examples and preferably mentioned are: methoxycarbonylamino,
  • (CrC 6 ) -alkanoyloxy stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double-bonded oxygen atom in the 1 position and another one in the 1 position Oxygen atom is linked. Examples that may be mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.
  • mono- (CrC 6 ) -alkylamino and mono- (CrC 4 ) -alkylamino represent an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms.
  • a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and t-butylamino.
  • di- (C 1 -C 6 ) -alkylamino and di- (C 1 -C 4 ) -alkylamino stand for an amino group with two identical or different straight-chain or branched alkyl substituents, each 1 to 6 or 1 to Have 4 carbon atoms.
  • Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. Examples and preferably are:
  • NN-dimethylamino NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pen- tylamino and Nn-hexyl-N-methylamino.
  • 5- to 6-membered heteroaryl with up to 3 identical or different heteroatoms from the series S, ⁇ and / or O preferably stands for an aromatic heterocycle in the context of the invention which is via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic is linked.
  • Examples include: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • Invention includes.
  • the compounds according to the invention can also be present as salts.
  • Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid are preferred , Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • Physiologically acceptable salts can also be salts of the invention
  • Be compounds with bases such as metal or ammonium salts.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example magnesium or calcium salts
  • ammonium salts which are derived from ammonia or organic amines, for example ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • the compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
  • X represents O or S
  • R 1 for (C 2 -C 4 ) alkenyloxy, (C 5 -C 6 ) cycloalkoxy or in particular for halogen or (C ⁇ -C) alkoxy,
  • R 2 and R 3 are the same or different and are independently hydrogen or methyl or ethyl, which may be substituted by phenyl, or together with the carbon atom to which they are attached
  • R 4 and R 5 each represent hydrogen
  • R. 0 represents hydrogen or methyl
  • R 7 represents hydrogen or methyl
  • R 8 represents hydrogen, (-CC 4 ) -alkyl, (dC 4 ) -alkoxy, fluorine or chlorine,
  • R 9 and R 10 are the same or different and are independently of one another
  • R 1 ' represents hydrogen or (-CC 4 ) alkyl.
  • R 1 represents pyridyl or, in particular, phenyl, which in turn can be substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino and dimethylamino,
  • R 2 represents hydrogen or methyl
  • R 3 represents methyl or phenethyl
  • R and R together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,
  • R 4 and R 5 each represent hydrogen, R 6 represents hydrogen or methyl,
  • R 7 represents hydrogen or methyl
  • R 8 represents methyl
  • R 9 and R 10 each represent hydrogen
  • R 1 ' represents ethoxy or in particular hydrogen.
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, irrespective of the respectively specified combinations of the radicals.
  • R 2 represents hydrogen
  • R 3 represents methyl or phenethyl
  • R 2 and R 3 both represent methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,
  • R, R and R each have the meaning given above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each have the meaning given above.
  • R 2 , R 3 , R 4 , R 5 and R 6 each have the meaning given above and
  • PG stands for a suitable hydroxyl protective group, such as methyl or benzyl
  • R 1 stands for (C 6 -C ⁇ o) aryl or 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which in turn each one to three times, identically or differently, by substituents selected from the group halogen, (Ci
  • C 6 ) alkyl, (-C-C 6 ) alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (-C-C 6 ) alkylamino may be substituted, and
  • R 13 represents hydrogen or methyl or both radicals together form a CH 2 CH 2 or C (CH 3 ) 2 -C (CH 3 ) 2 bridge, in an inert solvent in the presence of a suitable palladium catalyst and a base to give compounds of the general formula (IB) [cf. e.g. W. Hahnfeld, M. Jung, Pharmazie 1994, 49, 18-20; idem, Liebigs Ann. Chem. 1994, 59-64].
  • Inert solvents for process step (II) + (III) ⁇ (IB) or (IV) + (III) - (V) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl 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, ethyl acetate, acetone, dimethylformamide, dimethylyrrolidine, acetonitrile, acetonitrile, acetonitrile, acetic acid or
  • Suitable bases for process step (II) + (III) ⁇ (I-B) or (IV) + (III) ⁇ (V) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine , Amine bases such as triethylamine, pyridine or ethyldiisopropylamine are particularly preferred, optionally in the presence of catalytic amounts (approx. 10 mol%) of 4-NN-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • the base is used in an amount of 1 to 5, preferably 1 to 2.5, mol, based on 1 mol of the compound of the general formula (III).
  • the reaction generally takes place in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 75 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
  • Inert solvents for process step (IB) - »(IC) are, for example, halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol , isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene,
  • halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • alcohols such as methanol, ethanol, n-propanol ,
  • the usual inorganic bases are suitable as bases for process step (I-B) ⁇ (I-C). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, or alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate. Lithium or sodium hydroxide are particularly preferred.
  • the base is used in an amount of 1 to 5, preferably 1 to 3, mol, based on 1 mol of the compound of the general formula (I-B).
  • Suitable acids for process step (I-B) ⁇ (I-C) are the customary inorganic acids such as, for example, hydrochloric acid or sulfuric acid, or sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or carboxylic acids such as trifluoroacetic acid.
  • the reaction generally takes place in a temperature range from -20 ° C to
  • Inert solvents for process step (VI) + (VII) - »(I-D) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or
  • Diethylene glycol dimethyl ether such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, acetone, dimethyl formamide, dimethyl sulfoxide, acetonitrile or N-methyl pyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.
  • the usual inorganic bases are suitable as bases for process step (VI) + (VII) -> (I-D).
  • These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, or alkali metal hydrides such as sodium or
  • the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (VI).
  • the reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 100 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Inert solvents for process step (VI) - (VIII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol ethylene dimethyl ether or diethylene dimethyl ether or diethylene dimethyl ether Benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, Dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran or dichloromethane are preferred.
  • bases are suitable as bases for process step (VI) - »(VIII).
  • bases preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Triethylamine or ethyldiisopropylamine, particularly in the presence of catalytic amounts (approx. 10 mol%) of 4-N, N-
  • the base is used in an amount of 1 to 5, preferably 1 to 2.5, mol, based on 1 mol of the compound of the general formula (VI).
  • the reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 70 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Inert solvents for process step (VIII) + (IX) - (IB) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. -Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as
  • Dimethylformamide, acetonitrile or water It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or a mixture of dimethylformamide and water are preferred.
  • Suitable bases for process step (VIII) + (IX) -> (IB) are the customary inorganic or organic bases. These preferably include alkali or Alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali phosphates such as sodium or potassium phosphate, or organic amines such as triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Sodium or potassium carbonate or potassium phosphate are particularly preferred.
  • the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (VIII).
  • the reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 100 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • R, 2 represents (-CC 6 ) alkyl, which is optionally substituted by phenyl, and Y represents a suitable leaving group, such as halogen, mesylate or tosylate,
  • n the number 2, 3, 4, 5 or 6,
  • R 2 and R 3 have the meaning given above, but not both are hydrogen at the same time
  • R 4 and R 5 are both hydrogen, with the aid of a complex boron or aluminum hydride, such as, for example, lithium aluminum hydride or lithium borohydride, optionally in the presence of trimethylsilyl chloride,
  • R 4 and R 5 are each (C 1 -C 6 ) -alkyl, in a one-pot reaction or in two substeps with an organometallic compound of the general formula (XIV)
  • R 4 for (C, -C 6 ) alkyl
  • M represents Li, -Mg-Cl, -Mg-Br or -Mg-I,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each have the meaning given above,
  • Inert solvents for process step (X) + (XI) or (XII) ⁇ (XIII) are, for example, ethers such as diethyl 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 dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. A is preferred
  • the usual inorganic or organic bases are suitable as bases for process step (X) + (XI) or (XII) - »(XIII).
  • bases preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali hydrides such as sodium or potassium hydride, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide. Potassium hydroxide is particularly preferred.
  • the base is used in an amount of 1 to 10, preferably 2 to 5 mol, based on 1 mol of the compound of the general formula (X).
  • the reaction generally takes place in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 30 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar).
  • Inert solvents for process step (XV) - »(XVI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol ethylene or methyl dimethyl or diethylene dimethyl ether Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Xylene is preferred (with removal of the water formed during the reaction).
  • the formic acid is used in this reaction step in an amount of 1 to 5, preferably 1 to 3 mol, based on 1 mol of the compound of the general formula (XV).
  • the reaction generally takes place in a temperature range from 0 ° C to
  • + 150 ° C preferably from + 20 ° C to + 130 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Inert solvents for process step (XVI) + (IX) ⁇ (XVII) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert. -Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or acetonitrile are preferred.
  • the usual inorganic or organic bases are suitable as bases for process step (XVI) + (IX) - »(XVII).
  • bases preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali phosphates such as sodium or potassium phosphate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
  • Sodium or potassium carbonate or potassium phosphate are particularly preferred.
  • the base is used in an amount of 1 to 5, preferably 2 to 3, mol, based on 1 mol of the compound of the general formula (XVI).
  • the reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 100 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Inert solvents for process step (XVII) + (XVIII) ⁇ (XIX) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane,
  • Tetrachloromethane Tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. It is also possible to have the reaction without
  • the usual inorganic or organic acids are suitable as acids for process step (XVII) + (XVIII) ⁇ (XIX). These preferably include hydrochloric acid, sulfuric acid or phosphoric acid, or carboxylic acids such as formic acid,
  • Acetic acid or trifluoroacetic acid, or sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
  • the reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from + 20 ° C. to + 120 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
  • chlorosulfonic acid cf. e.g. P. D. Edwards, R.C. Mauger, K.M. Cottrell, F.X. Morris, K.K. Pine, M.A. Sylvester, C.W.
  • Inert solvents for process step (XX) + (XXI) ⁇ (XXII) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene,
  • the usual inorganic or organic bases are suitable as bases for process step (XX) + (XXI) - »(XXII).
  • bases preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine,
  • Ethyl diisopropylamine, N-methylmorpholine or N-methylpiperidine Ethyl diisopropylamine, N-methylmorpholine or N-methylpiperidine. Potassium carbonate is particularly preferred.
  • the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (XX).
  • the reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 80 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
  • the compounds of the general formula (IV) can be prepared analogously to processes known from the literature, for example, by adding a compound of the general formula (XXIII)
  • Q represents hydroxy, halogen or the complementary carboxylic anhydride radical
  • the compounds of formula (I) according to the invention show a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments.
  • they are suitable for the treatment of coronary artery disease, for myocardial infarction prophylaxis and for the treatment of restenosis after coronary angioplasty or stenting.
  • the compounds of formula (I) according to the invention are preferably suitable for the treatment of arteriosclerosis and hypercholesterolemia, for increasing morbidly low HDL levels and for lowering increased triglyceride and LDL levels.
  • they can be used for
  • the new active ingredients can be used alone or in combination with others if necessary
  • Active substances preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and / or thyroid mimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, squalene synthesis inhibitors Inhibitors, blood circulation enhancers, platelet aggregation inhibitors, anticoagulants, angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldolase reductase inhibitors, fibrates, niacin, anoretics, lipase inhibitors and / or PPAR- ⁇ and PPAR- ⁇ and ⁇ agonists can be administered.
  • CETP inhibitors preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and / or thyroid mimetics, inhibitor
  • the activity of the compounds according to the invention can e.g. Check in vitro using the transactivation assay described in the example section.
  • the activity of the compounds according to the invention in vivo can e.g. check by the examinations described in the example section.
  • all customary application forms come into consideration, that is to say orally, parenterally, by inhalation, nasally, sublingually, rectally, externally, such as, for example, transdermally, or locally, for example in the case of implants or stents.
  • parenteral administration intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, is particularly important call. Oral or parenteral administration is preferred. Oral application is very particularly preferred.
  • the active ingredients can be administered alone or in the form of preparations.
  • suitable preparations include Tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
  • the active ingredient must be present in such an amount that a therapeutic effect is achieved.
  • the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
  • the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
  • the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
  • the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
  • the active ingredient can be present in a concentration of 0.1 to 100% by
  • Concentration of the active ingredient is 0.5 to 90% by weight, i.e. the active substance should be present in amounts sufficient to achieve the dosage range indicated.
  • the active substances can be converted into the usual manner in a manner known per se
  • Preparations are transferred. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.
  • auxiliary substances are: water, non-toxic organic compound, and non-toxic organic compound, and non-toxic organic compound.
  • Solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flour (e.g. talc or silicates), sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (eg magnesium sulfate).
  • Paraffins e.g. sesame oil
  • alcohols e.g. ethanol, glycerin
  • glycols e.g. polyethylene glycol
  • solid carriers such as natural or synthetic rock flour (e.g. talc or silicates)
  • sugar e.g. milk sugar
  • emulsifiers e.g. polyvinylpyrrolidone
  • lubricants eg magnesium sulfate
  • tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.
  • doses of 0.001 to 5 mg / kg, preferably 0.005 to 3 mg / kg of body weight are preferably administered per 24 hours.
  • Device type GC HP 6890; Column: HP-5, 30 mx 320 ⁇ m x 0.25 ⁇ m (film thickness); Injector temp .: 250 ° C; Oven temp .: 60 ° C; Gradient: 60 ° C, 1 min ⁇ 16 ° C / min ⁇ 300 ° C, 1 min; Carrier gas: helium; constant flow: 1.5 mL / min; Ionization: EI / CI positive.
  • Injector temp . 250 ° C; Oven temp .: 60 ° C; Gradient: 60 ° C ⁇ 10 ° C / min ⁇ 300 ° C, 6 min; Carrier gas: helium; constant flow: 1.5 mL / min; Ionization: EI / CI positive.
  • 1,4-dibromobutane are dissolved in 100 ml of diethyl ether and cooled to 0 ° C.
  • 9.54 g (170 mmol) of potassium hydroxide are then suspended in 71 ml of dimethyl sulfoxide and added, and the mixture is stirred at room temperature overnight.
  • the mixture is poured onto ice and the aqueous phase is extracted with ethyl acetate.
  • the organic phase is dried over sodium sulfate and freed from solvent in vacuo.
  • the residue is recrystallized from ethanol. 11.6 g (84% of theory) of the desired product are obtained.
  • Example 68A Under argon, 0.68 g (1.19 mmol) of ethyl ⁇ 4 - [(7-hydroxy-4-spirocyclobutyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy ⁇ acetate (Example 68A) are added 50 ml of methylene chloride dissolved. 0.27 g (2.62 mmol) of triethylamine are added dropwise and the mixture is cooled to 0.degree. Then 0.37 g (1.31 mmol) of trifluoromethanesulfonic anhydride are added dropwise. Allow to come to room temperature and stir overnight.
  • Example 70A Under argon, 0.65 g (1.37 mmol) of ethyl ⁇ 4 - [(7-hydroxy-4-spirocyclohexyl-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl] -2-methylphenoxy ⁇ acetate (Example 70A) are added 5 ml of methylene chloride dissolved. 0.31 g (0.42 ml; 3.02 mmol) of triethylamine is added dropwise and the mixture is cooled to 0 ° C. Then 0.43 g (1.51 mmol) of trifluoromethanesulfonic anhydride are added dropwise. Allow to come to room temperature and stir overnight.
  • Potassium phosphate trihydrate and 8.4 mg (0.007 mmol) tetrakis (triphenylphosphine) - palladium in 2 ml of toluene is heated under reflux under argon for 2 hours. After cooling to room temperature, stirring is continued for 2 days. Then ethyl acetate and water are added, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated.
  • 3,4-dihydro-2 (1H) -isoquinolinyl] sulfonyl ⁇ phenoxy) acetate are made from 220 mg (0.380 mmol) of ethyl (2-methyl- ⁇ [7- ⁇ [(trifluoromethyl) sulfonyl] oxy ⁇ - 1, 4 , 4-trimethyl-3, 4-dihydro-2 (1H) -isoquinolinyl] sulfonyl ⁇ phenoxy) acetate, 108.1 mg (0.514 mmol) 4-
  • the mixture is flooded with argon for 15 minutes and then a spatula tip of tetrakis (triphenylphosphine) - palladium (O) is added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The clean fractions are combined and the solvent is removed in vacuo. 30 mg (30% of theory) of the desired product are obtained.
  • Toluene is given 77.05 mg (0.51 mmol) of 4-methoxyphenylboronic acid and 52.56 mg (0.38 mmol) of potassium carbonate. The mixture is flooded with argon for 15 minutes and then 13.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (O) are added. It is refluxed overnight. It is cooled and the mixture is freed from the solvent in vacuo. It is about
  • Ethanol is mixed with 1 ml (2.0 mmol) of 2 M sodium hydroxide solution and stirred overnight at room temperature. The mixture is then concentrated in vacuo, acidified with 1N hydrochloric acid and stirred for 1 hour. The resulting precipitate is filtered off and dried in vacuo. 60 mg (79% of theory) of the desired product are obtained as a colorless solid.

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Abstract

L'invention concerne de nouveaux dérivés substitués de tétrahydroisoquinoline, des procédés pour leur production, ainsi que leur utilisation dans des médicaments, notamment en tant que composés puissants activant les PPAR delta, pour la prophylaxie ou le traitement de maladies cardio-vasculaires, notamment de dyslipidémies, de maladies cardiaques coronariennes et de l'artériosclérose.
EP03725144A 2002-05-17 2003-05-05 Derives de tetrahydroisoquinoline Withdrawn EP1507763A1 (fr)

Applications Claiming Priority (3)

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DE10222034 2002-05-17
DE10222034A DE10222034A1 (de) 2002-05-17 2002-05-17 Tetrahydroisochinolin-Derivate
PCT/EP2003/004666 WO2003097607A1 (fr) 2002-05-17 2003-05-05 Derives de tetrahydroisoquinoline

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CA (1) CA2486764A1 (fr)
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DE10337839A1 (de) * 2003-08-18 2005-03-17 Bayer Healthcare Ag Indolin-Derivate
AR048523A1 (es) * 2004-04-07 2006-05-03 Kalypsys Inc Compuestos con estructura de aril sulfonamida y sulfonilo como moduladores de ppar y metodos para tratar trastornos metabolicos
JP2007536343A (ja) 2004-05-05 2007-12-13 ノボ　ノルディスク　アクティーゼルスカブ Ｐｐａｒアゴニストとしてのフェノキシ酢酸誘導体
WO2005105736A1 (fr) 2004-05-05 2005-11-10 Novo Nordisk A/S Nouveaux composes, leur preparation et leur utilisation
ES2372617T3 (es) 2005-06-30 2012-01-24 High Point Pharmaceuticals, Llc Ácidos fenoxiacéticos como activadores de ppar-delta.
CA2631390C (fr) 2005-12-22 2014-03-11 Per Sauerberg Nouveaux composes, leur preparation et leur utilisation
EP1999098A2 (fr) 2006-03-09 2008-12-10 High Point Pharmaceuticals, LLC Nouveaux composés, leur préparation et utilisation
EP1932843A1 (fr) 2006-12-14 2008-06-18 sanofi-aventis Dérivés de sulfonyl-phenyl-2H(1,2,4) oxadiazole-5-one, procédés de préparation de ceux-ci et leur usage sous forme de médicaments
EP2288607B1 (fr) 2008-06-09 2014-09-24 Sanofi Sulfonamides comprenant un hétérocycle et un groupe de tête oxadiazolone, procédés pour les préparer et leur utilisation comme produits pharmaceutiques
US8946212B2 (en) 2008-06-09 2015-02-03 Sanofi-Aventis Annelated N-heterocyclic sulfonamides with oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
MX2011004258A (es) 2008-10-22 2011-06-01 Merck Sharp & Dohme Derivados de bencimidazol ciclicos novedosos utiles como agentes anti-diabeticos.
CA2741672A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabetiques utiles avec des derives de benzimidazole cycliques
CA2786314A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux derives benzimidazole cycliques utiles comme agents antidiabetiques
KR101668514B1 (ko) 2011-02-25 2016-10-21 머크 샤프 앤드 돔 코포레이션 항당뇨병제로서 유용한 신규 시클릭 아자벤즈이미다졸 유도체
JP2015525782A (ja) 2012-08-02 2015-09-07 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 抗糖尿病性三環式化合物
RU2015140066A (ru) 2013-02-22 2017-03-30 Мерк Шарп И Доум Корп. Противодиабетические бициклические соединения
US9650375B2 (en) 2013-03-14 2017-05-16 Merck Sharp & Dohme Corp. Indole derivatives useful as anti-diabetic agents
EP3043789B1 (fr) 2013-09-09 2020-07-08 vTv Therapeutics LLC Utilisation des agonistes de ppar-delta pour le traitement de l'atrophie musculaire
WO2015051496A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
US10968232B2 (en) 2016-12-20 2021-04-06 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
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WO2023147309A1 (fr) 2022-01-25 2023-08-03 Reneo Pharmaceuticals, Inc. Utilisation d'agonistes ppar-delta dans le traitement d'une maladie

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DE10222034A1 (de) 2003-11-27
AU2003227712A1 (en) 2003-12-02

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